Experts debate folic-acid supplementation during methotrexate for RA

Allison Gandey

April 14, 2005

Apr 14, 2005

Rome, Italy - Should folate be added routinely for all patients receiving methotrexate for rheumatoid arthritis (RA)? Response to this question of clinical practice is mixed, but many say yes. "Folic-acid supplementation in patients with RA receiving methotrexate appears to be safe, inexpensive, and easily administered," said Dr Louis Bridges (University of Alabama at Birmingham and editorial board member). "It has been consistently shown to reduce side effects of methotrexate without adversely affecting efficacy and may have beneficial cardiovascular effects."

In a review article published in Rheumatology and previously reported by rheuma wire , Drs SL Whittle and RA Hughes (Ashford and St Peters NHS Trust, Chertsey, Surrey, UK) advocated for folic-acid supplementation for all RA patients on methotrexate [ 1 ]. They write, "We recommend a pragmatic dosing schedule of 5 mg of oral folic acid given on the morning following the day of methotrexate administration."

But not everyone agrees with this approach. Responding to the article, Dr R Manna (Catholic University of the Sacred Heart, Rome, Italy) and colleagues 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" [ 2 ]. The group's letter to the editor, published in the April 2005 issue of Rheumatology, notes, "Supplementation should not be given routinely because a normal diet can ensure an adequate amount of this vitamin and it can impair methotrexate therapeutic effects."

Conflicting opinions about the benefits of supplementation

Manna and colleagues point out that there are currently no guidelines available outlining doses and timing of use. They write, "In our opinion, low doses of methotrexate without concomitant folate administration are well tolerated for long periods in the absence of adverse events." The authors argue that folate supplementation should be administered only in circumstances leading to folate deficiency to prevent methotrexate adverse effects. They cite gastroduodenal atrophy as an appropriate example not previously described in the literature. "Prophylactic folate for all RA patients on methotrexate is not strictly required--except in the case of increased folate requirement."

Responding to the group's letter in an email interview, Bridges calls their conclusions "untenable." He explains that while the authors suggest that folic acid should be used only in situations where there is an increase in demand, such as during an infectious disease or during antibiotic therapy, it is difficult to definitively know when there will be increased demand. Bridges notes that since folic acid is inexpensive, safe, and easily administered, it makes sense to encourage its routine use.

He also questions the group's assertion that folic acid can impair methotrexate therapeutic effects. "No reference for this is provided, and I am not aware of any studies that support this conclusion."

Folic acid may prevent side effects other than elevated liver-function tests

"In contrast to this study," Bridges told rheuma wire , "other studies have shown that folic acid may prevent side effects other than elevated liver-function tests [LFTs]. The conclusion that folic acid does not prevent any toxicity except elevated liver-function tests does not suggest to me that folic acid should not be routinely used. In my opinion, the prevention of abnormal LFTs by a safe, inexpensive medication is advisable."

Bridges adds that while the authors' assertion that a normal diet can provide adequate folate is true, there may be beneficial effects of folic supplementation. "For example, the effects of methotrexate on homocysteine can be prevented with the replacement of folic acid," he said.

Dr Graciela Alarcon (University of Alabama at Birmingham) says she agrees. "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 µg through diet alone."

Alarcon says her clinic routinely administers folic-acid supplementation during methotrexate treatment to prevent side effects. "Why wait?" she says, "When negative effects can be prevented." Alarcon echoes Bridges's argument that supplementation is inexpensive and easily administered.

Regional and national differences for this practice remain pronounced. While folate supplementation has become routine in the US since roughly the 1990s, this has widely not been the case in the UK and Europe.



1. Whittle SL, Hughes RA. Folate supplementation and methotrexate treatment in rheumatoid arthritis: a review. Rheumatology 2004; 43:267-271.

2. Manna R, Verrecchia E, Diaco M. Folic acid supplementation during methotrexate treatment: nonsense? Rheumatology 2005; 44:563-564.