Diagnostic Criteria in Autoimmune Diseases

Yehuda Shoenfeld Tel-Aviv University, Tel-Aviv, Israel Ricard Cervera University of Barcelona, Barcelona, Catalonia, Spain M. Eric Gershwin University of California at Davis, Davis, CA, USA

Editors

With compliments of Editors Prof. Yehuda Shoenfeld Prof. Ricard Cervera Sheba Med. Center Hospital Clinic Dept. Medicine ‘‘B’’ Servei de Malalties 52 621 Tel-Hashomer Autoimmunes Israel Villarroel, 170 [email protected] 08036 Barcelona Catalonia, Spain [email protected]

Prof. M. Eric Gershwin University of California at Davis School of Medicine Division of Rheumatology, Allergy, and Clinical Immunology Davis, CA 95616 USA [email protected]

ISBN: 978-1-60327-284-1 (softcover) e-ISBN: 978-1-60327-285-8 ISBN: 978-1-60327-427-2 (hardcover)

DOI: 10.1007/978-1-60327-285-8

Library of Congress Control Number: 2008933364

# 2008 Humana Press, a part of Springer Science+Business Media, LLC All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Humana Press, 999 Riverview Drive, Suite 208, Totowa, NJ 07512 USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein.

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987654321 springer.com Preface

Autoimmune diseases are a family of more than 100 ill- strategies that arrest the autoimmune process before it nesses that develop when underlying defects in the immune can irreversibly damage the body, as also the ADCC system lead the body to attack its own organs, tissues, and points out. cells. While many of these diseases are rare, collectively But the first and most essential step in the management they affect, according to the Autoimmune Diseases Coor- of autoimmune diseases is, no doubt, the recognition of dinating Committee (ADCC) of the U.S. National Insti- the autoimmune disease itself by the attending physician. tutes of Health, between 14.7 and 23.5 million people in the Autoimmune diseases can affect any part of the body, and USA – up to 8% of the population – and their prevalence is have a myriad of clinical manifestations that make diag- rising. Because a complete cure is not available for nearly nosis an extremely difficult task. At the same time, auto- every one of these 100 autoimmune diseases, patients face a immune diseases share many features both at their onset lifetime of illness and treatment. And, because most of and during follow-up. In addition, overlapping genetic these diseases disproportionately afflict women, and are traits enhance susceptibilitytomanyofthediseases,so among the leading causes of death for young and middle- that a patient may suffer from more than one autoim- aged women, they impose a heavy burden on patients’ mune disorder, or multiple autoimmune diseases may families and on society. occur in the same family. For these reasons, major efforts in autoimmune disease Conversely, despite the diversity in their presentation research and development must be directed toward redu- and natural history, autoimmune diseases share a number cing the impact of these conditions. These efforts should of underlying mechanisms, and thus have the potential to include, among other goals and again according to the respond to treatment with the same or related therapies. ADCC, the generation of more accurate epidemiologic More selective and less toxic immunosuppressive and profiles of autoimmune diseases, the development of a immunomodulatory agents are currently being used to greater understanding of the fundamental biologic princi- treat these disorders, and promising immune tolerance ples underlying disease onset and progression, the provi- approaches are emerging. However, several factors limit sion of improved diagnostic tools to permit preclinical or our ability to conduct the most efficient clinical trials. For presymptomatic diagnosis, the creation of more effective example, we lack standardized classification and diagnos- interventions, and the production of public and profes- tic criteria for many autoimmune diseases. sional education and training programs. These problems have prompted us to gather in a com- For instance, the development of biomarkers can prehensive book a critical review of 103 autoimmune dis- enable earlier diagnosis as well as aid physicians in select- eases, dividing them into two main groups, namely ing and monitoring treatment. New technologies, such as systemic and organ-specific autoimmune diseases. We genomics and proteomics, can provide scientists with the hope to offer a contemporary overview of these conditions tools to study gene and protein patterns in tissue samples, with special emphasis on diagnosis. Each chapter contains providing vital insights into the onset and progression of the essential information required by attending physicians disease. However, we also need to gain a better under- as well as bench scientists to understand the definition of a standing of the distribution of these diseases through specific autoimmune disease, the diagnostic criteria, and epidemiologic studies, and of the environmental triggers the treatment. Moreover, established classification and that contribute to their onset. As we learn more about the diagnostic criteria have been quoted when available and, genetic and environmental factors contributing to these if not, authors have been asked to propose such criteria. diseases,wewillbeabletodevelop effective prevention Diagnostic Criteria in Autoimmune Diseases was conceived

v vi Preface for publication and debut on the occasion of the Sixth special thanks to Kathy Wisdom for her devotion and International Congress of Autoimmunity to be held in zeal in helping us to put this volume together. Porto, Portugal, on September 2008. Finally, and most importantly, this text is dedicated to We have tried to produce a book of considerable intel- the sufferers of autoimmune diseases in the hope that they lectual caliber and this would not have occurred without some day will be cured. the enthusiastic support of the authors. We wish to thank Yehuda Shoenfeld Richard Lansing and his staff at Springer for their hard Ricard Cervera work. The editors and all the contributors also extend M. Eric Gershwin Contents

Preface...... v Contributors ...... xiii

I. CLASSICAL SYSTEMIC AUTOIMMUNE DISEASES 1 Systemic Lupus Erythematosus ...... 3 Maria Laura Bertolaccini, Graham R.V. Hughes and Munther A. Khamashta 2 Antiphospholipid Syndrome ...... 9 Ricard Cervera and Ronald A. Asherson 3 Rheumatoid Arthritis ...... 15 Claudio Galarza-Maldonado, Loreto Massardo, Bernardo Pons–Estel and Mario H. Cardiel 4 Macrophage Activation Syndrome in Juvenile Idiopathic Arthritis ...... 21 Yackov Berkun and Shai Padeh 5 Adult Still Disease ...... 25 Alon Eisen and Howard Amital 6 Systemic Sclerosis ...... 31 Jennifer G. Walker and Marvin J. Fritzler 7Sjogren€ Syndrome ...... 37 Dimitris Mitsias and Haralampos M. Moutsopoulos 8 Mixed Connective Tissue Disease ...... 43 Marta Mosca, Rosaria Talarico and Stefano Bombardieri 9 Relapsing Polychondritis ...... 47 Mauro Galeazzi and Giovanni Porciello 10 Raynaud Phenomenon ...... 53 Mario Garcıá-Carrasco, Mario Jimeńez-Hernańdez, Ricardo O. Esca´rcega, Ivet Etchegaray-Morales and Juan Carlos Pe´rez-Alva 11 Drug-Induced Autoimmunity ...... 59 Martine Szyper-Kravitz and Yehuda Shoenfeld 12 The Multiple Autoimmune Syndromes ...... 65 Juan-Manuel Anaya, John Castiblanco and Adriana Rojas-Villarraga

