Rapidly identifying H₁ antihistamine nonresponders is central to managing chronic spontaneous urticaria (CSU). Dose escalation quickly clarifies refractoriness and allows the timely transition to omalizumab or to newer agents such as dupilumab and remibrutinib, each of which offers distinct response rates and trajectories. Minimizing the use of cyclosporine because of its safety profile is an important treatment goal, with its use increasingly reserved for patients who do not respond to recommended treatment options.

The latest international guideline states that the treatment of CSU should begin with second-generation H₁ antihistamines at the standard dose level, and if the patient is not responsive, you can go as high as 4 times the standard dose to achieve response. The guideline does not instruct on how rapidly to increase the H₁ antihistamine dose, but my opinion is that it should be done quickly. In fact, if the patient presents with significant symptoms, I may go ahead and start the H₁ antihistamine at 4 times the standard dose instead of increasing the dose over time. If this works and their hives stop, then you can gradually decrease the H₁ antihistamine dose. If this does not work, you then know that the patient is refractory to antihistamines, and you have saved a lot of time. More than 50% of patients with CSU are not going to respond to antihistamines, even at the increased doses.

For patients who do not respond to H₁ antihistamines alone, step 2 in the guideline is to begin omalizumab therapy. In CSU, we have 2 standard dose options for omalizumab: either 150 or 300 mg once a month by injection. Approximately 40% of H₁ antihistamine–resistant patients achieve complete disease control and 65% to 70% have a significant response, as assessed by both the Urticaria Control Test (UCT) score and the Urticaria Activity Score over 7 days (UAS7). For patients with a partial response, that response may continue to increase over time, or you can consider increasing the dose or increasing the dosing frequency, although insurance coverage for this approach may be difficult.

You can treat the majority of patients with CSU with H₁ antihistamines or omalizumab. However, for people who are refractory to both, we now have 2 additional therapy choices: dupilumab and remibrutinib. In the latest guideline, dupilumab and remibrutinib are conditionally recommended to treat patients who experience omalizumab failure or to avoid using cyclosporine. The response rate with omalizumab is better than that with dupilumab, so I would choose omalizumab first. Remibrutinib is a BTK inhibitor, which is a totally new approach to managing CSU. It has a high response rate in patients who are unresponsive to antihistamines alone. Remibrutinib is taken orally rather than through injection, and its side effects are minimal.

If you follow the guideline, the next drug that is recommended, particularly after H₁ antihistamine and omalizumab nonresponse, is cyclosporine. Cyclosporine also demonstrates good efficacy in combination with H₁ antihistamines, but it has significant safety concerns, such as its effects on blood pressure and kidney function.

The overwhelming majority of patients with CSU can be treated successfully with available therapies following the latest guideline-directed approach. There is still a need for other drugs for refractory patients, and we would like to minimize the use of cyclosporine in the future.