Homocysteine modulation as a reason for continuous folic acid supplementation in MTX-treated RA patients

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Rheumatology 2001; 40: 715-716

© 2001 British Society for Rheumatology

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Letters to the Editor

Homocysteine modulation as a reason for continuous folic acid

supplementation in methotrexate-treated rheumatoid arthritis patients

N. Erb and G. D. Kitas

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.

References

1.. Griffith SM, Fisher J, e 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.[Abstract/Free Full Text]

2.. Wald NJ, Watt HC, Law MR, Weir DG, McPartlin J, JM.

Homocysteine and ischemic heart disease: results of a prospective study

with implications regarding prevention. Arch Intern

Med1998;158:862-7.[Abstract/Free Full Text]

3.. 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]

4.. Banks M, Flint J, Bacon PA, Kitas GD. Rheumatoid arthritis is an

independent risk factor for ischaemic heart disease. Arthritis

Rheum2000;43(Suppl.):S385.

5.. Manzi S, Wasko MC. Inflammation-mediated rheumatic diseases and

atherosclerosis. Ann Rheum Dis2000;59:321-5.[Free Full Text]

6.. Roubenoff R, Dellaripa P, Nadeau MR et al. Abnormal homocysteine

metabolism in rheumatoid arthritis. Arthritis

Rheum1997;40:718-22.[Medline]

7.. 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]

8.. Landewe RB, van den Borne BE, Breedveld FC, Dijkmans BA.

Methotrexate effects in patients with rheumatoid arthritis with

cardiovascular comorbidity. Lancet2000;355:1616-7.[Medline]

9.. 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.[Medline]

Accepted 4 December 2000

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