Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis.

Systematic review and meta-analysis of six randomized trials in adults with rheumatoid arthritis receiving low-dose methotrexate in international hospital and clinic settings. The trials included 624 participants overall, with 385 treated with folic acid or folinic acid and the remainder receiving placebo; one study used a crossover design.

Low-dose folic acid or folinic acid was given during methotrexate therapy for rheumatoid arthritis and compared with placebo. Regimens included folic acid 1 mg/day or 5 mg/week, and folinic acid 1 mg/week, 2.5 to 5 mg/week, or approximately a methotrexate-equivalent weekly dose.

Folic acid or folinic acid supplementation was overall protective and did not reduce methotrexate’s anti-rheumatic efficacy. The review found fewer gastrointestinal side effects, less hepatic dysfunction measured by liver enzyme elevations, and fewer methotrexate discontinuations, with a trend toward fewer mouth ulcers. Individual trials showed lower gastrointestinal events in several studies, including 4/44 versus 14/48 in one folinic acid trial and 16/141 versus 55/137 in the largest folic acid trial, while liver toxicity was also reduced, such as 1/44 versus 11/48 and 16/141 versus 52/137. No clear difference was found between folic acid and folinic acid.

Haematologic side effects could not be clearly assessed because data were limited. The evidence base was small, with only six trials and several modest per-arm sample sizes, and dosing and trial designs varied across studies. Outcome reporting was incomplete for some endpoints, limiting certainty about the size of benefit.