Chronic spontaneous urticaria (CSU) is a biologically heterogeneous disease. A presentation at the recent 2026 AAAAI Annual Meeting highlighted the evolving understanding of CSU endotypes, phenotypes, and biomarkers.

Following this presentation, featured expert David M. Lang, MD, was interviewed by Conference Reporter Editor-in-Chief Tom Iarocci, MD. Clinical perspectives from Dr Lang on this discussion are presented here.

Historically, the mechanisms underlying CSU have not been well understood. Recent evidence implies that patients who present with CSU can be categorized into 4 endotypes. The first, type 1, includes individuals with a high rate of comorbid atopic diseases, such as allergic rhinitis, atopic dermatitis, and asthma. Their baseline total serum IgE level is either normal or high. These patients are more likely to have a salutary response to anti-IgE therapy such as omalizumab. The second endotype, known as type 2B CSU, includes individuals with a high rate of comorbid autoimmunity. They may have an autoimmune disease such as lupus or rheumatoid arthritis, but, more frequently, they have manifestations of autoimmunity on laboratory tests, such as a high level of thyroid autoantibodies. Their baseline total serum IgE level is low, and they tend to be less likely to have a favorable response to treatment with omalizumab. If these patients do respond favorably to omalizumab, the response tends to be delayed and may be a partial response. The third endotype includes individuals with both type 1 and type 2B CSU. Patients with the fourth endotype have neither type 1 nor type 2B CSU.

At the 2026 AAAAI Annual Meeting, I moderated a session on the role of biomarkers in CSU. During the presentation titled “Chronic Spontaneous Urticaria Phenotypes/Endotypes” from this session, Sarbjit Saini, MD, FAAAAI, discussed findings from a previously published study of 111 patients with CSU showing that type 1 and type 2B endotypes frequently coexist and that most patients with type 2B CSU also have type 1, but not vice versa. This still needs to be confirmed in larger cohorts and multicenter studies. We have made substantial progress in identifying these endotypes, but this landscape will likely continue to evolve.

Another interesting study that Dr Saini discussed during his presentation at this year’s AAAAI meeting was the CHAPEAU pilot study investigating the role of endotypes and their influence on whether patients with acute urticaria will progress to CSU. In this study, biomarkers for type 1 and type 2B endotypes were measured in adults presenting to emergency departments with acute urticaria and then again at least 6 weeks later. Approximately 1 in 4 patients progressed to CSU. The soluble, high-affinity, IgE receptor was a potential predictive biomarker and was protective against progression to CSU, but it was somewhat surprising that no autoantibody profiles differed between CSU and non-CSU subgroups, implying that the production of these autoantibodies may occur later in the course of CSU.

This was intriguing and suggests that the presence or absence of these autoantibodies does not define a patient with CSU. Properly characterizing endotypes in CSU is important, as this will ultimately enhance our ability to effectively care for patients by providing precision medicine at the point of care. To do this routinely in the clinic setting, we still need to validate predictive biomarkers, vis-à-vis prognostic biomarkers.

Phenotypes also remain clinically useful in CSU. The 3 major CSU phenotypes are urticaria, urticaria and angioedema, and angioedema alone. During his presentation at the 2026 AAAAI Annual Meeting, Dr Saini also discussed a large study based on the CURE registry that included 3698 patients with CSU; 59% had wheals and angioedema, 36% had wheals alone, and 5% had angioedema alone. In this study, 92% of the angioedema-alone cohort had a favorable response to omalizumab, compared with 67% of the wheals-and-angioedema cohort and 60% of the wheals-alone cohort. The angioedema-alone cohort also had the best response to antihistamines. This also still needs to be confirmed, but it is intriguing, and it makes sense that there might be some differences in response between these subgroups.

Another study that Dr Saini discussed during his presentation was a retrospective analysis of patients with antihistamine-resistant CSU from 3 phase 3 studies who were randomized to omalizumab 300 mg every 4 weeks for 12 weeks and had well-controlled (Urticaria Activity Score over 7 days [UAS7] ≤6) or poorly controlled (UAS7 >6) CSU at week 12 in the context of several hypothesized negative predictive biomarkers taken at baseline. Researchers found that the poorly controlled patients at 12 weeks of treatment with omalizumab were more likely to have, at baseline, a low total serum IgE level (≤40 IU/mL), basopenia (as defined by a blood histamine content of <8 ng/mL), and a positive Chronic Urticaria (CU) Index. Their data imply that these tests could have a role as negative predictive biomarkers for identifying patients who are less likely to experience benefit on anti-IgE therapy.

Similarly, a meta-analysis of 10 interventional studies that included 866 patients with CSU found that complete responders and partial responders to omalizumab had significantly higher IgE levels at baseline than nonresponders. These findings support the assertion that patients with a low baseline IgE level are less likely to respond to omalizumab.

It is an important time in CSU. In the near future, as our understanding and management of the disease continue to evolve, we will probably be in a different place than we are now. We can anticipate that our therapeutic options will continue to expand and that we will have validated (positive and negative) predictive biomarkers to guide treatment at the point of care.