IntheClinic Rheumatoid Arthritis · IntheClinic® Rheumatoid Arthritis RiskFactors Diagnosis...

In the Clinic®

RheumatoidArthritis Risk Factors

Diagnosis

Treatment

Rheumatoid arthritis (RA) is a common sys-temic inflammatory autoimmune diseasecharacterized by painful, swollen joints thatcan severely impair physical function and qualityof life. The presenting symptoms of musculoskele-tal pain, swelling, and stiffness are common in clin-ical practice, so familiarity with diagnosing andmanaging RA is crucial. Patients with RA are atgreater risk for serious infection, respiratory dis-ease, osteoporosis, cardiovascular disease, can-cer, and mortality than the general population. Inrecent years, early diagnosis, aggressive treat-ment, and expanded therapeutic options ofdisease-modifying antirheumatic drugs havemarkedly improved both the management andlong-term prognosis of RA.

CME/MOC activity available at Annals.org.

Physician WriterJeffrey A. Sparks, MD,MMScFrom Brigham and Women'sHospital, Harvard MedicalSchool, Boston,Massachusetts.

doi:10.7326/AITC201901010

CME Objective: To review current evidence for risk factors, diagnosis, and treatment ofrheumatoid arthritis.

Funding Source: American College of Physicians.

Acknowledgment: The author thanks Tom W.J. Huizinga, MD, PhD, and Theodore Pincus,MD, authors of the previous version of this In the Clinic.

Disclosures: Dr. Sparks, ACP Contributing Author, has nothing to disclose. The form can beviewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M18-2488.

With the assistance of additional physician writers, the editors of Annals of Internal Medicinedevelop In the Clinic using MKSAP and other resources of the American College ofPhysicians.

In the Clinic does not necessarily represent official ACP clinical policy. For ACP clinicalguidelines, please go to https://www.acponline.org/clinical_information/guidelines/.

Annals of Internal Medicine�

© 2019 American College of Physicians

http://www.annals.orghttp://www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M18-2488https://www.acponline.org/clinical_information/guidelines/

Rheumatoid arthritis (RA) is achronic, systemic inflammatorydisease that affects 0.5%–1% ofU.S. adults—an estimated 1.5 mil-lion people (1). It is more com-mon in women and may occur atany age; peak incidence is be-tween ages 50 to 60 years. Themost prominent feature is sym-metrical pain and swelling of thehands, wrists, feet, and knees(polyarthritis), although otherjoints may be affected. Patientsmay also present with monoar-thritis or oligoarthritis. Some pa-tients with RA may present orlater develop disease manifesta-tions in other organs (sometimeswithout obvious articular involve-ment), such as interstitial lungdisease (ILD), pericarditis, pleuraleffusion, or bronchiectasis. Giventhis clinical heterogeneity, RA isprobably a clinical syndrome thatencompasses several diseasesubsets, each characterized byimmune dysregulation that, if leftuntreated, can lead to chronicinflammation and irreversiblejoint or organ damage.

Although laboratory tests for theRA-related autoantibodies rheu-

matoid factor (RF) and anticitrulli-nated protein antibodies (ACPA)are abnormal (seropositive) inmany patients with RA, values arenormal (seronegative) in aboutone third of patients with RA.There is no single pathogno-monic laboratory finding or im-aging modality that definitivelydiagnoses RA. Therefore, RA isa clinical diagnosis based onthe pattern of symptoms, physi-cal examination, serologictesting results, and imagingfindings.

Historically, progressive disabilityand a shortened lifespan werenearly universal for patients withRA, but the long-term prognosishas improved over the past 2 de-cades (2–4). These improve-ments likely result from earlierdiagnosis, aggressive treatmentbefore onset of irreversible jointor organ damage, and control ofchronic inflammation by wide-spread use and expandedoptions of conventional and bio-logic disease-modifying antirheu-matic drugs (DMARDs) (5).

Risk FactorsAlthough the cause of RAremains unknown, significantprogress has been made in iden-tifying risk factors. HLA-DRB1 (the“shared epitope”) is the strongestof many known genetic risk fac-tors (6, 7). Cigarette smoking isthe best-established lifestyle riskfactor for seropositive RA (8).Elevated body mass index, lowalcohol consumption, unhealthydietary intake, poor dentalhealth, and low socioeconomicstatus may also affect RA suscep-tibility (9–12). Because womenare at higher risk than men, re-productive and menopausal fac-tors may play a role (13, 14).

Having an affected family mem-ber increases personal risk3-fold; however, most patientswith RA have no family history(15). RF and ACPA may be de-tectable in serum several yearsbefore onset, and their presencemarkedly increases subsequentrisk for RA (16). Early diseasemanifestations, such as palin-dromic rheumatism (intermittentself-limited episodes of inflam-matory arthritis with extendedperiods of remission), greatly in-crease risk for progression to RA(17).

1. Myasoedova E, CrowsonCS, Kremers HM, Ther-neau TM, Gabriel SE. Isthe incidence of rheuma-toid arthritis rising?: re-sults from OlmstedCounty, Minnesota, 1955-2007. Arthritis Rheum.2010;62:1576-82. [PMID:20191579]

2. Zhang Y, Lu N, PeloquinC, Dubreuil M, Neogi T,Avi a-Zubieta JA, et al.Improved survival in rheu-matoid arthritis: a generalpopulation-based cohortstudy. Ann Rheum Dis.2017;76:408-413. [PMID:27338777]

3. Markusse IM, Akdemir G,Dirven L, Goekoop-Ruiterman YP, vanGroenendael JH, Han KH,et al. Long-Term Out-comes of Patients WithRecent-Onset RheumatoidArthritis After 10 Years ofTight Controlled Treat-ment: A Randomized Trial.Ann Intern Med. 2016;164:523-31. [PMID:27089068]

4. Lacaille D, Avina-ZubietaJA, Sayre EC, Abrahamow-icz M. Improvement in5-year mortality in inci-dent rheumatoid arthritiscompared with the gen-eral population-closing themortality gap. Ann RheumDis. 2017;76:1057-1063.[PMID: 28031164]

5. Carpenter L, Norton S,Nikiphorou E, JayakumarK, McWilliams DF, RennieKL, et al; Early Rheuma-toid Arthritis Study andthe Early RheumatoidArthritis Network. Reduc-tions in RadiographicProgression in Early Rheu-matoid Arthritis OverTwenty-Five Years: Chang-ing Contribution FromRheumatoid Factor in TwoMulticenter UK InceptionCohorts. Arthritis Care Res(Hoboken). 2017;69:1809-1817. [PMID:28217885]

6. Raychaudhuri S, Sandor C,Stahl EA, Freudenberg J,Lee HS, Jia X, et al. Fiveamino acids in three HLAproteins explain most ofthe association betweenMHC and seropositiverheumatoid arthritis. NatGenet. 2012;44:291-6.[PMID: 22286218]

7. Okada Y, Wu D, Trynka G,Raj T, Terao C, Ikari K,et al; RACI consortium.Genetics of rheumatoidarthritis contributes tobiology and drug discov-ery. Nature. 2014;506:376-81. [PMID:24390342]

8. Sugiyama D, Nishimura K,Tamaki K, Tsuji G, Naka-zawa T, Morinobu A, et al.Impact of smoking as arisk factor for developingrheumatoid arthritis: ameta-analysis of observa-tional studies. Ann RheumDis. 2010;69:70-81.[PMID: 19174392]

� 2019 American College of Physicians ITC2 In the Clinic Annals of Internal Medicine 1 January 2019

DiagnosisWhat are the characteristicarticular symptoms andphysical examination findingsthat suggest RA?RA should be considered in anypatient with joint stiffness, pain,or swelling that persists for morethan a few weeks. Joint pain inRA is typically symmetrical andpolyarticular, but may be asym-metrical, oligoarticular (involving2 to 4 joints), or monoarticular atonset. Although not specific forRA, new-onset symmetrical jointswelling with morning stiffnesslasting longer than an hour thatimproves with use throughoutthe day is characteristic. Synovitisis important to recognize for RAdiagnosis and determining treat-ment response. Synovitis is de-fined as an inflamed joint capsulecharacterized by erythema,warmth, tenderness to palpation,and swelling; it is typically de-tected by physical examination,but advanced imaging may beuseful in patients with equivocalsigns. Arthralgia is generally re-lated to patient symptoms ofpain and stiffness and may notnecessarily be due to inflamma-tory arthritis. Patients with synovi-tis and symptoms lasting morethan 6 weeks are more likely todevelop a progressive diseaseversus a self-limited process.Hand, wrist, and foot involvementis most common in RA, but atypi-cal presentations may only in-volve large joints, such as theknee. The distal interphalangealjoints of the hand are not typi-cally involved, and dactylitis isuncommon. The axial skeleton,including the hips, also is not typ-ically involved, although severeand longstanding RA may involvethese joints, particularly the cervi-cal spine.

Physical examination may detectarticular and soft-tissue swellingwith tenderness to palpation due

to synovitis. Medium or largejoints may have obvious effusionsamenable to arthrocentesis. Mildjoint swelling can be subtle anddifficult to recognize, particularlyin the small joints of patients withobesity or concurrent fibromyal-gia. Laboratory testing and imag-ing, particularly bedside point-of-care musculoskeletal ultra-sonography, can be helpful todetect and quantify presenceand severity of synovitis in pa-tients with equivocal history andphysical examination findings.

Historically, patients with long-standing, inadequately treatedRA developed joint damage anddeformities, including character-istic ulnar deviation, swan neck,and boutonniere deformities ofthe hands (Figure 1; AppendixFigure 1, available at Annals.org), and flexion contractures ofthe knees and elbows. However,these “classical” deformities arebecoming less common, proba-bly because of aggressivetreatment with the goal of lowdisease activity or remission, aswell as more options for moderntargeted therapeutics.

RA is a systemic inflammatorydisease and thus may presentwith or be complicated by extra-articular organ manifestations ortreatment side effects (see theBox: Selected Extra-articularManifestations of RheumatoidArthritis by Affected OrganSystem).

