Pavel Kolkhir

Mast cells (MCs) are the principal effector cells in urticaria, orchestrating the release of mediators that drive wheal formation, angioedema, and pruritus. Although activation of MCs via the immunoglobulin (Ig) E and its high-affinity receptor (FcϵRI) axis, including autoimmune urticaria mediated by IgE and IgG autoantibodies, remains the best characterized pathway, increasing evidence indicates that additional mechanisms contribute to disease pathogenesis. These include Mas-related G protein-coupled receptor X2 (MRGPRX2), c-Kit (key regulator of mast cell differentiation, proliferation, and survival), complement, coagulation, and the microbiome. Emerging data suggest that multiple pathways may coexist and interact within individual patients. Variability in the relative contribution and interaction of these pathways likely underlies the clinical heterogeneity of urticaria and the differences observed in therapeutic responses. Improved characterization of molecular endotypes and identification of reliable biomarkers, will be essential for advancing precision medicine in urticaria, especially as emerging therapies, including BTK, KIT, and JAK inhibitors, provide opportunities to selectively target distinct components of disease pathogenesis. This review provides an overview of key players, signaling pathways and molecular mechanisms involved in MC activation and degranulation in urticaria, focusing on chronic urticaria, especially chronic spontaneous urticaria.

Chronic urticaria is a mast cell–driven inflammatory disease characterized by recurrent wheals, angioedema or both for more than 6 weeks, with substantial effects on sleep, quality of life, mental health and daily functioning. Type I autoallergic and type IIb autoimmune mechanisms represent major endotypes, but many patients show overlapping or mixed features, contributing to heterogeneous clinical courses and variable treatment responses. Current management relies on confirming the diagnosis, excluding differential diagnoses, identifying aggravating factors and comorbidities and monitoring disease activity and control using validated patient‐reported outcome measures. A limited, clinically guided diagnostic workup is preferred, with extended investigations reserved for selected cases based on history, examination, red flags or isolated angioedema. Second‐generation H1‐antihistamines remain the first‐line therapy, with up‐dosing recommended in insufficient responders. Omalizumab has transformed the treatment of antihistamine‐refractory disease, while newer options such as dupilumab and remibrutinib further expand the therapeutic landscape. Ciclosporin remains an effective option in selected patients, particularly those with severe or difficult‐to‐treat disease, but requires careful safety monitoring. In chronic inducible urticaria, provocation testing, threshold assessment, trigger counselling and individualized treatment are central to care. Despite recent advances, important unmet needs remain, including reliable biomarkers for endotyping, evidence‐based selection among emerging therapies, better data in children and other special populations, standardized definitions of remission and relapse and disease‐modifying strategies. Future management is expected to move towards biomarker‐driven, personalized care, enabling more precise treatment selection and sustained disease control.

Background and Objective Symptomatic dermographism (SD), the most common chronic inducible urticaria subtype, manifests as strip-shaped, pruritic wheals after skin friction. Conclusive data on its associated factors are limited, and direct comparisons between individuals with and without SD remain scarce. We aimed to identify factors associated with SD internationally. Methods The PREVALENCE-D (Prevalence Estimation of Dermographism) study was an international cross-sectional survey conducted from 2021 to 2024 across 19 countries. An expert-designed questionnaire diagnosed SD and assessed potential associated factors. SD participants were defined as those who self-reported chronic recurrent urticarial dermographism with itch. Factors associated with SD were identified by comparing participants with and without SD. Results Of 68,513 participants, 3101 had SD (female 73.3%). Their mean age was 40.2 ± 16.2 years. Key factors associated with SD included atopic dermatitis (adjusted odds ratio [aOR] 4.20, 95% confidence interval [CI] 3.62‒4.88) and allergic rhinitis (aOR 2.11, 95% CI 1.88‒2.37). Participants with at least one atopic condition (allergic rhinitis, atopic dermatitis, or asthma) were significantly more likely to have SD (aOR 2.70, 95% CI 2.47‒2.95). Those with all three atopic conditions had a further increased likelihood of SD (aOR 7.75, 95% CI 5.31‒11.29). Other associations included working and older age groups, female sex, dyslipidemia, and thyroid disease. Conclusions Atopic dermatitis and allergic rhinitis emerged as the strongest correlates of SD, especially those with all three atopic conditions. Thus, allergic comorbidities should be assessed in SD patients. Further research is needed to clarify the pathophysiological relationship between these conditions and SD. [Graphical abstract available online] Graphical Abstract

This update and revision of the international guideline for urticaria was developed in accordance with the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. It is an initiative of the Global Allergy and Asthma Excellence Network (GA ² LEN) and its Urticaria and Angioedema Centers of Reference and Excellence (UCAREs and ACAREs), with the participation of 210 delegates from 107 national and international societies, from 59 countries. The consensus conference was held on December 6th, 2024. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell‐driven disease, defined by a rapid appearance of wheals, angioedema, or both. The lifetime prevalence of acute urticaria is estimated to be approximately 20%. Chronic urticaria, categorized as either chronic spontaneous urticaria or chronic inducible urticaria, is disabling, impairs quality of life, and affects performance at work and school, however, novel therapies are available. This updated version of the international guideline for urticaria covers the definition and classification of urticaria and outlines expert‐guided and evidence‐based diagnostic and therapeutic approaches for the different subtypes of urticaria.

