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

Abbreviations

adverse event

B‐cell receptor

B‐cell linker protein

B‐lymphocyte stimulator

Bruton's tyrosine kinase

chronic lymphocytic leukemia

chronic spontaneous urticaria

chronic urticaria–basophil activation Test

desmoglein

granulocyte‐macrophage colony‐stimulating factor

hidradenitis suppurativa

immunoglobulin E

immunoglobulin G

inositol‐3,4,5‐phosphate

Lck/Yes novel tyrosine kinase

mast cell

natural killer

phospholipase C gamma 2

systemic lupus erythematosus

SH2‐domain‐containing leukocyte protein of 76 kDa

spleen tyrosine kinase

toll‐like receptors

INTRODUCTION

Almost 70 years ago, Ogden C. Bruton described the first case of agammaglobulinemia in an 8‐year‐old boy suffering from severe recurrent sepsis. 1 The underlying cause of this immunodeficiency remained unclear until the discovery, in the early 1990s, of a cytoplasmic protein tyrosine kinase involved in B‐cell development. 2 , 3 The X‐chromosome‐restricted mutations in this kinase, later named Bruton's tyrosine kinase (BTK), were established to be directly associated with X‐linked agammaglobulinemia. 4 , 5

Owing to its crucial role in B‐cell development, migration, and activation, BTK became—and remains—the subject of intensive study. It has been demonstrated that BTK plays a key role in the signaling cascade of receptors such as the B‐cell receptor (BCR), Fc receptors, chemokine receptors, toll‐like receptors (TLR), and CD40. 6 , 7 , 8 , 9 , 10 , 11 , 12 Further studies revealed the expression of BTK also in non‐B cells such as mast cells (MCs), natural killer (NK) cells, T cells, macrophages, neutrophils, monocytes, and basophils. 11 , 13 , 14 , 15 , 16 , 17

Based on these observations, the potential of BTK as a therapeutic target became apparent, and a series of inhibitors were developed. Ibrutinib (PCI‐32765) became the first BTK inhibitor available for clinical use, approved in 2014 for the treatment of B‐cell malignancies. 18 , 19 Subsequently, BTK has emerged as a promising therapeutic target for a number of malignant and non‐malignant disorders, 20 , 21 , 22 including various immunoglobulin E (IgE)‐mediated diseases driven by MCs and basophils. 16

Here, we review the current understanding of the role of the BTK pathway and consider the potential value of pharmacological inhibition of BTK as a therapeutic strategy in immune‐mediated dermatological conditions such as chronic spontaneous urticaria (CSU), pemphigus, and systemic lupus erythematosus.

ROLE AND RELEVANCE OF BTK IN HEALTH AND DISEASE

Role in signaling cascades in B cells and MCs

BTK is a member of the Tec family of tyrosine kinases. 23 It forms part of signaling cascades triggered by surface receptors such as the BCR in B cells and the high‐affinity IgE receptor FcεRI in MCs. 24 , 25 Activation of BTK correlates with increased phosphorylation of two regulatory tyrosine residues. 26 BTK is phosphorylated at Y551 (site 1) by kinases activated upstream of BTK, such as spleen tyrosine kinase (SYK) or members of the SRC family kinase (e.g., LCK/YES novel tyrosine kinase; LYN). 12 , 27 BTK then autophosphorylates at Y223 (site 2) in the SH3 domain, 28 enabling association with adapter proteins such as SH2‐domain‐containing leukocyte protein of 76 kDa (SLP‐76) 29 or B‐cell linker proteins (BLNKs). 30 This leads to phosphorylation of phospholipase C gamma 2 (PLCγ2). 31 Activated PLCγ2 generates inositol‐3,4,5‐phosphate (IP3) and also activates protein kinase C via diacylglycerol, resulting in calcium release and activation of transcription factors such as NF‐κB and NFAT. 12 Aside from integrating BCR‐ or FcεRI‐derived signals, BTK is also involved in other pathways such as chemokine‐mediated homing of pre‐B cells into lymphoid organs or TLR‐mediated signaling, as well as inhibition of FcγR signaling and inflammation driven by IgG immune complexes. 12 , 32 , 33 The role of BTK in signaling cascades in various cell types and its influence over multiple physiological processes is summarized in Figure 1 .

Role in B‐cell malignancies and other pathologies

Bruton's tyrosine kinase activity is crucial to maintain B‐cell survival, proliferation, and differentiation. It acts as a central node in the BCR signaling that drives B‐cell malignancies such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), Waldenström's macroglobulinemia (WM), follicular lymphoma, multiple myeloma, and marginal zone lymphoma. 12 The involvement of BTK in a range of other immunological pathways implicates it in the pathophysiology of inflammatory and systemic autoimmune disorders, as well as in allergic responses.

BTK signaling in autoimmune responses

B‐cell‐mediated systemic autoimmune diseases are associated with activation of autoreactive B cells and their differentiation into autoantibody‐producing cells. 22 Consistent with this, treatment with rituximab, an anti‐CD20 monoclonal antibody, which results in the depletion of mature B cells, has demonstrated clinical benefits in certain autoimmune conditions. 34 Studies have since revealed increased BTK expression in B cells of patients with systemic autoimmune diseases; indeed, there is some evidence for a correlation of BTK protein levels with autoantibody production. 22 , 35 It appears that BTK can modulate signaling, such that overexpression leads to autoimmunity while decreased levels improve autoimmune disease outcomes. 32

BTK signaling in allergic responses

The binding of an allergen to its specific IgE triggers crosslinking and activation of high‐affinity FcεRI on the surface of MCs and basophils. 36 The subsequent signaling cascade involves the phosphorylation of SYK and then BTK, and results in the release of mediators including cytokines. 16 , 36 Consistent with this, in vitro analyses have demonstrated that BTK inhibition is associated with reduced mediator release in human basophils 37 and reduced IgE‐mediated degranulation and cytokine production in human MCs. Furthermore, a study of two patients with food allergy receiving ibrutinib for CLL suggested that, through inhibition of IgE‐dependent basophil and MC activation, BTK antagonists may be able to block IgE‐mediated allergic reactions to food and other allergens. 38 BTK inhibition has been shown to reduce a skin‐prick test reaction to allergen in healthy adults with asymptomatic atopic diathesis in a Phase I trial. 39

During IgE‐mediated hypersensitivity reactions, activated MCs secrete preformed mediators such as histamine within minutes during the early‐phase reaction, as well as rapidly synthesized lipid mediators such as leukotrienes and prostaglandins. Various cytokines and chemokines are subsequently generated a number of hours later during the late‐phase response. 40 Passive cutaneous anaphylaxis experiments in mice have demonstrated that BTK regulates both early‐ and late‐phase MC effector functions driven by FcεRI‐mediated activation. 40 Indeed, BTK positively regulates almost any aspect of FcεRI‐mediated MC function (with the exception of interleukin‐4 production, which is enhanced in the absence of BTK). 40 That BTK may also have negative regulatory roles is an important consideration; the use of BTK inhibitors for treatment of malignancies has not suggested a tendency for allergen sensitization, but the potential for this should be considered moving into treatment of immune‐mediated conditions. A study in which MC activation was inhibited by the short‐chain fatty acid, butyrate, suggested that MC activation relies on a strong transcriptional silencing of critical molecules for IgE receptor‐induced signal transduction, including BTK. 41 Recent data have shown that—in contrast to FcεRI‐mediated MC activation—stem cell factor‐induced KIT signaling in bone‐marrow‐derived MC is largely independent of the phosphorylation and activation of BTK. 42

BTK signaling in other inflammatory responses

There is some evidence that BTK contributes to other inflammatory mechanisms, such as immunoglobulin G (IgG; FcγR)‐mediated activation of monocytes and neutrophil migration. 43 For example, a study found that ibrutinib did not affect monocyte FcγR‐mediated phagocytosis, even at supraphysiological concentrations, but suppressed FcγR‐mediated cytokine production. 44 However, although ibrutinib blocked BTK in isolated cultures, pro‐inflammatory intercellular communication was sufficient to overcome its inhibitory effects on monocytes and NK cells. 44 BTK‐deficient neutrophils have shown defects in granulocyte‐macrophage colony‐stimulating factor (GM‐CSF)‐signaling and GM‐CSF‐induced maturation accompanied with impaired function during an acute inflammatory response. 15

BTK PATHWAY INHIBITION IN THE TREATMENT OF SKIN DISEASES

On the basis of the involvement of the BTK pathway in autoimmune, IgE‐mediated allergic, and other inflammatory mechanisms, BTK inhibition is emerging as a candidate therapeutic approach for a number of dermatological disorders.

