Drug Insight: resistance to methotrexate and other disease-modifying antirheumatic drugs -- from bench to bedside

Joost W van der Heijden; Ben AC Dijkmans; Rik J Scheper; Gerrit Jansen

Disclosures

Nat Clin Pract Rheumatol. 2007;3(1):26-34. 

In This Article

Summary and Introduction

Summary

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.

Introduction

Despite the current success of biological therapies (inhibitors of tumor necrosis factor [TNF], interleukin-1β-receptor antagonists and antibodies to CD20),[1,2,3] disease-modifying antirheumatic drugs (DMARDs) have an established place in the treatment of rheumatoid arthritis (RA) because of their convenience, safety, and low related costs. One common phenomenon associated with chronic DMARD treatment, however, is a gradual reduction in drug efficacy, which could point to the onset of drug resistance. Increases in drug doses might partly regain therapeutic efficacy, but this approach also increases the risk of adverse effects and could ultimately lead to discontinuation of treatment. The issue of drug resistance as a cause for therapy failure has received considerable attention in the treatment of cancer and infectious diseases,[4] but has just started to be appreciated in RA treatment.[5,6] Whereas end-point evaluations for anticancer drug resistance usually refer to a loss of the antiproliferative effects on target cells, DMARD resistance might be defined as a loss of ability to block the release of proinflammatory cytokines, in addition to a loss of antiproliferative effects.

This Review describes the current knowledge of the molecular mechanisms of cellular resistance to DMARDs (methotrexate, sulfasalazine, chloroquine, hydroxychloroquine, azathioprine, auranofin, aurothiomalate, ciclosporin, gold, and leflunomide). The suggested mechanisms are mainly based on the results of in vitro laboratory studies and theories about the emergence of DMARD resistance in RA. We also discuss potential strategies to deal with drug resistance.

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