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BackgroundEosinophilic granulomatosis with polyangiitis (EGPA) is often associated with glucocorticoid-dependent asthma and/or ear, nose and throat (ENT) manifestations. When immunosuppressants and/or mepolizumab are ineffective, dupilumab could be an option. We describe the safety and efficacy of off-label use of dupilumab in relapsing and/or refractory EGPA.Patients and methodsWe conducted an observational multicentre study of EGPA patients treated with dupilumab. Complete response was defined by Birmingham Vasculitis Activity Score (BVAS)=0 and prednisone dose ≤4 mg/day, and partial response by BVAS=0 and prednisone dose >4 mg/day. Eosinophilia was defined as an eosinophil count >500/mm3.ResultsFifty-one patients were included. The primary indication for dupilumab was disabling ENT symptoms in 92%. After a median follow-up of 13.1 months, 18 patients (35%) reported adverse events (AEs), including two serious AEs. Eosinophilia was reported in 34 patients (67%), with a peak of 2195/mm3 (IQR 1268–4501) occurring at 13 weeks (IQR 4–36) and was associated with relapse in 41%. Twenty-one patients (41%) achieved a complete response and 12 (24%) a partial response. Sixteen (31%) patients experienced an EGPA relapse while on dupilumab, which was associated with blood eosinophilia in 14/16 (88%) patients. The median eosinophil count at the start of dupilumab was significantly lower in relapsers than in non-relapsers, as was the median time between stopping anti-IL-5/IL-5R and switching to dupilumab.ConclusionThese results suggest that dupilumab may be effective in treating patients with EGPA-related ENT manifestations. However, EGPA flares occurred in one-third of patients and were preceded by eosinophilia in 88%, suggesting that caution is required.

ObjectivesSyntenin-1, a novel endogenous ligand, was discovered to be enriched in rheumatoid arthritis (RA) specimens compared with osteoarthritis synovial fluid and normal synovial tissue (ST). However, the cellular origin, immunoregulation and molecular mechanism of syntenin-1 are undescribed in RA.MethodsRA patient myeloid and lymphoid cells, as well as preclinical models, were used to investigate the impact of syntenin-1/syndecan-1 on the inflammatory and metabolic landscape.ResultsSyntenin-1 and syndecan-1 (SDC-1) co-localise on RA ST macrophages (MΦs) and endothelial cells. Intriguingly, blood syntenin-1 and ST SDC-1 transcriptome are linked to cyclic citrullinated peptide, erythrocyte sedimentation rate, ST thickness and bone erosion. Metabolic CD14+CD86+GLUT1+MΦs reprogrammed by syntenin-1 exhibit a wide range of proinflammatory interferon transcription factors, monokines and glycolytic factors, along with reduced oxidative intermediates that are downregulated by blockade of SDC-1, glucose uptake and/or mTOR signalling. Inversely, IL-5R and PDZ1 inhibition are ineffective on RA MΦs-reprogrammed by syntenin-1. In syntenin-1-induced arthritis, F4/80+iNOS+RAPTOR+MΦs represent glycolytic RA MΦs, by amplifying the inflammatory and glycolytic networks. Those networks are abrogated in SDC-1-/- animals, while joint prorepair monokines are unaffected and the oxidative metabolites are moderately replenished. In RA cells and/or preclinical model, syntenin-1-induced arthritogenicity is dependent on mTOR-activated MΦ remodelling and its ability to cross-regulate Th1 cells via IL-12 and IL-18 induction. Moreover, RA and joint myeloid cells exposed to Syntenin-1 are primed to transform into osteoclasts via SDC-1 ligation and RANK, CTSK and NFATc1 transcriptional upregulation.ConclusionThe syntenin-1/SDC-1 pathway plays a critical role in the inflammatory and metabolic landscape of RA through glycolytic MΦ and Th1 cell cross-regulation (graphical abstract).

