What is the recommended first‑line treatment for rheumatoid arthritis in adults to prevent joint damage?

First-Line Treatment for Rheumatoid Arthritis

Methotrexate 15–25 mg weekly (rapidly escalated to 25–30 mg weekly within a few weeks) combined with short-term low-dose glucocorticoids (≤10 mg/day prednisone-equivalent for <3 months) is the recommended first-line treatment to prevent joint damage in adults with rheumatoid arthritis. 1

Methotrexate as the Anchor DMARD

• Methotrexate must be initiated immediately upon diagnosis because delaying disease-modifying therapy leads to irreversible joint damage and worse functional outcomes. 1

• Start methotrexate at 15–25 mg orally once weekly with folic acid supplementation, then rapidly escalate to the target dose of 25–30 mg weekly within a few weeks to maximize disease-modifying effect. 1, 2

• The maximal tolerated dose should be sustained for 8–12 weeks (or at least 3 months) before judging treatment response. 1

• If oral methotrexate at 20–25 mg weekly is poorly tolerated or ineffective, switch to subcutaneous administration before declaring treatment failure. 1, 3

• Methotrexate reduces comorbidities and mortality in RA, has the best efficacy-to-toxicity ratio among conventional DMARDs, and serves as the anchor drug for both monotherapy and combination strategies. 1, 4, 5

Glucocorticoid Bridge Therapy

• Add low-dose glucocorticoids (≤10 mg/day prednisone-equivalent) for rapid symptom control while methotrexate takes effect, using the lowest effective dose for the shortest duration (generally <3 months). 1, 2

• Glucocorticoids reduce pain, swelling, and structural progression but must be tapered and discontinued once remission is achieved because long-term use (>1–2 years) causes cumulative toxicity including osteoporosis, fractures, cataracts, and cardiovascular disease. 1

• High-dose corticosteroids alone do not prevent radiographic progression and are not disease-modifying therapy. 6

Alternative First-Line Options When Methotrexate Is Contraindicated

• If methotrexate is contraindicated or not tolerated early, leflunomide or sulfasalazine should be used as part of the first treatment strategy. 1, 2

• Leflunomide has similar clinical efficacy to methotrexate in early and established RA with comparable effects on radiographic progression. 2

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 (tender joint count ≤1, swollen joint count ≤1, CRP ≤1 mg/dL, patient global assessment ≤1 on 0–10 scale). 1, 6

• If remission is unattainable, low disease activity (SDAI ≤11 or CDAI ≤10) is an acceptable alternative target. 1, 6

• Assess disease activity every 1–3 months during active disease using composite measures that include joint counts, acute phase reactants, and patient/physician global assessments. 1, 6

• Expect ≥50% improvement in disease activity within the first 3 months of therapy; if this minimal change is not achieved, there is only a low likelihood of reaching the treatment target. 1, 6

• The predefined treatment target must be reached within 6 months of initiating therapy. 1, 6

When and How to Escalate Treatment

• If there is no ≥50% improvement by 3 months or the target is not achieved by 6 months, therapy must be adjusted. 1, 6, 2

• Adjustment includes optimizing methotrexate dose or route of administration, intra-articular glucocorticoid injections for residual active joints, or changing drugs if these measures fail. 1

For Patients Without Poor Prognostic Factors:

• Add or switch to another conventional synthetic DMARD (e.g., triple therapy with methotrexate + sulfasalazine + hydroxychloroquine). 1, 6, 2

For Patients With Poor Prognostic Factors:

• Poor prognostic factors include high rheumatoid factor or anti-CCP antibody levels, very high disease activity, early erosive changes, or failure of two conventional DMARDs. 1, 6

• Add a biologic DMARD (preferably a TNF inhibitor) or JAK inhibitor to methotrexate when inadequate response persists after 3–6 months of optimized conventional DMARD therapy. 1, 6, 2

• TNF inhibitors (infliximab, etanercept, adalimumab, certolizumab pegol, golimumab) are the preferred first-line biologic agents. 1, 6

• Alternative biologic classes include IL-6 receptor antagonists (tocilizumab), T-cell costimulation modulators (abatacept), and rituximab (after TNF inhibitor failure). 1, 6

• Biologic agents should be combined with methotrexate whenever possible because combination therapy demonstrates superior efficacy compared with biologic monotherapy. 6, 2

Critical Pitfalls to Avoid

• Delaying DMARD initiation permits irreversible joint damage—treatment must start immediately upon diagnosis, ideally within 3 months of symptom onset. 1, 6

• Using NSAIDs or corticosteroids alone provides only symptomatic relief without disease modification and does not prevent radiographic progression. 1, 6

• Undertreating with suboptimal methotrexate doses (<20–25 mg weekly) prevents achieving treatment targets; the maximal tolerated dose must be reached and sustained. 1, 6

• Failing to escalate therapy when <50% improvement at 3 months or target not reached at 6 months allows ongoing joint destruction. 1, 6

• Continuing long-term corticosteroids beyond 1–2 years leads to cumulative toxicity (fractures, cataracts, cardiovascular disease) that outweighs any benefit. 1, 6