Molecular Mechanisms of Spondyloarthropathies [1 ed.] 144190297X, 9781441902979

Citation preview

Molecular Mechanisms of Spondyloarthropathies

ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY Editorial Board: NATHAN BACK, State University of New York at Buffalo lRUN R. COHEN, The Weizmann Institute ofScienc e ABEL LAJTHA, N.S. Klin e Institute for Psychiatric Research JOHN D . LAMBRIS, University ofPennsylvania RODOLFO PAOLETTI, University ofMilan Recent Volumes in this Series Volume 641 CELLULAR OSCILLATORY MECHANISMS Edited by Miguel Maroto and Nick Monk Volume 642 THE SARCOMERE AND SKEL ETAL MUSCLE DISEASE Edited by Nigel G. Laing Volume 643 TAURINE? Edited by Junich i Azuma Volume 644 TROPOMYOSIN Edited by Peter Gunn ing Volume 645 OXYGEN TRANSPORT TO TISSUE XXX Edited by Per Liss, Peter Hansell, Duane F. Bruley, and David K. Harrison Volume 646 EARLY NUTRITION PROGRAMMING AND HEALTH OUTCOMES IN LATER LIFE Edited by Berthold Koletzko, Tamas Desci, Denes Molnar, and Anne De la Hunty Volume64? THERAPEUTIC TARGETS OF THE TNF SUPERFAMILY Edited by Iqbal Grewal Volume 648 ARTERIAL AND ALLIED CHEMORECEPTORS Edited by Constancio Gonzalez, Colin A . Nurse, and Chris Peers Volume 649 MOLECULAR MECHANISMS OF SPONDYLOARTHROPATHIES Edited by Carlos Lopez -Larrea and Roberto Diaz-Pcfia A Continuation Order Planis availableforthis series. A continuation order will bring deliveryof each new volume immediately upon publication. Volumes are billed only upon actual shipment. For further information please contact the publisher.

Molecular Mechanisms of Spondyloarthropathies Edited by

Carlos L6pez-Larrea, PhD Hospital Universitario Central de Asturias Oviedo, Spain Roberto Diaz-Pefia, BSc Hospital Universitario Central de Asturias Oviedo, Spain

Springer Science+Business Media, LLC Landes Bioscience

Springer Science+Business Media, LLC Landes Bioscience Copyright ©2009 Landes Bioscience and Springer Science+Business Media, LLC All rights reserved . No part ofthis book may be reproduced or transmitted in any form or by any means, electronic or mechan ical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher, with the exception ofany material supplied specifically for the purpose of being entered and executed on a computer system; for exclusive usc by the Purchaser of the work . Printed in the USA . Springer Science+Business Media, LLC, 233 Spring Street, New York, New York 10013, USA http ://www.springer.com Please address all inquir ies to the publishers : Landes Bioscience, 1002 West Avenue, Austin, Texas 7870 I, USA Phone: 512/637 6050; !'AX: 512/6376079 http ://www.Iandesbioscience.com The chapters in this book are available in the Madame Curie Bioscience Database. http ://www.landesbioscience.com/curie Molecular Mechanisms ofSpondyloarthropathies, edited by Carlos Lopez-Larrea and Roberto Diaz-Pcfia. Landes Bioscience / Springer Science+Business Media , LLC dual imprint / Springer series : Advances in Experimental Medicine and Biology

ISBN : 978-1-4419-0297-9

While the authors, editors and publisher believe that drug selection and dosage and the specifications and usage of equipment and devices, as set forth in this book, are in accord with current recommendations and practice at the time of publication, they make no warranty, expressed or implied, with respect to material described in this book . In view of the ongoing research, equipment development, changes in governmental regulations and the rapid accumulation of information relating to the biomed ical sciences, the reader is urged to carefully review and evaluate the information provided herein.

Library of Congress Cataloging-in-Publication Data Molecular mechanisms of spondyloarthropathies / edited by Carlos Lopez-Larrea, Roberto Diaz-Pefia. p. ; cm. -- (Advances in experimental medicine and biology ; v. 649) Includes bibliographical references and index. ISBN 978-1-4419-0297-9 I. Spondyloarthropathies--Molecular aspect s. I. Lopez-Larrea, Carlos, 1953- II. Diaz-Pena, Roberto , M.A. Ill. Series : Advances in experimental medicine and biology ; v. 649 . [DNLM: I . Spondyloarthropathies--genetics. WI AD559 v.649 2009 / WE 725 M718 2009] RC935 .S67M672009 616 .7'3--dc22 2009012986

PREFACE It is now over ten years since we edited the first edition of HLA-B27 in the Development ojSpondyloarthropathies (SpA) . It is obvious that over this period an enormous amount of information concerning SpA and HLA-B27 has accumulated, and this has been reflected in the knowledge of molecular mechanism ofthe spondyloarthropathies. Discussion for such a book took initial form at the outstanding 4th Gent Symposium on SpA in October 2006, but was not formally commissioned by Landes Bioscience until early 2007. Molecular Mechanisms ojSpondyloarthropathies aims to synthesize this growing knowledge and present all the current studies concerning the basic research ofSpA. Over the last decade, enormous progress has been made in the understanding ofthe molecular and cellular processes that lead to disease pathology. Recognition of the pathways involved in the pathogenic mechanisms of disease and the potential to target specific immune effector functions have opened the door to a wide range of innovative treatment opportunities for the SpA. Thus, we believe that the understanding of the specific molecular mechanisms involved would help to design highly specific drugs in the future. The contributors are among the best in their field and reflect the state of the art of research and current opinion of rheumatologists and immunologists. The first part covers the general clinical aspects of SpA . Established classification criteria for ankylosing spondylitis (AS) and SpA are less effective in early disease stages and thus contribute to delay in diagnosis. Major factors for improving the rate ofAS patients diagnosed early are HLA- B27 and imaging of the sacroiliac joints . The book begins with chapters on the available measures of major areas of clinical disease impact (disease activity, structural damage and functioning) in the spondyloarthropathies (Chapter I) and the role of imaging (MRI) in the evaluation and management of SpA (Chapter 2). MRI now permits the detection of patients at an earlier stage of their disease course with the potential for new insights into the pathogenesis of disease. These first chapters are followed by a section describing clinical similarities and differences with common enthesopathic disorders-e-spondylarthritis , chondrocalcinosis and diffuse idiopathic skeletal hyperostosis-which may help in the differential diagnosis (Chapter 3). v

vi

Preface

The second part focuses on the 'enthesis organ concept' and the osteoproliferation mechanisms in SpA (Chapter 4). The microdamage and propensity for bacterial involvment in the context of genetic factors such as HLA-B27 appears to lead to the characteristic inflammatory changes of AS. Understanding the "enthesis organ concept" helps to explain synovitis and osteitis in spondyloarthropathy. It is conceivable that disturbances in the sensing microorganisms at the mucosal interface or biomechanical stress at musculoskeletal sites is important for the initiation ofthe inflammation and the determination of predilection sites (Chapter 5). Bone loss is a common finding in the spondyloarthropathies. There is however increasing evidence to support a role for osteoclasts in bone erosions . Included in the book is an overview (Chapter 6) which contains recent literature related to the role of osteoclasts and the RANKL/OPG system in the various spondyloarthropathies. The inhibition ofRANKL seems to be a rational strategy to treat both localized and generalized bone loss in the inflammatory arthritides (Chapter 7). The interplay between inflammation and ankylosis is best illustrated in AS. Thus, prevention ofankylosis is a therapeutic aim in AS, which may either be achieved by early intervention or before bone proliferation has been established. Further understanding of the regulation of osteoproliferation in AS is thus warranted, and this will help to tailor the therapeutic interventions, which prevent structural remodeling in AS (Chapter 8). Many more biomarkers will need to be discovered and are now being evaluated (Chapter 9). Novel drugs specifically targeting biomarkers and their signaling pathways are expected to revolutionize the treatment of these pathologies. In recent years, clinical trials have proved that anti-TNFa is highly effective in the treatment of SpA . Thus, we believe that understanding of the specific molecular mechanisms involved could help to design highly specific drugs in the future (Chapter 10). The third part of the book focuses on the genetic and biochemical aspects of HLA-B27. The strong association of the human MHC class I allele HLA-B27 with the development ofAS is clear and has been known for over three decades. Besides the specificity of antigen presentation, which could provide a possible pathogenetic mechanism based on molecular mimicry, the peptide binding features ofHLA-B27 subtypes are important for their relationship with other biochemical properties. Yet it is far from clear how HLA-B27 is directly involved in AS. Several studies indicate that other genes may also be involved in SpA susceptibility. In Chapter 11 the genetic epidemiology ofAS and the gene-mapping studies performed to date have been reviewed. The successful identification ofARTS 1 and IL23R should give those involved in AS genetics research considerable encouragement in understanding the potential of this research. HLA-B27 represents a family of 38 closely related cell surface, proteins and the epidemiological data available have shown that some alleles (B*2706 and B*2709) are negatively associated with AS. Chapter 12 reviews the prevalence of HLA-B27 subtypes on large extended worldwide population. Molecular studies demonstrating the effects of the sequence variations on the peptide binding specificity of the molecule may yield clues to disease pathogenesis. The availability of HLA-B27 subtypes differentially associated with ankylosing

Preface

vii

spondylitis provides a unique tool for exploring the relationship between peptide specificity and pathogenetic potential. Subtype-specific polymorphic residues play a key role in determining whether an HLA-B27 subtype is AS-associated or not and opens the possibility for correlating the structural and functional characteristics of a given subtype with the disease association. The antigen peptide binding properties ofHLA-B27 subtypes are described in Chapters 13 and 14. The use of X-ray crystallography and various other biophysical techniques have revealed how several different peptides are accommodated within the binding groove of the molecules. Many studies have focused on defining the nature of subtype-bound repertoires. These aim to identify peptide features that may correlate with association to disease and to find constitutive self-ligands with sequence homology to microbial epitopes . These studies were undertaken on the assumption that molecular mimicry between self and foreign ligands of HLA-B27 might trigger autoimmunity. More recently, theories based on several non-antigen presentation properties have emerged. In this section recent data to determine whether any biochemical features of HLA-B27 can supply clues to its enigmatic role in AS have been reviewed, and comments are also made on future potential directions of biochemical research into HLA-B27. The study of the biochemistry of HLA-B27 has revealed a number of unique observation s, many of which center around the efficiency with which it undergoes folding within the endoplasmic reticulum (ER), leading to the presence of unfolded heavy chains which are predisposed to form dimmers B272 structures (Chapter 15). The observation that the HLA-B27 heavy chain has a tendency to misfold has raised the possibility that associated diseases may belong to a rapidly expanding category ofprotein misfolding disorders. In transgenic rats, overexpression of 132m results in a drastic decrease of the misfolded heavy chain in the ER, demonstrat ing that promoting the formation of HLA-B27/peptide complexes is sufficient to curb misfolding . Enhanced accumulation of misfolded heavy chains during the induct ion of class I expression by cytokines, can cause ER stress resulting in activation of the unfolded protein response (UPR). Adaptation to chronic ER stress is associated with modification of an NFKB-dependent pathway. Effects of UPR activation on cytokine production are beginning to emerge and may provide important missing links between HLA-B27 misfolding and spondyloarthritis. Chapter 16 reviews the current knowledge about HLA-B27 misfolding in human cells and in the transgenic rat model of spondyloarthritis-like disease and the consequences of HLA-B27induced UPR activation. These mechanisms could be relevant to the relationship between HLA-B27 and host-pathogen interaction. One form of SpA is reactive arthritis (ReA), which develops as a complication after certain bacterial infections. Since most of the patients suffering from ReA are HLA-B27 positive, it has been proposed that HLA-B27 may modulate the interaction between ReA-triggering bacteria and the host cell. Homodimer B272 formation and misfolding ofHLA-B27 heavy chain in the endoplasmic reticulum (ER) may trigger ER/stress signaling pathways in the host cell, which in turn may modulate cell signaling in favor of ReA-triggering. Chapter

