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Chronic spontaneous urticaria (CSU) should be on every dermatology practitioner's radar. CSU is a skin disorder marked by wheals, angioedema, or both for more than 6 weeks. Patients with CSU experience unexplained, itchy wheals that appear and disappear, traveling around the body and lasting less than 24 hours per area. Angioedema accompanies wheals for up to 48 hours in around half of cases. CSU is a diagnosis of exclusion, relying heavily on patient history to differentiate CSU symptoms from other causes of urticaria or angioedema. But reassuringly, CSU has a simple diagnostic algorithm and a clear initial treatment path. First-line strategies include non-pharmacologic approaches, and second-generation antihistamines (2gAH) administered up to 4 times their standard dose. Omalizumab and cyclosporine (off-label) are second- and third-line options, respectively. However, many patients will continue to have CSU symptoms despite consistent maximum-dose treatment. Novel therapies, including biologic agents and small molecule drugs targeting mast cell activation and inflammatory mediators, show promise in treating CSU refractory to standard therapy. However, further research is needed to establish their efficacy and safety in clinical practice. J Drugs Dermatol. 2024;23:9(Suppl 2):s5-14.Access the CME Activity.

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 + T H 17 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., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Limited information is available on the use of omalizumab (OMA) updosing since its introduction as a second-line therapy in chronic spontaneous urticaria (CSU) in 2014. Practical guidelines from health authorities are lacking, and the specific characteristics of patients requiring higher doses remain unknown. Our objectives were to characterize the patterns of OMA updosing (defined as changes in dose and/or injection intervals), to identify the predictive factors associated with updosing, and to improve CSU management., Methods: We conducted a prospective, multicentric, real-life observational study, including patients diagnosed with CSU and starting OMA. The data were collected at 0, 3, 6, and 9 months. The primary endpoint was the frequency of OMA updosing at 3 months. The secondary endpoints included an analysis of updosed patients' profile, and an assessment of OMA efficacy and safety., Results: We included 153 patients. Twenty percent of patients were updosed at 3 months, and 27% in total during the 9-month follow-up. Practitioners mainly chose to increase the frequency of injections (66%). At baseline, the updosed patients were more likely to have more severe CSU (UCT < 4, p < 0.030), a lower lymphocyte count (<2000/mm 3 , p = 0.037), and low IgE levels (<70 UI/mL, p = 0.024). The side effects of OMA were not more frequent after updosing., Conclusion: One in five patient underwent updosing within just 3 months. OMA updosing is frequent in particular in cases of severe disease and low IgE blood levels., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Chronic spontaneous urticaria (CSU) is a common, debilitating skin disorder characterized by recurring episodes of raised, itchy and sometimes painful wheals lasting longer than 6 weeks. CSU is mediated by mast cells which are absent from peripheral blood. However, lineage - CD34 hi CD117 int/hi FcεRI + cells in blood have previously been shown to represent a mast cell precursor., Methods: We enumerated FcεRI - , FcεRI + and FcεRI hi lineage - CD34 + CD117 + cells using flow cytometry in blood of patients with CSU (n = 55), including 12 patients receiving omalizumab and 43 not receiving omalizumab (n = 43). Twenty-two control samples were studied. Disease control and patient response to omalizumab was evaluated using the urticaria control test. We performed single-cell RNA sequencing (scRNA-Seq) on lineage - CD34 hi CD117 hi blood cells from a subset of patients with CSU (n = 8) and healthy controls (n = 4)., Results: CSU patients had more lineage - CD34 + CD117 + FcεRI + blood cells than controls. Lineage - CD34 + CD117 + FcεRI + cells were significantly higher in patients with CSU who had an objective clinical response to omalizumab when compared to patients who had poor disease control 90 days after initiation of omalizumab. scRNA-Seq revealed that lineage - CD34 + CD117 + FcεRI + cells contained both lymphoid and myeloid progenitor lineages, with omalizumab responsive patients having proportionally more myeloid progenitors. The myeloid progenitor lineage contained small numbers of true mast cell precursors along with more immature FcεRI - and FcεRI + myeloid progenitors., Conclusion: Increased blood CD34 + CD117 + FcεRI + cells may reflect enhanced bone marrow egress in the setting of CSU. High expression of these cells strongly predicts better clinical responses to the anti-IgE therapy, omalizumab., (© 2024 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

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., (© 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Certain guidelines recommend a second-generation H1-antihistamine (AH) as first-line treatment for patients with chronic urticaria (CU). However, some patients show insufficient response to a standard dose of this therapy and might benefit from adding leukotriene receptor antagonists (LTA). Therefore, we aimed to perform a systematic review and meta-analysis comparing LTA plus antihistamines with antihistamines alone. We performed a systematic review and meta-analysis, searching PubMed, EMBASE, and Cochrane Central for randomized clinical trial (RCT) data comparing LTA plus AH treatment to AH alone in patients with CU. Statistical analysis was performed using R Studio 4.3.2. Heterogeneity was assessed with I 2 statistics. Three studies comprising 234 patients with urticaria were included. The mean age was 37.23 years in the leukotriene antagonist + antihistamines (LTA + AH) group and 39.14 years in the antihistamines (AH) group. Follow-up ranged from 2 to 18 months between studies. There was no statistically significant difference between groups in terms of TSS level (SMD: -74.82; 95% CI: -222.66 to 73.02; P = 0.32; I 2  = 98%), neither in terms of pruritus (MD: -0.07; 95% CI: -0.42 to 0.28; P = 0.70; I 2  = 74%). After sensitivity analysis, with the systematic exclusion of each study from the grouped estimates, the result for TSS level did not change. These findings suggest that leukotriene receptor antagonists with antihistamines do not have better outcomes than antihistamines alone regarding TSS and pruritus in patients with CU., (© 2024 the International Society of Dermatology.)

Competing Interests: Disclosures Dr Welsh and Dr Schuldt have no conflicts of interest to report.