Chronic spontaneous urticaria

CSU is defined by the presence of wheals and/or angioedema occurring for more than 6 weeks without a specific trigger. 45 It is a common condition, affecting approximately 1% of the population worldwide, 46 and showing an increasing trend over time. 47 The burden experienced by patients with CSU can be considerable, with challenges such as sleep deprivation, sexual dysfunction, limitations on daily life, and reduced performance at work or school all affecting health‐related quality of life. 46 A lack of understanding of underlying cause has precluded development of curative treatments, 48 and patients often experience long delays in achieving effective management 46 ; indeed, many patients do not achieve symptom control. 49 Fewer than half of the patients with CSU respond to a standard‐dosed H1‐antihistamine, the first‐line recommended treatment. 50 The only other licensed treatment for CSU is the anti‐IgE monoclonal antibody, omalizumab, which, in a phase 2 head‐to‐head trial, showed a complete hive response rate of 26%, compared with 30%–51% with the anti‐IgE ligelizumab. 49 Agents such as cyclosporine, dapsone, and hydroxychloroquine are used off‐label. 45 Novel treatment options with improved effectiveness are urgently needed for patients with CSU.

The rationale for BTK inhibition in CSU is strong, as BTK is involved in both of the known pathways that lead to the degranulation of skin MCs, the key pathogenic driver of CSU (Figure 2A ). In type I (autoallergic) CSU, the occurrence of signs and symptoms is driven by IgE to autoallergens (e.g., against thyroperoxidase, thyroglobulin, tissue factor, interleukin‐24, and double‐stranded DNA), while type IIb autoimmune CSU is due to MC‐targeted IgG autoantibodies against IgE or FcεRI. 51 Type IIb CSU is the less common endotype, but is characterized by high disease activity and poor response to treatment with antihistamines and omalizumab. 51 , 52 , 53 , 54

BTK inhibitors have potential for efficacy in both autoallergic and autoimmune CSU due to inhibition of BTK‐mediated degranulation in MCs and autoantibody production in B cells. In particular, they may help to address the suboptimal levels of response to currently available treatments in type IIb CSU. 52 , 53 , 55

Pemphigus

Pemphigus is an autoantibody‐driven skin disease characterized by a loss of cell adhesion (acantholysis), leading to blisters or erosions of the skin and/or mucous membrane. 56 , 57 There are three major forms: pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus; of these, pemphigus vulgaris is the most common variant. 56 The pathology of pemphigus is based on IgG autoantibodies targeting various adhesion molecules in the epidermis, including desmoglein (DSG) 1 and 3. 56 Dendritic cells presenting DSG antigens can activate T cells, in turn triggering anti‐DSG antibody production from B cells (Figure 2B ). 57

The mainstay of pemphigus therapy is immunosuppression, primarily with systemic corticosteroids and rituximab. However, these agents can be associated with significant side effects; severe infection induced by an immunocompromised state is a major cause of death in patients with pemphigus. 58 , 59 Rituximab, while a very effective treatment option, requires intravenous administration and results in B‐cell depletion, potentially contributing to a higher rate of severe infections. There is an unmet need for steroid‐sparing agents with rapid onset, patient‐friendly administration, and an acceptable safety profile, including lack of chronic B‐cell depletion. Targeted approaches such as the use of engineered human cytotoxic chimeric autoantigen receptor (CAAR)‐T cells to specifically kill B cells producing autoantibodies are under clinical investigation for pemphigus. 60 Given the key role of BTK in the responses of autoreactive B cells, BTK inhibitors represent a promising therapeutic strategy for pemphigus.

Other skin conditions

CSU and pemphigus are the focus of attention with respect to the potential of BTK inhibition for efficacy in dermatological conditions, but patients with other chronic inflammatory skin diseases, including hidradenitis suppurativa (HS), systemic lupus erythematosus (SLE), and atopic dermatitis can be expected to also benefit from this therapeutic approach.

HS is a chronic inflammatory skin disease, characterized by cutaneous inflamed nodules, abscesses, and pus‐discharging tunnels developed in axillary, inguinal, gluteal, and perianal body sites. 61 Steroid injections, antibiotic creams, or oral antibiotics are first‐line options used to treat HS; for moderate‐to‐severe and/or recalcitrant cases, anti‐TNF treatment with adalimumab is currently the only approved therapy. 62 Surgery is necessary for some patients with HS, particularly when significant scarring has occurred. 63 The immunopathogenesis of HS is poorly understood, but B cells—particularly plasma cells—have been identified as a potential therapeutic target. Characterization of the inflammatory response in HS using proteomic and transcriptomic approaches has revealed enrichment of BTK signaling, thus supporting the potential value of BTK inhibition as a therapeutic strategy. 64

SLE is a chronic autoimmune disease characterized by autoantibodies against nuclear antigens. 65 Cutaneous disease is a common manifestation of SLE; indeed, skin is the second most affected organ after articular involvement. 66 The disease is characterized by altered B‐cell selection, triggering production of autoreactive antibodies and pro‐inflammatory cytokines, and the presentation of autoantigens to autoreactive T cells. 65 Due to the heterogeneity in the etiopathogenesis of SLE, numerous therapeutic targets have been investigated, 67 but the first drug approved by the FDA for the treatment of SLE in over 50 years was belimumab, a fully human IgG1 monoclonal antibody, which selectively targets and inhibits the B‐cell survival factor, B‐lymphocyte stimulator (BLyS). 68 Several components of BTK signaling pathways are altered in B cells from patients with SLE, and BTK is considered to be a promising therapeutic target for the treatment of cutaneous as well as CNS, renal, and articular manifestations of SLE. 65

Atopic dermatitis is the most common inflammatory skin disease, characterized by impaired barrier function. 69 Current pharmacological management strategies include topical agents such as corticosteroids, calcineurin inhibitors and phosphodiesterase‐4 inhibitors, and systemic agents including broad‐spectrum immunosuppressants, cyclosporine, methotrexate, mycophenolate mofetil, and azathioprine. 70 While BTK inhibition is one of a number of therapeutic strategies under investigation, 71 recent additions to the armamentarium include monoclonal antibodies (dupilumab and tralokinumab), along with Janus kinase inhibitors (baricitinib, upadacitinib and abrocitinib). 72 The penetration of antigens through the impaired dermatological barrier leads to production of cytokines such as thymic stromal lymphopoietin, which triggers BTK‐dependent signaling and this may be of therapeutic interest. 69

There may also be a role for BTK inhibitors in the treatment of pure IgE‐mediated conditions such as anaphylaxis of IgE‐mediated food allergy; further studies are warranted in this area.

BTK INHIBITORS IN CLINICAL PRACTICE

First‐generation BTK inhibitors

Since ibrutinib came to the market in 2013 for the treatment of adult patients with MCL, its range of indications has expanded, and a number of other BTK inhibitors, such as acalabrutinib, zanubrutinib, and orelabrutinib, have been developed for the treatment of B‐cell malignancies (Figure 1 ). 73 , 74 , 75 , 76 , 77 , 78 Acalabrutinib, for example, has demonstrated improved potency and selectivity, with reduced off‐target side effects, compared with ibrutinib, while zanubrutinib is another selective BTK inhibitor with superior oral bioavailability and greater BTK specificity than ibrutinib. 79 All of these agents, however, interact with their target via covalent bonding, a feature which, while affording impressive efficacy, has also been associated with drug resistance and a challenging tolerability profile. 77 Aside from BTK, covalent agents may also bind to other kinases, including—but not limited to—those that feature, a cysteine at the same position as BTK. 76 Severe adverse events (AEs) associated with early BTK inhibitors include hemorrhage, hypertension, cardiac arrhythmias and cardiac failure, second primary malignancies, and tumor lysis syndrome. 80 Some of the most common AEs, occurring in more than 30% of patients, are thrombocytopenia, diarrhea, fatigue, musculoskeletal pain, neutropenia, rash, anemia, and bruising. 80 As might be expected for a treatment that targets B cells, BTK‐inhibitor therapy elevates the risk of infection. 80 Ibrutinib treatment is associated with an increased risk of pneumonia, sinusitis, and infections of the upper respiratory and urinary tracts, as well as opportunistic skin infections including herpes simplex and herpes zoster virus reactivations, and Staphylococcus aureus superinfection. 81 The precise role played by BTK in pathogenic microorganism infections is not yet clear and remains the subject of investigation. 82

