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A Clinician's
Pearls & Myths
in Rheumatology
John H. Stone
Editor
Second Edition
123
A Clinician’s Pearls & Myths in Rheumatology
John H. Stone
Editor
A Clinician’s Pearls & Myths

in Rheumatology
Second Edition
Editor
John H. Stone
Massachusetts General Hospital
Harvard University Massachusetts General Hospital
Boston, MA, USA
ISBN 978-3-031-23487-3 ISBN 978-3-031-23488-0 (eBook)

https://doi.org/10.1007/978-3-031-23488-0
© Springer Nature Switzerland AG 2009, 2023

This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or
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To Sarah Lucretia (“Lu”) Stone
(1936–1991)
A mother holds her children’s hands for a short time, and their hearts forever.
Preface
When I was a child in the second grade, my mother developed an acutely painful index finger
on her right hand. After several sleepless nights with unrelenting pain that was disguised from
me, she was admitted to the hospital. The surgeon suspected a glomus tumor—a benign growth
that sometimes develops in the nailbed. But no tumor was found at surgery. Instead, the sur-
geon shared an astonishing observation with my father: “When I removed her fingernail, she
didn’t bleed.”
And at that point, the nature of her disease began to dawn on her doctors and on my father,
who was himself a physician. My mother had developed Raynaud’s phenomenon as a teenager.
When she and my father were newlyweds and he was a medical student, they had mused
together at the oddity of her intermittently pale white fingers, which developed sometimes
even in the summer. Around the time I was born, she suffered from a skin problem that I
learned—years later—was dermatitis herpetiformis. As a young boy, I remember her scratch-
ing her intensely itchy legs. As I grew up, I became aware of the subtle scars left on her face,
usually well-hidden with makeup.
The active skin inflammation faded after a few years, but other aspects of the autoimmune
kaleidoscope came into sharper focus. The ischemic finger in the context of her preceding
issues led to the diagnosis of scleroderma. In that light, most of the medical events in my
mother’s life make sense now. Her finger hadn’t bled at surgery because of the severity of
vasoconstriction. The shapes of her fingers that I can still see and remember dearly, including
the curved fingernail that never grew back normally, were the result of her disease. The calci-
noses and digital pitting that developed in her fingers were also consequences of her slow-
moving but relentless illness, as were the intermittent bouts of dysphagia caused by esophageal
dysmotility. For a time, during my teens, my mother often had to excuse herself from the din-
ner table because she just couldn’t swallow her food. A painful memory for me.
Despite that, Mom led a full life and it seemed to most that nothing slowed her down: rais-
ing two rambunctious boys; being a loving wife and returning to graduate school; becoming a
devoted first-grade teacher; using her hands constantly in spite of sensitive fingers on sewing,
knitting, cooking, and playing the piano; enjoying lifelong friends; attending our soccer games
with mittens on to counter Raynaud’s attacks; and delighting in family travel.
It all came to a halt far too early. When I was a medical intern, the hospital operator paged
me to return a call from my father. Mom had developed an acute bowel obstruction because of
scleroderma gut and had been taken to surgery that morning. I flew home, to her bedside in the
intensive care unit. There, far more fragile that anyone had realized, she died twelve days later
of adult respiratory distress syndrome. The real cause, of course, was scleroderma. She was 54
years old.
It is little consolation that traumatic health events in one’s family make a physician a better
doctor. Yet it is true. My mother’s nearly lifelong struggle with scleroderma—ironically
regarded as “limited”—helps me understand the uncertainties, frustrations, and tears of my
patients and their families. Mom’s illness, of course, contributed to my becoming a rheuma-
tologist and dedicating my career to helping patients address diseases like hers. It is only fit-
ting, then, that this book is dedicated to her.
vii
viii Preface
So much has happened since the First Edition was published in 2009. New rheumatic dis-
eases have been identified. (IgG4-related disease was scarcely mentioned in the First Edition!)
Biomedical science has witnessed important advances in assessment and diagnosis, some of
which have already altered approaches to patient care. Creative new therapies have been con-
ceived and studied. Some in fact have worked, been approved, and are already improving
patients’ lives. The world has endured (and still persists in) a viral pandemic that has under-
scored the importance of vaccines and public health and forced us to re-think how we apply
many of our existing treatments. Though many challenges remain, my inherent optimism - a
trait inherited from my mother - inspires confidence that the coming years will mark growing
progress for the patients we treat.
The judgment of inspired clinicians will remain fundamental to inspiring advances and
maintaining safe speeds on the paths ahead. It is in this spirit that this book is written: by clini-
cians, for clinicians. I am grateful to the more than 200 contributors who offer guidance here
from their own approaches to our art, sharing their hard-earned and frequently elegant clinical
wisdom.
Boston, MA, USA John H. Stone

Contents
1 Rheumatoid Arthritis�� 1

Kevin D. Deane, Daniel Aletaha, Joan M. Bathon, Paul Emery,
George E. Fragoulis, V. Michael Holers, T. W. J. Huizinga,
Jason R. Kolfenbach, James R. O’Dell, Duane W. Pearson, Elizabeth Park,
Josef Smolen, Yoshiya Tanaka, Peter C. Taylor, Annette van der Helm-van Mil,
Ronald F. van Vollenhoven, and E. William St. Clair
2 Rheumatoid Vasculitis �� 25
Ashima Makol, Tanaz Kermani, Kenneth Warrington, John H. Stone,
and Eric L. Matteson
3 Adult-Onset Still’s Disease�� 37
Yutong Su and Chengde Yang
4 Juvenile Idiopathic Arthritis �� 43
Randy Q. Cron, Sangeeta Sule, Jordan T. Jones, Tristan A. Kerr,
Kimberly A. Morishita, Ross E. Petty, and Carol B. Lindsley
5 Monogenic Autoinflammatory Syndromes�� 55
Ivona Aksentijevich and Eldad Ben-Chetrit
6 Juvenile Spondyloarthritis�� 79
Dax G. Rumsey, David A. Cabral, and Shirley M. L. Tse
7 Axial Spondyloarthritis �� 87
Xenofon Baraliakos, Dennis McGonagle, and Jürgen Braun
8 Psoriatic Arthritis�� 97
Philip Helliwell, Laura C. Coates, and Dafna Gladman
9 Reactive Arthritis �� 105
John H. Stone
10
Systemic Sclerosis (Scleroderma) and Raynaud’s Phenomenon �� 111
Ami A. Shah, Janet E. Pope, Dinesh Khanna, Maureen Mayes,
Virginia Steen, and Christopher Denton
11 Sjögren’s Disease�� 133
Alan Baer, Vatinee Bunya, Ava Wu, Xavier Mariette, and Frederick Vivino
12 Systemic Lupus Erythematosus�� 167
Michelle Petri, Martin Aringer, Isabelle Ayoub, Salem Almaani, Hermine
Brunner, Maria Dall’Era, Mengdi Jiang, Richard Furie, Jessica Greco,
Fiona Goldblatt, Jennifer Huggins, T. W. J. Huizinga, David Isenberg,
Nicholas L. Li, R. C. Monahan, Samir V. Parikh, David Pisetsky,
Abin P. Puravath, Brad Rovin, Daniel Wallace, Xuan Zhang,
and Lidan Zhao
ix
x Contents
13 Childhood-Onset
SLE and Neonatal Lupus Erythematosus �� 213
Deborah M. Levy, Jill Buyon, and Earl D. Silverman
14 The Antiphospholipid Syndrome�� 225
David P. D’Cruz, Jason S. Knight, Lisa Sammaritano, Jane Salmon,
Ricard Cervera, and Munther Khamashta
15 Reproductive
Health in the Rheumatic Diseases�� 241
Julia Sun, Laura Andreoli, Jane Salmon, Meghan Clowse, Caroline Gordon,
Jill Buyon, Rosalind Ramsay-Goldman, and Lisa Sammaritano
16 Inflammatory Myopathies�� 261
Chester Oddis, Vidya Limaye, Frederick Miller, and Lisa Christopher-Stine
17 Juvenile Dermatomyositis �� 275
Lauren M. Pachman, Sarah Tansley, Ann M. Reed, Clarissa M. Pilkington,
Brian M. Feldman, and Lisa G. Rider
18 Vasculitic Neuropathy�� 287
John H. Stone
19 Pediatric Vasculitis �� 297
Seza Ozen, Despina Eleftheriou, Anne Rowley, and Paul Brogan
20 Behçet Syndrome�� 311
Johannes Nowatzky, Gulen Hatemi, Vedat Hamuryudan, Hasan Yazici,
and Yusuf Yazici
21 Eosinophilic
Granulomatosis with Polyangiitis�� 327
John H. Stone
22 Granulomatosis with Polyangiitis�� 335
John H. Stone
23 Microscopic Polyangiitis�� 357
Duvuru Geetha and John H. Stone
24 Oral
Manifestations Associated with Rheumatic Diseases�� 369
Sonia Marino, Sook-Bin Woo, Roberta Gualtierotti, John A. G. Buchanan,
Shaiba Shandu, Francesco Spadari, and Massimo Cugno
25 Cryoglobulinemia�� 395
Franco Dammacco, Patrice Cacoub, John H. Stone, and David Saadoun
26 Polyarteritis Nodosa�� 405
John H. Stone
27 Giant
Cell Arteritis and Polymyalgia Rheumatica �� 417
Peter M. Villiger, Lisa Christ, Luca Seitz, Godehard Scholz,
Christoph Tappeiner, Francesco Muratore, Carlo Salvarani, Sue Mollan,
Vanessa Quick, Christian Dejaco, Michael Lee, Neil Basu, Neil Miller,
and John H. Stone
28 Takayasu’s Arteritis �� 447
Kaitlin A. Quinn, Durga P. Misra, Aman Sharma, Andrew Porter,
Justin Mason, and Peter C. Grayson
29 Central
Nervous System Vasculitis and Reversible
Cerebral Vasoconstriction Syndrome�� 465
Rula A. Hajj-Ali, David S. Younger, and Leonard H. Calabrese
Contents xi
30 Thromboangiitis Obliterans�� 473

Ashima Makol, Leslie T. Cooper, John H. Stone, and Eric L. Matteson
31 Less Common Vasculitides�� 481
Eric L. Matteson and John H. Stone
32 Relapsing Polychondritis�� 491
Jeremie Dion, Guillaume Moulis, and Nathalie Costedoat
33 Fibromyalgia�� 499
Daniel Clauw
34
Clinical Features of Gout�� 505
Robert Terkeltaub, Nicola Dalbeth, Naomi Schlesinger, Brian Mandell,
and Michael Pillinger
35 Epidemiology of Gout�� 513
Hyon K. Choi and John H. Stone
36 Treatment of Gout�� 519
Nicola Dalbeth, Michael Pillinger, Naomi Schlesinger, Brian Mandell,
and Robert Terkeltaub
37
CPPD and Other Microcrystalline Disorders �� 531
Ann K. Rosenthal, Mariano Andres, Abhishek Abhishek, and Robert
Terkeltaub
38 Inflammatory Eye Disease�� 545
Bart Chwalisz, Michael Lee, Lucia Sobrin, and Suzanne K. Freitag
39
Immune-Mediated Inner Ear Disease�� 569
Soumyajit Das and Steven Rauch
40 Osteoporosis: Epidemiology and Assessment�� 579
Mary Beth Humphrey, Bita Zahedi, Amy Warriner, Sarah Morgan,
Benjamin Z. Leder, Ken Saag, and Elaine W. Yu
41 Osteoporosis Prevention and Treatment�� 587
Mary Beth Humphrey, Bita Zahedi, Amy Warriner, Sarah Morgan,
Benjamin Z. Leder, Ken Saag, and Elaine W. Yu
42
Paget’s Disease of Bone�� 599
Ian R. Reid and Margaret Seton
43 Lyme�� 603
Sheila L. Arvikar, John J. Halperin, and Allen C. Steere
44 Osteoarthritis�� 611
Lauren King, Ian Stanaitis, and Gillian Hawker
45 Regional Musculoskeletal Problems�� 621
Atul Deodhar and John H. Stone
46
Low Back and Neck Pain�� 635
Rajiv K. Dixit, Daniel Tobert, and Joseph H. Schwab
47 The Ehlers-Danlos Syndromes�� 655
Marlies Colman, Anne De Paepe, and Fransiska Malfait
48 Sarcoidosis�� 667
Marc A. Judson, Elyse E. Lower, Edward S. Chen, Jeffrey A. Sparks,
Jocelyn R. Farmer, and Robert P. Baughman
xii Contents
49 Amyloidosis�� 687
Andrew Staron, Morie Gertz, and Giampaolo Merlini
50 IgG4-Related Disease�� 701
Mitsuhiro Kawano, Yoh Zen, Takako Saeki, Lingli Dong, Wen Zhang, Emanuel
Della-Torre, Philip A. Hart, Judith A. Ferry, and John H. Stone
51 Castleman Disease�� 727
Luke Chen and David C. Fajgenbaum
52 Erdheim-Chester Disease�� 737
Matthew J. Koster
53 Kikuchi-Fujimoto Disease �� 743
Guillaume Dumas and Olivier Fain
54 Whipple’s Disease�� 749
Rima N. El-Abassi, Daniel Raines, and J. D. England
Index�� 759
Contributors
Abhishek Abhishek University of Nottingham, Nottingham, UK

Ivona Aksentijevich Inflammatory Disease Section, National Human Genome Research
Institute, Bethesda, MD, USA
Daniel Aletaha Division of Rheumatology, Department of Medicine 3, Medical University of
Vienna, Vienna, Austria
Salem Almaani Department of Internal Medicine, The Ohio State Wexner Medical Center,
Columbus, OH, USA
Laura Andreoli Department of Clinical and Experimental Sciences, University of Brescia,
Brescia, Italy
Mariano Andres Sección de Reumatología, Hospital General Universitario de Alicante,
Departamento de Medicina Clínica, Universidad Miguel Hernández, and ISABIAL, Elche,
Spain
Martin Aringer Division of Rheumatology, Department of Medicine III, University Medical
Center and Faculty of Medicine Carl Gustav Carus, Dresden, Germany
Sheila L. Arvikar Center for Immunology and Inflammatory Diseases, Division of
Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical
School, Boston, MA, USA
Isabelle Ayoub Department of Medicine, Division of Nephrology, The Ohio State University
Wexner Medical Center, Columbus, OH, USA
Alan Baer Division of Rheumatology, Johns Hopkins University School of Medicine,
Baltimore, MD, USA
Xenofon Baraliakos Rheumazentrum Ruhrgebiet, Herne, Ruhr-University Bochum, Herne,
Germany
Neil Basu Institute of Infection, Immunity, and Inflammation, University of Glasgow,
Glasgow, UK
Joan M. Bathon Columbia University Irving Medical Center, New York Presbyterian
Hospital, New York, NY, USA
Robert P. Baughman Department of Medicine, University of Cincinnati Medical Center,
Cincinnati, OH, USA
Eldad Ben-Chetrit Rheumatology Unit, Hadassah-Hebrew University Medical Center,
Jerusalem, Israel
Jürgen Braun Rheumazentrum Ruhrgebiet, Herne, Germany
Paul Brogan Great Ormond Street Hospital for Children NHS Foundation Trust, University
College London Great Ormond Street Institute of Child Health, London, UK
xiii
xiv Contributors
Hermine Brunner Cincinnati Children’s Hospital Medical Center, University of Cincinnati,

Cincinnati, OH, USA
John A. G. Buchanan Centre for Education and Innovation, Dental Institute, Barts and the
London School of Medicine and Dentistry, Queen Mary University of London, London, UK
Vatinee Bunya Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA, USA
Jill Buyon New York University School of Medicine, New York, NY, USA
David A. Cabral Department of Pediatrics, British Columbia Children’s Hospital, Vancouver,
BC, Canada
Patrice Cacoub AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal
Medicine and Clinical Immunology, Sorbonne Université, Paris, France
Leonard H. Calabrese Cleveland Clinic Center for Vasculitis Care and Research, Cleveland,
OH, USA
Ricard Cervera Department of Autoimmune Diseases, Hospital Clinic, Barcelona, Spain
Edward S. Chen Division of Pulmonary and Critical Care Medicine, Department of Medicine,
The Johns Hopkins University, Baltimore, MD, USA
Luke Chen Division of Hematology, The University of British Columbia, Vancouver, BC,
Canada
Hyon K. Choi Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
Lisa Christ Department of Rheumatology and Immunology, Inselspital, Bern University
Hospital, Bern, Switzerland
Lisa Christopher-Stine Division of Rheumatology, Johns Hopkins University School of
Medicine, Baltimore, MD, USA
Johns Hopkins Myositis Precision Medicine Center of Excellence, Baltimore, MD, USA
Bart Chwalisz Harvard Medical School, Boston, MA, USA
Division of Neuroimmunology and Neuroinfectious Disease, Massachusetts General Hospital,
Boston, MA, USA
Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, MA, USA
Daniel Clauw Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA
Meghan Clowse Division of Rheumatology and Immunology, Duke University Medical
Center, Durham, NC, USA
Laura C. Coates Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal
Sciences, University of Oxford, Oxford, UK
Marlies Colman Center for Medical Genetics, Department of Biomolecular Medicine, Ghent
University and Ghent University Hospital, Ghent, Belgium
Leslie T. Cooper Department of Cardiology, Mayo Clinic, Jacksonville, FL, USA
Nathalie Costedoat UMR 1027 Inserm, University of Toulouse, Toulouse, France
Service de Médecine Interne, Hôpital Cochin, Paris, France
Randy Q. Cron University of Alabama at Birmingham, Birmingham, AL, USA
Massimo Cugno Department of Pathophysiology and Transplantation, Internal Medicine,
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Università degli Studi di
Milano, Milan, Italy
Contributors xv
David P. D’Cruz Louise Coote Lupus Unit, Guy’s Hospital, London, UK

