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 language | English |
|---|---|
| Pages (from-to) | 26-34 |
| Number of pages | 9 |
| Journal | Nature Clinical Practice Rheumatology |
| Volume | 3 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jan 2007 |
Cite this
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Drug Insight : resistance to methotrexate and other disease-modifying antirheumatic drugs--from bench to bedside. / van der Heijden, Joost W; Dijkmans, Ben A C; Scheper, Rik J; Jansen, Gerrit.
In: Nature Clinical Practice Rheumatology, Vol. 3, No. 1, 01.2007, p. 26-34.Research output: Contribution to journal › Review article › Academic › peer-review
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 -