The risk‐to‐benefit profile of these early BTK inhibitors requires re‐evaluation when considering their potential to offer therapeutic benefits outside of the oncology setting. An AE profile that is considered acceptable for the management of a life‐threatening cancer is different from that which can reasonably be recommended for chronic treatment of conditions that considerably affect patients’ quality of life but are not life‐threatening. As seen above, there is a strong rationale for the potential benefits of BTK inhibitors in some autoimmune and allergic conditions. While agents such as acalabrutinib and zanubrutinib offered improvements over ibrutinib, supporting potential roles in treating chronic, non‐malignant conditions such as food allergy or IgG4‐related disease, a need for the efficacy of BTK inhibitors with an improved AE profile has seen a shift toward development and investigation of a new generation of drugs in this class. 76 , 83

One strategy being used to address this is the use of BTK inhibitors that utilize non‐covalent binding mechanisms. 77 An important benefit in the use of covalent inhibitors is their ability to achieve high, sustained occupancy of the target without the need for extended drug exposure. 76 However, non‐covalent inhibitors may be able to overcome drug resistance, owing to a lack of dependence on binding to C481 mutations, which are a major mechanism for acquired resistance in oncologic indications. 77 Several non‐covalent BTK inhibitors are in development for B‐cell malignancies and, while longer‐term studies are required, early clinical data suggest high levels of specificity and an improved tolerability profile. 77 , 84 , 85

Next‐generation BTK inhibitors for dermatology/allergology indications

An overview of next‐generation BTK inhibitors in development for immune‐mediated dermatological indications is provided in Table 1 (also shown in Figure 1 ). Fenebrutinib (GDC‐0853, RG7845) is a highly selective, reversible, non‐covalent, oral BTK inhibitor. 86 Remibrutinib (LOU064), rilzabrutinib (PRN1008), and tirabrutinib (ONO/GS‐4059) are all oral agents, which bind covalently to their BTK target but with high levels of selectivity. 83 , 87 , 88 In the case of remibrutinib, improved selectivity and tolerability are likely attributable to its ability to bind to an inactive conformation of BTK. 83 Rilzabrutinib demonstrates high affinity and selectivity for the BTK receptor, combined with a long duration of action due to prolonged, but reversible, target occupancy. 87 Tirabrutinib binds in an irreversible covalent manner. High specificity of tirabrutinib binding to C481 on the BTK active site has been confirmed experimentally via mass spectrometry. 89

Clinical development of BTK inhibitors for the treatment of chronic inflammatory skin diseases

In the fields of dermatology and allergology, CSU is a focus of particular interest for the development of next‐generation BTK inhibitors. Remibrutinib and fenebrutinib are most advanced in their clinical development for CSU, both with phase II studies completed.

The first‐in‐human study of remibrutinib (in healthy and asymptomatic atopic volunteers; NCT03918980 ) demonstrated a very fast onset of action and full BTK occupancy for at least 24 h following single doses of 30 mg and higher, while repeated dosing did not cause accumulation. 39 Near‐complete inhibition of blood basophil degranulation was achieved with doses of at least 50 mg. 39 , 90 A phase II study of remibrutinib and an open‐label extension study have been initiated in CSU: initial data from the dose‐finding study in 311 patients with CSU inadequately controlled by H1 antihistamines ( NCT03926611 ) indicated that all tested remibrutinib doses provided significant improvements in urticaria activity score (UAS7) change from baseline at Week 4 and Week 12 compared with placebo, supported by a favorable safety profile. 91 , 92 The open‐label, multicenter, extension study ( NCT04109313 ) is ongoing to evaluate the long‐term safety and tolerability of remibrutinib in eligible patients with CSU; this has enrolled 195 participants and is due to complete in late 2022. 93 Phase III trials of remibrutinib for CSU inadequately controlled by H1 antihistamines are planned to initiate late in 2021 ( NCT05030311 , NCT05032157 , and an open‐label study in Japan: NCT05048342 ). 94 , 95 Also of note in the context of atopic disease, the first‐in‐human study of remibrutinib demonstrated a dose‐dependent reduction in wheal size in skin‐prick tests in individuals with atopic diathesis or atopic dermatitis. 39 , 90

Following a phase I study investigating a single, oral dose of fenebrutinib in healthy volunteers ( NCT03596632 ), 96 two phase II trials of fenebrutinib have been initiated in patients with CSU. In a double‐blind, placebo‐controlled trial in 93 adults with CSU refractory to antihistamines ( NCT03137069 ), fenebrutinib was associated with significant improvements from baseline in UAS7 over 7 days at week 8 (primary endpoint) at doses of 150 mg daily and 200 mg twice daily. 97 Patients with type IIb autoimmunity were apparently more responsive to lower doses of fenebrutinib than those without autoimmunity, and fenebrutinib substantially reduced IgG‐anti‐FcεRI relative to baseline. 97 Numbers of AEs were generally balanced across fenebrutinib and placebo groups and were mild or moderate in severity. Transient grade 3 elevations in alanine transaminase were noted with fenebrutinib 150 mg daily and 200 mg twice daily. Two serious AEs considered to be related to treatment were reported in the 200 mg twice‐daily fenebrutinib arm (periorbital cellulitis and an increase in hepatic enzymes), and led to treatment withdrawal. 97 The second, phase II study was an open‐label, multicenter extension of the double‐blind trial, designed to evaluate the long‐term safety and efficacy of fenebrutinib in patients with CSU. 98 This extension study was terminated following an interim analysis of data from the parent study. 98 Fenebrutinib (150 mg daily or 200 mg twice daily) was also evaluated in a placebo‐controlled, phase II trial in patients with SLE ( NCT02908100 ); it demonstrated evidence of strong pathway inhibition (reduced BTK‐dependent plasmablast RNA signature, anti‐dsDNA autoantibodies, total IgG and IgM, and increased complement C4, versus placebo), although the trial's primary endpoint (SLE Responder Index‐4 at week 48) was not met. 99 Safety results were similar across all arms, except that serious AEs were more frequent with 200 mg twice‐daily fenebrutinib. More AEs led to treatment withdrawal in the fenebrutinib 200 mg twice‐daily group (19%; n = 17) than in the fenebrutinib 150 mg once daily group (8%; n = 7) or placebo group (8%; n = 7). The most common reason for discontinuation was lymphopenia ( n = 1 and n = 3 in the 150 mg daily and 200 mg twice‐daily arms, respectively; n = 0 in the placebo arm). 99

In addition to these two “front runners,” other agents are in development for immune‐mediated dermatological conditions. Rilzabrutinib has been investigated in the multicenter, proof‐of‐concept, phase II, BELIEVE study in 27 patents with moderate and moderate‐to‐severe pemphigus vulgaris. 100 Rilzabrutinib is being studied further in the pivotal, phase III, PEGASUS trial (131 patients with pemphigus vulgaris or pemphigus foliaceus have been enrolled worldwide); this trial did not meet its primary or key secondary endpoints. 101 , 102 Tirabrutinib is already approved for recurrent or refractory primary central nervous system lymphoma and under regulatory review for WM and lymphoplasmacytic lymphoma in Japan, and is in clinical development in Japan for pemphigus. 88 , 103 Patients are currently being recruited for phase II trials of branebrutinib: one in atopic dermatitis and the second in a range of conditions including SLE. 104 , 105

The potential of BTK inhibitors to address unmet clinical needs in dermatology

Recent years have seen a number of therapeutic advances in immune‐mediated dermatological conditions such as CSU or pemphigus and also in SLE. The availability of monoclonal antibodies for the treatment of these conditions (e.g., omalizumab, rituximab, and belimumab, respectively 106 , 107 , 108 ) is a particularly exciting prospect. These biologic agents are, nonetheless, associated with limitations, such that important unmet needs remain in the management of these diseases.

