GOUT AND OTHER CRYSTAL ARTHROPATHIES Robert Terkeltaub, MD Chief, Rheumatology Section San Diego Veterans Affairs Medical Center; Professor of Medicine, Interim Chief Division of Rheumatology, Allergy and Immunology University of California San Diego School of Medicine La Jolla, California, USA 1600 John F. Kennedy Blvd. Ste 1800 Philadelphia, PA 19103-2899 GOUT AND OTHER CRYSTAL ARTHROPATHIES, First edition ISBN: 978-1-4377-2864-4 Copyright © 2012 by Saunders, an imprint of Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, with- out permission in writing from the publisher. Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our knowledge, changes in practice, treatment and drug therapy may become necessary or appropriate. Read- ers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of the practitioner, relying on their own experience and knowledge of the patient, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the Editors assumes any liability for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this book. The Publisher Library of Congress Cataloging-in-Publication Data Gout and other crystal arthropathies / [edited by] Robert Terkeltaub. p. ; cm. Includes bibliographical references and index. ISBN 978-1-4377-2864-4 (hardcover : alk. paper) 1. Gout. 2. Chondrocalcinosis. I. Terkeltaub, Robert. [DNLM: 1. Gout. 2. Calcium Compounds--metabolism. 3. Chondrocalcinosis. 4. Hyperuricemia. WE 350] RC629.G683 2012 616.3′999--dc23 2011032013 Acquisitions Editor: Pamela Hetherington Developmental Editor: Roxanne Halpine Ward Publishing Services Manager: Peggy Fagen Project Manager: Siva Raman Krishnamoorthy Design Direction: Steven Stave Printed in the United States of America Last digit is the print number: 9 8 7 6 5 4 3 2 1 I dedicate this book to my patients, mentors, colleagues in the field, and students and research trainees, who have inspired me and taught me so much about these disorders. I also dedicate the work to my wife Barbara, whose support was integral to the success of this endeavor. Acknowledgments I am grateful to acknowledge Robyn Austin and Wendy Geolina, who provided administrative support and editing assistance, as well as Pamela Hetherington for her strong vision and support, Roxanne Ward for manuscript preparation, and Peggy Fagen and the production staff at Elsevier for their hard work in bringing this book to print. I dedicate this book to my patients, mentors, colleagues in the field, and students and research trainees, who have inspired me and taught me so much about these disorders. I also dedicate the work to my wife Barbara, whose support was integral to the success of this endeavor. Acknowledgments I am grateful to acknowledge Robyn Austin and Wendy Geolina, who provided administrative support and editing assistance, as well as Pamela Hetherington for her strong vision and support, Roxanne Ward for manuscript preparation, and Peggy Fagen and the production staff at Elsevier for their hard work in bringing this book to print. Contributors Naohiko Anzai, MD, PhD Rebecca Grainger, BMedSci, PhD, Diego F. Lemos, MD Professor and Chairman MBChB, FRACP Assistant Professor of Radiology Department of Pharmacology and Toxicology Senior Lecturer Section Head Musculoskeletal Imaging Dokkyo Medical University School of Medicine Department of Medicine Department of Radiology Tochigi, Japan University of Otago Wellington Fletcher Allen Health Care and the University of Consultant Rheumatologist Vermont Joana Atxotegi Saenz de Buruaga, MD Wellington Regional Rheumatology Unit Burlington, Vermont, USA Assistant Physician Hutt Valley District Health Board Rheumatology Division Wellington, New Zeland Frédéric Lioté, MD, PhD Hospital de Cruces Professor of Rheumatology Vizcaya, Spain Pierre-André Guerne, MD Paris Diderot University Professor of Internal Medicine President, Sorbonne Paris Cité Hyon K. Choi, MD, DrPH and Rheumatology Deputy Head Professor of Medicine Associate Medical Officer Centre Viggo Petersen, Service de Rhumatologie Section of Rheumatology and the Clinical Division of Rheumatology (Pôle Appareil Locomoteur) Epidemiology Unit University Hospitals of Geneva Hôpital Lariboisière (Assistance Publique- Boston University school of Medicine Geneva, Switzerland Hôpitaux de Paris) Boston, Massachusetts, USA