Chronic Spontaneous Urticaria: A Review.

Importance: Chronic spontaneous urticaria affects approximately 1% of the general population worldwide, including approximately 3 million people in the US, impairs patients' quality of life, and is associated with multiple comorbidities. Observations: Chronic spontaneous urticaria affects patients of any age but is most common in females aged 30 to 50 years. Diagnosis is based on clinical presentation, ie, spontaneously recurring wheals, angioedema, or both. Chronic spontaneous urticaria persists for more than 1 year in most patients (1 or repeated episodes) and may present with comorbidities including chronic inducible urticaria (>10%), autoimmune thyroiditis (approximately 20%), metabolic syndrome (6%-20%), and anxiety (10%-31%) and depression (7%-29%). Known autoimmune endotypes (subtypes of urticaria defined by distinct pathogenesis) of chronic spontaneous urticaria are mediated by mast cell-activating IgE and/or IgG autoantibodies (>50%). Approximately 40% of patients with chronic spontaneous urticaria have a Dermatology Life Quality Index of more than 10, corresponding to a very large or extremely large negative effect on quality of life. Second-generation H1 antihistamines are first-line treatment; partial or complete response, defined as a reduction in urticaria symptoms of greater than 50%, is observed in approximately 40% of patients. The 2022 international urticaria guideline recommends the monoclonal anti-IgE antibody omalizumab as second-line treatment for antihistamine-refractory chronic spontaneous urticaria. However, at least 30% of patients have an insufficient response to omalizumab, especially those with IgG-mediated autoimmune urticaria. Cyclosporine, used off-label, can improve symptoms in approximately 54% to 73% of patients, especially those with autoimmune chronic spontaneous urticaria and nonresponse to omalizumab, but has adverse effects such as kidney dysfunction and hypertension. Conclusions and Relevance: Chronic spontaneous urticaria is an inflammatory skin disease associated with medical and psychiatric comorbidities and impaired quality of life. Second-generation H1 antihistamines are first-line treatment, omalizumab is second-line treatment, and cyclosporine is third-line treatment for chronic spontaneous urticaria.

Skin reaction patterns in cholinergic urticaria.

BACKGROUND: Skin reaction patterns vary across patients with cholinergic urticaria (CholU), but their definition, prevalence, and clinical significance remain ill characterized. METHODS: Patients with CholU underwent pulse-controlled ergometry provocation testing to analyze skin reaction patterns and their correlation with location, onset, severity, sweating behaviour, clinical features, disease control, and quality of life (QoL) impairment. RESULTS: Based on the size, color, spacing, and shape of wheals as well as their surrounding skin responses, we identified six distinct types of CholU skin reactions, which differed in prevalence, from 83% (Type I) to 11% (Type VI) of patients affected. Almost all patients (94%) had ≥1 type of skin reaction pattern. Sweating was reduced in the majority of CholU patients and most prominently reduced in patients with Type VI skin signs (very small, round, red, widely spaced wheals with surrounding anemic halo), which emerged exclusively on the extremities. Type V skin signs (large, irregular, anemic, widely spaced wheals with moderate size erythema) were associated with the most severe clinical presentation and poorest QoL. CONCLUSIONS: Our analysis showed that most patients have more than one type of skin reaction patterns and that different skin signs are linked to distinct features. Future studies should determine any links between treatment response and types of skin signs in CholU.

Neutrophil trapping and nexocytosis, mast cell-mediated processes for inflammatory signal relay.

Neutrophils are sentinel immune cells with essential roles for antimicrobial defense. Most of our knowledge on neutrophil tissue navigation derived from wounding and infection models, whereas allergic conditions remained largely neglected. Here, we analyzed allergen-challenged mouse tissues and discovered that degranulating mast cells (MCs) trap living neutrophils inside them. MCs release the attractant leukotriene B4 to re-route neutrophils toward them, thus exploiting a chemotactic system that neutrophils normally use for intercellular communication. After MC intracellular trap (MIT) formation, neutrophils die, but their undigested material remains inside MC vacuoles over days. MCs benefit from MIT formation, increasing their functional and metabolic fitness. Additionally, they are more pro-inflammatory and can exocytose active neutrophilic compounds with a time delay (nexocytosis), eliciting a type 1 interferon response in surrounding macrophages. Together, our study highlights neutrophil trapping and nexocytosis as MC-mediated processes, which may relay neutrophilic features over the course of chronic allergic inflammation.