Firstly, nearly a third of patients with CSU remain symptomatic when receiving licensed doses of omalizumab, even after 6 months of treatment. 109 Strategies such as updosing and biomarker profiling are being investigated to try and improve the rate of clinical response. 109 , 110 The second limitation relates to the route of administration of the monoclonal antibody treatments. Those administered subcutaneously require training in self‐administration from a healthcare professional, while treatments administered intravenously are associated with considerable healthcare resource burden as dosing must be carried out in a hospital setting. In terms of mode of action, biologic treatments target one specific molecule. For conditions such as CSU or SLE with multifactorial pathogenesis, this may not be the optimal therapeutic approach. It is also important to consider the tolerability profiles of these biologic agents. The safety profile of omalizumab is generally considered highly favorable, although it demonstrated an increased frequency of mild‐to‐moderate AEs, which were mainly upper respiratory tract infections, compared with placebo in clinical trials. 111 Rituximab is generally well tolerated, but treatment is associated with a rare, yet important, risk of infusion‐related reactions. 112 Moreover, there is also a risk of severe infections during rituximab treatment, which may be fatal. 113 Belimumab, which has been shown to improve mucocutaneous manifestations of SLE, 114 demonstrated a similar overall rate of AEs as placebo in SLE clinical trials. 115 However, it has also been associated with a risk of rare but severe AEs such as serious infections, neoplasms, and progressive multifocal leukoencephalopathy. 115

Drugs that target inhibition of the BTK pathway represent a new therapeutic approach for patients with immune‐mediated dermatological conditions and have the potential to address previously unmet needs. In contrast to monoclonal antibody treatments, these agents feature oral administration (although requiring more frequent dosing, so the likely impact on adherence is unclear) and a favorable mechanism of action that targets a significant pathogenic pathway rather than a single molecule. BTK inhibitors do not carry the safety concerns that have been associated with the biologic treatment options.

Generally speaking, across the immune‐mediated diseases market, small molecules are more accessible than biologics due to disparities in their science, production strategies, and existing government policies. 116 However, pharmacoeconomical comparisons should be informed by other aspects such as efficacy, safety, direct, and indirect health and societal costs of treating chronic inflammatory diseases. Regarding diseases such as CSU or pemphigus, small molecules such as BTK inhibitors are entering a space already populated with approved biologic therapies, and only time can tell how this market will evolve.

It is also worth considering that BTK inhibitors may prove a useful tool to address gaps in understanding of the functions of MCs, basophils, and B cells, and their roles in the pathogenesis of skin diseases. 117 For example, research with ibrutinib using the chronic urticaria–basophil activation test (CU‐BAT) has helped to show that the IgE/FcεRI‐BTK pathway is dominant for the degranulation of basophils treated with sera of patients with autoimmune CSU, but that its inhibition does not completely abrogate basophil activation in all patients. 118

CONCLUSIONS

The development of treatments for immune‐mediated dermatological conditions presents a particular challenge: A successful therapy not only must be effective but also boast a tolerability profile that is acceptable for the long‐term treatment of a chronic condition that affects quality of life but does not significantly reduce life expectancy. BTK inhibitors present themselves as promising candidates for this role. The wide‐ranging clinical potential of BTK inhibition is based on the involvement of BTK in various inflammatory mechanisms and in the pathogenesis of many immunological disorders. Somewhat paradoxically, BTK inhibitors may also offer high levels of specificity with improved tolerability versus existing treatment options, owing to reduced off‐target activity. There is currently a focus on development of these agents in CSU and pemphigus, but they also have potential in SLE and other allergic/autoimmune disorders. In addition to inhibition of FcεRI signaling in MCs and basophils, other effects such as blocking of BCR signaling and disruption of autoantibody production may contribute to the efficacy of these agents and are worthy of further study.

CONFLICTS OF INTEREST

PM‐B received honoraria for acting as a consultant and/or as a speaker for AbbVie, Janssen, Novartis, LEO Pharma, Almirall, Sanofi, Viatris, L’Oréal, and Cantabria Labs and served as a principal investigator in clinical trials supported by AbbVie, Sanofi, and Novartis. AB received honoraria for lectures and educational events for LEO Pharma, Janssen‐Cilag, AbbVie, and Novartis. PK received payment/honoraria for lectures/presentations outside of submitted work for Novartis and Roche.. SM‐R received funding from GA²LEN Global Allergy and Asthma European Network. MM served as a speaker and/or advisor for and/or has received research funding from Allakos, Amgen, Aralez, ArgenX, AstraZeneca, Blueprint, Celldex, Centogene, CSL Behring, FAES, Genentech, Gilead, GIInnovation, Innate Pharma, Kyowa Kirin, Leo Pharma, Lilly, Menarini, Moxie, Novartis, Roche, Sanofi/Regeneron, Third Harmonic Bio, UCB, and Uriach. SF and JS have no conflicts of interest to disclose.

ACKNOWLEDGMENT

We acknowledge Becky Fox‐Spencer, Ph.D. (on behalf of Bedrock Healthcare Communications), who provided writing support for this manuscript, funded by Novartis Pharma AG (Basel, Switzerland).

REFERENCES

1 Bruton OC . Agammaglobulinemia . Pediatrics . 1952 ; 9 ( 6 ): 722 ‐ 728 . 14929630

2 Vetrie D , Vořechovský I , Sideras P , et al. The gene involved in X‐linked agammaglobulinaemia is a member of the src family of protein‐tyrosine kinases . Nature . 1993 ; 361 ( 6409 ): 226 ‐ 233 . 8380905 10.1038/361226a0

3 Tsukada S , Saffran DC , Rawlings DJ , et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X‐linked agammaglobulinemia . Cell . 1993 ; 72 ( 2 ): 279 ‐ 290 . 8425221 10.1016/0092-8674(93)90667-f

4 Thomas JD , Sideras P , Smith CI , Vorechovsky I , Chapman V , Paul WE . Colocalization of X‐linked agammaglobulinemia and X‐linked immunodeficiency genes . Science . 1993 ; 261 ( 5119 ): 355 ‐ 358 . 8332900 10.1126/science.8332900

5 Rawlings DJ , Saffran DC , Tsukada S , et al. Mutation of unique region of Bruton's tyrosine kinase in immunodeficient XID mice . Science . 1993 ; 261 ( 5119 ): 358 ‐ 361 . 8332901 10.1126/science.8332901

6 Honigberg LA , Smith AM , Sirisawad M , et al. The Bruton tyrosine kinase inhibitor PCI‐32765 blocks B‐cell activation and is efficacious in models of autoimmune disease and B‐cell malignancy . Proc Natl Acad Sci USA . 2010 ; 107 ( 29 ): 13075 ‐ 13080 . 20615965 10.1073/pnas.1004594107 PMC2919935

7 Chang BY , Huang M , Francesco M , et al. The Bruton tyrosine kinase inhibitor PCI‐32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells . Arthritis Res Ther . 2011 ; 13 ( 4 ): R115 . 21752263 10.1186/ar3400 PMC3239353

8 Hendriks RW , Yuvaraj S , Kil LP . Targeting Bruton's tyrosine kinase in B cell malignancies . Nat Rev Cancer . 2014 ; 14 ( 4 ): 219 ‐ 232 . 24658273 10.1038/nrc3702

9 Hartkamp LM , Fine JS , van Es IE , et al. Btk inhibition suppresses agonist‐induced human macrophage activation and inflammatory gene expression in RA synovial tissue explants . Ann Rheum Dis . 2015 ; 74 ( 8 ): 1603 ‐ 1611 . 24764451 10.1136/annrheumdis-2013-204143

10 de Gorter DJ , Beuling EA , Kersseboom R , et al. Bruton's tyrosine kinase and phospholipase Cgamma2 mediate chemokine‐controlled B cell migration and homing . Immunity . 2007 ; 26 ( 1 ): 93 ‐ 104 . 17239630 10.1016/j.immuni.2006.11.012

11 Brunner C , Muller B , Wirth T . Bruton's Tyrosine Kinase is involved in innate and adaptive immunity . Histol Histopathol . 2005 ; 20 ( 3 ): 945 ‐ 955 . 15944945 10.14670/HH-20.945

12 Pal Singh S , Dammeijer F , Hendriks RW . Role of Bruton's tyrosine kinase in B cells and malignancies . Mol Cancer . 2018 ; 17 ( 1 ): 57 . 29455639 10.1186/s12943-018-0779-z PMC5817726