vii viii Contents

II. SYSTEMIC VASCULITIS 13 Giant Cell Arteritis ...... 73 Gideon Nesher 14 Polymyalgia Rheumatica ...... 77 Gideon Nesher 15 Takayasu Arteritis ...... 81 Rosa Maria Rodrigues Pereira, Joze´lio Freire de Carvalho, Maurıćio Levy-Neto and Eloı´sa Bonfa´ 16 Polyarteritis Nodosa ...... 87 Jose´ Hernańdez-Rodrı´guez and Maria C. Cid 17 Microscopic Polyangiitis ...... 93 Cees G.M. Kallenberg 18 Wegener Granulomatosis ...... 99 Julia U. Holle, Elena Csernok and Wolfgang L. Gross 19 Churg-Strauss Syndrome...... 103 Philippe Guilpain and Loic Guillevin 20 Buerger Disease ...... 107 Michael Ehrenfeld and Raphael Adar 21 Behçet Disease ...... 113 Gerard Espinosa 22 Susac Syndrome...... 117 Manuel Francisco Ugarte and Ricard Cervera 23 Goodpasture Disease ...... 121 Thomas Hellmark and Ma˚rten Segelmark 24 Kawasaki Disease ...... 125 Jordi Anton and Rosa Bou 25 Cogan Syndrome ...... 129 Aharon Kessel and Elias Toubi 26 Henoch-Shoenlein Purpura ...... 133 Margalit Lorber 27 Cryoglobulinemic Syndrome ...... 137 Suk Seo and Natalie Julia To¨ro¨k 28 Hypersensitivity Angiitis ...... 141 Shimon Pollack

III. IDIOPATHIC INFLAMMATORY MYOPATHIES 29 Polymyositis...... 149 Georgina Espı´gol and Josep M. Grau 30 Dermatomyositis ...... 153 Andrea Doria, Chiara Briani, Anna Ghirardello, Sandra Zampieri, Piercarlo Sarzi-Puttini and Riccardo Rondinone 31 Clinically Amyopathic Dermatomyositis ...... 159 Richard D. Sontheimer, Pedram Gerami and Hobart W. Walling Contents ix

32 Sporadic Inclusion Body Myositis...... 165 Josep M. Grau and Albert Selva-O’Callaghan 33 Antisynthetase Syndrome ...... 169 Ira N. Targoff 34 Granulomatous Myositis ...... 175 Sergio Prieto and Josep M. Grau 35 Eosinophilic Myositis ...... 179 Albert Selva-O’ Callaghan and Josep M. Grau 36 Eosinophilic Fasciitis ...... 183 Albert Selva-O’ Callaghan and Josep M. Grau

IV. OTHER IMMUNE-MEDIATED SYSTEMIC DISEASES 37 Sarcoidosis ...... 189 Juan Man˜a´ 38 Spondyloarthropathies ...... 195 Michael Ehrenfeld 39 Periodic Fever Syndromes ...... 201 Shai Padeh and Yackov Berkun 40 Fibromyalgia Syndrome ...... 209 Arnson Yoav, Dvorish Zamir, Amital Daniela and Amital Howard

V. ENDOCRINE AND REPRODUCTIVE AUTOIMMUNE DISEASES 41 Hashimoto Thyroiditis ...... 217 Roberto Rocchi, Noel R. Rose and Patrizio Caturegli 42 Atrophic Thyroiditis ...... 221 Luis J. Jara, Olga Vera-Lastra and Gabriela Medina 43 Subacute Thyroiditis ...... 227 Yemil Atisha-Fregoso and Mario Garcia-Carrasco 44 Graves Disease...... 231 Francesca Menconi, Yael L. Oppenheim and Yaron Tomer 45 Postpartum Thyroiditis ...... 237 Alex Stagnaro-Green 46 Autoimmune Diabetes Mellitus...... 241 Felicia Hanzu and Ramon Gomis 47 Autoimmune Addison Disease or Autoimmune Adrenalitis ...... 251 Joze´lio Freire de Carvalho and Rodrigo Antonio Branda˜o Neto 48 Autoimmune Hypophysitis ...... 255 Daria La Torre, Alberto Falorni, Elena Bartoloni Bocci and Roberto Gerli 49 Autoimmune Parathyroid Disease ...... 259 Corrado Betterle 50 Autoimmune Polyendocrine Syndromes ...... 265 Angela Tincani, Angela Ceribelli, Ilaria Cavazzana, Franco Franceschini, Alberto Sulli and Maurizio Cutolo 51 Endometriosis ...... 271 Maurizio Cutolo and Simone Ferrero x Contents

52 Autoimmune Ovarian Failure ...... 277 Francisco Carmona 53 Autoimmune Orchitis ...... 281 Clovis Artur A. Silva, Eduardo Ferreira Borba, Marcello Cocuzza, Joze´lio Freire de Carvalho and Eloı´sa Bonfa´

VI. HEPATOBILIARY AND PANCREATIC AUTOIMMUNE DISEASES 54 Autoimmune Hepatitis ...... 287 Miguel Bruguera 55 Primary Biliary Cirrhosis...... 291 Carlo Selmi and M. Eric Gershwin 56 Primary Sclerosing Cholangitis ...... 295 Sharonjeet Sangha and Christopher L. Bowlus 57 Extrahepatic Manifestations in Patients with Chronic Hepatitis C Virus Infection ...... 301 Pilar Brito-Zero´n, Albert Bove´ and Manuel Ramos-Casals 58 Autoimmune Pancreatitis ...... 307 Salvador Navarro and Francesc Balaguer

VII. GASTROINTESTINAL AUTOIMMUNE DISEASES 59 Autoimmune Gastritis ...... 315 Ban-Hock Toh, Senga Whittingham and Frank Alderuccio 60 Ulcerative Colitis ...... 323 Karsten Conrad and Martin W. Laass 61 Inflammatory Bowel Disease...... 329 Miquel Sans and Carolina Figueroa 62 Celiac Disease ...... 335 Nicola Bizzaro and Elio Tonutti

