New small molecules in dermatology: for the autoimmunity, inflammation and beyond

Abstract

Objective and design

The discovery of new inflammatory pathways and the mechanism of action of inflammatory, autoimmune, genetic, and neoplastic diseases led to the development of immunologically driven drugs. We aimed to perform a narrative review regarding the rising of a new class of drugs capable of blocking important and specific intracellular signals in the maintenance of these pathologies: the small molecules.

Materials/methods

A total of 114 scientific papers were enrolled in this narrative review.

Results

We describe in detail the families of protein kinases—Janus Kinase (JAK), Src kinase, Syk tyrosine kinase, Mitogen-Activated Protein Kinase (MAPK), and Bruton Tyrosine Kinase (BTK)—their physiologic function and new drugs that block these pathways of intracellular signaling. We also detail the involved cytokines and the main metabolic and clinical implications of these new medications in the field of dermatology.

Conclusions

Despite having lower specificity compared to specific immunobiological therapies, these new drugs are effective in a wide variety of dermatological diseases, especially diseases that had few therapeutic options, such as psoriasis, psoriatic arthritis, atopic dermatitis, alopecia areata, and vitiligo.

Introduction

The dermatological therapy has been revolutionized since the introduction of topical hydrocortisone by Sulzberger at the X International Congress of Dermatology, in 1952 in London (England), including 100 atopic patients among other 252 with distinct dermatosis [1]. However, the knowledge about the specific drugs to act on cell receptors or signaling signs started with Paul Ehrlich, in 1910 at Frankfurt, where he developed the concept of “magic bullets”, chemicals that may be applied to treat infectious diseases, such as the drug he developed, the compound 606, which he named Salvarsan, to treat syphilis [2]. Ehrlich had a visionary view on Translational Medicine: his concept of complement-mediated therapy reached our day in the twenty-first century as represented by two complement inhibitors, C1 esterase inhibitor (Cinryze^®, 2008) and eculizumab (Soliris^®, 2007) [2].

The introduction of biological agents at the beginning of the twenty-first century has changed the way we treat several skin diseases, including chronic urticaria, psoriasis, atopic dermatitis, hereditary angioedema, hidradenitis suppurativa, pemphigus, lymphoma, lupus, and others diseases, providing more effective and disease-specific therapies for these complex diseases [3]. Although excellent treatment options, biological agents have limitations: side effect profile, immunogenicity, contraindications, and lack or progressive loss of efficacy in some patients [3].

Therefore, since the “magic bullet” concept by Ehrlich to genetic revolutionary knowledge based on human genomics, the therapeutic has been changed to offer almost the precision medicine for each patient. This revision aims to provide a base of knowledge about the pathway signaling involved in the action of new small molecules for oral or topical use in dermatology and their state-of-the-art.

Three largest classes of cell-surface receptor proteins

All water-soluble signal molecules (including neurotransmitters and all signal proteins) bind to specific receptor proteins on the surface of the target cells that these specific molecules influence [4]. These cell-surface receptor proteins act as signal transducers [4]. They transform an extracellular ligand-binding event into intracellular signals that change the behavior of the target cell [5].

The main cell-surface receptor proteins belong to one of three classes, based on their transduction mechanism used: (i) ion-channel-linked receptors (also called transmitter-gated ion channels or ionotropic receptors) which are involved in rapid synaptic signaling among several electrically excitable cells; (ii) G-protein-linked receptors, which acts indirectly to regulate the activity of a separate plasma-membrane-bound target protein, often an enzyme or an ion channel, and (iii) enzyme-linked receptors when activated, either function directly as enzymes or are directly associated with enzymes that they activate (the great majority are protein kinases or are associated with protein kinases, and their ligand binding settle the phosphorylation of specific groups of proteins in the target cell) [4].

Principles of the intracellular signaling proteins pathways

Several intracellular signaling proteins behave as molecular switches: on receipt of a signal (like a cytokine binding to their specific receptor on the plasma cell membrane), they switch from a biologically inactive to an active state, until another process switches them off [4]. Signals received at the surface of a cell by either G-protein-linked or enzyme-linked receptors are carried into the cell interior by a combination of small and large intracellular signaling molecules [4].

When an extracellular signal (as biological molecules represented by histamine or a specific cytokine, respectively) acting through a single type of G-protein-linked or enzyme-linked (like tyrosine kinase) receptor, usually activates multiple parallel signaling pathways and can thereby influence multiple aspects of cell behavior—such as their shape, movement, metabolism, and gene expression on DNA [4].

Translation of the immune response and intracellular signaling pathways for dermatological conditions

Dermatological therapy is enhancing their potential field of action based on the new treatments using biological antibodies and new small oral molecules applied for inflammatory diseases, cutaneous cancer, and autoimmune or autoinflammatory conditions. The fundamentals of these new therapies are the result of the knowledge growth of immunology and genetics applied to skin diseases.

The human immune system, including adaptive and innate immunity, plays a pivotal role in efficient host defense against microbiological agents [5]. As the first immune barrier, innate immunity enables the body to fight against pathogen infection through signaling events, including sensing, integration and transmission of non-self or foreign dangerous signals by various pattern recognition receptors (PRRs) in Dendritic Cells (DCs), monocytes and macrophages, respectively, PAMPS (Pathogen-associated molecular pattern molecules, external agents as bacteria, fungi or viruses) and DAMPS (Damage-associated molecular pattern molecules, cell stressors or cytotoxic damage, as UV radiation, monourate crystals, etc.) [5]. PRRs can recognize pathogen-associated molecular patterns and initiate pro-inflammatory responses [5]. PRRs also recognize self-derived Nucleic Acids (NAs) to induce undesired inflammatory responses, resulting in autoinflammatory and autoimmune diseases [6], such as cryopyrin-related diseases (CINCA/NOMID, Muckle-Wells syndrome, and familial cold autoinflammatory syndrome), an inborn error of immunity and lupus erythematosus (Fig. 1).

Fig. 1.

JAK inhibitors and the blocking mechanisms of JAK2 and TYK2, in psoriasis

TLRs harbor extracellular leucine-rich repeats, a transmembrane domain, and a Toll/IL-1 receptor (TIR) domain, which signal through downstream signaling molecules, such as myeloid differentiation primary response gene 88 (MyD88) and TIR-domain-containing adapter-inducing interferon β (TRIF) [6]. TLR7, 8, and 9 are predominantly expressed in Plasmacytoid Dendritic Cells (pDCs), which abundantly produce type I IFNs during viral infections [6]; however, multiple Single Nucleotide Polymorphisms (SNPs) in NA-sensing TLRs have been identified in patients with autoinflammation, and some of these SNPs have been associated with higher expression of respective TLRs in pDCs or autoantibody production, leading to excessive signaling pathway activation and proinflammatory cytokine production in the development of various inflammatory diseases, such as Type 1 Diabetes Mellitus (T1DM), SLE, and Graves’ disease [6].