Paris, France Ana Maria Herrero-Beites, MD Nicola Dalbeth, MBChB, MD, FRACP Senior Assistant Ru Liu-Bryan, PhD Associate Professor and Rheumatologist Rehabilitation Division Associate Professor of Medicine Department of Medicine, Faculty of Medical and Hospital de Górliz University of California San Diego Health Sciences Vizcaya, Spain San Diego, California, USA University of Auckland Auckland, New Zealand Tudor H. Hughes, MD, FRCR Paul MacMullan, BComm, BSc Professor of Clinical Radiology (Physio), MBChB, BAO Hitoshi Endou, MD, PhD Radiology Resident Program Director Research Fellow Professor Emeritus Vice Chair of Education Department of Molecular and Cellular Department of Pharmacology and Toxicology Department of Radiology Therapeutics Kyorin University School of Medicine University of California at San Diego Royal College of Surgeons in Ireland Tokyo, Japan San Diego, California, USA Rheumatology Department Mater Misericordiae University Hospital Angelo L. Gaffo, MD, MSPH Dinesh Khanna, MD, MSc Dublin, Ireland Assistant Professor of Medicine Associate Professor of Medicine Division of Rheumatology Marvin and Betty Danto Research Professor Elisabeth Matson, DO University of Alabama at Birmingham Director Rheumatology Fellow Staff Rheumatologist University of Michigan Scleroderma Program Division of Rheumatology Birmingham VA Medical Center Division of Rheumatology The Warren Alpert Medical School at Brown Birmingham, Alabama, USA Department of Internal Medicine University University of Michigan School of Medicine Providence, Rhode Island, USA Amilcare Gentili, MD Ann Arbor, Michigan, USA Professor of Clinical Radiology Geraldine M. McCarthy, MD Department of Radiology Puja Khanna, MD, MPH Consultant Rheumatologist University of California San Diego Assistant Professor Department of Medicine Chief, Radiology Service Division of Rheumatology Mater Misericordiae University Hospital San Diego VA Health Care System Department of Internal Medicine Clinical Professor of Medicine San Diego, California, USA University of Michigan School of Medicine UCD School of Medicine Ann Arbor, Michigan, USA and Medical Science University of College Dublin Eswar Krishnan, MD, MPhil Honorary Associate Professor Assistant Professor of Medicine Molecular and Cellular Therapeutics Stanford University Royal College of Surgeons in Ireland Stanford, California, USA Dublin, Ireland vii viii Contributors Gillian McMahon, BSc, PhD, MRSC, Supriya G. Reddy, MPH Francisca Sivera, MD CChem, FICI Program Administrator Consultant in Rheumatology Analytical Chemistry Lecturer Clinical Immunology and Rheumatology Rheumatology Unit School of Chemical Sciences University of Alabama Hospital del Vinalopó Dublin City University at Birmingham Clinical Assistant Professor Dublin, Ireland Birmingham, Alabama, USA Department of Internal Medicine Doctoral Student (PhD candidate) ( Rheumatology) Tuhina Neogi, MD, PhD, FRCPC Department of Health Science Universidad Miguel Hernandez Associate Professor of Medicine The University of Alabama Alicante, Spain Sections of Clinical Epidemiology Research Tuscaloosa, Alabama, USA and Training Unit and Rheumatology Lisa K. Stamp, MBChB, FRACP, PhD Department of Medicine Anthony M. Reginato, PhD, MD Associate Professor Boston University School of Medicine Director, Rheumatology Research Department of Medicine Associate Professor of Epidemiology and Musculoskeletal Ultrasound University of Otago Christchurch Department of Epidemiology Division of Rheumatology Rheumatologist Boston University School of Public Health University of Medicine Foundation Department of Rheumatology, Immunology Boston, Massachusetts, USA Rhode Island Hospital and Allergy The Warren Alpert School of Medicine Christchurch Hospital George Nuki, MB, FRCP at Brown University Christchurch, New Zealand Emeritus Professor of Rheumatology Staff Physician Rheumatic Diseases Unit Medical Service/Rheumatology William J. Taylor, PhD, MBChB, Western General Hospital Providence VA Medical Center FRACP, FAFRM Emeritus Professor of Rheumatology Providence, Rhode Island, USA Associate Professor and Head of Unit Osteoarticular Research Group Rehabilitation Teaching and Research Unit Institute of Genetics and Molecular Medicine Philip L. Riches, BSc, MRCP