BTK signaling—a crucial link in the pathophysiology of chronic spontaneous urticaria

Abstract

Chronic spontaneous urticaria (CSU) is an inflammatory skin disorder that manifests with itchy wheals, angioedema, or both for >6 weeks. Mast cells (MCs) and basophils are the key pathogenic drivers of CSU; their activation results in histamine and cytokine release with subsequent dermal inflammation. Two overlapping mechanisms of MC and basophil activation have been proposed in CSU: type I autoimmunity, also called autoallergy, mediated via IgE against various autoallergens, and type IIb autoimmunity, mediated predominantly via IgG directed against the IgE receptor FcεRI or FcεRI-bound IgE. Both mechanisms involve cross-linking of FcεRI and activation of downstream signaling pathways and may co-occur in the same patient. In addition, B-cell receptor (BCR) signaling has been postulated to play a key role in CSU by generating autoreactive B cells and autoantibody production. A cornerstone of FcεRI and BCR signaling is Bruton’s tyrosine kinase (BTK), making BTK inhibition a clear therapeutic target in CSU. The potential application of early-generation BTK inhibitors, including ibrutinib, in allergic and autoimmune diseases is limited due to their unfavorable benefit–risk profile. However, novel BTK inhibitors with improved selectivity and safety profiles have been developed and are under clinical investigation in autoimmune diseases, including CSU. In Phase 2 trials, the BTK inhibitors remibrutinib and fenebrutinib demonstrated rapid and sustained improvements in CSU disease activity. With remibrutinib Phase 3 studies ongoing, it is hoped that BTK inhibitors will present an effective, well-tolerated option for patients with antihistamine-refractory CSU, a phenotype that presents a considerable clinical challenge. Chronic spontaneous urticaria (CSU) is an inflammatory skin disorder that manifests with itchy wheals, angioedema, or both for >6 weeks. Mast cells (MCs) and basophils are the key pathogenic drivers of CSU; their activation results in histamine and cytokine release with subsequent dermal inflammation. Two overlapping mechanisms of MC and basophil activation have been proposed in CSU: type I autoimmunity, also called autoallergy, mediated via IgE against various autoallergens, and type IIb autoimmunity, mediated predominantly via IgG directed against the IgE receptor FcεRI or FcεRI-bound IgE. Both mechanisms involve cross-linking of FcεRI and activation of downstream signaling pathways and may co-occur in the same patient. In addition, B-cell receptor (BCR) signaling has been postulated to play a key role in CSU by generating autoreactive B cells and autoantibody production. A cornerstone of FcεRI and BCR signaling is Bruton’s tyrosine kinase (BTK), making BTK inhibition a clear therapeutic target in CSU. The potential application of early-generation BTK inhibitors, including ibrutinib, in allergic and autoimmune diseases is limited due to their unfavorable benefit–risk profile. However, novel BTK inhibitors with improved selectivity and safety profiles have been developed and are under clinical investigation in autoimmune diseases, including CSU. In Phase 2 trials, the BTK inhibitors remibrutinib and fenebrutinib demonstrated rapid and sustained improvements in CSU disease activity. With remibrutinib Phase 3 studies ongoing, it is hoped that BTK inhibitors will present an effective, well-tolerated option for patients with antihistamine-refractory CSU, a phenotype that presents a considerable clinical challenge.

Topics & Concepts