Chronic spontaneous urticaria—status quo and future

Chronic spontaneous urticaria (CsU) is a chronic inflammatory dermatosis whose etiology is not yet fully understood. In affected patients, it is often associated with a high limitation of health-related quality of life, which necessitates effective therapeutic management. Different immune cell populations such as mast cells, eosinophilic and basophilic granulocytes, and T cells are involved in the pathogenesis of CsU, whereby mast cells playing a key role. In addition, type I autoallergic reactions with auto IgE antibodies or type IIb autoimmune reactions with auto IgG antibodies have been identified in a proportion of patients. The current international guideline initially recommends the use of second-generation H1 antihistamines, first in standard, then in off-label quadruple dosing. Subsequently, the anti-IgE antibody omalizumab should be added. However, this therapy algorithm does not lead to freedom from manifestations in all patients. Therefore, various targeted therapies are currently being evaluated for their efficacy in CsU, such as off-label use of the anti-interleukin receptor alpha (IL4Rα) antibody dupilumab, the anti-IL-17A antibody secukinumab, or interleukin‑5 blockade using mepolizumab, reslizumab, or benralizumab. In addition, new promising compounds such as the Bruton tyrosine kinase (BTK) inhibitors remibrutinib and fenebrutinib, the anti-cKIT antibody barzolvolimab, the anti-SIGLEC8 antibody lirentelimab, the anti-TSLP antibody tezepelumab, the anti-C5aR1 antibody advoralimab, or the topical application of Syk kinase inhibitors are being tested, which were developed according to new insights into the pathogenesis of CsU. The BTK inhibitor fenebrutinib is currently not being pursued due to a less favorable side effect profile compared to remibrutinib, as well as the anti-IgE antibody ligelizumab, which was inferior to omalizumab therapy in a phase 3 study. Overall, there is a high need for new therapeutic strategies to better treat CsU both symptomatically and curatively. This requires a more comprehensive understanding of pathogenesis of the disease in order to develop new targeted therapies.

alpha (IL4Rα) antibody dupilumab, the anti-IL-17A antibody secukinumab, or interleukin-5 blockade using mepolizumab, reslizumab, or benralizumab.In addition, new promising compounds such as the Bruton tyrosine kinase (BTK) inhibitors remibrutinib and fenebrutinib, the anti-cKIT antibody barzolvolimab, the anti-SIGLEC8 antibody lirentelimab, the anti-TSLP antibody tezepelumab, the anti-C5aR1 antibody advoralimab, or the topical application of Syk kinase inhibitors are being tested, which were developed according to new insights into the pathogenesis of CsU.The BTK inhibitor fenebrutinib is currently not being pursued due to a less favorable side effect profile compared to remibrutinib, as well as the anti-IgE antibody ligelizumab, which was inferior to omalizumab therapy in a phase 3 study.Overall, there is a high need for new therapeutic strategies to better treat CsU both symptomatically and curatively.This requires a more comprehensive understanding of pathogenesis of the disease in order to develop new targeted therapies.

Introduction
Urticaria is a polyetiological, acute or chronic dermatological disease, in which different forms are distinguished.The main symptom is itchy wheals that persist for less than 24 h.In addition, angioedema occurs in 40-50% of patients, although angioedema is thought to be underdiagnosed in patients with chronic spontaneous urticaria (CsU) [1].Angioedema alone is seen in 10% of patients.Here, it is unclear whether this is a distinct entity or a separate form of urticaria.
In most cases, urticaria is a spontaneously self-limiting condition, and the lifetime prevalence for acute spontaneous urticaria is 20% [2].Spontaneous remission occurs in most patients, but the course of the disease is unpredictable for the individual patient.If symptoms persist beyond 6 weeks on several days per week, the disease is referred to as CsU; the prevalence for this is 1-5%.Inducible forms of urticaria (CindU), such as delayed pressure urticaria, cold urticaria, or symptomatic dermographism, are distinguished from CsU.This work focuses on the treatment of CsU [3], whereas the therapy of the inducible forms is very similar to the CsU treatment.
Patients with CsU have a variable disease course that may be associated with comorbidities and have significantly lowered health-related quality of life [4].It is important to emphasize that currently there is no curative therapy for CsU, consequently only symptomatic treatment can be given until spontaneous remission occurs [5].Therefore, there is a high need for effective and well-tolerated therapeutic options.

