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WHAT IS THIS SUMMARY ABOUT?: This summary outlines the findings from the ANANKE study on the treatment of patients with severe eosinophilic asthma (SEA) with benralizumab. SEA is an inflammatory disease of the lungs caused by eosinophils. Patients with SEA may experience asthma attacks (exacerbations) and decreased ability to breathe (lung function) despite taking medications. Benralizumab (Fasenra®) is a biologic therapy (a medicine produced using living cells) approved for the treatment of SEA.The ANANKE study was conducted in Italy and evaluated the characteristics of patients with SEA who received benralizumab as prescribed by their doctors. It also described the effects of benralizumab on participants in terms of frequency of exacerbations, lung function and overall control of asthma, and their need to take oral corticosteroids (OCS) to control symptoms. The effects of benralizumab have been observed in participants treated for: 1) an average of 10.3 months, and 2) up to 96 weeks (approximately 2 years). The effects were also compared between different groups: 1) participants with chronic rhinosinusitis with nasal polyps (CRSwNP) and those without, and 2) participants who received other biologics before benralizumab (bio-experienced) and those who started with benralizumab as their first biologic (naïve). CRSwNP is an inflammatory condition that makes breathing even more difficult. WHAT WERE THE KEY FINDINGS?: Before receiving benralizumab, participants showed a high blood eosinophil count (the number of eosinophils in the bloodstream), frequent exacerbations, insufficient lung function, and poor disease control (symptom management). After 96 weeks, benralizumab almost eliminated exacerbations, improved lung function, reduced the use of OCS, and increased the control of SEA symptoms while lowering blood eosinophil count. Comparable effects were observed between participants with and without CRSwNP and between naïve and bio-experienced participants. WHAT WERE THE MAIN CONCLUSIONS REPORTED BY THE RESEARCHERS?: The ANANKE study showed that participants had frequent exacerbations and were characterized by eosinophilic inflammation before starting benralizumab. Overall, benralizumab improved the control of the disease for up to 2 years and induced similar beneficial effects regardless of the presence of CRSwNP and the use of previous biologics. These findings highlight the long-lasting and broad action of benralizumab.Clinical Trial Registration: NCT04272463 (ANANKE) (ClinicalTrials.gov).

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BACKGROUND: The underlying population of patients selected for each respiratory monoclonal antibody might change as other biologics are approved. OBJECTIVE: To evaluate effect modification by calendar time of the effectiveness of each respiratory biologics in asthma. METHODS: The Effectiveness of Respiratory biologics in Asthma (ERA) is a retrospective cohort of severe asthma patients from the Mass General Brigham clinics between January 2013 and September 2023. Periods were pre-specified as the anti-IgE (2013-2015), anti-IL5 (2016-2018), anti-IL4/13 (2019-2021) or anti-alarmin (2022-2023) era. We evaluated each biologic's effect on asthma-related exacerbations comparing the one-year period before and after therapy initiation using Poisson regression and Cox regression for time-to-first exacerbation. RESULTS: Of 647 biologic-naïve patients, 165 initiated omalizumab, 235 anti-IL5, 227 dupilumab, and 20 tezepelumab. Omalizumab's effectiveness improved as more biologics were approved: incidence rate ratio (IRR) 1.16 [0.94-1.43] anti-IgE era vs. 0.54 [0.37-0.80] anti-IL4/13-alarmin era. Omalizumab patients in the anti-IL4/13-alarmin era had lower blood eosinophil counts and less chronic rhinosinusitis with nasal polyps (CRSwNP). For anti-IL5s, effectiveness peaked in the anti-IL4/13 era (IRR 0.52 [0.42-0.64]) when patients had higher BMI and less concomitant CRSwNP. Dupilumab was most effective in the anti-IL4/13 era (IRR 0.60 [0.50-0.72]). There were fewer current smokers in dupilumab patients in the anti-IL4/13 era. Results were similar in time-to-event analyses and in sensitivity analyses accounting for the COVID-19 pandemic. CONCLUSION: There are temporal variations in the effectiveness of biologics partly explained by the shift in the underlying population, particularly for omalizumab. Though having more choices was associated with better patient selection for omalizumab, this was inconsistent for other biologics.

