Objective: P-glycoprotein (P-gp) of membrane transporters leads to drug resistance by the exclusion of intracellular drugs, including corticosteroids. Some patients with highly active systemic lupus erythematosus (SLE) show poor response to corticosteroids; however, the mechanisms of steroid resistance remain unclear. The aim of this study was to elucidate the clinical relevance of P-gp expression on lymphocytes to steroid resistance in patients with active SLE.
Methods: Flow cytometric analyses of the expression of P-gp on peripheral blood lymphocytes from 20 normal volunteers and 80 SLE patients were performed. Steroid-exclusion analysis of peripheral blood mononuclear cells (PBMCs) was conducted by using radioisotope-labeled dexamethasone.
Results: P-gp was expressed at significantly high levels on most of the peripheral blood lymphocytes from SLE patients, whereas normal lymphocytes had only marginal expression. The quantity of P-gp on SLE lymphocytes correlated with the disease activity in each patient, as estimated by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Furthermore, in SLE patients whose SLEDAI scores were >12 despite taking >0.5 mg/kg/day of prednisolone, P-gp expression on lymphocytes was markedly increased, and intracellular dexamethasone in their PBMCs was significantly decreased. However, intensive immunosuppressive treatment in these SLE patients resulted in successful control of disease activity, which occurred in parallel with a marked reduction of P-gp on lymphocytes.
Conclusion: The overexpression of P-gp on lymphocytes might lead to exclusion of corticosteroids from lymphocytes, resulting in steroid resistance in patients with highly active SLE. Reduction of P-gp expression achieved by intensive immunosuppressive treatment overcame the steroid resistance. We therefore propose that measurement of P-gp expression on lymphocytes is useful in the assessment of steroid resistance and is a good marker for indicating the need for intensive immunosuppressive treatment in patients with highly active SLE.