Comorbidity Profile of Chronic Mast Cell–Mediated Angioedema Versus Chronic Spontaneous Urticaria

<b>Background:</b> Chronic mast cell-mediated angioedema (MC-AE) and chronic spontaneous urticaria (CSU) both involve mast cell activation but may differ in long-term systemic outcomes. Limited data exist comparing their comorbidity profiles over extended follow-up. <b>Objective:</b> To compare systemic comorbidities in patients with chronic MC-AE versus CSU using a large, population-based dataset. <b>Methods:</b> We conducted a retrospective matched case-control study using electronic health records from Leumit Health Services, a nationwide Israeli health maintenance organization. Patients diagnosed with chronic MC-AE between 2005 and 2023 (<i>n</i> = 2133) were matched 1:1 by age, sex, and year of diagnosis to patients with CSU (<i>n</i> = 2133). Comorbidities were assessed at diagnosis and after a mean follow-up of 10.2 ± 2.9 years. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Multivariable logistic regression was used to assess the association between medications and MC-AE diagnosis. <b>Results:</b> MC-AE patients exhibited significantly higher baseline rates of hypertension (23.8% vs. 18.5%), ischemic heart disease (5.67% vs. 3.84%), and type 2 diabetes (10.45% vs. 6.42%) compared to CSU. These differences persisted or increased at follow-up, including myocardial infarction (4.13% vs. 2.25%) and chronic kidney disease (4.13% vs. 2.91%). CSU patients had consistently higher rates of atopic dermatitis, viral infections, and herpes zoster. Statin use was inversely associated with MC-AE (adjusted OR = 0.63; 95% CI: 0.44-0.90). <b>Conclusions:</b> Chronic MC-AE is associated with a distinct and sustained cardiometabolic and renal comorbidity burden compared to CSU, supporting its classification as a systemic disease phenotype requiring differentiated long-term care.