Exploring benralizumab in omalizumab-refractory chronic spontaneous urticaria: A case series of Portuguese patients

Chronic spontaneous urticaria (CSU) is a distressing condition marked by recurrent wheals and/or angioedema lasting for more than 6 weeks without an identifiable trigger [1]. Despite established treatment algorithms, disease control remains challenging, particularly in patients who do not respond to omalizumab, even with the addition of cyclosporine as a third-line therapy [1]. In these refractory cases, off-label therapies have been explored [2]. Eosinophils have emerged as key contributors to CSU pathophysiology through their interaction with mast cells and release of proinflammatory mediators. Benralizumab is an anti-Il-5 receptor monoclonal antibody that depletes eosinophils and may therefore represent a potential therapeutic approach for omalizumab-refractory CSU [3,4]. Recent research has also advanced to better characterize CSU through the identification of biomarkers to distinguish CSU endotypes, particularly autoimmune type I and autoimmune type IIb (CSU-IIb), to guide personalized therapy. IgG anti-thyroid peroxidase antibodies (IgG-anti-TPO)/total IgE ratio, C-reactive protein (CRP), and eosinophil/basophil counts have been associated with disease activity and differential treatment response, particularly in distinguishing autoimmune CSU endotypes and predicting poor response to omalizumab [1,5–8]. This article reports our experience with benralizumab in managing CSU refractory to conventional therapies. We conducted a retrospective study of patients with CSU treated with benralizumab between February 2023 and June 2025. The inclusion criteria required a confirmed diagnosis of CSU for ≥6 months and a persistent Urticaria Activity Score over 7 days (UAS7) >15 despite treatment with omalizumab 600 mg every 2 weeks, in combination with second-generation H1-antihistamines (sgAH) at 4-fold doses (4 times a day) and cyclosporine, unless contraindicated. The absence of any active infection or malignancy was also required. Autoimmune diseases were not considered exclusion criteria, provided they were clinically stable. Potential biomarkers of disease severity and treatment response were assessed at 4 time points: pre omalizumab (T0), 4 weeks post omalizumab (T1), pre benralizumab (T2), and 4 weeks post benralizumab (T3). All biomarker analyses were conducted in an ISO 9001:2015 15189–accredited laboratory. All patients (Pt) were treated according to ethical standards established in the Declaration of Helsinki. Written informed consent was obtained from all patients. Four female patients (Pt 1–Pt 4) were included (Table 1). The mean duration of CSU before omalizumab initiation was 28 ± 29.5 months. Comorbidities included pernicious anemia (Pt 1, under vitamin B12 replacement), Hashimoto thyroiditis without thyroid dysfunction (Pt 1), depression (Pt 3 and Pt 4), and medically controlled hypertension (Pt 4). Table 1. - Patients’ clinical, demographic, and laboratory characteristics during different stages of treatment: pre omalizumab (T0), 4 weeks post omalizumab (T1), pre benralizumab (T2), and 4 weeks post benralizumab (T3) Patient 1 Patient 2 Patient 3 Patient 4 Clinical and demographic characteristics Gender Female Female Female Female Age, y 53 54 56 55 CSU duration pre omalizumab, mo 11 17 60 24 Comorbidities Pernicious anemiaHashimoto thyroiditis none Depression DepressionHypertension Biomarkers Eosinophil count, ×109/L (NR: 0.0–0.5) T0 0.01 0.05 0.19 0.09 T1 0.1 0.09 0.25 0.08 T2 0.05 0.008 0.18 0.11 T3 0.00 0.0082 0.009 - Basophil count, ×109/L (NR: 0.0–0.2) T0 0.02 0.03 0.007 0.03 T1 0.01 0.05 0.01 0.02 T2 0.04 0.04 0.04 0.07 T3 0.01 0.06 0.0 - CRP, mg/dL T0 4.22 1.16 0.1 0.33 (NR: