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Medical Knowledge Self-Assessment Program@

Rheumatology

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rACP American College of Physicians@
Leading lnternal Medicine, lmproving Lives
Welcome to the RheumatologY
Section of MKSAP 191
In these pages, you will flnd updated information on approaches to the patient with rheumatologic disease, principles of
therapeutics, rheumatoid arthritis, osteoarthritis, spondyloarthritis, systemic lupus erythematosus, systemic sclerosis,
infectious arthritis, and other clinical challenges. A11 ofthese topics are uniquely focused on the needs ofgeneralists and
subspecialists outside of rheumatologz.

MKSAP 19 strives to provide the clinical knowledge its learners need to navigate their longitudinal learning paths. MKSAP 19's
core content contains essential, newly researched information in 11 subspecialty areas of internal medicine-created by
dozens of expert generalists and subspecialists. Development of MKSAP 19's syllabus and its 1200 all new peer-reviewed,
psychometrically validated multiple-choice questions (MCQs) has been informed by ABIM Certification and Maintenance
of Certification (MOC) requirements, emerging internal medicine knowledge, and our learners' feedback. MKSAP 19 contin-
ues to include HighValue Core (HVC) recommendations and MCQs, based on the concept of balancing clinical benefit with
costs and harms. Hospital-based internists can continue to trust that MKSAP's comprehensive hospitalist content, integrated
throughout the syllabus, and hospitalist focused MCQs, specially designated with the blue hospitalist icon (El), continue to
align with the ABIM's Focused Practice in Hospital Medicine MOC exam blueprint and enhance learning for hospital-based
practitioners.

More than ever before, MKSAP 19 Digital focuses on individualized learning and convenience. In addition to custom quizzes
and interlinked questions and sy'labus sections, MKSAP 19 Digital's new learning dashboard enables users to create a self
directed learning plan, with topic-specific links to resources within MKSAP and ACP Online. Multimedia formats, including
whiteboard animations and clinical videos, will benefit our audiovisual learners, while MKSAP's Earn as You Go CME/MOC
feature now allows subscribers to earn CME/MOC as they answer individual questions. In addition to Extension Questions
and New Info Updates, MKSAP 19 Complete and Complete Green continue to offer Virtual Dx and Flashcards and now offer
brand new enhancements: MKSAP Quick Qs, a set of concise questions mapped to high-frequency/high-importance areas
of the ABIM blueprint mirroring boards-style MCQs, and an embedded digital version of Board Basics for easy access
exam prep.

Language can be imprecise and imperfect, but MKSAP 19's Editors and contributors commit to using language and images
that support ACP's commitment to being an anti-racist organization that supports diversity, equity, and inclusion through-
out health care and health education. ACP also continues to ensure diversity among MKSAP's physician-contributors. When
appropriate, the MKSAP Editors also rely on MKSAP 19 Digital's expanded use of multimedia enhancements, including video
and audio, to explore and more fully explain issues surrounding the presentation of MKSAP 19 clinical content as it relates to
race and ethnicity. MKSAP 19 users are encouraged to contact the Editors at mksap_editors6acponline.org to help us identifiz
opportunities for improvement in this area.

On behalf of the many internists and editorial staff who have helped us create our new edition, we are honored that you have
chosen to use MKSAP 19 to meet your lifelong learning needs.

Sincerely,

Davoren Chick, MD, FACP

Editor-in-Chief
Senior Vice President
Medical Educat ion Division
American College of Physicians
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: Rheumatology

Committee Editor-in-Chief
Michael Pillinger, MD, EACE Section Editor Davoren Chick, MD, FACP
Professor of Medicine and Biochemistry and Molecular Senior Vice President. Medical Education
Pharmacologz American College of Physicians
Division of Rheumatologz Philadelphia. Pennsylvania
NYU Grossman School of Medicine
New York. New York
Senior Deputy Editor
Aryeh M. Abeles, MD Patrick C. Alguire, MD, EACP
Adjunct Associate Professor American College of Physicians
Division ol Rheumatologz Phi ladelphia. Pennsylvan ia
NYU Grossman School of Medicine
New York. New York
Deputy Editor
Gregory C. Gardner, MD, MACP
Janet A. Jokela, MD, MPH, EACP
Gilliland Henderson Professor of Medicine
Professor & Head, Department of Medicine
Division of Rheumatologz
Acting Regional Dean
University of Washington
University of Illinois College of Medicine
Seattle, Washington
Urbana, Illinois
Sharon L. Kolasinski, MD, FACP
Professor of Clinical Medicine
Division of Rheumatologz
Rheumatology Medicine Reviewers
University of Pennsylvania Perelman School of Medicine David Armstrong, DO, FACP
Ph iladelphia, Pen nsylvania Fawad Aslam, MBBS, MSc, FACP
Angelique Collamer, MD, FACP
Susan Faye Kroop, MD
Michael Guma, DO, FACP
Associate Professor of Medicine
Marie Kuchynski, MD
Division of Rheumatologz Ashima Makol. MD
Vanderbilt University Medical Center J. Suzanne Moore, MD, FACP
Nashville, Tennessee
Patricia J. Papadopoulos, MD
Vikas Majithia, MD, MPH, FACP Avis Ware, MD, FACP
Professor of Medicine Andrew L. Wong, MD, FACP
Division Director and Fellowship Program Director
Division of Rheumatologz
Hospital Medicine Rheumatology
University of Mississippi Medical Center
Jackson, Mississippi
Reviewers
Bernard Hildebrand, MD, MA, FACP
Bethany A. Marston, MD Julie Hildebrand, MD
Division Director, Pediatric Rheumatologz Kam A. Newman, MD, FACP
Program Director, Rheumatologz Fellowship Niluka Weerakoon, MD
Associate Professor of Medicine and Pediatrics
Pediatric Rheumatologr and Allergz/lmmunologz and
Rheumatologr Divisions
University of Rochester
Rochester, New York

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 l

'!

Rheumatology ACP Editorial Staff Aryeh M. Abeles, MD

Consultantship
Suzanne Meyers, Medical Editor, Assessment and Education
Bristol-Myers Squibb, Johnson & Johnson
Programs
Beclg Krumm, Director, Assessment and Education Programs Vikas Majithia, MD, MPH, FACP
Jackie Twomey, Managing Editor, Assessment and Research G rants / Contracts
Education Programs GlaxoSmithKline, Bristol-Myers Squibb, Janssen
Consultonfship
Novartis
ACP PrincipalStaff
Aduisory Board
Davoren Chick, MD, FACP UCB
Senior Vice President, Medicql Educqtion
Bethany Marston, MD
Tabassum Salam, MD, MBA, FACP Re search G rants / Co ntracts
Vice President, Medical Educqtion Rheumatologr Research Foundation
Margaret Wells, EdM Michael Pillinger, MD, FACP
Vice President, Learning Assessment, Accreditation, Reseo rch Grants / Contracts
ctnd Research Hikma Pharmaceuticals, Horizon Pharmaceuticals
Patrick C. Alguire, MD, FACP Consultontships
MKSAP Senior Deputy Editor Horizon Pharmaceuticals, Sobi, Ampel Biosciences

BeckyKrumm Tabassum Salam, MD, MBA, FACP

Director, Assessment and Education Programs Consultantship
Johnson & Johnson
Jackie Twomey
Managing Editor

Iulia Nawrocki Acknowledgments

Digital Con ten f Asso ciate / Edito r The American College of Physicians (ACP) gratefully
acknowledges the special contributions to the development
Linnea Donnarumma
and production of the 19th edition of the Medical
Senior Medical Editor
Knowledge Self-Assessment Program' (Vt<SAp' 19) made
Amanda Cowley by the lollowing people:
Medical Editor
Graphic Design: Barry Moshinski (Director, Graphic
Sandy Crump Services), Raymond DeJohn (Designer, Graphic Services),
Medical Editor Tom Malone (Print/Mail Production Manager, Graphic
Services), Mike Ripca (Technical Administrator, Graphic
Georgette Forgione
Services).
Medicol Editor
P roduction / Systems: Dan Hoffmann (Vice President,
Beth Goldner
Information Technology), Scott Hurd (Manager, Content
MedicalEditor
Systems), Neil Kohl (Senior Architect), and Chris
Suzanne Meyers Patterson (Senior Architect).
liledical Editor
MKSAP 19 Digital: Under the leadership of Steven Spadt
Elise Paxson (Senior Vice President, Information Technology and
MedicalEditor Chief Technology Officer), the development of the dig-
ital version of MKSAP 19 was implemented by ACP's
Chuck Graver
Digital Products and Services Department, directed and
Finance and Operations Administrqtor
led by Brian Sweigard (Vice President, Digital Products
Kimberly Kerns and Services). Other members of the team included Dan
Administratiu e Coordinator Barron (Senior Web Application Developer/Architect),
Callie Cramer (Data Visualization/Web Developer),
Disclosures of relationships with any entity producing, Chris Forrest (Senior Web Application Developer),
marketing, reselling, or distributing health care goods or Kathleen Hoover (Manager, User Interface Design and
services consumed by, or used on, patients. Individuals not Development), Kara Regis (Director, Product Design
listed below have nothing to disclose. and Development), Brad Lord (Senior Web Application

tv
 Developer/Architect), and John McKnight (Senior Web
Developer).
i
The College also wishes to acknowledge that many other
persons, too numerous to mention, have contributed to
the production of this program. Without their dedicated
efforts, this program would not have been possible.
MKSAP Resource Page
The MKSAP Resource Page (wwwacponline.org/mksap19-
resources) provides access to MKSAP 19 online answer
sheets for transcribing answers from the print eclition;
access to MKSAP 19 Digital; Board Basics '; information
on Continuing Medical Education (CME), Maintenance
of Certification (MOC), and international Continuing
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other new information.
lnternational MOC/CPD
Information and instructions on submission ol inter
national MOC/CPD is available by accessing the CME/
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Digital.
Continuing Medical Education
The American College of Physicians is accredited by the
Accreditation Council for Continuing Medical Education
(ACCME) to provide continuing medical education for
physicians.
The American College of Physicians designates this enduring
material, MKSAP 19, for a maximum of 300 AMA PRA
Category 1 CreditsrM. Physicians should claim only the
credit commensurate with the extent of their participation
in the activity.
Up to 24 AMA PRA Category 1 Creditdtu are available from
January 31,2022, to January 31, 2025, for the MKSAP l9
Rheumatology section.
Learning Objectives
The learning objectives of MKSAP 19 are to:
. Close gaps between actual care in your practice and
preferred standards of care, based on best evidence
. Diagnose disease states that are less common and sometimes
overlooked or confusing
. Improve clinical management decisions that affect patient
safety and quality of care
o Determine when to ref'er patients for care by medical
subspecialists, surgeons, and other members olthe health
care team
r Pass the ABIM Certification Examination
r Pass the ABIM Maintenance of Certification Examination
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. Residents preparing for the ABIM Internal Medicine
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Certification Longitudinal Assessment Option, pre-
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Focused Practice in Hospital Medicine program
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To earn CME credits or to apply for MOC points, MKSAP
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rectly (earning a score of at least 50%) and click the Submit
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MKSAP 19 Subscribers can enter their self assessment
question answers and submit for CME/MOC in two
ways:
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can also submit their answers directly within MKSAP 19
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Successful completion of the CME activity, which includes
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t
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and lnclusion Within MKSAP 19
MKSAP 19's Editors and contributors commit to using
Ianguage and images that support ACP's commitment to
being an anti racist organization that supports diversity'
equiry and inclusion throughout health care and health
education. ACP also continues to ensure diversity among
MKSAP's physician-contributors. When appropriate,
the MKSAP Editors will also rely on MKSAP 19 Digital's
expanded use of multimedia enhancements, including video
and audio, to explore and more fully explain issues sur-
rounding the presentation of MKSAP 19 clinical content as it
relates to race and ethnicity. MKSAP 19 users are encouraged
to contact the Editors at mksap editors6acponline.org to
help us identiSr opportunities for improvement in this area.
\
Hospital-Based Medici ne
For the convenience ofsubscribers who provide care in
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hospitalist icon (E).
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cepts (that is, concepts that discuss balancing clinical
benefit with costs and harms) are designated by the HVC
icon [HVC].
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Rheumatology ISBN: 978 I-938245 87 9
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vll
 Table of Contents

Approach to the PatientWith Rheumatologic Disease Uricosuric Agents 15

InflammatoryVersus NoninflammatoryPain . .. . . . . . . 1 Pegloticase 15
TheMusculoskeletalExamination ........... 1 Medications and Pregnancy 15

Arthritis .....1 Vaccination and Screening in Immunosuppression 15

Monoarthritis...... .....1 Nonpharmacologic and Nontraditional

Oligoarthritis ...........2 Management 15

Polyarthritis Physical and Occupational Therapy

.....2 15

Soft-TissueAbnormalities..... ......2 Complementary and Alternative Medicine . . . L7

Extra-Articular Manifestations of Rheumatologic RoleofSurgery .... 77

Disease ......2
Constitutionalsymptoms. .......2 Rheumatoid Arthiltis
Skinlnvolvement... ...........2 Pathophysiologr and Risk Factors. t7
Eyelnvolvement... .....2 Genetic Factors 17
InternalOrganlnvolvement.. ........... 2 Environmental Factors 17

LaboratoryStudies ..........2 Infectious Agents. t7

TestsThatMeasurelnflammation ........ 2 Hormones 17

AutoantibodyTests .. ...........5 Diagnosis 1B

ImagingStudies. .....5 ClinicalManifestations. . . . . . 18

Radiography. ...........5 Laboratory Studies 19
\t cT.... .........7 Imagrng Studies. t9
t
t MRI... .........7 Complications and Extra-Articular
Ultrasonography . . . . .7 Manifestations..... 20
I
..........
JointAspiration.... .........7 Joints. . 20

TissueBiopsy ........8 Skin... 20

MentalHealthScreening .....8 Eyes... 20

Lungs . 21.

Heart.. 2l
Principles of Therapeutics
Hematologic. 2t
Overview 8
Blood Vessels 2t
Anti-lnflammatory Agents. ,8
Management 2t
Glucocorticoids . . . . ,8
GeneralConsiderations. . . . . . 2l
NSAIDS ,9
Disease-Modi$zing Antirheumatic Drugs 22
Colchicine ,9
NSAIDS 22
Analgesics and Pain Pathway Modulators ,9
I Acetaminophen. . . . 10
Glucocorticoids.... 22
I

Surgery 23
I Tramadol 10
Pregnancy 23
Serotonin Norepinephrine Reuptake Inhibitors 10
:
Gabapentinoids.... 10
r
Disease-Modi$ring Antirheumatic Drugs. 10 Osteoarthritis
:
Nonbiologic Disease-Modi$ring Pathophysiolory .... 23
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Antirheumatic Drugs 10 Epidemiolory and Risk Factors 23
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I
Biologic Disease-Modifying Antirheumatic Drugs t2 Classification 24

Urate-Lowering Therapy 13 PrimaryOsteoarthritis. ... . 24

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I Allopurinol. 13 Secondary Osteoarthritis 25
t Febuxostat t4 Diffuse Idiopathic Skeletal Hyperostosis 25

tx
Diagnosis 25 Diagnosis 46
ClinicalManifestations. . . . . . .. 25 General Considerations. . . . . 46
Laboratory and Imaging Studies 27 Laboratory Studies 46
Differential Diagnosis 27 Differential Diagnosis. . . . . . 48
Management 28 Management 48
Nonpharmacologic Therapy. . . . 29 Pregnancy and Childbirth Issues. 50
Pharmacologic Therapy 29 Prognosis 51
Surgical Therapy 30
Sjtigren Syndrome
Fibromyalgia Epidemiologz and Pathophysiologr 51
Epidemiologr and Pathophysiologz 30 Clinical Manifestations. . . . . . . . . . . 5t
Diagnosis 30 Diagnosis 51
Management 32 Management 52
Nonpharmacologic . 32 Prognosis 52
Pharmacologic..... 32

ldiopathic lnflammatory Myopathies

Spondyloarthritis Overview 53
Overview 32 Evaluation of the Patient With Muscle Pain
Pathophysiolory .......... en or Weakness. 53
Genetic Factors 33 Epidemiologr and Pathophysiologz 53
Environmental Factors . 33 Clinical Features 54
Tissue Factors....... . . JJ Muscle Involvement 54
Classification JJ Pulmonary Disease 54
Anl<ylosing Spondylitis . J.) Skinlnvolvement... 55
PsoriaticArthritis . .. . . 36 Cardiac Disease 55
Enteropathic Arthritis. . Malignancy. 55
Reactive Arthritis. . . . . . 3B Types of Idiopathic Inflammatory Myositis . . . 55
Diagnosis 3B Dermatomyositis. . . 55
LaboratoryStudies .... 3B Polymyositis. 55
Imaging Studies. . . . . . . 39 Antisynthetase Syndrome 57
Management 4I Immune-Mediated Necrotizing Myopathy 57
General Considerations. 4t Inclusion Body Myositis 57
Ankylosing Spondylitis. 47 Overlap Syndromes. 57
PsoriaticArthritis ... . . 42 Diagnosis 57
Enteropathic Arrhritis. . 42 Classifi cation Criteria 57
Reactive Arthritis. . .. . . 42 Muscle-Related Enzymes 57
Autoantibodies .... 57
Systemic Lupus Erythematosus Imaging 58
Epidemiologr and Pathophysiologz 42 Electromyography. . . 58
Clinical Manifestations... . . . . . . .. 43 Histopathologz s8
Mucocutaneous Involvement. . 43 Management 59
Musculoskeletal Involvement. . 44 Prognosis 59
Kidney Involvement 44
Neuropsychiatric Involvement . 45 Systemic Sclerosis
Cardiovascular Involvement. . . 45 Epidemiologr and Pathophysiologz . 59
Pulmonary Involvement. . . . . . 45 Classification 59
Hematologic Involvement. . . . . 45 Clinical Manifestations and Diagnosis 60
Gastrointestinal Involvement . . 46 Cutaneous Involvement 60
Comorbidities .. _..... 46 Musculoskeletal Involvement. . ., 62

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 Vascularlnvolvement . . . . . . 62 LymeArthritis..... 75
Cardiac Involvement 63 My cobacterium tuberculosis Infection 7S
Gastrointestinal Involvement 63 Fungal Infections. 75
Kidney lnvolvement 63 Virallnfections ..... 76
Lunglnvolvement. ....... . 64 Prosthetic Joint Infections . . . . 77
Management 64 Management 77
Pregnancy 65
Systemic Uasculitis
Mixed Connectiye lissue Disease and Undifferentiated Overview ..........78
Connective fissue Disease Large-VesselVasculitis ......79
Overview ..........66 GiantCellArteritis .....79
EpidemiolograndPathophysiologz . . .......66 PolymyalgiaRheumatica .......80
ClinicalManifestations andDiagnosis . . . . . . . .......66 TakayasuArteritis ...... 8l
Management .......66 Medium-VesselVasculitis .... 81
Prognosis ..........66 PolyarteritisNodosa ....81
Primary Angiitis of the Central Nervous System . . . 82
CrystalArthropathies KawasakiDisease ......83
Gout .. 67 Small-VesselVasculitis ......83
Epidemiologr 67 ANCA-AssociatedVasculitis...... ...... 83
Pathophysiolory .... 67 Immune Complex-MediatedVasculitis. . . . . . . . . 85
Clinical Manifestations. . . . . . 67
Diagnosis 68 Other Rheumatologir Diseases
Management 69 Behqet Syndrome 87
Calcium Pyrophosphate Deposition. . . . ., 7l RelapsingPolychondritis . . ... ..... . 88

i
Epidemiologz and Pathophysiolory . , 7l AutoinflammatoryDiseases. . . . . . . . . 89
Clinical Manifestations and Diagnosis 7l Adult-Onset Still Disease 90
t Management 72 Sarcoidosis 90
\ Basic Calcium Phosphate Deposition . . . . 73 Igc4-Related Disease 92
Genetic Diseases of Connective Tissue 92
lnfectious Arthritis
Diagnosis 73 Bibliography 93
Clinical Manifestations. . . . . 73
Laboratory and Imaging Studies 73
Self-Assessment Test. 97
Causes. 74
Infection With Gram-Positive Organisms 74
Infection With Gram-Negative Organisms 74 lndex t75

xl
Rheumatology High Value Care
Recommendations
The American College of Physicians, in collaboration with
multiple other organizations, is engaged in a worldwide
initiative to promote the practice of High Value Care (HVC).
The goals of the HVC initiative are to improve health
care outcomes by providing care ofproven benefit and
reducing costs by avoiding unnecessary and even harmful
interventions. The initiative comprises several programs
that integrate the important concept ofhealth care value
(balancing clinical benefit with costs and harms) for a
given intervention into a broad range of educational mate-
rials to address the needs oftrainees, practicing physicians,
and patients.
HVC content has been integrated into MKSAP 19 in several
important ways. MKSAP 19 includes HVC-identified key
points in the text, HVC-focused multiple-choice questions,
and, in MKSAP Digital, an HVC custom quiz. From the text
and questions, we have generated the following list of HVC
recommendations that meet the definition below of high
value care and bring us closer to our goal of improving
patient outcomes while conserving finite resources.
HighValue Care Recommendation: A recommendation to
choose diagnostic and management strategies for patients in
specific clinical situations that balance clinical benefit with
cost and harms with the goal of improving patient outcomes.
Below are the High Value Care Recommendations for the
Rheumatology section of MKSAP 19.
o An accurate history and a thorough musculoskeletal
physical examination are essential to diagnose and differ-
entiate inflammatory and noninflammatory symptoms
and can help to avoid unnecessary testing.
o Antinuclear antibody testing should not be performed in
a patient with nonspecific symptoms and normal find-
ings on clinical examination because it does not establish
the diagnosis of a connective tissue disease.
r Antinuclear antibody (ANA) subserologr testing should
not be performed routinely, even in the setting of a pos-
itive ANA result, without strong clinical suspicion of an
underlying connective tissue disease.
. Radiography is usually the first imaging test ordered in
the evaluation of rheumatologic diseases because it is
readily available, is inexpensive, exposes patients to only
a low level of ionizing radiation, and is useful in monitor-
ing arthritis progression.
. Ultrasonography is an inexpensive means to assess
soft-tissue abnormalities, assess disease activity, and
assist with tendon or joint injections.
o All tumor necrosis factor inhibitors provide similar bene-
fit in patients with rheumatoid arthritis (see Item 36).
. Laboratory testing is usually not necessary to diagnose
osteoarthritis but is helpful if other causes of arthritis are
being considered or to help define the safety ofpotential
therapies.
. Topical NSAIDs are safe and effective for treatment of
knee and hand osteoarthritis and should be considered
before oral NSAIDs (see Item 24).
. The use of chondroitin sulfate (with or without glucos-
amine), biologics, intra-articular hyaluronic acid, platelet-
rich plasma, stem cells, or botulinum toxin is not recom,
mended in the treatment of knee osteoarthritis
(see Item 5o).
o Acetaminophen provides no benefit for hip or knee
osteoarthritis; it may be considered as add-on therapy
for short-term and episodic use but not as initial therapy
(see Item 54).
o Tai chi is as beneficial as physical therapy for knee and hip
osteoarthritis pain (see Item 34).
. Exercise is beneficial in hip, knee, and hand osteoarthri-
tis; no one exercise program is superior (see Item A2).
o Arthroscopic surgery is not indicated in patients with
osteoarthritis unless there is joint buckling, instability, or
locking, or a concomitant and symptomatic mechanical
disorder.
o Patients with fibromyalgia should not be treated with
anti-inflammatory drugs, including NSAIDs and glu-
cocorticoids, and do not respond to opioids, with the
exception of tramadol (see Item 7).
o Borrelia burgdorferi DNA can be detected by polymerase
chain reaction in slnovial fluid, but this test offers no
advantage to serologic testing (see Item 12).
o A muscle biopsy is not necessary to diagnose dermato-
myositis in patients with characteristic clinical and labo-
ratory findings (see Item 38).
. A muscle biopsy can help to confirm the diagnosis of
inclusion body myositis but is not needed when clinical
features are characteristic (see Item 45).
o In the absence of additional suggestive symptoms, physi-
cal findings, and supporting laboratory data, oral dryness
should not be attributed to a rheumatologic condition
(see Item 47).
o If a patient has many features of spondyloarthritis, a pos-
itive HLA-B27 result adds little to the posttest probability
(see Item 5).
o Antibiotics generally are not indicated in reactive arthritis
because they do not affect illness outcomes (see ltem 67).
xill
a
I
I
 Rheumatology

Approach to the Patient t(rY P0lflT5

. Inflammatory symptoms include pain, erythema, swell-
i
With Rheumatologic ing, and warmth; noninflammatory conditions usually
Disease lack these features, except for pain.
o An accurate history and a thorough musculoskeletal HVC
lnflammatory Versus physical examination are essential to diagnose and dif-

L
Noninflammatory Pain
The differentiation between inflammatory and noninflamma
tory signs and symptoms is central to the evaluation of
patients with musculoskeletal pain. Autoimmune conditions
typically present with inflammation, whereas mechanical or
degenerative disorders are characteristically noninflamma-
tory. The cardinal signs of inflammation are pain, erythema,
swelling, and warmth; noninflammatory conditions usually
lack these features, except for pain. Patients may simultane-
ously experience more than one type of pain. Table 1 com
pares the features of inflammatory and noninflammatory
arthritis.
The M usculoskeletal Examination
An accurate history and a thorough musculoskeletal physical
examination are essential to diagnose and differentiate inflam-
matory and noninflammatory symptoms and can help to
avoid unnecessary testing. Musculoskeletal pain may be
articular, periarticular, or referred. Pain with passive range
of motion suggests an articular condition, whereas pain
only with active range of motion suggests a periarticular
condition.
See MKSAP 19 General Internal Medicine 1 for more
information.
ferentiate inflammatory and noninflammatory symp-
toms and can help to avoid unnecessary testing.
Arthritis
Monoarthritis
Monoarthritis involves a single joint and is classified as acute
or chronic.
Acute monoarthritis can be noninflammatory (e.g.,
caused by trauma, hemarthrosis, or internal derangement) or
infl ammatory (e. g., crystal-induced or infectious). Evaluation
for infectious arthritis should be guided by the clinical presen-
tation and examination, but suspicion should always be high.
Joint aspiration is usually the most effective means of diagnos
ing the underlying cause.
Chronic inflammatory monoarthritis (>26 weeks) can be
caused by chronic infection (e.g., mycobacterial, fungal, or
Borrelia burgdorferi) or by autoimmune rheumatologic dis-
ease. Synovial fluid cell count analysis can help determine the
presence of inflammation but may be inadequate for diagnosis;
assessment for systemic disease (complete history; examina-
tion; and laboratory studies, including serologic testing) may be
indicated. Rarely, synovial biopsy may be required to rule out
chronic infection, deposition diseases, or malignancy.
Chronic noninflammatory monoarthritis is usually caused
by osteoarthritis.

TABLE I . Features of lnflammatory Versus Noninflammatory Arthritis

Feature lnflammatory Arthritis Noninf lammatory Arthritis
Morning stiffness >60 min; worsens with immobility <30 min
Constitutional sym ptoms Fever; fatigue; malaise Generally absent
Physical examination findings Erythema; warmth; soft-tissue swelling; joint Minimal or no warmth; no soft-tissue swelling;
effusions; reduced ROM is frequent bony enlargement and joint effusions may
occur in osteoarthritis; reduced ROM may occur
Synovialiluid Leukocyte count >2000/pL(2.0 x 10e /L), Leukocyte count of 200-2000/pL (0.2-2.0 x 1 0ell),
predominantly neutrophils in acute inflammation predominantly monocytes
and monocytes in chronic inflammation
Other laboratory findings Elevated inflammatory markers (ESR, CRP); lnflammatory markers usually normal or
anemia of inflammation minimally elevated

CRP = C reactive protein; ESR = erythrocyte sedimentation rate; ROI\l = range of motion
 Approach to the Patient With Rheumatologic Disease
Oligoanhritis
Oligoarthritis involves two to four joints, typically in an asym
metric pattem.
Acute inflammatory oligoarthritis may be caused by
gonorrhea or rheumatic fever. Chronic inflammatory oligoar
thritis can be caused by autoimmune conditions. such as
seronegative spondyloarthritis (e.g., psoriatic arthritis. reac-
tive arthritis, arthritis related to inflammatory bowel disease,
or ankylosing spondylitis).
Chronic noninflammatory oligoarthritis is usually caused
by osteoarthritis.
Polyarthritis
Polyarthritis involves five or more joints. In many cases, it
involves the small joints of the hands and/or feet.
Acute polyarthritis (<6 weeks in duration) can be caused
by viral infections (e.g., with parvovirus 819, HIV hepatitis
viruses, rubella, or chikungunya virus) or may be an early
manifestation of chronic (>6 weeks in duration) inflammatory
polyarthritis, such as rheumatoid arthritis (RA), systemic
lupus erythematosus (SLE), or psoriatic arthritis.
Soft-Tissue Abnormal ities
Common nonarticular sources of musculoskeletal symptoms
are the soft tissues (tendons, ligaments. and bursae) around or
away from the joints. Isolated tendon andi'or ligament involve
ment usually suggests noninflammatory disorders, such as
mechanical injury/irritation, overuse, or degeneration (e.9..
rotator cuff disorders or tennis elbow). Disorders of wide
spread musculoskeletal pain (e.g., fibromyalgia) also cause
symptoms localizing to these structures.
The enthesis is a complex structure at the site of the inser
tion of a tendon or ligament onto the bone. Severe persistent
inflammation of the enthesis (enthesitis) strongly suggests
spondyloarthritis, especially when it affects multiple sites. The
inflammation may extend along the associated tendon and
Iocal ligaments; it results in dactylitis ("sausage digits"), which
is typically a feature ofspondyloarthritis, particularly psoriatic
arthritis.
See MKSAP 19 General Internal Medicine 1 for more
information.
t(EY POlt{rs
HVC . Joint aspiration is usually the most effective means of
diagnosing the underlying cause of acute monoarthritis.
o Chronic noninflammatory arthritis is usually caused by
osteoarthritis.
r Internal Medicine 1 for discussion of pretest probabilities).
Isolated tendon and/or ligament involvement usually
suggests noninflammatory disorders, such as mechani-
cal injury/irritation, overuse, or degeneration.
o Ery.throcyte Sedimentation Rate
Persistent inflammation of the enthesis (enthesitis)
strongly suggests spondyloarthritis.
2
Extra-Articur M a n ifestatio ns
I a
of Rheumatologic Disease
Constitutional Symptoms
Fever, morning stiffness, and fatigue occur in numerous rheur-na
tologic conditions. Fever is usually low grade but may be high and
spiking in some conditions (e.g., adult onset Still disease and
autoinflammatory diseases). Morning stiflhess lasting more than
60 minutes is most commonly described in RA but also occurs
with other forms of inflammatory afthritis. Significant and even
disabling fatigue is a prominent feature of fibromyalgia.
Skin lnvolvement
Skin involvement is common in rheumatologic conditions and
may go unnoticed by the patient (Table 2). It may also be an
adverse eflect of n-redications used to treat rheumatologic con
ditions. including skin inf'ections secondary to immunosup
pressive therapy.
Eye lnvolvement
Eye involvement in different rheumatologic diseases usually
follons fairly distinct patterns, and the location and type of
involvement can help narro\{ the differential diagnosis
(Table 3).If not quickly recognized and treated. certain fbrms
ofeye involvement can have devastating consequences, includ
ing permanent loss of vision. See MKSAP 19 General Internal
'I
Medicine 2 {br additional information on ocular rnanifesta
tions of rheumatologic disease.
lnternal Organ lnvolvement
Rheumatologic diseases fiequently aft'ect internal organs. with
different diseases tending to follow characteristic patterns
(Table 4).
I(EY POIXI
o Rheumatologic disease can cause constitutional symp-
toms and extra-articular manifestations affecting the
skin, eyes, and internal organs.
Laboratory Studies
Laboratory studies are useful for diagnosing rheumatologic dis
eases. identilying the extent/severity of involvement, evaluating
disease activity, and monitoring therapeutic responses. Because
of limited specificity. results of these tests should always be
interpreted in the context of the clinical history and physical
examination and should be applied with great caution, if at all,
in the setting of low pretest probability(see MKSAP 19 General
Tests That Measure lnflammation
The erythrocyte sedimentation rate (ESR) measures the fall of
erythrocytes (in millimeters per hour) through anticoagulated
I
:
I

:
Approach to the Patient With Rheumatologic Disease
i

TABLE 2. Dermatologic Manifestations of Rheumatologic Disease

Rheumatologic Disease Dermatologic Manifestations
Systemic lupus erythematosus Acute cutaneous lupus erythematosus (commonly a malar rash); subacute cutaneous lupus
erythematosus; photosensitive rash; chronic cutaneous lupus erythematosus (most commonly
discoid lupus); oral ulcerations (on the tongue/hard palate; usually painless); alopecia; lupus
panniculitis (painful, indurated subcutaneous swelling with overlying erythema of the skin)
Dermatomyositis Gottron papules (erythematous plaques on extensor surfaces of MCP and PIP joints);
photodistributed poikiloderma, including shawl sig n (over the back and shoulders) and V sign
(overthe posterior neck/back or neck/upper chest); heliotrope rash (violaceous rash on the upper
eyelids); mechanic's hands (hyperkeratotic, fissured skin on the palmar and lateral aspects of fingers);
nailfold capillary abnormalities; holster sign (poikiloderma along lateralthigh); can occur in the
absence of myositis (a myopathic dermatomyositis)
Systemic sclerosis Skin tightening, thickening, and hardening; nailfold capillary changes; calcinosis; telangiectasias;
decreased oral aperture; bi- or tri-color Raynaud phenomenon
Vascu litis Palpable purpura; nodules; ulcers; necrosis; Raynaud phenomenon if cryoglobulins present
Behget syndrome Painful oral and genital ulcers; erythema nodosum; acne/folliculitis; pathergy (skin inflammation/
ulceration from minor trauma)
Sarcoidosis Erythema nodosum; infiltrated plaques; maculopapular and papular lesions; nodules; soft
infiltrates of the nose (lupus pernio); on blanching with a glass slide, sarcoid skin lesions reveal
"apple jelly" discoloration
Psoriatic arthritis Plaque psoriasis typically on extensor surfaces, umbilicus, glutealfold, scalp, and behind ears;
pustular psoriasis on palms and soles; nail pitting; onychodystrophy
Reactive arthritis Keratoderma blennorrhagicum (psoriasiform rash on soles, toes, palms); circinate balanitis
(psoriasiform rash on penis)
Adult-onset Still disease Evanescent, salmon-colored rash on trunk and proximal extremities
Rheumatic fever (secondary to Erythema marginatum (annular pink to red nonpruritic rash with central clearing)
streptococcal infection)
Lyme disease Erythema chronicum migrans (slowly expanding, often annual lesion with central clearing)

MCP = metacarpophalangea; PIP = proximal interphalangeal.

TABTE 3, Ocular Manifestations of Systemic lnflammatory Disease

Systemic lnflammatory Disease Ocular Manifestations
Ankylosing spondylitis, reactive arthritis, and inflammatory bowel Uveitis (inflammation of anterior and/or posterior chamber and/or
disease (anterior chamber); sarcoidosis and BehEet syndrome retina); anterior uveitis symptoms include pain, redness, visual
(anterior and/or posterior chamber); granulomatosis with change; posterior uveitis symptoms include painless visual change
polyangiitis (posterior chamber) or floaters
Rheu matoid arth ritis; spondyloarthritis; system ic vascu litis; rarely, Episcleritis; symptoms include redness, watering, and irritation but
SLE no vision loss
Rheumatoid arthritis; relapsing polychondritis; systemic vasculitis; Scleritis; symptoms include severe eye pain that is worse at night
inflammatory bowel disease; rarely, SLE and with eye movements; redness; photophobia
Systemic vasculitis; antiphospholipid syndrome; SLE Retinal ischemia; symptoms include painless vision loss or change
Sjogren syndrome Keratoconjunctivitis sicca; symptoms include dry eyes
Giant cell arteritis Anterior/posterior ischemic optic neuropathy; central retinal artery
occlusion; symptoms include loss of vision
Sarcoidosis; granulomatosis with polyangiitis; lgG4-related Proptosis/retrobulbar inf la m matory infiltrate
diseases
Reactive arthritis Conjunctivitis; symptoms include red eye

SLE = systemic lupus erythematosus.

plasma. Erythrocytes tend to be negatively charged on their
surfaces, leading to repulsion and a prolonged ESR. Fibrinogen
and other acute phase reactants, as well as hypergammaglobu
linemia (polyclonal or monoclonal), neutralize the erythro
cytes' surface charges, promoting their ability to settle at a
faster rate. Elevated fibrinogen levels and high ESRs are seen in
many rheumatologic diseases, as well as in nonrheumatologic
inflammatory conditions, such as chronic infections and
malignancies. The normal ESR increases with age and is usu
ally higher in women. A well accepted rule of thumb is to
adjust the upper limit of normal as (age in years)/2 lor men
and (age in years + l0) 2 for women.

3
Approach to the Patient With Rheumatologic Disease

TABLE 4. lnternal Organ lnvolvement in Rheumatologic Disease

Disease Type of lnvolvement
Heart
Kawasaki disease Coronary artery vasculitis
Systemic sclerosis Arrhythmia; myocardial fibrosis
SLE Pericarditis; valvular disease; myocarditis
RA Perica rditis; myocarditis

Rheumatic fever; antiphospholipid syndrome Valvular disease

Giant cell arteritis Aortic aneurysm/dissection; aortitis; large'vessel obstruction
Sarcoidosis Atrioventricular block; a mia; cardiom
Lung
RA Serositis; ILD; rheumatoid nodules
SLE; CTDs; myositis; Henoch-Schonlein purpura Serositis; pneumonitis; pulmonary hemorrhage from vasculitis
Pulmonary hemorrhage; cavitary nodules
Diffuse cutaneous systemic sclerosis ILD; pulmonary hypertension

Limited cutaneous systemic sclerosis Pulmonary hypertension

Antiphospholipid syndrome Pulmonary embolism; pulmonary hemorrhage in catastrophic antiphospholipid
syndrome
Sarcoidosis Hilar lymphadenopathy; ILD
Goodpasture syndrome Pulmonary hemorrhage
Kidney
SLE; CTDs; AAV systemic vasculitis (except PAN) G lomeru loneph ritis
PAN Renal artery vasculitis; pseudoaneurysms

Antiphospholipid syndrome Renal infarct; renal vein thrombosis

Sjogren syndrome Acute interstitial nephritis/renal tu bular acidosis

Goodpasture syndrome G lomeru lonephritis
Gastrointestinal System
PAN Mesenteric vasculitis
Henoch-Schonlein purpura lntestinal vasculitis and ulcerations
Diffuse and limited cutaneous systemic sclerosis Esophageal and small-bowel hypomotility
BehEet syndrome Mucosal ulcerations
Familial Mediterranean fever Peritonitis
Nervous System
SLE; CTDs; AAV; systemic vasculitis CNS involvement may include mental status changes, stroke, seizures;
peripheral involvement may include mononeuritis multiplex and peripheral
neuropathy
PACNS CNS vasculitis

AAV = ANCA associated vasculitis; CNS = central nervous system; CTD = con nective tissue disease; I LD = interstitial lung disease; PACNS = primar angiitis o{ the central nerous
system; PAN = polyarteritis nodosa; RA = rheumatoid afthritis; SLE = systemic lupus erythematosus.

In addition to inflammatory conditions, ESRs can be
elevated in pregnancy, diabetes mellitus, obesiry and end-
stage kidney disease. Because ofrheostatic properties, anemia
and macrocytosis are also associated with an increased ESR.
ESR can be excessively low in low-fibrinogen states, such as
liver or heart failure, and in conditions promoting rouleaux
formation (e.g., polycythemia vera). Sickle cell disease and
microcytosis (including spherocytosis) may also decrease
ESR.
A markedly elevated ESR (>100 mm/h) should alert phy-
sicians to conditions such as giant cell arteritis, multiple mye-
loma, metastatic cancer, or other overwhelming inflammatory
states (infection or autoimmune disease).
C-Reactive Protein
C-reactive protein (CRP) is produced by the liver mainly in
response to interleukin-6 generated by leukocytes during
the inflammatory state. CRP levels and ESR usually follow a

4

common pattern, but CRP is often more rapidly responsive to
changes in inflammation. In rheumatologic conditions, CRP is
typically elevated 2 to l0 times the normal level; a higher level
(especially >10 mg/dl [tOO mg/L]) should prompt considera,
tion of an alternative diagnosis, such as infection. CRP is
thought to be a better marker than ESR for measuring inflam
mation in spondyloarthritis. In contrast, in some patients with
SLE, ESR is a better marker of disease activity and the CRP
level may remain normal despite active disease. An elevated
CRP level in a patient with SLE is often related to infection.
CRP can be elevated in obesity and low with the use of certain
antibiotics and interleukin 6 blockers.
Complement
The complement system is an essential part of the immune
response, promoting vasodilation, attracting leukocy.tes, and
assisting in the lysis of opsonized bacteria during humoral
immunity.
Complement components are acute phase reactants that
are synthesized in the liver and rise in many inflammatory
states. However, in response to diseases that lead to immune
complex formation (SLE; cryoglobulinemic and urticarial vas-
culitis) and other states, such as infections (subacute bacterial
endocarditis, sepsis, viremia) and glomerulonephritis, com
plement cascades are activated, and complement levels fall
because of excessive consumption. Paradoxically, genetic defi
ciency of early complement components may increase the risk
tbr lupus like autoimmune diseases.
C3 and C4 are the commonly measured complement
components. The CH50 assay should not be perlbrmed rou
tinely because of cost and limited utility.
Autoantibody Tests
Rheumatologic diseases are commonly associated with
autoantibodies, but their presence does not equate with the
diagnosis ol an underlying condition because they lack speci
ficity and may be seen in patients with other conditions and in
healthy persons. In commercial laboratories, autoantibody
testing has been automated with enzyme-linked immuno-
sorbent assays in a sequential algorithm, which may simplify
physician assessment but tend to have reduced sensitivity and
specificity.
Rheumatoid lactor is an IgM antibody directed against the
Fc portion of IgG. Although characteristically associated with
RA. rheumatoid factor is present in less than 70'X, of patients
with RA and is common in several other diseases, such as bac-
terial endocarditis and hepatitis C vims infection' Anti cyclic
citrullinated peptide antibodies are more specific (95%) for RA
but less sensitive (67'7,). The presence of both autoantibodies
together increases the Iikelihood of RA. Patients with RA who
have anti cyclic citrullinated peptide antibodies are more
likely to experience rapid joint damage from erosive disease.
Patients with hepatitis C virus infection alone are typically
positive for rheumatoid factor but negative for anti-cyclic
citrullinated peptide antibodies.
Approach to the Patient With Rheumatologic Disease
Antinuclear antibodies (ANAs) are directed against
nuclear antigens and are traditionally associated with SLE. Up
to one third of the healthy population has a low titer (1:40) for
ANA, and up to 5'X, have a titer of 1:160 or more. ANA can also
be seen in other autoimmune conditions, infection, and
malignancy and may be drug induced. ANA testing should not
be performed in a patient with nonspecific symptoms and
normal findings on clinical examination because it does not
establish the diagnosis of a connective tissue disease.
A higher ANA titer is more often associated with an
underlying rheumatologic disease, although not always SLE.
However, almost all patients with SLE (>95'/") are positive for
ANA. ANA titer does not correlate with SLE disease activi!/
and should not be used fbr activity assessment.
ANA specificity or subserologz testing (i.e., testing for
antibodies to specific nuclear components, such as DNA or
centromeres) should be reserved for patients positive fbr ANA
and a clinical syndrome suggesting an underlying connective
tissue disease. ANA subserologr testing should not be rou
tinely performed, even in the setting of a positive ANA result,
without a strong clinical suspicion of an underlying connec
tive tissue disease.
Table 5 provides details on these and other autoantibodies
and their associations with specific conditions.
XEY POItrII
. Erythrocyte sedimentation rate and C-reactive protein
(CRP) levels usually follow a common pattern, but CRP
is often more rapidly responsive to changes in inflam-
mation.
o Antinuclear antibody testing should not be perfbrmed HVC
in patient with nonspecific symptoms and normal
a
findings on clinical examination because it does not
establish the diagnosis of a connective tissue disease.
. Antinuclear antibody (ANA) subserologr testing should HVC
not be routinely performed, even in the setting of a pos
itive ANA result, without strong clinical suspicion of an
underlying connective tissue disease.
lmaging Studies
Radiography
Radiography is essential in the evaluation of many rheuma
tologic diseases and can assess and differentiate inflamma
tory arthritis, osteoarthritis, and crystal arthropathies
(Table 6). Radiography has limitations because it gives a two
dimensional picture of three dimensional structures, is lim-
ited in its ability to visualize soft tissues, and may not detect
early or small erosive changes. Despite these limitations,
radiography is usually the first imaging test ordered in the
evaluation of rheumatologic diseases because it is readily
available, is inexpensive, exposes patients to only a low level
of ionizing radiation, and is useful in monitoring arthritis
progression.
5
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I

'l
1

Approach to the Patient With Rheumatologic Disease I

a

I
It
Autoantibody Rheumatologic Disease Sensitivity/Specificity Comments I

SLE: >95% sensitivity, Poor Does not correlate with disease activity
\I
ANA SLE; also SSc, Sjogren
syndrome, MCTD specificity; indirect IFA is the
most appropriate method i t

Anti-double-stranded SLE 507"- 60"/" se nsitivity, >9 5% Found in more severe disease, especially kidney
DNA specificity; Crithidia IFA or disease; antibody levels commonly follow disease I
Farr assays more specific
than ELISA
activity and are usefulto monitor l I

Most specific test for SLE; does not correlate

Anti-Smith SLE 30% sensitivity,99%
specificity with disease activity
I
Anti-U 1-RNP MCTD; SLE High sensitivity for MCTD High titer seen in MCTD (>1 :1 0,000); does not I
correlate with disease activity 1
I
Anti-Ro/SSA; Sjogren syndrome; SLE; Sjogren syndrome: 7095 Sicca symptoms; in SLE, associated with
anti-La/SSB RA; SSC sensitivity; SLE:20% photosensitive rash; offspring of mothers who
sensitivity are positive for anti-Ro/SSA or anti-La/SSB are at
)
increased risk for neonatal lupus erythematosus
t
(rash and congenital heart block) I

Antiribosomal P SLE 15% sensitivity Associated with CNS lupus and lupus hepatitis l
I
,,]

Anti-Scl-70 DcSSc 10%-30% sensitivity Seen more often in patients with DcSSc who have
(antitopoisomerase-1 ) ILD leading to pulmonary fibrosis ;
Anticentromere LcSSc (CREST) 10%-30% sensitivity Patients with LcSSc with this antibody are more
likely to develop pulmonary arterial hypertension

c-ANCA GPA 90% sensitivity when disease Correlation with disease activity is unclear
(antiproteinase-3) is active; high specificity in
classic presentations

p-ANCA MPA; EGPA MPA: 80% sensitivity; Atypical p-ANCA (antimyeloperoxidase

(antimyeloperoxidase) EGPA: 60% sensitivity; less negative) can be seen in inflammatory bowel I
specific than c-ANCA disease and with positivity for ANA; may be
seen in drug-induced vasculitis
Anti-Jo-1 Polymyositis 20%-30% sensitivity Associated with antisynthetase syndrome, which
may include mechanic! hands, Raynaud
phenomenon, and lung inflammation
Anti-SRP Polymyositis Found in 5% of patients with Associated with immune-mediated necrotizing
myositis myopathy with muscle fiber necrosis and
minimal inflammation on biopsy
Anti-Mi-2 Dermatomyositis Rare Acute onset of skin rash in shawl distribution,
usually responsive to treatment
Anti-TlF-1-1 Dermatomyositis Approximately 70% lncreased risk for malignancy; also seen in
sensitivity and 90% specificity juvenile dermatomyositis
Anti-MDA-5 Dermatomyositis Rare Associated with rapid lLD, cutaneous
ulcerations, Gottron papules; poorer prognosis
Rheumatoid factor RA; Sjogren syndrome; RA: 70% sensitivity; limited RF iscommon in multiple other diseases (e.9.,
cryoglobulinemia specificity, especially in hepatitis C virus infection, endocarditis, SLE);
patients without a classic 30% of patients with RA are RF negative but may
disease presentation become positive later in RA course
Anti-cyclic RA 70% sensitivity; Can be positive in RF-negative patients with RA;
citrullinated peptide 95% speciflcity often present before RF becomes positive;
associated with erosions; predicts disease
progression in undifferentiated arthritis
Antihistone DILE 95% sensitivity; poor Also seen in primary SLE
specificity
Cryoglobulins Vasculitis; hepatitis C Type ll or lll cryoglobulins May be present in connective tissue diseases in
virus infection; myeloma; seen in cryoglobulinemic the absence of vasculitis
SLE; RA vasculitis
ANA = antinuclear antibody; CNS = central nerous system; CREST = calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia; DcSSc = difuse
cutaneous systemic sclerosis; DILE = drug induced lupus erythematosus; EGPA = eosinophilic granulomatosis with polyangiitis; ELISA = enzyme-linked immunosorbent assay;

tissue diseasei MDA = melanoma diferentiation-associated; MPA = microscopic polyangiitis; RA = rheumatoid arthritis; RF = rheumatoid factor; RNp = ribonucleoprotein; SLE =
systemic lupus erythematosus; SRP = signal recognition particle; SSc = systemic sclerosis; TIF = transcription intermediary factor.

6
 Approach to the Patient With Rheumatologic Disease

TABLE 6. Standard Radiographic Findings of Common Rheumatologic Diseases

RheumatologicDisease RadiographicFindings
Rheumatoid arthritis
Osteoarthritis
Diffuse idiopathic skeletal
hyperostosis
Ankylosing spondylitis
Soft-tissue swelling and periarticular osteopenia early; bony marginal erosions and uniform joint-space
narrowing later
Swan neck deformity and ulnar deviation if unresponsive or untreated; MCB PIB wrist, and MTP involvement;
noncalcified soft-tissue nodules
Asymmetric joint space narrowing; osteophytes; subchondral sclerosis and cystic changes; degenerative
disk disease with collapse of disks; degenerative joint disease with facet joint osteophytes; spondylolisthesis
(anterior/posterior misalignment of the spine); kyphosis
Calcification (ossification)o{ anterior longitudinal ligament (bone spurs); bridging horizontal
syndesmophytes; usually seen in thoracic spine and more prominent on right side of spine
Sacroiliitis best seen on modified anteroposterior Ferguson view of sacrum on radiograph, usually
bilateral; squaring o{ the vertebral bodies in early disease; bridging vertical syndesmophytes (ossification
o{ annulus fibrosus) in later disease; shiny corners; ankylosis does not skip veftebrae

Psoriatic arthritis Destructive arthritis with erosions and osteophytes; DIP involvement is common; pencil-in-cup deformity
on hand radiograph; arthritis mutilans; syndesmophytes
Gout Soft-tissue swelling; punched-out erosions with sclerotic borders and overhanging edges; periarticular
tophi appear as high-density radiopaque deposits
Calcium pyrophosphate Chondrocalcinosis, most commonly of knees, shoulders, wrists, pubic symphysis; osteoarthritis, including
deposition in locations atypical for primary osteoarthritis (MCPs, wrists, shoulders); hooked osteophytes of second and
third MCP joints
DIP = distal interphalangeal; MCP = metacarpophalangeal; MTP = metatarsophalangeal; PIP = proximal interphalangeal.

CT
CT provides multiple views and orientations from a single
study but is more useful fbr bony abnormalities than for soft
tissue inflammation or fluid collections. CT is more sensitive
for detecting bone erosions than is radiography or MRI.
However, CT is more expensive than radiography and exposes
the patient to more radiation. It is mainly used in acute trauma
or when a patient cannot undergo MRl. Dual ener$/ CT may
be used to detect tissue urate deposits but is not indicated in
routine testing.
MRI
MRI is the most sensitive routine radiologic technique fbr
detecting soft tissue abnormalities, inflammation, and fluid
collections but is Iess eflective than CT in demonstrating bony
structures, and can provide real time data in the clinic with-
out exposure to ionizing radiation. It can assess soft tissue
abnormalities, including synovitis, tendonitis, bursitis, crystal
deposition, and effusions; assess disease activity using Doppler
technolory; and assist with tendon or joint injections.
Howeveq it is operator dependent, and training and practice
are needed to achieve competence.
t(tY P0t xTs
r Radiography is usually the first imaging test ordered in HVC
the evaluation of rheumatologic diseases because it is
readily available, is inexpensive, exposes patients to
only a low level of ionizing radiation, and is useful in
moniloring arthril is progression.
o CT is more sensitive for detecting bony abnormalities or HVC

abnormalities or erosions. MRI is sensitive for detecting early
spine and sacroiliac joint inflammation and may be indicated
for the evaluation of suspected spondyloarthritis ifradiographs
are negative. MRI is also indicated in the evaluation of osteo-
necrosis if the findings on plain imaging are normal and sus,
picion is high. MRI does not expose patients to radiation but is
associated with high cost, limited availability, and possible
patient intolerance due to claustrophobia or body habitus. The
American College of Rheumatolos/ Choosing Wisely list rec
ommends against routine MRI of the peripheral joints to mon-
itor RA because of inadequate data supporting its use.
Ultrasonography
The use of ultrasonography to evaluate patients with rheuma
tologic diseases has expanded dramatically. Ultrasonography is
relatively inexpensive, can scan across three-dimensional
erosions than is radiography or MRI, whereas MRI is the
most sensitive routine radiologic technique for detect
ing soft tissue abnormalities, inflammation, and fluid
collections.
o Ultrasonography is an inexpensive means to assess soft HVC
tissue abnormalities, assess disease activity, and assist
with tendon or joint injections, but it is operator
dependent.
Joint Aspiration
Joint aspiration and synovial fluid analysis are essential for
discriminating between inflammatory and noninflammatory
efTusions and for distinguishing between infectious arthritis
and acute crystal arthropathies. ln the evaluation of any
monoarthritis or when infection is being considered, joint

7
Principles of Therapeutics

TABTE 7. Synovial Fluid Analysis

Normal Noninflammatory lnflammatory Crystal-lnduced lnfectious Hemorrhagic
Appearance Clear/yellow/ Clear/yellow/ Yellow/white/ Yellow/white/ Yellow/white/ Red/opaque
transpa rent tra nspa rent translucenV tra nsl u ce nt/ opaq ue
opaque opaque
Leu kocyte <200/Stl(0.2x 200-2000/stL 2000-20,000/pL 1 0,000-50,000/pL >50,000/prL
cou nt 10e/L) (0.2 2.0 x 10e /L) (2.0-20 x 10e/l) (1050x1Oe/L) (50 x 1 Oell)
(may be higher) (may be higher) (may be lower)
Other studies Negative Gram Negative Gram Negative Gram Negative Gram Positive Gram Negative
stain; negative stain; negative stain; negative stain; positive stainb; positive Gram stain;
cu ltu re culture culture crystals" culture' negative
culture

blue when paralle to the axis and ye low when perpendicular.

stain sensitivity ior infection is approximately 30% to 50%.

all cultures are positive except for infection caused 6y Ndsseria gonorrhoeae, which may be posrtive in 507o or fewer cases.

aspiration should be performed to diagnose the underlying XEY POIl{TS

cause. Aspirated synovial fluid should be sent for leukocyte
. Synovial fluid leukocy.te counts greater than 50,000/pL
count. Gram stain, and cultures, as well as evaluation fbr crys-
(50 x 10e/L) with polymorphonuclear cell predomi
tals under polarized light. See Table 7 for more infbrmation.
nance have a high likelihood of infection; counts less
l'here is no absolute cutoff of synovial fluid leukocyte
than 2000/trrL (2.0 x 10'q/L) are usually associated with
counts for ruling out infectious arthritis; however. counts
noninflammatory causes.
greater than 50.000/gL (SO x 10e/L) with polymorphonuclear
cell predominance have a high tikelihood of inf'ection. Counts
. Tissue biopsy of involved organs can be helpful in diag-
less than 200019L (2.0 x 10e/t.) are usually associated with
nosing numerous rheumatologic conditions and in
assessing disease activity in some conditions.
noninflammatory causes. Notably, crystals can coexist with
inf'ection. and their presence does not rule out infection if
suspicion is high.

Pri nci ples of Therapeutics

Tissue Biopsy
When appropriate, tissue biopsy of involved organs can be
helpful in diagnosing numerous rheumatologic conditions.
such as vasculitis (lung, kidney, or temporal artery biopsy) and
SLE or dermatomyositis (skin biopsy). Tissue biopsy may also
help assess disease activity (e.g., kidney biopsy in SLE). The
Overuiew
This section reviews the indications for use. mechanisms ot'
action, major toxicities, and monitoring requirements of nredica
tions used in rheumatologic disease. Dmg applications in specific
disease states are elaboruted on in their respective sections.

benefits should be appropriately balanced with possible risks

of the procedure.
Mental Health Screening
Practitioners should be aware that patients with arthritis
experience mental distress and have :r history of depression at
higher rates than the general population. Concurrent depres
sion in chronic conditions, such as arthritis, is associated with
reduced adherence to medical treatment recommendations.
Among patients with rheumatoid arthritis, anxiety
depression are associated with reduced response to treatment
and poorer quality of life. Active screening for depression,
recommended lbr all adults, is therefore of still greater impor
tance in individuals with arthritis and may improve outcomes.
Actively engaging adults with arthritis in evidence based self-
management programs is helpful not only tbr arthritis but also
for reducing depression and improving self efficacy.
Anti-l nfla m matory Agents
Glucocorticoids
Clucocorticoids are eff'ective in many rheumatologic dise:rses,
including rheumatoid arthritis (RA), acute crystal arthropathy,
systemic vasculitis, polymyalgia rheumatica. systemic lupus
erythematosus, inflammatory myopathies, and autoinflam
matory diseases. Advantages include rapid onset, ease of use,
low cost, and universal availability; they are often disease
and modifzing and sometimes lifesaving.
Adverse eflects include osteoporosis, immunosuppression.
skin fragility, glaucoma, cataracts, weight gain. diabetes melli
tus. hypertension, psychomotor agitation, osteonecrosis. and
suppression of the hypothalamic pituitary adrenal axis. These
effects are more likely with higher doses and longer treatment.
The immunosuppressive adverse etfects of glucocorticoids
are apparent at moderate (prednisone at >20 mg/d) and high

8

doses but can also occur at lower doses (e.g., z.s mg/d for more
than a few weeks). The American College of Rheumatologr
(ACR) recommends that patients who are anticipated to be
receiving long term glucocorticoid treatment (prednisone at
>2.5 mg/d fbr >3 months) should have a baseline clinical risk
assessment for osteoporosis within 3 to 6 months of initiation
of therapy. Those with risk factors and those older than age
40 years should also undergo periodic bone mineral density
testing. Furthermore, those at moderate or high risk for osteo-
porotic fractures who are prescribed long-term glucocorticoid
therapy should be treated prophylactically with an antiresorp-
tive agent, preferably an oral bisphosphonate.
NSAIDS
NSAIDS prevent prostaglandin production by inhibiting the
two isofbrms of cyclooxygenase (COX): COX-1 and COX-2.
COX-2 is an inducible enzyme typically expressed in inflam
matory milieus, whereas COX 1 is constitutively expressed and
helps maintain organismal homeostasis. Nearly all available
COX inhibitors are nonselective (i.e., they inhibit both COX
isoforms), down regulating prostaglandin production in
inflammatory states, and interfering with functions of pros
tanoids (e.g., renal blood flow and gut mucosal integrity main
tenance) (Table 8). Nonselective COX inhibitors also inhibit
thromboxane Ar, thereby inhibiting platelet function.
Although they alleviate symptoms, COX inhibitors are not
modiffing, with the possible exception of ankylosing
disease
spondylitis. Major concerns surrounding all COX inhibitors
include increased risk lbr gastrointestinal bleeding and adverse
cardiovascular events; therefore, they should be prescribed at
the lowest dose fbr the shortest time possible. COX inhibitors
should generally be avoided in patients receiving concomitant
anticoagulation.
NSAIDs vary with regard to kinetics, COX-112 selectivity,
and other features, and they carry somewhat different degrees
oi cardiovascular and other risks; having experience with sev
eral different NSAIDs is beneficial in clinical practice.
A topical preparation of the NSAID diclofenac is available
both by prescription and over the counter fbr arthritis. It poses
a lower risk for systemic adverse effects compared with oral
NSAlDs. Topical NSAIDs are strongly recommended fbr
patients with knee osteoarthritis and conditionally recom
mended for patients with hand osteoarthritis. Topical
TABLE 8. Potential Toxicities of NSAID Use
Category Toxicity
Cardiovascular Myocardial infarction; exacerbation of heart failure
Hemostatic Platelet dysfunction
Gastrointestina I Dyspepsia; reflux; peptic ulcer disease; gastrointestinal bleeding
Obstetric/Gyn eco log ic Bleeding; delayed labor; premature ductus arteriosus closure
Pulmonary Asthma exacerbation
Renal Hypertension; decreased glomerular filtration; increased salt and water retention; increased renin produ
uncommonly, allergic interstitial nephritis or acute tubular necrosis
Principles of Therapeutics
diclofenac may also be prelerred fbr patients at high risk for
toxicity from oral NSAIDs or those 75 years of age or older.
Colchicine
Colchicine inhibits microtubules, impairs neutrophil func
tion. and inhibits inflammasome-mediated interleukin 1
activation. Inflammasome is a central signaling system that
regulates the inf'lammatory response. It is most commonly
used for gout and acute calcium pyrophosphate crystal arthri
tis (pseudogout). It is also a treatment for hypersensitivity
vasculitis and familial Mediterranean f'ever.
Gastrointestinal adverse eff'ects (particularly diarrhea) are
common but reversible with dose adjustment or discontinua
tion. With overdose, severe (even fatal) myelosuppression can
occur. Dosing must be adjusted fbr kidney disease. When
given over the long term, colchicine can rarely cause neuro
muscular toxicity, particularly if coadministered with strong
CYP3A4 inhibitors (e.9., clarithromycin) that reduce the
hepatic catabolism of colchicine. Such coadministration
should be avoided.
rtY P0rilTs
r Patients anticipated to be receiving long-term glucocorli
coid treatment (prednisone at >2.5 mg/d for >3 months)
should have a baseline clinical risk assessment for
osteoporosis within 3 to 6 months of initiation of
therapy.
. Because of the increased risk for gastrointestinal bleed
ing and adverse cardiovascular and renal events.
cyclooxygenase inhibitors should be prescribed at the
lowest dose for the shortest time possible.
Analgesics and Pain
Pathway Modulators
Pain is a central symptom for patients with inflammatory
arthritis and osteoarthritis. It is important to use a patient
centered approach while managing pain in these patients. ln
addition to pharmacologic interventions, treatment should
include patient education, guidance on physical activity and
exercise, orthotics, psychological and social interventions,
sleep hygiene education, and, il'indicated, sleep interventions.
9
Principles of Therapeutics
Acetaminophen
The efficacy of acetaminophen for osteoarthritis and lower
back pain has been questioned. Controlled trials and meta
analyses have shown no benefit from the drug, even at high
doses. Hor.never, because of its favorable safety profile, it may
be empirically tried fbr short-term or add on therapy. The
daily dosage should not exceed 3000 mg/d. ACR guidelines
conditionally recommend acetaminophen for patients with
knee, hip, or hand osteoarthritis and limited pharmacologic
options.
Tramadol
Tramadol is a mixed opioid analgesic and weak serotonin
norepinephrine reuptake inhibitor (SNRI) with a lower poten-
tial lor addiction than traditional opioids. It may be considered
in a limited number of patients for whom other methods of
analgesia were ineffective or not tolerated. Adverse efI'ects may
include nausea, vomiting, constipation. lightheadedness, and
sedation. Traditional opioids should generally be avoided in
rheumatologic treatment because of limited efficacy, high
toxicity, and high potential lbr dependence. See MKSAP 19
General Internal Medicine 1 fbr discussion of risk assessment
and monitoring of long term opioid therapy.
Serotonin-Norepineph rine Reu pta ke I n hi bitors
Duloxetine is an SNRI approved by the FDA fbr the manage
ment of chronic musculoskeletat pain and fibromyalgia.
Duloxetine provides modest pain relief for knee osteoarthritis,
chronic lower back pain. and fibromyalgia. Milnacipran
another SNRI approved for fibromyalgia. 'tb avoid withdrawal
symptoms, patients must be slowly weaned off SNRIs when
the drug is discontinued.
Gabapentinoids
Gabapentinoids (gabapentin and pregabalin) inhibit voltage
gated calcium channels. thereby reducing pain signaling from
the periphery to the central nervous system. Pregabalin is FDA
approved for fibromyalgia. Common adverse effects (dizziness,
disequilibrium, somnolence, weight gain. peripheral edema.
and cognitive difficulties) may limit its utility. The FDA has
issued a safety alert stating that serious breathing difficulties
may occur in patients using gabapentin or pregabalin who
have respiratory risk factors (e.g., older persons, patients with
COPD, and patients receiving opioids and other drugs that
depress the central nervous system).
I(EY POIilI5
. The American College of Rheumatologr conditionally
recommends acetaminophen for knee, hip, and hand
osteoarthritis.
o Traditional opioids should generally
be avoided in rheu-
matologic treatment because of limited efficacy, high
toxicity, and high potential for dependence.
10
Disease-Modifying
Antirheumatic Drugs
Nonbiologic Disease-Modifying
Antirheumatic Drugs
Table 9 summarizes the mechanisms of action, indications, and
common monitoring parameters of various nonbiologic disease
modi$zing antirheumatic drugs (DMARDs). See Medications and
Pregnancy tbr infbrmation on these drugs in pregnancy.
Methotrexate
Methotrexate is a first-line medication for RA and other auto
immune diseases. Once weekly dosing is generally 10 to
25 mg; the drug can be given orally or subcutaneously. At doses
above 15 mg, parenteral administration is more reliable but
much more expensive.
Potential adverse effects include headaches, latigue, and
nausea (particularly around the time of weekly dosing).
Hepatotoxicity and cytopenia can occur (especially macro
cytic anemia), and dose adjustment is required with kidney
disease. Methotrexate should be avoided in patients lvith sig
nificant hepatic or kidney disease and is absolutely contrain-
dicated around pregnanc),. Folic acid supplements minimize
toxicity while preserving efficacy. Limiting alcohol intake is
recommended.
Hydroxychloroquine
Hydroxychloroquine is an immunomodulator widely used in
systemic lupus erythematosus, in which it decreases mortality
is and the likelihood olnephritis. It is rarely sufficient as single
drug therapy fbr RA but is useful as an adjunctive therapy.
Sulfasalazine
Sulfasalazine is used to treat RA and nonaxial psoriatic arthri
tis. It is now most frequently used as part of combination
DMARD therapy fbr RA. Serious adverse effects include blood
dyscrasias, hepatitis, and hypersensitivity reactions. Because
ol the benefit of its salicylate moiety for inflammatory bowel
disease, it may be a useful strategr lbr patients with inflamma
tory bowel disease-associated arthritis.
Leflunomide
Leflunomide is FDA approved for RA and psoriatic arthritis,
with eflicacy similar to that ol methotrexate. Patients must be
monitored for hepatotoxicity and myelosuppression. Other
common adverse effects include nausea, headaches, rash. diar
rhea, and elevation o1'serum aminotransferase levels. Peripheral
neuropathy is an uncommon adverse effect that is usually self'
limited if the drug is discontinued. Leflunomide is highly tera
togenic and absolutely cclntraindicated around pregnancy.
Azathioprine
Azathioprine is an immunosuppressant used in various inflam
matory diseases. Its primary toxicity is myelosuppression,
especially in individuals with a decreased or absent thiopurine

TABLE 9. Nonbiologic Disease-ModifyingAntirheumatic
Agent Mechanisms of Action
Methotrexate Low dose: anti-inflammatory agent via
up-regulation of adenosine A2a signaling
High dose: antimetabolite/{olate
antagonist used in neoplastic disease
Hydroxych loroquine Uncertain; appears to involve
stabilization of lysosomal vacuoles,
leading to inhibition of antigen
processing and/or inhibition of Toll-like
receptor activation
Sulfasalazine Unknown; the prodrug is broken down
into 5-amino salicylic acid (active
metabolite in gastrointestinal tract) and
sulfapyridine (exerts systemic action)
Leflunomide lnhibits mitochondrial enzyme
dihydroorotate dehyd rogenase to block
pyrimidine synthesis (decreasing
lymphocyte prod uction); antiproliferative
Azathioprine Prodrug of 6-mercaptopurine; purine
analogue; inhibits DNA synthesis
essential for proliferating T and B
lymphocytes
Cyclophosphamide Alkylating agent; blocks DNA synthesis
and causes cell death, especially of
T cells
Mycophenolate Active metabolite (mycophenolic acid)
mofetil inhibits purine synthesis; preferentially
inhibits T and B lymphocytes
Cyclosporine, lnhibit calcineurin (transcription
voclosporin activating factor); preferentially target
T cells
Tofacitinib, Janus kinase inhibitors
baricitinib,
upadacitinib
Apremilast Phosphodiesterase-4 in hibitor
CBC=complerebloodcount; DM=dermatomyositis; IBD=in{lammatorybowel
lupus erythematosus; SpA = spondyloarthritis; SSc = systemic sclerosis.
methyltransferase enzyme. Because azathioprine is metabo-
lized by xanthine oxidase, concomitant use with xanthine
oxidase inhibitors (allopurinol, febuxostat) is contraindicated.
Cyclophosphamide
Cyclophosphamide has a rapid onset of action (days to weeks).
It is used to treat vasculitis, life threatening complications of
systemic lupus erythematosus, and interstitial lung disease.
Principles of Therapeutics
Drugs
lndications Common Monitoring Parameters
RA; psoriasis; psoriatic Baseline: chest radiography, hepatitis
arthritis; IBD; SLE screening, CBC, LCTs, serum creatinine
(arthritis only); reactive
Thereafter: CBC, LCTs, serum creatinine
arthritis; DM; PM;
after first month, then approximately
vasculitis
every 2-3 months"
SLE; RA Baseline: CBC, LCTs, serum creatinine
Retinal examinations at baseline and
annual examination after 5 years of
therapy to evaluate for retinopathy
RA; SpA; IBD Baseline: CBC, LCTs, serum creatinine
Thereafter: CBC, LCTs, serum creatinine
every 3-6 months
RA; psoriatic arth ritis Baseline: hepatitis screening, CBC, LCTs,
serum creatinine
Thereafter: CBC, LCTs, serum creatinine
after 4 weeks, then every 3 months
SLE; DM; PM; Baseline: CBC, LCTs, serum creatinine
vasculitis; IBD
Thereafter: CBC, LCTs, serum creatinine
every 3 monthsu
Severe and life- Close monitoring clinically and
threatening measuring CBC, chemistries, LCTs,
complications in SLE, urinalysis every 4-8 weeks
DM, PM, and vasculitis;
may be used when
other agents fail
SLE (especially lupus Baseline: CBC, LCTs, serum creatinine
nephritis); vasculitis
(maintenance Thereafter: CBC, LCTs, serum creatinine
after 4 weeks and then every 3 monthsa
therapy); DM; PM; SSc
SLE; psoriasis; RA Baseline: CBC, LCTs, serum creatinine
(cyclosporine)
Thereafter: CBC, LCTs, serum creatinine
Lupus nephritis every 2-3 months"
(voclosporin)
RA (tofacitinib, Baseline: CBC, LCTs, serum creatinine,
baricitinib, lipid panel
upadacitinib)
Thereafter: CBC, LCTs, serum creatinine
Psoriatic arthritis every 8 weeks, lipids after 8 weeks and
(tofacitinib) then every 6 months
Psoriasis; psoriatic Baseline: weight
arthritis; oral ulcers
Thereafter: weight, neuropsychiatric
associated with
effects
Behget syndrome
disease; LCT=liverchemistrytest; PM=polymyositis; RA=rheumatoidarthritis; SLE=systemic
Cyclophosphamide has largely been displaced by safer drugs
for first line treatment of ANCA-associated vasculitis and
lupus nephritis (rituximab and mycophenolate mofetil,
respectively) but is still used in severe cases or when these
agents fail. Serious potential adverse effects include severe
immunosuppression, leukopenia, hemorrhagic cystitis, and
ovarian failure, as well as long-term risk for bladder cancer,
leukemia, and lymphoma.
11
Principles of Therapeutics

Mycophenolate Mofetil Apremilast

Mycophenolate mofetil is the first-line agent for lupus nephri-
tis and may be effective for systemic sclerosis with associated
interstitial lung disease. Gastrointestinal adverse effects,
including diarrhea, are common. Myelosuppression may
occur.
Calcineurin Inhibitors
Calcineurin inhibitors include cyclosporine, tacrolimus, and
voclosporin. Cyclosporine is now rarely used for rheumato
logic conditions because of renal adverse effects, hyperten
sion, hyperuricemia (often presenting as gout), and need for
frequent drug level monitoring. Tacrolimus may be considered
as alternative therapy for some patients with lupus nephritis.
Voclosporin, a next generation calcineurin inhibitor with
higher potency and improved side effect profile, is FDA
approved for lupus nephritis.
Janus Kinase Inhibitors
Tofacitinib is an oral agent that inhibits Janus kinase (JAK)
1/3 signaling. Tolacitinib is FDA appro'"ed for RA and psori
atic arthritis, with efTicacy equal to that of biologic DMARDs.
Risks include hyperlipidemia, hepatotoxicity, leukopenia,
reactivation of zoster (at a rate higher than seen with bio-
logic therapies), and thrombotic events when used at higher
doses. Newer JAK inhibitors approved for rheumatologic
diseases include baricitinib (JAKI/2) and upadacitinib
(JAK1).
Apremilast is modestly elfective for psoriasis and psoriatic
arthritis. It does not cause immunosuppression or myelosup
pression. However, apremilast is less efficacious than biologic
DMARDs and has a slow onset of action, and its effect on pro
gression of erosive damage is unknown. Risks include gastro
intestinal adverse effects (mainly nausea and diarrhea) and
weight loss. It should be used with caution in patients with a
history of depression. Apremilast is also FDA approved for
treatment of oral ulcers in Behget syndrome.
TEY POIl{IT
. Methotrexate is a first-line medication for rheumatoid
arthritis and other autoimmune diseases.
. Hydroxychloroquine decreases mortality and the likeli-
hood of developing nephritis in patients with systemic
lupus erythematosus.
r Cyclophosphamide is used in severe cases of vasculitis
and lupus nephritis or when other agents fail.
o The oral Janus kinase inhibitor tofacitinib is FDA
approved for rheumatoid arthritis and psoriatic arthritis
and has efficacy equal to that ofbiologic agents.
Biologic Disease-Modifying Antirheumatic Drugs
Biologic DMARDs are highly specitic, parenterally adminis
tered, protein based agents with extracellular targets (cytokines,
cytokine receptors, or cell surface molecules on immune cells)
(Flgure 1). The end of the generic name of a biologic agent

Anakinra
Macrophage

Dendritic cell
Neutrophil z'Ji-:',ii,"' tL-1

proteases

tL-6

k/'INF-a rilumab
T cell
Cartilage MMPs
Synovial Tocacitini f-Abatacept
Baricitinib
Upadacitinib
Bone
B cell
MMPs
TNF Rituximab
Osteoclast
T
lnf liximab RF,
\
anti-CCP
Etanercept anti bod ies
Adalimumab
Golimumab
Certilizumab
tIGURE l.Thein{lammatorycascadeinrheumatoidarthritis(RA).Dendriticcells,macrophages,andBcellspresentincitingantigenstoTcells.Macrophagessecrete

and other enzymes that contribute to the degradation of articular cartilage and activate neutrophils, which mediate joint damage through proteases and other enzymes.
Activated osteoclasts additionally secrete MMPs that contribute to marginal erosions of bone. lLs, TNF, T cells, and B cells may all be targeted for inhibition by the various
disease-modifying antirheumatic drugs useful in RA. CCP = cyclic citrullinated peptide; lL= interleukin; LTB4 = leukotriene Ba; MMP = matrix metalloproteinase; 02 = oxygen;
PG E2 = prostag la ndi n Ez; RF = rheu matoid factor; IN F = tu mor necrosis factor.

12

TABLE 1O. Tumor Necrosis Factor lnhibitors"
Agent Agent Structure
lnflixima Er Chimeric (mouse-human) monoclonal antibody
Adalimumab Humanized monoclonal antibody
Etanercept Fusion protein made of two p75 TNF receptors linked to
lgG Fc segment
Certolizumab pegol Fab'segment of humanized monoclonal antibody
attached to polyethylene glycol strands
Golimumab Humanized monoclonal antibody
IBD = inf ammatory bowel d sease; RA = rheumatord arthr t s; TNF - tumor necrosis factor.
at baseline and every 3 to 6 months thereafter.
indicates what type of molecule it is: mcrb indicates a monoclo-
nal antibody, -kin indicates an interleukin |lpe substance. ro
is for a receptor antagonist, and .cept is for receptor based
molecule. A11 biologics require parenteral administration.
Table l0 and Table 11 summarize the structures. targets.
indications, and common monitoring parameters of various
biologic DN4ARDs. See Medications and Pregnancy fbr inlor
mation on these drugs in pregnancy. Biologic DMARDs increase
the risk fbr infection to varying degrees. Targeted screening is
therefore necessary before initiation (see Vaccination and
Screening in Immunosuppression).
The cost of biologic agents is significant and may be a bar
rier to access.
Tumor Necrosis Factor Inhibitors
Tumor necrosis factor (TNF) inhibitors (see Table 10) are
widely used for treating RA. psoriasis. psoriatic arthritis, and
ankylosing spondylitis, as well as several nonrheumatologic
diseases.
TNF inhibitors are generally well tolerated; increased risk
for infection is the primary safety concern. Because TNF
inhibitors pose a particul:rrly high risk for reactivation of
tuberculosis, all patients being considered for treatment must
be screened for latent infection and, if needed, receive treat
ment. Except for nonmelanoma skin cancer and possibly mel
anoma, l'NF inhibitors do not appear to increase the risk for
new cancers; the risk for malignant recurrence remains
unclear. TNF inhibitors may exacerbate heart failure and rarely
provoke a demyelinating condition. Over time, individual TNF
inhibitors may lose efficacy owing to fbrmation of antidrug
antibodies.
Other Biologic Disease-Modiffing Antirheumatic Drugs
Multiple biologic DMARDs with non TNF extracellular and
cell surface targets have been approved by the FDA. Most of
these agents are started after one or two TNF inhibitors have
tailed. See Table 11 for more information.
Biosimilars
Biosimilar agents are "copycat" versions of brand name bio
logic medications. The drugs are not exact replicas (hence the
Principles of Therapeutics
lndications
RA; psoriatic arthritis; ankylosing spondylitis; IBD
RA; psoriatic arthritis; ankylosing spondylitis; IBD
RA; psoriatic arthritis; ankylosing spondylitis
RA; psoriatic arthritis; ankylosing spondylitis
RA; psoriatic arthritis; ankylosing spondylitis
term "biosimilar"); therefbre, they must undergo phase III
testing to prove equivalent efficacy to the parent biologic. In
the United States, biosimilars are distinguished from their
originator molecules by the presence of a four character
alphabetic suffix. Biosimilars hoid promise lbr decreasing cost
and improving access, but those benelits have rarely been real
ized because of regulatory and market factors.
r(tY P0 t llTs
. All biologic agents increase the risk for infection; there
fore, targeted screening is necessary before initiation.
. Tumor necrosis factor inhibitors pose a particularly
high risk for reactivation of tuberculosis, and patients
must be screened for latent infection befbre initiation of
therapy.
. Biologic agents that are not directed at tumor necrosis HVC
factor (TNF) are usually started after one or two TNF
inhibitors have failed.
U rate-Loweri n g TheraPY
Allopurinol
Allopurinol is the recommended tjrst line urate lon'ering
agent. lt competitively inhibits the enzyme xanthine oxidase,
blocking the conversion of hypoxanthine (a breakdown prod
uct of purines) to uric acid. Allopurinol is metabolized kr oxy-
purinol, which also inhibits xanthine oxidase. Allopurinol is
FDA approved fbr dosages up to 800 mg/d. Allopurinol should
be initiated at 100 mg/d and titrated in 100 mg increments
until the therapeutic target is achieved. For patients with stage
chronic kidney disease, allopurinol should be initiated at
4 or 5
50 mg/d and titrated in 50 to 100 mg increments as needed.
Allopurinol use is rarely associated with a hypersensitivity
syndrome, most severely as DRESS (drug reaction with eosino-
philia and systemic symptoms), a potentially latal reaction'
DRESS is also increasingly being reterred to as drug induced
hypersensitiuity syndrome (DIHS) to emphasize the lact that
eosinophilia is not always present. Risk factors include chronic
kidney disease and diuretic use; allopurinol dosage titration
appears to substantially reduce the risk. Anclther DRESS risk
13
 a

t
I

Principles of Therapeutics !
!

t
I

I
1

Agent Agent Structure Target lndications Comments I

I I

Abatacept Soluble CTLA4 receptor/lgG CD8O/CD86; RA Preferred for patients with history of
Fc segment chimera blocks T-cell severe i n{ection; relatively !
costimulation contraindicated in COPD 1

Rituximab Chimeric (mouse-human) CD20* B cells RA; ANCA-associated Given as intravenous infusion over l
i

monoclonal antibody vasculitis; occasionally several hours; has higher risk for infusion I

I
for SLE (off-label); reactions than other biologic DMARDs;
lgG4-related disease can cause hypogammaglobulinemia

Tocilizumab Humanized monoclonal lL-6 receptor RA; JIA; Castleman Can cause elevated aminotransferase I

antibody disease; GCA levels, hyperlipidemia, leukopenia,

thrombocytopenia; avoid in patients
with history of diverticulitis because of I
attendant risk for bowel perforation
Sarilumab Human monoclonal antibody lL-6 receptor RA Can cause elevated aminotransferase
levels, hyperlipidemia, leukopenia,
throm bocytopenia

Belimumab Human monoclonal antibody BLyS/BAFF SLE; lupus nephritis Phase llltrials showed small but
statistical ly significant im provement
versus standard therapy alone, with
glucocorticoid-sparing effect
Ustekinumab Humanmonoclonalantibody tL-12/lL-23 Psoriasis; psoriatic lnjectable; less robust effect than other
a rth ritis biologic DMARDs
Secukinumab Humanmonoclonalantibody lL-17 a Psoriatic arthritis; Phase lll trials suggest efficacy egual to
ankylosing spondylitis that of TNF inhibitors; can cause IBD
flares

lxekizumab Humanized monoclonal lL-17 a Psoriatic arthritis; Phase lll trials suggest efficacy equal to
antibody ankylosing spondylitis that of TNF inhibitors; can cause IBD
flares

Guselkumab Human monoclonal antibody lL-23 Psoriasis; psoriatic Selective lL-23 inhibitor
afthritis
Anakinra Recombinant receptor lL-1 B receptor RA; CAPSb; AOSD(off Rarely used in RA because efficary is
antagonist label); acute gouty inferior to that of other biologic DMARDs;
arthritis (off-label) reversible neutropenia can develop

Canakinumab Human monoclonal antibody rL-1 p CAPSb More expensive lL-1p inhibitor
Ri lonacept Dual lL-1B receptors chimerically tL-1 CAPSb; refractory More expensive lL-1 inhibitor
attached to lgG Fc segment gout
Mepolizumab Humanized monoclonal tL-5 EGPA; eosinophilic Only biologic approved fortreatment of
antibody asthma EGPA

arthritis; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; TNF = tumor necrosis factor.

'Before initiation of any biologic, tuberculosis screening must be performed. Complete blood counts should be performed every 3 to 6 months for all biologics, and aspartate
aminotransferase/alanine aminotransferase and a lipid panel should be checked every 2 to 3 months for tocilizumab.
blhe cropyrin-associated periodic syndromes (CAPS) include familial cold autoin{lammator syndrome, Muckle-Wells syndrome, and neonatal-onset multisystem inflammator
disease (chronic infantile neurologic, cutaneous, articular syndrome).

factor is the HLA-B'58:01 allele, which is more common in
Black persons and persons of Han Chinese, Thai, and Korean
descent and increases the risk for hypersensitivity by several
hundred-fold. Screening for HLA 8'58:01 in these populations
is conditionally recommended before initiation of allopurinol.
Xanthine oxidase inhibitors should not be coadministered with
purine analogues (such as azathioprine). See MKSAP 19 General
Internal Medicine 2 for more information on DRESS.
Febuxostat
Febuxostat is a noncompetitive xanthine oxidase inhibitor.
Elevated aminotransferase levels can rarely occur, and liver
enzymes should be monitored. Concomitant use with purine
analogues is contraindicated. Incidence of hypersensitivity is
rarer and usually less severe than with allopurinol. In a 2018
safety study, febuxostat users had an increased risk for cardio
vascular death and all-cause mortality compared with patients
receiving allopurinol. These data do not define febuxostat
as raising risk compared with no treatment, and other studies
have failed to support this observation; however, the results
prompted the FDA to mandate a boxed warning for febuxostat
regarding increased risk compared with allopurinol. The FDA
has also limited the approved use of febuxostat to patients who
are unresponsive to or cannot tolerate allopurinol.

14

Uricosuric Agents
Probenecid is an organic acid transport inhibitor that decreases
renal reuptake of uric acid. It is uncornmonly used because of
limited eflficacy, inconvenience, and limitations on use (e.g.,
drug interactions and adverse effects).
Pegloticase
Unlike most other mammals, humans lack a functioning
uricase to break down uric acid. Pegloticase is a recombinant,
nonhuman, infusible pegzlated uricase that is highly efl'ective
at lowering serum urate. Pegloticase is reserved fbr severe
and/or refractory gout. Because of its extreme potency, mobi
lization flares of gout are common, and prophytaxis against
acute gouty attacks is required. Pegloticase is administered
intravenously every 2 weeks; if the preinfusion serum urate
increases to more than 6.0 mg/dl (0.35 nrnroll[-) on two occa
sions, antibodies have probably formed. and the drug should
be discontinued to prevent infusion reactions.
I(EY POIilIS
. Allopurinol is the first line urate-lowering agent; the
biggest risk the drug poses is DRESS (drug reaction
with eosinophilia and systemic symptoms).
o Concomitant use of xanthine oxidase inhibitors (allo
purinol or febuxostat) with purine analogues is contra-
indicated.
Medications and Pregnancy
Some rheumatologic medications can have adverse effects
on pregnancy. Table 12 lists these agents and tl.reir relative
risks.
I(EY PO IilIS
o Methotrexate is highly teratogenic and abortifacient; it
must be discontinued at least 3 months before pregnancy.
. Hydroxychloroquine is relatively safe in pregnancy and
should not be discontinued ifit is needed.
r Leflunomide is extremely teratogenic and must not be
used before or during pregnancy; upon discontinuation,
cholestyramine is required to remove the drug fiom the
body in all women of childbearing potential and specifi-
cally in those wishing to become pregnant.
Vaccination and Screening in
lmmunosuppression
Patients with autoimmune diseases should be assessed fbr
immunization status at diagnosis and/or initiation ol treat
ments. Whenever possible, patients should be updated with
vaccinations at least 2 to 4 weeks before initiating biologic
DMARD regimens. Vaccine response may be diminished
during biologic immunosuppressive treatment (particularly
with B-cell depleting therapy). and patients receiving biologic
Principles of Therapeutics
DMARDs and/or JAK inhibitors, such as tofacitinib, should not
receive live attenuated vaccines (e.g., for measles. mumps and
rubella; varicella herpes zoster; influenza; and yellor,r, fever)
because of risk fbr active inf'ection. Such patients can receive
the killed influenza and pneumococcal vaccines, as rtell as
recombinant herpes zoster vaccine as needed. Other non live
vaccines that are indicated should be administered as per
standard care (see MKSAP 19 General lnternal N4edicine 2 lbr
more information). Patients receiving traditional oral DMARDs
(e.g., hldroxychloroquine, methotrexate, and sulfasalazine)
may receive any vaccines as needed.
Before initiation ot immunosuppressive therapy, the fbl
lowing screening is recommended:
o Tuberculosis screening with tuberculin skin testing or
interferon y release assay, particularly for patients initiat
ing biologic DMARDs
. Hepatitis B and C virus serologic testing (for patients initi
ating biologic DMARDs and drugs that can cause hepato
toxicity)
o HIV screening
Patients with latent or active tuberculosis, active hepatitis
B virus infection, or untreated HIV infection require initiation
of appropriate therapy befbre initiating immunosuppression.
Patients with risk firctors fbr ongoing tuberculosis exposure
should have annual tuberculosis screening.
KtY POIlITS
o Whenever possible, vaccinations should be updated
before initiating biologic disease modifying antirheu-
matic drug regimens.
o Screening (and therapy ifneeded) for tuberculosis,
hepatitis B and C virus, and HIV is appropriate before
initiation of immunosuppressive therapy.
Nonpharmacologic and
Nontraditional Management
Because rheumatologic diseases fiequently aflect the muscu
loskeletal system. nonpharmacologic measures are ofter.r
used to address pain not eliminirted by medications. 'fhese
measures include physical therapy, occupational therapy.
surgery, weight reductior.r, psychosocial support, and self
management programs. Many patients turn to complemen
tary and alternative medicine as adjuncts to traditional
medical interventions.
Physical and Occupational Therapy
Physical therapists can help primary care physicians assess
aerobic fitness and conditioning as well as ability to carry out
activities of daily livir.rg. Pain and lunctional limitation can be
addressed through manual therapy, assistive devices, joint
protection techniques, irnd therntal treatments. A targeted
exercise program can be initiated, and adapting the program
15
Principles of Therapeutics

TABLE 12. Rheumatologic Medications and Pregnancy

Medication/Class Comments
Anti-l nflammatory Agents
NSAIDs May impede implantation and be associated with small increased risk for miscarriage when used before
20 weeks' gestation. NSAID use after 30 weeks' gestation can lead to premature closure of ductus arteriosus.

G lucocorticoids Whentakeninfirsttrimester,canincreaseriskforfetalcleftpalateandraiseriskformaternalgestational
diabetes throughout the pregnancy.
Useful in managing active autoimmune disease in pregnancy. Nonfluorinated glucocorticoids (e.9.,
prednisone, prednisolone, methylprednisolone) have limited ability to cross placenta and are preferred,
except when treating the fetus (e.g., neonatal lupus erythematosus).
Colchicine Should be used only i{ I benefit justifies potential risk to fetus.
Analgesics and Pain Pathway Modulators
Acetaminophen Generally considered safe at standard dosing but does cross the placenta.
Opiates Some opiates/opioids cross placenta; may cause fetal opioid withdrawal at birth.
Tramadol Should be used only if potential benefit justifies potential risk to fetus; postmarketing reports suggest
possibility of neonatal seizures, withdrawal syndrome, and stillbirth.
Topical agents Topical use may limit serum levels; individual agents should be reviewed {or pregnancy impact before use
Nonbiologic DMARDs
Methotrexate Highly teratogenic and abortifacient; must be discontinued at least 3 months before pregnancy.
Hyd roxych loroquine Relatively safe in pregnancy and should not be discontinued if it is needed.

Sulfasalazine Relatively safe during pregnancy.

Leflunomide Extremely teratogenic; must not be used before/during pregnancy; upon discontinuation, cholestyramine
administration is required to remove drug from the body in all women of childbearing potential and
specifically in those wishing to become pregnanU should be followed up with measurement of le{lunomide
and its metabolite levels to ensure removal of drug.
Azathioprine Routine use in pregnancy is not recommended; however, azathioprine may be safer than some other
DMARDs and may be used if immunosuppressive agent is imperative.
Cyclophospha m ide Not used in pregnancy unless absolutely necessary.
Mycophenolate mofetil Teratogenic; should not be used in pregnancy; discontinue for 3 months before pregnancy is attempted.
Cyclosporine May be used in pregnancy only if benefits outweigh risks.
Tofaciti ni b; baricitinib; May be teratogenic at high doses.
U citin ib
Biologic DMARDs
TNF inhibitors Accumulating retrospective data suggest low risk in pregnancy, but evidence is limited; can be continued if
absolutely needed; different agents may have different considerations regarding crossing placenta.
Ustekinumab; anakinra; Should be used only if potential benefit justifies undefined risk to fetus.
secukinumab; sarilumab;
ixekizumab; guselkumab
Abatacept; belimumab; Should be used only if potential benefit justifies potential risk to fetus.
canakinumab; rilonacept;
rituxi mab; tocilizumab

Urate-Lowering Therapy (rarely needed in premenopausal women)

Allopurinol Should be used only if potential benefit justifies potential risk to fetus.
Fe bu xostat Should be used only if potential benefit justifies potential risk to fetus.
Probenecid No current evidence for adverse impact on pregnancy.
Peg loticase Should be used only if potential benefit justifies potential risk to fetus.

Dl\,4ARD = d sease mod fying antirheumatlc drug; TNF = tumor necrosis factor
t

for home use is critical. Physical therapy ref'erral is appropriate Occupational therapists assess upper extremity function
for tendinitis; bursitis: many forms of arthritis; and chronic ing, including the ability to perform self care and job related
soft tissue pain due to overuse, injury and chronic pain syn tasks. Braces and splints may be provided for painful or unsta
dromes (e.g.. fibromyalgia). ble joints. An ergonomic evaluation of the workstation may

16

accompany instruction in improved body mechanics and
avoidance of repetitir,,e trauma.
Complementary and Alternative Medicine
Nontraditionai options for symptom management are used by
about one third of patients overall and up to 90'l. of patients
with chronic pain, including arthritis and rheumatologic dis
eases. Commonly used over the counter supplements include
fish oil. vitamins, glucosamine, and chondroitin. Providers
should ask about supplement use because patients rarely vol-
unteer this information. Significant drug interactions may
occur! for example, some herbal preparations can interact
with anticoagulants. See MKSAP 19 General Internal Medicine
1 for discussion of cannabis for pain management.
1\4ind body interuentions, such as tai chi, meditation, and
yoga, can improve psychological well being, strength, balance,
and pain level. Chiropractic and osteopathic manipulation as
well as massage remain popular. Randomized controlled trials
support the use of tai chi for arthritis; smaller trials suggest
benefit from meditation techniques, yoga, massage, acupunc
ture, and manipulative medicine for various musculoskeletal
problems.
Role of Surgery
Surgical procedures, such as carpal tunnel release or rotator
cuff tendon repair, can address conditions that arise from
repetitive trauma, injury and degenerative changes in the soft
tissue. Synovectomy of inflammatory pannus is occasionally
used when a single or limited number ofjoints in patients with
RA do not respond to medications. Total joint arthroplasty,
particularly of the knee or hip, can reduce or eliminate pain
and restore function in patients with an inadequate response
to medication and physical or occupational therapy.
rEY POITI
. dysbiosis has been postulated to promote early RA, possibly by
Nonpharmacologic measures used in rheumatologic
diseases include physical or occupational therapy,
surgery weight reduction, psychosocial support, and
self management programs.
Rheumatoid Arthritis
Pathophysiology and Risk Factors
Rheumatoid arthritis (RA) is a systemic autoimmune disease
characterized by chronic inflammatory polyarlhritis affecting
both large and small joints, with a characteristic predilection
for the joints of the hands and feet. RA has a prevalence of
0.5u1, to 1'2, in the general population; some specific popula-
tions have rates as high as 77,.
Genetic Factors
Genes are responsiblelbr 60'/. of the risk for RA. Among some
100 genetic loci recognized as associated with RA risk, the
Rheumatoid Arthritis
most important is the class II HLA group, especially HLA D
alleles. These risk alleles code for the shared epitope, a flve
amino acid sequence that preferentially binds and presents
citrullinated peptide antigens important in the pathophysiol-
ogr of RA. Citrullinated proteins are immunogenic, especially
in people who have the shared epitope.
Citrulline is not a native amino acid in humans; instead,
it is formed by the action of the enzyme peptidylarginine
deiminase (PADI), which deiminates arginine to form citrul-
linated peptides. PADI expression is typically limited to sites of
inflammation and may therefore provide a link between early
inflammation and subsequent autoimmunity. Many of the
other genes associated with RA modiflz immune responses to
provide a milieu for the development of autoantibodies.
Environmental Factors
Environmental factors are responsible for the other,l0% of the
risk for RA. One of the most provocative environmental factors
is smoking. Smoking can lead to lung inflammation, which
activates enzymes (including PADI), and may promote local
protein citrullination. Patients who smoke are at increased
risk for RA, particularly those with a family history of RA, and
should be counseled about smoking cessation. Exposure to
silica dust has also been associated with increased risk.
lnfectious Agents
One potential risk factor for RA is periodontal disease.
Porphyromonos gingiuolis, a bacterium associated with peri
odontitis, expresses its own PADI enzyme and provides a
potential link to formation of citrullinated peptide. Other
infectious agents implicated in RA include Mycoplasma spe-
cies, Epstein Barr virus, and parvovirus B19. However, a direct
infectious cause of RA has not been identified. There is also
interest in the role of the intestinal microbiome in RA. Gut
activating proinfl ammatory lymphocytes.
Hormones
Women are tvvo to three times as likely as men to develop RA.
The role of estrogen and other sex-specific factors is incom-
pletely understood, and estrogen and other sex hormones have
both stimulatory and inhibitory effects on the immune sys
tem. Estrogen receptors are present on synovial fibroblasts and
may drive the production of carlilage-damaging metallopro-
teinases. Stimulation of estrogen receptors on macrophages
can increase production of tumor necrosis factor, a key RA
inflammatory cytokine.
t( EY P0 t t{Ts
o Potential risk factors for rheumatoid arthritis include
genetic and environmental factors, infectious agents,
and hormones; genes make up 60% of the risk.
. Smoking is an important and modifiable risk factor for
rheumatoid arthritis.
17
 ;

I
Rheumatoid Arthritis

Another sign of early RA is the inability to make a fist, which

TABLE 13. 2010 American College of Rheumatology/ \
European League Against Rheumatism Classification Criteria is due to flexor tenosynovitis.
for Rheumatoid Arthritis The pattern of joint involvement is useful for diagnosing
Criteria 5core" RA. RA most characteristically affects the metacarpophalan .

geal joints, metatarsophalangeal joints, and proximal inter-

Joint lnvolvementb
phalangeal joints of the hands and feet but spares the distal
:

1 large joint (shoulders, elbows, hips, knees, ankles) U

interphalangeal joints of both the upper and lower extremities r
2-10 large joints 1
(Figure 2 and Figure 3). Wrists, elbows, shoulders, hips, knees, :
1-3 smalljoints (MCPs, PlPs, wrists, 2-5 MTPs) 2 and ankles also can be involved. RA tends to affect joints sym-
metrically (i.e., joints on both sides of the body are generally
!

4-10 smalljoints 3

>10 smalljoints 5 involved), but severity may be asymmetric. RA may occasion

ally present as persistent involvement in a single joint. RA
Serology
spares the thoracic and lumbar spine but affects the cervical :
Negativity for RF or anti-CCP antibodies 0
spine, especially the C1-C2 (atlantoaxial) articulation. See
Low levels of RF or anti-CCP antibodies (<3 times 2
Table 14 for more information.
the upper limit of normal)
High levels of RF or anti-CCP antibodies (>3 times 3
the upper limit of normal) :
Acute Phase Reactants
Normal CRP or ESR 0

Abnormal CRP or ESR 1

:

Duration" )
<6 weeks 0
:
>6 weeks 1

-\
CCP = cyclic citrullinated peptide; CRP = C-reactive protein; ESR = erythrocyte
sedimentation rate; N4CP = metacarpophalangeal; IVlTP = metatarsophalangeal;
PIP = proximal interphalangeal; RF = rheumatoid facton

"Six points needed {or classification as rheumatoid arthritis. :

bAt least one joint with definite clinical synovitis that is not better explained by
another disease. Joints excluded from this classification schema: first
carpometacarpal, distal interphalangeal, and {irst metatarsophalangeal. I

'A duration of 6 weeks or longer is less often seen with crystalline or viral causes.
l
From Aletaha D, Neogi T, Silman AJ, et al. 201 0 Rheumatoid arthritis classification
criteria: an American College of Rheumatology/European League Against t
Rheumatism collaborative initiative. Arthritis Rheum. 201 0 Sep;62(9):2569-81.
doi:1 0.1 002/art.27584. IPMID: 20872595] Copyright 20 1 0, American Col ege of
Rheumatology.Adapted with permission from John Wiley & Sons, lnc.