Potential future SLE therapies may involve the inhibition of IFN receptor subunits, such as Tyrosine Kinase Type 2 (TYK2) [6]. The inhibition of TYK2 selective inhibitors (BMS-986165) was addressed in early clinical and preclinical investigations, and a phase II study is ongoing to characterize the long-term safety and tolerability of TYK2 selective inhibitor (deucravacitinib) in SLE [6], (NCT03920267) [7]. TYK2 is an intracellular kinase that mediates interleukin (IL)-23, IL-12, and interferon (IFN type I) α/β signaling [8]. Individuals with loss-of-function genetic polymorphisms of TYK2 have a lower risk of developing psoriasis and other immune-mediated diseases, without substantial safety concerns [8]. These features made TYK2 an attractive target for psoriasis treatments [8]. Deucravacitinib is a novel, oral, selective inhibitor of TYK2 acting via binding to the TYK2 regulatory domain, approved by the FDA (EUA) for moderate-to-severe plaque psoriasis in 2022 after evaluation of the pivotal phase 3 POETYK PSO-1 study [8].

Inhibition of TLR7 and TLR8 activation, therefore, represents a potential target for Autoimmune Diseases (AID), including SLE. TLR signaling is an important mediator of coronavirus disease 2019 (COVID‐19) immunopathogenesis [9]. Molecular docking studies suggest that spike (S) protein of the SARS‐CoV‐2, binds to various cell surface TLRs (TLR1, TLR4, and TLR6) and generates pro‐inflammatory responses [9].

Enpatoran (Merk^®) is a potential small molecule dual TLR antagonist against both TLR7 and TLR8, suppressing disease activity in mouse models of SLE [9]. A phase 1, double‐blind, randomized, placebo‐controlled study was the first to use enpatoran in humans [9]. Actually, the sponsor is recruiting patients to phase 2, a double-blind, randomized, placebo-controlled study. Willow study and Willow LTE are recruiting patients to treat SLE, and SLE subacute and cutaneous LE, respectively [10, 11].

Tyrosine kinases and their inhibitors for other autoimmune and inflammatory mucocutaneous diseases

TYKs are involved in signalizing from several leukocyte antigen receptors, both on innate immune receptors, and cytokine receptors [12]. TYKs are intracellular enzymes mediating the tyrosine phosphorylation of downstream molecules [12]. They are relevant drugs to the pharmacological management of several human diseases, including malignant neoplasms, and immune-related diseases [12]. Figure 2 represents several cell membrane receptors and their intracellular signaling molecules involved in distinct cutaneous conditions related to host defense against pathogens, inflammatory responses, allergy, and autoimmunity, which nowadays are the target for new treatments in dermatological diseases using JAK/STAT inhibitors.

Fig. 2.

Influence of several cytokines and hormones on cell membrane receptors of the JAK/STAT pathway and its metabolic and clinical consequences

Non-receptor TYKs are intracellular TYKs without a direct function in sensing extracellular stimulus [12]. However, these TYKs are often coupled to various cell surface receptors and are closely involved in the transmission of extracellular signals to downstream intracellular signaling pathways and cellular effector functions [12]. There are now ten distinct non-receptors TYK families described [12]. We will discuss JAK (also known as JAK-Family kinases), Src-family kinases, and the Syk tyrosine kinase, MAPK pathway, as well as, members of the BTK family [12] applied clinically in dermatological conditions or under investigation for it. Figure 3 summarizes these distinct intracellular signaling pathways and their inhibitors.

Fig. 3.

The interaction among distinct intracellular signaling pathways and their inhibitors, represented by small molecules drugs commercially available or under pre-clinical or clinical investigation

JAK and signal transducer and activator of transcription (JAK/STAT) family

Multiple biologic processes such as cell proliferation, differentiation, function activation/inhibition, and survival/apoptosis are mediated by cell signalization driven by JAK/STAT family [13]. It is especially important for the signalization of a range of cytokines and growth factors. Nevertheless, it facilitates various cellular reactions to stress such as hypoxia, endotoxin, ultraviolet light, and hyperosmolarity [14]. Hence, the pharmacologic intervention on JAK/STAT pathway is promising for the mediation of several diseases and JAK inhibitors are currently being investigated for many indications [15].

The main JAK-STAT enzymes comprise four of the JAK type (JAK1, JAK2, JAK3, and tyrosine kinase 2 [Tyk2]), and seven of the STAT type (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6). The JAKs are situated in the intracellular domains of transmembrane receptors of cytokines, leptin, and growth factors, which are activated upon cytokine stimulation and phosphorylate STATs, resulting in the dimerization and translocation of STATs to the nucleus to activate or suppress the transcription of specific genes (Fig. 4). They are dimerized differently, according to the type of cytokine receptor and the cell type involved, different dimers are associated with different STAT phosphorylation leading to specific cell signaling (Fig. 2). Each JAK enzyme contains an ATP-binding pocket which is critical to its function. It is the ATP bound within the pocket that supplies the phosphate group intrinsic to JAK activity [16].

Fig. 4.

Step-by-step activation of JAKS and STATS by inflammatory cytokines

Janus is the Greek god of doorways, looking both outside and inside a room, and illustrates how JAKs facilitate signals from the cell surface into the cell. JAKs comprise distinct domains which are described as follows: N-terminal FERM domain, SH2 (Src homology 2), central pseudokinase domain, and a Protein Tyrosine Kinases (PTK) domain [16].

The human STAT family has extreme homology in the following regions: Unique N-terminus region involves in STAT regulation e.g. tyrosine dephosphorylation or STAT interactions, such as tetramer formation. Then, a coiled-coil domain is involved in protein–protein interactions and nuclear export. The DNA-binding domain contains an S-type immunoglobulin fold and is also found in p53 which facilitates sequence-specific binding. This region recognizes the TTCN3–4GAAA sequence found in the promoters of target genes. Finally, a C-terminus region which is also called Trans-Activation Domain (TAD) and contains a highly conserved tyrosine residue [17].

Type I and type II cytokine receptors do not have any enzymatic activity per se but they depend on JAKs to transduce intracellular signals. JAK proteins share four components: the kinase domain, the pseudokinase domain, the four-point-one protein, ezrin, radixin, moesin (FERM) domain, and the Src homology 2 (SH2)‑like domain [18].

