Reduced Sense of Smell in Patients with Severe Chronic Rhinosinusitis and its Implications for Diagnosis and Management: A Narrative Review.

Reduced sense of smell is a common symptom in patients with chronic rhinosinusitis (CRS). Although it is often under-diagnosed by healthcare providers, reduced sense of smell can have a substantial negative impact on patient's quality of life as measured by health-related quality of life (HRQoL) assessments and patient-reported outcomes. This narrative review describes current smell loss diagnosis and management guidelines in CRS, and the relationship between smell loss and CRS. Reduced sense of smell can be an indication of CRS disease severity in patients with (CRSwNP) and without nasal polyps (CRSsNP), and recovery of smell can be an indicator of successful CRS treatment. The current first-line therapeutic options for smell loss are intranasal corticosteroids and nasal irrigation, and second-line therapeutic options include systemic steroids and surgery. Shared decision-making between patient, caregiver, and healthcare provider is important when choosing the most appropriate CRS treatment option. Emerging biologic therapies that target type 2 inflammation signaling pathways, such as dupilumab, omalizumab, and mepolizumab, have been shown to improve smell and taste in randomized controlled trials of patients with CRSwNP.A graphical abstract and video abstract are available with this article.

Chronic rhinosinusitis (CRS) is an inflammatory condition often associated with a loss of smell and taste. Patients with CRS and a loss of smell often rate their quality of life as poor and are more likely to also suffer from depression and anxiety than patients without smell loss. Patients with severe smell loss are also more likely to have increased severity of CRS disease by other measures. Standard treatments for smell loss include topical steroids, corticosteroids absorbed into the whole body system (systemic), and/or sinonasal surgery, but the effects may not last, and patients may experience side effects when they use repeated short bursts or long-term treatment with systemic corticosteroids. A newer treatment option for CRS is biologic therapy, which targets the immunologic pathways associated with inflammation. Biologic therapies have been shown to be effective in the treatment of CRS with nasal polyps including improvement in sense of smell. Here, we review the most common diagnostic tests and treatment options for CRS-associated smell loss and show how severity of smell loss is linked to severity of CRS. Supplementary file1 (MP4 60193 kb).

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.

Association Between Smell Loss, Disease Burden, and Dupilumab Efficacy in Chronic Rhinosinusitis with Nasal Polyps.

OBJECTIVE: To evaluate the association between smell loss and other aspects of disease, and evaluate dupilumab efficacy in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) and moderate or severe smell loss. METHODS: This post-hoc analysis of the SINUS-24/52 studies (NCT02912468/NCT02898454) analyzed nasal polyp score (NPS, 0-8), nasal congestion/obstruction (NC, 0-3), Lund-Mackay CT-scan score (LMK-CT, 0-24), rhinosinusitis severity visual analog scale (RS-VAS, 0-10), and 22-item Sinonasal Outcome Test (SNOT-22, 0-110) according to baseline monthly average patient-reported loss of smell scores (LoS, 0-3) of >1 to 2 (moderate) or >2 to 3 (severe) in patients randomized to dupilumab 300 mg or placebo every 2 weeks. RESULTS: Of 724 patients randomized, baseline LoS was severe in 601 (83%) and moderate in 106 (15%). At baseline, severe versus moderate LoS was associated with 1-point greater severity of NC (odds ratio [OR] 6.01 [95% confidence interval, (CI) 3.95, 9.15]), 5-point greater severity of LMK-CT (OR 2.19 [1.69, 2.85]), and 8.9-point greater severity of SNOT-22 (OR 1.35 [1.20, 1.49]). At Week 24, least squares mean differences (95% CI) dupilumab versus placebo in change from baseline were: NPS -1.90 (-2.56, -1.25) and -1.95 (-2.20, -1.70) in the moderate and severe baseline LoS subgroups, respectively; NC -.35 (-.64, -.06) and -1.00 (-1.13, -.87); LMK-CT -6.30 (-7.88, -4.72) and -6.22 (-6.82, -5.63); RS-VAS -1.18 (-2.20, -.16) and -3.47 (-3.90, -3.03); and SNOT-22 -7.52 (-14.55, -.48) and -21.72 (-24.63, -18.82); all nominal P < .05 versus placebo. Improvements with dupilumab in NC, RS-VAS, and SNOT-22 were statistically greater in patients with severe versus moderate baseline LoS. CONCLUSION: Significant smell impairment in severe CRSwNP is associated with significant disease (NC, RS-VAS, LMK), health-related quality of life impairment (SNOT-22), asthma, and non-steroidal anti-inflammatory drug-exacerbated respiratory disease. Dupilumab significantly improved NPS, NC, LMK-CT, RS-VAS, and SNOT-22 in subjects with moderate and severe baseline smell loss.

