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Chronic inducible urticaria (CIndU) is characterized by wheals and/or angioedema for longer than 6 weeks induced by specific triggers. The data regarding epidemiology of CIndU is scarce with limited available literature on urticaria severity, investigations, and treatment responses in CIndU compared to CSU. We performed a retrospective chart review of all CIndU patients(cases) enrolled in our Urticaria clinic, past seven years between January 2017 to December 2023. Equal number of CSU patients enrolled during study period were taken as controls. Patients with absence of weals and both CSU and CIndU were excluded from the study. Urticaria severity was assessed by Urticaria activity score over 7 days (UAS7). Statistical analyses were performed using SPSS V29 with P < 0.05 as significant. Out of all records screened, 222 CIndU (cases) and 226 CSU (controls) were eligible based on complete availability of data. Both groups were comparable in terms of age and gender with slight female preponderance. Mean UAS7 at baseline was comparable(p = 0.619) between two groups [(11.49 ± 10.37 in CIndU vs. 10.9 ± 12.2 in CSU)]. The mean CRP (mg/dl) levels for CIndU vs. CSU patients was 2.8 ± 4.2 vs. 6.9 ± 11.2 (p < 0.001). Serum D-dimer levels (mg/dl) were also significant between cases(167 ± 220) and controls(265 ± 452) (p = 0.020). The quality of life assessed by CU-QOL score was 9.39 ± 9.5 in CIndU vs. 16 ± 14.8 in CSU (p < 0.001). 80% of CIndU patients and 52% of CSU patients required updosing of antihistamines upto 4 times and the difference was statistically significant between two groups(p = < 0.001). The mean time taken to achieve remission i.e. UAS7 = 0 (T 0 ) was 60 ± 42 days amongst CIndU while it was shorter in CSU (27.77 ± 27 days) (p < 0.001).Amongst all CIndU cases, commonest subtypes were symptomatic dermographism (SD) (39.5%) followed by cholinergic urticaria(4.2%) and cold urticaria(1.8%). Our study underscores the distinct clinical and laboratory profiles between CIndU and CSU patients. CIndU patients exhibit poorer response to standard antihistamine doses, requiring more frequent updosing and longer treatment duration. The time to attain remission as assessed by UAS7 score was also longer in CIndU patients than CSU patients (mean difference of 33 days). Further research is warranted to elucidate the underlying mechanisms and explore targeted treatment approaches for CIndU., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

BACKGROUND Chronic urticaria (CU) is a skin condition causing itchy hives that can significantly impact quality of life. While medications like omalizumab can help, some patients may seek additional relief. This study aimed to investigate the potential benefits of acupuncture, a traditional Chinese medicine practice, as an adjunctive therapy alongside omalizumab for CU patients. MATERIAL AND METHODS We enrolled 31 CU patients who received acupuncture in addition to omalizumab (study group) and 30 CU patients who received omalizumab only (controls). Mean scores of each CU-Quality of life (QoL) and urticaria control test (UCT) scores after acupuncture were compared with the pre-acupuncture scores and with the scores of the controls. RESULTS There was no significant difference in mean food limitation, symptom embarrassment, cosmetics, and sports scores before and after acupuncture (P>0.005). Other CU-QoL scores were significantly lower after acupuncture compared to pre-acupuncture scores (P<0.005). Mean total CU-QoL score was significantly lower (P<0.001) and mean UCT score was significantly higher (P=0.001) after acupuncture compared to pre-acupuncture scores. There was no significant difference in free time, falling asleep, waking up at night, tiredness, concentration, symptom embarrassment, public embarrassment, cosmetics, clothing limitation, and sports scores between the acupuncture and control groups (P>0.005). Other CU-QoL scores were significantly lower in the acupuncture group compared to the controls (P<0.005). Mean total CU-QoL score was significantly lower (P=0.006) and mean UCT score was significantly higher (P<0.001) in acupuncture group compared to the controls. CONCLUSIONS Acupuncture is an effective adjunctive therapy for CU patients already receiving omalizumab, and can improve quality of life and disease control in these patients.

