Tacrolimus, a calcineurin inhibitor, overcomes treatment unresponsiveness mediated by P-glycoprotein on lymphocytes in refractory rheumatoid arthritis

Katsunori Suzuki, Kazuyoshi Saito, Shizuyo Tsujimura, Shingo Nakayamada, Kunihiro Yamaoka, Norifumi Sawamukai, Shigeru Iwata, Masao Nawata, Kazuhisa Nakano, Yoshiya Tanaka

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50 Citations (Scopus)


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/Mratio. 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. The Journal of Rheumatology

Original languageEnglish
Pages (from-to)512-520
Number of pages9
JournalJournal of Rheumatology
Issue number3
Publication statusPublished - 2010 Mar
Externally publishedYes


  • Calcineurin inhibitor
  • Drug resistance
  • P-glycoprotein
  • Rheumatoid arthritis
  • Tacrolimus

ASJC Scopus subject areas

  • Rheumatology
  • Immunology and Allergy
  • Immunology


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