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OBJECTIVE: This study aimed to compare the clinical characteristics and treatment outcomes of allergic patients (AP) and non-allergic patients (NAP) with severe eosinophilic asthma (SEA) treated with anti-IL5/IL5R biologic agents (mepolizumab, benralizumab, or reslizumab) over one year. Sub-analyses assessed treatment response variations between AP and NAP based on the biological used and compared outcomes among AP with and without fungal allergy. METHODS: Observational retrospective analysis. Clinical characteristics, laboratory findings, pulmonary function tests, Asthma Control Test (ACT) scores, oral corticosteroid (OCS) usage, and exacerbation frequency were assessed at the initiation of biological treatment and after one year. RESULTS: Sixty-five patients with SEA were included, 41 AP and 24 NAP. 55.4% were treated with mepolizumab, 33.8% with benralizumab, and 10.8% with reslizumab. Before anti-IL5/5R treatment, AP had worse baseline outcomes but there were no differences in pulmonary function. Mean annual exacerbation rate and percentage of patients requiring OCS and dose of prednisone were higher in AP than NAP. AP had significantly higher total IgE values. After one year of treatment, more AP discontinued OCS than NAP (p = 0.025). Both experienced a significant reduction in exacerbation frequency (p = 0.001) and improved respiratory function. 70.7% of AP and 60% of NAP improved ACT ≥3 points. There was no significant difference between AP and NAP using mepolizumab (p = 0.145) or benralizumab (p = 0.174) in reducing OCS. CONCLUSIONS: Anti-IL5/IL5R reduced the need for OCS and improved asthma control, regardless of allergic status. Fungal allergy led to lower ACT scores and higher exacerbations than other allergens; both groups improved with anti-IL5/ILR.

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Background: Atopic dermatitis (AD) is a skin barrier dysfunction characterized by tissue eosinophilia. Objective: In patients with AD, we evaluated the effect of eosinophil depletion with benralizumab on markers of inflammation in skin after intradermal allergen challenge. Methods: A total of 20 patients with moderate-to-severe AD completed a randomized, double-blind, placebo-controlled parallel-group study comparing 3 doses of benralizumab (30 mg each) administered subcutaneously every 4 weeks (n = 9) with placebo (n = 11). Allergen and saline control intradermal challenges were conducted before and after treatment, with skin biopsy samples collected 24 hours after challenge. Early and late cutaneous responses were measured by skin wheal size. Levels of eosinophils and IL-5 receptor-α-bearing cells, including eosinophil progenitor (EoP) cells, basophils, and mast cells, in papillary dermis were measured by immunofluorescence microscopy, and levels of EoP cells, hematopoietic progenitor cells, and type 2 innate lymphoid cells in the blood were measured by flow cytometry. Outcomes were compared between the placebo and benralizumab treatment groups by using the Mann-Whitney U test. Results: Benralizumab reduced eosinophil counts in the blood (P < .0001) and allergen-challenged skin, as measured by hematoxylin and eosin staining and eosinophil cationic protein antibody concentration (P < .05). Benralizumab lowered the levels of EoP cells, mast cells, and basophils in the skin, as well as the levels of EoP cells, hematopoietic progenitor cells, and type 2 innate lymphoid cells in the blood (all P < .05). There was a trend toward improvement in the early cutaneous response (P = .095) but no effect on the late cutaneous response. Conclusion: In patients with moderate-to-severe AD, benralizumab treatment significantly inhibited accumulation of eosinophils and other IL-5 receptor-α-expressing cells in the papillary dermis after intradermal allergen challenge. Targeting IL-5 receptor-α-positive cells did not modulate the size of the allergen-induced skin wheal (ClincialTrials.gov identifier NCT03563066).

