The Effects of `Pulse' Corticosteroids on Mediators of Inflammation and Joint Damage in the Rheumatoid Synovium

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We have demonstrated that the dramatic reduction in clinical inflammation in rheumatoid arthritis (RA) joints caused by high-dose `pulse' methylprednisolone (MP) is associated with a rapid reduction in neutrophil ingress. MP also causes a reduction in L-selectin and β₂ integrin expression in synovial fluid neutrophils. To determine the mechanisms of these effects, arthroscopic synovial biopsies were taken before and 24 hours after MP and at disease relapse, and the expression of various cytokines and cell adhesion molecules were determined using standard immunohistochemical techniques. It was observed that MP caused a marked reduction in TNFα, IL-8, E-selectin, and ICAM-1 expression in the synovial membrane with 24 hours, thereby reducing the chemotactic gradient for neutrophils as well as neutrophil activation and adhesion in the synovial membrane. Disease relapse was associated with re-expression of these molecules. There was no effect on IL-1β, IL-1Ra, P-selectin, or PECAM expression.

Although no effect on macrohage infiltration was observed, there was a reduction in the expression of MCP-1 and MIP-1α expression in the synovial membrane within 24 hours of MP.

The effects of glucocorticoids on joint damage remain controversial. We have observed that MP significantly reduces MMP-1 and TIMP-1 expression but not MMP-3 expression in the rheumatoid synovium.

The role of the S100 proteins in RA remains unclear. We have observed that the expression of S100A8 and -A9 (MRP8 and -14) is increased by MP. The significance of these findings has yet to be determined.