Jonathan A. Bernstein, MD: University of Cincinnati

Jonathan A. Bernstein, MD

BTK Inhibitors, C-Kit Agents, and Remission in CSU: What the Pipeline Suggests

Can Patients with CSU Achieve True Remission?

is a realistic goal, but the field lacks the longitudinal data and validated biomarkers to reliably identify which patients will get there, according to Jonathan Bernstein, MD, professor of medicine at the University of Cincinnati and physician with Bernstein Allergy Group and the Bernstein Clinical Research Center.

Bernstein presented on endotyping and biomarker strategies in CSU at the 

 about where the pipeline stands and what clinicians can apply now.

Read parts 1 and 2 of the interview with Bernstein here: 

Endotyping & Biomarkers in CSU, With Jonathan Bernstein, MD

Sequencing Emerging Therapies in CSU, With Jonathan Bernstein, MD

Remibrutinib (BTK inhibitor) and c-kit inhibitors are among agents with theoretical potential for CSU remission; dupilumab and omalizumab are not expected to accelerate it

The CU index is not yet validated; basophil-based assays may not accurately reflect mast cell activity

Distinguishing spontaneous from drug-induced remission requires longitudinal study designs not yet available

Available biomarkers can support shared decision-making and expectation-setting even without full clinical validation

Which Agents Have the Best Shot at Inducing Remission?

Among emerging therapies, Bernstein cited remibrutinib, a BTK inhibitor positioned further downstream in the disease pathway, as a candidate with plausible mechanistic grounds for inducing remission. C-kit inhibitors were also flagged as potentially meaningful given their action on mast cells, the primary effector cells in CSU. By contrast, Bernstein said he would not expect dupilumab or omalizumab to accelerate remission.

"We don't have that information yet," he noted, adding that well-designed studies examining time course and patient-level predictors of remission are still absent from the literature.

Complicating the picture further: distinguishing drug-induced remission from spontaneous remission remains an unresolved methodological challenge. The World Allergy Organization Urticaria Committee has proposed defining CSU clinical remission as total resolution of urticaria signs and symptoms without pharmacotherapy for ≥ 6 months, though the implications of this definition in clinical practice must still be evaluated and validated in future studies.

Current data show no significant difference in CSU relapse between 6- and 12-month periods of remission.

Biomarker Implementation: Where the Gaps Are

On the barriers to routine biomarker use, Bernstein pointed to 3 core problems: lack of validation, unclear cut points, and uncertain predictive value across treatment responders and non-responders.

He highlighted the CU index as a specific example, which is not yet validated and primarily reflective of basophil activity rather than mast cell behavior. Because mast cells are tissue-based and represent a distinct lineage from basophils, translating basophil-derived assay data to clinical decision-making has limits.

Composite immunological signatures integrating multiple biomarkers hold promise for guiding therapeutic decisions, and implementing validated markers could enable earlier identification of difficult-to-treat patients and more targeted therapy.

 But that infrastructure is not yet in place.

Bernstein's message to clinicians leaving EAC: patients with CSU are diverse, and better phenotyping, even with imperfect tools, supports more productive patient conversations.

"Do we have the right biomarkers yet? Not necessarily," Bernstein said. "Do the ones we have add to the conversation with our patients? They certainly do. That’s where I think clinicians should take advantage of this, and I think it might also be more gratifying when you're treating patients to know that you can really give them some additional guidance in terms of treatment expectations and outcomes.”

Editor’s note: SANOFI-AVENTIS U.S., Pharming Healthcare, Novartis Pharmaceuticals Corporation, BioCryst Pharmaceuticals, Regeneron Healthcare Solutions, CSL Behring, Blueprint Medicines Corporation, Dermavant Sciences, Incyte Corporation, Eli Lilly and Company, and more.

Sánchez J, Pite H, Gómez RM, et al. Chronic spontaneous urticaria remission definition and therapy stepping down: World Allergy Organization position paper. J Allergy Clin Immunol. 2025;155:1050–1056. 

https://www.jacionline.org/article/S0091-6749(24)02413-8/abstract

Calzari P, Favale EM, Cugno M, et al. Predictors of early treatment response to antihistamines and omalizumab in chronic spontaneous urticaria. Front Allergy. 2026. doi:10.3389/falgy.2025.1728559. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12832613/

Videos

 Jonathan Bernstein, MD, discusses remibrutinib, c-kit inhibitors, and the current limits of biomarker-guided decision-making in chronic spontaneous urticaria.


