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 methylp rednisolone (MP; 1,000 mg intravenously) is related to the modulation of proinflammatory cytokines within the peripheral blood, synovial mem brane, or synovial fluid compartments, Methods. Eighteen patients with active rheumatoid arthritis (RA) were studied, Peripheral blood (11 p atients) 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 measur ed by enzyme-linked immunosorbent assay and biologic assays; prostagla ndin E-2 (PGE(2)) was measured by competitive radioimmunoassay, In 10 patients, arthroscopically directed synovial biopsies were obtained be fore and at 24 hours after treatment, at disease relapse (4 patients), and after retreatment (1 patient), Membranes were stained by immunohi stochemical techniques,vith monoclonal antibodies against TNF alpha, I L-8, IL-1 beta, and the IL-1 receptor antagonist protein (IL-1Ra), Res ults. MP therapy was associated with a rapid (within 24 hours) and sub stantial decrease in the expression of TNF alpha in the lining and sub lining regions of the synovial membrane, as well as substantial decrea ses 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 reduce d 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. Conclusi on, MP therapy rapidly reduces IL-8 and TNF alpha levels in the synovi al compartment, with cytokine changes in the serum and synovial fluid reflecting the changes in the synovial membrane, Alterations in TNF al pha expression in the synovial membrane correlated with clinical respo nse to, and subsequent relapse after, MP therapy.