Dupilumab response onset, maintenance, and durability in patients with severe CRSwNP.

BACKGROUND: Responder analyses of SINUS phase 3 study data have shown clinically meaningful improvements across multiple outcomes of treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) with dupilumab. OBJECTIVE: Our aim was to gain a better understanding of dynamics of the response to dupilumab over 52 weeks. METHODS: We used data from the SINUS-52 (ClinicalTrials.gov identifier NCT02898454) intention-to-treat population to perform a post hoc analysis of patients with severe CRSwNP who had received dupilumab, 300 mg once every 2 weeks, or placebo. Response, which was defined as an improvement from baseline of a least 1 point in Nasal Polyp Score (NPS), nasal congestion (NC) score, and loss of smell (LoS) score, as well as an improvement of at least 8.9 points on the 22-Item Sino-Nasal Outcome Test (SNOT-22), was assessed for rapidity, maintenance, and durability. RESULTS: The study included 303 patients (150 of whom received dupilumab and 153 of whom received placebo). For each outcome measure, a greater proportion of patients achieved a first response by week 16 (rapidity) with dupilumab versus with placebo; specifically, the respective differences in indicators between the 2 groups by week 16 were as follows: NPS, 75.3% versus 39.2%; NC score, 60.0% versus 24.2%; LoS score, 60.7% versus 15.7%; and SNOT-22 score, 83.3% versus 66.0%. Of those patients given dupilumab who had a response by week 16, more than 80% maintained their response at week 52 (maintenance). Over 52 weeks, greater proportions of those patients given dupilumab were responders on at least 80% of time points; specifically, the respective differences in indicators between the 2 groups by week 16 were as follows: NPS, 46.7% versus 2.6%; NC score, 46.7% versus 9.2%; LoS score, 47.3% versus 3.9%; and SNOT-22 score, 62.0% versus 21.6% (durability). CONCLUSION: Most patients with CRSwNP achieve clinically meaningful responses to dupilumab by week 16, and most such patients in our study had maintenance and durability of response with continued treatment over time.

EUFOREA/EPOS2020 statement on the clinical considerations for chronic rhinosinusitis with nasal polyps care.

Following the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) treatment algorithm for chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), patients suffering from severe uncontrolled CRSwNP are recommended to receive oral corticosteroids, (revision) sinus surgery, systemic biologicals and/or aspirin treatment after desensitization (ATAD). Given the major differences in indications, outcomes, practical considerations, risks and costs of these key pillars of treatment, there is a growing need to define criteria for each treatment option and list the clinically relevant and major considerations for them. This EUFOREA document therefore provides an expert panel overview of the expected outcomes, specific considerations and (contra)indications of the five major treatment arms of severe uncontrolled CRSwNP: oral corticosteroids, primary and revision sinus surgery, biological treatment and ATAD. This overview of treatment considerations is needed to allow physicians and patients to consider the different options in the context of providing optimal and personalized care for severe uncontrolled CRSwNP. In conclusion, the five major treatment options for severe uncontrolled CRSwNP have intrinsic advantages, specific indications and considerations that are of importance to the patient, the physician and the society. This EUFOREA statement supports the unmet need to define criteria for the indication of every treatment pillar of CRSwNP.

Pharmacokinetics/pharmacodynamics of benralizumab in chronic rhinosinusitis with nasal polyps: Phase III, randomized, placebo-controlled OSTRO trial.

AIMS: Benralizumab, a humanized, afucosylated monoclonal antibody against the interleukin 5 receptor, α subunit, causes rapid depletion of eosinophils by antibody-dependent cellular cytotoxicity. We investigated the pharmacokinetic and pharmacodynamic effects of benralizumab in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) from the phase III OSTRO trial. METHODS: Patients received a placebo or 30 mg of benralizumab by subcutaneous injection every 8 weeks (first three doses every 4 weeks) to week 48; a subset of patients continued in an extended follow-up period to assess treatment durability to week 80. Serum benralizumab concentrations and blood eosinophil and basophil counts were assessed to week 80. Biomarker assessments were performed on nasal polyp tissue biopsies at week 56 and nasal lining fluid at weeks 24 and 56 to examine changes in immune cells and inflammatory mediators. RESULTS: Among 185 patients in this analysis, 93 received benralizumab. Serum benralizumab concentrations reached a steady state by week 24 (median concentration 385.52 ng mL-1); blood eosinophils were almost fully depleted and blood basophils were reduced between weeks 16 and 56. Nasal polyp tissue eosinophils decreased with benralizumab from 57.6 cells mm-2 at baseline to 0 cells mm-2 at week 56 (P < .001 vs placebo), and tissue mast cells were numerically reduced. In nasal lining fluid, eosinophil-derived neurotoxin was significantly reduced at weeks 24 and 56 (P < .001) and interleukin-17 at week 56 (P < .05) with benralizumab. CONCLUSION: Benralizumab treatment led to rapid, sustained, nearly complete depletion of eosinophils from blood and nasal polyp tissue in patients with CRSwNP.