According to the canonical pathway, JAK-STATs signaling is activated by receptor binding to the ligand and it is inactivated by negative regulators such as SOCS (suppressor of cytokine signaling) and SHPs (SH2-domain-containing protein-tyrosine phosphatase). That is a conventional pathway in which other signaling molecules are involved, including PI3 kinase (PI3K), Mitogen Activate Kinase (MAPK), and Extracellular Receptor Kinase (ERK). In the noncanonical pathway, different from the canonical pathway, a number of the unphosphorylated STATs are localized on heterochromatin in the nucleus in association with proteins that contribute to the maintenance of the heterochromatin state. Whenever STAT phosphorylation is amplified (by JAKs or other TYKs) the amount of unphosphorylated STAT is reduced on the heterochromatin. Dispersed phosphorylated STAT binds to cognitive sites in euchromatin to induce gene expression [19].

Most cytokine receptors play their roles in the initiation and development of various immunological diseases through the JAK-STAT pathway, especially in T cell-mediated diseases. Several JAK inhibitors are approved to treat dermatologic conditions, and their profile defines the specificity of the cytokine network affected by each drug, which tailors the drug for each possible indication. In contrast, some of the major cytokines involved in RA pathogenesis, specifically IL-1, TNF-α, and IL-17, are not dependent on JAKs for their signaling, and the combination of strategies for the blockade of these simultaneous signaling is warranted [20].

JAK1 is widely expressed in tissues and can phosphorylate all STATs. The JAK1 pathway is important for cytokines that share the common gamma chain for type 1 cytokine receptors. JAK1 is also part of the canonical signaling pathway for IFN-alpha, IFN-beta, IFN-gamma, IL-2, IL-4, IL-6, IL-7, IL-9, IL-10, IL-11, IL-13, IL-15, IL-19, IL-21, IL-22, IL-27, IL-28, IL-29, IL-31, IL-35, CNTF, OSM and CT-1. The selective JAK1 inhibitors are upadacitinib, abrocitinib, itacitinib, and filgotinib. Baricitinib and Oclacitinib are non-selective JAK1 inhibitors, which exert some effect on JAK2 [20]. Several dermatologic conditions are under study for JAK1 inhibitors, such as atopic dermatitis (Fig. 4), hidradenitis suppurativa, lichen planopilaris, vitiligo, alopecia areata, dermatomyositis, and others [21–24].

The inhibition of JAK2 has a direct effect on the signaling of growth hormones and erythropoiesis, but some inflammatory cytokines such as IL-3, IL-5, IL-6, IL-10, IL-11, IL-13, IL-12, IL-19, IL-22, IL-23, IL-27, IL-35, IFN-gamma, GM-CSF, EPO, TPO, and leptin. JAK2-knockout mice die at approximately 12 days of gestation primarily due to the impaired hematopoietic function mediated by EPO. As JAK2 is the only subunit that composes a homologous dimer in the signalization for EPO, TPO, GM-CSF, GH, and leptin, the effects in hematopoiesis are relevant, and the systemic inhibition of JAK2 is indicated to treat myelofibrosis and polycythemia rubra vera, however, they can be used topically to treat skin disorders such as alopecia areata, atopic dermatitis vitiligo, and psoriasis, avoiding the hematopoietic adverse effects. Tofacitinib, ruxolitinib, and delgocitinib are non-selective JAK2 inhibitors that are being investigated as topical agents for inflammatory skin disorders [25, 26]. Fedratinib is a selective JAK2 inhibitor, which is indicated for the treatment of myelofibrosis [20].

As occurs with JAK1, JAK3 dimerizes differently among the receptors, and the blockade of JAK3 can promote a pleiotropic effect on the immune response and cell proliferation, affecting the signalization of IL-2, IL-4, IL-7, IL-9, IL-13, IL-15, and IL-21. JAK3-knockout mice are defective in lymphocyte production due to the lack of γC signaling. Peficitinib is a non-selective JAK1/JAK3 inhibitor that has been approved for the treatment of rheumatoid arthritis [27]. In dermatology, oral ritlecitinib has demonstrated efficacy and good tolerability in the treatment of vitiligo and alopecia areata [28, 29]. Decernotinib is an oral selective JAK3 inhibitor that revealed efficacy in the treatment of rheumatoid arthritis, despite some gastrointestinal side effects [20, 20].

The inhibition of Tyk2 is under investigation for the treatment of systemic lupus erythematosus and inflammatory bowel disease, despite it participates in the signaling of IFN-alpha, IFN-beta, IL-6, IL-10, IL-11, IL-12, IL-19, IL-22, IL23, IL-27, IL-28, and IL-29 [20]. Tyk2-knockout mice do not completely lose cytokine signaling and exhibit partial defects in IFN-α, IFN-β, and IL-12 signal transduction. Deucravacitininb is a selective Tyk2 inhibitor approved for the treatment of plaque psoriasis (Fig. 5) [30].

Fig. 5.

Cytokines that may influence the blockade of different JAK/STAT pathways in atopic dermatitis

Most JAK-STAT inhibitors can blockade other subunits according to the concentration of the drug. The difference among the concentrations need to inhibit other subunits defines the selectivity of the drugs. A highly selective JAK inhibitor (eg, with selectivity for JAK1), will compete with ATP on JAK1 with a higher potency than on JAK2, JAK3, or TYK2. However, as the intracellular concentration of the drug increases, it is likely to affect ATP binding to these other JAK family members, with loss of selectivity [31].

The profile of adverse effects varies according to the pattern of JAK subunit inhibition, time of exposure, and the characteristics of the patients. The blockade of the JAK1 pathway confers a small increase in the risk of infection, especially upper respiratory and zoster, nevertheless, severe atopic patients are prone to herpetic and respiratory infections [32].

Thromboembolic events were reported following the administration of tofacitinib baricitinib, and ruxolitinib, despite they being more incident among patients with multiple comorbidities. Gastrointestinal perforations were reported following tofacitinib and ruxolitinib, despite the baseline conditions of the patients were not assessed [32]. Lipid abnormalities were identified in patients under the most prescribed JAK inhibitors, but the role of these metabolic changes in the increased cardiovascular risk is not well defined [33].

The prevalence of skin and hematologic malignant neoplasms was increased in patients under JAK inhibitors. These drugs promote a reduction in NK cells and the effectiveness of some cytokines (e.g., IFN-gamma) which are chief for tumoral immune vigilance, however, a long-term follow-up is needed to identify high-risk patients for the development of these adverse effects [32, 34].

These small molecules cross the placental barrier and have proven to induce damage to animal embryos [34].

