Multidrug resistance-I (MDR-I) in rheumatic autoimmune disorders - Part I:increased P-glycoprotein activity in lymphocytes from rheumatoid arthritispatients might influence disease outcome

Background, Multidrug resistance (MDR) is characterized by overexpression o f P-glycoprotein, a pump molecule that decreases intracellular drug concent rations by increasing drug efflux from cells. Objective, To look for correl ations between clinical status and P-glycoprotein activity and/or TNF-alpha mRNA levels in patients with rheumatoid arthritis. Methods. Sixteen patien ts were studied. Based on response to therapy, eight were refractory and ei ght nonrefractory to treatment. Findings were compared to those in 24 healt hy controls. Flow cytometry was used to evaluate P-glycoprotein activity in peripheral blood mononuclear cells isolated by gradient centrifugation and incubated with the P-glycoprotein substrate daunorubicin. TNF-alpha mRNA l evels were determined using quantitative PCR, Results, Patients with rheuma toid arthritis showed an increased number of lymphocytes with high P-glycop rotein activity (p=0.0001) as compared to the normal controls. P-glycoprote in activity was higher in the refractory than in the non-refractory patient subgroup (p=0.006). Also, TNF-alpha mRNA levels were markedly higher in th e refractory subgroup than in the nonrefractory subgroup, and were undetect able in the normal controls. Conclusions, Enhanced P-glycoprotein activity may be closely related to an unfavorable clinical course and a poor respons e to treatment. Increased TNF-alpha expression and chronic exposure to vari ous drugs, including glucocorticoids, may contribute to increase P-glycopro tein activity. Both high P-glycoprotein activity and excessive amounts of T NF-alpha seem associated with poor outcome in rheumatoid arthritis. (C) 200 0 Editions scientifiques et medicales Elsevier SAS.