Folic-acid supplementation with methotrexate

[Guest guest]

Folic-acid supplementation with methotrexate

Jul 27, 2004 Nainggolan

Surrey, UK - A review on the use of folate as a supplement to methotrexate

therapy in rheumatoid arthritis (RA) has prompted at least 1 UK doctor to

change his prescribing habits.

Earlier this year, Drs SL Whittle and Rod A (St 's Hospital,

Chertsey, Surrey, UK) published a review in Rheumatology [1] that concluded

that folic-acid supplements should " be prescribed routinely to all patients

receiving methotrexate for the treatment of RA. "

In a letter to Rheumatology following publication of this review [2], Dr

Bamji (Queen 's Hospital, Sidcup, UK) explains how he has changed

practice since reading the paper.

Different countries and regions have different rules on folate

In their review, Whittle and explain that regional and national

differences in practice with regard to folate supplementation during

methotrexate therapy remain pronounced. For example, folate supplementation

has become standard practice in the US since the early 1990s, but practice

in the UK and Europe has differed, they note. They reviewed any literature

relevant to the use of folates as a supplement to methotrexate in the

treatment of RA.

They found that folic acid reduces the incidence of liver-function-test

abnormalities and gastrointestinal intolerance often associated with

methotrexate use. It may also offset the elevation in plasma homocysteine

associated with the use of methotrexate, and this in turn may reduce the

risk of cardiovascular disease, which is overrepresented among patients with

RA, they state. They found no evidence to suggest that folic acid

significantly reduces the efficacy of methotrexatesomething that has been

suggested by other researchers.

They recommend that a regimen of 5 mg of oral folic acid should be given

weekly on the morning following the day of methotrexate administration. " If

adverse effects still occur, an increase to a single dose of 10 mg per week

may be considered. " However, they conclude that further prospective studies

are needed to determine the best dose and regimen of folate administration.

Folate supplementation good, but regimen wrong?

In his letter, Bamji says, " Few papers change my practice. . . . Whittle and

's review of methotrexate supplementation with folate is likely to be

one. While I have not been in the habit of prescribing folic acid as a

routine, the argument that by doing so one may reduce the risk of

cardiovascular adverse events seems compelling. "

Few papers change my practice. . . . Whittle and 's review of

methotrexate supplementation with folate is likely to be one.

However, Bamji argues against the regimen suggested by Whittle and .

" There seem to be as many different regimes of folic-acid administration as

there are rheumatology departments, " he observes, " and the trials quoted in

the review reflect this. However, their pragmatic selection of a weekly dose

of 5 mg of folate, given the morning after the methotrexate, would not be my

choice. "

He goes on to explain why. " Most patients who have physical side effects

[from methotrexate] get what I term the 'Monday blues': taking their

methotrexate on a Sunday, they feel sick and unwell the following day. If we

want to block this effect, then the folate should be given the day before,

not the day after. " He says this is supported anecdotally by the clinical

improvement of patients inherited from elsewhere who are on daily or

day-after folate. " So I vote for a pragmatic (but patient-friendly) regime

of 15 mg of folate given the day before. "

Any folate regimen better than none

In reply [3], Whittle and say the issue raised by Bamjithat

prescribing habits for folic-acid supplementation differ widely among

rheumatologistswas discussed by them in their review and " reflects the lack

of sufficient data to make an evidence-based judgment on the optimum dose

and timing of folic-acid supplements.

" Given our incomplete understanding of the mechanisms of either the action

or the side effects of methotrexate, it is difficult to predict the optimum

timing of a once-weekly folate supplement from a mechanistic perspective, "

they note. " One might argue that providing a 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. "

Regardless of the regimen, supplementation with folic acid is likely to

improve MTX continuation rates.

They continue: " It was the intention of our review . . . 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, which found that 67% of those receiving supplementary

folate were still on methotrexate at 5 years compared with 31% of those who

were not taking folate (p<0.001), they note [4].

" We are pleased that the publication of such a review has contributed to the

practical management of RA, " they conclude.

Sources

1. Whittle SL and RA. Folate supplementation and methotrexate

treatment in rheumatoid arthritis: a review. Rheumatology 2004;

43:267-271.

2. Bamji A. Methotrexate and folic acid: what is the optimal

combination? Rheumatology 2004; 43(8):1060-1061.

3. S Whittle and R A . Methotrexate and folic acid: what is the

optimal combination? Reply Rheumatology 2004 ; 43(8):1061

4. Hoekstra M, van de Larr MA, Bernelot Moens HJ, et al. Longterm

observational study of methotrexate use in a Dutch cohort of 1022 patients

with rheumatoid arthritis. J Rheumatol 2003; 30:2325-2339.