Drug Insight: resistance to methotrexate and other disease-modifying antirheumatic drugs--from bench to bedside.
The chronic nature of rheumatoid arthritis (RA) means that patients require drug therapy for many years. Many RA patients, however, have to discontinue treatment because of drug-related toxic effects, loss of efficacy, or both. The underlying molecular cause for loss of efficacy of antirheumatic drugs is not fully understood, but it might be mediated, at least in part, by mechanisms shared with resistance to anticancer drugs. This Review outlines molecular mechanisms that could be involved in the onset of resistance to, or the loss of efficacy of, disease-modifying antirheumatic drugs in RA patients, including methotrexate, sulfasalazine, chloroquine, hydroxychloroquine, azathioprine, and leflunomide. The mechanisms suggested are based on findings from experimental laboratory studies of specific drug-uptake and drug-efflux transporters belonging to the superfamily of multidrug-resistance transporters, alterations in intracellular drug metabolism, and genetic polymorphisms of drug transporters and metabolic enzymes. We also discuss strategies to overcome resistance and the current clinical studies aiming to predict response and risk of toxic effects. More in-depth knowledge of the mechanisms behind these features could help facilitate a more efficient use of disease-modifying antirheumatic drugs.
van der Heijden
Joost W
JW
Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands.
Dijkmans
Ben A C
BA
Scheper
Rik J
RJ
Jansen
Gerrit
G
D018501:Antirheumatic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004351:Drug Resistance / Q000235:genetics / Q000502:physiology; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000502:physiology; D011110:Polymorphism, Genetic
D018501:Antirheumatic Agents; D008727:Methotrexate; D027425:ATP-Binding Cassette, Sub-Family C Proteins