Virtual Issue 1

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ARIËNS et Al.
10
1
0.1
IL-4 (pg/mL)
**** ns ****
100
10
IL-13 (pg/mL) IL-22 (pg/mL)
ns * 100 ** ns ns *
Treatment duration (weeks)
TARC (pg/mL)
Treatment duration (weeks)
PARC (pg/mL)
Treatment duration (weeks)
Periostin (pg/mL) * **
****
****
**
****
1000000
100000
10000
10
****
ns
****
10
1
1000
100
250
100
50
F I G U R E
6000
Treatment duration (weeks)
Eotaxin (pg/mL) * *
*
Treatment duration (weeks)
Eotaxin-3 (pg/mL) **** ns
****
Treatment duration (weeks)
EosinophiLs (x10^9/L) 1.5 ns **
***
1
1.0
0.5
0.0
Treatment duration (weeks)
Treatment duration (weeks)
Treatment duration (weeks)
2 Serum biomarkers and blood eosinophil levels showing significant change over time during treatment with dupilumab
9509.3591547667
is comparable with the conjunctivitis rates in this study. The propor- tion of patients who discontinued dupilumab treatment due to oph- thalmological events was higher in the study by Faiz et al (10 patients [4.2%] compared to our study [2 patients 1.4%]).8 Moderate-severe conjunctivitis needing treatment with anti-inflammatory eyedrops/
ointment was observed in 27 patients (20% of total patient group) of whom the majority had a history of preexisting conjunctivitis (83%). However, in all patients, signs and symptoms significantly worsened and anti-inflammatory treatment was initiated during dupilumab treatment. In this cohort, patient-reported history of conjunctivitis
0
4
8
12
8
12
8
12
16
16
0
4
0
4
0
4
8
12
8
12
8
12
8
12
16
16
16
0
4
0
4
0
4
8
12
0
4
16
8
12
16
0
4
16
16


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and severity of AD at baseline were not predictors for the devel- opment of conjunctivitis during dupilumab treatment. In a previous study, we described the clinical characteristics of 13 moderate to severe dupilumab-treated AD patients developing conjunctivitis with inflammation of the conjunctiva and hyperemia of the limbus as prominent features.9 Nodular swelling of the limbus was present in the most severe cases. In addition, we described a remarkable scarcity of conjunctival goblet cells accompanied by an inflamma- tory T-cell and eosinophilic infiltrate in six dupilumab-treated pa- tients with an ophthalmologist-confirmed conjunctivitis requiring anti-inflammatory treatment.10 We hypothesized that the IL-13 blocking effect of dupilumab might lead to reduction of goblet cells and mucin production in a subpopulation of patients with AD, which may potentially result in irritative conjunctivitis. Given the high proportion of patients developing new onset or worsening of con- junctivitis during dupilumab in daily practice, potentially leading to serious ocular complications, optimal treatment and risk manage- ment is necessary. Remarkably, increased incidence of conjunctivitis was not observed in asthma and sinusitis trials with dupilumab, sug- gesting a disease-specific predisposition in a subpopulation of AD patients.11-13 A prospective study on ocular co-morbidity in moder- ate to severe AD patients before and during dupilumab treatment is already initiated in our center.
We observed elevated eosinophil levels in the peripheral blood during treatment with dupilumab. The proportion of patients with ob- served elevated eosinophil levels in our study was comparable with the patients included in the study by Faiz et al However, in our study none of the patients discontinued dupilumab treatment due to eo- sinophilia compared to 5 patients (2.1%) in the study by Faiz et al.8 Transient eosinophilia was also observed in clinical trials including patients treated with dupilumab for asthma, AD and chronic sinusitis and nasal polyposis.7,11-14 This supports the hypothesis that dupilumab inhibits the migration of eosinophils into the tissues by suppressing the IL-4- and IL-13-stimulated production of eotaxins without influ- encing the production or migration from the bone marrow. Eotaxins are released from endothelial cells that have been stimulated with IL-4 and IL-13 and attract eosinophils and other inflammatory cells. Eosinophils stimulate the production of Th2-associated cytokines by T-lymphocytes which in turn prolong the survival and mediate the ac- tivation and migration of eosinophils.15 Previous studies have shown that dupilumab decreased eotaxin-2 and eotaxin-3 levels locally in nasal polyp tissue, nasal secretion, and serum from chronic rhinosi- nusitis patients.11,16 In this study, we show that serum concentrations of eotaxin-1 and eotaxin-3 chemokines decreased during dupilumab treatment. These data suggest that dupilumab suppresses eosinophil chemokines both systemically and locally.