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.

Dupilumab improves outcomes in patients with chronic rhinosinusitis with nasal polyps irrespective of gender: results from the SINUS-52 trial.

Objectives: This post hoc analysis assessed disease characteristics and response to dupilumab treatment in male and female patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) (SINUS-52 study; NCT02898454). Methods: Patients received dupilumab 300 mg or placebo every 2 weeks for 52 weeks on background intranasal corticosteroids. Efficacy was assessed through Week 52 using nasal polyp score (NPS), nasal congestion/obstruction score, loss of smell score and University of Pennsylvania Smell Identification Test score. Disease-specific health-related quality of life (HRQoL) was assessed using the 22-item Sino-Nasal Outcome Test (SNOT-22). Results: The analysis included 192 male and 111 female patients. Female patients had higher mean SNOT-22 total score (56.6 vs. 49.1, P < 0.01) and more coexisting asthma (78.4% vs. 46.4%, P < 0.0001) and non-steroidal anti-inflammatory drug-exacerbated respiratory disease (NSAID-ERD) (38.7% vs. 18.8%, P = 0.0001) than male patients, but other baseline characteristics were similar. Dupilumab significantly improved CRSwNP outcomes vs. placebo at Week 52, regardless of gender: least squares mean differences (95% confidence interval) for NPS were -2.33 (-2.80, -1.86) in male and -2.54 (-3.18, -1.90) in female patients (both P < 0.0001 vs. placebo), and for SNOT-22 were -19.2 (-24.1, -14.2) in male and -24.4 (-31.5, -17.3) in female patients (both P < 0.0001 vs. placebo). There were no significant efficacy-by-gender interactions. Conclusion: Female patients had greater asthma, NSAID-ERD and HRQoL burden at baseline than male patients. Dupilumab treatment significantly improved objective and subjective outcomes compared with placebo, irrespective of gender.

The interleukin-4/interleukin-13 pathway in type 2 inflammation in chronic rhinosinusitis with nasal polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is predominantly a type 2 inflammatory disease associated with type 2 (T2) cell responses and epithelial barrier, mucociliary, and olfactory dysfunction. The inflammatory cytokines interleukin (IL)-4, IL-13, and IL-5 are key mediators driving and perpetuating type 2 inflammation. The inflammatory responses driven by these cytokines include the recruitment and activation of eosinophils, basophils, mast cells, goblet cells, M2 macrophages, and B cells. The activation of these immune cells results in a range of pathologic effects including immunoglobulin E production, an increase in the number of smooth muscle cells within the nasal mucosa and a reduction in their contractility, increased deposition of fibrinogen, mucus hyperproduction, and local edema. The cytokine-driven structural changes include nasal polyp formation and nasal epithelial tissue remodeling, which perpetuate barrier dysfunction. Type 2 inflammation may also alter the availability or function of olfactory sensory neurons contributing to loss of sense of smell. Targeting these key cytokine pathways has emerged as an effective approach for the treatment of type 2 inflammatory airway diseases, and a number of biologic agents are now available or in development for CRSwNP. In this review, we provide an overview of the inflammatory pathways involved in CRSwNP and describe how targeting key drivers of type 2 inflammation is an effective therapeutic option for patients.

Dupilumab Reduces Asthma Disease Burden and Recurrent SCS Use in Patients with CRSwNP and Coexisting Asthma.