FIGURE 2. Earlyrheumatoidarthritisofthehands,withswellingmostprominently

Diagnosis in the third and fourth proximal interphalangeal joints.

)
The 2010 American College of Rheumatolos/ (ACR)/European
League Against Rheumatism (EULAR) classification criteria
for RA are sensitive and emphasize early diagnosis and treat-
ment to prevent permanent consequences of chronic inflam .

mation (Table 13). .,

Clinical Manifestations
RA is a chronic disorder, and onset of symptoms is usually
gradual. Patients with RA typically report joint pain and
inflammatory symptoms, including swelling and morning
stiffness lasting at least 30 to 45 minutes and commonly sev-
eral hours. Stiffness is also worse following rest and alleviated
by ongoing activity. Slmovitis is palpable on joint examination,
)
manifesting as softness or bogginess of the affected joint. l
Gently squeezing the joints may also elicit tenderness. As part \
of screening examination, the metacarpophalangeal and/or t IGU R E 3. Severe rheumatoid arthritis 0f the hands, with ulnar deviation and
the metatarsophalangeal joints can together be squeezed. subluxation at the metacarpophalangeal joints on both sides.

18
 Rheumatoid Arthritis

TAgLE 14, Consequences of Persistent lnflammation on nor anti-CCP antibodies). Although categorized as having RA,
Joints and Supporting Structures these patients have somewhat different genetics and risk fac
Joint Area lmplications tors and generally have a better prognosis than those with
seropositive RA.
C1-C2 articulation Laxity of transverse ligament resuhs in
and transverse increased posterior motion of dens on Erythrocy.te sedimentation rate and C-reactive protein
ligament C2 because of atlantoaxial subluxation. level are elevated in 75% ofpatients with RA and can be used
Rheumatoid synovitis may lead to
to monitor treatment response. The systemic inflammation
erosion of dens; with neck flexion,
dens can affectthe midbrain and other inherent to RA is also commonly reflected by anemia of
vital neurologic structures. This must inflammation and modest thrombocytosis.
be evaluated before intubation or neck
manipulation in patients with long-
standing RA. lmaging Studies
Shoulder and rotator Restricted range of motion of Plain radiography of the hands and/or feet is the standard imag
cuff tendons glenohumeral joint and rotator cuff ing study for RA and can aid in diagnosis and assessing progres
tears sion. However, radiographs obtained early in the disease may be
Elbow joint Elbow contractures and difficulty with normal or reveal soft-tissue swelling only. Tlpical radiographic
hand pronation and supination
changes include periarticular osteopenia, marginal erosions,
Wrist carpaljoints Restricted range of motion of wrist; and joint-space narrowing (Figure 4 and Figure 5). Radiography
and finger tendons carpal tunnel syndrome; rupture of
of the cervical spine with flexion/extension views is appropriate
finger extensor tendons, especially
fourth and fifth ifCl-C2 subluxation is suspected.
MCPs and surrounding Ulnar deviation and subluxation of MRI and ultrasonography are more sensitive than plain
structures MCPs radiography for detecting abnormalities in joints and soft tis-
PlPs and surrounding Swan neck or boutonniere deformity sues and may have utility in monitoring disease, assessing risk
structu res due to inflammatory disruption of
periarticular su pport structures
Hip joint Axial migration of femoral head in
acetabulum (protrusio acetabuli)
Knee joint Tricompartmental joint-space narrowing
Ankle and mid-foot Restricted range of motion of ankle;
joints and tendons progressive pronated fl at foot deformity
MTPs and Fibular deviation of MTPs; cock-up
surrounding deformities; skin ulceration underneath
stru ctu res subluxed MTP heads
MCP = metacarpophalangeal; N4TP = metatarsophalangeal; PIP = proximal
interphalanqeal; RA = rheumatoid arthritis.

Laboratory Studies
The most useful laboratory studies to aid in the diagnosis of RA
are rheumatoid factor and anti-cyclic citrullinated peptide
(CCP) antibodies. Rheumatoid factor is an immunoglobulin,
usually IgM, directed against the Fc portion of IgG. Rheumatoid
factor occurs in approximately 70"/,, of patients with RA.
Because rheumatoid factor can be associated with other dis-
eases (e.g., viral hepatitis, endocarditis) and because its pres
ence increases with age, the specificity of rheumatoid factor
is limited at about 857,. Anti-CCP antibodies are also present
in 7ou/,, of patients with RA but have a specificity of 95'/u.
Nonetheless, a high pretest probability is required to make
both of these autoantibodies optimally useful for diagnosing
RA. Both of these antibodies may predate the onset of clinical F IGU R E 4. Radiograph showing advanced rheumatoid arthritis in the hand.

disease, but anti-CCP antibodies are more predictive than
rheumatoid factor for erosive disease in patients already diag
nosed with RA.
Approximately 70"/,' to 2O"/,, of patients diagnosed with RA
are seronegative (i.e., positive for neither rheumatoid factor
Shown are ulnar deviation at the metacarpophalangeal joints; marginal erosions
most prominently at the second through fifth metacarpophalangeal joints and the
second and third proximal interphalangeal joints (arows); and joint-space nanowing
at the wrist, metacarpophalangeal, and proximal interphalangeal joints and within
the carpus, which also represents erosive disease. Note the loss of the ulnar styloid
(anowhead), anolher common sign of bony erosion in rheumatoid arthritis.

19
 Rheumatoid Arthritis
t I G U R E 5. Radiograph of rheumatoid arthritis in the foot showinq marginal
erosions and joint,space nanowing at the third, fourth, and fifth metaiarsophalangeal
joints (arows). Erosion at the fifth metatarsophalangeal joint is often the first
radiographic sign of rheumatoid arthritis foot involvement.
for progression, and determining response to therapy.
Ultrasonography is becoming a common tool for detecting
joint fluid (effusion), synovial tissue thickening, early ero-
sions, and increased vascularity. MRI can be used to assess
20
bone marrow edema, synovitis, and erosions but in clinical
practice is generally reserved for assessment of soft-tissue
derangements, such as tendon ruptures. MRI of the cervical
spine is specifically indicated if atlantoaxial involvement is
suspected.
TEY POIIITI
. Tlpical clinical manifestations of rheumatoid arthritis
include pain, swelling, and prolonged morning stiffness
in a symmetric pattern, particularly in the joints of the
hands and feet.
o The most useful laboratory studies to aid in the diagno- HVC
sis of rheumatoid arthritis (RA) are rheumatoid factor
and anti-cyclic citrullinated peptide (CCP) antibodies;
anti-CCP antibodies have a specificity of 95% for RA.
. Plain radiography ofthe hands and/or feet is the stand- HVC
ard imaging study for rheumatoid arthritis; radiographic
changes include periarticular osteopenia, marginal ero-
sions, and joint-space narrowing, although early radio
graphs may be normal.
Com pl ications a nd Bcra-Articu la r
Manifestations
Joints
RA joint damage is a consequence of synovitis within the joint.
The synovial lining, normally only a few cells thick, becomes
significantly expanded through proliferation of resident fibro
blast-like synoviocytes and immune system cells (T cells, B
cells, macrophages), as well as angiogenesis. Various cl.tokines
(tumor necrosis factor, interleukins), often signaling through
Janus kinases, and cartilage-damaging metalloproteinases are
produced. Receptor activator ofnuclear factor kappa B ligand
(RANKL), produced by inflammatory cells, activates osteoclasts
to erode bone. The metalloproteinases and activated osteoclasts
result in various irreversible changes to the joints (see Table 14).
Skin
The most common RA skin changes are rheumatoid nodules
(Figure 6), present in up to 30% of patients. Nodules typically
occur in the olecranon region and can be confused with gouty
tophi, but they can also occur over the hand and feet joints and
even in the lungs. Nodulosis can rarely be induced by certain
drugs (e.9., methotrexate).
Patients with RA are also at an increased risk for neutro
philic dermatoses, such as pyoderma gangrenosum or Sweet
syndrome (see MKSAP 19 General Internal Medicine 2).
Palpable purpura and skin ulcers may rarely result from small-
vessel cutaneous vasculitis.
Eyes
The most common eye manifestation in RA is dry eye (kerato-
conjunctivitis sicca). It occurs in 10% to 15% ofpatients and can
be severe. Most of these patients also have dry mouth and are

7-
v"
F I G U R E 5. Rheumatoid nodules appear as slowly developing, firm, painless,
subcutaneous nodules (arows) located al pressure points or over the extensor
surfaces of joints and tendons.
classified as having secondary Sj6gren syndrome (see Sjogren
Syndrome). Less common (1'l.) are episcleritis (inflammation of
superficial scleral vessels) and scleritis (inflammation of deep
scleral vessels). RA is one of the most common diseases associ-
ated with scleritis, which can be vision threatening and lead to
thinning of the sclera and perforation. Keratitis (comeal inflam-
mation) can occur; it is ulcerative and occurs at the periphery of
the comea. Severe keratitis is known as corneal melt. Both
scleritis and keratitis require immediate referral to an ophthal
mologist (see MKSAP 1g General Internal Medicine 2).
Lungs
Interstitial lung disease may develop in 507, of patients with
RA; clinically significant disease is seen in 10'/. of patients and
contributes to excess mortality. Bronchiectasis and bronchioli
tis occur, and the bronchiolitis can be obliterative and/or
constrictive. Pleural disease occurs in up to 5% of patients;
pleural effusions are exudative and can be large. RA pleural
effusions are characterized by low glucose and pH (mimicking
bacterial or tubercular infection and malignancy) and low
complement levels, as well as elevated levels of total protein,
rheumatoid factor, and lactate dehydrogenase. Infl ammatory
cells in the RA effusion are characteristically mononuclear; a
neutrophil predominant effusion suggests infection. Upper
airway involvement from cricoarytenoid arthritis occurs
rarely; symptoms include hoarseness, sore throat, dysphagia,
and stridor. Cricoarytenoid arthritis can pose problems for
endotracheal intubation.
Heart
Atherosclerotic heart disease remains the major cause of
excess death in patients with RA, although some data suggest
that risk for cardiovascular disease may be decreasing toward
that of the general population. Patients with RA should be
considered at high cardiovascular risk for purposes ofperiop-
erative evaluation, and cardiovascular disease risk factors,
Rheumatoid Arthritis
such as dyslipidemia and hypertension, should be addressed.
Clinically significant pericarditis is rare. Granulomatous myo
carditis, valvular disease (mainly mitral), conduction block,
and aortitis can occur but are very rare.
Hematologic
Anemia of inflammation is the most common RA hematologic
abnormality Felty syndrome is a rare condition consisting of
neutropenia and splenomegaly; it occurs in patients with long-
standing, severe, seropositive RA. Patients with Felty syndrome
are at risk for serious bacterial infections, Iower extremity ulcer-
ation, lymphoma, and vasculitis. Patients with RA can also have
large granular lymphocyte syndrome, which can progress to
large granular lymphoqte leukemia. Findings overlap with
Felty syndrome and include neutropenia, anemia, thrombocy
topenia, splenomegaly, and recurrent infections. Patients with
RA are at increased risk for lymphomas (particularly large B-cell
lymphomas), and risk is correlated with disease activity.
Blood Vessels
Small-vessel cutaneous vasculitis occurs in a small percentage
of patients with RA, leading to palpable purpura or periungual
infarcts. A rare, larger-vessel vasculitis similar to po$arteritis
nodosa can affect multiple organ systems; before current ther-
apy, it had a s-year mortality rate of 30% to 50'2,.
IEY POIilT'
o Extra-articular manifestations and complications of
rheumatoid arthritis include rheumatoid nodules, dry
eye, interstitial lung disease, pleural effusions, and ane-
mia of inflammation.
. Rheumatoid arthritis conveys a significantly increased
risk for cardiovascular disease.
Management
See Principles ofTherapeutics for details on the uses, mecha
nisms of action, major toxicities, and/or monitoring require-
ments of the medications used in RA, as well as recommended
vaccines.
General Considerations
The 2015 ACR RA treatment guidelines advocate for early diag-
nosis and aggressive early therapy ofRA to prevent irreversible
cartilage and bone damage. A key treatment goal is to treat to
target, with the target being achievement of remission or low
disease activity. Disease activity assessment involves making a
measured determination using combinations of numbers of
tender and swollen joints (typically by using 28 joints that
exclude the feet); patient and physician impressions of disease
activity; and, in some activity scoring systems, measurement
of the erythrocyte sedimentation rate or C reactive protein.
These parameters are combined into a composite score, thus
assigning a disease activity ranging from remission to Iow
21
Rheumatoid Arthritis

to doses as high as 25 mg per week in partial responders; the

DMARD-
naiVe RA treating physician should generally maximize methotrexate
dosing before adding other agents. At doses greater than 15 mg
weekly, methotrexate oral absorption approaches its effective
DMARD Iimit; switching to subcutaneous administration allows for
monotherapy
(usually MTX) higher serum drug levels. Folic acid supplements minimize
toxicity without diminishing efficacy. Of patients with RA tak
ing methotrexate alone, 30% to 50'7, achieve remission or low
disease activity.
Moderate/high Low disease
disease activity activity Leflunomide may be useful in patients who cannot toler
ate methotrexate in both monotherapy and combination ther
apy. Hydroxychloroquine and sulfasalazine are less potent
Combination DMARD or Continue current agents and are rarely used as single agents since biologic
TNFi +/- MTX or therapy; if in disease modi$zing antirheumatic drugs (DMARDs) became
non-TNF biologic +/- MTX or remission, consider
available. However, both can be used in combination with
tofacitinib +/- MTX tapering medications"
methotrexate as triple therapy. Data suggest that triple therapy
is similar in efficacy to methotrexate combined with a tumor
Moderate/high Low disease necrosis factor (TNF) inhibitor, except in the area of radio-
disease activity activity graphic progression. Triple therapy, however, may be poorly
tolerated.
Tofacitinib, baricitinib, and upadacitinib constitute a class
Consider alternate
biologic/TNFi/small of FDA approved oral small molecule Janus kinase inhibitors
molecule/MTX therapy whose efficacy in RA is similar to that of the biologics.

FIGURE 7. Asimplifiedalgorithm presenting an initial approachtothe

treatment of both early and established rheumatoid arthritis (RA). All patients with
RA should receive a disease-modifying antirheumatic drug initially and be
advanced to more aggressive and/or combination therapy as needed to control
disease. Disease activity should be assessed, wherever possible, by using a Iormal,
validated, and consistent disease activity index. Refer to the 201 5 American
College of Rheumatology RA treatment guidelines for more complex algorithms
accounting for differences between agents and patient-specific complexities.
DMARD = disease-modifying antirheumatic drug; MTX = methotrexate;
rheumatoid arthritis; TNF = tumor necrosis factor; TNFi = tumor necrosis factor
in h ibitor.
rDo nol disco0tinue all RA trealments.
moderate, or high. The Clinical Disease Activity Index (CDAI)
and Disease Activity Score 28 (DAS28) are two commonly used
instruments to assess disease activity and response to treat
ment. Treating to target in RA results in less radiographic
damage, reduced cardiovascular risk, and increased work
productivity compared with conventional care.
The 2015 ACR RA treatment guidelines can assist in mak-
ing initial treatment decisions in early RA. Treatment is typi-
cally advanced at 12 week intervals with the goal of reaching
remission or low disease activity as rapidly as possible. Patients
who remain in remission or a state of low disease activity for
6 months or longer may be able to reduce treatment intensity.
Treatment decisions for established RA are more complex. An
initial approach to the treatment of both early and established
RA is outlined in Figure 7.
Disease-Modifying Antirheumatic Drugs
Nonbiologic Disease-Modiffing Antirheumatic Drugs
Methotrexate is the anchor drug in RA, used in both mono-
therapy and combination therapy. Methotrexate can be titrated
Biologic Disease-Modiffing Antirheumatic Drugs
Biologic DMARDs can be used as monotherapy but are typi-
cally added to methotrexate when moderate to high disease
activity persists. TNF inhibitors are the most frequently used
biologic DMARDs; they have a relatively rapid onset of action
and demonstrate synerry with methotrexate. The combination
RA = of methotrexate and a TNF inhibitor slows the rate of radio-
graphic damage to cartilage and bone, even in the setting of
continued clinical disease activity. This effect also has been
shown with other biologics in combination with methotrex
ate. Other biologic DMARDs used in RA include abatacept (a
selective T-cell costimulation modulator), tocilizumab (an
anti-interleukin-6 receptor antibody), and rituximab (an
anti-B-cell antibody).
Until better data are available to guide therapeutic deci
sions, choice of a biologic DMARD remains empiric and based
largely on patient characteristics, including what agents
should be avoided because of patient comorbidity (e.g., avoid
ing abatacept in a patient with COPD).
NSAIDS
NSAIDs are used as adjunctive therapy to control symptoms
while the full effect of DMARDs is being awaited. These agents
are not disease modifizing and do not prevent joint damage.
Use with glucocorticoids should be avoided and caution
should be exercised with concomitant methotrexate.
Glucocorticoids
Unlike NSAIDs, glucocorticoids can have a disease modi$zing
effect, in addition to their efficacy in symptom management.

22

Low dose prednisone (s-ts mg/d) can be used to rapidly
improve RA symptoms until long term medications become
effective, or they can be used short term for disease flares.
Although glucocorticoid use is associated with a reduction in
radiographic progression, long term therapy with glucocorti-
coitls has substantial potential adverse effects, including osteo-
porosis, diabetes mellitus, and intbction.
Surgery
Surgical therapy has become less common in RA because of
current treatment strategies. Nonetheless, some patients
may require synovectomy for a single persistently swollen
joint, carpal tunnel release, repair of a ruptured tendon,
total joint replacement (shoulder, metacarpophalangeal
joints, hip, knee), or joint fusion lbr a painful damaged
joint (wrist or ankle). See MKSAP 19 General Internal
Medicine 2 for a discussion of perioperative RA medication
management.
XEY POITIS
. In rheumatoid arthritis, treating to a target of remis-
sion or low disease activity results in less radio-
graphic damage, reduced cardiovascular risk, and
increased work productivity compared with conven-
tional care.
HVC o Methotrexate is the anchor drug in rheumatoid arthri-
tis; it is used as both monotherapy and a component of
combination therapy.
. Tumor necrosis factor inhibitors are the most fre
quently used biologics to treat rheumatoid arthritis;
they have a relatively rapid onset of action and demon-
strate synerS/ with methotrexate.
HVC o In rheumatoid arthritis, NSAIDs are not disease
modifying and do not prevent joint damage; they are
used primarily to control symptoms while the full
effect of disease-modifying antirheumatic drugs is
awaited.
. Low-dose prednisone can be used in rheumatoid
arthritis to rapidly improve symptoms until long,term
medications become effective, but long-term glucocor-
ticoid use carries significant comorbid risk.
Pregnancy
There is an increased risk for developing RA in the first year
after a first pregnancy. Breastf'eeding may decrease this risk.
Among women with established RA at the time of concep
tion, two thirds will go into remission or a state of low dis-
ease activity during pregnancy, and one third will not
improve or will get worse. Medication management is a
major issue, and pregnancy plans should be discussed with
any woman of childbearing age who will be placed on ther
apy. RA medications in pregnancy are discussed in Principles
of Therapeutics.
Osteoarthritis
xEY POtilts
. There is an increased risk for developing rheumatoid
arthritis in the first year after a first pregnancy.
. Among women with established rheumatoid arthritis
at the time of conception, two thirds will go into
remission or a state of low disease activity during
pregnancy, and one third will not improve or will get
worse.
Osteoarthritis
Pathophysiology
Osteoarthritis (OA) is a chronic progressive multifactorial
disorder of maladaptive cellular repair responses to joint
stress. Previously deemed a "wear and tear" disease and an
inevitable consequence ofaging, OA is now recognized as a
disorder driven by a complex interplay of genetics; biome-
chanics; cell stress; biochemical change in cartilage and
extracellular matrix components; and degradation and
inllammation, which is usually subclinical. It affects all tis
sues of the joint and is characterized by cartilage and
meniscal degradation, subchondral bone changes (bone
marrow lesions, subchondral sclerosis), and osteophyte
formation. OA is accompanied by low-grade synovitis and
is driven by imbalanced anabolic and catabolic processes
that represent aberrant joint responses and result in joint
tissue degeneration.
Epidemiology and Risk Factors
OA is the most common form of arthritis worldwide and is a
leading cause of pain and disability, affecting approximately
30 million U.S. adults. OA is the leading cause of lower extrem-
ity disability among older adults, with an estimated lifetime
risk for knee OA approaching 50%. Prevalence is projected to
more than double by 2030, Iargely because of increasing obe-
sity and the aging ofthe population. Incidence and prevalence
vary by joint and depend on whether a clinical or a radio
graphic definition is being applied.
Epidemiologic risk factors for OA include age older than
55 years, female sex, obesity, genetics, and occupations that
involve repetitive motions or physical labor. Age and female
sex are nonmodifiable risk factors for OA of different sites.
Obesity is the most important modifiable risk factor, especially
for knee OA. Increased body mass is also a risk factor fbr hand
OA, perhaps underscoring the systemic nature of obesity and
a role for metabolic and/or inflammatory mechanisms in the
pathogenesis of hand OA. Single inherited conditions rarely
predispose to OA; however, mutations in genes involved in
bone or articular cartilage structure or metabolism are possi
ble risk factors.
23
Osteoarthritis
Risk factors involving the joint itself include abnormal
loading, injury malalignment, and intrinsic cartilage or
bone tissue defects. Injury may be acute (e.g., anterior cruci-
ate ligament tear) or accumulate over time (e.g., physical
labor or overuse); regardless of cause, injuries have been
linked with the future development of OA of various sites.
Hip dislocation, congenital dysplasia, femoroacetabular
impingement, and knee malalignment are also associated
with incident OA.
Given the multifactorial causes, OA may develop as a con-
sequence of one or more risk factors; how the interaction of
these risk factors culminates in OA is complex and not fully
understood.
TEY POIIIIt
o Osteoarthritis is a chronic progressive disorder charac-
terized by cartilage and meniscal degradation, subchon-
dral bone changes, osteophyte formation, and low-grade
synovitis.
. Obesity is the most important modifiable risk factor for
osteoarthritis of the knee.
fir;t carpometacarpal joints (blue arows). Furthermore, metacarpophalangeal ioints
sclerosis aie present at both
24
Classification
Primary Osteoarthritis
In most cases, no identifiable proximal cause of OA is recog
nized. Although the term "primary OA" is commonly used for
this category a complex interplay of genetics, age, sex, biome-
chanics, biochemistry and inflammation is implicit. Primary
OA may affect almost any joint, but clinically significant
presentations occur in the small joints of the hands (distal
interphalangeal [DIP], proximal interphalangeal [PIP], carpo-
metacarpal) and feet (first metatarsal phalangeal, midfoot) and
in the spine, hips, and knees. One or more of these areas might
be affected and symptomatic in a given individual.
Erosive Osteoarthritis
Erosive (inflammatory) OA is a subset of primary hand OA.
Erosive OA prominently affects the DIP and PIP joints, Ieads to
more joint erythema and swelling than other forms of primary
hand OA, and is more common in women. Radiographs reveal
diagnosis-defining central erosions with a "seagull" or "gull
wing" appearance in the finger joints (Figure 8); joint
are spared'

anMosis (bony fusion) may also occur. Whether erosive
comprises a separate disease entity or is part ofthe continuum
ofl OA remains controversial.
Secondary Osteoarthritis
Secondary OA is historically defined in the presence ofa pre-
disposing disorder; however, an increasing number of risk
factors for primary OA are being identified, thus blurring the
line between the primary and secondary forms. Pathologic
changes, clinical presentations, symptoms, and management
are indistinguishable between primary and secondary OA.
When OA occurs in a joint not typically affected by primary
OA, or when it presents at a younger age, secondary causes
should be entertained. Commonly recognized causes of sec-
ondary OA include a history of joint damage, such as trauma,
infection, or surgical repair (e.g., anterior cruciate ligament
repair or meniscectomy); congenitally abnormal joints (e.g.,
hip dysplasia) and/or malalignment; systemic metabolic,
endocrine, and neuropathic disorders, particularly those that
affect cartilage (e.g., hemochromatosis and chondrocalcino
sis); and underlying inflammatory arthritis with accompany
ing damage (e.g., rheumatoid or psoriatic arthritis) (Table 15).
Diffuse tdiopathic Skeletal Hyperostosis
Diffuse idiopathic skeletal hyperostosis (DISH) is a noninflam-
matory condition characterized by calcification and ossifica
tion of spinal ligaments (especially the anterior longitudinal
ligament) and entheses (tendon and ligament attachments to
bone). DISH is more common in men. DISH usually presents
as back pain and stiffness, with the thoracic spine most often
involved. Although spinal ligamentous ossiflcation is also seen
in ankylosing spondylitis, the spinal calcifications in DISH are
more "flowing," wider, and less vertically oriented than those
seen with ankylosing spondylitis. DISH also lacks involvement
of the sacroiliac joints.
Radiographic changes characteristic of DISH include con
fluent ossification ofat least four contiguous vertebral levels,
usually on the right side of the spine (Figure 9). It has been
TABIE 1 5. Secondary Causes of Osteoarthritis
Secondary Cause Joint(s) Typically lnvolved
Hemochromatosis Second/third MCP joints
Calcium pyrophosphate MCP joints; wrists; knees; hips;
deposition shoulders; atlanto-axial joint
Alkaptonuria/och ronosis Spine; hips; knees
Acromegaly Knees; shoulders; spine
Hyperparathyroidism Wrists; MCP joints
Joint injury Knees
Sensory neuropathy Feet; ankles; knees
(Charcot joints)
lnflammatory arthritis Hands; wrists; feet; knees
MCP = metacarpophalangeal
Osteoarthritis
OA suggestedthat the aorta may serye as a mechanical barrier to
the production of bony hyperostosis on the left side of the
spine.
TEY POITIS
. In most cases, no identifiable proximal cause of osteoar-
thritis (OA) is recognized; this form is categorized as
primaryOA.
r Erosive osteoarthritis mostly affects the distal inter
phalangeal and proximal interphalangeal joints, is
characterized by erythema and swelling, and is more
common in women.
. Commonly recognized causes of secondary osteoarthri-
tis include a history of joint damage; congenitally
abnormal joints and/or malalignment; systemic meta-
bolic, endocrine, and neuropathic disorders; and
underlying inflammatory arthritis with accompanying
damage.
o Diffuse idiopathic skeletal hyperostosis is a noninflam-
matory condition characterized by calcification and
ossiflcation of spinal ligaments and entheses; radio-
graphs usually show confluent "flowing" ossification of
at least four contiguous vertebral levels, usually on the
right side of the spine.
Diagnosis
Clinical Manifestations
OA diagnosis is based on history and physical examination;
radiography is confirmatory but may be unnecessary. In early
OA, clinical findings may not be accompanied by radiographic
changes; conversely, some patients with prominent radio
graphic changes may have minimal or no symptoms. Patients
with OA are typically older than 50 years of age; diagnosis at
an earlier age should prompt inquiry into a history of joint
damage, endocrine or metabolic disorders, or a genetic pro
clivity for early disease.
Joints most commonly affected are the hands (DIP, PIP,
and first carpometacarpal joints) (Figure 1O), feet (especially
the first metatarsophalangeal and midfoot joints), knees, hips,
and spine, but the distribution varies. When OA affects a single
joint, it more often results from injury or joint asymmetry and
often occurs in weight bearing joints (hip or knee). Generalized
OA, which affects multiple joint groups, often symmetrically,
may be the result of a combination of genetic and environ
mental factors.
Patients with OA usually describe an insidious onset of
intermittent symptoms, which become more persistent and
severe over time. The most common symptom is joint pain
exacerbated by activity and alleviated with rest. Patients also
describe morning stiffness usually lasting less than 30 min
utes, in contrast to the prolonged moming stiffness of inflam-
matory arthritis. A single joint may initially be involved, with
eventual involvement of multiple loints.
2S
Osteoarthritis

B
€
€
?

€
?4 tl GU RE 9. Plain spinal radiographs showing diffuse idiopathic skeletal
hyperostosis. Note the calcification at sites of tendinous and ligamentous insertion
of the spine, taking the form of flowing ossification of multiple contiguous
€ vertebrae (yel/ow a rrows in A a nd 8). Also seen here is the typica I extensive
involvement of the right side of the spine and relative sparing of the left of the
thoracolumbar spine (/). (C) Calcification ol the anterior longitudinal ligament,
also common, is shown in the cervical spine (redarrows).Also shown is the thick/
wide osteophytes originating from the vertebral bodies, which ditfer from those
seen in ankylosing spondylitis (yel/ow arrowin C).

Pdn A r0urle,y o'50lprio' Gyhopoulos llD [./lSc

On joint examination, joint-line tenderness, crepitus,
without synovi
decreased range of motion, bony enlargement
tis. and sometimes eflusion (most commonly in the knees)
may be present. Patients with long-standing hand OA may
have Heberden and Bouchard nodes (bony enlargement ofthe
DIP and PIP joints, respectively) and squaring ofthe first car
pometacarpal joint. FIip involvement {ypically manifests as
groin pain and decreased range of motion, especially internal
rotation. Knee symptoms include pain on walking and clinlb-
ing stairs and difficulty transferring from a seated to a stand
ing position. OA affecting the spine (spondylosis) can affect
the vertebral bodies, facet joints, and neural foramina and may
Iead to spinal stenosis. See MKSAP 19 General Internal
Medicine 1 for further discussion of spinal stenosis.

26
 Osteoarthritis

FIGURE 10. Progressionof handosteoarthritis(0A).Thisimageillustratestheprogressionfromnormal handjoints(/eft),todistal interphalangeal (Dlp)jointbony

hypertrophy (Heberden nodes) of hand 0A (middle), to extensive hand 0A findings of Heberden nodes and proximal interphalangeal (plp) joint bony hypertrophy (Bouchard
nodes) (nght). Ihe hand on the right also displays a gouty nodule (tophus) overlying the Heberden node on the second Dlp joint, underlining the potential coexistence of these
two arthropathies. White arrowheads = Heberden nodes; black anows = Bouchard nodes; black asterisk = tophus.

Patients with OA generally do not have systemic features.

Pain and structural changes, however, ultimately result in
Differential Diagnosis
functional impairment, disability, psychosocial isolation, and Diagnosing OA can be challenging when OA is present in
reduced quality of life. Inability to exercise regular$ may have
atypical joints, an accurate history is difficult to obtain, or a
adverse consequences for general health.
concurrent inflammatory arthropathy may be present.
Calcium pyrophosphate deposition disease, gout, rheumatoid
arthritis, and psoriatic arthritis may coexist with OA or mimic
Laboratory and lmaging Studies
Laboratory testing is not necessary for diagnosis of OA but is
helpful ifother causes ofarthritis are being considered, such
as crystal arthropathy, rheumatoid arthritis, psoriatic arthritis,
or hemochromatosis (all of which can coexist with OA). Acute
phase reactant levels are not elevated in OA. Routine labora
tory tests (complete blood count, kidney and hepatic function)
are not necessary for diagnosing OA but may be important to
help define the safety of pharmacologic therapy, especially in
older persons and patients with comorbidities.
If a joint effusion is present, evaluation for concurrent
crystal arthropathy, infections, or other inflammatory causes
should be considered, ideally by synovial fluid analysis. OA
slmovial fluid is typically clear in appearance and noninflam-
matory with a leukoclte count of 2000/pL (2.0 x 10e/L) or less.
Although imaging is not necessary to diagnose OA, it can
be helpful to confirm the diagnosis, establish baseline severity
and/or monitor progressive severity, and exclude other diag
noses. Radiographic features of OA include asymmetric joint-
space narrowing, subchondral sclerosis, osteophytes, and
bone cysts (Figure 11); however, these changes may not be
present in early disease. Even in established OA, symptoms
may correlate poorly with imaging findings. Although MRI
and ultrasonography can detect subtle OA changes, they are ; I G U R E 1 1 . 0steoarthritis of the knee showing joint-space narrowing (JSN),
not needed for routine OA diagnosis. osteophytes (0P), subchondral sclerosis (SS), and bone cysts (BC).

27
 Osteoarthritis

OA. Calcium pyrophosphate deposition disease may occur in
joints also fypically affected by OA (hands or knees) but is
associated with intermittent "flares," and radiographs show
cartilage calcification (chondrocalcinosis). Gout and OA com-
monly co-associate, particularly in the DIP joints. Rheumatoid
and psoriatic arthritis can be differentiated from OA by pro-
longed morning stiffness, signs and symptoms of chronic and
persistent inflammation, and elevated inflammatory markers.
Unlike OA, rheumatoid arthritis typically spares the DIP joints,
and the presence of rheumatoid factor and/or anti-cyclic cit-
rullinated peptide antibodies favors the diagnosis of rheuma
toid arthritis. Psoriatic arthritis can involve the DIP joints, but
receive individualized, often multidisciplinary treatment that
considers their expectations, functional and activity levels, occu-
pational and vocational needs, joints affected, severity of disease,
and any coexisting medical problems. Instead of a single algo-
rithm, the practitioner should consider the patient's clinical state
and institute treatment, which may include single or multiple
modalities that may be rycled in and out as needed (Figure ljl).
Sttongly
reommended
Conditionally
recommended

dactylitis and a history of psoriasis help differentiate it from HAND KNEE HIP
OA. In older patients with psoriasis and insidious-onset arthri Exarcker
vl
tis, OA may be a more likely diagnosis than psoriatic arthritis. u,l
I
U Self.Efficary and Self-Management Prognms
Synovial fluid analysis can also help distinguish between OA
and these inflammatory disorders.
o Weight los
d
o-
Other conditions to consider in evaluating a patient for o.
Tai Chi
OA include nonarticular sources of pain, such as bursitis and o Cane
tendinitis. Hip pain that is not in the anterior groin but instead o
lo
around the lateral hip and buttock may indicate trochanteric o lstCMC Orthosis TF Knee Bmcet
z
bursitis or lumbosacral radiculopathy. Similarly, knee pain
Heat, Th€rapeutic Cooling
may be secondary to pes anserine bursitis or iliotibial band =
o
z
syndrome rather than intra-articular pathologz, which may Cognitive Behavioral Therapy
J
present with medial or lateral knee pain, respectively. See s Acupuncture
U
MKSAP 19 General Internal Medicine 1 for further discussion o
]i Kinesiotaping
of nonarticular pain conditions. o
I
U
f,EY POIIIS vt Balance Training
o-
o The most common symptom of osteoarthritis is joint J
Other Hand Orthosesn PF Knee Brace**
pain exacerbated by activity and alleviated with rest; U
6 Pamffin Yoga
morning stiffness usually lasts less than 30 minutes. I
o-
HVC o Laboratory testing is usually not necessary to diagnose
RFA

osteoarthritis but is helpful if other causes of arthritis

are being considered or to help define the safety of u Oml NSAIDs
I
potential therapies. U Topical NSAIDs Topical NSAIDs
. o
cL
Radiographic features of osteoarthritis include asym-
& l-A Steroids l-A Steroids (lmaging Guidance for Hip)
metric joint-space narrowing, subchondral sclerosis,
osteophl'tes, and bone cysts; however, these changes
I|9 Acetaminophen
o
I
J
may not be present in early disease, and symptoms may Tramadol
correlate poorly with imaging findings.
Duloxetine
=
c,
I
A.
Management Chondroitin Topical Capsaicin

To date, the FDA has approved no agents to prevent, delay, or

remit
the structural progression of OA. Instead, current treatment is
directed to the management of pain and disability Evidence
based guidelines for OA management are available from the
American College of Rheumatologr and Arthritis Foundation, the
FIGURE 1 2. Strongly and conditionally recommended therapies for
osteoarthritis (0A) of hand, knee, and/or hip. The figure implies no hierarchy within
categories; the various options may be used (and reused) at various times
throughout a patient's disease. lA= intra-articular; RFA= radiofrequency ablation.
*Exercise
for knee and hip 0A rould include walting, strengthening, neuromuscular training, and aquatic
erercise, with no hierarchyof0neoveranother. Exer(ise isassociated wilh better0uttomes when superuised

Osteoarthritis Research Society International, the European **Knee

brace recommendations: tibiolemoral (TF) brace for TF 0A (strongly recommended), patellofemoral (PF)
brace f0r PF 0A (conditionally recommended).
League Against Rheumatism, and other organizations. There is
*'*Hand orthosis re(0mmendati0ns: first (arpometacarpal (CMC) joinl neoprene or rigid orthoses for first CMC
considerable consensus among these guidelines, particularly that joint 0A (slrongly recommended),0rthoses for joints of the hand olher than the Ii6t j0int (conditionally
CMC

optimal OA management requires a comprehensive plan that may recommended).

include educational, psychological, and phlsical management, trom Kolasinski SL, Neogi I Hochberg MC, et al. 201 9 American College ol Rheumatology/Arthritis Foundation
guideline for the management of osteoarthritis 0f the hand, hip, and knee. Arthritis Care Res (Hoboken). 2020;72:
along with pharmacologic interventions. Patients with OA should 149 162.IPlVlD:31908149] Reproduced with permission fromJohnWiley& 50ns, lnc.

28

Nonpharmacologic Therapy
The nonpharmacologic approach to OA starts with assessment
of physical status, activities of daily living, health education,
motivation, beliefs, and other biopsychosocial factors. An indi
vidualized management plan includes education on OA and
joint protection, an exercise regimen, weight loss, proper foot-
wear, and assistive devices as appropriate. Recent data suggest
that participation in self-efficacy and self-management pro
grams that use a format based on multidisciplinary groups is
associated with improvement in OA symptoms. Physical activ-
ity includes graduated aerobic exercise and strength training,
with attention paid to strengthening periarticular structures
and minimizing injury. Tai chi has also been shown to be as
beneficial as physical therapy lbr knee OA pain and is strongly
recommended by the American College of Rheumatologr
(ACR) for knee and hip OA. The combination of diet and exer
cise is more effective at decreasing OA related knee pain and
dysfunction than diet or exercise alone; no evidence supports
following a specific diet to decrease OA symptoms. Weight loss
provides meaningful improvement in symptoms that increases
with greater loss of weight. The ACR also conditionally recom-
mends cognitive behavioral therapy, acupuncture, and thermal
interventions (locally applied heat or cold) for knee, hip, and
hand OA. Balance exercises are conditionally recommended for
knee and hip OA, and yoga is recommended for knee OA.
Pharmacologic Therapy
ln the absence of disease modiffing OA drugs, pharmacologic
treatment is considered when symptoms are bothersome to the
patient and are inadequately or incompletely addressed by
nonpharmacologic interventions. Pharmacologic therapy lor
OA includes oral, topical, and intra-articular medications.
Choice of treatment depends on individualized assessment,
with particular attention to comorbidities, concomitant medi
cations, and, especially, adverse treatment effects. See Principles
of Therapeutics for details on the medications used in OA.
Oral and Topical Agents
Oral agents for OA include NSAIDs, acetaminophen, duloxe
tine, and tramadol. NSAIDs are efficacious in OA, regardless of
anatomic location, and are the initial oral treatment of choice.
However, their side effect profiles make sustained use prob
lematic, especially in older persons and patients with comor
bidities. A proton pump inhibitor may improve tolerance and
minimize risk; the proper choice of an NSAID should consider
drug pharmacokinetics and gastrointestinal and cardiovascu
lar effects. For OA, NSAIDs should be used in the lowest pos
sible dose and for the shortest possible time. Nonetheless,
NSAIDs remain the mainstay of OA treatment.
Topical NSAIDs are saf'e, associated with the least sys
temic exposure, and effective for treatment of knee OA and
hand OA. For OA ofthe hands and knees, they are preferable
and should be considered before use oforal NSAIDs' They are
not effective for hip OA and have limited efficacy in OA of
Osteoarthritis
other sites. However, topical NSAIDs may be limited in use for
hand OA because of practical circumstances. They also may be
associated with more skin reactions and are more expensive
than oral NSAIDs. Other topical agents, such as capsaicin,
lidocaine, and methyl salicylate preparations, may also be used
as adjunctive measures, especially when NSAIDs are ineffec
tive or are not tolerated.
Recent systematic reviews and meta analyses suggest that
acetaminophen provides no benefit for hip or knee OA but
may be considered as an add on therapy, as well as for short
term and episodic use. ACR guidelines conditionally recom
mend acetaminophen for knee, hip, and hand OA in patients
with limited pharmacologic options.
Duloxetine, a serotonin norepinephrine reuptake inhibi
tor with central nervous system activity, has shown efficacy for
pain from knee OA, suggesting a role for central sensitization
in OA pain modulation.
Opioids for OA should be avoided because evidence
shows only slight benefit and a high risk for toxicity and
dependence. Opioid use should be considered only in limited
circumstances when no other alternatives exist. Tramadol. a
partial opioid with fewer adverse effects and less addictive
potential than pure opioids, may be considered in some
patients in whom other analgesics have not relieved pain.
Nonetheless, concerns about the potential for adverse effbcts
of tramadol continue.
Patients with OA frequently use glucosamine, an oral
dietary supplement. Although glucosamine appears to be safb,
substantial evidence suggests that it lacks efficacy. ACR guide
lines strongly recommend against glucosamine in patients
with knee, hip, and/or hand OA. Chondroitin sulfate is strongly
recommended against in patients with knee and/or hip OA, as
are combination products that include glucosamine and chon
droitin sulfate, but chondroitin is conditionally recommended
for patients with hand OA.
Intra-Articular Injections
Patients with knee or hip OA who have inefficacy, intolerance,
or contraindication to oral and topical therapies may benefit
from intra articular glucocorticoid injections. Despite the lack
of formal evidence for the utility of this therapy in joints other
than the knee and hip, there may be a possible benefit in other
joints, such as the first carpometacarpal joint. The ACR
strongly recommends using ultrasound guidance for hip-joint
glucocorticoid injections.
Long term harm from intra articular glucocorticoids has
not been consistently demonstrated; however, benefit is usu
ally short term and wanes within 3 months. Injections can be
administered repeatedly but are not usually given more often
than every 3 months. At least one study has suggested that
knee joints undergoing repeated injections may be more likely
to experience cartilage loss, but the effect size was small and
the clinical significance remains controversial.
Intra-articular hyaluronic acid injections are widely
used for knee OA in patients with inadequate response to
29
 Fibromyalgia
intra articular glucocorticoids. The quality of trials assessing
efficacy ofintra articular hyaluronic acid is variable, and the
degree of benefit is low. Hyaluronic acid injections may be
considered in patients with knee OA in whom other treat-
ments have failed and surgery is not feasible.
Intra articular stem cells, platelet rich plasma, biologics,
and botulinum toxin are not ef'ficacious and are not
recommended.
Surgical Therapy
Surgery for OA is considered when nonpharmacologic and
pharmacologic approaches fail to control pain or improve
functional limitation. Multiple high quality studies have
shown that arthroscopic surgery for knee OA provides no bet-
ter outcomes than conservative management unless there is
joint buckling, instability, or locking, or a concomitant and
symptomatic mechanical disorder.
In contrast, total joint replacement is a "curative" option
fbr patients in whom conservative therapies have failed; it
relieves pain and improves function. Overall, Iong-term out
comes are excellent, although hardware loosening and inf'ec
tion may occur.
Recent studies suggest that fbr patients with morbid obe
sity and knee OA, bariatric surgery may significantly improve
pain and function even without further OA management.
l(tY PotilTs
HVC o Nonpharmacologic therapy for osteoarthritis includes
education, an exercise regimen, weight loss, proper
footwear, and assistive devices as appropriate.
. Pharmacologic therapy for osteoarthritis includes oral,
topical, and intra articular medications; choice of treat-
ment depends on individualized assessment, with par
ticular attention to comorbidities and concomitant
medications.
HVC o NSAIDs and duloxetine are conditionally recommended
for hip and knee osteoarthritis; acetaminophen is sug-
gested as add on therapy.
HVC o Arthroscopic surgery is not indicated in patients with
osteoarthritis unless there is joint buckling, instability,
or locking, or a concomitant and symptomatic mechan-
ical disorder.
o Totaljoint replacement relieves pain and improves
function in patients with osteoarthritis in whom con-
servative therapies have failed.
Fibromyalgia
Epidemiology and
Pathophysiology
Fibromyalgia is characterized by widespread chronic pain,
fatigue, disturbed sleep, and mental fbgginess. This common
30
condition (prevalence, 2'X, 3'X,) is more predominant in women
than men, and age at onset is usually be[ween the third and
sixth decades.
Fibromyalgia is not an inflammatory condition but rather
appears to be a disorder ofpain perception and processing. lts
pathophysiologr is not well understood. However, it is thought
to relate to central sensitization, characterized by amplifica
tion of pain signaling within the central nervous system.
Neuroimaging of patients with fibromyalgia shows abnor
malities within structures responsible for pain transmission
and interpretation, and accruing data demonstrate a genetic
predisposition.
Diagnosis
The characteristic clinical features of fibromyalgia are wide
spread chronic pain; fatigue; sleep disorders (both disrupted
and nonrestorative sleep); and cognitive symptoms, often
termed "fibrofog." Patients flrequently have polysymptomatic
distress across multiple systems, including paresthesia,
chronic headaches, temporomandibular joint disorder, irri
table bowel syndrome, and chronic pelvic pain. Two instru
ments are available to aid in the diagnosis of fibromyalgia:
one issued jointly by the American Pain Society (APS) and
the FDA, called the Analgesic, Anesthetic, and Addiction
Clinical Trial Translations lnnovations Opportunities and
Networks (ACTTION) APS Pain Taxonomy, and a 2016 revision
of the 2010 American College ol Rheumatologr Preliminary
Diagnostic Criteria (Table f6 and Figure 13). A diagnosis of
fibromyalgia obtained by using these tools is valid irrespective
of other diagnoses and does not exclude other clinically
important illnesses.
These diagnostic tools are based entirely on patient
reporting of symptoms, and they dispense with the assess
ment of tender points that was incorporated into prior criteria
(see Table 16).
Although tender points may be characteristic of
fibromyalgia, especially in female patients, the finding of spe-
ciflc tender points on physical examination has multiple
shortcomings in practice, including lack of reproducibility
(particularly in men) and greater association of tender points
with anxiety than with the pain itself. Technically, tender
point assessments require properly administered pressure,
such as may be achieved with a dolorimeter, an instrument
not routinely available.
Extensive laboratory studies (e.g., antinuclear antibody
[ANA] testing) should also not be performed unless other
specific diagnoses are suspected. Positive ANA test results,
particularly at low titers, are nonspecific and have a low
positive predictive value. Positive findings on ANA screening
tests are highly prevalent in both the general population and
patients with fibromyalgia. In addition to ANA positivity
driving unnecessary additional testing, patients with fibro
myalgia and positive ANA results are often incorrectly
diagnosed with a connective tissue disease and given inap
propriate and potentially harmfut therapy. For example,
 Fibromyalgia

TABLE 16. Comparison of ACR Diagnostic Criteria and ACTTION-APS Pain Taxonomy Diagnostic Criteria for Fibromyalgia,
201 0 ACR Preliminary Diagnostic Criteria (2016 Revision) ACTTION-APS Pain Taxonomy Criteria (2019,
Widespread pain by Widespread Pain lndex (19-point scale) Musculoskeletal pain defined as >6 pain sites from total o{
assessing number of regions in which patient has painb,' 9 possible sites
Symptom severity by Symptom Severity Scale (1 2-point scale) Moderate to severe sleep problems orfatigue
assessing fatigue, nonrestorative sleep, and cognitive symptomsb'

Duration of symptoms >3 months Musculoskeletal pain plus fatigue or sleep problems must have
been present for >3 months
No other disorder explaining the pain

ACR=AmericanCollegeofRheumatology;ACTTION=Analgesic,Anesthetic,andAddictionClinica TrialTranslationslnnovationsOppodunitiesandNetworks;APS=American

"A diagnosis of fibromyalgia does not exclude the presence of other clinically important illnesses.
r'Fibromyalgia is diagnosed in the setting of Widespread Pain lndex 27 plus Symptom Severity Scale score >5, or Widespread Parn lndex >3 plus Symptom Sever ty Scale score )9.

Head

illl,*t,,,'n
ftight erm

i*f cn"'t
il j*ao,"n
i]l unoo, back and spine

ll io*u, back and spine. includangbuttocks

Lert leg

Right leg

back front
FIGURE l3.Numberof painfulbodysites.Patientsareaskedtochecktheareasinwhichtheyexperiencepainonthetwoviewmanikins(ignoringthepreshadedareas).
Alternatively, patients may use the checklist ol body sites. Ihe number of separate sites is summed from a maximum of nine body sites.

studies have shown that many patients with fibromyalgia
with a positive ANA result are unnecessarily treated with
high dose glucocorticoids.
Alternative diagnoses of treatable conditions that may
provoke or be associated with fibromyalgia include hypothy
roidism, polymyalgia rheumatica, and depression. Multiple
rheumatologic conditions (Slogren syndrome, systemic lupus
erythematosus, rheumatoid arthritis) are also associated with
a higher risk for coexistent fibromyalgia than seen in the gen
eral population. In patients with autoimmune disease and
comorbid fibromyalgia, it is crucial to recognize when comor
bid fibromyalgia is the primary driver of musculoskeletal
symptoms in order to avoid overtreatment with immunosul.l
pressive agents.

31
5 pondyloa rthritis
Management
Optimal management of fibromyalgia requires a holistic
approach, including education, exercise, and psychosocial
support. Pharmacotherapy is often warranted, although non
pharmacologic measures remain a cornerstone of treatment.
Nonpharmacologic
Patients should be educated regarding their condition, with
validation that their symptoms are real and reassurance that
their pain is not due to tissue injury and will not lead to per
manent disability. Aerobic exercise can improve well being
and function as well as reduce pain. Because patients initially
experience postexercise pain and thus may be unwilling to
continue, exercise must be introduced gradually and sup
ported encouragingly. Although evidence supporting their use
is modest, modalities that can be helpful include tai chi, medi
tation, and acupuncture.
Patients with fibromyalgia should be assessed for psycho-
social stressors and psychiatric illness, including a history of
trauma and abuse. In such cases, referral for psychological
support is essential, although access to practitioners with
experience treating chronic pain conditions is often a barrier.
Social work support may help reduce the stress burden. Even
in patients without specific psychosocial stressors, psychologi-
cal support for illness and pain management may be advisable.
Cognitive behavioral therapy has shown modest benefit in
reducing pain, negative mood, and disability.
Pharmacologic
Choice of pharmacologic therapy is based on symptom profile,
patient comorbidities, and medication adverse effects because
no trials have directly compared the efficacy of medications.
The antiepileptic agents gabapentin and pregabalin (the
latter FDA approved for fibromyalgia) improve quality of Iife
and decrease pain in the short term. In principle, these agents
act by reducing pain signals from the dorsal root ganglia to the
thalamus. Adverse effects, including sedation, disequilibrium,
weight gain, and peripheral edema, are frequent. In older
patients, gabapentinoid doses should initially be low and then
be slowly titrated, as appropriate. Pregabalin is now classified
as a controlled substance.
Tricyclic antidepressants (such as amitriptyline) raise
norepinephrine and serotonin levels and have mild benefit,
although efficacy may wane with time. These agents induce
drowsiness, with potential benefit for disordered sleep, and
should be taken just before bedtime. Anticholinergic and anti
histaminic adverse effects may be limiting; low doses are rec
ommended (e.g., fO 25 mg of amitriptyline).
Two serotonin-norepinephrine reuptake inhibitors
(SNRIs), duloxetine and milnacipran, are FDA approved for
fibromyalgia and have modest effects on pain. They may be
particularly appropriate in patients with concomitant depres-
sion. Some practitioners report that the administration of a
tricyclic antidepressant at bedtime, combined with a selective
32
serotonin reuptake inhibitor (e.g., sertraline) in the morning,
may mimic the aggregate effect of the SNRIs while helping
normalize the sleep-wake pattern.
Tramadol has a dual effect as both an agonist of p opioid
receptors and an SNRI. Although studies have shown tramadol
is helpful, it is now classified as an opioid, with associated
concerns of class side effects, including tolerance and addic-
tion. These concerns are less extreme than with other opioids,
which are contraindicated in fibromyalgia.
Evidence does not support NSAIDs for treating
fibromyalgia.
The patient and physician should understand that fibro
myalgia is a chronic illness. The benefit of treatment will likely
be partial and usually temporary often requiring a rotating
sequence of treatments. Nevertheless, treatment can help
patients manage and cope with their symptoms as well as
maintain function and autonomy.
xtY Poil{Ts
e The characteristic features of flbromyalgia are widespread
chronic pain, fatigue, sleep disorders, and cognitive
symptoms.
r The diagnosis of fibromyalgia is no longer based on HVC
physician examination findings but rather on a careful
characterization of symptoms using a validated scoring
tool.
. Nonpharmacologictherapy(education,exercise,psycho- HVC
social support) remains a cornerstone of treatment for
fibromyalgia, and pharmacotherapy is often warranted.
Spondyloafthritis
Overview
Spondyloarthritis comprises arthritic disorders classified
together by common genetic and environmental risk factors
and clinical manifestations. Spondyloarthritis includes anky
losing spondylitis, psoriatic arthritis, reactive arthritis, and
enteropathic arthritis. Their common feature is enthesitis
(inflammation at the points where tendons, ligaments, and
joint capsules insert into bone). Clinically, enthesitis mani
fests as inflammation, pain, and new bone formation in and
around peripheral joints; dactylitis (diflfuse digital swelling,
also called sausage digit, including the joint capsule, tendons,
and ligaments) (Figure 14); and, in many cases, ossiflcation at
the spinal entheses. The term spondyloarthritis reflects the
fact that most of these conditions also tend to involve the
spine.
Pathophysiology
Genes and the environment interact to contribute to spondy-
Ioarthritis pathogenesis. The exact mechanisms of these pro
cesses remain incompletely understood.

tIGURE 14. Dactylitisor'tausagedigit"oftheleftseconddigitinpatientwith
psoriatic arthritis, showing {usiform swelling (swelling extending throughout the
digit and not limited to the joint) of the metacarpophalangeal and interphalangeal
joints and interarticular soft tissue as compared to the normal third digit.
Genetic Factors
Certain subtypes of HLA-B27, a class I major histocompatibility
complex (MHC) molecule that presents antigens to immune
cells, are strongly associated with spondyloarthritis with axial
involvement (most commonly ankylosing spondylitis). Up to
90'2, of White patients with ankylosing spondylitis and 60% of
Black patients with ankylosing spondylitis are HLA-B27 posi-
tive. However, HLA 827 alone is insufficient to cause ankylos
ing spondylitis: Among White persons who carryr the HIA 827
gene, only 6% will develop disease. Other genes are therefore
also important to spondyloarthritis risk, some of which have
been identified (e.g., interleukin-23 receptor polymorphisms).
Environmental Factors
The prevalence of spondyloarthritis is low in West Africa, even
among HIA B27 positive people. However, when HIA B27
positive West Africans immigrate to the United States or
Europe, the prevalence of spondyloarthritis increases to the
local population level. This suggests acquired risk related to
environmental modifi cation.
Intestinal dysbiosis or a proinflammatory microbiome is
common in spondyloarthritis and may contribute to this
observation. Terminal ileitis, similar to that seen in Crohn
disease, occurs in up to 60% of patients with ankylosing spon-
dylitis, emphasizing the overlapping nature of the spondyloar
thritis disorders. Intestinal inflammation is thought to lead to
a permeable gut, allowing exposure of dysbiotic bacteria
(especially flagellated bacteria) to the intestinal immune sys
tem. Dysbiosis may also play a role in psoriatic arthritis.
Similarly, reactive arthritis has a well-known association with
enteropathic as well as urogenital infection.
I Tissue Factors
: The enthesis organ has a high content of fibrocartilage, which
seems to be a target in spondyloarthritis, especially ankylosing
I 33
Spondyloarthritis
spondylitis. Consistent with this observation, fibrocartilage
rich joint structures, such as the iiium and acetabulum, are
preferentially destroyed in ankylosing spondylitis; the hyaline
cartilage of the sacrum and femoral head are mostly spared.
Fibrillin 1, a protein commonly found in fibrocartilage, may be
a target molecule. The anterior eye, proximal aorta, and ace-
tabulum are all occasionally involved in spondyloarthritis and
are rich in flbrocartilage/fibrillin 1.
TEY POIIT'
r Spondyloarthritis comprises arthritic disorders classi-
fied by common genetic and environmental risk factors
and clinical manifestations; they include ankylosing
spondylitis, psoriatic arthritis, reactive arthritis, and
enteropathic arthritis.
o Certain subtlpes of HLA-B27 are strongly associated
with axial spondyloarthritis; however, HLA-827 alone is
insufficient to cause axial spondyloarthritis.
Classification
Four distinct but overlapping diseases comprise spondyloar
thritis (Table 17):
l. Ankylosing spondylitis
2. Psoriatic arthritis
3. Enteropathic arthritis
4. Reactive arthritis
Some taxonomies include a fifth, undifferentiated cate-
gory for patients with features of spondyloarthritis but insuf-
ficient manifestations to permit classification into one of the
four categories. For example, a patient with episodic dactylitis
and a history of uveitis would not flt neatly into one of the
standard categories but would be classified as having periph
eral spondyloarthritis by criteria discussed below.
Emphasizing the relatedness of all four categories, the
Assessment of SpondyloArthritis international Society devel
oped classification criteria that eschew individual diseases and
instead divide patients into those with axial involvement
(Figure 15) and those with involvement of peripheral joints
only (Figure 16). Although these criteria were designed for
study enrollment rather than clinical practice, they demon
strate the common clinical features that are part of the spon
dyloarthritis family.
Axial spondylarthritis can be categorized as radiographic
(definite radiographic sacroiliitis) or nonradiographic (mini
mal or no radiographic sacroiliitis). Although patients with
nonradiographic spondyloarthritis often have milder disease
and HLA-B27 is less common, these patients have lower rates
of response to current treatments.
Ankylosing Spondylitis
Ankylosing spondylitis is a chronic inflammatory disease
affecting the axial skeleton (including sacroiliac joints),
Spondyloa rth ritis

Ankylosing Spondylitis PsoriaticArthritis EnteropathicArthritis ReactiveArthritis

Musculoskeletal
Axial involvement Axial involvement is
hallmark; initially
symmetric involvement
o{ Sl joints and lower
spine, progressing
cranially
Peripheral Enthesitis; may have
involvement asymmetric large-joint
oligoarthritis, including
hips and shoulders; hip
involvement can cause
si gnifica nt functional
limitation; dactylitis
Dermatologic Psoriatic-like lesions
may rarely occur
May occur at any level;
may start in the cervical
spine; may skip regions
Clinical subtypes of PsA:
1. Oligoarthritis
2. Polyarthritis
3. DlP-predominant
4. Arthritis mutilans
5. Axial spine involvement
Enthesitis, dactylitis, and
tenosynovitis are
commonly seen
Psoriasis typically
precedes joint
involvement; nail
pitting; onychodystrophy
May have
asymptomatic or
asymmetric Sl joint
disease or have typical
ankylosing spondylitis;
axial disease does not
parallel bowel activity
Pauciarticular large and
medium joints;
peripheral arthritis can
parallel IBD activity
Polyarticular peripheral
arthritis of small and
large joints does not
parallel bowel disease;
dactylitis; enthesitis
hToderma
gangrenosum;
erythema nodosum
Less common than in
other forms of
spondyloarthritis but
may be asymmetric
Enthesitis, tenosynovitis
and asymmetric large-
joint oligoarthritis;
usually self-limited and
nonerosive; persistent
arthritis in up to 25olo
and may develop MTP
erosions
Keratoderma
blennorrhagicum and
circinate balanitis (rare)

Ophthalmologic Anterior uveitis
(unilateral, recurrent)
G astrointestina I 60% with ileocolitis on
colonoscopy
Genitourinary Urethritis (rare)
Cardiovascu lar lncrease in CAD; aortic
valve disease; aortitis;
conduction abnormalities
Pulmonary Restrictive lung disease
from costovertebral
rigidity; apical fibrosis
(rare)
Bone quality Falsely elevated bone
mineral density from
syndesmophytes;
increased risk for spine
fractu re
Conjunctivitis more
common than anterior
uveitis
Dysbiosis may play a
role in inflammation
lncrease in CAD
lncreased risk for
fracture (multifactorial)
Anterior uveitis most
common; conjunctivitis,
keratitis, and episcleritis
are rare
Gl inflammation is
hallmark
Thromboembolism
Rare cases of large
airway stenosis
High risk for vitamin D
deficiency, low bone
density, and fracture
Conjunctivitis more
common than anterior
uveitis
Preceding Gl infection
common
Prior GU infection in
some patients; sterile
urethritis; prostatitis;
cervicitis; salpingitis
Rare aortic valve disease
and conduction
abnormalities
Localized osteopenia

CAD = coronary artery disease; DIP = distal interphalangeal; Gl = gastrointestinal; GU = genitourinary; IBD = inflammatory bowel disease; MCP = metacarpophalangeal; MTP =
metatarsophalangeal; PIP = proximal interphalangeal; PsA = psoriatic arthritis; Sl = sacroiliac.

entheses, and peripheraljoints. Ankylosing spondylitis is also Articular Manifestations

known as a radiographic axial spondyloarthritis. Prevalence
is 0.32% in North America but only O.O7ok in Africa, largely
following the population prevalence of HLA-B27. Ankylosing
spondylitis is more frequent in men than women (ratio,
2 3:1). The penetrance of ankylosing spondylitis is 12'lu lrom
father to son and 5'2, from father to daughter, highlighting the
protective effect of female sex. The disorder usually begins in
the third to fourth decades (typically before age 45 years). It
can occur as early as the teen years and as late as the sixties
in rare cases.
Ankylosing spondylitis initially presents with subacute onset
of inflammatory low back pain, including pain and stiffness of
the low back and/or buttocks at night and in the morning that
improves with activity. The synovial facet joints are also
involved, and back extension may be painful. Over time, the
thoracic and cervical spine can become involved. The disease
has three phases: inflammation; fibrosis; and ossification,
which can drastically limit range of spinal motion. If untreated,
patients can assume a kyphotic stance and may only be able to
look at their shoes as they walk. This is due to the 40'l" flexion

34
 Spondyloarthritis

Back pain >3 months

and
Age at onset <45 years

Sacroiliitis on plain radiography or MRI

Yes No

1 or more features of spondyloarthritis HLA-B27 positivity

meet criteria for radiographic plus
axial spondyloarthritis 2 or more features of spondyloarthritis
meet criteria for nonradiographic
axial spondyloarthritis

Features of spondyloarthritis
. lnflammatory back pain
. Arthritis
. Enthesitis
o Uveitis
. Dactylitis
. Psoriasis
. lnflammatory bowel disease
. Good response to NSAIDs
. Family history of spondyloarthritis
. HIA-B.27 positivity
. Elevated C-reactive protein level

FIGURE 1 5. AssessmentofSpondyloArthritis international Societyclassification criteria foraxial spondyloarthritis.

rule of swollen synovial joints: Patients are most comfortable

Arthritis or enthesitis or dactylitis
when the spinal facet joints are in the 40% flexed position plus
when swollen; when lying down, patients will prop their back 1 or more additional spondyloarthritis feature

with two or three pillows to be comfortable. Fibrosis and ossi-

fication of the spine then occur in this position. Ossification of
the spine occurs at the vertebral entheses and is visible radio-
graphically as syndesmophytes and ossification of the spinal Spondyloarthritis features:
o Uveitis
ligaments.
o Psoriasis
Enthesitis is most commonly appreciated in the feet at the o Preceding infection
plantar fascia and where the Achilles tendon inserts into the . lnflammatory bowel disease
heel (Figure 17). Enthesitis of the costovertebral joints can also . HLA-827 positivity
o Sacroiliitis on imag;ng
affect the chest wall, leading to pain at night and in the morn-
ing that improves with movement.
Peripheral joint involvement may include the hips
(Figrre 18), shoulders, knees, and, less commonly, other joints.
The synovial fluid is inflammatory with a predominance of neu- lf none of the above spondyloarthritis
features are present, patient must
trophils and cell counts ranging from 10,000/pL to 50,000/pL have 2 or more of the following:
(ro to so x loell). . Arthritis
o Enthesitis
. Dactylitis
Extra-Articular Manifestations . History of inflammatory back pain
Anterior uveitis occurs in up to 27% of patients with ankylos . Family history of spondyloarthritis
ing spondylitis. It is episodic, unilateral, and typically self-
limited. It generally does not cause permanent visual tIGURE l6.AssessmentofSpondyloArthritisinternationalSocietyclassification
damage. criteria for peripheral spondyloarthritis.

35
Spondyloarthritis
FIGU R E I 7. Marked thickening of the distal right Achilles tendon and Achilles
insertion on the calcaneus (right) as the result of chronic Achilles tendinitis in a
patient with psoriatic arthritis (left image shows normal contralateral on Achilles
i nsertion).
Fibrosis affecting the upper lobes of the lung, visualized
by high-resolution CT, is reported in 7% of patients with early
ankylosing spondylitis and 2l% of patients after 10 years of
disease. Involvement of the thoracic spine, costochondral
junctions, and sternomanubrial joint can affect chest expan-
sion, contributing to restrictive lung disease.
Renal amyloidosis is a rare manifestation of chronic
inflammation from ankylosing spondylitis that occurs in
patients with long-standing, poorly controlled disease. AA
amyloid deposition can lead to proteinuria and eventually
kidney failure and is associated with increased mortality. In
patients with poorly controlled ankylosing spondylitis, AA
amyloidosis is the most common cause of kidney disease. IgA
nephropathy can also occur in anlcylosing spondylitis, pre-
senting as hematuria and proteinuria.
Cardiac involvement in ankylosing spondylitis includes
aortitis ofthe subaortic valve region (an area ofhigh fibrocar-
tilage content), leading to aortic dilatation and aortic valve
regwgitation. Atrioventricular block occurs more commonly
in patients with ankylosing spondylitis and those who are
HLA-827 positive without rheumatologic disease than among
the general population. Myocardial infarction occurs in
patients with antr<ylosing spondylitis at a rate two to three
times that in the general population; this increased rate is
thought to be due to chronic inflammation hastening the
development of atherosclerosis.
Vertebral fractures can occur in patients with ankylosing
spondylitis, often after only minor or minimal trauma. Fractures
can occur through the vertebral body or through a disk space
that has become fixed because of slmdesmophyte formation;
either can lead to nerve injury or myelopathy Another rare nzu-
rologic manifestation is cauda equine qmdrome, manifested by
saddle anesthesia and bowel and bladder incontinence. MRI of
the lumbar spine shows arachnoid diverticula in these patients.
36
Psoriatic Arthritis
Psoriatic arthritis is an inflammatory joint disease associated
with psoriasis. Psoriasis affects approximately 3% of the U.S.
population, and psoriatic arthritis may develop in up to 30% of
patients with psoriasis. Hyperuricemia and gout are comor
bidities associated with psoriasis and psoriatic arthritis.
An estimated 15% of patients with psoriasis who are
monitored by dermatologists have unrecognized psoriatic
arthritis. On the other hand, some patients considered to
have psoriatic arthritis because of concurrent psoriasis and
joint pain actually have an unrelated joint condition, most
commonly osteoarthritis. In most cases, psoriatic arthritis
develops years after psoriasis, but 15% of patients may
develop psoriatic arthritis concurrently with or even before
psoriasis.
The male to-female ratio for psoriatic arthritis is 1:1
(other forms of spondyloarthritis generally have a higher
prevalence in men). Risk factors include obesity, metabolic
syndrome, severe psoriasis, psoriasis involving the scalp or
genitals, or inverse psoriasis. Psoriatic nail changes are pre-
sent in more than 80% of patients with psoriatic arthritis.
The genetics of psoriatic arthritis are complex. HLA-C06 is
associated with psoriasis but not psoriatic arthritis. HLA-
BO8, -B27, -B38, and -B39 are seen in psoriatic arthritis, and
the particular HLA type can influence clinical expression. In
part because of HLA expression, psoriatic arthritis is rare in
Asians and Africans.
Five clinical subtypes ofpsoriatic arthritis are described:
1. Asymmetric oligoarthritis involving four or fewer, typically
large, joints. Occasionally, a single joint may be involved.
2. Polyarticular arthritis affecting multiple joints of the
hands, which may be symmetrical and resemble rheuma
toid arthritis.
3. Distal interphalangeal joint (DlP)-predominant variety,
which may occur with the preceding subtl,pes or in isolation
F IG UR E 1 8. Radiograph showing hip involvement in ankylosing spondylitis.
Note the fused sacroiliac joints bi lateral ly. Diffuse joi nt-space narrowi ng is present
in both hip joints, especially in the left hip.

t I G U n E t 9 . Distal interphalangeal joint swelling (best seen in the second and
third digits) and nail pitting (best seen in the fourth digit nail) in a patient with
psoriatic arthritis.
(Figure 19). Although inflammation in a DIP joint in a
patient with psoriasis strongly suggests psoriatic arthritis,
DIP involvement is also common in osteoarthritis, is occa-
sionally seen in gout, and also occurs in a rare condition
called multicentric reticulohistiocytosis.
4. Arthritis mutilans, a more aggressive form of psoriatic
arthdtis irvolving the hands. Telescoping of the digits from
zubstantial joint destruction may ocu:r. Arthritis mutilans is
probably a progressive form ofthe preceding thrce subtypes.
5. Axial spine involvement with sacroiliitis and spine involve-
ment. This may occur in isolation or in conjunction with
other subtypes. It occurs in up to 5Oo/. of patients with
psoriatic arthritis, more commonly among patients with
the HIA-827 gene. Axial psoriatic arthritis involvement
may be distinguished radiographicallyby asymmetry skip
lesions, and bulkier syndesmophytes.
Enthesitis is common in psoriatic arthritis and indicates
more severe disease. Dactylitis of the fingers or toes develops
in 4O% to 50% of patients with psoriatic arthritis (Flgur€ 2O);
enthesitis ofthe plantar fascia or Achilles tendon occurs in up
to 5O%.
Eye involvement also develops in psoriatic arthritis.
Conjunctivitis is more common than uveitis or iritis. Uveitis
occurs in up to 8% of patients with psoriatic arthritis.
Like ankylosing spondylitis, psoriatic arthritis is associ-
ated with an increased risk for cardiovascular disease, includ-
ing myocardial infarction, valvular disease, and conduction
abnormalities.
Spondyloarthritis
Enteropathic Arthritis
Ankylosing spondyloarthritis, isolated sacroiliitis, and periph-
eral arthritis occur in patients with Crohn disease, ulcerative
colitis, and unspecified inflammatory bowel disease (IBD).
Spondyloarthritis is the most common extra-articular mani-
festation of IBD.
The prevalence of ankylosing spondylitis is 47o in Crohn
disease and 2% in ulcerative colitis; the prwalence of isolated
sacroiliitis is 137" and 7olo, respectively. Of interest, HLA-827 is
found in 257o to 75% ofpatients with enteropathy-associated
ankylosing spondylitis but in only 7"/" to lSTo of those with
isolated sacroiliitis, suggesting a different pathophysiologr.
Isolated sacroiliitis is unilateral in 60% of cases and can be
associated with psoriasis, erythema nodosum, and peripheral
arthritis in patients with IBD. Dactylitis and enthesitis can also
occur with enteropathic spondyloarthritis.
There are two types of peripheral arthritis in IBD. Type I
is pauciarticular (fewer than five joints) and asymmetric;
usually involves medium to large joints, especially in the
lower extremities; is nonerosive; and parallels the activity of
the bowel disease. Type II is polyarticular (five or more
joints); is qmmetric; involves a wide range of joints, some-
times including the upper extremities; is nonerosive; and is
persistent and independent of bowel disease activity. The
prevalence of peripheral arthritis is highest in younger
patients (up to ZS%) and much lower in patients older than
age 5o years (2%).
The risk for IBD in patients with established spondy-
loarthritis is as high as 147o and is highest in patients with
ankylosing spondylitis. As noted previously, 60% ofpatients
with ankylosing spondylitis have evidence of asymptomatic
bowel inflammation, and most patients with ankylosing
spondylitis who develop IBD are in this group. Patients
with ankylosing spondylitis should be asked about bowel
symptoms on follow-up visits. Elevated serum and fecal
calprotectin levels can identi$r patients with ankylosing
spondylitis who have greater disease activity and those with
FTGURE 20. Dactylitisof thesecondtoesbilaterallyinapatientwithpsoriatic
arthritis.
37
Spondyloarthritis

more active bowel inflammation and may predict develop

ment of IBD.

Reactive Anhritis
Reactive arthritis occurs after specific bacterial infections. It is
classified as a spondyloarthropathy and represents only 2'7, of
patients in this category.
The most common organism responsible for reactive
arthritis is Chlomydio trachomatis; 4% to 8"/,' of infected
patients develop reactive arthritis. Gastrointestinal pathogens
include several species of Salmonella and Shigella,
Campylobacter jejuni, and Yersiniq species; reactive arthritis
occurs in approximately 1'X, of infected indMduals. Respiratory
pathogens, including Chlamydia pneumoniae and Mycoplosma tl GUR E 2 I . Keratoderma blennorrhagicum on the palms and circinate balanitis
on the glans penis are psoriasiform skin rashes seen in this patient with reactive
pneumoniae, are also known causes of reactive arthritis.
arthritis.
Clostridioides difficileis an uncommon but important cause of
reactive arthritis given its frequency in hospitalized patients. persistent disease. Complications of reactive arthritis can
Approximately 7.4% of patients with C. dfficile colitis will include erosive joint disease, especially at the metatar
develop reactive arthritis. An inciting organism is identifled in sophalangeal joints; aortitis with aortic valve insufficiency;
only about 50% of patients. Women develop reactive arthritis atrioventricular conduction block: and uveitis.
more commonly than men (relative risk, 1.5). H[A-B27 is found
in 50'/" to 80% of patients with reactive arthritis; the highest rEY PO I l{TS

frequency (90%) is seen in those who develop reactive arthritis
from Yersin io infection.
Reactive arthritis develops 2 to 3 weeks after genitouri
nary and gastrointestinal infections. Synovial fluid Ieukocyte
counts can be elevated, often around 50,000/pL (50 x 10e/L)
with a predominance olneutrophils. Synovial fluid in reactive
arthritis can also demonstrate rice bodies: small pieces ol
hypertrophic synovial tissue that are sloughed and accumulate
in the joint and may require a large bore needle to aspirate.
The arthritis is typically pauciarticular and involves
larger joints. Enthesitis of the Achilles tendon or plantar fas
cia is commoni enthesitis may also occur in the knee, a joint
with multiple entheses. Dactylitis of fingers and toes is also
common in reactive arthritis. Sacroiliac joint and spine
inflammation and pain are less common than peripheral
manifestations.
Mucocutaneous manifestations include genitourinary dis
ease (such as urethritis, cervicitis, cystitis, or prostatitis).
Patients can have painless oral ulcers, tlpically affecting the
hard palate. Conjunctivitis is the most common eye finding, but
anterior uveitis and even keratitis can occur. Keratoderma blen
norrhagicum, a psoriasiform skin rash, occurs on the palms and
soles but occasionally can become generalized (Figure 21). The
lesions begin as discrete plaques and then enlarge and coalesce.
Circinate balanitis is a similar psoriasiform lesion on the glans
penis in men. Erythema nodosum is rare.
Important differential diagnostic considerations include
infectious arthritis, disseminated gonococcal infection,
Whipple disease, IBD, or Behqet syndrome.
The typical course ofa reactive arthritis flare is 6 weeks to
6 months. Manifestations can last I year. Episodes may recur
in some patients; about 25% of patients will have chronic
. AnMosing spondylitis is a chronic inflammatory disease
affecting the axial skeleton (including sacroiliac joints),
entheses, and peripheral joints.
. Psoriatic arthritis is an inJlammatory ioint disease asso-
ciated with psoriasis, multiple possible joint patterns,
enthesitis, tenosynovitis, and dactylitis.
. Ankylosing spondyloarthritis, isolated sacroiliitis, and
peripheral arthritis can occur in patients with inflam
matory bowel disease.
. Reactive arthritis can occur 2 to 3 weeks following spe-
cific gastrointestinal and genitourinary infections; the
arthritis is tlpically pauciarticular and involves larger
joints, and dactylitis and enthesitis can occur.
Diagnosis
Laboratory Studies
Except for incidental overlap with other conditions, patients
with spondyloarthritis are negative fbr rheumatoid factor.
anti cyclic citrullinated peptide, and antinuclear antibodies.
Serologic testing should be performed only if an alternative
diagnosis is being considered.
For patients with inflammatory low back pain but normal
or nondiagnostic plain radiographs ofthe spine and sacroiliac
joints, a positive result on a test for HLA B27 antigen can be
useful for deciding to pursue advanced imaging. HLA-B27
antigen testing is never diagnostic but can help determine risk
for spondyloarthritis in uncertain situations. A patient with
inflammatory low back pain, uveitis, and radiographic evi
dence of bilateral sacroiliitis does not need HLA B27 antigen
testing because the diagnosis is clear.

38
 Spondyloarthritis

Patients with spondyloarthritis may have anemia of Figure 23 with findings seen in Figure 24. Radiographs of the
inflammation as a result of chronic inflammation. Erythroclte spine can show squaring of the vertebrae anteriorly (due to
sedimentation rate and C reactive protein help confirm an erosion at the insertion of entheses); sclerosis at the anterior
inflammatory process and can be monitored during therapy. edges of the vertebrae ("shiny corner" sign [Figure 25]);
However, these values are not always elevated, particularly in
ankylosing spondylitis. All patients with chronic spondyloar-
thritis should be monitored for standard risk factors for car
diovascular disease.

lmaging Studies
Radiography ofthe sacroiliac joints is an initial test for patients
suspected of having ankylosing spondylitis. Anteroposterior
radiography ofthe pelvis or a Ferguson view ofthe pelvis (in
which the x ray beam is directed 20 degrees cephalad to show
all sacroiliac joints in one plane) can depict the changes of
sacroiliitis (Figure 22). The radiographic changes are initially
more intense on the iliac side of the joint, with sclerosis and
erosions. Erosive changes lead to a pseudo-widening appear-
ance of the sacroiliac joints; in advanced cases, ankylosis of
the sacroiliac joints can occur; compare normal findings in
FIGU R E 24. CIscan of the sacroiliac joints in a patientwith sacroiliitis (same
patient shown in Figure 22). Note the marked sclerosis/new bone formation,
especially on the iliac side of the joint and erosions of the sacroiliac joints.

t IGU R E 22. Radiograph of the sacroiliac joints (Ferguson view) in a patient

with sacroiliitis (same patient shown in Figure 24). Note the iliacside sclerosis and
! i nd istinctness of the sacroi liac joi nts on both sides of the joi nt, i nd icati ng erosions.

F IG UR E 2 5. Lateral lumbosacral spine radiograph in a patient with ankylosing

spondylitis. Note the squared appearance of the anterior aspect of the lumbar
vertebrae and the "shi ny corner" sig n on the anterosu perior aspect of the L3 (anow)
FIGU R E 2 3. Normal CT scan of the sacroiliac joints. Note the intact sacroiliac vertebrae. The "fl uffy" appea rance to the facet joints posteriorly is typical of the new
joints and lack of subchondral sclerosis. bone formation seen in ankylosing spondylitis.

39
Spondyloarthritis

Peripheral joint changes in spondyloarthritis include ero-

sions and new bone formation. In psoriatic arthritis in par-
ticular, radiographic findings classically take the form of
erosions of the distal head of the proximal joint and juxta-
articular new bone formation at the proximal head of the
distaljoint, leading to a 'pencil-in-cup" appearance across the
joint (Figure 27).

. Except for incidental overlap with other conditions, HVC

patients with spondyloarthritis are negative for rheu-
matoid factor, anti-cyclic citrullinated peptide, and
antinuclear antibodies; HI,A-B27 antigen tesung can
help determine risk for spondyloarthritis in uncertain
situations.
r Erythrocyte sedimentation rate and C-reactive protein
can help confirm an inflammatory process and can
be monitored during therapy; however, these values
are not always elevated, particularly in ankylosing
spondylitis.
o Radiography of the sacroiliac joints is an initial diagnos-
tic test for patients suspected ofhaving ankylosing
spondylitis; radiographic widence of sacroiliitis
includes pseudo-widening of the joints, erosions,
sclerosis, and ankylosis.
e MRI of the sacroiliac joints is more sensitive than CT HVC

F IGUR E 26 . More advanced disease of the lumbar spine in late ankylosing

and can identiff sacroiliac inflammation even in the
spondylitis. Note the syndesmophyte formation or bony connections between absence ofradiographic changes; however, 25"/, of
vertebrae across the disc space ("bamboo" appearance). healthy individuals can have similar MRI changes.
(Continued)

syndesmophytes (delicate bony bridging between vertebrae

that can result in a "bamboo" appearance of the spine in
advanced ankylosing spondylitis [Figure 26]); sclerosis at the
facet joints; and, in more advanced cases, ossification of the
anterior longitudinal ligament. Patients with psoriatic arthritis
or reactive arthritis with spondylitis can also have syndesmo-
phytes; these tend to be bulkier and more asymmetrically
placed than syndesmophytes in ankylosing spondylitis.
Whiskering, the result of new bone formation at the insertion
of the hamstrings into the pelvis, is also seen on radiography.
Bony proliferation can occur in other entheses, such as the
Achilles tendon or plantar fascia insertion into the heel.
Low dose CT and MRI of the sacroiliac joints can be done if
necessary Low dose CT is more speciflc and is usefirl to clari$r
ambigrous changes seen on plain radiographs, whereas MRI is
more sensitive and can ident$ sacroiliac inflammation even in
the absence ofradiographic changes. However, 25% ofhealthy
indMduals can have MRI changes that meet Assessment of
SpondyloArthritis international Society criteria for sacroiliitis,
and up to 41% of persons who regularly participate in impact-
loading athletics may have similar MRI changes. The extent of J
involvement and presence of erosions on MRI increase the
tI G U R E 2 7 . Radiograph showing "pencil-in-cup' deformity of the fifth
speciflcity of the result. The presence of MRI changes also aids metatarsal joint and ankylosis of the fou rth metatarsal joint in a patient with
in the diagnosis of nonradiographic axial spondyloarthritis. psoriatic arthritis.

40
 Spondyloa rth ritis

f,EY P0lI|TS {ontinued)
. In psoriatic arthritis radiographic findings take the form
of erosions of the distal head of the proximal joint and
juxta-articular new bone formation at the proximal
head of the distal joint, leading to a "pencil in cup"
appearance across the joint.
Management
General Considerations
Management of spondyloarthritis focuses on treatment of inflam
mation and autoimmunit5r to address pain and prwent structural
damage. If damage has occurred, mechanical pain must be
addressed as well. Patient education, exercises to maintain range
of motion and control weight, and modilication of diet and life-
style habits to prevent cardiovascular disease are vital.
Ankylosing Spondylitis
Figure 28 details recommendations for initial treatment of
active ankylosing spondylitis. NSAIDs are recommended as
initial medication for most patients with ankylosing spondylitis
because they relieve pain and improve stiffness. Given the
unique potential for disease modiflzing effects (oniy in ankylos-
ing spondylitis), the American College of Rheumatolo$/ (ACR)
conditionally recommends continuous NSAID use (rather than
on demand use) for patients with active disease. Higher and
long-term doses of anti inflammatory agents (e.g., naproxen,
500 mg twice daily; piroxicam, 20 mg daily) are required to
modi$r new bone formation and decrease inflammation. A dose
of a longer acting NSAID at dinnertime can make the patient
comfortable throughout the night and into the moming.
According to the 2019 ACR guidelines, patients in whom
NSAIDs fail can be treated with a tumor necrosis factor (TNF)
inhibitor. Numerous randomized controlled trials have shown
improvements in clinical, radiographic, and MRI outcomes in
patients with active ankylosing spondylitis taking TNF inhibi
tors. Routine serial spine radiography for monitoring is not
recommended.
When a TNF inhibitor fails, patients should receive an
interleukin-l7 inhibitor in lieu of a second TNF agent. For
patients with significant peripheral arthritis, sulfasalazine is
recommended over methotrexate and can be added to the
biologic agent if needed. However, these agents have little or
no ellect on axial disease.
Uveitis is generally treated with topical glucocorticoids.
For severe or frequent recurrences, the TNF inhibitors adali-
mumab or infliximab can be considered. Etanercept, an anti
TNF receptor fusion protein, is effective for the spine but
probably not eye disease.
Physical therapy to maintain general range of motion is
essential. Patients with damage to hip or shoulder joints may
require total joint arthroplasty, which may dramatically
improve function and quality of life.

Assess for additional lsolated sacroiliitis

Axial disease
disease manifestations or enthesitis

Continuous NSAIDs Peripheral-predominant NSAIDs

and active, land-based disease
physical therapy

Symptoms controlled?
NSAIDs
Symptoms controlled?
Yes No

Yes No
Symptoms controlled? Continuous Local glucocorticoid
NSAIDs injections (avoid
Continuous Add TNF Achilles tendon, patella,
NSAIDs inhibitor Yes No and quadriceps)

Continuous <2 joints

NSAIDs
Symptoms
controlled? Yes No

Yes No Local glucocorticoid Sulfasalazine

injections

Continue TNF Switch to

inhibitor secukinumab
or ixekizumab

FIGURE 28. Recommendationsfortheinitialtreatmentofactiveankylosingspondylitis.INF=tumornecrosisfactor.

41
Systemic Lupus Erythematosus

Psoriatic Arthritis
Thble 18 lists agents available to treat psoriatic arthritis. In gen-
eral, most ofthese agents are also effective for psoriasis. Because
agents such as TNF inhibitors are often given in higher doses
for skin disease than for joint disease, the predominant feature
of the disease may drive the prescribing dose. Weight loss and
smoking cessation may positively affect disease activity.
For limited disease, such as a single digit with dactylitis or
a single swollen joint, an oral or topical NSAID or a local injec
tion of glucocorticoids may suffice. High dose oral glucocorti
coids should be avoided because eventual tapering of the
dosage raises the risk for erythrodermic psoriasis.
For more active disease, the ACR suggests initiating a TNF
inhibitor, methotrexate, or an interleukin 17 inhibitor. If one
agent is insufficient, another may be tried. Combination ther-
apy does not have the same effect in psoriatic arthritis as in
rheumatoid arthritis. Surgery may be indicated for significant
damage to larger joints.
For mild arthritic disease, NSAIDs or joint injections with
glucocorticoids may be sufficient until the disease self
resolves. For more persistent or severe disease, sulfasalazine
(preferred) or methotrexate may be required. There are few
data from controlled studies for either agent, but case series
and reports suggest efficacy. TNF inhibitors may also be needed
if these agents fail, but again data are scant. Given the mono-
phasic nature of reactive arthritis in many patients, a trial off
therapy is warranted 3 to 6 months after remission.
Topical glucocorticoids can be used to help address the
skin manifestations, and topical ocular glucocorticoids are
useful for uveitis.
KEY POITTS
. For ankylosing spondylitis, NSAIDs are recommended
as the initial medication to relieve pain and improve
stiffness; physical therapy to maintain general range of
motion is essential.
. Tumor necrosis factor inhibitors in patients with active HVC

Enteropathic Arthritis ankylosing spondylitis are associated with improvements

Enteropathic arthritis is best addressed by focusing on control of
in clinical, radiographic, and MRI outcomes.
bowel inflammation. For spondyloarthritis associated with o For psoriaticarthritis, limited disease can be treated with
bowel involvement, medications to address both peripheral atopical NSAID or local glucocorticoid injection; for
arthritis and bowel inflammation include sulfasalazine, azathio- more active disease, a tumor necrosis factor inhibitor,
prine, methotrexate, and glucocorticoids. The TNF inhibitors are methotrexate, or interleukin-l7 inhibitor can be used.
especially useful for bowel and joint symptoms, including . The peripheral arthritis tied to inflammatory bowel dis-
spine disease. Interleukin 17 inhibitors may cause IBD to flare ease is best addressed by focusing on control ofbowel
and are contraindicated in these patients. NSAIDs should be inflammation; for spondyloarthritis that is associated
avoided when possible because ofthe potential for IBD flare. with bowel involvement, medications to address both
peripheral arthritis and bowel inllammation include
Reactive Anhritis sulfasalazine, azathioprine, methotrexate, and gluco-
Because of a lack of benefit, antibiotic treatment of reactive corticoids.
arthritis due to enteric organisms is not usually warranted. o Because of a lack of benefit, antibiotic treatment of
However, patients with severe infections or immunosuppres-
reactive arthritis due to enteric organisms is not usually
sion or those with urogenital infection with C. trachomatis
warranted; for mild arthritic disease, NSAIDs or joint
may benefit from antibacterial therapy.
injections with glucocorticoids may be sufficient, and
for more persistent or severe disease, sulfasalazine or
TABLE 1 8. Medications to Treat Psoriatic Arthritis methotrexate may be required.
Category Medications
Anti-inflammatory agents NSAIDs; oral or intra-articular
glucocorticoids
Non biologic disease-modiiying Methotrexate, leflu nomide, Systemic Lupus
antirheumatic drugs sulfasalazine, cyclosporine,
apremilast Erythematosus
Tumor necrosis factor inhibitors Etanercep! adalimumab,
infliximab, certolizumab, Epidemiology and
golimumab Pathophysiology
lnterleukin-1 7 inhibitors Secukinumab, ixekizumab, Systemic lupus erythematosus (SLE) is a multisystem autoim-
brodalumab
mune disease characterized by a heterogeneous constellation
lnterleukin-1 2/interleukin-23 Ustekinumab
inhibitor oforgan involvement and the presence ofantinuclear antibod
ies (ANA) and other autoantibodies.
Cytotoxic T-lym phocyte Abatacept
antigen-4 immunoglobulin In SLE, a complex and varying interaction of genes, envi-
ronment, and random events leads to a breakdown of self-
Janus kinase inhibitor Tofacitinib
tolerance and autoimmunilr. Defects in cellular apoptosis

42
 Systemic Lupus Erythematosus

result in inadequate clearance of intracellular proteins, espe-

cially nuclear antigens, promoting the generation of self
directed T and B cells and the initiation/propagation of
autoimmunity. Cytokine generation supports autoreactiviry
with type I interf'erons playing a major role. Autoantibodies
may directly induce tissue damage or promote the formation
of immune complexes that lead to complement activation and
tissue inflammation and damage. Inheritance of SLE risk is
polygenic, including major histocompatibility complex genes.
The risk for SLE is higher in those with a family history
Incidence increases at pubefi and peaks in the third decade.
The disease is more common and more severe in Black and
Hispanic populations. Approximately 90% of adult patients are
women; SLE is frequently more severe in men than women.
tIGURE 29. Thefacial eruption of acutecutaneous lupuserythematosus
f,lY POrilTt (malar or butterfly rash). This patient has fixed erythematous raised lesions over the
. Systemic lupus erythematosus is a multisystem autoim malar eminences, the bridge of the nose with sparing of the nasolabial folds, and
mune disease characterized by a heterogeneous constella- the chin.

tion oforgan involvement and the presence ofantinuclear

antibodies and other autoantibodies. desquamation. The facial eruption of ACLE (the classic malar
. Approximately 9O"/" of adult patients with systemic lupus or butterfly rash) is characterized by fixed, rather than tran-
erythematosus are women. sient, erythema/edema over the cheeks and bridge ofthe nose,
sparing the nasolabial folds (Figure 29), but the neck, upper
chest, and dorsum ofthe arms and hands can also be involved.
In some patients, a bullous eruption occurs. ACLE usually
Clin ica I Manifestations responds to therapy and heals without scarring or atrophy.
Mucocutaneous lnvolvement Subacute cutaneous lupus erythematosus (SCLE) is a
Skin disease occurs in most patients with SLE and is classified photosensitive rash occurring especially on the arms, neck,
as acute, subacute, or chronic. and upper trunk, usually sparing the central face (Figure 3o).
Acute cutaneous lupus erythematosus (ACLE) presents as It consists of erythematous annular/polycyclic or patchy papu-
an erythematous, macular, patchy eruption, sometimes with losquamous lesions, often with a fine scale, that may leave

fIGURE 30. Subacutecutaneouslupuserythematosusischaracterizedbyerythematous,macular,orpatchyskinlesionsthatarescalyandcanevolveas(/)annular/polycyclic

lesions or (B) papulosquamous plaques.

43
Systemic Lupus Erythematosus

unexplained pain and/or reduced range of motion. Long-

F tGUn E 3 I . Discoid lupus erythematosus.This patient has hyperpigmented,
raised patches with keratotic scaling and follicular plugging involving the malar
and perioral areas as well as the bridge of the nose. Areas of atrophic scarring are
also present.
postinflammatory hypo- or hyperpigmentation. SCLE is asso-
ciated with anti-Ro/SSA autoantibodies (prevalence >75%) and
can occur in isolation or as a manifestation of underlying SLE.
Discoid lupus erythematosus (DLE) is the most common
manifestation of chronic cutaneous Iupus
erythematosus
and can cause scarring, atrophy, and permanent alopecia
(Figure 31 and Figure 32). DLE presents as hlpo- or hyperpig-
mented patches or plaques, with erythema during active dis-
ease, which may be variably atrophic or hyperkeratotic. Like
SCLE, DLE can occur as an isolated flnding in the absence ofSLE
and in such cases is typically limited to the neck, face, and scalp.
Painless oral or nasopharyngeal ulcerations occur in
5'1, of patients with SLE. Involvement of the hard palate is
characteristic. Rarely, DLE is associated with painful ulcers.
Nonscarring alopecia is a common feature of active SLE,
with hair regrowtha sign of disease control.
Raynaud phenomenon occurs frequently, reflecting arte-
rial vasospasm of digital arteries. Other vascular changes,
including livedo reticularis or periungual erythema, may be
present as well, although these findings are nonspecific. Some
patients with SLE may develop cutaneous vasculitis, most
often in the distal extremities.
term and higher-dose (>20 mg/d) prednisone treatment,
severe/active SLE, and vasculitis are associated with
increased risk for osteonecrosis. MRI may be needed to iden-
tiff early disease. Although small lesions can improve with
out invasive treatment, larger areas of involvement can lead
to bony collapse. Treatment requires extended non-weight-
bearing and, some cases, core decompression of the
in
affected bone. In the wake of collapse, joint replacement
may be necessary.
Myalgia and subjective weakness are common, but true
myositis is rare. Glucocorticoids often cause muscle weakness,
and, rarely, antimalarial agents can affect muscle. Thus, medi-
cation effects must be differentiated from active SLE disease.
Fibromyalgia is a common comorbidity (30%); symptoms may
overlap those of active SLE disease.
Kidney lnvolvement
Kidney disease occurs frequently among patients with SLE and
remains an important source of morbidity. Lupus nephritis can
present with minimal laboratory abnormalities (non-nephrotic
proteinuria, hematuria), nephritis (hypertension, edema,
active urine sediment, and elevated serum creatinine), and/or
nephrosis (nephrotic-range proteinuria, edema, hypoalbu-
minemia, hypercholesterolemia, and, in some cases, thrombo-
sis). Untreated active disease may progress to kidney failure, in
severe cases requiring dialysis or transplant.

M usculoskeletal I nvolvement
Joints are affected in 90% of patients with SLE. Many patients
have arthralgia, and a much smaller group exhibits arthritis.
Many patients with SLE may have evidence of synovitis on
imaging even with minimal symptoms or swelling on exami-
nation. Typical distribution includes small peripheral joints,
often resembling rheumatoid arthritis, but large joints are also
affected. SLE arthritis is nonerosive, but reducible subluxation
of the digits, swan neck deformities, and ulnar deviation
(Jaccoud arthropathy) can occur, a result of damage to the
tendons and ligaments.
Osteonecrosis is a serious complication of SLE that most
commonly affects the hips but can also involve other large FIGU R E 3 2. Active discoid lupus erythematosus ol the scalp with scaning hair
joints. It should be suspected in patients with otherwise loss.

