Translational Autoimmunity, Volume 6: Advances in Autoimmune Rheumatic Diseases 0323858317, 9780323858311

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Translational Immunology TRANSLATIONAL AUTOIMMUNITY, VOL. 6

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Translational Immunology

TRANSLATIONAL AUTOIMMUNITY, VOL. 6 Advances in Autoimmune ­Rheumatic Diseases Edited by

Nima Rezaei

Professor, Department of Immunology, School of Medicine; Head, Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences; Founding President, Universal Scientific Education and Research Network (USERN), Tehran, Iran Editorial Assistant

Niloufar Yazdanpanah

Managing Director, Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN); and School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright © 2023 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN 978-0-323-85831-1 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Stacy Masucci Acquisitions Editor: Linda Versteeg-Buschman Editorial Project Manager: Billie Jean Fernandez Production Project Manager: Omer Mukthar Cover Designer: Christian J. Bilbow Typeset by STRAIVE, India

Dedication This book would not have been possible without the continuous encouragement from my family. I dedicate this book to my daughters, Ariana and Arnika, in the hope that we learn enough from today to make a brighter future for the next generation.

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Contents Contributors xiii Preface xvii Series editor’s biography  xix Acknowledgment xxi Abbreviations xxiii

2 Pathogenesis of autoimmunity in rheumatic diseases (AIRDs)  29 3 Comparisons of the immunopathogenesis in various autoimmune rheumatic diseases 36 4 The clinical implications of the immunopathogenesis of autoimmunity  36 5 Conclusion  41 References 41

1.  Introduction on autoimmune rheumatic diseases Niloufar Yazdanpanah and Nima Rezaei

4.  Rheumatic fever: From pathogenesis to vaccine perspectives

1 Introduction  1 2 ARD through the history  2 3 Diagnosis of ARD  3 4 Treatment of ARD  4 5 Conclusion  6 References 6

Luiza Guilherme, Carlos Eduardo Branco, Samar Freschi de Barros, and Jorge Kalil

1 Introduction  47 2 Diagnosis of acute rheumatic fever 50 3 Major manifestation  51 4 Minor manifestations  53 5 Treatment  54 6 Conclusion  58 References 58

2.  Bone Health in autoimmune inflammatory rheumatic diseases İlke Coşkun Benlidayι

1 Introduction  9 2 Prevalence of bone health impairment in AIIRD 10 3 Risk factors for bone loss in AIIRD  10 4 Pathophysiology of bone loss in AIIRD  15 5 Evaluation and management of bone loss/osteoporosis in patients with AIIRD  17 6 Conclusion  21 References 21

5.  Changes in future rheumatoid arthritis treatment in the light of Epstein-Barr virus infection Nicole Hartwig Trier and Gunnar Houen

1 Introduction  61 2 Epstein-Barr virus  65 3 Epstein-Barr virus infections  66 4 Associations between Epstein-Barr virus and rheumatoid arthritis disease  67 5 Current and future treatment of rheumatoid arthritis disease  69 6 Conclusion  73 References 74

3.  Rheumatic diseases: From bench to bedside Syahrul Sazliyana Shaharir and Asrul Abdul Wahab

1 Introduction  27



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viii Contents 6.  Rheumatic diseases: The microbiotaimmunity axis in development and treatment Elena Niccolai, Silvia Bellando Randone, and Amedeo Amedei

1 Introduction  83 2 The microbiota and the immune system crosstalk 84 3 Microbiota and autoimmune rheumatic diseases 89 4 Microbiota shaping as a potential therapeutic target 98 5 Conclusion  100 References 101

7.  The diagnostic laboratory tests in rheumatic diseases Rossella Talotta

1 2 3 4 5

Introduction  113 Acute-phase reactants  114 Laboratory tests in rheumatoid arthritis  116 Laboratory tests in spondyloarthritis  118 Laboratory tests in autoimmune connective tissue diseases  121 6 Laboratory tests in vasculitis  132 7 Laboratory tests in infectious arthritis  134 8 Laboratory tests in microcrystalline arthritis 135 9 Laboratory tests in osteoporosis  135 10 Laboratory tests in periodic fevers  137 11 Appendix: Analysis of the synovial fluid  138 12 Conclusion  138 References 138

8.  Autoantibody profiling in autoimmune rheumatic diseases: How research may translate into clinical practice Nicola Bizzaro, Luigi Cinquanta, and Renato Tozzoli

1 Introduction  150 2 The clinical rationale of autoantibody profiling 150 3 Proteomic technology for multiautoantibody profiling 151 4 Autoantibody profiling in autoimmune rheumatic diseases 156

5 Antibody profiling in rheumatoid arthritis  161 6 Autoantibody profiling in autoimmune organ-specific diseases  162 7 Analytical challenges of multiplex technology 162 8 Conclusion  163 References 164

9.  Air pollution and rheumatoid arthritis: Current knowledge and state of the art Mickael Essouma

1 Introduction  169 2 Overview of air pollution and its health effects 170 3 Studies linking air pollution with rheumatoid arthritis 171 4 Mechanisms potentially linking air pollution with rheumatoid arthritis  174 5 Future directions  177 6 Conclusion  178 References 179

10.  Advanced therapies in rheumatoid arthritis Katie S. Turnbull and Martin E. Perry

1 Introduction  181 2 Etiology and pathogenesis  182 3 Presentation  182 4 Articular features of RA  182 5 Extra-articular features of RA  183 6 Diagnosis  183 7 Management of the disease  184 8 EULAR treatment recommendations  187 9 Horizon scanning for new agents  199 10 Conclusion  200 References 200

11.  A tolerogenic dendritic cell–based therapy targeting heat shock protein–specific regulatory T cells in rheumatoid arthritis Arie J. Stoppelenburg, Willem van Eden, Jacob M. van Laar, and Femke Broere

1 Introduction  208 2 Heat shock proteins  209



3 Preclinical and clinical studies of HSP-induced tolerance 210 4 Preclinical studies with tolDCs  212 5 Toward HSP-loaded tolDCs as a therapy for RA 213 6 Conclusion  216 References 217

12.  T-cell large granular lymphocytic leukemia in the setting of rheumatoid arthritis Vadim Gorodetskiy

1 Introduction  222 2 Epidemiology  223 3 Pathogenesis  223 4 Diagnosis  224 5 Clinical manifestations  224 6 Differential diagnosis  225 7 Treatment  225 8 Conclusion  227 References 228

13.  Biomaterials as tools for re-balancing skewed immunity in rheumatoid arthritis Peipei Zhang and Hongxing Jia

1 Introduction  234 2 Biomaterials-based strategies for rebalancing the skewed RA immunity  246 3 Conclusion  256 References 257

14.  Immunopathogenesis of systemic lupus erythematosus Maryam Akhtari, Elham Farhadi, and Mahdi Mahmoudi

1 2 3 4 5 6 7 8 9

Introduction  265 Genetic factors in SLE  266 Epigenetic mechanisms in SLE  267 Environmental factors and gender in SLE  268 Apoptosis and SLE  269 The complement system and SLE  270 Toll-like receptors and SLE  271 Innate and adaptive immunity  272 Tissue inflammation and clinical manifestations (organ-specific disease features) 274

Contents   ix

10 Treatment  280 11 Conclusion  283 References 283

15.  Challenges in systemic lupus erythematosus: From bench to bedside Win Min Oo and Sean O’Neill

1 Introduction  294 2 Pathogenesis  294 3 Diagnosis  306 4 Classification criteria  307 5 SLE phenotypes and key disease biomarkers 309 6 Management  313 7 Management of cardiovascular disease risk  314 8 Management of lupus nephritis (LN)  316 9 Management of refractory SLE with a focus on phase 2/3 clinical trials  318 10 Conclusion  323 References 324

16.  Therapeutic potential of the current options in treating systemic lupus erythematosus: Challenges and prospective Mostafa A. Abdel-Maksoud

1 Introduction  333 2 SLE progression and factors affecting it  334 3 Therapeutic options for SLE  336 4 Current strategies to combat ADS  341 5 Conclusion  343 References 343

17.  The pathology and potential clinical applicability of interfering T cells in systemic lupus erythematosus Anselm Mak

1 Introduction  350 2 Pivotal immunologic players in SLE pathophysiology 350 3 Physiology and anatomy of T cells  351 4 Current and evaluated therapies of SLE that manipulate T-cell physiology  360 5 Phenotypic and functional change of T-cell subsets after B-cell depletion  363 6 Conclusion  363 References 364

x Contents 18.  Rheumatic chorea Luiz Paulo Bastos Vasconcelos, Marcelle Cristina Vasconcelos, Maria do Carmo Pereira Nunes, and Antonio Lucio Teixeira

1 Introduction  374 2 Pathophysiology  374 3 Clinical features  378 4 Treatment options  379 5 Conclusion  383 References 383

19.  Evaluation and surgical management of the rheumatoid foot and ankle H. John Visser, Joshua Wolfe, Raul Aviles, Blake Savage, and Nicole Marie Smith

1 2 3 4

Introduction  389 History and physical exam  391 Preoperative considerations  391 Vascular evaluation in the rheumatoid patient 392 5 Preoperative testing  393 6 Preoperative medication considerations  394 7 Venous thromboembolism prophylaxis  394 8 Foot and ankle manifestations of rheumatoid arthritis 394 9 Extraarticular and soft-tissue disorders  396 10 Pathomechanics  401 11 Forefoot reconstruction  403 12 Midfoot  408 13 Rearfoot  410 14 Ankle  417 15 Conclusion  422 References 422

20.  Immunopathogenesis and treatment of scleroderma Ayda AlHammadi and Amer Ali Almohssen

1 Introduction  427 2 Pathogenesis  428 3 Treatment  432 4 Conclusion  434 References 434

21.  Skin manifestations and autoimmune disturbances in dermatomyositis Dominika Kwiatkowska and Adam Reich

1 Introduction  437 2 Cutaneous manifestations of DM correlate with specific autoantibodies  438 3 Myositis-specific autoantibodies in a new classification system  443 4 Conclusion  444 References 444

22.  T cells in the pathogenesis of systemic sclerosis Lazaros I. Sakkas and Theodora Simopoulou

1 2 3 4 5 6 7

Introduction  448 Pathogenesis of systemic sclerosis  448 T cells: A brief overview  449 T cells in systemic sclerosis  450 Th2/Th1 balance in systemic sclerosis  452 Th17 cells  454 Regulatory T cells (Tregs) and Tregs/Th17 balance 455 8 Tfh cells  457 9 Other Th subsets  457 10 Unconventional T cells  457 11 Angiogenic T cells  459 12 T cells and vasculopathy  459 13 Lessons from animal models of scleroderma  460 14 Immunotherapy and future prospects  463 15 Conclusion  464 References 464

23.  Etiopathogenesis of Behçet’s syndrome: The role of infectious, genetic, and immunological environmental factors Alessandra Bettiol, Giacomo Emmi, Irene Mattioli, and Domenico Prisco

1 Introduction  475 2 Microbial etiology  476 3 Genetic etiology  478 4 Epigenetic contribution  479



Contents   xi

5 Immunological etiology  480 6 Additional triggering factors  480 7 Conclusion  481 References 481

24.  Interleukin-1 family in Behçet’s disease: Inflammatory and antiinflammatory mediators Kamel Hamzaoui and Agnès Hamzaoui

1 Introduction  488 2 The biological characteristics of IL-1 family cytokines 489 3 The association of IL-1 family genes and BD  490 4 Expression and function of IL-1 family cytokines in BD  493 5 Clinical application and participation of IL-1 family cytokines in BD  499 6 Conclusion  501 References 501

25.  Salivary gland regeneration and repair in Sjögren’s syndrome Janaki Iyer, Parisa Khayambashi, and Simon D. Tran

1 Introduction  509 2 Salivary glands in Sjögren’s syndrome  515 3 Regenerative medicine  517 4 Regeneration of salivary glands  517 5 Conclusion  525 References 526

26.  Regulation of bone and joint inflammation by type 2 innate lymphoid cells Yasunori Omata, Mario M. Zaiss, Michael Frech, Georg Schett, and Sakae Tanaka

1 Introduction  532 2 Rheumatoid arthritis and T cell  533 3 Rheumatoid arthritis and ILC  534 4 Spondyloarthritis and ILCs  535 5 Role of ILC2 on the initiation phase of arthritis 535

6 Bone homeostasis and cytokines mediated by T cell  537 7 Bone homeostasis and ILC  538 8 Conclusion  539 References 539

27.  Arboviruses (Alphavirus) related to autoimmune rheumatic diseases: Triggers and possible therapeutic interventions Jean Moisés Ferreira, Jean Carlos Vencioneck Dutra, Bárbara Rayssa Correia dos Santos, Edilson Leite de Moura, Ithallo Sathio Bessoni Tanabe, Ana Caroline Melo dos Santos, José Luiz de Lima Filho, and Elaine Virgínia Martins de Souza Figueiredo

1 Introduction  544 2 Chikungunya virus (CHIKV)  547 3 O’nyong-nyong virus (ONNV)  549 4 Ross River virus (RRV)  550 5 Barmah Forest virus (BFV)  551 6 Mayaro virus (MAYV)  552 7 Sindbis virus (SINV)  554 8 Interface of possible treatments for alphaviruses in rheumatoid arthritis  555 9 Conclusion  556 References 556

28.  Rheumatologic manifestations of autoinflammatory diseases Kosar Asnaashari and Nima Rezaei

1 Introduction  566 2 Familial Mediterranean fever (FMF)  566 3 Mevalonate kinase deficiency (MKD)  569 4 Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS)  572 5 Cryopyrin-associated periodic syndromes (CAPS) 574 6 Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome  577 7 Conclusion  579 References 579

Index 585

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Contributors Mostafa A. Abdel-Maksoud  Department of Botany and Microbiology, College of Science, King Saud University, Riyadh, Saudi Arabia

Femke Broere Department of Biomolecular Health Sciences, Utrecht University, Utrecht, The Netherlands

Maryam Akhtari  Rheumatology Research Center; Inflammation Research Center, Tehran University of Medical Sciences, Tehran, Iran

Luigi Cinquanta  IRCCS S.D.N, Naples, Italy

Ayda AlHammadi  Core Teaching Faculty at Hamad Medical Corporation, Dermatology Residency Program, Doha, Qatar Amer Ali Almohssen  Alfardan Medical with Northwestern Medicine, Doha, Qatar Amedeo Amedei  Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy Kosar Asnaashari Department of Pediatrics, Children’s Medical Center, Tehran University of Medical Sciences; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran Raul Aviles  SSM Health DePaul Hospital Foot and Ankle Surgery Residency, St. Louis, MO, United States Samar Freschi de Barros  Heart Institute (InCor), University of São Paulo; Institute for Investigation in Immunology, National Institute of Science and Technology, São Paulo, Brazil İlke Coşkun Benlidayı  Department of Physical Medicine and Rehabilitation, Cukurova University Faculty of Medicine, Adana, Türkiye Alessandra Bettiol  Department of Experimental and Clinical Medicine, University of Firenze, Firenze, Italy Nicola Bizzaro  Laboratory of Clinical Pathology, San Antonio Hospital, Tolmezzo; Azienda Sanitaria Universitaria Integrata, Udine, Italy Carlos Eduardo Branco  Heart Institute (InCor), University of São Paulo, São Paulo, Brazil



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Maria do Carmo Pereira Nunes  Department of Internal Medicine, Federal University of Minas Gerais (UFMG), School of Medicine, Belo Horizonte, MG, Brazil Ana Caroline Melo dos Santos  Laboratory of Molecular Biology and Gene Expression— LABMEG, Federal University of Alagoas (UFAL)—Campus Arapiraca, Arapiraca, Alagoas, Brazil Bárbara Rayssa Correia dos Santos  Laboratory of Molecular Biology and Gene Expression—LABMEG, Federal University of Alagoas (UFAL)—Campus Arapiraca, Arapiraca, Alagoas, Brazil Jean Carlos Vencioneck Dutra  Secretary of State for Education Espírito Santo (SEDU), Vitória, Espírito Santo, Brazil Willem van Eden  Department of Biomolecular Health Sciences, Utrecht University, Utrecht, The Netherlands Giacomo Emmi  Department of Experimental and Clinical Medicine, University of Firenze, Firenze, Italy Mickael Essouma  Department of Internal Medicine and Specialties, Faculty of Medicine and Biomedical Sciences, University of Yaounde I; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Yaounde, Cameroon; Department of Rheumatolgy, Erasme Hospital, University of Brussels, Brussels, Belgium Elham Farhadi  Rheumatology Research Center; Inflammation Research Center, Tehran University of Medical Sciences, Tehran, Iran

xiv Contributors Jean Moisés Ferreira Keizo Asami-LIKA Immunopathology Laboratory, Center for Biosciences, Federal University of Pernambuco (UFPE), Recife, Pernambuco; Secretary of State for Education Espírito Santo (SEDU), Vitória, Espírito Santo; Laboratory of Molecular Biology and Gene Expression—LABMEG, Federal University of Alagoas (UFAL)— Campus Arapiraca, Arapiraca, Alagoas, Brazil Michael Frech  Department of Internal Medi­ cine 3, Rheumatology and Immunology, ­Friedrich-Alexander-University ­ErlangenNürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany Vadim Gorodetskiy  Department of Intensive Methods of Therapy, V.A. Nasonova Research Institute of Rheumatology, Moscow, Russia Luiza Guilherme  Heart Institute (InCor), University of São Paulo; Institute for Investigation in Immunology, National Institute of Science and Technology, São Paulo, Brazil Agnès Hamzaoui  University of Tunis El Manar, Medicine University of Tunis, Tunis; Laboratory Research (19SP02) [Chronic Pulmonary Pathologies: From Genome to Management]; Department of Respiratory Diseases, Abderrahman Mami Hospital, Pavillon B, Ariana, Tunisia Kamel Hamzaoui  University of Tunis El Manar, Medicine University of Tunis, Tunis; Laboratory Research (19SP02) [Chronic Pulmonary Pathologies: From Genome to Management], Ariana, Tunisia

Parisa Khayambashi  McGill Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC, Canada Dominika Kwiatkowska  Department of Dermatology, Institute of Medical Sciences, Medical College of Rzeszow University, Rzeszów, Poland Jacob M. van Laar  Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands José Luiz de Lima Filho  Keizo Asami-LIKA Immunopathology Laboratory, Center for Biosciences, Federal University of Pernambuco (UFPE), Recife, Pernambuco, Brazil Mahdi Mahmoudi Rheumatology Research Center; Inflammation Research Center, Tehran University of Medical Sciences, Tehran, Iran Anselm Mak Division of Rheumatology, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Republic of Singapore Irene Mattioli  Department of Experimental and Clinical Medicine, University of Firenze, Firenze, Italy Edilson Leite de Moura  Laboratory of Molecular Biology and Gene Expression—LABMEG, Federal University of Alagoas (UFAL)— Campus Arapiraca, Arapiraca, Alagoas, Brazil Elena Niccolai  Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy

Gunnar Houen Department of Neurology, Rigshospitalet, Glostrup; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark

Sean O’Neill  Rheumatology Department, Institute of Bone and Joint Research, Kolling Institute, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia

Janaki Iyer  McGill Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC, Canada

Yasunori Omata  Department of Orthopaedic Surgery, Faculty of Medicine; Bone and Cartilage Regenerative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan

Hongxing Jia  Department of Material Processing and Controlling, School of Mechanical Engineering and Automation, Beihang University, Beijing, China Jorge Kalil  Heart Institute (InCor), University of São Paulo; Institute for Investigation in Immunology, National Institute of Science and Technology, São Paulo, Brazil

Win Min Oo  Rheumatology Department, Institute of Bone and Joint Research, Kolling Institute, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia; Department of Physical Medicine and Rehabilitation, Mandalay General Hospital, University of ­Medicine-Mandalay, Mandalay, Myanmar

Contributors xv

Martin E. Perry  University of Glasgow, School of Medicine, Dentistry & Nursing; NHS Greater Glasgow and Clyde, Glasgow, United Kingdom Domenico Prisco  Department of Experimental and Clinical Medicine, University of Firenze, Firenze, Italy Silvia Bellando Randone  Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy Adam Reich  Department of Dermatology, Institute of Medical Sciences, Medical College of Rzeszow University, Rzeszów, Poland Nima Rezaei Research Center for Immunodeficiencies, Children’s Medical Center; Department of Immunology, School of Medicine, Tehran University of Medical Sciences; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran Lazaros I. Sakkas  Faculty of Medicine, School of Health Science, University of Thessaly, Larissa, Greece Blake Savage  SSM Health DePaul Hospital Foot and Ankle Surgery Residency, St. Louis, MO, United States Georg Schett  Department of Internal Medi­ cine 3, Rheumatology and Immunology, ­Friedrich-Alexander-University ­ErlangenNürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany Syahrul Sazliyana Shaharir  Department of Internal Medicine (Rheumatology Unit), Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia Theodora Simopoulou  Department of Rheumatology and Clinical Immunology, University General Hospital of Larissa, Larissa, Greece Nicole Marie Smith  SSM Health DePaul Hospital Foot and Ankle Surgery Residency, St. Louis, MO, United States

Arie J. Stoppelenburg  Department of Biomolecular Health Sciences, Utrecht University; Department of Rheumatology and Clinical Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands Rossella Talotta  Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Messina, AOU “G. Martino”, Messina, Italy Ithallo Sathio Bessoni Tanabe  Laboratory of Molecular Biology and Gene Expression— LABMEG, Federal University of Alagoas (UFAL)—Campus Arapiraca, Arapiraca, Alagoas, Brazil Sakae Tanaka Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan Antonio Lucio Teixeira  Institute of Education and Research, Santa Casa BH, Belo Horizonte, MG, Brazil; Neuropsychiatry Program, UTHealth Houston, Houston, TX, United States Renato Tozzoli Endocrinology Unit, Giorgio Policlinic, Pordenone, Italy

San

Simon D. Tran  McGill Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC, Canada Nicole Hartwig Trier  Department of Neurology, Rigshospitalet, Glostrup, Denmark Katie S. Turnbull  University of Glasgow, School of Medicine, Dentistry & Nursing, Glasgow, United Kingdom Luiz Paulo Bastos Vasconcelos  Três Rios Faculty of Medical Science (SUPREMA), Três Rios, RJ; University Hospital, Federal University of Juiz de Fora (UFJF), Juiz de Fora, MG, Brazil Marcelle Cristina Vasconcelos  University Hospital, Federal University of Juiz de Fora (UFJF), Juiz de Fora, MG, Brazil

H. John Visser  SSM Health DePaul Hospital Foot and Ankle Surgery Residency, St. Louis, MO, United States Elaine Virgínia Martins de Souza Figueiredo  Laboratory of Molecular Biology and Gene Asrul Abdul Wahab  Department of MicrobiExpression—LABMEG, Federal University ology and Immunology, Universiti Kebangof Alagoas (UFAL)—Campus Arapiraca, saan Malaysia Medical Centre, Kuala Lumpur, ­Arapiraca, Alagoas, Brazil Malaysia

xvi Contributors Joshua Wolfe  SSM Health DePaul Hospital Foot and Ankle Surgery Residency, St. Louis, MO, United States Niloufar Yazdanpanah  School of Medicine; Research Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran

Mario M. Zaiss  Department of Internal Medicine 3, Rheumatology and Immunology, ­Friedrich-Alexander-University ­ErlangenNürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany Peipei Zhang  Department of Material Processing and Controlling, School of Mechanical Engineering and Automation, Beihang University, Beijing, China

Preface

The scientific world has witnessed remarkable developments in the field of immunology during recent decades. The novel discovery of genes related to different immune-mediated diseases has enhanced ­ our knowledge about the immune system and its interactions with other systems in the human body and enlightened different aspects of its complexity that lead to promoting diagnostic strategies, designing more efficient therapeutic agents, and reducing potential morbidities and mortality. Due to the broad spectrum of immune-mediated diseases, from immunodeficiency to hypersensitivity and autoimmune diseases, the immune system diseases collectively contribute to a considerable prevalence, although every single immune-mediated disease represents a low prevalence. The responsibility of applying the latest research findings had long been a concern for scientists. Translational research is recognized as a potential tool to utilize scientific findings in clinical settings and patients’



care. Considering the wide spectrum of diseases related to the immune system besides the huge burden for individuals, healthcare settings, families, and society, identifying promising alternative diagnostic and therapeutic strategies through translational studies is of interest. The Translational Immunology book series is a major new suite of books in immunology, which covers both basic and clinical immunology. The series seeks to discuss and provide foundational content from bench to bedside in immunology. This series intends to discuss recent immunological findings and translate them into clinical practice. The first volumes of this book series are specifically devoted to autoimmune diseases. Translational Autoimmunity: Advances in Autoimmune Rheumatic Diseases is a comprehensive text that discusses recent advances in autoimmune rheumatic diseases (ARDs). A great interest for ARDs has appeared due to the massive burden of ARDs on patients, families, and the healthcare system because of the chronic nature of the disease and the fact that no definite cure is available and patients have to use immunomodulatory drugs lifelong, which in turn could predispose them to a wide variety of complications. In this book, advances in ARDs originated from translational research are explored, aiming to provide a brighter perspective for future research. This book starts with a review on recent advances on different aspects of autoimmune rheumatic diseases (ARDs) in Chapter 1. Chapter 2 focuses on bone health in the context of ARDs, while Chapter  3

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xviii Preface dives deep into the associated risk factors and the underlying immunopathology. In addition, Chapter 4 is devoted to rheumatic fever as an important childhood complaint. Chapter 5 explores the role of the microbiotaimmunity axis in ARDs. Chapters  6 and 7 provide a comprehensive overview of laboratory tests and antibody profile in ARD patients. Meanwhile, Chapters  8 and 9 focus on the contribution of some viral infections to the immunopathology of ARDs. Chapters  10 through 12 provide a focused view on some recent advances in rheumatic arthritis research. Besides, Chapters  13 through 16 dive deep into systemic lupus erythematosus research, discussing immunopathology, challenges, potential treatments, etc. Chapter  17 emphasizes on rheumatic chorea, and Chapter  18 comprehensively discusses rheumatic complications of hand and foot. In addition, Chapters  19 through 22 specifically explore autoimmune rheumatic conditions of the ­integumentary system. Moreover, Chapters 23 and 24 focus on Behçet’s disease, while Chapter  25 explores

Sjögren’s syndrome. Chapter 26 dives deep into the role of ILC2 in bone and joint inflammation. Chapter 27 explore the effect of arboviruses in the etiopathology of autoimmune diseases. Finally, Chapter 28 concentrates on medical conditions in which inflammation is known as the main culprit, including autoinflammatory diseases. The Translational Immunology book series is the outcome of the invaluable contribution of scientists and clinicians from well-known universities/institutes worldwide. I hereby appreciate and acknowledge the expertise of all contributors for generously devoting their time and considerable effort in preparing their respective chapters. I also express my gratitude to Elsevier for providing me the opportunity to publish this book. Finally, I hope this translational book will be comprehensible, cogent, and of special value to researchers and clinicians who wish to extend their knowledge in immunology. Nima Rezaei

Series editor’s biography

Professor Nima Rezaei earned his MD from Tehran University of Medical Sciences and subsequently obtained an MSc in molecular and genetic medicine and a PhD in clinical immunology and human genetics from the University of Sheffield, United Kingdom. He also spent a short-term fellowship in



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pediatric clinical immunology and bone marrow transplantation in the Newcastle General Hospital. Professor Rezaei is now Full Professor of Immunology and Vice Dean of Research, School of Medicine, Tehran University of Medical Sciences, and the cofounder and head of the Research Center for Immunodeficiencies. He is also the founding president of the Universal Scientific Education and Research Network (USERN). Professor Rezaei has already been the director of more than 55 research projects and has designed and participated in several international collaborative projects. Professor Rezaei is an editorial assistant and board member for more than 30 international journals. He has edited more than 35 international books, presented more than 500 lectures/posters in congresses/meetings, and published more than 1000 scientific papers in international journals.

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Acknowledgment I express my gratitude to the editorial assistant of this book, Dr. Niloufar Yazdanpanah, without whose contribution, this book would not have been completed. Nima Rezaei



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Abbreviations 2D 3D Ab ABI ACA ACE ACE-i ACPA ACPA ACR ADA ADAs AECA AFO AHR AIDs AIRE ALT AMA ANA ANA ANA ANCA ANG ANKH

Anti-ATA anti-CCP Anti-dsDNA Anti-PPM1A Anti-RNAP-III Anti-Sm Anti-TNF Anvisa APC API5 APL aPL APS



two-dimensional three-dimensional antibodies ankle brachial index anticentromere antibody angiotensin-converting enzyme angiotensin-converting enzyme inhibitor anticitrullinated protein antibodies anticyclic citrullinated peptide antibodies American College of Rheumatology adalimumab antidrug antibodies antiendothelial cell antibodies ankle foot orthoses aryl hydrocarbon receptor autoinflammatory disorders autoimmune regulator alanine aminotransferase antimitochondrial antibody antinuclear antigens anakinra antinuclear antibody antineutrophil cytoplasmic antibody angiopoietin inorganic pyrophosphate transporter progressive ankylosis protein homolog anti-topoisomerase antibody anticyclic citrullinated peptide anti-double-stranded DNA antibody to protein phosphatase magnesium-dependent 1A anti-RNA polymerase III antibody anti-Smith antitumor necrosis factor Brazilian Regulatory Agency antigen-presenting cell apoptosis inhibitory protein 5 altered peptide ligand antiphospholipid antibody antiphospholipid syndrome

APS1 aPTT AQP ARA ARDs ARF ARMD ARS AS ASAS ASCT ASDAS ASMA ASO AST ATA ATB ATFL ATP AuNPs AZA BAFF BAL BATF BBB BCDT BCL6 BDCA2 bDMARDs BDNF BFV BILAG BLK BLyS BMM BMP bNGF

xxiii

autoimmune polyglandular syndrome type 1 activated partial thromboplastin time aquaporin anti-RNA polymerase III antibody autoimmune rheumatic diseases acute rheumatic fever age-related macular degeneration aminoacyl tRNA synthetase ankylosing spondylitis Assessment of Spondyloarthritis International Society autologous stem cell transplantation ankylosing spondylitis disease activity score antismooth muscle antibody antistreptolysin O aspartate aminotransferase anti-topoisomerase I autoAbs absolute treatment benefit anterior talofibular ligament adenosine triphosphate gold nanoparticles azathioprine B-cell–activating factor bronchoalveolar lavage basic leucine zipper transcription factor blood-brain barrier B-cell depletion therapy B-cell lymphoma 6 blood DC antigen 2 biological disease-modifying antirheumatic drugs brain-derived neurotrophic factor Barmah Forest virus British Isles Lupus Assessment Group B-lymphoid tyrosine kinase B lymphocyte stimulator bone marrow–derived macrophage bone morphogenetic protein basic nerve growth factor

xxiv Abbreviations BPG BRD4 Bregs BTK BUD c/mDC C1q CA CA6 CaMK4 cAMP CAN c-ANCA

CAPS CBC CCB CCD CCJ CCP CD CD CDAI CDR3 CEL CFA CGRP CH50 CHD CHIKV CI CIA CINCA CLE CLIA CLIFT cN1A CNI CNS CO COVID-19 COX CPK CPPD CREB CREM CRP Cs A

benzathine penicillin G bromodomain-containing protein 4 regulatory B cells Bruton tyrosine kinase budesonide conventional/myeloid dendritic cell complement component 1q cricoarytenoid arthritis carbonic anhydrase 6 calcium/calmodulin-dependent protein kinase 4 cyclic adenosine monophosphate canakinumab antineutrophil cytoplasm antibodies with an IFI cytoplasmic pattern cryopyrin-associated periodic syndrome complete blood count calcium channel blockers charge-coupled device calcaneocuboid joint cyclic citrullinated peptide cluster of differentiation Crohn’s disease clinical disease activity index complementarity-determining region 3 celecoxib complete Freund’s adjuvant calcitonin gene–related peptide 50% hemolytic complement activity coronary heart disease chikungunya virus confidence interval collagen-induced arthritis chronic infantile neurologic cutaneous and articular syndrome cutaneous lupus erythematosus chemoluminescence immunoassay Crithidia luciliae immunofluorescence test cytosolic 5-nucleotidase 1A calcineurin inhibitor central nervous system carbon monoxide coronavirus disease 2019 cyclooxygenase creatine phosphokinase calcium pyrophosphate dehydrate CRE-binding protein AMP-responsive element modulator C-reactive protein cyclosporine A

csDMARDs CSF CSF CT CTD cTEC CTGF CTLA-4 CTLs CVD CyA CYC DAMPs DAS DC dcSSc DEP DEX DHODH DIL DIP DKK-1 DM DMARDS DNA DNMT1 DS DVT EAE EAU EBV ECL ECM EDA EDL EDTA EGF EHL ELISA EMA ENA EOMES EPCs ER ERAP-1 ERK

conventional synthetic diseasemodifying antirheumatic drugs cerebrospinal fluid colony-stimulating factor computed tomography connective tissue disease cortical thymic epithelial cells connective tissue growth factor cytotoxic T lymphocyte–associated antigen 4 cytotoxic T lymphocytes cardiovascular disease cyclosporine A cyclophosphamide damage-associated molecular patterns Disease Activity Score dendritic cell diffuse cutaneous systemic sclerosis diesel exhaust particle dexamethasone dihydroorotate dehydrogenase drug-induced lupus distal interphalangeal Dickkopf-related protein-1 dermatomyositis disease-modifying antirheumatic drugs deoxyribonucleic acid DNA methyl-transferase 1 dextran sulfate deep vein thrombosis experimental autoimmune encephalomyelitis experimental autoimmune uveitis Epstein-Barr virus electrochemiluminescence extracellular matrix extra-domain A extensor digitorum longus ethylenediaminetetraacetic acid epidermal growth factor extensor hallucis longus enzyme-labeled immunosorbent assay European Medicines Agency extractable nuclear antigens eomesodermin endothelial progenitor cells endoplasmic reticulum endoplasmic reticulum amino peptidase 1 extracellular signal-regulated kinases

Abbreviations xxv

ERV ES ESR ESRD ETA EULAR EULAR EZH2 Fab′ FBC Fc FCAS FcRγ FDA FDL FGF FGFR FH FHL FLCs FLS FMF FMT FOXP3 FR Fra-2 FS FSTL-1 FVC GABHS GALT GAS GCA GCs GCs GDNF GF GFP GFR GIT GM GM-CSF GMP GMR GMSF GOL gp

endogenous retrovirus erosion score erythrocyte sedimentation rate end-stage renal disease etanercept European Alliance of Associations for Rheumatology European League against Rheumatism histone-lysine N-methyl-transferase humanized antigen-binding fragment full blood count fragment crystallizable familial cold autoinflammatory syndrome Fc receptor γ Food and Drug Administration flexor digitorum longus fibroblast growth factor fibroblast growth factor receptor fibrin hydrogel flexor hallucis longus immunoglobulin free light chains fibroblast-like synoviocytes familial Mediterranean fever fecal microbiota transplantation forkhead box P3 folate receptors fos-related antigen-2 Felty's syndrome follistatin-related protein 1 forced vital capacity group A beta-hemolytic Streptococcus gut-associated lymphoid tissues group A Streptococcus giant cell arteritis germinal centers glucocorticoids glial cell line–derived neurotrophic factor germ free green fluorescent protein glomerular filtration rate gastrointestinal tract gut microbiota granulocyte-macrophage colonystimulating factor Good Manufacturing Practices giant magneto resistive gradient minimization smoothing filter golimumab glycoproteins

GPCRs GRPs GVHD GWAS GWS HA HA-PEI HAQ HBV HCQ HCs HCV HGF HIDS HLA HMGB-1 HMGCR hsCRP HSG HSP HSV HUVEC HVEM iBALT IBD IC ICAM ICOS IFI IFN IFX Ig IGF IIFA IIM IL ILC ILD ILE IM IM iNKT IP-10 IPEX

IPF IPK

G-protein–coupled receptors glycine-rich food proteins graft-versus-host disease genome-wide association studies whole-genome sequencing hyaluronic acid hyaluronic acid-poly(ethyleneimine) Health Assessment Questionnaire hepatitis B virus hydroxychloroquine healthy controls hepatitis C virus hepatocyte growth factors hyper immunoglobulinemia D syndrome human leukocyte antigen high mobility group box 1 hydroxy-methyl-glutaryl-betaCoA-reductase high-sensitivity C-reactive protein human salivary gland cell line heat-shock protein herpes simplex virus human umbilical vein endothelial cells herpes virus entry mediator inducible bronchial-associated lymphoid tissue inflammatory bowel disease immune complex intercellular adhesion molecule inducible costimulator indirect immunofluorescence interferon infliximab immunoglobulins insulin-like growth factor indirect immunofluorescence assay idiopathic inflammatory myopathies interleukin innate lymphoid cell interstitial lung disease incomplete lupus erythematosus intramuscular infectious mononucleosis invariant natural killer T interferon gamma–induced protein 10 immune dysregulation, polyendocrinopathy, and enteropathy X-linked syndrome ibuprofen intractable plantar keratosis

xxvi Abbreviations IPSC IRFs IRSs ISG ITAM ITGAM iTregs IU IV JAK JAK/STAT JDM JIA JNK JSNS kg KL‐6 LAC LAG-3 LBH lcSSc LDGs LDH LEF LGLs LIA LIF LMICs LN LPS LTi LtxA LYZ M1 M2 MA MAAs MAC MAIT MALT MAMPs MAPK MAX MAYV MBL MBP MBPs MCP MCP-1

induced pluripotent stem cells interferon regulatory factors interspersed repeated sequences IFN-stimulated gene immunoreceptor tyrosine-based activation motifs integrin subunit alpha M induced regulatory T cells international unit intravenous Janus kinase Janus kinase/signal transducer and activator of transcription juvenile dermatomyositis Juvenile idiopathic arthritis c-Jun N-terminal kinase joint space narrowing score kilogram Krebs von den Lungen‐6 lupus anticoagulant lymphocyte activation gene 3 limb bud and heart development limited cutaneous systemic sclerosis low-density granulocytes lactate dehydrogenase leflunomide large granular lymphocytes line immunoassay leukemia inhibitory factor low- and middle-income countries lupus nephritis lipopolysaccharide lymphoid tissue inducer leukotoxin A lysozyme classically activated macrophages alternatively activated macrophages mevalonic aciduria myositis-associated autoantibodies membrane attack complex mucosal-associated invariant T cells mucosa-associated lymphoid tissue microorganism-associated molecular pattern mitogen-activated protein kinase membrane attack complex Mayaro virus mannose-binding lectin myelin basic protein mannose-binding proteins metacarpophalangeal monocyte chemoattractant protein-1

MCs M-CSF MCTD MCV MDA5 mg MHC miRNAs MKD MLKL MMF MMP MNC MPLA MPO MRI mRNA MS MSC mtDNA mTEC mTOR MTP MTPJ MTX MWS MYD88 MZ NAC NALIA NCF2 NET NFkB Nf-M NGS NIND NIR NK NKT NLRP3

NLRs NMDAR NO NO2 NO2 NOD

mast cells macrophage colony-stimulating factor mixed connective tissue disease mutated citrullinated vimentin melanoma differentiation– associated protein 5 milligram major histocompatibility complex microRNAs mevalonate kinase deficiency mixed lineage kinase domain-like mycophenolate mofetil matrix metalloproteinase mononuclear cell monophosphoryl lipid A myeloperoxidase magnetic resonance imaging microRNA multiple sclerosis mesenchymal stem cells mitochondrial DNA medullary thymic epithelial cells mammalian target of rapamycin metatarsophalangeal metatarsophalangeal joint methotrexate Muckle-Wells syndrome myeloid differentiation primary response 88 monozygous N-acetylcysteine nanodot array luminometric immunoassay neutrophil cytosolic factor 2 neutrophil extracellular trap nuclear factor kappa B neurofilament medium next-generation sequencing noninflammatory neurologic disease near-infrared natural killer natural killer T cells nucleotide-binding domain, leucine-rich repeat containing family, and pyrin domaincontaining 3 nucleotide-binding oligomerization domain-like receptors N-methyl-d-aspartate receptor nitric oxide nitrogen oxide nitrogen dioxide nonobese diabetic

Abbreviations xxvii

NOMID NOX1 NPSLE NSAIDs NTDs NT-proBNP nTregs NuRD NXP2 NZB/W O3 OA OM ONNV OR PAD PAH PAMPs PAN PAS PBCs PBMC PCNA PCR PCs PD 1 pDC PDGF pDNA PEG PFAPA PH PI3K PIP P-JNK PLA PLA2 PLGA PlGF PLLA PMAT PMNs PMR PP2A PR3 Pro-BNP

neonatal-onset multisystem inflammatory disease NADPH oxidase 1 neuropsychiatric SLE nonsteroidal antiinflammatory drugs neural tube defects amino-terminal pro-brain natriuretic peptide type B natural regulatory T cells nucleosome remodeling deacetylase nuclear matrix protein 2 New Zealand black/white ozone osteoarthritis oral microbiota O'nyong-nyong virus odds ratios peptidyl arginine deiminase pulmonary arterial hypertension pathogen-associated molecular patterns polyarteritis nodosa periodic acid-Schiff peripheral blood cells peripheral blood mononuclear cell proliferating cell nuclear antigen polymerase chain reaction plasma cells programmed death 1 plasmacytoid dendritic cells platelet-derived growth factor plasmid DNA polyethylene glycol periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis pulmonary hypertension phosphatidylinositol-3-kinase proximal interphalangeal phospho- Jun N-terminal kinase polylactic acid phospholipase A2 poly(lactide-co-glycolytic) acid placental growth factor poly-l-lactic acid particle-based multianalyte technology polymorphonuclear cells polymyalgia rheumatica serine/threonine protein phosphatase 2A proteinase-3 enzyme pro-brain natriuretic peptide type B

PROMS PRRs PS PsA PTH PTM PTPN22 PTTD PVDF RA RANKL RASGRP1 RBPs RCTs RD ReA RES RF RF RGI2 RHD rhIL-2 RIA RIG-I RIPK1 RLM RLRs RNA RNP ROR RORγT ROS RP RPE RR RRV RT-PCR RTX RVT SAA SC SC SCFA SCID SCLE

patient-reported outcome measures pattern-recognition receptors psoriasis psoriatic arthritis parathyroid hormone posttranslational modifications protein tyrosine phosphatase nonreceptor type 22 posterior tibial tendon dysfunction poly (vinylidene fluoride) rheumatoid arthritis receptor activator of the nuclear factor kappa B ligand RAS guanyl releasing protein 1 RNA-binding proteins randomized controlled trials rheumatic diseases reactive arthritis reticuloendothelial system rheumatoid factor rheumatic fever Rho GDP-dissociation inhibitor 2 rheumatic heart disease recombinant human IL-2 radioimmunoassay retinoic acid–inducible gene I receptor-interacting protein kinase 1 robust linear model retinoic-like receptors ribonucleic acid ribonucleoproteins retinoic acid receptor–related orphan receptor retinoic acid receptor–related orphan receptor gamma T reactive oxygen species Renaud’s phenomenon retinal pigment epithelium relative risk Ross River virus reverse transcription-polymerase chain reaction rituximab renal vein thrombosis serum-amyloid A subcutaneous sydenham chorea short-chain fatty acids severe combined immunodeficiency subacute cutaneous lupus erythematosus

xxviii Abbreviations sDMARDs SE SFB SG SIGIRR SIMS SINV siRNA SLAM SLE SLEDAI SLICC SMR SNP SO2 SP1 SpA SP‐D SPR SPRED2 SR SRC SRP SS S. pyogenes SSc ssDNA ssSSc SSZ ST2 STAT STJ Syk SYNGR1 T1D T1DM TA Tac TAL Tang TAR TBX21 TcPO2 TCR TCZ

synthetic disease-modifying antirheumatic drugs shared epitope segmented filamentous bacteria salivary gland single immunoglobulin IL-1– related receptor submandibular gland ductal cell line Sindbis virus small interfering RNA signaling lymphocyte activation molecule systemic lupus erythematosus Systemic Lupus Erythematosus Disease Activity Index systemic lupus international collaborating clinics standardized mortality ratios single-nucleotide polymorphism sulfur dioxide salivary gland protein 1 spondyloarthritis surfactant protein‐D surface plasmon resonance sprouty-related EVH1 domain containing 2 scavenger receptors severe renal crisis signal recognition particle Sjögren’s syndrome Streptococcus pyogenes systemic sclerosis single-stranded DNA systemic sclerosis sine scleroderma sulfasalazine suppression of tumorigenicity 2 signal transducer and activator of transcription subtalar joint spleen tyrosine kinase synaptogyrin 1 type 1 diabetes type 1 diabetes mellitus tibialis anterior tacrolimus tendo Achilles lengthening angiogenic T cells total ankle replacement T-box transcription factor transcutaneous oxygen pressures T-cell receptor tocilizumab

Teff Tfh TGF TGF Th TIA-1 TIF1γ TIF1-γ TIGIT TIM3 TIMP T-LGL leukemia TLR TMA TMAO TMTJ TNF TNFAIP3 TNFi TNJ tolDC TP TRAF TRAF1 TRAIL TRAPS

Treg tsDMARDs TSLP TSS TYK2 UA UBE2L3 UC UCTD UV UVR VCA VCAM VDRL VEGF

effector T cells T follicular helper transforming growth factor tumor growth factor T helper T-cell intracellular antigen 1 transcription intermediary factor 1 gamma transcriptional intermediary factor 1-gamma T-cell immunoglobulin and ITIM domain T-cell immunoglobulin domain and mucin domain 3 tissue inhibitor of metalloproteinase T-cell large granular lymphocytic leukemia Toll-like receptor thrombotic microangiopathy trimethylamine N-oxide tarsometatarsal joint tumor necrosis factor TNF alpha induced protein 3 tumor necrosis factor inhibitors talonavicular joint tolerogenic dendritic cell tibialis posterior tumor necrosis factor receptor (TNFR)–associated factor TNF receptor–associated factor 1 tumor necrosis factor–related apoptosis-inducing ligand tumor necrosis factor (TNF) receptor–associated periodic syndrome regulatory T cell targeted synthetic diseasemodifying antirheumatic drugs thymic stromal lymphopoietin total Sharp score tyrosine kinase 2 uric acid ubiquitin-conjugating enzyme E2 L3 ulcerative colitis undifferentiated connective tissue disease ultraviolet ultraviolet radiation viral capsid antigen vascular cell adhesion molecule venereal disease research laboratory test vascular endothelial growth factor

Abbreviations xxix

VISTA VLA4 VTE WBC

V-domain Ig suppressor of T-cell activation very late activation antigen 4 venous thromboembolism white blood cells

WDFY4 XO ZAP-70 β2M

WDFY family member 4 xanthine oxidase ζ-associated protein 70 β-2 microglobulin

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C H A P T E R

1 Introduction on autoimmune rheumatic diseases Niloufar Yazdanpanaha,b,d and Nima Rezaeib,c,d,⁎ a

School of Medicine, Tehran University of Medical Sciences, Tehran, Iran, bResearch Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran, cDepartment of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran, dNetwork of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran *Corresponding author

Abstract The term autoimmune rheumatic diseases (ARDs) correspond to a wide spectrum of diseases that share some common symptoms and genetic susceptibility factors. The very first evidence of studying ARDs dates back to the 1800s when a medical student described a type of severe joint pain in a group of patients that were not categorized in already defined joint diseases. From that date, vast investigations aiming to recognize this group of burdensome diseases have started, which resulted in numerous advances in the understanding of the etiopathogenesis, diagnosis, treatment, and prognosis of ARDs.

Keywords Autoimmune, Rheumatic, ARD, Treatment, Diagnosis

1  Introduction A greater number of rheumatic diseases are attributed to an autoimmune pathology, named autoimmune rheumatic diseases (ARDs), while some have different pathophysiology, including osteoarthritis and gout. The term ARDs includes a spectrum of clinical conditions that share joint disease as their main remarkable manifestation while presenting various systemic manifestations. Progression of ARDs to a complete clinical phenotype can take either

Translational Autoimmunity, Vol. 6 https://doi.org/10.1016/B978-0-323-85831-1.00001-2

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1.  Introduction on autoimmune rheumatic diseases

a short period or up to many decades. Due to the prolonged course of the disease, patients with ARDs face several complications and disabilities during their life, even before the time of diagnosis. Not a specific etiology is determined for ARDs; whereas genetic and epigenetic factors, as well as environmental triggers such as infections, stress, and nutrition, contribute to the pathogenesis of ARDs. The incidence of many ARDs has shown a remarkable increasing trend in recent years. Nevertheless, no single etiology is determined to be responsible for the increasing trend. Affecting the multiple systems in the body, ARDs lead to different complications during patients’ life. Besides, joints and the musculoskeletal system are mainly targeted by ARDs, putting patients at risk of mobility problems and reducing the ability to work, which in turn increases the unemployment that itself affects the patient’s social life, mental health, and family’s economic status. In addition, some ARDs are associated with nonrheumatic autoimmune diseases such as vitiligo and type 1 diabetes mellitus (T1DM), which potentially further increase the burden on the patients and the healthcare system. Different mortality rates are recorded for each ARD, with systemic lupus erythematosus (SLE) being reported to have the highest mortality rate among others [1]. Mortality in ARDs is mainly due to uncontrolled active disease for a long period, infections, and cardiovascular complications [2,3]. Putting together, ARDs impart a huge burden on patients, families, the healthcare system, and the society due to the morbidity, mortality, and complications associated with the disease, besides the fact that no definite cure is available for ARDs. Hence, to improve the treatment armamentarium of ARDs, a translational approach applying the results of molecular and cellular studies on mechanisms involve in disease predisposition, initiation, exacerbation, and progression to clinical usage and drug development could result in promising results. In this chapter, advances in ARDs research based on translational studies are reviewed, aiming to provide a comprehensive guide for future research.

2  ARD through the history The historical footprint of rheumatic diseases dates back to 7000 BCE and observation of kidney stones composed of urate and great toe (also known as tophus) in mummies buried in ancient Egypt. Later in 400 BCE, Hippocrates put forward the first clinical description for gout, although the term gout was coined many years later [4]. Hence, gout might be the first rheumatic disease described in history. However, no autoimmune pathogenesis is described for gout. In the history of advances in the discovery, diagnosis, and treatment of ARDs, rheumatoid arthritis (RA) seems to be the very first condition being studied. The initial definition for RA that was conceded by the medical science community was suggested in the doctoral thesis of Augustin Jacob Landré-Beauvais in 1800. He assessed and treated patients suffering from severe joint pain, which was not explicable by already identified joint and bone diseases at the time [5]. As gout was a known disease in those years that commonly affect rich patients, most physicians preferred to focus on treating gout while other joint problems, including the condition now we recognize as RA, were neglected [6]. He named the unknown joint pain

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“primary asthenic gout,” which inspired physicians and scientists to study the disease in more depth [5]. During the years of mid-late 19th century, Alfred Garrod observed higher levels of uric acid in blood samples from gout patients, while he did not observe the same in patients with other arthritic diseases [7]. He was the first who could suggest criteria to distinguish gout from the disease we recognize as RA, which at the time, he named it “rheumatic gout” [7]. In 1890, Archibald Garrod named the condition discovered by Landré-Beauvais “rheumatoid arthritis” based on the disease’s effects on the human body [8]. To have a brief historical review of rheumatic diseases with autoimmune pathogenesis (or ARDs), in 1901, Paul Ehrlich proposed the doctrine of “horror autotoxicus,” which is appreciated as the turning point in research on autoimmunity [9]. Later, antibodies were identified as a contributor to cold hemoglobinuria while autoimmunity was not accepted as the disease etiology [10]. During the next 3–4 decades, although different antibodies directed against body tissues were discovered, research on the concept of autoimmunity went into an eclipse era [11]. In 1945, research on autoimmunity was reinvigorated through attempts aiming to boost experimental induction of autoimmune diseases by the application of adjuvants. Finally, in 1965, the history of science witnessed the acceptance of the autoimmunity concept while the true mechanisms and pathogenesis of many autoimmune diseases were being discovered [11].

3  Diagnosis of ARD Diagnosis of ARDs is chiefly based on the clinical picture of the patient and the detected profile of autoantibodies. Nevertheless, in some cases, diagnosis is changed after initiation of the treatment or as the disease progresses since more distinct symptoms of the disease manifest. Although rare, conversion in diagnosis is possible due to many common traits of different ARDs. Therefore, developing more sensitive and specific diagnostic tools is of utmost importance to optimize the diagnosis process for ARDs. Autoantibodies have been known as useful tools in the diagnosis of ARDs. Not only in diagnosis, but these markers are also helpful in disease classification, monitoring the response to the treatment, and evaluating disease activity. Regardless of the benefits of autoantibodies in disease diagnosis and follow-up, there are some limitations. For instance, autoantibodies could be detected in healthy individuals with any history of ARDs, particularly in elderly ages [12,13]. Therefore, it is recommended to use autoantibodies only as a part of the diagnostic workup and not to rely only on a positive autoantibody to make a diagnosis. As another limitation, there are many variations reported among reagent producers concerning the advised method and the used antigen, which could lead to variations between cut-off values, reference ranges, and measuring ranges [12]. Although many diagnosis kits have become accredited by main standard tools that have made these variations less remarkable than decades ago, some discrepancies remained to be solved. Rheumatoid factors (antibodies against Fc part of immunoglobulin G), anti-cyclic citrullinated peptide (anti-CCP) antibodies, antinuclear antibodies (ANA, including anti-dsDNA, anti-Ro (SS-A), anti-La (SS-B), anti-Sm, anticentromere, antiribonuclear protein, anti-Scl-70, and anti-Jo antibodies), antineutrophil cytoplasmic antibodies (ANCA), anticardiolipin and anti-β2-glycoprotein I antibodies, immunoglobulins, cryoglobulins, complement factors, and C-reactive protein (CRP) are being used in clinical settings as markers for disease diagnosis and follow up.

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1.  Introduction on autoimmune rheumatic diseases

Besides serology tests and autoantibody profiling, physicians benefit from other diagnostic tools to confirm their diagnosis. For instance, imaging, including X-ray, MRI, and sonography, and electrodiagnostic tools are helpful in some cases. Meanwhile, the important role of physical examination is deniable in the diagnosis of ARDs. Antigen microarrays and mass spectrometry have shown expected efficient results in determining the patient’s profile of proteins and antibodies [14]. Moreover, next-­generation sequencing (NGS) techniques have enabled the researchers to understand more about interactions between the two main contributors to the etiopathogenesis of ARDs, genetics and environmental factors. As the obtained information has been extensive, so have the advances in the diagnosis of ARDs. Transcriptomics (which incorporates technologies for high-throughput recognition of RNA species), epigenomics, and metagenomics have revealed many unknown molecular and cellular responsible components and pathways in ARDs that are being used to develop diagnostic and prognostic tools by using translational approaches [15,16]. Whole-genome sequencing and exome sequencing have identified many mutations that account for some rare ARDs, particularly Mendelian autoinflammatory diseases [16].

4  Treatment of ARD 4.1  Pharmacological treatment Suppressing the immune system has been the mainstay in the treatment of the immune system so far. Although the initial treatments nonspecifically inhibited the immune system and resulted in a vast variety of adverse effects, newer treatments developed that could target different parts of the immune system of components of the underlying mechanisms, resulting in more desirable results. Meanwhile, recognizing immune dysregulation as the underlying cause of autoimmune disease highlighted the concept of reprogramming or fixing the regulation of the immune system rather than inhibiting it. As an overview of the development of treatments for ARDs, glucocorticoid therapy was primarily suggested in the 1950s by Philip Hench and colleagues [17]. Injectable gold was introduced in the 1930s as the first agent classified as disease-modifying antirheumatic drugs (DMARDs), which were acknowledged as antirheumatic treatments [18]. In the 1950s and 1960s, hydroxychloroquine and azathioprine were introduced, respectively; about 25 years later, in the 1980s, sulfasalazine and methotrexate entered the medical setting [19,20]. The already mentioned agents are classified as conventional DMARDs (cDMARDs). Newer immunomodulatory agents, also known as biological DMARDs (bDMARDs), have emerged since 1998 [20]. Moreover, the first monoclonal antibody (MAB) was produced in 1975, while the first Food and Drug Administration (FDA) approval on MABs dates back to 1986, on ­muromonab-CD3, designed for preventing renal transplant rejection [21]. Antibody discovery appeared with the immunization of mice to induce the production of immunoglobulins (Igs) and obtain rodent Igs for clinical benefits. However, due to improvements in genetic studies and protein engineering, the production of fully humanized antibodies is available today [22]. These newer agents could be better tolerated by patients and yielded more desirable outcomes. 4



Niloufar Yazdanpanaha and Nima Rezaei

4.2  Exercise and physical activity Chronic systemic inflammation is an important characteristic trait of ARDs, which remarkably influence the disease severity, symptoms, and progression. That being the case, controlling or modulating inflammation is the mainstay of treatment. Patients with ARDs experience different complications attributed to the prolonged inflammation during their disease, including increased propensity to cardiovascular diseases, dyslipidemia and atherosclerosis, hematological abnormalities such as anemia, insulin resistance, and metabolic impairments [23–26]. Of note, these complications considerably decrease the patient’s ability and power for physical activity [27,28]. Consequently, lack of exercise and physical activity exacerbates the inflammation and initiates the vicious cycle of prolonged inflammation in ARD patients. Recommending physical activity as an antiinflammatory therapeutic measure for ARD patients is based on the newly raised concept of muscle’s secretome, consists of myokines, by which muscle cells communicate with other tissues such as pancreas, liver, brain, bone, and fat tissue in the body [29,30]. Myokines incorporate different cytokines, such as interleukin (IL)-7, IL-6, and leukemia inhibitory factor, and various peptides, such as insulin-like growth factor 1 (IGF-1), brain-derived neurotrophic factor (BDNF), fibroblast growth factor 2 (FGF-2), follistatin-related protein 1 (FSTL-1), and irisin [29,30]. Through exercise, muscles contract and relax intermittently, which facilitates the release of muscles’ secretions into the circulation, making IL-6 the first detectable mediator in the blood after physical activity. IL-6 induces antiinflammatory effects by enhancing the production of IL-1 receptor antagonist (IL-1ra) and IL-10 by peripheral blood mononuclear cells (PBMCs) [31]. Moreover, other products of physical activity such as IL-15 and FSTL-1 in association with IL-6 reduce the cardiovascular risk factors; for instance, improving the endothelial functions and modifying fat distribution in the body [30,31]. In addition, regular exercise help patients maintain their proper weight and BMI, which in turn prevent obesity that, itself, could be an inducer of chronic inflammation and a risk factor for cardiovascular atherosclerotic diseases and metabolic complications [32]. Besides, physical activity promotes individuals’ psychological health and triggers a feeling of well-being [33]; therefore, it can benefit patients with ARDs both physically and mentally.

4.3  Microbiota modulation Having in mind the core concept of immune tolerance breakdown as a contributor to the pathophysiology of ARDs, it is suggested to consider mucosal barriers, which are in direct contact with different bacterial and foreign antigens, as primary sites of tolerance breakdown [34,35]. Therefore, different approaches have been introduced aimed to modulate the microbiota composition of their metabolic products for therapeutic purposes. For instance, the gut microbiome species are capable of transforming dietary fibers into short- and medium-chain fatty acids (SCFAs and MCFAs, respectively). SCFAs have demonstrated different immunoregulatory properties. For example, SCFAs affect T regulatory cells (Tregs) and dendritic cells (DCs) by utilizing G-protein coupled receptors (GPCRs) to restrain histone deacetylases [36]. Also, SCFAs contribute to the activation of inflammasomes [36]. 5



1.  Introduction on autoimmune rheumatic diseases

Microbiota modulation has become an interesting field of research for alleviating ARDs. Different strategies are being studied for exploiting the body’s microbiome for therapeutic aims. For instance, modulation through dietary products, administration of probiotics and prebiotics, fecal microbiota transplantation, and other strategies such as oral administration of useful microorganisms [36]. Furthermore, the body’s microbiome is being studied to discover certain drug-microbiota interactions to optimize the drug’s efficacy and reduce the adverse effects [37].

4.4  Epigenetic modification It is widely accepted that genetic susceptibility is an important factor predicting the individual’s risk for developing an autoimmune condition in later life, including ARDs; for instance, HLA genes, PTPN22, STAT4, and IRF5 [38]. Nevertheless, this effect is not only dependent on genetics, but also on epigenetics since the function of the gene is mediated according to the genetic sequence and the epigenetic mechanisms such as DNA methylation and protein’s posttranslational modifications [39]. Epigenetic processes regulate gene expression and are modifiable by external factors. Given that the genetics of the creatures are nonmodifiable, epigenetics has emerged as a potential link between environmental and genetic contributors to the pathophysiology of ARDs and brought promises for the treatment of patients. Studies on monozygotic twins who were discordant for an autoimmune disease have strengthened the role of epigenetic modifications in the pathophysiology of autoimmune diseases since genetic variability is bypassed in these studies [39–41]. DNA methylation and histone modification are known as the most relevant epigenetic mechanisms in the pathophysiology of ARDs [42]. Detection of specific cells undergoing epigenetic alterations in ARDs could be beneficial to be used as diagnostic and prognostic markers and for developing a method to evaluate disease response to the treatment.

5  Conclusion Despite extensive advances in understanding the etiopathogenesis, diagnosis, and treatment of ARDs, further advances are possible and in progress. Translational studies, from bench to bedside, have had a significant role in advances in ARDs. Nevertheless, many questions remained to be addressed to progress the diagnosis and treatment, consequently the treatment outcome, of ARDs; translational studies have shown great promises to tackle existing challenges.

References [1] M.J. Amador-Patarroyo, A. Rodriguez-Rodriguez, G. Montoya-Ortiz, How does age at onset influence the outcome of autoimmune diseases? Autoimmune Dis. 2012 (2012). [2] B. Mehta, et al., Serious infection risk in rheumatoid arthritis compared with non-inflammatory rheumatic and musculoskeletal diseases: a US national cohort study, RMD Open 5 (1) (2019) e000935. [3] A. Villa-Forte, B.F. Mandell, Cardiovascular disorders and rheumatic disease, Rev. Esp. Cardiol. 64 (9) (2011) 809–817.

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[4] C.R. MacKenzie, Gout and hyperuricemia: an historical perspective, Curr. Treat. Options Rheumatol. 1 (2) (2015) 119–130. [5] A.J. Landré-Beauvais, The first description of rheumatoid arthritis. Unabridged text of the doctoral dissertation presented in 1800, Joint Bone Spine 68 (2) (2001) 130–143. [6] P. Entezami, et al., Historical perspective on the etiology of rheumatoid arthritis, Hand Clin. 27 (1) (2011) 1–10. [7] A.B. Garrod, Treatise on Nature of Gout and Rheumatic Gout. London: Walton and Maberly; 1859. [8] A.E. Garrod, A treatise on rheumatism and rheumatoid arthritis, Griffin, 1890. [9] JHT, Horror autotoxicus and other concepts of Paul Ehrlich, JAMA 176 (1) (1961) 50–51. [10] J.J.M.M.W. Donath, Uber paroxysmal haemoglobinurie, Munch. Med. Wochenschr. 51 (1904) 1590–1593. [11] I.R. Mackay, Travels and travails of autoimmunity: a historical journey from discovery to rediscovery, Autoimmun. Rev. 9 (5) (2010) A251–A258. [12] J. Sheldon, Laboratory testing in autoimmune rheumatic diseases, Best Pract. Res. Clin. Rheumatol. 18 (3) (2004) 249–269. [13] R. Giacomelli, et al., Guidelines for biomarkers in autoimmune rheumatic diseases—evidence based analysis, Autoimmun. Rev. 18 (1) (2019) 93–106. [14] M. Plebani, et al., Recent advances in diagnostic technologies for autoimmune diseases, Autoimmun. Rev. 8 (3) (2009) 238–243. [15] P. Cheung, et al., Single-cell technologies—studying rheumatic diseases one cell at a time, Nat. Rev. Rheumatol. 15 (6) (2019) 340–354. [16] L.T. Donlin, et al., Insights into rheumatic diseases from next-generation sequencing, Nat. Rev. Rheumatol. 15 (6) (2019) 327–339. [17] C.M. Burns, The history of cortisone discovery and development, Rheum. Dis. Clin. North Am. 42 (1) (2016) 1–14 (vii). [18] W. Kean, et al., The history of gold therapy in rheumatoid disease, in: Seminars in Arthritis and Rheumatism, Elsevier, 1985. [19] M.W. Whitehouse, Drugs to treat inflammation: a historical introduction, Curr. Med. Chem. 12 (25) (2005) 2931–2942. [20] J.K. Buer, A history of the term “DMARD”, Inflammopharmacology 23 (4) (2015) 163–171. [21] J.K.H. Liu, The history of monoclonal antibody development—progress, remaining challenges and future innovations, Ann. Med. Surg. (2012) 3 (4) (2014) 113–116. [22] A.S. Schmid, D. Neri, Advances in antibody engineering for rheumatic diseases, Nat. Rev. Rheumatol. 15 (4) (2019) 197–207. [23] I. Del Rincón, et al., High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors, Arthritis Rheum. 44 (12) (2001) 2737–2745. [24] M.J. Roman, et al., Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus, N. Engl. J. Med. 349 (25) (2003) 2399–2406. [25] S. Sitia, et al., Cardiovascular involvement in systemic autoimmune diseases, Autoimmun. Rev. 8 (4) (2009) 281–286. [26] G. Weiss, G. Schett, Anaemia in inflammatory rheumatic diseases, Nat. Rev. Rheumatol. 9 (4) (2013) 205–215. [27] C. Mancuso, et al., Perceptions and measurements of physical activity in patients with systemic lupus erythematosus, Lupus 20 (3) (2011) 231–242. [28] T. Sokka, et al., Physical inactivity in patients with rheumatoid arthritis: data from twenty‐one countries in a cross‐sectional, international study, Arthritis Rheum. 59 (1) (2008) 42–50. [29] B.K. Pedersen, Muscle as a secretory organ, Compr. Physiol. 3 (3) (2013) 1337–1362. [30] B.K. Pedersen, M.A. Febbraio, Muscles, exercise and obesity: skeletal muscle as a secretory organ, Nat. Rev. Endocrinol. 8 (8) (2012) 457–465. [31] A. Steensberg, et al., IL-6 enhances plasma IL-1ra, IL-10, and cortisol in humans, Am. J. Physiol. Endocrinol. Metab. 285 (2) (2003) E433–E437. [32] M.S. Ellulu, et al., Obesity and inflammation: the linking mechanism and the complications, Arch. Med. Sci. 13 (4) (2017) 851–863. [33] R. Graham, J. Kremer, G. Wheeler, Physical exercise and psychological well-being among people with chronic illness and disability: a grounded approach, J. Health Psychol. 13 (4) (2008) 447–458. [34] The Human Microbiome Project Consortium, Structure, function and diversity of the healthy human microbiome, Nature 486 (7402) (2012) 207.

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[35] B. Li, et al., The microbiome and autoimmunity: a paradigm from the gut-liver axis, Cell. Mol. Immunol. 15 (6) (2018) 595–609. [36] S. Abdollahi-Roodsaz, S.B. Abramson, J.U. Scher, The metabolic role of the gut microbiota in health and rheumatic disease: mechanisms and interventions, Nat. Rev. Rheumatol. 12 (8) (2016) 446–455. [37] M.R. Rizkallah, et al., The Human Microbiome Project, personalized medicine and the birth of pharmacomicrobiomics, Curr. Pharmacogenomics Pers. Med. 8 (3) (2010) 182–193. [38] B.A. Lie, E. Thorsby, Several genes in the extended human MHC contribute to predisposition to autoimmune diseases, Curr. Opin. Immunol. 17 (5) (2005) 526–531. [39] M.F. Fraga, et al., Epigenetic differences arise during the lifetime of monozygotic twins, PNAS 102 (30) (2005) 10604–10609. [40] S.E. Baranzini, et al., Genome, epigenome and RNA sequences of monozygotic twins discordant for multiple sclerosis, Nature 464 (7293) (2010) 1351–1356. [41] Z.A. Kaminsky, et al., DNA methylation profiles in monozygotic and dizygotic twins, Nat. Genet. 41 (2) (2009) 240–245. [42] M. Kato, S. Yasuda, T. Atsumi, The role of genetics and epigenetics in rheumatic diseases: are they really a target to be aimed at? Rheumatol. Int. 38 (8) (2018) 1333–1338.

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C H A P T E R

2 Bone Health in autoimmune inflammatory rheumatic diseases İlke Coşkun Benlidayı⁎

Department of Physical Medicine and Rehabilitation, Cukurova University Faculty of Medicine, Adana, Türkiye ⁎

Corresponding author

Abstract Bone health impairment is a common comorbidity in patients with autoimmune inflammatory rheumatic diseases (AIIRD). The prevalence of low bone mineral density/osteoporosis varies depending on numerous factors such as demographic variables, underlying rheumatic disease, medications, and comorbid conditions. There are general and disease-related risk factors of bone loss/osteoporosis in patients with AIIRD. Immune and inflammatory pathways play a big role in the development of osteoporosis. Patient assessment should include anamnesis, clinical examination, fracture risk assessment, laboratory investigations, and imaging techniques. Management strategies comprise patient education, lifestyle modifications, fall prevention strategies, proper intake of bone-healthy nutrients (i.e., calcium and vitamin D), appropriate control of rheumatic disease activity, and antiosteoporotic medications when necessary.

Keywords Autoimmunity, Bone, Bone loss, Bone mineral density, Fractures, Inflammation, Osteoporosis, Rheumatic diseases

1  Introduction Patients with autoimmune inflammatory rheumatic diseases (AIIRD) often challenge distinct comorbidities during their disease course. These comorbid conditions include, but not limited to, cardiovascular diseases (hyperlipidemia, hypertension, heart failure, etc.), hematologic conditions, psychological problems (depression, anxiety, etc.), infections (tuberculosis, viral infections, etc.), malignancies (lung cancer, lymphoma, breast cancer, skin cancer, etc.), respiratory diseases (interstitial lung disease etc.), gastrointestinal problems ­(diverticulitis,

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2.  Bone Health in autoimmune inflammatory rheumatic diseases

colorectal cancer, etc.), cognitive dysfunction, and bone-related health conditions [1,2]. Extraarticular comorbidities among patients with AIIRD increase disease burden and impair the patients’ quality of life [1]. Impairment in bone health is a common comorbid condition in patients with AIIRD. Bonerelated health conditions such as osteoporosis and osteoporotic fractures are related to increased morbidity and mortality rate among patients with AIIRD. Bone health issues also increase health-care costs in this particular patient group. The present chapter aimed to provide evidence-based knowledge on bone-related health conditions in AIIRD in the context of bone loss/osteoporosis and osteoporosis-related fragility fractures.

