Leflunomide, a novel immunomodulating drug, inhibits homotypic adhesion of peripheral blood and synovial fluid mononuclear cells in rheumatoid arthritis

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Abstract
Objective and Design: A novel immunomodulating drug, leflunomide has been shown recently to be effective and well tolerated in patients suffering from rheumatoid arthritis (RA). The present study evaluated the effect of the drug on cell adhesion in RA. Material and Treatment: Peripheral blood and synovial fluid mononuclear cells were obtained from a clinical trial, undertaken primarily to evaluate the efficacy and pharmacokinetic profile of multiple-dose pulsing leflunomide therapy in RA patients. PB MNC and corresponding synovial fluid (SF) MNC for in vitro homotypic aggregation (HA) assay were obtained from healthy volunteers and RA patients with active disease not treated with leflunomide in vivo. Methods: Expression of activation antigens (CD25, CD54, CD69, CD71, HLA-DR) on peripheral blood mononuclear cells (PB MNC), as well as ex vivo ability of cells to aggregate spontaneously were determined in patients before entering into the clinical trial and at the end of 6 months treatment. HA was measured by aggregation in vitro. Data were compared by Student's t-test. Results: There was a decreased expression of activation antigens and decreased spontaneous MNC clustering after leflunomide therapy. We found in the in vitro study that HA of PB and SF MNC was mainly mediated through β2-integrin molecules. The active metabolite of leflunomide, A77 1726, effectively suppressed both spontaneous and phorbol-ester (PMA)-induced HA. Disruption of cell aggregates by A77 1726 was dose-dependent and, most likely, unrelated to the quantitative modulation of integrin receptors. Conclusions: Results from this study support the idea that leflunomide elicits its immunomodulatory action, at least partially, by modulating the adhesion process.