44

All patients with SLE should be regularly evaluated for
kidney involvement through assessment of serum creatinine
and urine for protein and microscopic evaluation. Active kid-
ney disease should be suspected when there is active urine
sediment or proteinuria greater than 500 mgl24 h (or a spot
urine protein to creatine ratio >500 mg/g). Elevated or rising
anti-double stranded DNA antibody titers or complement
consumption are commonly associated with active kidney
disease.
Kidney biopsy defines both the histologic subtype and the
activity/chronicity of disease, which are important for thera
peutic decisions. Indications fbr kidney biopsy include an
increase in serum creatinine level, unexplained decrease in
glomerular filtration rate, or proteinuria greater than
5OO mgl24 h (or a spot urine protein-to-creatinine ratio
>500 mg/g), especially in the presence of hematuria or an
active urine sediment.
See MKSAP 19 Nephrologz fbr information on the classes
and treatment of lupus nephritis.
Neuropsychiatric lnvolvement
Neuropsychiatric systemic lupus erythematosus (NPSLE) may
involve the central and/or peripheral nervous systems. NPSLE
prevalence is high (75%), but most of the common manifesta
tions (headache, mild cognitive dysfunction, and mood disor
der) are nonspecific. Peripheral neuropathy occurs in 10"/n to
14% ofpatients. Severe acute presentations, including seizures
and psychosis, are uncommon (<5'1,) but require aggressive
symptomatic as well as disease speciflc treatment.
Patients suspected of having serious central NPSLE,
such as meningitis, stroke, and psychosis, should undergo
central nervous system imaging (CT, MRI, or PET) and cere-
brospinal fluid analysis as appropriate. ln some patients
with severe disease, measurement of cerebrospinal fluid for
NPSLE associated autoantibodies (antineuronal, anti
N methyl r) aspartate receptor, antiribosomal P, and others)
may be useful. For patients suspected of having peripheral
neuropathies, electromyography and nerve conduction
studies should be performed. Neuropsychologic testing may
help define and distinguish organic versus functional cogni
tive changes.
Cardiovascular lnvolvement
Asymptomatic pericarditis is the most frequent cardiac mani-
festation of acute SLE (40'1,). When symptomatic, features
include chest pain, exudative effusion, and, rarely, tamponade
or chronic constriction. Myocarditis occurs in 5'1, to 10% of
patients with SLE and usually presents as insidious heart fail
ure but can be acute.
Valvular abnormalities occurring in SLE include those
associated with antiphospholipid syndrome (nonspecific
thickening of the mitral and aortic valve leaflets, vegetations,
regurgitation, and stenosis). Libman Sacks endocarditis (non
infectious verrucous vegetations) preferentially affects the
mitral valve and can cause embolic complications.
Systemic Lupus Erythematosus
Pulmonary lnvolvement
Pulmonary involvement is common in SLE, with most patients
presenting with pleuritis (45"1, 6O'X,). Pleural effusions occur
in approximately half of these patients and are typically exu
dative; fluid analysis may reveal lymphocytic pleocytosis and
mildly depressed glucose levels.
Parenchymal lung involvement occurs in less than 10'1, of
patients with SLE. A nonspecific interstitial pneumonia pat-
tern is most common, and evaluation centers on assessing SLE
activity and excluding other causes of diffuse parenchymal
lung disease. Two rare but potentially life threatening compli
cations of SLE lung disease are acute lupus pneumonitis (pre-
senting as fever, cough, dyspnea, hypoxemia, pleuritic chest
pain, and infiltrates) and diffuse alveolar hemorrhage (pre-
senting with dyspnea, hypoxemia, diffuse alveolar infiltrates,
a dropping hematocrit, and a high Dr.co). Both carry a high
mortality rate (>50'X,). Early recognition, rapid evaluation (CT
and/or bronchoscopy with bronchoalveolar lavage or biopsy),
and aggressive respiratory support combined with high dose
glucocorticoids and immunosuppression are required. With
new pulmonary infiltrates, differentiation between these dis
orders and infection can be difficult. and antibiotics and
immunosuppressive therapy are often administered simulta
neously until the diagnosis is clear.
Shrinking lung syndrome is a rare but characteristic syn
drome consisting of pleuritic chest pain and dyspnea, with
progressive decrease in lung volumes. The cause is uncertain,
but pleuropulmonary disease and/or diaphragmatic dysfunc
tion may contribute. Immunosuppression may reverse the
process in some patients.
Hematologic lnvolvement
In patients with SLE, normocytic, normochromic anemia of
inflammation is common; autoimmune hemolytic anemia
occurs in approximately 10u1, of cases and correlates with SLE
activity. Lymphopenia/leukopenia is also common but usually
mild. Thrombocytopenia occurs in 30'1, to 50% of cases, and
approximately 10'2, of patients develop severe thrombocytope
nia (<50,000/pL [50 x 10e/L]) in isolation or in conjunction
with hemolytic anemia.
Cytopenia in SLE may be caused by immune and non-
immune destructive mechanisms (including microangiopa-
thy), medications, and kidney and liver disease. Moderate and
severe or rapidly progressive cytopenia requires prompt evalu-
ation with serologic studies and/or bone marrow biopsy. An
exact cause of cytopenia may be diflicult to ascertain, and a
trial of medication adjustment in concert with evaluation for
other causes is often necessary.
Antiphospholipid antibodies and lupus anticoagulant are
present in about 40'2, of patients with SLE and may be associ
ated with a false positive result on a rapid plasma reagin test
fbr syphilis. Most patients are asymptomatic. Thrombotic
events occur in about 30%, of patients; these include
venous and arterial thrombosis, miscarriage, stillbirth, livedo
45
Systemic Lupus Erythematosus
reticularis, and cardiac valve thickening/vegetations. The risk
for thrombosis is highest in the presence of triple positivity fbr
lupus anticoagulant, anti pr-glycoprotein, and anticardi
olipin antibodies. Patients with SLE are at increased risk for
thrombotic events even in the absence of antiphospholipid
antibodies. See MKSAP 19 Hematologz for more information.
Gastrointestinal lnvolvement
Gastrointestinal involvement is a common (+oy,) and under
recognized SLE manifestation. Serositis presents as abdominal
pain, is usually associated with active disease, and improves
with treatment. Mesenteric vasculitis, inflammation of the
small and large bowel, pancreatitis, protein losing enteropa-
thy, and diffuse peritonitis are uncommon but may be severe
and associated with cutaneous vasculitis.
Noninfectious hepatitis can occur and is associated with
the presence of antiribosomal P antibodies. Patients with
SLE who have Raynaud phenomenon and anti U1
ribonucleoprotein antibodies are at increased risk fbr esopha
geal disease and reflux.
Medications used to treat SLE (NSAIDs, prednisone,
mycophenolate, azathioprine) also frequently affect the gas-
trointestinal system and may cause esophagitis, gastritis, pan
creatitis, and other manifestations.
XEY PO Il{IS
. The facial eruption of acute cutaneous lupus erythema-
tosus (malar or butterfly rash) is characterized by ery
thema/edema over the chin, cheeks, and bridge of the
nose, sparing the nasolabial folds.
r myalgia, and/or arthralgia but lacking objective flndings most
Many patients with systemic lupus erythematosus have
arthralgia, and a much smaller group exhibits arthritis.
o A11 patients with systemic lupus erythematosus should
be regular$ evaluated for kidney involvement through
assessment of serum creatinine and urine for protein
and microscopic evaluation.
. The most common manifestations of neuropsychiatric
systemic lupus erythematosus are headache, mild cog-
nitive dysfunction, and mood disorder.
Comorbidities
Patients with SLE have a higher overall risk for malignancies
(particularly hematologic); the risk for non Hodgkin lym
phoma is at least two to three times higher than in the general
population. Malignancy risk in SLE is tied to the use of immu
nosuppressive agents. Higher cumulative cyclophosphamide
doses are associated with increased risk for solid organ tumors,
and azathioprine use is associated with an increased risk for
myeloproliferative syndromes. Cervical cancer is also increased
in patients with SLE, especially those receiving immunosup
pressive therapies. Hydroxychloroquine use does not appear to
increase malignancy risk and may be protective.
Patients with SLE have a 2- to 10 fold increased preva
lence of coronary artery disease. It is the most common cause
46
of death among older patients with SLE, even those whose
lupus has become quiescent. A history of high SLE disease
activity (especially nephritis) and prednisone dosages greater
than 10 mg/d are independent risk factors for coronary artery
disease. Patients with SLE are also at increased risk for
ischemic stroke.
XEY POIT{TS
o Patients with systemic lupus erythematosus are at
increased risk for malignancy; immunosuppressive use
contributes to this increased risk.
. Patients with systemic lupus erythematosus have a 2- to
10 fold increased prevalence of coronary artery disease;
high SLE disease activity and prednisone dosages
greater than 10 mg/d are independent risk factors for
coronary artery disease.
Diagnosis
General Considerations
The diagnosis of SLE should be considered in patients, espe
cially young women, with any individual manifestation of SLE
or with symptoms affecting multiple organ systems. The most
common presenting clinical features that differentiate patients
with SLE from those with other mimicking conditions include
malar rash, photosensitivity, inflammatory arthritis, weight
loss, and fever, along with such laboratory features as positiv
ity lor ANA, low complement levels, and presence of lupus
specific antibodies. Patients with subjective reports of fatigue,
likely have an alternative diagnosis and should not be evalu
ated for SLE.
Several classification criteria for SLE have been used;
although intended for recruitment of homogenous SLE popu-
lations for research sfudies, they can also be used to suggest a
clinical diagnosis ofSLE. A 2019 update ofthese criteria from
the European League Against Rheumatism/American College
of Rheumatologr includes the requirement for a positive ANA
result at least once, with the addition of clinical and/or immu-
nologic criteria totaling at least 10 points on a weighted scale
(Figure 33). These criteria compare favorably to prior pub
Iished criteria, with a sensitivity of about 96% and specificity
ofabout 93%.
Laboratory Studies
Initial evaluation for SLE includes routine laboratory test-
ing to establish organ specific involvement, including com
plete blood count, chemistry panel, and urinalysis with
microscopy.
ANA should be obtained to screen for nuclear directed
autoantibodies. The most appropriate method for testing
ANA is the indirect immunofluorescence assay, which is
highly sensitive (>9s'l.) for SLE but not specific. ANA tests
should be interpreted in the context of the probability of
 Systemic Lupus Erythematosus

Emry Grttetton

Antinuclear antibody at a titer >1:80 on

Hep-2 cells or equivalent positive test result

lf absent do not classify as SLE

lf present apply additive criteria

Addldvr Ct{trria
Do not count a criterion if there is a mora likely explanation than SLE, Occurrenca of a criterion on at least one occasion is
sufficient SLE classification requires at least one clinical criterion and >10 points. Criteria need not occur simultaneously.
Wrthin each domain, only the highest weighted criterion is counted toward the total score.

(llnlcd Domrlnr end Crlterlr Wclglrt lmmunologlc Domdnr rnd Critorle Wdgh0

Gonrtltrtlonrl
Fever (temparature >38.3 'C) 2 Anticardiolipin antibodi€s or
Anti-pr-glycoprotein I antibodies or
Lupus anticoagulant 2

H.m.tologlc Gmphmrntprctdm
teukopenia (<4000/yL [4.0 x 1 0'lL]) 3 Low C3 or low C4 3
Thrombocytopenia (<1 00,000/pL [1 00 x 1 0'lL]) 4 Low Crl and low C4 4
Autoimmune hemolysis (with positive 4
direct antiglobulin test result)

Nouroprydrlrtrlc SlErpeclfic endbodlor

Delirium 2 Anti-dsDNA antibody or
Psychosis (delusions and hallucinations in Anti6mith antibody 6
absence of delirium) 3
Seizure (primary generalized or focal seizure) 5

tlucocutrneout (obcorvcd by dlnlcien)

Nonscarring alopecia 2
Oral ulcers 2
Subacute cutaneous or discoid lupus 4
Acute cutaneous lupus 6

!hrcrel
Pleural or pericandial effusion 5
Acute pericarditis 6

Murculorkclctrl
Joint involvement (synovitis in >2 joints or
tendemess of >2 joints with >30 minutes of
moming stiffness) 6

Ronel
Proteinuria >0,5 g/24 h (or equivalent rpot urine
protein-to-creatinine ratio) 4
Renal biopsy showing class ll or V lupus nephritis 8
Renal biopsy showing class lll or lV lupus nephritis 10

is fulfilled'
Classifu as systemic lupus erythematosus with a score of 10 or more if entry criterion

DNA; Hep-2 = human epithelial 2; 5LE = systemic lupus erythematosus'

f IGUR E 33 . Classification criteria for systemic luPus erythematosus' dsDNA = dou ble*tranded

2019;78;I15i-1159. PMID: 3l383717 doi:10.1136/annrheumdis 20l8 214819

47
Systemic Lupus Erythematosus
disease because ANA may be present in patients with other
autoimmune diseases as well as in healthy individuals. Low
titer ANA (<1,80) is considered negative; even ANA at a more
positive titer in the absence ol specific features of SLE may be
noninformative.
lf the ANA result is positive and the clinical context sup
portive, SlE-specific autoantibodies (anti-double stranded
DNA, anti Smith, anti Ul ribonucleoprotein, anti Ro/SSA,
and anti LalSSB), as well as tests for other autoimmune
diseases under consideration. should be obtained to further
characterize the disease (Table 19).
Disease activity markers, including complements C3
and C4, should be assessed initially and regularly thereaf
ter. Complement levels are typically reduced during SLE
activity, reflecting immune complex formation and com
plement consumption. Rising titers of anti-double-
stranded DNA antibody levels may be concordant with SLE
kidney disease activity. Other SLE autoantibodies, includ-
ing ANA, do not reflect disease activity and need not be
repeated. Erythrocyte sedimentation rate and C reactive
protein are variably associated with disease activity;
some patients with SLE have little to no elevation in
C reactive protein during SLE flares, which may help dis
tinguish flares from infection once the individual patient's
pattern of responsiveness is established.
Differential Diagnosis
The differential diagnosis of SLE includes multisystem dis-
eases, acute and chronic infections, medication effect, malig-
nancies (particularly hematologic), and neurologic diseases
(e.g., multiple sclerosis). Multisystem autoimmune diseases
(ANCA associated vasculitis, rheumatoid arthritis, adult-onset
Still disease, dermatomyositis, Sjogren syndrome, and mixed
connective tissue disease) have overlapping features but may
be distinguished through a careful assessment oftheir unique
manifestations.
SLE should also be distinguished from undifferentiated
connective tissue disease, which presents with milder slmptoms
TABLE 1*. Common Autoantibodies in Systemic Lupus Erythematosus
Autoantibody Frequenry in
Antinuclear >95"/o
Anti-double-stranded DNA 50"/"-60"/"
Anti-Ro/SSA 30%
Anti-U I -ribonucleoprotein 35%
: Anti-Smith 30%
Anti LalSSB 20%
Antiribosomal P 150/"
CNS = central nervous system; MCTD = mixed connective tissue disease;
48
and objective abnormalities that cannot be categorized or
diagnosed as a specific connective tissue disease (see Mixed
Connective Tissue Disease and Undifferentiated Connective
Tissue Disease).
Certain medications can cause drug induced lupus ery
thematosus (DILE), which mimics SLE (Table 2o). The syn
drome is usually milder; malaise, fever, arthritis, and rash are
associated with transient positivity for ANA and antihistone
antibodies. Symptoms usually resolve after discontinuation of
the offending agent. Kidney and central nervous system dis
ease are uncommon. Patients with SLE are at no more risk for
DILE than the general population, and medications associated
with DILE are not contraindicated in patients with SLE.
f,EY POIilTt
. Patients with systemic lupus ery.thematosus typically
initially present with skin and joint manifestations;
many also have fever or weight loss.
. Initial evaluation for systemic lupus erythematosus
includes antinuclear antibody testing as well as routine
laboratory testing to establish organ-specific involvement,
including complete blood count, chemistry panel, and
urinalysis with microscopy.
o Ifresults ofantinuclear antibody testing are positive
and the clinical context is supportive, autoantibodies
specific to systemic lupus erythematosus (anti-double-
stranded DNA, anti-Smith, anti-Ul-ribonucleoprotein,
anti-Ro/SSA, and anti-LaiSSB) should be obtained to
further characterize the disease.
Management
SLE most often follows a relapsing remitting pattem (ZO'7,)
with periods of inactive disease, although some patients may
have a monophasic or persistently active pattern. The most
commonly used instrument for monitoring disease activity is
the SLE Disease Activity Index (SLEDAI), which incorporates
SLE Comments
Useful as an initial screening test; assesses multiple antigens simultaneously
Found in more severe disease, especially kidney disease; antibody levels
commonly {ollow disease activity and are useful to monitor
Associated with photosensitive rashes, discoid lupus erythematosus, and neonatal
lupus erythematosus; also common when secondary Sjogren syndrome is present
as.sgTrled with Raynaud phenomenon and esophageal dysmotility; also seen
in MCTD
Specific for SLE; often associated with more severe disease
Common in Sjogren syndrome; less common in SLE and neonatal lupus
erythematosus
Associated with CNS lupus and lupus hepatitis
SLE = systemic lupus e rlthematosus.
 Systemic Lupus Erythematosus

TABLE 20. Medications Commonly Associated With Drug-lnduced Lupus Erythematosus

Medication Antibodies Detected Comments
Procainamide ANA(75%); antihistone 207o develop DILE; fever; arthritis; serositis
Hyd ralazine ANA(20%); antihistone 5%-B% develop DILE; fever; arthritis; rare vasculitis and kidney
disease
Minocycline ANA; ANCA; anti-dsDNA rare Arthritis; vasculitis; autoimmune hepatitis
Antithyroid drugs ANA; ANCA; antihistone Vasculitic rash; rare pulmonary and kidney disease
Statins ANA; antihistone; anti-dsDNA SLE, SCLE, dermatomyositis, and polymyositis all reported
Calcium channel blockers ANA; anti-Ro/SSA; antihistone rare SCLE

Thiazide diuretics ANA; anti-Ro/SSA; antihistone rare SCLE

ACE inhibitors ANA; anti-Ro/SSA; antihistone rare SCLE

TNF inhibitors ANA (23%-57%); chromatin and anti DILE most common with in{liximab, uncommon for
dsDNA common; antihistone rare etanercept; SLE, SCLE, DLE all reported
ANA = antinuclear antibodies; DILE = drug induced lupus erghematosus; DLE = discoid lupus erythematosus; dsDNA = double stranded DNA; SCLE = subacute cutaneous lupus
erythematosus; SLE = systemic lupus erythematosus; TNF = tumor necrosis factor.

both clinical and laboratory measures. Clinical remission or
low disease activity are typical goals of therapy.
Pharmacologic therapy is almost always required; the
choice of agents should reflect disease activity and specific
organ involvement. Management requires frequent disease
assessment and adjustment of treatment to reflect changing
conditions (Table 21).
Hydroxychloroquine is a mainstay of treatment in
because it reduces disease-associated damage, prevents dis
ease flares, and improves kidney and overall survival. In addi
tion, hydroxychloroquine may reduce the risk for thrombosis,
liver disease, and myocardial infarction; improve lipid pro-
files; and improve outcomes in high-risk pregnancies. Almost
all patients with SLE without contraindications should receive
hydroxychloroquine. With very rare exceptions the dosage
should be limited to 5 mg/kg/d or less, and patients should
receive annual monitoring by an ophthalmologist after 5 years
of treatment to reduce the risk for retinal toxicity.
Hydroxychloroquine can be used alone for mild disease
(especially skin and joints) and in combination with other
agents in severe disease.
Glucocorticoids are also used in most patients with SLE,
particularly in acute disease. The glucocorticoid dose should be
determined by the level of disease activity and organ systems
threatened. For severe disease actMty (including profound cyto-
penia, class III/IV nephritis, and NPSLE), high-dose glucocorti
SLE coids are recommended. For life- or organ-threatening disease
(such as rapidly progressive glomerulonephritis or seizures),
high dose intravenous glucocorticoids are given, typically fol
lowed by daily oral glucocorticoids. After disease stability is
achieved, glucocorticoids are tapered to the lowest effective dos
age, preferably to no more than 7.5 mg/d within 4 to 6 months.
Literature supports limiting exposure to glucocorticoids, espe
cially at high doses, because ofassociated risk for organ damage,
infection, and premature mortality Glucocorticoids should be
discontinued entirely when possible.
For moderate or severe disease, immunosuppressive ther-
apy should be initiated concurrently with glucocorticoids to

TABLE 21 . Medications Commonly Used to Treat Systemic Lupus Erythematosus

Medication Common Uses in SLE lmportant Adverse Effects
NSAIDs Arthritis; pain; fever Hypertension; Gl bleeding; AKI
Prednisone Used for all manifestations in varying doses Hypertension; glucose intolerance; weight
gain; i nfection; osteonecrosis
Hydroxychloroquine Used in almost all patients without contraindications; Gl intolerance; rash; blurry vision; retinopathy;
especially useful{or skin involvement and to prevent vacuolar myopathy
disease flares
Mycophenolate mofetil Moderate to severe disease; as effective as Bone marrow suppression; elevation of liver
cyclophosphamide for remission induction for nephritis enzymes; infection
Azathioprine Moderate to severe disease Bone marrow suppression; elevation of liver
enzymes; hematologic malignancy
Cyclophosphamide Severe organ- or life-threatening disease Bone marrow suppression; hemorrhagic
cystitis; i nfection ; ma g na ncy; i nferti ity
Ii I

Belimumab Add-on therapy for moderate to severe disease lnfusion reactions; infections

AKI = acute kidney injury; Gl = gastrointestinal; SLE = systemic lupus erythematosus.

49
 Systemic Lupus Erythematosus

achieve and maintain disease control and to allow tapering of Pregnancy and Childbirth lssues
glucocorticoids. The choice of medication should be deter-
SLE is associated with a five to eightfold increase in miscar-
mined by the organs involved and disease severity. Intravenous
riage, stillbirth, premature delivery and intrauterine growth
cyclophosphamide is used as induction therapy for severe or
retardation. Outcomes are worse in patients with active dis
refractory disease (e.g., severe active nephritis, acute central
ease, nephritis, or anti-Ro/SSA and/or antiphospholipid anti-
nervous system lupus, diffuse alveolar hemorrhage, or myo-
bodies. The best time to consider pregnancy is when SLE is
carditis), followed by maintenance therapy with mycopheno
quiescent, and conception should be planned after at least
late mofetil or azathioprine. Mycophenolate mofetil is the
6 months ofadequate disease control.
preferred oral agent for lupus nephritis and is as effective as
Proteinuria may increase during pregnancy in patients
cyclophosphamide for induction therapy. The biologic agent
with SLE, making the distinction betlveen SLE and pre-
belimumab is FDA approved for patients with incomplete
eclampsia a challenge. Increases in anti-double stranded
response to conventional treatments and is useful for skin/
joint involvement and moderate/severe disease. Experience DNA antibody titers, decreasing complement levels, or the
development of active urine sediment suggests SLE as the
suggests a possible benefit as add on therapy for more severe
cause. In contrast. serum urate levels are increased in
organ involvement.
preeclampsia but not during SLE flares.
Less commonly used medications include quinacrine,
Fetuses of women who have anti-Ro/SSA or anti LalSSB
methotrexate, leflunomide, calcineurin inhibitors, and
antibodies are at risk for neonatal lupus ery.thematosus, which
rituximab. Other agents under investigation include pro
is characterized by rash and congenital heart block. Although
teasome inhibitors, Janus kinase inhibitors, interleukin 12
the risk for congenital heart block in the offspring ofan anti
and interleukin-23 inhibitors, and other B cell-acting
Ro/SSA positive woman is only 2'7,, this condition is associ
agents.
ated with significant fetal and neonatal morbidity and
Adjunctive agents may be used for specific clinical fea
mortality. After a woman bears a child with neonatal lupus
tures. NSAIDs can be used to treat arthritis and pleuropericar
erythematosus, the risk for congenital heart block is
ditis but are not disease modi[zing and may adversely affect
substantially increased (20%) in subsequent pregnancies.
kidney function and blood pressure. Statins and antihyper-
Hydroxychloroquine may reduce the overall risk. Women with
tensive agents are often used to reduce cardiovascular risks.
SLE who have concurrent antiphospholipid syndrome are at
ACE inhibitors should be considered in patients with pro-
increased risk lor miscarriage.
teinuria. Adequate vitamin D intake is important in patients
Management of medications during SLE pregnancy is
with SLE. Bone health should be monitored, with treatment
complicated. Hydroxychloroquine and low dose glucocorti-
for appropriate patients, especially those receiving glucocor
coids can be started during or continued throughout the preg
ticoids. Sun avoidance and regular use of sunscreen that
nancy. Higher dose glucocorticoids can be used to treat
blocks both UV-A and UV B should be recommended for all
patients with SLE.
flare ups or end-organ involvement. The preferred immuno
suppressive agent for SLE during pregnancy is azathioprine,
See Principles of Therapeutics for information on SLE
but this drug should be used only if necessary. Belimumab,
medication toxicities, monitoring parameters, and more. See
methotrexate, mycophenolate mofetil, and cyclophosphamide
MKSAP 19 Nephrologr for details on the treatment of lupus
should be avoided because of risks for teratogenic effects.
nephritis.
Cyclophosphamide is associated with age and dose dependent
XTY POIf,TS infertility. See Principles of Therapeutics for information on
HVC o Almost all patients with systemic lupus erythematosus medications and pregnancy.
without contraindications should receive hydroxychlo-
XEY POIilIS
roquine because it can reduce disease-associated dam-
age, prevent disease flares, and improve kidney and . Systemic lupus erythematosus is associated with a five-
overall survival. to eightfold increase in miscarriage, stillbirth, premature
o Glucocorticoids delivery and intrauterine growth retardation.
in most patients with systemic
are used
lupus erythematosus, particularly in acute disease; after o The best time to consider pregnancy is when systemic
disease stability is achieved, glucocorticoids should be lupus erythematosus is quiescent, and conception
tapered to the lowest effective dose, ideally to discontin- should be planned only after at least 6 months of ade-
uation. quate disease control.
. For moderate or severe systemic lupus erythematosus, o Fetuses of women who have anti-Ro/SSA or anti-La/SSB
immunosuppressive therapy should be initiated antibodies are at risk for neonatal lupus erlrthematosus
(rash and congenital heart block). 'l
concurrently with glucocorticoids to achieve and
maintain disease control and to allow tapering of . Hydroxychloroquine and low-dose glucocorticoids can
glucocorticoids. during or continued throughout preg-nancy.
be started

50

Prognosis
The prognosis in SLE has improved significantly. The 5 year
survival rate is 90u1,, although mortality remains high com
pared to that in age-matched controls. Early mortali[z is usu
ally related to SLE disease and infections, and late mortality is
related to cardiovascular disease. Factors adversely affecting
;
survival include myocarditis, nephritis, low socioeconomic
status, male sex, and age older than 50 years at diagnosis.
I(EY POIilI
. Factors adversely affecting survival in systemic lupus
erythematosus include myocarditis, nephritis, low soci-
oeconomic status, male sex, and age older than 50 years
at diagnosis.
Sjtigren Syndrome
Epidemiology and
Pathophysiology
Sjogren syndrome is a systemic autoimmune exocrinopathy
primarily affecting salivary and lacrimal glands. The condition
is female predominant, with a female-to-male ratio between 6
and 9 to 1. Sjogren syndrome most commonly presents in the
fifth and sixth decades of life, but patients of any age may be
affected; a pediatric variant is also recognized. Primary SjOgren
syndrome occurs in isolation; secondary Sjogren syndrome
develops with other rheumatologic diseases, most commonly
rheumatoid arthritis and systemic Iupus erythematosus.
Whereas the primary form is uncommon (ranging from 0.5
to 5 patients/l0O0), secondary Sjdgren syndrome is often
observed (10%-30%) among populations with predisposing
rheumatologic conditions. Sjdgren syndrome is thought to
result from activation of mucosal epithelial cells by unknown
stimuli. This, in turn, leads to tonic activation of the innate and
adaptive immune systems, including extensive influx of lym
I phocytes into exocrine glands. The resulting epithelial and
obliterative damage impairs the ability to produce or deliver
secretions.
Cli nica I Manifestations
The most common presentation of Sjdgren syndrome is sicca,
I
consisting of ocular and oral dryness. Patients report gritty
.
eyes or a foreign body sensation. Oral dryness can cause diffi
i
culty eating unmoistened food and increases the risk for den
tal caries. Symmetric parotid and lacrimal swelling can occur.
Other exocrine glands can be involved, leading to skin and
vaginal dryness. Pancreatic involvement has been reported.
I
Extraglandular manilestations may occur in some
patients (Table 22). Arthralgia and fibromyalgia are common,
but nonerosive arthritis in the absence of rheumatoid arthritis
is uncommon. Other common extraglandular manifestations
Sjiigren Syndrome
TABLE 22. Extraglandular Clinical Manifestations of
Sjcigren Syndrome
Site/Organ Manifestation/Frequency
General Fatigue (70%), fever (6%)
S kin Dry skin (xerosis), cutaneous vasculitis:
10o/"-1 67"
Joint Arthralgia/arthritis: 36%
Lung lnterstitial pneumonitis: 5%-9%
Kidney lnterstitial nephritis, type 1 (hypokalemic
distal) renal tubular acidosis,
glomeru loneph rilis: 57o- 60/"
Neurologic CNS: demyelinating disease, myelopathy,
cranial nerve neuropathy
Peripheral nervous system: small-fiber
neuropathy, mononeuritis multiplex,
peripheral neuropathy
8o/"-27"/ofor CNS and peripheral nervous
Gastrointestina I
system
Autoimmune hepatitis, primary biliary
cirrhosis: 3"/o-207"
Hematologic Lym p homa, cytope ni a : 27o
Other Systemic vasculitis (7%), cryoglobulinemia
1 2o/"), Rayna ud phe nomenon ( 1 6%),
(4o/"-
thyroid d isease (1 0"/"- 1 5"/")
CNS = central nervous system-
include fatigue and Raynaud phenomenon. Both peripheral
and central nervous system involvement may be seen, although
the former is more common. The typical peripheral nervous
system manifestation is axonal polyneuropathy. Central nerv
ous system involvement often presents as demyelinating dis
ease, such as optic neuritis, transverse myelitis, or a multiple
sclerosis-like presentation. Cutaneous, pulmonary and kid
ney disease are relatively rare. Nonspecific laboratory findings
include hypocomplementemia, hypergammaglobulinemia,
leukopenia, and anemia of inflammation.
Patients with Sjogren syndrome are at increased risk for
non Hodgkin lymphoma compared with the general popula
tion. Estimates suggest as much as a 44 fold increased risk fbr
mucosal associated lymphoid tissue lymphoma; this increase
presumably results from an elevated risk for lymphomatous
transformation due to chronic activation of tissue lympho-
cytes. Clinical features conferring a higher risk include lym
phadenopathy, recurrent parotid gland swelling, monoclonal
gammopathy, depressed C4 complement, and decreased rheu
matoid factor if titer is elevated at baseline. About 5'7, of
patients with Sjdgren syndrome develop lymphoma over time,
usually within the first decade after diagnosis.
Diagnosis
An evaluation for Sjogren syndrome is typically triggered
when the patient reports symptoms of ocular or oral dryness.
It requires objective confirmation of exocrinopathy along with
51
Sjtigren Syndrome
demonstration of autoimmunity (Table 23 shows validated
classification criteria). Ophthalmic dryness can be assessed
by using the Schirmer test, in which a strip of filter paper is
placed under the lower eyelid and wetting is measured; less
than 5 mm of wetting in 5 minutes indicates dryness. More
formally, dryness and corneal damage are ascertained with
slit lamp examination by an ophthalmologist. Topical stain-
ing may be used to identiff injury and fissures in the cornea.
Dry mouth is assessed by direct examination, with dental
caries and a lack of saliva suggesting the diagnosis.
Measurement of salivary flow, or sialometry should ideally be
performed to determine whether true dryness is present (and
to show ductal architecture). However, this is rarely done
because it requires special equipment that is not available in
most settings. Other forms of imaging (e.g., CT, gallium scan
ning) are not generally helpful but may rarely be useful in
defining organ involvement.
Multiple autoantibodies may be found in Sjdgren syn-
drome, but none are independently diagnostic. Antinuclear
antibodies and/or rheumatoid factor are often present at high
titers; their coexpression is more suggestive of Sjogren s1m-
drome than is positivity of only one. The presence of anti-Ro/
SSA autoantibodies is specific in primary Sjdgren syndrome
but less so in secondary Sjdgren syndrome because these anti
bodies are also common in systemic lupus erythematosus.
Anti LalSSB autoantibodies are characteristic ofSjogren syn-
drome but are not included in formal classification criteria.
When initial evaluation is uninformative, a lip (minor salivary
gland) biopsy should be considered. Characteristic histologic
features include aggregate foci (>50 cells/aggregate) of CD4 T
cells, B cells, and plasma cells surrounding secretory ducts.
The differential diagnosis of SjOgren syndrome tlpically
relates to the presence of sicca and/or parotid and lacrimal
TABLE 23.
American College of Rheumatology/European
League Against Rheumatism Classification Criteria for
Primary Sjogren Syndrome"
Presence of subjective finding of Sjtigren syndrome
(e.9., sicca) plus any combination of the following
resulting in a score of >4:
Item Score
Salivary gland biopsy specimen showing )1 foci of
lymphocytic infiltrate/4 mm2
Anti- Ro/SSA autoa ntibodies
Ocular staining score >5 in at least one eye
Schirmertest<5 mm/5 min in at least one eye
Unstimulated whole saliva flow rate <0.1 mUmin
nExclusion criteria include prior head/neck radiation and
history of active hepatitis
C virus infection, AIDS, sarcoidosis, amyloidosis, graft-versus host disease, and
lgG4 related d sease.
From Shiboski CH, Shib,oski SC, Seror R, et al; lnternational Sjogren's Syndrome
Criteria Working Group. 2016 American College of Rheumatology/European
League Against Rheumatism Classification Criteria for Primary Sjogren's
Syndrome: a consensus and data-driven methodology involving three
international patient cohorts. Arthritis Rheumatol. 201 7 Jan;69(1 ):35-45.
doi:1 0.1 002/art.39859. IPMID: 27785888]. Copyright 201 6, American College of
Rheumatology. Adapted with permission from John Wiley & Sons, lnc.
52
enlargement. Sarcoidosis, IgG4 related disease, granulomato
sis with polyangiitis, lymphoma, and infection (such as
mumps, hepatitis C virus infection, and HIV infection) may be
associated with similar findings. Ocular and oral dryness may
also occur with aging, in other disease states (such as rheuma-
toid arthritis), or as an adverse effect of medications or treat
ment (such as antidepressants and antihistamines or radiation
of the head and neck). Unilateral or single enlargement of a
gland should raise concern for obstruction or malignancy.
Management
Management of sicca centers on preserving moisture and
relieving symptoms. Eye dryness is treated with over the
counter artificial tears, gels, and ointmentsi lor refractory or
more severe symptoms, topical cyclosporine or a small
molecule integrin antagonist may be added. Plugging the lac-
rimal ducts to promote tear retention is widely performed, but
clinical trials have not shown its effectiveness. For oral
dryness, first-line treatment in patients with less severe
symptoms should be nonpharmacologic salivary stimulation,
both with gustatory stimulants (e.g., sugar-free candy) and
mechanical stimulants (e.g., sugar-free gum).
Pharmacologic therapies should be reserved for moder
ate or severe oral dryness. These include the muscarinic
agonists pilocarpine and cevimeline, which may not be well
tolerated; they are also contraindicated in narrow-angle
glaucoma. Artificial saliva may be used for severe dysfunc
tion, but its effects are so transient that most patients do not
find it useful. Meticulous dental care is essential to prevent
gingivitis and dental decay, regardless of symptom severity.
Vaginal symptoms may be treated with topical lubricants or
estrogen.
Active extraglandular autoimmune disease should be
treated with systemic therapies. In most cases, glucocorticoids
may be considered as a first line option, but only at the
minimum dose and length of time necessary to control the
active disease. Immunomodulatory/immunosuppressive (e.g.,
hydroxychloroquine, methotrexate, cyclophosphamide) and
biologic (e.9., anti-B cell therapy with rituximab or beli-
mumab) agents should be considered for second or third line
2 therapy, or for glucocorticoid sparing. To the extent possible,
decisions should be tailored to severity and the organ or organs
3 affected (e.9., pneumonitis, central nervous system disease).
Musculoskeletal pain is common in Sjogren syndrome but
should not be treated with immunomodulatory or biologic
therapy unless there is objective evidence of active inflamma-
tory arthritis. Myalgia and arthralgia, along with chronic non
specific pain, should be treated symptomatically.
Prognosis
The prognosis for primary Sj6gren syndrome is favorable, with
no overall increase in mortality. Management of sicca reduces
the risk for corneal damage or tooth loss. In rare instances,
 ldiopathic lnflammatory Myopathies

end-organ involvement can be life threatening. Secondary

Sj6gren syndrome may be associated with significant morbid-
ity from the primary condition.
rEY POITII
o Sjdgren syndrome is an autoimmune exocrinopathy
affecting salivary and lacrimal glands; the most com
mon presentation is sicca (dryness of the eyes and/or
mouth).
o Patients with Sjdgren syndrome are at increased risk for
non-Hodgkin lymphoma.
. A diagnosis of Sjogren syndrome is lzpically triggered
by the patient's report ofocular and oral dryness and
requires objective confirmation of exocrinopathy, along
with demonstration of autoimmunity
. In patients with Sjogren syndrome, management of
sicca centers on preserving moisture and relieving
symptoms; extraglandular involvement is treated with
immunosuppression.
ldiopathic lnflammatory
Myopathies
Overview
Idiopathic infl ammatory myopathies (llMs) are characterized
by muscle inflammation and proximal muscle weakness.
Subcategories in adult patients include polymyositis, dermato
myositis, immune mediated necrotizing myopathy, and inclu
sion body myositis.
Evaluation of the Patient With
Muscle Pain or Weakness
The differential diagnosis of muscle disease is broad and
includes hereditary environmental, infectious, and acquired
conditions (Table 2a). The IIMs commonly present with sym
metric proximal muscle weakness without substantial muscle
pain or tenderness. Serum creatine kinase levels are almost
universally elevated, and this elevation is a marker of muscle
damage. The presence of pain or tenderness should prompt
consideration of alternative causes, such as infectious, endo-
crine (thyroid), or drug induced myopathies. Medications and
drugs are common causes of muscle pain and weakness and
should also be considered in the differential diagnosis ofthe
inflammatory myopathies (Table 2S).
Muscle weakness must be differentiated from general
ized weakness, which is common and caused by conditions
such as cardiopulmonary disease, malignancy, depression,
and deconditioning. Primary neurologic disorders (e.g.,
spinal muscle atrophies, amyotrophic lateral sclerosis, and
myasthenia gravis) may cause muscle weakness but are dis
tinguished by involvement of nonproximal muscle groups
and nerve involvement on electromyography; an elevated
serum creatine kinase level is uncommon. Exercise-induced
weakness may point to a metabolic or mitochondrial cause
rather than an IIM.
Epidemiology and
Pathophysiology
IIMs are uncommon and heterogeneous. The annual incidence
is between 2 and 10 cases per million. Two peaks of onset

TABLE 24. Differential Diagnosis of Myopathy

Myopathy
ldiopathic inflammatory
myopathies
Systemic rheumatologic
disease
Muscular dystrophies
Metabolic myopathies
Common Examples
Dermatomyositis; polymyositis; immune-mediated
necrotizing myopathy; inclusion body myositis
Systemic lupus erythematosus; systemic sclerosis;
mixed connective tissue disease
Duchenne muscular dystrophy; Becker muscular
dystrophy
Glycogen storage diseases; carnitine
pal mitoyltra nsferase deficiency
Comments
Dermatomyositis and polymyositis: acute-subacute
onset, symmetric, proximal
Dermatomyositis: pathognomonic rash
lmmune-mediated necrotizing myopathy: acute
onset, symmetric, proximal
lnclusion body myositis: insidious onset, proximal
and distal
Prominent extramuscular features typical of
underlying disorder
Childhood onset; cardiomyopathy possible
Exercise intolerance

Mitochondrial myopathies
Endocrine disorders
Infection-ind uced
Kearns-Sayre syndrome; Leigh syndrome Variable age of presentation and features; isolated
myopathy or with neurologic, multisystem disease
Hypothyroidism; hyperthyroidism; adrena I Prominent myalgia
insufficiency
Bacterial: pyomyositis; viral: influenza; parasitic Prominent myalgia; sometimes accompanied by
trichinosis fever

53
ldiopathic lnflammatory Myopathies
TABLE 25. Drug-lnduced MyoPathies
Drug Time Course
Alcohol lncreased with long-term use
Antimalarials Can occur after prolonged use
Cocaine Can occur after single use
Colchicine Usually months to years; increased risk with
coad ministration of cytochrome P450 inhibitors
Glucocorticoids lncreased with long-term use
Statins Usually weeks to months but can occur at any time;
increased risk with preexisting neuromuscular disease,
hypothyroi d ism, kid n ey fa i I u re, a nd/o r coad m i n istrati o n
of cytochrome P450 inhibitors; may also trigger immune-
mediated necrotizing myopathy
Zidovudine Variable; may be more common after long-term use
occur: the first in childhood and the second in middle age. A
female adult predominance is approximately 2:1, with the
exception of inclusion body myositis, which preferentially
affects men.
Like many other autoimmune diseases, IIMs probably
result from interactions between genetic and environmental
factors. The clearest genetic association is with HLA alleles,
including HLA-DRBI.03:01 with polymyositis and HLA
DRB'08:01 with dermatomyositis. Distinct HLA alleles have
also been associated with different IIM subgroups, as
defined by myositis-specific antibodies. However, because
HLA associations in IIM vary by ethnic groups around the
world, their utility in diagnosis and categorization is
limited.
Environmental factors may activate or modify gene
expression and likely influence disease progression and sever
ity in addition to onset. Associations with infections, medica-
tions, occupational exposures, ultraviolet light, and other
factors have been reported. The clearest associations have been
with medications, including statins, cytokine-targeted thera
pies (interferons and tumor necrosis factor inhibitors), and
checkpoint inhibitors.
Immune mechanisms that contribute to IIM vary
between subtypes and include the presence of T- and
B-lymphocytic infiltrates, as well as increased cytokine and
chemokine levels in muscle tissue. Autoantibodies are
expressed in many but not all patients; specific autoantibod
ies and differing histologic patterns are associated with dis
tinct sets ofclinical characteristics, suggesting that pathogenic
mechanisms vary across subsets. Non-immune-mediated
mechanisms are also important, especially for the progres
sion to atrophy, fibrosis, and structural damage to muscle
tissue.
54
Clinical Presentation
Asymptomatic elevations of serum creatine kinase;
chionic muscle atrophy; acute, severe rhabdomyolysis
with kidney failure
lnfrequent elevation of serum creatine kinase (30%);
muscle weakness (50%); myopathic electromyog ram
findings (100%); cardiomyopathy can occur
Asymptomatic elevations of serum creatine kinase; acute,
severe rhabdomyolysis with kidney failure
Proximal muscle weakness with elevations of serum
creatine kinase; mild sensory symptoms; reduced reflexes
Proximal muscle weakness in the absence of elevations
of serum creatine kinase
Elevations of serum creatine kinase with myalgia and
weakness
Elevations of serum creatine kinase with myalgia and
weakness
f,EY POtrtt
. Inflammatory myopathies commonly present with
symmetric proximal muscle weakness without substan-
tial muscle pain or tenderness; elevation ofserum cre-
atine kinase level is almost universal and is a marker of
muscle damage.
o Muscle pain or tenderness should prompt consideration
of infectious, endocrine (thyroid), or drug-induced
myopathies.
Clinical Features
Muscle lnvolvement
Most patients with IIM present with symmetric weakness
affecting the proximal muscles. Neck flexors and shoulder and
hip girdle muscles are commonly involved. Patients may expe-
rience difficulty rising from a chair or climbing stairs.
Symptoms usually progress over months, except in inclusion
body myositis, which progresses over years. Respiratory mus-
cles can be affected, and some patients experience difficulty
swallowing (dysphagia or dysmotility) related to involvement
of the upper gastrointestinal tract. Cardiac muscle can be
involved in some subsets of IIM.
Pulmonary Disease
Interstitial lung disease, most commonly nonspecific intersti
tial pneumonitis, occurs in both polymyositis and dermato-
myositis and is an important cause of morbidity and mortaliry
particularly in patients the antisynthetase syndrome (see
below). Muscle weakness of the chest wall can also cause
breathing difficulties. Pulmonary involvement is not typically
seen in inclusion body myositis.
i
 ldiopathic lnflammatory Myopathies

Skin lnvolvement body myositis. Although clinically useful, these categories do

Pathognomonic skin findings are associated with dermatomy- not fully account for the varying features within each group,
ositis but not polymyositis. Mechanic's hands can occur in and alternative ways of subcategorizing patients are under
patients with the antisynthetase syndrome associated with development. Some patients with dermatomyositis or polymy
either polymyositis or dermatomyositis. ositis may further demonstrate the antisynthetase syndrome.

Cardiac Disease Dermatomyositis

In addition to cardiac muscle involvement, arrhythmias, atrio
ventricular block, and pericarditis have been reported. Patients
with myositis are at higher risk for heart failure and myocar
dial infarction.
Malignancy
There is a clear association between malignancy and IIM;
patients with dermatomyositis have a 3 to l2-fold higher risk
for malignancy than age matched populations. The associa-
tion between malignancy and polymyositis is smaller. The risk
for malignancy peaks in the 3 years after the diagnosis of der-
matomyositis or polymyositis. Commonly associated cancers
include ovarian, lung, pancreas, stomach, and colon cancers
and lymphoma. Malignancy risk varies by antibody associa-
tion (Table 26). Age and sex-appropriate cancer screening is
indicated at the time of diagnosis of dermatomyositis or poly-
myositis and regularly for several years thereafter. Many
experts advocate CT of the chest, abdomen, and pelvis, par-
ticularly in patients with dermatomyositis.
Types of ldiopathic
lnflammatory Myositis
IIMs can be subcategorized into dermatomyositis, polymyosi-
tis, immune-mediated necrotizing myopathy, and inclusion
In addition to muscle involvement, patients with dermatomy-
includ-
ositis usually have characteristic skin findings (Table 27),
ing heliotrope rash (Figure 34), Gottron papules (Figure 35), and
Gottron sign. Other skin findings include periungual erythema,
mechanic's hands (a dermatologic manifestation characterized
by rough, cracked, scaly skin along the lateral aspects of the
digits and palms with horizontal lines resembling the weath
ered hands of a laborer; Figure 36), facial erythema or photo
sensitive poikiloderma (shawl and V signs) (Figure 37), and
calcinosis cutis. Although both skin and muscle biopsies can be
helpful for diagnosis and prognosis, some cases of dermatomy
ositis can be diagnosed on the basis of characteristic skin find-
ings without a muscle biopsy.
A small subset of patients with dermatomyositis never
develop muscle involvement (amyopathic dermatomyositis) ;
these patients can be diagnosed with skin biopsy in the setting
of at least 6 months without muscle involvement.
Polymyositis
Patients with polymyositis have proximal muscle weakness
without the skin involvement of dermatomyositis. Because
patients with polymyositis lack pathognomonic clinical fea-
tures, a muscle biopsy is recommended to confirm the diagno
sis and differentiate this subgroup from other forms of myosi
tis. In general, patients with polymyositis have a lower risk for

TABLE 26. ldiopathic lnflammatory Myopathy-SpecificAntibodies

AntibodyTarget Type of llM Skin Features Muscle Features Other Clinical Features
TIF-1-1(formerly DM Classic skin rashes Typical lncreased cancer risk
p1 55/1 40)

Mi-2 DM Classic skin rashes Typical Low risk for cancer and ILD
NXP-2 DM Severe, ulcerative; high lncreased Low risk for ILD and high
risk for calcinosis risk for cancer

SAE DM, amyopathic DM Classic skin rashes Mild or none

MDA5
Jo- , EJ, OJ, PL-7
1 ,
PL-12,KS,Ha,Zo
DM, amyopathic DM Mechanic's hands Mild High risk for ILD
Antisynthetase Mechanic's hands Typical Very high risk for ILD; often
syndrome includes arthritis and
Raynaud phenomenon

SRP IMNM None Severe/necrotizing

HMG-CoA IMNM None Severe/necrotizi ng May be associated with
statin use
NT5c1A IBM (poor sensitivity) None May include hand/
forearm weakness,
may be asymmetric

DM=dermatomyositis;HMG-CoA=hydroxy-methylglutarylcoenzymeA;lBM=inclusionbodymyositis;lM=idiopathicinflammatorymyopathy;lLD=ioterstitiallungdisease;
IMNM = immune-mediated necrotizing myopathy; MDA5 = melanoma differentiation-associated gene 5; NXP 2 = nuclear matrix protein 2; SAE = small ubiquitin like modifier
activating enzyme; SRP = signal recognition particle; TIF- 1 -1= transcription intermediary factor 1 1.

55
Idiopathic lnflammatory Myopathies

TABLE ??. Cutaneous Manifestations of Dermatomyositis

Cutaneous Manifestation Location Clinical Appearance
Gottron rash (Gottron Metacarpophalangeal and proximal Erythematous to violaceous papules; occasional scale; can
papules and Gottron sign) interphalangeal joints (Gottron papules); ulcerate; atrophic scars may occur
occasionally on distal interphalangeal joints,
elbows, knees (Gottron sign)
Heliotrope rash Eyelids Subtle pink to deep purple or brown discoloration; may
be associated with edema of eyelids or periorbital edema
V sign V of neck Erythematous to violaceous papules to patches
Shawl sign Base of posterior neck to upper back Erythematous to violaceous papules to patches
Fixed erythema Malar area (may cross nasolabial folds); Erythematous to violaceous papules to patches
flanks of trunk
Nail area changes Periungual area; cuticles Periungual erythema; capillary dilatation and dropout;
cuticular hypertrophy; cuticular infarcts
Mechanic's hands Lateral aspects of digits and palms Hyperkeratotic fissuring of the palmar and lateral surfaces
of the fingers resembling the hands of a laborer

F IG UR E 3 4. The heliotrope rash of dermatomyositis is a distinctive purple or FtG U RE 36. MechaniCs hands with hyperkeratotic, fissured skin on the palmar
lilac, symmetric erythema of the eyelids that may be accompanied by slight edema, and lateral aspects of fingers seen in a patient with antisynthetase syndrome.
generally focused around the orbits.

f I G U R E 3 5 . Gottron papules are violaceous, slightly scaly plaques over the bony FIGURE 37. The shawl sign demonstrating a photodistributed erythematous
prominences on the hands. Ihe Gottron sign consists of similar findings over the patchy rash on the upper back in a patient with dermatomyositis.
extensor surfaces of joints other than the hands, usually the elbows, knees, and ankles.

56
I
i ldiopathic lnflammatory Myopathies
l
pulmonary or other extramuscular disease features than those
t with dermatomyositis.
i
I
Antisynthetase Syndrome
t The antiqmthetase syndrome occurs in approximately 30% of
I
patients with dermatomyositis or polymyositis. The syndrome is
associated with antibodies to aminoaryl-transfer RNA (IRNA)
qmthetases (most commonly anti-Jo 1, directed at histidyl-
IRNA rynthetase) and is characterized by a high risk for and
i greater severity ofinterstitial lung disease. Other features include
arthritis, Raynaud phenomenon, and mechanic's hands.
i
lmmune-Mediated Necrotizing Myopathy
Some patients previously included in the poll,rnyositis group
are now recognized as belonging to a distinct subset known as
immune mediated necrotizing myopathy. This condition is
characterized by rapidly progressive, severe muscle weakness;
increased likelihood of muscle pain; high serum creatine
kinase levels; and muscle biopsy specimens demonstrating
prominent myonecrosis with only limited inflammation. These
patients tlpically lack extramuscular features. An immune-
mediated mechanism is suggested by the presence of antibod
ies to signal recognition particle or 3-hydroxy 3 methylglutaryt
coenzyme A (HMG-CoA) reductase in about two thirds of
patients (see Table 26). HMG CoA is the clinical target of action
of statins in lipid lowering, and statin exposure may result in
antibodies to HMG-CoA reductase, which can sometimes lead
to immune-mediated necrotizing myopathy. However, statins
more commonly induce muscle disease through direct rather
than autoimmune myotoxicity. In addition, many patients with
anti HMG CoA reductase antibodies have never been exposed
to a pharmacologic statin. In patients with statin-triggered
immune mediated necrotizing myopathy, weakness may per
sist or progress even after statins are discontinued.
lnclusion Body Myositis
Inclusion body myositis is an insidious condition affecting
older adults. It is distinguishable from other forms of myositis
by its slow progression and different pattern of muscle involve-
ment. Patients report a history of weakness for an average of
5 years before seeking care. Both proximal and distal muscle
involvement occur; finger and forearm flexor involvement is
nearly pathognomonic. Muscle distribution is usually but not
always symmetric. Up to half of patients with inclusion body
myositis have cricopharyngeal muscle involvement, leading to
dysphagia and increased risk for aspiration.
Serum creatine kinase levels are elevated to a lesser extent
than seen in other forms of IIM. Autoantibodies are less often
present, but the anti NT5c1A autoantibody is found in up to
t
i half of patients and rarely in controls (see Table 26).
! Autoantibodies
Overlap Syndromes
I Other autoimmune connective tissue diseases may include
myositis as a clinical feature but typically have other prominent
I
I
clinical features and different antibody associations. See Mixed
Connective Tissue Disease and Undifferentiated Connective
Tissue Disease for further discussion.
.xIY P:01ilT5
'.
. Pulmonary and cardiac involvement are important
sources of morbidity and mortality in idiopathic
infl ammatory myopathies.
o Age- and sex-appropriate cancer screening is indicated
in dermatomyositis and polymyositis because of an
increased risk for malignancy.
r Gottron rashes and heliotrope rashes are characteristic
of dermatomyositis.
o Immune-mediated necrotizing myopathy is character-
ized by severe, rapidly progressive proximal muscle
weakness; high serum creatine kinase levels; and few
extramuscular manifestations.
o Inclusion body myositis is an insidious condition in
older adults that affects both the proximal and distal
flexor muscles.
Diagnosis
IIM should be considered in any patient who has progressive
proximal muscle weakness without another explanation.
Classification Criteria
Classification criteria are desigrred to allow researchers and cli-
nicians to better distinguish IIM from other conditions affecting
muscles and to better differentiate among IIM subgroups.
Although intended for research studies, classification criteria
can help support a clinical diagnosis. Current criteria may allow
classification without a muscle biopsy. These criteria first deflne
the probability of presence or absence of IIM and then apply the
classification tree for subgroups of IIMs (Figure 38). Limitations
include the fact that there are too few patients with immune-
mediated necrotizing myopathy or antisynthetase syndrome to
characterize these subsets, along with lack of inclusion of MRI
fi ndings or most myositis-specific antibodies.
Muscle-Related Enzymes
Elevated serum muscle en-4lrnes are useful in dffierentiating
intrinsic muscle disease from neurologic causes of weakness.
Elerated serum creatine kinase levels are a sensitive indicator of
muscle pathologz, and lwels uzually parallel the severity of involve-
ment. Aldolase level may be ele'"ated when serum creatine kinase
levels are normal. Serum aminotransferase and serum lactate
dehydrogenase levels may also be elevated but are nonspeciflc.
Troponins can be used to screen for cardiac muscle involvement.
Only about half of patients with IIM have identifiable autoan-
tibodies. Some autoantibodies, such as antinuclear antibodies,
lack specificity. The myositis specific antibodies have more
57
tdiopathic lnf lammatory Myopathies

Patient meets the EULAR/ACR classification criteria for llM

Age at onset of first

symptom <1 8 years
No Yes

Heliotrope rash or
Heliotrope rash or
Gottron papules or
Gottron papules or
Gottron sign Gottron sign

No Yes

Objective symmetric weakness, usually

progressive, of the proximal upper extremities or
Clinical features* Objective symmetric weakness, usually
or progressive, of the proximal lower extremities or
Muscle biopsy
feature** Neck flexors are relatively weaker than neck
extensors or in the legs, proximal muscles are
relatively weaker than distal muscles
No Yes

No Yes

PM Juvenile myositis
(rMNM) other than JDM ***
IBM ADM DM JDM

tIGURE 38.2017 classificationcriteriaforadultandjuvenileidiopathicinflammatorymyopathies(llM)andtheirmajorsubgroups,fromtheEuropeanLeague

Against Rheumatism (EULAR)/American College of Rheumatology (ACR). ADM = amyopathic dermatomyositis; DM = dermatomyositis; IBM = inclusion body myositis;
IMNM = immune-mediated necrotizing myopathy; Jltyl = juvenile dermatomyositis; pM = polymyositis.
*Finger flexor weakness and response to treatment: not improved.

**Muscle biopsy: rimmed vacuoles required for diagnosls.

***Juvenilemyositis0lherthanJDl\,4wasdeve0pedbasedonexpertopini0f l[./lN[,4andhyp0myopalhicD]\.,lwereloofewtoallowsubclassification.

IPMID:290795901d0i:10.1136/annrheumdis 2017 211468. Reproduced with permissi0n 01 BMJ Publishing Gr0up Ltd.

diagnostic and prognostic value and can be useful for identify- muscle fiber necrosis, degeneration, and regeneration, but
ing risk for specific features or subsets (see Table 26). differ in the types and locations of the cell infiltrates. Muscle
biopsy findings in inclusion body myositis include mononu-
lmaging clear cell infiltrates, "rimmed" vacuoles, and a lack of muscle
Although not required to diagnose IIMs, MRI is useful in iden cell necrosis. Electron microscopy can show characteristic
ti[zing regions of active muscle inflammation and in guiding inclusion bodies.
muscle biopsy. MRI can also assess the extent and severity of Skin biopsy can be useful in the diagnosis of dermatomy-
muscle involvement and therapeutic efficacy. ositis, with typical findings including a perivascular lympho
High-resolution CT should be used to assess for intersti- cytic infiltrate, vacuolar changes at the dermal-epidermal
tial lung disease in high risk patients. junction, and increased dermal mucin.

xtY P0tilTs
Electromyography o Elevated semm creatine kinase levels are a sensitive
Although no single linding is pathognomonic, electromyogra indicator of muscle pathologz, and levels usually parallel
phy may reveal findings characteristic of active myositis. This the severity of involvement.
test can be uncomfortable, and results may be falsely normal . Myositis specific autoantibodies can be used to diag-
in the presence ofactive disease because ofpatchy distribution
nose and subcategorize some idiopathic inflammatory
of muscle inflammation (sampling error).
myopathies but are not present in all patients.
r In patients with idiopathic inflammatory myopathies,
Histopathology MRI can help locate a site for muscle biopsy and assess
Muscle biopsy is valuable for diagnosing and distinguishing therapeutic efficacy.
IIMs and for excluding metabolic myopathies, mitochondrial
o Muscle biopsy is valuable for diagnosing idiopathic
disease, and infection.
inflammatory myopathies and for excluding metabolic
Polymyositis and dermatomyositis share common histo
myopathies, mitochondrial disease, and infection.
pathologic features, including inflammatory cell infiltrates,

58

l
Management
Glucocorticoids are the cornerstone of therapy for most forms
of tlMs. Starting dose varies by severity and organ involvement
but is fypically high (up to 1 mg/kg of prednisone) and should
be tapered within 6 months. Prr-rlonged exposure to high-dose
glucocorticoids, particularly in older patients, can lead to
glucocorticoid induced myopathy, resulting in proximal mus
cle weakness and diagnostic conlusion in a patient who had
previously been improving.
Immunomodulatory agents are used to better manage
intlammation or as glucocorticoid sparing agents; methotrex
ate and azathioprine are the prefbrred initial agents. Intravenous
immune globulin (IVIG) can be used in addition to or as an
alternative to traditional agents; evidence for IVIG is strongest
fbr dermatomyositis and immune mediated necrotizing myo
pathy. Mycophenolate, tacrolimus, cyclosporine, rituximab, or
cyclophosphamide can be considered in patients in whom
initial treatment has failed or who could not tolerate initial
treatment. Immune mediated necrotizing myopathy is often
acute and severe and should be treated aggressively with com-
binations of glucocorticoids and immunosuppressive agents; it
may respond particularly well to IVIG and rituximab. Statins
should be strictly avoided.
Inclusion body myositis usually does not respond to
immunosuppression, and any therapeutic trials should be
discontinued if benefit is not appreciated. An initial response
to empiric glucocorticoids should encourage the physician to
consider an alternative diagnosis. Reports suggest that IVIG
may occasionally be helpful in managing dysphagia.
Physical therapy can help maintain muscle lunction and
should be universally recommended.
Prognosis
The prognosis in IIM varies fiom resolution to severe,
treatment-resistant disease with functional impairment and
early mortality. The degree of serum creatine kinase elevation
at diagnosis does not predict outcome. Prolonged disease
activity before treatment, greater weakness at presentation,
extensive multisystem disease, and the co occurrence of
malignancy confers a poorer prognosis, as do certain myositis
specific autoantibodies or histologic features.
Patients with anti Jo 1 antibodies have worse outcomes
(due to interstitial lung disease), whereas those with anti
Mi 2 antibodies often respond completely, despite a rapidly
progressive course of dermatomyositis. Patients with
immune-mediated necrotizing myopathy may respond well
to statin discontinuation (if appropriate) and aggressive
immunosuppression.
Giren the lack of effective treatment, patients with inclu
sion body myositis typically demonstrate a slow and gradual
loss of function, with progression to wheelchair dependence
within 10 to 15 years of symptom development. However, life
expectancy does not appear to be affected.
Systemic Sclerosis
XEY POITII
o Initial treatment of most idiopathic inflammatory myo
pathies consists of glucocorticoids, with additional
immunomodulatory agents (most commonly metho
trexate and azathioprine) often required to control
inflammation or serve as glucocorticoid-sparing agents.
. Prolonged symptoms before treatment, greater weak-
ness at presentation, extensive multisystem disease, co-
occurrence of malignancy, and some autoantibodies
and histologic patterns confer a poorer prognosis in
patients with idiopathic infl ammatory myopathies.
r Inclusion body myositis usually does not respond to
immunosuppression and typically results in wheelchair
dependence within 10 to 15 years.
Systemic Sclerosis
Epidemiology and
Pathophysiology
Systemic sclerosis (SSc) is a multiorgan disease characterized by
fibrosis and vasculopathy. The skin is the most apparent target,
but intemal organs are also affected. SSc is relatively rare, with a
prevalence of 275 cases per million and an annual incidence of
19 cases per million. The peak incidence occurs in patients age 20 to
50 years. It is more common among women and Black persons.
Vascular injury vascular and visceral fibrosis, and innate
and adaptive immune activation with autoantibody production
play interactive roles in SSc. Genome wide association studies
have identified up to 28 risk loci for SSc and underlined the
importance of natural killer cell activity in SSc. One of the earli
est SSc manifestations is Raynaud phenomenon, suggesting that
vascular injury precedes the fibrotic reaction. With vascular
damage, the endothelial cells release endothelin-l, a potent
vasoconstrictor that also induces vascular smooth muscle prolif-
eration and fibroblast activation. Platelet activation occurs con
currentlywith subsequent release of growth factors that promote
further vasoconstriction, fibroblast activation, and collagen pro
duction. B cells are also activated and produce interleukin 6,
which further stimulates fibroblasts and leads to autoantibody
production. These and other processes cause increased collagen
production and deposition by activated scleroderma fibroblasts,
along with progressive obliterative vasculopathy
Classification
The 2013 American College of Rheumatology/European
League Against Rheumatism classification criteria for SSc pro
vide a rigorous definition of SSc that is not formally intended
Ibr diagnosis and may be too restrictive in clinical practice.
However, they can provide useful guidance when a patient
presents with features suggesting SSc (Table 28).
SSc is divided into three subtypes based on the extent
of skin involvement: Iimited cutaneous systemic sclerosis
59
Systemic Sclerosis

TABLE 28. American College of Rheumatology/European League Against Rheumatism Classification Criteria for Systemic Sclerosis
Manifestation Add:tional Manifestations WeighVScore"
Skin thickening of fingers of both hands extending I
proximalto the MCPs
Skin thickening of the fingers (count higher score Puffy fingers 2
only)
Sclerodactyly of fingers distal to the MCPs but proximal to PlPs 4
Fingertip lesions Digitaltip ulcers 2

Fingertip pitting scars 3

Tela ngiectasia 2

Abnormal nailfold capillaries 2

Pu lmonary hypertension and/or interstitial lung Pulmonary hypertension 2

disease (maximum score is 2)
lnterstitial lung disease 2

Raynaud phenomenon 3

SSc-related autoantibodies (maximum score is 3) Anticentromere )

Anti-Scl-70 (antitopoisomerase-1 ) 3

Anti-RNA polymerase lll 3

MCP = metacarpophalangeal; PIP = proximal interpha angeal; SSc = systemic sclerosis.

uThe total score is determined by adding the maximum weight (score) in each category- A score of 9 or more equates to definite systemic sclerosrs.

From van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 201 3 classification criteria for systemic sclerosis: an American College of Rheumatology/
European League Against Rheumatism Collaborative lnitiative. Ann Rheum Dis 201 3;72: T 747-55. doi:1 0.1 1 36/ann rheumdis-20 1 3-204424. IP MID: 240926821 Copyright 201 3,
American College of Rheumatology. Adapted with permission from BMJ Publishing Group Ltd.

(LcSSc), diffuse cutaneous systemic sclerosis (DcSSc), and

systemic sclerosis sine scleroderma (internal organ involve-
ment only). Specific long term complications may be more
likely in one subtype than another; however, overlap is com
mon. LcSSc, formerly known as the CREST syndrome, is less
commonly accompanied by fibrosis of internal organs than is
DcSSc but is more commonly associated with pulmonary arte-
rial hypertension. Patients with LcSSc have manifestations
that can include calcinosis, Raynaud phenomenon, esopha
geal dysmotility, sclerodactyly, and telangiectasia (CREST); all
five conditions may not be present.
Various disorders may present with skin thickening and
other manifestations that overlap with SSc findings; these
conditions should be considered in the differential diagnosis of
SSc (Table 29). These conditions are not typically associated
with Raynaud phenomenon, and the absence of Raynaud phe-
nomenon in a patient with skin thickening makes SSc unlikely.
t(EY port{Ts
. Systemic sclerosis is a multiorgan disease characterized
by fibrosis and vasculopathy; the skin is the principal
target, and Raynaud phenomenon is one ofthe earliest
manifestations.
. Systemic sclerosis is divided into three subtypes based
on the extent of skin involvement: limited cutaneous
systemic sclerosis, diffuse cutaneous systemic sclerosis,
and systemic sclerosis sine scleroderma.
o typically devoid of wrinkles.
The absence of Raynaud phenomenon in a patient with
skin thickening makes systemic sclerosis unlikely.
nifestations
Cl inica I Ma
and Diagnosis
The diagnosis of SSc depends on the presence of specific clini
cal findings and autoantibodies, which are present in 90'l, to
95"1, of patients (Table 30).
Cutaneous lnvolvement
The skin is the organ most commonly involved in SSc, with the
hands being universally affected. In LcSSc, the skin over the
fingers/hands, face, and neck is typically affected. In DcSSc,
skin involvement is more extensive and additionallv includes
the upper arms, trunk, and lower extremities.
The earliest skin manifestations in DcSSc are often dif
fusely swollen fingers/hands. This will later give way to thick
ened, bound down, atrophic skin. Skin thickening in LcSSc
may be more subtle than in DcSSc, and the inability to tent the
skin over the fingers (sclerodactyly) may be an important clue.
The skin changes can lead to joint contractures (Figure 39).
Small mat-like telangiectasias are common in LcSSc and occa
sionally occur in DcSSc. They are found on the hands and face
and can also be seen on the oral mucosal side of the lips. They
blanch with light pressure. Poikiloderma can occur in areas of
fibrosis and consists of areas of hyperpigmentation mixed
with hypopigmentation that give the skin a salt-and pepper
appearance. Facial skin involvement can lead to limitation of
the oral aperture and difficulty eating. In addition, the face is
Calcinosis occurs in approximately 25% of patients with
SSc, typically in the hands, forearms, elbows, gluteal region,

50
 l
L

Systemic Sclerosis
I

; TABLE 29. Common Manifestations/Features of Scleroderma Spectrum Disorders

Disorder Ma nifestation/Feature Comments
Systemic Sclerosis
t Diffuse cutaneous Distal and proximal skin thickening (face, chest, Skin involvement is extensive and is commonly
systemic sclerosis abdomen; proximalto elbows and knees); commonly accompanied by internal organ fibrosis and ILD
l (DcSSc) has visceral organ involvement
Limited cutaneous Distal (face, neck, hands, feet), but not proximal, skin More likely to develop PAH and Raynaud
systemic sclerosis thickening; typically not accompanied by internal phenomenon early in the disease and frequently
(LcSSc) organ fibrosis develop calcinosis cutis, telangiectasia, and
esophageal dysmotility
i, Systemic sclerosis Fibrosing organ involvement without skin thickening Difficult to diagnose; prognosis may be similar to
sine scleroderma LcSSc
t

Localized Scleroderma
Morphea Focal plaques of skin thickening, generally on the Systemic manifestations or Raynaud phenomenon is
trunk extremely rare
Linear scleroderma Streaks/lines of thickened skin Same as morphea

Scleroderma-like Conditions"
Eosinophilic fasciitis Orange peel induration (peau d'orange) of proximal
extremities with sparing o{ hands and face; peripheral
eosinophilia; skin retraction overthe superficial veins
may be more apparent with elevation of an affected
limb
Nephrogenic Secondary to gadolinium in patients with kidney
systemic fibrosis disease; brawny, wood-like induration of extremities,
sparing the digits
Scleredema lndurated plaques/patches on back, shoulder girdle,
and neck
Scleromyxedema Waxy, yellow-red papules overthickened skin of face,
upper trunk, neck, and arms; deposition of mucin with
large numbers of stellate fibroblasts in the dermis
Full-thickness skin biopsy demonstrates lymphocytes,
plasma cells, and eosinophils infiltrating the deep
fascia; glucocorticoids are mainstay of treatment
Skeletal muscle fibrosis with contractures and/or
cardiac muscle involvement can occur, with
cardiomyopathy and increased mortality; changes in
use and formulation of gadolinium have reduced
incidence
Typically seen in long-standing diabetes mellitus
Associated with paraproteinemia (lgG)") and may
therefore occur in the setting of multiple myeloma or
AL amyloidosis; more frequent in men

Chronic graft-versus- Lichen planus-like skin lesions, or localized or Occurs most commonly after hematopoietic stem cell
host disease generalized skin thickening transplantation; may occasionally be seen after blood
transfusion in immunocompromised host
Drug and toxin Can produce scleroderma-like tissue changes Examples: bleomycin, docetaxel, pentazocine,
exposure L-tryptophan, organic solvents

ILD = interstitial lung disease; PAH = pulmonary arterial hypertension.

oScieroderma-like skin changes may also be a manifestation of systemic endocrine, kidney, or infiltrative disorders.

TABLE 30. Autoantibodies and Their Associations in Systemic Sclerosis

Autoantibody MainClinicalAssociations Comments
Antinuclear antibodies DcSSc; LcSSc Overall prevalence in SSc, 70oZ; not associated with specific
manifestations
Anticentromere ( kinetochore proteins) LcSSc with or without PAH Overall prevalence in SSc, <30%; highly associated (>90%)
with LcSSc
Anti-Scl-70 (DNA topoisomerase-1 ) DcSSc; ILD Overall prevalence in SSc, <30%; highly associated with
DcSSc

Anti-RNA polymerase lll DcSSc; scleroderma renal crisis Useful in DcSSc with negativity for anti-Scl-70

Anti-U3-RNP (fibrillarin) DcSSc; PAH; myositis Associated with poor outcome; more common in Black men

Anti-PM-Scl Myositis Associated with overlap syndrome and polymyositis

Anti-Ku Myositis Rare

Anti-Th/To LcSSc; PAH Ra re

DcSSc = diffuse cutaneous systemic sclerosis; ILD - interstitial lung disease; LcSSc = limited cutaneous systemic sclerosis; PAH = pulmonary arterial hypertension;
RNP = ribonucleoprotein; SSc = systemic sclerosis.

61
Systemic Sclerosis
t IGUR E 3 9. Hands of a 35-year-old woman with diffuse cutaneous systemic
sclerosis. Note the shortening of fingers and tight atrophic appearance of the skin
This patient is unable to make a full fist.
and iliac crest (Figure 4O). These deposits can be seen or felt
and are easily detected on radiographs.
Musculoskeletal lnvolvement
Joint involvement occurs in 12'2, to 65'7, of patients with SSc; it
is mainly polyarticular and can be erosive, with hand/wrist
predominance. SSc is one of the few forms of inflammatory
arthritis that affects the distal interphalangealjoints. Between
FI G U R E 4 0. Calcinosis seen in limited cutaneous systemic sclerosis.Ihis
patient has deposits of calcium in the subcutaneous tissues around the elbow.
Calcinosis often occurs in the hands and forearms but can also affect other locations,
such as the trunk or lower extremities.
62
l'2, and 5'X, of patients have a rheumatoid arthritis-SSc over
lap. with positivity for anti cyclic citrullinated antibodies and
classic rheumatoid arthritis manifestations along with those
of SSc.
Patients with SSc may develop acro osteolysis. or
resorption of the terminal bony tuft of the fingers and,
less commonly. the toes; the prevalence is as high as 20'7,
to 4O"/, in more severe disease (Figure 41). This manifesta-
tion is typically seen in patients with significant distal
vascular involvement, including ulceration. ischemia, and
calcinosis.
Tendon rubs can be felt or heard with a stethoscope
because fibrosis affects tendons or tendon sheaths. These
occur in about 10'7, ol patients with DcSSc.
SSc-associated myositis occurs in 10'1, to 15% of patients.
Myalgia and proximal muscle weakness are common symp
toms. Serum creatine kinase and/or serum aldolase levels are
elevated, and electromyogram demonstrates myopathic
changes. There is a strong association between SSc-associated
myositis and myocardial involvement. The presence of anti
PM Scl antibodies identifies patients with an overlap between
polymyositis and SSc. These patients usually have less skin and
gastrointestinal involvement but have more calcinosis and
lung disease.
Vascular lnvolvement
Raynaud phenomenon occurs in approximately 95'2, of
patients with SSc; it is the most common early manifestation
of SSc, typically occurring years before recognizable SSc.
Raynaud phenomenon is initially episodic, but with'uascular
fibrosis, the blood supply becomes permanently restricted.
SSc will develop in approximately 80'7, of patients with the
combination of Raynaud phenomenon, an SSc-associated
autoantibody, and nailfold capillary changes in an SSc pattern
(Figure 42).
F IGUR E 4 1 . Posteroanterior radiograph of the hands in a patient with systemic
sclerosis and acro-osteolysis. Note the destruction of the distal phalanges, particularly
of the first and second digits bilaterally, which will eventually result in clinical
shortening of the affeoed digits.
 Systemic Sclerosis

Approximately B0% of patients with SSc have involve

ment of the lower two thirds (smooth muscle portion) of the
esophagus, manifesting primarily as symptoms of dysmotility
and/or gastroesophageal reflux disease. Esophageal involve-
ment is associated with an increased risk for Barrett esopha
gus and adenocarcinoma. A dilated esophagus on chest
imaging is a clue to esophageal involvement.
Gastric symptoms also result mainly from dysmotility.
Patients describe early satiety and may report nausea and
vomiting as a result of delayed gastric emptying. Gastric antral
vascular ectasia is most common in patients with DcSSc and
those with anti RNA polymerase III antibodies. Bleeding ecta
sias can cause significant blood loss.
Small intestinal bacterial overgrowth is common and
can cause malabsorption and diarrhea. The diarrhea is
described as explosive and t1pically follows a meal. Diagnosis
is established by a hydrogen breath test, although an empiric
trial of rotating antibiotics is often used. Small intestine dys
motility can result in pseudo-obstruction. Large intestine
dysmotility may lead to constipation, and vascular ectasia
can occur in the large intestine. Some patients may develop
fecal incontinence.

Kidney lnvolvement
Scleroderma renal crisis affects 5% of patients with DcSSc and
2% of patients with LcSSc. Scleroderma renal crisis was previ-
ously the chiefcause ofdeath in SSc. Risk factors for sclero
derma renal crisis include DcSSc, use of glucocorticoids
(>z.s mg/d), andthe presence of anti-RNA polymerase III anti-
bodies. The more recent lower incidence of scleroderma renal
crisis is ascribed to the avoidance ofglucocorticoids in SSc and
the use ofcalcium channel blockers, which are renal protec-
FIGU R E42. Capil lary loops i n systemic sclerosis. Iop, Early cha nges with loss
of capillary loop density (or drop out) with marked dilatation of the remaining
tive, to treat Raynaud phenomenon.
capillary loops. Bottom, Late changes with extensive loss of capillary loops.

Digital ulcers occur in about 15% of patients with SSc,

typically on the extensor surfaces and tips of the fingers
(Figure 43) and toes but also on the dorsum of hands and feet
and even on the lower extremities. Vascular changes in the
extremities may indicate similar involvement of internal organs.

Cardiac lnvolvement
Myocardial fibrosis is a consequence of microvascular disease
and a cause of early death. It results from repetitive ischemia-
reperfusion injury of the myocardium. Myocardial involve-
ment may lead to heart failure, intraventricular conduction
block, and arrhlthmias. Diastolic dysfunction is more com
mon than systolic dysfunction, and a right bundle branch
block is a predictor of early mortality in SSc.

Gastrointestina I I nvolvement
Symptoms of esophageal dysmotility and reflux are common
in all forms of
SSc and may offer an early clue to the diagnosis t IGUR E4 3. Digital pitting (soft'tissue defects and scarring in the pulp space
when associated with other symptoms. 0f the di$al phalanges) in a patient with systemic sclerosis.

63
Systemic Sclerosis
Scleroderma renal crisis occurs within 4 years of SSc
onset in 75'2, of cases. Patients characteristically present with
manifestations of hypertensive emergency, including head-
ache, encephalopathy, seizures, and hypertensive retinopathy.
Rarely, a normotensive form of scleroderma renal crisis can
occur. Risk factors for a poor prognosis include male sex, older
age, and heart failure. Changes in blood pressure from ambu-
latory baseline measurements may alert physicians to an
impending renal crisis.
Laboratory fi ndings include microangiopathic hemoly'tic
anemia, thrombocytopenia, and proteinuria. The serum cre-
atinine level is typically elevated and may remain so for some
time aflter blood pressure is controlled. Abnormalities in the
renin angiotensin-aldosterone system and in endothelin 1
are thought to contribute to the pathophysiologz. Although
ACE inhibitors have dramatically improved the outcome of
patients with scleroderma renal crisis, prophylactic use of
ACE inhibitors may actually worsen scleroderma renal crisis
outcomes and is not recommended even in high-risk patients.
Lung lnvolvement
Lung involvement in SSc includes pleuritis and pleural effu
sions, interstitial lung disease (lLD), pulmonary arterial
hypertension (PAH), bronchiolitis, pulmonary veno occlusive
disease, respiratory muscle weakness, and skin involvement of
the trunk that restricts chest wall movement. Patients are also
at increased risk for lung cancer.
Significant ILD occurs in 50'7, of patients with DcSSc (857,
of patients with anti-Scl-70 antibodies) and 35% of patients
with LcSSc and is the main cause of disease associated death.
In patients with SSc, men are more likely than women to
develop ILD, and Black persons tend to have more severe
disease than other ethnic groups. The most common high
resolution CT pattern is nonspecific interstitial pneumonitis
followed by usual interstitial pneumonitis. An abnormal FVC
early in the disease course (within the first 5 years) is highly
predictive of the development of more severe disease, as is
fibrosis of more than 20% of lung volume on baseline high-
resolution CT. There is a strong association between ILD and
gastroesophageal reflux disease, but whether the latter contrib
utes to ILD (through aspiration) is uncertain. All patients should
undergo pulmonary function testing and high resolution CT at
the time of initial SSc diagnosis, and pulmonary function test
ing with Dlco should be repeated every 6 to 12 months for
5 years. A 10% decline in FVC or l5'1, decline in DLCo within
12 months should raise concern for progression.
PAH has a prevalence of 10'7, in SSc. Patients with PAH
present with exertional dyspnea. With more advanced disease,
they may have chest pain and lower extremity edema. Patients
with SSc should undergo echocardiography annually. and for
new or concerning symptoms. Pulmonary function testing
can provide a clue to underlying PAH; an FVC/Dr-co ratio of 1.6
or greater suggests the diagnosis. See MKSAP 19 Pulmonary
and Critical Care Medicine for further discussion of diagnosis
and treatment.
64
f,tY PotxTs
. Raynaud phenomenon is the most common early mani-
festation of systemic sclerosis.
. The earliest skin manifestations of systemic sclerosis are
often diffusely swollen fingers/hands; with time, the skin
becomes thickened, atrophic, and immobile.
. Symptoms of esophageal dysmotility and reflux are
common in all forms of systemic sclerosis and may offer
an early clue to the diagnosis when associated with
other symptoms.
. Patients with scleroderrna renal crisis characteristically
present with manifestations of h)?ertensive emergency.
o Lung involvement in systemic sclerosis includes pul
monary arterial hypertension and interstitial lung dis-
ease (lLD); ILD is the main cause of disease-associated
mortality.
Management
Treatment options for systemic sclerosis are mainly sympto
matic and organ system specific. Table 31 outlines treatment
options for manifestations of SSc.
ACE inhibitors (typically captopril) can be lifesaving in
patients with scleroderma renal crisis and should be titrated to
control blood pressure. Dialysis may be needed temporarily for
scleroderma renal crisis. ACE inhibitor therapy should be con
tinued in scleroderma renal crisis even in the presence of a
rising serum creatinine level and the need for dialysis because
late improvement may occur. The addition of plasma exchange
to ACE inhibitors in patients with scleroderma renal crisis and
microangiopathic features has been suggested; angiotensin
receptor blockers should be considered only when ACE inhibi-
tors are not tolerated.
The Scleroderma Lung Study ll compared cyclophospha-
mide for 1 year versus mycophenolate mofetil over 2 years for
ILD in SSc. With both agents, FVC improved in approximately
75"/,, to BO"/,, and FVC worsened in 2O"1, to 25% of patients. In
7o"/,, of patients in each group (especially those with DcSSc).
skin scores improved significantly. Mycophenolate was better
tolerated and has become a mainstay of therapy in these
patients.
Nintedanib (a tyrosine kinase inhibitor) significantly
slowed the decline in lung function among patients with
ILD associated with SSc but did not affect other disease
manifestations. The combination of nintedanib plus
mycophenolate resulted in the slowest rate of decline in FVC
per year.
Rituximab is a promising agent in SSc. In a controlled trial
comparing rituximab versus cyclophosphamide for ILD asso
ciated with SSc, rituximab improved FVC and skin score to a
greater degree than did cyclophosphamide. Autologous hemat-
opoietic stem cell transplantation has been studied for several
years in patients with rapidly progressive, severe SSc; one third
 Systemic Sclerosis

TABLE 31. Treatment Options for Common Manifestations of Systemic Sclerosis

Manifestations Treatment
Cutaneous manifestations Methotrexate, mycophenolate, cyclophosphamide, and rituximab have been shown to improve skin

For pruritus, antihistamines can be tried; low-dose prednisone can also help but doses >7.5 mg/d
should be used with caution because of risk for scleroderma renal crisis.
Laser therapy can be used for telangiectasias.
Musculoskeletal NSAlDs, intra-articular or low-dose prednisone, hydroxychloroquine, or methotrexate can be used {or
ma nifestations arth ra g iala rth ritis.
I

Methotrexate, azathioprine, or mycophenolate can be used for significant myositis.

Raynaud phenomenon Cold avoidance; gloves; central warmth
Calcium channel blockers; sildenafil; losartan; prazosin
Topical nitrates; low-dose aspirin
Digital sympathectomy for refractory cases
Gastroesophageal refl ux Avoid eating close to bedtime; head-of-bed elevation
disease
H2 blockers; proton pump inhibitors
Surgical fundoplication
Gastrointesti na I dysmoti ity
I Metoclopramide (avoid long-term use); domperidone (investigational limited-access program),
erythromycin; cisapride (investigational limited-access program)
Gastric antral vascular ectasia Ablation laser therapy
Small intestine bacterial Rotating antibiotics; if fat malabsorption, cholestyramine
overgrowth
Pseud o-obstruction Promotility agent such as domperidone can be tried; if resistant, octreotide may be useful.
Constipation Fiber; stool softeners; polyethylene glycol
Scleroderma renal crisis ACE inhibitors (typically captopril), plasma exchange
Dialysis

lnterstitial lung disease Mycophenolate mofetil; cyclophosphamide; nintedanib; rituximab; stem cell transplant in rapidly
progressive cases
Lung transplantation
Pulmonary arterial Supplemental oxygen; treat right-sided heart failure
hypertension
Calcium channel blockers (if positive response to vasoreactivity testing); prostanoids; endothelin
receptor antagonists; phosphodiesterase-5 inhibitors; soluble guanylate cyclase stimulator
Combination therapy (ambrisentan and tadalafil); lung transplantation

to one half of patients had significant improvement in lung
function, skin thickening, and antibody status. However,
cost and potential toxicity limit the utility of stem cell
transplantation.
r( Ev P0 t 1{Ts
. Treatment options for systemic sclerosis are mainly
symptomatic and organ system specific.
r ACE inhibitors can be lifesaving in patients with sclero-
derma renal crisis and should be titrated to control
blood pressure even in the presence of rising serum
creatinine.
weight. A meta-analysis of pregnancies in patients with SSc
suggested that although disease manifestations, including
digital ulcers, may improve, 14'X, of patients may develop new
manifestations or worsening of current disease during preg-
nancy; in another 10'/., disease will worsen in the first
6 months postpartum. Contraindications to pregnancy in
patients with SSc include PAH and severe restrictive lung
disease (FVC <1 L).
t(EY P0ilaTS
. Pregnant patients with systemic sclerosis may experience
hypertensive disease, preeclampsia, preterm delivery
and low birth weight.

Pregnancy o Contraindications to pregnancy in patients with systemic

sclerosis include pulmonary arterial hypertension and
Pregnant patients with SSc may experience hypertensive
severe restrictive lung disease.
disease, preeclampsia, preterm delivery and low birth

55
 \

Mixed Connective Tissue Disease and Undifferentiated Connective Tissue Disease

Mixed Connestive nical Manifestations

Tissue Disease and
Undifferentiated
Connective Tissue Disease
Overview
Most patients with rheumatologic disease have well estab
lished and well classified diagnoses. However, given the com
mon underlying processes of autoimmunity and inflamma-
tion, it is not surprising that some patients have features of
more than one rheumatologic disease simultaneously or
sequentially (overlap syndromes). Other patients present with
signs and symptoms that are autoimmune in nature (often
including Raynaud phenomenon) but do not rise to the level of
a specific rheumatologic condition; such patients have undif-
ferentiated connective tissue disease (UCTD). Mixed connec
tive tissue disease (MCTD) is a specific variant of overlap syn-
drome that includes clinical manifestations meeting a dual or
triple diagnosis of systemic lupus erythematosus (SLE), auto-
immune myositis, and/or systemic sclerosis. MCTD is associ-
ated with positivity for anti Ul-ribonucleoprotein
antibodies.
See Table 32 for a comparison of MCTD and UCTD.
Epidemiology and
Pathophysiology
MCTD is rare, and B0% of patients are women. B-cell abnor
malities and an association with anti-U1-RNP antibody have
been described. The antibody binds to the 70 kD epitope of
the RNP complex, but its actual role in pathogenesis is not
understood. Genetic risk alleles include HLA DRBI-04:01
and HLA-B-O8, underlining the autoimmune nature of the
condition.
Cli
and Diagnosis
See Table 32 for details on the clinical manifestations and
diagnosis of MCTD. Raynaud phenomenon and pulmonary
involvement are common features; pufff hands and inflam
matory arthritis are also seen. Pulmonary arterial hyperten-
sion is the major cause of death; severe kidney and neurologic
diseases are uncommon. Although antinuclear antibodies,
rheumatoid factor, and anti-cyclic citrullinated peptide anti
bodies are often present, the presence of anti double
stranded DNA, anti-Smith, or anti-Ro/SSA antibodies makes
primary SLE a more likely diagnosis.
Management
Treatment for MCTD is directed at the specific organ system
involved in the individual patient and is guided by the man
agement of these manifestations as would occur in the "par-
ent" condition (see Table 32).
(RNP) Prognosis
Prognosis of MCTD depends on the spectrum and severity of
organ involvement. Patients with initially mild disease may
develop nelv and more severe manifestations over decades,
including interstitial lung disease and pulmonary arterial
hypertension. As in patients with other systemic inflamma-
tory disorders, patients with MCTD are at increased risk for
atherosclerotic cardiovascular disease.
UCTD usually remains mild and stable but in a minority
of patients may evolve into a more specific autoimmune
disorder, most commonly SLE. Most patients with UCTD
who develop a more specific disease do so within the first 2
to 5 years after presentation. A definite disease is more likely
to develop in patients with cytopenias; antibodies to

TAALE 32. Comparison of Mixed Connective Tissue Disease and Undifferentiated Connective Tissue Disease
Condition Typical Clinical Features Diagnosis Treatment
Mixed Raynaud phenomenon (bi- or Positivity for anti- Treatment determined by the management of
connective tricolor); puffy fingers; inflammatory U1-RNP antibodies, the specific disease diagnoses and organs
tissue disease a rthritis; sclerodactyly; serositis; 7O-kD protein involved; may include anti-inflammatory
esophageal dysmotility; myositis; immunomodulatory and biologic agents
Fulfills diagnostic
interstitial lung disease; PAH
criteria for at least two Vasodilators for PAH and Raynaud phenomenon
of the following: SSc,
PPI for esophageal disease
autoimmune myositis,
SLE

Undifferentiated Variable; most common include Does not meet Same as for mixed connective tissue disease
connective Raynaud phenomenon (bi- or diagnostic criteria for
tissue disease tricolor), particularly with abnormal any specific connective
nailfold capillaroscopy, persistent tissue disease; usually
inf la m matory a rth ritis/a rth ra g iaI positivity for ANA, with
unexplained by other diagnoses, titer >1 :80
skin rash, cytopenias, and serositis

PAH = pulmonary arterial hypertension; PPI = proton pump inhibitor; RNP = ribonucleoprotein; SLE = systemic lupus erythematosus; SSc = systemic sclerosis.

65

extractable nuclear antigens; anticentromere, anti-Ro/SSA,
or antiphospholipid antibodies; and/or abnormal nailfold
capillaries.
rTY POIT{15
o ]\rtixed connective tissue
disease includes clinical
manifestations of systemic lupus erythematosus,
autoimmune myositis, and/or systemic sclerosis;
anti-Ul-ribonucleoprotein antibodies are gzpically
present.
o Treatment for mixed connective tissue disease is
directed at the specific disease states and organ
systems involved.
r Undifferentiated connective tissue disease does not
meet criteria for a specific rheumatologic condition;
most cases are mild, but a minority of patients develop
a more specific autoimmune disorder.
Crystal Arthropathies
Gout
Epidemiology
Gout is characterized by intermittent painful flares of inflam
matory arthritis in response to crystals formed in joints
caused by excessive serrrm levels of urate. Gout is increas
ingly common, with a U.S. prevalence of approximately 4'l..
Factors contributing to this increase include dietary changes,
increasing obesity, and an aging population. Nearly all
patients with gout experience comorbidities, including
hypertension, coronary artery disease, hyperlipidemia, dia
betes mellitus, and chronic kidney disease (CKD). Some
comorbidities (e.g., CKD) contribute to hyperuricemia; all
comorbidities complicate treatment by posing relative con
traindications for appropriate therapeutics (e.g., NSAIDs in
patients with CKD).
Men reach a steady state serum urate level after puberty,
whereas premenopausal women are generally protected from
hyperuricemia by estrogenic effects. Men can have their flrst
gout flare in the third to fifth decade; women are more likely
to experience the first flare after menopause.
TA,8LE 33. Causos of Hyperuricemia
Primary renal uric acid underexcretion (hereditary, renaltubular basis)
Chronic kidney disease of any cause (secondary uric acid underexcretion)
Uric acid overproduction due to primary defea in purine metabolism:
Conditions of increased cellturnover leading to purine/urate generation: leukemia/lymphoma/other myeloproliferative disorders;
psoriasis; hemolytic a nemia; polycythemia vera
Drug-induced hyperuricemia (agents reducing renal glomerularfiltration and/ortubular urate excretion): thiazide and loop diuretics;
cyclosporine; tacrolimus; low-dose salicylates; ethambutol; pyrazinamide; lead ingestion/toxicity; alcohol; nicotinic acid
Diet-induced hyperuricemia (agents high in purines or inducing purine/urate biosynthesis): alcohol; shellfish; red meat; high-fructose
corn syrup-sweetened beverages and foods; impact on serum urate generally is limited in the absence of other causes
HPRT = hypoxanthine-guanine phosphoribosyltransferase; PRPP = phosphoribosylpyrophosphate
Crystal Arthropathies
Pathophysiology
Uric acid is the end product of purine metabolism, and about
two thirds ofurate production derives from cellular turnover of
nucleic acids; the remainder is derived from dietary intake. A
small proportion ofpatients overproduce urate on an inherited
metabolic basis. Unlike most mammals, humans do not express
uricase, an enzyme that converts urate into highly soluble
allantoin. Urate therefore accumulates and can precipitate as
crystals in joints and other tissues if serum concentrations
exceed the saturation point. At normal body temperature and
pH, the saturation point of urate is 6.8 mg/dl (0.40 mmol/L).
At lower temperatures and more acidic environments (e.g., in
the distal extremities), the saturation concentration is lower.
Almost all serum urate is filtered at the glomerulus, but
approximately 90% is reabsorbed in the proximal tubule; in
most patients with gout, hereditary underexcretion of uric acid
is the primary cause of hyperuricemia (Table 33). Not all
patients with hyperuricemia develop gout. The factors that lead
to the development of gout in hyperuricemia are unclear, but
degree ofelevation in serum urate level is predictive. A serum
urate Ievel greater than 10 mg/dl (0.59 mmol/L) is associated
with a 30'/o likelihood of an initial gout flare within 5 years.
A gout flare (acute gouty arthritis) is triggered when resi
dent synovial macrophages ingest monosodium urate crystals,
Ieading to activation of the NLRP3 inflammasome and genera-
tion of interleukin (lL)-18. IL 1p causes local vasodilation,
triggers production of other inflammatory cytokines, and
recruits and activates neutrophils. Complement activation
on the surface of urate crystals also promotes neutrophil
recruitment.
Clinical Manifestations
Three requirements generally must be f'ulfilled for onset of
clinically apparent gout: (1) hyperuricemia; (2) monosodium
urate deposition in joints and/or soft tissues; and (3) a reaction
to phagocytosed crystals that leads to an acute inflammatory
response.
Gout Flares
Ear$ acute gout flares are typically monoarticular, and at least
50% of first flares in men involve the first metatarsophalangeal
PRPP synthetase overactivity; HPRT deficiency
67
Crystal Arthropathies
tIGURE 44. Goutof theleftbigtoe.
(MTP) joint of the great toe (podagra) (Figure aa). Inflammatory
states, such as infection, surgery and myocardial infarction,
can provoke gout flares. The hallmarks ofa flare are pain, ten-
derness, swelling, redness, and warmth. Flares typically begin
at night and peak within 12 to 24 hours. Untreated, most gout
flares self resolve within days to a few weeks, although with
long standing disease, flares can persist for months. In men
with established disease, flares eventually affect the proximal
feet, ankles, and knees, and later almost any joint, including
the spine. Postmenopausal women may present differently,
with initial flares often involving the knees, or finger joints
affected by osteoarthritis. For patients with more severe or
long-standing disease, polyarticular flares may occur. Soft tis
sues can also be involved, manifesting as acute bursitis (olecra
non and prepatellar, most commonly), periarthritis, and gouty
panniculitis and cellulitis, the last of which can be misdiag-
nosed as a refractory bacterial soft-tissue infection.
Intercritical Gout
lntercritical gout is the period between gout flares. Early in the
disease course, the intercritical period can be years. As the
disease progresses, the intercritical period can progressively
shorten. Even in the absence of symptoms, urate crystals still
reside within joints and soft tissues, and low-grade systemic
inflammation persists.
68
Chronic Aspects of Gout
If gout is not treated relatively early in its course, gout flares
tend to become increasingly frequent and severe and are often
polyarticular. These flares may eventually evolve into persis
tent inflammatory arthritis (chronic gouty arthritis), with
intermittent flares superimposed on the baseline persistent
disease.
Some patients develop tophi. Tophi are solid chalky white
masses of uric acid, surrounded by inflammatory cells and a
rind of flbrous tissue. They are located around joints and in
soft tissues, with a predilection for the extensor surfaces ofthe
elbows, distal Achilles tendon, fingers (usually the proximal
and distal interphalangeal joints) (Figure 45), and helices of
the ears. Tophi are deforming, can interfere with function, and
directly erode bone. Ulceration of overlying skin can occur,
and accompanying infection can be difficult to treat because
tophi are avascular.
Diagnosis
A diagnosis ofgout (the chronic disease state) should be con
sidered in any patient who has had or is experiencing one or
more episodes of acute monoarticular or oligoarticular inflam
matory arthritis that may represent a gout flare. Although
designed primarily for research, gout classification criteria are
available, including as an online calculator (hftp://goutclassifi-
cationcalculator.auckland.ac.nz), and are 92'ln sensitive and
89'X, specific.
The differential diagnosis ofa gout flare is listed in Table 34.
The gold standard for diagnosing a gout flare is identification
of negatively birefringent, needle-like monosodium urate
crystals, along with neutrophils, in synovial fluid. Crystals
within neutrophils are usually also seen. "Negatively birefrin
gent" means that under polarized light, the crystals appear
yellow when parallel to and blue when perpendicular to the
polarizing axis of an optical filter. Arthrocentesis is not always
performed when gout flare is suspected, but when infection is
t IGUR E4 5. Fingers of a patient with numerous bulky tophaceous deposits of
monosodium uric acid crystals, a consequence of years of gout with uncontrolled
hyperu ricem ia.
 Crystal Arthropathies

TABLE 34. Differential Diagnosis of Acute Gout Flare

Condition Comments
lnfeclious arthritis Presentation may be identicalto gout. lnfectious arthritis is usually monoarticular but can be
polyarticular. Onset may be less acute than gout. Gout and infectious arthritis can coexist.
Acute calcium pyrophosphate crystal Pseudogout is less likely to present in the great toe, but acute presentations may otherwise
arthritis (pseudogout) be identicalto gout. Synovial fluid analysis can distinguish these entities. Gout and
pseudogout can coexist.
Basic calcium phosphate deposition Basic calcium phosphate deposition occurs in articular cartilage and periarticular tissues.
Because of their small size, basic calcium phosphate crystals are unlikely to be seen in
synovialfluid on light microscopy except as aggregates stained with alizarin red.
Trauma Trauma can lead to local pain and swelling, with or without a fracture, and can also trigger
a gout flare.

Other forms o{ inflammatory arthritis (e.g., Clinical context, affeaed joints, and pattern of arthritis help distinguish these entities.
reactive arthritis, rheumatoid arthritis, Synovial fluid analysis is particularly important when there is diagnostic uncertainty.
psoriatic arthritis, acute rheumatic fever)

a concern, joint aspiration for Gram stain and culture is Management

mandatory. See Principles of Therapeutics for details on the medications
In any acute arthritis in an adult, gout flare should be described in this section.
considered. Findings that support a gout flare diagnosis when
arthrocentesis is not feasible include onset of severe pain and Treatment of Gout Flares
swelling over several hours, involvement of the first MTP joint Treatment of acute gout flares focuses on anti-inflammatory
or midfoot/ankle, presence of erythema, and previous similar therapy; colchicine, NSAIDs, and glucocorticoids are all rea-
acute arthritis episodes. Male sex and associated cardiovascu- sonable options. Treatment choice should be determined by
lar disease are also supportive. The involved joints are warm, potential drug interactions and patient comorbidities. The
red, swollen, and very tender. Low grade fever may be pre- simplest is colchicine, 1.2 mg at the first symptoms of a gout
sent, particularly during polyarticular flares. Serum urate flare, followed t hour later by a 0.6-mg dose. Colchicine is
measured at time of flare may not be helpful because levels most effective when used less than 24 hours after symptom
can drop during acute systemic inflammation. Therefore,
although an elevated serum urate level supports the possibil-
ity of gout, hyperuricemia alone does not establish the diag-
nosis, and lack of hyperuricemia at time of an acute arthritis
does not definitively rule out gout. A serum urate level
2 weeks after gout flare resolution more accurately measures
baseline level. C reactive protein and erythrocyte sedimenta-
tion rate are elevated during gout flare but are nonspecific.
Joint fluid has an inflammatory leukoclte count (>2000ipl
[2.0 x 10e/L] and occasionally >100,000/pL [100 x 10ei L], with
neutrophil predominance). The presence of intracellular crys-
tals and leukocytes in synovial fluid does not rule out a con-
comitant infection.
Imaging is recommended when arthrocentesis is not pos-
sible and a clinical diagnosis of gout is uncertain. The charac-
teristic radiographic changes of established disease may help
confirm a history ofpreviously unrecognized gout and support
a diagnosis ofcurrent gout flare (Figure 46). Musculoskeletal
ultrasonography and dual energr CT can demonstrate mono-
sodium urate deposition in joints and are being assessed for
their role in diagnosis. Ultrasonography can show unsus-
pected tophi or a "double-contour" sign at cartilage surfaces
(Figure 47), which is highly specific for urate deposits in joints.
The double contour sign, identification of monosodium urate
F I G U R E 4 6, Periarticular bony erosions, appearing as punched'out bone
crystal deposition on dual-energr CT, and gout-related joint lesions with disruption of bone cortex (overhanging edges), represent areas of
damage on radiography are included in gout classification tophaceous monosodium uric acid deposition and accompanying inflammation in
criteria. a patient with severe, long-standing, inadequately treated gout.

