Rheumatoid Arthritis Diagnosis and Management for Family Physicians PDF
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University of Iowa
2024
Emily Peterson, Mary K. Gallagher, Jason Wilbur
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This article discusses rheumatoid arthritis (RA), a chronic inflammatory autoimmune disease. It covers diagnosis, management, and treatment approaches for family physicians, including a clinical prediction rule for undifferentiated arthritis. The article highlights the importance of early diagnosis and treatment to prevent joint destruction.
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This is a corrected version of the article that appeared in print. CME Rheumatoid Arthritis:Diagnosis and Management for the Family Physician Emily Peterson,...
This is a corrected version of the article that appeared in print. CME Rheumatoid Arthritis:Diagnosis and Management for the Family Physician Emily Peterson, PharmD, BCACP;Mary K. Gallagher, MD;and Jason Wilbur, MD Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that causes joint inflammation, erosion, and deformity. The prevalence of RA in North America is 0.5% to 1%. RA is associated with significant morbidity and disabil- ity and an increased mortality rate. The disease should be suspected in patients who present with joint inflammation, especially those who have polyarthritis. Additional characteristic features include symmetrical small joint polyarthritis, morning stiffness, and constitutional symptoms. Extra-articular manifestations are common and may affect multiple body systems. Application of a decision tool, such as the Leiden clinical prediction rule for undifferentiated arthritis, may facilitate early diagnosis of RA. Useful diagnostic tests include inflammatory markers such as C-reactive protein, rheumatoid factor, and anti-cyclic citrullinated peptide antibody. Initial therapy routinely includes oral methotrex- ate. The American College of Rheumatology and European Alliance of Associations for Rheumatology recommend a treat-to-target approach, including rapid interventions to reduce disease activity and achieve remission. Although RA remains incurable, patient quality of life has improved dramatically with biologic disease-modifying antirheumatic drugs (DMARDs) and targeted synthetic DMARDs. All DMARDs increase the risk of infection;therefore, routine vaccinations should be up to date in patients taking these drugs. Because patients with RA have increased risk of cardiovascular dis- ease, addressing other cardiovascular risk factors may reduce morbidity and mortality. Am Fam Physician. 2024;110(5):515-526. Copyright © 2024 American Academy of Family Physicians. R heumatoid arthritis (RA) is a chronic inflammatory auto- immune disease characterized by polyarthritis and a range of extra-articular manifestations. Effective treatments may The pathogenesis of joint and systemic inflammation in RA is poorly understood. In the preclinical phase of RA, autoanti- bodies are produced in response to genetic and environmental reduce the significant morbidity and mortality associated with triggers.2 The more recent identification of relevant inflam- RA.1 Because outcomes improve with early identification and matory cytokines, growth factors, and intracellular signaling treatment, primarily through prevention of joint destruction, molecules has enabled the development of advanced targeted RA should be considered in all patients who have clinical syno- therapies. These mediators drive an autoimmune response to vitis.2 Although rheumatologists provide advanced treatment, citrulline-containing endogenous proteins, resulting in syno- family physicians play an important role in high-quality care vitis, joint pain, erosions, and deformities.5 Inflammatory for patients with this complex disease. pathways affect multiple organ systems, increasing the risk of chronic conditions, such as myocardial infarction, stroke, and EPIDEMIOLOGY AND PATHOPHYSIOLOGY lymphoma.2 RA affects an estimated 0.24% of the global population and 0.5% to 1% of the North American population, with significant EMILY PETERSON, PharmD, BCACP, is a clinical phar- geographic variation.1,3 Development of the disease is multi- macy specialist in family medicine at the University of factorial. Well-established risk factors include genetics, female Iowa Hospitals and Clinics, Iowa City. sex, and increasing age. Middle-aged and older adults are at higher risk, with incidence increasing after age 40 and decreas- MARY K. GALLAGHER, MD, is a clinical assistant profes- ing after age 80, with peak age at diagnosis varying among sor in the Department of Family Medicine at the Univer- studies. Lifestyle factors, especially eating a diet rich in fish and sity of Iowa Hospitals and Clinics. avoiding cigarette smoking, may be protective.3 Smoking has JASON WILBUR, MD, is a clinical professor in the been associated with worse clinical outcomes, including more Department of Family Medicine at the University of Iowa significant joint disease and increased occurrence of rheumatoid Carver College of Medicine, Iowa City. nodules, vasculitis, and pulmonary fibrosis.4 Author disclosure:No relevant financial relationships. Additional content is available with the online version of Address correspondence to Emily Peterson, PharmD, this article. BCACP, at emily-a-peterson@uiowa.edu. 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TABLE 1 Clinical Rule for Predicting the Risk of RA in Patients With Undifferentiated Arthritis Patient characteristic Points Patient characteristic Points Age Years × 0.02 Laboratory findings Female sex 1 C-reactive protein level 5-50 mg/L 0.5 (50-500 mg/dL) [corrected] Distribution of involved joints (patient may receive C-reactive protein level > 51 mg/L 1.5 points for more than one) (500 mg/dL) [corrected] Small joints of the hands or feet 0.5 Rheumatoid factor test result positive 1.0 Symmetrical 0.5 Anti-cyclic citrullinated peptide anti- 2 Upper extremities 1 body test result positive Upper and lower extremities 1.5 Score for morning stiffness on a 100-mm visual No. with RA at analog scale Total points 1 year/total (%) 26 to 90 mm 1 4 risk groups > 90 mm 2 0 to 3.5 0/109 (0%) Number of tender joints > 3.5 to 6.5 41/258 (16%) 4 to 10 0.5 > 6.5 to 8.5 71/124 (57%) ≥ 11 1 > 8.5 63/74 (85%) Number of swollen joints 2 risk groups 4 to 10 0.5 0 to 6.5 41/367 (11%) ≥ 11 1 > 6.5 134/198 (68%) Note:A score > 6.5 should prompt referral to a rheumatologist. RA = rheumatoid arthritis. Adapted with permission from van der Helm-van Mil AH, le Cessie S, van Dongen H, et al. A prediction rule for disease outcome in patients with recent-onset undifferentiated arthritis. Arthritis Rheum. 