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Folic Acid with Methotrexate: the Debate

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Folic acid & methotrexate: a tug of war

Methotrexate is the most common medicine used to treat Rheumatoid Arthritis. However, some say it is still a mystery exactly how it works. Several sources I’ve read say that, because methotrexate is a folate antagonist, it inhibits the production of harmful cells with Rheumatoid Arthritis in a similar way that it does for some cancers.

This is the reason most doctors prescribe folic acid supplementation with methotrexate. Folic acid supplementation can reduce methotrexate side effects by replacing some folate. If you’re wondering whether that is counter intuitive, you’re not alone. I remember asking my first rheum doc, “Will the methotrexate still be effective? How can that work?” Doc said, “It just does.”

Well, others have also wondered. The Annals of Internal Medicine published a December 1994 study of 79 people with RA.  The patients were given folic acid supplements at weekly doses of either 5mg or 27.5 mg. They found that “Folic acid supplementation at either dose did not affect the efficacy of methotrexate therapy as judged by joint indices and patient and physician assessments of disease.”

Conflicting research about folic acid and methotrexate

All studies agree that folic acid reduces methotrexate side effects, but it is uncertain how much, if any, folic acid reduces the effectiveness methotrexate. It appears to be dependent upon what the doses are.

A small study (22 patients) showed that methotrexate is less effective at controlling psoriasis when folic acid is added. The folic acid dose in that study was 5 mg. daily, which is higher than the highest dose in the larger study previously mentioned. Conflicting results like these have prevented the formulation of a recognized guideline for all patients taking methotrexate for Rheumatoid Arthritis or other autoimmune disease. However, the consensus seems to be in favor folic acid supplementation since it is almost universal. Perhaps it will be determined that it is best to use as little folic acid as is necessary to counter methotrexate side effects.

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Additional protection of folic acid with methotrexate

Here’s a fascinating statement from one pharmacist writing on the issue: “Clinicians should consider that folic acid supplementation may have the additional benefit of cardiovascular protection due to its ability to prevent MTX-induced hyperhomocysteinemia.” What’s that? According to the Oxford Journal of Rheumatology, “Folate supplements do not appear to significantly reduce the effectiveness of MTX in the treatment of RA. Furthermore, supplemental folic acid offsets the elevation in plasma homocysteine associated with the use of MTX. This may in turn reduce the risk of cardiovascular disease, which is over-represented amongst patients with RA, and for which hyperhomocysteinaemia is now recognized as an independent risk factor.“ If one cause of the elevated homocysteine levels is methotrexate, folic acid could help prevent that.

Folic acid improves “methotrexate survival”

From a medical viewpoint, the most important effect of folic acid is that it improves the rate at which patients continue to use methotrexate or the “methotrexate survival” rate. “The use of supplemental folates, including folic and folinic acid, in RA patients treated with MTX has been shown to improve continuation rates by reducing the incidence of liver function test abnormalities and gastrointestinal intolerance,” Oxford Journal of Rheumatology.

What about leucovorin / folinic acid?

Leucovorin or folinic acid is a more stable and potent form of folic acid. It is used as a rescue drug with chemotherapy in cancer patients. Some Rheumatoid Arthritis patients are prescribed folinic acid if side effects of methotrexate are not relieved by folic acid. Folinic acid also seems to be more popular in some countries.

However, folinic acid may be more likely to reduce the effectiveness of methotrexate. “High-dose leucovorin (folinic acid) supplementation was tested in a prospective, unblinded manner for 4 weeks in 7 rheumatoid arthritis patients who were being treated successfully with low-dose methotrexate (MTX). Nausea caused by MTX disappeared; however, the underlying rheumatic disease worsened in all patients. Subjective clinical assessment, Ritchie articular index, grip strength, erythrocyte sedimentation rate, and levels of C-reactive protein showed statistically significant deterioration. All these parameters improved after the leucovorin was stopped. This is the first direct clinical evidence implying folate antagonism in the action of low-dose MTX therapy in rheumatoid arthritis patients,” Arthritis and Rheumatism.

Bottom line for folic acid supplementation w/ methotrexate?

No, I couldn’t find one. In case you aren’t already confused, a thorough examination of the records of 307 RA patients taking methotrexate and folic acid or folinic acid or neither found:

  1. No consistent differences in disease activity parameters were observed when comparing placebo and folic or folinic acid at low or high doses, although patients on high dose folinic acid had an increase in the number of tender joints, but not swollen joints.
  2. Large differences in costs across countries were found, but folinic acid was more expensive in all.
  3. The results support the protective effect of folate supplementation in reducing MTX side effects related to the oral and GI systems. We could not determine if folic was different from folinic acid.

Brief explanation about folic acid and methotrexate from DrDoc Online

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Kelly Young. All rights reserved.

This entry was posted on Thursday, July 22nd, 2010 at 7:00 am and is filed under RA Education. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.

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