European Handbook of Dermatological Treatments 3031151291, 9783031151293

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European Handbook of Dermatological Treatments Andreas D. Katsambas Torello M. Lotti Clio Dessinioti Angelo Massimiliano D‘Erme Editors Fourth Edition

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European Handbook of Dermatological Treatments

Andreas D. Katsambas  •  Torello M. Lotti Clio Dessinioti Angelo Massimiliano D’Erme Editors

European Handbook of Dermatological Treatments Fourth Edition

Editors Andreas D. Katsambas Andreas Syggros Hospital Athens State University Athens, Greece

Torello M. Lotti Research Center CSRMR Marconi University Rome, Roma, Italy

Clio Dessinioti Andreas Syggros Hospital Athens State University Athens, Greece

Angelo Massimiliano D’Erme Dermatoloy Unit Livorno Hospital Livorno, Italy

ISBN 978-3-031-15129-3    ISBN 978-3-031-15130-9 (eBook) https://doi.org/10.1007/978-3-031-15130-9 © Springer Nature Switzerland AG 2000, 2003, 2015, 2023 Originally published under: Andreas D. Katsambas, Torello M. Lotti (Eds.) This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface

It is with great pleasure that we introduce the fourth edition of the European Handbook of Dermatological Treatments. The book was first published in 2000 by editors Andreas Katsambas and Torello M. Lotti, and over the years has strived to meet the need for state-of-the-art treatments for patients with skin diseases in clinical practice. The updated fourth edition aims to provide a comprehensive textbook on treatments for skin diseases compiled by European specialists. Up-to-date treatments are discussed, including recent developments on biologic agents for atopic dermatitis and psoriasis, targeted therapies and immunotherapy for melanoma, as well as current guideline recommendations. Every chapter has been reviewed and updated with all the recent developments in treatment. The book has kept its attractive overall format, divided into three main parts: (1) skin diseases, (2) methods of treatment, (3) drugs, and each chapter describes the etiopathogenesis, the clinical characteristics, the diagnosis and differential diagnosis, while detailing the available treatments. Indications, dosing regimens, and treatment algorithms are accompanied by colored illustrations, informative tables, and synoptic key points. We want at this point to thank the authors. Through the editing process, we have made friends internationally, even though we have only met some through email correspondence. As we review and edit each chapter we recognize the talent, devotion, and expertise each author brings to his or her work. In the era of overwhelming information, we hope this book may serve as a reader-friendly reference in the field of Dermatology-Venereology. Athens, Greece Rome, Italy  Athens, Greece  Livorno, Italy 

Andreas D. Katsambas Torello M. Lotti Clio Dessinioti Angelo Massimiliano D’Erme

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Contents

Part I Diseases 1 Acne������������������������������������������������������������������������������������������������    3 Clio Dessinioti and Brigitte Dreno 2 Actinic Keratosis����������������������������������������������������������������������������   19 Mercedes Sendín-Martín and Julián Conejo-Mir Sánchez 3 Adamantiades-Behçet Disease������������������������������������������������������   29 Christos C. Zouboulis 4 Alopecia Areata������������������������������������������������������������������������������   43 Markus Böhm 5 Androgenetic Alopecia������������������������������������������������������������������   55 Anna Waśkiel-Burnat and Lidia Rudnicka 6 Aphthous Stomatitis����������������������������������������������������������������������   63 George Laskaris 7 Atopic Dermatis ����������������������������������������������������������������������������   69 Angelo Massimiliano D’Erme, Giovanni Bagnoni, and Jan D. Bos 8 Balanitis������������������������������������������������������������������������������������������   89 Derek Freedman 9 B  asal Cell Carcinoma��������������������������������������������������������������������  101 Dimitrios Papakostas and Eggert Stockfleth 10 Bowen’s Disease������������������������������������������������������������������������������  113 Mirna Situm and Maja Kovacevic 11 Bullous Pemphigoid ����������������������������������������������������������������������  123 Panagiotis G. Stavropoulos and George Larios 12 Candidiasis�������������������������������������������������������������������������������������  131 Dimitris Rigopoulos 13 C  heilitis and Oral Disease ������������������������������������������������������������  137 Eleni Gagari

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14 Chronic Actinic Dermatitis ����������������������������������������������������������  147 Cathal O’Connor, Gillian M. Murphy, Christian Gulmann, and Sally Jane O’Shea 15 Cicatricial Alopecia������������������������������������������������������������������������  153 Andjela Egger, Rebecca Quinonez, Bianca Maria Piraccini, and Antonella Tosti 16 Contact Dermatitis������������������������������������������������������������������������  161 Massimo Gola, Angelo Massimiliano D’Erme, Martin Röcken, and Sebastian Volc 17 Cutaneous Vasculitis����������������������������������������������������������������������  175 Serena Gianfaldoni, Angelo Massimiliano D’Erme, Jana Hercogova, and Torello M. Lotti 18 Darier Disease��������������������������������������������������������������������������������  189 Federico Bardazzi and Lidia Sacchelli 19 Dermatitis Herpetiformis��������������������������������������������������������������  195 Ines Lakoš Jukić and Branka Marinovic 20 Dermatomyositis����������������������������������������������������������������������������  205 Matteo Zanardelli, Bartłomiej Wawrzycki, and Aldona Pietrzak 21 Dermatophyte Infections ��������������������������������������������������������������  219 Rebecca Quiñonez, Bianca Maria Piraccini, and Antonella Tosti 22 D  rug Hypersensitivity Reactions��������������������������������������������������  229 Andrea Szegedi, Éva Remenyik, and Emese Gellén 23 Drug Photosensitivity��������������������������������������������������������������������  247 Margarida Gonçalo and Ana Giménez-Arnau 24 Epidermolysis Bullosa ������������������������������������������������������������������  273 Ankur Sarin, Jushya Bhatia, and Mohamad Goldust 25 Erysipelas����������������������������������������������������������������������������������������  283 Maria Balabanova 26 Erythema Multiforme��������������������������������������������������������������������  287 Kristina Semkova and Jana Kazandjieva 27 Erythema Nodosum ����������������������������������������������������������������������  297 Eva Remenyik 28 Erythrasma������������������������������������������������������������������������������������  307 Alexander Yu Turkevych 29 Erythroderma��������������������������������������������������������������������������������  311 Annalisa Patrizi and Michela Venturi 30 E  rythroplasia of Queyrat��������������������������������������������������������������  329 Konstantinos Krasagakis

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31 Factitial Dermatitis������������������������������������������������������������������������  335 Razvigor Darlenski and Nikolai Tsankov 32 F  uruncles and Carbuncles������������������������������������������������������������  339 Dimitrios Ioannides and Elizabeth Lazaridou 33 Granuloma Annulare��������������������������������������������������������������������  345 Rolland Gyulai and Ágnes Kinyó 34 Grover Disease��������������������������������������������������������������������������������  357 Bengu Gerceker Turk and Sibel Alper 35 Hailey-Hailey Disease��������������������������������������������������������������������  361 Carmen Maria Salavastru and George-­Sorin Țiplica 36 Hand Dermatitis����������������������������������������������������������������������������  369 John English, Angelo Massimiliano D’Erme, and Massimo Gola 37 Herpes Genitalis ����������������������������������������������������������������������������  387 Angelika Stary 38 H  erpes Simplex Virus Infection (Orofacial)��������������������������������  403 Theognosia Vergou 39 Herpes Zoster ��������������������������������������������������������������������������������  409 Uwe Wollina 40 H  irsutism and Hypertrichosis������������������������������������������������������  417 Clio Dessinioti and Andreas D. Katsambas 41 H  IV Infection and AIDS: The Present Status of Antiretroviral Therapy��������������������������������������������������  429 Vassilios Paparizos and Sofia Kourkounti 42 Hidradenitis Suppurativa��������������������������������������������������������������  443 Christos Zouboulis and Clio Dessinioti 43 Primary Hyperhidrosis������������������������������������������������������������������  457 Benedetta Brazzini, Bindi Gaglani, and Sana Sultan 44 Ichthyoses����������������������������������������������������������������������������������������  471 Aseem Sharma, Atula Gupta, and Mohamad Goldust 45 Impetigo������������������������������������������������������������������������������������������  479 Stefano Veraldi and Valentina Benzecry 46 Kaposi’s Sarcoma��������������������������������������������������������������������������  483 Ketty Peris and Laura Del Regno 47 K  eloids and Hypertrophic Scars��������������������������������������������������  495 Ivana Binic 48 Leg Ulcers ��������������������������������������������������������������������������������������  509 Severin Läuchli and Markus Streit

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49 Leishmaniasis ��������������������������������������������������������������������������������  531 Meltem Onder and Mehmet Ali Gürer 50 Lentigo Maligna ����������������������������������������������������������������������������  539 Jean Kanitakis 51 Leprosy��������������������������������������������������������������������������������������������  553 Ranthilaka R. Ranawaka, Vesna Pljakoska, and Andrej Petrov 52 Lichen Planus ��������������������������������������������������������������������������������  563 Alfredo Rebora, Giulia Ciccarese, and Francesco Drago 53 L  ichen Simplex Chronicus������������������������������������������������������������  575 Mary Gantcheva and Valentina Broshtilova 54 Lupus Erythematosus��������������������������������������������������������������������  585 Annegret Kuhn and Aysche Landmann 55 Lyme Borreliosis����������������������������������������������������������������������������  599 Jana Hercogová 56 Lymphogranuloma Venereum������������������������������������������������������  605 Alex Kubanov and Xenia Plakhova 57 P  rimary Cutaneous Lymphomas��������������������������������������������������  609 Wolfgang Bauer and Robert Knobler 58 Melanoma ��������������������������������������������������������������������������������������  623 Efthymia Soura and Alexander J. Stratigos 59 Mastocytosis������������������������������������������������������������������������������������  639 Dirk Van Gysel and Hannelore De Maeseneer 60 Melasma������������������������������������������������������������������������������������������  651 Clio Dessinioti, Torello M. Lotti, Alexander J. Stratigos, Katerina Damevska, and Andreas D. Katsambas 61 Molluscum Contagiosum��������������������������������������������������������������  663 Mirjana V. Milinkovic and Ljiljana M. Medenica 62 M  orphea (Localized Scleroderma) ����������������������������������������������  673 Aurora Parodi and Roberto Russo 63 N  evi (Benign Melanocytic)������������������������������������������������������������  679 Alexander C. Katoulis, Dimitrios Sgouros, and Nikolaos G. Stavrianeas 64 Necrobiosis Lipoidica��������������������������������������������������������������������  703 Istvan Juhasz 65 N  ummular Eczema: An Update����������������������������������������������������  711 Antonia Torodova, Alexander Boehner, Harald Bruckbauer, and Johannes Ring 66 Onychomycosis������������������������������������������������������������������������������  721 Dimitris Rigopoulos and Stamatis Gregoriou

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67 P  emphigus Foliaceus and Pemphigus Erythematosus����������������  731 Christoph M. Hammers, Enno Schmidt, and Luca Borradori 68 Pemphigus Vegetans����������������������������������������������������������������������  739 Christoph M. Hammers, Enno Schmidt, and Luca Borradori 69 Pemphigus Vulgaris������������������������������������������������������������������������  745 Alexandre Lemieux and Pascal Joly 70 Drug-Induced Pemphigus�������������������������������������������������������������  759 Nazipha Farah Mahmood, Atheer Al-Haddabi, Dushyanth Gnanappiragasam, Olga Golberg, and Karen Elizabeth Harman 71 Pityriasis Lichenoides Acuta ��������������������������������������������������������  765 Luca Fania and Biagio Didona 72 P  ityriasis Lichenoides Chronica ��������������������������������������������������  773 Paloma Borregón and Agustín España 73 Pityriasis Rosea������������������������������������������������������������������������������  777 Miloš Nikolić and Jovan Lalošević 74 P  ityriasis Rubra Pilaris (Divergie 1863, Besnier 1889)��������������  785 A. Petrov and V. Pljakoska 75 P  olymorphic Light Eruption��������������������������������������������������������  789 Miroslava Kadurina, Georgeta Bocheva, and Jana Kazandjieva 76 T  he Cutaneous Porphyrias������������������������������������������������������������  797 Robert P. E. Sarkany 77 Pruritus ������������������������������������������������������������������������������������������  815 Adam Reich and Jacek C. Szepietowski 78 D  ermatologic Diseases: Psoriasis and Psoriatic Arthritis��������������������������������������������������������������������������  831 Andrea Chiricozzi and Federico Pirro 79 Purpuras ����������������������������������������������������������������������������������������  843 Torello M. Lotti, Lara Tripo, Alice Garzitto, Aldona Pietrzak, Ilaria Ghersetich, Banu Farabi, and Mohamad Goldust 80 Pyoderma Gangrenosum��������������������������������������������������������������  859 Jana Kazandjieva and Nikolai Tsankov 81 Rosacea��������������������������������������������������������������������������������������������  867 Elizabeth Keeling and Siona Ni Raghallaigh 82 SAPHO Syndrome ������������������������������������������������������������������������  877 Vincenzo Bettoli and Natale Schettini 83 PAPA Syndrome ����������������������������������������������������������������������������  881 Vincenzo Bettoli and Natale Schettini

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84 Sarcoidosis��������������������������������������������������������������������������������������  885 Sven Quist 85 Scabies��������������������������������������������������������������������������������������������  899 Alessandra Massa, Claudio Feliciani, Torello M. Lotti, and Francesca Satolli 86 Seborrhoeic Dermatitis������������������������������������������������������������������  907 Mohamad Goldust and Mrinal Gupta 87 Seborrheic Keratosis����������������������������������������������������������������������  913 Emin Gündüz and Ümit Türsen 88 Sjögren’s Syndrome ����������������������������������������������������������������������  919 Andreas V. Goules, Loukas Chatzis, and Athanasios G. Tzioufas 89 S  kin Diseases from Metabolic, Endocrinologic Diseases������������  929 Franco Rongioletti 90 S  kin Diseases from Marine Environment������������������������������������  943 Giuseppe Monfrecola and Gabriella Fabbrocini 91 S  quamous Cell Carcinoma������������������������������������������������������������  953 Marta Grazzini and Vincenzo De Giorgi 92 Sweet Syndrome ����������������������������������������������������������������������������  965 Uwe Wollina 93 Syphilis��������������������������������������������������������������������������������������������  973 Michael Waugh 94 Systemic Sclerosis��������������������������������������������������������������������������  983 Matteo Zanardelli, Zoulikha Zarrab, and Aldona Pietrzak 95 A  cute and Chronic Telogen Effluvium����������������������������������������  991 Hugh D. Rushton 96 T  inea Versicolor (Pityriasis Versicolor)���������������������������������������� 1001 Matteo Zanardelli, Cezary Skobowiat, Rafal Kaliszuk, and Aldona Pietrzak 97 S  tevens–Johnson Syndrome and Toxic Epidermal Necrolysis�������������������������������������������������������������������� 1009 Mehmet Melikoğlu and Erdal Pala 98 Gonococcal Urethritis�������������������������������������������������������������������� 1029 Christina Stefanaki 99 Urethritis: Nongonococcal������������������������������������������������������������ 1039 Irene Stefanaki 100 Urticaria������������������������������������������������������������������������������������������ 1045 Frances Lawlor 101 Varicella������������������������������������������������������������������������������������������ 1055

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Theognosia Vergou 102 Vascular Birthmarks: Vascular Malformations and Haemangiomas������������������������������������������������������������������������ 1061 Fabio Arcangeli and Davide Brunelli 103 Vitiligo �������������������������������������������������������������������������������������������� 1075 Electra Nicolaidou, Andreas D. Katsambas, Torello M. Lotti, Aseem Sharma, Shikhar Ganjoo, Madhulika Mhatre, and Mohamad Goldust 104 Vulvar Diseases������������������������������������������������������������������������������ 1091 Silvestrs Rubins and Andris Rubins 105 Warts: Cutaneous and Anogenital������������������������������������������������ 1113 Antonios Kanelleas and Electra Nicolaidou 106 Xanthomas�������������������������������������������������������������������������������������� 1123 Dimitrios Sotiriadis and Aikaterini Patsatsi Part II Methods 107 Acne Scar Treatment �������������������������������������������������������������������� 1135 Antonio Rusciani, Francesco Ricci, and Giuseppe Curinga 108 Surgery�������������������������������������������������������������������������������������������� 1143 Myrto Trakatelli and Elena Rossi 109 Biopsy���������������������������������������������������������������������������������������������� 1163 Eckart Haneke 110 Botulinum Toxin in Aesthetic Medicine �������������������������������������� 1173 Barbara Boone, Andreas D. Katsambas, and Koen De Boulle 111 Capillaroscopy�������������������������������������������������������������������������������� 1191 Giorgio Filosa and Rossella De Angelis 112 Chemical Peelings�������������������������������������������������������������������������� 1199 Albina Kajaia and Anna Funikova 113 Cryosurgery������������������������������������������������������������������������������������ 1217 Paola Pasquali and Giedre Mickeviciute 114 Dermoscopy of Non-melanocytic Skin Lesions �������������������������� 1229 Stefano Caccavale, Aimilios Lallas, Zoe Apalla, and Giuseppe Argenziano 115 Dermoscopy of Pigmented Skin Lesions�������������������������������������� 1245 Silvija Duma, Pietro Rubegni, and Linda Tognetti 116 Electrosurgery�������������������������������������������������������������������������������� 1257 Eckart Haneke 117 Excimer Laser Therapy���������������������������������������������������������������� 1263 Carmen Salavastru

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118 Fillers and Soft Tissue Augmentation������������������������������������������ 1271 Christopher M. E. Rowland Payne, Ines Verner, and Sebastian Cotofana 119 Hair Examination�������������������������������������������������������������������������� 1307 Bianca Maria Piraccini, Francesca Bruni, and Michela Starace 120 Immunofluorescence in Various Skin Diseases �������������������������� 1315 Alessandra Massa, Francesca Satolli, Torello M. Lotti, and Claudio Feliciani 121 Lasers: Ablative������������������������������������������������������������������������������ 1325 Leonardo G. Marini and Aleksandar L. Krunic 122 Mohs Micrographic Surgery�������������������������������������������������������� 1339 David Moreno-Ramirez, Francisca Silva-Claveria, and Lara Ferrandiz 123 Mycological Examination�������������������������������������������������������������� 1351 Laura Atzori, Laura Pizzatti, Monica Pau, and Nicola Aste 124 Patch Testing���������������������������������������������������������������������������������� 1377 Anna Tagka and Alexandra Katsarou 125 Photodynamic Therapy for Benign Lesions�������������������������������� 1397 Marita Kosmadaki 126 Photodynamic Therapy for Malignant Skin Lesions������������������ 1403 Carolina Puyana, Ryan Bunney, Edidiong Celestine Ntuen Kaminska, Susan Pei, and Maria M. Tsoukas 127 Phototherapy���������������������������������������������������������������������������������� 1423 Marita Kosmadaki and Christina Antoniou 128 Psychotherapeutic and Psychiatric Approach in Dermatovenereology���������������������������������������������������������������������� 1431 Petar Vojvodic 129 Sclerotherapy���������������������������������������������������������������������������������� 1449 Simone Napoli, Matteo Zanardelli, Angelo Massimiliano D’Erme, and Torello M. Lotti 130 Sentinel Lymph Node Biopsy�������������������������������������������������������� 1455 Giovanni Bagnoni, Angelo Massimiliano D’Erme, Vanna Zucchi, and Paolo Viacava 131 Skin Resurfacing with Carbon Dioxide Laser���������������������������� 1461 Macrene Alexiades 132 Thread Methods in Aesthetic Medicine �������������������������������������� 1473 A. Kajaia 133 Trichopigmentation or Scalp Dermopigmentation �������������������� 1509 Elisabetta Belfiore

Contents

Contents

xv

Part III Drugs 134 Antibacterial Agents���������������������������������������������������������������������� 1527 Maria Souli, Garyfalia Poulakou, and Helen Giamarellou 135 Antifungal Drugs���������������������������������������������������������������������������� 1543 Roderick J. Hay 136 Antihistamines�������������������������������������������������������������������������������� 1555 Angelo Massimiliano D’Erme, Serena Gianfaldoni, Andreas D. Katsambas, and Torello M. Lotti 137 Antiviral Drugs in Dermatology and Venereology���������������������� 1563 Mihael Skerlev, Ivana Čulav, Andrija Stanimirović, and Dominik Kutlić 138 Beta-Blockers for Hemangiomas�������������������������������������������������� 1577 Carlo Gelmetti and Riccardo Cavalli 139 Biofeedback������������������������������������������������������������������������������������ 1587 Jacopo Lotti and Alberto Cossidente 140 Biologic Agents for Psoriasis �������������������������������������������������������� 1595 Marina Papoutsaki and Christina Antoniou 141 Skin Lightening Agents (Skin Bleaching Agents)������������������������ 1607 Evagelia Papadavid and Lampros Giannopoulos 142 Topical Calcineurin Inhibitors������������������������������������������������������ 1615 Andreas Wollenberg and Jelena Peric 143 Corticosteroids: Topical���������������������������������������������������������������� 1625 Alejandro Martin-Gorgojo, Francisco-Javier Bru-­Gorraiz, and Jeanne-Duus Johansen 144 Cytokine Therapy in Dermatology���������������������������������������������� 1637 Sushruta Kathuria and Torello M. Lotti 145 Dapsone������������������������������������������������������������������������������������������ 1645 Eftychia Platsidaki and Georgios Kontochristopoulos 146 Glucocorticoids: Systemic ������������������������������������������������������������ 1653 Sean Ekinde, F. Cambazard, and Elisa Cinotti 147 Skin Androgen-Related Disorders: Hormonal Treatment �������� 1661 Francesca Frizza, Mario Maggi, and Francesco Lotti 148 Hydroxychloroquine���������������������������������������������������������������������� 1679 Mohamad Goldust, Angelica Misitzis, and Mrinal Gupta 149 Imiquimod�������������������������������������������������������������������������������������� 1685 Mihael Skerlev, Ivana Čulav Košćak, Suzana Ljubojević Hadžavdić, and Maja Sirotković-Skerlev 150 Immunotherapy for Melanoma���������������������������������������������������� 1693 Eirini Pectasides and Helen Gogas

xvi

151 Insect Repellents���������������������������������������������������������������������������� 1713 Stefania Motta and Marcello Monti 152 Microbiota and Microbiome in Dermatology: Clues to New Treatments�������������������������������������������������������������� 1721 Sushruta Kathuria and Torello M. Lotti 153 Prodrugs������������������������������������������������������������������������������������������ 1735 Andy Goren, John McCoy, and Torello M. Lotti 154 Retinoids ���������������������������������������������������������������������������������������� 1741 Jean-Hilaire Saurat and Olivier Sorg 155 Scabicides and Pediculicides �������������������������������������������������������� 1763 Katerina Damevska 156 Sunscreens�������������������������������������������������������������������������������������� 1771 Ana-Maria Forsea 157 Targeted Treatments for Cutaneous Melanoma�������������������������� 1787 Efthymia Soura and Alexander Stratigos 158 Topical Preparations and Vehicles������������������������������������������������ 1801 Marcello Monti, Stefania Motta, and Elio Mignini 159 Vitamins and Nutritional Supplements���������������������������������������� 1809 Alexandru Tataru and Andreea Nicoleta Boca

Contents

Contributors

Macrene Alexiades  Dermatology and Laser Surgery Center, New York, NY, USA Yale University School of Medicine, New Haven, CT, USA Department of Dermatology, A. Syggrou Hospital, Athens, Greece Atheer Al-Haddabi  University Hospitals of Leicester, Leicester, UK Sibel Alper  Department of Dermatology, Istanbul Bilim University, Istanbul, Turkey Christina  Antoniou Department of Dermatology, Andreas Syggrus Hospital, University of Athens, Athens, Greece Zoe  Apalla First Department of Dermatology, Aristotle University of Thessaloniki, Thessaloniki, Greece Fabio Arcangeli  University of Rome Guglielmo Marconi, Rome, Italy Giuseppe  Argenziano Dermatology Unit, Department of Mental and Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Naples, Italy Nicola  Aste  Department of Dermatology, University of Cagliari, Cagliari, Italy Laura Atzori  Department of Dermatology, University of Cagliari, Cagliari, Italy Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy Giovanni Bagnoni  Dermatology Unit, Livorno Hospital, Livorno, Italy Maria Balabanova  Department of Dermatology, Sofia Medical University, Sofia, Bulgaria Federico  Bardazzi Unit of Dermatology, Department of Medical and Surgical Sciences Alma Mater Studiorum University of Bologna, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Policlinico Sant’Orsola Malpighi, Bologna, Italy Wolfgang  Bauer Department for Dermatology, Medical University of Vienna, General Hospital Vienna, Vienna, Austria xvii

xviii

Elisabetta Belfiore  Guglielmo Marconi University of Roma, Monza, Italy Valentina  Benzecry  Department of Pathophysiology and Transplantation, University of Milan, Foundation IRCCS, Cà Granda Ospedale Maggiore Policlinico, Milan, Italy Vincenzo  Bettoli Department of Medical Science, O.U. of Dermatology, Azienda Ospedaliera—University of Ferrara, Ferrara, Italy Jushya Bhatia  Sarin Skin Solutions, New Delhi, India Ivana Binic  Clinic of Dermatovenerology, Clinical Center Niš, University of Niš, Niš, Serbia Andreea  Nicoleta  Boca Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania Georgeta  Bocheva  Department of Pharmacology and Toxicology, Faculty of Mediicine, Medical University of Sofia, Sofia, Bulgaria Alexander  Boehner  Department of Dermatology and Allergology Biederstein, Technical University Munich (TUM), München, Germany Markus  Böhm Department of Dermatology, University of Münster, Münster, Germany Barbara  Boone Department of Dermatology, Ghent University Hospital, Ghent, Belgium Luca  Borradori Department of Dermatology, Bern University Hospital, Bern, Switzerland Paloma  Borregón Department of Dermatology, Dra Paloma Borregon, Madrid, Spain Jan D. Bos  University of Amsterdam, Amsterdam, Netherlands Benedetta Brazzini  Department of Dermatology, Ealing Hospital, London North West Hospitals Trust, Southall, UK Valentina  Broshtilova Department of Dermatology and Venereology, Military Medical Academy, Sofia, Bulgaria Harald  Bruckbauer Department of Dermatology and Allergology Biederstein, Technical University Munich (TUM), München, Germany Dermatology Medical Praxis, Neufahrn, Germany Francisco-Javier Bru-Gorraiz  Madrid City Council, Madrid, Spain Davide Brunelli  Operative Unit, Bufalini Hospital, Cesena, Italy Francesca  Bruni  Division of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy Ryan Bunney  Department of Dermatology, University of Illinois at Chicago, Chicago, IL, USA

Contributors

Contributors

xix

Stefano Caccavale  Dermatology Unit, Department of Mental and Physical Health and Preventive Medicine, University of Campania Luigi Vanvitelli, Naples, Italy F.  Cambazard  Department of Dermatology, University Hospital of Saint-­ Etienne, Saint Etienne, France Riccardo Cavalli  Dipartimento della donna, bambino, neonato, Fondazione Ca’ Granda “Ospedale Maggiore Policlinico”, Milan, Italy Loukas Chatzis  Pathophysiology Department, Athens School of Medicine, National and Kapodistrian University of Athens, Athens, Greece Andrea Chiricozzi  Dermatologia, Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy Giulia  Ciccarese Dermatology Unit, Ospedale Policlinico San Martino, Genoa, Italy University of Foggia, Section of Dermatology, Department of medical and surgical sciences, Foggia, Italy Elisa  Cinotti Division of Medical, Surgical and Neurological Sciences, Department of Dermatology, University of Siena, Siena, Italy Alberto  Cossidente Translational Medicine and Surgery (DMCT), University of Florence, Florence, Italy Dermatological Clinic, Interuniversity Center of Psychosomatic Biological Dermatology (CIDEBIP), Florence, Italy Sebastian Cotofana  Department of Clinical Anatomy, Mayo Clinic College of Medicine and Science, Rochester, MN, USA Giuseppe Curinga  Plastic Surgery Clinic Venuslab, Palermo, Italy Angelo  Massimiliano  D’Erme Dermatology Unit, Livorno Hospital, Livorno, Italy Katerina  Damevska  Clinic of Dermatology, Medical Faculty, University, “Ss. Cyril and Methodius”, Skopje, Republic of Macedonia Razvigor  Darlenski Department of Dermatology and Venereology, Acibadem Cityclinic Tokuda Hospital, Sofia, Bulgaria Department of Dermatology and Venereology, Trakia University, Stara Zagora, Bulgaria Rossella  De Angelis Rheumatology Unit, Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, Italy Ancona, Italy Koen De Boulle  Aalst Dermatology Clinic, Aalst, Belgium Vincenzo  De Giorgi  Department of Dermatology, University of Florence, Florence, Italy

Contributors

xx

Hannelore  De Maeseneer  Department of Pediatrics, Vrouwziekenhuis Aalst-Asse-Ninove, Aalst, Belgium

Onze-Lieve-­

Laura Del Regno  UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli - IRCCS, Rome, Italy Clio Dessinioti  Andreas Syggros Hospital, Athens State University, Athens, Greece 1st Department of Dermatology, Andreas Sygros Hospital, University of Athens, Athens, Greece Biagio  Didona  Department of Dermatology, dell’Immsacolata-IRCCS, Rome, Italy

Istituto

Dermopatico

Francesco  Drago Department of Health Sciences, University of Genoa, Genoa, Italy Dermatology Unit, Ospedale Policlinico San Martino, Genoa, Italy Brigitte Dreno  Nantes Université, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT, Nantes, France Silvija  Duma  University Clinic of Dermatology, Ss Cyril and Methodius University, Skopje, Republic of Macedonia Andjela Egger  Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA Sean  Ekinde Division of Medical, Surgical and Neurological Sciences, Department of Dermatology, University of Siena, Siena, Italy John English  Nottingham NHS Treatment Centre, Nottingham, UK Agustín España  Department of Dermatology, University Clinic of Navarra, School of Medicine, Pamplona, Spain Gabriella  Fabbrocini Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy Luca  Fania  Department of Dermatology, dell’Immsacolata-IRCCS, Rome, Italy

Istituto

Dermopatico

Banu  Farabi Dermatology Department, Ankara University School of Medicine, Ankara, Turkey Robert Wood Johnson Medical Center, Rutgers University, New Brunswick, NJ, USA Claudio Feliciani  Dermatology Unit, Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy Lara Ferrandiz  University Hospital Virgen Macarena, University of Seville, Seville, Spain

Contributors

xxi

Giorgio Filosa  Department of Dermatology, ‘Carlo Urbani’ Hospital, Jesi, Italy Ana-Maria  Forsea  Dermatology Department, Carol Davila University of Medicine and Pharmacy Bucharest, Elias University Hospital, Bucharest, Romania Derek Freedman  GUIDE Clinic, St. James’ Hospital, Dublin, Ireland Francesca  Frizza  Andrology, Female Endocrinology and Gender Incongruence Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy Anna Funikova  Medical Community Clinic, Kyiv, Ukraine Eleni  Gagari Department of Dermatology, First University Clinic of Dermatology, A. Syggros Hospital for Dermatologic and Venereal Diseases, University of Athens School of Medicine, Athens, Greece Bindi Gaglani  Department of Dermatology, Ealing Hospital, London North West Hospitals Trust, Southall, UK Shikhar  Ganjoo Department of Dermatology, SGT Medical College, Hospital and Research Institute, Gurugram, India Mary  Gantcheva Department of Dermatology, City Clinic Sofia, Sofia, Bulgaria Institute of Experimental Morphology, Pathology and Anthropology, Bulgarian Academy of Science, Sofia, Bulgaria Alice  Garzitto Division of Dermatology, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy Emese Gellén  Department of Dermatology, Centre of Excellence, Faculty of Medicine, University of Debrecen, Debrecen, Hungary Carlo  Gelmetti Department of Medical-Surgical Physiopathology and Transplants, University of Milan, Ca’Granda Foundation “Hospital Maggiore Policlinico”, Milan, Italy Ilaria  Ghersetich Division of Dermatology, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy Helen  Giamarellou  First Department of Internal Medicine and Infectious Diseases, Hygeia General Hospital, Athens, Greece Serena  Gianfaldoni Dermatologic Department, University of Rome “G. Marconi”, Rome, Italy Lampros  Giannopoulos Department of Dermatology and Venereology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece Ana  Giménez-Arnau Department of Dermatology, Hospital del Mar. Universitat Autonoma y Universitat Pompeu Fabra. Barcelona, Barcelona, Spain

Contributors

xxii

Dushyanth Gnanappiragasam  University Hospitals of Leicester, Leicester, UK Helen Gogas  First Department of Medicine, Laiko Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece Massimo  Gola Division of Dermatology, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy Olga Golberg  Mid and South Essex NHS Foundation Trust, Essex, UK Mohamad Goldust  Department of Dermatology, University Medical Center Mainz, Mainz, Germany Research Center CSRMR, Marconi University, Rome, Roma, Italy Department of Dermatology, University Hospital Basel, Basel, Switzerland Department of Dermatology, University of Rome G. Marconi, Rome, Italy Department of Dermatology and Allergy, University Hospital Basel, Basel, Switzerland Margarida  Gonçalo Clinic of Dermatology, University Hospital and Faculty of Medicine, University of Coimbra, Coimbra, Portugal Andy Goren  Applied Biology Inc., Irvine, CA, USA Andreas  V.  Goules Pathophysiology Department, Athens School of Medicine, National and Kapodistrian University of Athens, Athens, Greece Marta  Grazzini Department of Dermatology, Azienda Ospedaliera Tosacana Nord Ovest, Lucca, Italy Stamatis Gregoriou  1st Department of Dermatology, University of Athens Medical School, Andreas Sygros Hospital, Athens, Greece Christian Gulmann  Beaumont Hospital, Dublin, Ireland Emin Gündüz  Mersin University Medical Faculty, Mersin, Turkey Atula Gupta  g Skin-Aid Clinic, Gurugram, India Mrinal Gupta  Treatwell Skin Centre, Jammu, India Mehmet Ali Gürer  Department of Dermatology, Gazi University Medical Faculty, Ankara, Turkey Rolland  Gyulai  Department of Dermatology, Oncodermatology, University of Pecs, Pecs, Hungary

Venerology

and

Suzana  Ljubojević  Hadžavdić  Department of Dermatology and Venereology, Zagreb University School of Medicine and Zagreb University Hospital, Zagreb, Croatia

Contributors

xxiii

Christoph  M.  Hammers Department of Dermatology, University of Lübeck, Lübeck, Germany Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck, Lübeck, Germany Eckart  Haneke Department of Dermatology, Inselspital, University of Bern, Freiburgstrasse, Bern, Switzerland Dermatol Practice Dermaticum, Kaiser-Joseph-Strasse, Freiburg, Germany Centro Dermatol Epidermis, Inst CUF Rua Sete Bicas, Matosinhos, Porto, Portugal Department of Dermatology, Academic Hospital, University of Gent, Ghent, Belgium Karen Elizabeth Harman  University Hospitals of Leicester, Leicester, UK Roderick J. Hay  St John’s Institute of Dermatology, Kings College London, London, UK Jana  Hercogova Dermatovenereology Department, 2nd Medical Faculty, Institute of Clinical and Experimental Medicine, Bulovka Hospital, Charles University, Prague, Czech Republic Dimitrios  Ioannides 1st Department of Dermatology and Venereology, Aristotle University Medical School, Hospital of Skin and Venereal Diseases, Thessaloniki, Greece Jeanne-Duus Johansen  University of Copenhagen, Hellerup, Denmark Pascal  Joly Centre de référence des maladies bulleuses auto-immunes, Department of Dermatology, Centre Hospitalier Universitaire de Rouen, Rouen, France Istvan Juhasz  Dept of Dermatology at Faculty of Medicine and Faculty of Dentistry, University of Debrecen, Debrecen, Hungary Ines Lakoš Jukić  Department of Dermatology and Venereology, School of Medicine, University Hospital Centre Zagreb, University of Zagreb, Zagreb, Croatia Miroslava  Kadurina Department of Dermatology, University Acibadem City Clinic, Sofia, Bulgaria Albina Kajaia  Department of Medical Pharmacology, Tbilisi State Medical University, Tbilisi, Georgia Rafal  Kaliszuk Chair and Department of Forensic Medicine, Medical University of Lublin, Lublin, Poland Edidiong Celestine Ntuen Kaminska  Section of Dermatology, Department of Medicine, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA

Contributors

xxiv

Antonios  Kanelleas 2nd Department of Dermatology and Venereology, National and Kapodistrian University of Athens, “Attiko” University Hospital, Athens, Greece Jean Kanitakis  Department of Dermatology (Pav. R), Ed. Herriot Hospital Group, Hospices Civils de Lyon, Lyon, France Sushruta Kathuria  University of Rome G. Marconi, Rome, Italy Department of Dermatology, Safdarjung Hospital and Vardhaman Mahavir Medical College, Rome, Italy Alexander C. Katoulis  2nd Department of Dermatology and Venereology, National and Kapodistrian University of Athens Medical School, “Attikon” General University Hospital, Athens, Greece Andreas  D.  Katsambas  Andreas Syggros Hospital, National and Kapodistrian University of Athens Medical School, Athens, Greece 1st Department of Dermatology, Andreas Sygros Hospital,University of Athens, Athens, Greece Alexandra  Katsarou 1st Dermatology Department, Andreas Syggros Hospital, University of Athens, Athens, Greece Jana  Kazandjieva Department of Dermatology, Faculty of Medicine, Medical University of Sofia, Sofia, Bulgaria Department of Dermatology, Medical University—Sofia, Sofia, Bulgaria Elizabeth  Keeling Department of Dermatology, Beaumont Hospital, Dublin, Ireland Ágnes Kinyó  Department of Dermatology, Venerology and Oncodermatology, University of Pecs, Pecs, Hungary Robert  Knobler Department for Dermatology, Medical University of Vienna, General Hospital Vienna, Vienna, Austria Georgios  Kontochristopoulos  Department of Dermatology Venereology, Andreas Sygros Hospital, Athens, Greece

and

Ivana  Čulav Department of Dermatology and Venereology, University Hospital Center Sestre Milosrdnice, Zagreb, Croatia Marita Kosmadaki  Department of Dermatology, Andreas Syggrus Hospital, University of Athens, Athens, Greece Sofia Kourkounti  Unit of HIV/AIDS, Department of Dermatology, Andreas Syngros Hospital, University of Athens, Athens, Greece Maja  Kovacevic Department of Dermatovenerology, Sestre Milosrdnice University Hospital Centre, Zagreb, Croatia Referral Centre for Melanoma of the Ministry of Health of the Republic of Croatia, Zagreb, Croatia Referral Centre for Dermoscopy of the Ministry of Health of the Republic of Croatia, Zagreb, Croatia

Contributors

xxv

Konstantinos Krasagakis  Department of Dermatology, University General Hospital of Heraklion, Heraklion, Greece Aleksandar L. Krunic  Department of Dermatology, University of Illinois College of Medicine, Chicago, IL, USA Alex Kubanov  Research Centre for Dermatovenereology and Cosmetology, Ministry of Healthcare of Russian Federation, Moscow, Russia Annegret  Kuhn Department of Dermatology, University of Muenster, Muenster, Germany Interdisciplinary Center for Clinical Trials (IZKS), University Medical Center Mainz, Mainz, Germany Dominik Kutlić  Zagreb University School of Medicine, Zagreb, Croatia Aimilios  Lallas  First Department of Dermatology, Aristotle University of Thessaloniki, Thessaloniki, Greece Jovan  Lalošević Department of Dermatovenereology, University of Belgrade School of Medicine, Belgrade, Serbia Aysche  Landmann Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany George Larios  Department of Dermatology, Athinaiki Mediclinic, Athens, Greece George Laskaris  Medical School University of Athens, Athens, Greece Severin Läuchli  Department of Dermatology, University Hospital, Zürich, Switzerland Frances  Lawlor  Department of Cutaneous Allergy, St John’s Institute of Dermatology, GSTT, NHS Trust, London, UK Elizabeth  Lazaridou 1st Department of Dermatology and Venereology, Aristotle University Medical School, Hospital of Skin and Venereal Diseases, Thessaloniki, Greece 2nd Department of Dermatology-Venereology, Aristotle University Medical School, Papageorgiou General Hospital, Thessaloniki, Greece Alexandre Lemieux  Department of Dermatology, Hôpital du Sacré-Coeurde-Montréal, Montréal, QC, Canada Francesco  Lotti  Andrology, Female Endocrinology and Gender Incongruence Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy Jacopo  Lotti Nuclear, Sub-Nuclear and Radiation Physics (DFNSR), University of Rome “Guglielmo Marconi”, Rome, Italy Torello  M.  Lotti Research Center CSRMR, Marconi University, Rome, Roma, Italy

xxvi

University of Rome G. Marconi, Rome, Italy Department of Dermatology, First State Medical University of Moscow I.M. Sechenov, Moscow, Russian Federation Centro Studi per la Ricerca Multidisciplinare Rigenerativa (CSRMR), Rome, Italy Mario Maggi  Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy Nazipha Farah Mahmood  University Hospitals of Leicester, Leicester, UK Leonardo G. Marini  SDC – The Skin Doctors’ Center, Trieste, Italy Branka  Marinovic  Department of Dermatology and Venereology, School of Medicine, University Hospital Centre Zagreb, University of Zagreb, Zagreb, Croatia Alejandro Martin-Gorgojo  Madrid City Council, Madrid, Spain Alessandra  Massa Dermatology Unit, Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy John McCoy  Applied Biology Inc., Irvine, CA, USA Ljiljana M. Medenica  Bel Medic, Belgrade, Serbia Mehmet Melikoğlu  Department of Dermatology and Venerology, Atatürk University, Erzurum, Turkey Madhulika  Mhatre Department of Dermatology, Wockhardt Hospitals, Mumbai, India Giedre  Mickeviciute Lithuanian University of Health Sciences, Kaunas, Lithuania Elio Mignini  Italian Society of Cosmetic Chemists (SICC), Milan, Italy Mirjana  V.  Milinkovic Department of Dermatovenereology, Faculty of Medicine, Clinic of Dermatovenereology, Clinical Center of Serbia, University of Belgrade, Belgrade, Serbia Angelica  Misitzis 1st Department of Dermatology, National and Kapodistrian University of Athens, Athens, Greece Giuseppe  Monfrecola Section of Dermatology, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy Marcello Monti  Università degli Studi di Milano, Milano, MI, Italy David Moreno-Ramirez  University Hospital Virgen Macarena, University of Seville, Seville, Spain Stefania Motta  Università degli Studi di Milano, Milano, MI, Italy Gillian M. Murphy  Beaumont Private Clinic, Beaumont, Dublin, Ireland

Contributors

Contributors

xxvii

Simone Napoli  University of Rome “G. Marconi”, Rome, Italy Siona  Ni  Raghallaigh Department of Dermatology, Beaumont Hospital, Dublin, Ireland Electra Nicolaidou  Sexually Transmitted Diseases Unit, 1st Department of Dermatology and Venereology, National and Kapodistrian University of Athens, “A. Sygros” Hospital for Skin and Venereal Diseases, Athens, Greece Miloš Nikolić  Department of Dermatovenereology, University of Belgrade School of Medicine, Belgrade, Serbia Cathal O’Connor  South Infirmary University Hospital, Cork, Ireland Sally  Jane  O’Shea South Infirmary-Victoria University Hospital, Cork, Ireland Meltem  Onder Department of Dermatology, Laser and Dermatology Centrum, Landau, Germany Department of Dermatology, Gazi University Medical Faculty, Ankara, Turkey Erdal Pala  Department of Dermatology and Venerology, Atatürk University, Erzurum, Turkey Evagelia Papadavid  Department of Dermatology and Venereology, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece Dimitrios  Papakostas  Dr. Med. Dimitrios Dermatological Practice, Athens, Greece

Papakostas

Private

Vassilios  Paparizos Unit of HIV/AIDS, Department of Dermatology, Andreas Syngros Hospital, University of Athens, Athens, Greece Marina  Papoutsaki  Dermatologist and Venereologist University, Hospital “Andreas Syggros”, Athens, Greece Aurora  Parodi Section of Dermatology DiSSal, University of Genoa, Genoa, Italy Paola Pasquali  Pius Hospital of Valls, Tarragona, Spain Annalisa  Patrizi Dermatology, Department of Specialized, Experimental and Diagnostic Medicine, Saint Orsola—Malpighi Hospital, University of Bologna, Bologna, Italy Aikaterini  Patsatsi  2nd Department of Dermatology, Aristotle University Faculty of Medicine, Papageorgiou General Hospital, Thessaloniki, Greece Monica Pau  Department of Dermatology, University of Cagliari, Cagliari, Italy

xxviii

Eirini  Pectasides  Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA Susan  Pei Section of Dermatology, Department of Medicine, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA Jelena Peric  Clinical Center of Serbia, Belgrade, Serbia Ketty  Peris Dermatologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy UOC di Dermatologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli - IRCCS, Rome, Italy Andrej  Petrov Acibadem Sistina Hospital, Skopje, Republic of North Macedonia Faculty of Medical Sciences, University “Goce Delchev”, Shtip, Republic of North Macedonia Aldona Pietrzak  Department of Dermatology, Venereology and Paediatric Dermatology, Medical University of Lublin, Lublin, Poland Bianca Maria Piraccini  Division of Dermatology, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy Federico  Pirro UOC di Dermatologia, Dipartimento Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy Laura Pizzatti  Department of Dermatology, University of Cagliari, Cagliari, Italy Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy Xenia Plakhova  Research Centre for Dermatovenereology and Cosmetology, Ministry of Healthcare of Russian Federation, STI Department, Moscow, Russia Eftychia Platsidaki  Department of Dermatology and Venereology, Andreas Sygros Hospital, Athens, Greece Vesna  Pljakoska Acibadem Sistina Hospital, Skopje, Republic of North Macedonia Garyfalia Poulakou  Third Department of Internal Medicine, National and Kapodistrian University of Athens, School of Medicine, Sotiria General Hospital, Athens, Greece Carolina  Puyana Department of Dermatology, University of Illinois at Chicago, Chicago, IL, USA Rebecca  Quiñonez Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA

Contributors

Contributors

xxix

Sven  Quist  Otto-von-Guericke Germany

University

Magdeburg,

Magdeburg,

Ranthilaka R. Ranawaka  Teaching Hospital Kalutara, Kalutara, Sri Lanka Alfredo  Rebora Department of Health Sciences, University of Genoa, Genoa, Italy Adam  Reich Department of Dermatology, Institute of Medical Sciences, Medical College of Rzeszow University, Rzeszow, Poland Éva Remenyik  Department of Dermatology, Centre of Excellence, Faculty of Medicine, University of Debrecen, Debrecen, Hungary Department of Dermatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary ELKH-DE Allergology Research Group, Debrecen, Hungary Francesco Ricci  Istituto Dermopatico dell’Immacolata, Rome, Italy Dimitris  Rigopoulos 1st Department of Dermatology, Andreas Sygros Hospital, University of Athens Medical School, Athens, Greece Johannes  Ring  Department of Dermatology and Allergology Biederstein, Technical University Munich (TUM), München, Germany Martin  Röcken Division of Dermatology, Eberhard Karls University, Tübingen, Germany Franco Rongioletti  Dermatology Clinic, IRCCS Hospital San Raffaele and University Vita-Salute San Raffaele, Milan, Italy Elena Rossi  Department of Dermatology, University of Modena and Reggio Emilia, Modena, Italy Christopher M. E. Rowland Payne  The London Clinic, London, UK Pietro Rubegni  Dermatology Unit, University of Siena, Siena, Italy Andris Rubins  Latvian Dermatology Institute, Riga, Latvia Department of Dermatovenereology, Faculty of Medicine, University of Latvia, Riga, Latvia Silvestrs Rubins  Latvian Dermatology Institute, Riga, Latvia Department of Dermatovenereology, Faculty of Medicine, University of Latvia, Riga, Latvia Lidia Rudnicka  Faculty of Health Sciences, Medical University of Warsaw, Warsaw, Poland Antonio Rusciani  Skinlaser Center, Rome, Italy Hugh D. Rushton  The Rushton Clinic, London, UK Centre for Skin Sciences, Faculty of Life Sciences, University of Bradford, Bradford, UK

Contributors

xxx

Roberto Russo  Ospedale-Policlinico San Martino IRCCS, Genoa, Italy Lidia Sacchelli  Unit of Dermatology, Department of Medical and Surgical Sciences Alma Mater Studiorum University of Bologna, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Policlinico Sant’Orsola Malpighi, Bologna, Italy Carmen Maria Salavastru  Pediatric Dermatology Department, Colentina Clinical Hospital, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Julián  Conejo-Mir  Sánchez Dermatology Department, Virgen del Rocío University Hospital, Seville, Spain Ankur Sarin  Sarin Skin Solutions, New Delhi, India Robert  P.  E.  Sarkany Photodermatology Unit, St John’s Institute of Dermatology, London, UK Francesca Satolli  Dermatology Unit, Dipartimento di Medicina e Chirurgia, Università di Parma, Parma, Italy Jean-Hilaire Saurat  Faculty of Fundamental Medicine, University Medical Centre, University of Geneva, Geneva, Switzerland Natale  Schettini Department of Medical Science, O.U. of Dermatology, Azienda Ospedaliera—University of Ferrara, Ferrara, Italy Enno Schmidt  Department of Dermatology, University of Lübeck, Lübeck, Germany Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck, Lübeck, Germany Kristina Semkova  St John’s Institute of Dermatology, London, UK Mercedes  Sendín-Martín Dermatology Department, Virgen del Rocío University Hospital, Seville, Spain Dimitrios  Sgouros 2nd Department of Dermatology and Venereology, National and Kapodistrian University of Athens Medical School, “Attikon” General University Hospital, Athens, Greece Aseem  Sharma Dermatology Unit, Skin Saga Centre for Dermatology, Mumbai, India Francisca Silva-Claveria  University Hospital Virgen Macarena, University of Seville, Seville, Spain Maja  Sirotković-Skerlev  Department of Pathophysiology, University School of Medicine, Zagreb, Croatia

Zagreb

Mirna  Situm Department of Dermatovenerology, Sestre Milosrdnice University Hospital Centre, Zagreb, Croatia School of Dental Medicine, University of Zagreb, Zagreb, Croatia Referral Centre for Melanoma of the Ministry of Health of the Republic of Croatia, Zagreb, Croatia

Contributors

xxxi

Referral Centre for Dermoscopy of the Ministry of Health of the Republic of Croatia, Zagreb, Croatia Croatian Academy of Science and Arts, Zagreb, Croatia Mihael  Skerlev Department of Dermatology and Venereology, Zagreb University School of Medicine and Zagreb University Hospital, Zagreb, Croatia Cezary  Skobowiat Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Torun, Poland Olivier Sorg  Faculty of Fundamental Medicine, University Medical Centre, University of Geneva, Geneva, Switzerland Dimitrios Sotiriadis  2nd Department of Dermatology, Aristotle University Faculty of Medicine, Papageorgiou General Hospital, Thessaloniki, Greece Maria Souli  Duke Clinical Research Institute, Durham, NC, USA Efthymia  Soura 1st Department of Dermatology-Venereology, Andreas Sygros Hospital, National and Kapodestrian University of Athens, Athens, Greece Andrija  Stanimirović School of Medicine, European University Cyprus, Nicosia, Cyprus Michela  Starace Division of Dermatology, Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy Angelika Stary  Head of the Outpatients’ Centre for STI, Vienna, Austria Nikolaos  G.  Stavrianeas Emeritus of Dermatology and Venereology, National and Kapodistrian University of Athens Medical School, Athens, Greece Panagiotis  G.  Stavropoulos  1st Department of Dermatology, A.  Syggros Hospital, University of Athens Medical School, Athens, Greece Christina Stefanaki  Andreas Sygros Hospital, University of Athens Medical School, Athens, Greece Irene Stefanaki  1st Department of Dermatology - Venereology, University of Athens Medical School, ‘Andreas Sygros’ Hospital for Skin and Venereal Diseases, Athens, Greece Eggert Stockfleth  St. Josef-Hospital RUHR-University Bochum, Bochum, Germany Alexander  J.  Stratigos 1st Department of Dermatology-Venereology, Andreas Sygros Hospital, National and Kapodestrian University of Athens, Athens, Greece Markus  Streit Department of Dermatology, Kantonsspital Aarau, Aarau, Switzerland

xxxii

Sana  Sultan  Department of Dermatology, Ealing Hospital, London North West Hospitals Trust, Southall, UK Andrea Szegedi  Department of Dermatology, Centre of Excellence, Faculty of Medicine, University of Debrecen, Debrecen, Hungary ELKH-DE Allergology Research Group, Debrecen, Hungary Jacek  C.  Szepietowski Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, Poland Anna  Tagka 1st Dermatology Department, Andreas Syggros Hospital, University of Athens, Athens, Greece Alexandru Tataru  Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania George-Sorin  Țiplica 2nd Clinic of Dermatology, Colentina Clinical Hospital—“Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania Antonia  Torodova  Department of Dermatology and Allergology Biederstein, Technical University Munich (TUM), München, Germany Division of Public Health, City of Munich, Munich, Germany Linda Tognetti  Dermatology Unit, University of Siena, Siena, Italy Antonella Tosti  Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA Myrto Trakatelli  Second Department of Dermatology, Aristotle University, Papageorgiou Hospital, Thessaloniki, Greece Lara  Tripo Division of Dermatology, Department of Surgery and Translational Medicine, University of Florence, Florence, Italy Nikolai Tsankov  Department of Dermatology and Venereology, Acibadem City Clinic, Tokuda Hospital, Sofia, Bulgaria Maria  M.  Tsoukas  Department of Dermatology, University of Illinois at Chicago, Chicago, IL, USA Bengu Gerceker Turk  Department of Dermatology and Venereology, Ege University Medical Faculty, Izmir, Turkey Alexander  Yu  Turkevych Department of Dermatovenereology, Lviv National Medical University Named After Danylo Galytskuj, Lviv, Ukraine Department of Dermatology, Rome University “G. Marconi”, Rome, Italy Ümit  Türsen Mersin University Health Practice and Research Hospital, Mersin, Turkey Athanasios  G.  Tzioufas Pathophysiology Department, Athens School of Medicine, National and Kapodistrian University of Athens, Athens, Greece Dirk  Van Gysel Department of Pediatrics, Onze-Lieve-Vrouwziekenhuis Aalst-Asse-Ninove, Aalst, Belgium

Contributors

Contributors

xxxiii

Interdisciplinary Unit of Pediatric Dermatology, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Belgium Michela  Venturi Dermatology Unit and Burn Center, AUSL Romagna, Bufalini Hospital, Cesena, Italy Stefano  Veraldi Department of Pathophysiology and Transplantation, University of Milan, Foundation IRCCS, Cà Granda Ospedale Maggiore Policlinico, Milan, Italy Theognosia  Vergou Department of Dermatology, A.  Sygros Hospital for Skin and Venereal Diseases, University of Athens, Athens, Greece Ines Verner  Verner Clinic, Tel Aviv, Israel Paolo Viacava  Unit of Pathology, Livorno Hospital, Livorno, Italy Petar  Vojvodic  Specialized Medical Practice in the Field of Psychiatry Psihocentrala, Belgrade, Serbia Sebastian  Volc Division of Dermatology, Eberhard Karls University, Tübingen, Germany Anna Waśkiel-Burnat  Medical University of Warsaw, Warsaw, Poland Michael Waugh  Leeds Teaching Hospitals, Leeds, UK International Union against Sexually Transmitted Infections, Leeds, UK Bartłomiej  Wawrzycki Department of Dermatology, Venereology and Pediatric Dermatology, Faculty of Medicine, Medical University of Lublin, Lublin, Poland Andreas Wollenberg  Ludwig-Maximilian University, Munich, Germany Uwe Wollina  Municipal Hospital Dresden, Academic Teaching Hospital of the Technical University of Dresden, Dresden, Germany Matteo  Zanardelli Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy Zoulikha Zarrab  University of Rome “G. Marconi”, Rome, Italy Centro Studi per la Ricerca Multidisciplinare Rigenerativa (CSRMR), Rome, Italy Christos  C.  Zouboulis Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical School Theodore Fontane and Faculty of Health Sciences Brandenburg, Dessau, Germany European Hidradenitis Suppurativa Foundation e.V., Dessau, Germany Vanna Zucchi  Unit of Pathology, Livorno Hospital, Livorno, Italy

Part I Diseases

1

Acne Clio Dessinioti and Brigitte Dreno

Key Points • Acne vulgaris (acne) is a chronic inflammatory skin disease that may present in childhood, adolescence, or adulthood. • Hyperseborrhea, hyperkeratinization of the pilosebaceous follicle, loss of diversity of Cutibacterium acnes (Propionibacterium acnes) phylotypes, and inflammation contribute in the pathogenesis of acne. Exposome factors are environmental exposures that may influence acne and include nutrition, lifestyle factors, occupational factors (cosmetics, pollutants), medication, and climate. • Acne is diagnosed clinically and should be differentiated from acneiform eruptions such as acne cosmetica, perioral dermatitis, rosacea, folliculitis, and drug-induced acneiform eruptions. • Laboratory evaluations may be indicated to evaluate for an underlying hormonal disorder such as the polycystic ovary syndrome or nonclassical congenital hyperplasia. • Topical treatments for acne include retinoids, benzoyl peroxide [BPO], azelaic acid, antibi-

C. Dessinioti (*) 1st Department of Dermatology, Andreas Syggros Hospital, University of Athens, Athens, Greece B. Dreno Nantes Université, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT, Nantes, France e-mail: [email protected]

otics, and fixed-dose combination formulations. Oral acne treatments may include appropriate antibiotics, zinc, isotretinoin, and for women only, hormonal therapy. Recommendations are presented based on current updated guidelines. • The risk of bacterial resistance should be considered with the use of antibiotics. Antibiotics (oral or topical) should not be used for more than 3 months and always be combined with topical agents such as retinoids or BPO.

Definition and Epidemiology Acne vulgaris is a chronic inflammatory skin disease of the pilosebaceous unit (Thiboutot et  al. 2018). It affects the majority of adolescents, while it may also present during childhood or adulthood (Antoniou et al. 2009; Moradi Tuchayi et al. 2015). Acne during childhood may be classified depending on the age of presentation, in neonatal, infantile, mid-childhood, and prepubertal acne. In adolescents, acne presents around 12–14 years of age and usually resolves around 18–20 years of age. However, it may continue or first present in individuals older than 20–25 years in adulthood. Adult women are more frequently affected with acne than adult men (Cunliffe and Gould 1979; Collier et  al. 2008). Rates of reported adult female acne range from 14% to 54% (Poli et al. 2001; Goulden et al. 1999; Dreno

© Springer Nature Switzerland AG 2023 A. D. Katsambas et al. (eds.), European Handbook of Dermatological Treatments, https://doi.org/10.1007/978-3-031-15130-9_1

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2015). There are two subtypes of adult acne: late-­ onset acne (acne tarda) first presents in adulthood, and persistent acne refers to acne continuing from adolescence to the adult years of life. Persistent acne is the more common subtype of adult acne accounting for 80% of cases. Acne may lead to some degree of facial scarring in 35–95% of affected patients and it has been reported that long-term duration of acne correlates with the probability of scarring (Layton et  al. 1994; Tan et  al. 2017; Dessinioti et  al. 2018a). Acne may result in psychological distress and lower self-esteem and acne relapses have been associated with impaired quality of life, productivity loss, and absenteeism (Dreno et al. 2018a, 2019; Chernyshov et al. 2018).

Basic Concepts of Pathogenesis Hyperseborrhea, hyperkeratinization of the pilosebaceous follicle, Cutibacterium acnes, and inflammation contribute in the pathogenesis of acne. Recent research data have modified the concepts of acne pathogenesis. Concerning the role of the sebaceous gland, in addition to hyperseborrhoea, sebum fatty acid composition may regulate the skin barrier and the microbiome. Cutibacterium acnes strains (C.acnes, formerly named Propionibacterium acnes (Scholz and Kilian 2016)), along with other bacteria such as Staphylococcus.epidermidis (S.epidermidis), play a key role in the modulation of the innate and adaptive immunity (Moradi Tuchayi et  al. 2015; Dessinioti and Katsambas 2010; Claudel et al. 2019; Dreno 2017). C. acnes is the major skin commensal bacterium residing in the pilosebaceous unit of the skin. There is no quantitative difference of C. acnes in the skin of patients with acne compared with controls (Fitz-Gibbon et al. 2013). However, distinct C. acnes phylotypes have been associated with acne (Platsidaki and Dessinioti 2018). C. acnes phylotype IA1 is the most frequent phylotype both in mild and in severe acne, on the face and on the back (Dagnelie et  al. 2018; Nakase et al. 2017; Paugam et al. 2017). The loss of C. acnes phylotype diversity has been shown to trigger innate immune system activation and

C. Dessinioti and B. Dreno

cutaneous inflammation (Dagnelie et  al. 2019). There was no difference in C. acnes phylotypes of the skin of adult women with acne compared to adolescents (Saint-Jean et al. 2019). S. epidermidis belongs to the commensal bacterial group of Firmicutes. An interplay between S. epidermidis and C. acnes to regulate skin homeostasis has been recently described. S. epidermidis has shown antimicrobial activity against C.acnes, and in vivo S. epidermidis controls the proliferation of C. acnes and the inhibition of C. acnes-induced inflammation (Claudel et al. 2019). Furthermore, the exposome has been described as the sum of environmental factors that may influence the occurrence, duration, and severity of acne. Exposome factors include nutrition, lifestyle factors, occupational factors (cosmetics, mechanical factors causing rubbing or scrubbing, pollutants), medication, and climate (Dreno et al. 2018b).

Clinical Presentation Acne affects the face and trunk that represent body areas rich in pilosebaceous units. The primary clinical lesions in active acne vulgaris are either noninflammatory lesions including open or closed comedones or inflammatory lesions including papules, pustules, or nodules (Moradi Tuchayi et al. 2015). Also, scarring may be a secondary sequalae of acne primary lesions. Acne scarring may be hypertrophic or atrophic. Atrophic scarring is more common and has been subclassified into ice pick, boxcar, and rolling scars (Jacob et al. 2001; Carlavan et al. 2018). Acne may be classified according to severity as mild, moderate, or severe and according to the lesions that predominate in a given patient as comedonal, papulopustular, or nodular (Figs. 1.1 and 1.2). Severe cystic acne is characterized by the presence of cysts and usually numerous comedones, papules, and pustules. Acne conglobata (conglobate acne) is a chronic, severe variant of inflammatory acne vulgaris presenting with grouped comedones, cystic nodules, abscesses, and sinus tracts. It mainly affects adult men and leads to significant scarring. It has been described as part of the ‘follicular occlusion tetrad’, together with hidradenitis sup-

5

1 Acne

nodules on the lower third of the face, jaw-­line, and neck, referred to as ‘chin acne’ (Dreno 2015).

Diagnosis

Fig. 1.1  Mild facial acne with few papules and pustules. Several acne scars are present

Fig. 1.2  Moderate facial acne with some papules and pustules. Acne scars are present

purativa, dissecting cellulitis of the scalp and pilonidal disease (Dessinioti and Katsambas 2017a). Adult acne has a different clinical presentation from adolescent acne. Adult acne may present with two clinical forms: the comedonal form characterized by small closed comedones or macrocomedones and the inflammatory form consisting of papulopustules and deep inflammatory

The diagnosis of acne is clinical. The comedone is the sine qua nonclinical lesion in acne. Comedones are always present in acne and they are the key characteristic to guide diagnosis. Additional lesions may include papules, pustules, cysts, and potential scarring. Further clinical clues include the localization of these characteristic acne lesions on the face or trunk. Acne is not an allergy or an infection, so laboratory evaluations and skin biopsy are not necessary to confirm the diagnosis of acne, except if other conditions need to be ruled out. Routine endocrinologic evaluation is not recommended for the majority of patients with acne (Zaenglein et  al. 2016). There may be cases when hormonal evaluations may be indicated, including female patients with suspicion of an underlying hormonal disorder. In women, acne accompanied by other clinical signs of hyperandrogenism, such as androgenic alopecia or hirsutism, may prompt evaluations for the polycystic ovary syndrome (PCOS) or nonclassical congenital adrenal hyperplasia (NCAH). PCOS is characterized by clinical and/or biochemical evidence of hyperandrogenism with oligo- and/or anovulation and polycystic ovaries on ultrasound. The determination of serum 17-hydroxyprogesterone (17-OH PG), the immediate substrate for 21-hydroxylase, is used for the biochemical diagnosis of NCAH (Chen et al. 2011).

Differential Diagnosis The differential diagnosis of acne includes acneiform eruptions: (Dessinioti et al. 2014) • Acne cosmetica: characterized by small scattered comedones on the face. History of application of cosmetics with comedogenic ingredients, essential oils or greasy, oily foundations, powder make-up, and aggressive skin

6

cleansers and soaps with pH of 8.0. • Perioral dermatitis: it affects individuals mainly after the age of 30 years. It is located around the mouth, nose, and eyes. Comedones are absent. • Folliculitis: it presents with follicular pustules. Comedones are absent. • Rosacea: it affects individuals after the age of 30 years. Comedones are absent. • Drug-induced acneiform eruptions due to glucocorticosteroids, antiepileptics, antidepressants, growth hormone, cyclosporine, vitamin B12, epidermal growth factor receptor (EGFR) inhibitors, and BRAF inhibitors: recent or current history of drug intake; comedones are absent. • Cutaneous B-cell lymphoma: has been rarely reported to present with acneiform papules on the face that were resistant to anti-acne treatments. Skin biopsy and immunohistochemistry are needed to establish diagnosis in this case (Soon et al. 2011).

General Principles of Treatment The management of acne is based on the clinical classification of acne depending on predominant lesions, severity and presence of scarring, and further depends on the psychological impact of acne, the age, and medical history of the patient. Acne is a chronic disease and patient education is critical to improve adherence to proposed treatment and optimize clinical results. A discussion with the patient will address possible questions and dispel misconceptions they may affect his/her treatment-seeking behaviors and decisions. A patientcentered holistic approach is the future of optimizing acne treatments, considering the patient’s age group, smoking habits, and the possible psychological burden. Stress is often perceived by patients as a triggering factor for acne (Dessinioti et al. 2018b). This association may be due to the fact that patients with acne are more prone to suffer from stress or depression and anxiety as a consequence of their acne (Albuquerque et al. 2014). The possible negative impact and psychological implications of acne on the patients’ life should be considered and it was recommended to have empathy and understanding

C. Dessinioti and B. Dreno

of the impact of acne on personal and professional factors, to assess stress and sleep patterns and to consider the self-perception of acne severity (Dreno et  al. 2018a). Another common question often posed by acne patients is whether a specific food influences their acne. Dietary factors implicated in triggering acne include dairy products, especially skim milk, and hyperglycaemic carbohydrates. However, there are no randomized controlled clinical trials and high-quality evidence to allow the association between nutrition and acne to be confirmed (Claudel et al. 2018). No recommendation is given on dietary advice in the European Guidelines (Nast et  al. 2016). The AAD guidelines state that given the current data, no specific dietary changes are recommended in the management of acne (Zaenglein et al. 2016). We suggest our acne patients to follow a balanced diet as part of a healthier mode of life in general. It is advised to inform patients that acne treatment will continue over long periods of time and clinical improvement is not evident early but usually takes some (5, 6) weeks to show. Topical treatments are fundamental for the management of acne, so the importance of applying topical agents should be explained to patients. Topicals should be applied on the entire face and not just on the clinically visible lesions in order to effectively target the microcomedone, the primary acne lesion that is not visible to the naked eye. A mild cleanser may be used for washing the face twice daily. Cosmetics, sunscreen, and make-up products should be noncomedogenic. Skin care products are often necessary to either complement the use of acne drugs, or to counteract the drying effect of some acne medications. Moisturizing creams are usually needed during oral isotretinoin treatment and an appropriate anti-acne dermocosmetic may be used in the morning when topical retinoids are applied at nighttime, in order to avoid topical irritation. Pharmacological treatments for acne may be topical and systemic (oral). Topical treatments for acne include retinoids, azelaic acid, antibiotics, benzoyl peroxide, and fixed-dose combination formulations. Oral treatments include appropriate antibiotics, isotretinoin, zinc, and for women only, hormonal treatments. After ­induction therapy, maintenance topical therapy should be recommended to maintain the remission of acne.

1 Acne

Topical Treatments Topical Antibiotics Topical antibiotics include erythromycin, clindamycin, tetracycline, and nadifloxacin. They exert anti-inflammatory properties as well as antibacterial action against P. acnes. Τopical antibiotics are indicated for mild to moderate action. Due to risk of bacterial resistance, they should never be used as monotherapy, but should be used in combination with another topical treatment such as retinoid or benzoyl peroxide.

Benzoyl Peroxide (BPO) BPO has antibacterial, anti-inflammatory, and mild comedolytic actions. Topical BPO is indicated for mild papulopustular acne and for moderate to severe acne in combination with another topical treatment, such as retinoid, antibiotic, or azelaic acid. Also, it may be combined with systemic antibiotic therapy or, in women, with hormonal therapy. BPO is applied once or twice daily for a period that is determined by the treating dermatologist. It may be proposed as maintenance therapy.

Topical Retinoids Τopical retinoids include adapalene, isotretinoin, tazarotene, tretinoin, and trifarotene. They have comedolytic effects, and, in addition, adapalene exhibits mild anti-inflammatory action. Trifarotene is a selective RAR-γ agonist with ocomedolytic, anti-inflammatory, and antipigmenting properties (Aubert et  al. 2018). Trifarotene 0.005% cream was by EMA (Europe)and by US FDA-approved for the treatment of acne, and approval was based on two doubleblind randomized controlled trials of 12-week trifarotene for moderate acne for patients ≥9 years old. Local tolerability signs and symptoms related to trifarotene cream included erythema, scaling, dryness, stinging/burning, pruritus, and sunburn and were mostly mild to moderate in severity (Blume-Peytavi et al. 2020; Tan et al. 2019).

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Topical retinoids are indicated for comedonal and mild papulopustular acne. Also, they are indicated for moderate to severe acne in combination with another topical treatment, such as BPO, antibiotics, azelaic acid, and/or a systemic antibiotic or hormonal therapy. They are applied mostly once daily for a period that is determined by the treating dermatologist. They may be proposed as maintenance therapy.

Azelaic Acid Azelaic acid presents mild comedolytic, antimicrobial, and anti-inflammatory actions. Azelaic acid is indicated for comedonal and mild papulopustular acne. Also, it is recommended for moderate and severe acne in combination with another topical treatment such as BPO, retinoids, or antibiotic or in combination with a systemic antibiotic or hormonal therapy. It is applied twice daily, and treatment for at least 12  weeks is usually required for acne improvement.

Fixed-Dose Combination Topical Formulations Fixed-dose combination topical agents combine two different agents used for acne treatment, such as combinations of antibiotic/retinoid or antibiotic/ benzoyl peroxide or benzoyl peroxide/retinoid. Topical combination treatments target multiple pathogenetic factors at the same time, thus resulting in enhanced effectiveness and improved tolerability. Also, they present the advantage of a simpler application regimen, with a once- or twicedaily application of a single formulation, thus resulting in better adherence by the patient to the proposed regimen. For papulopustular acne, fixeddose combination agents were more efficacious compared to their ingredients used alone.

5% Dapsone Gel Dapsone is a sulfone with both anti-inflammatory and antimicrobial properties. Advances in cutaneous pharmacology have produced a new topical

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formulation of 5% dapsone gel, which was shown to be an effective and safe treatment, when applied twice daily for 12  weeks. Glucose-6-­phosphate dehydrogenase-deficient patients presented no laboratory abnormalities. It has been proposed that its action may be due to a direct inhibition of leukocyte trafficking and the generation of chemical mediators of inflammation by leukocytes. Alternatively, topical dapsone might act indirectly in acne, by altering the levels and/or activity of propionibacteria. Dapsone gel is approved for the treatment of acne by the US FDA.

1% clascoterone cream Clascoterone is a topical androgen inhibitor. It is approved for acne by the US FDA for patients 12 years and older. Two phase 3 randomized clinical trials showed efficacy for inflammatory and noninflammatory acne lesions after 12 weeks of application (Hebert et al. 2020). There were no systemic adverse events or laboratory findings (Eichenfield et al. 2020).

Topical Treatments at a Glance • Topical treatments (retinoids, BPO, azelaic acid, antibiotics) are recommended for mild comedonal or inflammatory acne and in combination with an oral agent for moderate and severe acne. • Topical antibiotics should not be used alone, but in combination with another agent (e.g., retinoid or BPO) to avoid the risk of bacterial resistance. • Fixed-dose combination agents aim to enhance effectiveness and tolerability and to improve patients’ adherence. • Maintenance treatment is necessary to maintain acne remission and includes topical application of retinoid, BPO, or azelaic acid.

Systemic (Oral) Treatments The use of systemic treatments is indicated for moderate to severe inflammatory acne, for acne that is resistant to topical treatments, and for acne

of the trunk (covering large body areas). Established systemic acne treatments include oral antibiotics, isotretinoin, and for women only, hormonal therapies.

Antibiotics Systemic antibiotics used for acne treatment include tetracyclines (tetracycline, doxycycline, minocycline, and limecycline) and macrolides (erythromycin, azithromycin). The efficacy of tetracycline derivatives in acne vulgaris is believed to be related, besides to their antibiotic effects, also to their anti-inflammatory effects. Anti-inflammatory action may be exerted via reduction in neutrophil chemotaxis, as well as via inhibition of proinflammatory cytokines and matrix metalloproteinase-9 (MMP-9). Nevertheless, data concerning antibiotic use in acne have been based on anecdotal reports, clinical experience, and small clinical trials. Recommended dosage regimens are 300 mg/day for lymecycline and 50–200  mg/day for doxycycline. Treatment should not exceed 3 months. Acne treatment with systemic antibiotics may be associated with vaginal candidiasis and gastrointestinal disturbances. Moreover, doxycycline has been associated with photosensitivity, while minocycline has been associated with pigment deposition in the skin, mucous membranes, and teeth, particularly among patients receiving long-term therapy and/or higher doses of minocycline. Rare adverse effects reported with minocycline use include autoimmune hepatitis, a systemic lupus erythematosus-like syndrome, and serum sickness-like reactions. Tetracyclines are indicated for individuals older than 8 years, after permanent dentition has been completed, and they are contraindicated during pregnancy and lactation. Oral minocycline is not recommended for the treatment of acne in the current European and UK NICE guidelines. (Nast et al. 2016, Xu J et al. 2021). Sarecycline is a narrowspectrum, third-generation tetracycline-class agent for the treatment of moderate to severe acne vulgaris (Del Rosso JQ et al. 2021). Azithromycin has been found to be effective in treating noninflammatory and inflammatory acne

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1 Acne

lesions. Azithromycin has been studied in acne in pulse dosing regiments ranging from 3 times/week to 4  days/month. A meta-analysis of randomized controlled trials reported no significant differences in efficacy of azithromycin pulse therapy compared to daily doxycycline for moderate to severe acne vulgaris at 12 weeks of treatment (Kim et al. 2018). According to AAD guidelines, although oral erythromycin and azithromycin can be effective, their use should be limited to those patients who cannot use the tetracyclines (Zaenglein et al. 2016).

Bacterial Resistance Bacterial resistance to antibiotics is an increasing health problem worldwide. Resistance of C. acnes to antibiotics has been rising over the years throughout European countries, Korea, US, and Hong Kong (Dessinioti and Katsambas 2017b; Ross et al. 2003). Resistance of C. acnes is more common with erythromycin; less common with tetracycline, doxycycline, and trimethoprim; and rare with minocycline. Azithromycin is a methyl derivative of erythromycin that effectively inhibits significant intracellular pathogens, as well as Gram-positive and Gram-negative aerobic and anaerobic bacteria, including C. acnes. Gonzalez et al. reported high resistance rates of 82% of C. acnes to azithromycin in 47 patients. As resistance breakpoints for azithromycin against anaerobes were not established, this study used the Haemophilus breakpoint. A possible explanation given by the authors for these high rates of resistance was the cross resistance between erythromycin and clindamycin due to point mutations in 23S rRNA which gives resistance to other macrolide antimicrobials such as azithromycin (Gonzalez et al. 2010). High rates of C. acnes resistance were reported to macrolides-lincosamides-streptogramins antibiotics, including azithromycin (58.6%), in a study in Southwest China (Zhu et  al. 2019). On the other hand, another study reported low rates of resistance of 5.1% of C. acnes to azithromycin and the authors attributed them to the recent onset of prescription of azithromycin in acne patients in Egypt (Abdel Fattah and Darwish 2013).

The use of antibiotics may result not only in an increase of resistance of C. acnes, but also in an increase in other resistant organisms, such as Staphylococcus aureus. In order to avoid this, it is recommended to prefer nonantibiotic treatment when feasible, to avoid antibiotic monotherapy, to restrict antibiotic use to up to 3 months, and to use combination treatments for acne.

Zinc Zinc sulfate and zinc gluconate have been used for the treatment of inflammatory acne vulgaris with conflicting results. Oral zinc salts have been used at a dose of 30–150 mg of elemental zinc daily for 3  months. Adverse events during zinc treatment involve the gastrointestinal tract. Zinc acts via inhibition of polymorphonuclear cell chemotaxis and inhibition of growth of P. acnes. Also, its anti-inflammatory activity could be related to a decrease in TNF-α production and the modulation of the expression of integrins and the inhibition of Toll-like receptor 2 (TLR2) surface expression by keratinocytes. Zinc gluconate has been proposed as an alternative therapy for inflammatory acne; it may be a useful treatment for pregnant women due to its favorable safety profile, and it may be proposed during summer as it causes no photosensitivity. In addition, zinc gluconate does not induce bacterial resistance, and when combined in a topical formulation with erythromycin, it has been shown to prevent the growth of erythromycin-­ resistant P. acnes strains and to be more effective in inflammatory acne than erythromycin alone. Oral zinc is recommended with a low strength of recommendations for mild to moderate papulopustular acne in the European guidelines (Nast et al. 2016).

Isotretinoin Systemic isotretinoin (13-cis retinoic acid), a vitamin A derivative, is the only therapeutic agent that targets all four major factors involved in acne pathogenesis. The European Agency for the Evaluation of Medicinal Products (EMEA) and drug licensing

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recommends that its use should be limited to severe acne, nodular and conglobate acne, that has not responded to appropriate antibiotics and topical therapy. Current European S3 guidelines (2016) recommend oral isotretinoin with a high strength of recommendation for severe papulopustular/moderate nodular acne and for severe nodular/conglobate acne. However, it is noted that limitations can apply that may necessitate the use of a treatment with a lower strength of recommendation as a first line therapy (e.g., financial resources/reimbursement limitations, legal restrictions, availability, drug licensing) (Dessinioti et al. 2020). A comparison of guidelines on the use of isotretinoin for acne reported recommendations on dosing, cumulative dose, monitoring, and special considerations (Dessinioti et  al. 2020). The recommended daily dose ranges from 0.3–0.5 mg/ kg in the European guidelines (Nast et al. 2016) to up to 1 mg/kg in the AAD guidelines (Zaenglein et  al. 2016). Isotretinoin should be taken with food. A cumulative dose is not proposed in the European guidelines and treatment should be continued for at least 6 months and until there is sufficient response. Intermittent dosing of isotretinoin is not recommended (Zaenglein et al. 2016). Relapse after treatment with oral isotretinoin has been reported in 15–45% of patients, and it has been associated with early acne, young age at the moment of isotretinoin initiation, family history of acne, prepubertal acne, localization on the trunk, important seborrhea, and a high number of inflammatory lesions at the end of treatment. According to the European guidelines, Laboratory evaluations, primarily liver enzymes and lipids, should be monitored before treatment, 1  month after starting treatment, and every 3  months thereafter (Nast et  al. 2016; Dessinioti et  al. 2020) Recent expert consensus proposed a less frequent laboratory evaluation schedule; only within a month before isotretinoin initiation and at peak dose, for generally healthy patients without underlying abnormalities, preexisting conditions, or clinical context warranting further investigation. (Xia et al. 2022). Mucocutaneous xerosis is the most common adverse event, resulting in dermatitis, cheilitis, epistaxis, and conjunctivitis. The most important

adverse events are teratogenicity and psychiatric disorders. Oral isotretinoin is teratogenic and it should be prescribed only under strict pregnancy prevention measures in women of childbearing potential. Before treatment initiation, women of childbearing potential should be informed about teratogenicity of isotretinoin and the absolute need of effective contraceptive measures throughout treatment and for at least 1 month after treatment completion. The European Guidelines state that there is continued uncertainty regarding isotretinoin, depression, and suicidal behavior and that caution and patient information appears reasonable. It is mentioned that the current literature comes to different conclusions and that there were important limitations in relevant studies. They recommend to assess prior symptoms of depression in the patient’s medical history before isotretinoin onset and during treatment and to inform patients about a possible risk of depression and suicidal behavior (Nast et al. 2016).

Hormonal Therapies Hormonal agents for acne treatment are indicated for female patients only, and they include antiandrogens and combined oral contraceptives (OC). Hormonal therapies exert their beneficial effects in acne by reducing circulating and local androgens and by opposing the actions of androgens in the pilosebaceous unit. Appropriate patient selection is important when considering initiating hormonal therapy. Contraindications should be ruled out and treatment should be individualized. Spironolactone is an antiandrogen that is gaining popularity in some countries as an off-label treatment for acne vulgaris in adult females. Spironolactone may be considered in addition to estroprogestins in females with moderate or severe hyperandrogenic adult acne, not responding to usual treatment (Carmina et al. 2022).

Systemic Treatments at a Glance • Among oral antibiotics, doxycycline and lymecycline are recommended as first-choice

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•

•

• •

•

agents for the treatment of moderate to severe inflammatory acne. Oral antibiotic therapy should be discontinued when response is achieved and after a maximum period of 3 months. Oral antibiotics should always be combined with a topical agent such as a retinoid, BPO, azelaic acid, or their fixed-dose combinations, to decrease the risk of bacterial resistance. Oral antibiotic should not be combined with a topical antibiotic alone. Oral isotretinoin is recommended at a dose of 0.3–0.5  mg/kg/day in the current European Guidelines. Hormonal therapy should be individualized for female acne patients.

Other Treatment Options for Acne Other therapeutic options that have been used for acne treatment include the removal of closed and open comedones, laser, and visible light sources, while chemical peels and lasers may be used for acne scarring. Laser and light therapies, including blue or red light, intense pulsed light (IPL), and pulsed-­dye laser (PDL), have been used for acne. It is known that P. acnes produces porphyrins, particularly coproporphyrin III. Visible light is able to activate these porphyrins to produce a photodynamic reaction that has the potential to destroy bacteria. Topical photodynamic therapy (PDT) uses light-activated agents (photosensitizers) that are selectively absorbed into the pilosebaceous unit to amplify the response to light/laser therapy. Topical photosensitizers used for PDT in acne include 5-aminolaevulinic acid (ALA) and methyl aminolevulinate (MAL). For the treatment of mild-to-moderate papulopustular acne, the current European Guidelines issued an “open recommendation” (neither for nor against) for the use of red light, laser, IPL, PDT, and a low strength of recommendation for blue light monotherapy. For severe papulopustular/ moderate nodular/severe nodular/conglobate acne, there was a negative recommendation for visible light a monotherapy and open recommendation for laser, IPL, and PDT. Artificial ultraviolet radiation is contraindicated for acne (Nast et al. 2016).

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European Evidence-Based Guidelines for the Treatment of Acne Treatment choice should be individualized and should take into account the age and the medical history of the patient, the type and severity of acne, the impact of acne on the patient’s quality of life, the risk of scarring, and the presence of prognostic factors such as a family history of acne, adult acne, hyperseborrhea, hyperandrogenemia, truncal acne, or a history of infantile acne. The European Evidence-based (S3) Guidelines for the treatment of acne have systemically reviewed well-designed clinical trials of acne treatments and included a structured consensus process. Guidelines were based on the clinical form and severity of acne (Nast et al. 2016). For comedonal acne, topical retinoids are recommended as first-line therapy (Fig. 1.3). Available topical retinoids were reported to have similar efficacy, but adapalene is preferred over tretinoin and isotretinoin, due to its better tolerability profile. For mild to moderate papulopustular acne, there is high strength of recommendation for the use of fixed-dose combination adapalene/BPO or clindamycin/BPO. AZA, BPO, clindamycin/tretinoin, and topical retinoids are recommended with a medium strength of recommendation. For more widespread moderate papulopustular acne, oral antibiotic combined with adapalene is recommended with a medium strength of recommendation. Blue light monotherapy has a low strength of recommendation (Fig. 1.4). For severe papulopustular/moderate nodular acne, oral isotretinoin has been recommended, while there is medium strength recommendation for systemic antibiotics combined with adapalene, or BPO/adapalene, or AZA. Even though the European Guidelines support oral isotretinoin as first-line treatment for severe papulopustular, moderate nodular, and severe nodular/conglobate acne, it is also noted that in the event of any medical problems, clinicians could be deemed liable if they have failed to follow recommended p­rescribing practice (Nast et al. 2016; Layton et al. 2006) (Figs. 1.5 and 1.6). Oral antibiotic therapy should always be combined with topical therapy (other than antibiotics). Among oral antibiotics, doxycycline should

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C. Dessinioti and B. Dreno

Fig. 1.3 Recommendations for comedonal acne. * Limitations can apply that may necessitate the use of a treatment with a lower strength of recommendation as a first-line therapy (e.g., financial resources/ reimbursement limit, legal restrictions, availability, drug licensing). (Adapted with permission from: Nast A, Dreno B, Bettoli V et al. European evidence-based (S3) guideline for the treatment of acne-update 2016-short version. J Eur Acad Dermatol Venereol 2016;30(8):1261-1268 (Nast et al. 2016))

Fig. 1.4  Recommendations for mild-to-moderate papulopustular acne. * Limitations can apply that may necessitate the use of a treatment with a lower strength of recommendation as a first-line therapy (e.g., financial resources/reimbursement limit, legal restrictions, avail-

ability, drug licensing). (Adapted with permission from: Nast A, Dreno B, Bettoli V et  al. European evidence-­ based (S3) guideline for the treatment of acne-update 2016-short version. J Eur Acad Dermatol Venereol 2016;30(8):1261-1268 (Nast et al. 2016))

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Fig. 1.5  Recommendations for severe papulopustular acne/moderate nodular acne. * Limitations can apply that may necessitate the use of a treatment with a lower strength of recommendation as a first-line therapy (e.g., financial resources/reimbursement limit, legal restric-

tions, availability, drug licensing). (Adapted with permission from: Nast A, Dreno B, Bettoli V et  al. European evidence-based (S3) guideline for the treatment of acne-­ update 2016-short version. J Eur Acad Dermatol Venereol 2016;30(8):1261-1268 (Nast et al. 2016))

Fig. 1.6  Recommendations for severe nodular/conglobate acne. * Limitations can apply that may necessitate the use of a treatment with a lower strength of recommendation as a first-line therapy (e.g., financial resources/ reimbursement limit, legal restrictions, availability, drug

licensing). (Adapted with permission from: Nast A, Dreno B, Bettoli V et al. European evidence-based (S3) guideline for the treatment of acne- update 2016- short version. J Eur Acad Dermatol Venereol 2016;30(8):1261-1268 (Nast et al. 2016))

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be preferred as first-line antibiotic, compared to minocycline or tetracycline, as minocycline has been associated with more serious side effects and tetracycline has a more complicated dosage regimen. Topical antibiotic monotherapy is to be avoided due to increased risk of bacterial resistance. Hormonal therapies (antiandrogens and/or oral contraceptives) may be used for female acne in the absence of contraindications. Hormonal therapy permits therapy without any risk of emergence of bacterial resistance associated with antibiotic therapy. Also, hormonal therapy is an alternative choice for females who have relapsed after multiple oral isotretinoin treatments. Current European guidelines recommend hormonal therapies alone or in combination with a topical agent or systemic antibiotics, with a low-­ strength recommendation for severe papulopustular/moderate nodular/severe nodular/ conglobate acne in females patients (Nast et  al. 2016). Maintenance therapy (e.g., with a retinoid or BPO or AZA) is of cardinal importance in order to maintain acne remission.

 reatment Approach for Acne T in Different Age Groups The abovementioned guidelines apply for acne vulgaris during adolescence. Additional special considerations apply for childhood acne and adult acne. A proposed treatment approach for acne in different age groups is summarized in Fig.  1.7. Topical treatments used or children in the clinical practice are similar to those used in adolescents. However, the majority of clinical trials for acne medications are conducted in patients 12 years of age or older, and there is not sufficient evidence for acne treatments in younger children (Eichenfield et al. 2013). Special considerations of adult female acne include the resistance of acne to standard treatments, the fact that adult skin is more sensitive to possibly irritant topicals, there may be slower response, and the possibility of needing to treat acne during pregnancy or lactation. Patient edu-

C. Dessinioti and B. Dreno

cation is important to increase therapeutic adherence. Topical monotherapy usually is not sufficient to treat adult acne, as it fails to target the multiple factors implicated in acne pathogenesis. It is proposed to use combination topical treatments or combine oral and topical agents for optimizing results. For adult women, topical retinoids are indicated for the treatment of mild comedonal and mild to moderate papulopustular acne. Adapalene is better tolerated compared to tretinoin and topical isotretinoin. Given the oral teratogenicity of retinoids, it is recommended that women avoid pregnancy while using topical isotretinoin, adapalene, or tretinoin. Azelaic acid (cream 20%, gel 15%) is proposed as first-line monotherapy for inflammatory and noninflammatory adult female acne, as it presents similar efficacy with other topicals, while it is characterized by a favorable tolerability profile. Azelaic acid has anti-­ tyrosinase action and is suitable to treat post-­ inflammatory hyperpigmentation associated with acne. Topical antibiotics are not proposed as monotherapy for adult female acne and they may be used as part of combination therapy. ΒΡΟ may cause photosensitivity and irritation to the adult female skin, presenting with erythema and dryness. Topical combination treatments are indicated for inflammatory adult female acne. The application of a fixed-dose combination agent is easier to use compared to the combined use of different agents, and it may improve the patients’ adherence to proposed treatment (Dreno et  al. 2013). Systemic treatment for adult female acne is indicated for moderate to severe acne, acne with risk of scarring, and acne resistant to therapies. Oral antibiotics are not recommended as monotherapy and they should be combined with topical therapies, such as BPO, to decrease the risk of bacterial resistance, or azelaic (15% or 20%) as an alternative choice for adult women with intolerability to ΒΡΟ. Special considerations for oral isotretinoin in adult females include the risk of teratogenicity during the childbearing years and strict adherence to adequate efficient pregnancy prevention measures is mandatory. Hormonal therapies may be recommended for

1 Acne

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Fig. 1.7  Proposed treatments for acne in different age groups. * For azelaic acid, adapalene, clindamycin, BPO (benzoyl peroxide), clindamycin/tretinoin topical fixed-­ dose combination (f.d.c), clindamycin/BPO f.d.c., erythromycin/BPO f.d.c.: safety and effectiveness in patients 3/12) Culture P.C.R. NAATS

D. Freedman

92 Condition Granuloma inguinale Gonorrhoea

Mycoplasma genitalium Trichomonas

Human Papilloma virus Buschke—Loewenstein

Clinical features Beefy lesions Painless Urethral discharge Acute ulcers and pustules Acute infection of glands and ducts, i.e. Tysonilis, Cowpers duct ± urethritis Acute erosive Adenopathy

Asymptomatic Patchy variable macular Hypoaesthesia—pruritis Chronic/recurrent Gross exophytic lesions Infiltrative Infections—possibility of sexual transmission Candida infection Short incubation burning, itching → Candida hypersensitivity pain. Erythema—variable blotchy—small papules, dry glazed and pustules Coalesce to form erosive patches Transient post-coital erythema and burning

Diagnosis Microscopy Biopsy Microscopy NAATS Culture NAATS NAAT detection Microscopy (wet prep) Aceto-white lesions (5% acetic acid stupes) ± confirm by biopsy HPV typing Biopsy—large deep

Microscopy KOH preparation Culture swab History Check partner Urinalysis for glucose/diabetic screen O/R immunosuppression/HIV ? Underlying dermatosis Anaerobic balanitis Mild symptoms—‘fishy’ odour Clinical amine odour Macular erythema—superficial Culture erosions Microscopy bacteria ++− anaerobes O/R trichomonas with NAAT Anaerobic erosive balanitis Tender ulcers Microscopy (Bacteroides spp.) Odour Pus cells, Occasionally prepuce swelling ± Bacteria ++ adenopathy Mixed spirochetes Aerobic infection Inflammation—Uniform erythema ± Culture oedema Group B Erythema—purulent discharge Culture Haemolytic streptococci Cellulitis—regional adenopathy Infections—sexual transmission unlikely Group A Pre-pubertal Culture Haemolytic streptococci Erythematous, moist Staphylococcus aureus Pre-pubertal boys (toxic shock Culture syndrome) Pityriasis versicolor Scaling—discrete fine ‘Woods’ light fluorescence Hypopigmented areas Herpes zoster Blisters grouped Clinical Pain ++ Dermatome distribution HVZ—DNA COVID 19 Erythema PCR Ulcers—Lipschütz like Specific balanitides

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8 Balanitis Condition Lichen sclerosus et Atrophicus

Lichen planus

Zoons plasma cell balanitis Zoonoid inflammation

Localised balinitides Fixed drug eruption

Clinical features Itchy, sore, post micturition dribble, dyspareunia Atrophic white papules or plaques. Fissures phimosis Lesions progress to sclerotic/ atrophic white/ivory/blue flat topped papules Inflammatory scarring dermatosis progressive chronic course Fibrosis—obliteration of anatomical features—coronal sulcus, phimosis, wasting, and meatal thickening Purple well-demarcated plaques ± erosive lesions on mucosa Lichen planus lesions elsewhere, especially oral lesions Plaque—solitary glazed-smooth red-orange ‘cayenne pepper’ Symmetrical distribution

Well-demarcated erythematous areas Occasionally bullous → ulcerated Irritant, allergic, and contact Mild erythema and irritation → dermatitis Pruritis/burning—intense Marked oedema Rapid onset Trauma Direct accidental Burn/scald/frostbite Suction/vacuum erection devices Zipper entrapment Sexually induced Pubic hair friction, dental induction, instrumentation, masturbation Implantation Studs, rings, balls, etc. Manifestation of systemic/generalised disease Psoriasis Plaques—well-demarcated erythematous without scale (inverse pattern) in uncircumcised. Normal scaly psoriasis plaques in circumcised Behçet’s syndrome Ulcers

Aphthous ulcers Circinate balanitis

Seborrheic dermatitis Lichen planus

Diagnosis Sclerotic white ring at tip of prepuce Biopsy O/R PeIN Sq. cell ca.

Clinical Biopsy

Clinical Biopsy NB Zoonoid inflammation may occur with other dermatoses, and biopsy may not make a specific diagnosis History Recur at same site on re-exposure to drug Exposure history Patch testing

History

Clinical Other stigmata of psoriasis Family history Biopsy

Extra genital lesions Biopsy Pathergy test Painful, solitary Outrule other causes of genital ulcers— Erythematous halo especially Behçets or Lipschütz Plaque—moist with irregular ragged Other clinical features of Reiter’s border: White syndrome margin—‘Geographic’ HLA B27+ve (80%) Circumcised—dry scaling Erythema Clinical Mild itch + occ scaling Polygonal violaceous flat topped Clinical papules Ulcers - lacy erosive

D. Freedman

94 Condition Erythema multiforme Pemphigus Dermatitis artefacta Neoplasia Erythroplasia of Queyrat

Bowen’s disease Bowenoid papulosis

Extra mammary Paget’s disease Penile carcinoma

Clinical features Erythematous papules Vesicles—ulcers Vegetating plaques Scratch marks

Diagnosis Clinical

Plaques: red glazed—velvety Slightly raised Sharp margins Scaly discrete erythematous patches/ plaques Wart like Papules → Plaques+/−grouped, pigmented or erythematous Plaques Red—brown Raised, scaly Pruritis/burning Papillary/flat Ulcer with rolled edge Thickening

Biopsy

Biopsy Clinical

Biopsy Biopsy

Biopsy

Biopsy

may also reduce the need for more invasive interventions. The use of a videodermoscope lessens the proximity between the examiner’s head and the patient’s genitalia.

 europathic Pain/Regional (Pelvic) N Pain Syndrome

Fig. 8.1  Retracted prepuce. Retraction of the prepuce dries out the epithelium, enhances keratinization, and resolves most cases of balanitis

Dermoscopy, as a non-invasive tool, can enhance diagnosis of prepuce lesions and outrule some conditions that have a similar visual appearance, but have a different dermoscopy pattern. It

Some patients may present with meatal sensation/pain, and a barely noticeable erythema. They are focussed on this complaint and may have attended several other medical consultations previously where the condition was managed as Balanitis. The complaint is often triggered by a specific episode, often a sexual encounter, and feelings of guilt may be commonplace. All investigations are negative, including an STI screen. The condition becomes intractable and debilitating. It may be dismissed as prostatitis on occasions, despite the absence of any findings. Effective management is usually challenging, but intensive reassurance and counselling and, occasionally, low dosage tricyclic antidepressants may help.

8 Balanitis

 alanitis: General Principles B of Treatment General Therapeutic Guidelines The principle is to change the micro-ecosystem of the sub-prepuce sac to one which will not readily become super-infected by Candida, anaerobes, or other bacteria. Exposure and drying of the skin encourages keratinisation and further enhancement of resistance to infection, abrasion, and trauma.

Recommended Therapies The vast majority of cases respond to. Simple Measures (a) Retraction of the foreskin. (b) Saline baths. (c) Simple drying powder.

Retraction of the Foreskin Advising patients to change their habits of a lifetime and maintain retraction of the foreskin requires considerable persuasion. Most find it uncomfortable and oversensitive initially and it takes about 3–4 weeks for the hypersensitivity to settle down as keratinisation occurs. Once this has been achieved, few wish to revert to their previous mode of wearing the foreskin down. Some men cannot achieve retraction because of a tight prepuce. Use of an emolument cream and stretching over a period of time may allow the desired effect to be achieved. Retraction may not be maintained by others because of a natural tendency of the prepuce to slip down. Use of a thin narrow surgical tape (Micropore® 12.5 mm, 3 M®) along the shaft of the penis may retain the prepuce back for a sufficient time for keratinisation to occur. Patients must be warned to guard against paraphimosis on retraction of the foreskin. This may occur at night, with erotic dreams, when patients may awake with an acute paraphimosis - a memorable experience.

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Some men have a non-retractile prepuce or phimosis. Use of a moderate to potent topical steroid, combined with gentle stretching over a period of several months, may facilitate retraction to take place, by thinning the skin and stratum corneum. The above warning regarding paraphimosis is particularly pertinent. On occasions, circumcision is warranted for persisting irritation.

Saline Baths These help to dry out the skin, encourage keratinisation, and may have a mild fungistatic/bacteriostatic effect. The observation that sea swimmers appear to have a lower incidence of balanitis reinforces this. Essentially, a domestic tablespoon (20  ml) of ordinary domestic table salt in a warm bath of water or, more convenient for frequent daily use, a pinch of salt in a tumbler glass or small jar. The penis and sub-prepuce area should be dried gently, by patting, rather than any rough or abrasive action. Care should be taken not to use too much salt, or the skin will become “pickled” or irritated, which would be counterproductive. This should become a regular lifelong routine to reduce recurrence. Cleaning should be carried out with a simple non-perfumed soap and water, and the organ gently patted dry, rather than rubbed with vigour. If retraction is not possible initially, one can wash out the sub-prepuce space with warm saline by the use of a small syringe to irrigate the area.  imple Drying Powder S Application of a simple drying powder to the sub-prepuce space can assist in maintaining dryness. A simple talcum powder may be used, or one with a mild antiseptic as commonly used for infants (calcium undecylenate 10% powder, Caldesene®). Care should be taken to ensure that there is no hypersensitivity to any of the constituents. Occlusive underwear, especially if tight, heavy, or synthetic, will increase local perspiration and exacerbate intertrigo. Loose light white cotton underwear should be recommended.

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Alternative Treatments Anti-Fungals and Steroids Anti-fungal creams are very commonly prescribed. Clinical experience has found them to be only useful in providing short-term symptomatic relief, and there is frequently recurrence shortly after discontinuation. There is danger of hypersensitivity to these agents and their vehicles. Anti-Fungal/AntiBacterial powders have produced better results, as they dry out the area. They are particularly useful in acute erosive Balanitis, with secondary bacterial infection. Miconazole powder, used three to four times a day, is one such agent. Local corticosteroid applications should only be used where there is a specific dermatitis, as they weaken the skin and may mask an infection. Particularly, steroids may reduce the local immune response and facilitate the expression of a latent HPV infection as Genital Warts.

The simple measures should be tried initially, and given sufficient time for patient compliance to be established and for them to show effect. With persisting Balanitis, much stronger consideration must be given to the differential diagnosis, taking special care to exclude a sexually transmitted infection, dermatosis, or a pre-­ cancer/cancer. At this stage, biopsy becomes mandatory.

Recalcitrant Balanitis While over 90% of balanitis will respond to the above measures, there are always some cases that are intractable. These may be caused by more specific infections, and one must be always vigilant for cancer or cancer precursors, with a low threshold to biopsy and to screen for Sexually Transmitted Infections.

Treatment for Specific Conditions Condition Herpes Genitalis (classical)

Syphilis—primary—secondary

Chancroid

Lymphogranuloma Venereum

Granuloma inguinale

Gonorrhoea

Treatment Valacyclovir Aciclovir See guidelines https://iusti.org/wp-­content/uploads/2019/12/Herpes.pdf Penicillin (BPG) See guidelines https://iusti.org/wp-­content/uploads/2020/11/2020-­Syphilis-­ guideline.pdf Ceftriaxone Azithromycin See guidelines https://iusti.org/wp-­content/uploads/2019/12/chancroid.pdf Doxycycline See guidelines https://iusti.org/wp-­content/uploads/2019/12/ IUSTILGVguideline2019.pdf Azithromycin See guidelines https://www.cdc.gov/std/tg2015/donovanosis.htm Ceftriaxone See guidelines https://iusti.org/wp-­content/uploads/2020/10/IUSTI-­ Gonorrhoea-­2020.pdf

8 Balanitis Condition Trichomonas

Human papilloma virus Buschke-Lowenstein

Candida infection Candida hypersensitivity Anaerobic balanitis Anaerobic erosive balanitis (Bacteroides spp.)

Aerobic infection Group B Haemolytic streptococci Group A Haemolytic streptococci Staphylococcus Aureus Pityriasis versicolor Herpes zoster Lichen Sclerosus Et Atrophicus

Lichen planus

Zoons plasma cell balanitis Zoonoid inflammation

Fixed drug eruption

Irritant, allergic, and contact dermatitis

Trauma

97 Treatment Metronidazole See guidelines https://www.cdc.gov/std/tg2015/trichomoniasis.htm Cryotherapy Podophyllotoxin Imiquimod Sinecatechins See guidelines https://iusti.org/wp-­content/uploads/2020/08/ IUSTIHPVGuidelines2020.pdf Ablative cryotherapy/laser Surgery Simple measures Antifungal powder Simple measures Miconazole powder Simple measures Miconazole powder + Metronidazole/clindamycin Simple measures Mild topical Miconazole powder Mupirocin ointment Severe Flucloxacillin Clarithromycin Pending antibiotic sensitivity Topical antifungal lotions/shampoos Ketoconazole shampoo/cream terbinafine spray Valacyclovir Famciclovir Avoidance of soaps, irritants, and allergens Topical steroids—Ultrapotent Calcineurin inhibitors Circumcision Surgery—Phimosis/meatal stenosis Follow-up—recurrence/neoplastic changes Avoidance of soaps, irritants, and allergens Topical steroids: Moderate → ultrapotent Calcineurin inhibitors Circumcision Circumcision Topical steroids +/− antibacterial creams Calcineurin inhibitors Imiquimod Avoidance of agent Steroids Antihistamines Systemic steroids if extremely severe Patch tests Avoidance of precipitants Emollients Hydrocortisone 1% → moderate potent steroid First aid/ surgery

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Behçet’s syndrome Aphthous ulcers Circinate balanitis

Seborrheic dermatitis Lichen planus Erythema multiforme Pemphigus Dermatitis artefacta Erythroplasia of Queyrat Bowen’s disease Bowenoid papulosis Extra mammary Paget’s disease Penile carcinoma

Treatment Removal Steroid—moderate potency only Emollients Topical Vit D Topical steroid Systemic steroid; colchicine, immunosuppressants Symptomatic/topical steroid Steroid—moderate potency only Emollients Topical Vit D Treat underlying infection/STI’s Antifungal cream +/− steroid Oral azole Steroid + see guidelines Antihistamines, steroids, analgesics Steroids topical/systemic immunosuppression Scratch marks Multidisciplinary dermatology/urology Topical—Imiquimod, fluorouracil cream, fluorouracil/salicylic acid cream Podophyllotoxin 0.5% Cryotherapy, photodynamic therapy, laser Surgical excision, Mohs Circumcision mandatory Glans resurfacing Smoking cessation Mandatory follow-up

Circumcision Circumcision is rarely required for Balanitis. However, it is occasionally necessary in the case of a long redundant prepuce, where retraction proves impossible. It may also be required with a tight phimosis, where retraction is impossible due to a fibrosed sclerotic ring; and simple stretching, even with the assistance of potent steroids, has failed. An underlying Lichen Sclerosus should always be considered, and the biopsy diagnostic. Circumcision has a dramatic impact on the sub-prepuce microbiota, which could explain the effect of circumcision on Lichen Sclerosus. Recent American Academy of Pediatrics guideline on male circumcision states that the benefits of neonatal circumcision outweigh the risks. The Canadian Urological Association guideline also noted definite advantages of neonatal circumcision, with a lack of any convincing

evidence of impact upon sexual function or sensation. Post-neonatal circumcision is obviously more invasive, requires anaesthesia, and is not undertaken lightly. In Africa, the benefit of male circumcision in reducing the risk of HIV acquisition has resulted in mass adult circumcision. There are no reports of significant compromise of sexual function, apart from some disinhibition. In essence, those who have a foreskin would not be without it; and, in clinical practice, there are very few consultations where those who have been circumcised miss it.

Screening for Sexually Transmitted Diseases This is mandatory in all cases where a history of potential acquisition has been obtained and is useful reassurance in the majority of other cases. Many patients who present with balanitis have an

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underlying anxiety regarding STIs and this must be definitively addressed.

Suggested Reading American Academy of Pediatrics Task Force on Circumcision. Male circumcision. Pediatrics. 2012;130(3):e756–85. https://doi.org/10.1542/ peds.2012-­1990. Balat A, Karakok M, Guler E, et al. Local defence systems in the prepuce. Scand J Urol Nephrol. 2008;42:63–5. https://doi.org/10.1080/00365590701472663. Bunker CB, Porter WM. Dermatoses of the male genitalia. In: Griffiths C, Barker J, Bleiker T, Chalmers R, Creamer D, editors. Rook’s textbook of dermatology. 9th ed. Oxford: Wiley-Blackwell; 2016. p. 111–41. Bunker CB.  Male genital skin disease. E-book: Bruce shrink, 2019. Canadian Urological Association. Canadian Urological Association guideline on the care of the normal foreskin and neonatal circumcision in Canadian infants (full version), 2022. Chan I, Hawkins D, Bunker CB.  Balanoposthitis. BMJ best practice. 2020. Available https://bestpractice.bmj. com/topics/en-­gb/401. Accessed 30 Jan 2021. Dave S, Afshar K, Braga LH, Anderson P.  Can Urol Assoc J. 2018;12(2):E76–99. https://doi.org/10.5489/ cuaj.5033. Edwards, SK, Brunker CB, van der Snoek EM and van der Meijden WI. 2022 European guideline for the management of balanoposthitis J Eur Acad Dermatol Venerol. 2023;37:1104–17. https://doi.org/10.1111/jdv.18954

99 Falkenhain-López D, Agud-Dios M, Ortiz-Romero P, Sánchez-Velázquez A.  COVID-19-related acute genital ulcers. J Eur Acad Dermatol Venereol. 2020;34:e655–6. https://doi.org/10.1111/jdv.16740. Horner PJ, Taylor-Robinson D.  Association of Mycoplasma genitalium with balanoposthitis in men with non-gonococcal urethritis. Sex Transm Infect. 2011;87:38–40. Lacarrubba F, Borghi A, Verzì AE, Corazza M, Stinco G, Micali G. Dermoscopy of genital diseases: a review. J Eur Acad Dermatol Venereol. 2020;34(10):2198–207. https://doi.org/10.1111/jdv.16723. Lisboa C, Santos A, Dias C, Azevedo F, Pina-Vaz C, Rodrigues A.  Candidal balanitis: risk factors. J Eur Acad Dermatol Venereol. 2010;24(7):820–6. Liu C, Hungate BA, Tobian AR, et al. Male circumcision significantly reduces prevalence and load of genital anaerobic bacteria. mBio. 2013;4:1–9. https://doi. org/10.1128/mBio.00076-­13. Shim H, Rose J, Halle S, Shekane P.  Complex regional pain syndrome: a narrative review for the practising clinician. Br J Anaesth. 2019;123(2):e424–33. Soto-Ramirez LE, Renjifo B, McLane MF, et  al. HIV-1 Langerhans’ cell tropism associated with heterosexual transmission of HIV.  Science. 1996;271:1291–3. https://doi.org/10.1126/science.271.5253.1291. Watchorn RE, van den Munckhof EHA, Quint KD, Eliahoo J, de Koning MNC, Quint WGV, Bunker CB.  Balanopreputial sac and urine microbiota in patients with male genital lichen sclerosis. Int J Dermatol. 2020;60:201. https://doi.org/10.1111/ ijd.15252. Online ahead of print.

9

Basal Cell Carcinoma Dimitrios Papakostas and Eggert Stockfleth

Key Points • Basal cell carcinoma (BCC) accounts for 80% of all nonmelanoma skin cancers (NMSC) and is the most common human malignancy with higher morbidity than mortality since metastases are extremely rare. • Sun exposure, genetic predisposition, and immunosuppression are the main risk factors; activation of the sonic hedgehog pathway plays a key role in BCC formation. • Prognosis, treatment strategies, and follow-up depend on BCC classification as high- or low-­ risk after thorough clinicopathological correlation. • Surgical excision remains the treatment of choice, radiotherapy retaining a complementary role as alternative treatment to surgery or postoperatively in selected cases. • Nonsurgical destructive methods such as cryotherapy, photodynamic therapy, electrodessication after curettage, and topical treatment with imiquimod should be reserved for the treatment of superficial BCCs, or in case of inoperability due to patient’s medical D. Papakostas (*) Dr. Med. Dimitrios Papakostas Private Dermatological Practice, Athens, Greece e-mail: [email protected] E. Stockfleth St. Josef-Hospital RUHR-University Bochum, Bochum, Germany e-mail: [email protected]

background or refusal of a more aggressive therapeutic approach. • Tumor eradication and limited recurrence rates without a disproportionate risk for the patient and an acceptable cosmetic outcome are the key points in the selection of the optimal treatment. Most primary BCCs treated according to guidelines have a low risk of recurrence. • Novel inhibitors of the hedgehog pathway found recently their way in the treatment of inoperable or metastasized BCCs. In case of primary or secondary resistance to hedgehog inhibitors, immune checkpoint inhibition has been tried with promising results. • Follow-up after treatment is essential, since many BCCs could recur even 5–10 years later. Approximately 45% of the patients treated will develop a new BCC within the first 3 years after initial diagnosis and treatment.

Definition and Epidemiology Basal cell carcinoma (BCC) is the most common cancer in Europe, Australia, and the U.S.A., accounting for more than a million cases per year in the U.S.A.  The annual incidence is globally increasing with a peak of 726/100,000  in Australia. In Germany, around 200 out of 100,000 inhabitants are diagnosed each year with an average age of presentation of 60  years, though an

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age shift is the current trend, proposing a further increase of the incidence of BCC in the next decades with a lifetime risk for fair skinned individuals up to 30%. BCCs account for 80% of all Nonmelanoma Skin Cancers (NMSC); they present as slowly growing tumors, with local invasive and destructive potential, infiltrating adjacent tissues with finger-like outgrowths remaining contiguous with the main tumor mass. However, most BCCs do not infiltrate adjacent tissues and are easy to treat. Metastasis is extremely rare (1:1000 to 1:35,000) and probably limited to giant BCCs (80% of metastatic BCCs) and atypical histological variants such as the metatypical BCCs.