13 Xia S , Liu X , Cao X , Xu S . T‐cell expression of Bruton's tyrosine kinase promotes autoreactive T‐cell activation and exacerbates aplastic anemia . Cell Mol Immunol . 2020 ; 17 ( 10 ): 1042 ‐ 1052 . 31431692 10.1038/s41423-019-0270-9 PMC7608443

14 Bao Y , Zheng J , Han C , et al. Tyrosine kinase Btk is required for NK cell activation . J Biol Chem . 2012 ; 287 ( 28 ): 23769 ‐ 23778 . 22589540 10.1074/jbc.M112.372425 PMC3390651

15 Fiedler K , Sindrilaru A , Terszowski G , et al. Neutrophil development and function critically depend on Bruton tyrosine kinase in a mouse model of X‐linked agammaglobulinemia . Blood . 2011 ; 117 ( 4 ): 1329 ‐ 1339 . 21063022 10.1182/blood-2010-04-281170

16 Smiljkovic D , Blatt K , Stefanzl G , et al. BTK inhibition is a potent approach to block IgE‐mediated histamine release in human basophils . Allergy . 2017 ; 72 ( 11 ): 1666 ‐ 1676 . 28328081 10.1111/all.13166 PMC5655929

17 Koprulu AD , Ellmeier W . The role of Tec family kinases in mononuclear phagocytes . Crit Rev Immunol . 2009 ; 29 ( 4 ): 317 ‐ 333 . 19673686 10.1615/critrevimmunol.v29.i4.30

18 Advani RH , Buggy JJ , Sharman JP , et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI‐32765) has significant activity in patients with relapsed/refractory B‐cell malignancies . J Clin Oncol . 2013 ; 31 ( 1 ): 88 ‐ 94 . 23045577 10.1200/JCO.2012.42.7906 PMC5505166

19 Cameron F , Sanford M . Ibrutinib: first global approval . Drugs . 2014 ; 74 ( 2 ): 263 ‐ 271 . 24464309 10.1007/s40265-014-0178-8

20 Wen T , Wang J , Shi Y , Qian H , Liu P . Inhibitors targeting Bruton's tyrosine kinase in cancers: drug development advances . Leukemia . 2021 ; 35 ( 2 ): 312 ‐ 332 . 33122850 10.1038/s41375-020-01072-6 PMC7862069

21 Carnero Contentti E , Correale J . Bruton's tyrosine kinase inhibitors: a promising emerging treatment option for multiple sclerosis . Expert Opin Emerg Drugs . 2020 ; 25 ( 4 ): 377 ‐ 381 . 32910702 10.1080/14728214.2020.1822817

22 Neys SFH , Hendriks RW , Corneth OBJ . Targeting Bruton's tyrosine kinase in inflammatory and autoimmune pathologies . Front Cell Dev Biol . 2021 ; 9 : 668131 . 34150760 10.3389/fcell.2021.668131 PMC8213343

23 Bradshaw JM . The Src, Syk, and Tec family kinases: distinct types of molecular switches . Cell Signal . 2010 ; 22 ( 8 ): 1175 ‐ 1184 . 20206686 10.1016/j.cellsig.2010.03.001

24 Aoki Y , Isselbacher KJ , Pillai S . Bruton tyrosine kinase is tyrosine phosphorylated and activated in pre‐B lymphocytes and receptor‐ligated B cells . Proc Natl Acad Sci USA . 1994 ; 91 ( 22 ): 10606 ‐ 10609 . 7524098 10.1073/pnas.91.22.10606 PMC45070

25 Gilfillan AM , Rivera J . The tyrosine kinase network regulating mast cell activation . Immunol Rev . 2009 ; 228 ( 1 ): 149 ‐ 169 . 19290926 10.1111/j.1600-065X.2008.00742.x PMC2669301

26 Wahl MI , Fluckiger AC , Kato RM , Park H , Witte ON , Rawlings DJ . Phosphorylation of two regulatory tyrosine residues in the activation of Bruton's tyrosine kinase via alternative receptors . Proc Natl Acad Sci USA . 1997 ; 94 ( 21 ): 11526 ‐ 11533 . 9326643 10.1073/pnas.94.21.11526 PMC23526

27 Rawlings DJ , Scharenberg AM , Park H , et al. Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases . Science . 1996 ; 271 ( 5250 ): 822 ‐ 825 . 8629002 10.1126/science.271.5250.822

28 Park H , Wahl MI , Afar DEH , et al. Regulation of Btk function by a major autophosphorylation site within the SH3 domain . Immunity . 1996 ; 4 ( 5 ): 515 ‐ 525 . 8630736 10.1016/s1074-7613(00)80417-3

29 Pivniouk VI , Martin TR , Lu‐Kuo JM , Katz HR , Oettgen HC , Geha RS . SLP‐76 deficiency impairs signaling via the high‐affinity IgE receptor in mast cells . J Clin Invest . 1999 ; 103 ( 12 ): 1737 ‐ 1743 . 10377180 PMC408386

30 Fu C , Turck CW , Kurosaki T , Chan AC . BLNK: a central linker protein in B cell activation . Immunity . 1998 ; 9 ( 1 ): 93 ‐ 103 . 9697839 10.1016/s1074-7613(00)80591-9

31 Takata M , Kurosaki T . A role for Bruton's tyrosine kinase in B cell antigen receptor‐mediated activation of phospholipase C‐gamma 2 . J Exp Med . 1996 ; 184 ( 1 ): 31 ‐ 40 . 8691147 10.1084/jem.184.1.31 PMC2192683

32 Crofford LJ , Nyhoff LE , Sheehan JH , Kendall PL . The role of Bruton's tyrosine kinase in autoimmunity and implications for therapy . Expert Rev Clin Immunol . 2016 ; 12 ( 7 ): 763 ‐ 773 . 26864273 10.1586/1744666X.2016.1152888 PMC5070917

33 Bame E , Tang H , Burns JC , et al. Next‐generation Bruton's tyrosine kinase inhibitor BIIB091 selectively and potently inhibits B cell and Fc receptor signaling and downstream functions in B cells and myeloid cells . Clin Transl Immunology . 2021 ; 10 ( 6 ): e1295 . 34141433 10.1002/cti2.1295 PMC8204096

34 Leandro MJ . B‐cell subpopulations in humans and their differential susceptibility to depletion with anti‐CD20 monoclonal antibodies . Arthritis Res Ther . 2013 ; 15 ( Suppl 1 ): S3 . 10.1186/ar3908 PMC3624669 23566754

35 Rip J , Van Der Ploeg EK , Hendriks RW , Corneth OBJ . The role of Bruton's tyrosine kinase in immune cell signaling and systemic autoimmunity . Crit Rev Immunol . 2018 ; 38 ( 1 ): 17 ‐ 62 . 29717662 10.1615/CritRevImmunol.2018025184

36 Dispenza MC . The use of Bruton's tyrosine kinase inhibitors to treat allergic disorders . Curr Treat Options Allergy . 2021 ; 8 ( 3 ): 261 ‐ 273 . 33880321 10.1007/s40521-021-00286-y PMC8050815

37 MacGlashan D Jr , Honigberg LA , Smith A , Buggy J , Schroeder JT . Inhibition of IgE‐mediated secretion from human basophils with a highly selective Bruton's tyrosine kinase, Btk, inhibitor . Int Immunopharmacol . 2011 ; 11 ( 4 ): 475 ‐ 479 . 21238622 10.1016/j.intimp.2010.12.018 PMC3345890

38 Regan JA , Cao Y , Dispenza MC , et al. Ibrutinib, a Bruton's tyrosine kinase inhibitor used for treatment of lymphoproliferative disorders, eliminates both aeroallergen skin test and basophil activation test reactivity . J Allergy Clin Immunol . 2017 ; 140 ( 3 ): 875 ‐ 879.e1 . 28389390 10.1016/j.jaci.2017.03.013 PMC7366359

39 Kaul M , End P , Cabanski M , et al. Remibrutinib (LOU064): a selective potent oral BTK inhibitor with promising clinical safety and pharmacodynamics in a randomized phase I trial . Clin Transl Sci . 2021 ; 14 ( 5 ): 1756 ‐ 1768 . doi: 10.1111/cts.13005 33834628 PMC8504815