The long-time pharmacovigilance of the use of JAK-STAT inhibitors will provide information regarding the shifts in immune response and overall safety regarding carcinogenesis, infection, cardiovascular risk, and modifications in the metabolism [34].

Src family and Syk tyrosine kinase

Back at the beginning of the last century, Peyton Rous discovered that sarcoma in domestic chickens was transmissible from one bird to another by an extract from the tumor passed through a filter too fine to contain chicken cells or even bacteria. In other words, the tumor-inducing agent was a virus, later known as the Rous sarcoma virus (RSV) [35, 36]. Over the next 20 years, the RSV studies yielded a rich mixture of new and surprising information, among which was that the cell transformation was caused by a single gene (v-Src) [37].

The c-Src gene, which encodes the non-receptor tyrosine kinase protein c-Src, was the first protooncogene to be described when it was identified as the cellular homolog of v-Src, the Rous sarcoma retrovirus transformation factor [35].

The c-Src protein is the prototypical member of a family of nine non-receptor tyrosine kinases (SRC, FYN, YES, LYN, LCK, HCK, BLK, FGR, YRK) that share the same four-domain structure: the catalytic domain (kinase domain-SH1) which contains the active site of tyrosine kinase; two domains that allow interaction with other proteins (SH2 and SH3); the single domain, which varies among family members. The aminoterminal (N-terminal) end includes a myristoylation site, important in anchoring the protein to the cytosolic portion of the membrane [38–40].

A protein kinase is characterized by the ability to phosphorylate multiple substrates. Regarding the SRC, there are already more than 50 different protein substrates described. The SRC protein presents, then, a pleiotropic action, since each substrate phosphorylated can be changed and keep changing the activities of its group of targets, downstream in the signaling cascade [41].

This family has been involved in a wide variety of essential functions: cell cycle progression, motility, proliferation, differentiation, and survival, among other cellular processes Therefore, their deregulated activity has been linked to malignant transformation, and small tyrosine kinase inhibitors have been indicated for the treatment of certain blood malignancies, including chronic myeloid leukemia (CML) [42].

Genetic alterations in the regulatory systems of the cell cycle are the primary mechanism of carcinogenesis. In this regard, two classes of genes and their mutations are fundamental in the origin of a tumor: the protooncogenes and the tumor suppressor genes. Protooncogenes are genes that normally help cells to proliferate. SRC tyrosine kinase acts as a positive regulator of the cell cycle. As already mentioned, SRC appears as a component of a signaling cascade for cell proliferation. The SRC protein, by the way, was the first oncoprotein to be studied, allowing researchers an initial insight into carcinogenesis [43, 44].

The c-SRC proto-oncogene has been strongly implicated in the development and may play a role in the progression, and metastasis of several human tumors, including gastric, colorectal, brain, breast, and pancreatic cancer. It has been reported that both the levels of SRC proteins and, to a greater extent, the activity of these kinases are frequently increased in human tumor tissues when compared to adjacent normal tissues. Furthermore, there seems to be a positive correlation between SRC protein levels and disease stages [43, 44].

It is now known that SRC kinases can be activated by certain G-protein units. The ability of G protein-coupled receptors (GPCRs) to activate mitogenic pathways suggests that dysregulation of signaling by these receptors, or of the associated G proteins themselves, may also contribute to cell transformation and carcinogenesis [44–48].

Src-family kinases are ubiquitously expressed, although different cells express different family members. T cells express Lck and Fyn, B cells express Fyn, Lyn, and Blk, and myeloid cells express Hck, Fgr, and Lyn [49]. Spleen Tyrosine Kinase (Syk) is a tandem SH2 domain-containing enzyme acting mostly downstream of Src-family kinases. Syk is expressed in most hematopoietic lineage cells except for T-cells where ZAP-70 is expressed and performs a similar function [50].

T cell development requires TCR-based signaling and Src-family kinases, particularly Lck. In the case of B lymphocytes, Lyn kinase a has a primary role in BCR signaling [50].

Myeloid cells primarily express Hck, Fgr, and Lyn which have a critical but overlapping role in the activation of neutrophils and macrophages through Fcγ receptors, as well as through β1 and β2 integrins [51, 52]. Unlike Jak kinases, Src-family members have functional overlap between individual family members. Individual Src family kinases are not essential for a given response and complete inhibition of a signaling pathway often requires the combined elimination of multiple kinases in myeloid cells [19]. Animals with the Hck-/-Lyn-/-Fgr-/- triple knockout, but not the single or double knockout, were completely protected from autoantibody-induced arthritis due to the defective generation of inflammatory environment without affecting the intrinsic migratory capacity of myeloid cells [53].

The Src-family inhibitors currently available have limited selectivity, also inhibiting various other tyrosine kinases such as c-Kit, EGFR, or Abl. Syk and ZAP-70 are also essential for the development of mature B and T cells, respectively [50, 54, 55]. Syk deficiency leads to perinatal lethality due to defective separation of lymphoid and blood vessels [56]. Deficiency of the Syk kinase produces profound defects in neutrophil/macrophage integrin signaling and responses to immune complexes, resulting in significantly reduced stimulation of respiratory burst, degranulation, and cell spreading [57–59].

Pemphigus vulgaris (PV) is caused by antibodies against desmoglein (Dsg) 1 and Dsg 3 [60] as well as non-Dsg antigenic targets [61]. Keratinocyte TK signaling pathways are critical in the pathogenesis of PV-IgG-mediated acantholysis. Src family kinases were implicated in autoantibody-mediated desmosome disassembly [62]. In a study, Src phosphorylation was induced in keratinocytes upon in vitro antibody treatment obtained from PV patients. Loss of cell cohesion caused by the anti-Dsg3 antibody was abolished upon Src inhibition by PP2 both in vitro and in vivo in a neonatal mouse model. However, inhibition of Src was not protective in some cases against PV-Ig-induced loss-of-keratinocyte-cohesion in keratinocyte monolayer, nor in intact human skin [62].

Pemphigoid diseases are characterized by autoantibody production against distinct components of the dermal–epidermal junction leading to dermal–epidermal separation and tense blister formation [63]. Bullous pemphigoid (BP) is the most prevalent autoimmune bullous disease. Antibody formation directed against key hemidesmosome components BP180 and/or BP230 results in a subepidermal blistering phenotype [64]. Signaling through complement receptors and recognition of deposited immune complexes by neutrophils through activating Fcγ receptors was essential for blister formation both in vitro using human cryosections and in in vivo mouse models [65–67].