viii

Preface

17 summarizes the observations of HLA-B27 modulating the interaction between ReA-triggering bacteria and the host cell and discusses the potential mechanisms behind the interaction. Transgenic models have now been developed that will hopefully allow a clearer view of the function of B27 in the pathogenesis of the disease. Chapter 18 evaluates the different models and presents an overview of the most prominent. Areas of investigation to which these models contribute include the role HLA-B27, processes of spinal and peripheral joint inflammation and calcification, immune responses to candidate antigens, and the role ofTNF. Finally, the last part ofthe book contains a section on the immunological aspects of SpA. Most immune responses, both innate and adaptive, involve activation of multiple cell types, as results of which may up-regulate the mechanism of cell activation in patients. SpA inflammation is most likely the result of defects at different levels in the immune system. The classical role ofHLA-B27 is to present peptides from intracellular pathogens for recognition by the T-cell receptor (TCR) of CD8+ T cells . Different studies have focused on a model of cross-reactivity based on self, viral and bacterial peptides that share sequence and structural similarities and trigger T-cell responses in a disease-susceptible context thus giving strong support to this hypothesis. According to this theory, traditionally reported as the "arthritogenic" peptide hypothesis, cytotoxic CD8+ T cell responses against cross-reactive self and foreign antigens presented by the HLA-B27 with AS could be the primary pathogenic event in the autoimmune process . The possible implications of T-cell crossreact ivity between self and viral epitopes (peptides) in AS pathogenesis is discussed in Chapter 19. Chapter 20 explores different aspects of dendritic cell (DC) function in relation to SpA. The response of DC is essential to the initiation and modulation of most antigen-specific inmunoresponse as well as being involved in innate immune responses. DC are particularly well equipped to detect these bacterial products using the immune innate Toll like receptors (TLR) and other bacterial sensors The response of DC to TLR ligands can be strongly influenced by the physiologic state of the endoplasmic reticulum of the cell. Also, NK recognition of non-canonical conformations of HLA-B27, in the form ofB27 2 homodimers by members ofthe killer cell immunoglobulin-like (KlR) and leukocyte immunoglobulin-like (LILR) receptor families, has been reported as a potential contributor to AS development (Chapter 21). Upregulation of B272 in spondyloarthritis and the differential interaction of ｾ Ｒ ｭ Ｍ｡ｳ ｯ｣ｩ｡ｴ･､ HLA-827 and B27 2 with NK immune receptors could be involved in the pathogenesis of 827associated spondyloarthritis (AS). In addition, several association studies based on a model in which KlRs synergize with HLAs have also been reported. This interaction may generate compound genotypes, which provide different levels of activation or inhibition. Furthermore, some of these have been associated with certain SpA, such as ankylosing spondylitis (AS) and psoriatic arthritis (PsA) (reviewed in Chapter 23). Finally, the contribution of other innate immune receptors, such as pathogenassociated molecular patterns (PAMP) and TLR in SpA, constitute an important group for attention. Their potential role in SpA is discussed in Chapter 22.

Preface

ix

I am extremely grateful to all authors for their contribution to this textbook. My hope is that such volume as Molecular Mechanisms ofSpondyloarthropies will help to provide a better knowledge of these complex diseases.

Carlos Lopez-Larrea

ABOUT THE EDITORS...

CARLOS LOPEZ-LARREA is a Professor of Immunology (UCM, Madrid, Spain) and currently Head ofthe Histocompatiblity Unit at the Hospital Universitario Central de Asturias, Oviedo, Spain. He is a world expert on spondyloarthropathies (SpA), in particular genetic (MHC) and immunologic factors that influence the development of SpA. His primary research is focused on understanding the role of HLA-B27 polymorphism in the development of ankylosing spondylitis (AS), and describing relevant associations of B27 subtypes with AS in large extended worldwide populations . In the last decade, the availability of HLA-B27 subtypes differentially associated with the disease has provided a unique tool for exploring the relationship between peptide specificity and pathogenetic potential. The main research interests of his group currently include the role of innate immunity (NKs) in SpA. He is a member ofseveral national and international scientific organizations. It is now over ten years since the first edition of HLA-B27 in the Deve/opement of Spondy/oarthropathies (SpA) edited by C. Lopez-Larrea was published. This current book aims to synthesize the growing knowledge in the field and present all recent studies concerning basic research in SpA.

xi

ABOUT THE EDITORS...

ROBERTO OiAZ-PENA is a predoctoral investigator in the Histocompatibility Unit of the Oepartment of Immunology, Hospital Universitario Central de Asturias. He graduated in biochemistry, at the University of Oviedo, Spain. His main research interests include the genetics ofspondyloarthropathies, especially ankylosing spondylitis, and the role of inhibitory and activating KlR receptors in this disease.

xii

PARTICIPANTS Allen P. Anandarajah Clinical Immunology Research Center Rochester, New York USA Antony N. Antoniou Bute Medical School University of St. Andrews Fife, Scotland

Bruno Filipe Bettencourt Hospital de Santo Espirito de Angra do Heroismo Azores and Institute for Molecular and Cell Biology Porto Portugal

UK Jacome Brogues Armas Immunogenetic Service Hospital de Santo Espirito de Angra do Heroismo Azores Portugal Dominique Baeten Clinical Immunology and Rheumatology Academic Medical Center University of Amsterdam Amsterdam The Netherlands Michael Benjamin School of Biosciences Cardiff University Wales

Miguel Angel B1anco-Gelaz Department of Immunology Hospital Universitario Central de Asturias Oviedo Spain Paul Bowness MRC Human Immunology Unit Weatherall Institute of Molecular Medicine John Radcliffe Hospital Headington , Oxford UK

Jiirgen Braun Rheumazentrum Ruhrgebiet Heme Germany

UK

xiii

Participants

xiv

Matthew A. Brown Diamantina Institute of Cancer Immunology and Metabolic Medicine Princess Alexandra Hospital Woolloongabba Australia and University of Oxford Institute of Musculoskeletal Sciences Botnar Research Center Nuffield Orthopaedic Center Headington, Oxford UK Chun-Hsiung Chen Institute of Clinical Medicine National Yang-Ming University and Veterans General Hospital Taipei Taiwan Chung-Tei Chou Division ofAllergy, Immunology and Rheumatology Veterans General Hospital Taipei Taiwan Robert A. Colbert Division of Rheumatology Cincinnati Children's Hospital Medical Center Cincinnati, Ohio USA Ana Rita Couto Hospital de Santo Espirito de Angra do Heroismo Azores and Institute for Molecular and Cell Biology Porto Portugal Monica L. DeLay Division of Rheumatology Cincinnati Children's Hospital Medical Center Cincinnati, Ohio USA

Roberto Diaz-Pefia Hospital Universitario Central de Asturias Oviedo Spain Maria T. Fiorillo Department of Cell Biology and Development University Sapienza Roma Italy J.S . Hill Gaston Department of Rheumatology University of Cambridge Addenbrooke's Hospital Cambridge UK Jane C. GoodaIl Department of Rheumatology University of Cambridge Addenbrooke's Hospital Cambridge UK Kaisa Granfors Department of Bacterial and Inflammatory Diseases National Public Health Institute Turku Finland Robert D. Inman University of Toronto Toronto Western Hospital Toronto, Ontario Canada Lorna B. Jarvis Department of Rheumatology University of Cambridge Addenbrooke's Hospital Cambridge UK

xv

Participants

Simon Kollnberger MRC Human Immunology Unit Weatherall Institute of Molecular Medicine John Radcliffe Hospital Headington, Oxford UK

Dennis McGonagle University of Leeds Leeds and Calderdale Royal Hospital Halifax UK

Gerlinde Layh-Schmitt Division of Rheumatology Cincinnati Children's Hospital Medical Center Cincinnati, Ohio USA

Herman Mielants Department of Rheumatology University Hospital Ghent Ghent Belgium

Andreas Leibbrandt Institute of Molecular Biotechnology Austrian Academy of Sciences Vienna Austria Bernhard Loll Max-Planck-Institut fllr Medizinische Forschung Abteilung fur Biomolekulare Mechanismen Heidelberg Germany Jose A. Lopez de Castro Centro de Biologia Molecular Severo Ochoa Universidad Autonoma de Madrid Madrid Spain Carlos Lopez-Larrea Hospital Universitario Central de Asturias Oviedo Spain Walter P. Maksymowych Alberta Heritage Foundation for Medical Research University ofAlberta Edmonton, Alberta Canada

Rolf Misselwitz Institut filr Immungenetik Charite -Universitatsmedizin Berlin Freie Universitiit Berlin Berlin Germany Josef M. Penninger Institute for Molecular Biotechnology Austrian Academy of Sciences Vienna Austria Markus A. Penttinen Department of Medical Microbiology and Immunology University ofTurku Turku Finland Simon J. Powis Bute Medical School University of St. Andrews Fife, Scotland UK John D. Reveille Division of Rheumatology and Clinical Immunogenetics University of Texas Health Science Center Houston, Texas USA

Participants

xvi

Anna S. Sahlberg Department of Bacterial and Inflammatory Diseases National Public Health Institute Turku Finland Susana G. Santos Bute Medical School University of St. Andrews Fife, Scotland

UK Georg Schett Department of Internal Medicine 3 Institute for Clinical Immunology University of Erlangen, Nuremberg Erlangen Germany Edward M. Schwarz Clinical Immunology Research Center Rochester, New York USA Rosa Sorrentino Department of Cell Biology and Development University Sapienza Roma Italy Dawn P. Sowders Division of Rheumatology Cincinnati Childrens Hospital Medical Center Cincinnati, Ohio USA Paul P. Tak Division of Clinical Immunology and Rheumatology Department of Internal Medicine Amsterdam The Netherlands

Joel D. Taurog Rheumatic Diseases Division Department of Internal Medicine University of Texas Southwestern Medical Center Dallas, Texas USA Barbara Uchanska-Ziegler Institut ftir Immungenetik Charite-Universitatsmedizin Berlin Freie Universitat Berlin Berlin Germany Bernard Vandooren Clinical Immunology and Rheumatology University ofAmsterdam Ghent Belgium Ruth Wittoek Department of Rheumatology University Hospital Ghent Ghent Belgium David Tak Yan Yu Rheumatology Division Rehabilitation Center University of California Los Angeles, California USA Libin Zhang Department of Rheumatology University of Cambridge Addenbrooke's Hospital Cambridge

UK Andreas Ziegler Institut fur Immungenetik Charite-Universitatsmedizin Berlin Freie Universitat Berlin Berlin Germany

CONTENTS 1. CLINICAL ASSESSMENT IN THE SPONDYLOARTHROPATHIES ••••• 1 Ruth Wittoek and Herman Mielants Abstract 1 Introduction .................••.....................................................•••......••....•...............•.•..•............•1 Ankylosing Spondylitis 2 Psoriatic Arthritis.................•...............................•.............•...•....•..•..............••••.•.........•.....•.9

2. IMAGING IN SPONDYLOARTHRITlS•..........•..•....••••••...•••••.••••••••••••••••••• 17 Walter P. Maksymowych Abstract.........•..•....•..••...........•.....•...............•.....•..................•....•..•.........••..•...••••..••..•.••....... 17 Introduction 17 Plain Radiography .............•............................•...................................•....•.••.•....••....•..•..•... 18 Computed Tomography 21 Isotopic Imaging 21 Ultrasound 22 Magnetic Resonance Imaging .........•....................•..............•..............•....•...........•............. 22 Sacroiliac Joint ......................••..•.........................................•..••....•.••.....•........••.........•........24 Spine 27 Conclusions 33

3. SPONDYLOARTHRITlS, DIFFUSE IDIOPATHIC SKELETAL HYPEROSTOSIS (DISH) AND CHONDROCALCINOSIS •••••••••••••• 37 Jacome Brogues Annas, Ana Rita Couto and Bruno Filipe Bettencourt Abstract Introduction Spoodyloarthritis Diffuse Idiopathic Skeletal Hyperostosis (DISH) Chondrocalcinosis/Crystal Deposition Disease (Cppd CDD) Molecular Genetics Conclusions

