Prediction of Methotrexate Response - A Pilot Study

The objective of this study is to identify genetic predictors of individual methotrexate
(MTX) response in patients with rheumatic diseases by determining genetic and metabolomic
factors related to nutrient metabolism and drug transport.

The development of better genetic predictors of individual MTX treatment response would
provide invaluable prognostic information prior to initiating treatment, which would allow
more appropriate choice of therapy, decreased adverse events, and more efficient
dose-escalation of the drug, with ultimate benefits of improved effectiveness and
tolerability rates in patients being treated with MTX for autoimmune diseases.

Despite being the gold-standard therapy for rheumatoid arthritis and other types of chronic
autoimmune diseases since 1951, MTX's efficacy and safety profile limit its use: MTX is
discontinued in greater than 50% of patients secondary to inefficacy or poor tolerability.
Upon initial treatment, discontinuation rates approach 12% because of drug toxicity, despite
prophylactic measures such as the co-administration of folic acid. The causes of primary
failure, secondary failure, and adverse events of MTX may be related to genetic variation of
dihydrofolate reductase (DHFR) and other genes involved in folate metabolism, one-carbon
transfer, and drug transport. The purpose of this study is to identify genetic variations
involved in methotrexate response so that we may better understand the pharmacodynamics of
MTX metabolism in patients with rheumatic diseases.