Journal of the European Academy of Dermatology and Venereology

<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Chronic spontaneous urticaria (CSU), a disease predominantly affecting females, has limited information available on its differences between females and males of varying ages.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>To investigate sex differences in age groups regarding disease activity, comorbidities, quality of life (QoL) and treatment patterns in CSU patients.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We analysed Chronic Urticaria Registry (CURE) data, an international real‐world registry for patients with chronic urticaria. Patients were recruited via an online platform using a standardized questionnaire. The data were analysed for demographics, age of onset, duration of urticaria, (Urticaria Activity Score [UAS], Urticaria Control Test [UCT], Chronic Urticaria Quality of Life Questionnaire [CU‐Q2oL]), family history, systemic symptoms, aggravating factors, comorbidities, smoking and alcohol consumption, laboratory parameters, burden of disease, treatment distribution and response rates, compliance to treatment and adverse events. Comparisons were made among age groups &lt;13, 13–17, 18–30, 31–50, 51–65 and &gt;65 years.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Across 4136 CSU patients (from 58 sites across 29 countries), 2994 (72.4%) were female. Statistically significant female predominance started at age 31 (&lt;0.001). Compared with males, females showed higher rates of angioedema (59.6 vs. 51.7%; <jats:italic>p</jats:italic> &lt; 0.001), systemic symptoms (34.6 vs. 25.4%; <jats:italic>p</jats:italic> &lt; 0.001), sleep disturbance (38.9 vs. 32.5%; <jats:italic>p</jats:italic> &lt; 0.001), QoL impairment (CU‐Q2oL score 32 vs. 27.7; <jats:italic>p</jats:italic> &lt; 0.001) and lower rates of urticaria control than males in all medication categories (<jats:italic>p</jats:italic> &lt; 0.05 for all). Females had more concomitant diseases, including asthma, thyroid disease, obesity, autoimmune disease, gastrointestinal disease and depression (<jats:italic>p</jats:italic> &lt; 0.05 for all). The disease was especially more burdensome and refractory in females aged 51–65 years than males, evidenced by more angioedema and systemic symptoms, worse QoL, lower UCT scores and more emergency visits (<jats:italic>p</jats:italic> &lt; 0.05 for all). However, these differences were not prominent in the elderly females (&gt;65 years).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Compared with males, female CSU patients experience more burdensome disease, which gets worse in midlife.</jats:p><jats:p><jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="http://clinicaltrials.gov">Clinicaltrials.gov</jats:ext-link> (or equivalent) listing (if applicable None).</jats:p></jats:sec>

publication_history

received

accepted

published

Sanofi

Moxie Foundation

Novartis

Chronic spontaneous urticaria: a review

JAMA

The international EAACI/GA2 LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria

Allergy

The global burden of chronic urticaria for the patient and society

Br J Dermatol

Chronic spontaneous urticaria: new evidences on the role of autoimmunity

Curr Opin Allergy Clin Immunol

Prevalence of chronic urticaria in children and adults across the globe: systematic review with meta‐analysis

The challenges of chronic urticaria part 1: epidemiology, immunopathogenesis, comorbidities, quality of life, and management

World Allergy Organ J

Urticaria

Nat Rev Dis Primers

Epidemiology of urticaria including physical urticaria and angioedema in Korea

Korean J Intern Med

Factors linked to disease severity and time to remission in patients with chronic spontaneous urticaria

J Eur Acad Dermatol Venereol

Burden of and trends in urticaria globally, regionally, and nationally from 1990 to 2019: systematic analysis

JMIR Public Health Surveill

Turkish version of the chronic urticaria quality of life questionnaire: cultural adaptation, assessment of reliability and validity

Acta Derm Venereol

Sleep quality as a predictor of quality‐of‐life and emotional status impairment in patients with chronic spontaneous urticaria: a cross‐sectional study

Int J Environ Res Public Health

Fatigue is common and predicted by female gender and sleep disturbance in patients with chronic spontaneous urticaria