BTK Inhibitors, C-Kit Agents, and Remission in CSU: What the Pipeline Suggests  

Jonathan Bernstein, MD, professor of medicine at the University of Cincinnati and physician with Bernstein Allergy Group and the Bernstein Clinical Research Center, outlined how clinicians may approach treatment sequencing in

 as newer targeted therapies expand options beyond antihistamines and omalizumab. Speaking with 

 in Palm Beach, Florida, Bernstein emphasized that treatment selection should remain individualized despite forthcoming guideline recommendations.

“If they [have] never been treated, then we're going to start using high-dose antihistamines to make sure they truly are not ineffective,” he said.

He added that this first trial of second-generation antihistamines should include dose escalation up to 4 times the standard recommended dose. He noted that some patients may not have used antihistamines consistently or appropriately before referral, making confirmation of treatment failure an important first step.

Bernstein indicated that updated CSU guidelines are expected to continue recommending omalizumab as the preferred next-line therapy based on the strength and certainty of available evidence, as well as its established safety profile. Although omalizumab carries a boxed warning for anaphylaxis, he noted that concerns largely stem from reports in asthma populations rather than patients with urticaria.

However, Bernstein emphasized that guideline recommendations may not be appropriate for every patient. Individuals with very low immunoglobulin E (IgE) levels and evidence of autoimmune disease may represent a distinct phenotype that could warrant consideration of alternative therapies, including dupilumab or remibrutinib.

He noted that biomarkers are not expected to be incorporated into formal treatment algorithms because evidence supporting biomarker-guided decision-making remains limited. Nevertheless, Bernstein encouraged clinicians to recognize differences among patients and consider how biomarkers may eventually help identify treatment-responsive subgroups.

Cyclosporine remains an option for patients with difficult-to-treat disease, particularly those with chronic autoimmune urticaria, according to Bernstein. However, he noted its use requires monitoring for adverse effects, including hypertension and renal toxicity, and it is expected to occupy a later position in treatment algorithms as biologic and targeted therapies become more widely available.

Bernstein also highlighted the importance of obtaining biomarker assessments before initiating omalizumab when testing is planned. He explained that measurements such as total IgE, thyroid peroxidase antibodies, the CU Index, and basophil activation testing can potentially help characterize disease subtypes, but results may be affected once omalizumab therapy begins.

As treatment options continue to expand, Bernstein said additional real-world evidence and controlled studies will be needed to clarify how biomarkers and patient phenotypes can inform therapeutic sequencing in CSU.

Bernstein J. CSU biomarkers and advanced treatments. Poster presented at EAC 2026 on May 29.

 Bernstein discussed treatment sequencing, biomarker use, and evolving chronic spontaneous urticaria management strategies during an interview at EAC 2026.


) 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.

 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?

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.

 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?

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.

 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?

 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.

Articles

Bernstein discussed the evolving role of biomarkers in chronic spontaneous urticaria  at EAC 2026.

Phase 2 data presented as a late breaker at the 

2025 American College of Allergy, Asthma, & Immunology (ACAAI)

 demonstrated that povorcitinib 75 mg rapidly and safely reduced itch and hives in patients with 

The phase 2 randomized, double-blind study assessed the efficacy and safety of povorcitinib, a selective kinase 1 (JAK1) inhibitor, in 136 adults with moderate to severe CSU who were ≥ 3 months refractory to second-generation H1 antihistamines. The primary endpoint was the change from baseline in weekly Urticaria Activity Score (UAS7) at week 12. Secondary endpoints included patients who achieved UAS7 ≤ 6 (disease control), patients with UAS7 = 0 (complete response), daily UAS, and safety and tolerability.