Purpose: 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 < 0.0001. The most frequent reasons for SCS use were nasal polyps (dupilumab 3% and placebo 27%) and asthma (2% and 9%, respectively). FEV1, percent predicted FEV1, and ACQ-6 were all significantly improved at Week 24 with dupilumab vs placebo irrespective of history of asthma exacerbation or prior SCS use (all p < 0.01). Conclusion: Dupilumab significantly reduced the requirement for SCS and improved asthma outcomes irrespective of history of asthma exacerbation or prior SCS use vs placebo in patients with CRSwNP and coexisting asthma, demonstrating concomitant reduction of SCS use and asthma disease burden in these patients.

Prevalence of type 2 inflammatory signatures and efficacy of dupilumab in patients with chronic rhinosinusitis with nasal polyps from two phase 3 clinical trials: SINUS-24 and SINUS-52.

BACKGROUND: This post hoc analysis of the international SINUS-24/-52 trials (NCT02912468/NCT02898454) aimed to assess dupilumab efficacy in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) according to different definitions of type 2 inflammatory signature. METHODS: Six definitions of type 2 inflammation were used: ≥150 eosinophils/µL or total immunoglobulin E (IgE) ≥100 IU/mL with a coexisting type 2 condition; ≥150 eosinophils/µL or total IgE ≥100 IU/mL; ≥150 eosinophils/µL; ≥250 eosinophils/µL or total IgE ≥100 IU/mL; coexisting asthma or ≥300 eosinophils/µL; presence of a coexisting type 2 condition. Odds ratios (ORs; dupilumab vs. placebo) for achieving clinically meaningful improvement (≥1 point) from baseline to week 24 (pooled SINUS-24/-52) and week 52 (SINUS-52) were calculated for nasal polyp score (NPS; range 0-8), nasal congestion/obstruction score (NC; 0-3), and loss of smell score (LoS; 0-3). RESULTS: At baseline (n = 724), most patients displayed a type 2 inflammatory signature across definitions (64.2%-95.3%). At week 24, ORs for clinically meaningful improvement ranged from 11.9 to 14.9 for NPS across type 2 definitions, 6.5-9.6 for NC, and 12.2-17.8 for LoS (all p < 0.0001). OR ranges were similar or greater at week 52: 19.0-36.6, 7.6-12.1, and 9.2-33.5, respectively (all p < 0.0001). CONCLUSION: Most patients with CRSwNP in the SINUS study had type 2 inflammation. Dupilumab demonstrated robust efficacy across definitions of type 2 inflammation, consistent with its profile as an inhibitor of Interleukin-4 and Interleukin-13 signaling, key and central drivers of type 2 inflammation in CRSwNP. KEY POINTS: This study assessed type 2 inflammation prevalence and dupilumab efficacy in chronic rhinosinusitis with nasal polyps according to algorithm-defined type 2 inflammation Dupilumab efficacy was similar across all type 2 definitions.

Real-world effectiveness of dupilumab in patients with asthma: Findings from the US ADVANTAGE study.

BACKGROUND: Dupilumab is approved as an add-on maintenance therapy for patients (≥6 years) with moderate-to-severe asthma. Better understanding of real-world effectiveness is needed. OBJECTIVE: To characterize the real-world effectiveness of dupilumab in asthma management. METHODS: This retrospective study included patients (≥12 years of age) diagnosed with asthma, initiating dupilumab between November 2018 and September 2020. The study used a US electronic medical record database (TriNetX Dataworks, Cambridge, Massachusetts). Asthma exacerbation rates before and after the initiation of dupilumab were analyzed using generalized estimating equations models with Poisson probabilistic link to estimate incidence rate ratios (IRRs). Sensitivity analyses were conducted based on previous exacerbation data, eosinophil levels, history of atopic dermatitis or chronic rhinosinusitis with nasal polyps, previous use of biologics, and presence of SARS-CoV-2 (COVID-19). RESULTS: A total of 2400 patients initiating dupilumab met all study criteria. After initiation of dupilumab, risk of asthma exacerbation was reduced by 44% (IRR, 0.56; 95% CI, 0.47-0.57; P = <0.0001) and systemic corticosteroid prescriptions by 48% (IRR, 0.52; 95% CI, 0.48, 0.56; P = <0.0001) compared with those before initiation of dupilumab. Adjustment for COVID-19 showed a greater reduction in asthma exacerbations (IRR, 0.50; 95% CI, 0.45-0.55; P = <0.0001). CONCLUSION: Current real-world efficacy evidence indicates that dupilumab reduces asthma exacerbations and total systemic corticosteroid prescriptions in clinical practice. The effectiveness of dupilumab was observed independent of exacerbation history, eosinophil levels, or COVID-19 impact.