What are the American Collegeof Rheumatology and EuropeanLeague Against Rheumatismcriteria for classifying RA, andhow are they most useful?The American College ofRheumatology (ACR) and theEuropean League Against Rheu-matism (EULAR) developedclassification criteria for RA to

9. Qin B, Yang M, Fu H, MaN, Wei T, Tang Q, et al.Body mass index and therisk of rheumatoid arthri-tis: a systematic reviewand dose-response meta-analysis. Arthritis Res Ther.2015;17:86. [PMID:25890172]

10. Sparks JA, Barbhaiya M,Tedeschi SK, Leather-wood CL, Tabung FK,Speyer CB, et al. Inflam-matory dietary patternand risk of developingrheumatoid arthritis inwomen. Clin Rheumatol.2018. [PMID:30109509]

11. Gan RW, DemoruelleMK, Deane KD, WeismanMH, Buckner JH, Gre-gersen PK, et al.Omega-3 fatty acids areassociated with a lowerprevalence of autoanti-bodies in sharedepitope-positive subjectsat risk for rheumatoidarthritis. Ann Rheum Dis.2017;76:147-152.[PMID: 27190099]

12. Lu B, Solomon DH,Costenbader KH, KarlsonEW. Alcohol consump-tion and risk of incidentrheumatoid arthritis inwomen: a prospectivestudy. Arthritis Rheuma-tol. 2014;66:1998-2005.[PMID: 24729427]

13. Orellana C, Saevarsdottir S,Klareskog L, Karlson EW,Alfredsson L, Bengtsson C.Oral contraceptives, breast-feeding and the risk ofdeveloping rheumatoidarthritis: results from theSwedish EIRA study. AnnRheum Dis. 2017;76:1845-1852. [PMID:28818831]

14. Bengtsson C, Malspeis S,Orellana C, Sparks JA,Costenbader KH, KarlsonEW. Association BetweenMenopausal Factors andthe Risk of Seronegativeand Seropositive Rheu-matoid Arthritis: ResultsFrom the Nurses' HealthStudies. Arthritis CareRes (Hoboken). 2017;69:1676-1684. [PMID:28085997]

15. Sparks JA, Chen CY,Hiraki LT, Malspeis S,Costenbader KH, KarlsonEW. Contributions offamilial rheumatoidarthritis or lupus andenvironmental factors torisk of rheumatoid arthri-tis in women: a prospec-tive cohort study. ArthritisCare Res (Hoboken).2014;66:1438-46.[PMID: 25103278]

16. Rantap -Dahlqvist S, deJong BA, Berglin E, Hall-mans G, Wadell G, Sten-lund H, et al. Antibodiesagainst cyclic citrullinatedpeptide and IgA rheuma-toid factor predict thedevelopment of rheuma-toid arthritis. ArthritisRheum. 2003;48:2741-9.[PMID: 14558078]

1 January 2019 Annals of Internal Medicine In the Clinic ITC3 � 2019 American College of Physicians

http://www.annals.orghttp://www.annals.org

identify patients with early dis-ease, before irreversible jointdamage occurs (18) (see theBox: ACR/EULAR 2010 Classifi-cation Criteria for RheumatoidArthritis). However, these criteriawere developed to classify pa-tients for research studies, not asdiagnostic criteria to be used forclinical purposes.

According to this classificationsystem, RA requires synovitis in atleast 1 joint and absence of amore likely clinical explanation.Three key factors indicate proba-ble RA rather than a self-limitedpolyarthritis: symmetrical arthritisof small joints, presence of ACPAor RF (particularly at titers morethan 3 times the upper limit ofnormal), and symptoms lastinglonger than 6 weeks.

The 2010 ACR/EULAR criteriahave been successful in enrollingpatients in research studies forRA prevention or early RA diag-nosed before onset of longstand-ing complications. However,clinical care patients who haveRA may require treatment de-spite not meeting these criteria.For example, a patient withchronic knee monoarthritis, high-titer RF and ACPA, and elevatedlevels of acute phase reactants

may be treated for RA even if heor she does not meet the criteria.They were developed for classify-ing patients with articular mani-festations of the disease and maynot apply to patients who presentwith predominant extra-articularmanifestations, such as ILD with-out obvious articular involvement(19). Therefore, clinicians shoulduse their best judgment whendeciding whether to diagnoseand treat RA and consider expertconsultation for ambiguouscases.

What differential diagnosisshould clinicians considerwhen evaluating a patient withpossible RA?Patients with the classical long-standing joint deformities areeasily recognized, but the currentparadigm is to prevent thesemanifestations by early RA diag-nosis and prompt treatment.Among patients with early poly-arthritis (< 4 weeks), the majordifferential diagnosis is a self-limited viral infection that typi-cally resolves spontaneously.Other diseases to consider whenevaluating a patient with articularsymptoms compatible with RAare listed in Appendix Table 1(available at Annals.org). Osteo-

Figure 1. Involvement of the hands in rheumatoid arthritis.

Early rheumatoid arthritis with mild fusiform soft tissue swelling of the proximal interphalangealjoints (left). Moderate to severe rheumatoid arthritis with synovitis of the metacarpophalangealjoints and swan neck deformities of the second and third digits (center). Severe deformingrheumatoid arthritis with ulnar deviation, multiple rheumatoid nodules, and proximal interpha-langeal joint subluxations (right). Reproduced with permission from Medical Knowledge Self-Assessment Program 17. Rheumatology. Philadelphia: American College of Physicians; 2015.

17. Chen HH, Chao WC, LiaoTL, Lin CH, Chen DY. Riskof autoimmune rheumaticdiseases in patients withpalindromic rheumatism:A nationwide, population-based, cohort study. PLoSOne. 2018;13:e0201340.[PMID: 30048527]

18. Aletaha D, Neogi T, SilmanAJ, Funovits J, Felson DT,Bingham CO 3rd, et al.2010 Rheumatoid arthritisclassification criteria: anAmerican College of Rheu-matology/EuropeanLeague Against Rheuma-tism collaborative initia-tive. Arthritis Rheum.2010;62:2569-81. [PMID:20872595]

19. Fischer A, Solomon JJ, duBois RM, Deane KD, OlsonAL, Fernandez-Perez ER,et al. Lung disease withanti-CCP antibodies butnot rheumatoid arthritis orconnective tissue disease.Respir Med. 2012;106:1040-7. [PMID:22503074]

20. Lee YC, Lu B, Boire G,Haraoui BP, Hitchon CA,Pope JE, et al. Incidenceand predictors of second-ary fibromyalgia in anearly arthritis cohort. AnnRheum Dis. 2013;72:949-54. [PMID: 22791744]

21. Sokka T, Pincus T. Erythro-cyte sedimentation rate,C-reactive protein, or rheu-matoid factor are normalat presentation in 35%-45% of patients with rheu-matoid arthritis seen be-tween 1980 and 2004:analyses from Finland andthe United States. J Rheu-matol. 2009;36:1387-90.[PMID: 19411389]

22. Katchamart W, KoolvisootA, Aromdee E, Chiowchan-wesawakit P, MuengchanC. Associations of rheuma-toid factor and anti-citrullinated peptide anti-body with diseaseprogression and treatmentoutcomes in patients withrheumatoid arthritis.Rheumatol Int. 2015;35:1693-9. [PMID:25903353]

23. Whiting PF, Smidt N,Sterne JA, Harbord R,Burton A, Burke M, et al.Systematic review: accu-racy of anti-citrullinatedPeptide antibodies fordiagnosing rheumatoidarthritis. Ann Intern Med.2010;152:456-64; W155-66. [PMID: 20368651]

24. Kelly S, Davidson B,Keidel S, Gadola S, Gor-man C, Meenagh G,et al. The impact ofrheumatologist-performed ultrasound ondiagnosis and manage-ment of inflammatoryarthritis in routine clinicalpractice. BMC Musculo-skelet Disord. 2017;18:487. [PMID: 29166885]


http://www.annals.org

Selected Extra-articular Manifestations of Rheumatoid Arthritis, by Organ SystemDermatologicRheumatoid nodulesVasculitisUlcersNeutrophilic dermatosesTreatment-related rashesLymphedemaOphthalmologicKeratoconjunctivitis sicca (secondary Sjögren syndrome)EpiscleritisScleritisScleromalacia perforansPulmonaryPulmonary fibrosisInterstitial lung disease (nonspecific interstitial pneumonia, usual interstitial

pneumonia, organizing pneumonia)NodulesPleural effusionPleuritisBronchiectasisCryptogenic organizing pneumoniaCardiovascularPremature atherosclerosis, coronary and peripheral vascular diseasePericarditisPericardial effusionValvular defectsArrhythmia, conduction defectsMyocarditisHeart failure (particularly with preserved ejection fraction)Cardiac nodulesGastrointestinalXerostomiaGastritis or peptic ulcer disease (e.g., from nonsteroidal anti-inflammatory drugs

or glucocorticoids)Stomatitis, mucositis (e.g., from methotrexate)RenalGlomerulonephritis (usually mesangioproliferative)Proteinuria (rarely due to secondary amyloidosis)Treatment-related kidney injuryHepaticNodular regenerative hyperplasiaPortal fibrosisTreatment-related hepatitis/cirrhosisNeurologicCervical spine subluxation/atlantoaxial instabilityPeripheral nerve entrapment (e.g., carpal tunnel syndrome)Mononeuritis multiplex (in rheumatoid vasculitis)Brain nodulesHematologicLymphadenopathySplenomegaly (as part of Felty syndrome)Leukopenia (as part of Felty syndrome)LymphomaAmyloidosisCryoglobulinemiaLarge granular lymphocyte syndrome


arthritis is the most commonform of arthritis and often causesdeformities and pain in thehands of older patients; how-ever, it is characterized by aninsidious course, usually withoutsigns or symptoms of systemicinflammation or autoimmunity.Fibromyalgia should also bestrongly considered in patientspresenting with widespread painbecause it is more common thanRA (5% vs. 0.5%–1%), particularlyin women aged 40–60 years—the same group that has thehighest incidence of RA. Further,some patients have fibromyalgiaalong with RA, or develop itsoon after diagnosis (20). Fibro-myalgia is characterized by

widespread pain in articular andnonarticular sites (particularly theforearms, arms, posterior neck,trapezius, and legs), but distin-guishing between these disor-ders can be difficult, particularlyearly in the course. Other causesof inflammatory arthritis shouldalso be considered. Expert diag-nosis may be required for atypi-cal presentations.

What is the role of laboratorystudies?Many patients with RA have anincreased erythrocyte sedimen-tation rate (ESR) or elevated lev-els of C-reactive protein (CRP);RF; or ACPA, particularly anticy-clic citrullinated peptide (anti-

ACR/EULAR 2010 Classification Criteria for Rheumatoid Arthritis*These criteria should be restricted to persons with ≥1 swollen joints in the

absence of a more likely diagnosis.A score of ≥6 points is classified as definite RA. In each domain, consider only

the category with most points.A. Joint involvement and distribution (0-5 points)Any swollen or tender joint on physical examinationLarge joints: Shoulders, elbows, hips, knees, and anklesSmall joints: Metacarpophalangeal, proximal interphalangeal, second through fifth

metatarsophalangeal, thumb interphalangeal, and wristsY 1 large joint: 0 pointsY 2–10 large joints: 1 pointY 1–3 small joints: 2 pointsY 4–10 small joints: 3 pointsY > 10 joints (and at least 1 small joint): 5 pointsB. Serology (0-3 points)Low-positive results are > 1 to 3 times the upper limit of normal of the assay used.