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BACKGROUND: Eosinophils are key therapeutic targets in severe asthma that are suppressed by IL5 (mepolizumab) and IL5 receptor (benralizumab) blockade. The effect of IL5 pathway biologics on recently described homeostatic (hEOs) and inflammatory (iEOs) eosinophil subsets is unknown. We aimed to determine the relative impact of mepolizumab and benralizumab treatment on eosinophil subset and phenotype, and explore clinical associations of eosinophil subsets with severe asthma characteristics and treatment response. METHODS: We performed a cross-sectional observational study of severe asthma (eosinophilic n = 32, non-eosinophilic n = 23, mepolizumab-treated n = 25), with longitudinal follow-up of 30 eosinophilic participants at two timepoints (4-24 weeks, >24 weeks) post-commencement of mepolizumab (n = 20) or benralizumab (n = 10). Blood hEOs and iEOs were measured by flow cytometry assessment of surface CD62L protein. RESULTS: iEO proportion was significantly lower in mepolizumab-treated participants in both the cross-sectional and longitudinal study. Mepolizumab and benralizumab depleted iEOs to a similar extent, however a significantly greater number of hEOs remained in mepolizumab participants at follow-up. Greater iEO proportion correlated with poorer asthma control in eosinophilic but not non-eosinophilic asthma. Higher residual iEO proportion correlated with poorer asthma control in mepolizumab-treated individuals. Reduced blood eosinophil viability was observed in around half of mepolizumab-treated participants, which was associated with significantly better asthma control and spirometry. CONCLUSIONS: Mepolizumab depletes iEOs and reduces circulating eosinophil viability in severe asthma but preserves a residual population of circulatory hEOs. In contrast benralizumab depleted both iEOs and hEOs. Higher iEO abundance and eosinophil viability are associated with poorer clinical outcomes following mepolizumab-treatment. Monitoring circulating eosinophil phenotype and viability may be useful to predict biologic treatment response in severe asthma.

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This article summarizes the current guidelines and recommendations published by the European Alliance of Associations for Rheumatology (EULAR), the Kidney Disease Improving Global Outcomes (KDIGO) and the American College of Rheumatology (ACR). In addition to glucocorticoids (GC), treatment with biologics is nowadays an established option to treat Anti-Neutrophil Cytoplasmic Antibody (ANCA)-associated vasculitis (AAV). Rituximab (RTX) is used for remission induction and maintenance in organ-threatening and non-organ-threatening granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). For eosinophilic GPA (EGPA) anti-interleukin 5 (IL5) strategies are an important component of treatment for remission induction and maintenance of refractory or relapsing non-organ-threatening diseases in conjunction with GC. The dosing of GC for remission induction in GPA and MPA is now lower than was previously used and additionally, avacopan is approved as a new GC-sparing medication for GPA and MPA over 52 weeks. Conventional strategies, such as cyclophosphamide (CYC) are important for remission induction in severe or refractory organ-threatening disease for all AAVs. The use of methotrexate (MTX) and azathioprine (AZA) is becoming less prominent. The most important unanswered questions in the treatment of AAVs are with respect to the duration of remission maintenance treatment and the individualized treatment guidance based on biomarkers.

