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Supplementation with Folic Acid during Methotrexate Therapy for Rheumatoid Arthritis: A Double-Blind, Placebo-Controlled Trial

Sarah L. Morgan, MD, RD; Joseph E. Baggott, PhD; William H. Vaughn, BS; Janet S. Austin, MA; Tonya A. Veitch, BS; Jeannette Y. Lee, PhD; William J. Koopman, MD; Carlos L. Krumdieck, MD, PhD; and Graciela S. Alarcon, MD, MPH
[+] Article, Author, and Disclosure Information

From the Birmingham Veteran's Administration Hospital and the University of Alabama at Birmingham, Birmingham, Alabama. Requests for Reprints: Sarah L. Morgan, MD, RD, 212 Webb, Department of Nutrition Sciences, U.A.B. Station, Birmingham, AL 35294-3360. Acknowledgments: The authors thank their patient volunteers and their referring rheumatologists (faculty and fellows) for participating in the study and the staffs of the General Clinical Research Center, the Kirklin Clinic, and the University of Alabama at Birmingham Clinical Vitaminology Lab for assisting in the investigation. Grant Support: In part by the National Institutes of Health Department of Research Resources Clinical Research Center grant RR-32-31S1; United States Public Health Service grants 5P01-CA-28103-10, 5P60-AR-20614, and AR-03555; and Veteran's Administration Merit Review Award AR-03555.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1994;121(11):833-841. doi:10.7326/0003-4819-121-11-199412010-00002
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Objective: To determine the effect of two different weekly doses of folic acid on the toxicity and efficacy of low-dose methotrexate therapy for rheumatoid arthritis.

Design: Randomized, double-blind, placebo-controlled study.

Patients: 79 persons between 19 and 78 years of age who fulfilled the American Rheumatism Association's criteria for rheumatoid arthritis.

Intervention: Participants were randomly assigned to visually identical placebo or to 5 mg or 27.5 mg of folic acid each week.

Measurements: Duration, intensity, and clinical severity of toxic events; efficacy (indices of joint tenderness and swelling and grip strength); plasma and erythrocyte folate levels; and other laboratory variables.

Results: Folic acid supplementation at either dose did not affect the efficacy of methotrexate therapy as judged by joint indices and patient and physician assessments of disease. Patients given folic acid supplements had lower toxicity scores than did participants given placebo (P ≤ 0.001). Low blood folate levels and increased mean corpuscular volumes were associated with substantial methotrexate toxicity, whereas daily dietary intakes of more than 900 nmol (400 µg) of folic acid were associated with little methotrexate toxicity.

Conclusions: Folic acid, an inexpensive vitamin, is safe in a broad range of doses and protects patients with rheumatoid arthritis who are taking methotrexate from toxicity while preserving the efficacy of methotrexate.


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Figure 1.
Study design for the double-blind, placebo-controlled trial.

The randomization was done by the statistician using a sequential treatment assignment program in which the algorithm was transparent and a coded vial number was used as the treatment assignment.

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Figure 2.
Median toxicity scores in the three study groups.PP

The placebo group had a statistically higher toxicity score ( = 0.001) than the folic acid supplementation groups. The toxicity score was not significantly different between the low-dose folic acid and high-dose folic acid groups ( = 0.71). ▴ = patients withdrawn from the trial because of toxic effects; ○ = patients who completed the trial.

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Figure 3.
Toxicity score as a function of dietary folate intake in the placebo group.

An exponential decay curve was fitted to the data. To convert micrograms to nanomoles, divide micrograms by 0.441 (the formula weight of folic acid is 441.4).

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