2007;56(2):436, with additional information from reference 7. DIAGNOSIS patients with synovial inflammation. A risk score greater than Clinical Presentation 6.5 should prompt referral to a rheumatologist.6,7 Patients who have RA present with symmetrical polyarthritis, predominately of the small joints in the hands, that includes Diagnostic Criteria effusion, erythema, warmth, and marked morning stiffness. Table 2 presents the 2010 American College of Rheumatol- Patients may also have constitutional symptoms such as fever ogy (ACR)/European Alliance of Associations for Rheu- and weight loss. Because the presentation of RA is highly vari- matology (EULAR) classification criteria for rheumatoid able, a laboratory evaluation should be considered in patients arthritis8 (https://w ww.mdcalc.com/calc/10092/acr-eular-2010- with synovitis. Laboratory testing includes complete blood cell rheumatoid-arthritis-classification-criteria). The 2010 criteria count (CBC), comprehensive metabolic panel, C-reactive pro- tein, erythrocyte sedimentation rate, rheumatoid factor, and WHAT’S NEW ON THIS TOPIC anti-cyclic citrullinated peptide antibodies. The differential diagnosis of RA is broad and includes other Rheumatoid Arthritis rheumatologic diseases (eg, inflammatory bowel disease, reac- tive arthritis, systemic lupus erythematosus), infections (eg, In 2021, a US Food and Drug Administration boxed septic arthritis, parvovirus, Lyme disease), and osteoarthritis warning was added to Janus kinase inhibitors because or other musculoskeletal conditions. Physicians should con- of increased risk of major adverse cardiovascular events sider using the clinical prediction rule for undifferentiated and thrombosis, compared with tumor necrosis factor arthritis developed at the Leiden Early Arthritis Clinic in the inhibitors, in patients 50 years and older with one or more Netherlands (Table 16,7; https://w ww.mdcalc.com/calc/10023/ cardiovascular risk factors. leiden-clinical-prediction-rule-undifferentiated-arthritis) for 516 American Family Physician Volume 110, Number 5 November 2024 RHEUMATOID ARTHRITIS (erythrocyte sedimentation rate and C-reactive protein) in TABLE 2 the classification of RA. However, a high clinical suspicion for RA must be maintained for patients with clinical synovitis The 2010 ACR/EULAR Classification Criteria in the absence of autoantibodies because diagnosis of patients for Rheumatoid Arthritis with seronegative RA is more likely to be delayed.10 Using the Criterion Points ACR/EULAR classification criteria, a person may still score 6 points (definite RA) in the absence of autoantibodies or ele- Joint involvement* vated inflammatory markers.8 1 large joint 0 Although classification criteria are designed to identify clin- 2 to 10 large joints 1 ical trial participants, not to diagnose disease, elements of the ACR/EULAR criteria are useful guides in the clinical assess- 1 to 3 small joints (with or without 2 ment for possible RA. For example, a person may meet the involvement of large joints) classification criteria for RA but instead have osteoarthritis, or 4 to 10 small joints (with or without 3 a person may have RA but not meet the classification criteria involvement of large joints) at the time of evaluation. > 10 joints (at least one small joint) 5 EXTRA-ARTICULAR MANIFESTATIONS Serology (at least 1 test result is needed for classification) Extra-articular manifestations of RA are common and may Negative RF and negative ACPA 0 affect multiple organ systems (Table 311,12). Although not all Low-positive RF or low-positive ACPA 2 patients with RA develop extra-articular disease, it is more High-positive RF or high-positive ACPA 3 likely in smokers, males, and those with seropositive RA. Atten- tion to the increased risk of cardiovascular disease is important, Acute-phase reactants (at least 1 test result is needed as this is the most common cause of death in patients with RA. for classification) Good control of RA is associated with decreased risk of extra- Normal CRP and normal ESR 0 articular manifestations.11 Abnormal CRP or abnormal ESR 1 TREATMENT Duration of symptoms Treatment goals for RA are to reduce pain and inflammation, < 6 weeks 0 improve quality of life, maintain and maximize joint func- ≥ 6 weeks 1 tion, and prevent disease progression.13,14 Guidelines from Scoring:≥ 6 points = definite RA;< 6 points = likely not RA. the ACR and EULAR recommend a treat-to-target approach, ACPA = anti-cyclic citrullinated peptide antibody; ACR/EULAR = which includes rapid interventions to reduce disease activity American College of Rheumatology/European Alliance of Associa- and achieve remission.15-17 The Simple Disease Activity Index tions for Rheumatology; CRP = C-reactive protein;ESR = erythrocyte (https://w ww.mdcalc.com/calc/2194/simple-disease-activity- sedimentation rate;RA = rheumatoid arthritis; RF = rheumatoid factor. index-sdai-rheumatoid-arthritis) and Clinical Disease Activity *—Joint involvement is defined as any examination finding of syno- Index (https://w ww.mdcalc.com/calc/2177/clinical-disease- vitis (eg, swelling, tenderness) in a specific joint. Large joints are activity-index-cdai-rheumatoid-arthritis) may be used to quan- shoulders, elbows, hips, knees, and ankles. Small joints are in the wrist and hand (excluding first carpometacarpal, first metacarpo- tify disease severity and guide treatment decisions.18 phalangeal, and distal interphalangeal joints). Treatments that maintain joint function are classified as Adapted with permission from Aletaha D, Neogi T, Silman AJ, et al. conventional synthetic, biologic, or targeted synthetic disease- 2010 rheumatoid arthritis classification criteria: an American Col- modifying antirheumatic drugs (csDMARDs, bDMARDs, lege of Rheumatology/European League Against Rheumatism col- or tsDMARDs, respectively). These drugs are summarized laborative initiative. Arthritis Rheum. 