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Hypereosinophilic syndromes (HES) represent a group of rare dis-immune conditions characterized by blood hyper-eosinophilia and eosinophilic related burden. Especially the idiopathic subtype (I-HES) is particularly difficult to diagnose because of its heterogeneous clinical presentation, the lack of specific findings on physical exam, lab tools, and imaging informative enough to unequivocally confirm the diagnosis and the overlap with other entities, including eosinophilic organ-diseases or systemic dis-immune conditions other than I-HES (from atopy to eosinophilic granulomatosis with polyangiitis [EGPA], the last often extremely difficult to distinguish from HES). Taken together, all the features mentioned above account for an extremely difficult early recognition HES and on-time referral to a specialized centre. The referral itself is challenging due to a not univocal specialist identification, because of the variability of physicians managing HES in different settings (including allergist/clinical immunologist, haematologist, internal medicine doctors, pulmonologist, rheumatologist). Furthermore, the approach in terms of personalized treatment identification and follow-up plan (timing, organ assessment), is poorly standardized. Further translational and clinical research is needed to address the mentioned unmet needs, but on practical grounds increasing the overall clinicians' awareness on HES and implementing healthcare pathways for HES patients represent a roadmap that every clinician might try to realize in his specific setting. The present review aims at providing an overview about the current challenges and unmet needs in the practical approach to HES and rare hypereosinophilic allergo-immunological diseases, including a proposal for an innovative multidisciplinary organizational model.

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BACKGROUND: Eosinophil accumulation is a main feature of eosinophilic gastritis (EoG) and is associated with its histologic diagnosis and pathology. However, a recent clinical trial has demonstrated that EoG endoscopic, noneosinophil histologic, and clinical features remain persistent despite complete eosinophil depletion. OBJECTIVE: Our aim was to examine gastric T-cell composition and associated cytokine levels of patients with EoG following benralizumab-induced eosinophil depletion versus following administration of placebo. METHODS: A cohort of subjects with EoG from a subset of subjects who participated in a recent phase 2 benralizumab trial was treated for 12 weeks with administration of 3 doses of benralizumab (anti-IL-5 receptor α antibody [n = 5]) or placebo (n = 4). Single-cell suspensions obtained by gastric biopsy were stimulated with phorbol 12,13-dibutyrate and ionomycin in the presence of brefeldin A and monensin. Harvested cells were fixed, stained, and analyzed by flow cytometry to examine T-cell populations and associated cytokines. RESULTS: Following benralizumab treatment but not placebo, blood and gastric eosinophil levels decreased 16-fold and 10-fold, respectively. Whereas histologic score and features were significantly decreased, no change was observed in endoscopic score and features. Following complete eosinophil depletion with benralizumab, gastric TH2 cell levels were 3-fold higher than the levels in the patients with EoG who were given placebo; and the levels of associated type 2 cytokine production of IL-4, IL-5, and IL-13 in the benralizumab-treated patients were, respectively, 4-, 5.5-, and 2.5-fold, higher than those in the placebo-treated patients. CONCLUSION: We have identified a putative positive feedback loop whereby eosinophil depletion results in a paradoxic increase in levels of TH2 cells and derived cytokines; this finding suggests an explanation for the limited success of eosinophil depletion as monotherapy in eosinophil-associated gastrointestinal disorders.

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It is an absolute necessity to achieve complete control of comorbidities to obtain optimal asthma control. Importantly, type 2 asthma and ECRS share the same inflammatory pathophysiology and are common co-morbidities. If the initial biologic is insufficiently effective, it is worth considering an alternative biologic.

