Dupilumab-induced eosinophilia in patients with diffuse type 2 chronic rhinosinusitis.

BACKGROUND Dupilumab, a monoclonal anti-IL-4Rα antibody, is approved for several type 2 mediated inflammatory diseases like asthma, atopic dermatitis, and diffuse type 2 chronic rhinosinusitis (CRS). Clinical studies had reported a transient increase in blood eosinophils during dupilumab therapy. This study aimed to assess the impact of elevated blood eosinophils on clinical outcome and to investigate the cause of high blood eosinophil levels under dupilumab therapy. METHODS Patients suffering from diffuse type 2 CRS treated with dupilumab were examined on days 0, 28, 90, and 180 after therapy start. Sino-Nasal-Outcome-Test Score (SNOT-22), Total Nasal Polyp Score (TNPS), and blood samples were collected. Cytokine measurements and proteomics analysis were conducted. Flow cytometry analysis measured receptor expression on eosinophils. RESULTS Sixty-eighty patients were included. Baseline eosinophilia ≥0.3G/L was observed in 63.2% of patients, and in 30.9% of patients, eosinophils increased by ≥0.5G/L under dupilumab. Subjects with eosinophilia ≥0.3G/L at baseline had the best SNOT-22 mean change compared to no eosinophilia. Eosinophil elevation during dupilumab therapy had no impact on clinical scores. The eosinophil adhesion molecule VCAM-1 decreased significantly during therapy in all patients. The chemokine receptor CXCR4 was significantly down- and IL-4 upregulated in subjects with eosinophil increase. CONCLUSION Our findings suggest that increased eosinophils in type 2 CRS are associated with a good clinical response to dupilumab. Patients with elevated IL-4 at baseline developed dupilumab-induced transient eosinophilia. We identified the downregulation of VCAM-1 and surface markers CD49d and CXCR4 on eosinophils as possible explanations of dupilumab-induced eosinophilia

Endotype-Phenotype Patterns in Meniere's Disease Based on Gadolinium-Enhanced MRI of the Vestibular Aqueduct

Two histopathological subtypes of Meniere's disease (MD) were recently described in a human post-mortem pathology study. The first subtype demonstrated a degenerating distal endolymphatic sac (ES) in the affected inner ear (subtype MD-dg); the second subtype (MD-hp) demonstrated an ES that was developmentally hypoplastic. The two subtypes were associated with different clinical disease features (phenotypes), suggesting that distinct endotype-phenotype patterns exist among MD patients. Therefore, clinical endotyping based on ES pathology may reveal clinically meaningful MD patient subgroups. Here, we retrospectively determined the ES pathologies of clinical MD patients (n = 72) who underwent intravenous delayed gadolinium-enhanced inner ear magnetic resonance imaging using previously established indirect radiographic markers for both ES pathologies. Phenotypic subgroup differences were evidenced; for example, the MD-dg group presented a higher average of vertigo attacks (ratio of vertigo patterns daily/weekly/other vs. monthly, MD-dg: 6.87: 1; MD-hp: 1.43: 1; p = 0.048) and more severely reduced vestibular function upon caloric testing (average caloric asymmetry ratio, MD-dg: 30.2% ± 30.4%; MD-hp: 13.5% ± 15.2%; p = 0.009), while the MD-hp group presented a predominantly male sex ratio (MD-hp: 0.06:1 [f/m]; MD-dg: 1.2:1 [f/m]; p = 0.0004), higher frequencies of bilateral clinical affection (MD-hp: 29.4%; MD-dg: 5.5%; p = 0.015), a positive family history for hearing loss/vertigo/MD (MD-hp: 41.2%; MD-dg: 15.7%; p = 0.028), and radiographic signs of concomitant temporal bone abnormalities, i.e., semicircular canal dehiscence (MD-hp: 29.4%; MD-dg: 3.6%; p = 0.007). In conclusion, this new endotyping approach may potentially improve the diagnosis, prognosis and clinical decision-making for individual MD patients

Dupilumab‐induced eosinophilia in patients with diffuse type 2 chronic rhinosinusitis

BackgroundDupilumab, a monoclonal anti‐IL‐4Rα antibody, is approved for several type 2 mediated inflammatory diseases like asthma, atopic dermatitis, and diffuse type 2 chronic rhinosinusitis (CRS). Clinical studies had reported a transient increase in blood eosinophils during dupilumab therapy.This study aimed to assess the impact of elevated blood eosinophils on clinical outcome and to investigate the cause of high blood eosinophil levels under dupilumab therapy.MethodsPatients suffering from diffuse type 2 CRS treated with dupilumab were examined on days 0, 28, 90, and 180 after therapy start. Sino‐Nasal‐Outcome‐Test Score (SNOT‐22), Total Nasal Polyp Score (TNPS), and blood samples were collected. Cytokine measurements and proteomics analysis were conducted. Flow cytometry analysis measured receptor expression on eosinophils.ResultsSixty‐eighty patients were included. Baseline eosinophilia ≥0.3G/L was observed in 63.2% of patients, and in 30.9% of patients, eosinophils increased by ≥0.5G/L under dupilumab. Subjects with eosinophilia ≥0.3G/L at baseline had the best SNOT‐22 mean change compared to no eosinophilia. Eosinophil elevation during dupilumab therapy had no impact on clinical scores. The eosinophil adhesion molecule VCAM‐1 decreased significantly during therapy in all patients. The chemokine receptor CXCR4 was significantly down‐ and IL‐4 upregulated in subjects with eosinophil increase.ConclusionOur findings suggest that increased eosinophils in type 2 CRS are associated with a good clinical response to dupilumab. Patients with elevated IL‐4 at baseline developed dupilumab‐induced transient eosinophilia. We identified the downregulation of VCAM‐1 and surface markers CD49d and CXCR4 on eosinophils as possible explanations of dupilumab‐induced eosinophilia

Predicting dupilumab treatment outcome in patients with primary diffuse type 2 chronic rhinosinusitis.