Pathogenesis Eighty percent of all BCCs appear on sun exposed areas of the face and the neck, preferably of fair skinned individuals, indicating ultraviolet exposure, genetic predisposition and skin type as the main predisposing factors, followed by immunosuppression, exposure to arsenic salts, ionizing radiation, and trauma. Ultraviolet light has a known mutagenic potential and signature mutations such as C → T are found in sun-exposed skin. Patients with Xeroderma pigmentosum, a rare genetic disease with impaired DNA correction, report an increased incidence of BCCs among other forms of NMSC. Still, in most BCC patients this is not the case; the study of the autosomal dominant inherited basal cell naevus syndrome (BCNS) or Gorlin’s syndrome improved our understanding of the molecular basis of this malignancy. These patients typically develop numerous BCCs at younger ages, they present with skeletal anomalies and other deformations regarding the embryogenesis, and they are prone to the development of other tumors such as the medulloblastoma. Not only in patients with BCNS, but also in most sporadic BCCs as well the sonic hedgehog pathway is activated. The hedgehog pathway plays a key role in developmental processes during embryogenesis. In most normal adult tissues, the pathway is silenced though and the reactiva-

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tion can lead to cancer. Central component of the hedgehog pathway is the transmembrane protein SMO, which is being inactivated by another transmembrane protein called Patched (from the PTCH-1 gene, which is mutated in patients with Gorlin syndrome, resulting in inactivation of the Patched Protein and activation of SMO). After binding of the hedgehog ligand to its receptor on Patched, the suppression on SMO is relieved and a downstream phosphorylation cascade is activated leading to activation of the GLI transcription factors, their accumulation in the nucleus and the active transcription controlling of hedgehog target genes. 80–90% of sporadic BCCs have a PTCH-1 mutation, about 10% a SMO mutation, a small minority of tumors has loss of function mutation in SUFU, a negative regulator of the hedgehog pathway. In all these cases, activation of the SMO signaling results in uncontrolled BCC formation. However, the clinical heterogeneity of basal cell carcinoma associated with different clinical outcomes cannot be explained fully on the hyperactivation of the hedgehog pathway alone and novel genome sequencing techniques have associated recently several other genes with basal cell carcinoma. UV-driven mutations in p53 have been proven to play a role in the pathogenesis. Furthermore, besides the well-documented BCNS, several extremely rare genetic syndromes have been described, such as the Bazex-Dupré-­ Christol-Syndrome, an X-linked dominant genetic disorder with hyperactivation of the hedgehog pathway driven by an ACTRT1 mutation.

Clinical and Histological Characteristics The typical nodular BCC on sun exposed areas of the face and the neck presents as a red-yellowish papule, slowly growing, with possible ulceration, remaining well-circumscribed with a pearly border. Superficial BCCs (Fig.  9.1) on the trunk impose on the other hand as slowly growing flat red plaques, being easily confused with inflammatory diseases of the skin or Bowen disease.

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Fig. 9.1  Superficial Basal Cell Carcinoma on the trunk Fig. 9.2  Pigmented basal cell Carcinoma

Aggressive variants of the BCC are the morpheic BCCs presenting like a scar with unclear borders making R0 Resection rather challenging, and the local destructive variants known as Ulcus rodens and Ulcus terebrans. Pigmented (Fig. 9.2), cystic, keratotic, and basosquamous variants emphasize the clinical diversity of BCCs and challenge the physician in making the right diagnosis. This clinical diversity may be the result of the tumor cells’ origin, probably from a stem or progenitor cell of the basal cell layer of the epidermis or the outer root sheath of the hair follicle. This explains the histological diversity as well; histological subtypes include superficial, nodular and micronodular, adenocystic, pigmented, sklerosing, keratotic, basosquamous/metatypical, infiltrating BCCs, and the Fibroepithelioma of Pinkus. The primary cellular components of the BCC resemble undifferentiated basal cells of the epidermis and the hair follicle; these cells form palisades at the tumor periphery and are distinctively separated from the adjacent fibroblastic stroma, characteristic for BCC. The clinical and histological diversity explains the broad spectrum of the clinical course of these skin malignancies stretching from slowly growing superficial tumors to recurrent and giant ulcerative, infiltrating and locally destructive tumors with perineural and perivascular involvement. However, most BCCs are indolent tumors that do not infiltrate or locally destruct tissues. Metastatic BCC (mBCC), though extremely rare, remains a possibility in the case of giant tumors or basosquamous/metatypical variants.

Diagnosis Clinical diagnosis should be no problem for the experienced dermatologist in most cases; good lighting, magnification, and dermoscopy could prove helpful improving the accuracy of the clinical diagnosis. Still, the variety of histological types with diverse clinical courses and the need for a tumor adapted optimal treatment emphasize the need for histopathological confirmation in ambiguous lesions and in lesions located in high-­risk areas. In an ideal clinical scenario, all BCCs would be biopsied prior to treatment selection; in many cases though, due to various patient-related circumstances such as age, comorbidities, medication, and logistical obstacles, the dermatologist could be justified to skip this diagnostic step. At the time of definite treatment though, e.g., after excision a pathological specimen should be always submitted for pathologic confirmation of the diagnosis. Modern apparative diagnostic methods such as high-frequency ultrasound, the confocal laser scan microscopy (CLSM), and the optical coherence tomography (OCT) try to bridge the gap between clinical and histological diagnosis and to make possible an individualized diagnostic approach in the cases mentioned above. In cases of multiple superficial tumors, biopsy (incisional or excisional) of a characteristic tumor should be performed prior to potential selection of non-excisional destructive methods. Further

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imaging such as CT/MRI/PET-CT should be considered to exclude metastasis in advanced tumors and in the diagnostic approach of locally invasive and destructive tumors.

Treatment A variety of treatment modalities has been successfully involved in the approach of BCC patients in past years, because of the diverse clinical appearance and course of the most common cancer accounting for 5% of all Medicare cancer costs in the U.S.A. To guide physicians through this labyrinth and with the goal of evidence-based treatment selection, several national and international guidelines have been developed recently. An algorithm for the therapeutic approach of BCC is depicted on Fig. 9.3. Though BCCs can be staged following the UICC classification like other skin malignancies (squamous cell carcinoma, malignant melanoma), the lack of lymph node involvement and

metastases in most cases makes this classification impractical for the choice of treatment. BCCs are currently assigned as low or high risk of recurrence per several prognostic factors with the goal of a tumor adapted choice of treatment. Tumor eradication and limited recurrence rates without a disproportionate risk considering the medical background and an acceptable cosmetic outcome for the patient are the key points in the selection of the optimal treatment. Clinical and pathological correlation prior to treatment selection, meaning a detailed history, clinical examination, including observation and palpation to determine exact location, size and possible infiltration of adjacent tissues, and the consideration of the histological findings actively influence the physician’s decision. Diverse criteria such as tumor size, tumor thickness, tumor site, definition of clinical margins, histological subtype, histological features of aggression, recurrence, and immunosuppression make stratification in high- and low-risk tumors possible (Table 9.1).

Fig. 9.3  Algorithm for the therapeutic approach of Basal cell carcinoma

9  Basal Cell Carcinoma Table 9.1  High-risk Basal cell carcinomas Tumor size depending on location: >20 mm in low-risk areas of the trunk and extremities, any size in high-risk areas of the head and neck, genitalia, pretibia, feet and hands Histological type: Sclerosing, metatypical, micronodular, infiltrating Histological findings: Perineural or vascular involvement, infiltration of adjacent tissues Poorly defined margins (e.g., after radiotherapy) Recurrence Immunosuppression Adapted from Bichakjian et al. (2016), Lang et al. (2019) and Schmults (2022)

The wide range of therapeutic modalities can be divided in surgical, destructive, topical, systemic treatments, and radiotherapy. Surgical excision with histological control remains the standard treatment. A conventional excision with respective safety margins should be effective in most primary BCCs. On the other hand, in more demanding clinical cases, Mohs micrographic surgery has superior results regarding histological verification, recurrence rates, and sparing of healthy tissue. Radiotherapy retains its role in the treatment of selected tumors, as a fair alternative to surgical treatment or in case of inoperability, incomplete excision, or patient’s refusal of surgical intervention. Nonsurgical destructive methods without histological margin control such as cryotherapy, curretage with electrodesiccation, photodynamic treatment (PDT), and topical treatments (immunological therapy with imiquimod 5%) should be preferably limited to superficial BCCs or in the treatment of BCNS (Gorlin’s syndrome) patients with multiple tumors. Still, the final choice of treatment should be individualized taking into consideration comorbidities, age, medication, and disproportionate risk of aggressive surgery or refusal of surgical intervention. The nonsurgical methods mentioned above, alone or in combination, could be reasonable alternatives in selected cases, after individualized risk-­ benefit evaluation. The broader clinical use of hedgehog inhibitors in recent years resulted in prompt definition

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of the locally advanced basal cell carcinoma (laBCC) as a destructive infiltrative tumor with expansion in the adjacent tissues that cannot be treated adequately surgically, either due to technical limitations (RO excision not feasible) or patient-related contraindications. These locally advanced tumors together with the rare metastatic BCC (mBCC) are defined as advanced basal cell carcinoma. An interdisciplinary tumor board is needed for the decision whether the tumor is resectable or treatable with radiotherapy and/or medical therapy. Patients with multiple tumors associated with the basal cell nevus syndrome should be offered, if possible, a treatment with the hedgehog inhibitors.

Surgical Treatments Mohs Micrographic Surgery This demanding technique is generally reserved for high-risk tumors on problematic locations of the face, the hands, and the genitalia, recurrent tumors, or BCCs of aggressive histological subtypes or with aggressive histological findings (Table  9.2). Long-term recurrence rates for primary tumors of less than 1–2% and for recurrent tumors of less than 6–7% have been reported. First described by Frederic Mohs (Mohs micrographic surgery, MMS) and further refined in following years, micrographic surgery aims to the total eradication of the tumor mass leaving no traces of tumor cells behind and thus limiting Table 9.2  Mohs surgery indications High-risk tumors in problematic locations of the face, hands, and genitalia where sparing of healthy tissue is essential for a good cosmetic and functional outcome Aggressive histological variants: Sclerosing, infiltrating, metatypical, micronodular Aggressive histological findings: Perineural or vascular involvement, infiltration of adjacent tissues Recurrence (e.g., after conventional excision or radiotherapy) Clinically poorly defined margins If technically and financially feasible, Mohs could be offered as first-line treatment in all operable cases

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recurrence rates. Keeping in mind the three-­ dimensional expansion of subclinical tumor outgrowths, especially in the case of more aggressive subtypes such as the sclerosing BCC, a subtler histological approach is asked to avoid wide excision margins in problematic locations where sparing of healthy tissue can prove of crucial importance for an acceptable cosmetic and functional outcome. Depending on the facilities of the surgery unit, re-excision and plastic reconstruction of the gap can take place within hours; histology performed using frozen tissue sections. In centers where the histology takes several days for evaluation, the gap is filled with use of alloplastic materials and the excisional material is being embedded in paraffin. Paraffin sections are of greater accuracy though, compared to frozen tissue section.

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excision with 3 mm safety margins of even low-­ risk tumors. Not all microscopically proven residual tumors would recur though; a safety margin of 3–5  mm is thus currently recommended for low-risk tumors. After conventional excision of aggressive histological variants with 5 mm safety margins, the probability of residual tumor is considerable (18%) though, requiring wider safety margins (13–15 mm, 5% likelihood of residual tumor) and highlighting the superiority of MMS in cases where sparing of healthy tissue is essential for a good cosmetic or functional outcome (Telfer et  al. 2008; Breuninger and Dietz 1991; Wolf and Zitelli 1987; Kimyai-Asadi et  al. 2005); a safety margin >5  mm is thus required for high-risk tumors when the superior MMS cannot be offered to the patient. In case of R1 Resection with histologically proven residual tumor without any clinically seen tumor rests, there is indeed, as mentioned above, Conventional Excision enough evidence that a clinical recurrence of the tumor is not obligatory. In such cases, wait and A standard surgical excision of primary BCCs is see in the context of an individualized follow-up a reliable therapeutic approach with rather lim- could be a reasonable approach. Still, when dealited recurrence rates when performed with tumor-­ ing with high-risk tumors or with tumors with adapted safety margins. Compared to MMS residual involvement of the deep safety margin, which allows a comprehensive margin examina- retreatment should be always performed, either tion in a three-dimensional manner, after conven- as re-excision with wider safety margins, MMS, tion excision only the peripheral and deep or even postoperative radiotherapy. surgical margins are examined in paraffin-­ embedded sections, thus making tumor-adapted safety margins necessary to limit the likelihood The Role of Radiotherapy of residual tumor and subsequent recurrence. The cosmetic and functional outcome is in most cases Radiotherapy retains its role in the nonsurgical good. Small tumors at any site as well as bigger treatment of BCC.  Effective in the treatment of tumors (>20  mm) on trunk and extremities are primary BCCs, it can be considered a fair alternagood candidates for conventional surgical exci- tive to conventional excision, especially in case sion. The safety margins vary and depend on of small tumors, tumors on problematic locations tumor size and histological subtypes, tumors big- such as the eyelid, the nose, the ear, elderly ger than 20 mm or of high-risk histological sub- patients or patients unwilling or not able to types (e.g., sclerosing, infiltrating, metatypical) undergo surgery. The efficacy of radiotherapy has requiring wider safety margins of clinically been validated with several clinical trials and rethealthy tissue excised to achieve an acceptable rospective reviews. Clinical control rates range 5% probability of residual tumor compared to from 92% to 99% for lower risk tumors and 4–5 mm safety margins for tumors smaller than 70–90% for higher risk tumors. However, data 20 mm or of nonaggressive histological subtypes from head to head randomized control trials comsuch as nodular or superficial BCCs. There is a paring radiotherapy with surgery are rather scarce 15% chance of R1 Resection after conventional and underpin the superiority of surgical proce-

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dures. Postoperatively, in case of incomplete elderly patients where better established methods excision (R1, R2) or demonstrated perineural with a higher evidence level are not feasible or involvement, radiotherapy could be used as an are being refused from the patient. In expert adjuvant treatment to reduce recurrence rates. hands, cryotherapy is an option for small, low-­ Scaring and radiodystrophy, altered pigmenta- risk, non-facial BCCs either alone or in combination, and telangiectasia are the most common tion with other methods, e.g., after curettage or in side effects. Lack of margin control and increased combination with modified imiquimod risk for future cancers should also be taken into protocols. consideration. In genetic disorders with predisGenerally double freeze/thaw cycles are recposition to skin cancer, such as Gorlin syndrome ommended, to the adverse reactions count pain, or Xeroderma pigmentosum and radiation-­ edema, and blister formation, hyper- or sensitive autoimmune disorders, radiotherapy is hypopigmentation. contraindicated. Radiotherapy should be avoided in younger patients (0.40 mm are more likely to recur, thus limiting its use to the treatment of superficial BCCs. Some authors report acceptable results in the treatment of smaller nodular tumors as well, especially after curettage or when combining with cryotherapy. These treatment strategies could be eventually discussed in selected cases, if surgery is refused or contraindicated due to patient-related limitations. Imiquimod, along with cryotherapy, topical 5-FU, and PDT, is also a reliable alternative to surgery in the treatment of patients with BCNS, dealing with multiple eruptive tumors constantly. Excessive topical inflammation during treatment or systemic flu-like symptoms could affect patient’s compliance and result in disruption of treatment. Despite the frequent inflammation of treated lesions, they may heal well with a good cosmetic result.

5-FU Like the topical immune response modifier imiquimod, the topical cytostatic agent 5-Fluoruracil (5-FU) could be used in the treatment of superficial BCCs and BCNS, if there are contraindications for surgery. 5-FU is applied topically twice daily for 4–6  weeks. It inhibits DNA synthesis (thymidylate synthase inhibitor) and prevents cell proliferation, thus resulting to necrosis of rapidly dividing cancer cells. Irritation of treated areas and adjacent skin could lead to treatment disruption.

Systemic Treatments Chemotherapy Before 2012 and the introduction of the hedgehog inhibitors, many chemotherapeutic protocols

9  Basal Cell Carcinoma

had been proposed, those based on cisplatin appearing to be the most commonly used but with very short lasting effects. Currently, ­chemotherapy has a role as a last line treatment when participation in a clinical trial is not possible. Electrochemotherapy, a nonthermal method for tumor ablation, is offered in specialized centers in selected cases such as the local destruction of multiple lesions in patients with basal cell nevus syndrome.

Hedgehog Inhibitors Understanding of the molecular biology of BCC and of the role of the sonic hedgehog pathway activation has been a breakthrough, making possible in recent years the development of elaborate targeted treatments inhibiting the pathway activation. Vismodegib and Sonidegib have been approved for the treatment of locally advanced BCC in patients who are not candidates for surgery or radiotherapy; Vismodegib has been also approved for the treatment of the rare metastatic BCC. Vismodegib was the first synthetic SMO inhibitor to complete early clinical evaluation successfully (Phase I); a dose of 150 mg/day was recommended as Phase II dose, and based on these data, FDA approved in January 2012 its use for the treatment of advanced basal cell carcinoma, clinically uncontrolled or metastasized, in the context of an early access program. Since about 80–90% of BCCs harbor PCTH mutations leading to SMO activation and another 10% demonstrate SMO mutations, the selected use of a SMO inhibitor like vismodegib appears reasonable in either case. Thus, treatment can be initiated without any genetic screening required, compared to malignant melanoma where B-Raf mutations are seen only in about 60% of melanoma patients. Elevated levels of Gli1, a downstream marker of the hedgehog pathway, have confirmed the role of the pathway activation in the pathogenesis of BCCs. The approval study Erivence for advanced BCCs showed remission rates up to 48% (laBCC) and 33% (mBCC). The median duration of response varied from 9.5 (laBCC) and 7.6

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(mBCC) months in the approval study to 14.8 (mBCC) and 26.2  months (laBCC) in the final 2017 update. The promising results were confirmed with the international clinical STEVIE, and in late 2017, updated results from the STEVIE trial showed remission rates up to 68.5% (laBCC) and 36.9% (mBCC) in 1215 evaluated patients in concordance with the Erivence study. Sonedigib, the second hedgehog inhibitor approved, has a comparable to vismodegib safety and efficacy profile, as confirmed with the approval study BOLT. In the 2017 study update remission rates of 56.1% in the central review process and 71.2% in the investigator assessment could be demonstrated for the laBCC; for the mBCC remission rates of 7.7% and 23.1%, respectively. Mean duration of response was reported 26.1  months for the laBCC and 24.0  months for the mBCC.  Vismodegib and Sonedigib show differences in the pharmacological properties; possible clinical consequences are under investigation. Patients with multiple tumors associated with BCNS should be offered a treatment with the hedgehog inhibitors as proposed in the European consensus-based interdisciplinary guidelines (Peris et  al. 2019). Smaller numbers of BCNS patients were included in the pivotal studies of both hedgehog inhibitors. Hedgehog inhibitors may be used in the neoadjuvant setting to reduce tumor mass prior to surgery. Primary and secondary drug resistance constitute a therapeutic challenge and the key limitation in the treatment of advanced BCC with the hedgehog inhibitors. Novel therapeutic strategies targeting not only SMO but other targets in the pathway cascade are currently in clinical investigation. Combinational treatments in the paradigm of current melanoma treatment are likely to emerge in the years to come. The most common adverse reactions include alopecia and dysgeusia, both probably directly related to inhibition of the pathway, since in related tissues the hedgehog pathway seems to retain some role after the embryogenesis. Muscle spasms, weight loss, nausea, and diarrhea are further clinical signs of hedgehog inhibitors-related toxicity which could lead to treatment discontinuation.

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Checkpoint Inhibitors Checkpoint inhibitors have revolutionized the treatment of melanoma in recent years. Cemiplimab, a PD-1 antibody, has been approved for patients with laBCC and mBCC previously treated with hedgehog inhibitors or for whom hedgehog inhibitors are not appropriate. The high mutational load of BCCs because of chronic UV exposure makes the advanced BCCs ideal candidates for immunotherapy. In an open-label, multi-centre, single-arm, phase 2 trial disease control was observed in 80% of the patients (67/84) with a median progression-free survival of 19 months. A complete response was observed in 6%, a partial response in 25% and stable disease in 49% of the patients. Median time to response was 4.3 months (Stratigos et al. 2021).  revention with Nicotinamide (Vit. B3) P Secondary prevention of new basal cell carcinomas in high-risk patients has been studied in a large Australian placebo-controlled double blind study, with promising results. Nicotinamide 500 mg when taken twice daily reduced the risk of new tumors by 20% in 386 patients (Chen et al. 2015).

Follow-up Follow-up is generally recommended after diagnosis and treatment of any new BCC, not only due to the considerable recurrence rates, but considering the possibility of new BCCs as well. Indeed, there is a tenfold increase compared to the general population. Τhe current European consensus-based interdisciplinary guidelines recommend follow-up in patients with BCC in 3, 6, or 12 monthly intervals according to the risk category. Patients with high-risk BCCs and advanced BCCs require a more intense and long-term follow-­up. Imaging techniques such as ultrasound or CT/MRI could be used if required to exclude metastasis. For patients with low-risk BCCs, a yearly clinical examination after an initial follow-­up 6 months postoperatively should be enough. In any case,

follow-up strategies should be individualized; in selected patient groups, such as the immune compromised or patients with genetic predisposition to BCC formation, a lifetime follow-up should be advised.

References Bichakjian CK, Olencki T, Aasi SZ, Alam M, Andersen JS, Berg D, et  al. Basal cell skin cancer, version 1.2016, NCCN Clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2016;14(5):574–97. https://doi.org/10.6004/jnccn.2016.0065. Breuninger H, Dietz K.  Prediction of subclinical tumor infiltration in basal cell carcinoma. J Dermatol Surg Oncol. 1991;17(7):574–8. https://doi. org/10.1111/j.1524-­4725.1991.tb03655.x. Chen AC, Martin AJ, Choy B, Fernández-Peñas P, Dalziell RA, McKenzie CA, et al. A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N Engl J Med. 2015;373(17):1618–26. https://doi. org/10.1056/NEJMoa1506197. Kimyai-Asadi A, Goldberg LH, Peterson SR, Alam M, Goldberg LH, Peterson SR, et  al. Efficacy of narrow-­margin excision of well-demarcated primary facial basal cell carcinomas. J Am Acad Dermatol. 2005;53(3):464–8. https://doi.org/10.1016/j. jaad.2005.03.038. Lang BM, Balermpas P, Bauer A, Blum A, Brölsch F, Dirschka T, et al. S2k guidelines for cutaneous basal cell carcinoma—part 2: treatment, prevention and follow-up. J Dtsch Dermatol Ges. 2019;17:214–30. https://doi.org/10.1111/ddg.13755. Peris K, Fargnoli MC, Garbe C, Kaufmann R, Bastholt L, Basset Seguinet N, et al. Diagnosis and treatment of basal cell carcinoma: European consensus-based interdisciplinary guidelines. Eur J Cancer. 2019;118:10– 34. https://doi.org/10.1016/j.ejca.2019.06.003. Schmults C, Blitzblau R, Aasi SZ, et al. NCCN (National Comprehensive Cancer Network) Clinical Practice guidelines in Oncology. Basal Cell Skin Cancer. Version 2.2022-March 24, 2022. Available at: https:// www.nccn.org/professionals/physician_gls/pdf/nmsc. pdf. Access on 28 August 2022. Stratigos AJ, Sekulic A, Peris K, et al. Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an open-label, multi-center, singlearm, phase 2 trial. Lancet Oncol. 2021;22:848–57. Telfer NR, Colver GB, Morton CA. British association of dermatologists guidelines for the management of basal cell carcinoma. Br J Dermatol. 2008;159(1):35–48. https://doi.org/10.1111/j.1365-­2133.2008.08666.x. Wolf DJ, Zitelli JA. Surgical margins for basal cell carcinoma. Arch Dermatol. 1987;123(3):340–4.

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Fecher LA.  Systemic therapy for inoperable and metastatic Basal cell cancer. Curr Treat Options in Oncol. 2013;14:237–48. https://doi.org/10.1007/ Abramson AK, Krasny MJ, Goldman GD.  Tangential s11864-­013-­0233-­9. shave removal of basal cell carcinoma. Dermatol Surg. Kadouch DJ, Leeflang MM, Elshot YS, Longo C, Ulrich 2013;39:387–92. https://doi.org/10.1111/dsu.12106. M, van der Wal AC, et  al. Diagnostic accuracy of Arits AH, Mosterd K, Essers BA, Spoorenberg E, confocal microscopy imaging vs. punch biopsy for Sommer A, De Rooij MJ, et al. Photodynamic therapy diagnosing and subtyping basal cell carcinoma. J Eur versus topical imiquimod versus topical fluorouracil Acad Dermatol Venereol. 2017;31:1641–8. https://doi. for treatment of superficial basal-cell carcinoma: a org/10.1111/jdv.14253. single blind, non-inferiority, randomised controlled Kasper M, Jaks V, Hohl D, Toftgård R. Basal cell carcitrial. Lancet Oncol. 2013;14:647–54. https://doi. noma—molecular biology and potential new theraorg/10.1016/S1470-­2045(13)70143-­8. pies. J Clin Invest. 2012;122:455–63. https://doi. Atwood SX, Chang AL, Oro AE.  Hedgehog pathway org/10.1172/JCI58779. inhibition and the race against tumor evolution. J Kim JYS, et  al. Guidelines of care for the manageCell Biol. 2012;199:193–7. https://doi.org/10.1083/ ment of basal cell carcinoma. J Am Acad Dermatol. jcb.201207140. 2018;78:540–59. https://doi.org/10.1016/j. Axelson M, Liu K, Jiang X, He K, Wang J, Zhao H, et al. jaad.2017.10.006. U.S.  Food and drug administration approval: vismoLiu LS, Colegio OR.  Molecularly targeted therapies degib for recurrent, locally advanced, or metastatic for nonmelanoma skin cancers. Int J Dermatol. Basal cell carcinoma. Clin Cancer Res. 2013;19:2289– 2013;52:654–65. https://doi.org/10.1111/ijd.12017. 93. https://doi.org/10.1158/1078-­0432.CCR-­12-­1956. Lang BM, Balermpas P, Bauer A, Blum A, Brölsch F, Basset-Seguin N, Bissonnette R, Girard C, Haedersdal M, Dirschka T, et al. S2k guidelines for cutaneous basal Lear JT, Paul C, et  al. Consensus recommendations cell carcinoma—part 1: epidemiology, genetics and for the treatment of basal cell carcinomas in Gorlin diagnosis. J Dtsch Dermatol Ges. 2019;17:94–103. syndrome with topical methylaminolaevulinate-­ https://doi.org/10.1111/ddg.13733. photodynamic therapy. J Eur Acad Dermatol Venereol. Lang BM, Balermpas P, Bauer A, Blum A, Brölsch F, 2014;28:626–32. https://doi.org/10.1111/jdv.12150. Dirschka T, et al. S2k guidelines for cutaneous basal Bichakjian CK, Olencki T, Aasi SZ, Alam M, Andersen cell carcinoma—part 2: treatment, prevention and JS, Berg D, et  al. Basal cell skin cancer, version follow-up. J Dtsch Dermatol Ges. 2019;17:214–30. 1.2016, NCCN clinical practice guidelines in oncolhttps://doi.org/10.1111/ddg.13755. ogy. J Natl Compr Cancer Netw. 2016;14(5):574–97. Rogers CR, Bentz ML.  An evidence-based approach to https://doi.org/10.6004/jnccn.2016.0065. the treatment of nonmelanoma facial skin malignanBlixt E, Nelsen D, Stratman E.  Recurrence rates of cies. Plast Reconstr Surg. 2011;127:940–8. https://doi. aggressive histologic types of basal cell carcinoma org/10.1097/PRS.0b013e318204aeb2. after treatment with electrodesiccation and curettage Papakostas D, Stockfleth E.  Topical treatment of basal alone. Dermatol Surg. 2013;39:719–25. https://doi. cell carcinoma with the immune response modifier org/10.1111/dsu.12122. imiquimod. Future Oncol. 2015;11:2985–90. https:// Cameron MC, Lee E, Hibler BP, Giordano CN, Barker doi.org/10.2217/fon.15.192. CA, Mori S, et al. Basal cell carcinoma: contemporary Peris K, Fargnoli MC, Garbe C, Kaufmann R, Bastholt L, approaches to diagnosis, treatment, and prevention. Basset Seguinet N, et al. Diagnosis and treatment of J Am Acad Dermatol. 2019;80:321–39. https://doi. basal cell carcinoma: European consensus-based interorg/10.1016/j.jaad.2018.02.083. disciplinary guidelines. Eur J Cancer. 2019;118:10– Cameron MC, Lee E, Hibler BP, Barker CA, Mori S, 34. https://doi.org/10.1016/j.ejca.2019.06.003. Cordova M, et  al. Basal cell carcinoma: epidemiRoozeboom MH, Arits AH, Nelemans PJ, Kelleners-­ ology; pathophysiology; clinical and histologiSmeets NW. Overall treatment success after treatment cal subtypes; and disease associations. J Am Acad of primary superficial basal cell carcinoma: a systemDermatol. 2019;80:303–17. https://doi.org/10.1016/j. atic review and meta-analysis of randomized and nonjaad.2018.03.060. randomized trials. Br J Dermatol. 2012;167:733–56. Cemiplimab in locally advanced basal cell carcinoma https://doi.org/10.1111/j.1365-­2133.2012.11061.x. after hedgehog inhibitor therapy: an open-label multiSekulic A, Mangold AR, Northfelt DW, LoRusso centre singlearm phase 2 trial. The Lancet Oncology. PM.  Advanced basal cell carcinoma of the skin: 2021;22(6):848–57. https://doi.org/10.1016/ targeting the hedgehog pathway. Curr Opin S1470-2045(21)00126-1. Oncol. 2013;25:218–23. https://doi.org/10.1097/ Dummer R, Ascierto PA, Basset-Seguin N, Dréno B, CCO.0b013e32835ff438. Garbe C, Gutzmer R, et al. Sonidegib and vismodegib Shokrollahi K, Javed M, Aeuyung K, Ghattaura A, in the treatment of patients with locally advanced basal Whitaker IS, O'Leary B, et  al. Combined carbon cell carcinoma: a joint expert opinion. J Eur Acad dioxide laser with photodynamic therapy for noduDermatol Venereol. 2020;34(9):1944–56. https://doi. lar and superficial basal cell carcinoma: almost org/10.1111/jdv.16230. scarless cure with minimal recurrence. 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112 Surg. 2014;73:552–8. https://doi.org/10.1097/ SAP.0b013e3182773ed2. Stockfleth E, Trefzer U, Garcia-Bartels C, Wegner T, Schmook T, Sterry W. The use of toll-like receptor-7 agonist in the treatment of basal cell carcinoma: an overview. Br J Dermatol. 2003;149(Suppl. 66):53–6. https://doi.org/10.1046/j.0366-­077x.2003.05626.x. Telfer NR, Colver GB, Morton CA. British association of dermatologists guidelines for the management of basal cell carcinoma. Br J Dermatol. 2008;159(1):35–48. https://doi.org/10.1111/j.1365-­2133.2008.08666.x. Trakatelli M, Morton C, Nagore E, Ulrich C, Del Marmol V, Peris K, et  al. Update of the European guide-

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Bowen’s Disease

10

Mirna Situm and Maja Kovacevic

Abbreviations 5-FU 5-Fluorouracil ALA 5-Aminolevulinic acid BD Bowen’s disease HPV Human papillomavirus MAL Methyl aminolevulinate PDT Photodynamic therapy SCC Squamous cell carcinoma

M. Situm (*) Department of Dermatovenerology, Sestre Milosrdnice University Hospital Centre, Zagreb, Croatia School of Dental Medicine, University of Zagreb, Zagreb, Croatia Referral Centre for Melanoma of the Ministry of Health of the Republic of Croatia, Zagreb, Croatia Referral Centre for Dermoscopy of the Ministry of Health of the Republic of Croatia, Zagreb, Croatia Croatian Academy of Science and Arts, Zagreb, Croatia e-mail: [email protected] M. Kovacevic Department of Dermatovenerology, Sestre Milosrdnice University Hospital Centre, Zagreb, Croatia Referral Centre for Melanoma of the Ministry of Health of the Republic of Croatia, Zagreb, Croatia

Key Points • Bowen’s disease (BD) is an intraepidermal squamous cell carcinoma (SCC) with a tendency for progressive growth and low invasive risk, characterized by slowly growing, erythematous plaque with an irregular border, surface scaling, and crusting. • The etiology of BD is multifactorial including irradiation, carcinogens (e.g., arsenic), immunosuppression, and viral infection. • The age and sun-exposed body distribution of BD suggests the importance of chronic sun damage as a factor in the carcinogenesis of BD. • The goal of therapy for Bowen’s disease is to reduce morbidity and to prevent complications. • The choice of treatment should be guided by its efficacy, location, size and number of lesions, availability of the therapy, the clinician’s expertise, patient’s age, immune status, concomitant medication, comorbidities and patient compliance and, not less important, cosmetic outcome of the treatment. • There is also an increasing choice of home-­ applied treatments, with less treatment-related morbidities. • Sun avoidance and regular skin check-up are strongly recommended for all patients with skin tumors.

Referral Centre for Dermoscopy of the Ministry of Health of the Republic of Croatia, Zagreb, Croatia © Springer Nature Switzerland AG 2023 A. D. Katsambas et al. (eds.), European Handbook of Dermatological Treatments, https://doi.org/10.1007/978-3-031-15130-9_10

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Definition and Epidemiology Bowen’s disease (BD) is an intraepidermal squamous cell carcinoma (SCC) with a tendency for progressive growth and low invasive risk, characterized by slowly growing, erythematous plaque with an irregular border, surface scaling, and crusting. It can be present on the skin and on the mucosa. BD is very common in the Caucasian population with an incidence of 14 per 100,000 in some populations. The peak age group for BD is the seventh decade. The ratio of Bowen’s disease is approximately equal between males and females. BD is most commonly reported on sun-­ exposed areas of Caucasian population  - on the head and neck of male patients and on the lower limbs and cheeks of female patients. BD is usually a solitary lesion, but in 10–20% of patients, it occurs at multiple sites. Prognosis of the disease is encouraging - the risk of progression to invasive SCC is 3–5% for extragenital lesions and 10% for genital lesions (genital BD or eryhtroplasia of Queyrat).

Etiology The etiology of BD is multifactorial including irradiation, carcinogens (e.g., arsenic), immunosuppression, and viral infection. Chronic sun damage is an important carcinogenic factor in BD and its effect is confirmed with the age group in which BD occurs and also with distribution of lesions on sun-exposed sites. Photochemotherapy and radiotherapy are also important irradiation etiologic factors. Arsenic exposure was more common in agricultural workers due to usage of pesticides and fungicides, but it was also common in patients with psoriasis and asthma due to application of Fowler and Gray solution for its treatment. It is estimated that arsenic exposure occurs after a time lag of up to10 years. Human papillomavirus (HPV) type 16 is the most common subtype isolated from lesions of Bowen’s disease, although other subtypes have also been found (e.g., type 18, 31, 33, 51). Etiological involvement of HPV has strong therapeutic implications, as HPV-induced BD is responsive

M. Situm and M. Kovacevic

to agents that have combined antiviral and antitumor effect. Immunosuppressed patients (e.g., renal transplant patients, AIDS) with BD are more likely to have multiple tumors and more aggressive tumors. Therefore, educating immunosuppressed patients about sun exposure is very important. Other possible causes include genetic factors, trauma, X-ray radiation, chronic injury, or other chemical carcinogens.

Clinical Presentation Asymptomatic, slowly growing, erythematous, well-demarcated scaly patch or plaque most frequently occurs on the lower legs, but it can occur anywhere on the skin or mucosal surfaces (Fig. 10.1). BD is most commonly reported on sun-exposed areas of Caucasian population; in male patients on the head, neck, and extremities, while the lower limbs and cheeks are most commonly affected in female patients. Areas such as lip, nipple, palm, feet, and the nail bed are rarely affected. Initially, BD presents as a small, red, scaly, slightly raised area that gradually enlarges in irregular fashion. The scales can easily be removed from the surface, without bleeding. The surface is usually flat, but may become hyperkeratotic or crusted. Lesions vary in size from a few millimeters to several centimeters in diameter. Lesions are rarely pigmented (Fig.  10.2), especially in the genital region and the nails. The appearance of nodules

Fig. 10.1  Bowen’s disease on the anterior neck

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Dermoscopic Features of BD

Fig. 10.2  Pigmented Bowen’s disease on the right groin

or ulceration indicates the development of invasive carcinoma, usually arising many years after the initial lesion. Bowen’s disease may also occur on mucous membranes. When it arises on the glans penis, it is known as erythroplasia of Queyrat and it is characterized by moist, velvety, or smooth plaques. Mucosal lesions in the oral cavity, vulva, or glans penis can also resemble leukoplakia. BD presents as a single lesion in two-thirds of cases. Multiple lesions are more commonly present in immunosuppressed patients. Periungual BD can have various clinical aspects, from leveled, red patches with little scale to verrucous plaques and nail deformity, lysis, and necrosis of the nail plate. Lesions on the nipple can resemble mammary Paget’s disease, therefore it is important to exclude BD in case of itching and pain of this region.

First description of dermoscopic features such as glomerular vessels and scaly erythematous plaques has been done in 2004 by Zalaudek et al. Several other studies elucidated further ­dermoscopic features of BD; glomerular vessels and a scaly surface were the most frequently reported features specific for BD, and the multicomponent global pattern and linear arrangement of brown/gray dots were also reported. Payapvipapong and Tanaka in 2015 classified BD in three different types: (1) classic BD, associated with the presence of atypical vascular pattern, whitish scale, and a pinkish network, (2) pigmented BD, revealing pigmentation without structure, pigmented stripes, and crusts; and (3) partially pigmented BD, which was a combination of the other two. In 2017, Yang et al. observed two new dermoscopic criteria of BD: the doubleedge sign, characterized by two parallel pigmented edges at the periphery of the lesion, and clusters of brown structureless areas often distributed at the periphery of the lesion, larger than the large ovoid nests seen in basal cell carcinoma. Dermoscopic features of BD are not specific and are shared with other lesions such as actinic and seborrheic keratoses, basal cell carcinoma, actinic keratoses, etc. In order to establish correct diagnosis using dermoscopy, it is important to be aware of dermoscopic features seen exclusively in certain lesions and also of shared dermoscopic features (Table 10.1).

Basal cell carcinoma Spoke wheel-like area Leaf-like area Large blue-gray ovoid nest

Ulceration Gray dots/ globules Arborizing vessel

Differential diagnosis Specific dermoscopy features

Shared dermoscopy features

Scales Pseudonetwork Gray granules Brown dots/globules

Actinic keratosis Annular-granular pattern Granules distributed around follicular Openings Hair follicle openings

Gray granules Linear irregular vessels Dotted vessels Scar-like depigmentation

Lichen planus like keratosis Granular pattern Granules unevenly distributed Blue-white structures

Pseudonetwork Gray granules Homogeneous pigmentation

Lentigo maligna melanoma Asymmetrical pigmented follicular openings Annular-granular pattern Rhomboidal structures

Table 10.1  Differential diagnosis of BD—dermoscopic features. (Reprinted with permission from Yang et al.)

Glomerular vessels Polymorphous vessels Dotted vessels Scar-like depigmentation Gray dots/globules Multiple colors

Melanoma Irregular streaks/ pseudopods Atypical pigment network Black blotches Blue-whitish veil Milky red areas Peripheral black dots/globules

Diffuse light brown Pigmentation Regression-like structure Linear irregular vessels

Mammary Paget’s disease Irregular black dots/globules Pepperring-like blue-gray dots Corkscrew vessels Chrysalis-like structures

Seborrhoic keratosis Sharp demarcation Comedo-like openings Multiple milia-like cysts Coral-like structure Moth-eaten border Hairpin vessels Linear irregular vessels Dotted vessels Glomerular vessels Yellow crusts and scales Brown pigmentation Focal hemorrhage

116 M. Situm and M. Kovacevic

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Diagnosis The diagnosis of BD is confirmed by skin biopsy. It is important to sample many areas of larger lesions to exclude evidence of invasion. The normal epidermis in its full thickness is replaced by abnormal keratinocytes, with loss of orientation and hyper- chromatic bigger nuclei. Large pale keratinocytes with abundant ground-glass cytoplasm, so-called pagetoid cells, with multiple mitotic figures are often distributed throughout the epidermis. There is a disturbance of epidermal organization, and cells keratinize prematurely losing their intercellular connections. The surface scale is formed by thickened, loose, parakeratotic cells. Dermo-epidermal junction is intact with variable acanthosis and thickened interpapillary ridges. There is a dense inflammatory infiltrate in the papillary dermis, although no atypical cells are present in the dermis. Despite of the intact basal cell layer, extension of keratinocyte atypia down the follicular epithelium is seen (Fig. 10.3a, b).

a

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Immunohistochemically, tumor cells in BD typically stain positive for p53, HPV, and high molecular weight cytokeratin (which includes cytokeratin 10). Complete skin examination must be performed in patients with BD, especially of sun-­ exposed skin, because of higher incidence of nonmelanoma skin cancer in these patients. Dermoscopy has become an integrative part of the clinical examination of skin tumors and premalignant lesions like actinic keratosis and Bowen’s disease.

Differential Diagnosis Differential diagnosis of well-demarcated pink-­ red plaque(s) of BD includes nummular eczema, contact eczema, psoriasis, lichen planus, seborrheic keratosis, tinea corporis, actinic keratosis, verruca vulgaris, condyloma acuminatum, superficial basal cell carcinoma, squamous cell carci-

b

Fig. 10.3 (a) Bowen’s disease on the left wrist (40×). (b) Bowen’s disease on the left wrist (200×)

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noma, melanoma, Merkel cell carcinoma, and Paget’s disease.

mended, but irritation and inflammation usually limit the treatment.

General Principles of Treatment

Imiquimod

The history of Bowen’s disease and other intraepithelial neoplasia is not yet completely understood; therefore, it is difficult to determine how aggressive treatment should be. The age group, number and size of lesions, location of affected site(s), and patient’s cosmetic expectations may all influence therapeutic choice. In the elderly patients with slow progressive thin lesions on the lower leg where healing is poor, there is an argument for observation rather than intervention. Therapeutic aim should be to avoid mutilating surgery and functional impairment. Most treatments have a recurrence risk; therefore a follow­up at 6–12 months interval is recommended. The shorter follow-up is recommended with history of past recurrence, presence of multiple lesions, and immunosuppression.

Topical 5% imiquimod cream should be used for the treatment of small and large, single lesions on poor healing sites, as well as on good healing sites and also for genital and perianal lesions. It is not licensed for BD treatment in many countries. It has both anti-HPV and antitumor effects and is therefore useful for HPV- and non-HPV-­ associated BD.  The recommended duration of treatment is 16  weeks and the dose varies from once weekly to five times per week. Five percent imiquimod cream is also beneficial in the treatment of BD in immunosuppressed patients. It can be used in combination with topical 5% 5-FU. There is an evidence that cytokines induced by imiquimod improve the therapeutic efficacy of 5% 5-FU in Bowen’s disease.

5-Fluorouracil Topical chemotherapy with 5-fluorouracil (5-FU) is used for the treatment of single or few small lesions at well healing sites like the face and scalp. It should be avoided for lesions at poor healing sites and for perianal lesions, due to a higher recurrence rate of perianal BD treated with 5-FU cream. Five percent 5-FU cream is applied once or twice daily for a period between 1  week and 2  months, and the treatment is repeated if required. Efficacy is increased by occlusion or iontophoresis. Compliance to this treatment is very well since it can be easily applied by patients, but its main disadvantage is penetration depth since the cream might not penetrate deep enough to treat any deep follicular extension of the tumor cells. Possible adverse effects include pain, burning sensations, redness, erosions, and ulcerations on the application site. In erythroplasia of Queyrat, application of 5% 5-FU cream twice daily for 4–5 weeks is recom-

Diclofenac Diclofenac 3% gel has been successfully used in the treatment of actinic keratosis. There are promising data of BD successfully treated with 3% diclofenac gel once or twice daily for 8  weeks. The treatment was well-tolerated with mild inflammation after 6  weeks and mild side effects like itching and dryness. Complete clinical and histological clearance was proven by biopsies taken 4  weeks after end of treatment. Given its mechanism of action, diclofenac 3% gel may have potential to halt the progression of actinic keratoses (AKs) in the setting of field cancerization and BD. These promising data have to be proven in randomized controlled trials, and recurrence rates in long-term follow-up have to be investigated.

Cryotherapy The results of BD treatment with cryotherapy depend on the used techniques and regimens.

10  Bowen’s Disease

Liquid nitrogen cryotherapy is used in single freeze-thaw cycle (FTC) of 30 s or two FTCs of 20  s with a thaw period. These regimens cause discomfort and may cause ulceration on the treated region. Cryotherapy is recommended for the treatment of multiple BD on good healing sites, facial BD as well as digital, penile and small, single lesions on poor healing sites. Cryotherapy has a good success rate with adequate technique. It is less effective than curettage and PDT, but also less expensive and less time-consuming.

Curettage with Cautery/ Electrocautery Curettage is the treatment of choice for small, single or few lesions on good or poor healing sites and for facial lesions. It should be avoided for the treatment of perianal BD and large lesions despite of the healing properties. Cure rates ranged from 81% for curettage up to 98% for curettage and cautery with a follow-up of 2.5–4 years. Curettage with cautery is a safe, common, and cost-effective therapy of BD.

Excision Surgical excision of BD is the treatment of choice for small and single lesions, as well as lesions located on fingers or perianal region. The main advantage is the opportunity to histologically examine the resection margins. With recommended safe margins of 5-mm, excision rate is up to 95%. Reducing the safety margin to less than 5 mm is not recommended for routine excision of BD, but Mohs surgery could be considered for a tissue-sparing technique and for localizations where tissue-sparing surgery is necessary (e.g., fingers, nail unit, and genital area). Mohs micrographic surgery uses the removal of skin cancers with very small margins of normal tissue followed by frozen section examination of nearly 100% of the tissue margin. It is also an excellent method for larger lesions, poorly demarcated

119

lesions, and recurrent lesions on the head and neck.

Photodynamic Therapy (PDT) Photodynamic therapy involves the introduction of a photosensitizing agent into the body, which is retained preferentially by the tumor cells. PDT is based on the combination of light and light-­ sensitive agents (e.g., porphyrins) in the presence of oxygen. The energy of photons is absorbed by porphyrins and then transferred to surrounding oxygen molecules resulting in formation of singlet oxygen and free radicals responsible for cell death. Most commonly used topical photosensitizers are 5-aminolevulinic acid (ALA) and methyl aminolevulinate (MAL). For the production and accumulation of these photoactive porphyrins, a sufficient period of time is necessary before the light activation, for MAL 3 h, for ALA 4–18 h. PDT is well suited for single or multiple large lesions and poor healing sites. The adverse effects include phototoxic side effects on the application site, such as burning, stinging, erosions, ulceration, and hyperpigmentation or hypopigmentation. PDT has been particularly useful in immunosuppressed subjects (e.g., transplant recipients) because of the possibility for repeated treatment of large areas.

Radiotherapy Different radiotherapy techniques like external beam radiotherapy, grenz rays, and radioactive skin patches have been used in the treatment of BD with reported cure rates between 94 and 100%. Radiation therapy should be considered for poor surgical candidates or patients with multiple lesions. It should be avoided for lower extremity lesions due to impaired healing.

Laser Lasers have been used to treat lesions at difficult sites, such as the fingers and genital area. Case

M. Situm and M. Kovacevic

120 Table 10.2  Summary of treatment options for Bowen’s disease Application 5-fluorouracil 5% Once or twice cream daily Topical Once daily imiquimod 5% cream Cryotherapy Single freeze-­ thaw cycle Curettage

Excision

PDT

Radiotherapy Laser

Topical PDT using topical 5-ALA External beam X-radiation CO2 laser

Treatment duration 1–8 weeks

Advantages High cure rates High cure rates

Disadvantages Irritant

Single treatment

Low recurrences Cheap, high cure rates

Slow healing, painful Morbidity

Single treatment

Cheap, high cure rates

Morbidity on lower leg wounds

One or two treatments

High cure rates

Expensive, painful

Single/ repeated Single/ repeated

High cure Acute radiation rates reactions Penile lesions Depth of treatment, progression to SCC

Up to 16 weeks 30 s

reports and series have shown a benefit of using argon, carbon dioxide, and Nd:YAG lasers in the treatment of some BD lesions. There are also reported laser treatment failures or progression to invasive SCC of lower leg lesions after 100% healing at 2  months and complete response at 6 months. Therefore, CO2 laser can be used for penile or digital BD, but there is limited data of recurrence rates (Table 10.2).

Other Treatments Acitretin Retinoids have been used alone or in combination with 5-FU in anecdotal cases, but the relative merits of each are unclear in the combination approach.

General Therapy Guidelines The goal of therapy for Bowen’s disease is to reduce morbidity and to prevent complications. The choice of treatment should be guided by its efficacy, location, size and number of lesions, availability of the therapy, the clinician’s exper-

Expensive

Lesion characteristics Small, single/few on poor healing site Large, single/poor healing site Facial, multiple, good healing site Small, single, few on good and poor healing site Perianal, digital, small, single/few on poor healing site Large or small, single, poor healing site Perianal, penile Penile, digital

tise, patient’s age, immune status, concomitant medication, comorbidities, patient compliance and not less important, and cosmetic outcome of the treatment. There is also an increasing choice of home-applied treatments, with less treatment-­ related morbidities. Sun avoidance is strongly recommended for all patients with skin tumors, and due to a 10% recurrence rate with most treatment options, patients with a history of Bowen’s disease or other skin cancers should be evaluated with a total body skin examination every 6–12 months.

Suggested Reading Arlette JP, Trotter MJ. Squamous cell carcinoma in situ of the skin: history, presentation, biology and treatment. Australas J Dermatol. 2004;45(1):1–11. Braathen LR, Szeimies RM, Basset-Seguin N, et  al. Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. International society for photodynamic therapy in dermatology, 2005. J Am Acad Dermatol. 2007;56(1):125–43. Brookes PT, Jhawar S, Hinton CP, Murdoch S, Usman T.  Bowen’s disease of the nipple—a new method of treatment. Breast. 2005;14(1):65–7. Bugatti L, Filosa G, De Angelis R.  Dermoscopic observation of Bowen’s disease. J Eur Acad Dermatol Venereol. 2004;18:572–4.

10  Bowen’s Disease Cameron A, Rosendahl C, Tschandl P, et al. Dermatoscopy of pigmented Bowen’s disease. J Am Acad Dermatol. 2010;62:597–604. Chung YL, Lee JD, Bang D, et al. Treatment of Bowen’s disease with a specially designed radioactive skin patch. Eur J Nucl Med. 2000;27(7):842–6. Clavel CE, Huu VP, Durlach AP, et al. Mucosal oncogenic human papillomaviruses and extragenital Bowen disease. Cancer. 1999;86(2):282–7. Cox NH, Eedy DJ, Morton CA.  Guidelines for management of Bowen’s disease. British Association of Dermatologists. Br J Dermatol. 1999;141(4):633–41. Cox NH, Eedy DJ, Morton CA. Guidelines for management of Bowen’s disease: 2006 update. Br J Dermatol. 2007;156(1):11–21. Dave R, Monk B, Mahaffey P.  Treatment of Bowen’s disease with carbon dioxide laser. Lasers Surg Med. 2003;32:335. Dawe SA, Salisbury JR, Higgins E. Two cases of Bowen’s disease successfully treated topically with 3% diclofenac in 2.5% hyaluronan gel. Clin Exp Dermatol. 2005;30:712–3. Derancourt C, Mougin C, Chopard-Lallier M, et  al. Oncogenic human papillomaviruses in extra-genital Bowen disease revealed by in situ hybridization. Ann Dermatol Venerol. 2001;128:715–8. Dragieva G, Hafner J, Dummer R, et  al. Topical photodynamic therapy in the treatment of actinic keratoses and Bowen’s disease in transplant recipients. Transplantation. 2004;77(1):115–21. Drake AL, Walling HW.  Variations in presentation of squamous cell carcinoma in situ (Bowen’s disease) in immunocompromised patients. J Am Acad Dermatol. 2008;59(1):68–71. Dupree MT, Kiteley RA, Weismantle K, Panos R, Johnstone PA. Radiation therapy for Bowen’s disease: lessons for lesions of the lower extremity. J Am Acad Dermatol. 2001;45(3):401–4. Fernandez-Flores A.  Cytokeratin 17 immunoexpression in actinic keratosis (bowenoid and nonbowenoid) and in Bowen disease. Ann Diagn Pathol. 2016;20:1–6. Holt PJ. Cryotherapy for skin cancer: results over a 5-year period using liquid nitrogen spray cryosurgery. Br J Dermatol. 1988;119(2):231–40. Idriss MH, Misri R, Böer-Auer A. Orthokeratotic Bowen disease: a histopathologic, immunohistochemical and molecular study. J Cutan Pathol. 2016;43(1):24–31. Kao GF.  Carcinoma arising in Bowen’s disease. Arch Dermatol. 1986;122(10):1124–6. Kossard S, Rosen R.  Cutaneous Bowen’s disease. An analysis of 1001 cases according to age, sex, and site. J Am Acad Dermatol. 1992;27(3):406–10. Kovács A, Yonemoto K, Katsuoka K, Nishiyama S, Harhai I.  Bowen’s disease: statistical study of a 10 year period. J Dermatol. 1996;23(4):267–74. Lallas A, Argenziano G, Zendri E, et al. Update on non-­ melanoma skin cancer and the value of dermoscopy in its diagnosis and treatment monitoring. Expert Rev Anticancer Ther. 2013;13:541–58.

121 Landthaler M, Haina D, Brunner R, Waidelich W, Braun-Falco O.  Laser therapy of bowenoid papulosis and Bowen’s disease. J Dermatol Surg Oncol. 1986;12(12):1253–7. Lee JD, Park KK, Lee MG, et  al. Radionuclide therapy of skin cancers and Bowen’s disease using a specially designed skin patch. J Nucl Med. 1997;38(5):697–702. Lee MM, Wick MM. Bowen’s disease. CA Cancer J Clin. 1990;40:237–42. Leibovitch I, Huilgol S, Seva D, et  al. Cutaneous squamous cell carcinoma in situ (Bowen’s disease): treatment with Mohs’ micrographic surgery. J Am Acad Dermatol. 2005;52:997–1002. Morton CA, Whitehurst C, Moore J, et al. Photodynamic therapy vs cryotherapy in the treatment of Bowen’s disease. Clin Exp Dermatol. 1996;21:79. Neagu TP, Ţigliş M, Botezatu D, Enache V, Cobilinschi CO, Vâlcea-Precup MS, GrinŢescu IM. Clinical, histological and therapeutic features of Bowen’s disease. Romanian J Morphol Embryol. 2017;58(1):33–40. Neubert T, Lehmann P.  Bowen’s disease—a review of newer treatment options. Ther Clin Risk Manag. 2008;4(5):1085–95. Patel MJ, Stockfleth E.  Does progression from actinic keratosis and Bowen’s disease end with treatment: diclofenac 3% gel, an old drug in a new environment? Br J Dermatol. 2007;156 Suppl 3:53–6. Payapvipapong K, Tanaka M.  Dermoscopic classification of Bowen’s disease. Australas J Dermatol. 2015;56(1):32–5. Plaza de Lanza M, Ralfs I, Dawber R.  Cryosurgery for Bowen’s disease of the skin. Br J Dermatol. 1980;103:14. Prinz BM, Hafner J, Dummer E, et  al. Treatment of Bowen’s disease with imiquimod 5% cream in transplant recipients. Transplantation. 2004;77:790–1. Quinn AG, Perkins W. Rook’s textbook of dermatology. In: Burns T, Breathnach S, Cox N, Griffiths C, editors. Non-melanoma skin cancer and other epidermal skin tumors. 8th ed. London: Wiley; 2010. p. 2644–6. Reizner GT, Chuang TY, Elpern DJ, Stone JL, Farmer ER.  Bowen’s disease (squamous cell carcinoma in situ) in Kauai. Hawaii. A population-based incidence report. J Am Acad Dermatol. 1994;31(4):596–600. Sardesai VR.  Bowen’s disease: an uncommon presentation. Int J Dermatol. 2002;41(10):69. Sarmiento JM, Wolff BG, Burgart LJ, et  al. Perianal Bowen’s disease: associated tumors, human papillomavirus, surgery, and other controversies. Dis Colon Rectum. 1997;40:912–8. Shannon RL, Strayer DS. Arsenic-induced skin toxicity. Hum Toxicol. 1989;8(2):99–104. Smith KJ, Germain M, Skelton H. Bowen’s disease (squamous cell carcinoma in situ) in immunosuppressed patients treated with imiquimod 5% cream and a COX inhibitor, sulindac: potential applications for this combination of immunotherapy. Dermatol Surg. 2001a;27:143–6. Smith KJ, Germain M, Skelton H.  Squamous cell carcinoma in situ (Bowen’s disease) in renal transplant

122 patients treated with 5% imiquimod and 5% fluorouracil therapy. Dermatol Surg. 2001b;27:561–4. Stevens DM, Kopf AW, Gladstein A, Bart RS. Treatment of Bowen’s disease with grenz rays. Int J Dermatol. 1977;16(5):329–39. Szeimies RM, Abels C, Fritsch C, et  al. Wavelength dependency of photodynamic effects after sensitization with 5-aminolevulinic acid in vitro and in vivo. J Invest Dermatol. 1995;105(5):672–7. Tantikun N.  Treatment of Bowen’s disease of the digit with carbon dioxide laser. J Am Acad Dermatol. 2000;43(6):1080–3. Thestrup-Pedersen K, Ravnborg L, Reymann F.  Morbus Bowen. A description of the disease in 617 patients. Acta Derm Venereol. 1988;68(3):236–9. Turpin IM.  Radionuclide therapy of skin cancers and Bowen’s disease using a specially designed skin patch. Plast Reconstr Surg. 1999;103:1333. Welch ML, Grabski WJ, McCollough ML, et  al. 5-­fluorouracil iontophoretic therapy for Bowen’s disease. J Am Acad Dermatol. 1997;36:956–8.

M. Situm and M. Kovacevic Westers-Attema A, van den Heijkant F, Lohman BG, Nelemans PJ, Winnepenninckx V, Kelleners-Smeets NW, Mosterd K.  Bowen’s disease: a six-year retrospective study of treatment with emphasis on resection margins. Acta Derm Venereol. 2014;94(4):431–5. Wojnarowska F, Cooper SM. Dermatology. In: Bolognia JL, Jorizzo JL, Rapini RP, editors. Anogenital (non-­ venereal) disease. Edinburgh: Mosby; 2003. p. 1106. Wolf JE Jr, Taylor JR, Tschen E, Kang S. Topical 3.0% diclofenac in 2.5% hyaluronan gel in the treatment of actinic keratoses. Int J Dermatol. 2001;40(11):709–13. Yang Y, Lin J, Fang S, Han S, Song Z. What’s new in dermoscopy of Bowen’s disease: two new dermoscopic signs and its differential diagnosis. Int J Dermatol. 2017;56(10):1022–5. Yerebakan O, Ermis O, Yilmaz E, Basaran E. Treatment of arsenical keratosis and Bowen’s disease with acitretin. Int J Dermatol. 2002;41(2):84–7. Zygogianni A, Kouvaris J, Tolia M, Kyrgias G, Beli I, Kantzou I, et al. The potential role of radiation therapy in Bowen’s disease: a review of the current literature. Rev Recent Clin Trials. 2011;7(1):42–6.

Bullous Pemphigoid

11

Panagiotis G. Stavropoulos and George Larios

Key Points • Bullous pemphigoid (BP) is considered the most common autoimmune blistering disease. • The target antigens are the BP antigens with molecular weights of 230 and 180  kDa, BPAG1 and BPAG2, respectively. • The aim of treatment is to suppress the clinical signs and symptoms of BP (stopping or significantly reducing new blister formation and pruritus) in order to improve the quality of life of BP patients. • Severity, age of patient, and presence of underlying disease must be considered in determining therapeutic agents and doses.

Definition and Epidemiology Bullous pemphigoid (BP) is an acquired, nonscarring, subepidermal blistering disease, usually occurring in the elderly, but may rarely affect children and younger adults.

P. G. Stavropoulos (*) 1st Department of Dermatology, A. Syggros Hospital, University of Athens Medical School, Athens, Greece e-mail: [email protected] G. Larios (*) Department of Dermatology, Athinaiki Mediclinic, Athens, Greece

BP is considered the most common autoimmune blistering disease. Women and men are equally affected and no racial or geographical predilection is recognized. BP poses a high burden on affected patients and has significant healthcare costs. There is no known specific HLA correlation. BP has been reported in association with a variety of autoimmune diseases, including systemic lupus erythematosus, lichen planus, rheumatoid arthritis, Hashimoto’s thyroiditis, pemphigus vulgaris, psoriasis, and neurological disorders (particularly dementia and Parkinson’s disease). There have been many reports of BP associated with malignancy, although there is much controversy over this association.

Basic Concepts of Pathogenesis BP is an autoimmune skin disease and the cause of the autoantibody production remains obscure. The target antigens are the BP antigens with molecular weights of 230 and 180 kDa, BPAG1 and BPAG2, respectively. BP180 is a type II transmembrane protein that spans the lamina lucida and projects into the lamina densa of the epidermal basement membrane. Furthermore, the 230-kDa protein called BP230, which was originally identified as the major antigen of BP, is a cytoplasmic component of hemidesmosomes that belongs to the plakin family; it promotes the link-

© Springer Nature Switzerland AG 2023 A. D. Katsambas et al. (eds.), European Handbook of Dermatological Treatments, https://doi.org/10.1007/978-3-031-15130-9_11

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age of keratin intermediate filaments to hemidesmosomes. Antibody binding to BP antigen is postulated to be the initial step in blister formation. Fixation of immunoglobulin G to the basement membrane zone activates the complement cascade (mainly C3, C5a), which causes chemotaxis of leucocytes and degranulation of mast cells. Eosinophils and neutrophils are recruited by mast cell-produced factors to the basement membrane zone, where they release tissue-­ destructive enzymes (proteases) resulting in dermal-­epidermal separation. Several drugs have been associated with the onset of BP including, PD-1/PD-L1 inhibitors, inhibitors of dipeptidyl peptidase 4 (gliptins), penicillin (and penicillin derivatives), neuroleptics, furosemide, spironolactone, sulfasalazine, and captopril. Local irritation and damage of the skin have been all implicated in the induction of disease. Ultraviolet (UV) light or psoralen and UVA (photochemotherapy), and other physical agents including thermal burns, wounds skin grafts, and radiotherapy have been reported to induce BP in normal skin.

a

Clinical Presentation Urticarial or eczematous lesions are common prodromal eruptions in BP, by weeks or months. Significant pruritus is frequently present. In some cases, bullae may not become clinically apparent. Subsequently, large tense blisters arise with a base of normal or erythematous skin. (Fig. 11.1). Grouping may be present and lower abdomen, inner thighs, groin, axillae, and flexural aspects of the forearms and legs are sites of predilection for the lesions. However, localized forms of BP are not uncommon. Pemphigoid nodularis, vegetans, and dyshidrosiform represent some rare clinical variants of “classical” BP. Nikolsky’s sign is negative and mucosal lesions are usually clinically insignificant, consisting of small tense bullae in the oropharynx. The natural history of BP is that of persistent disease with eventual remission occurring within 5 years in the majority of patients. The prognosis of patients with BP is influenced by age and general health condition, but not by disease activity.

b

Fig. 11.1 (a, b) Typical clinical pictures of BP, with tense blisters, erosions, and crusts

11  Bullous Pemphigoid

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Diagnosis and Differential Diagnosis (Table 11.1)

of circulating antiantibodies are not correlated with disease activity.

• Skin biopsy for histology and direct immunofluorescence testing.

General Principles of Treatment

A subepidermal split and a mixed dermal infiltrate of numerous eosinophils, some neutrophils, and lymphocytes are found in biopsy specimens. IgG and/or C3 is deposited along the basement membrane zone in virtually all active cases of BP (direct immunofluorescence).

• The aim of treatment is to suppress the clinical signs and symptoms of BP (stopping or significantly reducing new blister formation and pruritus) in order to improve the quality of life of BP patients. • Therapy is introduced and adjusted upward as required and slowly reduced to the lowest pos• Indirect techniques. sible level while maintaining a low level of disease activity. Complete withdrawal of therNovel serological assays, such as target-­ apy is carried out if possible. antigen-­specific Enzyme-linked Immunosorbent • The severity of disease, age of patient, and Assay (ELISA) or indirect immunofluorescence presence of underlying disease (diabetes melsystems (IIF) using BIOCHIP™ mosaic technollitus, hypertension, peptic ulceration, osteopoogy, allow serologic diagnosis in most BP rosis, and malignancy) must be considered in patients and the exact classification of the disease determining therapeutic agents and doses. entity at the molecular level. However, the titles • Localized disease may initially be managed with topical very potent steroids and adjunctive measures. • Moderate (20–60 lesions) to severe (more Table 11.1  Differential diagnosis of bullous than 60 lesions) disease will usually require pemphigoid systemic corticosteroids in moderate doses Pemphigoid Rare disease of pregnancy and alone or in combination with other immunogestationis postpartum period suppressives, dapsone, or tetracyclines. Mucous Scarring autoimmune bullous • Severe therapy-resistant disease requires sysmembrane disease primarily affecting mucosal temic corticosteroids in higher doses and pemphigoid surfaces Epidermolysis Trauma-induced blisters healing immunosuppressives, cyclosporin, Bullosa acquisita with scars, different target antigen ­plasmapheresis, or γ-globulin therapy as Dermatitis Young adults, pruritic papules and adjunctive agents. herpetiformis vesicles symmetrically distributed • Immunosuppressive agents, due to their over extensor surfaces. Enteropathy (80% of cases). HLA-B8-DR3 delayed onset of action (4–8  weeks), can be Linear IgA Younger age group, linear IgA started at the same time as systemic steroids. dermatosis deposition at basement membrane Thus, corticosteroids are used to achieve inizone (direct immunofluorescence) tial control then tapered at the time when the Erythema Typical distribution of lesions, immunosuppressives are taking effect. multiforme different immunofluorescence (bullous) Bullous systemic lupus erythematosus Other disorders

findings Lesions distributed on sun-exposed areas, subepidermal blisters with neutrophils, different immunofluorescence findings Porphyria cutanea tarda, drug reactions, insect bite reaction, bullous lichen planus, etc.

Recommended Therapies (Table 11.2)  upportive Care and Adjuvant Therapy S Wound management in BP requires similar care to burns, as well as fluid resuscitation and dietary

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Table 11.2  Algorithm of recommended therapies

care. Various goals of wound care management in BP include preventing infections, enhancing regeneration of the skin, encouraging patient mobility and quality of life, and providing nutritional support for tissue repair. A bed with specialized support mattresses or cushions is useful in severe disease. The blisters caused by a widespread cutaneous and mucosal erosive disease may also require oral analgesics. First-generation antihistamines are frequently given in the initial stages of BP to reduce pruritus. When the disease becomes severe, patients should typically be admitted to a burn care unit.

Oral Care Oral care includes appropriate dental hygiene, monitoring for candidiasis, and topical anesthetics for pain. Soft, bland foods may cause less injury to mucosa when disease is worsening. Topical Therapy Topical Corticosteroids Topical corticosteroids should be considered as first-line treatment in localized or moderate BP,

and they are also extremely useful adjuvants to systemic therapy when the disease is more severe. Very potent topical corticosteroids (topical clobetasol propionate 0.05% cream twice daily) are usually required initially, with tapering to lower potency agents. However, their use in extensive disease may be associated with systemic absorption and adverse events. In the event of secondary infection, topical antibacterial agents may be applied. Topical Tacrolimus The use of topical tacrolimus is limited due to local irritation and high price compared to topical steroids. It may be used as an alternative in localized disease as it is not implicated in skin atrophy.

Systemic Corticosteroids These are the most useful drugs in the treatment of BP, rapidly inducing remission in the majority of patients. Our experience and most large series show that the majority of patients respond to 40–80 mg daily of prednisone or prednisolone and it is only rarely necessary to exceed 100 mg daily.

11  Bullous Pemphigoid

In general, doses of prednisolone 0.75– 1.0  mg/kg daily in widespread BP are effective within 1–4  weeks in about 60–90% of the patients. However, depending on the severity of the disease and patient comorbidities, the doses can be adjusted. For patients with severe involvement, doses of 0.75–1  mg/kg are recommended and lower doses of 0.5  mg/kg for moderate disease and 0.3  mg/kg for mild or localized disease, respectively. Healing of existing lesions with cessation of pruritus and new blister formation reflects a positive response to therapy. Once the disease is under control, the corticosteroid dose should be tapered slowly to m ­ inimize the steroid side effects. The duration of systemic steroid treatment is likely to be many months. Caution must be recommended in utilizing this type of therapy, in elderly patients, particularly concerning the complications of systemic corticosteroid therapy which are numerous: diabetes mellitus, hypertension, gastrointestinal bleeding, osteoporosis, and increased susceptibility to bacterial, fungal, and viral infections.

Nonsteroidal Immunosuppressive Agents Azathioprine Azathioprine is commonly used as a glucocorticoid-­sparing agent in the treatment of BP. The usual dose is 50–100  mg daily. Side effects of azathioprine include: myelosuppression, malignancy, gastrointestinal disorders, hepatotoxicity, and increased susceptibility to infections. It is important to test patients for thiopurine methyltransferase (TPMT) activity before starting treatment with this drug, in order to determine the appropriate dose and minimize the risk for myelosuppression. However, a normal TMPT level does not totally prevent myelotoxicity. The complete blood count (CBC) with differential and renal and liver function tests should be repeated weekly for 12  weeks and monthly thereafter.

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Chlorambucil Chlorambucil has been used as a corticosteroid-­ sparing agent in the treatment of BP with excellent results. However, its use is not recommended except in special cases because of concern about the induction of hematological malignancy (acute myeloid leukemia). In an open study of 26 patients with BP, treatment was started with prednisolone 40–60  mg daily and chlorambucil at approximately 0.1– 0.15 mg/kg daily. After 2 weeks, the doses of both drugs were gradually reduced; the maintenance dose of chlorambucil was usually 2  mg daily. Prednisolone was gradually withdrawn over a 4-month period and chlorambucil has been discontinued some weeks later. The mean duration of therapy and the mean total corticosteroid requirement were both lower than in other studies using corticosteroids plus azathioprine. Side effects include bone marrow suppression, which can be severe, often resulting in transient dose-related thrombocytopenia. Appropriate monitoring is with baseline and weekly CBC with differential. Hematological malignancies may be related to a cumulative dose of 1 g or more of the drug. Cyclosporin Cyclosporin cannot be recommended in the routine treatment of BP. Experience with cyclosporin is limited to five individual case reports and a small series of seven patients. It has been used in the treatment of BP at doses of 5–8 mg/kg per day as a single agent or of 5  mg/kg/day in combination with steroids. Combined therapy has a significant steroid-­ sparing effect and induces remission of BP in all patients, with monotherapy being less successful. The side effects include hypertension, nephrotoxicity, hyperlipidemia, gastrointestinal disturbances, hypertrichosis, gum hyperplasia, susceptibility to infections, and increased risk of malignancy. Mycophenolate Mofetil (MMF) MMF is an inhibitor of purine synthesis in activated T and B cells and is considered a generally well-tolerated immunosuppressive agent. It has

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been used for the prevention of allograft rejection in transplantation medicine. MMF is a well-­ tolerated and effective corticosteroid-sparing agent in autoimmune bullous disease, and several authors suggest that complete remission is achieved more frequently with the use of MMF over azathioprine, with less hepatotoxicity. It has been used successfully at doses of 0.5–1 g twice daily to control BP, either as an adjunct to oral prednisolone or as monotherapy following disease relapse. Methotrexate Methotrexate (5–15 mg/week) can be effective at controlling BP in elderly patients, either as monotherapy or in combination with topical or systemic steroids. Patients treated with methotrexate should also be given folic acid. Therapeutic Plasmapheresis Plasmapheresis is an extracorporeal technique that eliminates macromolecules involved in pathological processes from plasma. Plasmapheresis is used as an adjuvant to corticosteroids in the treatment of BP, showing a steroid-sparing effect, but the effectiveness of this treatment needs further investigation. Cyclophosphamide Published experience with cyclophosphamide is very limited. Cyclophosphamide is more toxic than other immunosuppressive drugs used for BP and should be considered only if other treatments have failed or are contraindicated. Biologic Agents In recent years, there has been an ongoing effort to identify treatments for BP which specifically modulate immunoglobulin E (IgE) autoantibody levels, inhibit downstream effects of IgE, or target the T helper 2 (Th2) inflammatory axis. Such agents include omalizumab (anti-IgE antibody) bertilimumab (anti-eotaxin-1 antibody) and mepolizumab (antibody that blocks interleukin (IL-5) and dupilumab (monoclonal antibody targeting IL-4 receptor alpha). Rituximab, originally developed for the treatment of non-Hodgkin’s lymphoma, is an anti-CD20

P. G. Stavropoulos and G. Larios

humanized monoclonal antibody leading to transitory B-cell depletion. This B-cell-depleting effect of rituximab has been exploited successfully in various autoimmune disorders, including BP.  Available data, although potentially limited because of publication bias, suggest that rituximab and omalizumab have similar safety profiles and provide clinical benefit for patients with BP.  The reviewed data indicated that rituximab resulted in lower recurrence rates and a longer time until recurrence than omalizumab. Research also suggests that anti IL-17 and IL-23 monoclonal antibodies may be also potentially effective for BP.  Only a few reported cases have been treated with tumor necrosis factor-α (anti-TNF-α) and there is conflicting evidence as to whether these agents treat or induce BP. Until further supportive evidence is available, their role in BP remains limited. Tetracyclines/Niacinamide Tetracyclines and niacinamide (nicotinamide) have been utilized for the treatment of BP in adults, usually in combination with topical corticosteroids. Niacinamide has been used at doses of 500–1000  mg daily and gradually tapered down. Tetracycline has been used at doses of 500–2000 mg daily, doxycycline at 100–200 mg daily. Side effects included gastrointestinal symptoms (epigastric discomfort and nausea), photosensitivity, headache, and benign intracranial hypertension. Dapsone and Sulfonamides BP may respond well to dapsone or the sulfonamides (sulfapyridine and sulfamethoxypyridazine) either alone or in combination with other agents. Dapsone is usually started at 25 or 50 mg daily and increased to 100 mg daily after 5–7 days as tolerated. The response is rapid, within 2  weeks. Dapsone may be used in combination with topical steroids or may be added (150– 300  mg daily) to prednisolone or azathioprine therapy, achieving adequate control of disease activity and permitting a reduction in the steroid dose. Although these are not drugs of first choice for BP, they may be useful in the management of

11  Bullous Pemphigoid

patients in whom corticosteroids are contraindicated or not tolerated. Side effects include dose-related hemolysis and methemoglobinemia, agranulocytosis, cutaneous hypersensitivity reactions, peripheral neuropathy, hepatic damage, and renal failure. Glucose-6-phosphate dehydrogenase deficiency must be excluded prior to beginning therapy. A CBC with differential should be obtained at baseline and once weekly for 4 weeks, then every 2 weeks for 2 months, and every three to 4 months thereafter. Liver and renal function tests should also be obtained at least at baseline and every 3 months.

 hildhood Bullous Pemphigoid C Due to its rarity and benign nature, preference should be given to low-toxicity treatments (e.g., erythromycin) and topical steroids.

Further Reading Persson MSM, et  al. Incidence, prevalence and mortality of bullous pemphigoid in England 1998-2017: a population-based cohort study. Br J Dermatol. 2021;184:68–77. https://doi.org/10.1111/bjd.19022. Epub 2020 Apr 27. Silverii GA, et  al. Bullous pemphigoid and dipeptidyl peptidase-4 inhibitors: a meta-analysis of randomized controlled trials. Endocrine. 2020;69:504–7. https:// doi.org/10.1007/s12020-­020-­02272-­x. Epub 2020 Mar 31.

129 Hammers CM, Stanley JR.  Recent advances in understanding pemphigus and bullous pemphigoid. J Invest Dermatol. 2020;140:733–41. https://doi. org/10.1016/j.jid.2019.11.005. Verheyden MJ, Bilgic A, Murrell DF.  A systematic review of drug-induced pemphigoid. Acta Derm Venereol. 2020;100:adv00224. https://doi. org/10.2340/00015555-­3457. Ben-Shoshan D, et  al. The future of bullous pemphigoid (BP): new and promising drugs may revolutionize treatment course for BP patients. J Cutan Med Surg. 2020;24:191–2. https://doi. org/10.1177/1203475419888867. PMID: 32208024. Geller S.  Interleukin 4 and interleukin 13 inhibition: a promising therapeutic approach in bullous pemphigoid. J Am Acad Dermatol. 2020;83:37–8. https://doi. org/10.1016/j.jaad.2020.03.017. Du-Thanh A, et  al. Combined treatment with low-dose methotrexate and initial short-term superpotent topical steroids in bullous pemphigoid: an open, multicentre, retrospective study. Br J Dermatol. 2011;165:1337–43. Hideyuki U, et al. What’s new in bullous pemphigoid. J Dermatol. 2010;37:194–204. Orvis AK, et al. Mycophenolate mofetil in dermatology. J Am Acad Dermatol. 2009;60(2):183–99. Neff A, et al. Treatment strategies in mucous membrane pemphigoid. Ther Clin Risk Manag. 2008;4:617–26. Schmidt E, et al. Serum levels of autoantibodies to BP 180 correlates with disease activity in patients with bullous pemphigoid. Arch Dermatol. 2000;136:174–8. Tee S, et  al. Prevention of glucocorticoidinduced osteoporosis in immunobullous diseases with alendronate: a randomized, double-blind, placebocontrolled study. Arch Dermatol. 2012;148:307–14. Venning VA, et al. British Association of Dermatologists’ guidelines for the management of bullous pemphigoid 2012. Br J Dermatol. 2012;167:1200–14. Yancey KB, Egan CA.  Pemphigoid. Clinical, histology, immunopathology, and therapeutic considerations. JAMA. 2000;284(3):350–6.

12

Candidiasis Dimitris Rigopoulos

Key Points • Candidiasis refers to infections caused by Candida species. • The most common encountered infections include oral candidiasis, superficial cutaneous candidiasis, candida balanitis, vaginal candidiasis, candida paronychia, candida onychomycosis and chronic mucocutaneous candidiasis. • Therapy should always include removal of underlying predisposing factors with encouragement for dental and mouth hygiene, keeping dry skin folds, avoidance of detergents that flare up chronic paronychia and reduction of the Candida reservoir in the mouth and gut. • Topical agents used in the treatment of candidiasis include amphotericin B, nystatin, natamycin, miconazole, ketoconazole, econazole, omoconazole, tioconazole and clotrimazole. • Systemic agents used include itraconazole and fluconazole.

Definition and Epidemiology The term candidiasis refers to infections caused mainly by the classic opportunistic pathogen Candida albicans or occasionally by other speD. Rigopoulos (*) 1st Department of Dermatology, Andreas Sygros Hospital, University of Athens Medical School, Athens, Greece

cies of Candida, such as C. tropicalis, C. guilliermondii, C. parapsilosis, C. krusei, C. stellatoidea, C. pseudotropicalis and C. glabrata. These various yeast species differ in their potential to invade and colonize epithelial and epidermal sites, C. albicans being the species with the greatest such potential. Infections of the skin, nails and mucous membranes are the most often encountered candida infections.

Basic Concepts of Pathogenesis C. albicans, which is part of the normal human flora, is a dimorphic organism, developing in different morphological forms, such as yeasts, hyphae and pseudohyphae. This development is dependent on local conditions. Different predisposing factors exist, which lead to different types of candidiasis. Immunosuppression or leukopenia usually leads to systemic candidiasis, which is rare; endocrinopathies (hypoparathyroidism, hypothyroidism, diabetes mellitus), iron or zinc deficiencies and inherited defects of immunity lead to chronic mucocutaneous candidiasis, which is also rare; and diabetes, pregnancy, antibiotic therapy, high humidity, immersion in water and oral contraceptive drugs lead to localized cutaneous candidiasis, which is the commonest type of disease. These predisposing factors are extremely important in the management of candidiasis patients, since the reversal of these factors

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is of great significance and part of the treatment protocol.

Clinical Presentation Oral Candidiasis This disease is most commonly seen in infants and the elderly (associated with denture plates). The lesions may be situated on the mucosal surfaces of the tongue or at the corner of the mouth. One or more whitish, sharply defined, adherent plaques are the characteristic signs of the condition. If these plaques are wiped off, an underlying erythematous base is seen. Erosions or ulcerations are occasional complications. In some cases, patients present with erythema, soreness, marked pain, atrophic mucous membranes and lack of whitish plaques (acute atrophic oral candidiasis). Hyperplastic plaques on the cheek or the tongue that are not easily removed and develop especially in men who are smokers and over the age of 30 constitute a condition known as candida leukoplakia (chronic hyperplastic candidiasis). Median rhomboid glossitis is another condition associated with candidiasis and presents with erythema of the tongue surface in the absence of papillae, pain and tenderness. Chronic atrophic candidiasis (denture stomatitis) affects nearly 25% of all denture wearers and sometimes children with orthodontic appliances. The condition is characterized by bright red of dusky erythema of the palate and gums, with atrophy of the epithelium and sometimes oedema. Angular cheilitis (perleche) occurs at the corner of the mouth and it is not always associated with Candida. The area is moist, red and fissured, and the symptoms include pain.

 uperficial Cutaneous Candidiasis S (Candidal Intertrigo) Any occluded skinfold, especially in hot and humid weather, may become moist and macer-

ated, favouring the development of candidiasis. Erythema and moist exudation deep in the fold are the characteristic symptoms at the beginning. Erythema with well-defined borders though not razor sharp as in tinea cruris, subcorneal pustule, satellite pustular or papular lesions, itching and soreness make up the typical clinical pictures as the condition progresses.

Candida Balanitis Although candida balanitis (which is seen mostly in uncircumcised men) is usually acquired form a sexual partner with vulvovaginitis, the possible oral and anal origins of the disease should not be forgotten. In mild cases, erythema and tiny papules predominate and are seen after intercourse; in more severe cases, the entire glans can be involved, and soreness may prevent sexual intercourse as it becomes painful.

Vaginal Candidiasis It has been estimated that 75% of all adult women will suffer from vaginal candidiasis at some time during their lives. There are two types of the disease, the occasional and the recurrent. In the case of occasional vaginal candidiasis, C. albicans is the commonest causative yeast, accounting for over 80% of isolates. The predisposing factors are antibiotics (which alter the normal vaginal flora), peak production of oestrogen before menstruation or use of high-oestrogen contraceptives (increase of glycogen, a nutrient source of C. albicans), pregnancy (increased levels of circulating oestrogen and progesterone raise the glycogen content of vaginal epithelial cells), immunosuppressive drugs of disease, increased sugar levels of the urine and vaginal secretions and synthetic or tight-fitting clothes (they create a warm and moist environment). The condition presents with itching, soreness, erythema and a thick, creamy-white discharge. Vaginal candidiasis is recurrent in 10–20% of patients, and the male partner may play a part in reinfection (50% of male partners carry the same strain of Candida

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on the penis or in the mouth). Symptoms are the same as in occasional vulvovaginitis, and only in chronic cases does the vaginal mucosa become glazed and atrophic.

Candida Paronychia This is a chronic condition found mainly in those who frequently immerse their hands in water (housewives, chefs, etc.) The nail fold is red and swollen, thick white pus may be discharged and the patient complains of pain. Nail dystrophy, with onycholysis and nail plate discoloration, is also found.

Candida Onychomycosis C. albicans infection of the nail may be seen secondary to chronic paronychia or onycholysis. The nail plate is opaque, brownish-green in colour and altered in shape. There may be nail plate changes secondary to the inflammation of the nail fold.

Chronic Mucocutaneous Candidiasis This is an immunodeficiency disease, which is characterized by persistent candidiasis of mucous membranes, skin and nails. The infection may vary from mild, localized, persistent lesions to a severe, generalized condition. The disease usually starts in infancy and is often associated with endocrinopathy (mainly Addison’s disease and hypoparathyroidism). A few late-onset cases are associated with thymic tumours; candida granulomas may appear on the scalp and face.

Direct Microscopy Skin scrapings are examined microscopically for yeasts, pseudohyphae or hyphae, after the addition of 10% KOH solution to the slide preparation.

Culture Swabs from suspected areas are cultured on Sabouraud’s agar. C. albicans is a fast grower; colonies mature in 1–3 days (with the exception of nail-clipping cultures, which must be kept for at least 7 days). Other candida species may require longer time to mature.

Differential Diagnosis Leukoplakia

Does not clear with prolonged anti-Candida therapy Flexural psoriasis Histology, microbiology Bacterial intertrigo Microbiology Tinea Microbiology, sharp edges Seborrhoeic dermatitis Microbiology Hailey-Hailey disease Histology Flexural Darier’s Histology disease Trichomonas vaginitis Watery brown discharge, microbiology Contact dermatitis of Microbiology, history vagina Herpes simplex of the Anti-HSV antibodies positive penis (1gM), history Psoriasis of the penis Chronic psoriasis plaques in other body areas Erythroplasia Chronic, persistent more dusky colour Napkin dermatitis The skin deep in the fold is free of symptoms Bacterial paronychia Microbiology, acute onset

Diagnosis

General Principles of Treatment

Diagnosis is based on the clinical examination and the history and is usually confirmed by laboratory examination (direct microscopy and culture).

• Removal of underlying predisposing factors. • Denture hygiene and frequent mouth toilet plus abstention form smoking will help those suffering from oral candidiasis.

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• Infected skinfolds should be kept dry and if possible separated. • Patients with chronic paronychia should keep their hands warm and dry. • In most cases of candida infection, topical treatment alone is sufficient. • Consideration should always be given to reduction of the Candida reservoir in the mouth and gut.

Recommended Therapies (a) Topical therapeutic agents (b) Systemic therapeutic agents (c) Treatment of clinical forms Antifungal drugs belonging to the polyene and azole families are the ones used in the treatment of Candida infections. A morpholine antifungal agent, amorolfine, is also active.

Topical Therapeutic Agents These drugs are used in the forms of creams, solutions, suspensions, vaginal suppositories, lacquers, shampoos and powders. The members of the polyene family used are topical amphotericin B, nystatin and natamycin, while the azole family provides the imidazole derivatives miconazole, ketoconazole, econazole, omoconazole, tioconazole and clotrimazole for use in these conditions. Amorolfine is also used in the form of cream of nail lacquer. The use of topical preparations is effective in the majority of Candida infections, but their use is restricted by the extent of the area involved. Factors that should be considered when choosing topical agents include the lack of side effects of these drugs, when administered topically; the minimal development of resistance, except in the case of nystatin; and their lack of interaction with other classes of drugs. The topical formulations (except amorolfine nail lacquer) should be used one to three times daily, and their application should continue at least for 1 week after clinical resolution of the

D. Rigopoulos

disease, to allow reconstitution of the stratum corneum. The type of formulation selected for treatment depends on the site and the symptoms of the disease (for dry lesions, lotions of creams are preferable, for wet lesions powders, for oral lesions suspensions, for vaginal lesions pessaries and for nail lesions lacquers). Topical Treatment at a Glance • The use of topical preparations is effective in the majority of Candida infections, but their use is restricted by the extent of the area involved. • Use lotions or creams for dry lesions, powders for wet lesions, suspensions for oral lesions, pessaries for vaginal lesions and lacquers for nail lesions. • The main treatment agents for oral candidiasis are topical nystatin suspension and miconazole oral gel. • Amorolfine and ciclopirox nail lacquers for 12 months are the main treatment for mild nail candidiasis.

 ystemic Antifungal Agents S For systemic candidiasis or extensive skin disease, in immunosuppressed patients and when there are frequent relapses after topical treatment of high patient compliance is needed, the triazoles i traconazole and fluconazole and the imidazole ketoconazole are used for systemic treatment. The major disadvantages of these drugs are the potential toxicity (ketoconazole) and the development of both clinical and microbiologically proved resistance (fluconazole). Another serious disadvantage of these antifungals is their interaction with other drugs. The chief side effects of ketoconazole are nausea, pruritus, transient elevations in liver enzymes and significant liver toxicity, which can lead to death. The incidence of adverse events is higher during long-term itraconazole therapy (16.2%) than during short-term administration (7.0%). The side effects observed with itraconazole are not severe and mainly take the form of gastrointesti-

12 Candidiasis

nal disturbances (nausea, epigastralgia and diarrhoea). The most frequent side effects of fluconazole are gastrointestinal symptoms and rash. Use of the azoles is not recommended in pregnancy. Azole resistance is substantial problem. It is found in AIDS patients, in intensive care units and in leukaemia patients. It is manifested in two ways. The first is replacement of susceptible Candida isolates with resistant Candida spp., such as C. glabrata and C. krusei. The second is in situ development of resistance in a certain isolate. The problem of the resistance is focused chiefly on fluconazole, although cross-resistance to the other azoles in common. Some of the drugs with which ketoconazole interacts are agents decreasing gastric acidity: rifampicin, acyclovir, coumarins, cyclosporin, phenytoin, terfenadine and astemizole. Fluconazole is reported to interact with amphotericin B, coumarins, cyclosporin, phenytoin, oestradiol, cimetidine, astemizole, terfenadine, sulfonyl ureas, thiazides, etc. Itraconazole interacts mainly with cyclosporin, food, digoxin, phenytoin, rifampicin, H2 antagonists, terfenadine and astemizole. Systemic Treatment at a Glance • Itraconazole or fluconazole should be used for systemic candidiasis or extensive skin disease. • Fluconazole 50–100 mg daily for 1 week, or itraconazole 100 mg daily for 1–3 weeks are effective in persistent oral candidiasis. • Recurrent vulvovaginitis is treated with a single dose of 150 mg fluconazole, given on day 21 of each menstrual cycle or clotrimazole as a 500  mg vaginal pessary once a week for 6–12 months.

Treatment of Clinical Forms Oral Candidiasis and Perleche The main treatment agents are topical nystatin suspension and miconazole oral gel. For more persistent disease, oral antifungals are used: ketoconazole 200  mg daily for 1–2 weeks, flucon-

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azole 50–100 mg daily for 1 week or itraconazole 100  mg daily for 1–3 weeks. Fluconazole is reported to be effective with a single 150  mg dose. Perleche is treated with topical antifungal creams. Cutaneous Candidiasis Topical antifungal preparations are used, with excellent results. For widespread disease, oral antifungal drugs are used: itraconazole 200  mg daily for 1 week or fluconazole 50–100  mg for 1–3 weeks. A dose of 150 mg fluconazole once a week for 2 weeks has also proven to be very effective in the treatment of cutaneous candidiasis. Candida Balanitis Topical treatment has proven sufficient in treating this condition. Fluconazole in a single 150  mg dose is effective in more resistant cases Vaginal Candidiasis Topical treatment generally results in a good mycotic and clinical cure rate. Owing to common relapses and complaints from patients that intravaginal products are messy and often leak, oral treatment is prescribed. Cases of occasional vulvovaginitis are treated with fluconazole orally in a single dose of 150 mg, ketoconazole 200 mg daily for 5 days or itraconazole 400 mg in a single dose. Recurrent vulvovaginitis is treated with a single dose of 150  mg fluconazole, given on day 21 of each menstrual cycle for 6–12 months. Clotrimazole as a 500 mg vaginal pessary once a week has proven efficient in suppressing relapses of recurrent vaginitis. Candida Paronychia This condition requires prolonged topical treatment. The hands should be kept warm and dry. Candida Onychomycosis Topical treatment with the ordinary polyene or azole antifungal drugs is not effective, as these drugs are not absorbed from the nail plate. For mild candida onychomycosis of the hands involving not more than 60% of the entire nail plate,

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amorolfine nail lacquer is used once a week for 6 months. For more severe onychomycosis of the hands, itraconazole is used in a pulsed regimen of 400 mg daily for 1 week. This scheme is repeated for 3 months. For mild onychomycosis of the feet, amorolfine nail lacquer is used once weekly for 12 months and for more severe cases itraconazole pulse therapy with 400 mg daily for 1 week. This scheme is repeated for 4 months. Fluconazole is used in a dose of 150  mg weekly for 6 months for hand onychomycosis and for up to 9 months for foot onychomycosis. Chronic Mucocutaneous Candidiasis A combination of antifungal drugs and immunological reconstruction is needed in the treatment strategy for this condition. A restoration of T-cell function is attempted by using transfer factor of thymosin or by grafting compatible lymphocytes from blood or marrow or foetal thymic tissue. The antifungal drugs most commonly used are ketoconazole, fluconazole and itraconazole, which are used for some years. The main problems encountered with the use of these drugs are the growing problems of infection with Candida that has become resistant and hepatotoxicity with long-term use of ketoconazole.

Further Reading Bassi P, Kaur G.  Innovations in bioadhesive vaginal drug delivery system. Expert Opin Ther Pat. 2012;22:1019–32. Delsing CE, Bleeker-Rovers CP, Kullberg BJ, Netea MG.  Treatment of candidiasis: insights from host genetics. Exp Rev Anti Infect Ther. 2012;10: 947–56. Hay P.  Recurrent bacterial vaginosis. Curr Opin Infect Dis. 2009;22(1):82–6. Ng TB, Cheung RC, Ye X, Fang EF, Chan YS, Pan WL, Dan XL, Yin CM, Lam SK, Lin P, Ngai PH, Xia LX, Liu F, Ye XY, Wang HX, Wong JH. Pharmacotherapy approaches to antifungal prophylaxis. Expert Opin Pharmacother. 2012;13:1695–705. Rhodus NL.  Treatment of oral candidiasis. Northwest Dent. 2012;91:32–3. Rotta I, Otuki MF, Sanches AC, Correr CJ.  Efficacy of topical antifungal drugs in different dermatomycoses: a systematic review with meta-analysis. Rev Assoc Med Bras. 2012;58:308–18. Sardi JC, Scorzoni L, Bernardi T, Fusco-Almeida AM, Mendes Giannini MJ.  Candida species: current epidemiology, pathogenicity, biofilm formation, natural antifungal products and new therapeutic options. J Med Microbiol. 2013;62:10–24. Singal A, Khanna D.  Onychomycosis: diagnosis and management. Indian J Dermatol Venereol Leprol. 2011;77:659–72. Tripathi N, Watt K, Benjamin DK Jr. Treatment and prophylaxis of invasive candidiasis. Semin Perinatol. 2012;36:416–23.

Cheilitis and Oral Disease

13

Eleni Gagari

Key Points • Cheilitis presents with a variety of pathogenetic mechanisms and etiologies. Proper diagnosis is essential for effective treatment. • Combination of different types of cheilitis may be present in the same patient making this disease entity a therapeutic problem. • Biopsy is necessary in actinic cheilitis, cheilitis glandularis, and cheilitis granulomatosa. • Association of cheilitis with oral and systemic disease entails a different therapeutic approach than local disease and needs to be evaluated carefully. • Moisturizing agents are necessary for optimal effect of topical treatment modalities. • Choice of topical vs. systemic treatment depends on the type of cheilitis and the severity of the lesions.

Definition and Epidemiology Cheilitis is etymologically a term of Greek origin and indicates a nonspecific inflammation of the lips. It is therefore essential to qualify this term

with specific descriptors in order to provide diagnostic definitions, namely: • Angular cheilitis: Bilateral inflammation of the commissures of the lips of multifactorial etiology, presenting with redness, scaling, and erosions limited to the corner of the lips. • Allergic contact cheilitis: Redness, crusting, and superficial ulceration of the vermillion of the lips often associated with perioral dermatitis, caused by contact hypersensitivity to a variety of topical agents. • Exfoliative cheilitis: Increased production of keratin of the vermillion of the lips and persistent subsequent desquamation resulting in scaling and flaking appearance. Most frequently caused by habitual lip licking and self-caused injury (factitial cheilitis). • Actinic cheilitis: Mottled discoloration, scaling, and focal ulceration of the lower lip vermillion border, representing premalignant or malignant change (in later stages) caused by sun damage. • Cheilitis glandularis: Inflammation of the minor salivary glands of the lower lip causing suppuration and ulceration of the lower lip. A significant percentage (18–35%) is associated

E. Gagari (*) Department of Dermatology, First University Clinic of Dermatology, A. Syggros Hospital for Dermatologic and Venereal Diseases, University of Athens School of Medicine, Athens, Greece © Springer Nature Switzerland AG 2023 A. D. Katsambas et al. (eds.), European Handbook of Dermatological Treatments, https://doi.org/10.1007/978-3-031-15130-9_13

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with development of squamous cell carcinoma of the lower lip. • Cheilitis granulomatosa: Pronounced swelling of the lips caused by submucosal or subcutaneous granulomata. The condition may arise in the context of orofacial granulomatosis or as a clinical manifestation of granulomatous diseases (more frequently Crohn’s disease or sarcoidosis).

Basic Concepts of Pathogenesis The vermillion border of the lips represents a very finely constructed meeting point of skin and oral mucosa. The major pathogenetic m ­ echanisms involved can be separated into the following broad categories: • Reaction to mechanical or environmental stimuli or compromised anatomy (reduced vertical dimension due to lack of teeth and aging of the skin). • Allergy to local antigenic challenge (contact hypersensitivity) or part of a generalized allergic reaction that affects the orofacial structures. • Candidal and/or bacterial infection. • Systemic disease such as Crohn’s disease, sarcoidosis, tuberculosis, chronic granulomatous disease, and leprosy. Indirectly, anemia, iron deficiency, and diabetes may predispose to a candidal infection of the lips. • Idiopathic when there are granulomata present in the lips, but there is absence of any systemic disease that can account for them. Orofacial granulomatosis is a “blanket” term currently used to encompass entities such as cheilitis granulomatosa of Miescher and Melkersson-­ Rosenthal syndrome. Often, cheilitis may present with a composite of pathogenetic mechanisms. For example, angular cheilitis or exfoliative cheilitis may develop in the presence of cheilitis granulomatosa due to the altered anatomy of the swollen lips.

Clinical Presentation Angular Cheilitis The location of the lesions at the corners of the lips is characteristic. The lesions are red, occasionally speckled with white detachable plaques of candidal infection and may also have mildly erosive areas (Fig. 13.1). Several factors contribute to this clinical appearance and should be methodically evaluated. The loss of vertical dimension due to edentulous alveolar ridges or ill-fitting dentures, as well as slacking/wrinkling of the skin due to aging, creates a compromised anatomy of the area that allows pooling of saliva. This favors the development of a yeast infection that is combined with a bacterial infection. Microbiologic studies have indicated that 20% of these lesions represent C. albicans, 20% bacterial infection with S. aureus, and 60% of these lesions represent a mixed infection of the two. It is important to examine the oral cavity for presence of oral candidiasis and to rule out anemia, diabetes, immunosuppression, and B12 or iron deficiency as predisposing factors. Presence or absence of mucosal erythema, atrophic glossitis, or pseudomembranous/atrophic oral candidiasis should be carefully evaluated. Due to a feeling of irritation, the patient may engage in lip licking causing a secondary presentation of exfoliative cheilitis.

Fig. 13.1  Angular cheilitis

13  Cheilitis and Oral Disease

Allergic Contact Cheilitis Both lips appear red, crusted, fissured, and bleeding on occasion (Fig. 13.2). There is often perioral erythema and dermatitis. The sudden appearance and association with a cosmetic or topical agent being applied is important for the diagnosis. Occasionally, the local allergen is mild and may be more difficult to discover. A careful and thorough history of habits involving the area needs to be obtained. Usually there is no presence of oral disease, with the exception of oral food allergen syndrome where the lip manifestations are part of anaphylactic stomatitis (redness

Fig. 13.2  Allergic contact cheilitis to propolis

a

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and discomfort) in those parts of oral mucosa that come into contact with food the most during mastication (buccal mucosa, lips, tip of the tongue).

Exfoliative Cheilitis Scaling, cracking, and peeling of the vermillion borders of the lips are noted. Thick, yellowish hyperkeratotic crusts that may leave extensive fissuring or a hemorrhagic surface behind may also develop as the condition worsens (Fig. 13.3a, b). Perioral skin may become involved and exhibit the same features. It is prevalent in people younger than 30 years of age with a predilection for females. The exact cause is unknown, but it is thought chronic irritation of the area, such as lip licking and mouth breathing, is involved. There appears to exist a relationship with psychiatric disorders, atopy, and photosensitivity, although it has not been well-substantiated. A chronic form of candidiasis such as is encountered in immunosuppressed patients may also contribute to the clinical appearance. Exfoliative cheilitis is a common side effect of chronic isotretinoin use and appears to be linked to excessive dryness of the lips caused by the medication.

b

Fig. 13.3 (a) Exfoliative cheilitis. (b) Exfoliative cheilitis after topical tacrolimus 0.1% treatment

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Actinic Cheilitis Most common on the lower vermillion of the lip, actinic cheilitis represents a premalignant condition caused by chronic sun damage. The lack of homogeneity of color and the appearance of uneven scaly patches or focal ulceration are characteristic (Fig. 13.4). A biopsy is often indicated to rule out development of squamous cell carcinoma.

Cheilitis Glandularis The orifices of minor salivary gland ducts of the lower lip give rise to suppurating fistulae that can be probed using a dental probe (Fig. 13.5). The etiology of this inflammatory condition is unknown, but it is most common in middle aged or older men. A biopsy may be indicated due to the association with squamous cell carcinoma.

and other parts of the oral mucosa, such as buccal mucosa, palate, gingival, and mucobuccal fold, exists in the absence of systemic disease. There is a “cobblestone” appearance of the oral mucosa accompanied by erosions or focal ulcerations. The lips may be the only part affected, and this represents Miescher’s cheilitis. Concomitant presence of facial nerve paralysis and fissured tongue constitutes MelkerssonRosenthal syndrome. Cheilitis granulomatosa may represent a clinical manifestation of Crohn’s disease, especially in young male adults, and should be ruled out by colonoscopy. Other granulomatous diseases such as sarcoidosis and tuberculosis should also be ruled out with appropriate testing.

Cheilitis Granulomatosa Swelling, fissuring, and deformation of the upper lip are most common (Fig. 13.6), although swelling may also be present in the lower lip. Biopsy is needed to establish the presence of granulomata. This form of cheilitis may be part of a disease entity called “orofacial granulomatosis” in which granulomatous inflammation of the lips

Fig. 13.4  Actinic cheilitis

Fig. 13.5  Cheilitis glandularis

Fig. 13.6  Cheilitis granulomatosa

13  Cheilitis and Oral Disease

Differential Diagnosis Appropriate diagnostic workup and accurate diagnosis of the type of cheilitis present are essential in implementing the correct treatment. Step 1: Careful evaluation of clinical appearance of the lip lesions. Some clinical features are “hallmarks” of specific types of cheilitis: • Lesions confined to the commissures of the lips: angular cheilitis. • Presence of extensive swelling on one or both of the lips: cheilitis granulomatosa or allergic contact cheilitis. • Peeling, fissuring, and thick crusting of the lips: exfoliative cheilitis. • Suppuration of lower lip: cheilitis glandularis. • Discoloration and loss of distinct color margins of the vermillion of the lower lip: actinic cheilitis. Step 2: Evaluation of oral mucosa and perioral skin: • Erythematous oral mucosa, presence of red and white detachable lesions, atrophic glossitis, and point to oral candidiasis more often associated with angular cheilitis. • Erythematous patches of oral mucosa, “cobblestone mucosa,” and presence of erosions suggest orofacial granulomatosis and mandate diagnostic exclusion of Crohn’s disease. • Perioral redness and scaling: associated most often with exfoliative cheilitis and point to excessive lip licking. Step 3: Evaluation of medical history for medication and allergies: • Report of contact challenge with local factors such as lipstick, balms, or ointments and history of oral food allergy syndrome: allergic contact cheilitis. • Medical history of food allergies, atopy: cheilitis granulomatosa.

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• Use of isotretinoin for acne: exfoliative cheilitis. Step 4: Exclusion of underlying systemic disease: • If the clinical diagnosis is angular cheilitis, blood test evaluation for anemia, diabetes, and immunocompromised status may be required, especially if the condition recurs often. • If the clinical diagnosis is cheilitis granulomatosa, biopsy, colonoscopy, chest X-ray, SACE levels, and Mantoux are indicated along with detailed blood tests, in order to rule out Crohn’s disease, sarcoidosis, and tuberculosis. • If the clinical impression is swelling of the lips, angioedema must be ruled out with biopsy of the lip lesions.

General Principles of Treatment Cheilitis is a challenging treatment problem. Accurate diagnosis is the most important determining factor in obtaining optimal treatment outcome. The guidelines for successful treatment revolve around maintaining optimal anatomy and hydration of the vermillion border of the lips, reducing inflammation, treating local opportunistic infections, and managing underlying systemic disease. Depending on the etiology and pathogenesis of cheilitis, a wide variety of therapeutic agents have been used: • Moisturizing agents that create a “barrier” on the vermillion of the lips in order to avoid the detrimental effect of saliva. • Topical corticosteroids. • Intralesional corticosteroids. • Systemic corticosteroids. • Antibiotics. • Calcineurin inhibitors. • Immunomodulatory agents. • Monoclonal antibodies.

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It is essential to note that in those cases where cheilitis is a clinical manifestation of systemic disease, successful treatment of the underlying disease is required in order to achieve complete resolution of the lip lesions.

Topical Treatments Τopical Corticosteroids Τopical corticosteroids have been used widely for the treatment of cheilitis. The most popular formulations are cream and ointment formulations of hydrocortisone, fluticasone propionate, betamethasone, and clobetasol propionate in varying concentrations (0.05–0.1%) twice daily. They should be used along with moisturizing agents, especially where cream formulations are concerned as there is a drying effect on the lips that may worsen scaling and peeling. The use of topical steroids entails the risk of exacerbating a candidal or bacterial infection if used alone, especially in angular cheilitis. These formulations are not effective alone, but when used along with another immunomodulatory agent, they may improve allergic contact cheilitis, exfoliative cheilitis, and very mild cases of cheilitis granulomatosa. Complete resolution of cheilitis on the basis of single-agent topical steroid use can only be observed in very mild cases of cheilitis.

Topical Antibiotics Τopical antimicrobial agents and antibiotics, when used as a single-agent treatment, are not successful in cheilitis treatment. Neomycin and mupirocin ointments have been used, but they often worsen the condition because they cause dryness and they create an imbalance in microbial flora that predisposes to candidiasis. The bacterial component plays only a limited role in the etiology of cheilitis, and therefore topical antibiotic treatment is only relevant in cases of angular cheilitis.

Combination Topical Treatment The combination of topical antifungal, corticosteroid, and antimicrobial treatment is effective in cases of angular cheilitis. Triamcinolone acetonide 1 mg/g nystatin 100,000 units/g, neomycin 2.5 mg/g, and gramicidin 0.25 mg/g may be used twice daily for 7–10 days with good results. Triamcinolone counteracts the drying effects of neomycin and gramicidin, while nystatin controls the yeast infection that could worsen from the combined use of corticosteroid and antibacterial agents. Bacterial resistance is a potential caveat. Combination topical treatment is not useful in other forms of cheilitis.

Calcineurin Inhibitors Tacrolimus ointment (0.03% and 0.1%) and pimecrolimus ointment 1% have been used with considerable success in the treatment of exfoliative cheilitis at a regimen of twice daily for 7–10 days and with partial success as an adjunct to the treatment of cheilitis granulomatosa. Calcineurin inhibitor action is unknown, but thought to inhibit T-lymphocyte activation. Due to the “black box” warning of skin cancer or lymphoma, long-term use is not recommended. However, exfoliative cheilitis responds well with a short course, and the medication is well tolerated (Fig. 13.3b). The more serious side effects of HSV or HVZ infection are not encountered. Occasional burning sensation is the most common side effect observed in the above treatment regimen.

Intralesional Injections of Corticosteroids Triamcinolone acetonide 40  mg/mL has been used for intralesional injections in cases of cheilitis granulomatosa. The regimen is usually two to three injections every 14–21  days depending on the severity of the lesions and the response

13  Cheilitis and Oral Disease

after the first cycle. In a number of cases, intralesional injections require additional systemic immunomodulatory medication use to maintain a long remission. The regimen provides a systemic steroid-sparing effect to young patients. The most common side effect is local scarring or atrophy which is not often encountered. They are not used in any other form of cheilitis.

Systemic Treatments Antibiotics Systemic antibiotic treatment has been used in the treatment of cheilitis granulomatosa. Minocycline 100  mg/day, roxithromycin (an erythromycin derivative) (150–300 mg/day), and metronidazole 750–1000  mg/day have all been used in conjunction with systemic or intralesional corticosteroid treatment of cheilitis granulomatosa. The benefit from the use of these antibiotics lies in their anti-inflammatory not in their antibacterial properties. A significant drawback is that the protracted use of these agents (needed to achieve remission) may cause antibiotic resistance. Broad-spectrum antibiotics may also be prescribed if suppuration is present in cheilitis glandularis or if there is resistance to topical antibacterial agents in angular cheilitis.

Corticosteroids Systemic administration of prednisolone is often used in cheilitis treatment to reduce inflammation or the immune response (granulomata). In the literature, the dosage reported varies from 20 to 50 mg/day, although in the vast majority of cases, dosages no higher than 30 mg/day are enough to achieve satisfactory treatment outcome. Prednisolone is often administered together with an antibiotic for the treatment of cheilitis granulomatosa, or with an antifungal, systemic, or topical for angular cheilitis. Usually the duration of administration is not long enough to cause sig-

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nificant side effects, although caution should be exercised in young and in immunocompromised patients. Careful monitoring of development and endocrinological evaluation should be performed in patients 45 years of age at the time of diagnosis. Serologic markers for malignancy-associated DM are either antietranscription intermediary factor 1 or antienuclear matrix protein 2 antibodies. The estimated incidence of cancer in DM ranges from 7–30% in adults (Madan et  al. 2009), with most studies clustered around 15–20% (Kundrick et al. 2019). The highest risk of tumor recognition is in the first year after diagnosis (Leatham et  al. 2018; Zidane et al. 2020); nevertheless, it remains significant even up to 3–5 years thereafter (Aggarwal and Oddis 2011). The risk of cancer and ILD is also present among patients with purely cutaneous findings. Prevalence of specific cancer types depends on population. The most common associated cancers in Caucasians are ovary, breast, and lung cancer, melanoma, mycosis fungoides,

and lymphoproliferative malignancies, whereas nasopharyngeal cancer is the predominant cancer associated with DM in Asians.

Muscle Disease The muscular activity deficiency is characterized by the weakness and possible tenderness of the proximal muscles, leading to muscle wasting in chronic cases. An elevation in the serum level of CK is the most sensitive and specific laboratory indicator of muscle disease activity in DM.

The Course of DM The course shows significant variations. High level of Mi2 antibody can be associated with a chronic disease with milder skin and muscle symptoms. In rare case associated with anti-­ tRNA synthetase antibodies, the pathology affects pulmonary functionality (interstitial lung disease—ILD), and the symptoms are clearly visible. In chronic cases after the regression of cutaneous and inflammatory muscle changes, subcutaneous lipoatrophy, atrophy of muscles, and calcinosis are identifiable. The reported mortality rates vary from 25% to 80%. In the past two decades, the mortality rate has decreased considerably because of the more aggressive use of glucocorticoids and other immunosuppressives and better supportive medical care (Sontheimer and Costner 2008).

Diagnosis Clinical examination and the histopathology analysis of the muscle are fundamental for the diagnosis of IIM. Muscle involvement is evaluated by manual testing, functional performance, electromyography (preferably quantitative EMG), muscle MRI, and muscle enzyme levels (creatine phosphokinase, aldolase). The muscle biopsy, together with skin and muscular clinical signs, can confirm the diagno-

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20 Dermatomyositis

sis. Characteristic features of muscular involvement in DM are muscle fibers necrosis and regeneration, microinfarcts, perifascicular atrophy, inflammatory infiltrates of T cells, predominantly of CD4 type, and inflammatory vascular changes or capillary depletion. Some cutaneous lesions, as Gottron’s papules/sign, Heliotrope sign, are specific and distinctive of the disease. According to newer criteria, pathognomonic rashes in correlation with serological profile may even make muscle biopsy obsolete which could be particularly helpful in amyopathic DM. In the severe cases, characterized by pulmonary fibrosis, pronounced Raynaud’s phenomenon, arthralgia, and not infrequently scleroderma-like cutaneous changes, there is the need of respiratory function evaluation. A nail fold capillaroscopy is indicated in all cases (which shows characteristic “bushy,” highly enlarged capillaries of the subpapillary plexus, and extravasations). In adults over 40–50 years old, cancer screening is recommended (in females mammography and pelvic ultrasonography, and serological examination for the ovarian tumor with marker CA-125, and in all patients, lung and digestive tract studies). A wide variety of classification or diagnostic criteria were developed during the last decades. The Bohan and Peter criteria developed in 1975 are still the most widely used. Beside the description of new clinical subsets and a deeper understanding of IIM pathophysiology, there is a continuous effort of researchers and clinicians to improve and update criteria. For example, EULAR/ACR proposed a set of criteria for the classification of adult and juvenile Idiopathic Inflammatory myopathies and their major subgroups, which incorporates 16 weighted variables. A web-based calculator (www.imm.ki.se/ biostatistics/calculators/iim) provides a score that represents the probability of a particular individual to have an IIM. (Lundberg et  al. 2017). Recently, ENMC developed criteria for the clinicopathological classification of dermatomyositis (DM) (Mammen et  al. 2020). In comparison to EULAR/ACR, these criteria incorporate broader spectrum of DM-specific autoantibodies and skin

biopsy findings. Interestingly, both sets of criteria do not necessitate muscle biopsy for the diagnosis of DM.  Finally, the separate set of criteria have also been suggested for amyopathic dermatomyosits (Concha et al. 2019). Disease activity measures developed by IMACS (Rider et  al. 2011) and the recently published ACR/EULAR adult PM/DM and juvenile DM response criteria (Rohit Aggarwal et  al. 2017; Rider et  al. 2017) could be a valuable addition for disease monitoring.

