*4.2.1 Bruton's tyrosine kinase (BTK) inhibitors*

Bruton tyrosine kinase (BTK) is a tyrosine kinase which was found to play a major role in B cell development. At a later date, it was found to be expressed in various hematopoietic cells including macrophages, mast cells, and basophils. In the context of CSU pathogenesis, BTK was also found to play a major role in the FcεR activation and signaling in mast cells [41, 42]. BTK inhibitors are widely used today to treat several B cell malignancies and auto immune disorders [43]. Out of the many known BTK inhibitors, four (ibrutinib, dasatinib, AVL-292, CNX-774) are recognized to be effective suppressors of IgE-induced activation and histamine release from basophils and mast cells [44]. Ibrutinib (420 mg/day), was assessed in patients suffering from peanut/tree nut allergy and reported to suppress skin test responses to these food allergens within seven days, and without any discernable adverse events. No serious adverse events 100. Upon considering of the pivotal role of FcεRI signaling in CSU, it seems that the use of BTK inhibitors for CSU could be a potential new treatment option. LOU064 (remibrutinib), a more selective BTK inhibitor is being investigated in ongoing phase II clinical trials (NCT03926611, NCT04109313) for its efficacy and safety in adult patients with CSU. In an in-vitro study, the binding of BTK by remibrunitib was more efficient than fenebrutinib, thus it has a faster onset of action and its effects are maintained longer [45]. Another phase II study, investigating a new BTK inhibitor (fenebrutinib 200 mg orally twice a day), in adult patients suffering from CSU, has recently been

completed. The results of this study indicated that at week 8, a marked improvement of the UAS7 was achieved at 200 mg twice a day compared with the placebo group [33].
