{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T17:11:06Z","timestamp":1790097066849,"version":"4.0.1"},"reference-count":35,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibodies"],"abstract":"<jats:p>Background\/Objectives: Chronic spontaneous urticaria (CSU) is a mast-cell-driven disease with autoimmune mechanisms and an incompletely clarified aetiology, in which a substantial proportion of patients remain symptomatic despite second-generation H1-antihistamines; until recently, omalizumab was effectively the only targeted option, leaving a considerable non-responder fraction. Between February 2024 and September 2025 the landscape changed: dupilumab (anti-IL-4R\u03b1) and the first oral Bruton tyrosine kinase (BTK) inhibitor, remibrutinib, were approved for CSU; omalizumab biosimilars reached the market; the higher-affinity anti-IgE antibody ligelizumab was discontinued; and the investigational anti-KIT antibody barzolvolimab advanced to phase 3\u2014creating new therapeutic opportunities for non-responders while leaving the choice among these second-line options unresolved by current guidelines. We provide a critical synthesis and propose an evidence-graded process for agent selection, together with a proposed repositioning of the available agents, taking the 2022 EAACI\/GA2LEN\/EuroGuiDerm\/APAAACI guideline as the acknowledged reference. Methods: Critical narrative review with a structured but non-systematic search (PubMed, ClinicalTrials.gov) and a pre-specified evidence hierarchy (guideline to expert opinion); each clinical claim is annotated by its level of evidence. Results: Four agents are appraised in turn\u2014omalizumab (anti-IgE, first-line), dupilumab (anti-IL-4R\u03b1), remibrutinib (oral BTK inhibitor, small-molecule comparator) and barzolvolimab (anti-KIT, investigational). Current evidence appears to support omalizumab as first-line, with mechanism-guided second-line choices conditioned on endotype, comorbidity, prior biologic exposure and safety. Conclusions: The complexity of CSU and the incomplete response to currently available therapies support a patient-tailored approach to treatment selection.<\/jats:p>","DOI":"10.3390\/antib15050088","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T13:32:12Z","timestamp":1790083932000},"page":"88","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeted Therapy for Antihistamine-Refractory Chronic Spontaneous Urticaria: A Critical Narrative Review and an Evidence-Graded Approach to Agent Selection"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-9678-6409","authenticated-orcid":false,"given":"Luca","family":"Guarino","sequence":"first","affiliation":[{"name":"Section of Dermatology, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4367-0341","authenticated-orcid":false,"given":"Giuseppe","family":"Rizzuto","sequence":"additional","affiliation":[{"name":"Section of Dermatology, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Coppolelli","sequence":"additional","affiliation":[{"name":"Section of Dermatology, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Scipione","sequence":"additional","affiliation":[{"name":"Section of Dermatology, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9084-8798","authenticated-orcid":false,"given":"Mirella","family":"Scattone","sequence":"additional","affiliation":[{"name":"Section of Dermatology, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0727-8314","authenticated-orcid":false,"given":"Luca","family":"Gargano","sequence":"additional","affiliation":[{"name":"Section of Dermatology, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5743-8746","authenticated-orcid":false,"given":"Pietro","family":"Scribani Rossi","sequence":"additional","affiliation":[{"name":"Section of Dermatology, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7948-8536","authenticated-orcid":false,"given":"Ester","family":"Del Duca","sequence":"additional","affiliation":[{"name":"Section of Dermatology, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9504-5882","authenticated-orcid":false,"given":"Annunziata","family":"Dattola","sequence":"additional","affiliation":[{"name":"Section of Dermatology, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7222-2951","authenticated-orcid":false,"given":"Giovanni","family":"Pellacani","sequence":"additional","affiliation":[{"name":"Section of Dermatology, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3828-0883","authenticated-orcid":false,"given":"Steven","family":"Nistic\u00f2","sequence":"additional","affiliation":[{"name":"Section of Dermatology, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3142-1831","authenticated-orcid":false,"given":"Camilla","family":"Chello","sequence":"additional","affiliation":[{"name":"Section of Dermatology, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1111\/all.14037","article-title":"Prevalence of chronic urticaria in children and adults across the globe: Systematic review with meta-analysis","volume":"75","author":"Fricke","year":"2020","journal-title":"Allergy"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1111\/all.15090","article-title":"The international EAACI\/GA2LEN\/EuroGuiDerm\/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria","volume":"77","author":"Zuberbier","year":"2022","journal-title":"Allergy"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.jaci.2024.01.028","article-title":"Dupilumab 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