Differential Diagnosis The diagnosis is quite simple when the clinical features of DM are typical. Pronounced photosensitivity should be exploited to differentiate from systemic lupus erythematosus (SLE) associated with myositis (differs by visceral and cutaneous involvement and by serological markers). JDM cases can be confused with SLE, since that pronounced vasculitis and photosensitivity are common in both the pathologies. In these cases, clinicians should refer to the serological markers of SLE. Cases of amyopathic DM should be differentiated, besides systemic lupus erythematosus (SLE), subacute cutaneous lupus erythematosus (SCLE), and discoid lupus erythematosus (DLE), from polymorphous light eruption, lichen planus, seborrheic dermatitis (not infrequent scaling scalp lesions in DM), and erythema elevatum and diutinum.

General Principles of Treatment Therapy must be oriented in relation to the symptomatology and the severity of the disease. Pharmacological treatment is based on immunosuppressive agents, as glucocorticoids, azathioprine, or methotrexate, even their benefit/risk ratio is not so clear. Randomized controlled trials (RCTs), confirming the value of immunosuppressants in inflammatory myositis, are not available. For this reason, it is important for physicians and patients to appreciate the precise benefit and risk of immunosuppressants in inflammatory myositis.

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Additional considerations should be spent for the clinical assessment of juvenile DM. The evaluation of the involvement and severity of muscle inflammation has a significant importance in assessing disease activity and response to therapy in juvenile DM patients. Muscle strength is the primary clinical measure used to  assess muscle disease. The manual muscle testing (MMT) and Childhood Myositis Assessment Scale (CMAS) are among the main tests exploitable. In JDM, there is an imperfect correlation of serum muscle enzymes and myositis activity. Moreover, health-­related quality of life has been increasingly recognized as an important domain to be included in therapeutic trials and observational studies of patients with juvenile DM because it addresses aspects of disease that are not fully captured by other endpoints.

 herapeutic Ladder for Cutaneous T Dermatomyositis First Line Photoprotection. Topical and systemic corticosteroids. Topical calcineurin inhibitors Antipruritics. Antimalarials (single agent initially, consider combination if failed). Second Line Methotrexate. Mycophenolate mofetil. Human intravenous immunoglobulin IVIg. Third Line Dapsone. Thalidomide. Azathioprine. Rituximab. Calcineurin inhibitors.

Corticosteroids Topical Corticosteroids Topical corticosteroids are frequently used to manage the cutaneous inflammation and pruritus of DM. The application, in a vehicle most amenable to the patient and suitable for the area treated, should be once-twice daily. Appropriate breaks from use should be considered in order to prevent side effects as cutaneous atrophy, acneiform eruptions, striae, telangiectases, etc. For regions including the trunk, extremities, and scalp, a stronger (usually class 1 or 2) topical corticosteroid may be prescribed, whereas lower potency corticosteroids are suggested for the face. To increase potency and penetration, especially for hyperkeratotic refractory lesions, occlusion with a plastic wrap or steroid-impregnated tape is recommended. In addition, there is a low risk of transient adrenal suppression and other effects from systemic absorption when large body surface areas are being treated. When prolonged use is anticipated, practice of cyclic therapy (e.g., 2 weeks of continuous therapy followed by 1–2  weeks treatment-­free) is advised.  ystemic Corticosteroids Are S the Traditional First-Line Agent for the Management of DM In a typical clinical scenario with both skin and muscle involvement, the therapy consists of prednisone (or its equivalent) orally at around 1 mg/ kg per day (with an average dose of 60 mg daily for a patient with myositis, generally not exceeding 80 mg per day) (Oddis and Aggarwal 2018). Some authors suggest giving methylprednisolone intravenously at 1 g daily for 3–5 days, followed by oral therapy when muscle disease is severe. The dose is continued for at least 4 weeks and then based on the improvement of muscle function tapered monthly by 10–20% (alternatively, the dose is dropped by 5–10  mg/week) to the minimal effective one. Corticosteroid dose below

20 Dermatomyositis

the Cushing threshold should be aimed at the latest after 6  months. When the daily prednisone dose reaches 5–10 mg/day, the maintenance dose is usually held for 1 to 3 years to prevent relapses (Sunderkotter et al. 2016). There is also some evidence that prednisolone at 0.5 mg/kg per day or less could be sufficient to treat PM/DM in cases with less severe systemic involvement and/or when immunosuppressants are used concomitantly (Fasano et  al. 2016) (Kohsaka et al. 2019). Limited evidence from a retrospective, uncontrolled trial suggests that even lower doses (7.5 to 30 mg/day, equivalent to 40 kg: 250 mg daily for 4–6 weeks Oral alternative therapies Fluconazole 6 mg/kg daily for 3–6 weeks Pulsed therapy: 6 mg/kg once weekly for 6–12 weeks Itraconazole 5 mg/kg daily for 4–6 weeks Pulsed therapy: 3 mg/kg daily for 1 week each month for 2–3 months Adjunctive topical therapies Selenium Twice weekly sulfide Ciclopirox Twice weekly Ketoconazole Twice weekly

Notes More effective than terbinafine for Microsporum infections

As effective as griseofulvin for Trichophyton infections with shorter duration of treatment

1–2% shampoo 1% shampoo 2% shampoo

varies by organism, with M. canis requiring treatment for 6 weeks. Terbinafine is less effective in tinea capitis due to M. canis, but may be more efficacious compared to griseofulvin in treating infection by the Trichophyton species. Dosages used in this setting are 3.125–6.25 mg/kg per day for terbinafine, 3–5  mg/kg per day for itraconazole, and 4–6  mg/kg once a week for fluconazole. Duration of treatment ranges from 2 to 6 weeks. Oral or topical steroids can be given in association with systemic antifungals to reduce pain, swelling, and inflammation.

21  Dermatophyte Infections

Onychomycosis Dermatophytes account for more than 90% of onychomycosis with T. rubrum being the most common pathogen. They may produce four different clinical types of onychomycosis, depending on the modality of nail invasion by the fungus.

 istal and Lateral Subungual D Onychomycosis (DLSO) DLSO (Fig.  21.1) is the most common form of nail dermatophyte infections. They reach the nail bed horny layer through the hyponychium and findings include subungual hyperkeratosis, onycholysis, and yellow discoloration. It is also associated with longitudinal streaking and typically affects the toenails more frequently than fingernails. Since the skin of the palms and soles is the primary site of infection, DLSO is usually associated with tinea manum or tinea pedis.

 roximal Subungual Onychomycosis P (PSO) PSO is characterized by a primitive invasion of the nail matrix keratogenous zone through the proxi-

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mal nail fold horny layer. Fungal elements are typically located in the ventral nail plate with minimal inflammatory reaction. The affected nail shows proximal leukonychia organized in diffuse patches or transverse striates resulting in a subungual white patch of the lunula. The white patch progresses distally with nail growth, extending distally.

Superficial Onychomycosis (SO) In SO can be white or black, patchy or transverse. The defining characteristics are determined by the organisms involved. The fungi colonize the most superficial layers of the nail plate and the affected nail presents multiple friable white opaque spots that can be easily scraped away. In SO, deep invasion of the nail plate can occur in children, immunocompromised patients, and in cases of infection due to molds.

Endonyx Onychomycosis (EO) EO is characterized by massive nail plate parasitation in the absence of nail bed inflammatory changes. The affected nail is milky-white in colour. The nail plate is firmly attached to the nail bed and there is no nail bed hyperkeratosis or onycholysis.

Mixed Pattern Onychomycosis (MPO) MPO refers to different patterns of nail infection in the same nail. MPO consists mainly of DLSO with a combination of SO, or PSO with SO.

Totally Dystrophic Onychomycosis

Fig. 21.1  Distal subungual onychomycosis due to T. interdigitale involving the distal 1/3 of the nail

Totally dystrophic onychomycosis (TDO) is considered the end stage of nail plate invasion of many of the nail disorders. Most commonly, it occurs in DLSO and PSO.  The characterizing features are thickening of the nail bed, crumbling of the nail plate, and ridges covered with debris. TDO can be secondary to immunosuppression.

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Secondary Onychomycosis Nail changes like the ones seen in psoriasis (nail pitting) or trauma to the nail can predispose nail plate to fungal infections. Typically, the underlying condition causing the nail changes would need to be treated in order for onychomycosis to subside.

Treatment The treatment choice depends on the clinical type of the onychomycosis, the number of affected nails, and the severity of nail involvement. The Onychomycosis Severity Index is an algorithm that separates nail involvement into mild, moderate, or severe category in order to better predict the response to treatment. In sum, the score for area of involvement is multiplied by the score for the proximity of disease to the nail matrix. If there is dermatophytoma or subungual hyperkeratosis more than 2  mm, 10 points are added. Table 21.3 outlines the criteria used.

Topical Treatment Penetration of a topical antifungal through the nail plate requires a vehicle that is specifically formulated for transungual delivery. The two most commonly used agents are amorolfine 5% nail lacquer and ciclopirox 8% nail lacquer; how-

ever, recent studies on lipid diffusion enhancers and water soluble biopolymers show promise. Amorolfine nail lacquer is applied once a week, whereas ciclopirox nail lacquer is applied daily. Terbinafine nail solution and a terbinafine spray using lipid-based vesicles currently under development, labeled TDT 067, may be viable treatment alternatives in the future. Nail lacquers are effective as monotherapy in the treatment of superficial onychomycosis, with patch infiltration, and of DLSO, limited to less than 50% of the distal nail. Treatment duration should be 6–12 months (Fig. 21.2). Nail lacquers

Fig. 21.2  Complete cure of the onychomycosis after 6 months of topical application of a nail lacquer containing ciclopirox with hydroxypropyl chitosan as vehicle

Table 21.3  Onychomycosis severity score index Area of involvement

Proximity of disease to matrix Involvement from distal edge No. of points 3/4 4 Matrix involved 5

Presence of dermatophytoma or subungual hyperkeratosis >2 mm

Affected nail % No. of points Present 0 0 No 1–10 1 Yes 11–25 2 26–50 3 51–75 4 76–100 5 Scores (area of involvement) × (score for proximity of disease to matrix) = total score Add +10 points if presence of dermatophyte or subungual hyperkeratosis >2 mm 0 Cured 1–5 Mild 6–15 Moderate 16–35 Severe

No. of points 0 10

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Table 21.4  Topical treatment for onychomycosis Drug Amorolfine Ciclopiroxolamine Efinaconazole Tavaborole

Dose One weekly for 6 months One daily up to 48 weeks Once daily for 48 weeks Once daily for 48 weeks

are also utilized in combination with systemic antifungals or nail avulsion in severe onychomycosis to reduce duration of treatment and increase cure rate. Application of amorolfine nail lacquer once every 2 weeks after completion of treatment may be effective prophylaxis to prevent the recurrence of onychomycosis. Refer to Table 21.4 for a list of topical antifungal treatments options for onychomycosis. Photodynamic therapy has been reported to be effective in T. rubrum onychomycosis with either filing of the affected nail or treatment of affected nail with urea prior to application with ALA. Photodynamic therapy based on methylene blue dye is currently being researched and may be effective in the treatment of endonyx onychomycosis. The Nd:YAG laser and diode laser have been utilized to treat onychomycosis. Wavelengths of 750 to 1300 nm penetrate the nail plate and may target fungi; however, more research needs to be done in order to determine the efficacy of use.

Systemic Treatment DLSO that involves greater than 50% of the nail, Proximal subungual onychomycosis, and deeply infiltrating white superficial onychomycosis, require systemic therapy. Systemic treatment with terbinafine or itraconazole produces mycological cure in more than 90% of fingernail infections and in about 80% of toenail infections. These success rates can be increased by associating a topical treatment with a nail lacquer to the systemic treatment. However, compared to itraconazone, terbinafine has a higher mycological and clinical cure rate and a lower rate of recurrence. Terbinafine can be administered as a continuous therapy at 250 mg per day for 12 weeks or an intermittent regimen of 2 pulses of 250 mg/day for 4 weeks on and 4 weeks off. Itraconazole is administered as pulse therapy

Nail involvement 10 nM correlates with severity and persistence of cardiopulmonary manifestations or gastrointestinal manifestations, but as histamine needs to be measured within 1 h of the onset of anaphylaxis, this test is seldom used.

22  Drug Hypersensitivity Reactions

Measuring serum tryptase level within 12  h is more widely used, although this method also has its limitations (Montañez et al. 2017).

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Treatment

tory or circulatory failure. In case of severe laryngeal oedema, in order to maintain the airway, endotracheal intubation or tracheostomy should be carried out (Montañez et  al. 2017; Muraro et al. 2014; Simons et al. 2015).

Acute Stage In the majority of moderate drug-induced urticaria cases, stopping the causative agent and treatment with a non-sedative histamine H1 antagonist is sufficient. Locally, corticosteroid containing creams or lotions can be applied to decrease pruritus. In case of widespread lesions with oedema formation, oral corticosteroids provide symptomatic relief and attenuate the reaction (Kanani et  al. 2018). Patients with anaphylaxis should be lied down with their legs elevated and epinephrine should be administered at the first sign of respiratory failure or cardiovascular collapse. The intramuscular route for epinephrine administration is recommended when compared to subcutaneous mode (Muraro et  al. 2014; Simons et  al. 2015). The dose is usually 0.5  mL of a 1:1000 dilution in adults and this dose can be repeated in every 5–15  min until symptoms improve. Intravenous epinephrine (1:1000 dilution) should be given in case of inadequate response to 2–3 intramuscular adrenaline doses by trained staff because of the higher risk of cardiac arrhythmias, hypertension, and myocardial infarction. The most common side effects of epinephrine are anxiety, tremor, palpitation, and increased blood pressure. Beta-blockers may increase the severity of an anaphylactic reaction and antagonize the response to epinephrine; accordingly, the anaphylaxis of patients on beta-­ blockers can be severe and treatment-resistant. Corticosteroids are often used to decrease the risk of recurrent or protracted anaphylaxis, but it is still not entirely clear how steroids work. At least 3  L of normal saline (20  mL/kg rapidly under pressure) should be given and bolus should be repeated if hypotension persists. Patients should be warned of the possibility of an early relapse and kept under observation for 8 to 24 h, particularly if the patient has asthma, a history of biphasic response, or may continue to absorb the drug. Oxygen should also be applied in respira-

Chronic Stage The main purpose is the identification of the eliciting drug. Since both urticaria and anaphylaxis can be the result of immune-mediated and also of non-immune-mediated reactions, this often causes difficulties in the allergological investigations, which are recommended between 3 weeks and 6 months after the incident, when complete clearing of clinical signs and normalization of laboratory values occurred. In the case of acute urticaria, prick test which is less sensitive but safer should be the first skin test, and if it is negative, intradermal skin test can be carried out. The negative result is not a guarantee that the drug is tolerated, because of the weak sensitivity of these tests (Pichler 2007; Kanani et al. 2018; Montañez et al. 2017). Whenever possible, one should carry out in vitro tests, like drug-specific IgE measurements, basophil activation test (BAT), basophil sulphidoleukotriene or histamine release assays, or the lymphoblast transformation test (LTT) (Mayorga et al. 2019). The markers of basophil activation are CD63 and CD203c, which are expressed on the surface of the cell membrane and can be measured by flow cytometry. BAT is recommended mainly in case of selective NSAID (mainly pyrazolone) and beta-lactams induced immediate hypersensitivity reactions (IHR) as a complement of skin testing, and in neuromuscular blocking agents (NMBA) induced IHRs, even for the identification of cross-reactive NMBAs. Newer approaches are IFN-γ producing cells determination by Enzyme-linked immunospot assay (ELISpot) and its modified version, using pre-activated T cells. If the above-mentioned in vitro tests are negative, provocation is needed or with other words a graded challenge test is done (Mayorga et  al. 2019). In case of anaphylaxis, prick test and in vitro tests (e.g. BAT) can be performed, but intradermal test or provocation are usually not advised. Serum tryptase levels increase greatly after anaphylactic shock and

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anaphylaxis, but are negative in anaphylactoid non-IgE-mediated reactions. The concentration of tryptase peaks 1–2 h after the onset of the reaction and remains elevated with a half-life of 1.5– 2-5 h, so the samples for tryptase test should be collected within 6 h of initiation of anaphylaxis. According to the international consensus, in case of perioperative anaphylaxis in the acute phase, the mast cell tryptase level should be >1.2× baseline tryptase+2 mg/L and it is recommended to be measured 30–180  min after the onset of symptoms. In case of high tryptase level, the measurement should be repeated few weeks later to exclude mast cell disorders (Montañez et  al. 2017). In pseudoallergic reactions, skin tests and in  vitro tests are also negative, since adaptive immune reactions are not involved to our present knowledge (Zhang et al. 2018). Drug provocation test (DPT) is considered to be the gold standard for the confirmation or exclusion of drug hypersensitivity, but only recommended in case of negative skin tests and if the clinical history is not conclusive. Provocation tests can be informative but often negative suggesting that additional cofactors might be needed to develop clinical symptoms. DPT is also applied to find a safe alternative drug instead of the culprit drug (Pichler 2007; Kanani et  al. 2018; Montañez et al. 2017; Mayorga et al. 2019). Desensitization should be offered only when benefits outweigh the risks. Rapid desensitization protocols are available with antibiotics (penicillin), chemotherapeutic agents, and monoclonal antibodies, but with NSAIDs (e.g. aspirin) as well (Mayorga et al. 2019; Chastain et al. 2019). Patients may be advised to wear a Medical Alert bracelet and instructed on the use of a self-administration epinephrine device in the event of further episodes.

Maculopapular Drug Eruption (MDE) Definition, Epidemiology, Pathophysiology The so-called exanthematous reactions, the MDEs, are the most common drug hypersensi-

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tivity eruptions affecting the skin and present 31–95% of all drug-induced cutaneous reactions. Antimicrobials (beta-lactams, sulfamethoxazole, quinolons), anticonvulsants, NSAIDs, and allopurinol are the most frequently involved drugs, but it is important to know that any drug can play an initiating effect. There are a lot of cofactors in the development of MDEs, like viral infections, connective tissue diseases, older age, and genetic factors. MDEs belong to the Type B hypersensitivity reactions, so they are unpredictable and occur in individuals with personal susceptibility. Drug-specific, CD4+ cytotoxic T cells are the dominant effector cells, and MDEs are considered to be a Gell and Coombs type IVc, cell-­ mediated delayed type hypersensitivity reactions (Pichler 2019; Bellón 2019; Brockow et al. 2019).

Clinical Features The clinical picture characteristic of MDEs consists of hyperaemic or pink coloured papules and macules, which sometimes become confluent (See Fig.  22.2). The rush usually starts on the trunk and upper extremities and affects other body parts, like lower extremities, gradually. The palms, feet, and mucous membranes are free and this can be an important differential diagnostic feature. Moderate to severe pruritus can occur. Low-grade fever and eosinophilia can sometimes accompany it as well. In the uncomplicated forms, the skin lesions usually begin to evolve 4–14 days after the patient start to take the causative drug and disappear 1–2  weeks after discontinuation. MPE often heals with desquamation. On the other hand, in some cases the primary maculopapules can represent the beginning of more severe drug reactions, like SJS/ TEN or DRESS, so all patients should be monitored for markers of severe reactions (See Table  22.2). In late type reactions, including MDE, certain laboratory tests (complete blood count, liver function test, CRP, serum creatinin) are recommended to assess severity (Brockow et al. 2019).

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Fig. 22.2  Skin rash of MDE (maculopapular drug eruption) Table 22.2  Markers of severe reactions in patients with MDEa 1. Skin pain or burning 2. Widespread eruptions (i.e. confluent erythema) 3. Affecting more than 60% of the body surface area 4. Dusky red or purpuric macules 5. Atypical target lesions 6. Blisters or epidermal detachment 7. Positive Nikolsky sign 8. Involvement of mucous membranes 9. Facial oedema 10. Lymphadenopathy 11. Arthralgia 12. High fever (>40 °C) 13. Laboratory results: eosinophilia, atypical lymphocytes, and abnormal liver-function tests Maculopapular drug eruption

a

Differential Diagnosis In the differential diagnosis of MDE, dermatologist should consider acute viral infections, collagen vascular diseases, acute graft-versus-host disease, and secondary syphilis (See Table 22.3). Usually skin biopsy is not needed, anamnestic data, clinical picture, and some laboratory tests are enough to state the diagnosis (Brockow et al. 2019).

Treatment Acute Stage The suspected drug should be withdrawn as the first step of treatment. Sometimes it is not easy to identify the causative drug. In these cases, all drugs that are not essential and were started in the last few weeks should be stopped. In mild-­moderate cases, topical corticosteroid creams and systemic antihistamines can be used, in severe cases systemic corticosteroids can be ­initiated, and then gradually decreased when the symptoms disappear. Chronic Stage After the patient became symptom free, the next step is to identify the causative drug, if there are several suspected medications in the history. The patch test and the LTT can be performed after recovery and after stopping antihistamines and corticosteroids; however, Prick test and intradermal test (IDT) are potentially useful as well, according to a recent international consensus document. However, the European Academy of Allergy and Clinical Immunology (EAACI) and European Society of Contact Dermatitis (ESCD)

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236 Table 22.3  Differential diagnosis of MDEa 1. MDE 2. Acute viral infections (paramyxovirus, togavirus, Epstein-­ Barr virus, enterovirus, CMV, parvovirus) 3. Collagen vascular diseases

4. Acute graft-versus-graft reactions

5. Secondary syphilis

Clinical picture/histology Polymorphous clinical picture, frequent confluence, elderly age group Younger age groups, concomitant general symptoms, dermal hemorrhage

Laboratory alterations Eosinophilia in peripheral blood

General symptoms differ, epidermal atrophy, focal parakeratosis, thickening of the basement membrane zone on histology Specific anamnesis, epidermal atrophy, parakeratosis, necrotic keratinocytes on histology Palmoplantar lesions, plasma cell rich mononuclear infiltration in histology

Immunological alterations, (autoantibodies, complement serology)

Serological test for infections is positive, laboratory signs of infections (CRP, leukocytosis)

Specific serology

Maculopapular drug eruption

a

guidelines about how to perform delayed IDT are not uniform (Phillips et al. 2019). Patch tests are recommended to carry out within 6 months after the MDE, and they are not well standardized so false positive and false negative results can occur. LTT validation is also not well organized in different laboratories. Provocation tests after MDEs are questionable since they need longer time period and hold the risk of inducing a more severe reaction, although after negative skin test results and after mild exanthems it is considered to be performed (Brockow et al. 2019; Mayorga et al. 2019; Phillips et al. 2019). Desensitization may be considered in those cases where the drug is mandatory without available alternative and has been described with allopurinol, vemurafenib, dabrafenib, antituberculotic drugs, and in HIV patients with MDEs to sulphonamides (Dursun and Sahin 2014; Bar-Sela et al. 2015; Thong et al. 2014).

 cute Generalized Exanthematous A Pustulosis (AGEP) Definition, Epidemiology, Pathophysiology AGEP is a T cell-mediated, late type, IVd hypersensitivity drug-induced skin reaction with a rapid and dramatic appearance, but with a benign course. It is a rare disease with an estimated incidence equal to severe bullous skin diseases. The

main causative medications are aminopenicillins, cephalosporins, macrolides, celecoxib, diltiazem, and anti-malarial drugs such as hydroxychloroquine or chloroquine, but there are reports on the role of sulphonamides and terbinafine. Usually the onset of the skin reaction occurs 1–12  days after the initiation of the suspected medication (1–2 days in case of antibiotics, up to 12 days for other drugs) (Francheschini et al. 2019; Brockow et  al. 2019; Sidoroff et  al. 2001; Cho and Chu 2017). In the pathogenesis, drug specific T lymphocytes are supposed to migrate into the epidermis, where keratinocytes and T cells secrete IL-8, which attracts neutrophils and neutrophil recruitment will result in the formation of subcorneal pustules. Studies have also suggested the role of Th17 lymphocytes and IL-36 in the pathogenesis of AGEP (Bellón 2019).

Clinical Features In the course of AGEP, a widespread erythema suddenly occurs on the face, trunk, and extremities, mainly affecting the flexural surfaces and skin folds. On the top of the erythema, a lot of small non-follicular sterile pustules develop rapidly (See Fig.  22.3). Usually mucous membranes are not involved, but patients have fever and massive neutrophilia. Internal organ involvement is not typical, but transient renal failure or liver involvement can occur in elderly. A diagnostic score for validation of AGEP was introduced and this system distin-

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Fig. 22.3  Characteristic picture of AGEP

guishes definite, probable, and possible AGEP diagnosis according to the final score. Spontaneous resolution in less than 15  days and post-pustular desquamation is also characteristic (Brockow et al. 2019; Pichler 2007; Sidoroff et al. 2001).

Differential Diagnosis A pustular smear and culture should be taken to exclude infectious pustular disorders. A skin biopsy is also needed to differentiate other pustular skin diseases. Spongiform subcorneal and/or intraepidermal pustules and perivascular infiltrate of neutrophils with oedema of the papillary dermis are visible. Bacterial folliculitis, furunculosis, acne, acneiform eruptions, varicella, impetigo, Sweet syndrome, or staphylococcus ­ scalded skin syndrome (SSSS) are easy to differentiate from AGEP. On the other hand, psoriasis pustulosa generalisata and Sneddon-Wilkinson syndrome are rather difficult to distinguish. In the former one history of psoriasis and histological

signs of psoriasis can help, in the later one larger pustule with hypopyon formation and slower development are characteristic (Brockow et  al. 2019; Pichler 2007; Sidoroff et al. 2001).

Treatment Acute Stage Once the trigger was identified and discontinued, the disease has a self-healing resolution and symptomatic therapy is sufficient. In those cases, with severe and widespread inflammation, a short course of systemic corticosteroids can be useful (Pichler 2007; Sidoroff et al. 2001; Cho and Chu 2017). Chronic Stage During the latter allergological investigations, patch test is recommended, since it is frequently positive in AGEP. The patch test reaction at 48 h imitates the early phase of the disease with T cell infiltration,

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after 96 h pustules can be observed. Moreover, IDT can be potentially useful (Mayorga et  al. 2019; Phillips et al. 2019; Sidoroff et al. 2001).

 rug Reaction with Eosinophilia D and Systemic Symptoms (DRESS)

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in the development of this disease are aromatic anticonvulsants (phenytoin, carbamazepine, phenobarbital, lamotrigine), but there are reports on the triggering effect of minocycline, allopurinol, thalidomide, dapsone, sulphonamides, abacavir, and nevirapine. Neurologists who often indicate anticonvulsants should be aware of DRESS as it might occur in 1:3000 treated patients (Bellón 2019; Brockow et al. 2019; Cho and Chu 2017; Shiohara and Mizukawa 2019; Cho et al. 2017; Kardaun et al. 2007).

Definition, Epidemiology, Pathophysiology The term DRESS has been suggested in place of Hypersensitivity syndrome (HSS) or drug-­ induced hypersensitivity syndrome (DiHS) Clinical Features which has long been used to describe drug reac- The diagnosis of DRESS is definite if at least five tions with internal organ involvements. Th2 T out of the seven criteria (RegiSCAR) are fulfilled: cells and cytokines (IL-4, 5, 13) are considered to (1) acute skin rash, (2) reaction suspected drug play important role in the pathogenesis of DRESS related, (3) hospitalization, (4) fever (>38 °C), (5) (Shiohara and Mizukawa 2019; Cho et al. 2017; at least one present of laboratory abnormalities Kardaun et al. 2007). However, in a recent study (lymphocyte above or below normal; low platelet increased number of Tregs were detected in the count; eosinophilia), (6) involvement of at least acute phase, while in the resolution phase the one internal organ (hepatitis, nephritis, pneumoniamount of Th17 cells was elevated (Shiohara and tis, carditis, colitis, pancreatitis, arthritis), (7) Mizukawa 2019). In another previous study, enlarged lymph nodes >2 sites. DRESS is probaincreased number of CD8+ T cells were found as ble if the final score is 4–5 and possible in case of well. Moreover, it is also suggested that virus 2–3 points (Kardaun et al. 2013). In the beginning reactivation may be important in the development of the disease, the skin lesions mainly have a morof the disease due to the prolonged courses and billiform appearance, but can be eczema-like, flare-ups after the withdrawal of the culprit medi- target-like, and superficial pustules and vesicles cation. It is not clearly revealed whether reactiva- can appear as well. Facial oedema is quite comtion of latent herpes viruses (HHV-6, HHV-7, mon. As the disease progresses, erythroderma EBV, and cytomegalovirus) may play a causal develops with deeper infiltration, purpuric lesions role or just can be considered as complications and sometimes exfoliative dermatitis occurs. In (Bellón 2019; Cho and Chu 2017; Shiohara and the later stage, marked desquamation is visible. Mizukawa 2019; Cho et  al. 2017). In Europe, Fever accompanies the skin rash frequently. elevated HHV-6 IgG levels are not yet Lesions are distributed symmetrically on the included in the diagnostic criteria of trunk and extremities and then can be widespread. DRESS. Polymorphism in HLA alleles can also The clinical symptoms can temporarily worsen predispose to DRESS (e.g. HLA-B*58:01 and 3–4 days after discontinuation of the culprit drug allopurinol-induced DRESS; HLA-A*32:01 and (Bellón 2019; Brockow et al. 2019; Cho and Chu vancomycine-­ induced DRESS; HLA-B*13:01 2017; Shiohara and Mizukawa 2019; Cho et  al. and dapsone-­ induced DRESS, HLA-A*31:01 2017; Kardaun et al. 2007, 2013). and carbamazepine-induced DRESS in northern Europeans) (Bellón 2019; Mayorga et al. 2019). Differential Diagnosis After the initiation of the suspected drug, symp- During the development of DRESS, the initial toms can start up to 12 weeks, the disease often rash has a maculopapular appearance, so MDE persists for a long time even after stopping the has to be excluded. In MDE, mild liver or kidney indicated drug and introducing the correct treat- involvement can also occur, but prominent creatiment. Most commonly, registered causative drugs nine and transaminase elevation and haemato-

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logical abnormalities, which are characteristic to DRESS, cannot develop. As the skin lesions of DRESS progress, the infiltration becomes severe and erythroderma evolves. In this phase, lymphoma or pseudolymphoma should be taken into consideration. Acute viral infections (e.g. mononucleosis, parvovirus B19 infection, measles, Coxsackie virus infection) should also be excluded. During the diagnostic steps of DRESS, physicians have to keep in mind that skin changes and also histological findings are rather non-­ specific, the time-period of the application of the causative drug is variable, and the laboratory alterations can also develop in other diseases. Differential blood count, liver and kidney function tests, and also serum CK, CK-MB, troponin, and LDH levels should be determined (Brockow et al. 2019; Shiohara and Mizukawa 2019; Cho et al. 2017; Kardaun et al. 2007, 2013).

Treatment Acute Stage The first step in the management of DRESS is the immediate cessation of the offending medication. Systemic corticosteroid therapy in a minimum dose of 0.5–1.0 mg/kg/day is very effective both in the management of clinical and laboratory alterations. It is usually advised to decrease the systemic corticosteroid dose very slowly over 3–6 months in order to avoid relapse. However, immune reconstitution inflammatory syndrome has to be taken into consideration, due to the prolonged immunosuppression. Topical corticosteroids applied on the skin lesions can cause symptomatic relief. It is better to avoid empiric antibiotics or anti-inflammatory drugs, since they can exacerbate the symptoms. When DRESS is associated with severe exfoliative dermatitis lesions, the patients should be provided supportive care in an intensive care or burn unit. In some severe cases, other immunosuppressive medications should be considered (IVIG, plasmapheresis, cyclophosphamide, cyclosporine, mycophenolate mofetil, rituximab). Most patients recover completely, but chronic complications and mortality in about 10% can occur, primarily from visceral organ failure ().

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Chronic Stage In order to determine the culprit drug in DRESS, patch test and LTT are used. Results of patch tests vary significantly based on the specific drug and the higher specificity was detected when antiepileptic medications (carbamazepine, phenytoin) were tested. In the case of LTT, positive values are more informative than negative ones (Mayorga et  al. 2019; Phillips et  al. 2019; Shiohara and Mizukawa 2019; Cho et al. 2017).

 tevens-Johnson Syndrome (SJS) S and Toxic Epidermal Necrolysis (TEN) Definition, Epidemiology, Pathophysiology SJS and TEN, the later also called as Lyell syndrome, belong to the most severe drug-induced hypersensitivity reactions with a high mortality rate. SJS has a mortality of 9% and TEN of 48% and depends on the extent of the epidermal detachment and age of the patient. SJS and TEN are considered to be end points of a single disease, differing only by their extent of skin detachment. Acute and disseminated epidermal necrolysis on large skin areas and on the full thickness of the epidermis is the hallmark of this disease group together with a relatively mild inflammatory cell infiltration. SJS and TEN are rare diseases affecting approximately 1.5–1.8 cases per million inhabitants per year (Harr and French 2010). SJS and TEN are specific drug hypersensitivity reactions in which cytotoxic CD8+ T lymphocytes play a crucial role in the drug-specific immune response (type IVc), but the relative paucity of these infiltrating T cells suggests that non-drug-specific amplification mechanisms should accompany the immune reaction and cause the massive apoptosis of keratinocytes. On the basis of extensive research, the co-expression of the membrane form of the death ligand (FasL) and its cognate death receptor (Fas) on keratinocytes, perforin and granzyme B cytotoxic proteins secreted by cytotoxic T cells and NK cells, and granulysin (a cationic cytolytic protein secreted by Tc, NK cells, and NKT cells) are key players in the amplification of keratino-

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cyte apoptosis. In a recent study, IL-15 was iden- Clinical Features tified as a potential diagnostic and prognostic Typically, unspecific initial symptoms characterbiomarker in SJS/TEN. IL-15 not only promotes ize TEN and SJS, like throat pain, fever, malaise, the differentiation of cytotoxic T cells and NK and stinging eyes. Skin and mucous membrane cells, but influence the expression of granulysin lesions occur in a few days. Cutaneous manifesby these cells as well. Furthermore, IL-17 and tations are located first on the face and presternal IFN-γ also increase the release of proinflamma- region of the trunk and soon rapid progression tory cytokines by keratinocytes. TNF-α is also and involvement of large body parts develop as secreted and has a role in keratinocyte apoptosis, characteristic features. The palms and soles are making it a potential therapeutic target (Bellón often affected. Erythematous macules, patches, 2019; Cho and Chu 2017). Most cases occur atypical target lesions, flaccid blisters, and ero2 weeks (range 4–30 days) after the first exposure sions are visible, and the spots have a grey to vioto the suspected drug. It is well described that let colour. The Nikolsky sign is positive since certain polymorphism of HLA alleles predispose tangential mechanical pressure on erythematous to SJS/TEN (e.g. HLA-B*15:02 and carbamaze- zones induces epidermal detachment (detachable pine and HLA-B*58:01 and allopurinol-induced skin). These regions together with already SJS/TEN in Han Chinese patients and also to a detached regions (blisters, erosions) should be lesser extent in other populations; HLA-B*38:01 included in the evaluation of the extent of skin and lamotrigine-induced SJS/TEN; HLA-­involvement. According to the degree of epiderA*31:01 and carbamazepine-induced SJS/TEN mal detachment, we can distinguish SJS (30%) (See a

Fig. 22.4 (a–c) Clinical manifestations of SJS (30%)

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b

c

Fig. 22.4 (continued)

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Fig. 22.4c). Mucous membranes are involved in 95% of patients, most commonly the buccal, genital, and ocular mucosa and in some cases the respiratory and gastrointestinal tracts are also affected. Early oral lesions may resemble aphthae, but pain, rapid progression, skin lesions, and fever are important signs of a severe systemic disease. The lesions progress for 1  week as a mean, and then re-epithelization starts, sometimes the bullae formation is still progressing on lower parts of the body. The most common acute complications are hypovolemia, sepsis, shock, and multiple organ failure, but destruction of epithelium of the trachea and bronchial tree or other epithelial surfaces can also occur. The most frequent and severe sequelae are the ocular complications. On the skin hyper- or hypopigmentation will remain, but can fade with years if the patient pays attention to sun protection. Nail dystrophies are also common and may result in persistent nail abnormalities (Bellón 2019; Brockow et al. 2019; Cho and Chu 2017; Harr and French 2010).

Differential Diagnosis The diagnosis relies on clinical symptoms and on histological analysis. Characteristic clinical signs are erythematous, grey to livid macules on the skin, rapid progression with bulla formation, Nikolsky sign positivity (although it is not specific for TEN/SJS), simultaneous mucosal involvement, pain, anxiety, and fever. These severe signs should alert the physician and rapid diagnostic confirmation is needed with the help of skin biopsy. Histological evaluation of cryosections or formalin fixed sections demonstrates widespread necrotic epidermis involving all layers. In the differentiation of SJS/TEN from autoimmune bullous diseases, direct immune fluorescent staining is carried out, and neither immunoglobulin nor complement deposition is detected. The main diseases that should be ruled out are linear IgA dermatosis, paraneoplastic pemphigus, pemphigus vulgaris, bullous pemphigoid, AGEP, disseminated fixed bullous drug eruption, and SSSS (Bellón 2019; Brockow et al. 2019; Harr and French 2010).

Treatment Acute Stage In the acute stage, severity and prognosis of the disease should be evaluated, the suspected drug(s) should be withdrawn, and supportive care and specific therapy should be initiated. Evaluation of Severity The validated SCORTEN disease severity scoring system is generally used to determine the severity and progression of the disease and to define the further management. It consists in attributing 1 point to each of the following: age >40, detachment larger than 10% of body surface area, recent malignancy, tachycardia, serum urea>10  mmol/L, serum glucose>14  mmol/L, and bicarbonate>20  mmol/L.  Patients with a SCORTEN score of 3 or above should be managed in an intensive care unit because of the high mortality rate. The risk of dying is about 3% at a score of 0–1, but nearly 60% when it reaches 4 (Cho and Chu 2017). Withdrawal of Culprit Drug(s) To suspend the offending drug is a crucial step, since it has been shown that the earlier the pathogenic medication is withdrawn, the better the prognosis. Two data can help to identify the culprit drug, the chronology of drug use and the registered potential of the drug to cause TEN/ SJS. The overwhelming majority of cases occur in patients with normal metabolic pathways, after taking a normal dosage of medication for the first time and the development of TEN/SJS is between 1 and 4 weeks (mean 2 weeks), in case of agents with a long half-life even up to 6 weeks (allopurinol and some antiepileptics). Medications with high risk of inducing TEN/SJS are the followings: allopurinol, sulphonamide-antibiotics, antiepileptics (carbamazepine, phenytoin, phenobarbital, lamotrigine), oxicam NSAIDs, and nevirapine. Some authors underline the role of aminopenicillins, cephalosporines, and quinolones as well (Brockow et  al. 2019; Harr and French 2010).

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Supportive Care Since TEN/SJS is potentially a life-threatening disease with extensive skin and mucous membrane lesions accompanied by serious acute complications, management of patients is advised to be undertaken in specialized intensive care units or in burn units and the best is to place the patient on air fluidized bed or on Metalline sheet. The basic element of symptomatic therapy is the fluid and electrolyte supplementation. Patients with TEN/SJS usually require less fluid replacement than burn patients, about two-thirds to three-­ quarters as much. For the purpose of volume s­ubstitution, electrolyte solutions rather than colloidal infusion are preferred in the moderately severe cases; in severe hypotension the colloidal and electrolyte solutions should be used simultaneously. Purely prophylactic antibiotic usage can increase the risk of another hypersensitivity reaction and is not advised, but in case of definite infection or sepsis, targeted antibiotics must be initiated. To treat the wounds, it is usually advised to leave the necrotic epidermis in place, without skin debridement, to promote re-epithelization. Antiseptic solutions and non-adhesive wound dressings are used, but sulphonamide-based medications should be avoided. Antiseptic solutions and creams or dexpanthenolbased ointments are recommended for oral mucosa or lip lesions and also to treat genital erosions. Aggressive nutritional support should be initiated promptly to minimize protein loss and it is important to pay attention on warming of the environmental temperature. Mechanical ventilation is necessary in case of hypoxemia and correction of any organ failure if needed (Cho and Chu 2017; Harr and French 2010; Schneck et  al. 2008; Zimmermann et al. 2017).

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of the severe skin reaction if corticosteroids were given briefly at the beginning of the reaction in moderate-high doses (100–500 mg). In this study, compared to supportive treatment alone, the death rate was importantly, but not significantly, reduced in those who received corticosteroids too. Pulse therapy with high dose of methylprednisolone (500–1000 mg/day for 3 days) led to the survival of all the patients enrolled in two ­different studies (Cho and Chu 2017; Kardaun and Jonkman 2007; Bachot et al. 2003). High-Dose Intravenous Immunoglobulins (IVIG) The main mode of action that is supposed in the background of IVIG usage in TEN/SJS is the presence of antibodies with anti-Fas potential that can block Fas-mediated keratinocyte necrosis. Numerous case reports, non-controlled clinical trials, and meta-analysis studied the effect of IVIG in TEN/SJS and the results are contradictory. Nearly all studies confirmed the excellent tolerability and low toxic potential of IVIG when used with precaution in patients with potential risk factors, but the efficiency is not clearly proven yet, so definite conclusion cannot be drawn (Cho and Chu 2017; Bachot et al. 2003). In spite of this, many practicing physicians, based on clinical and laboratory evidences and also on the favourable effects of IVIG on infections and on fluid balance, prefer its use.

Specific Drug Therapy

Cyclosporin A There are case-control, case series, and meta-­ analysis studies with cyclosporin A.  All of these found decreased mortality rate in SJS/TEN after administration of cyclosporin A. The optimal dose is not clarified yet, but mainly 3 mg/kg/day was the initial dose divided twice daily and tapered gradually over 1 month (Cho and Chu 2017; Ng et al. 2018).

Systemic Corticosteroids There has been a lot of doubt on the use of systemic steroids considering the risks and benefits, but a retrospective monocentre study found that a short course pulse of high dose corticosteroids (dexamethasone) can exert good effect. One year later, another large retrospective multicenter study also found positive effect on the outcome

Thalidomide In a double blind, randomized, placebo-­controlled study thalidomide, an effective TNF-α blocker, was shown to have harmful effects when used in the therapy of TEN.  In the thalidomide-treated group, higher mortality was observed and therefore this drug must be avoided for this indication (Harr and French 2010).

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TNF-α Antagonists Mainly case reports have been published in the literature about the effect of TNF blockers, but randomized controlled trials are also available now. These showed the benefit of etanercept in patient survival (Cho and Chu 2017; Schneider and Cohen 2017; Wang et al. 2018). Plasmapheresis Current data are not enough to support the use of plasmapheresis in the therapy of TEN/SJS, due to the small number of treated patients and the variable treatment regimes. However, Japanese doctors recommend it in refractory cases of high-dose of corticosteroids (Cho and Chu 2017). Cyclophosphamide Larger studies are needed to gain clear-cut data on the efficiency and also on the potential side effects of this agent in TEN/SJS (Harr and French 2010). Chronic Stage In this stage treatment of sequelae and allergological testing is recommended. The treatment of sequelae is an interdisciplinary task, and since ocular complications can become serious, referral to an ophthalmologist is important. In a lot of cases, several medications are candidates to be the causative drug and after recovery allergological testing is needed to identify the most likely candidate. Patch testing is an option, but because of the low sensitivity, only positive test is relevant, while negative result cannot rule out a sensitization. The sensitivity of LTT test is also very low in SJS/TEN. Intradermal testing and provocation are not recommended because of the risk of another hypersensitivity reaction (Mayorga et al. 2019; Phillips et al. 2019).

References Bachot N, Revuz J, Roujeau JC.  Intravenous immunoglobulin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis. A prospective noncomparative study showing no benefit on mortality or progression. Arch Dermatol. 2003;139:33–6. Bar-Sela G, Abu-Amna M, Hadad S, et al. Successful desensitization protocol for hypersensitivity reac-

A. Szegedi et al. tion probably caused by dabrafenib in a patient with metastatic melanoma. Jpn J Clin Oncol. 2015;45(9):881–3. Bellón T. Mechanisms of severe cutaneous adverse reactions: recent advances. Drug Saf. 2019;42:973–92. Bova M, De Feo G, Parente R, et  al. Hereditary and acquired angioedema: heterogeneity of pathogenesis and clinical phenotypes. Int Arch Allergy Immunol. 2018;175:126–35. Brockow K, Ardern-Jones MR, Mockenhaupt M, et  al. EAACI position paper on how to classify cutaneous manifestations of drug hypersensitivity. Allergy. 2019;74:14–27. Chastain DB, Hutzley VJ, Parekh J, et al. Antimicrobial desensitization: a review of published protocols. Pharmacy (Basel). 2019;7(3):112. pii:E112. Cho YT, Chu CY.  Treatments for severe cutaneous adverse reactions. J Immunol Res. 2017;2017:1503709. Cho YT, Yang CW, Chu CY. Drug reaction with eosinophilia and systemic symptoms (DRESS): an interplay among drugs, viruses, and immune system. Int J Mol Sci. 2017;18(6):1243. Dursun AB, Sahin OZ. Allopurinol desensitization with a 2 weeks modified protocol in an elderly patient with multiple comorbidities: a case report. Allergy, Asthma Clin Immunol. 2014;10(1):52. Francheschini F, Bottau P, Caimmi S, et al. Mechanisms of hypersensitivity reactions induced by drugs. Acta Biomed. 2019;90:44–51. Harr T, French LE.  Toxic epidermal necrolysis and Stevens-Johnson syndrome. Orphanet J Rare Dis. 2010;16(5):39. Kanani A, Betschel SD, Warrington R.  Urticaria and angioedema. Allergy, Asthma Clin Immunol. 2018;14(Suppl 2):59. Kardaun SH, Jonkman MF.  Dexamethasone pulse therapy for Stevens-Johnson syndrome/toxic epidermal necrolysis. Acta Derm Venereol. 2007;87:144–8. Kardaun SH, Sidoroff A, Valeyrie-Allanore, et  al. Variability in the clinical pattern of cutaneous side-­ effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol. 2007;156(3):609–11. Kardaun SH, Sekula P, Veleyrie-Allanore L, et  al. Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study. Br J Dermatol. 2013;169:1071e80. Mayorga C, Fernandez TD, Montanez MI, et  al. Recent developments and highlights in drug hypersensitivity. Allergy. 2019;74(12):2368–81. Montañez MI, Mayorga C, Bogas G, et al. Epidemiology, mechanisms, and diagnosis of drug-induced anaphylaxis. Front Immunol. 2017;8:614. Muraro A, Roberts G, Worm M, et al. Anaphylaxis: guidelines from the European academy of allergy and clinical immunology. Allergy. 2014;69:1026–45. Ng QX, De Deyn MLZQ, Venkatanarayanan N, et al. A meta-analysis of cyclosporine treatment for Stevens-­

22  Drug Hypersensitivity Reactions Johnson syndrome/toxic epidermal necrolysis. J Inflamm Res. 2018;11:135–42. Phillips EJ, Bigliardi P, Bircher AJ, et al. Controversies in drug allergy: testing for delayed reactions. J Allergy Clin Immunol. 2019;143:66–73. Pichler WJ. Drug hypersensitivity. Basel: Karger; 2007. Pichler WJ.  Immune pathomechanism and classification of drug hypersensitivity. Allergy. 2019;74: 1457–71. Schneck J, Fagot JP, Sekula P, et al. Effects of treatment on the mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis: a retrospective study on patients included in the prospective EuroSCAR study. J Am Acad Dermatol. 2008;58(1):33–40. Schneider JA, Cohen PR.  Stevens-Johnson syndrome and toxic epidermal necrolysis: a concise review with a comprehensive summary of therapeutic interventions emphasizing supportive measures. Adv Ther. 2017;34(6):1235–44. Shiohara T, Mizukawa Y.  Drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS): an update in 2019. Allergol Int. 2019;68:301–8.

245 Sidoroff A, Halevy S, Bouwes Bavinck JN, et  al. Acute generalized ­ exanhematosus pustulosis (AGEP)—a clinical reaction pattern. J Cutan Pathol. 2001;28:113–9. Simons FER, Ebisawa M, Sanchez-Borges M, et al. 2015 update of the evidence base: world allergy organization anaphylaxis guidelines. World Allergy Organ J. 2015;8(1):32. Thong BY, Chia FL, Tan SC, et al. A retrospective study on sequential desensitization-rechallenge for antituberculosis drug allergy. Asia Pac Allergy. 2014;4(3):156–63. Wang CW, Yang LY, Chen CB, et al. Randomized, controlled trial of TNF-α antagonist in CTL-mediated severe cutaneous adverse reactions. J Clin Invest. 2018;128(3):985–96. Zhang BZ, Li Q, Shi C, Zhang X.  Drug-induced pseudoallergy: a review of the causes and mechanisms. Pharmacology. 2018;101:104–10. Zimmermann S, Sekula P, Venhoff M, et  al. Systemic immunomodulating therapies for Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis. JAMA Dermatol. 2017;153(6):514–22.

Drug Photosensitivity

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Margarida Gonçalo and Ana Giménez-Arnau

Key Points • Clinical manifestations of drug photosensitivity are polymorphic. • Exaggerated sunburn and acute eczema of photoexposed areas, occasionally with erythema multiforme lesions, are the main presentations of systemic photosensitivity. • Pseudoporphyria, photo-onycholysis, dyschromia, lichenoid reaction, telangiectasia, or purpura on sun-exposed areas and subacute lupus erythematosus are forms of subacute drug photosensitivity. • Phototoxic drugs, namely voriconazole or vemurafenib, enhance photoaging and increase the risk of nonmelanoma skin cancer (or melanoma), • It is not always easy to distinguish phototoxicity from photoallergy and both mechanisms may be involved in the final reaction. • Main topical drugs causing photosensitivity are the NSAID, particularly ketoprofen. • Photopatch testing, indicated mainly for the study of photoallergic contact dermatitis, can also be useful in systemic drug photosensitivity. M. Gonçalo (*) Clinic of Dermatology, University Hospital and Faculty of Medicine, University of Coimbra, Coimbra, Portugal e-mail: [email protected] A. Giménez-Arnau Department of Dermatology, Hospital del Mar. Universitat Autonoma y Universitat Pompeu Fabra. Barcelona, Barcelona, Spain

• Photoprovocation is time-consuming but can confirm the culprit drug and the responsible wavelength.

Definitions and Epidemiology Photosensitivity is an abnormal cutaneous reaction from light exposure that can be induced or enhanced by topical or systemic drugs, used for therapeutic or diagnostic purposes or in an occupational setting (Ferguson 1999; Kutlubay et  al. 2014). Druginduced photosensitivity is a potentially reversible adverse event that occurs when individuals are exposed to a drug and ultraviolet (UV) light or, eventually, visible light, but who tolerate the same amount of light exposure in the absence of the culprit drug (Ferguson 1999; Gonçalo 2020). Drug photosensitivity is certainly underrecognized as it presents under a wide spectrum of clinical patterns with different timelines which concerns the relation to drug and light exposure (Gonçalo 2020), and because new culprits are regularly identified (Alrashidi et  al. 2020; Blakely et al. 2019). In some settings the diagnosis of drug photosensitivity is easy, such as in severe sunburn or eczematous reactions on photoexposed areas in patients under treatment with drugs with known photosensitizing potential. In other settings the contribution of the drug to the cutaneous reaction is not easy to prove, namely when the drug triggers a reaction that may self-­

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perpetuate, as in drug-induced cutaneous lupus erythematosus (LE), or when it is just an aggravating factor, as in drug-enhanced photocarcinogenesis (Placzek et  al. 1999; McCarthy et  al. 2007; Jensen et  al. 2008; Cowen et  al. 2010). Moreover, it may be difficult to distinguish drug photosensitivity from idiopathic photodermatoses or genetic or acquired disorders with photosensitivity, namely in the case of drug-induced pseudoporphyria which may resemble porphyria cutanea tarda (Pérez et  al. 2014), or in ­photosensitivity as a manifestation of HIV infection (Bilu et al. 2004; Relvas et al. 2020). Also, it may be difficult to prove the contribution of the drug, as facilities for phototesting and photopatch testing are not widely available and diagnostic procedures are complex, time-consuming, and incompletely standardized (Gonçalo 2019). In a recently published study, drug-induced photosensitivity could be proved only in 5.4% of patients undergoing photoinvestigation in a referral photobiology unit (Alrashidi et al. 2020). More than 400 drugs from different pharmacological groups have been reported to cause photosensitivity and the list needs regular updating. Some photosensitizers used for therapeutic purposes may cause unwanted cutaneous reactions, namely in photochemotherapy, e.g. PUVA therapy, or in photodynamic therapy where many porphyrin derivatives are being developed to target cancer cells under visible light (Yanovsky et al. 2019). Some potent photosensitizers have been removed from the therapeutic armamentarium (benoxaprofen, carprofen, chlorproéthazine), whereas others whose therapeutic benefits outweigh the risk of photosensitivity are still in the market (tetracyclines, amiodarone, lomefloxacin, vemurafenib, topical ketoprofen), but sun avoidance or sun protection measures should be recommended during their use (Oliveira et  al. 1996; Gelot et  al. 2013). Some drugs cause photosensitivity in a minority of exposed individuals, either because they develop a specific immune reaction (photoallergy) to a photoproduct or they have a different response to UV light under the presence of the

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drug due to some genetic factors or other underlying conditions (e.g. immunosuppression) (Alrashidi et  al. 2020). Premarketing studies regularly performed in order to prevent the release of potential photosensitizing drugs, mostly based on in  vitro testing (Elkeeb et  al. 2012; Maciel et  al. 2019), do not completely prevent the release of drugs that induce photosensitivity. Drugs manipulated in an occupational setting can also induce photosensitivity: carprofen, a NSAID for animal use, induced photoallergic contact dermatitis in workers manufacturing the drug (Walker et al. 2006; Kerr et al. 2008a; Kiely and Murphy 2010), olaquindox in pig feeders induced airborne photoallergic contact dermatitis and persistent photosensitivity in animal breeders (Schauder et al. 1996; Emmert et al. 2007), and photosensitivity has been reported in nurses and family members who smashed the tablets of chlorpromazine to give to their patients/relatives (Cardoso et  al. 2009; Monteagudo-Paz et  al. 2011). Drug-induced photosensitivity is a field of intense research, with new clinical presentations being recognized, new drugs involved, with several underlying pathomechanisms that may explain their clinical expressions and orient the choice of the most adequate diagnostic tests, therapeutic and preventive measures.

Basic Concepts of Pathogenesis Drug-induced photosensitivity develops when the drug or a drug metabolite present in the skin behaves as an exogenous chromophore (Mang et al. 2011), but the photochemical and photobiological processes following photoactivation of the drug are complex and each drug may induce particular pathomechanisms conducting to different clinical aspects. Drug chromophores, which usually have double bonds or halogenated aromatic rings, are excited by UV-light in the skin and cause molecular and cellular damage that is not appropriately repaired by natural defensive mechanisms (e.g.

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antioxidant response, DNA repair mechanisms, Drug Phototoxicity melanin pigment). Otherwise, the drug may increase the quantity of endogenous chromo- Following photoactivation of the drug chromophores in the skin (Gelot et  al. 2013), interfere phore, the energy of UV photons excites the elecwith cutaneous UV-repair mechanisms, or acti- trons in the outer orbits of the molecule and, as vate/release a pro-inflammatory cytokine and these electrons come to their ground energy state, chemokine cascade (Lembo et al. 2020). the energy lost can produce photochemical modiAcute drug photosensitivity can result from fications in the molecule (isomerization, breaknon-specific inflammation—phototoxicity—or a ing of double bounds, oxidation) or the energy specific immune reaction, mostly T-cell-­can be transferred to neighbouring molecules, mediated—photoallergy—but other drug-­ initiating a chain of photochemical reactions. The induced or drug-enhanced immune reactions may energy can be directly transferred between two occur, namely in drug-induced cutaneous lupus molecules (type I photochemical reaction) or the erythematosus (LE) (Farhi et al. 2006). excited chromophore can react with oxygen, Phototoxic reactions can also induce photo-­ forming free radicals or reactive oxygen species immunosuppression and activate mechanisms (ROS) that will eventually also activate other involved in photocarcinogenesis and photoaging, molecules (type II photochemical reaction). If responsible for late reactions (premature skin cell repair mechanisms (anti-oxidant responses, aging, lentigines, actinic keratosis, non-­endonucleases for DNA repair) do not act immemelanoma skin cancer (NMSC), and melanoma) diately and control this reaction chain, there will (Gonçalo 2012; Williams et al. 2014; Siiskonen be damage of molecules relevant for cell survival, et al. 2013). namely unsaturated lipids of cell membranes, aromatic amino acids of proteins/enzymes, and pyrimidine bases of DNA or RNA, eventually Solar and UV Light in Drug progressing to cell damage or cell death. Some Photosensitivity cutaneous cells, namely keratinocytes, can undergo apoptosis (sunburn cells) or necrosis in Natural sun exposure is responsible for most cases phototoxic reactions. of drug photosensitivity, but it can also be caused The detection of ROS or other abnormal molby artificial light from UV lamps used for aesthetic ecules by intracellular sensors induces the activaor therapeutic purposes, from UV sources in occu- tion of intracellular signalling pathways (NF-κB, pational settings, or exceptionally from UV fluo- MAPkinases, the Nrf-2 antioxidant response elerescent lamps indoors (Boudewijns et  al. 2014). ment pathway) and the activated inflammasome From the solar spectrum that reaches the earth, the will generate the secretion of soluble mediators more energetic UVB (290–320 nm) and the more from keratinocytes and other cutaneous cells skin-penetrating UVA (320–400 nm) are responsi- (prostaglandins, leukotrienes, interleukins (IL)-1, ble for most cases of drug-­induced photosensitiv- 6, 8, TNF-alfa, other cytokines and chemokines). ity, but visible light and, eventually, infrared red Recruited inflammatory cells cause skin inflamenergy may also contribute (Alrashidi et al. 2020). mation which becomes clinically apparent within Many drug chromophores absorb energy mostly 24–48 h. This is the classical phototoxic reaction within the UVB wavelength in vitro, but UVA is that presents mostly as exaggerated sunburn with mainly involved in the induction of cutaneous painful erythema, bullae, or epidermal necrosis lesions, particularly for systemic drugs (Hawk and on histology with sunburn cells and dermo-­ 1999). Only few cases of exclusively UVB-induced epidermal inflammation (Ferguson 1999; drug photosensitivity have been documented Kutlubay et  al. 2014; Mang et  al. 2011; Hawk (Alrashidi et al. 2020; Fujimoto et al. 2009). 1999).

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In vitro studies with these phototoxic drugs usually show cell death in culture upon exposure to the drug and UV, as shown for clorpromazine, quinolones, quinine, propionic acid derivatives, and vemurafenib (Maciel et  al. 2019; Woods et al. 2015). In rare cases, the drug may increase the concentration of endogenous chromophores. Elevated erythrocyte porphyrins, namely zinc-­ protoporphyrin, was considered responsible for acute photosensitivity from vemurafenib (Woods et  al. 2015). Actually, transient skin burning shortly after sun exposure followed by erythema and oedema clearly limited by protective clothing, lasting a few days, simulates the genetic erythropoietic porphyria (Gelot et  al. 2013), but this mechanism has been more recently questioned. Other kinase inhibitors that interfere with porphyrin metabolism, namely vandetanib and, less often, imatinib and sorafenib, also cause acute photosensitivity (Chang et  al. 2009; Giacchero et  al. 2012). Protoporphyrins, elevated during treatment with docetaxel, may also be responsible for photosensitivity (Tokunaga et  al. 2013). Uroporphyrins were also increased in a case of photosensitivity from voriconazole associated with porphyria cutanea tarda (Hickman et  al. 2010), although voriconazole induces mostly pseudoporphyria with normal porhyrin levels (Tolland et al. 2007). Increased endogenous retinoids were explored as a possible cause of voriconazole photosensitivity but this was not proved (Haylett et  al. 2013), although exogenous retinoids increase photosensitivity from this antifungal (Hansford et  al. 2012), and photosensitivity has been described with therapeutic retinoids, namely isotretinoin (Alrashidi et al. 2020). Deficit of defensive mechanisms, namely reduced vitamin PP (niacinamide), may also contribute to photosensitivity from vemurafenib and other BRAF inhibitors (Gelot et al. 2013). Other individual factors or other mechanisms may be involved in induction or inhibition of photosensitivity, namely those associated with the pharmacologic target of the drug. For instance, in the case of vemurafenib-induced

M. Gonçalo and A. Giménez-Arnau

photosensitivity, the combination therapy with the MEK inhibitor cometinib reduces photosensitivity, as shown by the significant increase in MED-UVA when both drugs are used, compared to vemurafenib alone (Frenard et al. 2019).

I mmunologic Mechanisms in Drug Photosensitivity, Including Photoallergy In photoallergy, the energy of the UV photon transforms the chromophore into a stable photoproduct (photohapten) or enhances its bonding with an endogenous peptide forming a photoallergen. By analogy with allergic and photoallergic contact dermatitis, it is suggested that skin antigen-presenting cells become activated and present the new hapten to T cells in the context of HLA molecules and costimulatory signals. Sensitized T cells, including memory and effector T cells, mostly Th1 and CD8+ cells, will be activated in a further encounter with the same chemical and generate a specific T-cell immune reaction, a type IV hypersensitivity reaction (Elkeeb et  al. 2012; Mang et  al. 2011; Peiser et  al. 2012). This adaptive immune reaction to the new photoproduct is mandatory for drug photoallergy, but as in phototoxicity, initial photochemical reactions may also generate “danger signals” from an innate immune response. These alarming signals may cause a subclinical inflammatory reaction that enhances dendritic cell activation and antigen presentation to naïve T cells or the expression of adhesion molecules and release of chemokines/cytokines by endothelial cells, fibroblasts and keratinocytes. Together, they promote T-cell sensitization or the migration of specific effector T cells into the dermis and epidermis, causing the allergic reaction. Therefore, as in allergic contact dermatitis (ACD) where the innate immune skin response to the allergen is well recognized as an important step towards sensitization (Martin 2015; Neves et  al. 2008), this also occurs very probably in drug photoallergy. Other drug-induced or drug-enhanced immune pathomechanisms that are not completely under-

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stood may also occur. For instance, some drugs may enhance UV-induced expression of the Ro/ SSA antigen on the surface of keratinocytes, may interfere with apoptosis or cytokine production promoting photosensitivity, and the development of skin lesions in drug-induced subacute cutaneous LE (Sontheimer et al. 2008).

et al. 2013; Frick et al. 2010) may also contribute to enhanced photocarcinogenesis. Accelerated photoaging may also occur in the presence of photoactive drugs, as reported particularly for voriconazole in children (Blakely et al. 2019; Sheu et al. 2015).

Drug-Induced/Enhanced Photocarcinogenesis

Photosensitivity: Phototoxicity Versus Photoallergy

Apart from the capacity to generate free radicals and cell death responsible for acute phototoxicity, several phototoxic substances, like psoralens, chlorpromazine fluorquinolones, and ketoprofen, also enhance chromosomal damage in the presence of UV light, both in  vitro and in  vivo (Seto et  al. 2010; Ray et  al. 2013; Agúndez et  al. 2020). These drugs are, therefore, photogenotoxic and photomutagenic. Moreover, DNA aggressions also may cause photo-immunosuppression that further enhances photocarcinogenesis due to the lack of immunosurveillance against cancer cells (Urbach 1997; Klecak et  al. 1997; Müller et  al. 1998; Marrot et al. 2003; Lhiaubet-Vallet et al. 2009). Since 1999, epidemiological studies called the attention to the association between actinic keratosis and the exposure to potentially photosensitizing drugs (Placzek et  al. 1999) and recent reports reinforce this association, namely for diuretics, NSAIDs and cardiovascular drugs (Jensen et  al. 2008; Siiskonen et  al. 2013; Traianou et al. 2012), even without acute signs of photosensitivity. NMSC and melanoma are also increased in humans chronically exposed to photoactive drugs that cause acute photosensitivity, namely psoralens, voriconazole, and vemurafenib (Placzek et al. 1999; Cowen et al. 2010; Miller et  al. 2010; Rinderknecht et  al. 2013; Stern 2012). Apart from direct DNA damage, activation of alternative oncogenic intracellular pathways due to BRAF inhibition by vemurafenib (Rinderknecht et  al. 2013; Lacouture and Melasky 2008), and previous immunosuppression in voriconazole treated patients (Williams et  al. 2014; Haylett

Drug photosensitivity is mainly due to phototoxicity, but some phototoxic chemicals can also induce photoallergy in susceptible individuals (Dawe and Ibbotson 2014; Gonçalo and Giménez-­ Arnau 2015). Phototoxicity and photoallergy are, therefore, not mutually exclusive and there are some overlapping aspects (Oliveira et al. 1996). Classically, phototoxicity is more frequent, develops in every individual, as long as there is sufficient photosensitizer in the skin and enough UV exposure. It is usually dependent on the UV dose and the cutaneous concentration of photosensitizing chemical. Therefore, phototoxicity is somehow predictable. The skin reaction can occur after the first and single contact, with no flare-ups or cross-reactions in further exposures. Clinically it presents mainly as a sharply demarcated erythema exclusively on sun-exposed areas (mimicking exaggerated sunburn), usually resolves promptly but with hyperpigmentation. On histology, apoptotic keratinocytes (sunburn cells) are abundant within the epidermis and there is a sparce inflammatory infiltrate (Gonçalo 2018). Photoallergy develops only in a limited number of individuals, needs previous sensitization, but can develop also with chemically similar chemicals (cross-reactions). It is not strictly dose-dependent and can occur even with exposure to low UV doses. Photoallergy presents mostly as pruritic eczema that can spread to non-­ exposed sites and it takes longer to resolve. On histology, there is mainly a dermo-epidermal T-cell infiltrate with epidermal spongiosis and vesicles or a more lichenoid infiltrate. The reaction can usually be reproduced by a photopatch

M. Gonçalo and A. Giménez-Arnau

252 Table 23.1  Main differences between phototoxicity from photoallergy Frequency Latency period/sensitization Doses of UV/photosensitizer Cross-reactions Morphology of lesions sunburn, polymorphic Sharp limits Covered areas Resolution Residual hyperpigmentation Histology Pathomechanism ROS/inflammation

Phototoxicity High No High No Eczema, erythema multiforme Yes Not involved Quicka Yes Sunburn cells DNA/cell damage Photoproduct

Photoallergy Low Yes Low Yes No Possibly involved May recur, persistent reactors No Eczema Type IV hypersensitivity

This relates only to the acute phototoxic reaction, but late effects as photoaging and photodarcinogenesis may also occur a

test, particularly in photoallergic contact dermatitis. Photoallergic reactions may become persistent and eventually progress to chronic actinic dermatitis with extreme photosensitivity with no further exposure to the culprit chemical (Schauder et al. 1996; Hawk 2004; Béani 2009) (Table 23.1). These two typical polar presentations of drug photosensitivity are easily recognized, but it is not always possible to distinguish them based on the clinical aspects, histopathology, suspected culprit, or results of photopatch or photoprovocation tests. Except for a few chemicals with no intrinsic phototoxic potential that give rise to stable photoproducts and induce only photoallergy, like piroxicam (Figueiredo 1994), most substances can induce both phototoxic and photoallergic reactions. Actually some recognized phototoxic drugs can induce photoallergy, namely topical phenothiazines used as anti-pruritic drugs (Cardoso et  al. 2009; Kerr et  al. 2008b), oral fluoroquinolones (Oliveira et al. 1996; Kurumajin and Shono 1992; Gonçalo and GERDA 1998) or psoralens from plant extracts that are ingested or used topically in “folk Medicine” or during photochemotherapy (Ljunggren 1977; Möller 1990; Karimian-Teherani et al. 2008; Bonamonte et al. 2010). Photosensitivity on the first exposure to a drug is typical of phototoxicity. Nevertheless, photoallergy to piroxicam or ketoprofen can occur at the first exposure in individuals previously sensi-

tized/photosensitized to a related chemical, the contact allergen thiomersal and its moiety thiosalicylic acid in the case of piroxicam (Gonçalo et al. 1992; Hariva et al. 1993; Serra et al. 2008) or cinnamic alcohol or a benzophenone in the case of ketoprofen (Foti et  al. 2008; Avenel-­ Audrun et al. 2010; Stingeni et al. 2010; Infante Hernando et al. 2013; Karlsson et al. 2011). Phototoxicity is considered to occur in every patient as long as exposure to enough drug and sun occurs at the same time, but individual susceptibility for phototoxicity certainly exists. In systemic drug photosensitivity, differences in drug metabolism may generate different concentrations of the photoactive metabolite within the skin. Thickness of the horny layer or melanin pigmentation may also influence drug phototoxicity (Zaheer et al. 2016), but there are other susceptibility factors that need further investigation.

 linical Presentations of Drug C Photosensitivity Systemic drug photosensitivity presents mainly as exaggerated sunburn or acute eczema on sun-­ exposed areas, but also as urticaria, lichenoid reactions, telangiectasia, subacute cutaneous LE, bullae, hyperpigmentation, vitiligo-like lesions, or NMSC (Ferguson 1999; McCarthy et al. 2007; Gonçalo and GERDA 1998) (Table 23.2).

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Table 23.2  Clinical patterns of photosensitivity, mostly involving phototoxicity or photoallergy or other immune-­ mediated reactions Phototoxicity Exaggerated “sunburn” Pseudoporphyria Photo-onycholysis Hyperpigmentation Hypopigmentation (vitiligo-like lesions) Telangiectasia Purpura Pellagra-like reactions Actinic keratosis and skin cancer Accelerated photoaging

Immune-mediated reactions Urticaria Acute or subacute eczema Erythema multiform-like Lichenoid reactions Subacute/chronic lupus erythematosus

Skin reactions may occur immediately after sun exposure in photosensitivity from vemurafenib, may be delayed 1 or 2 days in most phototoxic or photoallergic contact dermatitis or systemic photoallergy, several days or weeks in pseudoporphyria, photo-onycholysis, or subacute cutaneous LE, or even years, in skin aging and skin cancers enhanced by exposure to photoactive drugs. In systemic drug photosensitivity, the reaction usually involves, in a symmetric distribution, the face and forehead, the V shaped area of the neck and upper chest, and dorsum of the hands and forearms. Shaded areas of the face (upper eyelids, upper lip, deep wrinkles) are usually spared (Fig. 23.1) as well as retroauricular and submandibular areas (Fig.  23.2) and other facial areas covered by the beard or hair. In more extensive sun-exposure, large body folds, like the axillae, groins, finger webs, and areas covered by clothing or other accessories (watch strip, shoes), are also usually spared. A different pattern in the distribution of skin lesions can occur when sun exposure is asymmet-

Fig. 23.1 Acute phototoxicity from amiodarone that mimics sunburn and spares the deep facial wrinkles

Fig. 23.2 Photosensitivity from systemic piroxicam, with confluent eczematous lesions of the face sparing the shaded submandibular area

ric, as in car drivers who only expose the left arm/ forearm. Sometimes, in systemic photosensitivity, the lower lip is mainly or almost exclusively involved (Fig.  23.3), because of its higher UV exposure and, very probably, because of the thinner the corneal layer (Hickman et  al. 2010; Auffret et  al. 2006; Canelas et  al. 2010). Occasionally, one or more nails may be involved

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Fig. 23.3  Photosensitivity from voriconazole with severe cheilitis and lip erosions

exclusively, as in photo-onycholysis (Baran and Juhlin 2002). In photoallergic or phototoxic contact dermatitis from topical drugs, lesions occur in the area of concomitant drug application and sun exposure, but distant lesions can occur in areas of accidental contact, as a in a contra-lateral limb (kissing faces of the legs) or in areas of inadvertent spread by the hands or contaminated objects (Hindsén et al. 2004; Lasa Elgezua et al. 2004). Cases of connubial dermatitis have been described, mainly for ketoprofen and benzydamine (Canelas et al. 2010; Matthieu et al. 2004; Hindsén et al. 2006; Devleeschouwer et al. 2008; Fernández-Jorge et  al. 2008). When used as a mouthwash, these NSAIDs induce mostly lip and chin dermatitis (Canelas et al. 2010; Conti et al. 2012). Some topical drugs applied in large skin areas can be considerably absorbed and induce lesions in a distribution similar to systemic drug photosensitivity.

 cute Patterns of Drug A Photosensitivity Immediate Reactions Immediate urticarial reactions, like photocontact urticaria, have been described with chlorpromazine (Lovell et  al. 1986) and with 5-­ aminolevulinic acid used in photodynamic therapy (Kerr et al. 2007).

M. Gonçalo and A. Giménez-Arnau

Amiodarone and benoxaprofen induce immediate prickling and burning with transient erythema (Ferguson 1999; Yones et  al. 2005). Immediate burning upon sun-exposure followed by well-limited painful oedema and erythema that persist for a few days occurs in 22–66% of patients when vemurafenib is used as a single drug for metastatic melanoma (Lembo et  al. 2020; Rinderknecht et  al. 2013), not so much when it is associated with the MEK inhibitor (Frenard et al. 2019). A similar pattern, although less intense and less frequent, is described by other BRAF inhibitors and other targeted therapies for cancer, namely the anaplastic lymphoma kinase (ALK) inhibitor brigatinib (Lembo et al. 2020; Morgado et al. 2019).

Acute Photosensitive Dermatitis Exaggerated sunburn is the main presentation of drug phototoxicity (Fig. 23.1). Non-pruritic and sometimes painful sharp limited erythema with vesicles and/or bullae in more severe forms develops in 12–24 h. It progresses to desquamation in the following days and further to residual hyperpigmentation. In acute drug photoallergy, lesions develop after 12–48 h in sensitized individuals and present mostly as confluent or non-confluent acute or subacute eczematous and pruriginous lesions (Fig. 23.2) that may also affect less exposed skin areas. After the culprit drug is stopped, lesions usually resolve with no residual pigmentation, but they may progress to lichenification or persistent chronic photosensitivity, sometimes even after the drug is withdrawn. In more severe cases of acute photoallergy, erythema-multiforme like lesions occur on photo-exposed locations with possible extension to covered areas (Rodríguez-Pazos et  al. 2013), as in severe cases of photoallergic contact dermatitis from ketoprofen (Matthieu et al. 2004) or systemic drug photosensitivity from tocilizumab (Hamada et  al. 2016), vandetanib (Caro-Gutierrez et  al. 2014), or statins (Rodriguez-Pazos et  al. 2010). Photo-induced cases of Stevens-Johnson syndrome/toxic epi-

23  Drug Photosensitivity

dermal necrolysis have also been associated with drug photosensitivity (Redondo et al. 1996; Moghaddam and Connolly 2014). In the case of photoallergy to piroxicam, pompholyx is often associated with non-confluent papular or vesicular facial lesions (Serra et  al. 2008).

 ubacute Patterns of Drug S Photosensitivity Pseudoporphyria Drug-induced pseudoporphyria develops within weeks to months as chronic skin fragility with flaccid bullae on non-inflamed UV-exposed skin, occasionally progressing to milia. It resembles porphyria cutanea tarda both clinically and on histopathology (bullae below the lamina densa with scarce inflammation), but patients have no inborn error of porphyrin metabolism and no increase of endogenous porphyrins, although some drugs like voriconazole may transiently increase uroporphyrin levels (Hickman et  al. 2010). Pseudoporphyria was initially described with nalidixic acid, furosemide and naproxen, predominantly in children (Ferguson 1999) but, more recently, many other drugs have been associated with this phototoxic reaction: celecoxib (Cummins et  al. 2000; Schmutz et  al. 2006), ciprofloxacin (Schmutz et  al. 2008), voriconazole (Tolland et  al. 2007; Auffret et  al. 2006), torasemide (PérezBustillo et  al. 2008), metformin (Lenfestey et al. 2012), finasteride (Santo Domingo et al. 2011), and imatinib (Pérez et  al. 2014; Timmer-de Mik et  al. 2009; Berghoff and English 2010). Pseudoporphyria represents a typical phototoxic reaction where the photoactivated drug generates singlet oxygen, as the uroporphyrin in the hereditary disease (Ferguson 1999).

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Photo-Onycholysis Photo-onycholysis is a typical pattern of phototoxicity, occurring often as the single manifestation of phototoxicity. It presents as a half-moon distal onycholysis of one or several nails (Fig. 23.4). It appears 2–3 weeks after drug intake and sun exposure and is sometimes preceded by pain in the nail apparatus. It occurs mainly with tetracyclines (demethylchlortetracycline, minocycline, or doxycycline) (Blakely et  al. 2019; Passier et al. 2004), but has also been described with psoralens, fluorquinolones (Baran and Juhlin 2002), paclitaxel (Hussain et  al. 2000), and antipsychotic drugs (Gregoriou et al. 2008). There is no definite explanation for the single involvement of the nail, but it is proposed that the nail bed has relatively less melanin and the nail plate may work as a lens to concentrate UV light (Baran and Juhlin 2002; Passier et  al. 2004; Gregoriou et al. 2008).

 rug-Induced Cutaneous Lupus D Erythematosus In a multicentre database analysis of the European Society of Cutaneous Lupus Erythematosus, drug-induced cutaneous LE was shown to represent 6% among 1002 patients with cutaneous lesions and 13.2% of those with the subacute variant of cutaneous LE (Biazar et al. 2013). This form of drug-induced subacute cutaneous LE is usually associated with photosensitivity and mild systemic manifestations and more than 80% of

Fig. 23.4  Photo-onycholysis from doxycycline

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patients have anti-Ro/SSA auto-antibodies, the hallmark of photosensitivity in LE. Cutaneous annular or papulosquamous lesions usually develop weeks or months after drug exposure (medium of 6  weeks) and can resolve on drug suspension, without scarring (Grönhagen et  al. 2012), mimicking the idiopathic form of cutaneous subacute LE. Lesions are localized in photoexposed areas (face, neck, upper-chest, and arms), but also in usually UV-shaded areas (Biazar et  al. 2013; Lamond et  al. 2013). Chronic cutaneous LE with more infiltrated plaques on the face or V of the neck can also be related with drugs. Subacute cutaneous LE was described initially in association with thiazide diuretics, calcium channel blockers, ACE inhibitors (Sontheimer et al. 2008), and more recently with terbinafine (Farhi et al. 2006), the drug associated with the highest Odds ratio for this adverse event (Grönhagen et  al. 2012). At present, there is a long list of other drugs capable of inducing cutaneous LE (Grönhagen et al. 2012), namely proton pump inhibitors (Almebayadh et  al. 2013; Dam and Bygum 2008), antiepileptics, TNF-alfa antagonists (Grönhagen et al. 2012), and the anticancer taxanes, paclitaxel, and docetaxel (Lamond et al. 2013; Chen et al. 2004).

Dyschromia Transient residual hyperpigmentation frequently follows acute phototoxicity. As in the usual UV-induced pigmentary response, IL-1alfa stimulates keratinocytes to produce melanotropins that activate melanocytic pigmentation (Rok et al. 2015; Khandpur et al. 2017). On the opposite, hypopigmentation (photoleukomelanoderma) was described in flutamide-induced photosensitivity (vitiliginous lesions with sharp limits after the acute reaction) (Vilaplana et  al. 1990; Gonçalo et al. 1999) and hydrochlorothiazide (Khandpur et al. 2017). Dyschromia with solar lentigines and other signs of photoaging have been recently described

M. Gonçalo and A. Giménez-Arnau

with voriconazole and vandetanib (Giacchero et al. 2012; Malani and Aronoff 2008). Dyschromia from the accumulation of the photoactive drug or its metabolites in the dermis occurs in a smaller percentage of patients after acute phototoxicity from amiodarone, minocycline, or phenothiazines (Vassileva et  al. 1998). Some patients with lower phototypes also develop a golden-brown, slate grey, or bluish colour on sun exposed areas that persists longer after stopping amiodarone (Ferguson 1999; Ammoury et al. 2008).

 ther Clinical Patterns of Subacute O Photosensitivity Photo-distributed lichen plannus or lichenoid reactions have been reported with several drugs, namely thiazides (Johnston 2002), tetracyclines (Susong and Carrizales 2014), quinidine (Dawson 1986), capecitabine (Hague and Ilchyshyn 2007; Walker et al. 2014; Shah et al. 2017), and anti-­ HCV agents, simeprevir and sofosbuvir (Simpson et al. 2015). This may represent an individual reaction pattern of photosensitivity as it has been described with two different drugs in the same patient (MuneraCampos et al. 2019). Telangiectasia as a manifestation of photosensitivity has been reported with nifedipine and other calcium channel blockers (Ferguson 1999; Collins and Ferguson 1993; Grabczynska and Cowley 2000), venlafaxine (Vaccaro et al. 2007), and with some cephalosporins (Blakely et  al. 2019; Borgia et al. 2000). A telangiectatic pattern of photoaging with lesions mainly in the lateral folds of the neck, sparing the shaded skin under the chin, is frequently observed in patients chronically exposed to the sun and photoactive drugs (Borgia et al. 2000). In rare cases, petechial purpura with sharp limits on the transition to the shaded areas was described with ciprofloxacin (Urbina et al. 2006). Pellagra is associated with the prolonged use of isoniazid that consumes niacin for its metabo-

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lism, and pellagroid reactions were reported with the anticancer agents, like 6-mercaptopurin and 5-fluoruracil (Blakely et al. 2019) and olanzapine (Singh and SKP 2015).

Table 23.3  Main drugs causing photosensitivity 1. Nonsteroidal anti-inflammatory drugs (NSAIDs) Arylpropionic acids:  Ketoprofena,c, tiaprofenic acidb, suprofen   Naproxend, ibuprofen, ibuproxam, carprofenc Piroxicama,c , Etofenamatea,c Benzydaminec Celecoxibd, Diclofenacc 2. Antimicrobials (antibiotics, antifungals, antivirals, antimalarials) Tetracyclinesb (doxycycline, minocycline, limecycline) Fluorquinolonese (lomefloxacinb, ciprofloxacina) Sulphonamides (sulfamethoxazole, dapsone) Isoniazid/pyrazinamide Voriconazoleb,e, itraconazole, terbinafine Efavirenz, tenofovir, Faldaprevir Quinine, Chloroquine, Hydrochloroquine 3. Psychotropic and related drugs Phenotiazines (chlorpromazinec, thioridazine)  Promethazinea,c Chorproethazinea,c Imipramine, clomipramine Serotonin reuptake inhibitors 4. Cardiovascular drugs Amiodaroneb, quinidine Hydrochlorothiazideae, Furosemide, torsemide Calcium-channel blockers (amlodipine, nifedipine) 5. Anticancer drugs Classical chemotherapy  methotrexate, 6-mercaptopurine, azathioprine, 5-FU  placlitaxel and taxanes  dacarbazine, vinblastine Targeted therapies Vemurafenibe Imatinib,d Sunitinibd Erlotinib, Vandetanib, Pazopanib Brigatinib 6. Miscellaneous drugs Psoralense Fenofibratea, simvastatin, atorvastatin Sulfonylureas, sitagliptin, metformin Flutamide, finasteride Pirfenidone Porphyrin analogues for photodynamic therapy Retinoids (isotretinoin) 7. Plants (used as drugs)b Hypericum perforatum (St John’s wort) Ruta graveolans (common rue) c Kava extracts

 elayed and Late Effects D of Photosensitivity Patients chronically exposed to photoactive drugs develop accelerated photoaging, actinic keratosis, and skin cancers, which, at least partially, can be explained by the photogenotoxic effect of some drugs. Voriconazole causing dyschromia, lentigines, and actinic keratosis, even in children, is such an example (Frick et al. 2010). Apart from psoralens, responsible for a dose-­dependent increased risk of skin cancers after PUVA therapy (Stern 2012), drugs like naproxen, chlorpromazine, and the fluorquinolones, particularly lomefloxacin, augment DNA aggression induced in vitro by UV and increase epidermal neoplasia in animals (Klecak et  al. 1997). In humans, potentially photosensitizing drugs like diuretics and cardiovascular drugs are also being associated with increasing cutaneous pre-­ cancerous lesions (Placzek et  al. 1999; Jensen et  al. 2008) and recent reports correlate human short-term exposure (weeks/ months) to voriconazole or vemurafenib and long exposure to diuretics and anti-hypertensive drugs with an increased risk of developing NMSC and, even, melanoma (Blakely et  al. 2019; McCarthy et al. 2007; Cowen et al. 2010; Gelot et  al. 2013; Miller et  al. 2010; Rinderknecht et al. 2013).

 ain Drugs Causing M Photosensitivity The catalogue of topical and systemic drugs inducing photosensitivity is large and constantly increasing and is not restricted to particular pharmacologic families. Photosensitivity is reported mainly with NSAIDs, antimicrobials (tetracyclines, fluorquinolones, sulphonamides), psychotropic, cardiovascular, and anti-cancer drugs (Table 23.3).

Mainly photoallergic Mainly phototoxic c Often also from topical exposure or airborne exposure, mainly in occupational settings d Often associated with porphyria cutanea tarda e An increase of actinic keratosis, NMSC and, occasionally, melanoma have been related with these drugs

a

b

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benzophenone UV absorbers, particularly oxybenzone (LeCoz et  al. 1998), and octocrylene which may contain benzophenone residues from NSAIDs cause photosensitivity when used topi- the manufacturing process (Karlsson et al. 2011). cally and also after systemic use. Arylpropionic Actually, previous sensitization to these UV filderivatives (benoxaprofen, carprofen, naproxen, ters or to fenofibrate may explain a photoallergic suprofen, tiaprofenic acid, ketoprofen, and ibu- reaction to ketoprofen at the first drug intake and profen) have been frequently associated with more severe reactions (Rato et  al. 2018; Tsai phototoxicity, with tiaprofenic acid at 5% pet et al. 2017). Photoallergy from piroxicam, frequent inducing phototoxic reactions in more than half of photopatch tested patients (Gonçalo and 20–30  years ago (Cardoso et  al. 2009; Gonçalo Figueiredo 1992; Neumann et  al. 2000). Other et al. 1992; Serra et al. 2008; Leonard et al. 2005; NSAIDs from this group have been reported to La Cuadra-Oyanguren et al. 2007; Pigatto et al. cause photoallergy, occasionally (carprofen and 2008), occurs in individuals with previous ­contact naproxen) or frequently (ketoprofen). Oral allergy to thiomersal (Cirne de Castro et  al. naproxen has been associated with photo-­ 1991), more precisely to its most frequent sensidistributed erythema multiforme or lichenoid tizing moiety, thiosalicylic acid (Gonçalo et  al. like-lesions, suggesting photoallergy (Gutierrez-­ 1992; Hariva et  al. 1993; Ikezawa et  al. 1992; Gonzalez et al. 2011), but also with pseudopor- Gonçalo et al. 1996a). Actually, upon UVA irraphyria (Levy et al. 1990). Ketoprofen is the main diation, piroxicam decomposes and gives rise to a cause of photoallergic contact dermatitis, photoproduct, which is structurally similar to although it seldom causes systemic photosensi- thiosalicylic acid and responsible for photoaltivity probably due to the low levels reached in lergy (Gonçalo et  al. 1992; Hariva et  al. 1993; Ikezawa et al. 1992). the skin after systemic use (Guy et al. 2014). Photosensitivity from piroxicam usually Ketoprofen used in gel or patches to relieve musculoskeletal pain has caused severe photoal- occurs within 24–48 h after the first drug intake lergic reactions (Béani 2009; Veyrac et al. 2002), and presents as an acute eczema involving difoften with oedema, bullae, or erythema fusely the whole face or as scattered erythemamultiform-­ like lesions, extending well beyond tous papules and vesicles on the face and dorsum the area of application (Devleeschouwer et  al. of the hands and dyshidrosis (Gonçalo 1998; 2008; Izu et  al. 2008; Sugiura et  al. 2000). Serra et al. 2008; Varela et al. 1998; Youn et al. Reactions may recur on sun exposure with no 1993). Photopatch tests with piroxicam at 1 or further drug application, as ketoprofen persists in 5% pet are positive in more than 90% of the the epidermis at least for 17 days after applica- cases, with no cross-reaction with tenoxicam, tion (Sugiura et  al. 2000) and in contaminated meloxicam, or lornoxicam, as these oxicams do objects, namely in clothing after machine wash- not share the thiosalicylate moiety (Gonçalo et al. ing (Hindsén et al. 2004). Irradiation of ketopro- 1992; Trujillo et  al. 2001). Nevertheless, it is fen originates a stable photoproduct that behaves important to remember that cross reactivity as a photoallergen (3-ethyl-benzophenone) (Imai between piroxicam and these oxicams occurs et  al. 2005), and cross-reacts with other chemi- regularly in fixed drug eruption (Gonçalo et  al. cals that share a similar benzophenone structure, 2002). Etofenamate also causes photoallergic contact namely some arylpropionic acid derivatives (tiaprofenic acid, suprofen, piketoprofen, and dermatitis or more frequently photo-aggravated dexketoprofen, but not naproxen or ibuprofen) ACD (EMCPPTS Taskforce et al. 2012; Sánchez-­ (Fernández-Jorge et  al. 2008; Asensio et  al. Pérez et al. 2001; Kerr et al. 2011). Photoallergic 2008), fenofibrate, a systemic hypolipemic agent contact dermatitis from benzydamine, frequent in (Veyrac et al. 2002; LeCoz et al. 1998; Kuwatsuka Southern Europe (Canelas et al. 2010; La Cuadra-­ et  al. 2016; Rato et  al. 2018; Tsai et  al. 2017), Oyanguren et  al. 2007; Gonçalo et  al. 2013),

23  Drug Photosensitivity

presents as a right hand dermatitis after its use as a vaginal wash (Lasa Elgezua et al. 2004) or as cheilitis and chin dermatitis when used as a mouthwash (Canelas et al. 2010). Topical diclofenac, used for the treatment of actinic keratosis, has caused allergic and photoallergic contact dermatitis (Kowalzick and Ziegler 2006), sometimes with cross-reactions to aceclofenac (Fernández-­ Jorge et al. 2009).

Antimicrobials Oral tetracyclines, doxycycline, and particularly demeclocycline are highly phototoxic and can induce exaggerated sunburn, photo-onycholysis, and pseudoporphyria (Vassileva et  al. 1998; Kuznetsov et al. 2011). Minocycline, though less phototoxic, can also induce a bluish persistent pigmentation and has caused photo-onycholysis (Fig.  23.4), like lymecycline (Wlodek and Narayan 2014; Monteiro et al. 2016). Nalidixic acid has caused phototoxicity presenting often as pseudoporphyria (Boisvert and Barbeau 1981; Birkett et al. 1969) and the fluoroquinolones with an halogen at C-8 (fleroxacin, lomefloxacin, sparfloxacin, pefloxacin) also induce frequent phototoxic reactions (4–15% of treated patients), whereas this adverse reaction is less frequent with ciprofloxacin, norfloxacin, ofloxacin, and enoxacin (Monteiro et al. 2016). Hyperpigmentation can occur after lomefloxacine (Connors et al. 2018) and ciprofloxacin has caused pseudoporphyria (Schmutz et  al. 2008; Vassileva et  al. 1998), purpura on photoexposed areas (Urbina et  al. 2006), and photo-induced Stevens-Johnson syndrome (Moghaddam and Connolly 2014). In vitro and in  vivo tests prove the phototoxic potential of fluoroquinolones, but photoallergy has also been reported with lomefloxacin (Oliveira et  al. 1996; Kurumajin and Shono 1992) and enoxacin (Vassileva et  al. 1998), sometimes with cross-reaction to other fluoroquinolones (ciprofloxacin and flerofloxacin) (Kimura and Kawada 1998; Correia et  al. 1994). Moreover, fluoroquinolones also photosensitize DNA and are photomutagenic and photocarcinogenic in vitro and in animal expe-

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riences (Klecak et  al. 1997; De Guidi et  al. 2011). Sulfonamides, sulfa-drug analogues (thiazide diuretics, hypoglycemic sulfonylureas, and celecoxib) and dapsone (diaminodiphenylsulfone) have caused photosensitivity within the spectrum of UVB and UVA (Blakely et al. 2019; Vassileva et al. 1998; Yazici et al. 2004; Joseph 1987). This adverse effect is not so frequent with cotrimoxazole, but trimethoprim has also been implicated (Chandler 1986). On rare occasions, other antibiotics have been considered the culprits in photosensitivity, namely the antituberculous drugs isoniazid and pyrazinamide (Blakely et al. 2019; Lee and Jung 1998) and betalactams ceftazidime and cefotaxime, the latter responsible for telangiectasia on sun-exposed areas (Borgia et al. 2000). The antifungal grisefulvin can cause an exaggerated sunburn-like reaction and aggravate lupus erythematosus (Kawabe et  al. 1988), and terbinafine can also induce subacute lupus erythematosus in patients with anti-Ro antibodies and Rowell syndrome with photo-distribution of skin lesions (Farhi et al. 2006; Murad et al. 2015). Among triazole antifungals, itraconazole has seldom been associated with photosensitivity (Blakely et al. 2019; Hawk et al. 2000), but phototoxicity affects more than 40% of patients treated with voriconazole longer than 4–6  months, particularly children (Sheu et  al. 2015; Goyal 2015). Cutaneous reactions are dependent on broad UVA, extend to the visible solar spectrum (Haylett et al. 2013), and include burning sensation immediately after sun exposure, sunburn like reaction, cheilitis, erosions of the lower lip (Fig.  23.3), and pseudoporphyria (Tolland et al. 2007; Hansford et al. 2012; Frick et al. 2010; Auffret et al. 2006; Riahi and Cohen 2011). On relative short exposures (1–2 years), patients develop accelerated photoaging with solar lentigines and actinic keratosis that soon progress to multifocal invasive squamous cell carcinoma (McCarthy et al. 2007; Cowen et al. 2010; Williams et al. 2014; Auffret et al. 2006; Morice et al. 2010) or melanoma (Miller et al. 2010). The immunosuppressed state of most patients on long-term voriconazole may enhance cutaneous carcinogenesis, but skin cancers

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related with voriconazole are distinct and more aggressive than those described in organ-transplanted or other immunosuppressed patients (Epaulard et al. 2013). Antivirals used for HIV or HCV infection have been associated with photosensitivity confirmed by photopatch or photoprovocation tests (Blakely et  al. 2019). Efavirenz induced mostly photo-distributed papulosquamous annular lesions within a few days or weeks of treatment and (Yoshimoto et  al. 2004; Isaacs et  al. 2013) tenofovir induced a severe photo-distributed reaction with further generalization interpreted as a photoallergy (Verma et al. 2012) and the combination of faldaprevir and deleobuvir caused photosensitivity in more than a quarter of patients involved in controlled clinical trials (Zeuzem et al. 2013). The old antimalarials quinine and quinidine have frequently caused photoallergic and phototoxic reactions (Armstrong et  al. 1985). Chloroquine and hydroxychloroquine, mostly used in dermatology to prevent photosensitivity in cutaneous lupus erythematosus and polymorphic light eruption, paradoxically also cause photosensitivity (Metayer et  al. 2001; Lisi et  al. 2004) and a similar reaction has also been described with the combination of atovaquone and proguanil used in malaria prophylaxis (Amelot et al. 2014).

Psychotropic Drugs Phenothiazines used systemically as antipsychotics (chlorpromazine, thioridazine, and flupenthixol) are typically phototoxic and cause sunburn, bullous and lichenoid eruptions, and photodistributed slate-grey hyperpigmentation on the long term (Blakely et al. 2019). Olanzapine has caused several cases of photosensitivity (Gregoriou et  al. 2008; Singh and SKP 2015; Reddy et al. 2018), as well clozapine, haloperidol, and riperidone (Blakely et al. 2019). Photoallergy occurs frequently after contact with phenothiazines, namely with creams containing promethazine or isothipendyl chlorhydrate used as topical antipruritics (Cardoso et al.

M. Gonçalo and A. Giménez-Arnau

2009; Katsarou et al. 2008; Bibas et al. 2012), chlorproethazine cream used for muscle pain (Kerr et  al. 2008b; Barbaud et  al. 2001a) or chlorpromazine manipulated by caregivers (Monteagudo-Paz et al. 2011). Among antidepressants, tricyclic drugs imipramine and clomipramine, as well as the newer selective serotonin reuptake inhibitors, fluoxetine, paroxetine, fluvoxamine, venlafaxine, and sertraline, have been proven as occasional causes of photosensitivity (Alrashidi et  al. 2020; Blakely et al. 2019), similarly to the anxiolytics alprazolam and chlordiazepoxide (Blakely et al. 2019).

Cardiovascular Drugs Soon after its introduction in the market, the diuretic hydrochlorothiazide was recognized as a cause of photosensitivity, often proven by positive photopatch tests. Exaggerated sunburn, photo-distributed eczema, lichenoid reactions, dyschromia, persistent photosensitivity (Gómez-­ Bernal et  al. 2014; Rosenthal and Herrmann 2019), and more recently increase of actinic keratosis and NMSC have been related with its wide use (Jensen et al. 2008; Karagas et al. 2007; Shin et al. 2019). The antiarrhythmic amiodarone frequently causes phototoxicity (7–50% of patients) presenting as burning/tingling sensation on sun-­ exposure, followed by erythema, eczema, and a bluish-gray hyperpigmentation in sun-exposed areas due to the dermal accumulation of drug metabolites (Ammoury et al. 2008; Kosior 2014). Other cardiovascular drugs have been associated with photo-induced reactions, like amlodipine and nifedipine (telangiectasia) (Collins and Ferguson 1993; Grabczynska and Cowley 2000), diltiazem (lichenoid reaction with hyperpigmentation) (Scherschun et  al. 2001), furosemide/ torsemide (pseudo-porphyria, subacute lupus erythematosus, photo-onycholysis) and, very occasionally, angiotensin conversing enzyme inhibitors (lisinopril, enalapril, and ramipril), candesartan, and the beta-blockers atenolol and bisoprolol (Alrashidi et al. 2020).

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Anticancer Drugs

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Other Drugs

Many classical anticancer drugs and particularly Despite its recognized phototoxic potential, the new targeted therapies have been increasingly anti-fibrotic agent pirfenidone was released for associated with photo-induced cutaneous lesions the treatment of interstitial lung disease and has (Lembo et al. 2020). Examples of classical drugs caused phototoxic reactions with photoleuinclude the antimetabolites, methotrexate (sun- komelanoderma (Gaikwad and Mukherjee burn recall reaction), 5-fluoruracil and related 2016; Papakonstantinou et  al. 2016; Tsuruta capecitabine and tegafur (sunburn, lichenoid and et  al. 2016) and photoallergy with lichenoid eczematous reactions, hyperpigmentation), reactions and positive photopatch or photo6-mercapto-purine and azathioprine (pellagra-­ provocation tests (Park et  al. 2017; Ferrerlike reactions and photocarcinogenesis) Guillén et  al. 2019; Jiang et  al. 2012; Adachi (Alrashidi et  al. 2020), dacarbazine (Blakely et al. 2015). et  al. 2019), paclitaxel and other taxanes (eryAs already reported, fenofibrate can cause thema multiforme, photo-onycholysis, drug-­ photoallergy with eczematous and lichenoid induced lupus erythematosus) (Lamond et  al. reactions due to its benzophenone structure and 2013), and vinblastine (Blakely et al. 2019). often exhibits cross-reactions with ketoprofen Among new targeted therapies, photosensitiv- (Kuwatsuka et  al. 2016; Rato et  al. 2018; Tsai ity has been described with imatinib (several et  al. 2017; Machet et  al. 1997). Statins, both cases of pseudoporphyria) (Pérez et  al. 2014; simvastatin and atorvastatin, have also induced Berghoff and English 2010; Batrani et al. 2016), photosensitivity with reduced sensitivity to UVA sunitinib (pseudoporphyria) (Sanz-Motilva et al. (Alrashidi et al. 2020). 2015), brigatinib (sunburn like reaction) Retinoids, namely isotretinoin, increases UV (Morgado et  al. 2019), erlotinib (Fukai et  al. sensitivity, and very occasionally photosensitiv2014) (also with acne-like reactions predominat- ity has been described with antidiabetics (glibening in sun-exposed areas), crisotinib (Blakely clamide and sitagliptin), the anticonvulsant et al. 2019), pazopanib (phototoxicity and hyper- carbamazepine (Alrashidi et al. 2020), flutamide pigmentation) (Udompanich et al. 2018), vande- (Vilaplana et al. 1990; Leroy et al. 1996; Yokote tanib (phototoxic and several photoallergic et  al. 1998), and finasteride (Santo Domingo reactions with erythema multiforme-like aspects, et al. 2011) and even with amoxicillin (Delaunay confirmed by photopatch tests) (Chang et  al. et al. 2019). Therefore, all suspected drugs have 2009; Giacchero et al. 2012; Udompanich et al. to be considered and photopatch or photoprovo2018), and, particularly, with vemurafenib. When cation tests should be performed to establish a used as a single therapy in metastatic melanoma, correct diagnosis. up to two thirds of patients develop vemurafenib Moreover, photosensitivity can be due to photosensitivity in the spectrum of UVA present- “folk” medicines, mostly based on plant extracts ing as immediate burning and painful sensation rich in furocoumarins, like “home-made” infuand a sharply demarcated erythema and oedema sions of St. John’s wort (Hypericum perforatum that appear still during UV irradiation, resem- L.) used to treat depression (Lovell 2000) bling solar urticaria, but erythema and oedema (Fig. 23.5) or Ruta graveolans infusions applied persist for a few days (Gelot et al. 2013; Dummer topically to relieve pain in fibromyalgia (Arias-­ et al. 2012; Brugière et al. 2014). Santiago et al. 2009).

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Fig. 23.5  Photosensitivity after drinking an infusion of Hypericum perforatum (St. John’s wort) for the management of depression

 iagnostic Procedures in Drug D Photosensitivity Whenever a patient has a cutaneous reaction in photoexposed areas it is mandatory to distinguish a photosensitive eruption from “airborne dermatitis” from chemicals present in the air and other eczemas. Involvement of the shaded areas, namely body folds, upper eyelid, retroauricular, and submandibular areas, which are not prone to receive UV light, favours an airborne dermatitis. But “airborne dermatitis” can also occur from photoactive drugs in an occupational setting, e.g. healthcare workers or caregivers who crash chlorpromazine tablets of to give their patients (Cardoso et  al. 2009; Monteagudo-Paz et  al. 2011), individuals involved in the manufacture of carprofen (Walker et  al. 2006; Kerr et  al. 2008a), and farmers who handle pig or rabbit feed containing olaquindox or cotrimoxazole (Schauder et  al. 1996; Emmert et  al. 2007; Watanabe et al. 2009). Atopic dermatitis frequently involves the face and can be aggravated by sun exposure, particu-

M. Gonçalo and A. Giménez-Arnau

larly in adolescents and adults, and facial ACD needs to be excluded. Other causes of photosensitivity also have to be ruled out, namely genetic diseases involving DNA repair mechanisms or DNA instability (xeroderma pigmentosum, thrichothiodistrophy, Cocakyne or Bloom’s syndrome), genetic or acquired disorders of metabolism (porphyria, pellagra), inflammatory/autoimmune diseases like lupus erythematosus and dermatomyositis, infectious diseases like HIV infection, and idiopathic photodermatoses, like solar urticaria, polymorphic light eruption, chronic actinic dermatitis, actinic prurigo, and hydroa vaciniforme. These disorders have particular clinical aspects and different evolution, but some drugs may enhance or induce these diseases, as in drug-­ induced LE or in porphyria cutanea tarda unveiled by estrogens or alcohol and some patterns of drug photosensitivity may resemble these diseases (pseudoporphyria). In suspected drug photosensitivity, it is very important to question the onset of drug use and the relation with sun exposure, with a particular emphasis into the amount and type of sun light received, including through a window glass which allows permeation of UVA mostly involved in drug photosensitivity. In typical cases of photosensitivity after exposure to a known photosensitizer and resolution on drug withdrawal, additional tests are not mandatory. Photopatch tests are indicated mainly for confirming the aetiology of photoallergic contact dermatitis, but they can also be useful in the study of systemic drug photosensitivity (Gonçalo and GERDA 1998; Barbaud et  al. 2001b; Gonçalo 2011; Gonçalo et  al. 1996b). For this procedure, allergens in patch test chambers are applied in duplicate on the back, followed by skin irradiation of one of the sets of allergens at day 1 or day 2 with 5 J/cm2 of UVA, whereas the other set is shielded from light. Readings should be performed immediately after irradiation and also 48 and/or 72  h thereafter, comparing the irradiated versus non-irradiated area of the back (Bruynzeel et al. 2004). Positive reactions both

23  Drug Photosensitivity

in the irradiated and non-irradiated sites mean contact allergy that may be photoaggravated if the reaction is 1+ more in the irradiated site. A photopatch test is positive when erythema and papules covering the whole test area are observed only in the irradiated side (Bruynzeel et  al. 2004). If the reaction is mainly erythema and oedema, without pruritus, exclusively limited to the test chamber area, with very sharp limits, begins shortly after irradiation, reaches its highest intensity by 24  h, and regresses by 48/72  h (decrescendo reaction) with hyperpigmentation, it suggests a phototoxic reaction. A pruritic erythema with vesicles, diffuse limits extending beyond the chamber limit, increasing in intensity until 48/72  h after irradiation ­(crescendo reaction), suggests photoallergy (Neumann et  al. 1994). Often these patterns are not so typical and the difficulties previously referred in the interpretation of clinical cases also occur in the interpretation of the photopatch tests. The recommended European Baseline photopatch test series includes many topical and systemic drugs, namely ketoprofen, etofenamate, piroxicam, benzydamine, and also piketoprofen, dexketoprofen, ibuprofen, diclofenac, fenofibrate, and chloropromazine in the extended series (Gonçalo et  al. 2013). In the absence of standardized commercial allergens, which are really few for the study of systemic drug photosensitivity, drugs can be photopatchtested after the powder of the commercial drug is incorporated in petrolatum or in water, as recommended for the study of other non-immediate cutaneous drug eruptions. Photopatch tests are often positive (Gonçalo et  al. 2013) in photoallergy to piroxicam (Gonçalo et  al. 1992), ketoprofen (EMCPPTS Taskforce et  al. 2012), fenofibrate (Rato et  al. 2018; Tsai et  al. 2017), and also occasionally with hydrochlorothiazide (GómezBernal et al. 2014), lomefloxacin (Oliveira et al. 1996), pirfenidone (Park et al. 2017), and vandetanib (Giacchero et al. 2012). Photoprovocation is also helpful to confirm the culprit in systemic drug photosensitivity (Alrashidi et  al. 2020). For photoprovocation, small areas of the back/buttocks are irradiated

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with increasing UV doses and, if possible, different UV-wavelengths. Readings are performed immediately or within 24–72  h. Reaction to very low UV doses for the phototype or a significant difference in the minimal erythema dose (after UVA or UVB irradiation) between phototests performed while the patient is exposed to the drug or after its withdrawal is considered positive. Photoprovocation using a monochromator allows identification of the precise UV-wavelength responsible for the photosensitivity in order to avoid it in future drug exposures. With highly phototoxic drugs, both photopatch and photoprovocation tests can be positive in the majority of tested individuals, therefore, they are not particularly useful for confirming the aetiology of a phototoxic reaction, but they can disclose a hidden photoallergy.

General Principles of Treatment Drug suspension and sun avoidance are recommended to resolve drug photosensitivity. When the drug is essential and life-saving, when there is no alternative drug, or the alternative drug is not adequate, sun avoidance, protection with clothing, and a broad-spectrum sunscreen that covers the UV spectrum of photosensitivity (mainly within the UVA) may be adequate to improve photosensitivity (Lankerani and Baron 2004). This protective effect of sunscreens can be helpful particularly in phototoxic reactions, as shown for voriconazole (Frisch et al. 2010), vemurafenib (Dummer et al. 2012), and amiodarone (Ferguson et  al. 1985). Broad spectrum sunscreens may reduce both acute and long-term effects of drug photosensitivity, like photoaging and photocarcinogenesis (Frisch et al. 2010), but they should always be associated with other sun avoiding measures. Moreover, they should be recommended as a preventive measure from the onset of therapy with known photosensitive drugs. Nevertheless, it is important to recognize that chemical UV filters represent an important cause of contact photosensitivity (Cardoso et al. 2009;

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264

EMCPPTS Taskforce et al. 2012), particularly in patients with previous dermatoses (Gonçalo et al. 1995). For drugs that have a short half-life, their administration at noon may be helpful to reduce concentration during solar exposure during the day. In cases of acute photoallergy from topical or systemic drugs, suspension of the culprit and sun avoidance will not resolve the skin lesions within a short time and, therefore, active treatment may be necessary. Topical corticosteroids, in a formulation and potency adapted to the localization and severity of the dermatitis, may be prescribed for a few days. In severe reactions, as often observed with topical ketoprofen and systemic piroxicam, an additional short course of oral corticosteroids (24–32 mg of methylprednisolone, or equivalent, for a few days followed by a quick dose tapering) may be necessary to reduce acute symptoms and skin lesions. In acute phototoxicity, presenting mainly as exaggerated acute sunburn, the efficacy of corticosteroids is highly questioned. Emollients and further photoprotection are advised for some time after resolution of acute photosensitivity.

Conclusions Phototoxic, photoallergic, and overlapping photosensitive reactions are still a frequent problem. They have highly polymorphic clinical presentations with different time courses concerning exposure to the drug and to the sun, and therefore the diagnosis can be difficult. Main culprits depend on geographic areas and over time, mostly related to prescription habits. The dermatologist must be highly alert to search for a possible involvement of a drug in a photosensitive patient and try to confirm its contribution to photosensitivity. A correct questionnaire should be conducted and, although not so important in phototoxic cases, complementary tests including photopatch and photoprovocation tests, may contribute to the final etiologic diag-

nosis. This is important in order to allow an adequate patient advice concerning further eviction of the photosensitizer and related chemicals, which, apart from acute symptoms, are being increasingly associated with accelerated photoaging and enhancement of skin cancers.

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23  Drug Photosensitivity Tolland J, McKeown P, Corbett J. Voriconazole-induced pseudoporphyria. Photodermatol Photoimmunol Photomed. 2007;23:29–31. Traianou A, Ulrich M, Apalla Z, De Vries E, Bakirtzi K, Kalabalikis D, et al. Risk factors for actinic keratosis in eight European centres: a case-control study. Br J Dermatol. 2012;167:36–42. Trujillo M, Barrio M, Rodríguez A, Moreno-Zazo M, Sánchez I, Pelta R, et  al. Piroxicam-induced photodermatitis. Cross-reactivity among oxicams. A case report. Allerg Immunol. 2001;29:133–6. Tsai K, Yang J, Hung S. Fenofibrate-induced photosensitivity—a case series and literature review. Photodermatol Photoimmunol Photomed. 2017;33:213–9. Tsuruta A, Washio K, Fukunaga A, Nishigori C. Pirfenidone-induced photoleukomelanoderma in a patient with idiopathic pulmonary fibrosis. J Dermatol. 2016;43:207. Udompanich S, Chanprapaph K, Rajatanavin N.  Phototoxic reaction induced by Pazopanib. Case Rep Dermatol. 2018;10:251–6. Urbach F.  Phototoxicity and possible enhancement of photocarcinogenesis by fluorinated quinolone antibiotics. J Photochem Photobiol B. 1997;37:169–70. Urbina F, Barrios M, Sudy E.  Photolocalized purpura during ciprofloxacin therapy. Photodermatol Photoimmunol Photomed. 2006;22:111–2. Vaccaro M, Borgia F, Barbuzza O, Guarneri B. Photodistributed eruptive telangiectasia: an uncommon adverse drug reaction to venlafaxine. Br J Dermatol. 2007;157:822–4. Varela P, Amorim I, Massa A, Sanches M, Silva E.  Piroxicam-beta-cyclodextrin and photosensitivity reactions. Contact Dermatitis. 1998;38:229. Vassileva S, Matev G, Parish L.  Antimicrobial photosensitive reactions. Arch Intern Med. 1998;158:1993–2000. Verma R, Vasudevan B, Shankar S, Pragasam V, Suwal B, Venugopal R, et  al. First reported case of tenofovir-­ induced photoallergic reaction. Indian J Pharm. 2012;44:651. Veyrac G, Paulin M, Milpied B, Bourin M, Jolliet P. Bilan de l’enquête nationale sur les effets indésirables cutanés do kétoprofène gel enregistrés entre le 01/09/1996 et le 31/08/2000. Therapie. 2002;57:55–64. Vilaplana J, Romaguera C, Azón A, Lecha M. Flutamide photosensitivity-residual vitiliginous lesions. Contact Dermatitis. 1990;38:68–70. Walker S, Ead R, Beck M.  Occupational photoallergic contact dermatitis in a pharmaceutical worker

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Epidermolysis Bullosa

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Ankur Sarin, Jushya Bhatia, and Mohamad Goldust

Key Points • Epidermolysis bullosa is distinguished in –– Inherited epidermolysis bullosa. –– Acquired epidermolysis bullosa. • Inherited epidermolysis bullosa is a group of inherited disorders characterized by increased skin and mucosal fragility, after minimal trauma. • The new classification includes four groups on the basis of site of blister formation- EB simplex (EBS), Junctional EB (JEB), Dystrophic EB (DEB), and Kindler syndrome. • Proteins involved in pathogenesis of EB include plakophilin 1, desmoplakin, plectin, α6β4integrin, keratin 5 and 14, collagen type 17, collagen 7, and kindlin 1. • Immunoflourescence and electron micrscopy help in diagnosis of EB subtypes. • The prenatal diagnosis in family at risk of disease recurrence is possible through molecular diagnosis. • The clinical pictures and course vary upon the EB type and subtype. The evolution is generally chronic; EBS: the evolution is chronic with improvement generally along the life;

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• A. Sarin · J. Bhatia Sarin Skin Solutions, New Delhi, India

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M. Goldust (*) Department of Dermatology, University Medical Center Mainz, Mainz, Germany e-mail: [email protected]

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JEB: generalized severe (previously known as JEB-Herlitz), the clinical picture may be mild at birth and worsens dramatically in the first weeks/months of life; severe generalized recessive DEB: (previously known as Hallopeau-­Siemens RDEB) is the most important form because of multisystem involvement and the high risk to develop squamous cell carcinoma; other subtypes may be associated to extracutaneous abnormalities, e.g. JEB with pyloric atresia (JEB-PA) and EBS-MD (EBS-­ muscular dystrophy). The management of EB patients is mainly supportive and requires a multidisciplinary team which is led by a dermatologist. Expert nursing care is must to ensure protection of the newborn from mildest forms of trauma. Newborn with EB should be protected from heat-induced blisters and use of incubators should be with caution. Non-adherent silicone dressings and foam dressings that absorb exudates are preferred. Bleach baths, topical antiseptics, and topical antibiotics are used to reduce the bacterial load in the wounds. Mild to moderate pain can be treated with paracetamol or NSAIDs. Opioids and anxiolytics can be used for severe pain. Nutritional support is required for patients with a severe form of EB.