Impact of Dupilumab on Sinonasal Symptoms and Outcomes in Severe Chronic Rhinosinusitis With Nasal Polyps.

OBJECTIVES: To assess the severity of the top 5 22-item Sino-Nasal Outcome Test (SNOT-22) items ranked most important by patients with chronic rhinosinusitis with nasal polyps (CRSwNP), the effect of dupilumab on these items, and their association with objective disease measures. STUDY DESIGN: Post hoc analysis of the SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454) clinical trials. SETTING: Multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies. METHODS: Patients ranked the SNOT-22 items most affecting their health at baseline. Item symptom severity (0-5 scale) was assessed at baseline, Week 24 (W24), and Week 52 (W52). Changes in nasal polyps score (NPS) and Lund-Mackay (LMK) scores were assessed in patients with/without SNOT-22 items improvements of at least 1 severity group point at W24 and W52. RESULTS: The SNOT-22 items ranked most important at baseline were "decreased sense of smell/taste" (87% of patients), followed by "nasal blockage" (82%), "postnasal discharge" (40%), "thick nasal discharge" (37%), and "wake up at night" (26%); 82%, 61%, 32%, 40%, and 26% of patients reported severe symptoms (score 4 or 5) for these items, respectively. Dupilumab improved score severity for all top 5 items versus placebo at W24 and W52. Improvements in NPS and LMK scores were numerically greater in patients with improvements in the SNOT-22 top 5 items. CONCLUSION: Loss of smell/taste was ranked as the most important symptom by patients with CRSwNP. Dupilumab reduced the severity of the top 5 most important SNOT-22 items versus placebo, in parallel with improvements in objective disease measures. CLINICAL TRIAL REGISTRATION: SINUS-24 and SINUS-52 clinical trials were registered with ClinicalTrials.gov, identifiers NCT02912468 and NCT02898454, respectively.

Dupilumab efficacy in patients with chronic rhinosinusitis with nasal polyps with and without allergic rhinitis.

Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammatory disease, which often coexists with allergic rhinitis (AR). Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation. Objective: This post hoc analysis investigated the efficacy and safety of dupilumab in patients with severe CRSwNP with or without coexisting AR in the pooled phase III SINUS-24/SINUS-52 studies. Methods: Patients randomized to subcutaneous dupilumab 300 mg (n = 438) or placebo (n = 286) every 2 weeks for 24 (SINUS-24) or 52 weeks (SINUS-52) were analyzed. Pooled data from the first 24 weeks of treatment are presented. Changes from baseline in disease outcome measures and biomarker levels were analyzed by the patient-reported history of AR status. Results: Overall, 338 of 724 patients (46.7%) had AR. Baseline characteristics were generally similar between patients with and those without AR. Dupilumab significantly improved objective and patient-reported measures of CRSwNP, including loss of smell, and reduced systemic and nasal biomarker levels versus placebo at week 24, with no significant treatment difference between patients with and those without AR. Use of systemic corticosteroids and/or sinonasal surgery during treatment was significantly reduced with dupilumab versus placebo, irrespective of AR status (p ≤ 0.0029). The safety profile of dupilumab was similar in patients with and in patients without AR. Conclusion: Dupilumab demonstrated significant improvements in both clinical end points and symptom scores versus placebo in patients with severe CRSwNP, irrespective of comorbid AR status, a common subgroup of patients often associated with poorer CRSwNP outcomes. Clinical trials NCT02912468 (SINUS-24) and NCT02898454 (SINUS-52), www.clinicaltrials.gov.

Dupilumab Improves Outcomes in Patients with Chronic Rhinosinusitis with Nasal Polyps and Coexisting Asthma Irrespective of Baseline Asthma Characteristics.

Purpose: 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.

Health-Related Quality of Life Impairment Among Patients with Severe Chronic Rhinosinusitis with Nasal Polyps in the SINUS-24 Trial.

Purpose: 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.

