Chronic spontaneous urticaria (CSU) is characterized by mast cell and basophil activation, resulting in the emergence of hives in different areas of the body. Two endotypes have been identified in CSU, and, although initial treatment selection may not be substantially influenced by endotype, total serum IgE levels may influence therapeutic decision making.

There are 2 endotypes relevant to CSU mediated by IgE or IgG autoantibodies. The endotype involving IgE autoantibodies has been estimated to account for as few as 30% to as many as 70% of cases. The endotype involving IgG autoantibodies may account for up to 40% of cases. Patients can have both processes going on simultaneously.

The implications for therapy are interesting. One of the main therapies for CSU after antihistamines fail is the monoclonal antibody omalizumab, which binds to IgE so that blood levels go down to almost nothing. If you eliminate IgE, it no longer binds to IgE receptors on mast cells and basophils and therefore no longer interacts with autoantigens that may be present. The relief of hives with omalizumab in patients with this endotype can be rapid, with some individuals not having any hives within 1 or 2 weeks after getting a single shot of omalizumab.

With the other endotype, omalizumab works a little differently because IgG autoantibodies are directed against unoccupied IgE receptors. When you bind IgE with omalizumab, the body downregulates the IgE receptors so that there are fewer unoccupied receptors for the IgG autoantibodies to activate. With this endotype, symptom relief may take longer (ie, perhaps 3 to 8 weeks) because it takes longer to see the effects from downregulating the IgE receptors than it does to simply bind to the existing IgE. Nonetheless, the vast majority of patients who respond to omalizumab do so with 2 or 3 monthly injections.

Time to response should not substantially impact treatment choice. Theoretically, there is a difference in the timing of response between the 2 CSU endotypes, but, regardless of endotype, you will know by the third injection whether you have a super-responder, a partial responder, or a nonresponder. The guidelines say that CSU therapy should begin with antihistamines. If patients fail antihistamine therapy, they receive omalizumab. If they fail omalizumab therapy, they are given cyclosporine. In short, treatment recommendations apply irrespective of patient endotype.

However, the consideration of a patient’s total serum IgE level remains important for reasons that are only partially related to mechanism. Generally, patients with allergies have elevated total IgE levels, but the question is: Do patients with CSU have higher-than-normal total IgE levels? Considering omalizumab’s mechanism of action, it is surprising that the difference in total IgE levels between nonallergic people and individuals with CSU is only a small increment in favor of CSU. When you look at people with CSU as a group, some patients have very low total IgE levels. This suggests that the total serum IgE level as a biomarker can influence choice of therapy such that you would be less likely to use omalizumab in a patient with a very low total IgE level. Providers may still choose to try omalizumab in these patients, hoping that it might work, or they may not and instead go directly to cyclosporine after an antihistamine failure, especially if the patient has very severe hives. In such cases, one could make the argument that the total serum IgE level might dictate the choice of therapy. Nevertheless, guidelines indicate that omalizumab should be tried, even for those with low IgE, mainly because of the side-effect profile of cyclosporine.

The consideration of total serum IgE levels also highlights a need for new drug targets in CSU. First, there are patients who do not respond to antihistamines, omalizumab, or cyclosporine. One investigational agent, barzolvolimab, is a monoclonal antibody against the KIT receptor, which is essential for mast cell survival and function. This antibody might actually deplete cutaneous mast cells. Another agent, remibrutinib, inhibits BTK, which is essential for mast cell function. Inhibiting BTK also makes mast cells less responsive to activating stimuli. Ongoing research suggests that mast cell–suppressive agents are the future for CSU treatment.