2010;62(9):2574. in Table 4,19-24 eTable A, and eTable B. Nonsteroidal anti- inflammatory drugs and glucocorticoids were standard of care update the 1987 ACR criteria with the primary goal of increas- until the development of DMARDs. ing early identification of RA, given increasing evidence that csDMARDs include hydroxychloroquine, leflunomide, early treatment improves clinical outcomes.9 In a person who methotrexate, and sulfasalazine.15,16 bDMARDs are made from has clinical evidence of synovitis, RA is unlikely with a score living organisms or contain components of living organisms, of 5 or less and definite with a score of 6 or greater. and tsDMARDs are low-molecular-weight agents that can be A 2014 systematic review found that the ACR/EULAR cri- administered orally. Whereas bDMARDs target specific steps teria have an overall sensitivity of 0.82 (95% CI, 0.79-0.84) in the pathogenesis of the inflammatory response, tsDMARDs and specificity of 0.52 (95% CI, 0.49-0.54), corresponding target a specific molecular structure.14,25 Before the develop- to positive likelihood ratio of 1.8 and negative likelihood ment of bDMARDs, remission with csDMARDs was often ratio of 0.29.9 The 2010 criteria give more weight to the pres- not feasible. However, because of improved treatment strategies, ence of autoantibodies and elevated inflammatory markers more patients can achieve and maintain remission. November 2024 Volume 110, Number 5 American Family Physician 517 TABLE 3 Extra-Articular Manifestations of Rheumatoid Arthritis Manifestation Symptoms/signs Prognosis Treatment Cardiovascular Coronary artery disease,* Variable Most common cause of Aggressive management of myocardial infarction, death in people with rheu- risk factors for cardiovascu- cerebrovascular disease, matoid arthritis;leads to lar disease congestive heart failure significant morbidity Pericarditis/pericardial Pleuritic chest pain, dyspnea; May be recurrent;rela- Colchicine (Colcrys), effusions* pericardial friction rub on exercise tively low mortality rate NSAIDs, glucocorticoids, tolerance testing drainage of effusion if needed Myocarditis Chest pain, dyspnea, syncope, Risk of cardiogenic shock; Glucocorticoids and immu- palpitations;electrocardiogram high mortality rate nosuppressive therapies abnormalities Dermatologic or musculoskeletal Nonspecific skin lesions Atrophy, fragility, palmar ery- Chronic Supportive care thema, multiple nail abnormalities, ulcerations Neutrophilic Erythematous papules and Variable prognosis Corticosteroids dermatoses† plaques, Sweet syndrome (acute febrile neutrophilic dermatosis) Vasculitis* Digital/nail fold lesions, leg ulcers, Variable prognosis Glucocorticoids, urticaria, neuropathy cyclophosphamide Rheumatoid nodules* Firm, usually painless, subcutane- Generally benign Consider surgical removal if ous modules ≥ 5 mm in diameter symptomatic Rheumatoid nodulosis Rheumatoid nodules associated Self-limited NSAIDs or other treatments with cystic bone lesions not needed Neurologic Atlantoaxial subluxation* Variable;asymptomatic, paresthe- Can cause severe neuro- Disease control, screening sia, weakness, headaches, vertigo logic injury or death (especially before general anesthesia), neurosurgery or orthopedics consultation Peripheral neuropathies Variable May be disabling Anti-inflammatories, surgi- cal consultation Meningitis, transverse Headache, neck stiffness, pares- Severe morbidity Glucocorticoids myelitis thesia, weakness, bowel or bladder dysfunction continues ➤ NSAID = nonsteroidal anti-inflammatory drug. *—Extra-articular manifestation with a prevalence > 10%. †—Uncommon. 518 American Family Physician Volume 110, Number 5 November 2024 RHEUMATOID ARTHRITIS TABLE 3 (continued) Extra-Articular Manifestations of Rheumatoid Arthritis Manifestation Symptoms/signs Prognosis Treatment Ocular Scleritis and episcleritis Diffuse monocular erythema and Episcleritis has good prog- Episcleritis:topical gluco- pain, with or without changes in nosis, severe scleritis can corticoids, often resolves visual acuity threaten vision spontaneously Scleritis:variable Peripheral ulcerative Erythema, pain, discharge, Variable, may threaten Systemic anti-inflammatory keratitis decreased visual acuity vision agents Dry keratoconjunctivitis* Burning, itching, foreign body Good prognosis, affects Artificial tears, pilocarpine sensation quality of life Pulmonary Interstitial lung disease* Shortness of breath, dry cough, Common cause of death Glucocorticoids, fatigue;examination may be in patients with rheuma- cyclophosphamide, myco- normal or demonstrate tachypnea toid arthritis phenolate;encourage or bibasilar crackles;abnormal smoking cessation findings on computed tomography and pulmonary function tests Pleural disease† Dyspnea, fatigue, cough, chest Variable prognosis May resolve spontaneously, pain, fever large effusions should be treated Caplan syndrome (rheu- Multiple nodules/opacities on Often asymptomatic, Treatment often not matoid pneumoconiosis) chest imaging rupture is possible needed;glucocorticoids for symptomatic disease Other Glomerulonephritis† Elevated creatinine, proteinuria, Variable prognosis Glucocorticoids, consider hematuria drug toxicity as a cause Hepatic dysfunction* Elevated liver enzymes, fibrosis, Variable prognosis No specific treatment;con- hepatosplenomegaly sider drug toxicity as a cause Felty syndrome Arthritis, leukopenia, spleno- Poor prognosis;associ- Sulfasalazine, hydroxychlo- megaly, rheumatoid nodules, ated with malignancy roquine, methotrexate, hyperpigmentation, skin ulceration rituximab NSAID = nonsteroidal anti-inflammatory drug. *—Extra-articular manifestation with a prevalence > 10%. †—Uncommon. Information from references 11 and 12. Nonsteroidal Anti-Inflammatory Drugs although they have significant risks (eg, gastrointestinal ulcers, Nonsteroidal anti-inflammatory drugs are often prescribed to hyperglycemia, weight gain, insomnia).26 relieve symptoms of joint inflammation in RA until defini- tive therapy is