J Allergy Clin Immunol Pract

The burden on cohabitants of patients with chronic spontaneous urticaria: a cross‐sectional study

J Clin Med

A systematic review and meta‐analysis of health utility estimates in chronic spontaneous urticaria

Front Med (Lausanne)

The German version of the chronic urticaria quality‐of‐life questionnaire: factor analysis, validation, and initial clinical findings

Why autoimmune disease is more common in women: X chromosome holds clues

Nature

Sex differences in the pathogenesis of chronic urticaria

J Allergy Clin Immunol

The chronic urticaria registry: rationale, methods and initial implementation

Patients with chronic spontaneous urticaria who have wheals, angioedema, or both, differ demographically, clinically, and in response to treatment‐results from CURE

The benefit of complete response to treatment in patients with chronic spontaneous urticaria‐CURE results

Natural course of new‐onset urticaria: results of a 10‐year follow‐up, nationwide, population‐based study

Allergol Int

Gender differences in autoimmune disease

Front Neuroendocrinol

Urticaria in pregnancy and lactation

Front Allergy

Effects of pregnancy on chronic urticaria: results of the PREG‐CU UCARE study

Effect of puberty, menstruation, pregnancy, lactation, and menopause on chronic urticaria activity

J Cutan Med Surg

Non‐skin related symptoms are common in chronic spontaneous urticaria and linked to active and uncontrolled disease: results from the chronic urticaria registry

The relationship between sleep quality and chronotype differences and urticaria severity in patients with chronic spontaneous urticaria

Acta Dermatovenerol Alp Pannonica Adriat

The burden of chronic spontaneous urticaria is substantial: real‐world evidence from ASSURE‐CSU

The urticaria control test and urticaria activity score correlate with quality of life in adult Japanese patients with chronic spontaneous urticaria

Most patients with autoimmune chronic spontaneous urticaria also have autoallergic urticaria, but not ViceVersa

The relation of autologous serum and plasma skin test results with urticarial activity score, sex and age in patients with chronic urticaria

Postepy Dermatol Alergol

Chronic urticaria sera increase basophil CD203c expression

Autoimmune comorbidity in chronic spontaneous urticaria: a systematic review

Autoimmun Rev

Comorbidity of chronic spontaneous urticaria and autoimmune thyroid diseases: a systematic review

Mechanisms driving gender differences in asthma

Curr Allergy Asthma Rep

Gender differences at the onset of autoimmune thyroid diseases in children and adolescents

Front Endocrinol (Lausanne)

Why women have more autoimmune diseases than men: an evolutionary perspective

Evol Appl

Sex‐ and gender‐related differences in common functional Gastroenterologic disorders

Mayo Clin Proc

Why is depression more prevalent in women?

J Psychiatry Neurosci

Depression scores change significantly after omalizumab treatment in patients with chronic spontaneous urticaria

Asian Pac J Allergy Immunol

C‐reactive protein is linked to disease activity, impact, and response to treatment in patients with chronic spontaneous urticaria

Biomarkers of chronic spontaneous urticaria and their clinical implications

Expert Rev Clin Immunol

Predictors of treatment response in chronic spontaneous urticaria

Omalizumab for the treatment of chronic spontaneous urticaria: association between body mass index and outcome

Dermatol Pract Concept

Effects of a pseudoallergen‐free diet on chronic spontaneous urticaria: a prospective trial

Do women ‘over‐report’ morbidity? Men's and women's responses to structured prompting on a standard question on long standing illness

