What is the recommended dose of methotrexate (disease-modifying antirheumatic drug (DMARD)) for an adult patient with rheumatoid arthritis?

Methotrexate Dosing for Rheumatoid Arthritis

Start methotrexate at 15 mg weekly by oral route and escalate by 5 mg per month to reach a target dose of 25-30 mg weekly or the maximum tolerated dose within 4-6 weeks. 1, 2

Initial Dosing Strategy

• Begin with 15 mg weekly orally as the evidence-based starting dose, which balances efficacy and tolerability better than lower starting doses 1, 2
• The oral route is preferred initially due to ease of administration, lower cost, and similar bioavailability at typical starting doses 1
• Starting doses of 7.5 mg weekly are acceptable but may delay optimal disease control 1, 3
• Avoid starting below 10 mg weekly, as this leads to inadequate disease control 4

Dose Escalation Protocol

• Increase the dose by 5 mg every 2-4 weeks (preferably monthly) until reaching 25-30 mg weekly or the maximum tolerated dose 1, 2
• This escalation should occur within 4-6 weeks of initiation 1
• Therapeutic response typically begins within 3-6 weeks but may take up to 12 weeks 3, 5
• The target dose of 25-30 mg weekly demonstrates superior clinical efficacy compared to slower escalation or lower maintenance doses 1, 2

Route of Administration Adjustments

• Switch to subcutaneous administration at the same dose if inadequate response occurs at 20-25 mg weekly oral dosing, rather than further dose escalation 1, 2
• Parenteral (subcutaneous or intramuscular) methotrexate has higher bioavailability and should be considered for 1:
  • Inadequate clinical response to oral therapy at optimal doses
  • Gastrointestinal intolerance (nausea, vomiting)
  • Poor compliance with oral medication
  • Doses exceeding 20 mg weekly (where oral absorption becomes less reliable)
• Subcutaneous administration at 15 mg weekly in early RA shows higher clinical efficacy than oral dosing, though with slightly more withdrawal due to toxicity 1

Essential Concurrent Therapy

• Prescribe at least 5 mg folic acid per week to reduce gastrointestinal and hepatotoxicity without compromising efficacy 1, 5
• Higher doses of folic/folinic acid (up to 7-35 mg weekly) may be needed if side effects persist 1

Monitoring Requirements

• Perform ALT/AST, creatinine, and complete blood count every 1-1.5 months until stable dose is reached, then every 1-3 months thereafter 1, 2
• Stop methotrexate if ALT/AST exceeds 3 times the upper limit of normal; may reinstitute at lower dose after normalization 1, 2
• Clinical assessment for side effects should occur at each visit 1

Maximum Dosing Considerations

• Doses exceeding 20 mg weekly significantly increase the risk of serious adverse reactions, particularly myelosuppression 1, 3
• The usual maximum dose is 25-30 mg weekly for adults 1, 2
• Do not ordinarily exceed 30 mg weekly for psoriasis indications 3

Alternative Dosing Strategies for Intolerance

• If oral weekly dosing is not tolerated, consider 1:
  • Split the oral dose over 24 hours (e.g., divided doses at 12-hour intervals)
  • Switch to subcutaneous administration
  • Increase folic/folinic acid supplementation
• These strategies should be attempted before switching to alternative DMARDs 1

Critical Pitfall to Avoid

The most common error is underdosing methotrexate, leading to inadequate disease control and premature switching to biologic agents. 2 Ensure optimization to 25-30 mg weekly (or maximum tolerated dose) and trial of parenteral administration before declaring methotrexate failure. 1, 2

Long-Term Use

• Methotrexate has an acceptable safety profile for long-term use and should be considered the anchor drug for combination therapy when monotherapy fails to achieve disease control 1
• Initial clinical improvement is typically maintained for at least two years with continued therapy 3
• Arthritis usually worsens within 3-6 weeks after discontinuation 3