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

Abstract

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.

Presence of the full-length KIR2DS4 gene reduces the chance of rheumatoid arthritis patients to respond to methotrexate treatment

“…Some studies suggest that ESR level, mentioned as a biomarker for chronic systemic inflammation as well as a parameter of disease activity, correlated with responsiveness to MTX (reviewed by Romao et al ) [37]. In the present study, we see that the effect of KIR2DS4f is strongest in individuals with medium susceptibility to the therapeutic effect of MTX characterized by an intermediate level of ESR.…”

STAT6 and STAT1 Pathway Activation in Circulating Lymphocytes and Monocytes as Predictor of Treatment Response in Rheumatoid Arthritis

“…However, at present there are virtually no reliable biomarkers to predict treatment response to the chosen treatment in RA. Several studies have been performed to examine the usefulness of clinical and laboratory variables, autoantibodies, cytokines and genetic factors as predictors of treatment response to methotrexate and other types of DMARDs as well as to anti-TNF agents and other biological drugs [5,6]. The most studied treatment response marker candidates may be plasma levels of inflammatory cytokines and other soluble mediators.…”

“…The most studied treatment response marker candidates may be plasma levels of inflammatory cytokines and other soluble mediators. However, the results concerning the treatment response marker ability of these candidates can be contradicting [5,7], or they may not provide additional predictive value to the levels of inflammatory activity markers that are already in clinical use (primarily C-reactive protein and erythrocyte sedimentation rate) [8–10]. Among demographics and clinical data, the treatment strategy seems to be the strongest predictor [11].…”

Methotrexate‐related lymphoproliferative disorder arising in the gingiva of a patient with rheumatoid arthritis

“…However, one adverse effect is the occurrence of iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPDs). 1,2 In addition, an association between LPDs and the appearance of EpsteinBarr virus (EBV) has been suggested. 3 Clinically, MTX-related LPDs arise as solitary or multiple masses in the whole body, and approximately 40-50% of cases occur in extranodal sites; gingival MTX-related LPDs are rare.…”