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 is commonly discontinued due to 
adverse effects. Adverse effects are thought to be mediated via folate 
antagonism. In this paper we summarize the current data on the use of folates as 
a supplement to MTX use in RA for the prevention of adverse effects and as a 
potential modulator of cardiovascular risk, and propose guidelines for standard 
practice.
METHODS: A Medline search was performed using the search terms "methotrexate", 
"folic acid", "folinic acid", "folate" and "homocysteine". Literature relevant 
to the use of folates as a supplement to MTX in the treatment of RA was reviewed 
and other papers referred to as references were explored.
RESULTS: 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. 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.
CONCLUSIONS: We propose that folic acid supplements be prescribed routinely to 
all patients receiving MTX for the treatment of RA. We recommend a pragmatic 
dosing schedule of 5 mg of oral folic acid given on the morning following the 
day of MTX administration.