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The most promising treatment options for severe uncontrolled asthma (SUA) have emerged in recent years with the development of monoclonal antibodies for blocking selective targets responsible for the underlying inflammation, such as mepolizumab and benralizumab. However, there is variability in treatment response that is not fully controlled. The variability of the response to mepolizumab and benralizumab could be influenced by single-nucleotide polymorphisms (SNPs), and it would be useful to detect these and use them as predictive biomarkers of response. We conducted a retrospective observational cohort study of 72 Caucasian patients recruited from a tertiary hospital with severe uncontrolled eosinophilic asthma treated with mepolizumab and benralizumab. Polymorphisms in the IL5 (rs4143832, rs17690122), RAD50 (rs11739623, rs4705959), IL1RL1 (rs1420101, rs17026974, rs1921622), GATA2 (rs4857855), IKZF2 (rs12619285), FCGR2A (rs1801274), FCGR2B (rs3219018, rs1050501), FCGR3A (rs10127939, rs396991), FCER1A (rs2251746, rs2427837), FCER1B (rs1441586, rs573790, rs569108), and ZNF415 (rs1054485) genes were analyzed by real-time polymerase chain reaction (PCR) using Taqman probes. The response was analyzed after 12 months of treatment. In patients under mepolizumab treatment, a treatment response defined as a reduction in exacerbations was associated with ZNF415 rs1054485-T (p = 0.042; OR = 5.33; 95% CI = 1.06-30.02), treatment response defined as a reduction in oral corticosteroids use was associated with the number of exacerbations in the previous year (p = 0.029; OR = 3.89; 95% CI = 1.24-14.92), and treatment response defined as improvement in lung function was associated with the age at the beginning of biological therapy (p = 0.002; OR = 1.10; 95% CI = 1.04-1.18), FCER1B rs569108-AA (p < 0.001; OR = 171.06; 95% CI = 12.94-6264.11), and FCER1A rs2427837-A (p = 0.021; OR = 8.61; 95% CI = 1.71-76.62). On the other hand, in patients under benralizumab treatment, treatment response, defined as a reduction in exacerbations, was associated with ZNF415 rs1054485-T (p = 0.073; OR = 1.3 × 108; 95% CI = 1.8 × 10-19-NA), FCER1B rs569108-AA (p = 0.050; OR = 11.51; 95% CI = 1.19-269.78), allergies (p = 0.045; OR = 4.02; 95% CI = 1.05-16.74), and sex (p = 0.028; OR = 4.78; 95% CI = 1.22-20.63); and treatment response defined as improvement in lung function was associated with polyposis (p = 0.027; OR = 9.16; 95% CI = 1.58-91.4), IKZF2 rs12619285-AA (p = 0.019; OR = 9.1; 95% CI = 1.7-75.78), IL5 rs4143832-T (p = 0.017; OR = 11.1; 95% CI = 1.9-112.17), and FCER1B rs1441586-C (p = 0.045; OR = 7.81; 95% CI = 1.16-73.45). The results of this study show the potential influence of the studied polymorphisms on the response to mepolizumab and benralizumab and the clinical benefit that could be obtained by defining predictive biomarkers of treatment response.

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Background: Indirect comparison among biologics in severe asthma (SA) is a challenging but desirable goal for clinicians in real life. The aim of the study is to define characteristics of a biologic-treated T2-driven-SA population and to evaluate the effectiveness of biologic treatments in a real-world setting by variation in intra/inter-biologic parameters in an up to 4-year follow-up. Methods: Demographic, clinical, functional, and biological characteristics were evaluated retrospectively in 104 patients recruited until July 2022 at baseline (T0) and over a maximum of 4 years (T4) of biologic therapy (omalizumab/OmaG = 41, from T0 to T4, mepolizumab/MepoG = 26, from T0 to T4, benralizumab/BenraG = 18, from T0 to T2, and dupilumab/DupiG = 19, from T0 to T1). Variations of parameters using means of paired Delta were assessed. Results: At baseline, patients had high prevalence of T2-driven comorbidities, low asthma control test (ACT mean 17.65 ± 4.41), impaired pulmonary function (FEV1 65 ± 18 %pred), frequent exacerbations/year (AEs 3.5 ± 3), and OCS dependence (60%). DupiG had lower T2 biomarkers/comorbidities and AEs, and worse FEV1 (57 ± 19 %pred) compared to other biologics (p < 0.05). All biologics improved ACT, FEV1%, FVC%, AEs rate, and OCS use. FEV1% improved in MepoG and BenraG over the minimal clinically important difference and was sustained over 4 years in OmaG and MepoG. A significant RV reduction in OmaG (T4) and DupiG (T1), and BenraG normalization (T2) of airflow limitation were found. We observed through inter-biologic parameters pair delta variation comparison a significant nocturnal awakenings reduction in BenraG vs. OmaG/MepoG, and neutrophils reduction in BenraG/DupiG vs. OmaG. Conclusions: Indirect comparison among biologics unveils clinical and functional improvements that may mark a different effectiveness. These results may highlight the preference of a single biologic compared to another with regard to specific treatable traits.