Clinical remission (CliR) achievement has been recognized as a new potential outcome in severe asthma. Nevertheless, we still lack a detailed profile of what features could better identify patients undergoing clinical remission. In this study, we aim to address this issue, tracing a possible identikit of patients fulfilling remission criteria. We enrolled 266 patients with severe eosinophilic asthma (SEA) treated with a 12-month course of anti-IL5/IL5 receptor (IL5r) monoclonal antibodies. Patients with no exacerbation, OCS withdrawal, ACT ≥ 20 and FEV ≥ 80% after 1 year of biologic treatment were classified as in clinical remission. 30.5% of the enrolled patients achieved remission after biologic administration. CliR group showed a lower number of baseline asthma exacerbations and better lung function parameters, with a trend for higher ACT scores and a less frequent history of a positive skin prick test. CliR achievement was unlikely in presence of a higher BMI, a positive skin prick test, an increased number of asthma exacerbations before biologic treatment, anti-muscarinic administration, and a previous diagnosis of EGPA, bronchiectasis or osteoporosis. In contrast, a better lung function, an increased blood eosinophilic count, the presence of chronic rhinosinusitis with nasal polyps and a more frequent use of reliever therapy predicts remission development. Changes in exacerbations number, OCS use, ACT scores and FEV % between remittent and non-remittent patients arise at specific follow up timepoints and are positively associated with CliR achievement. anti-IL5/IL5r biologics can induce CliR in a proportion of patients with SEA. Patients achieving remission demonstrate specific clinical, functional and inflammatory features, as well as a specific moment of improvement in all the CliR items.

Background:Eosinophilic granulomatosis with polyangiitis (EGPA) is frequently associated with refractory chronic rhinosinusitis with nasal polyps (CRSwNP), despite current treatments. Dupilumab demonstrated efficacy in the treatment of severe and uncontrolled CRSwNP.Objectives:We aimed to assess safety and efficacy of dupilumab in refractory CRSwNP in EGPA and analyze changes in nasal smears and tissue infiltrates.Methods:Consecutive EGPA patients suffering from refractory CRSwNP were enrolled prospectively between December 2021 and October 2023. Demographic, clinical, biological data and nasal cytology were collected at each evaluation.Assessment included patient-reported outcomes such as Asthma Control Test (ACT), Nasal Congestion Score (NCS), Sino-Nasal Outcome Test (SNOT-22), Visual Analogue Scales (VAS)), as well as objective measures including Peak Nasal Inspiratory Flow (PNIF), Nasal Polyp Score (NPS) and Sniffin’ Sticks Identification Test (SSIT).Complete response was defined by Birmingham Vasculitis Activity Score (BVAS)=0 and prednisone dose ≤4 mg/day, and partial response by BVAS=0 and prednisone dose >4 mg/day.Results:The study included 9 EGPA patients (age at diagnosis 51 [46-59] years, male 66.6%), with BVAS at diagnosis of 16 [11.5-19.5]. Median eosinophils at diagnosis were 4810/mmc [2100-9180], reduced to 330/mmc [175-640] at dupilumab initiation. Dupilumab was mainly used as third-line therapy, after a median disease duration of 66 [65-128] months. Two (22.2%) patients were previously treated with anti-IL5/IL-5R therapy. Median duration of treatment with dupilumab was 8 [3.5-6] months.A total of 26 nasal cytology tests were performed (min 2 – max 4 for each patient). At baseline, 66.7% patients showed a nasal cytology with eosinophilic patterns, 16.7% a neutrophilic pattern and 16.7% a mixed (eosinophils-neutrophils) pattern. The median eosinophils count was 8 (2-13) cells per field at the start of dupilumab, reduced to 0.2 (0-0.2) at 12 months, whereas median neutrophils count was (2-9) cells per field at the start of dupilumab, reduced to 0 (0-0) at 12 months.No differences were observed in median eosinophils count, prednisone dose and VDI during follow-up.Significant improvement was observed in VAS-nasal obstruction (p=0.011), VAS-smell (p=0.028), VAS anterior rhinorrhea (p=0.043), VAS sleep disorders (p=0.042), NCS (p=0.016), SNOT-22 (p=0.05) and NPS (p=0.011).At last follow-up complete response was achieved by 6 (66.6%) patients. Adverse events were reported in 4 (44.4%) patients. Hypereosinophilia occured in 2 (22.2%) patients within the first 3 months, leading to dupilumab discontinuation.Conclusion:Dupilumab showed improvement in patient reported outcomes and objective measures when used in refractory CRSwNP in EGPA. Treatment was associated with a good safety profile.REFERENCES:NIL.Table 1.Figure 1.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background Eosinophilic asthma is a common subtype of severe asthma with high morbidity and mortality. The cytokine IL-5 has been shown to be a key driver of the development and progression of disease. Although approved monoclonal antibodies (mAbs) targeting IL-5/IL-5R have shown good safety and efficacy, some patients have inadequate responses and frequent dosing results in medication nonadherence. Results We constructed a novel trivalent bispecific nanobody (Nb) consisting of 3 VHHs that bind to 2 different epitopes of IL-5 and 1 epitope of albumin derived from immunized phage display libraries. This trivalent IL-5-HSA Nb exhibited similar IL-5/IL-5R blocking activities to mepolizumab (Nucala), an approved targeting IL-5 mAb. Surprisingly, this trivalent Nb was 58 times more active than mepolizumab in inhibiting TF-1-cell proliferation. In primate studies, the trivalent IL-5-HSA Nb showed excellent pharmacokinetic properties, and peripheral blood eosinophil levels remained significantly suppressed for two months after a single dose. In addition, the trivalent IL-5-HSA Nb could be produced on a large scale in a P. pastoris X-33 yeast system with high purity and good thermal stability. Conclusions These findings suggest that the trivalent bispecific IL-5-HSA Nb has the potential to be a next-generation therapeutic agent targeting IL-5 for the treatment of severe eosinophilic asthma. Graphical Abstract

The drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome represents a severe hypersensitivity reaction. Up-to-date treatment is based on withdrawal of medication, supportive care, and immunosuppression using high-dose corticosteroid (CS) therapy. However, evidence-based data are lacking regarding second-line therapy for steroid-resistant or steroid-dependent patients. We hypothesize that the interleukin (IL)-5 axis plays a critical role in the pathophysiology of DRESS; hence, inhibition of this signaling pathway could offer a potential therapy for steroid-dependent and/or steroid-resistant cases, and it may offer an alternative to CS therapy in certain patients more prone to CS toxicity. Herein, we collected worldwide data on DRESS cases treated with biological agents targeting the IL-5 axis. We reviewed all cases indexed in PubMed up to October 2022 and performed a total analysis including our center experience with two additional novel cases. A review of the literature yielded 14 patients with DRESS who were treated with biological agents targeting the IL-5 axis as well as our two new cases. Reported patients are characterized by a female-to-male ratio of 1:1 and a mean age of 51.8 (17-87) years. The DRESS-inducing drugs, as expected from the prospective RegiSCAR study, were mostly antibiotics (7/16), as follows: vancomycin, trimethoprim-sulfamethoxazole, ciprofloxacin, piperacillin-tazobactam, and cefepime. DRESS patients were treated with anti-IL-5 agents (mepolizumab and reslizumab) or anti-IL-5 receptor (IL-5R) biologics (benralizumab). All patients have clinically improved under anti-IL-5/IL-5R biologics. Multiple doses of mepolizumab were needed to achieve clinical resolution, whereas a single dose of benralizumab was often sufficient. Relapse was noted in one patient receiving benralizumab treatment. One patient receiving benralizumab had a fatal outcome, although mortality was probably related to massive bleeding and cardiac arrest due to coronavirus disease 2019 (COVID-19) infection. Current treatment guidelines for DRESS are based on case reports and expert opinion. Understanding the central role of eosinophils in DRESS pathogenicity emphasizes the need for future implementation of IL-5 axis blockade as steroid-sparing agents, potential therapy to steroid-resistant cases, and perhaps an alternative to CS treatment in certain DRESS patients more prone to CS toxicity.

Introduction: Monoclonal antibodies (mAbs) targeting immunoglobulin E (IgE) [omalizumab], type 2 (T2) cytokine interleukin (IL) 5 [mepolizumab, reslizumab], IL-4 Receptor (R) α [dupilumab], and IL-5R [benralizumab]), improve quality of life in patients with T2-driven inflammatory diseases. However, there is a concern for an increased risk of helminth infections. The aim was to explore safety signals of parasitic infections for omalizumab, mepolizumab, reslizumab, dupilumab, and benralizumab. Methods: Spontaneous reports were used from the Food and Drug Administration’s Adverse Event Reporting System (FAERS) database from 2004 to 2021. Parasitic infections were defined as any type of parasitic infection term obtained from the Standardised Medical Dictionary for Regulatory Activities ® (MedDRA ® ). Safety signal strength was assessed by the Reporting Odds Ratio (ROR). Results: 15,502,908 reports were eligible for analysis. Amongst 175,888 reports for omalizumab, mepolizumab, reslizumab, dupilumab, and benralizumab, there were 79 reports on parasitic infections. Median age was 55 years (interquartile range 24–63 years) and 59.5% were female. Indications were known in 26 (32.9%) reports; 14 (53.8%) biologicals were reportedly prescribed for asthma, 8 (30.7%) for various types of dermatitis, and 2 (7.6%) for urticaria. A safety signal was observed for each biological, except for reslizumab (due to lack of power), with the strongest signal attributed to benralizumab (ROR = 15.7, 95% Confidence Interval: 8.4–29.3). Conclusion: Parasitic infections were disproportionately reported for mAbs targeting IgE, T2 cytokines, or T2 cytokine receptors. While the number of adverse event reports on parasitic infections in the database was relatively low, resulting safety signals were disproportionate and warrant further investigation.

