Second-generation H1-antihistamines do not alter dementia risk in type 2 inflammatory diseases: A target trial emulation using real-world data

BACKGROUND: Type 2 chronic inflammatory diseases such as chronic urticaria (CU), chronic sinusitis (CS), and allergic rhinitis (AR) are commonly treated with second-generation H1-antihistamines (sgAH). Although considered safe, concerns exist about a possible association with dementia risk. OBJECTIVE: To determine whether sgAH are associated with increased dementia risk in patients with CU, CS, or AR. METHODS: We conducted a target trial emulation using real-world data from the TriNetX electronic health record network. Patients aged ≥50 years with CU, CS, or AR and no prior dementia diagnosis were included. Treatment groups comprised users of sgAH, first-generation H1-antihistamines (fgAH), or non-antihistamine alternatives (intranasal steroids for AR/CS, oral steroids for CU). Propensity-score matching was applied across 38 covariates. Dementia incidence was assessed over 5 years using Kaplan-Meier survival analysis and Cox proportional hazards models. RESULTS: After matching, 48,238 patients with CU, 21,611 with CS, and 36,802 with AR were analyzed alongside equal-sized control groups. Across all comparisons, no increased dementia risk was observed for users of any antihistamine versus non-antihistamine controls. No differences were found between sgAH and fgAH or steroid users. Intranasal steroids use in patients with AR was associated with a slight decrease in dementia risk (p=0.007). CONCLUSION: Overall, our findings do not support increased dementia risk associated with sgAH use. Lower dementia rates in patients with AR treated with corticosteroids might be associated with the protective effects of corticosteroids rather than harmful effects of sgAH.