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Renal, hepatobiliary, endocrine, metabolic, hematologic, malignant, neuropathic and drug\u2010induced conditions account for approximately 10%\u201315% of chronic pruritus. In many patients, itch represents the earliest clinical signal of underlying pathology. Traditional explanations based on isolated circulating pruritogens, such as urea or bile acids, fail to explain the poor correlation between biochemical markers and itch severity and the limited efficacy of antihistamines in most systemic forms of pruritus. Increasing evidence supports the concept that systemic pruritus is best understood as a disorder of neuroimmune signalling. Chronic immune activation, cytokine\u2010mediated neuronal sensitization, altered endogenous opioid balance, peripheral nerve dysfunction and central nervous system amplification interact across primary, secondary and tertiary itch pathways to generate persistent and often severe symptoms. This review integrates current mechanistic insights into the neuroimmune basis of systemic pruritus with a structured diagnostic approach and a mechanism\u2010based therapeutic framework. Recognizing systemic pruritus as a neuroimmune disorder facilitates earlier identification of underlying disease and enables a rational, targeted approach to treatment aimed at improving symptom control and patient quality of life.<\/jats:p>","DOI":"10.1111\/jdv.70737","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T12:11:17Z","timestamp":1790856677000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Systemic pruritus as a neuroimmune disorder: Mechanistic insights and target\u2010driven therapy"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9421-3546","authenticated-orcid":false,"given":"Reinhart","family":"Speeckaert","sequence":"first","affiliation":[{"name":"Department of Dermatology Ghent University Hospital  Ghent 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