Background Benralizumab is a monoclonal antibody that binds to the human interleukin-5 (IL-5) receptor (IL-5R), thereby preventing IL-5 from binding to its receptor and inhibiting differentiation and maturation of eosinophils in the bone marrow. Because of its recent marketing approval, sufficient real-life evidence is lacking to confirm the efficacy and safety data from clinical trials. The purpose of this study was to evaluate the efficacy and safety of benralizumab for the treatment of severe refractory eosinophilic asthma in a real-world cohort of patients. Methods This was a cross-sectional multicentre study of consecutive patients with severe refractory eosinophilic asthma who received treatment with benralizumab during at least 6 months. Patient follow-up was performed in specialised severe asthma units. Results A total of 42 patients were enrolled and treated with benralizumab. Asthma control, as measured by the asthma control test (ACT), improved in all patients both at 3 months of treatment compared with baseline (13.9 ± 4 vs 20.1 ± 3.7, p  < 0.001) and at 6 months of treatment compared with the results obtained at 3 months (20.1 ± 3.7 vs 21 ± 2.7, p  = 0.037). Similarly, the number of emergency department visits decreased both at 3 months compared with baseline (1 [IR:0.7] vs 0 [IR:0.75], p  < 0.001) and at 6 months compared with the results at 3 months (0 [IR:0.75] vs 0 [IR:0], p  = 0.012). Reductions in the number of oral corticosteroid cycles, percentage of corticosteroid-dependent patients, and mean daily dose of oral or inhaled corticosteroid were also evidenced. Finally, mean lung function improvement was 291 mL ( p  < 0.001), and FEV1% improved both at 3 months compared with baseline (64.4 ± 9.3 vs 73.1 ± 9.1, p  < 0.001) and at 6 months compared to 3 months (73.1 ± 9.1 vs 76.1 ± 12, p  = 0.002). Side effects were mild and did not lead to treatment discontinuation. Conclusions This study confirms the efficacy and safety of benralizumab in a real-life setting with improved asthma control and lung function, and a reduced oral and inhaled corticosteroid use as well as fewer emergency department visits. In addition to a rapid initial improvement, it appears that patients continue to improve during the first 6 months of treatment.

As a part of the innate immune system, eosinophils are recruited during infectious diseases, to release their characteristic cytotoxic granules and catch pathogens in extracellular traps. Moreover, eosinophils have a crucial role in autoimmune diseases, for example allergies. The isolation of these densest and lowest abundant leukocytes is cost-and labor intense. This sets restrictions on many aspects of eosinophilic research. In this study, we performed a thorough characterization and functional assessment of the HL-60 clone 15 (HC15) cell line, which can be differentiated into eosinophil-like cells, to investigate its potential in eosinophil research. HC15 cells were differentiated with sodium butyrate with or without IL-5 and cells were characterized and compared to primary eosinophils, neutrophils and peripheral blood mononuclear cells. Cell features were analyzed using proteomics, morphologic assessment, RT-qPCR, immunofluorescent staining and flow cytometry. Based on these results, functional tests were performed, including transwell migration assays, flow cytometry-based aggregate formation assays, immunofluorescent microscopy-based adherence assays to endothelial cells and flow cytometry- and ELISA-based activation assays. The proteomes of the cell line cells differed from those of primary eosinophils and neutrophils. Differentiation of HC15 cells enhanced the expression of GATA-1 and altered the expression of surface markers IL-5R, EMR1, and TREM-1. Differentiated HC15 cells overexpressed the granule protein EPX compared to primary eosinophils and induced a distinct inflammatory milieu by secreting CCL-5, EPX and IL-8. The addition of IL-5 during differentiation increased this effect. Cell line cells responded weaker to activation than primary eosinophils but showed a similar migration and adherence pattern in multiple assays. These features were mostly unaffected by differentiation. Differentiation of HC15 cells induces an eosinophil lineage-committed precursor state. Hence, the differentiated cell line cells lacked characteristic features of eosinophils such as morphologic attributes, surface marker expression and the capacity to be activated. However, the cells were able to migrate, form aggregates with platelets and similarly adhere to endothelial cells as primary eosinophils. It is, therefore, advisable to use the cell line as an eosinophilic model only in research questions related to chemotaxis and migration.