Department of Medicine University of Edinburgh Consultant Rheumatologist University of Otago Wellington Edinburgh, Scotland, UK Rheumatic Diseases Unit Rheumatologist and Rehabilitation Physician Western General Hospital Wellington Regional Rheumatology Unit Eliseo Pascual, MD, PhD Honorary Senior Lecturer Hutt Valley District Health Board Professor of Medicine Institute of Genetics and Molecular Medicine Wellington, New Zealand Universidad Miguel Hernández University of Edinburgh Head, Rheumatology Section Edinburgh, Scotland, UK Robert Terkeltaub, MD Hospital General Universitario de Alicante Chief, Rheumatology Section Alicante, Spain Naomi Schlesinger, MD San Diego Veterans Affairs Medical Center Professor of Medicine Professor of Medicine, Interim Chief Fernando Perez-Ruiz, MD, PhD Chief, Division of Rheumatology Division of Rheumatology, Allergy, Specialist Faculty Department of Medicine and Immunology Rheumatology Division Robert Wood Johnson Medical School University of California San Diego School Hospital de Cruces University of Medicine and Dentistry of Medicine Vizcaya, Spain of New Jersey La Jolla, California, USA New Brunswick, New Jersey, USA Kenneth P.H. Pritzker, MD, FRCPC Ralf G. Thiele, MD, FACR Professor, Laboratory Medicine Jasvinder A. Singh, MBBS, MPH Assistant Professor of Medicine and Pathobiology; Surgery Staff Physician Department of Medicine University of Toronto Medicine Service and Center for Surgical Allergy/Immunology & Rheumatology Division Pathologist Medical Acute Care Research University of Rochester School of Medicine Mount Sinai Hospital and Transitions and Dentistry Toronto, Ontario, Canada Birmingham VA Medical Center; Rochester, New York, USA Associate Professor of Medicine Juan Garcia Puig, MD, PhD and Epidemiology Rosa J. Torres, MD, PhD Associate Professor Department of Medicine Biomedical Researcher Division of Internal Medicine Division of Rheumatology Biochemistry Laboratory, Metabolic Vascular Metabolic and Vascular Unit University of Alabama at Birmingham Unit, Idipaz Hospital Universitario La Paz, IdiPAZ Birmingham, Alabama, USA La Paz University Hospital Universidad Autónoma Research Collaborator Madrid, Spain Madrid, Spain Department of Orthopedic Surgery Mayo Clinic Collage of Medicine Rochester, Minnesota, USA Foreword Gouty arthritis was among the earliest of diseases to be rec- community-based epidemiologic studies have demonstrated ognized as a clinical entity; there is a description of gout in an age-related radiographic prevalence of chondrocalcino- ancient Egypt in the second millennium bc attributable to sis of approximately 10% in persons in the seventh decade Imhotep (the “Father of Medicine”). However, the role of of life. CPPD deposition in the form of chondrocalcinosis is crystals of monosodium urate (MSU) in the pathogenesis of positively associated with osteoarthritis (OA) but is also seen gout and recognition of other crystal-associated deposition in the absence of OA and variably influences progression of arthropathies emerged much later. Drawings of crystals taken articular cartilage loss in patients with knee OA. Basic cal- from a tophus from a patient with gout were made by the pio- cium phosphate (BCP) crystals are also frequently associated neer Dutch microscopist Antoni Van Leeuwenhoek in 1769, with OA as well as with age-related calcific periarthritis and although he was unaware that they were crystals and ignorant a destructive form of age-related, apatite-associated arthritis. of their chemical composition. A century later, the English Fifty years ago, gout became a paradigm for understanding, chemist Wollaston was able to show that a gouty tophus from treating, and preventing a chronic rheumatic disease after the his own ear was composed of sodium urate, following chemi- development of allopurinol as an effective uricostatic drug. A cal identification of uric acid in urinary calculi by the Swed- decade later, Seegmiller’s discovery that primary purine over- ish apothecary Scheele in 1776. Elevated levels of uric acid in production and severe premature gout in boys with Lesch- the serum of patients with gout were first demonstrated by Nyhan syndrome resulted from an inherited deficiency of the Sir Alfred Baring Garrod in 1848 using a semiquantitative