Spleen tyrosine kinase: a novel target for therapeutic intervention of rheumatoid arthritis

The Pathogenesis of Rheumatoid Arthritis

“…Moreover, inhibition of spleen tyrosine kinase by fostamatinib, which is effective in some subgroups of patients, is commensurate with its role in the function of B-cell and Fc receptors. 59,60 Other intracellular targets, including phosphatidylinositol 3-kinase, Bruton's tyrosine kinase, and other com- 2213 ponents of the NF-κB pathway, offer intriguing possibilities for therapeutic strategies. In contrast, despite a strong preclinical rationale, the targeting of p38 mitogen-activated protein kinase has been disappointing in clinical settings, which probably indicates that the molecular signaling network in rheumatoid arthritis has functional redundancy.…”

"Go upstream, young man": lessons learned from the p38 saga

“…Syk binds to the cytoplasmic region of receptors that contain the immune-receptor tyrosine-based activation motif (ITAM) 66. This motif is located in the cytoplasmic portion of FcγR, FcεR, Igα (B cells), CD3ζ (T cells) and integrins 67. Immune complexes or antigens that bind these receptors phosphorylate ITAMs, which in turn activate Syk.…”

Cardiovascular safety of biologic therapies for the treatment of RA

“…108 An oral agent, fostamatinib disodium (R406/R788, Rigel Pharmaceuticals Inc.), of which R788 is a prodrug of the active metabolite R406, has been reported in phase II trials to be effective in people who experienced an inadequate response to methotrexate, 109,110 but it was not shown to result in superior outcomes in patients for whom biologic therapy had failed. 111 Of note, all three RCTs of the drug consistently reported dose-dependent hypertension as one of the adverse effects of treatment.…”

“…111 Of note, all three RCTs of the drug consistently reported dose-dependent hypertension as one of the adverse effects of treatment. [109][110][111] Interestingly, data from a study in mice indicate that fostamatinib disodium can attenuate adhesion and migration of inflammatory cells to, as well as limit macrophage survival within, athero sclerotic lesions. 112 However, the long term cardio vascular safety of fostamatinib has not been studied.…”