Dupilumab has shown to normalize the RNA expression of Th2- related inflammatory molecules and reverse skin barrier abnormali- ties in biopsies from 18 AD patients treated with dupilumab in phase 1 studies.17 A recent study including 54 patients treated with dupi- lumab in a clinical trial showed a significant decrease of Th2-related serum biomarkers TARC, PARC, and periostin after 16 weeks of treat- ment.18 Both studies included a subgroup of patients from clinical
trials, and there are no data available on biomarkers in dupilum- ab-treated AD patients in daily practice. Moreover, only a selective group of biomarkers reflecting Th2 activation was studied, while it is known that besides Th2 signaling, activation of Th22, Th17, and Th1 is also observed in patients with AD.19 In this study, we showed that treatment with dupilumab significantly decreased serum biomarkers that have been implicated as biomarkers of AD severity and treatment response, including TARC, PARC, periostin, and IL-22. An interesting finding of this study was the increase of Th2 cytokines IL-4 and IL-13 during treatment with dupilumab, although levels were still relatively low. Since other Th2-related biomarkers (TARC, PARC, and periostin) did decrease, we hypothesize that IL-4 receptor alpha blockade with dupilumab might result in an increase of unbound circulating IL-4 and IL-13 levels. The increase of IL-4 and IL-13 might be a temporary phe- nomenon, since it is likely that long-term suppression of IL-4Rα will lead to a decreased production of IL-4 and IL-13 by T cells. Dupilumab treatment significantly decreased serum IL-22 levels. No effect on Th17 related biomarkers was observed. Nevertheless, it is ques- tionable whether the Th17 pathway plays a role in our population of European AD patients, since Th17 activation has been strongly asso- ciated with mainly Asian and pediatric AD subtypes, and in European- American populations with only the intrinsic AD subtype.20 The Th22 pathway is commonly activated in all major subtypes of AD.20
In conclusion, treatment with dupilumab significantly improved signs and symptoms of AD in patients with very difficult-to-treat AD in a daily practice setting with the majority of patients achieving a clinically relevant response after 16 weeks of treatment. Dupilumab treatment significantly suppressed disease severity-related serum biomarkers and systemically suppresses eosinophil chemokines. The most reported side effect in this daily practice cohort was conjunc- tivitis. Future, long-term daily practice data derived from the BioDay registry will provide important information on the long-term effec- tiveness and safety of dupilumab.
CONFLICTS OF INTEREST
Marjolein de Bruin-Weller is a principal investigator and advisory board member for AbbVie and Regeneron Pharmaceuticals, Inc; is a principal investigator, advisory board member, and consultant for Sanofi Genzyme; is a advisory board member for Eli Lilly; is a ad- visory board member for UCB; and is a principal investigator and advisory board member for Pfizer. Marie-Louise Schuttelaar: Sanofi Genzyme – advisory board member, consulting fees. The other au- thors have no conflict of interest to declare.
ORCID
Lieneke F. M. Ariëns https://orcid.org/0000-0001-5256-0091 Julia Drylewicz https://orcid.org/0000-0002-9434-8459 Judith L. Thijs https://orcid.org/0000-0003-2753-5235 Marjolein S. de Bruin-Weller https://orcid. org/0000-0002-1249-6993


126 | REFERENCES
1. Simpson EL, Bieber T, Guttman-Yassky E, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375(24):2335-2348.
2. Blauvelt A, de Bruin-Weller M, Gooderham M, et al. Long-term man- agement of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. Lancet (London, England). 2017;389(10086):2287-2303.
3. de Bruin-Weller M, Thaçi D, Smith CH, et al. Dupilumab with con- comitant topical corticosteroids in adult patients with atopic der- matitis who are not adequately controlled with or are intolerant to ciclosporin A, or when this treatment is medically inadvisable: a placebo-controlled, randomized phase 3 clinical trial (LIBERTY AD CAFÉ). Br J Dermatol. 2017;178(5):1083-1101.
