A Comparison of Chronic Spontaneous Urticaria Clinical Characteristics and Management between Canadian and Israeli Adults

Abstract

Introduction

Chronic spontaneous urticaria (CSU) is increasingly recognized as a significant health issue with significant impacts on quality of life in adult populations. Data are sparse regarding differences in clinical characteristics and management of CU in different countries. We aimed to compare adult CU populations in Canada and Israel to identify demographic, clinical, and management differences.

Methods

From 2013 to 2024, Canadian adults with CU were prospectively enrolled at allergy clinics, with clinical data including comorbidities, disease severity (UAS7), control (UCT), and treatment collected. Omalizumab was reserved for refractory cases per guidelines. Israeli adults were recruited from 2009 to 2022 at a dermatology clinic, excluding those with inducible CU or unclear diagnoses. Descriptive statistics and multivariable logistic regression were used to compare demographics and treatment patterns across cohorts using R software.

Results

From 2013 to 2024, 71 adults at the Montreal General Hospital (MGH) and adjutant clinic were diagnosed with spontaneous urticaria, with a median age of 45.8 years (35.2–59.3) and 22.5% male. Between 2009 and 2022, 151 adults at Sheba Hospital were diagnosed with CSU, with a median age of 48.5 years (32.3–60.0) and 32% male. The male prevalence was significantly higher in Israeli CU patients (p < 0.01). Israeli adults had lower reports of comorbidities, including atopic dermatitis (5.3% vs. 19.7%, p < 0.01) and asthma (7.9% vs. 25.4%, p = 0.04). Antihistamine use was higher in Israel (99.3% vs. 85.9%, p < 0.01), along with glucocorticoids (72.8% vs. 14.1%, p < 0.01).

Conclusion

Differences in the demographics, comorbidities, and treatment of CSU may be related to differences between populations and management practices in different countries.

Introduction

Chronic spontaneous urticaria (CSU) is characterized by recurrent wheals/angioedema or both that are present for at least 6 weeks [1]. The pathophysiology of CSU involves mast cell activation and degranulation as well as presence of immune infiltrates, including T cells, eosinophils, and basophils [2, 3].

CSU is a debilitating disease, affecting at least 1% of the global population [2]. Individuals with CSU experience significant comorbidity and reduction in quality of life due to symptoms such as pruritus, loss of sleep, mood disorders, anxiety, and poor productivity [4]. Furthermore, differing geographic, sociocultural, and healthcare factors across countries can influence the presentation and management of CSU [4, 5]. Access to healthcare and varied healthcare systems can impact the recognition, diagnosis, and treatment of CU, often creating regional disparities in outcomes. Large, international, longitudinal population studies are essential to better understand the current diagnostic, treatment, and health outcome landscape of this disease in populations. In this article, we aimed to compare CU databases from two countries (Canada and Israel) to evaluate differences in patient demographics, clinical presentation, disease progression, and management. This comparative approach will provide necessary insights to address regional disparities and improve care for individuals with CU.

Methods

Canadian Dataset

From 2013 to 2024, adults (>18 years) presenting to the allergy clinic at the Montreal General Hospital (MGH) and an adjutant outpatient clinic were prospectively recruited as part of a CU registry. Data were collected from consenting patients on age, sex at birth, comorbidities in patient and family (including autoimmune disease), severity, and control of the CU assessed by the urticaria activity score (UAS7) and the UCT (urticaria control test), respectively, and management. Omalizumab treatment was administered exclusively to adults with a UAS7 score of 16 or higher who had not responded to at least 4 weeks of high-dose second-generation antihistamines, in accordance with chronic urticaria guidelines and Canadian health insurance requirements (as outlined in the international EAACI/GA²LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria).

Israeli Dataset

From 2009 to 2022, adults (>18 years) presenting to the dermatology outpatient clinic of the Sheba Medical Centre with a diagnosis of spontaneous urticaria were recruited as part of the CU registry. The following patients with CSU were excluded: those with a follow-up period of <3 months, those whose CSU diagnosis was unclear, those with only inducible CU, whose trigger, including active infection, might cause CSU, or patients with missing data regarding autoimmunity.

