Do patients with RA established on MTX and folic acid 5 mg daily need to continue folic acid long term?

[Guest guest]

> Rheumatology 2000; 39: 1102-1109

> © 2000 British Society for Rheumatology

>

> Do patients with rheumatoid arthritis established on methotrexate and

> folic acid 5 mg daily need to continue folic acid supplements long term?

> S. M. Griffith, J. Fisher1, S. e1, B. Montgomery1, P. W. 2, J.

> Saklatvala1, P. T. Dawes1, M. F. Shadforth1, T. E. Hothersall1, A. B.

> Hassell1 and E. M. Hay1

>

> Department of Rheumatology, East Surrey Hospital,

> 1 Department of Rheumatology, Staffordshire Rheumatology Centre,

> Stoke-on-Trent and

> 2 Department of Mathematics, University of Keele, UK

>

> Background. It is postulated that some aspects of methotrexate toxicity

> may be related to its action as an anti-folate. Folic acid (FA) is often

> given as an adjunct to methotrexate therapy, but there is no conclusive

> proof that it decreases the toxicity of methotrexate and there is a

> theoretical risk that it may decrease the efficacy of methotrexate.

>

> Objectives. To look at the effect of stopping FA supplementation in UK

> rheumatoid arthritis (RA) patients established on methotrexate <20 mg

> weekly and FA 5 mg daily, to report all toxicity (including absolute

> changes in haematological and liver enzyme indices) and to report

> changes in the efficacy of methotrexate.

>

> Methods. In a prospective, randomized, double-blind, placebo-controlled

> study, 75 patients who were established on methotrexate <20 mg weekly

> and FA 5 mg daily were asked to stop their FA and were randomized to one

> of two groups: placebo or FA 5 mg daily. Patients were evaluated for

> treatment toxicity and efficacy before entry and then at intervals of 3

> months for 1 yr.

>

> Results. Overall, 25 (33%) patients concluded the study early, eight

> (21%) in the group remaining on FA and 17 (46%) in the placebo group (P

> = 0.02). Two patients in the placebo group discontinued because of

> neutropenia. At 9 months there was an increased incidence of nausea in

> the placebo group (45 vs 7%, P = 0.001). The placebo group had

> significantly lower disease activity on a few of the variables measured,

> but these were probably not of clinical significance.

>

> Conclusions. It is important to continue FA supplementation over the

> long term in patients on methotrexate and FA in order to prevent them

> discontinuing treatment because of mouth ulcers or nausea and vomiting.

> Our data suggest that FA supplementation is also helpful in preventing

> neutropenia, with very little loss of efficacy of methotrexate.

>

>

>

> It is possible that high concentrations of adenosine and related

> compounds may be directly toxic. Seitz [25] suggests that this may be

> the mechanism for methotrexate-related headache, renal insufficiency and

> nodule formation. It has been observed that combined therapy with

> methotrexate and hydroxychloroquine may lead to a reduction in liver

> test abnormalities [26] and may be associated with nodule regression

> [27, 28]. Fries et al. [26] proposed that the ability of

> hydroxychloroquine to increase the size and number of lysosomes in

> hepatocytes stabilizes the membrane and thereby exerts its protective

> effect. Reduced bioavailability of methotrexate may also account for

> these effects [20]. Indeed, it can also be argued that folic acid

> reduces the side-effects of methotrexate solely by reducing its

> bioavailability (methotrexate blocks dihydrofolate reductase, resulting

> in depletion of intracellular reduced folates, and competes with

> dihydrofolate to inhibit the distal steps in the synthesis of

> nucleotides [25]). If this were the case, then it would be expected that

> folate supplements would diminish the efficacy of methotrexate. One

> reason for the design of our study (stable patients on methotrexate plus

> folic acid randomized to placebo or folic acid) was to better observe

> changes in methotrexate efficacy between the two groups. If additional

> folic acid was reducing the biological actions of methotrexate, then an

> improvement in disease control in the placebo group would have been

> expected. Currently, the most promising strategy to reduce the toxicity

> of methotrexate therapy seems to be the concomitant prescription of

> folic acid. More research needs to be pursued into the mechanisms of

> action of methotrexate to facilitate the development of further

> strategies to reduce toxicity [20].

>

>

> http://rheumatology.oupjournals.org/cgi/content/full/39/10/1102

>

>

>

>

> I'll tell you where to go!

>

> Mayo Clinic in Rochester

> http://www.mayoclinic.org/rochester

>

> s Hopkins Medicine

> http://www.hopkinsmedicine.org

>

>

>

>