Methotrexate and folic acid: what is the optimal combination? Reply

S. Whittle and R. A. Hughes

Department of Rheumatology, Ashford and St Peter's Hospital Trust, Chertsey KT16 0PZ, UK

Correspondence to: R. A. Hughes. E-mail: hughesmd{at}btinternet.com

We thank Dr Bamji for his interest in our review of the use of folate supplementation with methotrexate (MTX) in rheumatoid arthritis (RA). We are pleased that the publication of such a review has contributed to the practical management of RA.

Dr Bamji points out that prescribing habits for folic acid supplementation differ widely between rheumatologists. As stated in our review, this reflects the lack of sufficient data to make an evidence-based judgement on the optimum dose and timing of folic acid supplements and, consequently, prescribing habits are often influenced by personal experience and observation.

Given our incomplete understanding of the mechanisms of either the action or the side-effects of MTX, it is difficult to predict the optimum timing of a once-weekly folate supplement from a mechanistic perspective. One might argue that providing supplementary vitamin during the period of effective deficiency (the day after treatment) may have a greater effect than at other times during the week. Clearly, further prospective clinical trials are required to answer these questions.

While it was the intention of our review to provide a basis for greater uniformity in practice, it was also intended to provoke debate and highlight deficiencies in the current evidence base. Regardless of the regimen, supplementation with folic acid is likely to improve MTX continuation rates. This is highlighted by a recent retrospective study of 1022 RA patients treated with MTX. In a multivariate analysis, folic acid use was the major determinant of continuation of MTX over the period of retrospective study. Cumulative MTX ‘survival’ at 5 yr was 67% for those receiving supplementary folate vs 31% in those who were not (P<0.001) [1]. Regimes of folate supplementation varied.

The importance of any strategy which improves MTX continuation is underscored by the published data from the Wichita database, which demonstrates a significant reduction in all-cause mortality in MTX-treated patients with RA, an effect not seen with other DMARDs [2].

We have found the folate supplementation regimen described in our review to be pragmatic and well accepted by our patients, with no apparent advantage conferred by other regimes, though we have not carried out any formal comparison. Alternative folate regimes may serve other clinicians well and any reasonable regime will be likely to share all, or at least some, of the advantages conferred by supplementation. Further prospective studies should be encouraged.

References

  1. Hoekstra M, van de Laar MA, Bernelot Moens HJ, Kruijsen MW, Haagsma CJ. Longterm observational study of methotrexate use in a Dutch cohort of 1022 patients with rheumatoid arthritis. J Rheumatol 2003;30:2325–9.[ISI][Medline]
  2. Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet 2002;359:1173–7.[CrossRef][ISI][Medline]
Accepted 19 April 2004





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