What is the recommended treatment regimen for rheumatoid arthritis using Methotrexate?

Methotrexate Regimen for Rheumatoid Arthritis

Oral methotrexate should be started at 10-15 mg/week, with escalation of 5 mg every 2-4 weeks up to 20-30 mg/week, depending on clinical response and tolerability, with parenteral administration considered in case of inadequate response or intolerance. 1, 2

Initial Dosing and Escalation

• Start with oral methotrexate at 10-15 mg/week 1, 2
• Escalate dose by 5 mg every 2-4 weeks 1
• Target dose range: 20-30 mg/week or highest tolerable dose 1, 2
• Higher starting doses (15 mg/week vs lower doses) have shown better clinical efficacy without increased toxicity 1
• Rapid dose escalation (5 mg/month) to target dose has demonstrated higher efficacy, though with potentially more adverse events 1

Route of Administration

• Begin with oral administration due to convenience 1, 2
• Switch to subcutaneous/intramuscular administration if:
  • Inadequate clinical response to optimized oral dosing 1, 2
  • Intolerable gastrointestinal side effects 1, 2
  • Poor compliance with oral regimen 2
• Subcutaneous administration has greater bioavailability and may result in higher efficacy with less gastrointestinal toxicity compared to oral administration 1

Folic Acid Supplementation

• Prescription of at least 5 mg folic acid per week with methotrexate therapy is strongly recommended 1, 2
• Folic acid reduces gastrointestinal and liver toxicity without reducing efficacy 1
• Do not administer folic acid on the same day as methotrexate to avoid interfering with efficacy 2

Monitoring Requirements

• Before starting methotrexate:

  • Complete blood count (CBC)
  • Liver function tests (AST, ALT, albumin)
  • Renal function (creatinine)
  • Chest X-ray (obtained within previous year)
  • Consider serology for HIV, hepatitis B/C 1

• During treatment:

  • Monitor ALT/AST, creatinine, and CBC every 1-1.5 months until stable dose is reached
  • Continue monitoring every 1-3 months thereafter
  • Clinical assessment for side effects at each visit 1, 2

Management of Toxicity

• Stop methotrexate if ALT/AST increases to >3 times upper limit of normal
• May reinstitute at lower dose after normalization
• Adjust dose if ALT/AST levels are persistently elevated up to 3 times upper limit of normal 1
• Consider diagnostic procedures for persistently elevated liver enzymes after discontinuation 1

Treatment Strategy

• Methotrexate monotherapy is favored over combination with other conventional DMARDs in DMARD-naive patients 1
• Consider methotrexate as the anchor for combination therapy when monotherapy does not achieve disease control 1, 3
• Follow a treat-to-target approach, aiming for low disease activity or remission 2
• Evaluate response every 4 weeks during dose escalation 2

Important Precautions

• Methotrexate should not be used for at least 3 months before planned pregnancy for both men and women
• Contraindicated during pregnancy and breastfeeding 1
• Can be safely continued during perioperative period for patients undergoing elective orthopedic surgery 1

Common Pitfalls and Caveats

1. Inadequate dose optimization: Many patients are maintained on suboptimal doses. Ensure proper dose escalation before considering treatment failure.

2. Insufficient folic acid supplementation: Folic acid is essential to reduce side effects and improve adherence.

3. Premature discontinuation: Based on its acceptable safety profile, methotrexate is appropriate for long-term use 1.

4. Improper monitoring: Regular laboratory monitoring is crucial to detect potential toxicity early.

5. Failure to consider route change: Before switching to biologics, ensure methotrexate has been optimized by reaching maximum tolerable dose and trying subcutaneous administration 2.

Methotrexate remains the cornerstone of rheumatoid arthritis therapy with one of the best efficacy/toxicity ratios among disease-modifying antirheumatic drugs 3, 4.