What is the recommended dosage and treatment regimen for methotrexate (disease-modifying antirheumatic drug) in patients with rheumatoid arthritis?

Methotrexate Dosing and Treatment Regimen for Rheumatoid Arthritis

For patients with rheumatoid arthritis, methotrexate should be started at 15 mg/week orally, with escalation by 5 mg every 2-4 weeks up to 25-30 mg/week or the highest tolerable dose, with consideration of switching to subcutaneous administration if response is inadequate. 1, 2

Initial Dosing and Titration

• Start with oral methotrexate at 15 mg/week to optimize efficacy while maintaining an acceptable safety profile 1, 2
• Escalate the dose by 5 mg every month to reach 25-30 mg/week (or the highest tolerable dose) for optimal clinical response 2, 1
• Fast escalation (5 mg/month) to 25-30 mg/week shows higher efficacy than slow escalation (5 mg every 3 months), though with potentially more adverse events 1, 2
• Continue treatment for at least 6 months (as long as there is some response within 3 months) to properly assess efficacy 3
• Therapeutic response typically begins within 3-6 weeks, with continued improvement for another 12 weeks or more 4

Route of Administration

• Oral administration is recommended as the initial route due to convenience, lower cost, and patient preference 1, 5
• Consider switching to subcutaneous or intramuscular administration if:
  • Patient shows inadequate response to optimal oral dosing 1, 2
  • Patient experiences intolerable gastrointestinal side effects 5
  • Patient has poor compliance with oral therapy 5
• Subcutaneous administration has greater bioavailability and may provide higher clinical efficacy in early RA patients 1, 5
• When transitioning from oral to subcutaneous administration, maintain the same dose rather than increasing it 3

Folic Acid Supplementation

• Prescribe at least 5 mg of folic acid per week with methotrexate therapy to reduce gastrointestinal and liver toxicity without reducing efficacy 2, 1
• Administer folic acid at a distance from the methotrexate dose (not on the same day) 6
• Higher doses of folic acid may be needed in some patients to further reduce side effects 2

Monitoring Protocol

• Before starting methotrexate:

  • Complete blood count (CBC)
  • Liver function tests (AST, ALT, albumin)
  • Renal function (serum creatinine with creatinine clearance)
  • Chest X-ray 1, 6

• During treatment:

  • Monitor ALT/AST, creatinine, and CBC every 1-1.5 months until a stable dose is reached
  • Continue monitoring every 1-3 months thereafter 1, 6
  • If ALT/AST increases to greater than three times the upper limit of normal, stop methotrexate and consider reinstituting at a lower dose after normalization 1, 2

Special Considerations

• For patients not tolerating oral weekly methotrexate, consider split dosing over 24 hours or switching to subcutaneous injections 1
• Methotrexate can be safely continued during the perioperative period for patients undergoing elective orthopedic surgery 2, 1
• Contraception is essential, and methotrexate should not be used for at least 3 months before planned pregnancy for both men and women 2, 1
• Twice weekly administration does not show advantages over once weekly dosing in terms of efficacy 7
• In DMARD-naive patients, methotrexate monotherapy is favored over combination with other conventional DMARDs initially 2, 1

Management of Common Side Effects

• Nausea is more common with higher starting doses (15 mg vs. 7.5 mg) 8
• Gastrointestinal side effects can often be managed with folic acid supplementation or by switching to parenteral administration 5, 6
• Hepatotoxicity risk can be minimized with appropriate monitoring and folic acid supplementation 2, 1

Clinical Pearls

• The optimal duration of therapy is unknown, but long-term studies indicate that initial clinical improvement is maintained for at least two years with continued therapy 4
• When methotrexate is discontinued, arthritis usually worsens within 3-6 weeks 4
• Subcutaneous formulation may lead to greater independence and improved quality of life for many patients 5
• If another RA treatment becomes necessary, maintain the methotrexate dosage and route of administration rather than discontinuing it 3