2  Prevalence of bone health impairment in AIIRD Bone health impairment is frequently observed in AIIRD [3–6]. Bone loss/osteoporosis, the main topic of the current chapter, is the prototype of bone-related health conditions in this particular patient group. The prevalence of bone mass loss varies among studies depending on the underlying rheumatic disease, patients’ demographics (age, gender, and ethnicity), glucocorticoid use, etc. In patients with systemic lupus erythematosus (SLE) from the Toronto Lupus Cohort, the overall prevalence of abnormal bone mineral density (BMD) was 31.5% [4]. Low BMD was detected in 15% of newly diagnosed pediatric SLE patients [7]. In a large cohort of women with rheumatoid arthritis (RA) (n  =  925), the frequency of osteoporosis was 28.8% and 36.2 at the lumbar spine and femoral neck, respectively. Of the sample, 74 revealed at least one vertebral fracture on lateral spinal radiographs [8]. A systematic review by Omair et al. revealed that the prevalence of low BMD was 27%–53% in systemic sclerosis [6]. The prevalence of low BMD is also high among patients with ankylosing spondylitis (AS), Sjögren’s syndrome, and vasculitides [9–11]. Low BMD was shown to be common among patients with AS even within 10 years of disease onset [10]. The prevalence of vertebral fractures varies in studies depending on the fracture detection method. In a systematic review and metaanalysis by Jin et al., the subgroup analysis based on fracture detection method showed that the pooled incidence rate of clinical vertebral fractures among patients with RA was 4.29 per 1000 person-years [12]. On the other hand, the pooled incidence of vertebral fractures detected by using spinal radiography was 42.4 per 1000 person-years [12]. A retrospective cohort study by Kim et al. found 1.5 times higher incidence rates for osteoporotic fracture at typical sites in patients with RA when compared to those with non-RA patients [5]. In a 100-patient sample with inflammatory myositis (adult dermatomyositis, polymyositis, connective tissue disease-associated myositis, and juvenile onset myositis), 46 patients had asymptomatic vertebral fractures detected on lateral dorsal and lumbar spine radiographs [13].

3  Risk factors for bone loss in AIIRD There are various risk factors for bone health impairment among patients with AIIRD. These can be classified as general risk factors and disease-related risk factors. General risk factors for osteoporosis and osteoporosis-related fragility fractures include (i) increased age, (ii) sex-related factors, (iii) low BMD, (iv) smoking and alcohol consumption, (v) genetic

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­ redisposition, (vi) sedentary lifestyle, (vii) hypovitaminosis D, (viii) bad nutrition, (ix) low p body mass index, and (x) falls. Factors related to AIIRD include (i) increased disease activity, (ii) use of glucocorticoids, (iii) reduced mobility, and (iv) disease-associated comorbid conditions (i.e., sarcopenia, renal failure) [14,15].

3.1  General risk factors for bone loss, osteoporosis and fractures Advanced age is an independent risk factor for osteoporosis and fractures among patients with AIIRD [16,17]. Age-dependent decrease in sex hormones and reduction in mobility are some of the underlying factors for age-related bone loss. On the other hand, increased risk of falls due to balance problems in elderly is related to an increased prevalence of osteoporotic fractures. A study on 104 men with RA revealed that the frequency of reduced bone mass (62%) and osteoporosis (42%) at any measured site (femur neck, trochanter, lumbar total, etc.) is highest in the older group (aged 60–69  years) [18]. In a study on 80 patients with AS, advanced age was found to be associated with vertebral fractures [19]. The same study showed that men with vertebral fracture(s) were significantly younger than female patients with fracture(s) (53.2 ± 10.2 and 63.4 ± 5.8 years, respectively). Besides, all patients who were diagnosed with a vertebral fracture before the age of 50 years were male [19]. This finding indicates the potential importance of sex-dependent factors on the development and progression of osteoporosis and osteoporotic fractures in patients with rheumatic diseases. Hu et al., in their analytical cross-sectional study, evaluated the prevalence and risk factors of bone loss in patients with rheumatic diseases (RA, AS, osteoarthritis, SLE, primary Sjögren’s syndrome, systemic scleroderma, gout, and mixed connective tissue disease) [20]. The researchers found that both young (34.3% vs. 18.2%) and elderly patients (92.7% vs. 87.2%) with rheumatic diseases had a higher prevalence of impaired BMD when compared to healthy controls [20]. This finding is consistent with the current knowledge that patients with AIIRD have higher risk for bone loss than the healthy population. In women with AIIRD, menopause was shown to be a strong risk factor for osteoporosis and related fractures. A study by Ghozlani et al. on a sample of patients with AS demonstrated that all women with a vertebral fracture were in menopause [19]. Hu et al. documented postmenopause as a significant risk factor for osteoporosis [20]. When compared to male patients, female patients revealed higher risk for osteoporosis. The risk was 3.5 times higher in women with former or current chronic glucocorticoid therapy. The risk was more evident (9.3 times higher) among females without glucocorticoid therapy [20]. Although menopause is a proven risk factor for osteoporosis and fractures, osteoporosis and related fragility fractures can be observed in premenopausal women with AIIRD, as well [21]. Yeap et al. evaluated BMD and the risk factors for reduced bone mass among premenopausal patients with SLE who were on corticosteroids [22]. Of the 98 premenopausal patients, 6 (6.1%) had osteoporosis and 41 (41.9%) had osteopenia. Only 52.0% of the patients revealed normal BMD. BMD was significantly correlated with the duration and cumulative dose of corticosteroid intake. Regardless of the menopause status, patients with AIIRD, particularly those on corticosteroid therapy, should be fully assessed and/or screened in terms of osteoporosis and fracture risk [22]. Smoking and alcohol consumption are well-known risk factors for bone health impairment. Fracture Risk Assessment Tool (FRAX) considers current smoking as one of the risk factors for the 10-year probability of hip fracture and the 10-year probability of a major osteoporotic

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fracture (clinical spine, forearm, hip, or shoulder fracture) [23]. Klingberg et al. investigated the prevalence and risk factors for vertebral fractures in patients (57% of being men) with AS. Of the patients, 24 (12%) were current smokers, while 101 (49.5%) were ever smokers (more than 6 months of smoking duration) [24]. The results revealed that the frequency of ongoing smoking was significantly higher in patients with at least one vertebral fracture (25%) when compared to that in patients without vertebral fracture (10%) [24]. The increased risk for osteoporosis and fractures relates to the direct and indirect effects of smoking over bone cells. The indirect effects include alteration in gonadal, calciotropic, or adrenocortical hormone levels (i.e., estradiol, 25-hydroxyvitamin D [25(OH)D], 1,25-OH2-D, cortisol, and dehydroepiandrosterone) [25]. Smoking also drives its detrimental effects through the receptor activator of nuclear factor kappa-B (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) system [26,27]. Three or more units of alcohol (where a unit of alcohol ranges from 8 to 10 g of alcohol in different countries) consumption per day is also regarded as a risk factor for hip and major osteoporotic fractures [23]. Szentpetery et al. investigated the changes in hand BMD in patients with early psoriatic arthritis compared to patients with RA prior to and 3 and 12 months after introducing an antirheumatic treatment [28]. Hand BMD was measured by digital X-ray radiogrammetry (DXR-BMD). Heavier alcohol intake was identified as one of the independent predictors for hand bone loss. The researchers concluded as alcohol might have a negative effect on periarticular bone in patients with inflammatory arthritis [28]. Proper nutrition and consumption of essential vitamins/minerals are important for bone health. In this regard, bad nutrition may contribute to bone loss. There are a number of studies regarding the potential impact of diet/nutrition on bone health among patients with AIIRD [29,30]. Tokumoto et al. retrospectively evaluated the records of 146 patients with RA receiving biological disease-modifying antirheumatic drugs (DMARDs) [30]. The Geriatric Nutritional Risk Index (GNRI) was calculated. Low GNRI was identified as a risk factor for low BMD of the femoral neck (defined as ≤  70% in young adult men) [30]. In their cross-­ sectional study, Chong et al. evaluated daily dietary calcium intake according to a structured validated food frequency questionnaire in 60 premenopausal women with SLE [29]. Patients estimated their food intake based on their last 2-month dietary habits. Median value for daily dietary calcium intake was 483 mg. Of the 60 patients, 8 (13.3%) had more than 1000 mg of daily dietary calcium intake. There was no correlation between daily dietary calcium intake and BMD measured at lumbar spine, femoral neck, and trochanter. This finding remained after adjusting for the cumulative corticosteroid dose and duration of corticosteroid use [29]. Future studies investigating the potential effects of dietary habits/nutrition on bone health among patients with AIIRD are required. The role of hypovitaminosis D in the development of osteoporosis is evident. Chen et al. found that low serum 25(OH)D levels correlated with low BMD, and serum 25(OH)D level was a significant predictor for low BMD among patients with RA [31]. Vitamin D deficiency can contribute to bone health impairment through indirect and direct mechanisms in patients with AIIRD. Vitamin D not only regulates calcium and phosphate hemostasis, but also plays an important role in controlling the inflammatory state and maintenance of muscle strength [32]. A cross-sectional study on patients with SLE revealed an inverse correlation between serum concentration of 25(OH)D and SLE disease activity index 2000 (SLEDAI-2 K) score [33]. A systematic review and metaanalysis by Guan et al. also confirmed that SLE patients with increased disease activity had lower vitamin D levels [34]. Hypovitaminosis D is common in

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patients with AIIRD [32,34,35]. Ben-Shabat et al. in their retrospective cohort study confirmed that serum level of 25(OH)D throughout the follow-up was significantly lower among patients with AS than that in age-, gender-, and enrollment time-matched controls [20.6 (14–26) ng/mL in patients with AS and 21.3 (15–27) ng/mL in controls] [35]. Vitamin D deficiency was found to be associated with several factors such as high disability and low serum total protein level among patients with RA [32]. Vitamin D receptor gene polymorphisms have been suggested as a risk factor for the development of osteoporosis [36,37]. Mosaad et al. identified the Ff genotype as a risk factor for osteoporosis among patients with RA [36]. Patients with osteoporosis revealed significantly higher frequency of the heterozygous genotype Ff of the FokI when compared to patients without osteoporosis [36]. In line with this finding, Yoshida et al. found that rs2282679 in the gene encoding group-specific component (vitamin D binding protein) locus was significantly associated with the occurrence of hip fracture among patients with RA [37]. Low BMD is a major risk factor for fractures in patients with AIIRD [21,24,38,39]. A cross-sectional study on patients with AS showed that patients with vertebral fracture(s) revealed significantly lower BMD at all measuring sites [24]. Ulu et al. evaluated the prevalence and risk factors of osteoporosis and vertebral fractures in patients with AS [39]. Morphometric measurements were performed on thoracic and lumbar X-rays. The presence of compression fractures was found to be significantly and independently associated with low lateral lumbar BMD [39]. In a study on patients with SLE who were on chronic glucocorticoid therapy (more than 6 months), the occurrence of fragility fractures was associated with both vertebral and femoral BMD [21].

3.2  Disease-related risk factors for bone loss, osteoporosis and fractures In addition to general risk factors, there are also disease-related factors that increase the risk of osteoporosis and fractures among patients with AIIRD. These include increased disease activity, glucocorticoids, reduced mobility, along with disease-related comorbid conditions such as sarcopenia and renal failure. Longer disease duration is another risk factor for the development of osteoporosis. Increased disease activity is one of the major determinants of comorbidities/organ involvements in inflammatory rheumatic diseases. Osteoporosis and osteoporosis associated fragility fractures are closely related to increased disease activity. Among patients with AS, higher inflammatory parameters [erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)], higher modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS), Bath Ankylosing Spondylitis Functional Index (BASFI), and Bath Ankylosing Spondylitis Radiology Index (BASRI) scores were determined as risk factors for vertebral body fractures [17,19]. Similarly, Sargın et al. found that disease activity measured by disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR) was significantly negatively correlated with the T- and Z-scores in patients with RA [40]. In the same study, further multiple regression analysis showed that DAS28-ESR, along with anticitrullinated peptide antibody (ACPA) and rheumatoid factor (RF) were risk factors for lower BMD of the femoral neck [40]. Physical disability is another determinant of bone health impairment in patients with AIIRD. Several studies confirmed that disability measures such as Health Assessment Questionnaire (HAQ) were associated with vertebral and/or nonvertebral fractures among patients with RA [41,42].

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Glucocorticoid therapy is a well-known risk factor for osteoporosis and osteoporotic fractures [43]. The risk depends on the duration and dose of glucocorticoid treatment [4,22,44]. Mendoza-Pinto et al. showed that hip BMD was associated with cumulative corticosteroid dose among premenopausal women with SLE [44]. Similarly, Yeap et  al. found that lumbar spine T-score was correlated with cumulative corticosteroid dose, while femoral neck T-score and trochanter T-score were correlated with the duration of corticosteroid intake in patients with SLE [22]. Glucocorticoids impair bone health through direct and indirect mechanisms [43]. Glucocorticoids can directly affect the number and functionality of bone cells [45]. Glucocorticoids activate the caspase 3 pathway and induce the apoptosis of osteoblasts and osteocytes. They also downregulate wingless-related integration site (Wnt) signaling by Diekkopf-1 (Dkk-1) and sclerostin. This action inhibits the stabilization of β-catenin, thereby impairs osteoblastogenesis. On the other hand, glucocorticoids can upregulate peroxisome proliferator-activated receptor-γ2 (PPAR-γ2) signaling and activate adipogenesis in bone tissue. Osteoclastogenesis is also upregulated in patients on continuous glucocorticoid therapy. Decreased OPG expression and increased synthesis of RANKL and macrophage colony-­ stimulating factor (M-CSF) enhances RANKL-RANK interaction on osteoclast lineage cells. Through this mechanism, glucocorticoids increase osteoclast number and function. Indirect effects of glucocorticoid therapy relate to the decrease in insulin-like growth factor-1 (IGF-1) and IGF-1 binding protein levels, down-regulation of sex steroids, impaired renal/intestinal calcium absorption, decreased muscle function and mass [43,45–47]. On the other hand, glucocorticoids, as potent inhibitors of inflammation, may counterbalance their adverse effects on bone hemostasis. In line with this point of view, a systematic review and metaanalysis found no difference in change in BMD at 24-month follow up between early and active RA patients treated with glucocorticoids (prednisone or prednisolone) and placebo [48]. Glucocorticoid therapy provided significant benefits on DAS28. The results of the systematic review and metaanalysis also prove the importance of appropriate disease activity control on bone health in patients with AIIRD [48]. If possible, it is recommended to use glucocorticoids at low doses and for short time when required [49]. Comorbid conditions in patients with AIIRD may impair bone health. For instance, renal involvement during the disease course may lead to chronic kidney disease-related ­mineral-bone disease. Carli et al. found that chronic renal failure was significantly associated with osteoporosis in patients with SLE [21]. In a large cohort study, patients with lupus nephritis revealed 1.6 times higher fracture risk when compared to patients without nephritis [50]. Sarcopenia is a frequent comorbidity in patients with AIIRD [51,52]. A recent review revealed that, depending on the definitions of skeletal muscle mass index, the prevalence of sarcopenia reaches up to 49.0% in patients with psoriatic arthritis, 45.1% in RA, and 54.8% in systemic sclerosis [51]. Along with well-known risk factors including advanced age and low body mass index, chronic inflammation and reduced mobility in patients with rheumatic diseases are associated with the development of sarcopenia. In a study on patients with systemic ­sclerosis, longer disease duration was identified as a risk factor associated with sarcopenia [53]. Since muscle-bone cross talk is important for proper bone health, loss of muscle mass and strength in sarcopenic individuals may lead to a gradual decrease in BMD [54]. A cross-­ sectional study by Mochiziku et al. revealed that sarcopenia was significantly associated with hip BMD among patients with RA [52].

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There are also disease-specific factors that may increase the risk of fractures among patients with AIIRD. In patients with AS, risk factors for vertebral body fractures include male gender, involvement of the peripheral joints, more extensive syndesmophyte formation, spinal restriction of movement, and increased level of bone resorption markers [17,19]. In patients with systemic sclerosis, premature ovarian failure related to cyclophosphamide therapy and gastrointestinal involvement-related malabsorption and low weight increase the risk of osteoporosis [55,56].

4  Pathophysiology of bone loss in AIIRD Bone loss in RA can be systemic or can occur at the joint level (local bone loss). In periarticular osteopenia, bone trabeculae decrease both in number and in dimension. Cortical bone thinning is observed at the insertion of the inflamed synovium. There is mechanistic overlap between local bone loss and systemic bone impairment [57]. Immune/inflammatory pathways, which characterize the pathophysiology of AIIRD such as RA, spondyloarthropathies and SLE, are associated with bone metabolism and bone loss. There are several drivers of this association [58–60]. There is a crosstalk between immune cells and cells of bone tissue. Key cellular players of bone-immune system crosstalk are hematopoietic stem cells, bone marrow macrophages, T cells, B cells, osteoblasts, osteoclasts, osteomacs, dendritic cells, and neutrophils [61]. This crosstalk is mediated by numerous factors including proinflammatory cytokines (i.e., tumor necrosis factor α [TNF-α], interleukin [IL]-1, IL-6, IL-17, and IL-23), costimulatory molecules as well as signaling pathways in which RANK, RANKL, OPG, M-CSF, and Wnt signaling play important roles [59]. Systemic inflammation and cytokine release are related to lower BMD and microstructural changes in bone tissue. A cross sectional study by Zhu et al. revealed that serum levels of IL-6, IL-1β, IL-12p70, and TNF were negatively correlated with biomechanical indices, cortical microstructural indices, and/or cross-sectional geometry (i.e., cortical area fraction, cortical moment of inertia) among male patients with RA [60]. In addition, IL-6 and IL-12 showed negative correlation with total volumetric BMD [60]. Bone cells including osteoclasts, bone-lining cells, osteoblasts, and osteocytes play important role in the maintenance of a balanced remodeling process in bone tissue. This process becomes unbalanced in patients with AIIRD. Among bone cells, osteoclasts are the key cells in the development of local and systemic bone loss [57,59]. This role depends on the osteoimmunological network of osteoclasts with other cells such as osteoblasts, osteocytes, activated T cells, activated B cells, and synovial fibroblast-like cells [59]. M-CSF-1 and RANKL are the main differentiation factors for osteoclasts, interacting with colony-stimulating factor-1 receptor (CSF-1R, also known as c-FMS) and RANK receptor on osteoclast precursors, respectively [57,61]. On the other hand, OPG produced by osteoblasts and B lymphocytes inhibits osteoclast differentiation, thereby serves as a protector of bone tissue [61]. Proinflammatory cytokines such as TNF-α and IL-1 can directly increase the expression of osteoclast-­associated receptor (OSCAR), an important costimulatory molecule in osteoclastogenesis. They can also induce the expression of RANKL. Receptor activator of nuclear factor-kappa B ligand can be expressed not only on osteocytes and bone lining cells/osteoblasts but also on ­activated T lymphocytes and synovial fibroblasts [57,58,62]. T helper 17 cells further induce the p ­ roduction of

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RANKL by fibroblast like synoviocytes (FLS) [63]. In patients with AIIRD, RANKL produced by synovial fibroblasts of inflamed joints is responsible for periarticular osteopenia, while RANKL secreted from inflammatory cells (i.e., T cells) through stimulation by proinflammatory cytokines drives systemic bone loss. Compared to CD28+ T cells, circulating senescent CD4+  CD28− T cells express higher levels of RANKL [57,64]. Monocytes, as the precursors of macrophages, are one of the main drivers of inflammation [63,65]. They are mainly bone marrow derived cells in the circulation. Monocytes subsets with CD14+ expression can differentiate into osteoclasts [63]. Komano et  al. in their study demonstrated that osteoclasts originated from CD16− monocytes, but not form the CD16+ monocyte subset, and integrin β3 was necessary for osteoclastogenesis [66]. When stimulated with RANKL and M-CSF, integrin-β3 mRNA and the integrin-αvβ3 heterodimer were selectively expressed on CD16− monocytes [66]. Since monocytes serve as precursors of osteoclasts, they play a big role in bone loss among patients with AIIRD. Both the numbers and the proportions of intermediate monocytes (IMs) and nonclassical monocytes are higher in patients with RA. Decreased expression of zinc-finger protein A20 on nonclassical monocytes in RA was suggested as an accelerator of RANKL-induced osteoclastogenesis [65]. In addition to ­osteoblast-osteoclast crosstalk, osteocytes—the descendants of osteoblasts—also play important role in bone remodeling. Osteocytes embedded within the bone matrix can affect osteoblast and osteoclast formation through the release of sclerostin, RANKL, and Dickkopf-1 (DKK1). Continuous stimulation of osteocytes by proinflammatory cytokines in patients with AIIRD increases the RANKL/OPG ratio and thereby induces osteoclastogenesis [67]. On the other hand, cytokines can inhibit transcription factors Runx2/Cbfa and osterix, which are essential regulators of osteoblast differentiation [59]. In addition, enhanced expression of DKK1 and sclerostin by osteocytes also downregulates osteoblastogenesis [67]. Dickkopf-1, along with sclerostin, is a natural inhibitor of Wnt signaling [68]. Wnt/β-catenin signaling enhances the differentiation of mesenchymal stem cells in osteoblasts, while suppressing the chondrogenic and adipogenic differentiation. In addition, Wnts inhibit osteoclast activation by triggering the secretion of OPG [69]. Rossini et al. found that serum levels of DKK1 were increased among patients with RA when compared to healthy controls [68]. In addition, DKK1 level showed significant correlation with serum parathyroid hormone. When DKK1 levels were adjusted for age and parathyroid hormone, they showed negative correlation with total hip BMD. Furthermore, DKK1 level was positively correlated with serum levels of carboxy-terminal crosslinked telopeptide of type 1 collagen (CTX-1) among RA patients who were not receiving bisphosphonates [68]. This finding indicates the role of Dickkopfs on bone loss and osteoporosis in patients with AIIRD. Secreted frizzled-related proteins (sFRPs), composed of five secreted glycoproteins in mammals, also modulate the activation of Wnt signaling pathways. When the concentration of sFRPs is very high, they prevent Wnt ligand binding the frizzled receptor, turning the Wnt pathway signaling off. Therefore, upregulation of sFRPs (sFRP1, in particular) in AIIRD may lead to bone loss and local bone erosion. It should also be noted that sFRP1 also acts independently of Wnt/b-catenin pathway and has the potential to decrease bone resorption by binding to RANKL [69]. Apart from their osteometabolic effects, certain cytokines released as part of the innate or adaptive immune response are potent activators of hypothalamic-­pituitary-adrenal axis [59,70]. Immunomodulation of the human hypothalamic-pituitary-­adrenal axis by cytokines such as IL-6 can contribute to bone loss through the increased release of glucocorticoids [59,70–72].

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5  Evaluation and management of bone loss/osteoporosis in patients with AIIRD Evaluation of bone loss/osteoporosis in patients with AIIRD includes anamnesis, clinical examination of the patient, assessment of fracture risk, BMD measurement by dual energy X-ray absorptiometry (DXA), vertebral fracture assessment, and laboratory measures including bone turnover markers (Table 1). Anamnesis should focus on the history of the underlying AIIRD, medications, dosage, and duration of glucocorticoid therapy, comorbidities (renal

TABLE 1  The assessment of bone loss/osteoporosis in patients with AIIRD. Anamnesis

− − − − − − −

History of the underlying AIIRD Medications (including dosage and duration of glucocorticoid therapy) Comorbidities (renal involvement, hepatic diseases, etc.) Lifestyle factors (i.e., dietary habits, smoking, alcohol use, physical activity level) History of falls Previous fragility fracture history Parent history of osteoporosis and/or osteoporotic fractures

Clinical examination

− − − −

Body height, body weight and body mass index Systemic examination Musculoskeletal examination (including postural analysis) Assessment of balance

Imaging investigationsa

− DXA − Spinal radiographs − Further imaging interventions if required (MRI, heel QUS, etc.)

Laboratory investigationsa

− Inflammatory and immune markers − Hemogram − Hepatic and renal function tests − 25(OH)D − Calcium, inorganic phosphate, albumin − Thyroid function tests and parathyroid hormone level − Urine tests (i.e., urine calcium level, urine creatinine level, urinary calcium/ creatinine ratio) − Bone biomarkers (i.e., bone formation markers; osteocalcin, total ALP, BALP, P1NP P1CP and bone resorption markers; CTX-1, NTX-1, hydroxyproline, hydroxylysine, deoxypyridinoline, pyridinoline, bone sialoprotein, osteopontin, cathepsin K, TRAP 5b)

Assessment of fracture risk

− Patient history (previous fractures, parents’ fracture history, historical height loss, fall history, comorbidities, medications, etc.) − Fracture Risk Assessment Tools (i.e., FRAX) − DXA (BMD measurement ± TBS) − Vertebral fracture assessment (by DXA and/or spinal radiographs)

a

Investigations should be tailored and/or diversified based upon each patient’s underlying rheumatic disease, comorbidities and other clinical features. DXA, dual energy x-ray absorptiometry; MRI, magnetic resonance imaging; QUS, quantitative ultrasound; 25(OH)D, 25-hydroxyvitamin D; FRAX, Fracture Risk Assessment Tool; BMD, bone mineral density; ALP, alkaline phosphatase; BALP, bonespecific alkaline phosphatase; P1NP, procollagen type 1 N-terminal propeptide; P1CP, procollagen type 1C-terminal propeptide; CTX-1, carboxy-terminal crosslinked telopeptide of type 1 collagen; NTX-1, amino-terminal crosslinked telopeptide of type 1 collagen; TRAP 5b, tartrate-resistant acid phosphatase 5b

17



2.  Bone Health in autoimmune inflammatory rheumatic diseases

involvement, hepatic diseases, etc.), lifestyle factors (i.e., dietary habits, smoking, alcohol use, physical activity level), history of falls, previous and/or current fragility fracture history, parent history of osteoporosis, and/or osteoporotic fractures. Physical examination of the patient should include systemic and musculoskeletal evaluation. Postural abnormalities (i.e., thoracic kyphosis), body height and body weight should be evaluated. Clinical assessment of fracture risk is of great value in this patient group. In all adults and children receiving glucocorticoids (prednisone at >  2.5 mg/day for ≥  3 months), the American College of Rheumatology (ACR) recommends initial clinical fracture risk assessment as soon as possible, at least within 6 months of the initiation of treatment [73]. There are also tools used for future fracture risk estimation. For instance, FRAX tool can be used in adults aged between 40 and 90 years in order to estimate 10-year probability of hip and major osteoporotic fractures [23]. However, it should be noted that FRAX tool does not consider number of fractures, fall risk and fall history, rheumatic disease activity, and disability level [49]. Therefore, comprehensive evaluation of patients to identify other potential clinical risk factors for future fractures would be of benefit. In patients receiving glucocorticoids at a dose of ≥  7.5 mg/day, adjustment of fracture risk generated with FRAX is recommended; the unadjusted hip and major osteoporotic fracture probabilities should be increased by 20% and 15%, respectively [74]. Diagnosis of bone loss/osteoporosis in patients with AIIRD is based upon BMD measurement by DXA. Central DXA, which measures bone density of the hip and posteroanterior spine, is used as a screening tool and as a measure to evaluate treatment response. Forearm DXA can be used in patients with hyperparathyroidism, those weighing above the limit of DXA machine and when hip and/or spine cannot be measured or interpreted [75]. The International Society for Clinical Densitometry (ISCD) latest official positions for adults recommended BMD testing among women aged 65 years and older [75]. The committee also recommends BMD testing for postmenopausal women younger than age 65 who have a risk factor for low bone mass. Testing for BMD is required for men aged ≥  70  years. For men younger than 70 years of age, bone density test is recommended if they have a risk factor for low BMD. Diseases and conditions related to bone loss are stated as a risk factor [75]. In patients receiving glucocorticoids (prednisone at >  2.5  mg/day for ≥  3  months) and aged ≥  40 years, BMD testing is recommended as soon as possible, at least within 6 months of the initiation of treatment. For adults aged −2.0 are defined as “within the expected range for age” [75]. A study on patients with SLE showed that only 50% of patients with fragility fractures had a low first BMD reported [4]. This finding highlights the importance of serial BMD measurements among patients with AIIRD. The ISCD recommends using serial BMD testing [along with clinical fracture risk assessment, bone turnover markers, and other factors including height loss and trabecular bone score (TBS)] to initiate antiosteoporotic therapy in untreated individuals, to evaluate response to therapy in treated patients, and to monitor individuals after cessation of treatment [75]. Clinical assessment of fracture risk can be potentialized by the evaluation of TBS, which is an index derived from a computer

18



İlke Coşkun Benlidayı

analysis of lumbar spinal DXA [57]. This index has been proposed as a complementary tool in combination with FRAX and BMD to adjust FRAX-probability of fracture in postmenopausal women and older men [75]. Vertebral fracture assessment provides a comprehensive risk estimation for future fractures in patients with bone loss/osteoporosis [76]. Prevalent fractures in patients with AIIRD incur high risk for future fractures [77,78]. A study on patients with inflammatory myositis revealed that individuals with previous vertebral fractures had higher risk of developing subsequent fractures [77]. This finding highlights the importance of baseline vertebral fracture assessment. The ISCD recommends vertebral fracture assessment when T-score is below 1 SD and at least one of the following factors is present: (i) females at the age of 70  years or older, (ii) males at the age of 80 years or older, (iii) historical height loss more than 4 cm (>  1.5 in.), (iv) self-reported but undocumented previous fracture of the vertebra, and (v) at least 3 months of glucocorticoid treatment (equivalent to ≥  5 mg/day of prednisone or equivalent) [75]. Vertebral fracture evaluation can be performed by densitometry or by using lateral spinal radiographs. Lee et al. compared the diagnostic accuracy of densitometric vertebral fracture assessment with that of conventional spinal radiography for detection/identification of vertebral fractures [79]. Densitometric vertebral fracture assessment revealed moderate sensitivity and high specificity for detecting vertebral fractures when compared to spinal x-ray [79]. A metaanalysis by Malgo et al. identified that the pooled sensitivity of densitometric vertebral fracture assessment to detect an individual with a vertebral fracture ≥  Genant grade 2 was 0.84 [80]. The Genant’s semiquantitative technique can be used to assess vertebral fractures on conventional radiographs [75,81]. In this visual semiquantitative assessment technique, grade 0 refers to normal shaped vertebra, grade 1 represents mildly deformed vertebra with an approximately 20%–25% reduction in anterior, middle, and/or posterior height and 10%–20% reduction in area, grade 2 covers moderately deformed vertebra with an approximately 25%–40% reduction in any height and 20%–40% reduction in area, and grade 3 represents severely deformed vertebra (approximately 40% reduction in any height and area). An additional grade (grade 0.5) can be assigned to a borderline deformed vertebra [81]. Laboratory investigations such as hemogram, hepatic and renal function tests, serum 25(OH)D, calcium, inorganic phosphate, albumin, and alkaline phosphatase level, thyroid function tests, CRP, ESR, plasma parathyroid hormone, urine calcium, and creatinine level would be beneficial in excluding comorbidities (e.g., renal failure) and/or other metabolic bone diseases (e.g., osteomalacia). Evaluation of baseline hepatic and renal functions is also important in treatment decision-making in patients with bone loss/osteoporosis. Bone biomarkers would be of value in early assessment of patients along with BMD testing via DXA, as well as in monitoring antiosteoporotic treatment efficiency. It is postulated that BMD testing by DXA may be overestimated due to osteoproliferation in patients with advanced AS and Z-scores of bone turnover markers can be used for a more accurate assessment of bone loss [82]. Bone formation markers are osteocalcin, total alkaline phosphatase, bone-specific alkaline phosphatase (BALP), procollagen type 1 N-terminal propeptide (P1NP), and procollagen type 1 C-terminal propeptide (P1CP). On the other hand, bone resorption markers include CTX-1, amino-terminal crosslinked telopeptide of type 1 collagen (NTX-1), hydroxyproline, hydroxylysine, deoxypyridinoline, pyridinoline, bone sialoprotein, osteopontin, cathepsin K, and tartrate-resistant acid phosphatase 5b (TRAP 5b) [83]. The laboratory test can be further diversified on an individual basis.

19



2.  Bone Health in autoimmune inflammatory rheumatic diseases

Prevention and/or treatment of bone loss/osteoporosis among patients with AIIRD comprise patient education, lifestyle modifications, optimization of vitamin D level, prevention of falls, appropriate control of rheumatic disease activity, and antiosteoporotic drug therapy. Lifestyle modifications for the prevention and/or treatment of bone-related health conditions include proper nutrition, quitting smoking, avoidance of excessive alcohol intake, and ensuring optimal level of physical activity. Proper intake of bone-healthy ingredients such as protein, calcium, vitamin D, magnesium, potassium, vitamin C, omega-3 fatty acids, and vitamin K is important. In this regard, patient education is an essential component of disease management. A randomized controlled trial by Stark et al. examined the effectiveness of behavioral intervention to increase calcium intake and bone mass among children with juvenile RA [84]. Information regarding nutrition and child behavior management strategies was given to parents. Children were provided with the importance of high‑calcium foods and given practice meals to help them achieve daily calcium intake goals. Six-session behavioral intervention was found to be effective in increasing calcium intake and bone mineral content over a 12-month period [84]. In terms of physical activity/exercising, weight-bearing activities such as jogging, running, dancing, jumping rope, muscle-strengthening exercises by using free weights, exercise bands, and weight machines is beneficial [85]. Appropriate preventative measures include assessment of home-safety, balance exercises, visual correction if required, careful monitoring of antihypertensive medications and central nervous system depressants [85]. Given the important role of immune/inflammatory pathways and related proinflammatory cytokines/chemokines in bone hemostasis, appropriate control of the underlying AIIRD is essential in the management and/or prevention of bone impairment in this particular patient group [49,86]. It is also important to keep serum 25(OH)D at optimal levels. Replacement therapy should be tailored to patients with vitamin D deficiency or insufficiency [49]. Pharmacological treatment of bone loss/osteoporosis should not only be based upon BMD testing, but several factors such as patient’s age, gender, menopause status, dose and duration of glucocorticoid therapy, prevalent fracture(s), and comorbid conditions should be considered meticulously. Patient preferences should also be incorporated into pharmacological management plan [87]. National Osteoporosis Foundation’s guideline to the prevention and management of osteoporosis recommends counseling in terms of adequate intake of calcium and incorporating dietary supplements when needed [85]. Patients should also be advised in terms of proper intake of vitamin D, including supplements when required [85]. The latest clinical practice guideline by the European Society of Endocrinology also suggests that calcium and vitamin D can be used as an adjunct to antiosteoporotic treatment in postmenopausal women [87]. For postmenopausal women and older men on bone-protective therapy, the United Kingdom National Osteoporosis Guideline Group recommends calcium supplementation if the daily dietary intake is ĂͿ

/EEd /DDhE Wd,tz

sĂƐĐƵůŝƟƐ ;EͿ

Wd/s /DDhE Wd,tz

FIG. 1  Spectrum of the autoimmune rheumatic diseases and their predilections of either innate or adaptive immune pathways with their autoantibodies. Their immune pathways may overlap and hence lead to some similarities in their clinical phenotypes including treatment response and auto-antibody productions. ACA, anticentromere antibody; ACPAs, antibodies to citrullinated protein antigens; ARA, anti-RNA polymerase III antibody; ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibody; Anti-dsDNA, antidouble-stranded DNA; Anti-ATA, antitopoisomerase antibody; sJIA, systemic juvenile idiopathic arthritis; SLE, systemic lupus erythematosus; SpA, spondyloarthritis; SSc, systemic sclerosis; MSAs, myositis specific antibodies; RA, rheumatoid arthritis; RF, rheumatoid factor.

Majority of AIRDs predominantly involve adaptive immune system, but there is also involvement of innate immunity, as illustrated in Fig. 1 [1]. Autoimmune rheumatic diseases (AIRDs) can emerge at any stage of life, but there is a gender and age predilection for different types of AIRDs. Majority of AIRDs typically affect the young adults, particularly women in their childbearing age. Due to the chronicity of the disease, affected individuals often experience incapacitating symptoms, organ damage, reduced work productivity, and high medical expenses. These various rheumatic diseases have their own unique manifestations with underlying distinct immunopathogenesis such as erosive arthritis in RA, organ and vascular fibrosis in SSc, and axial joint inflammation in SpA. However, their clinical manifestations and immune pathways may overlap as they do share some gene loci [2,3]. Fig. 1 illustrates the predominant immune pathways of either innate or adaptive immunity in various AIRDs. Pathogenesis of AIRDs encompasses a complex interaction between multiple genes with various other factors to initiate a multifaceted immune cascade that subsequently lead to autoimmunity. With the advancement of whole genome sequencing (GWS), several pathogenic deoxyribonucleic acid (DNA) sequence variants have been identified to be associated with autoimmune diseases. This includes variation across the major histocompatibility complex (MHC) locus, which contains the human leukocyte antigen (HLA) genes and single nucleotide polymorphisms (SNPs) [4]. Genetically susceptible individuals interact with intrinsic factors such as hormones [5] and external triggers such as environmental insults [6], infections [7] and gut ­microbiomes [8], which 28



Syahrul Sazliyana Shaharir and Asrul Abdul Wahab

Infecon Environment: Smoking Air polluon Ultraviolet Organic and inorganic chemical e.g., silica, dust, solvent, pescides

Hormones

Microbiome

Vitamin D Diet

Genecs & Epigenec

↓Treg

↑Pro-inflammatory ↑TH17

Autoimmune Rheumac Diseases (AIRDs) FIG.  2  Complex interactions between various endogenous and exogenous factors in a genetically susceptible individual that disrupt the immune hemostasis and cause autoimmunity.

lead to disruption of the immune hemostasis and enhancement of inflammatory response [9]. Fig. 2 illustrates various triggers and factors in the pathogenesis of AIRDs. The role of epigenetics is increasingly recognized in the pathogenesis of AIRDs. They are reversible DNA and chromatin modifications without alteration in DNA sequence, which can affect the gene expression [10]. This process can be activated by external factors such as infection and environmental insults. Epigenetics modifications are inheritable and their mechanisms include DNA methylation, histone proteins modifications, and changes in gene expression by microRNA (mRNA) and other noncoding ribonucleic acid (RNA). It is probably a binding gap between the various external insults and the genetic factors in developing AIRDs [11]. Indeed, the efforts to decipher the pathogenesis of AIRDs are relentless. This chapter summarizes some of the key pathogenesis of AIRDs and the implications of the fundamental immune-­ pathogenesis in clinical practice including their clinical features, serology, and treatment.

2  Pathogenesis of autoimmunity in rheumatic diseases (AIRDs) Autoimmunity is the hallmark pathogenesis of rheumatic diseases and it involves the activation of the adaptive immune system, including both T and B cells that recognize self-­antigens, as well as the innate immune system such as macrophages and dendritic cells (DCs). This complex immune cascade is initiated by the factors as explained above and illustrated in Fig. 2. 29



3.  Rheumatic diseases: From bench to bedside

Autoimmunity occurs when there is a breakdown in self-tolerance against self-antigens. Normal physiological tolerance mechanism is crucial to maintain immune hemostasis and to prevent self-destructive immune reactions. This process occurs centrally in bone marrow and lymph nodes for B cells and thymus for T cells during thymic education. The autoreactive B and T lymphocytes with receptors specific for self-antigens undergo negative selection and are deleted at an early stage in lymphoid cell development. Meanwhile, positive selection allows T cell receptors with the correct antigen signals to receive survival signals and to be released to the periphery. Some of the autoreactive T cells differentiate into T regulatory cells (Tregs), which are also released to the periphery. If the central tolerance process is incomplete and self-reactive lymphocytes manage to escape into the periphery, peripheral tolerance will ensure the continuity of tolerance process. Formation of autoreactive B cells may also occur in the periphery if there is a presence of autoantigens. Peripheral tolerance process will take place through various mechanisms such as clonal deletion, anergy (unresponsiveness of T cells or B cells due to the absence of a required costimulatory signal in the presence of the antigen-specific stimulus), ignorance or immunoregulation by Tregs [12,13]. Several inhibitory molecules (such as CTLA-4, PD-1, LAG-3, TIM3, VISTA, TIGIT, FcγRIIb, and certain Siglec proteins), which are expressed on the surface of T cells and B cells play major role in inhibiting exaggeration of the normal and antiself-­ immune responses [12]. Defects on these mechanisms lead to activation of the immunological cascades causing autoreactive lymphocytes and their autoantibodies to act against the organism’s self-antigens. Fig. 3 summarizes the normal central and peripheral tolerances and the mechanisms of the breakdown in self-tolerance. The breakdown of self-tolerance and induction of autoimmunity by the triggering factors described earlier in Fig. 2 occur through various mechanisms such as molecular mimicry or cross-reactivity [14], aberrant apoptosis [15], formation of neoantigens and autoantigenesis [16,17], and dysregulation of the innate and adaptive immune response [18].

2.1  Molecular mimicry Molecular mimicry is classically associated with infection as some bacteria and viruses contain antigens that are identical to the host. This term was formally coined by Damian in 1964, which denotes similarities of the antigens by the infectious agents and their human host [19] after few evidence of such phenomenon through demonstration of cross-reactivity of group A streptococcal cells to human heart tissue in patients with rheumatic fever [20]. Since then this concept has evolved into one of the fundamental pathogeneses of AIRDs. There are four criteria for identification of molecular mimicry causing autoimmunity, which include [14]: (1) Evidence of homology between host epitopes and an epitope of the microorganism. (2) Detection of autoantibodies or autoreactive T cells or B cells against both epitopes in humans and the microbes. (3) Epidemiological link between the exposure to the environmental agent and the development of autoimmunity. (4) Reproducibility of autoimmunity in an animal model. Except for Campylobacter jejuni infection in Guillain-Barre syndrome [21] and bovine milk protein butyrophilin in the development of MS [22], these prerequisites criteria are

30



Syahrul Sazliyana Shaharir and Asrul Abdul Wahab

THYMUS MARROW Y

aT

Y

aT

aB

aB

Receptor eding

Y

B

Deleon

Deleon

Y

B

Y

aT

Differenaon Treg

-

+

aB

Inhibitory molecules Apoptosis/ anergy Ignorance Suppression (by Treg)

-

Molecular mimicry Neo-angens & autoangens Aberrant apoptosis Dysregulaon immunity

AUTOIMMUNITY aT=auto-reacve T cells aB=auto=reacve B cells Treg= T-regulatory cells

FIG. 3  Normal central and peripheral tolerance and the mechanisms of breakdown in self-tolerance. Autoreactive B and T cells undergo negative selection centrally in thymus and bone marrow. However, some may escape into peripheries and presence of autoantigens or various mechanisms such as molecular mimicry and aberrant apoptosis may also produce new auto-reactive cells. Peripheral tolerance will act by suppressing the autoreactive cells through T-regulatory cells, inhibitory molecules, ignorance and anergy. The peripheral tolerance may also be compromised by the presence of the various triggers and mechanisms as mentioned earlier.

very difficult to be proven in AIRDs. Majority of the studies in AIRDs only proved the presence of associations with the infectious agents as summarized in Table 1. These infections induce self-reactive B or T cells, which may escape from the thymus deletion (central tolerance) into the periphery. Therefore, even when the infection has resolved, these remaining memory T cells may attack the host tissue that express the similar antigens, leading to autoimmunity.

31



3.  Rheumatic diseases: From bench to bedside

TABLE 1  Infectious agents associated with the pathogenesis of autoimmune rheumatic diseases (AIRDs). Infectious agent

Autoimmune rheumatic disease

Virus Epstein-Barr virus

SLE [23], RA [24], JIA [25], Sjögren [26], Behcet’s [27]

Hepatitis B

Polyarteritis nodosa [28], RA [29]

Hepatitis C

Behcet’s [27], Polyarteritis nodosa, Cryoglobulinemic vasculitis [30], Sjögren [31]

Cytomegalovirus (CMV)

Behcet’s [27], SLE [32], Systemic sclerosis, Vasculitis, RA [33]

Human T-cell leukemia virus (HTLV-1)

SLE, RA, Sjögren [34]

Human Immunodeficiency Virus (HIV-1)

SLE [32], Polyarteritis nodosa [33]

Herpes simplex virus (HSV-1)

Behcet’s [27]

Parvovirus B19

Behcet’s [27], SLE [32], RA [35]

Bacteria Streptococcus sp.

Behcet’s [27]

Porphyromonas gingivalis

RA [36]

Proteus mirabilis

RA [37]

Escherichia coli (E. coli)

Behcet’s [27], RA [38]

Enteropathic and urogenital microbial: Campylobacter, Salmonella, Shigella, Yersinia sp, Chlamydia sp.

Spondyloarthritis, reactive arthritis [39]

Klebsiella sp.

Ankylosing spondylitis [40]

Saccharomyces

Behcet’s [27]

Helicobacter pylori

Behcet’s [27]

Mycobacterial

RA [41], Behcet’s [27]

JIA, Juvenile idiopathic arthritis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.

Molecular mimicry or cross-reactivity of certain dietary antigens and proteins may also induce autoimmunity [42]. The classical examples include consumption of cow’s milk at infancy that may induce T1DM [43], and wheat proteins or gluten in celiac disease [44]. However, the evidence of direct pathogenic role of dietary antigens in AIRDs is not well established, but there are emerging attentions on their immunomodulatory effects in patients with AIRDs. Food antigens that are implicated in autoimmunity include glycine-rich food proteins (GRPs) that are commonly found in meat, chicken, egg, fruits, vegetables, seeds, cereals, rice, soy protein, and gelatin [42]. Enhancement of the B and T cell immune responses by the peptides from GRPs are demonstrated in several AIRDs such as SLE and RA [45]. Increased levels of intestinal food antibodies against antigens originated from cow’s milk, cereals, eggs, cod, and pork were found in RA patients [46]. A more recent study has developed a new comprehensive database of dietary-human autoimmune epitope overlap (Gershteyn-Ferreira index), 32



Syahrul Sazliyana Shaharir and Asrul Abdul Wahab

which revealed a new link between autoimmune diseases in humans and the consumption of foods, particularly pork [47]. However, the majority of the clinical studies involving patients with AIRDs are limited by the small sample size; hence, further research is needed in determining the direct causative effect of dietary antigens in AIRDs. Exposure to some drugs and chemicals particularly pesticides and other toxic metals (e.g., mercury, plumbum, silica) may also induce autoimmunity as they may display molecular mimicry [48] or ionic mimicry [49]. Up to date, there are many agents that have been recognized to induce autoimmunity through molecular mimicry and a recent database called miPepBase (Mimicry Peptide Database) provides a comprehensive information about physicochemical properties of protein and mimicry peptides [50].

2.2  Apoptosis and secondary necrosis from apoptosis Apoptosis or programmed cell death is a normal physiological immune response to regulate tissue growth. Apoptotic cells undergo a systematic and highly regulated clearance process, which are mediated primarily by macrophages, DCs, and other cells such as endothelial cells, mesenchymal cells, and cardiocytes [51]. This process is crucial in order to prevent outflow of the intracellular content, which contain autoantigens that potentially elicit unwarranted immunological response toward host, which is the hallmark of autoimmunity. The release of autoantigens from the apoptotic cells will further activate the adaptive immune response through antigen presenting cells (APCs). This subsequently leads to T cell and B cell stimulations with autoantibody production. The first evidence of the role of necrotic cells as an initiator of autoimmunity was demonstrated in the early 1930s. In the study, antibrain antibodies were induced among rabbits who were immunized with homologous brain suffering from spontaneous necrosis [52]. SLE is one of the AIRDs that have been strongly associated with impaired clearance of the apoptotic cells ever since it has been shown that nucleosomes released from the necrotic cells could stimulate the production of anti-DNA antibodies in murine models [53]. Subsequent studies have demonstrated that SLE patients have impaired macrophages to engulf apoptotic neutrophils [54–56]. Meanwhile, the C1q/calreticulin/CD91-mediated apoptotic pathway has reduced ability to recognize and remove apoptotic neutrophils [57]. The accumulated apoptotic cells then undergo secondary necrosis, which leads to the exposure of the autoantigens and release of cellular contents, which can induce autoimmunity. Neutrophils extracellular traps (NETs), a specialized cell death form in neutrophil, is considered as a major source of modified and/or externalized autoantigens in SLE and also in other AIRDs such as vasculitis [58]. Ultraviolet (UV) light exposure is one of the important triggers of AIRDs such as SLE, dermatomyositis, and Sjögren’s disease as they may cause oxidative damage to DNA, lipids, and proteins and can ultimately induce apoptosis [59]. Other chemicals and toxicants may also induce autoimmunity by similar mechanism [16].

2.3  Neoantigens or autoantigens formation Neoantigens and autoantigens are formed due to the changes that arise in self-proteins in the cells. The changes of self-proteins are mediated by posttranslational modifications (PTMs). This process can occur spontaneously or by chemical or enzymatic modification in various

33



3.  Rheumatic diseases: From bench to bedside

protein targets in the surfaces and within cells or in extracellular spaces. Environmental insults such as smoking, organic and inorganic dust, air pollution, and chemicals may induce autoimmunity through the formation of neoantigens and autoantigens by binding of the toxic chemicals to the tissue, causing altered protein structure [16]. The neoantigens and autoantigens will subsequently break the tolerance and activate the adaptive immune system. Organic solvents such as dry cleaning (e.g., tetrachloroethylene), paint thinner (e.g., toluene, turpentine), nail polish removers, glue solvents (acetone, methyl acetate, ethyl acetate), spot removers (e.g., hexane, petrol ether), detergents (citrus turpenes), perfumes (ethanol), nail polish, and chemical synthesis have been associated with the development of various autoimmune diseases [60].

2.4  Dysregulation of innate and adaptive immune system in autoimmunity Aberrant in both innate and adaptive immune response is the major contribution to the development and perpetuation of the AIRDs. These abnormalities can be found in the complement activation, inflammasome activation, macrophage dysfunction, and abnormal activation of T- and B-lymphocytes. Complement system plays very important role in immune responses not only in innate immune system, but also in linking the innate and adaptive immune systems. The abnormalities in the component of complement system have been shown to result in autoimmune condition [61]. Deficiency in C1q component for example predisposed the individual to develop SLE. C1q complement is shown to repress the expression of the inflammasome such as nucleotide-binding oligomerization domain (NOD)-like receptor family, pyrin domain containing 3 (NLRP3) in the macrophages and serves as an inhibitor to type I IFN response in DCs [62]. C5a and its receptors (C5aR) also play significant role in the pathogenesis of RA and psoriatic arthritis. The synovial of both RA and psoriatic arthritis has been shown to have an increased number of C5aR + macrophages and neutrophils with higher concentration of C5a than the normal synovia [63]. Thus, the abnormalities in complement system in different ways contribute significantly to the development of autoimmune diseases. Activation of the inflammasome is another important aspect of the autoimmune pathogenesis. The inflammasome refers to the complex molecules that are able to activate an enzyme known as caspase-1. The example of such inflammasome includes NLRP3 (NLR Family Pyrin Domain Containing 3). Caspase-1 is the enzyme responsible for the activation of the proinflammatory cytokines such as Interleukin-1 (IL-1) and Interleukin-18 (IL-18) [62]. Caspase-1 can also be activated by NETs, which is released from the low-density granulocytes. NETs result in immune complex formation and type-1 IFN in SLE (63). Similarly, inflammasome activation and caspase-1 activity are shown to be involved in the development of fibrosis in systemic sclerosis as well [64]. Innate immune cells such as macrophages and natural killer (NK) cells contribute to the development of autoimmune diseases. Macrophages can be divided into 2 populations namely M1 and M2. M1 is mainly participate in the active inflammatory process by producing the proinflammatory cytokines, while M2 is mainly involve in the resolution of inflammation by releasing mediators for tissue remodeling and angiogenesis. The imbalance of M1 and M2 ratio is one of the key factors in the pathogenesis of RA [65]. In SLE, the macrophages role is ­ineffective at clearing the apoptotic cells, while the involvement of the macrophages in systemic sclerosis is mainly related to the fibrosis formation in the skin and pulmonary tissues [66]. 34



Syahrul Sazliyana Shaharir and Asrul Abdul Wahab

The abnormalities in B- and T-lymphocytes in adaptive immunity contribute significantly to the development of autoimmune diseases. The B-lymphocytes plays an important role in the production of autoantibodies, while the imbalance between T-helper 17 (Th17) and Treg cells also contribute to autoimmunity. Th17 causes autoimmunity while Treg inhibits autoimmunity. Mechanisms that lead to the imbalance of Th17 and Treg include abnormal T cell receptor (TCR) caused by deficiency or mutation of TCR signaling components, abnormalities in costimulatory and coinhibitory signals, and aberrant cytokines signaling [67]. Thus, many abnormalities in the immune response contribute to the development of autoimmune diseases. In any particular condition, these factors are not mutually exclusive and different mechanisms can overlap with each other leading to the autoimmune condition. Fig. 4 illustrates the role of both innate and adaptive immune pathway in AIRDs. An-pDC (BIIB059)

Impaired innate immunity

Infecon Apoptoc cells NETs Neoangens/ auto-angens

Targeted-cytokine blockade *

+ pDC + Macrophage + +

Pro-inflammatory cytokines (IL-1, IL-6, IL-17), IL-12/23, TNF-α, Type I IFN, Type III IFN)

+ Proinflammatory cytokines

+

+

T Cell

+ B Cell

B Cell

JAK inhibitor

BTK inhibitor

Co-smulaon Tcell blocker (Abatacept)

An-B Cell (Rituximab, Belimumab)

+ Plasma cell

Y

Y Y Y Y

Autoanbodies An-PC (Bortezomib)

FIG. 4  Various immune pathways involving innate and adaptive immunity in autoimmune rheumatic diseases (AIRDs). Current therapeutic targets include against both B and T cells, plasmacytoid dendritic cells (pDCs), plasma cells (PCs), and pro-inflammatory cytokines particularly IL-1, IL-6, IL-17, IL-12/23, TNF-α, and IFNs. Intracellular signaling pathways through JAK (Janus Kinase) and BTK (Bruton Tyrosine Kinase) inhibitions are also one of the therapeutic target in AIRDs.

35



3.  Rheumatic diseases: From bench to bedside

3  Comparisons of the immunopathogenesis in various autoimmune rheumatic diseases Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease and rheumatoid arthritis (RA) is a representative disease of inflammatory arthritis. On the other hands, systemic sclerosis is characterized by fibroblast dysfunction leading to excessive collagen and other matrix components accumulation in skin, blood vessels, and internal organs. Meanwhile, spondyloarthritis is characterized by the axial and peripheral joints inflammation and associated with new bone formation and ankylosis. Some of these AIRDs share an autoimmune etiology including their genetic loci but they have their own distinct immune pathways, which determine their clinical phenotype and treatment response. Table 2 summarizes the comparisons between these four prototypes of AIRDs.

4  The clinical implications of the immunopathogenesis of autoimmunity 4.1  Biomarkers in diagnosis and disease activity Autoantibodies have long been used to diagnose AIRDs, and their presence in different types of AIRDs is illustrated in Fig. 1. However, their sensitivity and specificity may vary, and the majority are nonspecific. For example, antinuclear antibodies (ANA) and rheumatoid factor (RF) are found in many other acute or chronic infections [68]. Apart from being a potential trigger of AIRDs, these infectious agents may also induce the production of other autoantibodies such as Antineutrophil Cytoplasmic Antibodies (ANCA) and cyclic citrullinated peptide antibodies (anti-CCP) that were detected in approximately 40% of tuberculosis (TB) patients [69,70]. The recent Coronavirus (COVID-19) pandemic has also revealed the role of this virus in inducing autoantibodies particularly antiphospholipid antibodies [71] and autoantibodies involve in vasculitis [72]. This phenomenon may mislead or confuse clinical judgments on the diagnosis and treatment as both infections and autoimmune diseases have a different approach of management. Hence, clinical correlations are vital before making a definite ARD diagnosis in the event of concomitant infection. Recent discoveries of various genes and immune pathways have led to many new diagnostic and disease activity biomarkers such as autoantibodies, cytokines, and chemokines. Although abundant of biomarkers have been identified using the latest technologies, there are significant challenges as many of them have not been vigorously validated to be used in clinical practice. Nonspecific inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are still largely used in many AIRDs to help clinicians in assessing disease activity and treatment response of patients. Nevertheless, the search for more specific and reliable biomarkers are ongoing to fulfill this unmet need. This can help in early diagnosis of rheumatic diseases, accurate disease activity, prognostication, and risk stratification that serve as a stepping stone to precision medicine. Table 3 illustrates the biomarkers that are currently used in clinical practice and other potential biomarkers to diagnose and assess disease activity in various AIRDs.

36

TABLE 2  Comparisons of four prototypes of autoimmune rheumatic diseases; rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis, and spondyloarthropathies. Characteristics

Rheumatoid arthritis

SLE

Systemic sclerosis

Spondyloarthropathies

Main clinical features

Arthritis with extraarticular (e.g., pulmonary)

Multisystemic and organ inflammation due to autoantibodies and immune complex deposition

Fibroproliferative of the blood vessels (vasculopathy), skin, and internal organs

Arthritis (peripheral and axial skeleton) with skin (psoriasis), gut (IBD) and eye (uveitis) manifestations

HLA

MHC-II: HLA-DR4, HLA-DRB1*04 HLA-DRB1*01

MHC-II: HLA-DR2, DR3 HLA-DRB1*1501 HLADRB*0301

MHC-II: HLA-DRB1*01, HLA-DRB1*11, HLA-A*30, and HLA-A*32

MHC-I: HLA B27

Non-HLA

PADI4, CTLA4, TRAF1C5, TRAF6

FcγR, ITGAM, TNFSF4, TRAF6

IRF5, STAT4

ERAP1 & 2 (endoplasmic reticulum aminopeptidase 1 & 2) and IL23R

Shared gene loci (non-HLA)

PTPN22, STAT4, TNFAIP3, NOX, JAZF1, FCGR2A, FCGR2B, LBH, SPRED2, IRF5, BLK, WDFY4, RAD51B, RASGRP1, CD226, CD40, UBE2L3-YDJC, SYNGR1

Main genetic risk factors

Runt-related transcription factor 3 (RUNX3) with SLE

KIAA0319L, PXK, and JAZF1 Main immunopathogenesis

Synovial macrophages mediate recruitment of lymphocytes, cartilage damage, joint erosion, angiogenesis and fibroblast proliferation

Molecular mimicry and defective apoptosis leads to adaptive immune system dysregulation with autoantibody and immune complex productions which leads to tissue damage

Macrophages and pDCs activations causing dysregulation of adaptive immunity with autoantibody, cytokines and growth factors productions resulting in progressive fibrosis

Activation of innate and adaptive immune cells producing cytokines causing joint damage/erosion while mesenchymal stem cells differentiate to osteoblasts to form new bone and ankyloses

Autoantibodies

Anticitrullinated protein antibodies (ACPAs), Rheumatoid Factor (RF)

ANA, anti-dsDNA, anti-Sm

Anticentromere, Anti-SCL70

Absence (seronegative)

Cytokines

↑ TH17:IL-17, IL-21, IL-22 and IL-23  ↑ TNF‐α, IL‐6 and IL‐1β, ↑ IFN‐γ  ↓ IL10

↑ IFN-α, IFN-γ  ↑ interleukin (IL)-1, IL-2, IL-4, IL-6 and IL-8, IL12  ↑ Th2 cytokine IL-5 Th17: IL-17, IL-21, IL-23 B cells: B cell activating factor (BAFF), APRIL (a proliferation-inducing ligand)

IL-4 and IL-13, and Th17, IL-17, IL-10, IL-21, and IFN-γ, producing IL-17 TNF‐α B cells CD19, CD21, costimulatory molecules, and BAFF

ANA, antinuclear antibody; anti-dsDNA, antidouble-stranded DNA; anti-Sm, anti-Smith; BLK, B-lymphoid tyrosine kinase; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; FcγR, Fcγ receptors; FCGR2A, Fcgamma Receptor IIa; FCGR2B, Fc fragment of IgG receptor IIb; HLA, human leukocyte antigen; IBD, inflammatory bowel disease; IL, interleukin; IFN, interferon; IRF5, interferon regulatory factor 5; ITGAM, Integrin Subunit Alpha M; JAZF1, JAZF Zinc Finger 1; LBH, limb bud and heart development; KIAA0319L, KIAA0319 Like; MHC, major histocompatibility complex; NOX1, NADPH Oxidase 1; PADI4, peptidyl arginine deiminase 4; PXK, PX domain containing serine/threonine kinase like; RAD51B, RAD51 Paralog B; RASGRP1, RAS guanyl releasing protein 1; SLE, systemic lupus erythematosus; SPRED2, sprouty-related EVH1 domain containing 2; STAT4, signal transducer and activator of transcription 4; SYNGR1, Synaptogyrin 1; TNF‐α, tumor necrosis factor-α; TNFAIP3, TNF alpha induced protein 3; TNFSF4, TNF superfamily member 4; TRAF, tumor necrosis factor receptor (TNFR) associated factor; UBE2L3, ubiquitin-conjugating enzyme E2 L3; WDFY4, WDFY Family Member 4; YDJC, YdjC Chitooligosaccharide Deacetylase Homolog.



3.  Rheumatic diseases: From bench to bedside

TABLE 3  Biomarkers in current clinical practice and potential or investigational biomarkers in rheumatic diseases. Disease

Current biomarkers

Investigational biomarkers

Systemic lupus erythematosus

Complement C3 and C4 Anti-dsDNA CD19+ B cells

Interleukin-6 (IL-6), and circulating immune complexes (CIC) [73] Type 1 interferons [74] Cell-bound complement activation products (CB-CAPs) [75] ↑Th1‐, Th2‐, and Th17‐type cytokines, soluble tumor necrosis factor receptor type I (TNFRI), TNFRII, Fas, FasL, and CD40L predict flare while  ↑ regulatory cytokines, i.e., interleukin‐10 and transforming growth factor β associated with nonflare [76]

Rheumatoid arthritis

ESR and CRP

Anticarbamylated protein antibodies [74,77] Antiporphyromonas gingivalis antibody [73] Multibiomarkers disease activity test (MBDA) including VCAM-1, IL-6 and TNF-RI, MMP 1 & 2 [78]

Systemic sclerosis

ESR and CRP

IL‐6 [79] CXCL10 and CCL2 chemokines [80] IFN‐inducible chemokine score [81] KL-6 and SP-D in lung disease [82]

Spondyloarthritis

ESR and CRP

Anti-CD74 [83], Anti-PPM1A [84] Calprotectin [85] IL-6 [86]

Systemic vasculitis ANCA (PR3-ANCA or MPO-ANCA)

Neutrophil microparticles (NMPs) [87] Urinary MCP-1 [88] and urinary soluble CD163 (sCD163) in renal vasculitis [89] IL-21 [90]

Sjögren’s disease

BAFF, β2M, and FLCs [91] IFN type I [92]

ESR, CRP, Immunoglobulin level

ANCA, antineutrophil cytoplasmic antibody; Anti-PPM1A, antibody to protein phosphatase magnesium-dependent 1A; BAFF, B-cell-activating factor; β2M, β-2 micgroglobulin; CRP, C-reactive protein; EGF, epidermal growth factor; ESR, erythrocyte sedimentation rate; FLCs, immunoglobulin free light chains; IL-6, interleukin-6; IFN, interferon; KL‐6, Krebs von den Lungen‐6; MCP-1, monocyte chemoattractant protein 1 (MCP-1); MPO, myeloperoxidase; MMP, matrix metalloproteinases; PR3, proteinase 3; SP‐D, surfactant protein‐D; TNF-R1, tumor necrosis factor receptor 1; VCAM-1, vascular cell adhesion molecule-1; VEGF-A, vascular endothelial growth factor A.

4.2  Therapeutic implications By recognizing the potential triggers and bridging with the genetic-immune pathways, the prevention and treatment of the disease has been revolutionized. The classical example is through understanding the link between infectious agents in the pathogenesis of the AIRDs. The therapeutic concept of combining antiviral treatment of hepatitis C and B with immunosuppression and/or plasma exchange is advocated in polyarteritis nodosa (PAN) and cryoglobulinemic vasculitis-associated hepatitis B and C infection [93,94]. Several case reports and case series studies reported improvement of the autoimmune disease with the suppression of the viral infection alone or with minimal immunomodulators [95]. The presence of Epstein-Barr virus (EBV) genome was also associated with a better clinical response

38



Syahrul Sazliyana Shaharir and Asrul Abdul Wahab

to rituximab [96]. The prevention of infection with vaccination may play a strategic role in reducing autoimmunity. For example, immunization against hepatitis B has indeed reduced the incidence of hepatitis B associated PAN [93]. This millennium has certainly witnessed a major revolution in the treatment paradigm of various AIRDs through a more targeted immunotherapy method, using biologics and small molecules. B cell targeting therapy is one of the treatment strategies in SLE and other seropositive rheumatic diseases such as RA [97], vasculitis [98], myositis [99], and Sjögren’s disease [100]. Despite failure in achieving primary endpoints in the phase III of B cells depletion therapy in SLE, i.e., LUNAR (Lupus Nephritis Assessment with Rituximab) [101] and EXPLORER (Exploratory Phase II/III SLE Evaluation of Rituximab) [102], the treatment is still used as off-label treatment for refractory SLE patients in various clinical guidelines [103,104]. Belimumab, a fully humanized monoclonal antibody that specifically binds to soluble trimeric B cell activating factor (BAFF), is the only biologic approved to be used in extrarenal SLE and currently is seeking approval for lupus nephritis after showing its efficacy in achieving renal response [105]. A recent Phase II trial of Obinutuzumab, an anti-CD20 monoclonal antibody in lupus nephritis has demonstrated its efficacy in achieving renal response [106]. A more specific therapeutic target against antiinterferon α receptor, anifrolumab has demonstrated its efficacy [107] and currently seeking approval from the regulatory bodies to be used in SLE patients. IL-6 inhibitor, tocilizumab showed promising result in phase I study of SLE with arthritis, but it was associated with dose-related neutropenia [108]. Baricitinib, a Janus kinase inhibitors (JAK1 and JAK2), has demonstrated an encouraging result in the phase II trial [109] and currently its phase III is still ongoing. IL-17–producing Th17 cells is also a potential target for SLE treatment [110]. There is currently an ongoing trial of secukinumab (IL-17 inhibitor) in discoid lupus (NCT03866317) and lupus nephritis (NCT04181762). Future direction of plasma cell depletion therapy (bortezomib) in SLE patients is emerging [111–113] after showing to be successful in reducing ­anti-dsDNA antibody levels and ameliorates lupus nephritis in mice models [114]. A phase II of BIIB059, a humanized monoclonal antibody targeting bdca2 on plasmacytoid dendritic cells (pDC) also shows promising result [115]. Other B cell targeting therapies such ocrelizumab (anti CD20) [116], epratuzumab ­(anti-CD22) [117], and tabalumab (anti-BAFF) [118] demonstrate discouraging and mixed results in the clinical trials and hence their development were halted. Abatacept, a selective T-cell costimulation modulator, has also been studied in SLE. Improvements in serological markers and proteinuria were demonstrated but it did not meet its primary endpoints [119]. Therapy targeting IL12/23 axis by ustekinumab initially was encouraging in phase II but it was discontinued in phase III trial due to lack of efficacy [120]. Fenebrutinib, an inhibitor of Bruton’s tyrosine kinase (BTK) did not meet primary end points in SLE phase II study [121]. Despite discouraging results, these immune pathways remain the potential targets in SLE and further clinical trials with better study design and methodology are needed. The evidence of biologics and small molecules are more robust in RA and SpA as compared to other AIRDs. The use of antitumor necrosis factor α (TNF-α), interleukin-6 (IL-6), janus kinase (JAK) inhibitors, and abatacept are proven to improve disease activity and outcome in RA [122]. Meanwhile, anti-TNF, anti-IL-17, and anti-IL12/23 have demonstrated their efficacy in disease control and progression in SpA [123]. Table 4 and Fig. 4 summarize the various therapeutic targets in multiple immune pathways in AIRDs.

39

TABLE 4  Overview on the therapeutic targets of various autoimmune rheumatic diseases and their efficacy evidence from clinical trials. Disease/target

IL-6

IL17

IL 12/23

B-cell

T-cell

TNF-α

JAK/STAT

IFN-α

pDCs

Plasma cells

SLE

+

++

++a

+++

++b

xc

++

++

++

+

RA

+++

x

x

+++

+++

+++

+++

SpA

x

+++

+++

x

x

+++

+++

+++

SSc Vasculitis a

+++

+++

Failed Phase III (Ustekinumab). Abatacept did not meet primary endpoint but improvement in proteinuria and serological markers were reported. c The use of anti-TNF can induce lupus autoantibodies. IL, interleukin; JAK, Janus Kinase; pDCs, plasmacytoid dendritic cells; RA, rheumatoid arthritis; SpA, spondyloarthritis; SLE, systemic lupus erythematosus; SSc, systemic sclerosis; STAT, signal transducer and activator of transcription 4; TNF-α, tumor necrosis factor-α. +: Phase I, ++: Phase II/III, +++: Approved by American or European regulatory bodies or recommended in clinical guidelines. x: Failed phase II/III or not recommended due to lack efficacy. b



Syahrul Sazliyana Shaharir and Asrul Abdul Wahab

5  Conclusion In this chapter, we have reviewed the pathogenesis of AIRDs and its implications in clinical practice. AIRDs encompass a wide spectrum of clinical manifestation with pathogenetic heterogeneity. The pathogenesis of AIRDs involves a complex interaction between genes and various external or environmental triggers that causes a breakdown in self-tolerance against self-antigens. Although the exact pathogenesis is not completely understood, a tremendous progress has been made recently, with discoveries of various disease-susceptible genes and their designated molecular pathways. Indeed, improvements in our understanding of the cellular mechanisms in AIRDs have revolutionized the treatment landscape of AIRDs by translating the basic immune-pathogenesis to develop new targeted biological drugs that addressed specific inflammatory molecules. However, despite increasing clarity on the complexity of AIRDs, there are still many more unmet needs such as reliable disease biomarkers and effective treatments. Nevertheless, the relentless research on the immune-pathogenesis of AIRDs will assist in mapping the disease complexity and leads to exciting glimpse of the potential biomarkers and effective therapeutic targets in the future.