Soc Sci Med

Chronic spontaneous urticaria (CSU), a disease predominantly affecting females, has limited information available on its differences between females and males of varying ages.
To investigate sex differences in age groups regarding disease activity, comorbidities, quality of life (QoL) and treatment patterns in CSU patients.
We analysed Chronic Urticaria Registry (CURE) data, an international real-world registry for patients with chronic urticaria. Patients were recruited via an online platform using a standardized questionnaire. The data were analysed for demographics, age of onset, duration of urticaria, (Urticaria Activity Score [UAS], Urticaria Control Test [UCT], Chronic Urticaria Quality of Life Questionnaire [CU-Q2oL]), family history, systemic symptoms, aggravating factors, comorbidities, smoking and alcohol consumption, laboratory parameters, burden of disease, treatment distribution and response rates, compliance to treatment and adverse events. Comparisons were made among age groups <13, 13-17, 18-30, 31-50, 51-65 and >65 years.
Across 4136 CSU patients (from 58 sites across 29 countries), 2994 (72.4%) were female. Statistically significant female predominance started at age 31 (<0.001). Compared with males, females showed higher rates of angioedema (59.6 vs. 51.7%; p < 0.001), systemic symptoms (34.6 vs. 25.4%; p < 0.001), sleep disturbance (38.9 vs. 32.5%; p < 0.001), QoL impairment (CU-Q2oL score 32 vs. 27.7; p < 0.001) and lower rates of urticaria control than males in all medication categories (p < 0.05 for all). Females had more concomitant diseases, including asthma, thyroid disease, obesity, autoimmune disease, gastrointestinal disease and depression (p < 0.05 for all). The disease was especially more burdensome and refractory in females aged 51-65 years than males, evidenced by more angioedema and systemic symptoms, worse QoL, lower UCT scores and more emergency visits (p < 0.05 for all). However, these differences were not prominent in the elderly females (>65 years).
Compared with males, female CSU patients experience more burdensome disease, which gets worse in midlife.
gov (or equivalent) listing (if applicable None).

Sex matters in CSU: Women face greater burden and poorer urticaria control, especially in midlife-CURE insights.

Sex matters in <scp>CSU</scp>: Women face greater burden and poorer urticaria control, especially in midlife—<scp>CURE</scp> insights

JAMA Dermatology

<jats:sec><jats:title>Importance</jats:title><jats:p>Chronic spontaneous urticaria (CSU) is a skin disease driven mainly by the activation of cutaneous mast cells through various mechanisms. Bruton tyrosine kinase (BTK), expressed in B cells and mast cells, plays a critical role in multiple immune-mediated disease processes.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>To determine the efficacy and risk profile of rilzabrutinib (SAR444671), an oral, reversible, covalent, next-generation BTK inhibitor, in treating patients with CSU.</jats:p></jats:sec><jats:sec><jats:title>Design, Setting, and Participants</jats:title><jats:p>The Rilzabrutinib Efficacy and Safety in CSU (RILECSU) randomized clinical trial was a 52-week phase 2 study comprising a 12-week, double-blind, placebo-controlled, dose-ranging period, followed by a 40-week open-label extension. The trial was conducted from November 24, 2021, through April 23, 2024. Fifty-one centers enrolled and randomized participants across 12 countries in Asia, Europe, North America, and South America. The trial participants included adults aged 18 to 80 years with moderate to severe CSU (weekly Urticaria Activity Score [UAS7] of 16 or more; weekly Itch Severity Score [ISS7] of 8 or more) not adequately controlled with H<jats:sub>1</jats:sub>-antihistamine treatment.</jats:p></jats:sec><jats:sec><jats:title>Interventions</jats:title><jats:p>Patients were randomized 1:1:1:1 to rilzabrutinib, 400 mg, once every evening (400 mg/d), twice per day (800 mg/d), 3 times per day (1200 mg/d), or matching placebo.</jats:p></jats:sec><jats:sec><jats:title>Main Outcomes</jats:title><jats:p>The primary end point was change from baseline at week 12 in ISS7 (for US and US reference countries) or UAS7 (for non-US reference countries).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>A total of 160 omalizumab-naive and omalizumab-incomplete responders were randomized (mean [SD] age, 44.1 [13.4] years; 112 [70.0%] female). The primary analysis population included only the 143 omalizumab-naive patients. Significant reductions at week 12 were observed with rilzabrutinib, 1200 mg/d, vs placebo from baseline in ISS7 (least squares [LS] mean, −9.21 vs −5.77; difference, −3.44 [95% CI, −6.25 to −0.62]; <jats:italic>P</jats:italic> = .02) and UAS7 (LS mean, −16.89 vs −10.14; difference, −6.75 [95% CI, −12.23 to −1.26]; <jats:italic>P</jats:italic> = .02). In addition, improvements in weekly Hives Severity Score (HSS7) and weekly Angioedema Activity Score (AAS7) were observed. Improvements in ISS7, UAS7, HSS7, and AAS7 were observed as early as week 1. CSU-related biomarkers, including soluble Mas-related G protein–coupled receptor X2, immunoglobulin (Ig)-G antithyroid peroxidase, IgG anti-Fc-ε receptor 1, and interleukin-31, were reduced compared to placebo at week 12. Rilzabrutinib demonstrated a favorable risk-benefit profile; adverse events occurring at a higher frequency with rilzabrutinib vs placebo included diarrhea, nausea, and headache.</jats:p></jats:sec><jats:sec><jats:title>Conclusions and Relevance</jats:title><jats:p>The results of the RILECSU randomized clinical trial demonstrated efficacy and rapid onset of action of rilzabrutinib, 1200 mg/d, over 12 weeks, in addition to an acceptable adverse event profile. Together, these data support the use of rilzabrutinib in treating patients with moderate to severe CSU refractory to H<jats:sub>1</jats:sub>-antihistamines. Further research is needed to determine long-term efficacy and potential harms.</jats:p></jats:sec><jats:sec><jats:title>Trial Registration</jats:title><jats:p>ClinicalTrials.gov Identifier: <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://www.clinicaltrials.gov/study/NCT05107115">NCT05107115</jats:ext-link></jats:p></jats:sec>