High-positive results are > 3 times the upper limit of normal of the assay used• Negative RF and negative ACPA: 0 points• Low-positive RF or low-positive ACPA: 2 points• High-positive RF or high-positive ACPA: 3 pointsC. Acute-phase reactants (0-1 point)• Normal CRP and normal ESR: 0 points• Abnormal CRP or abnormal ESR: 1 pointD. Duration of symptoms (0-1 point)Patient's self-report on the maximum duration of symptoms of any joint clinically

involved at the time of assessment• < 6 wk: 0 points• ≥6 wk: 1 pointACPA = anticitrullinated protein antibodies; ACR/EULAR = American College of

Rheumatology/European League Against Rheumatism; CRP = C-reactive protein;ESR = erythrocyte sedimentation rate; RA = rheumatoid arthritis;RF = rheumatoid factor.

*Data from reference 8.

25. van der Linden MP, leCessie S, Raza K, van derWoude D, Knevel R,Huizinga TW, et al. Long-term impact of delay inassessment of patientswith early arthritis. Arthri-tis Rheum. 2010;62:3537-46. [PMID:20722031]

26. van der Heide A, JacobsJW, Bijlsma JW, Heu-rkens AH, van Booma-Frankfort C, van der VeenMJ, et al. The effective-ness of early treatmentwith “second-line” anti-rheumatic drugs. A ran-domized, controlled trial.Ann Intern Med. 1996;124:699-707. [PMID:8633829]

27. Smolen JS, Landewé R,Bijlsma J, Burmester G,Chatzidionysiou K, Dou-gados M, et al. EULARrecommendations for themanagement of rheuma-toid arthritis with syn-thetic and biologicaldisease-modifying anti-rheumatic drugs: 2016update. Ann Rheum Dis.2017;76:960-977.[PMID: 28264816]

28. Singh JA, Saag KG,Bridges SL Jr, Akl EA,Bannuru RR, SullivanMC, et al. 2015 Ameri-can College of Rheuma-tology Guideline for theTreatment of Rheuma-toid Arthritis. ArthritisRheumatol. 2016;68:1-26. [PMID: 26545940]

29. Lau CS, Chia F, HarrisonA, Hsieh TY, Jain R, JungSM, et al; Asia PacificLeague of Associationsfor Rheumatology.APLAR rheumatoid arthri-tis treatment recommen-dations. Int J Rheum Dis.2015;18:685-713.[PMID: 26334449]

30. Prevoo ML, van ‘t HofMA, Kuper HH, van Leeu-wen MA, van de PutteLB, van Riel PL. Modifieddisease activity scoresthat include twenty-eight-joint counts. Devel-opment and validation ina prospective longitudi-nal study of patients withrheumatoid arthritis.Arthritis Rheum. 1995;38:44-8. [PMID:7818570]

31. Smolen JS, BreedveldFC, Schiff MH, Kalden JR,Emery P, Eberl G, et al. Asimplified disease activ-ity index for rheumatoidarthritis for use in clinicalpractice. Rheumatology(Oxford). 2003;42:244-57. [PMID: 12595618]

32. Aletaha D, Nell VP,Stamm T, Uffmann M,Pflugbeil S, Machold K,et al. Acute phase reac-tants add little to com-posite disease activityindices for rheumatoidarthritis: validation of aclinical activity score.Arthritis Res Ther. 2005;7:R796-806. [PMID:15987481]


CCP) antibodies. However,none of these tests is sufficientlysensitive for exclusion, becauseresults are normal in about 30%of patients with RA (21). Patientswith seropositive RA may have amore severe course than thosewith seronegative disease (22).Laboratory studies are fre-quently normal in patients withRA.

In an observational study of more than 2500patients with newly diagnosed RA in Finlandand the United States, ESR was less than 28mm/h in 44% of patients and CRP levels werenormal in 48% (21). A review of 151 studies ofpatients with early symptoms of RA found thatsecond-generation anti-CCP antibodies and RFhad similar sensitivity (67% vs. 70%), but thatsecond-generation anti-CCP antibodies hadgreater specificity (96% vs. 86%) (23). The rel-atively low sensitivity of both anti-CCP and RFmeans that negative results do not rule out RA.

Appendix Table 2 (available atAnnals.org) lists laboratory andimaging tests to consider forpatients presenting with signsand symptoms suggestive of RA.

What is the role of imagingstudies?Radiographic changes (juxta-articular osteopenia, joint spacenarrowing, or bone erosions) injoints with signs or symptoms onplain films (Figure 2; AppendixFigure 2, available at Annals.org)are not required for a definitivediagnosis of RA or to initiatetherapy. Indeed, a major goal oftreatment is to prevent theseradiographic changes, whichgenerally do not develop untilpatients have had symptoms formonths or years. RA is often di-agnosed in patients whose ra-diographs are normal or showonly subtle juxta-articular os-teopenia in the hands or feet,and in early inflammatory arthri-tis, these changes may occur inthe feet before the hands. It maybe reasonable to obtain base-line plain radiographs of the feetand hands, regardless of symp-toms, to screen for occult in-

volvement, establish a baseline,and evaluate for alternativecauses.

Ultrasonography and magneticresonance imaging (MRI) aremore sensitive than plain radio-graphs for detecting soft tissueinflammation and synovitis (par-ticularly tenosynovitis) beforedevelopment of joint damage,but these tests are less specific.Rheumatologists are increasinglybeing trained in point-of-caremusculoskeletal ultrasonographyto aid in diagnosis and earlytreatment of patients with RA(24). Similarly, MRI or other ad-vanced imaging techniques, suchas dual-energy computed to-mography, may be consideredwhen physical examination find-ings are equivocal in detectingsynovitis and when alternate di-agnoses are being considered.Referral to a rheumatologisttrained in musculoskeletal ultra-sonography to determinewhether advanced imagingwould be useful if RA is in thedifferential diagnosis should beconsidered.

When should synovial fluid beobtained to help in diagnosis?Obtaining synovial fluid is gener-ally not required to diagnose RA,particularly in patients who pres-ent with polyarthritis. However, itshould be obtained, usually frommedium or large joints (such asknees, shoulders, ankles, or el-bows) when septic arthritis, gout,or other diagnoses requiring sy-novial fluid assessment are beingconsidered. Septic arthritis ismore common in patients withRA and should be suspected in apatient with monoarthritis that iswarm or erythematous with largeeffusions and systemic signs,such as fever or hypotension. Ifsuspicion for septic arthritis ishigh, clinicians should considerreferring to specialists for image-guided arthrocentesis to evaluate

33. Pincus T, Swearingen CJ,Bergman M, Yazici Y.RAPID3 (Routine Assess-ment of Patient IndexData 3), a rheumatoidarthritis index withoutformal joint counts forroutine care: proposedseverity categories com-pared to disease activityscore and clinical diseaseactivity index categories.J Rheumatol. 2008;35:2136-47. [PMID:18793006]

34. Centola M, Cavet G,Shen Y, Ramanujan S,Knowlton N, Swan KA,et al. Development of amulti-biomarker diseaseactivity test for rheuma-toid arthritis. PLoS One.2013;8:e60635. [PMID:23585841]

35. Haavardsholm EA, AgaAB, Olsen IC, LillegravenS, Hammer HB, Uhlig T,et al. Ultrasound in man-agement of rheumatoidarthritis: ARCTIC ran-domised controlled strat-egy trial. BMJ. 2016;354:i4205. [PMID:27530741]

36. Aletaha D, Alasti F, Smo-len JS. Optimisation of atreat-to-target approachin rheumatoid arthritis:strategies for the3-month time point. AnnRheum Dis. 2016;75:1479-85. [PMID:26420577]

37. Visser K, Katchamart W,Loza E, Martinez-LopezJA, Salliot C, Trudeau J,et al. Multinationalevidence-based recom-mendations for the useof methotrexate in rheu-matic disorders with afocus on rheumatoidarthritis: integratingsystematic literatureresearch and expertopinion of a broad inter-national panel of rheu-matologists in the 3EInitiative. Ann RheumDis. 2009;68:1086-93.[PMID: 19033291]

38. van der Heijde D, Klares-kog L, Rodriguez-Valverde V, Codreanu C,Bolosiu H, Melo-GomesJ, et al; TEMPO StudyInvestigators. Compari-son of etanercept andmethotrexate, alone andcombined, in the treat-ment of rheumatoidarthritis: two-year clinicaland radiographic resultsfrom the TEMPO study, adouble-blind, random-ized trial. ArthritisRheum. 2006;54:1063-74. [PMID: 16572441]

39. Yazici Y, Sokka T, Kauti-ainen H, Swearingen C,Kulman I, Pincus T. Longterm safety of methotrex-ate in routine clinicalcare: discontinuation isunusual and rarely theresult of laboratory ab-normalities. Ann RheumDis. 2005;64:207-11.[PMID: 15208176]


http://www.annals.orghttp://www.annals.org

for small joint involvement or foreffusions that are difficult to aspi-rate at bedside. If obtained, syno-vial fluid should be evaluated for

cell count with differential, crys-tals using polarized microscopy,and Gram stain with culture.

In patients without suspectedseptic arthritis who have effusionof a large joint (such as in theknee), aspiration of synovial fluidcombined with intra-articular glu-cocorticoids may reduce symp-toms while limiting systemic ex-posure to glucocorticoids.

When should cliniciansconsider consulting arheumatologist?Delay of RA diagnosis and effec-tive treatment has been associ-ated with poor outcomes (25).Patients with suspected inflam-matory arthritis or new-onsetjoint pain, stiffness, and swelling(without history of overuse ortrauma) that persists for severalweeks should be referred to arheumatologist. Inflammatoryarthritis may also be the present-ing symptom of a multisystemdisease. Generally, patients sus-pected to have RA should haveESR, CRP, anti-CCP, and RF mea-sured by their primary care clini-cian before being referred to arheumatologist.

TreatmentWhat is the overall approach todrug therapy for RA?Pharmacologic treatment of RAshould tightly control inflamma-

tion with the goal of low diseaseactivity or remission (AppendixTable 3, available at Annals.org).Methotrexate is considered the

Figure 2. Radiograph showingadvanced rheumatoid arthritis ofthe hand.

Ulnar deviation occurs at the metacarpopha-langeal joints; marginal erosions most prom-inently at the second through fourth meta-carpophalangeal joints and the second andthird proximal interphalangeal joints (ar-rows); and joint-space narrowing at the wrist,metacarpophalangeal, and proximal inter-phalangeal joints, which also represents ero-sive disease. Note the loss of the ulnar sty-loid (arrowhead), another common sign ofbony erosion in rheumatoid arthritis. Repro-duced with permission from Medical Knowl-edge Self-Assessment Program 18. Rheuma-tology. Philadelphia: American College ofPhysicians; 2018.

