LEFLUNOMIDE, A NOVEL IMMUNOMODULATING DRUG, INHIBITS HOMOTYPIC ADHESION OF PERIPHERAL-BLOOD AND SYNOVIAL-FLUID MONONUCLEAR-CELLS IN RHEUMATOID-ARTHRITIS

Objective and Design. A novel immunomodulating drug, leflunomide has b een shown recently to be effective and well tolerated in patients suff ering from rheumatoid arthritis (RA), The present study evaluated the effect of the drug on cell adhesion in RA. Material and Treatment: Per ipheral blood and synovial fluid mononuclear cells were obtained from a clinical trial. undertaken primarily to evaluate the efficacy and ph armacokinetic profile of multiple-dose pulsing leflunomide therapy in RA patients. PB MNC and corresponding synovial fluid (SF) MNC for in v itro homotypic aggregation (HA) assay were obtained from healthy volun teers and RA patients with active disease not treated with leflunomide in vivo. Methods: Expression of activation antigen (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 determine d in patients before entering into the clinical trial and at the end o f 6 months treatment. HA was measured by aggregation in vitro. Data we re compared by Student's t-test. Results. There was a decreased expres sion of activation antigens and decreased spontaneous MNC clustering a fter leflunomide therapy. We found in the in vitro study that HA of PB and SF MNC was mainly mediated through beta 2-integrin molecules. The active metabolite of leflunomide, A77 1726, effectively suppressed bo th 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. Res ults from this study support the idea that leflunomide elicits its imm unomodulatory action, at least partially, by modulating the adhesion p rocess.