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. 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. Of 68,513 participants, 3101 had SD (female 73.3 Symptomatic dermographism (SD) is the most common type of chronic inducible urticaria. It is a skin condition in which red, itchy hives appear after the skin is scratched or rubbed. The PREVALENCE-D study was conducted to better understand which health conditions are commonly associated with SD. Between 2021 and 2024, 68,513 adults from 19 countries completed an online survey. Among them, 3101 participants reported having SD. The study compared people with SD to those without SD to identify health conditions that were reported more often among people with SD. The study found that people with SD more often reported having atopic dermatitis and allergic rhinitis. Reporting more than one allergic condition was also more common among people with SD, particularly when atopic dermatitis, allergic rhinitis, and asthma occurred together. In addition, being female, older age, working age, and having thyroid disease or dyslipidemia were also related to SD. These findings suggest that clinicians may consider evaluating allergic comorbidities, particularly atopic dermatitis and allergic rhinitis, in patients with SD. Better awareness of these associated conditions may help improve care and quality of life for people affected by SD.

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:Chronic spontaneous urticaria (CSU) can cause psychosocial and quality of life burden on patients and their family members and caregivers. Despite its recognition as a debilitating disease, limited data exist regarding the impact of CSU on family members, hindering a comprehensive understanding of the disease's broader effects. This study aimed to assess how CSU affects the quality of life of family members who support patients in their daily challenges by applying the Family Dermatology Life Quality Index (FDLQI) questionnaire across multiple countries. METHODS:A cross-sectional, multicentre and international study conducted between January and December 2024 in Urticaria Centres of Reference and Excellence (UCARE) centres located in several countries including Brazil, China, Ecuador, Greece, India, Oman, Poland, Russia, Thailand, Turkey, Peru and North Macedonia. Statistical analyses, including non-parametric tests and multiple regression models, were employed to explore associations between disease severity/control and family burden. RESULTS:Poorly controlled CSU significantly deteriorated family members' quality of life, particularly in emotional, physical and social domains. Higher disease severity and lower disease control scores were associated with increased stress, greater caregiving burden and elevated health expenditures. In opposition to family relations, older age and longer time since diagnosis mitigate negative impacts, while insufficient treatment regimens exacerbated them. CONCLUSIONS:Inadequate control of CSU amplifies the burden on families, underscoring the need for effective and supportive care strategies.

Skin diseases manifest as visually observable eruption patterns, making image-based assessment a central component of dermatological diagnosis. While recent artificial intelligence (AI)-based approaches have achieved remarkable progress in classifying skin diseases from images, their utility remains largely limited to pattern recognition tasks, such as disease identification or severity grading. Crucially, most existing AI frameworks operate as black-box classifiers and do not provide interpretable links between eruption morphology and the underlying in vivo pathophysiological states, thereby offering limited support for personalized treatment decisions. To date, no practical framework has been established to systematically translate eruption morphology into mechanistic insights or treatment-relevant predictions for inflammatory skin diseases such as chronic urticaria. Here, we propose a novel integrative framework that infers patient-specific pathophysiological states directly from skin eruption morphology. Our approach unifies mechanistic mathematical modeling with data science that encompasses machine learning and topological data analysis, together with in vitro experiments and clinical data into a single coherent system. By constructing a mathematical model that explicitly links disease pathophysiology to eruption morphology, we develop a computational parameter inference tool, the System for Skin Eruption Morphology-based Parameter Inference (SEMPi), that estimates patient-specific physiological parameters directly from real-world skin eruption images. Importantly, these inferred parameters are interpretable in terms of underlying biological processes, enabling direct insight into patient-specific disease states rather than mere image-level classification. Furthermore, by incorporating drug interactions into the mathematical model, our framework enables treatment-response prediction and optimization of individualized therapeutic strategies across multiple drugs. This study introduces a paradigm shift from morphology-based classification toward morphology-driven interpretation of patient physiology, providing a foundation for predictive diagnosis and precision treatment in inflammatory skin diseases. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the Japan Science and Technology Agency(JST) CREST (JPMJCR2111) and Grant-in-Aid for Transformative Research Areas(A) (22H05110). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The institutional ethics review board approved the study protocol (Ethical Committee for Epidemiology of Hiroshima University, Hiroshima, Japan, approval number: E2020-2388). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