Chronic spontaneous urticaria (CSU) is associated with skin mast cell activation, and its triggering mechanisms are not completely elucidated. Evidence suggests an autoimmune component of CSU. Our aim was to assess the usefulness of an autoimmune mast cell activation test (aiMAT) for diagnosing and differentiating CSU into different subtypes. We enrolled 43 patients with active, uncontrolled CSU before starting treatment with omalizumab and 15 controls. Patients were evaluated based on omalizumab response. aiMATs were performed using non-IgE-sensitized (NS) or myeloma IgE-sensitized (S) LAD2 cells, which were then stimulated with CSU/control sera (25 µL and 10 µL). The expression of CD63 was assessed with flow cytometry. CD63 response on NS-LAD2 was significantly increased in CSU patients compared to controls after the stimulation with 25 µL CSU/control sera ( p = 0.0007) and with 10 µL CSU/control sera ( p = 0.0001). The ROC curve analysis demonstrated an area under the curve (AUC) of 0.82. The cutoff for autoimmune-non-IgE-sensitized-MAT was 40.3% CD63+ LAD2, which resulted in 73.3% sensitivity and 81.4% specificity. CD63 response on S-LAD2 was significantly increased in CSU patients compared to controls after the stimulation with 25 µL CSU/control sera ( p = 0.03). The ROC curve analysis demonstrated an AUC of 0.66. The cutoff for the autoimmune-myeloma IgE-sensitized-MAT was 58.4% CD63+ cells, which resulted in 62.8% sensitivity and 66.7% specificity. Overall, 36 out of 43 (84%) patients responded to omalizumab, and 7 (16%) were nonresponders. We found no differences between LAD2 CD63 response and response to omalizumab. In conclusion, aiMAT could represent a new diagnostic tool in CSU. Additional studies are needed to evaluate the potential benefits during omalizumab therapy.

Background: Chronic spontaneous urticaria (CSU) is a highly prevalent and difficult to manage cutaneous disease characterized by the presence of recurrent urticaria, angioedema, or both, for a period of 6 weeks or longer. One of the biological treatments used for patients with CSU with an autoimmune background and bad control of the disease is omalizumab, an anti-IgE monoclonal antibody. The understanding of the mechanism of action of this biological drug in CSU along with the identification of potential biomarkers of clinical response can be helpful in the personalized management of the disease., Objective: The purpose of this study was to analyze the effect of omalizumab on peripheral blood lymphocyte subpopulations in patients with CSU in order to identify potential biomarkers of treatment response., Methods: We analyzed 71 patients with CSU [33 under omalizumab and 38 under non-immunomodulatory drugs (treated with antihistamines; NID)] and 50 healthy controls. An exhaustive immunophenotyping of whole blood T-cell subpopulations, including naïve, central memory, effector memory, effector cells, Th1, Th2, and Th17 was performed by multiparametric flow cytometry. Moreover, in CSU patients, we analyzed markers of inflammation (ESR, DD, CRP), atopy (prick test, IgE quantification), and autoimmunity (anti-thyroid antibodies and indirect basophil activation test).To evaluate the clinical activity, the Urticaria Activity Score 7 (UAS 7) test was used., Results: In patients with CSU under treatment with omalizumab, there was a significant decrease in the percentage of naïve and an increase in the percentage of central memory CD4 T cells as well as a decrease in the percentage of naïve and increase in the percentage of effector CD8 T-cell subsets. Moreover, patients under treatment with omalizumab had higher percentages of Th1 and Th2 cells than patients under treatment with NID., Conclusion: The immune monitoring of T-cell subpopulations in patients with CSU starting omalizumab, may be a useful strategy to analyze treatment response in the clinical practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 López, Depreux, Bielsa, Roger, Quirant-Sanchez, Basagaña, Jurgens, Padró, Miquel, Martinez-Caceres and Teniente-Serra.)

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., Competing Interests: Disclosure MMu: is or recently was a speaker and/or advisor for and/or has received research funding from AstraZeneca, Blueprint, Takeda and Roche. E. Kocatürk is or recently was a speaker and/or advisor for and/or has received research funding from Novartis, Menarini, LaRoche Posey, Sanofi, Bayer, Germany. M. Maurer is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, Allerdia, Amgen, United States, Aralez, Argenx, Netherlands, AstraZeneca, United Kingdom, Celldex, United States, Centogene, CSL Behring, United States, FAES, United States, Genentech, United States, GIInnovation, Innate Pharma, France, Kyowa Kirin, LEO Pharma, Denmark, Lilly, Menarini, Moxie, Novartis, Switzerland, Pfizer, United States, Roche, Switzerland, Sanofi, United States/Regeneron, United States, Third Harmonic Bio, UCB, Belgium, and Uriach. P. Kolkhir was a speaker/consultant and/or advisor for and/or has received research funding from Novartis, ValenzaBio and Roche outside of submitted work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Chronic inducible urticaria (CIndU) management often follows chronic spontaneous urticaria (CSU) guidelines, but a step-by-step evaluation of their effectiveness in CIndU is lacking., Objective: To assess the clinical impact of adapting CSU international guidelines for CIndU management., Methods: We conducted a prospective cohort study involving patients diagnosed with CIndU based on challenge tests and a Urticaria Control Test (UCT) score of ≤11 points. Following the guidelines, a stepwise approach was used: avoidance measures, antihistamines, omalizumab, and cyclosporine. Treatment steps were added based on individual response, with control defined as UCT ≥12 points. Pharmacological steps were evaluated for at least 1 month, with the next step initiated in case of a UCT score ≤11 points., Results: We enrolled 194 patients with CIndU. Of them, 134 patients had CIndU with concomitant CSU and 60 had CIndU only. Following the step-by-step approach outlined in the guidelines, a total of 159 (81.9%) patients reach a UCT ≥12 points, with avoidance measures 23 (11.8%) patients, antihistamines 84 (43.2%), omalizumab 35 (18%), and cyclosporine 17 (8.7%)., Conclusions: This study supports the use of a stepwise approach based on CSU guidelines for CIndU management. However, a significant proportion of patients, particularly those with CIndU only, did not achieve adequate control. This highlights the heterogeneity within CIndU and the need for further research to develop new therapies for patients with CIndU who remain uncontrolled., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

In a double-blind, randomized controlled trial, we investigated the effectiveness of adding antiplatelet drugs to up-dosing antihistamines for the treatment of chronic spontaneous urticaria (CSU) in patients with elevated D-dimer levels who had an inadequate response to conventional antihistamine doses. Twenty patients with Urticaria Activity Score over 7 days (UAS7) ≥16 and D-dimer >500 ng/mL were randomized to receive either antiplatelet therapy (cilostazol 150 mg/day + dipyridamole 50 mg/day) with antihistamine (desloratadine 20 mg/day) or antihistamine alone for 4 weeks. The antiplatelet group demonstrated a greater decrease in UAS7 compared to the control group (28.10 to 8.90 vs. 22.90 to 16.40, p < 0.001 vs. p = 0.054). Both groups experienced improved quality of life (DLQI), but the improvement was greater in the antiplatelet group (p = 0.046). D-dimer levels decreased only in the antiplatelet group (1133.67 ng/mL to 581.89 ng/mL, p = 0.013) with no significant change observed in the control group. This suggests that combining dipyridamole and cilostazol with up-dosing antihistamines may be more effective for CSU patients with high D-dimer levels compared to up-dosing antihistamines alone. This could be due to a reduction in platelet activation, as evidenced by the decrease in D-dimer levels observed in the antiplatelet group., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (© 2024. The Author(s).)