Participants were randomized 1:1:1 to placebo (n = 34) or daily povorcitinib, either 15 mg (n = 33), 45 mg (n = 34), or 75 mg (n = 35) for the 12-week placebo-controlled period. Participants on povorcitinib 75 mg had a greater least squares mean (LSM) change in UAS7 from baseline than those on placebo (-23.91 vs -17.90; 

 =.0470). Moreover, more patients on the 75 mg dose achieved disease control at week 12 (44.1%) than those on placebo (29.4%) or on the 45 mg (44.1%) or 15 mg doses (30.3%).

Compared with placebo (23.5%) and the doses 45 mg (29.4%) and 15 mg (24.2%), more participants on povorcitinib 75 mg became symptom-free at week 12 (42.9%). By day 3, povorcitinib 75 mg showed rapid improvement in daily UAS (mean change from baseline, -1.3 vs -0.7). All povorcitinib doses were well tolerated, with no safety signals.

 sat down with Jonathan A. Bernstein, MD, from the University of Cincinnati, to discuss the significance of these findings.

 Based on the phase 2 results, how would you characterize povorcitinib’s efficacy across different doses in reducing hives, angioedema, and pruritus compared with placebo?

 The data was very interesting. It showed that there was a dose-response improvement in the reduction of hives. This was sustained at different time points, both at week 4, at week 8, and at week 12. However, the placebo also tended to increase a little bit. The effect change was approximately 5.8 points, so there was a significant improvement in urticaria.

There were no unexpected safety signals identified in this population. If you looked at the most common side effects, there may have been some worsening acne, some other minor problems [such as] headache [and] nasopharyngitis.

[We didn’t see] any difference between subgroups, but this was a small study.

 How do these findings compare with the efficacy profiles of existing standard-of-care CSU treatments, including antihistamines and omalizumab?

 We see a similar response in other therapies. The magnitude of response is comparable. It might be a little lower than what you see with some of the other therapies in terms of UAS7, where people had complete control.

There was about a 24 percent reduction in UAS, and the absolute point difference in scores was 17.9. So, there was an effect difference. It probably wasn't as great of a magnitude as other therapies, but it was considered statistically significant.

 What aspects of the povorcitinib data might warrant caution or closer monitoring?

 You would expect that you'd see more separation from placebo at the end of the 12 weeks, and the placebo had a 17.9-point reduction, whereas the active drug 75 mg was [a] 23.9-point [reduction]. That was a little disappointing. It was statistically significant, but not of great magnitude, as you'd expect with others that we've seen with other drugs. Especially in a phase 2 study, you'd expect to see a greater magnitude of an effect.

 Is there anything else you would like to highlight about these findings?

 JAK inhibitors are an interesting target. There are certainly more downstream in the IgG pathway, and there seems to be an effect. The safety was good, which is encouraging, so I think it is feasible that there could be a role for JAK inhibitors in the management of chronic spontaneous urticaria.

Relevant disclosures for Bernstein include SANOFI-AVENTIS U.S. LLC, Pharming Healthcare, Inc., Novartis Pharmaceuticals Corporation, BioCryst Pharmaceuticals, Inc., Takeda Pharmaceuticals U.S.A., Inc., Regeneron Healthcare Solutions, Inc., CSL Behring, Blueprint Medicines Corporation, Dermavant Sciences, Inc., Incyte Corporation, Eli Lilly and Company, and GENZYME CORPORATION.

Metz M, Bernstein J, Pinter A, et al. EFFICACY AND SAFETY OF POVORCITINIB IN ADULTS WITH CHRONIC SPONTANEOUS URTICARIA: PHASE 2 RESULTS. 

. 2025;135(5):S3. doi:https://doi.org/10.1016/j.anai.2025.10.020

Phase 2 data from the ACAAI 2025 meeting revealed that povorcitinib 75 mg effectively reduced itch and hives in chronic spontaneous urticaria (CSU) patients. The study involved 136 adults with moderate to severe CSU, refractory to second-generation H1 antihistamines. The primary endpoint was the change in Urticaria Activity Score (UAS7) at week 12. Povorcitinib 75 mg showed significant improvement compared to placebo, with rapid symptom relief by day 3. All doses were well tolerated, with no unexpected safety signals, suggesting a potential role for JAK inhibitors in CSU management.

New phase 2 data reveals povorcitinib effectively reduces itch and hives in chronic spontaneous urticaria, showing promise as a treatment option.