Pine PR et al. (2007) Inflammation and bone erosion are suppressed in models of rheumatoid arthritis following treatment with a novel Syk inhibitor. Clin Immunol 124: 244–257

The response to immune-complex signaling, mediated through Fc receptors, has been implicated in the development of rheumatoid arthritis (RA). Spleen tyrosine kinase (Syk) is a critical component in immune-complex-mediated signal transduction. Pine et al. evaluated the anti-RA activity of R406, a small-molecule Syk inhibitor, in a rat model of RA. R406, or its prodrug R788, suppressed bone erosion and joint inflammation in rats with collagen-induced arthritis.

A severe clinical arthritis developed in the rats 10–11 days after injection of type II collagen. When inflammation was observed in at least one hind paw (clinical arthritis score =1), twice-daily administration of R406 (10 or 30 mg/kg) or control commenced. In control animals, mean arthritis score peaked at 5.6 ± 0.5, and remained unchanged for the 18-day duration of the study. The 30 mg/kg dose of R406 resulted in complete remission of arthritis by study end (arthritis score 0.1 ± 0.1); the 10 mg/kg dose resulted in delayed onset and reduced severity of RA compared with vehicle. The prodrug R788 also reduced RA severity. Radiographs of hind paws showed significant protection against bone erosion by R406 and R788 versus vehicle. Cytokine levels elevated in arthritic rats were completely suppressed by R406, and the half-life of anti-tumor necrosis factor antibodies was significantly increased by co-administration of R406.

The authors conclude that inhibition of Syk with R406 can suppress bone erosion and inflammation in RA, and can also extend the half-life of anti-RA biological agents. Phase II clinical trials of R406 are ongoing.