Current issues of ACP Journal Club are published in Annals of Internal Medicine


Leucovorin reduced the side effects of methotrexate in rheumatoid arthritis without affecting efficacy

ACP J Club. 1994 Jan-Feb;120:14. doi:10.7326/ACPJC-1994-120-1-014

Source Citation

Shiroky JB, Neville C, Esdaile JM, et al. Low-dose methotrexate with leucovorin (folinic acid) in the management of rheumatoid arthritis. Results of a multicenter randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 1993 Jun;36:795-803.



To determine whether the addition of leucovorin reduces the side effects of low-dose methotrexate without reducing its efficacy in patients with rheumatoid arthritis (RA).


1-year, randomized, double-blind, placebo-controlled trial.


6 hospital clinics in Canada.


Patients were 18 to 70 years of age, had active RA by American Rheumatism Association criteria, had ≥ 10 involved joints, had been treated unsuccessfully with nonsteroidal anti-inflammatory drugs and ≥ 1 second-line agents, and were taking ≤ 10 mg prednisone daily. Exclusion criteria were previous use of methotrexate; lactation or possible pregnancy; renal insufficiency; known liver abnormalities; alcohol consumption > 200 mL/wk; major complicating illnesses; low platelet or leukocyte counts; low hemoglobin levels; history of major gastrointestinal bleeding; major surgery in the previous 2 months; treatment with folate, warfarin, allopurinol, sulfonamides, or second-line drugs; changes in medications within 1 month of enrollment; Steinbrocker functional class IV; or history of poor compliance. 64 patients completed the study.


All patients received oral methotrexate, 7.5 mg taken weekly. This could be increased by 2.5 to 7.5 mg every 6 weeks to a maximum of 30 mg/wk. 44 patients were allocated to receive leucovorin, 2.5 mg, 24 hours after taking methotrexate. 48 patients received placebo. The leucovorin dose could be doubled when methotrexate exceeded 15 mg.

Main outcome measures

Withdrawal from the study because of side effects, inefficacy, or both. Secondary outcomes were frequency of side effects and relative efficacy of methotrexate.

Main results

17 patients taking placebo and 5 taking leucovorin withdrew because of side effects (P < 0.01) (Table). 1 patient taking leucovorin developed non-life-threatening angioedema. 1 patient in the leucovorin group withdrew because of lack of efficacy. Patients taking leucovorin had a lower rate of clinic checkups at which side effects were reported than patients taking placebo (17% vs 32%, P < 0.001). The groups did not differ for final mean weekly doses of methotrexate or for efficacy at 1 year except that patients taking placebo had greater decreases in disability scores as measured by the Stanford Health Assessment Questionnaire.


Leucovorin reduced side effects in patients with rheumatoid arthritis who were taking low-dose methotrexate and did not affect the efficacy of methotrexate.

Source of funding: Canadian Arthritis Society.

For article reprint: Not available.

Table. Leucovorin (folinic acid) vs placebo in patients with rheumatoid arthritis who were treated with methotrexate*

Outcome at 1 year Leucovorin Placebo RRR (95% CI) NNT (CI)
Withdrawal because of side effects 11% 35% 68% (25 to 87) 5 (3 to 15)

*Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.


Many additional papers have been published showing the benefits of using folate supplementation to reduce the side effects of methotrexate therapy in rheumatoid arthritis. The problem is which agent to choose: folic or folinic acid. A meta-analysis of trials using either of these suggests that folic acid is the more cost-effective agent when compared with folinic acid in reducing side effects and preserving the efficacy of methotrexate (1). Despite this review, some authors still passionately argue the benefits of folinic acid over folic acid, pointing out that no clinical trials directly compare one with the other (2). The limitations of meta-analysis that compares reports of different study designs mean that the question is still not answered. The American College of Rheumatology has recommended using either folate supplement (3). Until the controversy is resolved, the cost savings and availability of folic acid makes it the more desirable choice in most clinical practices.

Bruce A. Baethge, MD
University of Texas Medical BranchGalveston, Texas, USA


1. Oritz Z, Shea B, Suarez Almazor M, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Review, latest version 30 Nov 1997. In: The Cochrane Library. Oxford: Update Software.

2. Shiroky JB. The use of folates concomitantly with low-dose pulse methotrexate. Rheum Dis Clin North Am. 1997;23:969-80.

3. Alarcon GS, Morgan SL. Guidelines for folate supplementation in rheumatoid arthritis patients treated with methotrexate: comment on the guidelines for monitoring drug therapy [Letter]. Arthritis Rheum. 1997;40:391; discussion 391-2.