A recently updated Cochrane Review by Beverley Shea and colleagues looks at the evidence for low-dose folic acid or folinic acid supplementation for reducing side effects of methotrexate (MTX) in patients with rheumatoid arthritis. The review highlights some key aspects of the use of folic acid that merit further discussion.
MTX is an effective and commonly used disease-modifying anti-rheumatic drug (DMARD) for treating rheumatoid arthritis.[2-4] It is used alone and in combination with other DMARDs or newer biologic therapies targeting various inflammatory cytokines and cells. Treatment guidelines from the American College of Rheumatology (2012) and the European League Against Rheumatism (2010) highlight MTX as the first line of treatment alone or in combination therapy.[5,6] Although its exact mechanism of action in rheumatoid arthritis is unclear, we know that polyglutamate metabolites of MTX interfere with folate-dependent enzymes such as dihydrofolate reductase and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase. The resulting accumulation of AICAR leads to the extracellular release of adenosine, which interacts with receptors on neutrophils and mononuclear cells, and this is likely to contribute to MTX's anti-inflammatory effects.
Several aspects of MTX treatment are particularly attractive to patients, rheumatologists, and other healthcare providers: once-weekly oral administration; efficacy in treating signs and symptoms of rheumatoid arthritis; and relatively few serious side effects. The main challenges to the continued use of MTX are its few side effects and its lack of efficacy in some patients.[7,8] A common reason for discontinuation is gastrointestinal side effects (nausea, vomiting, abdominal pain) followed by stomatitis (oral ulcers), liver function abnormalities, bone marrow suppression, alopecia, and other side effects. Patients and physicians alike are looking for ways to continue MTX for longer without side effects. One well-known solution is folic acid or folinic acid supplementation. (Folinic acid is a derivative of tetrahydrofolic acid that has vitamin activity equivalent to that of folic acid, but its function is unaffected by drugs such as MTX.) The use of folic or folinic acid has been variable, ranging from regular use in everyone who starts MTX to use only in those with side effects, or no use at all (because of an unfounded fear of reduction in MTX efficacy).
The updated Cochrane Review provides important data on this topic. The review includes six randomised controlled trials involving 624 rheumatoid arthritis patients taking MTX, of whom 385 also took low-dose folic acid (≤ 7 mg/week). The concomitant use of folic acid significantly reduced: (1) gastrointestinal toxicity by 26% relative and 9% absolute risk reduction (relative risk [RR], 0.74); (2) abnormal serum transaminase elevation by 77% relative and 16% absolute risk reduction (RR, 0.23); and (3) patient withdrawal from MTX for any reason by 61% relative and 15% absolute risk reduction (RR 0.39). There was no significant reduction in MTX efficacy, as measured by disease activity measures such as tender and swollen joint counts or physician's global assessment scores.
What are the implications of these findings for patients and rheumatologists? I believe that this Cochrane Review provides conclusive evidence for the efficacy of low-dose folic or folinic acid supplementation in patients taking MTX to treat rheumatoid arthritis. The reductions in two major MTX side effects (gastrointestinal toxicity and liver enzyme elevations) are impressive. The review provides estimates for these reductions based on recent trial data that we can now share with patients. A key consideration is that the risk of bias was assessed to be low (or unclear) for key domains and there was no significant heterogeneity between trials when folic acid and folinic acid were pooled.
The review's findings also have major implications for rheumatology practices. In my practice (and I suspect similarly in several of my colleague rheumatologists' practices) the three most common reasons for patients stopping MTX are inefficacy, gastrointestinal toxicity, and liver enzyme elevations. That a single daily folic acid pill (or equivalent) can significantly and dramatically overcome two of those three reasons is spectacular and confirms the classic teaching of the benefits of folic acid supplementation.
Another important message from the review is that patient withdrawal from MTX for any reason was lower in those receiving folic acid than in those who did not. Strategies that improve the persistence of MTX in rheumatoid arthritis patients are increasingly important and are likely to help patients, as most DMARD and DMARD-biologic combination regimens include MTX. These findings are relevant given the recent emerging evidence that MTX-based conventional DMARD regimens may be as effective as MTX-biologic combinations.[9-11] As MTX monotherapy and combination regimens are mainstays of treatment, folic acid supplementation is an important therapeutic intervention.
Considering the low cost of folic acid supplementation and its overwhelming benefits without any evidence of reduction of MTX efficacy, its use should be considered in all rheumatoid arthritis patients taking or starting MTX. Due to cost differences between folic acid and folinic acid, and the availability of folic acid in multivitamin preparations that are available easily over the counter in many countries, folic acid may be more affordable for patients than folinic acid. Low-dose folic acid (equivalent to ≤ 7 mg/week), commonly as a 1 mg daily pill, should be prescribed to rheumatoid arthritis patients taking MTX. A higher persistence to MTX and less switching may also reduce healthcare utilisation and excess medication costs from use of more expensive biologics and other DMARDs. Policy makers and guideline developers should consider including folic acid supplementation for MTX users in their recommendations as a cost-effective and perhaps cost-saving treatment strategy for every rheumatoid arthritis patient starting treatment with MTX. Some might even consider requiring that a folic acid prescription accompany MTX prescription for all new starters and those continuing MTX.
