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.

Figure 1

Methotrexate mode of action. Methotrexate (MTX) is actively transported into the cell by the reduced folate carrier 1 (RFC1; also known as SLC19A1) and is then polyglutamated by folylpolyglutamate synthetase (FPGS) to form MTX polyglutamates (MTX PG), which are kept inside the cell [221] and are responsible for MTX anti-inflammatory intracellular actions [17,174]. Glutamates can be removed by γ-glutamyl hydrolase (GGH) and MTX monoglutamate is rapidly effluxed from the cell via membrane transporters of the ATP-binding cassette (ABC) family [222], especially ABCC1-4 and ABCG2 [223,224]. Inside the cell, MTX PG exert their anti-inflammatory actions through inhibition of essential enzymes of the folate pathway: dihydrofolate reductase (DHFR) [225], blocking the conversion of dihydrofolate (DHF) to tetrahydrofolate (THF) and ultimately leading to depletion of methionine and decreased DNA methylation; thymidylate synthase (TYMS) [226,227], interfering with de novo pyrimidine synthesis; and 5-aminoimidazole-4-carbox-amide ribonucleotide (AICAR) transformylase (ATIC) [148,228], an enzyme of the de novo purine synthesis, causing accumulation of AICAR, which will finally result in increased secretion of adenosine, a strong anti-inflammatory mediator [229,230]. The enzyme 5,10-methylene-tetrahydrofolate reductase (MTHFR) is not directly inhibited by MTX, but is affected by it because of its action in the folate pathway [176]. ADA, adenosine deaminase; AMPd, adenosine monophosphate deaminase; dTMP, deoxythymidine monophosphate; dUMP, deoxyuridine monophosphate; FAICAR, 10-formyl 5-aminoimidazole-4-carboxamide ribonucleotide; IMP, inosine monophosphate; Methyl-THF, 5-methyl-tetrahydrofolate; Methylene-THF, 5,10-methylene-tetrahydrofolate; MS, methionine synthase; SHMT, serine hydroxymethil transferase.