40. O’Dell JR, Curtis JR,Mikuls TR, Cofield SS,Bridges SL Jr, RanganathVK, et al; TEAR Trial In-vestigators. Validation ofthe methotrexate-firststrategy in patients withearly, poor-prognosisrheumatoid arthritis:results from a two-yearrandomized, double-blind trial. ArthritisRheum. 2013;65:1985-94. [PMID: 23686414]

41. Humphreys JH, WarnerA, Costello R, Lunt M,Verstappen SMM, DixonWG. Quantifying thehepatotoxic risk of alco-hol consumption inpatients with rheumatoidarthritis taking metho-trexate. Ann Rheum Dis.2017;76:1509-1514.[PMID: 28341765]

42. Melles RB, Marmor MF.The risk of toxic retinopa-thy in patients on long-term hydroxychloroquinetherapy. JAMA Ophthal-mol. 2014;132:1453-60.[PMID: 25275721]

43. Haagsma CJ, van Riel PL,de Jong AJ, van de PutteLB. Combination of sul-phasalazine and metho-trexate versus the singlecomponents in earlyrheumatoid arthritis: arandomized, controlled,double-blind, 52 weekclinical trial. Br J Rheu-matol. 1997;36:1082-8.[PMID: 9374925]

44. Maillefert JF, Combe B,Goupille P, Cantagrel A,Dougados M. Long termstructural effects of combi-nation therapy in patientswith early rheumatoidarthritis: five year followup of a prospective doubleblind controlled study.Ann Rheum Dis. 2003;62:764-6. [PMID: 12860733]

45. Bansback N, Phibbs CS,Sun H, O’Dell JR, BrophyM, Keystone EC, et al; CSP551 RACAT Investigators.Triple Therapy VersusBiologic Therapy for ActiveRheumatoid Arthritis: ACost-Effectiveness Analysis.Ann Intern Med. 2017;167:8-16. [PMID:28554192]

46. Sparks JA, Krumme AA,Shrank WH, Matlin OS,Brill G, Pezalla EJ, et al.Brief Report: Intensifica-tion to Triple TherapyAfter Treatment WithNonbiologic Disease-Modifying AntirheumaticDrugs for RheumatoidArthritis in the UnitedStates From 2009 to2014. Arthritis Rheuma-tol. 2016;68:1588-95.[PMID: 26866506]

47. O’Dell JR, Mikuls TR,Taylor TH, Ahluwalia V,Brophy M, Warren SR,et al; CSP 551 RACATInvestigators. Therapiesfor active rheumatoidarthritis after methotrex-ate failure. N Engl JMed. 2013;369:307-18.[PMID: 23755969]

Diagnosis... Rheumatoid arthritis should be considered in patients with jointpain, stiffness, or swelling lasting more than a few weeks. However, in manypatients these symptoms may resolve spontaneously. Diagnosis requires adetailed history as well as joint swelling found on physical examination that isunexplained by another diagnosis. Neither radiologic nor laboratory abnor-malities are required for diagnosis. While some patients diagnosed with RAhave normal values for ESR, CRP, anti-CCP, and RF, abnormalities in these testscan aid in diagnosis. When the diagnosis is uncertain or treatment may beneeded, evaluation by a rheumatologist should be strongly considered.

CLINICAL BOTTOM LINE



“backbone” of RA treatment be-cause of its known efficacy andsafety as initial monotherapy orcombination treatment, For pa-tients with moderate or severedisease, methotrexate shouldbe initiated, typically as mono-therapy. If treatment response isinadequate, other DMARDs maybe added to (rather than replac-ing) methotrexate to enhanceefficacy and reduce the potentialfor formation of antidrug anti-bodies. Patients with mild RAcan sometimes be treated withhydroxychloroquine as initialmonotherapy; if response is in-adequate, other DMARDs, suchas methotrexate, should be initi-ated. Clinicians and patientsshould agree on a treatmentplan using a shared decision-making approach, weighing therisks and benefits of methotrex-ate with those of alternativestrategies.

Nonsteroidal anti-inflammatorydrugs (NSAIDs) are generallyused on an as-needed basis forpain because of their quick on-set of action. Glucocorticoidsmay be used as “bridge ther-apy” during episodes of highdisease activity given quick on-set of action and efficacy in re-lieving pain and stiffness. How-ever, because they have manylong-term negative conse-quences, patients should beweaned completely or given thelowest possible dose, withDMARDs used as steroid-sparing therapy. Notably, datashow that the “step-up” pyramidapproach used in the past forRA treatment, in which NSAIDsand glucocorticoids were usedfirst and DMARDs were usedlater only if the response was in-adequate, is inferior to early initi-ation of DMARD therapy.

In a randomized trial of 238 patients with re-cently diagnosed RA, initial therapy with aDMARD was superior to therapy with NSAIDsfollowed by DMARDs in patients with inade-quate responses (26). By 1 year, 29% of pa-tients treated initially with NSAIDs alone haddiscontinued therapy, compared with 8% ofpatients whose initial therapy included aDMARD. Patients in the early-DMARD grouphad less pain and disability and better jointscores than the NSAID-only group.

What is the target oftreatment?Treatment guidelines recom-mend a treat-to-target of low dis-ease activity or remission accord-ing to a validated disease activitymeasure (27–29). Several mea-sures have been developed andvalidated for use in clinical careto assess RA activity and aid intreatment decisions. The compo-nents of the 4 most commonlyused measures are presented inTable 1. A widely used measureis the Disease Activity Score 28(DAS28) (30), which involves ten-der and swollen joints counted at28 sites (in the upper extremitiesand knees), the patient's self-assessment of global status, andmeasurement of acute-phase re-actants (ESR or CRP). These rawvalues can be entered into anonline calculator to obtain anoverall DAS28 score (www.das-score.nl/dasculators.html). TheSimplified Disease Activity Indexis similar to the DAS28 but iseasier to calculate and thus maybe more amenable to real-timeuse if laboratory results are avail-able (31). The Clinical DiseaseActivity Index uses the tender/swollen joints and patient/physi-cian global assessments, anddoes not require laboratory test-ing or a calculator (32). As a re-sult, it may be easier to use andinterpret in real-time with pa-tients during clinic visits whiletreatment decisions are beingmade. Other versions of thesemeasures use expanded jointcounts to include other sites,

48. Raaschou P, Söderling J,Turesson C, Askling J;ARTIS Study Group. Tu-mor Necrosis FactorInhibitors and CancerRecurrence in SwedishPatients With Rheuma-toid Arthritis: A Nation-wide Population-BasedCohort Study. Ann InternMed. 2018;169:291-299. [PMID: 30105374]

49. Bridges SL Jr, White DW,Worthing AB, GravalleseEM, O’Dell JR, Nola K,et al; American College ofRheumatology. The Sci-ence Behind Biosimilars:Entering a New Era ofBiologic Therapy. ArthritisRheumatol. 2018;70:334-344. [PMID: 29411547]

50. Chingcuanco F, Segal JB,Kim SC, Alexander GC.Bioequivalence of Bio-similar Tumor NecrosisFactor-a Inhibitors Com-pared With Their Refer-ence Biologics: A System-atic Review. Ann InternMed. 2016;165:565-574. [PMID: 27479870]

51. Kremer J, Li ZG, Hall S,Fleischmann R, Geno-vese M, Martin-Mola E,et al. Tofacitinib in com-bination with nonbio-logic disease-modifyingantirheumatic drugs inpatients with active rheu-matoid arthritis: a ran-domized trial. Ann InternMed. 2013;159:253-61.[PMID: 24026258]

52. Nissen SE, Yeomans ND,Solomon DH, Lücher TF,Libby P, Husni ME, et al;PRECISION Trial Investi-gators. CardiovascularSafety of Celecoxib,Naproxen, or Ibuprofenfor Arthritis. N Engl JMed. 2016;375:2519-29. [PMID: 27959716]

53. Bakker MF, Jacobs JW,Welsing PM, VerstappenSM, Tekstra J, Ton E, et al;Utrecht RheumatoidArthritis Cohort StudyGroup. Low-dose predni-sone inclusion in amethotrexate-based, tightcontrol strategy for earlyrheumatoid arthritis: arandomized trial. AnnIntern Med. 2012;156:329-39. [PMID:22393128]

54. van Vliet-DaskalopoulouE, Jentjens T, Scheffer RT.Intra-articular rimexolonein the rheumatoid knee:a placebo-controlled,double-blind, multicen-tre trial of three doses. BrJ Rheumatol. 1987;26:450-3. [PMID: 3318993]

55. H kkinen A, Sokka T, Kauti-ainen H, Kotaniemi A,Hannonen P. Sustainedmaintenance of exerciseinduced muscle strengthgains and normal bonemineral density in patientswith early rheumatoidarthritis: a 5 year followup. Ann Rheum Dis.2004;63:910-6. [PMID:15249317]


http://www.das-score.nl/dasculators.htmlhttp://www.das-score.nl/dasculators.html

such as the feet and ankles. TheRAPID3 (Routine Assessment ofPatient Index Data 3) uses onlypatient-reported measures; thus,remote administration can bedone easily, with the resultsreadily available to clinicians tomonitor and aid in treatmentdecisions (33). Although someclinicians use commercial multib-iomarker disease activity scoresthat measure several serum in-flammatory markers, clinicalmeasures are generally pre-ferred (34). Research is ongoingon whether advanced imaging,such as ultrasonography or MRI,should be incorporated seriallyto monitor RA disease activity(35).

All of the measures provide ascore that can categorize diseaseactivity into remission or low,moderate, or high activity (Table2). Treatment should be tailoredso that patients are in either re-mission or a low category, unlessclinically contraindicated (36).

In a randomized trial in the Netherlands, 508patients with early RA were assigned to 1 of 4treatment strategies, all aimed at achievinglow disease activity (3). At 10 years, all partici-pants had similar functional ability and lowrates of radiographic progression. Comparedwith the general population, there was no ev-idence of excess mortality. This study providesevidence of favorable outcomes for a treat-to-target of low disease activity, regardless of thedrugs used.

Although measures of diseaseactivity provide objective dataand have improved long-term RAoutcomes, some patients may bemisclassified as having active dis-ease based on subjective reportsof pain or joint tenderness unre-lated to active RA (e.g., mechani-cal pain or tenderness from jointdamage, fibromyalgia, coexistentosteoarthritis, back pain, depres-sion, stress, or poor sleep). Con-versely, the tools may misclassifypatients with active RA as havinglow activity or being in remissiondespite the need for treatmentintensification (e.g., foot-predominant inflammatory arthri-tis, refractory monoarthritis).These tools are helpful in guidingmanagement; however, deci-sions should be informed by theclinical scenario.

Which traditional DMARDs areused? What are their risks andbenefits?

MethotrexateMethotrexate is the appropriatefirst-line agent for most patientsdiagnosed with RA, along withfolic acid (typically started at 1mg daily) (37). Low doses (≤25mg/week) usually do not reduceleukocyte or platelet counts.About half of all patients treatedwith methotrexate have little orno radiographic progression,although 30% will require addi-

Table 1. Disease Activity Measures for Clinical Use in Patients WithRheumatoid Arthritis

Component DAS28 CDAI SDAI RAPID3

Number of tender joints* X X X —Number of swollen joints* X X X —Physician global assessment (0–10) — X X —ESR or CRP laboratory results X — X —Patient global assessment (0–10) X X X XPatient function — — — XPatient pain — — — X

CDAI = Clinical Disease Activity Index; CRP = C-reactive protein; DAS28 = DiseaseActivity Score with 28 joints; ESR = erythrocyte sedimentation rate; RAPID3 = RoutineAssessment of Patient Index Data 3; SDAI = Simplified Disease Activity Index.*The 28 joints assessed = hands, wrists, elbows, shoulders, and knees.

