Effects of folic/folinic acid supplements on methotrexate therapy

[Guest guest]

I found this on the arthritis news-group. Unfortunately, it didn't

provide a URL to the report.

~ Georgina

Effects of folic/folinic acid supplements on methotrexate therapy

Written by Larry W. Moreland, M.D.

September 10, 2001

Although methotrexate (MTX) has become the most common disease modifying

anti-rheumatic drug used to treat rheumatoid arthritis (RA), one of the

major limitations has been the long-term acceptability due to adverse

events. About 30% of RA patients discontinue MTX within one year because

of toxicity. Since methotrexate is a folate antagonist, several

publications have suggested that daily folic acid or folinic acid

supplements would decrease MTX toxicity, but the studies have been

small.

Now, van Ede, et al, report on a much larger, multicenter,

placebo-controlled study in the Netherlands; 434 patients with RA were

randomly assigned to receive MTX plus either placebo, folic acid (1

mg/day), or folinic acid (2.5 mg/week). The initial MTX dose was 7.5

mg/week and increases were allowed up to 25 mg/week, based on clinical

responses. Folic acid doses were doubled when the MTX dose reached 15

mg/week. The primary outcome measure was MTX withdrawal because of

adverse events. Secondary endpoints were the MTX dose and parameters of

efficacy and toxicity.

The primary findings were that both folate supplementation regimens

reduced the incidence of elevated liver enzyme levels during MTX

therapy. Thus, MTX was discontinued less frequently in patients

receiving either folic acid or folinic acid as supplementation.

Toxicity-related discontinuation of MTX occurred in 38% of the placebo

group, 17% of the folic acid group, and 12% of the folinic acid group.

There were no differences between groups with regards to the frequency

or duration of other adverse events.

More importantly, there was no evidence that folic acid or folinic acid

supplementation altered the efficacy of MTX. The disease activity

parameters improved equally in all groups. However, the mean dose of MTX

at the end of this study was lower than in the placebo group (14.5

mg/week) than in the folic acid or folinic acid groups (18.0 and 16.4

mg/week, respectively).

Further, much higher doses of MTX were encouraged by the practicing

physicians so that more realistic doses could be evaluated. Thus, the

mean dose of MTX, higher than in previous published studies, is more

consistent with the clinical practice today.

Some questions are not answered by this study. It does not provide

long-term data on the use of the MTX and folic/folinic acid combination

beyond two years. The effect of the concomitant use of alcoholic drinks

was not clarified. Patients were allowed to consume up to 20 alcoholic

drinks per week, reflecting current practice in the Netherlands. The

analysis performed in this study did not show an influence of alcohol

consumption on the occurrence of elevated transaminase values. It is

unknown whether higher doses of folate supplementation would provide

even

better results from an adverse events standpoint. However, this would

raise the question of whether higher doses of folate acid

supplementation would alter the efficacy of MTX.

This study was probably underpowered to determine if folate

supplementation could have an effect on the efficacy of MTX. In summary,

folate acid supplementation is now becoming standard in patients

receiving MTX to decrease adverse events and allow MTX use for longer

periods of time and, perhaps, at higher doses. Folic acid has other

positive effects from a cardiovascular standpoint (lowering serum

homocysteine levels). Since

folic acid is less expensive, it is probably preferable to folinic acid.