Pathogenesis
The pathogenesis of CsU has not been conclusively clarified, but it is certain that different immune cell populations are involved.In the pathogenesis of CsU, autoimmune and non-autoimmune processes are distinguished.Of central importance are the mast cells.Mast cells are highly plastic cells that can mature in the tissues in which they reside and form different subtypes with divergent properties.Histamine, which is released from the granules of mast cells, contributes significantly to the symptoms of CsU through activation of sensory nerves, vasodilation, and increased vascular permeability [6][7][8][9].
In skin biopsies of CsU patients, infiltrates consisting of various cells of the immune system such as mast cells, eosinophils, basophils, neutrophils, and CD4 + T cells are found [10,11].
In the skin of CsU patients, mast cells are primarily of the MTC subtype, which express tryptase and chymase and are considered to be independent of T cells.Mast cells are activated by IgE-mediated stimulation; IgE binds to the high-affinity IgE receptor FcεRI.Subsequently, IgE cross-links and activates intracellular signaling cascades and eventually releases various mediators such as histamine.Furthermore, mast cells can be activated by an IgE-independent mechanism mediated by the Mas-related G protein-coupled receptor X2 (MRGPRX2).There is evidence that higher numbers of MRGPRX2 + mast cells are found in the skin of CsU patients than in healthy individuals [11].
Since significantly increased eosinophils were detected in skin biopsies of CsU patients, eosinophils are thought to be involved in the pathogenesis of CsU.Eosinophils, together with mast cells, are thought to prime the skin for wheal formation.In nonlesional and lesional skin of CsU patients, besides to increased numbers of eosinophils and mast cells, increased numbers of CD31 + -endothelial cells and blood vessels have also been identified, suggesting that immune cells contribute to increased vascular permeability [12].
In addition, there are numerous interactions between eosinophils and mast cells.Mast cells and T cells produce IL-5, which mobilizes eosinophils from the bone marrow and prolongs their half-life.Furthermore, eosinophils can induce degranulation in mast cells via the release of eosinophil peroxidase (EPO) or major basic protein (MBP) via MRGPRX2.In addition, eosinophils produce tissue factor and thus can activate the coagulation cascade, which in turn can act as a mediator for mast cell activation [11,13,14].
Basophils also appear to be important in the pathogenesis of CsU.They also express FcεRI, to which IgE binds and activates the basophils.In addition, basopenia has often been found in the peripheral blood of CsU patients, which is why it is suspected that basophils migrate from the peripheral blood to the skin [11,15].
Regarding an autoimmune/autoallergic pathogenesis, both type I autoallergic reactions and type IIb autoimmune reactions according to Coombs and Gell review have been identified in patients with CsU [16].In type I autoallergy, IgE antibodies against autoantigens/autoallergens such as thyroperoxidase (TPO), interleukin-24, or double-stranded DNA could be detected.The IgE autoantibodies bind to the FcεRI, crosslinking occurs, and finally mast cell degranulate [11,14].
Type IIb autoimmunity involves IgG autoantibodies to FcεRI or to IgE [17,18].The IgG autoantibodies against FcεRI or IgE bound to FcεRI can directly lead to mast cell degranulation or activate complement factor C5.In addition, IgG anti-FcεRII antibodies can activate eosinophils, which can also initiate mast cell degranulation [11,14].IgM or IgA anti-FcεRI antibodies have been identified in addition to IgE and IgG autoantibodies; furthermore, IgE and IgG autoantibodies may coexist in an affected individual [14,19].
Depending on the Coombs and Gell type present, patients show different characteristics.Patients with type IIb reaction show higher disease activity and higher scores in UAS7 score, later onset of disease, preferential occurrence in females, and increased prevalence for autoimmune comorbidities [17].
Overall, however, it should be emphasized that approximately 50% of patients have neither IgE nor IgG autoantibodies, which is why non-autoimmune processes are also involved in the pathogenesis, such as the coagulation cascade.The serum of CsU patients shows increased levels of prothrombin fragments F1 and F2, activated factor VII, and D-dimers.In particular, D-dimers were shown to be elevated only in active disease and returned to normal in remission.