VIII. CUTANEOUS AUTOIMMUNE DISEASES 63 Cutaneous Lupus Erythematosus ...... 341 Annegret Kuhn, Vincent Ruland and Gisela Bonsmann 64 Pemphigus and Bullous Pemphigoid ...... 349 Daniel Mimouni and Michael David 65 Vitiligo ...... 353 Sharon Baum, Aviv Barzilai and Henri Trau 66 Psoriatic Arthropathy ...... 359 Gleb Slobodin and Elias Toubi

IX. CARDIOVASCULAR AND PULMONARY AUTOIMMUNE DISEASES 67 Autoimmune Dilated Cardiomyopathy ...... 367 Udi Nussinovitch and Yehuda Shoenfeld 68 Are Autoimmune Manifestations in Human Dilated Cardiomyopathy Primary or Secondary Events? . . . . . 373 Lara Elizabeth Pereira and Aftab Ahmed Ansari 69 Rheumatic Fever ...... 379 Yaniv Sherer and Yehuda Shoenfeld Contents xi

70 Accelerated Atherosclerosis in Autoimmune Diseases ...... 383 Nicoletta Ronda and Pier Luigi Meroni 71 Idiopathic Interstitial Pneumonias ...... 389 Antoni Xaubet, Maria Molina-Molina and Anna Serrano-Mollar 72 Pulmonary Arterial Hypertension ...... 393 Isabel Blanco and Joan Albert Barbera`

X. NEUROLOGICAL AUTOIMMUNE DISEASES 73 Multiple Sclerosis ...... 401 Ron Milo and Ariel Miller 74 Myasthenia Gravis ...... 407 Alexander Gorshtein and Yair Levy 75 Lambert-Eaton Myasthenic Syndrome ...... 413 Bethan Lang 76 Amyotrophic Lateral Sclerosis ...... 417 Bethan Lang 77 Paraneoplastic Neurological Syndromes ...... 421 Tomeu Rossin˜ol and Francesc Graus 78 Guillain-Barre´and Other Immune-Mediated Neuropathies...... 427 Avraham Unterman, Yehuda Shoenfeld and Joab Chapman 79 Neuromylelitis Optica (Devic Syndrome) ...... 433 Joab Chapman 80 Central Nervous System Vasculitis ...... 435 Gisele Zandman-Goddard and Yehuda Shoenfeld 81 Autoimmune Epilepsy ...... 441 Sarosh R. Irani and Bethan Lang 82 Autoimmune Chorea ...... 445 Ziv Paz, Yehuda Shoenfeld and Joab Chapman 83 Autoimmune Sensorineural Hearing Loss ...... 449 Aharon Kessel and Elias Toubi

XI. OCULAR AUTOIMMUNE DISEASES

84 Autoimmune Retinopathies ...... 457 Joan Giralt and Alfredo Adan 85 Autoimmune Uveitis ...... 461 Francisco Assis de Andrade, Ivan Foeldvari and Roger A. Levy 86 Vogt-Koyanagi-Harada Disease ...... 467 Joze´lio Freire de Carvalho and Joyce Hisae Yamamoto 87 Orbital Myositis...... 471 Sergio Prieto and Josep M. Grau

XII. RENAL AUTOIMMUNE DISEASES 88 IgA Nephropathy ...... 477 Jordi Ara i del Rey xii Contents

89 Membranous Nephropathy ...... 487 Ziv Paz and Yehuda Shoenfeld 90 Minimal Change Nephropathy ...... 491 Pilar Arrizabalaga Clemente 91 Focal and Segmental Glomerulosclerosis ...... 497 Jose´ A. Ballarıń, Cristina Cabrera, Carlos Quereda and Montserrat Dıáz 92 Membranoproliferative or Mesangiocapillary Glomulonephritis ...... 503 Montserrat M. Dıáz, Laia Sans, Yolanda Arce and Jose´ Ballarin

XIII. HEMATOLOGIC AUTOIMMUNE DISEASES 93 Autoimmune Hemolytic Anemia...... 509 Urs E. Nydegger 94 Pernicious Anemia ...... 513 Mario Garcıá-Carrasco, Mario Jimeńez-Hernańdez, Claudia Mendoza-Pinto, Alejandro Ruiz-Arguëlles and Salvador Fuentes-Alexandro 95 Idiopathic Aplastic Anemia ...... 519 Baraf Lior and Levy Yair 96 Acquired Adult Pure Red Cell Aplasia ...... 525 Hedi Orbach, Gisele Zandman Goddard, Asher Winder and Yehuda Shoenfeld 97 Myelodysplastic Syndromes ...... 529 Laura F. Newell and Joseph M. Tuscano 98 Autoimmune Lymphopenia ...... 535 Amani Mankaı¨, Sophie Hillion, Vale´rie Devauchelle-Pensec, Alain Saraux, M. Eric Gershwin and Pierre Youinou 99 Autoimmune Neutropenia...... 539 Pierre Youinou, Amani Mankaı¨, Sophie Hillion, Yehuda Shoenfeld Christian Berthou and Ibtissem Ghedira 100 Autoimmune Thrombocytopenic Purpura ...... 543 Nurit Rosenberg, Yulia Einav and Boris Shenkman 101 Thrombotic Thrombocytopenic Purpura and Other Thrombotic Microangiopathic Hemolytic Anemias . . 547 Boris Shenkman, Yulia Einav and Ophira Salomon 102 Heparin-Induced Thrombocytopenia ...... 551 Gowthami M. Arepally and Douglas B. Cines 103 Autoimmune Coagulopathies ...... 557 Fabio Tucci and Rolando Cimaz

