METHOTREXATE INDUCED FOLATE DEFICIENCY IN PATIENTS WITH RHEUMATOID ARTHRITIS: A REVIEW

Objectives: The folate antagonist methotrexate (MTX) has become established as the most commonly used disease-modifying anti-rheumatic drug (DMARD) in the treatment of rheumatoid arthritis (RA), but it is frequently discontinued due to adverse effects. The negative effects are thought to be mediated by folate antagonism. In this paper, we summarise the current data on the use of folates as a supplement to MTX in RA for the prevention of adverse effects and as a potential modulator of cardiovascular risk, and we propose guidelines for standard practise. Methods:A Medline search was conducted using the terms'methotrexate,' 'folic acid,' 'folinic acid,' 'folate,' and 'homocysteine'. The literature on the use of folates as a supplement to MTX in the treatment of RA was reviewed, and other papers referred to as references were investigated. Results: Supplemental folates, such as folic and folinic acid, have been shown to improve MTX adherence by lowering the incidence of liver function test abnormalities and gastrointestinal intolerance. Folate supplements do not appear to reduce the effectiveness of MTX in the treatment of RA. Furthermore, supplemental folic acid reduces the increase in plasma homocysteine caused by MTX use. This may reduce the risk of cardiovascular disease, which is over-represented in RA patients and for which hyperhomocysteinaemia is now recognised as an independent risk factor. Conclusions: We propose that all patients receiving MTX for the treatment of RA be given folic acid supplements on a regular basis. We recommend a practical dosing schedule of 5 mg of oral folic acid given the morning after MTX administration. Key words: Methotrexate, Folic acid, Folinic acid, Homocysteine