What dose of folic acid to use with methotrexate in rheumatoid arthritis?
Diane M Bramley
Abstract
### Key learning points Methotrexate is a first-line, conventional, synthetic, disease-modifying antirheumatic drug (DMARD) used in the management of rheumatoid arthritis.1 2 It is an antifolate agent with a chemical structure similar to that of folic acid and folinic acid, but its exact mechanism of action in treating this condition is unclear.3–5 Administered orally or by subcutaneous injection in low doses, methotrexate inhibits a number of folate dependent metabolic steps, including a very potent inhibition of dihydrofolate reductase which reduces folic acid to dihydrofolic acid and to tetrahydrofolate.3 This causes a depleted pool of reduced folates and produces a state of effective folate deficiency.6 The half-life of methotrexate in the serum is in the range of 6–8 hours for low-dose treatment and is undetectable in the serum by 24 hours.4 Therefore, the effects of methotrexate persist after it has been cleared from the serum. It is likely that some of the adverse effects of methotrexate are due to folate antagonism, and the main factor affecting adherence to methotrexate is the occurrence of adverse effects, rather than lack of response.6 7 Between 7% and 30% of patients discontinue methotrexate in the first year due to toxicity.8 The common adverse effects associated with methotrexate …