© Springer Nature Switzerland AG 2023 A. D. Katsambas et al. (eds.), European Handbook of Dermatological Treatments, https://doi.org/10.1007/978-3-031-15130-9_24

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• Ocular lubricants and ointments are suitable for most eye lesions. Severe cases may require autologous transplantation of limbal epithelium or allogeneic corneal transplantation. • Oral hygiene is to be encouraged with gentle tooth brushing and normal saline rinses. • Disabling and severe complications of recessive dystrophic EB such as pseudosyndactyly, and squamous cell carcinoma, require surgical management. • Acquired EB is a rare mechanobullous disorder characterized by subepithelial mucocutaneous blistering disease that develops sporadically in adults. It is characterized by skin fragility, non-inflammatory tense bullae, milia, and scarring. • EBA is due to antibodies to collagen 7, which is a component of anchoring fibrils in basement membrane zone of skin and mucosae. • The clinical diagnosis can be confirmed by ELISA, from IFD of salt-split skin and immunoelectron microscopy. • Colchicine, dapsone, immunosuppressants, steroids, intravenous IgG and plasmapheresis, and rituximab are used as therapy with some success.

Epidemiology The UK has reported a prevalence rate ranging from 15 to 32 cases per million. The National EB Registry in the US has reported the EB prevalence as 11 per million and the incidence of 20 per million live births. Australian EB Registry reported a prevalence of 10 cases per million live births. EB simplex represents 92%, dystrophic EB 5%, and junctional EB (JEB) 1% of the total EB cases; 2% remain as unclassified.

 linical Presentation (Figs. 24.1, 24.2 C and, 24.3)

Definition Inherited Epidermolysis Bullosa Inherited EB is a group of inherited mechanobullous disorder presenting with skin and mucosal fragility in the form of blisters and/or erosions on minor trauma. Clinical, pathophysiologic, and molecular criteria define many types of EB. There are four major types of EB based on site of split. Type EB simplex Junctional EB Dystrophic EB Kindler syndrome

Site Intraepithelial Lamina lucida Lamina densa or upper dermis Intraepithelial, lamina lucida, or sub lamina densa

Fig. 24.1 Epidermolysis bullosa lesions on upper extremity

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Epidermolysis Bullosa Simplex Type Mutation Localized EB/ AD, KRT weber cockayne 5& 14

EBS, generalized severe/dowling meara

Fig. 24.2 Epidermolysis bullosa lesions on lower extremity and feet

Fig. 24.3  Epidermolysis bullosa lesions on trunk

Clinical features Onset infancy and 3rd decade Blistering mainly limited to the palms and soles Palmoplantar hyperhidrosis Hair and teeth are normal No scarring or milia Calluses Onset at birth; characterized by grouped blisters with a “herpetiform” arrangement Oral mucosa involved Confluent keratoderma Nail dystrophy Telogen effluvium Milia and atrophy

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J unctional Epidermolysis Bullosa (JEB) JEB, generalized severe (Herlitz)

JEB, generalized intermediate (non-herlitz)

AR, mutations in the laminin 332 subunit

Onset at birth; generalized mucocutaneous blistering; often lethal Secondary lesionsatrophic scarring, webbing, contractures, and milia Granulation tissue presenting around the mouth, central face, or nose is pathognomonic Onychodystrophy, onychogryphosis, anonychia Enamel hypoplasia Serous or hemorrhagic blisters at sites of friction Recurrent blistering and healing results in skin atrophy with poikilodermatous changes and faint stellate scars Dystrophic or absent nails Dental enamel hypoplasia Mucous membranes involved without scarring

Dystrophic Epidermolysis Bullosa Generalized severe recessive dystrophic EB (RDEB) or Hallopeau-­ Siemens type

Generalized dominant Dystrophic EB (DDEB)

AR, COL7A1 gene coding for the alpha-1 chain of type VII collagen

Onset at birth; blistering spontaneously or after the mildest trauma Scarring and milia Early contractures of hands and feet Pseudosyndactylypartially fused interdigital spaces due to proximal webbing and synechiae Mitten deformitycompletely fused digits in a cocoon-like, scarred mass Scarring alopecia Mucosal erosions and mutilating scarring Dystrophic teeth and decreased mouth opening High risk of developing squamous cell carcinomas, Most severe form of DEB Blistering predominantly in the skin overlying bony prominences Mucosal involvement is rare Normal teeth Blisters heal with scarring and milia Nail dystrophy

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Kindler Syndrome Kindler syndrome

AR, Onset in early infancy; trauma FERMT 1 induced skin blistering Gene In later childhood, blistering subsides and gives way to poikiloderma localized to sun-exposed areas Photosensitivity Gingivitis and periodontitis

Investigations Diagnosis of EB is generally straight forward for an expert; however, the identification of specific subtype requires skin biopsy for immunofluorescence mapping (IFM) to identify the level of cleavage. If IFM is normal, transmission electron microscopy (TEM) or mutational analysis can be used. Immunohistochemistry (IHC) with antibodies to cytokeratin 5, 14, plectin, type 17 collagen, and laminin 332 is a cheaper alternative but provides variable success in diagnosis.

Treatment of EB General Principles The treatment varies upon the age of the patient, the subtype of EB, the level of systemic involvement, and the complication. Treatment of EB is primarily supportive and is focused on wound care for faster healing and control of infection, providing nutritional support, and prevention and treatment of complications. The management of EB involves a multidisciplinary team lead by a dermatologist and includes plastic surgeon, dentist, general physician, social worker, and occupational therapist. Specialists, including ophthalmologists, gastroenterologist, nephrologist, endocrinologist, cardiologist, pain management, and psychiatry, may be involved as needed. There is an enormous burden on families with children suffering from severe forms of EB.  Support groups like the Dystrophic Epidermolysis Bullosa Research Association (www.debra-­international.org) are important for

such families as they run free programs and provide services to the EB community.

Care of Newborn with EB The focus is to provide expert nursing care and restrict even the mildest forms of trauma. Upon delivery of a newborn suspected with EB, secure the umbilical cord with a ligature and avoid the use of plastic clamps. The name tag can be placed on clothing instead of the wrist. The infant must be protected from direct heat and use of incubator must be with caution. If suction is required, use a soft catheter with minimal suction pressure. Avoid skin prick test as it carries the risk of degloving of the heel. Place the newborn in a thick foam pad and use it for transporting the infant (e.g. from the bed to the mother’s arm). Whenever possible, Kangaroo care with parents should be encouraged. During breastfeeding, friction can be decreased by applying soft paraffin on the nipple and breast of the mother, and on the lips of the infant. If breastfeeding is still traumatic, oral feeding should ensue. Teats of infant’s feeding bottle can be softened by boiling in hot water and extra holes can be made to facilitate suckling. For bathing, use warm isotonic normal saline in baby bathtubs. Normal saline baths can be prepared by dissolving approximately 1 kg of table salt or pool salt (cheaper) in a full tub (160 L) of warm water. This will reduce pain, body odour, and skin exudates due to wounds. Use of disposable diapers lined with soft material is advisable. Erosions in the diaper area can be prevented by liberal use of white soft paraffin and liquid paraffin mixed in equal parts. There is no contraindication to immunization. The infant should be sent home after stable health condition and after training of the parents in EB specific nursing care. In infants with severe EB, follow-up visit can be scheduled after 2  weeks of discharge and must include a complete clinical examination, wound dressing, and continuing medical education of the parents. If the infant care is being properly performed, the next follow up can be after 1 month, then every 3 months until the first year of life. In mild EB subtypes, the follow-up visits can be 3 monthly.

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Skincare

Bacterial colonization of wounds, with Staphylococcus, Streptococcus, and Emollients should be used daily to prevent dry- Pseudomonas aeruginosa, is common; clinical ness which will prevent blistering, pain, and itch- signs of colonization like excessive exudates, ing. The frequency of bathing depends on the red, friable tissue, debris and odour, and systemic type of dressing and the condition of the wound. signs including lymphadenopathy, fever, and Toys should be in soft material without traumatic malaise may be present. In colonized wounds, angles and frequently cleaned. diluted beach baths (100  mL of bleach in an Hobbies and sports should be at the lowest adult-sized bathtub, patients are soaked in the risk of skin trauma. Vulnerable skin sites, such as bath for 10 min and then rinsed with lukewarm knees and elbows, should be protected when the water) are used to decrease the bacterial load. child begins to walk and during sport activities or Topical antiseptics (chlorhexidine, benzalkonium hobbies. For patients of Kindler syndrome, pho- chloride, and silver sulfadiazine) and topical antitoprotection is mandatory to prevent photosensi- biotics (mupirocin and fusidic acid) can be used. tivity. Palmoplantar keratoderma (PPK) and Bacterial cultures of wounds are not routinely hyperhidrosis are frequently associated with performed. Wounds with frank infection usually EB.  PPK can be treated by ammonium lactate, require systemic antibiotics. The choice of antibiurea, or salicylic acid and hyperhidrosis can be otic therapy should be based on bacterial culture treated by applying corn flour. Iontophoresis or results. Mechanical debridement, when necesbotulinum toxin is used for severe hyperhidrosis. sary, should be performed gently with previous Foot blisters are common in EB patients due to analgesia. trauma; blisters can be ruptured at the lowest Caution: use of silver preparations over large point to allow drainage. Use of moulded orthot- wounds may induce systemic silver toxicity ics, bamboo, or double layer sock with soft well-­ (argyria) and slate-grey metallic skin ventilated footwear is advocated. discolouration.

Wound Care

Care of the Mucosa

For dry wounds, nonadhesive soft silicone, thin polyurethane-soft silicone foams, and hydrogels appear to be the most suitable. For heavily exuding wounds, Hydrofiber dressings or soft silicone foam with super-absorbers are preferred. If dressings get adhered, remove them by soaking them in a bath. The following measures will help in the reduction of discomfort and pain during a change of dressing.

A soft, small brush should be used to gently clean teeth if there is severe mucosal involvement and mouth can be rinsed with normal saline. Frequent thorough cleaning and fluoride therapy by a dentist is useful. Ocular involvement in EB ranges from mild conjunctival irritation to severe blistering and scarring of the conjunctiva and/or cornea. Regular use of preservative-free ocular lubricants is generally sufficient. Corneal erosions may require the application of amniotic membranes or cell sheets derived from the autologous oral or limbal epithelium and corneal transplants.

• Turning off the fans to reduce pain from circulating air. • Cutting all dressing before starting the dressing. • Using bandages rather than tapes to hold the dressing in place. • Advanced dressings (hydrogels, hydrofibers, and foams) delay the frequency of dressing change.

Itch Management EB patients develop itch commonly due to dry skin, sensitization from topical treatment, and during the process of wound healing. Itch-­

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induced scratching damages the skin and increases the chances to develop blisters and infections. General measures like maintaining skin hydration with emollients and avoiding exposure to a hot and dry environment may help in reducing itching. Relaxation techniques like yoga and deep breathing and educating the patient may help in breaking the vicious itch-­ scratch cycle. If the itching persists, a short course of topical mid potent steroid and sedating antihistamines may be given.

Pain Management Pain is a constant feature of EB and can be due to skin blisters and wounds, oral or corneal erosions, dental problems, and dress changing. For mild to moderate pain, analgesics like paracetamol or a nonsteroidal anti-inflammatory drug can be used. Opioids (codeine and morphine) and anxiolytics (diazepam, lorazepam, and midazolam) are reserved for severe pain. During a change of dressings, topical opioids (containing 10  mg of morphine in 30  g of hydrogel) can be applied directly to open wounds.

Nutritional Supplementation Breastfeeding is recommended for infants with EB.  If breastfeeding is not possible failing to thrive, temporary supplementing with feeding using nasogastric (NG) tubes can be made. However, NG tubes should not be used for more than 6 to 8 weeks, since they can cause mucosal trauma and scarring. A gastrostomy tube may be beneficial for children with severe dystrophic EB who require long-term supplementation. Children receiving enteral feeding should be encouraged to maintain oral sucking and swallowing skills. This is important for social eating and development later in life. The serum levels of micronutrients such as Iron, Zinc, Selenium, Vitamin B12, Vitamin A, and Folate should be checked and supplemented at regular intervals.

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Surgical Treatment for Deformity and Cancer Pseudosyndactyly or “mitten” deformity of the hands and feet is a major complication of Recessive Dystrophic EB and is treated by surgery. Postoperative use of custom-made splints and physiotherapy is necessary to maintain the benefits of surgery. Squamous cell carcinoma (SCC) may arise in chronic wounds and is a major cause of death in patients with RDEB.  Wide local excision with 2  cm margins is considered the treatment of choice for SCCs. Punch grafting can be helpful for the treatment of deep ulcers.

 atient Education and Genetic P Counseling Continuous education of patients and their family members is necessary for patient-centric medical care; this enables them to better manage their illness. Patient education contributes to improve quality of life (QoL) and prevent complications. Genetic counseling should be offered to affected families so that they can better understand their reproductive risks and options, such as prenatal diagnosis and preimplantation genetic diagnosis.

Experimental Therapies Gene Therapy Replacing a defective gene using a retrovirus-­ mediated gene correction in keratinocyte has been successful in individual cases of JEB. However, gene therapy brings with it complex issues like future risk of malignancy and the long duration of treatment. “Natural gene therapy” using revertant mosaicism, a phenomenon based on the fact that in inherited mutation in an

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individual cell is compensated by a second, somatic mutation that reverts the phenotype by restoring the expression of the lacking protein.

Cell Therapy Intradermal injections of fibroblasts have improved the dermal-epidermal adhesion in dystrophic EB.  However, this mode of therapy is very painful and the results are inconsistent. Bone marrow transplantation has improved symptoms of EB in severe cases. Intravenous infusions with mesenchymal stromal stem cells from the bone marrow have shown to relieve symptoms such as itch. Protein Therapy Intravenous or intradermal injection of recombinant collagen VII injections for treatment of Dystrophic EB has given some promising results. Antisense Oligonucleotide The treatment has been used to treat the collagen VII gene defect. The treatment allows restoring the synthesis of normal protein that lacks a small fragment encoded by the deleted exon.

Prognosis Prognosis depends heavily on the subtype of EB. However, with meticulous medical care life can be prolonged. EBS: The prognosis for patients with localized EBS is good and most patients have a normal life expectancy. In contrast, patients with generalized EBS Dowling-Meara experience inflammatory flares throughout their life. Children with recessive forms of EBS usually do not survive beyond infancy. JEB: Most patients with junctional EB, both Herlitz and non-Herlitz type, do not survive past infancy. DEB: With improved nutritional support, wound care, and management of complications, patients with recessive dystrophic EB usually survive to their early 30s to 40s. Patients having dominant dystrophic EB survive to adulthood with few complications.

Kindler syndrome: Patients with Kindler syndrome generally have a good prognosis. However, they have increased photosensitivity and are at risk of developing squamous cell carcinoma.

Acquired Epidermolysis Bullosa (EBA) EBA is a rare chronic autoimmune bullous disease of the skin and mucosa due to the formation of IgG autoantibodies directed against collagen VII, the main constituent of anchoring fibrils. It generally affects adults but may occur in all ages. Clinically, it is characterized by skin fragility and subsequent formation of subepidermal blisters, predominantly in  locations subjected to trauma, that heal with scar formation and milia, in a similar way to dystrophic epidermolysis. Nail loss may also occur. There are some variations, like inflammatory bullous pemphigoid or Brunsting-­ Perry pemphigoid-like and also IgA linear dermatosis. A genetic predisposition has emerged in some cases. The clinical diagnosis can be confirmed by ELISA, from IFD of salt-split skin and immunoelectron microscopy. Therapy is often frustrating because patients often do not respond to treatment with systemic steroids and immunosuppressive drugs, and there are no therapeutic guidelines. Medications that have been used with some success are colchicine, dapsone, immunosuppressants (cyclosporine, methotrexate, azathioprine, mycophenolate mofetil), steroids, intravenous IgG and plasmapheresis, and rituximab. Acknowledgment A special thanks goes to previous authors of the chapter for their kind contribution and support.

Further Reading Arbuckle HA. Bathing for individuals with epidermolysis bullosa. Dermatol Clin. 2010;28:265. El Hachem M, Zambruno G, Bourdon-Lanoy E, et  al. Multicentre consensus recommendations for skin care in inherited epidermolysis bullosa. Orphanet J Rare Dis. 2014;9:76. Fassihi H, McGrath JA. Prenatal diagnosis of epidermolysis bullosa. Dermatol Clin. 2010;28:231.

24  Epidermolysis Bullosa Fine JD, Eady RA, Bauer EA, et  al. The classification of inherited epidermolysis bullosa (EB): report of the third international consensus meeting on diagnosis and classification of EB.  J Am Acad Dermatol. 2008;58:931. Grocott P, Blackwell R, Weir H, Pillay E. Living in dressings and bandages: findings from workshops with people with epidermolysis bullosa. Int Wound J. 2013;10:274. Hubbard L, Haynes L, Sklar M, et  al. The challenges of meeting nutritional requirements in children and adults with epidermolysis bullosa: proceedings of a multidisciplinary team study day. Clin Exp Dermatol. 2011;36:579. Intong LR, Murrell DF. How to take skin biopsies for epidermolysis bullosa. Dermatol Clin. 2010;28:197. Intong LR, Murrell DF.  Inherited epidermolysis bullosa: new diagnostic criteria and classification. Clin Dermatol. 2012;30:70.

281 Khan MT, O’Sullivan M, Faitli B, et al. Foot care in epidermolysis bullosa: evidence-based guideline. Br J Dermatol. 2020;182:593. Pohla-Gubo G, Cepeda-Valdes R, Hintner H. Immunofluorescence mapping for the diagnosis of epidermolysis bullosa. Dermatol Clin. 2010;28:201. Pope E, Lara-Corrales I, Mellerio J, et  al. A consensus approach to wound care in epidermolysis bullosa. J Am Acad Dermatol. 2012;67:904. Uitto J, Richard G.  Progress in epidermolysis bullosa: genetic classification and clinical implications. Am J Med Genet C Semin Med Genet. 2004;131C:61. Uitto J, Has C, Bruckner-Tuderman L. Cell-based therapies for epidermolysis bullosa—from bench to bedside. J Dtsch Dermatol Ges. 2012;10:803. Yiasemides E, Walton J, Marr P, et al. A comparative study between transmission electron microscopy and immunofluorescence mapping in the diagnosis of epidermolysis bullosa. Am J Dermatopathol. 2006;28:387.

25

Erysipelas Maria Balabanova

Key Points • Erysipelas is a distinctive type of superficial cellulitis of the skin with prominent lymphatic involvement. • Its hallmark is a well-defined, raised edge reflecting the more superficial (dermal) involvement. • Seventy to eighty percent of the lesions are on the lower extremities and 5–20% are on the face. • Erysipelas is almost always due to beta-­ haemolytic streptococci group A (uncommonly S. dysgalactiae group G or S. dysgalactiae group C). • Mild early cases of erysipelas in adult can be treated with intramuscular procaine penicillin (600,000 units once or twice daily), oral penicillin V (250–500 mg every 6 h), and erythromycin (250–500 mg every 6 h). • More extensive erysipelas is treated with hospitalization and parenteral aqueous penicillin G (600,000–2,000,000  units every 6  h for 5–10  days); clindamycin should be added in case of septic shock. • Extensive cellulitis or necrotizing fasciitis requires surgical debridement of the necrotic tissue and intensive care for the shock syndrome. M. Balabanova (*) Department of Dermatology, Sofia Medical University, Sofia, Bulgaria

• Alternative treatment includes the other macrolides (roxithromycin, clarithromycin, azithromycin); they appear to be as effective as parenteral penicillin G.  Cephalosporins also may be used as a second-line treatment. Quinolones are not indicated in the treatment of erysipelas. • Prophylactic treatment includes benzylpenicillin benzathine (Tardocillin) 2.4 million units every 3 weeks for 1 or 2 years and erythromycin 250 or 500 mg twice a day. Of importance for prophylaxis is the rigorous disinfection of minor injuries that may provide a portal for bacteria.

Definition and Epidemiology Erysipelas is a distinctive type of superficial cellulitis of the skin with prominent lymphatic involvement. It is more common in infants, young children, and older adults. Its incidence has declined since the middle of the twentieth century, probably due to the greater use of antibiotics and improved sanitation. Formerly, the face was most commonly involved. Now the distribution of erysipelas has changed: 70–80% of the lesions are on the lower extremities and 5–20% are on the face. This is most probably because of the ageing population and risk factor such as lymphoedema.

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lesion with a bright red oedematous, indurated (‘peau d’orange’) appearance, and an advancing, Erysipelas is almost always due to beta-­ raised border that is sharply demarcated from the haemolytic streptococci group A (uncommonly adjacent normal skin. The affected area is hot, S. dysgalactiae group G or S.dysgalactiae group tender, and painful to palpation and may burn. A C). Group B streptococci have produced erysip- common form of erysipelas involves the bridge elas in newborns and may be the cause of abdom- of the nose and the cheeks. Local clinical signs, inal or perineal erysipelas in postpartum women. without fever and inflammation, characterize the S. aureus, Pneumococcus species, Klebsiella recurrent forms. Uncomplicated erysipelas pneumoniae, Yersinia enterocolitica, and remains confined primarily to the lymphatics and Haemophilus influenzae type B have also been the dermis. Occasionally, the infection extends more deeply and produces cellulitis, subcutaneknown to cause an erysipelas-like infection. The portal of entry commonly includes skin ous abscess, and necrotizing fasciitis. Other comulcers, local trauma or abrasions, psoriatic or plications may include streptococcal bacteraemia eczematous lesions, or fungal infections; in the which occurs in about 5% of patients with erysipneonate, erysipelas may develop from an infec- elas; when the infection resolves, desquamation and postinflammatory pigmentary changes may tion of the umbilical stump. Predisposing factors include venous stasis, occur. paraparesis, diabetes mellitus and alcohol abuse, lymphoedema, and obesity. Other predisposing factors and ports of entry are surgical wounds, Diagnosis fissures of the nares, under the lobes of the ears, on the anus or penis, and between or under the The diagnosis is based on the: toes and athlete’s foot. Location and hepatic and renal disease are the • General symptoms. most important risk factors, while diabetes is • Local symptoms. probably of less significance than previously sug- • Biopsy reveals diffuse oedema of the dermis and a dermal neutrophilic infiltrate. gested. Patients with the nephrotic syndrome are There is commonly dilation of lymph vesparticularly susceptible. Erysipelas tends to occur sels, dermal foci of suppurative necrosis, and in areas of preexisting lymphatic obstruction or a dermal–epidermal separation. There is no oedema (e.g., after a radical mastectomy). Also, primary necrotizing vasculitis, thrombosis, or because erysipelas itself produces lymphatic leukocytoclasis. obstruction, it tends to recur in an area of an earlier infection. Over a 3-year period, the recur- • Gram or Giemsa stain, direct immunofluorescence, throat swabs, culture technique, swabs rence rate is about 30%, predominantly in from the local portal of entry and serological individuals with venous insufficiency or lymphtests. oedema. An antecedent streptococcal respiratory tract infection preceded cutaneous involvement in about one-third of patients, even though streptococci might not be found on culture at the time Differential Diagnosis that the skin lesions become evident. • Early herpes zoster involving the second division of the fifth cranial nerve. • Contact dermatitis. Clinical Presentation • Giant urticaria. Erysipelas has an abrupt onset of fever, chills, • Deep venous thrombosis. malaise, and nausea. A few hours to a day later, • Diffuse inflammatory carcinoma of the breast. these general symptoms are followed by a painful • Erythema chronicum migrans.

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• An erysipelas-like skin lesion in patients with hypogammaglobulinaemia. • Campylobacter jejuni bacteraemia. • Lupus (butterfly pattern on the face).

(nafcillin or oxacillin) or a first-generation cephalosporin is warranted.

General Principles of Treatment

• Benzylpenicillin benzathine (Tardocillin) 2.4 million units every 3 weeks for 1 or 2 years. • Erythromycin 250 or 500 mg twice a day.

Oral or parenteral penicillin is the treatment of choice. Elevation of the affected leg, bed rest, and saline wet dresses are recommended. Mild early cases of erysipelas in adult can be treated with: • Intramuscular procaine penicillin (600,000 units once or twice daily). • Oral penicillin V (250–500 mg every 6 h). • Erythromycin (250–500 mg every 6 h). More extensive erysipelas is treated as follows: • Hospitalization and parenteral aqueous penicillin G (600,000–2,000,000  units every 6  h for 5–10 days). • Clindamycin should be added in case of septic shock. • Extensive cellulitis or necrotizing fasciitis requires surgical debridement of the necrotic tissue and intensive care for the shock syndrome.

Alternative Treatment The other macrolides—roxithromycin, clarithromycin and azithromycin—appear to be as effective as parenteral penicillin G.  Cephalosporins also may be used as a second-line treatment. Quinolones are not indicated in the treatment of erysipelas. Although typical erysipelas can be readily distinguished from cellulitis (which can be of staphylococcal as well as streptococcal etiology), differentiation may not be clear-cut in occasional circumstances. Under such conditions, particularly in an acutely ill patient, intravenous administration of penicillinase-resistant penicillin

Prophylactic Treatment

Of importance for prophylaxis is the rigorous disinfection of minor injuries that may provide a portal for bacteria usually streptococci and the physical oedema therapy described by comprising manual lymph drainage and compression. • Opinions differ about the duration of antibiotic prophylaxis. It has been established that recurrences are reduced, but the effect is not dramatic. Continuous antibiotic prophylaxis is indicated only in patients with high recurrence rate. Prophylactic antibiotic therapy should be considered as a long-term, even lifetime, treatment especially for certain predisposed subject (i.e., postphlebitic syndrome, lymphoedema, diabetes, and immunocompromised hosts). • Treatment of the local point of entry does not guarantee that there will be no recurrences. Recurrent episodes of erysipelas/cellulitis have also been associated with post-cellulitic oedema, which is a risk factor for recurrent disease. Reduction of the oedema would seem beneficial as well as a vigorous treatment of local factors.

Treatment Algorithm First-Line Treatment • Intramuscular procaine penicillin (600,000 units once or twice daily). • Oral penicillin V (250–500  mg every 6  h); erythromycin (250–500 mg every 6 h). • Hospitalization and parenteral aqueous penicillin G (600,000–2,000,000  units every 6  h for 5–10 days).

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• Surgical debridement of the necrotic tissue and intensive care for the shock syndrome. • In case of septic shock, clindamycin should be added.

Second-Line Treatment • Macrolides—roxithromycin, clarithromycin, and azithromycin. • Cephalosporins also may be used as a second-­ line treatment.

Prophylactic Treatment • Benzylpenicillin benzathine (Tardocillin) 2.4 million units every 3 weeks for 1 or 2 years. • Erythromycin 250 or 500 mg twice a day. • Rigorous disinfection of minor injuries.

Further Reading Dupuy A, Benchikhi H, Roujeau JC, et  al. Risk factors for erysipelas of the leg (cellulitis): case-control study. BMJ. 1999;318(7198):1591–4. Ellis H. The last year before the dawn of antibiotics. Br J Hosp Med (Lond). 2009;70(8):475. [Medline]. Herpertz U. Erysipelas and lymphoedema. Fortschr Med. 1998;116(12):36–40. Heymann WR, Halpren AV.  Bacterial diseases. In: Bolognia JL, Jorizzo JL, Rapini RP, editors. Dermatology. 2nd ed. St. Louis, MI: Mosby Elsevier; 2008. p. 1082. Highet AS, Hay RJ, Roberas SOB.  Cellulitis and erysipelas. In: Champion RH, Burton JL, Eblings FJG, editors. Rook-Wilkinson-Ebling: textbook of dermatology. 5th ed. Oxford: Blackwell Scientific; 1992. p. 968–73. Mahe E, Toussaint P, Boutchnei S, Guiguen Y. Erysipeles dans la population jeune d’un hopital militaire. Ann Dermatol Venereol. 1999;126:593–9. Stevens DL, et  al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis. 2005;41(10):1373–406.

Erythema Multiforme

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Kristina Semkova and Jana Kazandjieva

Key Points • Erythema multiforme (EM) is an acute, immune-mediated dermatological condition affecting the skin and mucous membranes. The most commonly identified trigger for EM is infection with human herpesvirus (HSV). • A consensus clinical classification currently divides EM into EM minor and EM major. According to the frequency pattern, EM is classified into acute and chronic, including recurrent EM, and persistent EM. • The characteristic clinical presentation is with typical target lesions with mainly acral, symmetrical distribution with or without mucosal erosions. • Symptomatic therapy is the mainstay of treatment. Mild cutaneous involvement usually resolves without therapy within 1–2 weeks, but oral antihistamines or topical corticosteroids may be needed for symptomatic improvement. • Severe cases of EM major require special care for the mucous membranes to prevent complications. • Early ophthalmologic consultation is important in the evaluation and management of eye

K. Semkova (*) St John’s Institute of Dermatology, London, UK J. Kazandjieva Medical University—Sofia, Sofia, Bulgaria

involvement with daily examinations for signs of complications. • Recurrent and persistent EM requires systemic therapeutic interventions. In HSV-­ associated or idiopathic EM, the first-line management is long-term prophylaxis with antiviral medications.

Definition Erythema multiforme (EM) is an acute, immune-­ mediated dermatological condition affecting the skin and mucous membranes. It develops as a type IV hypersensitivity reaction to infections, medications, or other stimuli. The clinical presentation with target lesions and/or mucosal erosions with a history of exposure to a known trigger is usually sufficient for the diagnosis. Albeit self-limited in most cases, severe or recurrent forms of EM require systemic therapy. EM was first described by Hebra in 1866 in his atlas of skin diseases (Еrythema Еxudativum Мultiforme typus benignus Hebra). For many years, it was considered a variant from a continuous spectrum comprising EM, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Studying an extensive number of cases allowed for a more precise understanding of these diseases and their evidence-based distinction as separate entities (Table 26.1). A consen-

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288 Table 26.1  Consensus classification of EM, SJS, and toxic epidermal necrolysis and types of targetoid lesions (by Bastuji-Garin et al. 1993)

Consensus clinical classification EM—detachment of 10% of BSA, large epidermal sheets, and no purpuric macules

Types of targetoid lesions 1. Typical targets 2. Raised atypical targets 3. Flat atypical targets 4. Macules with or without blisters

sus clinical classification currently divides EM into EM minor and EM major (Bastuji-Garin et al. 1993). EM minor is characterized by typical targets or raised, edematous papules with predominantly acral distribution, while EM major presents with typical targets or raised, edematous papules distributed acrally with involvement of one or more mucous membranes. Epidermal detachment in EM major should involve less than 10% of the total body surface area.

Epidemiology The exact incidence of EM is not known, but is estimated to be between 0.01% and 1%. Young adults are most affected with a slight male predominance. EM before the age of 3 and after the age of 50 is exceedingly rare. Higher risk of EM was suggested in patients with HIV infection, bone marrow transplant, systemic lupus erythematosus (SLE), graft-versus-host disease (GVHD), and inflammatory bowel disease (IBD), as well as in patients on corticosteroid treatment, chemotherapy, or radiotherapy.

Basic Concepts of Pathogenesis The most common triggering factor for EM is infection with human herpesvirus (HSV). Other infectious agents and medications have been implicated as well. Nevertheless, about 50% of cases remain idiopathic with no identifiable etiologic factor.

Infections Infectious stimuli are linked to most cases of EM with known etiology. HSV, primarily type 1, is the most common, especially in patients experiencing recurrent episodes of EM minor and in young adults. A study with PCR detection and genotyping of HSV in EM patients revealed that 66.7% of the patients had HSV1, 27.8% had HSV2, and 5.6% had HSV1 and HSV2 coinfection (Sun et  al. 2003). Some of the idiopathic cases are also believed to be induced by a subclinical or silent HSV infection. In a PCR study of skin samples from 16 patients with idiopathic EM, HSV DNA was found in 25% of single-­ episode idiopathic EM and in 50% of recurrent idiopathic EM (Ng et al. 2003). Other viruses that may induce EM include cytomegalovirus (CMV), Epstein-Barr virus (EBV), influenza, adenovirus, coxsackievirus B5, echoviruses, enterovirus, hepatitis A/B/C viruses (HAV/HBV/HCV), measles, mumps, paravaccinia, parvovirus B19, poliomyelitis, and varicella-zoster virus (VZV). Bacterial infections that have been reported to precipitate EM include Mycoplasma pneumoniae, borreliosis, cat-scratch disease, diphtheria, hemolytic streptococci, legionellosis, leprosy, Neisseria meningitidis, Mycobacterium avium complex, pneumococci, tuberculosis, Proteus/ Pseudomonas/Salmonella/Staphylococcus/ Yersinia species, Treponema pallidum, tularemia, Vibrio parahaemolyticus, and rickettsial and chlamydial infections. M. pneumoniae is of particular importance as it is the most commonly identified known trigger in the pediatric population.

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Recently, EM-like lesions have been described in the setting of COVID-19 infection in both adults and children, including in cases with Multisystem inflammatory syndrome in children and adolescents (MIS-C) temporally related to COVID-19. Despite the distinctive clinical presentation with target lesions, histopathology in these cases shows features of perniosis with minimal or nil vacuolar interface reaction and necrotic keratinocytes, but with positive immunohistochemistry for SARSCoV/SARS-CoV-2 spike protein in the endothelia and eccrine epithelia (Torrelo et al. 2020).

Drugs Drug-related EM comprises less than 10% of all cases. Multiple drugs and substances can precipitate EM, the most common being nonsteroidal anti-inflammatory agents, sulfonamides, antiepileptics, and antibiotics. Newer agents, such as biologics (sunitinib, infliximab, secukinumab, mogazolimumab, etc.), as well as over-the counter preparations, such as weight loss pills and herbal medicines, can also trigger EM.  Various vaccines, including the human papillomavirus vaccines and the small pox vaccine, have been associated with EM with some patients showing similar skin changes after various vaccines. Vaccination is also a common trigger in infants. Topical medications, such as imiquimod 5% cream, are also known to induce EM or EM-like reactions.

Other Triggers Multiple other factors have been linked to EM development: menstruation; high intake of food preservatives, especially benzoic acid and cinnamon; hair dye exposure; tattoo dermatitis; and physical or mechanical factors, such as radiotherapy, tattooing, cold, and sunlight. However, a recent study challenged the role of radiation, as EM was observed predominantly in patients on concomitantly prescribed medications and only rarely in patients who were irradiated only. Albeit

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rarely, EM has been described in association with malignancy, mainly leukemias and lymphomas. Solid organ tumors, such as gastric adenocarcinoma, renal cell carcinoma, and extrahepatic cholangiocarcinoma, have been reported in patients with persistent and treatment recalcitrant EM. Thorough screening and physical examination may be thus warranted in these cases. The pathogenesis of EM is not yet clearly understood. Autoimmune nature of the disease has so far not been confirmed and there is no identified specific humoral autoreactivity in sera from patients with EM major. Its occurrence in a small proportion of the whole population exposed to the known triggers suggests a genetic predisposition. Specific HLA associations reported in the literature include HLA-DQB1*0301, HLA-­ DQB1*0302, HLA-B35, HLA-B62, and HLA-DR53. Different genetic background accounts for the difference in presentation and severity, and HLA-DQB1*0302 is particularly linked to severe mucous membrane involvement. Although HSV-induced and druginduced EM are delayed type hypersensitivity reactions, they evolve via different pathways. In HSV-associated EM, the main target are the keratinocytes which express HSV DNA fragments. These fragments are transported to the skin by blood CD34+ Langerhans cells progenitors after phagocytosis of the active virus. Skin homing receptors and upregulation of E-cadherin expression enhance the binding of these cells to keratinocytes. Expression of HSV DNA polymerase (pol) and other genes on the surface of basal layer keratinocytes results in recruitment of CD4 + T-helper cells, which produce cytokines and initiate an inflammatory cascade. The main effector cytokine in HSV-related EM is interferon-γ (IFN-γ). By contrast, the primary effector cytokine in druginduced EM is tumor necrosis factor-α (TNF-α).

Clinical Presentation Based on the frequency pattern, EM is classified into acute (short single episode) and chronic (recurrent EM and persistent EM). Recurrent EM is defined as multiple episodes of EM with an average of six episodes per year and a mean

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duration of 6–10 years. The most common association of recurrent EM is with HSV infection and complex aphthosis, but literature reports incriminate other factors as well, including menstruation, vulvovaginal candidiasis, hepatitis C, M. pneumoniae infection, and acetaminophen and benzoic acid ingestion. About 70% of patients have oral involvement and about 20% report genital lesions. Persistent EM is a rare variant c­ haracterized by continuous appearance of target and targetoid lesions without remissions. Its rarity impedes proper etiological identification, but association with HSV, Epstein-Barr virus, hepatitis C, influenza, cytomegalovirus, inflammatory bowel disease, and various neoplasms has been reported in the literature. The clinical presentation of EM may be variable from one patient to another and even in the same patient. A detailed history is important to identify the potential trigger and any possible morphological changes in the clinical manifestation of the rash before the initial presentation to the clinician. The hallmark of EM is the target lesion, but early or atypical target lesions may not have the characteristic appearance.

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pale, and edematous peripheral ring, surrounded by a second cyanotic or violaceous ring, thus forming the typical concentric, “target” lesion (Fig. 26.1). The central area of the target lesion represents necrosis of the tissue and may appear clinically as a dusty red area or blister (Fig. 26.2). As the disease evolves, the lesions may form polycyclic, geographic, or annular configurations. Residual post-inflammatory hyperpigmentation or hypopigmentation may develop thereafter. Atypical target lesions can also be observed, albeit uncommonly. They usually present as raised, edematous plaques that have only two concentric rings or poorly defined borders. In contrast to EM, atypical target lesions in Stevens Johnson syndrome are flat and not edematous. EM lesions are usually in a symmetrical distribution, affecting the acral extensor surfaces of the extremities. The eruption may spread to the trunk in a centripetal fashion. Palms, soles, and face are frequently involved (Fig. 26.1). Less commonly,

Prodromal Symptoms In EM minor prodromes are rarely observed and are usually mild, consisting of nonspecific upper respiratory tract infection-like symptoms within 3 days before the onset of the rash. In EM, major prodromes are common, and about half of the patients experience influenza-like symptoms, including malaise, fever, cough, sore throat, vomiting, chest pain, and diarrhea. These symptoms usually present 1–2 weeks prior to the cutaneous eruption, but in many cases it is not known whether they represent a genuine prodromal period or are part of the triggering infectious process.

Fig. 26.1  Typical target lesions on the feet of a 32-year old woman after an upper lip HSV infection

Skin Lesions Early EM presents with oval to round erythematous edematous macules or papules that expand gradually over a period of 24–48  h. During the first few days, the initial lesions develop a raised,

Fig. 26.2  Target lesions with bullous and hemorrhagic center

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other presentations, such as nail fold edema and grouping of lesions around the elbows and knees, may be observed. The lesions may appear on areas of previous physical trauma or sunburn, suggesting a Koebner (isomorphic) phenomenon. Photosensitive variants of EM and distribution along the lines of Blaschko have also been reported.

Mucosal Lesions Mucosal lesions are reported in as many as 60–70% of EM patients. They usually develop simultaneously with skin lesions, but can also precede or follow the cutaneous eruption within a time frame of several days. Isolated mucosal involvement is rare. The most commonly affected mucous membrane sites are the oropharynx (lips, palate, and gingiva) (Fig.  26.3), conjunctivae, and the anogenital area, but potentially all mucosal sites may be involved. Initial presentation of mucosal EM is with erythema and edema, sometimes flaccid bullae, which rapidly progress to superficial erosions. Occasionally, the erosive areas may be extensive. When the lips are involved, they are covered by hemorrhagic crusts. Interestingly, a study in patients with recurrent EM with oral lesions showed that recurrent attacks have different site distribution from initial attacks, with a greater proportion having genital as well as skin and oral mucosal involvement. The genital areas are affected in about 25% of cases. The typical EM lesions at this site com-

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prise painful, hemorrhagic bullae, and erosions. Eye involvement (9–17%) is usually mild and may present as injection of the conjunctivae, chemosis, and lacrimation.

Clinical Course and Prognosis Mild cases of EM are usually self-limited. In EM minor, the lesions develop over a period of 3–5 days and subside within 2–3 weeks without sequelae. The whole duration of the process is usually less than 4  weeks. Post-inflammatory dispigmentation may persist for several months after disease resolution. Scarring is not a feature, except after secondary infection. Despite the benign course, over one third of patients have repeating episodes over years (recurrent EM) or, rarely, a prolonged continuous disease without remissions (persistent EM). EM major usually has a protracted course, and resolution may take up to 6 weeks. It is associated with higher morbidity, primarily due to the pain and functional impairment with poor oral and fluid intake. Dehydration may result from the impeded fluid intake, diarrhea from bowel mucosal involvement, increased sweating due to elevated body temperature, and evaporation through denuded areas of skin. Rare serious complications include conjunctival scarring and permanent visual loss in ocular involvement, genital synechiae, esophageal strictures, and upper airway erosions leading to pneumonia. The mortality rate in EM major is less than 5% and correlates with the affected total body surface area with sepsis being the main cause of death. Advanced age, visceral involvement, increased serum urea nitrogen level, and previous bone marrow transplantation are poor prognostic factors.

Diagnosis

Fig. 26.3  EM major in a child after Mycoplasma pneumoniae infection

EM is primarily a clinical diagnosis with clue findings in the history and clinical presentation. The important points in the clinical history include acute presentation with episodic and self-­ limiting course, temporal association with infec-

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tions, and use of new medications. The typical clinical presentation includes target lesions in mainly acral distribution with or without mucosal involvement. There are no laboratory tests that confirm or refute the diagnosis. In severe cases, an array of nonspecific findings, such as elevated ESR, leukocytosis, thrombocytopenia, and mild anemia, may be expected. Electrolyte disturbance can also develop due to dehydration. Histopathologic examination of a biopsy specimen is useful to confirm the diagnosis of erythema multiforme (EM) and discriminate it from other clinically similar diseases in the differential diagnosis. Histologically, EM is characterized by vacuolar interface reaction at the basal cell layer of the epidermis with apoptosis of keratinocytes and perivascular and interstitial lymphohistiocytic infiltrate in the superficial dermis. Apoptotic keratinocytes may be focal in the basal layer or affect the whole epidermis. Pronounced basal cell vacuolar change may result in subepidermal clefting and vesiculation. The histopathological pattern depends on the evolutionary stage of the lesion and the site of biopsy. In early lesions and from the periphery, the changes may be predominantly dermal with edema of the papillary dermis with chronic inflammatory cell infiltrate and red blood cell extravasation. Epidermal changes are more prominent in evolving lesions and from the central portions of the target lesions. Blistering lesions with nonspecific histological features might require direct immunofluorescence (DIF) to exclude immunobullous disorders. In EM the DIF findings are usually nonspecific and include granular deposition of C3 and immunoglobulin M (IgM) at the dermoepidermal junction and around the superficial blood vessels. Homogeneous C3 and IgM can be observed in regions of epidermal necrosis.

Differential Diagnosis In typical EM, the clinical presentation and history are usually sufficient for a straightforward diagnosis. Nevertheless, it is important to

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exclude other possible diseases that can resemble EM, but have a more serious prognosis. Mimickers of EM include SJS, fixed drug eruption, vasculitis, bullous pemphigoid, paraneoplastic pemphigus, Behcet’s disease, Rowell’s syndrome, polymorphous light eruption, secondary syphilis, and Sweet’s syndrome. SJS is a distinct entity with similar mucosal lesions, but a different pattern of cutaneous involvement. In SJS, the eruption is usually widespread and comprises erythematous or purpuric macules or flat atypical targetoid lesions. Acral predominance is not a feature. Medications are the main culprit for SJS.  Timely diagnosis of SJS is essential as it may have function-­ threatening and life-threatening complications and may progress to toxic epidermal necrolysis. Immunobullous disorders usually have insidious onset and protracted, chronic course. DIF is positive with a characteristic histological presentation. The Nikolsky sign is negative in EM and positive in immunobullous dermatoses. Fixed drug eruption may look like EM clinically and histologically, but usually there is one single or just a few lesions and on H&E the infiltrate extends deeper and contains sparse neutrophils with prominent melanin incontinence. History of starting new medication within the previous 2 months is usually present. Rowell’s syndrome is a rare clinical entity believed to be a form of subcutaneous lupus erythematosus presenting with EM-like lesions. In Rowell’s syndrome, DIF shows continuous granular immunoglobulin and complement deposits, a speckled ANA pattern, and sometimes positive rheumatoid factor, anti-Ro, and anti-La antibodies, commonly in association with chilblains. Polymorphous light eruption (PMLE) may present with EM-like lesions, and clinical and histological distinction is challenging. In PMLE, vacuolar interface reaction and epidermal necrosis are rare findings. Photodistribution, seasonal recurrence, and lack of prior HSV infection may be clue to the diagnosis, but it should be noted that cases of photoincited or photo-aggravated EM have also been reported in the literature.

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General Principles of Treatment The management strategy for a patient with EM depends on the type, severity, site of involvement, and triggering factors, with special consideration for underlying conditions or age. The cause for EM should be identified when possible. If a drug is suspected as the inciting stimulus, it should be discontinued as soon as possible and reexposure to the same drug or to drugs with possible cross-reactivity due to similar chemical structures should be avoided. This includes all drugs and herbal supplements introduced within 2 months prior to the presentation. Suspected or known preceding infections should be treated accordingly after confirmatory cultures and/or serologic tests. The treatment objectives for acute EM are to reduce the time to complete resolution and to prevent complications, and for chronic EM, to prevent new flares or to reduce their frequency and severity. Symptomatic therapy should be the mainstay in every patient with EM. This includes oral antihistamines, analgesics, local skin care, and soothing mouthwashes. Mild EM is usually self-limited, and specific treatment is not required, unless recurrent or persistent. In severe cases of EM major, though, appropriate therapeutic and prophylactic measures are indispensable. Local supportive care for anogenital, upper respiratory tract, and ocular involvement is paramount to prevent serious complications (Table 26.2).

Isolated Episode of EM Minor Isolated episodes of EM are most commonly associated with HSV infection, but antiviral drugs do not change the course of an already established postherpetic EM.  Mild cutaneous involvement usually resolves within several weeks, but symptomatic improvement for occasional burning or pruritus may be achieved by using oral antihistamines or topical corticosteroids. For erosions developing from bullous EM lesions, topical antiseptics and wound care are sufficient to prevent secondary infection, and

293 Table 26.2  Treatment options for isolated, recurrent, and persistent EM Treatment options (suggested dose and treatment duration) Topical antiseptics Oral antihistamines Topical corticosteroids Systemic antibiotics (for secondary infection; dose and type of antibiotic depending on the isolated or suspected pathogen) Oral corticosteroids in severe mucous membrane involvement (prednisolone 40–60 mg once daily with tapering) Chronic Antivirals (acyclovir 400 mg/2× daily, (recurrent and valacyclovir 500 mg/day, famciclovir persistent 250 mg/2× daily) (treatment should EM) continue for at least 6 months up to 2 years) Oral corticosteroids (1–2 mg/kg/day in slowly tapering doses) Dapsone (100–150 mg/daily) Azathioprine (100–150 mg/daily) Mycophenolate mofetil (≤2 g/daily) Ciclosporine Thalidomide (100 mg/daily for suppression of a recurrent episode or 50 mg/daily to maintain remission) Immunoglobulins Type of EM Acute EM

analgesics are useful to manage the pain. In cases of extensive involvement, the use of liquid antiseptics, such as 0.05% chlorhexidine, during bathing may also decrease the risk of superinfection.

Isolated Episode of EM Major The treatment for cutaneous lesions should be the same as in EM minor. The approach to mucosal lesions should depend on site and severity. Minimal involvement, presenting as several painful erosions, can be managed with oral antiseptic washes, oral anesthetic solutions, and high potency corticosteroids in gel or spray form. For extensive mucosal involvement, some authors recommend early administration of a high dose of systemic steroids for a short period of time (such as prednisone 40–60 mg with tapering over 2–4  weeks). However, this approach remains controversial and one retrospective

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series reported protracted course of the disease in patients receiving systemic corticosteroids as compared to supportive care only. Another study of 25 patients, randomized into two groups, one on supportive treatment plus systemic steroids and one on supportive treatment only, found no outcome difference in the two groups. Short courses of acyclovir are not effective for treatment of acute EM or for episodes of recurrent EM. Early ophthalmologic consultation is important in the evaluation and management of eye involvement with daily examinations for signs of complications. Local supportive care includes topical lubricants for dry eyes, sweeping of conjunctival fornices, and disruption of fresh synechiae with the help of lubricating or antibiotic eye drops. Administration of eye preparations should be at the discretion of the ophthalmologist, and all procedures should be carried out by the appropriate specialist. Hospitalization is usually not required for EM patients, except in the rare cases of life-threatening complications such as dehydration, severe electrolyte imbalance, or secondary infection.

Recurrent and Persistent EM Treatment of recurrent EM is a challenge for the dermatologist. In HSV-associated or idiopathic EM, the first-line management is long-term prophylaxis with antiviral medications. The treatment target for long-term acyclovir is the reduction of HSV recurrences and, consequently, of EM episodes. Several ways of administration have been used, including continuous oral therapy, intermittent oral therapy, and topical therapy, but continuous oral antivirals for at least 6 months remain the most effective approach. The evidence does not support efficacy for topical application. Acyclovir at a dose of 400 mg twice daily is usually the preferred agent, but in acyclovir-resistant cases, other agents, such as valacyclovir at a dose of 500  mg once daily or famciclovir, can be an alternative. The treatment should continue for at least 6  months, and any extension should be guided by clinical response. Doses of antiviral

K. Semkova and J. Kazandjieva

drugs may be doubled in recalcitrant cases. Once achieved, remission is usually difficult to maintain after treatment discontinuation. In case of relapse of EM, patients who responded well to treatment should restart the antiviral agent at the lowest effective dose and continue the therapy for 6–12 months. Multiple therapeutic agents have been tried for recurrent EM resistant to prophylactic antiviral treatments (Wetter and Davis, 2010). These include dapsone, azathioprine, mycophenolate mofetil, thalidomide, cyclosporine, hydroxychloroquine, and cimetidine. Unfortunately, the scarcity of literature data and the limited experience with these agents impede guidance on the most optimum period of treatment. Dapsone is a drug with antibacterial, anti-inflammatory, and immunomodulatory effects. In a series of nine patients with treatment-­resistant recurrent EM, eight had complete or partial remission with dapsone at a dose of 100–150 mg/day (Schofield et al. 1993). Another study identified ten patients on dapsone therapy (dose monitoring for adverse events, including hemolytic anemia, methemoglobinemia, and agranulocytosis). Dapsone was also reported to induce EM with neutropenia in a patient with IgA linear dermatosis. Azathioprine has been used with variable success in patients who are not responsive to antiviral therapy. Most of the patients reported in one study of recurrent EM had a dose-dependent remission (at doses 100–150  mg/day), but relapsed after treatment discontinuation. Mycophenolate mofetil has also shown efficacy in the treatment of EM. Complete or partial remission was reported in about 75% of patients treated with ≤2 g/day. The clinical experience with cyclosporine for treatment of EM is limited. An intermittent short therapeutic course with initiation of treatment within 1–2 days of the onset of a new episode has been proposed as an effective and safe alternative to long-term treatment. Thalidomide is effective to suppress a recurrent episode of EM at a dose of 100 mg/day or to maintain remission at a lower dose. It could be used as an intermittent therapy for new episodes of recurrent EM or as a continuous course in persistent EM. Other treatments, such as antimalarials, immunoglobulin, cimetidine, tofaci-

26  Erythema Multiforme

tinib, and single dose etanercept, represented an effective treatment for isolated cases of patients with EM.  Topical tacrolimus 0.1% cream was used in one patient to achieve faster resolution of cutaneous lesions and induce remission.

Treatment of EM in Children Management principles in children should follow the guidance for adults with age-dependent modifications in drug therapy and dosage. Supportive care is first line in the management plan, and in almost all reported cases, it suffices on its own. Systemic steroids could be used in severe cases when the potential benefits outweigh the possible risks. Recurrent and/or persistent cases have only rarely been reported in children exclusively associated with a viral trigger. Immunosuppressive agents are hence only rarely used to treat EM in this population group.

References Bastuji-Garin S, Rzany B, Stern RS, et al. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol. 1993;129(1):92–6. Ng PP, Sun YJ, Tan HH, Tan SH.  Detection of herpes simplex virus genomic DNA in various subsets of erythema multiforme by polymerase chain reaction. Dermatology. 2003;207(4):349–53. Schofield JK, Tatnall FM, Leigh IM. Recurrent erythema multiforme: clinical features and treatment in a large series of patients. Br J Dermatol. 1993;128(5):542–5. Sun Y, Chan RK, Tan SH, Ng PP.  Detection and genotyping of human herpes simplex viruses in cutaneous lesions of erythema multiforme by nested PCR. J Med Virol. 2003;71(3):423–8. Torrelo A, Andina D, Santonja C, et  al. Erythema multiforme-­like lesions in children and COVID-19. Pediatr Dermatol. 2020;37(3):442–6. Wetter DA, Davis MD. Recurrent erythema multiforme: clinical characteristics, etiologic associations, and treatment in a series of 48 patients at mayo clinic, 2000 to 2007. J Am Acad Dermatol. 2010;62(1):45–53.

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Further Reading Auquier-Dunant A, Mockenhaupt M, Naldi L, et  al. Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study. Arch Dermatol. 2002;138(8):1019–24. de Risi-Pugliese T, Sbidian E, Ingen-Housz-Oro S, Le Cleach L.  Interventions for erythema multiforme: a systematic review. J Eur Acad Dermatol Venereol. 2019;33(5):842–9. https://doi.org/10.1111/jdv.15447. Farthing PM, Maragou P, Coates M, et al. Characteristics of the oral lesions in patients with cutaneous recurrent erythema multiforme. J Oral Pathol Med. 1995;24(1):9–13. Hoffman LD, Hoffman MD. Dapsone in the treatment of persistent erythema multiforme. J Drugs Dermatol. 2006;5(4):375–6. Lerch M, Mainetti C, Terziroli Beretta-Piccoli B, Harr T. Current perspectives on erythema multiforme. Clin Rev Allergy Immunol. 2018;54(1):177–84. https://doi. org/10.1007/s12016-­017-­8667-­7. Michaels B. The role of systemic corticosteroid therapy in erythema multiforme major and Stevens-Johnson syndrome: a review of past and current opinions. J Clin Aesthet Dermatol. 2009;2(3):51–5. Ohtani T, Deguchi M, Aiba S. Erythema multiforme-like lesions associated with lesional infiltration of tumor cells occurring with adult T-cell lymphoma/leukemia. Int J Dermatol. 2008;47(4):390–2. Schalock PC, Dinulos JG, Pace N, et al. Erythema multiforme due to mycoplasma pneumoniae infection in two children. Pediatr Dermatol. 2006;23(6):546–55. Sokumbi O, Wetter DA.  Clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist. Int J Dermatol. 2012;51:889–902. Tatnall FM, Schofield JK, Leigh IM.  A double-blind, placebo-controlled trial of continuous acyclovir therapy in recurrent erythema multiforme. Br J Dermatol. 1995;132(2):267–70. Urosevic-Maiwald M, Kerl K, Harr T, Allemann IB. Dapsone-induced erythema multiforme with neutropenia in a patient with linear IgA dermatosis: case report and review of the literature. Int J Dermatol. 2013;52(11):1369–71. Zoghaib S, Kechichian E, Souaid K, Soutou B, Helou J, Tomb R.  Triggers, clinical manifestations, and management of pediatric erythema multiforme: a systematic review. J Am Acad Dermatol. 2019;81(3): 813–22.

Erythema Nodosum

27

Eva Remenyik

Key Points • Erythema nodosum is an inflammation of the subcutaneous tissue (panniculitis), usually appears in acute fashion. It may recur but is rarely chronic. • Histopathologically, the mixed inflammatory cells involve the septa of the panniculus without vasculitis. • Erythema nodosum is a secondary hypersensitivity reaction to a known or unknown antigen. • Underlining causes always have to be vigorously investigated (most commonly streptococcal infections, sarcoidosis, and inflammatory bowel disease). • The diagnosis is mostly based on case history and the clinical picture (red-violet, tender, painful nodule usually on the shin). Deep biopsy is rarely needed to differentiate from other nodular inflammatory lesions mainly from vasculitides and other panniculitides. • The first step of treatment is to eliminate the antigen (or aggravating factor) and treat the underlying disease. • Symptomatic treatment is also indicated:

E. Remenyik (*) Department of Dermatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary e-mail: [email protected]; dermatologia@ med.unideb.hu

Physical: bed rest, elevation of the limbs, cold compresses, elastic bandage. Topical: anti-inflammatory (aluminum salt, NSAID). Systemic: NSAID, antihistamines, corticosteroids, antibiotics, potassium iodine, colchicine, dapsone, hydroxychloroquine, thalidomide.

Definition and Epidemiology Erythema nodosum (EN) is typically characterized by suddenly symmetrically appearing deep painful red-violaceous nodules on the pretibial area. It rarely recurs, but in some cases it becomes chronic. Histopathologically, EN is a septal panniculitis without vasculitis. It is presumed to be a hypersensitivity reaction. The most common underlying causes are infections, inflammatory bowel diseases, sarcoidosis, drugs, and it can also be idiopathic. It is self-limited, but reacts well and rapidly to anti-inflammatory therapy, healing without any remaining sign. It can occur in any ages, but more common in 25–40 years. Before puberty there is less gender difference (Aydin-Teke et al. 2014), but after 3–6 times more common in women than in man (Hafsi and Badri 2020; Chowaniec et al. 2016).

© Springer Nature Switzerland AG 2023 A. D. Katsambas et al. (eds.), European Handbook of Dermatological Treatments, https://doi.org/10.1007/978-3-031-15130-9_27

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298 Table 27.1  Possible etiologic factors of erythema nodosum Unknown Physiological conditions Drugs

Diseases

Incidence (%) 50–55 2–5

Idiopathic Gravidity Antibiotics Oral contraceptive Other Infective Bacterial

Viral Fungal Parasitic Chronic inflammatory

Malignancy

Sulfonamide, amoxicillin

3–4

Dabrafenib+trametinib, vaccines, PD-1 inhibitors Streptococcal infection (tonsillitis) 20–40 Bacterial gastroenteritis: Yersinia, Campylobacter, Salmonella; other bacterial: Mycobacteria, Rickettsia, Brucella, Bartonella, Treponema, Mycoplasma Mostly upper respiratory, but hepatitis B, EBV, HSV, HIV, SARS-CoV2 Coccidioidomycosis, blastomycosis, histoplasmosis, dermatophytes Giardiasis, amebiasis, ascariasis, toxoplasmosi, taeniasis Sarcoidosis 10–20 Inflammatory bowel diseases mostly Crohn 1–4 Neutrophilic dermatoses (Behcet’s disease, Sweet syndrome) Granulomatous mastitis, arthritis, SLE Haematology (Acute myeloid leukemia, Hodgkin disease) solid organ: cervix, renal, pulmonal, pancreatic, etc

Basic Concepts of Pathogenesis EN is probably a hypersensitivity reaction to a known or unknown antigen. Antigens from the underlying primary disease initiate the inflammatory process most likely via delayed-type hypersensitivity reaction (Silva et  al. 2019) T reg dysregulation (Negera et al. 2017), but the role of complement and immune complexes is also suspected especially in EN leprosum (Negera et al. 2018) and inflammatory bowel disease-­associated EN. It has a complex interaction of various parts of the immune system (Polycarpou et al. 2017). Histopathologically, there is a mixed inflammatory infiltrate in the septa of the panniculus and the overlying dermis without evidence of vasculitis. Histological features vary with the chronology of the lesions. Neutrophils may predominate during early septal edematous change, but eosinophils may also be present. A characteristic feature is Miescher’s granuloma (a group of histiocytes surrounded (Requena and Yus 2001) by neutrophils); giant cells are also frequently seen (De Simone et  al. 2016).

Latter perivascular lymphocytic infiltration predominates with fibrosis. A physician diagnosing EN always has to consider it as a secondary disease, and underlying causes must be sought (Varas et  al. 2016; Blake et al. 2014; Brodell and Mehrabi 2000). Possible initiating causes are shown in Table 27.1. Among them, streptococcal infection is the most common in children and adults besides sarcoidosis and inflammatory bowel disease (Kilic 2023). Socioeconomic conditions and access to healthcare have impact on disease presentation (Porges et al. 2018) example: new drugs like BRAF inhibitors (Mossner et  al. 2015) and the new coronavirus infection or the vaccination can also trigger EN (Suter et al. 2020, Damevska 2022).

Clinical Presentation Suddenly appearing painful 2–5 cm-diameter red tender oval nodules develop symmetrically on the anterior shins (see Fig. 27.1). Pain can be disabilitating. The skin is usually elevated at the center of

27  Erythema Nodosum

299

Fig. 27.1  Red painful nodules symmetrically on the shins

Fig. 27.2  Closer view of nodules

the nodule with poorly defined borders and more intensive bright red color in the middle during the acute eruptive phase (see Fig. 27.2). The color of the nodules may at times also be violaceous especially during the resolution phase turning to yellow, resembling a bruise (see Fig.  27.3). Suppuration, bulla formation, and ulceration never develop except EN leprosum (Walker et al. 2015). Sometimes only one nodule appears, but more often simultaneously and consecutively multiple lesions appear. Although extensor surface of the lower extremities is the typical site of the lesions, it is not rare for the nodules to present on thighs and arms or other body areas. Nontibial localization might be a sign of underlying systemic disease (Dogan et  al. 2016). Regional lymph node enlargement does not accompany the deep inflammation. Half of the patients experience joint pain mainly at the early development of the skin symptoms or preceding them. Signs of

systemic inflammation like fever, flu-like syndromes can precede and/or accompany the development of skin symptoms. Nodules can spontaneously resolve, but frequently patients seek medical care. Skin symptoms heal without scar formation. The nodules recur in a third of the patients (mainly in idiopathic cases), and rarely they may also remain chronic. Later, the discoloration of the affected area takes place, usually the more brownish the nodule becomes, the less elevated the central portion of the nodule will be. These lesions also show a tendency for centrifugal spread, arciform appearance. EN resolves spontaneously and rarely have complications like encapsulated fat necrosis or mobile encapsulated lipoma (Wendon 2010). Regardless of the initiating cause, the skin symptoms of EN are the same, but systemic complaints sometimes are modified by the symptoms of the underlying conditions.

E. Remenyik

300

Differential Diagnosis In typical cases, the clinical picture is characteristic, and the diagnosis can be established without the need for biopsy and histopathology. If biopsy is needed, it has to be deep enough to reach the subcutaneous fat and provide optimal amount of tissue sample from the inflammatory site. Usually incisional biopsy is preferred, but a double punch, with a larger-diameter superficial punch biopsy followed by a deeper smaller punch of the subcutis, may prove sufficient. In everyday clinical settings on the first examination, erysipelas/cellulitis, thrombophlebitis, insect bite, or sometimes urticaria are the most common differential diagnoses. After ruling out these diseases, other panniculitides and vasculitides have to be considered (see Fig.  27.4). EN ­leprosum is a separate disease characterized histopathologically with small vessel vasculitis.

Fig. 27.3 Erythema nodosum, nodules in resolution stage: bluish color Differential diagnoses of panniculitis Clinical picture Erythema nodosum

Not erythema nodosum biopsy

inflammation

(panniculitis)

non infective septal +

vasculitis

infektive agents granulomatous

lobular –

Thrombophlebitis

+

vasculitis

Vasculitis nodularis

Erythema nodosum

depositon

–

Sarcoidosis Granuloma anulare Rheumatic nodule

Weber Christian sy, Lipodystrophy, Pancreatic panniculitis, SLE profunda Traumatic

Fig. 27.4  Differential diagnosis of erythema nodosum after emergency

Bacteria Fungi Parasites Protosoa Worms

Calcium

tumor Benign Leiomyoma Malignant Leukaemia Lymphoma

27  Erythema Nodosum

Investigations From laboratory investigation, complete blood counts CRP, antistreptolysine titer, viral serology, Quantiferon Gold test are recommended. Stool culture and throat swab, Mantoux test, chest X ray and gastroenterological, ENT, and dental examination are also routinely implemented (Schwartz and Nervi 2007, Michelle 2021).

General Principles of Treatment EN is usually self-limited, and its outcome is not independent of the course of the underlying disease. Therefore, the therapy is often only symptomatic besides eliminating or treating aggravating causes (Blake et al. 2014). These latter interventions include discontinuation of possible aggravating drugs and initiation of adequate antimicrobial treatment if infection is suspected and intensification of regimen for underlying chronic uncontrolled diseases. The duration of EN is dependent on the aggravating factor and also from the treatment of choice. Usually resolve within weeks (Blake et al. 2014). Physical pain relief methods (bed rest and cooling the inflamed skin) are the bases of symptomatic care. EN quickly responds to systemic steroid, but in most cases its use is neither recommended nor necessary. Therapeutic options consist mainly of nonsteroidal anti-inflammatory drugs (NSAID), but are also influenced by the underlying conditions.

Topical Treatments Given the experienced pain, patients usually intuitively find relief in bed rest. Nevertheless, physicians have to counsel patients to avoid physical activity and potential trauma. Moreover, physical cooling of the inflamed area with cold compresses or ice packs helps also reduce subjective complaints. Elastic bandages or low pressure compression stockings are also recommended (Golisch et  al. 2017). Solutions with aluminum salt in cold compress and also in barrier creams further increase anti-inflammatory effects of

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topical therapy. Topical NSAIDs may also be used, but their higher sensitizing potential has to be considered. Potent topical corticosteroids can also be applied. Some reviews mention intralesional injection of corticosteroids (Acosta et  al. 2013), but only based on anecdotal evidence like heparin under occlusion (Schwartz and Nervi 2007). In resolving phase, Ichthyol can enhance the healing process, but its effect is also based on only personal clinical experiences. In pregnancy induced EN, mostly topical treatments are recommended (Acosta et al. 2013).

Topical Treatments at a Glance • Bed rest. • Cold compress. • Elastic bandage.

Systemic Treatments It is crucial to treat the underlying disease. However, in most EN cases systematic therapy is needed to reduce pain and speed up recovery even before the initiating factor is identified.

Salicylates and other NSAIDs Salicylates and other NSAIDs are the most commonly recommended drugs (Blake et  al. 2014; Leung et al. 2018; Passarini and Infusino 2013). Their main effect is inhibition of cyclooxygenase enzyme producing pro-inflammatory mediators like prostaglandins. NSAIDs modify cytokine production of T cells (Friedman et al. 2002). They are recommended in the regular anti-­ inflammatory dose. Pain and subjective symptoms react quicker than inflammation. ­ Continuous treatment is necessary for a few weeks, sometimes for an even longer period. The most frequently observed side effects are gastrointestinal, including hyperacidity, impairment of renal function, and also allergic reactions. Important warning! NSAIDs have to be avoided in inflammatory bowel disease-­ associated EN, because they may trigger exacerbation of bowel symptoms or compromise maintenance therapy (Tanaka et al. 2009).

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Systemic Corticosteroids dependent, rare and most common in GI system Systemic Corticosteroids As potent anti-­(nausea, bitter taste, excessive salivation) and inflammatory drug with immunosuppressive allergic reactions (urticaria, cutaneous small veseffects, corticosteroids effectively control sel vasculitis). For long-term application, chronic EN. Clinical symptoms react very well and rap- side effects are enlargement of salivary and lacriidly to systemic administration of corticosteroids mal glands, acneiform eruptions, headache, and (Passarini and Infusino 2013). The severity of the hypothyroidism or rarely hyperthyroidism. Dose symptoms of EN and the underlying diseases reduction can decrease the possibility of side determine their indication. It is recommended if effects. Thyroid functions should be monitored NSAIDs fail to reduce pain and inflammation. during therapy (Costa et al. 2013). Concomitant infection should be ruled out or treated with suitable anti-infective agent (antibi- Colchicine otics, antimycotics, antimycobacterials). Usually Colchicine is an antimitotic agent and arrests cell 0.5  mg/kg body weight prednisone-equivalent division by interfering with microtubule and dose substantially alleviates the symptoms within mitotic spindle formation, and it also has direct 24  h. The dose should be gradually tapered anti-inflammatory effect by reducing neutrophil according to the clinical symptoms and also to chemotaxis and adhesion to endothelial cells by the underlying disease (Fox and Schwartz 1992). decreasing expression of adhesion molecules. It Meanwhile other causative agent-dependent is widely used in acute gout. There is empirical treatment can also be recommended. Well-known evidence that Behcet’s disease-associated EN side effects of systemic steroid therapy have to be reacts well to colchicine and recurrences are also considered and preventive management has to be decreased by this medication (Davatchi et  al. initiated (Singh et al. 2015). 2009). It can also be effective in EN associated with other conditions (Wallace 1967). Close Potassium Lodide Solution monitoring is required during the therapy because The use of potassium iodide solution is another colchicine has relatively low therapeutic index. systemic therapeutic option in EN (Sterling and Kidney failure contraindicates its usage. Heymann 2000). Daily dosage is 300–1500  mg Hematological side effects are relatively comorally for adults dividing 3x a day. Symptoms can mon (anemia, neutropenia) and peripheral neurelieve within 24–48 h and the usual application ropathy can occur. time is 10–14 days (Hassan and Keen 2012). For better palatability, dissolving the recommended Dapsone amount in fruit juice or water is recommended Diaminodiphenyl sulfone is an antibacterial drug and start lower dose, then gradually increase it. commonly used in the treatment of leprosy in Its exact effect is not well established. It is combination with other agents. It inhibits bactethought to help in EN by suppression of neutro- rial synthesis of dihydrofolic acid via direct phil ROS release and chemotaxis and by inhibi- structural competition for dihydropteroate syntion of cell-mediated immunity via induction of thetase. It also has anti-inflammatory and immuheparin release from mast cells. For the onset of nomodulatory effects most likely by inhibiting therapeutic benefit, usually at least 2  weeks are myeloperoxidase in neutrophils (Wozel and needed. Thyroid gland function before and dur- Blasum 2014). Dapsone is mainly used in EN ing the application has to be checked. leprosum, but it can be considered in classical EN Contraindications are: goiter, Hashimoto thyre- refractory to conventional therapy (Song et  al. oiditis other thyroid gland diseases, impared kid- 2016), especially EN in Behcet’s disease. ney function, drugs can elevate potassium level, Hematologic side effects are the most pronounced active tuberculosis, dermatitis herpetiformis, including methemoglobinemia, aplastic anemia, urticarial vasculitis, diseases or treatments caus- leukopenia, agranulocytosis, eosinophilia, and ing immunosuppression, allergy to iodine and macrocytic anemia. Hemolytic anemia is more pregnancy/lactation. Acute side effects are dose- likely with doses greater than 200 mg/day or in

27  Erythema Nodosum

patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Before initiation of the drug, G6PD activity should be determined; if it is not available, closer monitoring of the red blood cell count, methemoglobin level, and evidence of hemolysis should be performed besides monitoring for clinical symptoms of peripheral neuropathy. Dizziness, vertigo, blurred vision, and headache have also been reported as side effects of dapsone (Ghaoui et al. 2020).

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nomodulating effects on the innate and adaptive immune system, as well as on tumorigenesis and angiogenesis (Walker et  al. 2007; Paravar and Lee 2008). A wide variety of diseases, several dermatological conditions among them (Kaposi sarcoma, lupus erythematosus, prurigo nodularis, erythema nodosum, Behcet’s syndrome, Langerhans cell histiocytosis, graft-versus-host disease, cutaneous sarcoidosis, erythema multiforme, Jessner-Kanof lymphocytic infiltration of the skin, lichen planus, melHydroxychloroquine anoma, pyoderma gangrenosum, and uremic is an antimalarial agent also used in rheumatoid pruritus), have been successfully treated with arthritis, lupus erythematosus, and some other thalidomide as off-label therapy (Wu et  al. photosensitive and inflammatory skin conditions. 2005). Due to its teratogenicity, proper contraIts anti-inflammatory mechanisms are broad, ception for women (two different methods) and involve immunocomplex production and T cell-­ also for men is inevitable during its use and mediated immune response, inhibit lysosomal 4  weeks after its administration. In everyday enzymes, reduce ROS and nucleic acid synthesis, practice, neuropathy is the most limiting side and also reduce antigen presentation by macro- effect, but prescribing physicians need to also phages (Sardana et  al. 2020). It is mainly used be aware of the relative frequency of anemia, and indicated in EN associated with Behcet’s leukopenia, constipation, and susceptibility to disease and EN leprosum (Alloway and Franks deep vein thrombosis (Porto et al. 2019). With 1995). Hydroxychloroquine is usually well tol- close monitoring and good counseling, several erated. Leukocytopenia and gastrointestinal and patients may benefit from thalidomide therapy. eye side effects rarely appear. During a long-term Newly developed thalidomide analogs (lenalinuse, minimum yearly ophthalmologic examina- omide and promalinomide) with reduced toxiction has been previously advised, although recent ity and enhanced therapeutic activity have not evidence questions the cost-effectivity of this had evidences in EN leprosum. practice, and after good triage of patients for risk, less frequent follow-up is acceptable (Sardana TNF-α Inhibitors et al. 2020). TNF alpha is a key cytokine in granulomatous inflammation. Its inhibitors reduce chronic Thalidomide inflammation in rheumatoid arthritis and psoriaLaunched as a hypnosedative drug in the 1950s, sis. Moreover, it has been published to be effecthalidomide later turned out to induce birth tive in EN refractory to conventional therapy. defect and was withdrawn from the market due Receptor antagonist etanercept in sarcoidosis-­ to its teratogenicity. After the discovery of its associated EN or EN leprosum (Chowdhry et al. excellent effect in EN leprosum (Darlong et al. 2016; Santos et  al. 2017), infliximab and adali2016; Walker et  al. 2007), it was relicensed in mumab in inflammatory bowel disease (IBD) some countries and since has proven its thera- -associated EN had therapeutic benefit according peutic efficacy in several autoimmune and to some reports (Zippi et al. 2013; Siemanowski inflammatory diseases. Thalidomide has EMA and Regueiro 2007). Another biological IL 12/23 approval only for treating EN leprosum and inhibitor ustekinumab also approved for IBD and multiple myeloma. Thalidomide can directly reported beneficial effect on EN associated with inhibit angiogenesis induced by bFGF or VEGF, Crohn disease in a clinical trial (Phillips et  al. also inhibit IL-6 and TNF alpha secretion, acti- 2020). vate apoptosis, and increase NK-dependent T Other immunosuppressants and chemotheracell cytotoxicity (Kim et al. 2015). It has immu- peutic agents (azathioprine and methotrexate,

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Daniela M, Pérez-Garza S, Chavez-Alvarez, OcampoCandiani M, Gomez-Flores. Erythema Nodosum: A Practical Approach and Diagnostic Algorithm American Journal of Clinical Dermatology. 2021;22(3)367–78. https://doi.org/10.1007/ s40257-021-00592-w. Darlong J, Govindharaj P, Charles DE, Menzies A, Mani S.  Experiences with thalidomide for erythema nodosum leprosum- a retrospective study. Lepr Rev. 2016;87(2):211–20. Davatchi F, Sadeghi Abdollahi B, Tehrani Banihashemi A, Shahram F, Nadji A, Shams H, et al. Colchicine versus placebo in Behcet’s disease: randomized, double-­ blind, controlled crossover trial. Mod Rheumatol. 2009;19(5):542–9. Systemic Treatments at a Glance De Simone C, Caldarola G, Scaldaferri F, Petito V, Perino Treat underlying infection or disease. F, Arena V, et al. Clinical, histopathological, and immunological evaluation of a series of patients with ery• NSAID. thema nodosum. Int J Dermatol. 2016;55(5):e289–94. Dogan S, Karaduman A, Evans SE. Clinical and labora• Corticosteroids tory characteristics of patients with erythema nodo• Potassium iodine sum. Skinmed. 2016;14(2):99–103. • Colchicine Fox MD, Schwartz RA.  Erythema nodosum. Am Fam • Dapsone Physician. 1992;46(3):818–22. Friedman ES, LaNatra N, Stiller MJ. NSAIDs in dermato• Hydroxychloroquine logic therapy: review and preview. J Cutan Med Surg. • Thalidomide 2002;6(5):449–59. • TNF alpha inhibitors Ghaoui N, Hanna E, Abbas O, Kibbi AG, Kurban M. Update on the use of dapsone in dermatology. Int J Dermatol. 2020;59(7):787–95. Golisch KB, Gottesman SP, Segal RJ. Compression stockings as an effective treatment for erythema nodosum: References case series. Int J Womens Dermatol. 2017;3(4):231–3. Hafsi W, Badri T.  Erythema nodosum. Treasure Island, FL: StatPearls; 2020. https://www.ncbi.nlm.nih.gov/ Acosta KA, Haver MC, Kelly B. Etiology and therapeutic books/NBK470369/#article-­21301.s1. management of erythema nodosum during pregnancy: Hassan I, Keen A.  Potassium iodide in dermatology. an update. Am J Clin Dermatol. 2013;14(3):215–22. Indian J Dermatol Venereol Leprol. 2012;78(3): Alloway JA, Franks LK. Hydroxychloroquine in the treat390–3. ment of chronic erythema nodosum. Br J Dermatol. Jitendra SSV, Bachaspatimayum R, Devi AS, Rita 1995;132(4):661–2. S.  Azathioprine in chronic recalcitrant erythema Aydin-Teke T, Tanir G, Bayhan GI, Metin O, Oz nodosum leprosum: a case report. J Clin Diagn Res. N.  Erythema nodosum in children: evaluation of 39 2017;11(8):FD01–FD2. patients. Turk J Pediatr. 2014;56(2):144–9. Blake T, Manahan M, Rodins K. Erythema nodosum—a Kar BR, Babu R.  Methotrexate in resistant ENL.  Int J Lepr Other Mycobact Dis. 2004;72(4):480–2. review of an uncommon panniculitis. Dermatol Online Katerina D, Viktor S. Covid‐19 vaccine associated eryJ. 2014;20(4):22376. thema nodosum: Factors to consider Dermatologic Brodell RT, Mehrabi D.  Underlying causes of erythema Therapy. 2022;35(5). https://doi.org/10.1111/dth.v35.5 nodosum. Lesions may provide clue to systemic dishttps://doi.org/10.1111/dth.15410. ease. Postgrad Med. 2000;108(6):147–9. Chowaniec M, Starba A, Wiland P.  Erythema nodo- Kilic Y, Kamal S, Jaffar F et al. Prevalence of Extraintestinal Manifestations in Inflammatory Bowel sum—review of the literature. Reumatologia. Disease (2023): A Systematic Review and Meta2016;54(2):79–82. analysis Abstract Inflammatory Bowel Diseases Chowdhry S, Shukla A, D’Souza P, Dhali T, Jaiswal https://doi.org/10.1093/ibd/izad061. P.  Treatment of severe refractory erythema nodosum leprosum with tumor necrosis factor inhibitor etaner- Kim BS, Kim JY, Lee JG, Cho Y, Huh KH, Kim MS, et al. Immune modulatory effect of thalidomide on T cells. cept. Int J Mycobacteriol. 2016;5(2):223–5. Transplant Proc. 2015;47(3):787–90. Costa RO, Macedo PM, Carvalhal A, Bernardes-­ Engemann AR.  Use of potassium iodide in derma- Leung AKC, Leong KF, Lam JM.  Erythema nodosum. World J Pediatr. 2018;14(6):548–54. tology: updates on an old drug. An Bras Dermatol. 2013;88(3):396–402.

cyclosporine) (Jitendra et al. 2017; Kar and Babu 2004), apremilast, have also been shown to have benefit in some forms of EN according to case reports (Narang et al. 2020). From the treatment choices, physicians should choose the best according to the possible or proven underlying/aggravating agent (see in Table  27.1) and also consider that most of the drugs recommended based on case reports and personal experiences are off-label.

27  Erythema Nodosum Mossner R, Zimmer L, Berking C, Hoeller C, Loquai C, Richtig E, et al. Erythema nodosum-like lesions during BRAF inhibitor therapy: report on 16 new cases and review of the literature. J Eur Acad Dermatol Venereol. 2015;29(9):1797–806. Narang T, Kaushik A, Dogra S.  Apremilast in chronic recalcitrant erythema nodosum leprosum: a report of two cases. Br J Dermatol. 2020;182(4):1034–7. Negera E, Walker SL, Bobosha K, Howe R, Aseffa A, Dockrell HM, et  al. T-cell regulation in erythema nodosum leprosum. PLoS Negl Trop Dis. 2017;11(10):e0006001. Negera E, Walker SL, Lema T, Aseffa A, Lockwood DN, Dockrell HM.  Complement C1q expression in erythema nodosum leprosum. PLoS Negl Trop Dis. 2018;12(3):e0006321. Paravar T, Lee DJ.  Thalidomide: mechanisms of action. Int Rev Immunol. 2008;27(3):111–35. Passarini B, Infusino SD.  Erythema nodosum. G Ital Dermatol Venereol. 2013;148(4):413–7. Phillips FM, Verstockt B, Sebastian S, Ribaldone DG, Vavricka S, Katsanos K, et  al. Inflammatory cutaneous lesions in inflammatory bowel disease treated with vedolizumab or ustekinumab: an ECCO CONFER multicentre case series. J Crohns Colitis. 2020;14:1488. Polycarpou A, Walker SL, Lockwood DN. A systematic review of immunological studies of erythema nodosum leprosum. Front Immunol. 2017;8:233. Porges T, Shafat T, Sagy I, Zeller L, Bartal C, Khutarniuk T, et  al. Clinical, epidemiological, and etiological changes in erythema nodosum. Isr Med Assoc J. 2018;20(12):770–2. Porto LAB, Grossi MAF, de Alecrim ES, Xavier M, Paiva ESF, Pires AS, et al. Deep venous thrombosis in patients with erythema nodosum leprosum in the use of thalidomide and systemic corticosteroid in reference service in belo horizonte, minas gerais. Case Rep Dermatol Med. 2019;2019:8181507. Requena L, Yus ES. Panniculitis. Part I. mostly septal panniculitis. J Am Acad Dermatol. 2001;45(2):163–83; quiz 84–6. Santos JRS, Vendramini DL, Nery J, Avelleira JCR. Etanercept in erythema nodosum leprosum. An Bras Dermatol. 2017;92(4):575–7. Sardana K, Sinha S, Sachdeva S.  Hydroxychloroquine in dermatology and beyond: recent update. Indian Dermatol Online J. 2020;11(3):453–64. Schwartz RA, Nervi SJ.  Erythema nodosum: a sign of systemic disease. Am Fam Physician. 2007;75(5):695–700. Siemanowski B, Regueiro M.  Efficacy of infliximab for extraintestinal manifestations of inflammatory bowel disease. Curr Treat Options Gastroenterol. 2007;10(3):178–84.

305 Silva PHL, Santos LN, Mendes MA, Nery JAC, Sarno EN, Esquenazi D. Involvement of TNF-producing CD8(+) effector memory T cells with immunopathogenesis of erythema nodosum leprosum in leprosy patients. Am J Trop Med Hyg. 2019;100(2):377–85. Singh SM, Narang T, Dogra S, Handa S. Self-perceived emotional side effects of systemic corticosteroid therapy in dermatology patients. Indian J Dermatol Venereol Leprol. 2015;81(6):655. Song JS, Halim K, Vleugels RA, Merola JF. Dapsone for treatment of erythema nodosum. Dermatol Online J. 2016;22(2):13030/qt8z782742. Sterling JB, Heymann WR.  Potassium iodide in dermatology: a 19th century drug for the 21st century-uses, pharmacology, adverse effects, and contraindications. J Am Acad Dermatol. 2000;43(4):691–7. Suter P, Mooser B, Pham Huu Thien HP. Erythema nodosum as a cutaneous manifestation of COVID-19 infection. BMJ Case Rep. 2020;13(7):e236613. Tanaka K, Suemasu S, Ishihara T, Tasaka Y, Arai Y, Mizushima T.  Inhibition of both COX-1 and COX-2 and resulting decrease in the level of prostaglandins E2 is responsible for non-steroidal anti-inflammatory drug (NSAID)-dependent exacerbation of colitis. Eur J Pharmacol. 2009;603(1–3):120–32. Varas P, Antunez-Lay A, Bernucci JM, Cossio L, Gonzalez S, Eymin G. Erythema nodosum: analysis of 91 hospitalized patients. Rev Med Chil. 2016;144(2): 162–8. Walker SL, Waters MF, Lockwood DN. The role of thalidomide in the management of erythema nodosum leprosum. Lepr Rev. 2007;78(3):197–215. Walker SL, Balagon M, Darlong J, Doni SN, Hagge DA, Halwai V, et  al. ENLIST 1: an international multi-­ centre cross-sectional study of the clinical features of erythema nodosum leprosum. PLoS Negl Trop Dis. 2015;9(9):e0004065. Wallace SL.  Erythema nodosum treatment with colchicine. JAMA. 1967;202(11):1056. Wendon D. In: Livingstone C, editor. Weedon’s skin pathology 3rd Edition; 2010. p. 477. http://www.sciencedirect.com/science/article/pii/B9780702034855000188. Wozel G, Blasum C. Dapsone in dermatology and beyond. Arch Dermatol Res. 2014;306(2):103–24. Wu JJ, Huang DB, Pang KR, Hsu S, Tyring SK.  Thalidomide: dermatological indications, mechanisms of action and side-effects. Br J Dermatol. 2005;153(2):254–73. Zippi M, Pica R, De Nitto D, Paoluzi P. Biological therapy for dermatological manifestations of inflammatory bowel disease. World J Clin Cases. 2013;1(2): 74–8.

28

Erythrasma Alexander Yu Turkevych

Key Points • Erythrasma is a chronic superficial infection of the intertriginous areas of the skin that causes brown, scaly skin patches. It occurs most often between the third and fourth toes, but it can also frequently be found in the groin, armpits, and under the breasts. • Erythrasma is caused by the Gram-positive bacterium Corynebacterium minutissimum, which usually is present as a normal human skin inhabitant. • The diagnosis can be made on the clinical picture alone. • Erythrasma can be treated with topical fusidic acid or topical erythromycin gel or clindamycin solution twice a day for 2 weeks. Extensive infection may benefit from the treatment with systemic macrolides.

enlarging area of pink or brown dry skin. It occurs most often between the third and fourth toes, but it can also frequently be found in the groin, armpits, and under the breasts. Because of the color and location, it is often confused with a fungal infection like jock itch. It is usually reported in the literature that the incidence could be over 20% in general population. Erythrasma is caused by the Gram-positive bacterium Corynebacterium minutissimum, which usually is present as a normal human skin inhabitant. This may coexist with the dermatophyte fungi or with Candida albicans. It is prevalent among diabetics and the obese and also in warm climates. Wearing occlusive clothing can worsen erythrasma.

Definition and Epidemiology

The patches of erythrasma are initially pink but progress quickly to become brown and scaly (as skin starts to shed), which are classically sharply demarcated. Erythrasmic patches are typically found in intertriginous areas (skinfold areas— e.g., armpit, groin, under breast). The slightly webbed spaces between toes (or other body region skinfolds) can be involved, making it difficult to distinguish from various tineas. The patient is commonly otherwise asymptomatic. Occasionally, itching, or burning sensation, may start because of sweating. Without treatment,

Erythrasma is a chronic superficial infection of the intertriginous areas of the skin that causes brown, scaly skin patches. It presents as a slowly A. Y. Turkevych (*) Department of Dermatovenereology, Lviv National Medical University Named After Danylo Galytskuj, Lviv, Ukraine Department of Dermatology, Rome University “G. Marconi”, Rome, Italy

Clinical Presentation

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lesions can persist for months, with exacerbations during the summer.

Diagnosis The diagnosis can be made on the clinical picture alone. However, to tell the difference between erythrasma and a fungal infection is to do a Wood’s lamp examination on the rash. Under the UV light of a Wood’s lamp, erythrasma turns a bright coral red, but fungal infections do not. Some other tests that may help include Gram stain (Gram stain of erythrasma shows delicate Gram-positive rods and filaments in the cornified layer), hematoxylin-eosin stains (there is orthokeratosis within which blue-staining organisms in the form of delicate rods and filaments can be found), and KOH test (test used to identify fungal elements and might be done to confirm that there is no fungus present). Also, skin biopsy can be done, if necessary. In the case of erythrasma, the bacteria can be seen in the upper layer of the specimen. Erythrasma can easily be missed on routine histopathologic sections as the inflammatory response is typically minimal; well-established lesions will reveal a sparse superficial perivascular infiltrate of lymphocytes.

Differential Diagnosis The main differential diagnoses are with the diseases involving intertrigo, tinea cruris or pedis, and candidal intertrigo. Pityriasis versicolor—Malassezia (formerly known as Pityrosporum) yeasts colonize the stratum corneum and also fail to elicit much of an epidermal response. The yeast forms are larger than Corynebacteria and fail to stain with Gram stain.

Pitted keratolysis—this may be indistinguishable from erythrasma without clinical correlation. Also erythrasma may be confused with impetigo, contact dermatitis, inverse psoriasis, and seborrheic dermatitis.

General Principles of Treatment General Recommendations Regular washing with antiseptic is helpful during the treatment and may prevent relapses. Given the fact that there is a pronounced tendency to recurrence, the intertriginous areas should be kept dry, with the use of suitable powders, while clothes, and/or shoes should be appropriate.

Topical Treatments Erythrasma is treated with topical fusidic acid or topical erythromycin gel or clindamycin solution twice a day for 2 weeks.

Systemic Treatments Extensive infection can be treated with systemic macrolides: • Erythromycin 250  mg four times a day for 7–10 days. • Clarithromycin 1 g once. • Azithromycin 1 g once. There is no sure way of knowing which of the above treatments should be preferred. It seems that systemic treatment is more effective. The disappearance of the red-coral fluorescence

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confirms the efficacy of the treatment. A brownish hyperpigmentation can persist for a while.

Further Reading Avci O, Tanyildizi T, Kusku E. A comparison between the effectiveness of erythromycin, single-dose clarithromycin and topical fusidic acid in the treatment of erythrasma. J Dermatolog Treat. 2013;24(1):70–4.

309 Chodkiewicz HM, Cohen PR.  Erythrasma: successful treatment after single-dose clarithromycin. Int J Dermatol. 2013;52(4):516–8. Koumantaki-Mathioudaki E.  Erythrasma. In: Katsambas L, editor. European handbook of dermatological treatments. 2nd ed. Berlin: Springer; 2003. Morales-Trujillo ML, Arenas R, Arroyo S.  Interdigital erythrasma: clinical, epidemiologic, and microbiologic findings. Actas Dermosifiliogr. 2008;99(6): 469–73.

29

Erythroderma Annalisa Patrizi and Michela Venturi

Key Points • Erythroderma (E), also named exfoliative dermatitis, is a rare severe skin disease and represents an extreme state of skin irritation involving the whole or most (more than 90%) of the skin surface. The resulting failure of the skin functions can coexist with other organ failures, so E is potentially life-threatening. • E may arise from or be caused by a preexisting dermatosis, a drug-induced reaction, a malignancy, an infection, a miscellaneous of rare diseases, or may represent an idiopathic disorder. In this last case, the term “red man” may be used when no primary cause can be found, despite serial examinations and tests. • Idiopathic E begins as a patch(es) of erythema accompanied by pruritus. The patch(es) enlarges and coalesces to form extensive areas of erythema which eventually spread to cover the whole or most of the skin surface. E is also associated with profuse scaling, which has its

A. Patrizi (*) Dermatology, Department of Specialized, Experimental and Diagnostic Medicine, Saint Orsola—Malpighi Hospital, University of Bologna, Bologna, Italy e-mail: [email protected] M. Venturi Dermatology Unit and Burn Center, AUSL Romagna, Bufalini Hospital, Cesena, Italy e-mail: [email protected]

onset 2–6  days after the erythema with individual variations. In the acute form of E, the formation of large scales is typical, while the chronic form is frequently characterized by small scales. The skin is notably dry, hot, and indurated. Mild to severe pruritus is usually present. Malaise and fever may occur. • Since E is mainly a secondary process, it is mandatory to establish its etiopathogenesis in order to facilitate its correct management. The diagnosis is mainly based on histology; immunocytochemistry (ICC) and molecular biology techniques can be helpful. • E is a severe disease; in fact the mortality rate is around 18–64% on the basis of its different etiology. The management frequently requires hospitalization, as well as general and local treatment. • The treatment of E varies according to the underlying condition and includes systemic treatment as systemic corticosteroids, antihistamines, and systemic antimicrobials. Moreover, according to the underlying condition, a systemic specific treatment is added.

Definition Erythroderma (E), first described by Hebra in 1868, is a reaction pattern, characterized by diffuse and confluent erythema with desquamation affecting most of or the entire body surface. E is

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usually accompanied by systemic manifestations including several metabolic changes. E may be the morphologic presentation of a variety of cutaneous and systemic, congenital or acquired diseases or, ultimately, the evolution of different skin disorders. Its phenotype varies from mild skin symptoms to lethal forms. E and exfoliative dermatitis are quite synonyms; however, E is the term currently preferred. Nonetheless, it is imperative to define both conditions. E is characterized by extensive and pronounced erythema with diffuse slight scaling, whereas exfoliative dermatitis presents a more conspicuous and marked scaling. The prerequisite to make the clinical diagnosis of E is a ≥ 90% involvement of the skin surface. The causative dermatoses can be referred by the mnemonic SCALPID: –– Seborrheic dermatitis/sarcoidosis. –– Contact (allergic or irritant) dermatitis (e.g., stasis dermatitis with generalization). –– Atopic dermatitis/autoimmune disease (systemic lupus/dermatomyositis/bullouspemphigoid/pemphigus foliaceus/lichen planus/ graft-versus-host disease). –– Lymphoma/leukemia (including Sézary syndrome). –– Psoriasis, with Reiter syndrome/pityriasis rubra pilaris (PRP). –– Infections (human immunodeficiency virus, dermatophytosis), ichthyoses, infestations (Norwegian scabies). –– Drug reactions.

Epidemiology The overall precise incidence of E is difficult to define as most reports are retrospective. E is surely a rare condition and its estimated annual incidence can vary from 1 to 2 per 100,000 general patients per year to 35 per 100,000 dermatologic outpatients, depending on the series. E accounts for about 1% of all hospital admissions with dermatologic conditions. In adults, a male predominance has been reported, with a male/

female ratio from 2:1 to 4:1 with no racial predilection. The most frequent reported age range is from 40 to 60  years, in the published series excluding children, but any age group may be affected; however, the affected patients are usually over 45  years of age (excluding hereditary disorders/atopic dermatitis), with an average onset age of 55  years. On the Indian subcontinent, the onset age is slightly lower. Even though E usually represents an adult disease, it shows another incidence’s peak in the pediatric age. Pediatric E has a mean onset age of 3.3 years, with a male/female ratio of 0.89:1 and a prevalence approximately estimated at 0.1% in pediatric dermatology populations.

Basic Concepts of Pathogenesis Adults E may be idiopathic when the personal and family history, the physical examination, and the laboratory data are inconclusive, or E may be due to different preexisting dermatoses, drug adverse reactions, malignancies, and systemic disorders. E is considered idiopathic in 9–47% of cases, while it may be linked to an exacerbation of a preexisting dermatosis in more than 50% of cases; therefore, patients should be carefully evaluated for an underlying skin disease. The subtle/sudden generalization of a preexisting dermatosis to E is an intriguing dilemma and may reflect individual variations. E may appear acutely over hours to days (usually in drug hypersensitivity reactions) or develop slowly in weeks or months (E from underlying cutaneous or systemic diseases). A detailed outline of the patient’s history is important to understand the possible triggering events as infections, drugs, sun/ultraviolet light exposure, vitamin deficiency, and other factors. In adults, the most common causes of protracted E are preexisting dermatoses, drug intake, pre-lymphomatous conditions, and occult malignancies, as cutaneous T-cell lymphoma (such as mycosis fungoides and Sézary syndrome), B-cell chronic lymphocytic leukemia and solid organ

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malignancies (such as gastric, esophageal, colon, liver, tongue, gallbladder, fallopiantube prostate, and lung cancer). The underlying diseases that more frequently can cause E are eczema (40% of cases, in particular atopic dermatitis in 4–24% of cases and nonatopic eczema in 5–25%), psoriasis (25%), lymphomas and leukemias (15%), drug intake (11–21% of cases), vitamin deficiency (10%), and, more rarely, other dermatoses as pityriasis rubra pilaris (in 1% to 8% of cases), skin infections and infestations (2%), or neoplastic or paraneoplastic conditions (1%) (Tables 29.1 and 29.2). When considering a patient affected with E, the list of drugs assumed should always be asked, including all prescription, over-the-counter, naturopathic, and herbal medications, as E’s pathogenesis may involve many drugs (Table 29.2). Topical and systemic drugs are notorious for triggering E. The agents that mainly and most frequently induce E are calcium channel blockers, carbamazepine, phenytoin, and phenobarbital. Other medications include antibiotics, corticosteroids, diaminodiphenyl sulfone, NSAIDs, phenothiazines, antihypertensive drugs, cimetidine, lithium and gold, synthetic antimalarials, sulfonamides, peptic ulcer drugs, sulfasalazine, allopurinol, thalidomide, cytokines, trimethoprim, sodium clodronate, zidovudine, and codeine. The same drug exanthems that commonly appear as morbilliform, lichenoid, or urticarial may progress to extensive erythema and exfoliation. E onset due to drugs is typically sudden and rapid and its resolution should be faster than in E induced by other causes. A different situation is E accompanied by systemic drug hypersensitivity reactions (DRESS, Drug Rash with Eosinophilia and Systemic Symptoms) due to antibiotics, anticonvulsants, and allopurinol. DRESS develops within 2–5 weeks after the start of treatment and may persist for weeks despite stopping the medication. Edema, fever, leukocytosis with marked eosinophilia, lymphadenopathy, organomegaly, and liver and renal dysfunction are characteristic of DRESS. Drug-induced E due to dapsone/antileprosy drug hypersensitivity may appear quite similar to a cutaneous T-cell lymphoma in the clinical features and histopathology. Anyway, it

313 Table 29.1  Dermatoses and diseases associated with E Eczema group

Infections and infestations

Malignancies

Inflammatory and immunological diseases

Rare and/or genetic diseases or idiopathic disorders

Irradiation

Atopic dermatitis Contact dermatitis Nummular eczema Photosensitive eczema Seborrhoeic dermatitis Stasis with auto eczematization Candidiasis HIV infection Viral hepatitis Staphylococcal scalded skin syndrome Toxic shock syndrome Dermatophytosis Scabies and norwegian scabies Leukemias, lymphomas, histiocytosis, malignant neoplasms Psoriasis Lichen planus Pemphigus Pemphigoid Cutaneous graft-versus-host disease Dermatomyositis Pityriasis rubra pilaris Prurigo Subacute cutaneous lupus erythematosus Systemic lupus erythematosus Lymphomatoid granulomatosis Angioimmunoblastic lymphadenopathy with dysproteinemia Darier’s disease Hailey-Hailey’s disease Ichthyosis Mastocytosis Ofuji papuloerythroderma Sarcoidosis Actinic reticuloid syndrome (chronic actinic dermatitis)

disappears after the withdrawal of the drug and the administration of a supportive therapy. Lymphomas and leukemias may cause E, for instance, Hodgkin’s and non-Hodgkin’s lymphomas, myeloid and lymphoid leukemias, and myelodysplasia. Cutaneous T-cell lymphomas (mycosis fungoides, Sézary syndrome) are one of

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314 Table 29.2  Drugs more frequently associated with E Class of drugs

Drugs Actinomycin D, aminoglycosides, aztreonam Cephalosporins Clofazimine Chloroquine Clotrimazole Dapsone Hydroxychloroquine Isoniazid Mefloquine Minocycline Neomycin Nitrofurantoin Para-amino salicylic acid Penicillins Quinacrine Rifampin Streptomycin Sulfadiazine Sulfonamides Tetracyclines Trimethoprim Vancomycin Anticonvulsants Carbamazepine Hydantoins Mephenytoin Phenytoin Antipsychotic Chlorpromazine Lithium Phenothiazines Hypoglycemics Tolbutamide Chlorpropamide Sulfonylureas Diuretics and uricosuric ACE inhibitors (enalapril, agents lisinopril) Chlorothiazide and thiazide Allopurinol Antihistamines and proton Cimetidine and ranitidine pump inhibitors Omeprazole, esomeprazole, pantoprazole Laxative Phenolphthalein Antidotes Dimercaprol Immunomodulators Interleukin-2 Interferon alpha Interferon beta Antiarrhythmics Amiodarone Mexiletene Quinidine (continued)

Table 29.2 (continued) Class of drugs Chemotherapeutic agents

β2-Adrenergic receptor agonist Tetrachloroethylene Arsenic Chinese herbs Codeine Cyclobenzaprine Iodine Gold Mercury and mercurials

Drugs Mitomycin-C Cisplatin Bevacizumab Imatinib Thalidomide Terbutaline

the most common malignancies associated with E. E may derive from a previous cutaneous T-cell lymphoma as a marker of progression and may appear simultaneously, or its onset may be antecedent to the cutaneous T-cell lymphoma lesions. When E precedes cutaneous T-cell lymphoma lesions, the interval between E’s appearance and cutaneous T-cell lymphoma’s manifestations ranges from months to years. Acute and chronic leukemia could cause E. The relative risk of leukemia inducing E is not well definite, varying from 11 to 50%. Reticular cell sarcoma and malignant histiocytoses are a few other implicated conditions. E may ultimately be one of the clinical expressions of reticuloendothelial neoplasms and internal malignancies. Malignant E invariably affects older individuals, and in the elderly age E is considered to be a cutaneous marker of an internal malignancy. Its incidence is around 1% and about 1% of all cases of E are due to visceral malignancies. The suspicion of an underlying malignancy may arise when the development of E is insidious, the patient becomes progressively debilitated, no previous skin diseases are recognized, and the lesions resist to standard therapies. In the literature, eosinophilic E is suggested to be a paraneoplastic syndrome.

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Children and Neonates In children, E due to atopic dermatitis is the most frequently observed. Other causes of children’s E are ichthyosis, Netherton syndrome, primary immunodeficiency syndromes (PIDS), and metabolic diseases in neonates (aged less than 1  month of life). Psoriasis, Omenn syndrome, seborrhoeic dermatitis, and atopic dermatitis usually appear after the first month of life. The pathogenesis of E is not clarified. A complex interaction of cytokines and cellular adhesion molecules, such as interleukins 1, 2, and 8, intercellular adhesion molecule-1 (ICAM-1), and tumor necrosis factor (TNF), is considered to be responsible for E, causing a strong increase in the epidermal turnover rate. In patients with this disorder, the mitotic rate and the absolute number of germinative skin cells are higher than normal. Moreover, the time required by the cells to differentiate and travel through the epidermis is shorter. This compressed maturation process results in an overall greater loss of corneocytes, which clinically appears as scaling and shedding. Normal epidermis undergoes some exfoliation every day, but the lost scales contain little, if any, important viable material, such as nucleic acids, soluble proteins, and amino acids. In patients with E, several pathological alterations appear, in particular regarding thermoregulation, metabolism, and water balance; in addition, some laboratory parameters show abnormal values. E causes a severe aberration of the body’s metabolism. The increased skin blood flow leads to higher skin temperature and heat loss. This elicits a cold sensation that induces a higher compensatory basal metabolic activity. The patient’s dehydration derives from the elevated transepidermal water loss (TEWL) and skin evaporation. Otherwise, hypoproteinemia is due to protein loss (because of the desquamation) and to the significant exudation. Hence, changes in laboratory parameters include hypoalbuminemia (brought by increased protein loss in the skin, decreased synthesis, and increased catabolism of proteins), anemia, electrolyte disturbances (hypernatremia), serum urea increase, and all alterations due

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to dehydration; lymphocytosis, possible eosinophilia, elevated inflammatory markers, and polyclonal gammaglobulinemia may be also observed. In specific forms of E, increased IgE serum levels or Sezary cells may be found.

Clinical Presentation Adults E’s phenotype varies from less severe skin symptoms to lethal forms. E can erupt simply with erythrodermic features or can be the aggravation of a preexisting dermatosis. The underlying disease is hidden by the erythrodermic nonspecific inflammatory manifestations, although it could emerge again during regression. Nonetheless, E’s clinical profile varies consequently to the nature of the underlying disease. A clinical classification distinguishes three different types of E: 1. Dry with large scales E (Wilson–Brocq) (Figs. 29.1 and 29.2). 2. Dry with small scales E (Hebra). 3. Vesiculo-bullous E (Fig. 29.3). From the clinical point of view, erythema is the first stage of primary E. It often erupts as single or multiple pruritic patches, localized most frequently in the head, trunk, and genitalia. In a few days or weeks, they tend to spread, and an erythematous, pruritic eruption comes to cover a great part of the skin. The palms, the soles, and the mucous membranes are usually not involved. The nose and the paranasal area are sometimes not affected. This is generally referred to as the “nose sign.” Two to six days after the appearance of erythema, scaling begins. The erythema has a variable intensity and scales are dandruff-like or lamellar, large in acute forms or small in chronic cases of E. Skin failure, that is the inability to maintain homeostatic functions, may occur. Edema is due to extravasation of proteins into the tissues because of the vasodilation. In E, the edema can be generalized or localized only on the lower limbs. In some cases, exudation may occur.

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Figs. 29.1 and 29.2  Erythroderma with large scales and skin dryness (Wilson–Brocq)

Fig. 29.3  Vesiculo-bullous E

In long-standing E, clinical presentation encompasses injuries due to scratching, dyschromia as hyperpigmentation or hypopigmentation, and palmar-plantar fissurated keratoderma when palms and soles are involved. The patient’s face can present a leonine appearance and/or ­ectropion. Changes in skin appendages may also be observed. Alopecia and eyebrow and eyelash thinning are frequently part of the clinical profile. Nails can appear thickened, corrugated, yellowish, and friable with transverse grooves. Some alterations may involve mucous membranes: cheilitis, conjunctivitis, and stomatitis could develop. Even lymph nodes may be moderately enlarged, hard-elastic, and painless (dermopathic lymphadenopathy). Pruritus, skin tension sensation (feeling tightness on the skin), and cold feeling are the subjective most frequently referred symptoms: itching occurs in nearly all patients. E may be complicated by some general signs and symptoms, such as fever (that may be present in more than half of patients), chills, asthenia, fatigue, myalgia, shortness of breath, weight loss,

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insomnia, gynecomastia, splenomegaly, hepatomegaly, and pedal edema. Psoriasis is a frequent cause of E.  Chronic plaque psoriasis precedes psoriatic E in more than 80% of patients. An identifiable/unidentifiable triggering factor drives to the transition from chronic plaque psoriasis to a more extensive involvement, characterized by the onset of an inflammatory phase; here, there are predominant erythema and limited scaling, as well as pruritus and burning. Triggers include sudden stopping of methotrexate, topical or systemic corticosteroids, the use of topical irritants as tars, systemic medications (antimalarials, lithium, terbinafine, gold, antimalarials, etc.), systemic illness, phototherapy burns, local and systemic infections (as HIV), pregnancy, and emotional stress. This unstable psoriasis could become a whole-­ body disease. Pustular and erythrodermic psoriasis (Figs. 29.4, 29.5, 29.6, 29.7, and 29.8) are the most severe clinical variants of the disease spectrum. In the erythrodermic psoriasis, generalized erythema, superficial scales, and loss of psoriatic clinical features are observed. Hence, psoriatic E is very similar to E due to other causes. Sometimes, scales do not look like those of chronic plaque psoriasis that are thick and adherent. Erythema involves the whole skin surface and derives from vasodilation, inducing a high heat loss. E can regress to extensive plaque psoriasis, but erythrodermic psoriasis recurs in 15% of patients after an initial clearing. In some patients, generalized pustular psoriasis may lead to erythrodermic psoriasis when there is no more pustular formation. E can follow pityriasis rubra pilaris. It often appears as a seborrheic dermatitis-like eruption of the scalp and, in a short time, evolves into a widespread erythema with islands of sparing. An early prominent feature is keratoderma. Pink papules may affect the hair follicles in the dorsal fingers, wrists, and elbows. Blisters and erosions are helpful for the diagnosis of E secondary to immunobullous diseases. Ruptured blisters may be highlighted by impetigo-­like erosions or collarettes, leading to the recognition of superficial pemphigus, and

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tense blisters are usually indicative of an erythrodermic bullous pemphigoid. E associated with dermatomyositis is rare, and in half the cases it is associated with digestive neoplasia (stomach and liver). Moreover, erythrodermic dermatomyositis may present Gottron’s papules, heliotrope rash, poikiloderma, periungual telangiectasias, and muscle weakness. E associated with mycosis fungoides (Fig.  29.9) is preceded by patches, plaques, or nodules, or there can be an E ab initio. An immunophenotypic study using advanced antibody panels may be required to distinguish it. Sézary syndrome, the leukemic variant of mycosis fungoides, is characterized by itching, infiltration of the skin, enlarged lymph nodes, hepatosplenomegaly, and circulating Sézary cells. A rapidly progressive E can be associated with lymphomatoid granulomatosis, a rare EBV-­ associated lymphoproliferative disorder. It affects mainly males in an immunodeficiency state. Clinical superficial lymph node swelling, subcutaneous nodules, and lung involvement are characteristic. The central nervous system is frequently involved. The diagnosis is based on histology.

Children and Neonates Atopic dermatitis may occur with E at birth but, more frequently, it develops in infants or small children. Atopic dermatitis presenting as E is usually observed after the first months of life. Skin lesions consist of vesicles or exudative areas mainly on the face and flexures. They can overlap those of infantile seborrheic dermatitis in smaller children. After the age of 1  year, the disease is often complicated by itch sensation and excoriations or overinfections (Figs. 29.10, 29.11, 29.12, and 29.13). E due to psoriasis is rare in children. It usually starts on the napkin area, but sometimes it may be yet observed at birth. Erythrodermic psoriasis should be differentiated by pityriasis rubra pilaris when it starts with erythematous scaly plaques.

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Figs. 29.4–29.8  Erythrodermic psoriasis

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In neonates with E, a delay in reaching the correct diagnosis can be fatal. Clinical evaluation, knowledge of familial anamnesis, and laboratory tests are key points in the differential diagnosis of E. A skin biopsy is essential.

Fig. 29.9  E associated with mycosis fungoides

Figs. 29.10–29.13  E in atopic dermatitis

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In particular, histology and immunohistochemistry could be useful tools for the distinction of severe diseases, such as PIDS and Netherton syndrome. Several varieties of ichthyoses can manifest as E in neonates or infants (see Chap. 44). Netherton syndrome is a rare skin disease classified within ichthyoses (Figs. 29.14 and 29.15). It has a recessive inheritance pattern. In small children with Netherton disease, scaly E is associated with fragile hair with trichorrhexis invaginata (named “bamboo hair”), immunological abnormalities of varying severity, IgE-mediated allergic reactions, infections, and defective temperature regulation. E of Netherton syndrome can be noted at birth or during the first weeks of life; it often induces retarded growth and development of the newborn.

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Figs. 29.14 and 29.15  E in Netherton syndrome: with picture of ichthyosis lineariscircumflexa. Notice the characteristic serpiginous erythematous plaque with double-edged scale at the margin

Neonatal E can be the early manifestation of PIDS such as Omenn syndrome. Omenn syndrome is a rare, autosomal recessive disease. Severe combined immunodeficiency, infections, E, alopecia, hypereosinophilia, hepatosplenomegaly, lymphadenopathy, hypogammaglobulinemia and elevated IgE serum levels, chronic diarrhea, and failure to thrive are characteristics of this condition.