Background: Population-based studies have highlighted the link between chronic urticaria (CU) and metabolic syndrome, and metabolic alterations have been revealed in CU. However, to our knowledge, a comprehensive metabolomics study on a large cohort of patients with CU has not been reported., Objective: We sought to explore the underlying metabolic subtypes and novel metabolite biomarkers for CU diagnosis and therapy., Methods: Plasma samples from 80 patients with CU and 82 healthy controls were collected for metabolomics quantification and bioinformatics analysis. Another independent cohort consisting of 144 patients with CU was studied to validate the findings. Bone marrow-derived mast cells and mice with IgE-induced passive cutaneous anaphylaxis were used for in vitro and in vivo experiments, respectively., Results: We observed clear metabolome differences between CU patients and healthy controls. Meanwhile, differential metabolites N 6 -acetyl-l-lysine, l-aspartate, maleic acid, and pyruvic acid were used to construct random forest classifiers and achieved area under receiver operating characteristic curve values greater than 0.85, suggesting their potential as diagnostic biomarkers of CU. More importantly, by exploring the underlying metabolic subtypes of CU, we found that the low abundance of pyruvic acid and maleic acid was significantly related to the activity of CU, poor efficacy of second-generation H 1 antihistamines, and short relapse-free time. The results were validated in the independent cohort. Moreover, supplementation with pyruvate or maleate could significantly attenuate IgE-mediated mast cell activation in vitro and in vivo., Conclusions: Plasma pyruvic acid and maleic acid may be effective biomarkers for predicting disease activity, therapeutic efficacy, and prognosis for patients with CU., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Chronic spontaneous urticaria (CSU) affects 0.5% to 1% of the general population and is often managed by allergy and immunology specialists. Guidelines have evolved over the past several decades with an emphasis on decreasing extensive screening laboratory testing as they are of low-yield and cost-ineffective. The utility of biomarkers remains under investigation but total immunoglobulin E may be helpful in determining specific endotypes and response to omalizumab. Antihistamines and omalizumab remain the primary therapeutic options for CSU, but an expanding body of evidence supports the use of immunosuppressants and anti-inflammatory medications in refractory cases., Competing Interests: Disclosure The authors declare the following competing financial interest(s): S.R. Joshi was a paid advisor for Novartis, Sanofi, Genentech, and Regeneron. K.M. Anstey and D. Khan have no financial interest to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of interests TZ has received honoraria for lectures from Amgen, AstraZeneca, AbbVie, ALK–Abelló, Almirall, Astellas, Bayer Health Care, Bencard, Berlin Chemie, FAES Farma, HAL Allergy, Henkel, Kryolan, Leti, L'Oreal, Meda, Menarini, Merck Sharp & Dohme, Novartis, Nuocor, Pfizer, Sanofi, Stallergenes, Takeda, Teva, Union Chimique Belge, and Uriach; fees for industry consulting from Abivax, Almirall, Bluprint, Celldex, Celltrion, Novartis, and Sanofi; he declares unpaid organisational affiliations: is a committee member of Allergic Rhinitis and its Impact on Asthma, is a member of the board of the German Society for Allergy and Clinical Immunology (DGAKI), head of the European Centre for Allergy Research Foundation (ECARF), President of the Global Allergy and Asthma European Network (GA(2)LEN), member of the committee on Allergy Diagnosis and Molecular Allergology, World Allergy Organization (WAO). LFE reports honoraria for lectures from Novartis, Sanofi, and Abbvie; and participation on an advisory board for Sanofi. AG-A reports grants from Uriach Pharma, Novartis, Instituto Carlos III-FEDER (PI11/00108); consulting fees from Uriach Pharma, Neucor, Genentech, Novartis, FAES Farma, GlaxoSmithKline, Sanofi–Regeneron, Amgen, Thermo Fisher Scientific, Almirall, Leo Pharma, Mitsubishi Tanabe, and Servier; honoraria for lectures and education from Uriach Pharma, Novartis, Genentech, Menarini, LEO-PHARMA, GlaxoSmithKline, Merck Sharp & Dohme, Almirall, Sanofi, and Avene; and participates on an advisory board for Celldex Therapeutics. CG has a consultancy with Celltrion and is on steering committees for AB Science and Blueprint Medicines. EK reports honoraria for lectures and consulting from Novartis. KK reports grants from Novartis (NCT05032157, NCT05513001, NCT06042478); and personal fees from Novartis, Menarini, and Takeda, outside the submitted work. PK reports personal fees from Novartis, Roche, and ValenzaBio, outside the submitted work. MM is or recently was a speaker, advisor, or both, for Allakos, Alexion, Almirall, Alvotech, Amgen, Aquestive, Arcensus, argenX, AstraZeneca, Astria, BioCryst, Blueprint, Celldex, Celltrion, Clinuvel, Cogent, CSL Behring, Escient, Evoemmune, Excellergy, GlaxoSmithKline, Incyte, Jasper, Kashiv, Kalvista, Kyowa Kirin, Leo Pharma, Lilly, Menarini, Mitsubishi Tanabe Pharma, Moxie, Noucor, Novartis, Orion Biotechnoloy, Pharvaris, Resonance Medicine, Sanofi–Regeneron, Santa Ana Bio, Septerna, Servier, Takeda, Teva, Third HarmonicBio, Valenza Bio, Vitalli Bio, Yuhan Corporation, and Zurabio; and he received institutional research funding from Allakos, Alexion, Amgen, AstraZeneca, Astria, BioCryst, Blueprint, Celldex, Clinuvel, Cogent, CSL Behring, Escient, Evommune, Incyte, Jasper, Kalvista, Kyowa Kirin, Leo Pharma, Lilly, Mitsubishi Tanabe Pharma, Noucor, Novartis, Pharvaris, Sanofi–Regeneron, Santa Ana Bio, Septerna, Servier, Takeda, ThirdHarmonicBio, and Yuhan Corporation., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Chronic spontaneous urticaria (CSU) is a relatively common skin disease associated with hives and angio-oedema. Eosinophils play a role in CSU pathogenesis. Benralizumab, an anti-interleukin-5 receptor-α monoclonal antibody, has been shown to induce nearly complete depletion of eosinophils., Objectives: To determine the clinical efficacy and safety of benralizumab in patients with CSU who were symptomatic despite H1 antihistamine treatment., Methods: The 24-week, randomized, double-blind, placebo-controlled, phase IIb portion of the ARROYO trial enrolled adult patients with CSU who were currently on H1 antihistamine treatment. Patients were randomized to one of five treatment groups according to benralizumab dose and regimen for a 24-week treatment period. The primary endpoint was change from baseline in Itch Severity Score (ISS)7 at week 12. The key secondary endpoint was change from baseline in Urticaria Activity Score (UAS)7 at week 12. Additional secondary endpoints included other metrics to assess CSU at week 24, blood eosinophil levels, and pharmacokinetics and immunogenicity assessments. Exploratory subgroup analyses were conducted to explore responses according to demographics, clinical features and biomarkers. Safety was assessed in all treatment groups., Results: Of 155 patients, 59 were randomized to benralizumab 30 mg, 56 to benralizumab 60 mg and 40 to placebo. Baseline and disease characteristics were consistent with what was expected for patients with CSU. There were no significant differences in change from baseline in ISS7 score at week 12 between benralizumab and placebo [benralizumab 30 mg vs. placebo, least-squares mean difference -1.01, 95% confidence interval (CI) -3.28 to 1.26; benralizumab 60 mg vs. placebo, least-squares mean difference -1.79, 95% CI -4.09 to 0.50] nor in change from baseline in UAS7 score at week 12 between benralizumab and placebo (benralizumab 30 mg vs. placebo, P = 0.407; benralizumab 60 mg vs. placebo, P = 0.082). Depletion of blood eosinophil levels was observed at week 24 in patients treated with benralizumab. All other secondary endpoints and exploratory/subgroup analyses indicated no significant differences between benralizumab and placebo. Safety results were consistent with the known profile of benralizumab., Conclusions: Although benralizumab resulted in near-complete depletion of blood eosinophils, there was no clinical benefit over placebo., Competing Interests: Conflicts of interest S.A. is or recently was a speaker and/or advisor for and/or has received research funding from AstraZeneca, BioCryst, Blueprint, CSL Behring, LEO Pharma, Moxie, Novartis, Pfizer, Pharvaris, Sanofi-Regeneron, Takeda and Thermo Fisher Scientific. A.M.G.