BACKGROUND Chronic rhinosinusitis with a type 2 inflammatory pattern (T2CRS) is believed to be restricted to the nose and sinuses and associated with polyps, without clear serologic markers. Dupilumab is a promising new therapy in difficult to treat T2CRS. No factors are known to predict dupilumab treatment outcome. METHODS Patients undergoing dupilumab treatment were assessed clinically to report ultra-short- and short-term outcome up to 90 days. Serum samples were taken on day 0 and 30 days of treatment, and proteomic analyses were performed using Olink®. The results were compared with healthy controls (HC). The aim was to identify clinical and serological markers associated with a treatment response to dupilumab. Confirmation of predictive parameters was evaluated in a prospective cohort of 20 T2CRS patients. RESULTS Thirty patients were included, 80% of which were treatment responders. SinoNasalOutcomeTest-20 (SNOT-20) scores and the total nasal polyp score improved significantly (p < .05) on Day 7. An improvement of 2.5 points at the first visit was associated with a favorable outcome with a sensitivity of 86%. Proteomic analyses revealed significant changes compared with HC. Furthermore, we could identify OPG in the serum of dupilumab-treated patients that may serve as a predictor of the clinical outcome of dupilumab treatment. The predictive value of OPG was confirmed in the second cohort. CONCLUSION Clinical response after 1 week of treatment with dupilumab is highly associated with a favorable outcome. High sensitivity proteomic analyses can identify T2CRS-specific dysregulated proteins in serum. Serum OPG may serve as a predictor for dupilumab treatment outcome before the initiation of any therapy

Predicting Dupilumab Treatment Outcome in Patients with Primary diffuse Type 2 Chronic Rhinosinusitis

Background: Chronic rhinosinusitis with a type 2 inflammatory pattern (T2CRS) is believed to be restricted to the nose & sinuses and associated with polyps, without clear serologic markers. Dupilumab is a promising new therapy in difficult to treat T2CRS. No factors are known to predict dupilumab treatment outcome. Methods: Patients undergoing dupilumab treatment were assessed clinically to report ultra-short- and short-term outcome up to 90 days. Serum samples were taken on day 0 and 30 days of treatment, and proteomic analyses were performed using Olink®. The results were compared to healthy controls (HC). The aim was to identify clinical and serological markers associated with a treatment response to dupilumab. Confirmation of predictive parameters was evaluated in a prospective cohort of 20 T2CRS patients. Results: 30 patients were included, 80% of which were treatment responders. SinoNasalOutcomeTest-20 (SNOT-20) scores and the total nasal polyp score improved significantly (p<0.05) on day 7. An improvement of 2.5 points at the first visit was associated with a favorable outcome with a sensitivity of 86%. Proteomic analyses revealed significant changes compared to HC. Furthermore, we could identify OPG in the serum of dupilumab treated patients that may serve as a predictor of the clinical outcome of dupilumab treatment. The predictive value of OPG was confirmed in the second cohort. Conclusion: Clinical response after one week of treatment with dupilumab is highly associated with a favorable outcome. High sensitivity proteomic analyses can identify T2CRS specific dysregulated proteins in serum. Serum OPG may serve as a predictor for dupilumab treatment outcome before the initiation of any therapy. Keywords: Anti IL-4/13; CRS; eosinophilia; predictor; proteomic

Endotype-Phenotype Patterns in Meniere's Disease Based on Gadolinium-Enhanced MRI of the Vestibular Aqueduct

Two histopathological subtypes of Meniere's disease (MD) were recently described in a human post-mortem pathology study. The first subtype demonstrated a degenerating distal endolymphatic sac (ES) in the affected inner ear (subtype MD-dg); the second subtype (MD-hp) demonstrated an ES that was developmentally hypoplastic. The two subtypes were associated with different clinical disease features (phenotypes), suggesting that distinct endotype-phenotype patterns exist among MD patients. Therefore, clinical endotyping based on ES pathology may reveal clinically meaningful MD patient subgroups. Here, we retrospectively determined the ES pathologies of clinical MD patients (n = 72) who underwent intravenous delayed gadolinium-enhanced inner ear magnetic resonance imaging using previously established indirect radiographic markers for both ES pathologies. Phenotypic subgroup differences were evidenced; for example, the MD-dg group presented a higher average of vertigo attacks (ratio of vertigo patterns daily/weekly/other vs. monthly, MD-dg: 6.87: 1; MD-hp: 1.43: 1; p = 0.048) and more severely reduced vestibular function upon caloric testing (average caloric asymmetry ratio, MD-dg: 30.2% ± 30.4%; MD-hp: 13.5% ± 15.2%; p = 0.009), while the MD-hp group presented a predominantly male sex ratio (MD-hp: 0.06:1 [f/m]; MD-dg: 1.2:1 [f/m]; p = 0.0004), higher frequencies of bilateral clinical affection (MD-hp: 29.4%; MD-dg: 5.5%; p = 0.015), a positive family history for hearing loss/vertigo/MD (MD-hp: 41.2%; MD-dg: 15.7%; p = 0.028), and radiographic signs of concomitant temporal bone abnormalities, i.e., semicircular canal dehiscence (MD-hp: 29.4%; MD-dg: 3.6%; p = 0.007). In conclusion, this new endotyping approach may potentially improve the diagnosis, prognosis and clinical decision-making for individual MD patients.</p