established. In patients who are unable to tol- Conventional Treatments erate nonsteroidal anti-inflammatory drugs (eg, due to kidney Because current ACR and EULAR recommendations empha- disease), systemic corticosteroids are an effective alternative, size the importance of early RA treatment with DMARDs to November 2024 Volume 110, Number 5 American Family Physician 519 TABLE 4 Conventional Synthetic Disease-Modifying Antirheumatic Drugs Approved for Rheumatoid Arthritis in Adults Time to symptom Drug Starting dosage improvement Contraindications Hydroxychloroquine 400-600 mg orally once/day* 3-6 months Hypersensitivity to 4-aminoquinoline compounds Leflunomide 20 mg orally once/day 3 months Pregnancy, severe liver disease, hypersensitivity (suggested loading dose of to leflunomide 100 mg orally once/day for Due to the long half-life of leflunomide, an elimi- 3 days is rarely used because nation protocol (detailed in the package insert) is of gastrointestinal effects) required in case of hypersensitivity, or current or intended pregnancy Methotrexate 7.5-15 mg orally once/week 3-6 months Pregnancy, liver disease, kidney disease, hyper- sensitivity to methotrexate Sulfasalazine 500 mg orally once or twice/ 3 months Hypersensitivity to sulfasalazine, sulfonamide, or day, titrating up to 1,000 mg salicylates twice/day CBC = complete blood cell count;LFT = liver function test. *—Maximum daily dosage:5 mg/kg (actual body weight). Information from references 19-24. prevent joint destruction, sufficient physician experience with interleukin-6 receptor antagonists, and the anti-CD20 mono- DMARDs can help avoid treatment delays.27,28 Methotrexate clonal antibody rituximab. monotherapy is typically the preferred first-line choice for mod- In those who have an inadequate response to at least one erate to high disease activity. Hydroxychloroquine is preferred csDMARD, use of bDMARDs has been shown to provide clin- for low disease activity. Other csDMARDs, bDMARDs, or ical benefit supported by radiographic changes. Efficacy data in tsDMARDs can be added if control is inadequate (Figure 117 csDMARD-naive patients with severe, active, and progressive and eFigure A). RA have recently become available for some bDMARDs, sup- porting their use earlier in treatment.29 Biologic DMARDs Head-to-head trials between agents and classes are limited, The bDMARDs currently available for treatment of R A making it difficult to identify the most effective bDMARD.30 include tumor necrosis factor (TNF) inhibitors, the recombi- Trials have shown greater efficacy with interleukin-6 recep- nant interleukin-1 receptor antagonist anakinra (Kineret), the tor antagonists compared with adalimumab when used selective T cell costimulation inhibitor abatacept (Orencia), as monotherapy.31-33 Rituximab has shown noninferiority 520 American Family Physician Volume 110, Number 5 November 2024 RHEUMATOID ARTHRITIS FIGURE 1 DMARD naive Moderate or high Low disease Adverse effects Monitoring disease activity activity 1% to 10%:retinal toxicity Baseline and < 1% or unknown:myelosuppression, periodic eye Oral* methotrexate Hydroxychloroquine, examinations; monotherapy † sulfasalazine, worsening of psoriasis or porphyria, methotrexate, or cardiomyopathy, QT prolongation, periodic CBC leflunomide‡ dermatologic reactions > 10%:alopecia, nausea, diarrhea, CBC, creatinine, Concomitant Moderate or high disease activity|| headache LFTs at baseline steroid use§ 1% to 10%:hypertension, abdominal and monthly for at least 6 months, Addition of bDMARD pain, abnormal hepatic function tests, or tsDMARD¶ asthenia, back pain, rhinitis, bronchitis then every 6-8 weeks bDMARD = biologic disease-modifying antirheumatic drug; csD- MARD = conventional synthetic disease-modifying antirheumatic drug; TNF = tumor necrosis factor; tsDMARD = targeted synthetic > 10%:diarrhea, nausea, oral ulcers, Baseline and peri- disease-modifying antirheumatic drug. emesis, cirrhosis, hepatotoxicity, dizzi- odic CBC, LFTs, *—Conditionally recommended over subcutaneous methotrexate. ness, fatigue, headache, cough creatinine, chest †—Strongly recommended over hydroxychloroquine or sulfasal- 1% to 10%:alopecia, dermatitis, radiography azine, bDMARD or tsDMARD monotherapy, methotrexate plus non–TNF inhibitor bDMARDs and tsDMARDs. Conditionally recom- photosensitivity, weight loss, anorexia, mended over leflunomide, dual or triple csDMARD therapy, meth- abdominal pain, anemia, neutropenia, otrexate plus a TNF inhibitor. Conditionally recommended over pancytopenia, thrombocytopenia, methotrexate plus bDMARDs or tsDMARDs in methotrexate-naive hepatic fibrosis, chest infection, patients treated with csDMARDs. blurred vision, fever ‡—All conditionally recommended. §—Initiation without short-term use (< 3 months) is conditionally > 10%:skin rash, anorexia, nausea, eme- Baseline and peri- recommended over initiation with short-term use. Initiation without sis, dyspepsia, oligospermia, headache odic CBC, LFTs, long-term use (> 3 months) is strongly recommended over initiation with short-term use. 1% to 10%:pruritus, abdominal pain, creatinine ||—3 months with no significant improvement or complete remission anemia, thrombocytopenia, abnormal not achieved at 6 months. LFT results, dizziness, cyanosis, fever ¶—Add a non–TNF inhibitor bDMARD or tsDMARD if patient has history of heart failure. Add rituximab if patient has history of lymphoproliferative disorder. American College of Rheumatology treatment guidelines for rheumatoid arthritis in adults. Information from reference 17. to TNF inhibitors in those with an inadequate response to csDMARDs.34 When added to methotrexate, abatacept has shown similar clinical benefits to TNF inhibitors in those with Compared with csDMARDs, which are more general immu- an inadequate response to methotrexate.35 Anakinra has been nosuppressive agents, bDMARDs target specific components shown to be less effective than other bDMARDs.36 of the immune system.37 However, all DMARDs increase the Despite the few aforementioned trials, guidelines do not risk of infection and thus routine vaccinations should be up to recommend one bDMARD or tsDMARD over another for date in patients using these drugs (Table 5).38 Table 