Fig. 1
Recommended treatment algorithm of chronic spontaneous urticaria of the international guideline.
s.c.subcutaneous (Figure was  In addition, eosinophils can release tissue factor, which leads to activation of the extrinsic coagulation cascade.Within the extrinsic coagulation cascade, thrombin and activated factor X increase vascular permeability.Furthermore, binding to the proteaseactivating receptors PAR-1 and PAR-2 and the formation of C5a result in mast cell degranulation [14].Furthermore, neuropeptides such as substance P, infections such as Helicobacter pylori gastritis, or nonsteroidal anti-inflammatory drugs (NSAIDs) play a role in the pathogenesis of CsU [14].In summary, the pathogenesis of CsU is polyetiologic and not yet fully understood.

Guideline-based diagnosis and therapy of chronic spontaneous urticaria
Diagnosis and therapy of CsU should be performed according to the guidelines.The international guideline was last updated in 2022 by the European Academy of Allergology and Clinical Immunology (EAACI), the Global Allergy and Asthma European Network (GA 2 LEN), the European Dermatology Forum (EDF), and the Asia Pacific Association of Allergy, Asthma, and Clinical Immunology (APAAACI), methodologically supported by the European Centre for Guidelines Development (EuroGuiDerm) [20].The current German AWMF guideline (AWMF Register No. 013-028, 2022) is strongly based on the international guideline.It entered into force on 01 February 2022 and is valid until 31 January 2025 [21,22].The goal of therapy for CsU is complete control of the disease.

review
For this purpose, the treatment algorithm should be regularly reevaluated and adapted to the disease activity ( [20]; Fig. 1).

Diagnostics
While no basic diagnostic routine measures are recommended for acute spontaneous urticaria, diagnostic clarification should be performed in patients with CsU.The goals of the diagnostic process are based on the "7 Cs", which include "confirm", "cause", "cofactors", "comorbidities", "consequences", "components" and "course" and are particularly highlighted in the new guideline.This includes excluding differential diagnoses, looking for indicators of triggering a type I or type IIb CsU, and identifying additional triggers or trigger factors, such as NSAIDs [20].
In addition, comorbidities such as chronic inducible urticaria, autoimmunity or psychiatric syndromes should be assessed and problems with sleep, work, or social environment should be identified.Furthermore, potential biomarkers and predictors of response to the chosen therapy and disease activity and control should be monitored [20].Specifically, laboratory determination of differential blood count, C-reactive protein (CRP) and erythrocyte sedimentation rate, IgG anti-TPO and total IgE are recommended.The determination of IgG anti-TPO and total IgE is a novelty, these parameters are determined for clarification regarding autoallergic or autoimmune genesis of CsU [20,21].

Measurement of disease activity
The new guideline emphasizes more strongly the importance of measuring disease activity using the UAS7 and, in particular, disease control using the Urticaria Control Test (UCT).This should be determined regularly during patient consultations and therapy adjustments should be made based on these values [20].In addition, health-related quality of life should be determined using the CU questionnaire [20,21].
Measurement of the disease activity of CsU should be performed by the UCT [23] or the urticaria activity score (UAS) [24,25].These are validated questionnaires that can be completed by patients themselves and ask about the most common urticarial signs and symptoms.The UAS7 is calculated as a sum score of seven consecutive days from the UAS.In particular, the UAS7 is also used in studies to ensure comparability [20,21].
Disease control is determined by UCT.Thresholds for UCT have been defined at which adjustment of therapy is recommended.At UCT = 16, complete disease control can be assumed and dose reduction of current therapy is recommended.At UCT = 12-15, well-controlled disease is assumed and the therapy regimen should be continued and optimized if necessary.Uncontrolled disease is assumed at UCT < 12, and in this case therapy should be intensified, for example, by increasing the dose of current therapy or switching therapy [20,22].

Therapy algorithm of the guideline
The overall treatment algorithm of the new international guideline has been streamlined, and specific dosing recommendations, including off-label use of omalizumab, have been made [20,22,26].
A list of treatment options has also been created that are no longer listed in the therapy algorithm, but for which clinical experience suggests that they may be successful if no therapeutic success occurs under the therapy algorithm or it cannot be implemented.For example, this list includes H2 antihistamines, leukotriene receptor antagonists, or the low pseudoallergen diet [20,22,26].