CD4+CCR5+ T cells and CCL3+ mast cells are increased in the skin of patients with chronic spontaneous urticaria.

Background: The proximity of activated T cells and mast cells in the lesional skin of patients with chronic spontaneous urticaria (CSU) is held to contribute to the development of wheals and angioedema. In a previous study, we demonstrated that increased IL-17 expression in T cells and mast cells in skin lesions of patients with CSU is associated with T/mast cell proximity, but the mechanisms that drive T cell/mast cell co-localization remain unknown. Objectives: To assess if chemokines expressed in lesional CSU skin contribute to T cell/mast cell proximity. Patients and methods: Biopsies from lesional CSU skin were compared to biopsies from healthy skin for expression of CCR5 and its ligand CCL3 by CD4+ T cells and mast cells, respectively. Results: Numbers of CCR5-positive CD4+ T cells in lesional CSU skin were significantly increased as compared to healthy normal skin (p < 0.0001). The number of mast cells expressing CCL3 (ligand for CCR5) in CSU skin was also increased (p < 0.0002) and significant association with T-cell close proximity (p < 0.0001) is noticed. Conclusions: The close proximity of T cells and mast cells in the skin of severe CSU may be driven, at least in part by increased CCR5 and CCL3 expression. Therapies that target CCL3 interaction with CCR5 should be assessed for their effects in CSU.

Expression of STAT3, IL-27p28, and IL-12p35 Is Deregulated and Linked to Autoimmune Markers in Chronic Spontaneous Urticaria.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a common inflammatory disorder characterized by wheals, angioedema, or both, for more than 6 weeks. Autoimmunity is held to be one of the most frequent causes, but little is known about the expression and relevance of autoimmunity-driving genes in CSU, such as STAT3, STAT1, IL-27p28, and IL-12p35. OBJECTIVE: To investigate CSU patients or the expression of STAT3, STAT1, IL-27p28, and IL-12p35 and possible links to clinical features. METHODS: Gene expression levels, in 26 CSU patients and 19 healthy controls (HCs), were determined by quantitative real-time PCR. CSU patients were assessed for total IgE and IgG-anti-TPO, markers of autoimmune CSU. RESULTS: Patients with CSU showed significantly higher expression of STAT3, but not STAT1, and 17 and 10 of 26 CSU patients had elevated STAT3 expression and STAT3/STAT1 ratios, respectively, as compared to only 1 of 19 HCs. High STAT3 expression and STAT3/STAT1 ratios were linked to low IgE and elevated IgG-anti-TPO. As compared to HCs, CSU patients had markedly lower and correlated IL-27p28 and IL-12p35 mRNA expression levels. Low IL-27p28 and IL-12p35 expression levels were linked to higher STAT3/STAT1 ratios and low IgE. CONCLUSION: STAT3 upregulation, higher STAT3/STAT1 ratios, and IL-27p28 and IL-12p35 downregulation cluster with features of autoimmune CSU. The role of STAT3 as a potential pathogenic driver of autoimmune CSU and target of treatment should be explored further.

Validation and correlations of the Angioedema Activity Score (AAS), Angioedema Quality of Life (AE-QoL) questionnaire, and Angioedema Control Test (AECT) in Chinese patients with angioedema.

Background: The impact of recurrent angioedema can be severely debilitating and remains difficult to quantify. Several standardized patient-reported outcome measures (PROMs), including the Angioedema Activity Score (AAS), Angioedema Quality of Life (AE-QoL) questionnaire, and Angioedema Control Test (AECT), have been developed and translated into different languages. However, these PROMs have yet to be validated in Chinese individuals, and their correlations in the Chinese population remain unknown. Objective: Our aim was to validate the Chinese versions of the AAS, AE-QoL questionnaire, and AECT and assess their intercorrelations. Methods: A prospective cohort of 118 Chinese patients with recurrent angioedema at the Angioedema and Urticaria Centre of Reference and Excellence in Hong Kong completed the traditional Chinese versions of the AAS, AE-QoL questionnaire, and AECT. We analyzed the reliability and validity of these PROMs and their correlations with each other as well as with generic PROMs. Results: The Chinese AAS, AE-QoL questionnaire, and AECT demonstrated excellent internal consistency (Cronbach α = 0.920, 0.976, and 0.832, respectively; McDonald ω = 0.972, 0.977, and 0.901, respectively). Confirmatory factor analysis for the AE-QoL questionnaire showed an acceptable fit with the 4-dimensional model (comparative fit index = 0.869; Tucker-Lewis index = 0.842). The AECT showed significant correlations with both the AAS and AE-QoL questionnaire (ρ = -0.750 and -0.456 respectively [both P < .05]). The AE-QoL questionnaire was moderately correlated with certain domains of generic PROMs such as the Work Productivity and Activity Impairment Questionnaire: General Health, version 2.0, and the Short Form 12-Item Health Survey, version 2 (all ρ < 0.60). Conclusion: The Chinese AE-QoL questionnaire, AAS, and AECT are valid and reliable tools for use with Chinese patients. More validated tools should be made available to improve patient care and research for all patients with angioedema globally.