69

Crystal Arthropathies
Soft tissue
Cartilage Double-contour sign
(urate on cartilage)
Bone-cartilage
inter{ace
Subchondral bone
FIGU R E4 7. Ultrasound of the tibial side of the knee showing monosodium
urate deposition on the cartilage surface of a patient with gout. Ihe light
heterogeneous area at the top represents soft tissue; the dark area at the bottom is
su bchond ral bone. The bottom brig ht wh it e line (green anow) represents the bone/
cartilage interface, and the clear zone aboueit(yellow arrow) is the cartilage. Above
the cartilage, and between the ca(ilage and the soft tissue, a second bright white
line may be seen (red arrow\,creatinga double-contour sign, which indicates the
presence of urale and is found in many patients with gout.
onset. High-dose NSAIDs for 5 to 7 days are effective, as are
glucocorticoids in any form: intra articular injection, intra
muscular injection (e.g., depo-methylprednisolone, 40 80 mg),
or an oral "burst" of prednisone (e.g., 0.5 mg/kg/d for
5 days). Topical ice helps reduce duration of the flare and may
be considered as adjunctive therapy.
Most gout flares respond to therapy lasting a week or less,
although more severe flares may require longer treatment. For
patients with severe and refractory flares, or with contraindi-
cations to other treatments, off label use of IL-lp inhibitors
(anakinra or canakinumab) can be considered. Gouty cellulitis
should be treated as any other acute gout flare.
Urate-Lowering Therapy
Guidelines conflict as to whether patients with gout should
receive dietary counseling to reduce serum urate levels. Ifrec-
ommended, patients may limit intake of shellfish, oily fish, red
meat, high-fructose foods, and alcohol. However, overly strict
diets that are unlikely to be adhered to are not helpful. Weight
loss (when appropriate) and increasing dairy intake may also
lower serum urate levels. In patients with hypertension, agents
other than diuretics (which block renal urate excretion) should
be considered; losartan may be a good alternative because it
has uricosuric effects.
The 2020 American College of Rheumatolory (ACR) and
2016 European League Against Rheumatism (EULAR) recom
mendations support a "treat-to-target" approach, reducing the
serum urate level to less than 6.0 mg/dl (0.35 mmol/L) and, in
the EULAR guidelines, to less than 5.0 mg/dl (0.30 mmol/L)
in patients with tophi.
The ACR strongly recommends initiating urate-lowering
therapy for patients with gout and any of the following: one or
70
!
I
:
't
more subcutaneous tophi; evidence of radiographic damage I
I
(any modality) attributable to gout; or frequent gout flares, .\
with "frequent" being defined as two or more annually. For
patients who are experiencing their first flare and have CKD
stage 3 or greater, a serum urate level exceeding 9.0 mg/dl
(0.53 mmol/L), or urolithiasis, the ACR conditionally recom-
mends initiating urate-lowering therapy. These guidelines
strongly recommend that patients taking urate-lowering ther-
apy continue it to achieve and maintain a serum urate target
less than 6.0 mg/dl (0.3s mmol/L).
Current evidence supports initiating urate-lowering ther-
apy during an acute flare, but only if adequate anti-inflamma-
tory therapy is concurrently started; doing so may improve
Iong-term adherence. Administering urate lowering therapy
during an acute flare, in the absence of anti-inflammatory
therapy, may extend the duration ofthe attack. Ifthe patient is
already receiving urate-lowering therapy, it should not be
stopped during an acute flare.
Three classes of urate-lowering therapy are available:
xanthine oxidase inhibitors (which reduce urate production),
uricosuric agents (which decrease renal urate resorption), and
pegloticase (a uricase).
Xanthine Oxidose I nhibitors
Allopurinol is the recommended flrst-line therapy for most
patients and is FDA approved for dosages up to 800 mg/d.
According to the ACR, allopurinol should be initiated at 100 mg/d
and the dosage titrated in 100-mg increments every several weeks
until a serum urate level less than 6.0 mg/dl (0.35 mmol/L) is
achieved (or lower as needed to control flares or resolve tophi).
For patients with stage 4 or 5 CKD, allopurinol should be initiated
at 50 mg/d and the dosage titrated in 50 to 100 mg increments
until serum urate target or dosage of 800 mg/d is achieved.
An uncommon but serious complication of allopurinol is
a hypersensitivity reaction heralded by a rash that may pro
gress to DRESS (drug reaction with eosinophilia and systemic
symptoms) syndrome (DRESS is also increasingly being
referred to as drug inducedhypersensitiuiru sundrome [DIHS]
to emphasize the fact that eosinophilia is not always present).
The drug should therelore be discontinued in patients who
develop a rash. Patients with the HLA-B.58:01 allele have a
much higher incidence of this syndrome. The 2020 ACR gout
guidelines therefore conditionally recommend genetic testing
for HLA-B.58:01 before initiation of allopurinol therapy in all
patients of southeast Asian (Han Chinese, Thai, and Korean)
and African descent, given the high prevalence (+% to'2,) of
the allele in those populations. Patients who are HLA-B'58:01
positive should usually receive alternative treatment.
Febuxostat is as efficacious as or more efficacious than
allopurinol. It is less likely to cause hypersensitivity reactions
than allopurinol and does not require dose adjustment in mild
to moderate CKD. In February 2019, the FDA mandated a
boxed warning regarding cardiovascular risk with febuxostat
compared with allopurinol and has limited the approved use
offebuxostat for patients who are unresponsive to or cannot

tolerate allopurinol. For patients taking febuxostat who have a
history of cardiovascular disease or a new cardiovascular
event, ACR guidelines conditionally recommend switching to
alternative urate lowering therapy if available.
Uricosuric Agents
The uricosuric agent probenecid is infrequently used as a sin
gle agent because it is less effective than xanthine oxidase
inhibitors; it should be avoided in patients with CKD (esti
mated glomerular filtration rate <50 mLlmirrl7.73 m2) or
nephrolithiasis. Combination therapy with a xanthine oxidase
inhibitor and probenecid (or the incidentally uricosuric agent
losartan) may be more effective than a xanthine oxidase inhib-
itor alone. A more effective uricosuric agent, lesinurad, is
available in Europe. Reversible kidney insufficiency may
develop in some palienls.
Pegloticase
Pegloticase is an option for patients with severe recurrent and/
or tophaceous gout who are intolerant ofor resistant to stand-
ard therapies. Infused every 2 weeks, pegloticase lowers semm
urate to nearly zero. However, 30% to 50% ofpatients develop
antibodies to the drug within weeks, rendering it ineffective
and increasing the likelihood of infusion reactions, including
anaphylaxis. Pegloticase should be discontinued in any patient
for whom it ceases to work because this suggests drug anti
body formation. Serum urate should be checked before each
infusion, and pegloticase should be discontinued if the serum
urate level exceeds 6.0 mg/dl (0.35 mmol/L) on two consecu
tive assessments.
Prophylaxis
Whenever urate lowering therapy is initiated for gout, mobili-
zation of monosodium urate crystals from joints and soft
tissues can provoke flares. Accordingly, patients starting urate
lowering therapy during intercritical periods should be pre-
scribed anti inflammatory prophyl&xis to prevent flares. The
ACR strongly recommends continuing prophylaxis for 3 to
6 months, with ongoing evaluation and continued prophylaxis
as needed ifflares continue. I\4ost patients tolerate colchicine,
0.6 mg once or twice daily; for those who do not, low-dose
NSAIDs or glucocorticoids are appropriate substitutes. Most
patients can use the same drug used for the acute flare, at a
lower dose lor prophylaxis.
KEY POIilTS
. The gold standard for diagnosis of gout flare is identifi-
cation of negatively birefringent, needle-like intracellular
and extracellular monosodium urate crystals within
synovial fluid.
. wrists (triangular fibrocartilage), pelvis (symphysis pubis),
The diagnosis ofgout flare, even when confirmed by
intracellular crystals in synovial fluid, does not defini-
tively rule out concomitant infection.
(Continued)
Crystal Arthropathies
l(tY P0 I tlTS (contlnucd)
o Colchicine, NSAIDs, and glucocorticoids are options for
treatment of acute gout.
o The American College of Rheumatolory strongly recom
mends that patients taking urate lowering therapy con
tinue doing so to achieve and maintain a serum urate
target less than 6.0 mg/dl (0.35 mmol/L).
o Patients starting urate-lowering therapy should receive
anti inflammatory prophylaxis to prevent flares.
Calcium Pyrophosphate
Deposition
Deposition of calcium pyrophosphate (CPP) crystals in cafti
lage can provoke an acute inflammatory arlhritis that clini
cally resembles a gout flare. CPP deposition (CPPD) disease is
less well characterized than gout, but four subgroups are
described: (1) asymptomatic CPPD, (2) acute CPP crystal
arthritis, (3) chronic CPP crystal inflammatory arthritis, and
(4) osteoarthritis with CPPD.
Epidemiology and Pathophysiology
CPPD primarily affects older patients, and prior joint trauma
is a significant risk factor. The risk for cartilage calcification
(chondrocalcinosis) doubles for every decade past 60 years,
and nearly halfofpatients in their late BOs have CPP visible on
plain radiographs. For younger patients with CPPD, laboratory
evaluation for contributory metabolic disease (hyperparathy
roidism, hemochromatosis, hypophosphatasia, hypomagne
semia) is warranted.
The pathophysiologz of CPPD is incompletely under
stood. Pyrophosphate produced by chondrocytes likely pre
cipitates with calcium to form CPP crystals, which then
deposit and can activate inflammatory pathways, resulting
in an acute arthritic flare. CPPD may also drive osteoarthritis
by causing mechanical damage and inducing proinflamma
tory activity in chondrocytes and synovial fibroblasts.
Epidemiologic evidence suggests that cartilage calcification
might play a role in osteoarthritis of the knees and wrists, but
not at the hip.
Clinical Manifestations and Diagnosis
Asymptomatic Calcium Pyrophosphate Deposition
Asymptomatic CPPD occurs with radiographic changes in
the absence of clinical symptoms. Cartilage calcification
appears as a Iinear opacity below the surface of articular
cartilage (Figure 48). It most commonly occurs in the knees,
and metacarpophalangeal (MCP) joints, in descending order.
Asymptomatic CPPD is common in older patients and in
osteoarthritic joints, and it may be a precursor of sympto
matic osteoarthritis with CPPD.
71
Crystal Arthropathies
FIGU R E 4 8. Cartilage calcification (chondrocalcinosis)
shows linearly arranged calcific deposits in the articular cartilage (arow).
Acute Calcium Pyrophosphate Crystal Arthritis
Acute CPP crystal arthritis (pseudogout) typically presents as a
monoarticular or oligoarticular inflammatory arthritis, char-
acterized by sudden onset of swelling, pain, loss of function,
tenderness, and warmth of the alfected joint (usually a knee or
wrist). Like acute gout, CPP flares may be provoked by sys
temic insults, such as major surgery or acute illness. Flares are
usually milder than those of gout and less commonly affect the
MTP joint, but if untreated they can persist for weeks or
months. Definitive diagnosis requires identification of CPP
crystals (along with leukocyes) in synovial fluid; in contrast to
urate crystals, CPP crystals are rhomboid-shaped and posi-
tively birefringent (blue when parallel to and yellow when
perpendicular to the polarizing axis ofan optical filter). As in
gout flares, joint infection may coexist with CPP arthritis, and
synovial fluid Gram stain and culture are usually warranted.
Radiographic evidence of cartilage calcification in older
patients with acute monoarticular arthritis suggests, but is not
diagnostic of, acute CPP crystal arthritis.
The crowned dens syndrome is a rare presentation of CPP
crystal arthritis involving the C2 vertebra. Radiographically it
may present as calcification of the cartilage over the dens.
TABLE 35. Management of Calcium Pyrophosphate Deposition
Clinical Presentation
Cartilage calcification (chondrocalcinosis)
Acute calcium pyrophosphate crystal
arthritis ( pseudogout)
Chronic calcium pyrophosphate crystal
inflammatory arthritis
Osteoarthritis with calcium pyrophosphate
deposition
72
Patients present with acute neck pain, fever, and headache
mimicking meningitis.
Chronic Calcium Pyrophosphate Arthropathy
Chronic calcium pyrophosphate arthropathy may be present
in one of two patterns: (t) chronic CPP crystal inflammatory
arthritis and (2) osteoarthritis with CPPD. Chronic CPP crystal
inflammatory arthritis is a polyarthritis involving the wrists
and MCP joints ("pseudo rheumatoid arthritis"); it is rare and
difficult to treat. Osteoarthritis with CPPD manifests as typical
osteoarthritic findings involving joints not commonly associ
ated with osteoarthritis (such as shoulders or MCP joints);
radiographic CPPD often precedes osteoarthritis onset, sug-
gesting a causal role for CPP
of the knee. This radiograph
Management
In contrast to gout, there is no known mechanism for dissolv
ing articular CPP crystals or preventing their formation.
lnstead, treatment aims at abrogating the inflammatory mani
festations of the disease (Table 35). Associated metabolic con-
ditions should be treated, but this treatment rarely results in
remission of the CPPD disease.
XEY POIIITS
. Asymptomatic calcium pyrophosphate deposition is
characterized by radiographic changes, including carti-
lage calcification (chondrocalcinosis).
. The presentation of acute calcium pyrophosphate crys-
tal arthritis (pseudogout) resembles gout; however,
crystals are rhomboid shaped and positively birefrin-
gent under polarized light.
o Chronic calcium pyrophosphate crystal inflammatory
arthritis often involves the wrists and metacar-
pophalangeal joints ("pseudo-rheumatoid arthritis").
o Osteoarthritis with calcium pyrophosphate deposition
causes typical osteoarthritic findings involving joints
not commonly associated with osteoarthritis (shoulders,
wrists, metacarpophalangeal joints).
TreatmenVComments
No specific treatment
Local treatment: joint aspiration, followed by intra-articular glucocorticoid injection, joint
immobilization; ice packs
Systemic treatment: anti-inflammatory doses of NSAIDs; colchicine; glucocorticoids (oral,
intramuscular, or parenteral); if there are contraindications to the preceding drugs,
anakinra may be considered off-label
Prophylaxis if recurrent attacks (three or more annual attacks): low-dose colchicine or daily
NSAI Ds (with gastrointestina I protection)
Low-dose colchicine or daily low-dose NSAIDs (with gastrointestinal protection);
low-dose glucocorticoids
Same treatment as for osteoarthritis without calcium pyrophosphate deposition (e.9.,
physical therapy, pain control, local glucocorticoids)
 Infectious Arthritis

Basic Calcium Phosphate
Deposition
Basic calcium phosphate (BCP) deposition occurs in older
persons and targets both articular cartilage and periarticu-
lar tendons and ligaments. BCP deposition is rarely associ-
ated with inflammatory arthritis and periarthritis, most
classically manifesting in older women as "Milwaukee
shoulder," an inflammatory state that causes progressive
destruction of the rotator cuff and glenohumeral joint.
Diagnosis is usually clinical; radiographs show calcium
deposition in the affected tissues. Visualization of BCP crys-
tals requires special stains and/or electron microscopy and
is rarely performed.
TEY ?OITT
. blood leukocyte count, erythrocyte sedimentation rate, and
Basic calcium phosphate deposition can rarely cause
"Milwaukee shoulder," a destructive inflammatory
arthritis and periarthritis ofthe shoulder; diagnosis is
usually clinical.
fluid leukocyte counts are typically greater than 50,000/pL
(50 x 10e/L) and often exceed 100,000/pL (100 x 10e/L), with
a polymorphonuclear cell predominance. Such high leuko-
cyte counts may occur in other conditions (e.g., crystal
arthropathies) but should be presumed infectious until
proven otherwise. Notably, the presence of crystals does not
exclude the possibility of concomitant infection. Synovial
fluid leukocyte counts may be lower in patients with gono
coccal, mycobacterial, or fungal infections; patients who
inject drugs; or those who are immunocompromised. A Gram
stain positive for bacteria should be considered definitive, but
the sensitivity of the test is inadequate for a negative result to
rule out infection when suspicion is high. Synovial fluid cul-
tures are usually positive in bacterial infections unless antibi-
otics were administered before arthrocentesis. Peripheral
C-reactive protein level are often elevated; however, normal
levels do not exclude the diagnosis, and elevated levels may
occur in noninfectious inflammatory arthritis and other
conditions.
Blood cultures should always be drawn before antibiotic
administration. When gonococcal arthritis is suspected, uro-

lnfestious Arthritis genital, rectal, and pharyngeal specimens should also be

obtained for nucleic acid amplification testing.
Diagnosis Plain radiographs are usually normal early in the course
of the infection, but baseline fllms are helpful to identi$/ other
Clinical Manifestations diseases or contiguous osteomyelitis. Radiographs obtained
Infectious arthritis typically presents with pain, swelling, later (from weeks to months) often show nonspecific changes.
warmth, and erythema of the affected joint, accompanied by In advanced or particularly virulent infection, periosteal reac-
fever and constitutional symptoms. Knee joint infection is tion, marginal or central erosions, and subchondral bone
common, but any joint may be affected. Previously damaged destruction may be seen (Figure 49). Bony ankylosis is a late
joints are at increased risk for involvement; acute monoarthri-
tis or new inflammation of a single joint in a patientwithwell-
controlled inflammatory arthritis should prompt evaluation
for infection.
Physical examination commonly shows loss of both active
and passive range of motion in addition to signs of inflamma-
tion. Careful skin examination can reveal signs suggesting
gonococcal infection (pustular skin lesions) or potential
portals of entry for pathogens (scratches, bites, or foreign
bodies).

Laboratory and lmaging Studies

In patients suspected of having infectious arthritis, the most
important diagnostic procedure is expeditious arthrocentesis.
The slmovial fluid should be sent for Gram stain, culture (bac-
terial and, when indicated, mycobacterial and/or fungal),
leukocyte count, and crystal analysis. Synovial fluid levels of
glucose, lactate dehydrogenase, and total protein do not aid in
diagnosis and should not be ordered. Depending on the
clinical picture, the fluid may be sent for polymerase chain
reaction assay to detect mycobacteria or Borrelia burgdorferi
DNA.
Bacteria-infected synovial fluid is cloudy and less viscous FIGURE 49. Radiographshowing infectiousarthritis-related bonedestruction
than that seen in noninflammatory arthritis. Elevated synovial of the hip.

73
lnfectious Arthritis
sequela. In joints that are difficult to evaluate clinically or have
complex anatomic structures, ultrasonography, Cl and MRI
can delineate the extent of an effusion and identi$r early bony
changes.
TEY POIXIS
o Infectious arthritis typically presents with pain, swell
ing, warmth, and erythema of the affected joint, accom-
panied by fever and constitutional symptoms.
o Acute monoarthritis or new inllammation of a single
joint in a patient with well-controlled inflammatory
arthritis should prompt evaluation for infection.
. Diagnosis of infectious arthritis is confirmed by arthro-
centesis and evaluation of the qmovial fluid for Gram
stain, culture, leukocyte count, and crystal analysis.
Causes
See MKSAP 19 Infectious Disease for details on the specific
infections and diseases discussed in this section.
lnfection With Gram-Positive Organisms
Bacterial arthritis is a medical emergency requiring immedi
ate diagnosis and treatment. Risk factors include an immuno
compromised state (including diabetes mellitus), injection
drug use, a history of joint surgery and having a prosthetic
joint. A recent break in the skin may be a contributing factor.
lnfections occur rarely after invasive procedures, such as
arthrocentesis or joint injection (Table 36). Most joint infec-
tions are monoarticular and derive from hematogenous seed-
ing to the synovium. Polyarticular infectious arthritis may
occur in persons who use injection drugs, those with systemic
inflammatory disorders (such as rheumatoid arthritis),
immunosuppressed patients, and patients experiencing over-
whelming sepsis.
Approximately 75"/,, of cases of nongonococcal infectious
arthritis in adults are caused by gram-positive cocci. Staphylcxrtccus
oureus is the most frequent microorganism in both native and
prosthetic joints. Stophylococcus epidermidis infections occur
more commonly in prosthetic than in native joints.
lnfection With Gram-Negative Organisms
Disseminated Gonococcal Infection
Neisserio gonorrhoeoe most typically occurs in younger, sexu-
ally active individuals. Disseminated infection occurs in 1% to
3'7, of patients infected with N. gonorrhoeae, with arthritis a
common feature.
Disseminated gonococcal infection may present in one
of two ways, although there may be overlap. The first
the arthritis-dermatitis syndrome, a triad of tenosynovitis,
dermatitis (usually painless pustular or vesiculopustular
lesions) (Figure 5O), and polyarthralgia without frank arthri
tis. Feveq chills, and malaise are common. Inf'lammation of
tendons of the wrists, fingers, ankles, and toes distinguishes
74
TABLE 36. Risk Factors for lnfectious Arthritis in Adults
General
Age >80 years
Alcoholism
Cutaneous ulcers or skin infections
Diabetes mellitus
End-stage kidney disease
lnjection drug use
Malignancy
Hereditary immunodeficiency states or therapy with
immunosuppressive agents
Preexisting arthritis or joint damage (e.g., rheumatoid arthritis
or osteoarthritis)
Prosthetic joint or recent joint surgery
Sickle cell disease
Gonococcal Arthritis
Sexually active patients
Terminal complement deficiency
Lyme Arthritis
Travel to or residence in an endemic area
Documented tick bite or erythema ns
Mycobacterial or Fungal Arthritis
HIV infection or other immunosuppression
Therapy with tumor necrosis factor inhibitors
Travel to or residence in an endemic area
Viral Arthritis
Chronic viral infection (HlV, hepatitis B virus, hepatitis C virus)
Exposure to infectious agent or vaccine (e.g., rubella)
Travel to or residence in an endemic area (e.9., chikungunya,
dengue, Zika)
Exposure to affected children (parvovirus B19, rubella)
this syndrome from other forms of infectious arthritis. Risk
factors for dissemination include HIV infection, pregnancy,
recent menstruation, and deficiencies in immunoglobulin
and terminal complement. The second presentation is a
purulent arthritis, usually without associated skin lesions or
fever. Patients present with acute onset of mono or oligo-
arthritis; the knees, wrists, and ankles are most commonly
involved.
Patients with the arthritis dermatitis syndrome are more
likely to have positive blood cultures, whereas those with
purulent arthritis are more likely to have positive synovial
fluid cultures. Nucleic acid amplification testing should also
is be obtained on samples from genital, rectal. and pharyngeal
sites.
Nongonococcal Gram-Negative Infections
Aerobic gram-negative bacilli are the predominant cause of
nongonococcal gram-negative joint infections. Predisposing

F I G U R E 5 0. Disseminated gonococcal infertion can present as a febrile
arthritis dermatitis syndrome with migratory polyarthralgia that may evolve to
infectious arthritis, tenosynovitis, and painless skin rash that may involve the
palms and soles. Skin lesions can vary from maculopapular to pustular, often with
hemorrhagic component.
Iactors include injection drug use, advanced age, and an
immunocompromised state. Pseudomones oerugirloso can
be seen in infection related to injection drug use. Patients
with sickle cell anemia may become infected with
Salmonella species. Gram negative anaerobes account fbr
only 5'7, to 7'7, of bacterial arthritis cases, most commonly in
prosthetic joint infections and/or immunocompromised
hosts.
Lyme Arthritis
Although arthralgia and myalgia often occur at the earlier
stages of Lyme disease, Lyme afthritis is a late-stage manifesta
tion. It is typically monoarticular, most commonly in the knee
(Figure 5l). It should be suspected in patients who may have
had untreated or incompletely treated Lyme disease, although
not all patients will have a history compatible with prior Lyme
disease. All patients with Lyme arthritis, however, shriuld have
lnfectious Arthritis
positive results on enzyme-linked immunosorbent assay and
Western biot confirmatory serologiesl this is the primary
means of diagnosing Lyme arthritis and is preferred to poly
merase chain testing for B. burgdorleri DNA or culture of
blood or synovial fluid.
Mycobaaerium tuberculosis lnfection
The most common musculoskeletal manifestation of tuber
culosis is vertebral osteomyelitis (Pott disease), usually
resulting from the hematogenous spread of Mycobacterium
tuberculosis into the cancellous bone ofthe vertebral bodies.
The onset of symptoms is commonly insidious and is not
accompanied by systemic symptoms. Disease progression is
slow sometimes resulting in delayed diagnosis. Predisposing
factors for skeletal tuberculosis include previous tuberculosis
infection, malnutrition, alcoholism, diabetes mellitus, and
a HIV infection.
Peripheral arthritis may also occur and typically presents
with chronic pain in a single weight-bearing joint, such as the
knee or hip. As in vertebral osteomyelitis, concurrent pulmo-
nary tuberculosis is present in only a minority of patients
with peripheral arthritis. Laboratory indicators of inflamma
tion may be only slightly abnormal, synovial fluid findings
can be nonspecific, and radiographic abnormalities can be
delayed. Synovial biopsy is usually necessary for diagnosis
because the yield of synovial fluid stain and culture is less
than 50'1,.
Atypical mycobacteria can occasionally infect joints.
Mycobacterium marinum is acquired through skin breaks
exposed to fresh or salt water (seen in fishermen and
aquarium hobbyists), and usually causes skin nodules and
arthritis.
Fungal tnfections
Fungi are uncommon but important causes of bone and joint
infections. Risk factors include immunosuppression and
FTGURE 51, Unilateral kneeeffusion in Lyme
arthritis.
75
lnfectious Arthritis
exposure to the fungi in endemic areas. Fungal joint infection
may be indolent and more difficult to diagnose than other
bone and joint infections. Fungal causes of osteomyelitis and
arthritis include coccidioidomycosis, blastomycosis, crypto-
coccosis, candidiasis, and sporotrichosis. Fungal arthritis is
usually a result of hematogenous dissemination but can occur
after direct inoculation of the joint. Some fungal inlections
(e.g., blastomycosis and sporotrichosis) can be diagnosed by
synovial fluid examination and culture, whereas serologic
testing and synovial biopsy may be needed for other organ-
isms (such as Coccidioides species). Synovial fluid leukocy.te
counts vary.
Viral tnfections
HTV
HIV infection is associated with several musculoskeletal
disorders, including painful articular syndrome, HIV-
associated arthritis, reactive arthritis, infectious arthritis,
and diffuse infiltrative lymphocytosis syndrome. Painful
articular syndrome consists of bone and joint pain, espe-
cially in the lower extremities in an asymmetric pattern,
lasting less than 24 hours. HIV associated arthritis is a non-
destructive arthritis that involves joints of the lower extrem-
ity in an oligoarticular pattern and usually lasts less than
6 weeks. Reactive arthritis is the primary form of spondy
loarthritis seen in patients with HIV infection and is more
likely due to a response to other sexually transmitted or
enteric infections than to the HIV infection itself. Reactive
arthritis in HIV may take a chronic relapsing course and may
be accompanied by enthesopathy and mucocutaneous man-
ifestations. Psoriatic arthritis may be more common and is
often more severe in patients with HIV infection, with disa-
bling enthesitis and joint erosion as well as axial involve-
ment (including sacroiliitis). Diffuse infiltrative lymphocy
tosis syndrome is a rare condition that resembles Sjogren
syndrome, but with CDB rather than CD4 cell infiltration of
the exocrine glands.
Hepatitis Viruses
Hepatitis B virus (HBV) infection causes a self-limited arthri
tis in up to 25% of infected patients during a prodromal stage
before the onset ofjaundice. Joint involvement can be sudden
and severe, with a pattern that is usually symmetric but can
be migratory or additive. Hand and knee joints are most often
affected; wrists, ankles, elbows, shoulders, and other large
joints may be involved as well. Morning stiffness is common.
Fusiform swelling of the small joints of the hand may be
found on physical examination. Patients with chronic HBV
infection may have recurrent but self limited polyarthralgia
or polyarthritis; it is not known to progress or cause joint
damage.
Acute hepatitis C virus (HCV) infection can cause acute
onset polyarthritis, including the small hand joints, wrists,
shoulders, knees, and hips. One third of patients have
75
oligoarthritis. Chronic HCV infection is often associated with
circulating immune complexes, which may produce the clini
cal syndrome of mixed cryoglobulinemia (purpura, weakness,
and arthralgia).
Both HBV and HCV infections may be accompanied by
the presence of rheumatoid factor, which can cause diagnostic
confusion.
Parvovirus B19
Up to 60% of adults with parvovirus B19 experience arthritis.
It often presents acutely, is symmetric and polyarticular, and
typically involves the proximal small joints of the hands.
Parvovirus B19 arthritis should be suspected when appropri
ate clinical features are present in someone who has exposure
to children, such as teachers and caregivers. (In contrast to
adults, children frequently experience parvovirus B19 infec-
tion as a fever accompanied by a facial rash [slapped cheek
appearancel, so-called fi flth disease.)
Acute parvovirus B19 infection is diagnosed by detecting
anti-parvovirus IgM antibodies in the serum. Anti parvovirus
IgG antibodies are highly prevalent in the general population
and indicate prior infection. Joint symptoms may persist for
weeks to months, and treatment is symptomatic (including
NSAIDs).
Rubella
Arthritis is uncommon in childhood rubella infection, but up
to 60% of adults with rubella develop joint symptoms, mainly
arthralgia, with the onset of rash. Joint involvement is usually
symmetric and migratory and most symptoms resolve within
2 weeks. The small joints of the hands, wrists, elbows, ankles,
and knees are most commonly affected. The pathogenesis of
rubella arthritis is thought to be due to immune complexes
and/or persistence of the virus in synovial cells or joint mac-
rophages. Diagnosis is usually made by detection of IgM
antirubella antibodies; the virus may also be cultured from
the nasopharynx or joint tissues. Joint fluid findings are
inflammatory.
Mosquito-Borne Viruses
Zika, dengue, and chikungunya viruses are transmitted by
Aedes mosquitos in tropical areas. Zika also can be vertically
and sexually transmitted, and localized transmission in the
southern United States has been reported. Zika infection is
symptomatic in 2O"1, of infected individuals and causes
arthralgia along with fever, rash, and conjunctivitis.
Symptoms tend to be mild and last a week or less. Dengue
fever causes arthralgia, fever, and rash but may be associated
with severe muscle and bone pain, headache, and hemor-
rhagic complications. In chikungunya infection, arthritis is a
predominant feature; patients may experience synovial
thickening and tenosynovitis, often involving the hands and
feet, in addition to fever and rash. The musculoskeletal symp
toms of Zika and dengue infections tend to subside within

days to weeks, whereas those ofchikungunya infection usu
ally last longer, resembling rheumatoid arthritis (without
rheumatoid factor or anti-cyclic citrullinated peptide anti
bodies) in some cases. Diagnosis of these mosquito-borne
diseases is based on clinical features and serologic testing.
Polymerase chain reaction testing on blood samples is also
available.
Prosthetic Joint lnfections
Bacterial infection complicates I"l, to 3"/,, of total knee and hip
replacements; rot€S are higher in immunocompromised
patients and those with rheumatoid arthritis. lnfection with
gram positive organisms, such as S. oureus, is most common.
Prosthetic joint infections are divided into early onset
(<3 months after placement), delayed (: to z+ months after
surgery), and late onset (>24 months after placement). These
definitions are controversial, with some sources defining
delayed infection as occurring 3 to 12 months after surgery.
Early and delayed infections are usually related to surgical
contamination at the time of the implantation, whereas late
infections result from hematogenous seeding of the joint.
Early and late prosthetic joint infections typically present with
pain, warmth, effusion, and fever. Peripheral leukocyte count
and inflammatory markers are usually elevated. Delayed
infections, however, may be more dif'ficult to recognize
because symptoms are less severe, and they are often caused
by less virulent microorganisms, such as coagulase negative
staphylococci and other skin organisms.
rEY POI]IIS
o Approximately
75'/" of cases of nongonococcal infectious
arthritis in adults are caused by gram positive cocci,
wlth Staphylococcus qureus the most frequent micro
organism in both native and prosthetic joints.
o Disseminated gonococcal infection may present as the
arthritis dermatitis syndrome (tenosynovitis, dermati
tis, and polyarthralgia) or as purulent arthritis that pre-
sents with mono- or oligoarthritis but usually without
skin lesions or fever.
. Lyme arthritis is a late-stage manifestation of the dis-
ease and istypically monoarticular (most commonly in
the knee) and inflammatory; diagnosis should be sus-
pected in patients who may have had untreated or
incompletely treated Lyme disease.
. MAcobacterium tuberculosis arthritis typically presents
as chronic pain in a single weight-bearing joint, such as
the knee; concurrent pulmonary tuberculosis is present
in only a minority of patients.
. Early and late prosthetic joint infections usually present
with pain, warmth, effusion of the joint, and fever;
delayed infections may be more difficult to recognize
because they are often caused by less virulent micro-
organisms, and symptoms may be less severe.
lnfectious Arthritis
Management
ln patients suspected of having infectious arthritis, blood and
synovial cultures (and any other cultures appropriate to the
clinical scenario) must be obtained before treatment. but
empiric antibiotic therapy should be started pending culture
results (Table 37). In suspected bacterial arthritis, the initial
antimicrobial coverage should be broad and account for host
factors, such as immunosuppression, as well as likely causa
tive microorganisms and regional antibiotic sensitivity data.
Antibiotics should initially be given parenterally. Given the
high prevalence of methicillin-resistant S. oureus, vancomycin
is often included initially. The duration of treatment depends
on the causative organism and patient response and comor
bidities, but bacterial arthritis usually requires 3 to 6 weeks of
treatment.
An infected joint must also be adequately drained. Needle
aspiration is an acceptable approach and should be performed
regularly (usually daily) as long as there is an effusion.
Ultrasound guidance may improve the ability to fully drain the
joint. Surgical drainage is an equally good alternative and is
more immediately definitive. Additionally, surgical drainage is
required for joints that are not easily accessible for needle
aspiration (e.g., sternoclavicular, sternomanubrial, shoulder,
and hip joints), if there is evidence of soft-tissue extension of
infection, or if the clinical response to antimicrobial therapy is
inadequate. The goal of surgery is to remove all purulent mate
rial and nonviable tissue and, in some cases, to perform syno-
vial biopsy or synovectomy.
Antibiotic treatment is recommended fbr all patients
with Lyme arthritis. Approximately 90"/,, of patients will
respond to a28 day course of oral doxycycline, amoxicillin, or
cefuroxime axetil. Patients with incomplete responses may
need treatment with a second course or a more aggressive
drug regimen, usually intravenous ceftriaxone. Treatment
beyond 1 month of ceftriaxone offers no benefit and should
not be used. Antibiotic refractory Lyme arthritis occurs in 107,
ofpatients or less, probably represents a progression to sterile
autoimmune arthritis, and responds to synovectomy or treat
ment with disease modifying antirheumatic drugs (such as
hydroxychloroquine or methotrexate).
Mycobacterial joint infections require at least 6 to
9 months of multidrug therapy. Treatment of arthritis associ
ated with viral infections is largely supportive, although spe
cific viral therapy is appropriate for HIV and HCV infections;
immunosuppressive therapy with glucocorticoids and rituxi
mab may be needed in refractory HCV related disease or severe
mixed cryoglobulinemia.
Treatment of prosthetic joint infections is challenging and
requires early surgical consultation. Orthopedic implants
serve as a nidus for microorganisms, and the avascularity of
the infected hardware limits antibiotic penetrance. Many
patients require removal ofthe orthopedic device as part ofa
two-stage procedure, with reimplantation of a new device
after an appropriate course of intravenous antibiotics.
77
Systemic Vasculitis

TABLf 3?. lnfectiousArthritisTreatment Based on Suspected Pathogen

Likely or ldentified
Gram-Positive Cocci
MRSA
MSSA
Gram-Negative Bacilli
Enteric gram-negative bacilli
Pse u d o m o n a s a e
Gram-Negative Cocci
Neisseria gonorrhoeae
Suspected Bacterial lnfection, No Gram Stain
Always initiate therapy with
coverage for MRSA; consider
patient risk factors and
community patterns of infection;
consider coverage for gram-
negative organism if patient is
immunocompromised and at
risk for gonococcal infection
Confirmed Diagnosis
Bo r re I i a b u rg d o rf e ri
arthritis)
M ycob a cte ri u m tubercu/osis
Fungal infections
Pathogen First-Line Therapy
Vancomycin
Nafcillin; cefazolin
Third-generation
cephalosporin (e.9.,
ceftriaxone or ce{otaxime)
ru g i n osa Ceftazidime; cefepime;
pi peracillin-tazobactam
lV ceftriaxone for >7 days
Oral doxycycline, 100 mg
orally twice daily for 7 days if
Chlamydia infection not
excluded
Vancomycin; vancomycin +
third-generation
cephalosporin; or
vancomycin +
antipseudomonal antibiotic
(Ly me Oral doxycycline, amoxicillin,
or cefuroxime axetil x 28 days
3- or 4-drug treatment (e.9.,
isoniazid, pyrazinamide,
ri{ampin, ethambutol,
streptomycin)
Amphotericin B,
echinocandin, or azoles
(f luconazole, itraconazole,
voriconazole, posaconazole)
depending on suspected
organism or culture data
Second-Line Therapy
Clindamycin;
daptomycin; linezolid
Fluoroquinolones
Carbapenems; aareonam;
fluoroq uinolones
Fluoroquinolones (only if
culture sensitivities
confirm susceptibility)
Comments
Narrow treatmentto MSSA coverage
asappropriate based on sensitivity data
ln absence of specific culture
sensitivity data, "stepping down" to
oral therapy is no longer
recommended because of increasing
resistance of N. gonorrhoeaeto
commonly used oral agents
Appropriate to start with broad
antibiotic coverage; narrow coverage
if culture data become available
lf inadequate response, lV
ceftriaxone x 2-4 wk
Duration mayvaryfrom 6 months or
longer depending on drug regimen
(shortertreatment if rifampin is used)
Prolonged treatment courses of
several months may be needed;
maintenance therapy may be
required in high-risk patients

lV = intravenous; MRSA = methicillin-resistant Staphy/oco ccus aureus; MSSA = methicillin sensitive Staphyloco ccus aureus.

TEY ?OIilIS Systemic Vasculitis

. For patients suspected of having infectious
blood and synovial cultures must be obtained before
treatment, but empiric antibiotic therapy should be
started pending culture results.
o In addition to antibiotic therapy, an infected joint must
also be adequately drained by needle aspiration or sur-
gical drainage.
. Many patients with prosthetic joint infections require
removal ofthe orthopedic device as part ofa two-stage
procedure, with reimplantation of a new device after an
appropriate course of intravenous antibiotics.
arthritis,
Overview
Vasculitis is inflammation of blood vessels, including capillar
ies, arteries, and/or veins. Clinical manifestations result from
tissue ischemia in the affected areas. Vasculitis can be primary
secondary to another underlying autoimmune disease, or
triggered by other causes (Table 38). Vasculitis mimics must
be considered in the differential diagnosis (Table 39). Primary
autoimmune vasculitis disorders are discussed in this
section.
Vasculitis is not one disease, but many. These conditions
are typically grouped into distinct categories according to

78
 Systemic Vasculitis

TABLE 38. Causes of Secondary Vasculitis

Medications
Common causes: antimicrobial agents (e.g., minocycline, sulfadiazine); antithyroid agents (propylthiouracil 180y"-907o1, methimazole,
carbimazole, benzylthiouracil [10o/o-20%; not available in the United States]); cardiovascular drugs (hydralazine); tumor necrosis factor
inhibitors
Rare causes: vaccines; antiepileptic agents; antiarrhythmic agents; diuretics; anticoagulants; antineoplastic agents; hematopoietic
growth factors; NSAIDs; psychotropic drugs; sympathomimetic agents; allopurinol; interferon alfa; levamisole (associated with cocaine)
lnfections
Hepatitis A, B, and C viruses; HIV; bacterial endocarditis; parvovirus 819
Neoplasms
Hairy cell leukemia (associated with polyarteritis nodosa); other hematologic and solid malignancies
Autoimmune Diseases
Systemic lupus erythematosus; rheumatoid arthritis; Sjogren syndrome; inflammatory myopathies; systemic sclerosis; relapsing
polychondritis; inflammatory bowel disease; primary biliary cirrhosis

clinical presentation and pathophysiolo$r A well-established
classification scheme focuses on size ofinvolved vessels. Vessel
size can provide insight into processes and presentations, but
conditions and vessel sizes may overlap.
I
including the external carotid, subclavian, axilIary temporal,
ophthalmic, ciliary occipital, and vertebral arteries. The vessel
involved dictates the clinical symptoms.
Clinical Manifestations and Diagnosis
Common GCA symptoms include headache (typically tempo

t,
Large-Vessel Vascu Iitis
L
Giant Cell Arteritis
I Epidemiolory and Pathophysiolory
Giant cell arteritis (GCA; also called temporal arteritis) usually
affects patients older than 50 years (peak incidence, 70 B0 years).
GCA is more common in White persons (incidence in Europe,
10-20/100,000). The female to male ratio is about 3:1.
Histologically, GCA is characterized by granulomatous
inflammation of large and medium-sized arteries, with infil-
tration of CD4 positive lymphocytes, macrophages, and mult
inucleated giant cells. Inflammatory disruption of the internal
elastic lamina is common. Involved vessels include the aortar
its major branches olfthe arch; and secondary branch vessels,
ral but occasionally more diffuse), constitutional symptoms,
concomitant polymyalgia rheumatica (PMR), and scalp ten
derness over the temporal artery. Symptoms can be unilateral
or bilateral. Jaw aching and fatigue with cherning indicate
ischemia (claudication) of the muscles of mastication. The
most feared complication of GCA is ischemic optic neuropathy
due to occlusion of the posterior ciliary or occasionally the
ophthalmic artery which can cause irreversible blindness.
Early recognition and treatment of any visual change (e.g.,
reversible diplopia or visual defect) are critical. Intracranial
ischemic strokes are rare.
Extracranial disease involving great vessels in the chest
and arms occurs in up to 50'/" of patients but is usually

TABLE 39. Differential Diagnosis (lncluding Mimics) of Vasculitis

Disease Comments
lnfection (sepsis, endocarditis, hepatitis) Rash and/or musculoskeletal symptoms can occur.
Dru g toxicity/poisoni ng Cocaine, amphetamines, ephedra alkaloids, and phenylpropanolamine may produce
vasospasm, resulting in ischemia.
Coagulopathy Thrombotic diseases (disseminated intravascular coagulation; antiphospholipid
syndrome; thrombotic thrombocytopenic purpura)can produce ischemic symptoms.
Malignancy Paraneoplastic vasculitis is rare. Any organ system may be affected, but the skin and
nervous system are the most common. Vasculitic symptoms may precede, occur
simultaneously with, or follow diagnosis of cancer. Lymphoma occasionally may
involve the blood vessels and mimic vasculitis. Consider malignancy in patients with
incomplete or no response to therapy for idiopathic vasculitis.
Atrial myxoma Classic triad of symptoms is embolism, pulmonary congestion or heart failure, and
constitutional symptoms (fatigue; weight loss; fever). Skin lesions can be identical to i

I
those seen in leukocytoclastic vasculitis. i
I

Cholesterol emboli Typically seen in patients with severe atherosclerosis. Embolization may occur after I

abdominaltrauma, aortic surgery, or angiography. May also occur after heparin, l

l
warfarin, orthrombolytictherapy. Patients may have livedo reticularis, petechiae and
purpuric lesions, and localized skin necrosis.

79
Systemic Vasculitis
subclinical; it only sometimes results in upper extremity clau
dication. Severe but uncommon complications include aortic
aneurysm and dissection. Up to 50% of patients with GCA
have PMR, which may occur before, concurrent with, or after
diagnosis of GCA (see Polymyalgia Rheumatica).
Physical examination may reveal scalp or temporal artery
tenderness and induration, reduced peripheral pulses, and
bruits. Laboratory studies almost always show elevated ery.th
rocyte sedimentation rate (ESR) and/or C reactive protein
(CRP). Rarely, however, the inflammatory markers may be
normal. Nonspecific evidence of inflammation may include
anemia, elevated serum ferritin level, and thrombocytosis.
Serologic testing reveals no specific autoantibodies (although
low-level antinuclear antibody levels and rheumatoid factor
are common in older patients).
GCA is suspected on the basis of clinical presentation
and should be confirmed, when possible, by temporal
artery biopsy and/or imaging of the great vessels. New or
atypical headache, jaw claudication, or visual changes in a
patient older than 50 years, especially with concurrent
PMR, should raise suspicion. Temporal artery biopsy is
diagnostic, but false-negative results are common because
of skip lesions; adequate biopsy sampling (>1-cm length of
temporal artery) is crucial; although bilateral temporal
artery biopsy can slightly increase the yield, unilateral
biopsy is recommended. Temporal artery biopsy findings
remain abnormal for up to 4 weeks after initiation of glu
cocorticoids. Given the risk for blindness. treatment should
therefore be initiated first and biopsy performed within
2 weeks. If the pretest likelihood of disease is high, treat
ment may be continued even in the presence of a negative
biopsy result.
Management
Suspected GCA should be treated immediately to prevent
visual loss. Beginning high-dose prednisone (1 mg/kg/d, up
to 80 mg) is recommended. Intravenous pulse methylpre-
dnisolone for 3 days is recommended for acute visual loss;
however, data on this approach are limited, and estab-
lished blindness is usually irreversible. Prednisone plus the
interleukin 6 inhibitor tocilizumab is conditionally recom-
mended as initial therapy because the combination is superior
to prednisone alone and typically permits faster glucocorti
coid taper. Symptoms and inflammatory markers usually
respond rapidly to treatment; lack of response should prompt
reconsideration of the diagnosis. High dose prednisone is
maintained for 2 to 4 weeks. Once symptoms resolve and
inflammatory markers normalize, prednisone is tapered as
tolerated, with a goal of reaching 20 mg/d within 2 to
3 months, at which point tapering is slowed. Glucocorticoids
should be discontinued, when possible, within 6 months, but
longer treatment may be warranted as dictated by disease
activity. Patients should be monitored for symptom recur
rence. ESR and/or CRP should be monitored monthly but
should not be the sole indication for adjusting glucocorticoid
80
dose. Mild flares can be managed with modest increases of
prednisone and slower tapering. The addition of low-dose
methotrexate may facilitate glucocorticoid tapering and may
be considered in patients with significant glucocorticoid
contraindications, although data are limited. At treatment
initiation, all patients should undergo bone densitometry
to stratify risk for glucocorticoid-induced osteoporosis and
receive prophylaxis.
GCA is self-limited (2-6 years) in some patients but may
be chronic in others. It also may recur. Appropriate and timely
treatment can reduce risk for blindness.
Polymyalgia Rheumatica
Epidemiologr and Pathophysiolory
Although not a vasculitis, PMR is an inflammatory disorder
that frequently (up to 50'7, of cases) accompanies GCA. PMR
and GCA likely reflect the clinical spectrum of a single
disease process, although PMR occurs 3 to 10 times more
frequently. Patients presenting with PMR should be asked
about arteritis symptoms because 107, to 20% have con
comitant GCA.
Clinical Manifestations and Diagnosis
The classic picture of PMR is pain and stiffness of the shoul
der girdle and hip girdle. Symptoms may affect some or all of
these areas; symmetric presentation is classic. Pain and stiff
ness are most pronounced in the morning. Peripheral arthri
tis, generally mild and affecting the knees and wrists, may
occur. Synovitis in the hands and feet is uncommon.
Constitutional symptoms and laboratory findings resemble
those of GCA, although normal inflammatory markers are
more common in PMR than GCA. PMR is diagnosed clini
cally. Temporal artery biopsy should be performed only if
GCA is suspected.
Management
Unlike GCA, PMR responds dramatically to moderate dose
prednisone (12.5 20 mg/d); lack of a rapid response should
prompt consideration of alternate diagnoses. Prednisone
taper is initiated 4 weeks after symptoms resolve and requires
months to years. Monitoring of recurrence is managed simi-
larly to the approach used for GCA. For relapses, guidelines
for the management of PMR (developed by the American
College of Rheumatologz and the European League Against
Rheumatism) recommend increasing the prednisone dose to
the last pre relapse dose at which the patient was doing well,
followed by a gradual reduction within 4 to 8 weeks to the
relapse dose. Methotrexate can be used in select cases as a
weak glucocorticoid-sparing agent.
Prognosis is good, although periodic recurrences are
common. If PMR treatment is initiated properly, patients
whose PMR is not accompanied by GCA rarely progress to
GCA. Several studies suggest the benefit of tocilizumab for
treating PMR in the absence of GCA, but the agent is not
approved for this purpose.
 Systemic Vasculitis

Takayasu Arteritis

t
Epidemiolory and Pathophysiolory
Takayasu arteritis (TA) causes inflammation of the large ves-
sels, most commonly the aorta, followed by the subclavian,
common carotid, and renal arteries; the pulmonary arteries
may also be involved. TA is rare, with a prevalence of 40 per
million in Japan and up to 8 per million elsewhere. Although #
vascular involvement and clinical features overlap some- E #
what with GCA, TA predominantly affects younger women.
Arterial lesions are often stenotic ("pulseless disease"), and
one third are aneurysmal. Histopathology is similar to that
ol GCA.

Clinical Manifestations and Diagnosis

TA manifestations include new onset hypertension, Iimb clau-
dication, postprandial abdominal pain due to mesenteric
ischemia, reduced pulses, arterial bruits, and blood pressure
discrepancies between the arms. Heart failure related to aortic
insufficiency or coronary artery disease may occur. Neurologic
manifestations include transient ischemic attack, stroke, and
acute visual changes. As with GCA, laboratory studies are non
specific and reveal anemia as well as elevated ESR and CRP.
Angiography may demonstrate arterial stenosis or aneurysm
(Figure 52).

Management
Primary treatment of TA is high dose oral glucocorticoids
(1 mg/kg/d, up to 80 mg/d) with a slow taper. Guidelines con

ditionally recommend adjunctive treatment with nonbiologic

immunosuppressive medications (e.g., methotrexate, Iefluno-
mide, mycophenolate mofetil, azathioprine, and cyclophos-
phamide) to mitigate glucocorticoid exposure. For refractory
disease, adding a tumor necrosis factor inhibitor is preferred
over adding tocilizumab. Endovascular or reconstructive vas-
cular procedures are sometimes required; if possible, these
t IGU R E 5 2. Aortic angiogram from a patient with Takayasu arteritis. Note the
high-grade stenosis of the proximal right subclavian artery (white arrcw) as well as
su bclavian artery just below the origin of the left v erlebral arhery (black anow\.
the left
lncidentally noted is an anatomic variation with a common origin of the right
brachiocephalic artery and the left common carotid artery.

should be performed during periods of inactive disease. The

leading cause ofdeath is heart failure; stroke and cardiovascu
lar disease also contribute to morbidity. The 1O-year survival
rate is 90'l".
I(EY POITTS
. Giant cell arteritis should be suspected in a patient
older than 50 years with new or atypical headache, jaw
claudication, or visual changes.
HVC . Suspected giant cell arteritis should be treated immedi-
ately with prednisone to prevent visual loss; diagnosis
can still be confirmed with temporal artery biopsy
within 2 weeks after initiation of prednisone.
HVC r Polymyalgia rheumatica is associated with pain and
stiffness ofthe neck, shoulder, and pelvic girdles; it
responds dramatically to moderate-dose prednisone.
. Takayasu arteritis occurs in younger women and causes
inflammation of the aorta and other major noncranial
vessels.
Mediu m-Vessel Vascu litis
Polyarteritis Nodosa
Epidemiolory and Pathophysiolory
Polyarteritis nodosa (PAN) is a rare systemic necrotizing vascu-
litis that affects medium-sized and sometimes small-sized
arteries. Prevalence is approximately 31 per million but declin
ing. Average age at onset is 50 years.
Historically, PAN has been strongly associated with hep-
atitis B virus (HBV). Because HBV prevalence has declined
with the advent of the HBV vaccine and antiviral treatment,
the proportion of patients with HBV-associated PAN has
declined from 36% to less than 5'/. of all PAN cases; most
contemporary cases are autoimmune. Pathophysiologr is not
well understood.
Clinical Manifestations and Diagnosis
PAN most commonly affects the skin and peripheral nerv
ous system, as well as the gastrointestinal tract and kidneys.

81
Systemic Vasculitis

ir: :r:, ,-li,' Clinical Features of Polyarteritis Nodosa

Organ System Symptoms Frequency Comments
Constitutional Fever; malaise; weight loss 65%
Musculoskeletal Arthralgia; myalgia 55%
Skin Purpura; nodules; necrotic ulcers 50%-600a
Neurologic Mononeuritis multiplex; peripheral neuropathy 79"/" Wrist drop; foot drop
Kidney Hypertension; hematuria; proteinuria 40% Renal artery microaneurysms with tissue
infarcVhematoma; no glomerulonephritis
Gastrointestina I Mesenteric ischemia; intestinal perforation; 38% One third of gastrointestinal cases manifest
pancreatitis; cholecystitis; appendicitis; as acute abdomen
gastrointestinal bleeding
Testicular Orchitis 17% Usually unilateral, due to testicular artery
involvement
Other Sensorineural hearing loss Case reports Bilateral; symmetric; sudden onset; rapidly
progressive
Laboratory Elevated erythrocyte sedimentation rate
in 82%; elevated C-readive protein;
leukocytosis; anemia; thromboqytosis;
increased liver chemistrytest result in 33%

Table 4O lists the clinical and laboratory findings of PAN. Management

The disease does not involve the lungs. When present, kid-
ney involvement is renovascular rather than glomerular
and often leads to hypertension. Cutaneous PAN is a vari-
ant confined to the skin. Cutaneous features of medium-
vessel vasculitis include livedo reticularis (Figure 53) and
painful deep ulcers and skin necrosis due ischemic infarc-
tion (Figure 54). Because of the intense inflammation of
medium-sized vessels, subcutaneous nodules may be
palpable.
Diagnosis is often confirmed via angiography of the mes-
enteric and/or renal vasculature, which demonstrates saccular
microaneurysms and areas of narrowing in medium-sized
vessels. The gold standard for diagnosing PAN is histologic
identification of focal segmental panmural necrotizing inflam-
mation of a medium-sized vessel, obtained on biopsy of
involved, easily accessible tissue (e.g., skin or a superficial
nerve).
Intravenous pulse glucocorticoids and ryclophosphamide are
indicated for severe organ-threatening disease; glucocorti
coids and disease-modirying antirheumatic drugs are used for
milder disease. HBV-associated PAN is treated with short-term
glucocorticoids, antiviral medication, and plasmapheresis if
necessary. The S-year survival rate for treated PAN is 80%, and
the relapse rate is 10% to 2O%.
PrimaryAngiitis of the Central Nervous System
Epidemiolory and Pathophysiolory
Primary angiitis of the central nervous system (PACNS) is a
rare small- and medium-vessel vasculitis of the central nerv-
ous system; it affects the brain parenchyma, spinal cord, and
leptomeninges. Incidence is 2.4 per 100,000. Median age at

F IGUR E 54 . Retiform purpura on the lower legs due to vasculitis characterized

FIGU R E 5 3 . Livedo reticularis on the feet, recognized as a red-blue, reticulated by dark red or purple net-like, branching, or stellate configuration. Skin necrosis and
vascular network. ulceration may occur.

82

onset is 50 years. The three histologic presentations have a
patchy distribution: granulomatous (most common), lympho
cytic, and necrotizing.
Clinical Manifestations and Diagnosis
Patients with PACNS usually present with gradual and progres
sive symptoms of headache, cognitive impairment, neurologic
deficits, transient ischemic attacks, and strokes. Laboratory
findings are normal. Cerebrospinal fluid is abnormal but non-
specific in 80'2, to 90% of patients, with elevated protein, lym
phocltic pleocy.tosis, and occasional oligoclonal bands. MRI
shows nonspecific white and gray mafter changes and infarcts.
Magnetic resonance angiography and CT angiography have
limited usefulness because of poor resolution. Cerebral angiog
raphy may demonstrate vessel "beading" (alternating dilations
and stenoses) but has limited sensitivity and specificity. Brain
biopsy should be performed in any patient in whom the diag-
nosis is seriously considered; however, the patchy distribution
of findings results in a 50'/n false-negative rate.
Evaluation also focuses on ruling out other conditions,
including infection, malignancy (e.g., intravascular CNS lym-
phoma), and reversible cerebral vasoconstriction syndrome.
Management
PACNS is treated with high dose glucocorticoids and cyclo
phosphamide. Patients often have permanent disability from
neurologic damage, and the recurrence rate is 27"/,,.
Kawasaki Disease
Kawasaki disease is a medium vessel vasculitis and the most
common type of vasculitis in children. It presents as fever,
rash, cervical lymphadenopathy, conjunctival congestion, and
mucositis. Coronary vessel vasculitis is the most feared compli-
cation and may leave permanent vasculopathy if not treated
promptly. Although Kawasaki disease almost never develops in
adulthood, adults who had Kawasaki disease as a child may have
residual coronary aneurysms that require monitoring and man-
agement. Recently a Kawasaki like syndrome (multisystem
inflammatory syndrome in children) has been identified in
patients (rarely, adults) who have been infected with COVID-l9.
r(EY POll{I5
r Polyarteritis nodosa most commonly affects the skin
and peripheral nervous system, as well as the gastroin-
testinal tract and kidneys; the gold standard for diagno-
sis is focal segmental panmural necrotizing inflamma-
tion of a medium-sized vessel on biopsy.
. Patients with primary angiitis of the central nervous
system usually present with gradual and progressive
symptoms of headache, cognitive impairment, neuro-
logic deficits, transient ischemic attacks, and strokes.
r purpura (both of which are nonblanching lesions; Figure 55),
Adults who had Kawasaki disease as a child may have
residual coronary aneurysms that require monitoring
and management.
Systemic Vasculitis
Sma I l-Vessel Vascu I itis
ANCA-Associated Vascu litis
ANCA-associated vasculitis includes three diseases character-
ized by the presence of ANCA (Table 4f), granulomatosis with
polyangiitis, microscopic polyangiitis, and eosinophilic granu
lomatosis with polyangiitis. (ANCA associated glomerulone
phritis is discussed in MKSAP 19 Nephrologr.) The presence of
ANCA can be detected on serologic testing and helps to define
the diseases.
The two types of vasculitis associated ANCA are p ANCA
(perinuclear, directed against the neutrophil enzyme myelo
peroxidase) and c ANCA (cl,toplasmic, directed against the
neutrophil proteinase 3). Perinuclear and cytoplasmic refer to
patterns of immunofluorescent staining; enzyme linked
immunosorbent assays against myeloperoxidase and protein-
ase 3 are used to confirm antibody positivity and in some cases
to replace immunolluorescence testing.
ANCA may play a direct role in disease propagation by
activating primed endothelial cells and neutrophils, leading
to vessel damage. The granulomatous inflammation in
some forms of ANCA associated vasculitis suggests a role for
cell-mediated immunity. Although most cases of ANCA-
associated vasculitis are idiopathic. a few are drug induced;
several drugs can cause this rare reaction, including pro-
pylthiouracil and levamisole (an adulterant often found in
cocaine).
See MKSAP 19 Nephrologr for details on kidney involve
ment in ANCA associated vasculitis.
Granulomatosis With Polyangiitis
EpidemiologA and Pathophy siology
Granulomatosis with polyangiitis (GPA) is the most common
ANCA-associated vasculitis. with an annual incidence of 7 to
12 per million.
Clinical Manifestations and Diognosis
GPA affects the small vessels of the upper and lower airways
(sinuses, lungs), kidneys, eyes (scleritis), skin, and peripheral
nerves. At least 50'X, of,patients have constitutional symptoms.
More than 95'7, of patients are ANCA positive, with antibodies
overwhelmingly (>SO'2, of cases) directed against proteinase 3
(anti PR3 antibodies; c ANCA).
GPA presents as systemic or localized disease. The sys
temic form is more common, involves major organs, and is
associated with positivity for anti PR3 antibodies. Patients
with localized disease are more likely to be younger and
female; have mainly ear, nose, and throat involvement; and are
less likely to be PR 3 positive. See Table 41 for clinical features
ofGPA.
Cutaneous leatures of GPA include petechiae or palpable
hemorrhagic bullae, and superficial ulcers. However, any
of the small vessel vasculitides may present with these
findings.
83
Systemic Vasculitis

TABLE 4'l . Clinical Features of ANCA-Associated Vasculitis Diseases

Granulomatosis With Microscopic Polyangiitis Eosinophili< Granulomatosis
Polyangiitis With Polyangiitis
ANCA c-ANCA (antiprotei nase-3 p-ANCA (anti myeloperoxidase p-ANCA (anti myeloperoxidase
antibodies) (>957o) antibodies) (507"-7 5"/") antibodies) (-50%)
Vascular histology Pauci-immune necrotizing Pauci-immune nongranulomatous Pauci-i m mu ne necrotizing
granulomatous vasculitis necrotizing vasculitis granulomatous vasculitis with
eosinophilic infiltration of vessel
walls and tissues; extravascular
granu lomas
Cardiac Pericarditis; myoca rd itis; Pericarditis; endomyocarditis;
conduction disorder (<1 0%) conduction disorder; heart failure
(27"/o-47"/")

Ea rslnose/th roat Crusting; rhinorrhea; sinusitis;
otitis media; chond ritis of ears and
nose with saddle nose deformity;
septal perforation (7 0"/"-1 00"/")
Gastrointestinal Ulceration; perforation (5"/"-1 1%l
Kidney Pauci-immune necrotizing
glomeru lonephritis (40%- 1 00%)
Sinusitis; sensorineural hearing Nasal polyps; rhinitis; sinusitis
loss (9%-30%) (prodromal)
Abdominal pain; bleeding Abdominal pain; bleeding
(30%-s8%)
Pauci-immune necrotizing Pauci-immune necrotizing
glomerulonephritis (80%- 1 00%) loneph ritis (25o/"\
g lome ru

Lung Alveolar hemorrhage; nodules; Alveolar hemorrhage; pulmonary Asthma (prodromal, >90%);
trachea l/su bg lottic stenosis infiltrates; pulmonary fibrosis nodular opacities; infiltrates
(500/"-907o) (25%-55"/") (257o-86o/"\

Ocular Scleritis; episcleritis; retinal

vasculitis; retro-orbital
pseudotumor; dacryoadenitis
(14"/"-60%)

Skin Petechiae/purpura; painful skin
lesions; maculopapular rash;
livedo reticularis; ulcers
Neurologic Mononeuritis multiplex,
sensorimotor peripheral
neuropathy (33%)
Centra I nervous system involvement
(pachymeningitis) (<5%)
Petechiae/purpura; painful skin Petechiae/purpura; painful skin
lesions; maculopapular rash; lesions; maculopapular rash;
livedo reticularis; ulcers livedo reticularis; ulcers
Distal symmetric polyneuropathy; Sensori motor peripheral
m o n o ne u riti s m ulti pl ex (37 "/"-7 2"/"1 neuropathy, mononeu ritis
multiplex (70%)
Central nervous system
pachymeningitis; cerebral
hemorrhage; infaras (<20%)

In the setting ofa classic clinical presentation and positiv-
ity for c-ANCA/anti-PR3 antibodies, diagnosis of GPA is
straightforward. However, because of significant risks of treat-
ment, biopsy of involved tissue is usually recommended
possible. Histopathologz of most tissues demonstrates pauci-
immune necrotizing granulomatous vasculitis; pauci-immune
necrotizing glomerulonephritis without granulomas is seen
on kidney biopsy.
Management
To induce remission in severe organ-threatening or life-
threatening disease, treatment of GPA consists of high-dose
oral glucocorticoids or intravenous glucocorticoids plus
rituximab (preferred) or cyclophosphamide; selected patients
may benefit from plasma exchange. Once remission is
achieved, patients should receive maintenance therapy con-
sisting of rituximab, methotrexate, or azathioprine; rituxi-
mab appears to be most effective for preventing relapse and
is preferred. It remains unclear whether suppressive mainte-
nance therapy can be fully withdrawn because relapse in
GPA is common (historically, >50'X, after initial remission).
Glucocorticoids alone are insufficient to control GPA. Patients
with limited presentations of GPA (such as arthropathy or
if upper airway disease) without organ threatening disease can
sometimes be treated with glucocorticoids plus methotrexate;
such patients should be carefully monitored for treatment
failure or development of kidney or other organ threatening
disease, necessitating a more aggressive regimen. With use of
these approaches, GPA mortality has declined from 90'ln to
around 10%. Kidney failure and infection remain the main
causes ofdeath.
Microscopic Polyangiitis
Ep idemiologA ond P ot ho p hg s iology
The annual incidence of microscopic polyangiitis (MPA) is
estimated al 2.7 per million in Europe and lower elsewhere.
Average age at onset is 50 to 60 years, with a predilection
for men over women (1.8:1). Compared with GPA, ANCAs are
Iess prevalent (507, 75'X,) and usually directed against
myeloperoxidase.

84

FIGU R E 5 5. Small-vessel vasculitis manifesting as palpable purpura and
petech iae.
Clinical Manifestations ond Dicgnosis
Like GPA, MPA characteristically affects the lungs and kid-
neys, along with other organ systems. In contrast to GPA,
MPA tends to spare the upper airways, and lung involve
ment is not granulomatous on biopsy. See Table 41 for the
clinical f'eatures of MPA. Diagnosis is suspected on the basis
of typical clinical findings and positivity for myeloperoxi
dase ANCA, although negativity for ANCA does not rule out
the diagnosis. The diagnostic gold standard is a biopsy
specimen demonstrating necrotizing pauci-immune vas
culitis of small vessels in any afl'ected tissue or pauci-
immune necrotizing crescentic glomerulonephritis in the
kidney. Absence of granulomas distinguishes MPA from
GPA.
Management
Treatment of MPA is similar to that of GPA.
Eosinophilic Granulomatosis With Polyangiitis
Ep id e mi olo gU ond P atho phy s io lo gy
Eosinophilic granulomatosis with polyangiitis (EGPA) is
the rarest ANCA associated vascuiitis. with an annual
incidence of 0.11 to 2.66 per million. Eosinophil infiltra
tion, activation, and degranulation participate in disease
pathogenesis.
Systemic Vasculitis
Clinical Manifestations ond Diognosis
The typical patient with EGPA has a prodromal history of
difficult-to-treat asthma (96% 7oo'k), rhinitis, and/or atopy. A
phase with increased peripheral and tissue eosinophilia
follows, with migratory pulmonary infiltrates and, Iess com-
monly, endomyocardial infiltration and gastrointestinal disease.
The subsequent acute vasculitic phase includes mononeuritis
multiplex or peripheral sensorimotor neuropathy (70'X,), kidney
involvement (2s'2,), and skin involvement (60'l,,). The vasculitis
phase is often associated with improvement of asthma. See
Table 41 for the clinical features of EGPA.
Laboratory findings show peripheral eosinophiiia of more
than 10'1,, or more than 1500/pL (1.5 x 10e/L). Only about 407,
to 60'l. of patients have a positive ANCA result, mostly directed
against myeloperoxidase.
Diagnosis is based on typical clinical findings, eosino
philia, and biopsy specimens demonstrating fibrinoid necrosis
and eosinophilic infiltration of vessel walls, as well as extravas
cular granuloma formation.
Management
In for mild
EGPA, glucocorticoids alone may be sufficient
disease without major organ involvement. With kidney,
gastrointestinal, cardiac, or neurologic involvement, cyclophos
phamide had been indicated in the past. However, mepoli
zumab, a monoclonal antibody that binds interleukin 5, has
been FDA approved for EGPA and has a more favorable safety
profi le than cyclophosphamide.
I\4ortality for EGPA is the lowest among all forms of
ANCA associated vasculitis. The S-year survival is 977,, and
the relapse rate is 2B%. If not treated early, neuropathy may
become permanent.
I( EY PO I ilTS
. Granulomatosis with po$angiitis affects the upper and
Iower airways, kidneys, eyes, skin, and peripheral nerves;
induction of remission in severe organ threatening or
life threatening disease consists ofhigh dose glucocor
ticoids rituximab (pref'erred) or cyclophosphamide.
r l\4icroscopic polyangiitis characteristically affects the
lungs and kidneys; treatment is the same as that for
granulomatosis with polyangiitis.
. Eosinophilic granulomatosis with polyangiitis is associ-
ated with asthma, rhinitis, sinusitis, atopy, peripheral
and tissue eosinophilia, migratory pulmonary infil
trates, and mononeuritis multiplex or peripheral senso
rimotor neuropathy; treatment consists of glucocorti-
coids for mild disease, with mepolizumab or
cyclophosphamide added for more severe disease.
lmmune Complex-Mediated Vasculitis
Immune complexes develop from cross linking of multiple
antigens and antibodies. Immune complexes can deposit
in small vessels, Ieading to complement and neutrophil
85
Systemic Vasculitis
activation, with consequent inflammation and tissue
damage. Although any tissue or organ may be affected, the
classic finding is invariably in the skin. Inflammation and
erythrocyte extravasation from damaged vessels result in
nonblanching palpable purpura, usually in dependent areas
(Figure s6). The various immune complex mediated vascu-
litides are distinguished by the antigen that drives them, the
class of antibody generated, and differences in clinical
presentations.
Cryoglobulinemic Vasculitis
Cryoglobulins cause an immune complex mediated small
vessel vasculitis primarily affecting the skin, peripheral nerv-
ous system, and kidneys. CNS involvement may rarely occur.
There are three types of cryoglobulins. Type I occurs as a
consequence of malignant monoclonal gammopathies and
B-cell lymphoma. Types II and III are polyclonal and "mixed"
in nature. Each is formed from the interaction of antigen
targeted antibodies with rheumatoid factor; tlpe II cryoglobu-
lins include a monoclonal IgM rheumatoid factor, whereas in
type III cryoglobulins the rheumatoid lactor is a polyclonal IgM.
The ability olrheumatoid factor to directly bind other antibod
ies facilitates the formation of immune complexes even in the
absence of persistent antigen. In addition to their ability to
form immune complexes, all cryoglobulins demonstrate the
unique feature of precipitating in the cold. See MKSAP 19
Hematologz for details on type I cryoglobulins and the differ-
entiation of cryoglobulinemia from cold agglutinin disease.
Epi demiolo gA a nd P athophy s iol ogy
Mixed cryoglobulinemia, which accounts for 75% to 90'l" of all
cases of cryoglobulinemic vasculitis, is rare, with an estimated
prevalence of 1in 100,000. About two thirds of mixed cryoglo
bulinemia (type II and type III) cases are related to hepatitis C
virus infection. Autoimmune diseases, such as systemic lupus
erythematosus and Sjdgren syndrome, more typically cause
type I I I cryoglobulinemia.
F IG UR E 5 6. Palpable purpura is the classic rash of any small-vessel, immune
complex-mediated vasculitis. The Iesions are nonblanching and represent
extravasations of blood from damaged vessels. Purpuric lesions are typically more
prominent 0n the lower exlremities, a consequence of the superimposed eflect of
gravity on hydrostatic pressure.
86
Clinical Monifestations and Diognosis
Cutaneous symptoms (palpable purpura, digital ischemia,
ulcers, necrosis, and livedo reticularis) are seen in about 90%
of patients. Other common manifestations include peripheral
neuropathy, arthralgia without arthritis, and glomerulone-
phritis (usually membranoproliferative). Pulmonary and/or
gastrointestinal involvement is rare. Testing for cryoglobulins
requires that a sample of blood be maintained at 37.0 "C
(98.6 'F) until clotting is complete to avoid incorporation of
the cryoglobulins into the clot. In addition to detection of
cryoglobulins, laboratory abnormalities frequently include
depressed C4 complement and low CH50 levels. Patients
with type II and type III cryoglobulinemia have positivity for
rheumatoid factor. A false-negative cryoglobulin result is not
unusual given the complexity of cryoglobulin testing.
Management
Treatment of cryoglobulinemia requires first addressing the
cause of the disease, such as instituting antiviral therapy for
hepatitis C virus related cryoglobulinemia. When the conse
quences of the cryoglobulinemia are severe (e.g., glomerulo
nephritis, ulcerating cutaneous lesions, digital gangrene), the
vasculitis itself must also be treated. Glucocorticoids and
rituximab in combination are the standard first line therapy.
IgA Vasculitis
See MKSAP 19 Nephrologr for information on IgA nephropa
thy and on kidney involvement in IgA vasculitis.
Ep ide miologA and Potho phy s iology
IgA vasculitis (Henoch-Schonlein purpura) is a common vas
culitis of childhood that rarely occurs in adults. Estimated
annual incidence in adults is 14 per million. Onset is usually
preceded by upper respiratory tract infection, often with
streptococcal bacteria.
Clinical Manifestations o nd Diognosis
Patients with IgA vasculitis typically present with palpable
purpura in dependent areas. Other common findings include
abdominal pain or gastrointestinal bleeding (50'1,), arthritis
and arthralgia (oo%), and glomerulonephritis. Although pro-
gressive renal damage may occur, 90% of adults with kidney
involvement fully recover.
There are no specific laboratory tests for diagnosis.
Diagnosis is confirmed by demonstrating IgA tissue deposi
tion, generally in the skin, by immunofluorescent microscopy.
Skin biopsy demonstrates leukocy.toclastic vasculitis with
healy deposits of IgA and complement on immunofluorescent
staining. Although rarely necessary renal histolory shows IgA
deposition within the mesangium.
Management
Although IgA vasculitis in children tends to be self-limited,
adults are more likely to develop persistent nephropathy and
may require glucocorticoids. Despite lack of evidence, some

patients may require additional immunosuppression (cyclo-
phosphamide or rituximab).
Hypersensitivity Vasculitis
Epidemiology and Pathophg siology
Hypersensitivity vasculitis is a small vessel vasculitis medi-
ated by immune complex deposition confined to the skin. It
may be triggered by an antigen, such as a drug or infection; in
50'/u of cases, the antigen is unknown. Men and women and
people of all ages are aflected.
Clinical Manifestations ond Diognosis
The most common presentation of hypersensitivity vasculi
tis is palpable purpura in dependent regions, often develop
ing 7 to 10 days after exposure to a triggering antigen; Iesions
appear in "crops" and resolve over a few weeks after the
antigen is removed. Internal organs are unaffected. Skin
biopsy with immunofluorescence demonstrates leukocyto
clastic vasculitis without heavy IgA deposits. Evaluation
should be guided by clinical signs and symptoms and may
require only a complete blood count, basic chemistries, and
urinalysis.
Management
Removal of the antigen (if identified) and supportive care are
usually sufficient. Resolution within a month is the rule. If
symptoms persist or recur, anti-inflammatory agents, topical
or low dose systemic glucocorticoids, colchicine, or dapsone
may be helpful.
XEY POIXTS
o Mixed cryoglobulinemia is associated with cutaneous
symptoms, peripheral neuropathy, arthralgia without
arthritis, and glomerulonephritis, with two thirds of
cases related to hepatitis C virus infection.
o IgA vasculitis (Henoch-Sch6nlein purpura) is character-
ized by palpable purpura and abdominal pain or gastro
intestinal bleeding and occurs mainly in children.
I
o The most common presentation of hypersensitivity vas-
culitis is palpable purpura, developing 7 to 10 days after
exposure to a triggering antigen.
L Other Rheumatologic
Diseases
Behget Syndrome
i Behqet syndrome, a systemic vasculitis, consists of a constel-
lation of characteristic signs and symptoms, including oral
and genital ulcers and inflammatory eye disease. Less com-
mon but more ominous features include vascular and central
nervous system disease. Epidemiologr varies widely; endemic
areas are along the historic Silk Route from East Asia to the
Other Rheumatologic Diseases
Mediterranean. Prevalence is highest in Turkey (20-600/
100,000). Outside of endemic areas, Behqet syndrome
tends to be less severe. The main genetic risk factor is the
major histocompatibility complex I antigen HLA-B51, sup
porting Behqet syndrome as an autoimmune disease.
However, many experts believe that the condition repre
sents mixed mechanisms involving both autoimmunity
and autoinflammation. Most patients with Behqet syn-
drome present with painful oral and/or genital ulcers
(Figure 57). Genital ulcers typically occur on the scrotum
and vulva and tend to scar.
Gastrointestinal involvement may be present, making the
distinction between Behqet syndrome and Crohn disease dif
ficult. Eye disease includes panuveitis, optic neuritis, and
retinal vasculitis. Arthritis and enthesitis may be present.
Cutaneous manifestations include pustular lesions, skin
ulcers, and erythema nodosum. Vascular involvement is seen
in both the arterial and venous systems. In the arterial bed,
both aneurysms and thrombosis may be seen. The pulmonary
bed may be affected, and Budd Chiari syndrome can occur.
The most common form of venous disease is thrombosis.
which occurs in the lower extremities but may also occur in
the cerebral and cardiac circulations. Central nervous system
disease may include parenchymal brain involvement, espe
cially in the brainstem. Pyramidal, motor, and behavioral
changes may occur.
Diagnosis of Behqet syndrome is based on the presence of
the characteristic signs and symptoms (Table 42). The pres-
ence of patherry-accumulation of a pustular neutrophilic
infiltrate after disruption of the skin with a sterile needle
strongly suggests Behget syndrome (Figure 58). However,
results of pathergz tests are often negative, particular\ in
nonendemic areas. lmaging may define typical, but nonpath-
ognomonic, patterns of vascular involvement.
Management involves selecting agents appropriate to the
type and severity of clinical involvement. For oral ulcers, both
topical and systemic glucocorticoids may be used. Apremilast,
a phosphodiesterase 4 inhibitor, is FDA approved for oral
FIGURE 57. Recurrent,painful genital mucosal ulcerationsareacharacteristic
clinical leature of BehEet syndrome. ln women, they typically appear on the vulva,
as shown, and may heal with disfiguring scarring.
87
Other Rheumatologic Diseases
TABLE 42. lnternational Criteria for Behqet Disease
Manifestations
Recurrent oral ulcers
Recu rrent genital ulcers
Pathergy
Skin lesions (pseudofolliculitis; skin ulcers;
erythema nodosum)
Eye lesions (anterior uveitis; posterior uveitis;
retinalvasculitis)
Central nervous system lesions
Vascular lesions (arterial thrombosis; large-vein
thrombosis; phlebitis)
'Four or more points are needed for the diagnosis of Behget syndrome.
F IGUR E 5 8. Pathergy associated with Behget syndrome, characterized by
pustular-appearing skin lesions occuning 48 hours after skin pricking with a sterile
need le.
ulcers in Behget syndrome. Thalidomide and colchicine are
both accepted treatments; colchicine may be better for
arthritis than for oral ulcers. Topical and/or oral 5-aminosali
cylic acid derivatives may be used for gastrointestinal
involvement. For resistant severe ulcers, or for vascular, oph
thalmologic, or central nervous system involvement, oral
disease modifying antirheumatic drugs, such as azathio
prine and cyclosporine, may be considered; tumor necrosis
factor inhibitor therapy, particularly infliximab and adali-
mumab, is frequently effective. In severe cases, cyclophos
phamide may be an option. Acute thrombosis should be
treated with immunosuppressives rather than anticoagulants
because the cause of the thrombosis is inflammatory rather
than thrombotic.
TEY POITIS
. Behqet syndrome is characterized by recurrent painful
oral and genital mucosal ulcerations, inflammatory eye
disease, and pathergr.
. Vascular, ophthalmologic, and central nervous system
involvement requires aggressive treatment with immu-
nosuppressive andior tumor necrosis factor inhibitor
therapy.
88
Rela psing Polychond ritis
Points" Relapsing polychondritis is a rare condition (annual incidence,
2 3.5 cases/l million) characterized by inflammation and
2 destruction of cartilage. The most apparent involvement of
relapsing polychondritis is in the helix and antihelix of the
external eari the initial presentation there is redness and
swelling, but it may progress to structural collapse and a floppy
appearance (Figure 59). Middle ear involvement may cause
2
hearing loss. Other cartilaginous structures that can be
affected include the bridge of the nose and articular cartilage,
Ieading to inflammatory arthritis. Involvement of the tracheal
rings can cause airway obstruction, requiring surgical inter
vention. Other connective tissue structures involving the eyes,
tendons, heart valves, and skin may be affected.
Pathogenesis of relapsing polychondritis is poorly under-
stood. An association with HLA-DR4 supports an autoimmune
cause, and antibodies to various cartilage components are
sometimes present. On biopsy specimens, cartilage shows a
polymorphic inflammatory cell infiltrate.
Diagnosis is made clinicallyi biopsies are rarely necessary.
Tracheobronchial involvement mandates an aggressive evalu-
ation, including imaging (typically CT), pulmonary function
testing, and, in some cases, tracheobronchoscopy. In 30'7, of
cases, relapsing polychondritis may be associated with other
autoimmune diseases, including ANCA-associated vasculitis.
The MAGIC (mouth and genital ulcerations with inflamed
cartilage) syndrome appears to represent a confluence of
relapsing polychondritis and Behqet syndrome.
Management depends on severity. For mild symptoms,
NSAIDs and dapsone may be considered. For acute and/or
severe involvement, high-dose glucocorticoids are the initial
management. Oral immunosuppressants (e.9., methotrexate)
may be added. The tumor necrosis factor inhibitors infliximab
and adalimumab have been used to good effect. The anti
interleukin-6 agent tocilizumab may also be effective.
F IG UR E 5 9. Floppy ear in a patient with relapsing polychondritis. Chronic
inflammation of the upper section of the ear eventually results in loss of cartilage
and structural collapse.The ear lobe, which does not contain cartilage, is unaffected.
 Other Rheumatologic Diseases

I(EY POII{I
. ensue. The cryopyrin-associated periodic fever syndromes
Relapsing polychondritis is characterized by inflamma-
tion and damage of cartilaginous tissues; tissues most
commonly affected include the cartilaginous portions
of the external and middle ear, nose, and tracheal rings.
Autoi nflam matory Diseases
Autoinflammatory diseases xre monogenic conditions in
which innate immune pathways are activated independently
of any specific known antigen. The result is periodic or chronic
inflammation, f'ever, and multiorgan involvement. The best
studied of these conditions result from mutations that cause
enhanced function of inflammasomes. multimolecular com,
plexes that raise the levels ofactivated interleukin 1p.
In familial Mediterranean fever, mutations of pyrin, a
protein, lead to inflammasome activation, causing fever,
arthritis, rash, and sterile peritonitis. Renal amyloidosis may
result from activation of the NLRP3 inflammasome. In the
pediatric version, neonatal onset multisystem inflammatory
disease, inflammation leads to permanent joint deformity,
encephalitis, and, ifnot treated, early death. Adult versions of
cryopyrin-associated periodic fever syndromes are milder and
may be triggered by cold. In TRAPS (tumor necrosis factor
receptor-associated periodic fever syndrome), mutations in
the tumor necrosis factor receptor lead it to be persistently
activated on inflammatory cells. Patients have fever, chills, and
severe muscle pain lasting more than 1 week. Other fbrms of
mutations can also lead to periodic fevers, such as through the
activation of the signaling molecule nuclear factor rB or
through the unstimulated production of interferons.
To the extent possible, treatments address the signaling
problem involved. Table 43 lists the features and treatment of
select autoinfl ammatory diseases.

TABLE 43. Features and Treatment of Select Autoinflammatory Diseases

FMFA TRAPS FCA5U MWSb NOMID/ Schnitzler Syndrome
ctNcAb
lnheritance AR AD AD AD AD Acquired
Gene MEFV TNFRSFlA NtRP3 NtRP3 NLRP3 Unknown
Protein furin TNF receptor Cryopyrin Cryopyrin Cryopyrin MGUS (hallmark but
type 1 not proven causal)
Age at onset 65% <1 0 years 50% <1 0 years <1 year of age Childhood Neonata I Adult(51 +10years)
o{ age;907"<20 of age; up to period
years of age fifth decade
Ethnicity Mediterranean Ail European European All White/European
Clinical
Ma nifestations

Attack duration 12-72 hours Days to weeks 12-24 hours 1-2 days Continuous Daily
Abdominal Pain; serositis Pain; serositis Nausea Pain

Pleuritis Common Common Rare Rare

M usculoskeleta I Monoarthritis Large joints Arthralgia Arthralgia; Epiphyseal Arthralgia; arth ritis;
of lower oligoarthritis overgrowth; bone pain
extremities co ntractu res

Rash Erysipeloid on Migratory with Cold- Urticaria-like U rticaria-like Urticarial rash

lower legs underlying induced;
myalgia urticaria-like
Oth er High risk for Conjunctivitis; Conjunctivitis; Sensorineural Sensorineural Leukocytosis;
amyloidosis periorbital headache; deafness; deafness; lymphadenopathy;
edema amyloidosis; conjunctivitis; aseptic hepatosplenomega ly;
sensorineural amyloidosis meningitis; MGUS (usually lgM r);
deafness mental may later develop
retardation; Waldenstrom
amyloidosis macrog lobu linem ia
Treatment Colchicine Glucocorticoids;
TNF inhibitors
lL-1 0
inh ibition
rL 1p
inhibition
lL-1 B
inh ibition
lL-1Ra or lL-1B
inhibition
AD=autosoma dominant;AR=autosomalrecessive;CINCA=chronicinfantileneurologic,cutaneous,articularsyndrome;FCAS=familialcoldautoinflammatorysyndrome;

syndrome;NOMID=neonatalonsetmultisysteminflammatorydisease;TNF=tumornecrosisfactor;TRAPS=tumornecrosisfactorreceptor associatedperiodicsyndrome.

i "FMF is the most common autoin{lammatory disease.

I disease (chronic infantiie neurologic, cutaneous, afticuiar syndrome).

89
Other Rheumatologic Diseases

rtY Potxl multiple organs and tissues. Although sarcoidosis most com
o Autoinflammatory monly affects the lungs (see MKSAP 19 Pulmonary and
diseases are characterized by epi-
Critical Care Medicine), approximately 50% of patients have
sodic and/or persistent inflammation and involve
extrapulmonary involvement, arrd 2"/,, have only extrapulmo
inherited or spontaneous mutation ofgenes that encode
nary involvement. The cause of sarcoidosis is unknown; the
for inflammatory responses.
primacy of lung involvement suggests an initial respiratory
exposure. ln the United States, Black persons are affected
more commonly and more severely than White persons.
Adult-Onset Still Disease Rheumatologic manifestations of sarcoidosis include
Adult onset Still disease is a rare systemic condition (preva arthritis involving multiple joints that may develop erosive
lence, 1 10 cases/l million) characterized by fever with daily damage, deformity, and dactylitis. Myopathy may also occur.
evening spikes, evanescent salmon colored macular or macu Bone involvement, reported in up to 15'X, of patients. is associ
lopapular rashes that peak with the fever, arthritis or arthral ated r,r,ith a chronic course and poorer prognosis (Figure 60).
gia, and elevated leukocyte counts. Other manifestations
include sore throat; lymphadenopathy; splenomegaly: and
inflammation of the lungs, heart, and liver.
The Yamaguchi criteria fbr adult-onset Still disease con-
sist of tbur major and four minor criteria. Diagnosis requires
the presence of at least five criteria, including at least two
major criteria. Major criteria are (1) daily evening spiking
fever to temperature of 39.0 'C (102.2 "F), (2) arthralgia/
arthritis fbr more than 2 weeks, (3) nonpruritic salmon
colored macular/maculopapular rash on trunk or extremities,
and (4) leukocyte count greater than 10.000/pL (10 x 10e/L),
with more than B0'2, neutrophils. Minor criteria are (t) lym
phadenopathy and/or splenomegaly, (2) elevated aspartate
aminotransferase, alanine aminotransferase, or lactate dehy
drogenase levels, and (3) negativig for antinuclear antibodies
or rheumatoid factor.
Erythrocyte sedimentation rate and C reactive protein
levels are elevatedl I'erritin levels are often extremely high.
Adult onset Still disease is thought to represent an overex
pression ofinterleukin-lB and other cytokines, and as such it
is sometimes conceptualized as a polygenic autoinflammatory
syndrome. The differential diagnosis is broad, including infec-
tious. malignant, and systemic autoimmune diseases. Adult-
onset Still disease may present as a single episode; be
recurrent; or, most commonly, be chronic and progressive
(zs"t, ol"t, of aflected patients). Past treatment options,
including glucocorticoids and methotrexate, were frequently
inadequate. The use of interleukin-B directed biologic thera
pies, including anakinra and canakinumab, has been success
ful. Anti-interleukin 6 therapies have shown promise in
clinical reports.
I(EY POItrI
. Adult-onset Still disease is characterized by fever with
daily evening spikes, evanescent salmon-colored rash,
arthritis, and leukocytosis.

Sarcoidosis
Sarcoidosis is an inflammatory disease of unknown cause F IGUR E 6 0. Hand radiograph showing the typical cystic lesions (red anow) and
characterized by fbrmation of noncaseating granulomas in a lacy pattern (green arrow\ characteristic of sarcoidosis.

90

Liver involvement is common but frequently asymptomatic:
more serious involvement includes central nervous system,
eye, and cardiac disease. Central nervous system sarcoidosis
most commonly presents as brainstem involvement with cra
nial nerve deficits, but any part of the brain may be involved.
Silent cardiac involvement occurs in at least 25',/, of cases:
cardiac sarcoidosis may also cause symptomatic arrhythmias
or heart failure.
Cutaneous sarcoidosis is scen in approximately 30'1, of
patients. The spectrum of skin involvement is broad, includ
ing asymptomatic or pruritic plaques or papules, often viola-
ceous, an),r,vhere on the body. Lr-rpus pernio is a specific lbrm
of sarcoidosis that manif'ests as violaceous infiltrative subcu
taneous plaques or nodules on the nasal tip and central face
(Figure 61).
The diagnosis of sarcoidosis can be confirmed through
tissue biopsy specimens showing noncaseating granulomas.
All patients with sarcoidosis should undergo ECG; furtl.rer
evaluation of systemic sarcoidosis should be defined by
apparent signs and symptoms. Laboratory studies should
include inflammatory markers. calcium, and vitamin
t IGU R E6 I . Lupus pernio manifests as violaceous infiltrative subcutaneous
plaques or nodules.
Other Rheumatologic Diseases
f IGU RE 62. Erythema nodosum mani{ests as painful, red-brown nodules on the
anterior shins.
Serum angiotensin converting enzyme levels are frequently
elevated and may support the diagnosis, but they are
D.
nonspecific. Cardiac assessment may involve echocardiogra
ph),: advanced cardiac imaging, and/or electrophysiologic
monitoring.
The treatment of symptomatic extrapulmonary sar
coidosis almost always requires high-dose glucocorticoids
(e.g., prednisone, 40 60 mg/d). If glucocorticoids are inef
fective or contraindicated or resist tapering, patients may
be treated with thalidomide, methotrexate, or azathio
prine. Cyclophosphamide or tumor necrosis factor inhibi
tors may be warranted in severe cases or when essential
organs are at risk. Asymptomatic extrapulmonary sar
coidosis does not always require treatment. Sarcoidosis
limited to skin may respond to topical or intralesional
agents or hydroxychloroquine or may require more aggres
sive systemic treatment.
L6fgren syndrome is a form ol systemic sarcoidosis
characterized by bilateral hilar lymphadenopathy, erythema
nodosum (Figure 62), and migratory polyarthralgia, usually
accompanied by fever. Ankle arthritis may also occur. It is
more common in younger patients, women, and Europeans
ol Scandinavian descent. When alt three parts of the triad
are present, there is a 95'1, diagnostic specificity fbr sar
coidosis, obviating the need for biopsy. Because L0fgren
syndrome is usually sell limited, treatment focuses on
symptom management, often with an NSAID, until the con-
dition resolves.
l(EY P0tt{Ts
. Rheumatologic manifestations of sarcoidosis include
arthritis involving multiple joints that may develop ero
sive damage, deformity, and dactylitis; bone disease;
and myopathy.
(Conttnued)
91
Other Rheumatologic Diseases

XEY P0lilTS (onttnud) I(EY POIXI

o The treatment of slmptomatic extrapulmonary sarcoido-
sis almost always requires high-dose glucocorticoids.
. L0fgren syndrome is a form of systemic sarcoidosis that
consists of bilateral hilar lymphadenopathy, erythema
nodosum, and migratory polyarthralgia, usually accom-
panied by fever.
lgG4-Related Disease
IgG4 related disease (lgGa-RD) is characterized by tumefac
tive infiltration of IgG4 bearing plasmablasts and other lym-
phocytes, along with storiform fibrosis, into one or multiple
organs, with resultant organ enlargement, fibrosis, and dys-
function. Although initial reports of IgG4-RD concerned
involvement of the pancreas (see MKSAP 19 Gastroenterologr
and Hepatolory), a range of organs can be involved (Table aa).
In 80'1, ofcases, serum levels oflgG4 antibodies are elevated.
The signs and symptoms ol IgG4 RD depend on the organ or
organs affected. Pathogenesis remains inconclusive, with
uncertainty about whether plasmablasts are a cause or a
consequence of the disease. An American College of
Rheumatologr/European League Against Rheumatism clas
sification process for identi$zing IgG4-RD involves the follow
ing: (1) identifying characteristic clinical or radiologic organ
involvement and/or a suspicious biopsy specimen; (2) exclud
ing alternative diseases; and (3) confirming the diagnosis on
the basis of characteristic pathologic findings, usually includ
ing IgG4 expression on biopsy tissue or in serum. Initial
management of IgG4-RD includes moderate to high-dose
glucocorticoids for 4 weeks, followed by a slow taper over 1 or
more years. Azathioprine is preferentially used as a glucocor
ticoid-sparing agent, and rituximab has been reported to have
significant efficacy. In some cases, surgical intervention may
be needed (e.g., to address a mass jeopardizing a particular
organ).
. The conditions comprising IgG4-related disease are
characterized by tumefactive infiltration of IgG4-bearing
plasmablasts and other lymphocl'tes, along with stori-
form fibrosis, into one or multiple organs, with resultant
organ enlargement, fibrosis, and dysfunction.
Genetic Diseases of
Connective Tissue
Mutations in genes encoding for collagen, fibrillin, and other
components of connective tissue can lead to poorly functional
skin and integument. Common clinical findings include skin
and joint laxity, skeletal fractures, and cardiovascular complica
tions related to involvement of the aorta and cardiac valves. The
three most common syndromes are Ehlers-Danlos syndrome,
Marfan syndrome, and osteogenesis imperfecta. Table 45 sum
marizes clinical findings and management of these syndromes.
Vascular monitoring is necessary in Marfan syndrome and
several types of Ehlers-Danlos syndrome. Patients with Marfan
syndrome should undergo echocardiography to assess the aor
tic root and ascending aorta at the time of diagnosis and
6 months later to ensure stability. Follow-up studies should be
completed at least annually; MRI and CT are often used to fur-
ther delineate risk. Patients with Marfan syndrome and Ehlers
Danlos syndrome should undergo expert consultation. See
MKSAP 19 Cardiovascular Medicine for more information.
IEY POITTS
. Common clinical findings of genetic diseases of connec-
tive tissue include skin and joint laxity, skeletal fractures,
and cardiovascular complications related to involvement
of the aorta and cardiac valves.
. Regular vascular monitoring is required for patients
with Marfan syndrome and several types of Ehlers-Danlos
syndrome.

TABLE 44. Select Conditions Associated With lgG4-Related Disease

Condition Organ lnvolved
Hypertrophic pachymeningitis Dura mater
Lymphocytic hypophysitis Pituitary gland
ldiopathic orbital inflammatory disease Periorbital often with involvement of the ocular adnexal tissues
Mikulicz disease Parotid glands
Dacryoadenitis Lacrimal glands
Kiittner tumor Submandibular glands
Riedel thyroiditis Thyroid
lnflammatory aortitis/vasculitis Aorta/arteries, often associated with retroperitoneal fibrosis
Autoimmune pancreatitis Pancreas
Ormond disease (retroperitoneal fibrosis) Periaortic mass
Tubulointerstitial nephropathy Kidneys
Sclerosing cholangitis Biliary tract

92
 Bibliography
I

Ehlers-Danlos Syndrome
Hypermobility Classic Kyphoscoliotic Vascular Marfan Osteogenesis
Syndrome Imperfecta
Genetic Testing Gene is COLSA|;COLSA2 PLOD| caL3A1 FBNl CAL
Available unknown
ln heritance AD AD AR AD AD AD orAR
Clinical Findings
Musculoskeletal Joint laxity; joint Hypermobility; Hypermobility; Hypermobility; Hypermobility; Bone fractures;
instability; joint dislocations; progressive joint tall stature; short stature
musculoskeletal pes planus scoliosis; dislocations d o lich oste no m e lia u;
pain; early marfanoid arachnodactyly;
osteoa rth ritis habitus pectus excavatum/
carinatum; scoliosis
Skin Easy bruising Smooth, velvety; Easy bruising; Thin; Hyperextensibility
mild laxity easy bruising; hyperextensibility translucent;
hyperextensibility; easy bruising
striae atrophicae
(widened stretch
marks)
Cardiovascular No risk for organ Mitral/tricuspid Medium-size Arterial Aortic aneurysm/
or
rupture valve prolapse; arterial rupture; ru ptu re; dissection; mitral
dissection aortic root dilation mitra l/tricuspid aneurysm; valve prolapse
(rare); arterial valve prolapse dissection
rupture (rare)
Other Muscular Muscular Organ rupture Myopia (most Dentinogenesis
hypotonia; hypotonia; scleral (uterus, bowel, common feature imperfectab;
delayed motor {ragility with risk rarely spleen, [60%]); ectopia hearing loss;
i
development for globe liver); lentis; high arched blue sclerae
rupture; pneumothorax; palate;
restrictive lung gingival pneumothorax;
disease; recession blue sclerae
recurrent
pneumonia;
heart failure
Managementc Joint protection; Joint protection; Joint protection; Joint Annual ophthalmic Bisphosphonates;
supportive care echo/vascular echo/vascular protection; examination; audiology
monitoring; monitoring; echo/vascu lar periodic aortic assessments;
preconception preconception monitoring; arch imaging; joint and bone
counseling counseling; preconception B-blockersd; joint protection; dental
physical therapy; counseling protection; evaluations
bracing pregnancy
counseling/
monitoring
AD = autosomal dominanU AR = autosomal recessive.

"Dolichostenomelia describes when the extremities are disproportionately long for the size oI the trunk.
bDentinogenesis imperfecta is de{ined as discolored (blue/gray or yellow/brown), translucent, weak teeth prone to breakage.

'Genetic consultation is appropriate for all listed conditions.

dMay slow the rate of aortopathy.

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Wallace ZS, Naden RB Chari S, et al; American College ofRheumatologr/European
l€ague Against Rheumatism IgG4 Related Disease Classification Criteria
Working Group. The 2019 American College of Rheumatologr/European
l.eague Against Rheumatism classification criteria for IgG4 related diseas€.
Arthritis Rheumatol. 2O2O :72i -19. [PMID: 31793250] doi:10.1002/art.41120
West SG. Current management ofsarcoidosis I: pulmonary cardiac. and neu
rologic manifestations. Curr Opin Rheumatol. 2018;30:243 248. [PMID:
293898281 doi:10.1097/BOR.000000oo00000489
t
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i
matology Self-Assessment Test o,
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This self-assessment test contains one-best-answer multiple-choice questions. Please read these directions carefully o
r^
I before answering the questions. Answers, critiques, and bibliographies immediately follow these multiple-choice ut
questions. The American College of Physicians (ACP) is accredited by the Accreditation Council for Continuing
q,
Medical Education (ACCME) to provide continuing medical education for physicians. t

The American College of Physicians designates MKSAP 19 Rheumatology for a maximum of 24 A MA PRA Category 1.
t
Credits'". Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of the CME activity, which includes participation in the evaluation component, enables
the participant to earn rp to 24 medical knowledge MOC points in the American Board of Internal Medicine's
Maintenance of Certiflcation (MOC) program. It is the CME activity provider's responsibility to submit participant
completion information to ACCME for the purpose of granting MOC credit.

Eqrn Credits or MOC Points Onltne

To earn CME credits or to apply for MOC points, MKSAP users need to answer at least one of two questions correctly
(earning a score of at least 50%) and click the Submit CME button. Each single MKSAP 19 self-assessment question
qualifles for one quarter of a CME credit hour or ABIM MOC point.

MKSAP 19 Subscribers can enter their self-assessment question answers and submit for CME/MOC in two ways:

1. Users of MKSAP 19 Complete who prefer to use their print books and a paper answer sheet to study and
record their answers can use the printed answer sheet at the back of this book to record their answers. The
corresponding online answer sheets, which are available on the MKSAP 19 Resource Page, may be used to
transcribe answers onto the online answer sheets. Users may then submit their answers to qualif,i for CME
credits or MOC points (see below for information on Opting in for MOC). Users who prefer to record their
answers on a paper answer sheet should save their answer sheet for future use. Users who study with MKSAP
19 print can also submit their answers directly within MKSAP 19 Digital by accessing the self-assessment
questions dashboard and selecting the preferred subspecialty section to begin answering questions.

