ABSTRACT
Background
Chronic spontaneous urticaria (CSU) is a mast cell‐driven condition defined by recurrent wheals and/or angioedema lasting over 6 weeks without an identifiable trigger. Though CSU is known to co‐occur with atopic diseases and share Th2‐dominant immunologic pathways, prior studies have not adequately addressed these relationships in diverse populations.
Objectives
To examine associations between CSU and atopic comorbidities in the All of Us (AoU) research program, a diverse, nationwide National Institutes of Health cohort focused on increasing enrollment from historically underrepresented groups.
Methods
We conducted a matched, case‐control study of AoU participants aged ≧ 18 years enrolled between May 6, 2018 and October 1, 2023. CSU cases were identified using SNOMED codes 51611005 and 42265009. Controls were matched 4:1 by age, sex, race, ethnicity, and smoking status. We compared rates of atopic dermatitis, allergic rhinitis, asthma, nasal polyps, food allergy, and drug allergy. Multivariable logistic regression adjusted for hypothyroidism, systemic lupus erythematosus, and rheumatoid arthritis given known associations with CSU.
Results
We identified 1171 CSU cases and 4684 matched controls with no significant demographic differences. CSU patients had significantly higher rates of atopic dermatitis (12.6% vs. 1.7%, p < 0.001), allergic rhinitis (58% vs. 13.2%, p < 0.001), asthma (46.2% vs. 13.2%, p < 0.001), nasal polyps (3.8% vs. 0.7%, p < 0.001), and food and drug allergies (p < 0.001). These associations persisted after multivariable adjustment (p < 0.001).
Conclusions
This study demonstrates a strong association between CSU and atopic disease in a racially and socioeconomically diverse cohort. Our findings highlight shared Th2‐driven pathways underlying CSU and atopy and reinforce the potential utility of type 2 targeted therapies (e.g., dupilumab) in patients with CSU and comorbid atopic disease. Clinicians should screen CSU patients for atopic disease to help guide comprehensive, targeted therapy.
Keywords: atopic dermatitis, autoimmune diseases, chronic urticaria, urticaria
1. Background
Chronic spontaneous urticaria (CSU) is defined by mast‐cell driven transient episodic eruption of wheals and/or angioedema lasting greater than 6 weeks with no identifiable trigger [1]. The association between CSU and atopic comorbidities, including atopic dermatitis, food and drug allergies, allergic conjunctivitis, rhinitis, and asthma, has been well established in the literature [2, 3]. CSU demonstrates upregulation of Th2‐associated pathways, particularly interleukin (IL)‐4 and IL‐13 signalling, which correlate with disease severity and underscore its immunologic overlap with atopic disorders [4]. However, despite the influence of various environmental and demographic factors may have on the development and severity of atopic disorders, the relationship between CSU and atopic disease in diverse populations remains unclear [5, 6]. Thus, there is a significant need in the dermatologic literature to re‐evaluate the link between CSU and atopic comorbidities utilizing diverse cohorts.
2. Objectives
In this study, we aim to identify atopic comorbidities associated with CSU in the All of Us (AoU) research program, a National Institutes of Health (NIH) database composed of health data from across the United States focusing on historically underrepresented groups in research. AoU is a registered service mark of the US Department of Health & Human Services [7, 8]. By enrolling participants from diverse demographic and socioeconomic backgrounds across the United States, the AoU program seeks to enable researchers to identify health patterns and disparities pertinent to underrepresented populations.
3. Methods
This study employed a matched, case‐control analysis of the AoU research database including participants older than 18 years of age recruited between May 6, 2018 and October 1, 2023. CSU cases were identified by SNOMED code 51611005, 42265009 and controls were matched in a 4:1 ratio for age, sex, race, ethnicity, and smoking status via propensity scores. Rates of atopic dermatitis (SNOMED 24079001), allergic rhinitis (61582004), asthma (195967001), nasal polyps (41931000119102), food allergy (416389007), and drug allergy (720588004) were compared between case and control groups using Fisher's exact test. Multivariable analyses (MVA) were performed using logistic regression and adjusted for hypothyroidism (40930008), systemic lupus erythematosus (SLE; 55464009), and rheumatoid arthritis (RA; 69896004) given the established relationship between these autoimmune conditions and CSU [9, 10]. Odds ratios (OR), 95% confidence intervals (CIs), and p‐values are reported with alpha set at 0.05. Statistical analyses were performed in Python, employing the Pandas, NumPy, SciPy, Statsmodels, and Seaborn libraries.
