Methotrexate Prescribing Protocol 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
Initial Dosing and Titration
- Start with oral methotrexate at 10-15 mg/week 1
- Escalate dose by 5 mg every 2-4 weeks until reaching 20-30 mg/week or the highest tolerable dose 1
- Target a weekly dose of at least 15 mg within 4-6 weeks of initiation 1
- Higher starting doses (25 mg/week) may be more effective but have increased gastrointestinal toxicity compared to lower doses 1
- Fast escalation (5 mg/month) to 25-30 mg/week shows higher efficacy but more adverse events than slow escalation 1
Route of Administration
- Oral administration is recommended as the initial route 1
- Consider switching to subcutaneous or intramuscular administration if: 1
- Inadequate clinical response to oral methotrexate at maximum tolerable dose
- Intolerance to oral administration (particularly gastrointestinal side effects)
- Subcutaneous administration has greater bioavailability and may provide higher clinical efficacy in early RA, though with potentially more withdrawal due to toxicity 1
- When transitioning from oral to subcutaneous, maintain the same dose rather than increasing it 2
Monitoring Protocol
Before starting methotrexate, obtain: 1
- Clinical assessment of risk factors for methotrexate toxicity (including alcohol intake)
- Patient education
- Laboratory tests: AST, ALT, albumin, CBC, creatinine
- Chest x-ray (within previous year)
- Consider: serology for HIV, hepatitis B/C, fasting glucose, lipid profile, pregnancy test
During treatment: 1
- Monitor ALT/AST, creatinine, and CBC every 1-1.5 months until stable dose is reached
- Once stable, continue monitoring every 1-3 months
- Perform clinical assessment for side effects at each visit
Folic Acid Supplementation
- Prescribe at least 5 mg folic acid per week with methotrexate therapy 1
- Administer folic acid at a distance from the methotrexate dose 3
- Folic acid supplementation reduces gastrointestinal and liver toxicity without reducing efficacy 1
Management of Adverse Effects
- Stop methotrexate if ALT/AST increases to greater than three times the upper limit of normal 1
- Consider reinstituting at a lower dose after normalization of liver enzymes 1
- For persistent ALT/AST elevation up to three times ULN, adjust methotrexate dose 1
- For patients not tolerating oral weekly methotrexate, consider: 1
- Split dosing over 24 hours
- Switching to subcutaneous injections
- Increasing folic acid dose
Special Considerations
- Methotrexate is appropriate for long-term use based on its acceptable safety profile 1
- In DMARD-naive patients, methotrexate monotherapy is favored over combination with other conventional DMARDs 1
- Methotrexate can be safely continued during the perioperative period for patients undergoing elective orthopedic surgery 1
- Contraception is essential - methotrexate should not be used for at least 3 months before planned pregnancy for both men and women, and is contraindicated during pregnancy and breastfeeding 1, 4
Common Pitfalls to Avoid
- Inadequate initial dosing (starting below 10 mg/week) may lead to suboptimal response 1, 3
- Premature discontinuation before 6 months may not allow sufficient time to assess efficacy 2
- Failure to provide folic acid supplementation increases risk of adverse effects 1
- Not considering parenteral administration when oral therapy fails 1, 2
- Inadequate monitoring of laboratory parameters may miss early signs of toxicity 1
By following this evidence-based protocol for methotrexate prescribing in rheumatoid arthritis, clinicians can optimize treatment efficacy while minimizing adverse effects, ultimately improving patient outcomes in terms of morbidity, mortality, and quality of life.