Quantifying corticosteroid burden in chronic rhinosinusitis with nasal polyps: A retrospective US database study.

BACKGROUND: Real-world burden data on systemic corticosteroid (SCS) use in chronic rhinosinusitis with nasal polyps (CRSwNP) are limited. OBJECTIVE: This study's objective was to describe the real-world burden of SCS in CRSwNP. METHODS: This retrospective cohort study included commercial/Medicare Advantage with Part D health plan members from the Optum Research Database with a first medical claim (index) for CRSwNP (January 2015 to July 2020). Primary outcomes/variables included SCS use, healthcare resource utilization (HCRU) and costs during the 12-month follow-up period. Outcomes were analyzed overall (N=21,172) and stratified by baseline comorbid asthma status and sinus surgeries during follow-up. RESULTS: Overall, 64.7% and 41.0% of patients used all-cause and CRSwNP-related SCS respectively, and 36.0% had ≥1 oral corticosteroid (OCS) burst (≥20 mg for 3-28 days); SCS use was higher in patients with asthma and those with a NP-related surgery (1, 2, ≥3) versus without. The mean (SD) all-cause cumulative OCS dose was 303.3 (675.0) mg/year and 23.5% had a cumulative annual dose ≥400 mg; these values were higher (p<0.001) in patients with versus without comorbid asthma (514.9 [956.1] vs. 247.5 [567.0]; 36.9% vs. 19.9%). All-cause and CRSwNP HCRU and costs increased with increasing number of surgeries; mean (SD) all-cause total medical costs were $14,472 (38,915), $26,909 (40,800), $29,816 (41,677), and $31,558 (37,143) with 0, 1, 2, and ≥3 surgeries, respectively. CONCLUSION: These data highlight the significant burden of SCS use in CRSwNP, particularly in patients with comorbid asthma and suggest a need to reduce SCS exposure.

Mild and symptom-free months in patients with chronic rhinosinusitis with nasal polyps treated with dupilumab.

BACKGROUND: Commonly reported outcomes of clinical trials in chronic rhinosinusitis with nasal polyps (CRSwNP) may have limited relatability for patients. OBJECTIVE: To enhance the patient relatability of outcomes in dupilumab clinical trials for CRSwNP, daily symptom scores were used to determine new patient­centered endpoints: mild-to-no-symptom months (MSM) and symptom-free months (SFM). METHODS: Post hoc analysis of patients receiving dupilumab 300 mg or placebo every 2 weeks for 24 weeks (SINUS-24 study; NCT02912468) or 52 weeks (SINUS­52; NCT02898454). Patients recorded symptom severity scores daily for each of nasal congestion, loss of smell, and anterior and posterior rhinorrhea on a scale of 0-3 (0 = no symptoms; 1 = mild; 2 = moderate; 3 = severe). We assessed the proportions of patients reporting only mild or no symptoms (MSM) or no symptoms (SFM) throughout the 28­day periods prior to randomization, Week 24 (pooled studies), and Week 52 (SINUS­52). RESULTS: Significantly more dupilumab­treated than placebo-treated patients achieved MSM for all four symptoms (Week 24: 31.0% vs 4.4%; OR 12.9 [6.4, 25.8]; Week 52: 38.3% vs 2.6%; OR 15.6 [5.9, 41.0]; both P < .0001). Additionally, significantly more dupilumab-treated than placebo­treated patients achieved SFM for at least one of the four symptoms (Week 24: 35.4% vs 10.8%; odds ratio [OR] 4.9 [95% confidence interval 3.1, 7.8]; Week 52: 50.0% vs 9.2%; OR 9.1 [4.6, 17.9]; both P < .0001). CONCLUSION: One-third of patients with severe CRSwNP treated with dupilumab achieved MSM for all four cardinal symptoms (nasal congestion, loss of smell, and anterior and posterior rhinorrhea). Moreover, half of patients achieved SFM for at least one of the four symptoms. These results support the benefit of dupilumab in improving patient­centered outcomes.