Diagnosis The diagnosis of E is usually easy, but finding the underlying disease of E is a hard work. A complete physical examination with documentation of the total body surface area involved and islands of skin sparing should be conducted. Moreover, palpation may reveal any organomegaly (liver-spleen) or lymphadenopathy and auscultation of the thorax (lungs and heart sound) should be performed looking for signs of congestive heart failure or infection as pneumonia. The diagnostic-therapeutic approach requires a multidisciplinary team, and a dermatology consultant should be considered. Unfortunately, the clinical profile of E is not contributive and certain clues such as scaling or pruritus cannot be related to a specific cause. So, the clinical picture

does not always contribute to the underlying skin disease’s diagnosis. Patients with dermatologic disorders resistant to the therapy may develop E during a flare-up. In such cases, the etiologic diagnosis of E is easy; otherwise, its origin remains a diagnostic challenge. Long-duration E may cause hair loss and/or nail dystrophy regardless of its origin, so these changes are sometimes nonspecific. In erythrodermic patients, the specific skin changes due to dermatoses or drug reactions are masked by the nonspecific changes induced by the inflammatory erythrodermic process. The diagnosis of E is mainly based on histology; immunocytochemistry (ICC) and molecular biology techniques can be helpful. Conclusive clinic-pathologic correlation may require multiple and repeated skin biopsies. The histopathology of E varies, according to the underlying pathology. Therefore, in a skin bioptic sample, it is important to perform a careful examination of all the skin layers. Anyway, specific diagnostic features are not found in biopsies in about one third of erythrodermic cases. Furthermore, only a half of histopathologic examinations are indicative of the underlying disease. Histopathology shows a context of nonspecific subacute or chronic dermatitis, even if there has been a previously well-known dermatosis, whose specific features are no more evident. The main histologic

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Fig. 29.16  Histopathology of E. Parakeratotic hyperkeratosis, acanthosis, spongiosis tending to vesiculation, exocytosis, dermal edema, and perivascular infiltrates mainly composed by lymphocytes

findings found in E are parakeratotic hyperkeratosis, acanthosis, spongiosis tending to vesiculation, exocytosis, dermal edema, and perivascular infiltrates mainly composed by lymphocytes with or without eosinophils (Fig. 29.16). The stage of the disease can make changes in the histopathologic features; the acute stage is mainly characterized by spongiosis and parakeratosis, while the chronic stage presents acanthosis and elongated rete ridges. Drug-induced E may often show a lichenoid interfacial dermatosis at the histopathologic evaluation. In E due to lymphoma, the infiltrate may progressively come to be polymorphic until it reveals its diagnostic aspects. A lymph node biopsy shows a histiocytic infiltrate in the place of the previous perifollicular lymphatic (dermopathic lymphadenopathy). In E due to epidermo-

tropic T-cell lymphoma, histopathology presents a band-like lymphoid infiltrate in the superficial dermis, intraepidermal exocytosis, cerebriform cells, and Pautrier microabscesses. If atypical lymphocytes are found in the inflammatory infiltrate, immunohistochemistry and T cell receptor gene rearrangement studies should be performed. Sometimes, in this kind of E, some aspects of chronic dermatitis coexist, and in the case of benign E, there are aspects of lymphoma. Thus, the ICC is not always decisive, nor it is even the molecular biology. Taking care of E, basic investigations include monitoring vital parameters as temperature, weight, pulse, and respiratory rate charting. Laboratory tests should explore a complete blood cell count and morphology, total and differential leukocyte counts, absolute platelet count, erythrocyte sedimentation rate, liver and kidney

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function tests, total and fractionated protidemia, serum electrolytes, fluid intake/output charting, and scheduled urine macro- and microscopy. Moreover, electrocardiogram and chest radiograph should be performed. Furthermore, disease-­specific investigations are required: • Scabies/skin mycosis: skin scrapings/KOH. • Allergic contact dermatitis, photoallergic contact dermatitis, and airborne contact dermatitis: patch test. • Atopic dermatitis: serum immunoglobulin E testing, RAST, and prick tests. • Multiple myeloma: serum and urine protein electrophoresis. • Sarcoidosis: angiotensin-converting enzyme levels and serum calcium level. • Bacterial overgrowth or herpes simplex virus: microbiologic cultures with antibiogram; if septicemia is suspected, blood cultures may be performed. • Acquired immunodeficiency syndrome: screening for human immunodeficiency virus 1 and 2. • Immunological disorders: antinuclear antibodies, anti-DNA antibodies, and rheumatoid factor. • Lymphoma/leukemia: lymph nodes examination, CD4/CD8 ratio, fine-needle aspiration cytology, bone marrow examination, immunophenotyping, peripheral blood flow cytometry, and B-cell and T-cell gene rearrangement analysis, computed tomography scan, positron emission tomography scan, magnetic resonance imaging, and lymph node biopsy. • Pemphigus, pemphigoid, lichen planus, lupus erythematosus, and graft-versus-host disease: cutaneous direct and indirect immunofluorescence, detection of circulating autoantibod-

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ies anti-desmoglein 1 and 3 (for pemphigus), or anti-bullous pemphigoid antigens BP180 or BP230 for the diagnosis of bullous pemphigoid. • Occult malignancy: stool search for occult blood, prostate examination, cervical smear ultrasonography of the abdomen, chest radiograph, computed tomography scan, mammography, and sigmoidoscopy. About 10–25% of patients with E do not receive a specific etiologic diagnosis. In these cases, E is defined as primary or idiopathic. In patients with primary, idiopathic E, laboratory abnormalities frequently comprise leukocytosis, lymphocytosis, eosinophilia, anemia, raised erythrocyte sedimentation rate, and hypergammaglobulinemia with elevated IgE serum levels. Other findings are increased creatinine level, hyperuricemia, and hypoalbuminemia. Eosinophilia is not diagnostic for the E’s etiology, as it may be associated with many drug reactions, allergic contact dermatitis, or bullous pemphigoid. In Sézary syndrome, more than 20% of circulating Sézary cells is a diagnostic point, whereas less than 10% is a nonspecific finding. Hence, this lower count of Sézary cells can be found in different benign dermatoses. An immunophenotype of T cells without mature T cell antigens (CD3+, CD4+, CD7-), the clonality of the T cell receptor gene rearrangement, CD4:CD8 ratio greater than 10, and the expression of the programmed death-1 (PD-1) can support the diagnosis of Sézary syndrome and the differential diagnosis of Sézary syndrome from erythroderma associated with inflammatory skin conditions. A diagnostic algorithm for an erythrodermic patient is presented in Fig. 29.17.

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Anamnesis

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- Family history - Careful remote and recent pathological anamnesis - Asking for recent pharmacological use - Asking for possible precipatitng causing factors

- Full skin examination looking for any sign of an underlying skin disease Objective examination

- Examination of hair, nails and mucosae - Examination of lymph nodes - Examination of the abdomen paying attention to any organomegaly - Multiple skin biopsies for routine histology and for immunohistochemistry

Multiple biopsies

- Biopsy of an enlarged lymph node - Skin biopsy for direct immunofluoresence in the suspicion of immunobullous disease - Skin biopsy for the gene rearrangement studies in the suspicion of a lymphoproliferative disease If the etiology has not been clarified, you can perform:

Further investigations

- a complete blood cell count with Sezary cell research - CD4:CD8 ratio - antinuclear antibodies - chest x-ray and abdominal ullrasound - patch testing

Fig. 29.17  Diagnostic algorithm for an erythrodermic patient

Complications and Prognosis In E, some complications may occur such as pressure ulcers, pneumonia, venous thrombosis, heart or renal failure, depressive syndrome, and side effects of systemic corticosteroids and immunosuppressors. Loss of fluid and electrolytes develops from leaky capillaries. E increases protein loss by 25–30% in psoriatic E and by 10–15% in non-psoriatic E.  This protein loss causes hypoalbuminemia, with fatigue, edema, and muscle wasting. Systemic complications include alteration of fluid and electrolyte imbalances, thermoregulatory disturbance, high-output cardiac failure, and acute respiratory distress syndrome. The inflamed, fissured, and excoriated skin is suscep-

tible to impetiginization and sepsis may occur. Staphylococcal sepsis is especially a risk for patients with cutaneous T-cell lymphoma and/or HIV positive. Post-inflammatory hypopigmentation or hyperpigmentation may occur. Generalized vitiligo or pyogenic granulomas have also been reported after drug-induced acute E.  Alopecia, nail dystrophy, nevi, and keloid formation rarely follow E. The clinical course of E is variable, but many patients have a bad prognosis; in fact, E is a severe disease; the mortality rate ranges from 18 to 64% of cases on the basis of the underlying disease. Pneumonia, septicemia, and heart failure represent the most common causes of death. In patients who develop complications (e.g., infec-

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tion, fluid and electrolyte abnormalities, cardiac failure), the mortality rate increases. Death from sepsis, cardiac failure, adult respiratory distress syndrome, and capillary leak syndrome continues to be present. The prognosis has improved with the advent of the innovative dermatologic therapies (e.g., cyclosporine and synthetic retinoids, biologic therapies) and the advances in the management of systemic manifestations. A high index of suspicion for complications must be maintained to facilitate an early medical intervention. The long-term prognosis is better in patients with drug-induced disease, because it usually disappears in 2–6 weeks after stopping the causative drug even if it can last longer. E associated with psoriasis and eczema may improve within several weeks or months, although lesions may recur. Otherwise, the course tends to remit and relapse in idiopathic E, although in some cases spontaneous resolution occurs. Patients with idiopathic E should be reevaluated at least every 6 months. Repeated skin biopsies and further laboratory tests or imaging studies may reveal the underlying cause of E.  For example, E may represent a prelymphomatous condition and a strict follow-up can help for the definitive diagnosis. The prognosis of cases associated with malignancies depends on the outcome of the u­ nderlying cancer. E in Sézary syndrome and paraneoplastic E are often refractory to therapy and have a poor prognosis.

General Principles of Treatment Treatment approach should include discontinuation of any potentially causative medications and a search for any underlying malignancy. The efficacy of treatment of E depends on supportive care and treatment of the underlying cause. The initial management of E of any etiology includes paying attention to nutrition, fluid, and electrolyte replacement, regulating environmental temperature and the institution of gentle local skin care measures. All cases should be considered as a dermatologic emergency and patients should preferably be hospitalized for treatment.

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Hospitalization is usually necessary for initial evaluation and for the administration of the general therapy. When dealing with a patient with E, local and systemic treatments are necessary (Table  29.3). First of all, bed rest and sedation of patient should be suggested with monitoring of temperature, fluid intake, and electrolyte balance. A nutritional support should be added. A local therapy with daily tepid baths, emollient creams, and soothing, in addition to low-­ power corticosteroids, is indicated. The maintenance of the skin hydration and avoiding of scratching and precipitating factors are mandatory as well as the treatment of the underlying cause of E (e.g., scabies) and of its complications (overinfections). As antipruritic agents, mild topical steroids/emollients can be used as well as wet wrap dressing. Systemic therapy is usually necessary to achieve a good improvement of E. Oral, i.m., or i.v. sedative antihistamines are frequently added. In severe cases, systemic corticosteroids are the first-choice drug. They reduce itching and improve the general status, but they have many side and rebound effects. To increase the skin improvement, further treatments can be used depending on the E’s etiology. Antimicrobials can be used to control secondary infections. Any hemodynamic or metabolic abnormalities must be correctly treated. The outcome is unpredictable in idiopathic E and the course is marked by multiple exacerbations, so prolonged steroid therapy is often needed. Erythrodermic psoriasis and eczematous E are usually severe; thus, patients should be treated with systemic drugs. Acitretin, cyclosporine, methotrexate, and biologic drugs (e.g., tumor necrosis factor-alpha blockers, anti IL-12/IL23, anti IL-17, anti IL-23 as ustekinumab, ixekizumab, secukinumab, guselkumab, brodalumab, risankizumab, golimumab, as well as the small molecule drug apremilast) are the treatment options in E due to psoriasis (see Chap. 81). E due to eczema usually improves within several weeks to several months, although chronic cases of atopic or contact eczematous E are not uncom-

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Table 29.3  Treatment of E General

Specific (topical)

Specific (systemic)

Treatment Hospitalization Fluid intake monitoring Electrolyte balance check Temperature measuring Hyper-proteic diet Nutritional implementation Stop of any unuseful drug Lukewarm bath every day Wet dressing with topical steroids and emollients (triamcinolone acetonide cream, 0.025–1.0%) Sedative antihistamine Systemic antimicrobials

Systemic steroids Acitretin Cyclosporin Specific disease Psoriasis Systemic corticosteroid Methotrexate Cyclosporin Acitretin Phototherapy Etanercept Infliximab Ustekinumab Adalimumab Secukinumab

Ixekizumab Brodalumab Guselkumab Tildrakizumab Risankizumab

Remarks (dose and period of treatment)

Every 2–3 h and slowly decrease frequency

Hydroxyzine hydrochloride, 25–50 mg per os every 4–6 h First- or second-generation cephalosporins or semisynthetic penicillins for 7–10 days, or macrolides, or clindamycin Because of the subsequent infection by S. aureus Prudence due to the worsening of a drug-induced erythroderma Prednisone 1 mg/kg/24 h, then gradually decreased 0.3–0.75 mg/kg Initial mean dose 4 mg/kg/day slowly reduced after remission by 0.5 mg/kg every 2 weeks It is better to avoid Initial dose 10–25 mg/week Maintenance dose 7.5–15 mg/week Initial mean dose 4 mg/kg/day slowly reduced after remission by 0.5 mg/kg every 2 weeks 0.3–0.75 mg/kg UVB, UVA, PUVA 50 mg subcutaneous injection twice a week, reduced 50 mg/ week after 3 months 5 mg/kg i.v. at week 0, 2, 6, and later every 8 weeks Can be combined with methotrexate or acitretin 45/90 mg (according to the weight) at week 0.4 and later every 12 weeks 80 mg at week 0, 40 mg at week 1, later 40 mg every 2 weeks 300 mg at week 0, week 1, week 2, week 3, and week 4, then every 4 week Maintenance dose: 300 mg every 4 week after initial 12 week 160 mg at week 0, then 80 mg every 2 week until week 12 Maintenance dose 80 mg every 4 week after week 12 210 mg at 0, 1, and 2 week, and 210 mg every 2 week thereafter 100 mg in week 0 and week 4, then every 8 week 100 mg at week 0 and week 4, then every 12 week 150 mg at week 0 and week 4, then every 12 week (continued)

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326 Table 29.3 (continued) Atopic dermatitis

Treatment Systemic steroids Antimicrobials Cyclosporin Phototherapy

Azathioprine Methotrexate Mycophenolate mofetil Dupilumab

Intravenous immunoglobulins Other

Pityriasis rubra pilaris Toxic epidermal necrolysis Lymphoma Scabies

Acitretin Methotrexate Systemic steroids Intravenous immunoglobulins Systemic steroids Tumor necrosis factor inhibitors Extracorporeal phototherapy, PUVA, alkylating agents Topical permethrin, 5% Oral ivermectin

Remarks (dose and period of treatment) Prednisone 1 mg/kg/24 h, then gradually decreased First- or second-generation cephalosporins or semisynthetic penicillins for 7–10 days, or macrolides, or clindamycin, etc. Initial mean dose 5 mg/kg/day, slowly reduced after remission by 0.5 mg/kg every 2 weeks Broadband UVB (280–320 nm) Narrowband UVB (311–313 nm) UVA (320–400 nm), UVA1 (340–400 nm), PUVA Bath-PUVA Possibility of combination of phototherapy (UVA/UVB) with corticosteroids 100–200 mg/day slowly reduced after remission 10–25 mg/week slowly reduced after remission 1–2 g/day slowly reduced after remission For patients 5  cm diameter and/or associated with fever or located on the forehead,

D. Ioannides (*) 1st Department of Dermatology and Venereology, Aristotle University Medical School, Hospital of Skin and Venereal Diseases, Thessaloniki, Greece e-mail: [email protected] E. Lazaridou 1st Department of Dermatology and Venereology, Aristotle University Medical School, Hospital of Skin and Venereal Diseases, Thessaloniki, Greece 2nd Department of Dermatology-Venereology, Aristotle University Medical School, Papageorgiou General Hospital, Thessaloniki, Greece e-mail: [email protected]

nose, cheeks, or upper lid in recurrent furunculosis and immunocompromised patients. • Isolated lesions on other areas of the body can be treated with only local care and surgical drainage of pus. • Semisynthetic penicillinase-resistant penicillins, macrolides, cephalosporins, fusidic acid, or quinolones can be used in nonMRSA cases. In CA-MRSA co-trimoxazole, clindamycin, and doxycycline are the most likely oral agents to be effective. • In recurrent furunculosis, treatment lasts longer and may consist of rifampicin, rifabutin, and clindamycin along with decolonization regimens.

Definition A furuncle (boil) is a deep, necrotizing form of folliculitis with involvement of the subcutaneous tissue. It occurs as the follicular infection progresses deeper and extends out of the follicle. Several furuncles may coalesce to form a carbuncle with several pustular openings. Staphylococcus aureus (S. aureus) is the causative agent.

Basic Concepts of Pathogenesis The initial pathophysiological event involves S. aureus colonization of the skin surface and proliferation with spread within follicles. The organ-

© Springer Nature Switzerland AG 2023 A. D. Katsambas et al. (eds.), European Handbook of Dermatological Treatments, https://doi.org/10.1007/978-3-031-15130-9_32

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ism may spread through follicular walls to the dermis or can be inoculated through cuts and scratches into the dermis leading to the formation of a furuncle. The attraction of polymorphonuclear leukocytes by the S. aureus chemotactic factors and the elaboration of several enzymes by the microorganism result in clinical inflammation. These enzymes include enterotoxins, proteases, hemolysins, and leukocidins.

Clinical Presentation

D. Ioannides and E. Lazaridou

aureus (CA-MRSA) and is associated with recurrent furunculosis. Such patients, who suffer from repeated infections, are usually nasal carriers of the infecting strain. It has been estimated that nasal carriage of S. aureus is the primary risk factor for recurrent furunculosis and accounts for 60% of the cases. Therefore, nasal colonization with CA-MRSA interspersing the PVL toxin is a very strong risk factor for recurrent furunculosis. The anterior nares can serve as a reservoir for spread into the skin and subsequent reinfection. Less common reservoirs for the pathogenic staphylococci may be found in the axillae, perineum, or even rectum.

A furuncle is manifested by a tender, round subcutaneous nodule, which is usually capped with a small pustule. It is a firm or fluctuant mass of walled-off purulent material. The follicular Differential Diagnosis abscess enlarges, becomes fluctuant, and then softens and ruptures spontaneously to discharge a Furuncles must be differentiated from other bactecore of necrotic tissue and pus and may result in rial infections, such as anthrax and tularemia, or scarring. Furuncles may occur anywhere on the from some other infections of the follicles, such as body, but have a predilection for hairy parts of conglobate acne and hidradenitis suppurativa. In areas exposed to friction and maceration, espe- the last case, the location and the multiplicity of cially the face, scalp, buttocks, and axillae. lesions usually lead to the correct diagnosis. A carbuncle forms a deep, swollen, erythematous, and painful mass with multiple draining sites and is found commonly on the neck, back, General Principles of Treatment and thighs. Predisposing factors are obesity, diabetes, Furuncles or carbuncles associated with fever or prolonged sitting, tight irritating pants, or located on the face are better to be treated with a immunodeficiencies. systemic antibiotic. Isolated lesions on other Systemic symptoms, such as fever and malaise, areas of the body can be treated with only local are more frequently present with carbuncles. If care and, sometimes, surgical drainage of pus. diagnosis and appropriate treatment is delayed, When feasible, swabs from lesional skin systemic involvement may rarely occur, including should be collected for bacterial culture. epidural abscess, bacterial endocarditis, and lung Eradication of recurrent lesions is often diffiinfection. When infection occurs in the nasolabial cult. Prolonged antibiotic therapy, along with area, extension via the vein draining into the cav- adjuvant measures, is often necessary. It is imporernous sinus may lead to thrombosis. Perinephric tant to consider modifiable exogenous risk facabscess and osteomyelitis are other complications. tors like hyperhidrosis, tight clothing, or obesity, Recurrent furunculosis is the sequential occur- which cause local moisture and occlusion, thus rence of many furuncles over a period of months promoting local bacterial growth and injury to or even years in the same patient and sometimes the hair follicle contributing to repeat infection. develops in patients in whom there is no evidence Endogenous risk factors like underlying acquired of harboring specific staphylococcal strains or immune dysfunctions must also be taken into having any deficiency in their host defense mech- account. These include diabetes mellitus, human anism. Panton-Valentine leukocidin (PVL) is the immunodeficiency virus, alcoholism, and malnuprimary virulence factor of community-­trition. If no skin colonization is detected, neutroassociated methicillin-resistant Staphylococcus phil dysfunctions should be investigated.

32  Furuncles and Carbuncles

Recommended Therapies (a) Systemic antibiotics. (b) Local treatment.

Systemic Antibiotics Antibiotics systemically are given in furuncles or carbuncles associated with severe disease exhibited as surrounding cellulitis and multiple sites of infection or lesions >5 cm diameter and/or associated with fever or located on the forehead, nose, cheeks, or upper lid. Patients with recurrent furunculosis, extremes of age, immunosuppression, or associated comorbidities, and lack of response to incision and drainage alone are also treated with systemic antibiotics. Due to lack of clinical trials with many patients, treatment guidelines for furuncles and carbuncles are often based less on evidence and more on expert opinion. Knowledge of antibiotic sensitivity of the responsible organism is desirable for the selection of treatment. If this is hard to pursue, it is reasonable to begin with a semisynthetic penicillinase-resistant penicillin by mouth, such as cloxacillin at a dose of 250  mg every 4–6 h or dicloxacillin at a dose of 500 mg every 6  h for 10  days. For penicillin-sensitive patients, erythromycin (500  mg every 6  h for 10–15  days), clindamycin (300–600  mg every 6–8 h for 10–15 days), or fusidic acid (500 mg 8-hourly) is suggested. For CA-MRSA cases, empiric therapy with penicillins or cephalosporins may be inadequate. MRSA sensitivities vary according to geography, but co-trimoxazole, clindamycin, linezolid, and doxycycline or minocycline are the most likely oral agents to be effective empirically against MRSA and most non-MRSA too. For hospitalized patients with MRSA infection, therapeutic options include intravenous (IV) vancomycin 1 g twice daily, oral or IV linezolid 600 mg twice daily, daptomycin 4 mg/kg/dose IV once daily, telavancin 10  mg/kg/dose IV once daily, tigecycline 100 mg IV load, then 50 mg IV twice daily, ceftarolin 600 mg IV twice daily, teicoplanin 6 mg/kg/dose IV every 12 h for the first 3 doses, thereafter 6  mg/kg as single dose each

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day and clindamycin 600  mg IV or oral three times a day. We prefer to start with azithromycin, one of the relatively newer macrolides, at a dose of 500 mg on day 1, followed by 250 mg on days 2–5. We believe that patient compliance is better with this dose schedule. If the organism is resistant to macrolides, we consider oral therapy with a cephalosporin such as cofactor or one of the newer quinolones, such as ciprofloxacin. In recurrent furunculosis, which represents a difficult therapeutic problem, the organism’s antibiotic sensitivity should be assessed. The appropriate drug, most often a semisynthetic penicillin, is usually given for 1–3 months, but it can be administered for longer periods (6–12 months), if necessary. Rifampicin (300–600 mg 12-hourly) or rifabutin (300 mg daily), because of the potential for fewer than rifampicin drug interactions and greater tissue penetration, can be given for 7–10 days, along with a semisynthetic penicillin. In especially stubborn cases, their administration for longer periods, alone or in combination with other antibiotics, can be considered. A proposed treatment regimen for recurrent disease is the so-­ called CMC regimen that consists of skin disinfection with chlorhexidine for 21  days, nasal mupirocin ointment for 5 days, and oral clindamycin 1800–2400 mg for 21 days.

Local Treatment Topical therapy consists of the application of warm normal saline compresses (1 teaspoon of table salt in 2 cups of tap water) followed by the application of an antibiotic ointment. A daily bath with antimicrobial soap is advisable. Incision and drainage, needed in 80% of cases, are particularly helpful to relieve the pressure and pain associated with furunculosis and usually suffice if lesions are 6 months or two relapse in 12 months) From Diepgen et al. (2009) modified

At the moment we can distinguish 4 main types of HE: Irritant (subtoxic-cumulative) HE, Allergic HE, Atopic HE, and other forms of HE. All these kinds of eczemas can become chronic with a chronic relapsing course. (chronic hand eczema, 5° type). The etiopathogenesis and clinical features of the “five main” types and of the CHE are reported in Table  36.3 (Fig.  36.1, 36.2, 36.3, 36.4, and 36.5) (Molin et al. 2011).

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Moderate

Mild

Almost clear

Clear

Features Erythema, scaling, hyperkeratosis/ lichenification Vesiculation, edema, fissures, pruritus/ pain Erythema, scaling, hyperkeratosis/ lichenification Vesiculation, edema, fissures, pruritus/ pain Erythema, scaling, hyperkeratosis/ lichenification Vesiculation, edema, fissures, pruritus/ pain Erythema, scaling, hyperkeratosis/ lichenification Vesiculation, edema, fissures, pruritus/ pain Erythema, scaling, hyperkeratosis/ lichenification Vesiculation, edema, fissures, pruritus/ pain

Intensity At least one moderate or severe At least one severe

Area involved >30% of affected hand surface

At least one mild or moderate At least one moderate

10–30% of affected hand surface

At least one mild

Less than 10% of affected hand surface

At least one mild At least one mild

Less than 10% of affected hand surface

Absent Absent

Not detectable

Absent

The area involved does not apply to patients with eczema localized to fingertips. In the evaluation the surface refers to the surface area of the more severely affected side of the more affected hand that has to be considered From Ruzicka et al. (2008) a

Table 36.3  Characteristics of irritant, allergic, and atopic hand eczema other forms, and chronic hand eczema 1. Irritant (Subtoxic Cumulative) Hand Eczema (IHD) (Fig. 36.1) Etiopathogenesis • It is the result of repeated irritating harmful substances over a longer period of time in concentrations too low to produce an acute and immediate reaction • When the irritant is within the work environment, an improvement during the weekend (and healing possible with extended periods away from work) has been reported • Constitutional factors, such as atopic skin diathesis and hyperhidrosis, promote its development Location • Backs of the hands, fingers, exposed areas of the forearms, and, later, the inner surfaces of the hands are the most common involved areas • Skin symptoms are limited to the hands Morphology • At the beginning, skin is raw, dry, scaly. Acute manifestations are usually rare • After prolonged or repeated exposure to one or more irritants, development of redness, infiltration, and lichenification • Lastly, painful rhagades development, and hyperkeratotic plaques interspersed with rhagades (hyperkeratosisrhagadiform eczema) • Lesions present relatively well-defined borders and are not so itching (as in allergic contact dermatitis) 2. Allergic Hand Eczema (AHD) (Fig. 36.2) Etiopathogenesis • It is the result of delayed contact hypersensitivity (type IV hypersensitivity) to one or more allergens in a sensitized individual (verification with patch test is mandatory) • Protein contact dermatitis is also reported (rarely) • In occupational causes, the development and exacerbation occur with working environment. It is often reported that there occurs an HE improvement during the weekend, up to a good improvement to healing on vacation, and a new relapse within days of returning to work

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Table 36.3 (continued) Location • The affected site corresponds to the area of exposure to the allergen • Involvement of exposed areas is typical (airborn dermatitis) • Spread of the dermatitis around the site of the exposure (d.d. irritant hand eczema) Morphology • Acute exudative phase: it is possible to observe redness, vesicles, exudation, and excoriation. Severe pruritus is often reported • Chronic stage: hyperkeratosis, scaling/lichenification, infiltration, rhagades • Irregular border around the exposure sites (different from IHD) 3. Atopic Hand Eczema (Fig. 36.3) (AE) Etiopathogenesis • Result of atopic eczema or atopic skin diathesis • Quite common the involvement of hands in adult atopic dermatitis(AD) • Frequently unrelated to occupation, but it is worthy to remember that irritant or occupational factors can trigger skin manifestation Location • Often involves the backs of the hands (especially the dorsal site of the fingers) • Involvement of the nails can be present • Hand eczema can be the only AD involvement, or the hand can be a site of an AD spreader involvement (other common location of adult AD flexor surfaces, face, neck) • Involvement of the wrist and of the “snuff box” Morphology • Vesicles (dyshidrosiform morphology) in palmar and interdigital • Poorly bordered lichenified patches at the backs of the hands, mainly fingers, flexor surfaces of wrists • Scaling, rhagades in the lichenified patches on backs of the fingers • Sometimes nummular lesions on backs of hands 4. Other Forms of Eczema • Vesicular (dyshidrosiform), hyperkeratotic-­rhagadiform (discussed in CHE), and nummular eczema • In this group, it is possible to highlight an irritant, allergic, and/or atopic etiology or a combination of thereof 4.1 Vesicular (dyshidrosiform) • A atopic skin diathesis is common to observe Location • Solitary blisters (pompholyx) mainly in the interdigital lateral spaces • Severe itching Morphology • Solitary blisters (pompholyx) accompanied by severe inflammatory redness around and severe itching 4.2 Nummular Eczema (Fig. 36.4) • A atopic skin diathesis and a history of AD is common to observe Location • Dorsum of the end • Other lesions can be present on the wrist, arms and, spread, on the body Morphology • Round-to-oval erythematous claque on the back of the hands 5. Chronic Hand Eczema (CHE) (Fig. 36.5) • It can be the result of the IHD, AHD, AE, or other form becoming chronic • Differences in etiology, morphology, and course explain the heterogeneity in the clinical manifestation and in the course of CHE • The hyperkeratotic-rhagadiform, vesicular, and mixed pattern HE are the most common manifestation Location • Palmar and dorsum site • Tendency to recur at the same site Morphology • Irregularly bordered, symmetrical, hyperkeratotic, lichenified lesions with painful rhagades • Absence or mild pruritus • The absence of vesicular eruptions is the characteristic

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Fig. 36.1  Irritant contact eczema

Fig. 36.3  atopic dermatitis of the hands

Fig. 36.4  nummular eczema at the hands

Fig. 36.2  Allergic contact eczema

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Diagnosis

Fig. 36.5  Chronic (hyperkeratotic) hand eczema

Chronic Hand Eczema (CHE) Chronic hand eczema (CHE) is not a uniform disease. There is no universally accepted classification for etiologically and clinically heterogeneous disease group. It can be described as persistent HE (with own etiology and clinical manifestation) over 6 months or returns twice or more within 12 months. Differences in etiology, morphology, and severity make accurate diagnosis difficult and challenging. The environment and individual factor interactions explain the different manifestations during the course. The correct diagnosis is further hampered by the lack of a systematic classification system. It is based on etiology when possible and morphology when necessary. Foot involvement is considered a distinguishing feature for idiopathic eczema if no other criteria (allergic or irritant contact dermatitis or atopic eczema) explain the plantar involvement (Coenraads et al. 2005).

Given these limitations, accurate diagnosis of the disease is challenging and should be based on a careful patient history and on clinical examination (morphology and distribution of the lesions) (Fig.  36.6). Differential diagnoses, as psoriasis, infections, or other causes, must be excluded. Diagnostic patch testing with the standard series, supplemented with additional specific series, other relevant allergens, and products used by the patient, according to the patient’s exposure, should be considered as a mandatory step. The positivity of patch test(s) has to be relevant for the disease activity of CHE (as emerged from carefully clinical history). Thus, the diagnosis of allergic contact hand eczema can be made. In a small studied group (22 patients with CHE and positive patch tests), the most common allergens are nickel (6), fragrance (3), medicaments (3), chromium (2), preservatives (2), permanent hair dye (2), and Compositae (1). If no contact allergy is found and the patient has had relevant exposure to irritants (emerged from carefully medical history), the dermatitis can be classified as irritant contact dermatitis. To confirm the diagnosis, an improvement of dermatitis with education and irritant avoiding has to be registered. Lastly, a history of atopic dermatitis and other AD involvement can allow to perform a diagnosis of AE. The combination of irritant and allergen factors and atopic constitution contribute to led the disease severe and chronic, the diagnosis diffiDiagnosis

The following exams may be request to perform/confirm the correct diagnosis • Allergy testing (pick and patch testing) • Histology examination • KOH examination

Clinical examination Location morphology of the lesion

Patient’s history Personal or family history for allergies Exposure history Occupational enviroment hobbies

Fig. 36.6  Diagnosis of HE

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cult, and the management challenging. The clinical presentation varies greatly, making allergic and irritant types of eczema of the hands difficult to distinguish clinically and histologically. Especially, the correct diagnosis of hyperkeratotic-­rhagadiform eczema can be very difficult due to its clinical and histological similarity to acral psoriasis. It is important to remember that allergen avoidance may improve the eczema considerably, but rarely leads to a complete cure underlying the multifactorial causes and features of HE.  Even with the individualization and the avoidance of irritant/allergens factors, HE develops into a chronic condition as other dermatological skin diseases. Moreover, the treatment is challenging and often unsuccessful despite adequate dermatological therapy and patient compliance (Augustin et al. 2011; Berthold and Weisshaar 2019; Bissonnette et al. 2010a; Boehm et al. 2012).

Differential Diagnosis Psoriasis, lichen ruber, and tinea manuum, in particular, can often be difficult to be differential diagnosed and are sometimes mistakenly treated as eczema. Secondary infection of hand dermatitis with S. aureus is common.

Histological analysis is suggested in any skin disorder of uncertain cause or where the clinical diagnosis is doubtful. Unfortunately, also histological examination cannot represent a valuable tool for the physician to distinguish clinically acral psoriasis from hyperkeratotic-rhagadiform eczema (whose similar clinical features are reported in Table 36.4). Table 36.5 lists diseases which should be considered as differential diagnoses. An accurate d­ iagnosis of hand eczema leads to better management.

Table 36.4 Different features of hyperkeratotic-­rhagadiform eczema Psoriasis Not usually itch Painful fissuring Dry, silvery scale Well-defined lesions Nail and knuckle involvement Koebner phenomenon Can be symmetrical Often the palmar site is first involved Chronic relapsing

psoriasis

and

Hyperkeratotic rhagadiform eczema Often itchy Painful fissuring Vesicular, scaly More diffuse lesions (border) Nail can be involved No Koebner phenomenon Often symmetrical The palmar and dorsal site can be involved Often chronic relapsing

From English et al. (2009) modified The clinical manifestations can be similar to each other

Table 36.5  List of diseases which should be considered in differential diagnosis with HE Disease Psoriasis vulgaris

Differential diagnoses Personal or family history and clinical examination

Psoriasis pustulosa

Personal or family history and clinical examination. Sterile pustules Personal or family history and clinical examination

Acrodermatitis continua Hallopeau Tinea manuum Lichen planus Mycosis fungoides Dermatitis (striata) pratensis Palmar (and plantar) keratoderma Scabies Fixed drug eruption

KOH examination Different location (wrist) and morphology lesions (papules) Personal or family history and clinical examination Histological examination Personal history. Dermatitis bullosa and striata Personal or family history and clinical examination

Pruritus and clinical examination Personal or family history and clinical examination. Histology Pitiryasis rubra Other body-sites affected pilaris Histology Lupus erythematosus Personal or family history and clinical examination Dermatomyositis Personal or family history and clinical examination Dorsum of the hand: Gottron papules

Notes Patch test and histological examination can help sometimes Neutrophils in the pustules

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36  Hand Dermatitis

Treatment General Therapeutic Guidelines Although there are different therapeutic strategies for each group of HE, all patients should be educated and should adhere to skin protection measures and lifestyle changes to minimize exposure to allergens or irritants. Allergen avoidance may also be beneficial, but not all contact allergies are clinically relevant. Table  36.6 lists measures that should be considered. In Fig.  36.7 are reported the general recommendation for HE in according to its severity. Despite HE is not a uniform disease, the basic therapy represents the first step in the long term management of HE. The treatment of hand eczema must take into account the following features in order to perform the correct management and therapy: • Disease etiology (atopic, allergic, irritant, vesicular) • Acuteness (acute vs. chronic eczema), • Morphology (redness, scaling, lichenification, blistering, hyperkeratosis, rhagades, pruritus, etc.) • Location (dorsal aspects of hands, interdigital spaces, palms).

Despite lots of literature data and clinical experience with various therapies, randomized controlled clinical (RCT) trials are still lacking. HE of recent onset should be treated promptly and vigorously in order to prevent the vicious circle of CHE.  In fact the barrier damage and inflammation favor the penetration of irritants and allergens that further damage the skin barrier. Generally, mild hand eczema should be treated with anti-inflammatory drugs (topical corticosteroids (TCS)) together with a proper skin protection measures. This therapy, if performed quickly, is effective in controlling the symptoms in lots of these patients. Then a longterm management has to be performed with basic therapy. The short and long term management aims to prevent new relapses and to avoid the condition becoming chronic (that happens in a considerable number of cases despite basic therapy and potent TCS). It is important to note that a complete functional regeneration of the epidermal barrier requires several weeks or months after healing. Chronic hand eczema is very difficult to treat and manage. They should be referred immediately and the treatment should not be delayed. A successful management requires treatments that restore the skin barrier and control the inflammation.

Table 36.6  List of skin protection measures and lifestyle changes to minimize exposure to allergens or irritants • Short-term prophylactic measure of using gloves; however, do not use gloves for a long time as this will induce sweating of the hands. Use cotton liners or loosely fitting neoprene gloves • Short-term use of disposable gloves to avoid contact with irritants: Washing powder, shampooing, dish-­washing liquid, cleaning liquid such as toilet cleaner, etc. • Even the gloves themselves can sometimes aggravate the condition • Wash hands with mild, non-perfumed soap to reduce amount of skin bacteria • Avoid contact with certain food items: Tomatoes, peeling of oranges, citrus fruits and such like. Avoid juice from fish, meat, and certain vegetables. The patient’s own experience will show what must be avoided • Reduce the amount of manual work at home and discuss where the partner could-and should-help, e.g., cleaning, dish-washing, helping the children with their baths, changing of the nappies, etc. • Avoid hair-dying and potent allergens (i.e., p-phenylenediamine, acrylic compounds, nickel, etc.) • Complete avoidance of the triggering agent in patients who are sensitized to one or more allergen. Patients must be educated about the relevant contact allergens and where they are present and how to avoid or protect their skin with appropriate care measures • Emollient creams are the standard therapy and they should be used alone or with all other treatments

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Phototherapy systemic treatments

Mil mode d to rate H

Topical antinflammatory therapy Topical corticosteroids, Topical calcineurin nihibitors

e eas

E

Alitretinoin, Ciclosporin A, Glucocorticoids,

is of d nsity Inte

Mode ra seve te to re HE

Fig. 36.7 General recommendation for HE in according to its severity

Basic therapy Skin hydratation, emollients, avoidance of irritants and allergenes, identification and addressing of specific trigger factors, antimicrobial treatment, skin protection measures and educational programs

Basic Therapy Successful basic therapy requires proper skin hydratation, use of emollients, identification and avoidance of irritants, allergens, and specific trigger factors, antimicrobial treatment, skin protection measures, and educational programs (as reported in Table 36.6).

Cleansing and Bathing Patients with HE should follow a correct cleansing of the hands. As for atopic dermatitis, oil bath has to be preferred. The patient’s washing habits have to be investigated. In fact, excessive number of hand washing can be irritant for the hands.

Emollients Consistent use of a moisturizing and emollient agent is key component in basic therapy. In particular, preparations should be free of any ­preservatives, fragrances, and perfumes (as well as for bath oils).

They should contain few ingredients (few or no potential allergens) in order to minimize a contact sensitization. It is also important that there is the vehicle of emollient: In acute disease, dressings, lotions, or creams are preferred. On the other hand, in subacute, lichenified, and chronic stages, ointments are used with better efficacy. Keratolytics substances can be useful in lichenified and in hyperkeratotic-rhagadiform eczema. Salicylic acid (up to 20%) and urea can be used with different concentrations. Urea, at a concentration at 5–10%, has a smoothing and water-binding effect and it can be useful in lichenified and hyperkeratotic eczema. Sodium lactate, glycerol, sodium chloride, and other molecules can represent an alternative for water-­ binding and stratum corneum regulation. Cream containing these molecules has to be used properly, because excessive or incorrect dosages can cause skin irritation and burning. They are also poorly tolerated on the rhagades. A list of the emollient recommendation has been reported in Table 36.7.

36  Hand Dermatitis Table 36.7 Topical therapy in hand eczema by morphology Morphology presumed effect topical therapy (examples) Vesicular (“dyshidrosiform”) • Astringent solutions (i.e., potassium permanganate 0,025%, eosin 2%, boric acid 3%) • Pasta exsiccans, zinc oxide barrier cream • When combined with hyperhidrosis, possibly used aluminum chloride hexahydrate Weeping/superinfection • Moisturizing (containing glycerol, urea 5–10%, coal tar, etc.) • Astringent solution • Disinfectant and antibacterial (chlorhexidine, polyhexanide, povidone iodine, hydrogen peroxide, silver sulfadiazine, triclosan, etc.) • Treat immediately the superinfection (when it is clinically manifest) with pharmacological treatment Hyperkeratosis • Keratolytic agents (salicylic acid-based ointments, ointments containing sodium chloride or urea) Rhagades/fissures • Hydrocolloid dressings (rhagades) Subacute eczematous reaction/lichenification • Anti-inflammatory substances, (Polidocanol (macrogol laurel ether), glicirreic acid, etc.) • Moisturizing (containing glycerol, urea 5–10%, coal tar, etc.) Dry, scaling • Moisturizing (containing glycerol, urea 5–10%, coal tar, etc.) They can be combined with more appropriate pharmacological treatment. From Diepgen et al. (2009) modified

Lastly, as for atopic dermatitis, educational programs and psychological counseling aim to improve the adherence in eczema management, the itch/scratching cognition, and the clinical and psychological condition.

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Basic Therapy at Glance

Successful basic therapy requires proper: • skin hydratation, • use of emollients, • identification and avoidance of –– irritants, –– allergens –– specific trigger factors • antimicrobial treatment • skin protection measures • educational programs They have to be personalized according to the features of HE

Topical Treatment The specific and proper use of topical corticosteroids (TCS) remains the first-line anti-­ inflammatory treatment of HE. They are fast acting and very effective in the short-term (few weeks when for controlling the disease when the disease severity is mild to moderate). The use is limited by rebound flare-ups, tachyphylaxis, and lack of efficacy in severely affected patients. Despite their efficacy in the short-term, long-term TCS use should be avoided because of their side effects. In particular, skin atrophy may contribute to further weakening of the skin barrier and further inflammation. The choice of the potency of corticosteroids and the duration of treatment depends on the morphology, location, and severity of hand eczema.

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As reported above (See atopic dermatitis chapter), the corticosteroid concentration and its efficacy may be different when the preparation and the vehicles changes. It is commonly suggested to use immediately a potent to very potent steroid (according to the severity of the disease and the age of the patient) once or twice a day, followed by a less potent preparation for few days. In case of chronic hyperkeratotic-rhagadiform hand eczema, the first treatment recommended is a high-potency corticosteroid (as clobetasol). In mild to severe forms of HE, TCS have to be combined with the basic therapy. It is worthy to remember that the hand barrier is not restored at all after the end of the treatment. Thus, a continued use of a nonsteroidal topical therapy (emollient) is necessary together to a basic education of the hand skin care in order to achieve a long-term remission. The possible utility of proactive therapy in the long-term management of HE (mainly chronic) does not have been evaluated yet. Before starting a TCS therapy, the correct diagnosis has to be performed. Other diseases, especially contact sensitivity (also to topical steroids, mainly when the symptoms get worse) and fungal infection, must be ruled out.

Other Topical Treatments Topical calcineurin inhibitors (TCI) have been studied long in atopic dermatitis and they can be used in atopic HE. TCI are not licensed for, but have been investigated in, the treatment of mild to moderate CHE. Studies investigating their efficacy in HE are still lacking. Despite their safe profile (atrophy and other corticosteroids’ side effects are not reported with TCI), their use in HE is considered a second line treatment in patients refractory to topical corticosteroids (TCS) or where the TCS use is contraindicated.

Topical Therapy at Glance

• The specific and proper use of topical corticosteroids (TCS) remains the first-­ line anti-inflammatory treatment of HE. • They are fast acting and very effective in the short-term (few weeks when for controlling the disease when the disease severity is mild to moderate). • Despite their efficacy in the short-term, long-term TCS use should be avoided because of their side effects. In particular, skin atrophy may contribute to further weakening of the skin barrier and further inflammation. • The choice of the potency of corticosteroids and the duration of treatment depends on the morphology, location, and severity of hand eczema. • Despite the safe profile of topical calcineurin inhibitors, their use in HE is considered a second-line treatment in patients refractory to topical corticosteroids (TCS) or where the TCS use is contraindicated.

Phototherapy UVA1, topical PUVA, and UVB have been studied in HE. Narrow band UVB or UVA1 devices as well as eccimers laser represent a valuable therapeutic option in these forms of hand eczema. The topical phototherapies have the advantage to limit therapy to the hands without a body irradiation. In this way some side effects (from erythema to potential carcinogenic risks) can be limited. Since this treatment cannot be easily undertaken at home, one of the major disadvantages is that the patient has to go to the hospital from 2 to 5 times a week for the treatment. From 15 to 30, treatments are usually need to achieve good

36  Hand Dermatitis

results. This treatment can also be useful in combination with other topical or systemic therapies. In the literature, there are few studies evaluating the efficacy of phototherapy strategies. It can be a therapeutic option in moderate to severe forms, as well in HE unresponsive to TCS, including also very potent TCS.

Phototherapy at Glance

• PUVA, narrow band UVB, or UVA1 devices as well as eccimers laser represent a valuable therapeutic option in HE. • This treatment can also be useful in combination with other topical or systemic therapies. • It can be a therapeutic option in moderate to severe forms, as well in HE unresponsive to TCS, including also very potent TCS.

Systemic Treatment The proportion of severe CHE is estimated to be 5–7% of all cases and approximately 2–4% of patients with severe CHE are refractory to topical treatment. The management of severe chronic hand eczema CHE is often challenging, difficult, and unsatisfactory, further worsened by not adequate response to local therapy. It interferes with social and working life and it has important and severe negative repercussion on the patients’ quality of life. Moreover, the majority of patients are workers, and high negative economic repercussion can be shown. The therapeutic options for these patients are extremely limited. There is a clear medical need for an effective intermittent, long-term therapy to treat this chronic condition. These patients may benefit (are candidate for) from a systemic therapy.

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Alitretinoin Alitretinoin (9-cis-retinoic acid) is a drug approved from 2008  in several European countries for treating severe, chronic hand eczema that does not respond, or with an unsatisfactory response to topical corticosteroids. Alitretinoin, isomer of isotretinoin (13-cis-­ retinoic acid), is an endogenous physiological retinoid, panaagonist of both vitamin A acid receptors (retinoic acid receptors (RARs) and retinoid X receptors (RXRs)). It has been specifically developed for the (long-term) management of chronic hand eczema (Bissonnette et al. 2010b). The exact mechanism of action of alitretinoin in the treatment of CHE is unknown. Alitretinoin’s anti-inflammatory and immunomodulatory properties have led to high response rates with a favorable safety-profile over the long-term management. There are two traded formulation of alitretinoin: 10 and 30 mg. The efficacy, safety, and tolerability of alitretinoin have been proved by multicentral and national trials and experiences (BACH study and others). A 75% improvement of clinical scores of CHE after 24  weeks was observed (48% of patients achieve ‘clear’ or ‘almost clear’ within 12–24 weeks). The highest response was obtained in cases of hyperkeratotic CHE. A relapse has been observed in a third of cases. Studies have demonstrated that patients who had achieved ‘clear’ or ‘almost clear’ hands and had relapsed within 6 months responded to a second course of treatment (Diepgen 2011; Diepgen et al. 2012; Diepgen et al. 2015). Patients who had not responded to an initial 24  weeks of alitretinoin treatment achieved ‘clear’ or ‘almost clear’ hands in half of the cases when an additional treatment course of alitretinoin 30 mg for up to 24 weeks was carried out. A small Italian experience has highlighted the positive impact of the alitretinoin treatment on the quality of life patients with CHE. These data are of

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considerable importance considering that the study included 15 people whose jobs required the use of their hands. Eleven of those (73%) reported moderately to severely impaired at work. Significant improvement of the point 7 of DLQI has been reported in this study. This point covers issues at work or studying (Dirschka et al. 2011; English 2010; English 2011; English et al. 2011), with scores ranging from 0 (no problem at work or studying) to 3 (severe difficulties at work or studying) (Gola et al. 2013; Gola et al. 2014). The recommended standard dose of oral alitretinoin is 30 mg daily for 12–24 weeks or until healing. Due to the possibility of increasing triglycerides, cholesterol and transaminases, and thyroids side effects, some patients should begin with 10 mg once daily. The most common reported side effect is headache (in about 20% of cases), within the first 10 days of therapy. It is very important to remember that alitretinoin, as any other vitamin A acid derivative, is a strong teratogen. Adherence to pregnancy prevention measures is strictly requested from before the beginning of the therapy up to 40 days after the end of the treatment for women of childbearing potential. In conclusion, alitretinoin is an effective, systemic, intermittent treatment for the long-term management of their chronic relapsing disease. The treatment has to be combined with topical therapies (Lynde et al. 2012).

Systemic Corticosteroids Systemic corticosteroids are commonly used to treat CHE.  Despite their large use, their side effect profile and the lacking clinical studies do not allow to use them for the treatment of this

disease. An acute relapse of CHE can benefit from a short period of oral corticosteroids.

Cyclosporine Cyclosporine is approved for atopic dermatitis (of hands) and it can be used in severe, treatment-­ refractory HE, as a second-line treatment in patients un-respondent to alitretinoin or where the use of alitretinoin is not possible or is contraindicated. The use of cyclosporine in hand eczema is off-label.

Other Systemic Treatment The use of other treatments such as methotrexate and azathioprine is reserved (off label) in patients unresponsive to other systemic treatments. Clinical large studies regarding the efficacy of these drugs are lacking (Lee et al. 2019).

Biologics Dupilumab is a fully human monoclonal antibody directed against the IL-4 receptor α subunit, which is a component of IL-4 receptors and the IL-13 receptor system. The blockade of IL-4/ IL-13-mediated inflammatory pathway was proven to be a successful therapeutic strategy in atopic dermatitis (AD). In adults with moderate-­ to-­severe AD, dupilumab, administered as monotherapy or in association with topical corticosteroids, achieved rapid and significant improvements in signs and symptoms of AD at the hands. Dupilumab resulted efficacious when dermatitis involved only the hands (D’Erme et al. 2017; Halling et al. 2020).

36  Hand Dermatitis

383

Systemic Treatment at Glance

• The management of severe chronic hand eczema CHE is often challenging, difficult, and unsatisfactory, further worsened by a not adequate response to local therapy. • The therapeutic options for these patients are extremely limited. • There is a clear medical need for an effective intermittent, long-term therapy to treat this chronic condition. • Alitretinoin (9-cis-retinoic acid) has been specifically developed for the (long-term) management of CHE. • The efficacy, safety, and tolerability of alitretinoin have been proved by multicenter trials and physician experience. • There are two traded formulation of alitretinoin: 10 and 30 mg. • A 75% improvement of clinical scores of CHE after 24  weeks was observed (48% of patients achieve ‘clear’ or ‘almost clear’ within 12–24 weeks). The highest response was obtained in cases of hyperkeratotic CHE. • The most common reported side effect is headache (in about 20% of cases), within the first 10 days of therapy, fol-

• •

•

•

lowed by increase of triglycerides, cholesterol, and transaminases. Alitretinoin, as any other vitamin A acid derivative, is a strong teratogen, Cyclosporine is approved for atopic dermatitis (of hands) and it can be used in severe, treatment-refractory HE, as a second-line treatment in patients un-­ respondent to alitretinoin or where the use of alitretinoin is not possible or is contraindicated. Despite the large use of oral corticosteroids, their side effect profile and the lacking clinical studies do not allow to use them for the treatment of this disease. The treatment with biologic drug dupilumab (fully human monoclonal antibody directed against the IL-4 receptor α subunit, which is a component of IL-4 receptors and the IL-13 receptor system) achieved good results in atopic hand eczema.

Conclusion The therapeutic approaches are summarized in Fig. 36.8a–e.

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HE severity

b

HE severity

a

TCS

UV therapy/ TCS

Basic therapy

Basic therapy

Time

Time

c

d

Alitretinoin

UV therapy/ TCS

e

HE severity

UV therapy/ TCS

HE severity

HE severity

Alitretinoin

TCS

Basic therapy

Basic therapy

Time

Time

Alitretinoin

Alitretinoin

UV therapy/ TCS TCS

Basic therapy

Time

Fig. 36.8 (a) mild and self-limiting HE. (b) moderate self-limiting HE. (c–e) chronic moderate to severe HE. Topical and systemic treatments have to be combined during the time in order to achieve HE good improvement to remission

References Augustin M, Kuessner D, Purwins S, Hieke K, Posthumus J, Diepgen TL. Cost-of-illness of patients with chronic hand eczema in routine care: results from a multicentre study in Germany. Br J Dermatol. 2011;165(4):845–51. Berthold E, Weisshaar E.  Treatment of hand eczema. Hautarzt. 2019;70(10):790–6. Bissonnette R, Diepgen TL, Elsner P, English J, Graham-­ Brown R, Homey B, Luger T, Lynde C, Maares J, Maibach HI. Redefining treatment options in chronic hand eczema (CHE). J Eur Acad Dermatol Venereol. 2010a;24 Suppl 3:1–20.

Bissonnette R, Worm M, Gerlach B, Guenther L, Cambazard F, Ruzicka T, Maares J, Brown TC. Successful retreatment with alitretinoin in patients with relapsed chronic hand eczema. Br J Dermatol. 2010b;162(2):420–6. Boehm D, Schmid-Ott G, Finkeldey F, John SM, Dwinger C, Werfel T, Diepgen TL, Breuer K. Anxiety, depression and impaired health-related quality of life in patients with occupational hand eczema. Contact Dermatitis. 2012;67(4):184–92. Coenraads PJ, Van Der Walle H, Thestrup-Pedersen K, Ruzicka T, Dreno B, De La Loge C, et al. Construction and validation of a photographic guide for assessing severity of chronic hand dermatitis. Br J Dermatol. 2005;152:296–301.

36  Hand Dermatitis Cortesi PA, Scalone L, Giannetti A, Angelini G, Belisari A, Cannavò SP, Cristaudo A, De Pità O, Gallo R, Gola M, Pigatto P, Mantovani LG, for the Italian Hand Eczema Study Group. Cost and quality of life in patients with severe chronic hand eczema refractory to standard therapy with topical potent corticosteroids. Contact Dermatitis. 2014;70:158–68. D’Erme AM, Romanelli M, Chiricozzi A.  Spotlight on dupilumab in the treatment of atopic dermatitis: design, development, and potential place in therapy. Drug Des Devel Ther. 2017;11:1473–80. Diepgen TL.  Life-style factors and hand eczema. Br J Dermatol. 2011;165(3):455. Diepgen TL, Elsner P, Schliemann S, Fartasch M, Köllner A, Skudlik C, John SM, Worm M, Deutsche Dermatologische Gesellschaft. Guideline on the management of hand eczema ICD-10 Code: L20. L23. L24. L25. L30. J Dtsch Dermatol Ges. 2009;7 Suppl 3:S1–16. Diepgen TL, Pfarr E, Zimmermann T. Efficacy and tolerability of alitretinoin for chronic hand eczema under daily practice conditions: results of the TOCCATA open study comprising 680 patients. Acta Derm Venereol. 2012;92(3):251–5. Diepgen TL, Andersen KE, Chosidow O, Coenraads PJ, Elsner P, English J, Fartasch M, Gimenez-Arnau A, Nixon R, Sasseville D, Agner T. Guidelines for diagnosis, prevention and treatment of hand eczema. J Dtsch Dermatol Ges. 2015;13(1):e1–22. Dirschka T, Reich K, Bissonnette R, Maares J, Brown T, Diepgen TL. An open-label study assessing the safety and efficacy of alitretinoin in patients with severe chronic hand eczema unresponsive to topical corticosteroids. Clin Exp Dermatol. 2011;36(2):149–54. English JS.  Managing chronic hand eczema. Br J Dermatol. 2010;162(2):237. English JS. Measure the extent of hand eczema rather than its severity? Br J Dermatol. 2011;165(1):1. English J, Aldridge R, Gawkrodger DJ, Kownacki S, Statham B, White JM, Williams J.  Consensus statement on the management of chronic hand eczema. Clin Exp Dermatol. 2009;34(7):761–9. English J, Graham-Brown R, de Sica Chapman A, Alexandroff AB.  Everyday clinical experience of alitretinoin in the treatment of severe chronic hand eczema: seven case studies. Clin Exp Dermatol. 2011;36(Suppl):1–2. Gola M, D’Erme AM, Milanesi N, Marmugi L.  Effects of alitretinoin on quality of life of patients suffering from chronic hand eczema: an observational study. Dermatitis. 2013;24:166–9. Gola M, Milanesi N, D’Erme AM. Clinical evaluation and assessment of the therapeutic effectiveness of alitretinoin in a group of patients with chronic hand eczema refractory to topical steroid therapy. G Ital Dermatol Venereol. 2014;149:435–9. Halling AS, Zachariae C, Thyssen JP.  Severe treatment-­ resistant acute and recurrent vesicular chronic hand eczema successfully treated with dupilumab. Contact Dermatitis. 2020;83:37. Ibler KS, Jemec GB, Diepgen TL, Gluud C, Lindschou Hansen J, Winkel P, Thomsen SF, Agner T. Skin care

385 education and individual counselling versus treatment as usual in healthcare workers with hand eczema: randomised clinical trial. BMJ. 2012;345:e7822. Lee GR, Maarouf M, Hendricks AK, Lee DE, Shi VY. Current and emerging therapies for hand eczema. Dermatol Ther. 2019;32(3):e12840. Lynde C, Cambazard F, Ruzicka T, Sebastian M, Brown TC, Maares J.  Extended treatment with oral alitretinoin for patients with chronic hand eczema not fully responding to initial treatment. Clin Exp Dermatol. 2012;37(7):712–7. Madan I, Parsons V, Ntani G, Coggon D, Wright A, English J, McCrone P, Smedley J, Rushton L, Murphy C, Cookson B, Williams HC.  A behaviour change package to prevent hand dermatitis in nurses working in the National Health Service: results of a cluster randomized controlled trial. Br J Dermatol. 2020;183:462. Molin S, Diepgen TL, Ruzicka T, Prinz JC.  Diagnosing chronic hand eczema by an algorithm: a tool for ­classification in clinical practice. Clin Exp Dermatol. 2011;36(6):595–601. Ruzicka T, Lynde CW, Jemec GB, Diepgen T, Berth-Jones J, Coenraads PJ, Kaszuba A, Bissonnette R, Varjonen E, Holló P, Cambazard F, Lahfa M, Elsner P, Nyberg F, Svensson A, Brown TC, Harsch M, Maares J. Efficacy and safety of oral alitretinoin (9-cis retinoic acid) in patients with severe chronic hand eczema refractory to topical corticosteroids: results of a randomized, double-blind, placebo-controlled, multicentre trial. Br J Dermatol. 2008;158(4):808–17.

Further Reading Oosterhaven JAF, Voorberg AN, Romeijn GLE, de Bruin-­ Weller MS, Schuttelaar MLA.  Effect of dupilumab on hand eczema in patients with atopic dermatitis: an observational study. J Dermatol. 2019;46(8):680–5. Parsons V, Williams HC, English J, Llewellyn J, Ntani G, Madan I. The development of a protocol for diagnosing hand dermatitis from photographic images. Contact Dermatitis. 2018;79(5):270–5. Russo F, Milanesi N, Iannone M, Bagnoni G, Bartoli L, Bellini M, Brandini L, Buggiani G, Cecchi R, Cuccia A, D’erme AM, Dini V, Gori A, Grazzini M, Marsili F, Masci G, Mazzoli S, Peccianti C, Pellegrino M, Pimpinelli N, Rubegni P, Taviti F, Tedeschi C, Tonini G, Mazzatenta C, Flori ML, Gola M.  Tuscan consensus on the diagnosis, treatment and follow up of adult atopic dermatitis. G Ital Dermatol Venereol. 2020;155:253. https://doi.org/10.23736/ S0392-­0488.19.06527-­1. Soltanipoor M, Kezic S, Sluiter JK, de Wit F, Bosma AL, van Asperen R, Rustemeyer T. Effectiveness of a skin care programme for the prevention of contact dermatitis in healthcare workers (the healthy hands project): a single-centre, cluster randomized controlled trial. Contact Dermatitis. 2019;80(6):365–73. Zirwas MJ.  Dupilumab for hand eczema. J Am Acad Dermatol. 2018;79(1):167–9.

Herpes Genitalis

37

Angelika Stary

Key Points • Genital herpes is a chronic viral infection caused by two types of herpes simplex virus (HSV-1, HSV-2); most cases of recurrent genital herpes are caused by HSV-2. • Clinical diagnosis of genital herpes is often insufficient. Unclear manifestations should be confirmed by laboratory diagnosis in order to enable appropriate treatment and counselling for the patient. • PCR is now the gold standard method for the diagnosis and identification of HSV Type 1 and 2. • Short course therapy with nucleoside analogues offers clinical benefit to symptomatic individuals with first episode or primary genital herpes as well as for recurrent herpetic episodes. • Transmission of HSV to the partner and neonates can occur by viral shedding and should be prevented by antiviral therapy or prophylaxis.

Introduction Genital herpes is caused by the herpes simplex virus type 1 or 2 and is regarded as one of the most common sexually transmitted infections (STI). It is the main cause of genital ulcer disease (GUD) in the developing world (Dillon et  al. 1997). HSV-2 infections are estimated to globally affect more than 500million individuals with an annual incidence of 25  million cases among 15–50 years of age. It is a chronic infection and may last life-long. Herpetic lesions in the genital region have already been observed in the ancient period and were described by Greek scholars for a disease with creeping lesions (Wildy 1973). During the late eighteenth century, oral and genital herpetic lesions were recognized to be eventually associated with the same pathogenesis. Studies in the last century were able to demonstrate type-­ specific differences in the antigenic pattern between both HSV-1 and HSV- 2. Although most infections are mild or even subclinical, frequent recurrences are a persistent health and psychological burden for the individual with uncertainness concerning the danger of

A. Stary (*) Head of the Outpatients’ Centre for STI, Vienna, Austria e-mail: [email protected] © Springer Nature Switzerland AG 2023 A. D. Katsambas et al. (eds.), European Handbook of Dermatological Treatments, https://doi.org/10.1007/978-3-031-15130-9_37

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transmission to the sexual partner and neonates. In addition, erosive and ulcerative lesions have an impact on the transmission rate of the human immunodeficiency virus (HIV) and may lead to dangerous manifestations and treatment problems in immunocompromised persons. Only 10–25% of persons infected with HSV-2 are aware of a genital HSV infection, mostly acquired from asymptomatic partners. The risk of sexual transmission correlates mainly on viral shedding in the large number of asymptomatic than symptomatic individuals. The risk of transmission of HSV infection to the neonate is high for infants born to mothers with clinical manifestations of first episode genital herpes. Early recognition and monitoring of first or recurrent genital herpes during pregnancy is therefore an important preventive strategy for neonatal HSV infections. Potent antiviral agents offer clinical benefits in the treatment of first and recurrent episodes of genital herpes and have proven to reduce the frequency of recurrences when used as daily suppressive therapy. However, they cannot eradicate the latent virus infection and influence the transmission risk or recurrence rate after discontinuation.

Biology of HSV Over 100 herpesviruses have been isolated in human beings, who are the only known reservoir host. The herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) are listed among the group of alpha herpesviridae (Table 37.1). Table 37.1  Classification of human herpesviruses Alphaherpesvirinae: Herpes simples virus (HSV-1 and HSV-2) Varicella- zoster vius (VZV) Betaherpesvirinae: Cytomegalovirus (CMV) Human herpesvirus 6 (HHV-6) Human herpesvirus 7 (HHV-7) Gammaherpesvirinae: Epstein-Barr virus (EBV) Human herpesvirus 8 (HHV-8)

The typical structure of herpesviruses is characterized by the double stranded linear DNA genome, an icosahedral capsid of approximately 120  nm, and an envelope with glycoprotein spikes called tegument. The DNA genome codes for about 80 different genes, which are either important for viral growth or infection and replication. The spikes on the tegument express a large number of viral enzymes and some glycoproteins are responsible for the interaction with the host cell and the cytopathic effect on the infected cells as well as the ability to establish latent infections in the host.

 asic Concept of Pathogenesis B of Genital Herpes Both virus types of the HSV enter the human body by the oral or genital mucosa or occasionally by small lesions in the skin. The infection of the cell occurs by the binding of the virus to the cell surface followed by the activation of a viral-membrane-fusing complex of glycoproteins (gB, gH, gL), which play a major role in the initial binding to heparan sulfate chains on cell surface proteoglycans (Shukla and Spear 2001). After the initial infection, the virus invades the sensory nerve endings within the epidermis and is then retrogradely transported along the axon to the sacral ganglion with production of the virus or restriction of viral replication entering an immediate state of “latency” within neurons. Latency can occur if the viral genome is maintained in the cell and only a small number of the DNA is replicated without protein expression during the period of latency (latencyassociated transcripts, LATs). The detection of LATs is a good marker for latency of HSV in the cells. Activation of latent viral genomes to the replicating state can be induced by in vitro cultivation of the latently infected tissue after explantation. The cells are not automatically killed by the virus, as it occurs in cell culture. A virion shut-off protein which is also introduced to the cell at the time of viral entry causes degradation of preexist-

37  Herpes Genitalis

ing cytoplasmic mRNAs and inhibits cell protein synthesis. It is assumed that cell fusion, typical for the presence of procaryocytes in infected epithelia, may be a different method for viral spreading and facilitate evasion from the immune response of the host. In human beings, latent infections can be converted to productive infection by factors or stimuli, which have not yet been fully defined and the mechanisms underlying reactivation are still a tool for investigation. Exposure to stress, fever, colds, sunlight, pneumococcal infections, menstruation, mechanic stimuli, tissue damage, immunosuppression, etc. is known to reactivate the virus from the sensory neurons. However, sometimes the occurrence of productive infection does not depend upon inducing stimuli and the reason for reactivation is inevident. The virus is subsequently transported along the axon to the nerve endings and crosses into the epidermis at the site of initial infection on the dermis or mucous membranes. There it causes the typical vesiculous herpetic lesions which may also be inapparent or hardly recognized. The frequency and clinical manifestation of the recurrent lesion depends on the immunocompetence of the host and the severity of the primary infection. Interestingly, HSV-1 reactivates more readily from the cervical sensory ganglia, whereas HSV-2 recurs from the sacral ganglia (Reeves et al. 1981). It is an assumption that this might be in connection with differences in the cell type and the viral proteins needed for reactivation. The replication of HSV in the epidermal cell layers has a cytopathic effect on keratinocytes followed by destruction and the occurrence of clinical lesions. The lesions, mostly vesicles, contain a high number of viral DNA, interferons, and other cytokines. Macrophages and CD4 lymphocytes can control the viral replication after 2 to 4  days, when the viral titres in the vesicle decline. It depends on the interaction of the immune response of the host and the inoculum of the herpesvirus whether the infection results in an asymptomatic relapse and how often asymptomatic shedding occurs between clinical visible lesions. Obviously, HSV is able to evade differ-

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ent host-dependent immune mechanisms: it has the capacity to downregulate MHC class I antigen expression on the surface of infected cells. It can also bind and inactivate complement and immunoglobulins by interactions with glycoproteins C, E, and I. In summary, after the invading virus has caused a productive primary mucocutaneous infection with an infection of the ganglia, the basic pathogenesis of HSV-1 and HSV-2 follows the sequence of latency, reactivation, and recurrent infection.

Epidemiology of Genital Herpes The incidence and prevalence of genital herpes vary considerably in countries and population groups, affecting 20–40% of adults in the developed and in an even higher percentage individuals in the developing world. The cumulative lifetime incidence of HSV-2 reaches 80% in African American women and 60% in African American men. Several reports showed an increase of the incidence during the last decades. In the USA, however, the most recent data show a decrease from 21.7% in 1991 to 17% in 2004 in the USA (Fleming et al. 1997). In most cases, infected individuals have acquired the HSV infection subclinically and can be identified only by antibody detection. It is therefore difficult to make exact calculations about the infection rates in different population groups worldwide. Reported data differ according to the presence and detection of clinical symptoms and are dependent on the technology used for the diagnosis of an infection. Type-­ specific serology assays provide information on the occurrence of type-specific HSV-2 and HSV-1 infections. The predominant cause of genital ulcers is HSV-2 accounting for up to 80% of diagnosed causes of GUD.  The frequency of HSV2-antibodies is higher among persons from STI clinics or MSM compared with the general population. In the last decade, an increase of genital lesions caused by HSV-1 has been reported in the developed world (Cowan et al. 2002; Coyle et al. 2003). A shift

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from HSV-2 to HSV-1 has been reported predominantly in young women and MSM. Reasons for that are unclear and can only be assumptions like an increase of oral sex or a decrease of HSV-1 infections during childhood. In a study on the cause of HSV-1 in genital herpes and its impact on surveillance and prevention, it was demonstrated that genital HSV-1 may often be acquired through receptive oral sex (Lafferty et al. 2000).

Transmission of Genital Herpes

A. Stary

 linical Manifestations of Genital C Herpes Genital herpes infections have a wide range of clinical features and may occur subclinical or asymptomatic in most of the cases. Clinical manifestations are influenced by viral and host factors and differ between primary infections and recurrences. Primary or first episode genital herpes infection: In primary infections, symptoms typically occur within 3 to 7 days after exposure often with a prodrome of tender lymphadenopathy, malaise, anorexia, and fever with localized pain and burning, followed by typical clinical lesions with vesicles and erosions (Figs. 37.1 and 37.2). Primary

Infections with HSV-2 types are nearly always sexually acquired while HSV-1 is already acquired in most individuals during childhood. However, these infections do not protect against an infection with type 2. HSV-1 is causing a high proportion of first episodes in young women and MSM, while recurrences and subclinical viral shedding are more frequently observed for HSV-2. Risk factors associated with transmission of genital herpes include age (15–30  years), the number of sexual partners, black or Hispanic race, female gender, homosexuality, HIV-­ positivity, and social status measured by lower income and education levels (Johnson et  al. 1989). HSV-2 is spread primarily by sexual contact through infected secretions via inoculation Fig. 37.1  First episode genital herpes HSV- Type 1 in a 14  years old adolescent, multiple erosions in the vulva onto susceptible mucosal surfaces. region with urinary retention The overall risk of HSV- 2 transmission to a seronegative partner is estimated to be 3–12% per year and seems to be higher for women (17%) than for men (4%) and higher when clinical lesions are present compared to subclinical genital herpes (Bryson et al. 1993). The reason for a higher risk for women is probably dependent on anatomic differences and a greater mucosal surface area compared with men. There is conflicting data on whether a past infection with HSV-1 has a protecting effect concerning the acquisition of an infection with HSV-2. The DNA of HSV could also be detected in the semen of men with genital HSV-2 infection which might also play a Fig. 37.2  First episode genital herpes Type HSV-2 in a role in transmission of infection (Wald et  al. 18  years old adolescent, multiple erosions on the penile 1999). shaft

37  Herpes Genitalis

genital herpes has prolonged local and systemic symptoms which usually reach a peak within the first 3–4 days after onset of lesions with massive local pain and edema. In women, lesions may involve the cervix and cause vaginitis, vulvitis, and dysuria. Genital lesions in men caused by a primary HSV infection are usually not as dramatic as in women. A history of primary genital herpes is often unknown and only reported in 50% of symptomatic infections in individuals with HSV-2 seropositivity (Mertz 1993). HSV cervicitis and proctitis: Cervical herpetic lesions are clinical features which are seldomly observed and are therefore easily overseen and often underdiagnosed. They may be asymptomatic or may result in vaginal discharge. Cervical HSV is a possible site of shedding and important for transmission of the virus to neonates or the sexual partner. HSV is the most frequent pathogen isolated in men with nongonococcal proctitis and is commonly associated with fever, bloody rectal discharge, and severe rectal pain. Both HSV 1 and 2 have been isolated from the rectal area of MSM, but can also occur in women and may result in subclinical viral shedding due to reactivation in latent sacral ganglia. Recurrent genital herpes: The major problem of genital herpes is the reactivation of the virus resulting in recurrences over months or years with varying frequency. Reactivation of HSV-2 from the sacral nerve root ganglia is widespread over a large anatomic area. It is less frequently observed with HSV-1 compared with HSV-2 infection and occurs in about 60% in the first year and 30% in the second year after first episode HSV-1 infection. In contrast to HSV-1 relapses, about 90% of individuals with HSV-2 infections develop recurrences in the first year with a higher frequency in men than in women (Benedetti et al. 1994). The frequency of recurrences correlates directly with the severity of primary infection with varying time intervals between relapses. Usually, recurrences are less severe and a limited number of blisters will appear on the genitalia which will resolve within a week. Lesions may even be subclinical and unobserved. (Fig. 37.3).

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Fig. 37.3  Recurrent genital herpes with blisters on the labium major; HSV-2-positive

Genital Shedding of HSV Asymptomatic viral shedding in patients with genital herpes is important for the understanding of transmission to the partner or neonates. It has been shown that beside shedding during symptomatic episodes of genital herpes, additional asymptomatic viral shedding occurs intermittently, mostly within a week of clinical recurrence (Wald et al. 1995). Individuals with more frequent recurrences had also more frequent subclinical shedding, as well as those who had recently acquired genital herpes. Viral DNA could be detected by PCR from the vulva, cervix, and rectum. These results may explain the viral transmission to partners of infected but asymptomatic individuals, unaware of eventually being a risk for their sexual partner. This has an important implication in terms of current or future relationships of individuals with genital herpes. In a multicenter study in the USA among individuals with symptomatic and asymptomatic genital HSV-2 infections, the frequency of genital shedding was evaIuated (Tronstein et  al. 2011) It could be demonstrated that persons with asymptomatic infections shed virus in the genital tract less frequently than persons with symptomatic infections, mainly because of a less frequent shedding from genital lesions. Even among persons with asymptomatic infection, shedding occurred in 10% of days. The issue of infectivity is of concern for partner management and public health: The DNA load necessary for transmission

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is unknown, but there is an estimation that even a quantitatively moderate shedding may result in transmission. It is important to actively inform and advise the infected individual and offer methods such as condom use or daily antiviral medication to decrease the risk for transmission.

Diagnosis of Genital Herpes In many infected individuals, clinical symptoms of genital herpes may present the presence of typical popular lesions progressing to vesicles and erosions as classical manifestations without the need of laboratory diagnosis. However, clinical diagnosis of atypical genital herpes should be confirmed or established by laboratory testing. Diagnostic procedures enable nowadays many more possibilities for both, diagnosis of an acute infection and insight in the incidence and prevalence of HSV-1 and HSV-2 infections in different risk groups and in the general population. Multiple diagnostic methods are available for the detection of the virus, viral DNA, or viral antigen (Fig. 37.4). They include culture, direct fluorescent antibody assays (DFA), and molecularbiological technology (Table  37.2). The Tzanck test is still often performed, but is no longer recommended except for rapid diagnosis in atypical clinical manifestations and in resource poor settings. The DFA is more sensitive and distinguishes between HSV

Fig. 37.4  Smear from the genital area of first episode genital herpes. Direct Fluorescence Antibody Assay: HSV-Type 1 positive

A. Stary

and VZV.  However, if used for the diagnosis of lesions which persist for a longer while, the sensitivity is low. Cell culture had been used in the past for viral detection and is useful for resistance testing and to generate enough viruses for special transmission studies. Compared with molecularbiological methods, the sensitivity of cell culture is low and declines rapidly when the lesions start to heal. HSV DNA detection by PCR or transcript mediation assays (TMA) is now considered as the gold standard method for HSV diagnosis. It is also the most sensitive and the preferred method for the diagnosis of severe cases of HSV infections such as herpes simplex encephalitis or infections in neonates. It is recognized as the reference method for the detection of HSV in the cerebrospinal fluid and in brain biopsies and should be the method of choice for special questions concerning immediate treatment recommendations (Mitchell et al. 1997). This might be the case at the term of labour for decisions concerning Caesarean section or for the diagnosis of HSV infection in the neonate. However, even amplification technology does not provide a 100% sensitive test and since viral shedding is intermittent, a negative result at the time of PCR testing does not exclude herpetic infections. Antibody detection for the differentiation between HSV-1 and HSV-2 antibodies in serological tests may be used for a better epidemiological insight. Type-specific antibody tests distinguish between both HSV types and are based on the type-specific glycoprotein gG-1 for HSV-1 and gG-2 for HSV-2 antibody detection. For prevalence or incidence studies and for prognosis and counselling, several reliable type- and non-type- specific antibody detection assays are available. The Western blot represents the gold standard for serologic methods and is both, highly sensitive with >97% and specific (>98%). However, it is still seldomly performed and not commercially available. The use of diagnostic methods is especially recommended to exclude other infectious or non-­ infectious reasons for genital erosions or ulcerations (Table  37.3). In asymptomatic partners, CDC recommends type-specific serologic testing for HSV infection (Workowski and Bolan 2015).

37  Herpes Genitalis

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Table 37.2  Diagnostic procedures for genital herpes Nucleic acid amplification (NAATs)

Sensitivity High up to 100%

Virus culture

High, dependent on age of lesions

Antigen detection (EIA) Antigen detection (immunofluoresce)

Up to 80% Lower, up to 50%

Specificity Advantage High Rapid, different material High Allows sensitivity testing High Speed, costs High Inexpensive

Table 37.3  Differential diagnosis of genital herpes Syphilitic chancre Chancroid LGV Scabies with excoriations Erosive genital candidiasis Traumatic lesions Fixed drug eruption Genital aphthe M. Behcet LRP Ulcus vulvae acutum Lipschuetz Inflammatory bowel disease (M.Crohn)

 eneral Management and Concept G of Treatment The management of genital herpes infections includes clinical and anamnestic evaluation, treatment recommendation, and counselling of patients and their sex partners. Management and treatment of genital herpes have different targets which should be approached after the diagnosis is established and the patient had the opportunity for counselling: • In primary genital herpes, it is of upmost importance to shorten the time of lesions and local and systemic symptoms and to prevent possible complications such as aseptic meningitis or urinary retention. • After first genital episode or primary infection, the prevention of latency and the development of recurrences is a further tool. In case

Disadvantage No resistance proof, expensive assays, different cross reactions, contamination Labour and time intensive, difficult transport, difficult storage, less sensitive Less sensitive, no viral typing Less sensitive

of already established latency, the reduction or prevention of subsequent recurrences is required. • Counselling has to include clear information about pregnancy and the transmission of the disease to the neonate. What has research contributed to these goals? Antiviral drugs against HSV can partially control and reduce acute symptoms and the frequency of recurrent episodes. However, despite major advantages during the last 25  years, it is not possible to prevent latency or eradicate the latent virus from the ganglion or to reduce the frequency of episodes and the possibility of transmission after the preventive treatment is discontinued.

Therapy of Genital Herpes Nucleoside Analogues Antiviral treatment with nucleoside analogues offers clinical benefit to symptomatic individuals with first episode or primary genital herpes as well as for recurrent herpetic episodes. Nucleoside analogues are also efficient in suppressing recurrent genital herpes in individuals with frequent episodes and are therefore recommended for long-term suppression in those with >6 episodes per year. Among FDAapproved oral antiviral drugs, acyclovir, valacylovir, and famciclovir are the drugs of choice for the treatment of genital herpes. Oral admin-

394

istration is more efficient than locally applied antiviral creams.

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rate of HSV detection on genital mucosa. However, it has no influence on the rate of recurrences if not permanently administered. 1. Acyclovir Beside the efficient impact of ACV on her 2. Valacyclovir petic lesions in the introital region of the genital 3. Famciclovir tract, it has also shown an improvement of herpetic proctitis in men having sex with men Acyclovir (ACV) (MSM) and on cervical lesions in women with ACV was the first guanosine analogue that was herpes cervicitis. introduced as antiherpetic agent. It selectively ACV has an excellent safety profile. Side inhibits the replication of HSV-1 and HSV-2 and effects are seldom reported and might include of the VZV.  It is phosphorylated by the virus-­ nausea, headache, and rash. In case of renal dysspecific thymidine kinase in HSV infected cells function, the treatment schedule has to be modito acyclovir monophosphate and then by cellular fied. Resistance is seldom observed and mostly enzymes to the active component, acyclovir tri- only occurs in immunocompromised individuphosphate, which inhibits viral DNA synthesis als. HSV resistance to ACV has been described by competing with guanosine triphosphate as a in immunosuppressed individuals (mainly HIV-­ substrate for the viral DNA polymerase. ACV has positive persons) in 2–9%. In those cases, resispotent in vitro activity against both serotypes of tance is not restricted to ACV only, but also HSV and markedly reduces the duration and includes treatment with valacyclovir and famciseverity of lesions in animal models. It can be clovir. Fully ACV-resistant strains are resistant administered topically, orally, and intravenously, to valacyclovir and gancyclovir and the majority and all 3 options lead to reduction of viral shed- are also resistant to famciclovir (Engel et  al. ding and a quick healing of lesions and to a 1990). reduction of the duration of symptom. However, only the systemic treatment offers the benefit of Valacyclovir accelerated improvement of general symptoms The main disadvantage of ACV is the low bioand avoids the development of new lesions. availability of ACV with only a small fraction of Therefore, oral treatment for both, first episode the drug is absorbed. Valacyclovir, the L-valyl and recurrent genital herpes is recommended and ester of acyclovir and a prodrug of ACV, is almost eventually intravenous administration in acute completely converted in the gastrointestinal tract primary genital herpes with severe general by hepatic and intestinal enzymes, which symptoms. increases the bioavailability of ACV from Numerous studies in primary and recurrent 10–20% to more than 50%. A dosage of 1000 mg herpes have shown ACV to efficiently decrease daily is similarly effective as intravenous ACV. the duration of symptoms and viral shedding, and Valacyclovir and ACV have been compared in in primary or first episode infection it rapidly numerous studies, demonstrating a similar profile reduces fever and systemic symptoms within of activity in primary, first-episode, and recurrent 48 h. It is important to initiate the antiviral treat- genital herpes with a more convenient dosage ment as early and as high as possible to have an frequency. immediate effect on viral shedding. The oral Different schedules of dosage for Valacyclovir administration of 400  mg ACV twice or three have been evaluated and compared with placebo times daily has shown similar antiviral effect as a or with ACV: dosage of 5 × 200 mg. For the treatment of first episode herpes, the For recurrent genital herpes, the influence of recommendation of antiherpetic therapy with 1 g ACV has also been studied concerning the fre- valacyclovir twice daily was similarly efficient as quency of recurrent episodes: daily ACV preven- 200 mg ACV 5 times daily. However, in individution reduces the number of recurrences and the als with first episode or recurrent herpes epi-

37  Herpes Genitalis

sodes, even the lower dosage of 500  mg valacyclovir twice daily was equally effective in the reduction of lesions and viral shedding as 1000  mg twice daily and also comparable with 200  mg ACV 5 times daily or 400  mg daily (Gupta et al. 2004). Both drugs decreased the risk of viral isolation by 95% and the rate of HSV detection by about 75%. Valacyclovir is also recommended for prevention of recurrent episodes in individuals with genital herpes: It has been compared with placebo for the prevention of recurrences in genital herpes and viral suppression in 382 patients with at least 8 recurrences per year for a period of 4 months: While about 70% of drug recipients were recurrence free, the corresponding data in the placebo group was about 10%. Valacyclovir 500 mg once daily is therefore recommended for persons with 9 or fewer recurrences per year. A different schedule of 250  mg twice daily or a higher dosage of 1000 mg is recommended in individuals with 10 or more recurrences per year. Valacyclovir has also been evaluated whether it has an impact on viral shedding and the transmission of HSV-2 between sexual partners: 500 mg once daily was able to reduce transmission of HSV-2 by 48% (Corey et al. 2004). To summarize, both drugs, ACV and Valacyclovir, are equal in their profile of efficacy and side effects, with the advantage for Valacyclovir of a more convenient dosage frequency. An early onset of therapy within 24 hours is essential for a successful influence of the clinical course of genital herpes. Resistance to ACV is very similar also to Valacyclovir (Engel et  al. 1990).

Famciclovir Famciclovir is the prodrug of penciclovir, which inhibits the replication of both HSV-types. It needs the viral thymidin kinase for phosphorylation to penciclovir monophosphat and – similar to ACV - is converted in the intestinal wall and liver to the active form penciclovir triphosphate. It has a high bioavailability of about 77% and a much longer intra-cellular halflife (10 hours versus 1 hour) (Pue and Benet 1993). The antiviral

395

drug is well tolerated with a very low profile of adverse effects. A reduced dosage is recommended in case of impaired creatinine clearance. For the treatment of first-episode genital herpes, famciclovir showed comparable results with ACV, concerning symptom resolution, viral shedding, and lesion healing (Loveless et  al. 1995). The efficacy of 125  mg famciclovir twice daily was evaluated in recurrent genital herpes and showed a significant difference to placebo with a shorter duration of lesions and a reduced viral shedding in all immunocompetent patients. A higher dosage did not show additional benefit (Sacks et al. 1996). Famciclovir has also demonstrated to be effective in suppressing recurrent genital herpes in individuals with frequent episodes when compared to placebo (up to 90% without episode within 4 months compared to 48% in placebo group). Compared with valacyclovir, the first recurrences were reported earlier and suppression was not as efficient (Wals et  al. 2006). The result of this study supposes that famciclovir was not as successful in HSV suppression and sexual transmission when compared to valacyclovir.

Treatment of First Clinical Episode Initial episodes of genital herpes include both, anti-HSV-1/-2 antibody-negative primary herpes and anti-HSV1 or -2 antibody-positive first episode genital herpes infection. First herpetic manifestations can cause prolonged clinical illness and concomitant systemic symptoms. Antiviral oral treatment should start as soon as possible after assumed diagnosis. Recommended regimens (CDC and IUSTI Europe) (Workowski and Bolan 2015; Patel et al. 2017) Acyclovir 400 mg orally three times a for day 5–10 days Acyclovir 200 mg orally five times a for day 5–10 days Famciclovir 250 mg orally three for times a day 5–10 days Valaciclovir 500 mg orally twice a for day 5–10 days

or or or ora

CDC recommends 1 g Valaciclovir orally twice a day

a

A. Stary

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CDC recommends in general treatment for 7–10  days and it can be extended if healing is incomplete after 10 days of therapy. All drugs have shown to be effective and the length of therapy should be extended if healing is incomplete, new lesions develop, or severe systemic complications are observed. Hospitalization and intravenous application of antiviral drugs may be required with extraordinary clinical symptoms or if the patient is unable to tolerate oral treatment. Concomitant counselling should include information on the natural course of the disease with the potential subclinical shedding, partner transmission, and recurrences. Screening on other STIs may be considered.

Treatment of Recurrent Episodes Management strategies of recurrent herpetic episodes include episodic antiviral therapy, ­counselling of the appropriate strategy for the individual patient management concerning suppressive and supportive therapy. Recurrent episodes are usually self-limited and require early initiation within 1  day of onset of lesions or prodromes. The reduction of healing of lesions may be one to 2  days. The patient should be provided with the drug with instructions for treatment to be started eventually patient-initiated within the first hours of onset of symptoms. Treatment schedules differ in length and dosage. All antiviral drugs are effective for treatment of episodes, and head-to-­head studies show no difference between the antiviral agents and length of therapy. Famciclovir may be less effective in the suppression of viral shedding. If symptoms are mild, patients may decide not to have antiviral therapy and may only need supportive advice. Short course therapies are recommended in the first instance (Patel et  al. 2017): Recommended regimens (CDC) (Workowski and Bolan 2015) Acyclovir 400 mg orally three times a for or day 5 days

Acyclovir 800 mg orally twice a day Acyclovir 800 mg orally three times a day Famciclovir 125 mg orally twice a day Famciclovir 1000 mg orally twice a day Famciclovir 500 mg orally once, followed by 250 mg twice a day Valaciclovir 500 mg orally twice a day Valaciclovir 1 g orally once a day

for 5 days for 2 days for 5 days for 1 day for 2 days

or

for 3 days for 5 days

or

or or or or

or

Recommended regimens (IUSTI Europe) (Patel et al. 2017) Short course therapies (in the first instance): Acyclovir 800 mg orally three times a for or day 2 days Famciclovir 1000 mg orally twice a day for 1 day or Valaciclovir 500 mg orally twice a day for or 3 days 5 days therapy schedules Acyclovir 400 mg orally three times a for or day 3–5 days Acyclovir 200 mg orally five times a for 5 days or day Valaciclovir 500 mg orally twice a for 5 days or day Famciclovir 125 mg orally twice a for 5 days day

Suppressive Therapy of Recurrent Genital Herpes Suppressive therapy reduces the frequency of episodes by 70–80% in patients with frequent relapses and is recommended in individuals with frequent and/or troubling recurrences. The decision for initiating suppression of genital herpes by the continuous treatment is very subjective and based on considerations including the frequency of relapses, the association with significant symptomatology and major psychosexual problems in the sexual relationship, costs, and the inconvenience of permanent drug administration. Suppressive treatment of recurrent genital herpes may lead to a significant improvement of life quality.

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37  Herpes Genitalis

Where relapses are less frequent (4–6 indicates hirsutism, taking into account that the degree and prevalence of hirsutism vary by ethnicity and that self-epilation can limit clinical assessment (Azziz et al. 2019; Jacob and Balen 2019). For the definition of hirsutism, it has been proposed that a cut-off value of ≥8 points is recommended for most populations, with the exception of women from the Far East, in whom a ≥2 cut-off value is recommended (Escobar-Morreale 2018). Hirsutism can be a presenting sign of PCOS, nonclassical CAH, Cushing’s syndrome, or androgen-secreting tumors.

40  Hirsutism and Hypertrichosis

Fig. 40.1  Hirsutism of the face in a 22-year-old woman

Fig. 40.2  Modified Ferriman–Gallwey scoring system for the diagnosis of hirsutism. Each of the nine body areas is assigned a score from 0 (no hair) to 4 (frankly virile).

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PCOS is the most common cause of hirsutism. The diagnosis is based on established criteria (Azziz et al. 2006, 2009; Rotterdam EA-SPcwg 2004). The current consensus is that the use of the revised Rotterdam criteria (2003 Rotterdam Consensus Group) is appropriate for the diagnosis of PCOS in adult women. The diagnostic criteria for adolescent girls are more problematic (Witchel et al. 2019; Pena et al. 2020). According to the revised Rotterdam criteria, PCOS in women is defined by the presence of at least 2 out of 3 of the following criteria: (1) oligo- and/or anovulation, (2) clinical and/or biochemical hyperandrogenism, and (3) polycystic ovaries and exclusion of other etiologies (congenital

(Reproduced with permission from Hatch et  al. (1981). © Elsevier (Hatch et al. 1981))

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adrenal hyperplasias, androgen-secreting tumors, and Cushing’s syndrome) (Rotterdam EA-SPcwg 2004). Polycystic ovary morphology on ultrasound is defined using strict criteria and requires the presence of an ovarian volume ≥10 ml and/or 25 follicles per ovary (Dewailly et  al. 2014). Cutaneous signs of hyperandrogenemia in PCOS may include hirsutism (as the primary clinical indicator of androgen excess), acne, and androgenic alopecia (Rotterdam EA-SPcwg 2004). CAH is an autosomal recessive disorder with a reported prevalence for nonclassical (late-­ onset) CAH ranging from 0.6% to 10% depending on the ethnic group. CAH can present with premature pubarche (appearance of sexual hair before 8 years of age in girls and 9 years in boys), hirsutism, acne, adult-type apocrine odor, tall stature in children, and advanced skeletal maturation. Nonclassical CAH is a progressive disorder, with the prevalence of hirsutism increasing with age in individuals >10 years old (Dessinioti and Katsambas 2009). Among 270 Spanish women with hirsutism, acne, androgenic alopecia, or irregular menses, nonclassical CAH was diagnosed in six women (2.2%) (Escobar-Morreale et al. 2008). The term “SAHA syndrome” was coined in 1982 by Orfanos and colleagues, to characterize the association of seborrhea, acne, hirsutism, and androgenic alopecia in women (Orfanos et  al. 2000). In approximately 20% of patients, all four major signs of SAHA syndrome are present; seborrhea is always present and androgenic alopecia occurs in 21%, acne in 10%, and hirsutism in 6% of patients. The SAHA syndrome is classified into idiopathic, ovarian, adrenal, and hyperprolactinemic types, depending on the underlying associated disorder (Chen et al. 2011).

Diagnostic Approach Hirsutism is a clinical diagnosis based on standardized visual scales, such as the F-G score, as described above. In order not to overestimate hirsutism, vellus hair needs to be differentiated from terminal hair. Only terminal hairs are considered

C. Dessinioti and A. D. Katsambas

in pathological hirsutism, with terminal hairs clinically growing >5 mm in length if untreated, varying in shape and texture, and generally being pigmented (Teede et al. 2018). The diagnostic evaluation of the hirsute woman should include a physical exam for androgenic alopecia, acne, seborrhea, galactorrhea (a sign of possible hyperprolactinemia), and acanthosis nigricans; signs of virilization (such as clitoromegaly, deepening of the voice, or increasing muscularity) suggest marked hyperandrogenemia due to androgen-secreting adrenal or ovarian tumors. Also, the time of onset and rate of progression of hirsutism, regularity of menstruation and fertility, will be noted in the medical history. The Endocrine Society issued a clinical practice guideline in 2018, for the evaluation and treatment of hirsutism in premenopausal women. Screening for elevated androgen levels was suggested in all women with a positive hirsutism score. On the other hand, they suggested testing for elevated androgen levels in eumenorrheic women with unwanted hair growth and a normal hirsutism score, because of the low probability of a positive result (Martin et  al. 2018; Mimoto et al. 2018). Positive hirsutism score was defined as an FG score of 8 or greater in white and black women, 2 to 7 or greater in Asian women, depending on ethnicity, and 9 to 10 or greater in Hispanic and Middle Eastern women (Mimoto et  al. 2018). Laboratory hormonal evaluations including total testosterone, free testosterone, sex hormone-binding globulin (SHBG), should be performed in the early follicular phase (Mimoto et  al. 2018). In women under hormonal contraception, this should be ideally discontinued for 8–12 weeks before the hormonal evaluation. A pelvic ovarian ultrasound examination may be used for PCOS. Ultrasound should not be used for the diagnosis of PCOS in those with a gynecological age of upper extremities; Figs. 65.1, 65.2 and 65.3). Etiology and Pathogenesis In severe cases, dissemination onto the trunk, face, and neck can be found. Some authors sugThe exact pathophysiology of nummular eczema gest an association between the eczema location is still unknown. Multifactorial trigger in combi- and an underlying xerosis cutis. nation with epidermal barrier dysregulation and Based on the clinical appearance and duration microbial skin colonization is assumed to play a of disease, nummular eczema can be classified as major role in the onset and maintenance of the acute or subacute/chronic. During the acute disease. Some authors discuss affection of the phase, erythematous plaques with diameter of small nerve fibers of the skin (Misery et al. 2014). 1–5  cm and distinct edges occur. Shortly upon Among the common aggravation factors are onset, papules, papulovesicles, and vesicles atopy and dry skin. Recent studies report up to develop on the surface of the plaques. Severe pru50% atopy in patients with nummular eczema. ritus is characteristic for this stage. After the vesContact sensitization to common allergens such icles once erode (Figs.  65.4 and 65.5), oozing, as metals, fragrance, rubber, preservatives but crusting, and scaling follow.

65  Nummular Eczema: An Update

Fig. 65.1  Nummular eczema and varicosis. (Courtesy of Derma am Biederstein, 2022, All Rights Reserved)

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Fig. 65.3  Nummular eczema: well-demarcated lesion and skin exsiccation. (Courtesy of Derma am Biederstein, 2022, All Rights Reserved)

a

b

Fig. 65.4  Nummular lesion in acute stage (a) wide spread eczema (b) detailed image). (Courtesy of Derma am Biederstein, 2022, All Rights Reserved) Fig. 65.2  Nummular eczema in chronic stage. (Courtesy of Derma am Biederstein, 2022, All Rights Reserved)

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Table 65.1  Evaluations performed to detect underlying disease Blood test Marker for bacterial infections • Leukocytosis •  Erythrocyte sedimentation rate (ESR) • Anti-staphylolysin antibodies (ASTA) • Anti-streptolysin antibodies (ASO) • Treponema pallidum particle agglutination (TPPA) Marker for viral infections •  Lymphopenia •  Monocytosis •  Hepatitis, HIV serology Allergy diagnostics •  Total-IgE, RAST, Prick test •  Patch test

Indication Bacterial infections Bacterial infections Staphylococcal infections Streptococcal infections Syphilis

Viral infection Viral infection Hepatitis A/B/C, HIV Atopy/atopic eczema Contact allergy

Histopathology

Fig. 65.5  Nummular eczema under topical treatment. (Courtesy of Derma am Biederstein, 2022, All Rights Reserved)

Diagnosis

Skin biopsy from affected area shows acanthosis, hyperkeratosis (ortho- and parakeratosis), spongiosis with diffuse lymphocytic infiltration, eosinophils, and neutrophils. Spongiosis with vesiculation may be found in the early stages. Periodic acid–Schiff (PAS) stain is performed to rule out tinea infection.

The diagnosis of nummular eczema is based primarily on the typical clinical features of coin-­ shaped eczema with sharp demarcated edges and severe pruritus in correlation with histological findings showing typical characteristics of eczema. To rule out differential diagnoses, a detailed history has to be taken. There are no specific laboratory markers available for nummular eczema. In some cases, trigger factors s.a. ­infection, atopy, and allergic contact sensitization can be determined.

Bacteriological Swabs

Blood Tests

Differential Diagnosis

Blood tests are performed to detect underlying infectious diseases (Table 65.1).

Common relevant differential diagnoses are listed in Table 65.2.

In cases of a superinfection, bacteriological swabs from the lesions can be useful to determine the affecting bacteria and resistance spectrum.

Mycological Culture Scales from affected area should be cultured to exclude Tinea corporis.

65  Nummular Eczema: An Update Table 65.2  Differential diagnoses of nummular eczema Name of disease Psoriasis with nummular pattern Parapsoriasis Atopic eczema with nummular pattern

Prurigo with nummular lesions Sulzberger–Garbe exudative discoid and lichenoid chronic dermatosis Allergic contact eczema Tinea corporis Impetigo contagiosa

Leprosy Mycosis fungoides

Clinical features Family history of disease, no vesicles, no/discrete pruritus No vesicles, typical distribution pattern in Langer’s lines Susceptibility for atopic diseases, manifestation in childhood, chronic eczema (lichenification) Prurigo nodules Polymorph clinical appearance, diffuse nummular and lichenoid pattern of lesions, genital affection (penis, scrotum) Distinct trigger +/− positive patch test Positive direct detection or culture, pets Positive bacterial analysis for streptococci or staphylococci, contagiousness No pruritus, dysesthesia Persisting lesions in same location, no vesicles

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Immunosuppressive and immunomodulatory therapy with topical calcineurin inhibitors (TCIs) can be applied for long-term treatment with similar anti-inflammatory efficacy. Combination therapies such as TCS with antiseptics and astringents (for acute stadium) or with keratolytic ointments (chronic eczema) have shown good outcome. In disseminated lesions, UV radiation (UVA and UVB) is used along with topical corticosteroids for its anti-inflammatory, immunosuppressive, and antipruritic effect. In severe and resistant cases, systemic corticosteroid treatment in combination with antibiotics should be applied. In severe pruritus, systemic antipruritic treatment with antihistamines is recommended; however, the efficacy in patients with nummular eczema can be limited. Psychosomatic counseling, relaxation techniques, and acupuncture can be beneficial as supportive approaches to minimize emotional stress.

Topical Treatments Dermoscopy has been postulated as a useful tool in the differential approach between nummular eczema and lichen aureus (Suh et al. 2017).

General Principles of Treatment Causative and symptomatic treatment should be performed according to clinical manifestations (stage of disease). Triggering factors as infections, dry skin, and contact with sensitizing substances need to be eliminated and avoided. Venous stasis should be treated. Medications, considered as trigger, should be withdrawn or substituted. In patients with xerosis cutis, sufficient basis therapy is essential. In case of systemic infections, causative systemic antibiotic or antiviral therapy has to be applied. Symptomatic treatment is based on anti-inflammatory, anti-eczematous, and immunomodulation approaches. Topical corticosteroids (TCSs) with diverse potency and formulation have been established as first-line therapy in every stage of disease.

 opical Corticosteroids (TCS) T Topical corticosteroids are used in the treatment of eczema lesions for their anti-inflammatory and immunosuppressive effects. According to their potency, there are four groups of TCS (group I: low potency—group IV: very potent), although clinical effect can depend on formulation, duration of treatment, extent of the treated area, and stage of disease. Mostly once daily application is recommended. In acute eczema, corticoid cream (O/W) in combination with topical antiseptics and astringent dyes ensures faster exsiccation. In severe cases, wet dressings applied over the treated area increase the penetration of the active agents and thereby contribute to accelerate healing. Limited treatment duration has to be considered with this approach, due to higher rate of side effects and possibility of systemic resorption of the corticosteroids. Lipophilic corticosteroid ointments and creams are appropriate in chronic eczema for higher penetration.

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In short-term treatment regiments, TCSs have low rate of side effects. Most common are skin atrophy, hypertrichosis, and steroid acne or acute contact dermatitis due to preservative agents. To avoid possible side effects, mild TCSs are applied once daily at the beginning of treatment (up to 14 days), potent TCS over 3–5 days with subsequent dose tapering (lower TCS potency or extension of application interval). In stable disease, proactive therapy with once/twice weekly application of a low-potent TCS can be offered in chronic recidivant cases as relapse prophylaxis.

 opical Calcineurin Inhibitors (TCIs) T Tacrolimus (0.03% and 0.1%) ointment and Pimecrolimus 1% cream are immunomodulatory agents with suppressive activity on T cells. As an alternative nonsteroid topical treatment, these agents became an essential part of the eczema therapy during the past years. They are mostly applied in mild-to-moderate eczema and can be used in delicate skin areas s.a. face, genital region, and intertrigines. Recent studies have shown that a long-term treatment on a daily basis over several months is well tolerated in children and adults. Most common side effects are burning or itching on the application side; in atopic patients, skin infections (herpes simplex, molluscum contagiosum) can occur and have to be treated with temporary discontinuation of the TCI therapy. Sun protection and skin disinfection on the application sites are recommended during use of TCI.  opical Antiseptics (TAS) T and Adstringents Topical antiseptics such as triclosan or octenidine have antimicrobial effect and help to reduce bacterial contamination in affected areas. Due to the compromised skin barrier in eczema lesions, short use of clioquinol, potassium permanganate (KMnO4), and diverse astringent solutions (Table  65.3) may be indicated rather than alcoholic solutions (irritation).

Table 65.3  Contact dermatitis can develop after sensitization; persistent skin and clothes coloration is seen in contact areas upon application Solution % Clioquinol KMnO4 aq. Sol. Solutio pyoctanini (Gentian violet aqueous 1%) Solutio castellani aq. Eosin aq. solution 1%

Coloration Yellow Pink Ink blue Magenta Red

This topical treatment is favored because of its broad antimicrobial spectrum and low risk of bacterial resistance. Contact dermatitis can develop after sensitization; persistent skin and clothes coloration are seen in contact areas upon application.

 opical Antibiotics (TAB) T Due to the risk of emerging bacterial resistance and contact allergy, the use of topical antibiotics is not recommended.

Supportive Approaches and Treatment Regiments Wet-Wrap Dressings Wet-wrap dressing is a technique of topical treatment during the acute stage of eczema with vesicles, erosions, and exudation. Oozing lesions are creamed with corticosteroid cream and dressed with wet bandages for 20  min. This causes enhanced penetration of the cream with more potent effect and faster drying of the vesicles. Dressings can be applied once daily, mostly up to 3 days and are sufficient to exsiccate the lesions. Caution is needed because of the higher penetration of corticosteroids with possible systemic side effects. Proactive Treatment Use of TCS or TCI in previously affected areas (once/twice weekly) to avoid exacerbation after clinical improvement.

65  Nummular Eczema: An Update

Topical Treatments at a Glance

–– Acute nummular eczema: Exsiccating agents with anti-­ inflammatory and antiseptic properties Wet dressings Glucocorticosteroid lotions and solutions in tapering dose Topical calcineurin inhibitors in delicate areas and for prolonged treatment (Phototherapy) –– Subacute and chronic eczema: Lipophilic TCS ointments in tapering dose Topical calcineurin inhibitors Keratolysis in hyperkeratotic lesions with salicylic acid 3–5% or urea 10% Intensive basis therapy (lipophilic lotions and creams) Tar preparations in combination with UVB phototherapy and UVA1 phototherapy

Systemic Treatment Systemic treatment is indicated in severe cases with disseminated eczema lesions, superinfection, or in relapsing cases.

 ystemic Antibiotics (SAB) S As in nummular eczema, a sensitization to staphlylococcal superantigens has been assumed as a trigger, and Staph. aureus superinfection is common in eczema lesions, antibiotic treatment is mostly performed with anti-staphylococcal agents (penicillins, cephalosporines, lincosamides). Beta-lactamase-resistant penicillins are recommended after performing an antibiogram. Possible adverse effects are intolerance reactions such as allergic exanthema or urticaria. Another

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challenge is the increasing bacterial resistance to penicillins. Cephalosporines and Carbapenems are well-­ tolerable and effective treatment alternatives. Significant side effect of Clindamycin is the pseudomembranous colitis. In cases of acute onset of diarrhea, Clindamycin should be withdrawn. Due to the wide spread resistance to Tetracyclines and Macrolides, these are no longer recommended in the therapy of Staph. aureus. Systemic antibiotic treatment is performed over 5–7 days, in case of an underlying infection (Tonsilitis, Urethritis, Bronchitis), specific antimicrobial therapy is recommended.

 ystemic Corticosteroids (SCS) S Systemic corticosteroids should be used restrictively and are only indicated in severe cases of acute eczema with widespread affection of the body and extremities and in chronic recurrent eczema. Daily application of 0.5–1.0  mg/kg Prednisolone equivalent is recommended for up to 7 days in tapering dose. Side effects on the skin s.a. atrophy, telangiectasia, striae distensae, purpura, hypertrichosis, or systemic side effects as Cushing, osteoporosis, suppression of the pituitary–adrenal axis occur usually after long-term treatment, but have to be reconsidered and monitored. Like in atopic eczema, relapse of disease after discontinuation of systemic corticosteroids can occur. Contraindications represent severe systemic infections, peptic ulcer disease, psychiatric disorders, glaucoma, hypertension, and osteoporosis. These should be ruled out. Antihistamines (AH) Antihistamines (AHs) are indicated as supportive treatment in patients with severe pruritus. Parenteral application is more effective than oral administration. First-generation antihistamines have pronounced antipruritic effect, also causing

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sedation and fatigue. AH are generally well tolerated. Caution is indicated patients with impaired renal function, cardiac diseases, or concomitant medication s.a. antidepressants. AHs are mostly part of a combination therapy with local and systemic corticosteroids.

Ciclosporin (CyA) Cyclosporin is a T-cell immunosuppressive drug with broad application in the transplantation medicine and in the field of dermatology in refractory atopic eczema, psoriasis, pemphigus, and other autoimmune diseases. For severe nummular eczema in atopic patients, Ciclosporin treatment can be reconsidered to achieve remission. Possible side effects are hypertension, impairment of the renal and liver function, hypertrichosis, gingival hyperplasia, infections. Regular laboratory checkup (blood cell count, hepatic and renal function parameter, ESR, CRP) and blood pressure should be monitored every 4–6 weeks during the long-term treatment. Based on the potential epithelial carcinogen effect, ciclosporin should not be combined with phototherapy and the duration of treatment should be limited (up to 1 year). Methotrexate (MTX) Methotrexate represents a cytostatic agent with immunosuppressive and antiproliferative effect, based on suppression of the folic acid synthesis. In autoimmune disorders, psoriasis, and rheumatic diseases, it has already found broad application. Recently, successful and well-tolerated treatment of refractory nummular eczema in children with MTX has been reported (Roberts et al.). Application limitations are pregnancy and lactation, hepatic and renal diseases, bone marrow suppression, or systemic infections. Regular checkup of blood cell count, liver and renal function, as well as contraception are required. Men should be aware of potential impairment of the spermiogenesis. Semen cryopreservation should be discussed with male patient before initiating therapy. In cases of cough and dyspnea under treatment, pulmonary toxicity and alveolitis should be ruled out.

A. Todorova et al.

Apremilast Apremilast is a small molecule that selectively inhibits the activity of phosphodiesterase 4 (PDE4), which showed efficacy in treating patients with atopic eczema. Currently, there is an ongoing phase II trial investigation of the efficacy and safety of Apremilast in nummular eczema (clinicaltrials.gov). Dupilumab Dupilumab is a monoclonal antibody against interleukin receptors IL-4 and IL-13, which has been recently implemented for the treatment of severe and refractory atopic eczema. Significant improvement of the clinical manifestation and quality of life in patients with atopy and nummular lesions has been reported under therapy with dupilumab (Patruno et al. 2020). Currently, there is an ongoing phase II trial investigation of the efficacy and safety of Dupilumab in nummular eczema (clinicaltrials.gov). Phototherapy (PT) Phototherapy is used for its immunomodulatory and anti-inflammatory effects as whole body irradiation alone (UVA; 320–400 nm) or in combination with photosensitizing substances (psoralen UVA / PUVA) or with tar preparations (UVB; 280–320  nm). According to irradiation type and minimal erythema dosis (MED) of the patient, procedures are performed three to five times per week over 3–4 weeks. Purpose of treatment is to maintain discrete erythema in order to achieve therapeutic effect (Fig.  65.6). According to this

Fig. 65.6  Nummular eczema after UVB phototherapy. (Courtesy of Derma am Biederstein, 2022, All Rights Reserved)

65  Nummular Eczema: An Update

reaction, UVB irradiation dosis is increased on a daily basis with 15–30%, beginning with the 80% of the personal MED (25–70 mJ/cm2). PUVA therapy starts usually with initial dosis 0.5–1.0 J/cm2. Phototherapy should only be performed in patients without increased photosensitivity. Medications causing phototoxicity (diuretics, Tetracyclines, Quinolones, herbs) should be withdrawn over the treatment duration. Patients should wear protective glasses and cover the face and genitalia during irradiation. Other side effects are acute dermatitis (overexposure), skin aging, and higher long-term risk for skin cancer. Phototherapy should not be performed more often than twice over several years. Systemic Treatment at a Glance

–– Systemic treatment should be applied in severe and recurrent eczema. –– Therapy of first choice is systemic corticosteroids in combination with broad-­ spectrum antibiotics. –– Combination with phototherapy is effective in disseminated eczema. –– Systemic immunosuppressive agents as CyA and MTX can be reconsidered in refractory cases to achieve remission. Immunosuppressive therapy should be performed over limited duration under regular laboratory checkups. –– Novel therapeutic prospects include Apremilast and Dupilumab.

Complementary Treatments Psychosomatic Counselling As in many cases with chronic recurrent disease, significant impairment of quality of life has been reported in patients with nummular eczema. Severe pruritus seems to have essential impact on the limitations in patient’s daily activities and social interactions. Psychological and psychosomatic techniques as behavioral therapy and autogenic training have shown significant supportive effect in controlling the itch-scratch behavior and eventually in improvement of the skin condition.

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Prognosis Chronic disease with relapsing and refractory course.

References Bruno MC, Vilela MA, Oliveira CA. Study on dermatoses and their prevalence in groups of confirmed alcoholic individuals in comparison to a non-alcoholic group of individuals. An Bras Dermatol. 2013;88(3): 368–75. Iwahira Y, Nagasao T, Shimizu Y, Kuwata K, Tanaka Y.  Nummular eczema of breast: a potential dermatologic complication after mastectomy and subsequent breast reconstruction. Plast Surg Int. 2015;2015:209458. Jiamton S, Tangjaturonrusamee C, Kulthanan. Clinical features and aggravating factors in nummular eczema in Thais. Asian Pac J Allergy Immunol. 2012;31:36–42. Julián-Gónzalez RE, Orozco-Covarrubias L, Durán-­ McKinster C, Palacios-Lopez C, Ruiz-Maldonado R, Sáez-de-Ocariz M.  Less common clinical manifestations of atopic dermatitis: prevalence by age. Pediatr Dermatol. 2012;29(5):580–3. Misery L, Bodere C, Genestet S, Zagnoli F, Marcorelles P.  Small-fibre neuropathies and skin: news and perspectives for dermatologists. Eur J Dermatol. 2014;24(2):147–53. Patruno C, Stingeni L, Hansel K, Ferrucci SM, Tavecchio S, Fabbrocini G, Nisticò SP, Foti C, De Prezzo S, Napolitano M.  Effectiveness of dupilumab for the treatment of nummular eczema phenotype of atopic dermatitis in adults. Dermatol Ther. 2020;33:e13290. Rzepecki AK, Wang J, Urman A, Amin B, McLellan B. Nummular eczema of the breast following surgery and reconstruction in breast cancer patients. Acta Oncol. 2018;57(11):1586–8. Suh KS, Park JB, Yang MH, Choi SY, Hwangbo H, Jang MS.  Diagnostic usefulness of dermoscopy in differentiating lichen aureus from nummular eczema. J Dermatol. 2017;44(5):533–7.

Further Reading Basler RS, Lynch PJ. Can you recognize and treat mycosis fungoides? Geriatrics. 1978;33(11):55–62. Belknap BS, Dobson RL. Efficacy of halcinonide cream, 0.1 percent, in the treatment of moderate and severe dermatoses. Cutis. 1981;27(4):433–5. Bettoli V, Tosti A, Varotti C.  Nummular eczema during isotretinoin treatment. J Am Acad Dermatol. 1987;16(3 Pt 1):617.