Antihistamines
First-generation antihistamines (H1-AH-1G) have been available for the treatment of CsU since the 1950s, but should no longer be used due to their sedating effects and possible impairment, for example, in road traffic, according to the GA 2 LEN position paper [27,28].Second-generation antihistamines (H1-AH-2G) have minimal or no sedative effect and no anticholinergic effect, so they are now recommended as first-line therapy for all forms of urticaria.Initially, H1-AH-2G should be administered at the standard dosage; if there is no therapeutic response under this, the dosage should be increased up to fourfold.
It should be noted here that this is an "off label use", although the benefit of increasing the dose has been shown in several studies [20,27,29].Off-label dosing has been recommended in the guideline since 2000, and so far no evidence of adverse events or side effects due to accumulation has been shown.In general, patient education should be provided regarding the potential side effects of antihistamines, which include dizziness, impaired driving ability, fatigue, and dry mucous membranes.In addition, written education should be provided regarding "off-label use" [20,22].

Omalizumab
In case of inadequate treatment response under H1-AH-2G, the guideline recommends additional therapy with omalizumab [20].Omalizumab is a monoclonal, humanized, anti-IgE antibody that exhibits direct competitive inhibition with IgE at FcεRI and FcεRII.Binding of IgE occurs, reducing the amount of free IgE, and downregulation of the FcεRI receptor occurs.In addition, the interaction between potentially present IgE autoantibodies and FcεRI is inhibited, and depletion of IgE autoantibodies has been described [30][31][32].

K
Chronic spontaneous urticaria-status quo and future 329 review Omalizumab is approved for the treatment of severe allergic bronchial asthma, in weight-adjusted doses.Since 2014, it has been approved as addon therapy in CsU in addition to H1-AH-2G at the fixed dosage of 300 mg s.c.every 4 weeks [20].The efficacy of omalizumab was demonstrated by the X-CUISITE trial, and dose finding was performed in the MYSTIQUE trial [33].
In general, there are two patient populations with different characteristics with regard to therapy response.There are patients in whom a significant improvement in symptoms already occurs in the first week of therapy, and a second patient population in whom an improvement in findings only occurs after 6-12 weeks [34,35].
Total IgE can be used as a biomarker for treatment response.The ratio of the total IgE at the start of therapy to the total IgE after 4 weeks of therapy can be calculated.Subsequently, the so-called 2 × 4 rule applies, which states that in the case of a ratio smaller than -0.5, only a therapy response of 32% is to be expected [36][37][38].To assess the response to therapy, it has been suggested that an unchanged UAS7 or > 16 points in the UAS7 should be considered a nonresponder and a reduction in the UAS7 of at least 30%, but not 90%, or a UAS7 > 6 points, but which has improved, should be considered a partial response to therapy.
With a good response to therapy, good disease control should be achieved for 4-6 months.Subsequently, a discontinuation trial is recommended to check whether CsU has resolved in the meantime.Alternatively, an interval extension of 1 week at a time can be considered off-label [39].Predictors of poor response to therapy include a positive autologous serum test or basophil activation test, eosinopenia, basopenia, or an elevated CRP [40,41].
Due to the mechanism of action of omalizumab, the drug has also been tested in the indications of isolated angioedema, where case reports of treatment response exist.In addition, the efficacy of omalizumab has been reported in chronic inducible urticaria and urticarial vasculitis [42,43].
Regarding the side effect profile of omalizumab, it should be noted that the therapy is usually well tolerated, but two single case reports exist on the occurrence of alopecia areata and methemoglobinemia.The underlying pathophysiology cannot be fully elucidated here.Regarding alopecia areata, an activation of the Th1 signaling pathway and a reduction of mast cell activity are discussed, since mast cells may influence the regulation of the hair cycle.Similarly, methemoglobinemia may be clearly temporally associated with omalizumab administration, but again the pathophysiology remains unclear.Heterozygous cytochrome B5 reductase deficiency increases the risk of developing methemoglobinemia.It is not known whether such a mutation was present in the affected patient, as the patient declined investigation [44,45].