4. Results
1171 participants were identified along with 4684 matched controls with no significant difference in baseline demographics (p = 1.00). Patients with CSU had significantly higher rates of all studied atopic and autoimmune conditions (p < 0.0001; Table 1). After adjusting for hypothyroidism, SLE, and RA in MVA, all atopic comorbidities remained strongly associated with CSU (p < 0.001; Table 2).
Table 1.
Patient demographics and Fisher's exact test.
| Characteristic | Patients with CU (n = 1171) | Matched controls (n = 4684) | p‐value |
|---|---|---|---|
| Age, mean (SD), years | 55.9 (16.1) | 55.9 (16.14) | 1.00 |
| Sex | 1.00 | ||
| Female | 959 (81.9%) | 3836 (81.9%) | 1.00 |
| Male | 193 (16.5%) | 772 (16.5%) | 1.00 |
| Otherb | < 20a | 76 (1.6%) | 1.00 |
| Race and ethnicity | 1.00 | ||
| Non‐Hispanic or Latino | |||
| Asian | 40 (3.4%) | 160 (3.4%) | |
| Black | 173 (14.8%) | 692 (14.8%) | |
| White | 633 (54.1%) | 2532 (54.1%) | |
| Otherc | 325 (27.7%) | 1300 (27.7%) | |
| Ever smoker | 1.00 | ||
| Yes | 328 (28%) | 1312 (28%) | |
| No | 843 (72%) | 3372 (72%) | |
| Atopic dermatitis | 147 (12.6%) | 79 (1.7%) | < 0.001*** |
| Allergic rhinitis | 679 (58%) | 620 (13.2%) | < 0.001*** |
| Asthma | 541 (46.2%) | 620 (13.2%) | < 0.001*** |
| Nasal polyps | 44 (3.8%) | 33 (0.7%) | < 0.001*** |
| Drug allergy | < 20a | < 20a | < 0.001*** |
| Food allergy | 46 (3.9%) | < 20a | < 0.001*** |
| Hypothyroidism | 292 (24.9%) | 505 (10.8%) | < 0.001*** |
| SLE | 57 (4.9%) | 48 (1%) | < 0.001*** |
| Rheumatoid arthritis | 82 (7%) | 112 (2.4%) | < 0.001*** |
Note: ***Signifies significance level of p < 0.001.
In line with the data and statistics dissemination policy of the NIH All of Us Research Program, any values involving fewer than 20 individuals are presented in this manner to ensure participant privacy.
Includes participants who either had no matching concept or who did not identify as male or female, preferred not to answer, or skipped the question.
Includes participants who did not indicate Hispanic or Latino, skipped, did not identify with any of the ethnicities, or belonged to single population not Hispanic or Latino.
Table 2.
Multivariable analysis controlling for hypothyroidism, systemic lupus erythematosus, and rheumatoid arthritis.
| Variable | Odds ratio (95% CI) | p‐value |
|---|---|---|
| Atopic dermatitis | 7.5 (5.6–9.9) | < 0.001*** |
| Allergic rhinitis | 8.1 (7.0–9.4) | < 0.001*** |
| Asthma | 4.9 (4.2–5.6) | < 0.001*** |
| Nasal polyps | 4.8 (3.0–7.7) | < 0.001*** |
| Drug allergy | 6.8 (2.2–20.3) | < 0.001*** |
| Food allergy | 20.6 (9.6–44.3) | < 0.001*** |
Note: ***Signifies significance level of p < 0.001.
5. Conclusions
To our knowledge, this is the first study establishing a strong correlation between CSU and atopic disease within a diverse patient cohort. Utilizing the AoU database and the diverse population of participants included from across the United States enhances the robustness of these findings by accounting for genetic, environmental, and lifestyle factors that may influence the prevalence and presentation of both CSU and atopic conditions [5, 6]. Additionally, while previous studies have proposed an immunologic overlap between CSU and autoimmunity, this study leverages this established relationship as well as clear association within this cohort to further highlight the link between CSU and atopic disorders [9, 10]. Taken together, these results reinforce and strengthen a shared immunologic basis between CSU and various atopic disorders, emphasizing the need for comprehensive evaluations in patients from all backgrounds to identify possible comorbidities.
Several cytokines and immune intermediates have been shown to be similarly elevated in patients with CSU and those with atopic diseases. Elevated serum IgE levels, common in asthma and allergic rhinitis, are frequently observed in CSU [3]. Additionally, the upregulation of Th2 cytokines such as IL‐4 and IL‐13 in CSU parallels that seen in asthma and nasal polyps, contributing to eosinophilia and mast cell degranulation [4, 11]. The timing of asthma exacerbations with CSU flares during seasonal transitions further supports a shared immunologic pathway [1].
