The efficacy of folic acid and folinic acid in reducing methotrexate gastrointestinal toxicity in rheumatoid arthritis. A metaanalysis of randomized controlled trials

J Rheumatol. 1998 Jan;25(1):36-43.


Objective: To assess the efficacy of folic acid and folinic acid in reducing the mucosal and gastrointestinal (GI) side effects of low dose methotrexate (MTX) in patients with rheumatoid arthritis (RA).

Methods: A systematic review was carried out using the methods recommended by the Cochrane Collaboration. We used MEDLINE and performed hand searches that included bibliographic references, Current Contents, abstracts of rheumatology meetings, and 4 rheumatology journals to select double blind randomized controlled trials (RCT) in which adult patients with RA were treated with low doses of MTX (< 20 mg/week), concurrently with folic or folinic acid. The quality of the RCT was assessed. The overall treatment effect across trials (reduction in toxicity) was estimated using a fixed effects model. Disease activity was evaluated using standardized mean differences to ensure comparability across outcome measures. Sensitivity analyses were conducted evaluating different doses and the quality of the trials. Costs per month in different countries were compared.

Results: Of 11 trials retrieved, 7 met inclusion criteria. The total sample included 307 patients, of which 147 were treated with folate supplementation, 67 patients with folic, and 80 with folinic acid. A 79% reduction in mucosal and GI side effects was observed for folic acid [OR = 0.21 (95% CI 0.10 to 0.44)]. For folinic acid, a clinically but nonstatistically significant reduction of 42% was found [OR = 0.58 (95% CI 0.29 to 1.16)]. No major differences were observed between low and high doses of folic or folinic acid. Hematologic side effects could not be analyzed, since details by patients of each event were not provided. No consistent differences in disease activity variables were observed when comparing placebo and folic acid or folinic acid at low doses; patients receiving high dose folinic acid had increased tender and swollen joint counts. Substantial differences in costs across countries were found; folinic acid was more expensive.

Conclusion: Our results support the protective effect of folate supplementation in reducing MTX side effects related to the oral and GI systems.

Publication types

  • Meta-Analysis
  • Systematic Review

MeSH terms

  • Adult
  • Antidotes / therapeutic use*
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Arthritis, Rheumatoid / drug therapy*
  • Drug Interactions
  • Folic Acid / therapeutic use*
  • Hematinics / therapeutic use*
  • Humans
  • Leucovorin / therapeutic use*
  • Methotrexate / therapeutic use*
  • Randomized Controlled Trials as Topic


  • Antidotes
  • Antimetabolites, Antineoplastic
  • Hematinics
  • Folic Acid
  • Leucovorin
  • Methotrexate