40 Ellmeier W , Abramova A , Schebesta A . Tec family kinases: regulation of FcepsilonRI‐mediated mast‐cell activation . FEBS J . 2011 ; 278 ( 12 ): 1990 ‐ 2000 . 21362140 10.1111/j.1742-4658.2011.08073.x

41 Folkerts J , Redegeld F , Folkerts G , et al. Butyrate inhibits human mast cell activation via epigenetic regulation of FcepsilonRI‐mediated signaling . Allergy . 2020 ; 75 ( 8 ): 1966 ‐ 1978 . 32112426 10.1111/all.14254 PMC7703657

42 Simonowski A , Wilhelm T , Habib P , Zorn CN , Huber M . Differential use of BTK and PLC in FcepsilonRI‐ and KIT‐mediated mast cell activation: a marginal role of BTK upon KIT activation . Biochim Biophys Acta Mol Cell Res . 2020 ; 1867 ( 4 ): 118622 . 31837347 10.1016/j.bbamcr.2019.118622

43 Xing Y , Chu KA , Wadhwa J , et al. Preclinical mechanisms of topical PRN473, a Bruton tyrosine kinase inhibitor, in immune‐mediated skin disease models . ImmunoHorizons . 2021 ; 5 ( 7 ): 581 ‐ 589 . 34326199 10.4049/immunohorizons.2100063

44 Ren L , Campbell A , Fang H , et al. Analysis of the effects of the Bruton's tyrosine kinase (Btk) inhibitor ibrutinib on monocyte Fcgamma receptor (FcgammaR) function . J Biol Chem . 2016 ; 291 ( 6 ): 3043 ‐ 3052 . 26627823 10.1074/jbc.M115.687251 PMC4742765

45 Zuberbier T , Aberer W , Asero R , et al. The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria . Allergy . 2018 ; 73 ( 7 ): 1393 ‐ 1414 . 29336054 10.1111/all.13397

46 Gonçalo M , Gimenéz‐Arnau A , Al‐Ahmad M , et al. The global burden of chronic urticaria for the patient and society . Br J Dermatol . 2021 ; 184 ( 2 ): 226 ‐ 236 . 32956489 10.1111/bjd.19561

47 Fricke J , Ávila G , Keller T , et al. Prevalence of chronic urticaria in children and adults across the globe: systematic review with meta‐analysis . Allergy . 2020 ; 75 ( 2 ): 423 ‐ 432 . 31494963 10.1111/all.14037

48 Maurer M , Weller K , Bindslev‐Jensen C , et al. Unmet clinical needs in chronic spontaneous urticaria. A GA(2)LEN task force report . Allergy . 2011 ; 66 ( 3 ): 317 ‐ 330 . 21083565 10.1111/j.1398-9995.2010.02496.x

49 Maurer M , Giménez‐Arnau AM , Sussman G , et al. Ligelizumab for chronic spontaneous urticaria . N Engl J Med . 2019 ; 381 ( 14 ): 1321 ‐ 1332 . 31577874 10.1056/NEJMoa1900408

50 Guillen‐Aguinaga S , Jauregui Presa I , Aguinaga‐Ontoso E , Guillen‐Grima F , Ferrer M . Updosing nonsedating antihistamines in patients with chronic spontaneous urticaria: a systematic review and meta‐analysis . Br J Dermatol . 2016 ; 175 ( 6 ): 1153 ‐ 1165 . 27237730 10.1111/bjd.14768

51 Maurer M , Eyerich K , Eyerich S , et al. Urticaria: collegium internationale allergologicum (CIA) Update 2020 . Int Arch Allergy Immunol . 2020 ; 181 ( 5 ): 321 ‐ 333 . 32224621 10.1159/000507218 PMC7265766

52 Ertas R , Ozyurt K , Atasoy M , Hawro T , Maurer M . The clinical response to omalizumab in chronic spontaneous urticaria patients is linked to and predicted by IgE levels and their change . Allergy . 2018 ; 73 ( 3 ): 705 ‐ 712 . 29083482 10.1111/all.13345

53 Kolkhir P , Church MK , Altrichter S , et al. Eosinopenia, in chronic spontaneous urticaria, is associated with high disease activity, autoimmunity, and poor response to treatment . J Allergy Clin Immunol Pract . 2020 ; 8 ( 1 ): 318 ‐ 325.e5 . 31472293 10.1016/j.jaip.2019.08.025

54 Altrichter S , Fok JS , Jiao Q , et al. Total IgE as a marker for chronic spontaneous urticaria . Allergy Asthma Immunol Res . 2021 ; 13 ( 2 ): 206 ‐ 218 . 33474856 10.4168/aair.2021.13.2.206 PMC7840871

55 Schoepke N , Asero R , Ellrich A , et al. Biomarkers and clinical characteristics of autoimmune chronic spontaneous urticaria: results of the PURIST Study . Allergy . 2019 ; 74 ( 12 ): 2427 ‐ 2436 . 31228881 10.1111/all.13949

56 Didona D , Maglie R , Eming R , Hertl M . Pemphigus: current and future therapeutic strategies . Front Immunol . 2019 ; 10 : 1418 . 31293582 10.3389/fimmu.2019.01418 PMC6603181

57 Kasperkiewicz M , Ellebrecht CT , Takahashi H , et al. Pemphigus . Nat Rev Dis Primers . 2017 ; 3 : 17026 . 28492232 10.1038/nrdp.2017.26 PMC5901732

58 Joly P , Horvath B , Patsatsi Α , et al. Updated S2K guidelines on the management of pemphigus vulgaris and foliaceus initiated by the European academy of dermatology and venereology (EADV) . J Eur Acad Dermatol Venereol . 2020 ; 34 ( 9 ): 1900 ‐ 1913 . 32830877 10.1111/jdv.16752

59 Izumi K , Bieber K , Ludwig RJ . Current clinical trials in pemphigus and pemphigoid . Front Immunol . 2019 ; 10 : 978 . 31130959 10.3389/fimmu.2019.00978 PMC6509547

60 Roth‐Walter F , Adcock IM , Benito‐Villalvilla C , et al. Immune modulation via T regulatory cell enhancement: Disease‐modifying therapies for autoimmunity and their potential for chronic allergic and inflammatory diseases‐An EAACI position paper of the Task Force on Immunopharmacology (TIPCO) . Allergy . 2021 ; 76 ( 1 ): 90 ‐ 113 . 32593226 10.1111/all.14478

61 Sabat R , Jemec GBE , Matusiak L , Kimball AB , Prens E , Wolk K . Hidradenitis suppurativa . Nat Rev Dis Primers . 2020 ; 6 ( 1 ): 18 . 32165620 10.1038/s41572-020-0149-1

62 Rumberger BE , Boarder EL , Owens SL , Howell MD . Transcriptomic analysis of hidradenitis suppurativa skin suggests roles for multiple inflammatory pathways in disease pathogenesis . Inflamm Res . 2020 ; 69 ( 10 ): 967 ‐ 973 . 32661800 10.1007/s00011-020-01381-7

63 Gulliver W , Zouboulis CC , Prens E , Jemec GB , Tzellos T . Evidence‐based approach to the treatment of hidradenitis suppurativa/acne inversa, based on the European guidelines for hidradenitis suppurativa . Rev Endocr Metab Disord . 2016 ; 17 ( 3 ): 343 ‐ 351 . 26831295 10.1007/s11154-016-9328-5 PMC5156664

64 Gudjonsson JE , Tsoi LC , Ma F , et al. Contribution of plasma cells and B cells to hidradenitis suppurativa pathogenesis . JCI Insight . 2020 ; 5 ( 19 ). doi: 10.1172/jci.insight.139930 PMC7566715 32853177

65 Lorenzo‐Vizcaya A , Fasano S , Isenberg DA . Bruton's tyrosine kinase inhibitors: a new therapeutic target for the treatment of SLE? Immunotargets Ther . 2020 ; 9 : 105 ‐ 110 . 32582577 10.2147/ITT.S240874 PMC7276208

66 Zhou H‐Y , Cao N‐W , Guo B , et al. Systemic lupus erythematosus patients have a distinct structural and functional skin microbiota compared with controls . Lupus . 2021 ; 30 ( 10 ): 1553 ‐ 1564 . doi: 10.1177/09612033211025095 34139926