720 Blum G, Yawalkar SJ.  Evaluation of halometasone cream in the treatment of paediatric patients with acute eczematous dermatoses. J Int Med Res. 1983;11(Suppl. 1):8–12. Bonamonte D, Foti C, Vestita M, Ranieri LD, Angelini G.  Nummular eczema and contact allergy: a retrospective study. Dermatitis. 2012;23(4): 153–7. Bos JD, van Garderen ID, Krieg SR, Poulter LW. Different in situ distribution patterns of dendritic cells having Langerhans (T6+) and interdigitating (RFD1+) cell immunophenotype in psoriasis, atopic dermatitis, and other inflammatory dermatoses. J Invest Dermatol. 1986;87(3):358–61. Burgdorf WHC, Plewig G, Wolff HH, Landthaler M, editors. Braun-Falco’s dermatology. 3rd ed. Berlin: Springer; 2009. Herz G, Yawalkar SJ, Weirich EG. Evaluation of halometasone ointment in the treatment of paediatric patients with chronic eczematous dermatoses. J Interferon Res. 1983;11(Suppl. 1):21–5. Hornstein OP.  Remarks and recommendations on the definition and classification of eczematous diseases. Z Hautkr. 1986;61(18):1281–96. Jansen T, Küppers U, Plewig G.  Sulzberger-Garbe exudative discoid and lichenoid chronic dermatosis (“Oid-Oid disease”)—reality or fiction? Hautarzt. 1992;43(7):426–31. Kim WJ, Ko HC, Kim MB, Kim DW, Kim JM, Kim BS.  Features of Staphylococcus aureus colonization in patients with nummular eczema. Br J Dermatol. 2013;168(3):658–60. Knöpfel N, Noguera-Morel L, Hernández-Martín A, Torrelo A.  Methotrexate for severe nummular eczema in children: efficacy and tolerability in a retrospective study of 28 patients. Pediatr Dermatol. 2018;35(5):611–5. Lange L, Rietschel E, Hunzelmann N, Hartmann K.  Elevated levels of tryptase in children with nummular eczema. Allergy. 2008;63:941–50. Moore MM, Elpern DJ, Carter DJ.  Severe, generalized nummular eczema secondary to interferon alfa-2b plus ribavirin combination therapy in a patient with chronic hepatitis C virus infection. Arch Dermatol. 2004;140:215–7. Noren P, Melin L. The effect of combined topical steroid and habit reversal treatment in patients with atopic dermatitis. Br J Dermatol. 1989;121:359–66.

A. Todorova et al. Paek SY, Koriakos A, Saxton-Daniels S, Pandya AG. Skin diseases in rural Yucatan, Mexico. Int J Dermatol. 2012;51(7):823–8. Parish WE, Welbourn E, Champion RH. Hypersensitivity to bacteria in eczema. IV. Cytotoxic effect of antibacterial anibody on skin cells acquiring bacterial antigens. Br J Dermatol. 1976;95:493–506. Pavithran K. Non-pruritic eczems as presenting manifestation of leprosy. Indian J Lepr. 1990;62(2):202–7. Ring J, Przybilla B, Ruzicka T, editors. Handbook of atopic eczema. 2nd ed. Berlin: Springer; 2005. Ring J, Alomar A, Bieber T, Deleuran M, Fink-Wagner A, Gelmetti C, et  al. Guidelines for treatment of atopic eczema (atopic dermatitis) part I. J Eur Acad Dermatol Venereol. 2012a;26(8):1045–60. Ring J, Alomar A, Bieber T, Deleuran M, Fink-Wagner A, Gelmetti C, et  al. Guidelines for treatment of atopic eczema (atopic dermatitis) part II. J Eur Acad Dermatol Venereol. 2012b;26(9):1176–93. Roberts H, Orchard D. Methotrexate is a safe and effective treatment for paediatric discoid (nummular) eczema: a case series of 25 children. Australas J Dermatol. 2010;51(2):128–30. Satoh T, Takayama K, Sawada Y, Yokozeki H, Nishioka K. Chronic nodular prurigo associated with nummular eczema: possible involvement of odontogenic infection. Acta Derm Venereol. 2003;83:376–7. Schuster B, Ziehfreund S, Albrecht H, Spinner CD, Biedermann T, Peifer C, Zink A.  Happiness in dermatology: a holistic evaluation of the mental burden of skin diseases. J Eur Acad Dermatol Venereol. 2019;34:1331. Silverberg NB. Typical and atypical clinical appearance of atopic dermatitis. Clin Dermatol. 2017;35(4):354–9. Veien NK, Hattel T, Justesen O, Nørholm A. Diagnostic procedures for eczema patients. Contact Dermatitis. 1987;17(1):35–40. Volden G. Successful treatment of therapy-resistant atopic dermatitis with clobetasol propionate and a hydrocolloid occlusive dressing. Acta Derm Venereol Suppl (Stockh). 1992;176:126–8. Yawalkar SJ, Macarol V, Maontanari C. An overview of international clinical trials with halometasone cream. J Int Med Res. 1983a;11(Suppl. 1):1–7. Yawalkar SJ, Macarol V, Maontanari C. An overview of international clinical trials with halometasone ointment in chronic eczematous dermatoses. J Int Med Res. 1983b;11(Suppl. 1):13–20.

Onychomycosis

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Dimitris Rigopoulos and Stamatis Gregoriou

Key Points • Onychomycosis is the most common nail disorder and has a severe impact on health-related quality of life. • Onychomycosis is caused by dermatophytes, yeasts, and non-dermatophyte molds and is more common in immunosuppressed and patients with nail trauma. • There are five major clinical presentations of onychomycosis: distal and lateral subungual onychomycosis (DLSO), proximal subungual onychomycosis (PSO), superficial white onychomycosis (SWO), endonyx, and total dystrophic onychomycosis (TDO). • Topical treatment is recommended for restricted disease. The most effective agents are 8% ciclopirox and 5% amorolfine nail lacquers. • Systemic treatment is recommended in extensive disease. Terbinafine is more effective in dermatophyte infections. • Treatment through the use of devices includes lasers and photodynamic therapy, but more evidence-based data are needed to obtain strong recommendation.

D. Rigopoulos (*) · S. Gregoriou 1nd Department of Dermatology, University of Athens Medical School, Andreas Sygros Hospital, Athens, Greece e-mail: [email protected]

• Chemical or surgical nail avulsion should not be used as monotherapy but rather in combination with topical or systemic treatment. • Treatment of choice should be individualized and should take into account the type of fungi isolated through direct microscopy and culture, the age of the patient, and concomitant use of other systemic medications.

Definition Onychomycosis is the most common nail disorder. Even though some consider it just a cosmetic problem, hand nail onychomycosis may lead to pain, discomfort, and impaired tactile functions, while toenail dystrophy can impair walking and exercise. Onychomycosis has significant impact on health-related quality of life with both emotional and social function affected in patients with onychomycosis (Belyayeva et al. 2013).

Epidemiology Onychomycosis affects up to 6% of the population and represents 20–40% of all nail disorders (Baran et  al. 2006). Onychomycosis is more common in aged populations and patients with HIV infection or under immunosuppressive therapy. Activities predisposing to onychomycosis include sports participation, swimming in swim-

© Springer Nature Switzerland AG 2023 A. D. Katsambas et al. (eds.), European Handbook of Dermatological Treatments, https://doi.org/10.1007/978-3-031-15130-9_66

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ming pools, and occlusive footwear. Toe nails are more frequently affected than fingernails probably due to slower growth rate. Other predisposing factors include nail trauma, peripheral vascular disease, smoking, and psoriasis (Sehgal et  al. 2010). Epidemiology of fungi causing onychomycosis varies according to geography. Dermatophytes are the most frequently implicated causative agents in onychomycosis (approximately 90% in toenail and 50% in fingernail). Trichophyton rubrum (T. rubrum) is the most common causative agent followed by T. mentagrophytes. Non-dermatophyte molds (NDMs) mainly affect the toenails and occasionally fingernails and include Scytalidium dimidiatum and Scytalidium hyalinum, Scopulariopsis brevicaulis, Aspergillus species, Onychocola canadensis, and Acremonium species (Singal and Khanna 2011). Molds are considered pathogens when the following criteria are fulfilled: 1. Nail features consistent with onychomycosis 2. Positive direct microscopy 3. Failure to isolate a dermatophyte in the culture 4. Growth of more than five colonies of the same mold in at least two consecutive nail samplings (Tosti et al. 2000) Yeasts can be either contaminants or pathogens in fingernail infections. Candida albicans accounts for 70% of cases, while C. parapsilosis, C. tropicalis, and C. krusei can also be isolated. Chronic exposure to moisture and chemicals, as seen in laundry workers, house and office cleaners, food handlers, cooks, dishwashers, bartenders, chefs, fishmongers, confectioners, nurses, and swimmers, contributes to chronic paronychia accompanied by Candida onychomycosis (Rigopoulos et al. 2008).

D. Rigopoulos and S. Gregoriou

• Superficial white onychomycosis (SWO) • Endonyx • Total dystrophic onychomycosis (TDO) DLSO is the commonest clinical variant affecting both fingernails and toenails. The fungus enters via the distal subungual and lateral nail groove and spreads proximally. Clinically, there is onycholysis and subungual hyperkeratosis. PSO is uncommon and often associated with immunosuppression. It affects both fingernails and toenails. The fungus first invades the proximal nail fold, migrates to the underlying matrix, and then spreads distally under the nail plate. Clinically, there is subungual hyperkeratosis, transverse leukonychia, and proximal onycholysis and eventually destruction of the proximal nail plate. SWO affects mostly the toenails. Clinically, small opaque white spots of leukonychia are present on the dorsal nail plates. Baran et al. have proposed a classification of SWO as classical SWO, dual invasion of the nail plate, superficial and ventral, and the pseudo-SWO with deep fungal invasion of the nail plate (Baran et al. 2004). In endonyx onychomycosis, the infection starts from the free edge, and the fungus penetrates the distal nail keratin of the nail plate where it forms milky white patches without subungual hyperkeratosis or onycholysis (Figs. 66.1 and 66.2). In TDO, there is total destruction of the nail plate where the nail crumbles and disappears leaving a thickened abnormal nail bed. Candida may cause onycholysis with distal subungual hyperkeratosis with a yellowish gray mass that lifts off the nail plate.

Clinical Presentation There are five major clinical presentations of onychomycosis: • Distal and lateral subungual onychomycosis (DLSO) • Proximal subungual onychomycosis (PSO)

Fig. 66.1 Dermatophytoma

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66 Onychomycosis

Table 66.1  Time needed to discontinue medication in order to obtain a nail sample for a credible direct microscopy and culture Drug Topical agent Itraconazole Terbinafine Fluconazole

Fig. 66.2 Endonyx

Diagnosis Identification of the pathogen before initiating treatment is important in order to select the appropriate therapeutic agent. Samples should be obtained from affected nails. The patient should have discontinued topical and systemic antifungal drugs for an appropriate duration (Table 66.1). The nail should be thoroughly cleaned with alcohol, the onycholytic nail plate should be clipped, and then scrapings should be obtained from the nail bed. Subsequently, direct microscopy of the specimen in 10–30% KOH should be performed. The nail is examined for fungal hyphae, spore, or yeast forms. Culture confirms the diagnosis and identifies the fungus. Specimens should be sent for culture even when direct microscopy is negative. Different media are used to grow different fungal species. Colonies of most dermatophytes are usually completely differentiated in 2  weeks. ­ Absence of growth after 3–6  weeks should be

4 weeks 9 months 8 weeks 1 week

considered as negative. False-negative results may be attributed to inappropriate nail sampling (Singal and Khanna 2011). Histopathology may be necessary when direct microscopy and culture are repeatedly negative in patients with clinical signs of onychomycosis. Nail plate clippings are stained with periodic acid–Schiff (PAS) staining to evaluate the presence or absence of fungi. Other less frequently used tests to diagnose onychomycosis include immunohistochemistry and dual flow cytometry especially for identifying mixed infections and for quantification of fungal load in the nail. DNA-based methods such as PCR-RFLP assays have been used recently for detecting fungi (Bontems et al. 2009). The role of scanning electron microscopy and confocal microscopy at present is primarily for research.

General Principles of Treatment Treatment options for onychomycosis include topical agents, systemic agents, chemical or surgical nail avulsion, and devices such as lasers and photodynamic therapy.

Topical Treatments Topical agents are the mainstay of onychomycosis treatment. A recent study with 1447 patients with onychomycosis showed that 89.1% were prescribed a topical agent either as monotherapy or in addition to other treatment (Di Chiacchio et  al. 2013). The 2005 consensus on treatment guidelines for onychomycosis suggests topical treatment if: (a) Nail surface involvement is less than 50%. (b) Number of nails involved are less than 5.

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(c) Nail matrix is not affected. (d) There is a contraindication for systemic treatment. In addition, topical treatment can be used as adjuvant to systemic treatment and nail avulsion or as prophylaxis after systemic treatment. Immunosuppressed patients or patients with nail thickness more than 2 mm should be considered for systemic treatment regardless of other factors (Lecha et al. 2005). Permeation of nail plate by water-soluble or lipophilic vehicles is poor. Nail plate shows a radically different biochemistry from the skin consisting of 15% water and less than 5% lipids (van de Kerkhof et al. 2005). Bovine hoofs often used as in vitro models for evaluating nail permeation have been reported to have 14-fold more permeation when compared to human nails (Monti et al. 2011). An ideal topical agent should be able to exhibit prolonged presence on the nail plate after application and increased concentration on the nail plate after evaporation of the vehicle. Treatment outcomes are also dependent on compliance, which is known to be compromised for prolonged therapies. A study on compliance of patients using topical agents for onychomycosis reported an overall compliance of 23.9%. Successful treatment was observed in 63% of patients with adequate compliance; on the other hand, only 2% of patients with poor response achieved complete remission of onychomycosis (Zhou et al. 2011).

 iclopirox 8% Lacquer C Ciclopirox is a synthetic hydroxypyridone antifungal agent. Glucuronidation is the main metabolic pathway of ciclopirox; therefore, it does not normally interact with drugs metabolized via the cytochrome P450. Ciclopirox does not interfere with ergosterol biosynthesis. It chelates trivalent cations, inhibits metal-dependent enzymes that are responsible for degradation of toxic metabolites in the fungal cells, and targets metabolic and energyproducing processes in microbial cells. Ciclopirox is a broad-spectrum antimicrobial that includes dermatophytes, yeasts, and non-­ dermatophyte molds. It is also effective against some Gram-

D. Rigopoulos and S. Gregoriou

positive and Gram-negative bacteria including resistant strains of Staphylococcus aureus. After evaporation of volatile solvents in the lacquer, the concentration of ciclopirox in the remaining lacquer film reaches approximately 35%, providing a high concentration gradient for penetration into the nail. It achieves fungicidal concentrations inside the nail plate for most pathogens. Although ciclopirox readily penetrates the nails, very low levels of ciclopirox are recoverable systemically, even after chronic use. This unique and multilevel mechanism of action provides a very low potential for the development of resistance in pathogenic fungi, with cases of resistance rarely reported (Subissi et al. 2010). Mycological cure rates after daily application for 48  weeks (negative culture and negative light microscopy) have been reported to range between 29% and 85.7%, while complete cure rate (clinical cure plus mycological cure) has been reported to range between 5.5% and 8.5%. The most common adverse event is the appearance of mild erythema in 5% of the treated population (Gupta et al. 2000).

 morolfine 5% Lacquer A Amorolfine is a structurally unique, topically active antifungal agent that belongs to morpholines. It inhibits ergosterol biosynthesis, modifies fungal cellular membrane permeation, and inhibits fungal metabolic pathways. It possesses both fungistatic and fungicidal activity in  vitro. Its spectrum of in  vitro activity includes dermatophyte, dimorphic, some dematiaceous and filamentous fungi, and some yeasts. The amorolfine concentration in the nail plate following application of 5% nail lacquer is 25%. In clinical trials, application of amorolfine 5% nail lacquer once or twice weekly for up to 6 months produced mycological and clinical cure in approximately 40–55% of patients with mild onychomycosis 3  months after cessation of therapy (Banerjee et al. 2011).  ioconazole 28% Nail Solution T Tioconazole is an imidazole antifungal agent. Percutaneous absorption of tioconazole is negligible suggesting that it is unlikely to produce systemic side effects. It has been shown to have a broad spectrum of activity in vitro against derma-

66 Onychomycosis

tophytes and yeasts, as well as against some chlamydia, trichomonads, and Gram-positive bacteria. It inhibits ergosterol synthesis and additionally has a toxic effect on fungal cellular membrane (Sobue and Sekiguchi 2004). Complete cure rate after twice daily application of tioconazole 28% nail solution for 48  weeks has been reported to be 22% (Hay et al. 1985).

Miconazole 2% Tincture There are scarce data in medical literature about the efficacy of miconazole 2% tincture on the treatment of onychomycosis. The tincture leaves a brownish hue on the nail after multiple applications. A study reported 13 dropouts out of 23 patients using miconazole treatment. At least partial response was observed in 80% after application for 32 weeks (Bentley-Phillips 1982). Nail Avulsion Nail avulsion can be performed either surgically or chemically. Application of urea 40% formulation followed by ketoconazole, oxiconazole, or bifonazole cream results in 50–75% mycological cure after 12 weeks (Grover et al. 2007; Tsuboi et  al. 1998). Removal of the nail by itself has poor or no result in mycological cure (Malay et  al. 2009). Compliance of therapy after nail avulsion could be compromised as all studies report a 50% dropout rate.  opical Agents for Prophylaxis T Topical application of amorolfine for 52  weeks after complete nail cure has been reported to decrease recurrence to 29.2% compared to 50% among those not using prophylactic application after 3 years (Sigurgeirsson et al. 2010).

Systemic Treatments A clinician should always evaluate efficacy, safety, and cost when deciding on systemic treatment options for onychomycosis. Oral therapy is recommended in: 1. Moderate to severe onychomycosis 2. Multiple nail involved

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3. Immunocompromised patients 4. Matrix involvement 5. Failure of previously used topical therapies Oral antifungals used to treat onychomycosis include griseofulvin; azoles including ketoconazole, itraconazole, and fluconazole; and the allylamine terbinafine. Azoles inhibit ergosterol synthesis and increase fungal cell membrane permeability by reducing the activity of various enzymes. Ketoconazole is rarely used nowadays because of risk of severe hepatic side effects. Griseofulvin takes a long time to achieve therapeutical concentration in the nail and persists for just 2 weeks after stopping therapy. Consequently, administration is prolonged (4–9 months for fingernails and 10–18  months for toenails,) and results in poor compliance. Mycological cure rates are low making griseofulvin the least preferred agent. The adult dose is 500  mg to 1  g daily to be administered after a fatty meal (Roberts et al. 2003).

Itraconazole Itraconazole is a triazole with spectrum against dermatophytes, Candida, and NDM. It is highly lipophilic, and bioavailability is increased if received after food intake. Itraconazole gets into the nail through both matrix and nail bed 7 days after starting therapy and remains for up to 6–9 months posttreatment. It achieves high concentrations even in subungual hyperkeratosis (567  ng/g). Itraconazole classical regimen is a dose of 200 mg once daily for 3 months. A pulse regimen with 200  mg twice daily for a week every month with two such pulses for fingernail onychomycosis and three for toenail disease has been reported to be as effective as the continuous regimen (Gupta and Ryder 2003). Drug interaction may potentially occur because of binding of itraconazole to cytochrome P450 3A4 system in the liver. Common adverse reactions include headache and gastrointestinal adverse events. Less common adverse events include asymptomatic liver function abnormalities and hepatitis. Monitoring for hepatic functions is recommended only in patients with preexisting liver disorders or concomitant uptake of hepatotoxic drugs. It is

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contraindicated in patients with congestive cardiac failure due to increased risk of negative ­inotropic effects and in patients receiving H1 and H2 inhibitors because it increases the risk for arrhythmia (Singal and Khanna 2011). Itraconazole is not approved for children less than 12 years old.

Fluconazole Fluconazole does not have an on-label use in the treatment of onychomycosis. However, it is highly effective against both Candida and dermatophytes. It has been detected in nails within 7  days after initial dose and remains for 3–6 months after treatment. Weekly administration is sufficient, and uptake should not necessarily be associated with meals. Dosage in published studies varies between 150 and 450 mg per week for 5–12  months. The common adverse effects include headache, skin rash, gastrointestinal complaints, insomnia, and palpitations. Fluconazole inhibits both CYP3A4 and CYP2C9, and close monitoring is required when prescribing drugs metabolized by these enzymes. Simultaneous use of fluconazole and terfenadine or cisapride is contraindicated (Singal and Khanna 2011). Terbinafine Terbinafine is an allylamine. It inhibits fungal squalene epoxidase, resulting in accumulation of squalene, dysfunction of fungal cell membrane, and death of the fungal cell. In vitro terbinafine is fungicidal against dermatophytes, NDM (Aspergillus fumigatus and Scopulariopsis brevicaulis), and C. parapsilosis and fungistatic against C. albicans. Terbinafine is well absorbed orally with >70% bioavailability. It is detectable in the nail 7–21 days after initial dose and up to 9  months after treatment. Approved continuous treatment consists of 250  mg daily for 6  weeks for fingernail and 12  weeks for toenail onychomycosis. Pulse regimens of terbinafine have also been used with success in the treatment of onychomycosis. Gupta et al. employed two courses of terbinafine (250 mg daily for 4 weeks) alternating with 4 weeks interval without terbinafine and found it to be as effective as continuous ter-

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binafine and more efficacious than pulse itraconazole for treatment of toe nail onychomycosis (Gupta et  al. 2009). Common adverse reactions with terbinafine include gastrointestinal symptoms, skin rash, pruritus, urticaria, asymptomatic liver enzyme abnormalities, and taste disturbances. Severe adverse drug reactions are infrequent and include agranulocytosis, hepatitis, acute generalized exanthematous pustulosis, and lupus erythematosus. Terbinafine is metabolized by cytochrome P450 enzymes, and therefore, concentration is decreased by rifampicin and increased by cimetidine. It decreases cyclosporin levels and inhibits the cytochrome P450 enzyme CYP2D6 responsible for metabolism of tricyclic antidepressants, beta-blockers, selective serotonin reuptake inhibitors, and monoamine oxidase inhibitors type B (Singal and Khanna 2011).

 ead on Comparative Studies H The LION study demonstrated superiority of the continuous terbinafine regimen over intermittent itraconazole regimen in both mycological and clinical cure and lower risk of recurrence (Sigurgeirsson et  al. 1999). A meta-analysis of randomized controlled trials by Gupta et  al. reported mycological cure rates of 73–79% for terbinafine, 56–70% for itraconazole pulse, and 54–64% for pulse itraconazole regimens. The corresponding values for clinical response were as follows: terbinafine 61–71%, pulse itraconazole 59–81%, and continuous itraconazole 65–75% (Gupta et al. 2004).

Device Treatment Device treatment seeks to address some of the unmet needs of onychomycosis therapy such as high rates of relapse, drug adverse events, and fungal resistance. Currently, there are four categories of device-based treatments: laser devices, photodynamic therapy, iontophoresis, and ultrasound.

Lasers Fungi are heat sensitive above 55 °C, so absorption of laser energy is likely to result in fungicidal

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effects. However, heating dermal tissue to temperatures above 40 °C results in pain and n­ ecrosis; therefore, the laser energy format must either be pulsed to allow the dissipation of heat by the tissue through its superior thermal conduction or delivered at a moderate energetic level to prevent tissue damage (Gupta and Simpson 2012). Long-pulse Nd:YAG lasers have been used to treat the nail in a spiral pattern with 30–40 J/cm2 energy fluence with a spot size of 4  mm and a pulse duration of 35 ms. Treatment was repeated after 2  min. Participants received two treatments per session with a 2 min interval, four sessions at 1  week intervals, and they were followed after therapy from 12 to 30+ months. A completely clear nail plate was achieved by 93.5% of participants (Kozarev and Vizintin 2010). Flashlamp pumped short-pulse Nd:YAG 1064 nm lasers have also been reported to be effective in the treatment of onychomycosis. Treatment protocol used was four sessions, at 1  week intervals with a pulse length of 0.3 ms, an energy fluence of 13 J/cm2, and a repetition rate of 6 Hz. Follow-up mycological culture was negative in 95% of patients (Gupta and Simpson 2012). Q-switched lasers emit the highest peak power per pulse of all the Nd:YAG lasers. They have also been reported to have efficacy in the treatment of onychomycosis(Gupta and Simpson 2012). The diode lasers that are currently under investigation for onychomycosis operate at near-infrared wavelengths. Studies have shown that 870 and 930 nm wavelength treatment comprising 4 min of dual-wavelength therapy, followed by 2 min of 930 nm treatment, showed an 85% improvement of infection in 26 toes treated at 180 days (Landsman et al. 2010). However, more evidence-­based data are needed.

cate that the nail plate should be pretreated with urea ointment to soften the nail plate prior to application of the photosensitizer. Treatment length has been reported to be 3–5 h for each session with an irradiation source of 570–670 nm at 36–100 J/cm2 repeated for one to three sessions (Watanabe et  al. 2008; Piraccini et  al. 2008; Sotiriou et al. 2010; Gilaberte et al. 2011).

Photodynamic Therapy 5-Aminolevulinic acid (ALA) and methyl aminolevulinate (MAL) are precursors of heme. They cause a buildup of protoporphyrin IX (PpIX) that, in the presence of the correct spectrum of light, generates reactive oxygen species that initiate apoptosis. Case reports and two case series have reported controversial results regarding efficacy in the treatment of onychomycosis. The protocols developed for these studies indi-

Treatment of onychomycosis in the elderly may include no therapy, mechanical or chemical debridement, topical and oral agents, or combination of these modalities. Debridement is more used more frequently than in younger patients because nail dystrophy is more common because of high prevalence of arthritis problems. Systemic treatment should be used with caution because the risk for drug interactions is increased due to multiple medications received.

Iontophoresis There are two iontophoresis devices currently in clinical trials. Iontophoresis has been reported to increase the amount of terbinafine accumulated in the nail plate. The nail plate then acts as a reservoir of terbinafine that is then released into the nail bed and matrix over 60–70 days. Mycological cure after three sessions of iontophoresis with terbinafine has been reported to reach 84% (Amichai et al. 2010).

Special Populations Children Prevalence of onychomycosis in children is extremely low, possibly because of faster nail growth. Griseofulvin has an on-label use in children in a dosage of 10 mg/kg daily. Terbinafine is approved for use in children above 4 years of age. However, terbinafine, fluconazole, and itraconazole have been used safely with favorable outcome in children aged 2 years and above (Gupta et al. 1998).

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Pregnancy and Lactation Terbinafine is category B drug, while itraconazole and fluconazole are in pregnancy category C.  Use of all these drugs should be avoided in pregnancy. All oral antifungals are excreted in breast milk and therefore contraindicated in lactating mothers.

Future Options Oxaboroles include tavaborole and benzoxaborole and have shown good efficacy against Trichophyton rubrum and Trichophyton mentagrophytes and excellent penetration of the nail plate (Alley et  al. 2007). A lacquer employing 10% eficonazole used once daily for 48  weeks has shown 15–18% complete cure in patients with onychomycosis (Elewski et  al. 2013). A solution of amphotericin B applied for 12 months resulted in 100% mycological cure in eight patients with NDM (Lurati et  al. 2011). Considerable resources have been allocated in the development of new permeation enhancers such transfersomes that release terbinafine and nanoemulsions (Sigurgeirsson and Ghannoum 2012). Systemic treatment with posaconazole has been reported to be as effective as treatment with terbinafine in patients with onychomycosis (Elewski et al. 2012). There are only case reports about the systemic use of voriconazole in the treatment of onychomycosis (Spriet et al. 2012).

References Alley MR, Baker SJ, Beutner KR, Plattner J. Recent progress on the topical therapy of onychomycosis. Expert Opin Investig Drugs. 2007;16:157–67. Amichai B, Nitzan B, Mosckovitz R, et al. Iontophoretic delivery of terbinafine in onychomycosis: a preliminary study. Br J Dermatol. 2010;162:46–50. Banerjee M, Ghosh AK, Basak S, Das KD, Gangopadhyay DN. Comparative evaluation of effectivity and safety of topical amorolfine and clotrimazole in the treatment of tinea corporis. Indian J Dermatol. 2011;56:657–62. Baran R, Hay R, Perrin C.  Superficial white onychomycosis revisited. J Eur Acad Dermatol Venereol. 2004;18:569–71.

D. Rigopoulos and S. Gregoriou Baran R, Hay R, Haneke E, Tosti A, editors. Onychomycosis: the current approach to diagnosis and therapy. London: Informa Healthcare; 2006. Belyayeva E, Gregoriou S, Chalikias J, et al. The impact of nail disorders on quality of life. Eur J Dermatol. 2013;23:366–71. Bentley-Phillips B. The treatment of onychomycosis with miconazole tincture. S Afr Med J. 1982;62(2):57–8. Bontems O, Hauser PM, Monod M. Evaluation of a polymerase chain reaction-restriction fragment length polymorphism assay for dermatophyte and nondermatophyte identification in onychomycosis. Br J Dermatol. 2009;161:791–6. Di Chiacchio N, Suarez MV, Madeira CL, Loureiro WR.  An observational and descriptive study of the epidemiology of and therapeutic approach to onychomycosis in dermatology offices in Brazil. An Bras Dermatol. 2013;88(Suppl 1):3–11. Elewski B, Pollak R, Ashton S, Rich P, Schlessinger J, Tavakkol A.  A randomized, placebo- and active-­ controlled, parallel-group, multicentre, investigator-­ blinded study of four treatment regimens of posaconazole in adults with toenail onychomycosis. Br J Dermatol. 2012;166:389–98. Elewski BE, Rich P, Pollak R, Pariser DM, Watanabe S, Senda H, Ieda C, Smith K, Pillai R, Ramakrishna T, Olin JT.  Efinaconazole 10% solution in the treatment of toenail onychomycosis: two phase III multicenter, randomized, double-blind studies. J Am Acad Dermatol. 2013;68:600–8. Gilaberte Y, Aspiroz C, Martes MP, et  al. Treatment of refractory fingernail onychomycosis caused by nondermatophyte molds with methylaminolevulinate photodynamic therapy. J Am Acad Dermatol. 2011;65:669–71. Grover C, Bansal S, Nanda S, Reddy BS, Kumar V. Combination of surgical avulsion and topical therapy for single nail onychomycosis: a randomized controlled trial. Br J Dermatol. 2007;157:364–8. Gupta AK, Ryder JE. The use of oral antifungal agents to treat onychomycosis. Dermatol Clin. 2003;21:469–79. Gupta A, Simpson F. Device-based therapies for onychomycosis treatment. Skin Therapy Lett. 2012;17:4–9. Gupta AK, Chang P, Del Rosso JQ, Adam P, Hofstader SL. Onychomycosis in children: prevalence and management. Pediatr Dermatol. 1998;15:464–71. Gupta AK, Fleckman P, Baran R. Ciclopirox nail lacquer topical solution 8% in the treatment of toenail onychomycosis. J Am Acad Dermatol. 2000;43:S70–80. Gupta AK, Ryder JE, Johnson AM.  Cumulative meta-­ analysis of systemic antifungal agents for the treatment of onychomycosis. Br J Dermatol. 2004;150:537–44. Gupta AK, Lynch LE, Kogan N, Cooper EA. The use of an intermittent terbinafine regimen for the treatment of dermatophyte toenail onychomycosis. J Eur Acad Dermatol Venereol. 2009;23:256–62. Hay RJ, Mackie RM, Clayton YM. Tioconazole nail solution–an open study of its efficacy in onychomycosis. Clin Exp Dermatol. 1985;10:111–5.

66 Onychomycosis Kozarev J, Vizintin Z.  Novel laser therapy in treatment of onychomycosis. J Laser Health Acad. 2010;1:1–8. Landsman AS, Robbins AH, Angelini PF, et al. Treatment of mild, moderate, and severe onychomycosis using 870- and 930-nm light exposure. J Am Podiatr Med Assoc. 2010;100:166–77. Lecha M, Effendy I, Feuilhade de Chauvin M, Di Chiacchio N, Baran R.  Task force on onychomycosis education. J Eur Acad Dermatol Venereol. 2005;19(Suppl 1):25–33. Lurati M, Baudraz-Rosselet F, Vernez M, Spring P, Bontems O, Fratti M, Monod M. Efficacious treatment of non-dermatophyte mould onychomycosis with topical amphotericin B. Dermatology. 2011;223:289–92. Malay DS, Yi S, Borowsky P, Downey MS, Mlodzienski AJ. Efficacy of debridement alone versus debridement combined with topical antifungal nail lacquer for the treatment of pedal onychomycosis: a randomized, controlled trial. J Ankle Foot Surg. 2009;48:294–308. Monti D, Saccomani L, Chetoni P, Burgalassi S, Tampucci S, Mailland F.  Validation of bovine hoof slices as a model for infected human toenails: in vitro ciclopirox transungual permeation. Br J Dermatol. 2011;165:99–105. Piraccini BM, Rech G, Tosti A. Photodynamic therapy of onychomycosis caused by trichophyton rubrum. J Am Acad Dermatol. 2008;59:S75–6. Rigopoulos D, Larios G, Gregoriou S, Alevizos A. Acute and chronic paronychia. Am Fam Physician. 2008;77:339–46. Roberts DT, Taylor WD, Boyle J, British Association of Dermatologists. Guidelines for treatment of onychomycosis. Br J Dermatol. 2003;148:402–10. Sehgal VN, Srivastava G, Dogra S, Chaudhary A, Adhikari T.  Onychomycosis: an Asian perspective. Skinmed. 2010;8:37–45. Sigurgeirsson B, Ghannoum M.  Therapeutic potential of TDT 067 (terbinafine in Transfersome): a carrier-­ based dosage form of terbinafine for onychomycosis. Expert Opin Investig Drugs. 2012;21:1549–62. Sigurgeirsson B, Billstein S, Rantanen T, Ruzicka T, di Fonzo E, Vermeer BJ, et  al. L.I.O.N. study: efficacy and tolerability of continuous terbinafine (Lamisil) compared to intermittent itraconazole in the treatment of toenail onychomycosis. Lamisil vs. itraconazole in onychomycosis. Br J Dermatol. 1999;141(Suppl 56):5–14.

729 Sigurgeirsson B, Olafsson JH, Steinsson JT, Kerrouche N, Sidou F.  Efficacy of amorolfine nail lacquer for the prophylaxis of onychomycosis over 3 years. J Eur Acad Dermatol Venereol. 2010;24:910–5. Singal A, Khanna D.  Onychomycosis: diagnosis and management. Indian J Dermatol Venereol Leprol. 2011;77:659–72. Sobue S, Sekiguchi K.  Difference in percutaneous absorption and intracutaneous distribution in Guinea pigs among topical antifungal drugs (tioconazole solution, tioconazole cream, miconazole nitrate solution and bifonazole solution). Biol Pharm Bull. 2004;27:1428–32. Sotiriou E, Koussidou-Eremonti T, Chaidemenos G, et al. Photodynamic therapy for distal and lateral subungual toenail onychomycosis caused by trichophyton rubrum: preliminary results of a single-Centre open trial. Acta Derm Venereol. 2010;90:216–7. Spriet I, Lambrecht C, Lagrou K, Verhamme B. Successful eradication of Scytalidium dimidiatum-induced ungual and cutaneous infection with voriconazole. Eur J Dermatol. 2012;22(2):197–9. Subissi A, Monti D, Togni G, Mailland F.  Ciclopirox: recent nonclinical and clinical data relevant to its use as a topical antimycotic agent. Drugs. 2010;70:2133–52. Tosti A, Piraccini BM, Lorenzi S.  Onychomycosis caused by nondermatophytic molds: clinical features and response to treatment of 59 cases. J Am Acad Dermatol. 2000;42:217–24. Tsuboi R, Unno K, Komatsuzaki H, Ogawa H, Kasai T, Oka K, Takiuchi I, Kitamura K, Higashi N, Nakashima Y, Nishimoto K. Topical treatment of onychomycosis by occlusive dressing using bifonazole cream containing 40% urea. Nihon Ishinkin Zasshi. 1998;39:11–6. van de Kerkhof PC, Pasch MC, Scher RK, Kerscher M, Gieler U, Haneke E, Fleckman P.  Brittle nail syndrome: a pathogenesis-based approach with a proposed grading system. J Am Acad Dermatol. 2005; 53:644–51. Watanabe D, Kawamura C, Masuda Y, et  al. Successful treatment of toenail onychomycosis with photodynamic therapy. Arch Dermatol. 2008;144:19–21. Zhou ZL, Zhang JP, Wang XM, Shao Q, Hu JY, Han QD.  Compliance of the patients and related influential factors on the topical antifungal treatment of onychomycosis. Zhonghua Liu Xing Bing Xue Za Zhi. 2011;32:720–3.

Pemphigus Foliaceus and Pemphigus Erythematosus

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Christoph M. Hammers, Enno Schmidt, and Luca Borradori

Key Points • Pemphigus foliaceus and its localized variant pemphigus erythematosus are autoimmune diseases of the skin associated with an autoantibody response against desmoglein 1, a component of desmosomes in human epidermis. • The incidence of pemphigus foliaceus greatly varies in different countries and continents. In South America and North Africa, endemic forms of pemphigus foliaceus exist. • Clinical presentation is characterized by fragile bullae, which rapidly rupture resulting in erosions, crusting, and scaling. Lesions may remain either localized to the seborrheic areas of the face, scalp, back, and chest, may spread to other body sites, or affect the entire body surface. • In patients with pemphigus erythematosus and the sporadic form of pemphigus foliaceus,

C. M. Hammers (*) · E. Schmidt Department of Dermatology, University of Lübeck, Lübeck, Germany Lübeck Institute of Experimental Dermatology (LIED), University of Lübeck, Lübeck, Germany e-mail: [email protected]; [email protected] L. Borradori Department of Dermatology, Bern University Hospital, Bern, Switzerland e-mail: [email protected]

drug-induced triggering should always be considered and excluded. • Management of pemphigus foliaceus does not greatly differ from that of pemphigus vulgaris. Rituximab in combination with systemic corticosteroids represents the mainstay of therapy.

Definition and Epidemiology Pemphigus foliaceus (PF) is a chronic autoimmune blistering disease of the skin, characterized by autoantibodies against a structural component of the epidermal desmosome, desmoglein 1 (Dsg1). Binding of anti-Dsg1 antibodies to the antigen results in subcorneal split formation, dissociation of keratinocytes with loss of cell–cell adhesion (acantholysis) in the superficial epidermis, and clinically, flaccid bullae (Hammers and Stanley 2020). The sporadic form of PF most commonly starts in adulthood, with about equal distribution in both sexes. Its incidence is low, with 0.1–1 new cases per million per year. In contrast, there is an endemic form of PF, which is relatively common in distinct subtropical areas of Brazil and Colombia, where the prevalence of the disease is up to 3–5% in certain remote geographical areas. Endemic PF affects predominantly young women with painful erosions (fogo selvagem, Portuguese for wild fire). Further endemic forms exist in Northern Africa (e.g., Tunisia, Mali,

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Egypt (Kasperkiewicz et al. 2017). Pemphigus erythematosus (PE; syn. Senear–Usher syndrome) is a localized form of PF with lesions typically developing in sun-­exposed areas on the face and the upper trunk and back.

Etiology and Pathophysiology Pemphigus diseases are prototypical examples of autoimmune-mediated diseases (Schmidt et al. 2019, Schmidt and Groves 2016). The mechanisms leading the human immune system to react against normal skin components are far from being understood in detail. In PF, IgG antibodies (abs) against Dsg1 are formed (with involvement of both B and T cells), circulate in the bloodstream, and bind to their target skin antigen. The direct pathogenicity of these antibodies has been shown convincingly in vitro and in vivo. Even as monovalent cloned single-chain variable fragments, these abs can cause loss of cell–cell adhesion in the superficial epidermis where Dsg1 is highly and specifically expressed. Interestingly, B cells from individuals without PF can potentially produce non-pathogenic antibodies against the precursor protein of Dsg1 (preDsg1). Furthermore, ELISA screening of individuals from endemic areas with fogo selvagem frequently detects serum anti-preDsg1 IgG1 antibodies, which are not found in control population cohorts from the USA or Japan. As suggested by this geographical clustering of cases, the transition from non-pathogenic to pathogenic IgG4 abs, which finally bind the mature Dsg1 protein, might be triggered by environmental factors in these typically rural areas. In case of Brazilian fogo selvagem, anti-Dsg1-specific PF sera have been described to cross-react with a salivary antigen transmitted by sand fly (Lutzomyia longipalpis) bites, implying a precipitating role for this vector. When PE was first described by Senear and Usher in 1926, they suggested that the presentation with a lupus-like rash or seborrheic dermatitis was a combination of pemphigus and cutaneous lupus erythematosus (CLE). This hypothesis has been abandoned, as, in most

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cases, serum anti-nuclear abs are absent in PE, and affected patients almost invariably do not meet the classification criteria for systemic lupus erythematosus. The previously described “lupus-­ band” phenomenon in PE patients is rather related to the UV irradiation-induced deposition of complexes of Dsg1 ectodomains and Dsg1-­ specific IgG abs along the epidermal basal membrane zone. These deposits should not to be confused with the immunodeposits detected in patients with cutaneous forms of lupus erythematodes.

 linical Characteristics and Course C of Disease In contrast to pemphigus vulgaris, in PF, lesions are limited to the skin without mucosal lesions (Fig. 67.1). Very rarely though, transitions from PF to pemphigus vulgaris and vice versa have been described. Whereas endemic PF also occurs in children and adolescents, sporadic PF frequently occurs in middle age. The seborrheic areas of the face, scalp, back, and chest are preferentially affected in both forms (Figs. 67.2 and 67.3). Because of

Fig. 67.1 Pemphigus foliaceus, localized disease. Presence of isolated erythematous, scaling lesions on the trunk. Superficial fragile blisters occur leaving eroded areas. Insert with close-up view of some lesions

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Fig. 67.2  Pemphigus foliaceus, localized disease with presence of isolated erythematous and scaling lesions on the scalp, ear, and neck. Based on these features mimicking seborrheic eczema, the condition is also called seborrheic pemphigus

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Fig. 67.4  Pemphigus foliaceus, extensive disease with erythrodermic involvement. Widespread erythematous psoriasiform lesions in a young woman living in North Africa

Erosions heal without scarring and typically result in post-inflammatory hyperpigmentation. In some cases, the exfoliation is widespread and results in erythroderma (Fig. 67.4), a complication commonly seen in fogo selvagem. All erosions are subject to bacterial and viral superinfection, which may lead to either localized or widespread infections including sepsis. Clinical features of PE on the face, back, and trunk may closely resemble those of CLE with erythema and scaling (Fig.  67.4). As patients with PE do not meet the criteria for systemic lupus erythematosus classification, PE should clearly be separated from the rare cases in which PF coincides with CLE.

Fig. 67.3  Pemphigus foliaceus, extensive disease with widespread erythema, erosions, crusts, and scaling of the gluteal region

Drug-Induced Pemphigus Erythematous and Pemphigus Foliaceus

the localization of acantholysis in the upper epidermis, the resulting blisters are very fragile and rapidly rupture (Figs.  67.1 and 67.3). The Nikolsky sign may be positive. In the course of disease, hyperkeratotic, crusting “puff pastry-­ like”, psoriasiform, or seborrheic scales develop.

Association of disease onset with certain drugs is well recognized and should be actively excluded in all patients with PE and PF.  Two groups of drugs have been implicated in potentially causing pemphigus: sulfur-containing drugs (thiol drugs) and drugs not containing sulfur. Penicillamine

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and captopril, both drugs that contain a thiol-­ ELISA values correlate well with the extent group, are the most frequently reported triggers. and activity of the disease. Among the other group, non-sulfhydryl angiotensin-­ converting enzyme inhibitors, pyrDifferential diagnoses of PF and PE include azolone derivatives, penicillin, and rifampicine, have been frequently described. Thiol com- • Pemphigus vulgaris (mucosal lesions always pounds have been particularly implicated in PF present; histopathology with suprabasal triggering. In these cases, pemphigus disease can “tombstone-like” acantholysis, ELISA, or remit spontaneously in up to 50% of cases after indirect IF microscopy for Dsg3-specific antidrug withdrawal. bodies positive) • Drug-triggered bullous eruptions (negative direct IF microscopy, negative Dsg1 ELISA) Diagnosis and Differential • The heterogenous group of intercellular IgA Diagnosis dermatoses (IAD), which include pemphigus forms associated with IgA autoreactivity to Following the European Guidelines for diagnosis either desmogleins and/or desmocollins and treatment of pemphigus, four criteria have to • Bullous impetigo (microbiology) and staphybe considered to confirm the diagnosis (Joly et al. lococcal scalded skin syndrome (negative IF 2020): microscopy/ELISA studies) • Neutrophilic dermatoses (negative IF micros 1. Clinical presentation (see above) copy/ELISA studies) 2. Histopathology; for histopathology a 4  mm-­ • Cutaneous lupus erythematosus (histopatholpunch biopsy should be taken of a fresh small ogy, direct IF microscopy, ACR criteria) vesicle or 1/3 of the peripheral portion of a • Other acantholytic dermatoses (Hailey–Hailey blister and 2/3 perilesional skin. In PF, acandisease, Darier’s disease, Grover’s disease, tholysis at the granular layer is expected, leadhere negative IF microscopy/ELISA studies) ing to subcorneal splitting. 3. Direct immunofluorescence (IF) microscopy of a strictly perilesional skin biopsy; for this Principles of Treatment purpose, a skin biopsy of perilesional skin is taken and analyzed for IgG and/or C3 depos- Therapy aims at induction and maintenance of its in the epidermis. In PE, “lupus-band-like” remission in patients, with reduction of pathodeposits may be noted along the cutaneous logic autoantibodies, and prevention of further basement membrane, in particular in sun-­ blistering, erosion of skin, or other complicaexposed areas. tions, including bacterial and viral infections. 4. Serological detection of serum antibodies that Given the rarity of PF and PE, data from large, label, by indirect IF microscopy studies, the randomized controlled clinical trials (RCTs) are cytoplasmic cell membrane of monkey or sparse, and the recent publication of consensus guinea pig esophagus as substrates. The pattern statements with common definitions and end of indirect IF microscopy on monkey esopha- points will help to conduct future studies. gus is expected to be reticular/“fishnet-­like.” Treatments for pemphigus vulgaris and PF do Alternatively, antibodies against recombinant-­ not differ, although it has been claimed that PF Dsg1 can be easily and reliably detected by and PE are better responsive to therapy. However, ELISA or indirect IF microscopy using trans- there are no robust comparative data supporting fected cells expressing Dsg1. For ELISA, two this idea. In the recent updated European guidecommercial systems are available to test for line for the management of pemphigus (Joly anti-Dsg1 antibodies (EUROIMMUN, Lübeck, 2020), the therapeutic approach depends on the Germany; MBL, Nagoya, Japan). In general, disease severity, that is, presence of mild disease

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(defined as PF with either an involved body surface area of 5%, a PDAI score of >15 and ≤45 for moderate pemphigus, and a PDAI score >45 for severe pemphigus). • For mild PF and pemphigus erythematosus, the recommended first-line therapeutic options include dapsone (e.g., 50–100  mg/day up to 1.5  mg/kg body weight), topical corticosteroids (if there are only very limited lesions), systemic corticosteroid therapy (prednisone 0.5–1.0  mg/kg/day), or rituximab (two infusions of 1 g 2 weeks apart) alone, or associated with topical corticosteroids or oral corticosteroids (prednisone 0,5  mg/kg/day) with a rapid decrease in order to stop corticosteroids after 3 or 4 months. It should be noted that approximately 50% of patients who are given dapsone alone further relapse and secondarily need a systemic treatment. • In case of moderate PF and PE or severe PF, the following first-line therapies are recommended: rituximab (two infusions of 1 g 2 weeks apart) associated with systemic corticosteroids (prednisone 1 mg/kg/day) with a progressive tapering in order to stop corticosteroids after 6  months. These recommendations are based on a randomized control trial with 90 pemphigus patients including 16 patients with PF (Joly et al. 2017; Schmidt 2017 Lancet). In this study, rituximab (day 1, 1 g, day 15, 1 g, month 12, 0.5 g; month 18, 0.5  g) in combination with low-dose prednisolone tapered over 6–12 months was significantly more effective and associated with less severe adverse events compared to standard therapy with prednisolone alone. This study resulted in the licensing of rituximab by EMA and FDA for moderate and severe pemphigus vulgaris but, due to the low number of PF patients in this trial, not for PF. Rituximab may be also administered as a monotherapy or associated with topical corticosteroids in patients with severe contraindications to oral corticosteroids. In case that rituximab is contraindicated or not available, it has been rec-

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ommended to use systemic corticosteroid therapy (e.g., oral prednisone 1 to 1.5  mg/kg/day) alone or associated with an immunosuppressive drug as corticosteroid-­ sparing agent (azathioprine, mycophenolate mofetil, or mycophenolate sodium). Corticosteroid-­sparing agents are either indicated in patients at high risk for side effects related to corticosteroid use or if rituximab is not available. Second-line and third-line therapies in therapy-resistant cases or in case of relapse have been recently reviewed. Besides systemic pharmacologic therapy, additional topical and external therapies have a place and are beneficial in management of the disease. • Intralesional corticosteroid injections for isolated lesions of the skin (such as triamcinolone acetonide) • Topical treatment of lesions with potent corticosteroids (clobetasol proprionate) or calcineurin inhibitors • Antiseptic baths • Covering of erosive lesions with low-adhesive wound dressings or local emollients • Analgesics

 ork-Up, Additional Supportive W Treatments, and Precautions Prior to initiation therapy, the following work-up and serological tests are indicated: complete cell blood count, blood electrolytes, creatinine, liver enzymes, fasting serum glucose (complemented by an oral glucose tolerance test, where applicable). Furthermore, depending on the patient’s comorbidities and proposed treatment, these additional investigations should be considered: Tuberculin skin test and/or interferon-gamma release assay (to prevent reactivation of latent or chronic TB), chest X-ray, serologies for HIV, Hepatitis B and C, testing for serum IgA deficiency (if IVIg is considered), thiopurine methyltransferase (TPMT) activity (if azathioprine is considered), G6PD serum activity (if dapsone is considered), beta-HCG (to exclude pregnancy in females of childbearing age), bone density scan

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(prior to corticosteroid treatment, especially in postmenopausal women), ocular examination (to exclude glaucoma or cataract). Last but not least, in all cases of either flares or treatment-resistant lesions, herpetic infections should be searched and excluded. Prolonged corticosteroid therapy and immunosuppression require additional measures of precaution (see for details, the recommendations of the corresponding guidelines), including: • Prophylaxis of osteoporosis (bone density scans, vitamin D and calcium supplementation) • Ophthalmologic controls • Use of antifungals, antivirals, and/or antibiotics, when clinically indicated. • Prevention of gastric/duodenal ulcers (H2-blockers, proton-pump inhibitors) • Anti-thrombotic prophylaxis, when appropriate • Vaccinations against seasonal influenza, ­tetanus, and pneumococcus (although the protection may be questionable during immunosuppressive therapy) • Support from psychologists, physiotherapists • Use of sunscreens and avoidance of bright sunlight

Follow-Up and Discontinuation of Therapy Due to the potential side effects from therapy and the chronic course of disease, patients should be monitored closely, not for disease control only, but for tolerance to treatment and side effects. Based on the evolution of disease, serological monitoring by Dsg1-ELISA and/or indirect IF should be performed regularly. The discontinuation of therapy is primarily based on the regimen/protocol first used to control the disease and on the clinical presentation and response to therapy with either complete absence of active cutaneous lesions on/off therapy. The recently updated guideline for the management of pemphigus summarize all recently

recommended approaches and molecules to be considered and duration of therapy. For example, in patients with complete remission on/off therapy at month 6 after an initial cycle of rituximab, one should consider an additional infusion of 500 mg or 1 g of rituximab as maintenance therapy. In contrast, in patients without complete remission on/off therapy at month 6, two infusions of 1 g rituximab 2 weeks apart may be recommended. In all patients, negative or low ELISA-Dsg1 values or negative direct IF microscopy findings may represent useful markers to support discontinuation of therapy, but prospective studies are needed to assess their exact role in guiding management.

References Recent Reviews and Outstanding Literature Hammers CM, Stanley JR.  Recent advances in understanding pemphigus and bullous pemphigoid. J Invest Dermatol. 2020;140(4):733–41. Epub 2020/03/24. Joly P, Maho-Vaillant M, Prost-Squarcioni C, Hebert V, Houivet E, Calbo S, et  al. First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial. Lancet. 2017;389(10083):2031–40. Epub 2017/03/28. Joly P, Horvath B, Patsatsi K, Uzun S, Bech R, Beissert S, et  al. Updated S2K guidelines on the management of pemphigus vulgaris and foliaceus Initiated by the European academy of dermatology and venereology (EADV). J Eur Acad Dermatol Venereol. 2020;34:1900. Kasperkiewicz M, Ellebrecht CT, Takahashi H, Yamagami J, Zillikens D, Payne AS, et al. Pemphigus. Nat Rev Dis Primers. 2017;3:17026. Epub 2017/05/12. Schmidt E.  Rituximab as first-line treatment of pemphigus. Lancet. 2017;389(10083):1956–8. Epub 2017/03/28. Schmidt E, Groves R.  Immunobullous diseases. In: Griffith C, Barker J, Chalmers BT, Creamer D, editors. Rook’s textbook of dermatology, part 3, chapter 50, vol. 50. 9th ed. Chichester: Wiley-Blackwell; 2016. p. 1–56. Schmidt E, Kasperkiewicz M, Joly P. Pemphigus. Lancet. 2019;394(10201):882–94. Epub 2019/09/10.

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Further Reading Aoki V, Sousa JX Jr, Diaz LA. Cooperative group on Fogo Selvagem R. pathogenesis of endemic pemphigus foliaceus. Dermatol Clin. 2011;29(3):413–8. viii Bastuji-Garin S, Souissi R, Blum L, Turki H, Nouira R, Jomaa B, et al. Comparative epidemiology of pemphigus in Tunisia and France: unusual incidence of pemphigus foliaceus in young Tunisian women. J Invest Dermatol. 1995;104(2):302–5. Epub 1995/02/01. Brenner S, Bialy-Golan A, Ruocco V.  Drug-induced pemphigus. Clin Dermatol. 1998;16(3):393–7. Epub 1998/06/27. Diaz LA, Prisayanh P, Qaqish B, Temple BR, Aoki V, Hans-Filho G, et al. A Lutzomyia longipalpis salivary protein induces cross-reactive antibodies to pemphigus autoantigen desmoglein-1. J Invest Dermatol. 2020;140:2332. Epub 2020/05/04. Empinotti JC, Aoki V, Filgueira A, Sampaio SA, Rivitti EA, Sanches JA Jr, et al. Clinical and serological follow-­up studies of endemic pemphigus foliaceus (fogo selvagem) in Western Parana, Brazil (2001-2002). Br J Dermatol. 2006;155(2):446–50. Hammers CM, Lunardon L, Schmidt E, Zillikens D. Contemporary management of pemphigus. Expert Opin Orphan Drugs. 2013;1(4):295–314. Epub March 6, 2013. Hertl M, Jedlickova H, Karpati S, Marinovic B, Uzun S, Yayli S, et al. Pemphigus. S2 guideline for diagnosis and treatment. https://www.edf.one/home/Guidelines/ Guidelines.html. Accessed 20 Jul 2020. Hubner F, Recke A, Zillikens D, Linder R, Schmidt E. Prevalence and age distribution of pemphigus and pemphigoid diseases in Germany. J Invest Dermatol. 2016;136(12):2495–8. Epub 2016/07/28. Ishii K, Lin C, Siegel DL, Stanley JR. Isolation of pathogenic monoclonal anti-desmoglein 1 human antibodies by phage display of pemphigus foliaceus autoantibodies. J Invest Dermatol. 2008;128(4):939–48. James KA, Culton DA, Diaz LA.  Diagnosis and clinical features of pemphigus foliaceus. Dermatol Clin. 2011;29(3):405–12, viii.

737 Jelti L, Cordel N, Gillibert A, Lacour JP, Uthurriague C, Doutre MS, et al. Incidence and mortality of pemphigus in France. J Invest Dermatol. 2019;139(2):469– 73. Epub 2018/09/22. Lee YB, Lee JH, Lee SY, Kim JW, Yu DS, Han KD, et al. Incidence and death rate of pemphigus vulgaris and pemphigus foliaceus in Korea: a nationwide, population-based study (2006-2015). J Dermatol. 2018;45:1396. Epub 2018/10/16. Martin LK, Werth V, Villanueva E, Segall J, Murrell DF.  Interventions for pemphigus vulgaris and pemphigus foliaceus. Cochrane Database Syst Rev. 2009;(1):CD006263. Murrell DF, Dick S, Ahmed AR, Amagai M, Barnadas MA, Borradori L, et al. Consensus statement on definitions of disease, end points, and therapeutic response for pemphigus. J Am Acad Dermatol. 2008;58(6):1043–6. Oktarina DA, Poot AM, Kramer D, Diercks GF, Jonkman MF, Pas HH.  The IgG “lupus-band” deposition pattern of pemphigus erythematosus: association with the desmoglein 1 ectodomain as revealed by 3 cases. Arch Dermatol. 2012;148(10):1173–8. Epub 2012/07/18. Qian Y, Jeong JS, Maldonado M, Valenzuela JG, Gomes R, Teixeira C, et al. Cutting edge: Brazilian pemphigus foliaceus anti-desmoglein 1 autoantibodies cross-react with sand fly salivary LJM11 antigen. J Immunol. 2012;189(4):1535–9. Epub 2012/07/17. Schmidt E, Goebeler M, Hertl M, Sardy M, Sitaru C, Eming R, et  al. S2k guideline for the diagnosis of pemphigus vulgaris/foliaceus and bullous pemphigoid. J Dtsch Dermatol Ges. 2015;13(7):713–27. Epub 2015/06/26. Stanley JR, Amagai M. Pemphigus, bullous impetigo, and the staphylococcal scalded-skin syndrome. N Engl J Med. 2006;355(17):1800–10. van Beek N, Zillikens D, Schmidt E. Diagnosis of autoimmune bullous diseases. J Dtsch Dermatol Ges. 2018;16(9):1077–91. Epub 2018/09/05. van Beek N, Kruger S, Fuhrmann T, Lemcke S, Goletz S, Probst C, et al. Multicenter prospective study on multivariant diagnostics of autoimmune bullous dermatoses using the BIOCHIP(TM) technology. J Am Acad Dermatol. 2020;83:1315. Epub 2020/02/01.

Pemphigus Vegetans

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Christoph M. Hammers, Enno Schmidt, and Luca Borradori

Key Points • Pemphigus vegetans is a rare variant of pemphigus vulgaris that is predominantly associated with autoantibodies directed against desmogleins. • Historically, two forms have been differentiated, the Hallopeau type and the Neumann variant. Nevertheless, there are overlaps between these two forms and with pemphigus vulgaris. • Treatment options are essentially based on the guidelines proposed for pemphigus as well as case reports.

Definition Pemphigus vegetans (PVeg) is a rare (7.5 mg/day for >3 months is a risk factor for patients of less than 40 years old and any dose for patients of more than 40 years old (Harman et al. 2017). An osteodensitometry may be done before and following the initiation of treatment, keeping in mind the first 6  months represent the most important loss of bone density. An ophthalmologic evaluation before initiation treatment, and a gastric prophylaxis, may also be needed in any patient receiving long-term CS. Patients should be up-to-date with their vaccination since adjuvant immunosuppressants contraindicate live vaccines, and seasonal influenza, H1N1, tetanus, and pneumococcal vaccines are recommended. Pneumocystis prophylaxis, however, is still a matter of debate after a cohort of 801 patients with blistering diseases showed an incidence of P. jirovecii penumonia of 0.1% despite any prophylaxis (Amber et  al. 2017). If used, the first-line prophylaxis is oral trimethoprim-sulfamethoxzole.

First-Line Treatment Options Corticosteroids

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side effects and deaths. CS induces a rapid therapeutic effect, and healing of skin lesions is achieved after 3–4 weeks of treatment, with the exception of mucosal lesions that tend to heal less rapidly. Some persistent localized erosive lesions may also complicate treatments, and tapering of CS might sometimes be needed despite the persistence of theses few lesions. Following initial treatment, if lesions do not improved within the next 10–15 days, doses should be increased from 0.5 to 0.75–1  mg/kg/day for moderate PV, and adjuvant immunosuppressive therapy should be considered for severe cases, in addition to increasing the dose of CS from 1 mg/ kg/day to 1.5  mg/kg/day, or using intravenous pulse therapy (describe below). Treatment failure is rare with the use of CS, but is defined as not reaching disease control despite 3  weeks of treatment with the equivalent of prednisone 1.5 mg/kg/day. Tapering and Withdrawal of Oral Corticosteroids When disease is well controlled at the end of the consolidation phase, oral CS may be slowly tapered. Several guidelines suggest to decrease prednisone dose by 25% every 2  weeks until 20  mg/day, then by 2.5  mg every week until 10  mg/day (which is a good aim of treatment), and a tapering of 1 mg thereafter. One exception is for patients treated with oral CS in combination with rituximab as a first-line treatment in whom a more rapid tapering over 3  months for moderate pemphigus and 6  months for severe pemphigus has been suggested lately (Joly et al. 2017) (Table 69.3).

Oral Corticosteroids Oral CSs are recommended as first-line agents in the treatment of PV, with prednisone or prednisolone being the most commonly use. They are effective in all stages of diseases. The initial dosage can be adjusted to the disease clinical extent Table 69.3  Systemic corticosteroids tapering regimen with 0.5–1 mg/kg/day for mild and moderate PV for patients receiving rituximab as first-line treatment and 1–1.5 mg/kg/day for severe PV. There is no Moderate to severe Mild pemphigus pemphigus evidence showing the initial CS dosing regimen Month 1 0.5 mg/kg/day 1 mg/kg/day directly influences long-term outcome, and very Month 2 0.3 mg/kg/day 0.75 mg/kg/day few data compare the use of low-dose prednisone Month 3 0.2 mg/kg/day 0.5 mg/kg/day to high-dose regimen, but the use of very high-­ Month 4 ± 0.1 mg/kg/day 0.3 mg/kg/day dose (120–400  mg/day) is not recommended Month 5 – 0.2 mg/kg/day anymore because of the increased risk of severe Month 6 – 0.1 mg/kg/day

752

There is no clear consensus on the attitude toward CSs withdrawal in patients in complete remission on minimal therapy (defined as a dose of prednisone 20 IU/mL at 3 months following the initial cycle of RTX (Mignard et  al. 2020). These specific patients could potentially benefit from additional RTX infusions.

754

RTX may also be combined with other therapeutic options. The concomitant use of IVIg has been shown to induce a long-lasting complete remission with a considerable lower risk of relapse when use as a first-line treatment. Ahmed et al. described a regimen using 10 infusions of RTX with IVIg over 6  months, which led to a long-term CR in 10 patients at the 10-year follow-­up (Ahmed et  al. 2016). Recently, Grando reported a retrospective cohort of 123 PV patients treated with a combination of systemic CS, RTX, IVIg, and minocycline and led to a CR in 100%, with a 12% relapse rate (Grando 2019). RTX has also been used with IA and showed the fastest time to disease control, but was associated with more severe adverse events (reviewed in (Didona et  al. 2019)). These regimens may be useful in severe and/or recalcitrant cases, but comparative studies are lacking. The side effects of RTX are mentioned in Table  69.2, with the most frequent being the infusion-­related reactions, which mostly happen during the first infusions and are generally mild. It can present with pruritus, rash, tachycardia, chest pain, and hypotension. It is recommended to administer paracetamol and diphenhydramine prior to the infusion to reduce the incidence, and CS and anti-histamines may lower the severity of the reaction (Hebert and Joly 2018). Monitoring following the first cycle should include monthly CBC, renal, and liver function tests.

 ther Adjuvants Immunosuppressant O and Treatments Cyclophosphamide CP is recommended as a second-line adjuvant in the treatment of severe or recalcitrant PV because of its less favorable side effects including infertility, risk of bladder carcinoma and hemorrhagic cystitis with long-term exposure. An adequate fluid intake may help prevent the latter. Considering these, treatment duration of maximum 6 months is recommended before switching to another adjuvant or discontinuing treatment. It can be prescribed with CS as a daily oral dose of 1–2  mg/kg/day (usually 75–150  mg/day) and

A. Lemieux and P. Joly

adjusted in case of renal failure or as a monthly IV pulse therapy. The latter is generally used with doses of 500–1000 mg/m2 every 4 weeks in combination with IV infusions or daily oral doses of CS. Few RCTs tried to compared this treatment with conventional MMF and AZA, but no clear superiority in terms of disease control and remission was seen. In general, a limited therapeutic effect is noted, but CP was shown to induce CR in few patients recalcitrant to MMF or AZA (Cummins et  al. 2003; Olszewska et  al. 2007). CP has a better corticosteroid-sparing effect than MMF, but less than AZA (Wang et al. 2015). This treatment is also contraindicated in pregnancy, and monitoring should include a CBC and urinalysis every week for 2–3  months, with a decrease in frequency if stable.

Methotrexate The use of methotrexate in the treatment of PV is only supported by very few retrospective studies with no control groups (Baum et al. 2012; Tran et al. 2013). It now has a limited use as a third-­ line adjuvant at a dose of 7.5–20 mg/week given orally or subcutaneously, in patients in whom other conventional adjuvants are contraindicated or have caused serious side effects. Other Agents Cyclosporine is not recommended in the treatment of PV since a small RCT showed no benefit and more side effects in the group treated with cyclosporine combined with CS, compared to CS alone (Ioannides et al. 2000), in addition to retrospective studies (Olszewska et  al. 2007). Other treatments with very few data except case reports and series, and that should only be considered in cases in which no other mentioned options are available include chlorambucil, dapsone, sulfasalazine, and pentoxifylline, and tetracycline in milder cases.

Interventional Treatments Intravenous Immunoglobulins High-dose IVIg is prescribed as 2 g/kg given over 3–5 days and may be repeated monthly to sustain

69  Pemphigus Vulgaris

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remission. According to international guidelines, this may be a first-line option for initially severe and extensive PV or in patients at risk of infection or could be used as an alternative in the maintenance phase for patients being recalcitrant to firstline adjuvants. In the former, it is combined with systemic CS with or without an additional adjuvant drug. In addition to many case series, its efficacy is also demonstrated in one RCT including PV patients refractory to systemic CS (Amagai et al. 2009) and was the only adjuvant treatment in a meta-analysis to show an increase in the rate of disease control (Atzmony et  al. 2015). IVIg has the advantages of acting quickly, with possible improvement in 8 days, and not being immunosuppressive. They have also been used in pregnancy.

Topical and Intralesionnal Treatments

Immunoadsorption and Plasmapheresis IA is an extracorporeal apheresis that selectively removes the serum IgG with the use of protein A, a staphylococcal wall component, or tryptophan, and leads to a rapid lowering of the circulating aAbs. It can be considered as a second-line treatment in recalcitrant cases and combined with CS and/or adjuvant immunosuppressant. According to some authors, it could also rationally be used in the initial treatment of severe and extensive cases in combination with conventional treatments, although its clear benefit as a first-line treatment in this context has not been demonstrated yet in any RCT. When performed, it is performed over three to four consecutive days to prevent a rebound increase in the circulating aAbs levels and can be repeated every month if needed (Meyersburg et al. 2012). Infections are the main complications of this procedure, and its availability is limited, but it has the advantage over plasmapheresis of not removing clotting factors and plasma proteins, which theoretically lowers the risk of complications. Indeed, plasmapheresis replaces plasma with albumin and fresh-­frozen plasma with the same objective of lowering the circulating aAbs. However, it is nowadays rarely used and recommended in the treatment of PV since a small RCT with 40 patients didn’t demonstrate any benefit, and it has also been shown to cause serious adverse events, including sepsis.

Intralesional Rituximab The use of IL RTX injections has been shown to induce clinical remission in few recalcitrant oral PV (Vinay et  al. 2015). The first three reported patients were treated with two injections of RTX 5  mg/m2 2 weeks apart, with only local pain in one of them as a side effect. It was recently shown to be an equivalent alternative to IL CS (Iraji et al. 2019).

Topical and Intralesional Corticosteroids Mild cases of PV with limited involvement and low levels of circulating anti-Dsg1 and/or anti-­ Dsg3 can sometimes be treated with potent topical CS, usually clobetasol propionate. This approach can be useful in situations where systemic CS are contraindicated and can be combined with rituximab, if needed. Intralesional (IL) CS injections may also be considered in specific cases. Indications include oral lesions, localized PV, refractory lesions, hardly accessible lesions for topical treatment, compliance issues, and particular cases where systemic CS are contraindicated.

Maganement of Oral Lesions A special care should be given for the treatment of oral lesions with the collaboration of dental specialists if needed. Proper dental care is essential with the use of a soft toothbrush and occasional antiseptic mouthwashes such as chlorexidine. Mouthwashes containing CS may also be useful for multiple oral erosions limiting food intake, and topical tacrolimus or cyclosporine has also been used in very few cases. The possibility of HSV infection may be considered in recalcitrant oral erosions (Konda et al. 2019).

Management of Relapses Strategies for the management of relapses are summarized in Fig. 69.1. A relapse is defined as the formation of at least three new lesions in

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Re-increase the dose of systemic CS Systemic CS alone

and/or Start an adjuvant IS (RTX > AZA, MMF)

Re-increase the dose of systemic CS Systemic CS and conventional IS

and/or Increase the dose of adjuvant IS or stop the adjuvant IS and give 2g of RTX

Relapse during the CS tapering

Re-increase the dose of systemic CS and give 2g of RTX as of month 4

Relapse after the CS tapering

An individual evaluation of the case is recommended

Systemic CS and rituximab

Fig. 69.1  Recommended options for management of relapses in patients treated with systemic corticosteroids (CSs) alone, systemic CS and a conventional immunosup-

pressant including azathioprine (AZA) and mycophenolate mofetil (MMF), or systemic CS and rituximab (RTX)

1  month that do not heal spontaneously after 1 wee, or by the sudden worsening of the existing lesions. An increase in the anti-Dsg aAbs serum levels may serve as an indicator of relapse before the advent of any clinical signs. In case of a relapse, the re-increase in the dose of systemic CS is adapted to the severity of the presentation and may vary from the last dose allowing disease control to the initial dose of treatment. Also, patients initially treated with RTX have been shown to be efficiently re-treated with repeated cycles of RTX (Wang et  al. 2015; Heelan et  al. 2014).

have both been used successfully in rare patients resistant to RTX. The use of Bruton’s tyrosine kinase (BTK) inhibitors, such as ibrutinib, and anti-neonatal Fc receptor (FcRn), such as efgartigimod, have also shown promising results in phase 2 clinical trials, and their use in PV will likely be more understand in the next few years (Izumi et  al. 2019). Finally, recently, a chimeric auto-antibody receptor (CAAR) T-cell therapy has been developed to specifically target anti-­ Dsg3 auto-reactive B cells and has shown promising results in preclinical studies.

Innovative Therapies In recent years, novel humanized anti-CD20 monoclonal antibodies have been developed, including veltuzumab and ofatumumab, which

References Ahmed AR, Nguyen T, Kaveri S, Spigelman ZS. First line treatment of pemphigus vulgaris with a novel protocol in patients with contraindications to systemic cortico-

69  Pemphigus Vulgaris steroids and immunosuppressive agents: preliminary retrospective study with a seven year follow-up. Int Immunopharmacol. 2016;34:25–31. Alpsoy E, Akman-Karakas A, Uzun S. Geographic variations in epidemiology of two autoimmune bullous diseases: pemphigus and bullous pemphigoid. Arch Dermatol Res. 2015;307(4):291–8. Amagai M, Ikeda S, Shimizu H, Iizuka H, Hanada K, Aiba S, et al. A randomized double-blind trial of intravenous immunoglobulin for pemphigus. J Am Acad Dermatol. 2009;60(4):595–603. Amber KT, Hertl M. An assessment of treatment history and its association with clinical outcomes and relapse in 155 pemphigus patients with response to a single cycle of rituximab. J Eur Acad Dermatol Venereol. 2015;29(4):777–82. Amber KT, Lamberts A, Solimani F, Agnoletti AF, Didona D, Euverman I, et  al. Determining the incidence of pneumocystis pneumonia in patients with autoimmune blistering diseases not receiving routine prophylaxis. JAMA Dermatol. 2017;153(11):1137–41. Amber KT, Valdebran M, Grando SA.  Non-desmoglein antibodies in patients with Pemphigus vulgaris. Front Immunol. 2018;9:1190. Atzmony L, Hodak E, Leshem YA, Rosenbaum O, Gdalevich M, Anhalt GJ, et  al. The role of adjuvant therapy in pemphigus: a systematic review and meta-­ analysis. J Am Acad Dermatol. 2015;73(2):264–71. Baum S, Greenberger S, Samuelov L, Solomon M, Lyakhovitsky A, Trau H, et  al. Methotrexate is an effective and safe adjuvant therapy for pemphigus vulgaris. Eur J Dermatol. 2012;22(1):83–7. Beissert S, Werfel T, Frieling U, Bohm M, Sticherling M, Stadler R, et al. A comparison of oral methylprednisolone plus azathioprine or mycophenolate mofetil for the treatment of pemphigus. Arch Dermatol. 2006;142(11):1447–54. Chams-Davatchi C, Mortazavizadeh A, Daneshpazhooh M, Davatchi F, Balighi K, Esmaili N, et al. Randomized double blind trial of prednisolone and azathioprine, vs. prednisolone and placebo, in the treatment of pemphigus vulgaris. J Eur Acad Dermatol Venereol. 2013;27(10):1285–92. Chee SN, Murrell DF.  Pemphigus and quality of life. Dermatol Clin. 2011;29(3):521–5, xi-ii. Cianchini G, Lupi F, Masini C, Corona R, Puddu P, De Pita O.  Therapy with rituximab for autoimmune ­pemphigus: results from a single-center observational study on 42 cases with long-term follow-up. J Am Acad Dermatol. 2012;67(4):617–22. Cummins DL, Mimouni D, Anhalt GJ, Nousari CH.  Oral cyclophosphamide for treatment of pemphigus vulgaris and foliaceus. J Am Acad Dermatol. 2003;49(2):276–80. Didona D, Maglie R, Eming R, Hertl M. Pemphigus: current and future therapeutic strategies. Front Immunol. 2019;10:1418. Grando SA.  Retrospective analysis of a single-center clinical experience toward development of curative

757 treatment of 123 pemphigus patients with a long-term follow-up: efficacy and safety of the multidrug protocol combining intravenous immunoglobulin with the cytotoxic immunosuppressor and mitochondrion-­ protecting drugs. Int J Dermatol. 2019;58(1):114–25. Hammers CM, Stanley JR.  Recent advances in understanding pemphigus and bullous pemphigoid. J Invest Dermatol. 2020;140(4):733–41. Harman KE, Brown D, Exton LS, Groves RW, Hampton PJ, Mohd Mustapa MF, et  al. British Association of Dermatologists’ guidelines for the management of pemphigus vulgaris 2017. Br J Dermatol. 2017;177(5):1170–201. Hebert V, Joly P.  Rituximab in pemphigus. Immunotherapy. 2018;10(1):27–37. Hebert V, Boulard C, Houivet E, Duvert Lehembre S, Borradori L, Della Torre R, et al. Large international validation of ABSIS and PDAI Pemphigus severity scores. J Invest Dermatol. 2019;139(1):31–7. Heelan K, Al-Mohammedi F, Smith MJ, Knowles S, Lansang P, Walsh S, et al. Durable remission of pemphigus with a fixed-dose rituximab protocol. JAMA Dermatol. 2014;150(7):703–8. Ingen-Housz-Oro S, Valeyrie-Allanore L, Cosnes A, Ortonne N, Hue S, Paul M, et al. First-line treatment of pemphigus vulgaris with a combination of rituximab and high-potency topical corticosteroids. JAMA Dermatol. 2015;151(2):200–3. Ioannides D, Chrysomallis F, Bystryn JC. Ineffectiveness of cyclosporine as an adjuvant to corticosteroids in the treatment of pemphigus. Arch Dermatol. 2000;136(7):868–72. Iraji F, Danesh F, Faghihi G, Siadat A, Mokhtari F, Talakoob M, et  al. Comparison between the efficacy of intralesional rituximab versus intralesional ­triamcinolone in the treatment refractory Pemphigus vulgaris lesions: a randomized clinical trial. Int Immunopharmacol. 2019;73:94–7. Izumi K, Bieber K, Ludwig RJ.  Current clinical trials in Pemphigus and pemphigoid. Front Immunol. 2019;10:978. Joly P, Maho-Vaillant M, Prost-Squarcioni C, Hebert V, Houivet E, Calbo S, et  al. First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial. Lancet. 2017;389(10083):2031–40. Kanwar AJ, Vinay K, Sawatkar GU, Dogra S, Minz RW, Shear NH, et al. Clinical and immunological outcomes of high- and low-dose rituximab treatments in patients with pemphigus: a randomized, comparative, observer-­ blinded study. Br J Dermatol. 2014;170(6):1341–9. Kasperkiewicz M, Ellebrecht CT, Takahashi H, Yamagami J, Zillikens D, Payne AS, et al. Pemphigus. Nat Rev Dis Primers. 2017;3:17026. Konda D, Chandrashekar L, Dhodapkar R, Ganesh RN, Thappa DM. Clinical markers of herpes simplex virus infection in patients with pemphigus vulgaris. J Am Acad Dermatol. 2019.

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758 Lunardon L, Payne AS.  Inhibitory human antichimeric antibodies to rituximab in a patient with pemphigus. J Allergy Clin Immunol. 2012;130(3):800–3. Meyersburg D, Schmidt E, Kasperkiewicz M, Zillikens D.  Immunoadsorption in dermatology. Ther Apher Dial. 2012;16(4):311–20. Mignard C, Maho-Vaillant M, Golinski ML, Balaye P, Prost-Squarcioni C, Houivet E, et  al. Factors associated with short-term relapse in patients with Pemphigus who receive rituximab as first-line therapy: a post hoc analysis of a randomized clinical trial. JAMA Dermatol. 2020;156:545. Murrell DF, Pena S, Joly P, Marinovic B, Hashimoto T, Diaz LA, et  al. Diagnosis and management of pemphigus: recommendations of an international panel of experts. J Am Acad Dermatol. 2020;82(3):575–85.e1. Olszewska M, Kolacinska-Strasz Z, Sulej J, Labecka H, Cwikla J, Natorska U, et  al. Efficacy and safety of cyclophosphamide, azathioprine, and cyclosporine (ciclosporin) as adjuvant drugs in pemphigus vulgaris. Am J Clin Dermatol. 2007;8(2):85–92. Saschenbrecker S, Karl I, Komorowski L, Probst C, Dahnrich C, Fechner K, et  al. Serological diagnosis of autoimmune bullous skin diseases. Front Immunol. 2019;10:1974. Schaeffeler E, Fischer C, Brockmeier D, Wernet D, Moerike K, Eichelbaum M, et  al. Comprehensive analysis of thiopurine S-methyltransferase phenotype-­ genotype correlation in a large population of German-­ Caucasians and identification of novel TPMT variants. Pharmacogenetics. 2004;14(7):407–17. Schmidt E, Kasperkiewicz M, Joly P. Pemphigus. Lancet. 2019;394(10201):882–94. Spindler V, Eming R, Schmidt E, Amagai M, Grando S, Jonkman MF, et al. Mechanisms causing loss of keratinocyte cohesion in pemphigus. J Invest Dermatol. 2018;138(1):32–7. Sukanjanapong S, Thongtan D, Kanokrungsee S, Suchonwanit P, Chanprapaph K.  A comparison of azathioprine and mycophenolate Mofetil as adjuvant drugs in patients with Pemphigus: a retrospective cohort study. Dermatol Ther. 2020;10(1):179–89.

Tran KD, Wolverton JE, Soter NA.  Methotrexate in the treatment of pemphigus vulgaris: experience in 23 patients. Br J Dermatol. 2013;169(4):916–21. Vinay K, Kanwar AJ, Mittal A, Dogra S, Minz RW, Hashimoto T.  Intralesional rituximab in the treatment of refractory oral Pemphigus vulgaris. JAMA Dermatol. 2015;151(8):878–82. Vodo D, Sarig O, Sprecher E. The genetics of Pemphigus vulgaris. Front Med. 2018;5:226. Wang HH, Liu CW, Li YC, Huang YC. Efficacy of rituximab for pemphigus: a systematic review and meta-­ analysis of different regimens. Acta Derm Venereol. 2015;95(8):928–32. Waschke J, Spindler V.  Desmosomes and extradesmosomal adhesive signaling contacts in pemphigus. Med Res Rev. 2014;34(6):1127–45.

Further Reading Frampton JE. Rituximab: a review in Pemphigus vulgaris. Am J Clin Dermatol. 2020;21(1):149–56. Hertl M, et  al. Pemphigus. S2 Guideline for diagnosis and treatment--guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV). J Eur Acad Dermatol Venereol. 2015;29(3):405–14. Jelti L, et  al. Update of the French recommendations for the management of pemphigus. Ann Dermatol Venereol. 2019;146(4):279–86. Mao X, Payne AS. Seeking approval: present and future therapies for pemphigus vulgaris. Curr Opin Investig Drugs. 2008;9(5):497–504. Martin LK, et  al. Interventions for pemphigus vulgaris and pemphigus foliaceus. Cochrane Database Syst Rev. 2009;1:Cd006263. Schmidt E, et al. S2k guideline for the diagnosis of pemphigus vulgaris/foliaceus and bullous pemphigoid. J Dtsch Dermatol Ges. 2015;13(7):713–27. Zhao CY, Murrell DF. Pemphigus vulgaris: an evidence-­ based treatment update. Drugs. 2015;75(3):271–84.

Drug-Induced Pemphigus

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Nazipha Farah Mahmood, Atheer Al-Haddabi, Dushyanth Gnanappiragasam, Olga Golberg, and Karen Elizabeth Harman

Abbreviations HLA Human leukocyte antigen IL-1 Interleukin-1 TNF-α Tumor necrosis factor alpha

Key Points • Drug-induced pemphigus is a rare variant of pemphigus. • Multiple drugs are reported to induce pemphigus, most commonly thiol drugs. The mechanisms include autoantibody formation and direct acantholysis. • The diagnosis requires an accurate drug history, a skin or mucosal biopsy for histology, and direct immunofluorescence and may be supplemented by serological tests including

N. Farah Mahmood, Atheer Al-Haddabi, and Dushyanth Gnanappiragasam contributed equally to this work.

indirect immunofluorescence and enzyme-­ linked immunosorbent assays. • The clinical, histological, and immunopathological features of drug-induced pemphigus are similar to those of idiopathic disease, and there may be a long latent period between starting a drug trigger and disease onset, making the diagnosis challenging. • Patients in whom the disease persists after removal of the drug require treatment with systemic corticosteroids and/or immunosuppressive therapy, as for idiopathic pemphigus.

Definition and Epidemiology Pemphigus comprises a group of autoimmune bullous diseases characterized by acantholysis (loss of adhesion between keratinocytes) that results in the formation of intraepithelial blisters in the skin and mucous membranes. Drug-­ induced pemphigus (DIP) is a rare but well-­ established type of pemphigus, which was first recognized in the 1950s. Epidemiological data on DIP are very limited. Many triggers are associ-

N. F. Mahmood · A. Al-Haddabi · D. Gnanappiragasam · K. E. Harman (*) University Hospitals of Leicester, Leicester, UK e-mail: [email protected] O. Golberg Mid and South Essex NHS Foundation Trust, Essex, UK © Springer Nature Switzerland AG 2023 A. D. Katsambas et al. (eds.), European Handbook of Dermatological Treatments, https://doi.org/10.1007/978-3-031-15130-9_70

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ated with pemphigus; however, drugs continue to be one of the leading causes (Tavakolpour 2018; Ruocco and Pisani 1982). It is estimated that approximately 10% of cases of pemphigus are drug-related. Pemphigus foliaceus is reported to be the commonest variant of pemphigus associated with drug exposure. DIP affects all races and both sexes and can occur at any age. A number of reports from Israel may suggest an increased incidence of the condition in Ashkenazi Jews (Brenner et al. 1998).

Basic Concepts of Pathogenesis While in the past, most cases of DIP were associated with penicillamine, a variety of other drugs have been implicated in recent decades (see Table  70.1). DIP is thought to be caused by a combination of biochemical interactions and aberrant stimulation of B cells leading to production of IgG autoantibodies (Pile et  al. 2020). Pemphigus-inducing drugs can be broadly divided in two categories: thiol and non-thiol drugs. Thiol drugs contain a sulfhydryl group (-SH) in their chemical structure and are the common-

est cause of DIP. Examples of thiol drugs include penicillamine, enalapril, and captopril. About 7% of patients treated with penicillamine for at least 6 months develop pemphigus, although this drug is rarely used nowadays. The sulfhydryl groups have been speculated to interact with desmogleins, enhancing their antigenicity and leading to autoantibody production. Thiol drugs have also been shown to induce acantholysis in vitro without antibody formation. The potential mechanisms for thiol-induced direct acantholysis include inhibition of enzymes of keratinocyte aggregation, disruption of cell adhesion by thiol– cysteine bonds, and activation of proteolytic enzymes such as plasminogen activators. Non-thiol drugs associated with pemphigus include penicillins, aspirin, rifampicin, levodopa, heroin, cephalosporins, angiotensin II receptor blockers, anticonvulsants, and glibenclamide. Some non-thiol drugs, such as penicillins and piroxicam, have sulfur in their chemical structure, which may be metabolized in vivo to form thiols. These are termed masked thiols, and their mechanism of acantholysis may be similar to thiol drugs. Other non-thiol drugs contain phenol groups, for example, levodopa and rifampicin. Phenol drugs have been postulated to induce

Table 70.1  Drugs implicated in pemphigus Thiol (SH) drugs D-penicillamine Bucillamine Captopril Gold sodium thiomalate Thiopronine Piroxicama Carbimazole Methimazole 5-Thiopyridoxineb Pyritinolb Mercaptopropionylglycine

Non-thiol drugs Phenol drugs Rifampicin Cephalosporinsb Aspirin Levodopa Progesterone Heroin Phenobarbital Pentachlorophenol

Pyrazolone derivatives Oxyphenbutazone Aminopyrine Azapropazone Phenylbutazone Aminophenazone

Miscellaneous drugs Penicillinsa Quinolones Other ACE inhibitors ARBs Phenytoin Carbamazepine NSAIDS Chloroquine/hydroxychloroquine Montelukast Interferon-α, β Nifedipine Propranolol Glibenclamidea Isotretinoin Imiquimod

ACE angiotensin-converting enzyme, ARBs angiotensin II receptor blockers, NSAIDS nonsteroidal anti-inflammatory drugs a Drugs containing sulfur in their molecules (masked thiols) b Both thiol and phenol drugs

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acantholysis by causing release of cytokines lesions may coalesce to cover large areas of the (TNF-α, IL-1) from keratinocytes, which partici- body and occasionally progress to an exfoliative pate in the regulation and synthesis of comple- erythroderma. The cutaneous lesions are often ment and proteases. An active amide group is associated with itching and burning. The mucous also found in the structure of many non-thiol membranes are typically spared. DIP may also drugs, and its role in the pathogenesis of DIP has present as pemphigus erythematosus (PE), which been questioned. is a variant of PF localized to the malar region of Non-thiol drugs are more likely to induce the face and associated with the laboratory feapemphigus via immunological mechanisms. tures of systemic lupus erythematosus. Studies have shown the presence of antibodies to Pemphigus induced by non-thiol drugs tends pemphigus antigens, desmoglein 3 (Dsg3), and to manifest as PV. Most patients develop mucosal desmoglein 1 (Dsg1), in most cases of thiol- and lesions, with painful erosions of the oral cavity non-thiol-induced pemphigus. However, 4–5% being the commonest presenting feature. Other of rheumatoid arthritis patients treated with thiol mucous membranes can be affected, in particular compounds produce antibodies to non-­the conjunctiva, esophagus, and genitalia. conformational epitopes of Dsg1 or Dsg3 with- Cutaneous involvement manifests with flaccid out developing pemphigus, suggesting that such blisters, which soon rupture, producing painful antibodies alone are not sufficient to induce acan- erosions that tend to ooze and bleed. The Nikolsky tholysis (Yamamoto et al. 2010). sign can usually be elicited. Patients with DIP have been found to carry the The prognosis seems to be more favorable in same HLA-DR4 susceptibility alleles that are DIP caused by thiol drugs. For these individuals, thought to predispose to idiopathic pemphigus if they also lack cell surface autoantibodies, the vulgaris (PV). Therefore, perhaps these drugs prognosis is good: withdrawal of the drug results trigger pemphigus in individuals who are geneti- in remission in up to 50% of thiol-induced cases cally susceptible. The clinical onset of DIP is of pemphigus compared with only 15% of highly variable depending on the causative drugs, patients with pemphigus induced by non-thiols. genetic predisposition, and other patient factors This observation led some authors to term thiol(Saito et al. 2018). and non-thiol-related disease “drug-induced” and “drug-triggered” pemphigus, respectively. In patients who do not remit upon drug withdrawal, Clinical Presentation the course and prognosis of DIP are similar to those of idiopathic pemphigus. Those who have DIP usually begins a few weeks to several months cell surface autoantibodies tend to have a chronic after initiation of an offending agent, although course similar to idiopathic PV. the onset of pemphigus after 6 years of anticonMortality rates for DIP are not known; howvulsant therapy has been described (Tang and ever, isolated deaths have been reported. Zhang 2012). The latency period may be much shorter on repeat exposure to the culprit drug. The clinical features of DIP are similar to idio- Diagnosis pathic disease although pruritus is more common. Pemphigus foliaceus (PF) is the most The diagnosis of DIP is challenging because it common pattern of DIP, observed in up to 70% of resembles idiopathic pemphigus, cannot concluthiol-induced cases. It is characterized by multi- sively be distinguished with investigations, and ple, superficial, fragile blisters over the sebor- the latency between drug initiation and disease rheic areas of the body, which easily rupture, onset may be variable. Furthermore, disease may evolving into erythematous, crusted, and scaly persist despite cessation of the suspected agent. erosions and plaques. The scalp, face, and upper In most published reports, the diagnosis of DIP trunk are the common sites of involvement. Skin was based on the history, resolution of disease

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after withdrawal of the drug (with or without treatment), and recurrence/worsening of pemphigus after re-exposure to the same or similar drug. Some authors have also noticed a poor response to standard systemic treatment before stopping the culprit agent. A thorough drug history is therefore crucial for the diagnosis of DIP and should be obtained in all cases of pemphigus. Patient’s medications should be cross checked against a list of those drugs reported to induce pemphigus (Table  70.1), and any potential triggers should be stopped, taking into account that there may be a prolonged latency period between starting the drug and the onset of pemphigus. In addition to a clinical assessment, the diagnosis of DIP always requires laboratory investigations. These must include a lesional skin or mucosal biopsy for histopathology and a biopsy of perilesional skin or mucosa for direct immunofluorescence (DIF). The histological findings in DIP are identical to those in idiopathic disease and correlate with the clinical variant of pemphigus. In drug-induced PF, superficial intraepidermal cleavage is found, with acantholysis beneath the stratum corneum or within the granular layer. In drug-induced PV, there is a suprabasal acantholysis and retention of basal keratinocytes along the basement membrane, known as a “row of tombstones.” Other findings in DIP include a mixed inflammatory infiltrate in the dermis, with possible eosinophil predominance, and eosinophilic spongiosis. DIF demonstrates intercellular epidermal deposition of IgG, with or without C3, in up to 90% of patients with DIP. Serological studies, indirect immunofluorescence (IIF), and enzyme-linked immunosorbent assay (ELISA) are often used to further support the diagnosis of pemphigus. IIF detects circulating antibodies to PF or PV antigens (Dsg1 and Dsg3 respectively), or both, in about 70% of patients with DIP and usually at low titer. DIF and IIF are negative in some patients, particularly in thiol-induced cases. ELISA is a very sensitive and specific test for the diagnosis of pemphigus and may be useful when IF studies are negative. In a small series of DIP, ELISA was positive for Dsg1 or Dsg3 antibodies in all six patients, while DIF and IIF were negative in one and two patients, respectively.

Unfortunately, the distinction between drug-­ induced and idiopathic pemphigus is not possible based on the histological features, nor routine immunopathology. However, novel tests have been proposed as adjuncts in the diagnosis of DIP. One study has shown differences in the pattern of immunostaining with the monoclonal antibody 32-2B, which binds desmogleins 1 and 3 (Maruani et  al. 2008). A normal pattern of immunostaining with 32-2B demonstrated a 70% sensitivity and 84% specificity for the diagnosis of DIP.  In comparison, 84% of idiopathic pemphigus cases showed a patchy pattern of immunostaining with 32-2B.  The normal pattern of immunostaining in DIP was also associated with a better prognosis. Another potential diagnostic tool is the in vitro interferon-gamma release test, performed by culturing lymphocytes of PV patients with and without suspected drugs and considered positive if interferon-gamma secretion is at least 30% higher from lymphocytes cultured with the drug compared with those cultured in medium alone (Goldberg et  al. 2008). This assay was positive in 10 out of 14 patients with suspected DIP and may be useful for identifying culprit drugs in pemphigus patients. However, neither 32-2B immunostaining nor the interferon release assays are widely available and at present represent research tools rather than routine diagnostic tests.

Differential Diagnosis The histopathology and immunopathology usually readily distinguish pemphigus from other diseases, but the differential diagnosis of DIP includes: • • • • • •

All other forms of pemphigus Mucous membrane pemphigoid Bullous pemphigoid Linear IgA disease Subcorneal pustular dermatosis Erythema multiforme and Stevens–Johnson syndrome. • Bullous impetigo and staphylococcal scalded skin syndrome (in children)

70  Drug-Induced Pemphigus

• Lupus erythematosus (subacute, bullous or systemic) • Severe seborrheic dermatitis (for drug-induced PF) • Hailey–Hailey disease • Other causes of mucosal ulceration

General Principles of Treatment The first and crucial step in the treatment of DIP is to identify and stop the offending drug. If the patient is taking any implicated drug, consider stopping it even if there has been a delay between drug initiation and disease onset. This may result in remission in many, but not all, patients and reduced disease severity in others. A rapid decline in circulating anti-desmoglein antibodies, associated with clinical improvement, has been observed after withdrawal of the offending drug (Nagao et al. 2005). Patients in whom the disease persists after cessation of the implicated agent, or those who present with severe disease that requires immediate treatment, should be managed as for pemphigus vulgaris (see Chap. 69 Hammers et  al.; see Chap. 71 Lemieux & Joly et  al.; Harman et  al. 2017; Joly et  al. 2020). However, it is possible that DIP may be easier to manage than pemphigus vulgaris such that a short course of corticosteroids may be sufficient. Prednisolone can be initiated at 0.5  mg/kg/day for mild disease or 1 mg/kg/day for more severe cases. Once there is disease control, when 80% of lesions have healed and there are no new lesions for a minimum of 2 weeks, tapering of corticosteroids should commence with the aim of reaching the lowest dose needed for remission maintenance and ideally tapering to zero. One approach is to reduce the dose of prednisolone by 5–10  mg/day weekly and more slowly below the dose of 20 mg/day. If disease control is not obtained, or if there is relapse upon tapering, DIP can be managed as for pemphigus vulgaris (see Chap. 69 Hammers et al.; see Chap. 71 Lemieux and Joly; Harman et al. 2017; Joly et al. 2020). For refractory disease and patients who cannot tolerate the first-line regimens, therapeutic

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options include cyclophosphamide, intravenous immunoglobulin (IVIG), rituximab, immunoadsorption, and plasmapheresis. Rituximab, a monoclonal antibody against CD20 on B-lymphocytes, has shown efficacy in paraneoplastic pemphigus and severe PV and PF.  Two dosage schedules are used: the lymphoma schedule of 375  mg/m 2 intravenously once weekly for 4  weeks and the rheumatoid arthritis schedule of 1  g IV given on two occasions, 2  weeks apart. Lower doses of rituximab (e.g., two 500 mg infusions 2 weeks apart) may also be effective. In those exhibiting a re-increase of anti-Dsg antibodies at month 18 after their initial disappearance following the initial infusions, additional rituximab infusion as maintenance therapy is required. Moreover, the use of biologics is an area of great importance, the advancement in anti-CD20 drugs, which can potentially be widely used in the future, is an area that requires further research.

References Brenner S, Bialy-Golan A, Ruocco V. Drug-induced pemphigus. Clin Dermatol. 1998;16(3):393–7. Goldberg I, Shirazi I, Brenner S.  In vitro interferon-­ gamma release test in patients with drug-induced pemphigus. Isr Med Assoc J. 2008;10(6):424–7. Harman KE, Brown D, Exton LS, Groves RW, Hampton PJ, Mohd Mustapa MF, Setterfield JF, Yesudian PD.  British Association of Dermatologists’ guidelines for the management of pemphigus vulgaris. Br J Dermatol. 2017;177:1170–201. Joly P, Horvath B, Patsatsi Α, Uzun S, Bech R, et  al. Updated S2K guidelines on the management of pemphigus vulgaris and foliaceus initiated by the european academy of dermatology and venereology (EADV). J Eur Acad Dermatol Venereol. 2020;34:1900–13. Maruani A, Machet MC, Carlotti A, et  al. Immunostaining with antibodies to desmoglein provides the diagnosis of drug-induced pemphigus and allows prediction of outcome. Am J Clin Pathol. 2008;130(3):369–74. Nagao K, Tanikawa A, Yamamoto N, Amagai M. Decline of anti-desmoglein 1 IgG ELISA scores by withdrawal of D-penicillamine in drug-induced pemphigus foliaceus. Clin Exp Dermatol. 2005;30(1):43–5. Pile HD, Yarrarapu SNS, Crane JS.  Drug induced pemphigus. [Updated 2020 Jul 20]. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2020. https://www.ncbi.nlm.nih.gov/ books/NBK499864/

764 Ruocco V, Pisani M. Induced pemphigus. Arch Dermatol Res. 1982;274:123–40. Saito Y, Hayashi S, Yamauchi A, et al. Tracing the origins of active amide group-positive drug-induced pemphigus vulgaris along the silk road: a case report of candesartan-induced pemphigus vulgaris and review of nonthiol drug-induced pemphigus. Int J Dermatol. 2018;57(11):e131–4. Tang X, Zhang X.  Drug-induced pemphigus after six years of treatment with phenytoin and carbamazepine. Int J Dermatol. 2012;51(4):485–6. Tavakolpour S.  Pemphigus trigger factors: special focus on pemphigus vulgaris and pemphigus foliaceus. Arch Dermatol Res. 2018;310(2):95–106. Yamamoto T, Takata-Michigami M, Hisamatsu Y, et al. A prospective analysis of anti-desmoglein antibody profiles in patients with rheumatoid arthritis treated with thiol compounds. J Dermatol Sci. 2010;59(3):170–5.

Further Reading Bae YI, Yun SJ, Lee SC, et  al. Pemphigus foliaceus induced by an angiotensin II receptor blocker. Clin Exp Dermatol. 2008;33(6):721–3. Brenner S, Bialy-Golan A, Anhalt GJ.  Recognition of pemphigus antigens in drug-induced pemphigus vul-

N. F. Mahmood et al. garis and pemphigus foliaceus. J Am Acad Dermatol. 1997;36(6 Pt 1):919–23. Brenner S, Ruocco V, Ruocco E, et al. A possible mechanism for phenol-induced pemphigus. Skinmed. 2006;5(1):25–6. Feng S, Zhou W, Zhang J, Jin P.  Analysis of 6 cases of drug-induced pemphigus. Eur J Dermatol. 2011;21(5):696–9. Goldberg I, Sasson A, Gat A, et  al. Pemphigus vulgaris triggered by glibenclamide and cilazapril. Acta Dermatovenerol Croat. 2005;13(3):153–5. Landau M, Brenner S.  Histopathologic findings in drug-induced pemphigus. Am J Dermatopathol. 1997;19(4):411–4. Marsden RA, Vanhegan RI, Walshe M, et al. Pemphigus foliaceus induced by penicillamine. Br Med J. 1976;2(6049):1423–4. Matzner Y, Erlich HA, Brautbar C.  Identical HLA class II alleles predispose to drug-triggered and idiopathic pemphigus vulgaris. Acta Derm Venereol. 1995;75(1):12–4. Ruocco V, De Angelis E, Lombardi ML.  Drug-induced pemphigus. II.  Pathomechanisms and experimental investigations. Clin Dermatol. 1993;11:507–13. Wolf R, Tamir A, Brenner S.  Drug-induced versus drug-triggered pemphigus. Dermatologica. 1991;182(4):207–10.

Pityriasis Lichenoides Acuta

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Luca Fania and Biagio Didona

Key Points • PLEVA (Pityriasis Lichenoides Et Varioliformis Acuta) is a heterogeneous disease whose cutaneous manifestation varies from cases with mild presentation as papulovescicular or papulo-squamous eruption to forms with multiple ulcero-necrotic lesions associated to high fever, malaise, and intense myalgias. • PLEVA generally is a self-healing process that resolves in a few months. Occasionally, the disease may evolve into pityriasis lichenoides chronica and may persist for years; some cases can progress to mycosis fungoides. • A rare febrile ulcero-necrotic variant, named Febrile Ulcero-necrotic Mucha–Habermann Disease (FUMHD), is a severe form of PLEVA that can last from 1  month to 2  years with recurrent acute episodes. Some cases can have a fatal outcome. • The treatment should be chosen depending on the clinical presentation. • If the patient presents fever, an antibiotic treatment is always useful. Erythromycin is the

L. Fania (*) · B. Didona Department of Dermatology, Istituto Dermopatico dell’Immsacolata-IRCCS, Rome, Italy e-mail: [email protected]; [email protected]

antibiotic of choice in children, while tetracycline is preferable in adults. • Cases with moderate cutaneous lesions, in the absence of fever, could be treated with topical corticosteroids and phototherapy. In adults, NB UVB or PUVA may be preferable. • In the FUMHD, usually associated to severe general condition, in addition to an oral antibiotic, it could be appropriate to prescribe a systemic steroid or methotrexate: the former is indicated in adults and children, while the latter only for adult patients. • Once an attenuation of clinical severity is obtained, it may be appropriate to begin a phototherapy session following the above criteria.

Definition Pityriasis lichenoides (PL) is an uncommon inflammatory skin disease of unknown etiology, generally classified in an acute form, called pityriasis lichenoides et varioliformis acuta (PLEVA) or acute guttate parapsoriasis or Mucha– Habermann disease and a chronic form, named pityriasis lichenoides chronica (PLC) or chronic guttate parapsoriasis. According to clinicopathologic features, however, they are considered as part of a spectrum rather than as single entities. A rare febrile ulcero-necrotic variant (FUMHD) has been described.

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Epidemiology Epidemiologic studies on PL are scarce, and it has been reported that about 20% of PL cases occur in the pediatric age. PLEVA incidence and prevalence are unknown, and racial predisposition or special geographical frequency has not been described. PLEVA has been observed mainly in adolescents and in young adults, less frequently in infancy, and rarely in old age.

be implicated are adenoviruses, Epstein–Barr virus, Toxoplasma gondii, parvovirus B19, and Gram-positive cocci.

Clinical Presentation

PLEVA manifests clinically with 10–50 erythematous, reddish brown, or purpuric macules or ovoid lichenoid papules that are 5–15  mm in diameter (Figs.  71.1, 71.2, 71.3, 71.4). Some papules present a pseudo-vesicular summit with Etiopathogenesis a central necrosis and a hemorrhagic crust. The lesions are distributed symmetrically or asymThe etiology and pathogenesis of PLEVA are not metrically on the trunk, buttocks, and proximal jet clarified. Three major etiopathogenetic extremities, with occasional acral involvement. hypotheses have been suggested: (a) an inflam- Sometimes, lesions may appear on the palmomatory reaction triggered by infectious agents or plantar surface, face, and scalp. Mucosal lesions drugs, (b) an inflammatory response secondary to can present with irregular erythema and superfia T-cell dyscrasia, and (c) an immune complex-­ cial ulcerations in the mucous membrane of the mediated hypersensitivity vasculitis. While con- mouth and on the palate. Generally, PLEVA is a sideration has been given to the possibility of a self-healing process that resolves in a few months, low-grade or self-limited lymphoproliferative but occasionally, the disease may evolve to PLC disorder for the presence of CD30 (Ki-1) cells, lasting for years with a course characterized by associated with large cell lymphoma, the hypoth- remissions and exacerbations. Occasionally, esis of a reaction to an infective organism is headache, malaise, and fever may precede or widely accepted. This hypothesis could be sup- accompany the onset of PLEVA. ported by the elevated incidence in young patients The FUMHD is characterized by a sudden and its self-limited course. Pathogens that could eruption of diffuse coalescent necrotic ulcer-

Figs. 71.1 and 71.2  Clinical presentation of a 30-year-­ old man that showed erythematous and purpuric macules with some ovoid lichenoid papules of 5–15 mm in diameter localized symmetrically on trunk and proximal

extremities (Fig.  1). Higher magnification of the same patient of the lesions localized on the left thigh (Fig. 2). (Photos received by courtesy of Professor Claudio Feliciani)

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Figs. 71.3 and 71.4 Clinical presentation of a 15-year-old man that showed erythematous macules with some ovoid lichenoid papules localized on trunk and extremities (Fig. 3). Higher magnification of the same patient of the lesions localized on the right abdomen region (Fig. 4)

ations associated with systemic manifestations such as high fever, asthenia, malaise, intense myalgia, and neuropsychiatric alterations. The lesions appear large, ulcero-necrotic and could be covered by a black oyster shell-like crust, resembling those of PLC.  Necrotic and ulcerating lesions may residue varioliform scars. This variant of PLEVA can last from 1 month to 2 years with recurrent acute episodes. Fatal cases of this variant have been described.

Diagnosis Histopathologically, PLEVA shares several similar features with PLC, confirming that both belong to a common clinicopathological spectrum. Some authors suggest that the histopatho-

logical distinction between PLEVA and PLC is artificial, and instead, the term PL should be used (Borra et  al. 2018). PLEVA presents histologically a vacuolization of the basal epidermal layer, as an interface dermatitis, with scattered apoptotic keratinocytes, confluent parakeratosis in the horny layer, a mostly superficial inflammatory infiltrate with exocytosis of lymphocytes within the epidermis; sometimes Pautrier microabscesses can be observed. In advanced stages, the epidermis can be invaded by a dense infiltrate, and the necrotic phenomenon is more pronounced. In the dermis, from the dermoepidermal junction until the reticular dermis, a lymphohistiocytic infiltrate with a predominantly perivascular arrangement is present. The vessels are dilated and sometimes occluded and could be surrounded or invaded by leucocytes with possi-

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Clinical features Discrete papules and macules with micaceous scales

Erythematous papules, rapidly evolving into red-brown, or hemorrhagic, or vesicular, or pustular, or necrotic lesions; occasional noduloulcerative lesions; in later phase, possible large plaques or nodules showing slow regression Varicella Small, erythematous macules on the scalp, face, and trunk, rapidly progressing into papules, vesicles, pustules with subsequent central umbilication and crust formation Guttate psoriasis Monomorphic lesions completely covered with stratified scales; bright underlying erythema; Auspitz’s sign positive Gianotti–Crosti Lack of necrosis; acral distribution disease of the lesions Erythema Involvement of mucous membranes; multiforme target lesions Small vessel Ulcero-necrotic papules and some vasculitis hemorrhagic vesicles with mostly acral distribution Rickettsiosis Diffuse necrotic papules associated to systemic signs

ble leukocytoclasis. Several laboratory alterations have been found in PLEVA patients but not relevant for its diagnosis. Direct immunofluorescence has shown vascular deposits of IgM and C3 and perivascular and interstitial deposits of fibrin. Clinical differential diagnosis of PLEVA includes conditions reported in Table 71.1.

General Principles of Treatment PLEVA is a self-healing disease, symptom-free, except sometimes accompanied by a low-grade fever and a mild pruritus. Generally, treatment is not necessary. Therapy is required in more severe forms, such as in the FUMHD. Considering the infectious agent that may be involved in the pathogenesis of PLEVA, an antibiotic treatment could be recommended at the onset of the disease. Although PLEVA presents similar charac-

teristics in adults and children, therapy could vary in the different age of the patients.

Topical Treatments Topical corticosteroids (TCSs) are frequently employed as first-line therapy due to their property to decrease inflammation and pruritus. No controlled studies have compared TCS with other treatments, and some authors did not find an improvement of TCS when used in monotherapy. Tacrolimus, which is a topical calcineurin inhibitor, has been utilized as topical therapy, but data are scarce and limited to case reports. Topical creams containing antiseptics or antibiotics could be utilized in the clinical form with ulcerated lesions.

Systemic Treatments Antihistamines may be utilized in adults and in children affected by PLEVA to relieve the pruritus and for their little influence on the course of the disease. Antibiotics such as tetracycline, erythromycin, and minocycline have been largely utilized, especially in the FUMHD, because infectious agents are possibly responsible of the disease and because of their anti-inflammatory properties. As known, tetracyclines are contraindicated in children, while erythromycin is commonly utilized in this population (Bellinato et al. 2019).

Tetracyclines Tetracyclines are effective even if no infection signs are evident because a possible inhibition of neutrophil chemotaxis is hypothesized. Piamphongsant et al. reported a case series of 13 patients treated with oral tetracycline 2  g daily obtaining a complete remission in 5 patients within 2–4  weeks while seven patients reported partial response and continued with the dosage of 1 g daily for 4 weeks (Piamphongsant 1974). Gritiyarangsan et al. reported a comparative study on 30 patients affected by PL treated with different therapies; 14

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patients were treated with oral tetracycline 1–2 g daily combined with topical triamcinolone cream 0.02–0.1% applied twice daily, and one patient obtained a complete remission, 11 partial responses, and two no responses (Gritiyarangsan et al. 1987). Minocycline and doxycycline can be alternative options at a dosage of 100 mg daily.

Erythromycin Ersoy-Evans et al. reported a retrospective study on 99 pediatric patients affected by PLEVA or PLC treated with oral erythromycin estolate or ethylsuccinate (30–50 mg/kg/day) either alone or in combination with TCS.  The median duration of the disease was 18 months for PLEVA patients and 20  months for PLC patients. The response rate was 66.6% with a median response time of 2 months (Ersoy-Evans et al. 2007). Hapa et al., more recently, reported in a retrospective study on 24 children (15 affected by PLC, 6 by PLEVA, and 3 by an overlap of both diseases) that oral erythromycin, at a dosage of 30–50 mg/kg/day in three to four divided dosages, for 1–4 months, is an effective and well-tolerated therapeutic option (Hapa et  al. 2012). Gelmetti et  al. reported a “moderate efficacy” of 1- or 2-week of oral erythromycin (20–40  mg/kg/day) prescribed in 12 children with PL (PLEVA or PLC) with a disease duration varying from 2  months to 10  years (Gelmetti et  al. 1990). Truhan et  al. reported a retrospective study on 15 children with PL (11 PLEVA and 4 PLC) with a disease duration that varied from 6  weeks to 18  months and treated with oral erythromycin (15–50  mg/kg/day): 11 patients (73%) had a remission, generally in 2 months, two patients had partial improvement, and two were unimproved. One patient had a recurrence 5 months after the suspension of the drug (Truhan et al. 1986).

Azithromycin There are only a few data that are case reports about this therapy. Ogrum et al. reported a complete remission in a 13-year-old boy with an

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overlap PL with 500  mg of azithromycin daily for three consecutive days, every other week, for three cycles (Ogrum et al. 2018).

Other Antibiotics Amoxicillin-clavulanic acid, cephalexin, cefaclor, and ciprofloxacin have been utilized for the treatment of PL in some case reports, generally in the case of erythromycin failure or in the case of gastrointestinal intolerance.

Corticosteroids Oral corticosteroids are utilized because they are able to reduce the intensity of the disease. A short treatment with prednisolone at 0.5  mg/kg daily induces the regression of the general symptoms and could be followed by other treatment such as phototherapy, mainly in patients with severe clinical lesions.

Methotrexate Methotrexate has been utilized generally for recalcitrant or more severe cases of PL and mainly in the FUMHD. Cornelison et al. reported an improvement after 2–6 weeks in six patients affected by a severe and long-lasting PLEVA treated with methotrexate 7.5–20  mg per os, weekly (Cornelison et  al. 1972). Other studies confirmed the efficacy of methotrexate in PLEVA patients, but due to its potential side effects and the tendency of the disease to recur after treatment, they suggest restricting the use of this drug only to selected patients.

Cyclosporine Cyclosporine has been utilized mainly in the FUMHD, while data are scarce for PLEVA.  Lis-­ Swiezty et  al. described an improvement in a 30-year-old woman affected by PLEVA with cyclosporine A 3 mg/kg/day (Lis-Swiezty et al. 2016).

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Pentoxifylline With scarce data and limited case reports, Sauer et al. utilized pentoxifylline 400 mg three times a day in two patients to treat the vasculitis aspect of PL with efficacy (Sauer 1985).

