For this study researchers wanted to examine the evidence for the benefits and harms of folate (folic acid or folinic acid) supplementation on methotrexate (MTX) treatment for rheumatoid arthritis (RA), and whether folate supplementation would reduce MTX toxicity or benefits, and determine whether a higher MTX dosage is required. From conception until 2 June 2016, They used a sensitive search strategy and thoroughly searched the Medline, Embase, Web of Science, and Cochrane Library databases. They also reviewed abstracts from major rheumatology meetings and major trial databases to find any randomized controlled studies that piqued our attention.

Seven trials with a total of 709 patients were included in the analysis. There was no significant difference between these studies. Patients with RA using MTX who were given folate were less likely to have increased transaminase (odds ratio [OR] 0.15; 95% confidence interval [95% CI] 0.10, 0.23 [p < 0.00001]) and gastrointestinal side symptoms such nausea and vomiting (OR 0.71; 95% CI 0.51, 0.99 [p = 0.04]). Folate seemed to improve MTX compliance by reducing patient withdrawal when compared to placebo (OR 0.29; 95% CI 0.21, 0.42 [p < 0.00001]). For mouth sores, there was no substantial difference between folate and placebo (OR 0.83; 95% CI 0.57, 1.22 [p = 0.35]). Because the disease activity indicators used in those trials were inconsistent, it was unable to determine whether folate supplementation impacted MTX effectiveness. Furthermore, they compared high-dose folate (≥25 mg per week) to low-dose folate (≤10 mg per week) on MTX effectiveness and found no significant difference (OR 2.07; 95% CI 0.81, 5.30 [p = 0.13]), nor on MTX toxicity (OR 1.56; 95% CI 0.80,3.04 [p = 0.19]).

Folate supplementation has been shown to lower the incidence of MTX hepatotoxicity and gastrointestinal adverse effects in RA patients. It may also help patients who are withdrawing from MTX medication. Although it did seem to help with mouth sores, there was no statistical significance. There was no significant difference in MTX effectiveness or toxicity between high-dose and low-dose folate.