Index...... 561 Contributors

ALFREDO ADAN, MD, PHD, Department of Ophthalmology, YEMIL ATISHA-FREGOSO, MD, Department of Internal Medicine, Institut Clinic dOftalmologia, Hospital Clinic Universidad de Instituto Nacional de Cienias Medicas y Nutricion, Salvador Barcelona, Barcelona, Catalonia, Spain Zubiran, Mexico RAPHAEL ADAR, MD, Department of Medicine C and the Rheu- FRANCESC BALAGUER, MD, Department of Gastroenterology, matic Disease Unit and the Department of Vascular Surgery, Institut Clinic de Malalties Digestives i Metabo` liques, Hospital Chaim Sheba Medical Center, Tel-Hashomer, Israel, and the Clıńic, Barcelona, Catatonia, Spain Tel-Aviv University Tel-Aviv, Israel JOSE´ BALLARIN, MD, PHD, Nephrology Department, Puigvert FRANK ALDERUCCIO, BSC HONS, PHD, Department of Immuno- Foundation, Universidad Autońoma de Barcelona, Barcelona, logy, Monash University, Australia Catalonia, Spain DANIELA AMITAL, MD, Department of Psychiatry B, Ness-Ziona JOAN-ALBERT BARBERA` , MD, Department of Medicine, Univer- Mental Health Center, Ness-Ziona, Israel sity of Barcelona, and, Senior Consultant, Department of Pul- HOWARD AMITAL, MD, MHA, Head of Department of Medicine monary Medicine, Thorax Institute, Hospital Clıńic, Barcelona, D, Meir Medical Center, Kfar-Saba, Israel, Affiliated to Sack- Catalonia, Spain ler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel ELENA BARTOLONI BOCCI, MD, Department of Clinical and JUAN-MANUEL ANAYA, MD, Professor of Medicine, Cellular Experimental Medicine, Rheumatology Unit, University of Biology and Immunogenetics Unit, Corporation for Biological Perugia, Perugia, Italy Research, Medellıń-Colombia, and, Universidad del Rosario, AVIV BARZILAI, MD, Dermatology Department, Sheba Medical Bogota´, Colombia Center (Affiliated to the Sackler Faculty of Medicine), Tel JORDI ARA, MD, Nephrology Department, Hospital Germans Aviv University, Israel Trias, Badalona, Barcelona, Catalonia, Spain SHARON BAUM, MD, Dermatology Department, Sheba Medical FRANCISCO DE ASSIS ANDRADE, Hospital do Olho and Centro Center (Affiliated to the Sackler Faculty of Medicine), Tel Oftalmolo´gico de Botafogo, Rio de Janeiro, Brasil Aviv University, Israel AFTAB A. ANSARI, PHD, Professor, Department of Pathology, YACKOV BERKUN, MD, Lecturer, Sackler Faculty of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA Tel-Aviv University, Rheumatology and Immunology Clinic, JORDI ANTON, MD, Associate Professor, Pediatric Rheumatology Associate Director of Safra Childrens Hospital, Sheba Medical Unit, Hospital Sant Joan de Deú, University of Barcelona, Center, Tel-Hashomer, Israel Barcelona, Catalonia, Spain CHRISTIAN BERTHOU, MD, PHD, Department of Immunopathol- YOLANDA ARCE, MD, Nephrology Department, Puigvert ogy, Brest University Medical School, Brest, France Foundation, Universidad Autońoma de Barcelona, Barcelona, MARIA LAURA BERTOLACCINI, MD, Lupus Research Unit, The Catalonia, Spain Rayne Institute, King’s College London School of Medicine, GOWTHAMI M. AREPALLY, MD, Division of Hematology, Duke St. Thomas’ Hospital, London, UK University Medical Center, Durham, North Carolina CORRADO BETTERLE, MD, Chair of Clinical Immunologo, Endo- PILAR ARRIZABALAGA CLEMENTE, MD, PHD, Nephrology and crine Unit, Department of Medical and Surgical Sciences, Renal Transplant Service, Hospital Clinic, Biomedicial Investi- University of Padova, Padova, Italy gation Institute August Pi I Sunyer, Barcelona, Catalonia, Spain NICOLA BIZZARO, MD, Laboratory of Clinical Pathology, Ospedale YOAV ARNSON, Department of Medicine D, MD, Meir Medical Civile, Tolmezzo, Italy Center, Kfar-Saba, Israel, Affiliated to the Sackler Faculty of ISABEL BLANCO, MD, Servei de Pneumologia, Institut Clıńic del Medicine, Tel-Aviv University, Tel-Aviv, Israel To´rax, Hospital Clıńic, Universitat de Barcelona, Barcelona, RONALD A. ASHERSON, Division of Immunology, School of Catalonia, Spain Pathology, University of the Witwatersrand, Johannesburg, STEFANO BOMBARDIERI, MD, Rheumatology Unit, Department South Africa of Internal Medicine, University of Pisa, Italy