56. Solomon DH, Fraenkel L,Lu B, Brown E, Tsao P,Losina E, et al. Compari-son of Care Provided inPractices With NursePractitioners and Physi-cian Assistants VersusSubspecialist PhysiciansOnly: A Cohort Study ofRheumatoid Arthritis.Arthritis Care Res (Hobo-ken). 2015;67:1664-70.[PMID: 26096922]

57. Lorig K, Ritter PL, Plant K.A disease-specific self-help program comparedwith a generalizedchronic disease self-helpprogram for arthritispatients. ArthritisRheum. 2005;53:950-7.[PMID: 16342084]

58. Nikiphorou E, Norton S,Young A, Dixey J, WalshD, Helliwell H, et al; EarlyRheumatoid ArthritisStudy and the EarlyRheumatoid ArthritisNetwork. The associationof obesity with diseaseactivity, functional abilityand quality of life inearly rheumatoid arthri-tis: data from the EarlyRheumatoid ArthritisStudy/Early RheumatoidArthritis Network UKprospective cohorts.Rheumatology (Oxford).2018. [PMID:29590474]

59. Tedeschi SK, Frits M, CuiJ, Zhang ZZ, MahmoudT, Iannaccone C, et al.Diet and RheumatoidArthritis Symptoms:Survey Results From aRheumatoid ArthritisRegistry. Arthritis CareRes (Hoboken). 2017;69:1920-1925. [PMID:28217907]

60. Proudman SM, JamesMJ, Spargo LD, MetcalfRG, Sullivan TR,Rischmueller M, et al.Fish oil in recent onsetrheumatoid arthritis: arandomised, double-blind controlled trialwithin algorithm-baseddrug use. Ann RheumDis. 2015;74:89-95.[PMID: 24081439]

61. Kreps DJ, Halperin F,Desai SP, Zhang ZZ,Losina E, Olson AT, et al.Association of weightloss with improved dis-ease activity in patientswith rheumatoid arthri-tis: A retrospective analy-sis using electronic medi-cal record data. Int J ClinRheumtol. 2018;13:1-10. [PMID: 29606976]

62. Matcham F, Scott IC,Rayner L, Hotopf M,Kingsley GH, Norton S,et al. The impact of rheu-matoid arthritis onquality-of-life assessedusing the SF-36: a sys-tematic review and meta-analysis. Semin ArthritisRheum. 2014;44:123-30. [PMID: 24973898]


tional DMARDs (38). Typicaldoses for RA range between 10mg and up to 25 mg per week .Side effects of nausea, stomatitis,diarrhea, alopecia, and post-dosing fatigue may be managedusing higher doses of daily folicacid supplementation (orswitched to leucovorin given8–12 hours after methotrexate),split dosing of methotrexate onthe day it is administered, switch-ing to subcutaneous administra-tion, or weaning down to themaximum tolerated dose. Long-term treatment with methotrex-ate is safe and well tolerated formost patients with RA (39).

In a randomized controlled trial of 755 pa-tients with early RA, participants were ran-domly assigned to methotrexate monotherapyor combination therapy consisting of eithermethotrexate with etanercept or methotrexatewith sulfasalazine and hydroxychloroquine(40). At week 102, patients assigned to meth-otrexate monotherapy had disease activity andrates of radiographic progression similar tothose assigned to combination therapy. Theseresults validate the strategy of initiating meth-otrexate as monotherapy in patients present-ing with RA.

Mild elevations of liver enzymesare a relatively common side ef-fect of methotrexate, particularlyin patients with metabolic syn-drome. Baseline liver functionshould be tested before metho-trexate is started, and cautionshould be used if enzymes areelevated. Methotrexate may becautiously continued even withmild elevations (< 3-fold above

normal) as long as monitoring isdone frequently and the dose isreduced if elevations persist.Liver function often returns tonormal after dose reduction. Itmay also normalize in some pa-tients without a change in dose,suggesting comorbid infection oreffects of other medications oralcohol intake. Moderate alcoholconsumption (≤2 drinks/day) ispermissible if there are no othercontraindications (41). Persistentelevation of liver enzymes shouldprompt discontinuation of themedication and further work-up,including imaging and referral toa hepatologist for possible liverbiopsy. Methotrexate is a knownteratogen; thus, women of child-bearing potential should use ef-fective contraception or be re-ferred to a gynecologist. Otherrare serious side effects of meth-otrexate include pneumonitisand pulmonary fibrosis.

HydroxychloroquineHydroxychloroquine is used insome patients with RA, particu-larly those presenting with mildseverity and in patients with over-lapping features of other dis-eases, such as systemic lupus ery-thematosus. Hydroxychloroquinemonotherapy is unlikely to con-trol moderate or severe disease;however, it may be helpful asadd-on therapy for patients witha partial response to otherDMARDs. Although hydroxy-chloroquine has only mild anti-

Table 2. Rheumatoid Arthritis Disease Activity Categories in the SDAI,DAS28, CDAI, and RAPID3

Disease Activity Category DAS28 CDAI SDAI RAPID3

High: Intensification of therapyvery likely needed

>5.1 >22 >26 >12

Moderate: Strongly considerintensifying therapy

3.2–5.1 10.1–22 11.1–26 6.1–12

Low: Consider intensifyingtherapy

2.7–3.2 2.9–10 3.4–11 3.1–6

Remission ≤2.6 ≤2.8 ≤3.3 ≤3

CDAI = Clinical Disease Activity Index; DAS28 = Disease Activity Score 28; RAPID3 =Routine Assessment of Patient Index Data 3; SDAI = Simplified Disease Activity Index.

63. Au K, Reed G, Curtis JR,Kremer JM, GreenbergJD, Strand V, et al; COR-RONA Investigators. Highdisease activity is associ-ated with an increasedrisk of infection in pa-tients with rheumatoidarthritis. Ann Rheum Dis.2011;70:785-91. [PMID:21288960]

64. Jin S, Hsieh E, Peng L,Yu C, Wang Y, Wu C,et al. Incidence of frac-tures among patientswith rheumatoid arthri-tis: a systematic reviewand meta-analysis. Os-teoporos Int. 2018;29:1263-1275. [PMID:29546507]

65. England BR, Thiele GM,Anderson DR, Mikuls TR.Increased cardiovascularrisk in rheumatoid arthri-tis: mechanisms andimplications. BMJ. 2018;361:k1036. [PMID:29685876]

66. Chatzidionisyou A, Ca-trina AI. The lung inrheumatoid arthritis,cause or consequence?Curr Opin Rheumatol.2016;28:76-82. [PMID:26599384]

67. Askling J. Malignancyand rheumatoid arthritis.Curr Rheumatol Rep.2007;9:421-6. [PMID:17915099]

68. Bongartz T, Nannini C,Medina-Velasquez YF,Achenbach SJ, CrowsonCS, Ryu JH, et al. Inci-dence and mortality ofinterstitial lung diseasein rheumatoid arthritis: apopulation-based study.Arthritis Rheum. 2010;62:1583-91. [PMID:20155830]

69. Sparks JA, Chang SC,Liao KP, Lu B, Fine AR,Solomon DH, et al.Rheumatoid Arthritis andMortality AmongWomen During 36 Yearsof Prospective Follow-Up:Results From the Nurses'Health Study. ArthritisCare Res (Hoboken).2016;68:753-62. [PMID:26473946]

1 January 2019 Annals of Internal Medicine ITC11 � 2019 American College of Physicians

inflammatory effects, it is unlikelyto increase infection risk and iswell tolerated. The most seriousside effect is retinopathy leadingto blindness, but this is relativelyuncommon and typically onlyoccurs in patients who haveused hydroxychloroquine for 5or more years (42). All patientsreceiving hydroxychloroquineshould be screened annually forretinopathy by an ophthalmolo-gist, particularly after 5 years onthe medication. Other rare sideeffects include hyperpigmenta-tion and severe rash. Hydroxy-chloroquine may be safe to useduring pregnancy.

SulfasalazineSulfasalazine is another tradi-tional DMARD that can be con-sidered in patients who cannottolerate or who have contraindi-cations to methotrexate. In clini-cal trials, efficacy of the drugswas similar after 1 year (43), butsulfasalazine may have less effi-cacy in the long term (44). Sideeffects may include nausea, diar-rhea, and liver function test ab-normalities, and these may bedose-related.

LeflunomideLeflunomide is another tradi-tional DMARD that could beconsidered as an alternative tomethotrexate either as mono-therapy or in combination withother traditional or biologicDMARDs. Side effects includenausea, diarrhea, and elevatedliver enzymes. Leflunomide isprobably teratogenic and has arelatively long half-life (detect-able in some patients for up to 2years after reaching steadystate), so its use should gener-ally be avoided in women ofchildbearing potential who maydesire to become pregnant inthe future.

Triple therapyTriple therapy consists of combi-nation therapy with methotrex-

ate, hydroxychloroquine, andsulfasalazine. Sometimes othertraditional DMARDs, such as le-flunomide or azathioprine, areused instead of sulfasalazine ormethotrexate. Triple therapy maybe considered in patients with RAwho respond inadequately tomethotrexate monotherapy andtherefore require combinationtherapy. Triple therapy is morecost-effective than combinationbiologic DMARDs and metho-trexate (45) and may have similarefficacy. However, it is used infre-quently compared with biologicDMARDs (46).

In a randomized controlled trial, 353 patientswere randomly assigned to triple therapy orcombination etanercept and methotrexate(47). After 24 weeks, improvements in diseaseactivity, rates of radiographic progression, andmeasures of health-related quality of life weresimilar in both groups.

When should biologic DMARDsbe considered, and what aretheir risk and benefits?About 30%–50% of patients re-spond inadequately to traditionalDMARDs. Biologic DMARDsshould be considered when theresponse to 2–6 months of meth-otrexate, as monotherapy orcombined with other traditionalDMARDs, is inadequate (27, 28).All current biologic DMARDsconsist of antibodies that targetimportant inflammatory or im-mune pathways that are adminis-tered either by infusion or subcu-taneous injection. Developmentand use of biologic DMARDshave helped to revolutionize thetreatment of RA over the past 2decades.

The U.S. Food and Drug Admin-istration has approved 10 bio-logic DMARDs for RA treatment(Appendix Table 3), and theyhave 5 separate mechanisms ofaction. Infliximab, etanercept,adalimumab, golimumab, andcertolizumab pegol are mono-clonal antibody- or receptor-antagonist therapies that inhibit

tumor necrosis factor (TNF)-�.Additional inflammatory or im-mune pathways targeted by bio-logical agents that are effective inRA include the T-cell receptorCTLA4 (abatacept), the B-cellmarker CD20 (rituximab),interleukin-6 receptor (tocili-zumab and sarilumab), andinterleukin-1 receptor (anakinra).There may be subtle differencesin efficacy between the classes ofbiologic DMARDs, and individualresponses vary considerably.Currently, patients with RA oftenwill initiate a TNF-� inhibitor asthe initial biologic DMARD afterinadequate response to metho-trexate, unless contraindicated(e.g., heart failure). BiologicDMARDs should not be com-bined but are often paired withtraditional DMARDs, particularlymethotrexate, because they mayenhance efficacy and reduce therate of development of antidrugantibodies.