37 37 37 40 40 42 47 xvii

xviii

Contents

4. THE ENTHESIS ORGAN CONCEPT AND ITS RELEVANCE TO THE SPONDYLOARTHROPATHIES...•.•............•.....•.•.•••..••..•••.• 57 Michael Benjamin and Dennis McGonagle Abstract 57 Introduction 58 Enthesis Organ Structure 58 Mechanisms for Reducing Stress Concentration at the Enthesis Itself 63 Related Concepts••..................................•...................••........................... .......................•... 66 Conclusions 67

5. SYNOVIAL AND MUCOSAL IMMUNOPATHOLOGY IN SPONDYLOARTHRITIS

71

Bernard Vandooren, Paul P. Tak and Dominique Baeten Abstract•......•......••....................................•.....•••.•....•.....••....................•...•..•........................ 71 Introduction ••..•...•...........•......•...•.............•.•.....•.•........•..•.....•....•.....••..•...•............•...•..•..•....71 Axial Versus Peripheral Spondyloarthritis.........••.....•.....•....•..•.......•........•.....•.....••.....••.• 73 Skeletal Remodeling in Spondyoarthritis ...........•••..•.....•..•.........•...••...••.•.............•.•.•.•.•..73 Synovial Biomarkers in Spondyoarthritis ......•...•.•..•.....•..•.•.......••...•..••••............•..•••.....•.75 Gut Inflammation in Spondyloarthritis ..•.•..•...........•...•.•.....•..•............••.........•.....•......•..• 76 The Pathogenesis of Spondyloarthritis: The Mucosa Hypothesis 77 Innate Immunity and Mucosal Inflammation 77 Adaptive Immunity and Mucosal Inflammation 78 The Pathogenesis of Joint Inflammation 78 Conclusions 79

6. BONE LOSS IN THE SPONDYLOARTHROPATHIES: ROLE OF OSTEOCLAST, RANKL, RANK AND OPG IN THE SPONDYLOARTHROPATHIES

85

Allen P. Anandarajah and Edward M. Schwarz Abstract..•..•...•...•.•.............•.......•......•.•................. ..•..••.....•.............••.....•.•..•..•........•.•.....•....85 Introduction ...•............................•...............................•....•............•••.•......................•.......... 85 Pathogenesis of Bone Loss 86 Bone Loss in the Spondyloarthritis .........•..•.........•........ ................... ................................ 91 Bone Loss in Ankylosing Spondylitis.•.•.......................•...•....•.........•................•.......••.•..... 91 Bone Loss in PsA 93 Bone Loss in Enteropathic Arthritis.................•......••.....•.....•..•......•....•..............••••..•....... 93 Bone Loss in Reactive Arthritis .•..•................................••......................................•.•........ 95 Conclusions.......•.......................•.....•................... .....•.......•.......•...................................... ..•.95

Contents

7. RANKL/RANK AS KEY FACTORS FOR OSTEOCLAST DEVELOPMENT AND BONE LOSS IN ARTHROPATHIES

xix

100

Andreas Leibbrandt and Josef M. Penninger Abstract Introduction Basic Characteristics of the Rankl-Rank-Opg Axis RANKL-RANK-OPG Interactions and Bone Remodeling RANK(L) SignaUng Pathways Modulators of Rankl-Mediated Osteoclastogenesis Rank-Rankl as Therapeutic Targets for Arthropathies Conclusions

100 100 101 l04 104 107 109 110

8. BONE FORMATION VERSUS BONE RESORPTION IN ANKYLOSING SPONDYLITIS

114

Georg Schett Abstract Introduction Lessons from Rheumatoid Arthritis Structural Damage in Ankylosing Spondylitis Mechanism of Joint Formation-Molecular Lessons for Joint Fusion Bony Protrusion as a Stress Response of the Joint Osteoblast-The Bone Forming Cells From the Osteoblast to the Osteophyte Molecular Regulation of Osteophytes Concepts of Osteophyte Formation Why Do Osteophytes Grow in AS and not in RA? Conclus ions

114 114 114 115 115 115 116 116 116 117 118 120

9. BIOMARKERS IN SPONDYLOARTHROPATHIES

122

Chun-Hsiung Chen, David Tak Van Yu and Chung-Tei Chou Abstract Introduction Purpose of Developing Biomarkers in Ankylosing Spondyltis How do Investigators Assess the Degree of Usefulness of SpondyUtis Biomarkers? Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of Metalloproteinases (TIMPs) Expression of MMP-3 in Ankylosing Spondylitis Correlation between Serum MMP-3 and Disease Activity Sensitivity and Specificity of Serum MMP -3 in Evaluation of Disease Acti vity Changes of Serum MMP-3 in Response to Therapies

122 122 122 125 125 126 126 126 127

xx

Contents

Serum MMP-3 as Predictor of Disease Progression Are Molecules Reflecting Cartilage Turnover Biomarkers of Ankylosing Spondylitis? Macrophage Colony Stimulating Factor (M-CSF) Serum Amyloid A (SAA) Interleukin-6 (IL-6) Conclusions

127

10. THERAPY OF SPONDYLOARTHRITIDES

133

128 128 128 129 129

Jiirgen Braun Abstract Introduction Management. Imaging Conclusions

133 133 134 138 143

11. GENOMEWIDE SCREENS IN ANKYLOSING SPONDYLITIS

148

Matthew A. Brown Abstract Introduction Methods for Identifying Disease-Causing Genes Linkage Studies and Ankylosing Spondylitis High Density Association Studies and Ankylosing Spondylitis MHC Genetics of Ankylosing Spondylitis Future Studies Conclusions

148 148 149 150 151 153 154 155

12. SUBTYPES OF HLA-B27: HISTORY AND IMPLICATIONS IN THE PATHOGENESIS OF ANKYLOSING SPONDyLITIS .... 159 John D. Reveille Abstract Introduction HLA-B27 Subtypes Associations with AS The Lack of Disease Association ofHLA-B*2706 and HLA-B*2709 How Amino Acid Differences Between HLA-B27 Subtypes May Impact on Disease Pathogenesis Conclusions

159 159 166 167 167 172

Contents

xxi

13. IMPLICATIONS OF STRUCTURAL AND THERMODYNAMIC STUDIES OF HLA-B27 SUBTYPES EXHIBITING DIFFERENTIAL ASSOCIATION WITH ANKYLOSING SPONDYLITIS ••••••••••••••••••••••••••••••••.•••••.•••••••••..••••••••••••••••••••••••••••••••••. 177 Andreas Ziegler, Bernhard Loll, Rolf Misselwitz and Barbara Uchanska-Ziegler Abstract Introduction General Structural Properties of HLA Class I Molecules HLA-B27 Subtypes Exhibiting Differential Disease Association HLA-B27: Peptide Complexes for Structural and Other Biophysical Studies Structural Studies with the m9 Peptide Structural Studies with the Proven HLA-B27 Self-Peptide Tis Structural Studies of the Viral Peptide pLMP2 HLA-B27 Subtype Dependent Conformational Peptide Dimorphisms HLA-B27 Subtype- and Peptide-Dependent Molecular Mimicry Thermodynamic Analyses of Selected HLA-B27: Peptide Complexes Conclusions

177 178 178 180

186 187 189 192

14. HLA-B27-BOUND PEPTIDE REPERTOIRES: THEIR NATURE, ORIGIN AND PATHOGENETIC RELEVANCE

196

180 181 183 185

Jose A. Lopez de Castro Abstract Introduction HLA-B27 Polymorphism and Association to AS Peptide Specificity of HLA-B27 Subtypes T-Cell Presentation of Shared Ligands by HLA-B27 Subtypes Molecular Mimicry between Self and Foreign Ligands of HLA-B27 The Origin of HLA-B27-Bound Peptide Repertoires: Role of the Proteosome Assisted Loading of the HLA-B27 Peptide Cargo Conclusions

196 196 196 199 202 203 204 204 206

15. BIOCHEMICAL FEATURES OF HLA-B27 AND ANTIGEN PROCESSING

210

Simon J. Powis, Susana G. Santos and Antony N. Antoniou Abstract Introduction The MHC Class I Assembly Pathway A Key Role for Cys-67? HLA-B27 in Dendritic Cells Conclusions

210 210 211 212 213 214

xxii

16. HLA-B27 MISFOLDING AND SPONDYLOARTHROPATHIES

Contents

217

Robert A. Colbert, Monica L. DeLay, Gerlinde Layh-Schrnitt and Dawn P. Sowders Abstract 217 Introduction 217 Usual, Unusual and Unique Features ofHLA-B27 and Their Potential Role in Disease Pathogenesis 218 Importance of Protein Folding 219 220 Consequences of Protein Misfolding HLA-B27 Misfolding 222 Evaluating the Role of HLA-B27 in Disease 223 HLA-B27 Subtypes and Spondyloarthritis 228 The Model of SpA...•.......•.........•......................... 229 Overexpression of Additional ｨｾＲｭＺ Conclusions 229

17. HLA-B27 AND HOST-PATHOGEN INTERACTION ..••...••...•...........•.. 235 Anna S. Sahlberg, Kaisa Granfors and Markus A. Penttinen Abstract Introduction The Molecular Characteristics of HLA-B27 HLA-B27 and Host-Pathogen Interaction HLA-B27 and Host Cell-Pathogen Interaction HLA-B27 and Survival of Intracellular ReA-Triggering Bacteria HLA-B27, ER Stress-Induced Signal Transduction Pathways and Host-Pathogen Interaction HLA-B27 and LPS-Induced Inflammatory Response Conclusions

235 235 236 236 237 238 239 240 241

18. ANIMAL MODELS OF SPONDYLOARTHRITIS

245

Joel D. Taurog Abstract Introduction Naturally Occurring Spondyloarthritis in Primates Proteoglycan-Induced Spondylitis and Arthritis in Mice Naturally Occurring Spontaneous Models Ankylosing Enthesopathy HLA-B27 Transgenic Mice TNF Transgenic Mice HLA-B27 Transgenic Rats A New, Improved AS Model in HLA-B27 Transgenic Rats Conclusions

245 245 245 246 246 247 248 248 248 249 250

Contents

xxiii

19. T-CELL RESPONSES AGAINST VIRAL AND SELF-EPITOPES AND HLA-B27 SUBTYPES DIFFERENTIALLY ASSOCIATED WITH ANKYLOSING SPONDyLITIS 255 Maria T. Fiorillo and Rosa Sorrentino Abstract 255 Introduction 255 Searching for the Holy Grail: From B27-Restricted Viral Antigens to Self-Ligands Eliciting Autoreactive Cytotoxic T-Cell Responses in Patients with Ankylosing Spondylitis.••••••••.••••.•.•....••••.....•••......••....••..•••..••.••••...256 Extension of T-Cell Cross-Reactivity to a Third Player: pGR.......••.....•••.••••.....•..••••... 259 T'-Cell Cross-Reactivity between Self and Non-Self: The tCR Point of View ••••••.•••.••260 Conclusions ..•.....•.••.•••••..•.....••.•..••...•....•.•.....•••.....•.•••.•....•.......••........••.......•...••••.....•..••••...261

20. DENDRITIC CELL: T-CELL INTERACTIONS IN SPONDYLOARTHRITIS•.••••......••....•.......•••....•••................•.••.••.••• 263 J.S. Hill Gaston, Lorna B. Jarvis, Libin Zhang and Jane C. Goodall Abstract•...•......................•...................................................•...•••......•.......••.........•.•.•••..••...263 Introduction.•.................•............................................................••......••...••...•....••.•..•........ 263 A Novel Subset of CD8+T Cells 264 The Influence ofthe Unfolded Protein Response on DC Function••......••..................••270 Conclusions................•............••...........•.•.....•.•...•....•.•.•.........•..•.•••...•..••..•.•...•....•..•..••....... 275

21. THE ROLE OF B27 HEAVY CHAIN DIMER IMMUNE RECEPTOR INTERACTIONS IN SPONDYLOARTHRITIS....•... 277 Simon Kollnberger and Paul Bowness Abstract...............................................................................•........................... ••...•..•...•..... 277 Introduction 277 Leukocytes Express Cell Surface B27 Heavy Chain Homodimers.•...•....•.....•...........•. 278 Immune Receptors Interacting with HLA-B27 Heterotrimers and Dimers .......••..... 279 Differential Binding ofB27 2 and B27 Heterotrimers to KIR, LILR and PIR•........•.•281 Involvement of KIRJDL2-Expressing T'-Cells and NK-Cells in Spondyloarthritis 282 Conclusions 282

22. KIR GENES AND THEIR ROLE IN SPONDYLOARTHROPATHIES

286

Roberto Diaz-Pefia, Miguel Angel Blanco-Gelaz and Carlos Lopez-Larrea Abstract Introduction Complexity of KIR Family KIR and Spondyloarthropathies Conclusions

286 286 287 292 295

xxiv

23. INNATE IMMUNITY OF SPONDYLOARTHRITlS: THE ROLE OF TOLL-LIKE RECEPTORS

Contents

300

Robert D. Inman Abstract.••...•..••..........•...........•....................................••......•.......................•....•................. 300 I ntroduction 300 Current Concepts in Innate Immunity 301 Innate Immunity in Host Response to Arthritogenic Bacteria 302 Innate Immunity and Spondyloarthritis 304 Conclusions 307

INDEX

311

ACKNOWLEDGEMENTS This book was supported in part by Spanish Grants SAF-2004 /02669, FYCIT (PC-07/006) and by CAJASTUR and ASHISTO.

xxv

CHAPTER!

