Why is Folic acid taken with methotrexate for Rheumatoid arthritis?

Over the years, Methotrexate has become the anchor drug for Rheumatoid arthritis. It was first tried for Rheumatoid Arthritis (RA) in 1951 & was approved for the same by FDA in 1988. Despite the advances & the introduction of biologics, Methotrexate still remains the anchor drug for RA.

The main mechanism of action of Methotrexate is inhibition of dihydrofolate reductase (DHFRase), an enzyme involved in the synthesis of DNA, RNA. However, in low doses used for RA, this does not seem to be the main mechanism responsible for its effect. Instead, inhibition of other enzymes involved in purine metabolism leading to inhibition of T cell activity & adenosine seems to be the main mechanism in RA. DHFRase is an enzyme involved in the metabolism of folic acid. The DHFRase inhibition, is responsible for the side effects of Methotrexate in RA. Folic acid competes with Methotrexate for the DHFRAse enzyme & can in turn reduce the side effects. Thus folic acid is combined with Methotrexate to reduce the side effects of the same.

Numerous studies have investigated the concept of adding folic acid to the Methotrexate regime in RA. 

Ede & colleagues studied the effect of folate supplementation on MTX-induced adverse effects in patients with RA. They found that patients on folate had lesser incidence of elevated liver enzymes as compared to the ones not on folate.

Hoekstra and colleagues found that patients with RA on Methotrexate with folate supplementation could tolerate Methotrexate better & remained on therapy longer than those not given folate supplementation. Needless to mention the importance of staying on Methotrexate longer; this being the main drug for RA. 

Griffith and colleagues also found that folic acid supplements decrease the nausea & oral ulcers associated with Methotrexate.

Since folic acid reduces the side effects of Methotrexate, technically it can reduce the effectiveness as well. Studies have not given a definite answer to this question. So, there is no consensus among the scientists & rheumatologists on this issue. To overcome this potential problem, folic acid is given on all days except on the days of Methotrexate.   

Cardiovascular effects. RA patients are at an increased risk of atherosclerotic vascular disease. Methotrexate leads to an increase in the level of homocystine which is an independent cardiovascular risk factor. Folate supplementation normalizes the homocystine level & takes care of this risk.

Studies have also shown folic acid supplementation to decrease the incidence of liver & marrow toxicity associated with Methotrexate.


1)      Johnston A, Gudjonsson JE, Sigmundsdottir H, Ludviksson BR, Valdimarsson H; (2005). “The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules”. Clin Immunol. 114 (Feb.): 154–163. doi:10.1016/j.clim.2004.09.001

2)      Van Ede AE, Laan RF, Rood MJ, et al. Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis. Arthritis Rheum. 2001;44:1515-1524

3)      Hoekstra M, van de Laar MA, Bernelot Moens HJ, Kruijsen MW, Haagsma CJ. Longterm observational study of methotrexate use in a Dutch cohort of 1022 patients with rheumatoid arthritis. J Rheumatol. 2003;30:2325-2329

4)      Baggott JE, Morgan SL. Folic acid supplements are good (not bad) for rheumatoid arthritis patients                                            treated with low-dose methotrexate (letter). Am J Clin Nutr. 2008;88:479-480.,   

5)      Arabelovic S, Sam G, Dallal GE, et al. Preliminary evidence shows that folic acid fortification of the food supply is associated with higher methotrexate dosing in patients with rheumatoid arthritis. J Am Coll Nutr. 2007;26:453-455

6)      S. M. Griffith , J. Fisher , S. Clarke , B. Montgomery , P. W. Jones , J. Saklatvala , P. T. Dawes , M. F. Shadforth , T. E. Hothersall , A. B. Hassell , and E. M. Hay Do patients with rheumatoid arthritis established on methotrexate and folic acid 5 mg daily need to continue folic acid supplements long term? Rheumatology 39: 1102-1109