Effects of pulse methylprednisolone on inflammatory mediators in peripheral blood, synovial. Fluid, and synovial membrane in rheumatoid arthritis

Objective. To establish whether the clinical efficacy of pulse methylprednisolone (MP; 1,000 mg intravenously) is related to the modulation of proinflammatory cytokines within the peripheral blood, synovial membrane, or synovial fluid compartments, Methods. Eighteen patients with active rheumatoid arthritis (RA) were studied, Peripheral blood (11 patients) and knee synovial fluid (9 patients, 10 knees) were obtained before and at 4 and 24 hours after MP therapy, Interleukin-1 beta (IL-1 beta), IL-8, and tumor necrosis factor alpha (TNF alpha) were measured by enzyme-linked immunosorbent assay and biologic assays; prostaglandin E-2 (PGE(2)) was measured by competitive radioimmunoassay, In 10 patients, arthroscopically directed synovial biopsies were obtained before and at 24 hours after treatment, at disease relapse (4 patients), and after retreatment (1 patient), Membranes were stained by immunohistochemical techniques,vith monoclonal antibodies against TNF alpha, IL-8, IL-1 beta, and the IL-1 receptor antagonist protein (IL-1Ra), Results. MP therapy was associated with a rapid (within 24 hours) and substantial decrease in the expression of TNF alpha in the lining and sublining regions of the synovial membrane, as well as substantial decreases in the levels of TNF alpha in serum and synovial fluid, There was also reduced IL-8 expression in the synovial lining, as well as reduced synovial fluid IL-8 levels, No effect on synovial membrane IL-1 beta and IL-1Ra or synovial fluid IL-1 beta and PGE(2) was found. Conclusion, MP therapy rapidly reduces IL-8 and TNF alpha levels in the synovial compartment, with cytokine changes in the serum and synovial fluid reflecting the changes in the synovial membrane, Alterations in TNF alpha expression in the synovial membrane correlated with clinical response to, and subsequent relapse after, MP therapy.