4. van Onzenoort HA, Menger FE, Neef C, et al. Participation in a clin- ical trial enhances adherence and persistence to treatment: a retro- spective cohort study. Hypertension. 2011;58(4):573-578.
5. Chalmers JR, Thomas KS, Apfelbacher C, et al. Report from the fifth international consensus meeting to harmonize core outcome mea- sures for atopic eczema/dermatitis clinical trials (HOME initiative). Br J Dermatol. 2018;178(5):e332-e341.
6. Thijs JL, Strickland I, Bruijnzeel-Koomen C, et al. Moving toward endotypes in atopic dermatitis: identification of patient clus- ters based on serum biomarker analysis. J Allergy Clin Immunol. 2017;140(3):730-737.
7. de Bruin-Weller M, Thaci D, Smith CH, et al. Dupilumab with con- comitant topical corticosteroid treatment in adults with atopic der- matitis with an inadequate response or intolerance to ciclosporin A or when this treatment is medically inadvisable: a placebo-con- trolled, randomized phase III clinical trial (LIBERTY AD CAFE). Br J Dermatol. 2018;178(5):1083-1101.
8. Faiz S, Giovannelli J, Podevin C, et al. Effectiveness and safety of dupilumab for the treatment of atopic dermatitis in a re- al-life French multicenter adult cohort. J Am Acad Dermatol. 2019;81(1):143-151.
9. Wollenberg A, Ariens L, Thurau S, van Luijk C, Seegräber M, de Bruin-Weller M. Conjunctivitis occurring in atopic dermatitis pa- tients treated with dupilumab-clinical characteristics and treat- ment. J Allergy Clin Immunol Pract. 2018;6(5): 1778.e1-1780.e1.
10. Bakker DS, Ariens LFM, van Luijk C, et al. Goblet cell scarcity and conjunctival inflammation during treatment with dupilumab in pa- tients with atopic dermatitis. Br J Dermatol. 2018;180(5):1248-1249.
11. Bachert C, Mannent L, Naclerio RM, et al. Effect of subcutane- ous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: a randomized clinical trial. JAMA. 2016;315(5):469-479.
ARIËNS et Al.
12. Busse WW, Maspero JF, Rabe KF, et al. Liberty asthma QUEST: phase 3 randomized, double-blind, placebo-controlled, paral- lel-group study to evaluate dupilumab efficacy/safety in pa- tients with uncontrolled, moderate-to-severe asthma. Adv Ther. 2018;35(5):737-748.
13. Rabe KF, Nair P, Brusselle G, et al. Efficacy and safety of dupi- lumab in glucocorticoid-dependent severe asthma. N Engl J Med. 2018;378(26):2475-2485.
14. Castro M, Corren J, Pavord ID, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med. 2018;378(26):2486-2496.
15. Ahmadi Z, Hassanshahi G, Khorramdelazad H, Zainodini N, Koochakzadeh L. An overlook to the characteristics and roles played by Eotaxin Network in the pathophysiology of food al- lergies: allergic asthma and atopic dermatitis. Inflammation. 2016;39(3):1253-1267.
16. Jonstam K, Swanson BN, Mannent L, et al. Dupilumab reduces local type 2 pro-inflammatory biomarkers in chronic rhinosinusitis with nasal polyposis. Allergy. 2018;74(4):743-752.
17. Hamilton JD, Suarez-Farinas M, Dhingra N, et al. Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol. 2014;134(6):1293-1300.
18. Guttman-Yassky E, Bissonnette R, Ungar B, et al. Dupilumab progres- sively improves systemic and cutaneous abnormalities in patients with atopic dermatitis. J Allergy Clin Immunol. 2018;143(1):155-172.
19. Gittler JK, Shemer A, Suarez-Farinas M, et al. Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins charac- terizes acute and chronic atopic dermatitis. J Allergy Clin Immunol. 2012;130(6):1344-1354.
20. Guttman-Yassky E, Krueger JG. Atopic dermatitis and psoriasis: two different immune diseases or one spectrum? Curr Opin Immunol. 2017;48:68-73.
SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting Information section.
