Should folic acid be taken with weekly methotrexate (MTX) for Rheumatoid Arthritis (RA)?

Folic Acid Supplementation with Methotrexate for Rheumatoid Arthritis

Prescription of at least 5 mg folic acid per week with methotrexate therapy is strongly recommended for patients with rheumatoid arthritis to reduce side effects while maintaining treatment efficacy. 1

Evidence for Folic Acid Supplementation

The recommendation for folic acid supplementation with methotrexate (MTX) is supported by strong evidence from multiple studies:

• A meta-analysis of nine studies including 788 RA patients demonstrated that folic acid supplementation reduces gastrointestinal and liver toxicity of methotrexate without reducing its efficacy 1
• Folic acid supplementation significantly reduces the risk of hepatotoxicity, with studies showing a protective effect with 1 mg/day folic acid (OR 0.17; 95% CI 0.09 to 0.32) 1
• Supplementation reduces the risk of gastrointestinal side effects by 26% relative (9% absolute) risk reduction (RR 0.74,95% CI 0.59 to 0.92) 2
• Folic acid supplementation reduces abnormal serum transaminase elevation by 76.9% relative (16% absolute) risk reduction (RR 0.23,95% CI 0.15 to 0.34) 2
• Patient withdrawal from MTX treatment is reduced by 60.8% relative (15.2% absolute) risk reduction with folic acid supplementation (RR 0.39,95% CI 0.28 to 0.53) 2

Dosing and Administration Guidelines

Recommended Dosage:

• At least 5 mg of folic acid per week 1
• Typically given as a single dose on a day when MTX is not administered 1

Timing Options:

1. Standard approach: 5 mg oral folic acid given on the morning following the day of MTX administration 3
2. Alternative approach: Daily folic acid except on the days when methotrexate is given 1

Clinical Benefits of Folic Acid Supplementation

Folic acid supplementation with MTX provides multiple benefits:

• Reduced hepatotoxicity: Significant reduction in liver function test abnormalities 1, 2, 4
• Improved gastrointestinal tolerance: Less nausea, vomiting, and abdominal pain 2, 4
• Better treatment adherence: Improved continuation rates of MTX therapy 2, 5
• No reduction in efficacy: Folic acid supplementation does not appear to significantly reduce the effectiveness of MTX in treating RA 1, 2

Folic Acid vs. Folinic Acid

While both folic acid and folinic acid (calcium folinate) are effective:

• No significant difference in efficacy between folic acid and folinic acid 4
• Folic acid is more cost-effective than folinic acid 4
• Low dosages (≤5 mg/week) of folinic acid do not reduce MTX efficacy, but higher doses (>5 mg/week) may increase tender and swollen joint counts 1

Common Pitfalls and Caveats

1. Dosing confusion: Some clinicians may hesitate to prescribe folic acid due to concerns about reducing MTX efficacy. Evidence shows that at recommended doses, folic acid does not reduce MTX efficacy for RA 2.

2. Timing issues: Folic acid should be taken on days when MTX is not administered to avoid potential interference with MTX efficacy 1.

3. Dose considerations: While at least 5 mg weekly is recommended, higher doses may be needed with higher MTX doses 1. However, there is no statistical difference between high-dose folate (≥25 mg per week) and low-dose folate (≤10 mg per week) on MTX efficacy or toxicity 5.

4. Monitoring requirements: Despite folic acid supplementation, regular monitoring of liver function, complete blood count, and creatinine is still required when using MTX 1.

Folic acid supplementation should be considered standard practice for all patients starting MTX therapy for rheumatoid arthritis, as it significantly improves the safety profile without compromising efficacy.