Fc receptor-mediated signaling is heavily dependent on intracellular tyrosine kinases such as Src-family and Syk kinases [50, 51]. Src-family and Syk kinases may have an important role in the development of antifungal diseases, due to their central role in immune complex recognition by Fc receptors of resident and recruited innate immune cells [53]. Syk tyrosine kinase, which is recruited to ITAM sequences phosphorylated by Src family kinases, has also been found to be essential for the effector phase of the disease [68, 69]. Src and Syk kinases are also responsible for amplifying the inflammatory process by releasing mediators that recruit neutrophils and/or directly damage the dermal–epidermal junction in experimental models of pemphigoid such as proteases and superoxide. Therefore, these non-receptor tyrosine kinases may be good candidates for therapeutic intervention in the future, although the development of specific inhibitors is still unresolved [12].

Some findings suggest that Syk may contribute to IL-17 production, but its actual relevance in the case of psoriasis needs further investigation. The PRR Dectin-1 was implicated in the disease process, suggesting that recognition of fungal antigens in a Syk and CARD9-dependent manner promotes the maturation of dendritic cells and their ability to induce IL-17 production by Th17 cells [70]. In addition, skin inflammation was ameliorated in mice lacking the adaptor molecule RhoH that recruits Syk to the TCR in the imiquimod-induced psoriasis model [71].

Neutrophilic dermatoses represent a group of disorders characterized by massive neutrophil infiltration in the skin without evidence of infection. Loss of function of the tyrosine phosphatase SHP-1 in mice causes severe cutaneous inflammation resembling human neutrophilic dermatoses [72]. The SH2 domain containing SHP-1 is crucial for inhibiting pro-inflammatory signal transduction. SHP-1 dysfunction leads to the release of Syk from inhibition, resulting in the overexpression of pro-inflammatory mediators and other effector molecules. Downstream of Syk, the adaptor protein CARD9 has also been considered a key mediator in skin inflammation [73].

Syk, which is critical for T-cell receptor, B-cell receptor, and activating Fc receptor signaling, is upregulated in lymphocytes from SLE patients, and Syk inhibition ameliorated disease in an animal model of SLE [74, 75].

Therapies for melanoma include treatments with checkpoint blockades or with vemurafenib and dabrafenib, small molecule inhibitors for BRAF and MEK. The combination therapy diminishes the activity of BRAF^V600E/K present in 40–50% of melanomas [76, 77] and inhibits the MAPK pathway. However, there is an urgent need to identify new molecular pathways for targeting melanomas because of the inherent or rapid emergence of resistance to MAPK inhibition [78–80]. Targeting Src in melanoma has been of interest for over a decade [81].

Src expression and activity are increased in melanoma cell lines and in melanoma tumors in vivo. [82] Src inhibition has recently become a target for drug therapy. In melanoma, it appears that Src regulates STAT5, STAT3, b-FGF receptors, N-cadherin and β-catenin. Variable expression of Src in human melanoma biopsies has been reported and Src inhibitor treatment synergizes with chemotherapy in various degrees in the melanoma cell lines. Src and STAT3 are expressed in their activated forms in both primary and metastatic melanoma in humans, although the expression level is variable [81].

Published results with three melanoma cell lines showed that dasatinib and bosutinib had a minor impact [81], and in another case, dasatinib did not affect cell proliferation, but inhibited migration and invasion [83].

SAB298, which binds to the ATP kinase domain of several SFKs, and inhibits melanoma cell proliferation in vitro and in vivo. The compound has multiple targets, the SFK family members and ERBB2/3, but has very little activity against BRAF, RAF1, ARAF, IGF1R, or CDK4/ Cyclin D1 [84]. Table 1 summarizes the main drugs of the Src family and Syk tyrosine kinase.

Table 1.

Drugs of the Src family and Syk tyrosine kinase, their indication in dermatologic conditions, and registered clinical trials

Drug	Company (Trade name)	Clinical indication or pre-clinical trial investigation	Clinical Trials.gov number or FDA approved
Fostamatinib		(i) Hidradenitis Suppurativa (ii) Rheumatoid Arthritis	(i) NCT05040698 (ii) NCT02092961; NCT01725230; NCT01640054; NCT01569074; NCT01563978; NCT01355354; NCT01336218; NCT01311622; NCT01309854; NCT01276262; NCT01264770; NCT01245790; NCT01242514; NCT01197755; NCT01197534; NCT01197521; NCT00805467; NCT00665925; NCT00665626
Lapatinib	(Tykerb®)	Malignant Melanoma	NCT01264081
Dasatinib	(Sprycel®)	Systemic Mastocytosis	NCT00979160

NCT National Clinical Trial

Mitogen-activated protein kinase inhibitors (MAPKs)

The activation of transcription factors are important tools in triggering cellular responses to extracellular agents than intracellular 'communication lines' that enable the transmission of signals to nuclear and cytoplasmic targets [85, 86].

Among protein kinases, there are some mitogen-activated, also known as MAPKs, which respond to extracellular stimuli and trigger vital cellular processes such as differentiation, proliferation, apoptosis, stress response, and death [85, 86].

Signal transmission is usually triggered by the activation of a small G protein or by the interaction of cascade components with adapter proteins. After this phase, the signals are transmitted downstream the cascade by cytosolic protein kinases that are organized in three to five tiers, of which three, MAPKKK (MAP3K), MAPKK, and MAPK are considered as the nucleus. The remaining MAPKKKK (MAP4K) and MAP kinase-activated kinase (MAPKAPK) are not required for signaling through the cascades [85].

Four MAPK cascades have been fully identified and named according to their component in their MAPK tier. ERK (Extracellular signal-regulated kinase 1 and 2); JNK (c-Jun N terminal kinase 1–3), p38 (ɑ,β, γ and δ) ERK5 [85, 87].

ERK 3/4 and ERK 7/8 have been identified but they are activated by distinct mechanisms than MPAKs, so they are not considered genuine MAPK [85, 88].

ERK cascade

Growth factors and hormones are some of the extracellular factors that can activate this cascade, through Tyrosine Kinase Receptors (RTK), G Protein-Coupled (GPCR), or ion channels, among others. From the activation of these receptors, signals are transmitted by several signaling processes, some of them involving the recruitment of adapter proteins such as Shc or Grb2 to activated receptors or their effector proteins (for example, Fak1). Furthermore, such adapters lead to the exchange of guanine nucleotide factors (GEFs) to small membrane-bound GTP-binding proteins (e.g. Ras, Rap) and with it the GTP-bound, active format [85].