Nicola Dalbeth Department of Medicine, University of Auckland, Auckland, New Zealand
Maria Dall’Era School of Medicine, University of California, San Francisco, CA, USA
Franco Dammacco Department of Biological Sciences and Human Oncology, Section of
Internal Medicine, University of Bari “Aldo Moro” Medical School, Bari, Italy
Soumyajit Das Department of ENT, All India Institute of Medical Sciences, Mangalagiri,
Andhra Pradesh, India
Kevin D. Deane Division of Rheumatology, University of Colorado Denver Anschutz Medical
Campus, Aurora, CO, USA
Christian Dejaco Rheumatology, Medical University Graz, Graz, Austria
Rheumatology, Hospital of Bruneck, Bruneck, Italy
Emanuel Della-Torre IRCCS San Raffaele Scientific Institute, Università Vita-Salute San
Raffaele, Milan, Italy
Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San
Raffaele Scientific Institute, Milan, Italy
Christopher Denton CL Division of Medicine, University College London, London, UK
UCL Centre for Rheumatology and Connective Tissue Diseases, Royal Free Hospital, London,
UK
Atul Deodhar Division of Arthritis and Rheumatic Diseases, Oregon Health and Science
University, Portland, OR, USA
Anne De Paepe Center for Medical Genetics, Department of Biomolecular Medicine, Ghent
University and Ghent University Hospital, Ghent, Belgium
Jeremie Dion National Referral Center for Rare Systemic Autoimmune Diseases, Hôpital
Cochin, AP-HP, Université Paris Descartes, Paris, France
Rajiv K. Dixit Northern California Arthritis Center, Walnut Creek, CA, USA
Lingli Dong Department of Rheumatology and Immunology, Tongji Medical College, Tongji
Hospital, Huazhong University of Science and Technology, Wuhan, China
Guillaume Dumas APHP, Service de médecine intensive et de réanimation, hôpital Saint-
Louis, Paris, France
Center of Epidemiology and Biostatistics, INSERM, Université de Paris, UMR 1153, Paris,
France
Rima N. El-Abassi Department of Neurology, School of Medicine, Louisiana State University
Health Sciences Center, New Orleans, LA, USA
Despina Eleftheriou Infection, Immunity and Inflammation Programme Research and
Teaching Department, UCL Great Ormond Street Institute of Child Health, University College
London, London, UK
Rheumatology, Great Ormond Street Hospital, London, UK
Paul Emery Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of
Leeds, Chapel Allerton Hospital, Leeds, UK
NIHR Leeds Musculoskeletal Biomedical Research Centre, Leeds Teaching Hospitals NHS
Trust, Leeds, UK
J. D. England Department of Neurology, School of Medicine, Louisiana State University
Health Sciences Center, New Orleans, LA, USA
xvi Contributors
Olivier Fain AP-HP, service de médecine interne, Hôpital Saint Antoine, Sorbonne Université,
Paris, France
David C. Fajgenbaum Center for Cytokine Storm Treatment and Laboratory & Division of
Translational Medicine and Human Genetics, Department of Medicine, Perelman School of
Medicine, University of Pennsylvania, Philadelphia, PA, USA
Jocelyn R. Farmer Department of Allergy and Immunology, Massachusetts General Hospital,
Boston, MA, USA
Brian M. Feldman Departments of Pediatrics and Medicine, IHPME, University of Toronto,
Toronto, ON, Canada
Division of Rheumatology, Hospital for Sick Children, Toronto, ON, Canada
Judith A. Ferry Department of Pathology, Massachusetts General Hospital and Harvard
Medical School, Boston, MA, USA
George E. Fragoulis Institute of Infection, Immunity and Inflammation, University of
Glasgow, Glasgow, UK
Suzanne K. Freitag Ophthalmic Plastic Surgery Service, Massachusetts Eye and Ear
Infirmary, Harvard Medical School, Boston, MA, USA
Richard Furie Division of Rheumatology, Northwell Health and Zucker School of Medicine
at Hofstra/Northwell, Great Neck, NY, USA
Duvuru Geetha Division of Nephrology, Johns Hopkins University, Baltimore, MD, USA
Morie Gertz Division of Hematology, Mayo Clinic, Rochester, MN, USA
Dafna Gladman Department of Medicine, Krembil Research Institute, University of Toronto,
Toronto Western Hospital, Toronto, ON, Canada
Fiona Goldblatt Department of Rheumatology, The Repatriation General Hospital, Adelaide,
SA, Australia
Caroline Gordon University of Birmingham, Birmingham, UK
Peter C. Grayson, MD, Mac National Institute of Arthritis and Musculoskeletal and Skin
Diseases, National Institutes of Health, Bethesda, MD, USA
Jessica Greco Department of Internal Medicine, Davis Heart and Lung Research Institute,
Ohio State University Medical Center, Columbus, OH, USA
Roberta Gualtierotti Department of Pathophysiology and Transplantation, Internal Medicine,
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Università degli Studi di
Milano, Milan, Italy
Rula A. Hajj-Ali Department of Rheumatology/Immunology, Cleveland Clinic, Cleveland,
OH, USA
John J. Halperin Atlantic Health System, Summit, NJ, USA
Vedat Hamuryudan Division of Rheumatology, Department of Internal Medicine, School of
Medicine, Behçet’s Disease Research Centre, Istanbul University-Cerrahpasa, Istanbul, Turkey
Philip A. Hart Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State
University Wexner Medical Center, Columbus, OH, USA
Gulen Hatemi Division of Rheumatology, Department of Internal Medicine, School of
Medicine, Behçet’s Disease Research Centre, Istanbul University-Cerrahpasa, Istanbul, Turkey
Gillian Hawker Department of Medicine, University of Toronto, Toronto, ON, Canada
Contributors xvii
Women’s College Research Institute, Women’s College Hospital, Toronto, ON, Canada
Philip Helliwell Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of
Leeds, Leeds, UK
Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust,
Leeds, UK
V. Michael Holers Division of Rheumatology, University of Colorado Denver Anschutz
Medical Campus, Aurora, CO, USA
Jennifer Huggins Cincinnati Children’s Hospital Medical Center and University of Cincinnati
College of Medicine, Cincinnati, OH, USA
T. W. J. Huizinga Leiden University, Leiden, The Netherlands
Mary Beth Humphrey University of Oklahoma Health Sciences Center, Oklahoma City,
OK, USA
David Isenberg Centre for Rheumatology, Division of Medicine, University College London,
London, UK
Department of Rheumatology, University College London Hospitals NHS Foundation Trust,
London, UK
Mengdi Jiang Department of Nephrology, Ruijin Hospital, School of Medicine, Shanghai
Jiao Tong University, Shanghai, China
Jordan T. Jones University of Kansas City Medical Center, Kansas City, KS, USA
Marc A. Judson Division of Pulmonary and Critical Care Medicine, Albany Medical Center,
Albany, NY, USA
Mitsuhiro Kawano Department of Rheumatology, Graduate School of Medical Science,
Kanazawa University, Kanazawa, Japan
Tanaz Kermani Division of Rheumatology, University of California, Los Angeles, Los
Angeles, CA, USA
Tristan A. Kerr Division of Pediatric Rheumatology, BC Children’s Hospital, Vancouver,
BC, Canada
Munther Khamashta Lupus Research Unit, The Rayne Institute, St Thomas’ Hospital,
King’s College University, London, UK
Dinesh Khanna University of Michigan, Ann Arbor, MI, USA
Lauren King University of Toronto, Toronto, ON, Canada
Women’s College Research Institute, Women’s College Hospital, Toronto, ON, Canada
Jason S. Knight Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA
Jason R. Kolfenbach Division of Rheumatology, University of Colorado Denver Anschutz
Matthew J. Koster Division of Rheumatology, Mayo Clinic, Rochester, MN, USA
Benjamin Z. Leder, MD Department of Medicine, Endocrine Unit, Massachusetts General
Hospital, Boston, MA, USA
Michael Lee Department of Ophthalmology and Visual Neurosciences, University of
Minnesota, Minneapolis, MN, USA
Department of Neurology, University of Minnesota, Minneapolis, MN, USA
Department of Neurosurgery, University of Minnesota, Minneapolis, MN, USA
xviii Contributors
Deborah M. Levy Division of Rheumatology, The Hospital for Sick Children, University of
Toronto, Toronto, ON, Canada
Vidya Limaye Discipline of Medicine, School of Medicine, University of Adelaide, Adelaide,
SA, Australia
Carol B. Lindsley University of Kansas City Medical Center, Kansas City, KS, USA
Nicholas L. Li Department of Internal Medicine, Division of Nephrology, The Ohio State
University, Columbus, OH, USA
Elyse E. Lower Department of Medicine, University of Cincinnati Medical Center, Cincinnati,
OH, USA
Ashima Makol Division of Rheumatology, Department of Internal Medicine, Mayo Clinic,
Rochester, MN, USA
Fransiska Malfait Center for Medical Genetics, Department of Biomolecular Medicine,
Ghent University and Ghent University Hospital, Ghent, Belgium
Brian Mandell Department of Rheumatic and Immunologic Diseases, The Cleveland Clinic,
Cleveland, OH, USA
Xavier Mariette Université Paris-Saclay, INSERM, CEA, Centre de recherche en
Immunologie des infections virales et des maladies auto-immunes, Paris, France
AP-HP, Université Paris-Saclay, Hôpital Bicêtre, Rheumatology Department, Le Kremlin
Bicêtre, Paris, France
Sonia Marino Department of Biomedical Surgical and Dental Sciences, Maxillo-Facial and
Odontostomatology Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico,
Università degli Studi di Milano, Milan, Italy
Justin Mason Vascular Sciences and Rheumatology, Imperial Centre for Translational and
Experimental Medicine, National Heart and Lung Institute, Imperial College London,
Hammersmith Hospital, London, UK
Eric L. Matteson Division of Rheumatology and Department of Health Sciences Research,
Mayo Clinic, Rochester, MN, USA
Maureen Mayes Division of Rheumatology and Clinical Immunogenetics, University of
Texas McGovern Medical School, Houston, TX, USA
Dennis McGonagle LTHT, Leeds NIHR Biomedical Research Centre, Leeds, UK
Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
Giampaolo Merlini Amyloidosis Research and Treatment Centre, Fondazione Istituto di
Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy
Department of Molecular Medicine, University of Pavia, Pavia, Italy
Frederick Miller Clinical Research Branch, National Institute of Environmental Health
Sciences, National Institutes of Health, Research Triangle Park, NC, USA
Neil Miller Johns Hopkins University School of Medicine, Baltimore, MD, USA
Durga P. Misra Department of Clinical Immunology and Rheumatology, Sanjay Gandhi
Postgraduate Institute of Medical Sciences, Lucknow, India
Sue Mollan Metabolic Neurology, Institute of Metabolism and Systems Research, University
of Birmingham, Birmingham, UK
R. C. Monahan Department of Rheumatology, Leiden University Medical Center, Leiden,
The Netherlands
Contributors xix
Sarah Morgan Division of Clinical Immunology and Rheumatology, The University of

Alabama at Birmingham, Birmingham, AL, USA
Kimberly A. Morishita Department of Paediatrics, The University of British Columbia,
Vancouver, BC, Canada
Division of Rheumatology, British Columbia Children’s Hospital, Vancouver, BC, Canada
Guillaume Moulis Department of Internal Medicine, Toulouse University Hospital (CHU de
Toulouse), Toulouse, France
CIC 1436, Toulouse University Hospital (CHU de Toulouse), Toulouse, France
Francesco Muratore Rheumatology Unit, Azienda Unità Sanitaria Locale IRCCS, Reggio
Emilia, Italy
Johannes Nowatzky Division of Rheumatology, Department of Medicine, NYU Langone
Behçet’s Disease Program, NYU Langone Ocular Rheumatology Program, New York
University Grossman School of Medicine, New York, NY, USA
James R. O’Dell Department of Internal Medicine, University of Nebraska Medical Center,
Omaha, NE, USA
Chester Oddis Division of Rheumatology and Clinical Immunology, University of Pittsburgh
School of Medicine, Pittsburgh, PA, USA
Seza Ozen Department of Paediatrics, Hacettepe University, Ankara, Turkey
Lauren M. Pachman Feinberg School of Medicine, Chicago, IL, USA
Northwestern University, Chicago, IL, USA
Department of Pediatrics, Division of Rheumatology, Ann and Robert H. Lurie Children’s
Hospital of Chicago, Chicago, IL, USA
Cure JM Center of Excellence in JM Research and Care, Chicago, LI, USA
Samir V. Parikh Division of Nephrology, Department of Internal Medicine, The Ohio State
University Wexner Medical Center, Columbus, OH, USA
Elizabeth Park Columbia University Irving Medical Center and New York Presbyterian
Hospital, New York, NY, USA
Duane W. Pearson Division of Rheumatology, University of Colorado Denver Anschutz
Michelle Petri Division of Rheumatology, Johns Hopkins University School of Medicine,
Baltimore, MD, USA
Division of Rheumatology, Department of Medicine III, University Medical Center and
Faculty of Medicine Carl Gustav Carus, Dresden, Germany
Ross E. Petty Department of Paediatrics, The University of British Columbia, Vancouver,
BC, Canada
Division of Rheumatology, University of British Columbia, Vancouver, BC, Canada
Clarissa M. Pilkington Adolescent and Pediatric Rheumatology, University College and
Great Ormond Street Hospital, London, UK
Michael Pillinger The Division of Rheumatology, New York University Grossman School of
Medicine, New York, NY, USA
The Section of Rheumatology, New York Harbor Health Care System, New York Campus of
the U.S. Department of Veterans Affairs, New York, NY, USA
xx Contributors
David Pisetsky Departments of Medicine and Immunology, Duke University Medical Center
and Medical Research Service, Veterans Administration Medical Center, Durham, NC, USA
Janet E. Pope Division of Rheumatology, St Joseph’s Hospital, Western University, London,
ON, Canada
Andrew Porter Rheumatology Department, Imperial College Healthcare NHS Trust,
Hammersmith Hospital, London, UK
Abin P. Puravath Division of Rheumatology, Johns Hopkins University School of Medicine,
Baltimore, MD, USA
Vanessa Quick Rheumatology, Luton and Dunstable University Hospital NHS Foundation
Trust, Luton, UK
Kaitlin A. Quinn, MD, MHS National Institute of Arthritis and Musculoskeletal and Skin
Diseases, National Institutes of Health, Bethesda, MD, USA
Daniel Raines Section of Gastroenterology, Department of Medicine, Louisiana State
University Health Sciences Center, New Orleans, LA, USA
Rosalind Ramsay-Goldman Department of Medicine, Rheumatology Division, Feinberg
School of Medicine, Northwestern University, Chicago, IL, USA
Steven Rauch Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye
and Ear, Boston, MA, USA
Department of Otolaryngology-Head and Neck Surgery, Harvard Medical School, Boston,
MA, USA
Ann M. Reed Cure JM Center of Excellence in JM Research and Care, Durham, NC, USA
Department of Pediatrics, Duke University Medical School, Durham, NC, USA
Ian R. Reid Department of Medicine, Faculty of Medical and Health Sciences, University of
Auckland, Auckland, New Zealand
Auckland District Health Board, Auckland, New Zealand
Lisa G. Rider Cure JM Center of Excellence in JM Research and Care, Washington, DC, USA
Environmental Autoimmunity Group, Clinical Research Branch, National Institute of
Environmental Health Sciences, National Institutes of Health, Bethesda, MD, USA
Ann K. Rosenthal Department of Medicine, Division of Rheumatology, Medical College of
Wisconsin, Milwaukee, WI, USA
Brad Rovin Department of Internal Medicine, The Ohio State Wexner Medical Center,
Columbus, OH, USA
Anne Rowley Department of Pediatrics, Northwestern University Feinberg School of
Medicine, Chicago, IL, USA
Department of Microbiology-Immunology, Northwestern University Feinberg School of
Medicine, Chicago, IL, USA
Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA
Dax G. Rumsey Department of Pediatrics, Division of Rheumatology, University of Alberta,
Edmonton, AB, Canada
David Saadoun AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal
Medicine and Clinical Immunology, Sorbonne Universités, Paris, France
Ken Saag University of Alabama at Birmingham, Birmingham, AL, USA
Contributors xxi
Takako Saeki Nagaoka Red Cross Hospital, Nagaoka, Japan

