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

Cochrane Database Syst Rev. 2013 May 31;2013(5):CD000951. doi: 10.1002/14651858.CD000951.pub2.


Background: Methotrexate (MTX) is a disease modifying antirheumatic drug (DMARD) used as a first line agent for treating rheumatoid arthritis (RA). Pharmacologically, it is classified as an antimetabolite due to its antagonistic effect on folic acid metabolism. Many patients treated with MTX experience mucosal, gastrointestinal, hepatic or haematologic side effects. Supplementation with folic or folinic acid during treatment with MTX may ameliorate these side effects.

Objectives: To identify trials of supplementation with folic acid or folinic acid during MTX therapy for rheumatoid arthritis and to assess the benefits and harms of folic acid and folinic acid (a) in reducing the mucosal, gastrointestinal (GI), hepatic and haematologic side effects of MTX, and (b) whether or not folic or folinic acid supplementation has any effect on MTX benefit.

Search methods: We originally performed MEDLINE searches, from January 1966 to June 1999. During the update of this review, we searched additional databases and used a sensitive search strategy designed to retrieve all trials on folic acid or folinic acid for rheumatoid arthritis from 1999 up to 2 March 2012.

Selection criteria: We selected all double-blind, randomised, placebo-controlled clinical trials (RCTs) in which adult patients with rheumatoid arthritis were treated with MTX (at a dose equal to or less than 25 mg/week) concurrently with folate supplementation. In this update of the review we only included trials using 'low dose' folic or folinic acid (a starting dose of ≤ 7 mg weekly).

Data collection and analysis: Data were extracted from the trials, and the trials were independently assessed for risk of bias using a predetermined set of criteria.

Main results: 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 GRADE, with the exception of haematologic 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) whilst on MTX therapy for rheumatoid arthritis, a 26% relative (9% absolute) risk reduction was seen for the incidence of GI 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).We analysed the effect of folic or folinic acid on the incidence of stomatitis / mouth sores, and whilst showing a trend towards reduction in risk, the results were not statistically significant (RR 0.72, 95% CI 0.49 to 1.06)It was not possible to draw meaningful conclusions on the effect of folic or folinic acid on haematologic side effects of methotrexate due to small numbers of events and poor reporting of this outcome in included trials.It does not appear that supplementation with either folic or folinic acid has a statistically significant effect on the efficacy of MTX in treating RA (as measured by RA disease activity parameters such as tender and swollen joint counts, or physician's global assessment scores).

Authors' conclusions: The results support a protective effect of supplementation with either folic or folinic acid for patients with rheumatoid arthritis during treatment with MTX.There was a significant reduction shown in the incidence of GI side effects, hepatic dysfunction (asmeasured by elevated serum transaminase levels) as well as a significant reduction in discontinuation of MTX treatment for any reason. A trend towards a reduction in stomatitis was demonstrated however this did not reach statistical significance.This updated review with its focus on lower doses of folic acid and folinic acid and updated assessment of risk of bias aimed to give a more precise and more clinically relevant estimate of the benefit of folate supplementation for patients with rheumatoid arthritis receiving methotrexate.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review
  • Systematic Review

MeSH terms

  • Abdominal Pain / chemically induced
  • Abdominal Pain / prevention & control
  • Adult
  • Antirheumatic Agents / adverse effects*
  • Antirheumatic Agents / therapeutic use
  • Arthritis, Rheumatoid / drug therapy*
  • Folic Acid / administration & dosage
  • Folic Acid / therapeutic use*
  • Folic Acid Antagonists / adverse effects*
  • Folic Acid Antagonists / therapeutic use
  • Gastrointestinal Diseases / chemically induced
  • Gastrointestinal Diseases / prevention & control
  • Hematologic Diseases / chemically induced
  • Hematologic Diseases / prevention & control
  • Humans
  • Leucovorin / administration & dosage
  • Leucovorin / therapeutic use*
  • Methotrexate / adverse effects*
  • Methotrexate / therapeutic use
  • Nausea / chemically induced
  • Nausea / prevention & control
  • Vomiting / chemically induced
  • Vomiting / prevention & control


  • Antirheumatic Agents
  • Folic Acid Antagonists
  • Folic Acid
  • Leucovorin
  • Methotrexate