In clinical practice, some cases of chronic spontaneous urticaria (CSU) remain difficult to treat, with up to 40% of patients showing no response to even high (4-fold) daily doses of antihistamines. Approximately 30% of CSU patients fail to achieve complete control and relief through treatment with omalizumab and may require alternative therapies. Abrocitinib is a small-molecule oral JAK1 inhibitor that suppresses intracellular signaling of multiple key cytokines involved in inflammation cascades, and has shown beneficial effects in patients with mast cell activation disorders. We conducted a retrospective analysis of the diagnosis and treatment records of adult patients with refractory CSU who were treated with abrocitinib after inadequate response to omalizumab (defined as no response to 300 mg/4 weeks of omalizumab treatment for 6 months, followed by adjustment to 300 mg/2 weeks for a further 3 months without controlling symptoms). We also collected data on relevant treatment modalities, clinical outcomes, and adverse events. Among these patients, various treatment modalities failed to adequately control symptoms, but switching to abrocitinib significantly improved clinical outcomes. Therefore, abrocitinib may represent a new treatment option for patients with refractory CSU., 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 Du, Wang, Yang, Zhang, Lyu, Min and Zhao.)

Chronic urticaria can be divided into 2 subsets: chronic spontaneous urticaria (CSU) with skin lesions occurring without a specific trigger and chronic inducible urticaria, which has an identified specific stimulus. The annual prevalence of chronic urticaria is 0.5% to 2.3% globally. The CSU is a self-limited disorder in most cases, with an average duration of 2 to 5 years, but symptoms persist beyond 5 years in up to 30% of patients. The first line of treatment is a daily nonsedating, second-generation H1-antihistamine. The CSU guidelines recommend using oral nonsedating antihistamines up to 4 fold in patients with CSU unresponsive to standard doses as the next step in treatment. A meta-analysis found that the rate of response in patients with CSU who responded to updosing was 63.2%. Therefore, approximately 40% of patients continue to have persistent hives and itching requiring treatment with the biologic omalizumab, based on evidence from randomized controlled trials. Although omalizumab has been shown to markedly relieve symptoms of CSU, omalizumab is not effective in all patients and has not been shown to induce long-term disease remission. Thus, there is an unmet need for more effective treatments that can lead to cure or long-term remission. In this review, we will provide an overview of new treatment targets and biologics that are under investigation for the treatment of CSU., Competing Interests: Disclosures Dr Saini reports receiving grant, research, and/or clinical trial support from the National Institutes of Health, Novartis, Sanofi, Regeneron, Amgen, Allakos, and Escient and served as a consultant or advisory boards to Allakos, Granular Therapeutics, Novartis, Aquestive, Regeneron, Escient, Innate, Celltrion, and Sanofi. Dr Min has no conflicts of interest to report., (Copyright © 2024. Published by Elsevier Inc.)

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.)