Does angioedema in patients with chronic spontaneous urticaria impact response to omalizumab?

The presence of angioedema, or deep skin swelling, in addition to hives (wheals) in patients with chronic spontaneous urticaria (CSU) can complicate disease management. There is evidence that omalizumab is effective for patients with CSU with angioedema, but the time to a clinically meaningful response has not been assessed. This post hoc analysis examined data from the phase 3, randomized, double-blind ASTERIA I and ASTERIA II studies: patients with CSU with hives were grouped by presence (n = 216) or absence of angioedema (n = 265) at baseline. The time to minimally important difference (MID, change from baseline of ≥11 points) in weekly Urticaria Activity Score (UAS7) was analyzed using Kaplan-Meier analyses. Median time to MID for omalizumab 300 mg was similar in patients with and without angioedema. Median time to MID for omalizumab 150 mg was similar to 300 mg for patients without angioedema, and was longer for patients with angioedema. Therefore, the response to omalizumab for patients with CSU with angioedema was dose dependent. We recommend that the best approach for clinicians, in line with guidelines, would be initial administration of omalizumab 300 mg every 4 weeks for all patients. Clinical trials registration: Clinicaltrials.gov NCT01287117 (registered 27 January 2011) and NCT01292473 (registered 7 February 2011).

New insights into chronic inducible urticaria.

PURPOSE OF REVIEW: Chronic inducible urticaria (CIndU) is a group of long-persisting and challenging to manage diseases, characterized by recurrent wheals and angioedema induced by definite triggers. In this review, we address recent findings on CIndU pathogenesis, diagnosis as well as its treatment, and we discuss novel potential targets that may lead to the development of more effective therapies for CIndU patients. RECENT ADVANCES: Meaningful advances in the understanding of its pathogenesis have been reported in the last decades. Novel CIndU-specific patient-reported outcome measures enable a closer and better evaluation of patients. CIndU is a hard-to-treat disease that highly impairs quality of life (QoL) of affected patients. Provocation tests allow to diagnose CIndU subtypes. The only licensed and recommended treatment for CIndU are second generation non-sedating H1-antihistamines, which lack efficacy in many cases. Omalizumab off-label use has been assessed in all types of CIndU with overall good outcomes. Promising emerging therapies currently assessed in chronic spontaneous urticaria are paving the path for novel treatments for CIndU.

Validity, reliability, and sensitivity to change of the traditional Chinese Urticaria Control Test (UCT) in Hong Kong.

Background: Uncontrolled chronic urticaria (CU) can severely affect physical and psychosocial health as well as quality of life. Patient-reported outcome measures are crucial for measuring disease control. The Urticaria Control Test (UCT) is recommended by guidelines to monitor CU and guide clinical management. However, the traditional Chinese version of the UCT has not yet been validated. Objective: We sought to validate the traditional Chinese UCT among Chinese CU patients in Hong Kong. Methods: Patients with CU were enrolled at a Urticaria Centre of Reference and Excellence (aka UCARE) in Hong Kong and completed the traditional Chinese UCT. The internal consistency, test-retest reliability, construct validity, convergent validity, known-group validity, and sensitivity to change of the traditional Chinese UCT were evaluated. Results: We recruited 162 CU patients (80.9% female; age 50 ± 14 years) with a mean (median) ± standard deviation baseline UCT score of 8.8 (8) ± 4.7. Overall, Chinese UCT showed excellent internal consistency (Cronbach α and McDonald ω = 0.948), as well as test-retest reliability (intraclass correlation coefficient = 0.916 [95% confidence interval = 0.866-0.953]). Exploratory factor analysis revealed a unidimensional structure and confirmed its construct validity. Strong correlation between UCT and the 7-day urticaria activity score (UAS7) attested to its convergent validity (ρ = -0.699, P < .001). Its known-group validity was supported by significantly different UCT scores among patient subgroups with different disease activity. The Chinese UCT also demonstrated good sensitivity to change, as reflected by the significant correlation between changes in UCT and UAS7 scores (ρ = 0.491, P < .001). Conclusion: The traditional Chinese UCT is a valid, reliable, and sensitive-to-change instrument among Hong Kong Chinese with CU.

