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

Research output: Contribution to journalReview articleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)26-34
Number of pages9
JournalNature Clinical Practice Rheumatology
Volume3
Issue number1
DOIs
Publication statusPublished - Jan 2007

Cite this

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title = "Drug Insight: resistance to methotrexate and other disease-modifying antirheumatic drugs--from bench to bedside",
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.",
keywords = "Antirheumatic Agents/metabolism, Arthritis, Rheumatoid/drug therapy, Drug Resistance/genetics, Humans, Methotrexate/pharmacology, Multidrug Resistance-Associated Proteins/genetics, Polymorphism, Genetic",
author = "{van der Heijden}, {Joost W} and Dijkmans, {Ben A C} and Scheper, {Rik J} and Gerrit Jansen",
year = "2007",
month = "1",
doi = "10.1038/ncprheum0380",
language = "English",
volume = "3",
pages = "26--34",
journal = "Nature Clinical Practice Rheumatology",
issn = "1745-8382",
publisher = "Nature Publishing Group",
number = "1",

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TY - JOUR

T1 - Drug Insight

T2 - resistance to methotrexate and other disease-modifying antirheumatic drugs--from bench to bedside

AU - van der Heijden, Joost W

AU - Dijkmans, Ben A C

AU - Scheper, Rik J

AU - Jansen, Gerrit

PY - 2007/1

Y1 - 2007/1

N2 - 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.

AB - 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.

KW - Antirheumatic Agents/metabolism

KW - Arthritis, Rheumatoid/drug therapy

KW - Drug Resistance/genetics

KW - Humans

KW - Methotrexate/pharmacology

KW - Multidrug Resistance-Associated Proteins/genetics

KW - Polymorphism, Genetic

U2 - 10.1038/ncprheum0380

DO - 10.1038/ncprheum0380

M3 - Review article

VL - 3

SP - 26

EP - 34

JO - Nature Clinical Practice Rheumatology

JF - Nature Clinical Practice Rheumatology

SN - 1745-8382

IS - 1

ER -