Chronic spontaneous urticaria: focus on pathophysiology to unlock treatment advances.

Chronic spontaneous urticaria: how to measure it and the need to define treatment success.

Dermatol Ther (Heidelb)

Urticaria.

Common but neglected problem in chronic spontaneous urticaria: sleep disturbance.

Allergy Asthma Proc

The efficacy and safety of high-dose nonsedating antihistamines in chronic spontaneous urticaria: a systematic review and meta-analysis of randomized clinical trials.

BMC Pharmacol Toxicol

The international EAACI/GA2LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria.

Bruton’s tyrosine kinase inhibition—an emerging therapeutic strategy in immune-mediated dermatological conditions.

Bruton’s tyrosine kinase inhibitors (BTKIs): review of preclinical studies and evaluation of clinical trials.

Molecules

Remibrutinib, a novel BTK inhibitor, demonstrates promising efficacy and safety in chronic spontaneous urticaria.

The use of Bruton’s tyrosine kinase inhibitors to treat allergic disorders.

Curr Treat Options Allergy

Bruton’s tyrosine kinase inhibition for the treatment of allergic disorders.

Ann Allergy Asthma Immunol

Remibrutinib demonstrates favorable safety profile and sustained efficacy in chronic spontaneous urticaria over 52 weeks.

Rilzabrutinib, a reversible covalent Bruton’s tyrosine kinase inhibitor: absorption, metabolism, excretion, and absolute bioavailability in healthy participants.

Clin Transl Sci

Preclinical efficacy and anti-inflammatory mechanisms of action of the Bruton tyrosine kinase inhibitor rilzabrutinib for immune-mediated disease.

J Immunol

Fenebrutinib in H1 antihistamine-refractory chronic spontaneous urticaria: a randomized phase 2 trial.

Nat Med

Elevated MRGPRX2 levels related to disease severity in patients with chronic spontaneous urticaria.

Allergy Asthma Immunol Res

IL-31-pruritus interleukin: serum values and clinical impact in chronic spontaneous urticaria—a Romanian retrospective study.

Interleukin-31 signaling bridges the gap between immune cells, the nervous system and epithelial tissues.

