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