To perform a systematic review of the benefits and harms of folic acid and folinic acid in reducing the mucosal, gastrointestinal, hepatic, and hematologic side effects of methotrexate (MTX); and to assess whether folic or folinic acid supplementation has any effect on MTX benefit.

We searched the Cochrane Library, MEDLINE, EMBASE, and US National Institutes of Health clinical trials registry from inception to March 2012. We selected all double-blind, randomized, placebo-controlled clinical trials in which adult patients with rheumatoid arthritis (RA) were treated with MTX (dose ≤ 25 mg/week) concurrently with folate supplementation. We included only trials using low-dose folic or folinic acid (a starting dose of ≤ 7 mg weekly) because the high dose is no longer recommended or used. Data were extracted from the trials, and the trials were independently assessed for risk of bias using a predetermined set of criteria.

Six trials with 624 patients were eligible for inclusion. Most studies had low or unclear risk of bias for key domains. The quality of the evidence was rated as "moderate" for each outcome as assessed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) working group, with the exception of hematologic side effects, which were rated as "low." There was no significant heterogeneity between trials, including where folic acid and folinic acid studies were pooled. For patients supplemented with any form of exogenous folate (either folic or folinic acid) while receiving MTX therapy for RA, a 26% relative (9% absolute) risk reduction was seen for the incidence of gastrointestinal side effects such as nausea, vomiting, or abdominal pain (RR 0.74, 95% CI 0.59 to 0.92; p = 0.008). Folic and folinic acid also appear to be protective against abnormal serum transaminase elevation caused by MTX, with a 76.9% relative (16% absolute) risk reduction (RR 0.23, 95% CI 0.15 to 0.34; p < 0.00001), as well as reducing patient withdrawal from MTX for any reason [60.8% relative (15.2% absolute) risk reduction, RR 0.39, 95% CI 0.28 to 0.53; p < 0.00001].

The results support a protective effect of supplementation with either folic or folinic acid for patients with RA during treatment with MTX. There was a clinically important significant reduction shown in the incidence of GI side effects and hepatic dysfunction (as measured by elevated serum transaminase levels), as well as a clinically important significant reduction in discontinuation of MTX treatment for any reason.