Endotyping & Biomarkers in CSU, With Jonathan Bernstein, MD

Chronic spontaneous urticaria (CSU) is increasingly recognized as a heterogeneous disease, with growing evidence supporting distinct endotypes characterized by different immunologic mechanisms and treatment responses. Investigators have focused on identifying biomarkers that may help distinguish between type I autoallergic and type IIb autoimmune CSU, particularly as newer targeted therapies expand treatment options.

Although several biomarkers, including total serum immunoglobulin E (IgE), thyroid peroxidase (TPO) antibodies, and functional basophil assays, have been associated with treatment outcomes, questions remain about their role in routine clinical practice. Much of the available evidence is derived from observational studies and post hoc analyses, and standardized approaches to biomarker-guided care have yet to be established.

At the 2026 Eastern Allergy Conference in Palm Beach, Florida, Jonathan Bernstein, MD, professor of medicine at the University of Cincinnati and a physician with Bernstein Allergy Group and the Bernstein Clinical Research Center, presented the session, “CSU Biomarkers and Advanced Treatments.” In an interview with HCPLive, Bernstein discussed the current landscape of CSU biomarkers, their potential clinical utility, and what additional evidence is needed to support biomarker-driven treatment selection.

HCPLive: The field has increasingly described two major CSU endotypes—type I autoallergic and type IIb autoimmune—with distinct biomarker profiles and treatment responses. In your clinical practice, how reliably can you actually distinguish these endotypes using currently available tests, and do you think most community allergists have the tools and workflow to do this?

Bernstein: The question about biomarkers came about because of response or poor response to antihistamines and also to omalizumab, and so people started looking at biomarkers and looking at characteristics to see what would predict response or nonresponse.

Part of this depends on [whether] you are looking at individual biomarkers or a compilation, a composite number of biomarkers, and where you cut, what levels you cut, [and] what cut point you use, for instance, for IgE. What is your cut point? Is it 40 international units? Is it 100? Is it lower than 10 or 20?

When you start looking at really low levels, they're more predictive for response or nonresponse to omalizumab. When you start putting IgE together with thyroid peroxidase antibody and even CU indexes, which measure expression of certain receptors on basophils, they become more predictive. But most allergists are not using these biomarkers routinely in their analysis.

When we [started] looking at the newer agents like dupilumab and remibrutinib, which have been approved, there's less information about the utility. It appears thus far that dupilumab works regardless [of] whether an IgE level is high or low, although the cut point has been not very low. It’s like 100. I wouldn't call that anything below that low.

And then remibrutinib, we know that it works in patients who have autoimmune urticaria, and so it seems to respond to patients who aren't responders to omalizumab. So the verdict is still out.

I still feel that it's useful to order biomarkers because it's a conversation that can help patients understand where they are in terms of the types of urticaria they have and what they can expect in terms of treatment outcomes. I think there is a utility, but what we found out from omalizumab doesn't necessarily translate to dupilumab and to remibrutinib.

And [for] the newer agents, we have very little information about biomarkers. I know companies who are developing these therapies are checking biomarkers as exploratory assessments, but we don't have that information yet.

I think it is helpful and useful to order a few of these biomarkers. I limit it to total IgE and thyroid peroxidase antibody, and then I also get something called a CU Index, but that latter test is not validated yet, and it's not standardized adequately.

There's also the basophil activation test, which is another surrogate marker for autoimmune urticaria. It really depends on the individual patient.

HCPLive: Biomarkers like total serum IgE, anti-thyroid antibodies, basophil counts, and functional assays have emerged as tools for differentiating between CSU subtypes. Which of these do you consider actionable today?

Bernstein: Very low IgEs, less than 20, are significant, and thyroid peroxidase antibodies are also very important. As I said, the CU Index is still [uncertain]. Some of the studies don't really show that by itself it's very predictive.

When you put these together, though, there is some value. We did a study that we published a few years ago, which showed that TPO was probably the most predictive, but when you looked at TPO in conjunction with IgE and CU index, that composite score was more predictive of poor response to omalizumab.

HCPLive: Connections between identified biomarkers, genetic risk loci (lo-sigh), phenotypes, and their corresponding endotypes remain insufficiently characterized, with much of the available data coming from real-world or small-scale studies. What would it take to actually move biomarker-driven treatment selection into routine care?

Bernstein: Well, it's going to take more real-world evidence to support these findings. Not everybody responds to these medications. Why do some people respond and others don't? It comes down to looking at responders and non-responders, their clinical characteristics, and then trying to identify other biomarkers.

It is important to characterize patients phenotypically because it's not one size fits all. The algorithm [does] not just start this and go to that. There [are]…some discussions that need to be had with patients.

Most of this is going to be longitudinal, real-world studies looking at responders and non-responders and trying to identify phenotypic and maybe genetic markers down the line. That's going to be a little bit more challenging, I think.