Jane Salmon Division of Rheumatology, Department of Medicine, Hospital for Special
Surgery and Weill Cornell Medicine, New York, NY, USA
Carlo Salvarani Rheumatology Service, Arcispedale S. Maria Nuova, Reggio Emilia, Italy
Lisa Sammaritano Weill Cornell Medicine, Hospital for Special Surgery, New York, NY,
USA
Naomi Schlesinger Division of Rheumatology, Rutgers—Robert Wood Johnson Medical
School, New Brunswick, NJ, USA
Godehard Scholz Department of Rheumatology, Immunology and Allergology, Inselspital,
Bern University Hospital, University of Bern, Bern, Switzerland
Joseph H. Schwab Massachusetts General Hospital, Boston, MA, USA
Luca Seitz Department of Rheumatology, Immunology and Allergology, Inselspital, Bern
University Hospital, University of Bern, Bern, Switzerland
Margaret Seton Boston, MA, USA
Ami A. Shah Division of Rheumatology, Johns Hopkins University School of Medicine,
Baltimore, MD, USA
Shaiba Shandu Department of Oral Medicine Infection and Immunity, Harvard School of
Dental Medicine, Boston, MA, USA
Aman Sharma Clinical Immunology and Rheumatology Services, Department of Internal
Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh,
India
Earl D. Silverman Division of Rheumatology, The Hospital for Sick Children, University of
Toronto, Toronto, ON, Canada
Josef Smolen Division of Rheumatology, Department of Medicine 3, Medical University of
Vienna, Vienna, Austria
Lucia Sobrin Retina Service, Department of Ophthalmology, Massachusetts Eye and Ear,
Boston, MA, USA
Francesco Spadari Department of Biomedical Surgical and Dental Sciences, Maxillo-Facial
and Odontostomatology Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico,
Università degli Studi di Milano, Milan, Italy
Jeffrey A. Sparks Brigham and Women’s Hospital, Harvard Medical School, Boston, MA,
USA
E. William St. Clair Duke University Medical Center, Durham, NC, USA
Ian Stanaitis Women’s College Research Institute, Women’s College Hospital, Toronto, ON,
Canada
Andrew Staron Amyloidosis Center, Boston University Chobanian & Avedisian School of
Medicine, Boston Medical Center, Boston, MA, USA
Virginia Steen Georgetown University Medical Center, Washington, DC, USA
Allen C. Steere Center for Immunology and Inflammatory Diseases, Division of
Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical
School, Boston, MA, USA
John H. Stone Division of Rheumatology, Allergy, and Immunology, Massachusetts General
Hospital, Harvard University, Boston, MA, USA
xxii Contributors
Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital,

Harvard University, Boston, MA, USA
Sangeeta Sule Children’s National Hospital, Washington, DC, USA
Julia Sun Department of Medicine, Rheumatology Division, Feinberg School of Medicine,
Northwestern University, Chicago, IL, USA
Yutong Su Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai Jiao
Tong University School of Medicine, Shanghai, China
Yoshiya Tanaka The First Department of Internal Medicine, School of Medicine, University
of Occupational and Environmental Health, Kitakyushu, Japan
Sarah Tansley Department of Life Sciences, University of Bath, Bath, UK
Christoph Tappeiner Department of Ophthalmology, Inselspital, University of Bern, Bern,
Switzerland
Peter C. Taylor Botnar Research Centre, University of Oxford, Oxford, UK
Robert Terkeltaub Rheumatology, Allergy-Immunology Section, San Diego VA Medical
Center, University of California at San Diego, San Diego, CA, USA
Daniel Tobert Department of Orthopedic Surgery, Orthopedic Spine Center and Orthopedic
Oncology Service, Massachusetts General Hospital, Boston, MA, USA
Shirley M. L. Tse Division of Rheumatology, University of Toronto/SickKids, Toronto, ON,
Canada
Annette van der Helm-van Mil Department of Rheumatology, Leiden University Medical
Center, Leiden, The Netherlands
Ronald F. van Vollenhoven Unit for Clinical Therapy Research, Inflammatory Diseases
(ClinTRID), Karolinska Institutet, Stockholm, Sweden
Peter M. Villiger Department of Rheumatology, Immunology and Allergology, Bern
University Hospital, University of Bern, Bern, Switzerland
Department for BioMedical Research, University of Bern, Bern, Switzerland
Frederick Vivino Division of Rheumatology, Penn Presbyterian Medical Center,
Philadelphia, PA, USA
Penn Sjogren’s Syndrome Center, Perelman School of Medicine, University of Pennsylvania,
Philadelphia, PA, USA
Daniel Wallace Division of Rheumatology, Cedars-Sinai Medical Center, Los Angeles, CA,
USA
Amy Warriner Division of Endocrinology, Metabolism and Diabetes, The University of
Alabama at Birmingham, Birmingham, AL, USA
Kenneth Warrington Department of Medicine, Mayo Clinic College of Medicine and
Science, Rochester, MN, USA
Sook-Bin Woo Department of Oral Medicine Infection and Immunity, Harvard School of
Dental Medicine, Boston, MA, USA
Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School,
Boston, MA, USA
Center of Oral Pathology, StrataDx, Lexington, MA, USA
Ava Wu Sjögren’s Syndrome Clinic, University of California, San Francisco, San Francisco,
CA, USA
Contributors xxiii
Chengde Yang Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai

Jiao Tong University School of Medicine, Shanghai, China
Hasan Yazici Division of Rheumatology, New York University School of Medicine, New
York, NY, USA
Yusuf Yazici Division of Rheumatology, New York University School of Medicine, New
York, NY, USA
David S. Younger Department of Neurology, Division of Neuro-Epidemiology, New York
University School of Medicine, New York, NY, USA
School of Public Health, City University of New York, New York, NY, USA
Elaine W. Yu, MD, MMSC Division of Endocrinology, Diabetes, and Metabolism,
Massachusetts General Hospital, Boston, MA, USA
Bita Zahedi, MD, MA Massachusetts General Hospital, Harvard Medical School, Boston,
MA, USA
Division of Endocrinology, Diabetes, and Metabolism, Massachusetts General Hospital,
Boston, MA, USA
Yoh Zen Institute of Liver Studies, King’s College Hospital, London, UK
Wen Zhang Peking Union Medical College Hospital, Beijing, China
Xuan Zhang Department of Rheumatology, Beijing Hospital, National Center of Gerontology,
Beijing, China
Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
Lidan Zhao Departments of Rheumatology, Peking Union Medical College Hospital, Clinical
Immunology Center, Chinese Academy of Medical Science and Peking Union Medical
College, Beijing, China
Rheumatoid Arthritis
1
Kevin D. Deane, Daniel Aletaha, Joan M. Bathon,
Paul Emery, George E. Fragoulis, V. Michael Holers,
T. W. J. Huizinga, Jason R. Kolfenbach,
James R. O’Dell, Duane W. Pearson, Elizabeth Park,
Josef Smolen, Yoshiya Tanaka, Peter C. Taylor,
Annette van der Helm-van Mil,
Ronald F. van Vollenhoven, and E. William St. Clair
Overview • RA typically affects distal joints (e.g., hands, wrists, and

• Rheumatoid arthritis (RA) affects all ethnic groups and feet) in a symmetrical polyarthritis, and there is increas-
has a wide age range of onset. The average ages at diag- ing awareness that tenosynovitis is a manifestation of RA
nosis for women and men are approximately 50 and Early disease, however, may be apparent in only a few
60 years, respectively. In general, the prevalence across joints.
the world is estimated to be between 0.5% and 1%. • The onset of RA is usually subacute in nature, with insidi-
Women are approximately three times as likely as men to ous accumulation of fatigue, joint pain, stiffness, and
develop RA. In addition, in some populations, such as swelling. However, waxing and waning symptoms and
indigenous peoples of the Americas, the prevalence range findings can occur, especially in early phases of the dis-
is higher, on the order of 5–7%. ease when RA can demonstrate “palindromic” features or
K. D. Deane (*) · V. M. Holers · J. R. Kolfenbach · D. W. Pearson J. R. O’Dell

Division of Rheumatology, University of Colorado Denver Department of Internal Medicine, University of Nebraska Medical
Anschutz Medical Campus, Aurora, CO, USA Center, Omaha, NE, USA
e-mail: Kevin.Deane@cuanschutz.edu; e-mail: jrodell@unmc.edu
michael.holers@cuanschutz.edu; jason.kolfenbach@ucdenver.edu;
E. Park
duane.pearson@cuanschutz.edu
Columbia University Irving Medical Center and New York
D. Aletaha · J. Smolen Presbyterian Hospital, New York, NY, USA
Division of Rheumatology, Department of Medicine 3, Medical e-mail: ep2899@cumc.columbia.edu
University of Vienna, Vienna, Austria
Y. Tanaka
e-mail: daniel.aletaha@meduniwien.ac.at;
The First Department of Internal Medicine, School of Medicine,
josef.smolen@meduniwien.ac.at
University of Occupational and Environmental Health,
J. M. Bathon Kitakyushu, Japan
Columbia University Irving Medical Center, New York e-mail: tanaka@med.uoeh-u.ac.jp
Presbyterian Hospital, New York, NY, USA
P. C. Taylor
e-mail: jmb2311@mail.cumc.columbia.edu
Botnar Research Centre, University of Oxford, Oxford, UK
P. Emery e-mail: peter.taylor@kennedy.ox.ac.uk
Leeds Institute of Rheumatic and Musculoskeletal Medicine,
A. van der Helm-van Mil
University of Leeds, Chapel Allerton Hospital, Leeds, UK
Department of Rheumatology, Leiden University Medical Center,
NIHR Leeds Musculoskeletal Biomedical Research Centre, Leeds Leiden, the Netherlands
Teaching Hospitals NHS Trust, Leeds, UK e-mail: a.h.m.van_der_helm@lumc.nl
e-mail: p.emery@leeds.ac.uk
R. F. van Vollenhoven
G. E. Fragoulis Unit for Clinical Therapy Research, Inflammatory Diseases
Institute of Infection, Immunity and Inflammation, University of (ClinTRID), Karolinska Institutet, Stockholm, Sweden
Glasgow, Glasgow, UK e-mail: r.vanvollenhoven@amsterdamumc.nl
T. W. J. Huizinga E. W. St. Clair
Leiden University, Leiden, The Netherlands Duke University Medical Center, Durham, NC, USA
e-mail: t.w.j.huizinga@lumc.nl e-mail: stcla003@mc.duke.edu
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 1

J. H. Stone (ed.), A Clinician’s Pearls & Myths in Rheumatology, https://doi.org/10.1007/978-3-031-23488-0_1
2 K. D. Deane et al.
a migratory oligoarthritis. In other cases, the onset of dis-

a
ease is explosive, with the development of severe symp-
toms over only a few days.
• If untreated (or undertreated), RA can lead to progressive
joint damage and disability.
• Autoantibodies, including rheumatoid factor (RF) and
antibodies to cyclic citrullinated protein antigens (ACPA),
are present in up to 80% of patients. A growing number of
other autoantibodies are now described, including anti-
bodies to carbamylated proteins.
• For patients in whom an inflammatory arthritis is present
in an RA-like pattern but autoantibodies are not detected,
the term “seronegative RA” can be used. In such cases,
however, it is important not to overlook other forms of
arthritis such as microcrystalline disease, spondyloarthri-
tis, virus-associated arthritis, or paraneoplastic
syndromes. b
• The principal goals of modern treatment is the prevention
of joint damage and to improve quality of life.
• Treatment approaches now emphasize early diagnosis
and interventions designed to suppress joint inflamma-
tion. Treat-to-target approaches in which frequent visits
to gauge disease activity and adjust medications accord-
ingly for the purpose of achieving low disease activity or
even remission are standard-of-care.
Early Rheumatoid Arthritis