The Cochrane Review also raises several interesting questions. Should folic acid supplementation be continued life-long? Would a higher dose provide even more benefit or would it interfere with MTX efficacy? With the trend in use of higher doses of MTX (35 to 50 mg/week) is a higher dose of folic acid needed? Considering that folic acid supplementation has almost no side effects and that many people take a multivitamin for health, life-long use may not be too different from what some are already doing for health living. Low-dose folic acid may also have additional benefits, such as cardiovascular risk reduction. The dose-effect relationship and the potential cardiovascular risk reduction are important questions that need further study.
Jasvinder A Singh
Medicine Service, Birmingham VA Medical Center, Birmingham, AL; Department of Medicine at School of Medicine, and Division of Epidemiology at School of Public Health, University of Alabama, Birmingham, AL; Department of Orthopedic Surgery, Mayo Clinic College of Medicine, Rochester, MN, USA. firstname.lastname@example.org
How to cite: Singh JA. Folic acid supplements for rheumatoid arthritis patients taking methotrexate: the good gets better [editorial]. Cochrane Database of Systematic Reviews 2013;7:ED000063. dx.doi.org/10.1002/14651858.ED000063
1. Shea B, Swinden MV, Tanjong Ghogomu E, Ortiz Z, Katchamart W, Rader T, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database of Systematic Reviews 2013;5:CD000951. dx.doi.org/10.1002/14651858.CD000951.pub2
2. Weinblatt ME, Coblyn JS, Fox DA, Fraser PA, Holdsworth DE, Glass DN, et al. Efficacy of low-dose methotrexate in rheumatoid arthritis. New England Journal of Medicine 1985;312(13):818-822. dx.doi.org/10.1056/NEJM198503283121303
4. Suarez-Almazor ME, Belseck E, Shea B, Tugwell P, Wells GA. Methotrexate for treating rheumatoid arthritis. Cochrane Database of Systematic Reviews 2000(2):CD000957. dx.doi.org/ 10.1002/14651858.CD000957
5. Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care & Research 2012; 64(5):625-639. dx.doi.org/10.1002/acr.21641
6. Smolen JS, Landewe R, Breedveld FC, Dougados M, Emery P, Gaujoux-Viala C, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Annals of the Rheumatic Diseases 2010;69(6):964-975. dx.doi.org/10.1136/ard.2009.126532
7. Weinblatt ME. Toxicity of low dose methotrexate in rheumatoid arthritis. Journal of Rheumatology 1985;12 Suppl 12:35-39.
8. Kapral T, Stamm T, Machold KP, Montag K, Smolen JS, Aletaha D. Methotrexate in rheumatoid arthritis is frequently effective, even if re-employed after a previous failure. Arthritis Research & Therapy 2006; 8(2):R46. dx.doi.org/10.1186/ar1902
9. O'Dell JR, Mikuls TR, Taylor TH, Ahluwalla V, Brophy M, Warren SR, et al. Therapies for active rheumatoid arthritis after methotrexate failure. New England Journal of Medicine 2013 Jun 11. dx.doi.org/10.1056/NEJMoa1303006
10. Moreland LW, O'Dell JR, Paulus HE, Curtis JR, Bathon JM, St Clair EW, et al. A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis & Rheumatism 2012;64(9):2824-2835. dx.doi.org/10.1002/art.34498
11. van Vollenhoven RF, Ernestam S, Geborek P, Petersson IF, Cöster L, Waltbrand E, et al. Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial. Lancet 2009;374(9688):459-466. dx.doi.org/10.1016/S0140-6736(09)60944-2
Competing interests: The author has completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available upon request) and declares (1) that this editorial is the result of work supported by the resources and use of facilities at the Birmingham VA Medical Center, Alabama, USA, and that JAS is also supported by grants from the Agency for Health Quality and Research Center for Education and Research on Therapeutics (AHRQ-CERTs), the National Institute of Aging, the National Cancer Institute, and the National Institute of Arthritis, Musculoskeletal and Skin Diseases; (2) no financial relationships with any entities that have an interest related to the submitted work; (3) that JAS's instution has received grants from Takeda and Savient, that JAS has received consultant fees from URL Pharmaceuticals, Savient, Takeda, Regeneron, Ardea, Allergan, and Novartis, and that JAS is on the steering committee of OMERACT, an international organisation that develops measures for clinical trials and receives arms-length funding from 36 pharmaceutical companies, but there are no other relationships or activities that could be perceived as having influenced, or giving the appearance of potentially influencing, what was written in the submitted work.
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Correction: This editorial was corrected on 25 September 2013. In the original version low-dose folic acid was defined as "≤ 7 mg/day". This should have read "≤ 7 mg/week", and this has been corrected. Also, the relative risk for gastrointestinal toxicity was stated as 0.76, but should have been 0.74. This has also been corrected.