Old drugs, old problems: where do we stand in prediction of rheumatoid arthritis responsiveness to methotrexate and other synthetic DMARDs?

Methotrexate (MTX) is the central drug in the management of rheumatoid arthritis (RA) and other immune mediated inflammatory diseases. It is widely used either in monotherapy or in association with other synthetic and biologic disease modifying anti-rheumatic drugs (DMARDs). Although comprehensive clinical experience exists for MTX and synthetic DMARDs, to date it has not been possible to preview correctly whether or not a patient will respond to treatment with these drugs. Predicting response to MTX and other DMARDs would allow the selection of patients based on their likelihood of response, thus enabling individualized therapy and avoiding unnecessary adverse effects and elevated costs. However, studies analyzing this issue have struggled to obtain consistent, replicable results and no factor has yet been recognized to individually distinguish responders from nonresponders at treatment start. Variables possibly influencing drug effectiveness may be disease-, patient- or treatment-related, clinical or biological (genetic and nongenetic). In this review we summarize current evidence on predictors of response to MTX and other synthetic DMARDs, discuss possible causes for the heterogeneity observed and address its translation into daily clinical practice.