Off-label use of omalizumab
If there is an inadequate response to therapy with omalizumab, the guideline recommends adjusting the dosage in an "off-label use" setting [20].In principle, there are two different approaches, either a shortening of the interval to 3 or 2 weeks or an increase of the dosage to 450 mg or 600 mg s.c.can be performed [46].Dosages up to 600 mg s.c.every 2 weeks were tested, under which no additional adverse effects occurred.With dosage adjustment, symptomatic improvement was achieved in 61% of patients [47].
In particular, patients with obesity (body mass index [BMI] > 30 kg/m 2 ), age older than 57 years, low total IgE, and prior therapy with ciclosporin A seem to benefit from dosage adjustment.In general, patients with signs of autoimmune etiology show a poorer response to omalizumab, such as positive antinuclear antibodies [48].It should be noted that administration of 150 mg omalizumab s.c.every 2 weeks is also possible, and this is not an off-label therapy [49].

Ciclosporin A
Ciclosporin A blocks T-cell functions as a calcineurin inhibitor and inhibits the release of histamine by mast cells and basophils.Due to the poorer side effect profile compared to omalizumab and the fact that ciclosporin A has no approval status for urticaria, therapy with ciclosporin A is recommended in the current guideline only after omalizumab therapy has been completed.Specifically, doses of ciclosporin A of up to 5 mg/kg body weight are recommended [20,22].In particular, patients with type IIb CsU show a better response to therapy with ciclosporin A, whereas they often respond poorly or slowly to therapy with H1-AH-2G or omalizumab [31].In principle, combination therapy of ciclosporin A and omalizumab can also be administered.Overall response rates of 76% have been reported [46].
If therapy with ciclosporin A is unsuccessful, reference is made to the list of other therapeutic alternatives in the international guideline, which includes various immunosuppressants such as methotrexate, mycophenolate mofetil or intravenous immunoglobulins [20].

Oral glucocorticoids
Oral glucocorticoids inhibit eosinophil recruitment and immune cell extravasation.Long-term therapy with oral glucocorticoids cannot be recommended due to the side effect profile.However, the current guideline indicates that short-term therapy with oral glucocorticoids may be considered in severe exacerbation, at doses of 20-50 mg prednisolone equivalent to break up the episode [20,22].

review Differentiation from the American guideline
The U.S. Joint Task Force on Practice Parameters (JTFPP) guideline, produced by the American Academy of Allergy, Asthma, and Immunology and the American College of Allergy, Asthma, and Immunology, and the international guideline have multiple differences [20,50].For example, the American guideline, like the international guideline, recommends the use of monotherapy of an H1-AH-2G first and then a dose increase to four times that amount.However, the addition of a second H1-AH-2G, an H2 antagonist, or an H1-AH-1G at night is recommended as an alternative.A mixture of different antihistamines is decidedly not recommended in the international and German guidelines [20,22].
Furthermore, the international and German guidelines recommend the addition of omalizumab as a third therapeutic step, whereas the American guideline recommends therapy with the H1-AH-1G doxepin or hydrazine.In the American guideline, omalizumab is listed only as a fourth therapeutic step, which is listed equally with ciclosporin A or other anti-inflammatory or immunosuppressive drugs or biologics.Ciclosporin is listed in the international guideline as the fourth therapeutic step following therapy with omalizumab [11,20,50].

New therapy options
In general, randomized controlled trials should be conducted for new therapeutic options, with a direct comparison to omalizumab therapy as the current gold standard [8].An overview of new therapeutic op-

Dupilumab
Dupilumab is a humanized anti-interleukin-4 receptor-alpha (IL4Rα) monoclonal antibody.Interleukin 4 (IL-4) and interleukin 13 (IL-13) contribute to a Th2 immune response and IgE class switching through their activity at the IL4Rα subunit.Increased levels of IL-4 and IL-13 were detected in serum from CsU patients, and increased numbers of IL-4 mRNA-expressing cells were also shown in skin biopsies from CsU patients [52].
Currently, dupilumab is approved for the treatment of atopic dermatitis, prurigo nodularis, bronchial asthma, chronic rhinosinusitis with nasal polyposis, and eosinophilic esophagitis.Because CsU has characteristics of a Th2 disease, dupilumab has been studied as an off-label therapy in CsU patients, and case reports have described a good therapeutic response in CsU patients [52][53][54][55].Currently, a randomized controlled trial (RCT) of dupilumab therapy in refractory CsU patients has been completed, while another RCT on this is still recruiting.Furthermore, clinical trials of dupilumab therapy in CindU have been initiated, as well as dupilumab therapy in children aged 2-12 years in CsU and CindU [14,56].

