---
title: "Moderate-to-severe chronic spontaneous urticaria linked to higher risk of rheumatoid arthritis and"
id: "plos-one-9-moderate-to-severe-chronic-spontaneous-urticaria-is-associated-with-increased"
canonical_url: "https://medichelpline.com/clinical-feed/plos-one-9-moderate-to-severe-chronic-spontaneous-urticaria-is-associated-with-increased"
content_type: "clinical_feed_article"
specialty: "General"
source_name: "PLOS ONE (Medicine)"
source_url: "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358883"
published_at: "2026-09-23T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Moderate-to-severe chronic spontaneous urticaria linked to higher risk of rheumatoid arthritis and
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/plos-one-9-moderate-to-severe-chronic-spontaneous-urticaria-is-associated-with-increased
- **Specialty:** [General](https://medichelpline.com/clinical-feed/general.md)
- **Primary Source:** PLOS ONE (Medicine)
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0358883)
- **Published At:** 2026-09-23T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- This retrospective cohort study used the **TriNetX** US Collaborative Network (2014–2026) to compare patients with treatment-defined moderate-to-severe chronic spontaneous urticaria (CSU) to matched patients with mild CSU. - Moderate-to-severe CSU was defined by ≥2 ICD-10 diagnoses of idiopathic urticaria and treatment with omalizumab, dupilumab, or cyclosporine; mild CSU patients had ≥2 ICD-10 diagnoses and no biologic or cyclosporine exposure. - Propensity score matching (1:1) balanced age, sex, race/ethnicity, baseline comorbidities, family history, and socioeconomic factors, producing two cohorts of 16,413 patients each. - After adjustment for covariates and Bonferroni multiplicity correction, moderate-to-severe CSU was associated with increased odds of developing **rheumatoid arthritis** (OR 1.34; 95% CI 1.12–1.60; p = 0.001) and **Sjögren’s syndrome** (reported OR and CI in source text; p < 0.0001). - Incidence rates: rheumatoid arthritis 1.52 vs 1.14 cases per 1000 person-years (incidence rate ratio 1.33, p = 0.0014); Sjögren’s syndrome 1.20 vs 0.59 cases per 1000 person-years (incidence rate ratio 2.03, p < 0.0001). - Cumulative incidence differences: rheumatoid arthritis 1.8% vs 1.4% (absolute risk difference 0.5%, p = 0.0013); Sjögren’s syndrome 1.4% vs 0.7% (absolute risk difference 0.7%, p < 0.0001). - No statistically significant increased odds were observed for autoimmune thyroiditis, vitiligo, systemic lupus erythematosus, celiac disease, Graves’ disease, inflammatory bowel diseases, scleroderma, type 1 diabetes, psoriasis, psoriatic arthritis, and several other conditions evaluated. - Authors discuss potential shared autoimmune and genetic pathways (including prior GWAS and PRS data) as possible mechanisms linking CSU severity to rheumatoid arthritis and hypothesize similar mechanisms for Sjögren’s syndrome but call for further research. - Limitations noted include use of treatment as a proxy for severity, potential misclassification, lack of medication indication in the database, possible detection bias from differential healthcare utilization, and unavailability of validated CSU activity measures in TriNetX.
