INTRODUCTION
A member of the tyrosine-protein kinase Tec (TEC) family of tyrosine kinases, Bruton's tyrosine kinase (BTK) is a cytoplasmic, nonreceptor kinase essential to myriad immunological pathways.1 Activity of BTK most notably underlies B cell development, migration, and activation through B cell receptor (BCR) activation.1 BTK is also critical for its role in receptormediated signal transduction of Fc receptors, toll-like receptors (TLRs), and chemokine receptors.1 For its dual activity in both adaptive and innate immunity, inhibition of BTK is a potential therapeutic target for autoimmune and allergic dermatologic diseases.2,3 Emerging applications of BTK-inhibiting drugs in dermatology will be reviewed herein, with a focus on chronic spontaneous urticaria (CSU) and pemphigus vulgaris (PV).
Mechanism of Action
The first-in-class BTK inhibitor, ibrutinib, arrests the enzymatic activity of BTK by forming a covalent, irreversible bond to the cysteine residue C481 of the kinase domain. By preventing downstream activation of BCR pathways, B cell growth, proliferation, and survival is halted. Although effective for the treatment of several lymphoproliferative disorders, ibrutinib inhibits other kinases causing several concerning adverse effects; the development of mutations conferring resistance to ibrutinib is also an arising problem.1
Second-generation BTK inhibitors such as acalabrutinib and zanubrutinib also bind irreversibly and covalently to C481 but with higher selectivity, exhibiting less off-target toxicities than ibrutinib.1,4 To further limit undesired toxicities and resistance, next-generation BTK inhibitors utilize novel mechanisms, such as employing reversible inhibition and targeting alternative binding sites, thus expanding their clinical potential to treat chronic, nononcological conditions.1,4
Chronic Spontaneous Urticaria
Chronic spontaneous urticaria (CSU) is a common and increasingly prevalent condition worldwide that imparts a profound burden on patient quality of life.5,6 For patients with disease inadequately controlled using first-line H1- antihistamines then anti-IgE monoclonal antibody biologic therapies, BTK inhibition is an emerging yet currently off-label treatment strategy as its activity is essential to the IgE-mediated activation of human mast cells and basophils underlying CSU.3 Through BTK inhibition, the signal cascade initiated by cross-linking of the high-affinity receptor FcεRI is arrested, preventing subsequent cellular degranulation, leukotriene and prostaglandin production, and cytokine synthesis.3 Currently two distinct pathophysiologic mechanisms promoting mast cell (MC) activation in CSU are recognized: type 1 (autoallergic) mediated by IgE molecules directed against self-antigens, and type IIb (autoimmune) mediated through IgG molecules directed against the Fc region of IgE or the FcεRI (Figure 1A).7 Although less common, type IIb CSU is associated with more severe disease and poor response to H1-antihistamines and omalizumab.7,8 With the ability to address both IgE- and B cell-mediated sources of MC degranulation, BTK inhibitors have the potential for greater efficacy than currently available treatments for CSU, even the more treatment-resistant autoimmune type.7
Mechanism of Action
The first-in-class BTK inhibitor, ibrutinib, arrests the enzymatic activity of BTK by forming a covalent, irreversible bond to the cysteine residue C481 of the kinase domain. By preventing downstream activation of BCR pathways, B cell growth, proliferation, and survival is halted. Although effective for the treatment of several lymphoproliferative disorders, ibrutinib inhibits other kinases causing several concerning adverse effects; the development of mutations conferring resistance to ibrutinib is also an arising problem.1
Second-generation BTK inhibitors such as acalabrutinib and zanubrutinib also bind irreversibly and covalently to C481 but with higher selectivity, exhibiting less off-target toxicities than ibrutinib.1,4 To further limit undesired toxicities and resistance, next-generation BTK inhibitors utilize novel mechanisms, such as employing reversible inhibition and targeting alternative binding sites, thus expanding their clinical potential to treat chronic, nononcological conditions.1,4
Chronic Spontaneous Urticaria
Chronic spontaneous urticaria (CSU) is a common and increasingly prevalent condition worldwide that imparts a profound burden on patient quality of life.5,6 For patients with disease inadequately controlled using first-line H1- antihistamines then anti-IgE monoclonal antibody biologic therapies, BTK inhibition is an emerging yet currently off-label treatment strategy as its activity is essential to the IgE-mediated activation of human mast cells and basophils underlying CSU.3 Through BTK inhibition, the signal cascade initiated by cross-linking of the high-affinity receptor FcεRI is arrested, preventing subsequent cellular degranulation, leukotriene and prostaglandin production, and cytokine synthesis.3 Currently two distinct pathophysiologic mechanisms promoting mast cell (MC) activation in CSU are recognized: type 1 (autoallergic) mediated by IgE molecules directed against self-antigens, and type IIb (autoimmune) mediated through IgG molecules directed against the Fc region of IgE or the FcεRI (Figure 1A).7 Although less common, type IIb CSU is associated with more severe disease and poor response to H1-antihistamines and omalizumab.7,8 With the ability to address both IgE- and B cell-mediated sources of MC degranulation, BTK inhibitors have the potential for greater efficacy than currently available treatments for CSU, even the more treatment-resistant autoimmune type.7