The choice of specific biologicDMARD should be made to-gether with the patient, withconsideration of personal prefer-ences regarding the route of ad-ministration (intravenous infusionvs. self-injection at home), fre-quency of administration, andfinancial and other individual fac-tors (such as adherence, otherorgan dysfunction, previous can-cer, and family history). Predict-ing which patients will respond toa biologic DMARD with a specificmechanism of action is an activearea of investigation for person-alized medicine in RA.

All biologic DMARDs affect im-mune function and increase riskfor infection, both common (suchas pneumonia, cellulitis, and uri-nary tract infection) and uncom-mon (such as tuberculosis andfungal infection). BiologicDMARDs should be used withcaution in patients with strongrisk factors for, or a history of,serious infection. They should be

� 2019 American College of Physicians ITC12 Annals of Internal Medicine 1 January 2019

withheld in the presence of ac-tive, serious infection. Screeningfor tuberculosis and viral hepati-tis is mandatory for all patientsbefore drug initiation. Patientsshould be vaccinated for influ-enza and pneumococcus, andherpes zoster unless contraindi-cated. Vaccination against her-pes zoster should be considered,but the live attenuated herpeszoster vaccine should not begiven after biologic DMARD initi-ation. Injection or infusion reac-tions are the most common sideeffects but are usually mild. Effi-cacy of biologic DMARDs may bereduced if antidrug antibodiesdevelop. Rarely, drug-inducedlupus or other immune side ef-fects can occur in patients receiv-ing these drugs.

In a nationwide observational study in Swe-den, 467 patients with RA who initiateda TNF-� inhibitor after a cancer diagnosis werematched to 2164 control patients with similarcancer history (48). Overall, there was no dif-ference in cancer recurrence in patients treatedwith the TNF-� inhibitor. These results providefurther evidence of the favorable long-termsafety profile of biologic DMARDs, even in pa-tients with a history of cancer.

What are biosimilars, and whatis their role in treatment?Biosimilars are molecules thathave a tight structural relation toanother biologic DMARD with anapproved indication, termed the“originator molecule.” Becausebiologic DMARDs are complexproteins, it is nearly impossible tocompletely replicate the origina-tor molecule in the same way thatgeneric drugs are molecular rep-licates of branded drugs. Beforeapproval, it must be proven thata biosimilar has no clinicallymeaningful difference in safety orefficacy compared with the origi-nator molecule (49). Biosimilarshave a 4-letter suffix appendedto the originator molecule name(e.g., etanercept-szzs). Six bio-similars are currently approvedfor use for RA in the UnitedStates, all to TNF-� inhibitors

(50). Research is ongoing regard-ing safety, efficacy, and immuno-genicity of biosimilars. The roleof these drugs for treatment ofRA in the United States is rapidlyevolving.

What are small molecule–targeted DMARDs, and what istheir role in treatment?Small molecule–targetedDMARDs are oral drugs that haveeffects similar to those of bio-logic DMARDs. In the UnitedStates, 2 of these drugs (tofac-itinib and baracitinib) are cur-rently approved for use in RA.Both drugs are inhibitors of januskinase (JAK), which are intracellu-lar molecules involved in signaltransduction of JAK/STAT path-ways. Inhibition of JAK thereforehas targeted downstream bio-logic consequences to modulateimmune cells and inflammation.These JAK inhibitors are gener-ally well tolerated, but side ef-fects may include serious infec-tion, kidney injury, anemia, liverfunction abnormalities, andthrombosis. Small molecule–targeted DMARDs are typicallyused for patients in whom otherbiologic DMARDs have failed orthose who cannot receive infu-sions or injections but research isongoing on whether to considertreating RA patients with smallmolecule–targeted DMARDs ear-lier in the disease course. They canbe used as monotherapy or com-bined with traditional DMARDs(51) but cannot be combined withbiologic DMARDs.

What is the role of NSAIDs?In patients with RA, NSAIDs areused primarily for controllingpain and stiffness. They are notbelieved to have disease-modifying properties, but areused by nearly half of patientswith RA, sometimes regularly butmore often on an as-needed ba-sis given their ability to providequick relief. They are particularlyhelpful in patients with mechani-

cal pain due to joint damagewithout active inflammation.These agents have well-knownlong-term cardiovascular, renal,and gastrointestinal risks, butthey remain useful for symptomcontrol (52).

When should cliniciansconsider using low-doseoral or intra-articularglucocorticoids?Glucocorticoids are generallybelieved to be most useful incontrolling the pain, stiffness,and swelling of RA but are lessuseful in halting disease pro-gression. They have many well-documented adverse effects,including infection, hyperglyce-mia, hypertension, osteoporosis,weight gain, mood instability,and sleep disturbance. Gluco-corticoids are most often used inRA for “bridging” therapy at di-agnosis or episodes of high dis-ease activity (typically 15 mg orless of prednisone per day)while DMARDs are being initi-ated. In some patients, glucocor-ticoids are the only agents thatcan control the inflammation ofRA; in such cases, DMARDs areused as steroid-sparing therapy.The goal should be to weancompletely off glucocorticoidsor use the lowest dose possible.However, low doses of predni-sone (≤5 mg/day) may offer effi-cacy and likely have a reducedrisk for side effects (53).

Intra-articular glucocorticoid in-jections may be a valuable ad-junct in patients with persistentor recurrent joint arthritis de-spite DMARD treatment. Injec-tions may lead to rapid symptomrelief, are well tolerated, and areconsidered generally safe if nomore than 3–4 injections perjoint are administered annually(54). Intra-articular glucocorti-coids are used primarily when 1or more medium or large jointsare swollen or excessively tendercompared with most other


joints. Ultrasonography, fluoros-copy, or computed tomographyimaging may be helpful in guid-ing needle placement for somejoints.

When should cliniciansconsider consultation with arheumatologist or orthopedistfor management?Optimal management of RA re-quires sufficient experience inassessment of disease activity,and the choice of DMARDsusually requires ongoing man-agement by a rheumatologist,particularly with the growing listof options. However, patients inunderserved areas who do nothave access to a rheumatologistwill require care from primarycare providers. Some patientswith early inflammatory arthritisof the knee or shoulder may beevaluated by an orthopedic sur-geon for possible synovectomyor osteotomy to aid in symptomrelief and rule out other diagno-ses, although these proceduresare being performed less fre-quently. Patients with extensivejoint damage or comorbid os-teoarthritis should be referred toan experienced orthopedic sur-geon for consideration of a totaljoint replacement procedureafter a sufficient DMARD trial.

What is the role of physicaland occupational therapy?Although some health profes-sionals cautioned against exer-cise for patients with RA in thepast, an appropriately designedprogram is now generally con-sidered beneficial. Physical andoccupational therapists may op-timize functional capacity in pa-tients whose RA limits perfor-mance of activities of daily living.Physical therapists may help im-plement a long-term exerciseprogram, focused on both aero-bic capacity and musclestrength. Occupational thera-pists can also assist patients withwork-related activities, using a

computer, such as homemakingactivities as cooking and cleaningand many other domains. Splintsmay be helpful to certainpatients.

In a randomized trial of patients with early RA,an exercise program directed at aerobic fitnessand muscle strength increased strength andimproved overall disease activity assessmentat 2 years, and these benefits were maintainedover the next 3 years (55). There was no evi-dence of joint or bone damage because of themoderately intense exercise regimen, indicat-ing its safety in patients with RA.

What is the role of other healthprofessionals?Nurses, pharmacists, nutritionists,physical and occupational thera-pists, podiatrists, social workers,and psychologists can each helpto address the needs of patientswith RA. Nurse practitioners andphysician assistants are increas-ingly being used in rheumatol-ogy practices (56). Nurse-educators can increase patients'knowledge about their diseaseand its treatments, which im-proves outcomes (57). Pharma-cists may help patients under-stand complex medicationregimens, particularly biologicDMARDs, which invoke anxietyfor some patients and their fami-lies. Patients with RA frequentlyface difficult vocational and inter-personal issues, for which socialworkers may be invaluable. Nutri-tionists are useful in providingadvice on dietary intake sinceobesity can affect RA outcomes(58).

Does evidence support specificdietary recommendations,vitamin supplements, orcomplementary–alternativetherapies?Although some patients reportdiet as an important factor in im-proving or worsening their clini-cal status, there is no strong evi-dence indicating that vitaminsupplements or complementary–alternative therapies benefit allpatients with RA (59). A random-

ized clinical trial suggested somebenefit of fish oil in patients withearly disease (60). Patientsshould be encouraged to loseweight if necessary and to main-tain or enhance physical fitnessonly as adjuncts to treatment withDMARDs (61).

What are the long-term clinicalconsequences and commoncomorbid conditions?In most patients, RA is a chronic,progressive disease character-ized by episodes of disease flaresor long-term chronic inflamma-tion. Only a few patients achievelong-term remission without theneed for long-term medications.Patients with RA may be morelikely to develop depression,anxiety, and social deprivation,perhaps related to chronic pain,poor sleep, and absenteeismfrom work or school. Therefore,patients with RA have diminishedhealth-related quality of life com-pared with the general popula-tion and this is most pronouncedin patients with low socioeco-nomic status (62).

Patients with RA are at increasedrisk for serious comorbid condi-tions, particularly severe infec-tion, osteoporosis, cardiovascularand respiratory disease, and can-cer (63–67). This excess risk iscomplex and probably related toautoimmunity, immunosuppres-sion, chronic inflammation, smok-ing, obesity, and poor functionalstatus. For example, risk for coro-nary artery disease and stroke isincreased for patients with RAcompared with healthy controlsin the general population. Thiselevated risk is not explained bytraditional cardiovascular risk fac-tors, suggesting that RA-specificfactors, such as systemic inflam-mation, autoantibodies, andmedications, are important con-tributors to the excess risk. Pa-tients with RA may also haveexcess cancer risk related to dys-functional immune surveillance

� 2019 American College of Physicians ITC14 Annals of Internal Medicine 1 January 2019

or from medication side effects.Serious infections related toDMARD side effects, as well asdisease-induced anatomicaldamage (bronchiectasis increas-ing risk for pneumonia and boneerosions increasing risk for septicarthritis), are a major contributorto excess RA morbidity, acceler-ated aging, and frailty. Osteopo-rosis and increased fracture riskin RA may be related to glucocor-ticoid use, systemic inflammation,frailty, and impaired bone qual-ity. Patients with seropositive RAare particularly at increased riskfor these comorbidities—espe-cially excess respiratory mortality,which is likely related to ILD as anRA-related disease manifestationand accumulation of other types

of lung damage related to inflam-mation and deconditioning (68).Patients with seropositive RA whodevelop ILD have median sur-vival of only 2.6 years (69). All-cause mortality is 50% higher inpatients with RA than in the gen-

eral population (69). However,this mortality gap seems to beclosing (2, 4), perhaps becauseof early aggressive treatment,expanded therapeutic options,and long-term control of chronicinflammation.