Dupilumab provides early and durable improvement of symptoms in patients with chronic rhinosinusitis with nasal polyps.

Objectives: To evaluate within-patient symptom improvement in the dupilumab SINUS-24/-52 studies in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP) (NCT02912468/NCT02898454). Methods: Patients received dupilumab 300 mg or placebo every 2 weeks for 24 (SINUS-24) or 52 weeks (SINUS-52) on background intranasal corticosteroids. Patients daily reported symptoms of nasal congestion (NC), loss of smell (LoS) and rhinorrhoea on a scale of 0-3 (0 - no symptoms, 1 - mild, 2 - moderate, 3 - severe symptoms). The proportions of patients with moderate-to-severe symptoms (score ≥ 2) at baseline who improved to no-to-mild symptoms (score ≤ 1) were determined at Weeks 2, 24 (pooled studies) and 52 (SINUS-52). Subgroups with prior sinonasal surgery and coexisting asthma were analysed. Results: At baseline in the pooled intention-to-treat population (n = 724), the proportions of patients with scores ≥ 2 for NC, LoS and rhinorrhoea were 87, 94 and 64%, respectively. Significantly, more patients achieved scores ≤ 1 (no/mild symptoms) with dupilumab vs placebo for each symptom at each time point {Week 2 NC 12% vs 2% [odds ratio 8.9 (95% CI 3.0-26.3)], LoS 5% vs 1% [4.6 (1.3-16.8)], rhinorrhoea 9% vs 2% [4.8 (1.5-15.4)], all P < 0.05; Week 24 NC 54% vs 14% [8.7 (5.6-13.5)], LoS 43% vs 6% [14.4 (7.9-26.0)], rhinorrhoea 53% vs 16% [6.6 (4.1-10.9)], all P < 0.0001}. Results were similar in subgroups with prior surgery and coexisting asthma. Conclusion: Significantly, more patients achieved improvement from moderate-to-severe symptoms to no-to-mild symptoms with dupilumab than placebo, regardless of prior surgery or coexisting asthma. Improvement was observed as early as Week 2 and continued through to Week 52.

Long-term efficacy of dupilumab in asthma with or without chronic rhinosinusitis and nasal polyps.

BACKGROUND: Coexisting chronic rhinosinusitis and nasal polyps (CRS-NPs) substantially increases the disease burden of asthma. Dupilumab, a fully human monoclonal antibody, has established efficacy and an acceptable safety profile in asthma and CRS with NP. OBJECTIVE: To evaluate long-term dupilumab efficacy in TRAVERSE (NCT02134028) patients with uncontrolled, moderate-to-severe (QUEST) or oral corticosteroid (OCS)-dependent (VENTURE) asthma with or without coexisting CRS-NP. METHODS: In TRAVERSE, 317 of 1530 (21%) QUEST and 61 of 187 (48%) VENTURE patients had self-reported CRS-NP; they received subcutaneous 300 mg dupilumab every 2 weeks up to 96 weeks. Patients were categorized by parent study treatment group (placebo/dupilumab, dupilumab/dupilumab). End points included annualized asthma exacerbation rates and mean change from parent study baseline in prebronchodilator forced expiratory volume in 1 second, Asthma Control Questionnaire 5 score, Asthma Quality of Life Questionnaire score, and OCS dose. RESULTS: Patients with coexisting CRS-NP had higher OCS dose and a history of more exacerbations. Concluding TRAVERSE, exacerbation rates decreased from 2.39 to 0.32 and 2.32 to 0.35 in dupilumab/dupilumab and 2.36 to 0.41 and 2.36 to 0.45 in placebo/dupilumab by week 96 from QUEST and VENTURE baselines, respectively. Non-CRS-NP results were similar. Improvements in forced expiratory volume in 1 second, Asthma Control Questionnaire 5 score, and Asthma Quality of Life Questionnaire score during parent studies were maintained in TRAVERSE; placebo/dupilumab patients achieved similar improvements to dupilumab/dupilumab by week 48. By week 96, 71% and 39% of OCS-dependent patients with CRS-NP and 83% and 47% without CRS-NP treated with dupilumab/dupilumab and placebo/dupilumab, respectively, stopped OCS. CONCLUSION: Long-term dupilumab efficacy was maintained in patients with asthma with or without self-reported coexisting CRS-NP, including OCS-sparing effects observed in OCS-dependent severe asthma. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT02528214, NCT02414854, and NCT02134028.

