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LETTER TO THE EDITOR |
Department of Nutrition Sciences
Schools of Health Professions, Medicine, and Dentistry
The University of Alabama at Birmingham
354A LRC
1714 9th Avenue South
Birmingham, AL 35294-1270
E-mail: slmorgan{at}uab.edu
Dear Sir:
The interesting and provocative commentary on folic acid fortification and supplementation by Smith et al (1) seems to contain a conceptual error in the "thought experiment" involving folic acid supplements and the use of methotrexate (MTX) in the treatment of autoimmune disease such as rheumatoid arthritis (RA) and psoriasis. Folic acid supplements are routinely used to reduce the toxicity of low-dose MTX (usually to the gastrointestinal system, liver, and bone marrow) in the treatment of autoimmune disease such that the patient may experience the efficacy of this drug without its toxicity (ie, an increase in the therapeutic index) (2). A major reason for stopping low-dose MTX therapy is drug toxicity, not a lack of efficacy (3). Thus, it is unethical to continue to use MTX to treat RA patients who develop conditions such as stomatitis, elevated concentrations of liver function enzymes, and cytopenias, even though their joint disease is greatly reduced. In addition, many nonsteroidal anti-inflammatory drugs (NSAIDs) are used in high doses with MTX in RA therapy, and many NSAIDs also have antifolate activities (4). Medical emergencies have been reported in patients taking MTX in combination with other antifolates (5). Because of its remarkable efficacy, MTX is the "gold standard" drug for RA therapy and an anchor drug to which other drugs or biologicals are added (6, 7). Over the past few decades, rheumatologists have become more confident in the use of MTX, especially because its associated toxicity is manageable with folic acid supplements; therefore, it is more widely used at higher doses to achieve better responses. Confidence in the use of higher doses has likely occurred at the same time as folic acid fortification; therefore, higher doses cannot necessarily be attributed only to folate fortification (8).
The post hoc analysis of the 2 randomized trials that found that patients who were taking folic acid had a poor clinical response to MTX (9) has been criticized because of 1) differences in the patient's baseline characteristics, 2) the lack of a placebo group in the European Study, 3) the post hoc data interpretation, 4) differences in mean disease duration between the patients in the European and American trials, 5) a larger proportion of patients receiving NSAIDs in the European study, and 6) the similarity in response rates in the European and American studies at 2 y. Therefore, we suggest caution in using this as a piece of confirmatory data (10).
There is no evidence that food folate fortification has resulted in an increase in the incidence or severity of RA in the United States; however, on the other hand, there is a large group of patients with RA who have better-controlled disease because folic acid supplements allow them to tolerate MTX therapy. Although we agree that folic acid supplements may have exposed the general population to certain risks, it is generally accepted that modest amounts of this vitamin are beneficial to patients chronically treated with low-dose MTX.
ACKNOWLEDGMENTS
No conflicts of interest were reported.
REFERENCES
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