xiii xiv Contributors

ELOI´SA BONFA´, MD, Rheumatology Division, University of Saõ ELENA CSERNOK, MD, Department of Rheumatology, University Paulo, School of Medicine, Saõ Paulo, Brazil Hospital Schleswig-Holstein, Campus Lu¨beck, Lu¨beck GISELA BONSMANN, MD, Department of Dermatology, Univer- Germany sity of Mu¨nster, Mu¨nster, Germany MAURIZIO CUTOLO, MD, Research Laboratory and Clinical RODRIGO ANTONIO BRANDAÕ NETO, MD, Emergency Depart- Academic Unit of Rheumatology, Department of Internal ment of Saõ Paulo University, School of Medicine, Saõ Paulo, Medicine, University of Genova, Italy Brazil MICHAEL DAVID, MD, Dermatology Department, Rabin Medical MIQUEL BRUGUERA, MD, Liver Unit, Hospital Clıńic, University Center, Beilinson Campus, Petah Tiqwa, Israel, Affiliated to of Barcelona, Barcelona, Catalonia, Spain Tel-Aviv University, Sackler Faculty of Medicine, Tel-Aviv, ROSA BOU, MD, Pediatric Rheumatology Unit, Hospital Parc Israel Tauli, Sabadell, Barcelona, Catalonia, Spain VALE´RIE DEVAUCHELLE-PENSEC, MD, PHD, Department of ALBERT BOVE´, MD, Laboratory of Autoimmune Diseases ‘‘Josep Immunopathology, Brest University Medical School, Brest, Font’’, IDIBAPS, Department of Autoimmune Diseases, France School of Medicine, University of Barcelona, Hospital Clinic, MONTSERRAT M. DIÁZ, MD, Clinical Nephrology Department, Barcelona, Catalonia, Spain Puigvert Foundation, Universidad Autońoma de Barcelona, CHRISTOPHER L. BOWLUS, MD, Division of Gastroenterology Barcelona, Catalonia, Spain and Hepatology, University of California at Davis Medical ANDREA DORIA, MD, Division of Rheumatology, University of Center, Sacramento, California, USA Padova, Padova, Italy CHIARA BRIANI, MD, Department of Neurosciences, University ZAMIR DVORISH, MD, Department of Medicine D, Meir Medical of Padova, Padova, Italy Center, Kfar-Saba, Israel, Affiliated to the Sackler Faculty of PILAR BRITO-ZEROŃ, MD, Laboratory of Autoimmune Diseases Medicine, Tel-Aviv University, Tel-Aviv, Israel ‘‘Josep Font’’, IDIBAPS, Department of Autoimmune Diseases, MICHAEL EHRENFELD, MD, Department of Medicine C and the Hospital Clinic, Barcelona, Catalonia, Spain Rheumatic Disease Unit and, the department of Vascular CRISTINA CABRERA, MD, Nephrology Department, Puigvert Surgery, Chaim Sheba Medical Center, Tel-Hashomer, Israel, Foundation, Universitat Autonoma de Barcelona, Barcelona, and, the Tel-Aviv University, Tel-Aviv, Israel Catalonia, Spain YULIA EINAV, PHD, Mathematical Biology Unit, Faculti of MARIO H. CARDIEL, MSC, Unidad de Investigacioń ‘‘Dr. Mario Sciences, Holon Institute of Technology, Israel Alvizouri Munõ’’, Hospital General ‘‘Dr. Miguel Silva, Morelia, ALON EISEN, MD, Department of Medicine D, Meir Medical Michoacań, Mexico Center, Kfar-Saba, Israel, Affiliated to Sackler Faculty of FRANCISCO CARMONA, MD, Head of the Service of Gynaecology, Medicine, Tel-Aviv University Tel-Aviv, Israel Hospital Clıńic, Barcelona, Catalonia, Spain URS.ENYDEGGER, MD, Consultant Octapharma Switzerland, PATRIZIO CATUREGLI, MD, Departments of Pathology and, Transfusion Therapy Consultancy TTC, Emeritus Medical Molecular Microbiology and Immunology, The Hohns Faculty University of Bern, Switzerland Hopkins University, Baltimore, Maryland, USA RICARDO O. ESCA´RCEGA, MD, Internal Medicine, Temple Uni- JOHN CASTIBLANCO, MD, Cellular Biology and Immunogenetics versity Hospital Philadelphia, Philadelphia, Pennsylvania, Unit, Corporation for Biological Research, Medellıń, Colombia USA ILARIA CAVAZZANA, MD, Rheumatology and Clinical Immu- GEORGINA ESPI´GOL, MD, Department of Autoimmune Diseases, nology, University and Spedali Civili of Brescia, Italy Medicine and Dermatology Institute, Hospital Clinic, University ANGELA CERIBELLI, MD, Rheumatology and Clinical Immu- of Barcelona, Barcelona, Catalonia, Spain nology, University and Spedali Civili of Brescia, Italy GERARD ESPINOSA, MD, PHD, Department of Autoimmune Dis- RICARD CERVERA, MD, PHD, FRCP, Department of Autoimmune eases, Hospital Clıńic, Barcelona, Catalonia, Spain Diseases, Hospital Clıńic, Associate Professor, Department of IVET ETCHEGARAY-MORALES, MD, Systemic Autoimmune Dis- Medicine, University of Barcelona, Catalonia, Spain eases Research Unit, HGR #36, CMN Manuel A´vila Camacho, JOAB CHAPMAN, MD, Department of Neurology, Sheba Medical IMSS, Puebla, Me´xico Center and Sackler Faculty of Medicine, Tel Aviv University, ALBERTO FALORNI, MD, PHD, Department of Internal Medicine, Israel. Section of Internal Medicine and Endocrine and Metabolic MARIA C. CID, MD, Vasculitis Research Unit, Department of Sciences, University of Perugia, Perugia, Italy Autoimmune Diseases, Institute of Medicine and Dermatology, EDUARDO FERREIRA BORBA, MD, PHD, Division of Rheumatol- Hospital Clinic, University of Barcelona, Institut d’Investiga- ogy, University of Sao Paulo, SaõPaulo,Brazil cions, Biome` diques August Pi i Sunyer (IDIBAPS), Barcelona, SIMONE FERRERO, MD, Department of Obstetrics and Gynecology, Catalonia, Spain San Martino Hospital and, University of Genoa, Italy ROLANDO CIMAZ, MD, Rheumatology, Meyer Hospital, Firenze, CAROLINA FIGUEROA, MD, Department of Gastroenterology, Italy Hospital Clıńic/IDIBAPS, CIBER EHD, Barcelona, Catalonia, DOUGLAS B. CINES, MD, Vice Chair, Pathology and Laboratory Spain Medicine, University of Pennsylvania School of Medicine, Phila- IVAN FOELDVARI, MD, Hamburger Zentrum fuer Kinder- and delphia, Pennsylvania, USA Jungerrheumatologie, Am Klinikum Eilbek Hamburg, KARSTEN CONRAD, MD, Institute of Immunology, Medical Germany Faculty of the Technical University Dresden, Dresden, FRANCO FRANCESCHINI, MD, Rheumatology and Clinical Immu- Germany nology, University and Spedali Civili of Brescia, Italy Contributors xv

