What is the recommended starting dose and monitoring protocol when initiating methotrexate (Disease-Modifying Antirheumatic Drug (DMARD)) for rheumatoid arthritis?

Methotrexate Initiation Protocol for Rheumatoid Arthritis

The recommended starting dose for methotrexate in rheumatoid arthritis is 10-15 mg/week orally, with escalation of 5 mg every 2-4 weeks up to 20-30 mg/week, depending on clinical response and tolerability. 1, 2

Initial Dosing and Titration

• Start with oral methotrexate at 10-15 mg/week, with a target of reaching at least 15 mg/week within 4-6 weeks of initiation 1, 2
• Escalate dose by 5 mg every 2-4 weeks up to 20-30 mg/week based on clinical response and tolerability 1, 2
• Higher starting doses (25 mg/week) may provide better efficacy but are associated with increased gastrointestinal side effects 3
• Therapeutic response typically begins within 3-6 weeks, with continued improvement possible for another 12 weeks or more 4

Route of Administration

• Oral administration is conditionally recommended over subcutaneous methotrexate for patients initiating therapy, due to ease of administration 1, 2
• Consider switching to subcutaneous or intramuscular administration in cases of:
  • Inadequate clinical response to oral methotrexate 1
  • Intolerance to oral formulation (particularly gastrointestinal side effects) 1, 2
  • Poor compliance with oral therapy 1
• Subcutaneous administration has greater bioavailability and may provide higher clinical efficacy 2, 5

Pre-Treatment Evaluation

• Before starting methotrexate, obtain the following mandatory tests 1, 2:
  • Complete blood count (CBC)
  • Liver function tests (AST, ALT, albumin)
  • Renal function tests (serum creatinine with creatinine clearance)
  • Chest X-ray (within the previous year)
• Consider additional testing 1, 2:
  • Hepatitis B/C serology
  • HIV serology
  • Fasting blood glucose
  • Lipid profile
  • Pregnancy test in women of childbearing potential
• Clinical assessment of risk factors for methotrexate toxicity, including alcohol intake 1
• Patient education regarding risks, benefits, and proper administration 1

Monitoring Protocol

• During dose escalation and initial treatment 1, 2:
  • Monitor ALT/AST, creatinine, and CBC every 1-1.5 months until a stable dose is reached
  • Perform clinical assessment for side effects at each visit
• After achieving stable dose 1, 2:
  • Continue monitoring ALT/AST, creatinine, and CBC every 1-3 months
  • Maintain regular clinical assessment for side effects

Folic Acid Supplementation

• Prescribe at least 5 mg folic acid per week with methotrexate therapy 1, 2
• Folic acid supplementation reduces gastrointestinal and liver toxicity without compromising efficacy 2
• Administer folic acid at a distance from the methotrexate dose 6

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 patients not tolerating oral weekly methotrexate, consider 1, 2:
  • Split dosing over 24 hours
  • Switching to subcutaneous injections
  • Increasing folic acid supplementation

Common Pitfalls and Caveats

• Avoid daily dosing - emphasize to patients that methotrexate for rheumatoid arthritis is taken weekly, not daily, as mistaken daily use has led to fatal toxicity 4
• Monitor for drug interactions, particularly with NSAIDs, which may increase methotrexate toxicity by reducing tubular secretion 4
• Ensure contraception during treatment, as methotrexate is contraindicated in pregnancy 4
• Be aware that gastrointestinal side effects (particularly nausea) are more common with higher starting doses 7, 3
• Recognize that therapeutic response may take several weeks to develop, and patients may continue to improve for up to 12 weeks or more 4
• When methotrexate is discontinued, arthritis typically worsens within 3-6 weeks 4