Acyclovir and Valaciclovir Boralevi et  al. reported an open trial on 12 patients affected by PL treated with acyclovir or valaciclovir. Aciclovir was used in patients aged 10 years. Complete remission was reported in two patients, a significant improvement of the cutaneous lesions in six cases, a slight improvement in two cases, and no change in two cases (Boralevi et al. 2003).

Pyrimethamine and Trisulfapyrimidine Zlatkov et al. reported a retrospective review on 11 patients affected by PL treated with pyrimethamine 50 mg daily for 5 days, repeated after an interval of 20  days. Complete remission was described in three patients and partial clearance in other three cases (Zlatkov and Andreev 1972).

Other Systemic Drugs Other drugs such as dapsone and high-dose immunoglobulins have been utilized for the treatment of PLEVA, but the number of cases is small and does not allow a reliable assessment.

Phototherapy Ultraviolet (UV) treatment, able to modulate the skin immune response, has been widely utilized in both PLEVA and PLC patients, but mainly for this latter disease. Besides the heliotherapy, it has been utilized in broadband UVB (BB UVB), narrow-­band UVB (NB UVB), PUVA, and UVA1

phototherapy. All these therapies, excluding PUVA, can be utilized in adults and in children. The exact mechanism of action of UV radiation in the treatment of PLEVA is not known. The therapeutic efficacy could depend on the UV radiation that inhibits the release of some inflammation mediators and, therefore, is able to interfere with lymphocyte infiltrate.

BB UVB Phototherapy Tay et al. described a retrospective study on five children affected by PLEVA and treated with BB UVB phototherapy, and mean total clearance dose of UVB was 4.2  J/cm2. All patients presented a clearance of lesions, needing an average of 26 treatments (range 22–33). Two patients relapsed after 7 and 9 months, respectively (Tay et al. 1996). Gelmetti et al. reported a retrospective study on 89 pediatric patients affected by PL and treated with four/eight courses of BB UVB phototherapy. They described a reduction of symptoms and a control of acute eruption, but the course of the disease was not modified (Gelmetti et al. 1990).

NB UVB Phototherapy NB UVB therapy with TL01 lamps provides further advantages. Pavlotsky et al. reported a retrospective analysis of 29 patients with PL and treated with BB UVB or NB UVB phototherapy. The mean total cumulative dose administered was 3.6 and 15 J/cm2, respectively, with a mean number of treatments of 11 and 9 weeks, respectively. Complete response was seen in 93% of the patients of both groups and relapsing in 27% of the patients of both groups (Pavlotsky et  al. 2006). Aydogan et  al. reported a retrospective analysis in 31 patients affected by PL, 23 PLEVA, and 8 PLC, treated with NB UVB.  Complete response was observed in 15 out of 23 patients affected by PLEVA and in seven out of eight with PLC, with a cumulative dose of 23 and 15.6  J/ cm2, respectively. The mean number of treatments was 32.3 and 19, respectively. They

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reported a partial response in eight patients (34.8%), and relapse occurred in four patients within 6 months (Aydogan et al. 2008).

PUVA Phototherapy Powell and Muller reported three PLEVA patients treated with PUVA therapy, for a period between 3 and 12  months, for a total dose between 189 and 370.5 J/cm2. The duration of the PLEVA varied from 7 to 24  months. The response was between 80% and 100%, and one patient reported a relapse (Powell and Muller 1984).

UVA1 Phototherapy Particularly interesting are the results with the UVA1 radiation. Calzavara Pinton et al. reported eight patients with PLEVA and PLC treated with UVA1 phototherapy. Patients received 60  J/cm2 UVA1, five times weekly, until remission. The mean cumulative dose was 1125 J/cm2. Complete remission was observed in six patients and partial remission in two patients. Relapse was observed in four patients after a mean interval of 7 months (Calzavara Pinton et al. 2002). Therefore, UVA1 therapy was an effective and well-tolerated treatment for PLEVA and PLC. The efficacy seems to be correlated to direct effects on cutaneous inflammatory infiltrates because the lesions in unexposed cutaneous areas did not respond.

Practical Suggestions at Glance PLEVA includes a wide spectrum of clinical manifestations, varying from cases with a few manifestations to forms with high fever, asthenia, malaise, intense myalgias, neuropsychiatric alterations, and multiple ulcero-necrotic lesions. The treatment should be chosen depending on the clinical presentation. Cases with moderate cutaneous lesions, in the absence of fever, could be treated with TCS and phototherapy. In adults, NB UVB or PUVA may be preferable. If the patient presents fever, an antibiotic treatment is

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always useful. Erythromycin is the antibiotic of choice in children, while tetracycline is preferable in adults. Once the fever has disappeared, it is suggested to start phototherapy. In FUMHD, in addition to an oral antibiotic, it could be appropriate to prescribe a systemic steroid or methotrexate. Systemic steroids are indicated in adults and children, while methotrexate only for adult patients. Subsequently to the improvement of the clinical severity, it could be indicated to start the phototherapy. Cutaneous lesions of FUMHD, characterized by large ulcerations, could be treated with topical antibiotic and local wound care.

References Aydogan K, Saricaoglu H, Turan H.  Narrowband UVB (311 nm, TL01) phototherapy for pityriasis lichenoides. Photodermatol Photoimmunol Photomed. 2008;24:128–33. Bellinato F, Maurelli M, Gisondi P, Girolomoni G. A systematic review of treatments for Pityriasis Lichenoides. J Eur Acad Dermatol Venereol. 2019;33:2039–49. Boralevi F, Cotto E, Baysse L, et  al. Is varicella-zoster virus involved in the etiopathogeny of pityriasis lichenoides? J Invest Dermatol. 2003;121:647–8. Borra T, Custrin A, Saggini A, et  al. Pityriasis lichenoides, atypical pityriasis lichenoides, and related conditions: a study of 66 cases. Am J Surg Pathol. 2018;42:1101–12. Calzavara Pinton PC, Capezzera R, Zane C, et al. Medium-­ dose ultraviolet al therapy for pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica. J Am Acad Dermatol. 2002;47:410–4. Cornelison RL, Knox JM, Everett MA. Methotrexate for the treatment of Mucha-Habermann disease. Arch Dermatol. 1972;106:507–8. Ersoy-Evans S, Greco MF, Mancini AJ, Subaşi N, Paller AS.  Pityriasis lichenoides in childhood: a retrospective review of 124 patients. J Am Acad Dermatol. 2007;56:205–10. Gelmetti C, Rigoni C, Alessi E, et al. Pityriasis lichenoides in children: a long-term follow-up of eighty-nine cases. J Am Acad Dermatol. 1990;23:473–8. Gritiyarangsan P, Pruenglampoo S, Ruangratanarote P.  Comparative studies of treatments for pityriasis lichenoides. J Dermatol. 1987;14:258–61. Hapa A, Ersoy-Evans S, Karaduman A. Childhood pityriasis lichenoides and oral erythromycin. Pediatr Dermatol. 2012;29:719–24. Lis-Swiezty A, Michalska-Bankowska A, Zielonka-­ Kucharzewska A, et  al. Successful therapy of cyclosporin A in pityriasis lichenoides et varioliformis

772 acuta preceded by hand, foot and mouth disease. Antivir Ther. 2016;21:273–5. Ogrum A, Takci Z, Seckin HY, et al. A case of pityriasis lichenoides: rapid resolution with azithromycin monotherapy in 3 weeks. Dermatol Ther. 2018;31:e12681. Pavlotsky F, Baum S, Barzilai A, et al. UVB therapy of pityriasis lichenoides – our experience with 29 patients. J Eur Acad Dermatol Venereol. 2006;20:542–7. Piamphongsant T. Tetracycline for the treatment of pityriasis lichenoides. Br J Dermatol. 1974;91:319–22. Powell FC, Muller SA. Psoralens and ultraviolet A therapy of pityriasis lichenoides. J Am Acad Dermatol. 1984;10:59–64. Sauer GC.  Pentoxifylline (Trental) therapy for vasculitis of pityriasis lichenoides et varioliformis. Arch Dermatol. 1985;121:1487. Tay YK, Morelli JG, Weston WL.  Experience with UVB phototherapy in children. Pediatr Dermatol. 1996;13:406–9. Truhan AP, Hebert AA, Esterly NB. Pityriasis lichenoides in children: therapeutic response to erythromycin. J Am Acad Dermatol. 1986;15:66–70. Zlatkov NB, Andreev VC.  Toxoplasmosis and pityriasis lichenoides. Br J Dermatol. 1972;87:114–6.

Further Reading Bowers S, Warshaw EM.  Pityriasis lichenoides and its subtypes. J Am Acad Dermatol. 2006;55:557–72. Farnaghi F, Seirafi H, Ehsani AH, Agdari ME, Noormohammadpour P. Comparison of the therapeutic effects of narrow band UVB vs. PUVA in patients with pityriasis lichenoides. J Eur Acad Dermatol Venereol. 2011;25:913–6. Fernandes NF, Rozdeba PJ, Schwartz RA, Kihiczak G, Lambert WC.  Pityriasis lichenoides et varioliformis: a disease spectrum. Int J Dermatol. 2010;49:257–61. Geller L, Antonov NK, Lauren CT, Morel KD, Garzon MC.  Pityriasis lichenoides in childhood: review of clinical presentation and treatment options. Pediatr Dermatol. 2015;32:579–92. Horie C, Mizukawa Y, Yamazaki Y, Shiohara T. Varicella zoster virus as a possible trigger for the development of pityriasis lichenoides et varioliformis acuta: retrospective analysis of our institutional cases. Clin Exp Dermatol. 2018;43:703–7. Ito N, Ohshima A, Hashizume H, Takigawa M, Tokura Y. Febrile ulceronecrotic Mucha-Habermann’s disease managed with methylprednisolone semipulse and subsequent methotrexate therapies. J Am Acad Dermatol. 2003;49:1142–8. Jung F, Sibbald C, Bohdanowicz M, Ingram JR, Piguet V. Systematic review of efficacies and adverse effects of treatments for pityriasis lichenoides. Br J Dermatol. 2020;183(6):1026–32. https://doi.org/10.1111/ bjd.18977.

L. Fania and B. Didona Karouni M, Abou Rahal J, Kurban M, Kibbi AG, Abbas O. Possible role of plasmacytoid dendritic cells in pityriasis lichenoides. Clin Exp Dermatol. 2018;43:404–9. Kaufman WS, McNamara EK, Curtis AR, et  al. Febrile ulceronecrotic Mucha-Habermann disease (pityriasis lichenoides et varioliformis acuta fulminans) presenting as Stevens-Johnson syndrome. Pediatr Dermatol. 2012;29:135–40. Khachemoune A, Blyumin ML.  Pityriasis lichenoides: pathophysiology, classification, and treatment. Am J Clin Dermatol. 2007;8:29–36. Kempf W, Pfaltz K, Vermeer MH, et al. EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Blood. 2011;118:4024–35. Kempf W, Kazakov DV, Palmedo G, et al. Pityriasis lichenoides et varioliformis acuta with numerous CD30(+) cells: a variant mimicking lymphomatoid papulosis and other cutaneous lymphomas. A clinicopathologic, immunohistochemical, and molecular biological study of 13 cases. Am J Surg Pathol. 2012;36:1021–9. Kim HS, Yu DS, Kim JW. A case of febrile ulceronecrotic Mucha-Habermann’s disease successfully treated with oral cyclosporin. J Eur Acad Dermatol Venereol. 2007;21:272–3. Macias VC, Marques-Pinto G, Cardoso J.  Phototherapy for pityriasis lichenoides: our experience. Cutan Ocul Toxicol. 2013;32:124–7. Marenco F, Fava P, Fierro MT, Quaglino P, Bernengo MG. High-dose immunoglobulins and extracorporeal photochemotherapy in the treatment of febrile ulceronecrotic Mucha-Habermann disease. Dermatol Ther. 2010;23:419–22. Menzinger S, Frassati-Biaggi A, Leclerc-Mercier S, Bodemer C, Molina TJ, Fraitag S.  Pityriasis lichenoides: a large histopathological case series with a focus on adnexotropism. Am J Dermatopathol. 2020;42:1–10. Miyamoto T, Takayama N, Kitada S, Hagari Y, Mihara M.  Febrile ulceronecrotic Mucha-Habermann disease: a case report and a review of the literature. J Clin Pathol. 2003;56:795–7. Romani J, Puig L, Fernandez-Figueras MT, de Moragas JM.  Pityriasis lichenoides in children: clinicopathologic review of 22 patients. Pediatr Dermatol. 1998;15:1–6. Zaaroura H, Sahar D, Bick T, Bergman R.  Relationship between pityriasis lichenoides and mycosis fungoides: a clinicopathological, immunohistochemical, and molecular study. Am J Dermatopathol. 2018;40:409–15. Zang JB, Coates SJ, Huang J, Vonderheid EC, Cohen BA. Pityriasis lichenoides: long-term follow-up study. Pediatr Dermatol. 2018;35:213–9.

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Key Points • Pityriasis lichenoides (PL) represents a unique group of inflammatory and acquired skin disorders that include pityriasis lichenoides et varioliformis acuta (PLEVA or Mucha– Habermann disease) and pityriasis lichenoides chronica (PLC). • PLEVA and PLC are two ends of a disease spectrum. The prevalence, incidence, and risk factors of PL in the general population are still unclear. • PLC is distinguished by gradually developing, small, dim, erythematous-to-brown flattened maculopapules with fine centrally attached shiny scales. These crops of lesions are usually scattered across the trunk and proximal extremities and fade with minor hypo-/hyperpigmentation in the absence of scarring. PLC histopathology shows superficial perivascular interface dermatitis. • PLC must be differentiated mainly from parapsoriasis, guttate psoriasis, and lichen planus.

P. Borregón (*) Department of Dermatology, Dra Paloma Borregon, Madrid, Spain A. España Department of Dermatology, University Clinic of Navarra, School of Medicine, Pamplona, Spain

• There are no diagnostic or therapeutic guidelines for PLC. • Phototherapy, topical corticosteroids, and oral tetracycline or erythromycin are the most recommended treatments.

Definition Pityriasis lichenoides (PL) is an uncommon, acquired skin condition. It represents a unique group of inflammatory skin disorders that include pityriasis lichenoides et varioliformis acuta (PLEVA or Mucha–Habermann disease) and pityriasis lichenoides chronica (PLC). PLEVA and PLC are two ends of a disease spectrum.

History PL was first described between 1894 and 1925. Neisser and Jadassohn described what would now be considered the acute and chronic forms, respectively. In 1899, Juliusberg described pityriasis lichenoides in a chronic form and thus coined the term pityriasis lichenoides chronica (PLC). In 1902, Brocq described pityriasis lichenoides as a form of parapsoriasis under the category of parapsoriasis en gouttes. This classification lasted for several years, and it was not until 1926 that PL was first distinguished on clinical grounds as an entity separate from parapsoriasis.

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Mucha separated the acute form of pityriasis lichenoides from PLC in 1916. But it was in 1925 when this acute form was given the name pityriasis lichenoides et varioliformis acuta (PLEVA) by Habermann.

Epidemiology The prevalence, incidence, and risk factors of PL in the general population are still unclear. Some investigators estimate the incidence to be around one in 2000 people. Neither an ethnic nor a geographic predisposition has been reported. However, PL does maintain a slight male predisposition and tends to present in late childhood and early adulthood.

Fig. 72.1  Old patient with diffuse scaly papules and plaques

Basic Concepts of Pathogenesis The etiology of PL is unknown. There are three major pathogenic theories: an inflammatory reaction triggered by infectious agents or drugs, an inflammatory response secondary to a T-cell dyscrasia, and an immune complex-mediated hypersensitivity vasculitis. Both PLEVA and PLC contain lesion T-cell infiltrates, with a general predominance of CD8+ cells in PLEVA and CD4+ cells in PLC.  Both types of lesions can exhibit dominant T-cell clonality, easily seen in PLEVA, where the infiltrate is denser. This clonality indicates that PL is a T-cell lymphoproliferative disorder such as lymphomatoid papulosis and some forms of T-cell cutaneous hyperplasia. This concept may help to explain the occasional association of PL with other lymphoproliferative disorders such as cutaneous T-cell lymphoma, Hodgkin’s disease, and other lymphomas.

Clinical Presentation The most common and subtle form of PL is PLC, which presents sequentially or concomitantly and, eventually, may overtake PLEVA.  PLC is distinguished by gradually developing, small, dim, erythematous-to-brown flattened maculopapules with fine centrally attached shiny scales (Figs. 72.1 and 72.2). These crops of lesions are

Fig. 72.2  Pityriasis lichenoides chronica in a 14-year-old boy: red scaly papules on the trunk

usually scattered across the trunk and proximal extremities and fade with minor hypo-/hyperpigmentation in the absence of scarring. Palms,

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soles, face, and scalp can be also affected. This rash may resolve in months or wax and wane for years with extended lengths of remission. Irregular erythema and superficial ulcerations on the oral mucosa and palate have been reported. In dark-skinned people, PLC may rarely present with widespread hypopigmentation rather than the typical papular morphology, especially common in children. PLC generally manifests a more indolent course than PLEVA.  The distribution of PLC lesions may predict its prognosis; a generalized rash may last months, but peripheral lesions can take years to resolve. The diagnosis of PLC is made by clinical evaluation of the skin and a biopsy with histopathologic examination as a confirmatory tool.

phous light reaction, generalized folliculitis, dermatitis herpetiformis, toxic epidermal necrolysis, graft-versus-host disease, and mycosis fungoides. PLC must be differentiated mainly from parapsoriasis, guttate psoriasis, and lichen planus. A thorough history and clinical, pathologic, and laboratory examinations are strongly recommended to distinguish PL from other diagnoses. An important skin entity to recognize and isolate from PLC is lymphomatoid papulosis, which is very similar clinically so that a biopsy is mandatory to make differential diagnosis by histopathology. The presence of atypical lymphocytes and CD30 positivity for most of these cells are seen in lymphomatoid papulosis but not in PL.

Diagnosis

There are no diagnostic or therapeutic guidelines for PLC. Dozens of different treatments are advocated for this disorder. PLC can regress spontaneously, and due to the low frequency of the disease, its unknown etiology, and the unpredictability of its course, it is difficult to evaluate the effectiveness of the recommended therapies.

PLC histopathology shows superficial perivascular interface dermatitis. The principal microscopic features are parakeratosis and mild lymphocytic infiltrate accompanied by focal keratinocyte necrosis and mild erythrocyte extravasation. They are similar changes to that observed in PLEVA but milder. While some observers allow occasional atypical lymphocytes, others regard this as a sign of lymphomatoid papulosis. Immunohistochemical studies have shown that T cells predominate in both the dermal and epidermal inflammatory infiltrates. Most studies indicate that CD4+ T cells predominate in PLC. Admixed in the infiltrate are variable numbers of macrophages and CD1a + epidermal dendritic cells (Langerhans or indeterminate cells).

Differential Diagnosis The differential diagnosis of the PLC is extensive and encompasses guttate psoriasis, lichen planus, papular eczematous dermatitis, tinea versicolor, Gianotti–Crosti syndrome, pityriasis rosea, drug or viral exanthemas (varicella), generalized arthropod bite reaction, erythema multiforme, cutaneous small vessel vasculitis, secondary syphilis, papulonecrotic tuberculid, polymor-

General Principles of Treatment

Phototherapy For some authors, phototherapy is by far the most successful therapy and is the first-line therapy for PLC. It is used for a variety of modalities (e.g., UVB, narrowband UVB, psoralen plus UVA, and UVA) and is well tolerated. The total amount of energy used has varied from 10 to 370.5 J/cm 2. Ultraviolet light therapy, especially UVB, has even shown therapeutic value and safety in the pediatric population. Recurrences after cessation of therapy or after long periods of remission are not uncommon, although complete clearing has also been documented.

Topical Treatments Topical corticosteroids are a good option for PLC, though no studies have specifically compared the efficacy of such agents with that of

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either placebo or other treatments. However, concerns about their side-effect profile have led to the increased utilization of nonsteroidal topical immune-modulating therapies. Topical tacrolimus has been reported to work in some patients with PLC, both 0.03% ointment and 0.1% ointment twice daily, probably because of its anti-­inflammatory ability to affect T cells. Topical coal tar preparations could be also helpful.

Systemic Treatments Oral agents most often used for treatment of PLC include antibiotics and methotrexate. The most common antibiotics include tetracycline and erythromycin. If a foreign antigen is the suspected trigger (as drug or infectious agent), cessation of the implicated drug or anti-pathogen therapy must be the treatment used. Oral tetracycline and erythromycin are used for their anti-inflammatory rather than antibiotic effect, with erythromycin favored in children younger than 12 years of age (to avoid possible adverse effects in dentition). Especially in the treatment of children, a long-term (4–8  weeks) high-dose treatment with erythromycin (30–50  mg/kg per day) can be effective. For adults, tetracyclines in high doses of about 2 g/day for at least 4 weeks have shown favorable results. Depending on the response, the dosage can be tapered over the course of several months to minimize the risk of relapses. Antihistamines may be helpful in cases with significant pruritus. Methotrexate is an effective treatment in some patients with severe forms of PLC in dosages of 7.5–20 mg/week. Recommended initial test dose of 5–10 mg/week can be gradually increased by 2.5–5 mg/week. Reduction of the dose can lead to recurrence. It is not recommended in children. Laboratory control of the treatment is essential. Before that, renal, hepatic, and bone marrow functions have to be monitored.

Systemic corticosteroids (e.g., prednisone 0.5–1.0  mg/kg of body weight per day with a slow taper) should be considered in PL cases with concurrent and chronic constitutional symptoms such as fever, arthritis, and myalgias (more frequent in PLEVA). Cyclosporine can be considered an alternative in refractory cases. The initial dose is 5  mg/kg per day over a period of about 6–8 weeks. Once the response is achieved, the dose should be slowly tapered. Blood pressure and renal function must be monitored every 2–4 weeks. According to the results of a systematic review from 1970 to 2019, the authors propose narrow-­ band UVB phototherapy as first-line treatment and oral erythromycin with or without topical corticosteroids and low-dose methotrexate as second-line therapies. However, high-powered studies and randomized controlled trials are needed to establish the optimal treatment for PL.

Further Reading Bellinato F, Maurelli M, Gisondi P, Girolomoni G. A systematic review of treatments for pityriasis lichenoides. J Eur Acad Dermatol Venereol. 2019;33(11):2039–49. Bowers S, Warshaw EM.  Pityriasis lichenoides and its subtypes. J Am Acad Dermatol. 2006;55:557–72. Jung F, Sibbald C, Bohdanowicz M, Ingram JR, Piguet V.  Systematic review of the efficacies and adverse effects of treatments for pityriasis lichenoides. Br J Dermatol. 2020;183(6):1026–32. https://doi. org/10.1111/bjd.18977. Khachemoune A, Blyumin ML.  Pityriasis lichenoides: pathophysiology, classification, and treatment. Am J Clin Dermatol. 2007;8:29–36. López-Villaescusa MT, Hernández-Martín A, Colmenero I, Torrelo A.  Pityriasis lichenoides in a 9-month-old boy. Actas Dermosifiliogr. 2013;104:829–30. Simon D, Boudny C, Nievergelt H, Simon HU, Braathen LR. Successful treatment of pityriasis lichenoides with topical tacrolimus. Br J Dermatol. 2004;150:1033–5. Wood GS, Reizner G.  Other papulosquamous disorders. In: Bolognia JL, Jorizzo JL, Rapini RP, editors. Dermatology. 2nd ed. St. Louis, MO. Mosby Elsevier; 2008. p. 139–141. Zang JB, Coates SJ, Huang J, Vonderheid EC, Cohen BA. Pityriasis lichenoides: long-term follow-up study. Pediatr Dermatol. 2018;35(2):213–9.

Pityriasis Rosea

73

Miloš Nikolić and Jovan Lalošević

Key Points • Pityriasis rosea (PR) is a common, acute, or subacute self-limiting exanthematous disease. • Approximately 1–2% of new dermatological patients are affected by PR. • PR affects mainly children, adolescents, and young adults. • PR usually remits within 3–6 weeks. • Etiology of PR is associated with the endogenous systemic reactivation of human herpesvirus (HHV)-6 and/or HHV-7. • Asymptomatic and mild cases may be left untreated. • If itch is important, topical corticosteroids are indicated. • Phototherapy (UVB or UVA1) may be useful in the treatment. • High-dose oral acyclovir, if introduced early in the course of PR, may reduce the disease duration. • PR in pregnancy, especially before the 15th week of gestation, may lead to complications.

Definition and Epidemiology Pityriasis rosea (PR) is a benign, self-limited skin disease characterized by a sudden onset; in its typical presentation, the eruption is preceded by a solitary lesion, “herald patch,” located mainly on the trunk. After few days, patients develop a characteristic papulosquamous rash along the Langer lines (cleavage lines) over the trunk and limbs. The prevalence of PR has been established at 1.3%, but it is probably underdiagnosed given the occurrence of atypical forms and the number of patients who are misdiagnosed by general practitioners and other nondermatologists. Most frequently, PR is mild, with an acute or subacute course, lasting from 2  weeks to a few months, with constitutional symptoms that may precede or accompany the skin eruption. In some cases, the eruption may disappear in 1 week, but in rare cases, PR may persist even 5 months or longer. The recurrence rate of PR varies from 1.8% to 3.7%.

M. Nikolić (*) ∙ J. Lalošević Department of Dermatovenereology, University of Belgrade School of Medicine, Belgrade, Serbia © Springer Nature Switzerland AG 2023 A. D. Katsambas et al. (eds.), European Handbook of Dermatological Treatments, https://doi.org/10.1007/978-3-031-15130-9_73

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Basic Concept of Pathogenesis Many clinical and epidemiological characteristics suggest an infective agent as the etiological factor. True epidemics have not been documented, but family outbreaks have been reported. Seasonal variations have been found: in Europe and North America, most cases have been diagnosed in winter months. The course of PR: herald patch/patches as sites of “inoculation,” disseminated lesions that appear after a certain period, mild constitutional symptoms, self-limited course, and relatively rare relapses are the characteristics compatible with an infectious disease. Worsening of the eruption that may appear in patients treated with systemic corticosteroids is also an argument that favors infective etiology. A viral etiology has been proposed after the microscopic observation of intranuclear and intracytoplasmic virus-like particles. An increase in CD4 lymphocytes and Langerhans cells in the dermis also suggests a viral etiology (Rebora et al. 2010). The most common viruses linked to pityriasis rosea are human herpesvirus-6 and 7 (HHV-6 and HHV-7). Children are usually infected by HHV-6 by 2  years of age and by HHV-7 by the age of 6 years. Roseola infantum (exanthema subitum) is a common presentation of these viral infections in children. The development of PR later in life suggests an endogenous systemic reactivation of these viruses (Drago et al. 2014). Even though the evidence supporting this theory is not completely affirmative, with studies linking HHV-6 and HHV-7 with PR being small and with conflicting results, the most probable cause of PR is indeed a viral infection. A small study did not detect HHV-6 nor HHV-7 DNA by polymerase chain reaction in the acute or convalescent plasma, despite having positive antibodies to HHV-6 and HHV-7 (Chuh et al. 2001). A more recent study using a calibrated quantitative real-time PCR assay found active HHV-6 and HHV-7  in the plasma and skin samples. These

M. Nikolić and J. Lalošević

results confirm the causal association between PR and active HHV-7 and, to a lesser extent, HHV-6 infection (Broccolo et al. 2005). Another study using PCR reaction testing with specific primers found active HHV-6 and HHV-7  in the plasma and tissue samples, favoring HHV-7 as the causative agent in PR. Another confirmation of the viral etiology was an electron microscopy study showing the presence of HHV particles in 71% of patients’ tissue samples (Drago et  al. 2002).

Clinical Presentation PR has been reported in all races and equally affects males and females. It may occur at any age, but most patients are between 10 and 35 years of age. In temperate climate zones, the incidence is highest in winter and lowest in summer months. The clinical presentation is frequently preceded by prodromal symptoms that are often neglected in many textbooks, but may affect as many as 69% of patients. The most frequently reported are: malaise, nausea, loss of appetite, headache, difficulty in concentration, irritability, gastrointestinal and upper respiratory tract symptoms, joint pain, swelling of lymph nodes, sore throat, and mild fever. These symptoms and signs may also be present during the course of the eruption. The most common and easily detectable manifestation of PR is the herald patch, present (or at least noticed) in 70–80% of patients. Herald patch is usually a solitary, oval, erythematous, and scaly plaque, measuring 2–6 cm in diameter. Within 2–3 days to 2 weeks, smaller, erythematous, round to oval macules, and/or slightly infiltrated plaques with crinkly surface and a rim of fine scale (collarette scale – free at the center of the lesion and attached at the periphery), measuring 1–3  cm in diameter, appear in crops on the trunk and proximal extremities (Figs. 73.1, 73.2, 73.3, and 73.4). The long axes of the lesions are

73  Pityriasis Rosea

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Fig. 73.3  Inverse PR in darkly pigmented skin (Courtesy of Prof. Vesna Petronic-Rosic, Georgetown University School of Medicine, Washington DC, USA)

Fig. 73.1  One of atypical variants of PR: disseminated, somewhere annular oval plaques with edge papulovesicles

Fig. 73.2  Disseminated small oval plaques with collarette scale

oriented along the skin tension lines, running parallel to the ribs, forming the classical “Christmas-­ tree-­like pattern.” The face, hands, and feet are usually spared. Especially in children, these areas may be involved. New lesions continue to appear over a few weeks, persist for a few weeks, and then gradually resolve over another few weeks. The entire course of PR usually lasts 3–6 weeks. Although many sources consider PR as an asymptomatic eruption, moderate to severe pruritus may occur in up to 50% of patients. In some cases, the lesions may persist up to 3 months and very rarely more than 5–6 months. Upon resolution of the inflammatory lesions, residual hyperor hypopigmented macules, lasting for another several weeks to months, may be found. There are several clinical variants of PR, and the variants may be as frequent as the “classical” cases. Herald patch may be absent, there may be more than one herald patch, or it can be found on an atypical location (sole, rather than the trunk). In children, the lesions are often papular or purpuric. Vesicular or bullous lesions can also be seen (Figs.  73.1 and 73.2). Inverse PR affects predominantly skin folds (Fig.  73.3). Urticarial lesions are rarely reported. In patients with darker skin, the lesions may have lichenoid aspect. More uncommon clinical forms are the erythema multiforme-­like, PR circinata and marginata, follicular and the PR gigantea of Darier.

M. Nikolić and J. Lalošević

780 Fig. 73.4  PR in pregnancy, annular polycyclic plaques with discrete scales on the periphery of the lesions

The extent of the eruption in PR may be variable  – in some patients the lesions are very numerous and disseminated, in other cases, there may be only several lesions (Figs.  73.1, 73.2, 73.3, and 73.4). Oropharyngeal lesions involving the palate and/or the pharynx may be present in 28% of patients, all of which were painless and can be classified into four categories: erythematomacular, macular and papular, erythematovesicular, and petechial lesions. Systemic symptoms, especially prodromal or accompanying symptoms, are more common in patients with PR enanthem. The recurrence rate is low; 1.8%–3.7% of patients will have a second attack, multiple recurrences are even rarer. The duration of relapses is usually shorter than that of the initial eruption. The previous classifications of PR are mainly based on its atypical morphological features rather than on the pathogenetic mechanisms that underlie the different presentations of the disease. Notably, most of the morphologically atypical forms follow a course amenable to the classic form. According to the new classification, proposed by Drago et al., PR may be divided into: Classic type (the most common), Relapsing, Persistent, Pediatric, PR in Pregnancy, and PR-like eruptions. The latter is questionable, if it

should be enlisted in the PR classification at all, given that these patients lack HHV-6/HHV-7 reactivation and have completely different histopathological findings.

Diagnosis There are no specific laboratory tests that could help in the diagnosis. Biopsy is relatively rarely performed in routine practice, and most frequently, it is not necessary for the diagnosis. The histopathological characteristics are not diagnostic, but may be suggestive. In the epidermis, spongiosis, vesicles, and focal parakeratosis are usually present. Also, exocytosis of mononuclear cells into the epidermis is frequently seen. In the upper dermis, edema and mild perivascular mononuclear cell infiltrate can be present, sometimes with extravasation of red blood cells.

Differential Diagnosis The differential diagnosis includes secondary syphilis, viral exanthems, guttate psoriasis, seborrheic dermatitis, pityriasis lichenoides (“guttate parapsoriasis”), small plaque parapsoriasis, dis-

73  Pityriasis Rosea

seminated nummular eczema, PR-like drug eruptions (induced by captopril, gold salts, ketotifen, barbiturates, metronidazole, isotretinoin, lamotrigine, adalimumab, rituximab, etc.), and disseminated tinea corporis. Herald patch(es) may mimic psoriasis, tinea corporis, or nummular eczema.

General Principles of Treatment The self-limited course of PR allows a watchful waiting and symptomatic treatment of pruritus in most patients. Many patients, especially those with mild and asymptomatic disease, will not need any treatment.

Topical Treatments If any treatment is necessary, most patients will benefit from mid-potency topical corticosteroids, applied twice a day. This approach will alleviate the itch and will hasten the regression of individual lesions. Pruritus can be also controlled using the topical antipruritics such as calamine lotion, lotions with menthol, camphor, or pramoxine. In disseminated forms, UVB phototherapy (both broad-band and narrow-band) may be ­helpful. Also, UVA1 phototherapy (30  J/cm2, 3 times weekly, for 3 weeks) has been found effective in the treatment of PR. In summer months, cautious exposure to sunshine can also be recommended. Phototherapy of PR may increase the risk of post-­inflammatory hyperpigmentation.

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Systemic Treatments If a patient with disseminated PR is seen early in the disease (first 7–10 days), oral acyclovir (based on the concept that HHV-6 and/or HHV-7 are causative agents) can significantly shorten the disease duration. Acyclovir tablets, 800  mg, should be given 5 times daily, for 7 days (the mean time for skin clearance in the acyclovir group was 18.5 days and in the placebo group 37.9  days). Further studies showed that even lower doses of acyclovir, 400 mg given 3 times daily, can be effective in achieving rash regression and reducing the pruritus. Although initial studies indicated that oral erythromycin might be useful in the treatment of PR, subsequent studies showed that erythromycin, azithromycin, and clarithromycin were ineffective. Oral corticosteroids have been given for disseminated forms of PR, but in some cases, this treatment even provoked a worsening of the eruption. Also, in a study that examined low-dose prednisolone, even though patients had a shorter disease duration and significantly reduced pruritus, they also had a higher recurrence rate in comparison to the control group. There are no controlled studies that would confirm the efficacy of oral H1 antihistamines in the treatment of PR, but they are widely prescribed given their safety profile, probable immunomodulatory effects, and sedating effects of some drugs.

Topical Treatments at a Glance

Systemic Treatments at a Glance

• Patients with itch will benefit from topical mid-potency corticosteroids. • Patients with disseminated and persistent PR may be treated with UVB or UVA1.

• For patients diagnosed early, oral acyclovir may be given for 7 days. • In pregnancy, if PR is diagnosed before the 15th week of gestation, oral acyclovir may be indicated.

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 reatment Approach in Special T Populations PR in children presents in a similar way as in adults. Pruritus has been reported more often in this population. Children with dark skin more frequently have facial (30%) and scalp involvement (8%) and also post-inflammatory pigmentary changes (62%). Pregnant women are more susceptible to PR because of their altered immune response. One study showed that 39% of investigated pregnant women with PR had pregnancy complications (miscarriage, hydramnios). The onset of PR before the 15th week of gestation, presence of constitutional symptoms, and involvement of >50% of body surface area may be considered major risk factors (Drago et al. 2018). In these women, oral acyclovir may be indicated (Alajmi et al. 2020).

Overview of Pityriasis Rosea Treatment at a Glance

• For cases with limited number of lesions, topical mid-potency corticosteroid can be given, twice a day. • If disseminated PR is diagnosed early, oral acyclovir (5  ×  800  mg or 3 × 400 mg) can be given for 7 days. • If disseminated PR is diagnosed with a delay, or in persistent forms of PR, UVB or UVA1 phototherapy can be recommended.

References Alajmi A, Jfri A, Pehr K.  Pityriasis rosea: risk and treatment during pregnancy. J Cutan Med Surg. 2020;24(2):207–8. Broccolo F, Drago F, Careddu AM, Foglieni C, Turbino L, Cocuzza CE, et  al. Additional evidence that pityriasis rosea is associated with reactivation of human herpesvirus-6 and -7. J Invest Dermatol. 2005;124(6):1234–40. Chuh AA, Chiu SS, Peiris JS. Human herpesvirus 6 and 7 DNA in peripheral blood leucocytes and plasma in patients with pityriasis rosea by polymerase chain

reaction: a prospective case control study. Acta Derm Venereol. 2001;81(4):289–90. Drago F, Malaguti F, Ranieri E, Losi E, Rebora A. Human herpes virus-like particles in pityriasis rosea lesions: an electron microscopy study. J Cutan Pathol. 2002;29(6):359–61. Drago F, Ciccarese G, Rebora A, Parodi A.  Relapsing pityriasis rosea. Dermatology. 2014;229(4):316–8. Drago F, Ciccarese G, Herzum A, Rebora A, Parodi A. Pityriasis rosea during pregnancy: major and minor alarming signs. Dermatology. 2018;234(1–2):31–6. Rebora A, Drago F, Broccolo F. Pityriasis rosea and herpesviruses: facts and controversies. Clin Dermatol. 2010;28(5):497–501.

Further Reading Broccolo F, Drago F, Careddu AM, Foglieni C, Turbino L, Cocuzza CE, et al. Additional evidence that pityriasis rosea is associated with reactivation of human herpesvirus-­6 and -7. J Invest Dermatol. 2005;124:1234–40. Chuh AA, Chiu SS, Peiris JS. Human herpesvirus 6 and 7 DNA in peripheral blood leucocytes and plasma in patients with pityriasis rosea by polymerase chain reaction: a prospective case control study. Acta Derm Venereol. 2001;81:289–90. Chuh A, Zawar V, Sciallis G, Kempf W.  A position statement on the management of patients with pityriasis rosea. J Eur Acad Dermatol Venereol. 2016;30:1670–81. Ciccarese G, Broccolo F, Rebora A, Parodi A, Drago F.  Oropharyngeal lesions in pityriasis rosea. J Am Acad Dermatol. 2017;77:833–7.e4. Drago F, Malaguti F, Ranieri E, Losi E, Rebora A. Human herpes virus-like particles in pityriasis rosea lesions: an electron microscopy study. J Cutan Pathol. 2002;29:359–61. Drago F, Ciccarese G, Rebora A, Parodi A.  Relapsing pityriasis rosea. Dermatology. 2014;229:316–8. Drago F, Ciccarese G, Rebora A, Broccolo F, Parodi A.  Pityriasis Rosea: a comprehensive classification. Dermatology. 2016;232:431–7. Drago F, Ciccarese G, Herzum A, Rebora A, Parodi A.  Pityriasis Rosea during pregnancy: major and minor alarming signs. Dermatology. 2018;234:31–6. Nikolić MM.  Eritemoskvamozne dermatoze. Pityriasis rosea  - Gibert. In: Lalević-Vasić BM, Medenica MM, Nikolić MM, editors. Dermatovenerologija sa Propedevtikom. 8th ed. Medicinski fakultet Beograd; 2019. p. 97–106. Rebora A, Drago F, Broccolo F. Pityriasis rosea and herpesviruses: facts and controversies. Clin Dermatol. 2010;28:497–501. Sonthalia S, Kumar A, Zawar V, Priya A, Yadav P, Srivastava S, et al. Double-blind randomized placebo-­ controlled trial to evaluate the efficacy and safety of

73  Pityriasis Rosea short-course low-dose oral prednisolone in pityriasis rosea. J Dermatolog Treat. 2018;29:617–22. Urbina F, Das A, Sudy E.  Clinical variants of pityriasis rosea. World J Clin Cases. 2017;5:203–11. Villalon-Gomez JM. Pityriasis Rosea: diagnosis and treatment. Am Fam Physician. 2018;97:38–44.

783 Wessman LL, Andersen LK, Davis MDP.  Incidence of diseases primarily affecting the skin by age group: population-based epidemiologic study in Olmsted County, Minnesota, and comparison with age-­ specific incidence rates worldwide. Int J Dermatol. 2018;57:1021–34.

Pityriasis Rubra Pilaris (Divergie 1863, Besnier 1889)

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A. Petrov and V. Pljakoska

Key Points • Chronic, inflammatory, papulosquamous disease with unknown etiology. • Six types of the disease. • Spearing “islands” of not affected skin are pathognomonic sign. • Palmo-plantar waxy keratoderma. • Oral retinoids, methotrexate in treatment. • Off-label use of biologics in PRP.

Definition and Epidemiology Pityriasis rubra pilaris (PRP) is chronic, inflammatory, papulosquamous disorder of keratinization with unknown etiology, characterized with affection of the body and palmopantar (“sandal”) affection. It appears in both hereditary and acquired forms. The first description of PRP is by Claudius Tarral, who, in 1835, published a case report in Rayer’s A Theoretical and Practical Treatise on the Diseases of the Skin of a patient he had seen 7  years earlier. Tarral did not recognize dermatosis as a distinct entity, and it was listed under the title of “general psoriasis.”

A. Petrov (*) · V. Pljakoska Clinical Hospital Acibademsistina, Skopje, North Macedonia e-mail: [email protected]; vesna. [email protected]

There is no sexual predilection it affects both male and female equally. The highest incidence is in first and sixth decades. Incidence is around 1:5000. There may be racial variation as the incidence of classical PRP was reported to be closer to one in 50,000 in India. The etiology is unknown. Even there are some similarities with psoriasis; it is a distinct disease, which is more disorder of keratinization than inflammatory disease. There are some clinical and histological evidence as well, about vitamin A deficiency. Infective etiology also is suggested with familial distribution. PRP could appear also after drug therapy and influence of some triggering factors, such as severe infection, especially in juvenile form. Concomitantly, PRP appears with other immunological disorder such as rheumatoid arthritis, and some malignancy—leukemia or Sezary syndrome, which indicates association with immunosuppression. Classic type of PRP has a good prognosis and usually disappears in 3 years.

Classification According to Griffith, there are six types of Pityriasis rubra pilaris, and the classic adult type is most common and has best prognosis. Remission appears after several years. Type 2 is atypical adult form with tendency to chronic. Type 3 classic inherited variant seems to have

© Springer Nature Switzerland AG 2023 A. D. Katsambas et al. (eds.), European Handbook of Dermatological Treatments, https://doi.org/10.1007/978-3-031-15130-9_74

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786 Table 74.1  Classification of Pityriasis rubra pilaris Type I. Classical adult II. Atypical adult III. Classical juvenile IV. Circumscribed juvenile V. Atypical juvenile

% of cases 55

25

Distribution Prognosis Generalized Most clear in 3 years Generalized Chronic Generalized Most clear in 1 year Focal Uncertain

5

Generalized Chronic

5 10

also good prognosis. Recently, type 6 has been described, which means PRP is associated with HIV, and this type has a poor prognosis (Table 74.1 ).

Characteristics 1. Classical adult. Commonest type (50% of cases). Spreads caudally. The patient is usually erythrodermic with diffuse thickening of the palms and soles. Ectropion often is present. 1. Atypical adult. Long duration. Involves a more ichthyosiform pattern in association with hair loss and areas of eczematous changes. 2. Classical juvenile. Similar to type 1 but affects children in the first decade. 3. Circumscribed juvenile. Affects children, with sharply demarcated areas of follicular hyperkeratosis and erythema on the knees and elbows. Usually does not progress. 4. Atypical juvenile. Appears in the first few years of life and is chronic. Characterized by follicular hyperkeratosis, whereas erythema is not a prominent feature. The skin on the hands and feet can appear scleroderma-like. 5. HIV-related. Symmetrical, pruritic eruption composed of erythematous papules is associated with late-onset acne conglobata.

Clinical Data Clinical picture is the basis for establishing the diagnosis of PRP.

Classic disease begins on the face with scaling and erythema and on lateral parts of the neck and trunk. Also, disease may appear on the extensor surface of the extremities and especially on the back of the first and second phalange. PRP starts with small plaque lesions, which spread all over the body. Typical lesion is follicular hyperkeratotic papule. Spearing “islands” of unaffected skin show pathognomonic sign. In 20% of the patients, mild pruritus and burning sensation are present. Also Koebner phenomenon may appear like in psoriasis. After some time, orange-red “salmon-like” discoloration of the skin is present. This is hallmark for PRP. Palms and soles are almost always involved often showing an orange color. Palmo-plantar waxy keratoderma appears after some period, with typical side spreading, producing so-called sandal pattern. Changes of the nails are often present, thickened nails with a distal discoloration, and subungual hyperkeratosis, but pitting of the nail and dystrophy like in psoriasis do not exist. Erythroderma can occur after 2–3  months. Erythroderma is very serious development of the disease and should be monitored carefully. However, usually PRP remains static and disappears after 12 months. Mild pruritus is present.

Histology Histopathological examination shows hyperkeratosis, acanthosis, and parakeratosis, both horizontal and vertical, and superficial perivascular lymphocytic infiltrate. There is prominent follicular plugging with dense keratotic material. Histopathological findings are not pathognomonical, and they can exclude other papulosquamous diseases.

Differential Diagnosis PRP has to be distinguished from psoriasis (which is sometimes very difficult) and other papulo-squamous disorders in adults and atopic dermatitis in childhood. Other reasons of erythro-

74  Pityriasis Rubra Pilaris (Divergie 1863, Besnier 1889)

derma should be excluded. T-cell lymphoma and medicamentous reaction should be taken into consideration. There is no diagnostic laboratory to confirm PRP.  Distinct clinical features of PRP include islands of normal, non-affected skin, follicular keratotic plugs, and orange-red discoloration of the affected skin.

Treatment Because of the variable clinical course and low incidence, assessment of the treatment modalities is difficult. Previously used vitamin A in high doses seems to be ineffective. Treatment modalities should include topical application of medications and systemic therapy.

Local Treatments Emollients are effective treatments for pityriasis rubra pillaris. Conservative approach is advised in juvenile cases. Keratolitics, such as salicylic acid and tar, are important in the treatment. Calcipotriol can also be effective in children. Urea is very helpful. Topical corticosteroids are not very effective. All irritating factors should be avoided. Palmoplantar keratoderma is difficult to treat. Keratolitics and corticosteroids under occlusion are advised. Dovonex (calcipotriene) should be considered. Tazarotene is also available in the treatment of PRP.

Systemic Treatments Oral synthetic retinoids are currently the treatment of choice for PRP and have largely replaced vitamin A therapy. Oral retinoids are the first choice in the treatment of widespread disease. Etretinate 0.5–1 mg/kg (in adults) or Isotretinoin 0.5–2 mg/kg is advised. Duration of treatment is from 3 to 6  months. The main disadvantage of retinoids is their teratogenic effect, which is necessary to have effective contraception, as preg-

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nancy is contraindicated for 2 years after acitretin treatment. Methotrexate is an alternative agent for refractory PRP.  Methotrexate is second line of treatment given orally 15–25 mg/weekly. Use of cyclosporine in a treatment of pityriasis rubra pillaris is still controversial. UV-light treatment (290–400  nm spectrum) uses a particular bend of the non-visible light spectrum to treat a variety of other skin diseases. It can be used alone or in combination with other medications applied directly to the skin or taken internally. PUVA and Re-PUVA are also applied in PRP with less success than in psoriasis vulgaris. UVB therapy used in psoriasis vulgaris with a success could have possible negative influence and aggravated pityriasis rubra pilaris. Oral antihistamines can be successful to decrease itching sensations. Oral megadose of vitamin seems to be not so effective. Biologics are new classes of medications that target immune system responses. The beneficial use of biologics in psoriasis is evidence-based. TNF has central role in psoriasis. There are some data emphasizing that blockade of tumor necrosis factor (TNF) alpha with antagonists of TNF-­ alpha also could have positive effect in PRP. They are administered orally (jakinibs, JAK inhibitors), by subcutaneous injection (Adalimumab, Ustekinumab, Etanercept) or by intravenous infusion (Ustekinumab, Infliximab). Biologics are in off-label use for PRP. In case of erythroderma, intensive supportive therapy is imperative.

Further Reading Albert RM, Mackool BT. Review: pityriasis rubra pilaris. Int J Dermatol. 1999;38:1–11. Ancevski G, Pavlova P.  Dermatovenerologija. 1st ed. Skopje: Kultura; 2005. Garcovich S, Di Giampetruzzi A, Antonelli G, Garcovich A, Didona B.  Treatment of pityriasis rubra pilaris. J Eur Acad Dermatol Venereol. 2010;24:881–4. https:// doi.org/10.1111/j.1468-­3083.2009.03511. Katsambas A, Lotti T.  European handbook of dermatological treatments. 2nd ed. Berlin: Springer; 2003.

788 Maloney NJ, et al. Type I pityriasis rubra pilaris treated with tumor necrosis factor inhibitors, ustekinumab, or secukinumab: a systematic review. J Am Acad Dermatol. 2018;79:585–7. Napolitano M, et  al. Biologics for pityriasis rubra pilaryis treatment: a review of the literature. J Am Acad Dermatol. 2018;79:353–9. Pearce DJ, Feldman SR. Update on infliximab: an intravenous biologic therapy for psoriasis. Expert Rev Dermatol. 2007;2(6):707–13. Petrof G, Almaani N, Archer C, Griffiths W, Smith C.  Treatment of pityriasis rubra pila-

A. Petrov and V. Pljakoska ris type 1 with TNF-antagonists. J Eur Acad Dermatol Venereol. 2013;27:e131–5. https://doi. org/10.1111/j.1468-­3083.2012.04456. Pincus DJ.  Pityriasis rubra pilaris: a clinical review. Dermatol Nurs. 2005;17(6):448–51. Roenneberg S, Biedermann T.  Pityriasis rubra pilaris: algorithms for diagnosis and treatment. J Eur Acad Dermatol Venereol. 2018;32:889–98. https://doi. org/10.1111/jdv.14761. Smith CH, et al. Biologic interventions in psoriasis. Br J Dermatol. 2009;161:987–1019.

Polymorphic Light Eruption

75

Miroslava Kadurina, Georgeta Bocheva, and Jana Kazandjieva

Key Points • Polymorphic light eruption (PLE) is the most common immuno-mediated photodermatosis affecting predominantly young women. • The itchy skin lesions of different morphology are provoked by the first intense sunlight exposures of the year. • Management of PLE nowadays is mainly focused on prophylactic strategies. • The new-generation broad-spectrum (UVA + UVB) sunscreens and sunscreens containing antioxidants or liposomal DNA repair enzymes successfully can prevent the eruption. • Prophylactic treatment with calcipotriol is a promising option for PLE. • Oral and topical antioxidants and substances with antioxidant properties could be also helpful. • Prophylactic desensitization (photohardening) temporary restores the UV-induced immunosuppression.

• Systemic treatments with corticosteroids or immunosuppressive agents are recommended mainly in the severe cases of PLE. • 20 mg of slow-release afamelanotide as a subcutaneous implant is a new therapeutic approach giving a long-lasting melanization in the skin.

Definition and Epidemiology Polymorphic light eruption (PLE) is considered the most common form of the immunologically medaited photodermatoses. This intermittent eruption has wide geographical distribution commonly in temperate than tropical places and affects about 18–20% of Europeans (mainly the fair skin types). PLE can occur at any age and in both genders, but young women suffer three to seven times more than men. Familial clustering can be seen in American Indians. This familial type of PLE has

M. Kadurina (*) Department of Dermatology, University Acibadem City Clinic, Sofia, Bulgaria e-mail: [email protected] G. Bocheva Department of Pharmacology and Toxicology, Faculty of Medicine, Medical University of Sofia, Sofia, Bulgaria J. Kazandjieva Department of Dermatology, Faculty of Medicine, Medical University of Sofia, Sofia, Bulgaria © Springer Nature Switzerland AG 2023 A. D. Katsambas et al. (eds.), European Handbook of Dermatological Treatments, https://doi.org/10.1007/978-3-031-15130-9_75

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an autosomal dominant mode with low penetrance of inheritance. Depending on the severity of the disease, patients with PLE can have significant discomfort and can lose their quality of life during spring and early summer.

Basic Concepts of Pathogenesis The main pathophysiological mechanisms in the pathogenesis of PLE include: abnormal immune response; inflammatory pathways; failure of apoptosis; decrease in antioxidant capacity, and vitamin D deficiency. PLE is considered as a delayed-type hypersensitivity response to one or more undefined, endogenous ultraviolet (UV)-induced skin antigens. These autoantigens potentially could be formed from modified proteins due to inefficient clearance of apoptotic cells. In fact, a functional failure of UV-induced immunosuppression is the crucial immunological abnormality presented by a resistance of Langerhans cells, a reduced expression of cytokines (mainly TNF-α, IL-4, and IL-10), and a decrease of neutrophil infiltration in the skin. Photo-provoked imbalance on skin microbiome may result in a release of antimicrobial peptides (AMPs) from keratinocytes. The unique expression profile of certain AMPs in PLE implicates their decisive role in the pathogenesis of the disease by modulating the inflammatory responses and by contributing to immunosuppression. The cross talk between AMPs, microbiome, and immune system needs to be further investigating. Disturbances of the antioxidant defense could contribute to onset of the disease. Vitamin D has modulating effect on the immune system and on the immunological processes in the skin. The lower vitamin D status found in PLE is risky for an increase of photosensitivity and for failure of its immunosuppressive effects on the skin. Female and thyroid hormones are likely to be involved also in the pathogenesis. Obviously, this eruption has prevalence among the women. Furthermore, hypothyroid state is more frequently found in patients with PLE.  In addition, a convincing evidence shows a link

between the pruritogenic IL-31 and the itch in PLE.

Photobiological Characteristics In PLE, UVA (320–400 nm) is mainly responsible for the induction of the lesions. Most patients with PLE have a normal minimal erythema dose (MED) value to both UVA or UVB but do not react to visible and infrared lights. The provocative phototesting is the most accepted way of reproducing the PLE lesions.

Clinical Presentation PLE usually occurs after the first intense sun exposure in spring or early summer. The skin eruption develops always within a few hours to several days after sunlight or artificial UV-light exposure and affects only the photo-exposed areas. V-area of the upper chest, arms and forearms, backs of the hands, legs, shoulders, and upper part of the back are the primary locations. The covered parts of the body are not affected unless UVA light penetrates though thin clothing. The clinical manifestations vary morphologically (explaining the name of the disease) from erythema to papules, papulovesicles and occasionally blisters, plaques, sometimes erythema multiforme (EM)-like, prurigo-like or insect bite (strophulus)-like lesions, and rarely hemorrhagic papules (purpura). Pinpoint micropapular variant presented by 1–2 mm pinpoint papules has been described as well (mainly within skin types IV– VI). In early spring, a peculiar localized forms limited to the elbows or to the helices of the ears of young boys (juvenile spring eruption) can be distinguished. Indeed, papular type of PLE is the most frequently observed (Fig. 75.1), followed by plaque type and papulo-vesicular type. Rarely, an intense pruritus on sun-exposed skin without skin eruption (PLE sine eruption) can also be seen. In the same patient, despite the name of the disease, the lesions are monomorphic. The skin

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phototest may be confirmatory. Measurement of circulating ANA and porphyrin blood levels is useful in excluding porphyrias and lupus erythematosus. The most common differential diagnoses are other photodermatoses:

Fig. 75.1  Clinical picture of polymorphic light eruption on sun-exposed skin of the upper chest of a young man

eruption lasts a few days and resolves spontaneously in about a week to 10  days when further sun exposure is avoided without leaving traces or rare with a small hyper- or hypopigmentation. Commonly, the disease has chronic course recurring annually in the same season with a tendency of gradual improvement as the summer progresses. In the most patients, a consistent lesion morphology over the years has been described. Sometimes, PLE shows progressive worsening or improvement during its course or even remits spontaneously. About 22% of patients with PLE, mainly women, develop an autoimmune disease mostly presented as Hashimoto thyroiditis (almost in 9%), systemic lupus erythematosus (SLE) (2–10%), vitiligo, and rheumatic arthritis.

Differential Diagnosis The course of eruption together with clinical manifestation of pruritic lesions on sun-exposed skin is the characteristic feature of PLE. In case of diagnostic difficulties, a provocative UV

• Solar urticaria could be confused with PLE by history, but it tends to have more rapid course with urticarial lesions developing a few minutes after sunlight exposure and resolving within 1–2 h. • Actinic prurigo is onset in early childhood, has family history of photosensitivity and atopy and lesions occurring throughout the year on both exposed and covered skin. • Hydroa aestivale-vacciniforme is another idiopathic photodermatosis characterized by a group of vesicles leaving vacciniform scars. Eczematous form of PLE should be differentiated from: • • • •

Allergic contact and photocontact dermatitis. Chronic actinic dermatitis. Airborne contact dermatitis. Exacerbated atopic dermatitis.

Patch and photopatch testing can help in such cases. PLE plaque type could be misdiagnosed with: • Tumidus type of discoid lupus erythematosus. Histology is specific and helps for the diagnosis. The other rare differential diagnosis is photosensitive erythema multiforme, which occurs after drug intake and affects also the oral mucosa.

General Principles of Treatment For all patients with PLE, basic photoprotective measures are fundamental therapeutic approach. Most cases are mild and respond successfully to prevention by avoidance of intense sun exposure, wearing protective clothing and hats, and

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topical application of broad-spectrum (UVA + UVB) sunscreens, especially during the first intense sun exposure of the year. However, the topical sunscreens mainly benefit UVBinduced PLE. The type and the amount of sunscreens used for prevention of PLE are very important. The new-­generation sunscreens with high sun protection factor (e.g., ≥30 SPF) for UVB, together with longer UVA protection capacity, could have beneficial effect even with minor applied thickness (1 mg/cm2) than guidelines suggest. If 2 mg/cm2 of sunscreen with high UVA filters is used, patients will not develop a relapse according to a recent study. Nevertheless, cases provoked by an extremely low UVA threshold cannot be prevented even with highpotent UVA filters.

Preventive Treatment Antioxidants The significantly lower level of many antioxidant enzymes in PLE suggests the use of topical and oral antioxidants. Beta-carotene as wellknown free radical scavenger has been recommended for prophylactic oral treatment at doses 75–100  mg/day. Oral administration of a nutritional supplement that contains lycopene, betacarotene, and Lactobacillus johnsonii in a 12-week treatment course has displayed a good antioxidant effect and could prevent a relapse of the disease. The oral use of nicotinamide is to correct a possible disturbance in tryptophan metabolism that was hypothesized in the PLE process. The preventive therapeutic benefit of nicotinamide (2–3  g/day before sun exposure for 2  weeks) is unconvincing as observations of the prevention have not been confirmed through controlled studies. The topical application of the plant-based antioxidants, ferulic acid, and tocopheryl acetate (the synthetic form of vitamin E), alone or in combination, may be used in practice as additional preventive measures.

Vitamin D3 and Vitamin D3 Analogues Vitamin D3 can have both preventive and therapeutic effects in PLE. A variety of abnormalities in PLE are thought to be linked with decreased vitamin D levels. Oral vitamin D supplementation could be useful in the process of restoring the immune system in PLE patients. Additional benefits from increasing of vitamin D might be a protection from UV-induced DNA damage and an improvement of the DNA repair. 1,25(OH)2D3 (the major active form of vitamin D3) and its analog calcipotriol have also shown to exhibit immunosuppressive properties. The immunosuppressive effect of calcipotriol is similar to UV irradiation in a murine study. Topical application of calcipotriol leads to dose-dependent decrease in the number and function of LCs in the epidermis. The effect of calcipotriol on LCs is found comparable with the effect of mometasone furoate (potent corticosteroid). Moreover, it has been suggested that calcipotriol exhibits beneficial anti-­ inflammatory effect probably through the modulation of AMP regulation via TH17 pathways. Topical pretreatment with calcipotriol twice daily over 1 week proved to prevent experimentally photo-provoked PLE lesions. Prophylactic treatment with calcipotriol is a novel, potentially safe, and a promising option for patients with PLE.

Phototherapy Prophylactic desensitization, known also as medical photohardening, is a helpful procedure that should begin about 1  month before the expected onset of the eruption by applying small doses of UV irradiation. Phototherapy stimulates the naturally occurring phenomenon of hardening and aims to induce photoadaptation without provoking the eruption. Medical photohardening increases the melanization in the skin and thickening of the stratum cor-

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neum, depletes neoantigen(s) and epidermal LCs, normalizes the impaired chemotaxis of neutrophils, and increases vitamin D3 serum levels. The basic phototherapeutic modalities for hardening include broadband UVB (290– 320  nm), narrow-band UVB (311  nm), and PUVA (psoralen + UVA). There is no standard regimen of PUVA or UVB therapy. The exposure is usually given 2–3 times per week for 4–6 weeks with suberythemal doses. The starting dose should be 50% of minimal phototoxic dose for PUVA or 75% of MED for UVB, followed by 20% increments. PUVA photochemotherapy shows good clinical response (65–100% photoprotection rate) but hides potential carcinogenic risk; therefore it is reserved for more severe forms of PLE. Narrow-band UVB phototherapy has become the most common method because of the ability to have equal efficacy with PUVA but less adverse effects. Photohardening temporarily restores the UV-induced immunosuppression, and this effect usually lasts for 4–6 weeks. Nevertheless, the natural photohardening is shown to be more preferable. In milder cases, graduate exposure to sunlight in early spring may be a sufficient preventive measure.

 iposomal DNA Repair Enzymes L in Sunscreens Sunscreens or after-sun lotions containing liposomal DNA repair enzymes such as photolyase from Anacystis nidulans and T4 endonucleases from Micrococcus luteus lysate have proved their effectiveness. In a photoprovocative test on volunteers, these enzymes incorporated through liposomes led to significantly diminished symptoms in PLE, most probably by enhancing both DNA repair and the removal of UV-induced DNA photoproducts immediately after UV exposure.

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Ectoin The natural substance from halophilic bacteria, ectoin might be helpful in PLE working via protection of LCs from UV impairment. Ectoin is used also for prevention of UVA-induced premature photoaging.

Polypodium Leucotomos Extract The hydrophilic extract of the tropical fern leaves, Polypodium leucotomos situated in Central and South America contains polyphenolic compounds and shows potent antioxidant and immunomodulatory effects. Preventive treatment before sun exposure (480  mg/day) can significantly reduce skin eruption and subjective symptoms.

 reventive Treatment at a Glance P • Oral antioxidants, such as beta-carotene, could be useful for restoring the antioxidant defense, especially in hypothyroid patients with PLE. • Topical application of suitable antioxidants could be helpful. • Liposomal DNA repair enzymes in sunscreens and after-sun lotions may diminish the symptoms of PLE. • Natural extract from Polypodium leucotomos administrated orally at 480 mg/day or locally before sun exposure would be helpful antioxidant and immunomodulatory agent. • Vitamin D3 and its analog calcipotriol are promising and safe preventive treatments. Topical calcipotriol twice daily over 1  week could prevent the eruption. • Photohardening includes PUVA, narrow and broad UVB, and is used to restore the UV-­ induced immunosuppression. This desensitization treatment should be done at least a month before the first intense sun exposure.

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• Natural photohardening is preferable. Graduate sun exposure in early spring may be sufficient preventive measure in milder cases.

Topical Treatments Topical Corticosteroids Topical corticosteroids can be used in the milder forms of PLE to reduce the inflammation and itch and to shorten the duration of the skin eruption. Mild to moderate topical corticosteroids in a cream and lotion form are preferred.

Systemic Treatments Systemic treatments are recommended mainly in the severe cases of PLE.

Systemic Corticosteroids Systemic corticosteroids can be administrated at the beginning of the eruption or even prior to the risk period to help suppress the reaction. Short course with oral prednisone (40–60  mg/ day for 7–10 days) or prednisolone (25–30 mg/ day for 5–7  days) is effective therapy at the onset of PLE.

Immunosuppressive Drugs Azathioprine (50–100 mg/day) could be a beneficial option in the treatment of severe and refractory cases. Cyclosporine (3–4  mg/kg/ day) is reported to be also effective in some

severe forms. Antimalarials (chloroquine and hydroxychloroquine 125–500  mg/day) as immunosuppressive agents have been considered as a successful therapy of PLE for a long period of time. Now, however, some studies have failed to show reproducible results. It is possible that the beneficial effect of chloroquine, reported earlier, was perhaps for cases of photosensitive lupus erythematosus, misdiagnosed as PLE.

Antihistamines Systemic non-sedative H1 blockers from second generation (loratadine, cetirizine, bilastine) and their active metabolites or isomers (desloratadine, levocetirizine, and fexofenadine) are occasionally used only to reduce itching.

 opical and Systemic Treatment at T a Glance • Topical corticosteroids and systemic antihistamines are widely used as first-line drugs in PLE to reduce itch. • Short courses with oral systemic corticosteroids are second-line drugs, which are effective at the beginning of the eruption. • Immunosuppressors azathioprine and cyclosporine could be a beneficial third-line option in some severe and refractory cases.

Future Perspectives The new therapeutic strategies based on a better understanding of the pathogenesis of PLE may also help to improve the prevention and treatment outcomes and ultimately patient satisfaction and quality of life in practice.

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Afamelanotide Afamelanotide is the first α-melanocyte stimulating hormone (MSH) analog implemented on volunteer participants. It was synthesized in 1980 and widely investigated in all aspects of pigmentation. Lately, afamelanotide is an innovative therapeutic option for a variety of refractory to other treatments of skin diseases, including PLE.  By increasing the skin pigmentation, afamelanotide has the potential to exert a photoprotection similar to an adaptation due to the photohardening. Additionally, afamelanotide via binding to the melanocortin-1 receptor enhances DNA repair and induces antioxidants. Only subcutaneous application demonstrates full bioavailability of the drug. Slow-release afamelanotide should be applied as 20 mg subcutaneous implant, thus leading to the decrease of the cutaneous reaction.

IL-31 The increased expression of IL-31 and its possible role in the pathogenesis of the pruritus in PLE open a new road for the development of future treatment strategies targeting IL-31.

Further Reading Bansal I, Kerr H, Janiga JJ, et al. Pinpoint papular variant of polymorphous light eruption: clinical and pathological correlation. J Eur Acad Dermatol Venereol. 2006;20:406–10. Bissonnette R, Nigen S, Bolduc C.  Influence of the quantity of sunscreen applied on the ability to protect against ultraviolet-induced polymorphous light eruption. Photodermatol Photoimmunol Photomed. 2012;28:240–3. Dover JS, Hawk JL. Polymorphic light eruption sine eruption. Br J Dermatol. 1988;118:73–6. Gruber-Wackernagel A, Byrne SN, Wolf P. Polymorphous light eruption: clinic aspects and pathogenesis. Dermatol Clin. 2014;32:315–34. Guarrera M. Polymorphous light eruption. Adv Exp Med Biol. 2017;996:61–70.

795 Kadurina M, Kazandjieva J, Bocheva G. Immunopathogenesis and management of polymorphic light eruption. Dermatol Ther. 2021;34(6):e15167. https://doi.org/10.1111/dth.15167. Kerr HA, Lim HW.  Photodermatoses in African Americans: a retrospective analysis of 135 patients over a 7-year period. J Am Acad Dermatol. 2007;57:638–43. Kim HS, Yosipovitch G. The skin microbiota and itch: is there a link? J Clin Med. 2020;9:1190. Kontos AP, Cusack CA, Chaffins M, Lim HW.  Polymorphous light eruption in African Americans: pinpoint papular variant. Photodermatol Photoimmunol Photomed. 2002;18:303–6. Lembo S, Raimondo A.  Polymorphic light eruption: what’s new in pathogenesis and management. Front Med (Lausanne). 2018;5:252. https://doi.org/10.3389/ fmed.2018.00252. McNeil MM, Nahhas AF, Braunberger TL, Hamzavi IH.  Afamelanotide in the treatment of dermatologic disease. Skin Therapy Lett. 2018;23:6–10. Minder EI, Barman-Aksoezen J, Schneider-Yin X.  Pharmacokinetics and pharmacodynamics of Afamelanotide and its clinical use in treating dermatologic disorders. Clin Pharmacokinet. 2017;56:815–23. Patra V, Wolf P. Microbial elements as the initial triggers in the pathogenesis of polymorphic light eruption? Exp Dermatol. 2016;25:999–1001. Patra V, Mayer G, Gruber-Wackernagel A, Horn M, et al. Unique profile of antimicrobial peptide expression in polymorphic light eruption lesions compared to healthy skin, atopic dermatitis, and psoriasis. Photodermatol Photoimmunol Photomed. 2018;34:137–44. Patra V, Strobl J, Gruber-Wackernagel A, et al. CD11b(+) cells markedly express the itch cytokine interleukin31  in polymorphic light eruption. Br J Dermatol. ­ 2019;181:1079–81. Rhodes LE, Bock M, Janssens AS, et  al. Polymorphic light eruption occurs in 18% of Europeans and does not show higher prevalence with increasing latitude: multicenter survey of 6,895 individuals residing from the Mediterranean to Scandinavia. J Invest Dermatol. 2010;130:626–8. Sharma L, Lamba S, Singh S.  Thyroid function tests in cases of polymorphic light eruption: a case-control study. Indian Dermatol Online J. 2014;5:291–5. Stratigos AJ, Antoniou C, Katsambas AD. Polymorphous light eruption. J Eur Acad Dermatol Venereol. 2002;16:193–206. Tanew A, Radakovic S, Gonzalez S, et al. Oral administration of a hydrophilic extract of Polypodium leucotomos for the prevention of polymorphic light eruption. J Am Acad Dermatol. 2012;66:58–62. Wolf P, Gruber-Wackernagel A, Rinner B, et  al. Phototherapeutic hardening modulates systemic cytokine levels in patients with polymorphic light eruption. Photochem Photobiol Sci. 2013;12:166–73.

The Cutaneous Porphyrias

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Robert P. E. Sarkany

Key Points • Porphyrias are caused by defects in the haem biosynthesis pathway. • Not all porphyrias cause skin disease. • Porphyrias can only be diagnosed by laboratory porphyrin analyses. • Porphyrias are generally hereditary diseases, except for porphyria cutanea tarda. • Porphyria cutanea tarda is often caused by other systemic diseases. • Photoprotection in the porphyrias must be against visible light. • Porphyria cutanea tarda and erythropoietic protoporphyria can be associated with liver disease. • Variegate porphyria can cause dangerous acute porphyric attacks.

The Biosynthesis of Haem

Definition and Epidemiology

Classification

The porphyrias all result from a partial deficiency of one of the enzymes required for the biosynthesis of haem, thus causing accumulation of the enzyme’s substrate. The toxicity profile of the accumulated molecule determines the clinical features of the resulting porphyria.

Porphyrias present with either skin disease or acute attacks or both. In any porphyria, a partial enzyme deficiency causes the accumulation of porphyrins. The porphyrias may be classified, according to the predominant site of porphyrin accumulation, into erythropoietic (congenital erythropoietic porphyria and erythropoietic protoporphyria) and

Haem is synthesized from simple biochemicals (glycine and succinyl CoA) via an eight-step pathway, each step being catalysed by an enzyme. Synthesis of the pyrrole ring (porphobilinogen (PBG)) is followed by assembly of the tetrapyrrole structure (hydroxymethylbilane). The carboxylic acid side chains of uroporphyrinogen III are progressively decarboxylated via coproporphyrinogen III to protoporphyrinogen, which is then oxidized to protoporphyrin IX. Finally, ferrous iron is chelated into the protoporphyrin’s central cavity to form haem. Around 80% of haem is synthesized in erythroid cell precursors in the bone marrow (for haemoglobin production) (Elder 1999a).

R. P. E. Sarkany (*) Photodermatology Unit, St John’s Institute of Dermatology, London, UK e-mail: [email protected] © Springer Nature Switzerland AG 2023 A. D. Katsambas et al. (eds.), European Handbook of Dermatological Treatments, https://doi.org/10.1007/978-3-031-15130-9_76

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Basic Concepts of Pathogenesis

Glycine + succinyl CoA ALA synthase

δ-aminolaevulinic acid ALA dehydratase

porphobilinogen Porphobilinogen deaminase

AIP

hydroxymethylbilane uroporphyrinogen III cosynthase

CEP uroporphyrinogen Ι

uroporphyrinogen ΙΙΙ uroporphyrinogen decarboxylase

PCT coproporphyrinogen Ι

coproporphyrinogen ΙΙΙ coproporphyrinogen oxidase

HC

protoporphyrinogen ΙΧ protoporphyrinogen oxidase

VP

Photons of violet light (wavelength peak 408 nm) transform the porphyrin molecule into an excited singlet state. This may revert to the unexcited ground state by emission of characteristic red fluorescence, but intersystem crossing can convert it to an excited triplet state, which interacts with other molecules, particularly molecular oxygen, converting it to excited singlet oxygen in the process. The singlet oxygen stimulates production of hydroxyl radicals which damage tissue directly and indirectly by stimulating complement activation (Lim et  al. 1984), mast cell degranulation (Glover et al. 1990) and matrix metalloproteinase activity (Herrmann et  al. 1996). The histological site of this phototoxic reaction in the skin determines the clinical characteristics of the porphyria (Brun and Sandberg 1991; Takeshita et al. 2004).

General Principles of Treatment

protoporphyrin ΙΧ Fe2+

ferrochelatase

EPP

haem

Fig. 76.1  The pathway of haem biosynthesis and the diseases caused by deficiency of each enzyme. Abbreviations: AIP acute intermittent porphyria, CEP congenital erythropoietic porphyria, PCT porphyria cutanea tarda, HC hereditary coproporphyria, VP variegate porphyria, EPP erythropoietic protoporphyria

hepatic (all the others) types (Elder 1999a) (Fig. 76.1). For the clinician, the key division is between porphyrias that cause acute attacks and those that cause skin disease: 1. Cutaneous disease only: (a) Porphyria cutanea tarda (PCT). (b) Congenital erythropoietic porphyria (CEP). (c) Erythropoietic protoporphyria (EPP). 2. Cutaneous disease and acute attacks: (a) Hereditary coproporphyria (HC). (b) Variegate porphyria (VP). 3. Acute attacks only: (a) Acute intermittent porphyria (AIP).

The management of the skin disease involves preventing violet (Soret wavelength) light penetrating the epidermis. The connection between sun exposure and symptoms is obvious in EPP but is not obvious in the bullous porphyrias where fragility and blistering are not related to individual episodes of sun exposure. Basic measures include sun avoidance behaviour, sun-protective clothing and hats. Most sunscreens do not protect against violet light. Sunscreens containing reflectant particles, particularly large particle-size titanium dioxide (pigmentary grade), zinc oxide and iron oxide, can effectively protect against violet light (e.g. Dundee sunscreen (Tayside Pharmaceuticals, Dundee, UK)) (Moseley et  al. 2001; Kaye et al. 1991). Some window films can absorb violet light and are useful on car or home windows, particularly in EPP and CEP.

Acute Attacks of Porphyria AIP, HC and VP can all cause acute attacks, and HC and VP may also cause cutaneous disease. Acute attacks are potentially fatal episodes of an

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acute systemic neurotoxic reaction, which are frequently triggered by drugs and hormones. This non-dermatological aspect is not covered here. Patients diagnosed by a dermatologist with a porphyria that has the potential to cause acute attacks (e.g. VP) should be referred to a specialist in the management of acute porphyria who will counsel the patient regarding avoidance of acute attack-­ precipitating factors, treat any acute attacks that occur and genetically test the family for the ­disease. The diagnosis of an acute porphyria cannot be excluded by porphyrin testing (outside the acute attack situation).

Laboratory Testing in Porphyria

What Samples to Send In an adult with suspected bullous porphyria, it is generally sufficient to analyse urine and either plasma (where fluorimetry is available) or faeces (where it is not). Urine, plasma and faeces need to be analysed in children, because of the increased complexity of the differential diagnosis. Faecal analysis is necessary when urine and plasma results do not differentiate HC from CEP and, in renal failure, where urine may be unavailable and plasma analysis unhelpful because renal failure increases plasma porphyrins. In suspected EPP, red cells and either plasma or faeces should be analysed.

Handling of Samples

Although clinical features may raise the possibility of a porphyria, the cutaneous presentations of several porphyrias are very similar. Precise diagnosis is essential because of the great differences in clinical management between porphyrias which can be clinically identical. An accurate diagnosis can only be made on the basis of porphyrin analyses carried out in an experienced laboratory. The clinician’s role is to suspect the diagnosis of cutaneous porphyria and to use laboratory testing to confirm whether this is the diagnosis and if so, to precisely identify the porphyria (Table  76.1) (Deacon and Elder 2001); Woolf et al. 2017).

Laboratory testing of body fluids measures porphyrins, since porphyrinogens are spontaneously oxidized to their respective porphyrins outside the body. Porphobilinogen has a tendency to polymerize to other molecules, but porphyrins are reasonably stable when protected from light. All specimens should be kept at room temperature (or 4 °C) in the dark and, ideally, should be analysed within 48 h of collection. For urine and faecal analysis, fresh random specimens (10–20 mL urine or 5–10 g dry weight faeces) are preferable to 24  h collections. Very dilute urine (creatinine  4/10 on a visual analogue scale

4. Localized pathergy phenomenon

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Table 80.1 (continued) Criteria

Su et al. (2004)

Additional criteria

Requirements Diagnosis requires both major criteria and at least two minor criteria

Delphi consensus (2018) PARACELSUS score (2019) 6. Multiple ulcers, at least one on the anterior lower leg 7. Cribriform or wrinkled paper scars at healed ulcer sites 8. Decrease in ulcer size after immunosuppressive treatment 5. Suppurative inflammation in histopathology 6. Undermined wound borders 7. Associated systemic disease Diagnosis requires single major Diagnosis requires a total score value of 10 points or higher criterion Each major criterion corresponds to The addition of 4 or more of the eight minor criteria yields a a value of 3 points Each minor criterion corresponds to sensitivity of 86% and a a value of 2 points specificity of 90% for PG Each additional criterion corresponds to a value of 1 point

Differential Diagnosis

General Principles of Treatment

Seven disease categories may imitate the clinical appearance of PG:

Treatment of PG is selected according to severity and rate of progression.

• Vascular occulusive or venous disease: calciphylaxis, venous stasis ulceration • Vasculitis: Wegener’s granulomatosis, Polyarteritis nodosa, Takayasu’s arteritis, Antiphospholipid syndrome • Infectious diseases: deep fungal infections (Sporotricosis, Zygomycosis); bacterial infections (ecthyma, erysipelas, gangrene, necrotizing fasciitis); parasitic infections; viral infections; late syphilis; cutaneous tuberculosis • Insect or spider bites • Drug reactions • Malignancy: malignant processes involving the skin (Keratoacanthoma, Squamous cell carcinoma, T and B-cell Lymphomas) • Dermatitis artefacta

Topical Treatment  ptimization of Wound Care O Dressings and compression are important in cases of classical PG on the leg where wound healing can be delayed by vascular disease. As most of the ulcers show heavy exudates, foam/ laminate dressings are recommended. In case of purulent ulcers, alginate dressings are optional. Hyperbaric oxygen therapy is also proposed as a good treatment method in a single case. Skin grafting, microvascular flap grafting, cultured keratinocyte autografts, and allografts might be therapeutic options in nonprogressive PG.

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Topical Corticosteroids Corticosteroids might be useful topically applied to the ulcer surface or intralesionaly injected at the active borders of the ulcer. Applications of beclomethasone inhaler in a case of peristomal PG have been reported to be successful.

Calcineurin Inhibitors Application of calcineurin inhibitors like tacrolimus or pimecrolimus over the ulcer surface may accelerate healing in some cases. Because of pathergy phenomenon, surgical debridement is contraindicated.

Systemic Treatments Systemic Corticosteroids Oral corticosteroids (0.5–2  mg/kg/day) or pulse therapy are widely used as an initial therapy. They are helpful especially in the acute, rapidly progressive form of the disease. Gulliver's sign can be used to guide the tapering of corticosteroids and other immunosuppressant therapies in the treatment of PG. Gulliver’s sign: The inflammatory stage of PG is characterized by wound borders, which are elevated, erythematous, and sometimes necrotic. This stage differs from the healing stage in which the borders are more flat and string-like growths of epithelium connect the border between the ulcer bed and the normal surrounding skin. This transition to the healing phase has been named “Gulliver's sign.”

J. Kazandjieva and N. Tsankov

Treatment with Azathioprine (100–150  mg/ day), Methotrexate, or Cyclophosphamide pulse therapy is another option for steroid-refractory PG.

Mycophenolate Mofetil Mycophenolate mofetil (2 g/day) used in peristomal PG.

Intravenous Immunoglobulin High doses of intravenous immunoglobulin (IVIG) are useful as adjuvant treatment, particularly in recalcitrant PG. The dose is 2 g/kg administered over 2–3 consecutive days, every month for at least 6 months.

Dapsone The combination of steroids with diaminodiphenylsulfone is used in milder cases of PG.  The dose is up to 200 mg daily. The formation of met-­ hemoglobin needs regular monitoring during this treatment. Screening for glucose-6-phosphate dehydrogenase deficiency is needed prior to Dapsone therapy.

Immunosuppressive Therapy

Clofazimine Alternative treatment with Clofazimine is another option. The dose is 300–400  mg/day. First, Michaelsson et  al. announced Clofazimine as being beneficial in the treatment of PG, particularly in recalcitrant cases. Several other authors reported about small case series with remarkably good effect after Clofazimine treatment, with rapid healing of the lesions commencing 3–14 days after treatment was started.

Immunosuppressive therapy with ciclosporin is helpful for widespread PG treatment. Ciclosporin can be used either alone or in combination with corticosteroids. Doses of 2–3 mg/kg body weight are effective. Ciclosporin A induces an early response but has no impact for the rate of PG relapses.

Thalidomide, Colchicin Thalidomide and Colchicin are another two drugs used with varying success, single or in combination with steroids. Thalidomide has its place in the modern medicine as it owns strong therapeutic potential, but its use is limited due to the potent teratogenic activity (phocomelia).

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Biologic Therapy Biologics use in PG is “off label” option, and there is still no consensus about the application of these drugs in the treatment of PG. Small studies for the efficacy of Infliximab, Etenercept, Adalimumab, Certolizumab pegol, Golimumab, Anakinra, Canakinumab (phase II clinical study), and Gevokizumab (phase II clinical study) were published. Most of these studies describe complete resolution or substantial improvement, but some patients were refractory to the biological therapy. The efficacy of Tocilizumab, Ustekinumab, Vedolizumab, and Visilizumab for the management of PG was discussed in several cases. New studies discuss the use of JAK/STAT inhibitors and phosphodiesterase 4 inhibitors as a treatment option in PG. Prognosis In the majority of patients, the long-term outcome of PG remains unpredictable. PG is still potentially life threatening with a mortality rate of up to 30% in some series. Death from PG may occur due to an associated disease or as a result of therapy. Factors possibly associated with poorer prognosis are clinical signs of wound infection, malignant variant of PG, presence of associated systemic disease, and unresponsiveness of the associated disease to treatment.

Further Reading Alberts JH, Sams HH, Miller JL, et al. Familial ulcerative pyoderma gangrenosum: a report of 2 kindred. Cutis. 2002;69:427–30. Ashchyan HJ, Butler DC, Nelson CA, et  al. The association of age with clinical presentation and comorbidities of pyoderma gangrenosum. JAMA Dermatol. 2019;154(4):409–13. Binus AM, Qureshi AA, Li VW, et  al. Pyoderma gangrenosum: a retrospective review of patient characteristics, comorbidities and therapy in 103 patients. Br J Dermatol. 2011;165:1244–50. Braun-Falco M, Kovnerystyy O, Lohse P, et al. Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH)—a new autoinflammatory syndrome distinct from PAPA syndrome. J Am Acad Dermatol. 2012;66:409–15. Brocq L.  Nouvelle contribution a l’etude du phagedenisme geometrique. Ann Dermatol Syphilogr (Paris). 1916;6:1–39.

865 Brunsting LA, Goeckerman WH, O’Leary PA. Pyoderma (ecthyma) gangrenosum: clinical and experimental observations in five cases occurring in adults. Arch Dermatol Syph. 1930;22:655–80. Fletcher J, Alhusayen R, Alavi A.  Recent advances in managing and understanding pyoderma gangrenosum. F1000Res. 2019;8:F1000 Faculty Rev-2092. Graham JA, Hansen KK, Rabinowitz LG, et al. Pyoderma gangrenosum in infants and children. Pediatr Dermatol. 1994;11:10–7. Haag CK, Ortega-loayza AG, Latour E, et  al. Clinical factors influencing the response to intravenous immunoglobulin treatment in cases of treatment-­ resistant pyoderma gangrenosum. J Dermatolog Treat. 2019;0(0):1–4. Jockenhöfer F, Wollina U, Salva K, et  al. The PARACELSUS score: a novel diagnostic tool for pyoderma gangrenosum. Br J Dermatol. 2019;180(3):615–20. Langan SM, Groves RW, Card TR, et al. Incidence, mortality, and disease associations of pyoderma gangrenosum in the United Kingdom: a retrospective cohort study. J Invest Dermatol. 2012;132:2166–70. Levell NJ, Skellett AM, Chriba M.  Beclomethasone inhaler used to treat pyoderma gangrenosum. Clin Exp Dermatol. 2010;35:337–8. Madke B, Kar S, Yadav N. Newly described signs in dermatology. Indian Dermatol Online J. 2015;6:220–1. Martinez-Rios C, Jariwala MP, Highmore K, et  al. Imaging findings of sterile pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome: differential diagnosis and review of the literature. Pediatr Radiol. 2019 Jan;49(1):23–36. Marzano AV, Fanoni D, Antiga E, et  al. Expression of cytokines, chemokines and other effector molecules in two prototypic autoinflammatory skin diseases, pyoderma gangrenosum and Sweet’s syndrome. Clin Exp Immunol. 2014;178:48–56. Maverakis E, Ma C, Shinkai K, et  al. Diagnostic criteria of ulcerative pyoderma gangrenosum: a delphi consensus of international experts. JAMA Dermatol. 2018;154(4):461–6. Mazokopakis EE, Kofteridis DP, Pateromihelaki AJ, et al. Improvement of ulcerative pyoderma gangrenosum with hyperbaric oxygen therapy. Dermatol Ther. 2011;24:134–6. Oka M.  Pyoderma gangrenosum and interleukin 8. Br J Dermatol. 2007;157:1279–81. Reichrath J, Bens G, Bonowitz A, et al. Treatment recommendations for pyoderma gangrenosum: an evidence– based review of the literature based on more than 350 patients. J Am Acad Dermatol. 2005;53:273–83. Su WPD, Davis MDP, Weenig RH, et al. Pyoderma gangrenosum: clinicopathologic correlation and proposed diagnostic criteria. Int J Dermatol. 2004;43:790–800. Wollina U. Pyoderma gangrenosum—a review. Orphanet J Rare Dis. 2007;2:19. Yamamoto T. Epidemiology of pyoderma gangrenosum in Japanese patients by questionnaire survey. J Dermatol. 2019;46(4):e145–6.

81

Rosacea Elizabeth Keeling and Siona Ni Raghallaigh

Key Points  • Rosacea is a common chronic inflammatory facial dermatosis, more frequently diagnosed in patients with lighter skin types. • Its pathophysiology remains incompletely understood; however, the process involves an abnormal cutaneous innate immunity, neurovascular dysregulation, altered vasculature and epidermal barrier dysfunction. • A classification system based on a phenotypic approach provides a useful guide to medical treatment. • Topical alpha-adrenoreceptor agonists are used to treat fixed facial erythema and flushing. Oral beta-blockers and vascular laser therapy may also be useful. Topical antibiotics and topical ivermectin are important in the management of papules and pustules. • For more severe disease, oral antibiotics, in particular tetracyclines are used. Low-dose doxycycline has been shown to be effective in papulopustular rosacea. Isotretinoin can be

Professor Frank Powell, the first edition author of this chapter, has provided his permission to include material used in the original edition of this chapter.

employed for treatment resistant rosacea or non-inflammatory phymatous change. • Ocular rosacea is managed with topical agents including antibiotics and ciclosporin; referral to ophthalmology may be necessary. • Skin care management, photoprotection, patient education and psychological support are important in optimising control of this disease.

Definition Rosacea is a chronic relapsing inflammatory dermatosis affecting mainly the centrofacial region of adults of Northern European heritage with fair skin. A spectrum of clinical signs and symptoms ranges from transient and persistent facial erythema, telangiectasia, inflammatory papules and pustules, sebaceous gland hypertrophy and ocular changes, according to the predominant phenotype of rosacea involved. Many patients report increased facial skin sensitivity and dryness and can often identify particular exacerbates, which worsen their condition. The progression of rosacea is variable and at times unpredictable, with sporadic periods of exacerbation and remission. For some patients, the psychosocial impact of this disorder can be marked.

E. Keeling (*) · S. Ni Raghallaigh Department of Dermatology, Beaumont Hospital, Dublin, Ireland © Springer Nature Switzerland AG 2023 A. D. Katsambas et al. (eds.), European Handbook of Dermatological Treatments, https://doi.org/10.1007/978-3-031-15130-9_81

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Epidemiology Rosacea is a common disorder. Exact prevalence rates vary between studies, likely due to discrepancies in disease definition, diagnostic methods and study populations. It is likely that the true prevalence is underestimated, as many patients do not seek medical care for the condition, viewing it as a cosmetic issue. A recent systematic review of the published literature, including 32 studies examining a total of 41 populations with over 26 million individuals, estimated that 5.46% of the adult population is affected by rosacea (Gether et  al. 2018). The highest prevalence of rosacea was observed among individuals aged 45–60 years. Although it had been believed that rosacea more commonly affects women, this systematic review did not reveal a difference in prevalence between genders (Gether et al. 2018). It is recognised that men are more likely to develop phymatous changes. Facial erythema and telangiectasia are commonly reported in rosacea. However, these features can be difficult to distinguish clinically from the facial skin changes induced by chronic exposure to ultraviolet light (heliodermatitis), creating diagnostic difficulty. Epidemiologic reports frequently state rosacea that occurs more commonly in fair-skinned individuals (Fitzpatrick skin types I and II), but rosacea is likely underdiagnosed in darkly pigmented skin as facial flushing, telangiectasia and erythema are less visible. This can lead to misdiagnosis and delayed diagnosis in this group (Alexis et al. 2019).

Classification and Clinical Presentation The most recent expert panel review on the classification of rosacea in 2017 by the global ROSacea COnsensus (ROSCO) panel recommended a phenotypic approach to diagnosis (Tan et al. 2017) (see Table 81.1). They agreed that the following were diagnostic of rosacea: (1) Fixed centrofacial erythema in a characteristic pattern that may periodically intensify and (2) phymatous changes. They also concluded that in the

Table 81.1 Phenotypic classification of rosacea— ROSCO 2017 update Diagnostic phenotypes Fixed centrofacial erythema in a characteristic pattern that may periodically intensify Phymatous changes

Major phenotypes Papules and pustules

Secondary phenotypes Burning and stinging

Flushing

Facial oedema Dry sensation of the skin

Telangiectasia

Ocular manifestations

Fig. 81.1  Inflammatory papules and pustules affecting the cheek with surrounding erythema. Note the coexistent rhinophyma as evidenced by tortuous, dilated vessels on the nose as well as large, patulous follicular ostia

absence of a diagnostic phenotype, the presence of 2 or more of the following major features can be diagnostic: papules and pustules (see Fig. 81.1); flushing; telangiectasia (see Fig. 81.2) and ocular manifestations (see Fig.  81.3). Secondary signs and symptoms include burning and stinging, facial oedema or dry sensation of the skin. A previous classification for rosacea developed in 2002 classified the condition into four main subtypes (erythematotelangectatic, papulopustular, phymatous and ocular) based on the predominant lesion morphology (Wilkin et al. 2002). However, this did not account for presen-

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The presentation of ocular rosacea can range from symptomatic dry eyes to more severe disease, such blepharitis and meibomian gland dysfunction (Thiboutot et  al. 2020). Approximately 20% of patients have ocular findings before dermatological evidence of rosacea, and the diagnosis may cause difficulty, particularly in those who never progress to develop cutaneous findings (Browning and Proia 1986). Other variants of rosacea include rosacea fulminans (very sudden onset of inflammatory lesions; may have associated fever), rosacea conglobata (inflammatory cysts and scarring) and granulomatous rosacea (persistent red-brown to skin coloured papules; non-caseating granulomatous histology).

Histopathology

Fig. 81.2  Telangiectatic vessels on the nose with surrounding erythema

Fig. 81.3  Ocular rosacea. Erythema, telangiectasia and oedema of the upper eyelid, with milder features evident on the lower lid. This patient also has features of papulopustular rosacea affecting the cheek

tations that span more than one subtype. Feature severity should be assessed using a 5-point categorical scale ranging from clear to severe.

The histopathological findings of rosacea are not diagnostic, and biopsy is not usually recommended. The microscopical features reflect the pathogenesis of the condition with a vascular and inflammatory response, associated dermal oedema and the frequent finding of Demodex mites, which stimulate further inflammatory reactions. The histopathological features vary. Erythema and telangiectasia show epidermal spongiosis and the presence of Demodex mites. The dermis shows vascular dilatation with angulated vessels in the superficial and mid-dermis. A perivascular lymphohistiocytic reaction, with primarily CD4 lymphocytes is usually seen. Papules and pustules in rosacea show epidermal spongiosis and exocytosis. Pustules are predominantly follicular based with a neutrophilic response around the infundibula and often associated with the presence of Demodex mites. Papules are typically associated with a perifollicular lymphocytic infiltrate. In addition, solar elastosis is typically present. Granulomatous rosacea shows large granulomas with central neutrophils, which frequently, on the evaluation of levels, show a Demodex mite. The vascular and inflammatory response is less marked in this subtype of rosacea.

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Phymatous rosacea is characterised by large sebaceous hyperplastic glands with a normal structure, but filled with lamellar keratin and the presence of Demodex mites. This may be associated with cysts, inflammation and adjacent fibrosis (Cribier 2013).

Basic Concepts of Pathogenesis The pathogenesis of rosacea is complex and multifactorial, involving numerous pathogenic pathways, many of which overlap. These include the following:

Genetic Factors While the genetic component of rosacea remains poorly understood, certain features suggest a genetic component in the pathogenesis of the condition. Rosacea is more common in those of Northern European descent and concordance in monozygotic twins has been demonstrated. Rosacea has also been shown to be associated with autoimmune conditions. The results of a genome wide association study including 22,952 individuals identified two single-nucleotide polymorphisms in association with rosacea, and three HLA alleles were shown to be associated with the condition (Chang et  al. 2015). Further research into this area is required.

Dysregulated Cutaneous Immunity Innate immunity leads to a controlled release of cytokines and antimicrobial molecules such as the peptide cathelicidin (LL-37). Dysregulation of the innate immune system plays an important role in the pathogenesis of rosacea. There is upregulation of cathelicidin and its processing serine protease (kallikrein 5). Cathelicidin peptides and their enzymes have pro-inflammatory and angiogenic activity. There are increased lev-

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els of toll-like receptor 2 (TLR2) in patients with rosacea. Toll-like receptors (TLRs) are pathogen-­ associated molecular pattern sensors that are involved in the innate immunity of the skin. In the lesional skin of patients with rosacea, keratinocytes express elevated levels of TLR2, leading to increased expression and activity of kallikrein proteases. Matrix metalloproteinases (MMPs), which activate kallikrein 5, are also increased in patients with rosacea. Dysfunction of the innate immune system may be related to other associated features of rosacea such as the skin’s response to ultraviolet radiation. In addition to abnormalities in the innate immunity of the skin, aberrancies in the adaptive immunity (TH1 and TH 17 cytokines and B cells) have also been demonstrated (Buhl et al. 2015).

Epidermal Barrier Dysfunction Dryness, stinging and burning are common features of rosacea. Abnormal skin barrier homeostasis has been demonstrated in rosacea patients, as evidenced by increased transepidermal water loss (TEWL) and increased sensitivity to a skin irritation test. Patients with papules and pustules have a more alkaline centrofacial region and reduced epidermal hydration levels as compared with controls (Ní Raghallaigh and Powell 2014). In addition, these patients have reduced levels of sebaceous long-chain saturated fatty acids, which are known to contribute to the barrier function of the stratum (Ní Raghallaigh et  al. 2012). It has been suggested that increased serine protease levels in rosacea subjects may contribute to decreased skin barrier function (Hachem et  al. 2006).

Neurogenic Inflammation Neuromediators, released by sensory nerve endings and other cells such as keratinocytes, activated endothelial cells and fibroblasts and induce neurogenic inflammation, resulting in vasodilata-

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tion, oedema and inflammation. Recent research in rosacea has focused on transient receptor potential (TRP) cation channels. Four vanilloid receptors and one ankyrin receptor within the TRP family of cation channels have been shown to play a role in neurogenic dysregulation in rosacea. Activation of TRPs results in the release of substance P and calcitonin gene-related peptide, important mediators of neurogenic inflammation and pain. TRPA channels are thought to mediate flushing in rosacea by neurogenic vasodilation. TRPA1 channels are thermosensitive and can also be activated by spices, such as mustard oil and cinnamaldehyde, the main constituent of cinnamon (Two et al. 2015). Rosacea patients have higher perceptions of burning compared with control subjects (Guzman-Sanchez et  al. 2007), which may be secondary to increased activity of both TRPV1 and TRPA1 receptors.

Vascular Alterations Increased blood flow in skin lesions of rosacea has been demonstrated. Rosacea patients flush more readily in response to heat as compared with controls, and their heat pain thresholds have been demonstrated to be lower. In addition, there is elevated expression of vascular endothelial growth factor (VEGF), CD31 and lymphatic endothelium marker D2–40, suggesting the presence of an increased stimulant for vascular and lymphatic cells in rosacea.

Role of Microorganisms Differences in the skin flora between those with rosacea and those without are thought to play a role in the pathogenesis of the condition. These include an altered burden of commensals including Demodex folliculorum and Staphylococcus epidermidis and the presence of organisms not typical to healthy skin flora such as Bacillus oleronius. It has been suggested that different strains of S. Epidermidis which secrete virulence

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factors not usually found in healthy skin are present in those with rosacea. These factors may upregulate the innate immune system (Two et al. 2015). Additionally it is thought D. folliculorum and S. epidermidis may stimulate Toll-like receptor 2 to enhance immune dysregulation. Demodex mites are commensals of normal skin but are found in greater numbers in rosacea patients, and infestation has been shown to be associated with an intense perifollicular infiltrate of predominantly CD4 helper T cells. Antigenic proteins related to a gram-negative bacterium (Bacillus oleronius) isolated from a Demodex mite have been shown to stimulate an inflammatory response in patients with rosacea. Demodex mites and their associated bacteria may induce an upregulation in surrounding cutaneous proteases, thereby potentiating the dysregulation of the local innate immune response. It has been proposed that chitin, released from these mites, could serve as the trigger for TLR2 on keratinocytes and link Demodex with increased protease activity and cathelicidin-induced inflammation in rosacea. The role of Helicobacter pylori and other intestinal bacteria in the pathogenesis of rosacea remain unclear (Jørgensen et al. 2017).

Ultraviolet Radiation While UVR is a well-known trigger of rosacea, a definite causal relationship has not been described. UVR exposure can cause flushing and exacerbations of rosacea. UVR has been shown to induce angiogenesis and increase the secretion of the angiogenic factors such as VEGF from keratinocytes. UVR also produces pro-­ inflammatory reactive oxygen species, which then leads to upregulation of MMPs, resulting in damage to the vasculature and the dermal matrix.

Differential Diagnosis The differential diagnosis of the various subtypes is outlined in Table 81.2.

872 Table 81.2  Rosacea subtypes—differential diagnosis Facial erythema Heliodermatitis Flushing due to systemic causes such as menopause, carcinoid syndrome and phaeochromocytoma Cutaneous lupus Seborrhoeic dermatitis Contact dermatitis Papules and pustules Acne Perioral dermatitis Pityriasis folliculorum Rosaceiform dermatitis due to topical calcineurin inhibitors Rosaceiform eruption due to EGFR inhibitors Steroid-induced rosacea Phymatous change Morbihan’s disease Lupus pernio (sarcoid of the nose) Lymphoma/angiosarcoma (rare) Ocular change Chronic blepharitis Chronic dry eye syndrome

E. Keeling and S. Ni Raghallaigh Table 81.3  Skin care management Use sunscreens with both UVA and UVB protection and a sun protection factor of 30 or greater. Sun-­ blocking creams containing the physical barriers titanium dioxide or zinc oxide are usually well tolerated Use soap-free, pH-balanced synthetic detergents (syndets) and lukewarm water to wash the face Use cosmetics and sunscreens that contain protective silicones Water-soluble make-up containing inert green pigment helps to neutralise the perception of erythema Camouflage make-up may also be useful Moisturiser-containing humectants (e.g. glycerin) and occlusives (e.g., petrolatum) may assist in restoring impaired epidermal barrier function Avoid astringents, toners and abrasive exfoliators and procedures such as dermabrasion Avoid waterproof cosmetics and heavy foundations that are difficult to remove without irritating solvents or physical scrubbing Avoid cosmetics that contain alcohol, menthols, camphor, witch hazel, fragrance, peppermint and eucalyptus oil Avoid environments that may overheat and/or dry the skin such as saunas, heater fans in cars and open fireplaces

General Principles of Treatment Rosacea is a chronic condition, and although there is no cure, it can be managed. Expert consensus advocates a phenotypic-based treatment approach (Schaller et al. 2017). The management of patients with rosacea should involve the following three aspects of care: (a) skin care management, (b) medical therapies and (c) patient education.

Skin Care Management Careful skin care management is an integral part of the treatment and control of rosacea (Del Rosso and Baum 2008). General principles of skin care useful in the management of rosacea are outlined in Table 81.3.

Medical Therapies Treatment options for specific phenotypes are outlined in Table 81.4, while Table 81.5 outlines specific antibiotic options.

Topical Treatments The topical treatment of erythema and flushing often includes adrenoreceptor agonists. Topical antibiotics and calcineurin inhibitors are used to a lesser extent. Topical brominidine tartrate gel 0.33% reduces facial erythema through vasoconstriction. It is a highly selective α2-adrenoreceptor agonist. It has been shown in controlled, prospective, randomised clinical trials to reduce the facial

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Table 81.4  Treatment options for rosacea Persistent and transient facial erythema/ telangiectasia First line: topical brominidine tartrate gel 0.33%

Papules and pustules First line: topical ivermectin cream 1%

Ocular manifestations First line: topical antibiotics such as fusidic acid/metronidazole

First line: topical oxymetazoline hydrochloride cream 1%

Second line: topical metronidazole gel 1%/0.75%

First line: topical ciclosporin 0.05% ophthalmic emulsion

Second line: laser techniques such as pulsed dye laser, intense pulsed light and potassium titanyl phosphate laser

Second line: topical azelaic Second line: oral acid 15% doxycycline 40 mg

Second line: low dose propranolol or carvedilol for flushing

Second line: topical sodium sulfacetamide 10% and sulphur 5%

Third line: topical tacrolimus 0.1%, pimecrolimus 1%

Second line: oral doxycycline 40 mg

Phymatous change Inflammatory First line: Oral doxycycline Inflammatory Second line: Oral isotretinoin Non-­ inflammatory First line: Surgical excision Non-­ inflammatory First line: Electrosurgery Non-­ inflammatory First line: CO2 laser

Third line: oral lymecycline 408 mg Third line: oral minocycline 100 mg

Table 81.5  Systemic antibiotics for papules and pustules in rosacea First line: Doxycycline (EMA-approved and FDA-approved antibiotic treatment for rosacea) 40 mg once daily (30 mg immediate release and 10 mg delayed release) Second line: Doxycycline 50–100 mg once or twice daily Minocycline 50–100 mg twice daily or sustained action formula once daily Lymecycline 408 mg Oxytetracycline 250–500 mg twice daily Third line: Erythromycin 250–500 mg once or twice daily Clarithromycin 250-500 mg once or twice daily Metronidazole 200 mg once or twice daily (for 4–6 weeks)

erythema of rosacea after single and repeated once-daily applications. Oxymetazoline hydrochloride cream, 1%, an alphaA1 adrenoceptor agonist has also been approved for treatment of persistent facial erythema in rosacea (Thiboutot

et al. 2020). Common side effects of these agents include rebound erythema, burning sensation and irritant dermatitis. Topical antibiotics such as metronidazole or other agents such as azelaic acid may reduce erythema in a select group of patients, but often cause irritation. Topical calcineurin inhibitors (tacrolimus, pimecrolimus) are used by some clinicians for the treatment of erythema; however, it should be noted that prolonged used over months can cause a rosacea-like dermatitis. Topical preparations of antibiotics and ivermectin are often employed for milder cases of papules and pustules in rosacea, or as maintenance therapy following clearance with systemic antibiotics to avoid relapse. A 2015 Cochrane review, which analysed 106 studies, confirmed the effectiveness of topical azelaic acid and metronidazole for the treatment of papules and pustules (van Zuuren et al. 2015). The results from three studies were contradictory on which of these two treatments was most effective. Topical

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ivermectin, which targets Demodex folliculorum, has been shown to be slightly more effective than topical metronidazole for the inflammatory lesions of rosacea, based on one study (Ebbelaar et  al. 2018). The combination of sodium ­sulphacetamide 10% and sulphur 5% has also been shown to be more effective than placebo in reducing erythema and inflammatory lesions. Other topical agents less commonly used include erythromycin 2% solution, benzoyl peroxide 5%, clindamycin 1% and tretinoin.

Use of non-selective beta-blockers such as propranolol or carvedilol to treat flushing in patients with rosacea can sometimes be used in carefully selected patients. Medications such as nonsteroidal anti-inflammatory drugs, antihistamines, clonidine are sometimes also employed off-label to treat flushing (Thiboutot et  al. 2020).

Laser Treatment

Laser techniques such as pulsed dye laser, intense Oral Medications pulsed light and potassium titanyl phosphate laser may be useful for the treatment of telangiecFor more severe cases of papules and pustules, tasia and erythema. Their use should be limited to oral antibiotics should be considered. The anti-­ experts familiar with the practice. inflammatory role played by tetracyclines in the management of rosacea is well recognised. Oral tetracyclines have been used in the treatment of Treatment of Phymatous Change rosacea since the 1950s. Tetracyclines have many mechanisms of action, which may contribute to Oral doxycycline can be used for inflammatory their effectiveness in their treatment of rosacea. phymatous changes (Schaller et  al. 2017). They have been shown to inhibit matrix metallo- Isotretinoin may help to slow the progression of proteinases (MMPs); downregulate the inflam- rhinophyma for active inflammatory area of phymatory cytokines TNF-α, IL-1β, IL-8 and IL-10 matous change. Surgical excision, electrosurgery and inhibit cell movement and proliferation, in or CO2 laser can be used to debulk and resculpt particular neutrophil migration (Golub et  al. non-inflammatory areas on the nose. The possi1984; Cazalis et  al. 2008; Gabler and Creamer bility of recurrence should be explained to the 1991). They have also been shown to inhibit patient. granuloma formation, reactive oxygen species and angiogenesis. A once-daily controlled-­ release formulation of doxycycline monohydrate Treatment of Ocular Rosacea (40 mg) became the first FDA-approved oral antibiotic treatment for rosacea. Clinical studies have Milder cases may be managed with eyelid shown this sub-antimicrobial dose of d­ oxycycline hygiene with warm cotton compresses and to be as effective as the 100 mg dose but with less artificial tears. Topical antibiotics such as adverse effects and less bacterial resistance (Del fusidic acid, metronidazole gel are commonly Rosso et  al. 2007). Alternative antibiotic treat- used to treat ocular manifestations. Ciclosporin ment options include metronidazole or a macro- 0.05% ophthalmic emulsion is also useful for lide (Table 81.3). Antibiotic courses are generally this subtype of rosacea. Systemic antibiotics given for 6–12 weeks, and repeated courses may such as doxycycline may be required for the be necessary for future exacerbations. treatment of more severe or persistent disease, Low-dose isotretinoin may be a viable useful and these patients should be referred to an alternative for difficult to treat papules and pus- ophthalmologist. Ophthalmology referral is tules (Sbidian et al. 2016). As isotretinoin is tera- also required for cases of blepharokeratocontogenic, appropriate patient counselling and junctivis, sclerokeratitis, anterior uveitis and contraception are vital for pregnancy prevention. blepharoconjunctivitis.

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line recommendations. Dermatol Ther (Heidelb). 2018;8(3):379–87. Gabler WL, Creamer HR.  Suppression of human neuWhile the chronicity of disease and the likelihood trophil functions by tetracyclines. J Periodontal Res. 1991;26(1):52–8. of exacerbations should be explained to the patient, reassurance of the benign nature of rosa- Gether L, Overgaard LK, Egeberg A, Thyssen JP. Incidence and prevalence of rosacea: a systematic review and cea is also important. Advice should be given on meta-analysis. Br J Dermatol. 2018;179(2):282–9. the avoidance of triggers as well as the impor- Golub LM, Ramamurthy N, McNamara TF, et  al. Tetracyclines inhibit tissue collagenase activity. A new tance of photoprotection. Direct patients to informechanism in the treatment of periodontal disease. J mation websites such as those of the National Periodontal Res. 1984;19(6):651–5. Rosacea Society (www.rosacea.org) or the Guzman-Sanchez DA, Ishiuji Y, Patel T, Fountain J, Chan American Academy of Dermatology (www.aad. YH, Yosipovitch G.  Enhanced skin blood flow and sensitivity to noxious heat stimuli in papulopustular org). Finally, acknowledging the psychosocial rosacea. J Am Acad Dermatol. 2007;57(5):800–5. impact of this disorder may help to guide patients Hachem JP, Houben E, Crumrine D, et al. Serine protease in need of psychological support towards the signaling of epidermal permeability barrier homeostaappropriate services such as counselling or cogsis. J Invest Dermatol. 2006;126(9):2074–86. Jørgensen AR, Egeberg A, Gideonsson R, Weinstock nitive behavioural therapy. LB, Thyssen EP, Thyssen JP.  Rosacea is associated with helicobacter pylori: a systematic review and meta-analysis. J Eur Acad Dermatol Venereol. 2017;31(12):2010–5. References Ní Raghallaigh S, Powell FC.  Epidermal hydration levels in patients with rosacea improve after minocycline Alexis AF, Callender VD, Baldwin HE, Desai SR, Rendon therapy. Br J Dermatol. 2014;171(2):259–66. MI, Taylor SC.  Global epidemiology and clinical Ní Raghallaigh S, Bender K, Lacey N, Brennan L, spectrum of rosacea, highlighting skin of color: review Powell FC. The fatty acid profile of the skin surface and clinical practice experience. J Am Acad Dermatol. lipid layer in papulopustular rosacea. Br J Dermatol. 2019;80(6):1722–9. 2012;166(2):279–87. Browning DJ, Proia AD. Ocular rosacea. Surv Ophthalmol. Sbidian E, Vicaut É, Chidiack H, et  al. A randomized-­ 1986;31:145–15. controlled trial of oral low-dose isotretinoin for Buhl T, Sulk M, Nowak P, et al. Molecular and morphodifficult-to-treat papulopustular rosacea. J Invest logical characterization of inflammatory infiltrate in Dermatol. 2016;136(6):1124–9. rosacea reveals activation of Th1/Th17 pathways. J Schaller M, Almeida LM, Bewley A, et  al. Rosacea Invest Dermatol. 2015;135:2198–208. treatment update: recommendations from the global Cazalis J, Bodet C, Gagnon G, Grenier D.  Doxycycline ROSacea COnsensus (ROSCO) panel. Br J Dermatol. reduces lipopolysaccharide-induced inflam2017;176(2):465–71. matory mediator secretion in macrophage and Tan J, Almeida LM, Bewley A, et al. Updating the diagex  vivo human whole blood models. J Periodontol. nosis, classification and assessment of rosacea: rec2008;79(9):1762–8. ommendations from the global ROSacea COnsensus Chang ALS, Raber I, Xu J, et al. Assessment of the genetic (ROSCO) panel. Br J Dermatol. 2017;176(2):431–8. basis of rosacea by genome-wide association study. J Thiboutot D, Anderson R, Cook-Bolden F, et al. Standard Invest Dermatol. 2015;135(6):1548–55. management options for rosacea: the 2019 update by Cribier B.  Rosacea under the microscope: characteristic the National Rosacea Society expert committee. J Am histological findings. J Eur Acad Dermatol Venereol. Acad Dermatol. 2020;82(6):1501–10. 2013;27(11):1336–43. Two AM, Wu W, Gallo RL, Hata TR.  Rosacea: part Del Rosso JQ, Baum EW. Comprehensive medical manI.  Introduction, categorization, histology, pathoagement of rosacea: an interim study report and literagenesis, and risk factors. J Am Acad Dermatol. ture review. J Clin Aesthet Dermatol. 2008;1(1):20–5. 2015;72(5):749–60. Del Rosso JQ, Webster GF, Jackson M, et  al. Two ranvan Zuuren EJ, Fedorowicz Z, Carter B, van der Linden domized phase III clinical trials evaluating anti-­ MM, Charland L. Interventions for rosacea. Cochrane inflammatory dose doxycycline (40-mg doxycycline, Database Syst Rev. 2015;2015(4):CD003262. USP capsules) administered once daily for treatWilkin J, Dahl M, Detmar M, et  al. Standard classifiment of rosacea. J Am Acad Dermatol. 2007;56(5): cation of rosacea: report of the National Rosacea 791–802. Society expert committee on the classification Ebbelaar CCF, Venema AW, Van Dijk MR. Topical iverand staging of rosacea. J Am Acad Dermatol. mectin in the treatment of papulopustular rosacea: 2002;46(4):584–7. a systematic review of evidence and clinical guide-

SAPHO Syndrome

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Vincenzo Bettoli and Natale Schettini

Key Points • SAPHO syndrome is considered an autoinflammatory disorder characterised by osteoarticular and cutaneous involvement. The acronym refers to the principle clinical signs of this disease that are synovitis, acne, pustolosis, hyperostosis and osteitis. • Pathogenesis is still not completely defined, but it seems to be linked to miscellaneous conditions represented by dysregulation of immune pathways, genetic predisposition and infections. • Clinical presentation typically consists of osteitis and hyperostosis of the anterior chest wall that may be associated with neutrophilic pustular dermatosis and severe forms of acne, including acne fulminans. • Diagnosis of SAPHO is based on a wide range of criteria mainly focused on osteoarticular manifestations; skin involvement appears to be not mandatory for diagnosis. • Non-steroidal anti-inflammatory drugs (NSAIDs) are used as first-line therapy; in unresponsive patients, conventional disease-­ modifying antirheumatic drugs or short-term use of systemic or intra-articular steroids can be prescribed. Recently, the efficacy of TNFα

V. Bettoli (*) · N. Schettini Department of Medical Science, O.U. of Dermatology, Azienda Ospedaliera—University of Ferrara, Ferrara, Italy

inhibitors and other biologics such as anti-­ IL-­1, anti IL-12/23 and anti IL-17 antibodies has been reported.