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[65] S. Fukui, N. Iwamoto, A. Takatani, T. Igawa, T. Shimizu, M. Umeda, et al., M1 and M2 monocytes in rheumatoid arthritis: a contribution of imbalance of M1/M2 monocytes to osteoclastogenesis, Front. Immunol. 8 (2018) 1958. [66] J.J. Chia, T.T. Lu, Update on macrophages and innate immunity in scleroderma, Curr. Opin. Rheumatol. 27 (6) (2015) 530–536. [67] B. Terrier, N. Costedoat-Chalumeau, M. Garrido, G. Geri, M. Rosenzwajg, L. Musset, et  al., Interleukin 21 correlates with T cell and B cell subset alterations in systemic lupus erythematosus, J. Rheumatol. 39 (9) (2012) 1819–1828. [68] C.M. Litwin, S.R. Binder, ANA testing in the presence of acute and chronic infections, J. Immunoass. Immunochem. 37 (5) (2016) 439–452. [69] P. Kakumanu, H. Yamagata, E.S. Sobel, W.H. Reeves, E.K.L. Chan, M. Satoh, Patients with pulmonary tuberculosis are frequently positive for anticyclic citrullinated peptide antibodies, but their sera also react with unmodified arginine-containing peptide, Arthritis Rheum. 58 (6) (2008) 1576–1581. [70] L.F. Flores‐Suárez, J. Cabiedes, A.R. Villa, F.J. van der Woude, J. Alcocer‐Varela, Prevalence of antineutrophil cytoplasmic autoantibodies in patients with tuberculosis, Rheumatology (Oxford) 42 (2) (2003) 223–229. [71] L. Bowles, S. Platton, N. Yartey, M. Dave, K. Lee, D.P. Hart, et al., Lupus anticoagulant and abnormal coagulation tests in patients with Covid-19, N. Engl. J. Med. 383 (3) (2020) 288–290. [72] R.C. Becker, COVID-19-associated vasculitis and vasculopathy, J. Thromb. Thrombolysis 50 (3) (2020) 499–511. [73] C. Thanadetsuntorn, P. Ngamjanyaporn, C. Setthaudom, K. Hodge, N. Saengpiya, P. Pisitkun, The model of circulating immune complexes and interleukin-6 improves the prediction of disease activity in systemic lupus erythematosus, Sci. Rep. 8 (1) (2018) 2620. [74] V. Oke, I. Gunnarsson, J. Dorschner, S. Eketjäll, A. Zickert, T.B. Niewold, et  al., High levels of circulating interferons type I, type II and type III associate with distinct clinical features of active systemic lupus erythematosus, Arthritis Res. Ther. 21 (1) (2019) 107. [75] R. Ramsey-Goldman, J. Li, T. Dervieux, R.V. Alexander, Cell-bound complement activation products in SLE, Lupus Sci Med 4 (1) (2017). e000236-e. [76] M.E. Munroe, E.S. Vista, J.M. Guthridge, L.F. Thompson, J.T. Merrill, J.A. James, Proinflammatory adaptive cytokine and shed tumor necrosis factor receptor levels are elevated preceding systemic lupus erythematosus disease flare, Arthritis Rheumatol. 66 (7) (2014) 1888–1899. [77] A. Yee, T. Webb, A. Seaman, M. Infantino, F. Meacci, M. Manfredi, et al., Anti-CarP antibodies as promising marker to measure joint damage and disease activity in patients with rheumatoid arthritis, Immunol. Res. 61 (1) (2015) 24–30. [78] M. Centola, G. Cavet, Y. Shen, S. Ramanujan, N. Knowlton, K.A. Swan, et  al., Development of a multi-­ biomarker disease activity test for rheumatoid arthritis, PLoS One 8 (4) (2013) e60635-e. [79] A. De Lauretis, P. Sestini, P. Pantelidis, R. Hoyles, D.M. Hansell, N.S.L. Goh, et al., Serum interleukin 6 is predictive of early functional decline and mortality in interstitial lung disease associated with systemic sclerosis, J. Rheumatol. 40 (4) (2013) 435–446. [80] A. Antonelli, C. Ferri, P. Fallahi, S.M. Ferrari, D. Giuggioli, M. Colaci, et al., CXCL10 (α) and CCL2 (β) chemokines in systemic sclerosis—a longitudinal study, Rheumatology 47 (1) (2008) 45–49. [81] X. Liu, M.D. Mayes, F.K. Tan, M. Wu, J.D. Reveille, B.E. Harper, et  al., Correlation of interferon-inducible chemokine plasma levels with disease severity in systemic sclerosis, Arthritis Rheum. 65 (1) (2013) 226–235. [82] K. Yanaba, M. Hasegawa, K. Takehara, S. Sato, Comparative study of serum surfactant protein-D and KL-6 concentrations in patients with systemic sclerosis as markers for monitoring the activity of pulmonary fibrosis, J. Rheumatol. 31 (6) (2004) 1112–1120. [83] E. Riechers, N. Baerlecken, X. Baraliakos, K. Achilles-Mehr Bakhsh, P. Aries, B. Bannert, et al., Sensitivity and specificity of autoantibodies against CD74 in nonradiographic axial spondyloarthritis, Arthritis Rheum. 71 (5) (2019) 729–735. [84] Y.-G. Kim, D.H. Sohn, X. Zhao, J. Sokolove, T.M. Lindstrom, B. Yoo, et  al., Role of protein phosphatase ­magnesium-dependent 1A and anti-protein phosphatase magnesium-dependent 1A autoantibodies in ankylosing spondylitis, Arthritis Rheum. 66 (1) (2014) 2793–2803. [85] H. Hu, F. Du, S. Zhang, W. Zhang, Serum calprotectin correlates with risk and disease severity of ankylosing spondylitis and its change during first month might predict favorable response to treatment, Mod. Rheumatol. 29 (5) (2019) 836–842.

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C H A P T E R

4 Rheumatic fever: From pathogenesis to vaccine perspectives ⁎

Luiza Guilhermea,b, , Carlos Eduardo Brancoa, Samar Freschi de Barrosa,b, and Jorge Kalila,b a

Heart Institute (InCor), University of São Paulo, São Paulo, Brazil, bInstitute for Investigation in Immunology, National Institute of Science and Technology, São Paulo, Brazil ⁎ Corresponding author

Abstract Rheumatic fever (RF) is considered a model of autoimmune disease due to untreated throat infection by ­S. ­pyogenes that affects children and teenagers. The autoimmune process is believed to be the basis of all of the clinical ­manifestations; for instance, arthritis by immune complex deposition, chorea by antibody binding to neuronal cells, skin and subcutaneous manifestations that are mediated by a delayed hypersensitivity reaction, and carditis that is caused by cross-reactive antibodies and T cells. This chapter presents an overview of the mechanisms leading to the tissue lesions, treatment, and future possibilities of a vaccine against S. pyogenes.

Keywords Rheumatic fever, Autoimmunity, T cells, HLA class II alleles

1  Introduction Rheumatic fever (RF), a prototype autoimmune disease, occurs due to untreated throat infection by S. pyogenes that affects susceptible children and teenagers. The bacteria initially colonize the throat (Fig. 1), developing a local inflammatory reaction and attracting monocytes, macrophages, and T and B lymphocytes to resolve the infection. However, the cells attracted to the local tissue to settle the condition will later culminate in an autoimmune attack. The disease was described first in 1945 by Calvetti, who observed streptococcal cross-reactive antibodies in sera from rheumatic fever patients. RF is a complication of group A streptococcal infection that results from a complex interaction between the genetic make-up of the host, the condition itself, and several other environmental Translational Autoimmunity, Vol. 6 https://doi.org/10.1016/B978-0-323-85831-1.00004-8

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4.  Rheumatic fever: From pathogenesis to vaccine perspectives

FIG.  1  S. pyogenes throat colonization. S. pyogenes (red) adhere to the oropharynx membrane (brown) and some macrophage (yellow) trying to combat the infection by phagocytosis of the bacteria. Image obtained by emission scanning EM. Kindly provided by Prof Dr. Manfred Rhode, HZI, Braunschweig, Ge.

factors, mainly reflecting poverty. It is estimated to affect 33.4 million and results in 10.5 million disability-adjusted life years lost globally [1]. The clinical profile, however, was described later by Cheadle in 1989. The disease manifests early by polyarthritis and, if not treated, can trigger lesions in the heart, mainly in the valves that cause rheumatic heart disease as the most severe sequelae of 48



Luiza Guilherme et al.

the disease. In ­addition, nonpruriginous circular lesions in the skin that follows S. pyogenes infections lead to Erythema marginatum and impetigo that present as pink circular lesions [2]. Another sequel is the Sydenham chorea, in which hypotonia and involuntary movements, and emotional instability lead to physical incoordination or movement difficulties [3]. Both RF and RHD, as well as Sydenham chorea, are controlled by several genes that predispose to the development of the lesions, and some HLA class II antigens, coded by HLA-DRB1 gene are involved with susceptibility to develop the disease and the molecules produced by these genes have a role in the antigen presentation and activation of the immune response (Fig. 2). The HLA class II alleles have been associated with the development of these lesions and are involved with the recognition of the pathogen (S. pyogenes) through some regions of N-terminal portion of the M protein, the major protein of the pathogen. The M protein extends from the cell wall and has two portions (N-terminal and C-terminal), from which N-terminal is polymorphic and defines the diverse serotypes of the S. pyogenes, nowadays more than 200. In the last 15 years, some mechanisms that trigger damage to human tissues, particularly the skin, central nervous system (CNS), and/or heart tissue (myocardium and/or valves) were described. Of note, the molecular mimicry mechanism mediates the recognition of self and pathogen proteins, causing tissue damage. Both T and B lymphocytes are attracted to the involved tissues (articulations, brain, and heart), and the constitutional proteins are damaged by the cross recognition with S. pyogenes antigens, a reaction mediated by both B and T lymphocytes. Cross reactive antibodies and several inflammatory cytokines as TNF-α, IL-1, IL-6, and IFN-γ amplify the tissue lesions and CD4+ T lymphocytes are attracted and infiltrate the heart. These cells recognize myocardium and valvular tissue by molecular mimicry, causing a local autoimmune reaction that leads to valvular lesions [4] (Fig. 3).

FIG. 2  Gross view of a rheumatic, stenotic aortic valve. The semilunar leaflets are diffusely thickened, with extensive fusion along part of one of the zones of apposition (commissure, arrows). Kindly provided by Dr Vera Aiello, from Department of Pathology of Heart Institute (InCor).

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4.  Rheumatic fever: From pathogenesis to vaccine perspectives

FIG. 3  Mitral valve as seen from the left atrium. Both leaflets are thickened and whitish, and the commissures are fused. The left atrium is massively dilated with a thickened endocardium. Kindly provided by Dr. Vera Aiello, from Department of Pathology of Heart Institute (InCor).

The autoimmune process is believed to be the basis of all of the clinical manifestations: (1) arthritis by immune complex deposition, (2) chorea by antibody binding to neuronal cells, (3) skin and subcutaneous manifestations that are mediated by a delayed hypersensitivity reaction, and (4) carditis that is caused by cross-reactive antibodies and T cells [5].

2  Diagnosis of acute rheumatic fever Rheumatic fever (RF) is underdiagnosed because there is no diagnostic laboratory test; so, diagnosis remains a clinical decision based on the ARF diagnostic algorithm known as Jones criteria (Table 1) [6]. The last revision of the Jones criteria mainly consists of the supplementation of the major criteria with an echocardiographic examination, the introduction of a concept of subclinical carditis, and the isolation of low, medium, and high-risk populations among the patients. American Heart Association (AHA) recommends that all the patients with suspected RF undergo Doppler echocardiographic examination after the Jones criteria have been verified, even if no clinical signs of carditis are present [5]. Because other illnesses may closely resemble ARF, laboratory evidence of antecedent group A streptococcal infection is needed whenever possible, and the diagnosis is in doubt when such evidence is not available. Exceptions to this include chorea, which may be the only manifestation of rheumatic fever at the time of its presentation, and rarely, individuals with chronic indolent rheumatic carditis with insidious onset and slow progression [7]. The pretest probability for the diagnosis of RF varies according to region risk of ARF (low or middle-high incidence) [8]. Therefore, to avoid overdiagnosis in low-risk and underdiagnosis in high-risk populations, variability in applying diagnostic criteria to the lowrisk compared with high-risk populations is reasonable [9]. Low-risk populations are those

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TABLE 1  Revised Jones criteria 2015. Initial ARF

Recurrent ARF

– Two major manifestation; or one major plus two minors

– Two major manifestations or one major plus two minor or three minors

Low-risk populations

Moderate and high-risk populations

Major criteria

Major criteria:

– Carditis (clinical and or subclinical)

– Carditis (clinical and or subclinical)

– Arthritis (polyarthritis only)

– Arthritis (monoarthritis or polyarthritis) polyarthralgia

– Chorea

– Chorea

– Erythema marginatum

– Erythema marginatum

– Subcutaneous nodules

– Subcutaneous nodules

Minor criteria

Minor criteria

– Polyarthralgia

– Monoarthralgia

– Fever (≥ 38.5°C)

– Fever (≥ 38°C)

– ESR  ≥ 60 mm in the first hour and or CRP ≥ 3 mg/dL

– ESR  ≥ 30 mm and or CRP ≥ 3 mg/dL

– Prolonged PR interval, after accounting, for aging variability (unless carditis is a major criterion)

– Prolonged PR interval, after accounting for aging variability (unless carditis is a major criterion)

with ARF incidence ≤ 2 per 100,000 school-aged children or all-age rheumatic heart disease prevalence of ≤ 1 per 1000 population per year [6]. High-risk groups are those living in communities with high rates of ARF (incidence > 30/100,000 per year in 5–14-year-olds) or RHD (all-age prevalence > 2/1000) [8]. The criteria divide the clinical features of ARF into major and minor manifestations based on their prevalence and specificity [10]. Major manifestations are those that make the diagnosis more likely, whereas minor manifestations are considered suggestive but insufficient on their own for a diagnosis of ARF. The exception is in the diagnosis of recurrent ARF, which may be made on minor manifestations alone [8]. The patients develop clinical features as carditis, arthritis, chorea, subcutaneous nodules, and erythema marginatum [5]. The most common presenting manifestation of ARF are arthritis (75% of patients) and fever (> 90% of patients) [4].

3  Major manifestation The most common major manifestations during the first episode of ARF remain carditis (50%–70%), arthritis (35%–66%), chorea (10%–30%), which have a female predominance, subcutaneous nodules (0%–10%), and erythema marginatum ( 3 mg/dL) and erythrocyte sedimentation rate (ESR) > 60 mm in the first hour in low-risk populations and > 30 mm in high-risk populations are considered as minor criteria, and > 30 mm in high-risk populations [15]. In RF, the serum CRP rises more rapidly than the ESR, but falls more quickly with the resolution of the attack. The ESR may remain elevated for 3–6  months, despite symptoms resolving within a much shorter period [8].

4.5  Evidence of streptococcal infection The gold standard laboratory diagnosis of streptococcal pharyngotonsillitis is a culture of throat swab. It is a laboratory diagnostic test to evaluate the presence of a streptococcal infection [26]. The sensitivity and specificity of the throat swab cultures are 81.1% and 94.9%, respectively [27].

5  Treatment The treatment focuses on four targets: (1) GAS pharyngitis treatment (primary prevention), (2) treatment of manifestations, (3) prevention of recurrences (secondary prevention), and (4) education of the patient and family [28]. 54



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5.1  Primary prevention (GAS pharyngitis treatment) Primary prevention focuses on recognizing and treating GAS pharyngitis to decrease the risk of RF [13]. It aims to interrupt the link between Strep A infection and the abnormal immune response to Strep A [8]. Research is needed to clarify whether other Lancefield groups and skin infections can cause RF [13]. Treatment of the GAS sore throat decreases the subsequent development of ARF by up to two-thirds [8]. Intramuscular benzathine penicillin G (BPG) remains the most widely used antibiotic for GAS pharyngitis (Table 2) [13]. Individuals receiving BPG secondary prophylaxis need active treatment of sore throats or skin sores to reach a prophylactic level because the level of penicillin achieved by BPG wanes by about 7 days [8].

5.2  Manifestation treatment 5.2.1  Fever Fever will respond to NSAID (nonsteroids antiinflammatory drug) therapy; however, it can be treated with paracetamol as well [8]. 5.2.2  Arthralgia and arthritis Arthralgia and arthritis responds within 1–3  days to treatment with high-dose aspirin ­(80–100 mg/kg/day in three or four divided doses) [15].

TABLE 2  Recommended antibiotic treatment for Strep A sore throat/tonsillitis.a Antibiotic

Dose

Route

Frequency

 25 years [13]. The biggest issue in second prophylaxis is the low adherence to the medications, while increased adherence to penicillin prophylaxis is associated with reduced ARF recurrence and a likely reduction in mortality [35]. New technologies may facilitate secondary prophylaxis adherence. Novel formulations of long-acting penicillin have the potential to reduce injection frequency. In addition, smart technologies utilizing mobile devices that provide patients with reminders are currently being trialed [34] (Table 4). 56



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TABLE 3  Duration of secondary rheumatic fever prophylaxis [33]. Category

Duration after last attack

Rheumatic fever without carditis

5 years or until 21 years of age (whichever is longer)

Rheumatic fever with carditis but no residual heart disease (no valvular disease)

10 years or until 21 years of age (whichever is longer), sometimes lifelong

Rheumatic fever with carditis and residual heart disease (persistent valvular disease)a

10 years or until 40 years of age (whichever is longer), sometimes lifelong prophylaxis

a

Clinical or echocardiographic evidence.

TABLE 4  Recommended antibiotic for secondary prophylaxis [8]. Antibiotic

Dose

Route

Frequency

1.200.00 units (≥ 20 kg) 600.000 UI ( 3 mg/L) in high-sensitivity (hs) CRP may be predictive of a higher cardiovascular risk [37]. The incidence of cardiovascular disease is significantly greater in rheumatic cohorts of patients than in general population on the ground of a chronic inflammatory background and endothelial dysfunction [38]. Thus, hsCRP monitoring in rheumatic cohorts along with the control of classical metabolic risk factors (hyperglycemia, dyslipidemia, hyper-homocysteinemia, hyperuricemia) may offer additional benefits for screening patients at risk of cardiovascular complications [39]. Serum-amyloid A (SAA) is another acute-phase protein synthesized by hepatic cells in response to proinflammatory cytokines. SAA has several biological functions, including lipid transport, chemotaxis, neutrophil activation, and tissue remodeling [40,41]. Physiologically, its serum concentration is about 1–3 mg/L, but this value can thousand-fold increase in case of infections or tissue damage. A persistently elevated SAA is associated with AA amyloidosis, a systemic disease resulting from protracted high inflammation that can follow RA, juvenile idiopathic arthritis (JIA), and familial Mediterranean fever (FMF), but also infections or malignancies [41]. SAA is in fact the precursor of fibrillar amyloid A protein, whose accumulation in kidney and other tissues may eventually lead to end-stage organ failure. Very high SAA values should prompt physicians to ascertain the occurrence of amyloidosis through an abdominal fat pad biopsy [41]. The measurement in biological samples of other proinflammatory biomarkers, such as cytokines, chemokines, and their receptors, is still hampered by methodological issues and high costs, being therefore seldom available in clinical practice [26,42].

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7.  The diagnostic laboratory tests in rheumatic diseases

3  Laboratory tests in rheumatoid arthritis The role of laboratory tests is of utmost importance in the diagnosis, prognosis, and f­ ollow-up of RA patients. Abnormal ESR and/or CRP values and serology, namely RF and/ or anticitrullinated protein antibodies (ACPA) positivity, represent two categories of the 2010 American College of Rheumatology/European League against Rheumatism (ACR/EULAR) RA classification criteria [3]. Either ESR or CRP are routinely used for the calculation of RA disease activity through composite indices [43]. Besides being a more specific inflammatory biomarker, CRP appears inversely correlated to therapeutic response and directly associated with erosive progression [32]. However, acute-phase reactants may be negative in 10% of cases with active disease [44]. RF is an IgM (but sometimes also IgA and IgG) originally isolated in the serum of RA patients by Erik Waaler and Harry M. Rose [45]. This antibody reacts against the Fc of an IgG and is found in about 70% of patients with RA, who are therefore considered seropositive [32]. RF can also be found in the serum of subjects affected by other rheumatic diseases, particularly Sjögren’s syndrome (SS), and in 6%–40% of elderly individuals [16,46]. RF seropositivity in otherwise healthy young subjects was shown to carry a 26-fold increased RA risk over the time, especially if different RF isotypes and high antibody titers are present [47]. High RF titers are also associated with rheumatoid vasculitis and systemic manifestations induced by the precipitation of immune complexes in small vessels. Several techniques are available for the measurement of RF, including enzyme-linked immunosorbent assay (ELISA), nephelometry, agglutination test, and radioimmunoassays (RIA). No technique is considered more advantageous than the others, but automated methods, such as nephelometry or ELISA, may be preferred due to better reproducibility and fastness. ACPA are IgG, IgM, or IgA directed against citrullinated peptides, present in 70% of fullblown RA patients as well as in the preclinical phase of disease [48]. The process of citrullination of extracellular matrix (ECM) proteins, including fibrin, fibrinogen, filaggrin, and vimentin, is particularly active in RA synovial membrane, and leads to the generation of autoantigens in turn responsible for a humoral response. ACPA are highly specific RA biomarkers and are associated with a more aggressive course of the disease, characterized by bone erosion and cardiovascular complications [32,49,50]. The detection of anticyclic citrullinated peptide (anti-CCP) antibodies using a second generation test (anti-CCP2) has 99% specificity and a good sensitivity in individuating patients with either early or longstanding disease [32]. Some studies have shown that the combination of ACPA, cigarette smoking, and some haplotypes of the MHC class II [14,51] leads to a 20-fold increased risk of RA development [52]. Other autoantibodies detectable in RA patients target carbamylated proteins and mutated citrulline-vimentin (MCV) [53]. The latter is a naturally citrullinated vimentin isoform, whose glycine residues are replaced by arginine. Like ACPA, anti-MCV antibodies have been associated with radiographic progression [54]. Similarly, antibodies against carbamylated proteins, described in approximately 45% of RA individuals, have been regarded as a risk factor of RA development and erosive disease [55]. Although their diagnostic role in real-life remains uncertain, the presence of these antibodies may help in individuating RA patients who are negative for anti-CCP [55,56].

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Studies showed that autoantibody positivity may predict the response to RA treatments. Patients with high RF titers were reported to respond better to rituximab and tocilizumab [57], while ACPA-positive patients may have a good response to abatacept [58]. Though rarely used in clinical routine, genotyping may be helpful in the early identification of RA patients. More than 30 genes are responsible for 50% of the whole genetic susceptibility to the disease [59]. Beyond specific human leukocyte antigen (HLA) haplotypes alone contributing by 30% to RA heritability, polymorphic variants of genes involved in the immune response or in the citrullination process have been described [52]. As RA patients may undergo several disease-related and iatrogenic complications, they should be periodically monitored for the risk of hematologic [60] and hepatorenal disorders (especially in patients taking methotrexate, leflunomide, and antiinflammatory drugs), as well as for metabolic disorders, osteoporosis biomarkers, and amyloidosis [61] (Table 1). Additionally, the screening for opportunistic infections, such as those sustained by hepatitis TABLE 1  Overview of the laboratory tests having diagnostic, prognostic, and clinical utility in rheumatoid arthritis. Laboratory tests for rheumatoid arthritis Blood biochemical tests

Autoantibodies

Clinical significance

↑ ESR and CRP

Active inflammation, disease activity, response to therapies (CRP), bone erosions (CRP), cardiovascular complications (hsCRP)

↑ SAA

Chronic inflammation, AA amyloidosis, risk of renal failure

↑ WBC

Still’s syndrome, opportunistic infections, steroids (↑ neutrophils)

↓ WBC

Felty’s syndrome, iatrogenic toxicity, lymphoma

↓ RBC

Chronic inflammation, iron or folate deficiency, iatrogenic toxicity

↓ PLT

Iatrogenic toxicity, vasculitis

↑ Transaminases

Iatrogenic toxicity, opportunistic infections (HBV, HCV)

↑ Creatinine and urea

Iatrogenic toxicity, amyloidosis, opportunistic infections (TBC)

↑ Glycemia

Meta-steroidal diabetes

↑ RF

26-fold risk of RA development in healthy individuals; present in up to 70% of RA patients, poor specificity, association with a more aggressive course of disease, risk of rheumatoid vasculitis and extraarticular manifestations, better response to rituximab and tocilizumab

↑ ACPA

20-fold risk of RA development in smoker seropositive individuals who carry the HLA-DRB1*04SE, HLA-DRB1*04:01 and HLA-DRB1*01 haplotypes; present in up to 70% of RA patients, high specificity and sensitivity, association with a more aggressive course of disease, risk of bone erosions and cardiovascular complications, better response to abatacept

↑ ANA

Juvenile forms, overlapping connective tissue diseases (e.g., Sjӧgren’s syndrome) Continued

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7.  The diagnostic laboratory tests in rheumatic diseases

TABLE 1  Overview of the laboratory tests having diagnostic, prognostic, and clinical utility in rheumatoid arthritis—cont’d Laboratory tests for rheumatoid arthritis

Clinical significance

Genotyping

+ HLA-DRB1*01 + HLA-DRB1*04SE + HLA-DRB1*04:01 + HLA-DRB1*10

Synovial fluid analysis

≥ 2000 cells/ Inflammation, differential diagnosis with infectious or microcrystalline mm3 (neutrophils, arthritis ragocytes), rice bodies, depolymerization of proteoglycans, increased protein and decreased glucose content

Microbiologic screening tests

HBV, HCV, HIV serology; tuberculin skin test or interferon gamma release assay

Genetic predisposition to RA, erosive disease and association with ACPA positivity

Opportunistic infections in patients at high risk of immunosuppression (treated with biologic agents)

ACPA, anticitrullinated protein antibodies; ANA, antinuclear antibodies; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HLA, human leukocyte antigen; hsCRP, high-sensitivity CRP; PLT, platelets; RA, rheumatoid arthritis; RBC, red blood cells; RF, rheumatoid factor; SAA, serum-amyloid A protein; TBC, tuberculosis; WBC, white blood cells.

B and C viruses (HBV and HCV) and Mycobacterium tuberculosis, should be offered to patients candidate for biological or synthetic drugs prior to the start of the treatment, and periodically repeated during the follow-up according to local guidelines [62–64]. When available, the measurement of serum antidrug antibodies (ADAs) and drug concentrations should be prescribed to patients developing resistance to biologic therapies [65].

4  Laboratory tests in spondyloarthritis The SpA group clusters together several diseases sharing clinical, laboratory, radiographic, and therapeutic aspects. These include AS, psoriatic arthritis (PsA), reactive arthritis (ReA), arthritis associated with chronic inflammatory bowel diseases (IBD), and undifferentiated SpA. The presence of the HLA-B27 allele and a CRP serum concentration above the upper limit are two laboratory features shared across different SpA diseases and therefore listed among the 2009 SpA classification criteria formulated by the Assessment of SpA International Society (ASAS) [4]. The HLA-B27 allele, with the pathogenic subtypes B*2705 and B*2702 in Caucasians and B*2704 and B*2707 in Asians, is highly indicative of AS, being detectable in more than 90% of AS patients [66]. This haplotype accounts for more than 20% of genetic AS heritability [18] and is also found in other diseases belonging to the SpA group, in which it predicts the risk of axial disease, enthesitis, and acute anterior uveitis [67]. Several hypotheses have been proposed concerning the contribution of HLA-B27 to SpA pathogenesis [66]; one of the most accredited

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theories suggests that a misfolding of the HLA-B27 heavy chains in the e­ ndoplasmic reticulum (ER) may lead to autophagy, ER stress, and consequent inflammation [12]. According to FitzGerald et al. [68], PsA patients carrying the HLA-C*06:02 haplotype have a higher risk of cutaneous rather than articular disease, while those who are HLA-B*08- or HLA-B*27-positive have a prevalent joint involvement [68]. Similarly, the HLA-B*35 and HLA-B*44 haplotypes may influence the clinical expression of IBD-related arthritis [69]. As emerged from genome-wide association studies (GWASs), non-MHC genetic variants may additionally contribute to SpA genetic risk. Among them, it is worth mentioning the variants of the IL-23 receptor, IL-12B, and ER aminopeptidase 1 (ERAP1) genes [70–72]. SpA inflammation and disease activity can be monitored through the measurement of serum CRP concentration, which has greater specificity than ESR [73]. Serum CRP concentration is increased in more than 60% of AS patients with an active disease; therefore, it represents one of the items for the calculation of the AS disease activity score (ASDAS) [33]. High serum CRP levels at baseline are predictive of a better response to anti-TNF agents as well as of syndesmophyte formation in AS patient cohorts [18]. As SpA immunopathogenesis is mostly sustained by cellular rather than humoral mechanisms [74], RF and ACPA are rarely found in SpA individuals [75]. Autoreactive cells may be activated at the gut mucosal interface following dysbiosis [76]. An unbalance in gut microbial species has been observed in fecal specimens and intestinal biopsies of SpA patients [77,78]. A recent 16S ribosomal RNA gene sequencing study showed that SpA patients have a unique intestinal microbiota signature, characterized by the overgrowth of Ruminococcus gnavus, in turn associated with disease activity and the HLA-B27 allele [79]. On the other hand, a reduction in Faecalibacterium prausnitzii, displaying antiinflammatory properties, has been reported in both pediatric and adult SpA subjects [78]. Though of great interest, the characterization of gut microbiota is not performed in clinical routine, mostly because of a lack of standardized procedures and high costs. The chronic activation of the immune system in response to dysbiosis may eventually result in subclinical or clinical colitis. Microscopic gut inflammation has been described in up to 50% of SpA patients [80]. In these cases, elevated values of fecal calprotectin [81,82] and serum CRP [83] may represent reliable biomarkers of subclinical colitis. Fecal calprotectin is a calcium- and zinc-binding protein released from neutrophils and other phagocytic cells during inflammation [84]. It is easily measurable in stool samples by ELISA thanks to its high stability [81]. Being a nonspecific intestinal inflammatory biomarker, its concentration (usually below the threshold of 50 μg/mg) may fourfold increase in IBD, infections or iatrogenic toxicities. As for RA, SpA patients need to be constantly monitored for disease complications and drug side effects (Table  2). Furthermore, PsA patients, who are at higher risk of metabolic syndrome than non-PsA SpA patients, should be evaluated for dyslipidemia and other metabolic disorders [85,86]. Biologic-treated SpA patients are more susceptible to drug immunogenicity (and thus ADA production) than RA subjects, due to a less common coprescription of immunosuppressants or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) that repress the production of ADAs [87]. Reactive arthritis (ReA) usually follows intestinal infections sustained by Gram-negative bacteria belonging to the Enterobacteriaceae family (Salmonella, Campylobacter, Yersinia, Klebsiella, and Shigella spp.), or genitourinary tract infections mostly induced by Chlamydia trachomatis. Uncommon microorganisms are species of mycobacteria, mycoplasma, clostridia, and vibrio [88]. Laboratory tests have a crucial role in the diagnosis of ReA by finding antibodies against

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7.  The diagnostic laboratory tests in rheumatic diseases

TABLE 2  Overview of the laboratory tests having diagnostic, prognostic, and clinical utility in spondyloarthritis. Laboratory tests for spondyloarthritis

Clinical significance

Blood biochemical tests ↑ CRP and less commonly ↑ ESR Active inflammation, disease activity, response to anti-TNF therapies, radiographic progression, cardiovascular complications (hsCRP) ↑ WBC

Opportunistic infections, uncommon: steroid use (↑ neutrophils)

↓ WBC  ↓ RBC  ↓ PLT

Iatrogenic toxicity

↑ Transaminases

Iatrogenic toxicity, opportunistic infections (HBV, HCV), liver steatosis

↑ Creatinine and urea

Iatrogenic toxicity, opportunistic infections (TBC)

↑ Uric acid

Psoriasis, concomitant metabolic syndrome (PsA)

↑ Glycemia

Concomitant metabolic syndrome (PsA)

↑ Blood lipids

Concomitant metabolic syndrome (PsA)

Urine biochemical tests ↑ Proteinuria, hematuria

IgA nephropathy

Fecal biochemical tests

↑ Fecal calprotectin

Clinical/subclinical gut inflammation; IBD

Autoantibodies

↑ ANA

Nonspecific, concomitant therapies (e.g., anti-TNF agents)

Genotyping

+ HLA-B*2705 (Caucasians) + HLA-B*2702 (Caucasians) + HLA-B*2704 (Asians) + HLA-B*2707 (Asians)

Present in more than 90% of AS individuals; genetic predisposition to AS and association with axial disease, male gender, uveitis; association with axial disease, bilateral sacroiliitis, enthesitis, uveitis in PsA patients; association with axial disease, bilateral sacroiliitis, enthesitis, uveitis in patients with IBD-related SpA; present in up to 80% of ReA patients with disease chronicization in ≥ 20% of carriers

+ HLA-C*06:02

Psoriasis, mild articular involvement in PsA

+ HLA-B*08

Erosive arthritis, deformities, asymmetrical sacroiliitis in PsA patients

+ HLA-B35

Pauciarticular arthritis, erythema nodosum and uveitis in IBD-related SpA patients

+ HLA-B44

Symmetrical or asymmetrical polyarticular arthritis in IBD-related SpA patients

Synovial fluid analysis

≥ 2000 cells/mm3 (mainly Inflammation, differential diagnosis with infectious or mononuclear cells), microcrystalline arthritis depolymerization of proteoglycans, increased protein and decreased glucose content No alive microorganisms, IgA against C. trachomatis or C. trachomatis detection at PCR

ReA diagnosis

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TABLE 2  Overview of the laboratory tests having diagnostic, prognostic, and clinical utility in spondyloarthritis—cont’d Laboratory tests for spondyloarthritis Microbiologic screening tests

Clinical significance

HBV, HCV, HIV serology; Opportunistic infections in patients at high risk of tuberculin skin test or interferon immunosuppression (treated with biologic agents) gamma release assay Stool culture for Enterobacteriaceae, Identification of microorganisms responsible for ReA genitourinary swab for C. trachomatis; determination of serum IgM, IgG, and IgA against suspected microorganisms

ANA, antinuclear antibodies; anti-TNF, anti-tumor necrosis factor; AS, ankylosing spondylitis; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HLA, human leukocyte antigen; hsCRP, high-sensitivity CRP; IBD, inflammatory bowel diseases; Ig, immunoglobulins; PCR, polymerase chain reaction; PLT, platelets; PsA, psoriatic arthritis; RBC, red blood cells; ReA, reactive arthritis; SpA, spondyloarthritis; TBC, tuberculosis; WBC, white blood cells.

intestinal or genitourinary microorganisms or even isolating responsible pathogens in coprocultures and genitourinary swabs [89]. The detection of enterobacteria in stool samples or of Chlamydia trachomatis in urethral swab represent two minor criteria for ReA according to the ACR guidelines [89]. However, the determination of IgM, IgG, and IgA against microorganisms showed better diagnostic sensitivity and higher specificity than the direct isolation of pathogens in biologic samples [88]. Notably, the presence of anti-Chlamydia IgA in the synovial fluid of inflamed joints can reach a specificity of 90% [88,90], and Chlamydia trachomatis may be directly revealed in the synovial membrane through polymerase chain reaction (PCR) [91]. The HLA-B27 haplotype, present in up to 80% of ReA patients, may further help in discriminating ReA from undifferentiated arthritis [88].

5  Laboratory tests in autoimmune connective tissue diseases 5.1  Systemic lupus erythematosus and antiphospholipid syndrome Systemic lupus erythematosus (SLE) is a CTD having a humoral immunopathogenesis and systemically affecting the human body. Laboratory is particularly helpful in the identification and follow-up of SLE patients. The disease is in fact characterized by cytopenia, autoantibody production, and hypocomplementemia. Hence, international taskforces have entered hematologic, serologic, and immunologic criteria in SLE classification algorithms in order to increase their sensitivity and specificity [5,92,93]. Cytopenia may be due to leukopenia ( 50 times above the upper normal limit) are usually found in necrotizing myopathy [133]. Modest increases are observed in polymyositis and dermatomyositis, while slight changes characterize inclusion body myositis. As abnormal values of CPK can also be found in other conditions (thyroid disorders, electrolyte imbalances, statin therapy, physical activity, or muscle trauma), an immune-­mediated etiopathogenesis should be confirmed by the detection of myositis-­ specific and/or myositis-­associated antibodies. Myositis-specific antibodies have a high diagnostic and prognostic value but are present in a small percentage of patients. Among them, anti-Jo1 antibodies, directed against a histidyl-tRNA synthetase, are found in about 20% of patients with dermatomyositis and polymyositis. Together with interstitial lung disease, arthritis, mechanic’s hands, and Raynaud’s phenomenon, the positivity of anti-Jo1 antibodies characterizes the antisynthetase syndrome and significantly correlates with the risk of lung involvement [134]. Anti-Mi-2 antibodies are present in up to 30% of patients with dermatomyositis and are directed against the Mi-2 antigen, a component of the nuclesome remodeling and histone deacetylase complex. They are associated with benign forms of dermatomyositis with a prevalent cutaneous involvement [134]. Antisignal recognition particle (SRP) antibodies are found in a small percentage (about 4%) of patients with necrotizing myopathy having a severe disease course and low response to treatments [134]. Novel myositis-­specific antibodies include antitranscription intermediary factor 1 gamma (TIF1γ) antibodies, associated with adult paraneoplastic myositis, anti-hydroxy-methylglutaryl-beta-CoA-­reductase (HMGCR) antibodies, often found in patients who take statins, and antimelanoma ­differentiation–associated gene (MDA)-5 antibodies detectable in 20% of patients with amyopathic dermatomyositis and lung fibrosis. Finally, anti-­cytosolic 5-nucleotidase 1A (cN1A) antibodies may be detected in up to 70% of patients with ­inclusion-body myositis [133]. Anti-Ro/SSA, anti-La/SSB, anti-U1-RNP, and other ­unspecific antibodies are often present as myositis-­associated antibodies [135,136]. ANA are positive in 50%–80% of IIM patients, and usually display cytoplasmic or speckled patterns.

5.4  Sjögren’s syndrome Sjögren’s syndrome (SS) is an immune-mediated inflammatory disease of the exocrine glands characterized by the polyclonal activation of B cells resulting in hypergammaglobulinemia, high levels of β2-microglobulin, and generation of specific and nonspecific autoantibodies. Most patients are positive for the anti-ENA anti-Ro/SSA and anti-La/ SSB antibodies, which represent specific hallmarks of the disease and have been included among the SS classification criteria by several international societies [137–139]. Anti-Ro/ SSA and anti-La/SSB antibodies are found in 50%–70% and in 30%–60% of SS patients, respectively [140]. Both of them may appear several years before the clinical onset [141] thus representing a predictive marker of disease development; nonetheless, their detection is quite common in individuals with SLE or lupus-like syndromes [142]. Anti-Ro/ SSA and anti-La/SSB antibody positivity has been reported in SS patients with a more active and complicated disease, having an increased risk of cryoglobulinemia, severe hypergammaglobulinemia, vasculitis, lung involvement, and lymphoma [140]. This may

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partly depend on the neutralization of the Ro52 and Ro60 RNP, which behave as negative regulators of inflammation and autoimmunity [143]. Furthermore, anti-Ro/SSA antibodies have been shown to interfere with the atrio-ventricular conduction in babies whose mothers are seropositive during pregnancy [142]. Though nonspecific [46], ANA (at a titer ≥ 1:320) and RF are often present in SS individuals [141], and consequently inserted in the 2012 ACR diagnostic criteria for SS [139]. Other nonspecific autoantibodies include anti-α-fodrin, anti‑carbon dioxide, and anti-muscarinic receptor antibodies [144]. Given the frequent association of SS with other rheumatic diseases, a number of SS patients may have multiple autoantibody positivity. ACPA, ACA, anti-dsDNA, anti-Sm, anti-Ku, anti-Ki/SL, aPL, antineutrophil cytoplasm (ANCA), antimitochondrial (AMA) and antismooth muscle (ASMA) antibodies have been described in less than 10% of patients with secondary SS. Research is currently focusing on novel autoantibodies that may work as diagnostic or prognostic biomarkers of SS. Among them, the antisalivary gland protein 1 (SP1), anti‑carbonic anhydrase 6 (CA6), and antiparotid secretory protein (PSP) antibodies, detectable earlier than anti-Ro/SSA and anti-La/SSB antibodies, have been associated with a milder course of the disease, while anti-cofilin-1, anti-α-enolase and anti-Rho GDP-dissociation inhibitor 2 (RGI2) antibodies have been correlated with the risk of mucosa-associated lymphoid tissue (MALT) lymphoma [145]. Cryoglobulins, consisting of antibodies that precipitate at low temperatures (4°C) and dissolve at 37°C [146], may be found in severe forms of SS, characterized by a neuropathic, cutaneous, and vasculitic involvement and a high risk of non-Hodgkin lymphoma [147]. Similarly, hypocomplementemia and monoclonal bands at electrophoresis may be associated with greater morbidity and mortality risk. Other unspecific SS laboratory abnormalities include elevated ESR and serum IgG values, a normocytic normochromic anemia, leukopenia, and an altered hepatorenal function.

5.5  Undifferentiated and overlapping connective tissue diseases Patients with undifferentiated connective tissue diseases (UCTD) usually have raised ESR values and ANA positivity without typical autoantibody specificities [148]. A small percentage of them may progress toward a definite CTD, and according to a recent study [149], cytopenia as well as anti-ENA and aPL antibody positivity may be considered as risk factors of disease progression. Patients affected by overlapping syndromes may be positive for ANA and typical antibodies of the underlying diseases. The anti-U1 RNP antibody, recognizing a 70 kD antigen expressed in the U1 ribonuclear complex, is the hallmark of mixed connective tissue disease (MCTD), characterized by overlapping manifestations of SLE, SSc, and IIM. Although highly specific to MCTD and hence included among the Kasukawa and Alarcón-Segovia classification criteria [150], anti-U1 RNP antibodies may be found at low titers in other autoimmune diseases such as RA, SSc, and SS [151]. Anti-U1 RNP antibody seropositivity can reach 100% in MCTD patients [152], and their titers may dictate prognosis and response to therapies. The laboratory tests for the aforementioned CTD are reported in Table 3.

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7.  The diagnostic laboratory tests in rheumatic diseases

TABLE 3  Overview of the laboratory tests having diagnostic, prognostic, and clinical utility in autoimmune connective tissue diseases. Laboratory tests for systemic lupus erythematosus

Clinical significance

↑ ESR and, less commonly, CRP

Active inflammation

↑ WBC

Opportunistic infections, steroids (↑ neutrophils)

↓ WBC ↓ RBC ↓ PLT

Immune-mediated cytolysis, iatrogenic toxicity, viral infections (e.g., Parvovirus B19)

+ Direct Coombs test

Hemolytic anemia

↑ Transaminases

Lupic hepatitis, iatrogenic toxicity, opportunistic infections (HBV, HCV)

↑ Amylase and lipase

Lupic pancreatitis, iatrogenic toxicity

↑ Creatinine and urea

Glomerulonephritis, iatrogenic toxicity

↑ Glycemia

Meta-steroidal diabetes

↑ CPK

Autoimmune myositis or steroid-induced myopathy

↓ C3 ↓ C4 ↓ CH50 ↑ Anti-C1q antibodies

Active disease or concomitant infections, immune complex deposition, risk of obstetric complications and aPL positivity, association with severe glomerulonephritis

Urine biochemical tests and cytology

↑ Proteinuria, erythrocytes, acanthocytes, and leukocytes at the urinary sediment

Active glomerulonephritis

Autoantibodies

↑ ANA

Positive in nearly the totality of patients, homogenous or nucleolar patterns, nonspecific biomarker

↑ Anti-dsDNA ↑ Anti-Sm antibodies ↑ Anti-PCNA antibodies

Specific, correlation with disease’s flares and glomerulonephritis

↑ Anticardiolipin IgM/IgG/IgA ↑ Anti-beta2 glycoprotein I IgM/IgG/ IgA + LAC test

Association with APS (in up to 20% of cases), risk of thromboembolic events

Blood biochemical tests

↑ Anti-ENA antibodies

Anti-Ro/SSA Drug-induced lupus, subacute cutaneous lupus, risk antibodies of fetal cardiac conduction disturbance if present in a pregnant woman Others

Potential overlap with other connective tissue diseases

Genotyping

+ HLA-DR2 (DRB1*15:01) + HLA-DR3 (DRB1*03:01) + HLA-DRB1*08:01 + HLA-DQA1*01:02

Increased genetic predisposition to SLE

Microbiologic screening tests

CMV, HPV, HBV, HCV, HIV serology; tuberculin cutaneous test or interferon gamma release assay

Opportunistic infections in patients at high risk of immunosuppression (treated with immunosuppressive or biologic agents)

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TABLE 3  Overview of the laboratory tests having diagnostic, prognostic, and clinical utility in autoimmune connective tissue diseases—cont’d Laboratory tests for systemic sclerosis

Clinical significance

↑ ESR and, less commonly, CRP

Active inflammation

↓ RBC

Chronic inflammation, intestinal malabsorption of micronutrients

↑ Creatinine and urea

Rapid increase: renal crisis

↑ CPK

Myositis

↑ proBNP or NT-proBNP

Pulmonary artery hypertension, cardiac dilatation or fibrosis, cardiac ischemia

Urine biochemical tests and cytology

↑ Proteinuria, erythrocytes and leukocytes at the urinary sediment

Renal involvement

Autoantibodies

↑ ANA

Positive in up to 70% of patients, speckled or centromeric pattern, nonspecific biomarker

↑ Anti-Scl-70 antibodies

Present in up to 70% of patients, specific, association with diffuse skin involvement, lung fibrosis and renal crisis (fibrotic subset)

↑ ACA

Present in up to 30% of patients, specific, association with limited cutaneous forms, calcinosis, digital ulcers and esophagopathy (vascular subset)

↑ Anti-RNAP-III antibodies

Present in up to 20% of patients, specific, association with diffuse cutaneous involvement and renal crisis

↑ Anti-Th/To

Present in 2%–5% of patients, associated with limited cutaneous subset and visceral involvement

+ HLA-DRB1*11

Genetic predisposition to SSc in Caucasian population, higher risk of diffuse cutaneous form and interstitial lung disease

+ HLA-DPB1 and HLA-DPB2

Genetic predisposition to SSc in Asian population

Blood biochemical tests

Genotyping

Laboratory tests for idiopathic inflammatory myopathies Blood biochemical tests

Urine biochemical tests

Clinical significance

↑ ESR and, less commonly, CRP

Active inflammation

↑ CPK ↑ Aldolase ↑ LDH ↑ Myoglobin

Muscular damage and/or inflammation

↑ Creatinine and urea

Rapid increase: renal crisis due to tubular obstruction secondary to myoglobinuria

↑ proBNP or NT-proBNP ↑ CPK-MB

Cardiac muscle damage

↑ Myoglobinuria

Acute muscular damage Continued

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7.  The diagnostic laboratory tests in rheumatic diseases

TABLE 3  Overview of the laboratory tests having diagnostic, prognostic, and clinical utility in autoimmune connective tissue diseases—cont’d Laboratory tests for idiopathic inflammatory myopathies Autoantibodies

Clinical significance

↑ ANA

Positive in about 50%–80% of patients, mostly cytoplasmic or speckled patterns, nonspecific disease biomarker

↑ Anti-tRNA synthetase antibodies

Specific, mostly found in dermatomyositis and polymyositis (15%–20% of patients), association with lung interstitial disease, arthritis, mechanic’s hands and Raynaud’s phenomenon (antisynthetase syndrome)

↑ Anti-Mi-2 antibodies

Specific, association with benign forms of dermatomyositis

↑ Anti-SRP antibodies

Specific, association with necrotizing myositis, severe disease course and low response to treatments

↑ Anti-TIF1γ antibodies

Association with malignancies

↑ Anti-MDA 5 antibodies

Detectable in 20% of amyopathic dermatomyositis patients, associated with interstitial lung disease

↑ Anti-HMGCR antibodies

Mostly found in necrotizing myositis, conflicting association with the use of statins

↑ Anti-PM-SCL antibodies ↑ Anti-C1D antibodies ↑ Anti-U1-RNP antibodies ↑ Anti-fibrillarin antibodies ↑ Anti-Ku antibodies ↑ Anti-Ro/SSA antibodies ↑ Anti-La/SSB antibodies ↑ Anti-cN-1A antibodies

Myositis-associated antibodies, poor specificity

Laboratory tests for Sjӧgren’s syndrome

Clinical significance

Blood ↑ ESR and, less commonly, CRP biochemical tests ↓ RBC

Active inflammation

Autoantibodies

Chronic inflammation, micronutrient deficiency

↓ WBC

High risk of lymphoma

Hypergammaglobulinemia, monoclonal peak at electrophoresis

High morbidity and mortality risk, lymphoma

↓ C3 ↓ C4 ↓ CH50

Severe systemic disease

↑ RF

Positive in 75%–95% of patients, nonspecific

↑ ANA

Positive in more than 70% of patients, speckled pattern, nonspecific

↑ Anti-Ro/SSA antibodies

Present in 50%–70% of patients, specific, association with active disease and extra-glandular manifestations

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TABLE 3  Overview of the laboratory tests having diagnostic, prognostic, and clinical utility in autoimmune connective tissue diseases—cont’d Laboratory tests for Sjӧgren’s syndrome

Clinical significance

↑ Anti-La/SSB antibodies

Present in 30%–60% of patients, specific, association with active disease and extra-glandular manifestations

↑ ACPA ↑ ACA ↑ Anti-dsDNA/Sm antibodies ↑ aPL antibodies ↑ ANCA ↑ AMA ↑ ASMA ↑ Thyroid-specific antibodies

Present in less than 10% of patients, nonspecific, overlapping autoimmune diseases

↑ Cryoglobulins

Neuropathic, cutaneous and vasculitic involvement, high risk of non-Hodgkin lymphoma

Laboratory tests for mixed connective tissue disease

Clinical significance

↑ ESR and, less commonly, CRP

Active inflammation

↓ RBC ↓ WBC ↓ PLT

SLE-associated blood disorders, iatrogenic toxicity

↑ CPK ↑ Aldolase ↑ LDH ↑ Myoglobin

Muscular damage and/or inflammation

↓ C3 ↓ C4 ↓ CH50

SLE-associated immunologic disorders

Urine biochemical tests and cytology

↑ Myoglobinuria ↑ Proteinuria and typical findings at urinary sediment

Acute muscular damage and SLE-related glomerulonephritis

Autoantibodies

ANA

Positive in up to 100% of patients, nonspecific

Anti-U1 RNP antibodies

Positive in up to 100% of patients, highly specific, association with therapy response and prognosis

Blood biochemical tests

ACA, anticentromere antibody; AMA, antimitochondrial antibodies; ANA, antinuclear antibodies; ANCA, antineutrophil cytoplasm antibodies; anti-dsDNA, anti-double stranded DNA antibodies; anti-ENA, antiextractable nuclear antigen antibodies; anti-HMGCR, anti-hydroxy-methyl-glutaryl-beta-CoA-reductase antibodies; anti-MDA 5, antimelanoma differentiation-associated gene 5 antibodies; anti-PCNA, antiproliferating cell nuclear antigen antibodies; anti-RNAP-III, anti-RNA polymerase III antibodies; anti-Sm, anti-Smith antibodies; anti-TIF1γ, antitranscription intermediary factor 1 gamma antibodies; APL, antiphospholipid antibodies; APS, antiphospholipid syndrome; ASMA, antismooth muscle antibodies; C3, complement fraction 3; C4, complement fraction 4; CH50, 50% hemolytic complement activity; CMV, cytomegalovirus; CPK, creatine phosphokinase; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HLA, human leukocyte antigen; HPV, human papillomavirus; Ig, immunoglobulins; LAC, lupus anticoagulant; LDH, lactate dehydrogenase; NT-proBNP, amino-terminal pro-brain natriuretic peptide type B; PLT, platelets; proBNP, pro-brain natriuretic peptide type B; RBC, red blood cells; RF, rheumatoid factor; RNP, ribonucleoprotein; SLE, systemic lupus erythematosus; WBC, white blood cells.

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6  Laboratory tests in vasculitis With some exceptions, the laboratory offers little help in the diagnosis of vasculitis. Nonspecifically altered laboratory tests include an increase in acute-phase reactants (especially ESR) and other indirect parameters of systemic inflammation, such as a normocytic normochromic anemia and an increase in α-globulins at electrophoresis. ESR values ≥ 50 mm/1st hour and an unexplained anemia are part of the revised ACR criteria for the diagnosis of GCA [153]. Serum CRP concentration above 20 mg/L and an increased platelet count (> 300 × 109/L) were shown to have similar sensitivity and specificity as ESR in predicting GCA development [154]. Alterations of biochemical parameters can indicate the presence of organ-specific damages. An impairment in the renal function is common to vasculitis affecting medium- and small-sized vessels. A positive HBV and HCV serology may be observed in individuals with polyarteritis nodosa (PAN) and cryoglobulinemia, respectively [155,156], due to the central role played by these viruses in the pathogenesis of the two diseases. Genotyping may be useful in the diagnostic algorithm of BD, a vasculitis affecting arterial and venous vessels of variable size [157]. The HLA-B51 haplotype is found in about 40%–70% of BD cases [158], in whom it is significantly associated with male gender and complete forms of disease. Immunologic laboratory tests may reveal the presence of ANCA, cryoglobulins, and other autoantibodies involved in the pathogenesis of vasculitis (Table 4). ANCA and/or antibodies reacting against lysosomal components of monocytes are the hallmark of ANCA-associated vasculitis [159]. These consist of a group of diseases affecting medium- and small-sized vessels and inducing granulomatous lesions of the upper and lower airways and a necrotizing glomerulonephritis [160]. ANCA are pathogenic antibodies, usually IgG, which recognize antigens expressed on the surface of neutrophils and monocytes. They play a crucial role in the recruitment and activation of neutrophils in small vessels [161]. ANCA can be easily detected at IFI on a substrate of human leukocytes and quantified through ELISA. ANCA immunofluorescence may give rise to a cytoplasmic pattern (c-ANCA) induced by antibodies directed against the proteinase-3 enzyme (PR3), or to a perinucleolar pattern (p-ANCA) due to antibodies binding the myeloperoxidase enzyme (MPO). Atypical ANCA patterns, underlying the presence of antibodies against elastases, lactoferrin or cathepsin G, may instead be observed in different clinical conditions such as hepatobiliary disorders, IBD or drug vasculitis [162,163]. In order to increase diagnostic sensitivity and specificity, IFI and ELISA are both indicated in case of a suspected ANCA vasculitis [164]. ANCA positivity is found in 90% of patients with granulomatosis with polyangiitis, in 80%–85% of patients with microscopic polyangiitis and in 50% of patients with eosinophilic granulomatosis with polyangiitis [165]. C-ANCA contribute by 70%–80% to ANCA positivity in individuals with granulomatosis with polyangiitis, while p-ANCA contribute by more than 60% to ANCA positivity in patients with microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis [162,165]. The usefulness of ANCA titers in monitoring disease activity is instead controversial [166]. C-ANCA seem associated with a higher risk of relapse compared to p-ANCA, especially in patients with glomerulonephritis and alveolar hemorrhage [167]. Hypereosinophilia (> 10%) [168] and augmented IgE serum titers are common laboratory findings in eosinophilic granulomatosis with polyangiitis [169] and may help in the differential diagnosis with other

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TABLE 4  Overview of the laboratory tests having diagnostic, prognostic, and clinical utility in autoimmune vasculitis. Laboratory tests for vasculitis

Clinical significance

Blood biochemical ↑ ESR and CRP tests

Active inflammation (high increase especially in giant cell arteritis and polymyalgia rheumatica)

↓ RBC

Chronic inflammation, renal involvement

↑ Eosinophils

Eosinophilic granulomatosis with polyangiitis

↑ Creatinine and urea, electrolyte alterations

Vascular inflammation, glomerulonephritis (polyarteritis nodosa, ANCA-associated vasculitis, Henoch-Schönlein purpura, Goodpasture’s syndrome, cryoglobulinemia, hypocomplementemic urticarial vasculitis)

↑ IgE

Eosinophilic granulomatosis with polyangiitis

↑ IgA or abnormally glycosylated IgA

Henoch-Schönlein purpura

↓ C3 ↓ C4 ↓ CH50

Hypocomplementemic urticarial vasculitis

Urine biochemical ↑ Proteinuria and tests, cytology hematuria, typical findings at urinary sediment

Active glomerulonephritis, high risk of renal relapse in patients affected by granulomatosis with polyangiitis or microscopic polyangiitis

↑ p-ANCA

Found in 20%–30% of ANCA-positive patients with granulomatosis with polyangiitis; 70%–80% of ANCA-positive patients with microscopic polyangiitis, and 60%–70% ANCA-positive patients with eosinophilic granulomatosis with polyangiitis, rarely found in polyarteritis nodosa, RA and SLE

↑ c-ANCA

Found in 80% of ANCA-positive patients with granulomatosis with polyangiitis, 20%–30% of ANCA-positive patients with microscopic polyangiitis, and 30%–40% ANCA-positive patients with eosinophilic granulomatosis with polyangiitis; association with relapse in patients with glomerulonephritis and alveolar hemorrhage

↑ Cryoglobulins

Cryoglobulinemic vasculitis, association with SS and HCV infection

↑ Anti-C1q antibodies

Hypocomplementemic urticarial vasculitis

↑ Anti-GBM antibodies

Goodpasture’s syndrome

Genotyping

+ HLA-B51

Behçet’s disease, association with male gender and complete forms of disease

Microbiologic screening tests

HBV and HCV positive serology

Association with polyarteritis nodosa and cryoglobulinemia

Autoantibodies

Anti-GBM, antiglomerular basement membrane antibodies; c-ANCA, antineutrophil cytoplasm antibodies with an IFI cytoplasmic pattern; C3, complement fraction 3; C4, complement fraction 4; CH50, 50% hemolytic complement activity; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; HBV, hepatitis B virus; HCV, hepatitis C virus; HLA, human leukocyte antigen; Ig, immunoglobulins; p-ANCA, antineutrophil cytoplasm antibodies with an IFI perinuclear pattern; RBC, red blood cells; SLE, systemic lupus erythematosus; SS, Sjögren’s syndrome; RA, rheumatoid arthritis.

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ANCA-associated vasculitis [170]. Laboratory tests for ANCA-associated vasculitis should additionally include acute-phase reactants and renal function biomarkers (like hematuria, proteinuria, and urinary sediment examination) [160]. According to a study [171], a persistent hematuria may represent a risk factor for renal relapses in granulomatosis with polyangiitis and microscopic polyangiitis patients. Cryoglobulinemic vasculitis develops following the precipitation of cryoglobulins in distal vascular districts [146]. Cryoglobulins are divided into type I cryoglobulins, consisting of monoclonal antibodies; type II cryoglobulins, consisting of monoclonal and polyclonal antibodies; and type III cryoglobulins, consisting of polyclonal antibodies. Type I cryoglobulins are usually found in lymphoproliferative disorders, while type II and III cryoglobulins can be detected in the serum of RA, SS, mixed essential cryoglobulinemia, CTD, and hepatitis C patients. Given the physical properties of cryoglobulins, biologic samples should be rigorously collected, transported and centrifuged in warmed (37–40°C) syringes and tubes, and the serum stored at 4°C for about a week. The quantification of the cryoprecipitate is made through the direct measurement of the proteins (cryocrite) by means of spectrophotometric or selective centrifugation methods. Immunofixation or immunoelectrophoresis assays are instead used to characterize the nature of cryoglobulins [156]. The precipitate may be revealed after 24 h if type I and II cryoglobulins are present, and after several days in case of type III cryoglobulin positivity [156].

7  Laboratory tests in infectious arthritis The laboratory is of utmost importance in the diagnosis of infectious arthritis. The most diriment test is the analysis of a synovial fluid sample obtained from an inflamed joint, which may show a huge increase in cellularity (> 50,000 elements/mm3, mostly neutrophils) and/or pathogens evidenced at Gram staining or in cultures [172]. The analysis of blood samples is less specific and may evidence leukocytosis, raised ESR and CRP serum values, microorganisms growing in blood cultures or antibodies, and elevated serum levels of procalcitonin [173]. The latter is a proinflammatory mediator released during bacterial infections, whose quantification in serum or synovial fluid may help in differentiating septic from nonseptic arthritis [174]. Staphylococcus aureus is the main cause of septic arthritis in adults and immunosuppressed people [173], followed by Streptococci spp., Hemophilus influenzae, Pseudomonas aeruginosa, Mycoplasma hominis, Mycobacteria, Escherichia coli, Shigella, Salmonella, and Borrelia burgdorferi. A viral etiology may be confirmed through serodiagnosis or a PCR assay performed on synovial fluid samples [175]. Parvovirus B19, HBV, HCV, ­adenoviruses, ­rubiviruses, Coxsackie A and B viruses, Epstein Barr virus, and retroviruses may all be responsible for joint infection. Fungi and parasites (Sporothrix schenckii, Coccidioides immitis, Candida albicans, Blastomyces dermatitidis, and Giardia lamblia) can cause infectious arthritis in immunocompromised individuals. In pediatric subjects, streptococci, Hemophilus, and enterococci are the most commonly isolated microorganisms, while infectious arthritis following invasive procedures, such as surgery or intra-articular injections, can be sustained by atypical microorganisms (Listeria monocytogenes, Mycobacterium tuberculosis, and Pseudomonas aeruginosa) [176].

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8  Laboratory tests in microcrystalline arthritis The term microcrystalline arthritis defines a group of rheumatological conditions characterized by the deposition of microcrystals of urate or calcium salts in articular, periarticular, or extra-articular sites. This group includes gout, chondrocalcinosis, and hydroxyapatite deposit-associated arthritis. During the acute phase, microcrystalline arthritis is characterized by a high degree of local and/or systemic inflammation, mirrored by leukocytosis and rapid and huge increases in serum inflammatory biomarkers (ESR and CRP) [177]. Gout patients usually have a past history of chronic hyperuricemia, which may depend on several predisposing factors and develops many years before the first arthritic attack [178]. While an asymptomatic hyperuricemia is estimated in 10%–20% of general population, gout occurs in about 7% of elderly people [179]. The precipitation of monosodium urate crystals in tissues is favored by either an increase in urate serum concentration over a threshold of 6 mg/dL [180] or altered ECM repairing mechanisms [181]. The research of crystals in the synovial fluid of joints or bursae is pathognomonic for making a definite diagnosis of gout. The 2015 ACR/EULAR gout classification criteria attribute a negative score to the absence of monosodium urate crystals in synovial fluid and hypouricemia [8]. Since serum urate may be within the normal range during the arthritic attack, its measurement should be made 4 weeks apart the acute episode and possibly after the discontinuation of urate-­ lowering medications. Chondrocalcinosis is due to the deposition of calcium pyrophosphate dehydrate (CPPD) crystals in hyaline and fibrous cartilage, and represents a frequent medical condition of the elderly, occurring in about 30% of individuals aged over 80 years [179]. Several metabolic alterations may be at the basis of an augmented production or a limited catabolism of pyrophosphate, ultimately leading to the disease [179]. Chondrocalcinosis patients should be screened for hypomagnesemia, hypophosphatemia, increased parathyroid hormone (PTH) serum values, hypercupremia, and hypersideremia [182]. Familial forms of disease may rely on polymorphic variants of the gene coding for the inorganic pyrophosphate transporter progressive ankylosis protein homolog (ANKH) [182]. As for gout, diagnosis should be confirmed through the identification of crystals in synovial fluid, but imaging may be preferred in case of sites inaccessible to aspiration or false negative laboratory findings [183]. Laboratory tests to be required in infectious and microcrystalline arthritis are reported in Table 5.

9  Laboratory tests in osteoporosis Imaging is considered the gold standard for the diagnosis of postmenopausal osteoporosis according to the most recent European guidelines [184]. Laboratory tests may have a prognostic value in predicting the fracture risk of already diagnosed patients. In cases of secondary osteoporosis, laboratory tests may also help in individuating the cause underneath the osteoporotic process (e.g., mineral deficiency, hypovitaminosis D, endocrinological or hematological disorders, renal diseases) [185] (Table 6).

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7.  The diagnostic laboratory tests in rheumatic diseases

TABLE 5  Overview of the laboratory tests having diagnostic, prognostic, and clinical utility in infectious and microcrystalline arthritis. Laboratory tests for infectious arthritis

Clinical significance

↑ ESR and CRP

Active inflammation

↑ WBC

Inflammation, concomitant infection

↑ Procalcitonin

Bacterial infection

Microbiologic and immunoserologic tests

Blood or synovial fluid culture IgM, IgA, and IgG serology

Identification of the causative microbial agent

Synovial fluid analysis

≥ 50,000 cells/mm3, ragocytes and polymorphs representing > 90% of total nucleated cells, microorganisms revealed at Gram staining and in cultures

Acute inflammation, detection of microorganisms (diagnostic disease biomarker)

Blood biochemical tests

Laboratory tests for microcrystalline arthritis Blood biochemical tests

Synovial fluid analysis

Clinical significance

↑ ESR and CRP

Active inflammation

↑ Uricemia

Risk of gout (preclinical stage)

↑ Iron ↑ Cupper ↑ PTH ↓ Phosphate ↓ Magnesium

Risk of chondrocalcinosis

≥ 50,000 cells/mm3 (neutrophils), monosodium urate, CPPD and hydroxyapatite crystals, depolymerization of proteoglycans, increased protein and decreased glucose content

Acute inflammation, detection of microcrystals under polarized light microscopy (diagnostic disease biomarker)

CPPD, calcium pyrophosphate dehydrate; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; Ig, immunoglobulin; PTH, parathyroid hormone; WBC, white blood cells.

TABLE 6  Overview of the laboratory tests having diagnostic, prognostic, and clinical utility in osteoporosis. Laboratory tests for osteoporosis Blood biochemical tests

Urine biochemical tests

Clinical significance

↓ Calcemia ↓ 25(OH) vitamin D ↓ Phosphatemia ↓↑ PTH ↑ Thyroid hormones ↑ Cortisol ↓ Sex hormones

Endocrine and metabolic disorders, micronutrient malabsorption, electrolyte unbalance

↑ Osteocalcin ↑ Alkaline phosphatase ↑ Amino-terminal fragment of procollagen type I

Increased bone turnover, response to treatments

↑ Carboxy-terminal telopeptide of collagen type I ↑ Amino-terminal telopeptide of collagen type I

Increased bone turnover, response to treatments

PTH, parathyroid hormone.

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The ratio between the markers of osteoblastic activity (serum osteocalcin, total alkaline phosphatase, and amino-terminal fragment of procollagen type I) and those of osteoclastic activity (serum and urinary carboxy-terminal telopeptide of collagen type I, urinary amino-­terminal telopeptide of collagen type I, and serum tartrate-resistant acid phosphatase), along with the serum concentrations of total and ionized calcium, PTH, and vitamin D isoforms may reflect bone turnover and be useful for monitoring the response to therapies [186]. Total serum calcium concentration is influenced by serum proteins (mostly albumin) to which the electrolyte is bound by 40%. A 1 g/dL reduction in the serum concentration of albumin may lower total calcium serum values by 0.8 mg/dL [187]. Ionized calcium, having a normal range of 1.1–1.3 mmol/L, instead represents the biological active form and is not influenced by serum protein concentration, being therefore a more reliable means of monitoring calcemia. Different isoforms of vitamin D can be measured by means of automated immunoassays [188]. The serum concentration of 1,25(OH)2 vitamin D, being the biologically active form, is in the order of picomoles and strictly influenced by hormones such as PTH or calcitonin. Its measurement may be useful in selected cases, like 1α-hydroxylase deficiency, granulomatous and lymphoproliferative disorders or hereditary vitamin D-resistant rickets [188]. On the contrary, the 25(OH) vitamin D isoform, whose physiologic serum concentration is above 30 ng/ mL, is less influenced by hormones and considered as the gold standard for testing a vitamin D deficiency [187]. Serum values below 20–30 ng/mL correspond to a mild deficiency; values between 10 and 20 ng/mL to a moderate deficiency; and values  40,000 patients undergoing total knee

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19.  Evaluation and surgical management of the rheumatoid foot and ankle

arthroplasty (TKR), RA patients were associated with a significant increase in postoperative joint infection [116]. Total ankle replacement has become a reasonable alternative to ankle arthrodesis in the RA patient.

15  Conclusion In summary, care should be taken to mitigate and prevent pre-, peri-, and postoperative complications in this patient population. RA patients are known to have increased complications related to their soft tissue and diminished bone quality. These factors should be taken into account when undertaking operative reconstruction of these patients. A thorough examination preoperatively will aid in elimination of some of these risks. A multidisciplinary approach must be taken when treating the RA patient to optimize patient outcomes.