Nasal allergen challenge (NAC): Practical aspects and applications from an EU/US perspective-a Work Group Report of the AAAAI Rhinitis, Rhinosinusitis and Ocular Allergy Committee.

Nasal allergen challenge (NAC) is applied in a variety of settings (research centers, specialty clinics, and hospitals) as a useful diagnostic and research tool. NAC is indicated for diagnosis of seasonal and perennial allergic rhinitis, local allergic rhinitis, and occupational rhinitis; to design the composition of allergen immunotherapy in patients who are polysensitized; and to investigate the physio-pathological mechanisms of nasal diseases. NAC is currently a safe and reproducible technique, although it is time- and resource-consuming. NAC can be performed by a variety of methods, but the lack of a uniform technique for performing and recording the outcomes represents a challenge for those considering NAC as a clinical tool in the office. The availability of standardized allergens for NAC is also different in each country. The objective of this workgroup report is to review the current information about NAC, focusing on the practical aspects and application for diagnosis of difficult rhinitis phenotypes (eg, local allergic rhinitis, occupational rhinitis), taking into account the particular context of practice in the United States and the European Union.

Review of evidence supporting the use of nasal corticosteroid irrigation for chronic rhinosinusitis.

OBJECTIVE: To analyze published reports on the efficacy and safety of CSI in CRS and evaluate the clinical implications of current gaps in evidence. Corticosteroid irrigation (CSI) is commonly used for management of chronic rhinosinusitis (CRS) with nasal polyps; however, such use is not approved by the US Food and Drug Administration (FDA). DATA SOURCES: Publications were obtained through PubMed searches through January 2022. STUDY SELECTION: Searches were conducted using 2 terms: "chronic rhinosinusitis" or "nasal polyps" as the first term and "corticosteroid irrigation," "steroid nasal lavage," or "sinus rinse" as the second term. We reviewed relevant, peer-reviewed literature (19 original research [9 controlled, 10 uncontrolled trials], 7 reviews, and 1 meta-analysis) reporting safety and efficacy of CSI in patients with CRS. RESULTS: Studies were difficult to compare because they used a variety of solution volumes (60 mL to 125 mL per nostril), corticosteroid agents (budesonide, betamethasone, mometasone, or fluticasone), corticosteroid doses, preparation protocols (by compounding pharmacy or by patient), and administration (frequency, time of day, body positioning). It is difficult to determine which parameters might substantially influence clinical effects because studies were generally small, showed marginal benefits, and rarely assessed safety. To date, no studies evaluating CSI have shown statistically significant differences in a type-I error-controlled primary end point over any comparator, possibly owing to small sample sizes. CONCLUSION: Designing more robust clinical trials may help determine whether CSI is a valid treatment option. Until more evidence supporting CSI use exists, health care professionals should strongly consider choosing FDA-approved therapies for the treatment of CRS.

Image guided dilation of sinus ostium in revision sinus surgery.

PURPOSE: Assess if a rigid, image-guided balloon could be used effectively and safely in revision sinus surgery. MATERIALS AND METHODS: A prospective, non-randomized, single-arm, multicenter study to assess the safety and device performance of the NuVent™ EM Balloon Sinus Dilation System. Adults with CRS in need of revision sinus surgery were enrolled for balloon sinus dilation of a frontal, sphenoid, or maxillary sinus. The primary device performance endpoint was the ability of the device to (1) navigate to; and (2) dilate tissue in subjects with scarred, granulated, or previously surgically-altered tissue (revision). Safety outcomes included the assessment of any operative adverse events (AEs) directly attributable to the device or for which direct cause could not be determined. A follow-up endoscopy was conducted at 14 days post-treatment for assessment of any AEs. Performance outcomes included the surgeon's ability to reach the target sinus (es) and dilate the ostia. Endoscopic photos were captured for each treated sinus pre- and post-dilation. RESULTS: At 6 US clinical sites, 51 subjects were enrolled; 1 subject withdrew before treatment due to a cardiac complication from anesthesia. 121 sinuses were treated in 50 subjects. The device performed as expected in 100 % of the 121 treated sinuses, with investigators able to navigate to the treatment area and dilate the sinus ostium without difficulty. Ten AEs were seen in 9 subjects, with 0 related to the device. CONCLUSION: The targeted frontal, maxillary or sphenoid sinus ostium were safely dilated in every revision subject treated, with no AEs directly attributed to the device.