Chronic urticaria: unmet needs, emerging drugs, and new perspectives on personalised treatment.

Chronic urticaria is a common and debilitating mast cell-driven skin disease presenting with itchy wheals, angio-oedema, or both. Chronic urticaria is classified as spontaneous (without definite triggers) and inducible (with definite and subtype-specific triggers; eg, cold or pressure). Current management guidelines recommend step-up administration of second-generation H1-antihistamines to four-fold the approved dose, followed by omalizumab and ciclosporin. However, in many patients, chronic urticaria does not respond to this linear approach due to heterogeneous underlying mechanisms. A personalised endotype-based approach is emerging based on the identification of autoantibodies and other drivers of urticaria pathogenesis. Over the past decade, clinical trials have presented promising options for targeted treatment of chronic urticaria with the potential for disease modification, including Bruton's tyrosine kinase inhibitors, anti-cytokine therapies, and mast cell depletion. This Therapeutics article focuses on the evidence for these novel drugs and their role in addressing an unmet need for personalised management of patients with chronic urticaria.

Characterization of cells and mediators associated with pruritus in primary cutaneous T-cell lymphomas.

Patients with primary cutaneous T-cell lymphoma (CTCL) often experience severe and difficult-to-treat pruritus that negatively affects their quality of life (QoL). However, the mechanisms of pruritus in CTCL, including mycosis fungoides (MF), remain largely unknown, and detailed characteristics of CTCL-associated pruritus is not fully elucidated. To characterize pruritus in CTCL, cutaneous B-cell lymphoma (CBCL), and large plaque parapsoriasis (LPP), and to identify potential itch mediators involved in the pathogenesis of pruritus in CTCL patients. Clinical data and blood samples were collected from 129 healthy subjects and 142 patients. Itch intensity, QoL impairment, psychological distress, and sleep quality were assessed using validated questionnaires and instruments. Blood levels of BDNF, CCL24, GRP, IL-31, IL-33, sST2, substance P, TSLP, tryptase and total IgE were measured using ELISA or ImmunoCAP. Pruritus was prevalent in CTCL, LPP and CBCL patients, with higher prevalence and severity observed in CTCL. In CTCL, pruritus correlated with significant impairment in QoL, sleep, psychological distress. Compared to healthy controls, elevated levels of IL-31, IL-33, substance P, total IgE, tryptase, and TSLP were found in MF patients. A comparison of MF patients with and without pruritus revealed higher levels of IL-31, substance P, GRP, and CCL24 in the former. Itch intensity positively correlated with IL-31, GRP, CCL24, and tryptase levels. Pruritus significantly burdens CTCL patients, necessitating appropriate therapeutic management. Our findings suggest that various non-histaminergic mediators such as tryptase and IL-31 could be explored as novel therapeutic targets for managing pruritus in MF patients.

Disease modification in chronic spontaneous urticaria.