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[105] K.L. Wapner, A.R. Ndu, Patient selection, surgical indications, and preoperative planning, in: J.K. DeOrio, S.G. Parekh (Eds.), Total Ankle Replacement: An Operative Manual, Wolters Kluwer/Lippincott Williams & Wilkins, Philadelphia, PA, 2014. [106] J. Day, P.S. Principe, K.C. Caolo, A.T. Fragomen, S.R. Rozbruch, S.J. Ellis, A staged approach to combined extra-articular limb deformity correction and total ankle arthroplasty for end-stage ankle arthritis, Foot Ankle Int. (2020). 1071100720965120. [107] R.M. Queen, S.B. Adams Jr., N.A. Viens, J.K. Friend, M.E. Easley, J.K. DeOrio, J.A. Nunley, Differences in outcomes following total ankle replacement in patients with neutral alignment compared with tibiotalar joint malalignment, JBJS 95 (21) (2013) 1927–1934. [108] A. Barg, C.L. Saltzman, Ankle replacement, in: M.J. Coughlin, C.L. Saltzman, R.B. Anderson (Eds.), Mann's Surgery of the Foot and Ankle, Saunders/Elsevier, Philadelphia, PA, 2013. [109] Zimmer Biomet, Zimmer trabecular metal total ankle—Zimmer Biomet. Trabecular Metal™ Total Ankle, 2017. Retrieved from: https://www.zimmerbiomet.com/content/dam/zb-corporate/en/products/specialties/ foot-&-ankle/trabecular-metal-total-ankle-system/zimmertrabecularmetaltotalanklebrochure.pdf. [110] J.K. Steck, J.M. Schuberth, J.C. Christensen, C.A. Luu, Revision total ankle arthroplasty, Clin. Podiatr. Med. Surg. 34 (4) (2017) 541. [111] E.P. Su, B. Kahn, M.P. Figgie, Total ankle replacement in patients with rheumatoid arthritis, Clin. Orthop. Relat. Res. 424 (2004) 32–38. [112] M. Nishikawa, T. Tomita, M. Fujii, T. Watanabe, J. Hashimoto, K. Sugamoto, et al., Total ankle replacement in rheumatoid arthritis, Int. Orthop. 28 (2) (2004) 123–126. [113] H.J. van der Heide, B. Schutte, J.W.K. Louwerens, F.H. van den Hoogen, M.C. de Waal Malefijt, Total ankle prostheses in rheumatoid arthropathy: outcome in 52 patients followed for 1–9  years, Acta Orthop. 80 (4) (2009) 440–444. [114] J. Kruidenier, L.W. van der Plaat, I.N. Sierevelt, D. Hoornenborg, D. Haverkamp, Ankle fusion after failed ankle replacement in rheumatic and non-rheumatic patients, Foot Ankle Surg. 25 (5) (2019) 589–593. [115] S.M. Raikin, J. Kane, M.E. Ciminiello, Risk factors for incision-healing complications following total ankle arthroplasty, JBJS 92 (12) (2010) 2150–2155. [116] E. Jämsen, O. Furnes, L.B. Engesæter, Y.T. Konttinen, A. Odgaard, A. Stefánsdóttir, L. Lidgren, Prevention of deep infection in joint replacement surgery: a review, Acta Orthop. 81 (6) (2010) 660–666.

Further reading [117] W. Miehlke, N. Gschwend, P. Rippstein, B.R. Simmen, Compression arthrodesis of the rheumatoid ankle and hindfoot, Clin. Orthop. Relat. Res. 340 (1997) 75–86. [118] B.M. Lamm, P.A. Stasko, M.G. Gesheff, A. Bhave, Normal foot and ankle radiographic angles, measurements, and reference points, J. Foot Ankle Surg. 55 (5) (2016) 991–998. [119] M.A. Glazebrook, K. Arsenault, M. Dunbar, Evidence-based classification of complications in total ankle arthroplasty, Foot Ankle Int. 30 (10) (2009) 945–949. [120] A.S. Franco, L.R. Iuamoto, R.M.R. Pereira, Perioperative management of drugs commonly used in patients with rheumatic diseases: a review, Clinics 72 (6) (2017) 386–390. [121] S.M. Goodman, B. Springer, G. Guyatt, M.P. Abdel, V. Dasa, M. George, et  al., 2017 American College of Rheumatology/American Association of Hip and Knee Surgeons guideline for the perioperative management of antirheumatic medication in patients with rheumatic diseases undergoing elective total hip or total knee arthroplasty, J. Arthroplast. 32 (9) (2017) 2628–2638. [122] J. Wolfe, J. Wolfe, H.J. Visser, Perioperative management of the rheumatoid patient, Clin. Podiatr. Med. Surg. 36 (1) (2019) 115–130.

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20 Immunopathogenesis and treatment of scleroderma Ayda AlHammadia,⁎ and Amer Ali Almohssenb,⁎ a

Core Teaching Faculty at Hamad Medical Corporation, Dermatology Residency Program, Doha, Qatar, bAlfardan Medical with Northwestern Medicine, Doha, Qatar ⁎

Corresponding authors

Abstract Scleroderma is a complex multisystem disease. Although the pathophysiology of the disease has not been completely discovered yet, multiple genetic, environmental, vascular, and immunological factors have been identified to play a role in the etiology of the disease. In certain genetically predisposed individuals, there is an altered immune response eventually leading to defective vasculogenesis and progressive fibrosis of the skin and affected organs. Some environmental factors have been implicated in the development of scleroderma-like disease. Those include exposure to solvents such as vinyl chloride, white spirit, trichloroethylene, aromatic solvents, chlorinated solvents, and ketones. Silica is another known risk factor. There is no universally approved protocol for the treatment of scleroderma. Treatment depends on the severity of the disease and organs affected. Agents like iloprost, calcium channel blockers, and ­angiotensin-converting enzyme (ACE) inhibitors have been used for the treatment of vascular manifestations of scleroderma. Phototherapy and stronger immunosuppressive agents such as mycophenolate and cyclophosphamide have also been attempted for treatment of extensive and severe cases. Newer targeted therapies like rituximab, abatacept, and tocilizumab are being investigated and showing promising results. It is of interest to individualize treatment plans based on the nature of the disease.

Keywords Scleroderma, Autoimmune, Etiopathogenesis, Monoclonal antibodies, Systemic sclerosis

1  Introduction Scleroderma is a multisystem autoimmune disease, characterized by progressive fibrosis of multiple body organs, most commonly skin, esophagus, lung, heart, and kidneys [1,2].

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20.  Immunopathogenesis and treatment of scleroderma

When scleroderma is limited to the skin, it is known as morphea. If scleroderma involves multiple organs, it is called systemic sclerosis (SSc). Skin involvement is a cardinal feature of SSc were only 1.5% of the SSc patients present with internal organ involvement without skin sclerosis, a.k.a. systemic sclerosis sine scleroderma (ssSSc) [3]. More than 90% of SSc patients present with Raynaud's phenomenon (RP) and 50% of the patients are affected by ­vasculop­athy-induced digital ulcers. GI involvement is the most common internal organ to be affected by SSc in more than 60% of patients. Renal involvement in the form of severe renal crisis (SRC) affects 5%–10% of SSc patients. Interstitial lung disease (ILD) is the most common cause of mortality while its estimated prevalence in SSc patients is up to 84% [4].

2  Pathogenesis Scleroderma has a complex autoimmune pathogenesis that includes the interaction of epithelial cells, lymphocytes, and fibroblasts. The initial trigger of the disease remains undetermined, but possible provoking factors include genetic susceptibility, environmental triggers, and chemical triggers.

2.1  Genetic factors Genetic contribution to SSc is mainly based on familial clustering studies and genetic analysis of individualized autoantibody profiles. Several studies suggest that a positive family history of SSc is the strongest risk factor, while an additional study suggests that family members of SSc patients tend to develop scleroderma-specific autoantibodies. Genetic analysis provides further support by emphasizing the ability of certain histocompatibility complex haplotypes to mount an immune response against SSc-associated antigens. For example, human lymphocyte antigen (HLA)‐A*30, HLA‐DRB1*01, and HLA‐A*32 have been associated with SSc susceptibility. On the other hand, HLA‐Cw*14 has been associated with a decreased risk of SSc. Additionally, increased mortality has been linked to HLA‐DRB1*0802 and DQA1*0501 [5]. HLA-DRB1 ∗ 1302 and HLA-DQB1 ∗ 0604/0605 haplotypes have been linked to antifibrillarin antibodies positivity, while HLA-SRB1 ∗ 0301 has been demonstrated in patients with anti-Pm-Scl antibodies positivity, which is correlated with SSc polymyositis syndrome. A novel HLA-DRB1*10 association with juvenile-onset SSc was reported by one study in 10% of the juvenile patients. Protective HLA alleles on the other hand (DRB1 ∗ 07, DQB1 ∗ 02:02), were reported in adult-onset SSc [6]. Additionally, in the European and Hispanic populations, a connection to HLA‐DQB1, HLADRB1*1104, HLA‐DQA1*0501, and HLA‐DQB1*0301 has been discovered. Moreover, HLA‐DPB1*1301 Scl70 positivity has been observed in the White population. In both the white and Chinese populations, HLA‐DQB1*26 and HLA‐DQB1*0501 were linked to an increased expression in a subgroup of anticentromere antibodies (ACA) positive SSc patients. In Chinese and Korean populations, an association of HLA‐DPB1 and HLA‐DPB2 with SSc risk has been determined. HLA-DPB1*0901 and HLA‐DPB1*1301 were more common in the Korean SSc population, while HLA‐DQB1*06:11, HLA-DPB1*03:01, HLA‐DQB1*03:03, HLA‐ DQB1*05:01, and HLA‐DPB1*13:01 have prevailed in the Chinese SSc population [7].

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About 10% of SSc patients express anti-RNA polymerase III antibodies, which are closely related to breast, lungs, esophagus, urinary bladder, and hematopoietic malignancies. This suggests that those subsets of patients may present with the paraneoplastic syndrome with autoimmune manifestations [8]. Additionally, epigenetic regulation of gene expressions of multiple cytokines and growth factors without alteration in the DNA sequence likely has a critical role in the pathogenesis of scleroderma, resulting in activated immune response and fibrotic events. These m ­ echanisms involve DNA methylation, histone modification, and the recently investigated posttranscriptional mRNA regulation by noncoding RNAs, named microRNAs. Di Benedetto et al. have found that bone marrow-derived mesenchymal cells and adipose tissue-derived mesenchymal cells from patients with SSc express a high level of microRNA associated with profibrotic tendency [9]. In recent years, single nucleotide polymorphism (SNP) of the gene encoding interleukin (IL)-1A cytokine has been linked to increased SSc risk in Caucasian, Chinese, and Japanese populations. IL-1β SNP, on the other hand, shows conflicted results. It demonstrates the increasing risk of ventilatory restriction risk in SSc patients in one study; however, the SSc risk was significantly lower in patients harboring the SNP of IL-1β in an Italian study [10].

2.2  Environmental factors Numerous environmental exposures have been repeatedly reported as a cause of s­ cleroderma-like syndromes, including solvents such as vinyl chloride and drugs such as bleomycin among other substances. A recent study showed that silica and solvents are chemicals that are highly implicated in the pathogenesis of SSc [8,11]. Exposure to silica was mostly related to some occupations. Some other causative solvents include white spirit, trichloroethylene, aromatic solvents, chlorinated solvents, and ketones. Welding fumes have also been identified as risk factors [11]. However, chemical exposures play a role in a small fraction of SSc patients, which is mainly an initiating event in the modulation of the epigenetic determinants of the disease onset and progression. The environmental effect is likely triggering SSc initiation through the generation of reactive oxygen species (ROS), which was supported by a study demonstrating greater mitochondrial DNA base oxidation resulting in DNA damage and a decrease in mitochondrial DNA copy numbers [12].

2.3  Vasculopathy Vasculopathy in SSc is a primary pathogenic process involving micro-vasculatures. The earliest event is represented by the imbalance between vasodilatory mediators, including nitric oxide (NO), prostacyclin, and calcitonin-gene-related peptide (CGRP), and vasoconstrictive mediators, including endothelin-1, angiotensin II, alpha 2 adrenoreceptors, impairing the blood flow and resulting in tissue hypoxia. Consequently, vascular endothelial growth factor (VEGF) release is induced with a resultant defect in vasculogenesis. Intravascular and structural changes in addition to functional abnormalities are the main contributors to the RP and progression of the blood flow reduction along with vascular obliteration. The endothelium overgrowth and scar tissue deposits are the earliest sign of the disease and

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are demonstrated in the nail fold capillaroscopy. Additionally, they are major causes of the disease’s serious complications, including pulmonary arterial hypertension and severe renal crisis [13].

2.4  Immunological factors The innate immunity is the first line of defense against pathogens in humans. Its response is rapid and nonspecific. The innate immune system has both cellular and noncellular ­components. The cellular component includes neutrophils, eosinophils, macrophages, mast cells, and natural killer (NK) cells. The noncellular component includes toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD)-like receptors (NLRs). Those two components recognize pathogen-associated molecular patterns (PAMPs). Activation of TLRs signals the expression of multiple proinflammatory cytokines and chemokines [14]. Although the immunopathology of SSc remains poorly understood, emerging data suggest the role of innate immunity, in particular TLRs, as pathogenic mediators in the disease pathophysiology. Evidence has already established that monocytes and macrophages are elevated in the blood of SSc patients and epigenetic therapy could also be a viable way to alter TLRs' signaling to reduce fibrosis [15]. Additionally, there is increased expression of interleukin-1 (IL-1) family cytokines in SSc [10]. The IL-1 family comprises eleven pro- and antiinflammatory cytokines. Recent discoveries show that in many autoimmune diseases, including SSc, there was an abnormal expression of many IL-1 family cytokines such as IL-1α, IL-1β, IL-18, and IL-33. Similarly, SSc susceptibility correlated with gene polymorphisms of IL-1α, IL-1β, IL-18, and IL-33 [10]. IL-1α has been reported in several studies as a possible inducer of the fibroblast differentiation to the SSc phenotype. This concept is linked to the observed higher level of the cytokine in the SSc fibroblasts. IL-1α promotes the production of IL-6 and platelet-derived growth factor (PDGF) [2]. IL-1β is an additional related cytokine observed in several studies to be elevated in the lesional skin of SSc patients and is associated with the severity of sclerosis. Nucleotide-binding domain, leucine-rich repeat containing family, and pyrin domain-­containing 3 (NLRP3) inflammasomes have a critical role in activating caspase-1 and cleaving the precursor of IL-1β, inducing myofibroblast activation similarly as the IL-1α does. Caspase-1 inhibition could reduce myofibroblasts induction [16]. In addition to the overexpression of IL-1 family cytokines, the innate immunity was found to be malfunctioning in patients with SSc. For a long period of time, it was believed that the immune system reacted to nonself only. This was acceptable until the discovery of a group of molecules called damage associated molecular patterns (DAMPs), which are host-derived molecules that can function to regulate the activation of pattern recognition receptors (PRRs). Multiple sources have been identified for DAMPs; for instance, dying cells and the extracellular matrix ECM). DAMPs can be both TLRs' agonists and antagonists [17]. A group of molecules that belongs to the DAMP family is high mobility group box  1 (HMGB-1), which along with other DAMP molecules have been found to be elevated in SSc. As for the cellular sources, one identified source was noted to be damaged endothelium since vascular damage is an early event in SSc [15].

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In addition, it has been found that TLR4 is upregulated in SSc. TLR4 binds to lipopolysaccharides (LPS) in gram-negative bacteria. However, it is unlikely that the activation of TLR4 in SSc resulted from bacterial LPS, but rather an internal DAMP. It has been demonstrated that a glycoprotein (Tenascin-C) is elevated in SSc and was found to be the activating factor for TLR4 to mediate profibrotic effects observed in SSc [18,19]. Another possible DAMP is the extra-domain A (EDA) of fibronectin. The skin and blood of SSc patients were found to have elevated levels of fibronectin EDA. Transforming growth factor-B1 (TGFb-1) appears to be the regulating factor stimulating myofibroblast stimulation and matrix stiffening [20]. Another upregulated TLR in SSc is TLR8, which is an intracellular TLR that recognizes nucleic acid, usually of viral type. TLR8 is the receptor for single stranded RNA (ssRNA). In SSc, it plays a role in mediating fibrosis through enhanced tissue inhibitor of m ­ etalloproteinases-1 (TIMP-1). TIMP-1 is a matrix metalloproteinase (MMP) inhibitor, which in turn means a process that favors the deposition of ECM as opposed to its breakdown [15]. Later on the disease process, the adaptive immune system starts coming into place. T lymphocytes predominate in the immune response, which is primarily of CD4+ T helper 2 (Th2) phenotype. Those cells are driven by antigen-specific proliferation exhibited by the oligoclonal expansion. Consequently, Th2 cytokines are released, including IL-2, IL-4, IL-10, and IL-13. IL-4/13 stimulates the profibrotic events through signal transducer and activator of transcription (STAT)-6 signaling [8]. Th17 is another supported axis in the pathogenesis of the profibrotic process by the production of IL-17B and E. IL-17A on the other hand has antifibrotic effect via downregulation of connective tissue growth factor (CTGF) and α1 collagen. The c-Jun N-terminal kinases (JNKs), which is a subfamily of mitogen activated protein kinases (MAPK), is activated by the TGF-β and PDGF in SSc fibroblasts. The phosphorylated JNK (the active form) was observed in higher levels in SSc neutrophils, monocytes, fibroblasts, and smooth muscle cells of endothelial vessel lining. Phosphorylated JNK is a common mediator of the activation of the STAT-3 and Wnt/β-catenin, which in turn activates profibrotic signaling and augment gene expressions [21]. In addition to T cells, several studies support the B cell ability of inducing extracellular matrix production through the secretion of TGF-β and IL-6. It has additionally a major role in autoantibodies production. Several of those autoantibodies are directed against cell surface antigens (e.g., antiendothelial cell antibodies, antifibrillin antibodies, and anti-PDGF receptor antibodies), their functional impacts in the SSc pathogenesis is under investigation [22]. A subset of SSc patients with concomitant malignancy has a characteristic RNA polymerase antibody, raising the hypothesis that SSc may represent an immune response against tumor antigens [23]. In summary, the process of fibrosis is influenced by several key cytokines and growth factors, including TGF-β, CTGF, PDGF, and endothelin-1. Myofibroblasts have a great capacity for ECM production, cytokine release, and contractility. This function along with the disrupted ECM remodeling exemplified by the initial hypoxia-induced production of the ­thrombospondin-1, fibronectin-1, and lysyl hydroxylase-2 by the fibroblasts. Consequently, the fibroblasts are persistently activated with an excessive ECM deposition among different organs [24]. Fig. 1 summarized the pathophysiology of SSc.

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20.  Immunopathogenesis and treatment of scleroderma

FIG. 1  In certain genetically predisposed individuals, there is aberrant activation of the immune system against an unknown self or foreign antigen resulting in the release of proinflammatory cytokines and consequently endothelial wall damage and fibrosis. IL, interleukin, Mo, macrophage; NLRP3, nucleotide-binding domain, leucine-rich repeat containing family, and pyrin domain-containing 3; PAH, pulmonary hypertension; PDGF, platelet-derived growth factor; P-JNK, phospho-Jun N-terminal kinase; SRC, severe renal crisis; STAT, signal transducer and activator of transcription; TGFb, transforming growth factor beta; VEGF, vascular endothelial growth factor.

3  Treatment 3.1  Treatment of morphea SSc has been divided into two subsets with different severity and survival outcomes. A milder disease that is localized to the skin, and a more severe disease that has multiorgan involvement. The skin-limited disease seen in morphea patients with cutaneous lesions only, can often be treated with topical steroids, topical tacrolimus with occlusion, Phototherapy, intralesional skin steroid injections, and extracorporeal photopheresis.

3.2  Treatment of multiorgan SSc The more severe systemic sclerosis disease does not have a uniformly proven effective therapeutic approach. Systemic diseases is often treated by trying to attenuate the vascular complications, or tackling the immune cascade. 432



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3.2.1  Managing vascular manifestations The observed vasoconstrictive-vasodilators imbalance in SSc patients is the main concept of using iloprost, a prostacyclin analog, in the treatment of SSc related RP. Intravenous (IV) iloprost is effective in reducing the frequency and severity of RP attacks, treatment of digital ulcers, and improving renal vasospasms. The sequential IV iloprost efficacy in the modulation of SSc course needs to be investigated. Calcium channel blockers (CCBs) are other vasodilators investigated for the treatment of RP related vasospasms with b ­ eneficial efficacy. Angiotensin-converting enzyme inhibitors (ACEI) are associated with improved survival and successful discontinuation of dialysis in patients with severe renal crisis. Additionally, losartan, an angiotensin II receptor antagonist, has demonstrated good efficacy for RP treatment [25]. Sildenafil is another medication with vasodilator effect, which was investigated for the treatment of SSc associated digital ulcer, RP, and pulmonary arterial hypertension (PAH). Sildenafil shows highly efficacious results in improving the digital infarction, RP, and PAHrelated dyspnea [26]. Bosentan, an endothelin receptor antagonist, usage in PAH has demonstrated improved quality of life, exercise capacity, and survival outcomes [27]. 3.2.2  Immunosuppressive agents Another treatment strategy to reduce the profibrotic events in SSc is by using immunosuppressive medications. Methotrexate, mycophenolate, and systemic prednisolone have shown consistent efficacy in the treatment of cutaneous sclerosis. Cyclophosphamide, on the other hand, showed good efficacy for ILD and could be a promising disease-modifying agent. Mycophenolate mofetil (MMF) is often used as a first-line treatment for patients with ILD based on the results of the Scleroderma Lung Study II, showing good response and better tolerability and safety profile. Cyclosporine may improve skin induration, but has no efficacy on internal organs and its renal toxic effect minimize its use in SSc [25,28]. 3.2.3 Targeted therapy Immunomodulators (biologics), another class of medications targeting specified pathophysiologic points in the inflammatory pathway, have been investigated for the treatment of SSc. Imatinib is a multitarget inhibitor of tyrosine kinase with the capability of PDGF inhibition that improved cutaneous sclerosis and stabilized pulmonary functional capacities, but it was also associated with severe adverse effects [29]. Rituximab, an anti-CD-20 agent, has been tried in SSc. Although consistent results were observed on biomarkers, such as lesional and circulating B cell populations, clinical results were conflicting. Some studies show some benefit on skin thickening and lung fibrosis after treatment with rituximab, while others show no improved clinical outcome [29]. Abatacept, a fusion protein that interferes with the immune activity of T cells, has also been tested. Data suggest that abatacept might be considered in SSc patients with predominantly musculoskeletal features, including patients with overlapping SSc and rheumatoid arthritis (RA), as a 12-month, randomized, double-blind, placebo-controlled trial in 88 diffuse cutaneous SSc (dcSSc) patients did not show a major impact on change in the skin score of abatacept versus placebo [29,30]. Two placebo-controlled clinical trials with tocilizumab (TCZ) in early dcSSc have been finished, the phase 2 faSScinate trial [31,32], and the phase 3 FOCUSSCED trial [33]. Although 433



20.  Immunopathogenesis and treatment of scleroderma

both studies were unsuccessful to reach the primary endpoint on the mRSS, interestingly, both revealed a statistically significant benefit on pulmonary function, forced vital capacity (FVC), an important secondary outcome measure. Moreover, in placebo-treated patients from the faSScinate trial who were switched to TCZ, skin scores improved and FVC stabilized. However, there was an increased risk of serious infections. As a result, IL-6 inhibition could possibly slow the progression of subclinical alveolitis to fulminant lung fibrosis. Nevertheless, further trials are needed to prove this theory. TCZ also showed promising results in 9 SSc case series with already established diagnosis of ILD [29,30].

4  Conclusion In conclusion, scleroderma is a complex autoimmune disease that could be limited to the skin in the form of morphea, or diffused and more severe to involve multiple organs in the form of SSc. The pathogenesis of scleroderma is complex and remains to be only partially understood. Multiple genetic, environmental, vascular, and immunological factors play different roles in the disease pathophysiology. There is abnormal activation of the immune system, resulting in injury to the vascular endothelium followed by defective neovascularization and compromised vascular remodeling, consequently leading to extensive fibrosis of the skin and involved organs [34]. Internal organ involvement is variable among patients and is the main predictor of disease morbidity and mortality. Although scleroderma is not curable, a better understanding of the immunopathogenesis of this disease may contribute to new treatment strategies. Patients may exhibit a wide variety of presenting features but early diagnosis and treatment are key to reducing morbidity and mortality rates and improving patients' quality of life. Treatment depends on the extent of the disease and organs affected, ranging from conventional drugs such as prostaglandin analogs, CCB, and ACEI, to systemic ultraviolet A (UVA) to newer targeted treatments such as rituximab, abatacept, and TCZ.

Acknowledgment We would like to express our gratitude to Dr. Fatimah Al Muqarrab who helped us with the figure.

References [1] O. Distler, et  al., Predictors of progression in systemic sclerosis patients with interstitial lung disease, Eur. Respir. J. 55 (5) (2020) 1902026. [2] M. Cutolo, S. Soldano, V. Smith, Pathophysiology of systemic sclerosis: current understanding and new insights, Expert. Rev. Clin. Immunol. 15 (7) (2019) 753–764. [3] H. Poormoghim, M. Lucas, N. Fertig, T.A. Medsger Jr., Systemic sclerosis sine scleroderma: demographic, clinical, and serologic features and survival in forty-eight patients, Arthritis Rheum. 43 (2) (2000) 444–451. [4] D. Roofeh, S. Jaafar, D. Vummidi, D. Khanna, Management of systemic sclerosis-associated interstitial lung disease, Curr. Opin. Rheumatol. 31 (3) (2019) 241–249. [5] S. Assassi, et al., Clinical and genetic factors predictive of mortality in early systemic sclerosis, Arthritis Rheum. 61 (10) (2009) 1403–1411. [6] A.M. Stevens, K.S. Torok, S.C. Li, S.F. Taber, T.T. Lu, F. Zulian, Immunopathogenesis of juvenile systemic sclerosis, Front. Immunol. 10 (2019) 1352. [7] R. Rezaei, S. Aslani, N. Dashti, A. Jamshidi, F. Gharibdoost, M. Mahmoudi, Genetic implications in the pathogenesis of systemic sclerosis, Int. J. Rheum. Dis. 21 (8) (2018) 1478–1486.

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[8] C.-Y. Tsai, et al., Pathogenic roles of autoantibodies and aberrant epigenetic regulation of immune and connective tissue cells in the tissue fibrosis of patients with systemic sclerosis, Int. J. Mol. Sci. 21 (9) (2020) 3069. [9] P. Di Benedetto, et al., Mesenchymal stem cells of systemic sclerosis patients, derived from different sources, show a profibrotic microRNA profiling, Sci. Rep. 9 (1) (2019) 7144. [10] D. Xu, R. Mu, X. Wei, The roles of IL-1 family cytokines in the pathogenesis of systemic sclerosis, Front. Immunol. 10 (2019) 2025. [11] F. Ingegnoli, N. Ughi, C. Mihai, Update on the epidemiology, risk factors, and disease outcomes of systemic sclerosis, Best Pract. Res. Clin. Rheumatol. 32 (2) (2018) 223–240. [12] S. Movassaghi, S. Jafari, K. Falahati, M. Ataei, M.H. Sanati, Z. Jadali, Quantification of mitochondrial DNA damage and copy number in circulating blood of patients with systemic sclerosis by a qPCR-based assay, An. Bras. Dermatol. 95 (3) (2020) 314–319. [13] S.I. Nihtyanova, G.M. Brough, C.M. Black, C.P. Denton, Clinical burden of digital vasculopathy in limited and diffuse cutaneous systemic sclerosis, Ann. Rheum. Dis. 67 (1) (2008) 120–123. [14] S. Jain, Dermatology: Illustrated Study Guide and Comprehensive Board Review, first ed., Springer, 2017. [15] M. Brown, S. O’Reilly, Innate immunity and Toll-like receptor signaling in the pathogenesis of scleroderma: advances and opportunities for therapy, Curr. Opin. Rheumatol. 30 (6) (2018) 600–605. [16] Z. Li, J. Guo, L. Bi, Role of the NLRP3 inflammasome in autoimmune diseases, Biomed. Pharmacother. 130 (2020), 110542. [17] L.B. Tolle, T.J. Standiford, Danger-associated molecular patterns (DAMPs) in acute lung injury: DAMPs in ALI, J. Pathol. 229 (2) (2013) 145–156. [18] S. Bhattacharyya, et al., TLR4-dependent fibroblast activation drives persistent organ fibrosis in skin and lung, JCI Insight 3 (13) (2018), e98850. [19] J. Henderson, S. Bhattacharyya, J. Varga, S. O’Reilly, Targeting TLRs and the inflammasome in systemic sclerosis, Pharmacol. Ther. 192 (2018) 163–169. [20] S. Bhattacharyya, J. Varga, Endogenous ligands of TLR4 promote unresolving tissue fibrosis: implications for systemic sclerosis and its targeted therapy, Immunol. Lett. 195 (2018) 9–17. [21] M. Hammouda, A. Ford, Y. Liu, J. Zhang, The JNK signaling pathway in inflammatory skin disorders and cancer, Cells 9 (4) (2020) 857. [22] A. Adrovic, et al., Tocilizumab therapy in juvenile systemic sclerosis: a retrospective single centre pilot study, Rheumatol. Int. 41 (1) (2021) 121–128. [23] M.d.l.Á. Gargiulo, et al., Anticuerpos anti-RNA polimerasa III en esclerosis sistémica: estudio multicéntrico de Argentina, Reumatol. Clín. (2021). S1699258X21000590. [24] M.E. Semkova, J.J. Hsuan, TGFβ-1 induced cross-linking of the extracellular matrix of primary human dermal fibroblasts, Int. J. Mol. Sci. 22 (3) (2021) 984. [25] A. Fernández-Codina, K.M. Walker, J.E. Pope, The Scleroderma Algorithm Group, Treatment algorithms for systemic sclerosis according to experts, Arthritis Rheumatol. 70 (11) (2018) 1820–1828. [26] C. Antinozzi, et al., Sildenafil counteracts the in vitro activation of CXCL-9, CXCL-10 and CXCL-11/CXCR3 axis induced by reactive oxygen species in scleroderma fibroblasts, Biology 10 (6) (2021) 491. [27] R. Kimura, K. Sugita, T. Sugihara, H. Isomoto, O. Yamamoto, Treatment of digital ulcers and reflux oesophagitis in a patient with systemic sclerosis: increased risk of hepatotoxicity due to a potential drug-drug interaction between bosentan and vonoprazan, Acta Derm. Venereol. 101 (11) (2021). adv00600. [28] C.P. Denton, P. Sweny, A. Abdulla, C.M. Black, Acute renal failure occurring in scleroderma treated with cyclosporin A: a report of three cases, Rheumatology 33 (1) (1994) 90–92. [29] L.L. van den Hoogen, J.M. van Laar, Targeted therapies in systemic sclerosis, myositis, antiphospholipid syndrome, and Sjögren’s syndrome, Best Pract. Res. Clin. Rheumatol. 34 (1) (2020), 101485. [30] D. Khanna, et al., Abatacept in early diffuse cutaneous systemic sclerosis: results of a phase II investigator‐ initiated, multicenter, double‐blind, randomized, placebo‐controlled trial, Arthritis Rheumatol. 72 (1) (2020) 125–136. [31] D. Khanna, et  al., Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate), Ann. Rheum. Dis. 77 (2) (2018) 212–220. [32] D. Khanna, et al., Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial, Lancet 387 (10038) (2016) 2630–2640. [33] D. Khanna, et al., Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial, Lancet Respir. Med. 8 (10) (2020) 963–974. [34] Y. Asano, Systemic sclerosis, J. Dermatol. 45 (2) (2018) 128–138.

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C H A P T E R

21 Skin manifestations and autoimmune disturbances in dermatomyositis Dominika Kwiatkowska and Adam Reich⁎ Department of Dermatology, Institute of Medical Sciences, Medical College of Rzeszow University, Rzeszów, Poland ⁎

Corresponding author

Abstract Dermatomyositis (DM) is a chronic autoimmune disorder classified into the spectrum of idiopathic inflammatory myopathies. It is mostly characterized by the presence of cutaneous lesions and symptoms of muscle involvement. Based on clinical features, one could distinguish the classic variant of DM, juvenile DM, paraneoplastic DM, drug-induced DM, and amyopathic/hypomyopatic DM. The clinical outcome of DM may vary depending on comorbidities, such as interstitial lung disease, calcification, or malignancies. Similarly to many other autoimmune rheumatic diseases, there is an association of specific circulating autoantibodies with peculiar clinical phenotypes of DM. A better understanding of the exact role of specific autoantibodies in the formation of distinct clinical features could help to plan more personalized and more efficacious treatment strategy.

Keywords Autoantibodies, Dermatomyositis, Gottron’s sign, Heliotrope sign, Inflammatory myopathies

1  Introduction Dermatomyositis (DM) is a chronic acquired autoimmune disorder classified into the spectrum of idiopathic inflammatory myopathies (IIM) [1]. Although it is a heterogeneous entity with different phenotypes, it is mostly characterized by the presence of cutaneous lesions and symptoms of muscle involvement. DM disproportionately affects both adults and children. Based on clinical features, one could distinguish the classic variant of DM, juvenile DM, paraneoplastic DM, drug-induced DM, and amyopathic/hypomyopatic DM [2]. Similar to

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21.  Skin manifestations and autoimmune disturbances

TABLE 1  Myositis-specific autoantibodies correlated with specific clinical features and cutaneous manifestations. Autoantibody

Autoantigen

Clinical phenotype

Anti-MDA5 (anti-CADM-140)

Melanoma differentiationassociated protein 5

Cutaneous symptoms: erythematous papules and macules on the palmar surfaces of the metacarpal and interphalangeal joints, mechanic’s hands, ulcerations Interstitial lung disease

Anti-TIF1-γ (anti-p155)

Transcription intermediary factor 1-γ

Cutaneous symptoms: erythematous lesions, V-sign, shawl sign, holster’s sign, verruca-like papules, psoriasis-like lesions, periungual erythema, hypopigmented and telangiectatic patches, poikiloderma Increased incidence of malignancy

Anti-NXP2

Nuclear matrix protein 2

Calcinosis Muscle weakness Joint contractures Intestinal vasculitis Polyarthritis Dysphagia Peripheral edema

Anti-SAE

Small ubiquitin-like modifier activating enzyme

Cutaneous symptoms: heliotrope sign, shawl sign, Gottron’s sign, V-sign, periungual erythema, angelwing sign Myositis Dysphagia

Ani-Mi-2

Nucleosome remodeling deacetyalse complex (NuRD)

Cutaneous symptoms: Gottron’s papules, heliotrope rash, shawl sign, and V-sign

many other autoimmune rheumatic diseases, there is an association of specific circulating autoantibodies with peculiar clinical phenotypes of DM (Table 1) [3]. More importantly, some studies showed the potential role of specific autoantibodies as early diagnostic markers [4]. Current treatment recommendations for DM, based mainly upon case series, include the use of corticosteroids, immunomodulatory, and immunosuppressive agents. However, a better understanding of the exact role of specific autoantibodies in the formation of distinct clinical features could help to plan a more personalized and more efficacious treatment strategy.

2  Cutaneous manifestations of DM correlate with specific autoantibodies DM is a chronic remitting diseases and determining its severity and prognosis is of great importance as it enables proper patient’s stratification and treatment. The clinical outcome of DM may vary depending on comorbidities, such as interstitial lung disease, calcification, or malignancies. Multiple studies have highlighted the importance of myositis-associated autoantibodies (MAAs) as specific markers of DM. Hence, the differentiation of antibody-­ associated clinical phenotypes with distinct dermatological features could result in a better assessment of prognosis and response to treatment. 438



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2.1  Anti-Mi-2 phenotype Anti-Mi-2 antibodies target the components of the nucleosome remodeling deacetylase complex (NuRD) and play an integral role in the regulation of transcription. The positive predictive value of anti-Mi-2 autoantibodies in DM is high. Nevertheless, the prevalence has varied across studies. In the research conducted by Hamaguchi et al., anti-Mi-2 autoantibodies were detected in only 9 of 376 (2%) cases [5]. On the contrary, an investigation assessing two DM cohorts from Mexico City and Guadalajara exhibited a significantly higher prevalence of anti-Mi-2 autoantibodies in the first group—59% versus 12% [6]. Many studies to date have demonstrated the coexistence of ani-Mi-2 antibodies with the classic DM features such as Gottron’s papules, heliotrope rash, shawl sign, and V-sign (Fig. 1). The risk of developing ILD and cancer appears to be lower in this group compared to other DM phenotypes. This group of patients has a relatively good prognostic profile and tends to respond well to the steroid therapy.

2.2  Anti-MDA5 phenotype Autoantibodies against melanoma differentiation-associated protein 5 (MDA5) have been described to be associated with many cases of amyopathic DM presenting rapidly progressive interstitial lung disease (ILD). Anti-MDA5 antibodies were previously reported as

FIG. 1  A patient with dermatomyositis positive for Mi2 antibodies. (A) Typical face erythema involving periorbital area. (B) Positive Gottron’s sign. (C) Gottron’s papules also present over the elbows.

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21.  Skin manifestations and autoimmune disturbances

a­ nti-CADM‑140 antibodies that interacted with a 140-kDa cytoplasmic protein [7]. A recently conducted study on the combined European cohort, in which 87.4% of enrolled patients were Caucasians, showed that MDA5 autoantibodies were present in 1.3% DM cases [8]. The majority of anti-MDA5 antibody positive patients showed a strong association with several cutaneous manifestations. In research provided by Fiorentino et al. erythematous papules and macules on the palmar surfaces of the metacarpal and interphalangeal joints were found in half of the patients, and contrary to the Gottron’s papules, were often painful [9]. MDA5 antibodies are also associated with cutaneous ulcerations located on the lateral nailfolds as well as over the elbows and knees (Fig.  2). Other findings include an increased incidence

FIG. 2  A patient with amyopatic dermatomyositis positive for MDA5 antibodies. (A) Gottron’s sign with some necrotic alterations. (B) Erythematous lesions on the palmar surfaces of the fingers. (C) Ulceration located over the elbow within the erythematous plaque.

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of mechanic’s hands, fever, and inflammatory arthritis, which frequently presents as symmetric one, involves small joints of the hands and is associated with morning stiffness [10]. Symptoms such as ulcerations and gum pain may be due to severe vasculopathy, which is observed in many cases [9]. DM patients with anti-MDA5 antibodies showed high type I interferon (IFN-I) signatures in serum and skin lesions [11]. Moreover, previous studies demonstrated alterations in phenotype and function of endothelial progenitor cells (EPCs) in DM patients caused by a high IFN-I signature [12]. These findings might suggest the relationship between IFN-I and patients’ vasculopathy. However, the exact mechanisms leading to vascular changes in this disorder have not been fully characterized yet.

2.3  Anti-TIF1-γ phenotype Autoantibodies against transcriptional intermediary factor 1-gamma (TIF1-γ) are of clinical significance in both adult DM and juvenile DM (JDM) patients. These antibodies were originally reported as anti-p155 or anti-p155/140 and were found to strongly correlate with an increased incidence of malignancies. It is estimated that over 50% of cancer-associated DM cases comorbid with anti-TIF1-γ antibodies [13]. However, this relationship is not observed in pediatric patients, as JDM is rarely associated with cancer [14]. Several studies demonstrated that typical DM dermatological features are more common in this group of patients. Erythematous lesions may be present on the face, neck (V-sign), shoulders (shawl sign), extensor surfaces of the extremities (holster’s sign), dorsal part of hands, and the scalp. Children are at a lower risk of developing V-sign compared to adults, but the incidence of this rash is higher than in other autoantibody subgroups [15]. Cutaneous presentations also include round, palmar hyperkeratotic and verruca-like papules, psoriasis-like lesions, periungual erythema, as well as hypopigmented and telangiectatic patches. Lipodystrophy is an infrequent but serious complication of JDM [16]. Moreover, the presence of anti-TIF1-γ antibodies seems to be associated with poikiloderma located on the forehead and upper back [17]. Regarding extracutaneous features, patients are more likely to develop dysphagia [18]. It is worth noting that calcinosis, ILD, Raynaud phenomenon, and arthritis/arthralgia are rarely found in anti-TIF1-γ-positive patients [19].

2.4  Anti-NXP2 phenotype The antinuclear matrix protein 2 (NXP2) antibodies, formerly known as anti-MJ antibodies, were first described in a group of JDM patients and were correlated with severe muscle weakness, joint contractures, intestinal vasculitis, and polyarthritis [20]. The prevalence of anti-NXP-2 antibodies in adult DM patients ranges from 1.6% to 30% [17]. To date, many studies have shown that patients with anti-NXP-2 antibodies had a greater risk of calcinosis, the severity of which is considerably worse in the young children population [21–23]. In the study conducted by Rogers et al., dysphagia and peripheral edema were observed in 74% and 35% cases, respectively [24]. The risk of pathognomonic cutaneous features of DM, Gottron’s papules, and Gottron’s sign seems to be lower. The presence of concomitant malignancy was described in several studies [25,26]. Nevertheless, the correlation of anti-NXP2 antibodies with cancer-associated DM required further investigation.

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2.5  Anti-SAE phenotype Autoantibodies to small ubiquitin-like modifier activating enzyme (anti-SAE) were reported in DM patients with a frequency of 8% [27]. The presence of anti-SAE antibodies has been shown to be correlated with skin rashes such as heliotrope sign, shawl sign, Gottron’s sign, V-sign, and periungual erythema (Fig. 3). Many patients developed dysphagia and muscle weakness. Furthermore, skin symptoms may precede the onset of muscle weakness. A case series, provided by Inoue et al., described extensive erythema over the shoulder and lumbar regions, with the preservation of the area of the scapula. This specific clinical presentation was called an angel-wing sign [28]. It has been suggested that this distribution may be characteristic of anti-SAE antibodies-associated DM. Interestingly, a subset of patients with anti-SAE autoantibodies has been shown to be more susceptible to hydroxychloroquine-related skin eruptions in contrast to the presence of anti-MDA-5 autoantibodies, which were negatively associated with the risk of adverse cutaneous reactions linked to h ­ ydroxychloroquine [29].

FIG. 3  A patient with dermatomyositis positive for anti-SAE antibodies. (A) Classic heliotrope sign. (B) Positive Gottron’s sign with periungual erythema. (C) Positive V-sign. (D) Positive shawl sign.

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2.6  Anti-ARS phenotypes The group of anti-aminoacyl tRNA synthetase (anti-ARS) autoantibodies includes a­ nti-Jo1, anti-PL-7, anti-PL-12, anti-EJ, anti-OJ, anti-KS, anti-ZO, and anti-YRS/HA autoantibodies (Table 2). The set of unique and common clinical features related to the presence of the above antibodies allowed for the distinction of the so-called antisynthetase syndrome. The characteristic symptoms encompass myositis, ILD, fever, Raynaud’s phenomenon, arthritis, and mechanic’s hands. Nonetheless, there are some significant differences in clinical manifestations. A frequently described autoantibody, anti-Jo1 as well as anti-EJ, and anti-PL‑7 are mostly related to myositis, which seems to be more severe in the group of anti-Jo1-positive patients. The risk of developing cancer, as well as joint manifestations, including erosive arthritis is higher with anti-Jo1 autoantibodies, whereas, anti-PL-12 autoantibodies turned out to be strongly associated with the presence of early and severe ILD, but less with myositis and arthritis [30]. Gastrointestinal complications, especially intestinal pseudo-obstruction, were reported in connection with the presence of anti-PL7/PL12 autoantibodies [31].

3  Myositis-specific autoantibodies in a new classification system Based on clinical symptoms and the presence of myositis-specific autoantibodies, a new classification scheme for IIM was introduced [32]. In this system, four clusters of IIM were distinguished, namely inclusion body myositis, immune-mediated necrotizing myopathy, DM, and antisynthetase syndrome. The first cohort included males, white, and at least 60 years old patients. The most relevant clinical features encompass finger flexors and quadriceps weakness, characteristics of inclusion body myositis. In the second cluster patients were mostly women and no race predilection or specific skin lesions were found. However, in this group, severe proximal muscle weakness in the area of lower limbs was observed. Moreover, many patients had high creatine phosphokinase level and anti-SRP or anti-3-hydroxy-3-­methylglutarylcoenzyme A reductase (HMGCR) antibodies, which link to immune-­mediated necrotizing myopathy. The third cluster regrouped patients represented characteristic DM features, predominantly Gottron’s papules, heliotrope rash, shawl sign, skin ulcers as well as limb edema, TABLE 2  The group of antiaminoacyl tRNA synthetase autoantibodies. Autoantibody

Autoantigen

Anti-Jo1

Histidyl-tRNA synthetase

Anti-PL-7

Treonyl-tRNA synthetase

Anti-PL-12

Alanyl-tRNA synthetase

Anti-EJ

Glycyl-tRNA synthetase

Anti-OJ

Isoleucyl-tRNA synthetase

Anti-KS

Asparaginyl-tRNA synthetase

Anti-Zo

Phenylalanine-tRNA synthetase

Anti-YRS/Ha

Tyrosyl-tRNA synthetase

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21.  Skin manifestations and autoimmune disturbances

calcinosis, panniculitis, and alopecia. The anti‑Mi2, anti-MDA5, and anti-TIF1-γ antibodies, were often detected. The patients also showed the severe weakness of the deltoid muscles. It is worth noting that this group was predisposed to cancer. Finally, the fourth group correlates with the presence of anti-Jo1 and anti-PL-7 antibodies, which are characteristic of the antisynthetase syndrome. Many patients presented rheumatologic disorders, such as arthralgia, arthritis, or Raynaud phenomenon. Among specific skin features, mechanic hands were mostly observed. Furthermore, lung involvement was present in all patients from this cluster. The EULAR/ACR classification criteria are used to evaluate the probability of IIM [33]. Anti‑Jo1 autoantibodies were found to be an additional part of these criteria for adult-onset and juvenile IIM. Other laboratory measurements of clinical significance are elevated serum levels of creatine kinase, lactate dehydrogenase, aspartate aminotransferase, or alanine aminotransferase. The EULAR/ACR classification criteria allow for the waiver of muscle biopsy only in patients with pathognomonic skin rashes such as heliotrope rash, Gottron’s papules, and/or Gottron’s sign of JDM or DM. In other cases, a muscle biopsy is recommended. In the future, a wider evaluation of different myositis-specific autoantibodies could improve the precision of classification.

4  Conclusion Advances in the field of immunology are transforming our current view of DM. Recent discoveries allow considering DM as a heterogeneous disease in which particular clinical phenotypes correlate with the presence of specific autoantibodies. Effective usage of MAAs as biomarkers could improve the appraisal of the risk of many complications, such as cancer, ILD, and calcinosis. However, these findings require further investigations as there are some discrepancies in the prevalence of specific autoantibodies in different populations.

References [1] S. Mahil, D. Marks, M. McCormack, A. Rahman, Dermatomyositis, Br. J. Hosp. Med. 73 (2012). [2] D. Samotij, J. Szczęch, A. Reich, Diagnostic and therapeutic advances in dermatomyositis, Przegl. Dermatol. 102 (2015) 183–197. [3] N. Okiyama, M. Fujimoto, Cutaneous manifestations of dermatomyositis characterized by myositis-specific autoantibodies, F1000Res 8 (2019). [4] C. Cassius, H. Le Buanec, J.D. Bouaziz, R. Amode, Biomarkers in adult dermatomyositis: tools to help the diagnosis and predict the clinical outcome, J. Immunol. Res. 2019 (2019). [5] Y. Hamaguchi, M. Kuwana, K. Hoshino, M. Hasegawa, K. Kaji, T. Matsushita, et al., Clinical correlations with dermatomyositis-specific autoantibodies in adult Japanese patients with dermatomyositis: a multicenter cross-sectional study, Arch. Dermatol. 147 (2011) 391–398. [6] M.H. Petri, M. Satoh, B.T. Martin-Marquez, R. Vargas-Ramírez, L.J. Jara, M.A. Saavedra, et  al., Implications in the difference of anti-Mi-2 and -p155/140 autoantibody prevalence in two dermatomyositis cohorts from Mexico City and Guadalajara, Arthritis Res. Ther. 15 (2013) R48. [7] S. Sato, M. Hirakata, M. Kuwana, A. Suwa, S. Inada, T. Mimori, et al., Autoantibodies to a 140-kd polypeptide, CADM-140, in Japanese patients with clinically amyopathic dermatomyositis, Arthritis Rheum. 52 (2005) 1571–1576. [8] Z. Betteridge, S. Tansley, G. Shaddick, H. Chinoy, R.G. Cooper, R.P. New, et al., Frequency, mutual exclusivity and clinical associations of myositis autoantibodies in a combined European cohort of idiopathic inflammatory myopathy patients, J. Autoimmun. 101 (2019) 48–55.

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[9] D. Fiorentino, L. Chung, J. Zwerner, A. Rosen, L. Casciola-Rosen, The mucocutaneous and systemic phenotype of dermatomyositis patients with antibodies to MDA5 (CADM-140): a retrospective study, J. Am. Acad. Dermatol. 65 (2011) 25–34. [10] J.C. Hall, L. Casciola-Rosen, L.A. Samedy, J. Werner, K. Owoyemi, S.K. Danoff, et  al., Anti-melanoma ­differentiation-associated protein 5-associated dermatomyositis: expanding the clinical spectrum, Arthritis Care Res. 65 (2013) 1307–1315. [11] N. Ono, K. Kai, A. Maruyama, M. Sakai, Y. Sadanaga, S. Koarada, et al., The relationship between type 1 IFN and vasculopathy in anti-MDA5 antibody-positive dermatomyositis patients, Rheumatology (United Kingdom) 58 (2019) 786–791. [12] L. Ekholm, J. Michelle Kahlenberg, S.B. Helmers, A. Tjärnlund, S. Yalavarthi, W. Zhao, et al., Dysfunction of endothelial progenitor cells is associated with the type I IFN pathway in patients with polymyositis and dermatomyositis, Rheumatology (United Kingdom) 55 (2016) 1987–1992. [13] K. Hoshino, Y. Muro, K. Sugiura, Y. Tomita, R. Nakashima, T. Mimori, Anti-MDA5 and anti-TIF1-γ antibodies have clinical significance for patients with dermatomyositis, Rheumatology 49 (2010) 1726–1733. [14] H. Gunawardena, L.R. Wedderburn, J. North, Z. Betteridge, J. Dunphy, H. Chinoy, et al., Clinical associations of autoantibodies to a p155/140 kDa doublet protein in juvenile dermatomyositis, Rheumatology 47 (2008) 324–328. [15] L.G. Rider, M. Shah, G. Mamyrova, A.M. Huber, M.M. Rice, I.N. Targoff, et al., The myositis autoantibody phenotypes of the juvenile idiopathic inflammatory myopathies, Medicine (United States) 92 (2013) 223–243. [16] A. Bingham, G. Mamyrova, K.I. Rother, E. Oral, E. Cochran, A. Premkumar, et al., Predictors of acquired lipodystrophy in juvenile-onset dermatomyositis and a gradient of severity, Medicine (Baltimore) 87 (2008) 70–86. [17] M. Best, M. Jachiet, N. Molinari, F. Manna, C. Girard, V. Pallure, et  al., Distinctive cutaneous and systemic features associated with specific antimyositis antibodies in adults with dermatomyositis: a prospective multicentric study of 117 patients, J. Eur. Acad. Dermatol. Venereol. 32 (2018) 1164–1172. [18] N. Mugii, M. Hasegawa, T. Matsushita, Y. Hamaguchi, S. Oohata, H. Okita, et al., Oropharyngeal dysphagia in dermatomyositis: associations with clinical and laboratory features including autoantibodies, PLoS One 11 (2016). [19] D.F. Fiorentino, K. Kuo, L. Chung, L. Zaba, S. Li, L. Casciola-Rosen, Distinctive cutaneous and systemic features associated with antitranscriptional intermediary factor-1γ antibodies in adults with dermatomyositis, J. Am. Acad. Dermatol. 72 (2015) 449–455. [20] C.V. Oddis, Clinical and serological characterization of the anti-MJ antibody in childhood myositis, Arthritis Rheum. 40 (9) (1977) 139. [21] A. Ceribelli, M. Fredi, M. Taraborelli, I. Cavazzana, F. Franceschini, M. Quinzanini, et al., Anti-MJ/NXP-2 autoantibody specificity in a cohort of adult Italian patients with polymyositis/dermatomyositis, Arthritis Res. Ther. 14 (2012) R97. [22] A. Valenzuela, L. Chung, L. Casciola-Rosen, D. Fiorentino, Identification of clinical features and autoantibodies associated with calcinosis in dermatomyositis, JAMA Dermatol. 150 (2014) 724–729. [23] S.L. Tansley, Z.E. Betteridge, G. Shaddick, H. Gunawardena, K. Arnold, L.R. Wedderburn, et  al., Calcinosis in juvenile dermatomyositis is influenced by both anti-NXP2 autoantibody status and age at disease onset, Rheumatology (United Kingdom). 53 (2014) 2204–2208. [24] A. Rogers, L. Chung, S. Li, L. Casciola-Rosen, D.F. Fiorentino, Cutaneous and systemic findings associated with nuclear matrix protein 2 antibodies in adult dermatomyositis patients, Arthritis Care Res. 69 (2017) 1909–1914. [25] Y. Ichimura, T. Matsushita, Y. Hamaguchi, K. Kaji, M. Hasegawa, Y. Tanino, et al., Anti-NXP2 autoantibodies in adult patients with idiopathic inflammatory myopathies: possible association with malignancy, Ann. Rheum. Dis. 71 (2012) 710–713. [26] H. Yang, Q. Peng, L. Yin, S. Li, J. Shi, Y. Zhang, et  al., Identification of multiple cancer-associated myositis-­ specific autoantibodies in idiopathic inflammatory myopathies: a large longitudinal cohort study, Arthritis Res. Ther. 19 (2017). [27] Z.E. Betteridge, H. Gunawardena, H. Chinoy, J. North, W.E.R. Ollier, R.G. Cooper, et al., Clinical and human leucocyte antigen class II haplotype associations of autoantibodies to small ubiquitin-like modifier enzyme, a dermatomyositis- specific autoantigen target, in UK Caucasian adult-onset myositis, Ann. Rheum. Dis. 68 (2009) 1621–1625. [28] S. Inoue, N. Okiyama, M. Shobo, S. Motegi, H. Hirano, Y. Nakagawa, et al., Diffuse erythema with ‘angel wings’ sign in Japanese patients with anti-small ubiquitin-like modifier activating enzyme antibody-associated dermatomyositis, Br. J. Dermatol. 179 (2018) 1414–1415.

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[29] P.W. Wolstencroft, L. Casciola-Rosen, D.F. Fiorentino, Association between autoantibody phenotype and cutaneous adverse reactions to hydroxychloroquine in dermatomyositis, JAMA Dermatol. 154 (2018) 1199–1203. [30] M. Kalluri, S.A. Sahn, C.V. Oddis, S.L. Gharib, L. Christopher-Stine, S.K. Danoff, et  al., Clinical profile of ­anti-PL-12 autoantibody: cohort study and review of the literature, Chest 135 (2009) 1550–1556. [31] I. Marie, S. Josse, O. Decaux, S. Dominique, E. Diot, C. Landron, et al., Comparison of long-term outcome between anti-Jo1- and anti-PL7/PL12 positive patients with antisynthetase syndrome, Autoimmun. Rev. 11 (2012) 739–745. [32] K. Mariampillai, B. Granger, D. Amelin, M. Guiguet, E. Hachulla, F. Maurier, et al., Development of a New classification system for idiopathic inflammatory myopathies based on clinical manifestations and myositis-­ specific autoantibodies, JAMA Neurol. 75 (2018) 1528–1537. [33] I.E. Lundberg, A. Tjärnlund, M. Bottai, V.P. Werth, C. Pilkington, M. de Visser, et al., European league against rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups, in: Ann. Rheum. Dis, Ann. Rheum. Dis. 2017 (2017) 1955–1964.

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22 T cells in the pathogenesis of systemic sclerosis Lazaros I. Sakkasa,⁎ and Theodora Simopouloub a

Faculty of Medicine, School of Health Science, University of Thessaly, Larissa, Greece, Department of Rheumatology and Clinical Immunology, University General Hospital of Larissa, Larissa, Greece

b

⁎

Corresponding author

Abstract Systemic sclerosis (SSc) is a complex disease characterized by excessive and widespread deposition of collagen and other extracellular matrix proteins, microvasculopathy, and the presence of autoantibodies. Fibrosis and microvasculopathy lead to organ impairment and increased mortality. The pathogenesis of the disease is complex and incompletely understood. Activated fibroblasts and myofibroblasts producing excessive collagen are likely to get involved in the pathophysiology of the disease by cytokines and growth factors and immune cells. T cells appear to be key players in the pathogenesis of SSc. Various T-cell subset abnormalities have been reported in SSc including T helper (Th)2 cells, T follicular helper (Tfh) cells, Th17 cells, Th22 cells, Th1 cells, T regulatory cells (Tregs), CD4+ cytotoxic T cells, and CD8+ cells. T-cell infiltrates appear early in skin lesions along with microvascular changes before histological fibrosis. T cells help B cell to produce IgG autoantibodies some of which have profibrotic actions. T cells are predominantly of Th2 type producing profibrotic cytokines and induce alternatively activated (M2) macrophages which are profibrotic whereas Th1 cells which decrease fibroblast’s collagen production are decreased. Regulatory T cells exhibit decreased suppressive capacity and differentiate into effector Th2 and Th17 cells. Endothelial cells in skin lesions are activated by proinflammatory Th17 cells and produce profibrotic cytokines but they are targets of cytotoxic CD4+ and CD8+ cytotoxic T cells as well. Hence, T cells trigger molecular cascades leading to fibrosis and microvasculopathy in SSc.

Keywords Cytotoxic T lymphocyte, Lymphocyte, Th2 cells, Th1 cells, Th17 cells, Tregs, Tfh cells

Translational Autoimmunity, Vol. 6 https://doi.org/10.1016/B978-0-323-85831-1.00022-X

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Copyright © 2023 Elsevier Inc. All rights reserved.



22.  T cells in the pathogenesis of systemic sclerosis

1  Introduction Systemic sclerosis (SSc) is a rare systemic autoimmune disease characterized by excessive deposition of collagen and other extracellular matrix (ECM) proteins in the skin (scleroderma) and internal organs, associated with vasculopathy and different autoantibodies. The excessive ECM deposition leads to progressive internal organ impairment, most commonly interstitial lung disease (ILD), and increased mortality [1]. According to the extent of skin involvement, SSc is classified as diffuse cutaneous (dcSSc) and limited cutaneous disease (lcSSc). Microvasculopathy, functional at first and manifested with excessive reaction to cold and stress (Raynaud’s phenomenon), is the earliest manifestation of the disease, and later becomes structural with fibrointimal proliferation causing microvascular lumen stenosis that leads to pulmonary arterial hypertension (PAH), digital ulcers, and scleroderma renal crisis [2]. Many autoAbs are detected in SSc, and the most common autoAbs, anti-Topoisomerase I (ATA) (formerly known as anti-Scl70 antibody), anticentromere (ACA), and RNA polymerase III (RPA) autoAbs are included in the classification criteria for the disease [3].

2  Pathogenesis of systemic sclerosis The etiology of SSc is unknown and its complex pathogenesis is incompletely understood. Cells of the adaptive and innate immune systems, interacting with together and with other cell types, such as fibroblasts, endothelial cells, adipocytes, and epithelial cells via direct cell–cell contact, cytokines, and growth factors, are involved in SSc pathogenesis [4–6]. Interleukin (IL)4, IL-13, and transforming growth factor β (TGF-β) are major profibrotic factors in SSc. The detection of autoAbs, many of which exhibit profibrotic actions and some targeting endothelial cells put SSc in the autoimmune spectrum of diseases [7]. Apart for autoAbs, B cells contribute to SSc pathogenesis via other means; they are hyperactivated, producing inflammatory and profibrotic cytokines, presenting antigens to T cells, and talking to fibroblasts [7]. Innate immunity also contributes to SSc pathogenesis. Mast cell, eosinophil, and macrophage infiltrates were detected in early SSc skin lesions. Type 2 innate lymphoid cells (ILC2) were increased in skin and peripheral blood of SSc patients, correlated with skin and lung fibrosis [8] and can produce profibrotic IL-13. Macrophages in peripheral blood of SSc patients exhibit a profibrotic profile with markers of alternatively and inflammatory activated macrophages (M2) and activate SSc fibroblasts, which are enriched in skin lesions being correlated with skin fibrosis [9]. Soluble factors activate M2 macrophages, as plasma from SSc patients induced a profibrotic phenotype (expression of CD163, CD206 and production of TGFβ1, CC chemokine ligand 2 [CCL2, monocyte chemoattractant protein 1], and IL-6) in macrophages of healthy controls [9]. Endothelial cells were the first cells to undergo apoptosis in the University of California at Davis-200/206 chicken model of scleroderma, and apoptosis of endothelial cells were detected in the early inflammatory stage of SSc [10]. More recently, a large number of apoptotic cells, mostly activated endothelial cells expressing HLA-DR, likely to be targets of CD4+ cytotoxic T cells, were found in the skin of untreated patients with early dcSSc [11]. In the early inflammatory stage of SSc skin lesions, most endothelial cells and fibroblasts express markers of activation, such as HLA-DR and intercellular adhesion molecule 1 (ICAM-1) [12]. Activated fibroblasts and myofibroblasts produce excessive collagen and other extracellular matrix proteins. Fibroblasts respond to a

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variety of cytokines and growth factors and proliferating fibroblasts activate latent TGF-β1 into active TGF-β1 through integrin interactions [13]. Myofibroblasts are activated fibroblasts with contractile properties producing large amounts of extracellular matrix (ECM) proteins. In SSc, myofibroblasts exhibiting increased formation and decreased apoptosis, derive from activated fibroblasts and trans-differentiation of other cell types including adipocytes, pericytes, endothelial cells, and epithelial cells [14]. Cells of intermediate stages of endothelial to mesenchymal transition were identified in dermal vessels of SSc patients and in b ­ leomycin-induced scleroderma model, whereas treating healthy skin microvascular endothelial cells with SSc sera or TGF-β1, a major inducer of this trans-­differentiation to myofibroblasts, resulted in the acquisition of myofibroblast-like phenotype [15]. There is a large body of evidence suggesting that T cells are major players in the pathogenesis of SSc [4,16].

3  T cells: A brief overview T cells recognize antigens through their T-cell antigen receptor (TCR). TCR comprises of α and β chains in the great majority of peripheral blood T cells (Tαβ cells) and recognize antigenic peptides sitting on particular HLA molecule (HLA-restriction). CD4+ T cells are T helper (Th) cells and recognize peptides from extracellular antigens presented on HLAclass II molecules, and help B cells in antibody production, while CD8+ T cells are cytotoxic T cells and recognize peptides from intracellular antigens presented on HLA-class I molecules. There are several subsets of Th cells based on their cytokines produced and function. In the early 80s, Th1 and Th2 subsets were identified as major subsets and these were reciprocal and associated with disease outcome, playing a major role in immune response to pathogens [17]. Later, new T-cell effector subsets have been identified, including Th17, Th9, and Th22, whereas another T-cell subset, regulatory T cells (Tregs) was suppressive of proinflammatory effector T cells [18]. Th1-associated cytokines, IL-12 and IFN-γ, are involved in host defense against intracellular pathogens promoting Th1 polarization and inhibiting Th2 polarization. Th2 cells induced by IL-4 and IL-13 cytokines produce IL-4, IL-5, IL-13, and IL-31 and are involved in parasitic and allergic diseases. Th2 cells, producing IL-4 and IL-13 also suppress Th1 and Th17 polarization. IL-21, also produced by Th2 cells, inhibits differentiation of naïve T cells into Th1 cells [19]. However, IL-31, which is mainly produced by Th2 cells [20] does not affect Th1 cells [21]. Thymic stromal lymphopoietin (TSLP), an IL-7 cytokine family member and IL-25 (IL-17E), produced by mast cells and eosinophils, also promote Th2 responses [22,23]. Th17 cells differentiate from naïve T cells in the presence of any of these cytokine combinations, IL-6 plus TGF-β, IL-21 plus TGF-β, or IL-6, IL-23, and IL-1β, with IL-23 are required for the proliferation and survival of Th17 cells. IL-6 secreted by Th2 cells promotes switching of Tregs to Th17 cells. Th17 cells express the transcription factor retinoic acid receptor-related orphan receptor gamma T (RORγT). IL-17 cytokines include six members IL-17A, IL-17B, IL17C, IL-17D (IL-27), IL-17E (IL-25), and IL-17F. IL-17 is a proinflammatory cytokine involved in host defense against extracellular bacteria and fungi [23–25]. T follicular helper (Tfh) cells produced IL-21 and increased levels of ICOS, programmed death (PD)-1, IL-4, and signaling lymphocyte activation molecule (SLAM) adaptor protein

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and are of particular interest in SSc, since they are located in B-cell follicles and provide critical help for B-cell differentiation into plasma cells and antibody production [26]. Markers of Tfh cells include CXCR5, ICOS costimulatory receptor, IL-21, and Bcl-6 transcription factor [27]. Epigenetics, such as DNA methylation, histone modifications, and noncoding RNA changes, also affect Tfh differentiation and function [28]. Th9 is a novel Th subset induced by IL-4, TGF-β1, and the epithelial cytokine TSLP (a member IL-7 cytokine family). It is characterized by the PU.1 transcription factor and produces IL-9 [29,30]. IL-9 induced neutrophil extracellular trap (NET) release by neutrophils, expansion of mast cells, and ATA production by B cells. Th subsets play a major role in immune response and disease outcome, although Th plasticity is widely recognized [17,31]. For instance, molecular antagonism and plasticity were demonstrated in Tregs and Th17 differentiation [32]. Epigenetics and local cytokines, such as IL1β, were found to differentiate Tregs (CD4+ CD25highFoxp3+ CD127− CD27+) into Th17 cells [33]. T cells can also produce monokines, IL-1α, IL-6, and TNFα, by various subsets except IL-1α whose production is restricted to memory T cells (CD4+ CDRO+) [34]. IL-1α is of particular interest in SSc, as it was found to be constitutively expressed in SSc fibroblasts but not in normal fibroblasts, and induced SSc fibroblast production of profibrotic factors IL-6 and platelet-­ derived growth factor (PDGF)-A [35]. Tregs, although a small proportion of peripheral blood T cells, are of paramount importance in maintaining immune self-tolerance and preventing autoimmunity, by suppressing activated effector T cells and antigen-presenting cells (APCs), via cell–cell contact, and inhibitory IL-10, TGF-β, and IL-35 cytokine production. The importance of Tregs is exemplified in the mutation of FOXP3, the most specific marker of Tregs, which leads to immune dysregulation, polyendocrinopathy, and enteropathy X-linked (IPEX) syndrome [36]. The development of SSc may be the result of a failure of Tregs to maintain immune homeostasis. Tregs are either natural or induced Tregs. Induced Tregs result from peripheral CD4+ T-cell activation in the presence of TGF-β1 and the absence of proinflammatory cytokines. Tregs are usually characterized by the FoxP3 transcription factor, and CD25, the α chain of IL-2 receptor. However, the study of Tregs is fraud with difficulties because of the heterogeneity of Tregs definition, since the transcription factor FoxP3 is also expressed in nonregulatory cells, and CD25 is also expressed in activated effector T cells. Furthermore, FoxP3 is intracellular and the isolation of Tregs for functional studies is challenging [37]. Investigators used additional markers to further characterize Tregs, such as CD45RA, CD127, the α chain of IL17 receptor, and the absence of CD49d, the α chain of integrin very late activation antigen 4 (VLA-4) [38]. As already mentioned, FoxP3 is a specific marker for Tregs, but its expression can be induced in activated conventional T cells without suppressive properties. For instance, CD4+ CD45RA− FoxP3lowCD25+ are nonregulatory FoxP3+ T cells [39,40]. In addition, human Tregs can differentiate into IFNγ-producing cells or IL-17-producing cells upon exposure to Th1-inducing or Th17-inducing cytokines, respectively [41,42]. Of note, IL-17-producing Tregs may retain their suppressive function [41] or become pathogenic [43].