Long-term efficacy and safety of omalizumab for nasal polyposis in an open-label extension study.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) frequently remains uncontrolled despite maximal medical therapy and sinonasal surgery, presenting several unmet needs and challenges. Omalizumab previously demonstrated efficacy in CRSwNP in duplicate phase 3, randomized, placebo-controlled trials (POLYP 1, POLYP 2). OBJECTIVE: This open-label extension evaluated the continued efficacy, safety, and durability of response of omalizumab in adults with CRSwNP who completed POLYP 1 or 2. METHODS: After 24 weeks of omalizumab or placebo in POLYP 1 and 2, patients (n = 249) received open-label omalizumab plus background nasal mometasone therapy for 28 weeks and were subsequently followed for 24 weeks after omalizumab discontinuation. Efficacy end points assessed change from baseline for the coprimary end points, Nasal Polyp Score and Nasal Congestion Score, and the secondary end points of Sino-Nasal Outcome Test 22, Total Nasal Symptom Score and its components, and University of Pennsylvania Smell Identification Test scores. Safety objectives included incidence of adverse events and adverse events leading to omalizumab discontinuation. RESULTS: Patients who continued omalizumab experienced further improvements across coprimary end points and secondary end points through 52 weeks. Patients who switched from placebo to omalizumab experienced favorable responses across end points through week 52 that were similar to POLYP 1 and 2 at week 24. After omalizumab discontinuation, scores gradually worsened over the 24-week follow-up, but remained improved from pretreatment levels for both groups. The safety profile was similar to previous reports. CONCLUSIONS: The efficacy and safety profile from this study supports extended omalizumab treatment up to 1 year for CRSwNP with inadequate response to nasal corticosteroids.

Mepolizumab for chronic rhinosinusitis with nasal polyps: Treatment efficacy by comorbidity and blood eosinophil count.

BACKGROUND: In the phase III SYNAPSE study, mepolizumab reduced nasal polyp (NP) size and nasal obstruction in chronic rhinosinusitis with NP. OBJECTIVE: We sought to assess the efficacy of mepolizumab in patients from SYNAPSE grouped by comorbid asthma, aspirin-exacerbated respiratory disease (AERD), and baseline blood eosinophil count (BEC). METHODS: SYNAPSE, a randomized, double-blind, 52-week study (NCT03085797), included patients with severe bilateral chronic rhinosinusitis with NP eligible for surgery despite intranasal corticosteroid treatment. Patients received 4-weekly subcutaneous mepolizumab 100 mg or placebo plus standard of care for 52 weeks. Coprimary end points were change in total endoscopic NP score (week 52) and nasal obstruction visual analog scale score (weeks 49-52). Subgroup analyses by comorbid asthma and AERD status, and post hoc by BEC, were exploratory. RESULTS: Analyses included 407 patients (289 with asthma; 108 with AERD; 371 and 278 with BEC counts ≥150 or ≥300 cells/µL, respectively). The proportion of patients with greater than or equal to 1-point improvement from baseline in NP score was higher with mepolizumab versus placebo across comorbid diseases (asthma: 52.9% vs 29.5%; AERD: 51.1% vs 20.6%) and baseline BEC subgroups (<150 cells/µL: 55.0% vs 31.3%; ≥150 cells/µL: 49.5% vs 28.1%; <300 cells/µL: 50.7% vs 29.0%; ≥300 cells/µL: 50.4% vs 28.1%). A similar trend was observed in patients without comorbid asthma or AERD. More patients had more than 3-point improvement in nasal obstruction VAS score with mepolizumab versus placebo across comorbid subgroups. CONCLUSIONS: Mepolizumab reduced polyp size and nasal obstruction in chronic rhinosinusitis with NP regardless of the presence of comorbid asthma or AERD.

Efficacy and safety of benralizumab in chronic rhinosinusitis with nasal polyps: A randomized, placebo-controlled trial.

BACKGROUND: Eosinophilic inflammation has been implicated in the pathogenesis, severity, and treatment responsiveness of chronic rhinosinusitis with nasal polyps (CRSwNP). OBJECTIVE: We sought to assess the efficacy and safety of benralizumab-mediated eosinophil depletion for treating CRSwNP. METHODS: The phase 3 OSTRO study enrolled patients with severe CRSwNP who were symptomatic despite treatment with intranasal corticosteroids and who had a history of systemic corticosteroid (SCS) use and/or surgery for nasal polyps (NP). Patients were randomized 1:1 to treatment with benralizumab 30 mg or placebo every 4 weeks for the first 3 doses and every 8 weeks thereafter. Coprimary end points were change from baseline to week 40 in NP score (NPS) and patient-reported mean nasal blockage score reported once every 2 weeks. RESULTS: The study population comprised 413 randomized patients (207 in the benralizumab group and 206 in the placebo group). Benralizumab significantly improved NPS and nasal blockage score compared to placebo at week 40 (P ≤ .005). Improvements in Sinonasal Outcome Test 22 score at week 40, time to first NP surgery and/or SCS use for NP, and time to first NP surgery were not statistically significant between treatment groups. Nominal significance was obtained for improvement in difficulty in sense of smell score at week 40 (P = .003). Subgroup analyses suggested influences of comorbid asthma, number of NP surgeries, sex, body mass index, and baseline blood eosinophil count on treatment effects. Benralizumab was safe and well tolerated. CONCLUSION: Benralizumab, when added to standard-of-care therapy, reduced NPS, decreased nasal blockage, and reduced difficulty with sense of smell compared to placebo in patients with CRSwNP. TRIAL REGISTRATION: ClinicalTrials.gov NCT03401229.

Efficacy and safety of dupilumab in patients with uncontrolled severe chronic rhinosinusitis with nasal polyps and a clinical diagnosis of NSAID-ERD: Results from two randomized placebo-controlled phase 3 trials.

BACKGROUND: About one-tenth of patients with difficult-to-treat chronic rhinosinusitis with nasal polyps (CRSwNP) have comorbid non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD). Dupilumab, a fully human monoclonal antibody that blocks the shared interleukin (IL)-4/IL-13 receptor component, is an approved add-on treatment in severe CRSwNP. This post hoc analysis evaluated dupilumab efficacy and safety in patients with CRSwNP with/without NSAID-ERD. METHODS: Data were pooled from the phase 3 SINUS-24 and SINUS-52 studies in adults with uncontrolled severe CRSwNP who received dupilumab 300 mg or placebo every 2 weeks. CRSwNP, nasal airflow, lung function, and asthma control outcomes at Week 24 were evaluated, and treatment-subgroup interactions were assessed for patients with and without NSAID-ERD. RESULTS: Of 724 patients, 204 (28.2%) had a diagnosis of NSAID-ERD. At Week 24, least squares mean treatment differences demonstrated significant improvements in nasal polyp score, nasal congestion (NC), Lund-Mackay computed tomography, 22-item Sinonasal Outcome Test (SNOT-22), Total Symptom Score (TSS), rhinosinusitis severity visual analog scale, peak nasal inspiratory flow (PNIF), six-item Asthma Control Questionnaire score, and improvement in smell with dupilumab versus placebo (all p < .0001) in patients with NSAID-ERD. Treatment comparisons demonstrated significantly greater improvements with dupilumab in patients with versus without NSAID-ERD for NC (p = .0044), SNOT-22 (p = .0313), TSS (p = .0425), and PNIF (p = .0123). CONCLUSIONS: In patients with uncontrolled severe CRSwNP, dupilumab significantly improved objective measures and patient-reported symptoms to a greater extent in the presence of comorbid NSAID-ERD than without. Dupilumab was well tolerated in patients with/without NSAID-ERD.

From DREAM to REALITI-A and beyond: Mepolizumab for the treatment of eosinophil-driven diseases.