## Clinical Analysis & Structured Key Points
Moderate-to-severe chronic spontaneous urticaria is associated with increased risk of immune-mediated diseases: A population-based study | PLOS One Browse Subject Areas ? Click through the PLOS taxonomy to find articles in your field. For more information about PLOS Subject Areas, click here . Article Authors Metrics Comments Media Coverage Reader Comments Figures Figures Abstract Chronic spontaneous urticaria (CSU) is characterized by the idiopathic appearance of wheals and/or angioedema lasting more than six weeks. There is a critical need to evaluate whether the severity of CSU influences the risk of future immune-mediated comorbidities. We aim to evaluate if patients with moderate-to-severe chronic spontaneous urticaria (CSU) have an increased risk of developing immune-mediated comorbidities compared with matched patients with mild CSU. We conducted a retrospective cohort study using the TriNetX US Collaborative Network database from 2014–2026. We propensity matched patients with ≥2 ICD-10 diagnoses of idiopathic urticaria treated with omalizumab, dupilumab, or cyclosporine (moderate-to-severe disease) to age-, sex-, race-, ethnicity-, comorbidity-, and family history-matched counterparts who were never treated with biologics or cyclosporine (mild disease). After matching, 16,413 patients were included in the moderate-to-severe group, and 16,413 patients were included in the mild group. Patients with moderate-to-severe CSU had a significantly increased risk of developing rheumatoid arthritis OR=1.34 (95% CI: 1.12 to 1.60, p = 0.001) and Sjögren’s syndrome OR=1.04 (1.63–2.56, p < 0.0001), after adjusting for clinical factors and multiple hypothesis testing (Bonferroni’s alpha ≤0.00333). Moderate-to-severe CSU is associated with an increased risk of rheumatoid arthritis and Sjögren’s syndrome compared to mild CSU. Citation: Smart K, Ure A, Johnsen N, Aflatooni S, Cortes JA, Palma G, et al. (2026) Moderate-to-severe chronic spontaneous urticaria is associated with increased risk of immune-mediated diseases: A population-based study. PLoS One 21(9): e0358883. https://doi.org/10.1371/journal.pone.0358883 Editor: Cheorl-Ho Kim, Sungkyunkwan University - Suwon Campus: Sungkyunkwan University - Natural Sciences Campus, KOREA, REPUBLIC OF Received: March 4, 2026; Accepted: September 7, 2026; Published: September 23, 2026 Copyright: © 2026 Smart et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The data that support the findings of this study are available from TriNetX, but restrictions apply to the availability of these data, which were used under license for the current study and are not publicly available. Data request inquiries can be submitted via https://trinetx.com/ . Funding: The author(s) received no specific funding for this work. Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: AWA has served as a research investigator, scientific advisor, or speaker to AbbVie, Alumis, BMS, Galderma, Leo, UCB, J&J, Lilly, Novartis, Sun, Sanofi, Takeda, Regeneron, and Pfizer. KS, AU, NJ, SA, JAC, GP, YN, AJB, and PCL have no conflicts of interest to disclose. Introduction Chronic spontaneous urticaria (CSU) affects approximately 1% of individuals and is most prevalent in females aged 30–50 years old, highlighting the need to further investigate the immune-mediated comorbidities associated with CSU [ 1 – 3 ]. Approximately 10.5% to 28% of individuals with CSU are estimated to have at least one autoimmune comorbidity [ 3 – 6 ]. To our knowledge, no prior studies have analyzed whether the risk of developing these immune-mediated conditions differs based on CSU disease severity. Therefore, while a diagnosis of CSU has been associated with an increased risk of autoimmune conditions, there is a critical need to evaluate whether the severity of CSU influences the likelihood of developing immune-mediated comorbidities [ 4 , 7 – 9 ]. The severity of CSU can be considered as two groups: mild and moderate-to-severe. Those with mild disease are typically controlled with second generation antihistamines [ 10 ]. Those with more moderate-to-severe disease typically need additional therapies. These patients then can be considered candidates for treatment with omalizumab, dupilumab, remibrutinib, and cyclosporine [ 11 ]. This study aims to elucidate whether patients with treatment-defined moderate-to-severe CSU are at greater risk for developing immune-mediated conditions compared to patients with milder disease. Materials and methods Data source We conducted a retrospective cohort study using the TriNetX US Collaborative Network database from 2014 to 2026. Data was captured and analyzed on May 24, 2026. All data were de-identified, and this study was considered exempt from review by the University of California, Los Angeles Institutional Review Board. Study population The moderate-to-severe disease cohort was defined as patients ≥18 