c
Myth Symmetrical polyarthritis at presentation is the rule
for RA.
Reality: RA that has been clinically apparent for a pro-
longed period of time classically involves a symmetrical pat-
tern of affected joints (Fig. 1.1) (Arnett et al. 1988). This
symmetry may not be present in early disease, however.
Studies have shown that a significant proportion of patients
who subsequently meet classification criteria for RA have
only one or two clinically inflamed joints as the initial mani-
festation (Barra et al. 2013). Presentations with arthritis
involving only one joint for many months – e.g., the wrist –
are well-described.
A migratory oligoarthritis pattern of joint inflammation
Fig. 1.1 (a–c) Symmetric involvement with inflammatory arthritis in
may also occur early on. In a migratory oligoarthritis, inflam- rheumatoid arthritis. The patients in (a, b) principally have involvement
matory joint disease affects only one joint (e.g., the shoulder) of the proximal interphalangeal (PIP) joints. Note sparing of the distal
very briefly, and then migrates to another joint such as a interphalangeal joints in both cases. Metacarpophalangeal (MCP)
involvement may not be appreciated easily in these images. The patient
knee, typically not stopping at any joint for more than a day
in (c), however, has newly diagnosed RA with intense synovitis at both
or two. In addition, in some individuals joint inflammation the MCP and PIP joints, severely restricting his ability to make a fist
may come and go in the same joints; when this occurs, it can and use his hands for activities of daily living
be termed ‘palindromic rheumatism’ (Mankia and Emery
2019). logical findings of rheumatoid factor (RF) positivity or anti-
For patients with inflammatory joint symptoms that are bodies to cyclic citrullinated protein antigens (ACPA) have
not the classic symmetrical small-joint polyarthritis, sero- important diagnostic significance.
1 Rheumatoid Arthritis 3
Myth Seropositive RA begins in the joint. Reality: Genetic and epidemiologic studies suggest
Reality: Although seropositive RA can sometimes pres- that seronegative RA is a distinct illness with unique
ent with an explosive clinical onset of arthritis, retrospective pathophysiologic characteristics. It generally responds to
studies and an increasing number of prospective studies have the same types of medications as the seropositive disease –
demonstrated that RA-related autoantibodies (e.g., ACPA although there are some exceptions – but differences
and RF) are often present for many years before the appear- between “seropositive” and “seronegative” RA are impor-
ance of clinical arthritis (Malmström et al. 2017, Deane and tant and need to be acknowledged in the interest of under-
Holers 2021). These observations suggest that the disease standing them better (Klareskog et al. 2011). Little is
process is initiated outside of the joint, perhaps at mucosal known about the preclinical processes that are present in
sites (e.g., the respiratory mucosa), only targeting the joints seronegative patients with RA prior to the onset of clini-
and other sites of disease later (Holers et al. 2018). cally apparent arthritis.
An increasing number of autoantibodies are being discov-
Myth The earliest joint-related target of the systemic auto- ered that in some individuals characterize patients who oth-
immune disease process that characterizes preclinical RA is erwise lack both ACPA and IgM RF antibodies (Trouw et al.
the synovium. 2017). These can include antibodies to carbamylated or
Reality: Although clinically one assesses for the presence methylated proteins.
of synovitis, some studies suggest that the initial manifesta-
tion of RA may be interosseous tendonitis and tenosynovitis. Myth There is no good advice to give patients with RA and
This can be apparent magnetic resonance imaging (MRI) or those at risk for RA about dietary or lifestyle changes that
ultrasound studies (Mankia et al. 2019). can alter the likelihood of developing future RA or the course
of disease once established.
Pearl Tenosynovitis is more specific for RA than synovitis. Reality: Epidemiologic studies have suggested that higher
Comment: RA is typically regarded as being a disease levels of omega-3 fatty acid intake decrease the likelihood of
consisting of synovitis and bony erosions of small joints. future RA development (Gan et al. 2017). Similarly, other
This classic picture was derived from comparing the clinical environmental and personal lifestyle factors such as absence
and radiographic characteristics of patients with RA with of smoking, maintenance of a lower BMI and potentially a
those of patients with other rheumatic diseases affecting the Mediterranean-style diet are associated with a decreased like-
joints. Advanced imaging modalities now reveal that tenosy- lihood of developing RA (Karlson and Deane 2012;
novitis at the level of the hand and feet joints is a feature Zaccardelli et al. 2019). Although clinical trials have not yet
worthy of recognition as another classic trait of RA (Rogier been performed to validate these approaches, these lifestyle
et al. 2019). and exposure modifications are not unreasonable to discuss
The reported prevalence of tenosynovitis depends on the with patients with RA and those at risk for future disease.
number of tendon sheaths studied. The tendon sheaths tar-
geted for imaging typically include those of the wrist, meta- Myth Individuals who exhibit a high titer ACPA or RF anti-
carpophalangeal (MCP) and metatarsophalangeal (MTP) bodies and arthralgias but who do not have clinical exami-
joints. MRI studies in consecutive early RA showed a sensi- nation or imaging evidence of synovitis or tenosynovitis
tivity of tenosynovitis of 75%–87%. In contrast, imaging should be treated with a disease-modifying antirheumatic
studies in persons from the general population typically drug (DMARD) such as hydroxychloroquine.
show a prevalence of tenosynovitis at small joints ranging Reality: Although there is an increasing tendency to uti-
from 0% to 3% (Mangnus et al. 2015, 2016). The specificity lize hydroxychloroquine in individuals who are thought to be
of finding tenosynovitis on imaging is therefore on the order “on their way” to getting RA (which may be termed ‘pre-
of 97% or higher. RA’), no clinical trial evidence demonstrates that this is the
The specificity in patients with other arthritides as refer- correct approach. In fact, in preliminary results from interim
ence is also high. A study at the tendon level of the wrist and analyses of the STOPRA trial Deane et al. (2022) showed no
MCP joints, comparing consecutive patients with RA and benefit of hydroxychloroquine in the prevention of progres-
other early arthritis (including psoriatic arthritis), reported a sion to RA in ACPA positive individuals who did not have
specificity ranging from 82% to 99% (Krabben et al. 2015). inflammatory arthritis at baseline. However, there are intrigu-
Thus, tenosynovitis at the level of small joints (MCPs, wrist, ing findings from the TREAT EARLIER study where metho-
MTPs) has high sensitivity and specificity for RA. trexate use in individuals with ‘subclinical arthritis’ (defined
as MRI evidence of joint inflammation without clinical
Myth Seropositive and seronegative RA have similar examination findings of inflammatory arthritis) was associ-
genetic origins and likely differ only in the presence or ated with the development of a milder form of clinical RA
absence of ACPA and RF. although overall progression to RA was not significantly
reduced (Krijbolder et al. 2022). At this time, rather than Clinical Features
starting a medication with the intention of preventing evolu-
tion to RA, it is likely better to educate patients carefully Myth A patient must have a score of 6 or more out of 10 on
about the symptoms and signs of RA, to perform a close the 2010 American College of Rheumatology (ACR)/
follow-up and to consider treatment only if or when inflam- European League Against Rheumatism (EULAR) classifica-
matory arthritis evolves becomes present. However, there are tion criteria to be diagnosed as having RA.
multiple prevention trials in RA underway and we may see a Reality: Diagnostic criteria do not exist for RA. The 2010
shift to possible pharmacologic preventive interventions in ACR/EULAR classification criteria (as well as the earlier
RA in the near future (Deane and Holers 2021). 1987 ACR criteria) were not intended for the purpose of
diagnosing individual patients, but rather for defining patient
Myth The absence of a smoking history in some patients populations that are comparable across different clinical
who develop seropositive RA suggests that pulmonary expo- studies (Aletaha et al. 2010; Arnett et al. 1988). The gold
sures do not have a role in the pathogenesis of their standard for the diagnosis of RA continues to be the clinical
disease. judgment of a rheumatologist.
Reality: The association of RA development with a The 2010 criteria were designed in part to be able to clas-
smoking history is most striking in those patients with the sify RA patients earlier, and subsequent studies have dem-
HLA-shared epitope alleles, which are only present in ~2/3 onstrated success in that regard. The 2010 criteria diverge
of patients with RA. However, other lung exposures such as from the 1987 criteria in their incorporation of ACPA; the
air pollution and silica dust exposure might account for lung- inclusion of acute-phase reactant elevation; the requirement
related risks that are not directly tied to smoking for exclusion of alternative causes for the inflammatory
In addition, there is increasing understanding that other arthritis; and reduced emphasis on disease manifestations
mucosal sites such as the periodontal region and gut may that are characteristic of later disease stages (bone erosions,
play some role in the development of RA. rheumatoid nodules (Table 1.1).
Table 1.1 The 1987 ARA (ACR) and 2010 ACR/EULAR RA classification criteria
1987 criteria (Arnett et al. 1988) 2010 criteria (Aletaha et al. 2010)
1. Morning stiffness defined as morning stiffness in and around the Target population (Who should be tested?) 0
joints lasting at least 1 hour before maximal improvement Individuals with the following should be included: 1
2. Arthritis of three or more joint areas defined as at least three joint 1. ≥1 joint with definite clinical synovitis 2
areas simultaneously have had soft tissue swelling or fluid (not bony 2. Synovitis not better explained by another disease 3
overgrowth alone) observed by a physician. The 14 possible areas are A. Joint Involvementa 5
the right or left PIP, MCP, wrist, elbow, knee, ankle, and MTP joints 1 large joint¶ 0
3. Arthritis of hand joints defined as at least one area is swollen (as 2–10 large joints 2
defined above) in a wrist, MCP, or PIP joint 1–3 small joints (with or without involvement of large joints)b 3
4. Symmetric arthritis defined as simultaneous involvement of the same 4–10 small joints (with or without involvement of large 0
joint areas (as defined in 2) on both sides of the body (bilateral joints) 1
involvement of PIPs, MCPs, or MTPs is acceptable without absolute >10 joints (at least one small joint) 0
symmetry) B. Serology (at Least One Test Result Is Needed for 1
5. Rheumatoid nodules defined as subcutaneous nodules, over bony Classification)
prominences, or extensor surfaces, or in juxtaarticular regions, Negative RF and negative ACPA
observed by a physician Low-positive RF or low-positive ACPA
6. Serum rheumatoid factor defined as the demonstration of abnormal High-positive RF or high-positive ACPA (>3× upper limit of
amounts of serum rheumatoid factor by any method for which the normal)
result has been positive in <5% of normal control subjects C. Acute-Phase Reactants (at Least One Test Result Is
7. Radiographic changes defined as radiographic changes typical of Needed for Classification)
rheumatoid arthritis on posteroanterior hand and wrist radiographs, Normal CRP and normal ESR
which must include erosions or unequivocal bony decalcification Abnormal CRP or abnormal ESR
localized in or most marked adjacent to the involved joints D. Duration of Symptoms
(osteoarthritis changes alone do not qualify) <6 weeks
For classification purposes, a patient shall be said to have RA if he/ ≥6 weeks
she has satisfied at least four of the seven of these criteria. Criteria 1 Classification Criteria for RA (Score-Based Algorithm:
through 4 must have been present for at least 6 weeks. Patients with Add Score of Categories A–D; A Score of ≥6/10 Is Needed
two clinical diagnoses are not excluded for the Classification of a Patient as Having Definite RA)
a
Joint involvement refers to any swollen or tender joint on examination. Distal interphalangeal joints, first carpometacarpal joints, and first meta-
tarsophalangeal joints are excluded from assessment. “Large joints” refers to the shoulders, elbows, hips, knees, and ankles
b
“Small joints” refers to the metacarpophalangeal joints, proximal interphalangeal joints, second through fifth metatarsophalangeal joints, thumb
interphalangeal joints, and wrists
Myth Patient with rheumatoid arthritis do not get gout. Table 1.2 The 2011 ACR/EULAR definitions of remission in rheuma-
Reality: This myth may be an artifact of mid-twentieth toid arthritis clinical trials (Felson et al. 2011)
century RA treatment regimens that utilized high-dose aspi- Boolean-based definition
rin, a uricosuric agent, for most RA patients. In fact, in a At any time point, the patient must satisfy all of the following:
Tender joint count ≤1a
large cohort of RA patients, 17% had elevated uric acid Swollen joint count ≤1a
(>6.8 mg/dl), and 6.1% were diagnosed with gout over time C-reactive protein ≤1 mg/dL
(Chiou et al. 2020). In another study, not only was gout Patient global assessment ≤1 (on a 0–10 scale)b
shown to be prevalent in RA compared to controls, 1.61% vs Index-based definition
Simplified Disease Activity Index score of ≤3c
0.92%; p < 0.001, RA was statistically associated with gout a
For tender and swollen joint counts, use of a 28-joint count may miss
and in a multivariable analysis (OR = 1.72; 95% CI 1.45– actively involved joints, especially in the feet and ankles, and it is pref-
2.05) (Merdler-Rabinowicz et al. 2017). These observations erable to include feet and ankles also when evaluating remission
confirm that gout and RA actually co-exist frequently. b
For the assessment of remission, we suggest the following format and
With the development of more effective treatment regi- wording for the global assessment questions. Format: a horizontal
10-cm visual analog or Likert scale with the best anchor and lowest
mens for RA that do not involve high-dose aspirin, it is not score on the left side and the worst anchor and highest score on the right
uncommon to see the two diseases in the same patient (Olaru side. Wording of question and anchors: For patient global assessment,
et al. 2017). Indeed, gout or other crystalline diseases (e.g., “Considering all of the ways your arthritis has affected you, how do you
CPPD) should be considered in a patient with a diagnosis of feel your arthritis is today?” (anchors: very well–very poor). For physi-
cian/assessor global assessment, “What is your assessment of the
RA who has mono- or oligo-articular flares of arthritis. When patient’s current disease activity?” (anchors: none-extremely active)
patients with RA do not respond as expected to disease- c
Defined as the simple sum of the tender joint count (using 28 joints),
modifying treatment, it is worthwhile to take a step back, swollen joint count (using 28 joints), patient global assessment (0–10
consider the possibility of a co-existing crystalline-induced scale), physician global assessment (0–10 scale), and C-reactive protein
level (mg/dl)
arthritis, and perform appropriate diagnostic studies (i.e.,
arthrocentesis and synovial fluid analysis).
Myth Rheumatoid nodules are an important finding in the
Myth RA burns out with time in many patients. early diagnosis of RA.
Reality: Some clinicians refer to “burned out” Comment: The presence of rheumatoid nodules is one
RA. Patients to whom this term is applied generally have of the items in the 1987 classification criteria for RA.
long-standing disease, severe joint damage, and little evi- Rheumatoid nodules are not typically present within the
dence of active synovitis on physical examination. Most are first few months of the onset of synovitis, and thus their
on minimal therapy for RA, albeit some have tried multiple absence at presentation does not preclude the diagnosis of
agents in the past. Many patients with “burned out” RA may RA. Furthermore, rheumatoid nodules are found in only
have moderately elevated inflammatory parameters and con- one-third of patients with established RA. Hence, their
tinue to deteriorate radiographically despite having symp- presence remains an insensitive marker for disease even in
toms that are minimal compared to patients with early later stages (Turesson and Jacobsson 2004). In rare cases,
disease. Moreover, if these patients are treated, their symp- individuals may have rheumatoid nodules and circulating
toms improve, indicating a response to therapy. Thus, the autoantibodies without appreciable synovitis (Hewitt and
label of “burned out” RA is probably appropriate only on Cole 2005).
rare occasions. Strong consideration should be given to treat-
ing patients who fit the operative definition of burned out RA Myth Troublesome rheumatoid nodules cannot be treated.
with anti-inflammatory therapies. Reality: Nodules that are painful or interfere with func-
This concept of burned out RA is distinct from the more tion require an intervention. In general, DMARDs do not
formal definition of disease remission in RA. A patient with reduce nodules significantly. Some case reports, however,
RA in remission has little to no discernible disease activity suggest that biologic therapies such as rituximab and anti-
according to the history, examination, laboratory measure- IL6 therapy help decrease nodule size and number (Sautner
ments, and imaging. Remission can be defined by various et al. 2013; De Stefano et al. 2011; Andres et al. 2012). Direct
criteria, including the ACR/EULAR remission criteria cre- injection of the nodule with a mixture of local anesthetic and
ated for clinical trials in 2011 (Table 1.2) (Felson et al. 2011). glucocorticoids may be beneficial as well (Baan et al. 2006).
It is not yet clear how to select patients in remission who The procedure for injecting rheumatoid nodules is as fol-
may safely reduce or stop their medications. Drug-free lows. Up to 0.3 mL of methylprednisolone or triamcinolone
remission, however, is achieved only rarely (Schett et al. 40 mg/mL is mixed in 1:1 ratio with 1% lidocaine. Following
2016; Terslev et al. 2021a, b). local anesthesia of the overlying skin, the needle is inserted
directly into the center of the nodule. The medication is incidence of both seems to be declining with modern thera-
injected slowly as the needle is withdrawn. Considerable pies (Nakamura et al. 2019; Myasoedova et al. 2011). Cases
force on the plunger of the syringe is needed in some cases in of RA-associated amyloidosis and Felty’s syndrome occur-
order to express the mixture into the nodule. Surgical exci- ring in the absence of active synovitis have been reported in
sion is necessary for some nodules, although recurrence may the literature (Owlia et al. 2014). One must maintain a high
occur (Riches et al. 2016). index of suspicion for RA-related extra-articular disease
Surgical removal of a nodule from sites other than the even if joint disease is not active.
skin may be necessary for diagnosis, such as a pulmonary
nodule that must be differentiated from a malignancy. Myth RA does not affect the central nervous system.
Finally, limited data suggest a potential association between Reality: RA can directly affect the central nervous sys-
methotrexate and the development of rheumatoid nodules, tem in multiple ways (Atzeni et al. 2018). These include ero-
i.e., “rheumatoid nodulosis” (Patatanian and Thompson sive disease and pannus formation in the C1 and C2 area,
2002). Possible mechanisms relate to folate and adenosine leading to spinal cord impingement. Meningeal involvement
pathways (Soukup et al. 2017). If rheumatoid nodulosis is can also occur in RA, though thankfully it is rare. Meningeal
suspected, an alternative to methotrexate may be considered disease may present with clinical findings of headache,
after balancing this potential risk against the benefits of encephalopathy, and cranial nerve defects. Imaging in such
methotrexate in RA. cases confirms meningeal thickening, nodularity, and
enhancement. Biopsy may be required for diagnosis and to
Myth Rheumatoid nodules frequently occur in the heart differentiate RA-associated disease from that caused by
and cause conduction defects. ANCA-associated vasculitis, IgG4-related disease, malig-
Reality: Although mentioned in most textbooks as an nancy, and other conditions, depending on the individual
extra-articular complication of RA, this is a surpassingly rare patient’s circumstances. In some cases, cerebrospinal fluid
phenomenon (Thery et al. 1974; Ahern et al. 1983). elevation of RA-related autoantibodies can be seen and aid in
Rheumatoid nodules are not likely to be the explanation for the diagnosis, especially if articular disease is absent
conduction defects in a patient with RA. When tissue has (McKenna et al. 2019).
been available from the unusual cases in which rheumatoid
nodules occur in the heart, the atrioventricular node may Myth Rheumatoid arthritis is associated with severe
show a variety of histopathologic findings, including granu- neutropenia.
lomata (resembling that of a typical rheumatoid nodule), dif- Comment: Neutropenia is not rare in the context of
fuse lymphocytic inflammation, or fibrosis (Ben Hamda RA. It occurs in about 5%–10% of patients treated with con-
et al. 2004). ventional DMARDs and in 15%–20% of patients treated
with biologic DMARDs. The neutropenia is usually is mild,
Pearl Rheumatoid pleural effusions can mimic empyemas. however, and seldom leads to treatment discontinuation. Few
Comment: RA is one of the few causes of a low pH in RA patients with neutropenia will develop serious infec-
pleural effusions (Balbir-Gurman et al. 2006; Light 2011). tions. In the differential diagnosis of RA patients with neu-
Two other major ones are empyema and esophageal rupture. tropenia, Felty’s syndrome and large granulocytic leukemia
Pleural effusions in RA are exudates, characterized by high should be included (Fragoulis et al. 2018).
protein and lactate dehydrogenase levels and low glucose
concentration. Cholesterol may be elevated in chronic effu- Myth RA goes into remission during pregnancy.
sions, leading to a milky appearance to the pleural fluid. Reality: Some studies have suggested that RA disease
White blood cell counts are frequently elevated in RA effu- activity improves during pregnancy in a high percentage of
sions, although often less than 5000/mm3. In contrast to cases – approximately 60% – to the extent that treatment
empyemas, lymphocytes tend to predominate over neutro- reduction is possible in some. Among women with RA
phils unless the fluid collection is tapped early in its course. whose disease does improve during pregnancy, improve-
Pleural effusions in RA should be evaluated carefully to ments in disease activity generally start in the first trimester
ensure that infection and malignancy are not missed. and last through delivery. In fact, however, remission by
defined criteria such as the DAS28-CRP occurs in only about
Pearl Amyloidosis and rheumatoid vasculitis pose less of a 25% of patients overall (Jethwa et al. 2019; de Man et al.
threat than they did before the availability of effective 2014). The universal statement that RA “resolves” temporar-
therapy. ily during pregnancy is wishful thinking.
Comment: Two potentially lethal complications of RA Disease flares during pregnancy have actually been
are the development of secondary amyloidosis and the occur- reported in 29% of patients with RA. Some of these flares are
rence of rheumatoid vasculitis. Fortunately, however, the associated with discontinuation of anti-TNF biologics in
early pregnancy (van den Brandt et al. 2017). One-third of ation in a patient with inflammatory arthritis improves the
RA patients may have active disease at some point during overall sensitivity for detection of disease. Finally, both RF
pregnancy, and active disease during any trimester has a high and ACPA can be elevated in individuals prior to the onset of
correlation with preterm delivery (Zbinden et al. 2018). clinically apparently inflammatory arthritis, during a period
Moreover, 47% of RA patients experience disease flares in termed “pre-RA” (Deane and Holers 2021).
the immediate post-partum period.
Pearl In patients with early inflammatory arthritis who do
Pearl Tenosynovitis should not be disregarded. not meet RA classification criteria, ACPA positivity is an
Reality: Although tendon sheath inflammation is not excellent predictor of persistent inflammatory arthritis and
part of the ACR/EULAR criteria for RA, it is recognized disease that should be classified as RA.
as a common feature pf active RA and may be a major Comment: In patients with early undifferentiated arthri-
source of pain, stiffness, and functional impairment. The tis who are ACPA positive, at least 93% have persistent
fact that it is not part of the classification criteria does inflammatory arthritis and ultimately can be classified as
mean it should be disregarded. On the contrary, tenosyno- having RA (by 1987 criteria) within 3 years (van Gaalen
vitis may be one of the earliest findings (on ultrasound or et al. 2004).
MRI) of early RA.
Myth All ACPA tests provide the same diagnostic accuracy
for RA.
Serological Features and Radiology Reality: Many commercially available ACPA tests are
available for clinical care. Most of these use a cyclic citrul-
Pearl High levels of rheumatoid factor (RF) or antibodies linated peptide (CCP) as the antibody target, although there
to citrullinated protein antigens (ACPA) are of diagnostic is also an antibody to mutated citrullinated vimentin. A vari-
and prognostic value. ety of other antibody tests for specific citrullinated antigens
Comment: Seropositive RA is characterized by the will be available soon. All have similar sensitivities for the
presence of autoantibodies, among which RF was the first diagnosis of RA, but the assays differ in terms of specificity,
described. The finding of a serum RF is relatively nonspe- ranging between 92% and 99% (Whiting et al. 2010). These
cific in the sense that it may be associated with a variety of differences are sometimes large enough to be clinically rele-
other conditions that can cause an inflammatory arthritis. In vant, and clinicians should be aware of which tests are being
particular, connective tissue diseases, cryoglobulinemia, performed by their local laboratory.
chronic hepatitis, and certain hematologic malignancies A growing number of autoantibodies are known to be
(e.g., Waldenstrom’s macroglobulinemia) are often associ- present in RA. These include antibodies to carbamylated
ated with RF positivity. In addition, up to 15% of the proteins (anti-CarP), antibodies to peptidyl arginine deimi-
healthy elderly population have RF, albeit usually in low nases (PADs), and others (van Delft and Huizinga 2020).
levels. A high cut-off point for a positive assay (e.g., 50 IU/ Some of these are available clinically, but their true value in
ml) enhances the positive predictive value of RF for clinical care remains to be fully determined.
RA. Indeed, the 2010 ACR/EULAR classification criteria
for RA implement this practically by awarding greater Myth Clinically detectable synovitis and radiographic pro-
weight to the presence of an RF level that is >3 times the gression in RA are linked tightly, such that the control of one
upper limit of normal. High levels of RF are a marker for leads to control of the other.
patients at risk for aggressive, destructive joint disease, and Reality: This dogma, believed widely for decades, is now
extra-articular complications of RA. When it comes to recognized as potentially false. Several trials have shown
RA-associated autoantibodies, height matters! that continued radiographic deterioration can proceed despite
Assays for ACPA have a sensitivity similar to that of RF excellent control of clinical features of RA activity (e.g.,
but achieve a higher specificity for RA. For example, the RA joint tenderness and swelling on examination, patient-
specificities for a variety of ACPA assays exceed 90% reported pain, stiffness, and swelling).
(Whiting et al. 2010). Moreover, ACPA also have prognostic As an example of the uncoupling of joint inflammation
value. They identify a subset of patients more likely to and damage, clinical trials have shown that treatment with
develop erosive disease. Some data indicate that ACPA pre- denosumab (an anti-RANK-ligand monoclonal antibody)
dict erosive disease more accurately than RF. Most patients reduces radiographic progression despite achieving little
with ACPA are also RF-positive, and vice versa; however, effect on clinical measures of disease activity (Takeuchi
the overlap is not perfect, and studies suggest that ~10%– et al. 2019). Subclinical disease activity as detected by ultra-
15% of patients with RA have one of these antibodies but not sound or magnetic resonance imaging may explain why
the other. Testing for both ACPA and RF at the initial evalu- some RA patients show evidence of radiographic progres-
sion of joint damage despite the absence of clinically overt Among the individuals who were ACPA-positive but
signs of joint inflammation (Brown et al. 2008; Conaghan RF-negative, the shared epitope was associated with an
et al. 2009; Terslev et al. 2021a, b). The converse is also increased risk of RA, but cigarette smoking had a more lim-
true – i.e., patients who show no radiologic evidence of dam- ited effect. The same strong interaction between the shared
age can have clinical signs of ongoing synovitis. epitope and cigarette smoking was found in that group, as
It is not clear whether treatment should be altered in a well. In contrast, among individuals that were ACPA-
patient whose disease is controlled well by clinical parame- negative, the effect of the shared epitope was either marginal
ters yet has evidence of disease activity detected with (in the ACPA-negative, RF-positive group) or nonexistent
advanced imaging. (ACPA-negative, RF-negative). The impact of smoking on
the development of RA is clearly magnified in the subset of
individuals who are ACPA-positive.
Risk Factors The interplay between the shared epitope and cigarette
smoking as a predictor of serum levels of ACPA was recently
Pearl Exposure to tobacco, especially cigarette smoke, is investigated in Japanese persons with RA. In this study, an
harmful in many aspects of RA. interaction between cigarette smoking and serum ACPA lev-
Comment: Several studies show a significant and inde- els was found only in individuals with the shared epitope;
pendent association between smoking and susceptibility to however, cigarette smoking was independently predictive of
RA. In particular, some studies suggest that tobacco smoke RF levels regardless of the shared epitope (Ishikawa et al.
interacts with the HLA-DRB1-shared epitope to heighten 2019). Moreover, these risks declined if cigarette smoking
RA susceptibility (Ishikawa and Terao 2020). Smoking is had stopped prior to disease onset.
also associated with extraarticular manifestations and RF The sum of studies to date on the relationship between
positivity. In addition, smoking increases the risk for infec- cigarette smoking and RA suggests a model in which ciga-
tion, cardiovascular disease, progression of lung disease, and rette smoking triggers anti-CCP antibodies in patients with
cancer among patients with RA. Finally, smoking is associ- RA bearing the shared epitope.
ated with increased disease activity and reduced responses to
DMARDs (Gianfrancesco et al. 2019; Nyhall-Wahlin et al. Pearl Obesity may be a risk factor for RA and may also
2009; Floris et al. 2021). All of these are reasons to empha- contribute to disease activity.
size smoking cessation in patients with RA and in those at Comment: Several studies show that obesity is a risk fac-
risk for future RA. tor for RA (Zaccardelli et al. 2019). This may be due to
inflammation generated in fat cells, or other factors such as
Pearl Cigarette smoking can worsen RA disease activity. diet and lack of exercise. Furthermore, obesity has been asso-
Comment: Much has been published regarding the associated with increased disease activity. (Paradoxically, low
ciation between smoking and risk of developing RA. Less is body weight may also be associated with higher disease activ-
known regarding the potential of worsening existing RA ity – perhaps because of cachexia due to poorly controlled
through smoking. One longitudinal study (Gianfrancesco inflammation.) Addressing obesity through diet and exercise
et al. 2019) demonstrated that smoking was associated with may ultimately be an important part of management in RA.
a 0.64 unit increase in patient global score (p = 0.01) and
2.58 more swollen joints (p < 0.001). One cross-sectional
study (Hammam and Gheita 2017) reported higher DAS28 in Disease Assessment
RA patients exposed to second-hand smoking, while another
(Sokolove et al. 2016) also reported higher DAS28 in ACPA- Pearl “Treat-to-target” leads to improved outcomes in RA.
positive RA patients who were current smokers compared Comment: Prospective data indicate that the adjustment
with nonsmokers. Patients should be counselled about the of RA therapies every 8–12 weeks, with the goal of a “treat-
potential detrimental effect that smoking may have on con- to-target” approach of improving specific indices of disease
trolling their RA. activity, leads to improved outcomes (Stoffer et al. 2016;
The contribution of the shared epitope and cigarette Smolen et al. 2016). The frequent assessment of disease
smoking to the risk for RA has been studied in a large, activity in patients is important in both clinical trials and
population- based, case-controlled study from Sweden clinical practice.
(Hedström et al. 2019). In the ACPA-positive, RF-positive Composite disease activity indices are superior to indi-
individuals, the shared epitope and cigarette smoking inde- vidual variables in the assessment of disease activity
pendently conferred increased risk for RA. Moreover, there (England et al. 2019). Two major factors pose potential bar-
was also a strong interaction between these two risk factors. riers to the routine use of validated disease activity indices in
clinical practice. First, many validated scores require a cal- or fibromyalgia or other nonarticular pain source or even due
culator for computation. Second, some composite indices to depression? If so, pushing additional or alternate DMARDs
require the results of laboratory tests (e.g., an ESR or will not improve the patient’s situation. The updated ACR
C-reactive protein level) before they can be completed. These guidelines caution against using a blanket approach of treat-
issues reduce the ability to use such scores immediately in a to-target to remission in all patients, especially those who have
clinic visit. failed other DMARDs (Fraenkel et al. 2021).
No single disease activity measure is clearly the best. The
DAS28-CRP is commonly used in clinical trials and there- Myth Assessing joint counts and composite disease activity
fore may be useful in comparing a current patient to findings indices is too time-consuming to be practical in routine clini-
from clinical trials. The Clinical Disease Activity Index cal care.
(CDAI) is a simple numerical index that is calculated by
summing the number of tender and swollen joints using the Comment: The 28-joint count is valid, reliable, and cor-
28-joint count and the patient and physician global assess- relates well with the total joint count. More importantly, the
ments on a 10-centimeter visual analogue scale. The CDAI 28-joint count requires only a minute or two for a trained
does not include laboratory measurements in its calculation, person to calculate. The clinician’s 28-joint count is com-
making it easier to complete at clinical encounters. The bined with the physician’s disease assessment, patient global
CDAI also has the most stringent remission criteria among assessment, and laboratory tests to calculate multiple disease
the disease activity measurements. activity measures.
The Routine Assessment of Patient Index Data (RAPID3) The 28-joint count may underestimate disease activity in
can also be calculated using only patient-recorded outcomes, some individuals, especially those with significant lower-
without requiring laboratory tests or physician assessment. extremity disease. The ACR/EULAR criteria for remission
RAPID3 can therefore be utilized as a disease measurement suggest it is preferable to include the feet and ankles in the
between office visits or in the telehealth environment. The joint count when evaluating high-stake criteria such as remis-
DAS28-CRP, CDAI, and RAPID3 are valid, reliable mea- sion (Felson et al. 2011).
sures that are sensitive to change (England et al. 2019).
Myth Adding imaging criteria to the definition of remission
Pearl Obtaining the HAQ disability index (HAQ-DI) pro- will lead to better outcomes in RA.
vides helpful insights into the patient’s daily situation. Reality: Attainment of clinical remission is associated
Comment: The HAQ-DI is a simple, one-page form that with less radiographic joint damage and better function
the patient completes in a minute or two. If completed before (lower HAQ scores) over time in patients with RA. But
a visit and reviewed by the rheumatologist at the encounter, patients in clinical remission may still exhibit persistent
the HAQ-DI provides important information about what the synovitis by ultrasound or MRI. Furthermore, positive
patient is and is not able to do in daily life. This information Doppler signal predicts flare and progressive radiographic
can inform management decisions and clinical care. damage. Therefore, wouldn’t the addition of a radiologic
measure of remission (e.g., absence of Doppler signal in 28
Myth Remission must be the goal for all treat-to-target joints) increase rates of good clinical outcomes?
approaches. No, actually. A group of studies randomized early RA
Comment: Multiple studies confirm that treat-to-target patients to a target of clinical remission (DAS28-based) or a
strategies lead to lower disease activity and less joint damage combined target of clinical plus imaging remission (Dale
than usual care approaches. However, treat-to-target to et al. 2016; Haavardsholm et al. 2016; Møller-Bisgaard et al.
remission may not be feasible or logical in all patients. 2019). The imaging features targeted in the imaging groups
Remission is likely more attainable in early disease than in were with joint count (by power Doppler) or bone edema (by
later disease. Moreover, trying to force a patient already in MRI). All three studies showed no significant differences in
low disease activity into remission may lead to overtreat- rates of radiographic progression detected by clinical fea-
ment, drug toxicity, and greater expense. tures alone compared with the imaging-enhanced approach
Several studies have shown that in patients who are in “near although there was improvement in HAQ scores in individu-
remission,” the most common requirement for remission that als who had therapy escalated based on imaging findings.
was not met was the patient global score (PtGA). That is to say However, the patients in the combined target group were
the number of tender joints, swollen joints, and CRP level exposed to more drugs than those in the single target arm.
were all <1, but the PtGA was ≥1, indicating low disease state These studies show that adding a radiologic requirement for
but not remission. In this situation, one should look carefully remission does not necessarily improve outcomes attained
at the source of the PtGA. Is it due to secondary low back pain beyond those using only a clinical measure of remission.
Treatment methotrexate monotherapy at the outset, others go immedi-

