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Multidrug resistance proteins and DMARD efficacy in rheumatoid arthritis


Upregulation of drug efflux pumps belonging to the family of ATP-binding cassette (ABC) transporters can confer loss of efficacy/resistance to muliple cytostatic drugs, a phenotype referred to as multidrug resistance (MDR). In clinical rheumatology practice, loss of efficacy of disease-modifying antirheumatic drugs (DMARDs) is observed following long-term treatment of rheumatoid arthritis (RA) patients. Whether loss of efficacy/resistance to DMARDs and cytostatic drugs share common molecular mechanisms is not known.


The aim of this study was to delineate the potential role of MDR proteins in the loss of efficacy/resistance to DMARDs.


In vitro model systems of human T cells and monocytic/macrophage cell lines were used to provoke resistance to the DMARD sulfasalazine (SSZ). SSZ-resistant cell lines, as well as macrophages from RA patients and healthy controls, were characterized for expression of MDR proteins.


Development of SSZ resistance in T cells and monocytic/macrophage cell lines was accompanied by a marked induction of the MDR protein ABCG2. Of note, SSZ-resistant cells displayed cross-resistance to methotrexate, but showed enhanced sensitivity to glucocorticoids (prednisone, dexamethasone). Immunohistochemical studies revealed increased expression of MDR proteins in macrophages from RA patients as compared with controls.


These results suggest that MDR proteins, originally identified for their role in resistance to cytostatic drugs, could also be involved in DMARD resistance [1]. Beyond this, resistance to one particular DMARD can influence the sensitivity to other antirheumatic drugs.


  1. Jansen G, Scheper RJ, Dijkmans BAC: Multidrug resistance proteins in rheumatoid arthritis, role in disease-modifying antirheumatic drug efficacy and inflammatory processes: an overview. Scand J Rheumatol. 2003,

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Supported by a grant (NRF 03-40I) from the Dutch Arthritis Association.

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Jansen, G., Oerlemans, R., van der Heijden, J. et al. Multidrug resistance proteins and DMARD efficacy in rheumatoid arthritis. Arthritis Res Ther 6 (Suppl 1), 87 (2004).

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