2. Users of MKSAP 19 Digital can enter their answers within the digital program by accessing the self-assessment
questions dashboard and selecting the preferred subspecialty section to begin answering questions and click-
ing the Submit CME button once they quali$z for CME and are ready to submit. Learners should keep in mind
their yearly CME and MOC deadlines when determining the appropriate time to submit.
Learners' CME/MOC submission progress will be shown on the MKSAP 19 Digital CME/MOC/CPD page.

Optinginfor MOC
MKSAP 19 users can opt in for simultaneous submission of CME and MOC points as they answer self-assessment
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only once.

97
 Directions
Each of the numbered rtems is followed by lettered answers. Select th e ONE lettered answer that is BESI in each case. tl
o,

o
UI
Item 1 joints. There are similar flndings on the thumb and second rrt
flnger on the left hand. Several of the affected proximal o
ta
A 23 year-old man with Behqet syndrome is evaluated for vt
recurrent oral and genital ulcers. He is currently not hav- interphalangeal joints have a slight purple discoloration.
There is a right knee effusion. The second and fourth toes on
ing a flare. The episodes typically last a few days to a few (I,
weeks. He reports no eye or skin symptoms or neurologic the right foot are diffusely swollen, as are the flrst and third tl
disease. He is taking a therapeutic dosage ofcolchicine to toes on the left foot. Two small psoriatic plaques one in the
prevent disease flares but has had three episodes ofpainful umbilicus and one on the scalp are noted.
oral ulcers in the last 6 months during this treatment. He Laboratory evaluation reveals a negative rheumatoid
has received tapering doses of prednisone to control the factor result.
disease during these episodes.
On physical examination, vital signs are normal. There Which of the following is the most likely diagnosis?
are no active mucocutaneous ulcerations. Healed scars in (A) Osteoarthritis
the scrotal area are present. Joints are not warm or swollen.
(B) Psoriaticarthritis
Laboratory evaluation reveals a blood C-reactive
protein level of 1.2 mg/dl (tz mglL) .
(C) Seronegativerheumatoidarthritis
(D) Systemic lupus erythematosus
Which of the following is the most appropriate
treatment?
(A)
(B)
Apremilast
Ixekizumab
Item 4
A 67-year-old woman is evaluated in the hospital fbr mal tr
aise. fatigue, arthralgia, and rash of B weeks' durationl
(C) Leflunomide dry cough and sinus congestion ol6 weeks' dura[ion; and
(D) It4ycophenolatemofetil painless eye redness and dyspnea that began several days
ago.
oC
On physical examination, temperature is 38.2
Item 2 (100.8 'F), blood pressure is 122176 mm Hg, pulse rate is
A 23 year old man is evaluated for fever, abdominal pain, 104/min, respiration rate is 24lmin, and oxygen saturation
rash, and arthritis of the right knee of 3 days' duration is 92'li with the patient breathing ambient air. Bilateral,
that resolved 1 week ago. He has had more than 20 similar localized ocular injection is seen. Scattered rhonchi are
episodes, the last three occurring in the past year. The flrst heard on lung auscultation. and petechiae and purpura are
episode occurred at age 5 years and presented as abdominal visible on the legs.
pain; the patient underwent appendectomy but no appen Laboratory studies:
dicitis was found. His paternal grandfather and maternal Erythrocyte 87 mm/h
grandmother had a similar syndrome. sedimentation rate
Physical examination flndings, including vital signs, Creatinine 2.1mg/dl (185.6 pmoli L)
are normal. ANCA Pending
Laboratory evaluation shows an erythrocyte sedimen- Urinalysis 3+ blood; 2+ protein; 20-30
tation rate of 23 mm/h, a normal serum creatinine level, dysmorphic erythrocytes/hpfl 5 10
and 1+ protein on urinalysis. Ieukocyteslhpf; erythrocyte casts
Chest CT scan is shown.
Which of the following is the most appropriate
treatment?
(A) Canakinumab
(B) Colchicine
(C) Indomethacin
(D) Prednisone

Item 3
A 50 year oldwomanisevaluatedfora6 monthhistoryof
pain and swelling in the hands, knees, and feet. She reports
t hour of joint stiffness in the morning.
On physical examination, vital signs are normal. The
thumb and second and third flngers on the right hand are
diflusely swollen, with tenderness and swelling at the meta-
carpophalangeal and proximal and distal interphalangeal

99
 Self-Assessment Test

tn
.D
l[ Which of the following is the most appropriate diagnostic behavioral therapy, land and aquatic therapy, and tai chi.
ut E testtoperformnext? She also has depression, treated with escitalopram.
UI
(D
CONT.
On physical examination, vital signs are normal. There
vt (A) Kidneybiopsy
is tenderness at multiple soft-tissue sites with soft palpa-
(B) Sinus biopsy
a

tion. All other flndings are normal.

o (C) Skin biopsy
(D) Ihoracoscopic lung biopsy Which ofthe following is the most appropriate additional
(D
vr treatrnent?

Item 5 (A) Duloxetine

(B) Medical cannabis
A 32-year-old man is evaluated forlowbackpain of 6 months'
duration. He experiences back pain at night and back pain (C) Oxycodone
and stifftress in the morning for more than 30 minutes. He (D) Prednisone
feels less back pain when he exercises. He had an episode of (E) Pregabalin
left Achilles tendinitis 4 months ago and continues to have
some pain and swelling at the Achilles insertion.
On physical examination, vital signs are normal. Item 8
Peripheral joints are normal. Lumbar spine flexion is lim- A 56-year-old man is evaluated for a 2-year history of mid
ited, and hip flexion, abduction, and external rotation to lower back pain and stiffness. He reports no buttock pain.
cause discomfort in the buttocks bilaterally. He has tried home-based exercises, with minimal benefit.
Laboratory evaluation reveals normal erythrocyte On physical examination, there is diffuse tenderness
sedimentation rate and blood C-reactive protein level. to palpation of the lower thoracic spine and upper lumbar
Anteroposterior pelvic radiograph shows no evidence spine, with reduced flexion and extension. There is no sa-
ofsacroiliitis. croiliac joint tenderness.
taboratory evaluation reveals a normal blood C-reactive
Which of the following is the most appropriate diagnostic protein level.
test to perform next? Radiograph of the spine is shown. Sacroiliac joint
(A) Additional radiographic views of sacroiliac joints radiographs are normal.
(B) CTofsacroiliacjoints
(C) HLA-B27 antigen testing
(D) MRI of sacroiliac joints
(E) Rheumatoid factor and anti-cyclic citrullinated peptide
antibodies

Item 6
A 2S-year-old woman is evaluated for a 3-year history of
joint pain involving her hands with more than L hour of
morning stiffness. She also has intermittent photosensitive
facial rash, fatigue, and intermittent subjective fever.
On physical examination, vital signs are normal. There
is tenderness to palpation with swelling of the second and
third metacarpophalangeal joints bilaterally.
Complete blood count, serum creatinine level, and urinal-
ysis are normal. Erythroclte sedimentation rate is 35 mm/h.

Which of the following is the most appropriate diagnostic

test to perform next?
(A) Anti-double-stranded DNA antibodies
(B) Antinuclearantibodies
(C) Anti-Ro/SSA, anti-La/SSB antibodies
(D) Anti-Smith antibodies
(E) Anti-Uf-ribonucleoprotein antibodies

Item 7
A 43-year-old woman is evaluated for flbromyalgia. She
continues to be symptomatic with poor sleep qualit5r and
diffuse stiffness despite her participation in cognitive

100
 Self-Assessment Test

Which of the following is the most likely diagnosis?
(A) Ankylosingspondylitis
(B) Diffuse idiopathic skeletal hyperostosis
(C) Spinal calcium pyrophosphate deposition disease
(D) Spondylosis deformans
Item 9
A 36 year-old woman is evaluated during a routine well-
ness visit. She is asymptomatic and has no medical prob
lems. She works as an accountant and rarely engages in
physical activity. She drinks a glass of red wine with dinner
five times weekly. Her diet is rich in protein and starches
and low in fruits, vegetables, and nuts. She has smoked
one pack ofcigarettes per day for 5 years. Her mother has
rheumatoid arthritis, and the patient is concerned that she
might also develop the disease. Her only medication is a
combined oral contraceptive.
Physical examination, including vital signs, is normal.
Which of the following is most likely to reduce this patient's
risk for developing rheumatoid arthritis?
(A) Alcohol cessation
(B) Discontinuation of combined oral contraceptive
(C) Increased physical activity
(D) Mediterranean diet
(E) Smoking cessation
Item 10
A 75-year-old man is evaluated for facial redness and hand,
elbow, and knee rash that have progressed over the past
6 months. He has no other medical problems and takes no
medications.
On physical examination, vital signs are normal. There
is an erythematous, slightly elevated, irregular rash over
both cheeks, forehead, and chin, sparing the nasolabial
folds. Eyelids also appear pink and swollen. There is faint
erythema over the dorsal hands. An indurated rash with
faint scale is present over the extensor surfaces of the
elbows and knees. Muscle strength and the remainder of
the examination are normal.
Complete blood count, comprehensive metabolic
panel, and serum aldolase and creatine kinase levels are
normal.
I to walk and climb stairs. She has a history of similar symp
Which of the following is the most likely diagnosis?
(A) Acute cutaneous lupus erythematosus
(B) Amyopathic dermatomyositis
(C) Psoriasis
(D) Rosacea
tr Item 11
A 36 year old rvoman is evaluated lbr abdominal pain
and diarrhea. She has a 3 year history of ankylosirtg spon
dylitis. For the past 6 months. she l-ras had fbur or five
bowel movements daily and over the past month she has
t
o,
experienced unintentional weight loss of 3 kg (0.0 lb). the
abdominal pain is poorly localized and unrelated to delcca
o
tion. Stools are loose but not greasy, mucoid, or bloody. Shc tr
has been taking naproxen twice daily, with good control of' tt
t
her ankylosing spondylitis. She reports no recent travel or q,
t,l
antibiotic therapy. She has no other medical problems and tt
t:rkes no additional medictrtions.
On physical eramination, vital signs are normal. o
rrl
There is mild nonlocalizing abdominal tenderness. Range
of motion of cervical and lumbar spine is normal. Sacroiliac
joints are not tender.
Which of the following is the most likely diagnosis?
(A) Celiac disease
(B) Inflammatory bowel disease
(C) Irritable bowel syndrome
(D) Small intestinal bacterial overgrowth
Item 12
A 68-year-old man is evaluated for recent onset of mild
pain and signiflcant swelling of his left knee. He lives in
eastern Pennsylvania and is an avid golfer. Several months
ago he had an illness characterized by an enlarging ery
thematous annular skin lesion in the left popliteal fossa
associated with fever, arthralgia, and myalgia that sponta
neously resolved after several days.
On physical examination, vital signs are normal. Joint
examination shows diffuse swelling of the left knee with
minimal warmth but no erythema, slight reduction in full
flexion of the knee but pain-free range of motion, and a
popliteal cyst.
Results of serologic testing are positive for Borrelio
burgdorferi.
Which of the following is the most appropriate treatment?
(A) Ceftriaxone
(B) Doxycycline
(C) Hydroxychloroquine
(D) Methotrexate
Item 13
An 85 year old woman is evaluated ftir a 10 day history ol'
tr
right knee pain and swelling. which is impairing her ability
toms over the past 2 years. [iach episode has lasted about
ll wecks and resolves with rest and ice.
On physical examination. vital signs are normal. She
has moderate swelling of the right knee, with warmth and
tenderness, and decreased range of motion related to pain.
No skin lesions or tophi arc noted.
l-aboratory studies:
Erythrocyte seditnentation rate
Cornplete blood count
Comprehensive metabolic panel
65 mmrh
Normal
Normal
Urate Normal
Radiograph ofthe right knee is shown (top ofnext page).

101
 Self-Assessment Test

vt
(D
? On physical examination, temperature is 37.0 "C
vt (98.6 "F), blood pressure is 2.,101120 mm Hg. pulse rate is
lrt 90i min, respiration rate is ltllmin. and oxygen saturation
(D
ut is 96'1, with the patient breathing ambient air. The skin
art
J
over the hands. forearms, trunk, lower legs, and feet is
.D
tight and appears thickened. The fingers on both hands
show cyanosis. No nuchal rigidity is noted. and flndings on
.D
UI neurologic examination are normal.
laboratory studies:
[]ematocrit .).) t,
Leukoclle count Normal
Platelet count 90,0001pL (90 x 1O'q L)
Creatinine 2.4 mg1dl. (212.2 pmol, L)
Urinalysis 2+ protein; no blood or casts

Peripheral blood smear reveals diminished platelet

numbers and schistocytes.

Which of the following is the most appropriate intravenous

treatment?
(A) Captopril
(B) Cyclophosphamide
(C) Methylprednisolone
(l)) Metoproloi
Wtictr of the following is the most likely diagnosis?
f,l
cour. (A)
(tl)
Acute calcium pyrophosphate crystal arthritis
Gout flare
Item 16
A 78-year-old man is evaluated at a follon'-up visit. Two tr
(C) Inlectiousarthritis r.r,eeks ago, he presented n,ith severe nelv onset head
(D) Rheumatoid arthritis aches, claudicative ja$, pain, and proximal myalgia of
all four limbs. He r.t,as diagnosed with biopsy-confirmed
giant cell arteritis. and prednisone. 60 mg d, was initiated.
Item 14 Since initiation of prednisone. his presenting symptoms
have improved but he has also developed mood su,ings,
A 35 year old woman is evaluated in follow-up for a recent insomnia. significant hypergtycemia. elevated blood pres
diagnosis of ankylosing spondylitis. Despite the use of sure, and dependent edema. His other medical problems
three different NSAIDs and physical therapy, she continues are type 2 diabetes mellitus. hypertension, dyslipidemia,
to have night pain and morning stiffness/pain lasting more and atherosclerotic coronary artery disease. Other current
than t hour. medications are aspirin. metfbrmin. metoprolol. atorvas
On physical examination, vital signs are normal. There tatin, losartan. and hydrochlorothiazide.
is pain at the sacroiliac joints with hip flexion, abduction, On physical examination, blood pressure is 172,'94 mm I Ig
and external rotation. Lumbar spine range of motion is and pulse rate is 90/min. Other than pitting pedal edema. the
mildly limited. Peripheral joints are normal. cardiopulmonary examination is normal.
Initial anteroposterior radiograph of pelvis showed Point-of-care blood glucose level is 310 mgrdl
bilateral sacroiliitis. (t2.2 mmol;L).
Changes in the patient's current medical regimen.
Which of the following is the most appropriate next including prednisone taper, are made to control glucose.
treatment? blood pressure. and edema.
(A) Etanercept
(B) Methotrexate Which of the following is the most appropriate additional
treatment?
(C) Prednisone
(D) Sulfasalazine (A) Cyclophosphamide
(B) Infliximab
(C) Methotrexate
tr AItem 15
36 year-old r,r,oman is evaluated in the emergency
(D) 'focilizumab

department after experiencing a tonic-clonic seizure. For

I week she has had severe headaches. Eight months ago, Item 17
Raynaud phenomenon of the hands and feet developed. A 62 year old man is evaluated for worsening exertional
Current medication is sustained release nifedipine. dyspnea and nonproductive cough over the past year. He

102
 Self-Assessment Test

Ut
has a 6 year history of seropositive rheumatoid arthri- Item 20 €,
F
tis. Current medications are tofacitinib, methotrexate, and
A 66 year-old man is evaluated fbr a 10-year history of
folic acid.
pain affecting the flngers and bases of the thumbs, hips,
o
On physical examination, vital signs are normal. Car-
and knees. Morning stiffness lasts less than l5 minutes, and UI
t
diac examination reveals normal jugular venous pressure c,
pain is worse with activity. UI
and S, without extra sounds. There are reduced breath vl
Physical examination reveals bony hypertrophy of
sounds throughout the lung flelds, with bibasilar inspi
the distal and proximal interphalangeal joints of the hands
ratory crackles. Lung percussion is resonant throughout. o
and squaring of the thumb bases bilaterally. Both knees are ta
Joint examination shows advanced changes of rheumatoid
tender to palpation medially and laterally. Bony enlarge,
arthritis involving the hands and wrists. The remainder of
ment of medial knees and crepitus on range of motion
the examination is unremarkable.
are noted. There is no soft tissue swelling, warmth, or
effusion.
Which of the following is the most likely cause of this
patient's exertional dyspnea?
Which of the following is the most appropriate test?
(A) Heart failure (A) Antinuclear antibodies
(B) Interstitial lung disease (B) Rheumatoid factor
(C) Pulmonaryarterial hypertension (C) Serologic testing for Borrelia burgdorferi
(D) Rheumatoid arthritis pleural eflusion (D) Synovial fluid analysis
(E) No additional laboratory studies

tr Item 18
A 50 year old man is evaluated for severe pain and swell
ing in the left knee of 2 days' duration. He has a long
history of psoriasis and polyarticular psoriatic arthritis.
He reports no fever, chills. or pain in other joints. Current
medications are methotrexate, lolic acid, and topical clo-
betasol propionate.
:
On physical examination, vital signs are normal. There
:
are psoriatic plaques on the elbows. sacrum, and anterior
shins. The lelt knee is swollen and warm; the patient holds
it at 45 degrees olflexion, and he is unwilling to further flex
I or extend. There is no othcr joint swelling.
Arthrocentesis of the left knee reveals a synovial fluid
lcukocl,te count of 40,0001pL (a0 x 10eiL) with 90'7, neu-
trophils. Gram stain is negative, and synovial fluid analysis
for crystals and bacterial culture are pending.
Which of the following is the most likely diagnosis?
(A) Gouty arthritis
I (B) lnf'ectir-rusarthritis
(C) Osteoarthritis
(D) Psoriatic arthritis
Item 21
EI
A 56 year old woman is evaluated at a folkrw-up visit.
She has polyarticular tophaceous gout affecting her hancls,
Ieet, and knees bilaterally. She is receiving a tapering dose
of prednisone following an acute gout flare. She had previ
ously received allopurinol but discontinued it atter devel
oping a rash. She has hypertensicln and chronic kidney
disease. Current medications are losartan and prednisone.
s mgid.
Laboratory studies show a serum creatinine level ol
1.8 mgidL (159.1pmol/L), a serum urate level of 10.1 mg/dl
(0.60 mmolrL), and an estimated glomerular filtration rate
of 31 ml-imin 11.73 m).
Which of the following is the most appropriate additional
treatment?
(A) Allopurinol
(B) Colchicine
(C) Febuxostat
(D) Pegloticase
(E) Probcnecid

tr
L

!
Item 19 Item 22
A 3O-year-old woman is seen in follow up. She was diag- A 35 year old woman is evaluated in the emergency
nosed with systemic lupus erythematosus 12 years ago. department lbr sudden vision loss in the lefl eye. Two years
1 She was treated for lupus nephritis, which is now quies ago, she had developed intermittent fever. myalgia, and
I cent. Clinical and laboratory flndings have been stable for
! chronic tatigue. She reports recent postprandial abdominal
5 years, with no disease flares. Medications are hydroxy pain and eflbrt related left arm pain.
chloroquine and azathioprine. On physical examination, bltnd pressure is 160/100 mm
Ilg in the lefl arm and 130i 80 mm I Ig in the right arm. Pulse
Which of the following health risk assessments should be rate is 88/min. Radial pulse in the left arm is abscnt; left-sided
performed now? subclavian bruit is present.
:
Laboratory studies reveal an erythrocyte sedimenta
(A) Breast cancer
tion rate o1 76 mm/h and a blood hemoglobin level o1'
I (B) Cardiovasculardisease e.2 gtdL (e2 s,tL).
i
(C) Iron overload Magnetic resonance angiogram of the chest and
(D) Pulmonary disease abdomen shows focal luminal narrorving in several areas.
:
103
 Self-Assessment Test

t,l
ID

t,l
UI
tr
CONT,
including the ascending aorta. lelt subclavian artery. supe
rior mesenteric artery. and right renal artery.
Item 25
A 26 year-old woman is evaluated for a 3-month history of
increasing left hip pain that is worse with prolonged stand-
o
6
UI Whieh of the following is the most likely diagnosis? ing. Systemic lupus erythematosus was diagnosed 5 years
=
(D (A) Cryoglobulinemic vasculitis ago, characterized by small joint arthralgia, malar rash,
cytopenias, and Raynaud phenomenon. At diagnosis she
(B) Giant cell arteritis
{
.D (C) Polyarteritisnodosa
required high-dose prednisone, hydroxychloroquine, and
an azathioprine therapy. Prednisone dosage was tapered over
(D) Takayasu arteritis 6 months. Periodic flares have been treated with increased
dosages ofprednisone. Current medications are hydroxy
chloroquine, azathioprine, and low-dose prednisone.
Item 23 On physical examination, internal rotation and
A 62 year-old man is evaluated in the hospital for an arthro- full flexion of the left hip are limited and elicit pain. The
centesis conflrmed diagnosis of acute polyarticular gout remainder of the examination is normal.
involving the right knee, left ankle, and forefoot. Joint fluid Complete blood count, erythrocyte sedimentation
Gram stain and culture were negative. He was hospitalized rate, and serum complement levels are normal. Anti
4 days ago with heart failure complicated by pulmonary double-stranded DNA antibody titer is low and has been
embolism. He has a history of recurrent acute gout. The flrst unchanged for 6 months.
night ofhis hospital stay, he developed polyarticular gout Radiograph of the left hip is normal.
that has not responded to appropriate prednisone doses. He
also has hypertension, hyperlipidemia, type 2 diabetes mel- Which ofthe following is the most appropriate
litus, and stage G3a chronic kidney disease; he underwent management?
kidney transplantation 10 years ago. Current medications
(A) Change azathioprine to mycophenolate mofetil
include low molecular-weight heparin, metoprolol, Iosar
tan, furosemide, insulin glargine, and tacrolimus. (B) Increase prednisone dosage
The right knee, left ankle, and forefoot are swollen, (C) MRI of left hip
tender. and warm. (D) Physical therapy

Which of the following is the most appropriate

treatment? Item 26
(A) Anakinra A 48 year old woman is evaluated for sicca. She has a2 year
(B) history of Sjdgren slmdrome. Chewing sugarless gum and tak
Colchicine
ing frequent small sips ofwater are increasingly less helpful for
(C) Intra-articulartriamcinolone oral dry,rress. Current medications are artificial tears and oph
(D) Naproxen thalmic cyclosporine. She has no other conceming symptoms.
On physical examination, vital signs are normal.
Other than dry oral mucosa, the examination is normal.
Item 24
A 66 year-old woman is evaluated for a 10 year history Which of the following is the most appropriate treatment? I

of pain in the hands and knees. She has tried occupa-

tional therapy, with minimal beneflt; she is enrolled in a (A) Cevimeline !

weight loss program. She has hypertension and chronic (B) Hydroxychloroquine
kidney disease. Current medications are lisinopril and (C) Low-doseprednisone
amlodipine. (D) Rituximab
On physical examination, Heberden and Bouchard :

nodes are present and there is carpometacarpal joint ten-

derness. The medial joint line of each knee is tender to
palpation. There is bony enlargement of the medial knees,
with crepitus on range of motion.
ltem 27
A 58-year-old \\"oman is evaluated fbr brief episodes of
pain, swelling. and rcdness in thc right wrist for ,1 days.
tr
Laboratory evaluation shows a serum creatinine level
of 2.2 mgldL (194.5 pmouL) and an estimated glomerular During the past 2 years, she has had similar episodes in her
flltration rate of lcf't wrist and left third metacarpophalangeal joint, which
45 ml/min/l.73 m2.
resolved without treatment.
On physical ex:rmination, vital signs are normal. Joint
\
Which of the following is the most appropriate
examination reveals swelling. warmth, and redness olthe
treatment?
Ieft wrist and redness and bony enlargement of'the left
(A) Hydrocodone third metacarpophalangeal joint. Othcr joints are normal.
(B) Meloxicam Laboratory studies show norntal complete blood count.
(C) conrprehensive metabolic panel, and serum calcium, mag
Topical capsaicin
nesium, and thyroid stimulating hormone levels.
(D) Topical diclofenac
Radiographs of wrist and melacarpophalangeal joir.rts
(E) Topical lidocaine are sholvn (top ofnext page).
:

1(J4
 Self-Assessment Test

vt
6'
h
E
o
=
t!
UI
c,
UI
l,t

€,
tt

Fl 51 novial ftuid from tl.re left nrist shonrs a leukocyte to control rheumatoid arthritis. She has no sicca symp
l*l c,runt tl1 30.000 pl. (30 x 10'),'1.) u,ith 90')1, neutrophilsl torns. Current medications are preclnisone. methotrexatc.
coNT pollrizing microscopy shou,s nunrerous positively bire ftrlic acid. and adalimumab.
fiingent rhomboid crystals within ncutrophils. Synovial On physical examination, vital signs are normal.'lhere
Ilnid Cram stain and cullure are ncgative. are rheumatoid nodules over the olecranon processes. Thc
spleen tip is palpable. Joint examination reveals ulnar
Which of the following is the most appropriate laboratory deviation, subluxation at the mct:rcarpophalangeal joints,
study to perform next? rcduced range of motion at the wrists, and bilateral swell
ing of the \,\,rists and Ieft ankle.
(A) Antinuclelr anlihodies
Laboratory studies:
(B) llrythrocytesedimentation rate
Absolute neutrophil count 1l00rpL (1.1 x 10'r,L)
(C) Itheumatoid factor l-cr-rkocyte count :l800i pL (3.8 x 10'q,'l-)
(l)) Serum ferritin Absolute lymphocyte count Normal
count
Platelet Normal
Item 28 Urir-ralysis Normal

A 52 year-old woman is evaluated at a follow-up visit. Der
matomyositis was diagnosed 4 weeks ago; she was positive
fbr anti Mi 2 antibodies. Prednisone has improved helio-
trope and photosensitive rashes and proximal muscle weak
ness. She is currently asymptomatic. Current medication is
prednisone, 60 mg/d. She is participating in physical therapy.
On physical examination, vital signs are normal. There
is no rash. Muscle strength is normal.
Serum creatine kinase level is 200 U/L, decreased from
520 U/L I month ago.
Results of screening colonoscopy, mammography,
and cervical cancer screening are all normal.
Which of the following is the most appropriate treatment?
(A) Add hydroxychloroquine
(B) Add methotrexate
(C) Add rituximab
(D) Continue current therapy
Which of the following is the most likely diagnosis?
(A) AA amyloidosis
(B) Fclty syndrome
(C) Sjdgren syndrome
(l)) Systemic lupus erytl.renrlitosus
Item 30
A 27-year-old woman is evaluated for a 4-year history of
progressive achy and stiff low back pain that wakes her
up at night and a 2-year history of intermittent, severe,
sharp bilateral buttock pain. She has stiffness for 90 min
utes each morning. Exercise and ibuprofen help relieve
pain. She has a history of unilateral uveitis. She has no
children.
On physical examination, vital signs are normal.
Range of motion of the lumbar spine is decreased in all
directions. The eye examination, occiput-to-wall distance,
chest expansion, and peripheral joints are normal.
Laboratory studies reveal an elevated blood C-reactive

tr Item 29
A :)9 year-old woman is evaluated for newly discovered
protein level and negative HLA- 827 antigen result.
Radiographs of the pelvis and lumbar spine are
normal.
ncutrcpenia. She has a 10 year history of severe, diflicult

105
 Self-Assessment Test

l/r
.D
Which of the following is the most appropriate diagnostic On physical examination, vital signs are norrnal. Exam-
D
Ut test to perform next? ination ofthe hands reveals bilateral polyarticular joint swell-
u) ing and tenderness involving the metacarpophalangeal joints.
lD
u! (A) Bone scanning
vt
(B) CT of pelvis Which of the following is the most likely cause of this
(D
(C) MRI of pelvis patient's joint pain?
(D) Rheumatoid factor and anti-cyclic citrullinated peptide
.D (A) Ankylosingspondylitis
u) antibodies
(B) Erosive osteoarthritis
(C) Reactive arthritis
Item 31 (D) Rheumatoidarthritis
A22 year old woman is evaluated for a l-month history of
progressive rash on the face, chest, and arms following sun
exposure. She also has experienced wrist arthralgia and
malaise for the past 2 weeks.
On physical examination, blood pressure is l42l
Item 33
A 73 year-old woman is hospitalized for progressive dys-
tr
pnea. Six months ago, she developed chronic sinusitis and
82 mm Hg, pulse rate is 88/min, and respiration rate is
nose bleeds. Four months ago, a persistent dry chronic
16/min. The facial rash is shown.
cough developed, followed by myalgia and distal paresthe-
sia. She has lost 13.6 kg (30 lb).
On physical examination, temperature is 38.2 'C
(100.8 "F), blood pressure is 148/96 mm Hg, pulse rate is
104/min, respiration rate is 24lmin, and oxygen saturation
is 94% with the patient breathing ambient air. Dry crack-
les are heard at the lung bases. There is loss of sensation
to light touch in the left foot. Numerous small palpable
red-purple lesions are present on the lower legs.
laboratory studies:
Ery.throcyte 120 mm/h 't
I
sedimentation rate I

Creatinine 1.7 mgldL (150.3 pmol/L)

ANCA Positive
Antiproteinase-3 70 antibody index (normal 1
I
antibodies <1 antibody index)
Urinalysis 3+ blood; 2+ protein; 20-30
dysmorphic erythrocltes / hpfi
5-10 leukocytes/hpf
Chest radiograph shows peripheral pulmonary paren
Similar-appearing patchy skin lesions are seen over chymal opacities. Chest CT scan shows multiple opacities
the upper chest in a V-neck distribution and the dorsal and nodules throughout both lungs.
forearms. Active and passive wrist extension elicits dis- Kidney biopsy results are pending.
comfort. The remainder of the examination is normal. High-dose glucocorticoids are started.

Which of the following is the most likely diagnosis? Which of the following will most likely be the appropriate
additional treatment?
(A) Acute cutaneous lupus erythematosus
(A) Azathioprine
(B) Lupus pernio
(C) Rosacea
(B) Methotrexate
(C) Mycophenolatemofetil
(D) Subacute cutaneous lupus erythematosus
(D) Rituximab

Item 32
A 33 year-old woman is evaluated for a 1-month history of
pain in the hands. She also has stiffness in the hands upon
arising in the morning that lasts 90 minutes. She otherwise
has been well. She reports no tingling or numbness in the
flngers; changes in the color of the digits; or rash, oral
ulcers, or alopecia. Her vaccinations are up to date. She
works in her home as a computer software engineer, is not
sexually active, has no contact with children, and has not
traveled.
Item 34
A S0-year-old woman is evaluated for a 2-year history
of pain affecting the knee joints. The pain is associated
with walking or standing and occurs 1 to 2 days per week.
She has tried acetaminophen with minimal beneflt; she
is enrolled in a weight loss program. She prefers a home-
based self-management treatment option.
On physical examination, vital signs are normal. BMI
is 33. there is mild tenderness to palpation of knee medial

106
 Self-Assessment Test

UI
joint lines bilaterally. Knee joints are not warm or swol- coronary artery disease, COPD, and a history of diverticuli Fo,
len and have normal range of motion. No other joints are tis. Current medications are aspirin, lisinopril, metoprolol,
involved. a tiotropium inhaler, methotrexate, and sulfasalazine. €,
On physical examination, blood pressure is 136/84 mm E
UI
vt
Which of the following is the most appropriate Hg. BMI is 29. Multiple metacarpophalangeal joints are (u
U!
treatment? tender to palpation, and there is active synovitis. UI

(A) High-impact aerobic exercise Result of an interferon-gamma release assay is

negative. (l,
(B) Tai chi Hand radiographs show joint space narrowing and t
(C) Transcutaneouselectrical nerve stimulation three new erosions.
(D) Vegan diet
Which of the following is the most appropriate
treatment?

tr Item 35
An 85-year-old woman is evaluated lbr worsening chronic
(A) Abatacept
(B) Adalimumab
right shoulder pain of 1 year's duration. 'lhe pain is
more severe with use. She has no history of trauma to the
(C) Anakinra
shoulder. (D) Tocilizumab
On physical examination, vital signs are normal. The (E) Tofacitinib
right shoulder is swollen and tender, with no warmth or
redness. There is pain-related decreased range of motion
of the shoujder in all directions. Other joints are normal. Item 37
Ervthrocfie sedimentation rate and blood C reactive A 42 year old woman is evaluated for 3 months of pain
protein level are normal.
and swelling in her hands and multiple other joints, as
Radiograph of right shoulder is shown. well as morning stiflness lasting more than t hour. She has
increasing difficulty with daily activities, such as walking
and making the bed. She has no other symptoms or medi-
cal problems and takes no medication.
On physical examination, vital signs are normal. She
has swelling and tenderness of the second and third proxi-
mal interphalangeal joints bilaterally, right second and left
third metacarpophalangeal joints, left wrist, and bilateral
ankles.
laboratory studies:
C reactive protein 6.4mgldL(64mglL)
Rheumatoid factor Positive
Antinuclearantibodies 1:80(>1:160positive)
Anti-cyclic citrullinated Positive
peptide antibodies

Which of the following is the most likely diagnosis?

(A) Chikungunya virus infection
Synovial fluid from the right shoulder is blood-tinged;
(B) Parvovirus 819 infection
analysis of fluid reveals a lcukocyte count of 500rpl
(0.5 x 10'i L), negative Gram stain and culture results. and (C) Rheumatoidarthritis
no crystals. (D) Systemic lupus erythematosus

Which of the following is the most likely diagnosis?

(A) Adhesivecapsulitis
(B) Basic calcium phosphate associated arthritis
(C) Calcium pyrophosphate deposition disease
(D) Rheumatoidarthritis
Item 36
A 58 year-old man is evaluated at a follow-up visit. He has
had rheumatoid arthritis for 5 years. Increasing morning
stiffness, fatigue, increasing joint pain, and swelling of
small hand joints have developed in the past 6 months. His
disease activity score shows moderate activity. He also has
Item 38
A 65 year-old man is evaluated for a 4-month history of
a rash over the face and hands and a 3 month history of
progressive proximal muscle weakness. He also reports
a 6.8-kg (15-lb) unintentional weight loss. He has had no
fevers, respiratory symptoms, or sensory changes.
On physical examination, vital signs are normal. There
is weakness in the proximal muscles of the arms and legs.
A thickened, red rash is seen on the cheeks, forehead, and
upper chest. Photograph ofhand is shown (top ofnext page);
similar flndings are seen on both elbows. There is no muscle
tenderness, joint swelling, or edema. The remainder of the
examination is normal.

107
 Self-Assessment Test

vr
TD
Which of the following is the most likely diagnosis?
D
UI (A) Adult-onset Still disease
ra
.D
ta (B) Familial Mediterranean fever
art
(C) Infectiousendocarditis
(D
(D) Systemic lupus erythematosus
{
.D t
(,l
Item 40
A 47-year-old woman is evaluated for a 3-year history of
pain in all of her muscles and joints. She is a commercial
truck driver. Her sleep is poor, and she awakens unre-
freshed. She completes a flbromyalgia diagnostic ques-
tionnaire and meets the criteria for flbromyalgia. She has
anxiety and depression, with a history of opioid use disor-
der. She takes no medications.
On physical examination, vital signs are normal.
Physical examination flndings are limited to widespread
muscle tenderness with normal strength.
Laboratory evaluation reveals an erythrocyte sedi-
mentation rate of 19 mm/h, a blood C reactive protein level
of 0.3 mg/dl (3 mg/L), and a thyroid-stimulating hormone
level of 1.6 pU/mL (1.6 mU/L).
Low-impact aerobic exercise is recommended.
Laboratory evaluation reveals a hemoglobin level of
Which of the following is the most appropriate additional
12.5 g/dl (125 g/L) and serum creatine kinase Ievel of4500 U/L.
treatment?

Which of the following is the most appropriate test to (A) Amitriptyline

perform next? (B) Diclofenac
(A) Antinuclear antibody testing (C) Duloxetine
(B) Colonoscopy (D) Pregabalin
(C) Muscle biopsy (E) Tramadol
(D) Pulmonary function testing
Item 41
Item 39
A 46 year-old woman is evaluated at a follow-up visit to
A 24-year-old man is evaluated for fever of 6 weeks' dura-
discuss results of bone mineral density testing. She has
tion. He also has joint pain, myalgia, and occasional sore a l0-year history of myasthenia gravis and is receiving
throat. The fever begins in the early evening and resolves long-term glucocorticoid therapy. Current medications
by morning. His most recent temperature in the eve- are azathioprine, prednisone, calcium/vitamin D, and
ning was 39.5 'C (103.1 'F). The fever is accompanied by a pyridostigmine.
salmon-pink macular rash on the trunk and arms, which Dual energy x ray absorptiometry shows T-scores of
resolves with the fever. He has no history of travel. Current 2.1 at the lumbar spine and 1.9 at the femoral neck, with
medication is acetaminophen. corrected Fracture Risk Assessment Tool scores of 3.5u1, at
On physical examination, temperature is 37.5 'C the hip and17% overall.
(99.6'F). The remaining vital signs are normal. There is
bilateral cervical lymphadenopathy. A friction rub is heard
Which of the following is the most appropriate
bilaterally at the lung bases. Abdomen is tender without
treatment?
guarding. The knees have eflusions. Cardiac examination
is normai. (A) Alendronate
[.aboratory studies: (B) Calcitonin
Erythrocyte sedimentation rate 125 mm/h (C) Romosozumab
Leukocyte count 22,OOOl1tL (22xtoe lL) (D) Teriparatide
Hemoglobin 11.5 g/dl (11s g/L)
Ferritin 5200 ng/ml (5200 pg/L)
Blood cultures are pending. Item 42
A chest CT scan shows small pleural effusions bilater- A 32 year-old woman is evaluated for pain in the right elbow
ally with moderate pleural thickening. An abdominal CT of a few months' duration. She has no history of injury. The
scan shows a small amount of ascitic fluid with evidence of pain worsened after she began a new exercise program that
peritoneal thickening. includes weights, and it is exacerbated with use. The pain

108
 Self-Assessment Test

Ul
makes it hard to lift things. She also has increased fatigue. On physical examination, vital signs are normal. Sym att
Acetaminophen partially alleviates the pain. metric proximal and distal weakness in both arms is noted.
There is local tenderness over the right lateral epicon Hip flexor strength is diminished, and he has a waddling c,
dyle, and active wrist extension against resistance elicits gait. Otherwise, Iower extremity strength is normal. Upper ra
pain. She has full range of motion of the shoulder, elbow, t!
extremity examination is notable for atrophy of the fore o
vt
and wrist. There is no warmth, redness, or swelling. All arm muscles and a weak grip. No muscle tenderness, joint tt
other joints are normal. swelling, edema, or rash is observed.
Serum creatine kinase level is 310 U/L. Erythrocyte
+q,
Which of the following is the most likely cause of the sedimentation rate, serum aminotransferase levels, and
(a
patient's symptoms? thyroid-stimulating hormone level are normal.
(A) Degenerat ive joint disease
Which of the following is the most likely diagnosis?
(B) Disorder ofcenlral pain processing
(C) Inflammatoryarthritis (A) Inclusion body myositis
(D) Mechanical soft-tissue injury (B) Polymyositis
(C) Statin myopathy
(D) Systemic lupus erythematosus
Item 43
A Sl-year old woman is evaluated for an immigration
physical examination. She has a 2 year history of rheuma
toid arthritis. Immigration requirements include multiple
Item 46
A 28 year old man is seen in lbllow up for management of tr
vaccinations, and she has no recollection or record ofher a multisystem febrile illness. Up until 6 neeks ago he was
immunizations. Current medications are oral methotrex in good health. He takes no medications.
ate, tofacitinib, and folic acid. On physical examination, temperature is ll8.2 'C
(10o.8 'F), and blood pressure is 1SBi 84 nlm Hg. Bilateral
Which of the following vaccines is contraindicated in this 2+ ankle edema and bilateral tenderness and swelling of
patient? the metacarpophalangeal joints and wrists are observed.
'lhe remainder of the examination is normal.
(A) Hepatitis B virus
Laborato4r studies:
t (B) Measles, mumps, and rubella Henroglobin B.e gi dL (Be g/L)
(C) Quadrivalentinfluenza Leukocyte count 3U00/pt- (3.8 x 10erL)
(D) Tetanus toxoid, reduced diphtheria toxoid, and acel- Platelet count 90.000iirl (90 x 10ei L)
lular pertussis Cl) complement l.ow
(E) 13-Valent pneumococcal conjugate
04 cornplement Low
(lreatinine 1.6 mgrdl. (t41.4 pn-rolrL)
Anti double-stranded Positivc
Item 44 DNA antibodies
Antinuclear antibodies I :1 280 (speckted pattern)
; A 40 year old woman is evaluated fbr a 6 month history Urinalysis 2+ blor-rd; 3+ protein; dysmorphic
of bilateral hand and wrist pain and swelling. She has erythrocytes; no casts
morning stiflness lasting for t hour. Her hands and wrists Urine protein -creatinine :150 mg/g
i are swollen. ratio
Soft tissue swelling and warmth and tenderness of the
second through fourth metacarpophalangeal joints and Kidney biopsy results are pending.
t Prednisone is initiated.
wrists bilaterally are noted. Range of motion of these joints
i is normal but painful.
A diagnosis of rheumatoid arthritis is being considered. Which of the following is the most appropriate additional
;
treatment?
Which of the following will be most helptul in establishing (A) Azathioprine
It the diagnosis?
(B) Ilydroxychloroquine
(A) Anti-cyclic citrullinated peptide (CCP) antibodies (C) I Iydroxychloroquine and mycophenolate mofetil
(B) Anti-CCP antibodies and rheumatoid factor (D) No additional therapy
5
(C) C3 and C4 complements
(D) Rheumatoid factor
i Item 47
A S7-year-oldwomanisevaluated forfatigue, generalDed ach
Item 45 iness, and oral dryness without ocular dryness. Her review of
A 73 year old man is evaluated lor a 3-year history of systems is unremarkable. She has hypothyroidism, migraine
progressive weakness. He has a 7-year history of hyper- headaches, major depressive disorder, and chronic allergic
lipidemia and hypertension treated with atorvastatin and rhinitis. Current medications are levothyroxine, amitripty
Iisinopril. line, citalopram, intranasal glucocorticoids, and cetirizine.

109
 Self-Assessment Test

ln
(D
On physical examination, vital signs are normal. Oral Which of the following is the most likely diagnosis?
D
vt dryness is noted. There is no ocular inflammation or dry- (A) Eosinophilic granulomatosis with polyangiitis
UI ness or salivary gland enlargement. The remainder of the
t,D
gr (B) Hypersensitivityvasculitis
tt examination is normal.
(C) Polyarteritisnodosa
.D
Laboratory studies:
Ery.throcyte sedimentation rate 18 mm/h (D) Rheumatoidvasculitis
{
.D
Thyroid-stimulating hormone 1.6 pU/mL (1.6 mU/L)
Ut Rheumatoid factor Negative
Antinuclear antibody 1:80 Item 49
Anti-La/SSB antibody Negative A ss-year old man is evaluated for urate-iowering ther-
Anti Ro/SSA antibody Negative apy. He has experienced three gout flares over the past
year. He also has hypertension and chronic stable angina.
Which of the following is the most likely cause of this Current medications are low dose aspirin, metoprolol,
patient's oral dryness? atorvastatin, and lisinopril. He is of Han Chinese descent.
(A) Hypothyroidism Laboratory evaluation reveals a serum urate level of
9.8 mg/dL (0.s8 mmol/L).
(B) Medication adverse effects
(C) Sjogren syndrome
Which ofthe following is the most appropriate management?
(D) Systemic lupus eqthematosus
(A) Allopurinol
(B) Discontinuation of aspirin
Item 48 (C) Febuxostat
A 63-year-old woman is evaluated for fatigue and a leg rash
(D) HLA B.57:01 allele testing
that began 4 days ago. She has no other symptoms. She has
recently diagnosed hypertension, and hydrochlorothiazide
(E) HLA B-58:01 allele testing
was initiated 2 weeks ago.
On physical examination, vital signs are normal. The
rash is shown. The larger lesions are palpable. The remain Item 50
der of the examination is normal. A72 year old man is evaluated for a 15-year history of pain
and stiffness in the knees. He can walk only 50 yards before
needing to stop because ofthe knee pain. He has tried exer-
cises and physical therapy without relief. Intra articular
glucocorticoids provide minimal relief. He has no other
medical problems. Current medications are maximum
dosages of celecoxib, duloxetine, and acetaminophen.
On physical examination, the medial joint line of
each knee is tender to palpation. He has crepitus r,l'ith
movement.

Which of the following is the most appropriate treatment?

(A) Arthroscopic knee surgery
(B) Chondroitin sulfate and glucosamine
(C) Intra-articular hyaluronic acid injection
(D) Intra articular platelet rich plasma injection
(E) Total knee replacement

Laboratory evaluation reveals normal complete blood
count, comprehensive metabolic panel, and urinalysis results.
Item 51
A 53 year old man is evaluated in the emergencl'depart tr
ment for abdominal pain. Four rt'eeks ago. fatigue and
malaise developed. followed 1 u,eek later by a rash. Trvo
r,r,eeks ago. he began tripping or,er his left fbot. Three da1,s
ago. he developed abdominal pain after a meai; abdominal
pain is nolt constant.
On physical examination. temperature is 38.0 "C
(100.,1 "F). and blood pressure is 154 96 mm Hg: other vital
signs are normal. The abdomen is soft and nontender. N{us
cle strength at dorsiflexion of the left ankle is 315. Erythem
atous nodules are present on the lower legs. The remainder
of the examination is normal.

110
 Self-Assessment Test

vt
o
tr ffia.;fl;**o'
g
coNT reactiveprotein
8.7 gidL(87 s,tLj
Item 54
A 56 year old woman is evaluated for a 2 year history of
F
€,
13.8 mg/dl mg/L)
(138
osteoarthritis involving the flngers, bases of the thumbs,
Creatinine 7.7 mgldL (rSO.: pmol/L) hips, and knees. She has tried physical and aquatic therapy UI
(,}
Urinalysis Normal (u
with minimal beneflt, and she is enrolled in a weight loss vt
Hepatitis C virus serology Negative program. She has no other medical problems and takes no t!
HIV testing Negative
medications.
(u
Chest radiograph is normal. On physical examination, vital signs are normal. vt
BMI is 29. Heberden and Bouchard nodes and squaring
Which of the following is most likely to establish the of the bilateral flrst carpometacarpal joints are present.
diagrrosis? The flrst carpometacarpal joints and medial joint line of
both knees are tender to palpation. There is pain in the
(A) ANCA panel anterior left groin on internal rotation of the hip. There
(B) Hepatitis A virus serology is bony enlargement of the knees, with crepitus on range
(C) Kidney biopsy of motion.
(D) Magnetic resonance angiography of abdomen
Which of the following is the most appropriate
treatment?

tr Item 52
A 45-year old man is evaluated 2 weeks after an ernergency
department visit for gouty olecranon bursitis. Naproxen was
initiated at 500 mg twice daily; after clinical improvement,
the dosage was tapered. He has a 5 year history of acute gout
that occurs three times a year. He also has a history of kidney
stones. Current medication is naproxen, 250 mg twice daily.
There is left olecranon bursal thickening without redness,
warmth, orfluid. Tophi are presentbilaterallyinthe flrst meta-
tarsophalangeal joints without swelling, redness, or warmth.
Kidney f'unction is normal. Serum urate level is
10.5 rng/dl (0.02 rnmolll).
Which of the following is the most appropriate additional
treatment?
(A) Allopurinol
(B) Colchieine
(C) Febuxostat
(D) Probenecid
Item 53
A 35-year-old man is evaluated for a 3-day history of
abrupt polyarticular joint pain in both hands. His S-year-
old daughter recently had a low grade fever and malaise
with 1 day offrequent loose stools; 2 days later she had an
erythematous rash over her cheeks.
On physical examination, vital signs are normal. Joint
examination shows tenderness of the right second, third,
and fourth proximal interphalangeal joints; tenderness
ofthe right second and third metacarpophalangeal joints;
tenderness of the left second and third proximal interpha
langeal joints; and tenderness ofthe left second and third
metacarpophalangeal joints.
Results of serologic tests are pending.
Which of the following is the most appropriate treatment?
(A) Diclofenac
(B) Etanercept
(C) Hydroxychloroquine
(D) Methotrexate
(A) Acetaminophen
(B) Duloxetine
(C) Gabapentin
(D) Piroxicam
(E) Tramadol
Item 55
A 65-year-old man is evaluated for "pain everyr,vhere."
Two months ago, he developed neck and upper back pain,
fatigue, and malaise. Over the next few weeks, stiffness and
achiness developed in the shoulders and upper arms. He has
no headaches, visual changes, or jaw discomfort. He takes
no medications.
On physical examination, vital signs are normal. There
is no scalp tenderness. Temporal artery pulses are normal.
There are no swollen or tender joints. Discomfort limits
range of shoulder motion bilaterally and causes difficulty
with standing from a seated position. Extremity strength
and reflexes are normal.
Laboratory evaluation shows a normal complete
blood count, normal serum thyroid stimulating hormone
level, and blood C-reactive protein level of 6.8 mg/dl
(os mg/L).
Which of the following is the most appropriate
management?
(A) Measurement of rheumatoid factor, antinuclear anti
bodies, and ANCA
(B) Prednisone, 15 mg/d
(C) Prednisone, 60 mg/d
(D) Pregabalin
Item 56
A 63-year old man is evaluated for an S-week history
of a spreading rash on the feet and legs, fatigue, and
arthralgia.
On physical examination, vital signs are normal. The
rash is shown (top of next page). Some lesions are palpable.
He cannot extend his left wrist. Findings on pulmonary,

111
 Self-Assessment Test

vr
(D
cardiac, and gastrointestinal examinations are unremark- Item 58
vt able. There are no swollen or tender joints. A 62-year-old woman is evaluated for joint pain. She has a
l/}
(D
UI
10-year history ofpsoriasis and a 3-year history ofarthritis.
t Her psoriasis has been controlled with adalimumab, but
(D joint symptoms persist. She has stiffness in the affected
joints for less than 30 minutes every morning, and pain
.D
increases with activity. There is no dactylitis. Current
t^ medication is adalimumab.
On physical examination, there are small psoriatic
plaques on the left elbow and right knee. She has bony
enlargement, without swelling, of most distal and prox
imal interphalangeal joints of the hands. the left knee
has a small effusion. The remainder of the examination is
normal.
Radiographs of the hands show joint-space narrow-
ing and osteophytes at the distal and proximal interpha-
Iangeal joints of both hands. Radiographs of the knees
show medial joint-space narrowing and subchondral
sclerosis of the left medial compartment.
laboratory studies:
Erythrocyte sedimentation rate 110 mm/h Which of the following is the most likely cause of this
Alanine aminotransferase 93UIL patient's joint pain?
Aspartate aminotransferase 89 U/L (A) Chronic gout
C3 complement 113 mg/dl (rrao mg/L) (B) Osteoarthritis
C4 complement Not detected
Creatinine 2.r mgl dL (18s.6 pmol/L) (C) Psoriaticarthritis
Rheumatoid factor 118 U/mL (118 kU/L) (D) Rheumatoidarthritis
Anti-cyclic citrullinated Not detected
peptide antibodies
Urinalysis 2+ blood; 2+ protein; Item 59
dysmorphic A 40 year-old woman is evaluated for a 9-month history
erythrocytes; no casts of Raynaud phenomenon. She reports no dilficulty swal-
lowing, dyspnea on exertion, or hand stiffness. She has
Which of the following is the most likely diagnosis?
recently developed gastroesophageal reflux disease.
(A) Cryoglobulinemicvasculitis On physical examination, vital signs are normal. The
(B) Hlpersensitivityvasculitis skin between the distal and proximal interphalangeal
joints ofthe flngers is difficult to tent. Ihree telangiectasias
(C) Polyarteritisnodosa
on the right hand and four on the left are noted. She also
(D) Rheumatoidvasculitis has two small telangiectasias on the face and one on the
inside bottom lip. No digital pitting is seen.
Laboratory evaluation reveals a positive antinuclear
Item 57 antibody titer (1:SZO) and positive anticentromere antibody
A 36-year-old woman is evaluated for preconception titer (1:160).
counseling. She has a 3 year history of rheumatoid arthri-
tis well controlled with leflunomide, hydroxychloroquine, Which of the following is the most likely diagnosis?
and certolizumab. Her most recent disease activity score
showed remission. In the past, attempts to discontinue her
(A) Diffuse cutaneous systemic sclerosis
medications have been unsuccessful because ofrecurrent (B) Eosinophilicfasciitis
active disease. (C) Limited cutaneous systemic sclerosis
On physical examination, vital signs are normal. BMI (D) Mixed connective tissue disease
is 24. Range of motion is normal, and joints are not warm
or swollen.
Item 6O
Which of the following is the most appropriate
A 60-year-oldwoman is evaluated for achiness and fatigue.
preconception management?
She reports dry mouth, irritated eyes, and discoloration of
(A) Discontinue all drugs flngers after exposure to cold temperature that rapidly
(B) Discontinuecertolizumab responds to rewarming.
(C) Discontinuehydroxychloroquine
On physical examination, vital signs are normal.
Parotid glands are enlarged, and salivary pooling is
(D) Discontinueleflunomide decreased. There is no lymphadenopathy. All appendicular
(E) No changes are needed joints have preserved range of motion without discomfort.

112
 Self-Assessment Test

ta
Laboratory evaluation reveals erythrocyte sedimen On physical examination, respiration rate is 18/min c,
F
tation rate of 77 mmlh, a blood C-reactive protein level of and oxygen saturation is 97% with the patient breathing
0.23 mg/dl (2.3 mglL), and a rheumatoid factor level of ambient air. On a 6 minute walk test, oxygen saturation €,
202UtmL(202kUtL). drops to 90%. Crackles are heard at both lung bases. Heart tt
vt
sounds are normal. Skin changes consistent with diffuse (l,
ra
Which of the following is the most appropriate diagnostic cutaneous systemic sclerosis are present. t,
test to perform next? A high-resolution CT scan shows ground glass
changes in the lower lung flelds. (l,
(A) ANCA Pulmonary function tests show an FVC of 82% of tt
(B) Anti-cycliccitrullinatedpeptide antibodies predicted and a Dr-co of 65% of predicted.
(C) Anti Ro/SSA antibodies
(D) Cryoglobulins Which of the following is the most appropriate treatment?
(A) Hydroxychloroquine
Item 61 (B) Methotrexate
A 70 year-old woman is evaluated for a S-year history of (C) Mycophenolatemofetil
tophaceous gout in both hands. Previous treatment with allo- (D) Nintedanib
purinol resulted in rash. Over the past year, maximum-dose
febuxostat has decreased serum urate levels to 9.5 mg/dl
(O.SO mmol/L). She also has hlpertension and stage G3b
chronic kidney disease. Current medications are febuxostat
Item 63
An 18 year old woman is evaluated for f'ever, chills. and tr
and losartan- malaise that developed 5 days after her last menstrual
Radiograph of the right hand obtained before initia period. The following day, she developed arthralgia that
tion of febuxostat therapy is shown. first involved the left wrist and then the right knee: the left
flfth toe became exquisitely painful and diffusely swollen,
with limited range of motion. She is sexually active with
one male partner. Her only medication is a combined oral
contraceptive.
\ On physical examination, temperature is 38.1 'C
(i00.6 'F). Her feet and left hand are shown.
i

Which of the following is the most appropriate treatment? Which of the following is the most likely diagnosis?
(A) Addhydroxychloroquine (A) Disseminated gonococcalinfection
(B) Addprobenecid (B) I{epatitis B virus infection
(C) Stop febuxostat and start pegloticase (C) HtV associated ar-thritis
I

(D) No treatment changes (D) l.yme arthritis

Item 62
A 52 year old man is evaluated for treatment of intersti
tial lung disease. Over the last 6 months, he develgped a
nonproductive cough and dyspnea on exertion. He has
a 3 year history of diffuse cutaneous systemic sclerosis
and gastroesophageal reflux disease. Current medication
is pantoprazole.
(E) Systemic lupus erythematosus
Item 64
A 50 year-old woman is evaluated for a 6-month history of
progressive difficulty getting out of a chair and raising her
arms above her head. She has a l0-year history ofRaynaud
phenomenon and gastroesophageal reflux. Current medi-
cations are omeprazole and acetaminophen.

113
 Self-Assessment Test

vr
(D
On physical examination, vital signs are normal. Fin- the proximal interphalangeal joints, metacarpophalangeal
la gers are pufflz bilaterally, without digital ulcers or skin joints, wrists, elbows, ankles, and metatarsophalangeal joints.
UI thickening. Neurologic examination shows bilateral prox
(D
UI imal muscle weakness; distal muscle strength in upper and
UI Infection with which of the following is the most likely
lower extremities is normal bilaterally. The remainder of diagnosis?
.D
the examination is normal.
(A) Chikungunya virus
Iaboratory studies:
(D
tt (B) Hepatitis B virus
Complete blood count Normal
C3 complement Normal (C) Hepatitis C virus
C4 complement Normal (D) HIV
Creatine kinase 2000 u/L
Antinuclear antibodies Strongly positive
Anti-U1-ribonucleoprotein antibodies Positive Item 67
Anti-Ro/SSA antibodies Negative A 26-year-old man is evaluated for a 1 week history of
Anti-La/SSB antibodies Negative pain and swelling in the left ankle, along with pain in
Anti-smooth muscle antibodies Negative the toes and tenderness in the left heel. Three weeks ago,
Anti-double-stranded DNA antibodies Negative he returned from a vacation in Central America. Before
Urinalysis Normal returning home, he experienced 4 days of diarrhea that
spontaneously resolved. Current medication is acetamin-
Which of the following is the most likely diagnosis?
ophen as needed.
(A) Mixed connective tissue disease On physical examination, vital signs are normal. The
(B) Rheumatoidarthritis left ankle is swollen, with reduced range of motion. Several
(C) Systemic lupus erythematosus toes are swollen, as shown, and the Achilles insertion on
the left is swollen and tender.
(D) Undifferentiated connective tissue disease

Item 55
An 82-year-old man is seen in follow-up for inclusion body
myositis. A prednisone taper over the past 4 months was
completed without clinical improvement.
On physical examination, vital signs are normal. There
is weakness in the shoulders, forearms, hand grip, hip gir-
dle, and knee extensors that is unchanged from previous
examinations.
Serum creatine kinase level is 370 U/L, minimally
decreased from 4 months ago.
Laboratory evaluation reveals a blood C-reactive pro-
tein level of 3.5 mg/dl (ss mg/L).
Which of the following is the most appropriate treatment?
(A) Addcyclophosphamide Which of the following is the most appropriate
(B) Add intravenous immune globulin management?
(C) Add methotrexate (A) Azithromycin
(D) Initiate physical therapy (B) HLA-B27 testing
(E) Restart prednisone (C) Piroxicam
(D) Stool cultures for enteric pathogens

tr Item 56
A 45 year-old man is hospitalized for incapacitating poly
arthralgia and fever. One week before hospitalization, pain
in multiple joints of the hands, wrists, elbows, ankles, and
feet developed over a 24-hour period. Five days before
hospitalization. fever, malaise, and intensification of the
joint pain developed. Two days before hospitalization, a
rash appeared on the extremities and trunk and spread to
the face. He lives in southern Florida and has not recently
traveled outside the United States.
On physical examination, temlxrature is 39.1'C (102.4.F)
and pulse rate is 116/min. He has bilateral conjunctivi
tis and a maculopapular rash on the face, extremities, and
trunk. Joint examination shows swelling and tendemess of
Item 58
tr
A 72-year-old woman is evaluated for a 3-month history
of abdominal and back pain and 4-month history of an
increasingly rounded face.
On physical examination, vital signs are normal. BMI
is 29. Bilateral lacrimal and parotid glands are enlarged.
Laboratory evaluation shows a hemoglobin A,. value
of 5.4"1,, an alkaline phosphatase level of 255 UlL, and an
estimated glomerular filtration rate of 59 mliminll.T3 m2
(same as l year ago).
An abdominal CT scan shows periaortitis with a retro
peritoneal mass that extends bilaterally and encircles both
ureters without hydronephrosis.

114
 Self-Assessment Test

tt
c,
m
llJ
cONT
Needle biopsy of the mass reveals dense fibrous tissue
in a storifbrm pattern, interspersed with an inflammatory
irrg11."1., including increased numbers of IgG4 positive
Item 71
A 38-year old woman is evaluated fbr pain in multiple tr (u
fingers. She fractured her left second digit 1 year ago after
plasmablasts. Serum IgG,l levels are not elevated. |a
a minor trauma. For the past 2 years, she has occasionally |n
(l,
experienced f'ever and night sweats. a
In addition to prednisone, which of the following is the most On physical examination, vital signs are normal. Parotid
vt
appropriate treatment? and lacrimal glands are eniarged. Multiple coin-sized pink.
(u
(A) Cevimeline red, and violaceous papular skin lesions are present on the t
(B) arms and anterior chest. The right second and flfth digits are
Methotrexate
swollen and tender. Hepatomegaly is present.
(C) Rituximab
l-aboratory studies:
(D) Surgicaldebridement
Complete blood count Normal
Erythrocl.tesedimentationrate 62mmlh
Item 69 Alkaline phosphatase 166U lL
Alanine aminotransferase 58 UIL
A 50 year-old woman is evaluated for exertional dyspnea Aspartate aminotransferase 64UlL
of 6 months'duration. Limited cutaneous systemic sclerosis FIIV test Negative
was diagnosed 6 years ago. She reports no other cardiopul- Purified protein derivative skin test Negative
monary symptoms. Other medical problems include sclero
dactyly, Raynaud phenomenon, and gastroesophageal reflux Chest radiograph shows hilar lymphadenopathy.
disease. Current medications are nifedipine and omeprazole. Abdominal ultrasound reveals liver enlargement with
On physical examination, oxygen saturation is 97%
multiple infiltrating nodules. A hand radiograph is shown.
with the patient breathing ambient air. Other vital signs
are normal. Sclerodactyly of the flngers is noted. Telangi-
ectasias are present on the hands and face. Lungs are clear
to auscultation. Heart examination is normal.
Twelve months ago, a baseline high resolution chest
CT scan was normal.
FVC is 96% of predicted, and Dr-co is 58% of predicted.
Twelve months ago, these values were 97"/. and 75ok of
predicted, respectively.

Which of the following is the most appropriate diagnostic

test to perform next?
(A) Cardiac magnetic resonance imaging
(B) Repeat high resolution chest CT
(C) nignt heart catheterization
(D) Transthoracic echocardiography

Item 70
A 40 year old woman is evaluated for several months of
joint pain and stiffness in the hands and feet. Over the past
7 weeks, she has developed swelling in several of her flnger
joints and in her right wrist.
On physical examination, vital signs are normal. Joint
examination shows bilateral swelling and tenderness of the
second metacarpophalangeal joints, third proximal inter
phalangeal joints, and right wrist, along with tenderness
of the metatarsals.

Which of the following will be the most helpful diagnostic

tests?
(A) C-reactive protein and erythrocyte sedimentation rate
(B) Lyme disease enzyme linked immunosorbent assay
and Western blot serologies
(C) Rheumatoid factor and anti-cyclic citrullinated pep-
tide antibodies
(D) Rubella and parvovirus serologies

115
 Self-Assessment Test

tt
(D

D
l^
UI
tr
CONT.
Which of the following is the most appropriate diagnostic
test to perform next?
Item 74
A 70 1'ear-old man is evaluated for a 3 n'eek history of
tr
.D
U! (A) Bone biopsy gradually increasing pain ar-rd swelling in the left knee.
vt
(B) Bronchoscopicbiopsy I{e has osteoarthritis. Six months ago he underu'ent total \
=
o joint arthroplastl, of the left knee. Current medication is
(C) Lip biopsy
acetaminophen.
(D) Skin biopsy On phl,sical examination, vital signs are normal.
.D
tt Examination of the left knee shows slight n'armth. a small
Item 72 effusion u'ithout erythema, and a well healed midline scar.
A 60-year-old man is evaluated for a l-year history of Examination olthe right knee is normal.
lower extremity edema. He has a 30-year history of poorly Laboratory evaluation reveals an er1'throc1,'te sedi
controlled ankylosing spondylitis. He also has intermit- mentation rate of 40 mm/h, leukocl,te count of 8000 pl.
tent uveitis. His only medication is naproxen; he has been (8.0 x 10'r,'L). and blood C-reactive protein level of 1.2 mg
reluctant to initiate biologic agents. dL (12 mg'l-).
On physical examination, blood pressure is 158/90 mm Hg.
Other vital signs are normal. He has kyphosis with immo Infection with which of the following organisms is most
bility of the cervical, thoracic, and lumbar spine. There is likely?
decreased range of motion of the shoulders and hips with
(A) Neisserio gonorrhoeae
30-degree flexion contractures at both hips. There is 2+
bilateral swelling of the lower extremities.
(B) Pseudomonas oeruginosa
(C) Stophylococcus epidermidis
laboratory studies:
Albumin 2.5 gldL(2s glL) (D) StreptococcLts pAogenes
C-reactive protein 6.3 mg/dl (0S mg/L)
Creatinine 1.8 mg/dl (fSg.f pmol/L)
Urinalysis 3+ protein; no erythrocytes, Item 75
leukocytes, casts, or eosinophils 19 year old woman is evaluated for recent onset of a
A
Protein-creatinine ratio 5200 mg/g malar rash and arthralgia, which Iimits her daily activities.
On physical examination, vital signs are normal. She
Which of the following is the most likely diagnosis?
has an edematous, erythematous malar rash and small joint
(A) Analgesicnephropathy tenderness and swelling in several proximal interphalan
(B) IgAnephropathy geal joints, metacarpophalangeal joints, wrists, and ankles.
(C) Interstitialnephritis The remainder of the physical examination is normal.

(D) Renal amyloidosis laboratory studies:

Erythrocyte sedimentation rate 35 mm/h
Platelet count 92,OOOl1tL(92xr}elL)
Item 73
Comprehensive metabolic panel Normal
A 36-year-old woman is evaluated for a recent diagnosis C3 complement Normal
of rheumatoid arthritis. Over the past 2 months she has C4 complement Normal
had increasingly severe pain and swelling in the hands and Anti-double stranded DNA Positive
wrists and pain in the feet. Her only medication is a com antibodies
bined oral contraceptive. Antinuclear antibodies 1:1280 homogenous
On physical examination, vital signs are normal. Joint Urinalysis Normal
examination reveals swelling and tenderness of the left
second, third, and flfth proximal interphalangeal joints; Chest radiograph is normal.
right second and third proximal interphalangeal joints; Sun protection, including use of a broad spectrum
bilateral second, third, and fourth metacarpophalangeal sunscreen, is recommended.
joints; right wrist; left ankle; and left second and third
metatarsophalangeal joints. Which of the following is the most appropriate additional
Radiographs of hands and feet demonstrate juxta treatment?
articular osteopenia without erosions. (A) Prednisone
Laboratory evaluation reveals a hemoglobin level of
10.8 g/dl (108 g/L), leukocyte count of s4O0/pL (5.4 x
(B) Prednisoneandhydroxychloroquine
l0eil) with normal diflerential, and platelet count of (C) Prednisone, hydroxychloroquine, and cyclophospha-
435,000/gL (435 x l0'/L). mide
(D) Topical hydrocortisone cream
Which of the following is the most appropriate treatment?
(A) Diclofenac
(B)
(C)
Methotrexate
Mycophenolatemofetil
Item 76
A 50 year-old man is evaluated for pain, swelling, ten- tr
derness, and redness ofthe right great toe that began last
(D) Rituximab lright. He has hacl several similar episodes over the past

116
 5elf-Assessment Test

tt
pl 2years. He has type 2 diabetes mellitus and a recent diag- Which of the following is the most appropriate diagnostic
G'

l*l nosis of deep venous thrombosis. Current medications are test to perform next?
(l,
coNT apixaban, metfbrmin, and rosuvastatin.
(A) Brain MRI E
On physical examination, the right first metatarso tt
vt
phalangeal joint is tender. red. warm, and swollen. (B) ChestCT (l,
ta
Laboratory evaluation reveals a serum urate level of (C) Echocardiography ta
9.0 mg/dl (0.53 mmol/L). (D) Kidney biopsy
Radiograph of the right foot is shown. =
tto
Item 78
A 31-year old man is evaluated following a recent diagno-
sis of ankylosing spondylitis. He has low back and pelvic
pain that interrupts his sleep. Acetaminophen has not
helped.
On physical examination, vital signs are normal. The
FABER (Flexion, ABduction, and External Rotation) test of
the hip elicits pain at both sacroiliac joints. Lumbar spine
range of motion is slightly limited. There is good range of
motion of the cervical spine and peripheral joints, includ-
ing the hips. No peripheral joint swelling or tenderness is
noted.
Radiographs of the lumbar spine show bilateral
sacroiliitis.
The patient is referred to physical therapy.

Which of the following is the most appropriate additional

treatment?
(A) Etanercept
(B) Methotrexate
(C) Naproxen
Which of the following is the most appropriate initial (D) Sulfasalazine
treatment?
(A) Allopurinol
Item 79
(B) Colchicine
A Sl-year-old woman is evaluated at a follow-up visit.
(C) Indomethacin Sj0gren syndrome was diagnosed 3 years ago. For the past
(D) Prednisone 4 weeks she has experienced arthralgia, unintentional
weight loss, fever, and drenching night sweats. She has
hypothyroidism. Current medications are levothyroxine,

tr Item 77
A24 year old woman is hospitalized fbr rapidly progressive
artiflcial tears, and ophthalmic cyclosporine suspension.
On physical examination, vital signs are normal.
Parotid glands are enlarged, and the oropharynx is dry.
lower extremity edema and rising serum creatinine level. She
Lungs are clear to auscultation. There are no skin lesions or
is diagnosed with new-onset systemic lupus ery,.thematosus.
On physical examination, blood pressure is 162/94 mm
evidence of joint synovitis.
Hg, and pulse rate is 98/min. An erythematous malar rash Laboratory studies:
is present. The metacarpophalangeal joints are swollen Erythrocyte sedimentation rate 73mm/h
bilaterally. Lower extremity edema and facial puffiness Hemoglobin ro.2gldL (102 g/L)
are present.'lhe cardiopulmonary examination is normal. C3 complement 102mg/dl (1020 mg/L)
C4 complement 8 mg/dl (80 mg/L)
Laboratory studies:
Thyroid-stimulating hormone 3.0 pU/mL (3.0 mU/L)
C3 complement Low
Rheumatoid factor 442UlmL(442kUlL)
C4 complement Low
Anti-cyclic citrullinated peptide Negative
Creatinine 1.3 mg/dl (114.9 pmol/L)
antibodies
Anti double stranded DNA Positive
Anti-La/SSB antibodies Negative
antibodies
Anti Ro/SSA antibodies >8 U/L (normal, <1 U/L)
Antinuclear antibodies 1:1280 (speckled pattern)
Urinalysis O 1+ protein; no
Urinalysis 3+ protein; 2+ blotidl 35
erythrocytes, Ieukocytes,
erythrocytes/hpf: no
or casts
leukocytes; no casts
Spot urine protein creatinine 600 mg/g Immunoflxation studies show a monoclonal IgM
ratio gammopathy (r type).

117
 Self-Assessment Test

ur
.D
+
D
Which of the following conditions is most likely (C) Polymyalgia rheumatica
U! responsible for her recent symptoms? (D) Rheumatoid arthritis
Ut
.D
UI (A) AL amyloidosis (E) Systemic lupus erythematosus
(a
J (B) Hypothyroidism
.D (C) Lymphoma Item 82
(D) Rheumatoidarthritis
.D A72 year-old man is evaluated for chronic right knee pain
t^ with morning stiffness lasting 15 minutes. He is experi
encing increased difficulty walking because of knee pain.
tr Item 8O
An 18 year old woman is evaluated lbr a I week history
He has no other medical problems other than overweight.
His only medication is acetaminophen, which provides
of'f'ever and dilfuse myalgia, and pain and slvelling in the minimal pain relief.
hands and knees that have progressed over the last month. On physical examination, BMI is 34. There is bony
She also has acnc. Current medicatiorrs are minocl,cline. hypertrophy of the knee without effusion or signs of
topical tretinoin, and an oral contraceptive. inflammation. He has moderate pain with lull knee flexion
On physical examination, temperature is 38.3 'C but no restriction of motion. The remainder of the exam
(100.9 "F)i other vital signs are normal. She has synovitis ination is noncontributory.
in her hands and wrists and inflammatory acne on the Iace Topical diclofenac is prescribed.
and upper back.
laboratory studies: Which of the following is the most appropriate additional
Complete blood count Normal treatment?
Erythrocyte sedimentation rate 36mm h
Normal
(A) Exercise and weight loss
Creatinine
Anti cyclic citrullinated peptide Negative (B) Massage therapy
antibodies (C) Mobilization/manipulation and passive range of
Antinuclear antibodies 1 :320 (speckled pattem) motion
ANCA Positive (p ANCA (D) Transcutaneous electrical nerve stimulation
pattern)
Rheumatoid factor Negative
Urinalysis Nornral Item 83
Test results ft-rr antihistone and othcr specific autoanti A 42 year-old woman is evaluated for increasingly severe
bodies are negative. and serum complement levels are normal pain and swelling in both hands for the last 6 months. She
has morning stiffness that lasts t hour. Current medication
Which of the following is the most likely diagnosis? is ibuprofen.
On physical examination, vital signs are normal. Joint
(A) Drug induced lupus erythematosus examination reveals bilateral swelling and tenderness of
(B) Granulonratosis'^'ith polyangiitis the second and third metacarpophalangeal joints and third
(C) Rheumatoidarthritis proximal interphalangeal joint.
(D) Systemic lupus erythematosus laboratory studies:
Hemoglobin 10.8 gi dL (108 g/L)
Rheumatoid factor Positive
Item 81 Anti-cyclic citrullinated Positive
A 37 year-old woman is evaluated for a l-year history of peptide antibodies
widespread joint and muscle pain, fatigue, poor sleep, Antinuclear antibodies Negative
and difflculty focusing. She also has irritable bowel syn
Which of the following is the most appropriate test to
drome and migraine headaches. Current medications are
perform next?
sumatriptan and topiramate.
On physical examination, vital signs are normal. No (A) ANCA
rash is present on the face or extremities. Joint examina (B) Anti double stranded DNA antibodies
tion shows normal range of motion and no joint swelling. (C) MRI of hands
Most soft tissue is tender to light palpation. Muscle strength
is normal.
(D) Plainradiographyofhands
Laboratory evaluation shows a normal complete blood
count, serum thyroid stimulating hormone level, and
urinalysis as well as an erythrocyte sedimentation rate of Item 84
20 mm/h. A 3O-year old woman is evaluated for a 2 month history
of skin changes, primarily on her chest and arms. She
Which ofthe following is the most likely diagnosis? has no other symptoms. Her only medication is an oral
contraceptive.
(A) Fibromyalgia On physical examination, vital signs are normal. The
(B) Generalized osteoarthritis rash on her chest is shown (top ofnext page).

118
 )
Self-Assessment Test
t
I v!
I 6'
swollen and warm, with erythema, tenderness to palpation,
and limited range of motion due to pain. Other joints are
I

t (u
normal.
t r/l
r,l
I Which of the following is the most appropriate diagnostic (l,
t
test to perform next? vt
t
t (A) Aspiration of the left knee o
(B) Erythrocyte sedimentation rate arl
t
(C) Radiographyoftheleft knee
t (D) Serum urate level
t
t
t
Item 87
A S5-year old woman is evaluated for a 5,day history of tr
There is no evident scarring or lesions in the scalp increasing pain, swelling,, and warmth in the left knee.
She has a 30-year history of rheumatoid arthritis. Current
t or ears, hair loss, or joint swelling. The remainder of the
medications are etanercept, prednisone, methotrexate,
examination is normal.
t Laboratory evaluation reveals an antinuclear antibody folic acid, and meloxicam.
titer of 1:640 with speckled pattern; result for anti-Ro/SSA On physical examination, temperature is 37.5 "C
t antibody is positive.
(99.s "F); nther vital signs are normal. Joint examina-
tion of the hands reveals nonpainful deformities and
L
restricted movement characteristic of advanced but
Which of the following is the most likely diagnosis?
quiescent rheumatoid arthritis. The left knee exhibits
t (A) Acute cutaneous lupus erythematosus warmth and a moderate effusion without erythema; flex-
t (B) Cutaneousleukocytoclasticvasculitis ion is restricted because of pain. The right knee shows
I
(C) Discoid lupus erythematosus bony hypertrophy.
L Laboratory evaluation shows an erythroqrte sedimen,
(D) Subacute cutaneous lupus ery,thematosus
I tation rate of 7O mmlh and leukocyte count of 13,500/pL
L (13.5 x lOelL).

t
I
I
tr Item 85
A 78-year-old woman is evaluated for constant bilateral
Which of the following is the most appropriate diagnostic
test to perform next?
headache of I week's duration. Two months ago, she was
diagnosed with polymyalgia rheumatica. Symptoms were (A) C'reactive protein
;
:
relieved with prednisone, 15 mgld. Headache appeared (B) Serum procalcitonin
i shortly after the dosage was tapered to 5 mg/d. She also (C) Synovial biopsy
has experienced new-onset intermittent muscular jaw dis, (D) Synovial fluid analysis
; comfort with chewing.
On physical examination, vital signs are normal. The
scalp and temporal arteries are not tender to palpation. No
bruit is heard over the great vessels; temporal artery pulses
Item 88
are intact. A 3O-year-old woman is seen for preconception coun-
Laboratory evaluation shows a blood C reactive pro- seling. Three years ago, she was diagnosed with systemic
tein level of 12.8 mg/dl (128 mg/L). lupus erythematosus and nephritis. She responded rapidly
to induction therapy with combination immunosuppres-
Which of the following is the most likely diagrrosis? sants and has been maintained on mycophenolate mofetil
and hydroxychloroquine for the past 2 years. An intrauter
(A) Giant cell arteritis ine device is used for contraception.
(B) Granulomatosiswith polyangiitis Laboratory evaluation is consistent with quiescent
(C) Microscopicpolyangiitis disease, and there is no evidence of kidney dysfunc-
(D) Polyarteritisnodosa tion.

Which of the following is the most appropriate

preconception management?

tr Item 86
A 72-year-old man is evaluated for severe left knee pain
(A) Advise against pregnancy
(B) Continue current medications
with swelling that has worsened over the past 5 days. Pain
is exacerbated with weight bearing. He has no history of (C) Discontinue hydroxychloroquine and mycophenolate
trauma. Current medication is acetaminophen. mofetil; add prednisone
On physical examination, temperature is 38.2 "C (D) Discontinue mycophenolate mofetil; add azathio-
(100.8 "F). Other vital signs are normal. The left knee is prine

119
 Self-Assessment Test

t/t
o
t^
t^
tr Item 89
A 60-year old man is evaluated in follow up after an
l-aboratory studies:
I Iematocrit
Leukocyte count
30"1,
4000/prl (4.0 x 10e,il). \^,ith lymphopenia
.D
t, episode of podagra. which u,as treated with colchicine.
UI This r.r,as his first gout flare. f{e also has hypertension and Platelet count T2,OOO StL (72 x 10'q L)

hyperlipidemia. Current medications are hydrochlorothi C reactive protein s.s mg/dl (55 mgrL)
.D
azide and atorvastatin. Creatinine 1.4 mg/dL (12:l.B pmollL)
Urinalysis 1+ protein, 1+ blood; 2 3 ery'throclles:
(D On physical examination. blood pressure and other
u) findings are normal. no leukocytes; no casts
Laboratory evaluation reveals a semm urate level of' Which of the following is the most likely cause of this
9.0 mgldl. (o.se mmoliL). patient's pericarditis?

Which of the following is the most appropriate
treatment?
(A)
Start allopurinol
(B)
Start vitamin C
(C) Stop atorvastatin and start fenofibrate
(D) Stop hydrochlorothiazide and start losartan
Item 90
A 57-year-old woman is evaluated for a 2.5 year history
of pain and swelling in the hands and wrists. She also has
joint stiffness for over an hour after awakening.
On physical examination, vital signs are normal. She
has swelling and tenderness of the following: second, third,
and fourth proximal interphalangeal joints of the right
hand and third and fourth proximal interphalangeal joints
of the left hand; the left second and right third metacarpo-
phalangeal joints; and both wrists.
Laboratory evaluation reveals a blood C*reactive pro
tein level of 4.8 mg/dl (+s mg/L) and positive results on
tests for serum rheumatoid factor and anti cyclic citrulli-
nated peptide antibodies.
Radiographs of the hands show periarticular osteo-
penia and joint-space narrowing of the proximal inter-
phalangeal joints, periarticular osteopenia and marginal
erosions at the second proximal interphalangeal and meta-
carpophalangeal joints of both hands, and radiocarpal
joint-space narrowing.
(A) Adult onset Still disease
(B) Coxsackievirus infectior-t
(C) Idiopathicpericarditis
(D) Systemic lupus erythenlatosus
Item 92
A 4S-year-old woman is evaluated for progressive short
ness of breath for 6 months, hearing impairment, and knee
pain. She has no additional medical problems and takes no
medications.
I
On physical examination, vital signs are normal; oxygen
saturation is 98% with the patient breathing ambient air. She
has swelling and redness of the helices of the ear, with sparing
of the lobule; diminished hearing bilaterally; bilateral con-
junctivitis; and redness, tendemess, and flattening of the nasal
bridge. Lung examination reveals inspiratory stridor loudest
over the trachea. Knees show joint-line tendemess bilaterally.
The remainder of the physical examination is normal.
Laboratory tests, chest radiography, and CT of the
upper airways and chest are ordered.
Which of the following is the most likely diagnosis?
(A) Cryoglobulinemia
(B) Granulomatosiswithpolyangiitis
(C) Relapsingpolychondritis
(D) Rheumatoidarthritis

Which of the following imaging studies should be done Item 93

next? A 58-year-old woman is evaluated for a 4-month history
(A) Bone scanning of diarrhea and weight loss. Diffuse cutaneous systemic
sclerosis was diagnosed 10 years ago. She reports explosive
(B) MRI of hands diarrhea soon after eating a meal. She has lost 5 kg (11 lb)
(C) Ultrasonographyofhands since the symptoms began. She also has Raynaud phe
(D) No further imaging nomenon and gastroesophageal reflux disease controlled
with pantoprazole once a day. Current medications are
sustained release nifedipine and pantoprazole.

tr Item
A
91
40 year-old man is hospitalized for acute pericarditis. He
On physical examination, vital signs are normal. Skin
changes consistent with diffuse cutaneous systemic scle
rosis are present. Findings on the abdominal examination
also reports pain in the wrists, ankles, and knees for I week
are normal.
but no other symptoms. He has otherwise been well and
takes no medications.
On physical examination, temperature is 38.0 'C Which of the following is the most appropriate treatment?
(10o.+ "F): the ren.rainder of'the vital signs are normal. (A) Cholestyramine
A pericardial friction rub is present. The wrists, knees. (B) Ciprofloxacin
and ankles are tender. There are small bilateral wrist
and knee effusions. The remainder of the examination is (C) Increase in pantoprazole dosage
unrcmarkable. (D) Loperamide

120
 Self-Assessment Test

ut
q,
Item 94 Which of the following is the most appropriaG
A 29-year-old man is evaluated after an episode of anterior management?
(u
uveitis. He has 2 year history of low back stiffness at night (A) Cyclophosphamide E
and in the morning that improves with activity. Current (B) Immediate delivery ut
t
medication is meloxicam as needed. (l,
(C) Magnesium sulfate vt
On physical examination, he cannot touch his toes, UI

and there is flattening of the normal lumbar lordosis. Inter- (D) Prednisone
nal rotation and flexion elicit pain in the right hip; range (u
r/t
of motion of the right hip is diminished. Flexion, external
rotation, and abduction ofthe hips cause pain in the right Item 96
hip and low back. The remainder of the examination is
unremarkable. A 46-year old man is evaluated for a S-year history of
pain in the lower spine, knees, and hands. The hand
pain is associated with occasional swelling. Morning
Which of the following is the most appropriate diagnostic
stiffness lasts less than 30 minutes. Type 2 diabetes
test to perform next?
mellitus was diagnosed 2 years ago. His only medication
(A) Anteroposteriorradiographyofpelvis is metformin.
(B) Antinuclear antibody assay On physical examination, there is bilateral enlargement
(C) HLA-B27 testing of the second, third, and fourth metacarpophalangeal joints
as well as all proximal and distal interphalangeal joints. The
(D) Sacroiliac joint MRI medial joint line of each knee is tender to palpation.
Iaboratory studies:
Alanine aminotransferase
tr Item 95
A 2S-year-old woman is hospitalized at 26 weeks of preg-
48UlL
Aspartate aminotransferase 52U lL
Calcium Normal
nancy for lower extremity swelling, proteinuria, and elevated
C-reactive protein Normal
blood pressure. Systemic lupus erythematosus was diagnosed Ferritin Elevated
last year. Her disease has been well controlled, with stable Transferrin saturation Elevated
laboratory values and no recent clinical evidence of disease
activity. Her only medication is hydroxychloroquine. Radiograph of both hands is shown.
On physical examination, blood pressure is 152/
90 mm Hg, and pulse rate is 80/min. Facial swelling, bilat-
eral lower extremity edema, swelling of both hands, and
tenderness over the metacarpophalangeal joints are pres-
ent. She has a gravid abdomen with normal fetal heart
tones.
Iaboratory studies:
8 Weeks Ago Current
Platelet count Normal 85,000/pL (85 x
t}e tL)
Alanine Normal Normal
aminotransferase
Aspartate Normal Normal
aminotransferase
Serum urate 4.5. mg/dl
(0.30 mmoliL)
Anti-double 50 250
stranded DNA
antibodies
C3 complement 85 mg/dl 60 mg/dl
(8so mg/L) (600 mg/L)
C4 complement 16 mg/dl 4mgldL (aO mg/L) Which of the following is the most appropriate diagnostic
(160 mg/L) test to perform next?
Urinalysis Normal 3+ protein; no (A) HFEgenetesting
erythrocytes; no (B) Insulin-like growth factor 1
leuko€ytes; no casts
(C) Parathyroidhormone
Protein-creatinine 50mglg 32Omglg
ratio (D) Rheumatoid factor

121
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Answers and Critiques
Item 1 Answer: A Item
Educational Objective: Treat mucocutaneous
ulcerations in Behqet syndrome with apremilast.
The most appropriate treatment is apremilast (Option A).
Behqet syndrome is a systemic vasculitis characterized by
recurrent oral aphthae. Other manifestations include gen,
ital aphthae, ocular disease, skin lesions, gastrointestinal
involvement, neurologic disease, vascular disease, and
arthritis. The treatment of oral and genital ulcers is guided by
the severity of symptoms and the presence of other disease
manifestations. This patient's disease does not seem to be
responding adequately to colchicine, which is an appropriate
flrst line therapy for mucocutaneous ulcerations. Hence, an
alternate or additional treatment should be tried. Apremilast
is an oral phosphodiesterase 4 inhibitor approved for treat
ment of psoriasis, psoriatic arthritis, and prevention of oral
ulcers in Behget syndrome. It is a reasonable alternative to
colchicine as a glucocorticoid-sparing agent for patients
with recurrent oral ulcers. Apremilast must be started at a
low dose and uptitrated over a few days to achieve a main
tenance dosage of 30 mg twice daily. Clinical trial data also
suggest a positive impact on genital ulcers, with a trend
toward improvement, but the studies were not powered to
assess this outcome. Apremilast is usually well tolerated but
is associated with adverse events, such as diarrhea, nausea,
and headache. It should be used cautiously in patients with
depression. Systemic glucocorticoids in tapering doses can
be used in patients who are refractory to colchicine and
apremilast. However, if the patient requires continued sys
temic glucocorlicoid therapy, azathioprine. thalidomide, or
tumor necrosis factor inhibitors are most appropriate.
Ixekizumab (Option B) is an interleukin-l7a inhibitor
approved for psoriasis, psoriatic arthritis, and ankylosing spon-
dylitis. It has not been studied for or shown to be eflective in
treating mucocutaneous manifestations of Behqet syndrome.
There are no data on use of leflunomide (Option C) in
the treatment of mucocutaneous manifestations of Behget
syndrome.
Mycophenolate mofetil (Option D) is not effective in
the treatment of mucocutaneous manifestations of Behget
syndrome and should not be used unless the patient has
tried and not responded to other agents.
XEY POIT{I
. Apremilast is a reasonable alternative to colchicine as
a glucocorticoid-sparing agent for recurrent oral
ulcers in Behqet syndrome.
Bibliography
Hatemi C, Christensen R, Bang D. et al. 2018 update ofthe EULAR recom
menditions fbr the management of Behqet's syndrome. Ann Rheum Dis.
2018;77:8o8 gtA. IPMlD, 296259681
2 Answer: B
Educational Objective: Treat familial Mediterranean fever.
The most appropriate treatment is colchicine (Option B).
Autoinflammatory syndromes are monogenic diseases that
result in periodic episodes of system inflammation. This
patient demonstrates multiple episodes of a systemic inflam-
matory syndrome characterized by fever, abdominal pain, Ut
(t,
rash, and arthritis, each lasting only several days. This constel ET
lation is characteristic of familial Mediterranean f'ever (FMF),
a disease driven by several mutations in the MEFV gene. tJ
.C,
This gene encodes pyrin, a protein important to the pro
duction and/or overproduction of interleukin 1B. Although C,
vl
the genetics continue to be studied, from a clinical point of (l,
view the disease is most commonly found in Jewish, Arab,
Ul
and Turkish populations and follows an autosomal recessive =
pattern. Other symptoms may include other forms of serositis,
including pericarditis. During episodes, inflammatory mark
ers are elevated; in between episodes the physical examina
tion and laboratory results may be normal. Diagnosis is made
clinically and can be confirmed definitively in most patients
through genetic testing. One long term consequence of the
episodic inflammation of FMF is amyloidosis, including of the
kidneysr this patient's low level proteinuria may be an early
manifestation. Other autoinflammatory syndrornes are rarer
and have similar but nonidentical features that allow them to
be distinguished from FMF. First-line treatment oIFMF is lile
long daily prophylaxis u,'ith colchicine. which in most cases
prevents attacks, prevents renal amyloidosis, and can inhibit
neutrophils and suppress interleukin 1 B generation.
Canakinumab (Option A) is a monoclonal antibody to
interleukin-lB that has been reported to successfully treat
patients with FMF, including those in whom colchicine has
failed. However, canakinumab is expensive and immuno
suppressive and has not been FDA approved for FMF treat
ment. Given the long experience with colchicine and its
efficacy, canakinumab should be reserved for patients with
FMF in whom colchicine has failed or is not tolerated.
NSAIDs, such as indomethacin (Option C), may alle-
viate symptoms during FMF attacks but do not address the
underlying mechanisms of FMD and are not appropriate
preventive or long term therapy.
Glucocorticoids. such as prednisone (Option D). n.ray
decrease the duration of attacks but also increase their fre
quency. Thus, they are not appropriate for long-term or
preventive FMF therapy.
xtY P0l1lr5
. Familial Mediterranean fever is a systemic inflamma
tory syndrome characterized by fever, abdominal pain,
rash, and arthritis, each lasting only several days.
(Continued)
123

Answers and Critiques
l(EY P0lllTS (confnrcd)
r This patient's presentation is not compatible with SLE.
First-line treatment of familial Mediterranean fever is
lifelong daily prophylaxis with colchicine, which in
most cases prevents attacks, prevents renal amyloido-
sis, and can inhibit neutrophils and suppress
interleukin-1 p generation.
Bibliography
Georgin-Lavialle S, Ducharme-Benard S, Sarrabay G, et al. Systemic autoin
flammatory diseases: Clinical state of the art. Best Pract Res Clin
Rheumatol. 2020r34:101529. IPMID: 32546426]
TA
Item 3 Answer: B
(D
= Ed ucati o na I O bjective : Diagnose psoriatic arthritis.
UI
o,
The most likely diagnosis is psoriatic arthritis (PsA) (Option
CL
B). Five clinical subtypes of psoriatic arthritis, which often
n overlap, are recognized: symmetric polyarthritis, asym-
llg metric oligoarthritis, distal interphalangeal-predominant
(D disease, spondyloarthritis, and arthritis mutilans. Enthesi-
ta
tis, tenosynovitis, and dactylitis often occur. Dactylitis is
found in 40'X, to 50% of patients with PsA and should
always prompt consideration of a spondyloarthropathy.
This patient has a classic distribution for PsA. The distal
interphalangeal joints and an entire digit are involved (i.e.,
dactylitis), with sparing of other digits. This patient has evi-
dence of limited psoriasis, but the extent of psoriatic skin
involvement may not correlate with the extent of arthritis.
In patients with PsA, affected peripheral joints sometimes
take on a purplish discoloration due to hypervascularit5r.
The Classification Criteria for Psoriatic Arthritis (CASPAR)
include evidence of psoriasis (current, past, and family
history in first or second degree relatives), nail dystrophy,
dactylitis (current or past), radiographic flndings showing
new bone formation, and a negative rheumatoid factor
result. Each of these is assigned 1 point except for current
psoriasis, which is assigned 2 points. These criteria are
91% sensitive and 98% speciflc for the diagnosis of PsA if
3 or more points are present. This patient's score is greater
than 3.
This patient's symptoms are inflammatory making
osteoarthritis (Option A) unlikely despite involvement of
the distal interphalangeal joints. In addition, osteoarthritis
does not cause dactylitis.
Rheumatoid arthritis can be seronegative (Option C)
in 15% to 2O"1, of patients classifled as having the disease,
but rheumatoid arthritis is typically a symmetric arthri-
tis and does not affect all of the joints in an entire digit,
including the distal interphalangeal joint, as seen in this
patient.
Joints are affected in 90'1, of patients with systemic
lupus erythematosus (SLE) (Option D). The most common
involvement is polyarthralgia, with lrank arthritis occur-
ring in 40%. Typical distribution involves the small periph
eral joints. Dactylitis is not seen in SLE. Most patients with
SLE and arthritis also have characteristic mucocutaneous
124
i
:
!
flndings, including malar rash, discoid rash, and alopecia.
I
IEY POITTS
o Five clinical subtypes of psoriatic arthritis, which may ;
overlap, are recognized: symmetric polyarthritis,
:
i
asymmetric oligoarthritis, distal interphalangeal- :
predominant disease, spondyloarthritis, and arthritis !
I
mutilans.
o Enthesitis, tenosynovitis, and dactylitis often occur in
psoriatic arthritis; dactylitis is found in 40"/,' to 50% of
patients and should always prompt consideration of a
spondyloarthropathy.
Bibliography
Ritchlin CI, Colbert RA, Gladman DD. Psoriatic arthritis. N Engl j Med.
2017 ;376:957 -97O. [PMID: 28273019] doi:10.1056 NEJMral505557
.i
Item 4 Answer: A
Educational Objective: Diagnose granulomatosis with
polyangiitis.
The most appropriate diagnostic test to perfbrnr next is kid
ney biopsy (Option A). lhis patient's presentation is highly
suspicious lor granulomatosis r.r,ith polyangiitis (GPA).
The disease course began with nonspecific symptoms but
progressed to involve the upper and lower ainvays, eyes.
skin. and kidneys. lhe skin rash. glomerulonephritis.
and nodular lung disease are consistent with a vasculitic
process. In GPA lvith kidney involvement. kidney biopsy
is expected to show pathognomonic findings of pauci
imnrune crescentic necrotizing giomerulonephritis.
Whenever possible. it is important to confirm a diagnosis
of GPA r,vith tissue pathology before beginning treatment.
given the many risks that accompanv intensive immuno
suppression; prognostic data can help guide therapy as
well. Guideline directed initial therapy fbr active. severe
GPA is either intravenous pulse glucocorticoids or high-
dose oral glucocorticoids plus rituximab (prelerred) or
cyclophosphamide. If the diagnosis is clear and urgent
treatment is necessary. however, biopsy may be bl,passed
(in this case. for example, if the ANCA panel u'ere positive
and the patient \ rere more acutely ill).
biopsy (Option B). although less invasive than
Sir.rus
kidney or lung biopsy, has poor sensitiviry- and therefore
shoulcl not be performed ur.rless the diagnosis is in question
and no other tissue is alailable.
Althor.rgh skin biopsl, (Option C) should shon abnor-
malities collsistent rvith a small vessel vasculitis. the find
ings lvould be nonspecific.
Thoracoscopic lung biopsy (Option D) might show vas
culitic changes consistent with GPA. but this procedure
has greater morbidiry than kidnel, biopsli particularly in
a patient u'ith tenuous respiratory status. Transbronchial
biopsy is more benign thar.r open lung biopsy but is generally
not perfbrmed. given its low sensitivity (about l0'7,).

