Clinical Immunology 2007; 124:244-57This study investigated the capacity of the novel oral spleen tyrosine kinase (Syk) inhibitor R406, and its prodrug R788 (fostamatinib), to suppress the reversed passive Arthrus reaction (RPA) and collagen-induced arthritis (CIA) in rats. R406 (0.1, 1, 5 and 10 mg/kg) and R788 (10 and 30 mg/kg) reduced the cutaneous RPA reaction and inflammatory oedema in a dose-dependent manner, with statistically significant reductions in extravascular leakage and tissue swelling (72% reduction with R406 10 mg/kg; 70% with R788 10 mg/kg and 90% with 30 mg/kg) compared with controls. In CIA, R788/R406 reduced progression and severity of clinical arthritis, bone erosions, pannus formation and synovitis. Serum anti-collagen type II antibody levels were unaltered, but the half-life of exogenous antibody was extended when co-administered with R406. Expression of Syk in synovial tissue correlated with joint levels of inflammatory cell infiltrates and was virtually undetectable in treated rats. Syk inhibition suppressed synovial cytokines and cartilage oligomeric matrix protein (COMP) in serum, suggesting this may be a sensitive and reliable biomarker for R406 activity. The investigations reported in this paper showed that pharmacological interruption of the FcR signalling cascade via Syk inhibition can effectively ameliorate CIA, suggesting Syk may be an important therapeutic target for autoimmune diseases, including RA.