Best First-Line Medication for Rheumatoid Arthritis
Methotrexate should be the first medication started for rheumatoid arthritis, combined with short-term low-dose glucocorticoids (prednisone) for the first 6 months to achieve superior clinical and structural outcomes. 1
Core First-Line Strategy
Start methotrexate at 15 mg weekly and rapidly escalate to 20-25 mg weekly (approximately 0.3 mg/kg) within 4-6 weeks, as this is the optimal therapeutic dose in Western populations. 1, 2
Add low-dose prednisone (≤10 mg daily) at treatment initiation, then taper as rapidly as clinically feasible over the first 6 months—this combination produces better clinical and structural outcomes at 1-2 years than methotrexate alone. 1
Always prescribe folic acid supplementation to reduce gastrointestinal and mucocutaneous adverse events. 1, 2
Route of Administration
Begin with oral methotrexate due to ease of administration and low cost. 3, 2
Switch to subcutaneous methotrexate if inadequate response or intolerance occurs at oral doses ≥15 mg weekly, as subcutaneous administration has superior bioavailability at higher doses and better tolerability. 3, 2
Alternative First-Line Options (If Methotrexate Contraindicated)
Use leflunomide or sulfasalazine as the anchor DMARD if methotrexate is contraindicated or causes early intolerance. 1
The same principle of combining with short-term low-dose glucocorticoids applies. 1
Timeline and Monitoring
Expect maximal efficacy only after 4-6 months of optimal-dose methotrexate therapy—maintain the maximum tolerated dose (20-25 mg weekly) for at least 8-12 weeks before declaring treatment failure. 1
Assess response at 3 months—if no improvement occurs, therapy must be adjusted. 1, 4
The treatment target (remission or low disease activity) should be achieved by 6 months. 1, 4
Why Methotrexate Remains the Anchor Drug
The 2020 EULAR guidelines explicitly state that methotrexate remains the anchor drug in rheumatoid arthritis because it is efficacious as monotherapy and serves as the foundation for all combination therapies with other conventional DMARDs, biologics, or targeted synthetic DMARDs. 1 No biologic plus methotrexate has shown superiority compared to methotrexate plus glucocorticoids in DMARD-naïve patients. 1
Common Pitfalls to Avoid
Do not use inadequate methotrexate doses—many patients never reach the optimal 20-25 mg weekly dose, leading to premature escalation to biologics. 1
Do not wait 6 months to escalate the dose—reach the target dose within 4-6 weeks, then maintain it for at least 8 weeks. 1
Do not omit glucocorticoids in the initial strategy—the evidence clearly shows superior outcomes when low-dose prednisone is added initially and tapered over 6 months. 1
Do not start with biologic therapy—biologics are reserved for patients who fail methotrexate-based strategies, particularly those with poor prognostic factors (high disease activity, positive RF/anti-CCP, early erosions). 1
Do not use triple conventional DMARD therapy (methotrexate + sulfasalazine + hydroxychloroquine) as initial treatment—under tight control conditions, immediate triple therapy shows no advantage over methotrexate monotherapy with step-up as needed. 1
When to Escalate Beyond Methotrexate
If treatment target is not achieved by 6 months despite optimal methotrexate dosing (with or without glucocorticoids), then escalate therapy based on prognostic factors. 1
Patients with poor prognostic factors (high disease activity, RF/anti-CCP positivity, early erosions) should receive a biologic DMARD (TNF inhibitor, abatacept, or tocilizumab) added to methotrexate. 1
Patients without poor prognostic factors can be switched to another conventional DMARD strategy before considering biologics. 1