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Background: Biologics are the important drugs for severe asthma, but clinical trials included few elderly patients. Data on the safety and efficacy of benralizumab in elderly asthma patients are limited. Methods: This clinical study was a multicentre, retrospective, observational study at two hospitals. Patients aged ≥18 years diagnosed with severe asthma treated with benralizumab were included. Elderly patients were defined as those aged 70 years or older. Efficacy and safety were then analyzed in elderly and non-elderly patients. The primary endpoints were the annual number of asthma exacerbations for efficacy and the discontinuation rate due to adverse events for safety. Results: Between August 2016 and October 2022, 61 patients were enrolled; 10 patients were excluded, and 51 (22 elderly, 29 non-elderly) patients were analyzed. In elderly patients, the annual number of asthma exacerbations before treatment with benralizumab (pre-benralizumab) was 3.78, and the number during treatment with benralizumab was 1.26, a decrease of 2.52 (95% confidence interval [CI], 1.3 to 3.74, p < 0.001). In non-elderly patients, the annual number of asthma exacerbation in the pre-benralizumab period was 3.24, and during treatment with benralizumab it was 0.68, a decrease of 2.56 (95% CI, 1.3 to 3.82, p < 0.001). There was no significant difference in discontinuation due to treatment-related adverse events (elderly vs non-elderly, 2 (9%) vs 0 (0%), p = 0.18). Conclusion: Benralizumab reduced the annual number of asthma exacerbations and was well tolerated in elderly patients.

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Benralizumab, a monoclonal antibody targeting IL-5 receptors, reduces exacerbations and oral corticosteroid requirements for severe, uncontrolled eosinophilic asthma. In Japan, geographic disparities in asthma outcomes suggest differential prescribing and access. This study aimed to quantify regional prescribing variations for benralizumab nationwide. Using Japan's National Database (NDB) of insurance claims (2009-2019), benralizumab standardized claim ratios (SCRs) were calculated for 47 prefectures. Correlations between SCRs and other biologics' SCRs, economic variables like average income, and physician densities were evaluated through univariate analysis and multivariate regressions. Income-related barriers to optimal prescribing were examined. Wide variation emerged in benralizumab SCRs, from 40.1 to 184.2 across prefectures. SCRs strongly correlated with omalizumab (r = 0.61, p < 0.00001) and mepolizumab (r = 0.43, p = 0.0024). Average monthly income also positively correlated with benralizumab SCRs (r = 0.45, p = 0.0016), whereas lifestyle factors were insignificant. Respiratory specialist density modestly correlated with SCRs (r = 0.29, p = 0.047). In multivariate regressions, average income remained the most robust predictor (B = 0.74, p = 0.022). Benralizumab SCRs strongly associate with income metrics more than healthcare infrastructure/population factors. Many regions show low SCRs, constituting apparent prescribing gaps. Access barriers for advanced asthma therapies remain inequitable among Japan's income strata. Addressing affordability alongside specialist allocation can achieve better prescribing quality and asthma outcomes.