BACKGROUND:Chronic spontaneous urticaria (CSU) is a chronic skin disorder primarily driven by mast cell activation and basophil involvement. CSU is often associated with autoimmune mechanisms, positioning Bruton's tyrosine kinase (BTK) inhibition as an attractive therapeutic strategy. TAS5315 is a once-daily oral inhibitor of BTK with activity against Tec tyrosine-protein kinase and IL-2-inducible T-cell kinase (ITK). This study evaluated the efficacy and safety of TAS5315 in patients with CSU inadequately responding to non-sedating second-generation H1 receptor antagonists (ns-antihistamines). METHODS:This Phase 2a, randomized, double-blind, parallel-group, multicenter study randomized patients (1:1:1:1:1:1) with CSU to TAS5315 4 mg, 2 mg, 1 mg, 0.5 mg, 0.25 mg, or placebo for 12 weeks. The primary endpoint was the change from baseline in Weekly Urticaria Activity Score (UAS7) at Week 12. RESULTS:Of 126 patients enrolled, all received study treatment (n = 21 per dose group). The primary endpoint, mean changes from baseline in UAS7 at Week 12 were -17.15, -16.01, -15.19, -11.63, -17.84, and -9.06 for the TAS5315 4 mg, 2 mg, 1 mg, 0.5 mg, 0.25 mg, and placebo groups, respectively. Similar improvements were observed with TAS5315 versus placebo for other efficacy endpoints. Adverse events (AEs) were reported in over half of patients in each treatment group, and most were mild in severity. The most frequently reported AE with TAS5315 was petechiae. CONCLUSIONS:Once-daily TAS5315 was well tolerated and showed promising efficacy, making it a potential treatment option for CSU patients with inadequate response to ns-antihistamines.

Remibrutinib, an oral, highly selective, Bruton’s tyrosine kinase (BTK) inhibitor, has shown efficacy and favorable safety in pivotal global phase 3 studies in patients with chronic spontaneous urticaria (CSU). This 52-week safety study evaluated the effect of remibrutinib in Japanese patients with CSU. BISCUIT, a phase 3 (NCT05048342), open-label, single-arm study, investigated the safety and efficacy of remibrutinib 25 mg twice-daily as an add-on medication in Japanese patients with CSU who remain symptomatic despite treatment with H1-antihistamines. The primary endpoint was the proportion of patients with ≥ 1 adverse events (AEs). Overall, 71 Japanese patients (mean age 43.5 years) had a median remibrutinib exposure of 52.1 weeks; 87.3

This update to the 2019 Canadian Hereditary Angioedema (HAE) Guideline broadens its focus to include the management of patients with HAE worldwide, building on its established international framework. It has been developed through a collaboration of Canadian and international HAE experts and patient groups, coordinated by the Canadian Hereditary Angioedema Network. The objective is to provide evidence-based recommendations, using the Grading of Recommendations Assessment, Development and Evaluation system, for the management of patients with HAE. These include recommendations for the treatment of attacks, short-term prophylaxis, and long-term prophylaxis, as well as recommendations for self-administration, individualized therapy, health-related quality of life, and comprehensive care. New to the 2024 edition are specific recommendations for the treatment of angioedema attacks in individuals with HAE who are breastfeeding/lactating, as well as a dedicated section on shared decision-making. HAE results in spontaneous and often unpredictable attacks of painful swelling, typically affecting the extremities, bowel mucosa, genitals, face, and upper airway. These attacks are associated with significant functional impairment, reduced health-related quality of life, and in the case of laryngeal attacks, a high risk of mortality. Managing HAE is complex, and patient care in Canada, similar to many other countries, remains inconsistent and suboptimal. Care delivery lags behind nations that have implemented more structured management models for HAE, and offer broader access to a wider range of approved therapies. This guideline is intended to be used to optimize HAE management, highlight the importance of individualized care, and provide guidance to healthcare providers, policymakers, patients, and advocates. Primary target users include healthcare providers who are managing patients with HAE, as well as emergency and intensive care physicians, primary care physicians, gastroenterologists, dentists, otolaryngologists, pediatricians, hematologists, dermatologists, and gynecologists who will encounter patients with HAE and need to be aware of this condition. Hospital administrators, insurers and policy makers may also find this guideline helpful.