XEY POIl{TS
o It is important to confirm a diagnosis of granulomato-
sis with polyangiitis by using tissue pathologr before
beginning treatment, given the many risks that
accompany intensive i m munosuppression.
o Standard therapy for granulomatosis with polyangiitis
includes high-dose glucocorticoids plus rituximab
(preferred) or cyclophosphamide.
Bibliography
Geetha D. Jefferson JA. ANCA-associated vasculitis: core curriculum 2020.
Am J Kidney Dis. 2020;75:124 137. [PMID: 3135$11] doi:10.1053/j.ajkd.
2019.0,1.031
Item 5 Answer: C
Ed u catio n a I O biective : Evaluate for spondyloarthritis
with HIA-B27 testing.
The most appropriate diagnostic test to perform next is HLA
B27 antigen testing (Option C). The test assesses for the
presence ofthe HLA B27 antigen on the surface ofcells and
not the presence of the actual gene. This patient has inflam-
matory low back pain manifesting as night pain, morning
stiffness, and pain that improves with activity. He also has
enthesitis of the Achilles tendon, which is seen in spon
dyloarthritis. A positive HLA P.27 antigen test result in the
setting of a compelling clinical picture conflrms the diagno
sis of axial spondyloarthritis. If the HLA,-827 antigen result
is negative, MRI of the pelvis to evaluate for sacroiliac joint
inflammation is warranted. In a patient with inflammatory
low back pain and a positive HLA-827 antigen result but no
other features of spondyloarthritis, MRI is also indicated. In
general, HLA B27 antigen testing adds probabilistic certainty
to the evaluation oflow back pain. Ifdiagnostic certainty is
already high (i.e., the patient has many features of spon-
dyloarthritis), then a positive test result adds little to the
posttest probability; if there are few features of spondyloar
thritis, then a positive HLA-827 antigen result is helpful.
An anteroposterior radiographic view of the pelvis is
useful and is the recommended view for detecting sacro-
iliitis. However, plain radiographs may not show evidence of
sacroiliitis for 1 to 2 years after symptoms develop. Thus, if
the anteroposterior radiograph is unremarkable, additional
views (Option A) are not needed.
In cases of suspected sacroiliitis, low dose CT (Option
B) is useful to clarify ambiguous changes seen on plain
radiographs, whereas MRI (Option D) is more sensitive and
can identiflz sacroiliac inflammation even in the absence of
radiographic changes. Neither imaging test is indicated at
this time, pending results of HIA B27 testing.
Rheumatoid arthritis is an inflammatory polyarthritis
with a predilection lor the small joints of the hands and feet.
Rheumatoid arthritis can affect the cervical spine but not the
lumbar spine or sacroiliac joints. This patient has no clinical
flndings that suggest rheumatoid arthritis; thus, serologic
testing (Option E) is not indicated.
Answers and Cr itiques
I(EY POITIS
o A positive HLA-P.27 test result in the setting of a com-
pelling clinical picture confirms the diagnosis of axial
spondyloarthritis.
. If a patient has many features of spondyloarthritis,
then a positive HLA-827 result adds little to the post-
test probability; ifthere are few features ofspondy-
loarthritis, then a positive HLA-B27 result is helpful.
Bibliography
Danve A, Deodhar A. Axial spondyk)arthritis in the USA: diagnostic chal
lenges and missed opportunities. Clin Rheumatol. 20l9rll8:625 634 U!
IPMID: 305885551 doi:10.1007/slO067 O18 4397 3 o
ET
Item 6 Answer: B (J
E'
Educational Objective: Evaluate a patient by using
tu
antinuclear antibody testing. Ut
(l,
The most appropriate laboratory test to perform next is anti-
ta
=
nuclearantibody (ANA) measurement (Option B). This patient E
has speciflc features of autoimmune disease, inflan.rmatory
polyarthritis, and photosensitive facial rash, along with fever (a
nonspecific systemic feature). ANA is directed against nuclear
antigens and associated with systemic lupus erythematosus
(SLE). Up to one third of the healthy population has a low
titer (1:40-1:80) for ANA, and up to 5'7, has a titer of 1:160 or
higher. ANA can also be seen in other autoimmune condi
tions, infection, and malignancy or may be drug induced. An
isolated positive ANA result with nonspecific symptoms and
normal clinical examination does not establish the diagnosis of
a connective tissue disease. In a patient with flndings strongly
suggesting an underlying rheumatologic disease, such as this
patient with features of SLE, ANA testing is appropriate. ANA
testing should be done befbre any subserolog, testing. Il the
ANA test result is positive, then specific subserologies are indi
cated on the basis ofthe clinical scenario. Ifthe ANA test result
is negative, then the ANA subserologic findings are typically
negative. Therefore, if the initial ANA result is negative, then
subserologr testing is not indicated.
ANA specificity or subserologr testing (i.e., testing lor
antibodies to specific nuclear components, such as DNA or
centromeres) should be reserved for patients with a positive
ANA result and a clinical syndrome suggesting an underly
ing rheumatologic disease. lf the ANA result is positive and
clinical flndings suggest a specific autoimmune inflamma
tory disease, then subserolos/ testing is appropriate. ln this
patient, if the ANA result is positive, SLE specific autoan
tibodies (anti-double stranded DNA [Option A], anti Ro/
SSA and anti LalSSB antibodies [Option C], anti Smith
[Option D], anti Ul ribonucleoprotein [Option E]) should
be obtained to further characterize the disease. Anti double
stranded DNA antibodies are 95'1, specific for SLE and
approximately 50'7, to 60'1, sensitive. They are typically found
in more severe disease, especially kidney disease. Antibody
levels commonly follow disease activity and are useful to
monitor during therapy. Anti-Smith antibodies are the most
125
 Answers and Critiques
speciflc for SLE (99%) but have low sensitivity. Antibody
levels do not correlate with disease activity. Anti-Ul-
ribonucleoprotein antibodies (particularly high titers) are
sensitive for mixed connective tissue disease. Antibody levels
do not correlate with disease activity. In patients with SLE,
anti-Ro/SSA and anti-La/SSB antibodies are associated with
photosensitive rash. In addition, offspring of mothers who
are positive for anti-Ro/SSA or anti LalSSB are at increased
risk for neonatal lupus erythematosus (rash and congenital
heart block). However, none of these antibodies should be
obtained until the ANA test result is conflrmed positive.
ltY PottT
D of its inhibition of serotonin and norepinephrine reuptake.
(a . Antinuclear antibody (ANA) specificity or subserologz
testing (testing for antibodies to specific nuclear com-
=
.D
ponents) should be reserved for patients with a posi-
IA
o, tive ANA result and a clinical syndrome suggesting an
underlying connective tissue disease.
n inflammatory agents. Trials consisting of therapeutic doses of
.st Bibliography
(D
Mulhearn B. Tansley SL. McHugh NJ. Autoantibodies in connecti\e tissue
disease. Best Pract Res Clin Rheumatol. 2020r3.1:101.162. IPMID,
UI
318,180551 doi: t0. 1016, j.berh.2019.101.162
Item 7 Answer: E
Educationa I Objective: Treat fibromyalgia with
pregabalin.
The most appropriate additional treatment is pregabalin
(Option E). Optimal management of fibromyalgia requires a
holistic approach, including education. exercise, and psycho-
social support. Pharmacotherapy is often warranted, although
nonpharmacologic measures remain a cornerstone of treat-
ment. Pregabalin, an antiepileptic drug. improves quality of
life and decreases pain. It is one of only a few medications that
are FDA approved for treating flbromyalgia. The medication
should be initiated at low doses at night (i.e.. 50 or 75 mg at
bedtime) and slowly titrated as tolerated up to a maximum
dosage of 225 mg t\,vice daily. Common adverse effects include
drowsiness, dizziness, and peripheral edema. Weight gain of
7% or more is seen in nearly 10'/. of patients. Off label use
of gabapentin. another antiepileptic drug, has demonstrated
effectiveness in a randomized controlled trial and is frequently
used for this disorder in dosages up to 600 mg twice daily.
Prescribing duloxetine (Option A) would be appro
priate in a patient with flbromyalgia. particularly one with
depression, but not in one receiving escitalopram. Adding a
serotonin-norepinephrine reuptake inhibitor atop a selec
tive serotonin reuptake inhibitor would pose an unaccept
able risk for serotonin syndrome. Duloxetine is otherwise
an appropriate medication to use in Iibromyalgia, at a dos
age of up to 60 mg daily; consultation with the patient's
psychiatrist would be essential if duloxetine needed to be
considered. Other medications that would be appropriate
for a patient not already taking a selective serotonin reuptake
inhibitor would include milnacipran and off label use of
tricyclic antidepressants (amitriptyline and nortriptyline).
126
Medical cannabis (Option B) is increasingly available for
use in patients with chronic pain. Many states have passed
laws legalizing the use of cannabis or allort'ing its use for
certain medical conditions, although it is still classifled by
the U.S. Drug Enfbrcement Administration as a schedule I
agent. Current data on the effectiveness of medical cannabis
for chronic pain are characterized by signiflcant heterogene
ity in both patient populations and cannabis preparations.
There are no high quality data on the efficacy of medical
cannabis speciflcally for fi bromyalgia.
Although tramadol may be beneficial in moderating
symptoms in patients with fibromyalgia, possibly because
other opioids, such as oxycodone (Option C). have no evi
dence of efficacy. In patients with flbrom),algia. the use of
opioids other than tramadol is more likely to result in harm
than in beneflt.
Patients with flbromyalgia do not respond to anti-
naproxen, ibuprofen, and prednisone (Option D) have found
each to be equivalent to placebo in randomized clinical trials.
These agents are not indicated in patients with fibromyalgia.
xEY ?OTXTS
. FDA approved medications for fibromyalgia include
pregabalin, duloxetine, and milnacipran.
o Patients with fibromyalgia do not respond to anti
inflammatory drugs, including NSAIDs and glucocor
ticoids. and do not respond to opioids, with the
exception of tramadol.
Bibliography
Nlacfarlane (iJ. Kronisch C. Dean L[:. et al. F-ULAR revised recommendations
fbr the management of fibromlalgia. i\nn Rheum Dis. 2017:76:318 :128.
[P1\,1 I D: 27:]7781 5l doi : I 0. I I i]6 annrheumdis 2J16 2097 21
Item 8 Answer: B
Educational Obiective: Diagnose diffuse idiopathic
skeletal hyperostosis.
The most likely diagnosis is diffuse idiopathic skeletal hyperos
tosis (DISH) (Option B). DISH is a noninflammatory condition
that occasionally is associated w,ith elevated inflammatory
markers and causes calcification and ossification of spinal
ligaments (especially the anterior longitudinal ligament) and
entheses (tendon and ligament attachments to bone). This
leads to pain and stiffness as well as reduced range of motion
of the spine. DISH is more common in men aged 45 years and
older and most often involves the thoracic spine. DISH does
not affect the sacroiliac joints. This patient presents u,ith clas
sic epidemiologic features: he is an older man. he has typical
symptoms and findings of DISH consisting of back pain and
stiffness without sacroiliac pain. and his radiograph shows
the distinctive finding of flowing linear calcification and ossi
fication along the anterolateral aspects of the vertebral bodies
(Figure [top of next pagel). These distinctive radiographic
findings are most easily visualized on lateral images.
I

Answers and Critiques

t
I

Item 9 Answer: E
Educational Objective: Advise smoking cessation in a
I
patient at risk for rheumatoid arthritis.

The intervention most likely to reduce this patient's risk for

: developing rheumatoid arthritis is counseling for smoking ces-
sation (Option E). One of the most provocative environmental
: factors for the development of rheumatoid arthritis is smoking.
i A dose dependent relationship exists between smoking and
I

the development of seropositive rheumatoid arthritis. Smoking

can lead to lung inflammation, which activates such enzymes
I

as peptidylarginine deiminase, which deaminates arginine to

fbrm citrullinated peptides. HtA D alleles code for the shared UI
epitope. The shared epitope, a five amino acid sequence, pref-
o
erentially binds and presents citrullinated peptide antigens. ET

This leads to the production of anti-cyclic citrullinated peptide

rr,
antibodies that could initiate inflammation by fixing comple- E'
ment in the tissues. Patients who smoke are at increased risk for tg
rheumatoid arthritis, particularly those with a tamily history of la
rheumatoid arthritis, and should be counseled about smoking o
Arkylosing spondylitis (AS) (Option A) is an inflamma-
cessation. The risk for RA increases with an increasing number
tory arthritis ofthe spine, usually presenting as chronic back
ofsmoking pack years, and the risk decreases as the interval of
cUt=
pain and stiflness, typically before age 45 years. Radiographic
smoking cessation increases. Combining behavioral counseling
flndings include squaring of the vertebral bodies due to ante
with pharmacotherapy is more effective than either modality
rior and posterior inflammation, bone erosions, and formation
alone in achieving long term smoking abstinence.
of syndesmophytes, which are typically thin and vertically ori
A reduced risk for rheumatoid arthritis has been
ented and lead to anlrylosis. Involvement of the sacroiliac joints
associated with moderate alcohol consumption in some
is a hallmark of AS, and affected patients have elevated serum
observational studies. There is no reason for this patient to
inflammatory markers. This patient does not have the clinical,
discontinue alcohol consumption (Option A) to reduce her
radiographic, or laboratory findings characteristic ofAS.
risk for rheumatoid arthritis.
Calcium pyrophosphate deposition disease (Option C)
This patient should not be counseled to discontinue her
can involve the spine and has been associated with spine
combined oral contraceptive pill (Option B). Observational
stiffness and pain, as well as cartilage calcification and bony
studies have detected either a reduced risk fbr rheumatoid
an$osis. However, thick, flowing osteophytes are not typ
arthritis or no impact on its development in patients taking
ical ofthis disease.
a combined oral contraceptive.
Spondylosis defbrmans (degenerative disk disease with
lncreasing physical activity (Option C) has been incon-
osteophl.te formation) (Option D) is an important disorder
sistently associated with a reduced risk for developing rheu
to be considered in the differential diagnosis of DISH. This
matoid arthritis. There are other reasons to recommend
condition is usually seen in patients older than 55 years.
increased physical activity to this patient, but this recom
Although the spurs in the cervical and lumbar spine can
mendation should not be based on the possibility of reduc
resemble those seen in DISH. involvement of the anterior
ing the risk for rheumatoid arthritis.
longitudinal ligament in the thoracic spine characteristic of
Consumption of a Mediterranean diet (Option D) is not
DISH is not observed in spondylosis.
specifically shown to reduce the risk for rheumatoid arthri
xEY Potx?s tis. Higher intake of flsh may be associated with a lower risk
. Diffuse idiopathic skeletal hyperostosis is a nonin- for rheumatoid arthritis, but studies on this association are
flammatory condition that causes back pain and inconclusive, as are studies on the effect of red meat, coflee
consumption, and use of' antioxidants.
stiffness without sacroiliac pain, typically in men aged
45 years and older.
f,tY P0lft!,. .:.:..
o Diffuse idiopathic skeletal hyperostosis is associated
. Patients who smoke are at increased risk for rheuma-
with distinctive radiographic finding consisting of
a
toid arthritis, particularly those with a family history
flowing linear calcification and ossification along the
of rheumatoid arthritis, and should be counseled to
anterolateral aspects of the vertebral bodies.
stop smoking.

Bibliography
. Exercise, alcohol use, and dietary factors are not
Mader R, Verlaan JJ, Eshed l, et al. DifTuse idiopathic skeletal hyperostosis firmly associated with either increased or decreased
(DISH): where we are now and where to go next. RMD Open. 2017;3: risk for rheumatoid arthritis.
eOOO472. IPMID: 28955488] doi:10.1136/rmdopen 2017 000472

127
 Bibliography
Salliot C. Nguyen Y Boutron Ruault MC, et al. Environment and lifestyle:
their influence on the risk of RA. J Clin Med. 2020;9. IPMID: 32993091]
Item 10 Answer: B Item
Educational Objective: Diagnose amyopathic
dermatomyositis.
The most likely diagnosis is amyopathic dermatomyosi
tis (Option B). Some patients with dermatomyositis never
develop muscle involvement (amyopathic dermatomyositis) ;
these patients can be diagnosed with skin biopsy conflrma-
D tion of dermatomyositis in the setting of at least 6 months
(a without muscle involvement. A characteristic skin rash
E
.D should prompt consideration of dermatomyositis even with
UI normal muscle strength and a normal serum creatine kinase
o,
level. This patient has a typical photosensitive distribution
TL
rl of dermatomyositis rash on the face, including a probable
early heliotrope rash over the eyelids. He also has Gottron
4t papules on the elbows and knees. Skin biopsy would likely
.D show characteristic interface dermatitis. Further evaluation
U!
can include antibody and additional testing for subtle mus
cle inflammation, using electromyography or MRI, but even
if the results are normal, this patient should be treated for
dermatomyositis. Patients with amyopathic dermatomyo
sitis also have a high risk for interstitial lung disease and
cancer; screening for these conditions should also be part of
the initial evaluation.
Acute cutaneous lupus erythematosus (Option A) can
be difficult to distinguish clinically from dermatomyositis,
especially on the face, because it can present in the same
distribution and can have similar flndings on skin biopsy.
However, lupus is not likely to cause a heliotrope rash or
Gottron papules on the hands, elbows, and knees.
This patient's Gottron papules on the elbows and knees
can be difficult to distinguish from psoriasis (Option C)
by description or physical examination, but psoriasis is
less likely to cause the photosensitive rashes seen in this
patient.
Rosacea (Option D) is the most common cause of
red rash in a malar distribution in an adult. Rosacea is an
inflammatory skin condition that produces small pink pap
ules and pustules on the central face with a variety of speciflc
patterns. The erythema ol the cheeks can mimic the malar
rash of systemic lupus erythematosus or dermatomyositis
but would not be expected to cause skin changes on the
extremities.
(tY P0rxTs
o Some patients with dermatomyositis never develop
muscle involvement (amyopathic dermatomyositis)
and are diagnosed by using skin biopsy in the setting
of at least 6 months without muscle involvement.
o A characteristic skin rash should prompt considera-
tion of dermatomyositis even with normal muscle
strength and a normal serum creatine kinase level.
128
Bibliography
DeWane ME. Waldman R, Lu J. Dermatomyositis: clinical teatures and
pathogenesis. J Am Acad Dermatol. 2o2o;82:267 -281. IPMID: 312798081
11 Answer: B
Educational Objective: Diagnose inflammatory bowel
EI
disease in a patient with an$osing spondylitis.
The most likely diagnosis is inflammatory bo$'el disease
(lBD) (Option B). IBD occurs in up to 14'L of patients with
anl<11osing spondylitis (AS), a much higher rate than the
approximately 0.5'7, seen in the general population. Among
patients \\.ith AS who develop IBD. Crohn disease and ulcer
ati\€ colitis occur with equal frequencyl IBD in AS is slightll,
more common among men and occurs early in the course
ofAS. By 10 years ofAS, the risk lor IBD has returned to the
general population level. The bowel inflammation and gut
dysbiosis that are common in IBD may drive the inflam
mation in the spine, leading to AS. Clinical nranifestations
of IBD in patients with combined AS and IBD are similar tir
those in patients with IBD alone.
Celiac disease (Option A) is an immune mediated dis
ease that primarily affects the small intestine in response
to dietary gluten. It is one of the most common causes of
malabsorption. Celiac disease has no association u,ith AS
or other rheumatologic diseases. Although patients with
chronic diarrhea should be evaluated lor celiac disease. IBD
is a more likely diagnosis in a patient with AS.
Irritable bowel syndrome (lBS) (Option C) is a func
tional bor,tel disorder defined by the presence of abdominal
pain in association with defe'cation and, or a change in bolr,el
habits. The diagnosis of IBS requires symptoms ol recurrent
abdominal pain at least I day a u,eek fbr :l months, along
with at least two ol the fbllou,ing three additional crite
ria: pain related to defecation. change in stool fiequency
or change in stool consistenc'y This patient's pain is not
related to defecation. and her recent unintentional weight
loss makes IBS unlikell:
Small intestinal bacterial overgronth (SIBO) (Option D)
a is caused by various conditions. including impaired motility
strictures. or blind loops. Diagnosis requires t1.'pical symp
toms and a confirmatory test (usually breath testing). SIBO
is associated with systemic sclerosis but l.ras not been irssoci
ated with AS unless there is another predisposing condition.
XEY POIf,IS
o Inflammatory bowel disease occurs in patients with
ankylosing spondylitis at a much higher rate than in
the general population.
o Patients with ankylosing spondylitis who develop
abdominal pain, diarrhea, or a change in bowel habits
should be evaluated for inflammatory bowel disease.
Bibliography
Fragoulis GE, Liava C, Daoussis D, et al. Inflammatory bowel diseases and spon
dyloarthropathies: from pathogenesis to treatment. World J Gastroenterol.
2019;25:2162 2176. IPMID: 31143068] doi:10.3748/wjg.v2s.i18.2162
I
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Item 12 Answer: B
Educational Objective: Treat Lyme arthritis.
t The most appropriate treatment is doxycycline (Option B).
Although arthralgia and myalgia often occur at the earlier
t (CPP) crystal arthritis (pseudogout) (Option A). Acute CPP
stages of Lyme disease, Lyme arthritis is a late-stage manifes
i
tation. It is typically monoarticular, most commonly in the
I knee. It should be suspected in patients who may have had
L
untreated or incompletely treated Lyme disease, although
not all patients will have a history compatible with previous
Lyme disease. All patients with Lyme arthritis, however,
I
should have positive results on enzyme-linked immunosor
;
bent assay and Western blot confirmatory serologies; this is
the primary means of diagnosing Lyme arthritis, although a
:
I second enzyme immunoassay can be used as a confirmatory
test. In addition, Borrelia burgdorJ'ert DNA can be detected
by polymerase chain reaction in synovial fluid, but this test
t offers no advantage to serologic testing. Randomized con-
trolled trials have suggested that 90'1, of patients with Lyme
arthritis are eflectively treated with a 28-day course oforal
antibiotics. Doxycycline is the most widely recommended
I E
first choice in antibiotic treatment of Lyme arthritis. Treat-
ment with a 28-day course of amoxicillin is an alternative
flrst line therapy. For patients whose arthritis improves but
does not completely resolve, a second 28-day course of the
same antibiotic can be prescribed. For pregnant and lactat
ing women, tetracyclines are generally avoided in favor of a
p Iactam antibiotic.
Ceftriaxone (Option A) is unnecessary in most cases
of Lyme arthritis because patients generally respond to oral
antibiotics. Celtriaxone is not the first choice for treatment
of Lyme arthritis unless concomitant neurologic symptoms
are present. It may be given for moderate to severe persistent
arthritis after the failure of oral antibiotics.
A small subset of patients may have persistent arthri
tis that suggests a reactive arthritis, which may respond
to immunosuppressive therapy. For moderate to severe
persistent symptoms, treatment with hydroxychloroquine
(Option C) or methotrexate (Option D) may be appropriate,
but only after failure of treatment with oral and intravenous
antibiotics.
XEY POIXTS
. All patients with Lyme arthritis should have positive
results on enzyme linked immunosorbent assay and
Western blot confirmatory serologies; this is the
primary means of diagnosing Lyme arthritis, although
a second enzyme immunoassay can be used as a
conflrmatory test.
. Ninety percent of patients with Lyme arthritis are
effectively treated with a 28-day course of oral
doxycycline or amoxicillin.
Bibliography
ArvikarSL, Steere AC. Diagnosis and treatment of Lyme arthritis. Infect Dis
Clin North Am. 2O15;29:269-80. IPMID: 259992231 doi:10.1016/j.idc.2015.
02.004
Answers and Critiques
Item 13 Answer: A
Educationa I Objective: Diagnose acute calcium
tr
pyrophosphate crystal arthritis.
'lhe most likely diagnosis is acute calcium pyrophosphate
crystirl arthritis is an episoclic nrthritis that most commonly
occurs in older women. tt usually develops over several days
and may last fbr weeks. The knee and wrists are common
sites. 'lhe pre'sentation is usually inflammatory with pain,
swellir.rg. and warmth <-rf the inv'olved joint. Systernic markers
of ir.rf lammation may be elevated. such as tl-re erythrocyte sed
imentation rate in this patient. Plain radiographs, like the one l,t
(l,
shown fbr this patient, may demonstrate cht.rndrocaicinosis.
ET
Chonclrocalcinosis is seen as a thin white Iine that tracks below
the surface layer ol the cartilage because it represents CPP (,
deposition within the cartilage. A definitive diagnosis n'ould -t
include aspiration of the joint fluid and the clemonstration of ag
CPP crystals, which are weakly positively biretiingent (blue Ul
when parallel to and yellow wher.r perpendicular kr the polar o
izing axis of'an optical filter) and classically rhon.rboid shaped. vt
=
(lout flare (Option B) is a less likely diagnosis given the
involvement of the knee without current or prior lypical
joint i nvolvement (first metatarsophalangeal joi nt, ibrefeet.
ankles, ancl flngers). The ll week duration of the previ-
ous episodes is longer than that usually seen with gout
(t-z weeks). The normal serum urate level also makes gout
unlikely, although serum urate levels may occasionally lall
into the normal range during an acute flare. Monosodiun.r
urate crystals are needle shaped and negatively birefrin
gent uncler polarized light; they appear lellow when par
allel ar.rd blue when perpendicular to the polarizing a.xis.
lnfectious arthritis (Option C) is unlikely because the
patient has no fever or other systemic sympt(nns afler 10
days, as well as a normal complete biood count. IIer history
of similar episodes also argues against in{ection as the cause.
Nevertheless. a1l patients with acute monoiirticular arthritis
should undergo synovial fluid analysis that inclucles a Gram
stain anct culture to help cxclude inf'ectious arthritis.
Ill.rcumatoid arlhritis (Option D) is not a likcly diag-
nosis because the patient has monoarticular knee afihritis,
without the symmetric joint involvement of hancls. wrists, or
feet typical of rheumatoid arlhritis. Finally, chonclrocalcino-
sis is not a feature of rheumatoid arthritis.
XEV POI]ITI
. Acute calcium pyrophosphate cr).stal arthdtis (pszudogout)
is characterized by the sudden onset of pain, warmth, ten-
demess, and swelling of the affected joint, usually a knee
or wrist; flares are typicaUy longer than those ofgout.
. Definitive diagnosis of calcium pyrophosphate crystal
arthritis would include aspiration of the joint fluid and
demonstration of calcium plrophosphate crystals,
which are weakly positively birefringent (blue when
parallel to and yellow when perpendicular to the polar
izing axis of an optical filter) and rhomboid-shaped.
129
 Answers and Critiques
Bibliography
Rosenthal AK. Ryan l.M. Calcium pyrophosphate deposition disease. N Engl
J Med. 2016;37.1:2575 tt.1. IPMID: 27355536] doi:10.1056'NEJMral511117
Item 14 Answer: A
Ed ucati o na I O bjective : Treat ankylosing spondylitis with
a tumor necrosis factor inhibitor.
The most appropriate next treatment is etanercept (Option
A). This patient has a clear diagnosis of ankylosing spon-
dylitis (AS). and first line therapy with NSAIDs has failed.
The American College of Rheumatolory (ACR) recommends
the use of a tumor necrosis factor (TNF) inhibitor after fail
la ure of a trial of at least two NSAIDs for 2 tri 4 weeks each.
(D
= or if NSAIDs cannot be tolerated. TNF inhibitors. such as
UI etanercept (a fusion protein), adalimumab, or infliximab
q,
(monoclonal antibodies), can be used. The selection may
CL depend on the presence of comorbid disease, such as uve
n itis or inflammatory bowel disease, where the monoclonal
lt antibodies would be more appropriate. 'fNF inhibitors have
been shown to be disease modiffing in AS. Interleukin-l7
rD
UI inhibitors, such as secukinumab, could be used in patients
in whom a TNF inhibitor fails or in whom a TNF inhibitor
may be contraindicated. The ACR conditionally recommends
TNF inhibitors over interleukin 17 inhibitors in patients in
whom NSAIDs fail or who cannot tolerate NSAIDs.
Nonbiologic disease-modifying antirheumatic drugs,
such as methotrexate (Option B) or sulfasalazine (Option
D), have no ellicacy in axial disease and limited efflcacy in
peripheral disease. Treatment with sulfasalazine is recom
mended primarily fbr patients with prominent peripheral
arthritis and few or no axial skeleton symptoms and in these
patients, it may be more eflective than methotrexate. How
ever, a TNF inhibitor may be the best option fbr these patients.
The ACR strongly recommend against treatment with
systemic glucocorticoids, such as prednisone (Option C).
Glucocorticoids have numerous adverse efl'ects. which are
more likely to occur with higher doses and longer treatment,
and lower doses are not as efficacious as TNF inhibitors.
XEY POIXI
o Tumor necrosis factor inhibitors are useful in patients
with ankylosing spondylitis in whom NSAIDs have
failed or cannot be tolerated.
Bibliography
Ward MM, Deodhar A, (lensler LS, et al. 2019 update of'the American College
ol Rheumatolos//Spondylitis Association ol America/Spondyloarthritis
Research and Treatment Network Recommendations fi)r the treatment of
ankylosing spondylitis and nonradiographic axial spondyloarthritis.
Arthritis Rheunlatol. 2019:71:1599-1613. IPMID: l]t+3OO:lOl doi:10.1002
irrt.41042
tr Item 15 Answer: A
Educational Objective: Treat scleroderma renal crisis.
The most appropriate intravenous treatment is captopril
(Option A). This patient has hypertensive crisis due to
130
underll-ing sl,stemic sclerosis, which is best treated rvith
an ACE inhibitor. Captopril in particular is usefirl in this
situation because it has a relatively short half lif'e and
can be titrated rapidly to control blood pressure. Sclero
derma renal crisis can occur in Iimited or dilluse cutaneous
systemic sclerosis but is more common in dilluse dis
ease. Risk factors ir.rclude recent onset of sl'sternic sclerosis
((4 years). diffuse skin discase, presence olanti RNA pol1,
nrerase III antibodies, and recent use of glucocorticoids.
'lhe pathophl,'siology is thought to be related to endothe
lial injury leading to vascular constriction. intirnal thick
ening. ar-rd fibrin deposition. 'uvith endothelin I plaf ing
an important role in tl.ris process. Also inrportant in the
pathophl-siology is activatior.r of the renin angiotensin
irldosterone s),stemr interrupting this pathual'hrs been a ke1'
to therap)'. Manifestations ol scleroderma renal crisis are
those seen in patients with hypertensive emergenc)'. such
as headache, encephalopathy, retinopath)'. acute kidney
injury'. and heart tailure. Anemia. thrombocl'topenia, and
proteinuria are comnlon laboratory features. Evidence of
rnicroangiopathic hernoll'tic anemia u'ith schistoc)'tes on
the peripherai blood smear is a clue to the diagnosis. ACE
inhibitors are disease modiff ing agents ftrr this pcltentialll'
Iirtal complication, regardless of the serum creatinine level.
Patients may need telnporary diirlysis. and kidney function
may improve during therapy' fbr up to 2.1 months after
presentation. Prophylactic use of'ACE inhibitors does not
prevent scleroderma renal crisis and n.ra1' lead to poorer
renal outcomes.
Immunosuppressior.r has no role in modiff ing the
course of scleroderma renal crisis. so neither intravenous
cyclophosphamide (Option B) nor intravenous methylpred
nisolone (Option C) is indicated. Recent use ot glucocor
ticoids is a risk factor fbr scleroderma renal crisisr tl.tus.
glucocorticoids should be avoided.
Intravenous rnetoprolol (Option D) does not address
the pathophl,siolory of scleroderma renal crisis. p Blockers
are generally not first line therapy ftir rnost causes of'
hl,pertensive emergencies other than episcldes associ
ated with eclampsiai preeclampsia, acute coronary syn
drome. and aortic dissection: in these cases, labetalol or
a short acting agent such as esmolol is typically pref'erred
to metoprolol.
f,EY POIilTS
. Patients with scleroderma renal crisis may exhibit
anemia, thrombocytopenia, proteinuria, and schisto-
cytes on the peripheral blood smear.
o ACE inhibitors (typically captopril) can be lifesaving
in patients with scleroderma renal crisis, and dosages
should be titrated to control blood pressure regardless
of serum creatinine level.
Bibliography
Zanatta E, Polito P, lavaro M, et al.'lherapy ofscleroderma renal crisis: state
ot the art. Autoimmun Rev 2018;17:882-889. [PMID: 30005860] doi:
10. l016ii.autrev2018.03.0l2
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t Answers and Cr i!iqg9_s
1
tr Item 16 Answer: D
Educational Objective: Treat giant cell arteritis with
glucocorticoid-sparing agent.
lhe most appropriate aclditional lreatment is tocilizumab
(Option D). Ciant cell arteritis (GCA) is a medical enrer
ger.rcy that requires inrmediate therap1,. the risk fbr sr-rdden
and irreversible loss of vision is imminent in the absence
:
ol appropriate treatnlerlt. Synrptoms ancl inflamrlabry
nrarkers usualll,' respond rapiclll to gluc<lc'orticoids. Hort,
ever. glucocorticoids ha'n'e nrany adverse eflects, ancl this
patient will henefit Iron.r the adclition rit a glucocorticoid-
sparing agcnt. Generally acceptccl indicalior.rs for a gluco-
corticoid sparing agent include the presence of comorbid
cliseases that are negatively afiected by glucocorticoids,
development of glucocorticoici related adverse efI'ects, and
prolonged neecl lbr treiltnlent. 'lhis patient nreets all indi-
cations firr a glucocrlrticoid sparing ager.rt. Tocilizumab, an
interleukin 6 blocker, is highly eflective for the treatnlent
of' GCA n,hen administered during glucocurticoid tapering
or :rs monotherapy fbllor,r,ing discontinuation of' gluco
corticoids. 'lhe 2021 American College of Rheumatologr
guidelines make a conditional recomme'nclation fbr gluco
corticoids r,r,ith tocilizumab over oral glucocorticoids alone
in patients u,ith newly diagnosccl (iCA.
Cyclophosphamide (Option A) is an immunosuplrres.-
sive agent used to treat systelnic virsculitis, such as gran
ulomatosis poll,ar.rgiitis. Its use and ellectiveness in
patients with "t'ith
GCA are unproven, consistir.rg m:rinly of
l f'ew uncontrollecl studies involving small nunrbers of
patients.
A randomized clinical trill demonstrated that inflix
imab (Option B) dicl not reduce the proportion of patients
with GCA relapses or increase the proportirtn of'paticnts
uho could taper glucocorticoid dosages. Infliximab is not
an eflective agent fbr thc treatmellt of GCi\ and should not
be used.
Methotrexate (Option C) is a glucocorticoid sparing
drug used in the treatment of GCA. Evidence on its eflec
tiveness is mixed. ancl clinical eftect seerns to be r.nodest
irt best.
XEY POIf,IS
. Generally accepted indications for a glucocorticoid-
sparing agent in patients with giant cell arteritis
include the presence of comorbid diseases that are
negatively affected by glucocorticoids, development of
glucocorticoid reiated adverse effects, and prolonged
need flor glucocorticoids.
. Tocilizumab, an interleukin 6 blocker, is an effective
glucocorticoid sparing agent in the treatment of giant
cell arteritis.
Bibliography
Maz M, Chung SA. Abril A. et al. 2021 American College ol Rheumatolory/
Vasculitis lbundation guideline for the management ol giant cell arteritis
and Takayasu arteritis. Arthritis Rheumatol. 2021. IPMID: 342358841
17 Answer: B
a
Item
Ed u cati ona I O bj ective: Diagnose interstitial lung disease
in a patient with rheumatoid arthritis.
The most likely cause of this patient's exertional dyspnea is
interstitial lung disease (lLD) (Option B). ILD may develop
in 507, of patients with rheumatoid arthritis, particularly
those who are seropositive for rheumatoid factor and anti-
cyclic citrullinated peptide antibodies; clinically signifl
cant disease is seen in 10'1, of patients and contributes to
excess mortality. ILD types include bronchiolitis, organiz
ing pneumonia, nonspeci{ic interstitial pneumonia, and
usual interstitial pneumonia. Patients may also have pul U!
monary rheumatoid nodules. Patients with rheumatoid
o
ET
arthritis treated with methotrexate are also at risk for
possible drug-induced parenchymal lung disease. Nonpro-
ductive cough and dyspnea are the most common present
t,
!,
ing symptoms of ILD. Lung examination findings vary and tr
.!
may be normal. Inspiratory fine crackles suggest intersti- Ut
(l,
tial flbrosis. The evaluation of suspected ILD includes full
pulmonary function testing (restrictive physiologr), chest ta
=
E
radiography (which may be normal), and high-resolution
CT of the chest.
Heart failure (Option A) is more common in patients
with rheumatoid arthritis than in the general population
and may contribute to increased mortality. The increased
prevalence of heart failure may be due to the presence of
inflammatory mediators, antirheumatic drug therapy, amy
loidosis, or ischemic heart disease. Heart failure is unlikely
in the absence of jugular venous distention, edema, or an Sr.
Patients with rheumatoid arthritis rarely develop pul-
monary arterial hypertension (Option C); that condition is
often associated with rheumatoid vasculitis. In patients with
long-standing ILD, secondary pulmonary hypertension can
develop. Pulmonary arterial hypertension is unlikely in this
patient with a normal S, and normal jugular venous pres
sure. The presenceofinspiratory crackles also argues against
pulmonary arterial hypertension.
Pleural disease (Option D) occurs in up to 5% of patients
with rheumatoid arthritis; pleural effusions are exudative
and can be large. Rheumatoid arthritis pleural effusions are
characterized by low glucose, pH, and complement levels,
as well as elevated levels of total protein, rheumatoid factor,
and Iactate dehydrogenase. A pleural effusion large enough
to cause dyspnea on exertion is most likely to be associated
with absent breath sounds and dullness to percussion over
the affected lung fleld. Inspiratory crackles would not be
expected as the only flnding.
XEY POIlITS
r Interstitial lung disease may develop in 50% of
patients with rheumatoid arthritis; clinically signifi-
cant disease is seen in 10% of patients and contributes
to excess mortality.
. Nonproductive cough and dyspnea are the most com-
mon presenting symptoms of interstitial lung disease.
131
 Answers and Critiques
Bibliography
Spagnolo p lung in rheumatoid arthritis:
Lee JS, Sverzellati N, et al. The
focus on interstitial lung disease. Arthritis Rheumatol. 2018;70:1544
1554. IPMID: 29806092] doi:10.1002/art.40574
tr Item 18 Answer: A
Educational Objective: Diagnose gouty arthritis in a
patient with psoriasis and psoriatic arthritis.
'lhe most likely diagnosis is gout!' arthritis (Option
A). This
patient has an acute painful joint in the setting ofpsoriasis
and psoriatic arthritis (PsA). Hyperuricemia and gout are
D comorbidities associated lvith psoriasis. It is thought that
ul the rapid tllrnover of skin cells in patients r,r'ith psoriasis
E drives protein metabolism and increases serum urate levels.
.D
tt A recent study oftwo large cohorts, the Health Professionals
o, tbllorv up Study ancl the Nurses' Health Study: fbund that
EL the risk fbr gout in participar.rts with psoriasis rvas almost
r.t double that of participants witl.rout psoriasis; the risk was
flve times greater in participants nith PsA than in those
.ct
n,ithout either conclition. This Ope of joint preser.rtation
rD
t^ (acute swelling, severe pain. unwillingness to flex or extend
joint) can have one ol three ciuses: infectious arthritis.
hemarthrosis. or crystalline arthritis. Joint fluid analysis is
necessary to rnake thc correct diagnosis.
Inf'ectious arthritis (Option B) is always possible in
a patient with acute monoarticular arthritis. particu-
larly r,lhen the knee is involved. Hortever. r,r'ith intectious
arthritis, fluid leukocyte counts
f'ever is common, synovial
rrlnge f'rom 50.000 to 100.0001pL (50 100 x 10'),'L) or
higher. and the Gram stain is positive in up to 50')i, of
patients. In PsA. joint infection is much less common than
gouty arthritis.
Patients r,l,ith osteoarthritis (Option C) usually
describe an insidious onset of intermittent symptoms,
which become more persistent and severe over time.
Patients with osteoarthritis generally do not have systemic
features. 'lhe lvpical synovial tluid analysis rtill shor,v 200
to 2000 lcukocytes'pl. (O.Z-Z.O x l0q'L). 'lhis patient's joint
fluid count of 40,000 leukocytesi gL (40 x 10"/l-) with 90'7,,
neutrophils indicatc's that he has an inflammatory arthritis.
not osteoarthritis.
Flares ol PsA (Option D) are not typically this pain-
ful and usually develop more skrwly. In addition. an acute
arthritis of this magnitude is unlikely in someone \{,ith PsA
rtho is receiving methotrexate and has no other afl'ected
joints. Acute monoarticular arthritis morc strongly suggests
hemarthrosis. infectious arthritis, or gout.
I(EY POITIS
o Acute monoarticular arthritis is due to infectious
arthritis, hemarthrosis, or acute crystalline arthritis;
joint fluid analysis is necessary to make the correct
diagnosis.
. Hlperuricemia and gout are comorbidities associated
with psoriasis and psoriatic arthritis.
132
Bibliography
MerolaJF, Wu S. Han J, et al. Psoriasis, psoriatic arthritis and risk ofgout
in US men and women. Ann Rheum Dis. 2015:74:1495 500. [PMID:
246516201 doi:10.1136/annrheumdis 2014 205212
Item 19
Educational Objective:
Answer: B
Assess a patient with systemic
lupus erythematosus for cardiovascular risk.
The most appropriate assessment to perform is for cardio-
vascular disease risk (Option B). Patients with systemic
lupus erythematosus (SLE) have a high risk for cardiovascu
lar disease compared with the general population, including
a greater risk for myocardial infarction and ischemic stroke,
even in younger patients. Control of the underlying SLE
may be the most important way to minimize this risk, but
patients should also be screened for other modifiable risk
factors. Assessment of diet, exercise, hypertension, diabetes
mellitus, smoking, and potentially lipids are indicated in
patients, including young patients, with SLE.
Patientswith SLE have a higheroverall riskformalignan-
cies (particularly hematologic) but not cancer-related mor
tality; the risk for non Hodgkin lyrnphoma is at least two to
three times higher than in the general population. There may
be an increased risk for cancers ofthe lulva, cervix, lung, thy-
roid, and possibly liver. Malignancy risk in SLE is tied to the
use of immunosuppressive agents. Breast cancer risk (Option
A) does not seem to be increased, but appropriate screening
should be initiated in the future as indicated by guidelines.
In patients with SLE, normocytic, normochromic
inflammatory anemia is common; autoimmune hemoll'tic
anemia occurs in approximately 10% and correlates with
SLE activity. Lymphopenia/leukopenia is also common but
usually mild. Thrombocltopenia occurs in 30% to 50% of
patients with SLE, and approximately 10'7, develop severe
thrombocytopenia (platelet count <50,000/pL [50 x 10e/L])
in isolation or in conjunction with hemolytic anemia. Iron
overload syndromes (Option C), such as hemochromatosis,
are not a morbidity of SLE unless associated with increased
transfusion requirements.
Some patients with SLE or overlap syndromes can have
interstitial lung disease that would warrant additional test
ing with pulmonary function testing or chest CT. However,
this patient is asymptomatic, and assessment for pulmonary
disease (Option D) is not warranted.
XEY POIXIS
o Patients with systemic lupus erythematosus have a
high risk for cardiovascular disease compared with
the general population, including a greater risk for
myocardial infarction and ischemic stroke, even in
younger patients.
o Control of the underlying systemic lupus erythemato-
sus may be the most important way to minimize car-
diovascular risk, but patients should also be screened
for other modifiable risk factors.

Bibliography
Andrades C. Fuego C. Manrique Ariia S. et al. Management ofcardiovascular
risk in systemic lupus erythematosus: a systemxtic review. Lupus. 2017i
26:1407 7419. [PMID: 284571 97]
Item 20 Answer: E define the safety of potential therapies.
Educational Objective: Diagnose osteoarthritis with
history and physical examination.
No additional laboratory studies are needed (Option E).
Osteoarthritis (OA) diagnosis is based on history and physi
cal examination; radiography is conflrmatory but may not be
necessary. In early OA, clinical flndings may not be accompa
nied by radiographic changes; conversely, some patients with
prominent radiographic changes may have minimal or no
symptoms. Patients with OA are typically older than 50 years
of age; diagnosis at an earlier age should prompt inquiry into
a history of previous joint damage, endocrine or metabolic
disorders, or a genetic proclivity fbr early disease. Joints most
commonly affected are the hands (first carpometacarpal
joints, distal and proximal interphalangeal joints), feet (first
metatarsophalangeal joint and mid foot), knees, hips, and
spine, but the distribution varies. Localized OA, in which a
single joint is affected, is more often a consequence of injury
or joint asymmetry and often occurs in weight-bearing joints
(hip or knee). Furthermore, this patient has noninflamma
tory arthritis, as evidenced by minimal morning stiffness
and no evidence of warmth, soft tissue swelling, or effusion;
these lindings further support the diagnosis of OA. Addi
tional tests would be helpful if other causes of arthritis were
being considered or would aid in decisions about therapeutic
options. No additional tests are needed in this patient.
The cardinal signs of inflammation are pain, erythema,
swelling, and warmth; with the exception of pain, non
inflammatory conditions usually lack these features. This
patient's history and clinical flndings do not suggest inflam
matory arthritis, in particular inflammatory autoimmune
disorders (such as systemic lupus erythematosus or rheuma
toid arthritis). Evaluation for these conditions with testing
of antinuclear antibodies (Option A) or rheumatoid factor
(Option B) is not needed.
Lyme arthritis is an infectious arthritis with an inflam
matory synovial response. It is usually monoarticular and
occasionally polyarticular. This patient has polyarticular
arthritis and does not have flndings suggestive of inflam-
matory arthritis; serologic testing for Borrelia burgdorferi
(Option C) is unnecessary.
Synovial fluid analysis (Option D) is helpful if effusion
is present and there is concem about other causes of arthri
tis, such as concurrent crystal arthritis, infections, or other
inflammatory causes. This patient does not meet these criteria.
t(EY PO!ltrS
o The cardinal signs of inflammation are pain, ery-
thema, swelling, and warmth; with the exception of
pain, noninflammatory conditions such as osteoar-
thritis usually lack these features. (continued)
Answers and Critiques
t(EY POIilIS (onttnaed)
o Laboratory testing and imaging are usually not neces-
sary to diagnose osteoarthritis but are helpful if other
causes of arthritis are being considered or to help
Bibliography
Martel-Petletier J, Maheu E, Pelletier JR et al. A new decision tree fbr diag
nosis of osteoarthritis in primary care: international consensus of
experts. Aging Ctin Exp Res. 2019:31:19 30. IPMID, 305395'111
vt
Item 21 Answer: C
Educational Objective: Treat tophaceous gout in a
tr c,
ET
patient with contraindications to allopurinol.
|.,
'lhe most appropriate additional trcatment is f'ebuxtlstat -,-
(Option C). this patient has tophaceous gout, which is an |!
tt
inclication fbr urate lor,r,ering therap!: ll.re American Gtllege o
of' Rheumatology (ACR) strongly recotnmencls treatntent
la
=
with allopurinol (Option A) as the prel'erred first line agent
over all other uratc lor,r,ering therapies, includitrg in patients
u,ith moderate'to severe chronic kidney clisease (CKD)
(stage >3). \,\,ith appropriate dose adjustment. Ilort'ever. she
ciinnot take allopurinol because of a history ol a rasl.r rt'ith
previous use. An uncommon but scrious complication of'
alkrpurinol is a hypersensitivity reaction. which may lead
to organ dysfunction and death. 'lherefore. allopurinol is
not appropriate, and therapy with fbbuxostat. a nonpurine,
noncompetitive xanthine oxidase inhibitor. is indicltecl.
Beciruse only 3'l'" of fbbuxostat is renally cleared, it n-ray be
uscd in patients with CKD without dose adjustment if the
estimated glomerular filtration rate is 30 to 60 ml-/mini
1.7i1 m). The starting I'ebuxostat dosage is ,10 mgrd, r'r,hich
nr:ry be increased to up to itO mg/d if needed on the basis of
scrum urate lelel. Achieving and n-raintaining a serum urate
target ollcss than 6.0 mg,'dl. (0.35 mmol, L) are strongly rec-
ommended Ibr all patients receiving urate-lowering thcrapy.
Prophyiaxis with prednisone should be continued along
u,ith febuxostat for 3 to 6 months or until the serum urate
level is at target.
Colchicine (Option B) is used lbr treatir.rg acute gout
flares and fbr long term prevention of flares while urate
lowering therapy is begun. Colchicine dcles not aftect serum
urite concentrations. Colchicine requires dose adjustmcnt
fbr kidney disease and rthen it is takcn concurrently rt'ith
drugs that aflbct its n.retabolism.
'Ihe ACR strongll, recommends against pegloticase
(Option D) as a first line urale lor,vering therapy: Pegloticase
is indicated in paticnts in whom allopurinol and febuxostat
have failed or cannot be tolerated. It is inlravenously adtnin -
istered and expensive and thus should be reserved lbr an
appropriilte clinical setting. Ircbuxostat has not lailed in this
piitientr thus. pegloticase is not indicated.
Probenccid (Option E) lolvers serum urate by bbck
ing uric acid reabsorption in the kiclney proximal tubule.
'll-re ACR strongly recommends allopurinol or tebuxostat
133
 Answers and Critiq_ues
tr
CONI
over probenecid fbr urate-lowering therapy in patients
rt,ith moderate to severe CKD. Probenecid is not cftective
in patients with CKD (estimatecl glomerular filtration rate
<50 mLiminr1.73 nt2) and is contraindicated in patients \\,ith
nephrolithiasis.
r(lY P0rilIS
. Febuxostat is recommended for patients with indica-
tions for urate-lowering therapy who have contraindi-
cations to allopurinol therapy.
o Allopurinol and febuxostat are both strongly recom
mended over probenecid as urate-lowering therapies
D in patients with moderate-to-severe chronic kidney
Ut disease.
E
.D
u! Bibliography
o,
FitzGerald JD. t)albeth N. Mikuls T, et al. 2020 American College of'
EL Rheunratolopgr guideline lbr the management ol gout. Arthritis Care Res
rt (Hobrrken). 2O2O:72:741 760. Il,MID: 32391934] doi:10.1002iacr.24180
.€l
.D Item 22 Answer: D litides. Rheum:ltol Int. 2019:i]9: 169 1 8.5. IPMI D: 3022]3271 doi: 10.1007r
la
EI Ed ucationa I Objective: Diagnose Takayasu arteritis.
lhe most likely diagnosis is Takayasu arteritis (Option
lhis rare large vessel vasculitis disproportkrnately affects
young women ancl is much more conrmon in East Asia
(prev:rlence is 40imillion in Japan and up to B/million else
where). Onset is usually indolent. rvith nonspecific symp
toms and signs presenting months to years before onset of'
frank vasculitis. The disease causes infiammation and subse
quent stenoses in the large arterics, including the aorta and
its branches. Manif'estations can include limb ischenria and
associated diminished (or absent) pulses, mesenteric isch
emia, and hypertension due to renal aftery stenosis. Clues
on exalnination include bruits over large vessels, absent
pulses, discrepancy in blood pressure between limhs. and
hypertension. Laboratory findings indicate active systemic
inflammation but are not diagnostic. lmaging of the aorta
and its branches is diagnostic: biopsy of an involvecl vessel
is not fbasible. Thirty percent of patients can present with
ocular ir-l,olvement, much olwhich is attributed to'lakayasu
retinopathy and hypertensive retir.ropathy.
this patient does not have the cutaneous features (pal
pable purpura, digital ischemia, ulcers, necrosis, livedo
reticularis) that are the nrost conlmon symptoms ol cryo
globulinemic vasculitis (Option A), seen in mrtre than 90',1
of patients. Other common manif'estations ir.rclude periph
cral ncuropathy and glomerulonephritis.
Ciant cell arteritis (CCA) (Option B) is not present.
Nearly all patients rvith GCA are older than 50 years. Absent
pulses are typical in Takayasu arteritis but do not occur in
GCA. In addition. GCA rarely aflbcts the descending aorla
and its branches: thus, renovascular hypertension tronr
renal ar1ery steltosis and nlesenteric ischemia dre not man
ifbstations of GCA.
This patient's findir.rgs do not suggest polyarteritis
nodosa (PAN) (Option C). Although IAN can cause renal
134
iirtery stenosis leading to hypertension, as r,rell as mesenteric
ischemia. it affects ntedium-sized vessels and so lr,ould not
:
:
invoive the subclavian artery. ln addition, the most common
n.ranifbstations of PAN are cutaneous findings (such as pal
I
pable purpura) and neurologic involvernent. Roughly 7O"/,, of
patients \,vith PAN have neurologic disease. most commonly \
rnanifesting as mononeuritis multiplex. Unlike in Takayasu \
arteritis, pulselessness is r.rot chlmcteristic of PAN.
t(EY P0ilrIS 1
. Takayasu arteritis is a rare large vessel vasculitis caus
i
ing inflammation and subsequent stenoses in the
:
large arteries, including the aorta and its branches.
o Manifestations of Takayasu arteritis can include limb
ischemia and associated diminished (or absent)
pulses, mesenteric ischemia, and hypertension due to
renal artery stenosis.
Bibliography
Keser C. Aksu K. l)iagnosis and diflerential diagnosis of large vessel vascu
s00296 018 .11.57 ll
D). Item 23 Answer: A
Educational Objective: Treat refractory gout with
anakinra.
The most appropriate treatment is anakinra (Option A).
Anakinra is a recombinant human interleukin (lL)-1 recep
tor antagonist. IL 1 cytokine activity is an important part
of the inflammatory process in acute gout. This patient has
a severe polyarticular gout flare likely provoked by diure
sis. In patients with severe refractory gout that has not
responded fully to other agents or in r,r'hom other agents are
contraindicated, anakinra may be used as ofllabel treat-
ment. It has a short half life and is given by subcutaneous
injection, 100 mg/d, usually for 3 to 5 days. The dose is
decreased in patients with stage 4 or 5 chronic kidney dis
ease (CKD). Canakinumab, a monoclonal antibody to ll-lp,
which blocks binding to the IL 1 receptor, is a longer-acting
IL I inhibitor that may be used in refractory gout flares but
is more expensive than anakinra.
Colchicine (Option B) is not appropriate because this
patient has CKD and is receiving tacrolimus. Colchicine
use should be avoided in patients taking concomitant cyto-
chrome P450 3A and P glycoprotein inhibitors, particularly
in the setting of CKD. Long term use of colchicine with tac
rolimus or cyclosporine may result in neuromyopathy.
Intra-articular, intravenous, or intramuscular gluco-
corticoids (Option C) may be used to treat acute gout in
hospitalized patients in whom both NSAIDs and colchicine
are contraindicated or those who cannot take medications
orally. This patient has not responded to appropriate doses
of oral glucocorticoids, and his comorbidities (hypertension,
hyperlipidemia, type 2 diabetes mellitus, heart failure) pres-
ent relative contraindications to additional or higher dose
glucocorticoid use in any form. In addition, the polyarticular
I
t
t
I
nature of his gout flare makes the use of intra articular
glucocorticoid injection more challenging.
! Naproxen, an NSAID (Option D), is contraindicated
in this patient because he has heart failure and is taking
I
Iow molecular weight heparin. NSAIDs can contribute to
i worsening heart and kidney failure and increase the risk for
i
bleeding in patients taking anticoagulants.
TEY POIXT
o In patients with severe refractory gout that has not
responded fully to other agents or in whom other
agents are contraindicated, anakinra, a recombinant
human interleukin l receptor antagonist, may be
used as off-label treatment.
Bibliography
Fitz(ierald JD. Dalbeth N, Mikuls 1l et al. 2020 American College ot
Rheumatology guideline fbr the management of gout. Arthritis (lare Res
I
(l loboken).')O2O ;7 2:74 760. IPM ID: 3239 19:]41 doi : I 0. 1002iircr.24180
Item 24 Answer: D =
Educational Objeaive: Treat osteoarthritis of the knees
and hands with a topical NSAID.
The most appropriate treatment is topical diclof'enac (Option
D). Topical NSAIDs, such as diclofbnac, are saf'e and ef fective
for treatment of knee and hand osteoarthritis (OA). For OA
in those locations, the 2019 American College of Rheuma
tolory (ACR)/Arthritis Foundation (AF) guideline suggests
that topical NSAIDs should be considered betbre oral NSAIDs
because of f'ewer safety concerns. Topical NSAIDs are not
effective for hip OA and have limited eflicacy in OA of other
sites.
There is minimal benefit of opioid therapy, including
hydrocodone (Option A), for chronic pain control in patients
with OA. Opioids pose a high risk lor toxicity and depen
dence and should not be used to treat OA.
Oral NSAIDs, such as meloxicam (Option B). are an
ACR/AF guideline recommended first-line treatment fbr
hand, knee, and hip OA. However. they should be used
cautiously in patients older than age 50 years and avoided
in those with comorbidities, such as a history of peptic ulcer
disease or gastrointestinal bleeding, and in patients with
hypertension, cardiovascular disease, or chronic kidney dis
ease, as in this patient.
The ACR/AF guideline conditionally recommends topi
cal capsaicin (Option C) for patients with knee OA and con
ditionally recommends against topical capsaicin in patients
with hand OA. The guideline notes limited data supporting
the efficacy of topical capsaicin for knee OA. No direct evi
dence supports topical capsaicin in the treatment ol hand
OA, and eye contamination is possible when it is used on
the hands.
Other topical agents are available, such as lidocaine
(Option E) and methyl salicylate preparations, but they are
not as well studied or as eflicacious as topical NSAIDs. They
may be used as adjunctive measures.
Answers and Critiques
r(EY P0tllTS
. Topical NSAIDs are safe and effective for treatment of
knee and hand osteoarthritis and should be consid
ered before oral NSAIDS.
. Oral NSAIDs are recommended for the treatment of
hand, knee, and hip osteoarthritis but should be
avoided in patients with comorbidities, such as peptic
ulcer disease, cardiovascular disease, and chronic
kidney disease.
Bibliography
Kohsinski Sl.. Neogi 1', Hochberg MC. et lr1. 2019 An.rerican Oollege ol t,t
(u
Rheumat(rogi 'Arthritis Founclation guideline fbr tlte manrgement {)l'
osteoarthritis of the hand. hip, and knee. Arthritis Rheuntttol. 2020r ET
72:220 23:1. LPMID: :ll 908163 | doi:10.1 002/art.4l l.l2
L'
!t
E
Item 25 Answer: C ag
a
Educational Objective: Diagnose cause ofjoint pain in a (I,
patient with systemic lupus erythematosus. tt
The most appropriate management is MRI of the left hip
(Option C). Isolated new pain in the hip is an uncommon
manifestation of a systemic lupus erythen-ratosus (SLE) flare.
A serious complication ol SLE is osteonecrosis, which most
commonly affects the hips but can also involve other large
joints, and should be suspected when there is otherwise unex
plained pain and/or reduced range of motion in a single joint.
Long-term and high prednisone dosages (>zO mgld), severe/
active SLE. and vasculitis are all associated with increased
risk. In patients with osteonecrosis, the plain radiograph can
remain normal for months after symptoms begin. MRI is the
modality of choice for sensitive evaluation of early disease,
with plain radiography uselul to diagnose and monitor later
stages. Small lesions can improve and resolve spontaneously,
but larger lesions usually lead to bony collapse and stmctural
sequelae. New hip pain in patients with a history of SLFI
should prompt evaluation for osteonecrosis with N4RI.
If the patient were experiencing a more global flare
or intolerance to her current medications, switching her
maintenance therapy from azathioprine to mycophenolate
mof'etil (Option A) could be reasonable. However, she has
no other signs of SLE activity, and so this change r.t'ould not
be appropriate.
This patient has a normal erythrcicyte sedimenta
tion rate, normal serum complement levels, and low titer
anti double strandedDNA antibodies. Becausethispatient's
isolated hip pain is unlikely to be caused by increased inflam
mation. and because her disease is otherwise well controlled.
increasing her prednisone dosage (Option B) would not be
appropriate and could accelerate damage fiom osteonecrosis.
Physicat therapy (Option D) can be useful fbr reha
bilitation of joint pain in SLE and may be helpful for this
patient, but diagnosing the cause of this patient's hip pain
should take priority because the diagnosis and stage of
osteonecrosis are important for determining the need for
potential surgical intervention.
135

Answers and Critiques
TEY POITIS
o Patients with systemic lupus erythematosus, espe-
cially those who have received high cumulative doses
ofglucocorticoids, are at risk for osteonecrosis, espe-
cially in the hip.
. MRI is the imaging modality of choice for suspected
osteonecrosis at earlier stages of disease.
Bibliography
Tse SM, Mok CC. Time trend and risk factors ofavascular bone necrosis in
patients with systenric lupus erythematosus. Lupus. 2017)6:715 722.
lPMtD,27831s.101
D livedo reticularis, or Raynaud phenomenon).
ta
€ I(
(D Item 26 Answer: A
Ut
o, Educational Obiective: Treat oral dryness of Sjdgren
a syndrome.
rl The most appropriate treatment is cevimeline (Option A). The
patient's primary symptom is worsening oral dryness associ
ll
E
(D ated with Sjogren syndrome. There is no disease modifying
l,I treatment to globally address manifestations of Sjogren
syndrome. and no medication alters the natural history of
chronic oral and ocular dryness. However, treatments can
alleviate xerostomia and xerophthalmia. For oral dryness,
behavioral management may be enough to allay symptoms.
This can include chewing sugarless gum or sucking on sugar
free sour candies or lozenges to stimulate saliva, taking fre
quent small sips of water, or using a spray bottle to moisten
mucosal surfaces (to limit oral intake). Saliva substitutes are
available commercially in the form of oral sprays, gels, and
rinses for more severe symptoms but are often not eflective.
Cevimeline, a cholinergic muscarinic agonist, stimulates
salivation and is appropriate for moderate oral dryness that
does not improve with the aforementioned interventions.
Pilocarpine, another muscarinic agonist, is an equally effica-
cious alternative to cevimeline. Cholinergic adverse efl'ects of
cevimeline and pilocarpine can include sweating, abdominal
pain, nausea, flushing, and increased urination. Ocular dry
ness can be treated with over the counter remedies. such
as artificial tears (used during the day) and eye lubricants
(usually used betbre bedtime). Refractory or severe ocular
dryness may be managed by using topical immunosuppressive
containing drops, such as cyclosporine (a calcineurin inhib
itor) or lifitegrast (an integrin inhibitor).
Hydroxychloroquine (Option B) does not alter the nat
ural history of Sjdgren syndrome or improve oral or ocular
dryness. This medication was widely favored by Sjogren
syndrome specialists until a randomized controlled trial
published in2Ol4 demonstrated no efficacy for oral or ocular
dryness or fatigue after 24 weeks compared with placebo.
Hydroxychloroquine can, however, beneflt patients with
Sjogren syndrome who experience inflammatory arthritis or
subacute cutaneous lupus erythematosus.
There is no indication to prescribe prednisone (Option
C). Glucocorticoids will not improve oral or ocular dryness,
and therefore the risks of prednisone in this patient are not
136
:
.:
1
balanced by any benefits. Glucocorticoids are used in the
)
treatment of Sjogren syndrome related systemic disease,
such as interstitial lung disease, demyelinating diseases,
autoimmune hepatitis, and arthritis. It is recommended that
glucocorticoids be used at the minimum dose and length of
time necessary to control active systemic disease.
Rituximab (Option D) is not approved for the treat
ment of SjOgren syndrome and has shown no efficacy in
treating oral dryness. It is appropriately prescribed to the
small subset ol patients with Sjogren syndrome who have
cryoglobulinemic vasculitis, but this patient has no signs
of vasculitis (cutaneous ulcers, necrosis, palpable purpura,
EY PO t TIS
. Nonpharmacologic therapies are the first-line treat
ment of Sjdgren syndrome-related oral dryness,
including local moistening with water, sugar-free
acidic candies, lozenges, and/or mechanical stimu-
lants (such as sugar free chewing gum).
o Pharmacologic stimulation of salvia with cevimeline
or pilocarpine is indicated for oral dryness not relieved
with nonpharmacologic therapies.
Bibliography
Ramos Casals M, Brito Zenin P, Bombardieri S, et al; EULAR Sjogren
Syndrome Task Force Group. EULAR recommendations for the manage
ment of Sjogren's syndrome s,ith topical and systemic therapies. Ann
Rheum Dis. 2O2O:79:3 18. [PMID: 316727751
llem27 Answer: D
Educational Objective: Diagnose a secondary cause of
EI
acute calcium pyrophosphate crystal arthritis.
The laboratory study most appropriate to perform next is
measurement of serum f'erritin (Option D). This patient's
recurrent acute flares of pain and srvelling in tl-re r,l'rists
and third metacarpophalatrgeal (MCP) joint are consistent
with acute calcium pyrophosphate (CPP) crystal arthritis
(pseudogout). 'lhe radiograph ol the MCP joints shows a
small hooked osteophyte of the lef t tl-rird MCP joint. Hooked
osteophytes ol the second and third MCP joints are a charac
teristic feature of CPP crystal arthritis. The radiograph of the
wrist shows calcification along the flbroarticular cartilage
collsistent u,ith chonclrocalcinosis. Synovial fluid analysis
shows CPP crystals, nhich confirm the diagnosis. Given the
patient's age (<60 years), secondary causes ofCPP deposition
(sr.rch as hyperparathyroidism. hypothyroidism, hypophos
phatasia, hypomagnesemia. and hemochromatosis) should
be sought. Iler norrnal comprehensive metabolic parlel,
serunr magnesium level, and tlryroid stimulating hormone
level exclude all secondary causes other than henrochroma
tosis. Measurements of serun-r f'erritin and transferrin satu
ration are appropriate screening tests for hemochromatosis.
Henrochromatosis typically presents in men age 40 years or
older and in women generally after menopause because of
slower iron accumulation in the premenopausal years.

m Testing fbr antinuclear antibodies (Option A) would be
IIJ .pptnpriate il the patient displayed characteristic signs or
toNl ,ynrptoms ot
sysl5'n-r1a lupus erytlrernatosus, such as malar
msh, photosensitivity, inflammakiry arthritis, weight loss,
and fever. Howevel this test is not indicated because the his,
tory, examination. ancl Iaboratory findings arc not consistent
with system ic lupus erythematosus.
Erythrocyte sedintentation rate (Option B) is a nonspe
cific test fbr inflammation. It may be elevated in any inflam
nratory state and \"'ould not help determine the cause of this
pat ient's in flummation.
Rheumatoid factor (Option C) is useful in the diagnosis
of rheumatoid arthritis (RA). Although RA often afl'ects the
hands and \ /rists, it typically presents with morning stiff
ness and the gradual onset of pain, stiflncss, and swelling
in a symmctric distribution of hands and feet. Plain radio
graphs in early RA would not show a hooked osteophlrte or
calcifi cations in the fi brocartilage.
rEY POITIS
. For patients with acute calcium pyrophosphate crystal
arthritis who are younger than age 60 years, labora-
tory evaluation for contributory metabolic disease
(hyperparathyroidism, hemochromatosis, hypophos-
phatasia, hypomagnesemia) is warranted.
o Hooked osteophytes of the left third metacar-
pophalangeal joints and cartilage calcification are
radiographic findings consistent with calcium
pyrophosphate crystal arthritis.
Bibliography
Rosenthal AK, Ryan LM. Calcium pyrophosphate deposition disease. N Engl
J Med. 2016;374:2575 84. IPMID: 27355536j doi:10.1056/NEJMralSlll17
Item 28 Answer: B Bibliography
Educational Objective: Treat dermatomyositis with the
addition of a glucocorticoid-sparing agent.
The most appropriate treatment is to add methotrexate
(Option B). This patient has classic clinical and laboratory
leatures of dermatomyositis with myositis-associated auto-
antibodies and no evidence of associated malignancy or
other complications. In particular, the presence of anti Mi-2
antibodies predicts a good prognosis with a low risk for
interstitial lung disease and cancer. Her symptoms have
completely resolved with an initial course of oral prednisone,
typically initiated at 1 mg/kg/d. Combination therapy with
glucocorticoid-sparing agents is important for maintaining a
clinical response and for minimizing glucocorticoid adverse
effects in patients with dermatomyositis. Initiation of meth-
otrexate or azathioprine at diagnosis or after an early initial
response to glucocorticoids is the most appropriate next
step to achieve Iong term disease control and to allow effec
tive tapering of the prednisone dose. Intravenous immune
globulin can be added as flrst or second-line treatment for
patients with an inadequate response to initial combination
Answers and Critiques
therapy or with more severe disease. There is no guidance
for optimal duration of therapy, but in the absence of flares,
most patients can discontinue treatment in 9 to 12 months.
Physical therapy may help maintain muscle function and
should be used in all patients.
Hydroxychloroquine (Option A) may be helpful as
adjunct therapy for skin rashes in some patients with der
matomyositis who do not want, tolerate, or obtain adequate
relief from topical agents and other systemic therapies. How
ever, antimalarial agents do not impact muscle disease and
are not sufflcient as glucocorticoid-sparing therapy.
Rituximab (Option C) is sometimes used if the disease
does not respond adequately to glucocorticoids plus either ut
(t,
azathioprine or methotrexate, or ifthose agents are not tol
ET
erated. However, this patient should receive a trial of meth
otrexate or azathioprine and intravenous immune globulin (J
before using rituximab. !t
Although this patient has had a good response to pred .!
nisone, symptoms are likely to recur if the glucocorticoid tt
o
dose is tapered without glucocorticoid sparing therapy.
Long-term use of moderate or high doses of glucocorticoids r^
=
(Option D) should be avoided if possible because of cumula-
tive adverse effects, including bone loss, weight gain, meta-
bolic changes, and risk for cataracts and glaucoma.
r(EY P0ll{T5
. In patients with dermatomyositis, initiation of metho-
trexate or azathioprine at diagnosis or after an early
initial response to glucocorticoids is the most appro-
priate next step to achieve long-term disease control
and to allow effective tapering ofthe prednisone dose.
. Physical therapy may help maintain muscle function
and should be used in all patients with inflammatory
myopathy.
Oddis CV Aggarwal R. Treatment in myositis. Nat Rev Rheumatol. 2018;
14:279 289.lPMlD : 295933431 doi:10.1038/nrrheum.2018.42
29 Answer:
Item
Ed ucationa I Objective :
B
Diagnose Felty syndrome.
tr
'lhe most likely diagnosis is Felty syndronre (Option B).'this
rare syndrcme is a complication of r.tell established rheu
nratoid arthritis characterized by neutropenia and spleno
megaly. Patients witlr t'elty syndrome are at risk for serious
bacterial intbctions. lower extremity ulceration. lymphoma.
ancl r,,asculitis. Patients may present rt''ith an asympk)nlatic
clecline in the neutrophil cor.rnt that is detected on routine
laboratory testing ibr n-redication toxicity. Because a decline
in leukocyte count can also be irn adverse ellbct of nunterous
nredications used to treat rheumatoid artl.rritis. it is import-
ant to evaluate this possibility. llowever, medications are far
less likely kr specifically reduce only the ncutrophil count
and are not likely to be associated with splenomegall,: Some
patients prcsent with an infection related to neutropenia.
137
 tr
CON].
In this instance. the total leukocyte count mav be normal irt
the time of presentation but fall ."r'ith treatment of the inf'ec
tion. Patients rtith rhcun.ratoid arthritis can also have large
granullr lymphocyte syndrome, w'hicl.r can progress to lirrgc
granular lymphocytic ler-rkemia. Finclings overlap rvith Felty
synclrome and include ncutropenia. ancrnia. thromlloc),to
penia. splenotnegallt ancl recurrent inlections.
AA amyloidosis (Option A) is a rare complication of'
long standing and poorly controlled rheumatoid arthritis.
In a minority of patiellts, it can leacl to splenomegaly as a
consequence of infiltration of the spleen b1, amyloid protein.
Hovvever. AA aml,loiclosis r'r,ould not be erpected to result in
D neutropenia. making it an unlikely diagr.rosis in this p:rtient.
UI Paticnts rvith rhcumatoid arthritis may develop an
E
(D overlap syndrome characterized by features olanother auto
UI immune disease. such as Sj6gren s1,'ndrome (Option C) or
o, s),stelnic lupus er1'themakrsus (SLU) (Option D). Hou'ever.
EL the patient r'r,ould not be designated as having an overlap
a.t
syndronre in the absence ol t-vpical features of the other
4t autoimmune disease. When SLE occurs in patients with
rheumrrtoicl arthritis, a more typical hematologic picture
.D
t^ u,oulcl include l1,mphopenia. hemolytic anemia. or throm
bocl'topenia. A positive antinuclear antibodl'test result xncl
clinicirl rnanifestations secn in SLII but not in rheunratoid
arthritis, such as kiclncy disease, might appear. Similarly.
Sjogren syndrome is diagnosed in patients with rheumatoid
arthritis r,r'hen sicca symptoms are prcsent. Typicallyl this
r,r,ould be accompanied by anti-Ro SSi\ antibodies anci occa
sionally anti La SSII antibodies.
KEY POIl{I5
. Felty syndrome is a complication of well-established
rheumatoid arthritis characterized by neutropenia
and splenomegaly.
. Patients with Felty syndrome are at risk for serious
bacterial infections, lower extremity ulceration, lym-
phoma, and vasculitis.
Bibliography
Gazitt T, Loughran TP Jr. Chronic rreutropenia in l.Gl. leukemia and rheuma
toid arthritis. Hematololl/ Am Soc Hematol [.]cluc Program. 2017 l)ec 8;
2017(l):181 186. I PMID: Z9'l'lZ'ZS,l] doi:10.1182/asheducation 20l7.l.l8l
Item 30 Answer: C Bibliography
Educational Objective: Diagnose inflammatory
sacroiliitis by using MRI.
The most appropriate diagnostic test to perform next is
MRI of the pelvis (Option C). This patient has sympton.rs
of inflammatory back pain with sacroiliitis consistent with
ankylosing spondylitis. She has developed symptoms at a
young age (<45 years) and has morning stiffness, nighttime
pain, improvement of symptoms with exercise and ibupro-
fen, and a history of uveitis. Her decreased range of motion
of the lumbar spine in all directions is typical of this disease.
Early in the disease, radiographs may be normal. When plain
radiographs are normal and the clinical suspicion is high on
138
the basis of history and physical examination, MRI of the
pelvis may reveal erosions, edema, fatty metaplasia, and
changes of inflammation (synovitis, enthesitis, or capsuli
tis) along the sacroiliac joints. These changes are diagnos-
tic of inflammatory spondylitis. Later in the disease, plain
radiographs of the sacroiliac joints may show narrowing,
erosions, sclerosis, or fusion. Later flndings on plain radio-
graphs of the lumbar spine may reveal early squaring of the
vertebral bodies, followed by syndesmophyte formation.
Bone scanning (OptionA) is sensitive in the diagnosis of
inflammatory arthritis, and a negative scan excludes inflam
mation; however, this test is rarely used in the diagnosis of
sacroiliitis or other inflammatory arthritides because it is
nonspecific. MRI is more speciflc than bone scanning in the
detection of early sacroiliitis and is preferred when plain
radiography is nondiagnostic.
A CT scan of the pelvis (Option B) may show bony
changes of inflammatory spondylitis, such as bony erosions.
sclerosis, and ankylosis, but CT exposes the patient to more
radiation. Therefore, it is not appropriate unless the patient
cannot undergo MRI.
Rheumatoid factor and anti-cyclic citrullinated peptide
antibodies (Option D) are diagnostic tests for rheumatoid
arthritis. Results of these tests are not typically positive in
patients with ankylosing spondylitis. Rheumatoid arthritis
does not cause low back pain because it does not affect the
lumbar spine. This patient has no peripheral inflammatory
joint symptoms consistent with rheumatoid arthritis, so
these tests are not indicated. Although adults with rheu
matoid arthritis may have eye involvement, it is typically
scleritis, not uveitis as in this patient.
r(tY PolilT5
. When plain radiographs are normal and the clinical
suspicion is high, MRI of the pelvis may reveal ero-
sions, ankylosis, fatty metaplasia, and inflammatory
changes along the sacroiliac joints that are diagnostic
of inflammatory spondylitis.
. A CT scan of the pelvis may show bony changes of
inflammatory spondylitis, but CT exposes the patient
to radiation and is reserved for patients who cannot
undergo MRI.
Maksymonlch WP lmaging in axial spondyloarthritis: evalu:rtion of
inflammatory and structural changes. Rheum Dis Clin North Am. 2016:
12:645 662. IPMID; 27712019] doi:10.1016ii.rdc.2016.07.003
Item 31 Answer: A
Educational Objective: Diagnose acute cutaneous lupus
erythematosus.
The most likely diagnosis is acute cutaneous lupus erythe-
matosus (ACLE) (Option A). Cutaneous lupus erythematosus
can exist with or without systemic disease. There are three
primary patterns of lupus-speciflc skin rashes: ACLE, sub-
acute cutaneous lupus erythematosus, and chronic cutaneous

lupus erythematosus. The lupus speciflc skin diseases are not
found in other conditions and have varying associations with
systemic lupus erythematosus (SLE). Identifing the pattern
of the skin disease can be important for guiding additional
evaluation and treatment. ACLE often presents with a pho
tosensitive malar or butterfly rash, with patchy, edematous,
e4,.thematous areas on the cheeks and over the nose. sparing
the nasolabial folds. Similar rashes can occur on other sun
exposed skin, including the neck, upper chest, and arms.
Nearly all patients with ACLE have SLE, and as such tend to
have systemic symptoms and positive serologic results (typi
cally antinuclear, anti Ro/SSA, and anti-La/SSB antibodies).
Lupus pernio (Option B) is a skin manifestation seen in
some patients with sarcoidosis. Skin lesions can occur on the
face, including the cheeks, nose, lips, forehead, or ears, and
are firm and purple. These skin lesions are not photosensi
tive and do not appear on the chest or arms.
Rosacea (Option C) is the most common cause of an
erythematous rash in the malar distribution. Rosacea is
more likely to include pustular lesions and visible telangiec
tasias and does not spare the nasolabial fold.
Subacute cutaneous lupus erythematosus (SCLE)
(Option D) appears as one of two variants: annular and
polycyclic photosensitive plaques on the back. chest, and
extremities, or psoriasiform scaly plaques in a similar distri
bution. SCLE does not scar but may resolve with temporary
pigmentary changes. Fewer than one in f,our patients with
SCLE have SLE, and as many as one in three cases are drug
induced. The latter may resolve with withdrawal of the caus
ative agent. This patient's rash does not match the typical
presentation ofSCLE.
l(EY POl]tT5
o Acute cutaneous lupus erythematosus often presents
with the classic photosensitive malar or butterfly rash,
with patchy, edematous, erythematous areas on the
cheeks and over the nose, sparing the nasolabial folds;
similar rashes can occur on other sun exposed skin,
including the neck, upper chest, and arms.
. Nearly all patients with acute cutaneous lupus erythe
matosus have systemic lupus erythematosus and as
such tend to have systemic symptoms and positive
serologies.
Bibliography
\t'enzelJ. Cutaneous h-lpus erythematosus: new insights into pathogenesis
and therilpeutic strNtcflies. Nat Rev Rheumatol. 201911.5:519 532. [PMID:
31 39971 1 I
Item 32 Answer: D
Educational Objective: Diagnose rheumatoid arthritis
by the pattern ofjoint involvement.
The most likely cause of this patient's joint pain is rheuma
toid arthritis (Option D), given joint involvement that is poly
articular and includes the metacarpophalangeal (MCP) joints.
In rheumatoid arthritis. both hands are usuallv involved,
Answers and Critiques
and, if MCP joints on one hand are tender and swollen,
there are usually MCP joints on the other hand (although
not always the same digits on each side) that are symptom
atic and abnormal on physical examination as well. Other
frequently involved joints are the proximal interphalangeal
joints and wrists. Corresponding joints in the feet (interpha
langeal joints. metatarsophalangeal joints. and ankles) are
also often affected.
Ankylosing spondylitis (Option A) is a chronic inflam
matory disease affecting the axial skeleton, entheses, and
peripheral joints. [n contrast to other forms of spondyloar
thritis, sacroiliac joint involvement is considered an essential
feature of ankylosing spondylitis. About one third ofpatients UI
(,
develop hip joint involvement, and about one third develop
ET
peripheral arthritis elsewhere, often in the shoulders but not
the N4CP joints. L'
Erosive (inflammatory) osteoarthritis (OA) (Option E'
B) is a subset of primary hand OA. Clinically, erosive OA .E
mostly afl'ects the distal interphalangeal and less commonly Ul
affects the proximal interphalangeal joints. Erosive OA is
o
more inflammatory and painlul than typical hand OA and is ta
=
more common in women. Erosive OA is not associated with
generalized OA and usually spares the thumb bases. Erosive
arthritis does not involve the MCP joints.
Reactive arthritis (Option C) is a rare cause of inflamma
tory arthritis that can occur following speciflc genitourinary
and gastrointestinal infections. Arthritis is asymmetric and may
be monoarticular or oligoarticular; joints commonly affected
include the knee, ankle, and wrist. Enthesitis is especially com
mon; Achilles tendinitis and plantar fasciitis occur in up to 90'X,
of cases. l)actylitis can also occur. The spine and sacroiliac joints
are less commonly involved. Symmetric involvement of the
MCP joints is not characteristic of reactive arthritis.
t(EY P0ilaIS
. In rheumatoid arthritis, both hands are usually
involved, most commonly manifesting as symmetric
involvement of the MCP joints.
o In rheumatoid arthritis, the interphalangeal joints,
metatarsophalangeal joints, and ankles are often also
symmetrically affected.
Bibliography
Sparks JA. Rheumatoid arthritis. Ann Intern Med. 2019r170:lTC1 ITCl6.
IPMID: 110.5968791 doi: 10.71126 rAITC2OI90l010
33
Item Answer: D
Educational Objective: Treat newly diagnosed
tr
ANCA associated vasculitis.
The most appropriate treatnlent is high dose glucocorticoids
and rituximab (Option D). This patient has granulomatosis
n,ith polyangiitis (CIA). ANCA-associated vasculitis is sug-
gestecl lry the scvere ancl inflammatory multisystemic il]ness.
Clues that this is GPA specifically include sinus, kidney. and
h-rng involvcnrent; the skin flndings (palpable purpura is not
specilic fbr GPA but strongly sugqests a small vessel vasculitis);
139
 Answers and Critiques
tr
CONT,
peripheral nervous svsteln inr,olvement (left foot senson, bss):
and the presence of antiproteinase 3 antibodies. To conflrn.r
the diagnosis irnd guide management, tissue biopsl' (in this
case. kidnel') rnay be done i{'possible. High dose glucocorti
coids plus either rituximab (preferred) or c),clophosphamide
is the appropriate treirtment for induction of remission in
selere orgarl threatening or lif'e threatening GPA. Selecteci
patients nray benefit frorn plasma erchange. Once rernission
is achieved, patients should receive maintenance therapl.con
sisting of rituxinrirb, methotrexate. or azathioprine: rituximab
appears to be most effective for prer,,enting relapse and is
guideline pret.erred. On their olr,n. high dose glucocorticoids
are not suf ficient fbr induction and maintenance treatment ol
tt ANCA associated vasculitis. Mortality rates in patients receiv-
(D ing only glucocorlicoids are high. Observational studies from
=
gt the 1970s ar.rd l9U0s demonstrated that glucocorlicoids plus
o, cyclophosphamide was associated r,r,ith a significant improve
CL ment in sunival. fivc times that of historical controls. and a
n lou,er frequency ol relapse.
lt Clucocorticoicls plus azathioprine (Option A) is not
adequate ftrr inducing remission of GPA. Azathioprine has
.D
vl been usecl to maintain remission once achiel.ed (although
rituximab is superior firr maintenance o{'remission). but this
combination has never been shou'n tcl induce remission in
active ANCA associated vasculitis.
Although glucocorticoids plus methotrexate (Option B)
are pref'erred for active. nonsevere GPA. this patient has
se\ere slistemic CPA ancl tl.rerefore requires high-dose glu
cocorlicoids plus rituxin.rab.
Althougl.r glucocorlicoids plus mlcophenolate moletil
(Option C) can induce remission in ANCA associated \ascu
litis, patients treated u,ith this therap-v" ha'"e a higher rate of
relapse than those treated with glucocorticoids plus rituximab.
Because ANCA associated vasculitis is a chrcnic condition. the
treatment least associated with relapse is the most preferable.
XEY POIilIt
o High-dose glucocorticoids alone are not sufficient for
induction and maintenance treatment of ANCA-
associated vasculitis.
. High-dose glucocorticoids plus rituximab are the pre-
ferred treatment for induction of remission in severe
organ-threatening or life-threatening granulomatosis
with polyangiitis.
Bibliography
Chung SA, Langford CA, Maz M, et al. 2021 American College of
Rheumatolos//Vasculitis Foundation Guideline for the management of
antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis
Rheumatol. 2021. IPMl D: 34235894]
Item 34 Answer: B
Educational Objective: Manage osteoarthritis of the knee
with tai chi.
The most appropriate treatment is tai chi (Option B). This
patient has knee osteoarthritis (OA). A comprehensive plan
140
for the management of OA includes educational. behav-
ioral, psychosocial, and physical interventions. as r.tell as
pharmacologic therapy. In some patients, physical. psycho
social, mind-body interventions may be adequate to con-
trol symptoms; others may need sequential or combination
approaches. For a motivated patient like this one, mind body
interventions, such as tai chi, are appropriate to consider
as an adjunct option. Tai chi is a traditional Chinese mind
body practice that combines meditation with slon. gentle,
graceful movements; deep diaphragmatic breathing: and
relaxation. Tai chi has been shown in a randomized trial to
be as beneficial as physical therapy for knee and hip OA pain
and is strongly recommended by the American College of
Rheumatologz (ACR)/Arthritis Foundation (AF) guideline
for the management of knee and/or hip osteoarthritis.
Strong evidence supports the use of exercise in the
treatment of knee and hip OA. Most studies that assessed the
role ol aerobic exercise in the management of OA evaluated
walking and found it to be beneficial. However, high-impact
exercises (Option A) are not tolerated by patients with knee
OA and may be harmful. Thus, they are not appropriate for
this patient.
Patients frequently use transcutaneous electrical nerve
stimulation (TENS) (Option C) to help relieve the pain asso-
ciated with knee and/or hip OA. Holr,'ever, studies have
demonstrated a lack of benefit. and TENS should not be
recommended to the patient.
Weight loss is associated with a meaningful improve
ment in knee, hip, and hand OA symptoms that is propor
tional to the loss of weight. The efficacy of weight loss for OA
symptom management is enhanced by use of a concomitant
exercise program. Beyond that, speciflc diets, such as a vegan
diet (Option D), have not been shown to decrease OA related
symptoms and should not be recommended.
XEY POI lITS
. A comprehensive plan for the management of osteoar-
thritis includes educational, behavioral, psychosocial,
and physical interventions, as well as pharmacologic
therapy.
o Tai chi is as beneficial as physical therapy for patients
with osteoarthritis of the knee and/or hip.
Bibliography
Kolasinski SL, Neogi T, Hochberg MC. et al. 2019 American College of
Rheumatologl/Arthritis Foundation guideline for the management of
osteoarthritis of the hand. hip. and knee. Arthritis Rheumatol. 2020:
72:220 - 233. IPMID: 319081 63] doi:10. 1002 art.41142
35
Item
Ed
Answer: B
ucational Objective: Diagnose basic calcium
tr
phosphate-associated arthritis.
The most likely diagnosis is basic calcium phosphate asso
ciated arthritis (Option B). Deposition of basic calcium
pl.rosphate crystals (hydroxyappatite) occurs in older per
sons and targcts pcriarticular tendons and ligaments. In
q

fi rare instances, basic calcium phosphate crystal deposition
E is associated with inflammatory arthritis and periarthritis.
GONI
most classically manifesting in older women as "Milwau
kee shoulder." '[his inflammatory state causes progressive
destruction of the glenohumeral joint. and destruction of
the rotator cuff as shown in the radiograph below. The red
arrow pointing to the humeral head, illustrates aggressive
bone destruction at the glenohumeral junction. The blue
arrow illustrates distended subacromial/subdeltoid bursa
with fluid and calcific debris. Basic calcium phosphate crys-
tals are not seen on routine synovial fluid analysis because
visualization requires special stains and/or electron micros-
copy. Unlike in other crystal induced diseases. pain onset is
gradual.
Adhesive capsulitis (frozen shoulder) (Option A) usually
occurs in patients aged 40 to 70 years. The cause appears to
involve glenohumeral joint capsular thickening and fibrosis.
Patients describe shoulder pain that is often constant but
is worse at night and in cold weather: shoulder stiffness
is common. Adhesive capsulitis can be idiopathic but is
also associated with prolonged immobilization, anteced
ent shoulder surgery or injury. diabetes mellitus, hypo
thyroidism, and autoimmune disorders. On examination.
patients have limited passive and active range of motion in
all directions. Plain radiographs are of limited diagnostic use
in patients with adhesive capsulitis: most often the radio
graphs are normal, except for osteopenia in some cases. This
patient's abnormal shoulder radiograph is not consistent
with adhesive capsulitis.
Calcium pyrophosphate deposition (CPPD) disease
(Option C) is an unlikely diagnosis. Although it may involve
the shoulder joint, it is typically associated with osteoar-
thritis, not severe erosive joint destruction. Calcium pyro-
phosphate crystals, which are weakly positively birefringent
(blue when parallel to and yellow when perpendicular to
the polarizing axis ol'an optical filter) and classically rhom'
boid shaped, are usually identified in the joint fluid. Chon.
drocalcinosis, visible as a thin white line that tracks below
the surface layer of the cartilage within the joint. may be
visible on plain radiograph. Flxtensive soft tissue calcifica
tion such as seen in this radiograph is not typical of CPPD.
Answers and Critiques
Rheumatoid arthritis (Option D) rarely presents in the
shoulder in older patients. It is associated with in{lamma
tory joint fluid (leukocyte count, 2000 20.000/pl. [2.0 20 x
fOe/L]) and is not associated with periarticular calcifications
on plain radiographs. Monoarticular presentations of rheu
matoid arthritis are uncommon.
KTY POIXTS
o Deposition of basic calcium phosphate crystals
(hydroxyappatite) occurs in older persons and targets
periarticular tendons and ligaments.
. In rare instances, basic calcium phosphate crystal
deposition is associated with inflammatory arthritis vt
(u
and periarthritis, most classically manifesting in older ET
women as "Milwaukee shoulder," an inflammatory
state that causes progressive destruction of the rotator rJ
cuff and glenohumeral joint. !,
.E
ul
BibHography (l,
McCarthy GM, Dunne A. Calcium crystal deposition diseases beyond gout.
t=
Nat Rev Rheumatol. 2018;14:592-602. IPMID: 30190520] doi:10.1038/
s41584 018 0078-5
Item 35 Answer: B
Educational Objective: Treat rheumatoid arthritis with
the most appropriate biologic therapy.
The most appropriate treatment is adalimumab (Option B).
Rheumatoid arthritis treatment is aimed at controlling clin-
ical disease and joint damage. Patients whose condition is
unresponsive to initial treatment with methotrexate, with
or without another nonbiologic disease modifying anti-
rheumatic drug, could receive triple therapy (methotrexate,
sulfasalazine, and hydroxychloroquine) or a biologic agent.
The choice of a drug regimen in such patients depends on
many factors, including disease activity, comorbid condi-
tions, patient preferences for route of administration and
frequency ofdosing, adverse prognostic features, and regu-
latory and cost barriers to drug access. This patient has active
clinical disease and radiographic evidence ofworsening joint
damage despite combination treatment with sulfasalazine
and methotrexate. Escalation to additional therapy with a
tumor necrosis factor (TNF) inhibitor, such as adalimumab,
is an appropriate choice. Despite multiple comorbidities, this
patient has no contraindications to treatment with a biologic
(such as active infection or heart failure). All TNF inhibitors
provide similarbeneflt and maybe used in this patient based
on the factors outlined above. These regimens may have a
faster onset of action than triple therapy with nonbiologic
disease-modi$zing antirheumatic drugs.
Reasonable alternatives to a TNF inhibitor include sev
eral other parenterally administered agents, including aba
tacept (Option A), the anti-interleukin-6 receptor antibody
tocilizumab (Option D), and the oral targeted synthetic
Janus kinase inhibitor tofacitinib (Option E). However,
these agents are usually used after failure or intolerance of
a TNF inhibitor. Furthermore, this patient has signiflcant
141
 Answers and Critiques
comorbidities that should prompt caution with consid
eration of these therapies. Abatacept has been associated
with exacerbations of COPD in clinical trials but not in
real world practice. However. it must be given cautiously
in patients with COPD. Tocilizumab increases the risk for
bowel perforation in patients with a history of diverticuli-
tis, and tofacitinib poses an increased risk for thrombotic
events.
Anakinra (Option C) is an interleukin-1 blocker
approved for rheumatoid arthritis. but it is less efficacious
than other biologics and rarely used for this indication.
TEY POIXI
D Almost all patients with SLE will be positive for antinuclear
vt
o Patients with rheumatoid arthritis not responding to
€
.D
methotrexate, with or without another nonbiologic
UI disease modiffing antirheumatic drug, could receive
o, triple therapy (methotrexate, sulfasalazine, and
EL hydroxychloroquine) or a biologic agent.
n f,EY POITIS
Bibliography
lr
Smolen JS, Landewd RBM, Bijlsnla lWJ. d al. EULAR recommendations fbr
.D the management of rheun'latoid rrthritis with synthetic and biological
ut
disease-modifying antirheumatic drugs, 2019 update. Ann Rheum Dis.
2O2O:79 :685 699. IPMl D: 319693281
Item 37 Answer: C matoid arthritis include rheumatoid factor, anti-cyclic
Educational Objective: Diagnose rheumatoid arthritis.
The most likely diagnosis is rheumatoid arthritis (Option
C). Rheumatoid arthritis is characterized by the subacute
onset of pain and swelling in multiple joints, including the
proximal interphalangeal joints of the hands and feet, meta
carpophalangeal and metatarsophalangeal joints, wrists,
knees, and ankles. Prolonged morning stiffness is common;
physical examination reveals polyarticular synovitis. Joint
involvement is characteristically symmetric. Distal interpha-
langeal joints are rarely. ilever, involved. Laboratory studies
supporting the diagnosis include rheumatoid factor (present
in 7O"/,, of patients. but of limited specificity), anti-cyclic
citrullinated peptide antibodies (present in 70'l,, of patients
and 9511, specific), and elevated inflammatory markers.
Arthritis due to chikungunya virus (Option A) may
mimic rheumatoid arthritis with polyarticular involvement
of small and large joints. Onset is typically more rapid than
in rheumatoid arthritis; follows travel to endemic areas: and
is preceded by fever, headaches, and rash. Autoantibodies
would not be expected to be positive, although inflamma
tory markers may be elevated.
Parvovirus B19 infection (Option B) causes a symmet
ric inflammatory arthritis involving the hands that mimics
rheumatoid arthritis. Although polyarticular synovitis may
be present initially, joint swelling resolves in days to weeks
in most cases. Onset typically occurs after exposure to a par
vovirus-infected child, such as in a daycare setting. Adults
with parvovirus B19 arthritis usually do not display the char
acteristic "slapped cheek" rash seen in children. Anti cyclic
citrullinated antibodies are typically absent.
142
Arthritis is common in patients with systemic lupus
ery,thematosus (SLE) (Option D). SLE arthritis can have an
acute or subacute onseti can be mono . oligo . or poll,artic
ular; frequently affects small joints of the hands. elbon's. and
knees: and can lead to malalignment deformities similar to
rheumatoid arthritis. However. SLE arthritis does not lead
to underlying bony erosions as seen in rheumatoid arthritis.
The number of joints involved is usually fbrt'er than seen in
rheumatoid arthritis. Characteristic mucocutaneous flnd
ings of SLE accompany arthritis onset. including malar rash.
discoid rash, and alopecia. Systemic involvement (e.g.. leu
kopenia. thrombocytopenia, nephritis) may also be present.
antibodies. Because this patient lacks any additional features
of SLE. and because positivity for anti cyclic citrullinated
peptide antibodies is not a feature of SLE arthritis. a diagno
sis of SLE is unlikely.
o Rheumatoid arthritis is characterized by the subacute
onset of pain and swelling in multiple small joints of
the hands and feet, associated with prolonged morn-
ing stiffness and physical examination evidence of
polyarticu lar synoviti s.
. Laboratory studies supporting the diagnosis of rheu
citrullinated peptide antibodies, and elevated inflam-
matory markers.
Bibliography
Sparks JA. Rheumatoid arthritis. Ann lntern l\{ed. 2019:170:lTCl ITCl6.
IPMID: 305968791 doi: 10.7326 AITC2OI90l0l0
Item 38 Answer: B
Educational Objective: Screen for cancer in a patient
with dermatomyositis.
The most appropriate test to perform next is a colonos
copy (Option B). This patient has dermatomyositis. A mus-
cle biopsy is not necessary to diagnose dermatoml,ositis in
patients with characteristic clinical and laboratory findings,
including proximal muscle weakness. strikingly elevated
serum creatine kinase levels. and skin manifestations that
are unique to dermatomyositis. The most typical feature is
the Gottron rash (Gottron papules and Gottron sign), which
is characterized by erythematous to violaceous areas over the
metacarpophalangeal and proximal interphalangeal joints.
There is an association between risk for malignancy and
dermatomyositis (3- to 12-fold higher in patients with new
dermatomyositis than in age-matched populations) and, to a
lesser extent, polymyositis. The risk for malignancy is great
est in the 3 years following the diagnosis of dermatomyositis
or polymyositis. Common associated cancers are ovarian.
lung, pancreas, stomach, and colon cancer and lymphoma.
The most important initial step is symptom-directed test-
ing and age and sex-appropriate cancer screening because

patients with active malignancy associated with dermato-
myositis need prompt. appropriate treatment fbr both can
cer and the autoimmune disease. lf an initial directed cancer
screen is normal, many experts will order CT of the chest,
abdomen, and pelvis. Because this patient has unintentional
weight loss and anemia, the flrst test should be a colonos-
copy to assess for colorectal cancer.
Results of antinuclear antibody testing (Option A) are
positive in about 50'X, of patients with dermatomyositis, but
a positive result would not meaningfully add to the diagnos
tic or prognostic evaluation.
Muscle biopsy (Option C) would likely confirm the
diagnosis and can be useful to improve understanding
of prognosis. However, this test is not necessary to diag-
nose dermatomyositis when the clinical features are this
typical.
Pulmonary function testing (Option D) and other
evaluation for lung disease may also be warranted in most
patients with dermatomyositis. especially those with symp
toms or findings, antisynthetase antibodies, or factors pos
ing high risk for interstitial lung disease. In a patient without
active pulmonary symptoms, however, this testing is less
urgent than is an evaluation for cancer.
I(EY POITTS
. A muscle biopsy is not necessary to diagnose dermat
omyositis in patients with characteristic clinical and
laboratory findings, including proximal muscle weak-
ness, strikingly elevated serum creatine kinase levels,
and skin manifestations that are unique to dermato-
myositis.
o The risk for malignancy is 3- to 12 fold higher in
patients with new dermatomyositis than in age
matched populations; symptom-driven testing
and age- and sex appropriate cancer screening are
indicated.
Bibliography
Qiang JK. Kim WB. Biribergenova A. et tl. Risk of maligniinc) in dermato
myositis and polymyositis. J Cutan Med Surg. 2017;21:l3l 136. [PMID:
'lts:tltzgl
Item 39 Answer: A
Ed u cati o n a I Obj ective : Diagnose
adult-onset Still disease.
The most Iikely diagnosis is adult onset Still disease (AOSD)
(Option A). This patient's symptoms (daily evening fevers
accompanied by salmon-pink rash, inflammatory arthritis,
sore throat, and serositis) and laboratory evidence ol high
inflammatory markers and leukocytosis are most consistent
with AOSD, a condition of unknown cause. His high serum
ferritin level, although not specific, is fairly characteristic of
AOSD. Because no speciflc test exists fbr AOSD, it remains a
diagnosis of exclusion, and other causes should be consid
ered. Past treatment options for AOSD, including glucocor
ticoids and methotrexate, were frequently inadequate. The
use of interleukin-p directed biologic therapies, including
Answers and Critiques
anakinra and canakinumab, has been successful. Anti inter-
leukin 6 therapies have shown promise.
Like AOSD, familial Mediterranean f'ever (FMF) (Option
B) is a disease of systemic inflammation; it is also associated
with fever, joint pain, abdominal pain, and rash in the set
ting of high inflammatory markers. However, patients with
FMF typically experience lifelong recurrent intermittent
episodes of inflammatory disease, typically lasting several
days and occurring approximately monthly, rather than the
persistent inflammatory state experienced by this patient.
Patients with infectious endocarditis (Option C) expe
rience fevers, petechial rashes, and arthritis/arthralgia.
Although infectious endocarditis should always be consid UI
o
ered in patients with fever ol unknown origin, the pattern
ET
of daily evening fevers accompanied by salmon pink rash is
not characteristic, and the lack of a cardiac murmur argues (J
against the diagnosis. -t
Patients with systemic lupus erythematosus (SLE) tg
(Option D) may experience a wide constellation of symp- UI
(l,
toms, including rash, arthritis, and serositis. Fever in SLE
UI
may be present but is not typically as high as seen here, and =
E
it does not cycle daily. Moreover, the salmon pink rash seen
here, directly associated with fever, is not characteristic of
SLE. SLE is much less common in men, n.raking it less likely
in this patient.
f,EY POII{T
. Adult onset Still disease, a condition of unknown
cause, is characterized by daily evening fevers;
salmon pink rash; inflammatory arthritis; sore throatl
serositis; and Iaboratory findings of high inflamma-
tory markers, elevated ferritin level, and leukocytosis.
Bibliography
Giacomelli R. Ruscitti P, Shoenfbld \'. A comprehensi\.e review on ,dult
onset Still's disease. J Autoimmun. 2018193:2.1 36. IPMID: 300771'251
Item 40 Answer: C
Educational Objective: Treat fibromyalgia in a patient
with depression and anxiety.
The most appropriate treatment is duloxetine (Option C).
ln addition to discussing the diagnosis at length and pro
viding education regarding nonpharmacologic recommen
dations, such as low impact aerobic exercise, a medication
is warranted. Choice of pharmacologic therapy is based
on symptom proflle, patient comorbidities, and medication
adverse effects because few trials have directly compared
the efflcacy of medications. Of the available choices, duloxe
tine (a serotonin norepinephrine reuptake inhibitor) is most
appropriate tbr a patient with fibromyalgia and comorbid
depression and anxiety because it is FDA approved for these
indications as well. Duloxetine should be started at 30 mgrd
and titrated to 60 mg/d after a week or so to mitigate nausea,
a frequent early adverse effect that usually dissipates over
time. If the drug is stopped, a slow taper should be used
because withdrawal symptoms often occur with sudden
143
 Answers and Critiques
discontinuation. Patients should be made aware that ben-
efits of the medication will not be seen for several weeks.
To measure interval improvement, the Fibromyalgia Impact
Questionnaire (a validated clinical tool) or other validated
clinical tool should be completed before and an appropriate
time after an intervention to assess change in clinical status.
Although amitriptyline (Option A) is an acceptable
off label therapy for flbromyalgia, it is sedating and not
appropriate for someone with a job such as truck driving.
Amitriptyline is not an effective antidepressant at the low
doses recommended for flbromyalgia.
Diclofenac (Option B) is an NSAID. Anti-inflammatory
D medications, including NSAIDs and glucocorticoids, are not
Ut more effective than placebo in treating flbromyalgia.
€
.D Pregabalin (Option D), although an FDA-approved med
ar. ication for flbromyalgia, is not the best option fbr someone
o, with a physically hazardous occupation because both seda
EL tion and dizziness are frequent adverse effects. Pregabalin
n would also not address this patient's depression or anxiety.
It Although tramadol (Option E) is helpful fbr treating
E fibromyalgia in the short term, prescribing an opioid is inap-
.D
UI propriate in a patient with a history of opioid use disorder or
someone with a job that requires a constant state of alertness.
I(EY POI]ITS
r Choice of pharmacologic therapy for fibromyalgia is
based on symptom profile, patient comorbidities, and
medication adverse effects.
o Duloxetine is appropriate for a patient with fibromy
algia and comorbid depression and anxiety because it
is approved for these indications as well.
Bibliography
Mactarlane GJ. Kronisch C. Dean LE. et al. I:ULAR revised recommendations
Ibr the management ol fibromyalgia. Ann Rheum Dis. 2017;76:318-328.
IPMID, 27377815) doi:10.11 36/annrheumdis 2016 209724
Item 41 Answer: A be assessed for bone loss and fracture risk and treated
Educational Objective: Treat glucocorticoid-induced
osteoporosis with an oral bisphosphonate.
The most appropriate treatment is alendronate (Option A).
Glucocorticoid therapy is a major risk factor for bone loss
and increased fracture risk. In addition, fractures occur at
higher bone mineral density values than in patients with
postmenopausal osteoporosis. The risk increases with dos
age and duration, but even low dosages of5 to 7.5 mg/d are
associated with increased risk for fracture. Thus, patients
receiving long term glucocorticoids should be assessed for
bone loss and fracture risk and treated on the basis of the
assessment. Both bone density measurement and gluco
corticoid-corrected (addition of 15'2, to the risk), Fracture
Risk Assessment Tool (FRAX)-calculated, 10 year proba
bility can be helpful in this assessment. This patient has
a corrected FRAX score for the hip of 3.5'1,, placing her at
a high risk for fracture and above the treatment thresh-
old to prevent hip fracture (>s'2, at the hip or >20% for
144
major osteoporosis-related fracture). Thus, treatment for
glucocorticoid-induced osteoporosis is appropriate. This
approach also applies to patients at moderate or interme
diate risk for fracture (FRAX risk score for the hip ofl?, to
3%); those with a score of 10% to 19'1, overall would also be
a candidate for preventive treatment. Oral bisphosphonates,
such as alendronate, are flrst-line therapy because of their
efficacy, cost, availability, and ease of administration. They
are preferred in guidelines not only because ofcost, safety,
and e{ficacy but also because ofa lack ofsuperiority ofother
osteoporosis medications. Clinical trial data show that both
alendronate and risedronate have elficacy in glucocorticoid
induced osteoporosis. For patients who cannot tolerate oral
bisphosphonates or have other circumstances precluding
their use, intravenous zoledronic acid may be used.
Calcitonin (Option B) is not typically used to treat or
prevent glucocorticoid induced osteoporosis because effi
cacy data are lacking and other, more effective drugs are
available.
Romosozumab (Option C) is a dual anabolic and anti
resorptive agent that works by inhibiting sclerostin. No data
yet support the use of romosozumab for preventing or treat
ing glucocorticoid-induced osteoporosis.
Other options are teriparatide (a parathyroid hormone
analogue) (Option D) and denosumab (a receptor activator
of nuclear factor rB [RANK] ligand inhibitor). Teriparatide
is the next best option for patients who cannot tolerate
bisphosphonates or who continue to sustain fractures while
taking bisphosphonates. However, it is not the preferred first
choice for this patient. Denosumab is used as a backup to
bisphosphonates and teriparatide, primarily because of the
increased risk for vertebral fracture after discontinuation.
t(EY POll{TS
o Glucocorticoid therapy is a major risk factor for bone
loss and increased fracture risk.
. Patients receiving long-term glucocorticoids should
on the basis of the assessment.
Bibliography
Buckley L, Cuyatt G, Fink HA, et al. 2017 American College ofRheumatologr
guideline fbr the prevention and treatment of glucocorticoid induced
osteoporosis. Arthritis Rheumatol. 2017 ;69:1521 1537. IPMID: 28585373]
Item 42 Answer: D
Educational Objective: Diagnose a mechanical
soft-tissue injury.
This patient has a mechanical soft tissue injury (Option D),
likely lateral epicondylitis. Common nonarticular sources
of musculoskeletal symptoms are the soft tissues (tendons,
ligaments, and bursae) around or away from the joints.
Isolated tendon and/or ligament involvement usually sug-
gests noninflammatory disorders, such as mechanical
injury/irritation, overuse, or degeneration (e.g., rotator cuff
disorders or tennis elbow).