Effective treatment of inflammatory diseases is often challenging owing to their heterogeneous pathophysiology. Understanding of the underlying disease mechanisms is improving and it is now clear that eosinophils play a complex pathophysiological role in a broad range of type 2 inflammatory diseases. Standard of care for these conditions often still includes oral corticosteroids (OCS) and/or cytotoxic immune therapies, which are associated with debilitating side effects. Selective, biological eosinophil-reducing agents provide treatment options that improve clinical symptoms associated with eosinophilic inflammation and reduce OCS use. Mepolizumab is a humanized monoclonal antibody that binds to and neutralizes interleukin-5, the major cytokine involved in eosinophil proliferation, activation, and survival. Mepolizumab is approved for the treatment of severe eosinophilic asthma, eosinophilic granulomatosis with polyangiitis and hypereosinophilic syndrome. Additionally, the efficacy of add-on mepolizumab has been observed in patients with severe chronic rhinosinusitis with nasal polyposis and chronic obstructive pulmonary disease with an eosinophilic phenotype. Here, we review the development, approval, and real-world effectiveness of mepolizumab for the treatment of patients with severe eosinophilic asthma, from the DREAM to REALITI-A studies, and describe how knowledge from this journey extended to the use of mepolizumab and other biologics across a broad spectrum of eosinophilic diseases.

Variations in utilization and clinical outcomes for endoscopic sphenopalatine artery ligation and endovascular arterial embolization in a single multi-hospital network.

PURPOSE: Endoscopic sphenopalatine artery ligation (ESPAL) and endovascular arterial embolization (EAE) are increasingly common treatment options for patients with refractory epistaxis. The objective of this study was to compare the utilization pattern and clinical outcomes between these interventions within our single multi-hospital network. MATERIALS AND METHODS: A retrospective study of all patients undergoing ESPAL and/or EAE within any of the hospitals in a single healthcare network between 2008 and 2017 was conducted. We compared differences in procedure utilization with various hospital characteristics. Secondarily, we evaluated clinical outcomes and costs associated with each procedure. RESULTS: Forty-three ESPAL and 33 EAE procedures were performed across 7 hospitals, with the majority of procedures being performed at teaching institutions (65% and 91%, p = .013). The majority of both interventions were performed in larger hospitals and EAE patients were more likely to undergo inter-hospital transfer compared to ESPAL patients (48.5% and 16.3%, p = .02). Success rates for ESPAL and EAE were comparable (95% and 93%); however, the median direct cost of treatment for EAE was significantly higher than the cost for ESPAL ($12984.89 and $5002.02, p < .0001). CONCLUSIONS: The majority of both ESPAL and EAE interventions were performed at teaching and larger hospitals. Transfers occurring prior to EAE may have been due to the limited availability of interventional radiology services, and likely contributed to the increased cost of treatment. ESPAL is a known cost-effective management strategy and should be considered early in treatment algorithms of refractory epistaxis.

Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials.