Chronic spontaneous urticaria (CSU) is a debilitating, inflammatory skin condition characterized by infiltrating immune cells. Available treatments are limited to improving the signs and symptoms. There is an unmet need to develop therapies that target disease-driving pathways upstream of mast cell activation to inhibit or delay the progression of CSU and associated comorbidities. Here, we aim to define disease modification due to a treatment intervention and criteria that disease-modifying treatments (DMTs) must meet in CSU. We have defined disease modification in CSU as a favorable treatment-induced change in the underlying pathophysiology and, therefore, the disease course, which is clinically beneficial and enduring. A DMT must fulfil the following criteria: (1) prevents or delays the progression of CSU, (2) induces long-term, therapy-free clinical remission, which is the sustained absence of CSU signs and symptoms without the need for treatment, and (3) affects the underlying mechanism of CSU, as demonstrated by an effect on disease-driving signals and/or a biomarker. DMTs in CSU should slow disease progression, achieve long-lasting disease remission, target disease-driving mechanisms, reduce mast cell-activating IgE autoantibodies, target cytokine profile polarization, and normalize the gut microbiome and barrier. Treating CSU at the immune system level could provide valuable alternatives to pharmacotherapy in CSU management. Specific DMTs in CSU are yet to be developed, but some show potential benefits, such as inhibitors of Bruton's Tyrosine Kinase, IL-4 and IL-13. Future therapies could prevent CSU signs and symptoms, achieve long-term clinical benefits after discontinuing treatment, and prevent associated concomitant disorders.

Multinational Drug Survival Study of Omalizumab in Patients With Chronic Urticaria and Potential Predictors for Discontinuation.

Importance: Treating patients with chronic urticaria using omalizumab has been shown to be safe and effective in randomized clinical trials. Multinational studies on long-term omalizumab performance in chronic urticaria in clinical practice settings are lacking, especially on drug survival. Drug survival, which refers to the length of time that patients are treated with a specific drug, is a comprehensive outcome covering effectiveness, safety, and patient and physician preferences. Furthermore, little is known about the reasons and potential predictors for omalizumab discontinuation. Objective: To investigate omalizumab drug survival as well as reasons and potential predictors for discontinuation in a large, diverse population. Design, Setting, and Participants: This international multicenter cohort study was conducted at 14 Urticaria Centers of Reference and Excellence in 10 countries, including all patients with chronic urticaria from these centers who were ever treated with omalizumab. Main Outcomes and Measures: Drug survival analysis was performed to assess time to discontinuation. Patient characteristics and treatment protocols were investigated by Cox regression analysis to identify potential predictors for omalizumab discontinuation. Results: In 2325 patients with chronic urticaria who started omalizumab between June 2009 and July 2022, the mean (SD) age of the cohort was 42 (6) years, and 1650 participants (71%) were female. Overall omalizumab survival rates decreased from 76% to 39% after 1 to 7 years, respectively (median survival time, 3.3 [95 % CI, 2.9-4.0] years), primarily due to discontinuation from well-controlled disease in 576 patients (65%). Ineffectiveness and adverse effects were reasons for discontinuation in a far smaller proportion of patients, totaling 164 patients (18%) and 31 patients (4%), respectively. Fast treatment response was associated with higher rates of omalizumab discontinuation due to well-controlled disease (hazard ratio, 1.45 [95% CI, 1.20-1.75]), and disease duration of more than 2 years was associated with lower rates of discontinuation due to well-controlled disease (HR, 0.81 [95% CI, 0.67-0.98]). Immunosuppressive cotreatment at the start of omalizumab and autoimmune disease was associated with a higher risk for discontinuation due to ineffectiveness (HR, 1.65 [95% CI, 1.12-2.42]). The presence of spontaneous wheals (HR, 0.62 [95% CI, 0.41-0.93]) and access to higher dosages (HR, 0.40 [95% CI, 0.27-0.58) were both associated with a lower risk for discontinuation of omalizumab due to ineffectiveness. Conclusion and Relevance: This multinational omalizumab drug survival cohort study demonstrated that treatment of chronic urticaria with omalizumab in a clinical setting is effective and safe, and well-controlled disease is the main reason for treatment discontinuation. These findings on omalizumab drug survival rates and reasons and potential predictors for discontinuation may guide patients and physicians in clinical decision-making and expectation management. These results may call for the identification of biomarkers for chronic urticaria remission in complete responders to omalizumab treatment.

Dupilumab Reduces Urticaria Activity, Itch, and Hives in Patients with Chronic Spontaneous Urticaria Regardless of Baseline Serum Immunoglobulin E Levels.

