好酸球性副鼻腔炎

BACKGROUND: The phase 3 WAYPOINT study (NCT04851964) showed that tezepelumab improved outcomes in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) including nasal polyp size, nasal congestion and sinonasal symptoms, and reduced need for surgery and systemic corticosteroids (SCS). OBJECTIVE: To evaluate the efficacy and safety of tezepelumab across Japanese Epidemiological Survey of Refractory Eosinophilic Chronic Rhinosinusitis-defined eosinophilic chronic rhinosinusitis (ECRS) subgroups. METHODS: Adults with severe CRSwNP were randomized to tezepelumab 210 mg or placebo every 4 weeks. Coprimary endpoints were change from baseline to week 52 in total Nasal Polyp Score (NPS) and bi-weekly mean Nasal Congestion Score (NCS). Secondary endpoints included loss of smell score, SinoNasal Outcome Test 22-item total score, Lund-Mackay total score, Nasal Polyposis Symptom Diary total symptom score and surgery and/or SCS requirement. Safety was also assessed. RESULTS: Of 408 patients, ECRS classifications were non-ECRS (11.5%), mild (18.9%), moderate (37.0%) and severe (32.6%). Compared with placebo, tezepelumab provided greater reductions from baseline to week 52 in total NPS (least squares mean difference [95% confidence interval], -1.68 [-2.27, -1.09] and -2.25 [-2.64, -1.87], in non-/mild and moderate/severe subgroups respectively; both P<0.0001) and bi-weekly mean NCS (-0.78 [-1.11, -0.46] and -1.15 [-1.35, -0.94], respectively; both P<0.0001). Improvements in secondary endpoints were also greater with tezepelumab versus placebo and were consistent across subgroups. No new safety concerns were identified. CONCLUSION: Tezepelumab demonstrated robust efficacy across ECRS subgroups, supporting its potential as a treatment for severe CRSwNP regardless of eosinophilic phenotype.

BACKGROUND: Up to 50% of patients with nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD) exhibit a noneosinophilic airway inflammatory phenotype, with paucigranulocytic asthma being the most prevalent. The aim was to identify clusters within N-ERD and aspirin-tolerant asthma (ATA) controls with a paucigranulocytic asthma phenotype. METHODS: Two separate hierarchical cluster analyses were performed using 23 variables in 36 N-ERD patients and 19 ATA controls. Variables included demographic, clinical, treatment-related, and hematologic parameters; sputum cytology; sinus computed tomography findings; and eicosanoid levels in induced sputum supernatant (ISS) and urine. RESULTS: Two clusters were identified in each group: 1N-ERD, 2N-ERD, 1ATA, and 2ATA. Cluster 1N-ERD patients had less severe asthma and required lower doses of inhaled corticosteroids (ICS) but showed higher blood eosinophil counts, Lund-Mackay (LM) scores, and ISS leukotriene E4 (LTE4) levels than those in cluster 2N-ERD. Cut-off values defining a T2-high paucigranulocytic asthma profile in N-ERD included LM score ≥ 18, blood eosinophils ≥ 300 cells/mm3, and ISS LTE4 ≥ 30 pg/mL, with the LM score demonstrating the highest AUC at 0.8. Among ATA controls, cluster 1ATA had more severe asthma, higher ICS doses, more severe sinonasal disease, and increased ISS leukotriene D4 and LTE4 levels compared with cluster 2ATA. CONCLUSION: Two clusters were identified among N-ERD patients with a paucigranulocytic asthma phenotype. Cluster 1N-ERD was characterized by milder asthma, more severe sinonasal disease, elevated blood eosinophil counts, and elevated ISS LTE4. This T2-high-like cluster may represent a subgroup requiring further evaluation for anti-T2 biologic therapy targeting chronic rhinosinusitis with nasal polyps, although further validation is required.

BACKGROUND: Eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP) is characterized by intense type 2 inflammation and high recurrence rate. The precise spatial determinants and cellular mechanisms sustaining tissue eosinophilia within the polyp microenvironment remain unkown. This study aimed to identify the spatially cellular niches driving eosinophil recruitment and evaluate the therapeutic efficacy of targeting specific macrophage-driven pathogenic loops in eCRSwNP. METHODOLOGY: Transcriptomic profiles were analyzed using bulk RNA-sequencing of nasal polyp tissues from CRSwNP patients (n = 30, stratified by eosinophilic severity) and healthy controls (HC, n = 10). Spatial transcriptomics (GeoMx DSP) and single-cell RNA sequencing analyses were utilized to map macrophage niches. Mechanistic findings were validated ex vivo and in vitro using human sinonasal explant models and migration assays, incorporating an independent cohort of healthy controls (n = 12). RESULTS: Bulk transcriptomics of nasal polyps stratified across a gradient of tissue eosinophil density identified ALOX15 and CCL13 as top candidates positively correlating with tissue eosinophilia. Spatial transcriptomics revealed that subepithelial ALOX15+ macrophages served as the primary source of CCL13, and the localized CCL13 expression significantly correlated with eosinophil density in epithelial areas. Mechanistically, IL-4/IL-13 induces ALOX15-ERK-CCL13 axis in macrophages. Functional explant assays confirmed that ALOX15+ macrophages drive eosinophil recruitment via CCR3. IL-4Ra blockade with Dupilumab or Stapokibart abrogated the pathogenic ALOX15-CCL13 loop and attenuated eosinophil chemotaxis. CONCLUSIONS: Our findings identify the subepithelial ALOX15+ macrophage niche as a pivotal spatial determinant of eosinophilia in eCRSwNP. Targeting this specialized immune hub with emerging biologics offers a promising precision therapeutic strategy.

BACKGROUND: Chronic rhinosinusitis (CRS) is often driven by type 2 inflammation and is characterized by nasal obstruction/ discharge, facial pain/pressure, and/or reduced smell, either with or without nasal polyps (CRSwNP or CRSsNP). OBJECTIVE: To test whether dupilumab improves radiographic features in CRSsNP. METHODS: ORION (NCT04678856), a phase 2, randomized, multicenter, double blind, placebo-controlled study, assessed dupilumab efficacy and safety in adults with uncontrolled CRSsNP. Patients were randomized 1:1 to dupilumab or placebo for 24 to 52 weeks. Endpoints included changes from baseline at week 24 in Lund-Mackay computed tomography (LMK-CT) score (dupilumab only [primary] and vs placebo [secondary]), sinus Total Symptom Score (sTSS), University of Pennsylvania Smell Identification Test (UPSIT) score, and 22-item Sino-Nasal Outcome Test(SNOT-22) score. Primary analysis was conducted in the intention-to-treat population with screening blood eosinophil count (sBEC) ≥300 cells/μL. Safety data were evaluated in all patients. RESULTS: Seventy-one patients were randomized (dupilumab, n = 38; placebo, n = 33). In the dupilumab group with sBEC ≥300 cells/μL (n = 16), mean (95% CI) week 24 change from baseline in LMK-CT was -6.63 (-8.71 to -4.54); week 24 mean differences vs placebo (95% CI) for LMK-CT, sTSS, UPSIT, and SNOT-22 were -5.95 (-8.38 to -3.51), -1.43 ( 3.28 to 0.41), 5.91 (-1.56 to 13.38), and -14.71 (-34.35 to 4.94). Treatment-emergent adverse events were balanced between treatment groups. CONCLUSION: Dupilumab was associated with improvement in LMK-CT score and a trend toward improvement in sinonasal symptoms at week 24 in adults with severe, uncontrolled CRSsNP with sBEC ≥300 cells/μL.