BACKGROUND: Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) generally have a high symptom burden and poor health-related quality of life, often requiring recurring systemic corticosteroid use and repeated sinus surgery. Dupilumab is a fully human monoclonal antibody that inhibits signalling of interleukin (IL)-4 and IL-13, key drivers of type 2 inflammation, and has been approved for use in atopic dermatitis and asthma. In these two studies, we aimed to assess efficacy and safety of dupilumab in patients with CRSwNP despite previous treatment with systemic corticosteroids, surgery, or both. METHODS: LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52 were two multinational, multicentre, randomised, double-blind, placebo-controlled, parallel-group studies assessing dupilumab added to standard of care in adults with severe CRSwNP. SINUS-24 was done in 67 centres in 13 countries, and SINUS-52 was done in 117 centres in 14 countries. Eligible patients were 18 years or older with bilateral CRSwNP and symptoms despite intranasal corticosteroid use, receiving systemic corticosteroids in the preceding 2 years, or having had sinonasal surgery. Patients in SINUS-24 were randomly assigned (1:1) to subcutaneous dupilumab 300 mg or placebo every 2 weeks for 24 weeks. Patients in SINUS-52 were randomly assigned (1:1:1) to dupilumab 300 mg every 2 weeks for 52 weeks, dupilumab every 2 weeks for 24 weeks and then every 4 weeks for the remaining 28 weeks, or placebo every 2 weeks for 52 weeks. All patients were randomly assigned centrally with a permuted block randomisation schedule. Randomisation was stratified by asthma or non-steroidal anti-inflammatory drug-exacerbated respiratory disease status at screening, previous surgery at screening, and country. Patients with or without comorbid asthma were included. Coprimary endpoints were changes from baseline to week 24 in nasal polyp score (NPS), nasal congestion or obstruction, and sinus Lund-Mackay CT scores (a coprimary endpoint in Japan), done in an intention-to-treat population. Safety was assessed in a pooled population of both dupilumab groups in SINUS-52 up to week 24 and the dupilumab group in SINUS-24 and the placebo groups in both studies until week 24. The trials are complete and registered at ClinicalTrials.gov, NCT02912468 and NCT02898454. FINDINGS: Between Dec 5, 2016, and Aug 3, 2017, 276 patients were enrolled in SINUS-24, with 143 in the dupilumab group and 133 in the placebo group receiving at least one study drug dose. Between Nov 28, 2016, and Aug 28, 2017, 448 patients were enrolled in SINUS-52, with 150 receiving at least one dose of dupilumab every 2 weeks, 145 receiving at least one dose of dupilumab every 2 weeks for 24 weeks and every 4 weeks until week 52, and 153 receiving at least one dose of placebo. Dupilumab significantly improved the coprimary endpoints in both studies. At 24 weeks, least squares mean difference in NPS of dupilumab treatment versus placebo was -2·06 (95% CI -2·43 to -1·69; p<0·0001) in SINUS-24 and -1·80 (-2·10 to -1·51; p<0·0001) in SINUS-52; difference in nasal congestion or obstruction score was -0·89 (-1·07 to -0·71; p<0·0001) in SINUS-24 and -0·87 (-1·03 to -0·71; p<0·0001) in SINUS-52; and difference in Lund-Mackay CT scores was -7·44 (-8·35 to -6·53; p<0·0001) in SINUS-24 and -5·13 (-5·80 to -4·46; p<0·0001) in SINUS-52. The most common adverse events (nasopharyngitis, worsening of nasal polyps and asthma, headache, epistaxis, and injection-site erythema) were more frequent with placebo. INTERPRETATION: In adult patients with severe CRSwNP, dupilumab reduced polyp size, sinus opacification, and severity of symptoms and was well tolerated. These results support the benefits of adding dupilumab to daily standard of care for patients with severe CRSwNP who otherwise have few therapeutic options. FUNDING: Sanofi and Regeneron Pharmaceuticals.

Clinical aspects of sublingual immunotherapy tablets and drops.

BACKGROUND: Sublingual immunotherapy (SLIT) is administered via tablets (SLIT-T) or liquid drops (SLIT-D). In North America, currently 4 SLIT-T formulations are approved by the US Food and Drug Administration for allergy immunotherapy, and SLIT-D is an off-label use of subcutaneous immunotherapy (SCIT) extracts. OBJECTIVE: To compare and contrast aspects of SLIT-T and SLIT-D, including physical characteristics, mechanism of action, dosing, efficacy, safety, adherence, and cost. DATA SOURCES: PubMed literature review (no limits), product prescribing information, and manufacturer websites. STUDY SELECTIONS: Publications related to physical characteristics, mechanism of action, dosing, efficacy, safety, and adherence. RESULTS: Published evidence indicates that tablet and drop formulations differ in regard to physical characteristics, dosing, and strength of evidence for efficacy. Whether there are any differences in absorption and mechanism of action between the 2 formulations is currently unknown. Optimal dosing, efficacy, and safety have been established for SLIT-T. In contrast, in North America there is little support for efficacy of SLIT-D from randomized double-blind, placebo-controlled trials, and dose ranges have not been appropriately evaluated. SLIT-T treats a single allergen, whereas in the United States SLIT-D often contains multiple allergens to treat polysensitization. The safety profiles of SLIT-T and SLIT-D appear similar, and both formulations are considered safer than SCIT. CONCLUSION: Professional guidelines should make a clear distinction between SLIT-T and SLIT-D in their recommendations to minimize confusion with the umbrella term SLIT.

Endoscopic and three-dimensional radiographic imaging of the pterygopalatine and infratemporal fossae: improving surgical landmarks.

