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Nijra L Lugogo,1 Enrico Heffler,2,3 Vicente Plaza,4 Ole Hilberg,5 Changming Xia,6 Scott Nash,6 Nami Pandit,7 Juby A Jacob-Nara,7 Harry J Sacks,6 Paul J Rowe,7 Yamo Deniz,6 Megan Hardin,8 Xavier Soler6 1University of Michigan Medical School, Ann Arbor, MI, USA; 2IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy; 3Humanitas University, Pieve Emanuele, Milan, Italy; 4Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 5Lillebaelt Hospital, Vejle, Denmark; 6Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA; 7Sanofi, Bridgewater, NJ, USA; 8Sanofi, Cambridge, MA, USACorrespondence: Nijra L Lugogo, University of Michigan Medical School, 300 North Ingalls St, Suite 2C40, Ann Arbor, MI, 48109, USA, Email nlugogo@med.umich.edu

Mark Gurnell,1,2 Amr Radwan,3 Claus Bachert,4– 6 Njira Lugogo,7 Seong H Cho,8 Scott Nash,9 Haixin Zhang,9 Asif H Khan,10 Juby A Jacob-Nara,11 Paul J Rowe,11 Yamo Deniz9 1Department of Medicine, Wellcome–MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK; 2NIHR Cambridge Biomedical Research Centre, Addenbrooke’s Hospital, Cambridge, UK; 3Global Medical Affairs, Regeneron Pharmaceuticals Inc., Uxbridge, UK; 4Department of Otorhinolaryngology – Head and Neck Surgery, University Hospital of Münster, Münster, Germany; 5International Airway Research Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 6Division of ENT Diseases, CLINTEC, Karolinska Hospital, Stockholm University, Stockholm, Sweden; 7Division of Pulmonary & Critical Care Medicine, University of Michigan, Ann Arbor, MI, USA; 8Division of Allergy-Immunology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA; 9Medical Affairs, Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA; 10Global Medical Affairs, Sanofi, Chilly-Mazarin, France; 11Global Medical Affairs, Sanofi, Bridgewater, NJ, USACorrespondence: Mark Gurnell, Metabolic Research Laboratories, Wellcome–MRC Institute of Metabolic Science, Level 4, Box 289, Addenbrooke’s Hospital, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK, Tel +44 1223 336792, Email mg299@medschl.cam.ac.ukPurpose: Dupilumab significantly reduced the requirement for systemic corticosteroids (SCS) in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP). Patients with CRSwNP and coexisting asthma typically have a higher disease burden and have more difficulty in managing disease. Here, we report an analysis of asthma outcomes and SCS use in patients with CRSwNP and coexisting asthma.Patients and Methods: This was a post hoc analysis of the randomized, placebo-controlled SINUS-24 and SINUS-52 studies (NCT02912468/NCT02898454) in patients with severe CRSwNP and coexisting asthma (patient self-reported) from the pooled intention-to-treat population randomized to dupilumab 300 mg every 2 weeks or placebo. On-treatment SCS use was estimated using Kaplan–Meier analysis. Forced expiratory volume in 1 s (FEV1), percent predicted FEV1, and the 6-item Asthma Control Questionnaire (ACQ-6) were assessed at baseline and Week 24 (pooled SINUS-24/52) in patients with/without history of asthma exacerbation or prior SCS use.Results: Of 337 patients with coexisting asthma, 88 (26%) required on-treatment SCS use. The requirement for on-treatment SCS use for any reason was significantly lower with dupilumab (20/167 patients; 12%) vs placebo (68/170; 40%); hazard ratio (95% confidence interval) 0.248 (0.150– 0.409); p

