What is the recommended treatment approach for rheumatoid arthritis in adults?

Treatment for Rheumatoid Arthritis

Start methotrexate 15–25 mg weekly with folic acid supplementation immediately upon diagnosis, rapidly escalating to 25–30 mg weekly within a few weeks, combined with short-term low-dose prednisone (≤10 mg/day for <3 months) as a bridge to rapid symptom control. 1

Initial Disease-Modifying Therapy

Methotrexate is the anchor DMARD for all patients with active rheumatoid arthritis and must be initiated as soon as the diagnosis is confirmed; delays are associated with irreversible joint damage. 1

• Begin methotrexate at 15–25 mg weekly with folic acid 1 mg daily, escalating rapidly to the optimal dose of 25–30 mg weekly within a few weeks to maximize disease-modifying effect. 2, 1
• If oral methotrexate is not tolerated or ineffective at 20–25 mg weekly, switch to subcutaneous administration before declaring treatment failure. 1
• When methotrexate is contraindicated (e.g., severe liver disease, significant renal impairment), leflunomide or sulfasalazine should be used as first-line alternatives. 1

Glucocorticoid Bridge Therapy

• Add low-dose oral prednisone (≤10 mg/day or equivalent) immediately for rapid symptom control while methotrexate takes effect. 1
• Limit glucocorticoid duration to less than 3 months and use the lowest effective dose; prolonged use beyond 1–2 years markedly increases risks of osteoporosis, fractures, cataracts, and cardiovascular disease. 2, 1, 3
• Taper and discontinue prednisone as soon as disease control is achieved with DMARD optimization. 1

Treatment Targets and Monitoring Schedule

The primary therapeutic goal is clinical remission, defined as SDAI ≤3.3, CDAI ≤2.8, or ACR-EULAR Boolean criteria (≤1 tender joint, ≤1 swollen joint, CRP ≤1 mg/dL, patient global ≤1 on 0–10 scale). 1

• If remission is not attainable, low disease activity (SDAI ≤11 or CDAI ≤10) is an acceptable alternative, particularly in patients with long-standing disease. 1
• Assess disease activity every 1–3 months during active disease using composite measures (tender/swollen joint counts, patient and physician global assessments, ESR or CRP). 1
• Expect at least 50% improvement in disease activity within the first 3 months of therapy; failure to reach this threshold mandates immediate treatment escalation. 1
• The treatment target must be reached within 6 months; if not, therapy must be escalated or modified. 1

Escalation Strategy for Inadequate Response

Patients Without Poor Prognostic Factors

• Add combination conventional synthetic DMARDs (triple therapy: methotrexate + sulfasalazine 500 mg twice daily titrated to 1000 mg twice daily + hydroxychloroquine 400 mg daily) when immediate biologic therapy is not indicated. 1, 4
• Triple-DMARD therapy yields higher sustained improvement rates (approximately 77% vs 33% with methotrexate alone) and is particularly effective in patients with poor prognostic factors. 1

Patients With Poor Prognostic Factors

Poor prognostic factors include high rheumatoid factor or anti-CCP titers, high baseline disease activity (DAS28 >5.1), early erosive changes, or failure of two conventional synthetic DMARDs. 1

• Add a biologic DMARD or JAK inhibitor to methotrexate when an inadequate response persists after 3–6 months of optimized conventional DMARD therapy. 1
• TNF-α inhibitors (infliximab, etanercept, adalimumab, certolizumab pegol, golimumab) are the preferred first-line biologic agents. 1
• Alternative biologic classes include IL-6 receptor antagonists (tocilizumab, sarilumab), T-cell costimulation modulators (abatacept), and rituximab (particularly for seropositive patients or those with prior lymphoma). 1, 5
• JAK inhibitors (tofacitinib, baricitinib, upadacitinib) are appropriate when biologics are unsuitable or after biologic failure. 1
• Biologic agents should be combined with methotrexate whenever possible because combination therapy demonstrates superior efficacy compared with biologic monotherapy. 1

Management After First Biologic Failure

• Switch to a biologic with a different mechanism of action rather than a second agent from the same class; registry and observational data show superior efficacy with a mechanism-switch. 1
• After failure of a first TNF inhibitor, either another TNF inhibitor or a biologic from a different class may be used, but a mechanism-switch is now preferred. 1
• Allow 3–6 months to fully assess the efficacy of any newly introduced biologic or targeted synthetic DMARD before making further therapeutic changes. 1

Baseline Safety Screening Before Starting DMARDs

• Obtain complete blood count with differential, hepatic function tests, renal function tests, and chest radiograph before initiating methotrexate. 1
• Screen all candidates for tuberculosis (TST or IGRA such as QuantiFERON-TB Gold) prior to biologic DMARD initiation. 1, 5
• Screen for hepatitis B surface antigen, surface antibody, and core antibody before rituximab; if core antibody is positive, initiate prophylactic antiviral therapy. 1
• Administer age-appropriate vaccines, including recombinant herpes zoster vaccine, at least 2–4 weeks before starting biologic therapy; live vaccines are contraindicated after B-cell depletion. 1

De-escalation in Sustained Remission

• When sustained remission is maintained for ≥1 year, cautious tapering of therapy can be considered, beginning with prednisone discontinuation followed by gradual reduction of conventional DMARD dose. 1
• Approximately 15–25% of patients may achieve sustained drug-free remission after de-escalation. 1

Critical Pitfalls to Avoid

• Delaying DMARD initiation leads to irreversible joint damage—start treatment immediately upon diagnosis. 1, 6
• Do not rely on NSAIDs or corticosteroids as sole therapy; they provide only symptomatic relief without disease modification and do not prevent radiographic progression. 2, 1
• Do not delay DMARD escalation when <50% improvement is observed at 3 months or the target is not reached at 6 months; ongoing joint damage can become irreversible. 1
• Do not underdose methotrexate; it must reach 20–25 mg weekly before concluding inadequate response. 1, 3
• Do not continue systemic corticosteroids beyond 1–2 years because cumulative adverse effects (fractures, cataracts, cardiovascular disease, osteoporosis) outweigh symptomatic benefits. 2, 1, 3