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The underlying mechanisms remain poorly understood, complicating diagnosis and treatment. This systematic review examines the diagnostic work\u2010up and therapeutic approaches for CPUO, evaluating the quality of treatment studies using the Strength of Recommendation Taxonomy (SORT) algorithm. Our paper also uniquely integrates a review of potential pathogenic mechanisms. A comprehensive literature search was conducted in PubMed, EMBASE, Ovid MEDLINE, and Cochrane databases through September 2025 using terms including \u201cCPUO,\u201d \u201cchronic idiopathic pruritus,\u201d and \u201cpruritus of unknown origin.\u201d Studies discussing pathogenesis, diagnostic strategies, or treatment were included. Treatment interventions were assessed based on the SORT algorithm. Of 228 identified records, 52 met inclusion criteria: 18 addressing pathogenesis, 5 discussing competing etiological hypotheses, 3 focusing on diagnostic work\u2010up, 23 on treatment, and 3 on non\u2010pharmacological therapies. CPUO pathogenesis appears multifactorial, involving Th2 dysregulation, neurogenic factors (JAK1, GRPR, TRPV4), metabolic alterations, and aging\u2010related immune changes. Current diagnostic approaches emphasize exclusion of systemic, dermatologic, and neurologic causes. Treatment options include topical agents (calcineurin inhibitors, capsaicin), systemic immunomodulators (JAK inhibitors, dupilumab, nemolizumab), neuromodulators (gabapentin, pregabalin), and phototherapy. However, available treatment studies are of low quality, with few randomized controlled trials (RCTs). CPUO remains a challenging condition with unclear pathophysiology and limited high\u2010quality therapeutic evidence. Further research, particularly RCTs, is needed to establish evidence\u2010based management strategies.<\/jats:p>","DOI":"10.1111\/ijd.70259","type":"journal-article","created":{"date-parts":[[2026,1,14]],"date-time":"2026-01-14T11:04:51Z","timestamp":1768388691000},"page":"706-723","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Pathogenesis and Therapeutics for Chronic Pruritus of Unknown Origin: A Systematic Review"],"prefix":"10.1111","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9851-8523","authenticated-orcid":false,"given":"Yagiz Matthew","family":"Akiska","sequence":"first","affiliation":[{"name":"Department of Dermatology University of Maryland School of Medicine  Baltimore Maryland USA"},{"name":"Maryland Itch Center University of Maryland School of Medicine  Baltimore Maryland 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