Mepolizumab, reslizumab, and benralizumab
Mepolizumab and reslizumab are anti-interleukin-5 (IL-5) antibodies, while benralizumab is an anti-K Chronic spontaneous urticaria-status quo and future 331 review interleukin-5 receptor (IL5R) antibody.IL-5 is produced by mast cells and Th2 T cells and recruits mast cells, eosinophils, and basophils from bone marrow.In addition, IL-5 has an anti-apoptotic effect and leads to upregulation of chemotactic receptors on eosinophils, prolonging the half-life of eosinophils in tissues [8].Blockade of IL-5 is thought to result in decreased disease activity.
IL-5 and IL-5R antibodies are used in eosinophilic bronchial asthma.Mepolizumab is additionally approved for the treatment of chronic rhinosinusitis with nasal polyps, hypereosinophilic syndrome (HES), and eosinophilic granulomatosis with polyangiitis.A single-center, single-label study of benralizumab therapy in 12 antihistamine-refractory CsU patients has already been conducted, showing significant improvement in UAS7, comparable to that of therapy with omalizumab [57,58].Currently, additional clinical trials with mepolizumab and benralizumab are being conducted for the treatment of CsU, the results of which are currently pending [14,[59][60][61].

Secukinumab
Secukinumab is an anti-interleukin-17A (IL-17A) antibody used in the treatment of psoriasis vulgaris and psoriatic arthritis.An increase in IL-17 is seen in numerous autoimmune diseases, including CsU both in the blood and in the skin [62].Patients with proven IL-17 elevation who received therapy with secukinumab showed remission of CsU [61].

Ligelizumab
Ligelizumab is a humanized anti-IgE monoclonal antibody that binds to a different epitope than omalizumab.Ligelizumab has a 50-fold higher affinity for and lower dissociation rate of IgE than omalizumab [52].Thus, IgE circulating in peripheral blood is bound longer than by omalizumab.However, omalizumab has stronger direct competitive inhibition at FcεRII than ligelizumab.A phase 2b study demonstrated superiority of ligelizumab compared with omalizumab.However, in the phase 3 study, ligelizumab therapy was superior to placebo therapy but not to omalizumab therapy, and therefore the development and approval of this antibody are currently not being pursued further [8,63].

Advoralimab and avacopan
Advoralimab is an anti-C5aR1 antibody and avacopan is a C5aR1 inhibitor.Activation of the complement cascade results in the production of C5a, which leads to degranulation of mast cells and basophils via C5aR1.C5aR1 is preferentially expressed by mast cells in the skin, whereas mast cells in the lung, uterus, or tonsil do not express C5aR1 [52].Administration of the antibody or inhibitor can inhibit mast cell degranulation [64].Currently, no clinical trials of therapy with advoralimab or avacopan are being conducted in CsU patients.

Tezepelumab
Tezepelumab is a humanized antibody against thymic stromal lymphopoietin (TSLP).TSLP is an alarmin and type II immunity-inducing cytokine released by epithelial cells.Increased numbers of TSLP-expressing cells have been detected in lesional skin from CsU patients, and some studies have shown increased serum TSLP levels.Tezepelumab is approved in Germany and the United States for the treatment of severe bronchial asthma and is another promising candidate for the treatment of CsU [52,65].

Barzolvolimab
This is an anti-cKIT antibody.cKIT is expressed by mast cells, which is why this antibody leads to mast cell depletion.In addition, the tryptase in the serum decreases when administered [8,66].An open-label phase 1b study was conducted in 21 patients suffering from chronic inducible urticaria (cold urticaria and symptomatic dermographism), in which a single administration of barzolvolimab was administered.This showed improvement in symptoms in all patients and complete remission in 95%, for cold urticaria for 77+ days and for symptomatic dermographism for 57+ days with good tolerability of the drug [66].Currently, two RCT studies are recruiting for therapy with barzolvolimab, the one CsU patients and the CindU patients [56].