Such steps culminate in the greater transmission of the signals. This allows further transmission of the signal to the components of the MAP3K layer of the cascade, especially the Raf kinases (Raf-1, B-Raf, A-Raf), but also TPL2 and stress-activated MEKK1 and MLTK [85].

c-Jun N terminal kinase cascade

This cascade is related to response to stress, induces apoptosis, but also can have a role in other process. Its receptors are also stress/apoptosis-related receptors, receptor-independent physical stresses, GPCRs, and RTKs and transmit the signals to adaptor proteins that can by themselves activate kinases in the MAP4K, and sometimes, MAP3K tiers of the JNK cascade [85].

A network of proteins can be alternatively activated by membranal receptors that induce activator changes in adaptor proteins or activation of small ones [85].

After this, the signal is transmitted by activating directly MAP3K tiers or MAP4K. Activated MAP3Ks transmit the signals to kinases at the MAPKK level, which are MKK4, MKK7, and MKK3/6 [85].

p38 cascade

This cascade primarily participates in cell response to stress induced by various factors and ligands that operate via different receivers like apoptosis-related receivers, GPCRs, and RTKs or via receiver-independent machinery that requires changes in membrane fluidity or other specialized signaling systems in case of physical stress. [85]

Recently, this cascade was also related to immune response and inflammation. After this, the signals are transmitted by induction of a network of molecules that results in the activation of small GTPases or adapter proteins. MAP3K is activated mainly by small GTPases, but also by adapter proteins or by MAP4KS. The MAP3K-level kinases transmit the signals to the MAPKKs, phosphorylating on Ser and Thr residues in a typical Ser-Xaa-Ala-Xaa-Ser/Thr. The next tier of the cascade is composed of products of four MAPKs genes, including p38 ɑ, β, γ, and δ that are activated to transmit the signals for the level components MAPKAPK, MAPKAPK2, MAPKAPK3, MNK1/2, MSK1/2 and MK5/PARK. [85]

ERK5 cascade

ERK5 cascade is activated by oxidative stress, hyperosmolarity, and mitogens. Its activation has not been fully understood but probably includes.

Protein Tyr kinases, that either transmit their signals to the adaptor protein Lad1, or WNK1 and then activate the MAP3K level. After the MAP3K phosphorylation, two alternatives MEK5a and MEK5b are activated. Then, MAPK and ERK5 are activated by phosphorylating it on both Thr and Tyr residues with similarity with ERK1/2. However, despite the similarity in the activation [85].

Diseases such as cancer, diabetes, and autoimmune can result from misregulation of the cascades. Targeting the MAPK pathway has attracted significant interest, especially in cancer therapy. Tumorigenesis which is the result of genetic mutations allows uncontrolled growth. In melanoma has been described that in roughly 90% of cases, there is activation of the MAPK pathway with RAF kinase dimerization. Mutation in v-RAF murine sarcoma viral oncogene homolog B1(BRAF) is observed in 40–60% of melanoma patients. This mutation results in hyperactive MAPK signaling and consequently uncontrolled cell proliferation [88–90].

BRAF inhibitors

Vemurafenib: Approved by the FDA in 2011 and the European Union in 2012, as an inhibitor of oncogenic BRAF for the treatment of patients with unresectable or metastatic melanoma with the BRAF-V600E mutation. Its mechanism of action binds selectively to the ATP-binding site of the BRAFV600E mutation, resulting in reduced proliferation and downstream inhibition of ERK phosphorylation. It was associated with a relative risk reduction of death of 63% and a reduction in tumor progression of 74% [90, 91].

Dabrafenib: Approved by FDA and European Union 2013 as an option for unresectable or metastatic melanoma with BRAF-V600 E mutations. As vemurafenib is an inhibitor of the kinase BRAF harboring the V600E or V600k mutation. It is contraindicated in patients with wild-type BRAF (BRAF^WT) due to the risk of tumor progression in these patients [90–92].

Encorafenib: The newest BRAF-inhibitor FDA approval for use with binimetinib in unresectable or metastatic melanoma with V600 E or V600 K mutations [92, 93].

Arthralgias, headaches, fevers, and fatigue are the most common adverse events. In the majority of patients, they are being mild and not necessitating the discontinuation of treatment. Cutaneous eruptions and photosensitivity can also occur. Cutaneous squamous cell carcinomas and keratoacanthomas are related in approximately 14 to 26% of patients on BRAF-inhibitor monotherapy, as a paradoxical activation of the downstream MAPK pathway. Those carcinomas are more frequent with vemurafenib [92–94].

Nonetheless after initial results approximately half of the treated patients develop resistance within 6 to 10 months, probably mediated by selective pressure on the tumor microenvironment, which can start downstream mutations or MAPK activation independent of BRAF, BRAF gene amplification, alternative splicing of BRAF, or loss of other tumor suppressors, as mechanisms of resistance [93, 94].

MEK inhibitors

Selumetinib: Approved by FDA in 2020 for the treatment of pediatric patients from 2 years of age with neurofibromatosis type 1 who present symptomatic, inoperable plexiform neurofibromas [95]. Currently, there is a phase III clinical study being carried out to prove the results in plexiform neurofibromas in adults under the name: Efficacy and safety of selumetinib in adults with NF1 who have symptomatic, inoperable plexiform neurofibromas (KOMET). ClinicalTrials.gov Identifier: NCT04924608 [96]. Selumetinib is an inhibitor of MEK1/2 proteins, which plays an important role in the MAPK signaling pathway related to tumor growth [97].

Trametinib: Approved by FDA in 2013 and by European Union in 2014 for monotherapy to metastatic melanoma harboring BRAF mutations (V600E OU V600K). It is a reversible selective allosteric inhibitor of MEK1/2. Adverse events include edema, rash, fatigue, diarrhea, decreased ejection fraction/ventricular dysfunction, and ocular toxicities [92–94].

Cobimetinib: Approved by FDA and by European Union in 2015 for treatment of advanced stage BRAF V600E or BRAF V600K-mutated melanoma in conjunction with Vemurafenib and not approved for monotherapy [92–94].

Binimetinib: Approved by FDA in 2017 for use in combination with BRAF inhibitors [92–94].

Monotherapy with BRAF inhibitor is related to resistance that occurs generally within 6–7 months the use of a combination of BRAF and MEK-inhibitors was proposed to block MAPK pathways in many. Some studies had showed that resistance to combinatorial treatments still occurs, but the time until the beginning is about 11 to 15 months which is significantly longer than with monotherapy. Current guidelines consider combination therapy as a first-line option for the treatment of patients with metastatic or unresectable melanoma if BRAF-V600 activating mutations are confirmed [92–94].