6 compares RA in the general population;however, insurance companies bDMARDs and tsDMARDs.14,15,17,36,39,40 often require that a TNF inhibitor be used first.15,17 If treat- In general, bDMARDs are more expensive than csDMARDs, ment with one bDMARD fails, ACR recommends switching but they are better tolerated, require less frequent laboratory to an alternative bDMARD class;EULAR does not specify monitoring, and are superior in slowing joint damage compared between switching within the same class or switching to an with csDMARDs. However, triple therapy (methotrexate, sulfas- alternative class.16,17 alazine, and hydroxychloroquine) may achieve similar results.30 November 2024 Volume 110, Number 5 American Family Physician 521 TABLE 5 Vaccine Recommendations for Adults Taking DMARDs for Rheumatoid Arthritis Influenza (nonlive Other nonlive attenuated DMARD attenuated) vaccine vaccines Live attenuated vaccines Anti-CD20 monoclonal Continue* Administer vaccine when next dose Hold before:6 months antibody is due, then hold rituximab for at Hold after:4 weeks least 2 weeks after vaccination Janus kinase inhibitors Continue Continue Hold before:1 week Hold after:4 weeks Methotrexate Hold 2 weeks after Continue methotrexate Hold before:4 weeks vaccination† Hold after:4 weeks Other DMARDs‡ No specific No specific recommendation Hold before:4 weeks recommendation Hold after:4 weeks Interleukin-1 antagonist Continue Continue Hold before:1 dosing interval Interleukin-6 antagonist Hold after:4 weeks Selective T-cell costim- ulation inhibitor TNF inhibitors DMARD = disease-modifying antirheumatic drug;TNF = tumor necrosis factor. *—Give influenza vaccine on schedule, and delay subsequent rituximab dose for at least 2 weeks after vaccination if disease activity allows. †—Hold only if disease activity allows. Physicians who are not rheumatology specialists should administer the influenza vaccine and then contact a rheumatologist about holding methotrexate to avoid missed vaccine opportunity. ‡—Methotrexate ≤ 3 mg/kg per day. Hold times can be shortened if vaccine is critical and risk of disease flare-up is high without immunosuppression. Information from reference 38. Cost, insurance requirements, infections, and adverse events Lifestyle Modifications can limit bDMARD use. Response is also not universal, with Physicians should consider how exercise, rehabilitation, diet, 30% to 40% of patients unresponsive to bDMARDs.41-43 and other integrative interventions can be used with medi- Biosimilars are considered equivalent to bDMARD origi- cations;an interprofessional approach with shared decision- nators approved by the US Food and Drug Administration making is essential. The only strong recommendation from the (FDA), and individual agents are not discussed in this article. 2022 ACR integrative interventions guidelines is that patients who have RA should consistently engage in exercise because it Targeted Synthetic DMARDs has been shown to improve pain and physical function. Type, Janus kinase inhibitors are the most recent therapeutic options intensity, frequency, and duration should be tailored to indi- for RA.39 Two groups of these agents have been FDA approved, vidual needs and capabilities.49 one that inhibits the signaling of a broad range of cytokines Physicians should also recommend rehabilitation services and a second generation that is more selective.39 In patients for appropriate patients. This may include hand therapy; receiving methotrexate, tsDMARDs have similar efficacy to occupation and physical therapy;joint protection techniques; adalimumab.44 joint health preservation methods (splinting, taping, com- Janus kinase inhibitors include an FDA boxed warning for pression, bracing); activity pacing, activity modification, increased risk of major adverse cardiovascular events (ie, cardio- energy conservation, and fatigue management; assistive vascular death, myocardial infarction, stroke) and thrombosis, devices, adaptive equipment, and environmental adaptions; compared with TNF inhibitors, in patients 50 years and older and vocational rehabilitation and worksite evaluations and with one or more cardiovascular risk factor.45-47 The warning modifications. was added in 2021 after this risk was demonstrated in a ran- Low- to moderate-certainty evidence has demonstrated that domized noninferiority trial of tofacitinib (Xeljanz).48 a Mediterranean diet improves pain with no change in physical 522 American Family Physician Volume 110, Number 5 November 2024 RHEUMATOID ARTHRITIS TABLE 6 Biologic and Targeted Synthetic Disease-Modifying Antirheumatic Drugs Precautions/ Drugs and dosing contraindications Monitoring Clinical pearls TNF inhibitors Adalimumab,* 40 mg subcu- Increased risk of TB, invasive Baseline:TB, hepatitis B Certolizumab pegol preferred taneously every 14 days fungal infection, and hepatitis B and C, CBC, LFT, serum in pregnancy Certolizumab pegol (Cim- reactivation creatinine Hold these drugs in the pres- zia), 400 mg subcutaneously Malignancy Continuous:serum ence of infections at weeks 0, 2, and 4, then New-onset or exacerbation creatinine, LFT, CBC Concomitant conventional 200 mg every 14 days of demyelinating disease and (periodically) synthetic disease-modifying Etanercept (Enbrel),* 50 mg congestive heart failure antirheumatic drug use subcutaneously every 7 days Lupus-like syndrome increases response to TNF Golimumab (Simponi), 50 inhibitors and decreases anti- mg subcutaneously every 4 body formation weeks or 2 mg/kg intrave- nously at weeks 0 and 4, then every 8 weeks Infliximab,* 3 mg/kg intrave- nously at weeks 0, 2, and 6, then every 8 weeks Interleukin-1 receptor antagonist Anakinra (Kineret), 100 mg Serious infections Baseline:TB, hepatitis B Inferior efficacy compared subcutaneously once/day and C, CBC with differen- with other biologics approved tial, serum creatinine, LFT for rheumatoid arthritis Continuous:CBC Increased risk of injection site (monthly for 3 months, reactions, which can last weeks then every 3 months for Neutropenia 1 year) Not discussed in recent guide- lines due to infrequent use Selective T cell costimulation inhibitor (CD 80/86) Abatacept (Orencia), 125 mg Chronic obstructive pulmo- Baseline:TB, hepatitis