-A. is or recently was a speaker and/or advisor for and/or has received research funding from Almirall, Amgen, AstraZeneca, Avene, Celldex, Escient Pharmaceuticals, Genentech, GlaxoSmithKline, Instituto Carlos III-FEDER, LEO Pharma, Menarini, Mitsubishi Tanabe Pharma, Novartis, Sanofi-Regeneron, Servier, Thermo Fisher Scientific and Uriach Pharma/Neucor. J.A.B. has been a consultant for Escient Pharmaceuticals, Jasper Therapeutics and Ono Pharmaceutical, and has been a principal investigator and consultant for Amgen, AstraZeneca, Celldex Therapeutics, Genentech, Novartis and Sanofi-Regeneron. M.M. has received honoraria as a speaker and/or consultant for AbbVie, Amgen, argenx, AstraZeneca, Bayer, Beiersdorf, Celldex, Escient Pharmaceuticals, Galderma, GlaxoSmithKline, Incyte, Jasper Therapeutics, Novartis, Pfizer, Pharvaris, Sanofi, Teva, Third Harmonic Bio and Vifor. L. Bahadori, M.B., L.Brooks, C.N.H., P.J., P.B.L., E.R.-S., C.W. and C.J.D. are or were employees of AstraZeneca at the time of the study and may own stock or stock options., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Anti-Ku autoantibodies are associated with several autoimmune inflammatory diseases. We aimed to review our anti-Ku positive pediatric patients in this study. Four pediatric patients (all female) who had anti-Ku positivity were included (Patients 1-2-3 with idiopathic inflammatory myopathy (IIM); Patient 4 with chronic urticaria). Patient 1 (onset:10.5 years) had proximal muscle weakness, Raynaud phenomenon, sclerodactyly, hyperpigmentation, joint contracture, and tenosynovitis. The disease course was progressive despite treatment with corticosteroids, intravenous immunoglobulin (IVIG), plasma exchange, and 11 different immunosuppressive drugs. Patient 2 (onset:15 years) presented with proximal muscle weakness, fatigue, weight loss. She recovered normal muscle strength after treatment with corticosteroids, IVIG, methotrexate, cyclosporine A, mycophenolate mofetil. Patient 3 (onset:10 years) had juvenile dermatomyositis with proximal muscle weakness, Gottron's papules, and calcinosis. She also had anti-NXP2 positivity. Remission was achieved with corticosteroids, methotrexate, azathioprine, and infliximab. Muscle biopsy findings revealed a variable spectrum of necrosis, regeneration, perifascicular pattern, and inflammation. Patient 4 had only chronic urticaria (onset: 6.5 years). The striking features of this series were heterogeneity in clinical presentations including solely chronic urticaria and IIM; variable response to immunosuppressive treatments; and histopathology revealing a spectrum of necrosis, regeneration and inflammatory infiltration. Expanding the spectrum of anti-Ku positivity will allow better understanding of anti-Ku-associated phenotype clusters., Competing Interests: Declaration of competing interest Ezgi Deniz Batu received payment for the speakers bureau from Novartis. Seza Özen received consultancy fees and payment for speakers bureau from Novartis and Sobi. Other authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Background: Short courses of adjunctive systemic corticosteroids are commonly used to treat acute urticaria and chronic urticaria flares (both with and without mast cell-mediated angioedema), but their benefits and harms are unclear., Objective: To evaluate the efficacy and safety of treating acute urticaria or chronic urticaria flares with versus without systemic corticosteroids., Methods: We searched the MEDLINE, EMBASE, CENTRAL, CNKI, VIP, Wanfang, and CBM databases from inception to July 8, 2023, for randomized controlled trials of treating urticaria with versus without systemic corticosteroids. Paired reviewers independently screened records, extracted data, and appraised risk of bias with the Cochrane 2.0 tool. We performed random-effects meta-analyses of urticaria activity, itch severity, and adverse events. We assessed certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluations (GRADE) approach., Results: We identified 12 randomized trials enrolling 944 patients. For patients with low or moderate probability (17.5%-64%) to improve with antihistamines alone, add-on systemic corticosteroids likely improve urticaria activity by a 14% to 15% absolute difference (odds ratio [OR], 2.17, 95% confidence interval [CI]: 1.43-3.31; number needed to treat [NNT], 7; moderate certainty). Among patients with a high chance (95.8%) for urticaria to improve with antihistamines alone, add-on systemic corticosteroids likely improved urticaria activity by a 2.2% absolute difference (NNT, 45; moderate certainty). Corticosteroids may improve itch severity (OR, 2.44; 95% CI: 0.87-6.83; risk difference, 9%; NNT, 11; low certainty). Systemic corticosteroids also likely increase adverse events (OR, 2.76; 95% CI: 1.00-7.62; risk difference, 15%; number needed to harm, 9; moderate certainty)., Conclusions: Systemic corticosteroids for acute urticaria or chronic urticaria exacerbations likely improve urticaria, depending on antihistamine responsiveness, but also likely increase adverse effects in approximately 15% more., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Chronic spontaneous urticaria (CSU) is a chronic inflammatory disease characterized by recurrent pruritic wheals (hives) and/or angioedema. Patients with CSU could remain symptomatic despite standard-of-care H 1 antihistamines (H1-AH) or anti-IgE (omalizumab) treatment. Dupilumab blocks IL-4/IL-13 signaling and is approved for multiple type 2/atopic indications., Objective: We conducted two phase 3, randomized, placebo-controlled, double-blind trials comparing dupilumab with placebo in patients with symptomatic CSU despite H1-AH., Methods: In LIBERTY-CSU CUPID Study A, patients were omalizumab-naive (n = 138, aged ≥6 years). In Study B, patients were omalizumab-intolerant/incomplete responders (n = 108, aged ≥12 years). The primary end point was either change from baseline over 7 days in the Urticaria Activity Score (UAS7) or Itch Severity Score (ISS7) at week 24, with the other as a key secondary end point, depending on regional regulatory requirements. Studies were pooled for safety assessment., Results: In Study A, UAS7 and ISS7 improved with dupilumab versus placebo (difference -8.5 [95% CI, -13.2 to -3.9; P = .0003] and -4.2 [95% CI, -6.6 to -1.8; P = .0005]). In Study B, tested at α = 0.043 after interim analysis, UAS7 improved (difference -5.8 [95% CI, -11.4 to -0.3; P = .0390]), with a numerical trend in ISS7 (difference -2.9 [95% CI, -5.7 to -0.07; nominal P = .0449, not significant]). Pooled safety data were consistent between dupilumab and placebo and with the known dupilumab safety profile., Conclusions: Dupilumab reduced urticaria activity by reducing itch and hives severity in omalizumab-naive patients with CSU uncontrolled with H1-AH. Although the primary end point for Study B was not met, dupilumab effects were small in patients who were omalizumab-intolerant/incomplete responders., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Chronic spontaneous urticaria (CSU) is a common disease with complex pathogenesis. Patients' clinical characteristics and responses to treatment vary. Objective: We aimed to investigate the role of data obtained from routinely recommended tests in predicting the response to omalizumab, the only biologic agent approved for treatment, and in defining the clinical characteristics of the patients. Methods: A retrospective study of patients who started omalizumab treatment for CSU between 2015 and 2022 at the Department of Dermatology, Pamukkale University, was conducted. Response criteria were based on the urticaria control test, and patients with a urticaria control test score <12 at 6 months were considered treatment non-responders. Eosinophil and basophil counts, neutrophil-lymphocyte ratio (NLR), systemic immune inflammation index (SII), systemic inflammation response index (SIRI), and total immunoglobulin E (IgE) levels of the patients were evaluated before treatment and at the sixth month of treatment. Results: A total of 23.1% of the patients were unresponsive to omalizumab. The response rate to the omalizumab treatment of the patients with a total IgE level ≤ 30 IU/L (n = 4 [5.7%]) was significantly lower than patients with total IgE level > 30 IU/L (n = 66 [94.3%]) (p = 0.015). The mean ± standard deviation SIRI levels were significantly higher in non-responders versus responders (1.53 ± 1.03 versus 1.15 ± 7.76; p = 0.026). Eosinophil counts positively correlated with basophil counts (r = 587; p < 0.001) and IgE levels (r = 0.290; p = 0.005) but a negative correlation was found with levels of NLR (r = -0.475; p < 0.001), SIRI (r = -0.259; p = 0.013), and SII (r = -0.285; p = 0.006). NLR levels were lower in CSU patients with atopy, than in those without atopy (1.9 ± 0.9 vs 2.9 ± 2.1, p = 0.022). Conclusion: We suggest that eosinopenia and high NLR levels are linked to autoimmune CSU. Predicting a poor response to omalizumab seems possible with total IgE levels < 30 IU/L and high SIRI levels.