The elbow is a very unlikely location for a degenera-
tive joint disease (Option A), such as osteoarthritis. Localized
osteoarlhritis, in which a single joint is affected, is more often a
consequence of injury or joint asymmetry and often occurs in
weight bearing joints (hip or knee), not the elbows or shoul
ders. Because this patient has no history of injury and has full
range of elbow motion, localized osteoarthritis is unlikely.
Disorders of central pain processing (Option B), such
as fibromyalgia, have hyperresponsive pain centers in the
brain and spinal cord. Patients characteristically note allody-
nia (a heightened sensitivity to stimuli that are not normally
painful) and hyperalgesia (an increased response to painful
stimuli). An additional characteristic feature is "wind up"
or temporal summation. When repeatedly exposed to a
mildly uncomfortable stimulus, patients with flbromyalgia
experience progressively additive pain, indicating that the
pain stimuli are both persistent and inadequately damped.
Finally, patients fypically have difluse rather than localized
pain. This patient has no features characteristic of a central
pain processing disorder. The local nature of her pain also
argues against flbromyalgia. which is a disease of wide
spread pain.
The differentiation between inflammatory and non-
inflammatory signs and symptoms is central to the evalu
ation of patients with musculoskeletal pain. Autoimmune
conditions typically present with inflammation, whereas
mechanical or degenerative disorders are characteristically
noninflammatory. The cardinal signs of inflammation are
pain, erythema, swelling, and warmth; with the excep,
tion of pain, noninflammatory conditions usually lack these
features. These features are absent in this patient, making
inflammatory arthritis (Option C) an unlikely diagnosis.
I(EY POITTS
. Isolated tendon and/or ligament involvement usually
suggests noninflammatory disorders, such as mechan-
ical injury/irritation, overuse, or degeneration.
. The cardinal signs of inflammation are pain, ery-
thema, swelling, and warmth; with the exception of
pain, noninflammatory conditions usually lack these
features.
Bibliography
Ilatten R. Coady D. The rheumatological examination. Medicine.
2018;46:161 165. doi.orgi 10. l0161j.mpmed.2O17.12.OO2
Item 43 Answer: B 100 genetic loci currently recognized as associated with
Educational Objedive: Avoid live vaccines in a patient
receiving biologic therapy.
The measles, mumps, and rubella vaccine (Option B) is
contraindicated in this patient. Patients with autoimmune
rheumatologic diseases, such as rheumatoid arthritis, are
at increased risk for infections because of multiple factors,
and infection prevention and vaccination are crucial. Ide-
ally, patients with autoimmune diseases should be updated
Answers and Critiques
with vaccinations 2 to 4 weeks before initiating immu-
nomodulatory agents, but this is not easy to accomplish.
Evidence suggests attenuation of response to vaccines in
patients receiving biologic agents. Patients receiving tra
ditional immunomodulatory agents (disease modifying
antirheumatic drugs) in doses that cause only low grade
immunosuppression can receive any immunizations, killed
or live, without any problems. Low-grade immunosuppres
sion is deflned as short term prednisone use of less than
20 mgld, methotrexate dosage of less than 0.4 mg/kg/wk,
and azathioprine dosage of less than 3.0 mg/kg/d. Patients
who are receiving these immunosuppressive agents at higher
dosages should not receive live vaccines. Similarly, patients t
o
receiving biologic or small-molecule therapies should not
ET
receive live vaccines, such as measles, mumps, and rubella,
or live attenuated vaccines, such as influenza and herpes (,
zoster, because ofrisk for infection by the vaccine agent. In -tE
this patient, methotrexate at a low dosage (0.2 mg/kg/wk) ag
would not constitute a contraindication to administration vt
L
!,
of any vaccination. However, she is also is being treated
with tofacitinib, and vaccination with measles, mumps, and vt
=
E
rubella is therefore contraindicated.
The hepatitis B virus (Option A), quadrivalent influenza
(Option C), tetanus toxoid, reduced diphtheria toxoid, and
acellular pertussis (Option D), and 13 valent pneumococcal
conjugate (Option E) are killed vaccines and are not contra
indicated in this patient.
f,EY POII{T
. Patients receiving biologic or small-molecule thera-
pies should not receive live vaccines (such as measles,
mumps, and rubella) or live attenuated vaccines (such
as influenza and herpes zoster) because of risk for
infection by the vaccine agent.
Bibliography
Furer V, Rondaan C, Heijstek MW, et al. 2019 update of EULAR recommen
dations for vaccination in adult patients with autoimmune inflammatory
rheumatic diseases. Ann Rheum Dis. 2020;79:39 52. IPMID: et+tgOOSl
Item 44 Answer: B
Educational Objective: Confirm the diagnosis of
rheumatoid arthritis with autoantibody testing.
The combination of anti-cyclic citrullinated peptide (CCP)
antibodies and rheumatoid lactor (Option B) will be
most helpful in establishing the diagnosis. Among some
rheumatoid arthritis (RA) risk, the most important is the
class II HLA group, especially HLA D alleles. These alleles
code for the shared epitope, a five-amino acid sequence that
binds and presents citrullinated peptide antigens important
in the pathophysiologz of RA. Because citrulline is an amino
acid that does not normally occur in humans, citrullinated
proteins are immunogenic, especially in people who also
have the shared epitope. Citrulline is formed by the action of
the enzyme peptidylarginine deiminase, which is found at
145
 Answers and Critiques
sites olinflammation and deiminates arginine to form citrul
Iinated peptides. Anti-CCP antibodies are closely associated
with the pathogenesis of RA and are highly speciflc (9S'1,).
In addition, anti-CCP antibodies may be positive in patients
with RA who are negative for rheumatoid factor. Rheumatoid
factor is less speciflc tbr RA, is present in only about 70'l. of
patients with RA, and may be seen in other diseases (such as
hepatitis C virus infection, endocarditis, and systemic lupus
erythematosus). However, a f'ew patients, particularly early
in the course of the disease, may be negative for anti CCP
antibodies but positive for rheumatoid factor; thus, both anti
CCP antibodies and rheumatoid factor, rather than either
D alone (Options A, D), should be measured to increase the
UI diagnostic speciflcity and sensitivity of testing. When they
E are present together, their specificity is further increased.
.D
-
U) tsoth antibodies are included in the diagnostic criteria for RA.
q,
The complement system is an essential part ol the
CL immune response, promoting vasodilation, attracting leu
a.l
kocytes, and assisting in the lysis of opsonized bacteria
ll during humoral immunity. Complement components, such
E as C3 and C4 (Option C), are acute phase reactants that
.D
l^ are synthesized in the liver and rise in many inflammatory
states. However, in response to diseases that lead to immune
complex formation (systemic lupus erythematosus; cryo
globulinemic and urticarial vasculitis) and other states, such
as inlections (bacterial endocarditis, sepsis, viremia) and
glomerulonephritis, complement cascades are activated, and
serum C3 and C4 levels fall because of excessive consump
tion. Although serum C3 and C,1 levels may be elevated in
patients with RA, this nonspecific finding will not be helpful
in establishing the diagnosis.
rEY POIIITS
r Anti cyclic citrullinated peptide antibodies are a diag-
nostic marker of rheumatoid arthritis and have a high
specificity (95%) but may be absent in early disease
when rheumatoid factor is positive.
. The presence of both anti-cyclic citrullinated peptide
antibodies and rheumatoid factor increases the diag
nostic likelihood of rheumatoid arthritis.
Bibliography
\Vlrburtor.r L, Hider St.. Mallen CD. et al. Suspected very early inflammatory
rheumatic diseases in prinrirry cart. Best Pract Res CIin Rheumatol.
2019:33:101,119. IPMID: 318105501 doi: 10. lOl6r'j.berh.2019.06.001
Item 45 Answer: A
Ed u cati o na I O bj ective : Diagnose inclusion body myositis.
'lhe most likely diagnosis is inclusion body myositis (Option
A). h.rclusion body myositis is an uncommon cause of weak
ness generally seen in older adults, characterized by a slow
insidious onset. It can be distinguished clinically from poly
myositis by the involvement of distal muscle groups in addition
to proximal muscle groups. Weakness in flnger flexors and
atrophy of tbrearm muscles are characteristic features. Muscle
distribution is usually but not always symmetric. Up to half of
146
patients with inclusion body myositis have cricopharyngeal
muscle involvement, leading to dysphagia and increased risk
fbr aspiration. Patients with inclusion body myositis can have
elevated serum creatine kinase levels. but elevations are usu
ally more modest, less than 10 times the upper limit of normal,
as compared with other forms of idiopathic inflammatory
myopathies in which serum creatine kinase levels are gener
ally higher. A muscle biopsy can help to conflrm the diagnosis
but is not needed when clinical fbatures are characteristic.
Polymyositis (Option B) can also present with prcigres
sive muscle weakness. However, it generally progresses more
rapidly over weeks or months and involves only the proximal
muscles. Activities such as arising from a chaiq climbing
stairs, and lifting objects above shoulder height are typically
afl'ected. Onset over several years with a more modest degree
of weakness, as seen in this patient, would be unusual in poly
myositis. In addition, polymyositis would not be expected to
cause weakness of the hands or the distal arm muscles.
Statins are generally safe and well tolerated. 'lhey can
cause asymptomatic. dose related elevations in aminotrans
t'erase levels in approximately 1'l, of patients, but liver injury
occurs in less than 0.001'X, ofpatients. The incidence ofstatin
associated muscle symptoms is no greater than 1u1,, and the
incidence of myopathy (Option C) and rhabdomyolysis is
less than 0.1'ln. However, some patients can have muscle
symptoms from statin therapy without an elevation in serum
creatine kinase levels. and it can then be difficult to be cer
tain whether muscle symptoms are due to statin therapy.
'[he patient's prolonged course, minor serum creatine kinase
elevation. and muscie weakness distribution are more char
acteristic of inclusion body myositis than statin myopathy.
Other autoimmune disorders, such as systemic lupus
erythematosus (Option D), can cause myositis. However,
they generally have other characteristic features, such as
arthralgia and skin rashes, that are not seen in this patient.
I(EY POII{T
o lnclusion body myositis can be distinguished from
other forms of idiopathic inflammatory myopathy by an
insidious onset, slower progression, and involvement of
distal muscle groups as well as proximal muscles.
Bibliography
l.undberg lE, de \risser M. Werth Vll Chssilication ol m),-ositis. Nat Rev
Rheunratol. 2O18:14i269 278. lPMll): 2965112i1 doi:l0.1038inrrheunr.
201rJ.4l
ttem 46 Answer: C
Educational Objective: Treat systemic lupus
tr
erythematosus with nephritis.
'lhe most appropriate treatlrent is prednisone plus hldrory
chlorocluine and mycophenolirte mofetil (Option C)' this
prtient has new onset s1'sten-ric lupus erythematosus (SI.F.)
r,r,ith nephritis. t.upr.rs nephritis can present with rrlini
r.r.ral laboratory abnorntalities (non nephrotic proteinuria.
hcmaturia), fiank neph ril is ( hypertensiort, lower extreln i ty

tr
CONT.
edema, active urine sediment, and elevated serum creati
nine level), and/or nephrosis (nephrotic range proteinuria.
dependent edema, and thrombosis). Anti double-stranded
DNA antibody titers are a marker for risk, and complement
consumption is a common phenomenon during active kid
ney disease. Untreated active disease may progress to kidney
tailure. He has f'ew other symptoms ot'SLE, but laboratory
findings and clinicai presentation strongly suggest this diag
nosis. Although kidney biopsy is indicated to determine
histologic subtlpe and chronicity, treatment should not be
delayed. I{igh dose or "pulse" glucocorticoicls are indicated
fbr new or recurrent active nephritis and should be fblloued
by a glucocorticoid taper. Ilydroxychloroquine is indicated
in almost all patients rn'ith newly diagnosed SLE. In addition,
fbr moderate or severe disease that is organ threatening,
i
additional immunosuppressive therapy is indicated to con-
trol disease and to allow {br tapering of glucocorticoid ther
apy. For most patients with new nephritis, induction with
mycophenolate mof'etil is the preferred agent. lntravenous
cyclophosphamide can also be used if patients have severe
disease or are intolerant to mycophenolate.
Prednisone plus azathioprine (Option A) could be used
as maintenance therapy; typically along with hydroxychlor
oquine. but azathioprine is not first-line therapy fbr ner.r,
onset lupus nephritis.
Prednisone plus hydroxychloroquine (Option B)
is appropriate initial therapy for mild SLE. However, in
a patient with organ threatening disease, such as lupus
nephritis, combination immunosuppressant tl-rerapy that
includes mycophenolate mofetil or cyclophosphamide is
rreeded tocontrol the disease.
Prednisone alone (Option D) will help control immedi
ate symptoms, but nithout additional immunosuppressive
agents, return of disease activity is likely as the prednisone
dosage is tapered. Prolonged use ofmoderate or high-dose
glucocorticoids is associated r.tith a r,ariety of adl.erse out
comes and should be avoided.
(EY POITT'
. For systemic lupus erythematosus that is organ-
threatening, combination immunosuppressive
therapy is indicated to control disease.
o For most patients with newly diagnosed lupus nephri-
tis, induction with glucocorticoids and mycophenolate
mofetil is the preferred immunosuppressive treatment.
Bibliography
Fanouriakis A, Kostopoulou M, Alunno A, et al. 2019 update of the EULAR
recommendations for the management of systemic lupus erythematosus.
Ann Rheum Dis.2019;78:736 745. [PMID: 30926722]
Item 47 Answer: B Item
Educational Objective: Diagnose medication-induced
xerostomia.
The most likely cause of this patient's oral dryness is medi-
cation adverse effects (Option B). Medication adverse effects
Answers and Critiques
and mouth breathing are among the most common causes of
dry mouth. Her symptoms do not suggest a speciflc rheuma-
tologic disorder. In particular, she is unlikely to have Sjogren
syndrome (Option C). Oral dryness is a common symp
tom, whereas Sjdgren syndrome is relatively rare. She has
no ocular dryness; has a serologic proflle that does not com
port with a diagnosis of Sj0gren syndrome (absence of high
titers of antinuclear antibodies and/or rheumatoid factor,
anti Ro/SSA, and anti LalSSB autoantibodies); and has no
other symptoms, physical examination flndings, or labora
tory results to suggest the disease. Although it is not impos-
sible that she has Sj6gren syndrome, the oral dryness is more
likely the result of another cause. Several medications (such ur
(u
as antidepressants and antihistamines) frequently cause oral
ET
dryness. The patient takes three such medications (amitripty
line, cetirizine, and citalopram). It is important that patients (J
like this are not misdiagnosed with rheumatologic disease !t
and treated inappropriately with immunosuppressive agents. rE
Hypothyroidism in adults (Option A) is often associated U!
with a buming sensation of the mouth, but oral dryness is o
not a commonly reported symptom. This patient has appro- =
a
priately treated hypothyroidism, with a normal thyroid-
stimulating hormone level, making this diagnosis unlikely.
This patient's history review of systems, and physical
examination do not suggest systemic lupus ery.thematosus
(Option D). Prominently absent from this patient's history
are indications ofskin disease, serositis, and kidney disease;
other than dry mouth, the physical examination is normal.
The normal ery.throcyte sedimentation rate argues against a
system inflammatory or autoimmune condition. An antinu
clear antibody titer of 1:80 is nonspecific and unremarkable
and may be seen in up to 50% of persons tested. Even at much
higher titers, a positive antinuclear antibody result alone does
not imply the presence of systemic lupus erythematosus.
t(EY PO$tT5
o ]\{edications, such
as antidepressants and antihista-
mines, and mouth breathing are common causes of
drymouth.
. In the absence of additional suggestive symptoms,
physical findings, and supporting laboratory data, oral
dryness should not be attributed to a rheumatologic
condition.
Bibliography
Shiboski CH, Shiboski SC, Seror R, et al; International Sjogren's Syndrome
Criteria 'Working Group. 2016 American College of Rheumatolos//
European League Against Rheumatism classification criteria fbr primary
Sjdgren's syndrome: a consensus and data driven methodolos/ involving
three international patient cohorts. Ann Rheum Dis. 2ol7;76:9 16.
IPMID : 27 7 a9 4661 doi : 1 0. 113 6 /annrheumdis 201 6 21057 7
48 Answer: B
Ed u cati o na I O bj ective : Diagnose hypersensitivity
vasculitis.
The most likely diagnosis is hypersensitivity vasculitis
(Option B), a limited cutaneous small vessel vasculitis.
147
 Answers and Critiques
This patient has a vasculitic rash, with a large crop of pete-
chiae and palpable purpura. The appearance of the rash
suggests small-vessel rather than medium vessel involve-
ment (for example, there are no subcutaneous nodules or
necrosis). Several types ofsmall vessel vasculitis can affect
the skin. The first step in the evaluation of a cutaneous
vasculitis is to determine whether systemic symptoms or
flndings are present. In this case, no flndings suggest a sys-
temic illness. The physical examination is unremarkable
aside from the rash, and results of laboratory testing are
similarly unrevealing. This strongly suggests that the diag
nosis is hypersensitivity vasculitis. This condition is often
triggered by medications (thiazide diuretics are among
Ut the most lrequent culprits) or infections, although about
€
(D 50'1, of patients have no known precipitant. Drug-induced
ut hypersensitivity vasculitis most often occurs 7 to 10 days
o, after the introduction of a new medication, and recovery
EL is likely with discontinuation of the drug. If symptoms
n persist or recur, anti-inflammatory agents, topical or low
dose systemic glucocorticoids, colchicine, or dapsone may
,tr
E be helpful.
.D
.,t This presentation is not congruent with eosinophilic
granulomatosis with polyangiitis (Option A). This systemic
small vessel vasculitis invariably involves the lungs (usually
with a prodromal phase of rhinitis and asthma and other
pulmonary manifestations with disease progression) and
often affects the peripheral nervous system and skin. Lab
oratory testing reveals the presence of ANCA antibodies
(myeloperoxidase subtype) about half the time, and periph-
eral eosinophilia is expected.
Polyarteritis nodosa (Option C) is unlikely. Although
it can present with palpable purpura, as in small-vessel
vasculitis, other skin flndings indicating medium-vessel
involvement would be present (e.g., livedo reticularis, sub
cutaneous nodules, painful deep ulcers, or skin necrosis).
This patient has no other features of polyarteritis nodosa,
such as constitutional and musculoskeletal symptoms,
peripheral nervous system involvement, or gastrointestinal
disease.
Rheumatoid vasculitis (Option D) is rare. It develops
in patients with long-standing and severe rheumatoid
arthritis and is almost nonexistent in properly treated
patients. It most often affects the skin but is a medium-
vessel vasculitis. This patient does not have rheuma
toid arthropathy; thus, rheumatoid vasculitis is not
possibility.
XEY POIilTS
o The first step in the evaluation of a cutaneous vasculi
tis is to determine whether systemic symptoms or
findings are present.
. Hypersensitivity vasculitis, a limited cutaneous small-
vessel vasculitis, is often triggered by medications or
infections, although about 50% ofpatients have no
known precipitant.
148
Bibliography
Frumholtz I-. I-aurent Roussei S, Lipsker D, et al. Cutaneous vasculitis:
reviei( on diagnosis and clinicopathologic correlations. CIin Rev Allerg'
Immunol.2020. [PMID:32378145] doi:10.1007 s12016 020 08788 l
Answer:
Item 49 E
Educational Objective: Screen for Hl-{-B's8:Ol allele
before starting allopurinol therapy.
The most appropriate management is HIA 8'58:01 allele test
ing (Option E). Presence of this allele has been associated with
a higher incidence of allopurinol hlpersensitivity Testing for
this allele is conditionally recommended by the American Col-
lege of Rheumatologr (ACR) in high-risk populations (includ
ing persons ofKorean, Han Chinese, Thai, and African descent,
in whom HLA-B'58:01 is more common) before initiation of
allopurinol given the potential severity of a hypersensitivity
reaction. This reaction is heralded by a rash that may progress
to DRESS (drug reaction with eosinophilia and systemic rymp
toms) syndrome (DRESS is also increasingly being referred
to as drug induced hypersensitivity syndrome [DIHS] and
drug hypersensitivity syndrome [DHS]). Hypersensitivity to
allopurinol may also include Stevens Johnson syndrome and
toxic epidermal necrolysis. This patient has risk factors for
allopurinol hypersensitivity, including Han Chinese descent.
and should undergo HLA-B'58:01 allele testing. Additional
risk factors for severe cutaneous reactions include female sex,
history of rash with allopurinol, and concurrent use of thia-
zide or loop diuretics. Drug hypersensitivity can still occur in
patients negative for the HLA 8'58:01 allele, and patients must
be counseled to stop the drug immediately if a rash occurs.
If the allele is present, allopurinol (Option A) should
be avoided and a different urate-lowering agent, such as
febuxostat (Option C), should be used. However, allopurinol
remains the urate lowering drug of choice, and caution
should be used when prescribing febuxostat to patients with
a history of cardiovascular disease. Allele testing remains
the best choice for this patient. Allopurinol desensitization
is conditionally recommended for patients with a previ-
ous allergic response to allopurinol who cannot be treated
with other oral urate-lowering agents, such as febuxostat or
probenecid.
Low-dose aspirin can raise the serum urate level
through renal uric acid retention. However, the ACR con-
a ditionally recommends against stopping aspirin (Option B)
in patients with gout who are taking it for appropriate indi
cations. This patient should continue his low dose aspirin
as secondary prevention of coronary artery disease events.
Abacavir is a nucleoside analog used in the treatment ol
HIV infection. Abacavir is associated with a severe hypersen
sitivity reaction in individuals identifled by the HLA-B-57:01
allele (Option D). Patients who are prescribed abacavir must
flrst undergo testing to show they are HLA 8'57:01 negati've
in order to reduce the risk for a hypersensitivity reaction.
As with allopurinol, absence of the allele does not protect
patients from hypersensitivity reactions, and appropriate
counseling should be provided.

rEY POI IIIS
o Presence ofthe HLA-B.58:01 allele has been associ-
ated with a higher incidence of allopurinol hypersen-
sitivity and is more prevalent in persons of Korean,
Han Chinese, Thai, and African descent.
o Testing for the HLA-B.58:01 allele is recommended in
high-risk populations before initiation of allopurinol
given the potential severity of a hypersensitivity
reaction.
Bibliography
FitzGerald JD, Dalbeth N, Mikuls 1l et al. 2020 American College of
Rheumatolos/ guideline for the management ol gout. Arthritis Care Res
(Hoboken). 2020;72:744 760. [PMID: 323919341 doi:10.1002/acr.24180
Item 50 Answer: E =,
Educational Objective: Treat advanced, symptomatic
osteoarthritis with joint replacement surgery.
The most appropriate treatment is total knee replacement
(Option E). This patient has osteoarthritis (OA) that has
not responded to nonpharmacologic and pharmacologic
approaches and is limiting function. Total joint replace
ment is a curative option for patients in whom conservative
therapy has failedl it relieves pain and improves function.
Overall, outcomes are excellent, with small risk for hardware
loosening and Iate infection. Osteotomy is an alternative for
younger patients with varus or valgus knee and predomi
nantiy unicompartmental disease.
Multiple high quality studies have shown that
arthroscopic surgery for knee OA (Option A) provides no
advantage over conservative management unless joint buck
ling, instabili0r, or locking is present. This patient does not
have these indications.
Because of lack of efhcacy, the 2019 American College
of Rheumatologz (ACR)/Arthritis Foundation (AF) guideline
strongly recommends against the use of chondroitin sulfate
in patients with knee and/or hip OA, as well as combination
products that include glucosamine and chondroitin sulfate
(Option B).
The ACR/AF guideline recommends against the use of
hyaluronic acid injections (Option C). The guideline recog-
nizes the limited evidence for the benefit of this treatment.
particularly when other alternatives have failed to provide
beneflt. Debate about the role of these injections contin-
ues because of conflicting efhcacy data across trials and
meta-analyses, as well as their high cost. However, they are
frequently used in practice for knee OA.
Intra-articular platelet-rich plasma (Option D) is not
efflcacious in the treatment of knee OA. The ACR/AF guide
I
line strongly recommends against it; the lack of standardiza-
tion in availabie preparations of platelet-rich plasma makes
it difficult to identifiz exactly what is being injected. The
guideline also recommends against other similar therapies,
such as intra-articular injection of stem cells, biologics, or
botulinum toxin.
Answers and Criti ques
t(EY POlt{IS
. Total joint replacement is a curative option for patients
with osteoarthritis in whom conservative therapy has
failed; it relieves pain and improves function.
. The American College of Rheumatologr/Arthritis
Foundation recommends against the use of chondroi-
tin sulfate (with or without glucosamine), biologics,
intra-articular hyaluronic acid, platelet-rich plasma,
stem cells. or botulinum toxin in the treatment of
knee osteoarthritis.
Bibliography 9t
c,
Kolasinski SL. Neogi 1. llochberg M(1, et al.2019 American (irllege ol'
RheumatololyiArthritis I,bundation guideline tbr the management of E
osteoarthritis ol the hand. hip. ancl knee. Arthritis Rheumatol. 2020: L
7 2:220 233. I PM I D: 3 I 9081 63 I doi : I 0. l002irrt..4 I 1.'12 rr,
.!
ah
Item 51 Answer: D o
Educational Objective: Diagnose polyarteritis nodosa. ut
=
Magr.retic resonilnce angiographv ol the abtiomen (Option
D) is nrost liliely to establish the diagnosis. lhe nrost lil<cly
cliagnosis is polyarteritis r.rodosir (PAN), a nredium vessel
r,asculitis. The patient hls an inllarnrnatory disease n,ith
neu, onset kidney disease but rtrithout evidence of glonrcru
lar involvernent. Unlike small vessel '"'asculitis, r,r'l-riclr causes
glomerulonephritis, t']AN afiects the renal virsculirturcr there
fbre. it does not generallv cause rn active urinary secli
rnenl but can crusc rcnal insufficiencl- rnd hypertension.
'lhe nodular skin lesions sLlggest r-neclium vessel virsculitis.
The postprlr.tdial abdominal pain points to nrcscnteric iscl.r
emia. 'lhc patient has a left fbot drop. sr-rggesting periphcral
nenropathl,. Mononeuritis multiplex. which c:rn be seen in
small or medium vessel disease. is cornmon in PAN. Whcn
a patient suspectecl ot having PAN has abdominal sympbrns.
inraging of the mesenteric vasculature c:rn be diagnostic. In
this casc. rxignctic resonrnce angiography lr,ould clenron
stratc characteristic findings of tAN allecting the gut: lnulti
plc iureurysms and lnminul irregularities (stenosis) in bigger
irrteries. r,t ith occlusive lesions in smaller ones.
The clinical scenario cloes not suggest any ol the
ANCi\ rssociated vasculitides. AN(lA associirtcd vasculiti
des involve small vessels, and paticnts may havc sympk)rns
relatecl kr the upper and loner airw:iys, kidneys (glon.rerr-rlo
rrephritis). and eyes, ears. iu'rcl skin (pllpablc'purpura): cor.r
stitutional s],'nlptonrs arc also comrnon. Therefbre, testing fbr
ANCi\ (Option A) is unlikcly to be helpful.
llepatitis A virus testing (Option B) nould not aicl in
diagr.rosis.llepatitis IJ vims (llBV) and tllV. Ibr r,vhich the
paticnt is ncgativc. cau cilLlse PAN (and. rnure rarelyl so car-r
hepatitis C virus). Heprtitis A vims docs not. Llecause IlllV
prevalence has declir.rccl since tl.re advent of the I IBV r,accir.re
ancl antiviral treatmcnt, the proportion ot' paticnts with
HBV associated PAN hls dcclitred fiom :16'2, to less than
5')1, of all IAN cascs; most contemporxry cascs are tlterefbre
considerccl to irc prirnarily autoimnrunc.
149
 Answers and Critiques
m PAN spares the glomerulus but can affect the larger
IIJ 1qns1 vessels, leading to hypertension and renal insuffi-
coNT
cien.y. A biopsy of the kidney (Option C) would therefore be
nondiagnostic (unless medium vessels were included in the
biopsy, which would result in bleeding).
{EY POIIIIS
. Polyarteritis nodosa is a medium-vessel vasculitis that
affects the renal vasculature and causes nodular skin
lesions, abdominal pain, and mononeuritis multiplex.
. In a patient who has polyarteritis nodosa with
abdominal symptoms, magnetic resonance angiogra-
D patients with gout and any of the following indica-
phy can be diagnostic.
UI
(D
= Bibliography
l^
De Virgilio A. Greco A. Magliulo G. et al. Polyarteritis nodosa: a contempo-
q,
rary overvie$,. Autoimmun Rev 2016;15:56.1 70. [PMID: 2688.1100]
doi:10.1016/j.autrev2016.02.015
CL
rl
l!
(D
art
tr Item 52
Educational Objective:
Answer: A
Treat chronic recurrent gout
urate-lowering therapy.
The most appropriate treatment to add is aliopurinol (Option
A). this patient has a recent history ol gouty bursitis as well
as a history ofrecurrent episodes ofgouty arthritis. tophi. and
elevated serum urate. The American College of Rheumatologr
(ACR) strongly recommends initiating urate-lowering therapy
for patients with gout and any of the following indications:
one or more subcutaneous tophi; evidence of radiographic
damage (any modalifi) attributable to gout; or frequent gout
flares, with "frequent" being deflned as tvvo or more annuaily
This patient has two indications for urate-iowering therapy:
t'wo or more recurrent episodes per year and tophi. Allopu-
rinol, a xanthine oxidase inhibitor, is strongly recommended
by the ACR as first-line urate-lowering therapy in all patients,
including those with moderate to severe chronic kidney dis-
ease, with appropriate dose adjustments. In patients tak-
ing aliopurinol, the HLA-B.58:01 allele is associated lvith a
markedly elevated risk for acute hypersensitiviS reaction,
also known as DRESS (drug reaction with eosinophilia and
systemic symptoms) syndrome. Testing for the HLA-B-58:01
allele before starting allopurinol is conditionally recom-
mended for patients of southeast Asian (e.g., Han Chinese.
Korean, Thai) or African descent. It is appropriate to continue
naproxen as prophylactic therapy for 3 to 6 months along with
the initiation of urate lowering therapy to prevent flares whiie
the serum urate level is lowered.
Colchicine (Option B) may be used for treatment of
acute gouty arthritis or for long term prevention of flares
while urate-lowering therapy is initiated. If it is used to
prevent flares during urate lowering therapy, it should be
continued for 3 to 6 months or until serum urate is at target
level. This patient has responded to naproxen and therefore
does not need additional acute treatment ofhis gout or addi-
tional medication for prevention. Colchicine does not affect
the serum urate level.
150
Like allopurinol, f'ebuxostat (Option C) is a urate 1or,r.
ering agent that inhibits xanthine oxidase. It is indicated in
patients in n,hom allopurinol has failed or lvho cannot toler
ate allopurinol. This patient has ner,er receired urate lowering
therapy; therefore, febuxostat is not indicated.
Probenecid (Option D) is not a preferred medication
for this patient. Allopurinol is strongly recommended as the
preferred urate lowering agent. In addition. probenecid is
contraindicated in patients with nephrolithiasis.
TEY POtl{T5
. Urate lowering therapy is strongly recommended for
tions: one or more subcutaneous tophi; evidence of
radiographic damage (any modality) attributable to
gout; or frequent gout flares, with "frequent" being
defined as tvvo or more episodes annually.
. Allopurinol is strongly recommended as the preferred
urate lowering agent, over all other agents, including
with
in patients with moderate to severe chronic kidney
disease (stage >3).
Bibliography
Fitzcerald JD. Dalbeth N, Mikuls T. et al. 2020 American College of
Rheumatolos/ guideline lbr the management of gout. Arthritis Care Res
(Hoboken). 2O2O:72:714 760. LPMID: 32391%41 doi:10.1002racr.24180
Item 53 Answer: A
Educational Objective: Treat parvovirus B19 arthropathy
The most appropriate treatment is an NSAID, such as
diclofenac (Option A). The patient has an acute onset of
polyarticular arthralgia with minimal flndings of inflam
matory synovitis on physical examination. The history of
a recent febrile illness with the subsequent appearance of
a facial rash in the patient's child suggests parvovirus B19
infection (Iifth disease). Up to 60% of adults with parvovirus
B19 infection experience arthritis. It often presents acutely,
is symmetric and polyarticular, and typically involves the
proximal small joints of the hands. Parvovirus B19 arthri-
tis should be suspected when appropriate clinical features
are present in someone who has exposure to children.
Acute parvovirus B19 inlection is diagnosed by detecting
anti parvovirus IgM antibodies in the serum. The patient's
symptoms could also suggest rheumatoid arthritis or pso
riatic arthritis, but the brief duration of symptoms does not
permit diagnosis of either of these entities at this time. It is
appropriate to relieve symptoms with an NSAID but not to
start immunosuppressive therapy now.
Etanercept (Option B) is a tumor necrosis factor inhib
itor that can be chosen as flrst line therapy for rheumatoid
arthritis. The diagnosis of rheumatoid arthritis would need
to be conflrmed by a longer duration of symptoms and
additional laboratory testing (such as complete blood count.
erythrocy.te sedimentation rate, C-reactive protein, rheuma-
toid factor, and anti cyclic citrullinated peptide antibodies)
and radiographic studies.

Hydroxychloroquine (Option C) is indicated for the
treatment of signs and symptoms of systemic lupus erythe
matosus, dermatoml,ositis, and rheumatoid arthritis. In the
absence of a diagnosis of one of these conditions, hydroxy
chloroquine is not appropriate empiric treatment fbr an
acute polyarthritis.
lVlethotrexate (Option D) is appropriate flrst line ther
apy for rheumatoid arthritis and psoriatic arthritis. How
ever, before initiation of an immunosuppressive therapy. the
diagnosis of rheumatoid arthritis or psoriatic arthritis must
be confirmed. When symptoms are present for only a few
days, causes ofjoint pain and swelling, such as viral inf'ection
and drug reactions, are in the diftbrential diagnosis. When
symptoms are present for at least 6 weeks, these diagnostic
possibilities become less likely and higher suspicion for
rheumatologic diseases will emerge. On the basis of the time
frame over which this patient reports symptoms, initiation
of methotrexate is not appropriate.
I(EY POIIITS
o Parvovirus arthropathy often presents acutely, is
B19
symmetric and polyarticular, and typically involves
the proximal small joints of the hands.
o Parvovirus B19 arthropathy should be suspected when
appropriate clinical features are present in someone
who has exposure to children and is diagnosed by
detecting anti parvovirus IgM antibodies in the serum.
Bibliography
Mauermann M. Ilochiluf Stange K. Klelntrrnn A, et al. Paru^,irus inli,ction
in early arthritis. Clin Exp Rheumirkrl. 2016 Mar Apr:3.1:207 13. It,l\'llI):
268866871
Item 54 Answer: D
Educational Objective: Use NSAIDs for initial
osteoarthritis treatment.
The most appropriate initial treatment for this patient with
osteoarthritis (OA) is an NSAID, such as piroxicam (Option
D). NSAIDs inhibit cyclooxygenase enzymes, blocking gen
eration of the lipid prostaglandin E,,,. NSAIDs are efhca
cious in OA and are strongly recommended by the 2019
American College of Rheumatology/Arthritis Foundation
for hand, hip, and knee OA. However, their adverse efl'ect
proflles make sustained use problematic, especially in older
persons and patients with comorbidities. Topical NSAIDs are
effective and because of their saf'ety profile are preferred to
oral NSAIDs. However, topical NSAIDs are ineffective in the
treatment of hip OA. For this patient with hand, knee, and
hip OA, oral NSAIDs are the initial treatment of choice. This
patient has no risk factors for common contraindications
and adverse effects, such as peptic ulcer disease or kidney
disease. Hence, piroxicam would be a reasonable choice as
initial treatment and may adequately relieve her symptoms.
It would also be prudent lbr the patient to take piroxicam
regularly for a limited time and consider taking it as needed
in the future.
Answers and Critiques
Systematic reviews and meta-analyses suggest that acet
aminophen (Option A) provides no beneflt for hip or knee
OA. Acetaminophen may be considered as add on therapy
for short term and episodic use but is not appropriate as
initial therapy for this patient.
Duloxetine (Option B), a serotonin-norepinephrine
reuptake inhibitor with central neryous system activity, has
shorn,n efllcacy for OA pain and would also be reasonable
for this patient. However, it should be used only if NSAIDs
are inadequate and is not the best choice for initial therapy.
Gabapentin (Option C) and pregabalin are more effec
tive than placebo in the treatment of neuropathic pain
conditions, such as postherpetic neuralgia and diabetic t
(u
neuropathy. There is no evidence of their eflectiveness for
ET
chronic OA pain. Furthermore, they may be associated with
dose dependent dizziness and sedation. Thus, gabapentin is U
not appropriate for this patient.
Opioid therapy provides limited benefit fbr chronic
=,
IE
pain control in patients with OA and poses a high risk for la
(t,
toxicity and dependence. Opioid use should be avoided for
OA treatment. Tramadol (Option E), a partial opioid with UI
=
fewer adverse effects and less addictive potential than pure
opioids, may be considered in some patients, but it should
be used only in limited circumstances, and never as an initial
therapy.
KEY POI]IIS
. NSAIDs are often the initial treatment of choice for
osteoarthritis if used judiciously in low risk patients,
with minimizing and monitoring of adverse effects.
o Acetaminophen provides no benefit for hip or knee oste
oarthritis; it may be considered as add on therapy for
short term and episodic use but not as initial therapy.
Bibliography
Kolasinski SI-. Neogi T. Hochberg MC. et al. 2019 Americilr.r College of
Rheumrtololl/ Arthritis Foundirtion guideline for the mi:lncgement of
ostcorrthritis of the hand. hip. and knee. Arthritis Rhcr"lnliltol. 2020i
72:220 233. IPMID: 31908163] doi:10.1002,'art.411,12
Item 55 Answer: B
Educational Objective: Treat polymyalgia rheumatica.
The most appropriate management is prednisone, l5 mg/d
(Option B). This patient has polymyalgia rheumatica (PMR)
characterized by symmetric proximal myalgia and stiflhess,
accompanied by constitutional symptoms and an elevated
C reactive protein level. Symptoms are most pronounced
in the morning and improve after several hours. Although
some patients also have peripheral arthritis (usually of the
knees and wrists), most do not. Physical flndings are usu-
ally limited to difficulty moving the affected areas (shoul
ders and hips). There is no diagnostic test specific fbr PMR.
With a reasonable degree ol suspicion for PMR, an empiric
glucocorticoid trial is appropriate. Initiating prednisone at
12.5 to 20 mg/d is appropriate for this generally self limited
illness. Symptoms usually improve dramatically within
151
 Answers and Critiques
48 hours (diagnostically helpful), and tapering may begin
after 2 weeks.
This patient has a clear diagnosis of PMR, and there is
no need to seek an alternative diagnosis that is not suggested
by the clinical presentation. Testing for rheumatoid factor,
antinuclear antibodies, and ANCA (Option A) is unnecessary
because this patient shows no evidence of diseases such as
rheumatoid arthritis, systemic lupus erythematosus (SLE),
or granulomatosis with polyangiitis. Rheumatoid arthritis
is characterized by a chronic inflammatory polyarthritis
affecting large and small joints, with a predilection for the
small joints of the hands and feet. SLE is a multisystem auto
immune disease affecting mainly women (90"1,), and skin
gt rash and joint symptoms aflect 90'1, of patients. Granuloma
€
(} tosis with polyangiitis aflects the upper and lower airways,
vt kidneys, eyes, and ears.
q,
A prednisone dosage of 60 mg/d (Option C) is much too
EL high and unnecessary for PMR. This dosage is used to treat
('!
giant cell arteritis.
Although the patient's primary concern is "pain every
,tr
(} where," further questioning reveals that the patient has pain
gl in distinct areas. It is crucial to pinpoint areas of discomfort
via history because different disease processes result in dis
tinct patterns of pain. Patients with chronic widespread pain
syndromes, such as flbromyalgia, may indeed have difluse
pain. However, patients with other, more localized issues
often report "pain every.where," and in the absence ofa good
history premature closure may lead to an incorrect diagno-
sis. In this case, diagnosing fibromyalgia and prescribing
pregabalin (Option D) would be incorrect.
IEY POITIS
. Polymyalgia rheumatica is characterized by symmet-
ric proximal myalgia and stiffness, accompanied by
constitutional symptoms and elevated infl ammatory
markers.
. For polymyalgia rheumatica, initiating prednisone at
12.5 to 20 mg/d is appropriate treatment.
Bibliography
Matteson El-, I)ejaco C. Polymyalgia rheumatica. Ann lntern Med. 2017:
166:l'IC65 ll'(180. [PMID: 284603951 doi: 10.71]26 AITC2Ol7O5O2O
Item 55 Ansyyer: A
Educational Objective: Diagnose cryoglobulinemic
vasculitis.
The most likely diagnosis is cryoglobulinemic vasculitis
(Option A). Cryoglobulinemic vasculitis results from cryo-
globulin containing immune complexes depositing in small-
and medium-sized arteries, leading to an inflammatory
response. Of the three types of cryoglobulinemia, only types
II and III (mixed cryoglobulinemia) cause vasculitis. Type II,
which usually results from certain viral infections and auto
immune disease, is typifled by a monoclonal IgM with activ
ity against IgG (i.e., a rheumatoid factor) as well as polyclonal
152
IgG. Type III is usually associated with autoimmune disease
and is characterized by polyclonal IgG and polyclonal IgM.
This patient has severe cryoglobulinemia, r,r'ith ne\\' onset
kidney failure, palpable purpura, and peripheral neuropathy
affecting the left radial nerve. Cutaneous involvement (pal-
pable purpura, digital ischemia, ulcers, necrosis. and livedo
reticularis) occurs in about 90'7, of patients. Other common
manifestations include glomerulonephritis (usually mem
branoproliferative) and arthralgia without arthritis. Pulmo
nary and or gastrointestinal involvement is rare. In addition
to detection of cryoglobulins, laboratory abnormalities fre
quently include depressed C4 complement and low CHro,
as well as a positive rheumatoid factor result; this patient's
undetectable C4 level in conjunction with a high rheumatoid
factor level therefore strongly support a cryoglobulinemia
diagnosis. Most cases of mixed cryoglobulinemia result from
another underlying condition, the most common of which
is hepatitis C virus infection (suggested by elevated amino
transferase levels). Patients with cryoglobulinemia should
undergo hepatitis C virus testing and be treated ifthe result
is positive. Severe cryoglobulinemia requires urgent treat
ment r,r,ith high-dose glucocorticoids plus rituximab.
Hypersensitivity vasculitis (Option B) can appear as
showers of purpura on the extremities but does not lead to
systemic disease (glomerulonephritis, hypocomplemente-
mia, neuropathy, and nephropathy).
Polyarteritis nodosa (Option C), a medium vessel
vasculitis, most commonly aflects the skin (tender erythem
atous nodules akin to erythema nodosum, palpable pur
pura, livedo reticularis, ulcers), peripheral nervous system
(mononeuritis multiplex), and gut. However, polyarteritis
nodosa does not cause glomerulonephritis, hypocomple
mentemia. or an elevated rheumatoid factor. It can cause
purpuric lesions, but not to the degree seen in cryoglobu
linemia.
Rheumatoid vasculitis (Option D) is seen in patients
with long-standing and severe rheumatoid arthritis. This
patient has no history of arthropathy, and, despite his
arthralgia, does not have fiank arthritis. The rheumatoid fac
tor level is elevated, but this test is not speciflc (results can be
elevated in chronic bacterial or certain viral infections and
Sjdgren syndrome, for example). Anti-cyclic citrullinated
peptide antibodies, which are more speciflc for rheumatoid
arthritis. are not present. Finally, kidney involvement is pres
ent in this case but rare in rheumatoid vasculitis.
XEY POITTS
r Clinical manifestations of cryoglobulinemia include
cutaneous involvement (palpable purpura, digital
ischemia, ulcers, necrosis, and livedo reticularis),
peripheral neuropathy, arthralgia, and glomerulone-
phritis (usually membranoproliferative).
o In addition to detection of cryoglobulins, cryoglobu-
Iinemia-associated laboratory abnormalities fre
quently include depressed C4 complement and low
CHro, as well as a positive rheumatoid factor result.

Bibliography
Fuentes A, Mardones C, Burgos PI. Understanding the cryoglobulinemias. Curr
Rheumatol Rep. 2019;21:60. [PMID: 317,11077] doi:10.1007/sll926 019
0859 0
Item 57 Answer: D
Ed ucationa I Objective : Treat rheumatoid arthritis
during pregnancy.
The most appropriate preconception management is
discontin-
uation of leflunomide (Option D). Leflunomide is highly tera-
togenic and absolutely contraindicated with pregnancy. During
the preconception phase, leflunornide should be discontinued.
The active metabolite of leflunomide (teriflunomide) under
goes enterohepatic circulation and has a half life of nearly
3 weeks. Because 5 half-lives are required for a metabolite to
be significantly cleared, leflunomide levels have been detected
in the serum months following discontinuation of the drug.
Demonstration of undetectabie blood levels is needed befbre
conception. An ll day cholestyramine washout must be used
to remo\e teriflunomide and should be followed up with mea
surement of leflunomide and its metabolite levels to ensure
removal of drug. Management of rheumatoid arthritis (RA)
during pregnancy is complicated.
Discontinuation of medications used to treat RA
(Option A) may be feasible in some patients whose disease
is well controlled, but most patients need to continue ther
apy during pregnancy especially if de escalation of therapy
reactivates disease, as in this patient. She is likely to require
continued therapy during pregnancy.
Patients with active disease who are receiving tumor
necrosis factor inhibitors can continue these medications
through conception; the duration of use during pregnancy
depends on the speciflc agent. Certolizumab (Option B)
may be continued throughout pregnancy because it crosses
the placenta in low to undetectable amounts. Other tumor
necrosis factor inhibitors, such as etanercept, adalimumab,
infliximab, and golimumab, may be continued safely until
the start of the third trimester.
Hydroxychloroquine (Option C) crosses the placenta.
However, the dose typically used to treat systemic lupus ery-
thematosus or other rheumatologic diseases does not pose
a risk for letal toxicity. It is safe to continue hydroxychloro
quine in this patient.
Because leflunomide is absolutely contraindicated
during any stage of pregnancy, continuation of all three
medications is inappropriate (Option E).
l(EY por{Ts
o Leflunomide is highly teratogenic and absolutely con-
traindicated during any stage of pregnancy; during
the preconception phase, leflunomide should be dis-
continued and cholestyramine used to remove its
metabolite.
. Hydroxychloroquine can be continued throughout
pregnancy.
Answers and Critiques
Bibliography
Sammaritano LR, Bermas BL, Chakravarty EE, et al. 2020 American College
of Rheumatologr guideline fbr the management of reproductive health
in rheumatic and musculoskeletal diseases. Arthritis Rheumatol. 2020r
72:529 556. [PMtD, 32090480]
Item 58 Answer: B
Educational Objective: Diaglose the cause ofjoint pain
in a patient with psoriasis.
The most likely diagnosis is osteoarthritis (OA) (Option B).
Psoriatic arthritis (PsA) is one of the few forms of inflam
matory arthritis that affects the distal interphalangeal joints. Ut
o
This Iocation is also commonly aflected by OA. This patient
ET
has a classic history for OA, with minimal morning stiffness,
pain with increasing use, and a classic distribution in the (,
hands (distal interphalangeal and proximal interphalangeal
joints). Her radiographs are also typical for OA and show no
=t
E
tu
r,l
erosions. The literature conllrms thal 47n/,' of patients with q,
psoriasis who were thought to have PsA had another cause
of joint pain, most commonly OA.
vl
=
g
Hyperuricemia is reported to have a high prevalence
in patients with psoriasis. This metabolic derangement can
be associated with gout development. In chronic recur
rent gout (Option A), patients experience increasingly fre-
quent and severe, and often polyarticular, arthritic attacks.
These attacks may eventually evolve into a persistent chronic
arthritis. The characteristic radiographic changes of estab-
lished disease include punched-out lesions with overhang-
ing edges ofcortical bone. This patient's clinical history and
radiographic flndings are not consistent with chronic gout.
Patients with PsA (Option C) have an inflammatory
form of arthritis that manif'ests with prolonged morning
stiffness (>30 minutes) and symptoms that improve with
activity. PsA affects up to 25'X, of people with psoriasis, and
the associated joint disease develops after the appearance
of skin changes in 85% of patients. The joint manifestation
can be pauciarticular or polyarticular and can be accompa-
nied by axial involvement. Enthesitis (inflammation where
tendons/ligaments insert into bone) is seen in almost half
of patients with PsA, and dactylitis is equally common. Nail
changes are common and are associated with distal inter-
phalangeal arthritis and enthesitis. These flndings are not
present in this patient, making PsA unlikely at this time.
Rheumatoid arthritis (Option D) characteristically affects
the metacarpophalangeal joints, metatarsophalangeal joints,
and proximal interphalangeal joints of the hands and feet but
spares the distal interphalangeal joints ofboth the upper and
lower extremities. This patient's pattern of joint involvement
is most compatible with OA, not rheumatoid arthritis.
rEY POIl{II
o Psoriatic arthritis is one of the few forms of inflamma-
tory arthritis that affects the distal interphalangeal joints.
. The most common missed diagnosis in patients with
psoriasis and arthritis is osteoarthritis.
153
 Answers and Critiques
Bibliography
Cladman DD. Clinical features and diagnostic considerations in psoriatic
arthritis. Rheum Dis Clin North Am. 2015:41:569 79. [PMID: 26.1762191
doi: I 0.1016/j.rdc.20l 5.07.003
Item 59 Answer: C with a higher risk for interstitial lung disease.
Ed ucational Objective: Diagnose limited cutaneous
systemic sclerosis.
The most likely diagrosis is limited cutaneous systemic scle
rosis (LcSSc) (Option C). Anticentromere antibodies (titer of
1:80 or higher) are rare in healthy people. The finding ofanti-
centromere antibodies (ACAs) in the setting of Ralnaud phe
D nomenon is 60'X, sensitive and 98'7, speciflc for LcSSc, which
t was previously knov,n as the CREST slmdrome. Patients with
E Ed
(D LcSSc have manifbstations that can include calcinosis, Ray
ta naud phenomenon, esophageal dysmotility, sclerodactyly, and
A'
3 telangiectasia (CREST); all flve conditions may not be present.
EL
The presence of anticentromere antibodies increases the risk
n for pulmonary hypertension, which occurs in 20"1, of
tt patients. Patients who have only Raynaud phenomenon and
(D ACA must be followed for development of LcSSc. This patient
t^ with recent onset of Ra,,naud phenomenon is showing features
ofLcSSc. Although gastroesophageal reflux disease is common
in the general population, the recent onset oftelangiectasias and
sclerodactyly suggests LcSSc. The telangiectasias seen in LcSSc
are matted; these clusters of dilated vessels appear as small pink
or red macules that blanch on light pressure. They are most
commonly seen on the face, mucous membrane, and hands.
Patients with diffuse cutaneous systemic sclerosis (DcSSc)
(Option A) have skin involvement that is more extensive than
that found in LcSSc and additionally includes the arms, trunk,
and lower extremities. Anti Scl 70 antibodies are generally
associated with DcSSc, with a prevalence approaching 30'1,,
and these antibodies are associated with a higher risk for inter
stitial lung disease. ACAs are uncommon in DcSSc.
Eosinophilic fasciitis (Option B) is associated with
orange peel induration (peau d'orange) ofproximal extrem
ities, with sparing of hands and face, and the presence of
peripheral eosinophilia. The presence of Raynaud phenom
enon and the positive ACA result make eosinophilic fasciitis
an unlikely diagnosis.
Mixed connective tissue disease (Option D) is a speciflc
overlap syndrome that includes clinical manif'estations of at
least two of the following: systemic lupus erythematosus,
polymyositis, and systemic sclerosis. Positive results for anti-
Ul-ribonucleoprotein antibodies are the primary laboratory
feature in many patients. The absence of flndings associated
with another connective tissue disease and a positive ACA
titer support the diagnosis of LcSSc rather than mixed con
nective tissue disease.
XEY POIf,IS
. The finding of anticentromere antibodies in the set
ting of Raynaud phenomenon is 60% sensitive and
98% specific for the development of limited cutaneous
systemic sclerosis.
(Continued)
154
(EY P0IXTS (orilinued)
o Anti-Scl 70 antibodies are generally associated with
diffuse cutaneous systemic sclerosis, with a prevalence
approaching 30'7,, and these antibodies are associated
Bibliography
Stochmal -\. Czuu'ara J, 'lrojanor,r,ska M. et al. Antinuclear antibodies in
s)stemic sclerosis: an update. CIin Rev Allerg, Immunol. 2o20:58:-10 51.
lP\llD:306077491 doi:10.1007 s12016 018 8718 8
Item 60 Answer: C
ucationa I Objective: Diagnose Sjogren syndrome.
The most appropriate diagnostic test to perform next is
anti Ro/SSA antibodies (Option C). This patient has flnd
ings highly suggestive of Sjogren syndrome, oral and ocular
these dryness and enlarged parotid glands. She also has other non
specific symptoms (achiness, fatigue. and Raynaud phenom
enon) that are common in patients with Sjdgren syndrome.
Anti Ro/SSA antibodies are the most speciflc diagnostic test.
The patient also has an elevated rheumatoid factor lerel.
a flnding seen often in patients with Sj6gren syndrome.
Although rheumatoid factor is more common in Sj6gren
syndrome than in rheumatoid arthritis, it is not speciflc to
either disease.
ANCA testing (Option A) would not be informative for
this case because the patient's presentation does not suggest
systemic vasculitis. Clinical manifestations of vasculitis are
the result of tissue ischemia associated with the involved
vessels. ANCA associated vasculitides involve small vessels.
and patients may have symptoms related to the upper and
Iower airways, kidneys, eyes, ears, and skin; constitutional
symptoms are also common.
Anti cyclic citrullinated peptide (CCP) antibodies
(Option B) are more speciflc than rheumatoid factor for
diagnosing rheumatoid arthritis. Ho'nrever, in a patient who
seems likely to have Sjdgren syndrome, anti CCP antibody
testing is not helpful. Only a small proportion of people
presenting with joint discomfort have rheumatoid arthritis.
The normal joint examination provides another clue that
rheumatoid arthritis is unlikely.
Cryoglobulinemia can be caused by Sjdgren syndrome,
but there is no reason to suspect cryoglobulinemia in this
patient. Cryoglobulinemic ischemia is fixed rather than
reversible (digital tips often appear gangrenous). Cryoglob
ulins (Option D) cause small and medium vessel vasculitis
by depositing in vessel walls and inciting an inflammatory
response. Cryoglobulinemia almost always causes a rash (e.g..
leukocytoclastic vasculitis manifesting as palpable purpura)
and often causes mononeuritis multiplex and arthralgia.
Kidney disease, usually membranoproliferative glomerulo
nephritis, is also frequently seen. Rheumatoid factor and an
elevated erythrocyte sedimentation rate are expected in cryo
globulinemia, but the rest of this patient's clinical picture
does not support the diagnosis of cryoglobulinemia.

XEY POITIS
e Anti
Ro/SSA antibodies are the most specific labora-
I tory test for diagnosis of Sj6gren syndrome.
. Although rheumatoid factor is more common in
Sjdgren syndrome than in rheumatoid arthritis, it is
not specific to either disease.
Bibliography
Shiboski (lFI, Shiboski SC, Seror R, et ali lnternrtional Sjdgren's Syndrome
Criteria Working Group. 2016 American College of Rheumatolos//
European l-eague Against Rheumatism classification criteria for primary
Sjogren's syndromei a consensus and data driven methodolos/ involving
three international patient cohorts. Ann Rheum Dis. 2017;76:9 16-
IPMID : 277 89 1661 doi : I 0. 1 I 36 /a nnrheumdis 2O1 6 21 O 57 1
Item 61 Answer: C U
Ed u cati ona I Objective : Treat refractory tophaceous
gout with pegloticase.
The most appropriate treatment is to stop febuxostat and
start pegloticase (Option C). This patient has chronic topha
ceous gout with a persistently elevated urate level above
target (<6.0 mg/dl [O.ss mmol/L]) despite maximum dose
febuxostat. Switching to pegloticase rather than continuing
current urate lowering therapy is strongly recommended
for patients with gout for whom allopurinol, febuxostat,
or uricosurics have failed to achieve the serum urate target
and who continue to have frequent gout flares (two or more
flares per year) or who have subcutaneous tophi. Because
this patient is allergic to allopurinol and febuxostat
failed, pegloticase is indicated. Pegloticase is recombinant
pegrlated uricase administered intravenously every 2 weeks.
All patients should be screened for glucose 6 phosphate
dehydrogenase (G6PD) activity before administration of
pegloticase; low activity of G6PD poses a risk for hemo
lytic anemia and methemoglobinemia, and pegloticase is
contraindicated in that setting. Pegloticase rapidly lowers
the serum urate level, and prophylactic therapy (colchicine,
NSAIDs, or glucocorticoids) must be administered concur
rently with treatment. Formation of antibody to pegloticase
may occur (30% 50% of patients) and cause severe infusion
reactions. Serum urate level must be checked before each
infusion. After the initial dose, a serum urate level greater
than 6.0 mg/dl (0.35 mmol/L) on t\,vo consecutive assess-
ments indicates loss of efficacy due to antibody formation.
necessitating discontinuation of pegloticase. Pegloticase
should not be given with any other urate lowering therapy
so that interpretation of the serum urate level before each
infusion is clear. Therefore. this patient should discontinue
febuxostat.
Hydroxychloroquine (Option A) is used in the treat-
ment of rheumatoid arthritis. This patient does not have a
history of rheumatoid arthritis. The erosions seen on her
radiographs are typical of gout with sclerotic borders and
overhanging edges. Typical rheumatoid arthritis radio
graphic changes include periarticular osteopenia, mar
ginal erosions without overhanging edges, and joint space
Answers and Critiques
narrowi ng. Thus, adding hydroxychloroquine to febu xostat
would not be appropriate.
Probenecid (Option B), a uricosuric drug, is not eflec
tive as a urate-lowering agent in patients with chronic kid
ney disease (estimated glomerular llltration rate <50 mL/
min/1.73 m2) and should not be added to febuxostat in this
patient.
Continuing febuxostat alone (Option D) wiil not further
lower serum urate levels; the patient has been receiving this
therapy for 1 year and has steady state levels, and therefore
she will not likely benefit further from it.
I(EY POIilI ta
q,
. Switching to pegloticase rather than continuing cur
rent urate-lowering therapy is strongly recommended ET
.P
for patients with gout for whom allopurinol, febux
ostat, or uricosurics have failed to achieve the serum E
urate target and who continue to have frequent gout tli'
UI
flares (two or more flares per year) or who have non-
resolving subcutaneous tophi.
o
(,t
=
E
Bibliography
Fitzcerald lD. Dalbeth N. Mikuls T. et al. 2020 American College of
Rheumatologr guideline fbr the management of gout. Arthritis Cirre Res
(Hoboken). 2020;72:714 760. IPMID: 3239193.11 doi:l0.lOO2/acr24luo
Item 62 Answer: C
Educational Objective: Treat interstitial lung disease in
systemic sclerosis.
has
The most appropriate treatment is mycophenolate mofetil
(Option C). This patient with systemic sclerosis has classic
manif.estations of interstitial lung disease (lLD), which occurs
in 50'2, of patients with difluse cutaneous systemic sclerosis.
The prevalence is even higher in those who have anti Scl
70 antibodies (857,). This patient has dyspnea on exertion,
cough, a reduction in FVC and DIco, and a high resolution
CT scan th:rt is typical for nonspecific interstitial pneumo
nitis. Patients may also have usual interstitial pneumoni-
tis. A usual interstitial pneumonitis pattern demonstrates
honeycombing on high resolution CT and is less responsive
to therapy than nonspeciflc interstitial pneumonitis. The
6-minute r,r,alk test provides afunctional assessment; if oxy
gen desaturation of 88'2, or below occurs while the patient is
walking, the patient is a candidate for home oxygen therapy.
Some studies suggest that aggressive treatment of gastro
intestinal reflux disease may have a positive effect on ILD
progression. Mycophenolate mofetil is a mainstay of therapy
for ILD in systemic sclerosis. Data from open-label trials sug
gest that mycophenolate mofetil can stabilize and, in some
cases, improve lung function. The Scleroderma Lung Study ll
compared oral cyclophosphamide for 1 year to mycopheno
Iate mofletil for 2 years. Both agents were equally eflicacious
in improving and stabilizing FVC; however, mycophenolate
mofetil was better tolerated and can be used for many years.
whereas cyclophosphamide has a time limited utility due to
toxicity. Expert opinion places mycophenolate mofetil flrst
155
 An swe-11
-1 1
d 9.!!'q.! :t
for both induction and maintenance therapy in patients with
systemic sclerosis and ILD.
Hydroxychloroquine (Option A) may be useful for
arthritis in systemic sclerosis but does not play a role in other
manifestations of the disease, including ILD.
Methotrexate (Option B) has utility in skin disease and
arthritis of systemic sclerosis, but no data suggest it is useful
for ILD.
Nintedanib (Option D), a tyrosine kinase inhibitor, slows
the progression of idiopathic pulmonary flbrosis and ILD in
the setting of systemic sclerosis. However, the patients who will
beneflt the most, when to initiate therapy, and optimal duration
D of therapy are unclear. Most experts reserve nintedanib for
UI patients who cannot take mycophenolate mofetil or cyclophos
E phamide or who progress while receiving these treatments.
.D
ul
o, XEY POIXIS
CL . Interstitial lung disease occurs in 50'/. of patients with
f.l diffuse cutaneous systemic sclerosis; the prevalence is
85% in the presence ofanti-Scl 70 antibodies.
It
(D
. Mycophenolate mofetil is a mainstay of therapy for
tn interstitial lung disease in systemic sclerosis.
Bibliography
Volkmann ER. Tashkin Dq Li N. et al. Mycophenolate mofetil versus placebo
tt)r systemic sclerosis related interstitial lung disease: an lnttlysis of
Scleroderma l.ung Studies I and ll. Arthritis Rheumatol. 2ol7t69:1451
1.160. IPMID: 28376288] doi:10.1002/art.,1011,1
tr Item
Ed
63
ucationa
Answer: A
I Objective : Diagnose disseminated
gonococcal infection.
'[he most likely diagnosis is disseminatecl gonococca] infec
tion (Option A). Although gor.rococcal arthritis may present
as an acute inflammatory monoarthritis, the most typical
llresentation is an arthritis dermatitis syndrome charac
terized by fbver, chills, malaise, acutely painful tenosynovi
tis, migratory arlhralgia. and pustular or vesiculopustular
skin lesions. More rarely, hemorrhagic nracules or papules
rnay be seen. Most patients have 2 to 10 skin lesions, most
commonly on the distal extremities. Women nlay present
cluring or immediately after menstrual periods. However.
genital s1'mptoms are often absent. Disserninated gonococcal
infbction should be part of the difl'erential diagnosis fbr any
sexually active patient presenting'nvith possible inf'ectious
arthritis or inf'ectious tenosynovitis, rcgardless of age.
Acute l.repatitis B virr.rs (HBV) inf'ection (Option B) is
included in the difl'erential cliagnosis of'disseminated gono
coccal infection. Patients with acute IIUV infection can also
develop fever, chills, polyar-thritis, tenosynovitis. and rash.
Hortever, the arthritis of ircute HBV inf'ection is usually
polyarticular and symmetric. In addition. the rash may be
urticarial. lichenoid, or palpable purpura, but not pustular.
tllV infection (Option C) has been associatecl with a
variety of musculoskeletal presentations, including a short
lived (<24 hour) painful :rrticular syndrome. oligoarticular
156
inflammatory lower extremity arthritis, reactive arthritis.
and psoriatic arthritis. Upper extrenriry findings make lllV
infbction less likely. this patient's skin finding is typical of'
dissen.rinated gonococcirl infection rather than I I I\r associated
arthritis, nrhich may have no skin nrani{estations or may be
associated with kerakrderma blenorrhagicum, cir-cinate bal
anitis. ancl psoriasis.
Arlhritis due to lyrne disease (Option D) tends to have
a subacute onset and nronoarticulirr presentation. typically
causing a swollen but not exquisitely painful knee. Patients
sometinres note accompanying firtigue but not constitutional
symptoms. No skin nranifestations are associated Lyme
"vith
irrthritis because it is a late n.ranifestation of Borrelia burgdor
lbri inl'ection and is not associated with erythema nrigratrs.
The cliflerential cliagnosis of nerv onset oligoarticular
inflanrmatory arthritis in a 1'oung \r'oman should include
systemic lupus ery4hematosus (SLE) (Option E). Arthralgia and
arthritis are presellt in up to 95',1, ot patients with SLE at some
point in their disease. l]ouever, the abrupt onset of symptonrs
in this case and the absence of skin n.ranifbstations lvpical of
SLE (alopecia. discoid lesions. malar rash) make Sl.E less likely
X EY PO Il{IS
o Gonococcal arthritis may present as an acute inflam
matory monoarthritis.
o An arthritis-dermatitis syndrome characterized by
acutely painful tenosynovitis, migratory arthralgia,
and pustular or vesiculopustular skin lesions is the
most common manifestation of gonococcal arthritis.
Bibliography
Ross JJ. Septic arthritis of native ioints. lnfect Dis Clin North Am. 2017;
31:2O3 218. IPMID: 28366221]
Item 64 Answer: A
Educational Objective: Diagnose mixed connective
tissue disease.
The most appropriate diagnosis is mixed connective tissue dis
ease (MCTD) (Option A). MCTD is an overlap syndrome that
includes clinical features of systemic sclerosis, systemic lupus
erythematosus, andior inflammatory myositis. It is associated
with anti-Ul ribonucleoprotein (RNP) antibodies. Clinical
features may present sequentially over time, as in this patient
presenting with proximal muscle weakness consistent with
inflammatory myositis. Ralmaud phenomenon is common
in patients with MCTD. Gastroesophageal reflux may be due
to esophageal dysmotility, a systemic sclerosis-like condition;
the presence of diffusely puffi fingers is also a common find
ing in early systemic sclerosis. Treatment of MCTD is based on
the speciflc organ system involved. The presence ofnew myo-
sitis requires treatment with immunosuppressive medication.
Rheumatoid arthritis (Option B) causes an inflamma-
tory arthritis, typically involving the metacarpophalangeal
joints and wrists, and may be associated with Raynaud phe
nomenon. However, it is not associated with anti UI-RNP
t
antibodies or myositis and thus is an unlikely diagnosis in
I
this patient.
Systemic lupus ery.thematosus (SLE) (Option C) is asso
ciated with such clinical features as photosensitive rash, sero-
: sitis, kidney disease, cytopenias, and hypocomplementemia.
Myositis may be a feature of SLE, but the lack of other features
of SLE in this patient, coupled with the features of systemic
sclerosis (puffu fingers and gastroesophageal reflux), makes
this a less likely diagnosis. The presence ofantinuclear anti-
bodies helps establish a diagnosis of SLE but is not speciflc
for SLE, and antinuclear antibodies are commonly fbund in
other rheumatologic diseases, including MCTD.
Undifferentiated connective tissue disease (Option D) is
associated with milder symptoms of arthritis and Raynaud
phenomenon. It is not associated with myositis or systemic
sclerosis features. Although patients are positive for antinu-
clear antibodies, they are usually negative for the specific
extractable nuclear antigen subsets (e.g., anti-double-stranded
DNA, anti Ro/SSA, anti LalSSB, anti UI-RNP antibodies,
and anti smooth muscle antibodies).
xtY PotilIs
r Mixed connective tissue disease is an overlap syndrome
that includes clinical features of systemic sclerosis, sys
temic lupus erythematosus, and/or inflammatory
myositis; it is associated with Raynaud phenomenon
and anti-Ul ribonucleoprotein antibodies.
. Treatment of mixed connective tissue disease is based
on the specific organ system involved.
I
Bibliography
Cunnarsson R, tletlevik SO, Lilleby V et al. N,lixed connective tissue disease.
Best Pract Res Clin Rheumabl. 2016;30:9.5 lll. [PMID: 27121219) doi:t}.
l0l 6ij.berh.2016.03.002
Item 65 Answer: D daily living.
Educational Objective: Treat inclusion body myositis.
The most appropriate treatment is to initiate physical ther
apy (Option D). Inclusion body myositis is an insidious con
dition affecting older adults. It is distinguishable from other
forms of myositis by its slow progression and different pat
tern of muscle involvement. Both proximal and distal muscle
involvement occur; finger and forearm flexor involvement
is nearly pathognomonic. Up to half of patients with inclu
sion body myositis have cricopharyngeal muscle involve-
ment, leading to dysphagia and increased risk for aspiration.
Serum creatine kinase levels are elevated to a lesser extent
than seen in other forms of idiopathic inflammatory myopa-
thies. Autoantibodies are less often present, but anti NTSc1A
autoantibodies are found in up to half of patients and rarely
in healthy persons. Patients with inclusion body myositis,
unlike those with other forms of idiopathic myositis, often
have little improvement while receiving immunosuppressive
therapies. Therapeutic trials should not be continued if they
are not effective. Physical therapy may help patients to main
tain muscle function for activities of daily living.
Answers and
Cyclophosphamide (Option A) can be considered as sal
vage therapy for patientswith severe inflammatory myositis
refractory to other therapies but is not considered flrst or
second Iine treatment. The potential for harm outweighs the
expected benefit in patients with inclusion body myositis,
and cyclophosphamide should not be initiated.
Intravenous immune globulin (Option B) can be used
in patients with polymyositis or dermatomyositis who have
an inadequate response to initial combination therapy with
glucocorticoids and traditional immunosuppressive agents,
such as methotrexate or azathioprine. However, it would
not be likely to add beneflt in patients with inclusion body
myositis without a glucocorticoid response. a^
o
For patients with most forms of idiopathic inflamma-
ET
tory myopathies, adding methotrexate (Option C) to gluco
corticoids for combination therapy is a good initial practice IJ
that can reduce the total amount and duration ofglucocor t,
ticoid use. Ilowever, there is little evidence for methotrexate .E
or other glucocorticoid sparing therapy in patients with UI
inclusion body myositis, especially if they have no meaning o
ful clinical response to high-dose glucocorticoids. vt
=
Restarting prednisone (Option E) in this case is unlikely
to benefit the patient because he had little to no meaningful
response to prednisone when initially instituted. Adverse
elfects associated with long-term glucocorticoid use, includ
ing glucocorticoid myopathy, could exacerbate his reduced
muscle function.
t(EY POtl{TS
. Patients with inclusion body myositis often have little
improvement while receiving immunosuppressive
therapies; these therapies should be discontinued ifthey
are not effective.
o Physical therapy may help patients with inclusion body
myositis to maintain muscle function for activities of
Bibliography
Creenberg SA. Inclusion body myositis: clinical features rrnd pathogenesis.
Nat Rev Rheumatol. 2019 May;15(5):257 272. I PMID: 308377081 doi:
10.10i18/s41584-Ol9-O186 x
66
Item
Ed ucationa
Answer: A
I Objective : Diagnose Chikungunya arthritis.
tr
Inf'ection with chikungunya virus (Option A) is the most
likely diagnosis. Chikungunya is an arbovirus spread by
nrosquitocs. Acute infbction is heralded by the abrupt onsct
of serere. polyarticuhr arthralgiir artcl fever, an exanthen-r:r
lhat may bc fbcal or difluse, ancl conjunctivitis. 'lhe distri
bution o{ the arthritis is often bilaterally syrnmetric and
usually involves 10 or nrore joints. Ihe temperature is olten
greater than 119.0 "C (102.2 "F). ancl fel.er persists fbr 3 to
5 days. l,aburatory testing may rcvcal leukopcnia, lymph
openia, thrombocytopenia. ancl elevated scrunr arninr.r
translerase and creatinine levels. Chikungunya virus can be
detected b1, polymerase chain reaction for 1 u,eek after onset
157
 Answers and Critiques
ot syll.lptoms. after lt,hich testing becrtmes unreliable. Spe
EX cific lgM antibody is detectable ill 5 to 10 da1,'s afler symp
CONT.
tolr onset and remains positivc fbr up kt 2 to 3 rnonths. This
patient's intensity of pain, lnrgc trunrber of joints involvcd,
higl.r temperature. and residence in an endemic area make
chikungunya the most likely diagn<tsis.
Acute hepatitis B virus infection (Option B) ma1' be
lccompanied by an abmpt. severe onset olpoly'articular joint
pain that antedates and ternrinates r,r'ith the onset of jaunclicc.
Hort'eler. it is not associatecl r'r'ith irn ircr-rte f'ebrile onset or
'uvidespread maculopapular rash: other skin findings. such as
urticaria, small vessel vasculitis. and ery.tl.rema multifbrme,
D have been associated with acute hepatitis B virus infection.
la I lepatitis C virus inf'ection (Option C) is largely asynrp
E bmatic but occasionally is acctimpanied by polyarthritis.
lD
aa llowever, it is not associated with an acute febrile onset or
o, nracukrpapular rash. When hepatilis C virus inlection is
CL associated with cryoglclbulinenria. arthralgia ma1' be seen
rl but the r:rsh is purpuric. Other skin mar.ritestations of hep
lt atitis C virus infection nrav inclutle livedo reticularis. ery
(D
thema multiforme. and lichcn ltlanus.
Ut HIV infbction (Option D) is associirted u,ith sereral mus
culoskeletal syndromes. Although the painful articular syn
clrome is characterized by an abrupt onset of arthralgia and
nryalgia, it is not associatecl witl.r fl'ver, is oligoarticular and
asymnretdc, most lrequently involves the joints of the lower
cxtrcmities, and typically resolves r,r'ithin a day HlV associated
arthritis, leactive afillritis. and psoriatic arthritis are some
times seen in patients u,ith tllV infbctior.r but do not hare ln
acute onset and are not associated \\'ith fe\,er and rash.
I(EY POITIS
. Acute infection with chikungunya virus is heralded by
the abrupt onset of severe, polyarticular arthralgia,
high temperature, rash, and conjunctivitis and often
with bilaterally symmetric polyarticular arthritis.
. Chikungunya virus can be detected polymerase chain
reaction for 1 week after onset of symptoms; specific
IgM antibody is detectable in 5 to 10 days after symp-
tom onset and remains positive for up to 2 to 3 months.
Bibliography
Pathak H. Mohan MC, Ravindran V Chikungunya arthritis. Clin Med (Lond).
2019;19:381 385. [PMID: 31530685] doi:1o.7861 clinmed.2019-0035
Item 67 Answer: C inflammatory doses for at least 2 weeks.
Ed ucationa I Objective : Treat reactive arthritis.
The most appropriate management is an NSAID, such as
piroxicam (Option C). The patient has post enteric infection
reactive arthritis, with asymmetric pauci arthritis involv
ing the lower extremities, enthesitis involving the Achilles
tendon, and dactylitis of the right fourth toe and left third
and fourth toes. Reactive arthritis is the least common form
of spondyloarthritis (2'l,,
of cases). Reactive arthritis typi
cally entails arthritis/enthesitis in the lower extremities 2
158
to 3 weeks after an enteric infection or a bout of nongono
coccal urethritis or cervicitis. loint inflammation can be
intense, with high leukocyte counts in the synovial fluid.
The sacroiliac joints and spine may be involved. Enthesitis
usually affects the heel (plantar fasciitis or Achilles ten-
dinitis) or may present as dactylitis of the flngers or toes.
Extra articular features can include nonpainful oral ulcers:
ocular inflammation (conjunctivitis, keratitis, episcleritis.
or anterior uveitis)r and a psoriasiform rash (keratoderma
blennorrhagicum), typically on the hands and feet. Some
patients also develop circinate balanitis on the glans penis
or erythema nodosum on the lower extremities. Reactive
arthritis is treated with NSAIDs at anti inflammatory doses
tbr at least 2 weeks. If relief is incomplete, intra-articular
glucocorticoid injections and oral glucocorticoids can be
used. If symptoms persist beyond 3 to 6 months, the use of
disease modifliing antirheumatic drugs. such as sulfasala
zine, methotrexate, or tumor necrosis factor inhibitors. may
be necessary for symptom control and to prevent joint ero
sion. Therapy is discontinued 3 to 6 months follor,r'ing dis-
ease remission. Most cases of reactive arthritis last 6 weeks
to 6 months; only 25'X, of patients have persistent disease.
[.ong term complications can include erosive arthritis, usu
ally of the metatarsophalangeal joints; aortitis with aortic
valve insufficiency; atrioventricular heart block; and uveitis.
Antibiotics, such as azithromycin (Option A), generally
are not indicated in reactive arthritis because they do not
affect illness outcomes. Antibiotics may be used for per
sistent enteritis and for patients with symptoms of acute ure-
thritis or persistent Chlomydio associated reactive arthritis.
This patient has no indication for antibiotic therapy
Between 50% and B0'7, of patients with reactive arthritis
are HLA B27 positive. but testing for HLA B27 (Option B) is
useful only if the diagnosis is uncertain. In this patient. the
diagnosis is not in question and HLA B27 results would not
change treatment.
Stool cultures (Option D) would be useful only if the
diarrhea persisted. This patient had short-lived enteritis, so
stool studies are not indicated.
I(EY POITTS
. Reactive arthritis typically entails arthritisienthesitis
in the lower extremities 2 to 3 weeks after an enteric
infection or a bout of nongonococcal urethritis or
cervicitis.
. Reactive arthritis is treated with NSAIDs at anti-
Bibliography
Schmitt SK. Reacti\€ arthritis. Intl,ct [)is Clin North Am. 2017:31:265 277
lPl\'llD: 282925.101 doi:10.1016 i.idc.20l7.ol.002
Item 68 Answer: C
Educational Obiective: Treat lgG4-related disease.
'llre rnost irppropriate trealnrent is rituximab (Option C). The
ir.rfiltrative involvement of'the parotid and lacrimal glands,

tr
CONT
together \,ith retroperitonell fibrosis and periaortitis. is
nrost consistent \\rith [gG.1 relatecl disease. IgG.l positive
plasnrablasts on biopsy con[irnt thc dirrgnosis. The patient's
clevated alkaline phosphatasc lcvcl suggests associated bil
iary involvement. 'lhe absencc of elevated serum IgG4 anti
boclies is not exclusior-rary because serum antibodies are
often not present. Treatment of lgG4 related disease r.nost
often consists of initial high dose glucclcorticoids lbllo"vecl
bv a slort, taper. Beciruse the cliserrse often recurs ciuring
tape'r. nr-rd because glucocorticoirls bear significtrnt toxic
itr': co:rdministration ol rituxinrab (irn anti CD20 antibody
that indirectly depletes plasnrablirsts) is olten initiated to
pernlit accelerated glucocorticoid taper. l{or,r,ever. ritux
inrab nronotherapy is also eltec'tive and can be used alonc
in pltients with absolute or relative contraindications tcl
glucocorticoid theraplr
Cevimeline (Option A) is rr lrarirsympathetic musca
rinic agonist used to trcrt sicca in patients with Sjogrerr
syndrune. Because this paticnt has parotid enlargement.
shc n.rigl.tt hare sicca and rnight bcnefit fiom cevimeline.
Ilou,e."'er. cevimeline h:rs not becn stuclied in the context of
IgG.1 parotitis, and tlre patient hls r.rot reported dry nrouth.
Methotrexate (Option B) is a clisease r.r-rodify-ir-rg anti
rheumatic drug used as x glucocorticoici sparing agent fbr
nrrrly diseases, including ANCA vlsculitis. Methotrexate hrs
llso been used extensively lbr icliopathic retroperitoneal
li brosi s. I Ioweveq limited evidence supports methotrL'xxtc
to xssist in glucocorlicoid trpering or as a single agent in
Ig(i1 rclated disc'ase. [t rryor-rlcl therefbre not be the first
choicc in this instance.
Surgical debridement of the retroperitoneal mrrss
(Option D) may'be necessary if the mlss threatens to erode
into thc aorta. but thirt is not the cirse in this patient.'lhe
rnass is \ryrapped around both uretersl however, there is nt-r
hydnrnephrosis or deterioration ot'kidney function to sug
gest obstructive nephropathy, which would require ureteral
stcnt plrcement. At this ciisease stage, medicai treatnlent is
nlore appropriate.
s
I( EY POI TI
. Treatment of IgG4-related disease most often consists
of initial high-dose glucocorticoids and rituximab;
rituximab can be used alone in patients with absolute
or relative contraindications to glucocorticoid therapy.
Bibliography
I)erugino CA, Stone lFI. IgG4 relxted disease: rn Lrpdate on pathophysiologl
and inrplications for clinicll clre. Nrt Rcv Rheumatol. 2020;76:702-714.
lPMll):1129390601
Item 69 Answer: D size and
Educational Objective: Diagnose pulmonary arterial
hypertension in a patient with limited cutaneous systemic
sclerosis.
The most appropriate diagnostic test to perform next
is transthoracic echocardiography (TTE) (Option D).
Answers and Critiques
Pulmonary arlerial hypertension (PAH) occurs in roughly
10'7, of patients with systemic sclerosis and is more prevalent
in the limited form (in this patient, evidenced by distal only
skin involvement). PAH is a major cause of morbidity and
mortality. Risk factors include anticentromere antibodies,
antibodies to U1 ribonucleoprotein, antiphospholipid anti
bodies, disease duration greater than 6 years, and telangi
ectasias. TTE provides an estimation of pulmonary arterial
systolic pressure and assessment of both right and left
heart size and function. Current recommendations based
on expert opinion vary. but PAH screening with pulmo
nary function tests and TTE at baseline and at the time of'
development of any new signs or symptoms is reasonable. ta
o
ln addition, most experts obtain pulmonary function tests
ET
and TTE annually. PAH is typically associated with a Dt.c<r
that is less than 60'X, of predicted and is disproportionately (J
low compared with the decrease in lung volumes (FVC/ .E,
Dr.co ratio >1.6) or a decrease in Dt.co ctf 2O''1, or greater in .E
1 year. In this patient, an elevated FVC/Dr-co ratio (1.66) tl
(,
suggests the possibility of PAH and mandates the need fbr
'l"l'E. Because TTE may be more sensitive than specific. fur vt
=
E
ther testing is required il the results indicate possible PAH.
Cardiac magnetic resonance imaging (Option A) can
measure right ventricular mass, and right ventricular hyper
trophy can be a clue to the presence of PAH. However, this
test is expensive and cannot estimate pulmonary artery
pressure. TTE, on the other hand, can be used fbr that
purpose.
High resolution CT o1' the chest (Option B) is most
useful to Iook for underlying interstitial lung disease (which
is more prevalent in dilluse than in limited cutaneous sys-
temic sclerosis). However, the normal pulmonary examina
tion, normal FVC, and significantly diminished DLco more
strongly suggest PAH and the need fbr TTE.
Right hearl catheterization (Option C) is the gold stan
dard fbr conflrming PAH, but it is invasive and is typically
done after noninvasive tests suggest PAH. Right heart cath
eterization should be performed in most patients with an
abnormal TTE result to confirm the diagnosis of PAH and tcl
guide therapy.
t( EY P0 t ilI3
o In systemic sclerosis, pulmonary arterial hypertension
is tlpically associated with a Dlco less than 60%
of predicted and is disproportionately low compared
with the decrease in lung volumes (FVC/Drco
ratio >1.6)
r In patients with systemic sclerosis, transthoracic
echocardiography can estimate pulmonary arterial
systolic pressure and assess both right and left heart
function.
Bibliography
Sundaram SM, Chung L. An update on systentic sclerosis associated pulmo
nJry arterial hypertension: a review ol the current literature. (lurr
Rhcumatol Rep. 2018;20:10. I PMlt): 29,1880161 doi:10.1007is11926 ol8
o7o9 5
159
 Answers and Critiques
Item 70 Answer: C Bibliography
Ed u catio n a I O bj ective: Evaluate for rheumatoid
arthritis using laboratory testing.
The most helpful diagnostic studies will be rheumatoid
factor (RF) and anti cyclic citrullinated peptide (CCP)
antibodies (Option C). Rheumatoid arthritis presents
with symmetric, polyarticular inflammatory synovitis and
prominently involves the small joints of the hands and
feet. These include the proximal interphalangeal, metacar-
pophalangeal, and interphalangeal joints of the toes and
metatarsophalangeal joints. RF is found in approximately
70% of patients with rheumatoid arthritis and may be
present at the time of disease onset; however, it has limited
ta
E speciflcity. Anti CCP antibodies are also present inTO% of
.D
patients with rheumatoid arthritis but have a speciflcity
UI
o, of 95%. Positivity for both tests increases the likelihood of
EL rheumatoid arthritis and may assist in early diagnosis.
rl C reactive protein and ery.throcyte sedimentation rate
(Option A) are inflammatory markers that can be elevated
.tt
in a host of infectious conditions, as well as reflect systemic
(D
ta inflammation in diseases such as rheumatoid arthritis. How-
ever, they have no diagnostic specificity for any particular
disease and do not distinguish among forms of inflamma
tory arthritis.
Enzyme linked immunosorbent assay and Western blot
serologies (Option B) can be useful in the diagnosis of Lyme
disease, including Lyme arthritis. However, this testing is
not appropriate in this patient. The patient has po$articular
symmetric inflammatory arthritis, which is not a pattern
of presentation of Lyme disease. The Spical presentation of
Lyme arthritis is a subacute onset of monoarticular inflam
matory arthritis of the knee.
Viral infections, such as rubella and parvovirus B19,
are associated with an acute polyarthritis syndrome that
may mimic rheumatoid arthritis. These viral syndromes
lzpically last only a few days to several weeks, usually less
than 6 weeks. Serologic testing (Option D) can help identify
viral syndromes in some individuals with early disease.
Anti-CCP antibodies are usually negative in patients with
viral syndromes causing po\zarthritis. Early identiflcation of
rheumatoid arthritis is important for initiation of effective
therapy to prevent joint damage. Initial measurement of RF
and anti CPP antibodies is the best diagnostic test option in
this patient with a 7 week history of symmetric, polyartic
ular inflammatory synovitis that prominently involves the
small joints of the hands.
I(lY POlttrs
. The most useful laboratory studies to aid in the diag
nosis of rheumatoid arthritis are rheumatoid factor
and anti-cyclic citrullinated peptide antibodies.
o Rheumatoid factor and anti
cyclic citrullinated pep-
tide (CCP) antibodies are approximately 70% sensitive
in the diagnosis of rheumatoid arthritis, but anti-CCP
antibodies are 95"L specific.
160
Martinez Prat L. Nissen MJ, Lamacchia C, et al. Comparison of serological
biomarkers in rheumatoid arthritis and their combination to impro\€
diagnostic performance. Front tmmunol. 2018:9:1113. lPlvllD: 29928272]
doi:10.3389 fimmu.2018.01113
Item 71 Answer: D
Educational Objective: Diagnose sarcoidosis.
EX
The most appropriate diagnostic test to perform next is
skin biopsy (Option D). The combination of inflltrative and
destructive bone lesions. skin lesions. parotid and lacrimal
enlargement. l-rilar lymphadenopath)', and hepatic nodules
strongly sllggests sarcoidosis, an inflammatory disease tl-rat
is characterized by formation of noncaseating granulomas
that can infiltrate almost any organ. Sarcoidosis is best diag
nosed b-r- histologic assessment of a biopsl' specimen o{'
afl'ected tissue. In this case. skin is the most accessible tissue
and is clinically involved; granulomatous skin inrolrement
is common in sarcoidosis and aflects approximatell' 25'li, of
patients.
I nfi ltratir,e involvement ol bone suggests the possibilig'
of a malignant condition. potentialll' a lymphoma. Such a
diagnosis could be supported by the hilar l1'mphadenopa-
thy or-r chest radiograph, as rvell as by the parotid (but not
commonly lacrimal) enlargement. Horverer. the patient has
no other li,mphadenopathli her complete blood cour-rt is
nomal. and the nodular ir.rvolvement of the liver and skin
r,r,oulcl be atypical. Moreover. sympton.l duration ot 2 vears
isr-rot cor-rsister-rt lvith 11,'n.rphoma. Bone biopsy (Option A)
and bronchoscopic biopsl ol'a hilar t; mph node (Option B)
coulcl distinguish lymphoma f'rom sarcoidosis. bnt both tests
are irlasive and are not needed if a skin biopsv confirms
sarcoidosis.
Parotid and lacrimal enlargement couid be consistent
u,ith Sjogren syndrome, an infiltrative disease of exocrine
glands. Sj6gren s_v-.ndrome can affect the skin and joints;
honever. in the skin it q,pically produces a non nodular
rash, and in the joints it produces a nonerosi'ue arthritis
rather than iin infiltratire disease of bone. Nodular liver
involvement would not be expected. Diagnosis of Sj6gren
syndrorne could involve obtaining a lip biopsy (Option C).
along r,vith anti Ro/SSA rtr anti LaTSSB antibodl testing:
houever. sarcoidosis is more likely and a skin biopsy u'ould
be definitive.
l(tY Porlrls
o Sarcoidosis is an inflammatory disease that is charac
terized by formation of noncaseating gtanulomas and
can infiltrate almost any organ, including bone.
o Sarcoidosis is best diagnosed by histologic assessment
of a biopsy specimen of affected tissue; when skin is
involved, biopsy is simple and can be definitive.
Bibliography
Kuchaz EJ. Osseous manifestations of sarcoidosis. Reumatologia. 2020;
58:93 100. IPMID: 324766821

