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

Abstract

The main purpose of treatment of rheumatoid arthritis (RA) with disease modifying antirheumatic drugs (DMARDs) is to control activation of lymphocytes, although some patients do not respond adequately to such treatment. Among various mechanisms of multidrug resistance, P-glycoprotein (P-gp), a member of ATP-binding cassette transporters, causes drug-resistance by efflux of intracellular drugs. Certain stimuli, such as tumor necrosis factor-α, activate lymphocytes and induce P-gp expression on lymphocytes, as evident in active RA. Studies from our laboratories showed spontaneous nuclear accumulation of human Y-box-binding protein-1, a multidrug resistance 1 transcription factor, in unstimulated lymphocytes, and surface overexpression of P-gp on peripheral lymphocytes of RA patients with high disease activity. The significant correlation between P-gp expression level and RA disease activity is associated with active efflux of drugs from the lymphocyte cytoplasm and in drug-resistance. However, the use of biological agents that reduce P-gp expression as well as P-gp antagonists (e.g., cyclosporine) can successfully reduce the efflux of corticosteroids from lymphocytes in vitro, suggesting that both types of drugs can be used to overcome drug-resistance and improve clinical outcome. We conclude that lymphocytes activated by various stimuli in RA patients with highly active disease acquire P-gp-mediated multidrug resistance against corticosteroids and probably some DMARDs, which are substrates of P-gp. Inhibition/reduction of P-gp could overcome such drug resistance. Expression of P-gp on lymphocytes is a promising marker of drug resistance and a suitable therapeutic target to prevent drug resistance in patients with active RA.

Keywords: Multidrug resistance 1 gene, P-glycoprotein, Lymphocytes, Disease activity, Rheumatoid arthritis

Core tip: In patients with refractory rheumatoid arthritis (RA) and high disease activity, overexpression of P-glycoprotein (P-gp) on lymphocytes can cause resistance to anti-rheumatic drugs through efflux of intracellular drugs from these cells. Lymphocytes activated by various stimuli, including tumor necrosis factor-α in RA patients apparently acquire P-gp-mediated multidrug resistance against certain anti-rheumatic drugs, which are substrates of P-gp. The use of biological agents that reduce P-gp expression as well as P-gp antagonists can successfully reduce the efflux of drugs from lymphocytes, suggesting that they can be used to overcome drug-resistance and improve clinical outcome.