years old with at least 2 ICD-10 diagnoses of idiopathic urticaria (L50.1, L50.8, L50.9) six weeks apart who were treated with omalizumab, dupilumab, or cyclosporine. These treatments were chosen as they are the most commonly prescribed medications for patients who fail second-generation antihistamines [ 10 ]. Our mild disease cohort was defined as patients ≥18 years old with at least 2 ICD-10 diagnoses of idiopathic urticaria six weeks apart who were never treated with biologics or cyclosporine. Patients with a diagnosis of atopic dermatitis (AD) were excluded from both cohorts to avoid confounding as patients may be treated with dupilumab for AD. ICD-10 and RxNorm codes used are listed in Table 1 . Download: PNG larger image TIFF original image Table 1. ICD-10 Codes and RxNorm Codes Used For Cohort Creation and Propensity Score Matching. https://doi.org/10.1371/journal.pone.0358883.t001 We propensity matched patients with moderate-to-severe disease to age-, sex-, race-, and ethnicity-matched counterparts with mild disease. Patients were also matched on comorbid asthma, obesity, tobacco use, family history of several autoimmune conditions, and socioeconomic factors related to insurance coverage and income. Propensity score matching was performed within the TriNetX platform using logistic regression to estimate the propensity score and 1:1 greedy nearest-neighbor matching with caliper width of 0.1 pooled standard deviations (SD). Standard mean differences (SMD) are reported in Table 2 . After matching, 16,413 patients were included in the moderate-to-severe cohort, and 16,413 patients were included in the mild cohort. Baseline characteristics after matching are listed in Table 2 . Download: PNG larger image TIFF original image Table 2. Baseline Characteristics After 1:1 Greedy Nearest Neighbor Propensity Score Matching. https://doi.org/10.1371/journal.pone.0358883.t002 Time period The index date was defined as the second diagnosis of idiopathic urticaria in both groups. Patients with the outcomes of interest (immune-mediated comorbidities) prior to the index date were excluded. Patients were censored at the earliest diagnosis of the comorbidity of interest or at the end of the study period. Data analysis Analysis was conducted using the TriNetX software. Odd ratios of developing each immune-mediated comorbidity at least 1 day after the index date (second diagnosis of idiopathic urticaria) were calculated. The incidence rates of immune-mediated comorbidities were calculated, and these rates were compared using the incidence rate ratio. Results Cohort demographics The average age at diagnosis of CSU was 45.7 years in both groups. Our cohort was 77.6% female, 20.2% male, 72.0% non-Hispanic/Latino, 8.0% Hispanic/Latino, 20.0% Unknown Ethnicity, 70.3% White, 11.0% Black, 4.2% Asian, 0.4% American Indian/Alaska Native, 0.2% Native Hawaiian/Other Pacific Islander, 4.4% Other Race, and 9.4% Unknown Race. Odds of immune-mediated comorbidities Patients with moderate-to-severe CSU had a statistically significant increased odds of developing rheumatoid arthritis OR=1.34 (95% CI: 1.12 to 1.60, p = 0.001) and Sjögren’s syndrome OR=1.04 (1.63–2.56, p < 0.0001), after adjusting for clinical factors and multiple hypothesis testing (Bonferroni’s alpha ≤0.00333). There was no statistically significant difference in the odds of developing autoimmune thyroiditis OR=1.17, (95% CI: 0.97–1.41), vitiligo OR= 0.98 (95% CI: 0.61–1.56), pernicious anemia OR=0.54 (95% CI: 0.32–0.92), systemic lupus erythematosus (SLE) OR=1.03 (95% CI: 0.80–1.32), celiac disease OR=1.32 (95% CI: 0.94–1.85), Graves’ disease OR=0.89 (95% CI: 0.63–1.25), Crohn’s disease OR=1.32 (95% CI: 0.88–1.98), ulcerative colitis (UC) OR=0.97 (95% CI: 0.71–1.31), scleroderma OR= 1.44 (95% CI: 0.76–2.73), fibromyalgia OR=1.23 (95% CI: 1.06–1.43, type 1 diabetes mellitus OR= 1.09 (95% CI: 0.79–1.52), psoriatic arthritis OR=1.37 (95% CI:0.96–1.96), and psoriasis OR= 1.21 (95% CI: 0.98,1.49). Odds ratios are depicted in Fig 1 . Download: PNG larger image TIFF original image Fig 1. Forest plot showing odds ratios (ORs) and 95% confidence intervals for immune-mediated comorbidities among patients with chronic spontaneous urticaria (CSU). Odds ratios were adjusted for demographic and clinical covariates including age, sex, race/ethnicity, baseline comorbidities, and family history. Error bars represent 95% confidence intervals, and statistical significance was defined as p ≤ 0.00333. https://doi.org/10.1371/journal.pone.0358883.g001 Incidence rates of immune-mediated comorbidities The incidence rate for rheumatoid arthritis in the moderate-to-severe CSU cohort was 1.52 cases per 1000 person-years, while the incidence rate for rheumatoid arthritis in the mild CSU cohort was 1.14 cases per 1000 person-years. The incidence rate ratio for rheumatoid arthritis was 1.33 (95% CI: 1.12 to 1.60, p = 0.0014). The incidence rate for