Clinical Assessment in the Spondyloarthropathies Ruth Wittoek and Herman Mielants'"

Abstract n order to measure disease activity. progression and response to therapy, it is important to use accurate, reliable and feasible outcome measures that can ideally be used in longitudinal cohorts. clinical trials and clinical practice . With emerging therapies, the focus on the methodology ofoutcome assessment has increased to ensure that discriminant and responsive instruments are used. This chapter reviews available measures of three major areas of disease impact in the spondyloarthropathies (disease activit y. structural damage and functioning) and discusses the relevance for use in clinical practice. First. the outcome measures available for the assessment of different domains in ankylosing spondylitis, composite-indice s and response criteria for use in clinical trials and clinical practice in ankylosing spondylitis are discussed. Secondly, the performance ofthe se in psoriatic arthritis and more disease-specific instruments in psoriatic arthritis are discussed.

I

Introduction The spondyloarthropathies (SpAs) are a group ofdisorders with common clinical, radiological and genetic features, clearly distinct from other inflammatory rheumatic d isorders such as rheuma toid arthritis (RA). Ankylosing spondylitis (AS) is the prototype disease belonging to this concept. Other diseases that are considered to be part of this group are psoriatic arthritis (PsA), arthritis associated with inflammatory bowel diseasessuch as Crohn'sdiseaseand ulcerative colitis and reactive arthritis. Patients are classified as having SpA if the y have either inflammatory low back pain or a peripheral arthritis with any ofthe following: positive family history, psoriasis, alternating buttock pain , enrhesopathy or sacroiliitis (the European Spondyloarthropathy Study Group (ESSG)).I Specific classification criteria are made for AS and PsA (the CASPAR criteria for PsA2 and the modified New York criteria for AS3).Patients fulfilling the ESSG criteria but cannot be classified into one of the more specific subgroups are termed undifferentiated spondyloarthropathies. There a major heterogeneity in the clinical landscape of the SpAs. There 's a possibility of combination in any individual patient ofaxial disease (sacroiliids, spondylitis), several peripheral articular disease manifestations, going from peripheral arthritis (generally pauci-articular, asymmetrical and by preference involving the joints ofthe lower limbs) to enrhesitis and dactylitis and extra-articular manifestations (such as uveitis, psoriasis, inflammatory bowel disease). Due to the broad clinical spectrum of the manifestation of the disease, it is obviously difficult to assess the disease activity by a single outcome measure.

' Cor respo nd ing Author: Herman Mielants-Department of Rheumatology, University Hospital Ghent, De Pintelaan 185, 900 0 G hent, Belgium. Email: herman.miel [email protected]

Molecular Mechanisms ofSpondyloarthropathies, edited by Carlos Lopez-Larrea and Roberto Diaz-Peiia. ©2009 Landes Bioscience and Springer Science+Business Media.

2

Molecular Mechanisms ofSpondyloarthropathies

In order to measure disease activity, progression and change with therapy, it is important to use accurate , reliable and feasible measures that can ideally be employed in longitudinal cohorts, clinical trials and clinical practice. Over the past SO years, multiple outcome measures and composite scoring systems have been developed and are availablefor clinical application. Frequently these measurements have not been standardized or assessedfor reliability, validity, or sensitivity to change. Moreover, performance of some measures is time-consuming and may not be feasible in clinical practices. Therefore the goal would be to identify a minimum number of individual clinically appropriate measures to accurately assess the different manifestations of disease. Therefore, the OMERACT (Outcome measures in rheumatoid arthritis clinical trials) process involves consensus on outcome measures and is based on the 'OMERACT filter: composed ofthree key components: truth, discrimination and feaslbiliry," Truth addresses the issuesofface, content, construct and criterion validity; or does the instrument measure what it is intended to? Is the result unbiased and relevant? Discrimination addresses issues ofreliability (inter- and intraobserver) and sensitivity to change . Does the instrument detect differences between groups? Feasibility addresses whether the measure can be easily applied or used with regard to time, money, training, scoring , interpretability and acceptance by physician and patient. The assessment ofdiseasein SpA is a subject that has attracted increasing attention over the last few years. The advent of biologic treatments, such as tumor necrosis factor (TNF) inhibitors, has provoked a therapeutic breakthrough in inflammatory rheumatic diseases and consequently raised the interest in the development and validation ofobjective and standardized tools to assessdifferent aspects of the disease in order to investigate the efficacy ofthe newer therapeutical options.' In particular, groups such as the Assessments in Ankylosing Spondylitis (ASAS) international working group and later also the group for Research and Assessments in Psoriasis and Psoriatic Arthritis (GRAPPA), in conjunction with the Society for Outcome measures in Rheumatology, have contributed to the development ofsuch instruments and their diffusion amongst the rheumatologic community. The most important question is to decide what to measure in a patient and how to measure it? Therefore it is important to determine which aspects of the disease are the most appropriate to measure.

Ankylosing Spondylitis Disease activity in ankylosing spondylitis (AS) is measured by multiple measures including metrology, radiology, laboratory, functioning and disabiliry," The ASAS group established a core set offive domains and also the choice ofmeasure to represent each domain: the domains are the patient's global assessment, pain, physical function, spinal stiffuess/inflammation and spinal rnobility,?·8 The patient's global assessment is represented by the VAS (visual analogue score) global assessment score (0-100 scale), pain is represented by the VAS pain score (0-100 scale), function is represented by the BASFI score (0-100 scale) and inflammation is represented either by (first choice) the mean ofthe two morning stiffness-related BASDAI VAS scores or by (second choice) morning stiffness duration with a maximum of 120 minutes. With regard to spinal mobility, ther e is lower consensus about the preferred measure to assess this domain. The ASAS working group has recommended that spinal mobility measures be used as part of the disease controlling antirheumatic therapy criteria."

Symptoms and Disease Activity The predominant symptoms ofthe disease are related to the spine. Acute symptoms, pain and stiffness represent the inflammatory activity of the disease.

Axial Pain Spinal involvement is the characteristic and most prominent feature ofAS. The pain is mostly located in the sacroiliacal joints and the spine. Inflammatory low back pain (IBP) (Table 1) is thought to originate from the active disease process and mechanical back pain is thought to originate from structural damage due to ongoing disease. Classically, IBP is associated with morning

Clinical Assessment in the Spondyloarthropathies

3

Table 1. Criteria for inflammatory low back pain Chronic back pain >3 months and Onset of disease 30 minutes 2. Awakening due to pain in the second half of the night 3. Improvement upon exercise, not with rest 4. Alternating buttock pain 3 out of 4 criteria: high likelihood of IBP

stiffness and nocturnal pain (in the second halfofthe night) and improves upon physical activity. Alternating buttock pain is often present in AS. In contrast, mechanical pain worsens by activity and improves by rest. Recently, a new set of criteria for IBP is established and performed better than previous criteria in AS patients with established disease (Table 1).9 A prospective study is needed to validate the diagnostic properties ofthe new candidate criteria set in patients with early disease. The ASAS core set specifies nocturnal spinal pain and general spinal pain as the two most useful measures for monitoring pain in patients with AS. Pain can be measured quantitatively and qualitatively on a number ofscales.The most commonly used scales are visual analogue scales (VAS) on which the patient can indicate the level of pain that was experienced over a period of time on a continuous line of 100 mm length running between 'no pain' and 'unbearable pain' and numerical rating scales (NRS) where the patient rates the experienced pain between 0 ('no pain') and 10 ('unbearable pain').

Stiffness In AS, morning stiffness primarily refers to stiffness ofthe spine due to inflammation. During the development of the ASAS response criteria , the average ofduration and severity ofmorning stiffness performed better than either of the two scales separately. The easiest method to assess morning stiffness is to measure ftom the time of awakening . This can be done quantitatively or by indicating the duration on a VAS scale using 'no spinal stiffness' and 'two hours or more ' as extremities on the 100 mm line. Peripheral Disease Manifestations Although AS is primarily a disease of the axial joints (spine , sacroiliacal and hip joints), extra-axial manifestations ofthe disease are frequent and need separate assessment. Approximately 25% of the patients will have active peripheral joint involvement, typically oligoarticular, asymmetrical and by preference involving the lower limbs. There are no specific assessment tools available for AS, however the existing tools in RA are widely used in clinical trials in AS. A 44-joint count has been proposed to measure peripheral joint involvement in clinical trials, which covers the joints most commonly affected in AS and is thus more specific than the customary 28-joint count in RA. Although a useful tool for baseline assessment in clinical practice, this is clearly insufficient for monitoring the individual patient for disease progression or treatment response in affected joints. The assessment of enthesitis in AS patients is even more problematic. Many potential sites of enthesitis are clinically inaccessible and therefore difficult, if not impossible , to assess. Clinical examination of enthesitis in the lower limbs has a sensitivity of only 22.6% and a specificity of 79.9%, giving a positive predictive value ofIess than 60%.10 There are currently three validated instruments used in clinical trials for measuring enthesitis: the Mander (Newcastle) Enthesitis Index (MEl) was the first standardized instrument to assess the tenderness over entheses in AS patients. I I More recently, two other indices has been described and validated; the Maastricht Ankylosing Spondylitis Enthesitis Scale (MASES) and the Berlin Entheslris Index (BEl). The MASES is the most accepted and takes into account the 13 most specific and sensitive sites from the MEl (first costochondral joint, seventh costochondral joint,

4

Molecular Mechanisms ofSpondyloarthropnthies

posterior superio r iliac spine, anterior superio r iliac spine, iliac crest, fifth lumbar spinous process and proximal insertion of the Achill es tendon). It sco res each site as 0 ('no pain') or 1 ('painful'), giving a total pos sible score of 0-13. It is certainly a more feasible instrument, but it has not been assessed in other diseases ofthe SpA concept including PsA. Moreover, the fact that it does not sco re one of th e m ain enthesitis sites of th e feet (inse rt ion of the plantar fascia on the calcaneus) gives rise to so me co ncern with mo st clinici ans. To overcome this, Braun et aJl2used an enthesis index composed of 12 major entheses reported to be commonly affected in the inflammato ry process in AS in a stu dy on infliximab in AS. It is scored sim ilarly as the MASES, giving a po ssible score of 0-12. The index did not perform better compared to the MASES in th e above -mentioned stu dy, however Gladman et al 13 have reported on the performance of inve stigators from the C anadian Spondyloarthropathy Group in the ir ability to reliably assess four different enthesitis area: the plantar fascia, the Achilles tendon, tibial tuberosity and rotator cuff insertions. Observer agreement was 'moderate' in the first three locations and 'poo r' in the fourth. Fatigue Fatigue is an important cause of morbidity in AS. It's reported in up to 65% of patients, but oft en under-recognized by physicians. It has an important impact on many different aspects ofthe general wellbeing ofa patient, including the ability to perform daily act ivitie s and social contacts. There is no specific instrument or questionnaire that mea sure s fatigue in AS but the general fat igue questionnaires perform well in AS . The simplest tool is a VAS scale ranging from 'no fatigue' to 'very severe fatigue'. The ASAS international working group ha s selected the BASDAI question on fatigue as the preferred instrument to assess fatigue in AS. Mobility It is not possible to differentiate between changes in spinal mobility due to inflammation and those due to spinal ankylosis. Therefore, isolated spinal measurements are not informative, but have to be interpreted alongside other information on the patient's status. Different individual measures are available and are all feasible to perform in clinical practice. Performance of those measurements in practice are de scribed by the ASAS working group on the website."

