Autoimmune arthritis – such as rheumatoid arthritis – affect a significant proportion
of the population, which can cause everyday joint pain, decreased mobility and reduced
quality of life. Despite having more and more therapeutic options available, there
are still a lot of patients who cannot reach remission or low disease activity by
current therapies. This causes an urgent need for the development of new treatment
options. The Syk tyrosine kinase plays an essential role in B cell receptor, Fc receptor
and integrin signaling. It has been shown that the hematopoietic cell-specific deletion
of Syk resulted in a complete protection against autoantibody-induced experimental
arthritis. This prompted us to test the effect of entospletinib, a second generation,
Syk-selective inhibitor, which has a tolerable safety profile according to hematological
clinical trials, in experimental autoimmune arthritis. We found that entospletinib
dose-dependently decreased the macroscopic signs of joint inflammation, while it did
not affect the health status of the animals. In line with these findings, local neutrophil
accumulation and cytokine levels were reduced compared to the vehicle-treated group,
while macrophage accumulation and synovial fibroblast numbers were not significantly
altered. Meanwhile, entospletinib dose-dependently decreased the cell responses of
immune complex- or integrin ligand-activated neutrophils. Overall, we found that selective
Syk inhibition by entospletinib reduced the activity of autoantibody-induced experimental
arthritis, which seems to be based mainly on the effect of the inhibitor on neutrophil
functions. Our data raise the possibility that entospletinib could be a good drug
candidate in the treatment of human autoimmune arthritis.
