What is the recommended dosing for methotrexate (disease-modifying antirheumatic drug) in adults with rheumatoid arthritis?

Methotrexate Dosing for Rheumatoid Arthritis

The optimal methotrexate dosing regimen for adults with rheumatoid arthritis is to start at 10-15 mg/week orally, with escalation of 5 mg every 2-4 weeks up to 20-30 mg/week or the highest tolerable dose, with a subsequent switch to subcutaneous administration if oral therapy provides inadequate response. 1

Initial Dosing Strategy

• Starting dose: 10-15 mg/week orally 1, 2

  • Doses below 10 mg/week are associated with suboptimal response 1
  • Higher starting doses (15 mg/week) may cause more nausea than lower doses (7.5 mg/week) 3

• Dose escalation: Increase by 5 mg every 2-4 weeks 1

  • Fast escalation (5 mg/month) to target dose of 25-30 mg/week shows higher clinical efficacy but may cause more adverse events 4, 1
  • Slow escalation (5 mg every 3 months) results in lower maximum doses (mean 18 mg/week) with potentially fewer side effects 4

• Target dose: 20-30 mg/week or highest tolerable dose 1, 5

  • Maximum recommended oral dose is 25-30 mg/week 1, 2
  • Limited evidence shows significant increase in serious toxicity, especially bone marrow suppression, at doses greater than 20 mg/week in adults 2

Route of Administration

• Initial route: Oral administration is recommended for patients initiating methotrexate 1

• Consider switching to subcutaneous/intramuscular route when:

  • Inadequate clinical response to oral methotrexate at maximum tolerable dose 4, 1
  • Intolerance to oral methotrexate (especially gastrointestinal side effects) 1
  • Doses exceed 15 mg/week (due to decreased oral bioavailability at higher doses) 1

• Subcutaneous administration: Starting with 15 mg/week subcutaneously shows higher clinical efficacy but may cause more withdrawal due to toxicity in early RA 4

Monitoring and Toxicity Management

• Required laboratory monitoring:

  • Complete blood count, liver enzymes (ALT/AST), and serum creatinine 1, 6
  • Monitor every 1-1.5 months until stable dose, then every 1-3 months 1, 6

• Folic acid supplementation:

  • At least 5 mg per week is strongly recommended to reduce toxicity 1, 6
  • Should be given at a distance from the methotrexate dose 6

• Managing gastrointestinal side effects:

  • Consider split dosing (three doses given 12 hours apart) 1
  • Switch to subcutaneous administration 1
  • Increase folic acid supplementation 1

Common Pitfalls to Avoid

• Starting with inadequate doses (below 10 mg/week) 1
• Insufficient dose escalation or failure to reach target dose 1
• Not switching to subcutaneous route when oral therapy is inadequate 1
• Inadequate folic acid supplementation 1, 6
• Insufficient monitoring of laboratory parameters 1, 6

Clinical Response Timeline

• Therapeutic response typically begins within 3-6 weeks 2
• Patients may continue to improve for another 12 weeks or more 2
• When methotrexate is discontinued, arthritis usually worsens within 3-6 weeks 2

The evidence strongly supports starting with at least 10-15 mg/week of oral methotrexate with rapid escalation to 20-30 mg/week for optimal clinical outcomes in rheumatoid arthritis, while maintaining appropriate monitoring and folic acid supplementation to minimize toxicity.