Data Synthesis

Descriptive statistics were used to present demographic, clinical management characteristics, and levels of biomarkers. All statistical data were analyzed using R 4.2.3 binary for macOS 10.3 (R Foundation for Statistical Computing, Vienna, Austria). Categorical data were presented as percentages, and continuous data as a mean with standard deviation. Chi-square test was used for comparison of categorical variables between Israeli and Canadian adults, whereas parametric t test was used for comparison of numerical variables. A multivariable logistic regression analysis was conducted to assess the association between cohort nationality (Israeli vs. Canadian) and the use of specific medications, including first- and second-generation antihistamines, glucocorticoids, and cyclosporine, while adjusting for potential confounders such as age and male sex.

Results

General Characteristics

From 2013 to 2024, 71 adults presented to the Montreal General Hospital (MGH) and were found to have CSU. Within these adults, the median age was 45.8 (35.2–59.3) and 22.5% were males (Table 1).

Table 1.

General demographics of populations from Canada and the Israel CSU cohorts

​	Canadian adults, (N = 71)	Israeli dataset, (N = 151)	p value
Male sex, N (%)	16 (22.5)	103 (68.2)	<0.01
Median age at reaction (IQR), years	45.8 (35.2–59.3)	48.5 (32.3–60.0)	0.84
Asthma, N (%)	18 (25.4)	12 (7.9)	0.04
Atopic dermatitis, N (%)	14 (19.7)	8 (5.3)	<0.01

From 2009 to 2022, 151 adults presented to Sheba hospital and had a diagnosis of spontaneous urticaria. The median age was 48.5 (32.3–60.0) and 32% were males. The prevalence of male was significantly higher in Israeli adults when compared to adults (68.2% vs. 22.5%, respectively, p < 0.01). The prevalence of atopic comorbidities was lower in Israeli adults when compared to Canadian adults, including atopic dermatitis (5.3% vs. 19.7%, respectively, p < 0.01) and asthma (7.9% vs. 25.4%, respectively, p = 0.04).

Management of Urticaria

Antihistamines were the most common treatment choice in both Canadian and Israeli datasets, with a significantly higher use in Israeli adults compared to Canadians (99.3% vs. 85.9%, respectively, p < 0.01). The use of second-generation antihistamines was higher in Israeli cohort compared to Canadian cohort (82.0% vs. 73.2%, respectively, p = 0.13). The use of first-generation antihistamines was significantly higher in the Israeli dataset compared to the Canadian cohort (34.0% vs. 15.5%, p < 0.01). The prevalence of patients being on simultaneous first- and second-generation antihistamines was significantly higher in the Israeli Cohort compared to the Canadian cohort (25.8% vs. 11.3%, respectively, p < 0.01). Similarly, the prevalence of steroid use was significantly higher in the Israeli dataset (72.8% vs. 14.1%, respectively, p < 0.01). The use of methotrexate was significantly higher in the Israeli dataset when compared to the Canadian dataset (14.6% vs. 0%, respectively, p < 0.01). No significant differences were noted in omalizumab or cyclosporine use between both datasets (Table 2).

Table 2.

Comparison of treatment for CSU in Canadian and Israeli cohort

​	Canadian adults, (N = 71)	Israeli dataset, (N = 151)	p values
Antihistamines	61 (85.9)	150 (99.3)	<0.01
Steroids	10 (14.1)	110 (72.8)	<0.01
Methotrexate	0	22 (14.6)	<0.01
Cyclosporine	2 (2.8)	8 (5.3)	0.41
Omalizumab	13 (18.3)	35 (23.2)	0.41

When adjusted for male sex and age, Israeli patients were more likely to use first-generation antihistamines (OR 1.34, 95% confidence interval [CI]: 1.15–1.58, p < 0.01) and less likely to use second-generation antihistamines (OR 0.68, 95% CI: 0.59–0.80, p < 0.01). Israeli patients were more likely to use glucocorticoids (OR 1.77, 95% CI: 1.53–2.03, p < 0.01). There were no statistical differences regarding use of cyclosporine or omalizumab (Table 3).

Table 3.