JOZE´LIO FREIRE DE CARVALHO, MD, PHD, Assistant Professor, THOMAS HELLMARK, PHD, Department of Clinical Sciences in Faculdade de Medicina e Hospital das Clıńicas da Faculdade de Lund, Lund University, Sweden Medicina da Universidade de SaõPaulo,SaõPaulo-SP,Brazil JOSE´ HERNAŃDEZ-RODRI´GUEZ, MD, Vasculitis Research Unit, MARVIN J. FRITZLER, MD, PHD, University of Calgary, Calgary, Department of Autoimmune Diseases, Institute of Medicine Alberta, Canada and Dermatology, Hospital Clinic, University of Barcelona, SALVADOR FUENTES-ALEXANDRO, MD, Internal Medicine CMN Institut d’Investigacions, Biome` diques August Pi i Sunyer siglo XXI, Instituto Mexicano del Seguro Social, DF, Mexico (IDIBAPS), Barcelona, Catalonia, Spain CLAUDIO GALARZA-MALDONADO, MD, Unidad de Enferme- SOPHIE HILLION, PHD, Department of Immunopathology, Brest dades Reumaticas y Autoinmunes (UNERA), Hospital University Medical School, Brest, France Monte Sinaı´, Cuenca, Ecuador JULIA U. HOLLE, MD, Department of Rheumatology, University MAURO GALEAZZI, MD,Unita` Operativa Complessa di Rheuma- Hospital Schleswig-Holstein, Campus Lu¨beck, Lu¨beck tologia, University of Siena, Siena, Italy Germany MARIO GARCIA-CARRASCO, MD, PHD, Systemic Autoimmune GRAHAM R. V. HUGHES, MD, Lupus Research Unit, The Rayne Diseases Research Unit, HGR #36, CMN Manuel A´vila Cama- Institute, King’s College London School of Medicine, St. cho, IMSS, Puebla, Me´xico, and, Rheumatology Department, Thomas’ Hospital, London, UK Benemerita Universidad Autonoma de Puebla, School of Medi- SAROSH R. IRANI, BA, MRCP, Department of Clinical Neurol- cine, Puebla, Me´xico ogy, University of Oxford, John Radcliffe Hospital, Oxford, PEDRAM GERAMI, MD, Northwestern University Medical Center, UK Chicago, Illinois LUIS J. JARA, MD, Direction of Education and Research, Hospital ROBERTO GERLI, MD, Rheumatology Unit, Department of de Especialidades, Centro Me´dico, La Raza, Instituto Mexicano Clinical and Experimental Medicine, University of Perugia, del Seguro Social, Mexico City, Mexico Perugia, Italy MARIO JIMEŃEZ-HERNAŃDEZ, MD, Rheumatology Department, M. ERIC GERSHWIN, MD, Division of Rheumatology, Allergy School of Medicine, Beneme´rita Universidad Autońoma de and Clinical Immunology, University of California at Davis, Puebla; Systemic Autoimmune Diseases Research Unit, School of Medicine, Davis, California, USA HGR #36, CMN Manuel A´vila Camacho, IMSS, Puebla, IBTISSEM GHEDIRA, PHARMD, PHD, Laboratory of Immunology, Mexico Faculty of Pharmacia, Monastir, Tunisia CEES G. M. KALLENBERG, MD, PHD, Professor of Medicine, Head ANNA GHIRARDELLO, MD, Division of Rheumatology, Univer- Department of Clinical Immunology, University Medical sity of Padova, Padova, Italy Center Groningen, University of Groningen, Groningen, The JOAN GIRALT, MD,InstitutClinicdOftalmologia, Hospital Clinic. Netherlands Universidad de Barcelona, Barcelona, Catalonia, Spain MARTIN KAASS, MD, Department of Pediatrics, Medical RAMON GOMIS, MD, PHD, Department of Endocrinology, Hospi- Faculty of the Technical University of Dresden, Dresden, tal Clıńic, Barcelona, Catalonia, Spain Germany ALEXANDER GORSHTEIN, MD, Department of Internal Medicine AHARON KESSEL, MD, Allergy and Clinical Immunology, Bnai- E, Meir Hospital, Kfar Saba, Israel Zion Medical Center, The Bruce Rappaport Faculty of JOSEP M. GRAU, MD, PHD, Department of Internal Medicine, Medicine, Technion Medical School, Haifa, Israel Muscular Research Group, Hospital Clıńic, Professor of MUNTHER A. KHAMASHTA, MD, Senior Lecturer/Consultant Medicine, University of Barcelona, Barcelona, Catalonia, Physician, Lupus Unit, The Rayne Institute, St. Thomas Spain Hospital, London, UK FRANCESC GRAUS, MD, Service of Neurology, Hospital Clinic, AANNEGRET KUHN, MD, Department of Dermatology, Univer- Universitat de Barcelona and, Institut d’ Investigacio´Biome` dica sity of Duësseldorf, Duësseldorf, Germany August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain BETHAN LANG PHD, Neurosciences Group, Department of WOLFGANG L. GROSS, MD, Department of Rheumatology, Uni- Clinical Neurology, Weatherall Institute of Molecular versity Hospital Schleswig-Holstein, Campus Lu¨beck, Lu¨beck Medicine, John Radcliffe Hospital, Oxford University, Germany Oxford, UK LOI¨C GUILLEVEN, MD, Department of Internal Medicine and, YAIR LEVY, MD, Department of Internal Medicine E, Meir Referral Center for Necrotizing Vasculitides and Systemic Hospital, Kfar Saba, Israel Sclerosis, Cochin Hospital, Paris, France, and, Systemic Dis- ROGER A. LEVY, MD, Diagno´sticos da Ame´rica SA and, Disci- eases Study Group, University Paris 5 – Rene´Descartes, Paris, pline of Rheumatology, Faculdade de Cieˆncias Me´dicas, Uni- France versidade do Estado do Rio de Janeiro, Brasil PHILIPPE GUILPAIN, MD, Department of Internal Medicine and, MAURIĆIO LEVY-NETO, MD, PHD, Rheumatology Division, Referral Center for Necrotizing Vasculitides and Systemic University of Saõ Paulo, School of Medicine, Saõ Paulo, Sclerosis, Cochin Hospital, Paris, France, and, Systemic Dis- Brazil eases Study Group, University Paris 5 – Rene´Descartes, Paris, BARAF LIOR, MD, Department of Medicine E, Meir Medical France Center, Kfar-Saba, Affiliated to the Sackler Faculty of Medi- FELICIA A. HANZU, MD, Diabetes and Obesity Laboratory, cine, Tel-Aviv University, Tel-Aviv, Israel Institut d’Investigaciones Biomediques August Pi I Sunyer MARGALIT LORBER, MD, Autoimmune Disease Unit, Division of (IDIBAPS), University of Barcelona, Barcelona, Catalonia, Medicine, Rambam Health Campus, The Rappaport Faculty Spain of Medicine, Technion, Haifa, Isreal xvi Contributors