Item72 Answer: D Bibliography
Educational Objective: Diagnose renal amyloidosis
associated with poorly controlled anlgdosing spondylitis.
The most likely diagnosis is renal amyloidosis (Option D).
Patients with long-standing, poorly controlled inflammatory
diseases, such as ankylosing spondylitis (AS) or rheumatoid
arthritis, can develop renal amyloidosis (AA amyloidosis).
The prevalence of kidney disease in AS is 2',/, to 13'l.; in the
past, AA amyloidosis was the leading cause of kidney disease
(and remains a major cause) in patients with uncontrolled AS.
With the advent of biologic therapy and subsequent control
ot inflammation in AS, the prevalence of AA amyloidosis has
declined. AA amyloidosis most commonly aflects the kid
neys, manifesting as proteinuria and eventually end stage
kidney disease. It less commonly affbcts the gastrointesti
nal tract, heart, and peripheral nerves. In AS, AA amyloi
dosis is most often seen in men, patients with peripheral
joint disease, and patients with a history of uveitis. Affected
patients will usually manilest high levels of inflammatory
markers, such as erythrocyte sedimentation rate and C
reactive protein, indicating insufficient control of disease
related inflammation. Treatment with efl'ective medications.
such as tumor necrosis factor inhibitors, may stabilize or
improve the kidney manif'estations of AA amyloidosis in
patients with AS. When AA amyloidosis is suspected, Congo
red staining of biopsy specimens from the kidney, rectum, or
abdominal subcutaneous fat will reveal amyloid deposition.
Analgesic nephropathy (Option A) may develop after
years of NSAID use and typically presents with abnormali
ties on routine urinalysis, including pyuria, proteinuria, and
hematuria. Chronic kidney disease and end stage kidney
disease can develop in some patients. This patient's urine
findings are not compatible with analgesic nephropathy.
lgA nephropathy (Option B) is seen in patients with
AS but typically manifests as hematuria and proteinuria,
not isolated proteinuria. lgA nephropathy in patients with
AS tends to be milder, with less renal insufficiency, than
in those with idiopathic IgA nephropathy. More aggressive
treatment of AS does not seem to afl'ect the clinical course of
the AS-related IgA nephropathy.
Interstitial nephritis (Option C) can be caused by a
variety of medications, including NSAlDs. antibiotics, and
proton pump inhibitors. Symptoms may include fever, rash,
ancl eosinophilia/eosinophiluria. All patients will have a rise
in serum creatinine levels as well as pyuria, hematuria, and
proteinuria. Leukocyte casts are typically seen on urinalysis.
This patient lacks these laboratory findings.
KEY POI l{TS
o Patients with long-standing, poorly controlled anky-
losing spondylitis can develop renal (AA) amyloidosis,
the major cause of kidney disease in these patients.
r AA amyloidosis most commonly affects the kidneys,
manifesting as proteinuria and, eventually, renal
insufficiency.
Answers and Critiques
Mercieca C, van der Horst Bruinsm, IE, Borg AA. Pulmonary, renal irnd
neurological comorbidities in patients with ankylosing spondylitis;
implications fbr clinical practice. Curr Rheumatol Rep. 2O14;16:434.
IPMID: 249255891 doi:10.1007/sll926 o14 O4:r4 7
Item 73 Answer: B
Educational Objective: Treat rheumatoid arthritis with
disease modiffing antirheumatic drugs.
The most appropriate treatment is methotrexate (Option B).
The patient has rheumatoid arthritis, and methotrexate is
considered the flrst line treatment ol a patient with a new I,l
diagnosis of rheumatoid arthritis. Methotrexate can be used o,
alone for rheumatoid arthritis, and the dose can be titrated ET
up over a period of weeks, with periodic assessment of .E
the clinical response and laboratory measures of systemic
(J
inflammation (erythrocyte sedimentation rate, C reactive =,
E
.!
protein) and monitoring fbr medication toxicity. Contra' vt
ceptive use in women of child bearing age is recommended q,
because methotrexate can be associated with pregnancy loss U!
=
E
and fetal abnormalities. Il methotrexate alone is inadequate
after a trial for an appropriate length of time, it can also
be used in combination with additional disease modifying
agents, including tumor necrosis factor inhibitors, abata
cept, tofacitinib, and rituximab.
NSAIDs, such as diclofenac (Option A), are not indicated
fbr the treatment of rheumatoid arthritis and should not be a
substitute for initiating treatment with a disease modifying
ergent. NSAIDs may be used in patients with rheumatoid
irrthritis and other fbrms of inflammatory arthritis to relieve
symptoms. However, they would not be expected to alter the
natural history of the disease or prevent permanent deformi
ties or radiographic damage. NSAID use with glucocorticoids
should be avoided. and caution should be exercised with
concomitant methotrexate.
IVlycophenolate mof'etil (Option C) is an immunosup
pressive drug that reversibly inhibits inosine monophos
phate dehydrogenase and aflects lymphocyte stimulation
and proliferation. It is important in the treatment of systemic
lupus erythematosus and in transplant recipients but has no
role in the management of rheumatoid arthritis.
Rituximab (Option D) is indicated for the treatment ol
rheumatoid arthritis. However, it is not an appropriate choice
fbr initial therapy in this patient. Rituximab is indicated fbr
treatment of patients who have had an inadequate response
to methotrexate alone or in whom multiple other agents have
firiled. Rituximab is given via intravenous administration ot'
two doses 2 weeks apart every 6 months. Thus, the time
liame over which it would be expected to work in rheumatoid
arthritis would be inappropriate for a patient with new onset
disease who has not yet been treated with methotrexate.
I(EY POITTS
o Methotrexate first-line treatment of a patient
is the
with a new diagnosis of rheumatoid arthritis.
(Continued)
161
 Answers and Critiques
XEY POlllTS (otldiawd)
. If methotrexate alone is inadequate, it can be used in
combination with additional disease-modifying
agents, including tumor necrosis factor inhibitors,
abatacept, tofacitinib, and rituximab.
Bibliography
Singh JA. Saag KG. Bridges St- Jr. et ill. 2015 American College of
Rheumatologl guideline lbr the treatment of rheumatoid arthritis.
Arthritis Rheumatol. 2016:68:l 26. IPNIID: 265.159.10] doi:10.1002
art.39.180
D 74
UI
E
(D
tr Item
Ed
Answer: C
ucational Objective: Diagnose prosthetic joint
infection with coagulase-negative staphylococcus.
vt
o,
Irrfection \ ,ith Stoph.Ulococ'cris epirlermidis. a coagulasc
a- negative staphylococcus. is nlosl likel1, (Option C). Earll
n onset (<:l nlonths after surgerv) prosthetic joint infectior.rs
lt are often due to Stciph.qkrc'oc'clls olu?Lls. gram negirtivc
(D bacilli. anaerobes. or pollmicrobial infection. Delalecl
UI
onset (3 to 12 months after surgery) infections are ofter.r
dtrc to coagulase-negative staphylococci. Cutibocteriunt
species, or enterococci. [.:rte onset infections (>12 rnonths)
irre often due to S. crurzu.s, gram negative bacilli. clr p
hcnrolytic streptococci. '[ris patient de'veloped ne\\r symp
toms in a prosthetic knec about 6 nronths after tot:rl joint
arthroplasty: His history is t-v-pical of delayed prosthetic
joint infection, with an insidious rather than abrupt olrset
of initially mild but then persistr.rlt s) mptoms. The phl,sical
e\ilmination Iindings are subtle: an absence of fever. krcal
pain onl1,. slight r'r,armth. and mild efiirsion. The orglnisrn
most commonly irnplicatecl in prosthetic joint ir.rfection
in this setting with subacutc onsct. subtle findings :l to 12
months trfter surgery is coirgulirse negative staphylococ
cus. Because of the fiequency of staphylococcal infectior.rs,
it is ah^,ays appropriate to initiate ernpiric treatment ibr
infcction r.r,hile awaitirrg culturc rcsults: r,ancomlcin is au
appropriate first choice. Whcn aspiratior-r ol a prosthetic
joint is required. the procedure shoulcl be perfbrn.recl b1'an
orthopedic surgeon.
Prosthetic joint infection uith Neisseria gonorrhoeae
(Option A) almost never occurs. Ihe arthritis associated \\'it11
gonorrheal infection is generirlly abrupt in onset and oftell
acconrpanied by exquisitely p:iinful tenos)inovitis, fever. ancl
skir.r lesions. The lesions rangc fiont single pustules to a le."l,
lesions that might be papular. pustular. ur hemorrhagic lnd
ltre nrost fiequently firund on the distal extremities. Thesc
findings are not seen in this patient.
I)seirdomonos oeruginoso (Option B) is occ:rsionall_r'
implicated in prosthetic joint infcctions but is considerablv
less common than grarn positivc organisms. often repre
sented in iess than 10'.1, of positive cultures. A l.ristory o1
gastrointestinal or genitourinlr_"- infecti<-rn or immunosup
pression puts patients at higher risk fbr prosthetic joint
infcction with Pseudornoncrs sltecies. 'll.ris patient does not
have a hisbry compatiblc with suclr infection.
152
Streptococci (Option D) are less commonll intpli
cated in prosthetic joint in{'cctittrts than are staph}lococci.
accollnting tbr about i0')1, of positive sy'noYial fluid culturcs
from infbcted prosthetic joiltts.
XEY POIXTS
r Early onset (<3 months) and late-onset (>12 months)
prosthetic joint infections are most commonly due to
Staphylococcus oureus; delayed onset (3 to 12 months)
infection is most often due to coagulase-negative
staphylococcus.
o Delayed-onset (3 to 12 months) prosthetic joint infec-
tion is characterized by an insidious onset and subtle
physical examination findings (absence of fever, local
pain only, slight warmth, mild effusion).
Bibliography
Beanr E. Osmon D. Prosthetic joint infection update. Infect Dis Clin North
Anr. 2018:32:843 859. [PMID: 3o2-ll7 17 | doi:10.1016 i.idc.2018.06.005
Item 75 Answer: B
Educational Obiective: Treat mild systemic lupus
erythematosus.
The most appropriate treatment is prednisone and hydroxy
chloroquine (Option B). This patient has clear flndings of
new but relatively mild systemic lupus erythematosus (SLE).
She has skin and joint involvement and thrombocytope
nia without evidence of other organ involvement. First line
therapy for mild SLE includes hydroxychloroquine. often
with glucocorticoids if a more rapid response is needed.
Many patients will need additional immunomodulatory
therapy at some point in their disease. Hydroxychloroquine
is a mainstay of treatment in SLE because it reduces disease
associated damage, prevents disease flares, and improves kid
ney and overall survival. In addition, hydroxychloroquine
may reduce the risk for thrombosis, liver disease, and myo
cardial infarction and improve lipid profiles. Glucocorticoids
are also used in most patients with SLE. particularly in acute
disease. After disease stabilizes, glucocorticoids are tapered
to the lowest effective dosage. pref'erably to no more than
7.5 mgrd within 4 to 6 months. and should be discontinued
entirely if possible. Glucocorticoid exposure. especially at
high doses, should be limited because of associated risk for
organ damage, infection, and premature mortality. Azathio
prine or methotrexate is recommended if patients with mild
disease have refractory symptoms. All patients with SLE
should be counseled on sun protection, vaccinations. and
lifestyle modiflcations to optimize cardiovascular health.
Prednisone alone (Option A) is likely to help with her
current symptoms but is unlikely to provide Iasting benefits
after it is tapered or discontinued.
For patients with more severe SLE manifestations.
including nephritis, central nervous system disease, or
other more severe manifestations, additional therapy is war
ranted. Induction with mycophenolate or cyclophosphamide

(Option C) would be reasonable, in addition to glucocorti-
coids and hydroxychloroquine, in that setting. This patient
does not require this degree of pharmacotherapy unless her
disease progresses.
Alt patients with a new diagnosis of SLE probably
I require some immunomodulatory therapy, such as hydroxy
i
chloroquine. Those with cutaneous symptoms alone can also
: quency of flare occurrence.
be treated with topical agents, such as hydrocortisone cream
t (Option D), and monitored carefully, but this patient has
I joint inflammation and hematologic Iindings that warrant
t intervention with additional systen.ric theraplt
t
I
(EY POIilIS
I
t o First-line therapy for most patients with systemic
lupus erythematosus includes hydroxychloroquine
t with glucocorticoids.
I
I . Hydroxychloroquine is a mainstay of treatment in
systemic lupus erythematosus because it reduces
i .
I disease-associated damage, prevents disease flares,
t and improves kidney and overall survival.
i 24 hours.
Bibliography
:
r Fanouriakis A. Kostopoulou M. Alunno A, et al. 2019 update of the EULAR
;
recommendations fbr the management of systemic lupus erythematosus.
Ann Rheum Dis. 2019;78:736-745. IPMI D: 309267221
:
Item 76 Answer: B Bibliography
;
t EX Educational Objective: Treat acute gout with colchicine.
i
'lhe nrost appropriate treatnrent is colchicine (Option B).
'lhis patient's presentrtion is consistent lvith an ircute flare
of classic podagra (gor-rt ol the great toc) lvitl.r pain. swelling,
and reclness ol the first r.netatarsophalangeal joir.rt. His r-:rdio-
gruph shou's changes consistent u'itl.r chronic gout),arthritis
in the rnetatarsophalangeal joint, with soft tissue swelling.
tophus. trnd r'rell defined erosions that havc sclerotic bor-
dcrs and ovcrhanging margins. (lolcl'ricine is an eft'ective
trcatlxenl of acute grut u,ithin the first 24 hours of the
eirisoclc. [n the iibsence of chronic kidrrclr discase. the initial
dose is 1.2 mg, lbllowed by a singlc 0.6 mg close t hour later
ancl then 0.6 mg dail1, therealter if' r.reedcd. Colchicine.
0.(r mg dail1,, 6ny be continued ancl ttsed as prophyhxis
u'hile urate lowering therap), is initiirted. Oolchitine rnal'
result in gastrointestinal toxicity, ancl ckrsing may be limited
b)'gastrointestinal tolerance. 'lbpical icc l.relps reduce clura
tion of the flrrre and ma1, be r-rsed as adjunctive theraplr
the Americar.r College <tf Rhcumatology (ACR) strongly
rccomnrencls initiating urate lornerir.rg therapy tbr patients
with gout and any of thc fbllor,l,ing inclications: onc or more
subcntlneous tophi; e\riclencc of rldiographic darnage (any
moclality) attributable to gout: or lreqnent gout flares. with
"frequent" being clefined as two or more annually 'lhe ACR
rccommends treating to a maxinrum serum uratt: levcl of
lcss thirn 6.o nrg,dL (0.:15 mrnol,L). Allopurinol (Option A)
is indicirted ir-r tl'ris patient lbr long term trclltnrcnt girren
the racliographic changes ol gouty arthritis. Current ACR
guidelines support initiating nratc lor,r'cring therapy during
Answers and Critiques
ll1 acute flare, ntainly to improve {irtr-ire adherence' but
only il tl-re patient is also treing adequately treated ftlr the
acute flare. Allopurinr-rl i,vill not 1.reat the acute flare and'
if adrninisterecl alone. may' actr-rally prolong the f lare dura
tion. When initiating allopr-rrinol, paticnts shoulcl cotrtinue
tiking anti inflantnratory f lare prophylaxis ft)r irt least 3 to
6 months because urate lowcring transiently raiscs the fre
NSAIDs. such as indontcthacin (Option C). given fbr 5 t<r
7 clays are also ef lective in treating acute gout. NSAIDs have
an antiplatclet ef I'cct atrd are associated r,r'ith risk ftrr gastro
intestinal ulcer:rtion and bleeding. This patient is receiving
UI
anticoagulation: thus. NSAIDs arc contraindicated. (l,
Prednisone (Option )) may be an eflective trcatment ol
ET
acute gout. l-lowcver, it raiscs the blood glucose Ievel and is
not tl'rc best choicc in a patient rvith type 2 diabetes mellitus.
(J
t(EY POfi{Tt g
=,
IE
In the absence ofchronic kidney disease, colchicine, tt
1.2 mg, lollowed by a single 0.6 mg dose in t hour, is
o
an effective treatment of acute gout within the first
yt
=
E
o Administering urate-lowering therapy, such as allopu-
rinol, in the absence of anti-inflammatory therapy may
result in recurrent flares of acute gout.
tritzcerald JD, Dalbcth N. l\,tikuls T, et al. 2020 American College ol'
Rheumatolos/ guideline fbr the management of gout. Arthritis Care Res
(Hoboken). 2o2o..l 2:741 760. [PMID: 323919341 doi:10.1002/acr.24180
Item 77 Answer: D
Educational Objective: Diagnose lupus nephritis with a
kidney biopsy.
'lhe most appropriate diagr.rostic test to perfbrm ncxt is
kidncy biopsy (Option D). This patierlt has acute systemic
h"tpus crythernatosus (St.E) with proteinuriir ancl hematuria
conccnring fbr kidne-y involvement. Iler positive results lor
antinuclear and anti double-strandecl DNA antibodies ancl
dcpressed serum complement values support this cliagnosis.
Additional evaluation in patients suspected ol having lupus
nephritis should include 2.1 hour urine measLrrcment fbr
quantitation of lrroteinuria ancl a kidney biopsy. Patients
lvith SLE with any sign of kidney involvement ilre can
didates for kidney biops1,. Indications include proteinuria
grcater than 500 mg.24 h, urine pnltein creatinine ratio
greater than 500 mg,'g (especialll, in thc setling ol hematuria
andior cellular casts), tir unexplained decrease in estirnatecl
glomcrrrlar filtriition rate. Biops), results are important for
choosing incluction thcrapy and cletermining prognosis.
S[.E can cause nellropsl,chiatric rnanif'estations (cerebri
tis). including seizure. delirium, psychosis, or stroke, which
can be importanl to iclentify rvhen choosirlg management
strategies. Ilrair.r MRI (Option A) is sensitive tbr cletection of'
abnormalitics associated r,vith cerebritis buI can be difficu]t
to inlerpret. This paticnt has no symptr)ms to sugigest central
153
 l11we_1s and Critiqtes
tr
CONT.
nervous syslent discase. so a brain MRI is less likelr,to Lle
useful in this case.
Chest CT (Option B) can be useful lbr identificalion of
serositis, interstitial lung disease. or pulmona4, cmbolisru.
u'hich can all be associated."r ith Sl.E, but this patient has no
cLlrrent cardiopuintonary s!mptonls or exanlination abn<tr
malities. CT with contrast poses a risk fbr contrxst-induced
nephropathf in this patient \\'ith an increased serum creat
inine level.
S[-E is associatecl n,ith pcricarditis. pericarclill or pleu
ral eflusions. and other nranifestations ofserositis. Echocar
diography (Option C) can be useful to assess fbr the presencc
and severity of pericarditis lnd effusions. as uell as the
UI possibility of valvular clisease. In a patient u'ith a norntal
€ cardiopulrnonlrry examination ancl no cardiac s!'mptoms.
o
Ut echocardiographf is less uselul fbr guiding management
o, than is a kidney biopsy.
=
EL
n t(tY P0tilTt
=. o Recognized indications for kidney biopsy in patients
=.
,EI
tr with systemic lupus ery.thematosus include glomeru-
(D
ta lar hematuria and/or cellular casts, spot urine
protein-creatinine ratio greater than 500 mg/g, or
unexplained decrease in estimated glomerular
filtration rate.
. In patients with lupus nephritis, kidney biopsy results
are important for choosing induction therapy and
determining prognosis.
Bibliography
Fanouriakis A. Kostopoulou M. Cheema K, et al. 2019 Update ofthe Joint
Eur()pean League Against Rheumatism and European Renal Association
European Dialysis and Transplant Association (EULAR/ERA ED'IA) rec
ommendations for the management of lupus nephritis. Ann Rheum Dis.
2020:79:713 723. [PMID: 322208341
Item 78 Answer: C Lymphoma (Option C) is most likely responsible for this
Educational Objective: Treat an$losing spondylitis
with NSAIDs.
The most appropriate treatment is naproxen (Option C). This
patient has classic ankylosing spondylitis (AS), as suggested
by inflammatory Iow back pain with signs of sacroiliac joint
irritation, limitation of lumbar spine motion, and changes of
sacroiliitis on radiograph. NSAIDs are recommended flrst-
line therapy for AS. In general, an NSAID must be dosed
toward the higher end of the dosing range to modif,z new
bone formation and have a significant impact on inflamma
tion. If an NSAID is started early in the course of AS (<3 years),
35%, of patients will enter remission compared with only
12'1, to 15"/,, of those starting it later. Unlike with other rheu-
matologic diseases, evidence suggests that NSAID use in AS
has a disease modi$zing effect. Patients should be aware of
and monitored for NSAID toxicity, such as hypertension, gas
trointestinal bleeding, and kidney disease. Physical therapy
is the most important nonpharmacologic intervention in AS.
The goals of therapy include improving pain and stiffness,
164
maintaining range of motion, and reducing disability: transi
tion to an ongoing daily exercise program is optimal.
If NSAIDs fail or the patient cannot tolerate NSAIDs,
a tumor necrosis factor (TNF) inhibitor. such as etaner
cept (Option A), is recommended as second line disease-
modi$ring therapy. The eflicacy of TNF inhibitors in patients
with active AS has been demonstrated in numerous ran-
domized controlled trials, which showed improvements in
clinical. radiographic, and MRI outcomes. Patients in whom
a TNF inhibitor fails should receive an interleukin 17 inhib-
itor, such as secukinumab or ixekizumab.
Nonbiologic agents, such as methotrexate (Option B) or
sulfasalazine (Option D), do not play a role in axial disease
but could be used as additional therapy as needed for signif
icant peripheral joint disease. Sulfasalazine is the preferred
agent. This patient has no evidence of peripheral joint dis-
ease. and these nonbiologic agents are not indicated.
XEY POIIITI
. Physical therapy and NSAIDs are the recommended
first-line therapies for ankylosing spondylitis.
. If NSAIDs fail or the patient cannot tolerate NSAIDs, a
tumor necrosis factor inhibitor is second line therapy
for ankylosing spondylitis.
Bibliography
Ward MM. Deodhar A, Gensler I-S, et al. 2019 Update of the American
College of RheumatoloEl//Spondylitis Association ol Americar
Spondyloarthritis Research and Treatment Net$ork Recommendations
for the Treatnlent ofAnkylosing Spondylitis and Nonradiographic Axial
Spondyloarthritis. Arthritis Rheumatol. 2019:71:1599 1613. IPMID:
314360361
Item 79 Answer: C
Educational Objective: Identi$ probable lymphoma in
a patient with Sjdgren gmdrome.
patient's recent symptoms. Patients with Sjogren syndrome
are at high risk for lymphoma (5'7, lifetime risk); 60'2, of
these cases are mucosa associated lymphoid tissue lym
phomas. Risk factors include parotid gland enlargement.
depressed C4 complement level, elevated rheumatoid fac-
tor level, elevated anti Ro/SSA and/or anti La/SSB antibody
levels, monoclonal gammopathy, and cryoglobulinemic vas
culitis. ln addition to having several of these risk factors,
this patient has systemic "B symptoms" associated with
lymphoma: fever, weight loss, and drenching night sweats.
Light-chain (AL) amyloidosis (Option A) is a clonal
plasma cell dyscrasia characterized by production of amy
loidogenic )" or r free light chains. These light chains can
deposit in various organs, resulting in varying clinical pre
sentations of the disease, most commonly the nephrotic
syndrome, restrictive cardiomyopathy, peripheral neuropa
thy, and hepatomegaly. AL amyloidosis can be a rare com-
plication of IgM associated monoclonal gammopathy and
can rarely inflltrate the parotid glands. This patient's pre-
sentation, however, is most consistent with classic Sjogren

syndrome, with exocrinopathy afl'ecting salivary and lacri
mal glands, laboratory test results consistent with Sjdgren
syndrome, and recent onset of systemic disease symptoms
suggesting lymphoma.
Prominent symptoms of' hypothyroidism (Option B)
include fatigue, weight gain, myalgia, and arthralgia. Lab
oratory iindings may include anemia, elevated LDL choles
terol, and hyponatremia. Hypothyroidism cannot explain
the patient's weight loss, low C4 complement level, or
monoclonal gammopathy. In addition, the patient's thyroid
stimulating hormone level is normal, excluding hypothy
roidism as a cause of the patient's recent symptoms.
Primary Sjogren syndrome occurs in isolation; second
ary Sjogren syndrome occurs in the setting of other rheu
matologic diseases, most commonly rheumatoid arthritis
(Option D) and systemic Iupus erythematosus. Patients with
rheumatoid arthritis and Sj0gren syndrome may have lab
oratory findings similar to those found in this patient, but
this patient has Sj0gren syndrome antibodies and negative
results fbr anti cyclic citrullinated peptide antibodies. In
addition, examination does not suggest synovitis (the patient
has arthralgia rather than arthritis). The recent onset of
weight loss, fbver, and night sweats in the absence of syno-
vitis favors the diagnosis ol lymphoma over rheumatoid
arthritis.
XEY POITIT
. Patients with Sjogren syndrome are at high risk for
lymphoma (5% lifetime risk).
o Risk factors for lymphoma in patients with Sj0gren
syndrome include parotid gland enlargement,
depressed C4 complement level, elevated rheumatoid
factor level, elevated anti-Ro/SSA and/or anti-La/SSB
antibody levels, monoclonal gammopathy, and cryo
globulinemic vasculitis.
Bibliography
Fragkioudaki S, M:rvragani CP, Moutsopoulos llM. Predicting the risk fbr
lymphoma clevelopment in Sjogren syndrome: an easy tool for clinical
use. Medicine (Baltinrore). 2016i95 r3766. lPMlDt 273368631 doi:10.1097,
M D.0000000000003766
tr Item
Ed
80
ucationa I Objective
Answer: A
: Diagnose drug-induced lupus
erythematosus.
The nrost likelv diagnosis is clrug induced lupus erythen-ra
tosus (Option A). Several medications, inclucling nrinoc)-
cline, can cause drug induced lupus erythenratosus. This
syndrome is often r.nilcler tl.ran idiopathic systemic lupus
erythematosus (SLE). Patients may hirve skin ar.rd joint
symptoms but are at a mucl.r lower risk for organ dam
age. Patients u,ith drug induced lupus erl,thematosus oflen
have transiently positive antinuclear arltibodies but may lack
typicirl aukrantibodies specific to Sl.E. Classically, paticnts
with drug induced lupus erytl.rematosus may have antihis
tone antibodies. although these :rntibodies arc' not always
Answers and Critiques
presc'nt and are not specific. Otl'rer antibr-rdies. including ANCA
(especially p ANCA) and F-actin, can bc seen with min(,1)'.
clinc use. Most patier.rts with dmg-induced lupus sympk)n-Is
r"iII improve lr,ith discontinuation of the rnedicirtiort e:tusing
the qrmpton,s, bLlt solre may r.reed synrpkrmatic treatmcnt.
Granulonrrtosis w'ith polyangiitis (Option B) is a
small vessel vasculitis associated with ANCA that ry'picrlll
causes constitutional symptoms, upper and krwer lint'ay
disease. and glomerulonephritis. this pirtient has an ANCA,
which can be seen in a variety of aut<.rimnrune:rncl infectious
states, but her clinical presentation is not suggestive of an
AN(.A associ:rted rast'ulitis.
Rheumatoid arthritis (RA) (Option C) cirn also cause la
(l,
joint findings in the distribution describecl. lncl lacli of 3
ET
rheunratoicl factor ar.rd anti cy,clic citrullinatcci pcpticle
.=
antiboclies does not rule out ItA. This cliagnosis coulcl llso L'
be considere<l if'synovitis persists aftcr discontinuation ol E'
mir.rocycline.
E
.E
SLE (Option D) is also in the diflerer.rlirrl
diagnosis. ra
(I,
although it is lcss likely than clrug induced lupus erytl.re
lr:ltoslls in x patient t:rking urirrocl,clir.rc. [t shou]d be c<ln- =
Ut
sidered if syn.rptoms fail to inrprove after discontinuation of
minocycline.
XEY POIilT
o DruB induced lupus erythematosus is often milder
than idiopathic systemic lupus erythematosus and is
characterized by more skin and joint symptoms and a
much lower risk for organ involvement or damage.
Bibliography
Kawktt t.. Mertz tl Chasset F. et al. Charucterization of drug induced cutane
ous lupus: analysis of 199,1 cases using the WHO pharmacovigilance
database [Letter]. Autoimmun Rev 2021;20:102705. IPMll): 33188917]
Item 81 Answer: A
Educational Obiective: Diagnose fibromyalgia.
The most likely diagnosis is fibromyalgia (Option A). This
patient presents with ',r,idespread pain, fatigue, poor sleep,
and cognitive symptoms of 1 year's duration. These symp-
toms are the hallmarks of flbromyalgia, a poorly understood
but common chronic pain syndrome affecting 2"/,, to 3"/,, of
the population. Diagnosis is suggested by history and can be
conlirmed with validated criteria (e.g., the 2016 revisions to
the American College of Rheumatologz Preliminary Diag
nostic Criteria). This illness is not autoimmune or inflamma
tory and extensive laboratory testing is not advised unless
another comorbid disease is suggested. Although some
patients may have tender points, assessment of tender points
on examination is unreliable (particularly in men) and no
Ionger among the clinical criteria for diagnosis. Fibromyal-
gia tends to be associated with other medically unexplained
syndromes, including irritable bowel syndrome, and is espe-
cially common in patients with migraine headaches.
Generalized osteoarthritis (Option B) affects multiple
joint groups. On joint examination, crepitus, decreased
165
 Answers and Critiques
range of motion. bony enlargement, and sometimes effu
sion may be present. Ger.reralized osteoarthritis is an unlikely
diagnosis because it would not cause the widespread pain
seen in this patient and occurs in older patients. In addition,
the examination demonstrates no evidence of osteoarthritis
in any joint.
Polymyalgia rheumatica (PMR) (Option C) is a clinical
diagnosis based on characteristic symptoms in a patient
older than 50 years and is supported by an elevated eryth
rocyte sedimentation rate. PMR is associated with pain and
stiffness of the shoulder girdle and hip girdle. This patient's
age, difiuse pain, and normal erythrocyte sedimentation rate
are not compatible with PMR.
UI Rheumatoid arthritis (Option D) is an inflammatory
€
o arthritis that primarily affects small joints. Patients with
ta rheumatoid arthritis present r,r,ith discomfort in discrete
q,
3 joints. not di{fuse pain. In addition, rheumatoid arthritis
EL does not cause axial pain or myalgia. The musculoskele
n tal examination in a ptrtient u,ho has a l-year history of'
i. untreated rheumatoid arthritis should reveal multiple
tt
tr swollen joints.
o ulation and passive range of motion (Option C) for knee and/
ta Systemic lupus erythematosus (SLE) (Option E) is an
autoimmune disease that can allect any system in the body,
including the skin, blood cells, joints, lung, central nervous
systenl. and kidneys. Although patients with SLE can have
concurrent fibromyalgia, patients with fibromyalgia rarely
have SLE. This patient also has none ol the hallmarks ol
SLE. such as autoimmune c).topenia, inflammatory arthritis.
rash, kidney disease, or systemic inflammation.
[[Y P0lilrt
. Fibromyalgia is characterized by widespread pain,
fatigue, poor sleep, and cognitive symptoms; diagno-
sis is suggested by history and can be confirmed with
a validated questionnaire.
. Assessment of tender points on examination is unreliable
and no longer among the clinical criteria for diagnosis
of fibromyalgia.
Bibliography
Wolfe F, Clauu,l)J. Fitzcharlcs MA. et aI.2016 Revisions to the 2010/2011
fibnrmyalgia dixgnostic criteria. Semin Arthritis Rheum. 2ol6r.t6::ll9
329. IP1\{lD:')79l6278ldoi:10.1016 j.scmarthrit.20l6.08.0l2
Item 82 Answer: A
Ed u catio na I O : Treat osteoarthritis
bjective with exercise
and weight loss.
The most appropriate additional treatment for this patient
is exercise and weight toss (Option A). The 2019 Ameri
can College of Rheumatolory (ACR)/Arthritis Foundation
(AF) guideline strongly recommends exercise for all patients
with osteoarthritis (OA). The most robust evidence supports
exercise in the treatment of knee and hip OA: less evi
dence is available for hand OA. Many helpful exercises are
available for knee and hip OA, and the evidence indicates
that no one exercise program is superior. However. the best
155
program is likely the one to which the patient will adhere.
Walking is the most common form o1'aerobic exercise eval-
uated in studies, either on a treadmill or as part of a super-
vised community program. Strengthening exercises with
the use of isokinetic weight machines, resistance exercises,
and isometric exercise also provide value. Aquatic exercise
often encompasses aspects of aerobic fitness exercises and
exercises fbr enhancing joint range of motion in a low
impact environment. The ACR/AF guideline notes a dose
response relationship of weight loss and resultant symptom
and functional improvement in patients with OA who have
overweight or obesity. Weight loss attempts coupled with an
exercise program increase the benefit to the patient. Even
small amounts of weight loss (5'1,) can have a positive elfect
on pain and function.
The ACR/AF recommends against the use of massage
therapy (Option B) in the treatment of OA because elficacy
data are lacking. Massage therapy may have other benefits,
but none that pertain to outcomes speciflc to knee OA have
yet been demonstrated.
The ACR/AF recommends against mobilization/manip
or hip OA. Although manual therapy can be of benefit for
certain conditions, such as chronic low back pain, data show
little additional benefit over exercise alone lor managing OA
symptoms.
Studies examining the use of transcutaneous electrical
nerve stimulation (TENS) (Option D) have failed to demon-
strate benefit in patients with knee OA. The ACR/AF guide
line strongly recommends against the use of TENS.
rEY POIlIIS
. Exercise is beneficial in hip, knee, and hand osteoar
thritis; no one exercise program is superior.
o There is a dose-response relationship of weight loss and
slmptom and functional improvement in patients with
overweight or obesity and osteoarthritis that begins
with 5'7, loss of bodyweight.
Bibliography
Kohsinski Sl.. Neogi li llochberg MC, et al.2019 American College of
Rheumirkrlol5,', Arthritis Foundation guideline for the mrnagemrnt of
osteoarthritis ofthe hand. hip. and knee. Arthritis Care Res (Hoboken).
2O2OJ2:149 162. [PI\'Ill): 31908149]
Item 83 Answer: D
Educational Objective: Evaluate rheumatoid arthritis
with hand radiography.
The most appropriate diagnostic test to perfbrm next is
plain radiography of the hands (Option D). No single
radiographic feature is diagnostic of rheumatoid arthritis.
However, f'eatures such as periarticular osteopenia, joint
space narrowing, and bony erosions are characteristic of
established disease and may help solidify the diagnosis of
rheumatoid arthritis when physical examination findings
:rre equivocal. Ifpresent, they can also underscore the need

for early treatment with disease modifying agents. which
can include biologics, because the presence ofradiographic
damage at the time of diagnosis of rheumatoid arthritis
predicts a more severe course of disease. Thus, plain radi
ography may aid in both diagnostic and therapeutic deci
sion making as well as help establish a baseline to assist in
monitoring disease activity.
ANCAs (Option A) are directed against antigens fbund
i
in the cytoplasmic granules of neutrophils and monocytes.
ANCA testing is usually performed to help diagnose or
exclude granulomatosis with polyangiitis and microscopic
polyangiitis. However, polyarticular, symmetric inflamma
tory arthritis of the small joints of the hands as seen in
this patient is not a feature of ANCA positive vasculitis.
The choice of which autoantibody tests to order should be
guided by an accurate history and careful physical exanrina
tion. ln this case, ANCA testing is not the most appropriate
:
diagnostic test.
Anti double stranded DNA antibody testing (Option
B) is not indicated. Antinuclear antibody (ANA) specificiff
testing (i.e., testing fcrr antibodies to specific nuclear com
j
ponents, such as DNA or centromeres) should be reserved
for patients with a positive ANA test result and a clinical
syndrome suggesting an underlying rheumatologic disease.
An anti double stranded DNA antibody test should not be
perfbrmed in the absence of a positive ANA result.
MRI (Option C) can be a valuable tool in the evaluation
of specific concerns in patients with musculoskeietal dis
ease, but it lacks speciflcity fbr the diagnosis of rheumatoid
arthritis. The first step in radiologic evaluatior.r of a patient
with joint symptoms is usually plain radiography because
it is relatively inexpensive, is readily available, and per,
mits assessment for findings characteristic of rheumatoid
arthritis.
r(EY POt t{IS
. No single radiographic feature is diagnostic of rheu-
matoid arthritis, but features such as periarticular
osteopenia, joint-space narrowing, and bony erosions
are characteristic of established disease.
. Radiographic features of rheumatoid arthritis can
underscore the need for early treatment with disease
modi8zing agents because radiographic damage at
the time of diagnosis predicts a more severe disease
course.
Bibliography
Aletaha D, Smolen JS. Diagnosis ancl management of rheul.uirtoid artltritis:
a review. JAMA.2018 Oct 2:320(13):1360 1372. IPMID:3028.51831 cloi: 10.
1001 iama.20lB.l3103
Item 84 Answer: D
Ed ucationa I Objective: Diagnose subacute cutaneous
lupus erythematosus.
The most likely diagnosis is subacute cutaneous lupus ery-
thematosus (SCLE) (Option D). SCLE appears as one of two
Answers and Critiques
variants: annular and polycyclic photosensitive plaques
on the back, chest, and extremities, or psoriasiform scaly
plaques in a similar distribution. SCLE does not scar but
may resolve with temporary pigmentary changes. Fewer
than one in four patients with SCLE has systemic lupus ery-
thematosus (SLE), and as many as one in three SCLE cases
are drug induced. The latter may resolve with withdrawal of
the causative agent. Up to 70'7, of patients with SCLE have an
elevated antinuclear antibody titer, with anti RoTSSA and
anti La/SSB being overrepresented.
The malar "butterfly" rash is characteristic of acute
cutaneous lupus erythematosus (ACLE) (Option A); holt'
ever, ACLE can also manifest as a maculopapular variant t,l
G,
that is photosensitive and distributed over the chest, upper
C'
back, and arms. Both rashes have a range ol presentation
from pink-to-violet macules to scaly papules and plaques. tr,
Essentially all patients with ACI-E have SLE and as such ter.rd rE
to have systemic symptoms and positive serologic results. .g
,
The rash ofACLE does not scar.
Cutaneous leukocytoclastic vasculitis (Option B)
o
results from inflammation of small blood vessels and can ta
=
be seen in isolation or in association with a variety of
systemic diseases, including autoimmune disorders (such
as SI-E, rheumatoid arthritis, inflammatory bowel disease,
and systemic vasculitides), but also infection, hypersen
sitivity to medications, and malignancy. Rashes consist of
red or purple discrete skin lesions, are more common on
the lor.r,er extremities than on the trunk or fbrearms. and
rarely occur on the face.
Chronic cutaneous lupus erythematosus (CCLE)
defines a category of related skin diseases of which dis
coid lupus erythematosus (DI-E) (Option C) is the most
common. DLE lesions start as red to violet plaques that
develop a hyperpigmented border and thick adherent scale
in the center. The centers of the lesions eventually become
atrophic and depigmer.rted, causing permanent alopecia if
occurring in hair bearing areas. Plaques favor the head and
neck, particularly the scalp and the hollow ot the auricle
of the ear. CCLE in general has a low association with Sl.E,
and t)LE poses approximately a 10'X, risk for underlying
systemic disease.
I(EY POIilTS
o Subacute cutaneous lupus erythematosus is a photo
sensitive rash occurring especially on the arms, neck,
and upper trunk, usually sparing the central face and
consisting of erythematous annular/polycyclic or
patchy papulosquamous lesions.
. Fewer than 25'l. of patients with subacute cutaneous
Iupus erythematosus have systemic lupus
ery.thematosus.
Bibliography
Alniemi l)T. Gutierrez A Jr. l)ruge I-A. el xl. Subrcule cutilncous lupus ery
themrtosus: clinic:rl cluracteristics. clisease associatior.ts. treiltnlents.
and outcomes in a series ol'90 patients at Meyo Clinic. 1996 2011. l\,hyo
CIin l)roc. 20l7;92:,106 41.1. IPl\4lD: 2U1856561
167
 Answers and Critiques
tr Item 85 Answer: A
Educational Objective: Diagnose giant cell arteritis.
The rnost likely diagnosis is giant cell arteritis (GCA) (Option
A). 'lhis patient h:rs polymyalgia rl.reumatica. and 10'/, to
20'll, of patients n,ith polyntyalgia rheumatica have con
collritilnt CCA at presentatior.r or dcvelop GCA later in the
disc:rse course. Ileadachc is present in mure than 607, o1'
paticnts r,r'ith GCA and may be frontal, occipital, unilateral.
or gcneralized; it nra1,' be constant, intermittent, or waxing
and u'aning. Ihe irnpofiant point is that the headache is
ner,ri A frecluent nor.rheadache manif'estation of GCA is jaw
D clauclication, or,r,ing to decreased blood flow to the muscles
ut of mirstication. Jar,r'claudication is ttrund in nearly 50?; of
E patients with GCA, and this symptom should always be
.D
UI explored on revie\.t, ol svstems in a patient with polymyal
o, gia rheun.ratica. Other key questions to ask such patients
=L
C include whcther thcy havc recent changes in vision (e.g.,
n short lir,ecl episodes of amaurosis firgax. diplopia. or blur
=.
lr3.
g
riness) ancl scalp tenderness (e.g., r,r,ith hair brushing). A
blood C-reactive protein level of l2.B mg/dl (128 mgil)
(D
Ut r'rru-rld be unusual lbr polvml,algia rheunratica alor.re; this
degree of systemic inflammation is r.nore in keeping with a
vasculitis. such as (lCA.
Granulomatosis r,r,ith polyangiitis (GPA) (Option B) is
the n-rost common ANCA associatecl vasculitis. Typical age
at onset is bctu,een .15 ancl 60 !'ears. GPA afl'ects the upper
and lorter ainr,ays. kidneys, eyes. and ears. At least 50u/. of
paticnts havc constitutional symptoms. GPA can cause visual
chxnges bllt is not t1'picall1.'associated \vith ncrn onset head
ache or jau, claudication.
Like (lPA. microscopic polyangiitis (MtA) (Option C)
is a small vessel r,asculitis that characteristically aflects thc
lungs anci kidneys, along with other organ systems. Absence
of granulonras distinguishes N,IPA iiom GPA. MPA cannot
account ibr tl-tis patient's syrnptoms.
Polyrrteritis r.rodosa (Option D) is a medium
l,essel lasculitis tlrat can af fect any organ in the body but
most comnronly involves the renal vasculirture (resulting
irr renal insufficicncy and hypertcnsion), skin (produc
ing nodular skin lesions). mesenteric vessels (causing
abdominal pain, including postprandial abdominal pain),
ancl peripheral ncrves (typically presentir.rg as mononeu
ritis multiplex). The patient does not have this symp
toln compler, making polyarteritis nodosa an unlikely
dirrgr-rosis.
KEY POIilTS
o Concomitant giant cell arteritis develops in 10'2, to
20% of patients with polymyalgia rheumatica.
o Common symptoms of giant cell arteritis include
headache, jaw claudication, and changes in vision.
Bibliography
Maz M, Chung SA, Abril A, et al. 2021 American College of Rheumatologr/
Vrsculitis l.bundation guideline fbr the nlanagement ofgiant cell arte
ritis and Takayasu irrteritis. Arthritis RheumrtOl. 2021. fPMID:
3123s8841
168
Item 86 Answer: A
Educational Objective: Diagnose the cause of acute
tx
monoarthritis by using arthrocentesis.
The most appropriate diagnostic test to perfbrm next is
aspiration of the left knee (Option A). This patient has
acute inf lammatory arthritis of the knee characlerized by
pain. swelling, and redness for less than 1 rveek. Physical
examination shows swelling r,rritl-r warmtl-r ancl redness.
as well as tenderness with palprrtion and limited range
of' motion. The clifl'erential diagnosis ol acute monoar
thritis includes crystal induced disease (gout or calciunr
pl,rophosphate deposition), infection. and hemarthrosis
(bleeding into the joint). Joint aspiration is necessary' to
make an accurate diagnosis and distinguish amor.rg these
causes. Synovial fluid should be analyzecl for cell count
ar.rd diflerential. crystal examination, Cram stain, and
culture.
Erythrocyte sedimer-rtation rate (Option B) is a blood
test that indicates systemic inflammation. It may be elevatecl
in any inflammatory process. inclucling crystal induced dis
ease and intectiorr. but docs r.rot distinguish betu,een the t$o 1
diagnoses.
Radiography ol the knee (Option C) rnay be a useful
test but is not adequate to distinguish the cause of acute
monoarthritis unless there is a history of traunra and frac
ture lvith hemarthrosis is suspected. This patient has no
hislory ol trauma.
Serum urate (Option D) is not l-relpful for deterntining
the causc of this patient's acute ntonoarthritis. Although
an elevated level might increase clinical suspicion of goul
as the cause, only knee aspiration with fluid analysis fbr
cell count and crystals can determine the cause of the knee
intlammation. The presence of soclium urate crystals in thc
synovial fluid polymorphonuclear cells is diagnostic for
gout. Gout and infection may coexist. so aspirati<tn wottld
be indicatcd even if the serum urate lcvcl was elevated.
Finall1,, evcn in patients with acute gout. scrum urate level
rnny be normal at the tirne of the flare. Thus, a norntirl
serunl urate level would not rule out gout as the cause ol
acute monoarthritis.
TEY POTITI
o Joint aspiration is necessary to make an accurate
diagnosis and distinguish among causes of acute
monoarthritis, including crystal-induced disease
(gout or calcium pyrophosphate deposition), infec-
tion, and hemarthrosis.
. ln patients with an acute inflammatory arthritis,
synovial fluid should be ana\zed for cell count and
differential, crystal examination, Gram stain, and
culture.
Bibliography
Singh N. Vrgelgesang SA. Monoarticuhr arthritis. Med (llin North
Am. 20l7: lOl :607 6 13. IPMI I): 283727 16l doi:lo. I Ol 6,'i.mcnir.2016. 12.
00,1
t Answers and
I
9'r!qv.::
I
i

t
i
\ tr Item 87 Answer: D
Educational Objective: Evaluate new monoarticular pain
Bibliography
Ross JJ. Septic arthritis of native joints. lnfect Dis Clin North Am.
31:203,218. IpMID, ZSgOOZ:2t] doi:10.1016/j.idc.2017.01.001
2017;

I
in a patient with rheumatoid arthritis.
The nrost appropridte diagnostic test to perfbrm next
:

\ is synovial fluid analysis (Option D). 'lhe abrupt onset of

Item 88 Answer: D
acllte nronoarticular inllamnratory rrthritis in any patient Educational Objective: Treat systemic lupus
shor-rld suggest a joint inf'ection. llris patient has a history e4rthematosus in a patient planning pregnancy.
o1' krng standing rheumatoid arthritis that has damaged
The most appropriate preconception management is to
nurrerous joints. Previiius joint clamage incre:rses the risk
discontinue mycophenolate mofetil and add azathioprine
tbr joint inf'ection. 'lhe patient irlso reccives multiple inrnru- (Option D). In some very stable patients with systemic
nosupirressive irgents. u{rich also increase risk fbr joint
: lupus erythematosus (SLE), mycophenolate mofetil could
intbction. tier joint ex:rmination, apart from the left knee, ra
be discontinued with maintenance on hydroxychloroquine (l,
suggests quiescent rhcumatoicl arthritis rather than a gcn
alone. SLE is associated with increased risk for miscarriage, CT
eralizecl flirre of disease. turther raising suspicion lor an
:

premature delivery and other pregnancy complications.

inlected joint. In patients suspectecl of having infections
;
Patients with SLE who desire pregnancy should be advised rr,
arthritis. the most important cliagnostic proceclure is crpe E
to wait until disease has been well controlled for at least
ditious afihrocentesis to obtiiin joint lluid :rncl conduct syncr .g
6 months to reduce these risks. Certain therapies, such
vi:rl fluid analysis (Cram stain. culture lbacterial and. when tl
: as mycophenolate mofetil, belimumab, and methotrex o
indicated, mvcobacterial and,or fungall. leukocyte count.
ate, should be avoided in patients considering pregnancy
and crystal analysis). t
=
:
because they are teratogenic. Cyclophosphamide is associ
(l reactive protein (CRP) (Option A) is ar.r acute phase
ated with age and dose-dependent infertility and should
reactant. Although elevation oI CRP level can signal ar.r irrfec
not be used in patients contemplating pregnancy without
tion, it is a nonspecific indicator. Indeed. an elevated CRP
a compelling life or organ threatening indication. This
level can be seen in a Ilare of rheumatoicl arthritis. as well as
patient has well controlled SLE but is taking mycopheno
in other conditions. and may not help distinguish betr,r,een
late mofetil, which should be discontinued 3 months before
iniL'ction and a rheunratoid arthritis Ilare.
conception is attempted. Routine use of azathioprine in
Measurenrent of serum procalcitonin levels (Option B)
pregnancy is not advised; however, this drug is safer than
has lreen proposed to help clistinguish ini'ectious arthritis
other agents and can be used if necessary. In this patient
tiom inflan.rmatory arthritis. Ilowever, serum procalcitonin
with a history of Iupus nephritis, azathioprine can reduce
is 11ot sensitivc lor the presencc of joint infectir>n. and ir neg
the risk for flare or disease progression. Hydroxychloro
atir,e result cloes not elirr.rinate infectioLrs arthritis.
quine can be safely used during pregnancy in most patients
ln patients suspccted ot having lr joint inf'ection. a
to reduce the risk for SLE flare or other complications and
sy'no','ial biopsy (Option C) is rarell, necessaryi Syr.ulvial
should be continued.
biopsies may be helpfll in patients in r,r,hont concurrent
Patients should be advised about the risks of preg-
contiguous osteomyelitis or tubercukrsis (or infection with
nancy in the setting of an SLE diagnosis (Option A), but
arrother 5low grou'ing organism, such as a fungus) is a
given this patient's excellent disease control, a careful
diagnostic possibility. 'lhe paticrrt's shrtrt durati<ln olsymp
decision to proceed with attempts to conceive would be
toms nrakes concurrent ostcomyelitis or ir.rf'ection witl-r
reasonable.
slorv gror,.",ing organisms unlikell,. Although tulterculosis
This patient's current medications (Option B) must be
or fLngal infection callnot be absolutely excluded irr this
changed before conception given the risk for teratogenicity
patient receiving intr.nunosuppressallt clrugs. the first cliag,
associated with mycophenolate mofetil. Azathioprine is the
nostic test remains a synovial fluid analysis. A syr.rovial
best option to control the patient's lupus nephritis and may
biopsy may be consiclered in patients without an cstab
be considered following a frank discussion with the patient
lishecl diagnosis after joint f luicl analysis or those in rvhom
regarding risks and beneflts and shared decision making.
antibiotic therapy has failed.
Patients who have SLE flares during pregnancy can be
treated with prednisone or other glucocorticoids. If the risk
rEY POIilIS
for flare is considered high, empiric addition of low-dose
. The abrupt onset of acute monoarticular inflamma- prednisone (Option C) could be considered, but this patient
tory arthritis in any patient should suggest a joint currently has no indication for a glucocorticoid.
infection.
. In patients suspected of having infectious arthritis, ftY Pottrs
the most important diagnostic procedure is expedi- . Systemic lupus erythematosus is associated with
tious arthrocentesis to obtain joint fluid and conduct increased risk for miscarriage, premature delivery
synovial fluid analysis (Gram stain, culture, leukocyte and other pregnancy complications.
count, and crystal analysis). (Continued)

169
 Answers and Critiques
l(E? P0IXIS (onfinucdl
o Certain therapies used to treat systemic lupus ery-
thematosus, including mycophenolate mofetil, beli,
mumab, and methotrexate, should be avoided in
patients contemplating pregnancy becrruse they are
teratogenic; cyclophosphamide is associated with
age- and dose-dependent infertility and should not
be used in patients contemplating pregnancy
without compelling life- or organ threatening
indications.
D Bibliography
UI Lazzaroni MG, Dall'Ara F, Fredi M, et al. A comprehensive revieu, ot the
clinical approach to pregnancy and systemic lupus erythematosus. J
E
(D Autoimmun. 2016;74:106 117. [PMID: 273774*l
UI
o,
CL
n
4t
tr Item 89 Answer: D
Educational Objective: Treat gout by switching
hydrochlorothiazide to losartan.
(D
Ut
lhe most appropriate treatment is to stop hl.drocl.rlorothia
zide ancl start losartan (Option D). 'lhis patient has had a first
episode of poclagra (gout of'tl.re gre:rt toe) treated efl'ectir.ely,
with colchicine. He has a nrininrally elevated senul urate
level. Flvdrochlorothiazide lr.rd clther loop diuretics cluse
hyperuricen.ria and miry have contributed to this gout epi
sode. l-osartan is an angiotensin receptor blocker that lray
l.tltre sorne uricosuric effect in adciition to lorvering bkrod
pressure. For patients with gout. the Arnerican College of
Rheun.rirblory (ACR) concli t ional h, reconr mends sr,r,itch i ng
hydroch krroth i azide to an irlt ernate anti hyperterlsive r,r,hen
feasibte.'lire ACR also conditionalh' recornmends sr,vitchir.rg
to losartan prefbrentially as an antihypertensi\€ agent rvhen
t'easibtc. Although this patient has had rlnly a single flure.
nrodifying his iatrogenic risk factors for gout is reasorrable
at this time.
Alkrpurinol (Option A) is a urate kxrering lgent. but
this therapy is r.rot inclicated after rr single gout episode in a
pltienl rvithont tophi or radiographic damage. Urate lor,rerir.rg
therapy is strorrgly recomrnended by the ACR fbr patients
with one or more subcutaneous topl-ri: evidence <tf raclio
graphic damage (an1- ntodality) attributable to gouti or fie
quenl gout llares. with "fiecluent" being definecl ils two or
rnore iurnually. Urate lou,ering therripl,' is conclitionallt, rec
ommencied filr patients erperiencing their first flare when
moderate to severe chronic kidnel, disease (stage 213). serr_rm
urate concentralion greater than 9.0 mgidl_ (0.511 nrrnoliL),
or urolithiasis is present.
l.irr patients with gor-rt. the A(.R conditionirlly recolll-
nrends against aclding vitamin C sr-rpplententation (Option
B) to decrease serulr urate levels. The ACR conclr.rdecl tl.rat
clrrta on vitanlin C wcre insufficierrt to sLlpport continued
recornrnendation of its usc in paticnts rt'itlt gout. Tu'o stud
ies showed clinically insignificant changes in senlm urlte
concentrations fbr patients rvith gout taking vitantin C sup
plementation.
170
'lhe ACR conditionally recornmends against su,itching
statill agents. such as aton,astirtilt. to fenoflbrate (Option
C). I,'errofibrute has urate lowering ellects. but the ACR has
deterrninecl that the risks (inclucling aclverse eff'ects of the
tnedication) outweigh potcntial benefits of sr,r,ilching among
patients u'ith gout. regarclless of clisease activitl:
XEY POIXIS
. For patients with gout, the American College of
Rheumatologz conditionally recommends switching
hydrochlorothiazide to an alternate antihypertensive
agent when feasible.
. For patientswith gout, the American College of
Rheumatologr conditionally recommends switching
hydrochlorothiazide to losartan as an antihypertensive
agent when feasible.
Bibliography
Fitzcerald JD, Dalbeth N, Mikuls T. et al. 2020 American College of
Rheumatolos/ guideline for the management of gout. Arthritis C:lre Res
(Hoboken). 2020;72:744 760. IPMID: 323919341 doi:10.1002r'acr.2,ll80
Item 9O Answer: D
Educational Objective: Diagnose rheumatoid arthritis
with appropriate imaging studies.
The most appropriate next step in diagnosis is no lurther
imaging (Option D). The history physical examination,
and laboratory studies are all consistent with a diagnosis of
rheumatoid arthritis. Plain radiography of the hands and/or
feet is the standard imaging study for rheumatoid arthritis
and can aid in diagnosis. Radiography ofthe hands and/or
feet may also detect changes suggesting other diseases that
may mimic rheumatoid arthritis, such as psoriatic arthri
tis, spondyloarthritis, gout, or chondrocalcinosis. Although
early radiographs may be normal, this patient has the typi
cal radiographic changes of rheumatoid arthritis, including
periarticular osteopenia. marginal erosions, and joint-space
narrowing. These radiographic flndings add to the diagnostic
certainty that the patient has rheumatoid arthritis and are
helpful not only in establishing the diagnosis but in moni
toring the course ofthe disease.
Bone scanning (Option A) has no diagnostic value in
rheumatoid arthritis and is not used in evaluation of this
disease. No speciflc flndings on bone scanning would point
to the diagnosis of rheumatoid arthritis.
In the setting of characteristic features of rheuma-
toid arthritis seen on plain radiographs, MRI of the hands
(Option B) has no additional diagnostic value. Although MRI
can show flndings that cannot be visualized on plain radio-
graphs, such as bone edema and inflammatory synovitis.
these are not diagnostic of rheumatoid arthritis and are not
needed to confirm the diagnosis.
Musculoskeletal ultrasonography (Option C) has
gained popularity in the diagnosis and treatment of rheu-
matoid arthritis because it is noninvasive and may demon
strate a variety ofsoft-tissue flndings not visualized on plain
I Answers and Critiques
\
t radiographs. However, similar to MRI, when diagnostic fea
I
tures of rheumatoid arthritis are seen on plain radiographs,
I lrthralgia, cytopcrtirt, ar.rtl llossible kidne-v" tlisease. SI-E is
musculoskeletal ultrasonography is not needed to confirm
\
I
the diagnosis.
\
I
XEY POI l{TS
o Plain radiography
of the hands and/or feet is a stan
\ dard imaging study for rheumatoid arthritis and can
\
I
detect typical radiographic changes, including periar
ticular osteopenia, marginal erosions, and joint-space
r myopericarditis.
narrowing.
L . Hand and/or feet radiography can detect changes sug
gesting other diseases that may mimic rheumatoid
t Dein E. DouglasI
arthritis, such as psoriatic arthritis, spondyloarthritis,
:
I gout. or chondrocalcinosis.
\ Item
Bibliography
Shiraishi M, Irukuda T. Igarashi T. et al. Differentiating rheumrtoid and
: psoriatic arthritis of the hand: multimodality imaging characteristics.
I
Rxdiographics. 2020 Sep Oct:,10:1339 1354. [PMID: i27351741
\
tr Item 91 Answer: D
Edu cational Objective: Diagnose systemic lupus
i erythematosus as the cause ofacute pericarditis.
'lhe mosl lil<ely cause ol 1his patient's pcricrrditis is systemic
i
lupus cn,thcrnatosus (Sl.fl) (Option D). 'lhe nranv possible
I causcs of' acute pericarditis includc idiopathic pericarditis,
irrlt'ction. nredications. neolrlasm. injury fiom trrluma or
ischcnria. rncl irutoirnrnune irnd inf lanrmatory diseases. Fac
tors that suggest SLli as the cituse ol't his patit:nt's pericarditis
inclucle joint s,,velling, eviclence of' lrossiblc l<idney cliseasc,
ancl cytopcnias. particularly thrornbocykrpeniir. All of these
arc scen in Sl.Fl. Pericarditis is a relatively colrmon manif'es
tation ol SLli ancl can be asynrptorllatic (rnosl conrmonly) or
can ci"luse chcst pain rnd myollericarditis; tlrnponacle is rare.
Aclnlt onset Still disease (Option A) is another rheu
mrrtologic cliagnosis that can present u,ith Icver. synovitis.
irncl serclsitis. including acute pericarclitis. Ilowever, patients
lrrith aclult onset Still disease gencrally havc high platelet
coLlnts. suggcsting a generalized inllanrmatorv statc. Many
paticnts irlso have a rash thirt occurs ltrith ltvcrs. Thcse fea
trlres are nol present in tl-ris patier-rt.
(loxsackievirus (Option B) is onc of the nrost common
infbctious lgcrrts tlut can cruse acute pericarclitis: as rtith
milnt'other pathogens, it cirn also cause fevers and musculo
ske le tal p:rin. It woulcl be reasonablc to considcr coxsackievi
rus irrlection. but he lacks other features suc'h ls exanthem.
oropharyngell lesions, ancl nreningitic or encephalitic symp
toms. \,'iral infbctions can cause ll,mphopc'uia, but <lther
finclings prescnt in this paticnt. including thrombocytopenia
ancl rbnornral urinalysis, wonld r.rol bc expected with a viral
intbction.
Although most cases of acute pericarclitis lre icliopatl.ric
(Option C), a search fbr otl.rer causes is appropriate; a cause
is tirund in about 16')ti, of patients. lhe cause of isolated ircute
pericarditis in most patients is presunted to be viral, but
supporting evidence is otten not s<lught because ot t'ost ancl
lack o{'efll'ct on therapy or prognosis' in this patient with
high rin the list of clilgnostic possibilities. irnd a positive SLll
cliirgnosis r,rould exclude idiopath ic pcricarditis.
I(EY POIIIT
o Pericarditis is a relatively common manifestation of
systemic lupus erythematosus that can be asympto
matic (most commonly) or can cause chest pain and
Bibliography UI
(l,
I. Petri l\,1. et al. Pericarditis in lupus. Cureus. 2019:11:e4166 3
IPMID: 310867511 ET
(J
92 Answer: C t,
.9
Ed u cati o na I O bj ective : Diagnose rclapsing polychondritis. UI
(l,
The most likely diagnosis is relapsing polychondritis (Option B
vl
C). This patient has a chronic inflammatory disease involv c
ing the cartilage (but not noncartilaginous structures) ofthe
ears, nasal bridge (saddle nose deformity), joints, and tra
chea. as well as involvement of the connective tissue of the
eye. Hearing loss is likely related to inflammation of the car
tilage of the middle ear. Because relapsing polychondritis is
a clinical diagnosis for which no speciflc tests exist (although
certain autoantibodies, including those to lype 2 collagen,
may be supportive), other causes should be considered and
ruled out as appropriate. Management depends on severit5z:
NSAIDs and dapsone for mild symptoms and high dose glu
cocorticoids for initial management of acute and/or severe
involvement. Oral immunosuppressants (e.g., methotrexate)
may be added. The tumor necrosis factor inhibitors inflix-
imab and adalimumab and the anti-interleukin 6 agent
tocilizumab may also be effective.
Like relapsing polychondritis, cryoglobulinemia
(Option A) can affect the ears and nose. However, cryoglob
ulinemic involvement of these tissues is typically ischemic/
necrotic rather than inflammatory and usually affects the
tip rather than the bridge of the nose. Cryoglobulinemia
can affect the lungs but not the trachea. Moreover, most
cryoglobulinemias (excepting type I cryoglobulinemia) are
secondary to hepatitis C virus infection or primary autoim
mune disease; testing for hepatitis C virus and autoimmune
antibodies can be considered.
Like relapsing polychondritis, granulomatosis with
polyangiitis (GPA) (Option B) can afiect the upper and lower
airways, ears, and eyes and can cause a saddle nose defor
mity. It can also cause arthralgia, although the arthralgia is
usually migratory. However, GPA involvement of the lungs
is typically parenchymal and does not involve the trachea.
Because 90'7, of patients with GPA are positive for antipro
teinase 3 antibodies, testing can be considered.
Rheumatoid arthritis (Option D) can involve the
knees symmetrically and in severe presentations can
cause a systemic illness that involves the eyes and glottis
171
 Answers and Critiques
(cricoarytenoid joints). However, it does not typically
affect the ears or trachea. This patient also lacks the classic
symmetric polyarthritis of the hands, and his knee pain
severity is not commensurate with severe rheumatoid
arthritis.
TEY POIf,I
. Relapsing polychondritis is a chronic inflammatory
disease involving the cartilage (but not noncartilagi-
nous structures) ofthe ears, nasal bridge (saddle nose
deformity), joints, and trachea, as well as involvement
of the connective tissue of the eye.
D r
tt Bibliography
E
o Borgia F. Ciuffrida R, Guarneri F, et al. Relapsing polychondritis: an updated
review. Biomedicines. 2018r6. IPMID: 3007259t]l
Ut
o,
EL
a.l Item 93 Answer: B lblkou,ska Pruszynska B, Gerkowicz A. Szczepanik Kulak P et al. Small
Educational Objective: Treat small intestinal bacterial
a overgrowth in a patient with dilluse cutaneous systemic
E
(D
Ut sclerosis.
The most appropriate treatment is ciprofloxacin (Option
B). This patient is experiencing the manifestations of small
intestinal bacterial overgrowth (SIBO), which affects 39'l,
of patients with systemic sclerosis. SIBO occurs in both the
limited and diffuse cutaneous forms of systemic sclerosis.
The most frequent symptoms include diarrhea, abdominal
pain, bloating, and nausea. The diarrhea is often explosive
and typically follows a meal. Over time, SIBO can lead to
malabsorption, malnutrition, and weight loss. Jejunal aspi
rate is considered the gold standard but is often not used in
clinical practice because ofthe requirement for endoscopy
to obtain cultures and the patchy nature of small intesti
nal overgrowth. Glucose and lactulose breath tests have
acceptable speciflcity (around B0'/,) but poor sensitivity
(30'/,, 40"1,) fbr diagnosing SIBO. Diagnosis requires typi
cal symptoms and a confirmatory test, although empiric
antibiotic therapy with monitoring for improvement in
symptoms may be reasonable in patients with a high prob
ability of SIBO, such as this patient. The protocol is to a
take a different antibiotic with activity against bowel flora
(e.g., ciprofloxacin, doxycycline, amoxicillin/clavulanic
acid, and rifaximin) for the flrst 10 days of the month for
4 months. Systemic sclerosis affects both smooth muscle
and autonomic nerves and leads to small intestine hypo
motility. Hypomotility results in food and liquid stasis,
which then fosters bacterial overgrowth. SIBO also causes
bile acid deconjugation, leading to dietary malabsorption
of fats and fat soluble vitamins. A low lat diet may help
reduce the intensity ofthe diarrhea.
Cholestyramine (Option A) is often prescribed for bile
acid diarrhea following limited ileal resection, after abdom.
inal radiation therapy, or for postcholecystectomy diarrhea.
Patients with SIBO have bile acid insufficiency, and treat
ment with a bile acid binding resin, such as cholestyramine,
is likely to worsen this patient's symptoms.
172
Pantoprazole, a proton pump inhibitor, is useful for
gastrointestinal reflux disease. This patient's reflux disease is l
stable: flurther reducing gastric acid production by increas :
ing the pantoprazole dosage (Option C) may contribute to
bacterial overgrowth and may worsen the problem.
Loperamide (Option D), an opioid agonist, will slow
intestinal motility further and potentially worsen SIBO.
TEY POII'IS
o Small intestinal bacterial overgrowth affects patients
with systemic sclerosis, causing diarrhea, abdominal
pain, bloating, and nausea.
Small intestinal bacterial overgrowth is best treated
with monthly antibiotics in a rotating fashion to
decrease the bacterial load in the small intestine.
Bibliography
intestinal bacterial overgrowth in systemic sclerosis: a revie\\'of the liI
erature. Arch Dermatol Res. 2o191311:l 8. IPMID, 30382339] doi:lo.loo7,
s00'10:l 018 1874 0
Item 94 Answer: A
Ed u catio na I : Diagnose ankylosing spondylitis.
Obj ective
The most appropriate diagnostic test to perform next is
anteroposterior radiography of the pelvis (Option A). This
patient has had classic inflammatory low back pain for
several years. Flexion, external rotation, and abduction of
the hips elicit pain in this patient's right hip as well as lor,r'
back pain. These flndings, along with involvement of the
right hip, suggest ankylosing spondylitis (AS). This patient
was diagnosed with uveitis. Spondyloarthritis accounts
for approximately 40'l" of cases of acute anterior uveitis
in the United States, and most of these patients will have
AS. Acute anterior uveitis has been reported to affect 27'f,'
of patients with AS and rarely causes permanent visual
damage.
An antinuclear antibody test (Option B) can help
evaluate for autoimmune diseases, such as systemic lupus
ery.thematosus, but these diseases rarely cause uveitis. More
over, the patient's inflammatory back pain symptoms and
right hip restriction of motion are more compatible with
a spondyloarthropathy than an autoantibody associated
rheumatologic disease.
The prevalence of AS in the HLA B27 positive popula
tion is only about 5'2,; positive results for HLA B27 may be
absent in up to 15'1, of patients with confirmed AS. There
fore, HLA-B27 testing (Option C) cannot independently con
flrm or exclude a diagnosis of AS. According to Assessment
of SpondyloArthritis international Society (ASAS) criteria,
HLA-827 positivity would be helpful if the pelvis radiograph
is normal in a patient with high likelihood of AS. The pres
ence of back pain plus HLA-B27 positivity plus two other
features of spondyloarthritis (in this case, uveitis and hip
arthritis) would classifz this patient's disease as an axial
spondyloarthritis.

MRI of the sacroiliac joint (Option D) can identify sac
roiliac inflammation even in the absence of radiographic
changes. However, 25')1, of healthy individuals can have MRI
changes that meet criteria for sacroiliitis, and up to 47"/,, of
persons who regularly participate in impact loading athlet
ics may have similar MRI changes. The extent of involvement
and presence of erosions on MRI increase the speciflcity of
the result. However, plain radiography remains the corner
stone of radiographic diagnosis in spondyloarthritis and
has sufficient specificity to confirm a diagnosis. Sacroiliitis
shown by MRI is included in the ASAS classification criteria
and would be useful ilthe plain radiograph was normal. In
this case, checking HLA P27 antigen would be more cost-
effective lor classiflcation as an axial spondyloarthritis if the
plain radiograph was normal. Plain radiography is the initial
imaging choice in patients suspected olhaving AS because of
its relatively low cost and safety.
XEY POIilTt
. Spondyloarthritis accounts for BS'X, ofcases ofacute
anterior uveitis in the United States, and most of these
patients will have ankylosing spondylitis.
o Anteroposterior radiography of the pelvis is the
initial imaging examination for suspected ankylosing
spondylitis.
Bibliography
Mandl P, Nxvarro Compdn V, Terslev L, et alr l.)uropern League Agtinst
Rheumatism (tlULAR). IjULAR recomnrendations lbr the use of imalling
in the diagnosis rnd managenrcnt of spondvkr:rrthritis in clinical prac
tice. Ann Rheum Dis.2015;74:1327 39. IPMID:258371481
\
tr Item 95 Answer:
Educational Objective: Treat
D
a flare of systemic lupus
erythematosus during pregnancy.
a
The lnost appropriatc marlagenrent is prednisonc (Option
D). I rngrkgid, to trext a llare o( systernic lupus erythentirto
sus (SI-h-) durirrg pregnanc): An St-E fhre during pregnancy
carr be difficult to clistinguish fiorn precchntpsia. (lonrnron
I'eatures inclucle proteinuria u'ith hl,perterrsion ancl ederna
as well ls heaclachcs and othcr nonspecific svntptolrs.
Thronrbocy'topenia is ir relltively conlnlon feature oISLE but
is also sect.t with preeclampsia, cspecially with progression
to the HF.l.l.P (llcmoll'sis. Iilerratecl Lir:cr enz_r,mes. and l.on
Platelets) syndrome. Clues to an Sl"Fl f lare include rnarkcrs
of lupus activitli snch as rising anti ckruble strirnrled I)NA
antil)ody titers and falling serunt contplement levels. 'll.re
serunr urate level is often cler,ated ir-r preeclarlpsiu but not
in Sl,E tlares. this patient's clinicirl features suggest a f lare
ol'lupus nephritis. l'reatmcnt oI SLL during pregnancl is
dillicult lrccausc many meclications that could otherwise
be r:sed to trext a flare are colrtraindicrlted in ltrcgnanct.
including cvclophosphamiclc, mvcophenolate rnolbtil. metl.r-
otrexate. and belimunrab. In this casc. first line treatnrcnt
would ir.rclude addition of high closc or "pulse" glucocor
ticoicl therap1,. Concurrent treatnrcnt fbr preeclanrpsia rlrr\'
Answers and ues
also be considered if diagnostic unccrlainty remains. Bkrod
pressure managemellt with labetalol would be inclicatecl lor
systolic blood pressure of. l60 nrnr Hg or grcater <lr diastolic
bkxrd pressurc of 110 mm I lg or greater.
lntralenous cyclophospharnide (Option A) r'voulcl be
a reasonable consiclcratiotl fbr treatmellt o1 a flirre of lupus
ncphritis in a nonpregt.tant patient. In screre cases. cyclophos
phamide could be considcred itl pregnancy afler tlle first tri
nresler bLlt is zrssociated rvith an illcreasecl risk fbr fetal detnise.
'Ihe best treatmcnt fbr preeclampsia is clelivery (Option
B) if the baby is adecluately n1atLlre. Al 26 r,t'eeks. this letus is
not adequatelv mature lbr delivcry I)elivery is lil<cly ttl lead
to little ur no improvemcnt in her lupus nephritis; other UI
6'
therapies are rrcedecl.
ET
lntravenous magnesium sulfate (Option C) can be used
L.
to pre.ucnt seizures in preeclanrpsia ancl rrigl.rt be appro (J
priate trcatmer.rt if this patient's findings were related to
preeclampsiir rathcr thart SLfi. Ir-r sonle cllses, it rlll' be
t
=l
.E
t,l
lppl'opriate to treat lbr both cortditions.
o
XEY POIf,IS B
tt
o In pregnant women, differentiating a flare of lupus
nephritis from preeclampsia can be difficult; a lupus
flare may be identified by rising anti-double-stranded
DNA antibody titers and falling complement levels.
o In a pregnant patient with a life or organ threatening
flare of systemic lupus erythematosus, first-line treat-
ment is the addition of glucocorticoid therapy.
Bibliography
Lazzaroni MG. Dall'Ara H Fredi M. et al. A comprehensive review of the
clinicirl approlch to pregnancy and systemic lupus erythematosus.
J Autoinrmun. ')016;74:106 ll7. [PM]l): 273774fi1
Item 96 Answer: A
Educational Objective: Diagnose hemochromatosis as a
cause of secondary osteoarthritis.
The most appropriate diagnostic test to perform next is HFE
gene testing (Option A). Underlying disorders can predis
pose patients to the development ofsecondary osteoarthritis
(OA) and should be suspected when OA occurs at an early
age or involves joints not typical for OA, such as the meta
carpophalangeal (MCP) or shoulder joints. Hereditary hemo
chromatosis can be associated with an arthropathy that
causes symptoms of arthritis, arthralgia, and accompanying
radiologic findings. These patients particularly develop OA in
the hands, where characteristic hook like osteophytes com
monly in the second and third MCP joints and sometimes
the fourth MCP joint can be seen on radiographs (Figure [top
of next pagel). Men are more commonly affected. and the
symptoms usually appear in the lourth to fifth decades. This
patient has hook shaped osteophytes of the second, third,
and fourth MCP joints; onset of type 2 diabetes mellitus in
the last few years; abnormal aspartate and aminotransferase
levels: and elevated serum ferritin and transf'errin saturation
levels, all suggesting hereditary hemochromatosis. The HFE
173
 tl:}t9tsgl{_c,t!iqy.:

Hlperparathyroidism can be associated with calcium

pyrophosphate deposition (CPPD) disease and can cause
secondary osteoarthritis. Calcifl cation of articular cartilage
(chondrocalcinosis), most commonly affecting the wrists
and knees. would be seen in a patient with CPPD and hyper
parathyroidism but is absent in this patient. Furthermore,
this patient has a normal serum calcium level, and measur
ing the serum parathyroid hormone level (Option C) is not
indicated.
Inflammatory arthritis, such as rheumatoid arthritis,
can lead to secondary joint damage and OA. This patient,
however. has no history physical examination, or laboratory
findings suggesting rheumatoid arthritis. Measuring rheu-
UI matoid factor (Option D) is not indicated.
E
.D IEY
Ut
o, . 'OIITI
Secondary osteoarthritis (OA) should be suspected
CL when OA occurs at an early age or involves joints not
a.l typical for OA.
gene mutation is diagnostic for this condition, and testing
It should be performed. o Hereditary hemochromatosis can be associated with
.D
Acromegaly due to growth hormone excess is a rare an arthropathy that causes arthritis, arthralgia, and
tr secondary cause of secondary OA. These patients present radiologic findings, such as characteristic hook-like
with enlarged hands, feet, jaw and other bones. Joint symp osteophytes in the second and third metacarpophalangeal
toms may be the presenting feature of the disease, and back joints.
pain with spinal kyphosis or scoliosis is frequently reported.
Testing for insulin-like growth factor 1 (Option B) would be Bibliography
appropriate if there were a high suspicion lor the disorder, Kiely PD. Haemochromatosis arthropathy a conundrum of the Celtic
but this patient has no findings of acromegaly. curse. J R Coll Physicians Edinb. 2018:48:233-238. IPMID:30191911]

174
lndex

Note: Page numbers followed by f and t denote figure and table, respectiveiy. Anti-Scl-70 antibody, 6t
Test questions are indicated by Q. Anti-Smith antibody, 6t, 48t
Anti-SRP antibody,6t
A Antisynthetase syndrcme, 54, 57
Abatacept, 141, 16t Anti TIF 1 Tantibody,6t
ACE inhibitors.64 Anti-U1-ribonucleoprotein, 6t, 48t
Acetaminophen, 10, 161, 29 Anxiety, fibromyalgia and, Q4o
Achilles tendon, 361 38 Aortic valve regurgitation, 36
Acromegaly, OA and, 25t Apremilast, 11t, 12, Q1
Acro-osteolysis, 62, 62f Arthritis. See olso Specific forms of
Acute cutaneous lupus erythematosus (ACLE), 43, Q31 Ieatures ol 1-2
Acute gouty arthritis, 67-68 Arthritis mutilans. 37
Acute monoarthritis, Q86 Arthrocentesis, 68 69, Q86
Adalimumab, l3t. Q36 Asymmetric oligoarthritis, 36
Adenocarcinoma, 63 Atherosclerotic heart disease, 21
Adult onset Still disease (AOSD), 3t, 90, Q39 Atrioventricular block, 36
Aerobic exercise for fibromyalgia, 32 Autoinflammatory diseases, 89-90, 89t
Alcohol, myopathy induced by, 54t Axial spine, sacroiliitis, 37
Aldolase levels, 57 Azathioprine
Alendronate, Q41 for AAV. 84
Alkaptonuria/ochronosis, 25t adverse effects, 49t
Allopurinol, 13-14, 161, 70 71, Q2l, Q49 characteristics of. 11t
Alternati\€ medicine, 17 [br enteropathic arthritis, 42
Amoxrcrllrn_ // /l{ for tgG4 related disease, 92, 92t
Amyopathic dermatomyositis, Q10 during pregnancy, 16t, 50
Anakinra,14t, 16t, Q23 toxicity of, 10-11
Analgesics for rheumatoid diseases, 9-10 use ol 10 11
ANcA-associated vasculitis (AAV), 4t, 83-85, 84t, Q33
Ankylosing spondylitis, 33-34, 39f, 40f B
diagnosis ol Q94 Baricitinib, 111, 16t
enteropathic arthritis and, 37 Barrett esophagus, 63
hip involvement, 36f Basic calcium phosphate (BCP),73
inflammatory bowel disease in, Qll Behqet syndrome, 87 88, 87f
management of, 41, 4lf criteria for, 88t
ocular manifestations of, 3t internal organ involvement in, 4t
radiologic findings, 7t ocular manil'estations of, 3t
renal amyloidosis in, Q72 patherry associated with, 88f
treatment oi Q14, Q78 ulcerations in, Q1
Anterior uveitis, ankylosing spondylitis and, 341, 35 Belimumab, 141, 161, 49t, 50
Antibody tests, 5, 6t Biologic disease-modifying antirheumatic drugs, 12 13,
Anticentromere antibody, 6t 12f,22
Anticoagulants, drug interactions with, 17 Biosimilar drugs, 13
Anti cyclic citrullinated peptide Bor re lia burgdorfer i, 7 3, 7 8t
diagnostic use o{ 19, Q44, Q70 Bouchard nodes, 26
specificity oftests, 5, 6t Bronchiectasis. 21
Anti-double-stranded DNA, 6t, 48t Bronchiolitis. 21, 64
Antihistone. 6t Budd Chiari syndrome, 87
Anti inflammatory agents, 8 9
Anti Jo 1 antibody,6t c
Anti-La/SSB antibody, 6t, 48t, 50, 52 Calcineurin inhibitors, 12, 50
Antimalarials, 54t Calcinosis,60, 62f
Anti-MDA-5 antibody, 6t Calcinosis cutis. 55
Anti Mi 2 antibody,6t Calcium phosphate-associated arthritis, Q35
Antimyeloperoxidase antibody, 6t Calcium pyrophosphate deposition (CPPD), Q13, Q27
Antinuclear antibodies (ANA) management of, 72t
in inclusion body myositis, 57 manifestations of, 71
in mixed connective tissue disease, 66 osteoarthritis secondary to, 25t,27 28
in Sjdgren syndrome, 52-53 physiolory of,71
in SLE, 42-43, 46-48, Q6 radiographic fi ndings, 7t
in systemic sclerosis, 6lt CampAlobacte r jejuni, 38
targets ol 5, 6t, 30-31 c ANCA antibody, 6t
Antiphospholipid antibodies, 45 Canakinumab, 14t,16t
Antiphospholipid syndrome, 3t, 4t, 45 Cancer in dermatomyositis, Q38
Antiproteinase 3 antibody, 6t Capsaicin for osteoarthritis, 29
Antiribosomal P antibody. 6t,48t Captopril for scleroderma renal crisis, Q15
Anti Ro/SSA antibody, Q60 Cardiovascular disease risk, Q19
in pregnancy,50 Carpal tunnel release, 17
in rheumatologic diseases, 6t Cauda equine syndrome, 36
in Sjogren syndrome, 52 Celuroxime axetil. 77 78
in SLE,48t, 49t Certolizumab pegol, 13t
in subacute cutaneous lupus erythematosus, 44 Cevimeline, Q26

175
lndex

Charcot joints, 25t Enthesis.2

Chikungunya virus, 76, Q66 Enthesitis, 35, 37, 87
Childbirth, SLE and, 50 Eosinophilic fasciitis, 61t
Chlamy dia trochomotis, 38, 42 Eosinophilic granulomatosis with polyangiitis (EGPA),
Chondroitin sulfate. 29 85
Chronic graft-versus-host disease, 6lt Epicondyliris, lateral, Q42
Chronic infantile neurologic, cutaneous, articular syndrome (CINCA), 89t Episcleritis, 21
Circinate balanitis, 38, 38f Epstein Barrvirus, 17
Citrulline, lT Erythema nodosum,9lf
Clostridtoides dfficile, 38 Erlthrocyte sedimentation rate (ESR), 2 4, 19
Cocaine, myopathy induced by, 54t Esophageal dysmotility, 63
Cognitive behavioral therapy, 32 Estrogen receptors, 17
Colchicine Etanercept, 13t
for acute gout, Q76 Exercise for osteoarthritis, 29, Q82
adverse effects of, 9 Eyes, rheumatologic disease and. 2, 20 2l
for Behqet syndrome, 88
for familial Mediterranean fever, Q2 f
function of. 9 Facet joints, synovial, 34-35
for gout, 69-70 Familial cold autoinflammatory syndrome (FCAS), 89, 89f
myopathy induced by, 54t Familial Mediterranean fever, 4t, 9, 89. 89t, Q2
in pregnancy, 16t Fatigue. rheumatologic disease and, 2
Complement,5,48 Febuxostat, Q21, Q61
Complementary medicine, 17 contraindications. 1l
Conjunctivitis, 37, 38 description o[ 14
Connective tissue disease,4t, 92 93 urate-lowering therapy with, 16t,70 7l
Constipation, treatment options, 65t Felty syndrome, 21, Q29
Corneal melt.21 Ferritin, serum, Q27
c-reactive protein (cRP),4-5, 19 Fever, rheumatologic disease and, 2
Creatine kinase, 53 Fibrillin 1, fibromyalgia and, 33
CREST syndrome,60 Fibromyalgia, Q81
Cricoarytenoid arthritis, 21 classifi cation of. 33-38
Cryoglobulinemia, 86 diagnosis of,30 31, 311,311, Q81
Cryoglobulinemic vasculitis, 86, Q56 epidemiolos/ ol 30
Cryoglobulins, 6t, 86 genetic factors, 33
crystal arthritis, 721 Q27 management ol 32
Crystal arthropathies, T, 67 -73 milancipran for, 10
Crystal deposition, T pain taxonomy for, 31f
cf,7, 40, s8, 64, 69 SLE and. 44
Cutaneous lupus erythematosus (CLE), Q31 treatment of, Q7, Q40
Cutaneous systemic sclerosis, Q69 Fungal infections, 75 7 6, 7 at
Cyclooxygenase, 9t
Cyclophosphamide G
adverse effects ol 11, 49t Gabapentin, 10,32
for Behqet syndrome, 88 Cabapentinoids, 10
characteristics ol 11, 11t Gastroesophageal reflux disease, 65t
for IlM. 59 Gastrointestinal dysmotiliry 65t
in prcgnancy, 16t Genital ulcerc, 87, 87f
for SSc. 64 Giant cell arteritis (GCA), Q16, Q85
Cyclosporine, 111, 161, 59 cardiac manifestations of. 4t
C)topenia, SLE and, 45 diagnosis of,79-80
epidemiolory ol 79
D management ol 80
1
Dactylitis, 2, 32, 33f , 37f ocular manifestations of. 3t
Dengue virus, 76 pathophysiolog/ of.79
Depression, Q40 Glucocorticoids :
Dermatomyositis, 54, 55, 58 for AAV Q33
amyopathic, Ql0 adverse effects. 8
cancer in, Q38 for enteropathic arthritis, 42 :
cutaneous manifestations of 561 56t immunosuppression by, 8-9
dermatologic manifestations of, 3t intra-articular iniections of, 29 30
treatment of, Q28 myopathy induced by, 54t
Diffuse cutaneous systemic sclerosis (DcSSc), 4t, 611, Q93 osteoporosis induced by, Q4l
Diffuse idiopathic skeletal hyperostosis (DISH), 7t, 25, 26f. Q8 during pregnancy, l6t, 50
Digital pitting, 63f RA management and, 22 - 23 i
Discoid lupus erlthematosus (DLE), 44, 44f for reactive arthritis. 42
Disease-modifuing antirheumatic drugs (DMARDs), 10-13, Q73 for rheumatologic diseases, 8-9
Distal interphalangeal joints (DIP), 36, 37f for SLE. 49
Doxycycline, 77 -78 , Ql2 tapering of, 50
DRESS (drug reaction with eosinophilia and systemic symptoms), Glucocorticoid-sparing agents, Q16
70-71 Glucosamine for osteoarthritis. 29
Drug-induced hypersensitivity syndrome (DIHS), 13 14,49t,70 77 Golimumab. 13t
Drug-induced lupus erythematosus (DILE), 48, 49t Gonococcal arthritis,73, 75t, Q63
Dryeye,20 27,52 Goodpasrure syndrome, 4t
Dry mouth, 20-27, 52, Q26, Q47 Gottron papules, 55, 56f
Duloxetine,10,29, Q40 Cottron sign, 55,56f
Dysbiosis,33 Gout,36,67 71
Dyspnea, SLE and,45 acute flare of, 69 70,69t
chronic recurrent, Q52
E intercritical. 68
Ehlers-Danlos syndrome, 92, 93t management of, 9, 13 15, 69 77
Electromyography, 58 radiologic findings, 7t
Enteropathic arthritis, 34t, 37 -38, 42 refractory Q23

176
 lndex

tophaceous, Q21 osteoarthritis and, 25t

treatment ol Q76, Q89 rheumatoid arthritis, 20
Gouty arthritis, Q18
Granulomatosis with polyangiitis, 31,83-8s, Q4, Q33 l(
Granulomatous myocarditis, 21 Kawasaki disease, 4t, 83
Gullwing erosions, 24, 24f Keratitis, ocular manifestations of, 21
Guselkumab, l4t,16t Knees
Lyme arthritis,75f
H monosodium urate deposition, 70f
Hands osteoarthritis of, 27\ Q24, Q34
acro-osteolysis, 62f
osteoarthritis of 24f,26f, Q24 I
rheumatoid arthritis, l8t 19t 20f, Q83 Laboratory studies
systemic sclerosis, 62f in osteoarthritis, 27
Heart, RA and, 21 in rheumatoid arthritis, 19
Heberden nodes, 26 in rheumatologic disease, 2-5
Hemochromatosis, 251, Q96 in spondylitis,38
Henoch-Sch0nlein purpura, 4t, 86 in systemic lupus erJ,thematosus, 46
Hepatitis, SLE and, 46 Large granular lymphoryte leukemia, 21
Hepatitis B virus, 76, 81-82 Iarge granular lymphoclte syn&ome, 21
Hepatitis C virus,76 lateral epicondylitis, Q42
Herbal supplements, 17 Leflunomide, 10, 11t, 161, 50
Hip. anlVlosing spondylitis. 36f Leukopenia, SLE and,45
Histopatholos/ in IIM, 58 Libman Sacks endocarditis, 45
HlV, musculoskeletal disorders in, 76 Lidocaine for osteoarthritis, 29
H[A-B27 testing,37, Qs Limited cutaneous systemic sclerosis (LcSSc),41, 6ft, Q59
HI-A-B'58:01 allele, 14,70, Q49 Linear scleroderma, 61t
Hormones, RA and, U Livedo reticularis, 44, 82f
Hyaluronic acid, 29-30 Losartan, Q89
Hydrochlorothiazide, Q89 Lungs,21,36
Hydrorychloroquine Lupus er,'thmatosus, drug-induced, Q80
adverse effects,49t Lupus nephritis, 12,14t,44, Q46, Q77
characteristics of, llt Lupus pernio,9l, 91f
for nephritis in SLE, Q46 Lyme arthritis, 75, 751 Q12
during pregnency, 16t, 50 Lyme disease, 3t
for SLE, 46,49, Q75 Lymphomas
toxicity,49 RA and, 21
use of 10 in Sjogen syndrome, Q79
Hyperparathyroidism, 25t Lymphopenia,45
Hlpersensitivity vasculitis, 9, 87, Q48
Hlperuricemia, 36, 67, 67t ]t
MAGIC (mouth and genital ulcerations with inflamed cartilage), 88
I Malignanry, SLE and, 46
Idiopathic inflammatory myopathies olM), 53-59, 55t,58f Marfan syndrome, 92
IgA nephropathy,36 Measles, mumps, and rubella vaccine, Q43
IgA vasculitis, 86-87 Mechanic's hands, 3t, 55,551,56f
IgG4 related diseases, 3t, 92, 921, Q68 Meditation, 17
lmmune complex mediated vasculitis, 85-87, 86f Mental health screening, 8
Immune-mediated necrotizing myopathy, 57 Mepolizumab, 14t
Immunosuppression, 15 Metacarpophalangeal joints, I 8l'
Inclusion body myositis, 57, 59, Q45, Q65 Metalloproteinases, joint damage and, 20
Infectious arthritis, 73-78, 73f Methicillin-resistant S. oureus (MRSA), 78t
causes of,74-z Methicillin-sensitive S. oureus (MSSA), 78t
joint aspiration in,7 Methotrexate, l0
management of 77-78 for AAV, 84
pathogens, T8t adverse effects of, 10
risk factors, 74t characteristics of, llt
lnllammation for dermatomyositis, Q28
pain ol 1, 1t for enteropathic arthritis, 42
persistent, l9t for polymyalgia rheumatica, 80
signs of, I in pregnancy, 16t
Infl ammatory arthritis, 25t for psoriatic arthritis, 42
Inflammatory bowel disease, 3t, 37, Q1l for RA, 22, Q73
lnfl ammatory sacroiliitis, Q30 for reactive arthritis, 42
ankylosing spondylitis and, 7t for SLE, 50
radiographic imaging, 33 use of,10
Infliximab, l3t Methylsalicylate, 29
Intercritical gout, 68 Microscopic polyangiitis, 84-85
Interleukin-1 receptor antegonists, 891, Q23 Milnacipran, 10
Interleukin-17 inhibitors, 41, 42 Milwaukee shoulder, 73, Q35
Interstitial lung disease (lLD), 21,54, 64,651, Q17, Q62 Mind-body interactions, 17
Intestinal bacterial overgrowth, Q93 Mixed connective tissue disease (MCTD), 66-67, 66t, Q64
lxekizumab Monoarthritis, 1
characteristics of, l4t Monosodium urate deposition, 67-68
in pregnancy, 16t Morphea,6lt
MRI,7,20,40, s8, Q2s, Q30
J Muckle-Wells syndrome (MWS), 89t
Janus kinase inhibitors, 12 Muscle pain, evaluation ol 53
Joint replacement surgery Q50 Musculoskeletal examination, 1
Joints Mycobacteria, T3
aspiration ol 1,7-8 MAcobacterium marinum, 7 5
inflammation of, 7, 19t Ml.tcobacterium fuberculosis, 75, 78t

177
lndex

Mycophenolate mofetil Peripheral neuropathy, 45

adverse effects, 49t
characteristics ol 11t, 12
Periungual erythema, 55
Physical therapy
\
for IlM, 59 for ankylosing spondylitis, 41
for ILD, Q62 for inclusion body myositis, Q65
I
I
for nephritis in sLE, Q46 for osteoarthritis, Q82
in pregnancy, 16t in rheumatic disease, 15-17 \
for SLE, 50 Pleural effusions
I

for SSc, 64
Mucoplosmo spp., 17, 38
RA and.21 \It
SLE and. 45
Myelosuppression, 10, 11
Myocardial fibrosis, 63
SSc and, 64
Pleuritis, SSc and, 64 \
Myocardial infarction, 36 Poikiloderma,55, 60
Myocarditis, SLE and, 45 '1
Polyarteritis nodosa (PAN), 4t, 81 82, 821, esl
Myopathies Polyadhritis,2
differential diagnoses, s3t
drug-induced,54t
Polyarticular arthritis, 36 \
Polymyalgia rheumatica (PMR), 79, 80, Qss, Q8S )

T
Polymyositis, 54-58 \
Po rphgromonos gingiv alis, 17 I
Naproxen, Q78
Prednisone
Neisserio gonorrhoe ae, 7 4, 7 8t
adverse effects,49t
1
Neonatal lupus erlthematosus, 50 I
Neonatal onset multisystem inflammatory syndrome (NOMID), 89t
Nephrogenic systemic fibrosis, 6lt
long term use, 9
for nephritis in sLE, Q46 \
for polymyalgia rheumatica, Q55
Neutrophilic dermatoses, 20
Nintedanib.64
for SLE, 44, Q75
Pregabalin, 10, 32, Q7
\l
Nonbiologic disease modirying antirheumatic drugs, lO-t2, 22
Noninflammatory pain, l, lt
Pregnancy !
medications in, 15, 16t I
Nonselective COX inhibitors, 9t
Nonsteroidal antiinJlammatory drugs (NSAIDs), S
preconception planning, Q88
RA in,23 \
adverse effects. 49t i
RA treatment during, Q57
for anlgilosing spondylitis, Q78
for osteoarthritis, 29, Q24, Q54
SLE and, 50 \I
SLE flares in, Q95
for parvovirus B19 arthropathy, Q53
in pregnancy, 16t
RA management and, 22
SSc in.65
Primary angiitis ofthe central nervous system (PACNS),4t. 82-83
i:
Probenecid, 161, 7l 1
for reactive arthritis, Q67 Prosthetic ioint infections, 77, Q74 I
topical,9 Proteinuria, 36, 44, 45, 50
toxicities, 9t Proton pump inhibitors, 29
Pse udomonos oeruginoso, 78t :
0
Obesity, osteoarthritis and, 23 Psoriasis, Q18, Q58 \
Occupational therapy, l5 17 Psoriatic arthritis. 36 37
Oligoarthritis, fearures of, 2 dermatologic manifestations of, 3t
Opiates in pregnancy, 16t description ol 2 I
Opioids for osteoarthritis, 29 features ol 34t
gouty arthritis in patients with, Q18
Optic neuritis, 87 l
Oral ulcers,38,87
joint pain in, Q58
Osteoarthritis (OA) radiologic flndings, 7t
classification of. 24-25 risk factors,36
sex and. 36
i
diagnosisof,25 27,Q2O
differential diagnosis of, 27-28 subtypes, Q3 \
epidemiolory, 23-25 treatment of, 42,42t
Pulmonary arterial hypertension (PAH), 64, 651, Q69 \I
erosive, 24-25
hand,24f,27f Pulmonary veno occlusive disease, 64
joint pain in, Q58 Pyoderma gangrenosum, 20 \
knee,27f, Q34 Pyrin mutations, 89
management of 28 30
NSAIDs for. 29, Q54 o :
pathophysiolory ol 23 Quinacrine,50
primary 24 \
radiologic findings, 7t R I
risk factors,23 25 Radiography
secondary 25,251, Q96 in calcium pyrophosphate deposition disease, 71 :

in gout, 69
treatment of, 281, Q24, Q82
Osteogenesis imperfecta, 92 in infectious arthritis. 73 l
Osteonecrosis, 7, 44, Q25 in osteoarthritis, 27
Osteoporosis, drug-induced, Q41 in rheumatoid arthritis, 19, Q83, Q90
in rheumatologic diseases, 5-6, 7t
P in sarcoidosis. 90f
Pain in spondyloarthritis, 39, Q94
inflammatory vs. noninflammatory I Raynaud phenomenon, 44, 46, 62 63
pathway modulators, 9-10 Reactive arthritis, 3t, 34t, 38, 42, Q67
soft tissue abnormalities and. 2 Receptor activator of nuclear factor kappa B ligand (RANKL), 20
p ANCA antibody,6t Relapsing polychondritis, 3t, 88-89, 88f, Q92
Panuveitis,87 Renal amyloidosis, Q72
Parvovirus 819, 17,76, Q53
Patient history
Repetitive motion, OA and, 23
Retiform purpura,82f
\:
musculoskeletal examination and, 1, Q2o Retinal vasculitis. 87
Pegloticase, 15, 161,71, Q61 Rheumatic disease ..

Pencil-in-cup deformity, 40f MMR vaccine in, Q43

Pericarditis, SLE and, 45, Q91 physical therapy,15 u
Periodontal disease, RA and, 17 therapeutics, S 17 ;

l
178
\

Rheumatic fever. 3t
Rheumatoid arthritis (RA)
approach to, 22f
classification criteria, 18t
diagnosis of, 18-20, Q32, Q37, Q44
evaluation of, Q83
hands, 18f
imaging studies, 19-20, Q90
inflammatory cascade in, 12f
internal organ involvement in,4t
interstitial lung disease in, Q17
laboratory studies, 19, Q70
management of, 21-23
monoarticular pain, Q87
ocular manifestations o[, 3t
patholory of, 17
radiologic findings, 7t
risk factors, 17, Q9
treatment during pregnancy, Q57
treatment of, Q36
Rheumatoid factor, 5, 61, 19, Q44, Q7o
Rheumatoid nodules. 21f
Rheumatologic disease
extra-articular features of 2
laboratory studies in, 2 5
Rilonacept, 14t,16t
Rituximab
for AAV 84, Q33
characteristics of, 14t
for IgG4 related diseases, 92, 92t, Q68
for IIM. 59
in pregnancy, 16t
for RA. 22
for SLE. 50
for SSc. 64 65
Rotator cufftendon repair, 17
Rubella, T6
5 pericarditis in, Q91
Sacroiliac joints, 391
Sacroiliitis, 37, 39f
Saliva, artificial, 52
Solmonello,38
Sarcoidosis. 3t, 4t, 90 92, gof, Q71
Sariiumab, 14t, 16t
Sausage digits, 2
Sclerederma, 61t
Scleritis, 21
Scleroderma spectrum disorders, 611, 63 64, Q15
Scleromyxedema, 61t
Seagull erosions, 24, 24f
Secukinumab, l4t, l6t
Sensory neuropathy, 25t
Serotonin-norepinephrine reuptake inhibitors (SNRIs),
10,32
Shawl sign, 56f
Shigello,38
Sicca, management of, 52
Sjogren syndrome
diagnosis of, Q60
epidemiolory, Sl
Iymphomas in,51, Q79
ocular manifestations of, 3t,
oral dryness in, Q26
prognosis,52 53
Skin
rheumatoid arthritis, 20
rheumatologic disease and, 2
Sleep hygiene, 9
Small vessel cutaneous vasculitis, 21
Smoking, inflammation and, u Tophaceous gout, Q21, Qbl
Smoking cessation, Q9
Soft-tissue abnormalities, 2
Soft tissue iniuries, mechanical, Q42
Spine, ossification ol 35
Spondyloarthritis, 2 syndrome), 89,891
assessment of 35t
features of. 34t
HLA-B27 testing, QS
imaging studies, 39-41
laboratory studies in, 38 39
MRI.7
lndex
ocular manifestations of, 3t
pathophysiolos/,32 33
Staphylococcus oureus, 74
Staphylococcus epidermidis, 74 , Q74
Statins, myopathy induced by, 54t
Stiffness, morning,2
Still disease, adult-onset, 3t, 90, Q39
Subacute cutaneous lupus erythematosus (SCLE), 43, Q84
Sulfasaiazine, 10, 111, 161, 42
Surgery
ioint replacement, Q50
for osteoarthritis, 30
for RA, 23
Sweet syndrome, 20
Synovial fluid, 1, 8, 8t, 73
Synovitis, 7, 20
Systemic lupus erythematosus (SLE)
autoantibodies in, 48t
cardiovascular involvement. 45
ciassiflcation of. 47t
clinical manifestations, 43-46
dermatologic manifestations of, 3t
diagnosis ol 46 48
epidemiolog/ of, 42 43
flares in pregnancy, Q95
hematologic involvement, 45 46
internal organ involvement in, 4t
ioint pain in, Q25
kidney involvement, 44 45
lupus nephritis, Q77
medications tirr. 49t
musculoskeletal in\,0lvement, 44
nephritis in, Q46
neuropsychiatric involvement, 45
ocular manifestations of. 3t
osteonecrosis and. 4'l
pathophysiolog/ of l2-43
patient assessment, Q19
pregnancy and, Q88
prognosis, 51
pulmonary involvement. 45
subcutaneous. 43f
treatment of, Q75
Systemic sclerosis (SSc), 59 65
capillary loops in. 63f
classiflcation ln.60t
cutaneous, Q59
digital pitting. 63f
internal organ involvement in, 4t
interstitial lung disease in, Q62
manifestations of, 3t, 60-64
treatment of, 65t
Systemic sclerosis sine scleroderma, 60, 61t
Systemic vasculitis. 3t, 78-87
T
Tacrolimus, fbr llM, 59
Tai chi, 17, Q34
Takayasu arteritis, 81.811. Q22
Telangiectasias, mat like. 60
Tendonitis, ultrasonography of, 7
21 Thalidomide for Behqet syndrome, 88
Thrombocytopenia. SLE and. 45
Tissue biopsies, 8
Tocilizumab, 141, 161, 22. 88
Toes
dactylitis, 37f
gout,68,68f
Tofacitinib,
11t, 16t
Tophi,68
Totalioint arthroplasty. 17
Tramadol, 10, 161. 29. 32
TRAPS (tumor necrosis factor receptor-associated periodic fever
Tricyclic antidepressants, 32
Tumor necrosis factor inhibitors, 13, 13t, 161, 41, 42t, Q14
U
Ulcerations in Behqet syndrome, Q1
Ultrasonography, 7. 79 20, 69
179
lndex

Undifferentiated connective tissue disease (ICTD), 66t Viral infections, T6-z

Upadacitinib, 111, 16t Vision loss, 2
Urate-lowering therapy, 13-15, 70, Q52 Vitamin D, intake of 50
Uric acid, gout and, 67 Voclosporin, Ut
Uricosuric agents, 15, 71
Ustekinumab, 141, 16t w
Uveitis, treatment of, 41 Weight loss for osteoarthritis, Q82

U
x
Vaccination in immunosuppression, 15 Xanthine oxidase inhibitors, 70-71
Vasculitis Xerostoma, medication-induced, Q47
derrnatologic manifestations of, 3t Y
differential diagnoses, 79t Yamaguchi criteria, 90
hypersensitivity, 9 Yersinio spp., 38
ocular manifestations of, 3t Yoga,77
RA and,21
secondary 79t z
skin manifestations, 20 Zidorudine, myopathy induced by, 54t
Vertebral fractures, 36 Zika virus.76

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