Multivariate regression models examining association between medication usage and cohort nationality (Israeli or Canadian) (OR [95% CI], p value)

​	First-generation antihistamine	Second-generation antihistamine	Cyclosporine	Steroids	Omalizumab
Age at reaction	0.99 (0.98–1.00), 0.38	1.02 (1.00–1.04), 0.21	1.02 (0.98–1.05), 0.29	0.99 (0.99–1.00), 0.33	1.00 (0.98–1.02), 0.84
Male sex	1.09 (0.91–1.25), 0.23	0.91 (0.80–1.05), 0.19	1.02 (0.99–1.03), 0.98	1.01 (0.88–1.15), 0.16	0.95 (0.46–1.98), 0.90
Israeli cohort	1.34 (1.15–1.58), 0.01	0.68 (0.59–0.80), 0.01	1.02 (0.94–1.10), 0.59	1.77 (1.53–2.03), 0.01	1.02 (0.88–1.19), 0.75

Discussion

Our analysis highlights for the first time some key differences in the demographic population affected by CU, including a higher predominance of asthma and allergic rhinitis comorbidities in the Canadian population and lower use of glucocorticoids in Canada.

CU has been associated with atopic diseases in a Scandinavian study, where 19.6% of individuals with CU reported comorbid asthma and 16.5% reported comorbid allergic rhinitis [6]. A large-scale Korean study reported that asthma was one of the top comorbidities associated with CU [7]. Asthma can also be triggered by air pollution, antibiotic and acetaminophen exposure as well as microbial environment, highlighting the importance of the environment in disease prevalence and severity [8, 9]. Our results highlight that the increased prevalence of asthma and allergic rhinitis association in the Canadian cohort could be attributed to the differing environmental landscape compared to Israel or genetic differences between populations. Indeed, studies suggest that AD prevalence is substantially lower in Israel versus North America [10]. Hence, the difference observed may reflect the difference in these atopic conditions between Israel and Canada regardless of the presence of CU.

Antihistamine use, notably first-generation antihistamine, in the Canadian cohort is significantly reduced compared to the Israeli cohort, despite both countries adhering to the same clinical guidelines. According to the EAACI/GA²LEN/EDF/WAO guideline, the first line of treatment of CU is a second-generation antihistamine with potential for an increase of four times the original dose in certain cases, although not recommended [11]. The second line of treatment is introduction of omalizumab and finally cyclosporine if symptoms do not resolve. Guidelines recommend treatment until disease control and maintenance of UAS7 at zero [11]. Of note, Canadian adults were more likely to suffer from concurrent asthma and allergies. Studies show that patients with comorbid atopic illnesses are more likely to suffer from refractory CU, warranting the need for stronger treatments or biologics, possibly explaining the reduced use of antihistamines [12, 13]. However, it remains unclear whether methotrexate use in the Israeli cohort (14.6%) was due to limited access to biologics or due to clinician preference. Future studies should assess whether methotrexate was chosen as a last resort therapy or actively recommended in Israeli clinical practice.

Although antihistamine use was common in both cohorts, first-generation antihistamine use was significantly lower in Canada (15.5%) compared to Israel (34.0%, p < 0.01). The lower use of antihistamines in Canada may reflect differing prescribing habits, greater adherence to international guidelines, or a preference for alternative treatments. Studies have shown that prescribing patterns for first-generation antihistamines vary widely, often influenced by national guidelines and physician preferences. For instance, a South Korean study found that prescription rates for allergic rhinitis treatments, including antihistamines, fluctuated between 2010 and 2018, reflecting changes in treatment guidelines and increased preference for newer generation drugs [14]. Additionally, inappropriate use of first-generation antihistamines, particularly in older adults, has been linked to increased risks of cognitive impairment and other adverse effects, contributing to more cautious prescribing patterns in some countries [15, 16]. These factors may partially explain why first-generation antihistamines were less frequently prescribed in the Canadian cohort compared to the Israeli cohort.

Our analysis demonstrates that Israeli patients are more likely to be administered glucocorticoids to control their CU compared to the Canadian cohort, potentially reflecting differences in daily clinical practice between both countries. Patients in the Israel cohort were administered glucocorticoids for a minimum of 3 months, as recommended by the National Health Basket, before trials of biologics. Typically, patients in Israel requiring omalizumab, a biologic with the potential to reduce the need for glucocorticoids and cyclosporine, must be approved by an independent committee based on their individual situation [17]. Furthermore, omalizumab was only recently included in the National Healthcare Basket, which encompasses all services and medications that patients can receive in Israel [18]. In 2015, the Ministry of Health approved use of omalizumab for CSU in patients who have exhausted all previous treatment options [19]. Since the Israeli database contains information from patients recruited from 2009 to 2022, it is likely that patients treated prior to 2015 were most often treated with glucocorticoids or methotrexate if antihistamines failed to control their symptoms, despite not demonstrating significant efficacy [20]. Compared to Canada, Israel’s differing clinical practices and medical regulations surrounding the use and distribution of omalizumab could potentially explain the increased use of methotrexate and glucocorticoids.