4  T cells in systemic sclerosis Early studies detected mononuclear cell (MNC) infiltrates with T cells and macrophages as the predominant cell types in skin lesions of SSc patients [44–48]. These infiltrates correlated

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with skin thickening suggesting a relationship between inflammation and fibrosis [44]. T-cell infiltrates appear early in the skin before any histological evidence of fibrosis in SSc [46] and T cells predominate over B cells in skin lesions of untreated patients with dcSSc [11]. T-cell infiltrates are also present in affected internal organs, such as in lungs with interstitial lung disease [49]. T cells also exhibit signs of activation in peripheral blood and skin lesions [48,50,51]. In skin lesions from patients with early SSc, T cells were found to express markers of early T-cell activation [48], whereas ongoing T-cell activation was also found in untreated patients with early dcSSc [11]. Sequencing of TCR revealed that T cells in skin lesions were oligoclonal, whereas some T-cell clones persisted over months, indicating an antigen-driven proliferation of T cells [52]. Interestingly, TCR repertoire of skin lesions from early SSc patients, assessed by complementarity-determining region 3 (CDR3) length analysis, revealed a skewed TCR repertoire suggestive of oligoclonal T-cell expansion, whereas co-culture of fibroblasts with peripheral blood mononuclear cells (PBMCs) from SSc patients showed the same T-cell clones. These findings suggest that the fibroblasts may be the likely source of antigenic stimulation of T cells in SSc [53]. By cytofluorimetric analysis, T-cell clones were also found in another study [54]. Skewed TCR repertoire, assessed by CDR3 length analysis, was also found in bronchoalveolar lavage (BAL) CD8+ T cells from SSc patients [55]. Endothelial cells might also be targets of T-cell immune response as cell surface antigens shared by fibroblasts and endothelial cells have been recognized as targets of Abs in SSc [56] and it is well known that T cells provide help for IgG antibody production. Another study using TCR CDR3 length analysis did not find oligoclonality in peripheral blood total T cells, CD4+ T cells or CD8+ T cells from patients with late disease and this may be related to the disease stage [57]. In some SSc women male fetal cells (microchimerism) were detected in T cells from peripheral blood and skin lesions raising the possibility that fetal antimaternal graft-vs-host disease (GVHD) reactions may operate in some women with SSc [58]. Male-offspring T-cell clones, generated from peripheral blood and skin lesions of female patients with SSc who had a male child, reacted with maternal HLA antigens and exhibited Th2 profile, producing high levels of profibrotic IL-4 [59]. In contrast, male-offspring T-cell clones from healthy women who had a male child were less frequent and did not produce IL-4, giving further support to the GVHD hypothesis in the pathogenesis of SSc [59]. Activated T cells can activate fibroblasts via direct cell–cell contact or via cytokines/chemokines. Activated T cells also provide help to B cells for the production of IgG profibrotic autoAbs [7,16]. The inducible T-cell costimulator (ICOS), a member of CD28 superfamily that affects T-cell proliferation, germinal center formation, B-cell antibody production, and antibody class switching [60] was upregulated in peripheral blood T cells in early dcSSc [61,62]. ICOSexpressing T cells were increased in skin lesions in early dcSSc whereas in vitro stimulation of ICOS increased the production of proinflammatory (IFN-γ and IL-17A) and profibrotic (IL-4) cytokines from T cells in early dcSSc but not in healthy controls (HCs) [61]. Another costimulatory molecule CD40 ligand (CD40L, CD154) was also upregulated in activated CD4+ cells in SSc [63]. CD40, initially described on the surface of B cells was highly expressed on the surface of fibroblasts from early SSc, whereas stimulation of CD40 in SSc fibroblasts but not normal fibroblasts increased the production of IL-6, IL-8, and monocyte chemoattractant protein-1 (MCP-1) [64]. Transcriptome analysis (mRNA sequencing) of T and B cells from peripheral blood of SSc patients revealed an activated phenotype of CD4 and innate-like mucosal-associated invariant

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T cells, suggesting exhausted T cells in response to chronic stimulation [65]. However, other studies showed that T cells are active effector cells. In the skin of early dcSSc patients, CD4+ cytotoxic (CD57highCD4+) and CD8+ T cells were major contributors to inflammatory infiltrates. In addition, apoptotic cells were frequent and endothelial cells expressing HLA-DR antigens (activated) were frequent targets of apoptosis and were in close proximity to cytotoxic T cells (CTLs). A TCR repertoire analysis of CD28lowCD57highCD4+ CTLs from the peripheral blood of these patients revealed marked clonal expansion of these cells compared to naïve CD4+ T cells with a couple of clones most prevalent, accounting for 50%–75% of all TCRs. Furthermore, this CTL clonal expansion correlated with skin fibrosis [11]. This seminal study suggests that it is very likely that endothelial cells expressing HLA-class II besides HLA-class I, activated by an unknown agent, present antigens to CD4+ and CD8+ T cells and become the targets of CD4 and CD8 T cells and undergo apoptosis [11]. CD28lowCD57highCD4+ CTLs had transcriptional signatures linked to cytotoxicity, fibrosis, and metabolic activity [11]. The latter findings argue in favor of activated effector CTL population and against exhausted T-cell population. This study by Maehara et al. is important because it identified apoptotic endothelial cells in close proximity to CTL in skin lesions and suggested that endothelial cells are the targets of CTLs in SSc. It should be reminded that SSc CD8+ T cells are cytotoxic, expressing the cytotoxic enzymes granzyme B and perforin, while the cytotoxic killing mediated by granzyme B and perforin can generate autoantigens that initiate and/or perpetuate immune responses. Indeed, self-protein fragments generated by granzyme B were targets of autoAbs in SSc [66]. IL-6, increased in PHA-stimulated peripheral blood mononuclear cells (PBMCs) and T-cell lines from SSc patients [67], induced fibroblast collagen production in vitro [68], whereas IL-6 expression was prominent in mononuclear cells, fibroblasts, and endothelial cells of skin biopsies for early dcSSc patients [69]. Innate immunity cross-talking with adaptive immunity in SSc contributes to SSc pathogenesis. Toll-like receptor 9 (TLR9) expression was increased in SSc T and B cells, whereas nucleosomes, a ligand for TLR9, were elevated in SSc sera and induced T-cell expression of IL-4 and IL-17, B-cell IgG production, and lymphocyte proliferation [70]. Also, genome-wide methylation analysis of CD4+ and CD8+ T cells from SSc peripheral blood revealed that the type I interferon signaling pathway was enriched in both CD4+ and CD8+ T cells [71].

5  Th2/Th1 balance in systemic sclerosis The Th1/Th2 balance is crucial for the development of fibrosis as IL-4 producing Th2 cells induce fibrosis while IFN-γ producing Th1 cells inhibit fibrosis in experimental models of fibrosis [72]. Early studies recognized the predominance of profibrotic Th2 cells over antifibrotic Th1 cells in SSc. Serum levels of IL-4 and IL-13 were increased in both dcSSc and lcSSc [73]. Serum IL-4 appear to come from Th2 cells as IL-4 mRNA was increased in PBMCs from SSc patients and correlated with plasma IL-4 levels. Furthermore, alternatively-spliced IL-4 mRNA (designated IL-4δ2) was also increased in SSc peripheral blood T cells [51]. Early studies in SSc perivascular skin infiltrates detected IL-4 mRNA by in situ hybridization [74,75], but little or no IFN-γ mRNA [75], and CD30, a marker of Th2 cells, was detected on many CD4+ T cells [75,76]. In the great majority of dcSSc patients, serum levels of soluble CD30

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were elevated [75]. Furthermore, most T-cell clones generated from skin lesions were Th2 producing IL-4 but no IFN-γ [75]. In a longitudinal analysis of serum Th1 and Th2 cytokines in SSc, Th2 cytokines decreased as skin fibrosis regressed, whereas levels of IL-12, a Th1inducing cytokine increased by 15-fold and associated with regression of skin fibrosis [77]. Also, early on it was apparent that IL-4 is a profibrotic cytokine, inducing fibroblast collagen production in vitro [78], whereas IFN-γ is antifibrotic, inhibiting the collagen production [79]. Th2 cytokines, IL-4 and IL-13, stimulate a profibrotic phenotype in human fibroblasts [76,78]. They induce collagen production by normal fibroblasts, inhibit IL-1β-induced matrix metalloproteinase (MMP)-1 and MMP-3 production, and increase tissue inhibitor of metalloproteinase (TIMP) by normal fibroblasts [80]. IL-13 induces tissue fibrosis through a TGFβ1dependent [81] and a TGFβ1-independent [82] pathway. IL-4 decreases TGF-β1 production in fibroblast [83], but induces CD30+ B cells producing granulocyte macrophage-colony stimulating factor (GM-CSF), which are increased in SSc, particularly in patients with ILD [84]. Of note, GM-CSF induced trans-differentiation of monocytes to myofibroblasts [85]. IL-4 signaling also stimulated proliferation of fibro/adipogenic progenitors (FAPs) in vitro [86]. IL-4 stimulates macrophages to an alternatively activated phenotype, whereas blockade of IL-4 receptor (IL-4Rα) decreases alternatively activated (M2) macrophages and attenuates profibrotic changes in mice [87]. IL-4/IL-13-activated macrophages promote fibrosis, which is enhanced by IL-21 and IL-33, as IL-33 also enhances M2 macrophage polarization [88]. IL-33 can be produced by M2 macrophages [89]. One study found that Th2 cells inhibited collagen production in normal fibroblasts in a contact-dependent manner through membrane-associated TNF-α, but SSc skin fibroblasts were resistant to inhibition by T-cell contact [90]. However, it should be noted that the agent used for the stimulation of T cells is important in in  vitro T-cell studies, as Th1 cells (but not Th2 cells) that were stimulated by IL-2 inhibited collagen production by skin fibroblasts, whereas both Th1 and Th2 cells that were stimulated by anti-CD3 monoclonal antibody inhibited collagen production by skin fibroblasts [90]. Several studies analyzed Th2 and Th1 cytokines produced by T-cell subsets. Freshly isolated CD8+ T cells from early dcSSc patients produced IL-13 [91] and IL-4 [92] with a significant contribution of memory CD8+ T cells, whereas high levels of intracellular IL-4 and IL-13 were associated with the presence of ATA and ACA [92]. CD8+ T cells from peripheral blood of SSc patients produced high levels of IL-13 upon activation, while CD4+ T cells produced lower and more variable levels of IL-13 [93]. Also, peripheral blood CD8+ T cells, expressing skin homing receptors CCR10 were increased in SSc and contained a higher frequency of IL13+ cells [76]. In addition, mononuclear cell (MNC) infiltrates of skin lesions were abundant in early disease with higher proportion of CD8+ T cells compared to CD4+ T cells and contained high numbers of IL-13+ cells [76], whereas in late disease MNC infiltrates were sparse and CD4+ T cells predominated over CD8+ T cells. Furthermore, supernatants from SSc CD8+ T cells induced normal dermal fibroblasts collagen production, which was inhibited by IL-13 neutralizing antibody [76]. Peripheral blood and skin CD8+ CD28− T cells were increased in SSc and their numbers correlated with the extent of skin fibrosis [94]. These cells exhibited an effector memory phenotype, producing high levels of IL-13 and IFN-γ with a strong cytolytic activity ex vivo, and induced a profibrotic phenotype in SSc and normal fibroblasts [94]. CD226+ CD8+ T cells, also increased in SSc and associated with skin and lung fibrosis [95], producing high levels of IL-13, and inducing cytolysis of endothelial cells, as neutralization

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of CD226 in CD8+ T cells impaired IL-13 production and cytolysis of human umbilical vein endothelial cells (HUVEC) [95]. CD8+ Th2 cells are the dominant subtype in the BAL from SSc patients, and appear to be expanded in response to antigens while CD8+ T cells form SSc BAL were oligoclonal by TCR CDR3 length analysis [55], were mostly of Th2 type, and correlated with decline of lung function over time. Another study also confirmed the Th2 type of CD8+ T cells from SSc BAL, which produced profibrotic factors IL-4 and oncostatin M and expressed β2 integrin, which activates latent TGF-β into an active form [96]. CD4+ CCR7− memory T cells were also producers of IL-13, IL-4, and TNF-α particularly in dcSSc [97]. CD4+ cytotoxic T lymphocytes (CTLs) also appear to be Th2 cells in SSc. CD4+ CTLs are heterogeneous populations of cells and express granzymes and perforin and secrete IL-1β and TGF-β1. CD4+ CTLs and CD8+ T cells were prominent in SSc skin infiltrates. Th2 cells were also increased in skin infiltrates and prominent in peripheral blood of these patients [11]. CD4+ CD8+ double positive T cells producing very high levels of IL-4 were also detected in SSc skin lesions [90,98]. IL-31 is another cytokine that is mainly produced by Th2 cells [20,99] and after binding to its receptor, comprised of IL-31RA and oncostatin M, activates the JAK/STAT pathway in many cell types [100]. IL-31 was increased in skin and lung lesions of SSc patients. Furthermore, IL31 induced skin fibroblasts expression of genes associated with cell growth and proliferation, and collagen production and negatively associated with angiogenesis and vascular repair, whereas in mice IL-31 injections induced skin and lung fibrosis [101]. The differentiation of naïve T cells to Th2 requires the local presence of IL-4 or IL-13. It is very likely that cells of the innate immune system provide the appropriate environment in the vicinity of T cells. Type 2 innate immune response cells, such as eosinophils, mast cells, and alternatively activated (M2) macrophages, were detected in SSc and can induce Th2 immune response [4,102,103]. Innate-type lymphoid cells type 2 (ILC2) express the inducible T-cell costimulator (ICOS) and produce IL-13 in response to IL-33 [104]. Of note, dermal and peripheral blood ILC2 were increased in SSc and correlated with skin and lung fibrosis [8]. B cells can also contribute to Th2 polarization in SSc. For instance, B cells, through direct contact, induce dendritic cell (DC) maturation that promotes Th2 differentiation, whereas their ability to function as APCs also favors Th2 response [7]. IL-6 can polarize naïve CD4+ T cells into IL-4-producing Th2 cells [105] and IL-33, a member of IL-1 cytokine family expressed in epithelial and endothelial cells [106], also induces Th2 cytokines [107]. Platelet-derived Dickkopf-related protein-1 (DKK1), a Wnt antagonist, is also an inducer of Th2 cell polarization [108].

6  Th17 cells The role of Th17 cells in SSc remains unclear. IL-17 is an inflammatory cytokine stimulating the expression of adhesion molecules in endothelial cells. It is noted that endothelial cells and fibroblasts express functional IL-17 receptors [25]. Serum IL-17A levels were elevated in SSc in some studies [109–111], decreased in few other studies [112], probably reflecting different stages of the disease. Serum IL-17B, IL-17E, and IL-17F were also elevated in SSc and serum IL-17E and IL-17F were associated with digital ulcers [113,114]. Serum IL-21 levels were found to be elevated in SSc, more in dcSSc than lcSSc [111,112].

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Th17 cells were increased in SSc [115,116] and decreased after immunosuppressive treatment [117]. IL-17 mRNA was expressed in skin and lung lymphocytes along with elevated serum IL-17 levels in early SSc [109]. An increased frequency of CD146+ Th17 was inversely correlated with SSc-associated ILD (SSc-ILD) [116]. Increased IL-17A+ cells [118,119], decreased IL-17C+ cells, and IL-17E+ cells were found in SSc skin [119]. The effect of Th17 cells on fibrosis in SSc is proinflammatory and likely to be profibrotic. IL-17A increased MCP-1, IL-6, IL-8, and adhesion molecules in normal fibroblasts in a dose dependent manner [109,120] and induced the expression of IL-1β and intercellular adhesion molecule 1 (ICAM1) in human endothelial cells in a dose dependent manner [109]. In turn, the aberrant production of IL-1β in endothelial cells can promote fibrosis, as IL-1β induced the production of IL-6 and platelet-derived growth factor (PDGF), which are mediators of collagen synthesis in normal and SSc fibroblasts [35]. Of note, serum IL-6 levels were elevated in SSc [121]. Although IL-17A enhanced the proliferation of fibroblasts in a dose-dependent manner, it did not affect collagen production or decreased collagen expression and production in fibroblasts from healthy individuals and SSc patients [109,122,123]. Co-cultures of PB T cells from SSc patients with very early dcSSc with autologous fibroblasts revealed a decrease in collagen gene expression and overexpression of IL-17A [124] and this antifibrotic and proapoptotic effect on autologous fibroblasts was mediated by IL-17A signaling. In addition, supernatants of Th17 clones enhanced MCP-1, IL-8, and MMP1 and strongly inhibited collagen production in HC and SSc fibroblasts [120] and this inhibition was mediated by IL-17A, TNF-α, and partly by IFN-γ. IL-17E (IL-25) directly induced fibroblast collagen production whereas IL-25 blockade reduced lung IL-4, IL-5, and IL-13, and significantly increased IFN-γ in house dust mite-treated mice [125]. However, impaired IL-17A signaling may contribute to increased collagen production in SSc fibroblasts [122]. Although IL-17A was found to be increased in peripheral blood and skin lesions in SSc, IL-17A receptor (IL-17RA) expression was decreased in SSc fibroblasts due to intrinsic TGF-β1 activation in these cells [122]. However, another study found that IL-17 and Th17 cells were profibrotic, increasing fibroblast collagen production. Serum IL-17 levels were increased in early SSc; supernatants of PBMCs from active SSc induced fibroblast collagen production, which is mediated by IL-17 since it was inhibited by anti-IL-17 neutralizing antibody [126]. Further, supernatants of Th17 cells for active SSc patients induced more collagen production by fibroblasts than HC Th17 cells [126]. Thus, Th17 cells contribute to SSc pathogenesis through proinflammatory cytokines and might contribute to SSc fibrosis either directly or indirectly through endothelial cell IL-1β production.

7  Regulatory T cells (Tregs) and Tregs/Th17 balance Studies of Tregs in SSs reported Tregs frequencies and Tregs function. The Tregs suppressive capability is generally reduced in SSc [38]. Tregs were also reduced, although some studies found increased numbers, probably in a compensatory inefficient attempt [38,127,128] or no alterations in numbers and function [129]. Liu et  al. reported increased frequency of CD4+ CD25+ FoxP3+ Tregs in peripheral blood of SSc patients but diminished immunosuppressive capacity; they found decreased

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­ roportions of activated Tregs (FoxP3highCD45RA−) and resting Tregs (FoxP3lowCD45RA+) p with diminished immunosuppressive capacity [128]. More importantly, FoxP3lowCD45RA− T cells were increased but they lacked suppressive capacity and produced IL-17A. Also, FoxP3+ IL-17+ cells were increased. These findings suggest that Tregs have been transformed into effector Th17 cells [128]. Tregs may be increased secondary and in parallel with activated CD4+ T cells. Thus, Tregs (CD4+ CD25highFoxP3+) were increased in peripheral blood of SSc but the ratio of Tregs/activated CD4+ T cells (CD4+ CD25+) was constant and no different from that of HCs [130]. Similarly, CD25highFoxP3highCD127− Tregs were highly increased in peripheral blood of early SSc patients, as were activated CD4 T cells (CD4+ CD25+) [131]. It should be stressed that it is more meaningful to take into account the ratio of Tregs to proinflammatory T cells, instead just the frequencies/numbers of Tregs. Most studies reported decreased Tregs/Th17 ratio, either in terms of percentages or function in SSc. Thus, in peripheral blood from dcSSc patients, Th17 cells were increased, while Tregs (CD4+ CD25+), NKT cells, and Th1 cells were decreased, and the ratio of Th17/Tregs was increased [132]. The suppressor activity of CD4+ CD25+ Tregs was diminished, as was the serum IL-10 levels [132]. Similarly, Th17 cells were increased but CD4+ CD25+ CD127− Tregs were not affected in peripheral blood of early SSc patients [126] and peripheral blood CD4+ CD25+ FoxP3+ Tregs were not different from HCs, while Th17 cells were increased [133]. In another study, Tregs and Th17 cells were both increased in peripheral blood of SSc patients and strongly associated with early active and severe disease, but Tregs exhibited diminished suppression on autologous T cells [134]. Similarly, a decreased proportion of activated Tregs in early SSc peripheral blood was found with no alteration of Th17 cells [40]. IL-10-producing regulatory B cells (Bregs), which inhibit Th1 and Th17 differentiation and expand Tregs, were decreased and functionally impaired in SSc, particularly in SSc-associated ILD [135] and inversely correlated with IL-17-producing and IFNγ-producing T cells [136]. Also, semaphorin 3A, which affects the activation of Tregs, was reduced in SSC sera and its expression was also decreased in Tregs [137]. In summary, Tregs may be increased or decreased in peripheral blood of SSc patients but they are functionally impaired, failing to produce inhibitory cytokines TGF-β1 and IL-10 and to suppress effector T cells [138]. This functional impairment is probably related to soluble factors as plasma from early dcSSc patients completely abrogated the suppressive capacity of Tregs from healthy individuals [131]. How are Tregs impaired in SSc? Epigenetics is a likely mechanism. Hypermethylation of FOXP3 promoter associated with reduced expression of FOXP3 mRNA was found in CD4+ T cells from SSc patients [139]. Another mechanism for Tregs impairment in SSc may be skewing X-chromosome inactivation (instead of random inactivation), which was associated with lower expression of FOXP3 and less efficient suppressive activity [140]. Soluble factors for SSc plasma inhibited Tregs function, and the diminished suppressive activity of Tregs (CD4+ CD25highCD127−) was associated with decreased Tregs surface expression of CD69 and intracellular expression of TGF-β [131]. The local lesional tissue environment is another means by which Tregs suppressive activity is impaired by converting suppressive Tregs into effector T cells. CD4+ FoxP3+ Tregs were found decreased in SSc skin lesions but not in the peripheral blood [129]. CD4+ FoxP3+ Tregs were decreased in skin lesions as were TGFβ+ cells; but CD25+ cells were increased, implying a predominance of effector T cells in SSc skin lesions, whereas peripheral blood Tregs

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(CD4+ CD25highFoxP3+) were decreased in these patients [127]. Another study found both IL17+ lymphocytes and FoxP3+ lymphocytes to be increased in early SSc skin lesions [126]. MacDonald et al. reported that Tregs (FOXP3+) from SSc skin but not from peripheral blood Tregs (CD4+ FOXP3+) produced IL-14 and IL-13 [141]. IL-33, an IL-1-like cytokine, caused differentiation of normal skin Tregs into Th2-like cells producing IL-13 (but not IL-4) and furthermore, IL-33+ cells were in close proximity to CD3+ T cells in SSc skin lesions [141]. Of note, SSc fibroblasts exposed to inflammatory cytokine IL-1β and TNF-α significantly upregulated IL-33 mRNA [141]. Therefore, it is likely that the differentiation of Tregs in SSc skin into Th2-like cells is due to IL-33. IL-33 induced Th2 differentiation and was elevated in peripheral blood [142–144], the affected skin, and internal organs [145] of SSc patients.

8  Tfh cells Peripheral blood Tfh were increased in SSc particularly in dcSSc and exhibited an activated phenotype with enhanced capacity to produce IL-21 and to stimulate plasmablast’s secretion of IgG and IgM [146]. IL-21 augmented Th2 effector function and alternative activation of macrophages [147]. Also, CD4+ ICOS+ Tfh-like cells were present in SSc skin lesions and correlated with skin fibrosis [148].

9  Other Th subsets Other less well studied subsets include Th9 cells that produce IL-9 and Th22 cells that produce IL-22 without IL-17A. Serum IL-9 was decreased in SSc and associated with lower frequency and severity of SSc-ILD [149]. TSLP was upregulated in dcSSc skin, expressed mostly by alternatively activated macrophages and less frequently by T cells. TSLP induced a TGF-β1 canonical activation in vitro in human dermal fibroblasts and expression of MRC1, a marker of alternatively activated (M2) macrophages, in PBMCs, whereas MRC1 was highly expressed in dcSSc skin [22]. Th22 in addition to Th2 and Th17, but not Th1 cells, were increased in SSc and associated with ILD [150]. IL-22+ IL17− (Th22) cells were increased in epidermis and skin lesions of early SSc [40,151]. IL-22 promoted inflammation by increasing monocyte chemotactic protein 1 (MCP1), IL-8, and MMP1 production induced by TNF-α. In addition, fibroblasts increased collagen production by supernatants of IL-22-stimulated keratinocytes, whereas dermal thickness in mice was maximal after injection of both IL-22 plus TNF-α [151]. The functions of Th cells and their relevance to fibrosis are shown in Table 1.

10  Unconventional T cells A subset of T cells carries a TCR comprising of a γ and a δ chain and these Tγδ cells constitute a small proportion of peripheral blood T cells and recognize nonpeptide antigens. The most prevalent Tγδ cells in human PBMCs were the Vδ2 and Vδ1 Tγδ cells. In peripheral blood from SSc patients, Tγδ cells were reduced or showed no different from HCs [152–155], but the proportion of activated Tγδ cells was increased in dcSSc, as Tγδ cells

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TABLE 1  Major T helper cell subsets and their role in systemic sclerosis. Th subset

Induction cytokine

Transcription factor

Cytokine production

Th1

IL-12

T-bet

IFNγ

– Defend against intracellular pathogens – Inhibits collagen production through IFNg

Th2

IL-4

GATA3

IL-4, IL-5, IL-13, IL-31

– Defend against parasites – Involved in allergic diseases – Induce collagen production through cytokines and likely through direct contact

Th17

IL-21 or IL-6 plus TGFβ1, IL-23

RORγt

IL-17A, IL17F, IL-21

Tfh

IL-21

Bcl6

IL-21

– They provide B cell help for antibody production

Tregs

TGFβ1

FoxP3

TGFβ, IL-10

– They suppress effector T cells – SSc skin Tregs differentiate into profibrotic Th cells

Function

– Defend against extracellular pathogens and fungi – They promote inflammation They induce fibrosis through endothelial cells

expressing the early activation antigen, CD69, were increased [153]. However, Tγδ cells were markedly increased in perivascular MNC infiltrates of early disease, with the majority of cells expressing Vδ1 [152]. By analyzing size distribution of Vδ1 chain junctional distribution, oligoclonality of Vδ1+ Tγδ cells was found in peripheral blood and at multiple tissue sites [156]. Contrary to Tαβ cells which are predominantly Th2 cells in peripheral blood of SSc patients, circulating Tγδ cells and Vδ1 Tγδ cells were predominantly IFNγ+ Th1 cells over IL-4+ Th2 cells [152,157]. However, Tγδ cells from SSc patients co-cultured with fibroblasts increased collagen expression compared to Tγδ T cells from healthy individuals [153]. Other studies found reduced responsiveness of particular Tγδ cells. Vγ9Vδ2 Tγδ cells from SSc PB exhibited reduced responsiveness to stimulation and produced less IFN-γ and TNF-α [158], whereas SSc Vg9+ Tγδ cells induced apoptosis of fibroblasts ex vivo, as did Vγ9+ Tγδ cells from healthy controls [159]. Similarly, the proportion of CD161+ Vδ1+ Tγδ cells was lower in SSc PB, particularly in SSc-ILD, and furthermore, these cells from SSc-ILD patients produced less IFN-γ than healthy controls [160]. Mucosal-associated invariant T (MAIT) cells are innate-like cells mostly located at mucosal sites and the liver and characterized by invariant TCR, high CD161 expression, and production of IL-17, TNF-α, and IFN-γ [161]. These cells were reduced in SSc peripheral blood [154].

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Of note, CD161 is homologous to mouse NK cell marker NK1.1 and is expressed on human NK cells, NKT cells, and some T cells. Invariant NK T cells, a subset of NK T cells, non-MHCrestricted, expressing the semi-invariant TCR Vα24-J18 in humans, and recognizing glycolipids presented on CD1d, and influencing Th differentiation, were deficient and functionally impaired in SSc failing to expand upon stimulation [162]. In this cohort of patients of the latter study Th17 cells were increased [162]. Tγδ cells also exhibited clonal expansion in SSc, as suggested by two studies. Peripheral blood TCRγ chain gene rearrangement analysis by polymerase chain reaction (PCR) and electrophoresis revealed clonal expansion of Tγδ cells in PB more frequently in lcSSc than in dcSSc [163,164]. Similar analysis revealed clonal expansion of Tγδ cells in skin lesions [164]. In summary, Tγδ cells, increased in tissue lesions, are likely to contribute to SSc fibrosis and initiate endothelial cell damage [165].

11  Angiogenic T cells T cells termed angiogenic T cells (Tang) are characterized by CD3, platelet endothelial cell adhesion molecule-1 (CD31), and the chemokine receptor CXCR4 (CD184), (CD3+ CD31+ CXCR4+), can express CD4 or CD8 and can promote new blood vessel formation and endothelial cell repair [166]. Tang numbers were increased in SSc patients with digital ulcers perhaps reflecting an ineffective attempt to compensate the need for angiogenesis and endothelial cell repair [167]. In another study, Tang cells were increased in SSc, particularly in patients with SSc-associated pulmonary arterial hypertension (SSc-PAH) and in patients with nucleolar immunofluorescence pattern of antinuclear antigens (ANA), and were correlated with serum levels of vascular endothelial growth factor (VEGF) and vascular cell adhesion molecule-1 (VCAM-1) [168]. CD8+ Tang cell percentages were also increased in SSc-PAH, but the numbers of CD4+ Tang and CD8+ Tang did not differ from healthy controls [168].

12  T cells and vasculopathy The very early infiltration of T cells in skin of SSc patients along with dysfunction of endothelial cells led to the hypothesis that T cells could drive both fibrosis and endothelial dysfunction and damage. trans-Endothelial migration of CD4+ T cells was enhanced in SSc [169], whereas increased and activated CD4+ CD8+ T cells along with activated endothelial cells were detected in gastric biopsies of SSc patients [170]. A new study by Maehara et  al. which analyzed T-cell infiltrates and T cells from peripheral blood of patients with untreated early dcSSc [11] significantly contributed to better understand the endothelial cell damage. These authors found that activated (expressing HLA-DR antigens) endothelial cells in skin biopsies were frequently undergoing apoptosis whereas CD4+ cytotoxic T cells were dominant CD4+ T-cell subset in skin infiltrates and enveloped endothelial cells undergoing apoptosis. In addition, CD57, a marker of T cells cytotoxicity, was increased in peripheral blood CD4+ cytotoxic T cells, and peripheral blood CD57highCD4+ cytotoxic T cells were active effector cells exhibiting transcriptional signature of cytotoxicity, fibrogenesis and metabolic activity, were clonally expanded and correlated

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22.  T cells in the pathogenesis of systemic sclerosis

with activated myofibroblasts in skin biopsies [11]. It should be mention that CD4+ cytotoxic T cells express TGF-β1, IL-1β, and granzyme A, and can induce apoptosis of target cells [171]. These findings strongly suggest that endothelial cells in skin lesions are targets of CD4+ cytotoxic T cells in SSc. Tγδ cells may initially be involved in endothelial cell damage as SSc Tγδ cells more than Tαβ cells adhered to cultured endothelial cells, proliferated and exhibited increased cytotoxicity to endothelial cells [165].

13  Lessons from animal models of scleroderma Various animal models of scleroderma were used to study the pathophysiology of fibrosis, including genetic models, such as the Tsk1/+ mice caused by tandem duplication of fibrillin (Fbn) gene, the Tsk2/+ mice caused by gain-of-function mutation in the Col3a1 gene [172] and bleomycin-induced fibrosis. Bleomycin, an antineoplastic agent, can cause lung fibrosis in humans and is used to induce scleroderma and lung fibrosis in mice. These mice exhibited accumulation of collagen and mononuclear cell infiltrates in the dermis and autoantibodies, ANA, anti-Topo I antibodies, and anticentromere antibodies [173]. Chronic graft-vs-host disease (GvHD) that develops after bone marrow transplantation exhibits SSc-like manifestations and anti-Topo I antibodies [174]. Transgenic mice expressing the transcription factor fos-related antigen-2 (Fra-2) gene exhibit lung fibrosis microvasculopathy and pulmonary hypertension, which closely resemble human SSc [175,176]. Hypochlorous acid-induced scleroderma model exhibits increased infiltrations of CD4+ T cells, CD8+ T cells, CD20+ B cells, and myofibroblasts in skin and lung tissues [177]. Early on, the importance of immune cells has been emerged. Transfer of bone marrow cells from TSK1 + mice to littermates led to skin fibrosis and the appearance of autoAbs [178]. Early studies confirmed that agonists of Th1 response, such as IFN-γ, IL-12, and CpG oligonucleotides are protective of scleroderma in animal models, whereas Th2 cytokines were profibrotic [72,179]. The Th1/Th2 balance is crucial for the development of fibrosis with IL-4 producing Th2 cells and inducing fibrosis, and IFNγ-producing Th1 cells inhibiting fibrosis in experimental models of fibrosis [72]. Anti-IL-4 neutralizing antibodies prevented scleroderma in Tsk1/+ mice by a direct effect on fibroblasts as Tsk1/+ fibroblasts that express IL-4 receptor and when stimulated by IL-4 increase collagen production [180]. Furthermore, the development of Th2 cells and skin fibrosis were abrogated by null mutation of IL-4 gene ­(IL-4  −/−) [181]. In TSK1+ mice, a T-cell reactivity, analyzed by delayed-type hypersensitivity, to ­elastase-solubilized lung peptides was reported [182] whereas the introduction of particular TCR transgene containing the Vβ8.2 gene segment in T cells was sufficient to prevent scleroderma [181]. In the bleomycin-induced scleroderma, the infiltration of CD4+ T cells into the dermis preceded dermal fibrosis [64]. The profibrotic role of Th17 cells was evident in the bleomycin-­ induced skin fibrosis model. Bleomycin skin injections induced IL-17 expression in the skin and Th17 cell in the spleen [183]. IL-17A induced TGF-β1, CTGF, and collagen production in fibroblast cell line in vitro, whereas mice deficient in IL-17A exhibited significantly attenuation of bleomycin-induced skin fibrosis [183]. Inflammatory infiltrates with Th17 cells in skin

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and lung were increased and serum, skin, and lung levels of IL-17A, IL-6, TGF-β1, and RORγt were increased. Furthermore, IL-17A induced fibroblast proliferation and collagen production in vitro, which was inhibited by anti-IL-17A treatment [184]. Neutralization of IL-17A not only prevented lung fibrosis but also attenuated lung fibrosis [185,186]. IL-17A promoted collagen production also in mouse alveolar epithelial cells [186]. IL-23, a survival and proliferation factor for Th17 cells, induced skin fibrosis in bleomycin-induced mouse model [187]. The above studies clearly showed a profibrotic effect of Th17 cells in ­bleomycin-induced scleroderma. Apart from Th17 cells, CD4+ IL-21+ cells and IL-21+ Th17 cells were also increased in peripheral blood, skin, and lung tissues of bleomycin-treated mice, whereas IL-21 induced the differentiation of CD4+ T cells isolated from bleomycin-treated mice into Th17 cells in vitro, suggesting an important role for IL-21 in this model [188]. The interaction of T cells with fibroblasts via CD154-CD40 signaling was critical for fibroblast activation in the bleomycin-induced skin fibrosis. Dermal fibroblasts in b ­ leomycin-treated mice expressed CD40 whereas CD4+ T cells and mast cells expressed CD154 and electron microscopy analysis revealed that fibroblasts were attached to T cells and mast cells suggesting that fibroblasts are likely to communicate with T cells via CD40-CD154 pathway [189]. Furthermore, anti-CD154 antibody inhibited bleomycin-induced fibrosis by suppressing fibroblast proliferation, and MCP-1 expression [189] in a dose-dependent manner [64]. The importance of T cells in fibrosis was also shown in another study. Intratracheal administration of bleomycin increased lung fibrosis and IFNγ+ Th1 cells, and decreased IL-4+ Th2 cells in lung and lymph nodes, but administration of anti-CD3 monoclonal antibody diminished lung fibrosis and increased survival, again indicating the key role of T cells in fibrosis of this model [190]. However, a study found that bleomycin-induced scleroderma can still develop in the absence of adaptive immune system as it can develop in RAG2 knock out (RAG2 −/−) mice [191]. The transcription factor T-bet, a master regulator of Th1 response, by activating Th1 cytokines and repressing Th2 cytokines, can still operate in bleomycin-induced scleroderma in mice lacking T and B cells by repressing innate cells’ expression of IL-13 [191]. In bleomycin-induced lung fibrosis model of SSc, both Tregs (CD4+ CD25highFoxP3+) and effector T cells were increased in lungs in parallel with lung fibrosis [192]. Tregs significantly ameliorated bleomycin-induced lung fibrosis, as splenocytes induced Treg-mediated significant amelioration of bleomycin-induced lung fibrosis, and adoptive transfer of Tregs had a similar effect [193]. However, CD4+ CD25highFoxP3+ Tregs expanded in vivo via injection of IL-2 complexed with anti-IL-2 monoclonal antibody, exacerbated bleomycin-induced lung fibrosis, by downregulating Th1 and increasing Th2 response, whereas adoptive transfer of Tregs into bleomycin-challenged Rag1 −/− mice (mice with no lymphocytes) resulted in downregulation of CD25 and exacerbated lung fibrosis [192]. Tγδ cells appear to have a protective role in bleomycin-induced scleroderma, as mice lacking Tγδ cells (TCRδ −/−) exhibited enhanced lung fibrosis in bleomycin-induced fibrosis model [194]. Abatacept, a fusion protein composed of cytotoxic T lymphocyte antigen 4 (CTLA4), is an immune checkpoint inhibitor that inhibits T-cell activation by competing with costimulatory molecule CD28, and the Fc region of IgG1, is an effective treatment for rheumatoid arthritis. This agent was used to inhibit T-cell activation in animal models of SSc. In b ­ leomycin-induced SSc model, abatacept not only prevented bleomycin-induced skin fibrosis, but also a­ meliorated

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22.  T cells in the pathogenesis of systemic sclerosis

established fibrosis with parallel decreased in total and activated T but did not protect CB17severe combined immunodeficiency (SCID) mice from bleomycin-induced skin fibrosis, indicating the requirement of T cells for the antifibrotic effect of abatacept [195]. Similar decrease in fibrosis was also observed in GvHD model, but no antifibrotic effect in TSK1 + mice [195]. Abatacept also decreased T-cell proliferation and macrophage infiltration of lung lesions, alleviated lung fibrosis, and reversed pulmonary hypertension in Fra-2 transgenic mice [196]. Rapamycin, that binds to FK506-binding protein and inhibits the mammalian target of rapamycin (mTOR), also prevented skin fibrosis in TSK1 and bleomycin-induced mouse models of scleroderma [197]. ICOS+ Tfh-like cells were increased in the skin of GvHD mice and contributed to dermal fibrosis via IL-21 and MMP12 [148]. In addition, anti-ICOS antibody prevented the expansion of Tfh cells in GvHD mice and inhibited inflammation and skin fibrosis, whereas IL-21 neutralization also inhibited dermal fibrosis [148]. Putting together, all aforementioned studies show that T cells are the major players in the pathogenesis of SSc (Table 2 and Fig. 1).

TABLE 2  Evidence supporting T-cell involvement in the pathogenesis of systemic sclerosis (SSc). Supporting evidence

References

1. T cells predominate in mononuclear cell infiltrates in skin lesions and appear along endothelial cell changes before histological fibrosis

[10,11,44–48]

2. T cells in peripheral blood, skin and other tissue lesions exhibit oligoclonal expansion, evidence of response to an as yet unidentified antigen

[11,52,53,55]

3. T cells in skin lesions interact directly with fibroblasts via CD-40-CD40L and [53,56,63,64] may recognize antigens present on fibroblasts 4. Cytotoxic CD4+ and CD8+ T cells target endothelial cells causing damage

[11,56,95]

5. T cells provide help to B cells for antibodies production many of which are profibrotic and vasoconstrictive

[7]

6. Th2 cells predominate in SSc and produce profibrotic cytokines

[51,55,73,75–78,81,82,86,92–96,98]

7. Th2 cells promote alternatively activated (M2) macrophages which are profibrotic

[9,87,88]

8. Th17 cells, increased in SSc, are profibrotic in animal models of SSc. In humans they are proinflammatory and induce fibroblast proliferation, and endothelial cell production of profibrotic soluble factors

[35,51,75–77,109,115–117,119– 121,123,124,127]

9. Th1 cells, which inhibit fibroblast collagen production, are decreased in SSc

[51,75–77]

10. Tregs differentiate into effector Th2 and Th17 cells and display diminished suppressive capacity

[38,40,127,129,130,133,134,140–142]

11. Tγδ cells are increased in skin lesions, and may contribute to fibrosis and initial endothelial cell damage (Refs. [154, 166])

[154,166]

12. Anti-T-cell treatments are effective in animal models of SSc and promising treatments in humans

[64,72,149,180– 182,184,185,190,191,194,196–209]

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Environmental factor EC

Innate cell

T cell

M2 macrophage

B cell

Fibroblast

collagen

FIG. 1  Schematic depiction of T-cell involvement in systemic sclerosis. T cells orchestrate interactions with other cell types. They probably recognize antigens on fibroblasts and endothelial cells. They provide profibrotic signals to fibroblasts and exert cytotoxicity on endothelial cells (EC). B cells may present antigens to T cells and get help from T cells for autoantibody production.

14  Immunotherapy and future prospects Today, general immunosuppressives are the main treatment for SSc by using steroids, cyclophosphamide, methotrexate, mycophenolate mofetil, and anti-CD20 monoclonal antibody (rituximab), and autologous stem cell transplantation (ASCT) [198]. These medications affect T cells. Administration of steroids was associated with higher IFN-γ production and was negatively associated with IL-4 and IL-13 production in peripheral blood CD8+ T cells [92]. It is of interest that specific B-cell depletion treatment with rituximab decreased skin and peripheral blood CD4+ IL-4+ T cells and peripheral blood CD4+ CD40L+ T cells [199]. ASCT, used to reset the immune system in SSc, is the most effective treatment thus far for the disease [210,211]. Of note, after ASCT there was a predominant immune reconstitution with CD4+ Th1 cells [212], and functional renewal and diversification of Tregs with better suppressive capacity [213]. Type I collagen, a candidate autoantigen of T cells in SSc has been tried as oral treatment in SSc with limited success [214]. Cyclosporine, an inhibitor of T-cell activation, and rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), have been tried in a small number of SSc patients and improved skin tightness [215]. More specifically targeting T cells is a promising therapeutic strategy for this frequently devastating disease. Thus, targeting costimulatory molecules to inhibit T-cell activation has been tried in SSc [200]. Abatacept, which inhibits T-cell activation by competing with costimulatory molecule CD28, was used in small observational studies [201–203], and randomized trials [204,205]. A decreased in skin fibrosis, observed in small studies, did not reach statistical significance in the randomized trial [205]. Targeting activated T cells with anti-CD25 monoclonal antibody (basiliximab) was first used in one SSc patient [206] and then in an open-label study [207] and showed promising effects, reducing skin fibrosis and healing digital ulcers. 463



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Targeting IL-6 has already been tried with promising results [208], as well targeting IL-23, a proliferation factor for Th17 cells, in a patient with SSc and psoriasis, where Ustekinumab (anti-IL-12/IL-23 monoclonal antibody) improved skin tightness [216]. Restoring the Tregs/T effector cells balance with small IL-2 doses that increase Tregs may be another strategy [217]. The results of immunosuppressive treatment in SSc and the experience from everyday practice can summated as guarded optimism. However, it has become apparent that once fibrosis ensues any treatment is ineffective. The development of new classification criteria was a big step toward early diagnosis of SSc and brought some optimism [209]. What we should change in SSc treatment is the development of prediction algorithms to help define very early SSc patients who are going to develop progressive disease. This group of patients will be the target of very early immunosuppressive treatment and this has the greatest chance of being efficacious.

15  Conclusion Systemic sclerosis is a complex disease characterized by fibrosis, microvasculopathy, and the presence of autoantibodies. T cells appear to be key players in the pathogenesis of SSc; triggering molecular cascades leading to fibrosis and microvasculopathy, while they also help B cell to produce autoantibodies, some of which have profibrotic actions. Herein, we provided in depth analysis of the crucial role of various T-cell subsets in SS.

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23 Etiopathogenesis of Behçet’s syndrome: The role of infectious, genetic, and immunological environmental factors Alessandra Bettiol, Giacomo Emmi⁎, Irene Mattioli, and Domenico Prisco Department of Experimental and Clinical Medicine, University of Firenze, Firenze, Italy ⁎ Corresponding author

Abstract This chapter introduces current knowledge regarding the etiopathogenesis of Behçet’s syndrome (BS). It focuses on the classification of BS, highlighting how it shares common features with autoimmune diseases, autoinflammatory diseases, and MHC-I-opathies. The chapter subsequently presents the main individual and exogenous factors involved in the etiopathogenesis of BS. Particularly, it explains the contribution of microbial triggers, genetic susceptibility, epigenetics, and immunological factors to the etiopathogenesis of BS. Understanding the etiopathogenesis of BS is essential to identify modifiable risk factors for the occurrence or exacerbation of the disease and to develop targeted treatments.

Keywords Behçet’s syndrome, HLA-B51, Immunity, Inflammation, Microbiome, Neutrophils, Pathogenesis

1  Introduction Behçet’s syndrome (BS) is a systemic vasculitis, associated with a considerable morbidity and mortality, mainly because of the vascular and neurological manifestations. Understanding the etiopathogenesis of BS is essential to identify modifiable risk factors for BS occurrence or exacerbation and to develop targeted treatments. Translational Autoimmunity, Vol. 6 https://doi.org/10.1016/B978-0-323-85831-1.00023-1

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23.  Etiopathogenesis of Behçet’s syndrome

Although far from being fully understood, the knowledge of BS etiopathogenesis has significantly evolved over the last decades. Indeed, BS has been listed for many years among autoimmune diseases, with this notion being supported by the evidence of antigen-specific T-cell responses (particularly to heat shock proteins of Streptoccus spp. and Mycobacterium tuberculosis) and the detection of autoantibodies against endothelial cells, enolase, and retinal S-antigen. However, unlike “classic” autoimmune diseases, BS does not present a remarkable sex difference in its prevalence nor an increased risk of additional autoimmune comorbidities. Thus, BS has been also included among polygenic autoinflammatory conditions, as it is characterized by episodes of inflammation without antigen-specific T-cell responses or autoantibodies, massive neutrophils activation, and increased levels of the pro-inflammatory interleukin (IL)-1β. However, unlike autoinflammatory diseases, BS most frequently begins after puberty rather than during childhood, usually presents a prominent vasculitic involvement, which is quite uncommon in autoinflammatory diseases, and is poorly controlled by anti-IL-1β therapies [1,2]. More recently, clinical, biochemical, and molecular findings led to the idea that BS shares similarities with seronegative spondyloarthritides (SpA), thus introducing the concept of BS as belonging to major histocompatibility complex (MHC)-I-opathies. Evidence in support of BS as being related to SpA stems from its association with the human leukocyte antigen (HLA) class I, particularly with HLA-B51 and HLA-B27. Much evidence supports this concept: (1) HLA-B51 is epistatic with the endoplasmic reticulum aminopeptidase 1 (ERAP-1) gene, encoding a molecule in the endoplasmic reticulum that is involved in peptides MHC class I presentation of peptides to effector cells; (2) the increased T helper (Th)17 responses; (3) the neutrophils’ hyperactivation; and (4) the barrier dysfunction in environmentally exposed organs in BS patients [1,2]. The current view is that BS cannot be uniquely classified under the group of autoimmune, autoinflammatory, or SpAs, but rather shares common features with all the three groups of diseases (Fig. 1). Indeed, BS etiopathogenesis involves a complex genetic background that interacts with epigenetic, immunological, and microbial factors (Fig. 2) [1,2].

2  Microbial etiology Infections have long been suspected to be directly involved in the pathogenesis of BS. Particularly, considering that oral ulcers are almost pathognomic of BS, it has been suggested that oral impairment and buccal infections might be directly involved in the pathogenesis of the disease. An impaired oral health has been observed in BS patients as compared to healthy control subjects [3–6], and relapses of oral ulcers have been observed after dental procedures [6]. Indeed, high levels of various Streptococci strains have been found in the oral mucosa of BS patients [6]. This finding, together with the observation that the pustular lesions of BS patients are infected by several microorganisms including Staphylococcus, Streptococcus, and Prevotella strains, led to the concept of an infectious etiology, at least for the mucocutaneous and articular BS phenotype [7].

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FIG.  1  Common features of Behçet’s syndrome and autoimmune diseases, autoinflammatory diseases and MHC-I-opathies.

FIG. 2  Individual and exogenous factors involved in the etiopathogenesis of Behçet’s syndrome.

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Beside the hypothesis of a bacterial involvement, other three major hypotheses supporting an infectious etiology of BS have been formulated: (i) viral etiology and (ii) indirect infectious etiology via heat shock proteins (HSP) or via cross-reactivity or molecular mimicry. Regarding the viral etiology, viral infections from herpes simplex virus (HSV), varicella zoster virus, human cytomegalovirus, Epstein–Barr virus, and human herpes virus 6 and 7, have been proposed as possible etiological factors of BS [8]. The hypothesis of an indirect infectious etiology is supported by the fact that antigens from different infectious agents have been identified as triggering factors for BS. Namely, the homology between antigens from HSV-1 or Streptococcus species such as Streptococcus sanguinis and human proteins such as HSP has been proposed as a cause of cross-reaction, leading to the activation of immune responses [9,10]. Indeed, in situ DNA-RNA hybridization studies have demonstrated the presence of portions of the HSV-1 genome in mononuclear cells of BS patients [11]. As for Streptococcus species, the development of BS manifestations in hypersensitivity tests against streptococcal antigens has been described [12]. Specifically, mechanisms of ­molecular-mimicry between the neurofilament medium (Nf-M) of BS patients and the streptococcal 65-kDa HSP, α-enolase, and glyceraldehyde 3-phosphate dehydrogenase have been reported [13,14]. In addition, the S. sanguinis GroEL protein seems to be an additional triggering factor, correlated to reactivity against recombinant human hnRNP A2/B1 [15]. On the other hand, no associations between Borrelia burgdorferi, Helicobacter pylori, Cytomegalovirus, Epstein-Barr virus, Parvovirus B19, Varicella zoster virus, and Hepatitis virus, and BS pathogenesis have been demonstrated [1]. Beside infectious agents, the endogenous microbiota has been proposed as possibly associated with BS pathogenesis. Namely, a significantly poorer and dysbiotic salivary and fecal microbial community has been described in BS patients as compared to healthy controls [16,17]. In particular, fecal samples from BS patients have lower bacterial diversity in terms of Roseburia, Subdoligranulum, Megamonas, Prevotella, and of butyrate-producing bacteria Clostridum spp. and methanogens [18], whereas a higher abundance of Bifidobacterium, Eggerthella, Bilophilia spp., and of opportunistic pathogens has been described [19,20]. The reduced microbial diversity has been associated with an impaired butyrate production, leading to reduced T regulatory cells (Tregs) responses and mediating the activation of immunopathological T-effector responses [17]. Notably, loss of microbiome diversity and changes in microbiome composition have been reported also in different chronic immune-mediated diseases, such as ankylosing spondylitis, rheumatoid arthritis, systemic lupus erythematosus, diabetes mellitus, and multiple sclerosis [21]. Understanding the effects of the oral and gut microbiome on the multifactorial nature of the pathophysiology of these disorders might help identifying new therapeutic strategies [21].

3  Genetic etiology The peculiar geographical distribution of BS has always suggested a genetic susceptibility to the disease. Indeed, the HLA-B51, located inside the region coding for the MHC class I, has been identified as the strongest genetic susceptibility factor for BS [22].

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According to a systematic review and metaanalysis of case-control genetic association studies including data from 4800 BS patients and 16,289 controls from 78 independent studies, subjects carrying the HLA-B51/B5 allele had a more than five-fold higher risk of developing BS compared with noncarriers (pooled odds ratio of 5.78 (95% CI 5.00–6.67)) [23]. Other susceptibility loci have been identified inside and outside HLA genes, including GIMAP [24], STAT4 [25], IL23R-IL12RB2, IL10 [26–28], IL1A-IL1B, IRF8, and CEBPB-PTPN [29], loci situated between HLA-B-51 and ERAP1 [30], and variations in the promoter region of TNF [31]. In addition, according to a recent metaanalysis, a significant (although weak) correlation exists between HLA-B27 and BS, and environmental and additional genetic factors seem to influence this genetic predisposition, determining the onset and progression of the disease [32]. Overall, the loci associated with BS susceptibility are mainly confined in genes coding for molecules involved in immune responses, or encoding cytokines and adhesion molecules. According to a recent combined analysis of the transcriptome and interactome of peripheral blood cells (PBCs) from BS patients, 5 clusters enriched in T- and B-cell activation pathways and 2 clusters enriched in type I interferon (IFN-I), Janus kinase (JAK)-signal transducer and activator of transcription (STAT), and Toll-like receptors (TLRs) signaling pathways, were identified, and all resulted to be implicated in autoimmune diseases [33]. Of particular note, polymorphisms in these genes associated with BS susceptibility have been also positively associated with the development of other autoimmune or immune-­ mediated disorders; in particular, polymorphisms in ERAP1 have been related to ankylosing spondylitis and psoriasis as well [34,35]. Of relevance, ERAP1 polymorphisms are a risk factor preferentially in patients with HLA-B51 positivity, probably in force on an alteration in peptide presentations by HLA-B51 and a consequent altered recognition by T cells and natural killer (NK) cells [36,37].

4  Epigenetic contribution Increasing evidence supports the role of epigenetics in the pathogenesis and in the course of BS [2,38]. Specifically, differential methylation of some interspersed repeated sequences (IRSs) and of genes associated with cytoskeletal remodeling and cell adhesion has been described in circulating CD4 + T cells and monocytes of BS patients [2,39]. Of particular note, the alternated methylation pattern of genes involved in microtubule structure (KIFA2 and TPPP) reverted to the normal pattern after pharmacological treatment, thus suggesting that the variation in the methylation pattern might be used as a biomarker of treatment efficacy or as a therapeutic target in BS [2]. In addition, growing literature evidence is addressing the possible role of specific miRNA and pre-miRNA polymorphisms in the susceptibility and pathogenesis of BS. Specifically, impaired expression of miRNA-155, miRNA-638, and miRNA-4488 has been described in BS [40–42]. In addition, the homozygous CC genotype and C allele of pre-miRNA-146a rs2910164 polymorphism was found to be protective against BS, whereas the rs3746444 and rs28362491 polymorphisms in miRNA-499 and in NFKB1 promoter were found to be involved in the genetic susceptibility of BS [43].

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5  Immunological etiology Innate immunity plays a major role in the etiopathogenesis of BS and represents a trait d’union between the infectious and genetic etiologic factors. Among innate immune cells, neutrophils are known to play a central role in BS, which has been traditionally considered a neutrophilic perivasculitis [44]. Hyperactivated proactive neutrophils have been described in BS patients as involved in perivascular infiltration and tissue injury [45,46], and a phagocytic dysfunction has been observed in patients with more severe disease activity, as compared to patients with mild activity [47,48]. The sustained activation of neutrophils represents a major source of oxidative stress, and a consistent oxidation of fibrinogen via the neutrophil NADPH oxidase has been demonstrated [49]. Notably, hyperactivated neutrophils mediate the secretion of cytokines involved in the stimulation of CD4 + T cells toward the differentiation to Th1 cells [48]. Besides neutrophils, NK cells seem to be directly involved in the stimulation of the CD4 + Th1 response in BS [50,51]. Indeed, CD4 + Th1 response represents a key feature of BS lesions, and the pathogenesis of BS seems to be directly related to the Th1/Th17 expansion and the decreased regulation by Tregs [1,9,44]. Namely, at the level of antigen-presenting cells (APCs), a panel of molecules including ERAP1 is responsible for processing microbial antigens, which are then exposed on APCs surface through MHC class I and class II molecules. The binding of activated CD4 + and CD8 + T lymphocytes with APCs presenting these antigens on MHC molecules that is responsible for the upregulation of Th17 and Th1 lymphocytes, and for the downregulation of Tregs. The upregulation of Th17 and Th1 lymphocytes, together with the upregulation of neutrophils mediated by APC and by the microbial antigens themselves, are responsible for the final tissue and vascular damage typical of the disease [1]. Cytotoxic Th1 and Th17 cells are directly involved in the mucosal damage in early stages of intestinal BS involvement [52]. Furthermore, increased levels of IL-17, IL-23, and IFN-γ as cytokines secreted by Th1 cells, have been described in patients with active ocular, mucocutaneous, and articular involvements [37,53,54]. On their turn, IL-17 and IFN-γ secreted by lymphocytes of BS patients have been shown to mediate innate responses, late adaptive immunity, and neutrophil infiltration [55].

6  Additional triggering factors Beside infections, (epi)genetic, and immunological mechanisms, a wide spectrum of additional triggering factors contributes the etiopathogenesis of BS [56]. According to two recent studies, one from France and the other from Turkey, evaluating triggering factors for the development of oral ulcers [57,58], 37%–47% and 78% of patients, respectively, identified fatigue and/or stress as the most frequent trigger. On the other hand, fatigue itself might be influenced by the illness perception and by the clinical disease activity [59]. The development of oral ulcerations might be triggered also by the consumption of hard, spicy, or acidic food, among which are tomato and spices, and in general by histamine-rich (cheeses) or histamine-releasing (fruits) food [57,58].

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In addition, the occurrence of oral epithelial trauma, mostly due to dental or periodontal procedures, and the consequent activation of the local immune system, might have a role in triggering oral ulcerations. Indeed, dental treatments and tooth brushing have been reported as triggering agents for oral ulcers in 17% and 14% of BS patients, respectively [57]. As for patient’s related factors, hormonal levels have been associated with the disease activity. Specifically, testosterone has been associated with neutrophils activation and Th1-type alterations in male BS patients [60,61], whereas menstruation has been described as a triggering factor for skin mucosa lesions in BS women [62]. Conversely, smoking has a well described positive impact on BS [63,64]. This is probably related to the enhanced epithelial proliferation mediated by nicotine, as well as by the increased resistance to trauma and tolerance to microbial factors commonly seen in smokers [65]. Nevertheless, smoking habit, while reducing oral mucocutaneous BS flares, is responsible for an increased atherosclerosis and a higher risk of vascular events, particularly in male BS patients carrying glutathione S-transferase polymorphisms [66,67]. Of particular note, also the presence of allergic diseases, such as respiratory, cutaneous or food allergies, and/or of atopy have been associated with a lower risk of BS [56]. This is probably due to the balance between Th1- and Th17-associated, proinflammatory responses typical of BS, and Th2 type, IL-4 and IL-13 associated responses typical of allergies [68].

7  Conclusion In conclusion, exogenous microbial and environmental risk factors can promote an inflammatory state and the activation of adaptive immune responses. These triggers act on top of individual genetic susceptibility and epigenetic factors, thus contributing to the final development of the syndrome. However, to date, the etiopathogenesis of BS is far from being fully understood. The progress in molecular methods and basic research studies, such as genome-wide association studies (GWAS), will help gaining knowledge on these mechanisms and on the reasons beyond the inter- and intra-subjects’ differences in the clinical expression of the disease.

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C H A P T E R

24 Interleukin-1 family in Behçet’s disease: Inflammatory and antiinflammatory mediators Kamel Hamzaouia,b,⁎ and Agnès Hamzaouia,b,c a

University of Tunis El Manar, Medicine University of Tunis, Tunis, Tunisia, bLaboratory Research (19SP02) [Chronic Pulmonary Pathologies: From Genome to Management], Ariana, Tunisia, c Department of Respiratory Diseases, Abderrahman Mami Hospital, Pavillon B, Ariana, Tunisia ⁎

Corresponding author

Abstract The IL-1 family consists of 11 cytokines, 7 ligands with agonistic activity (IL-1a, IL-1b, IL-18, IL-33, IL-36α, IL36β, and IL-36γ) and 4 members with antagonistic activity (IL-1 receptor antagonist (IL-1Ra), IL-36Ra, IL-37, and IL-38). Most members of IL-1 family cytokines are involved in innate and adaptive immunity. In addition, IL-1 cytokines contribute to uveitis and skin lesions in Behçet’s disease (BD). IL-1 family gene polymorphisms and abnormal expression of IL-1 as well as its potential role in the uveitis process have been explored in BD. IL-33 has also been discussed in recent years. IL-33 may contribute to systemic lesions, while IL-37 suppresses inflammatory cytokines. There is a lack of studies on the pathophysiological roles of IL-36 and IL-38 in BD, which might provide us with a new study area. Here, we aim to give an overview of IL-1 family cytokines and discuss their pivotal roles in the pathogenesis of BD.

Keywords IL-1 family, Cytokines, Behçet’s disease, Receptors, Inflammation, Autoinflammatory diseases, Innate immunity, Adaptive immunity, Genetic, Single-nucleotide polymorphisms

Translational Autoimmunity, Vol. 6 https://doi.org/10.1016/B978-0-323-85831-1.00024-3

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24.  Interleukin-1 family in Behçet’s disease

1  Introduction Behçet’s disease (BD) is a systemic inflammatory disease with a chronic relapsing-­remitting course, with an unknown etiology. The disease is characterized by a range of clinical manifestations, including oral aphthae, genital ulcers, and skin lesions, ocular, vascular, articular, gastrointestinal, urogenital, pulmonary, and neurologic involvement. BD is prevalent in regions along the “Silk Road,” extending from Japan to Mediterranean countries. The disease is equally distributed between men and women and the diagnosis can be made only based on clinical symptoms and signs. The course of the disease is more severe in male patients with younger age at onset and an increased number of organs affected at diagnosis [1–4]. The disease can be recognized by clinical findings because of the absence of a universally accepted diagnostic laboratory test. BD diagnosis is largely based on mucocutaneous symptoms, which are a common characteristic of various diagnostic criteria used in the diagnosis of the disease so far. The International Study Group for Behçet’s disease criteria (requires the presence of oral ulcer plus any two of recurrent genital ulcer, typical eye lesions, typical cutaneous lesions, or a positive skin pathergy test) is the most commonly used and internationally recognized diagnostic criteria by the authors of this field [1,5]. Besides considerable morbidity, BD has increased mortality because of the pulmonary artery and large vessel, vasculitis, as well as neurological and gastrointestinal involvements. Therefore, knowing the etiopathogenesis of BD is extremely important to better understand the disease and, more importantly, to develop targeted therapies. BD has been listed among autoinflammatory diseases because of unprovoked episodes of inflammation without evidence of antigen-specific T cells or autoantibodies, increased activity of neutrophils, and elevated levels of interleukin (IL)-1β. Most authors evaluate the disease as a spondyloarthropathy (MHC-I-opathy) based on human leukocyte antigen (HLA) class I association and epistatic endoplasmic reticulum amino peptidase 1 (ERAP-1) interactions, increased T helper (Th)17 type immune response, neutrophilic inflammation, and barrier dysfunction in environmentally exposed organs (such as central nervous system, lung, and skin) [6]. According to the current literature, BD cannot be definitely classified under any of these three groups and defining it as autoimmune, autoinflammatory or spondyloarthropathy appears to be a simplified approach [7]. BD shares some common features with all the above-mentioned entities and involves more than one pathogenic pathway triggered by environmental factors such as infectious agents in genetically predisposed subjects [1]. Activated innate immunity plays an important role in the pathogenesis of BD. Microbial triggers are sensed and processed by the innate immune system via pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Overproduction of inflammatory cytokines by innate immune cells such as macrophages and dendritic cells (DCs) may cause a higher production of adaptive Th1- and Th17-related cytokines [8–11]. BD lesions in their early stages are predominated by neutrophils, which are major immunoregulatory cell group of the innate immune system. Another member of innate immunity, natural killer (NK) cells are also found in BD lesions [12,13]. BD is considered as a neutrophilic vasculitis and the role of neutrophils in BD pathogenesis has long been known [14]. Infectious agents have long been proposed as triggering factors in BD development. Antigens from viruses such as herpes simplex virus (HSV)-1 or bacteria belonging to Streptococcus species such as Streptococcus sanguinis have been suspected to have high ­homology with human

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proteins such as heat-shock proteins (HSP); the cross-reaction leads to an immune response in genetically predisposed individuals [15]. Consolandi et al. [16] compared the fecal microbiota of BD patients with healthy controls. They reported both a peculiar dysbiosis of the gut microbiota and a significant decrease of butyrate production in BD patients. The authors speculated that a defect of butyrate production might lead to both reduced Treg cells responses and activation of inflammatory T responses. The alteration of T-cell balance, especially Th1/Th17 expansion and decreased regulation by regulatory T (Treg) cells, are supposed to have a significant role in BD pathogenesis [9,17,18] Increased production of IL-17, IL-23, and IFN-γ besides increased frequencies of IL-17 and IFN-γ producing T cells in BD patients with active uveitis was reported [19,20]. IL-17 levels of BD patients with active stages of uveitis, oral and genital ulcers, and articular symptoms were significantly higher compared with patients with inactive stages of the same symptoms. The percentage of circulating Th17 cells and plasma IL-17 levels were increased in active BD [21]. Increased neutrophil activity and infiltration in the affected organs of BD might be caused by the increased IL-17 response [8,21,22]. A recent study reported that, under Th17-stimulating conditions, T cells express both IL-17 and IFN-γ. Production of large amounts of IL-17 and IFN-γ by all lymphocyte subsets in BD patients were associated with increased innate responses, early tissue neutrophil infiltrations and late adaptive immunity [18]. Moreover, in experimental autoimmune uveitis (EAU) the role of Herpes virus entry mediator (HVEM), a member of the tumor necrosis factor receptor (TNFR) family, has been evaluated. The HVEM seemed to be involved as a cosignaling molecule inducing both Th1 and Th17 responses in EAU. In addition, in the same experimental mouse model, the use of anti-HVEM antibodies blocking HVEM cosignal ameliorated EAU [23]. IFN-γ appears to be an important cytokine in BD. CXCL10 could also be associated with BD. CXCL10 has been found in excess in uveitis, in cerebrospinal fluid (CSF) and in histological samples of BD [24–28]. Then the IFN-γ-CXCL10 pathway is of interest in BD pathology. Monocytes have dysfunctional posttranscriptional regulation of CXCL10 mRNA, resulting in overexpression of CXCL10 protein upon IFN-γ stimulation. As CXCL10 is a chemokine that recruits mononuclear cells, this abnormality may contribute to the exaggerated inflammatory responses that characterizes BD [29].

2  The biological characteristics of IL-1 family cytokines The immune system is divided into two different related responses: the innate and the adaptive immunity. The effectors cells of the innate immune system are monocytes, macrophages, neutrophils, and natural killer (NK) cells. They are in the first line of defense in the event of viral/bacterial attack and are considered as mediating rapid and nonspecific, while they are unable to build memory cells. However, the adaptive immunity in turn takes longer to develop, and develops immunological memory. When human antigen presenting cells (APCs) are exposed in  vitro to certain PAMPs or DAMPs, and are restimulated with nonrelated pathogens a week later, they display an enhanced production of proinflammatory cytokines [30]. This process of nonspecific memory in innate immune cells is termed “trained Immunity” [31]. Emerging data suggest that cytokines of the IL-1 family may play a crucial role in trained immunity. This should perhaps come as no surprise, given the fundamental

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role of IL-1 cytokines and receptors in the induction and modulation of innate immune responses as reported by Moorlag et al. [32]. The IL-1 cytokines family and their receptors play a central role in the modulation of innate immunity and inflammation as reported by Dinarello et al. [33]. The IL-1 family is a group of 11 proinflammatory and antiinflammatory cytokines. Recent findings show that expression of most IL-1 family cytokines, such as IL-1β, IL-18, and IL-33, was abnormal in many autoimmune diseases, including BD. Gene polymorphisms of certain members of the IL-1 family were reported to be correlated with BD susceptibility. Therefore, in this chapter, we provide a brief introduction on IL-1 family cytokines biological functions, the association between IL-1 family genes and BD, and the roles of IL-1 family cytokines in the expression and pathogenesis of BD. The IL-1 family cytokines and their roles in BD are briefly summarized in Table 1.

3  The association of IL-1 family genes and BD It is thought that genetic predisposition and immune dysregulation seem to be critical factors in the pathogenesis of BD. Most of the studies reported that BD is driven primarily by proinflammatory and Th1 cytokines [34–36]. Some studies have shown that the maximal capacity of cytokine production varies among individuals and correlate with single-nucleotide TABLE 1  Members of the IL-1 family of ligands and receptors. Common name

IL-1 family name

Receptor

Description/expression in BD patients

IL-1α

IL-1F1

IL-1R1/IL-1RAcP, IL-1R2

Proinflammatory cytokines. Increased circulating level

IL-1β

IL-1F2

IL-1Ra

IL-1F3

IL-1R1

Receptor antagonist. Anakinra: Used in clinics

IL-18

IL-1F4

IL-18Rα/β, IL-18BP

Proinflammation cytokine involved in activation of Th1 and NK cells, strong inducer of IFN-γ. Increased circulating level

IL-33

IL-1F11

ST2, IL-1RAcP

Proinflammatory cytokine. Increased circulating level

IL-36α, IL-36β, IL-36γ

IL-1F6

IL-36R, IL-1RAcP

Proinflammatory cytokines

IL-36Ra

IL-1F5

Acting as a receptor antagonist

IL-38

IL-1F10

Antiinflammatory cytokine/receptor antagonist. Decreased circulating level

IL-37

IL-1F7

Proinflammatory cytokine. Increased circulating level

IL-18Rα/β, SIGIRR, IL-18BP

Antiinflammatory cytokine. Decreased circulating levels

Members of the IL-1 superfamily are grouped together based on subfamily; their receptors are given, as well as their main characteristics.