In the Clinic

Tool KitRheumatoid

Arthritis

Patient Informationwww.rheumatology.org/I-Am-A/Patient-Caregiver

/Diseases-Conditions/Rheumatoid-Arthritiswww.rheumatology.org/I-Am-A/Patient-Caregiver

/Enfermedades-y-Condiciones/Artritis-ReumatoideInformation for patients and caregivers on rheumatoid

arthritis in English and Spanish from the American Col-lege of Rheumatology.

www.niams.nih.gov/health-topics/rheumatoid-arthritis

www.niams.nih.gov/es/informacion-de-salud/artritis-reumatoide

Patient handout on rheumatoid arthritis and questionsand answers on arthritis and rheumatic diseases in Eng-lish and Spanish from the National Institute of Arthritisand Musculoskeletal and Skin Diseases.

Clinical Guidelineswww.rheumatology.org/Portals/0/Files

/ACR%202015%20RA%20Guideline.pdf2015 American College of Rheumatology Guideline for the

Treatment of Rheumatoid Arthritis.

www.nice.org.uk/guidance/ng100Guidelines from the National Institute for Health and

Clinical Excellence on management of rheumatoidarthritis in adults.

Inthe

Clinic

Treatment... The goal of RA treatment is to achieve remission as as-sessed by a disease activity measure. Treatment with DMARDs shouldstart early, because a delay results in worsened outcomes. Weekly low-dose methotrexate (10-25 mg/week) should be initiated in most pa-tients at the time of diagnosis. If the response is inadequate after 3–4months, hydroxychloroquine, sulfasalazine, or a biologic DMARDshould be substituted or added. Low-dose corticosteroids (≤5 mg pred-nisone/day) may also be appropriate, although long-term side effectsmake higher doses undesirable. Nonsteroidal anti-inflammatory drugsare used as needed to control pain and other symptoms. Regular exer-cise is usually safe and may improve disease and overall health status.

CLINICAL BOTTOM LINE


http://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Rheumatoid-Arthritishttp://www.rheumatology.org/I-Am-A/Patient-Caregiver/Diseases-Conditions/Rheumatoid-Arthritishttp://www.rheumatology.org/I-Am-A/Patient-Caregiver/Enfermedades-y-Condiciones/Artritis-Reumatoidehttp://www.rheumatology.org/I-Am-A/Patient-Caregiver/Enfermedades-y-Condiciones/Artritis-Reumatoidehttp://www.niams.nih.gov/health-topics/rheumatoid-arthritishttp://www.niams.nih.gov/health-topics/rheumatoid-arthritishttp://www.niams.nih.gov/es/informacion-de-salud/artritis-reumatoidehttp://www.niams.nih.gov/es/informacion-de-salud/artritis-reumatoidehttp://www.rheumatology.org/Portals/0/Files/ACR%202015%20RA%20Guideline.pdfhttp://www.rheumatology.org/Portals/0/Files/ACR%202015%20RA%20Guideline.pdfhttp://www.nice.org.uk/guidance/ng100

WHAT YOU SHOULD KNOWABOUT RHEUMATOIDARTHRITIS

What is Rheumatoid Arthritis?Rheumatoid arthritis (RA) happens when your

body's defense system—the immune system—attacks your joints and causes them to becomepainful and swollen. Joints are where 2 or morebones join together, such as at your hands,wrists, feet, or knees. RA usually causes inflamedjoints on both sides of your body.

Am I at Risk?RA is more common in women than in men. It may

occur at any age, but is most common in olderadults. Other risk factors include:

• Having a family member with RA• Cigarette smoking• Being overweight• Unhealthy diet• Poor dental health

What Are the Symptoms?• Joint pain or stiffness on both sides of your body,

especially in the hands, wrists, feet, or knees• Joint pain or stiffness lasting more than a few

weeks• Stiffness or pain that is worse in the morning,

lasts for more than 1 hour, and improvesduring the day

• Feeling tired and unwell

How Is It Diagnosed?• Your health care provider will ask you questions

about your symptoms and medical history.• You will have a physical examination.• You will have simple blood tests.• You might also get an imaging test, like an

X-ray or ultrasound.• You might be referred to a rheumatologist.

This is a doctor who specializes in diseases ofthe joints, muscles, and bones.

How Is It treated?Early diagnosis and treatment are important to

stopping joint pain and preventing long-termdamage to your joints.

• There are several medicines available that cankeep your RA from getting worse and helpyou with your symptoms. Talk to your healthcare provider about which one is best for you.

• Your provider might also talk to you aboutphysical or occupational therapy. Occupationaltherapy may help you work and do dailyactivities.

• Exercise is safe and may help you feel better.• If you smoke, ask your health care provider to

help you quit.

Questions for My Doctor• If I have swollen joints, does that mean that I

have RA?• How will my symptoms change over time?• What medicines are best for me?• What are the side effects of the medicines?• Will other medicines interact with my RA

medicines?• What exercise is safe for me to do?• Should I see a physical or occupational

therapist?• Do I need to see any other doctors?

For More InformationMedline Plushttps://medlineplus.gov/rheumatoidarthritis.html

National Institute of Arthritis and Musculoskeletaland Skin Diseases

www.niams.nih.gov/health-topics/rheumatoid-arthritis

In the ClinicAnnals of Internal Medicine

Patie

ntIn

form

atio

n

1 January 2019 Annals of Internal Medicine � 2019 American College of Physicians

https://medlineplus.gov/rheumatoidarthritis.htmlhttp://www.niams.nih.gov/health-topics/rheumatoid-arthritis

Appendix Figure 1. Early rheumatoid arthritis of the hands, with swelling in the third and fourth proximalinterphalangeal joints.

Reproduced with permission from Medical Knowledge Self-Assessment Program 18. Rheumatology. Philadelphia: American College of Physicians;2018.

Annals of Internal Medicine • Vol. 170 No. 1 • 1 January 2019 Annals.org


Appendix Table 1. Differential Diagnosis of Rheumatoid Arthritis

Disease History Physical Examination Comments

Self-limited polyarthritis Symmetrical polyarthritis, pain,morning stiffness, fatigue

Symmetrical joint swelling and tenderness 40%–60% of patients withacute polyarthritis have aself-limited process (such asa postviral syndrome);usually resolves within 8weeks

Fibromyalgia Widespread musculoskeletalpain, fatigue, poor sleep

Tenderness of articular and nonarticularanatomic sites; no swelling

Much more common than RA(5% of women aged 40–60years); 20%–30% of patientswith RA may also havefibromyalgia

Erosive handosteoarthritis

Oligoarthritis, often symmetric Bony enlargement and tenderness ofdistal interphalangeal (Heberden'snodes) and/or proximalinterphalangeal joints (Bouchard'snodes). Metacarpophalangeal jointstypically spared

Hands may have severedeformities, but functionrelatively preservedcompared to RA; distalinterphalangeal jointsprominently involved unlikeRA; metacarpophalangealjoints typically spared unlikeRA; first carpometacarpaljoint often affected

Ankylosing spondylitis Primarily axial skeletoninvolvement, back and neckpain

Limited motion of cervical and lumbarspine, hips, shoulders, knees, limitedchest expansion

Involves primarily axialskeleton and large ratherthan small joints

Psoriatic arthritis Usually history of psoriasis, butarthritis may precedepsoriasis

May be mono-, oligo-, or polyarthritisinvolving the peripheral or axial joints.Psoriatic patches on skin includingscalp or gluteal fold

May mimic RA or ankylosingspondylitis; more likely tohave distal interphalangealjoint involvement anddactylitis than RA

Reactive arthritis Axial or peripheral inflammatoryarthritis, typically after viral orbacterial gastrointestinal orurinary tract infection

May be mono-, oligo-, or polyarthritisinvolving the peripheral or axial joints

May mimic RA or ankylosingspondylitis

Polymyalgia rheumatica Acute or subacute onset of painand stiffness in the neck,shoulders, and hip in patient>50 years of age

Impaired rotation of the neck, shoulders,and hips. Sometimes with

Rarely has distal jointinvolvement in the remittingseronegative symmetricalsynovitis with pitting edema(RS3PE) syndrome

Other systemic rheumaticdiseases (systemiclupus erythematosus,adult-onset Still'sdisease, juvenileidiopathic arthritis,scleroderma,polymyositis, acuterheumatic fever,systemicvasculitis-related, Lymedisease, inflammatorybowel disease-related,other rare syndromes)

May include symmetricalpolyarthritis, pain, morningstiffness, fatigue

May include symmetrical joint swellingand tenderness of the axial orperipheral joints

Seek rheumatologyconsultation for accuratediagnosis if unclear cause

Septic arthritis History of trauma or knowninfection or gonococcalexposure may be seen

Usually monoarticular, rarely involves >1joints. Swollen red and warm joint,fever

Emergent joint aspiration toconfirm diagnosis if suspectto prevent septicemia andjoint destruction. Morecommon in patients with RAthan in general population

Gout Usually acute attacks, but maybe insidious and chronic

Tophi. Swollen, red joints. Mono- oroligoarticular

Should document crystals foraccurate diagnosis

Calcium pyrophosphatedeposition,pseudogout, andhydroxyapatite crystalarthritis

Usually acute attacks, but maybe insidious and chronic

Swollen, red joints. Mono- oroligoarticular

Should document crystals foraccurate diagnosis

Cancer-related Variable presentation Swollen joints Some cancers may haveparaneoplasticphenomenon causinginflammatory arthritis;immune-related adverseevents from immunotherapysuch as checkpointinhibitors may causeinflammatory arthritis

RA = rheumatoid arthritis.