ately to the combination of biologic and methotrexate, and
Myth RA is a problem solved. The vast majority of patients yet others starting a biologic alone. Regardless of the initial
do well with modern treatments. decision with regard methotrexate and TNF inhibition, glu-
Reality: Although new therapeutics including biologics cocorticoids are often part of the initial mix, as well.
and JAK inhibitors have greatly improved overall results for
RA patients, the problem is far from solved. EULAR has
defined the “difficult-to-treat” RA patient, and several stud- Glucocorticoids, Methotrexate,
ies have shown that this moniker applies to up to 20% of all and Conventional DMARDs
RA patients (Nagy et al. 2021).
Pearl Active conventional treatment for newly diagnosed
Myth RA is a benign disease for which therapy can be RA brings half of patients into remission.
delayed safely for a while. Comment: In newly diagnosed RA, methotrexate is not
Reality: A cardinal feature of RA is its propensity to very effective by itself. However, when combined with glu-
destroy joints. Joint destruction can lead to irreversible physi- cocorticoids (either orally or as injections) or other conven-
cal disability, additional comorbidities (e.g., complications of tional DMARDs, nearly half of patients achieve a remission
joint surgery), economic losses, and a reduction in life expec- in 3–6 months (Hetland et al. 2020).
tancy. Radiographic evidence of joint disease is detected in a
large percentage of seropositive RA patients within 2 years of Myth Once an RA patient is started on glucocorticoids, he
diagnosis, and within several months in some patients (Plant or she will never be able to discontinue the medication.
et al. 1998). Both joint damage and subsequent disability are Reality: Clinical trials in the era of biologic agents have
related directly to the activity of inflammation and disease shown that this once oft-quoted refrain is a myth. With the
duration. Indeed, the best approaches to optimize disease use of effective DMARD therapy – conventional synthetic,
control in RA is to identify and treat patients early (Rosa et al. targeted synthetic, or biologic – RA patients can be tapered
2020; Bykerk and Emery 2010). to low doses of glucocorticoids, and many discontinue them
entirely.
Myth Early intervention in undifferentiated arthritis pre- Of note, glucocorticoids are an effective therapy for RA,
vents progression to RA. and some studies suggest they act as DMARDs. Decades
Reality: Trials investigating early interventions in patients after their introduction, however, we still struggle to under-
who have definite inflammatory arthritis just not meeting stand the optimal way to use glucocorticoids in RA. There
classification criteria have generally shown a delay in pro- is growing evidence of the harms of even low-dose gluco-
gression to classifiable RA, but to date true prevention of corticoids in this disease. Although the optimal dose and
evolution to RA has been elusive. duration of glucocorticoid use in RA is unknown, a general
principle should be to use the lowest dose possible (less
Myth The best initial therapy for early, aggressive RA is than 10 mg/day of prednisone equivalent ideally) for the
methotrexate in combination with a biologic agent. shortest period of time. It is widely considered that any
Reality: In truth, the best initial therapy for RA is uncer- dose greater than 7.5 mg/day is toxic for any patient
tain, and there are likely many patient-specific factors that (Huscher et al. 2009). Some patients are able to tolerate
influence the optimal therapy in any individual with RA. With lower doses (< 5 mg/day) reasonably well if they do not
that said, methotrexate remains a cornerstone in the treat- have significant comorbidities that predispose to glucocor-
ment of RA and is often suggested as the preferred initial ticoid complications.
therapy. Several randomized controlled trials, including trial Some patients are maintained on a low dose of prednisone
involving patients with seropositive, erosive disease, have (e.g., 5 mg/day) to enable disease control in the absence of
demonstrated no clinical advantage of initial combination other viable treatment options. Nevertheless, the updated
therapy with methotrexate and a biologic DMARD com- ACR guidelines for the treatment of RA emphasize the
pared to a step-up approach that begins with methotrexate importance of avoiding prednisone therapy, if possible, and
alone (Moreland et al. 2012; O’Dell et al. 2013), although thereby circumventing its potential complications (Fraenkel
other trials suggest that patients treated with a combination et al. 2021).
of TNF inhibition and methotrexate may have higher remis-
sion rates (Emery et al. 2008). Pearl Despite the cautions about prednisone and other glu-
Practice on the initial treatment for early, aggressive RA cocorticoids, there is no question that these medications
varies substantially not only from country to country but “work” in RA. In fact, in some settings, the initiation of the
from practitioner to practitioner – and also influenced by treatment cascade using methotrexate plus short-term gluco-
financial considerations (e.g. insurance coverage, govern- corticoids is viewed by some as the optimal approach to RA
mental payment plans). Indeed, some practitioners favoring therapy in terms of efficacy, safety, and costs.
Comment: For many years, EULAR RA management lated to 20 mg/week over the next 4 weeks, as tolerated. The
recommendations suggested starting treatment with metho- dose can be increased to 25 mg/week or even higher in some
trexate plus short-term glucocorticoids. The EULAR task cases.
force did not see an advantage of initiating RA treatment As methotrexate doses rise, dividing the dose (e.g., 10 mg
with either a biologic DMARD or combination (triple) ther- orally in the morning and 10 mg orally at night) may improve
apy with conventional synthetic disease DMARDs (i.e., absorption.
using some mix of methotrexate, sulfasalazine, leflunomide,
or hydroxychloroquine). Pearl Methotrexate therapy may be optimized by switching
The value of methotrexate plus glucocorticoids at the start from oral to subcutaneous administration.
of therapy is supported by significant evidence (Smolen et al. Comment: Oral bioavailability becomes less predictable
2020). For example, the CareRA trial compared methotrexate for individuals at doses greater than 15 mg, and therefore
plus intermediate-dose rapidly tapered oral glucocorticoids doses above this amount may not achieve the desired effect
with methotrexate plus either leflunomide or sulfasalazine on disease activity. If patients do not achieve an adequate
plus glucocorticoids. That trial showed no advantage in effi- treatment response at methotrexate doses above 15 mg/week,
cacy of combining the conventional synthetic DMARDs, and switching from oral to subcutaneous administration may
indeed there were more adverse events in the combination increase bioavailability and improve treatment response (Li
group (Verschueren et al. 2015). Similarly, the tREACH trial, et al. 2016). Alternatively, patients may split their weekly
which compared methotrexate to triple therapy with both oral dose of methotrexate into a morning and evening doses,
groups receiving glucocorticoids did not show a significant thereby increasing bioavailability. Although this strategy is
advantage of combination therapy (de Jong et al. 2014). rational strategy based on the known pharmacokinetics of
How do biologic DMARDs stack up against the combina- methotrexate, the evidence supporting it is limited (Hoekstra
tion of methotrexate and glucocorticoids? Well, the IDEA et al. 2006).
trial compared methotrexate plus a single intravenous dose
of methylprednisolone (250 mg) with methotrexate plus inf- Two Myths (Myth 1) Methotrexate is generally poorly tol-
liximab. No differences in outcomes were observed in the erated but… (Myth 2) …it does not have cancer as a risk.
two groups (Nam et al. 2014). Reality: The safety and tolerability of methotrexate was
Finally, the NORD-STAR trial compared methotrexate never studied as well as in a cardiovascular prevention study
plus glucocorticoids to methotrexate plus glucocorticoids in which nearly 5000 patients were randomly assigned to
and one of three bDMARDs (an anti-TNF, an anti-IL-6 R, or methotrexate or placebo. Contrary to what many expected, if
a costimulation inhibitor). Again, no superiority in any of the methotrexate was tolerated initially, it was tolerated well
bDMARDs was observed (Smolen et al. 2020). over the long term. About 20% of the patients stopped early
In short, the combination of methotrexate and short-term on because of side effects. In the remaining majority of
glucocorticoids has substantial efficacy. The GC may be patients, however, side effects such as nausea or malaise
applied orally at low to intermediate doses with tapering to were uncommon. Though methotrexate was tolerated well
discontinuation within 3 to 4 months or as a single parenteral overall, the study unexpectedly revealed an increase in the
application. For patients at low risk for glucocorticoid toxic- occurrence of non-melanoma skin cancer. Glass half full,
ity, for those who are risk-averse to the idea of using a bio- glass half empty (Ridker et al. 2019).
logic agent, and for patients in low-resource areas,
methotrexate plus glucocorticoids makes a lot of sense. Pearl Leflunomide remains in the body for years after
administration.
Myth When using methotrexate, start low and go slow. Comment: Because of its extensive enterohepatic re-
Comment: Methotrexate has been the cornerstone of the circulation, leflunomide persists in the body for years after
treatment for RA since the mid-1980s. In the early years of discontinuation. This is an important fact when toxicities
methotrexate use, the prevailing maxim was to “start low and occur or if pregnancy is considered, because leflunomide has
go slow.” Most clinicians began methotrexate at 7.5 mg/ significant teratogenic potential. In these situations, a wash-
week and advanced the dose slowly over many months, never out with cholestyramine may be desired. If the persistence of
exceeding 15 mg/week for many patients. leflunomide is a potential concern, blood levels may be
However, clinical trials of the biologic agents changed the checked.
way methotrexate is used in practice. The trials did so by Given its teratogenic potential, the use of this medication
demonstrating safety and efficacy in methotrexate control in women of child-bearing potential should be considered
arms that employed high starting doses (15 mg/wk) and with caution. It is important to recognize, however, that not
rapid dose escalation (Weinblatt 2013). all pregnancies exposed to leflunomide have resulted in birth
Based on these findings, methotrexate therapy in most defects. In one study, no increased risk of congenital malfor-
patients should begin at 10–15 mg/week, and then be esca- mations was observed either in 51 pregnancies in which the
mother was exposed to leflunomide during the first trimester (chrysotherapy). Because of unequivocal advances in RA
or 21 pregnancies exposed to this drug during the second or treatment since the 1980s, the truth or falsity of this state-
third trimesters (Bérard et al. 2018). ment will remain forever unknown. However, when injec-
tions of gold sodium thiomalate were compared to weekly
Myth Hydroxychloroquine is not an effective DMARD. methotrexate therapy in a double-blind, randomized trial,
Reality: There is a paucity of direct evidence that gold produced twice as many clinical remissions as the latter
hydroxychloroquine slows radiographic progression in (24.1% vs 11.5%) (Rau et al. 1997). Gold was also associ-
RA. However, multiple studies have shown that if hydroxy- ated with more side effects and withdrawals due to toxicity.
chloroquine is started early in the course of disease, patients Gold therapy has fallen out of use and is largely of historical
experience better outcomes, including less radiographic pro- interest only. References to the time only a few decades ago
gression. The combination of methotrexate and hydroxy- when gold salts were the standard of care for RA and patients
chloroquine is the most common tandem of DMARD attended clinic weekly for gold salt injections are a pleasing
regimen used for the treatment of RA. The potency of the reminder of how far we have come.
methotrexate-hydroxychloroquine combination may be
explained at least in part by a patient’s increased exposure to Myth Patients with RA who have achieved clinical remis-
methotrexate (e.g., increased area under the curve) when sion should continue treatment indefinitely owing to the risk
methotrexate and hydroxychloroquine are administered for losing disease control.
together. Comment: Well, yes and no. Most studies have focused
Dosing recommendations for hydroxychloroquine pub- on the question of whether withdrawal (or de-intensifying)
lished in 2016 of a daily dose of <5 mg per kilogram of TNF inhibitor therapy in patients who had achieved remis-
actual body weight per day are based on observations that sion or low disease activity led to an increase in disease
this dose is associated with less ocular toxicity (Marmor activity. A systematic review of randomized, controlled trials
et al. 2016). This dose is lower than those used in other pub- testing this hypothesis concluded that reducing the dose of
lished studies, however (Rosenbaum et al. 2021). the TNF inhibitor resulted in little or no increase in disease
An additional benefit of hydroxychloroquine is that the activity, while complete discontinuation led to a significant
use of this drug may reduce the incidence of diabetes among increase in disease activity compared to those that continued
patients with RA (Wasko et al. 2007). These metabolic ben- their TNF inhibitor (Verhoef et al. 2019). In general, com-
efits were recently confirmed in a meta-analysis of 16 studies plete discontinuation of disease-modifying therapy is
involving patients with RA comparing users and non-users strongly discouraged because of the high risk for relapse, but
of hydroxychloroquine (Rempenault et al. 2018). dose reductions after the achievement of remission can be
considered and include patient preferences and shared deci-
Pearl Combination therapy with oral triple therapy (metho- sion-making approaches.
trexate, sulfasalazine, and hydroxychloroquine) DMARDs is
superior in clinical efficacy to treatment with methotrexate
alone. Biologic Agents
Comment: Combination therapies of traditional
DMARDs were advocated strongly for the treatment of RA Myth Nearly all patients with RA respond to tumor necrosis
until well into the 1990s. A major trial that preceded the era factor (TNF) inhibitors.
of biologic treatments indicated that the combination of Comment: In general, the numerous clinical trials testing
methotrexate, sulfasalazine, and hydroxychloroquine was various TNF inhibitors (etanercept, adalimumab, infliximab,
superior to methotrexate alone (O’Dell et al. 1996). However, golimumab, certolizumab pegol) for the treatment of early and
many clinical trials comparing combination therapy to established RA have shown ACR response rates in the 40%–
monotherapy have not shown superiority of the combination 50% range, with slightly higher response rates in patients with
therapy arms. Moreover, combination treatment regimens early disease as compared to established disease. An ACR50
more often in the current era consist of methotrexate and a response is considered to be a clinically significant treatment
biologic or targeted synthetic DMARD. response by most rheumatologists. However, the current goal
of treatment of RA is remission or low disease activity.
Pearl Gold shots are dramatically efficacious for the treat- Currently, not more than 15% of patients treated with a TNF
ment of RA in one of every three patients. inhibitor realize sustained remissions (Hamann et al. 2017).
Comment: No one knows for certain whether or not this TNF inhibitors, though clearly a signal advance in the history
statement is a pearl or a myth, but it is echoed widely by of RA treatment, are inadequate for controlling disease in the
practitioners who treated RA in the heyday of gold use majority of patients over the long term.
Myth When a TNF inhibitor fails, other TNF inhibitors are beyond TNF inhibitors. Abatacept and rituximab also work
unlikely to work. better when prescribed in combination with methotrexate.
Comment: Several open-label studies or analyses from
registries have suggested that a second TNF inhibitor can be Pearl Interleukin-6 receptor blockade (e.g., tocilizumab) in
efficacious following the failure of a first TNF inhibitor. This RA appears to work almost as well when used as monother-
appears to be true even if the first and second TNF inhibitors apy as it does when employed in tandem with methotrexate.
are pharmacologically similar, for example, the case of adali- Comment: In a randomized, double-blind, double-
mumab following infliximab. Both medications are mono- dummy clinical trial of newly diagnosed patients with active
clonal antibodies, yet if one fails the other may still be RA, tocilizumab (administered 8 mg/kg intravenously every
successful. 4 weeks) produced similar rates of remission as tocilizumab
These data from uncontrolled investigations have now plus methotrexate (Bijlsma et al. 2016). These results were
been expanded in a double-blind, controlled clinical trial of confirmed in the FUNCTION trial (Burmester et al. 2016).
golimumab. These data reveal that a third TNF inhibitor can And in a third randomized, controlled trial, patients with
be effective even after two have failed. However, if all three active RA who had inadequate responses to methotrexate
other TNF inhibitors (etanercept, infliximab, and adalim- therapy and subsequently achieved low disease activity
umab) have failed before golimumab, then golimumab is through the addition of subcutaneous tocilizumab 162 mg
unlikely to be effective. Randomized, controlled trials have weekly could discontinue methotrexate without significant
now shown that patients who failed an initial TNF inhibitor loss of disease control (Kremer et al. 2018).
may benefit by switching to a second TNF inhibitor (Smolen
et al. 2017). However, this is a controversial area as other Myth When a biologic DMARD (bDMARD) needs to be
studies have suggested that a ‘second’ TNF inhibitor may not chosen for an RA patient with moderate or severe disease
be as effective as using a non-TNF inhibitor’ in particular 3 activity who has had an inadequate response to methotrex-
non-TNF inhibitors (tocilizumab, rituximab and abatacept) ate, TNF inhibitors should be prioritized over non-TNF
significantly improved disease activity at 24 weeks when inhibitors.
compared to a second TNF inhibitor (Gottenberg et al. 2016). Reality: TNF inhibitors are used most often among the
As such, choosing the ‘next’ agent after failure of a first TNF bDMARDs, perhaps because they were the first biological
inhibitor can be challenging. agents to be approved. The reason for this is more regulatory
than scientific. IL-6 receptor inhibitors (tocilizumab and
Pearl/Myth TNF inhibitors are more effective for the treat- sarilumab), a T-cell selective co-stimulation modulator
ment of RA than is methotrexate. (abatacept), and an anti-CD20 antibody (rituximab) are
Comment: Many studies confirm the superiority of meth- available for use as non-TNF biological DMARDs. Two ran-
otrexate plus a biologic or targeted synthetic disease- domized controlled trials comparing abatacept and TNF
modifying agent versus methotrexate alone; however, a inhibitor use reported no significant differences in efficacy
substantial proportion of patients in these studies respond between these two approaches, considering improvements in
adequately to methotrexate alone (Smolen et al. 2017). These disease activity; inhibition of structural damage of joints;
findings explain why treatment guidelines recommend that and safety. Abatacept and TNF inhibitors appear to have
patients with early, active RA should be initially treated with similar efficacy and safety profiles (Schiff et al. 2014).
methotrexate alone, with subsequent escalation of disease- There have been no randomized controlled trials of IL-6
modifying therapy as warranted to meet the goal of therapy. receptor inhibitors versus TNF inhibitors. However, tocili-
Clinical practice around this situation varies substantially zumab and abatacept showed no significant differences in
and is affected by a number of variables: the patient’s degree efficacy and safety in one study in which patient characteris-
of symptomatology, the patient’s preference, medication tics were adjusted statistically using propensity score match-
availability, and physician practice style, among others. ing (Kubo et al. 2016). The 2019 EULAR recommendations
for the treatment of RA support the equivalent use of TNF
Pearl TNF inhibitors work better in combination with meth- and non-TNF inhibitors for active RA patients who respond
otrexate than alone. poorly to methotrexate treatment (Smolen et al. 2020).
Comment: Clinical trials that have addressed this ques-
tion have found that the combination of methotrexate plus Pearl If methotrexate is contraindicated, and a biological
infliximab, etanercept, adalimumab, golimumab, or certoli- DMARD must be initiated as monotherapy, IL-6 receptor
zumab pegol is more effective than methotrexate alone or inhibitors should be prioritized over TNF inhibitors.
any of the TNF inhibitors by themselves. This is true for both Comment: Two randomized controlled trials compared
clinical response (ACR20 or DAS) and radiographic out- monotherapy using IL-6 receptor inhibitors (tocilizumab and
comes. The synergistic effects of methotrexate extend sarilumab) and TNF inhibitors in RA patients with active
disease who could not use or had an inadequate response to Reality: A variety of features characterize “difficult-to-
methotrexate therapy. In both trials, IL-6 receptor inhibitors treat” RA include the following:
had a significantly greater effect on improving disease activ-
ity. There were no significant differences in safety (Burmester • Refractoriness to conventional synthetic DMARDS and
et al. 2017; Gabay et al. 2013). IL-6 receptor inhibitors are to at least two bDMARDs
therefore recommended when no conventional synthetic • Moderate disease activity or greater, with clinical signs
DMARD is used concomitantly. and symptoms indicating active disease
• Inability to reduce glucocorticoids
Pearl Patients with active RA who have an inadequate • Progressive disease on imaging despite ongoing
response to a TNF inhibitor – the so-called TNF-IR patients – treatment
should switch to a non-TNF inhibitor rather than another
TNF inhibitor. The JAK inhibitors upadacitinib and filgotinib have high
Comment: In a randomized controlled trial that exam- efficacy in difficult-to-treat RA (Nagy et al. 2021; Genovese
ined switching from a TNF inhibitor to a second TNF inhibi- et al. 2016, 2019).
tor compared to a non-TNF inhibitor, the effect of the
non-TNF inhibitor for improving disease activity at week 24 Myth Methotrexate should be avoided in elderly RA
was significantly greater than that of a second TNF inhibitor. patients.
The three biologic DMARDs included in this comparison Reality: Once RA is diagnosed, strong consideration
against a second TNF inhibitor were tocilizumab, rituximab, should be given to starting methotrexate treatment promptly,
and abatacept (Gottenberg et al. 2016). There were no sig- even in elderly patients, provided there is no contraindication
nificant differences in adverse events among the groups. to that drug. RA in the elderly is likely to have high disease
Thus, switching to a non-TNF inhibitor is recommended for activity, with a high ACPA positivity rate and rapid progres-
patients who had an inadequate response to the first TNF sion of joint destruction. Since approximately 70% of meth-
inhibitor. Drugs should be selected carefully based on a bal- otrexate is excreted in the urine, particular attention should
ance of the potential risks and benefits in individual patients. be paid to patients with decreased renal function, mindful of
the fact that the elderly may have decreased creatinine clear-
Pearl RA patients are more likely to respond to abatacept ances. Elderly patients may require methotrexate dose
when they are seropositive. adjustments downward but can use this drug safely and ben-
Comment: Seropositivity is linked with higher probabil- efit from its efficacy if it is used carefully.
ity of response to abatacept. Patients who are positive for the
shared epitope might have additional benefit (Courvoisier Myth Biologic DMARDs cannot be recommended for
et al. 2021). In addition, there is some data that suggests that elderly RA patients.
rituximab may be more effective in seropositive compared to Reality: Many elderly patients with RA will not achieve
seronegative RA (Lal P, et al. 2011). remissions with methotrexate, partly because of the long
duration of the disease in many of these patients and the fact
Pearl The Janus kinase 1 (JAK1) inhibitors, including that the percentage of patients who are treatment-refractory
tofacitinib, baricitinib, and upadacitinib, are effective for is high among the elderly. Thus, many elderly patients will
both the treatment of early and established RA both alone be candidates for additional therapies, namely, bDMARDs
and in combination with methotrexate. and small molecules. Judicious use of these treatments in the
Comment: The JAK1 inhibitors, increasingly used for elderly is preferable to permitting undertreated disease to
the treatment of RA, offer the advantage of oral administra- persist and to using excessive doses of glucocorticoids on the
tion. Clinical trial results attest to their efficacy in patients misbegotten notion that glucocorticoids are a safer approach
who are either DMARD-naive (Lee et al. 2014) or who have in this population.
failed to respond adequately to methotrexate therapy (van
der Heijde et al. 2019; Fleischmann et al. 2019). JAK1 inhib- Pearl Patients who fail a primary induction course with
itors slow radiographic progression of RA and compare rituximab may benefit from a second try.
favorably with bDMARDs for clinical efficacy. In RA Comment: For seropositive RA patients treated with
patients who have an inadequate response to methotrexate, RTX who are primary nonresponders, second cycles often
the addition of a JAK inhibitor is equally or more effective produce better results. A possible explanation is that patients
than the addition of a TNF inhibitor. with high plasmablast numbers require higher doses of RTX
for depletion, but still respond eventually. Another possibil-
Pearl JAK inhibitors may be useful in difficult-to-treat RA. ity is that deeper depletion of B cells overall is required to
achieve a response in some patients, and this deeper deple- tor for this complication and is a contraindication to
tion is achieved with a second course of rituximab. tocilizumab use.
Investigators in one study that examined this question for-
mally found that 26 weeks after the second cycle in primary Pearl Use caution when employing JAK inhibitors in a RA
nonresponders, there was a significant improvement in the patient with risk factors for cardiovascular disease or
Disease Activity Score in 28 joints (DAS28). By that time, thrombosis.
72% of the previously refractory patients had exhibited a Comment: A meta-analysis of randomized clinical trials
EULAR response (Vital et al. 2010). of JAK inhibitors reported no difference in venous thrombo-
embolism (VTE) rates after short-term exposure to these
Pearl Neutralizing antibodies (human anti-chimeric anti- drugs (Xie et al. 2019). However, an increased risk of VTE,
bodies (HACA)) may decrease the efficacy of infliximab or particularly pulmonary embolism, was associated with long-
other injectable biologics over time. term tofacitinib use (Mease et al. 2020). It should be noted
Comment: Secondary failure, i.e., the loss of a response that this risk was observed at doses higher than those
after an initial improvement, may be due in part to the devel- approved by the FDA for RA treatment. In addition, sub-
opment of neutralizing antibodies (Moots et al. 2017). analyses of RA patients receiving tofacitinib demonstrated
Strategies for managing this potential complication include that those with baseline cardiovascular and thromboembolic
concomitant use of an immunosuppressive agent such as risk factors were more likely to experience thromboembolic
methotrexate. For infliximab, prolonged intervals between events compared to those without such risk factors. Thus,
stopping and re-starting infliximab are associated with a these medications should be avoided or used with extreme
greater risk of HACA development. caution in RA patients with histories of or risk factors for
thromboembolism.
Myth Antidrug antibodies occur rarely in patients treated
with monoclonal antibodies but often cause problems when
they develop. Comorbidities
Reality: The vast majority of patients who are treated
with monoclonal antibodies do develop antibodies against Pearl Screening for diabetes is important in primary pre-
the drugs (Atiqi et al. 2020). Fortunately, in most cases, there vention of cardiovascular disease in RA.
are no clinical consequences. In some cases, however, these Comment: RA is associated with an increased risk of
antidrug antibodies lead to either adverse effects or loss of diabetes mellitus (Tian et al. 2021), a fact supporting the
efficacy over time. concept that inflammatory pathways are involved in the
pathogenesis of diabetes. In a cross-sectional study of the
Myth Complete remission without the need for treatment is Canadian Early Arthritis Cohort, metabolic syndrome was
hardly ever seen in RA. found to be common in patients at presentation, affecting
Reality: Several long-term studies have suggested that up 30% of patients at baseline (Kuriya et al. 2019). Pro-
to 15%–20% of patients achieve treatment-free remissions. inflammatory cytokines block the effects of insulin
Understanding the mechanisms of these “cures” is of one (Hotamisligil et al. 2017).
rheumatology’s holy grails. One meta-analysis found that RA patients on methotrex-
ate treatment have a lower risk of developing type 2 diabetes
compared to those not exposed to methotrexate (Baghdad
Adverse Effects 2020). A reduction in the incidence rate of type 2 diabetes
has also been reported among patients using other conven-
Pearl Tocilizumab is linked with increased risk for lower tional synthetic DMARDs, including hydroxychloroquine
gastrointestinal perforation. (Wasko et al. 2007), as well as biologic TNF inhibitors and
Comment: Patients treated with tocilizumab have a IL6 receptor blockers. Regular cardiovascular risk assess-
higher risk for lower gastrointestinal perforation compared ment and screening for cardiovascular disease risk factors
to patients receiving other bDMARDs. Of note, symptom- such as diabetes mellitus are essential first steps in the pri-
atology can be subtle, and the laboratory effects of tocili- mary prevention of cardiovascular disease in RA (Schmidt
zumab may blunt clinical suspicion of this complication et al. 2018).
(e.g., the C-reactive protein concentration may be suppressed
by tocilizumab’s mechanism of action, interleukin-6 recep- Pearl Depression is often underestimated in rheumatoid
tor blockade). Previous diverticulitis is an important risk fac- arthritis.
Comment: Prevention of deformity and functional loss ejection fraction. Other milder inflammatory states such as
has become an imperative of RA management and the moti- obesity and diabetes are also associated with
vation for treat-to-target approaches in pharmacological HFpEF. Nevertheless, RA patients with heart failure are less
management. However, many areas of contemporary unmet likely compared with controls to report typical heart failure
need are subjective in nature and may be overlooked if the symptoms such as paroxysmal nocturnal dyspnea or orthop-
only treatment emphasis is on protocol-driven management nea (Davis III et al. 2008). For these reasons, heart failure
of composite scores of disease activity (Taylor and Pope may be underdiagnosed in RA.
2019). For example, depression is often underestimated in Cardiac imaging findings predictive of heart failure may
patients with RA and its management too-long delayed be found in some RA patients without clinical signs or symp-
(Hider et al. 2009; Taylor and Jain 2018). Depression, toms of heart failure. These include higher left ventricular
encountered in about 15% of RA patients, is associated with mass in RA than controls (Aslam et al. 2013; Corrao et al.
worse clinical outcomes (Matcham et al. 2013). 2015), as well as higher rates of late gadolinium enhance-
Mood symptoms may be ameliorated by antidepressives ment on cardiac MRI or 18fluoro-deoxyglucose (18FDG)
and non-pharmacological intervention strategies including uptake on positron emission-computed tomography (PET/
yoga, mindfulness meditation, and emotion regulation ther- CT) scans. These imaging studies indicate the presence of
apy (Zautra et al. 2008; Gautam et al. 2019). These interven- subclinical myocardial fibrosis or myocarditis in some RA
tions, in turn, contribute toward improvement in composite patients without cardiac symptoms (Ntusi et al. 2015;
scores of disease activity (Michelsen et al. 2017). In some Amigues et al. 2019).
cases, TNF or IL6 inhibition may also improve depressive In summary, RA patients with new-onset of dyspnea or
symptoms as well as symptoms and signs of inflammatory peripheral edema should be evaluated for heart failure – par-
joint disease. Whether this is because improving inflamma- ticularly HFpEF. The possibility of interstitial lung disease, a
tory arthritis serves to improve mood or whether there is well-known extrapulmonary manifestation of RA, should
some central effect of these anti-cytokine approaches on also be remembered.
depression has not been delineated clearly.
Myth Cardiovascular risk factors confer the same risk for
Pearl RA is an independent risk factor for cardiovascular cardiovascular outcomes in patients with RA as they do in
disease. the general population.
Comment: Several studies show that cardiovascular dis- Reality: Several studies have demonstrated that the impact
ease is the leading cause of death in patients with RA. In a of conventional cardiovascular risk factors on ischemic events
meta-analysis, the risk of cardiovascular death was 50% (including heart failure) is less pronounced in RA compared to
higher in patients with RA compared with the general popu- non-RA patients. Such risk factors include hypertension, dys-
lation (Avina-Zubieta et al. 2012; England et al. 2018). The lipidemia, abnormal body mass index, diabetes, and alcohol
elevated risk of developing cardiovascular disease in RA is abuse. The heightened risk of poor cardiovascular outcomes in
hypothesized to be due to robust systemic and vascular RA therefore likely stems from complex interactions between
inflammation, glucocorticoids, and an enhanced prevalence these traditional risk factors and unmeasured inflammation
of traditional cardiovascular risk factors. Seropositivity forassociated with RA (Crowson et al. 2005).
RF or ACPA are also recognized to be risk factors for cardio- The upshot of these findings is that in the interest of car-
vascular mortality (Symmons and Gabriel 2011), suggesting ing for the full patient, rheumatologists must strive not only
a pathway between RA-associated autoimmunity and inflam- to control joint inflammation but also to identify and modify
mation and cardiovascular risk. traditional cardiovascular risk factors whenever possible,
recognizing that RA itself is an important risk factor for car-
Pearl Heart failure is prevalent in RA and is under- diovascular disease (Blanken et al. 2021).
recognized as a cause of cardiovascular mortality in RA
patients. Pearl Patients receiving long-term hydroxychloroquine use
Comment: Multiple studies demonstrate a nearly two- should be monitored for cardiotoxicity.
fold increased risk of heart failure and heart-failure- Comment: Hydroxychloroquine is not used in RA as fre-
associated mortality in RA compared to non-RA (Nicola quently as other DMARDs due to higher efficacies of the
et al. 2005, 2006; Davis III et al. 2008). This observation other DMARDs. However, when used over a prolonged
holds true even when adjusting for coronary artery disease, period of time, hydroxychloroquine use requires monitoring
supporting an independent contribution of inflammation to for cardiotoxicity in addition to its more widely recognized
heart failure risk in RA. retinal toxicity.
Recent data suggest that the predominant phenotype of Hydroxychloroquine-related retinopathy, hyperpigmenta-
heart failure in RA is “HFpEF” – heart failure with preserved tion, and cardiomyopathy are thought to arise from long-
term storage of its metabolite, 4-aminoquinolone, in the In short, some RA patients have an increased risk of ILD
retinal pigment epithelium, in the skin, and in the myocar- associated with their underlying disease, but there appears to
dium. Accumulation of hydroxychloroquine metabolites in be no enhancement of that risk associated with methotrexate
the myocardium may lead to concentric ventricular hypertro- treatment (Ibfelt et al. 2021). Methotrexate use is sometimes
phy and heart failure with restrictive physiology, as well as avoided in patients with pre-existing RA-ILD in order to
conduction system abnormalities. Both third-degree atrio- avoid further lung function compromise in the event of an
ventricular block and fatal tachyarrhythmias are known com- allergic bronchopulmonary reaction. Discontinuation of
plications of long-term hydroxychloroquine. longstanding methotrexate treatment, however, is unneces-
The characteristic histopathologic feature in hydroxy- sary and perhaps counterproductive if the ILD is detected in
chloroquine cardiomyopathy is the presence of vacuoles a patient who has been on the drug for many years to good
inside cardiomyocytes that are periodic acid Schiff stain effect (Sparks et al. 2019; Juge et al. 2021).
negative. Fifteen of the 42 case reports of hydroxychloro-
quine cardiomyopathy confirmed by endomyocardial biopsy Pearl The effects of biologic therapies in patients with viral
were RA patients who had used hydroxychloroquine for hepatitis differ depending on the specific form of hepatitis.
more than 10 years on average, achieving a mean cumulative Comment: Well-documented, life-threatening, or fatal
dose of >1600 g (Yogasundaram et al. 2014). The other cases flares of hepatitis B virus infection can occur in patients
were patients with other rheumatic diseases. treated with rituximab (Loomba and Liang 2017). Clinicians
Current ACR guidelines do not make any specific state- should also exercise caution in patients with prior hepatitis B
ments regarding screening for cardiac toxicity with hydroxy- exposure (hepatitis B core antibody positive). However,
chloroquine. However, given the potential morbidity and the rituximab can be used safely in patients with hepatitis B
fact that early hydroxychloroquine-associated cardiotoxicity virus infection provided that antiviral agents are employed
is reversible if the drug is stopped, screening long-term users simultaneously. Treatments to prevent hepatitis B reactiva-
with an electrocardiogram is reasonable. Transthoracic echo- tion such as entecavir are simple to take (once-a-day oral
cardiography, cardiac MRI, and even endomyocardial biopsy medications) that are tolerated extremely well. They should
can be considered in patients with abnormalities identified in be used along with rituximab if B cell depletion is the opti-
the screening algorithm. mal approach for treating the patient.
Hepatitis C virus infection, in contrast, does not appear to
Myth Methotrexate causes interstitial lung disease (ILD) be a pose a major obstacle to therapy with rituximab.
in RA. Although an increase in viral load has been reported with
Reality: Methotrexate is an established cause of pneumo- rituximab use, this is not typically associated with worsening
nitis. Methotrexate pneumonitis, however, which is consid- of the underlying liver disease (Vigano et al. 2012).
ered to be a hypersensitivity reaction to the drug, usually Patients on TNF inhibitors are also at risk for hepatitis B
occurs early after methotrexate commencement. reactivation if they are anti-hepatitis B core antibody posi-
Methotrexate-associated pneumonitis should not be con- tive. They should also be treated prophylactically with
fused with the ILD caused by RA itself. The presence of ILD entecavir.
in RA is not a contraindication for treatment with methotrex-
ate (Fragoulis et al. 2019a, b). Myth Biologic agents can be used safely in combination to
The prevalence of ILD in RA over a quarter century was treat RA.
investigated in two early inflammatory arthritis inception Reality: A recent meta-analysis indicated the combina-
cohorts recruited in the UK and Ireland (Kiely et al. 2019). tion of two biologic therapies for RA increased the risks for
The diagnosis of ILD in these RA patients was confirmed by side effects, particularly the risk for serious infections
plain radiography, high-resolution CT, and pulmonary func- (Boleto et al. 2019). In 2004, the results of a randomized,
tion tests. A smaller percentage of patient treated with meth- controlled clinical trial were published that showed a dou-
otrexate developed ILD compared to those not treated with bling of serious infections in patients receiving etanercept
that medication: 2.5% versus 4.8%, respectively. and anakinra in combination compared to etanercept alone,
Patients developing RA-ILD were more likely to have an without any incremental clinical benefit (Genovese et al.
older age at RA onset and certain other risk factors, as well: 2004). This trial was followed by a 1-year, randomized,
male sex, smoking, seropositivity for either RF or ACPA, placebo-controlled, double-blind trial that compared intrave-
rheumatoid nodules, higher disease activity, and delayed nous abatacept therapy plus etanercept versus etanercept
time between symptom onset and treatment initiation. These alone (Weinblatt et al. 2007). Although the ACR20 response
data suggest that the early use of methotrexate may in fact be rates were not significantly different between the combina-
protective against RA-ILD. tion regimen and etanercept alone, only 3 of 85 participants
in the combination arm had serious infections compared titers against influenza than the group that continued metho-
with 1 of 36 participants treated with etanercept alone. Other trexate, without significant flare of RA disease activity.
combination trials suggest a low but higher rate of serious Therefore, for RA patients on stable doses of methotrexate,
infections using various combination biologic therapies and consideration should be given to holding methotrexate for
little evidence to support any additive benefit from using the 2 weeks after influenza vaccine. There is additional guidance
two biologics in tandem. Clinicians should avoid using two on adjustment of DMARDs around vaccines for COVID19
biologic or targeted synthetic disease-modifying drugs at the that are put forth by the American College of Rheumatology;
same time unless it is part of a research study. this is an evolving area but recommendation including hold-
ing conventional DMARDS such as methotrexate for 1–2
Myth DMARDs and biologic therapies reduce the occur- doses after each vaccine, as disease activity allows (Curtis
rence of adverse cardiovascular events in RA. et al. 2021).
Comment: Retrospective case-controlled studies suggest Myth The shingles vaccine is not recommended for patients
that methotrexate and TNF inhibitors decrease cardiovascu- receiving a TNF inhibitor.
lar morbidity and mortality in RA and that glucocorticoid Reality: Patients with RA receiving a TNF inhibitor and
use may increase risk (Ozen et al. 2021; Day and Singh other biologic and targeted synthetic disease-modifying ther-
2019; van Halm et al. 2006). However, these outcomes have apies are warned to avoid live vaccines. Indeed, the first vac-
not been substantiated by evidence from prospective studies cine for shingles (herpes zoster) was a live vaccine and was
or randomized, controlled clinical trials. The challenge has contraindicated in patients taking biologics. However, the
been the low cardiovascular event rate in patients with RA newest shingles vaccine (Shingrix) is a recombinant zoster
and therefore the need to investigate this question using sur- vaccine and may be administered to any patient with RA
rogate biomarkers of cardiovascular outcomes. regardless of their treatment regimen.
In an early RA inception cohort, patients were allo- It remains possible that concomitant treatment with
cated randomly to receive etanercept, methotrexate, or disease-modifying agents may attenuate the immune
methotrexate using a treat-to-target therapy and followed response to the shingles vaccine. The optimal approach to
for 2 years using cardiac magnetic resonance imaging administering this vaccine has not been established in a clini-
(Plein et al. 2020). They found that patients with early RA cal trial. Nevertheless, the new recombinant zoster vaccine
had reduced aortic distensibility and left ventricular mass appears to be relatively safe and disease flares have occurred
and higher myocardial extracellular volume (e.g., diffuse in fewer than 10% of patients with RA that had received it
myocardial fibrosis) compared with controls. The results (Stevens et al. 2020).
from this study showed that DMARD therapy regardless
of treatment assignment was associated with improve-
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LARGE HOUSES FOR SMALL TENANTS.
In Australia there is a bird—the Megapodius—that builds for its