Cervical Rotation Cervical rotation can be tested in several ways. By using a Myrin inclinometer full rotation from left to right can be measured or with a tape measure the change in difference between the chin and the coronoideus process in maximal cervical rotation from left to right can be measured. Another method using a tape mea sure assesses the d ifference in the distance between a mark in the suprastern al notch and the tragus ofth e right ear when the neck is rotated from left to rlght." The Bath Ankylosing Spondyliti s Metrology index (BASMI) measure s cervical ro tation using a gravity-action goniometer. The inter- and intraobserver reliability is 0.98 and 0.99 respectively." All different ways have shown to be reliable. However, measurements th at require specific instrument may be less feasible in daily practice.

LateralFlexion ofthe Neck Thi s can be me asured by using an incl inometer or by measuring the distance between the tragus and th e coronoideus process ofthe clavicle in maximal lateral bending of the head to the left and right. Both methods correlate moderate with radiological change (r = 0.57 and r = 0.60, respectively) and show excellent inter- and intraobserver reliability (ICC 0.90 and 0.96 , respectively for mea suring by inclinometer and ICC 0.97 and 0.98, resp ectively for tape mea suring)."

Chin to Chest Th e mea sure of the forward flexion of th e ne ck is found to correlate poorl y with radiological di sease. It is, ho wever, found to be reliable, with inter- and intraobserver co rrel ation of 0.92 and 0.95 , respecrively.v It has not been included as an outcome measure in clinical trials, so sens itivity to cha nge is not available.

ClinicalAssessment in the Spondyloarsbropatbies

5

Occiput to Wall Distance (OWD) This measures the distance between the occiput and the wallwhen the patient stands with heels and shoulder against the wall with the back straight. It is found to correlate with radiographic change and is also proved to be sensitive to change, with an effect size of0.25. 16 Tragus to Wall Distance (TWD) The distance between the tragus of the ear and the wall is measured when the patient stands with heels and buttocks against the wall, knees straight, shoulders back and places the head as far as possible,keeping the chin in . Correlation with radiographs washigh (r ｾ 0.92) and intraobserver reliability is very good (r = 0.99). OWD and TWD are equally reliable in assessing thoracic spine extension. It's recommended to measure the OWD over TWD since in the former a value ofzero easily distinguishes patients with normal thoracic spine extension from kyphotic patients.'? Schober's Test Several variations exist on the Schober's test. The original report in 1937 18 described the Schober's test as the distance between the lumbosacral junction and a mark 10 em above this, recorded when the patient bends maximally forward. A first modification was done by Macrae and Wright,19 which added an additional mark 5 cm below the first mark and showed that both the original Schober and their modification reflected forward flexion (confirmed by radiographs). Moll and Wright further refined the Schober's test by providing an anchor for the lumbosacral junction using a line across the upper limit ofthe dimples ofVenus.20 The subject was asked to bend forward maximally and the new distance between the upper and lower marks was measured. A moderate correlation between spinal mobility and duration ofsymptoms in patients with AS and no correlation with age were found." The modified Schober is included as one ofthe measures of the BASMI. However, in the BASMI the first mark is made as a line across the iliac crests, which is at the level of L5 rather than at the lumbosacral junction. Inter- and intraobserver reliability of the Macrae and Wright modification of the Schober's test is excellent (ICC 0.96 and 0.94) and it correlates well with the radiographic changes in the spine (ICC 0.7l).22The modified Schober is demonstrated to be sensitive to change (ES 0.24), following intensive physiotherapy, although another study could not confirm rhis." Moreover, the Schober's test did not distinguish between patients treated with active drug or placebo in a placebo controlled Randomized Clinical Trial(RCT) with infliximab in AS.24 Finger to Floor Distance Forward flexion of the spine using finger to floor distance was included among the measures stud ied by Viitanen et al l6 and proved to have a good reliability and sensitivity, but did not correlate with radiographic changes. Another study demonstrated that finger to floor distance improved following physiotherapy in patients with AS.23 Lateral Lumbar Flexion The distance between the tip ofthe third finger and the floor when the patient stands upright with heels, buttocks and shoulder against the wall and when the patient maximally bends sideways without lifting the opposite foot offthe ground is measured . This method provides excellent reliability and is easy to perform using only a tape measure and requires minimal training. Chest Expansion This is measured by difference in chest circumference between full expiration and inspiration at the fourth intercostal space. Chest expansion did not correlate with radiographic changes (r = 0.38).16.22 However, intra- and interobserver reliability is good (ICC 0.95 and 0.85, respectively) and sensitivity to change was noted, with an effect size of0.42. Although chest expansion did not correlate with radiographic change, it did provide reliability and discrimination and is included in the BASMI and the ASAS response criteria.

6

Molecular Mechanism s ofSp ondyloarthropathies

Intermalleolar Distance Intermalleolar distance measures abduction ofthe hips. Keeping the knees straight and the legs in contact with the resting surface, the patient is asked co take the legs as far apart as po ssible and the distance between the medial malleoli is measured. Intermalleolar distance provides excellent inter- and intraobserver reliability (ICC 0.98 and 0.99, respectively) and is part of th e BASMI. Although widely used, the occiput-co-wall di stan ce and modified Schober's test primarily reflect irreversible structural damage and demonstrate limited sensitivity co change in studies of intensive physiotherapeut ic interventions. I3,23.25 BASMI (Bath Ankylosing Spondylitis Metrology Index) The ASAS core set initially recommended the use ofthre e measurement s: the occiput-co-wall distanc e, co reflect the cervical and thoracic mobility, chest expan sion , which evaluates the thoracic expansion capacity and the modified Schober index, to measure the lumb ar mobility. At a later stage, the lateral lumba r flexion was added co the ASAS core set. Another possibility is the composite index of several measures, the entire Bath Ankylosing Spondylit is Metrology Index (BASMI) (Table 2). This score includes the measurements of cervical rotation , tragus-to-wall d istanc e (which showed to be equivalent co the OWD in a direct comparative stu dy, I? anterior lumbar flexion (modified Schober test), lateral lumbar flexion and intermalleolar d istance. The HASMI was published with a 0-2 answer ing scale (BAM SI2) and a 0-10 mod ification (BAMSIlO) : co calcu late the BASMI2 each of the five assessments is scored between 0 and 2 based on a conversion table ; the BASMI lOuses categories between 0 and 10. BASM12 the sum ofthe five separate assessments, BASMI lOis the sum ofthe five assessments divided by five, thus giving a range between 0 (best possible) and 10 (worst possible) (Table 3). Amongst all five assessments, the lateral lumbar flexion seems co have the highest standardized response mean (thus the best representing the total BASMI),26 followed by the Schober's test." Finally, chest expansion, the only assessment of rib cage mobility, although no t used in the BASMI has proved to be sensitive to change during anti-TNF trialS.28•29

Table 2. Outcome measure to assess movements of the spine and hip. The respective elements of the BASMI and fDASMI Location Cerv ica l spi ne

Lumbar spine

Direction of Movement

BASMI

X Cervical rot ation by grav ity actio n goniometer Cervica l rotation by tape measure between chin and the corono ideus pro cess Lateral flexion Lateral flexion of the neck Forw ard flexion Chin to chest Occi put to w all Tragus to w all X Forward flexion Schober's test

EDASMI

Rot ation

M odified Scho ber Finger to floo r distance Lateral lumbar flexion Chest expansion

X

Abduction Intermalleolar distance Internal rotation

X

Lateral flexion Thoracic spine Hi p

Outcome Measure

X

X

X X

X

7

Clinical Assessment in the Spondyloartbropatbies

Table 3. Conversion table BASMI BASMI

o

Tragus-to-wall (em) Cervical rotation n Lumbarside flexion (em) Modified Schober's (em) Intermalleolar distance (em)

70 >10 >4 >100

2 15-30 20-70 5-10 2-4 70-100

>30 0.1) and thus are very unlikely to be truly associated with the condition. Insufficient markers were studied in the other genes , which await further studies to determine their true significance.

MHC Genetics ofAnkylosing Spondylitis The MH C , situated on chromosome 6 (6p21.3), extends over 3.6Mb and contains about 220 genes, many of which have immunoregulatory functions. There is compelling evidence that the MHC contains several other nonB27 determinants ofdisease-susceptibility, including the HLA-B allele, HLA-B60 and nonHLA-B genes. The association ofHLA-B60 with AS is much weaker than the association with B27, with an odds ratio of3.6.67It is uncertain as to whether HLA-B60 is also disease-causing itself, or a marker ofan MHC haplotype bearing other disease causing genes. The association ofHLA-B60 with disease is well established in B27 -positive cases67 ,68 and there is data suggesting a role in B27 -negative AS. 67 To identify other MHC genes involved in AS, investigators have studied association ofother MHC Class II and III genes with disease. We have reported association ofHLA-D RB 1*01 with AS in a B27 -matched case-control study" and in twins." Carriage ofHLA-DRBl*08 in B27 -positive A S cases is associated with younger age of symptom onset and the occurrence of uveitis ,?l,n and weakly with susceptibility to AS,?osuggesting that nonB27 MHC gene s may also influence severity and clinical manifestations of AS. Several small association studies have implicated other MHC gene s in A S, although the studies have been too small and targeted to determine whether these are primary associations or due to linkage disequilibrium with other loci (reviewed in ref. 73). A recent study investigating the protective effect of HLA-B*2709 from AS in Sardinians has suggested that this may be due to linkage disequilibrium with a nonsynonymous SNP in HLA-E (rsI264457, P = 6 x 10-6) , which encodes a R128G substitution." Strangely, comparing B*2705 and B*2709 haplotypes for thi s SNP, no significant difference is noted, so it is hard to see how it can explain the protective effect of B*2709, unless B*2705 Sardinians have different MHC haplotypes to those seen elsewhere in Italy and Europe. This data is interesting but as it involves only a small sample size and for some control sets genotype data was available from fewer than half of the cohort, clearly further studies are required. Controlling for linkage disequilibrium acros s the MH C is also challenging and in many studies not properly handled. Analyses that involve imputation of haplorypes in unrelated individuals should determine the posterior probability of correct haplotype assignment. Many studies use the EM algorithm for haplotype imputation; this algorithm depends on the presence of significant linkage disequilibrium between markers for accuracy. In many implementations of the algorithm, imputed haplotype outputs can even be produced for markers where no linkage disequilibrium exists between them (e.g., even on separate chromosomes) which is obviously nonsense. Clearly analysis ofthis region, which is characterised by extreme allelic diversity yet major haplotypic preservation, requires a sophisticated and skilled analysis to avoid erroneous findings. The WTCCC AS study genotyped 897 MHC SNPs in 1000 AS cases and 1500 healthy controls. These studies showed extremely strong and broad association of the MHC with AS,