Lirentelimab
Lirentelimab is an anti-SIGLEC8 antibody.SIGLEC8 is an inhibitory receptor of the CD33-related family of sialic acid-binding immunoglobulin-like lectins.It is expressed on the cell surface marker of mast cells, eosinophils, and basophils.Activation of SIGLEC8 on eosinophils leads to their apoptosis and thus causes eosinophil depletion [52,[67][68][69].In addition, SIGLEC8 has been shown to inhibit mast cell activation.In a phase 2a study, positive clinical effects have already been shown in patients with CsU [52,70].Currently, another phase 2 study is recruiting antihistamine-refractory CsU patients for therapy with lirentelimab [71].

Remibrutinib, fenebrutinib
Bruton tyrosine kinase inhibitors such as remibrutinib or fenebrutinib also represent promising new approaches.BTK is involved in the FcεRI signaling pathway, which ultimately leads to mast cell degranulation review [72].In addition, BTK is involved in the synthesis of IgG and IgE by B cells.Thus, BTK inhibitors can reduce both mast cell degranulation and synthesis of IgE and IgG, providing efficacy in both type I autoallergy and type IIb autoimmunity [73].
Fenebrutinib is an oral, selective, noncovalent BTK inhibitor, whereas remibrutinib is an oral, selective, but covalent BTK inhibitor [52,72].A phase 2 study already demonstrated the efficacy of fenebrutinib in CsU patients with significant improvement in urticaria symptoms, and another phase 2b study showed that remibrutinib therapy resulted in a reduction in UAS7 score [72].Few adverse events were seen, but reversible transaminase elevation was a side effect of fenebrutinib.
Currently, two phase 3 RCTs of remibrutinib therapy for CsU are underway, the results of which have not yet been published.In addition, a follow-up study on the efficacy, safety, and tolerability of remibrutinib patients who have already received remibrutinib in clinical trials is recruiting [56,61].

Topical spleen tyrosine kinase (Syk) inhibitors
Syk is a component of the intracellular FcεRI receptor signaling cascade and is involved in the release of histamine, leukotrienes, and cytokines by mast cells and basophils.Topical Syk inhibitors enter the dermis to inhibit IgE-mediated release of histamine [52].An early phase I study of therapy with topical Syk inhibitors has already been performed in CsU and other CindU patients.Here, a reduction of the critical temperature threshold was shown in patients with cold urticaria, whereas no conclusive conclusions could be drawn for CsU patients due to the small number of patients [11,52,74].

Special patient groups
Children and pregnant women represent special patient groups.For a detailed discussion of urticaria therapy in children, please refer to the paper on this topic in the current issue.Therapy with omalizumab is approved from the age of 12 years, but is also used in the indication of bronchial asthma in children of younger age [75,76].
Therapy with omalizumab for the indication of allergic asthma was investigated in pregnant women in the EXPECT study, in which no increased incidence of congenital abnormalities, miscarriages, or stillbirths was observed [77,78].

Conclusion and outlook
CsU is a chronic inflammatory dermatosis, whose etiology is not yet fully understood and which is associated with a high restriction of health-related quality of life in affected patients.Currently, there is no curative therapeutic approach, therefore only symptomatic therapy can be administered or a spontaneous remission can be waited for.
In dermatology, the improved understanding of chronic inflammatory diseases such as psoriasis vulgaris and atopic dermatitis has led to major advances in therapy by means of targeted, anti-inflammatory therapies.Since an autoimmune/autoallergic genesis could be identified in at least some of the patients with CsU, such a therapeutic approach could also be promising here.The anti-IgE antibody omalizumab already represents such a selective therapy, which, however, does not lead to therapeutic success and freedom from manifestations in all patients.Consequently, there is a high need for new therapeutic strategies to treat CsU both symptomatically and curatively.In this context, several promising treatment approaches are currently being tested in clinical trials.
Other phenotypes of CsU are currently not fully characterized and the role of other immune cells such as T cells, eosinophils and basophils is not yet conclusively understood.For better treatment, a more comprehensive understanding of the pathogenesis is first required in order to develop new targeted therapies.