family an enormous dwelling. It is not a large bird, being about the
size of our partridge, but it seems to have very lofty ideas. If a man
built a house in the same proportion to his size, as that of this bird is
to its size, his house would be twice as large as the Great Pyramid of
Egypt. It would be very inconvenient to have such residences as
these, and they would be very difficult to keep clean, to say nothing
of the great expense of building them. A man would have to call in
the aid of hundreds of workmen, and pay them well, and years would
be required to complete such a mansion, and a great many different
instruments would be called into use. Whereas two of these birds will
build their huge dwelling in a few weeks, with no tools but their own
beaks and claws, and with no expense whatever.
The Megapodius does not believe in gay clothes, and is always
dressed in plain and sombre brown. It is an intelligent, patient,
industrious, persevering little creature, as you will see from the way it
constructs its nest.
It begins by gathering together a mass of leaves, branches, and
plants. With these it spreads out on the ground, in the place it has
selected for its nest, a thick bed of a circular form. Upon this it heaps
up earth and stones, and packs them well together, continuing to
labor perseveringly until it raises a mound from eight to fourteen feet
high. Some of these mounds measure a hundred and fifty feet round
the base, and as much as twenty-four feet up the slope. A circular
opening is left in the center of this mound, and extends from the top
to the ground.
NEST OF THE MEGAPODIUS.
In this opening herbs and leaves are heaped up; and, on this the
Megapodius places its eggs, eight in number, arranged in a circle, at
equal distances from each other, with the points downward.
After the female has performed this task of arranging the eggs,
both of the parent birds leave the nest, for they are of no use
whatever to the young birds after they are hatched. So you see this
great labor, in which they have shown so much skill is not for
themselves, but for their children.
The leaves and herbs, enclosed in this great mass of compact
earth, become so heated after a time that fermentation commences,
and this heat hatches the eggs. How does the Megapodius know
this? And how does it know what plants will produce poisonous
vapors, so that it never brings these to its nest?
Most birds, you know, are born naked, or covered with a soft
down, and they have to be fed for several weeks until their feathers
grow, and they can be taught to fly. But the young Megapodius, we
are told by travelers, comes out of its shell fully provided with
feathers. They say that it throws off the hot leaves that surround it,
and mounts to the top of the mound, looks about for a few minutes,
flaps its wings, and then, at once, soars up in the air, and comes
back to its nest no more. If this be true, it knows where to look for
food, and how to take care of itself as soon as it is born.
Another Australian bird, the Telegalla, also builds a large nest,
though, by no means equal in size to that of the Megapodius. The
bird is larger, too. It is about the size of a turkey, and, like that fowl,
carries itself with quite an important air. It works in the grassy fields.
It cuts down grass by the handful; or rather, I should say, by the
clawful. For, after it has gathered a small bunch of grass, it grasps it
with one claw, and hops proudly along on the other claw to the spot it
has chosen for its nest.
TELEGALLAS MAKING THEIR NESTS.
The male and female bird work for a long time in this way, and
make a vast number of journeys to and fro, always bearing to the
nest a little bundle of grass. They heap this up, as haymakers build
up their haycocks. In fact a Telegalla’s nest is not unlike a haycock,
and is about the size of one.
Having reared up their nest as high as they think proper, the
female carefully places her eggs in the center; and then, with her
mate, takes her departure. They do not trouble their minds any more
about either eggs or nest. They know, in some mysterious way, that
the grass they have piled up will dry, when exposed to the sun, and
that it will be heated by this process. And they know that this heat
will hatch the eggs; and that the young birds will be able to take care
of themselves as soon as they issue from the shell. So, why should
they worry themselves about the matter?
In the Cape of Good Hope, Southern Africa, there are birds, not
larger than our sparrows, that build cities to live in. They belong to
the family of Grossbeaks, and these are called Social Grossbeaks,
because they live in communities. Hundreds of birds will unite in
building an immense nest, high up the trunk of some tree. They work
away with twigs, and sticks, and grass, and feathers, and moss. And,
when the structure is completed, it looks at a little distance as if men
had built some great timber work around the tree trunk. It is in reality
a city, consisting of rows of single nests, each one inhabited by a
pair of birds.
There they lay their eggs, and hatch them, and raise their children,
and teach them how to fly, and to get their living. Hundreds of
families live thus peaceably together, and have a good time helping
and visiting each other. Policemen do not seem to be necessary in
these cities, where each bird behaves just as well as he knows how.
NESTS OF SOCIAL GROSSBEAKS.
No doubt, after their hard work is done, they have fine fun at their
parties, and merry-makings. Whether they have “town meetings,”
and public lectures, and parades, I know not. Private lectures, and
concerts, I am sure they must have! And the liveliest jigs and waltzes
among the branches of the trees!
A traveler in Africa once brought one of these nests away with
him. It contained 340 little nests. So it had been inhabited by 340
pairs of birds, and their families. It was so heavy that several men
were necessary to remove it from the tree; and it was taken away in
a wagon.
THE WONDERFUL ADVENTURES OF
GUTEFUNDUS.
Once upon a time—it was four hundred years ago—the great
Gutefundus, of blessed memory, made up his mind that he would go
all over the world, and do good to everybody. A great part of the
world as we know it, had not then been discovered, and there were
not so many people in those times as there are now. But still it was
something of an undertaking to go all over the world, and do good to
everybody.
Nevertheless, Gutefundus resolved to do it.
He decided, in the first place, that he would kill the great Sea
Serpent. This was a snake three or four miles long, which amused
itself by winding its coils around ships, thus crunching them up, after
which it would eat the crews at its leisure. If it were not very hungry it
would follow a ship a long time, rising out of the water occasionally,
and picking off a man or two at a time, until it had made an end of
the whole ship’s company.
Nobody ever knew where to find this snake, for it traveled all over
the ocean with incredible swiftness; and, it had such an extremely
hard and horny skin, that no dart or knife could pierce it. It was
therefore not an easy thing either to find the Sea Serpent, or to kill it.
Nevertheless Gutefundus determined to find it and kill it.
He embarked on this expedition in mid-summer, in the very best
vessel that could be made in those days, and with a crew of picked
men. Fortune favored him, and in the second month of the cruise,
the great Sea Serpent was after the ship of Gutefundus, little
dreaming that that very ship was after him.
The sailors were frightened nearly out of their wits when they first
saw the long line of this monster’s body rising and falling on the
waves, far in their rear. But the stout heart of Gutefundus knew no
fear. He took in sail, and waited for his foe. But the serpent was in no
hurry. He kept his distance for a couple of days, and then he sank
into the water and disappeared. Gutefundus feared the snake had
escaped him; but, a few days afterwards, it unexpectedly popped its
head out of the water, close to the ship’s sides, and, in an instant,
seized a sailor in its enormous jaws, and went down again with a
tremendous splash.
IT SEIZED A SAILOR IN ITS JAWS.
At that moment Gutefundus thought that, so far, he had done no

