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.
Copyright © 2023. Published by Elsevier Inc.