Background: Many patients with chronic spontaneous urticaria (CSU) remain symptomatic despite receiving second‐generation H ₁ ‐antihistamines (sgH ₁ ‐AH). This data analysis from the Chronic Urticaria Registry (CURE) aimed to describe treatment patterns and identify unmet needs in real‐world practice. Methods: CURE is an international, prospective registry of patients with chronic urticaria. Treatment responses were categorized as Urticaria Control Test (UCT) changes from baseline (BL) to 6‐month follow‐up (FU). Complete response was defined as UCT = 16 with a ≥ 3‐point increase. Results: Data were available from 3995 adult patients with CSU at BL and 1288 at FU with evaluable UCT. After treatment escalation from BL to FU, 5.3% (no treatment to licensed‐dose sgH ₁ ‐AH), 6.0% (licensed‐dose sgH ₁ ‐AH to up‐dosed sgH ₁ ‐AH), and 28.4% (any dose sgH ₁ ‐AH to omalizumab) achieved complete response. Factors associated with a lower probability of treatment escalation at FU were UCT ≥ 12 and omalizumab treatment at BL (both p < 0.0001). About one‐third (28.6%) of patients clinically eligible for escalation at BL (UCT < 12) did not receive step‐up treatment (18.0%) or were even stepped down (10.6%) and remained poorly controlled at FU. Factors associated with lack of escalation in this group included younger age ( p = 0.014), shorter disease duration ( p = 0.071), presence of wheals and angioedema ( p = 0.002), better quality of life ( p = 0.001), and treatment with up‐dosed sgH ₁ ‐AH ( p = 0.031). Conclusion: Appropriate treatment escalation improves CSU control, although only about a quarter of patients achieve a complete response, indicating the need for novel treatments. Many patients with poorly controlled CSU do not receive guideline‐recommended treatment escalation and remain symptomatic on their current treatments, which deserves further attention.

Introduction: Chronic urticaria (CU) is a common, burdensome mast cell-mediated skin disease. However, little is known about physician estimation of the disease prevalence and clinical impact. This study assessed physicians’ perceptions of CU and compared them with data from peer-reviewed literature. Methods: We conducted a cross-sectional, questionnaire-based study distributed worldwide via UCARE (Urticaria Centers of Reference and Excellence) network to 198 UCAREs and forwarded to GPs (general practitioners). Questionnaire data was analyzed using SPSS and subgroup analysis was performed using appropriate non-parametric statistical tests depending on the number of comparison groups and the distribution of the data. Results: In total, 234 participants from 46 countries completed the survey [54.3% female, median age: 48.5, interquartile range (IQR) 38.3–58.0 years]. Median age of disease onset reported for chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU) was 30.0 and 25.0 years, respectively. Median estimated prevalence of CU in adult and pediatric patients was 2.5% and 1.0%, respectively. The most affected aspects of patient life, estimated by physicians, were sleep (CSU), physical activities (CIndU), and mental status (CSU, CIndU). Physicians working at UCARE (78.9% (183/232) vs. non-UCARE (21.1% (49/232) sites differed in their estimation of adult CU prevalence (median: 2.0% vs. 4.5%, p < 0.001), proportion of adult CSU patients among CU patients (median: 70.0% vs. 60.0%, p = 0.027), and proportion of CSU patients with severe impact (median: 50.0% vs. 30.0%, p = 0.042). When asked how confident participants were in their estimations regarding CU prevalence and burden, UCARE experts reported significantly higher median confidence compared to other physicians. Conclusion: Although physicians’ estimations of CU prevalence and burden generally align with literature data, non-UCARE physicians may underestimate the burden and overestimate the prevalence. This might affect CU management in primary care potentially leading to a less effective treatment and underscores the need for increased urticaria awareness among non-UCARE physicians via publications, masterclasses, webinars, or other educational initiatives.

Background: Mobile health technologies may improve the management of chronic diseases, such as chronic spontaneous urticaria. However, effectiveness of mHealth tools largely depends on patient adherence, which can be influenced by various demographic, clinical, behavioural, psychosocial factors, and apps characteristics (appealing and simplicity of use). Understanding these adherence patterns is crucial for optimizing mHealth interventions. In this study, we aimed to assess adherence patterns associated to the use of CRUSE, a mHealth app designed for patients with CSU. Methods: We assessed users of the CRUSE app with self‐reported CSU or suggested by a physician. For each user, we evaluated the number of days they completed the CRUSE daily monitoring questionnaire (app adherence) within the first 3 months after installation. We constructed univariable and multivariable ordered beta regression models to identify predictors of 3‐month adherence to the app. Results: We analysed data from 2085 patients (66,114 days). Median adherence to the CRUSE app was of 22 days (24.4% of 90 days). In multivariable regression models, the variables more strongly associated with increased adherence to CRUSE included age (average increase = 0.16 percent points [pp] per additional year; 95% credible interval [CrI] = 0.08; 0.23 pp), male sex (average difference = 4.24 pp; 95% CrI = 1.77; 6.39 pp), being from a European country (average difference = 2.66 pp; 95% CrI = 0.59; 5.19 pp), and using monoclonal antibodies (average difference = 4.60 pp; 95% CrI = 2.26; 6.65 pp). Conclusions: Our findings suggest that age, male sex, residence in Europe, and the use of monoclonal antibodies are significant factors associated with increased adherence to the CRUSE app. These insights may help identify patient subgroups who would benefit most from mHealth support in managing CSU.