*4.3.2 Spleen tyrosine kinase (SYK) inhibitors*

Spleen tyrosine kinase (SYK) is a pivotal player that regulates histamine release and the synthesis of immune mediators (e.g. leukotriene, prostaglandin) upon FcεRI activation in mast cells [55]. Nowadays, oral SYK inhibitors such as fostamatinib are used extensively in the treatment for autoimmune diseases such as immune thrombocytopenic purpura, chronic graft-versus-host disease and Rheumatoid Arthritis. A new intranasal SYK inhibitor, R112, was also proven to suppress FcεRI-related mediator release following mast cell degranulation, thereby suggesting that SYK inhibitors are extremely efficient in suppressing mast cell degranulation [56]. Based on the above data the use of SYK inhibitors to successfully treat CSU patients was not surprising. The first study to use SYK inhibitors was an in vitro study where a topical SYK inhibitor, was used in an ex vivo human skin model, GSK2646264. In this study it was shown that this inhibitor blocked the histamine release from mast cells through IgE signaling [57]. Following this study, a randomized, placebo-controlled phase I trial (NCT02424799) was conducted in order to evaluate the efficacy and safety of GSK2646264 0.5% and 1% topical cream in patients with CSU and cold urticarial. The results of this study are not available yet. In another in vitro study, the expression level of SYK was evaluated in mast cells from CSU patients. These patients were categorized according to the clinical out- come as responders and non-responders; the degree of basophil's histamine release and the expression of SYK protein in mast cells. This study found that the SYK protein was expressed significantly higher in responders when compared with non-responders and healthy controls. It also revealed that the increased expression of SYK was correlated with the spontaneous histamine release from mast cells in these patients [58].
