What is the typical starting dose of methotrexate (Disease-Modifying Antirheumatic Drug (DMARD)) for an adult patient with rheumatoid arthritis (RA)?

Methotrexate Dosing in Rheumatoid Arthritis

Start methotrexate at 15 mg weekly and escalate by 5 mg per month to reach 25-30 mg weekly or the maximum tolerated dose. This evidence-based strategy, recommended by the American College of Rheumatology, achieves optimal disease control while balancing efficacy and toxicity 1, 2.

Starting Dose

• Begin with 15 mg weekly orally as the optimal starting dose based on systematic review of randomized controlled trials 1, 2.
• The FDA label describes alternative starting regimens of 7.5 mg weekly or divided doses of 2.5 mg at 12-hour intervals for 3 doses weekly, but these represent older, suboptimal approaches 3.
• Starting at 7.5 mg versus 15 mg shows no significant difference in efficacy at 12 weeks when both groups undergo rapid escalation, but the 15 mg starting dose reaches therapeutic levels faster 4.
• Starting doses of 25 mg weekly show greater efficacy but trend toward more gastrointestinal toxicity compared to 15 mg weekly 2.

Dose Escalation Strategy

• Escalate by 5 mg every month (every 2-4 weeks per EULAR) until reaching 25-30 mg weekly or the maximum tolerated dose 1, 2.
• Rapid escalation (5 mg/month to 25-30 mg/week) achieves higher efficacy but increases adverse events compared to slow escalation (5 mg every 3 months) 5, 2.
• The target dose of 25-30 mg weekly demonstrates superior clinical efficacy compared to slower escalation or lower doses 1.
• Continue escalation if DAS28 remains >2.6 and no laboratory abnormalities occur 4.

Route of Administration

• Start with oral administration due to patient preference and lower cost 5, 6.
• Switch to subcutaneous administration at the same dose (rather than further oral dose escalation) if inadequate response occurs at 20-25 mg weekly oral dosing 1.
• Subcutaneous methotrexate at 15 mg weekly achieves significantly more ACR20 responses (85% vs 77%, OR 1.7) compared to oral administration at the same dose 5.
• Parenteral bioavailability is higher than oral, particularly at doses above 15-20 mg weekly 6.

Critical Dosing Pitfall

The most common error is underdosing methotrexate, leading to inadequate disease control and premature switching to biologics 1. Ensure optimization to 25-30 mg weekly or maximum tolerated dose before declaring methotrexate failure 1.

Essential Concurrent Therapy

• Prescribe at least 5 mg folic acid weekly with methotrexate therapy—this is a strong recommendation 1, 2.
• Folic acid significantly reduces gastrointestinal and liver toxicity without reducing efficacy 5, 2.

Monitoring Requirements

• Before starting: Obtain AST, ALT, albumin, CBC, creatinine, chest X-ray (within past year), and assess alcohol intake 2.
• During initiation/escalation: Check ALT, creatinine, and CBC every 1-1.5 months until dose is stable 1, 2.
• After stabilization: Monitor every 1-3 months 1, 2.
• Stop methotrexate if ALT/AST exceeds 3× upper limit of normal 1.

Timeline for Response

• Therapeutic response typically begins within 3-6 weeks, with continued improvement for another 12 weeks or more 3.
• After dose increases, allow up to 4 weeks for clinical response to occur 5.

Maximum Dosing

• The FDA label states that doses greater than 20 mg/week in adults show significantly increased incidence and severity of serious toxic reactions, especially bone marrow suppression 3.
• However, current evidence-based guidelines recommend 25-30 mg weekly as the target dose when tolerated, reflecting evolution in clinical practice supported by systematic reviews 5, 1, 2.
• Weekly dosages typically range from 7.5 to 25 mg, with 30 mg/week not ordinarily exceeded per FDA guidance 5, 3.