What is the recommended dosing regimen for methotrexate (MTX) and folic acid in patients with rheumatoid arthritis (RA)?

How to Take Methotrexate and Folic Acid for Rheumatoid Arthritis

Start with oral methotrexate 15 mg once weekly and escalate by 5 mg every 2-4 weeks to reach 20-25 mg weekly (maximum 30 mg) within 4-6 weeks, while taking at least 5 mg of folic acid per week to reduce side effects. 1, 2, 3

Initial Dosing Strategy

Begin with oral methotrexate at 15 mg once weekly rather than lower starting doses, as this provides superior disease control without compromising safety. 1, 3

• The starting dose should not be less than 10-15 mg/week, with 15 mg being the preferred initial dose. 1, 2, 3
• Escalate the dose by 5 mg increments every 2-4 weeks until reaching 20-25 mg weekly (up to 30 mg weekly maximum) based on clinical response and tolerability. 1, 2, 3
• Target a weekly dose of at least 15 mg within 4-6 weeks of starting treatment. 1, 2
• Fast escalation (5 mg/month) to 25-30 mg/week shows higher efficacy than slow escalation, though it may cause more adverse events. 1

Common pitfall: Do not start at doses below 10-15 mg weekly, as this delays achieving therapeutic effect and optimal disease control. 3

Folic Acid Supplementation

Take at least 5 mg of folic acid per week to reduce gastrointestinal and liver toxicity without reducing methotrexate's effectiveness. 2, 3

• Folic acid should be prescribed concurrently with methotrexate therapy from the start. 1
• Increase the folic acid dose if tolerability issues arise, such as nausea or mouth sores. 3
• The folic acid can be taken on any day except the day you take methotrexate. 2

Route of Administration

Start with oral methotrexate, but be prepared to switch to subcutaneous administration if needed. 1, 2, 3

• Oral administration is recommended as the initial route for most patients. 1
• Switch to subcutaneous methotrexate (at the same dose, not increased) if oral therapy at the maximum tolerated dose fails to achieve adequate disease control. 1, 3
• Subcutaneous administration has greater bioavailability and may provide higher clinical efficacy, though with potentially more withdrawal due to injection-related issues. 2, 4
• Consider subcutaneous route earlier for patients with gastrointestinal side effects, poor compliance, obesity requiring doses >20 mg/week, or very active disease. 5, 4

Managing Intolerance to Oral Methotrexate

If you experience gastrointestinal side effects (nausea, vomiting) with oral methotrexate:

• Try splitting the oral dose over 24 hours (taking half in the morning and half 12 hours later). 1, 3
• Switch to subcutaneous injections at the same weekly dose. 1, 3
• Increase folic acid supplementation beyond the minimum 5 mg/week. 1, 3

Important: These strategies should be attempted before switching to alternative medications entirely. 1, 3

Timing and Frequency

• Take methotrexate once weekly on the same day each week. 1, 6
• Weekly dosing is the standard and preferred frequency of administration. 1
• The medication can be taken as a single dose or divided into 2-3 doses given 12 hours apart over 24 hours (2.5 mg at 12-hour intervals for 3 doses). 6

Expected Timeline for Response

• Therapeutic response usually begins within 3-6 weeks of starting treatment. 6, 7
• Full therapeutic effect often requires 12 weeks or longer, so patience is essential. 3, 7
• Assess treatment response at 3 months; if no improvement is seen, modify treatment. 3
• The treatment target is remission or low disease activity within 6 months. 3

Common pitfall: Do not switch to alternative medications prematurely; continue oral methotrexate for at least 6 months (as long as some response is seen within 3 months) before declaring treatment failure. 3

Required Monitoring

Before Starting Methotrexate:

• Complete blood count (CBC), liver enzymes (ALT/AST), albumin, creatinine with creatinine clearance calculation. 2, 6
• Chest radiograph (within the previous year). 2, 6
• Screen for hepatitis B/C and latent tuberculosis. 3

During Treatment:

• Monitor ALT/AST, creatinine, and CBC every 1-1.5 months until a stable dose is reached. 2, 5
• After stabilization, monitor every 1-3 months. 2, 5
• Clinical assessment for side effects at each visit. 2

When to Stop or Reduce Dose:

• Stop methotrexate if ALT/AST increases to greater than 3 times the upper limit of normal. 2
• Consider reinstituting at a lower dose after liver enzymes normalize. 2
• Reduce dose if significant cytopenia (low blood counts) develops. 6

Absolute Contraindications

Methotrexate must not be used during pregnancy or for at least 3 months before planned pregnancy in both men and women. 2, 3

• Effective contraception is essential during methotrexate therapy. 6
• The drug can cause severe birth defects and fetal death. 6

Key Advantages of This Approach

• Methotrexate remains the gold standard disease-modifying drug for rheumatoid arthritis due to its favorable efficacy, acceptable toxicity profile, and low cost. 1, 8, 7
• At 1 year, one-third of patients on methotrexate have no radiographic progression of joint damage. 7
• Methotrexate is appropriate for long-term use based on its acceptable safety profile. 2
• The initial clinical improvement is maintained for at least two years with continued therapy. 6