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Background: Chronic pruritus (CP) is a poorly characterized condition associated with intense pruritus without a primary skin eruption. This condition tends to emerge more commonly in older adults, and there is limited research on triggering factors., Objective: To explore the clinical characteristics and pathophysiology of CP following exposure to an immune stimulus., Methods: Clinical characteristics and plasma samples were collected from 15 patients who developed CP following an immune stimulus such as checkpoint inhibitors or vaccination. A multiplex panel was used to analyze plasma cytokine concentrations within these patients., Results: Most immunotherapy-treated patients experienced CP during treatment or after 21 to 60 days of receiving treatment, while vaccine-stimulated patients developed pruritus within a week of vaccination. Plasma cytokine analysis revealed elevated levels of 12 cytokines in patients with immune-stimulated CP compared to healthy controls. Notably, T helper 2 (Th2) related cytokines interleukin (IL)-5 (fold change 2.65; q < 0.25) and thymic stromal lymphopoietin (fold change 1.61 q < 0.25) were upregulated., Limitations: Limitations of this study include limited sample size, particularly in the plasma cytokine assay., Conclusions and Relevance: This study reveals triggers of CP development and describes alterations in blood Th2 markers in patients with CP, including IgE, increased blood eosinophils, and cytokines IL-5 and thymic stromal lymphopoietin., Competing Interests: Dr Shawn Kwatra is an advisory board member or consultant for AbbVie, Celldex Therapeutics, Incyte Corporation, Galderma, Pfizer Inc, Regeneron Pharmaceuticals, and Menlo Therapeutics; and is a recipient of a Dermatology Foundation Medical Dermatology Career Development Award., (© 2024 by the American Academy of Dermatology, Inc. Published by Elsevier Inc.)