Chronic urticaria (CU) is characterized by weals (hives) angio-oedema (or both) that last for ≥ 6 weeks, with chronic spontaneous urticaria (CSU) being the most common subtype. Patients with omalizumab-refractory CSU represent an unmet clinical need. In this study, we aimed to assess the prevalence and predictors of omalizumab failure in a large cohort of patients with CU and assess the effectiveness of dupilumab for omalizumab-refractory CU. Of 338 patients with CU, 33 received omalizumab; 69.7% (n = 23) were responders and 30.3% (n = 10) were nonresponders. Bivariate regression demonstrated that female sex [adjusted odds ratio (aOR) 1.53, 95% confidence interval (CI) 1.14-2.06], higher baseline weekly urticaria activity score (aOR 1.05, 95% CI 1.01-1.09) and older age (controlling for sex) (aOR 1.00, 95% CI 1.00-1.01) were associated with omalizumab failure. Of 10 patients with omalizumab-refractory CU, 3 were well controlled with ciclosporin (all children), whereas the 7 adults failed a mean [standard deviation (SD)] of 5.6 (2.6) treatments, including ciclosporin. All seven achieved a complete response with dupilumab, with time to response varying between 1 and 6 months. While our results suggest a favourable efficacy of dupilumab in patients with omalizumab-refractory CU, future confirmatory studies are required., Competing Interests: Conflicts of interest EN has been a speaker or consultant, or has received investigator-initiated research funding from AbbVie, Arcutis, Bausch Health, Boehringer Ingelheim International, Bristol Myers Squibb, Galderma, Janssen, LEO Pharma, Medexus, Novartis Pharmaceuticals, Pfizer, Sanofi Genzyme, Sun Pharmaceuticals, Eli Lilly and UCB. EN is the founder of Montreal Derm FilEZ website, which is a non-profit educational resource. M.B.-S. is a consultant for Novartis and Sanofi. The other authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Background: For treating patients with refractory chronic spontaneous urticaria (CSU) resistant to standard doses of 2 nd generation H1-antihistamines (H1AH) the International and Japanese guidelines recommend increasing H1AH dose. The latter also recommends switching to a different H1AH. This study explored if the efficacy of the standard dose of bilastine 20 mg is non-inferior to that of double-dose of H1AH in patients with refractory CSU., Methods: This phase IV, multicenter, open-label, randomized, parallel-group trial evaluated the efficacy and safety of switching treatment to bilastine compared to treatment with a 2-fold dose of H1AH in patients with CSU refractory to standard dose H1AH. The primary endpoint was the mean total symptom score (TSS) at Day 5-7 after the start of administration., Results: Treatment efficacy and safety were evaluated in 128 patients (bilastine, n=64; 2-fold dose of H1AH, n=64). The mean TSS at Day 5-7 after the start of administration was smaller than the non-inferiority margin of 0.8, demonstrating non-inferiority of the bilastine switching group to the double-dose H1AH group (0.17 (95% CI -0.32, 0.67)). No difference in Japanese version of Epworth Sleepiness Scale (JESS), DLQI, and urticaria activity score over 7 consecutive days (UAS7) was observed between the two groups. There were no serious adverse events in either group. H1AH-related adverse events occurred in 5 subjects (8 cases) and 2 subjects (3 cases) in the double-dose H1AH and bilastine groups, respectively., Conclusions: Switching treatment to bilastine demonstrated non-inferiority to a double-dose of H1AH in terms of efficacy in patients with CSU refractory to standard dose H1AH with a favorable safety profile., Clinical Trial Registration: https://jrct.niph.go.jp/latest-detail/jRCTs051180105, identifier jRCTs051180105., Competing Interests: AF reports study grants and honoraria from Novartis and Taiho, and honoraria as a speaker from Sanofi, Kyowa Kirin, Kyorin, Mitsubishi-Tanabe, and Kaken Pharmaceutical. KM reports speaking fees from Sanofi, Eli Lilly Japan K.K. Maruho Co. Ltd, Mitsubishi Tanabe Pharma Corporation, and honoraria as an investigator of Eli Lilly Japan K.K. MJ reports study grants from Sanofi. KW reports speaking fee from Sanofi, Novartis, Eli Lilly, Pfizer, Kyowa Kirin, Otsuka Pharmaceutical, Mitsubishi-Tanabe, Kyorin, and Taiho. HA declares receiving consulting fees and speaker fees from Taiho. ST reports research grant from Sanofi, Maruho, Tanabe-Mitsubishi, Eli Lilly, Torii and Taiho Pharmaceutical, honorarium from Tanabe-Mitsubishi, Taiho Pharmaceutical, CSL Behring, Kaken, Maruho, Otsuka and Abbvie, advisory fees from Sanofi, and gift of a medication for a clinical study from Takeda. NIs reports study grants from Maruho. KH reports study grants and honoraria from Kaken Pharmaceutical, Kyowa Kirin, Meiji Seika Pharma, Mitsubishi-Tanabe, and Taiho, and honoraria as a speaker from Kyorin, and honoraria as a speaker and advisory fees from Novartis and Sanofi. NIn reports study grants and honoraria from Taiho, and honoraria as a speaker from Sanofi, Novartis, Kyowa Kirin, Mitsubishi-Tanabe, and Kaken Pharmaceutical. MH has received lecture and/or consultation fees from Kaken Pharmaceutical, Kyorin Pharmaceutical, Kyowa-Kirin, Mitsubishi Tanabe Pharma, Novartis, Sanofi/Regeneron, TAIHO Pharmaceutical, and Teikoku Seiyaku. The remaining 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 Fukunaga, Kakei, Murakami, Kan, Masuda, Jinnin, Washio, Amano, Nagano, Yamamoto, Otsuka, Takahagi, Takenaka, Ishiguro, Hayama, Inomata, Nakagawa, Sugiyama and Hide.)