Bruton’s tyrosine kinase (BTK) family

BTK is a cytoplasmatic kinase member of the Tec kinase family, expressed by hematopoietic and plasm cells, and it mediates B cell signaling and is also present in innate immune cells, but not on T cells and terminally differentiated plasma cells [98–102]. BTK regulates different signals, including the PI3K, MAPK, and NF-κ pathways [98–102]. B cell signaling is critical to B cell tolerance, and BTK plays a central role [98]. Approximately, 70–80% of developing B cells are autoreactive, but most of them are abrogated at the immature stage via a process known as receptor editing or through apoptosis. [98] In the presence of a genetic predisposition that favors autoimmunity, this selection process is missing, and there is an increased population of naïve autoreactive B cells available to cooperate with T cells [98]. Then, these B cells act as antigen-presenting cells (APCs) that drive T-cell-mediated immunity [98].

BTK is an important regulator of immunity, because is an essential component of C-cell receptor (BCR) Fc receptors, and other innate immunity-related pathways [99]. BTK is necessary, also, for antibody (Ab)-IgG and IgE-mediated immune complex signaling through the concorded FcR and Fcε signaling pathways [99]. The relevance of innate immune cells in immunologically mediated skin diseases is currently unappreciated, however, eosinophils, neutrophils, and mast cells are activated and accumulate in the lesioned skin in several dermatoses, which is ordinarily identical to tissue impairment and disease acerbity, and myriad BTK-reliant cells lead to skin inflammation [99]. These residents and trespassing immune cells can be treated topically or systemically [99].

BTK inhibition has been proven in preclinical studies to determine the specificity of immune-mediated dermatological conditions [99]. BTK inhibitors have been demonstrated to curtail proteinuria, the kidney microenvironment, and cutaneous brims in heterogeneous rodent models of arthritis and lupus [99, 100]. In representations of the Ab-induced type III Gel-Coombs reaction and murine passive cutaneous anaphylaxis, BTK inhibitors also prevent acute skin inflammation and vasculitis [99, 101].

Based on their mechanisms of action and binding modes, BTK inhibitors (BTKIs) can be classified into two types: (i) irreversible inhibitors, characterized by a Michael acceptor moiety able to form a covalent bond with the conserved Cys481 residue in the ATP-binding site, or (ii) reversible inhibitors that bind to a specific pocket in the SH3 domain through weak, reversible interactions (e.g., hydrogen bonds or hydrophobic interactions), causing an inactive conformation of the enzyme [102]. More recently, a new hybrid BTKIs emerged: BTK can bind in a reversible covalent manner, forming reversible covalent bonds with Cys481 residue and temporarily inactivating the enzyme [102]. Particularly, this class of inhibitors is highly potent and selective, showing prolonged, tunable residence times and fewer off-target effects, combining the advantages of the covalent and non-covalent inhibitors [102]. In Table 2, we summarized the main small BTKIs commercially disposable and under clinical trials or experimental investigation.

Table 2.

Name, company, of some irreversible and reversible BTK inhibitors commercially disposable or under pre-clinical or clinical investigation

Irreversible or Reversible BTKIs	Drug	Company (Trade name)	Clinical indication or pre-clinical trial investigation	Clinical Trials.gov number or FDA approved
Irreversible	Ibrutinib	(Imbruvica®)	(i) Chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Waldenström’s macroglobulinemia (WM), marginal zone lymphoma (MZL), and relapsed/refractory mantle cell lymphoma (MCL); (ii) Chronic graft-versus-host disease (cGVHD); (iii) COVID-19 treatment hospitalized patients; (iv) Refractory/relapsed autoimmune hemolytic anemia; (v) Anaphylaxis (food allergy); (vi) Aggressive systemic mastocytosis or mast cell leukemia	(i) FDA approved in 2013; (ii) FDA approved in 2017; (iii) NCT04375397; (iv) NCT 04398459 and NTC 03827603; (v) NCT03149315; (vi) NCT 02415608
Irreversible	Acalabrutinib	(Calquence®)	(i) CLL, SLL, MCL; (ii) COVID-19 treatment hospitalized patients; (iii) Chronic graft-versus-host disease (cGVHD); (iv) Anti-MAG neuropathy mediated neuropathy; (v) Rheumatoid arthritis	(i) FDA approved in 2017; (ii) NCT04497948 (study prematurely terminated), NCT04380688, NCT04346199; (iii) NCT04198922; (iv) NCT05065554; (v) NCT02387762
Irreversible	Zanubrutinib	(Brukinsa®)	(i) MCL; (ii) COVID-19 treatment hospitalized patients	(i) FDA approved in 2019; (ii) NCT04382586;
Irreversible	Tirabrutinib	(Velexbru®)	(i) CNS lymphoma, WM, CLL; (ii) Sjogren Syndrome; (iii) Rheumatoid arthritis	(i) Approved in Japan; (ii) NCT03100942; (iii) NCT02626026;
Irreversible	Orelabrutinib	(?®)	(i) Relapsed or refractory MCL; (ii) Phase I study for neuromyelitis optica spectrum disorder (iii) Phase 2 study for immune thrombocytopenia (ITP) (iv) Phase 2 study for relapsing–remitting Multiple Sclerosis	(i) FDA approved in 2021 (for MCL); (ii) NCT05284175; (iii) NCT05020288; (iv) NCT04711148
Irreversible	Evobrutinib	Merk®	(i) Relapsing–remitting multiple sclerosis	(i) NCT04032171 (terminated) and NCT04338061 (ongoing)
Irreversible	Spebrutinib	Avila Therapeutics/Calgene®		Pre-clinical studies
Irreversible	Remibrutinib	Novartis®	(i) Phase III for Chronic spontaneous urticaria; (ii) Allergy to Peanuts; (iii) Relapsing multiple sclerosis	(i) Expanded access study NCT05170724; (ii) NCT05432388; (iii) NCT05147220
Irreversible	Tolebrutinib	Sanofi®/Principia Biopharma®	(i) Multiple sclerosis; (ii) Myasthenia gravis	(i) NCT04742400; (ii) NCT05132569
Irreversible	Olmutinib	Hamni Pharmaceuticals®	Non-small cell lung cancer	NCT04510415 (terminated), NCT03228277, NCT02722161, NCT02444816, NCT01894399, NCT01588145, NCT02485652 (terminated)
Irreversible	Branebrutinib	Bristol-Myers Squibb®	(i) Atopic dermatitis; (ii) Rheumatoid arthritis, systemic lupus erythematosus, and primary Sjögren syndrome	(i) NCT05014438 (recruiting); (ii) NCT04186871 (recruiting)
Irreversible	TAK-020	Takeda®	Healthy volunteers	NTC02723201 and NCT02413255 (both completed)
Irreversible	Elsubrutinib	AbbVie®	Moderately to severely active systemic lupus erythematosus	NCT03978520
Irreversible	Rilzabrutinib	Sanofi®	(i) Chronic spontaneous urticaria; (ii) IgG4-related disease; (iii) Warm autoimmune hemolytic anemia wAIHA); (iv) Healthy volunteers (v) Atopic dermatitis; (vi) Immune thrombocytopenia; (vii) Asthma; (viii) Pemphigus	(i) NCT05107115 (recruiting); (ii) NCT04520451 (recruiting); (iii) NCT05002777 (recruiting); (iv) NCT04748926 (completed); (v) NCT05018806 (recruiting); (vi) NCT04562766 (recruiting) (vii) NCT05104892 (proof of concept study, recruiting); (viii) NCT03762265 (terminated)
Reversible	Vecabrutinib	SNSS®	Lymphoid cancers	NCT03037645 (phase 1b, terminated)
Reversible	GNE-431	Genetech®	Pre-clinical investigation
Reversible	RN-489	Roche®	Pre-clinical investigation
Reversible	BMS-935177	Bristol-Myers Squibb®	Pre-clinical investigation
Reversible	BMS-986142	Bristol-Myers Squibb®	(i) Rheumatoid arthritis; (ii) Sjögren syndrome	(i) NCT02762123 (completed), NCT02456844 (completed); (ii) NCT02843659 (proof of concept study, terminated)
Reversible	GGI-1746	GGI/Genetech®	Pre-clinical investigation
Reversible	GDC-0834	Gilead/Genetech®	Pre-clinical investigation
Reversible	G-744	Gilead/Genetech®	Pre-clinical investigation
Reversible	G-278	Gilead/Genetech®	Pre-clinical investigation (abandoned)
Reversible	Fenebrutinib	Genetech	(i) Relapsing multiple sclerosis; (ii) Healthy participants; (iii) Multiple sclerosis, primary progressive; (iv) Chronic spontaneous urticaria	(i) NCT05119569, NCT04586010, NCT04586023 (all recruiting); (ii) NCT03596632 (completed) (iii) NCT04544449 (recruiting); (iv) NCT03693625 (terminated)