AROMA: real-world global registry of dupilumab for chronic rhinosinusitis with nasal polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a predominantly type 2 inflammatory disease of the nasal and paranasal sinuses. Dupilumab is a monoclonal antibody that blocks the shared receptor component for interleukin-4 and interleukin-13, which are key and central drivers of type 2 inflammation. In clinical trials, dupilumab significantly improved objective and patient-reported measures of CRSwNP versus placebo and was well tolerated. Dupilumab is approved in the European Union, USA and Japan as add-on maintenance treatment for adults with inadequately controlled CRSwNP. There exists an important evidence gap between efficacy and effectiveness data for dupilumab in severe CRSwNP. In order to bridge this gap, the AROMA prospective global registry (ClinicalTrials.gov: NCT04959448) was established. AROMA will collect long-term data on the utilisation, effectiveness and safety of dupilumab for CRSwNP treatment in real-world clinical practice. AROMA will enrol approximately 1000 adults starting dupilumab for severe CRSwNP across 120 global sites. Baseline data will include patient demographics, medical/surgical history and presence of type 2 comorbidities. Effectiveness outcome assessments will include objective measures of CRSwNP assessed as part of routine clinical care and various patient-reported questionnaires. Treatment patterns, concomitant medications and long-term safety will also be recorded. Results from AROMA, the first prospective, real-world, global registry to characterise patients with severe CRSwNP starting dupilumab, will provide evidence on the real impact of dupilumab in patients with CRSwNP and complement the data from randomised clinical trials. The registry will also provide evidence on disease progression in patients with CRSwNP, including those with coexisting diseases.

Dupilumab efficacy in subgroups of type 2 asthma with high-dose inhaled corticosteroids at baseline.

BACKGROUND AND OBJECTIVE: Dupilumab blocks the shared receptor component for interleukin (IL)-4/IL-13, key and central drivers of type 2 inflammation in multiple diseases. In phase 3 QUEST (NCT02414854), add-on dupilumab 200 and 300 mg every 2 weeks reduced severe exacerbations, improved pre-bronchodilator forced expiratory volume in 1 s (FEV1), and was generally well tolerated in patients with uncontrolled moderate-to-severe asthma. This post hoc analysis assessed dupilumab efficacy in subpopulations of patients with type 2 asthma and high-dose inhaled corticosteroids (ICS). METHODS: Adjusted annualized severe exacerbation rates over the treatment period, least squares (LS) mean change from baseline at Week 12 in pre-bronchodilator FEV1, and LS mean change from baseline at Week 24 in 5-item Asthma Control Questionnaire (ACQ-5) scores were analyzed in subgroups of patients receiving high-dose (>500 µg) ICS with baseline blood eosinophils ≥150 cells/µL and/or fractional exhaled nitric oxide ≥25 ppb. Subgroups included allergic phenotype (with/without), comorbid chronic rhinosinusitis and/or nasal polyposis (with/without), pre-bronchodilator FEV1/forced vital capacity (<70%/≥70%), blood eosinophil level, exacerbation history, median baseline pre-bronchodilator FEV1, age at asthma onset (≤40/>40 years), median FEV1 reversibility, body mass index (<30/≥30 kg/m2), and sex. RESULTS: Dupilumab vs placebo reduced exacerbations and improved pre-bronchodilator FEV1 at Week 12 and ACQ-5 at Week 24 across subgroups of patients with type 2 asthma and high-dose ICS at baseline. Dupilumab was also effective in patients receiving medium-dose ICS. CONCLUSION: Dupilumab reduced severe exacerbations and improved lung function and asthma control in subgroups of patients with type 2 asthma and high-dose ICS at baseline. CLINICAL TRIAL REGISTRATION NUMBER: NCT02414854.

Improvement in Health-Related Quality of Life with Dupilumab in Patients with Moderate-to-Severe Asthma with Comorbid Chronic Rhinosinusitis with/without Nasal Polyps: An Analysis of the QUEST Study.

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.