INTRODUCTION: In chronic spontaneous urticaria (CSU), interleukin (IL)-4 and IL-13 may promote mast cell activation directly via IL-4 receptor expression, or indirectly via upregulated immunoglobulin E (IgE) production. Dupilumab significantly improved CSU signs and symptoms in the phase 3, randomized, placebo-controlled LIBERTY-CSU CUPID Study A. This analysis explores the impact of dupilumab on CSU signs and symptoms and serum IgE levels in patients from LIBERTY-CSU CUPID Study A with serum total IgE above and below 100 IU/mL at baseline. METHODS: Patients with H1-antihistamine-refractory CSU received dupilumab (n = 70) or placebo (n = 68) for 24 weeks. Efficacy endpoints were change from baseline to weeks 12 and 24 in serum total IgE levels, Itch Severity Score over 7 days (ISS7), Urticaria Activity Score over 7 days (UAS7), and Hives Severity Score over 7 days (HSS7) in dupilumab- or placebo-treated patients with serum total IgE above and below 100 IU/mL at baseline. RESULTS: Dupilumab treatment significantly reduced median (interquartile range) IgE levels at week 12 [dupilumab: -31.9% (-41.9; -22.6); placebo: -6.3% (-21.3; 14.9)] and week 24 [dupilumab: -48.2% (-56.8; - 39.5); placebo: - 6.3% (-34.5; 14.8)]. Similar IgE reductions relative to baseline were observed in dupilumab-treated patients regardless of baseline IgE level. Dupilumab treatment improved ISS7, UAS7, and HSS7 over 12 and 24 weeks, regardless of baseline serum IgE level (interaction p ≥ 0.59 for all treatment by subgroup comparisons), with weak correlations (r < 0.2) observed between IgE level changes and ISS7, UAS7, and HSS7 outcomes. CONCLUSIONS: Dupilumab significantly improved CSU signs and symptoms and reduced serum IgE, regardless of baseline IgE levels. In the current analysis, baseline total IgE had no predictive value as a dupilumab treatment response biomarker in CSU. Downregulation of IgE, a key mediator of mast cell activation and histamine release, may at least partially explain the effectiveness of dupilumab in reducing CSU signs and symptoms. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04180488.

In chronic spontaneous urticaria, increased Galectin-9 expression on basophils and eosinophils is linked to high disease activity, endotype-specific markers, and response to omalizumab treatment.

BACKGROUND: Galectin-9 (Gal-9) has been implicated in allergic and autoimmune diseases, but its role and relevance in chronic spontaneous urticaria (CSU) are unclear. OBJECTIVES: To characterize the role and relevance of Gal-9 in the pathogenesis of CSU. METHODS: We assessed 60 CSU patients for their expression of Gal-9 on circulating eosinophils and basophils as well as T cell expression of the Gal-9 receptor TIM-3, compared them with 26 healthy controls (HCs), and explored possible links with disease features including disease activity (urticaria activity score, UAS), total IgE, basophil activation test (BAT), and response to omalizumab treatment. We also investigated potential drivers of Gal-9 expression by eosinophils and basophils. RESULTS: Our CSU patients had markedly increased rates of circulating Gal-9+ eosinophils and basophils and high numbers of lesional Gal-9+ cells. High rates of blood Gal-9+ eosinophils/basophils were linked to high disease activity, IgE levels, and BAT negativity. Serum levels of TNF-α were positively correlated with circulating Gal-9+ eosinophils/basophils, and TNF-α markedly upregulated Gal-9 on eosinophils. CSU patients who responded to omalizumab treatment had more Gal-9+ eosinophils/basophils than non-responders, and omalizumab reduced blood levels of Gal-9+ eosinophils/basophils in responders. Gal-9+ eosinophils/basophils were negatively correlated with TIM-3+TH17 cells. CONCLUSION: Our findings demonstrate a previously unrecognized involvement of the Gal-9/TIM-3 pathway in the pathogenesis CSU and call for studies that explore its relevance.

Emerging Therapeutics in Chronic Urticaria.

Chronic urticaria (CU) is a common and long-lasting mast cell-mediated skin disease associated with psychiatric and autoimmune comorbidities, high economic costs, and considerable impact on quality of life. Available therapies show limited efficacy in many CU patients, which may be related to distinct underlying pathophysiology. Targeted and disease-modifying treatments with higher and broader efficacy are needed and are under development for CU. These novel drugs, small molecules, and monoclonal antibodies target mast cells and their receptors, signaling pathways, or mediators and other immune cells. In this article, the authors focus on the most promising emerging therapeutics in advanced development and discuss their potential place in future management of CU.