What is the recommended dosing of methotrexate (Disease-Modifying Antirheumatic Drug (DMARD)) and folic acid (Vitamin B9) in patients with Rheumatoid Arthritis (RA)?

Methotrexate and Folic Acid Dosing in Rheumatoid Arthritis

Methotrexate Dosing Recommendations

For optimal outcomes in rheumatoid arthritis, start methotrexate at 15 mg/week orally, escalate by 5 mg/month to 25-30 mg/week or the highest tolerable dose, with a switch to subcutaneous administration if there is inadequate response. 1, 2

Initial Dosing:

• Start with oral methotrexate at 15 mg/week (not less than 10 mg/week) 2, 3
• The starting dose should be determined based on disease severity and patient factors 3
• Higher starting doses (15 mg vs. 7.5 mg) may cause more nausea but don't significantly improve efficacy when using a fast escalation protocol 4

Dose Escalation:

• Increase dose by 5 mg every month to reach 25-30 mg/week (maximum) 1, 2
• Fast escalation (5 mg/month) to 25-30 mg/week shows higher efficacy than slow escalation (5 mg every 3 months) but may have more adverse events 2, 5
• Dose should be increased if there is inadequate clinical response at intervals of 6 weeks 3

Route of Administration:

• Oral administration is recommended as the initial route 1, 2
• Switch to subcutaneous or intramuscular administration if: 1, 2
  • Inadequate clinical response at highest tolerable oral dose
  • Intolerance to oral route (particularly gastrointestinal side effects)
  • Poor compliance
• Subcutaneous administration has greater bioavailability and may provide higher clinical efficacy in early RA 2, 5

Folic Acid Supplementation

Prescription of at least 5 mg folic acid per week with methotrexate therapy is strongly recommended to reduce gastrointestinal and liver toxicity without reducing efficacy. 1

Dosing:

• Minimum of 5 mg folic acid per week 1, 2
• Should be administered at a distance from the methotrexate dose 3
• Some evidence suggests higher doses (7-35 mg/week) may provide better protection against gastrointestinal side effects, particularly with higher methotrexate doses 1

Benefits:

• Reduces gastrointestinal toxicity 1, 3
• Reduces liver toxicity 1, 2
• Does not reduce the efficacy of methotrexate 1, 3

Monitoring Protocol

Before Starting Methotrexate:

• Clinical assessment of risk factors for methotrexate toxicity 2
• Laboratory tests: AST, ALT, albumin, CBC, creatinine 2, 3
• Chest x-ray (within previous year) 2, 3

During Treatment:

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

Management of Adverse Effects

• Stop methotrexate if ALT/AST increases to greater than three times the upper limit of normal 1, 2
• Consider reinstituting at a lower dose after normalization of liver enzymes 1, 2
• For patients not tolerating oral weekly methotrexate, consider: 2, 5
  • Split dosing over 24 hours
  • Switching to subcutaneous injections

Special Considerations

• Methotrexate is appropriate for long-term use based on its acceptable safety profile 1, 2
• In DMARD-naive patients, methotrexate monotherapy is favored over combination with other conventional DMARDs 1, 2
• Methotrexate can be safely continued during the perioperative period for patients undergoing elective orthopedic surgery 1, 2
• Methotrexate should not be used for at least 3 months before planned pregnancy for both men and women 1, 2

Common Pitfalls and Caveats

• Inadequate dosing: Many clinicians start with doses that are too low (less than 10 mg/week) or fail to escalate quickly enough 3, 6
• Premature discontinuation: Before declaring methotrexate ineffective, ensure adequate dose (at least 20-25 mg/week) and consider switching to subcutaneous route 5, 6
• Inadequate folic acid supplementation: Failure to prescribe adequate folic acid leads to unnecessary side effects and discontinuation 1, 3
• Overlooking route optimization: Patients with inadequate response to oral methotrexate may benefit from switching to subcutaneous administration before adding biologics 5, 6