Sjögren’s syndrome in the moderate-to-severe CSU cohort was 1.20 cases per 1000 person-years, while the incidence rate for Sjögren’s syndrome in the mild CSU cohort was 0.59 cases per 1000 person-years. The incidence rate ratio for Sjögren’s syndrome was 2.03 (95% CI: 1.62 to 2.53, p < 0.0001). Cumulative incidence of immune-mediated comorbidities The cumulative incidence of rheumatoid arthritis was 285 patients (1.8%) in the moderate-to-severe CSU cohort compared to 217 patients (1.4%) in the mild CSU cohort (p = 0.0013). The cumulative incidence of Sjögren’s syndrome was 226 patients (1.4%) in the moderate-to-severe CSU cohort and 115 patients (0.7%) in the mild CSU cohort (p < 0.0001). Kaplan Meier estimates depicting time to event analyses for rheumatoid arthritis and Sjögren’s syndrome are shown in Figs 2 and 3 . Download: PNG larger image TIFF original image Fig 2. Kaplan-Meier curve demonstrating time to development of rheumatoid arthritis among patients with moderate-to-severe CSU compared with mild CSU. Time-to-event analyses were performed using Cox proportional hazards modeling adjusted for relevant demographic and clinical covariates, including age, sex, race/ethnicity, baseline comorbidities, and family history. https://doi.org/10.1371/journal.pone.0358883.g002 Download: PNG larger image TIFF original image Fig 3. Kaplan-Meier curve demonstrating time to development of Sjögren’s syndrome among patients with moderate-to-severe CSU compared with mild CSU. Time-to-event analyses were performed using Cox proportional hazards modeling adjusted for relevant demographic and clinical covariates, including age, sex, race/ethnicity, baseline comorbidities, and family history. https://doi.org/10.1371/journal.pone.0358883.g003 Absolute risk difference of immune-mediated comorbidities The absolute risk difference of developing these immune-mediated conditions in patients with moderate-to-severe CSU compared to those with mild CSU was calculated. Patients with moderate-to-severe CSU had a 0.5% increased absolute risk of developing rheumatoid arthritis (p = 0.0013) and a 0.7% increased absolute risk of developing Sjögren’s syndrome (p < 0.0001), as shown in Fig 4 . Download: PNG larger image TIFF original image Fig 4. Absolute risk of immune-mediated comorbidities among age-, sex-, race/ethnicity-, baseline comorbidity-, and family history-propensity score-matched patients with moderate-to-severe CSU and mild CSU. For each outcome, the number of patients who developed the immune-mediated comorbidity was calculated among patients at risk within each matched cohort and compared between groups. Absolute risk is presented as the proportion of patients developing each outcome during the study period. Statistical significance was adjusted using Bonferroni’s alpha ≤0.00333. https://doi.org/10.1371/journal.pone.0358883.g004 Discussion This is among the initial efforts to characterize CSU-associated immune-mediated conditions based on treatment-defined disease severity. More severe CSU disease correlates with an increased risk of new-onset rheumatoid arthritis and Sjögren’s syndrome. While CSU has been associated with various autoimmune conditions in the literature, our findings corroborate and expand upon the existing literature by demonstrating that CSU disease severity correlates with the risk of some, but not all, new-onset immune-mediated comorbidities [ 2 , 4 , 5 , 10 , 12 ]. Our findings are based on robust analysis using multiplicity adjustment. This knowledge is important to anticipate the prognosis and disease course of CSU and optimize care management for these patients. The pathogenesis of CSU may be linked to the development of rheumatoid arthritis through shared autoimmune pathways, genetic susceptibility, and the presence of autoantibodies. Patients with CSU have an increased prevalence of rheumatoid factor and antinuclear antibody, possibly indicating a shared autoimmune pathogenesis between rheumatoid arthritis and CSU [ 4 ]. A prior genome-wide association study (GWAS) revealed that the PTPN22 gene is associated with increased risk for both rheumatoid arthritis and CSU [ 12 ]. Another study using polygenic risk score (PRS) found a genetic relationship between CSU and rheumatoid arthritis [ 13 ]. Additionally, a mendelian randomization analysis also showed a genetic association between rheumatoid arthritis and CSU, but not between CSU and SLE, UC, or Crohn’s disease [ 14 ]. These shared genetic pathways observed in prior literature potentially further explain our finding that more severe CSU disease is associated with an increased risk of rheumatoid arthritis. Prior research on Sjögren’s syndrome is much more limited. The authors hypothesize that this association between more severe CSU disease and Sjögren’s syndrome may be due to shared immune-mediated pathways; however, further research is needed to elucidate this mechanism. Given that we did not find