Definition and Epidemiology SAPHO syndrome is a rare condition characterised by osteoarticular and cutaneous involvement. The acronym refers to the clinical signs that characterise the disease: synovitis, acne, pustolosis, hyperostosis and osteitis. It has been described for the first time in 1987 by Chamot et al. to unify a group of disorders with uncertain aetiology distinguished by chronic and relapsing episodes of arthritis and various dermatosis (Chamot et  al. 1987). The syndrome shows a great heterogeneity because the definitions allow both the presence of all clinical conditions either simultaneously or separated and the lack of one or more of them (Benhamou et  al. 1988; Kahn 2003; Kahn and Khan 1994). Therefore, making diagnosis can be challenging. Considering the rarity of SAPHO syndrome, epidemiologic data are not well defined. The prevalence in Caucasians is estimated to be 2  months of age, and it is considered safe in pregnancy due to its low absorption. Second-line treatments for pregnant women include topical sulfur and benzyl benzoate. Although the risk associated with oral ivermectin may be low, data on use in this population are limited. Permethrin is a topical synthetic pyrethroid agent that impairs function of voltage-gated sodium channels in insects, leading to disruption of neurotransmission. Permethrin 5% cream should be applied from neck to the soles of the feet including areas under the fingernails and toenails and washed after 8–12 h. In young children, scalp involvement is common. Therefore, permethrin should also be applied to the scalp and face (avoiding the eyes

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and mouth) in this population. The treatment must be repeated after 7–14 days. When permethrin is unavailable, 10%–25% benzyl benzoate can be used. Treatment regimens vary. It may be applied once daily at night on 2 consecutive days with re-application at 7 days. It is considered safe in infancy and pregnancy, and it is widely used globally. Oral ivermectin is a safe and efficacious systemic option with the benefit of simple administration and low cost. It is not recommended for use in pregnant women or young children ( retinol  =  retinaldehyde >> retinoic acid Another use of topical retinaldehyde, based on its specific activity, is its high potential in induc-

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Fig. 154.4  Intracrine mechanism of endogenous retinoids. Retinoic acid precursors such as retinyl esters, retinol, and retinal are converted within keratinocytes to retinoic acid, which exerts its biological action via its binding to nuclear receptors, which are expressed in keratinocytes too. Retinoic acid is (partly) deactivated by CYP26 to 4-oxoretinoids, which are eliminated via conjugation to glucuronic acid. ARAT acyl-CoA:retinol acyl-

transferase, CRABP 1/2 cellular retinoic-acid-binding protein 1 or 2, CRBP1 cellular retinol-binding protein 1, LRAT lecithin:retinol acyltransferase, RA retinoic acid (tretinoin), RAH retinyl ester hydrolase, RAL retinaldehyde, RALDH retinaldehyde dehydrogenase, RAR retinoic acid receptor, RDH retinol dehydrogenase, RE retinyl esters, ROL retinol, RXR retinoid X receptor

ing hyaluronate production by keratinocytes: this explains its use in association with defined hyaluronate fragments of intermediate size in ­ dermatoporosis [i.e., chronic skin insufficiency (Kaya and Saurat 2007)] and the prevention of topical steroid-induced skin atrophy (Barnes et al. 2010; Kaya et al. 2006).

et al. 1986). It is available in the concentrations of 0.025, 0.05, and 0.1% for the treatment of acne and photoaging (0.05%). Other uses include a large number of skin conditions. Acute promyelocytic leukemia (APL), characterized by a chromosomal translocation involving the retinoic acid receptor alpha gene, is treated by oral retinoic acid in combination with an anthracycline chemotherapeutic agent (daunorubicin or idarubicin) or arsenic trioxide (Douer 2000). To overcome retinoic acid resistance in APL, tamibarotene, a more stable and more potent oral reti-

Retinoic Acid Topical retinoic acid has a long history of clinical and cosmeceutical use due to its high biological activity (Craven and Griffiths 1996; Kligman

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Alitretinoin (9-cis-Retinoic Acid) Alitretinoin is an endogenous pan-agonist retinoid that binds to both RAR and RXR retinoid receptors (Grahovac et  al. 2010); likewise, it is Isotretinoin (13-cis-Retinoic Acid) considered as the natural endogenous ligand for Isotretinoin is a naturally occurring physiologic RXRs. Topical alitretinoin gel (0.1%) is indicated compound resulting from the metabolism of vita- for cutaneous Kaposi’s sarcoma, whereas sysmin A. 13-cis-RA and at-RA are two intercon- temic alitretinoin is effective in refractory chronic vertible isomers that differ in their elimination hand eczema in adult patients. The absorption of half-lives: approximately 20  h for isotretinoin alitretinoin from the gastrointestinal tract is variand 1 h for retinoic acid. Isotretinoin undergoes able and dose-proportional over the therapeutic first-pass metabolism in the liver and subsequent range from 10 to 30 mg. The absolute bioavailenterohepatic recycling. In plasma, isotretinoin is ability of alitretinoin has not been determined. greater than 99% bound to plasma proteins, Alitretinoin is metabolized by oxidation by mainly albumin. There is neither liver storage nor CYP3A4 isoenzymes of the liver into 4-oxo-­ adipose tissue storage, in sharp contrast to vita- alitretinoin. Both compounds undergo isomerizamin A.  The major metabolite of isotretinoin tion into all-trans-retinoic acid and (4-oxo-isotretinoin) is produced by oxidation. 4-oxo-all-trans-retinoic acid. The major metaboIsotretinoin and its major metabolites are excreted lite 4-oxo-alitretinoin is further glucuronidated in the urine and feces. and eliminated in the urine. Alitretinoin concenAfter discontinuation of isotretinoin, natural trations return to normal range within one to concentrations of 13-cis-RA and its major metab- three days after treatment cessation, and eliminaolites are reached within two  weeks, ranging tion is mainly in the urine. Elimination half-life from two days for at-RA to ten days for 4-oxo-­ of unchanged alitretinoin ranges between 2 and isotretinoin. Therefore, one  month of post-­ 10 h. The mechanism of action of alitretinoin in therapy contraception provides an adequate chronic hand eczema is unknown. According to safety margin. Nada et al., it could be due to a downregulation of Among natural and synthetic retinoids, only retinoid receptors in hand skin (Nada et al. 2020). oral isotretinoin significantly suppresses sebum Alitretinoin has demonstrated immunomodulaproduction and considerably improves acne. tory and anti-inflammatory effects that are releSince no clear affinity with isotretinoin has been vant to skin inflammation. Alitretinoin suppresses identified for any retinoid receptor, other mecha- the expansion of cytokine-activated leucocyte nisms of action must be considered (Törmä subsets and antigen-presenting cells. 2001). It may even be that isotretinoin is a prodrug that targets the sebaceous gland with sebo- Acitretin suppressive metabolites. Isotretinoin has a Acitretin is the major metabolite and the pharmaspecific antiproliferative effect on human sebo- cologically active compound of etretinate. cytes due to cell cycle arrest and sebocyte apop- Although acitretin and etretinate are equally tosis, which was not recapitulated by alitretinoin effective, acitretin has a profound pharmacokior tretinoin. Isotretinoin-induced apoptosis was netic advantage because of its more rapid elimishown to be an RAR-independent mechanism. nation compared with etretinate. The major Transcriptional profiling of patient skin and cul- serious adverse effect of synthetic retinoids is tured human sebaceous gland cells indicated that teratogenicity, and, therefore, the length of time lipocalin-2 was among the genes most highly that these drugs are present in the body is of great upregulated by 13-cis RA (Nelson et al. 2008). importance. Acitretin has an elimination half-life noic acid agonist, was designed (Miwako and Kagechika 2007; Kojima et al. 2016); it is commercially available in Japan.

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of two days. Paradoxically, acitretin activates all three RAR subtypes, but binds poorly to them. Re-esterification of acitretin to etretinate may occur when acitretin is taken simultaneously with alcohol. This finding prompted the manufacturer to extend the time of contraception in patients taking acitretin to two  years after discontinuation, as it is for etretinate. The U.S.  Food and Drug Administration (FDA) advises a contraceptive period of at least three  years for acitretin, based on the pharmacokinetics of acitretin and etretinate observed in clinical trials and on previous safety experience with etretinate. The pharmacokinetic advantage of acitretin over etretinate still holds true for all women who strictly avoid alcohol during treatment and for two  months thereafter (Wiegand and Chou 1998). The mechanism of action is still not clearly understood. Evidence supports a normalization of differentiation and proliferation as well as a modification of inflammatory responses and neutrophil function.

Motretinide Motretinide is an arotinoid, a second-generation retinoid that activates RAR-α. It is a soft topical retinoid with a less irritative potential than tretinoin. It had been commercially available in Switzerland. Adapalene Adapalene is a light-stable, rigid, synthetic retinoid with higher affinity for RAR-β/RAR-γ than for RAR-α. Since RAR-β is not expressed in keratinocytes, RAR-γ is the primary retinoid target receptor for adapalene in the epidermis, provided the effects are receptor mediated. Tazarotene Tazarotene is a prodrug that is rapidly converted by skin esterases to its free carboxylic acid (tazarotenic acid), which is the active metabolite. It has a higher affinity for RAR-β/RAR-γ than for RAR-α and no affinity for RXR. Because of its rapid metabolism, systemic exposure is low. Tazarotenic acid upregulates tazarotene-­inducible genes (TIG-1,2,3) and has antiproliferative properties.

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Bexarotene Bexarotene, a specific RXR-selective retinoid (rexinoid), was approved in 1999 in the USA for treatment of cutaneous T-cell lymphoma (CTCL) refractory to at least one systemic therapy. This compound is about 100-fold more potent at binding to RXR than to RAR.  Bexarotene probably has a clearance profile similar to that of isotretinoin, with a terminal half-life between 7 and 9 h (Ethan-Quan and Wolverton 2001). The exact mechanism of action of bexarotene in CTCL is still unknown, but bexarotene probably acts through regulation of cellular differentiation and proliferation and induction of apoptosis. Clinical and biochemical central hypothyroidism frequently occurs with bexarotene and is probably mediated through suppression of thyrotropin β-subunit (TSH-β) secretion by the thyrotrope cells of the anterior pituitary, which express RXR-γ. A new synthetic retinoid, UAB110, has a high selectivity for RXR-α, and does not elevate triglycerides in animal studies; it is thus an interesting candidate for the treatment of CTCL with less adverse effects than bexarotene (Chou et al. 2019). Trifarotene Trifarotene is a fourth-generation topical retinoid with a high selectivity toward RAR-γ. It is active and stable in keratinocytes but is rapidly metabolized in the liver, thus avoiding unwanted activity in internal organs (Aubert et al. 2018). Seletinoid G Seletinoid G is a fourth-generation topical retinoid designed to be a selective RAR-γ agonist for the treatment and prevention of skin aging with a low irritative potential (Kim et  al. 2005). It increases the expressions of type I procollagen, tropoelastin, fibrillin-1, and reduced matrix metalloproteinase-1 (MMP-1) in old skin in vivo, and improves wound re-epithelialization in in  vitro models of wound healing (Kim et  al. 2005; Lee et al. 2019, 2020). Tamibarotene Tamibarotene is a fourth-generation oral retinoid designed to overcome all-trans-retinoic acid

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(tretinoin) resistance for the treatment of acute promyelocytic leukemia in combination with arsenic trioxide (Miwako and Kagechika 2007; Kojima et al. 2016). It is better tolerated and has a longer half-life than tretinoin.

Indications and Other Uses Topical Retinoids The most important element in topical therapy with retinoids is education of the patient. Local skin irritation can be expected with some but not all compositions, and noticeable beneficial effects may take weeks or months to appear. Administration of topical retinoids should be titrated depending on cutaneous irritant reactions, which may mean decreasing the concentration or the frequency of application. It is generally wise to begin with the lowest strength formulation and then increase the concentration as tolerance builds. Another tactic is to start by applying a given concentration every other day. Daytime moisturizers with sunscreen are important components of any topical retinoid regimen. Of interest is the fact that irritation was initially considered as a sine-qua-non condition for efficacy. Recent molecular and kinetic data indicate that retinoic-acid-induced irritation is rather the mere indication of a toxic overload, whereas optimal gene regulation and therefore adequate response may be reached with either lower concentrations or ligands with controlled delivery to the receptors through the intracrine pathway (see Figs. 154.2 and 154.4).

Acne Topical retinoids, of which tretinoin is the prototype, are mainstays in the treatment of comedonal acne, even if their effect is slow and almost never reaches complete clearance. The primary mode of action is believed to be normalization of abnormal differentiation and proliferation of the follicular epithelium, which leads to the loosening and unseating of microcomedones. In addition, topical retinoids may have anti-inflammatory

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activity. The mechanism of action of topical isotretinoin is similar to that of topical tretinoin because of intraepithelial isomerization of isotretinoin to tretinoin. In contrast to oral isotretinoin, topical isotretinoin (as well as all topical retinoids) fails to suppress sebum production to the same extent. Isotretinoin is less irritating, but it is probably somewhat less effective than tretinoin. Because of the birth defects induced by the oral formulation, topical isotretinoin has not received FDA approval in the USA. The newer synthetic derivatives, adapalene and tazarotene, are intended to improve tolerability while maintaining similar efficacy when compared with topical tretinoin. In company-sponsored studies of patients with acne, adapalene 0.1% gel was as effective as tretinoin 0.025% gel against open and closed comedones and more effective against inflammatory lesions and with less irritation (Cunliffe et al. 1997a). Tazarotene 0.05 and 0.1% topical gels significantly decreased acne lesions compared with control patients, with tolerability clinically comparable to tretinoin. Topical trifarotene 50  μg/g cream has been approved by the U.S. FDA for topical treatment of acne vulgaris for patients as of 9  years old (JAMA 2020) and was shown to be safe and effective in moderate facial and truncal acne in a recent 52-week clinical trial enrolling 342 patients (Blume-Peytavi et al. 2020). Topical retinoids should be applied to the entire face, once a day (if tolerated) and in the evening to minimize inactivation by UV.  The medication should be applied on dry skin to minimize dermal absorption correlating with skin irritation. Patients should be advised that the therapeutic response is slow, and beneficial effects do not become evident for weeks to months. An apparent exacerbation may occur during the first month of therapy, representing the externalization of deeper-seated acne lesions as the follicular epithelium is loosening. Topical retinoids, except in very mild acne, should be used concomitantly with antibiotics (oral or topical) or benzoyl peroxide, which have different modes of action and which target primarily inflammatory lesions.

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Psoriasis Topical application of tretinoin or isotretinoin has limited efficacy in psoriasis. Tazarotene has been the first topical retinoid proven effective in treating mild to moderate plaque-type psoriasis not exceeding 10–20% of the body surface area. When compared with twice-daily fluocinonide cream, tazarotene 0.05 and 0.1% gels applied once daily were shown to produce similar reductions in plaque elevation. Nevertheless, tazarotene 0.1% gel carries a significantly lower risk of relapse than does fluocinonide cream after 12  weeks off therapy. A combination of tazarotene and a mid-potency corticosteroid improved efficacy and reduced the incidence of local adverse effects; this combination may also reduce the risk of corticosteroid-induced atrophy. Photoaging Photoaging is the consequence of UV-induced damage to the skin characterized by decreased expression of RXR-α and RAR-γ in the acute setting, by upregulation of AP1-driven matrix metalloproteinases, as well as severe depletion of the vitamin A content of the epidermis (since retinoids are destroyed by the UV) (Wang et  al. 1999). Topical retinoids promote cellular dedifferentiation and extracellular matrix synthesis, including an increase in hyaluronic acid via a CD44-mediated mechanism (Calikoglu et  al. 2006). Histologic findings after repeated topical application of tretinoin include: compaction of the stratum corneum, epidermal hyperplasia (acanthosis), correction of atypia (e.g., actinic keratoses), dispersion of melanin granules, increased dermal collagen synthesis, and angiogenesis. These findings explain the reported smoother skin, rosy glow, decrease in blotchy pigmentation, and diminished fine lines and wrinkles. Several controlled studies have clearly demonstrated that topical retinoids, particularly tretinoin, and more recently tazarotene cream, improve fine wrinkling and lighten uneven pigmentation. It generally takes three to six months of daily applications to see significant clinical improvement. Cutaneous irritation is usually the limiting factor. It is not clear if the observed

J.-H. Saurat and O. Sorg

effects on parameters of skin aging with these retinoids are associated with a beneficial long-­ term effect. It has been reported that long-term use of retinoic acid for the prevention of actinic keratosis in fact resulted in a trend to increased incidence of actinic keratosis and squamous cell carcinoma. One hypothesis was that retinoic acid does not reverse the UV-induced vitamin A epidermal depletion due to the irreversible bioconversion of retinaldehyde to retinoic acid. This suggests that cosmeceutical retinoids such as retinaldehyde, which do restore epidermal vitamin A pool, warrant consideration (see section “Retinaldehyde”). Seletinoid G, a new retinoid with a selective RAR-γ activity, was designed to be less irritant than tretinoin in the treatment and prevention of skin aging and photoaging. Although the preliminary studies seem promising (Kim et  al. 2005; Lee et al. 2019), randomized controlled trials are required to confirm its place in this indication.

Other Indications Other approved indications include topical treatment of cutaneous Kaposi’s sarcoma by alitretinoin (9-cis-RA) 0.1% gel and topical treatment of CTCL by bexarotene (Breneman et al. 2002). Non-approved indications of topical retinoids are numerous.  etinoids in Cosmeceutical Ranking R and Issues As mentioned in section “Retinaldehyde,” the tolerance profile and the clinical efficacy are inversely correlated: • Tolerance profile: retinyl esters > retinol = retinaldehyde >> retinoic acid • Clinical efficacy: retinoic acid > retinaldehyde > retinol >>> retinyl esters There is a need to determine the best dose of each retinoid, specifically natural retinoids, in consideration of the above.

 opical Retinoids and the Sun T Retinoids strongly absorb light in the ultraviolet A (UVA) to ultraviolet B (UVB) range (260–

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400  nm), which means that cutaneous retinoids are photo-unstable (Sorg et  al. 2001, 2005; Ferguson and Johnson 1989). Indeed, in vitro and human in  vivo studies demonstrated a dose-­ dependent decrease in epidermal retinoids, leading to epidermal vitamin A deficiency (Sorg and Saurat 2014). Given that cutaneous vitamin A deficiency is a risk factor for skin cancer ­development (Fields et  al. 2007), those topical retinoids that replenish endogenous levels of epidermal vitamin A might exert a preventive effect against sun-induced skin cancers (Carr et  al. 2011). The use of topical retinoids, which are photosensitive, raises the question of the possible phototoxic reactions. Although no photoallergic or phototoxic reactions have been proven for topical retinoids, many patients note a decreased tolerance to UV radiation shortly after sun exposure (Sachs and Voorhees 2011). This reaction is often accentuated by a sensation of heat, raising the question of involvement of infrared irradiation. For this reason, it is recommended to avoid sun exposure after the application of topical retinoids.

Systemic Retinoids Pustular Psoriasis/Acitretin The efficacy of acitretin in plaque-type and pustular psoriasis has been established on several randomized multicenter trials. The best results have been obtained in acral or generalized (von Zumbusch) pustular psoriasis, in which acitretin is considered to be first-line therapy. The lesions of both localized and generalized pustular psoriasis, as well as those of erythrodermic psoriasis, cleared more rapidly with etretinate or acitretin monotherapy than with most other therapies. Rebound does not usually occur after stopping treatment, and reintroduction produces a beneficial response. Plaque-Type Psoriasis/Acitretin Plaque-type psoriasis responds variably to acitretin. The decrease in the Psoriasis Area and Severity Index (PASI) score is approximately

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60–70%, depending on the dosage and duration of treatment. Many of the plaques may remain, but they are thinner with less scale and erythema. Approximately 20% of patients may be considered treatment failures (Lowe 1991). An initial worsening of the disease with an increase in erythema and/or extent of the involvement may occur within a few days of starting therapy at a dosage of 0.5–1  mg/kg/day (i.e., 30–70  mg/day in adults). A therapeutic dosage scheme utilizing a low-dosage (10  mg/day) acitretin initially, followed by progressively increasing the dosage, seems preferable. Different dosages (10–75 mg/day) were compared to placebo in a double-blind fashion. At the end of an eight-week treatment period in two studies, acitretin at doses of 25 and 50 mg/day or 50 and 75 mg/day was superior to placebo. Total clearance of psoriatic lesions usually requires a combination of therapies, such as topical corticosteroids, topical vitamin D derivatives, anthralin (dithranol) or photochemotherapy (psoralen plus ultraviolet A [PUVA]), bath PUVA, and narrowband UVB phototherapy (Lebwohl 1999; Saurat et al. 1988). Isotretinoin is less effective on psoriasis than acitretin although some efficacy has been shown in combination with PUVA (Saurat 1998). Nevertheless, isotretinoin is still used in women of childbearing age with psoriasis who need systemic retinoids to avoid the long post-acitretin contraception period.

Acne/Isotretinoin Isotretinoin is still the only compound that has been shown to induce long-term remissions and even “cure” acne, because it is the only one that affects, albeit not to the same degree or permanently, all the etiologic factors implicated in acne: sebum production, comedogenesis, and colonization with Cutibacterium acnes. Only oral isotretinoin, among all natural and synthetic retinoids tried in humans, was found to suppress sebum excretion and to significantly improve acne. The “sebo-specificity” of oral isotretinoin still remains unexplained in 2020. In the early 1980s, isotretinoin use was restricted to patients suffering from severe nodu-

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locystic acne. Its use has been extended to (1) patients with less severe disease who have responded unsatisfactorily to conventional therapies such as long-term antibiotics, (2) patients with moderate acne that may induce scars, and (3) patients with significant psychosocial consequences of acne due to interpersonal and work-­ related difficulties (Layton 2009). Studies with quality-of-life instruments have shown that isotretinoin treatment significantly improves sociability and self-esteem. It was initially considered that optimal benefit would be achieved with a high daily dose of approximately 1 mg/kg/day (Layton et al. 1993). However, this high dose can induce undesirable effects, and similar short-term therapeutic results were obtained with doses below 0.5 mg/kg/day. In order to avoid the higher incidence of relapses associated with low-dose isotretinoin, the latter approach required that the treatment be maintained over a longer period of time in order to reach a critical cumulative dose threshold. The concept of cumulative dose (mg/kg body weight), introduced by Harms in 1989 (Harms et al. 1989), is the total amount of oral isotretinoin taken by the patient over the entire duration, divided by the body weight. A patient weighing 50  kg and receiving 25 mg/day of isotretinoin for 100 days would have received a cumulative dose of 50 mg/ kg (25  mg × 100  =  2500  mg, divided by 50  kg  =  50  mg/kg). Data from several centers indicated that post-therapy relapse was minimized by a treatment course amounting to a total of at least 120  mg/kg (Lehucher-Ceyrac and Weber-Buisset 1993), with no further therapeutic gain beyond about 150  mg/kg (Cunliffe et  al. 1997b). Low dose (20 mg/daily) was also found to be effective in the treatment of moderate acne with a low incidence of severe side effects and at a lower cost than higher doses (Amichai et  al. 2006). Although some European guidelines no longer mention the cumulative dose as a mandatory threshold to reach, we consider it as an invaluable way to monitor patients on a case-to-­ case basis. A lag period of one to three months may exist before the onset of the therapeutic effect. Continued healing after the discontinuation of

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therapy is regularly observed. Approximately one-third of patients with acne require a second course of therapy, either for persistent disease or for relapse. The only predictive factor of resistance to isotretinoin treatment is closed comedonal acne and microcystic acne (Lehucher-Ceyrac et  al. 1999). Interestingly, the new comedolytic Silybum marianum fruit extract (SMFE) (Fontao et al. 2020) has been found to synergize with oral isotretinoin to control these types of acne. A flare of disease during the first few weeks of treatment, and subsequent evolution of acne cysts into lesions resembling pyogenic granulomas, may be observed with isotretinoin treatment. The incidence of this side effect may be reduced by using lower doses of isotretinoin during the first three to four weeks of therapy. Women of childbearing potential must have a (in the USA, two) negative pregnancy test(s) and practice effective contraception for one  month prior to therapy, during therapy, and for one month after completing therapy. To afford a sufficient safety margin, a one-month post-therapy contraceptive period is mandatory because plasma concentrations of isotretinoin return to physiologic levels within ten days of completing therapy. Isotretinoin has a more limited effect on hidradenitis suppurativa and dissecting cellulitis of the scalp. These disorders may occur together as part of the follicular occlusion tetrad. Some investigators recommend oral isotretinoin during the weeks or months preceding surgery for hidradenitis suppurativa, and sometimes also during the postoperative period (Boer 2017; Huang and Kirchhof 2017).

Cutaneous T-Cell Lymphoma/ Bexarotene The FDA approved bexarotene as oral therapy for the treatment of CTCL that is refractory to at least one systemic therapy, and as a gel formulation for cutaneous manifestations of early-stage refractory or persistent CTCL (Duvic et  al. 2001a). Toxicity including hypothyroidism was a significant problem at high oral doses. Response rates are approximately 50% for the patients with advanced CTCL (Duvic et al. 2001b). Bexarotene combination therapies with PUVA/narrowband-­

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UVB, interferon alpha (IFN-α), denileukin diftitox, and methotrexate have also been evaluated by various clinical trials and case reports (Gniadecki et al. 2007). Isotretinoin and acitretin are somewhat effective and are considered to be of equal potency in the treatment of mycosis fungoides (MF). They can be used in combination with PUVA, interferon, or systemic chemotherapy. Despite ­ initial improvement in the various stages of MF, it is often impossible to maintain remissions with these retinoids as monotherapy.

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therapy suitable for the long-term management of chronic hand eczema. A head-to-head comparison of alitretinoin (high-cost therapy) with acitretin (lower-cost therapy) would be interesting, since it is not unlikely that revisiting acitretin in this indication with an adequate randomized controlled trial may help some patients.

Other “Off-Label” Clinical Uses The pleomorphic effects of retinoids explain the broad potential benefit they could provide to patients with skin diseases. Many other skin disorders respond to retinoids, but the benefit has been established in controlled studies for only a few of them (Arechalde and Saurat 2000).

 hronic Hand Eczema/Alitretinoin C A multicenter study of six-month duration in adults with severe chronic hand eczema has shown responses to oral alitretinoin of this complex and difficult-to-define condition. Responses defined as “clear or almost clear hands” were seen in up to 47% of patients treated with 30 mg, Ichthyosis/Acitretin 27.5% with 10  mg, and 16.6% with placebo. The best results can be obtained by using acitreTreatment was well tolerated, with dose-­ tin for non-bullous congenital ichthyosiform dependent adverse events including headache, erythroderma and lamellar ichthyosis. Good mucocutaneous events, hyperlipidemia, and results have also been observed in patients with decreased free thyroxine and thyroid stimulating recessive X-linked ichthyosis and ichthyosis vulhormone. The median time to relapse, defined as garis; however, the more limited severity of these recurrence of 75% of initial signs and symptoms, diseases does not usually require systemic retiwas 5.5–6.2 months in the absence of anti-eczema noid therapy. Given the lifelong duration of these medication (Ruzicka et al. 2008). disorders, intermittent courses are sometimes Alitretinoin is indicated in adults who have prescribed. severe chronic hand eczema that is unresponsive to potent topical corticosteroids (Ruzicka et  al. Darier’s Disease/Acitretin 2008; Bollag and Ott 1999). Treatment should be Severe forms of Darier’s disease are often treated initiated at 30 mg daily and duration should not with systemic retinoids, but therapy should be exceed 12–24  weeks. Low dosage of 10  mg is initiated with a very low dose (e.g., acitretin indicated in patients experiencing adverse events 10 mg/day) in order to prevent an initial exacerat high dosage. High dosage induces a more rapid bation of the disease; usually 20 mg/day is suffiimprovement and has a higher response rate. cient for significant improvement. Clinical signs of improvement appear after only four weeks of treatment. Patients with a marked Pityriasis Rubra Pilaris/Acitretin hyperkeratosis are best responders to treatment. Early treatment with retinoids appears to offer Therapy should be interrupted in case of a nonre- the best chance for clearing pityriasis rubra pilasponse after 12  weeks. Eighty percent of the ris (PRP). In extensive cases, concomitant use of patients who previously achieved “clear” or methotrexate may be advantageous. Etretinate “almost clear” hands following treatment with (now acitretin) has been considered to be supealitretinoin 30 mg per day also respond to a sec- rior to isotretinoin for the treatment of adult-­ ond course of treatment, making intermittent onset PRP (Clayton et al. 1997).

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Rosacea/Isotretinoin In severe forms or treatment-resistant rosacea, isotretinoin often has a greater effect on inflammatory lesions than on vascular lesions (Erdogan et  al. 1998). A low daily dose (10  mg) is often sufficient, although acne vulgaris regimens are sometimes used in severe disease.  remalignant and Malignant Skin P Lesions/Acitretin Acitretin was shown to be effective in the treatment of premalignant skin lesions, including human papilloma virus (HPV)-induced tumors and keratoses (Joshipura et  al. 2017; Smit et  al. 2004). In the nevoid basal cell carcinoma syndrome and in xeroderma pigmentosum, these drugs are able to dramatically reduce the incidence of malignant evolution of cutaneous lesions. A double-blind study demonstrated that acitretin (30  mg/day for six months) prevented the development of premalignant and malignant cutaneous neoplasms in renal transplant recipients (Bavinck et al. 1995). Graft-Versus-Host Disease In an open study, three months of etretinate therapy produced encouraging responses among patients with refractory sclerodermatous chronic graft-versus-host disease (GVHD) resulting from allogeneic bone marrow transplantation (Marcellus et al. 1999). Lichen Sclerosus The use of acitretin is an effective treatment for patients with severe vulvar (and, occasionally, non-genital) lichen sclerosus. It may be used intermittently in patients who are intolerant of or resistant to topical therapies. Lupus Erythematosus Both isotretinoin and acitretin have been used successfully in patients with various forms of lupus erythematosus (LE). Recurrence of the lesions after completion of the treatment is a limiting factor. Comparable therapeutic efficacy has been observed for acitretin and hydroxychloroquine in chronic cutaneous LE and in subacute cutaneous LE (Ruzicka et al. 1992).

Side Effects Topical Retinoids By far the most common side effect of topical retinoids is skin irritation. This “retinoid dermatitis” occurs within the first month of treatment and tends to recede thereafter. It responds to a temporary reduction in the frequency or amount of retinoid application and to application of moisturizers. Desquamation and peeling correspond to the hyperproliferative response of the epidermis to tretinoin mediated by RARs, but the erythema does not seem to be receptor mediated (Kang et  al. 1995). The perioral area of the face is most sensitive to peeling and use in this area can be limited or avoided. Although no photoallergic or phototoxic reactions have been proven for topical retinoids (Sachs and Voorhees 2011), many patients note a decreased tolerance to UV radiation shortly after sun exposure. This reaction is often accentuated by a sensation of heat, raising the question of involvement of infrared irradiation. Potential teratogenicity from long-term use of topical retinoids is very low: systemic absorption of topically applied retinoids is inconsequential in both animal and human studies (Jick 1998; Nohynek et al. 2006), and there is no evidence that application of tretinoin causes congenital disorders (Panchaud et  al. 2012). Temporary worsening of acne may occur within the first weeks of therapy. Uncommon side effects include transitory hypo- or hyperpigmentation, koebnerization of psoriasis (especially tazarotene), allergic contact dermatitis, and ectropion.

Systemic Retinoids Teratogenicity is the most troublesome adverse effect of oral retinoids. The side-effect profile of systemic retinoids qualitatively resembles the toxic effects of vitamin A or hypervitaminosis A syndrome.

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Teratogenicity Systemic retinoids are potent teratogens, and this is the major concern in treating fertile women with oral retinoids. With regard to teratogenicity, no safe minimal dose during pregnancy has been established. The range of defects seen in retinoid embryopathy includes multiple abnormalities (Lammer et  al. 1985). The abnormalities may lead to premature birth, spontaneous abortion, or fetal death. The putative mechanism involves toxic effects on neural crest cells, particularly in the case of exposure during the fourth week of gestation. All systemic retinoids are teratogenic and are absolutely contraindicated during pregnancy and lactation (FDA category X), which should be excluded by a pregnancy test before considering retinoid therapy and then at regular intervals (e.g., monthly in the case of isotretinoin) during its administration. Two pregnancy tests are recommended before instituting isotretinoin therapy. Pregnancy is not only an absolute contraindication to starting therapy; it must also be avoided throughout therapy and for an appropriate interval after completion of therapy. Adequate contraception for at least one month before therapy is required for all systemic retinoid therapy. Acitretin requires contraception for three  years (USA) or two  years (Europe) after cessation of therapy, whereas isotretinoin, bexarotene, and alitretinoin require contraception for just one month after cessation of therapy. Although no evidence exists for teratogenicity of topical retinoids in humans (Nohynek et  al. 2006; Sorg et al. 2007), they are nevertheless not recommended for use during pregnancy. Since no dermatologic condition that is known to be responsive to topical retinoids, and that may be observed during pregnancy, is life threatening to the mother or fetus, it is wiser to postpone treatment until after delivery (primarily due to medicolegal rather than scientific data in the opinion of these authors). The same recommendations are also valid for lactating women, as it is not known whether topical retinoids pass into the breast milk. Consequently, topical retinoid use is not recommended during breastfeeding; it may cause

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unwanted effects on the nursing baby (On and Zeichner 2013). No typical retinoid embryopathy malformations have been reported in pregnancies where the male partner had been the one taking acitretin or isotretinoin at the time of conception.

 kin and Mucous Membrane Adverse S Effects Dose-dependent mucocutaneous toxicity is the most commonly observed side effect with oral retinoids, and it mainly reflects a decreased production of sebum, reduced stratum corneum thickness, and altered skin barrier function. Dry lips or cheilitis is the earliest and the most frequent sign that appears after starting therapy. Dryness of the mouth accompanied by thirst and dryness and fragility of the nasal mucosa leading to epistaxis are also frequently observed. Systemic retinoids do have different mucocutaneous side-effect profiles. Isotretinoin causes more mucosal dryness, and acitretin has been associated with higher incidences of alopecia and palmoplantar peeling, whereas bexarotene induces milder mucocutaneous and ocular side effects than do other classes of retinoids. Dyslipidemia Hypertriglyceridemia is the most frequently observed systemic effect of retinoid therapy. Isotretinoin and etretinate/acitretin elevate triglycerides in 50% and cholesterol in 30% of treated patients (Pilkington and Brogden 1992; Tangrea et al. 1993), whereas bexarotene induces elevated triglycerides and cholesterol in approximately 79% and 48% of patients, respectively (Duvic et al. 2001a). Baseline serum lipids should be obtained before initiating bexarotene therapy, as well as every one to two weeks during therapy until levels become stable (generally in four to eight weeks). For other oral retinoids, monitoring levels monthly for the first two months and then at two- to three-month intervals (if there are no increases in dosage) is adequate in cases of normal baseline lipid levels and an absence of risk factors (obesity, high alcohol intake, diabetes).

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Discontinuation of therapy is suggested if fasting triglycerides reach 800  mg/dL (8  g/L). Less severe increases may be treated by dose reduction, withdrawing therapy until normalization of serum lipids occurs, and dietary or physical management. In some instances, lipid-lowering agents may be indicated. Co-administration of statins, including atorvastatin, in case of ­hypercholesterolemia, or fenofibrate for hypertriglyceridemia (or both) with bexarotene is recommended to treat the retinoid-induced hyperlipidemia and to lower the risk of pancreatitis (Wiegand and Chou 1998; Talpur et al. 2002). Some authors even recommend to start in all patients a fibrate (e.g., fenofibrate) on day 7 before bexarotene treatment initiation (Gniadecki et al. 2007). The effect of retinoid-induced hyperlipidemia, and its management during long-term therapy, on the development of atherosclerotic cardiovascular disease is unknown. Retinoids probably cause hyperlipidemia by interfering with lipid clearance. Bexarotene increases the expression of apolipoprotein C-III, which prevents the uptake of lipids from very-low-density lipoproteins (VLDL) into cells.

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chrome P450 isoenzymes (CYP3A4) and undergo partial biliary elimination, significant hepatic insufficiency may be expected to interfere with drug elimination. Transaminase elevations to greater than three times the upper limit of normal should lead to discontinuation of retinoid therapy. With two- to three-fold transaminase elevations, therapy should be withdrawn until normalization of tests of liver function occurs (Wiegand and Chou 1998). Other causes should simultaneously be excluded.

 phthalmologic Side Effects O The most common ocular retinoid effects are dryness and irritation. Alterations in visual function, mainly nyctalopia, excessive glare sensitivity, and changes in color perception have also been reported (Safran et al. 1991). Competitive inhibition of ocular retinol dehydrogenase by retinoids, resulting in decreased rhodopsin formation, may be the cause of hemeralopia.

 entral Nervous System and Psychiatric C Effects Central nervous system (CNS) side effects are rare. Although individual signs of increased intracranial pressure, such as headache, nausea, Liver Toxicity and vomiting, are occasionally observed, the Transitory abnormal elevations in serum trans- complete syndrome with papilledema (pseudotuaminases have been reported in approximately mor cerebri) and blurred vision is considered 20% of patients treated with either etretinate or very rare. Concomitant use of other drugs associacitretin, occurring much less frequently with ated with intracranial hypertension (e.g., cyclines) isotretinoin or bexarotene therapy. Circulating is considered a major risk factor for developing levels of alkaline phosphatase, lactate dehydro- pseudotumor cerebri and should therefore be genase, and bilirubin may also become elevated avoided. Examination for papilledema should be during retinoid therapy. Liver function abnormal- performed immediately when a patient receiving ities, mostly mild, usually occur between two and retinoid therapy complains of persistent headeight weeks of starting therapy, and they return to ache, especially if it is accompanied by visual normal within another two to four weeks, despite changes, nausea, or vomiting, or when pseudotucontinued therapy. Severe or persistent hepato- mor cerebri is otherwise suspected. toxic reactions have been seen in less than 1% of There have been anecdotal reports suggesting patients. Acitretin therapy elicited no biopsy-­ a causal association between isotretinoin therapy proven hepatotoxicity in a two-year prospective in acne patients and severe depression, psychosis, study, thus suggesting that periodic liver biopsy and suicide attempts. That isotretinoin increases is not necessary (Roenigk Jr. et al. 1999). No spe- the risk of depression has actually not been cific studies have evaluated the use of retinoids in proven (Bigby 2008). Indeed, a successful treatpatients with hepatic insufficiency. However, ment of acne seems to improve both depressive since retinoids are metabolized by hepatic cyto- and anxiety symptoms, thus improving the qual-

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ity of life (Kaymak et  al. 2009). Patients with depressive symptoms or suicidal ideation should, however, be carefully monitored and advised before treatment initiation (Bigby 2008).

Osteoporosis has been observed with hypervitaminosis A and after long-term therapy with etretinate but not with isotretinoin (DiGiovanna et al. 1995).

Hypothyroidism Clinical and biochemical central hypothyroidism occurred in 40% of patients in the CTCL trials with bexarotene and it was rapidly and completely reversible with cessation of therapy without any clinical sequelae (Duvic et  al. 2001a; Sherman et  al. 1999). This effect is probably mediated through suppression of thyrotropin β-subunit (TSH-β) secretion by the thyrotrophic cells of the anterior pituitary, which express RXR-γ. Free T4 levels should therefore be monitored before and during bexarotene therapy and normalized with thyroid hormone replacement as necessary. Some authors recommend an initial dose of levothyroxine 0.05 mg daily, increased to 0.1–0.125 mg daily, depending on the bexarotene dose and the free T4 level, which should be normal (Gniadecki et al. 2007).

Muscle Effects Muscular pain and cramps can be observed in patients taking acitretin; however, these symptoms are associated primarily with isotretinoin, especially in individuals involved in vigorous physical activity. Occasionally, elevated creatine kinase levels may be observed. Increased muscle tone as well as axial muscle rigidity and myopathy were reported to be related to etretinate and acitretin therapy, respectively (Lister et al. 1996). Hematologic Toxicities A high incidence (28%) of dose-related leukopenia was reported in the studies of bexarotene in CTCL, occurring as early as two to four weeks, with a decrease in neutrophils rather than lymphocytes (Duvic et  al. 2001a). Hematologic abnormalities are much less common with other retinoids, but careful hematologic monitoring in human immunodeficiency virus (HIV)-infected patients is warranted.

 astrointestinal Side Effects G Uncommon nonspecific gastrointestinal complaints have been reported in association with retinoid therapy. Synthetic retinoids have been temporally linked with other toxicities, such as inflammatory bowel disease; however, no cause-­ Contraindications and-­effect relationship has been established. Topical Retinoids Bone Toxicity Several reports have implicated synthetic reti- Topical retinoids should be avoided during pregnoids, including acitretin and isotretinoin, after nancy and nursing, due primarily to medicolegal long-term use, in the formation of diffuse hyper- issues raised by the teratogenicity of oral isotretiostosis of the spine (diffuse idiopathic skeletal noin. Concomitant use of irritating topical prodhyperostosis [DISH]), as well as calcification of ucts should be avoided. tendons and ligaments, particularly in the ankles. Prospective studies have shown that the effect of retinoids on bone, if present at all, is likely to Systemic Retinoids involve worsening of pre-existing skeletal overgrowth rather than induction of de novo changes. The absolute contraindications are pregnancy or Even long-term use of isotretinoin in acne women contemplating becoming pregnant, non-­ patients rarely causes clinically significant radio- compliance with contraception, breastfeeding, logic abnormalities, as most hyperostoses are and hypersensitivity to preservatives present in asymptomatic and clinically insignificant (Ling acitretin’s capsule (parabens). It must be pointed et al. 2001). out, however, that adverse reactions induced by

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parabens are neither frequent nor severe. Indeed, it seems that the only persons susceptible to develop a cutaneous reaction to parabens do it only on injured skin, but not on healthy skin, leading to the concept of “paraben paradox” (Hafeez and Maibach 2013; Sasseville et  al. 2015). Relative contraindications are leukopenia, moderate to severe hypercholesterolemia or hypertriglyceridemia, significant hepatic (especially bexarotene) or renal dysfunction, ­ hypothyroidism (especially bexarotene), and young children.

Drug Interactions The following should be avoided or used with caution: • Cyclines such as tetracycline, doxycycline, and minocycline may increase intracranial pressure. This side effect was in fact related to the very high doses of isotretinoin used in the early development of the drug (up to 2  mg/ kg). Currently the doses used are much lower, and patients given isotretinoin 0.25 mg/kg for severe rosacea may benefit of short periods of association with a cyclin. • Alcohol may increase conversion of acitretin to etretinate (special problem in women, see above) and hepatotoxicity. • Methotrexate may have synergistic liver toxicity with retinoids; however, combination may be used with caution in patients with PRP or severe psoriasis. • Vitamin A supplement carries the risk of hypervitaminosis A. • Azoles and macrolides are CYP3A4 inhibitors that may increase retinoid drug levels, resulting in potential toxicity. • In contrast, antituberculotic drugs (rifampin) and anticonvulsants (phenytoin and carbamazepine) may decrease the drug levels of retinoids via CYP3A4 induction. • Retinoids may also increase the drug levels of cyclosporine via competition for CYP3A4 metabolism.

Use in Infant Children and Elderly There are no significant age-related problems with prescribing retinoids, provided contraindications and drug interactions cited above are considered.

References Amichai B, Shemer A, Grunwald MH. Low-dose isotretinoin in the treatment of acne vulgaris. J Am Acad Dermatol. 2006;54(4):644–6. Antille C, Tran C, Sorg O, Saurat JH.  Penetration and metabolism of topical retinoids in ex  vivo organ-­ cultured full-thickness human skin explants. Skin Pharmacol Appl Ski Physiol. 2004;17(3):124–8. Arechalde A, Saurat JH.  Retinoids: unapproved uses or indications. Clin Dermatol. 2000;18(1):63–76. Aubert J, Piwnica D, Bertino B, Blanchet-Rethore S, Carlavan I, Deret S, et  al. Nonclinical and human pharmacology of the potent and selective topical retinoic acid receptor-gamma agonist trifarotene. Br J Dermatol. 2018;179(2):442–56. Barnes L, Tran C, Sorg O, Hotz R, Grand D, Carraux P, et  al. Synergistic effect of hyaluronate fragments in retinaldehyde-induced skin hyperplasia which is a CD44-dependent phenomenon. PLoS One. 2010;5(12):e14372. Bavinck JN, Tieben LM, Van der Woude FJ, Tegzess AM, Hermans J, ter Schegget J, et  al. Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study. J Clin Oncol. 1995;13(8):1933–8. Bellemère G, Stamatas GN, Bruère V, Bertin C, Issachar N, Oddos T.  Antiaging action of retinol: from molecular to clinical. Skin Pharmacol Physiol. 2009;22(4):200–9. Bigby M.  Does isotretinoin increase the risk of depression? Arch Dermatol. 2008;144(9):1197–9. discussion 234–235 Blomhoff R, Blomhoff HK. Overview of retinoid metabolism and function. J Neurobiol. 2006;66(7):606–330. Blume-Peytavi U, Fowler J, Kemeny L, Draelos Z, Cook-­ Bolden F, Dirschka T, et  al. Long-term safety and efficacy of trifarotene 50 mug/g cream, a first-in-class RAR-gamma selective topical retinoid, in patients with moderate facial and truncal acne. J Eur Acad Dermatol Venereol. 2020;34(1):166–73. Boer J.  Are there indications for isotretinoin treatment of hidradenitis suppurativa? Dermatology. 2017;233(2–3):111–2. Bollag W, Ott F.  Successful treatment of chronic hand eczema with oral 9-cis-retinoic acid. Dermatology. 1999;199(4):308–12.

154 Retinoids Breneman D, Duvic M, Kuzel T, Yocum R, Truglia J, Stevens VJ.  Phase 1 and 2 trial of bexarotene gel for skin-directed treatment of patients with cutaneous T-cell lymphoma. Arch Dermatol. 2002;138(3):325–32. Calikoglu E, Sorg O, Tran C, Grand D, Carraux P, Saurat JH, et  al. UVA and UVB decrease the expression of CD44 and hyaluronate in mouse epidermis which is counteracted by topical retinoids. Photochem Photobiol. 2006;82(5):1342–7. Carr DR, Trevino JJ, Donnelly HB. Retinoids for chemoprophylaxis of nonmelanoma skin cancer. Dermatol Surg. 2011;37(2):129–45. Chou C-F, Esla J, Atigadda V, Muccio D, Grubbs C, Craig E, et al. Preclinical assessment of retinoid X-receptor agonist, UAB110, for potential treatment of cutaneous T-cell lymphoma. AACR Annual Meeting 2019; July 2019; Atlanta: Cancer Research; 2019. Clayton BD, Jorizzo JL, Hitchcock MG, Fleischer AB Jr, Williford PM, Feldman SR, et al. Adult pityriasis rubra pilaris: a 10-year case series. J Am Acad Dermatol. 1997;36(6 Pt 1):959–64. Craven NM, Griffiths CEM.  Topical retinoids and cutaneous biology. Clin Exp Dermatol. 1996;21(1):1–10. Creidi P, Vienne MP, Ochonisky S, Lauze C, Turlier V, Lagarde JM, et al. Profilometric evaluation of photodamage after topical retinaldehyde and retinoic acid treatment. J Am Acad Dermatol. 1998;39(6):960–5. Cunliffe WJ, Caputo R, Dreno B, Forstrom L, Heenen M, Orfanos CE, et al. Clinical efficacy and safety comparison of adapalene gel and tretinoin gel in the treatment of acne vulgaris: Europe and U.S. multicenter trials. J Am Acad Dermatol. 1997a;36(6 Pt 2):S126–S34. Cunliffe WJ, van de Kerkhof PC, Caputo R, Cavicchini S, Cooper A, Fyrand OL, et  al. Roaccutane treatment guidelines: results of an international survey. Dermatology. 1997b;194(4):351–7. DiGiovanna JJ, Sollitto RB, Abangan DL, Steinberg SM, Reynolds JC.  Osteoporosis is a toxic effect of long-term etretinate therapy. Arch Dermatol. 1995;131(11):1263–7. Douer D.  Acute promyelocytic leukemia. Curr Treat Options in Oncol. 2000;1(1):31–40. Duvic M, Martin AG, Kim Y, Olsen E, Wood GS, Crowley CA, et al. Phase 2 and 3 clinical trial of oral bexarotene (Targretin capsules) for the treatment of refractory or persistent early-stage cutaneous T-cell lymphoma. Arch Dermatol. 2001a;137(5):581–93. Duvic M, Hymes K, Heald P, Breneman D, Martin AG, Myskowski P, et  al. Bexarotene is effective and safe for treatment of refractory advanced-stage cutaneous T-cell lymphoma: multinational phase II-III trial results. J Clin Oncol. 2001b;19(9):2456–71. Erdogan FG, Yurtsever P, Aksoy D, Eskioglu F. Efficacy of low-dose isotretinoin in patients with treatment-­ resistant rosacea. Arch Dermatol. 1998;134(7):884–5. Ethan-Quan HN, Wolverton S.  Systemic retinoids. In: Wolverton S, editor. Comprehensive dermatology drug therapy. Philadelphia: WB Saunders; 2001. p. 269–310.

1759 Ferguson J, Johnson BE.  Retinoid associated phototoxicity and photosensitivity. Pharmacol Ther. 1989;40(1):123–35. Fields AL, Soprano DR, Soprano KJ.  Retinoids in biological control and cancer. J Cell Biochem. 2007;102(4):886–98. Fontao F, von Engelbrechten M, Seilaz C, Sorg O, Saurat JH. Microcomedones in non-lesional acne prone skin. New orientations on comedogenesis and its prevention. J Eur Acad Dermatol Venereol. 2020;34:357–64. Fortuna VA, Martucci RB, Trugo LC, Borojevic R. Hepatic stellate cells uptake of retinol associated with retinol-­ binding protein or with bovine serum albumin. J Cell Biochem. 2003;90(4):792–805. Gniadecki R, Assaf C, Bagot M, Dummer R, Duvic M, Knobler R, et  al. The optimal use of bexarotene in cutaneous T-cell lymphoma. Br J Dermatol. 2007;157(3):433–40. Grahovac M, Molin S, Prinz JC, Ruzicka T, Wollenberg A. Treatment of atopic eczema with oral alitretinoin. Br J Dermatol. 2010;162(1):217–78. Hafeez F, Maibach H.  An overview of parabens and allergic contact dermatitis. Skin Therapy Lett. 2013;18(5):5–7. Harms M, Duvanel T, Williamson C, Masouyé I, Saurat JH. Isotretinoin for acne: should we consider the total cumulative dose? In: Marks R, Plewig G, editors. Acne and related disorders. London: Martin Dunitz; 1989. p. 203–6. Huang CM, Kirchhof MG. A new perspective on isotretinoin treatment of hidradenitis suppurativa: a retrospective chart review of patient outcomes. Dermatology. 2017;233(2–3):120–5. JAMA.  Trifarotene (Aklief)  – a new topical retinoid for acne. JAMA. 2020;323(13):1310–1. Jick H. Retinoids and teratogenicity. J Am Acad Dermatol. 1998;39(2 Pt 3):S118–S22. Joshipura D, Goldminz A, Greb J, Gottlieb A. Acitretin for the treatment of recalcitrant plantar warts. Dermatol Online J. 2017;23(3) Kang S, Duell EA, Fisher GJ, Datta SC, Wang ZQ, Reddy AP, et al. Application of retinol to human skin in vivo induces epidermal hyperplasia and cellular retinoid binding proteins characteristics of retinoic acid but without measurable retinoic acid levels or irritation. J Invest Dermatol. 1995;105:549–56. Kasraee B, Tran C, Sorg O, Saurat JH.  The depigmenting effect of RALGA in C57BL/6 mice. Dermatology. 2005;210(Suppl 1):30–4. Kaya G, Saurat JH. Dermatoporosis: a chronic cutaneous insufficiency/fragility syndrome. Clinicopathological features, mechanisms, prevention and potential treatments. Dermatology. 2007;215(4):284–94. Kaya G, Tran C, Sorg O, Hotz R, Grand D, Carraux P, et  al. Hyaluronate fragments reverse skin atrophy by a CD44-dependent mechanism. PLoS Med. 2006;3(12):e493. Kaymak Y, Taner E, Taner Y. Comparison of depression, anxiety and life quality in acne vulgaris patients who

1760 were treated with either isotretinoin or topical agents. Int J Dermatol. 2009;48(1):41–6. Kim MS, Lee S, Rho HS, Kim DH, Chang IS, Chung JH. The effects of a novel synthetic retinoid, seletinoid G, on the expression of extracellular matrix proteins in aged human skin in  vivo. Clinica Chimica Acta. 2005;362(1–2):161–9. Kligman AM, Grove GL, Hirose R, Leyden JJ.  Topical tretinoin for photoaged skin. J Am Acad Dermatol. 1986;15(4 Pt 2):836–59. Kojima M, Ogiya D, Ichiki A, Hara R, Amaki J, Kawai H, et al. Refractory acute promyelocytic leukemia successfully treated with combination therapy of arsenic trioxide and tamibarotene: a case report. Leuk Res Rep. 2016;5:11–3. Kolesar JM, Andrews S, Green H, Havighurst TC, Wollmer BW, DeShong K, et  al. A randomized, placebo-controlled, double-blind, dose escalation, single dose, and steady-state pharmacokinetic study of 9cUAB30  in healthy volunteers. Cancer Prev Res (Phila). 2019;12(12):903–12. Lammer EJ, Chen DT, Hoar RM, Agnish ND, Benke PJ, Braun JT, et al. Retinoic acid embryopathy. N Engl J Med. 1985;313:837–41. Layton A.  The use of isotretinoin in acne. Dermatoendocrinol. 2009;1(3):162–9. Layton AM, Knaggs H, Taylor J, Cunliffe WJ. Isotretinoin for acne vulgaris - 10 years later: a safe and successful treatment. Br J Dermatol. 1993;129:292–6. Lebwohl M.  Acitretin in combination with UVB or PUVA. J Am Acad Dermatol. 1999;41(3 Pt 2):S22–S4. Lee E, Park N, Ahn Y, Jung W, Bae IH, Yoo JW, et al. The wound healing effect of a novel synthetic retinoid, seletinoid G, on cultured keratinocytes and human skin equivalents. J Invest Dermatol. 2019;139:S164. Lee ES, Ahn Y, Bae IH, Min D, Park NH, Jung W, et al. Synthetic retinoid seletinoid G improves skin barrier function through wound healing and collagen realignment in human skin equivalents. Int J Mol Sci. 2020;21(9):3198. [1–12] Lehucher-Ceyrac D, Weber-Buisset MJ. Isotretinoin and acne in practice: a prospective analysis of 188 cases over 9 years. Dermatology. 1993;186(2):123–8. Lehucher-Ceyrac D, de La Salmoniere P, Chastang C, Morel P.  Predictive factors for failure of isotretinoin treatment in acne patients: results from a cohort of 237 patients. Dermatology. 1999;198(3):278–83. Ling TC, Parkin G, Islam J, Seukeran DC, Cunliffe WJ. What is the cumulative effect of long-term, low-­ dose isotretinoin on the development of DISH? Br J Dermatol. 2001;144(3):630–2. Lister RK, Lecky BR, Lewis-Jones MS, Young CA.  Acitretin-induced myopathy. Br J Dermatol. 1996;134(5):989–90. Lowe NL. When systemic retinoids fail to work in psoriasis. In: Saurat JH, editor. Retinoids: 10 years on. Basel: Karger; 1991. p. 341–9. Marcellus DC, Altomonte VL, Farmer ER, Horn TD, Freemer CS, Grant J, et  al. Etretinate therapy for

J.-H. Saurat and O. Sorg refractory sclerodermatous chronic graft-versus-host disease. Blood. 1999;93(1):66–70. Miwako I, Kagechika H. Tamibarotene. Drugs of Today. 2007;43(8):563–8. Nada HR, Rashed LA, Elantably DMM, El Sharkawy DA. Expression of retinoid receptors in hand eczema. Int J Dermatol. 2020;59(5):576–81. Nelson AM, Zhao W, Gilliland KL, Zaenglein AL, Liu W, Thiboutot DM.  Neutrophil gelatinase-associated lipocalin mediates 13-cis retinoic acid-induced apoptosis of human sebaceous gland cells. J Clin Invest. 2008;118(4):1468–78. Nohynek GJ, Meuling WJ, Vaes WH, Lawrence RS, Shapiro S, Schulte S, et  al. Repeated topical treatment, in contrast to single oral doses, with Vitamin A-containing preparations does not affect plasma concentrations of retinol, retinyl esters or retinoic acids in female subjects of child-bearing age. Toxicol Lett. 2006;163(1):65–76. On SC, Zeichner J. Isotretinoin updates. Dermatol Ther. 2013;26(5):377–89. Orfanos CE, Zouboulis CC, Almond-Roesler B, Geile CC. Current use and future potential role of retinoids in dermatology. Drugs. 1997;53:358–88. Panchaud A, Csajka C, Merlob P, Schaefer C, Berlin M, De Santis M, et  al. Pregnancy outcome following exposure to topical retinoids: a multicenter prospective study. J Clin Pharmacol. 2012;52(12):1844–51. Péchère M, Pechere JC, Siegenthaler G, Germanier L, Saurat JH.  Antibacterial activity of retinaldehyde against Propionibacterium acnes. Dermatology. 1999;199(Suppl 1):29–31. Péchère M, Germanier L, Siegenthaler G, Pechere JC, Saurat JH.  The antibacterial activity of topical retinoids: the case of retinaldehyde. Dermatology. 2002;205(2):153–8. Pilkington T, Brogden RN.  Acitretin. A review of its pharmacology and therapeutic use. Drugs. 1992;43(4):597–627. Roenigk HH Jr, Callen JP, Guzzo CA, Katz HI, Lowe N, Madison K, et al. Effects of acitretin on the liver. J Am Acad Dermatol. 1999;41(4):584–8. Ruzicka T, Sommerburg C, Goerz G, Kind P, Mensing H. Treatment of cutaneous lupus erythematosus with acitretin and hydroxychloroquine. Br J Dermatol. 1992;127(5):513–8. Ruzicka T, Lynde CW, Jemec GB, Diepgen T, Berth-­ Jones J, Coenraads PJ, et  al. Efficacy and safety of oral alitretinoin (9-cis retinoic acid) in patients with severe chronic hand eczema refractory to topical corticosteroids: results of a randomized, double-blind, placebo-controlled, multicentre trial. Br J Dermatol. 2008;158(4):808–17. Sachs DL, Voorhees JJ. Age-reversing drugs and devices in dermatology. Clin Pharmacol Ther. 2011;89(1):34–43. Safran AB, Haliaoua B, Roth A, Saurat JH. Ocular side-­ effects of oral treatment with retinoids. In: Saurat JH, editor. Retinoids: 10 years on. Basel: Karger; 1991. p. 315–26.

154 Retinoids Sasseville D, Alfalah M, Lacroix JP. “Parabenoia” Debunked, or “Who’s afraid of parabens?”. Dermatitis. 2015;26(6):254–9. Saurat JH.  Systemic retinoids. What’s new? Dermatol Clin. 1998;16(2):331–40. Saurat JH, Geiger JM, Amblard P, Beani JC, Boulanger A, Claudy A, et al. Randomized double-blind multicenter study comparing acitretin-PUVA, etretinate-PUVA and placebo-PUVA in the treatment of severe psoriasis. Dermatologica. 1988;177(4):218–24. Saurat JH, Didierjean L, Masgrau E, Piletta PA, Jaconi S, Chatellard-Gruaz D, et al. Topical retinaldehyde on human skin: biological effects and tolerance. J Invest Dermatol. 1994;103(6):770–4. Sherman SI, Gopal J, Haugen BR, Chiu AC, Whaley K, Nowlakha P, et al. Central hypothyroidism associated with retinoid X receptor-selective ligands. N Engl J Med. 1999;340(14):1075–9. Smit JV, de Sevaux RG, Blokx WA, van de Kerkhof PC, Hoitsma AJ, de Jong EM. Acitretin treatment in (pre) malignant skin disorders of renal transplant recipients: Histologic and immunohistochemical effects. J Am Acad Dermatol. 2004;50(2):189–96. Sorg O, Saurat JH.  Topical retinoids in skin ageing: a focused update with reference to sun induced epidermal vitamin A deficiency. Dermatology. 2014;228(4):314–25. Sorg O, Tran C, Saurat JH. Cutaneous vitamins A and E in the context of ultraviolet- or chemically-induced oxidative stress. Skin Pharmacol Appl Ski Physiol. 2001;14(6):363–72. Sorg O, Tran C, Carraux P, Grand D, Hugin A, Didierjean L, et  al. Spectral properties of topical retinoids prevent DNA damage and apoptosis after acute UVB exposure in hairless mice. Photochem Photobiol. 2005;81(4):830–6.

1761 Sorg O, Antille C, Kaya G, Saurat JH. Retinoids in cosmeceuticals. Dermatol Ther. 2006;19(5):289–96. Sorg O, Kuenzli S, Saurat JH. Side effects and pitfalls in retinoid therapy. In: Vahlquist A, Duvic M, editors. Retinoids and carotenoids in dermatology. New York: Informa Healthcare; 2007. p. 225–48. Talpur R, Ward S, Apisarnthanarax N, Breuer-Mcham J, Duvic M.  Optimizing bexarotene therapy for cutaneous T-cell lymphoma. J Am Acad Dermatol. 2002;47(5):672–84. Tangrea JA, Adrianza E, Helsel WE, Taylor PR, Hartman AM, Peck GL, et al. Clinical and laboratory adverse effects associated with long-term, low-dose isotretinoin: incidence and risk factors. The Isotretinoin-Basal Cell Carcinomas Study Group. Cancer Epidemiol Biomark Prev. 1993;2(4):375–80. Törmä H. Interaction of isotretinoin with endogenous retinoids. J Am Acad Dermatol. 2001;45(5):S143–S9. Tran C, Sorg O, Carraux P, Didierjean L, Saurat JH. Topical delivery of retinoids counteracts the UVB-­ induced epidermal vitamin A depletion in hairless mouse. Photochem Photobiol. 2001;73(4):425–31. Tran C, Kasraee B, Grand D, Carraux P, Didierjean J, Sorg O, et  al. Pharmacology of RALGA, a mixture of retinaldehyde and glycolic acid. Dermatology. 2005;210(Suppl 1):6–13. Wang Z, Boudjelal M, Kang S, Voorhees JJ, Fisher GJ.  Ultraviolet irradiation of human skin causes functional vitamin A deficiency, preventable by all-trans retinoic acid pre-treatment. Nat Med. 1999;5(4):418–22. Wiegand UW, Chou RC.  Pharmacokinetics of acitretin and etretinate. J Am Acad Dermatol. 1998;39(2 Pt 3):S25–33.

Scabicides and Pediculicides

155

Katerina Damevska

Key Points • Scabies and pediculosis are the most common ectoparasitoses in a dermatologist’s practice. • As epidermal parasitic skin diseases, host– parasite interactions are restricted to the corneal layer. • Pruritus is the most common presenting symptom with both conditions. • The primary goal in the management is to treat the patient successfully and to take control measures to effectively prevent transmission. • Topical medications are the mainstay of treatment and many topical agents with different efficacies are used. • The drugs should be administrated taking into consideration the life-cycle of the parasites. • For the treatment of scabies, combination permethrin plus oral ivermectin, topical ivermectin, and synergized pyrethrins had the strongest evidence for the highest cure and lowest adverse reactions. • Мalathion and permethrin remain the most widely used pediculicides. Noninsecticidal agents, including products with a physical mode of action, show promise in the treatment

K. Damevska (*) Clinic of Dermatology, Medical Faculty, Ss. Cyril and Methodius University, Skopje, Republic of Macedonia

of pediculosis. Oral ivermectin should be used with caution and only in selected cases. • Community-based mass drug administration, particularly the administration of single-dose ivermectin, has become a central strategy for the control of scabies in a population with endemic disease. • Treatment depends on the availability of the drug in different countries.

General Principles Scabies and pediculosis are recognized as “neglected tropical diseases” by the World Health Organization (WHO). Worldwide, approximately 200 million people are infected with scabies each year, and this number appears to be rising (World Health Organization 2020). Scabies, pediculosis capitis, and pediculosis pubis occur worldwide but pediculosis corporis is restricted to cold-climate countries. Scabies is increasing in resource-poor settings. High population density, lack of access to health care, inadequate treatment, and social attitudes contribute to the high burden of scabies in these settings (Feldmeier and Heukelbach 2009). In developed countries, scabies outbreaks are common in residential and nursing care homes (Chandler and Fuller 2019). In resource-poor settings, scabies is usually not a sexually transmitted disease, while this seems to be a common

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mode of transmission in high-income countries (Feldmeier and Heukelbach 2009). Head lice infestation is very common among schoolchildren, whatever their hygiene status. Adults with poor personal hygiene are also commonly affected. Body lice infestation is related to poor hygiene and cold-weather conditions (Amanzougaghene et al. 2020). Pruritus is the most common presenting symptom with both conditions. Severe itching can lead to excoriations in which a secondary bacterial infection is considerable (Chandler and Fuller 2019). Although rare, secondary infection with group A streptococci is a major precipitant of post-streptococcal glomerulonephritis and rheumatic fever (Feldmeier and Heukelbach 2009). There are many therapeutic options for pediculosis (Table 155.1), including chemical insecticides, topically applied physical agents, herbal formulations, and mechanical methods; malathion and permethrin remain the most widely used medications (Gunning et al. 2019). For the treatment of scabies, combination permethrin plus oral ivermectin, topical ivermectin, and synergized pyrethrins had the strongest evidence for the highest cure and lowest adverse reactions (Thadanipon et al. 2019). While effective treatments exist, it is unknown which treatment strategies result in the best outcomes against the lowest costs (van der Linden et al. 2019).

Acaricide Resistance Although a variety of other factors including reinfestation, incorrect application of the drug, or poor patient compliance influence the efficacy of treatments for ectoparasites, drug resistance is emerging as a significant factor in treatment failure (Eremeeva et al. 2017). Of particular concern is the unexpected emergence of resistance to oral ivermectin and 5% permethrin (Mounsey et  al. 2008). Various resistance mechanisms such as avoidance of treated surfaces, reduced sensitivity of target site, and metabolic degradation mediate pesticide resistance of arthropods. An effective way to manage pesticide resistance is the coformulation of synergists with the pesticide.

For example, piperonyl butoxide (PBO) has been used as a synergist to pyrethrins in commercially available treatment for head lice to counteract metabolic resistance (Pasay et al. 2009).

Topical Treatments Pyrethrins and Pyrethroids Pyrethrins and pyrethroids are effective insecticides for both, humans and animals. Pyrethrum extract, a mixture of chemicals found in some chrysanthemum flowers, has six individual chemicals, called pyrethrins, with insecticidal properties. Pyrethrins are only slightly soluble in water, but they dissolve in organic solvents like alcohol, and chlorinated hydrocarbons. Pyrethroids are synthetic chemical insecticides that are very similar in structure to the pyrethrins. Most commercial pyrethroids are combined with other chemicals (synergists), which enhance the insecticidal activity (Agency for Toxic Substances and Disease Registry (ATSDR) 2003).

Permethrin Permethrin is a synthetic pyrethroid, which is primarily a neurotoxin causing respiratory paralysis of the affected arthropod (Nanda and Juergens 2020). Permethrin 1% lotion or shampoo is the first-­ line treatment for pediculosis, where permethrin 5% cream or lotion is the first-line treatment for scabies (Gunning et al. 2019). Permethrin is not ovicidal. Thus, a second application is needed seven to ten days after the first to ensure complete eradication (Thadanipon et al. 2019). For classical scabies, permethrin is applied as 5% cream to all areas of the body from head/neck to toe. It is left on overnight or up to 24 hours and then rinsed off. Children aged two months or older can also be treated. For crusted scabies, permethrin cream can be applied topically every day for one week, followed by application twice a week until resolution, along with oral ivermectin (Table 155.1) (Rosumeck et al. 2018). For the treatment of pediculosis capitis, 1% permethrin shampoo or lotion is an effective and

CNS central nervous system, S scabicide, P pediculicide Source: Reproduced and modified from Bernigaud et al. 2016 with permission

Recommended treatments 200 mcg/kg on day 0 and 2 weeks later

Efficacies Commercial preparations (%) Side effects Stromectol, Ivomec, Iver-DT, 70–100 Nausea, rash, itching, Ivexterm, Scabo-6 dizziness, eosinophilia, abdominal pain, fever, tachycardia Ivermectin lotion Sklice lotion (head lice in 10-minute application 78 – 0.5% children >6 months of age) on dry hair Permethrin 5% Scabicide: Lyclear dermal Apply for 8–12 hours 86–100 Pruritus, burning, cream, 1% cream cream (5%); Pediculicide: on day 0 and 1 week stinging, eczema rinse Lyclear cream rinse (1%), nix later (1%), Lythrin cream rinse Benzyl benzoate Ascabiol, Tenutex, Ascabin, Apply for 12 h on 48–92 Pruritus, burning, 10–25% lotion or Ascarbin, days 1 and 2 and stinging, eczema emulsion repeat after 7 days Crotamiton Eurax 10% lotion/ointment, Overnight on days 1 63–88 Pruritus, eczema, 5–10% Euraxil 5% gel and 2 anaphylactic reaction Precipitated sulfur Wilkinson’s ointment 3 consecutive nights 39–100 Messy application, 2–10% malodor Malathion 0.5–1% Derbac-C shampoo (S) Two applications, 7 47–72 Pruritus, burning, CNS lotion, solution, Derbac-M (P/S) days apart; 12 h (P), toxicity, dizziness, shampoo Prioderm lotion (S) or 24 h (S) seizure Prioderm shampoo (P) Malathion powder, disinfection of clothes Quellada M (P) Lindane 1% Quellada lotion (S), shampoo Overnight repeat after 64–96 CNS, renal, and hepatic (P) 7 days toxicity

Drugs/ Formulations Ivermectin 200 mg/kg pills

Table 155.1  Treatments in use to treat scabies and pediculosis

Not recommended

–

Use in breastfeeding women Only recommended in France

Authorized

–

Withdrawn from the European market

Withdrawn from the European market

Withdrawn from the European market

Not approved in Not recommended Not recommended children 6 months of age Safe in children Approved >2 months of age

Use in children Not approved in children  15 (>30 by some guidelines), applied in amount of 2  mg/cm2, on UV-exposed skin, 20  min before and repeated at least every 2  h during sun exposure, in addition to other photoprotection measures like wearing protective clothing, seeking shade, and avoiding peak-hour sun exposure and artificial tanning devices.

A.-M. Forsea (*) Oncologic Dermatology Department, Carol Davila University of Medicine and Pharmacy Bucharest, Elias University Hospital, Bucharest, Romania

General Principles Ultraviolet radiation (UVR) of both natural solar and artificial origin has a wide range of effects on the human skin, depending on the radiation’s wavelength and the host’s sensitivity. While sunlight is necessary for health, excessive sun exposure, which is individually determined, has negative consequences. The immediate clinical effects of UVR include sunburn (ranging from mild erythema to painful blistering), pigmentation, cutaneous immunity modulation (suppression of acquired immunity, enhancement of innate immunity), and vitamin D synthesis in the skin. The chronic, cumulative UVR effects include the photoaging (with its clinical complex of skin dispigmentation, telangiectasia, fine and coarse wrinkles and elasticity loss) and, importantly, the development of skin cancers. UV exposure is considered the principal environmental factor of cutaneous oncogenesis, with about 90% of keratinocyte cancers and 65% of melanoma burden currently attributed to UV exposure(Robyn et al. 2006). In predisposed individuals, sunlight is also responsible for a vast array of photo-induced and photo-aggravated dermatoses. These effects result from the molecular mechanisms of UVR action within the skin cells, which comprise: structural DNA damage, with formation of cyclobutane pyrimidine dimers (CPDs) and C-T, CC-TT mutations (mainly UVB

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effect); the generation of reactive oxygen species (ROS) toxic for DNA and other cell structures (mainly UVA effect); gene expression modulation; melanogenesis stimulation; induction of apoptosis; and depletion of skin immune cells. Vitamin D production is initiated by the UVB-­ induced conversion of epidermal 7-­dehydrocholesterol into pre-vitamin D (Young et al. 2017; Suozzi et al. 2020). These complex mechanisms are triggered by the interaction between the UVR and the UV-absorbing chromophore molecules within the skin, either endogenous like DNA, porphyrins, or melanins, or exogenous—derived from systemic or cutaneous exposure to various drugs or ­chemicals. The absorption of UVR induces energetic and structural changes in the chromophore molecules, resulting in the production of ROS and other potentially toxic metabolites, function alterations, or binding to other molecules and triggering chain effects. Topical sunscreens are formulations applied on the skin in order to protect it from the various negative UVR effects. Their fundamental mechanism of action is to block the UVR from reaching its target molecules within the skin, either by reflecting or scattering the incident UVR away from the skin or by absorbing the UVR energy and converting it in the less harmful form of heat (Young et al. 2017; Mancuso et al. 2017). In order to be effective protectors, the topical sunscreens must meet certain requirements. Principally, they must protect both against UVB (280–320  nm) and UVA (320–400  nm) radiation, taking into consideration that the solar UVR reaching the Earth surface is represented by 5% UVB and 95% UVA. While UVB is the main inducer of erythema, the other acute and chronic UV pathogenic effects, including photocarcinogenesis, may result from cumulative exposure to sub-erythemogenic doses of both UVB and UVA (Young et  al. 2017). Further, topical sunscreens must be photostable, should be nontoxic to the skin and display negligible percutaneous systemic adsorption. They should be cosmetically acceptable for the general public, safe for humans and the environment, and must comply

with the patent and marketing regulations relevant for their area of use. As the skin protection from UVR exposure is now the cornerstone of prevention of skin cancers and photoaging, the topical sunscreens have become an important part of the preventive efforts, along with other physical protection methods like photoprotective clothing and sunglasses and behavioral measures of avoiding excessive sun exposure and artificial tanning.

Sunscreen Structure and Classification Topical sunscreens exist in various forms of creams, gels, lotions, or sprays that incorporate molecules acting as UV filters by absorbing or/ and scattering the UV radiation. UV filters fall into two broad categories: the organic filters, also called chemical filters, that penetrate within the epidermis and act at this level mainly by absorbing and redistributing the UVR energy; and the inorganic filters, also called physical or mineral filters, that remain largely at the surface of the epidermis and act mainly by reflecting or scattering the incident UVR away from the skin surface, in addition to also absorbing UVR.  Sunscreen formulations can contain one or both filter types.

Organic Filters Organic filters are aromatic compounds that contain series of conjugated π-electron systems on their aromatic rings, giving them the ability to absorb UVR energy and subsequently dissipate it in the form of heat (Young et al. 2017; Mancuso et  al. 2017). Several classes of organic filters exist (Table 156.1), with absorption properties in UVB, UVA spectrum, or both. Organic filters penetrate within the epidermis and act at this level. Hence they are not visible on the skin surface after application, so they are cosmetically acceptable and the widest prescribed and used class of commercially available sunscreens (Maier and Korting 2005). At the same time, their interaction with the UVR within the living epider-

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Table 156.1  UV filters contained in sunscreens (Mancuso et al. 2017; FDA FaDA 2019; Yap et al. 2017; Regulation (EC) No 1223/2009; European Commission 2022) Filter type Organic

Chemical class Compounds Aminobenzoates Para amino-benzoic acid (PABA)

UVR filtering spectrum UVB

Padimate O

UVB

Oxybenzone (Benzophenone-3)

UVA2 (320– 340 nm), UVB

Dioxybenzone

UVB, UVA2

Sulisobenzone

UVB, UVA2

Cinoxate Octinoxate

UVB UVB

Amiloxate (isoamyl p-methoxycinnamate)

UVB

Salicylates

Octisalate Homosalate Trolamine salicylate

UVB

Other UVB filters

Enzacamene (4-methylbenzylidene camphor) Benzylidene-camphor-sulfonic acid Camphor-benzalkonium-­ methosulfate Polyacrylamidomethyl benzylidene camphor

UVB

Benzophenones

Cinnamates

UVB UVB UVB

Observations

Common contact allergen; systemic absorption; potential endocrine effects; rarely used Easily photo-oxidable; frequent cause of photoallergic reactions; stabilizes avobenzone; most frequently found UV filter contaminant in water and fish species; experimental toxicity on corals; limited maximal concentration allowed in EU

Strong UVB absorbers; cinnamates may cross react with same class contact sensitizers in cosmetics; octinoxate is widely used; destabilizes avobenzone Cinnamic acid-related antioxidant; anti-­ inflammatory properties Weak UVB absorbers; photostable; used mostly in combination with stronger filters; possible skin irritants; homosalate is investigated for endocrine disruptive potential in the EU

Market approval USA, EU, Australia USA, EU, Australia

EU, Australia USAa

EU, Australia, USA EU, Australia, USA EU, Australia, USAa

EU

EU, Australia, USA

Australia, EU Australia, EU Australia, EU EU (continued)

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Chemical class

Other UVA filters

Compounds Octyl triazone (ethylhexyl triazone) Avobenzone

UVR filtering spectrum UVB UVA

Observations Highly stable and strong UVB absorber Strong UVA protector but highly photo-unstable; stabilized and protection enhanced by octocrylene; stabilized by oxybenzone; destabilized by octinoxate

Meradimate (menthyl anthranilate) UVA2

Other UVB and UVA filters

Dimethicodiethylbenzalmalonate (polysilicone-15) Diethylamino hydroxybenzoyl hexyl benzoate Octocrylene

UVA UVA1 (340– 400 nm) UVB, UVA2

Ecamsule (Mexoryl™ SX)

UVB, UVA Drometrizole trisiloxane (Mexoryl UVB, ™XL) UVA2 Bemotrizinol (Tinosorb ™S) UVB, UVA2

Inorganic filters

Bisoctrizole (Tinosorb™ M)/ Bisoctrizole nano

UVB, UVA2

Ensulizole

UVB, UVA

Bisdisulizole disodium (disodium phenyl dibenzimidazole tetrasulfonate) Tris-biphenyl triazine/(nano)

UVB, UVA2

UVB, UVA Iscotrizinol (diethylhexyl UVB, butamido triazone) UVA2 Titanium dioxide/Titanium dioxide UVB-­ nano UVAb Zinc oxide/(nano) UVB-­ UVAb

Low transepidermic absorption

Very stable; it stabilizes avobenzone and synergizes by increasing its UVA-PF; maximal allowed concentration in sunscreens reduced by EU regulation Photostable; low percutaneous absorption Synergistic with ecamsule Highly photostable; stabilizes other UV absorbers like avobenzone and octinoxate Highly photostable; synergistic activity with higher UVA protection when combined with 8% bemotrizinol and 5% octinoxate

Market approval EU, Australia EU, Australia, USA

EU, Australia, USA EU, Australia EU, Australia Australia, EU, USA

EU, Australia EU, Australia EU, Australia

EU, Australia

EU, Australia, USA EU, Australia EU, Australia Highly stable; liposoluble EU EU, USA, Australia USA, EU, Australia

Sunscreens containing oxybenzone and octinoxate are banned for sale in Hawaii state (2018), U.S.  Virgin Islands (2019), and Key West, FL (2019) b Depending on the particle size a

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mis can generate neoantigens that may induce photoallergic reactions (Collaris and Frank 2008); thus organic filters cause more frequently photoallergic contact dermatitis than inorganic ones. Further, organic filters may degrade under UV irradiation, generating ROS that are toxic to the surrounding cells’ structures including DNA. The highly effective but highly photolabile UVA1 ­filter avobenzone is such an example. The paradoxical increased DNA damage through oxidative mechanisms induced by organic UV filters-derived ROS, despite the filters’ protective effect against UVBsignature CPD formation, has been proven in in  vitro and in  vivo studies (Bastien et  al. 2010; Hanson et al. 2006). The photodegradation can be aggravated or, on the contrary, attenuated by particular filter combinations, and therefore modern commercial formulations focus on combining filters with reciprocal stabilizing effects and complementing UVB/UVA spectrum (Mancuso et  al. 2017).

Inorganic Filters Inorganic filters are metal oxides, like titanium dioxide (TiO2) or zinc oxide (ZnO). They are efficient filters for both the UVB and UVA radiation and are active also in the visible light (VL) spectrum. Their reflective properties and the fact that they remain at the epidermis surface make them less likely to induce photoallergic reactions or skin-toxic products by photodegradation, so they have been “generally recognized as safe and effective” (GRASE) by the U.S. Food and Drug Administration (FDA), unlike organic ones (FDA FaDA 2019). The main limitation of inorganic filters’ use has been the cosmetically unfavorable whitish hue they leave on the skin surface, which lowers them in consumers’ preference rankings (Varedi et al. 2019). The mitigation of this effect has been attempted by supplementing the filters with universal skin tone tints that counter the white color and bring a more skin-natural hue to the product applied on the skin. Another strategy to reduce their visibility on the skin consists in the micronization, and more recently in the nanosizing of the filter particles incorporated in the

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sunscreen formulation (Jansen et  al. 2013). Nanosizing has potential downsides, as it may increase the filter’s penetrance within the living epidermis and hence the risk of photoallergic/ phototoxic reactions (Sha et  al. 2015; Crosera et al. 2015); it may also reduce the filter’s spectrum, changing the ratio between its UVR reflecting/scattering and UVR absorption properties. Micronization of TiO2 has been shown to increase its UVB absorption, but decrease the absorption in UVA range and lower its scattering and reflection of visible light (VL) spectrum, making it a less effective filter for UVA and VL (Jansen et al. 2013). These particle-size-dependent effects have not been shown though for ZnO (Cole et al. 2016).

Sunscreen Measurements and Regulation Sunscreen formulations are classified and approved for consumers’ use primarily according to their UVR filtering performance and spectrum. Further parameters that influence their effects, marketing approval, and labeling include their resistance to water, their photostability and their cosmetic effect. These parameters are subject to different methods of measurement, labeling and regulation in different countries.

 he UV Filtering Spectrum T and Efficiency The sun protection factor (SPF) was the first parameter introduced in the 1950s, as sunscreens were initially developed to protect against the sunburn erythema (Schulze 1956). SPF is calculated as the ratio between the doses of UVR needed to cause skin erythema with and without sunscreen applied. As erythema is induced mainly by UVB, SPF is primarily an indicator of the filtering efficiency in the UVB spectrum. Different methodologies of measuring SPF exist worldwide; the most widely used ones currently are the ISO 24444 standard methodology, published in 2010 by the International Standards

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Organization (Technical Committee ISO/TC 217 2010) and adopted in Europe, Australia, Canada, and Japan (Young et al. 2017), and the FDA standard methodology valid in the USA and many other countries (Young et al. 2017; FDA 2011). These methodologies are based on the same principle of SPF measurement in vivo, by irradiating the living skin of healthy volunteers with a standardized range of UVB doses, before and after applying a standardized dose of 2 mg/cm2 of sunscreen, and measuring the degree of ensuing erythema. There is no standardized in vitro method of measuring SPF to date and the in vivo testing has a certain degree of result variability, depending on the testing site, methodology, and volunteer subjects’ characteristics. In the European Union (EU) area and in the USA the regulatory bodies allow a superior limit of 50+ for the SPF labeling of sunscreens, justified by the attempt to avoid misleading the consumer, as the protective effect against sun damage does not increase linearly with the SPF, nor should, e.g., an SPF100 product be mistakenly considered to provide 100% blockage of UVR.  This labeling cap has recently been proposed to be raised to SPF60+ in the USA (FDA FaDA 2019), acknowledging the increased benefit of using higher-SPF sunscreens, especially in the context of real-life application of suboptimal sunscreen amounts (Williams et al. 2018; Ou-Yang et al. 2012) and in the long term to protect against cumulative sun exposure. The testing for measuring the degree of UVA protection of sunscreen products was developed later, as the photocarcinogenic and photoaging effects of UVA were being discovered and the necessity of broad-spectrum UVR protection was recognized. Modern sunscreens are required to have broad spectrum, UVB and UVA filtering properties (Cosmetics Europe 2005). The standardized UVA testing procedure mostly used at present is set out by the ISO 24443 methodology, issued in 2012 (International Organization for Standardization 2012). It consists of an in  vitro procedure to determine the UVR spectral absorption curve, based on which further parameters can be calculated including the UVA protection factor (UVA PF), critical wavelength, and UVA absorbance proportionality (International Organization for Standardization 2012). These

parameters are used by different market regulation authorities to evaluate the sunscreens claiming broad UVB/UVA protection spectrum. The FDA requires a critical wavelength of 370  nm (FDA 2011) and within the EU it is required the same critical wavelength and a UVA PF of at least 1/3 of the product’s SPF for the sunscreen to be labeled as providing broad-spectrum UV protection (Cosmetics Europe 2005). Earlier in vivo testing methods, based on the pigmenting effect of UVA on the living human skin (persistent pigment darkening, PPD), are still mandatory for market approval only in Japan and Korea (Young et al. 2017). The ISO 24443 UVA testing methodology requires prior in vivo measurement of SPF as the basis for the scaling of the UV absorbance curve. The topical sunscreens’ role for protection against solar visible light (VL) and infrared radiation (IR) was not addressed until recently. Visible light and IR have been shown to contribute to the cutaneous oxidative photodamage, as they induce up to 50% of the free radicals produced in the skin by sunlight exposure (Zastrow and Lademann 2016). Visible light induces persistent pigmentation, especially in darker skin phototypes (Mahmoud et al. 2010), may contribute to melasma and post-inflammatory hyperpigmentation induction (Regazzetti et  al. 2018; Schalka 2017) and plays a triggering role for various photodermatoses (Nahhas et  al. 2018). Currently, VL protection can be provided by the inorganic UV filters like zinc and titanium oxides, depending on their particle size (Moseley et  al. 2001), and by iron oxides, which are not regulated as UV filters, but are highly effective in reflecting/scattering VL.  They are available in less cosmetically acceptable tinted sunscreen formulations (Schalka 2017). There is currently no standardized method to measure the VL/IR protection and this parameter is not routinely measured or required on current sunscreens.

Water Resistance In the EU and the USA the methods of testing the sunscreens’ water resistance are based on measuring the product’s SPF before and after immersion

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in water for a specified period. In the European Union, the labeling as “water resistant” and “very water resistant” is awarded to products that maintain at least 50% of their pre-immersion SPF value after 2 and respectively 4 periods of 20  minutes water immersion (Cosmetics Europe 2005). In the USA, the FDA has stricter requirements for the same labeling, as sunscreens need to maintain the same value of SPF before and after water immersion in the same conditions (FDA 2011). Water resistance has been increased in newer sunscreens by adding polymer molecules like acrylates.

Photostability The photostability of a sunscreen can be determined in vivo or in vitro, based on measuring the UVR filter amount contained in the tested sunscreen formulation before and after UV irradiation through high-performance liquid ­ chromatography or spectrophotometry. The photostability is a critical characteristic of a topical sunscreen, however its testing is not mandatory for market licensing in the EU, Australia, or the USA. Nonetheless, a guideline for photostability testing of sunscreens has been issued by Cosmetics Europe (Guidelines on stability testing of cosmetic products Cosmetics Europe 2004) and in the USA the FDA requires the photostability evaluation as prerequisite for the critical wavelength testing for the UVA protection (FDA 2011). The photostability of a product in real-life use may however differ from in-­ laboratory testing, as it can be considerably impacted by the UV filter combinations, the interaction with the non-active sunscreen ingredients, and the exposure to environmental heat (Mancuso et  al. 2017; Jung et  al. 2012) among many other factors.

Sunscreen Regulation The regulations for sunscreen testing, labeling and marketing vary worldwide. In the USA sunscreens are considered over the counter drugs, regulated by the FDA. Similarly, sunscreens are

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considered drugs in Canada (with the exception of mineral filters or para amino-benzoic acid (PABA)-containing products (Sunscreen Monograph 2013)) and therapeutic goods in Australia, if with SPF  >  4 (Yap et  al. 2017). In contrast, in the EU sunscreens are considered and regulated as cosmetics (Regulation (EC) No 1223/2009), as they are in South American Mercosur, Southeast Asian nations, in China, India, and Japan, with different criteria but with ensuing less strict regulation and scrutiny than medicine products (Mancuso et  al. 2017). Consequently, the number of filters that are available and of new filters being approved in the USA and Canada is significantly lower than in the rest of the world, raising some concerns that new, more photostable and stronger UVA protectors are not available on North American markets. In 2019, the FDA has proposed a new ruling, where the inorganic filters have been “generally recognized as safe and effective” (GRASE), but the term was not granted also to 12 organic filters, on which the FDA is seeking additional safety testing (FDA FaDA 2019).

Clinical Benefits of Sunscreens Developed initially to protect skin from sunburn erythema, sunscreens are currently developed, recommended and used for their benefits in protecting the skin against a wide range of negative effects of the UVR-exposure, most prominently the skin cancer development, but also the photoaging and the many photodermatoses and photo-­ aggravated disorders.

 enefits of Sunscreens in Preventing B Skin Cancer The benefit of sunscreens in preventing cutaneous oncogenesis is well grounded theoretically, and widely supported by in vitro and animal studies (Young et  al. 2017; Suozzi et  al. 2020; Mancuso et al. 2017), but is challenging to prove in clinical setting due to the large latency of skin cancer development after sun exposure and the

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many confounding variables, including behaviorand compliance-related, of the potential study participants. The strongest evidence comes from the largest randomized clinical trial to date addressing the skin cancer prevention through sunscreen use— the Nambour Skin Cancer prevention Trial, carried out in Australia. In this study, 1621 randomly selected Nambour city residents were randomly assigned to daily application of an SPF 16 sunscreen to head and arms or discretionary sunscreen use and followed-up initially for up to 4.5  years between 1992 and 1996, and further until 2006 (Green et al. 1999; van der Pols et al. 2006). The study found that regular daily sunscreen use had no significant effect on the incidence of basal-cell carcinoma (BCC) but was associated with a significantly lower incidence of cutaneous squamouscell carcinoma (cSCC) than in the discretionary sunscreen group (0.61 [0.46–0.81]) by 4.5  years follow-up. The effect was maintained after prolonged follow-up 8 years after study, with a nonsignificant decrease in BCC tumor rates and a significant decrease by 40% in incident cSCCs in people formerly randomized to daily sunscreen use compared with the control group. The same study cohort revealed that ten years after the study’s end the regular sunscreen group had a nonsignificant lower incidence of melanoma, but a significant reduction (3 vs. 11 tumors) in invasive melanoma incidence (Green et al. 2011). The sunscreens’ protective effect against SCCs is clinically supported by studies in immunosuppressed organ transplant recipients (OTRs), who are at high risk of multiple and aggressive SCCs. In a single-center study, 60 OTRs who applied daily a broad-spectrum sunscreen (>50 SPF, high UVA filter) on sun-exposed areas for 24 months had a significant reduction in the number of actinic keratoses (AKs) (−120 vs. +82), and significantly less new SCCs (0 vs. 8) than the control group of OTR patients, matched for age, and type of and duration since transplant, who were using discretionarily sunscreens of their choice (Ulrich et al. 2009). The sunscreen intervention had a positive but not significant effect against BCC development. The Nambour trial and a number of other studies showed that regular sunscreen application

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has a protective effect against the development of actinic keratoses, as patients in sunscreen-daily intervention groups manifested lower overall counts of AKs and lower rates of new AKs development after up to 24 months treatment than the control groups with placebo or discretionary sunscreen use (Green et al. 1999; van der Pols et al. 2006; Darlington et al. 2003). In conclusion, the regular application of sunscreen has prolonged preventive effects against cSCC, may protect against invasive melanoma, but has no clear benefit in reducing BCC. Despite methodological concerns (Sanchez et  al. 2016), this clinical evidence remains the strongest to date.

 enefits of Sunscreens in Preventing B Photoaging Few small clinical studies have shown a beneficial effect of regularly used broad spectrum, high UVB and UVA protection sunscreens in preventing photoaging. The benefit was measured either directly— as the reduction in clinical or histological signs of solar elastosis after up to two years of sunscreen use (Boyd et al. 1995)—or indirectly through the reduction in the cellular and molecular markers of photodamage, like the tissue expression of metalloproteinases MMP1, 9, number of sunburn cells, Langerhans cells depletion, and CPD formation or p53 expression in the UV-irradiated skin (Cole et al. 2014). The largest clinical trial addressing the issue was the Nambour study (Hughes et al. 2013), in 903 subjects, which showed 24% less clinical signs of skin aging over 4.5  years in the intervention group subjects using daily sunscreens, versus control subjects with discretionary sunscreen use.

 unscreens’ Effect on the Number S of Melanocytic Nevi The number of melanocytic nevi is currently considered the strongest predictive marker for melanoma risk (Gandini et al. 2005; Olsen et al. 2010). A randomized controlled study in 309 white children, aged 6–10 years, showed a reduction in the median nevus count (24 vs. 28) in the study group

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that applied regularly broad spectrum, SPF 30 sunscreen on sun-exposed areas for 3 years, compared with the children who used no sunscreen (Gallagher et al. 2000). Based on this study, regular sunscreen use in children may prevent the later occurrence of estimatedly 30–40% of acquired nevi (Gallagher et al. 2000; Lee et al. 2005). Given the recognized connection between nevogenesis and melanogenesis (Bastian 2014), these results add arguments that regular sunscreen use started early in childhood may have additive benefit on melanoma prevention at adult age.

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performance of their labeled SPF, the same amount must be applied on the skin as that used for the regulatory-required tests, i.e., 2 mg/cm2. This equals to approximately 30–35  mL (about the cream amount covering one’s palm) to cover the entire body surface (How to select a sunscreen 2020), or a teaspoon (~5  mL) for each body part (limb, front and back of the trunk, face-neck-head). The amount applied by people in real life however is usually much less, estimatedly in the range 0.5–1  mg/cm2 (Petersen and Wulf 2014). The real SPF decreases with the reduction in the sunscreen amount applied, in a linear or even Benefits of Sunscreens exponential manner (Petersen and Wulf 2014; in the Management Bimczok et al. 2007), so the actual SPF achieved of Photodermatoses by real-life users likely decreases to 20–50% of the labeled value (Petersen and Wulf 2014). Photoprotection through sunscreens has a con- Using a high-SPF (>50) sunscreen might comfirmed place in the treatment and prevention of a pensate to a certain extent the underuse of subopwide range of photo-induced and photo-­ timal amounts (Ou-Yang et al. 2012), for limited aggravated dermatoses, ranging from genetic periods of time, but the importance of applying DNA repair disorder syndromes (e.g., xeroderma the correct amount of sunscreen should be claripigmentosum) and porphyrias to polymorphic fied to the consumers. light eruption and chronic actinic dermatitis, and Sunscreens should be applied 20  minutes from cutaneous lupus erythematosus and derma- before the sun exposure and then reapplied every tomyositis to rosacea, seborrheic dermatitis and 2  hours when outdoors, more often after swimhyperpigmentation disorders (Schalka 2017; ming, sweating, or using towels. This optimal Nahhas et  al. 2018; Bylaite et  al. 2009; Kuhn frequency is also rarely observed in real life et  al. 2011; O’Gorman and Murphy 2014). (Petersen and Wulf 2014). The development of Broad-spectrum sunscreens, with UVA protec- highly water-­ resistant sunscreen formulations tion and optimally with additional short-­ has helped to compensate to some degree this wavelength VL filters are the ones recommended effect. in these situations (Lyons et al. 2020). The reguThe correct application is strongly impacted lar application of the correct amount and the inte- by the sunscreen’s formulation and vehicle, as gration of sunscreen use in a comprehensive gels, lotions and sprays are easier and more comphotoprotection strategy (Bellutti Enders et  al. fortable to apply, even on large surfaces and for 2017) including photoprotective clothing, seek- oily skin types, than creams and ointments, but ing shade and avoiding artificial UVR exposure they are usually applied in thin-layered, suboptiare essential and emphasized across all clinical mal amount. practice recommendations. The current recommendations by the World Health Organization (WHO), medical professional societies and clinical guidelines worldSunscreens Dosage and Use wide support in consensus the regular use of Recommendations sunscreens with broad UVB and UVA spectrum, SPF >15 [or >30 by some recommendations The protective effect of topical sunscreens (How to select a sunscreen 2020)], applied in depends critically on the correct use, in terms of 2 mg/cm2 amount, before and repeatedly during both amount and frequency of application on the sun exposure, in conjunction with other physical skin. For the sunscreens to achieve the filtering and behavioral methods of sun protection like

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using photoprotective clothing including hats and sunglasses, seeking shade, and avoiding peak-­ hour sun exposures and artificial tanning devices (sunbeds).

Adverse Effects of Sunscreens The adverse effects reported after topical sunscreen application include irritative and allergic contact dermatitis, acne and acneiform rashes and photoallergic and phototoxic dermatitis (Heurung et al. 2014). The vast majority of these reactions are caused actually by the inactive ingredients within the sunscreen formulations. However, in rare cases phototoxic or photoallergic reactions may be caused by photo-absorbing, epidermis-penetrating active UV filters (Darvay et al. 2001). The benzophenones and dibenzoylmethanes are the UV filters most commonly implicated in allergic and photoallergic contact dermatitis reactions, with oxybenzone as the leading allergen and photoallergen within this class, frequently used in commercial formulations (Heurung et al. 2014). Nevertheless, taking into account the enormous increase in sunscreen use, the occurrence of true UV-filter-induced phototoxic/photoallergic reactions remains a very rare event (Darvay et al. 2001).

Sunscreens: Concerns and Controversies Beyond the significant proven benefits of sunscreens and their good tolerance profile, some concerns have been raised lately over their potential longer-term harms for human users and the environment alike.

Increased Duration of Sun Exposure An important concern is that widespread sunscreen use induces a false safety feeling and are actually increasing the photoexposure duration. It was indeed showed that the use of higher-SPF sunscreens that canceled the limiting erythema of the sunburn significantly increased the duration

of recreational sun exposure, including sunbathing, of young white Europeans (Autier et  al. 1999). This behavior has higher impact on photocarcinogenesis if the sunscreen used provides UVB but not adequate UVA protection. Hence the need to emphasize to the public the necessity to use regularly broad-spectrum sunscreens, with high SPF and UVA protection, in the correct amount, in addition to and not replacing sun-­ avoidance behaviors.

 aradoxical Increase in Skin P Cancer Risk Some earlier case-control studies associated sunscreen use with higher risk of melanoma (Westerdahl et  al. 2000; Wolf et  al. 1998). However, it is now considered that this effect was likely due to increased time spent in the sun by the sunscreen users who escaped the painful sunburn thanks to the UVB filters, to the use of earlier sunscreens without efficient UVA protection, or to the use of overall low-level protection (SPF /= 70) may provide ultraviolet protection above minimal recommended levels by adequately compensating for lower sunscreen user application amounts. J Am Acad Dermatol. 2012;67(6):1220–7. Passeron T, Bouillon R, Callender V, Cestari T, Diepgen TL, Green AC, et  al. Sunscreen photoprotection and vitamin D status. Br J Dermatol. 2019;181(5):916–31. Petersen B, Wulf HC. Application of sunscreen − theory and reality. Photodermatol Photoimmunol Photomed. 2014;30(2-3):96–101. Regazzetti C, Sormani L, Debayle D, Bernerd F, Tulic MK, De Donatis GM, et  al. Melanocytes sense blue light and regulate pigmentation through opsin-3. J Invest Dermatol. 2018;138(1):171–8. Regulation (EC) No 1223/2009 of the European Parliament and of the Council of 30 November 2009 on cosmetic products. OJ L 342. 2009(22.12.2009):59–209. Robinson G, McMichael A, Wang SQ, Lim HW. Sunscreen and frontal fibrosing alopecia: a review. J Am Acad Dermatol. 2020;82(3):723–8. Robyn L, McMichael T, Smith W, Armstrong B.  Solar ultraviolet radiation: global burden of disease from solar ultraviolet radiation. World Health Organization; 2006. Sanchez G, Nova J, Rodriguez-Hernandez AE, Medina RD, Solorzano-Restrepo C, Gonzalez J, et  al. Sun protection for preventing basal cell and squamous cell skin cancers. Cochrane Database Syst Rev. 2016;7:CD011161. Schalka S.  New data on hyperpigmentation disorders. J Eur Acad Dermatol Venereol. 2017;31(Suppl 5):18–21. Schneider SL, Lim HW. Review of environmental effects of oxybenzone and other sunscreen active ingredients. J Am Acad Dermatol. 2019;80(1):266–71. Schulze R.  Einige Versuche und Bemerkungen zum Problem der handelsüblichen Lichtschutzmittel. Parf Kosm. 1956;37:310–5. Sha B, Gao W, Cui X, Wang L, Xu F. The potential health challenges of TiO2 nanomaterials. J Appl Toxicol. 2015;35(10):1086–101. Stucci LS, D'Oronzo S, Tucci M, Macerollo A, Ribero S, Spagnolo F, et  al. Vitamin D in melanoma: controversies and potential role in combination with immune check-point inhibitors. Cancer Treat Rev. 2018;69:21–8. Sunscreen Monograph. 2013. Suozzi K, Turban J, Girardi M.  Cutaneous photoprotection: a review of the current status and evolving strategies. Yale J Biol Med. 2020;93(1):55–67. Syring F, Weigmann HJ, Schanzer S, Meinke MC, Knorr F, Lademann J.  Investigation of model sunscreen formulations comparing the sun protection factor, the universal sun protection factor and the radical formation ratio. Skin Pharmacol Physiol. 2016;29(1):18–23.

156 Sunscreens Technical Committee ISO/TC 217, Cosmetics. ISO 24444: 2010. Cosmetics -sun protection test methods - in vivo determination of the sun protection factor (SPF). 2010. Ulrich C, Jurgensen JS, Degen A, Hackethal M, Ulrich M, Patel MJ, et al. Prevention of non-melanoma skin cancer in organ transplant patients by regular use of a sunscreen: a 24 months, prospective, case-control study. Br J Dermatol. 2009;161(Suppl 3):78–84. van der Pols JC, Williams GM, Pandeya N, Logan V, Green AC. Prolonged prevention of squamous cell carcinoma of the skin by regular sunscreen use. Cancer Epidemiol Biomark Prev. 2006;15(12):2546–8. Varedi A, Wu YP, Klein SZ, Leachman SA, Grossman D. Mineral sunscreens not recommended by Consumer Reports: suggestions to improve the review process. J Am Acad Dermatol. 2019;80(3):832–3. Vaughan-Shaw PG, O'Sullivan F, Farrington SM, Theodoratou E, Campbell H, Dunlop MG, et al. The impact of vitamin D pathway genetic variation and circulating 25-hydroxyvitamin D on cancer outcome: systematic review and meta-analysis. Br J Cancer. 2017;116(8):1092–110. Watanabe Y, Kojima H, Takeuchi S, Uramaru N, Sanoh S, Sugihara K, et al. Metabolism of UV-filter benzophenone-­3 by rat and human liver microsomes and its

1785 effect on endocrine-disrupting activity. Toxicol Appl Pharmacol. 2015;282(2):119–28. Westerdahl J, Ingvar C, Masback A, Olsson H. Sunscreen use and malignant melanoma. Int J Cancer. 2000;87(1):145–50. Williams JD, Maitra P, Atillasoy E, Wu MM, Farberg AS, Rigel DS. SPF 100+ sunscreen is more protective against sunburn than SPF 50+ in actual use: Results of a randomized, double-blind, split-face, natural sunlight exposure clinical trial. J Am Acad Dermatol. 2018;78(5):902–10 e2. Wolf P, Quehenberger F, Mullegger R, Stranz B, Kerl H.  Phenotypic markers, sunlight-related factors and sunscreen use in patients with cutaneous melanoma: an Austrian case-control study. Melanoma Res. 1998;8(4):370–8. Yap FH, Chua HC, Tait CP. Active sunscreen ingredients in Australia. Australas J Dermatol. 2017;58(4):e160– e70. Epub 2017/03/16 Young AR, Claveau J, Rossi AB.  Ultraviolet radiation and the skin: Photobiology and sunscreen photoprotection. J Am Acad Dermatol. 2017;76(3S1):S100–S9. Zastrow L, Lademann J.  Light  - instead of UV protection: new requirements for skin cancer prevention. Anticancer Res. 2016;36(3):1389–93.

Targeted Treatments for Cutaneous Melanoma

157

Efthymia Soura and Alexander Stratigos

Key Points • Targeted therapies in melanoma include several medications that target the MEK/ERK pathway, such as inhibitors of BRAF and MEK. • Mutated BRAFv600E is mandatory for these medications to be administered. • BRAF inhibitors are almost universally administered in combination with MEK inhibitors in order to achieve improved patient responses and milder adverse event profiles. • These medications are approved for ≥Stage IIIc melanoma and are also considered as adjuvants (dabrafenib) in lower stages. • Adverse events include cutaneous, cardiovascular, ocular, and gastrointestinal manifestations, among others.

 rief Discussion on Melanoma B Pathogenesis The genetic mutations found in melanoma are associated with key signaling cascades that control the cellular cycle (CDKN2A, p16INK4A, p14ARF), cellular metabolism and growth with a wide range of differences depending (PTEN)) and (KIT), survival (TP53), multiplication (BRAF, neuroblastoma ras

E. Soura · A. Stratigos (*) 1st Department of Dermatology-Venereology, Andreas Sygros Hospital, National and Kapodestrian University of Athens, Athens, Greece

viral oncogene homolog (NRAS) και neurofibromin 1 (NF1)), differentiation (AT-rich interaction domain 2, ARID2), and senescence Telomerase reverseTranscriptase (TERT), among others (Hodis et al. 2012; Huang et al. 2013; Horn et al. 2013). The importance of understanding these mutations and their role in the pathogenesis of melanoma is translated in the discovery of targeted treatments for melanoma such as vemurafenib, dabrafenib, encorafenib, trametinib, cobimetinib, and binimetinib.

 he RAS-RAF-MEK-ERK (MAPK) T Pathway The mitogen-activated protein kinase (MAPK) pathway consists of RAS, RAF, mitogen-­activated extracellular signal-regulated kinase (MEK), and extracellular signal-regulated kinase (ERK).  This sequence is responsible for relaying proliferative signals from cell surface receptors and through cytoplasmic signaling into the nucleus (Grimaldi et  al. 2017). More specifically, RAF activation phosphorylates MEK, leading to activation of ERK and subsequent phosphorylation of various targets that result in cell proliferation. MAPK pathway mutations are common in melanomas. For instance, NRAS and BRAF mutations are encountered in 15–30% and 50–70% of melanomas, respectively (Curtin et al. 2005; Ball et al. 1994; Davies et al. 2002; Gray-Schopfer et al. 2007). BRAF mutations (serine/threonine kinase) are considered to be the

© Springer Nature Switzerland AG 2023 A. D. Katsambas et al. (eds.), European Handbook of Dermatological Treatments, https://doi.org/10.1007/978-3-031-15130-9_157

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E. Soura and A. Stratigos

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most common mutations in melanoma (present in about 50% of melanomas), with 90% of those usually being a transition in T1796 → A, which leads to V600E changes on exon 15 (van Dijk et  al. 2005). This mutation allows BRAF to be extremely active, independently of the status of RAS or other tumor suppressive signals (Davies et  al. 2002). However, mutations in BRAF are usually mutually exclusive with other mutations in the MAPK pathway, though exceptions have been reported (Wong and Ribas 2016). Therefore, the MAPK pathway is considered as one of the most important therapeutic targets for melanoma with several drugs targeting BRAF (Hingorani et al. 2003; Hoeflich et al. 2006; Sharma et  al. 2006) and MEK (Grimaldi et al. 2017) already being used in everyday clinical practice.

BRAF Inhibitors Three BRAF inhibitors (BRAFis) are currently used in the treatment of melanoma: vemurafenib, dabrafenib, and encorafenib. All three

are orally bioavailable, adenosine triphosphate (ATP)-competitive, small-molecule inhibitors of BRAF kinase (Mackiewicz and Mackiewicz 2018). Vemurafenib and dabrafenib are both approved to be used as monotherapy or in combination with cobimetinib or trametinib, respectively, in the treatment of adult patients with unresectable or metastatic melanoma with a BRAFV600 mutation (Vemurafenib (Zelboraf) 2016; Dabrafenib (Taniflar) 2018). The dabrafenib/trametinib combination has also been approved for adjuvant treatment of adult patients with Stage III melanoma with a BRAFV600 mutation, following complete resection (Dabrafenib (Taniflar) 2018). Encorafenib is the newest of these three medications to be approved in both the USA and Europe and is administered for the treatment of adult patients with unresectable or metastatic melanoma with a BRAFV600 mutation in combination with binimetinib only (Encorafenib (Braftovi) 2018). Dosing recommendations can be found in Table 157.1.

Table 157.1  Dosing recommendations for targeted therapies in melanoma (Vemurafenib (Zelboraf) 2016; Dabrafenib (Taniflar) 2018; Encorafenib (Braftovi) 2018; Cobimetinib (Cotellic) 2015; Trametinib (Mekinist) 2019; Binimetinib (Mektovi) 2018) Monotherapy 4 tablets of 240 mg twice daily (equivalent to a total daily dose of 1920 mg)

Combination therapy Same as monotherapy

Cobimetiniba (MEKi)

–

Dabrafeniba (BRAFi)

2 capsules of 75 mg twice daily (equivalent to a total daily dose of 300 mg)

3 tablets of 20 mg once daily (equivalent to a total daily dose of 60 mg) for 21 days, then re-administer after day 28; combined with vemurafenib Same as monotherapy Until disease progression or development of unacceptable toxicity 2 mg once daily (combined with – dabrafenib) 6 capsules of 75 mg once daily (equivalent Until disease to a total daily dose of 450 mg) progression or development of unacceptable toxicity 3 tablets of 15 mg twice daily (equivalent – to a total daily dose of 90 mg), combined with encorafenib

Vemurafeniba (BRAFi)

Trametiniba (MEKi) Encorafeniba (BRAFi)

Binimetiniba (MEKi)

N/A

N/A

BRAFi BRAF inhibitor, MEKi MEK inhibitor, N/A not available a Dose reduction is possible if specific types of adverse events (AEs) are presented

Duration of treatment Until disease progression or development of unacceptable toxicity –

157  Targeted Treatments for Cutaneous Melanoma

Vemurafenib Mean absolute bioavailability for vemurafenib is ≈64%. Vemurafenib is absorbed with a median time to the maximum observed concentration (Tmax) of approximately four  hours post-dose and is able to potently inhibit several mutated BRAF kinases (BRAFV600E, BRAFV600R, V600K V600D BRAF , BRAF enzymes) in melanoma patients. In addition, vemurafenib exhibits a moderate inhibitory effect on wild-type BRAF kinases, as demonstrated by half-maximal inhibitory concentration (IC50) values observed in cellular anti-proliferation assays (Vemurafenib (Zelboraf) 2016). Vemurafenib has shown benefit when administered as monotherapy in several Phase II and Phase III clinical trials. The BRIM-3 study investigated the efficacy of vemurafenib compared to dacarbazine (as monotherapy) in melanoma IIIC or Stage IV patients (Vemurafenib (Zelboraf) 2016; Chapman et  al. 2017; McArthur et  al. 2014). The primary endpoints of the study were overall survival (OS) and progression-free survival (PFS). It was reported that the median OS was 13.6 months for patients receiving vemurafenib compared with 9.7 months for patients receiving dacarbazine at the time of study database lock (hazard ratio [HR] 0.81; 95% confidence interval [CI] 0.7–1.0; p = 0.03) (Chapman et al. 2017). In addition, OS rates at 1, 2, 3, and 4 years were reported to be 55.7%, 30.2%, 20.8%, and 17.0%, respectively, in the vemurafenib arm, and 46.0%, 24.5%, 18.9%, and 15.6%, respectively, in the dacarbazine arm (Chapman et  al. 2017). Median progression-free survival was also found to be significantly longer in the vemurafenib group compared to the dacarbazine group (6.9  months [95% CI 6.1–7.0] vs 1.6  months [1.6–2.1]), respectively; HR 0.38; 95% CI 0.32– 0.46; p