Abstract
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.
Key Points
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Disease-modifying antirheumatic drugs (DMARDs) and anticancer drugs share common molecular mechanisms of resistance
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Resistance to DMARDs can be acquired by upregulation of drug-efflux proteins belonging to the family of multidrug-resistance transporters
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Multidrug-resistance proteins exert primary physiologic functions in the cellular export of inflammatory mediators
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The current knowledge of molecular mechanisms of resistance to methotrexate facilitates the prediction of patient response to methotrexate by target-directed genetic and biochemical screening of blood cells
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Identification of the molecular mechanisms of resistance to various DMARDs opens up new strategies for circumvention of drug resistance
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Acknowledgements
Work described in this Review was supported by grants from the Dutch Arthritis Association and The Netherlands Organization for Scientific Research. JW van der Heijden is a recipient of the 2006 Rheumatology Grant from the Dutch Association for Rheumatology. We apologize to authors whose work could not be cited for space reasons.
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van der Heijden, J., Dijkmans, B., Scheper, R. et al. Drug Insight: resistance to methotrexate and other disease-modifying antirheumatic drugs—from bench to bedside. Nat Rev Rheumatol 3, 26–34 (2007). https://doi.org/10.1038/ncprheum0380
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DOI: https://doi.org/10.1038/ncprheum0380
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