William Walter Busse,1 Ian Douglas Pavord,2 Shahid Siddiqui,3 Asif Hameed Khan,4 Amy Praestgaard,5 Scott Nash,3 Juby Anne Jacob-Nara,6 Paul Jonathan Rowe,6 Yamo Deniz3 1Department of Medicine, Division of Allergy, Pulmonary and Critical Care, University of Wisconsin, Madison, WI, USA; 2Oxford Respiratory NIHR BRC, Nuffield Department of Medicine, University of Oxford, Oxford, UK; 3Medical Affairs, Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA; 4Global Medical Affairs, Sanofi, Chilly-Mazarin, France; 5Department of Biostatistics, Sanofi, Cambridge, MA, USA; 6Global Medical Affairs, Sanofi, Bridgewater, NJ, USACorrespondence: William Walter Busse, Department of Medicine, Division of Allergy, Pulmonary and Critical Care, University of Wisconsin, Madison, WI, USA, Tel +1 608 263-6183, Email wwb@medicine.wisc.eduPurpose: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammatory disease frequently coexisting with other type 2 conditions including asthma and non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD). Coexisting asthma leads to increased CRSwNP symptom burden. Dupilumab, a monoclonal antibody that blocks the shared receptor component for interleukin-4 and -13, demonstrated efficacy in adults with severe CRSwNP in the Phase 3 SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454) studies, including in patients with coexisting asthma/NSAID-ERD. However, the impact of different asthma characteristics on dupilumab treatment in this population is unknown. We report CRSwNP and asthma outcomes with dupilumab in patients with CRSwNP and coexisting asthma according to baseline asthma characteristics.Methods: Change from baseline at Week 24 (pooled studies) and Week 52 (SINUS-52) in CRSwNP outcomes (nasal polyp score, nasal congestion, 22-item Sino-Nasal Outcome Test [SNOT-22], loss of smell score, University of Pennsylvania Smell Identification Test) and asthma outcomes (5-item Asthma Control Questionnaire [ACQ-5], pre-bronchodilator forced expiratory volume in 1 second [FEV1]) were analyzed post hoc for placebo and dupilumab 300 mg every 2 weeks according to baseline blood eosinophils ≥ 150/≥ 300 cells/μL, ACQ-5 scores < 1.5/≥ 1.5, and FEV1 < 80%.Results: In the pooled studies, 428/724 patients (59.1%) had coexisting asthma, of which 181/428 (42.3%) had coexisting NSAID-ERD. Dupilumab significantly improved all CRSwNP and asthma outcomes vs placebo at Week 24 (P < 0.001) regardless of baseline eosinophil or ACQ-5 category, or FEV1 < 80%. Similar magnitude of improvement was seen at Week 52 (SINUS-52) and in patients with NSAID-ERD (pooled studies, Week 24). By Week 24, improvements with dupilumab exceeded the minimum clinically important differences for ACQ-5 and SNOT-22 in 35.2% to 74.2% and 72.0% to 78.7% of patients, respectively.Conclusion: Dupilumab improved CRSwNP outcomes in patients with CRSwNP and coexisting asthma, and improved asthma outcomes, regardless of differences in baseline asthma characteristics.Keywords: chronic rhinosinusitis with nasal polyps, dupilumab, asthma

Jorge F Maspero,1 Asif H Khan,2 Carl Philpott,3 Peter W Hellings,4 Claire Hopkins,5 Martin Wagenmann,6 Shahid Siddiqui,7 Jérôme Msihid,8 Scott Nash,7 Chien-Chia Chuang,9 Siddhesh Kamat,7 Paul J Rowe,10 Yamo Deniz,7 Juby A Jacob-Nara10 1Allergy & Respiratory Research Unit, Fundación CIDEA, Buenos Aires, Argentina; 2Global Medical Affairs, Sanofi, Chilly-Mazarin, France; 3Rhinology and ENT Research Group, Norwich Medical School, University of East Anglia, Norwich, UK; 4Department of Otorhinolaryngology – Head and Neck Surgery, University Hospitals Leuven, Leuven, Belgium; 5Department of Otorhinolaryngology, King’s College London, London, UK; 6Department of Otorhinolaryngology, Düsseldorf University Hospital (UKD), Düsseldorf, Germany; 7Medical Affairs, Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA; 8Health Economics and Value Assessment, Sanofi, Chilly-Mazarin, France; 9Health Economics and Value Assessment, Sanofi, Cambridge, MA, USA; 10Global Medical Affairs, Sanofi, Bridgewater, NJ, USACorrespondence: Jorge F Maspero, Allergy & Respiratory Research Unit, Fundación CIDEA, Paraguay 2035, 2SS, Buenos Aires, Argentina, Tel +54 9 11 4183-7294, Email jorge.maspero@fundacioncidea.org.arPurpose: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammatory disease with a high symptom burden. Data are lacking on the comparative health status of patients with CRSwNP. This analysis compared baseline physical and mental health-related quality of life (HRQoL) and overall health status of patients with severe CRSwNP enrolled in a Phase 3 clinical trial with general population norms and with other chronic diseases.Methods: In this post hoc cross-sectional analysis of baseline data from the SINUS-24 study (NCT02912468), HRQoL was measured using the 36-item Short Form (SF-36) questionnaire and general health status was measured using the EuroQol-5 Dimension visual analog scale (EQ-VAS). Analyses included the intention-to-treat (ITT) population and subgroups defined by prior sinonasal surgery, systemic corticosteroid use, and coexisting asthma or non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD). Scores were compared with published values for population norms (50 for SF-36 physical component summary (PCS) and mental component summary (MCS), 70.4− 83.3 for EQ-VAS) and for rheumatoid arthritis, type 2 diabetes, and asthma.Results: In the ITT population (n=276), mean SF-36 physical component summary (PCS), SF-36 mental component summary (MCS), and EQ-VAS scores were below general population norms (46.4, 48.6, and 66.0, respectively). Mean SF-36 PCS and EQ-VAS scores were below population norms across all subgroups; mean SF-36 MCS scores were below the population norm in all subgroups except no prior surgery. SF-36 PCS and MCS scores from SINUS-24 were generally similar to other chronic diseases, except SF-36 PCS which was lower in rheumatoid arthritis. EQ-VAS scores in SINUS-24 were lower than in other chronic diseases. HRQoL scores weakly correlated with objective measures of disease severity.Conclusion: In patients with severe CRSwNP, including those with coexisting asthma/NSAID-ERD, HRQoL was worse than population norms and as burdensome as diseases such as type 2 diabetes, asthma, and rheumatoid arthritis.Graphical Abstract: Keywords: chronic rhinosinusitis with nasal polyps, health-related quality of life, symptom burden

Claire Hopkins,1 Kathleen M Buchheit,2 Enrico Heffler,3,4 Noam A Cohen,5 Heidi Olze,6 Asif H Khan,7 Jérôme Msihid,8 Shahid Siddiqui,9 Scott Nash,9 Juby A Jacob-Nara,10 Paul J Rowe,10 Yamo Deniz9 1Department of Otorhinolaryngology – Head and Neck Surgery, Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 2Division of Allergy and Clinical Immunology, Brigham and Women’s Hospital, Boston, MA, USA; 3Personalized Medicine, Asthma & Allergy – Humanitas Clinical and Research Center IRCCS, Milan, Italy; 4Department of Biomedical Sciences, Humanitas University, Milan, Italy; 5Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; 6Department of Otorhinolaryngology, Head and Neck Surgery, Charité-Universitätsmedizin Berlin, Berlin, Germany; 7Global Medical Affairs, Sanofi, Chilly-Mazarin, France; 8Health Economics and Value Assessment, Sanofi, Chilly-Mazarin, France; 9Medical Affairs, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 10Global Medical Affairs, Sanofi, Bridgewater, NJ, USACorrespondence: Claire Hopkins, Department of Otorhinolaryngology – Head and Neck Surgery, Guy’s and St Thomas’ NHS Foundation Trust, Great Maze Pond, London, SE1 9RT, UK, Tel +44 2071882215, Email clairehopkins@yahoo.comAbstract: Patients with asthma frequently have comorbid chronic rhinosinusitis (CRS) with or without nasal polyps, increasing disease burden and complicating