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Background: The objective of this study was to evaluate, the clinical benefit of benralizumab in patients with uncontrolled severe asthma associated with chronic rhinosinusitis with nasal polyposis (CRSwNP). Methods: The study included patients with uncontrolled severe asthma associated with CRSwNP who started therapy with benralizumab. Pulmonary function, eosinophilia, IgE, comorbidity, changes in the Asthma Control Test (ACT), Asthma Control Questionnaire (ACQ), Visual Analogue Scale (VAS), Quality of Life (AQLQ), VAS (obstruction, drip, anosmia, facial pressure), SNOT-22, decrease or withdrawal of steroids and other medication, hospital admissions and emergency visits were analysed. The FEOS scale and EXACTO were employed in the assessment of response. Results: We analyzed 58 patients who completed minimal treatment at 12 months. After treatment with benralizumab, exacerbations were reduced by 82% (p < 0.001), steroid cycles by 84% (p < 0.001), emergencies visit by 83% p < 0.001) and admissions by 76% (p < 0.001), improving all the scales for asthma control, (p < 0.001). In terms of lung function, differences were observed in FVC% (p < 0.001), FEV1% (p < 0.001), and FEV1/FVC% (69.5 ± 10 vs. 74 ± 10, p < 0.001). In relation to CRSwNP, differences were observed in SNOT-22 (54.66 ± 17 vs. 20.24 ± 9, p < 0.001), VAS obstruction (7.91 ± 1 vs. 1.36 ± 1, p < 0. 001), VAS drip (7.76 ± 1 vs. 1.38 ± 1, p < 0.001), VAS anosmia (7.66 ± 1 vs. 1.38 ± 1, p < 0.001) and VAS facial pressure (7.91 ± 1 vs. 1.22 ± 1, p < 0.001). The mean FEOS score after treatment was 73 ± 14. A complete response/super response was achieved in 33 patients (57%), good response in 16 (28%) and partial response in 9 (15%). Conclusions: The administration of benralizumab to patients with uncontrolled severe asthma associated with CRSwNP has been demonstrated to improve nasal symptoms, asthma control and lung function. This resulted in a reduction in the need for oral steroids, maintenance and rescue medication, emergency room visits, and hospital admissions, with 57% of patients achieving the clinical remission criteria.

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Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare autoimmune disorder characterized by necrotizing vasculitis, asthma, and eosinophilia. We report a case of EGPA that developed during benralizumab treatment for severe asthma and provide a literature review. A 79-year-old Japanese male with severe asthma presented with generalized purpura 4 months after initiating benralizumab treatment. He had reduced his oral prednisolone dose from 7.5 to 2 mg/day. Laboratory tests revealed eosinophilia, and skin biopsy showed vasculitis with eosinophilic infiltration. He was diagnosed with EGPA and treated with corticosteroids, azathioprine, and mepolizumab, which led to rapid improvement and sustained remission. Five cases of EGPA developing during benralizumab treatment have been reported, with onset ranging from 14 to 36 weeks after initiation. Clinicians should monitor for EGPA development in patients receiving benralizumab, particularly during oral corticosteroid reduction.

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BACKGROUND: Benralizumab has been reported to lead to clinical remission of severe eosinophilic asthma (SEA) at 1 year in some patients. However, whether this is maintained over a longer term remains unclear. Additionally, the impact of pulmonary and extrapulmonary comorbidities on the ability to meet remission is poorly understood. METHODS: Clinical outcomes including remission of SEA with benralizumab at 1 and 2 years were assessed retrospectively in a real-world UK multi-centre severe asthma cohort. The presence of clinically relevant pulmonary and extrapulmonary comorbidities associated with respiratory symptoms was recorded. Analyses to identify factors associated with the ability to meet remission were performed. RESULTS: In total, 276 patients with SEA treated with benralizumab including 113 patients who had switched from a previous biologic to benralizumab were included. Overall, clinical remission was met in 17% (n = 31/186) and 32% (n = 43/133) of patients at 1 and 2 years, respectively. This increased to 28% at 1 year and 49% at 2 years once patients with pulmonary and/or extrapulmonary comorbidities were excluded. Body mass index (BMI) and maintenance OCS (mOCS) use demonstrated a negative association with clinical remission at 1 (BMI: OR: 0.89, 95% CI: 0.82-0.96, p < 0.01; mOCS: OR: 0.94, 95% CI: 0.89-0.99, p < 0.05) and 2 years (BMI: OR: 0.93, 95% CI: 0.87-0.99, p < 0.05; mOCS: OR: 0.95, 95% CI: 0.89-0.99, p < 0.05). CONCLUSIONS: In this long-term, real-world study, patients with SEA demonstrated the ability to meet and sustain clinical remission when treated with benralizumab. The presence of comorbidities including obesity, which are known to be independently associated with respiratory symptoms, reduced the likelihood of meeting clinical remission.