good to any body, and had been the means of leading the poor sailor
to his death.
But he did not despair. The Sea Serpent would come again, he felt
sure, and now that he knew the enemy’s tactics, he made his
preparations. The next time the Sea Serpent reared his head over
the ship’s side Gutefundus was ready for it. Barrels filled with water
were arranged all along the sides of the deck, and the moment the
great head was level with the deck, Gutefundus was in front of it;
and, in a twinkling, he rolled a barrel into the gaping mouth of the
creature. The astonished snake gulped down this unusual morsel
with some difficulty; and Gutefundus took advantage of this interval
of choking to plunge his long spear into one of the eyes of the
monster. It sank heavily into the water; and, for several days, the
ship sailed over a sea reddened with its blood.
And that was the last of the great Sea Serpent. It is a pity that the
Serpent’s body never rose to the surface, so that our hero might
have had its skin.
The next expedition of Gutefundus was to the Orkney Islands.
Wonderful trees grew in the marshes of those distant isles. They
bore eggs for fruit! At the proper season these egg-like fruits opened,
and out dropped little ducks into the water, where they immediately
began to swim about. These trees were called Bird Trees.
It was rather a singular thing that, although the learned men wrote
full accounts of these trees, and all the common people talked about
them, nobody had ever seen one of them.
Now, in Gutefundus’ country it sometimes happened that the poor
people had nothing to eat, and there would be a famine. He wisely
thought that if he could get some roots and slips of this Duck Tree,
and plant them along all the water courses, in a few years there
would be ducks enough for the very poorest family.
It was considered a very dangerous thing to take a voyage to
these savage islands, but Gutefundus decided he would do it.
And he did it. He met with some fearful adventures on the way,
but, after many weary months, he arrived at the Orkneys. And there,
sure enough, right before his eyes, was the wonderful Bird Tree! Its
long trunk stretched far out over the water. Its branches were loaded
with fruit. Some of this fruit was as close shut as an egg; but some of
it was splitting open, and the little ducks coming out. Some of the
ducks were just ready to drop into the water, and others had only a
small piece of bill stuck out of the egg. Hundreds had already fallen,
and were swimming gaily about.
THE BIRD TREE.
The delighted Gutefundus plucked some of the fruit that had not
yet opened, and stored it away to take home to show to his
countrymen. His next proceeding was to take measures for
introducing the culture of bird-trees into his country. He concluded he
would cut off some of the smaller branches, and some little twigs,
and would put some of their native soil in tubs on the ship, and in
these he would root his slips. From these few slips bird-trees could
be spread over the country in a few years.
The task of choosing and cutting these slips he took upon himself,
and climbed the tree for that purpose. But, no sooner had he cut the
first little twig than he felt a great shudder running all through the
tree. It shook from top to bottom. The roots tore themselves loose
from the soil with such a wrench that the whole tree fell violently
forward into the water, and sank beneath the waves as if it were
made of iron. The ducks that were swimming around went down with
it, and were seen no more. Gutefundus, entangled in the branches,
would inevitably have gone down also with the tree, had he not
caught fast hold of some sedges on the shore, and, by a great effort,
got his feet free from the branches.
He, and the ship’s company knew then that this was a magic tree.
The gathered fruit they had, was therefore accursed, and they
immediately threw it all overboard. On touching the water it burst
with a great explosion. They then sailed away from the spot as
quickly as possible.
From that day to this there has never been another bird tree found
anywhere. And the poor people of Gutefundus’ country lived and
died without ever tasting tree-ducks.
His next expedition was the greatest of all the undertakings of
Gutefundus. Immense stores of gold, silver, and precious stones lay
buried in the rocks of certain caverns in the mountains. But men
could not go there to dig out the treasures, because the entrance to
these caverns was guarded by a terrible dragon. A few daring
individuals had ventured near this entrance, and, peeping in, had
seen heaps of bones. These, no doubt, were all that was left of men,
who, in some previous time had attempted to get the treasures. They
even got a sight of the dragon, and represented it as a gigantic
creature, partly beast, partly bird, and partly serpent.
These venturesome men were thankful to have escaped from the
neighborhood without going any nearer the cave; and, from that
time, no one had ever been within miles of it. But Gutefundus
resolved that these treasures should no longer lie there useless.
Mankind should have the benefit of them. Nobody believed he could
conquer this dragon. Nobody would accompany him on such a mad
enterprise. It did seem like going to certain death. Nevertheless
Gutefundus made up his mind to do it.
He set out alone. It took him three years to reach the forest that
surrounded the mountain, of which he was in search. He had passed
through strange countries, and had taken part in many a good fight,
but he arrived at the edge of the forest, a day’s journey only from the
caverns, well and in good spirits for the fight with the dragon.
But here something befell him more wonderful than all he had
gone through in his life.
Night was approaching, and he looked about for a resting-place.
He heard the tinkling sound of a little bell, and bent his steps in that
direction. It led him some distance into the forest to a small hut,
made of dried mud. A little wooden belfry was built upon this, and the
bell was ringing at the close of day. Gutefundus, believing it to be the
dwelling of some hermit, entered it to ask for a night’s lodging. There
was no one there, and he wondered by what contrivance the bell
rang itself. While waiting for the owner to appear, he stretched
himself upon a couch of dried moss; and, being very tired, he soon
fell asleep.
When he awoke, he started up, and looked around in surprise. He
was still alone. His clothes were in rags; his feet were bare, for his
shoes had fallen to pieces on the floor; the hut had crumbled until it
was only a shattered mound; the wooden belfry lay around in broken
bits; the little bell was half buried in the dried mud, by his side, and
was nearly eaten up with rust. This reminded him of his sword, and
he looked anxiously for it. He saw it directly, on the earthen floor
close by him. It had, evidently, just fallen out of the scabbard, which,
all full of rents, was still attached to his rusty belt. The sword was as
bright as ever. He remembered now that it was the clattering it had
made in falling that had awakened him. Just then the gleam of
something white crossed his eyes. It was his beard, grown very long,
and perfectly grey. He was conscious then that his head felt cold. He
clapped his hands there, and found he was bald!
He understood the whole matter now. He had been in a magic
sleep! How many years he had slept he could not guess. Maybe two
or three hundred years. Such instances were not so very
uncommon. He recalled the names of several great men, who had
slept for a hundred years and more. Some of them were sleeping
still. It was clear that the dragon was a magician, and had led him
into the wood to put him into a magic sleep.
Gutefundus, upon this, arrived at two comfortable reflections.
Firstly, that the dragon was afraid of him, or it would not have sent
this sleep upon him; and, secondly, that it had no power over his
trusty sword, which was there by him unharmed. He took it up, felt
the edge, and found it sharp and keen.
He walked out of the wood, and sought the nearest town. His
appearance at first alarmed the people in the market place; but when
he told who he was, and on what errand he had come, and what had
befallen him, they received him with joy. They had heard all about
him, but everybody supposed he had been killed by the dragon
twenty years before.
He had slept for twenty years! He went into the hut a man in the
prime of life. He came out of it an old, bald-headed man.
But he was as courageous as ever. The dragon, it appeared, was
still alive, and no mortal man dared go near the treasures he
guarded. No one would go with Gutefundus to attack the fearful
beast. He could get no kind of armor in the town; and no suit to wear
except a blouse, and a pair of baggy trowsers. Such was the
costume of the place.
But he had his bright and trusty sword that had never yet failed
him, and he marched boldly into the wood again after the dragon.
He entered the cavern, and had proceeded unmolested for some
distance, when he heard a fearful roar, and out upon him rushed the
dragon. It stretched its beast’s body; opened its huge jaws; ran out
its hissing, serpent tongue; flapped loudly its bird’s wings; and curled
its snake tail.
THE DRAGON OF THE CAVERN.
But Gutefundus stood his ground undaunted. He felt from the tips
of his toes to his bald crown that that serpent’s time had come. He
swung his sword on high. Up rushed the dragon; down came the
sword, whack! and cut the terrible head into two parts! The beast
was stunned, but not killed. Another stroke severed the body; and
the third cut off its tail.
The dragon was dead, and the treasures thus became the
property of mankind.
Gutefundus contented himself with a small share of the spoils, and
passed the rest of his days quietly at home. He had been pretty
much all over the world; and, if he had not done good to everybody,
he had certainly taken some of the evil out of the earth.
I suppose none of my readers believe that these adventures
actually befell any man who ever lived upon the face of the earth.
But I have told you nothing that was not held to be true at the time
Gutefundus lived; and at a much later period too. Such wild legends
were fully credited, and not by ignorant people only. The three
pictures I have given in the story were drawn by the most learned
men of that olden time; and they had no doubt whatever of the
existence of the Dragon, the Sea Serpent, and the Bird Tree.
SOME BIG GUNS.
Ever since the invention of gunpowder, the men who have been
devoting their attention to the science of gunnery for purposes of war
have been making their cannon larger and larger.
A COLUMBIAD.
This is not the case with the weapons that are carried by soldiers;
for our rifles and muskets are much smaller than those used by our
ancestors. A hundred or two years ago, the great flint-lock muskets
and blunderbusses were twice as large as the rifles now used,
although they did not carry a ball half the distance, or with any thing
like the accuracy of our improved arms.
But the cannon that used to be in fashion were but little things
compared to those of the present day.
You might put one of the old-fashioned cannon into one of our
great columbiads and fire it out of it instead of a ball.
And while the cannon have been growing larger and larger, the
defenses against cannon-shot are growing stronger and stronger.
Now our men-of-war are generally what are called “iron-clads.”
The hull is covered with immense plates of iron or steel, which it is
almost impossible to pierce with the heaviest balls or conical shot.
And the forts are so constructed that the great masses of metal that
are sometimes hurled against them in time of war seem to have but
little effect upon their massive sides. And so the competition
between the weapons of offense and the means of defense goes on.
As the cannon are made larger, the iron plates on the ships are
made thicker and stronger, and the forts are built with walls that are
more massive and more thoroughly ball-proof.
Which party will succeed in this contest it is impossible to say.
If walls and ships could be constructed that would be impervious
to the heaviest cannon balls, warfare would probably soon come to
an end, for if a nation could have such forts and such ships it would
be useless for any other nation to make attacks upon it.
And if cannon could be made that would send balls through the
sides of any iron-clad, or through the walls of any fortification, war
would probably soon cease, for no country could resist a hostile
nation thus armed.
Therefore it is almost to be hoped that one of these parties—the
manufacturers of great cannon or the builders of ships and forts will
so far surpass the other that the trials between them in time of war
will be considered useless.
But it seems very doubtful if a limit to the size and force of cannon,
and the strength of iron-clads and forts will soon be found.
THE GREAT CANNON OF MALTA.
Although our cannon are so large, we hear stories of guns of the
kind that were very large and yet not at all modern.
It is said that the Knights of the island of Malta had a tremendous
cannon, which, when it was fired off, made everybody, even old
gunners stop their ears for fear that they would be deafened by the
terrific noise.
And the Chinese, who certainly invented gunpowder long before
we thought of it, have a tradition that their country once possessed a
most enormous cannon. It was constructed of pieces that were
fastened together by great bands, like the hoops on our barrels and
casks.
It is said that this enormous cannon, the bore of which was so
large that you might sleep inside of it if you felt sure it was not to be
used before you came out, was never fired but once, and the
inhabitants of the locality where it stood (or still stands, for all I
know,) believe that the ball is flying yet.
It would certainly be unpleasant if any of us happened to be taking
a walk through a pleasant country, to meet this ball so suddenly that
there would be no time to turn out for it.
But one of our great American guns, that carry a five-hundred
pound ball for five or six miles, would certainly be able to knock this
Chinese cannon into a thousand splinters, if it could but once get a
fair crack at it.
I wonder what the ancients, with their battering rams, and
catapults, and javelins, and slings, and arrows, would have thought,
if an American field-battery had opened upon one of their bravest
armies.
In that case I think that even Achilles would have thought it as
necessary to take the same care of his whole body as he had before
taken of his heel—which you remember was the only part of him that
was vulnerable to the weapons of that day.

