Folic Acid Dosing in Rheumatoid Arthritis Patients on Methotrexate
Prescribe at least 5 mg of folic acid per week for all patients with rheumatoid arthritis taking methotrexate. 1
Standard Dosing Protocol
The minimum recommended dose is 5 mg folic acid weekly, which can be administered as a single weekly dose or divided into daily doses (e.g., 1 mg daily for 5-6 days). 1, 2
Administer folic acid on all days except the day(s) when methotrexate is taken to avoid theoretical competition for cellular uptake that could reduce methotrexate efficacy. 2, 3
For practical implementation, a common regimen is 5 mg oral folic acid given the morning after methotrexate administration, though daily dosing (skipping methotrexate day) is equally acceptable. 4
Dose Adjustment Considerations
For patients on higher methotrexate doses (>15 mg/week), consider increasing folic acid to 7-10 mg weekly, as the protective effect is most significant at lower methotrexate doses (<10 mg/week). 2
Do not exceed 5 mg/week of folinic acid (leucovorin) if using this alternative form, as higher doses have been associated with reduced methotrexate efficacy (increased tender and swollen joints). 2
Recent evidence shows no additional benefit from very high doses: a randomized controlled trial comparing 10 mg versus 30 mg weekly folic acid found no difference in toxicity reduction or efficacy, even with methotrexate doses up to 25 mg/week. 5
Evidence for Benefits
Folic acid supplementation reduces gastrointestinal side effects by 26% (relative risk reduction), including nausea, vomiting, and abdominal pain. 6
Hepatotoxicity is reduced by 77% (relative risk reduction), with significant protection against elevated serum transaminases. 6
Patient discontinuation of methotrexate for any reason is reduced by 61% (relative risk reduction) with folate supplementation. 6
Meta-analysis of 788 RA patients demonstrated that folic acid reduces gastrointestinal side effects (OR 0.42) and hepatotoxicity (OR 0.17) without reducing methotrexate efficacy. 2
Critical Clinical Caveats
Folic acid does not compromise methotrexate efficacy when dosed at ≤5 mg/week, as demonstrated in multiple randomized controlled trials showing no significant effect on disease activity parameters (tender/swollen joint counts, physician global assessment). 6, 2
Prefer folic acid over folinic acid for routine supplementation due to lower cost and similar effectiveness in preventing side effects. 2
Do not confuse routine supplementation with leucovorin rescue therapy, which is reserved for methotrexate overdose or severe toxicity and requires immediate administration regardless of timing. 2
Continue regular monitoring (ALT/AST, CBC, creatinine every 1-1.5 months initially, then every 1-3 months) even with folic acid supplementation, as folate does not eliminate all risks. 1, 3