treatment. These post hoc analyses investigated disease-specific health-related quality of life (HRQoL) and general health status in the randomized, placebo-controlled QUEST study (NCT02414854) in patients treated with dupilumab for moderate-to-severe asthma with comorbid CRS. Patients received 300 mg of dupilumab or placebo every 2 weeks for 52 weeks. CRS HRQoL was assessed by the 22-item Sino-Nasal Outcome Test (SNOT-22; items scored 0– 5). The 22 items are categorized into 5 domains (nasal, ear/facial, sleep, function, and emotion), and patients report the top 5 most important items affecting their health. General health status was assessed by Euro-QoL visual analog scale (EQ-VAS). Of 1902 patients, 382 (20.1%) self-reported comorbid CRS; 193 patients receiving dupilumab 300 mg q2w or matched placebo were included in this analysis. At baseline, the most impacted SNOT-22 domain was nasal, and general health status was below population norms. Patients rated “decreased sense of taste/smell,” “nasal blockage,” “cough,” “reduced productivity,” and “wake up tired” as the 5 most important SNOT-22 items affecting their health. Percentage change from baseline in SNOT-22 total score was significantly greater for dupilumab vs placebo at Weeks 24, 36, and 52 (all p < 0.05). Improvements from baseline were significantly greater for dupilumab vs placebo at Week 52 for all SNOT-22 domains (p < 0.05), except emotion. At Week 52, significant changes from baseline with dupilumab vs placebo were observed for all 5 most important SNOT-22 items affecting their health (all p < 0.05). EQ-VAS was significantly improved with dupilumab vs placebo by Week 12, with improvements sustained to Week 52 (all p < 0.01). In patients with moderate-to-severe asthma who self-reported comorbid CRS, dupilumab treatment vs placebo improved CRS-specific HRQoL and general health status.Keywords: asthma, chronic rhinosinusitis, nasal polyps, dupilumab, health-related quality of life, SNOT-22

Claus Bachert,1– 3 Asif H Khan,4 Claire Hopkins,5 Michael S Blaiss,6 Zachary M Soler,7 Scott Nash,8 Shahid Siddiqui,8 Amy Praestgaard,9 Yamo Deniz,8 Paul J Rowe,10 Juby A Jacob-Nara10 1Upper Airways Research Laboratory and Department of Otorhinolaryngology, Ghent University, Ghent, Belgium; 2Division of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden; 3International Airway Research Center, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People’s Republic of China; 4Global Medical Affairs, Sanofi, Chilly-Mazarin, France; 5Department of Otorhinolaryngology – Head and Neck Surgery, Guy’s and St Thomas’ Hospitals, London, UK; 6Department of Pediatrics, Medical College of Georgia at Augusta University, Augusta, GA, USA; 7Department of Otolaryngology – Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, USA; 8Medical Affairs, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 9Department of Biostatistics, Sanofi, Cambridge, MA, USA; 10Global Medical Affairs, Sanofi, Bridgewater, NJ, USACorrespondence: Claus Bachert, Upper Airways Research Laboratory and Department of Otorhinolaryngology, Ghent University, Ghent, B-9000, Belgium, Tel +32 9332 5513, Email claus.bachert@ugent.bePurpose: In the phase 3 SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454) studies in adults with severe chronic rhinosinusitis with nasal polyps (CRSwNP), dupilumab significantly improved the co-primary endpoints of change from baseline to Week 24 in nasal polyp score (NPS) and nasal congestion/obstruction (NC) vs placebo on background intranasal corticosteroids (standard of care [SOC]). This post hoc analysis of SINUS-24/-52 investigated the direction and magnitude of within-patient change in these endpoints over time.Methods: NPS (scale 0– 8) was