Bruton's tyrosine kinase inhibition-An emerging therapeutic strategy in immune-mediated dermatological conditions

Abstract

Bruton's tyrosine kinase (BTK), a member of the Tec kinase family, is critically involved in a range of immunological pathways. The clinical application of BTK inhibitors for B-cell malignancies has proven successful, and there is strong rationale for the potential benefits of BTK inhibitors in some autoimmune and allergic conditions, including immune-mediated dermatological diseases. However, the established risk-to-benefit profile of "first-generation" BTK inhibitors cannot be extrapolated to these emerging, non-oncological, indications. "Next-generation" BTK inhibitors such as remibrutinib and fenebrutinib entered clinical development for chronic spontaneous urticaria (CSU); rilzabrutinib and tirabrutinib are being studied as potential treatments for pemphigus. Promising data from early-phase clinical trials in CSU suggest potential for these agents to achieve strong pathway inhibition, which may translate into measurable clinical benefits, as well as other effects such as the disruption of autoantibody production. BTK inhibitors may help to overcome some of the shortcomings of monoclonal antibody treatments for immune-mediated dermatological conditions such as CSU, pemphigus, and systemic lupus erythematosus. In addition, the use of BTK inhibitors may improve understanding of the pathophysiological roles of mast cells, basophils, and B cells in such conditions.

Keywords: Bruton's tyrosine kinase inhibitor; chronic spontaneous urticaria; fenebrutinib; pemphigus; remibrutinib.

FIGURE 1

Role of BTK in immune cell signaling. The Tec‐family kinase BTK is expressed in various cells including not only MCs and B cells but also NK cells, monocytes/macrophages, neutrophils, and platelets, where it functions as a major signaling element in diverse receptor signaling pathways. Upon receptor activation, BTK is recruited to the plasma membrane via interaction of its pleckstrin homology (PH) domain with phosphatidylinositol trisphosphate (PIP3). Phosphorylation at tyrosine Y551 by Src‐family kinases triggers autophosphorylation at Y223 and the switch into the active conformation. This enables interaction with various downstream signaling and adapter molecules, leading subsequently to calcium release and activation of transcription factors such as NF‐κB, NFAT, FOXO, AP‐1, and MYC. In MCs and B cells, BTK signaling has been primarily—but not exclusively—connected to FcεRI and BCR signaling, respectively. BTK controls IgE‐dependent MC activation and degranulation responses as well as B‐cell survival and differentiation, thereby linking its activity to allergy and autoimmunity. BTK inhibitors are designed to specifically either covalently or reversibly target the active site of BTK, preventing ATP binding and stabilizing the inactive conformation. ANKRD54, ankyrin repeat domain 54; AP‐1, activator protein‐1; ATP, adenosine triphosphate; BCR, B‐cell receptor; BLNK, B‐cell linker protein; BTK, Bruton's tyrosine kinase; GPCR, G protein‐coupled receptor; IBTK, inhibitor of Bruton's tyrosine kinase; IgE, immunoglobulin E; NFAT, nuclear factor of activated T cells; NF‐κB, nuclear factor kappa‐light‐chain‐enhancer of activated B cells; NK, natural killer; PH, pleckstrin homology; PIP5K, phosphatidylinositol 4‐phosphate 5‐kinase; PKC, protein kinase C; PLC, phospholipase C; SYK, spleen tyrosine kinase; TLR, toll‐like receptor; WASP, Wiskott–Aldrich syndrome protein

FIGURE 2

Overview of the role of BTK in the pathophysiology of (A) CSU and (B) pemphigus. BCR, B‐cell receptor; BTK, Bruton's tyrosine kinase; CSU, chronic spontaneous urticaria; IgE, immunoglobulin E; IgG, immunoglobulin G. (A) CSU: The pathogenesis of CSU involves antibody‐mediated MC and basophil activation, occurring via IgE (“auto allergic” or type I CSU) or IgG (“auto immune” or type IIb) generated by differentiated B cells. In type I CSU, crosslinking of FcεRI via autoreactive IgE molecules directed against self‐antigens such as thyroid peroxidase promotes MC/basophil degranulation. In type IIb CSU, IgG molecules directed against the Fc portion of IgE or the FcεRI promote spontaneous cellular degranulation. The role of eosinophils is debated, but eosinophil proteins may promote mast cell degranulation in CSU, and eosinopenia has been linked to high disease activity, type IIb autoimmunity, and poor response to treatment. In addition to its well‐established role in B‐cell signaling, evidence suggests that BTK is specifically required for IgE‐mediated activation of basophils and in MC FcεRI‐induced cytokine secretion. (B) Pemphigus: Dendritic cells presenting desmoglein (DSG) antigens activate T cells, in turn triggering BTK‐mediated anti‐DSG antibody production from B cells