<p>Chronic spontaneous urticaria (CSU) is driven by multiple complex immune pathways. Advances in the understanding of CSU pathogenesis, especially the roles of mast cells, IgE, and cytokines, have led to the introduction of novel therapies. New biologics and small molecules are helping clinicians move beyond antihistamines toward more targeted and effective treatment.</p>

CSU is not typically attributable to an allergen or irritant, which is a common misconception. Patients with CSU have symptoms of itchiness and hives that last for at least 6 weeks, and this can lead to significant morbidity and decreased quality of life. Right now, the paradigm for management is using a nonsedating H₁ antihistamine, but many patients do not respond to the standard dose; even at 4 times the recommended dose, approximately 40% to 45% of patients still do not achieve satisfactory control. For these individuals, we add omalizumab therapy, which provides relief for many patients with CSU. We have learned more about CSU pathogenesis from omalizumab because it works by binding to IgE to rapidly reduce IgE levels, and patients with higher IgE levels typically have a good response to omalizumab.

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We know that mast cells are critical for urticaria pathogenesis, so shutting off the mast cell might lead to more effective therapies, or at least alternative therapies. One therapeutic strategy that is being investigated is mast cell activation inhibition by, for example, targeting BTK, which can lead to mast cell degranulation. The BTK inhibitor remibrutinib was just studied in the completed phase 3 REMIX-1 and -2 trials, in which add-on remibrutinib therapy demonstrated improved urticaria control as early as week 2, as measured by the weekly Urticaria Control Test (UCT7), with sustained improvements through week 52. Another BTK inhibitor, rilzabrutinib, was studied in the completed phase 2 RILECSU trial and was also shown to be effective in patients with moderate to severe CSU.

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There are multiple other strategies that are also being investigated for inhibiting mast cell activation. For example, there was a recent trial of tezepelumab, which blocks the alarmin TSLP, although it was not successful. Another possibility that is being explored in clinical trials is to block MRGPRX2, a receptor on mast cells that acts independently of IgE. A third approach to inhibiting mast cell activation could be through SIGLEC6 molecules. These molecules have a potential dual mechanism, both by inhibiting mast cell activation and by reducing mast cell numbers, but positive results are lacking.

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Finally, taking out mast cells by inhibiting KIT might be a way to effectively treat CSU. Both barzolvolimab and briquilimab are KIT inhibitors. In phase 2 trials, barzolvolimab significantly improved weekly Urticaria Activity Scores (UAS7) and weekly Itch Severity Scores (ISS7) at 12 weeks. In the phase 1b/2a BEACON study, briquilimab promoted reductions in serum tryptase and improved symptom scores.

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Attacking key cytokines is another therapeutic strategy that is being investigated for CSU. IL-4 and IL-13 are critical for making IgE, upregulating adhesion molecules, increasing itch, and amplifying the type 2 inflammatory response. The monoclonal antibody dupilumab binds to IL-4Rα, which is the common receptor for both IL-4 and IL-13. In the pivotal 24-week phase 3 LIBERTY-CSU CUPID Study A trial, dupilumab significantly reduced itch and UAS7.

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With all these agents, we are getting new strategies for treating CSU. Ultimately, our challenge will be to define specific phenotypes and corresponding endotypes with point-of-care biomarkers that can lead a clinician to determine whether a patient is most likely to respond to a particular drug and, hopefully, provide a better therapeutic approach for patients with CSU.