BACKGROUND:Remibrutinib, an oral, highly selective Bruton's tyrosine kinase inhibitor, showed sustained efficacy in phase 3 REMIX trials in chronic spontaneous urticaria. OBJECTIVE:To report detailed safety outcomes from the REMIX trials, including key findings pertinent to Bruton's tyrosine kinase inhibitor safety, such as bleeding, infections, cytopenia, and liver safety. METHODS:This was a pooled analysis of REMIX-1 and REMIX-2 consisting of a 24-week, randomized, double-blind, placebo-controlled period, followed by a 28-week open-label treatment period. Adverse event (AE) frequencies and laboratory parameters were examined through week 52, and differences versus placebo were evaluated in the controlled period. RESULTS:AE frequencies and risk differences (95% CI) for remibrutinib (n = 606) versus placebo (n = 306) were as follows: any AE 64.9% versus 64.7%, difference 0.1% (-6.4% to 6.7%); bleeding (including laboratory abnormalities) 10.6% versus 5.2%, difference 5.3% (1.6% to 8.7%); infections 33.5% versus 34.3%, difference -0.8% (-7.4% to 5.6%); cytopenia AEs 3.6% versus 2.0%, difference 1.7% (-0.7% to 3.8%); hepatic disorders 3.3% versus 4.9%, difference -1.6% (-4.6% to 1.1%). Imbalance in bleeding was due to petechia and similar mucocutaneous events (predominantly mild, none severe) occurring in 9.1% of patients on remibrutinib versus 2.0% of patients on placebo. No other AEs with significantly increased frequency occurred on remibrutinib. Findings during the entire study period were consistent with those in the controlled period. CONCLUSIONS:Remibrutinib showed a favorable safety profile with slightly higher incidence of petechia and similar predominantly mild mucocutaneous events. There were no notable differences in the frequency of other safety outcomes between remibrutinib and placebo in the REMIX trials.

Background: Hereditary angioedema is a rare disorder characterized by recurrent episodes of swelling of the skin and mucous membranes. Since 2021, the introduction of long-term prophylactic therapies in Japan has transformed treatment strategies; however, real-world data on attack frequency and patient-reported quality of life remain limited. Evidence from Japanese patients is needed to elucidate the clinical and social significance of prophylactic therapy. Methods: We analyzed longitudinal data from 16 patients with hereditary angioedema enrolled in RUDY JAPAN, a patient-participatory registry for rare diseases, between 2019 and 2024. Patients were categorized into three groups: those who never received prophylaxis throughout the study period, those observed before starting prophylaxis, and the same patients after starting prophylaxis. Attack frequency and patient-reported quality of life were compared across these groups. Results: A total of 191 attack episodes and 81 quality of life questionnaires were collected. The mean number of attacks was highest in patients before prophylaxis and lowest after initiation, demonstrating substantial suppression of attacks with long-term prophylaxis. Overall, quality of life scores showed only modest changes, but domain-specific improvements were observed, particularly in the functional and fears/shame domains, reflecting reduced psychological and social burden. Treatment behaviors also varied across groups: only half of the attacks were treated in patients without prophylaxis, whereas nearly all attacks were treated in those who later received prophylaxis. Conclusions: This study provides the first real-world evidence from Japan that long-term prophylaxis substantially reduces attacks and improves selected quality of life domains in hereditary angioedema. Despite ongoing challenges, the findings demonstrate that prophylaxis represents a transformative advance in clinical management, offering patients protection against life-threatening attacks and relief from the disease’s psychosocial burden.

Chronic spontaneous urticaria (CSU) can cause psychosocial and quality of life burden on patients and their family members and caregivers. Despite its recognition as a debilitating disease, limited data exist regarding the impact of CSU on family members, hindering a comprehensive understanding of the disease's broader effects. This study aimed to assess how CSU affects the quality of life of family members who support patients in their daily challenges by applying the Family Dermatology Life Quality Index (FDLQI) questionnaire across multiple countries. A cross-sectional, multicentre and international study conducted between January and December 2024 in Urticaria Centres of Reference and Excellence (UCARE) centres located in several countries including Brazil, China, Ecuador, Greece, India, Oman, Poland, Russia, Thailand, Turkey, Peru and North Macedonia. Statistical analyses, including non-parametric tests and multiple regression models, were employed to explore associations between disease severity/control and family burden. Poorly controlled CSU significantly deteriorated family members' quality of life, particularly in emotional, physical and social domains. Higher disease severity and lower disease control scores were associated with increased stress, greater caregiving burden and elevated health expenditures. In opposition to family relations, older age and longer time since diagnosis mitigate negative impacts, while insufficient treatment regimens exacerbated them. Inadequate control of CSU amplifies the burden on families, underscoring the need for effective and supportive care strategies.