67 Mathias LM , Stohl W . Systemic lupus erythematosus (SLE): emerging therapeutic targets . Expert Opin Ther Targets . 2020 ; 24 ( 12 ): 1283 ‐ 1302 . 33034541 10.1080/14728222.2020.1832464

68 Stohl W , Hilbert DM . The discovery and development of belimumab: the anti‐BLyS‐lupus connection . Nat Biotechnol . 2012 ; 30 ( 1 ): 69 ‐ 77 . 22231104 10.1038/nbt.2076 PMC3264947

69 Szilveszter KP , Nemeth T , Mocsai A . Tyrosine kinases in autoimmune and inflammatory skin diseases . Front Immunol . 2019 ; 10 : 1862 . 31447854 10.3389/fimmu.2019.01862 PMC6697022

70 Lipman ZM , Labib A , Yosipovitch G . Current clinical options for the management of itch in atopic dermatitis . Clin Cosmet Investig Dermatol . 2021 ; 14 : 959 ‐ 969 . 10.2147/CCID.S289716 PMC8349193 34377004

71 Bieber T . Atopic dermatitis: an expanding therapeutic pipeline for a complex disease . Nat Rev Drug Discov . 2021 ; 21 ( 1 ): 21 ‐ 40 . 34417579 10.1038/s41573-021-00266-6 PMC8377708

72 Svoboda SA , Johnson N , Phillips M . Dermatologic applications and safety considerations of Janus kinase inhibitors . Skin Therapy Lett . 2020 ; 25 ( 4 ): 6 ‐ 11 . 33017108

73 Burger JA , Barr PM , Robak T , et al. Long‐term efficacy and safety of first‐line ibrutinib treatment for patients with CLL/SLL: 5 years of follow‐up from the phase 3 RESONATE‐2 study . Leukemia . 2020 ; 34 ( 3 ): 787 ‐ 798 . 31628428 10.1038/s41375-019-0602-x PMC7214263

74 Sharman JP , Egyed M , Jurczak W , et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment‐naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial . Lancet . 2020 ; 395 ( 10232 ): 1278 ‐ 1291 . 32305093 10.1016/S0140-6736(20)30262-2 PMC8151619

75 Tam CS , Opat S , D'Sa S , et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenstrom macroglobulinemia: the ASPEN study . Blood . 2020 ; 136 ( 18 ): 2038 ‐ 2050 . 32731259 10.1182/blood.2020006844 PMC7596850

76 Gabizon R , London N . A Fast and clean BTK Inhibitor . J Med Chem . 2020 ; 63 ( 10 ): 5100 ‐ 5101 . 32401033 10.1021/acs.jmedchem.0c00597 PMC7304894

77 Gu D , Tang H , Wu J , Li J , Miao Y . Targeting Bruton tyrosine kinase using non‐covalent inhibitors in B cell malignancies . J Hematol Oncol . 2021 ; 14 ( 1 ): 40 . 33676527 10.1186/s13045-021-01049-7 PMC7937220

78 Xu W , Song Y , Li Z , et al. Safety, tolerability and efficacy of orelabrutinib, once a day, to treat Chinese patients with relapsed or refractory chronic lymphocytic leukemia/small cell leukemia . Blood . 2019 ; 134 : 4319 .

79 Wu J , Liu C , Tsui ST , Liu D . Second‐generation inhibitors of Bruton tyrosine kinase . J Hematol Oncol . 2016 ; 9 ( 1 ): 80 . 27590878 10.1186/s13045-016-0313-y PMC5010774

80 Ibrutinib prescribing information . Accessed September 6, 2021. https://www.imbruvica.com/files/prescribing‐information.pdf

81 Sibaud V , Beylot‐Barry M , Protin C , Vigarios E , Recher C , Ysebaert L . Dermatological toxicities of Bruton's tyrosine kinase inhibitors . Am J Clin Dermatol . 2020 ; 21 ( 6 ): 799 ‐ 812 . 32613545 10.1007/s40257-020-00535-x

82 Ye B , Zhou C , Guo H , Zheng M . Effects of BTK signalling in pathogenic microorganism infections . J Cell Mol Med . 2019 ; 23 ( 10 ): 6522 ‐ 6529 . 31397086 10.1111/jcmm.14548 PMC6787465

83 Angst D , Gessier F , Janser P , et al. Discovery of LOU064 (Remibrutinib), a potent and highly selective covalent inhibitor of Bruton's tyrosine kinase . J Med Chem . 2020 ; 63 ( 10 ): 5102 ‐ 5118 . 32083858 10.1021/acs.jmedchem.9b01916

84 Byrd JC , Smith S , Wagner‐Johnston N , et al. First‐in‐human phase 1 study of the BTK inhibitor GDC‐0853 in relapsed or refractory B‐cell NHL and CLL . Oncotarget . 2018 ; 9 ( 16 ): 13023 ‐ 13035 . 29560128 10.18632/oncotarget.24310 PMC5849192

85 Allan JN , Patel K , Mato AR , et al. Ongoing results of a phase 1B/2 dose‐escalation and cohort‐expansion study of the selective, noncovalent, reversible Bruton's tyrosine kinase inhibitor, vecabrutinib, in B‐cell malignancies . Blood . 2019 ; 134 : 3041 .

86 Crawford JJ , Johnson AR , Misner DL , et al. Discovery of GDC‐0853: a potent, selective, and noncovalent Bruton's tyrosine kinase inhibitor in early clinical development . J Med Chem . 2018 ; 61 ( 6 ): 2227 ‐ 2245 . 29457982 10.1021/acs.jmedchem.7b01712

87 Smith PF , Krishnarajah J , Nunn PA , et al. A phase I trial of PRN1008, a novel reversible covalent inhibitor of Bruton's tyrosine kinase, in healthy volunteers . Br J Clin Pharmacol . 2017 ; 83 ( 11 ): 2367 ‐ 2376 . 28636208 10.1111/bcp.13351 PMC5651318

88 Dhillon S . Tirabrutinib: first approval . Drugs . 2020 ; 80 ( 8 ): 835 ‐ 840 . 32382949 10.1007/s40265-020-01318-8

89 Liclican A , Serafini L , Xing W , et al. Biochemical characterization of tirabrutinib and other irreversible inhibitors of Bruton's tyrosine kinase reveals differences in on ‐ and off ‐ target inhibition . Biochim Biophys Acta Gen Subj . 2020 ; 1864 ( 4 ): 129531 . 31953125 10.1016/j.bbagen.2020.129531

90 clinicaltrials.gov . Single dose and multiple dose study to assess safety and tolerability of LOU064 ( NCT03918980 ) . Accessed July 2, 2021. https://clinicaltrials.gov/ct2/show/NCT03918980?term=LOU064&draw=2&rank=3

91 Maurer M , Berger W , et al. The Bruton’s tyrosine kinase inhibitor remibrutinib (LOU064) in chronic spontaneous urticaria: top line results of a phase 2b dose‐finding study . Presented at the EADV Congress. 2021 .

92 clinicaltrials.gov . Dose‐finding study to evaluate efficacy and safety of LOU064 in patients With CSU inadequately controlled by H1‐antihistamines ( NCT03926611 ) . Accessed July 2, 2021. https://clinicaltrials.gov/ct2/show/NCT03926611?term=LOU064&draw=2&rank=5

93 clinicaltrials.gov . Open‐label, multicenter, extension study to evaluate long‐term safety and tolerability of LOU064 in subjects with CSU ( NCT04109313 ) . Accessed July 2, 2021. https://clinicaltrials.gov/ct2/show/NCT04109313?term=LOU064&draw=2&rank=1

94 clinicaltrials.gov . A phase 3 study of efficacy and safety of remibrutinib in the treatment of CSU in adults inadequately controlled by H1 antihistamines (REMIX‐1) ( NCT05030311 ) . Accessed October 11, 2021. https://clinicaltrials.gov/ct2/show/NCT05030311?term=NCT05030311&draw=2&rank=1

95 clinicaltrials.gov . A safety and efficacy study of remibrutinib in the treatment of CSU in Japanese adults inadequately controlled by H1‐antihistamines (REMIX‐Japan) ( NCT05048342 ) . Accessed October 11, 2021. https://clinicaltrials.gov/ct2/show/NCT05048342?term=NCT05048342&draw=2&rank=1