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A Clinician's Pearls & Myths in

Rheumatology (2nd Edition) John H.

A Clinician’s Pearls & Myths

ISBN 978-3-031-23487-3 ISBN 978-3-031-23488-0 (eBook)

© Springer Nature Switzerland AG 2009, 2023

Boston, MA, USA John H. Stone

30 Thromboangiitis Obliterans��������������������������������������������������������������������������������������� 473

Abhishek Abhishek University of Nottingham, Nottingham, UK

Hermine Brunner Cincinnati Children’s Hospital Medical Center, University of Cincinnati,

David P. D’Cruz Louise Coote Lupus Unit, Guy’s Hospital, London, UK

Sarah Morgan Division of Clinical Immunology and Rheumatology, The University of

Takako Saeki Nagaoka Red Cross Hospital, Nagaoka, Japan

Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital,

Chengde Yang Department of Rheumatology and Immunology, Ruijin Hospital, Shanghai

Overview • RA typically affects distal joints (e.g., hands, wrists, and

K. D. Deane (*) · V. M. Holers · J. R. Kolfenbach · D. W. Pearson J. R. O’Dell

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 1

a migratory oligoarthritis. In other cases, the onset of dis-

Early Rheumatoid Arthritis

Treatment methotrexate monotherapy at the outset, others go immedi-

In Australia there is a bird—the Megapodius—that builds for its

IT SEIZED A SAILOR IN ITS JAWS.

At that moment Gutefundus thought that, so far, he had done no

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Boston, MA, USA John H. Stone

30 Thromboangiitis Obliterans�� 473

Early Rheumatoid Arthritis

Treatment methotrexate monotherapy at the outset, others go immedi-