Background: The anti-pruritic effect of placebo in patients with chronic urticaria has gained increasing attention in clinical research. However, the extent of placebo effect and its influencing factors in the treatment of chronic urticaria are not well understood., Objective: The objective of this systematic review and meta-analysis was to investigate the effect of placebo on pruritus in patients with chronic urticaria and to explore relevant influencing factors., Methods: PubMed, Embase, Web of Science, Cochrane Library, and PsycINFO were searched from inception to 10 July, 2024. Primary outcome included pruritus scores. The secondary outcomes focused on global symptoms and quality of life. Subgroup analyses and meta-regression analyses were conducted based on drug types, sample size, participants' age, and other variables. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system and a trial sequential analysis were employed to establish the reliability of evidence., Results: A total of 65 eligible publications (including 67 randomized controlled trials) involving 10,704 patients with chronic urticaria were included. The pruritus scores decreased following placebo treatment (moderate evidence). In addition, favorable results were observed in global symptoms (moderate evidence) and quality of life (low evidence) after placebo treatment. Subgroup analyses indicated that the type of active medication in intervention groups was an influencing factor of placebo effect of pruritus. Meta-regression analyses demonstrated that the anti-pruritic effect of placebo was inversely correlated with sample size and positively correlated with participants' age. A trial sequential analysis provided further support for the anti-pruritic effect of placebo., Conclusions: A substantial improvement of pruritus after placebo treatment was observed in patients with chronic urticaria. The anti-pruritic effect of placebo varied with sample size, participants' age, and type of active medication used. Future research should further investigate the effect size of placebo and clarify the potential mechanism., Prospero Registration: The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) as CRD42023482608., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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.)

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.

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.)

Introduction: Biomarkers that could reliably anticipate the effectiveness of antihistamines and omalizumab in treating chronic spontaneous urticaria (CSU) have not been conclusively identified. Our objective was to examine how eosinophilic cationic protein (ECP), tryptase, D-dimer, and total Immunoglobulin E (IgE) impact the response to antihistamine and omalizumab treatments in individuals with CSU., Methods: In this cross-sectional retrospective study, CSU patients that had undergone treatment with either antihistamines or omalizumab for a minimum of 12 weeks between 2015 and 2021 at an Allergy and Immunology Department were analyzed. Several demographic and laboratory parameters including eosinophil counts, mean platelet volüme (MPV), sedimentation, C-reactive protein (CRP), antinuclear antibodies (ANA) and Anti-thyroperoxidase (Anti-TPO) and total IgE, tryptase, ECP and D-dimer were retrived from patient files. The association of these biomarkers with Urticaria Control Test (UCT) and the effect of these biomarkers on treatment response were evaluated. Treatment response was assessed using the UCT, with a score of UCT ≥ 12 indicating a responder and UCT < 12 indicating a non responder., Results: The patients in the omalizumab group were older, had a longer disease duration and had worse urticaria control (lower baseline UCT scores). 421 patients were treated with antihistamines and 88 patients were treated with omalizumab. ECP was found to be inversely correlated with baseline UCT ( p  < 0.001 r=-0.268). ECP and D-dimer levels of non-responder patients in the antihistamine group were significantly higher than in responder patients (ECP: 49 ng/mL vs 28.1 ng/mL, p  < 0.001) (D-dimer: 0.60 mg/L vs 0.30 mg/L, p  < 0.001), while there were no significant difference in terms of tryptase and total IgE. These four biomarkers were similar, in omalizumab responders and non responders., Conclusion: In this study with CSU, we looked at predictors of responses to treatments. ECP can serve as a marker of poor urticaria control and may predict antihistamine refractoriness along with D-dimer.

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.