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Interleukin-5 functions as a B-cell differentiation factor, but more importantly, in the context of this review, it plays a variety of roles in eosinophil biology, including eosinophil differentiation and maturation in the bone marrow, and facilitates eosinophil migration to tissue sites, usually in the context of an allergic reaction. Given the availability of selective anti-IL-5 drugs such as mepolizumab and reslizumab, as well as the IL-5 receptor antagonist benralizumab, it is worth investigating whether they could be used in some cases of allergic disease. Asthma has a well-documented involvement of IL-5 in its pathophysiology and has clear benefits in the case of anti-IL-5 therapy; therefore, current knowledge is presented to provide a reference point for the study of less-described diseases such as atopic dermatitis, chronic rhinosinusitis, chronic spontaneous urticaria, and its association with both IL-5 and anti-IL-5 treatment options. We then review the current literature on these diseases, explain where appropriate potential reasons why anti-IL-5 treatments are ineffective, and then point out possible future directions for further research.

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Background: Severe asthma often remains uncontrolled despite optimized inhaled treatment. The rise of biologic therapy in severe asthma represented a major advance for the disease management. However, correct phenotyping and monitoring of severe asthma patients is key to the success of targeted biologic therapy. Materials and Methods: We present the case of a 63-year-old female, never a smoker, diagnosed with asthma at the age of 45 and associated persistent mild rhinitis, without other notable comorbidities. She was prescribed medium-dose ICS/LABA, administered inconstantly in the first years after the diagnosis, with poor overall control of the disease. After several exacerbation episodes, treatment compliance improved, but the control of the disease remained poor despite adding an antileukotriene. In January 2019, she presented an exacerbation episode requiring treatment with oral corticosteroids (OCS) and she was afterwards put on high-dose ICS/LABA and continued the antileukotriene. She was referred for a skin allergy test, which revealed mild sensitization to Dermatophagoides pteronyssinus and farinae, with a total IgE level of 48.3 IU/mL. The blood eosinophil level was 270 cells/mm3. The lung function was variable, going from mild impairment to severe fixed obstruction during exacerbations. Despite optimized inhaled treatment, good adherence and inhaler technique, and allergen avoidance strategies, asthma control was not achieved, and she continued to experience severe episodes of exacerbation requiring OCS. Results: In October 2019, she was initiated on biologic therapy with omalizumab, which allowed asthma control to be achieved and maintained for 18 months, with preserved lung function, good symptom control, no exacerbations and slightly elevated blood eosinophil level (340-360 cells/mm3). In April 2021, she started experiencing exacerbation episodes requiring OCS (three episodes within 6 months), with a progressive increase in blood eosinophil level (up to 710 cells/mm3), and progressive deterioration of asthma control and lung function, despite continuation of previous therapy. A specific IgE test against Aspergillus was negative, and total IgE level was 122.4 IU/mL. In December 2021, the patient was switched from omalizumab to benralizumab. Asthma control was again achieved, lung function improved significantly and the patient did not experience any other exacerbation episodes up until today, which allowed for a reduction in ICS dose. Intriguingly, a relapsing eosinophilia was also noted under anti-IL5-R treatment prior to the dose administration, but with preserved asthma control. Conclusions: This case underscores the pivotal role of meticulous phenotyping in severe asthma management on one side, and careful monitoring of patient evolution and possible side effects of treatment on the other side. By showcasing how diverse inflammatory pathways can coexist within a single patient and impact treatment outcomes, it highlights the necessity of tailored biologic therapy for sustained control.