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: <0.5) T1 2.3 0.51 0.32 0.23 T2 1.82 0.29 0.19 0.15 T3 1.67 0.31 0.11 - ESR, mm (NR: ≤19) T0 28 3 10 29 T1 23 2 10 16 T2 50 13 27 18 T3 30 13 14 - Total IgE, U/mL (NR: <100) T0 4.3 4.2 36.3 0.6 T1 26.1 13.8 126.2 1.7 T2 27.3 2.6 38.5 1 T3 27.2 1.7 39 - IgG anti-TPO, U/mL (NR: <37) T0 403 <5 6 <5 T1 347 <5 9 13 T2 548 <5 <5 11 T3 523 11 10 - IgG anti-TG, U/mL (NR: <115) T0 281 <10 <10 16 T1 276 11 12 14 T2 304 18 15 15 T3 308 18 13 - D-dimers, µg/mL (NR: 0.0–0.5) T0 0.33 0.18 0.17 0.44 T1 0.53 <0.15 0.62 0.27 T2 0.38 0.51 2.04 0.5 T3 0.27 0.32 0.56 - IgG anti-TPO/total IgE ratio (poor OMA response cutoff: >0.154; sensitivity 87.7%; specificity 22.4%) [7] T0 93.7 <1.19 0.17 8.3 Bold values indicate results outside the NR; light gray values indicate low values that are still within the NR.CRP, C-reactive protein; CSU, chronic spontaneous urticaria; ESR, erythrocyte sedimentation rate; IgG anti-TG, immunoglobulin G anti-thyroglobulin; IgG anti-TPO, immunoglobulin G anti-thyroid peroxidase; NR, normal range; OMA, omalizumab. At baseline (T0), all patients presented with low total serum IgE and elevated IgG-anti-TPO/IgE ratios. Pt 1 had markedly elevated IgG-anti-TPO, erythrocyte sedimentation rate (ESR), and CRP, along with eosinopenia and basopenia, features consistent with CSU-IIb and predictive of poor response to sgAH and omalizumab. Additional biomarkers of severity or poor response were observed in Pts 2 to 4: Pt 2 had eosinopenia and high CRP; Pt 3 had basopenia; and Pt 4 had eosinopenia and elevated ESR. Before initiating benralizumab, all patients had received standard and escalated-dose sgAH (up to 4 times a day) for at least 6 months, without achieving disease control. Subsequently, omalizumab was introduced at 300 mg every 4 weeks for a minimum of 6 months, followed by up-dosing to 600 mg every 2 weeks for at least 3 additional months, still without achieving symptom control. All patients required additional monthly oral corticosteroids to manage flares. During omalizumab therapy, cyclosporine (ranging 100–200 mg/d) was initiated in Pts 1 to 3 for 3 to 6 months. Pt 2 achieved a partial response with a UAS7 between 7 and 15, whereas Pts 1 and 3 remained nonresponders. Pt 1 discontinued cyclosporine due to headache and hypertension, and Pt 4 did not start it owing to a history of hypertension. After excluding secondary causes and confirming CSU with predominant eosinophilic infiltration on skin biopsy, all patients underwent benralizumab 30 mg monthly, maintaining the same dose and administration frequency in subsequent maintenance treatments. During the first months, Pts 2 and 3 continued cyclosporine while transitioning to benralizumab, but it was successfully tapered and discontinued within 6 months. All patients remained on sgAH (up to 4 times a day) at treatment initiation, with progressive tapering according to response. The mean time duration of benralizumab treatment was 16 ± 7.8 months. Patient-reported outcomes (Figure S1, https://links.lww.com/PA9/A86) showed rapid and sustained improvement: Pt 1 achieved complete response (UAS7 = 0) at 4 months of treatment and reduced sgAH to standard dose after 12 months; Pt 2 achieved complete response since the first month of treatment and discontinued cyclosporine, and after 1 year, stopped sgAH, with plans to extend the benralizumab dosing interval soon; Pt 3 achieved good control (UAS7 ≤ 6) within the first 6 months, tapered off cyclosporine over the following 6 months, and maintained complete symptom control for an additional year with sgAH 2 times a day; Pt 4 achieved symptom control within the first month of benralizumab with complete resolution by month 6 and maintained on sgAH 2 times a day. No adverse reactions were reported, and all patients transitioned successfully to benralizumab home administration. These findings reinforce previous studies and suggest that benralizumab is safe, well-tolerated, and effective in achieving disease control, with all 4 patients reaching complete remission [9]. Notably, those with pronounced eosinophilic infiltration in the skin and concurrent peripheral eosinopenia showed particularly good responses. These findings align with prior reports that implicate IL-5 and eosinophils in CSU pathophysiology, supporting the hypothesis that targeting the IL-5/IL-5Rα pathway may modulate eosinophil-mediated inflammation, reduce mast cell activation, and ultimately lead to clinical improvement [4,10]. Although the sample size is limited, these results provide additional real-world evidence supporting the role of eosinophils in disease severity and their potential as a biomarker for response to IL-5–targeted therapy. This case series highlights the practical value of baseline and dynamic biomarkers, such as the IgG-anti-TPO/IgE ratio, CRP, and eosinophil and basophil blood counts, in CSU management. These accessible tests provide important prognostic and therapeutic guidance, aiding early identification of patients at risk of treatment failure and informing tailored use of therapies like omalizumab or cyclosporine. For patients with CSU-IIb features and eosinophilic infiltration, benralizumab offers a promising therapeutic alternative for omalizumab-refractory CSU when conventional treatments fail. Although promising, our results are limited by the small sample size, the retrospective design, lack of long-term follow-up, and absence of a comparator group, which should be considered when interpreting the findings. However, it supports growing evidence for using biomarkers to guide personalized treatment in CSU. Future studies are needed to confirm these findings and further evaluate eosinophil-targeted therapies. Conflicts of interest The authors have no financial conflicts of interest. Author contributions Conceptualization, formal analysis, writing—original draft: Ana Graça Bernardino, Célia Costa. Methodology, data curation, writing—review and editing: Ana Graça Bernardino, Célia Costa, Margarida Gomes. Supplementary material Figure S1 can be found via 10.5415/apallergy.2022.12.e38 Figure S1 Click here to view