Journal of the American College of Nutrition, Vol. 26, No. 5, 453-455 (2007)
Published by the American College of Nutrition
Preliminary Evidence Shows That Folic Acid Fortification of the Food Supply Is Associated with Higher Methotrexate Dosing in Patients with Rheumatoid Arthritis
Senada Arabelovic, DO,
Gina Sam, MD,
Gerard E. Dallal, PhD,
Paul F. Jacques, ScD,
Jacob Selhub, PhD,
Irwin H. Rosenberg, MD and
Ronenn Roubenoff, MD, MHS
US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University (S.A., G.S., G.E.D., P.F.J., J.S. I.H.R., R.R.)
Division of Rheumatology/Immunology, Arthritis Treatment Center, Tufts-New England Medical Center (S.A., R.R.), Boston, Massachusetts
Address reprint requests to: R. Roubenoff, Nutrition, Exercise, Physiology, and Sarcopenia Laboratory, USDA HNRCA, 711 Washington St., Boston, MA 02111. E-mail: ronenn.roubenoff{at}biogenidec.com
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ABSTRACT
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Background: Fortification of the diet with folate has been used in the United States since 1997 to prevent neural tube defects in newborn babies. However, an increase in dietary folate intake could theoretically reduce the effectiveness of the anti-folate medication, methotrexate (MTX) in treating rheumatoid arthritis (RA) and other inflammatory diseases.
Objective: To investigate whether dietary fortification with folic acid interferes with MTX function in patients with RA.
Methods: We computed MTX dose per patient per year for the years 1988 to 1999 and plotted these against time, comparing the overall mean MTX dose before and after 1997, when dietary fortification with folic acid was instituted in the USA. Thirty-six subjects met eligibility criteria.
Results: Mean annual MTX dose was stable between 1988 and 1996 (12.4 ± 4.0mg), but then rose linearly from 1997 to 1999 (16.6 ± 5.1 mg, p < 0.001).
Conclusions: This preliminary study suggests that folic acid supplementation may contribute to higher MTX dosing in patients with RA.
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INTRODUCTION
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Methotrexate (MTX) is widely used for the treatment of rheumatoid arthritis (RA), the most common inflammatory arthritis in adults [1]. MTX inhibits dihydrofolate reductase, which reduces folate to its biologically active form, depleting intracellular stores of "activated" folate and disrupting cellular metabolism. Toxicity rather than the lack of efficacy is the primary reason for discontinuation of MTX. Mild toxicity occurs in about 60% of patients, and 45% of patients will be forced to stop treatment at three years due to toxicity [2]. Either folic acid or leucovorin (folinic acid) is given with MTX to prevent adverse side effects of the drug [3]. Several reports suggest that such treatment does not diminish the effectiveness of MTX [3, 5].
In 1996, the U.S. Food and Drug Administration (FDA) issued a regulation, to be effective by January 1998, requiring that all enriched flour, rice, pasta, cornmeal, and other grain products contain 140 micrograms of folic acid per 100 grams in addition to the thiamine, riboflavin, niacin, and iron already present in such products. The goal of this folic acid fortification was to increase the intake of folate by women of childbearing age to reduce their risk of having a pregnancy affected by neural tube defects. This fortification has raised the population levels of blood folate and reduced blood homocysteine levels [4]. However, it is not known whether long-term daily increased dietary folic acid could interfere with MTX's effectiveness in patients on long term treatment for rheumatoid arthritis. We reasoned that if such interference occurred, the mean dose of MTX used in clinical practice would begin to rise after the beginning of dietary folate fortification.