154

Molecular M echanism s ofSpondyloarthropathies

CHROMOSOME 6

50 45 40

35

ｾ ro

30

ｾ 25 ,9; ｾ 20

I

15 10

5

o 30

31

31

32

32

33

33

34

34

Distance (Mb)

Figure 2. MHC findings from WTCCC AS study. The y-axis is -logt p-values) and x-axis distance fro m the p-telomere of chromosome 6 (March 20 0 6 hum an reference sequence (NCBI Build 36 .1 )). HLA-B lies at 31.4Mb a nd HLA-DRB1 at 32.7 Mb. with association with p-values 0 pre sent from 30.9 Mb to 32.5 Mb from th e p -relomere of chromosome 6 (see Fig. 2) . As th e cont rols in this anal ysis are not matched for HLA-B27 with th e cases, th is association probably reflect s both linkage disequilibrium with HLA-B27 and the pre sence of nonB27 MHC associated genes. To test for the pre sence of nonB27 MHC associations of AS, we recently completed a stu dy of B27-matched MHC haplorypes in cases and controls." The program 'PH ASE' was used to impute haplotypes and only haplotypes with >90 % posterior probability of correct assignment were carried forward in analysis. Comparing B27-rnarched case and control haplotypes, strong association was observed with DRBI irrespective of whether the haplotype carried HLA-B27 (B27-positive stran d P = 4 X 10-4, B27 -negative strand P = 5 X 10-8) . Specific MH C haplotypes were demonstrated to have highly Sign ificant association with AS, controlling fully for the carriage of B27. The effect size of these associations is substantial. The p opulation attributable fractions from spe cific MHC haplotypes range from 16.5% for the B27-/DR1+ haplotype, down to 3.5% for the B27 + / D RB 1*07;76 assuming an additive model, the attributable risk from these haplotypes is 34%. Thi s strongly suggests that further stu dies of the MHC for AS- susceptibility genes other than B27 are likely to be quite fruitful.

Future Studies In an ongoing study, a conso rtium of Australian, Briti sh and North Am erican investigators (the TA SC group) is performing a genom ewide association stu dy in AS. It is expected that thi s will be completed early in 200 8 and will involve 2000 AS cases and >6000 health y cont rols. The record of pre viou s genom ewide associati on stu dies suggests that thi s scan is likely to produce a small number ofclear-cut hits (low-hanging fru it ) and a moderately large number ofintermediate streng th associations (higher-hanging fru it ) wh ich will require further studies to determine th eir true sign ifican ce. Thi s scan will also be underpo wered to dete ct gen es invo lved in disease severity,

Genomewide Screens in Ankylosing Spondylitis

155

although arms ofthe consortium are investigatinggenetic determinants ofclinical and radiographic severity.Thus there will remain a need for scanning further cases, particularly those characterised for 'disease-severity' measures and AS-associated features, such as uveitis. Other areas which will require further research include the role ofcopy number variation and methylation patterns and the genetic determinants of the disease in other populations. There is a notable paucity of nonMHC genetic data about both AS and rheumatoid arthritis in Asian populations, despite clear evidence in the case of rheumatoid arthritis at least that the genetic determinants are different in Asian ethnic groups. Thus there will be a need for further studies involving even more cases. Studies in different ethnic groups may also be required to identify genes specific to those ethnic groups and to assist with defining the true associated variants in involved genes. Successful follow-up studies to genomewide association studies in other common diseases have required the study of thousands ofcases to produce convincingly clear cut findings, generally requiring the collaboration ofmany research and clinical groups. Thus whilst the TASC study will provide an unprecedented view of the genetic determinants ofAS susceptibility and clinical manifestations, it should be considered the foundation of future research programs into AS aetiopathogenesis rather than answering all the questions itself. Unfortunately the record in AS genetics and in other diseases is that the field has been considerably muddied by publication of numerous follow-up studies with inadequate sample sizes. Small cohorts can be ofuse when combined in prospective meta -analysis, such as in the meta-analysis of IL-l variants discussed above.

Conclusions The successful identification of ARTS] and IL23R should give those involved in AS genetics research great encouragement of the potential of this research. Hypothesis-free genetics research can identify the genes which are the main determinants ofwho develops AS and its clinical manifestations . The early experience in genomewide association studies indicates that some diseases are much more tractable to the approach than others. This relates to issues such as heritability, phenocopies and diagnostic uncertainty and the underlying genetic model. AS appears, like Crohns disease, to be highly tractable to investigation by this approach. The challenge will then be for the hypothesis-driven researchers to work out why these genes are associated with AS and what to do about it. Each additional piece of the jigsaw that genetic studies turns up brings us a little closer to cracking the aetiopathogenesis ofthe disease and some pieces,such as the IL2 3R finding, point directly to treatments. The findings we already have are ofdiagnostic utility. Given the rapid pace of advance of th is field over the last two years, the future of this field looks extremely promising.

Acknowledgements MAB is funded by an NHMRC (Australia) Principal Research Fellowship . Research presented in this review was largely funded by the Arthritis Research Campaign (U.K.),Wellcome Trust and National Institute ofArthritis, Musculoskeletal and Skin Diseases (USA).

References 1. Taurog JD, Richardson JA, Crofi JT et al. The germfree state prevents development of gut and joint

inflammatory disease in HLA-B27 transgenic rats. J Exp Med 1994; 180(6) :2359-64. 2. Brown MA, Kennedy LG, MacGregor AJ et al. Susceptibility to ankylosing spondylit is in twins : the role of genes, HLA and the environment. Arthritis Rheum 1997; 40(10) :1823-8. 3. Pedersen 0, Svendsen A, Ejstrup L er al. Heritabilit y estimates on ankylosing spondylitis. Clin Exp Rheumaro] 2006 ; 24(4) :463. 4. Brown MA, Brophy S, Bradbury L et al. Identification of major loci controlling clinical manifestations of ankylosing spondylitis. Arthritis Rheum 2003; 48(8) :2234-9. 5. Hamersma J, Cardon LR, Bradbury L et al. Is disease severity in ankylosing spondylitis genetically determined? Arthritis Rheum 2001 ; 44(6 ):1396-400. 6. Brophy S, Hickey S, Menon A et al. Concordance of disease severity among family members with ankylosing spondylitis? J Rheurnatol 2004; 31(9):1775 -8. 7. Rowland-Jones S, Colbert RA, Dong T et al. Distinct recognition of closely-related HIV-l and HIV-2 cytotoxic T-cell epiropes presented by HLA-B'2703 and B'2705 . AIDS 1998; 12(11) :1391-3.

156

Molecular Mechanisms ofSpondyloarthropathies

8. Risch N . Linkage strategies for genetically complex traits 1. Multilocus models. Am J Hum Genet 1990; 46(2):222-8. 9. Brown MA, Laval SH, Brophy S et aL Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis. Ann Rheum Dis 2000; 59( 11):883-6. 10. Lander ES, Botstein D. Strategies for studying heterogeneous genetic traits in humans by using a linkage map of restriction fragment length polymorphisms. Proc Nad Acad Sci USA 1986; 83(19):7353-7. 11. Hugor JP, Chamaillard M, Zouali H er aL Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 2001; 411(6837):599-603. 12. Laurin N , Brown JP, Morissette J et aL Recurrent mutation of the gene encoding sequestosome 1 (SQSTMl/p62) in Paget disease of bone. Am J Hum Genet 2002; 70(6) :1582-8 . 13. Ferrari SL, Deutsch S. Choudhury U ct aL Polymorph isms in the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with variation in vertebral bone mass. vertebral bone size and stature in whites. Am J Hum Genet 2004 ; 74(5):866-75. 14. Koay M , Woon P-¥, Zhang Y et aL Influence of LRP5 polymorphisms on normal variation in BMD . Journal of Bone and Mineral Research 2004; 19(10):1619-1627. 15. Little R, Carulli J, Del Mastro R et aL A mutation in the LD I. receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet 2002 ; 70:11-19. 16. Consortium WTCC. Genomewide association study of 14,000 cases of seven common diseases and 3000 controls. Nature 2007 ; 447:661-83. 17. Zhang G, Luo J, Bruckd Jet aL Genetic studies in familial ankylosing spondylitis susceptibility. Arthritis Rheum 2004; 50(7):2246-54. 18. Miceli-Richard C , Zouali H, Said-Nahal Ret aL Significant linkage to spondyloarthropathy on 9q31-34. Hum Mol Genet 2004; 13(15) :1641-8 . 19. Laval SH, Timms A. Edwards S et aL Whole-genome screening in ankylosing spondylitis : evidence of nonMHC genetic-susceptibility loci. Am J Hum Genet 2001; 68(4) :918-26. 20. Brown MA , Pile KD, Kennedy LG er aL A genome-wide screen for susceptibility loci in ankylosing spondylitis. Arthritis Rheum 1998; 41(4) :588-95 . 21. Carter KW; Pluzhnikov A, Timms AE er aL Combined analysis of three whole genome linkage scans for Ankylosing Spondylitis . Rheumatology (Oxford) 2007; 46(5):763-71. 22. Timms AE, Crane AM, Sims AM ct aL The interleukin 1 gene cluster contains a major susceptibility locus for ankylosing spondylitis . Am J Hum Genet 2004; 75(4) :587-95 . 23. van der Paardt M, Crusius JB, Garcia-Gonzalez MA er al. Inrerleukin-Ibeta and ineerleukin-I receptor antagonist gene polymorphisms in ankylosing spondylitis. Rheumatology (Oxford) 2002; 41(12) :1419-23. 24. McGarry F, Neilly J, Anderson N et al. A polymorphism within the interleukin 1 receptor antagonist (IL-IRa) gene is associared with ankylosing spondylitis. Rheumatology (Oxford) 2001 ; 40(12):1359-64. 25. Chou CT, Timms AE, Wei JC et al. Replication of association of 11.1 gene complex members with ankylosing spondylitis in taiwanese chinese. Ann Rheum Dis 2006; 65(8):1106-9. 26. Brown MA, Edwards S, Hoyle E et aL Polymorphisms of the CYP2D6 gene increase susceptibility to ankylosing spondylitis. Hum Mol Genet 2000; 9( 11): 1563-6. 27. Beyeler C, Armstrong M, Bird HA er aL Relationship between genotype for the cytochrome P450 CYP2D6 and susceptibility to ankylosing spondylitis and rheumatoid arthritis. Ann Rheum Dis 1996; 55(1):66-8. 28. WTCCC, TASC. A genome-wide scan of 14,000 nonsynonymous coding SNPs in 5.500 individuals : The Wellcome Trust Case Control Consortium. Nat Genet 2007; 39(11):1329-37. 29. Park H, Li Z, Yang XO et aL A distinct lineage of CD4 T-cells regulates tissue inflammation by producing interleukin 17. Nat Immuno12005; 6(11):1133-41. 30. Cua DJ, Sherlock J. Chen Y et aL Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003; 421(6924):744-8. 31. Murphy CA, Langrish CL. Chen Y et aL Divergent pro- and anti-inflammatory roles for 11.-23 and 11.-12 in joint autoimmune inflammation . J Exp Med 2003; 198(12):1951-7. 32. Duerr RH , Taylor KD, Brant SR et aL A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006; 314(5804):1461-3. 33. Tremelling M, Cummings F, Fisher SA et al. IL23R variation determines susceptibility but not disease phenotype in inflammatory bowel disease. Gastroenterology 2007; 132(5):1657-1664. 34. Cargill M, Schrodi S, Chang M er aL A large-scale genetic association study confirms ILl2B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 2007 ; 80(2):273-290. 35. Reveille JD, Zhou X. McGinnis Ret aL lnterleukin-23 receptor polymorphisms are a major determinant of susceptibility to ankylosing spondylitis. Nat Genet 2007; Submitted.

