Overcoming drug resistance induced by P-glycoprotein on lymphocytes in patients with refractory rheumatoid arthritis

Tsujimura, Shizuyo; Saito, Kazuyoshi; Nawata, Masao; Nakayamada, Shingo; Tanaka, Yoshiya

doi:10.1136/ard.2007.070821

Cited by 90 publications

(73 citation statements)

References 37 publications

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“…In blood of RA patients with highly active disease, high MDR1 expression has been evidenced on memory B cells, involved in the physiopathology of the disease. 79 This strongly contrasts with the MDR1 expression restricted on naïve B cells observed in healthy donors. 57 The most commonly used treatments in RA and PsA rely on synthetic disease modifying anti rheumatic drugs (DMARDs) like methotrexate (MTX), sulfasalazine (SSZ), leflunomide (LEF) or glucocorticoids (GC).…”

Section: Introductionmentioning

confidence: 90%

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MDR1 in immunity: friend or foe?

et al. 2018

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MDR1 is an ATP-dependent transmembrane transporter primarily studied for its role in the detoxification of tissues and for its implication in resistance of tumor cells to chemotherapy treatment. Several studies also report on its expression on immune cells where it plays a protective role from xenobiotics and toxins. This review provides an overview of what is known on MDR1 expression in immune cells in human, and its implications in different pathologies and their treatment options.

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Section: Introductionmentioning

confidence: 90%

“…82 Strategies combining drugs that are not substrates of MDR1 (e.g., MTX, infliximab) with MDR1 inhibition by tacrolimus partially restored response to treatment in refractory RA patients and decrease MDR1 expression on both T and B lymphocytes. 79 …”

Section: Introductionmentioning

confidence: 99%

MDR1 in immunity: friend or foe?

et al. 2018

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“…Evidence indicates that Pgp expression level on lymphocytes characteristically correlates significantly with RA disease activity, estimated by the disease activity score (DAS) 283 [27] , and that its levels on CD4 + T cells and CD19 + B cells are markedly increased in patients with inadequate response to one DMARD treatment with corticosteroids or to at least two DMARDs for at least 2 years, compared with responders and normal volunteers ( Figure 3). To elucidate the relationship between Pgp expre ssion and Pgpmediated efflux of intracellular drugs in vitro, intracellular and extracellular concentrations of dexamethasone, a representative substrate of P-gp (Table 1), were determined by the C/M ratio, an index of intracellular concentration of dexamethasone (C) and extracellular concentration of dexamethasone in the conditioned medium (M).…”

Section: Biological Agents Can Overcome P-gp-mediated Drug Resistancementioning

confidence: 99%

Disease control by regulation of P-glycoprotein on lymphocytes in patients with rheumatoid arthritis

Tsujimura

Tanaka

2015

WJEM

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“…Treatment of RA includes the use of antirheumatic drugs designed to correct the autoreactive lymphocytes 1 . However, some patients respond poorly to such drugs 2 or develop resistance to them after an initial response 3 .…”

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confidence: 99%

Tacrolimus, a Calcineurin Inhibitor, Overcomes Treatment Unresponsiveness Mediated by P-glycoprotein on Lymphocytes in Refractory Rheumatoid Arthritis

et al. 2010

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ABSTRACT. Objective. Tacrolimus, a calcineurin inhibitor, is used for treatment of rheumatoid arthritis (RA). It also inhibits functions of P-glycoprotein, which is involved in drug resistance. We examined the mechanisms of early response to 2-week tacrolimus treatment in patients with RA. Methods. One hundred thirteen patients with refractory RA despite at least 3 antirheumatic agents, including methotrexate, were treated with tacrolimus (1.5-3 mg/day) and the response was assessed at 2 weeks. Expression of the multidrug resistance (MDR-1) gene and P-glycoprotein was assessed in peripheral blood mononuclear cells (PBMC) collected from 113 patients and 40 healthy subjects. The drug exclusion function by the P-glycoprotein was measured by the residual amount of intracellular tritium-labeled dexamethasone cell/medium ratio (C/M ratio).Results. The disease activity of enrolled patients was 5.8 ± 1.2 (mean ± SD) by DAS28 erythrocyte sedimentation rate. A good response to tacrolimus was noted at 2 weeks in 22 of 113 patients. At baseline, PBMC of patients with RA showed upregulated expression of MDR-1 gene and P-glycoprotein and low C/M ratio. The response to tacrolimus correlated with P-glycoprotein expression and C/M ratio. A significant improvement in C/M ratio was noted after 2 weeks of treatment. The C/M ratio correlated significantly with P-glycoprotein expression on CD4+ lymphocytes. Conclusion. Early efficacy of tacrolimus treatment depended on its inhibitory effect on the drug exclusion function of P-glycoprotein, leading to restoration of intracellular therapeutic levels of corticosteroids and clinical improvement. Evaluation of P-glycoprotein expression on lymphocytes is potentially useful for predicting the response to RA treatment. (First Release Jan 15 2010;

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Overcoming drug resistance induced by P-glycoprotein on lymphocytes in patients with refractory rheumatoid arthritis

Cited by 90 publications

References 37 publications

MDR1 in immunity: friend or foe?

MDR1 in immunity: friend or foe?

Disease control by regulation of P-glycoprotein on lymphocytes in patients with rheumatoid arthritis

Tacrolimus, a Calcineurin Inhibitor, Overcomes Treatment Unresponsiveness Mediated by P-glycoprotein on Lymphocytes in Refractory Rheumatoid Arthritis

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