a statistically significant difference in the odds of new onset autoimmune thyroid disease (AITD), we suggest that the type IIb CSU subtype, rather than more severe CSU, is associated with increased risk for AITD. This hypothesis is driven by prior studies that showed CSU patients who had increased IgE-anti-TPO expression also had increased IgG-anti-TPO expression, a diagnostic indicator of AITD [ 15 , 16 ]. In this subset of CSU patients, IgE-anti-TPO antibodies, among others, bind to and degranulate mast cells, resulting in recurrent hives [ 17 ]. Further studies are needed to investigate this possible association. Importantly, the risk of several other autoimmune conditions, namely vitiligo, pernicious anemia, systemic lupus erythematosus, celiac disease, Graves’ disease, Crohn’s disease, ulcerative colitis, scleroderma, fibromyalgia, type 1 diabetes mellitus, psoriatic arthritis, and psoriasis, was not significantly increased in patients with more severe CSU disease. Therefore, we suggest that these immune-mediated conditions may not share the same pathway as CSU. However, further research is necessary to elucidate these relationships. In our study, there is a potential for misclassification due to the nature of utilizing large database electronic health record (EHR) data and the use of treatment type as a proxy for disease severity. Medication indication is not available within this database, resulting in potential misclassification and off-label use. Another limitation is the potential for detection bias, as patients with more severe CSU may have more frequent healthcare visits, potentially leading to earlier diagnosis of comorbidities. Because validated CSU activity measures were unavailable in TriNetX, treatment escalation was used as a proxy for moderate-to-severe disease. This treatment-defined severity measure may be influenced by access, insurance coverage, prescribing patterns, and healthcare utilization, creating potential misclassification. Thus, findings should be interpreted as associations with treatment-defined moderate-to-severe CSU rather than direct clinical severity. Nevertheless, our findings emphasize the importance of comprehensive interdisciplinary management of patients with CSU, especially those presenting with more severe disease. These patients will need to be followed closely for the development of comorbid immune-mediated diseases, particularly rheumatoid arthritis and Sjögren’s syndrome. Acknowledgments IRB approval: This study was considered exempt from review by the University of California, Los Angeles Institutional Review Board because the study used deidentified data. References 1. Pourali SP, Gutierrez Y, Kucharik AH, Rajkumar JR, Jones ME, Armstrong AW. Chronic spontaneous urticaria in the United States: Patient characteristics and treatment patterns. Int J Dermatol. 2022;61(8):e308–9. pmid:34370872 View Article PubMed/NCBI Google Scholar 2. Sánchez-Borges M, Ansotegui IJ, Baiardini I, Bernstein J, Canonica GW, Ebisawa M, et al. The challenges of chronic urticaria part 1: Epidemiology, immunopathogenesis, comorbidities, quality of life, and management. World Allergy Organ J. 2021;14(6):100533. pmid:34221215 View Article PubMed/NCBI Google Scholar 3. Kolkhir P, Bonnekoh H, Metz M, Maurer M. Chronic spontaneous urticaria: a review. JAMA. 2024;332(17):1464–77. View Article Google Scholar 4. Confino-Cohen R, Chodick G, Shalev V, Leshno M, Kimhi O, Goldberg A. Chronic urticaria and autoimmunity: Associations found in a large population study. J Allergy Clin Immunol. 2012;129(5):1307–13. pmid:22336078 View Article PubMed/NCBI Google Scholar 5. Kolkhir P, Altrichter S, Asero R, Daschner A, Ferrer M, Giménez-Arnau A, et al. Autoimmune diseases are linked to type IIb autoimmune chronic spontaneous urticaria. Allergy Asthma Immunol Res. 2021;13(4):545–59. pmid:34212543 View Article PubMed/NCBI Google Scholar 6. Buttgereit T, Vera C, Aulenbacher F, Church MK, Hawro T, Asero R, et al. Patients with chronic spontaneous urticaria who have wheals, angioedema, or both, differ demographically, clinically, and in response to treatment-results from CURE. J Allergy Clin Immunol Pract. 2023;11(11):3515–3525.e4. pmid:37604426 View Article PubMed/NCBI Google Scholar 7. Patel D, Pathak N, Alani O, Singal A, Lipner SR. Autoimmune associations with chronic spontaneous urticaria: A retrospective cohort analysis. JAAD Int. 2025;21:44–6. pmid:40672397 View Article PubMed/NCBI Google Scholar 8. Pourali SP, Kohn AH, Jones ME, Armstrong AW. Chronic spontaneous urticaria: A 16-year analysis of pediatric patient demographics, treatment patterns, and comorbidities. Dermatol Online J. 2021;27(8). pmid:34755971 View Article PubMed/NCBI Google Scholar 9. Kaplan A, Lebwohl M, Giménez-Arnau AM, Hide M, Armstrong AW, Maurer M. Chronic spontaneous urticaria: Focus on pathophysiology to unlock treatment a
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