Genomewide Screens in Ankylosing Spondylitis

157

36. de Vlam K, Mielants H, Cuvelier C et al. Spondyloarthropathy is underestimated in inflammatory bowel disease: prevalence and HLA association. J Rheumatol 2000; 27( 12):2860-5. 37. Palm 0, Mourn B, Ongre A et al. Prevalence of ankylosing spondylitis and other spondyloarthroparhies among patients with inflammatory bowel disease: a population study (the IBSEN study). J Rheumatol 2002; 29(3):511-5. 38. Salvarani C , Vlachonikolis IG, van der Heijde DM et al. Musculoskeletal manifestations in a population-based cohort of inflammatory bowel disease patients. Scand J Gastroenterol 2001; 36(12):1307-13. 39. Scarpa R, del Puente A, D'Arienzo A er aI. The arthritis of ulcerative colitis: clinical and genetic aspects . J Rheumatol 1992; 19(3) :373-7. 40. Steer S, Jones H, Hibbert J et al. Low back pain, sacroiliitis and the relationship with HLA-B27 in Crohn's disease. J Rheurnatol 2003; 30(3) :518-22. 41. Thjodleifsson B, Geirsson AJ, Bjornsson S et al. A common genetic background for inflammatory bowel disease and ankylosing spondylitis: a genealogic study in Iceland. Arthritis Rheum 2007; 56(8):2633-9. 42. Hammer GE, Gonzalez F, Champsaur M er aI. The aminopeptidase ERAAP shapes the peptide repertoire displayed by major histocompatibility complex class I molecules. Nat Immunol 2006; 7(1) :103-12. 43. Kanaseki T, Blanchard N, Hammer GE er al. ERAAP synergizes with MHC class I molecules to make the final Cut in the antigenic peptide precursors in the endoplasmic reticulum. Immunity 2006; 25(5):795-806. 44. Cui X, Rouhani FN, Hawari F et al. Shedding of the type II IL-l decoy receptor requires a multifunctional aminopeptidase, aminopeptidase regulator of TNF receptor type 1 shedding. J Immunol 2003; 171(12):6814-9. 45. Cui X, Rouhani FN, Hawari F er al. An aminopeptidase, ARTS-I, is required for interleukin-6 receptor shedding. J Bioi Chern 2003; 278(31):28677-85. 46. Cui X, Hawari F, Alsaary S et al. Identification of ARTS-l as a novel TNFRl-binding protein that promotes TNFRI ecrodomain shedding. J Clin Invest 2002 ; 110(4) :515-26. 47. Vazquez-Dei MM, Garcia-Gonzalez A, Munoz-Valle JF er al. Inrerleukin Ibeta (IL-lbeta), IL-I0, rumor necrosis factor-alpha and cellular proliferation index in peripheral blood mononuclear cells in patients with ankylosing spondylitis. J Rheumatol 2002; 29(3):522-6. 48. Maksymowych WP, Rahman P, Reeve JP er al. Association of the III gene cluster with susceptibility to ankylosing spondylitis : an analy sis of three canadian populations. Arthritis Rheum 2006; 54(3) :974-85. 49. Rahman P, Sun S, Peddle L er al. Association between the inrerleukin-I family gene cluster and psoriatic arthritis. Arthritis Rheum 2006 ; 54(7) :2321-5. 50. Sims A-M, Timms A, Bruges Armas Jet al. Prospective meta-analysis of IL-l gene complex polymorph isms confirms associations with ankylosing spondylitis . Ann Rheum Dis 2007; Submitted. 51. Timms AE, Zhang Y, Bradbury L er al. Investigation of the role of ANKH in ankylosing spondylitis. Arthritis Rheum 2003 ; 48(10):2898-902. 52. Tsui FW; Tsui HW; Cheng EY et al. Novel genetic markers in the 5'-flanking region of ANKH are associated with ankylosing spondylitis. Arthritis Rheum 2003; 48(3):791-7. 53. Adam R, Sturrock RD, Gracie JA . TLR4 mutations (Asp299Gly and Thr399lle) are not associated with ankylosing spondylitis. Ann Rheum Dis 2006 ; 65(8):1099-101. 54. Gergely P jr, Blazsek A, Weiszhar Z et al. Lack of genetic association of the Toll-like receptor 4 (TLR4) Asp299Gly and Thr399lle polymorphisms with spondylarthropathies in a Hungarian population. Rheumatology (Oxford) 2006; 45(10):1194-6. 55. Snelgrove T, Lim S, Greenwood C et al. Association of toll-like receptor 4 variants and ankylosing spondylitis: a case-control study. J Rheurnarol 2007 ; 34(2):368-70. 56. van der Paardt M, Crusius JB, de Koning MH et al, No evidence for involvement of the Toll-like receptor 4 (TLR4) A896G and CD14-C260T polymorphisms in susceptibility to ankylosing spondylitis. Ann Rheum Dis 2005 ; 64(2):235-8. 57. Crane AM, Bradbury L, van Heel DA et al. Role ofNOD2 variants in spondylarthritis. Arthritis Rheum 2002 ; 46(6) :1629-33. 58. Miceli-Richard C, Zouali H, Lesage S et al. CARDI5/NOD2 analyses in spondylarchroparhy, Arthritis Rheum 2002; 46(5):1405-6. 59. van der Paardt M, Crusius JB, de Koning MH et aI. CARD15 gene mutations are not associated with ankylosing spondylitis. Genes Immun 2003; 4(1) :77-8. 60. van Heel DA, McGovern DP, Cardon LR et al. Fine mapping of the IBD 1 locus did not identify Crohn disease-associated NOD2 variants: implications for complex disease genetics. Am J Med Genet 2002; 111(3):253-9.

158

Molecular Mechanisms ofSpondyloarthropathies

61. van Heel DA , Dechairo BM, Dawson G er al. The IBD6 Crohn's disease locus demonstrates complex interactions with CARD15 and IBD5 disease-associated vari ants. Hum Mol Genet 2003: 12(20):2569-75. 62. D'Amato M . The Crohn's associated NOD2 3020InsC framesh i/i mutation does not confer susceptibility to ankylosing spondylitis. J Rheumatol 2002 : 29( 11):2470-1. 63. Ferreiros-Vidal I. Amarelo J. Barros F et al. Lack of association of ankylosing spondylitis with the most common NOD2 susceptibility alleles to Crohn's disease. J Rheumatol 2003 : 30(1):102-4. 64. Peeters H . Vander Ccuyssen B, Laukens D et al. Radiological sacroiliitis, a hallmark of spondylitis, is linked with CARD 15 gene polymorphisms in patients with Crohn's disease. Ann Rheum Dis 2004: 63(9):1131-4. 65. Kim TH. Rahman P.Jun JB et al. Analysis of CARD 15 polymorphisms in Korean patients with ankylosing spondylitis reveals absence of common variants seen in western populations. J Rheumarol 2004: 31(10) :1959-61. 66. Lopez-Larrea C, Blanco-GelazMA. Torre-Alonso JC et al. Contribution of KIR3DU /3DSI to ankylosing spondylitis in human leukocyte antigen-B27 Caucasian populations . Arthritis Res Ther 2006: 8(4):RI01. 67. Brown MA , Pile KD. Kennedy LG et al. HLA class I associations of ankylosing spondylitis in the white population in the United Kingdom . Ann Rheum Dis 1996: 55(4):268-70. 68. Robinson WP. van der Linden SM, Khan MA et al. HLA-Bw60 increases susceptibility to ankylosing spondylitis in HLA-B27+ patients. Arthritis Rheum 1989: 32(9) :1135-41. 69. Wei JC, Tsai WC. Lin HS er al. HLA-B60 and B61 are strongly associated with ankylosing spondylitis in HLA-B27-negative Taiwan Chinese patients. Rheumatology (Oxford) 2004: 43(7):839-42. 70 . Brown MA. Kennedy LG, Darke C et al. The effect of HLA-DR genes on susceptibility to and severity of ankylo sing spondylit is. Arthritis Rheum 1998; 41(3):460-5 . 71. Ploski R. Maksymowych W; Forre O. HLA-DR8 and susceptibility to acute anter ior uveitis in ankylosing spondylitis: comment on the article by Monowacul Islam er al. Arthritis Rheum 1996: 39(2):351-2. 72. Monowacul Islam SM. Numaga J. Fujino Y et al. HLA-DR8 and acute anterior uveitis in ankylosing spondylitis. Arthritis Rheum 1995: 38(4):547-50. 73. Sims AM, Wordsworth BP. Brown MA. Genetic susceptibility to ankylosing spondylitis. Curr Mol Med 2004; 4( I) :13-20. 74 . D'Arnaro M. Fiorillo MT, Carcassi C er al. Relevance of residue 116 of HLA-B27 in determining susceptibility to ankylosing spondylitis. Eur J Immunol1995: 25(11):3199-201. 75. Sims AM. Barnardo M, Herzberg I et al. Non B27 MHC associations of ankylosing spondylitis. Genes Immun 2007; 8(2) :115-23. 76 . Miettinen OS . Proportion of disease caused or prevented by a given exposure, trait or intervention. Am J Epidemiol 1974; 99(5) :325-32.

CHAPTER

12

Subtypes ofHLA-B27: Historyand Implications in the Pathogenesis ofAnkylosingSpondylitis John D. Reveille" and Rashmi M. Maganti

Abstract

H

LA-B27 represents a family of38 closely related cell surface proteins (encoded by the alleles HLA-B'2 70 J -39) called subtypes ofHLA-B27, mo st ofwhich have evolved from the ubiquitous HLA-B'2705 (specifically the B '27052 allele).1-2\ HLA-B27 subtypes are largelycharacterized by nucleotide substitutions (mostly nons ynonymous) in exons 2 and 3 which encode a 1and a2 domainsofthe peptide binding groove respectively. Table 1shows the description ofsequences ofHLA-B27 allele sequences. The subtypes could have arisen from B"2705 by point mutation (B"2703, B"2709 . B"2704 ). gene conversion (B"270 1. B"2702, B"2708) and reciprocal recombination(B"2707 )26B"270 6 could have arisen by interlocus gene conversion. Studies from different parts of the world reveal differences in the population distribution.

Introduction The Migrations ofHomo Sapiens and the Evolution ofHLA-B27 Subtypes Anthropologic and geneti c data strongly point to Eastern Africa as the site of origin Homo sapienssapi ens approximately 200 .000 years ago (Fig. 1).27After expanding into surrounding parts of Africa. H omo sapiens sapiens left Africa by successive migration s between 50,000 and 80 ,000 years ago, assumedly via two major routes-from the north across the Sinai peninsula, travelling th ough the middle East to Europe and Cent ral and Eastern Asia and via a southern route between th e horn of Africa and Arabia (where th e lower sea levels during periods of polar ice cap expansion made such travel po ssible). The latter group gave rise to the populations of southern India. the aboriginal groups ofSoutheast Asian and Indonesia and the Australian Aborigines.P''Ihe first group , travelling the northern route. migrated across northern and central Asia and crossed the Bering strait, which formed a land bridge due to the lower sea levels called Beringia, which gave rise to th e groups which would be event ually called Native Americans. HLA-B*270S is present nearly all populations ofthe world. It is the dominant subtype among the native populations ofeastern Siberia and North America and is present in approximately 90% of the B27 -positive individuals of northern European origin. B*2705 is further subdivided into B '270S2, B*270S3 and B*27054 by single silent nucleotide substitutions." Given its ubiquitous prevalence, it is likelyHLA-B'27052 originated, like Homo sapiens, in Africa. Further splits appear to have developed later, either through point mutation or gene conversion events and the resultant subtypes seem to have largely followed three patterns corresponding to directions of migrations from Africa (Figs. 1 and 2).1-25 "Correspond ing Author: John D. Reveille-Division of Rheumatology and Clinical Immunogenetics, University ofTexas Health Science Center, 5656 Kelly St., Houston, TX 77026, USA. Ema il: [email protected] Molecular M echanisms ofSpondyloarthropathies, ed ited by Carlos Lop ez-Larrea and Roberto Diaz-Pefia. ©2009 Landes Bioscience and Springer Science+Business Media.

