RESEARCH - Reduction of the efficacy of MTX by the use of folic acid: post hoc analysis

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Arthritis & Rheumatism

Volume 52, Issue 10, Pages 3030-3038

Published Online: 30 Sep 2005

Research Article

Reduction of the efficacy of methotrexate by the use of folic acid:

Post hoc analysis from two randomized controlled studies

Dinesh Khanna 1 *, Grace S. Park 2, Harold E. us 2, M.

Simpson 3, Elashoff 2, Stanley B. Cohen 4, Emery 5,

Catharine Dorrier 6, E. Furst 2

1University of Cincinnati and Veterans Affairs Medical Center, Cincinnati, Ohio

2University of California, Los Angeles

3sanofi-aventis Pharmaceuticals, Bridgewater, New Jersey

4Radiant Research, Dallas, Texas

5University of Leeds, Leeds, UK

6HD Consulting, Washington, DC

Abstract

Objective

To examine the effect of folic acid on the efficacy of methotrexate

(MTX) treatment in rheumatoid arthritis (RA) at 12 months in 2 phase

III randomized controlled trials (RCTs) of leflunomide in which MTX

was used as a comparator.

Methods

Analyses were restricted to patients randomized to receive MTX who had

rheumatoid factor data. The US study recruited 482 patients with

active RA; 179 received at least 1 dose of MTX, and all were mandated

to receive 1 mg of oral folic acid once or twice daily. The

multinational European study recruited 999 patients with active RA;

489 received at least 1 dose of MTX, and oral folic acid was not

required, although 50 received folate after developing an adverse

event. Because of similar entry criteria for both studies, the data

for patients with available primary outcome data at week 52 were

pooled (n = 668), and the patients were grouped by folic acid use (n =

225) and nonuse (n = 443). To account for the significant

between-study differences in the MTX groups, baseline covariates were

adjusted using propensity scores so that folic acid users could be

matched with nonusers. This allowed for a comparison of differences in

American College of Rheumatology (ACR) 20% improvement criteria at

week 52.

Results

At study entry, non-folic acid users had a significantly lower mean

body weight, shorter mean RA duration, and higher mean disease

activity (measured by joint counts, patient's and physician's global

assessments, and acute-phase reactant levels). The mean MTX dosage at

week 52 was similar in the 2 RCTs. Using propensity score matching

techniques, the proportion of patients achieving an ACR 20% response

at week 52 averaged 17% higher in the non-folic acid group than in the

folic acid group (range 15-21%). Similarly, the proportion of patients

achieving ACR 50% and ACR 70% responses averaged 14% (range 12-16%)

and 12% (range 9-14%) higher, respectively, in the non-folic acid

group. Adverse events were reported in 93% of US study patients and

94% of the multinational study patients. Elevated liver transaminase

levels (above the upper limit of normal) were reported in 29% of the

US study patients (majority receiving folic acid) and 62% of the

multinational study patients (majority not receiving folic acid).

Conclusion

After using propensity scores to adjust for differences in the

baseline characteristics of folic acid users and non-folic acid users,

9-21% fewer MTX-treated RA patients taking folic acid had ACR 20%,

50%, or 70% improvement at 52 weeks compared with those who did not

receive folic acid in the 2 phase III RA clinical trials. As a post

hoc analysis, the results of this data analysis should be considered

hypothesis generating and an impetus for future studies regarding the

effects of folic acid on the efficacy of MTX in RA.

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