assessed at Weeks 4, 8, 16, 24, 40, and 52 in SINUS-52 and Weeks 8, 16, and 24 in SINUS-24. Daily patient-reported NC scores (0 [no symptoms]– 3 [severe symptoms]) were averaged over 28 days. Within-patient changes from baseline were assessed through Week 24 in pooled SINUS-24/-52 (n = 438/286 dupilumab/SOC) and through Week 52 in SINUS-52 (n = 150/153).Results: In SINUS-52, NPS improved in 70.0% of dupilumab-treated patients at Week 4 vs 31.8% with SOC (odds ratio [OR] 5.2 [95% confidence interval 3.1– 8.8]) and 78.7% vs 28.2% at Week 52 (OR 10.6 [6.0– 18.7]) (all p < 0.0001). NC improved in 73.3% of dupilumab-treated patients at Week 4 vs 46.7% with SOC (OR 3.2 [2.0– 5.3]) and 86.9% vs 50.7% at Week 52 (OR 6.4 [3.5– 11.5]) (all p < 0.0001). Clinically meaningful (≥ 1 point) improvements in NPS occurred in 55.7% and 72.3% of dupilumab-treated patients at Weeks 4 and 52, respectively, vs 16.9% and 16.2% with SOC. Clinically meaningful (≥ 1 point) improvements in NC occurred in 16.7% and 67.6% of dupilumab-treated patients at Weeks 4 and 52, respectively, vs 3.9% and 20.8% with SOC. At Week 52, NPS worsening from baseline was observed in 5.7% of dupilumab-treated patients vs 40.1% with SOC and NC worsening in 2.1% vs 20.8%, respectively.Conclusion: Dupilumab provided rapid, continuing, and clinically relevant improvements over time in NPS and NC in most patients with severe CRSwNP in the SINUS studies.Graphical Abstract: Keywords: chronic rhinosinusitis with nasal polyps, dupilumab, nasal polyp score, nasal congestion

Leiomyomas are the most common pelvic tumors. Submucosal fibroids are a common cause of abnormal bleeding and infertility. Hysteroscopic myomectomy is the definitive management of symptomatic submucosal fibroids, with high efficacy and safety. Several techniques have been introduced over time and will be covered in depth in this manuscript. Advances in optics, fluid management, electrosurgery, smaller diameter scopes, and tissue removal systems, along with improved training have contributed to improving the safety and efficiency of hysteroscopic myomectomy.

Abstract Purpose We investigated the etiology of acute hepatitis in three children with systemic Juvenile Idiopathic Arthritis (sJIA) taking Interleukin-1 receptor antagonist (IL1RA). Methods Laboratory and clinical data for three children with sJIA diagnosed at ages 13 months to 8 years who developed acute hepatitis during treatment with IL1RA were reviewed for evidence of sJIA flare, infection, macrophage activation syndrome (MAS), malignancy, and drug reaction. Results In all patients, hepatitis persisted despite cessation of known hepatotoxic drugs and in absence of known infectious triggers, until discontinuation of IL1RA. Liver biopsies had mixed inflammatory infiltrates with associated hepatocellular injury suggestive of an exogenous trigger. At the time of hepatitis, laboratory data and liver biopsies were not characteristic of MAS. In two patients, transaminitis resolved within one week of discontinuing IL1RA, the third improved dramatically in one month. Conclusions Although sJIA symptoms improved significantly on IL1RA, it appeared that IL1RA contributed to the development of acute hepatitis. Hepatitis possibly occurred as a result of an altered immune response to a typical childhood infection while on IL1RA. Alternatively, hepatitis could have represented an atypical presentation of MAS in patients with sJIA taking IL1RA. Further investigation is warranted to determine how anti-IL1 therapies alter immune responsiveness to exogenous triggers in patients with immune dysfunction such as sJIA. Our patients suggest that close monitoring for hepatic and other toxicities is indicated when treating with IL1RA.