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

The Cochrane database of systematic reviews

May 2013

DOI: 10.1002/14651858.CD000951.pub2

Citations:17

Influential Citations:0

Systematic Reviews / Meta-Analyses

Enhanced Details

Methods

Adults with rheumatoid arthritis (≥18 years). Six randomized, double-blind, placebo-controlled trials; methotrexate dose ≤25 mg/week; folate supplementation started with MTX; study durations 8–52 weeks; outcomes included GI symptoms, stomatitis, liver enzymes, haematologic side effects, and MTX discontinuation.

Intervention

Low-dose folic acid or folinic acid given concurrently with methotrexate for rheumatoid arthritis. Dosing examples include folic acid 1 mg daily; folinic acid 2.5 mg weekly (with MTX dose adjustments sometimes doubling when MTX ≥15 mg/week). Some regimens varied with MTX dose. Durations ranged from 8 to 52 weeks; route typically oral.

Results

Co-supplementation with low-dose folic acid or folinic acid reduces MTX-related liver toxicity (elevated transaminases) and MTX discontinuation in rheumatoid arthritis. GI side effects show a non-significant trend toward reduction; stomatitis shows a non-significant trend toward reduction. MTX efficacy on disease activity is not reduced. Overall, folate supplementation improves tolerability of MTX without compromising efficacy; no clear difference between folic acid and folinic acid, with folic acid being more cost-effective.

Limitations

Small sample sizes in several trials; some trials had risk of bias or unclear allocation concealment; heterogeneity in dosing regimens and study durations; underreporting or underpowering of haematologic adverse events; liver toxicity assessed by transaminases may not reflect true liver injury; potential publication bias; results may not generalize beyond adults with RA on MTX.

Abstract

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. show less