BACKGROUND:Hereditary angioedema (HAE) is a rare inherited disorder characterized by unpredictable and potentially life-threatening attacks of swelling. This international Delphi panel aimed to address questions related to on-demand treatment of HAE attacks. METHODS:A modified Delphi method was conducted with three rounds of surveys. Two non-voting co-chairs designed and managed the surveys, data collection, and analysis with a third-party administrator. The international panel consisted of 19 expert HAE clinicians. Consensus was defined as ≥ 75% agreement with ≥ 75% of panelists voting. RESULTS:The panel confirmed 24 statements across five key areas related to on-demand treatment: defining "early" treatment, barriers to early administration, burden of treatment, tolerability and convenience, and patient-clinician interactions. Panelists defined early treatment as ≤ 60 min after onset of an HAE attack. Obstacles to early treatment include recognition of an HAE attack, and embarrassment/anxiety about administering parenteral treatment. Access to on-demand treatment (i.e., carrying medication, cost, insurance coverage, regulatory approval) can be a burden for patients with HAE, and increasing access may improve adherence to guidelines. Logistical obstacles of parenteral administration that impact convenience, tolerability concerns (e.g., side effects), and cost of medication can all limit early use of on-demand treatment. Additional options for on-demand therapies beyond parenteral treatments could reduce some of the burdens. Panelists agreed that patient-physician shared decision-making should be utilized. CONCLUSIONS:The Delphi consensus statements demonstrate the need for accessible and convenient on-demand treatments for HAE attacks that will enable patients with HAE to improve adherence to guidelines.

BACKGROUND:Chronic spontaneous urticaria is an idiopathic syndrome defined by recurring itch, hives, or angioedema (or a combination of these symptoms) for more than 6 weeks. Remibrutinib, an oral, highly selective Bruton's tyrosine kinase inhibitor, showed efficacy and favorable safety in phase 2b trials. Data from phase 3 trials are needed. METHODS:In the identical, multicenter, double-blind, randomized, placebo-controlled REMIX-1 and REMIX-2 trials, we evaluated the efficacy and safety of remibrutinib in patients with symptomatic chronic spontaneous urticaria after treatment with second-generation H1-antihistamines. Patients were randomly assigned in a 2:1 ratio to receive oral remibrutinib at a dose of 25 mg twice daily or placebo. The primary end point was the change from baseline to week 12 in the urticaria activity score during a 7-day period (UAS7), which comprises severity scores for itch and hives during 1 week (scores range from 0 to 42, with higher scores indicating greater severity). Key secondary end points included adverse events and a UAS7 of 6 or lower at weeks 2 and 12 and a UAS7 of 0 at week 12. RESULTS:A total of 470 patients in REMIX-1 and 455 in REMIX-2 were randomly assigned to receive either remibrutinib (313 and 300 patients, respectively) or placebo (157 and 155 patients, respectively). The remibrutinib group had a significantly greater decrease in the UAS7 at week 12 than the placebo group (least-squares mean [±SE] change, -20.0±0.7 vs. -13.8±1.0 [P<0.001] in REMIX-1 and -19.4±0.7 vs. -11.7±0.9 [P<0.001] in REMIX-2), which appeared to be sustained through week 24. At week 12, significantly more patients in the remibrutinib group than in the placebo group had a UAS7 of 6 or lower (REMIX-1, 49.8% vs. 24.8% [P<0.001]; REMIX-2, 46.8% vs. 19.6% [P<0.001]) and a UAS7 of 0 (REMIX-1, 31.1% vs. 10.5% [P<0.001]; REMIX-2, 27.9% vs. 6.5% [P<0.001]). The percentages of patients with any adverse event and with serious adverse events were similar in the remibrutinib group and the placebo group, although a higher percentage of patients in the remibrutinib group than in the placebo group had petechiae (3.8% vs. 0.3% in the combined groups). CONCLUSIONS:Treatment with oral remibrutinib resulted in a significant improvement in a composite measure of itching and hives at week 12. (Funded by Novartis Pharmaceuticals; REMIX-1 and REMIX-2 ClinicalTrials.gov numbers, NCT05030311 and NCT05032157, respectively.).