Background: Chronic urticaria (CU) is a prevalent dermatologic disease that negatively affects life, current therapies remain suboptimal. Hence, there is an urgent need to identify effective and safe treatment., Objective: Assess the efficacy and safety of compound glycyrrhizin (CG) combined with second-generation nonsedated antihistamine for the treatment of CU., Methods: Nine databases were queried to screen RCTs related. Two reviewers independently assessed the risk of bias using Cochrane Collaboration. Primary objective was the total efficiency rate, while secondary was rate of recurrence, adverse events, and cure. Statistical analyses using Review Manager 5.4 and Stata17., Results: Twenty-four RCTs were identified. Significant differences were noted in rate of total efficiency ( n  = 2649, RR = 1.36, 95%CI:1.30-1.43, p  < 0.00001), cure ( n  = 2649, RR = 1.54, 95%CI:1.42-1.66, p  < 0.00001) and recurrence ( n  = 446, RR = 0.34, 95%CI:0.20-0.58, p  < 0.00001) between the combination of CG with second-generation non-sedated antihistamine and antihistamine monotherapy. Contrastingly, adverse events rate ( n  = 2317, RR = 0.76, 95% CI:0.59-0.97, p  = 0.03) was comparable between the two groups. Our results indicated that CG combined with second-generation non-sedated antihistamine could significantly mitigate the symptoms in CU compared with antihistamine monotherapy. No serious adverse events were reported., Conclusions: CG combined with second-generation nonsedated antihistamine is effective for CU. Nevertheless, higher-quality studies are warranted to validate our results.