Proof of concept for the clinical effects of oral rilzabrutinib, the first Bruton tyrosine kinase inhibitor for pemphigus vulgaris: the phase II BELIEVE study.

Rilzabrutinib, an oral BTK inhibitor, in immune thrombocytopenia.

N Engl J Med

Bruton’s tyrosine kinase inhibitors: the next frontier of B-cell-targeted therapies for cancer, autoimmune disorders, and multiple sclerosis.

Fast symptom improvement and favorable safety profile with remibrutinib in chronic spontaneous urticaria: REMIX-1/-2 studies.

Barzolvolimab significantly decreases chronic spontaneous urticaria disease activity and is well tolerated: top line results from a phase 2 trial.

Chronic spontaneous urticaria (CSU) is a skin disease driven mainly by the activation of cutaneous mast cells through various mechanisms. Bruton tyrosine kinase (BTK), expressed in B cells and mast cells, plays a critical role in multiple immune-mediated disease processes.
To determine the efficacy and risk profile of rilzabrutinib (SAR444671), an oral, reversible, covalent, next-generation BTK inhibitor, in treating patients with CSU.
The Rilzabrutinib Efficacy and Safety in CSU (RILECSU) randomized clinical trial was a 52-week phase 2 study comprising a 12-week, double-blind, placebo-controlled, dose-ranging period, followed by a 40-week open-label extension. The trial was conducted from November 24, 2021, through April 23, 2024. Fifty-one centers enrolled and randomized participants across 12 countries in Asia, Europe, North America, and South America. The trial participants included adults aged 18 to 80 years with moderate to severe CSU (weekly Urticaria Activity Score [UAS7] of 16 or more; weekly Itch Severity Score [ISS7] of 8 or more) not adequately controlled with H1-antihistamine treatment.
Patients were randomized 1:1:1:1 to rilzabrutinib, 400 mg, once every evening (400 mg/d), twice per day (800 mg/d), 3 times per day (1200 mg/d), or matching placebo.
The primary end point was change from baseline at week 12 in ISS7 (for US and US reference countries) or UAS7 (for non-US reference countries).
A total of 160 omalizumab-naive and omalizumab-incomplete responders were randomized (mean [SD] age, 44.1 [13.4] years; 112 [70.0%] female). The primary analysis population included only the 143 omalizumab-naive patients. Significant reductions at week 12 were observed with rilzabrutinib, 1200 mg/d, vs placebo from baseline in ISS7 (least squares [LS] mean, -9.21 vs -5.77; difference, -3.44 [95% CI, -6.25 to -0.62]; P = .02) and UAS7 (LS mean, -16.89 vs -10.14; difference, -6.75 [95% CI, -12.23 to -1.26]; P = .02). In addition, improvements in weekly Hives Severity Score (HSS7) and weekly Angioedema Activity Score (AAS7) were observed. Improvements in ISS7, UAS7, HSS7, and AAS7 were observed as early as week 1. CSU-related biomarkers, including soluble Mas-related G protein-coupled receptor X2, immunoglobulin (Ig)-G antithyroid peroxidase, IgG anti-Fc-ε receptor 1, and interleukin-31, were reduced compared to placebo at week 12. Rilzabrutinib demonstrated a favorable risk-benefit profile; adverse events occurring at a higher frequency with rilzabrutinib vs placebo included diarrhea, nausea, and headache.
The results of the RILECSU randomized clinical trial demonstrated efficacy and rapid onset of action of rilzabrutinib, 1200 mg/d, over 12 weeks, in addition to an acceptable adverse event profile. Together, these data support the use of rilzabrutinib in treating patients with moderate to severe CSU refractory to H1-antihistamines. Further research is needed to determine long-term efficacy and potential harms.
ClinicalTrials.gov Identifier: NCT05107115.

Rilzabrutinib in Antihistamine-Refractory Chronic Spontaneous Urticaria: The RILECSU Phase 2 Randomized Clinical Trial.

Rilzabrutinib in Antihistamine-Refractory Chronic Spontaneous Urticaria

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