OBJECTIVES: We sought to define the surgical endoscopic anatomy of the pterygopalatine fossa (PPF) and infratemporal fossa (ITF) through endoscopic cadaver dissections and radiographic imaging analysis. METHODS: Eleven fresh cadavers were submitted to computed tomography (CT) and endoscopic dissection. We used 3-dimensional (3-D) CT reconstruction and endoscopic video imaging for analysis of the bony and soft tissue landmarks. One fixed cadaver head was grossly dissected to confirm the endoscopic anatomic findings. RESULTS: The CT and 3-D CT reconstruction measurements between the pterygoid canal and the foramen rotundum averaged 4.36 mm and 5.09 mm, respectively. An osseous ridge (pterygoid ridge) was identified on the anterior face of the pterygoid process as a novel identifiable anatomic landmark in all of the specimens. The average length of the pterygoid ridge on 3-D CT reconstruction was 7.84 mm. The internal maxillary artery entered the PPF posteromedial to the temporalis tendon and anterolateral to the lateral pterygoid muscle. The average distance from the anterior edge of the lateral pterygoid plate to the foramen ovale was 17.1 mm. CONCLUSIONS: The pterygoid ridge is a novel and reliable osseous landmark that could assist surgeons during endoscopic surgery on the PPF and ITF. The neurovascular and muscular anatomic relationships were characterized for both the PPF and the ITF.

Postmarketing Analysis of Eosinophilic Adverse Reactions in the use of Biologic Therapies for Type 2 Inflammatory Conditions.

BACKGROUND: Temporary eosinophilia is a potential adverse reaction of monoclonal antibody therapies in the treatment of a variety of type 2 inflammatory conditions, including asthma and chronic rhinosinusitis with nasal polyposis (CRSwNP). The pathophysiology, epidemiology, and clinical significance of eosinophilia and eosinophilic adverse reactions following the initiation of biologic therapy are unclear. OBJECTIVES: To describe the postmarketing, eosinophilic adverse reactions with clinical significance in patients treated with the 3 biologic therapies approved by the U.S. Food and Drug Administration (FDA) for CRSwNP: dupilumab, omalizumab, and mepolizumab. METHODS: The FDA Adverse Event Reporting System (FAERS) Public Dashboard was searched for eosinophilic adverse reactions related to dupilumab, omalizumab, and mepolizumab treatments from November 2004 to December 2022. Data regarding each of the eosinophilic adverse reactions were extracted and analyzed. RESULTS: A total of 218, 270, and 134 reports of eosinophilic adverse reactions were reported among patients who were treated with dupilumab, omalizumab, and mepolizumab, respectively. The most common eosinophilic adverse reaction was eosinophilic granulomatosis with polyangiitis (338 patients), followed by eosinophilic respiratory tract reactions (158 patients). The most common indication for biological treatment among the reaction groups was asthma. CONCLUSIONS: Eosinophilic adverse reactions are rare but consequential complications of biological treatment. They are more common among patients treated for asthma and chronic rhinosinusitis with nasal polyposis. Measuring and monitoring blood eosinophil levels may be appropriate in specific clinical instances when patients are started on different biologic therapies for type 2 inflammatory conditions.

The Role of Inhalant Allergens on the Clinical Manifestations of Atopic Dermatitis.

BACKGROUND: Inhalant allergens provide a source of environmental factors that contribute to the development of clinical symptoms in patients with atopic dermatitis (AD). OBJECTIVE: To review the relationship between inhalant allergens and AD. METHODS: A literature review was conducted using three databases: PubMed/MEDLINE, ClinicalKey, and Web of Science. Search terms, including "atopic dermatitis," "atopic eczema," and "eczema," were used in combination with "inhalant allergen," "inhaled allergen," and "aeroallergen" to identify relevant published manuscripts that highlight the relationship between AD and exposures to inhalant allergens. RESULTS: Fifteen articles were suitable for review. The studies included in the review investigated the effect of inhalant allergens on the clinical manifestations of AD through bronchial provocation, direct skin contact, and allergen sensitization. CONCLUSION: There is a significant relationship between exposures to inhalant allergens and AD. Inhalant allergens may aggravate AD symptoms by either bronchial provocation or direct skin contact. Sensitization of inhalant allergens, mainly house dust mites, follows a specific age-related pattern.