JUAN MANÃ´, MD, Associate Professor of Medicine, Department SHAI PADEH, MD, Pediatric Rheumatology, Safra Children of Internal Medicine, Institut d’Investigacio´Biome` dica de Hospital, Chaim Sheba Medical Center, Tel-Hashomer, Israel, Bellvitge (IDIBELL), Bellvitge University Hospital, Univer- and, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, sity of Barcelona, Barcelona, Catalonia, Spain Israel AMANI MANKAI, PHD, Department of Immunopathology, ZIV PAZ, MD, MSC, Department of Medicine ’B’, Center for Brest University Medical School, Brest, France, and, Autoimmune Diseases, Chaim Sheba Medical Center, Laboratory of Immunology, Faculty of Pharmacia, Mon- (Affiliated to Tel-Aviv University), Tel-Hashomer, Israel astir, Tunisia LARA E. PEREIRA, PHD, Department of Pathology and Labora- LORETO MASSARDO VEGA, MD, Departamento de Immunologıá tory Medicine, Emory University, Atlanta, Georgia, USA Clıńica y Reumatologıá, Facultad de Medicina, Pontificia JUAN CARLOS PE´REZ-ALVA, MD, Cardiovascular Institut., Hospi- Universidad Catolica de Chile, Santiago, Chile tal Angeles, Puebla, Mexico GABRIELA MEDINA, MD, MSC, Clinical Research Unit, Hospital SHIMON POLLACK, MD, Associate Professor of Medicine & de Especialidades, Centro Me´dico, La Raza, Instituto Mexicano Immunology, Rappaport Faculty of Medicine – Technion, del Seguro Social, Mexico City, Mexico Israel Institute of Technology, Director, Institute for Allergy, FRANCESCA MENCONI, MD, Division of Endocrinology, Univer- Immunology & AIDS, Rambam Medical Center, Haifa, Israel sity of Cincinnati College of Medicine, Cincinnati, Ohio, BERNARDO PONS-ESTEL, MD 3, Hospital provincial de Rosario, USA Universidad Nacional de Rosario, Rosario Argentina CLAUDIA MENDOZA-PINTO, MD, Systemic Autoimmune Dis- GIOVANNI PORCIELLO, MD, Unita` Operativa Medicina Interna, eases Research Unit, HGR &, CMN Manuel A´vila Camacho, Ospedale Misericordia e Dolce, Prato, Italy IMSS, Puebla, Me´xico SERGIO PRIETO, MD, Department of Autoimmune Disease, Med- PIER LUIGI MERONI, MD, Department of Internal Medicine, icine and Dermatology Institute, Hospital Clıńic, University of University of Milan and IRCCS Instituto Auxologico Ita- Barcelona, Barcelona, Catalonia, Spain liano, Italy CARLOS QUEREDA, MD, Nephrology Department, Hospital ARIEL MILLER, MD, PHD, Multiple Sclerosis and Brain Research Ramoń y Cajal, Madrid, Spain Center, Rappaport Facility of Medicine & Research Institute, ROBERTO ROCCHI, MD, Institute of Endocrinology, University of Technion-Israel Institute of Technology, Department of Pisa, Italy Neurology, Carmel Medical Center, Haifa, Israel ROSA MARIA RODRIGUES PEREIRA, MD, PHD, Rheumatology RON MILO, MD, Department of Neurology, Barzilai Medical Division, University of Saõ Paulo, School of Medicine, Saõ Center, Ashkelon, Ben-Gurion University of Negev, Israel Paulo, Brazil DANIEL MIMOUNI, MD, Dermatology Department, Rabin Medi- NOEL R. ROSE, MD, PHD, Professor of Pathology, Professor of cal Center, Beilinson Campus, Petah Tiqwa, Israel, Affiliated to Molecular Microbiology and Immunology, Director, Johns Tel-Aviv University, Sackler Faculty of Medicine, Tel-Aviv Hopkins Center for Autoimmune Disease Research, Bloomberg Israel School of Public Health, Baltimore, Maryland, USA DIMITRIS MITSIAS, MD, Department of Pathophysiology, School MANUEL RAMOS-CASALS MD, PHD, Department of Autoimmune of Medicine, National University of Athens, Athens, Greece Diseases, Hospital Clıńic, Barcelona, Catalonia, Spain MARIA MOLINA-MOLINA, MD, PHD, Departament Investiga- ADRIANA ROJAS-VILLARRAGA, MD, Cellular Biology and cions de Patologıá Experimental, Institut d’Investigacions Bio- Immunogenetics Unit, Corporation for Biological Research, me` diques de Barcelona, Consejo Superior de Investgaciones Medellıń-Colombia, and, Universidad del Rosario, Bogota´, Cientı´ficas, Institut d’Investigacions Biome` diques August Pi I Columbia Sunyer, Barcelona, Catalonia, Spain NICOLETTA RONDA, MD, Department of Clinical Medicine, MARTA MOSCA, MD, Rheumatology Unit, Department of Internal Nephrology and Health Science, University of Pharma, Italy Medicine, University of Pisa, Italy RICARDO RONDINONE, MD, Division of Rheumatology, Univer- HARALAMPOS M. MOUTSOPOULOS, MD, FACP, FRCP, Depart- sity of Padova, Padova, Italy ment of Pathophysiology, School of Medicine, National Uni- NURIT ROSENBERG, PHD, Amalia Biron Research Institute versity of Athens, Athens, Greece of Thrombosis and Hemostasis, Sheba Medical Center, Tel- SALVADOR NAVARRO, MD, PHD, Department of Gastroenterol- Hashomer, Israel ogy, Institut Clinic de Malalties Digestives i Metabo` liques, TOMEU ROSSINÕL, MD, Service of Neurology, Hospital Clinic, Hospital Clıńic, Barcelona, Catatonia, Spain Universitat de Barcelona and, Institut d’ Investigacio´Biome` dica GIDEON NESHER, MD, Department of Internal Medicine A and, August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain The Rheumatology Service, Shaare-Zedek Medical Center, ALEJANDRO RUIZ-ARGUËLLES, MD, Laboratorios Clıńicos de Jerusalem, Israel Puebla, Puebla, Mexico LAURA F. NEWELL, MD, Department of Hematology, University VINCENT RULAND, MD, Department of Dermatology, University of Washington, Seattle, Washington, USA of Duësseldorf, Duësseldorf, Germany UDI NUSSINOVITCH, MD, Department of Medicine B, Chaim OPHIRA SALOMON, MD, Amalia Biron Research Institute of Sheba Medical Center, Tel-Hashomer, Israel Thrombosis and Hemostasis, Sheba Medical Center, Tel- YAEL L. OPPENHEIM, MD, Endocrinology and Diabetes Hashomer, Israel Associates of Long Island, Rockville Center, NY, USA SHARONJEET SANGHA, MD, Department of Internal Medicine, HEDI ORBACH, MD, Head of Internal Medicine B Department, University of California at Davis Medical Center, Sacramento, Wolfson Medical Center, Holon, Israel California, USA Contributors xvii