Antihistamine refractory chronic spontaneous urticaria (CSU) has a prevalence of up to 50%. Anti-immunoglobulin E (IgE) therapies have revolutionized management of CSU, yet refractory cases persist, suggesting a role for biologic agents that impact alternative routes of mast cell stimulation independent of cross-linking at FcεR1. This review addresses anti-IgE and Th2-targeted therapies in the management of CSU. In addition, we explore novel treatments targeting alternative pathways of mast cell activation including MAS-related G protein-coupled receptor-X2 and sialic acid-binding immunoglobulin-like lectin-6, inhibiting intracellular signaling via Bruton's tyrosine kinase, and disrupting KIT activation by SCF., Competing Interests: Disclosure J.S. Bernstein has no conflicts of interest to disclose. J.A. Bernstein has served as PI and consultant for Sanofi Regeneron, Novartis, Genentech, Amgen, GSK, Celldex, Jasper, Escient, Astra-Zeneca, Allakos, Blueprint, Cogent, Telios, CSL Behring, Takeda/Shire, Pharming, Biocryst, Kalvista, Ionis, Biomarin, GSK, and Merck. Serves on AAAAI BOD, WAO BOD, Interasma BOD, UCARE COE, and AIM COE as well as on the editorial boards for Journal of Allergy and Clinical Immunology, Journal of Allergy and Clinical Immunology: In Practice, Annals of Allergy, Asthma and Clinical Immunology, Allergy and Asthma Proceedings. D.M. Lang has served as a consultant for, received honoraria from, and/or has carried out clinical research with AstraZeneca, Blueprint, Celldex, Genentech, Novartis, Sanofi-Regeneron, serves as Guest Editor for Journal of Allergy and Clinical Immunology in Practice, and also on the Editorial Boards of Allergy and Asthma Proceedings and DynaMed, and Delegate to National Quality Forum representing the American Academy of Allergy, Asthma, and Immunology., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background and Study Aim: Data from the AWARE study (A Worldwide Antihistamine-Refractory chronic urticaria patient Evaluation) illustrate a substantial disease burden in German patients with H1-antihistamine (-H1-AH)-refractory chronic spontaneous urticaria (CSU). Detrimental effects on patients' quality of life, poor disease control and impairment in the ability to work and perform other daily activities are reported. Based on these findings, this study aims to quantify the epidemiological and socio-economic burden of H1-AH-refractory CSU in Germany., Methods: To determine the epidemiological burden of H1-AH-refractory CSU, the age- and gender-specific prevalence of CSU and the proportion of H1-AH-refractory patients in Germany anonymized data from the InGef research database have been used. In a second step, the socio-economic burden in terms of lost numbers of hours in paid and unpaid work was calculated by extrapolating the age- and gender-specific work productivity and activity impairment (WPAI) observed in AWARE to the H1-AH-refractory CSU population in Germany. Finally, productivity losses in paid and unpaid work were monetized using the human capital and the friction cost approach respectively. Moreover, socio-economic burden was calculated depending on symptom control of the patients (measured by urticaria control test [UCT])., Results: In Germany, over 203,000 patients (20 years or older) had H1-AH-refractory CSU in 2018. The avoided lost paid and unpaid work hours attributable to H1-AH-refractory CSU summed up to over 100 million. Overall, the socio-economic burden of H1-AH-refractory CSU in monetary terms was evaluated at € 2.2 billion and the majority of this was due to unpaid work loss. Patients with poor disease control, as indicated by UCT score < 12, were more likely to suffer from high impairment than patients with controlled disease, resulting in a higher socio-economic burden., Conclusions: The results of our analyses picture the substantial socio-economic burden of H1-AH-refractory CSU and therefore the tremendous impact it has on daily lives of individuals and society overall., (© 2024 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

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: Hymenoptera stings can produce IgE-mediated reactions, toxic reactions, or atypical reactions, which are rare. Cold urticaria has been described among the cutaneous manifestations in the atypical ones, but there is only one case of chronic urticaria., Case Report: A 56-year-old female patient experienced palmoplantar pruritus and generalized urticaria 60 minutes after two vespid stings, requiring medical assistance and several cycles of home treatment with oral antihistamines and corticosteroids for resolution in 12 weeks. Allergological studies showed normal tryptase and primary sensitization to Polistes dominula venom. Given the patient's profession, venom immunotherapy was started with Polistes dominula 100% without recurrence of urticaria after its administration., Conclusions: We present a case of IgE-mediated systemic reaction followed by self-limited chronic urticaria, related chronologically to the same vespid sting trigger.

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.