Targeted Therapy for Antihistamine-Refractory Chronic Spontaneous Urticaria: A Critical Narrative Review and an Evidence-Graded Approach to Agent Selection

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-4Rα) 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—creating 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—omalizumab (anti-IgE, first-line), dupilumab (anti-IL-4Rα), 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.