These findings have important clinical implications. Patients with CSU and atopic comorbidities may significantly benefit from more comprehensive management strategies that intervene on shared inflammatory intermediates. In particular, this observed immunologic overlap raises interest in type 2‐targeted therapies like omalizumab and ligelizumab (anti‐IgE), anti‐IL‐5 antibodies (e.g., reslizumab), and IL‐31 inhibitors (e.g., nemolizumab) [4]. The recent approval of dupilumab—a monoclonal antibody that inhibits both IL‐4 and IL‐13 signalling—for the treatment of antihistamine‐refractory CSU highlights the therapeutic potential of simultaneously targeting pathways involved in both CSU and atopic diseases. Recently published data from phase 3 clinical trials assessing dupilumab's safety and efficacy demonstrated that patients assigned to dupilumab achieved a significantly greater reduction in the Weekly Urticaria Activity Score and were more likely to reach complete treatment response when compared to placebo. Dupilumab and placebo were also found to have similar rates of treatment‐emergent adverse events [12, 13]. Given dupilumab's prior approval and use for the treatment of several type 2 inflammatory diseases, the strong data exhibited within these clinical trials indicate promising outcomes for patients with both CSU and atopic disease.
Limitations of this study include its retrospective design and reliance on accurate electronic health record documentation. Additionally, while AoU prioritizes outreach to and inclusion of populations of patients from historically underrepresented backgrounds, its cohort may not be fully representative of the entire United States. Likewise, despite the use of propensity score matching and multivariable analysis within a diverse database to reduce confounding in the relationship between CSU and atopic comorbidities, unmeasured factors such as environmental exposures, socioeconomic status, and healthcare access may still influence this association. Although CSU has been linked to autoimmune mechanisms and a strong association was identified within this cohort, future studies may further explore the relationship between CSU and autoimmunity.
Nevertheless, this study elucidates a strong association between CSU and various atopic comorbidities within a diverse cohort of patients from across the United States. Dermatologists should perform a thorough review of systems to identify potential targets for therapeutic intervention and optimize comprehensive patient care.
Author Contributions
Julian Cortes: conceptualisation (lead), investigation (lead), methodology (lead), project administration (lead), supervision (lead), validation (lead), visualisation (lead), writing – original draft (lead), writing – review and editing (lead). Nana Ama Adjei‐Frimpong: conceptualisation (lead), data curation (lead), methodology (lead), writing – review and editing (support), supervisor (lead). Savannah K. Fakhouri: conceptualisation (lead), methodology (lead), writing – original draft (lead), writing – review and editing (lead). Francesco Delacqua: data curation (lead), formal analysis (lead), methodology (lead), resources (lead), software (lead), validation (lead), writing – review and editing (support). Reid Oldenburg: conceptualisation (lead), project administration (lead), supervision (lead), validation (lead), writing – review and editing (lead).
Ethics Statement
The University of California, San Diego (UCSD) Institutional Review Board has been deemed our study (809009) exempt human subjects research.
Conflicts of Interest
RO—Blueprint Medicine and Novartis. The remaining authors declare no conflicts of interest.
Acknowledgements
A special thank you to the participants in the All of Us program. The All of Us Research Program is supported by the National Institute of Health, Office of the Director: Regional Medical Centers grants 1OT2‐OD‐026549, 1OT2‐OD‐026554, 1OT2‐OD‐026557, 1OT2‐OD‐026556, 1OT2‐OD‐026550, 1OT2‐OD‐026552, 1OT2‐OD‐026553, 1OT2‐OD‐026548, 1OT2‐OD‐026551, and 1OT2‐OD‐026555, and IAA grant AOD 16037, Federally Qualified Health Centers: grant HHSN 263201600085‐U, Data and Research Center: grant 5U2C‐OD‐023196, Biobank: grant 1U24‐OD‐023121, The Participant Center: grant U24‐OD‐023176, Participant Technology Systems Center: grant 1U24‐OD‐023163, Communications and Engagement: grants 3OT2‐OD‐023205 and 3OT2‐OD‐023206, and Community Partners: grants 1OT2‐OD‐025277, 3OT2‐OD‐025315, 1OT2‐OD‐025337, and 1OT2‐OD‐025276.
Julian A. Cortes and Nana Ama Adjei‐Frimpong are co‐first authors.
Data Availability Statement
The data accessed in this study is available in the All of Us database v8.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data accessed in this study is available in the All of Us database v8.