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­ olymorphisms (SNPs) in various cytokine genes [37]. Different SNPs may result in the prop duction of structurally different proteins with specific transcription rate and biological function. Investigating the correlation between SNPs of a specific gene and BD seems to be inducible to understand the disorder’s pathogenesis and find biomarkers for predicting the risk of BD. Findings expanded previous results showing increased prevalence of IL-10 promoter polymorphisms in BD patients [38]. Functional tests showed lower IL-10 production after lipopolysaccharide (LPS) stimulation by variant carriers, suggesting that low regulatory cytokine IL-10 expression may be a risk factor for BD [39]. In recent years, genome-wide association studies have revealed associations between genes encoding IL-1 family cytokines and BD, which further supported the participation of IL-1 family cytokines in pathogenesis of the disease. The IL-1 family gene complex is located on chromosome 2q13–21. Allele frequencies and genotype distributions of IL-1a, IL-1b, IL-1R, and IL-1RA were investigated by Özçimen et al. [40]. Comparing BD patients to healthy controls, the frequencies of IL-1Ra, IL-1α, and IL-1R gene polymorphisms were not significantly different. The frequency of IL-1β-511 TT genotype was higher in the BD group in comparison to the control group. Interestingly, the authors demonstrated that IL-1β + 3962 gene polymorphism was associated with the presence of erythema nodosum in BD patients. The frequency of IL-1Ra mspa111100 TT genotype (minor) was found to be apparently higher in BD patients compared to healthy control subjects, but not statistically significant when the Bonferroni correction was performed. Özçimen et al. concluded that the polymorphisms in IL-1β gene might affect BD susceptibility. In contrast to the results of Özçimen et al., Karasneh et al. [41], Coskun et al. [42], and Akman et al. [43] demonstrated that there was no significant difference in genotype and allele frequencies of IL-1β-511T allele between the patients with BD and controls. Only one previous study reported that the frequency of IL-1β511T CC genotype is significantly higher in BD patients compared to healthy controls [44]. Coskun et al. [42] reported a possible association of specific polymorphisms of IL-1α, IL1β, and IL-1 receptor antagonist genes with BD susceptibility. Comparison of the IL-1β − 3953 T allele and TT genotype frequencies showed a significant difference between patients with BD and controls. However, no difference was observed in the genotype or allele frequencies of IL-1α − 889, IL-1β − 511, and IL-1 receptor antagonist between the patients with BD and the controls. In conclusion, these results indicate that susceptibility to BD is increased in individuals carrying the IL-1β − 3953 T allele and TT genotype. These studies carried out on the Turkish population are often contradictory and the cause would be the small number of patients studied or the heterogeneity of the studied patients. The association of IL-33 gene rs1342326 polymorphism and its expression in BD-Azari population of Iran were reported [45]. The authors indicated that rs1342326 T/G polymorphism of the IL-33 gene may contribute to the genetic susceptibility to BD. Koca et al. [46] genotyped 4 SNPs of IL-33 gene (rs7044343, rs1157505, rs11792633, and rs1929992). The TT variants of rs7044343 and rs11792633 polymorphisms were very rare, and the T allele frequencies of these polymorphisms were lower, in the BD group compared to the healthy group. The rs7044343 and rs11792633 variants of IL-33 gene are associated with the decreased risk of BD. They concluded that IL-33 has a protective role on the pathogenesis of BD, knowing that IL-33 is defined as alarmin produced by epithelial cells. The IL-18 gene polymorphisms were not associated with BD susceptibility in the Korean population. Patients carrying the GG genotype at position -137 had a higher risk of ­developing

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BD ocular lesions [47], which is a profound lesion leading to blindness. The distribution of IL-18 promoter -607 C/A and -137 G/C polymorphisms were also investigated in Korean BD patients [48]. BD patients had a significantly higher frequency of the -607 CC genotype and a higher frequency of the -607 C allele. Haplotype analysis showed that BD patients had significantly less -607A/-137G haplotype and -607A/-137G haplotype homozygote than control subjects. In addition, the frequency of -607C/-137G haplotype homozygote was significantly higher in BD patients than in control subjects. These results suggest that the IL-18 promoter gene is a candidate susceptibility gene in BD patients. IL-18 SNPs at -607 and -137 regions were analyzed in an Egyptian cohort [49]. A positive association was found in BD patients regarding -607 promoter site. Moreover, patients with BD carrying the GG genotype at position -137 had a higher risk of developing ocular manifestations. The association between SNPs of IL-18Rap and IL-37 were investigated in Han Chinese BD patients by Tan et al. [50]. The results demonstrated significant differences between BD cases and healthy controls for two SNPs (rs2058660 and rs3811047) in two genes (IL18Rap and IL-37). Compared to controls, the frequency of the IL-37/rs3811047 AG genotype was significantly lower in BD. A significant increase in the frequency of the GG genotype and G allele was observed. The frequency of the IL-18RAP/rs2058660 AA genotype and A allele was significantly decreased in BD as compared to healthy controls. The frequencies of the IL-37/rs3811047 AA genotypes and the frequencies of the IL-18RAP/ rs2058660 AG and GG genotypes were not significantly different between BD cases and healthy controls. The authors concluded that a novel association between IL-37/rs3811047 and IL-18RAP/rs2058660 polymorphisms with BD in Han Chinese, which supports the important role of the IL-1 pathway in the BD disease and may provide a future target for the treatment [50]. Assessment of IL-37 gene SNP (rs3811047) was performed by Özgüçlü et  al. in Turkish patients with BD [51]. IL-37 gene rs3811047 G/A polymorphisms were similar in BD patients and healthy controls. A significantly lower frequency of the AG genotype, and a higher frequency of the GG genotype and G allele of IL-37/rs3811047 were observed in BD as compared to Vogt-Koyanagi-Harada (VKH) syndrome [50]. Functional studies performed in healthy controls showed that rs3811047 AG genotype carriers had a higher IL-37 gene expression in peripheral blood mononuclear cells (PBMCs) than GG carriers. GG carriers showed a higher cytokine expression as compared to AG carriers. No association was detected between the tested SNPs and VKH [50]. Behçet’s disease, considered as an autoinflammatory disease is a condition that could be caused by genetic abnormalities affecting the innate immunity and inducing inflammatory processes. Previous therapeutic strategies had been mainly based on results from retrospective studies and physicians’ experience. However, during the last years, the significant improvement in understanding of the disease genetic background and pathogenesis has been accompanied by a remarkable progress in the clinical management of the disease. The relatively recent identification of the inflammasome as the crucial pathogenic mechanism causing an aberrant production of cytokines of IL-1 family led to the introduction of anti-IL-1 agents and other biologic drugs as part of the previously limited therapeutic armamentarium available. The association of inflammatory and antiinflammatory cytokines based on the results of SNPs and their correlations with different systemic manifestations would probably be of great benefit for treatments.

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4  Expression and function of IL-1 family cytokines in BD 4.1  The expression and function of IL-1β in BD Interleukin-1 beta (IL-1β) is a proinflammatory cytokine important for local and systemic immunity. IL-1β secretion has been implicated in Behçet’s disease with ocular lesions and in age-related macular degeneration (ARMD) [52,53]. Intraperitoneal administration of IL-1β during priming phase of experimental autoimmune uveitis (EAU) increases disease severity, suggesting that IL-1β might play a pathogenic role in the eye [54]. Wan et al. reported that myeloid cells produce IL-1β in the retina of mice during EAU (a model of human uveitis) [54]. Analysis of Il1r-deficient mice provides direct evidence that IL-1 signaling is required for the development of uveitis. Zhao et al. [55] showed that the reduced severity of intraocular inflammation in Il1r-deficient mice correlates with impaired Th17 cell differentiation and decreased recruitment of inflammatory cells into the retina. These interesting data indicated that agents blocking IL-1 signaling pathway might have a considerable potential for treating uveitis. The authors suggested the possible utility of IL-1R (IL-1RA: anakinra) as blocking agents for the treatment of ocular inflammatory diseases.

4.2  The expression and function of IL-33 in BD IL-33, was identified as a member of the IL-1 superfamily, in 2005 by GenBank databases [56]. IL-33 protein is constitutively and extensively present in healthy mice and humans, and is primarily stored in the nucleus of nonhematopoietic cells, including epithelial cells, endothelial cells, and keratinocytes, particularly in tissue barrier sites and fibroblastic reticular cells (FRCs) of lymph nodes, as well as mesenchymal cells [57–60]. It has been proposed that IL-33 was described as an alarmin that is stored in the nucleus and functioned as an extracellular cytokine in its full-length form (amino acid 1–270) when released in response to cell or tissue damage [58]. Full-length IL-33 (IL-33FL) is biologically active, but proteases derived from different cellular sources, such as neutrophils and mast cells, process bioactive IL-33FL into N-terminally truncated forms (IL-3395–270, IL-3399–270, IL-33107–270, IL-33109–270, and IL-33111–270) that have up to 30-fold higher biological activity than IL-33FL [61]. Another protein ST2 (suppression of tumorigenicity 2), also called T1 or IL-1 receptor-like 1 (IL1RL1), is the only well documented receptor for IL-33. Upon ligand binding, the receptor-associated kinase undergoes recruitment and phosphorylation, which exerts IL-33 cytokine activity and leads to a series of downstream reactions. Primarily, IL-33 was associated with type 2 immune response [61,62]. Expression of ST2 was discovered in dendritic cells (DCs), mast cells (MCs), basophils, eosinophils, neutrophils, macrophages, group 2 innate lymphoid cells (ILC2s), Th2 cells, B cells, and Tregs [63]. However, recent studies show that IL-33 also drives type 1 immune responses [64–66]. NK cells, NKT cells, CD8+ T cells, and particularly Th1 cells were shown to feature ST2 expression [65,67]. This pleiotropic nature of IL-33 and unique ST2 expression likely explains why IL‐33 participates in infection, inflammation, tissue homeostasis, and repair within these immune cellular networks [66]. Despite this pleiotropic spectrum, important questions remain regarding how IL-33 acts on different immune cell populations during Th1 and Th2 cell-mediated inflammation as observed in BD, which require clarification. We summarized the current understanding of IL-33 in BD.

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4.2.1  Regulatory T (Treg) cells and IL-33 expression IL-33 is required for the development and maintenance of functional Tregs. Studies have described that IL-33 promotes the TGF-β–mediated Treg differentiation in association with IL-10 [66]. In this research, IL-33 induces the expression of Fopx3, a transcription factor that functions as a master regulator of the Treg phenotype [68]. It also induces the expression of GATA‐3, which is essential for ST2 expression and stabilizes Foxp3 expression, in the form of a feed forward reinforcing manner, and enhances expression [68]. Analysis of ST2 −/− Tregs in vivo showed that Foxp3 expression is deficient [68]. In another study, combined IL-33 and IL-2/STAT5 (signal transducer and activator of transcription 5) signals also boost GATA3 (trans-acting T-cell-specific transcription factor) expression and therefore promote the Treg development [69]. Specifically, the transcription factors IRF4 (interferon regulatory factor 4) and BATF (basic leucine zipper transcription factor) are required for the development of Treg in adipose tissue. IL-33 promotes the expression of its own receptor by inducing high expression of IRF4 and BATF [69]. 4.2.2  IL-33 in tissue remodeling and regeneration Immune cells identified in the skin, lungs, and brain constitutively express ST2 [70,71]. When activated by IL-33, immune cells can release abundant quantities of cytokines such as IL-5, IL-6, IL-13, GMSF, and epithelial growth factors like IL-33 and TSLP [72]. IL-33 is primarily secreted by inflamed or injured tissue and has been shown to have tissue regenerative functions. The tissue regeneration function of IL-33 in the muscles has been attributed in part to its ability to expand ST2+ Tregs. These Treg cells reside and accumulate in the muscle after injury [73]. IL-33 promotes tissue integrity and functional repair, by enhancing the expression of the tight junction protein Claudin 1 and the secretory mucin gene Muc2 [74]. 4.2.3 The expression and function of IL-33 in BD Studies showed that IL-33 played an important role in the pathogenesis of multiple autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD) [75–77]. Recently, an increasing number of studies have shown the potential role of IL-33 in BD. IL-33 and its receptor ST2 in the peripheral circulation and skin lesions

Aberrant IL-33 expression in BD suggests its participation in the initiation and progression of diseases. Two different studies reported elevated serum IL-33 and soluble ST2 (sST2) levels in patients with BD compared to those in healthy controls [78,79]. In active BD patients, IL-33 was increased at protein and mRNA level [79]. Lower levels of IL-33 were found in BD compared to multiple sclerosis (MS) and RA patients [79], studied as control diseases. However, Koca et  al. reported that serum IL-33 level in BD patients was correlated with BD having uveitis [46]. In the same way, a significant correlation was also associated between IL-33 level and BD patients having retinal vasculitis [79]. Recent data reported that IL-33 was highly expressed in the inner nuclear cells of the retina of naïve mice, and its expression was elevated in experimental autoimmune uveitis (EAU) mice. Administration of IL-33 to WT mice significantly reduced EAU severity. The attenuated EAU in IL-33-treated mice was accompanied by decreased frequency of IFNc+ (croaker type I interferons) and CD4+ IL-17+ T cells 494



Kamel Hamzaoui and Agnes Hamzaoui

reducing the secretion of IFN-c and IL-17 mediators. Endogenous IL-33/ST2 pathway plays an important role in EAU, and suggest that IL-33 represents a potential option for the treatment of uveitis [80]. IL-33 is specifically released during necrotic cell death, which is thought to be associated with tissue damage during trauma or infection. In BD, as reported in other inflammatory/autoimmune diseases (RA, SLE, MS) [81–83] and under these conditions, extracellular IL-33 may engage the ST2 receptor on immune cells in order to alert the immune system of tissue damage and infection and to promote the initiation of healing responses. Stimulated macrophages from BD patients produced higher IL-33 levels than healthy controls [80]. A correlation was found between IL-33 mRNA expression and NF-κB, suggesting a possible mechanism of transcriptional upregulation of IL-33 in leukocytes of patients with active BD [84]. NF-κB contributes to regulate apoptosis-related factors and death receptors leading to apoptosis resistance of T-cell subsets in BD patients. NF-κB activity downregulation by thalidomide usually administrated in BD patients, could represent an alternative therapeutic approach [82]. IL-33 has been shown to act on monocytes, DCs, and macrophages to induce the expression of cytokines, chemokines, and other proinflammatory genes [85]. In the same way, serum IL-33 levels are found higher in active BD patients compared to inactive BD patients or healthy controls in a Turkish population reported by Çerçi et al. [86], indicating that increased IL-33 secretion is associated with the inflammatory process. IL-33 secretion was correlated with the severity of arthritis in BD patients [86]. Another study from Turkish BD patients reported that serum IL-33 level was not significantly different between BD and healthy control groups and that IL-33 level was found lower in the active BD patients compared to the inactive ones [46]. Discrepancies were observed in these two Turkish population about serum IL-33 levels between Cerçi et al. [86] and Koca et al. [46]. However, at the genetic polymorphism level, Koca et al. [46] indicated that IL-33 gene variants (rs7044343 and rs11792633) are associated with the decreased risk of BD and that IL-33 has a protective role on the pathogenesis of BD. What emerges from these two studies is that there would probably be a problem with laboratory methodology or the number of patients studied is reduced. An interesting report from Kim et al. [87] indicated that serum levels of both IL-33 and sST2 (soluble ST2) were highly expressed in patients with BD compared with those in healthy controls. IL-33 and sST2 expression in skin tissue, investigated by immunohistochemistry, were highly expressed in patients with BD compared with that in the healthy controls [87]. These data were confirmed by a significant positive correlation observed between serum ­IL-33 levels and BD skin lesions. IL-33 mRNA expression in the skin lesions of patients with active BD was significantly increased compared to that in healthy skin biopsies [79]. IL-33 and its receptor ST2 in the cerebrospinal fluid

Immunological and molecular pathways are involved in neuro-BD (NBD) and include the release of IL-1, IL-6, IL-8, TNF-α, and IFN-γ into the cerebrospinal fluid (CSF), which reflects a nonspecific inflammatory pattern that is compatible with autoinflammatory disease pathways. Neurological involvement in NBD causes devastating central nervous system (CNS) complications and is present in 5%–30% of patients with BD. A comparative study between NBD, noninflammatory neurologic disease (NIND), and headache attributed to BD (HaBD) was investigated for IL-33 level. The expression of IL-33 in NBD [88] was increased at the protein and mRNA transcripts compared to the control diseases [88]. A significant c­ orrelation

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was observed between CSF-IL-33 mRNA expression and the IL-33 protein levels in NBD patients. Significant correlations were also observed between IL-33 mRNA expression and MCP-1 and IP-10 chemokines in NBD patients. Chemokine mRNAs (MCP-1 and IP-10) were highly expressed in NBD-CNS mononuclear cells compared to the disease controls. These data pointed to a possible inflammatory role of IL-33 in the CNS of NBD patients that could contribute to immune cell activation and augment signaling pathways that mediate oligodendrocyte and neuronal injury [88]. 4.2.4  IL-33 in Behçet’s disease The IL-33 and ST2 studies suggested that IL-33 is a key immune orchestrator. ST2-expressing immune cells are involved in a complex dialogue with IL-33. Through interaction with other immune cells, IL-33 amplifies inflammatory responses and contributes to immune pathology, especially during allergic and autoimmune inflammation. There are no clinical trials for the treatment of BD via blockade of IL-33 in progress. Furthermore, IL-33 also has unique roles in driving tissue protection and regeneration, as well as homeostasis. Most importantly, a recent report identified an IL-33 expression in mesenchymal cell in adipose tissue, thus termed as IL-33 reservoir. Upon inflammatory stimuli, the release of IL-33 could promote antiinflammatory effects and maintain tissue homeostasis in autoinflammatory diseases. The discovery of the role of IL-33 in the context of BD as in inflammatory/autoinflammatory diseases could open an array of research opportunities to investigate the systemic effects of inflammation.

4.3  The expression and function of IL-18 in BD The inflammatory role of IL-18 is much less clear than that of IL-1β IL-18 is a major inducer of IFN-γ production; IFN-γ as a purely inflammatory cytokine in BD, is a central activator of Th1, cytotoxic T, innate lymphoid cells 1 (ILC1), and natural killer (NK) cells and ­inflammation-related defensive responses such as antiviral activity, cytotoxicity, and longterm memory [89]. IL-18 is present in circulation at significant levels and has a clear protective role in maintaining the homeostasis and integrity of the mucosal epithelial tissue. During inflammation, it seems that IL-18 can contribute to inflammation. The activity of IL-18 is regulated by a soluble inhibitor, the IL-18 binding protein (IL-18BP), and possibly by the soluble forms of its receptors, sIL-1R4 and sIL-1R7. While the role of the soluble receptors is still unclear, IL-18BP is very effective in regulating IL-18 activity. It is notable that another IL-1F cytokine, IL-37, binds to the same receptor of IL-18, named IL-1R4, and also to IL-18BP, apparently in a noncompetitive allosteric fashion [89]. IL-37 is an antiinflammatory factor that acts both as soluble cytokine and as intracellular unprocessed protein. Serum IL-18 levels were increased in BD patients, suggesting that these cytokines are linked with disease pathogenesis. The increased level of IL-18 was correlated with tumor necrosis factor (TNF)-α expression supporting Th1 predominance in BD activity [35,90,91]. IL-18 in association with nitric oxide (NO) production were investigated by DjaballahIder et  al. [92]. The authors observed that IL-18 and NO levels were higher in active BD patients. Interestingly, this high production differed according to the clinical manifestations and was associated with an increased risk of mucocutaneous and vascular involvement. Corticosteroid therapy reduced significantly these inflammatory mediators regardless of the clinical manifestations. The authors suggested that concomitant high production of IL-18 and

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NO in active BD patients is related to an increased risk of mucocutaneous lesions and vascular involvement. IL-18 could be a good biomarker for monitoring disease activity and its regression in BD demonstrated the effectiveness of treatment (glucocorticoids) on the underlying immunopathologic process [92].

4.4  The involvement of IL-36, IL-37, and IL-38 in BD Limited information is available on the new IL-1 family members IL-36 and IL-38, and few studies have evaluated their expression and their pathophysiological roles in BD. IL-36 is a group of three isoforms (α, β, γ) that have clear-cut inflammatory activity. The difference between the three isoforms mainly lies in their different transcriptional regulation that results in a differential tissue expression and reactivity to different stimuli [93]. IL-36 is involved in several inflammation-based diseases as a soluble extracellular cytokine that binds to its receptor complex IL-1R6 plus IL-1R3 on the membrane of target cells [94]. A receptor antagonist, IL-36Ra, controls IL-36-mediated inflammation by competing for IL-1R6 [95]. Notably, IL-1R6 uses the same accessory chain as IL-1R1, i.e., the common chain IL-1R3. IL-38 cytokine, an IL-1 family member, is secreted by activated immune cells, including macrophages and lymphocytes, and possesses antiinflammatory functions. IL-38, by binding IL-36 receptor (IL-36R), provokes suppression of inflammation in many immune-mediated diseases. In particular, IL-38 inhibits the generation of IL-1, IL-6, and IL-8 along with other cytokines/chemokines. IL-38 could play a role suppressing the inflammatory response in certain diseases, exerting beneficial therapeutic effect [96]. 4.4.1  Interleukin-37: A new target for the treatment of Behçet disease IL-37 was discovered as an antiinflammatory and immunosuppressive cytokine of the IL-1 family. Significant advancements in the understanding of signaling pathways associated with IL-37 in BD have been made in recent years. The antiinflammatory cytokine IL-37 includes different variants which bind to the IL-18 receptor [95–103]. However, instead of acting as a receptor antagonist, the IL-37/IL-18R complex relays its antiinflammatory function via noncanonical TIR8 (single immunoglobulin IL-1-related receptor; SIGIRR) signaling [97]. IL-37 strongly reduces the expression of proinflammatory cytokines, including IL-1α, IL-18, IL-17, IL-26, IL-33, TSLP, TNF-α, and IFN-γ and impairs IL-1β induced expression of IL-1α, IL-6, and TNF-α in various cell types [98–103]. IL-37 has been reported to be expressed in various human tissues and cell lines after proinflammatory stimuli. Recent evidence indicated that IL-37 has antiinflammatory functions in different autoimmune and infectious disease [97,99,100]. Recent investigations have reported the important role of IL-37 in BD where it could play a crucial role in protecting patients in active stage by damping excessive inflammatory reactions and helping them to go into remission stage. IL-37 comprises five variants a, b, c, d, and e, and is produced by several cell types including PBMCs, serum, synovial cells, epithelial cells, macrophages, and dendritic cells (DCs) [97]. However, IL-37 is not constitutively expressed by blood monocytes from healthy subjects but rather induced by IL-1β and Toll-like receptor (TLR) agonists [97]. Many studies have revealed that IL-37 were increased in inflammation to prevent excessive tissue damage from the host immune responses against microbial infections [98–103]. Herein, we review the role of IL-37 in the immune-pathogenesis of BD.

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A detailed analysis of IL-37 expression in active and inactive BD patients were investigated in the peripheral circulation, CSF, and skin lesion [101,102]. IL-37 could play a key role in maintaining homeostatic balance of the immune system, particularly in barrier immunity owing to its characterized expression and production [103–105]. IL-37 transcripts could barely be detected in resting PBMCs and monocytes from healthy donors as a result of the short half-life of its mRNA [106]. Aberrant IL-37 expression have been associated with multiple human diseases such as autoimmune diseases [106,107], asthma [108,109], and infections [110–112]. Dysregulated immune reactions with abnormal cytokines can result in chronic inflammation in BD. In this regard, aberrant expressions of IL-37 have been reported. Expansion of Th1 and Th17 cells and suppression of Tregs, in association with increase of various cytokines such as IL-17, IL-23, and IL-21, contribute to the etiology of BD [8,113]. IL26 was increased in BD patients, leading to the upregulation of IL-17 and IL-23 and downregulation of IL-10 and transforming growth factor beta (TGF-β) [114]. Of interest, a significant negative correlation was also detected between IL-26 and IL-37 [114]. Studies have demonstrated a diminished expression of IL-37 mRNA and IL-37 protein in active BD patients versus healthy controls [115]. Paradoxically, Ye et al. found no significance of IL-37 mRNA expression between inactive BD patients and healthy controls [116], while Bouali et al. depicted lower expression in active BD group than in remission group and healthy controls [117]. Özgüçlü et al. subgrouped BD patients according to their clinical manifestations and did not find significant IL-37 levels between BD and healthy control. Elevated IL-37 in mucocutaneous BD lesions and arthralgia instead of systemic involvement group indicated that IL-37 has a protective role in BD patients [51]. However, these inconsistencies may be due to the variability of the experimental assays used and incongruent grouping methods. Although management of BD is increasingly successful, it is still tough to deal with refractory ones, in which even anti-IL-1, anti-IL-6, anti-IL-17, and anti-TNF agents have been administered [116]. Remarkably, while applying corticosteroid treatment in BD at high doses, IL-37 was unregulated in association with clinical remission [117]. In addition, IL-37 reversed the increase in IL-6, IL-1β, and TNF-α and promoted IL-27 in BD patients [107,117]. IL-37 also markedly decreased IL-17 expression in PBMCs and CD4+ T cells from active BD patients, and inhibited the production of ROS and the activation of ERK1/2, JNK, and P38 MAPK. IL-37 also suppressed DC-mediated activation of Th1 and Th17 cells in BD patients. Furthermore, IL-37 reversed the elevation of TSLP and IL-33 in ex vivo cultured skin tissue from BD patients [99]. Recent data investigated BD with neurological manifestations (NBD). CSF level and mRNA expression of IL-37 were decreased in NBD patients compared to those in NIND and HaBD patients [101]. Levels of IL-6, IL-17, IL-21, and TSLP were found to be increased in NBD patients and were inversely associated with IL-37 level. Moreover, TGF-β level in CSF of NBD patients was positively correlated with IL-37 levels. IL-37 increased significantly after treatment and in remission group, but TGF-β was only increased in the treatment group [101]. Recently, it has been found that IL-37 inhibits the IL-1β released by microglia stimulated by neurotensin and/or LPS, as well as mast cells stimulated by substance P and/or IL-33 [115]. It was reported that the treatment of human microglia cells with IL-37 inhibits the gene expression of IL-1β and chemokine ligand 8 stimulated with the neuropeptide named neurotensin [115]. In fact, some neurotransmitters and/or cytokines, including IL-1β and TNF-α, increase

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the gene expression of IL-37 in vitro. The increase in IL-1β causes the stimulation of IL-37 in microglia, as a protective response of the brain tissue. Although the expression and clinical relevance of IL-37 in the pathogenesis and management of BD require further investigation, current finding indicate that IL-37 may be a diagnostic tool and a prognostic predictor. IL-37 could be a disease marker in NBD; however, further studies are required. With better understanding of BD as evidence continues to emerge, manipulation of IL-37 might offer a new therapeutic target for BD patients. In conclusion, IL-37 may acts as an antiinflammatory modulator in BD. IL-37 has critical impacts in reducing inflammation induced by several pathogens. However, homeostasis between effector cells, Th1, Th17 and Treg cell responses are required for the elimination of pathogens and the regulation of tissue damage resulting from excessive inflammation should exist to prevent exacerbation of the disease. Several publications have evaluated the potential therapeutic role of IL-37 in various diseases as in BD; nevertheless, a lot remain to be elucidated. 4.4.2  New IL-1 family members: IL-36 and IL-38 Proinflammatory cytokines IL-36α, IL-36β, and IL-36γ and their receptor antagonists IL36Ra and IL-38, which belong to the IL-36 subfamily, are some of the most recently identified members but rarely studied in BD. These members possess proinflammatory and antiinflammatory activities. There has been no report concerning the role of IL-36 in BD. IL-38 has been reported to have antiinflammatory properties, and its serum levels was significantly lower in BD patients in comparison with healthy controls [118]. IL-38 levels were higher in female patients with a positive pathergy test and those patients with eye involvement. As healthy controls showed higher IL-38 serum levels than BD patients, a protective antiinflammatory role of IL-38 in BD is suggested. These results indicated that the positive relationship between serum IL-38 levels and eye involvement suggested that IL-38 may play a role in this clinical feature of the disease.

5  Clinical application and participation of IL-1 family cytokines in BD Monoclonal antibody therapies have revolutionized the treatment of autoinflammatory disease, including spondylarthritis, asthma, and RA. BD is a multisystemic vasculitis, which is generally associated with recurrent aphthous lesions (RAL) as well as ocular and skin lesions. The immunopathogenesis of BD is mostly unknown. The IL-1 family is essential in both innate and acquired immunity. The proinflammatory cytokines IL-1β, IL-18, IL-33, and their antagonists are among the most recently studied in BD and participate actively in the disease pathogenesis. Recent studies show that the IL-1 family also has antiinflammatory activities. Growing body of literature demonstrates that IL-37 plays a vital role in inhibiting both innate and adaptive immune responses as well as inflammatory reactions. IL-37 may prove to be a new and potentially useful target for effective cytokine therapy. The importance of the IL-1 family described in BD may be a determining factor for potential clinical applications. A recent study from Chekaoui et al. [119] investigated the mechanism underlying the involvement of xanthine oxidase (XO) and uric acid (UA) in BD and the direct effects of allopurinol (UA and XO inhibitor) on nitric oxide (NO) and caspase-1-mediated IL-1β release in

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PBMCs of BD patients. Allopurinol exerted an immunomodulatory effect in reducing NO, IL-1β, and Caspase-1 levels in the peripheral blood mononuclear cells (PBMCs) of BD patients particularly during the active stages. These data indicate firstly a potential clinical use of XO as a tool for assessing BD activity, and secondly the in vitro immunomodulatory effect of allopurinol, which may have a promising therapeutic value in BD management. BD patients present leukocyte infiltration in the mucocutaneous lesions as well as neutrophil hyperactivation. Neutrophils and monocyte have been extensively studied in BD. MendesFrias et al. [120] observed a worsening of mitochondrial function, with lower mitochondrial mass and increased ROS production, on circulating monocytes of BD patients. Incubation of monocytes from healthy donors with the plasma of BD patients mimicked the observed phenotype, strongly suggesting the involvement of serum mediators. BD patients, regardless of their symptoms, had higher levels of serum TNF-α and IP-10 and IL-1β/IL-1RA ratio. Untargeted metabolomic analysis identified a dysregulation of glycerophospholipid metabolism on BD patients, where a significant reduction of phospholipids was observed concomitantly with an increase of lysophospholipids and fatty acids. These observations converged toward an enhanced phospholipase A2 (PLA2) activation. Indeed, inhibition of PLA2 with dexamethasone or the downstream cyclooxygenase (COX) enzyme with ibuprofen was able to significantly revert the mitochondrial dysfunction observed on monocytes of BD patients. These results show that the plasma inflammatory environment coupled with a dysregulation of glycerophospholipid metabolism in BD patients contribute to a dysfunction of circulating monocytes [120]. Fabiani et al. [121] evaluated the role of IL-1 inhibitors, anakinra (ANA) and canakinumab (CAN), in the treatment of BD-related uveitis. Uveitis is the most significant cause of morbidity in BD from 50% to 70% of cases; in this context, blindness is reported with a frequency rate of about 25% in BD. IL-1 has shown to be a key proinflammatory cytokine in BD pathogenesis and its inhibition might have a promising future among the novel therapeutic opportunities [122]. The authors evaluated the efficacy of ANA and CAN on functional, morphological, and clinical parameters of eye involvement in a large series of patients affected by BD-related refractory or long-standing uveitis. They evaluate the efficacy of ANA and CAN on BD uveitis during a 12-month follow-up period. The authors show that ANA and CAN represent an effective and safe therapeutic option for BD-related uveitis with a significant reduction of the rate of ocular inflammatory flares, the resolution of active retinal vasculitis, the preservation of visual acuity, and the significant decrease of steroid dosages. Treatment with IL-1 inhibitors is effective in the management of BD-related uveitis and provides a long-term control of ocular inflammation in refractory and long-lasting cases [121]. Omalizumab (anti-IgE humanized monoclonal antibody) therapy is given for severe persistent allergic asthma; unintentionally, it has some effect on recurrent aphthous lesions (RAL) [123]. Patients having asthma and BD were treated with omalizumab. The levels of white blood cells (WBC) were decreased. The patient’s hsCRP decreased from 3 to 0.1 and eosinophil cationic protein (ECP) levels decreased from 78 to 21. The most important result was the significant decrease of IL-33, IL-6, IL-25, and IL-1β. Clinically, a significant improvement was noticed in the RAL and in the asthma symptoms (cough, shortness of breath). Serum proinflammatory cytokines and coagulant proteins could also play an important role in the relationship between RAL and IgE-dependent vascular autoinflammation. The authors concluded that further studies have to be conducted in order to examine the relationship between IgE and proinflammatory cytokines expression in BD [123].

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6  Conclusion An imbalance between agonist and antagonist levels can lead to exaggerated inflammatory responses. Several genetic modifications or mutations associated with dysregulated IL-1 activity and inflammatory/autoinflammatory disorders were identified in patients with BD. These findings paved the road to the successful use of IL-1 inhibitors in diseases that were previously considered untreatable. Cytokines have been shown to play a vital role in the pathogenesis of BD and the certain gene polymorphisms have been demonstrated to be closely associated with BD. Recent studies have investigated the abnormal expression of IL-1 and its potential role in the ocular lesions. However, many aspects of IL-1 family members in BD were ongoing to be elucidated. There is large room for studying the mechanism of IL-1 family cytokines, especially IL-1β, IL-33, and IL-37. Anti-IL-1 strategies have had a tremendous impact in the therapy of inflammatory disorders sustained by inflammasome activation and, to a lesser extent, autoinflammatory disorders. Ongoing studies suggest that blocking IL-1 may have a broader clinical impact on relatively rare (e.g., Behçet uveitis) and common (e.g., cardiovascular) diseases. Better understanding of the pathophysiology of IL-1 and its relatives holds promise of innovative therapeutic tools and targets.

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C H A P T E R

25 Salivary gland regeneration and repair in Sjögren’s syndrome Janaki Iyer, Parisa Khayambashi, and Simon D. Tran⁎ McGill Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dental Medicine and Oral Health Sciences, McGill University, Montreal, QC, Canada ⁎

Corresponding author

Abstract Sjögren’s syndrome (SS) is a chronic autoimmune disease involving the exocrine glands with occasional extraglandular manifestations. SS has remained a dilemma to cure over the years. The available therapies do not act directly on the underlying pathogenesis and are short-lived. With innovative regenerative medicine, and its applications toward degenerated salivary gland, promising permanent therapy may be administered to patients. Regeneration of the atrophied acinar cells through stem cell transplantation, tissue engineering, and gene therapy has demonstrated potential toward unraveling the underlying cause of xerostomia in SS. Isolated stem cells have shown prospective results in regenerative therapy. Biocompatible scaffolds have found their purpose toward reproducing salivary organoids using tissue engineering. Applications of genetic therapy toward prevention of SS and renewal of degenerated salivary tissue have also been recently experimented. Thus, this chapter focuses on recent exploratory techniques of regeneration or replacement of damaged salivary gland to restore its functional capacity.

Keywords Sjögren syndrome, Autoimmune, Salivary gland, Xerostomia, Stem cell regeneration

1  Introduction 1.1  Demographics Sjögren’s syndrome (SHOW-gren’s syndrome—SS) is a chronic, progressive, irreversible, systemic, autoimmune disease with a global prevalence of 0.1%–3% [1–3]. With a worldwide disease load afflicting about 400,000 to 3.1 million adults, SS is no longer considered a rare

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25.  Salivary gland regeneration and repair in Sjögren’s syndrome

­ athology [4]. SS is globally accounted for as the second most common rheumatic disease, with p approximately half the incidence of rheumatoid arthritis [4]. Women seem to be predominantly affected, with a female:male ratio of approximately 9:1 [1–4]. SS is known to demonstrate a disease predilection between the third to sixth decades of life, falling under the perimenopausal and postmenopausal years. In addition, although rare, SS could affect men and children [4]. Incidence and prevalence of SS have been studied globally via regional population-based epidemiological studies. All the studies are centered around North America, Europe, and Asia, with data lacking in Africa, Oceania, and South America [5]. A meta-analysis in 2014, reported Asia to have a relatively higher incidence of SS, from 6.0 to 11.8 per 100,000 ­person-years, followed by Europe with 3.9–5.3. North America was reported to have the least, among the three continents, with 3.9 [5].

1.2  Etiopathogenesis Autoimmunity is defined as a condition in which structural or functional damage is produced by the action of immunologically competent cells or antibodies against the normal components of the body [6]. Although the pathogenesis of SS is not entirely understood, it is considered multifactorial; as a combination of predisposed genetic involvement, deranged immune mechanisms, hormonal imbalances, and viral infections [7–9] (Fig. 1). It primarily seems to be a multistep cascade of interactive events and aberrant functions of both cellular and humoral immune systems, culminating as inflammation, lymphoproliferation, and glandular destruction and dysfunction [2,3,10]. Immune dysregulation as noted by polyclonal B-cell hyperactivity reflecting lack of regulation by T-cell subpopulation has been identified as the main offender. The sequence of these etiopathological events, at a molecular level, is depicted in Fig. 2 [11,12]. The aforementioned pathological events can be well confirmed on a cytological level, by characteristic lymphocytic aggregation around the interlobular and intralobular ducts of the salivary gland tissue [13]. Further widespread lymphocytic infiltration of the parenchymal tissue results in the loss of architecture and atrophic involution of the acini, resulting in glandular degeneration [13]. The lymphocytic foci predominantly comprise T cells (80%) and B cells (20%) [13]. This elaborate series of events with prolonged B-cell stimulation and proliferative activity, replicating within extraglandular and extranodal target tissues, may clinically present with multisystemic features of SS as well as promoting complications such as lymphoma [13].

1.3  Clinical features SS principally affects the exocrine glands such as the salivary and lacrimal glands. Due to an autoimmune-induced inflammation, SS is a heterogeneous multiorgan disorder, which manifests itself as xerostomia and xeropthalmia [7] (Table 1). The extraglandular systems involved include the musculoskeletal system, respiratory system, genitourinary system, nervous system, skin, and blood vessels [2]. Owing to the clinical presentation, SS is further classified as Primary SS and Secondary SS. Primary SS is also known as sicca syndrome, affecting the exocrine glands and presenting with xerostomia and xeropthalmia [2,7]. Secondary SS, accounting for over half the

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FIG. 1  Pathogenesis of Sjögren’s syndrome. (A) Initial phase in the pathogenesis of SS and (B) later phase in the pathogenesis of SS [7–9].

cases, is encountered with constitutional features and gets complicated by the occurrence of other rheumatic autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) [2]. The prevalence of xerostomia and xeropthalmia, extraglandular involvement, and lymphoma in primary SS cases is reported as 96%–97%, 13%, and 4.9%, respectively [21]. Systemic presentation of SS occurs in 30%–40% of cases [22] (Table 2). Although the pathogenesis of extraglandular SS still remains unclear, various mechanisms have been proposed to give rise to the extraglandular multisystem presentation of SS [31]. Organs such as the liver, kidneys, and lungs demonstrate primary biliary cholangitis and interstitial nephritis owing to the autoimmune induced inflammation of the ductal epithelium [31]. The cryoglobulinemia and autoantibodies produced by B-cell hyperactivity are ­responsible for the extraglandular manifestations, such as vasculitis, purpura, glomerulonephritis, peripheral nephropathy, and most seriously, lymphoma [32].

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FIG. 2  (A) Sequence of etiopathological events at a molecular level. [*BAFF (B-cell-activating factor; CD, cluster of differentiation; DC, dendritic cell; IL, interleukin; INF, interferon; PDC, precursor dendritic cell; Tfh, T follicular helper; Th, T helper; TLR, Toll-like receptor; TNF, tumor necrosis factor)]. (Continued)

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FIG. 2, CONT’D  (B) Sequence of etiopathological events at a molecular level. An inset of panel (A). (B) Sequence of etiopathological events at a molecular level. An inset of panel (A). Illustration recreated with permission from S. Pringle, R. Van Os, R.P. Coppes, Concise review: adult salivary gland stem cells and a potential therapy for xerostomia, Stem Cells 31 (4) (2013) 613–619; P. Brito-Zerón, et al., Sjögren syndrome, Nat. Rev. Dis. Primers 2 (2016) 16047.

TABLE 1  Clinical manifestations of SS (exocrine gland disease). Exocrine gland tissue Features

Pathogenesis

Source

Eyes

Xeropthalmia, irritation, itching, mucous Aqueous tear-deficient dry eye, exudate, grittiness, foreign body sensation, meibomian gland dysfunction photophobia and blurry vision, corneal ulcerations, eyelid infections

[14–16]

Mouth

Xerostomia, dysphagia, glossodynia, dysgeusia, dysphonia, inability to speak continuously for long periods, cotton mouth sensation, adherence of food to buccal surfaces, problems with dentures, Increased rate of dental caries, periodontal complications, change in oral flora, including an increase in oral candidiasis, peripheral neuropathies

[14–16]

Salivary and eye gland enlargement (30%–50%)

Firm, diffuse, and nontender enlargement., Inflammatory sialadenitis from unilateral nodular and less commonly lymphocytic infiltration bilateral, may be a sign of lymphoma development

Degeneration of salivary acini and hyposecretion of saliva

[14–17]

Continued

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TABLE 1  Clinical manifestations of SS (exocrine gland disease)—cont’d Exocrine gland tissue Features

Pathogenesis

Source

Skin (31%–72%)

xerosis, pruritis, cutaneous vasculitis, Specific alteration in the [14–16,18] annular erythema, Raynaud’s phenomenon protective function of the skin’s outer layer, the stratum corneum

Respiratory tract manifestations (50%–70%)

Epistaxis, recurrent nonallergic rhinitis and sinusitis, a nonspecific, persistent and irritating cough

Hyposalivation, lymphocytic infiltration of the submucosal glands in the nasopharynx, larynx, trachea, and bronchi leads to desiccation of the mucosa of the respiratory tree

[14–16,19]

Lymphoma (nonHodgkin lymphoma mucosa associated lymphoid tissue) (5%–10%)

Persistent unilateral or bilateral glandular swelling, especially when previous swelling has been transient or intermittent, hard, nodular texture to the gland, presence of cutaneous vasculitis or palpable purpura, hypocomplementemia, systemic features (malaise, weight loss, fever)

Lymphocytic infiltration within the glands, followed by glandular destruction

[1,14–16]

Vaginal

Dryness associated with dyspareunia

Lymphocytic infiltration and vaginal atrophy

[14–16,20]

TABLE 2  Clinical manifestations of SS (extraglandular disease—systemic). Extraglandular tissue (systemic) Symptom

Pathogenesis

Source

General symptoms (68%–85%)

Fatigue, fever, weight loss, fibromyalgia (15%–31%)

Autonomic nervous system dysfunction, due to the active inflammation

[14,16,23]

Skin

Xeroderma (23%–67%), purpura, Raynaud’s phenomenon (13%– 30%), cutaneous vasculitis (10%), annual erythema (9%), eyelid dermatitis, angular cheilitis, vasculitis

Disruption to the biochemical biology of the epidermis, expressed as increased epidermal proliferation and perturbation of epidermal differentiation

[14,16,18,24]

Musculoskeletal

Arthralgia (50%), rheumatoid factor (60%–70%), arthritis— nonerosive, also rheumatoid arthritis—like myositis (40%), myopathy (2.5%–47%)

Autonomic nervous system dysfunction, due to the active inflammation

[14,16,25]

Lungs (10%–20%)

Cough (50%), dyspnea, interstitial lung disease

Epithelial tissue damage caused by the immune system

[14,16]

Heart and cardiovascular System

Pericarditis, pulmonary hypertension

Immune-mediated, concomitant infection may play a role

[14,16]

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TABLE 2  Clinical manifestations of SS (extraglandular disease—systemic)—cont’d Extraglandular tissue (systemic) Symptom

Pathogenesis

Source

Gastrointestinal system (pancreas, liver)

Dysphagia (30%–81%), dyspepsia (15.6%–23%), gastrointestinal reflux, chronic gastritis, primary biliary cirrhosis (4%–9%), Autoimmune hepatitis, Hepatomegaly (11%–21%)

Dryness of pharynx and esophagus, atrophy of the gastric glands

[14,16,26]

Genito-urinary tract (kidneys, bladder)

Distal renal tubular acidosis (RTA type 1), nephrocalcinosis (in same cases due to RTA), nephritis/ glomerulonephritis, chronic renal insufficiency

Autoimmune induced inflammation, deposition of immune complexes

[14,16]

Gynecological system Episodes of amenorrhea lasting for Lymphocytic infiltration and vaginal more than 3 months, menorrhagia atrophy or metrorrhagia, endometriosis

[14,16]

Neurological disease—central nervous system, peripheral nervous system (2%–70%)

Peripheral sensory or motorsensory polyneuropathy, cranial neuropathy, mononeuritis multiplex, sensorineural hearing loss, SM-like syndrome

Direct infiltration of the central nervous system by mononuclear cells, vascular involvement, ischemia secondary to small vessel vasculitis

[14,16,23,25]

Hematologic manifestation (25%–50%)

Autoimmune hemolytic anemia, Immune thrombocytopenia, myelodysplastic syndrome, neutropenia, aplastic anemia, red cell aplasia

Peripheral destruction of mature red blood cells, alteration in the production of red blood cells, hematopoietic alterations secondary to autoimmune mechanism

[14,16,27]

Lymphoma (5%) (1)

Non-Hodgkin (low grade B cells) Lymphocytic infiltration within lymphomas aka mucosa associated the glands, followed by glandular lymphoid tissue (MALT), parotid destruction swelling, palpable purpura, splenomegaly

[1,7,28]

Thyroid (10%–70%)

Autoimmune thyroiditis

Common genetic predisposition, immune mechanism deficiency

[7,16,29]

Psychiatric disorders (up to 80%)

Depression, anxiety

Ischemic damage caused by vasculitis, secondary psychological distress

[16,30]

2  Salivary glands in Sjögren’s syndrome 2.1  Salivary gland—Anatomy and physiology The human body comprises three major salivary glands, namely parotid glands, submandibular glands, and sublingual glands, with an additional 800–1000 minor salivary glands in the oral cavity [33]. The glands arise from ectodermal (parotid gland) and endodermal (submandibular and sublingual glands) components of the primary embryonic germ layers

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25.  Salivary gland regeneration and repair in Sjögren’s syndrome

at about 6–8 weeks of gestation. Although macroscopically different, all the salivary glands share a similar histological encapsulated arborized acinoductal structure, consisting of serous acinar cells, mucous acinar cells, and myoepithelial cells in varying proportions [33,34]. Therefore, glandular structure influenced the salivary secretions produced—parotid gland secretes serous watery saliva, whereas the submandibular and sublingual glands produce thick mucous-filled saliva. The autonomic nervous system further impacts the salivary secretions. Parasympathetic stimulation of muscarinic receptors (especially M3) via neuropeptides increases serous watery secretions. On the other hand, triggering the adrenergic signaling pathways by sympathetic stimulation, results in protein-rich secretion [33,34]. The secretion of saliva is stimulated upon sight, smell, and taste of food and is mediated by two integral steps. Initially, the acinar cells form and secrete an isotonic primary saliva, chiefly composed of sodium chloride. Thereafter, the sodium gets actively reabsorbed and chloride gets passively reabsorbed. Further modifications through the ductal network give rise to a hypotonic salivary secretion in the oral cavity [35]. Dysfunctional glandular architecture or innervation leads to salivary gland pathologies [36].

2.2  Xerostomia and therapy in Sjögren’s syndrome Xerostomia associated with SS can be attributed primarily to an inflammatory mediated glandular dysfunction of the salivary glands. The pathogenesis of SS is known to involve both the acinar as well as ductal cells. Inflammatory apoptosis and atrophic destruction of the gland decrease the secretory ability of the acini, while the ductal cells play a role in the inflammation cascade by functioning as antigen presenting cells (APCs) [37–39]. Various factors such as autoantibodies, inflammatory mediators and apoptotic signals interfere with the degree of atrophy of the exocrine glands [37,38]. Autoantibodies and parasympathetic signaling against muscarinic M3 receptors have additionally proven significant in affecting saliva secretions by action on aquaporin 5 (AQP5) [37,39,40]. SS cases have also displayed overexpression and accumulation of mucins [41]. Recently, however, researchers observed that the lymphocytic focus score in primary SS were inconsistently proportional with reduced less salivary flow rate, proving the pathology was partly independent of the rate of inflammation [42]. Such findings suggest the role of cholinergic dysfunction as an alternative hypothesis to explain the pathogenesis of SS, probably antimuscarinic (M3) autoantibodies and clinically manifested as xerostomia and xeropthalmia [42–45]. Advances in the understanding of SS pathogenesis have enabled researchers to clinically test various therapeutic modalities ranging from palliative topical treatment to clinical trials using immunomodulatory and biological therapies. Symptomatic/supportive therapy involving patient education, lifestyle behavior modifications, oral prophylaxis, topical lubricating agents (saliva substitutes), and pharmacological aids (pilocarpine, cevimeline) have shown significant symptomatic improvement. Immunosuppressive and immunomodulatory drugs have proven effective in severe cases [14,46,47]. Use of these medications, as therapy for SS, is rather short-lived and has been associated with a plethora of adverse effects on prolonged intake. Moreover, these drugs fail to repair and restore glandular function. Recent advances and a better understanding of the immune dysregulation etiopathogenesis of SS have encouraged various clinical trials, to test the effectiveness of biological agents and targeted therapy. These drugs target specific molecules, such as c­ ytokines, cell 516



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surface markers, cluster of differentiation, and receptors. However, biological therapies have been known to be associated with severe complications such as opportunistic infections, depression, cardiovascular complications, viral infection, neurological complications, and tumors [48–55]. Despite the scientific developments, a significant and satisfactory treatment for xerostomia is yet to be established [56,57]. Recent literature suggests the clinical application of regenerative medicine as a promising and powerful tool in the management of xerostomia associated with oropharyngeal cancer, irradiation injury, and autoimmune disorders such as SS.

3  Regenerative medicine Repair of a tissue is defined as the restoration of the tissue architecture and function after injury [58]. Tissue regeneration is a process of repair involving new growth that completely restores the damaged tissue to a functionally normal state [58]. Functional organ restoration, which utilizes the applications of developmental biogenesis, stem cell therapy, and tissue engineering, has recently emerged as a promising therapeutic tool [59]. Regenerative medicine, an interdisciplinary experimental science, exploits the natural healing potential of the body and employs the fundamentals of graft cells, growth factors, and scaffolds to engineer a functionally restored organ [60].

4  Regeneration of salivary glands Tissue regeneration works as a mimicker of embryonic developmental biogenesis. Various exogenous and endogenous factors such as cells, growth factors, signaling molecules and a cascade of molecular mechanisms are applied to reproduce the damaged organ [33,60,61]. The embryogenesis of human salivary glands is initiated at about 6–8 weeks of intrauterine life, from the ectodermal and endodermal layers of the embryonic germ layers. Epithelial– mesenchymal interactions (between the oral epithelium and the underlying neural crest mesenchymal cells) and factors such as fibroblast growth factor (FGF)-10, fibroblast growth factor receptor (FGFR)-2b, paired-like homeodomain (Pitx)-1, and tumor protein-p63, play a pivotal role in the initiation and bud formation [34,59,62]. Multidirectional cellular proliferation and branching morphogenesis lead to the macroscopic structural form, while functional differentiation is responsible for the formation of acinar (serous, mucous), ductal cells and excretory, striated and intercalated ducts [34,59,62]. These steps of embryogenesis are replicated to repair partial damage of the gland or totally restore the damaged gland back to function. Activated molecular signaling pathways such as mitogen activated protein kinase (MAPK), the Wnt and Notch pathways have been elaborated during the glandular regeneration system [62]. Regeneration of the salivary gland can be broadly categorized depending on the various experimental techniques [59] (Fig. 3). Regeneration of the atrophied salivary acinar cells through stem cell transplantation, tissue engineering and gene therapy. Stem cells are isolated in their autologous, mesenchymal or pluripotent forms for transplantation and regeneration. Salivary organoids are generated using two dimensional or three-dimensional scaffolds, via tissue engineering. Gene therapy works toward genetic modification for prevention of SS. 517



25.  Salivary gland regeneration and repair in Sjögren’s syndrome

FIG. 3  Regeneration of salivary glands [59].

4.1  Stem cell transplantation Stem cells display characteristic potentials for uninterrupted proliferation and self-­renewal, as well as a capacity of differentiating into specialized cell types [63]. Stem cells are broadly classified as adult stem cells and embryonic stem cells depending on the origin [64]. The human body has a store of stem cells predominantly in the bone marrow and fat, with a few widespread innate remnants. Salivary gland stem cells have been identified and isolated from parotid and submandibular glands, and have been known to induce the formation of acinar and ductal cells [33,59]. Mesenchymal stem cells (MSCs) derived from bone and umbilical cord have revealed promising results at improving secretory function of salivary glands in SS [33,65]. The use of MSC extract (or cell soup) has been shown to restore glandular function by means of its regenerative and protective capacity [66]. Delivery methods of induced pluripotent stem cells (iPSCs) have been experimented since Yamanaka’s report in 2007. iPSC mimic embryonic stem cells and have shown regenerating capacity into a variety of cell types such as neuroectodermal components, thyroid, intestine, pancreas, salivary glands, liver, and kidneys and restore partial loss of organ function [67–69]. The literature reports a number of studies to exploit the therapeutic and regenerative ability of stem cells to treat xerostomia in SS [70]. 4.1.1  Autologous transplantation of salivary gland epithelial cells One potential treatment for restoring symptoms in hyposalivation is transplantation of salivary gland stem cells. The identification, purification, and characterization of salivary gland stem cells have yet to be accomplished [71]. One of the most important achievements in autologous transplant, is the development of a salivary gland organoid or salisphere, from a single acinar cell [72]. Salispheres are spheroid-like cultures of salivary gland (SG) progenitor cells that may be used in autologous transplantation of SG cells to restore s­ alivary 518



Janaki Iyer et al.

function [72]. In  vitro studies of salisphere cultures have shown SG stem/progenitor cell populations that are positive for KIT, CD117, Sca-1, and Mushashi-1 [72]. KIT + cells are heterogeneous, and they comprise a limited number of SG cells [72]. Some of the subcultures of KIT + cells co-express other markers such as CD24 (HSA) and CD49f (Itga6), which signify their higher functional recovery and more enrichment for SG stem/progenitor cells compared to other subcultures [72]. Isolating and transplanting as few as 300 mouse KIT + cells (or 1200 cells in humans) was shown to be efficient enough to improve salivatory secretions in mouse models by a significant level [73]. Obtaining the same salisphere models in humans is yet to be determined [72]. In order to mimic the salisphere structure in the laboratory setting, Urkasemsin and Ferreira set up a novel three-dimensional (3D) spheroid bioprinting cell assembly system in which human dental pulp stem cells positive for KIT were tagged with magnetic nanoparticles [72]. Studies show that submandibular gland cells isolated based on the status of four surface markers (Lin_, CD24+, c-kit+, Sca1+) have the highest efficiency in forming spheroids and when transplanted in irradiated mouse submandibular glands, exhibited multilineage capacity [73]. The four surface markers transcribe to cytokeratins K14 and K5, which are expressed by stem cells located in the basal layer of excretory ducts and at the intercalated duct/excretory duct junction [73]. Even though c-kit markers had given promising results to locate SG stem cells in vitro, the in vivo results regarding c-kit + cells’ function is still unclear [73]. 4.1.2 Transplantation of nonepithelial cells Mesenchymal stem cells

Initially, MSCs were isolated from the bone marrow as a rare heterogeneous population of cells—from 0.001% to 0.01% of the total cells—capable of differentiation and self-renewal [74]. Subsequently, MSCs were successfully and extensively isolated from other tissues, including adipose tissue, umbilical cord, Wharton’s jelly, and fetal tissue [74]. Cells that express surface markers CD73, CD90, and CD105 and are negative for CD45, CD34, CD14, CD80, CD86, CD 40, and major histocompatibility complex (MHC) class II, are capable of renewing and differentiating into different cell types such as bone, fat, and chondrocytes [74]. In the early stages of salivary gland development, epithelial-mesenchymal interaction signaling plays an important role in gland initiation of gland’s formation and the number and location of glands to be formed [75]. On combining the nonepithelial component with pseudoglandular stage gland mesenchyme, the induction of FGF-10 in the mesenchyme is noticed to induce gland development within the nongland tissues [75]. FGF signaling plays an important role in the formation of early glands aiming the development of salivary glands, lacrimal glands, and lung beds [75]. In various inflammatory diseases, application of MSCs is a promising therapy; from myocardial infarction, graft-vs-host disease (GVHD) and central nervous system (CNS) trauma to several autoimmune diseases [76]. Compact bone marrow derived MSCs have demonstrated promising results in nonobese diabetic (NOD) mice with SS-like symptoms by dual action of glandular regeneration and immunoregulatory effect [77]. Khalili and colleagues tested the preventive and salivary regenerative capacity of injectable complete Freund’s adjuvant (CFA) and MHC class I-matched normal bone marrow cells in NOD mice [78]. In 2011, Tran et al., reviewed the reports on bone marrow-derived cells transplantation to reduce xerostomia in Sjögren’s syndrome patients and head and neck cancer survivors who had received 519



25.  Salivary gland regeneration and repair in Sjögren’s syndrome

­radiotherapy [70]. They found that bone marrow derived cells improve the salivary organ function via a possible combination of cell trans-differentiation, vasculogenesis, and paracrine effect; however, the underlying responsible mechanisms remained unclear [70]. Although their precise therapeutic mechanisms are still being studied in many clinical trials, it has been suggested that MSCs promote their benefits via secretion of paracrine factors, which also suggests the plausible application of MSCs in drug delivery and their use as a vehicle in the local inflammatory milieu to maximize their interactions with the host cells [76]. MSCs are also capable of migrating to the site of injury and secreting their trophic factors locally [79]. In fact, it is believed that MSCs might behave intelligently by responding to cytokines residing at the site of injury hence revealing their potential as a site-specific drug releasing cell [80]. The trophic factors secreted by the MSCs include collagen α-1 and α-2, fibronectin, vitronectin, metalloproteinases and their inhibitors, FGF-2, basic nerve growth factor (bNGF), insulin-like growth factor-1 (IGF-1), brain-derived neurotrophic factor (BDNF), glial cell-line derived neurotrophic factor (GDNF), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), hepatocyte growth factors (HGF), epidermal growth factor (EGF), certain cytokines and chemokines, angiogenic factors, and placental growth factor (PlGF) [80]. MSCs can be expanded and scaled-up ex  vivo for cellular therapies. The high doses of cells required for their clinical applications (0.4–9 × 106 cells/kg) demand optimized methods for an efficient production of clinical-scale cell counts to meet Good Manufacturing Practices (GMP) [79]. Traditional methodologies for large-scale MSC production involve using alternative culture static system, expansion in bioreactor system, stirred bioreactor system, microcarriers, spinner flask, and WAVE bioreactor TM [79]. New techniques aiming for disposable bioreactors that are GMP-compliant with efficient downstream protocols for cell purification is still an ongoing trend [79]. There is a rising interest in using MSCs as a successful and efficient source of cells to preserve the exocrine function of the salivary glands and lacrimal glands in SS patients [66]. Previously, Khalili et al. had concluded that a combination of MSCs and CFA (CD450/TER1990- cells or MSC) when injected into NOD mice, was effective in reducing inflammatory mediators and lymphocytic influx in salivary glands [81,82]. Abughanam and colleagues found that not only MSCs but their extract can be used as a therapy in Sjögren-like mice (NOD) as both cells and the extract upregulate the expression of AQP5, EGF, FGF, bone morphogenetic protein 7 (BMP7), lysozyme (LYZ1), and interleukin-10 (IL-10) while downregulating tumor necrosis factor-α (TNF-α), matrix metallopeptidase 2 (MMP2), caspase 3 (CASP3), and IL-1β [66]. They also found that glands proliferate at a higher rate with a higher serum level of EGF and consequently due to a more consistent tear flow rate, cornea integrity, and epithelial thickness had been maintained [66]. Their results indicated a lower lymphocytic filtration and anti-SS-A antibodies with less B-cell-activating factor (BAFF) secretion, higher serum IL-10 and FoxP3 + Treg cells [66]. In an attempt at quantitatively analyzing the protein and gene expression in glands of SS, by treating NOD mice with bone marrow cell extract (cell soup), Misuno et al. enlisted over 1800 proteins associated with the inflammatory and apoptotic pathophysiology of SS as well as altered cytokine levels in salivary glands of treated mice [83]. In another study by Shi and colleagues, the significance of MSC transplantation for SS was indicated as a suppressor of IL-12 production in NOD mice [84]. It was recorded that IL-12 treatment in NOD mice reduced saliva flow and promoted lymphocyte infiltration and the IL-12 antibodies decreased the population of T helper cell 1 (Th1), Th17, and T follicular

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helper (Tfh) cells [84]. After the transplantation of MSCs in both NOD mice and SS patients, Th17 and Tfh were reduced [84]. In some studies, the spleen is considered as a MSC reservoir of a promising therapy for SS [85]. It was reported that infused splenocytes are enabled to migrate into damaged salivary glands in NOD mice and differentiate into salivary epithelial cells [85,86]. Khalili et al. compared the therapeutic effect of bone marrow and spleen cells toward reversing salivary hypofunction of NOD mice [81]. They concluded that although spleen cells proved comparatively significant in initial phases of SS, a reduction in TNF-α and TGF-β1, and increased EGF were demonstrated by both therapies in advanced stages of SS [81]. Induced pluripotent stem cells

Prof. Yamanaka’s discovery of iPSCs using four factors to successfully reprogram human somatic cells to become pluripotent has emerged into a revolutionary science over recent years. The potential of iPSCs to originate from human somatic cell and yet mimic embryonic stem cells, under the influence of transcription factors and signaling molecules has been exploited to generate patient specific stem cells [87]. iPSCs have been successfully applied to form cells from the pancreas, nerves, liver, stomach, skin, and the adipose tissue [87]. Patient specific iPSCs can be generated with the goal of drug development and screening, disease modeling, and regenerative cell therapy. Studies utilizing iPSC have investigated into the epigenetic factors affecting diseases, such as cancer, to permit safer potential regenerative strategies [88]. The use of transcription factors such as octamer-binding transcription factor 3/4 (Oct 3/4), sex determining region Y- box 2 (Sox2), L-MYC, and LIN28 transfected in a single plasmid using the nucleofector (Lonza), when applied to adult human skin derived fibroblasts, proved successful to investigate the therapeutic effects of iPSC on salivary gland squamous cell carcinoma [88]. Upon transplantation, iPSC characterization was successfully monitored by reverse transcription-polymerase chain reaction (RT-PCR) that demonstrated Oct4 and Sox2 expression in successful cell lines as well as positive immunostaining for Oct4. These findings were further confirmed histologically under hematoxylin and eosin sections, showing normal glandular architecture with increased ductal structures. The regenerated transplanted salivary gland proved functionally active by positive therapeutic markers such as cyclooxygenase 1 (COX-1), cyclooxygenase 2 (COX-2), and α-amylase [88]. Organ replacement regenerative technology has successfully transplanted structurally and functionally efficient ectodermal organs such as teeth, hair follicles, and lacrimal glands by recapitulating organogenesis. Reproducing this similar strategy, Ono Minagi regenerated salivary glands using embryonic salivary glands and iPSC in vivo and in vitro using green fluorescent protein (GFP)-iPS cell line (APS0006: iPS-Stm-FB/gfp-99-3), derived from stomach cells. They successfully induced an organ by forming a microenvironment using optimal transcription factors to form salivary gland rudiment, using monoculture of submandibular gland cells and coculture with GFP-iPS cells [69]. The iPSC salivary glands showed positive pluripotency using teratoma assay and quantitative PCR (Sox2, Nanog, c-Myc, Kruppel-like factor 4 (Klf4), Aqp5, Amy, and M3r), while the transplanted glandular structure showed positive immunofluorescence for salivary specific markers such as α-amylase, parotid secretory protein, E-cadherin, GFP, Sox2, and AQP5. The rudimentary organoid structurally and functionally mimicked salivary glands, hence, could be applied as a promising therapeutic tool for salivary gland diseases [69].

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Tanaka et  al. attempted to regenerate an orthotopically functional salivary gland by means of transplantation of an induced salivary gland primordium through self-­organized mouse embryonic stem cells [68]. Vital factors such as BMP4, SB-431542 (inhibitor of TGF-β), LDN-193189 (inhibitor of BMP), FGF2, FGF7, and FGF10 were used to promote an ideal microenvironment for iPSC generation. The salivary gland organoid formed showed pan-­cytokeratin-positive epithelial cells, AQP5 +, acinar-like cells (CK18-positive ductal-like cells and α-smooth muscle actin-positive SMA +), and expressed salivary gland markers, such as K18, AQP5, α-SMA, and muscarinic receptor-1 (M1) and 3 (M3) via RTPCR. Structurally, the glandular structure showed histopathological resemblance to salivary gland architecture by routine hematoxylin and eosin and as well as special staining by periodic acid-Schiff (PAS) staining. The transplanted salivary gland resembled salivary gland structurally and functionally expressing positive salivary gland markers as well as tubulin beta 3 class III (TUBB3-expressing nerve fibers) and CD31 (expressing vessels). This study concluded the possibility of further prospects toward fully functional organ transplant regeneration using iPSCs [68]. Son et  al. used nonintegrating oriP/Epstein–Barr nuclear antigen-1 (oriP/EBNA-1)based episomal vectors and reprogrammed dermal fibroblasts into iPSCs in patients affected with SS and other autoimmune disorders such as ankylosing spondylitis (AS) and systemic lupus erythematosus (SLE) [89]. They further differentiated these iPSCs into hematopoietic and mesenchymal cells, proving pluripotency by differentiation into three germ layers, hence accomplished successful autologous transplantation as patient specific iPSC application in regenerative therapy in autoimmune diseases such as SS, preventing immune rejection [89]. Hai et  al. studied the underlying immune dysfunction etiology of SS by inhibiting lymphocytic infiltration into the salivary glands of NOD mice with SS-like disease, using iPSC-MSC derived from bone marrow and their extracellular vesicles [90]. Their study witnessed a suppressed inflammatory activity by administering the iPSC-MSC in mice models with SS, thereby targeting the etiology prior to onset on lymphocytic infiltration and sialadenitis. This study also helped overcome limitations of MSC such as limited growth and significant donor variations by exploiting the unlimited pluripotent potential of iPSC [76]. Splenocytes have been used to successfully regenerate salivary gland cell by Faustman et  al. [91] and Tran et  al. [86]. In 2010, Faustman and Davis as well as Dieguez-Acuña et al. explored the multipotent and possibly pluripotent potential of the sequestered stem cells within the spleen [91,92]. The experimental applications of splenic stem cells, of Hox11 lineage, into pancreatic islets, salivary gland cells lymphocytes and other differentiated cells have been used to treat diseases such as diabetes mellitus type I and SS. The freshly harvested healthy splenic donor cells upon secondary treatment reduced the autoreactive lymphocytic reaction when transplanted into the recipient, thus reducing chances of inflammatory rejection and degradation. CD45- splenic stem cells expressed iPSC proteins such as Oct3/4, Sox2, Klf4, c-MYC, and NANOG as well as Hox11, Gli3, Wnt2, and Adam12 (factors found in embryonic stem cells). Due to this innate potential, splenic stem cells are emerging as vital components in the regenerative therapy of type I diabetes, SS, cranial nerve defects, and post infarction cardiac tissue, in autologous or heterologous forms [93].

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4.2  Tissue engineering Tissue engineering is the application of biochemical sciences and bioengineering to develop alternative tissues that are structurally and functionally similar to their natural equivalents in the body [33,94]. Cell-cell adhesion, cell-extracellular matrix adhesion, adhesion with the compatible bioengineered scaffold, and various synthetic signaling molecules and proteins are vital parameters toward generating the replica of the natural environment appropriate for the reproduction and development of the glandular organ [33,59]. Two-dimensional (2D) and 3D scaffolds incorporating collagen gel, hyaluronic acid (HA), polyglycolic acid, Matrigel, or recycled natural salivary extracellular matrix have been successfully applied in salivary gland engineering studies [33,59,95]. Su et al. studied human salivary slice culture model to maintain functional and structural integrity in 3D organization for 14 days [96]. Lilliu et al. studied the capability of residual connective tissue (natural extracellular matrix scaffolds) as a recycled natural scaffold. Upon comparison with native salivary tissue, the natural extracellular matrix scaffolds showed structural and functional similarities and promoted viable seeding of cells [97]. Recently, a serum-free scalable suspension 3D culture system has also been experimented upon to demonstrate salivary spheroids as salivary functional units [95]. Long-term treatments of xerostomia involve implanting polymeric substrates or synthetic scaffolds [98]. The hollow branched ductile network of salivary glands that terminate in the saliva-producing acini is mapped in a way that its luminal surface polarizes the epithelial cells [99]. Toward the apical side of the lumen, the presence of tight junction proteins such as occludin maintain the clustered cell organization; therefore, the epithelial barrier function and proliferation remains at a normal level [99]. For a bioengineered scaffold to promote this apico-basal polarization is a critical requirement to restore salivary function especially in SS patients [99]. Regenerating salivary epithelium is based upon recreating the fibrous sheets of basement membrane proteins and the extracellular matrix (ECM) and their physical, chemical and mechanical features [99]. One of the biomaterials known to have the composition of basement membrane and the ECM very similar to the salivary glands are scaffolds made of poly-lactic-co-glycolic acid (PLGA) nanofiber [99]. Other biomaterials considered as candidates to engineer salivary gland tissue are modified fibrin hydrogel (FH), poly-l-lactic acid (PLLA), nanofibers, and chitosan [100]. The important aspect of using these biomaterials is to avoid rejection by the host while maintaining the process of tissue repair and its inflammatory counteract, which involves recruitment of the immune system cells [100]. Tissue engineering methods to restore salivary gland function is classified into three approaches, 2D culture, 3D culture, and ex vivo culture of embryonic tissues [98]. In the 3D culture, primary cells from salivary gland are cultured to form a monolayer lining on a blind-end tubular biodegradable polymer; the polarized epithelial cell structure would be capable of directing fluid secretions [98,101]. An initial prototype of an artificial salivary gland that could be surgically implanted into a pouch created in the buccal mucosa was proposed by comprising three components—a porous biodegradable substratum, a coating of an extracellular matrix protein on the luminal (internal) surface, and a polarized epithelial cell layer [101]. The first approach is using 2D scaffolds. The most common 2D culture biomaterials used in salivary gland tissue engineering are polylactic acid (PLA) and polyglycolide flat disks combined with immortalized human salivary gland cell line (HSG) and PLGA fibrous scaffolds combined with immortalized adult mouse submandibular gland ductal cell line (SIMS)

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or immortalized adult rat parotid gland acinar cell line (ParC10) [98]. Fibrous scaffolds are more rounded compared to the flat disks therefore they create more clustered cell morphology as the polarization and expression of tight junctions require some curvature [98]. The 3D cultures include porous scaffolds of silk fibrin combined with primary gland epithelial cells from rat submandibular/parotid gland and HA hydrogels combined with primary human salivary gland acinar-like cells from the parotid gland [98]. Among the two, HA hydrogels had ­acini-like structures on them and tight junctions, alpha-amylase and an apoptotic central lumen were present together [98]. Two other types of hydrogels used in 3D culture are polyethylene glycol (PEG) hydrogels and HA/PEG hydrogels, which one is combined with primary acinar and ductal cells from mouse submandibular gland and the other one is combined with primary human salivary gland acinar-like cells from the parotid gland [98]. A polymer used in the 3D culture approach is PEG (arginylglycylaspartic acid-) C12 ([PEG(RGD-)C12]n) and it guides myoepithelial cells by providing them with space for attachment and elongation once combined with human primary salivary gland myoepithelial cells [98]. The second approach is 3D culture during which epithelial cell populations are encapsulated in hydrogel matrices and would be implanted post radiation [98]. The 3D biodegradable scaffolds may be constructed using 2D microfabricated membranes with a specific shape, porosity, and pore size [102]. The biomaterial used for this purpose requires to be capable of undergoing the microfabrication process for the micropillars and micro holes to be imprinted reproducibly [102]. Stacking the membranes needs to be suitable enough to withstand the cellular organization of the stem cells as well as their attachments [102]. The conventional techniques to create topographical shapes have certain limitations that may be overcome using the nanotechnologies, hot-embossing and soft lithography [102]. These topographical cues promote cell adhesion and guide cell growth so that nanometer-sized features can be achieved [102]. In the third approach, ex  vivo culture is created using embryonic salivary gland cells in vitro followed by branching morphogenesis of the salivary tissue [98]. Among the studies involving ex vivo culture of embryonic tissues, a combination with PLGA fibrous scaffold, poly(vinylidene fluoride) PVDF/chitosan membrane or alginate/polyacrylamide gels with mouse embryonic submandibular glands can be mentioned [98]. Alginate or polyacrylamide gels require additional factors to immobilize cell adhesive peptide and exogenous growth factors [98].