Background: There is a lack of real-life safety data on treatment options for chronic urticaria in the presence of comedication and comorbidities., Methods: We present a single-center UCARE pilot study of 212 outpatients with chronic urticaria. Patients were divided into three groups according to different CU therapies according to international guidelines., Results: Of 212 patients, 108 (mean age 48.9 years, 71.3% female) had 59 comorbidities, including cardiovascular, autoimmune and malignant diseases. Patients were followed for a mean of 24.6 months (SD ± 21.3). Urticaria therapies were divided into three groups: A: 105 (97.2%) with omalizumab and 2nd generation antihistamines), B: 16 patients (14.8%): dual therapy with antihistamines and cyclosporine in 10 (9.3%), montelukast in five (4. 6%), dapsone in four (3.7%), hydroxychloroquine in one patient (0.9%), C: 12 (11.1%) patients received a third drug for 4.9 months (SD ± 3.2) and one quadruple therapy (2.1 months). 10 out of 12 (83.3%) patients received montelukast, two (16.7%) cyclosporine, two (16.7%) dapsone and one (8.3%) hydroxychloroquine as a third drug for chronic urticaria., Conclusions: Combining treatment modalities for chronic urticaria and comorbidities are available and feasible with a good safety profile.

Purpose of Review: Chronic spontaneous urticaria (CSU) patients sometimes do not respond to second-generation antihistamine, and 10-50% patients do not even respond to four-fold the usual dose of nonsedating H1 antihistamine, which further leads to repeated courses of oral corticosteroids to abate the symptoms. There are third-line agents approved by EAACI guidelines, which include omalizumab and cyclosporine. Certain patients are even resistant to the third-line agents. In this review, various other treatment options will be discussed in patients of refractory CSU., Recent Findings: Recently, we demonstrated azathioprine as a possible third-line option, which was found noninferior to cyclosporine in antihistamine refractory CSU. There have been trials, studies, case series and reports, which suggest other putative options for refractory CSU management., Summary: Studies on the management of refractory CSU are accumulating thereby expanding the armamentarium of dermatologists and allergologist against difficult-to-treat urticaria patients., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Several studies have shown that subcutaneous injections of omalizumab can treat chronic idiopathic/spontaneous urticaria (CIU/CSU) patients by only assessing the efficacy on specific endpoints. This study aimed to quantitatively analyze different doses of omalizumab in CIU/CSU and compare it with ligelizumab., Methods: Literature searches were performed in PubMed, Embase, and Web of Science databases. A model-based meta-analysis (MBMA) was utilized to develop a model incorporating time since the initiation of treatment and dose for omalizumab, with the change from baseline in Urticaria Activity Score (CFB-UAS7) as the primary efficacy endpoint. The time-course and dose-effect relationship throughout the omalizumab treatment period was analyzed, and the findings were compared with those of the investigational ligelizumab., Results: The model equation for the CFB-UAS7 was established as E = -E max  × time/(ET 50 + time) × (b 0 + b 1 × dose). The estimated values of the model parameters E max , ET 50 , b 0 , and b 1 were -1.16, 1.26 weeks, -9.90, and -0.0361 mg -1 , respectively. At week 12 after the first dose, the model-predicted CFB-UAS7 for 150 mg and 300 mg of omalizumab were -16.0 (95% CI, -17.2 to -14.8) and -21.7 (95% CI, -22.9 to -20.5), respectively. In the PEARL-1 trial, the CFB-UAS7 for 72 mg and 120 mg of ligelizumab were -19.4 (95% CI, -20.7 to -18.1) and -19.3 (95% CI, -20.6 to -18.0), respectively. In the PEARL-2 trial, these values were -19.2 (95% CI, -20.5 to -17.9) and -20.3 (95% CI, -21.6 to -19.0), respectively., Conclusion: Omalizumab showed a significant dose-dependent effect in the treatment of CSU. Both 72 mg and 120 mg ligelizumab might have the potential to outperform 150 mg (but not 300 mg) omalizumab., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

To examine the prevalence of comorbidities in Chinese urticaria patients and assess medication use patterns across different ages (6-11 years, 12-17 years, above 18 years), a retrospective cohort study was performed in 192,647 urticaria patients within the Health Database. After 1:1 propensity score matching, 166,921 people were divided into the urticaria group and the control group, and the follow-up data were collected within 2 years. During the 12-month and 24-month follow-up period, significant comorbidities identified included allergic rhinitis and asthma, with distinct patterns observed across age groups. Chronic urticaria patients often have complications, such as allergic rhinitis, upper respiratory infection, oropharyngeal infection, and dental caries. The study underscores the need for age-specific treatment strategies in urticaria management.

Background: Omalizumab is a safe and effective treatment for antihistamine-refractory chronic spontaneous urticaria (CSU) but is insufficient in one-third of patients. For serious cases in which omalizumab is ineffective, cyclosporine or methotrexate may be preferred. Most drug trials in CSU have focused on omalizumab or cyclosporine monotherapy., Objective: This retrospective study evaluated responses to monotherapy or combined therapy and real-life data on the effectiveness and safety of omalizumab in antihistamine-refractory CSU., Methods: A total of 133 patients who received omalizumab due to antihistamine-refractory CSU were evaluated in terms of 7-day urticaria activity score, total IgE, anti-thyroid peroxidase, C-reactive protein, skin prick test with aeroallergens and disease duration. Partial or nonresponders to omalizumab monotherapy were given antihistamine, omalizumab, cyclosporine, and methotrexate as combined or monotherapy., Results: Ninety-eight (73.7%) of the 133 patients were female and the mean age was 40.7 ± 14.4 years; 70.6% of the patients received omalizumab monotherapy and the others received combined or non-omalizumab monotherapy. Omalizumab monotherapy was effective in 66.9% of the patients. Of those with complete response to omalizumab monotherapy, 65.4% had early recurrence after discontinuing treatment. Treatment response was significantly better in patients who had high total IgE (p = 0.001). Patients with longer disease duration had significantly higher likelihood of early recurrence (p = 0.035)., Conclusions: Omalizumab monotherapy was as effective in real life as in placebo-controlled trials. Omalizumab was well tolerated by all patients. Treatment responses were comparable in patients treated with combined therapy and those who received monotherapy.

