Predicting treatment response in chronic spontaneous urticaria (CSU) remains challenging. Antihistamines help many patients, but nonresponders may require advanced therapies, for which clear predictive biomarkers are still lacking. Emerging data on omalizumab response groups and evolving insights into CSU endotypes highlight the need for additional research to help guide individualized treatment.

The goal for my patients with CSU is to achieve total control, and that means no hives, no itch, and no swelling. A recent guideline recommends starting treatment for CSU with a licensed dose of a second-generation H₁ antihistamine and up-dosing up to 4-fold the standard dose, as needed. This approach is effective in many patients, has a favorable safety profile, and is accessible. However, if a patient is not responding to 4-fold the licensed dose of the second-generation H₁ antihistamine within 2 to 4 weeks, then we will consider advanced therapies.

With omalizumab, 3 response groups have been identified. Group 1 (approximately 60% to 70% of patients) includes early responders who respond well within 1 to 4 weeks. Group 2, making up approximately 15% to 20% of patients, consists of late responders who respond well before week 24. Finally, the 5% to 10% of patients who do not respond to omalizumab by week 24 or beyond, even with up-dosing beyond the licensed dose, are in group 3. My colleagues and I published a paper showing that late responders to omalizumab therapy (ie, individuals who respond by week 24) tend to have lower baseline IgE, a higher body mass index, are younger, and have greater disease activity. For patients who may be in this group, I can set expectations for them by saying that we have to give the treatment some time to work.

For dupilumab and remibrutinib, which came on the market for CSU more recently, it might still be too soon to say what predicts response. It would be great to have highly specific biomarkers to identify who is going to be an early or late responder to CSU treatments to help guide therapy selection and set patient expectations. However, right now, we do not have definitive predictive biomarkers. A lot more research is needed.

Knowing the different CSU endotypes (type 1 and type 2B) is important for understanding how different advanced therapies may work. In type 1 CSU (autoallergic), an IgE antibody binds to the FcεRI receptor on a mast cell. When 2 IgE antibodies that are bound to the FcεRI receptor are cross-linked by an autoantigen, they send a signal into the cell, and the mast cell degranulates and releases histamine. The type 2B (autoimmune) endotype is more IgG mediated, but everything still goes through the FcεRI receptor to cause the mast cell to degranulate.

Omalizumab binds to free IgE in the bloodstream and downregulates the number of FcεRI receptors on the mast cells, and dupilumab blocks IL-4, reducing class switching to IgE. Remibrutinib acts as a BTK inhibitor, stopping the process wherein the FcεRI receptor sends the signal downstream intracellularly through BTK to cause mast cell degranulation.

However, type 1 CSU and type 2B CSU are only 2 mechanisms of action. There are also other mechanisms and pathways that we are identifying. It is so exciting that we are continuing to learn so much about CSU and all these different pathways.