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MATERIALS AND METHODS
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We performed a retrospective chart review of medical records on all individuals with RA attending Tufts-New England Medical Center Rheumatology Clinic from 1988 to 1999, who met the American College of Rheumatology (formerly the American Rheumatism Association) criteria for RA and who were taking MTX for at least 3 months. The patients were either treated with folinic acid or folic acid during the whole time they were receiving MTX. We did not find patients who changed dose or form during that time. Also, the number of patients starting treatment each year was stable over time. The study was approved by the Human Investigations Review Committee of Tufts-New England Medical Center. We compared MTX doses over time before and after 1997, when the fortification with folic acid began. Data abstracted from clinic charts included: MTX dose, folic acid dose, leucovorin dose, prednisone dose, erythrocyte sedimentation rate (ESR), and mean corpuscular volume (MCV). We computed average weekly dose of MTX per year for the years 1988 to 1999 and plotted these against time, comparing the overall mean MTX dose before and after 1997 using repeat measures analysis of variance (SAS, Carey NC).
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RESULTS
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Thirty-six subjects with RA were studied (Table 1). The subjects’ ages ranged from 21 to 77 years. Of the group, 89% were women and 11% were men. Twenty-seven patients were prescribed 1 mg/d folic acid. Nine patients were taking leucovorin.
Fig. 1 shows a plot of average weekly dose of MTX per year. Mean annual MTX dose was stable between 1988 and 1996 (12.4 ± 4.0mg [mean ± SD], but then rose linearly from 1997 to 1999 (16.6 ± 5.1 mg, p < 0.001).
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DISCUSSION
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This preliminary study demonstrates that patients’ MTX dose increased significantly since 1997, when dietary fortification with folic acid was instituted, after a decade of stable dosing. This suggests that folic acid supplementation may cause increased MTX dosing after 1997. It was also possible that higher levels of MTX were necessitated by a progressive resistance to the drug with prolonged use, but our data cannot directly support such a conclusion.
There are several limitations to this preliminary study. First, the sample size is small, limited to tertiary care patients, and all the data are collected retrospectively from clinical charts. Thus, we do not have blood levels of folate or MTX, nor do we have direct information about patients’ compliance with either MTX or folate or leucovorin supplementation. However, RA is a severe, painful disease, and compliance with treatment is generally good [1, 3].
It was also likely that some of this increase reflects rheumatologists’ increasing comfort with higher doses of MTX, rather than an unintended result of dietary fortification. We cannot say whether the observed rise would have occurred in the absence of fortification, but comparison with countries in which folate fortification has not been mandated should be informative. On the other hand, we do not know of no sudden change in clinical practice that occurred after 1997 to support higher doses of MTX for RA, whereas the change in dietary fortification regulations in the United States is temporally linked to the observed increase in MTX dose in our patients. The use of MTX increased in the 1990's on an ongoing and continuous basis, not with a significant inflection point as we saw. Several previous papers examined the effect of folate treatment on MTX efficacy. However, none specifically investigated the window of time during which dietary fortification was instituted, and none had the initial hypothesis that dietary fortification could affect MTX effect [6, 7, 8].
These preliminary data warrant further investigation in a larger cohort of patients with RA, ideally with access to blood folate levels for validation of the hypothesis generated by this study. Furthermore, comparison to countries in which folate fortification has not been introduced would also be useful. Based on this study, it is possible that higher doses of MTX will be needed for treatment of RA and other inflammatory diseases in countries where folate fortification is instituted.
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ACKNOWLEDGMENTS
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We thank the Samantha Cunha, RN, and the staff of the Tufts-New England Medical Center Arthritis Treatment Center for their assistance.
Contributions of Authors: Senada Arabelovic collected the data and wrote the manuscript. Gina Sam collected the data. Gerard Dallal analyzed the data. Paul Jacques, Jacob Selhub, and Irwin Rosenberg reviewed and edited the manuscript. Ronenn Roubenoff came up with the scientific idea and reviewed the manuscript.
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FOOTNOTES
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Supported by USDA Cooperative Agreement 58-1950-9-001 and by an Arthritis Foundation grant. GS was supported by a Medical Student Research Fellowship through the General Clinical Research Center under NIH grant M01-RR00054, The content of this publication does not necessarily reflect the views or policies of the USDA or DHHS, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
Disclosure: Ronenn Roubenoff is an employee of Biogen Idec, Inc.
Received May 24, 2005.
Accepted December 21, 2007.
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