Background: Clinical trials showed the efficacy of 300 mg/4 weeks of omalizumab (OMA) during 6 months in patients with severe chronic spontaneous urticaria (CSU). Nevertheless, in real life, many patients require higher doses and/or longer treatment. This study assesses the real-life performance of OMA in severe CSU and identifies factors associated with the response., Methods: CSU patients eligible for OMA were recruited prospectively. Clinical data and a blood test were collected before OMA initiation. Urticaria Activity Score 7 (UAS7) was calculated at baseline and every 3 months during OMA treatment. CSU control was defined as UAS7 <7 points. This work was partially sponsored by OMA manufacturer., Results: Eighty-nine adults (19.1% males) with severe CSU were recruited. Median duration of CSU prior to OMA initiation was 2 years, and median severity by UAS7 at baseline was 24 points (range 10-42 points). OMA controlled 94.4% of patients, but 17.9% of responders required doses >300 mg/4 weeks. A blood basophil count >20 cells/μL (OR 13.33; 95% CI 3.32-52.63; p < .001) and the absence of hypothyroidism (OR 3.65; 95% CI 0.78-16.95; p = .099) were identified as predictive factors to achieve control with 300 mg/4 weeks. Twelve patients were able to stop OMA during the study (responders in remission, RR). RR had received OMA for a median of 29 months (12-53 months). Conversely, 32 patients had been on OMA for >29 months at the end of the study (active responders, AR). AR had received OMA for a median of 45 months (30-100 months). There were no significant differences in clinical or analytical factors between RR and AR patients., Conclusions: Low blood basophil count and the presence of hypothyroidism might serve as biomarkers for the controller dose of OMA in severe CSU patients., (© 2024 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.)

Aim: Neurogenic inflammation has been recognized as an important contributing factor in the pathogenesis of allergic rhinitis. The aim of this study was to investigate the clinical values of substance P, vasoactive intestinal peptide (VIP), and neuropeptide Y as biomarkers of disease severity and treatment outcomes of chronic urticaria complicated with allergic rhinitis., Methods: Our prospective study included 150 patients with chronic urticaria complicated with allergic rhinitis and 80 healthy control patients. Before treatment, the serum samples of all study subjects were collected and analyzed using enzyme-linked immunosorbent analysis. The intervention group received imipramine of 10 mg/day orally for 2 weeks, and the Symptom Score Reduction Index (SSRI) was used to analyze clinical outcomes, which were categorized as effectual and ineffectual., Results: Our data suggested that substance P, VIP, and neuropeptide Y were significantly correlated to each other. Lower levels of substance P, VIP, and neuropeptide Y were associated with better treatment outcomes. A good detection sensitivity (69.49%) and specificity (80.22%) could be achieved using a combination of these markers (area under curve = 0.85)., Conclusions: Our data indicates that substance P, VIP, and neuropeptide Y levels before treatment correlate strongly with the treatment outcomes of the patients, which could potentially serve as a decision support tool in clinical management of chronic urticaria complicated with allergic rhinitis., (© 2023. The Author(s), under exclusive licence to Royal Academy of Medicine in Ireland.)

Introduction: This study examined the remission probability and duration in chronic spontaneous urticaria (CSU) patients resistant to second-generation H1-antihistamines (sgAHs) undergoing omalizumab treatment., Methods: This is a retrospective observational study of 176 adult CSU patients exhibiting a significant pruritus component (≥ 8) of the weekly urticaria activity score (UAS7) despite four daily sgAH tablets and starting omalizumab treatment with 300 mg every 4 weeks. After excluding 13 nonresponders, we analyzed 163 omalizumab responders (mean age 51.8 years, 74.4% female). The intervals between applications were increased. Discontinuation was considered for patients that remained asymptomatic on a gradually reduced dosage (to 150 mg every 12 weeks) without sgAHs., Results: Omalizumab discontinuation was possible in 25.8% (42/163). The duration of omalizumab treatment before remission ranged from 7 to 63 months. Twenty-one patients (50.0%) maintained complete remission until the end of the observation period (September 2021) for 8 to 68 months. Of the relapsed patients, 71.4% (15/21) effectively controlled CSU with sgAHs. Six patients (28.6%; 6/21) required omalizumab reintroduction after 6 to 40 months of remission, responding favorably., Conclusions: The study shows that a quarter of severe CSU patients achieve long-term remission. In addition, sgAHs effectively manage symptoms in a majority of relapsed cases, and those requiring omalizumab reintroduction respond favorably.

Background: Chronic spontaneous urticaria (CSU) is frequently associated with psychiatric comorbidities., Objective: We aimed to determine if depressive symptoms were present in CSU patients who received omalizumab and if depression scores got better with omalizumab treatment and whether the presence of depressive symptoms impaired treatment responses., Methods: CSU patients who received at least three injections of omalizumab were included in the study. Changes in Urticaria Activity Score (UAS), Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL), Beck Depression Inventory (Beck-D) and Urticaria Control Test (UCT) scores were compared before and after treatment., Results: From 49 patients, 20 (40.8%) had depressive symptoms at baseline. After treatment, UAS7, CU-Q2oL, Beck-D scores decreased and UCT-scores increased significantly (p < 0.001, for all). UCT scores were lower at baseline and at 3rd month following treatment in patients with depressive symptoms compared to patients without (baseline median (interquartile range-IQR) 2.5 (1-5) vs 5 (2.5-6.5); p = 0.04 and 3rd month 12 (9-13) vs 14 (12-16); p = 0.006, respectively). Omalizumab non-responders had higher baseline Beck-D-scores [18.5 (15.2-22) vs 12 (6-22.5); p = 0.031]. The number of omalizumab non-responders were significantly higher among patients with depressive symptoms compared to patients without. (40% vs 13.8%; p = 0.048). Only 6 patients scored as having depressive symptoms after treatment; of these 6 patients only one was an omalizumab responder., Conclusions: Omalizumab not only provides symptom control for urticaria but also improves psychological conditions of the patients. Coexistent psychiatric comorbidities should be taken into account in CSU patients since these conditions might impair treatment response.

While several studies have examined the role of T cells and related cytokines in the development of chronic spontaneous urticaria (CSU), there is a limited amount of research focusing on the changes in cytokine levels during omalizumab treatment. The primary objective of this study was to investigate the inflammatory cytokine profile (including IL-4, IL-5, IL-10, IL-13, IL-17, IL-31, IL-33, and TNFα) among CSU patients undergoing to omalizumab treatment. Plasma levels of cytokines were measured using ELISA. Measurements were taken before CSU treatment, at the 3rd and 6th months of omalizumab treatment, and once in the control group. The severity of the patients' disease was assessed using the weekly Urticaria Activity Score(UAS7), and disease control was evaluated using the Urticaria Control Test(UCT). Thirty-one CSU patients and 56 age- and gender-matched healthy controls were included. Plasma levels of IL-4 and IL-33 were significantly lower in patients with CSU compared to healthy controls (p = 0.001; p = 0.038, respectively). During omalizumab treatment, IL-4 levels showed a significant increase in the 3rd month compared to baseline (p = 0.01), and IL-5 levels significantly decreased in the 6th month compared to both the 3rd month and baseline (6th month vs. baseline; p = 0.006, 6th month vs. 3rd month; p = 0.001). One potential mechanism of action for omalizumab may involve its regulatory effects on type 2 inflammatory cytokines in CSU patients. This finding partially explains the efficacy of anti-IL-4/13 treatments in chronic spontaneous urticaria. Further investigations on drugs targeting type 2 inflammatory cytokines in CSU are warranted., (© 2024. The Author(s).)