B Decreased infection rate; subcutaneously every 7 days nary disease and C, CBC with differen- conditionally recommended or 500-1,000 mg (weight- tial, serum creatinine, LFT over TNF inhibitors in those based dosing) intravenously Continuous:CBC with infections at weeks 2 and 4, then every (periodically) Risk of chronic obstructive pul- 4 weeks monary disease exacerbation Hold in the presence of infections continues ➤ CBC = complete blood cell count; LFT = liver function test; TB = tuberculosis;TNF = tumor necrosis factor. *—Biosimilar approved but may not be available. function or disease activity. A standardized self-management PROGNOSIS program, cognitive behavior therapy, acupuncture, mas- Patients with RA have an increased mortality rate, with early sage, or thermal modalities are other options that may be reports showing a twofold increase and more recent studies considered.49 showing a 38% to 60% increase.50-52 People who have RA are November 2024 Volume 110, Number 5 American Family Physician 523 TABLE 6 (continued) Biologic and Targeted Synthetic Disease-Modifying Antirheumatic Drugs Precautions/ Drugs and dosing contraindications Monitoring Clinical pearls Interleukin-6 receptor antagonist Tocilizumab (Actemra), 162 Serious infections Baseline:body weight, Also used to treat polymyalgia mg subcutaneously every Use with caution in those TB, hepatitis B, CBC with and rheumatic and giant cell 7 or 14 days (weight-based at risk of gastrointestinal differential, serum creati- arteritis dosing) or 4 mg/kg intrave- perforation nine, lipids, LFT Hold in the presence of nously every 4 weeks Continuous: infections Absolute neutrophil count Sarilumab (Kevzara), 200 < 2,000/mm 3 LFT and CBC with Discontinue in those with mg subcutaneously every differential 4 to 8 weeks diverticulitis Platelet count < 100,000/mm 3 14 days after starting therapy, transaminase > than 1.5 times then every 3 months the upper limit of normal Lipids at weeks 4 and 8, then every 6 months Serum creatinine (periodically) Anti-CD20 monoclonal antibody Rituximab,* 1,000 mg intra- Serious infections Baseline:TB, hepatitis B, Best for those who have venously at weeks 0 and 2, Cardiac adverse reactions CBC vasculitis, cryoglobulinemia, then every 24 weeks Continuous:CBC with or cancer Renal toxicity differential every 2 to 4 Bowel obstruction/perforation months Janus kinase inhibitors Baricitinib (Olumiant), 2 mg Increased risk of bacterial, Baseline:TB test, hep- Oral administration orally once/day fungal, viral, and opportunistic atitis B and C, CBC with Increased risk of herpes zoster Tofacitinib (Xeljanz), 5 mg infections differential, lipids, LFT Risk of increased lipid levels orally twice/day or 11 mg Higher all-cause mortality rate Continuous: Mortality, major adverse (XR) once/day Use with caution in those LFT and CBC with dif- cardiovascular events, and Upadacitinib (Rinvoq), 15 at risk of gastrointestinal ferential (4 to 8 weeks malignancy studies with mg orally once/day perforation after starting therapy, tofacitinib Increased risk of major adverse then every 3 months) cardiovascular events and Lipids (4 to 8 weeks malignancies in those older after starting therapy, than 50 years with at least one then every 6 months) cardiovascular risk factor CBC = complete blood cell count; LFT = liver function test; TB = tuberculosis;TNF = tumor necrosis factor. *—Biosimilar approved but may not be available. Information from references 14, 15, 17, 36, 39, and 40. more likely to die of infection, cardiovascular disease, and smoking), and the immunosuppressive medications used to respiratory disease than the general population.53 treat RA contribute to the higher prevalence of comorbidities. Patients with RA have higher rates of serious comorbid Although functional outcomes and disability vary in patients disease, including cardiovascular disease, infections, chronic with RA, disability is more common than in the general pop- kidney disease, and lymphoproliferative disorders.54 Inflam- ulation. Early DMARD therapy reduces disability;however, matory effects of RA, risk factors associated with RA (such as controlling inflammation alone is not sufficient to eliminate 524 American Family Physician Volume 110, Number 5 November 2024 RHEUMATOID ARTHRITIS SORT:KEY RECOMMENDATIONS FOR PRACTICE Evidence Clinical recommendation rating Comments Use a clinical decision tool such as the Leiden clinical prediction rule for C Expert consensus guidelines undifferentiated arthritis for patients with synovial inflammation.7,18 Begin DMARDs as soon as possible after a rheumatoid arthritis diag- A Clinical practice guidelines based on nosis because DMARD therapy has been shown to reduce the risk of randomized controlled trials and sys- long-term joint damage.1,2,9,27,28 tematic reviews showing reductions in radiographic and clinical progression Assure that routine vaccinations are up to date in patients receiving C Expert consensus guidelines DMARDs because the risk of infection is increased with the use of these drugs. DMARD administration should be delayed after some vaccinations.38 Address cardiovascular risk factors in patients who have rheumatoid C Expert consensus guidelines arthritis because cardiovascular disease is the most common cause of death in these patients.50-54 DMARD = disease-modifying antirheumatic drug. A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease- oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://w ww.aafp. org/afpsort. disability.55 A functional assessment tool, such as the Health 6. van der Helm-van Mil AH, le Cessie S, van Dongen H, et al. A prediction rule for disease outcome in patients with recent-onset Assessment Questionnaire-II (https:// r heuminfo.com/ undifferentiated arthritis. Arthritis Rheum. 2007;56(2):4 33-4 4 0. physician-tools/health-assessment-questionnaires-haq-haq-ii- 7. Mochan E, Ebell MH. Predicting rheumatoid arthritis risk in adults mdhaq), can be used to measure baseline function and changes with undifferentiated arthritis. Am Fam Physician. 2008;77(10): over time. 1451-1453. 8. Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria:an American College of Rheumatology/ Data Sources:A PubMed search was conducted in Clinical Que- European League Against Rheumatism collaborative initiative. ries and the Cochrane database using the key terms rheumatoid Arthritis Rheum. 2010;62(9):2569-2581. arthritis, synthetic disease-modifying antirheumatic drugs 9. Radner H, Neogi T, Smolen JS, et al. Performance of the 2010 ACR/ EULAR classification criteria for rheumatoid arthritis:a systematic (csDMARDs), biologic DMARDs (bDMARDs) and targeted syn- literature review. Ann Rheum Dis. 2014;73(1):114-123. thetic DMARDS (tsDMARDs). The American College of Rheuma- 10. Coffey CM, Crowson CS, Myasoedova E, et al. Evidence of diagnostic tology and European Alliance of Associations for Rheumatology and treatment delay in seronegative rheumatoid arthritis:missing the practice guidelines were also searched. Studies included window of opportunity. Mayo Clin Proc. 2019;94(11):2241-2248. meta-analyses, randomized controlled trials, clinical trials, and 11. Conforti A, Di Cola I, Pavlych V, et al. Beyond the joints, the extra- articular manifestations in rheumatoid arthritis. Autoimmun Rev. reviews. Reference lists of retrieved articles were also searched. 2021;20(2):102735. Search dates:January to June 2023 and May to June 2024. 12. Figus FA, Piga M, Azzolin I, et al. Rheumatoid arthritis:extra-articular manifestations and comorbidities. Autoimmun Rev. 2021;20(4): REFERENCES 102776. 1. Cross M, Smith E, Hoy D, et al. The global burden of rheumatoid 13. Alam J, Jantan I, Bukhari SNA. Rheumatoid arthritis:recent advances arthritis:estimates from the global burden of disease 2010 study. 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Efficacy and safety of 61(12):4687-4701. abatacept or infliximab vs placebo in ATTEST:a phase III, 526 American Family Physician Volume 110, Number 5 November 2024 RHEUMATOID ARTHRITIS eTABLE A bDMARDs Approved for Rheumatoid Arthritis in Adults:Summary of Efficacy Trials Medication Participant characteristics Efficacy end points and outcomes* Adverse events† Anti-CD20 monoclonal antibody RituximabA1,A2‡ REFLEX REFLEX Not studied Inadequate response to TNF End point:ACR20 at 24 weeks inhibitors Dosage:1,000 mg/day on days 1 and 15 NNT = 3 IL-1 receptor antagonist Anakinra Kineret II Kineret II Headache, infections, injection (Kineret)A3-A5 Inadequate response to End point:ACR20 at 12 weeks site reaction, sinusitis, URTI methotrexate Dosage:0.04-2 mg/kg daily NNT = 4-16 Kineret III Kineret III Inadequate response to End point:ACR composite score at 24 weeks csDMARD Dosage:30 to 150 mg daily NNT = 6-14 IL-6 receptor antagonist Tocilizumab AMBITION AMBITION Gastrointestinal disorders, (Actemra)A6-A11 Inadequate response to meth- End point:ACR20 at 24 weeks infections, musculoskeletal and otrexate or biologic agents Dosage:8 mg/kg every 4 weeks connective tissue disorders, nervous system disorders, skin NNT = 6 disorders, subcutaneous tissue Actemra II Actemra II disorder Inadequate response to End point:ACR20 at 52 weeks > 5% in at least 1 treatment group methotrexate Dosage:4 or 8 mg/kg every 4 weeks (AMBITION, OPTION):diarrhea, NNT:3 or 4 dyspepsia, headache, hyperten- sion, nasopharyngitis, nausea, OPTION OPTION rash, increased ALT and AST, URTI Inadequate response to End point:ACR20 at 24 weeks ≥ 4 per 100 patient-years methotrexate Dosage:4 or 8 mg/kg every 4 weeks (Actemra II):acute myocardial NNT = 3-5 infarction, anaphylactic shock, basal cell carcinoma, cellulitis, TOWARD TOWARD gastroenteritis, gastroenteritis Inadequate response to at End point:ACR20 at 24 weeks viral, pneumonia, prostate cancer least one csDMARD Dosage:8 mg/kg every 4 weeks NNT = 3 RADIATE RADIATE Inadequate response to TNF End point:ACR20 at 24 weeks inhibitors Dosage:4 or 8 mg/kg every 4 weeks NNT = 3-5 continues ➤ ACR = American College of Rheumatology;ALT = alanine transaminase;AST = aspartate transaminase;bDMARD = biologic disease-modifying antirheumatic drug; csDMARD = conventional synthetic disease-modifying antirheumatic drug; IL = interleukin; NA = not applicable; NNH = number needed to harm; NNT = number needed to treat;TNF = tumor necrosis factor;URTI = upper respiratory tract infection. *—ACR20, ACR50, and ACR70 refer to percentage improved when comparing disease activity at 2 discrete time points;> 20% improvement, ≥ 50% improvement, and > 70% improvement, respectively. †—Occurred in > 10% of at least 1 treatment group unless otherwise stated. ‡—Biosimilar approved, may not be available. November 2024 Volume 110, Number 5 American Family Physician 526A eTABLE A (continued) bDMARDs Approved for Rheumatoid Arthritis in Adults:Summary of Efficacy Trials Medication Participant characteristics Efficacy end points and outcomes* Adverse events† IL-6 receptor antagonist (continued) Sarilumab MOBILITY MOBILITY > 5% in at least 1 treatment (Kevzara)A12-A14 Inadequate response to End point:ACR20 at 52 weeks group:bronchitis, nasopharyngi- methotrexate Dosage:150 or 200 mg every 2 weeks tis, neutropenia, increased ALT, URTI, urinary tract infection NNT:4 or 5 TARGET TARGET Inadequate response to TNF End point:ACR20 at 24 weeks inhibitors Dosage:150 or 200 mg every 2 weeks NNT = 4 or 5 Selective T cell costimulation inhibitor (CD 80/86) Abatacept Orencia I Orencia I Diarrhea, headache, nasopharyn- (Orencia)A15-A19 Inadequate response to one End point:ACR20 at 3 months gitis, nausea, URTI csDMARD Dosage:0.5-10 mg/kg on days 1, 15, 29, and 57 > 5% in at least 1 treatment group NNT (CTLA-4Ig) = 5-11 (Orencia I and ATTAIN):back pain, bronchitis, diarrhea, fatigue, NNT (LEAD29Y) = 8-61 headache, nasopharyngitis, nau- AIM AIM sea, vomiting, sinusitis, URTI Inadequate response to End point:ACR20 at 6 months methotrexate Dosage:10 mg/kg on days 1, 15, and 29, then every 28 days NNT = 4 ATTAIN ATTAIN Inadequate response to TNF End point:ACR20 at 6 months inhibitors Dosage:10 mg/kg on days 1, 15, and 29, then every 28 days NNT = 3 AGREE AGREE Methotrexate naive End point:ACR50 at 12 months Dosage:10 mg/kg on days 1, 15, and 29, then every 28 days NNT = 7 continues ➤ ACR = American College of Rheumatology;ALT = alanine transaminase;AST = aspartate transaminase;bDMARD = biologic disease-modifying antirheumatic drug; csDMARD = conventional synthetic disease-modifying antirheumatic