4.3  Gene therapy Gene therapy is an experimental science that employs the application of genes to prevent or cure diseases. This novel therapy has proven beneficial at treating diseases such as genetic inherent diseases, viral diseases, and certain cancers. Gene delivery approach works by either replacing or inactivating a mutant gene, or addition of a new gene into the system, to compensate for the faulty gene. The location and accessibility of the salivary glands is advantageous for minimal invasive gene delivery systems [60]. Due to the placement of the salivary gland ducts directly superficial into the oral cavity, the viral or nonviral vectors expressing a particular gene can conveniently be injected into the epithelium via conventional cannulation techniques [59,60]. This technique also proves beneficial due to limited spread within the encapsulated salivary gland that prevents systemic exposure [60].

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AQPs, water channel proteins essential for cellular water transport, have been extensively reviewed in terms of their expressions, localizations, and physiological functions [103]. When water channel AQP1 is genetically introduced into irradiated salivary glands, xerostomia has shown marked improvement [59]. The preclinical trials in nonhuman models such as rodents and pigs, although showed promising results by human AQP1 gene transfer, displayed varying salivary gland regeneration in human subjects [34]. Strategy behind gene modification has proven beneficial in treating severe combined immunodeficiency (SCID) with some adverse reactions [62], proposing the need for further studies to optimize the vector dose. Upon injecting miniature pigs with luciferase and β-galactosidase genes with adenoviral vector, successful gene transfer was demonstrated using rAd5 vectors [60] Experimental approaches have also proven successful in the gene transfer of significant molecules such as IL-17 receptor antibodies, growth hormones, and erythropoietin [59]. Gene delivery systems have recently evolved as a relatively new glandular regenerative technique to cure xerostomia in SS, by targeting inflammatory mediators, cell–cell interaction, or intracellular molecules. A vector coded IL-10 molecule, rAAVhIL10, when injected within the salivary glands of NOD mice with SS-like disease, demonstrated higher salivary flow rate over controls [60]. A study involving recombinant serotype 2 adeno-associated virus encoding the human VIP transgene (rAAV2hVIP) administration in NOD mice with SS-like disease demonstrated increased salivary flow rate with a reduction in interleukins and TNF-α [60]. Studies have been conducted to prove that efficient potential of gene therapy can be exploited beyond salivary gland disorders, such as diabetes and hemophilia. However further studies should be conducted to the interactive cellular mechanisms of extracellular matrix and other cellular components with the introduced gene [60].

5  Conclusion Clinical findings associated with SS continue to perplex clinicians and impact patient’s quality of life. Although therapeutic advancements have been accomplished through biological drugs, there exist a significant percentage of related complications such as infections and cardiovascular and neurological issues [48,49]. The limitation of these drugs is that they do not directly target the underlying etiopathogenesis of SS [56,102]. With the innovative advent of regenerative medicine and its applications toward degenerated and atrophied salivary glands, promising permanent therapy may be administered to many patients. The pathogenesis of SS, although unclear, being autoimmune in nature, is chiefly concerned with immune dysfunction caused by autoantigens. There is also a probable impact due to degenerated cholinergic innervation. Regeneration of the atrophied acinar cells and the nervous components through stem cell transplantation, tissue engineering techniques, and gene therapy have demonstrated a potential toward unraveling the underlying cause of xerostomia in SS. Autologous and transplanted stem cells either as MSCs or iPSCs have been reported with significant clinical improvement. iPSCs have been used at successfully regenerating organs such as the pituitary gland due to its innate pluripotent capacity, suggestive of further exploratory studies directed toward salivary glands. Tissue engineering and organ regenerative techniques have been experimental to create functional salivary gland organoids via 2D and 3D scaffolds, under optimal microenvironment. The usage of autologous graft scaffolds

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significantly diminishes further complications such as rejection or mechanical degradation. Genetic recombination directed toward the underlying cause of SS, through gene therapy, is a challenge in regenerative medicine. As a therapeutic modality for xerostomia related to irradiation and autoimmune disorders, the introduction of modified genes with viral or nonviral vectors into the salivary gland system deliver attractive results. This promising strategy, complemented by the other means of regenerative medicine, may be used as a prospective permanent correction of hyposalivation and related findings in autoimmune disorders such as SS.

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C H A P T E R

26 Regulation of bone and joint inflammation by type 2 innate lymphoid cells Yasunori Omataa,b, Mario M. Zaissc, Michael Frechc, Georg Schettc, and Sakae Tanakaa,⁎ a

Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan, bBone and Cartilage Regenerative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo, Japan, cDepartment of Internal Medicine 3, Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany ⁎

Corresponding author

Abstract The innate and adaptive immune systems regulate inflammation in arthritis. The innate immune system works as one of the “first responders” against the invasion of pathogens, followed by adaptive immunity activation. The cross-talk between innate and adaptive immune cells has protective roles against pathogens and induces immunological responses. Recently, a new type of innate immune cells, innate lymphoid cells (ILCs), was discovered; it was found that they play a profound role in immunological responses. ILCs function closely with T helper cells, depending on their respective subsets. In this chapter, we mainly focus on one subset, type 2 ILCs (ILC2s), and review their role in inflammatory arthritis and bone homeostasis.

Keywords Innate lymphoid cells (ILC), T cell, Arthritis, Bone, Osteoclast, Innate immunity, Adaptive immunity

Translational Autoimmunity, Vol. 6 https://doi.org/10.1016/B978-0-323-85831-1.00026-7

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26.  Regulation of bone and joint inflammation by type 2 innate lymphoid cells

1  Introduction The immune system in a mammalian body consists of both innate and adaptive immunity against external pathogens. The innate immune system is regulated by various immune cells such as macrophages, dendritic cells (DCs), mast cells, granulocytes, and natural killer (NK) cells. The innate immune system acts as the first-line defense by recognizing pathogen-­ associated molecules, and in turn stimulates inflammatory responses and/or phagocytosis in the host to prevent infection and attack the invading pathogens. The innate immune responses drive the adaptive immune system, in which B and T cells play major roles. T cells are activated upon recognition of antigen peptides in the context of major histocompatibility complex (MHC) molecules by T-cell receptors. Two major subsets of helper T cells, Th1 and Th2 cells, differentiated from naïve T cells were identified, and their functions were elucidated [1,2]. Additional subsets of T cells were subsequently discovered, namely IL-17-producing T cells (Th17 cells), IL-22-producing Th22 cells, and IL-9-producing Th9 cells. The adaptive immune cells communicate with innate immune cells both directly and indirectly to induce synergistic immune responses. During the present decade, a new immunological player, innate lymphoid cells (ILCs), has been discovered, and the immunological functions of these cells have been investigated. In 2010, the existence of NK-cell-like lymphocytes that did not express antigen receptors, unlike B and T lymphocytes, was reported by several groups [3–5]. These innate lymphocytes, named type 2 ILCs (ILC2s), produce type 2 cytokines such as IL-4, IL-5, and IL-13 in response to IL-25 and IL-33, and show a functional similarity to Th2 cells. ILC2s are characterized by the expression of a transcriptional factor GATA-binding protein3 (GATA3), and originate from common lymphoid progenitors. ILCs mainly comprise three subsets, types 1–3, or broadly five subsets, including lymphoid tissue inducer (LTi) cells and natural killer (NK) cells. They have tissue-resident characteristics and are maintained and expanded in local tissues depending on the circumstances [6]. ILC1 is a subset of ILCs induced by IL-12, IL-15, or IL-18, which has a functional similarity to Th1 cells, producing interferon gamma (IFN-γ) (Tables 1 and 2). Their transcriptional regulation is also shared with Th1 cells, and is regulated by T-bet, without eomesodermin TABLE 1  Primary markers for differentiating ILCs. Essential surface markers and transcriptional markers for human and mouse ILCs.

Mouse

Human

Surface marker

Transcription factor

ILC1

CD45, CD127, CD90, CD253, CD161, CD69, CD335, Sca-1, CD117

T-bet, Eomes

ILC2

CD45, CD127, CD90, CD278, CD294, IL-17R, KLRG1, Sca-1, CD25, ST2

Gata3, Rorα

ILC3

CD45, CD127, CD90, CD254, CD49, CD335, CD161

Rorγτ, AhR

ILC1

CD45, CD127, CD161, CD69, CD196, IL-12R

T-bet, Eomes

ILC2

CD45, CD127, CD278, CD294, IL-17R, KLRG1, CD117, CD25, CD194, ST2

GATA3, AHR

ILC3

CD45, CD127, CD161, CD278, CD117, CD254, IL-23R, CD336

RORγτ, AHR

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TABLE 2  Secreting cytokines and function of ILCs. Cytokines

Function

ILC1

IFNγ, TNF

Macrophage activation

ILC2

IL-4, IL-5, IL-9, IL-13, Areg

Macrophage activation, Metabolic homeostasis

ILC3

IL-17, IL-22, GM-CSF, TNF

Phagocytosis, Intestinal homeostasis

(EOMES gene). ILC3, which is another subset of ILCs, develops following stimulation by IL-1β and IL-23 and produces IL-17 and IL-22, similar to Th17 cells and Th22 cells. ILC3 differentiation is regulated by retinoic acid receptor-related orphan receptor-γτ (RORγτ). ILC3 expresses RANKL (receptor activator of nuclear factor kappa-B ligand) [7,8], an essential cytokine for the differentiation of osteoclasts, and RANKL regulates the production of CCR6+ ILC3. RANKL/RANK signaling is also essential for ILC3–ILC3 interactions [9]. Thus, adaptive and innate immune cells share functional similarities, and they stimulate each other. Furthermore, ILCs have substantial flexibility and plasticity, and change into other subsets following cytokine stimulation, depending on the tissue microenvironment [10]. For example, immature ILC2s usually develop following stimulation by IL-33 and thymic stromal lymphopoietin (TSLP) and express GATA3. However, they have the ability to differentiate into T-bet-expressing ILC1 in response to IL-1β and IL-12 stimulation, and into RORγτ-expressing ILC3 in response to IL-1β and IL-23. Likewise, ILCs work as a T-cell counterpart with its plasticity, depending on the local circumstances. In this chapter, we review the role of innate immunity via ILCs comparing with adaptive immunity via T cell in the bone and joint pathological conditions such as rheumatoid arthritis (RA), spondyloarthritis (SpA), and osteoporosis.

2  Rheumatoid arthritis and T cell Rheumatoid arthritis (RA) is an autoimmune disease characterized by both acute and chronic joint inflammation. The symptoms of RA may be influenced by various factors, including genetic, environmental, and dietary factors. Synovitis developed in the joints of patients with RA leads to the destruction of bones and joints. It has been established that various subsets of T cells are involved in the pathology of RA. T-bet-expressing Th1 cells protect the host from pathogens and promote the initiation of arthritis, developing inflammation at local sites by secreting proinflammatory cytokines such as IFN-γ and IL-1β. Adoptive transfer of T cells demonstrated that T cells acquired arthritogenic capacity in rat strains with a prevailing Th1 response [11]. IL-18 and IL-15 are essential cytokines for the induction of Th1 cells, and these cytokines are upregulated in the synovial fluid of patients with RA [12]. The transcription factor GATA3 is essential for naïve T cells to differentiate into Th2 cells. Th2 cells secrete IL-4, IL-5, and IL-13 that have antiinflammatory properties. They inhibit proinflammatory cytokines and reduce inflammation. In the murine model of type II collagen-induced arthritis (CIA), continuous administration of IL-4 delayed the onset of arthritis and protects the cartilage [13,14]. IL-4 induces Ig class switching to the Th2 associated isotypes IgG1 and IgE [15] and suppresses the proliferation of synoviocytes. IL-4 has antiinflammatory effect on 533



26.  Regulation of bone and joint inflammation by type 2 innate lymphoid cells

macrophages and suppresses TNF-α and IL-1β [16]. In collagen induced arthritis mice, the severity and the incidence were suppressed by the treatment of IL-13 [17], which has antiinflammatory property. Th17 cells are characterized as transcription factor RORγτ and secrete IL-17A, IL-17F, IL-21, and IL-22. IL-17 stimulates synovial fibroblasts and macrophages to secrete proinflammatory cytokines [18]. IL-17 synergizes with TNF-α and stimulates fibroblasts to produce IL-1, IL-6, and IL-8 [19]. Although IL-17 plays an essential role in perpetuating inflammation and seems to be a potential therapeutic target, several clinical studies have shown that therapies used to neutralize IL-17 could not alter the progression of arthritis [20–22]. Regulatory T cells (Tregs) have antiinflammatory properties and are transcriptionally regulated by the FOXP3 gene. Although Tregs have an antiinflammatory effect on arthritis, some studies have shown no difference in the effect of Tregs, and their function in arthritis remains controversial.

3  Rheumatoid arthritis and ILC Previous reports have indicated the localization of ILCs in the synovial fluid of patients with RA. Dalbeth et al. reported that CD3− CD56+ NK cells were enriched in the inflamed joints of patients with inflammatory diseases compared with their expression in peripheral blood mononuclear cells (PBMCs), including RA. This subset was sensitive to stimulation by IL-12/ IL-15 and secreted cytokines such as IFNγ that can activate macrophages [23]. Furthermore, CD14+ monocytes promoted IFNγ production [24]. Synovial NKp44+/CCR6+ CD3− CD56+ NK cells are enriched in patients with RA [25]. Leijten et  al. examined ILC3s in the blood and synovial fluid of patients with psoriatic arthritis (PsA). They showed that ILC1s in synovial fluid increased more prominently in patients with RA than those with PsA [26]. IL-17A–­ producing ILCs were remarkably increased in PsA than those in RA. Interestingly, disease activity was inversely correlated with the distribution of CCR6+/NKp44+/MCAM+ ILC3s in peripheral blood. Rodriguez-Carrio et al. examined ILCs in inguinal lymph nodes in patients with early RA and found that the frequency of ILC1s was increased in patients at risk of RA and that of ILC3s was increased in patients with established RA [27]. These observations indicate that ILCs are implicated in inflammation during RA. Takaki-Kuwahara et al. examined the distribution of ILCs in CIA mice and found that CCR6+ ILC3s that express IL-17A and IL-22 were increased in arthritic joints [28]. Rauber et  al. analyzed the role of ILC2s on the resolution of arthritis in the KBxN ­serum-transferred mice, which develop autoantibodies against glucose-6-phosphate isomerase. The overexpression of IL-9 did not affect the initiation of arthritis or its severity, but induced a prolonged resolution of arthritis. IL-9-producing ILC2s accelerated the resolution of arthritis in mice, and human RA patients with remission exhibited a high number of IL9+ ILC2s. Furthermore, ILC2s were located close to CD3+ FoxP3+ Treg cells, indicating that receptor-ligand interactions between ILC2s and Treg cells mediated the disease suppressive effect of Tregs [29]. ILC2s and T cells stimulate each other [30]. T-cell-producing IL-2 drives ILC2 cytokine production such as IL-4 and IL-5. We previously showed that the blood serum levels of bone resorption markers such as TRAP5b and CTX-1 inversely correlated with the frequency of circulating Tregs in healthy control and RA patients [31]. These studies suggest that ILCs regulate the duration of joint inflammation.

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4  Spondyloarthritis and ILCs ILCs are also involved in the pathology of enthesopathy. Spondyloarthritis (SpA) includes rheumatic diseases such as ankylosing spondyloarthritis (AS), psoriatic arthritis (PsA), reactive arthritis (ReA), and inflammatory bowel disease (IBD)-related SpA. Soare et al. reported that circulating ILCs were increased in patients with PsA, and that the number of ILC3s was positively correlated with disease activity of PsA [32]. In addition, they found that the ILC2/ILC3 ratio was negatively correlated with the scores of synovitis, erosion, and disease activity of PsA. It has been reported that half of the patients with SpA have gut inflammation. IL-17producing ILC3s were significantly expanded in the gut of AS patients with gut inflammation as compared with healthy controls. The number of α4β7+ IL-23R+ IL-17/IL-22+ ILC3 increased in the gut, blood, bone marrow, and joint fluid of patients with AS [33]. As IL-17/IL-22producing ILC3 shares the phenotype of RORγτ− T-bet+ ILC1, the plasticity of ILC3 and ILC1 might be involved in gut inflammation of SpA patients. Furthermore, human ILCs are more enriched in entheseal soft tissues than in the blood, and NKp44+ ILC3s are dominant ILCs.

5  Role of ILC2 on the initiation phase of arthritis We investigated the impact of ILC2s on the pathogenesis of inflammatory arthritis in both humans and mouse models, in particular, at the initial phase of the disease [34] (Fig. 1). We defined human ILC2s as the CD3− Lineage− CD127+ CD161+ CRTH+ GATA3+ cell population (Table 1). The number of GATA3+ ILC2s was increased in the peripheral blood of RA patients compared with healthy controls, while inversely correlated with the disease activity of the

Bone marrow ILC2

Osteoporotic bone

Bone & Joint

IL13

IL4

Arthritic joint

Osteoclast Joint / Synovium Synovitis

Macrophage TNFα

IL13

Blood vessel

IL1β IL4 ILC2

FIG. 1  ILC2s regulate inflammation and bone homeostasis. ILC2s have a function influencing synovial macrophages and osteoclasts in bone and joint. ILC2s secrete IL-4 and IL-13 and suppress the production of TNFa and IL-1b. ILC2s regulate osteoclast in bone differentiation by the secretion of IL-4 and IL-13.

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26.  Regulation of bone and joint inflammation by type 2 innate lymphoid cells

patients. From a paired samples analysis of patients with RA, ILC2s were located in both the synovial tissue and the peripheral blood of patients with RA. The presence of ILC2s at local sites in RA patients led us to speculate that ILC2s worked to mitigate arthritis in the patients. Therefore, we investigated two RA mouse models. One was the K/BxN serum-induced arthritis model (SIA), in which arthritis is induced by passive transfer of antibodies. The other was the type II CIA mouse model, in which arthritis is induced by active immunization with chicken type II collagen followed by a booster injection of collagen 21 days later. ILC2s were rapidly induced following the induction of arthritis in both models, leading to an increase in T cells. In mice, we defined ILC2s as CD3− Lineage− CD90.2+ KLRG1+ ST2+ GATA3+. The proportion of IL-4+ ILC2s was enriched, followed by IL-5+ and IL-13+ ILC2s. In terms of T cells, CD4+ T-bet+ Th1 cells were modestly increased. Interestingly, the induction of ILC2s in the bone marrow preceded that in synovial tissues, suggesting the existence of primed ILC2s in the bone marrow. Bone marrow chimera mice, in which bone marrow cells from RORαcre TdTomato mice were transplanted, showed the infiltration of ILC2s to synovial tissues after SIA induction. Briefly, ILC2s are dominant systemically and locally in both human and mouse arthritis. Two conditional knockout mice deleting ILC2s, RORαcre/GATA3fl/fl mice and Tie2creRORαfl/fl mice, are available to investigate the functions of ILC2s. RORα and GATA3 are essential transcription factors for ILC2 development. ILC2-deficient mice exhibited worse arthritis progression in both arthritis mice models than their littermate controls. Histologically, erosive areas, inflamed areas, and osteoclast numbers were increased in the ILC2-deficient mice. CD11b+ F4/80+ macrophages, the source of proinflammatory cytokines such as IL-1β, were increased in ILC2-deficient mice. In contrast, the proportion of T-cell subsets did not differ during arthritis. These facts indicate that the arthritic inflammation is negatively regulated by ILC2s at the initiation phase. There are three methods to induce ILC2s in vivo, including administration of IL-25/IL-33 mini-circle vectors, administration of IL-2/IL-2 antibody complex, and the adoptive transfer of wild-type ILC2. IL-25 and IL-33 are known to proliferate and stimulate ILC2s, and IL-33 also egress ILC2 from bone marrow. Airway exposure to IL-25 and IL-33 induced IL-5 and IL-13 production and eosinophilia in lung of mice [35–37]. Induction of ILC2s, in particular IL-4+ ILC2s, by administration of mini-circle vectors [38] of IL-25/IL-33 reduced the eroded area, the inflamed area, and the number of osteoclasts, and increased bone volume in arthritis model mice. The technology of hepatocyte-specific minicircle vector with tail hydrodynamic injection enables systemic overexpression of encoding proteins systemically [39]. The treatment with IL-2/IL-2 antibody complex also induced ILC2s [40], and attenuated arthritis [41]. In addition, adoptive transfer of ILC2s after expanding the sorted ILC2s proved the antiinflammatory properties of ILC2s affect the initiation of arthritis. IL-4+ ILC2s comprised the majority of transferred ILC2s, which were transferred intravenously before the induction of arthritis. To obtain enough number of ILC2s for adoptive transfer, we established the culturing method to expand in vitro with stimulation using cytokines such as IL-2, IL-7, IL-25, IL-33, and TSLP [42], then we transferred expanded ILC2s to the mice. The progression of arthritis was mitigated in the ILC2 transferred model from the beginning of arthritis, demonstrating the upregulation of IL-4. Remarkably, the adoptive transfer of IL-4/IL-13-deficient ILC2s partially abrogated the suppressive effect of ILC2s on arthritis. The adoptive transfer of ILC2s could modulate the induction of arthritis.

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These findings suggest that ILC2s affect the progression of arthritis at an early stage. In vitro co-culture experiments of ILC2s with lipopolysaccharide (LPS)-induced macrophages showed decreased IL-1β and TNF-α, reflecting the antiinflammatory effect of ILC2s. The increase in IL-4+/IL-13+ ILC2s is essential for regulating the initiation phase of arthritis.

6  Bone homeostasis and cytokines mediated by T cell Bone tissue not only supports the body, but also protects the internal organs and bone marrow from mechanical damage, and acts as a reservoir of calcium and phosphate. Bone homeostasis is maintained by various cells, including osteocytes, osteoblasts, chondrocytes, and osteoclasts [43]. Osteocytes develop during the process of bone matrix production by osteoblasts. They produce a transmembrane protein RANKL, which induces differentiation of osteoclasts, multinucleated giant cells essential for bone resorption. RANKL is a member of the TNF superfamily, and binds to its receptor (RANK), expressed in monocytes and macrophages, to transduce signals for the differentiation of osteoclasts. RANKL was originally discovered as a protein expressed on activated T cells, and the subsequent studies demonstrated that RANKL is also induced in osteoblasts in response to calciotropic hormones and inflammatory cytokines. The deletion of RANKL (Tnfsf11 −/−) or RANK (Tnfrs11a −/−) in mice resulted in severe osteopetrotic phenotypes due to the lack of osteoclasts, confirming the essential role of RANKL/RANK signaling for the regulation of osteoclast differentiation. The relationship between osteoclast differentiation and immune cells, in particular T cells, has been extensively studied. Th1 cells produce IFN-γ, TNF-α, and granulocyte macrophage colony-stimulating Factor (GM-CSF) following stimulation by IL-12, to provide protection against intracellular pathogens, inducing the phagocytosis of pathogens and the production of complements [44]. IFN-γ is a signature cytokine of the Th1 subset involved in the pathogenesis of several autoimmune diseases such as RA and IBD. Takayanagi et al. reported that IFN-γ rapidly degrades the RANK adaptor protein TRAF6 (tumor necrosis factor receptor-­ associated factor 6) and then inhibits the differentiation of osteoclasts [45]. Th2 cells play an essential role in host defense against parasites and regulate allergic reactions [46]. Th2 cells produce type 2 signature cytokines such as IL-4, IL-5, and IL-13 interacting with antigen presentation by antigen-presenting cells. Several studies have demonstrated that the type 2 cytokines, IL-4 and IL-13, inhibit osteoclast differentiation. The first observation was that IL-4 inhibited bone resorption under co-culture conditions [47]. IL-4 inhibited RANKL-induced osteoclast differentiation dependent on signal transducer and activator of transcription 6 (STAT6), suppressing the activity of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) [48]. IL-4 strongly inhibited osteoclastic bone resorption stimulated by TNF-α [49]. The study for dendritic cells (DCs) showed IL-4 was more effective for the differentiation and the function of DCs than IL-13 [50]. A comparison of the inhibitory effect between IL-4 and IL-13 showed that IL-4 affected osteoclast precursors more strongly than IL-13, and IL-4 effectively induced phosphorylation of STAT6 [51]. These findings showed that type 2 cytokines, especially IL-4, strongly suppressed osteoclast differentiation in a STAT6-dependent manner. Previous studies reported a positive regulatory role of Th17 cells in osteoclast differentiation. Th17 cells express RANKL and TNF-α, and not only directly stimulate osteoclast

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­ ifferentiation, but also stimulate RANKL expression in osteoblasts [52,53]. IL-17A, IL-17F, d and IL-22 are Th17 signature cytokines, and their receptors are expressed in osteoclasts, synoviocytes, chondrocytes, and osteoblasts. Treg is a subset of Th cells with immunosuppressive properties and known to ameliorate inflammation. Tregs also suppress osteoclast differentiation and bone resorption, independent of their antiinflammatory effect [31].

7  Bone homeostasis and ILC As described above, ILCs play essential roles in the immune system [54,55]. ILCs regulate murine and human periodontitis and alveolar bone loss [56,57]. Experimental gut inflammation was shown to activate NF-κB, with ILC1s and ILC3s enriched during the inflammation associated with bone loss in IBD [58]. ILC3s are located at the tendon-bone junction in patients with PsA [59]. ILC3s express IL-17A and stimulate osteoclast function via Wnt signaling [60]. ILC2s are implicated in the initiation and resolution of arthritis as mentioned above [29,34]. Stier et al. reported that injection of IL-33 or the administration of pulmonary fungal allergen mobilized ILC2 progenitors to exit the bone marrow [61]. To further investigate the effect of ILC2s on bone in steady-state bone homeostasis, we focused on the association between ILC2s and osteoclast differentiation [41] (Fig.  1). By in  vitro co-culturing of bone marrow-­ derived macrophages (BMMs) with sorted and expanded ILC2s, RANKL-induced osteoclast differentiation was markedly suppressed, and the bone-resorbing ability decreased in a dose-­ dependent manner. Histological analysis revealed that ILC2s were localized in the vicinity of osteoclasts in bone tissues. Tie2creRORafl/fl mice, which lack ILC2s, exhibited reduced bone volume due to the increased number of osteoclasts, suggesting that ILC2s negatively regulate osteoclast formation. The transfer of ILC2s affects T-cell distribution, suggesting the possibility of an association with T cells and ILC2-mediated bone homeostasis. The additive effect of ILC2s was investigated by using a light-sheet microscope, which enabled us to visualize and analyze three-dimensional (3D) structures [41]. An adoptive transfer of sorted and expanded ILC2s to wild-type mice showed the migration of the transferred ILC2s into the bone in association with a decreased number of osteoclasts. In addition to the physiological role of ILC2s on bone homeostasis, they have an effect on bone in pathological conditions, such as osteoporosis. The number of ILC2s was slightly decreased in ovariectomized mice with no significant difference. When sorted and expanded ILC2s were adoptively transferred to ovariectomized mice, bone volume was increased with a decreased number of osteoclasts. Interestingly, the effect of ILC2 transfer was not observed using IL-4/IL-13 deficient-ILC2s, indicating that bone anabolic effects of ILC2 were mainly caused by IL-4 and IL-13 produced by ILC2s. In vitro co-culture assays of sorted ILC2 and RANKL-induced osteoclasts showed a decreased number of multinucleated osteoclasts, whereas this reduction in osteoclasts was rescued by the addition of IL-4− IL-13− ILC2s [41]. The supernatant media collected from the osteoclast culture with ILC2s, suppressed the number of mature osteoclasts. Therefore, the effect of ILC2s on osteoclast differentiation was considered to be mediated by soluble factors generated by ILC2s. The adoptive transfer of ILC2s increased the number of Tregs, which was not observed by the transfer of IL-4/IL-13-deleted ILC2s, suggesting a direct association between ILC2s and Tregs, as previously demonstrated [29]. The osteoclast-related gene

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c­ athepsin K was downregulated by the addition of ILC2s, and co-culturing with IL-4− IL13− ILC2s inhibited this. IL-4/IL-13 signaling was transduced by the downstream molecule STAT6 [62]. STAT6-knockout BMMs differentiated into mature osteoclasts more efficiently than wild type BMMs even in the presence of ILC2s. Based on these findings, it could be considered that ILC2s negatively regulate osteoclast differentiation by the IL-4/IL-13 they secrete, and by transducing STAT6 signaling in osteoclasts.

8  Conclusion In summary, we reviewed the role of ILCs in arthritis and bone homeostasis, mainly focusing on ILC2s. ILCs secrete effective cytokines as synergistic effectors and influence the progress of arthritis and bone homeostasis. However, since there is complex plasticity in the immune system, to precise understanding of the regulatory mechanisms of bone homeostasis by the immune cells still remains elusive. Further immunological studies will help to understand this intricate mechanism.

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27 Arboviruses (Alphavirus) related to autoimmune rheumatic diseases: Triggers and possible therapeutic interventions Jean Moisés Ferreiraa,b,c,⁎, Jean Carlos Vencioneck Dutrab, Bárbara Rayssa Correia dos Santosc, Edilson Leite de Mourac, Ithallo Sathio Bessoni Tanabec, Ana Caroline Melo dos Santosc, José Luiz de Lima Filhoa, and Elaine Virgínia Martins de Souza Figueiredoc a

Keizo Asami-LIKA Immunopathology Laboratory, Center for Biosciences, Federal University of Pernambuco (UFPE), Recife, Pernambuco, Brazil, bSecretary of State for Education Espírito Santo (SEDU), Vitória, Espírito Santo, Brazil, cLaboratory of Molecular Biology and Gene Expression—LABMEG, Federal University of Alagoas (UFAL)—Campus Arapiraca, Arapiraca, Alagoas, Brazil ⁎ Corresponding author

Abstract The relationship between rheumatic autoimmune diseases and alphaviruses infections is a theme already present in the literature that raises a series of questions, whose answers are still not easy to understand. Hypotheses that associate autoimmune diseases such as rheumatoid arthritis (RA) in patients after infection by alphavirus are reinforced by comparative results of cellular responses, profile of circulating cytokines, reported cases, in addition to predictive studies. In this way, we present a compilation of this information that approximates the infections of chikungunya virus (CHIKV), O’nyong-nyong virus (ONNV), Ross River virus (RRV), Barmah Forest virus (BFV), Mayaro virus (MAYV), and Sindbis virus (SINV) with the particularities seen in rheumatic autoimmune diseases like RA. However, all considerations about arthritogenic alphaviruses must be taken with care, and generalizations must be avoided in order to avoid speculation.

Translational Autoimmunity, Vol. 6 https://doi.org/10.1016/B978-0-323-85831-1.00027-9

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Copyright © 2023 Elsevier Inc. All rights reserved.



27.  Arboviruses (Alphavirus) related to autoimmune rheumatic diseases

Keywords Mimicry hypothesis, Arboviruses, Rheumatoid arthritis, Immunology, Cytokines

1  Introduction Alphaviruses are known as arboviruses (ARthropode + BOrn + Viruses) [1] capable of infecting humans and animals and inducing acute diseases, with disabling polyarthralgia and polyarthritis as the main symptoms, with variable recovery phases [2]. The persistence of symptoms of chronic arthritis may be related to the persistence of viral RNA or its products in cells/tissues in which there is viral tropism (such as synovial cells and macrophages of joints and bones), with consequent accumulation of inflammatory mediators such as interleukin (IL)-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) [3–6]. In addition, concern has grown with infectious agents such as alphaviruses since publications from the last decade have hypothesized the emergence of chronic rheumatic diseases induced by viral infections [7]. Among alphaviruses with arthritic ability, viruses with the ability to spread in different populations and the most relevant to human health are the chikungunya virus (CHIKV), O’nyong-nyong virus (ONNV), Ross River virus (RRV), Barmah Forest virus (BFV), Mayaro virus (MAYV), and Sindbis virus (SINV) [7–9]. While alphaviruses are a growing concern considering the high number of infected patients, further concerns about their association with autoimmune diseases has grown, as autoimmune diseases are a heterogeneous group of diseases that already affect about 5% of the world population [10,11]. Autoimmune rheumatic diseases (ARDs) are defined as a set of diseases that affect connective tissues, causing significant damage to the joints and periarticular tissues such as muscles, bones, ligaments, and tendons. ARDs are generally chronic, causing pain, stiffness, and physical disability [12,13]. There are more than 100 rheumatic diseases, which correspond quantitatively to the largest group of known autoimmune diseases with a large number of patients worldwide [14]. Therefore, extensive studies are focused on ARDs with the aim of understanding the immunopathology, finding promising treatment options, and improving patients’ quality of life [15,16]. Although autoimmune diseases are clinically distinct and complex, many of them have similar immunopathological mechanisms and risk factors [10]. The triggering factors are not yet clear, but it is known that aspects related to the patient’s genetics (and its resulting proteasome), environmental factors, and chronic inflammatory immune responses may be decisive for disease development [14]. However, the hypothesis of molecular mimicry can shed light on the triggers of autoimmune diseases. The molecular mimicry hypothesis assumes that a pathogenic microorganism produces structurally, antigenically, and functionally similar (homologous) molecules to those of the host. Based on these homologous structures, the hypothesis raises questions about the relationship between molecules synthesized by microorganisms and autoimmune diseases [17]. Bacteria and viruses are of the environmental factors, and their entry into the host’s body induces formation of antibodies capable of recognizing such infectious agents; however, this process can also provide the opportunity for immunological recognition of autoantigens, which are homologous to peptides present in such viruses and bacteria [17–19].

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Thus, recognition of patient’s autoantigens by antibodies causes chronic inflammatory responses, contributing to the onset of autoimmune diseases [20,21]. In this context, it is important to emphasize that infection by a single agent is not sufficient to generate any chronic inflammatory mechanism because, even if a large part of the world population is infected by such agents, not all infected individuals develop rheumatic diseases, while it is proposed that the hosts must be genetically susceptible [17]. The literature describes several genetic polymorphisms, contributing to susceptibility to infections [22–25]. Genetic polymorphisms are defined as variations that occur in genes, with single nucleotide polymorphisms (SNPs) being the most common, representing the majority of these variations [26,27]. However, a single variant nucleotide is capable of altering the final protein conformation after the gene expression [24,28]. It is important to note that cell recognition protein genes can be affected by polymorphisms, exhibiting structural variations and, consequently, variations in their binding and recognition sites, as in human leukocyte antigen (HLA) [24,28,29]. As a consequence of polymorphic variations in genes of recognition molecules, certain proteins such as HLA may exhibit greater or lesser interaction of their recognition sites and binding with specific pathogens [28,29]. Studies such as those carried out by Hogeboone [18] and Venigalla [30] demonstrated a series of microorganisms capable of binding certain variations of HLA-DRs (highly polymorphic glycoproteins found on the surface of antigen presenting cells (APCs)) [18,19,30]. However, proteins of these microorganisms that are recognized by HLA-DR molecules have high homology with several structural and nonstructural human proteins [18,19,30]. In autoimmune rheumatic diseases, including rheumatoid arthritis (RA), effective antibodies against the host’s proteins may be found in patients. Among these antibodies, those targeting collagen II (CII) are found in the joints of RA patients [31,32]. Following prediction analysis, CII is able to bind to HLA-DR, a molecule that has been associated with RA; in addition, HLA-DR show strong homology with capsid proteins of a series of alphaviruses. Another 11 human proteins related to RA have 100% homology with conserved regions of alphaviruses structural polyproteins [30]. Likewise, there are 17 other human proteins related to RA, with at least 75% homology with conserved regions of alphaviruses structural polyproteins [30]. Thus, it is plausible that HLA-DR molecules may recognize both proteins and then effectively initiate immune responses against both. The immune responses in autoimmune diseases and against viral infections can be characterized by the activation, differentiation, and migration of cells, which when becoming effectors, produce antibodies and release cytokines and chemokines. Cytokines are the main tools in the control of immune reactions in the immune system [33]. The profile of cytokines released in RA patients is reasonably similar to the profiles observed in experimental conditions with infections induced by certain alphaviruses [3,7,34]. The characterization of these molecular profiles of both manifestations is important, as it can help to elucidate the relationship between alphavirus infections and autoimmune rheumatic diseases such as RA, in addition to helping to understand the real contribution of the molecular mimicry hypothesis in this topic. This clarification may also contribute to the development of appropriate treatment strategies for practical therapeutic actions. Therapeutic strategies for RA treatment could be based on the profile of cytokines observed in patients [35–41], making the cytokine profile a relevant key to achieve these therapeutic strategies.

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In summary, with respect to the current evidence, alphavirus infections besides the host’s genome variations can result in an inflammatory immune response and development of autoimmune rheumatic diseases such as RA [18,30,34]. In this process, the importance of analyzing cytokine profiles and the participation of autoreactive cells such as B and T cells is evident, as they are involved in the production of cytokines and antibodies [17]. In this work, the objective was to synthesize the similarities between the immune response mediated against specific alphaviruses and autoimmune rheumatic diseases. These similarities have been investigated in the literature, looking for the genetic profile of patients, the profile of cytokines and chemokines, and the immune response by activating effector cells. However, understanding the link between alphavirus infections and autoimmune rheumatic diseases can be difficult since comparisons in the literature are scarce and the link between infection and RA remains unclear. These data open a discussion for the triggers of these diseases through these viral infections.

1.1  Alphavirus overview Alphavirus genus, belonging to the Togaviridae family, possesses a single stranded RNA genome of approximately 11,000 base pairs in length. Genes that encode nonstructural proteins (nsP1, nsP2, nsP3, and nsP4), responsible for the replication of the genetic material and mRNA transcription, are located in the 5′ region of the viral genome. The 3′ region contains the genes encoding the structural proteins that form the capsid (C) and the envelope (E1 and E2). The virion has a dimension of 40–50 nm in diameter, containing an icosahedral nucleocapsid surrounded by an envelope (lipid bilayer and E1 and E2 proteins) [42,43]. The Togaviridae family draws attention to the symptoms that may vary between infected patients and the types of infectious viruses. Alphaviruses may induce severe acute encephalitis in patients from chronic arthralgia. Arthralgia resulting from these infections may last for weeks or months, even after the resolution of the acute symptoms of the infection [44]. The pathogenesis of alphaviruses occurs mainly through the inoculation of the virus by the mosquito bite, where the viral particles spread through the skin into the bloodstream, reaching different organs such as the liver, spleen, and lymph nodes. After inoculating the virus with the bite, the viral particles penetrate the cell by binding to receptors such as Mxra8 [45,46]. During replication of the single-stranded RNA genome, pathogen associated molecular patterns (PAMPs) (viral RNA) are accumulated within the cell, causing the recognition of the invading agent through pattern recognition receptors (PRRs), which include the Toll-like receptors (TLR3, TLR7, and TLR8) and cytosolic receptors, such as retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs). This recognition activates transcription factors that promote the expression of inflammatory factors and antiviral cytokines, such as the interferon family (IFNs) [47]. Type I IFNs (IFN-α and β) play an important role in the defense of the host, due to their antiviral activity. This response is essential in the early elimination of alphaviruses [48]. In the innate immune response against alphaviruses, infiltration of monocytes/macrophages and natural killer (NK) cells occurs [49]. Infected macrophages secrete inflammatory mediators, such as IL-8, IFN-γ, and monocyte chemoattractant protein-1 (MCP-1), which

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stimulate the recruitment and differentiation of monocytes in the blood [50]. During the infection, activation of the complement system may also occur, which contributes to opsonization and recruitment/activation of leukocytes [51,52]. After activation of the adaptive immune system, infiltration of CD4+ and CD8+ T lymphocytes occurs.

2  Chikungunya virus (CHIKV) 2.1  General aspects The Chikungunya virus (CHIKV) is currently one of the most well-known members of Alphavirus genus, belonging to the Togaviridae family [53,54]. This virus has become a global concern after its resurgence and recent distribution around the globe [24,55,56]. CHIKV can be transmitted through the bite of the Aedes mosquitoes, triggering Chikungunya fever. Virus infections and Chikungunya fever disease occur endemically in Asia, Africa, and the Indian subcontinent. However, in 2005, after an outbreak on the Indian Ocean islands, several consecutive outbreaks occurred around the world. Currently, more than 60 countries in Africa, America, Asia, and Europe report cases of the disease [57].

2.2  Clinical manifestations of CHIKV infection CHIKV causes a self-limiting disease called Chikungunya fever, characterized by high fever, headache, myalgia, rash, and arthralgia that may persist for years in some patients [58–60]. Cases of chronic joint pain, polyarthralgia, and arthritis-like syndromes have been reported by patients after CHIKV infection worldwide [61]. During the acute phase of the disease, viral replication occurs, followed by an inflammatory response in the target tissues, characterized by large infiltration of lymphocytes, NK cells, neutrophils, and macrophages, with macrophages being the main cell observed in the innate immune response against alphaviruses infections. Increased levels of proinflammatory cytokines and chemokines at the site of infection and in the plasma are also associated with myositis and arthralgia/arthritis [62].

2.3  Immune response against CHIKV and rheumatoid arthritis During the chronic phase of Chikungunya disease, the patient may develop a condition that resembles some diseases such as RA, spondyloarthritis, and fibromyalgia [63]. Interestingly, Bouquillard and Combe report a series of 21 cases of patients who developed RA after CHIKV infection [64]. In CHIKV infection, monocytes appear to play an important role in the pathology involving the joints. Tanabe et al. describe that the internal lining of synovial joints is formed by synovial cells similar to macrophages and fibroblast-like synoviocytes (FLS), the latter of which were susceptible to CHIKV infection in vitro [65] and are related to the pathogenesis of RA. The cultivation of the supernatant of these synoviocytes induces the migration of monocytes and the differentiation of macrophages in cells similar to osteoclasts, producing mediators of arthritis; in addition, bone homeostasis involves bone-forming osteoblasts (OB) and bone resorption osteoclasts (OC). CHIKV infects OB cells, however, expressing RANKL and OPG (osteoprotegerin), which are molecules

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involved in the bone remodeling process. In addition, the increase in the RANKL/OPG ratio supports the formation of osteoclasts, leading to bone damage and, consequently, the development of arthritis [61,62,66–68]. NK cells are activated during the acute phase of CHIKV and cause the death of the infected cells by lysis, in addition to a strong production of cytokines, mainly by IFN-γ. NK cells are also an important source of IFN-γ, which may contribute to inflammation in RA, promoting B-cell activation and class switching and promoting dendritic cell maturation, which may elevate RA chronicity [8,69,70]. In addition to IFN-γ, studies that analyzed cytokines and chemokines levels in the serum samples from acute patients infected with CHIKV has also shown an increase in IL-4, IL-6, IL-7, IL-10, IL-8, IL-2Rα, IL-1Rα, CCL2/MCP-1, anaphylatoxin C5a, IFN-α, G-CSF, CXCL10/ IP-10, and CXCL9/MIG levels [65,71]. IL-6, commonly known as pleiotropic cytokine, has a wide range of biological activities in several target cells and its elevated levels have been associated with persistent arthralgia induced by CHIKV infection. Similarly, the levels of IL-6 observed in serum and synovial fluid in patients were correlated with RA, playing pathological roles in disease pathophysiology [72,73]. Recent works have shown that intense viremia is associated with the activation of type I interferon and IL-6 in the host [74,75]. Studies correlating high viral load and levels of IL-6, IL-12, IL-1RA, IFN-α, CXCL10/IP-10, and CCL2/MCP-1 have shown a positive correlation [73,76,77]. These findings suggest that cytokine expression in serum and viral load are correlated with chronic arthralgia (chronicity) in chikungunya disease, with viral load being elevated in the viremic phase and other factors, such as age, identified as risk factors for the development of chronic arthralgia [74]. Chronic inflammation caused by CHIKV infection consequently results in severe tissue damage. More critically, chronic inflammation has been identified as an important risk factor for the development of inflammatory/autoimmune diseases, such as RA [14]. The similarities between CHIKV infection and RA inflammatory process may be explained by similar genetic expression. Nakaya and collaborators [78] performed in vivo experiments and showed significant high overlap in the genes expressed in the CHIKV arthritis model and in RA. In addition, the findings by Nakaya et al. also suggest that overlapping agreement increased with RA severity. Interestingly, this study reveals in the biochemical pathway analysis an overlap between the spread of these arthritis and a range of different inflammatory processes [78]. Although the profile of cytokines during infection may have a predictive role for future chronic arthritis, this remains unclear since the robust cytokine response during acute infection was correlated with a lower incidence of chronic joint pain [79]. It is also suggested that lower levels of TNF-α, IL-2, IL-4, and IL-13 during acute infection were predictive of chronic joint pain. Such a response is necessary for the elimination of the virus, especially TNF-α. In addition, cytokines related to immune tolerance during acute infection may have a protective role for the pathogenesis of chronic arthritis [61,62,79]. This clinical condition of chronic arthritis is often associated with the persistence presence of anti-CHIKV IgM and IgG antibodies [80]. Whereas, in RA, the clinical condition is usually associated with anticollagen antibodies.

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3  O’nyong-nyong virus (ONNV) 3.1  General aspects The O’nyong-nyong virus (ONNV) is a neglected arbovirus that has triggered epidemics in African populations since 1950 [81]. Transmission occurs by anopheline mosquitoes, and humans are possibly a necessary host for viral replication during epidemics [82]. Although ONNV has the potential to cause important outbreaks, this virus has been poorly studied, which may be related to the fact that it presents the same vectors as the etiologic agent of malaria [83]. ONNV cases are commonly underreported or the clinic is confused with other diseases with similar symptoms, such as infection mediated by the Chikungunya virus [81]. In addition, the Mxra8 receptor has been identified as an important mediator for the entry of ONNV into eukaryotic cells; the same receptor used by other alphaviruses to access host cell machinery, as in the Chikungunya and Ross River viruses [84].

3.2  Clinical manifestations of ONNV infection Patients affected by ONNV develop a combination of symptoms with arthritogenic characteristics that include symmetrical polyarthralgia, lymphadenopathy in the cervical region, low fever, rash, severe pain during the infection period, and few occurrences of nose and/ or gingival bleeding [85]. However, the pathogenesis involved in the course of the infection remained unclear, requiring avid investigations [83].

3.3  Immune response against ONNV and rheumatoid arthritis Few studies on the immune response against ONNV are described in the literature, mainly evaluating human beings. Recently, an in vivo study on mice has indicated that arthritogenic symptoms caused by ONNV infection are closely related to CD4+ T cells in joints [81]. The infiltration of CD4+ T cells into synovial tissues in RA patients plays an important role in the development of RA related to ONNV infection [86]. The activation of CD4+ T cells requires proper antigen presentation by other cells. In both ONNV infection and RA, infiltration of CD4+ cells is induced by the presentation of proteins that are structurally similar in silico (CII and alpha-viral polyproteins); in other words, the similar immunological manifestations might be the result of cross-reactivity [18,30]. Research suggests that neutralizing antibodies to other alphaviruses are competent to protect against ONNV infection in vivo [87] potentially due to structural similarities in antigens [30,43]. In this way, the activation of CD4+ T cells could occur through the recognition of other infectious alphaviruses. In RA patients, the levels of IFN-α and IFN-β transcripts are elevated in the peripheral blood compared to the healthy group. An IFN type I signature was suggested in a group of patients with RA, characterized by a distinct biomolecular phenotype that shows increased activity of the innate defense system, coagulation and complement cascades, and fatty acid metabolism [88].

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Added to that, IFN-α and IFN-β (type I interferons) are commonly observed in alphavirus infections and immune response, as observed in ONNV infection [83,88], indicating an overlap between the immune responses of RA patients and alphavirus infected patients.

4  Ross River virus (RRV) 4.1  General aspects Ross River virus (RRV) causes Ross River fever [89] and is considered the most common arbovirus infection in Australia, with approximately 5000 cases reported annually [90]. The main route of RRV transmission is through the bite of the vector, the infected mosquito. There are more than 40 species with vectorial capacity to transmit RRV, with emphasis on Aedes vigilax, Aedes camptorhynchus, Aedes notoscriptus, and Culex annulirostris [91,92].

4.2  Clinical manifestations of RRV infection After the bite of the RRV-infected mosquito, the human host may remain asymptomatic or develop the first symptoms of the disease after an incubation period between 7 and 9 days, which generally include fever, arthralgia, myalgia, maculopapular rash, headache, and fatigue. Other symptoms such as nausea, lymphadenopathy, eye pain, and diarrhea appear less frequently [50]. In some rare cases, the infection may expand and cause splenomegaly [93], glomerulonephritis [94], hematuria [95], meningitis [96], and encephalitis [97]. No case of lethality associated with RRV infection was recorded. The most prominent clinical condition in RRV infection is arthritis, in which patients can develop from monoarthritis to polyarthritis. Peripheral joints such as knees, ankles, wrists, and fingers are the most affected regions [50]. Previous studies have shown an association between osteoarthritis and exacerbated RRV infection, in which changes in the bone absorption pathway can increase osteoclastogenesis and worsen arthralgia after infection [98,99].

4.3  Immune response against RRV and rheumatoid arthritis In the literature, there are few studies that associate RA with RRV infection. Despite this, historically, it is reported that 8 patients developed RA after the RRV or Barmah Forest virus infection [100]. Additionally, a study detected anticollagen antibodies in individuals infected with RRV [101]. In autoimmune diseases such as RA, a high level of macrophage migration inhibitory factor (MIF) in the patient’s synovial fluid and tissue samples can be found, which potentially linked to the severity of the disease [102]. MIF is a proinflammatory cytokine that plays an important role in monocyte/macrophage chemotaxis and activation [103]. Considering the similarities between RA and Alphavirus-induced arthritis, a study using an animal model evaluated the role of MIF in RRV-induced arthritis. The authors observed that wild mice (normal for MIF expression) infected with RRV developed the severe form of the disease. The severity of the disease was associated with high expression of MIF in serum and tissues. Also, according to the authors, the high expression of MIF was able to induce exacerbated

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inflammation and tissue damage. On the other hand, in experimental conditions, mice with MIF deficiency (MIF−/−) and infected with RRV developed a mild form of the disease, with a reduction in inflammatory infiltrates, suggesting that MIF plays an important role in the development of the disease [104]. Macrophages are reported as the main cells responsible for the immunopathology of inflammation caused by RRV and undergo chemoattraction due to the production of MIF. These cells showed an M2-like (immunosuppressive) phenotype in the rheumatic symptoms phase of the infection, demonstrating that damage to synovial tissue can induce the differentiation of macrophages by an alternative route [50]. M2 macrophage polarization appears to be uncommon in RA patients [105]; however, even during a common RRV infection, the production of cytokines for immune suppression must be mediated by eliminating the virus. Nevertheless, in RA, due to the continuous process of antibody recognition, the polarization of macrophages to M2 and immune suppression are hampered. Hence, similar to what observed in the RA, the inflammatory process probably will be persistent if RRV continues in the synovial tissue. In summary, to point out similarities between RA and RRV infection, the critical involvement of macrophages in persistent inflammation, the central participation of inflammatory mediators such as MIF, and the production of some cytokines are reported through the literature [104,106]. However, it is important to note that, to date, there is no concrete evidence in the literature to indicate that RRV infection predisposes to autoimmune joint diseases.

5  Barmah Forest virus (BFV) 5.1  General aspects Barmah Forest virus (BFV) is transmitted by Culex annulirostris, Aedes normanensis, Aedes notoscriptus, and Aedes vigilax mosquitoes [107], being the second most prevalent virus in Australia, behind RRV [107–109].

5.2  Clinical manifestations of BFV infection In general, BFV infection shows symptoms similar to those of RRV infection, including fever, rash, and joint pain; meanwhile, skin rash is the most common symptom reported in BFV infection [107–109]. In BFV infection, the fever resolves within a week, while the pain in the muscles and joints may last for more than 6 months [110]. There is no specific treatment for the disease; thus, the main focus is to relieve the symptoms [111].

5.3  Immune response against BFV and rheumatoid arthritis Although BFV may replicate more effectively in the tissues of the joints and cause arthritogenic symptoms [112], following the perspective of molecular mimicry, it can be one of the alphaviruses with the least capacity to trigger RA. Certain HLA genotypes, including the HLA-DR4 haplotype, have already been associated with a predisposition to rheumatic diseases such as RA [18]. However, BFV was not

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a­ ssociated with a high rate of binding to the high-risk allele HLA-DR4 in predictive studies, which could suggest the absence of a relationship between BFV infection as a possible trigger of RA, being verified by the low frequency of HLA-DR4 alleles in the Australian population [18]. Since a moderate rate of HLA-DR4 is observed in these population [18], it is possible that the virus has not triggered molecular mimicry. However, it is important to highlight that RA appears to be more common in individuals over 75 years of age in Australia [113], which may be associated with the time of exposure to environmental factors such as BFV infection. The most important proinflammatory cytokines in the immune response of alphaviruses are TNF-α and IL-6 [3]. An in vivo study showed an increase in the level of TNF-α and IL-6 in BFV infection, in addition to a significant increase in the levels of IL-1β and IFN-γ transcripts, where IFN-γ has inflammatory functions and is recognized as the main M1 macrophage differentiator [112]. However, TNF-α and IL-6 are also two of the main inflammatory mediators in RA, which chronically induce osteoclast activity and cause severe bone erosion, both focally (in the cartilage–pannus junctions) and diffusely [14,37,72]. Although these two cytokines are involved in several inflammatory processes, their physiological actions in BFV infection and RA are related to the induction of bone mass loss [3,14,37,72].

6  Mayaro virus (MAYV) 6.1  General aspects Three genotypes of Mayaro virus (MAYV) are currently recognized, namely D (dispersed), L (limited), and N (new) [114–118]. Serological indications and viral isolations in birds show that this virus might present from the south of the USA (Louisiana) to the Midwest of Brazil (Mato Grosso do Sul), suggesting an extensive coverage area of MAYV [119–121]. The transmission of MAYV to humans is described in the literature by means of bites from the Haemagogus janthinomys mosquito. This species of mosquito is rarely described outside of forests and is commonly found infected with the virus; therefore, they are considered the most important vectors for MAYV [122–124]. However, laboratory tests report that Ae. aegypti and Ae. albopictus may be able to spread the infection since both mosquitoes have equal spread competence and may act as a potential vector for an urban MAYV cycle [118,125,126]. MAYV may infect a wide variety of vertebrate species, while it is documented as an unusual infection in human, where the regular form of virus infection is related to the wild cycle of MAYV [6,127]. In contrast, MAYV infection in humans is observed in several countries, such as Bolivia, Peru, Venezuela, Brazil, Trinidad and Tobago, Ecuador, French Guiana, Colombia, Guatemala, Ecuador, Honduras, Guyana, Panama, Suriname, and Haiti [128,129].

6.2  Clinical manifestations of MAYV infection The symptoms of Mayaro Fever are the general symptoms of infections, including fever, fatigue, headache, retro-orbital pain, myalgia, joint swelling, polyarthritis, polyarthralgia, and joint stiffness (fingers, feet, hands, joints, and ankles in general), and rash which occurs in more than 40% of cases, appearing before, simultaneously, or after symptoms of arthralgia.

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Symptoms such as rash and arthralgia last 7–10 days. Hemorrhage cases are recorded, but without lethality [6,130–135]. However, after the acute phase and by the resolution of fever, some symptoms may last indefinitely, characterizing a chronic phase that occurs in up to 50% of symptomatic infected patients and associated with a long-term disabling polyarthralgia [114,116,130,131,136–138].

6.3  Immune response against MAYV and rheumatoid arthritis Few studies are available on the immune response of MAYV and it remains largely unknown. In vitro and in vivo assays are the most recent sources of knowledge about the response induced against MAYV [139–143]. Studies in humans infected with MAYV are limited to profiling of cytokines in the acute and chronic phases of the disease [133,137]. Literature reports suggest that there is an increase in VEGF and IL-12p70 cytokines in the acute phase, while in the chronic phase with rheumatic signs there is an increase in the cytokines IL-6, IL-7, CXCL8/IL-8, IL-13, IL-17, and IFN-γ in the serum of patients [144]. In RA patients, each cytokine may play a different role in disease development. VEGF performs proinflammatory and antiapoptotic roles in the pathogenesis of RA and, in peripheral blood and joint synovium, can promote the enhancement of internal environment, which is beneficial for RA, and has also been used as a serum biomarker [145–147]. On the other hand, IL-12 in RA is associated with proinflammatory responses, supported by macrophages in the pathogenesis of the disease. VEGF is produced by macrophages, dendritic cells (DCs), and granulocytes and is present in the synovial tissue of RA, raising the level of IFN-γ in addition to inducing Th1 differentiation [35]. Monocytes appear attracted to inflamed lesion/synovial stromal cells by CXCL8/IL-8 in RA [148]. IL-6 and CXCL8/IL-8 are highly associated in several studies with RA patients [146,149]. Besides, some chemokines (CCL2/MCP-1, CCL5/RANTES, and CXCL12/SDF-1) enhance the expression of IL-6 and CXCL8/IL-8 in FLS of RA patients [37]. IL-7 is considered an important mediator in RA development [150] and showed a correlations with IL-37 in RA patients [41]. High level of CCL2, CXCL10, IL-6, STAT4, and IL-17 mediators are also present in patients with RA [18]. In this context, IL-13 and IL-4 may have a modest stimulatory effect on interleukins in RA patients, including IL-1 and IL-17, which in turn may induce IL-6 production and inhibit the leukemia inhibitory factor. In addition, IL-13 is a cytokine from Th2 profile, which can be released as an immunomodulatory response to the Th1 profile produced by T cells present in the synovium [151]. Elevated levels of IL-17 have been found in chronic inflammation as in psoriasis, multiple sclerosis (MS), and RA (resistant to anti-TNF therapy); it also shows potential role in periodontitis and muscle inflammation [152]. IL-4 and IL-13 downregulates IL-17 synthesis in T-cell-rich synovial tissues on RA. Supporting these findings, an SNP in IL4R gene was associated with the absence of the Th17 inhibition, which leads to the increase of Th17, enhancing the activity and progression of early RA [152–154]. IFN-γ is a Th1 cytokine response, and the cytokines of this group are essential to promote the activation of cellular immunity. In RA, the role of IFN-γ have been controversial since it can contribute to tissue damage [8]. Miao et al. [155] suggest an immunomodulation of IFN-γ in RA patient status, which is followed by the significantly increased circulating

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CD4+ CD161+ IL-17+ IFN-γ T cells in comparison between patients with RA disease in active and low status. However, some research have demonstrated a beneficial positive role of IFN-γ both in vivo and in vitro. IFN-γ can promotes significant inhibition of the basal HTRA1 (high temperature requirement A1), which a protease involved with RA while this cytokine can also interfere with the LPS-induced expression in fibroblasts and macrophages, which are two major cells for RA progression [156].

7  Sindbis virus (SINV) 7.1  General aspects In 1952, in the district of Sindbis, Northern Cairo, Egypt, an epidemic of febrile disease with rash and arthritis was observed. By means of biochemical techniques, a virus was isolated from mosquitoes and serological tests suggested a new circulating virus as the causative agent of the epidemic, the Sindbis virus (SINV) [157]. Since its discovery, a number of outbreaks of SINV infection have been reported in South Africa; however, these outbreaks have not been observed in all countries on the African continent. Between 1963 and 1974, the largest outbreaks of SINV and its spread to Northern Europe occurred concurrently, with antibodies to SINV infection being detected in children and birds [158–160]. SINV is classified as a zoonosis, present birds as amplifying hosts and ornithophilic mosquitoes as vectors, while human hosts become accidentally infected [161]. Over time, SINV has spread across the globe and today is widely distributed in tropical, subtropical, and temperate zones of Africa, Asia, Southern Asia, and Europe, with five genotypes [162].

7.2  Clinical manifestations of SINV infection The first symptoms of dengue infection usually appear 4 days after the mosquito bite, ranging from 2 to 18 days, and about 2 days after the onset of symptoms, patients seek medical attention [163,164]. SINV causes a febrile illness and symptoms developed by patients include arthritis, arthralgia, rash, encephalomyelitis and malaise [165–167]. Acute phase symptoms usually last 2 weeks, with relief from general symptoms and rash [168]. In addition, 6–8 months after infection, approximately 39% of patients develop chronic arthralgia and, as an aggravating factor, infections transmitted by SINV vectors can spread quickly, reaching new areas and causing the acute and/or chronic forms of the disease [169].

7.3  Immune response against SINV and rheumatoid arthritis Alphavirus infections can present similar clinical conditions to each other, which has stimulated the development of studies dealing with pathology, clinical presentation, epidemiology, and genetic susceptibility to SINV. Sane et al. [170] suggest associations between HLAs and autoantibodies in SINV-induced arthritis. The authors investigated 49 patients with symptomatic SINV infection confirmed serologically. Patients were followed up after acute infection and the study showed an association between symptomatic SINV infection and the HLA

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class II DRB1*01 allele, an allele related to the development of RA [171]. Sane et al. [170] also suggest that autoantibody titers are elevated in serum of patients, even 3 years after an infection, and conclude that SINV induced arthritis exhibits similar features and/or predisposing genetic determinants with autoimmune diseases. There are few studies on SINV-induced arthralgia/arthritis. Thus, to discuss and understand the pathogenesis of SINV, it is common to compare SINV infection with alphaviruses related to more conclusive information in the literature, such as CHIKV and RRV. In infected patients, virus replication may induce direct cell damage. In addition, the infection can lead to injuries to the target tissues by indirect immune mediation. Thus, after SINV infection, the combination of these factors in target tissues leads to the arthritogenic manifestations in patients [158]. Similar to that seen in other alphaviruses, after inoculation via mosquito bite, the virus spread to the liver, spleen, muscle, lymph nodes, and connective tissues around the bones and joints through the circulation. During SINV replication, an inflammatory response occurs with infiltration of lymphocytes, natural killer cells, neutrophils, and macrophages in the target tissues. Furthermore, during the inflammatory process there is also a positive regulation of various proinflammatory cytokines and chemokines [3,6,172]. Macrophages are reported as crucial appeals for the development of arthritis. Assunção‐ Mirandal and collaborators [173] demonstrate that by SINV infection, the activation of macrophage occurs, with subsequently release of macrophage migration inhibitor factor (MIF). This process induces the expression and secretion of TNF-α, IL-1β, and IL-6, as well as matrix metalloproteinases (MMPs) 1 and 3, compounds that may be related to the articular damage observed in SINV disease. In addition, the authors found that the action of blocking MIF showed that cytokine secretion and MMP expression are regulated by MIF throughout the infection, which suggests this cytokine acts in an autocrine and paracrine manner, upstream of the macrophage activation. Regardless of the different etiologies of infectious and autoimmune arthritides, these are the most important similarities between macrophage responses in SINV infection and RA.

8  Interface of possible treatments for alphaviruses in rheumatoid arthritis There is no specific treatment for RA. However, clinical studies have been carried out to find drugs that can assist in the treatment of the disease such as abatacept and infliximab. Secukinumab is a high affinity monoclonal antibody used against IL-17A, a cytokine that has been associated with RA [174]. While abatacept and infliximab have been studied for the treatment of patients who have an inadequate response to methotrexate (MTX). Abatacept is an agent that costimulates T cells and modulates the CD80/CD86:CD28 costimulatory signal necessary for the activation of T cells [175,176] and infliximab is a TNF inhibitor. These drugs are reported to be safe in the treatment of RA [176]. Regarding the chronic symptoms caused by alphaviruses, treatment is based on the use of nonsteroidal antiinflammatory drugs (NSAIDs) or corticosteroids [177]. However, in search of new treatment strategies for rheumatic diseases, we have compiled some studies that seek to treat the symptoms caused by alphaviruses, because the similarities

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in the symptoms of these two conditions can present a shared path for the treatment of the patient and relief symptoms. Recent studies have shown a promising results for chronic symptoms caused by RRV; pentosan sodium polysulfate (PPS) has been shown to significantly decrease inflammatory infiltrates (increasing antiinflammatory cytokines such as IL-10 and decreasing proinflammatory cytokines associated with disease, such as IL-6), and efficiently reduce cartilage damage mice infected with RRV. In addition, it has been shown that the antiinflammatory effect of PPS does not harm the host’s viral “clearance” [106]. Due to the successful results in the first phase of the study, clinical trials in humans are in phase 2 and have surprising results [178]. Another study for the treatment of alphavirus infections is based on the importance of macrophages in the pathogenesis of these infections. Studies have investigated the performance of monocyte recruitment inhibitors as possible therapeutic models for ­alphavirus-induced arthritis. One study demonstrated that mice treated with bindarit, an MCP inhibitor, had mild symptoms, reduced inflammatory cell infiltration, and decreased production of NF-κB and TNF-α, demonstrating a protective mechanism against RRVinduced arthritis [179]. Finally, mice infected with RRV and treated with liposomes containing clodronate (a substance that promotes macrophage depletion) showed a substantial reduction in inflammatory infiltrates in the muscle tissue and ankle joints. This study also showed that mice treated with clodronate induced a drastic reduction in proinflammatory factors, such as TNF-α, IFN-γ, and MCP-1, demonstrating the importance of macrophages in the persistence of rheumatic symptoms [180].

9  Conclusion In summary, evidence supports alphavirus infections are associated with the development of autoimmune rheumatic diseases, such as RA. When the patient is susceptible to the development of RA, relationships with the host’s molecular and immunological mechanisms have been reported such as genetic variations in the HLA locus, pathogen recognition proteins, activation, migration, and recognition of defense cells, and production of immunomodulators such as proinflammatory cytokines. The new and classic similarities in viral infection with long-term disabling arthritis and autoimmune rheumatic disease demonstrate that there are complex immunological factors related to the development and treatment of these diseases. Thus, new research on this topic should shed light on the association between these two conditions.

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28 Rheumatologic manifestations of autoinflammatory diseases ⁎

Kosar Asnaasharia,d and Nima Rezaeib,c,d, a

Department of Pediatrics, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran, bResearch Center for Immunodeficiencies, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran, cDepartment of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran, dNetwork of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran ⁎ Corresponding author

Abstract This chapter reviews some of the most well-known autoinflammatory disorders (AIDs) and depicts their manifestations. AIDs are recently introduced diseases of innate immunity that can affect several organs. The presented AIDs in this chapter are familial Mediterranean fever (FMF), mevalonate kinase deficiency (MKD), cryopyrin-associated periodic syndromes (CAPS), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), and periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome. The aim of this elaboration is to emphasize on the importance of acquaintance with AIDs symptoms so that the genetic analysis is requested instantly and the treatment is initiated as soon as possible.

Keywords Autoinflammatory disorders, Familial Mediterranean fever, FMF, Mevalonate kinase deficiency, MKD, Cryopyrin-associated periodic syndromes, CAPS, Tumor necrosis factor (TNF) receptor-associated periodic syndrome, TRAPS, PFAPA syndrome

Translational Autoimmunity, Vol. 6 https://doi.org/10.1016/B978-0-323-85831-1.00028-0

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28.  Rheumatologic manifestations of autoinflammatory diseases

1  Introduction The discovery of autoinflammatory disorders (AIDs) nearly 20 years ago has opened up the door to a new world in the galaxy of rheumatologic diseases [1]. AIDs are disorders of the innate immune system exhibited by sterile inflammations that can involve several organs; the adaptive immune system and elevated levels of autoantibodies are spared in the pathophysiology of AIDs. Although this is the key difference between autoinflammatory and autoimmune disorders by definition, studies have shown that adaptive immune system plays parts in autoinflammatory disorders’ pathogenesis as well, and that footprints of autoinflammatory disorders can be found sometimes in the entities of autoimmunity and primary deficiencies [2,3]. AIDs can affect several organs and might resemble one another in many presentations. The key to diagnosis of AIDs is to be acquainted with their clinical manifestations. Moreover, genetic testing can be beneficial when in doubt of a certain AID. AIDs can be categorized by different methods; one is to place them in groups of inflammasomopathies, disorders of TNF/NF-κB activity, cytokine signaling disorders, interphrenopathies, and complex autoinflammatory disorders [4]. In this chapter, we intend to explicate some of the most well-known autoinflammatory disorders, namely familial Mediterranean fever (FMF) and mevalonate kinase deficiency (MKD) from the group of pyrin inflammasomopathies, cryopyrin-associated periodic syndromes (CAPS) as an NLRP3 inflammasomopathy, tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) as a disorder of TNF/NF-κB activity, and periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome as a complex autoinflammatory disorder. Management of AIDs proposes complex challenges. Unlike autoimmune diseases, corticosteroids have not shown ample benefit and in some cases might even induce shorter intervals between attacks. Colchicine has proven benefits in treatment of FMF. Targeting the involved cytokines by monoclonal antibodies is an approved method, like administering anakinra and canakinumab (antiinterleukin (IL)-1 antibodies) in case of CAPS, MKD, and TRAPS. Stem cell transplantation has introduced a new horizon in the treatment of AIDs [5]. The present chapter is going to introduce the most prevalent disorders of each group and discuss the manifestations of each one. We hope that our depictions can shed light on the diagnosis of AIDs, leading to proper genetic counseling and minimizing adverse effects due to late initiation of the treatment.

2  Familial Mediterranean fever (FMF) 2.1  Background Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disorder worldwide. It is interesting to note that FMF was first defined at 1945, which was before the discovery of the basics of AIDs [6]. The hallmarks of FMF are recurrent periods of fever, serositis, and arthritis, typically initiating from early childhood [7]. Although most of the patients experience self-remitting attacks, some might have to struggle with a dire complication, amyloidosis, which can induce renal damage and failure of other organs [8].

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FMF is mostly found in Mediterranean and Middle Eastern ethnicities, i.e., Turks, non-­ Ashkenazi Jews, Armenians, Arabs, Iranians, and Kurds. Moreover, FMF cases can be found with a lower prevalence in countries like Greece, Italy, China, North America, and Japan, most probably due to immigration of the ancestor ethnic groups [9,10]. FMF is mostly caused by autosomal recessive mutations in Mediterranean fever gene (MEFV), located on chromosome 16 (16p13.3) [11]. This 10-exon gene encodes the 781 amino acid pyrin (Greek for fever), a cytoskeleton-associated protein, which is expressed in granulocytes, dendritic cells (DCs), monocytes, and synovial, dermal, pleural, and peritoneal fibroblasts. When intrigued, pyrin triggers a multiprotein inflammasome called pyrin inflammasome, leading to the activation of Caspase 1, which then causes an accentuated production of IL-1β and IL-18 [12–15]. This can explain the inflammation in serosa and synovium during FMF attacks. The most recognized mutations of MEFV that encompass FMF pathology are p.M694V, p.V726A, p.M680I, E148Q, and p.M694I, all located on exon 10 except for E148Q, which is located on exon2 [9]. The prevalence of each mutation differs according to the studied population [16].