Background: Cholinergic urticaria (CholU) is a common subtype of chronic inducible urticaria, where signs and symptoms (e.g. pruritic wheals and angioedema) are triggered by sweating due to physical exercise, passive warming and by other sweat-inducing situations. While guidelines recommend treatment with second-generation H1 antihistamines, approximately 90% of patients report uncontrolled disease. Targeting the histamine 4 receptor (H4R) has shown promise in preclinical/clinical studies of allergic/inflammatory diseases. Izuforant (LEO 152020) is a selective oral H4R antagonist with expected dual antipruritic and anti-inflammatory effects., Objectives: To assess the effects of izuforant in adults with CholU, a common type of chronic urticaria driven by histamine and characterized by high skin levels of H4R expression., Methods: This was a phase IIa randomized double-blind placebo-controlled multicentre crossover trial where patients with CholU with an inadequate response to ≥ 1 standard dose of H1 antihistamine received izuforant 100 mg twice daily or placebo (EUCTR2020-004961-38-DE; NCT04853992). The primary endpoint was change from baseline in Urticaria Activity Score. Exploratory endpoints included CholU activity score over 7 days, urticaria control test, Physician Global Assessment, patient global assessment of severity (PGA-S), provocation tests, Dermatology Life Quality Index and CholU quality of life (CholU-QoL). Pharmacokinetic and pharmacodynamic parameters, and serum biomarkers were assessed, as well as safety and tolerability., Results: Nineteen patients were randomized and included in the full analysis set; 18 completed treatment [mean (SD) age 29.5 (9.8) years; mean (SD) CholU duration 8.0 (6.3) years]. The primary and most of prespecified exploratory endpoints were not met; there were significant improvements in PGA-S for izuforant vs. placebo (P = 0.02), and nonsignificant improvements for other endpoints in quality of life and histamine skin prick test. All adverse events (AEs) experienced with izuforant were considered mild. The most frequently reported (> 1 patient) were nausea (three patients) and upper abdominal pain (two patients), occurring more frequently with izuforant vs. placebo (one patient each). There were no treatment-related serious AEs and no patient receiving izuforant discontinued the study. Treatment with izuforant did not cause downregulation of H4R., Conclusions: This is the first study to explore the role of H4R as a therapeutic target in urticaria. Targeting H4R with izuforant was well tolerated but did not demonstrate significant improvements vs. placebo in the primary endpoint and all but one prespecified exploratory endpoint in CholU., Competing Interests: Conflicts of interest E.G. was an advisor for Novartis. M. Metz is or recently was a speaker and/or advisor for Amgen, AstraZeneca, argenx, Celldex, Escient, Jasper Therapeutics, Novartis, Pharvaris, Sanofi-Aventis and Third Harmonic Bio. S.A. is or recently was a speaker and/or advisor for and/or has received research funding from AstraZeneca, Allakos, Biocryst, CSL Behring, Phavaris, Sanofi, Takeda, ThermoFisher, Moxie and Novartis. A.B. is or has recently been a speaker/advisor/investigator and/or received research funding from AbbVie, Almirall, Amgen, AstraZeneca, Biofrontera, Blueberry Therapeutics, Celldex, Centogene, Galderma, Genentech, Gilead, Incyte, LEO Pharma, Lilly, L’Oréal, Novartis, Sanofi, Regeneron and Shire/Takeda. L.L. has received consulting fees/medical writing/direction strategy fees from Regeneron, Celldex, Gossomer Bio, Kenjockety, Gamida Cell, Arvelle Therapeutics, Sun Pharma, Halozyme, UCARE and Noema Pharma. K.B. is or recently was a speaker and/or advisor for AstraZeneca, Novartis, Biomarin, Synlab, Blueprint, ThermoFisher, Bencard and ALK. G.H. declares grants from Deutsche Forschungsgemeinschaft (DFG) and personal fees from Allergopharma, Biotest, Eli Lilly, Sanofi, AbbVie and Leti outside the submitted work. K.K.S., T.H. and O.E.S. are employees of LEO Pharma. M. Maurer is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, Alvotech, Amgen, Aquestive, Aralez, AstraZeneca, Astria, Bayer, BioCryst, Blueprint, Celldex, Celltrion, Centogene, CSL Behring, Evoemmune, GSK, Ipsen, Kalvista, Kyowa Kirin, LEO Pharma, Lilly, Menarini, Mitsubishi Tanabe Pharma, Moxie, Noucor, Novartis, Orion Biotechnoloy, Pharvaris, Resonance Medicine, Sanofi/Regeneron, Septerna, Takeda, Teva, Trial Form Support International AB, Third HarmonicBio, Valenza Bio, Yuhan Corporation and Zurabio., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Chronic spontaneous urticaria (CSU) poses significant challenges, especially in pediatric and adolescent patients, impacting physical, emotional, and social well-being. Recent biologic breakthroughs offer promise, however, data on safety and efficacy in this population remain limited., Areas Covered: This review examines current biologic treatments in pediatrics and adolescents with CSU and explores the rapidly emerging landscape., Expert Opinion: Despite omalizumab's approval for allergic asthma in children since 2009, its delayed approval for CSU raises questions. Ligelizumab, a next-generation anti-IgE mAb, showed effectiveness in adults but lacks pediatric studies. CT-P39, a biosimilar to omalizumab, demonstrates promise, yet adolescent-specific outcomes are undisclosed. Dupilumab's recent approval for atopic dermatitis in children from 6 months onwards signifies progress. Expert opinion underscores the scarcity of controlled trials in pediatric and adolescent CSU, emphasizing the need for comprehensive studies. Age-specific data and collaboration are crucial for addressing research gaps and expanding indications for pediatric CSU treatment. The recently validated UAS7 parameter in children marks a milestone for prospective clinical trials. Despite challenges, the biology therapy outlook for pediatric and adolescent CSU is promising. Importantly, studies indicate that pediatric CSU is at least as prevalent as in adults, highlighting the need for approved treatments in this population.