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Rheumatology 2001; 40: 715-716
© 2001 British Society for Rheumatology
Letters to the Editor |
Homocysteine modulation as a reason for continuous folic acid supplementation in methotrexate-treated rheumatoid arthritis patients
Department of Rheumatology, Dudley Group of Hospitals NHS Trust, The Guest Hospital, Tipton Road, Dudley DY1 4SE, UK
SIR, We read with interest the article by Griffith et al [1]. about whether patients with rheumatoid arthritis (RA) who are established on methotrexate (MTX) and folic acid 5 mg daily need to continue folic acid supplements in the long term. We concur fully with their conclusion that it is important to continue folic acid supplementation to encourage compliance due to the reduced incidence of side-effects. However, we would also suggest that modulation of homocysteine levels is another, possibly more important, reason for continuing folic acid supplementation in RA patients treated with MTX.
Raised levels of homocysteine are associated with accelerated atherosclerosis and increased rates of ischaemic heart disease (IHD) [2]. Elevated homocysteine levels have been estimated to account for up to 10% of coronary artery disease in the general population [3]. RA is associated with an increased prevalence of IHD compared with the normal population [4], with cardiovascular death accounting for the majority of the excess mortality seen in RA (reviewed in [5]). Homocysteine levels are frequently elevated in RA [6], and low-dose MTX treatment may increase them further [7]. Alarmingly, a recent study suggests that RA patients with prior atherosclerotic vascular disease and/or hypertension commenced on MTX therapy had a significantly higher cardiovascular mortality compared with RA patients on other disease-modifying anti-rheumatic drugs, and they postulated that this was due to an MTX-induced rise in homocysteine [8]. Some studies suggest that in the general population levels of homocysteine can be reduced by the administration of folic acid and that this results in reduced formation of atherosclerotic lesions [9]. Large prospective intervention studies are now under way to confirm this.
In view of the already elevated risk of IHD in the RA population and the adverse effect of MTX on homocysteine levels, we would suggest that all patients on MTX should continue folic acid supplements regardless of their side-effect profile with respect to MTX. The exact dose and administration regimen for folic acid supplementation needs to be assessed further.
Notes
References
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Griffith SM, Fisher J, Clarke S et al. Do patients with rheumatoid arthritis established on methotrexate and folic acid 5 mg daily need to continue folic acid supplements long term? Rheumatology2000;39:1102–9.
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Wald NJ, Watt HC, Law MR, Weir DG, McPartlin J, Scott JM. Homocysteine and ischemic heart disease: results of a prospective study with implications regarding prevention. Arch Intern Med1998;158:862–7.
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Booth GL, Wang EE. Preventive health care, 2000 update: screening and management of hyperhomocysteinemia for the prevention of coronary artery disease events. The Canadian Task Force on Preventive Health Care. Can Med Assoc J2000;163:21–9.
[Abstract/Free Full Text] - Banks M, Flint J, Bacon PA, Kitas GD. Rheumatoid arthritis is an independent risk factor for ischaemic heart disease. Arthritis Rheum2000;43(Suppl.):S385.
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Manzi S, Wasko MC. Inflammation-mediated rheumatic diseases and atherosclerosis. Ann Rheum Dis2000;59:321–5.
[Free Full Text] - Roubenoff R, Dellaripa P, Nadeau MR et al. Abnormal homocysteine metabolism in rheumatoid arthritis. Arthritis Rheum1997;40:718–22.[ISI][Medline]
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Haagsma CJ, Blom HJ, van Riel PL et al. Influence of sulphasalazine, methotrexate, and the combination of both on plasma homocysteine concentrations in patients with rheumatoid arthritis. Ann Rheum Dis1999;58:79–84.
[Abstract/Free Full Text] - Landewe RB, van den Borne BE, Breedveld FC, Dijkmans BA. Methotrexate effects in patients with rheumatoid arthritis with cardiovascular comorbidity. Lancet2000;355:1616–7.[ISI][Medline]
- Vermeulen EG, Stehouwer CD, Twisk JW et al. Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of subclinical atherosclerosis: a randomised, placebo-controlled trial. Lancet2000;355:517–22.[ISI][Medline]
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