Folic acid and folinic acid (leucovorin) for reducing side effects in patients receiving MTX for RA

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From The Cochrane Library, Issue 1, 2004. Chichester, UK:

Wiley & Sons, Ltd. All rights reserved.

Folic acid and folinic acid for reducing side effects in patients

receiving methotrexate for rheumatoid arthritis (Cochrane Review)

Ortiz Z, Shea B, Suarez Almazor M, Moher D, Wells G, Tugwell P

ABSTRACT

A substantive amendment to this systematic review was last made on 14

July 1999. Cochrane reviews are regularly checked and updated if

necessary.

Background: Methotrexate (MTX) is classified pharmacologically as an

antimetabolite due to its antagonistic effect on folic acid metabolism.

Although its mechanism of action is uncertain, it has become the second

line drug of choice for many rheumatologists

Objectives: To assess the effects of folic acid and folinic acid in

reducing the mucosal and gastrointestinal (GI) and haematologic side

effects of low-dose of Methotrexate (MTX) in patients with Rheumatoid

Arthritis (RA) and to determine whether or not folate supplementation

alters MTX efficacy.

Search strategy: We searched the Cochrane Controlled Clinical Trial's

Register (CCTR), the Cochrane Musculoskeletal Group Specialized Register

and MEDLINE up to and including June 1999, using the search strategy

developed by the Cochrane Collaboration (Dickersin 1994).We also

handsearched the following: (i) bibliographic references; (ii) current

contents of the last 6 months; (iii) abstracts of the rheumatology

meetings; and (iv) all issues of four journals; Journal of Rheumatology,

Arthritis & Rheumatism, Clinical and Experimental Rheumatology, and

British Journal of Rheumatology.All languages were included. Principal

investigators were also contacted in order to look for unpublished

literature.

Selection criteria: We selected all double-blind, randomized,

placebo-controlled, clinical trials (RCTs), in which adult RA patients

were treated with a low dose of MTX (<20 mg / week) concurrently with

folate supplementation.

Data collection and analysis: Two observers extracted the data and

assessed the quality of the trials. (BS, Z0) The overall treatment

effect across trials was calculated using a fixed effect model. Disease

activity was evaluated using standardized mean differences to ensure

comparability across outcome measures. Results are presented with 95%

Confidence Intervals (95% CI). Subgroup analyses were conducted

evaluating different doses and sensitivity analysis looking at the

quality of the trials. Publication bias was assessed with an inverted

funnel plot technique. Heterogeneity of the trials was measured using a

standard chi square test. Costs per month in different countries were

compared.

Main results: Of the 12 trials retrieved, 7 met the inclusion

criteria. The total sample included 307 patients, of which 147 were

treated with folate supplementation, 80 patients with folinic acid and

67 patients with folic 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 non-statistically significant

reduction of 43% was found [OR = 0.57 (95% CI 0.28 to 1.15)]. No major

differences were observed between low and high doses of folic or folinic

acid. Haematologic side effects could not be analyzed, since details of

each haematologic side effect by patients were not provided. No

consistent differences in disease activity parameters were observed when

comparing placebo and folic or folinic acid at low or high doses,

although patients on high dose folinic acid had an increase in the

number of tender joints, but not swollen joints. Large differences in

costs across countries were found, but folinic acid was more expensive

in all.

Reviewers' conclusions: The results support the protective effect of

folate supplementation in reducing MTX side effects related to the oral

and GI systems. We could not determine if folic was different from

folinic acid. Therefore, for folinic acid to be considered

cost-effective it must be found more effective than folic acid at

reducing MTX side effects.

Citation: Ortiz Z, Shea B, Suarez Almazor M, Moher D, Wells G, Tugwell

P. Folic acid and folinic acid for reducing side effects in patients

receiving methotrexate for rheumatoid arthritis (Cochrane Review). In:

The Cochrane Library, Issue 1, 2004. Chichester, UK: Wiley & Sons,

Ltd.

This is an abstract of a regularly updated, systematic review prepared

and maintained by the Cochrane Collaboration. The full text of the

review is available in The Cochrane Library (ISSN 1464-780X).

http://www.update-software.com/abstracts/AB000951.htm

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