What is the recommended first‑line treatment for an adult with confirmed rheumatoid arthritis, including preferred disease‑modifying antirheumatic drug (DMARD) choice, dosing, and adjunctive therapy?

First-Line Treatment for Rheumatoid Arthritis

Methotrexate monotherapy is the strongly recommended first-line treatment for adults with confirmed moderate-to-high disease activity rheumatoid arthritis. 1

Methotrexate Dosing and Administration

Start methotrexate at 15 mg weekly orally and rapidly escalate to at least 15 mg (ideally 20-25 mg) within 4-6 weeks. 1, 2 The 2021 American College of Rheumatology guideline conditionally recommends initiating/titrating methotrexate to a weekly dose of at least 15 mg within 4-6 weeks over lower doses. 1

• Oral methotrexate is conditionally recommended over subcutaneous administration when initiating therapy. 1
• Maintain the maximal tolerated dose (20-25 mg weekly) for at least 3 months before assessing efficacy. 3
• If oral methotrexate is not tolerated, switch to subcutaneous administration or use split dosing over 24 hours. 1
• Always prescribe folic acid supplementation (typically 1 mg daily or 5 mg weekly) to reduce toxicity. 2, 4

Glucocorticoid Bridging Therapy

Short-term low-dose glucocorticoids (≤10 mg/day prednisone equivalent) for less than 3 months are conditionally recommended as bridging therapy while methotrexate takes effect. 1, 2 However, the 2021 ACR guideline notes this is conditional, and initiation without short-term glucocorticoids is also acceptable. 1

• Use the lowest effective dose for the shortest duration possible. 2, 5
• Longer-term glucocorticoid use (≥3 months) is strongly recommended against due to cumulative toxicity risks including osteoporosis, cardiovascular disease, and cataracts. 1, 3
• Taper and discontinue glucocorticoids once disease control is achieved. 3

Treatment Targets and Monitoring Strategy

Adopt a treat-to-target approach with the goal of achieving remission (SDAI ≤3.3 or CDAI ≤2.8) or low disease activity (SDAI ≤11 or CDAI ≤10) within 6 months. 1, 2, 3

• Monitor disease activity every 1-3 months using validated measures (DAS28, CDAI, or SDAI). 2, 5
• Expect at least 50% improvement within 3 months of initiating therapy. 2, 3
• If the target is not reached by 3 months or there is inadequate response, escalate therapy. 2, 3
• The target must be attained within 6 months. 2, 3

Treatment Escalation for Inadequate Response

If methotrexate monotherapy at optimal doses fails after 3 months, add a biologic DMARD (preferably a TNF inhibitor) or consider triple conventional synthetic DMARD therapy (methotrexate + sulfasalazine + hydroxychloroquine). 2, 3

• TNF inhibitors (adalimumab, etanercept, infliximab) are typically first-line biologic agents and should be combined with methotrexate for optimal efficacy. 2, 3
• Triple therapy with conventional synthetic DMARDs is particularly effective in patients with poor prognostic factors (high RF/anti-CCP, erosive disease). 3
• Allow 3-6 months to fully assess efficacy of any new treatment before switching. 3

Special Considerations for Low Disease Activity at Presentation

For patients with low disease activity at diagnosis, hydroxychloroquine is conditionally recommended as first-line therapy over other conventional synthetic DMARDs. 1

• Sulfasalazine is conditionally recommended over methotrexate in this population. 1
• This represents a less aggressive initial approach appropriate for milder disease. 1

Critical Pitfalls to Avoid

• Never delay DMARD initiation – start treatment immediately upon diagnosis as delays lead to irreversible joint damage. 2, 3
• Do not undertreate with suboptimal methotrexate doses – doses below 20-25 mg weekly prevent achieving treatment targets. 2, 3
• Avoid using NSAIDs or glucocorticoids alone – these provide only symptomatic relief without disease modification. 2, 3
• Do not continue ineffective therapy – if there is less than 50% improvement at 3 months or target not reached at 6 months, escalate treatment. 2, 3
• Screen for tuberculosis before starting biologics and ensure age-appropriate vaccinations are current. 3