purine salvage enzyme hypoxanthine guanine phosphoribo- “thread test”—an early milestone in the development of the syltransferase led to an explosion of knowledge and scientific discipline of clinical chemistry. literature about the regulation of purine metabolism that was In a set of remarkably prescient propositions published in characterized as the “purine revolution.” Much of this was 1859 in his book A Treatise on Gout and Rheumatic Gout, A. included in a comprehensive monograph, Gout and Hyperurice- B. Garrod was the first to show a clear understanding of the mia, by Wyngaarden and Kelley published in 1976, and evolving importance of hyperuricemia and the pivotal role of urate crys- knowledge of calcium crystal deposition and disease, which was tals in the pathogenesis of gout. At the turn of the nineteenth slower to develop, was included in a shorter monograph, Crys- century, Freudweiler demonstrated that intra-articular injec- tals and Joint Disease, by Dieppe and Calvert published in 1986. tions of crystals of sodium urate could mimic acute attacks of Following the introduction and use of allopurinol 40 years gout and showed that subcutaneous injections of microcrystals ago, a widespread perception developed that gout was no lon- were followed by the development of tophus-like lesions. The ger a clinical problem. For many years, gout has been largely historical importance of these experiments only came to light, managed in general practice and has ceased to be at the fore- however, in the early 1960s after rediscovery of the capacity of front of interest for rheumatologists and clinical investigators. microcrystals of sodium urate to induce inflammation in joints, Recent studies have, however, shown that this potentially cur- skin, and subcutaneous tissues by Faires and McCarty and by able condition is being inadequately treated and that the inci- Seegmiller and his colleagues. These experiments followed dence and prevalence of gout have doubled over the past 30 publication of McCarty and Hollander’s seminal paper demon- years. Gout is now the most common inflammatory joint dis- strating the diagnostic value of detecting negatively birefringent ease in men and an increasingly frequent cause of inflamma- crystals of MSU, by polarizing light microscopy, within syno- tory joint disease in postmenopausal women. The changing vial fluid leukocytes during acute attacks of gouty arthritis, and epidemiology of gout is largely attributable to rising levels of a series of landmark publications demonstrating the presence serum urate, associated with the changing age structure of the of positively birefringent microcrystals, which were confirmed population, as well as with the worldwide epidemic of obe- by x-ray diffraction to be calcium pyrophosphate dihydrate sity and a dramatic increase in the prevalence of the metabolic (CPPD) in patients with acute synovitis and “pseudogout.” syndrome. Additional risk factors include the use of diuret- Although experiments demonstrating that acute synovitis ics, consumption of alcoholic beverages (especially beer), could also be induced by injections of microcrystals of CPPD diets containing increased quantities of red meat or shellfish into normal canine and human joints appeared to confirm a purines, and heavy consumption of fructose-sweetened soft pathogenic role for CPPD crystals in patients with pseudo- drinks. Complicated gout associated with comorbidities such gout, the extent to which deposition of CPPD crystals are the as hypertension and cardiovascular and renal disease is also cause, or the consequence, of other pathology in the wide an increasing problem. Overt tophi are now seen in 30% of range of clinical settings subsequently described and classi- untreated patients within 5 years of the first acute attack. fied by McCarty as manifestations of CPPD deposition dis- Developments in imaging with ultrasound, computed tomog- ease remains much less certain. Cadaver studies undertaken raphy, and magnetic resonance imaging are also revealing more than 80 years ago had shown that meniscus calcifica- more widespread evidence of crystal deposition in patients tion in the knee was a frequent age-related finding, and recent with gout much earlier in the course of the disease. ix