Does folic acid reduce methotrexate efficacy?

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Does folic acid reduce methotrexate efficacy?



Oct 26, 2005



Gandey



Cincinnati, OH - A new post hoc analysis of two randomized controlled

studies suggests that folic acid diminishes the efficacy of

methotrexate in the treatment of rheumatoid arthritis [1]. " The

results of this data analysis should be considered hypothesis-

generating and be used as an impetus for future studies, " comment the

researchers, led by Dr Dinesh Khanna (University of Cincinnati and

Veterans Affairs Medical Center, OH). Their work appears in the

October 2005 issue of Arthritis and Rheumatism. This hotly contested

question of clinical practice continues to be debated, and many argue

that folate should be added routinely for all patients receiving

methotrexate.

Drs SL Whittle and Rod (Ashford and St s NHS Trust,

Chertsey, Surrey, UK) advocate this position and recommend clinicians

administer 5 mg of oral folic acid on the morning following the day

of methotrexate treatment. In a review article previously reported by

rheumawire [2], Whittle and argue that folic acid reduces the

incidence of liver-function-test abnormalities and gastrointestinal

intolerance often associated with methotrexate use. They say that 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. The reviewers found no evidence to suggest that folic acid

significantly reduces the efficacy of methotrexate.

" There has always been a very minor worry that by giving folic acid—

which works via antagonism of the folic-acid enzyme pathways and

discourages cells that proliferate quickly—we might be actually

reducing the beneficial effect of methotrexate, " said during

an interview. " Hence the reason we decided on a small dose to

preserve protection rather than prevent response. "

Many clinics have started to routinely administer folic acid on top

of methotrexate therapy. In April, Dr Graciela Alarcon (University of

Alabama at Birmingham) told rheumawire that her clinic has joined

this trend. " The vast majority of the population does not consume a

diet that is sufficiently rich in folic acid. While this would be an

effective means to receive folate, most people do not consume the

necessary 400 g through diet alone, " Alarcon said. " Why wait, " she

asks, " when negative effects can be prevented? "

Folic acid

Regional and national differences in use remain pronounced.

While supplementation has become routine in the US since roughly the

1990s, this has widely not been the case in the UK and Europe.



Dr R Manna (Catholic University of the Sacred Heart, Rome, Italy)

argues this is for good reason [3]. In a letter published in

Rheumatology and previously reported by rheumawire, Manna and

colleagues report that folic acid can impair the therapeutic effects

of methotrexate. They write, " Although folate use reduces the rate of

side effects of methotrexate treatment, the guidelines for folate

supplementation should state that folate should be added only when

its actual demand increases, such as during an infectious disease or

during antibiotic therapy. "



" The results of this data analysis should be considered hypothesis-

generating. "



In this study, funded by Aventis Pharmaceuticals, researchers looked

at the effect of folic acid on the efficacy and toxicity of

methotrexate. They evaluated data from two phase 3 randomized

controlled trials of leflunomide in which methotrexate was used as a

comparator. Analyses were restricted to patients randomized to

receive methotrexate who had rheumatoid-factor data. The first trial

was a US-based study of more than 480 patients with active RA.

Roughly 180 subjects received at least one dose of methotrexate, and

all were mandated to receive 1 mg of oral folic acid once or twice

daily. The second trial was a multinational European study that

recruited approximately 1000 patients with active RA. Of these, about

490 received at least one dose of methotrexate. Although oral folic

acid was not required, 50 patients received doses after developing an

adverse event.

Khanna and colleagues report that because of similar entry criteria

for both studies, the findings for patients with available primary

outcome data at week 52 were pooled and the patients were grouped by

folic-acid use and nonuse. To account for the significant between-

study difference in the methotrexate groups, they adjusted baseline

covariates with propensity scores so that folic-acid users could be

matched with nonusers. They say this allowed for a comparison of

differences in American College of Rheumatology (ACR) 20% improvement

criteria at week 52.

At study entry, non-folic-acid users had a significantly lower mean

body weight, shorter mean RA duration, and higher mean disease

activity. The investigators observed that the mean methotrexate

dosage at week 52 was similar in the two trials. They found that

patients taking folic acid had lower ACR responses at 52 weeks than

those who did not take folic acid.

ACR response measures at week 52

Outcome (n=544)

Percentage of patients taking folic acid (n=177)

Percentage of patients not taking folic acid (n=367)

With propensity score adjustment

ACR20

57.3

61.5

ACR50

35.9

39.4

ACR70

12.8

16.4

Without propensity score adjustment

ACR20

48.4

65.7

ACR50

27.1

43.6

ACR70

8.0

17.8

To download table as a slide, click on slide logo below

Khanna and colleagues note that adverse events were reported in 93%

of US study patients and 94% of the multinational study patients.

Elevated liver transaminase levels were reported in 29% of the US

study patients and 62% of the multinational study patients. The

authors consider these findings preliminary in nature and call for

additional study of this important and unresolved issue.

" While this may be a relevant conclusion, it doesn't have the weight

or certainty to lead to a change in practice, and I suggest most docs

using methotrexate will still use folic-acid supplements, "

told rheumawire. " Medical ethics argue that to do no harm is

important. Therefore, with the evidence convincing only for the

protective effect of folic acid, it would be premature to discard

this—although in some cases, patients may be taking the folic acid

unnecessarily, as they might not develop adverse methotrexate

reactions even if they hadn't taken folic acid. "

Khanna D, Park GS, us HE, et al. Reduction of the efficacy of

methotrexate by the use of folic acid: Post hoc analysis from two

randomized controlled studies. Arthritis Rheum 2005; 52:3030-3038.

16200612 Whittle SL, RA. Folate supplementation and

methotrexate treatment in rheumatoid arthritis: A review.

Rheumatology 2004; 43:267-271. 14963199 Manna R, Verrecchia E, Diaco

M. Folic acid supplementation during methotrexate treatment:

Nonsense? Rheumatology 2005; 44:563-564. 15657069