drug; IL = interleukin; NA = not applicable; NNH = number needed to harm; NNT = number needed to treat;TNF = tumor necrosis factor;URTI = upper respiratory tract infection. *—ACR20, ACR50, and ACR70 refer to percentage improved when comparing disease activity at 2 discrete time points;> 20% improvement, ≥ 50% improvement, and > 70% improvement, respectively. †—Occurred in > 10% of at least 1 treatment group unless otherwise stated. ‡—Biosimilar approved, may not be available. §—Placebo greater than treatment group. ||—Compared with methotrexate only. 526B American Family Physician Volume 110, Number 5 November 2024 RHEUMATOID ARTHRITIS eTABLE A (continued) bDMARDs Approved for Rheumatoid Arthritis in Adults:Summary of Efficacy Trials Medication Participant characteristics Efficacy end points and outcomes* Adverse events† TNF inhibitor AdalimumabA20-A25‡ ARMADA ARMADA Accidental injury, arthralgia, Inadequate response to End point:ACR20 at 24 weeks back pain, clinical flare reaction, methotrexate Dosage:20-80 mg every 14 days diarrhea, dizziness, influenzalike syndrome, gastrointestinal pain, NNT:2 or 3 headache, injection site reac- Humira II Humira II tion, joint disorder, nausea, pain, Inadequate response to one End point:ACR20 at 26 weeks pruritus, rash, rhinitis, sinusitis, csDMARD Dosage:20 or 40 mg every 7 or 14 days sore throat NNT:3-6 > 1 per 100 patient-years (PRE- MIER):infectious adverse events, Humira III Humira III serious adverse events, serious Inadequate response to End point:ACR20 at 52 weeks infections methotrexate Dosage:20 mg every 7 days/40 mg every 14 days NNT = 3 STAR STAR Inadequate response to csD- End point:type and frequency of adverse MARDs, low-dose steroids, or events at 24 weeks nonsteroidal anti-inflammatory Dosage:40 mg every 14 days drugs NNH at 24 weeks:adverse events = 26; life-threatening adverse events = NA§; adverse events leading to withdrawal = 167; infection = 35;serious infection = NA§ PREMIER PREMIER Methotrexate naive End point:ACR50 at 1 year Dosage:40 mg every 14 days NNT = 6 Certolizumab pegol RAPID-1 RAPID-1 Infection, headache, hyperten- (Cimzia)A26-A29 Inadequate response to End point:ACR20 at 24 weeks sion, urinary tract infection methotrexate Dosage:400 mg subcutaneously at weeks 0, 2, > 5% in at least 1 treatment group and 4, then 200 or 400 mg (FAST4WARD):diarrhea, head- NNT = 2 ache, nasopharyngitis, sinusitis, URTI RAPID-2 RAPID-2 Inadequate response to End point:ACR20 at 24 weeks methotrexate Dosage:400 mg subcutaneously at weeks 0, 2, and 4, then 200 or 400 mg NNT = 2 FAST4WARD FAST4WARD Inadequate response to one End point:ACR20 at 24 weeks csDMARD Dosage:400 mg every 4 weeks NNT = 3 continues ➤ ACR = American College of Rheumatology;ALT = alanine transaminase;AST = aspartate transaminase;bDMARD = biologic disease-modifying antirheumatic drug; csDMARD = conventional synthetic disease-modifying antirheumatic drug; IL = interleukin; NA = not applicable; NNH = number needed to harm; NNT = number needed to treat;TNF = tumor necrosis factor;URTI = upper respiratory tract infection. *—ACR20, ACR50, and ACR70 refer to percentage improved when comparing disease activity at 2 discrete time points; > 20%, ≥ 50%, and > 70% improvement, respectively. †—Occurred in > 10% of at least 1 treatment group unless otherwise stated. ‡—Biosimilar approved, may not be available. §—Placebo greater than treatment group. eTABLE A (continued) bDMARDs Approved for Rheumatoid Arthritis in Adults:Summary of Efficacy Trials Medication Participant characteristics Efficacy end points and outcomes* Adverse events† TNF inhibitor Etanercept Enbrel 1 Enbrel 1 Abdominal pain, accidental injury, (Enbrel)A30-A34‡ Inadequate response to one to End point:ACR20 at 3 and 6 months alopecia, asthenia, back pain, four csDMARDs Dosage:10 or 25 mg twice weekly bleeding at injection site, cough, diarrhea, dizziness, dyspepsia, NNT at 3 months = 3-5, at 6 months = 2 or 3 ecchymosis, headache, infection, End point:ACR50 at 3 and 6 months influenzalike syndrome, injection Dosage:10 or 25 mg twice weekly site reaction, mouth ulcer, nau- NNT at 3 months = 3-20, at 6 months = 3-5 sea, rash, rhinitis, sinusitis, skin Enbrel II Enbrel II infection, URTI, vomiting Inadequate response to End point:ACR20 at 24 weeks methotrexate Dosage:25 mg twice weekly NNT = 2 Enbrel III Enbrel III Methotrexate naive End point:ACR20 at 3 and 6 months Dosage:25 mg twice weekly NNT at 3 and 6 months = NA|| TEMPO TEMPO Inadequate response to one End point:ACR20 at 12 months csDMARD Dosage:25 mg twice weekly NNT = NA|| Golimumab GO-FURTHER GO-FURTHER > 5% in at least 1 treatment (Simponi)A35-A37 Inadequate response to End point:ACR20 at 14 weeks group:URTI methotrexate Dosage:2 mg/kg at weeks 0 and 4, then every 8 weeks NNT = 3 InfliximabA38-A40‡ ATTRACT ATTRACT Headache, nausea, pharyngitis, Inadequate response to End point:ACR20 at 54 weeks serious adverse events, sinusitis, methotrexate Dosage:3 or 10 mg/kg at weeks 0, 2, and 6, URTI then every 4 or 8 weeks NNT = 2-4 ASPIRA ASPIRA Methotrexate and TNF inhib- End point:ACR20 at 54 weeks itor naive Dosage:3 or 6 mg/kg at weeks 0, 2, and 6, then every 8 weeks NNT = 8-2 continues ➤ ACR = American College of Rheumatology;ALT = alanine transaminase;AST = aspartate transaminase;bDMARD = biologic disease-modifying antirheumatic drug; csDMARD = conventional synthetic disease-modifying antirheumatic drug; IL = interleukin; NA = not applicable; NNH = number needed to harm; NNT = number needed to treat;TNF = tumor necrosis factor;URTI = upper respiratory tract infection. *—ACR20, ACR50, and ACR70 refer to percentage improved when comparing disease activity at 2 discrete time points;> 20% improvement, ≥ 50% improvement, and > 70% improvement, respectively. †—Occurred in > 10% of at least 1 treatment group unless otherwise stated. ‡—Biosimilar approved, may not be available. §—Placebo greater than treatment group. ||—Compared with methotrexate only. 526D American Family Physician Volume 110, Number 5 November 2024 RHEUMATOID ARTHRITIS eTABLE A (continued) bDMARDs Approved for Rheumatoid Arthritis in Adults:Summary of Efficacy Trials Information from: A1. 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