The Canadian cohort is notable for not using any methotrexate to manage patients CU. The EAACI/GA²LEN/EDF/WAO guidelines do not include methotrexate in the treatment algorithm [11]. Indeed, recent systematic reviews have identified no significant benefit to adding methotrexate as an adjunct therapy for CU management, despite it being well tolerated [20]. These findings in addition to the lack of recommendations in the clinical guidelines could explain the lack of use of methotrexate in the Canadian cohort. Importantly, there exists better alternatives to methotrexate, such as omalizumab, which is a highly efficient and safe third-line treatment recommended for use in severe or refractory CU [21]. Use of methotrexate in Israel could be attributed to stricter regulations surrounding the use of biologics, prompting the need for alternative therapies for severe CU [17]. In addition, differences in methotrexate use could reflect the varying clinical practices and adherence to clinical guidelines between both countries, with medical regulations and the clinical landscape affecting prescribing practices and subsequent management of patients with CU.

Patients treated in Israel were not assessed for disease severity, as this was not a practice routinely employed in the outpatient clinic, while Canadian patients were regularly assessed using the Urticaria Activity Score (UAS7) [22]. These differences in clinical practices could have affected the patient’s management, as in Canada, the Montreal Hospital is part of the UCARE centers of excellence [23]. UAS7 scores are used as an important metric to evaluate disease severity and efficacy of treatment and are part of the management guidelines required for a center to qualify as a UCARE center. Current guidelines recommend treating patients until a UAS7 score of zero is achieved and maintained [11]. The Israeli cohort may have received treatment based solely on the treating physician’s opinion, rather than being guided by a clinical tool. Coupled with the strict regulations surrounding omalizumab use, these practices could explain the observed differences in CU management between countries.

There exist several limitations in this study. First, the retrospective nature of the analysis may introduce biases, such as incomplete or inconsistent documentation of treatment regimens and patient characteristics, making comparison difficult. Due to different registry initiation dates between both countries, recruitment periods were not matched between cohorts, which may introduce variability due to evolving treatment practices over time. Additionally, the study was limited to two tertiary care centers, which may affect generalizability to other clinical settings or regions. Second, the study did not control for potential confounders such as disease severity, comorbidities, or prior treatment history, which could have impacted medication use. Furthermore, omission of socioeconomic and environmental information may impact outcomes related to asthma and allergic rhinitis. Finally, the Israeli CSU registry was developed in a dermatology clinic without allergist involvement, reflecting national practice patterns that may contribute to variation in care. In contrast, our Montreal site is a UCARE center, where collaborative care between dermatologists and allergists may facilitate closer adherence to international CSU guidelines. Promoting interdisciplinary models like UCARE may help reduce disparities in management and improve treatment outcomes.

Conclusion

This study demonstrates significant differences in patient demographics, clinical presentation, and management of CU. Future research should include larger cohorts, account for socioeconomic and environmental variables, and incorporate cost analysis to better understand differences in disease manifestation and treatment. It is crucial that all centers treating patients with CU adhere to the same management guidelines, e.g., through the UCARE centers of excellence to appropriately compare management strategies. These findings emphasize the need to enhance cross-specialty education and promote implementation of international CSU guidelines among both dermatologists and allergists to harmonize care practices and improve patient outcomes.

Statement of Ethics

This study was performed in accordance with the Declaration of Helsinki. This human study was approved by the McGill University Health Center Ethics Board – approval: IRB00010120. All adult participants provided written informed consent to participate in this study.

Conflict of Interest Statement

The authors declare no conflicts of interest.

Funding Sources

This study was not supported by any sponsor or funder.

Author Contributions

K.P. led the investigation, visualization, and writing of the draft and supported the methodology, data curation, and formal analysis. R.K. led the data curation and formal analysis and supported the writing. A. Baum and A. Barzilai lead the resource management and supported project conceptualization. E.N., M.N.F., and M.B.-S. led the supervision, conceptualization, and were the benefactors of the project.

Funding Statement

This study was not supported by any sponsor or funder.

Data Availability Statement

The data supporting the findings of this study are not publicly available due to privacy concerns but can be made available upon reasonable request from the corresponding author, subject to institutional approval and data-sharing agreements.