96 Herman AE , Chinn LW , Kotwal SG , et al. Safety, pharmacokinetics, and pharmacodynamics in healthy volunteers treated with GDC‐0853, a selective reversible Bruton's tyrosine kinase inhibitor . Clin Pharmacol Ther . 2018 ; 103 ( 6 ): 1020 ‐ 1028 . 29484638 10.1002/cpt.1056

97 Metz M , Sussman G , Gagnon R , et al. Fenebrutinib in H 1 ‐antihistamine‐refractory chronic spontaneous urticaria: a randomized phase 2 trial . Nat Med . 2021 ; 27 : 1961 ‐ 1969 . 34750553 10.1038/s41591-021-01537-w PMC8604722

98 clinicaltrials.gov . A study to evaluate the long‐term safety and efficacy of fenebrutinib in participants previously enrolled in a fenebrutinib chronic spontaneous urticaria (CSU) study ( NCT03693625 ) . Accessed July 5, 2021. https://clinicaltrials.gov/ct2/show/NCT03693625?term=fenebrutinib&draw=2&rank=1

99 Isenberg D , Furie R , Jones NS , et al. Efficacy, safety, and pharmacodynamic effects of the Bruton's tyrosine kinase inhibitor, fenebrutinib (GDC‐0853), in systemic lupus erythematosus . Arthritis Rheumatol . 2021 ; doi: 10.1002/art.41811 34042314

100 Murrell DF , Patsatsi A , Stavropoulos P , et al. Proof‐of‐concept for clinical effects of oral rilzabrutinib, the first Bruton tyrosine kinase inhibitor for pemphigus vulgaris: the phase 2 BELIEVE study . Br J Dermatol . 2021 ; 185 ( 4 ): 745 ‐ 755 . 33942286 10.1111/bjd.20431 PMC8518737

101 clinicaltrials.gov . A study of PRN1008 in patients with pemphigus ( NCT03762265 ) . Accessed October 11, 2021. https://clinicaltrials.gov/ct2/results?cond=&term=NCT03762265&cntry=&state=&city=&dist=

102 Sanofi provides update on Phase 3 study evaluating rilzabrutinib for the treatment of pemphigus . September 9 2021. Accessed October 1, 2021. https://www.sanofi.com/en/media‐room/press‐releases/2021/2021‐09‐09‐07‐00‐00‐2293920 [press release]

103 Yamagami J , Ujiie H , Aoyama Y , et al. A multicenter, open‐label, uncontrolled, single‐arm phase 2 study of tirabrutinib, an oral Bruton's tyrosine kinase inhibitor, in pemphigus . J Dermatol Sci . 2021 ; 103 ( 3 ): 135 – 142 . 34376340 10.1016/j.jdermsci.2021.07.002

104 clinicaltrials.gov . A study of BMS‐986166 or branebrutinib for the treatment of participants with atopic dermatitis ( NCT05014438 ) . Accessed October 11, 2021. https://clinicaltrials.gov/ct2/show/NCT05014438?term=NCT05014438&draw=2&rank=1

105 clinicaltrials.gov . Study to assess safety and effectiveness of branebrutinib treatment in participants with active systemic lupus erythematosus or primary Sjögren's syndrome, or branebrutinib treatment followed by open‐label abatacept treatment in study participants with active rheumatoid arthritis ( NCT04186871 ) . Accessed October 11, 2021. https://clinicaltrials.gov/ct2/show/NCT04186871?term=NCT04186871&draw=2&rank=1

106 Maurer M , Khan DA , Elieh Ali Komi D , Kaplan AP . Biologics for the use in chronic spontaneous urticaria: when and which . J Allergy Clin Immunol Pract . 2021 ; 9 ( 3 ): 1067 ‐ 1078 . 33685605 10.1016/j.jaip.2020.11.043

107 Murrell DF , Pena S , Joly P , et al. Diagnosis and management of pemphigus: recommendations of an international panel of experts . J Am Acad Dermatol . 2020 ; 82 ( 3 ): 575 ‐ 585 e571 . 29438767 10.1016/j.jaad.2018.02.021 PMC7313440

108 Kleinmann J‐F , Tubach F , Le Guern V , et al. International and multidisciplinary expert recommendations for the use of biologics in systemic lupus erythematosus . Autoimmun Rev . 2017 ; 16 ( 6 ): 650 ‐ 657 . 28434948 10.1016/j.autrev.2017.04.011

109 Metz M , Vadasz Z , Kocaturk E , Gimenez‐Arnau AM . Omalizumab updosing in chronic spontaneous urticaria: an overview of real‐world evidence . Clin Rev Allergy Immunol . 2020 ; 59 ( 1 ): 38 ‐ 45 . 32418171 10.1007/s12016-020-08794-6 PMC7351799

110 de Montjoye L , Darrigade AS , Gimenez‐Arnau A , Herman A , Dumoutier L , Baeck M . Correlations between disease activity, autoimmunity and biological parameters in patients with chronic spontaneous urticaria . Eur Ann Allergy Clin Immunol . 2021 ; 53 ( 2 ): 55 ‐ 66 . 31965967 10.23822/EurAnnACI.1764-1489.132

111 Gimenez‐Arnau AM . Omalizumab for treating chronic spontaneous urticaria: an expert review on efficacy and safety . Expert Opin Biol Ther . 2017 ; 17 ( 3 ): 375 ‐ 385 . 28125304 10.1080/14712598.2017.1285903

112 Paul F , Cartron G . Infusion‐related reactions to rituximab: frequency, mechanisms and predictors . Expert Rev Clin Immunol . 2019 ; 15 ( 4 ): 383 ‐ 389 . 30580638 10.1080/1744666X.2019.1562905

113 Tavakolpour S , Mahmoudi H , Balighi K , Abedini R , Daneshpazhooh M . Sixteen‐year history of rituximab therapy for 1085 pemphigus vulgaris patients: a systematic review . Int Immunopharmacol . 2018 ; 54 : 131 ‐ 138 . 29132070 10.1016/j.intimp.2017.11.005

114 Manzi S , Sánchez‐Guerrero J , Merrill JT , et al. Effects of belimumab, a B lymphocyte stimulator‐specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials . Ann Rheum Dis . 2012 ; 71 ( 11 ): 1833 ‐ 1838 . 22550315 10.1136/annrheumdis-2011-200831 PMC3465857

115 Blair HA , Duggan ST . Belimumab: a review in systemic lupus erythematosus . Drugs . 2018 ; 78 ( 3 ): 355 ‐ 366 . 29396833 10.1007/s40265-018-0872-z

116 Makurvet FD . Biologics vs. small molecules: drug costs and patient access . Med Drug Discov . 2021 ; 9 : 100075 .

117 Kolkhir P , Elieh‐Ali‐Komi D , Metz M , Siebenhaar F , Maurer M . Understanding human mast cells: lesson from therapies for allergic and non‐allergic diseases . Nat Rev Immunol . 2021 . doi: 10.1038/s41577-021-00622-y 34611316

118 Jorg L , Mueller‐Wirth N , Pecaric‐Petkovic T , Diaz C , Pichler W , Hausmann O . The Fcepsilon receptor I pathway is crucial but not exclusive for basophil activation in patients with autoimmune forms of chronic spontaneous urticaria . J Eur Acad Dermatol Venereol . 2020 ; 34 ( 12 ): e825 ‐ e827 . 32491222 10.1111/jdv.16703

119 Bracken SJ , Abraham S , MacLeod AS . Autoimmune theories of chronic spontaneous urticaria . Front Immunol . 2019 ; 10 : 627 . 30984191 10.3389/fimmu.2019.00627 PMC6450064

120 Altrichter S , Frischbutter S , Fok JS , et al. The role of eosinophils in chronic spontaneous urticaria . J Allergy Clin Immunol . 2020 ; 145 ( 6 ): 1510 ‐ 1516 . 32224275 10.1016/j.jaci.2020.03.005

121 Iyer AS , Morales JL , Huang W , et al. Absence of Tec family kinases interleukin‐2 inducible T cell kinase (Itk) and Bruton's tyrosine kinase (Btk) severely impairs Fc epsilonRI‐dependent mast cell responses . J Biol Chem . 2011 ; 286 ( 11 ): 9503 ‐ 9513 . 21212279 10.1074/jbc.M110.165613 PMC3059023