As the treatment landscape for chronic spontaneous urticaria (CSU) continues to evolve, new targeted therapies are expanding the options for patients who do not respond to second-generation nonsedating H₁ antihistamines. These targeted therapies, which include omalizumab, dupilumab, and remibrutinib, offer distinct mechanisms of action and broaden the treatment choices for individual patients with CSU, increasing the potential for symptom relief and control.

I always tell people that the first thing to do is to make sure that the patient really does have CSU. Urticaria can present in many different forms, and the patient could be resistant to therapy if the diagnosis is wrong.

If we are convinced that the patient really has CSU, then we start with second-generation nonsedating H₁ antihistamine therapy. Sedating antihistamines have not demonstrated that they work better than nonsedating antihistamines, and we are concerned about sedation, impairment, and work and school productivity. If the patient does respond to second-generation nonsedating H₁ antihistamines, the response tends to be fairly rapid (ie, usually within 2 weeks). If there is no response, we go to 2-fold the licensed dose, and then to 4-fold the licensed dose after another 2 weeks. However, even at 4-fold the licensed dose, nearly 50% of patients do not have a full resolution of their CSU.

We now have 3 US Food and Drug Administration (FDA)–approved options for patients with CSU who are unresponsive to second-generation nonsedating H₁ antihistamines, opening up new avenues for treatment. In the past, after patients failed antihistamine therapy, we would start with omalizumab 150 mg or 300 mg because that was the only FDA-approved targeted therapy for CSU. But now we also have dupilumab and remibrutinib, which were just added to the new international urticaria guidelines.

Dupilumab, an injectable IL-4Rα blocker that inhibits the signaling of IL-4 and IL-13, can be administered at home every 2 weeks. In pivotal studies, dupilumab reduced itch and urticaria activity at week 24 in patients who were uncontrolled with antihistamines.

Remibrutinib, an oral medication taken twice daily, represents an entirely different paradigm for treating CSU. Remibrutinib blocks BTK, an important downstream signaling factor involved with IgE and high-affinity IgE receptors. Stimulating those receptors leads to mast cell and basophil degranulation, which can cause the signs and symptoms of CSU. So, whereas omalizumab prevents binding to the IgE receptor, remibrutinib prevents the downstream effects of stimulating that receptor. In a recent study, at 12 weeks, remibrutinib also had very good data for improvement of Urticaria Activity Score over 7 days (UAS7), which was sustained through week 24, and the drug was shown to be fairly safe.

Once we put patients on 1 of these 3 therapies, we typically bring them back periodically to see if they are responding. If they are not responding to 1 of them, my personal approach is to try another from the remaining agents in the group next vs considering cyclosporine. The data for cyclosporine use in CSU are limited, and it is not FDA approved. The other problem with cyclosporine is, of course, its significant safety concerns, so I would consider using these other agents instead.