cGVHD chronic graft-versus-host disease, CNS central nervous system, CLL Chronic lymphocytic leucemia, ITP immune thrombocytopenia, MAG myelin-associated, MCL relapsed/refractory mantle cell lymphoma, MZL marginal zone lymphoma, NCT National Clinical Trial, SLL small lymphocytic lymphoma, wAIHA warm autoimmune hemolytic anemia, WM Waldenström’s macroglobulinemia WM

Ibrutinib, an irreversible BTKI and other similar, unfortunately also inhibit other intracellular kinases (Tec, itk, and Blk), and receptor (e.g. epidermal growth factor receptors [EGFR]) tyrosine kinases [102]. This lack of selectivity is responsible for the many off-target undesirable side effects (skin and dermatological reactions, allergic reactions, fever, lymphadenopathy, edema, albuminuria, infections, headaches bleeding, atrial fibrillation, and diarrhea [102].

The irreversible BTKIs, regarding the aromatic core, in some cases, compounds are characterized by a single aromatic ring (particularly a substituted pyrimidine ring as in Spebrutinib, Evobrutinib, and Remibrutinib a different bicyclic structure (Olmutinib, Elsubrutinib, Tolebrutinib, Branebrutinib, and Rilzabrutinib) [102]. Evobrutinib is under clinical investigation for autoimmune disorders and, when orally administered, it showed good efficacy in mouse models of RA and SLE, as demonstrated by a reduction of disease severity and histological damage [100, 102, 103]. Remibrutinib exhibits a good kinase selectivity due to binding to a BTK inactive conformation, which demonstrates potent in vivo activity with an EC₉₀ of 1.6 mg/kg and dose-dependent efficacy in rat collagen-induced arthritis [100, 102–104]. It is currently being tested in phase II clinical studies for chronic spontaneous urticaria and Sjögren syndrome [102].

From a chemical point of view, reversible BTKI presents different chemical scaffolds, such as pyrimidines, 2,4-diaminopyrimidines, and 1,3,5-triazines; as well as condensed structures such as pyrazole-pyrimidines, pyrazole-pyridines, pyrrole-pyrimidines, pyrrole-triazines, imidazo-pyrazines, imidazo-pyrimidines, imidazo-quinoxalines; and purines, such as Vecabrutinib, Fenebrutinib, RN-486, and GNE-431, which are under clinical investigation for hematological disorders and autoimmune diseases [100, 102–106].

Pemphigus vulgaris (PV) is a potentially life-threatening autoimmune [106]. The efficacy and safety of oral rilzabrutinib in PV were confirmed in a recent multicenter, phase 2 trial, with 52% and 70% of patients showing control of disease activity at 4 weeks and 8 weeks, respectively [107]. In the phase 2 BELIEVE study part B the control of disease activity by week 4 was reached by 60% of the 14 enrolled patients [108]. However, the phase 3 placebo-controlled trial (PEGASUS) evaluating rilzabrutinib in 131 patients with pemphigus did not show any difference between rilzabrutinib and the placebo with regards to its primary endpoint, i.e., complete remission from week 29 to week 37 [109].

Ibrutinib and other BTKIs are not approved for the treatment of RA, SLE, MS, or other autoimmune diseases, mainly due to toxicities related to their potential adverse effects [106]. However, the development of new, more specific drugs can change this clinical scenario [106].

Conclusions

The advent of new small molecule therapies that act on intracellular signaling contributes to a revolution in the treatment of several dermatological diseases. Its use in inflammatory, neoplastic and even infectious diseases shows the versatility of these new therapies and is already a reality for patients suffering from skin diseases that previously had few therapeutic options.

It is necessary, however, to evaluate its long-term efficacy and safety profile. The fact that they are administered orally or even topically facilitates and reduces the cost of their production and storage when compared to immunobiological agents, as well as the lack of anti-drug antibodies formation against these new drugs, as eventually occurs in some cases against anti-TNF drugs.

Author contributions

All authors whose names appear on the submission: (1) made substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data; or the creation of new software used in the work; all of the authors wrote equally the manuscript, except for MI who were responsible to review the manuscript. (2) drafted the work or revised it critically for important intellectual content; all of the authors, especially FROC and MI (3) approved the version to be published; and all of the authors approved it. (4) agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. all of the authors.

Declarations

Conflict of interest

The authors declare no competing interests.