LAIA SANS, MD, Nephrology Department, Puigvert Foundation, ROSARIA TALARICO, MD, Rheumatology Unit, Department of Universidad Autońoma de Barcelona, Barcelona, Catalonia, Internal Medicine, University of Pisa, Italy Spain IRA N. TARGOFF, MDDepartment of Medicine, University of MIQUEL SANS, MD, PHD, Department of Gastroenterology, Hos- Oklahoma Health Sciences Center, Veterans Affairs Medical pital Clıńic I Provincial/IDIBAPS, CIBER EHD, Barcelona, Center, Oklahoma Medical Research Foundation, Oklahoma Catalonia, Spain City, Oklahoma, USA ALAIN SARAUX, MD, PHD, Department of Immunopathology, ANGELA TINCANI, MD, Rheumatology and Clinical Immunology, Brest University Medical School, Brest, France University and Spedali Civili of Brescia, Italy PIERCARLO SARZI-PUTTINI, MD, Department of Rheumatology, BAN-HOCK TOH, MBBS, DSC, Autoimmunity Laboratory, Cen- Rheumatology Unit, L Sacco University Hospital, Milan, tre for Inflammatory Diseases, Department of Medicine, Italy Southern Clinical School, Faculty of Medicine, Nursing MA˚RTEN SEGELMARK, MD, Department of Nephrology, Clinical and Health Services, Monash University, Clayton, Victoria, Sciences in Lund, Lund University, Sweden Australia CARLO SELMI, MD, PHD, Division of Rheumatology, Allergy and YARON TOMER, MD, FACP, Division of Endocrinology, Uni- Clinical Immunology, University of California at Davis, versity of Cincinnati College of Medicine, Cincinnati, Davis, CA, and, Division of Internal Medicine, Department Ohio, and, Cincinnati VA Medical Center, Cincinnati, of Clinical Sciences ‘Luigi Sacco’, University of Milan, Milan, Ohio, USA Italy ELIO TONUTTI, MD, Immunopatologia e Allergologia, Azienda ALBERT SELVA-O’CALLAGHAN, MD, PHD, Internal Medicine Ospedaliero-Universitaria S. Maria della Misericordia, Udine, Department, Hospital Vall d’Hebroń, Universitat Autońoma Italy de Barcelona, Barcelona, Catalonia, Spain NATALIE J. TOROK, MD, Division of Gastroenterology and SUK SEO, MD, Pfleger Liver Institute, David Geffen School of Hepatology, University of California Davis Medical Center, Medicine at UCLA, Los Angeles, California, USA Sacramento, California, USA ANNA SERRANO-MOLLAR PHD, Departament de Patologıá DARIA LA TORRE, MD, Department of Internal Medicine, Sec- Experimental, Institut d’Investigaciones Cientı´ficas, Institut tion of Internal Medicine and Endocrine and Metabolic d’Investigaciones Biome` diques August Pi I Sunyer, Barce- Sciences, University of Perugia, Perugia, Italy lona, Catalonia, Spain ELIAS TOUBI, MD, Bnai-Zion Medical Center, The Bruce Rap- BORIS SHENKMAN, MD, PHD, Amalia Biron Research Institute of paport Faculty of Medicine, Technion Medical School, Thrombosis and Hemostasis, Sheba Medical Center, Tel- Haifa, Israel Hashomer, Israel HENRI TRAU, MD, Dermatology Department, Sheba Medical YANIV SHERER, MD, Department of Medicine B, Center of Center (Affiliated to the Sackler Faculty of Medicine), Tel Autoimmune Diseases, Sheba Medical Center, Tel-Hasho- Aviv University, Israel mer, and, Sackler Faculty of Medicine, Tel-Aviv University, FABIO TUCCI, MD, A. Meyer Children’s Hospital, Firenze, Israel Italy YEHUDA SHOENFELD, MD, FRCP (HON.), Department of JOSEPH M. TUSCANO, MD, Department of Internal Medicine and, Medicine B, And Sackler Faculty of Medicine, Tel-Aviv The UC Davis Cancer Center, Division of Hematology and University, Israel, and, Incumbent of the Laura Schwartz Oncology, University of California, Davis School of Medicine, Kipp Chair, for Research of Autoimmune Diseases, Tel- Sacramento, California, USA Aviv University, Israel MANUEL FRANCISCO UGARTE, MD, Universidad Nacional CLOVIS ARTUR A. SILVA, MD, PHD, Pediatric Rheumatology Mayor de San Marcos, and, Department of Rheumatology, Unit, Department of Pediatric, University of Sao Paulo, Brazil Hospital Almenara, Lima, Peru GLEB SLOBODIN, MD, Department of Internal Medicine A, AVRAHAM UNTERMAN, MD, Department of Medicine ‘B’ and, Bnai-Zion Medical Center, Technion Medical School, Center for Autoimmune Disease, Sheba Medical Center, Tel- Haifa, Israel Hashomer, Israel RICHARD D. SONTHEIMER, MD, Department of Dermatology, OLGAVERA-LASTRA, MD, Internal Medicine Department, Hos- Richard and Adeline Fleischaker Chair in Dermatology pital de Especialidades, Centro Me´dico, La Raza, Instituto Research, University of Oklahoma Health Sciences Center, Mexicano del Seguro Social, Mexico City, Mexico Adjunct Investigator, Oklahoma Medical Research Founda- JENNY WALKER, MD, University of Calgary, Calgary, Alberta, tion, Oklahoma City, Oklahoma, USA Canada ALEX STAGNARO-GREEN, MD, MHPE, Senior Associate Dean for HOBART W. WALLING, MD, PHD, Private Practice of Dermatol- Academic Affairs, Touro University College of Medicine, ogy, Coralville, Iowa, USA Hackensack, New Jersey, USA SENGA WHITTINGHAM, MBCHB, PHD,DepartmentofBio- ALBERTO SULLI, MD, Research Laboratory and Clinical chemistry and Molecular Biology, Monash University, Academic Unit of Rheumatology, Department of Internal Australia Medicine, University of Genova, Italy ASHER WINDER, MD, Tel-Aviv University, Israel, And, MARTINE SZYPER-KRAVITZ, MD, Center for Autoimmune Hematology Department, Wolfson Medical Center, Diseases and, Department of Medicine B, Chaim Sheba Holon, Israel Medical Center Tel-Hashomer, Sackler Faculty of Medicine, ANTONI XAUBET, MD, PHD, Department of Respiratory Diseases, Tel Aviv University, Israel Hospital Clıńic. Barcelona, Associate Professor of Medicine, xviii Contributors

University of Barcelona, Servei de Pneumologia, Hospital JOYCEHISAE YAMAMOTO, MD, PHD, University of Saõ Paulo, Clıńic, Barcelona, Catalonia, Spain School of Medicine, Saõ Paulo, Brazil BERKUN YACKOV, MD, Associate Director, Pediatric Rheumatol- PIERRE YOUINOU, MD,DSC, Department of Immunopathology, ogy, Safra Children Hospital, Chaim Sheba Medical Center, Tel- Brest University Medical School, Brest, France Hashomer, Israel, and, Sackler School of Medicine, Tel-Aviv SANDRA ZAMPIERI, MD, Division of Rheumatology, University University, Tel-Aviv, Israel of Padova, Padova, Italy LEVY YAIR, MD, Department of Medicine E, Meir Medical GISELE ZANDMAN-GODDARD, Department of Medicine C, Center, Kfar-Saba, Affiliated to the Sackler Faculty of Wolfson Medical Center, Holon, Israel, And, Sackler Faculty Medicine, Tel-Aviv University, Tel-Aviv, Israel of Medicine, Tel-Aviv University, Israel