160

M olecular Mechanisms ofSpondyloarthropathies

Table 1. First description of sequences of HLA-B27 allele sequences (http://www.ebi. ac.uklimgtlhla/alle/e.html) HLA-B Allele

Year Assigned

Reference

8* 2705 8*2702 8*2707 8*2703 8*2704 8*2706 8*2707 8*2708 8*2709 8*2770 8*2777 8*2772 8*2773 8*2774 8*2775 8*2776 8*2777 8*2778 8*2779 8*2720 8*2727 8*2722 8*2723 8*2724 8*2725 8*2726 8*2727 8*2728 8*2729 8*2730 8*2737 8*2732 8*2733 8*2734 8*2735 8*2736 8*2737 8*2738 8*2739

1985 1986 1987 1987 1987 1987 1991 1993 1994 1996 1996 1997 1998 1998 1998 1999 1999 1999 1999 2000 2000 2000 (revoked 2002) 2000 2001 2001 2004 2004 2005 2005 2005 2005 2005 2006 2006 2006 2007 2007 2007 2007

1 2,3 4 5 6 7 8 9 10

http://www.ebi.ac.uk / imgt/hla/allele .html 11

12 13 14 15 16 17 18 19 20 21 http://www.ebi .ac.uk/imgt/hla/allele.html 22 23 24 25 http ://www.eb i.ac.uk/imgt/hla/all ele .html 26 http ://www.ebi. ac .uk/imgt/hla/allele.html 27 http ://www.ebi .ac.uk/imgt/hla/allele.html http ://www.ebi .ac.uk/imgt/hla/all ele .html http://www.ebi .ac.uk/imgt/hla/allele.html 28 http ://www.ebi .ac.uk/imgt/hla/allele.html 29 http ://www.ebi .ac.uk / imgt/hla/allele.html http://www.ebi .ac.uk/imgt/hla/allele.html http://www.ebi .ac.uk/imgt/hla/allele .html

Subtypes with Substitutions in the First Domain (Group 1) The first pattern is characterized by specific amino acid sub stitutions in the a l domain and a mostly uniform a2 domain. The B27 subtypes following this pattern are found largely in African, Middle Eastern and European group (Figs. 2 and 3) . *2702 is the most frequently occurring allele ofthis group (Fig. 3), occurringprimarily in those ofMiddle Eastern (where it achieves the highest prevalence (Table 2)) , Northern African and

SubtypesofHLA-B27: Hi story and Implications in the Pathogenesis ofAnkylosing Spondylitis

161

Figure 1. The migration of modern Homo sapiens and presumed origins of HLA-B27 subtypes. The scheme outl ined above begins with a radiation from EastAfrica to the rest of Africa about 100 ,000 years ago and is fo ll ow ed by an expansion from the same area to Asia, probably by two routes, southern and northern between 60,000 and 40,000 years ago . Oceania, Europe and America were settled from Asia in that order. Listed are only geographic origins HLA-B27 subtypes of known population specificity. Those whose orig ins are not known (or originating from North American Caucasians of unspec ified ancestry, such as HLA-B*2701 , B*2710, B*2717, B*2721 , B*2728, B*2731 , B*2733, B*2734, B*2737, B*2738) are not listed.

European ancestry, being more frequent in Southern European groups. It is restricted to Caucasoids and accounts for 5-10% ofHLA-B27 subtypes in Europeans.HLA-B'2702 has also been described in Mestizo Mexicans and South American populations, probably reflecting European admixture. Its absence in subSaharan Africa, relatively high frequency in some groups and occasional occurrence in even Asian populations suggest that this subt ype is quite ancient, (perhaps occurring first soon after the initial migrations out of Africa) . It likely arose from HLA-B '2705 by a gene conversion event from other HLA-B alleles." The next most commonly occurring subtype in this group, HLA-B'2703, differs from B '2705 by only one amino acid, a substitution of histidine to tyrosine at position 59 in the u l domain. HLA-B'2703 likely evolved in West Africa, in where it occurs in up to 45% of B27 positive individuals." It is been observed outside Africa primarily among people of African descent," though ha s been reported in Lebanon, Greece, the Azores and even as far away as Taiwan (Table 2) . HLA-B'2708, although first identified in the British population.'? occurs most frequently in Asian Indian and Venezuelan controls (Table 2).38.39 It has also been reported less commonly in Turkey;" northwestern Spain" and was found to be associated with AS in a large family from the Azores, a Portuguese archipelago in the Atlantic ocean. This seemingly disparate occurrence is more difficult to explain, though the otherwise uncommon occurrence ofthis allele could be consistent with Portuguese colonization of western India in the seventeenth century. Alternatively, its widespread distribution and relationship to other rarer and more geographically discrete HLA-B27 subtypes (B'2712, B'27I8, B'2723, B'2733) suggest B'2708 may be a very ancient subtype that could have originated soon after early Homo sapiens sapiens left Africa (Fig. 1). HLA-B'2712 was first reported in a healthy family in Spain on the MHC haplotype A2-Cw2-B '2712- DRI 5-DQ6,42The presence ofthis subtype has also been reported in a Caucasian family from the British population on a haplotype containing HLA-A'29; B'27I2; Cw'1203;

162

M olecular M echanisms ofSpondyloarthropathies

HLA-B* 270S Afn calMtddle EastfEurope

MKtdi e East/Southern As ia

Eastern ASIa

Group

01 02 8 '2713

0

8'2703

1

0

8 '2717

1 0

CaUCilSlan

8'2737

1 0

CaUca&13l"I

8'2739

1

Atncan

01 02

0

HispaniC

8 '2731

0

Caucasian

8'2701

0

Ca uc

8 '2702

0

Caucas.lan

0

CaUCAlatl

0

caucasian

8'2716 8'2708

4

8 '2726

4 0

8'2729 8 '2712

7

8 '2723

Afr

Afncan

0

Cauea&lan

0

Cauca$lan

0

caucasian

8 '2730

3

1

Caucasian

8 '2733

3

4

Unknown

Group

0102

Cauc.lan

0

Group

8 '2736

1 0

A.... n

8 '2704

1

1

lI.,.n

8 '2715

1

2

ASian

8'2708

1

3

A.... n

8 '2725

1 3

8'2721

1 4

lI.,.n caucasian

8 '2711

1 5

ASian

8'2720

1 5

lI.,.n

8'2724

1

7

ASian

8'2718

9

1

A5lOn

1

Caucasian

1

Caucasian

8'2709

0

8 '2710

0

8 '2732

0

8'2738

0

1

UnknONn

8 '2726

0

2

caucasian Caucasian

caucasian

8 '2735

0

2

8'2727

0

3

Hlspamc:

8'271 4

0

3

Caucasian

MtddleEas.t

8 '2719

0

3

8'2734

0

4

8 '2707

0

caucasian We5/ A$lO

Figure 2. Subt ypes of HLA-B2 7 developed over Three Ancestral Pathways. PDai,t.l.on

10

'0

8'270502

mr rrv

.'2701 .'2702

-

. -.703 . '2704

.'270' . '"'2707 . '2708 . "270' 8 ·2710 ."2711 . '"'2712 . '2713 8 "271. . '2715 8 '"'271' ."2717 .'2718

8'271' .'2720 8'2721 8'2723 . '"'27:24 . '272& . '272. . ' 272 7 9 "2728

. ' 272' 8 ·2730 8'"'27 31 .'"' 273 2 . '2733

. ' 2734 8 '2735 8 '"'273'

8 '2737 8'"'2738

. '"'273'

eo

70 Ｚｭｾ｡ｷ

ｾ

so =nNcsn ｾ

100

110

or.P=u.

120 131 151 =aQ=:X: SSIlT1 ＢＬｾｮＮ］ｃＧｉｌｬｲ

160

172

A---- ---- ---- ---- -- ---------

- - - - - - ＭｹＭｾＭ

J.---- ---- ---- ---- -- --------- - - - - - - - - - - - - - - - - - -1:-------- - - - - - - - - - - - -:>-Y-- - - -1:-------- - - - - - 5 - - - - - - --Hlf-Y--;c- - - ---- ---- - - - - - - --------- - - - - - - - - - - - --11-- - - - - - - - - - - -- ---- ------------- ---- ---- -- -1:-------- - - - - - 5 - - - - - - - - 5 - - - - - - --Hlf-Y--

-- - - - - --N--I ---- ---- ---- ---- ---- ---- -- ---------

-

-8------

-

- - - - -Dr T- -

-

- - - - - - - - - - - - - - --tf-T-- - L - - - - - - - - - - - - - - - - - -

----------------

--5---5----- - 5--11 ----

;>-- - - - - - - - - -

;>-- - - - - - - - -5- -II - ; 0 : - - - - - - - - - - - - - - - - - - - - - - - - - -

- -- ---- --5-- ---- ---- ---- ---- -- -I----T----

-

-- - - -nz

T--- - ---- ------- - - - - -- ----------- ---- ---- -- ---------

-F- - - - - - - - - - - - -iIC---- - - - - - - - - - - - -- - - - - --1-- - - - -

-- - - s -nr T-Y-S--N

---- ---- ---- -- -[--------II-II-- - - - - - - - - - - - - - - - - - - - - - - - - - - --HN-Y-- i l - -

- -- - - - - --5-- - -- - - - ll-- - - - -

-:>-Y-- -

-

-1--------(--------

-

- - -H-T-Dl T-Y-5-- - - - - - - - - - - - - - - - - - - - - - - - - - - --Hlf-Y-- ;>--

-

-- - - - - --5-- - - - - - - - - - - - - - - - - - - -l-If----L----

-

-- ----(l - - 5 - - -;0:--- - - - - - - - - - - - - - - - - - - - - - - -

- -- ---- --5-- ---- --5-- ----

-1--------

- - - - - - - - - - - - - - - - - - - - -ilIf-Y-- - - - -- - - - - - --- ------ ------- ---- ---- ---- ---- -- -----T---R- - S - Dr T - Y - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

- - - - - - - -11--1 A - - - - - I I - I I - - - - - - - - - - - - - - - - - - - - -

-

-- ----(l

-

-- - - - - - - - - - - - - - - - - - - - - -

--5-- - - - - - - - - - - - - - - - - - - - - - - - - - - -- -- - -- -----5--- ---------- -----5-- ----a;- - - -5-- ------- -----HN--- a-- - - - - - - - - - -- ---- ---- ---- --5-- ---- --11>-- a-- - - - - - - - -... - - - ---- --5-- ---- ---- ---- ---- - - ---------Y- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -- - - - - -- ------- ------- ------- ----- -------------L----- ----- -x,------- ------- -If--- - - - - - - - - - - -

Figure 3. Am ino acid sequence of human leuko cyte anti gen HLA-B2 7 subt ypes in the di versit y regions of the first and second dom ains. + demonstrating onl y the po sitions show ing amino acid var iability. **HLA-B2713 differs from other B*270 5 alleles onl y in the leader pept ide of the first domain .

Northern Europe Denmark Sout hern Europe Spain (Galici a) Northern Spain Az ores Italy Sardini a Greece Cyprus (Greeks) Turkey Lebanon Jew ish Siber ia Nor thern Indi a Western Ind ia Japan Chi nese Singapore (Chinese) Taiwan Taiwan (Han- Chinese) Taiwan (Aborigi nes) Chinese Indonesian Native Indo nesians Ma lays Thailand M aor is Brazil N orth Af rica W est Africans

Populations

0.05

7

*2701

6

10 50

32

3

12

8

7

*2703

0.5

2

30 3 34 52 30 24 48 14

10 10 20 18 7

*2702

89 87 94 100 38 6 19 42 36

66

33 34 82

3

*2704

6 6 5 64 80 50 68

90 90 80 80 91 86 65 77 50 32 43 35 38 84 61 34 18 31 2 4 6

*2705

53

72

62 89

9 7

*2706

3

2

2

6 18

13

8 17 14 30

1 7 2

*2707

3

0.02

12

5

3

*2708

3 20

*2709

Table 2. HLA-B27 subtype frequencies % in different world populations. Only first 14 subtypes are shown

0.02

*2711

1

*2713