Dupilumab and BTK Inhibitors Expand Options in CSU

Chronic spontaneous urticaria (CSU) remains a challenging condition to manage, particularly in patients with persistent symptoms despite antihistamine therapy.¹ Recent clinical investigations have expanded the therapeutic landscape, with biologics and targeted oral therapies emerging as viable options. In a recent interview with Dermatology Times, Jonathan Bernstein, FAAAAI, FACAAI, FACP, MD, professor of medicine at the University of Cincinnati and past president of the American Academy of Allergy, discussed pivotal data on dupilumab and Bruton tyrosine kinase (BTK) inhibitors in CSU.²

Dupilumab in CSU: Findings from CUPID Studies

Dupilumab, an IL-4 receptor alpha antagonist already approved for multiple type 2 inflammatory diseases, recently demonstrated efficacy in CSU. Bernstein described the results of 2 pivotal phase 3 studies—CUPID A and CUPID B—that enrolled patients with persistent urticaria despite antihistamines. Eligible participants had an urticaria activity score over 7 days (UAS7) greater than 16 and significant itch burden.

According to Bernstein, “dupilumab treatment improved the UAS7 score from week 3 through week 24…this was an early response, and it was a sustained improvement in hives activity over the duration of the study.” The pooled analysis included 144 patients on dupilumab and 145 on placebo, with balanced demographics and baseline disease activity. The treatment not only improved itch and hive severity but also demonstrated a favorable safety profile consistent with prior dupilumab indications.

Secondary endpoints, including patient-reported outcomes, also trended positively. Bernstein noted, “it was consistent with the findings that quality of life parameters were improved during these studies.” For many clinicians, the ability to achieve both symptom control and measurable quality of life gains may influence adoption into practice.

Positioning Dupilumab in the Treatment Paradigm

CSU management traditionally escalates from antihistamines to omalizumab, with immunosuppressants considered in refractory cases. Dupilumab may now offer another option, particularly for patients with contraindications or incomplete response to omalizumab. Importantly, Bernstein emphasized safety and convenience advantages: “with omalizumab, when the IgE level is very low, it doesn’t seem to work as quickly or as well. So I think this could be a distinct advantage as well.” Additionally, the lack of anaphylaxis boxed warning may increase physician and patient comfort with dupilumab compared to some alternatives.

Given its approval across 8 indications, dupilumab may be especially beneficial for patients with comorbid type 2 conditions such as asthma, atopic dermatitis, or nasal polyps. Bernstein concluded, “having another indication for chronic spontaneous urticaria just provides another important option for our patients.”

Emerging Role of BTK Inhibitors

Bernstein also highlighted the potential of BTK inhibitors, particularly remibrutinib and rilzabrutinib, as oral therapies under investigation for CSU. These small-molecule inhibitors target the IgE pathway and have demonstrated sustained improvements in urticaria activity and quality of life.

Rilzabrutinib has shown encouraging results in patients with CSU and associated angioedema, a subgroup often more difficult to treat. In a phase 2 study, patients randomized to high-dose rilzabrutinib achieved rapid reductions in angioedema activity scores. Bernstein explained, “angioedema was reduced with rilzabrutinib at the 1200 milligram a day dose versus placebo. These improvements were seen as early as week 1.” Importantly, up to 61% of participants at 12 weeks achieved complete resolution of angioedema compared with 31% on placebo.

Outlook

The therapeutic landscape for CSU is evolving rapidly. Dupilumab now offers an FDA-approved option with early and sustained efficacy, favorable safety, and applicability across comorbid conditions. Meanwhile, oral BTK inhibitors are advancing through clinical development, showing promise in refractory and angioedema-predominant CSU. As Bernstein summarized, these advances “offer advantages [as] alternative treatments for these more difficult to treat patients.”

For clinicians, integrating these emerging therapies requires careful consideration of patient phenotype, prior treatment response, and comorbidity burden. Ongoing real-world data will be essential in clarifying their optimal placement in CSU management algorithms.

References

1. Kolkhir P, Fok JS, Kocatürk E, et al. Update on the treatment of chronic spontaneous urticaria. Drugs. 2025;85(4):475-486. doi:10.1007/s40265-025-02170-4
2. Maurer M, Casale TB, Saini SS, et al. Dupilumab in patients with chronic spontaneous urticaria (LIBERTY-CSU CUPID): Two randomized, double-blind, placebo-controlled, phase 3 trials. J Allergy Clin Immunol. 2024;154(1):184-194. doi:10.1016/j.jaci.2024.01.028