Annals.org Annals of Internal Medicine • Vol. 170 No. 1 • 1 January 2019


Appendix Table 2. Tests for Patients With Signs and Symptoms Suggestive of Rheumatoid Arthritis

Test Comments

Laboratory

Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) Useful to detect systemic inflammation and establish a baseline,but nonspecific and may be normal in patients with RA;component of 2010 ACR/EULAR criteria for RA

Rheumatoid factor (RF) Present in 50%–65% of patients with RA; may be present in otherconditions (primary or secondary Sjögren's syndrome,systemic lupus erythematosus, aging, infections); componentof 1987 ACR and 2010 ACR/EULAR criteria for RA

Anticyclic citrullinated protein (anti-CCP) or anticitrullinated proteinantibodies (ACPA)

Present in about 60%–70% of patients with RA, specific for RAbut sometimes present without disease, in other systemicrheumatic diseases, in autoimmune lung diseases or inindividuals at-risk for future RA; component of 2010ACR/EULAR criteria for RA

Antinuclear antibody (ANA) Nonspecific finding and may be negative in patients with RA

Extractable nuclear antibodies (ENAs) and anti–double-stranded DNA(anti-dsDNA)

Useful in making alternate or overlap diagnoses such as systemiclupus erythematosus or primary Sjögren's syndrome; mayaide in diagnosis of secondary Sjögren's syndrome in patientswith RA

Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody (HBsAb),and Hepatitis core antibody (HBcAb)

Screen for hepatitis B infection which may prompt treatment andaffect DMARD choice for RA; consider vaccination for patientswithout immunity

Hepatitis C antibody Screen for hepatitis C infection which may prompt treatment andaffect DMARD choice for RA

Basic metabolic panel including creatinine Evaluate electrolytes and renal function to establish a baselineand may affect DMARD choice for RA

Liver function testing including AST (aspartate transaminase) and ALT(alanine transaminase)

Evaluate liver function to establish a baseline and may affectDMARD choice for RA

Complete blood count (CBC) with differential Establish a baseline and screen for hematologic diseasemanifestations or disease mimickers

Creatine kinase (CK) Screen for myositis and establish a baseline

Thyroid stimulating hormone (TSH) Screen for autoimmune thyroid disease as a disease mimickerand as a common comorbidity in patients with RA

Screening for tuberculosis with interferon-� release assays (IGRAs) orpurified protein derivative (PPD) placement

Screen for latent tuberculosis which may prompt treatment andaffect DMARD choice for RA

Commercial multi-biomarker disease activity assay Consider if using to monitor RA disease activity to establish abaseline; controversial utility in both diagnosis andmonitoring disease activity

Lipid panel and hemoglobin A1c (HbA1c) Consider screening for dyslipidemia and diabetes mellitus inpatients with RA

14-3-3 � (14-3-3 eta) May aide in diagnosing RA in patients with negative RF andCCP; controversial utility

Synovial fluid studies (cell count/differential, crystals, Gram stain, culture) Consider as clinically indicated for patients with atypicalpresentation such as monoarthritis or oligoarthritis involvingmedium/large joints with moderate/large effusions

Other laboratory testing (interleukin-6, serum protein electrophoresis andimmunofixation, angiotensin converting enzyme, 25(OH)vitamin D,other vitamins, ionized calcium, uric acid, parathyroid hormone, otherhormones, HLA-B27, other genetics, HIV antibody, parvovirus B19antibody, Lyme antibody, other infection screens, otherautoantibodies, etc.)

Consider as clinically indicated for some patients and atypicalpresentations

Imaging

Musculoskeletal plain film imaging (hands, wrists, feet, other affectedjoints)

Evaluate for RA-related damage, establish a baseline, anddisease mimickers; consider imaging hands, wrists, and feeteven without signs or symptoms

Musculoskeletal ultrasound of affected or unaffected joints Detect and quantify subclinical or clinical synovitis, establishbaseline, and detect alternate diagnosis; may aide in jointaspirations/injections; many rheumatologists are now trainedin point-of-care ultrasound and may be used to monitordisease activity

Magnetic resonance imaging of affected joint Detect and quantify subclinical or clinical synovitis, establishbaseline, and detect alternate diagnosis; useful for detectingsubtle synovitis and soft tissue involvement

Computed tomography scan of affected joint Detect and quantify bone erosions, establish baseline, anddetect alternate diagnosis; useful for detecting bone erosions

Chest plain film Establish a baseline prior to DMARD treatment; screen forpulmonary manifestations such as interstitial lung disease,pleural effusions, nodules, or bronchiectasis; screen for otherdiseases such as cancer and pulmonary infections such astuberculosis

Other imaging (positron emission tomography, bone scan, dual-energyX-ray absorptiometry, musculoskeletal dual-energy computedtomography scan, chest/abdomen/cervical spine computedtomography scan, abdominal ultrasound, transthoracicechocardiogram, etc.)

Consider as clinically indicated for some patients and atypicalpresentations

DMARD = disease-modifying antirheumatic drug; RA = rheumatoid arthritis.



Appendix Figure 2. Radiograph of rheumatoid arthritis of the hands.

Periarticular osteopenia is present at the metacarpophalangeal joints. Marginal erosions are present at the second proximal interphalangeal andmetacarpophalangeal joints, as well as the ulnar styloid. Both are characteristic of rheumatoid arthritis and findings that can aid in diagnosis.Joint-space narrowing (a nonspecific finding) is seen at the second and fifth proximal interphalangeal joints. Reproduced with permission fromMedical Knowledge Self-Assessment Program 17. Rheumatology. Philadelphia: American College of Physicians; 2015.

Annals.org Annals of Internal Medicine • Vol. 170 No. 1 • 1 January 2019


Appendix Table 3. Drugs for Treatment of Rheumatoid Arthritis

Agent Mechanism of Action Dose Notes and Side Effects

Commonly used traditionalDMARDs

Methotrexate Anti-inflammatory in weekly lowdoses

PO 5–25 mg/weekSC injection 5–25 mg/week

Initial therapy and backbone for moderate/severeRA, used by >80% of patients. Highesteffectiveness, fewest adverse events, besttolerated over 5 years. Combination use withbiologic DMARDs enhances efficacy and lowersrisk for anti-drug antibody formation. Alwaysadminister with either folic acid (1 mg/day orhigher doses) or leucovorin (8–12 hours after.Caution in liver disease, contraindicated inpregnancy. Rarely may cause pneumonitis orpulmonary fibrosis (consider CXR before starting).Monitor CBC, BMP, LFTs monthly for first 2–3months, then every 8–24 weeks.

Hydroxychloroquine Antimalarial, immunomodulator PO 200–400 mg/day(maximum dose of 5mg/kg/day)

Consider as initial therapy for mild RA. May be usefulin combination with methotrexate and otherDMARDs. Consider testing for G6PD deficiency.May be safe in pregnancy. Ophthalmologicexamination yearly to screen for rare retinaltoxicity (risk occurs after 5 years on drug). Minimalneed for blood test monitoring.

Sulfasalazine Anti-inflammatory salicylate andsulfa moieties

PO 2–3 g/day in divideddoses

Alternative to methotrexate. May be used incombination with methotrexate andhydroxychloroquine as “triple therapy”. GIintolerance common at doses >2 g/d. MonitorCBC, BMP, and LFTs every 3 months.

Leflunomide Pyrimidine-synthesis inhibitor PO 100 mg/day PO for 3days, then 20 mg/day

Alternative to methotrexate. May be used as part oftriple therapy. Very long half-life, caution use inwomen of childbearing potential. Contraindicatedin pregnancy. GI intolerance, headache. MonitorCBC, BMP, and LFTs monthly for 3 months, thenevery 8–12 weeks.

Unusual or rarely usedtraditional DMARDs

Azathioprine Purine analog inhibiting purinesynthesis

PO 50–250 mg/day with food(typically 2 mg/kg/day)

Alternative to methotrexate. May be used as part oftriple therapy. Check thiopurine methyltransferase(TPMT) prior to initiation. May cause GI sideeffects and bone marrow suppression. Caution inpregnancy, liver disease, or kidney disease andwith concomitant use of allopurinol. Monitor CBC,BMP, and LFTs at 1 and 2 weeks after dosechange, then every 1–3 months.

Mycophenolate mofetil Inhibits guanosine nucleotidesynthesis

PO 0.5–3 g/day divided in1–2 doses

Not FDA approved for RA. Side effects includecolitis, diarrhea, nausea, and vomiting. Consideruse in interstitial lung disease. Monitor CBC every8–12 weeks.

Cyclosporine Inhibition of T-cell activation byIL-2

PO 2.5–5 mg/kg/day Limited by nephrotoxicity, may be useful for flaresand recalcitrant cases. Avoid long-term use.Monitor serum creatinine and blood pressure 2–4weeks until stable dose, then monthly. MonitorCBC, BMP, LFTs, and blood pressure monthly.

Minocycline Matrix metalloproteinaseinhibitor

PO 100 mg twice daily Not FDA approved for RA. Slow onset. Side effectsinclude rash, hepatitis, hyperpigmentation,dizziness, headache, GI distress, vaginal candidainfections, photosensitivity.

Penicillamine Chelator of sulfhydryl groupsinhibiting T-cells

PO 250–1000 mg/day in 3doses

Not FDA approved for RA. Slow onset. Side effectsinclude bone marrow suppression, anorexia,diarrhea, rash fever, stomatitis, dysgeusia,proteinuria. Monitor CBC, chemistry, urinalysisevery 2–4 weeks until stable, then every 1–3months.

Cyclophosphamide Alkylating agent disrupting cellcycle

PO 2 mg/kg dailyIV infusion 1000 mg monthly

Not FDA approved for RA. Use only inlife-threatening rheumatoid vasculitis or in otherserious manifestations such as interstitial lungdisease. Side effects include bone marrow andgonadal suppression, alopecia, hemorrhagiccystitis, infection, long-term risk for bladder andhematologic cancer. Generally contraindicated inpregnancy. Monitor CBC every 1–2 weeks untilstable, then every 1–3 month. Monitor chemistryand urinalysis every 6–12 weeks.

Gold thiomalate,aurothioglucose,auranofin

Decreases cellular proliferation,reduce cytokine release, andinhibit collagenase

IM injection 10 mg week 0,then increase to 25–50mg/week

PO 3–9 mg/day

Slow onset. Infrequently used because of otheroptions and bone marrow suppression, stomatitis,photosensitivity, proteinuria. Monitor CBC,platelet count, and urinalysis for protein every 1–2week for 20 weeks, then monthly or at time ofinjection.

Biologic anti-TNF DMARDs

Infliximab (Remicade)Biosimilars*:Infliximab-dyyb (Inflectra)Infliximab-qbtx (Ixifi)Infliximab-abda (Renflexis)

Chimeric mouse-monoclonalantibody to TNF-�

IV infusion 3–10 mg/kg atweek 0, 2, and 6, thenevery 4–8 weeks

Side effects include upper respiratory tract infection,urinary tract infections. Increased risk foropportunistic infections. Lymphoproliferativediseases, worsening or new-onset heart failure,anaphylaxis or serious allergic reactions,demyelinating disease, local injection-sitereactions. Perform permanent partial disabilitybefore starting. Use caution in infection. Efficacyincreased when used with concomitantmethotrexate. Live vaccines are contraindicated.Caution in heart failure.

Continued on following page



Appendix Table 3—Continued

Agent Mechanism of Action Dose Notes and Side Effects

Etanercept (Enbrel)Biosimilar:Etanercept-szzs (Erelzi)

Anti-TNF-�–receptor protein SC injection 50 mg everyweek or 25 mg twice perweek

IntheClinic Rheumatoid Arthritis · IntheClinic® Rheumatoid Arthritis RiskFactors Diagnosis...

Documents

Transcript of IntheClinic Rheumatoid Arthritis · IntheClinic® Rheumatoid Arthritis RiskFactors Diagnosis...