2.2  Clinical presentation FMF is characterized by self-remitting bouts of fever accompanied by pleuritis, peritonitis, and synovitis. The attacks generally last for about 12–72 h and recur rather unpredictably from every week to several years. Patients tend to be symptom-free between the attacks [17]. They might complain of prodromal symptoms before the onset of an attack, such as nausea, anxiety, irritability, paresthesia, and myalgia [18,19]. Some stimulants can provoke an FMF episode, namely cold exposure, exercise, stress, tiredness, surgery, infection, and menstruation [20]. Inflammatory markers such as leukocyte count and C-reactive protein (CRP) increase during a flare and subside as the flare resolves. Disease onset in normally in the early childhood; however, it can occur after the age of 40 in less than 20% of the cases. The onset can be divided into early (before 18 years) or late (after 18 years). Arthritis, arthralgia, myalgia, and erysipelas-like erythema are more frequent in the early-onset group [21]. Patients with disease onset at less than 2 years old might present with mere fever attacks [22]. As the patients grow older, the episodes are likely to happen in a milder and less frequent pattern.

2.3  Fever Fever is the most common among the constellation of symptoms of FMF. It might be mild to high grade, and can be absent if the patient is on treatment [23]. Fever can rarely be the only manifestation of recurrent attacks in FMF [24].

2.4  Pleuritis About 30% of FMF patients suffer from a unilateral chest pain that exacerbates upon breathing in the course of an attack. In Armenians and Japanese, however, the prevalence of

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pleuritis is higher than arthritis, whose prevalence comes right after peritonitis in most of the reports [25].

2.5  Pericarditis Acute pericarditis, felt as sustained retrosternal chest pain and diagnosed by electrocardiography (ECG) and echocardiography, occurs less frequently than other types of serositis during an FMF episode (about 2%) [21,26]. Cardiac tamponade is rarely observed in the course of FMF [21,27].

2.6  Peritonitis Abdominal pain is a dominant feature of FMF in almost all patients [21]. Unlike pleuritis, this “benign paroxysmal peritonitis”, as described by Siegal [6], starts as a localized event but tends to spread and involve the whole abdomen. The presentation might strongly resemble acute abdomen scenario; abdominal pain, rebound tenderness, rigidity, and decreased bowel sounds might be present [28]. Ileus and constipation are frequent, but diarrhea can also be occasionally noted [29]. Unlike an episode of acute abdomen, the symptoms of FMF peritonitis normally resolve as other presentations of the attack terminate. In rare cases, however, the inflammation in the peritoneal cavity might lead to development of adhesions and thus induce mechanical obstruction [30].

2.7  Musculoskeletal manifestations Affecting more than half of the FMF patients, arthralgia and arthritis are generally found in one or two joints in the setting of an attack, most probably in the large joints of the lower extremities. Joint aspiration demonstrates a sterile inflammatory effusion [31,32]. Although most of the episodes of arthritis resolve without any sequela, some patients might develop chronic arthritis [33]. Myalgia, felt in upper or lower extremities, exertional leg pain, and less frequently protracted febrile myalgia, constitute musculoskeletal manifestations of FMF [34]. Sacroiliitis is a rare association of FMF and the affected patients are mostly negative for HLA-B27 [35]. Patients with musculoskeletal symptoms are more likely to be homozygous for the M694V mutation [31].

2.8  Skin manifestations Erysipelas-like erythema is a characteristic feature of FMF episodes. Appearing as sharp-bordered red patches, it is a cellulitis-resembling lesion, which most commonly appears unilaterally on the dorsum of the foot, over the ankle, or on the extensor surface of the leg. The symptom develops in 2–3 days and resolves spontaneously [17]. Fig.  1 shows Erysipelas-like erythema and painful purpura on the dorsum of the foot of FMF patients, as described by Tufan et al. [32]. Urticaria, Henoch–Schoenlein purpura, Raynaud-like phenomenon, and pyoderma gangronosum are other cutaneous presentations of FMF delineated in the literature [36–39].

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FIG.  1  Cutaneous manifestation of Familial Mediterranean fever. (A) Erysipelas-like erythema and (B) painful purpura on the dorsum of the foot.

2.9  Neurologic manifestations Several neurologic presentations are recorded in association with FMF, some of which appear to be directly related to the disease and its complications [40]. Headache [41,42], seizures [43], optic neuritis [44], and aseptic meningitis [45] are the most commonly described manifestations.

2.10  Amyloidosis The most threatening complication of FMF is amyloidosis. Serum amyloid A is an acute phase reactant whose cleavage leads to formation and deposition of AA amyloid in the tissues, thus provoking diverse manifestations according to the affected organ. Renal complications are often the most prominent features of amyloidosis. The accumulation of protein fibrils in the kidney can lead to proteinuria, nephrotic syndrome, and uremia. FMF amyloidosis can lead to damages in other organs, such as the gastrointestinal (GI) tract, liver, spleen, heart, thyroid, and the uterus [29,46,47]. The incidence of amyloidosis in FMF patients has declined noticeably since the introduction of colchicine, a breakthrough in management of FMF, which prompted milder manifestations during the attacks and longer intervals between them [48].

2.11  Other manifestations Acute scrotal swelling due to inflammation of tunica vaginalis has been described in patients with FMF [49]. As there are increasing numbers of reports being published introducing a novel manifestation in FMF attacks, further investigations need to be conducted to prove the associations.

3  Mevalonate kinase deficiency (MKD) 3.1  Background Mevalonic aciduria/hyperimmunoglobulinemia D and periodic fever syndrome (MA/ HIDS) is generally introduced as a disease spectrum encompassing higher severity (MA) 569



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to lower severity (HIDS). However, since the distinction between these two entities is blur, some prefer to use the term mevalonate kinase deficiency (MKD) to describe the whole spectrum [50]. MKD is an ultra-rare autosomal recessive disease whose pathogenesis is attributable to mutations in MVK gene, which is translated into the protein mevalonate kinase. This protein is an important enzyme in the pathway, which leads to the synthesis of cholesterol and nonsterol isoprenoids. The mutation leads to a certain reduction in the activity of mevalonate kinase, and the level of remaining activity establishes the clinical phenotype. MVK can have a residual activity of up to 15% in HIDS, yet less than 1% residual activity can be found in MA [51].

3.2  Clinical presentation of HIDS phenotype HIDS attacks are typically characterized by fever, abdominal pain, arthritis/arthralgia, skin lesions, adenopathy, and occasionally elevated levels of Immunoglobulin D (> 100 U/mL). In addition to typical attacks, MA patients are usually presented with dysmorphic feature and psychomotor retardation [52,53]. The flares of HIDS usually initiate before 5 years old, typically in infancy [53,54]. They can be triggered by stimulants such as vaccination, stress, trauma, and infection. Chills, malaise, and fatigue can be prodromal symptoms of HIDS [55].

3.3  Fever Fever is the constant feature of the attacks. The duration range is normally between 3–7 days, with variable degrees [55–57].

3.4  Lymphadenopathy and hepatosplenomegaly Lymphadenopathy is the most common presentation, occurring in nearly 90% of the patients. The tender lymph nodes can be mainly found in the cervical region. Generalized lymphadenopathy is sometimes disclosed [55,56]. Splenomegaly can be noticed in about one-third of the patients, and hepatomegaly is less commonly reported than splenomegaly [55,57].

3.5  Gastrointestinal manifestations Abdominal pain is the second most common presentation after lymphadenopathy. Other GI manifestations include vomiting, diarrhea, bleeding, GI ulcers, and occasionally abdominal adhesions, possibly due to recurrent episodes of adhesion [55,58].

3.6  Musculoskeletal manifestations Arthralgia, myalgia, and arthritis, that can rarely become chronic, are the most common presentations in this area [56].

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3.7  Cutaneous and mucocutaneous manifestations Various skin lesions can be found in about 60% of the patients. Erythematous macules, papules, nodules, and urticarial lesions are most frequently observed. Oral or genital aphthous ulcers, that resemble those presented in Behcet’s disease, can occur in HIDS. Urticarial and maculopapular rash might be found even between the episodes. Biopsies of the lesions are consistent with mild vasculitis in many cases [55,59]. Some studies have reported pharyngitis in flares of genetically confirmed MKD patients, which can complicate the differentiation from PFAPA [53]. Fig.  2 depicts some of the manifestations of patients with MKD, described by van der Burgh et al. [52].

3.8  Neurologic manifestations Headache is the most prevalent neurologic involvement in HIDS. Seizures and cerebellar disorders are also reported [53]. The incidence of neurologic manifestations independent of periodic flares is also announced to be higher than normal population.

FIG. 2  Clinical manifestations of MKD. (A) Maculopapular rash, (B) periorbital erythema, (C) cervical lymphadenopathy, (D) pneumonia, (E) beau lines, caused by recent febrile episodes, (F) arthritis in the knees, and (G) intestinal obstruction as a result of peritoneal adhesions.

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3.9  Macrophage activation syndrome Macrophage activation syndrome (MAS) can be a dreadful complication of certain rheumatologic diseases, and it has also been noted, albeit rarely, in patients with HIDS. It is a life-threatening condition, which happens due to excessive immune activation. The patient can become very ill and multiple organs might be damaged. Fever, hepatosplenomegaly, lymphadenopathy, pancytopenia, elevated liver enzymes, elevated triglyceride level, hyperferritinemia, hypofibrinogenemia, and abnormal coagulation profile are markers of MAS. Unfortunately, mortality rate is high unless treated instantly [56,60].

3.10  Amyloidosis Amyloidosis, mostly with renal involvement, has been found as a morbid condition in a few MKD patients in most case series, especially in the patients with delayed diagnosis [55,56].

3.11  Other manifestations Septicemia has been outlined in a few patients in a couple of MKD case series. Staphylococcal, pneumococcal, and meningococcal septicemia, sometimes lethal, have been found, proposing an immunodeficient condition in patients affected by MKD [55,57,58]. Ophthalmic presentations such as retinitis pigmentosa and cataracts, pericarditis, and glomerulonephritis are rare manifestations described in MKD patients, and their association with MKD needs to be further assessed [56,61–63].

3.12  Clinical presentation of MA phenotype MA can be presented much earlier than HIDS, even in the prenatal period. It has been reported as a reason for hydrops fetalis [64]. Patients experience similar flares to HIDS and might even present the symptoms persistently. In addition, they might have a dysmorphic feature, i.e., abnormal head morphology, downward palpebral fissures, and blue sclerae, skeletal malformations, failure to thrive, developmental delay, and growth failure [65]. Hematologic abnormalities and cholestatic liver disease are occasionally described in MA patients [66]. In the most severe forms, MA can be quite mortal [51].

4  Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) 4.1  Background TNF receptor-associated periodic syndrome (TRAPS) is a rare autosomal dominant autoinflammatory disorder caused by mutations in TNFRSF1A, which encodes for TNF-receptor 1 (TNFR1). The disorder was formerly known as familial Hibernian fever since it was first

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described in a Scottish-Irish family in 1982, in which 13 cases in three generations were found to be affected [67]. The disorder was also found in other ethnicities afterward, yet the majority of the patients trace their roots back to Northern Europe.

4.2  Clinical presentation TRAPS is characterized by flares of fever, abdominal pain, preorbital edema, and rash, characteristically tender and centrifugal shaped. These periods usually last for 5 days to 4 weeks. There can be an interval of weeks to months between attacks. Patients might less commonly present a continuous form of symptoms and a chronic disease course with or without exacerbations. In about 20% of the cases, the attacks can be triggered by stress, trauma, infection, vaccination, or menstrual cycle. Symptoms initiate to occur at childhood and infrequently in adolescence or even adulthood [68–71]. As the presentations of TRAPS can resemble those of FMF, special attention to the hallmarks and the possible chronic nature of TRAPS can help in their distinction.

4.3  Fever The constant feature of TRAPS attacks is fever and it can have a range of low to high.

4.4  Skin manifestations The hallmark of TRAPS are tender, migratory, well-demarcated erythematous and urticarial patches and plaques, which are known as erythema annulare, most prevalently seen on the lower legs but also found on the trunk. Myalgia is usually felt on the affected site. Histopathology of these lesions show mild perivascular lymphocytic infiltration [72,73]. Ecchymotic lesion can also be spotted in some patients [74].

4.5  Gastrointestinal manifestations Abdominal pain is the most frequent feature of TRAPS bouts after fever according to some case series [75], and is the third after fever and myalgia in others [70]. Although vomiting and aphthous stomatitis have been described in a minority of patients in the previous cohorts [70,71], their absence gains positive scores according to Eurofever Classification criteria, as they are uncommon presentations of TRAPS and more common in other autoinflammatory disorders [76].

4.6  Musculoskeletal manifestations A cramp-like myalgia is described in nearly all of the patients, which is adjacent to the typical erythematous rash, and the pain migrates alongside the rash. Arthralgia might be present in some patients. Arthritis, however, is not a common manifestation, but appears in oligo or monoarticular nondestructive form if present [70,71,75].

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4.7  Ocular manifestations Periorbital edema is a trademark for TRAPS; however, it might not be observed in many cases. In the large cohort of 158 patients with adult and childhood onset TRAPS conducted by Lachmann et al., only 20% of the patients presented this sign. In the recent published case series of 80 TRAPS patients of AIDA network, only 14% manifested periorbital edema [77]. Conjunctivitis and uveitis can also be found in TRAPS patients [70,74].

4.8  Cardiorespiratory manifestations Chest pain, pleurisy, and pericarditis are reported in some case series studies [70,71]. There have been patients reported in the literature with recurrent pericarditis as the single presentation of TRAPS [78].

4.9  Neurologic manifestations Headache is the most prevalent neurologic manifestation in these patients. Aseptic meningitis and behavioral changes are also reported [79,80].

4.10  Amyloidosis The most catastrophic complication of TRAPS is amyloidosis, as it is the case for the other autoinflammatory syndromes. The amyloid depositions are mainly found in the kidney, while skin, thyroid, testes, liver, lung, spleen, and intestine can also be affected [81].

4.11  Other manifestations Cervical tender or nontender lymphadenopathy and painful and swollen scrotum are reported in some TRAPS patients. Pharyngitis has been reported with variable proportions in different case series, suggesting that attention should be paid not to confuse it with PFAPA [70,77]. Fig. 3 shows some of the clinical manifestations of TRAPS, described by Zhao et al. [82].

5  Cryopyrin-associated periodic syndromes (CAPS) 5.1  Background Cryopyrin-associated periodic syndromes (CAPS or cryopyrinopathies) were first introduced at 1940 as a form of cold-induced rash [83]. CAPS constitutes of an array of clinical entities, from mild (familial cold autoinflammatory syndrome or FCAS), to moderate (Muckle–Wells syndrome or MWS), and severe (neonatal-onset multisystem inflammatory disease or NOMID, also known as chronic infantile neurologic cutaneous and articular (CINCA) syndrome) [84]. The continuum is indeed a rare autoinflammatory syndrome caused by mutations in NLRP3 gene, which encodes for the protein cryopyrin. As a part of NLRP3 inflammasome, cryopyrin augments the activity of caspase 1 when triggered, which 574



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FIG. 3  Clinical manifestations of TRAPS patients. (A) Periorbital edema, (B) erythema annulare, (C) maculopapular rash, and (D) intestinal obstruction.

leads to overproduction of IL-1B and the consequent autoinflammatory response [85]. CAPS is basically an autosomal dominant disease, but somatic mutations have also been described.

5.2  Clinical manifestations The age of onset can range from infancy or even the first few days of life usually seen in FCAS and NOMID, to adulthood, mostly seen in MWS patients. In addition to cold, which is a well-known trigger for FCAS attacks, stress, infection, trauma, and sleep deprivation can lead to the onset of symptoms. Patients might experience chronic symptoms as well as flares lasting from a few hours to several days. Fatigue, myalgia, headache, chills, night sweats, extreme thirst, nausea, and drowsiness are the most prominent systemic symptoms [86–88].

5.3  Fever Fever, which is the hallmark of most autoinflammatory diseases, is not as commonly seen in FCAS patients. However, temperature increase of less than 1 degree can be found in many patients [89,90].

5.4  Cutaneous manifestations The typical dermatologic manifestation of CAPS, observed in most CAPS patients, is an urticarial rash that might be itchy, painful, or both. The lesion is mainly found on limbs or trunk, less commonly on the face, and almost never on the palms or soles. Some patients report limb swelling in form of angioedema [87]. Although cold exposure triggers the initiation of flares in FCAS, lesions do not necessarily appear on the area in direct contact with the cold stimuli (Fig. 4) [91]. 575



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FIG. 4  Urticaria-like rash on the trunk of a 1-year-old.

5.5  Ocular manifestations Conjunctivitis is the most common ocular presentation of CAPS, which can be manifested during the flares of all the phenotypes. The patients complain of pink and watery eyes, blurred vision, and ocular pain [87]. Keratitis, episcleritis, corneal neovascularization, and anterior and posterior uveitis are reported mostly in NOMID patients. Posterior eye segment inflammation occurs less frequently; however, there are reports of vitritis, chorioretinitis, and retinal vasculitis in patients with NOMID. Increased intracranial pressure can lead to papilledema and optic nerve atrophy in a minority of NOMID patients. Decreased visual acuity and peripheral vision and blindness are occasionally described [92,93].

5.6  Otologic manifestations A disastrous sequela of CAPS is progressive sensorineural hearing loss (SNHL), which affects the high frequencies in the beginning and might progress to involving both low and high frequencies. The condition is often seen in patients with NOMID and MWS, but might be found in FCAS as well. Conductive and mixed hearing loss has also been disclosed in patients with CAPS, yet infrequently [94]. The pathogenesis lies in inflammation of cochlear structures, and cochlear enhancement might be found in magnetic resonance imaging (MRI) [95].

5.7  Musculoskeletal manifestations Muscle and joint manifestations depend on the severity and phenotype of CAPS disease. Arthralgia and myalgia are common presentations in FCAS flares. Acute arthritis is often found in MWS. Chronic polyarticular arthritis can be found in NOMID and severe forms of MWS. Bone and joint deformation can sometimes be found in NOMID due to a­ bnormal

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epiphyseal growth and calcification and uncontrolled growth of the cartilage. Frontal ­bossing is a characteristic feature for NOMID patients making the patients distinguishable in the ­autoinflammatory spectrum. Limb discrepancies, osteopenia, digital clubbing, and low height can be found in severe cases [90,92,96].

5.8  CNS manifestations CNS involvement is known as the most catastrophic outcome of CAPS. The severe presentations are predominantly found in NOMID patients. These patients might suffer from chronic aseptic meningitis, presenting with severe headache, irritability, seizures, nausea, and vomiting. Persistently elevated intracranial pressure in these cases contributes to hydrocephalus, arachnoid adhesions, enlarged ventricles, atrophic brain, and intellectual disability. Seizures and episodes of aseptic meningitis are also presented in MWS. Headaches, on the other hand, are general complaints of all FCAS patients [93]. Stroke is rarely manifested in NOMID patients [92].

5.9  Amyloidosis Similar to most other autoinflammatory disorders, amyloidosis can be a complication of CAPS. As anticipated, the frequency is higher in NOMID and severe cases of MWS. It is usually presented by renal damage and nephrotic disease, but amyloid deposits are also reported to be found in adrenal and spleen in CAPS patients [96,97].

5.10  Other manifestations Fertility problems such as oligospermia, ovarian failure, and infertility of unknown cause are reported [96,98].

6  Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome 6.1  Background Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, is considered to be the most common periodic fever syndrome in children [99]. It is an autoinflammatory disorder with a polygenic origin. Researchers have found several mutations responsible for this disorder, and it has been proposed that environmental factors can trigger inflammasome activation and initiate PFAPA attacks [100]. The disease onset is believed to be before 5 years of age [101], but there are reported cases whose presentations fulfill the criteria and occur later than the age of 5 [102]. Corticosteroids, colchicine, and tonsillectomy are the most frequent therapeutic approaches for PFAPA syndrome that efficiently restrain the progression. Even without treatment, PFAPA usually has a naïve course and does not lead to catastrophic outcomes [103].

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6.2  Clinical manifestations PFAPA attacks have the intriguing feature of clockwise periodicity and they normally last for 3–7 days and recur each 2–8 weeks [104]. However, adults experience less-regular attacks with longer periods in between. The patients appear well between the episodes and have a normal growth and development. Since each episode of PFAPA strongly resembles an infectious process with presentations of fever, pharyngitis, and lymphadenopathy, it is crucial to rule out a source of infection to confirm the diagnosis of PFAPA. The stereotypic presentations of PFAPA flares and the abrupt cessation of symptoms when corticosteroids are administered make it unique and distinguishable from other periodic fever syndromes.

6.3  Fever Fever is the hallmark of PFAPA flares and its presence is obligatory for the diagnosis. It can last for 3–7 days and then subsides rather abruptly. Durations for longer than 7 days raise the suspicion of other febrile syndromes [105–108]. In a cohort of 108 patients with regular febrile attacks, half of the patients’ attacks presented with fever alone, and all the patients were completely cured after tonsillectomy; as a result, it was suggested that PFAPA should be considered in case of regular bouts of fever even when not accompanied by any other symptom and tonsillectomy should be proposed [109].

6.4  Pharyngitis About 65%–100% of the patients experience pharyngitis, which is mostly exudative and involves the tonsils bilaterally [101,105–108,110].

6.5  Cervical adenitis Cervical adenitis can be found in 60%–100% of the patients. It is usually bilateral, almost never suppurative, and the enlarged lymph nodes are sometimes tender [101,105–108,110].

6.6  Aphthous stomatitis A few aphthous ulcers can be found in the oral cavity, mainly on the inner surface of the lips or oral mucosa [101,105–108,110]. Due to the smaller size and less painful nature of these ulcers in comparison with those of Behcet’s disease, they are not as prominent and might occasionally be missed upon physical examination.

6.7  Other manifestations Gastrointestinal symptoms, i.e., abdominal pain and vomiting, headache, arthralgia, myalgia, diarrhea, and rash are the symptoms occasionally found in patients with PFAPA, in the order of prevalence [101,105–108,110,111]. Interestingly, these symptoms tend to occur more frequently in adult patients with PFAPA [112,113].

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7  Conclusion The tableau of AIDs has been changing continuously in the last 20 years, introducing a new autoinflammatory disorder every day. These disorders might resemble in many features, but each of them has some specific characteristics that make it unique. Since they are rare disorders, introduction of the cases via the published articles helps in the disclosure of AIDS’ unknown characteristics. In this chapter we introduced some of the best-known AIDs as a representative of the group to which they belong and emphasized on their clinical manifestations. Pathogenesis and treatment of these disorders need much extensive discussions. Although we are still far from fully understanding AIDs, efforts to illuminate the known characteristics of AIDs can enable the clinicians to diagnose these disorders much faster and hence prevent the drastic complications.

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Index Note: Page numbers followed by f indicate figures and t indicate tables.

A Abatacept, 318, 320–321t, 396t administration, 196 for alphaviruses in rheumatoid arthritis, 555 contraindications, 197 evidence, 197 indications, 197 mechanism of action, 196 for multiorgan systemic sclerosis (SSc), 433 for systemic sclerosis (SSc), 463 Abetimus sodium, 320–321t Activated partial thromboplastin time (aPTT), 123–124 Acute-phase reactants, 114–115 Acute rheumatic fever (ARF) diagnosis, 50–51 major manifestation arthritis, 52 carditis, 52 Erythema marginatum, 53 subcutaneous nodules, 53 sydenham chorea (SC), 52–53 minor manifestations arthralgia, 54 electrocardiogram, prolonged PR interval on, 54 elevated acute phase reactants, 54 fever, 54 streptococcal infection, evidence of, 54 treatment manifestation treatment, 55–58 primary prevention, 55 Acyclovir, 71 Adalimumab (ADA), 245, 396t Adaptive immunity dysregulation of, 34–35 in rheumatoid arthritis inflammation, 238–241 B-Lymphocytes, 238–239 dendritic cells, 239 T cells, 239–241 systemic lupus erythematosus (SLE) B lymphocytes, 274 T lymphocytes, 273–274 Aggregatibacter actinomycetemcomitans, 88, 90 AIDs. See Autoinflammatory disorders (AIDs) AIIRD. See Autoimmune inflammatory rheumatic diseases (AIIRD)



Air pollution, and health effects definitions, 170 health impact, 171 molecular composition, 170 with rheumatoid arthritis, 169–170 arthritis, 176–177 biomarkers/disease activity markers, 174 from exposure to autoantibody release, 175–176 mechanisms, 174–177 risk factor, 171 sources, 170 Akkermansia muciniphila, 89 Alcohol consumption, 11–12 Alphaviruses, 546–547 pathogenesis, 546 in rheumatoid arthritis Barmah Forest virus (BFV), 551–552 chikungunya virus (CHIKV), 547–548 Mayaro virus (MAYV), 553–554 O’nyong-nyong virus (ONNV), 549–550 Ross River virus (RRV), 550–551 Sindbis virus (SINV), 554–555 treatments, 555–556 Amyloidosis cryopyrin-associated periodic syndromes (CAPS), 577 familial Mediterranean fever (FMF), 569 mevalonate kinase deficiency (MKD), 572 tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), 574 ANA. See Antinuclear antibodies (ANA) Anaerglobus geminatus, 90 Anakinra, 500 Angiogenic T cells, 459 Anifrolumab, 281–282t, 320–321t, 322 Animal models, of scleroderma, 460–462 Ankle-brachial index (ABI), 392–393 Ankle manifestations, 394–395 Anti-aminoacyl tRNA synthetase (anti-ARS) antibodies, 443, 443t Anti-B-cell agent, 193–194 Antibody profiling, 151 Anticardiolipin antibodies, 123–124 Anti-CD40L, 361 Anti-CD20 treatment, 71

585

586 Index Anticentromere (ACA), 124–125 Anticitrullinated protein antibodies (ACPAs), 62, 68–69, 90, 116, 183–184 Anti-DNA antibodies, 122, 312 Anti-dsDNA antibodies, 122 Antiendothelial cell antibodies (AECAs), 279 Antiepileptic drugs (AEDs), 56, 380–381 Antigen microarray, 162–163 Antigen-presenting cells (APCs), 480 Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies, 443–444 Antimalarials, 336–337 Anti-MDA5 antibodies, 438t, 439–441, 440f Anti-Mi-2 antibodies, 125–126, 438t, 439, 439f Antineutrophil cytoplasm (ANCA), 132–134 Antinuclear antibodies (ANA), 36, 114, 121–122, 294–295, 307 Antinuclear antibody, 310 Antinuclear antigens (ANA), 459 Antinuclear matrix protein 2 (NXP2) antibodies, 438t, 441 Antiphospholipid antibodies (aPL), 123–124, 312–313 Antiphospholipid syndrome (APS), 312–313 autoantibody profiling in, 159 laboratory tests in, 121–124 Antiproliferative drugs, 280, 281–282t Anti-RNA polymerase III (RNAP-III) antibodies, 124–125 Anti-Ro/SSA antibodies, 126–127 Anti-SAE antibodies, 438t, 442, 442f Anti-Scl-70, 124–125 Anti-single stranded DNA (ssDNA), 122 Anti-Sm antibodies, 122–123 Anti-TIF1-γ antibodies, 438t, 441 APCs. See Antigen-presenting cells (APCs) Aphthous stomatitis, 578 Apoptosis, 33, 269–270, 336 Aquaporin 5 (AQP5), 516 Arboviruses. See Alphaviruses ARD. See Autoimmune rheumatic diseases (ARDs) ARF. See Acute rheumatic fever (ARF) Arthralgia, 54–55, 576–577 Arthritis, 52, 55 ILC2 role on initiation phase, 535–537, 535f SINV-induced, 554–555 Artificial intelligence in autoimmune diseases, 342t Aryl hydrocarbon receptor (AhR) ligands, 85 Aspirin, 55 Atacicept, 281–282t, 320–321t Attention-deficit and hyperactivity disorder (ADHD), 379 Autoantibodies, 3, 28f, 36, 182 production rheumatoid arthritis (RA), 176

profiling, 151 in antiphospholipid syndrome, 159 in autoimmune inflammatory myositis (AIM), 160 in autoimmune organ-specific diseases, 162 in autoimmune rheumatic diseases, 156–160 clinical rationale, 150–151 in rheumatoid arthritis (RA), 161–162 in systemic lupus erythematosus (SLE), 156–159 in systemic sclerosis, 159–160 Autoantigen, 33–34 arrays, 156 formation, in rheumatoid arthritis (RA), 176 microarrays, 156 Autoimmune connective tissue diseases laboratory tests in, 121–127, 128–131t Autoimmune diseases (AID), 150 artificial intelligence in, 342t machine learning in, 342t Autoimmune inflammatory myositis (AIM) autoantibody profiling in, 160 Autoimmune inflammatory rheumatic diseases (AIIRD) bone health impairment, prevalence of, 10 bone loss evaluation, 17–21 management, 17–21 pathophysiology, 15–16 risk factors for, 10–15 overview, 9–10 Autoimmune movement disorder. See Rheumatic chorea (RC) Autoimmune organ-specific diseases autoantibody profiling in, 162 Autoimmune polyglandular syndrome type 1 (APS1), 352 Autoimmune process, 50 Autoimmune regulator (AIRE), 351–352 Autoimmune rheumatic diseases (ARDs), 28, 37t, 544–545 autoantibody profiling in, 156–160 diagnosis, 3–4 immunopathogenesis biomarkers, 36 therapeutic implications, 38–39 infectious agents associated with, 32t overview, 1–2 pathogenesis, 28–35 apoptosis, 33 innate and adaptive immune system, dysregulation of, 34–35 molecular mimicry, 30–33 neoantigens/autoantigens formation, 33–34 secondary necrosis, 33 therapeutic targets, 40t

Index 587

through history, 2–3 treatment, 4–6 epigenetic modification, 6 exercise and physical activity, 5 microbiota modulation, 5–6 pharmacological treatment, 4 Autoimmunity, defined, 510 Autoinflammatory disorders (AIDs), 566 cryopyrin-associated periodic syndromes (CAPS), 574–577 familial Mediterranean fever (FMF), 566–569 mevalonate kinase deficiency (MKD), 569–572 periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, 577–578 TNF receptor-associated periodic syndrome (TRAPS), 572–574 Autologous stem cell transplantation (ASCT), 463 Autologous transplantation of salivary gland epithelial cells, 518–519 Azathioprine, 4, 395t systemic lupus erythematosus (SLE), 283

B Bacterial infections, 64 Bacteroides fragilis, 85, 91 Baculovirus-insect cell expression system, 157 Baricitinib, 320–321t, 396t Barmah Forest virus (BFV), 551 infection, clinical manifestations of, 551 and rheumatoid arthritis immune response, 551–552 Basal ganglia, 375–376 B-cell activating factor (BAFF), 274, 295–299, 338–341, 520 B-cell depletion therapy (BCDT), 363 B cell infection, 66–67 B-cell lymphoma 6 (BCL6), 357 Bead arrays, 153 Behavioral disorders, 378 Behçet’s disease (BD), 488 activated innate immunity in pathogenesis, 488 interleukin (IL)-1 family cytokines in clinical application and participation, 499–500 expression and function, 493–499 genes, 490–492 ligands and receptors, 490t Behçet’s syndrome (BS), 475, 477f epigenetics, 479 etiology genetic, 477f, 478–479 immunological, 477f, 480 microbial, 476–478, 477f triggering factors, 480–481 Belimumab, 281–282t, 320–321t, 338–341

Benzathine benzylpenicillin, 56 BFV. See Barmah Forest virus (BFV) BIIB059 systemic lupus erythematosus (SLE), 281–282t Bilophila wadsworthia, 86–87 Bindarit, RRV-induced arthritis, 556 Biological disease-modifying antirheumatic drugs (bDMARDs), 4, 186, 186t, 396t anti-B-cell agent (rituximab), 193–194 costimulatory blockade, 196–197 IL-6 inhibitors (IL-6i), 195–196 JAK inhibitors, 197–199 TNF inhibitors (TNFi), 191–193 Biomarkers autoimmune rheumatic diseases (AIRDs), 36 microbiota as, 100 systemic lupus erythematosus (SLE), 309–313 Biomaterials-assisted immune modulation, 246 Biosensor technology, 155 Bleomycin-induced lung fibrosis model, 461 Blisibimod, 320–321t Blood-brain barrier (BBB), 279 B-lymphocytes, 35, 49, 238–239, 274 B lymphocyte stimulator (BLyS), 302, 338–341 Bone biomarkers, 19 Bone cells, 15–16 Bone homeostasis and innate lymphoid cells (ILC), 538–539 mediated by T cell, 537–538 Bone loss, AIIRD disease-related risk factors, 13–15 evaluation, 17–21 management, 17–21 pathophysiology, 15–16 risk factors for, 10–15 Bone marrow-derived macrophages (BMMs), 538 Bone mineral density (BMD), 10–12, 18–19 Borrelia burgdorferi, 134 Bortezomib, 313 Bosentan, for multiorgan systemic sclerosis (SSc), 433 BS. See Behçet’s syndrome (BS) Budesonide (BUD), 243–245 Bursitis, 397–399 Butyrophilin, 30–31

C Calcineurin inhibitors, 360–361 Calcium, 12, 20–21 Calcium channel blockers (CCBs), 433 Canakinumab (CAN) in Behçet’s disease (BD), 500 CAPS. See Cryopyrin-associated periodic syndromes (CAPS) Carbamazepine, 56

588 Index Cardiovascular disease (CVD), 391–392 risk management, 314 Carditis, 52, 56 Carfilzomib, 313 Caspase-1, 34, 567 CD4+ regulatory T cells, 359 CD8+ regulatory T cells, 359 CD4+ T cells, 355–356, 451–454 CD8+ T cells, 358, 451–454 Celecoxib (CEL), 243 Central nervous system (CNS), 279 Cerebrospinal fluid, IL-33 and ST2 receptor in, 495–496 Certolizumab pegol, 396t Cervical adenitis, 578 Cervical tender, 574 Chikungunya virus (CHIKV), 547 infection, clinical manifestations, 547 and rheumatoid arthritis immune response, 547–548 Chitosan, 246 Chlamydia trachomatis, 119–121 Chondrocalcinosis, 135 Chorea, 56, 378 Chronic systemic inflammation, 5 Ciclosporin, 395t Cidofovir, 71 Cimetidine, 71 Circulating Tfh cells, 357–358 Clostridium difficile infections, 99 Col3a1 gene, 460 Colchicine, for PFAPA syndrome, 577 Collagen II (CII), 545 Complementarity-determining region 3 (CDR3) length analysis, 451 Complete Freund’s adjuvant (CFA), 519–520 Conjunctivitis, 576 Connective tissue growth factor (CTGF), 431 Conventional disease-modifying antirheumatic drugs (cDMARDs), 4 Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) hydroxychloroquine, 189 leflunomide, 189 methotrexate, 187–188 sulfasalazine, 188–189 Corneal neovascularization, 576 Corticosteroids, 100, 382 for PFAPA syndrome, 577 systemic lupus erythematosus (SLE), 280, 281–282t Corynebacterium amycolatum, 94–95 Costimulatory blockade, 196–197 CPK enzyme, 125–126 Cramp-like myalgia, 573 C-reactive protein (CRP), 36, 114–116, 567

Crithidia luciliae, 122 Crithidia luciliae immunofluorescence test (CLIFT), 312 CRP. See C-reactive protein (CRP) Cryoglobulinemic vasculitis, 134 Cryoglobulins, 127, 134 Cryopyrin-associated periodic syndromes (CAPS), 574–577 amyloidosis, 577 clinical manifestations, 575f CNS manifestations, 577 cutaneous manifestations, 575 fever, 575 musculoskeletal manifestations, 576–577 ocular manifestations, 576 otologic manifestations, 576 CTLs. See Cytotoxic T cells (CTLs) CXCL10, 489 Cyclooxygenase (COX) enzyme, 500 Cyclophosphamide (CTX) for multiorgan systemic sclerosis (SSc), 433 systemic lupus erythematosus (SLE), 281–282t T-cell large granular lymphocytic (T-LGL) leukemia, 226 Cyclosporin (CSA), 360 for multiorgan systemic sclerosis (SSc), 433 Cyclosporine A (CyA) T-cell large granular lymphocytic (T-LGL) leukemia, 226 Cytokines, 182, 545 Cytotoxic T cells (CTLs), 451–452, 454 Cytotoxic T lymphocyte antigen 4 (CTLA4), 461–462

D Damage associated molecular patterns (DAMPs), 430 Dapirolizumab, 320–321t Deep vein thrombosis (DVT), 394 Delanzomib, 313 Dendritic cells (DCs), 212–213, 237, 239, 272, 532 Densitometric vertebral fracture assessment, 19 2-deoxycoformycin, 226 Dermatomyositis (DM), 437–438 cutaneous manifestations correlation with, 438–443 anti-ARS phenotype, 443, 443t anti-MDA5 phenotype, 438t, 439–441, 440f anti-Mi-2 phenotype, 438t, 439, 439f anti-NXP2 phenotype, 438t, 441 anti-SAE phenotype, 438t, 442, 442f anti-TIF1-γ phenotype, 438t, 441 Dexamethasone (DEX), 215, 243–245 Dextran sulfate (DS), 248 Dickkopf-1, 15–16 1,25-dihydroxyvitamin D3, 215 Disease activity score (DAS), 185 Disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR), 13

Index 589

Disease-modifying antirheumatic drugs (DMARDs), 4, 100, 185–186, 243, 391–392 rheumatoid arthritis (RA), 69–71 systemic lupus erythematosus (SLE), 280 DM. See Dermatomyositis (DM) DNA methylation, 267 DNA-reactive autoantibodies, 301 Drug-induced lupus erythematosus (DIL), 305 Dual energy X-ray absorptiometry (DXA) autoimmune inflammatory rheumatic diseases (AIIRD), 18–19 Dual labeling strategy, 153 Dysarthria, 378

E EBV. See Epstein-Barr virus (EBV) Eculizumab, 281–282t E. faecalis, 99 Eggerthella lenta, 92 Electrophoretic TAG (eTAG) assay, 153 Elevated acute phase reactants, 54 Endothelial progenitor cells (EPCs), 439–441 Enterococcus gallinarum, 88, 94, 99 Episcleritis, 576 Epithelial cell infection, 66 Epratuzumab, 281–282t, 320–321t, 338–341 Epstein-Barr virus (EBV), 64–66, 73–74, 305 infections, 66–67 and rheumatoid arthritis disease, 67–69, 69t structure, 65, 66f ERAP1 polymorphisms Behçet’s syndrome (BS), 479 Erysipelas-like erythema, 568, 569f Erythema annulare, 573, 575f Erythema, face, 439f Erythema marginatum, 53 Erythrocyte sedimentation rate (ESR), 36, 114–116 Escherichia coli, 134 ESR. See Erythrocyte sedimentation rate (ESR) Etanercept (ETA), 245, 396t EULAR/ACR classification criteria, 444 Exercise autoimmune rheumatic diseases (ARD), 5 Exome sequencing, 4 Experimental autoimmune uveitis (EAU), 489, 493 Extraarticular disorder, 396–401 Extracellular matrix (ECM), 448

F Faecalibacterium prausnitzii, 119 Familial Mediterranean fever (FMF), 115, 137, 566–569 amyloidosis, 569 clinical presentation, 567 fever, 567

musculoskeletal manifestations, 568 neurologic manifestations, 569 pericarditis, 568 peritonitis, 568 pleuritis, 567–568 skin manifestations, 568 Farr assay, 312 Fecal calprotectin, 119 Fecal microbiota transplantation (FMT), 88, 96, 99 Felty’s syndrome (FS), 225 Fever, 54–55 cryopyrin-associated periodic syndromes (CAPS), 575 mevalonate kinase deficiency (MKD), 570 periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, 578 tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), 573 Fibrillin (Fbn) gene, 460 Fibroblastic reticular cells (FRCs), 493 Fibroblasts, 448–449 FMF. See Familial Mediterranean fever (FMF) FMT. See Fecal microbiota transplantation (FMT) Follicular T helper cells, 357 Food antigens, 32–33 Foot manifestations, 394–395 Forefoot manifestations, 401–403, 404–405f Forefoot reconstruction, 403–407 Fos-related antigen-2 (Fra-2) gene, 460 Fracture Risk Assessment Tool (FRAX), 11–12, 17–18 Fractures disease-related risk factors, 13–15 general risk factors for, 11–13 Full blood count (FBC), 184

G Gaft-vs-host disease (GVHD), 451 Ganciclovir, 71 GAS pharyngitis treatment acute rheumatic fever (ARF), 55 Gastrointestinal tract (GIT), 91, 95 symptoms, 97t GATA-binding protein3 (GATA3), 532–533 γδ regulatory T cells, 360 Genant’s semiquantitative technique, 19 Gene delivery systems, 525 Gene therapy salivary glands regeneration in SS, 524–525 Genome wide association studies (GWASs), 333–334, 341 Genotyping, 114, 132 Geriatric Nutritional Risk Index (GNRI), 12 Giant magnetoresistive (GMR) nanosensors, 154 Glucocorticoids (GCs), 14, 69–71, 185–186

590 Index Glucocorticosteroids (GCs), 56, 243–245, 337 GM-CSF. See Granulocyte macrophage-colony stimulating factor (GM-CSF) Gold nanoparticles (AuNPs), 249–250 Golimumab (GOL), 245, 396t Good Manufacturing Practices (GMP), 520 Gottron’s papules, 439–441, 439f Gottron’s sign, 439–440f, 442, 442f Granulocyte colony-stimulating factor, 227 Granulocyte macrophage-colony stimulating factor (GM-CSF), 453, 537 Granulocytes, 532 Green fluorescent protein (GFP)-iPS cells, 521

H Haemagogus janthinomys, 552 Heat shock proteins (HSP), 209–212, 488–489 Helicobacter hepaticus, 85 Heliotrope sign, 442, 442f Hemophilus influenzae, 134 Henoch-Schoenlein purpura, 568, 569f Hepatitis B virus, 117–118 Hepatitis C virus, 117–118 Hepatosplenomegaly, 570 Herpes virus entry mediator (HVEM), 489 High mobility group box 1 (HMGB-1), 430 Histone modifications systemic lupus erythematosus (SLE), 267–268 HLA-B51, 476, 478 HLA-DRB1 shared-epitope (HLA-SE), 214 Household air pollution (HAP), 177–178 HSP. See Heat shock proteins (HSP) Human leukocyte antigen (HLA) polymorphisms, 377 Hydroxychloroquine, 4, 189, 395t Hydroxychloroquine (HCQ), 280, 281–282t administration, 189 evidence, 189 indications, 189 mechanism of action, 189 Hypocomplementemia, 124 Hypovitaminosis D, 12–13

I Ibuprofen (IPF), 243, 500 Idiopathic inflammatory myopathies (IIM) laboratory tests in, 125–126 IL-6, 5 IL-18 binding protein (IL-18BP), 496 ILC2 role, on initiation phase of arthritis, 535–537, 535f ILCs. See Innate lymphoid cells (ILCs) IL-6 inhibitors (IL-6i), 195–196 administration, 195 contraindications, 196 evidence, 196

indications, 195 mechanism of action, 195 IL-2, systemic lupus erythematosus (SLE), 273 Imatinib, 433 Immune system, 532 Immunochemoluminescence methods, 150 Immunodot, 150 Immunoenzymatic methods, 150 Immunoglobulin G (IgG), 156–157 Immunoglobulin M (IgM), 156–157 Immunosuppressant, 338 Immunosuppressive agents, 433 Immunotherapy systemic sclerosis (SSc), 463–464 Incomplete lupus erythematosus (ILE) syndrome antibody profiling, 157 Indirect immunofluorescence (IFI), 121–122 Induced pluripotent stem cells (iPSCs), 518, 521–522 Inducible T-cell costimulator (ICOS), 451 Infectious agents, 32t Infectious arthritis, laboratory tests in, 134 Inflammasome, 34 Inflammation, 176 Inflammatory rheumatic diseases, 114 Infliximab (IFX), 245, 396t, 555 Injectable gold, 4 Innate immunity dysregulation of, 34–35 in etiopathogenesis of BS, 480 in rheumatoid arthritis inflammation, 235–238 dendritic cells, 237 macrophages, 236–237 mast cells, 237–238 natural killer (NK) cells, 237 neutrophils, 236 systemic lupus erythematosus (SLE) dendritic cells (DCs), 272 monocytes, 272–273 neutrophils, 272 Innate lymphoid cells (ILCs), 85 bone homeostasis and, 538–539 rheumatoid arthritis (RA) and, 534 secreting cytokines and function, 533t spondyloarthritis (SpA) and, 535 surface and transcriptional markers, 532t Innate lymphoid cells 1 (ILC1), 496 In situ DNA-RNA hybridization, 478 Interferon gamma (IFN-γ), 532–534 Interleukin-1 (IL-1) biological characteristics of cytokines, 489–490 Interleukin-18 (IL-18) in Behçet’s disease (BD), 496–497 Interleukin-31 (IL-31), 11–12 Interleukin-33 (IL-33)

Index 591

in Behçet’s disease (BD) expression and function, 493–496 regulatory T (Treg) cells, 494 tissue remodeling and regeneration, 494 Interleukin-36 (IL-36), 499 Interleukin-37 (IL-37), 497–499 Interleukin-38 (IL-38), 499 Interleukin-1 beta (IL-1β), 493 Interspersed repeated sequences (IRSs), 479 Intestinal microbiome, 91, 95 Intravenous (IV) iloprost in multiorgan systemic sclerosis (SSc), 433 Intravenous immunoglobulin (IVIG), 382 iPSCs. See Induced pluripotent stem cells (iPSCs) Ixazomib, 313

J JAK inhibitors, 197–199 administration, 198 contraindications, 198 evidence, 198–199 indications, 198 mechanism of action, 197–198 Juvenile idiopathic arthritis (JIA), 115

K Keratitis, 576

L Laboratory tests in antiphospholipid syndrome, 121–124 in autoimmune connective tissue diseases, 121–127, 128–131t in idiopathic inflammatory myopathies (IIM), 125–126 in infectious arthritis, 134 in microcrystalline arthritis, 135, 136t in osteoporosis, 135–137 in periodic fevers, 137 in rheumatoid arthritis, 116–118 in Sjögren’s syndrome (SS), 126–127 in spondyloarthritis, 118–121 in systemic lupus erythematosus (SLE), 121–124 in systemic sclerosis (SSc), 124–125 in undifferentiated connective tissue diseases (UCTD), 127 in vasculitis, 132–134 Lactobacillus casei, 98–99 Lactobacillus communities, 91 Lactobacillus reuteri, 94 Large granular lymphocytes (LGLs), 222 Leflunomide (LEF), 189, 243, 395t administration, 190

contraindications, 190 evidence, 190 indications, 190 mechanism of action, 189–190 Line-immunoassays (LIA), 150–151, 159 Low bone mineral density, 10, 12–13, 18–19 Low density granulocytes (LDGs), 303–304 Low-dose IL-2, 362–363 Lumbar spine bone mineral density (LS-BMD), 419–420 Lung inflammation, 176 Lupus glomerulonephritis, 124 Lupus nephritis (LN) management, 316–318 Lupus T cells metabolism, 354 signaling pathways, 353–354 Lymphadenopathy, 570 Lymphoid tissue inducer (LTi) cells, 532–533

M MAAs. See Myositis-specific autoantibodies (MAAs) Machine learning in autoimmune diseases, 342t Macrolides, 56 Macrophage activation syndrome (MAS), 572 Macrophages, 34, 236–237, 532, 551 Maculopapular rash, 571, 571f, 575f Magnetic resonance imaging (MRI), 184 Maribavir, 71 Mast cells, 237–238, 532 Mayaro virus (MAYV), 552 infection, clinical manifestations of, 552–553 and rheumatoid arthritis immune response, 553–554 Mediterranean fever gene (MEFV), 567 Melanoma differentiation-associated protein 5 (MDA5), 439–441 Menopause, 11 Mesenchymal stem cells (MSCs), 518–521 Metagenomics, 4 Methotrexate (MTX), 4, 187–188, 243, 245–246, 248–250, 256, 395t administration, 187 contraindications, 188 evidence, 188 indications, 181 mechanism of action, 187 for multiorgan systemic sclerosis (SSc), 433 systemic lupus erythematosus (SLE), 283 T-cell large granular lymphocytic (T-LGL) leukemia, 225–226 Mevalonate kinase deficiency (MKD), 569–572 amyloidosis, 572 clinical presentation, 570 cutaneous and mucocutaneous manifestations, 571

592 Index Mevalonate kinase deficiency (MKD) (Continued) fever, 570 gastrointestinal manifestations, 570 hepatosplenomegaly, 570 lymphadenopathy, 570 macrophage activation syndrome (MAS), 572 musculoskeletal manifestations, 570 neurologic manifestations, 571 Microarray, 157, 163 Microbiota, 84–89 and autoimmune rheumatic diseases, 89–96 psoriatic arthritis (PsA), 93, 98 rheumatoid arthritis (RA), 90–92 Sjögren’s syndrome (SS), 94–95 spondyloarthritis (SpA), 92–93 systemic lupus erythematosus (SLE), 93–94 systemic sclerosis (SSc), 95–96 to autoimmunity, 87–89 as biomarker, 100 in immune-mediated disorders, 86–87 and immune system crosstalk, 84–89 modulation, 6 shaping as potential therapeutic target, 98–100 Microchimerism, 451 Microcrystalline arthritis laboratory tests in, 135, 136t Microfluidics, 155 Microorganism-associated molecular patterns (MAMPs), 88 MicroRNAs (miRNAs), 268 Migration inhibitory factor (MIF), 550–551 Mitogen activated protein kinase (MAPK), 431, 517 Mixed connective tissue disease (MCTD), 127 MKD. See Mevalonate kinase deficiency (MKD) Molecular mimicry, 30–33, 68, 88 Molecular mimicry hypothesis rheumatic chorea (RC), 374–375 Monoclonal antibody (MAB), 4 Monocytes, 272–273 Mononuclear cell (MNC), 450–451 Monophosphoryl lipid A (MPLA), 215 Morphea treatment, 432 mRNA sequencing, 451–452 MSCs. See Mesenchymal stem cells (MSCs) Mucosal-associated invariant T (MAIT) cells, 458–459 Multiautoantibody profiling, 151–156 Multiparametric autoantibody testing, 152t Multiparametric line-immunoassays, 160 Multiparametric microarray technology, 162 Multiplex bead-based antigen arrays, 161 Multiplex electrochemiluminescence (ECL) assay, 154–155 Multiplex technology analytical challenges of, 162–163

Muscle-bone cross talk, 14 Myalgia, 568, 573, 576–577 Mycobacteria, 134 Mycobacterium tuberculosis, 117–118, 476 Mycophenolate, 433 Mycophenolate mofetil, 283, 395t Mycophenolate mofetil (MMF) for multiorgan systemic sclerosis (SSc), 433 Mycoplasma hominis, 134 Myelin basic protein (MBP), 208 Myofibroblasts, 431, 448–449 Myositis-specific antibodies, 125–126 Myositis-specific autoantibodies (MAAs), 438t, 443–444

N N-acetylcysteine, 362 Natural killer (NK) cells, 34, 237, 358–359, 496, 532–533 Natural killer T (NKT) cells, 358–359 Neoantigens, 33–34 Nephritis, 275–277 Neutrophil extracellular traps (NETs), 303–304 Neutrophils, 236, 480 systemic lupus erythematosus (SLE), 272 Nonepithelial cells, transplantation of induced pluripotent stem cells (iPSCs), 521–522 mesenchymal stem cells (MSCs), 519–521 Nonplanar arrays, 153 Nonsteroidal antiinflammatory drugs (NSAIDs), 185–186, 243 fever, 55 rheumatoid arthritis (RA), 69–71 systemic lupus erythematosus (SLE), 280, 281–282t Nucleosome remodeling deacetylase complex (NuRD), 439

O Obinutuzumab, 281–282t, 320–321t Obsessive-compulsive disorder (OCD), 378 Obsessive-compulsive symptoms (OCS), 378 Ocrelizumab, 281–282t, 320–321t Omaciclovir, 71 Omalizumab, 500 O’nyong-nyong virus (ONNV), 549 infection, clinical manifestations of, 549 and rheumatoid arthritis immune response, 549–550 Organ replacement regenerative technology, 521 OriP/Epstein-Barr nuclear antigen-1 (oriP/EBNA-1), 522 Osteoblasts (OB), 547–548 Osteoclastogenesis, 14 Osteoclasts (OC), 15–16, 547–548 Osteocytes, 537 Osteoporosis, 10–11

Index 593

disease-related risk factors, 13–15 general risk factors for, 11–13 laboratory tests in, 135–137 Osteoporosis-related fragility fractures, 10–11 Oxidative stress, 176

P Particle-based multianalyte technology (PMAT), 155 Pathobionts, 86–88, 98 Pathogen associated molecular patterns (PAMPs), 546 Pattern recognition receptors (PRRs), 430 Pentosan sodium polysulfate (PPS) for RRV in rheumatoid arthritis, 556 Peptide, 208–209, 212, 217 Peptide nanosensor microarrays, 154 Peptidyl ariginine deiminase (PADI) enzymes, 176 Pericarditis, 568 Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome, 577–578 aphthous stomatitis, 578 cervical adenitis, 578 clinical manifestations, 578 fever, 578 pharyngitis, 578 Periodic fevers, laboratory tests in, 137 Periodontitis (PD), 90 Periorbital edema, 574, 575f Peripheral blood mononuclear cells (PBMCs), 5, 451–452, 534 Peritonitis, 568 Periungual erythema, 442, 442f PFAPA. See Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome Pharyngitis, 574, 578 Phenoxymethylpenicillin, 56 Planar antigen arrays, 153 Planar surface arrays, 152 Plasmapheresis, 382 Pleiotropic cytokine, 548 Pleuritis, 567–568 Poly(lactide-co-glycolytic) acid (PLGA), 246, 523 nanoparticles, 249–250 Polyarthralgia, 52 Polyethylene glycol (PEG) hydrogels, 523–524 Porphyromonas gingivalis, 90–91 Posttranslational modifications (PTMs), 33–34 Prednisolone, 56 for multiorgan systemic sclerosis (SSc), 433 Prednisone, 226 Prevotella/Leptotrichia, 90 Prevotella nigrescens, 91 Proinflammatory cytokines, 15–16 Proteasome inhibitors, 323

Protein microarray, 157–159, 158f Proteome microarray, 152, 157 Pseudomonas aeruginosa, 134 Psoriatic arthritis (PsA) microbiota and, 93, 98 Pulmonary artery hypertension (PAH), 125 Pyoderma gangronosum, 568

R RA. See Rheumatoid arthritis (RA) RANKL, 537 Rapamycin, 361 Raynaud’s phenomenon (RP), 428, 568 Regenerative medicine, 516–517 Regulatory T cells (Tregs), 359–360 and IL-33 expression, 494 in systemic sclerosis (SSc), 455–457 Reticuloendothelial system (RES), 252 Reverse transcription-polymerase chain reaction (RTPCR), 521 Rheumatic chorea (RC) clinical features, 378–379 molecular mimicry hypothesis, 374–375 neuropsychiatric manifestations, 379 overview, 374 pathophysiology autoimmune molecular pathophysiology, 374–375 fronto-striatal dysfunction, 375–376 genetics, 375–376 treatment options, 379–382 antibiotic treatment, 380 immunomodulatory treatment, 381–382, 383t symptomatic treatment, 380–381 Rheumatic diseases (RDs), 83–84, 87f Rheumatic fever (RF), 374, 383 diagnosis, 50–51 genetics, 375–376 overview, 47–50 Rheumatic heart disease (RHD), 52 Rheumatoid arthritis (RA), 2–3, 37t, 73–74, 181, 200, 256–257, 389–391 adaptive immunity, 238–241 air pollution with, 169–170 arthritis, 176–177 biomarkers/disease activity markers, 174 from exposure to autoantibody release, 175–176 mechanisms, 174–177 risk factor, 171 articular features, 182–183 autoantibody profiling in, 161–162 biologic DMARDS anti-B-cell agent (rituximab), 193–194 costimulatory blockade, 196–197 IL-6 inhibitors (IL-6i), 195–196

594 Index Rheumatoid arthritis (RA) (Continued) JAK inhibitors, 197–199 TNF inhibitors (TNFi), 191–193 csDMARDS hydroxychloroquine, 189 leflunomide, 189 methotrexate, 187–188 sulfasalazine, 188–189 diagnosis blood tests, 183–184 diagnostic criteria, 184 radiological investigations, 184 disease management, 184–186 epstein-Barr virus (EBV) (see Epstein-Barr virus (EBV)) etiology, 182 extra-articular features, 183 horizon scanning, 199–200 HSP-loaded tolDCs as therapy, 213–216 immune response Barmah Forest virus (BFV), 551–552 chikungunya virus (CHIKV), 547–548 Mayaro virus (MAYV), 553–554 O’nyong-nyong virus (ONNV), 549–550 Ross River virus (RRV), 550–551 Sindbis virus (SINV), 554–555 innate immunity, 235–238 and innate lymphoid cells (ILC), 534 laboratory tests in, 116–118 medicines and impacts on immunity, 243–245 microbiota and, 90–92 overview, 61–64, 73–74, 234–235 pathogenesis, 182 radiographic forefoot presentation of, 390f skewed immunity, 234f, 235–243 and T cell, 533–534 therapies, 70f treatment, 69–73 Rheumatoid arthritis interstitial lung disease (RA-ILD), 391–392 Rheumatoid factor (RF), 36, 114, 116 Rheumatoid nodules, 397f, 399–400 Rheumatoid patient management ankle, 417–422 extraarticular disorder, 396–401 foot and ankle manifestations, 394–395 forefoot reconstruction, 403–407 history, 391 midfoot, 408–410 pathomechanics forefoot, 401–403 synovectomy, 403 physical exam, 391 preoperative considerations, 391–392 preoperative medication considerations, 394

preoperative testing, 393–394 rearfoot, 410–416 soft-tissue disorder, 396–401 vascular evaluation, 392–393 venous thromboembolism prophylaxis, 394 Rheumavax trial, 215 Rhodotorula glutinis, 96 Rhodotorula mucilaginosa, 92 Risperidone, 56 Rituximab (RTX), 193–194, 226–227, 320–321t, 338–341, 396t administration, 194 contraindications, 194 evidence, 194 indications, 194 mechanism of action, 193–194 for multiorgan systemic sclerosis (SSc), 433 systemic lupus erythematosus (SLE), 281–282t Robust linear model (RLM), 163 Rontalizumab, 281–282t, 320–321t Ross River virus (RRV), 550 infection, clinical manifestations of, 550 and rheumatoid arthritis immune response, 550–551 Ruminococcus gnavus, 93–94, 119

S Salispheres, 518–519 Salivary gland anatomy and physiology, 515–516 regeneration in Sjögren’s syndrome (SS), 517–525, 518f gene therapy, 524–525 stem cell transplantation, 518–522 tissue engineering, 523–524 Salivary organoids, 517 Saliva, secretion of, 516 Salmonella, 134 Sarcopenia, 14 Scleroderma, 427 animal models of, 460–462 bleomycin-induced, 460–461 pathogenesis environmental factors, 429 genetic factors, 428–429 immunological factors, 430–431 vasculopathy, 429–430 treatment of morphea, 432 of multiorgan SSc, 432–434 Secreted frizzled-related proteins (sFRPs), 15–16 Segmented filamentous bacteria (SFB), 85–86 Sensorineural hearing loss (SNHL), 576 Septicemia, 572 Serum-amyloid A (SAA), 115

Index 595

Severe renal crisis (SRC), 428 Shawl sign, 442, 442f Shigella, 134 Short chain fatty acids (SCFA), 5, 85, 89 Sicca syndrome, 510–511 Sifalimumab, 281–282t, 320–321t Signaling lymphocyte activation molecule (SLAM), 449–450 Signal transducer and activator of transcription 6 (STAT6), 537 Sildenafil, for multiorgan systemic sclerosis (SSc), 433 Sindbis virus (SINV), 554 infection, clinical manifestations, 554 and rheumatoid arthritis immune response, 554–555 Single nucleotide polymorphism (SNP), 429 Sirukumab, 320–321t Sjögren’s syndrome (SS) clinical manifestations, 510–511, 513–515t demographics, 509–510 etiopathogenesis, 510, 512–513f laboratory tests in, 126–127 microbiota and, 94–95 pathogenesis, 510, 511f primary, 510–511 salivary glands in, 515–517 regeneration, 517–525, 518f secondary, 510–511 xerostomia and therapy in, 516–517 Skewed rheumatoid arthritis immunity, 234f, 235–243 biomaterials-based strategies for rebalancing, 246–256 drug vivo delivery, engineering live cells surfaces for, 252–254 improving RA therapy, 247–250 polarizing immune cell phenotypes, 254–256 portable therapies, 256 smart RA treatment, 250–252 inflammation adaptive immunity in, 238–241 innate immunity in, 235–238 Skin lesion, IL-33 and ST2 receptor in, 494–495 SLE. See Systemic lupus erythematosus (SLE) Smoking, 11–12, 481 SNP. See Single nucleotide polymorphism (SNP) Sodium valproate, 56 Soft-tissue disorder, 396–401 Splenocytes, 522 Splenomegaly, 570 Spondyloarthritis (SpA), 36, 476 and innate lymphoid cells (ILC), 535 laboratory tests in, 118–121 microbiota and, 92–93 Spondyloarthropathies, 37t SS. See Sjögren’s syndrome (SS)

SSc. See Systemic sclerosis (SSc) Staphylococcus aureus, 134 Stem cells, 518 transplantation autologous transplantation of salivary gland epithelial cells, 518–519 nonepithelial cells, 519–522 salivary glands regeneration in SS, 518–522 StreptInCor, 57–58 Streptoccus spp., 134, 476 Streptococcal infection, 54 Streptococcus pyogenes, 47–49, 48f, 58 Streptococcus sanguinis, 478, 488–489 Subcutaneous nodules, 53 Sulfasalazine (SSZ), 4, 188–189, 243, 395t administration, 188 evidence, 189 indications, 188 mechanism of action, 188 Surface plasmon resonance (SPR) biosensor, 155–156 Sydenham chorea (SC), 48–49, 52–53 Sydenham’s chorea. See Rheumatic chorea (RC) Synergistic antiinflammatory effect, 249–250 Synovectomy, 403 Synovial fluid, 138, 215 Synovitis, 182, 533–534 Synthetic disease-modifying antirheumatic drugs (sDMARDs), 186, 186t, 395t Systemic lupus erythematosus (SLE), 10, 33, 36, 37t, 265–266, 283, 294 adaptive immune cells B lymphocytes, 274 T lymphocytes, 273–274 anti-DNA antibodies, 312 antinuclear antibody, 310 antiphospholipid antibodies, 312–313 apoptosis, 269–270, 336 autoantibody profiling in, 156–159 biological agents, 338–341 biomarkers, 309–313 classification criteria, 307–309 complement system, 270–271, 312 diagnosis, 306–307 environmental factors, 268–269, 335 epigenetic mechanisms, 267–268 DNA methylation, 267 histone modifications, 267–268 microRNAs (miRNAs), 268 female predominance in, 300–301 gender, 268–269 genetic factors, 266–267 genetics, role of, 334–335 genomic regions annotated with, 296–298t glomerular involvement, 276f

596 Index Systemic lupus erythematosus (SLE) (Continued) hormonal factors, 335 innate immune cells dendritic cells (DCs), 272 monocytes, 272–273 neutrophils, 272 laboratory tests in, 121–124 management, 313–314 of cardiovascular disease risk, 314 of lupus nephritis (LN), 316–318 of refractory SLE with focus on phase 2/3 clinical trialslupus nephritis (LN), 318–323 microbiota and, 93–94 pathogenesis, 294–306 autoantibody production, 301 climates, 304 cytokine networks, 302–304 drug-induced lupus erythematosus (DIL), 305 environmental risk factors, 304 genetic susceptibility, 295–300 immune cells, 302–304 immune disturbance, 300–301 lifestyle factors, 306 occupational exposures, 306 ultraviolet radiation (UVR), 304 viral infection, 305 pathophysiology, 350–351 phenotypes, 309–313 serological vs. clinical activityantibodies, 313 therapeutic options antimalarials, 336–337 current strategies to combat ADS, 341 glucocorticosteroids, 337 immunosuppressant, 338 tissue inflammation and clinical manifestations, 274–279 central nervous system (CNS), 279 nephritis, 275–277 skin involvement, 277–279, 278f toll-like receptors and, 271 treatment, 280–283, 281–282t Systemic sclerosis (SSc), 37t, 428, 448 anti-RNA polymerase III antibodies, 429 autoantibody profiling in, 159–160 chemical exposures, 429 diffuse cutaneous, 448 genetic factors, 428 immunopathology, 430 immunotherapy, 463–464 interleukin-1 (IL-1), increased expression of, 430 laboratory tests in, 124–125 limited cutaneous, 448 microbiota and, 95–96 multiorgan, treatment of, 432–434 immunosuppressive agents, 433

targeted therapy, 433–434 vascular manifestations management, 433 pathogenesis, 448–449 T cells in, 450–452, 462t, 463f angiogenic, 459 unconventional, 457–459 and vasculopathy, 459–460 Tfh cells in, 457, 458t Th17 cells in, 454–455 Th subsets in, 457 Th2/Th1 balance in, 452–454 TLR4 upregulation in, 431 Tregs/Th17 balance in, 455–457 vasculopathy in, 429–430

T Tabalumab, 281–282t Tacrolimus (Tac), 360 Targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs), 186 Targeted therapy, multiorgan systemic sclerosis (SSc), 433–434 T-cell antigen receptor, 449 T-cell large granular lymphocytic (T-LGL) leukemia clinical manifestations, 224–225 diagnosis, 224 differential diagnosis, 225 epidemiology, 223 overview, 222 pathogenesis, 223 treatment, 225–227 T-cell receptor (TCR), 351–353 T cells, 211, 239–241, 449–450 bone homeostasis and cytokines mediated by, 537–538 rheumatoid arthritis (RA) and, 533–534 in systemic sclerosis (SSc), 450–452, 462t, 463f angiogenic, 459 unconventional, 457–459 and vasculopathy, 459–460 T cells, systemic lupus erythematosus after B-cell depletion, 363 current and evaluated therapies anti-CD40L, 361 calcineurin inhibitors, 360–361 low-dose IL-2, 362–363 N-acetylcysteine, 362 rapamycin, 361 development, 351–352 diversity, 354–359 CD4+ T cells, 355–356 CD8+ T cells, 358 circulating Tfh cells, 357–358 follicular T helper cells, 357

Index 597

NK cells, 358–359 NKT cells, 358–359 Th9, 356–357 functional anatomy, 353 lupus metabolism, 354 signaling pathways, 353–354 physiology, 353 regulatory T cells, 359–360 TCR. See T-cell receptor (TCR) Tfh cells. See T follicular helper (Tfh) cells T follicular helper (Tfh) cells, 86, 457, 458t Th17 cells, 431, 454–455 Three-dimensional (3D) scaffolds, 523 Th2/Th1 balance, in systemic sclerosis (SSc), 452–454 Thymic stromal lymphopoietin (TSLP), 533 Tissue engineering salivary glands regeneration in SS, 523–524 Tissue inhibitor of metalloproteinases-1 (TIMP-1), 431 Tissue regeneration, 517 Tissue remodeling and regeneration interleukin-33 (IL-33) in, 494 T lymphocytes, 35, 49, 273–274 Tocilizumab (TCZ), 249–250, 396t, 433–434 Tofacitinib, 396t Tofacitinib citrate, 226–227 Togaviridae, 546 Tolerogenic dendritic cell (TolDC), 212–213 Toll-like receptors (TLRs) and systemic lupus erythematosus (SLE), 271 in systemic sclerosis (SSc), 430–431 Tonsillectomy, for PFAPA syndrome, 577 Total ankle replacement/arthroplasty (TAR), 419 Transcriptomics, 4 Transforming growth factor β (TGF-β), 448–449 Transforming growth factor-B1 (TGFb-1), 431 Transplantation, of nonepithelial cells induced pluripotent stem cells (iPSCs), 521–522 mesenchymal stem cells (MSCs), 519–521 TRAPS. See Tumor necrosis factor (TNF) receptorassociated periodic syndrome (TRAPS) Tregs. See Regulatory T cells (Tregs) Tumor necrosis factor-alpha (TNF-α), 245 Tumor necrosis factor inhibitors (TNFi), 191–193 administration, 191 contraindications, 191 evidence, 193 indications, 191 mechanism of action, 191 Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), 572–574 amyloidosis, 574 cardiorespiratory manifestations, 574 clinical presentation, 573

fever, 573 gastrointestinal manifestations, 573 musculoskeletal manifestations, 573 neurologic manifestations, 574 ocular manifestations, 574 skin manifestations, 573 Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), 249 Two-dimensional (2D) scaffolds, 523 Type 1 diabetes mellitus (T1DM), 2

U Ultrasound, 184 Ultraviolet (UV) light exposure, 33, 277 Ultraviolet radiation (UVR), 304 Unconventional T cells, 457–459 Undifferentiated connective tissue diseases (UCTD) laboratory tests in, 127 Uric acid (UA), 499–500 Urticaria, 568 Urticaria-like rash, 576f Ustekinumab, 320–321t, 464 Uveitis, 576

V Valganciclovir, 71 Valproic acid, 56 Valpromide, 72 Vascular endothelial growth factor (VEGF), 429–430 Vascular lesions, 393f, 399 Vasculitis, laboratory tests in, 132–134 Vasculopathy in systemic sclerosis (SSc), 429–430 T cells and, 459–460 Venous thromboembolism (VTE), 394 Vertebral fracture assessment, 19 Vinyl chloride, 429 Viral infection, 305 Vitamin D, 20–21 deficiency, 12–13 Vitamin D3, 212–213 Vitiligo, 2 Voclosporin, 318, 360–361 V-sign, 442, 442f

W Whole-genome sequencin, 4

X Xanthine oxidase (XO), 499–500 Xerostomia long-term treatments of, 523 and therapy in Sjögren’s syndrome, 516–517

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