How to cite this article: Ariëns LFM, van der Schaft J, Bakker DS, et al. Dupilumab is very effective in a large cohort of difficult-to-treat adult atopic dermatitis patients: First clinical and biomarker results from the BioDay registry. Allergy. 2019;75:116–126. https://doi.org/10.1111/all.14080


Received: 28 September 2018 | Revised: 28 May 2019 | Accepted: 5 June 2019 DOI: 10.1111/all.13984
ORIGINAL ARTICLE
Basic and Translational Allergy Immunology
Dupilumab improves health‐related quality of life in patients with chronic rhinosinusitis with nasal polyposis
Claus Bachert1,2 |
Philippe Gevaert1,2 |
Leda P. Mannent8 |
Chunpeng Fan10 | Gianluca Pirozzi10 | Neil M. H. Graham7 | Heribert Staudinger10 | Asif Khan8
1Ghent University Hospital, Ghent, Belgium
2CLINTEC, Karolinska Institute, Stockholm, Sweden
3University Hospitals Leuven, Leuven, Belgium
4IDIBAPS (Hospital Clínic de Barcelona, University of Barcelona, and CIBERES), Barcelona, Spain
5Massachusetts General Hospital, Boston, MA, USA
6Johns Hopkins Hospital, Baltimore, MD, USA
7Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA
8Sanofi, Chilly‐Mazarin, France
9Altran Technologies, Vélizy‐Villacoublay, France
10Sanofi, Bridgewater, NJ, USA
Correspondence
Claus Bachert, Upper Airway
Research Laboratory, Department of Otorhinolaryngology, Ghent University Hospital, De Pintelaan 185, B‐9000 Ghent, Belgium.
Email: [email protected]
Present address
Vijay N. Joish, Lexicon Pharmaceuticals, Inc, Basking Ridge, NJ, USA
Funding information
Sanofi and Regeneron Pharmaceuticals Inc., Grant/Award Number: NCT01920893
Adeline Abbe is a former employee at Sanofi, Chilly‐Mazarin, France
148 | © 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.
wileyonlinelibrary.com/journal/all
Allergy. 2020;75:148–157.
Peter W. Hellings3 | Joaquim Mullol4 | Daniel L. Hamilos5 |
Robert M. Naclerio6 | Vijay N. Joish7 | Jingdong Chao7 | Nikhil Amin7 | Adeline Abbe8* | Christine Taniou9 |
Puneet Mahajan10 |
Abstract
Background: Chronic rhinosinusitis with nasal polyposis (CRSwNP) negatively affects health‐related quality of life (HRQoL). In a previously reported randomized clinical trial (NCT01920893), addition of dupilumab to mometasone furoate in patients with CRSwNP refractory to intranasal corticosteroids (INCS) significantly improved endo‐ scopic, radiographic, and clinical endpoints and patient‐reported outcomes. The ob‐ jective of this analysis was to examine the impact of dupilumab treatment on HRQoL and productivity using secondary outcome data from this trial.
Methods: Following a 4‐week mometasone furoate nasal spray run‐in, patients were randomized to commence subcutaneous dupilumab (600 mg loading dose, then 300 mg once weekly for 15 weeks [n = 30], or matched placebo [n = 30]). Outcomes included scores on the CRS disease severity visual analog scale (VAS), 22‐item Sino‐ Nasal Outcome Test (SNOT‐22), 5‐dimension EuroQoL (EQ‐5D) general health status VAS, and 36‐item Short‐Form Health Survey (SF‐36) for HRQoL and nasal polyp‐re‐ lated healthcare resource use questionnaires.
Results: Following 16 weeks of treatment, the proportion of patients with moder‐ ate‐to‐severe CRSwNP (VAS > 3‐10) decreased from 86.2% to 21.4% with dupilumab and 88.0% to 84.2% with placebo. Dupilumab (vs placebo) resulted in significantly greater improvement in HRQoL, based on SNOT‐22, SF‐36, and EQ‐5D VAS scores. The dupilumab group had a significantly lower adjusted annualized mean number of sick leave days (0.09, vs 4.18 with placebo, P = .015) and significantly greater im‐ provement (vs placebo) in the SNOT‐22 item “reduced productivity.”
Conclusions: In adults with CRSwNP refractory to treatment with INCS alone, the addition of dupilumab reduced disease severity, significantly improved HRQoL, and improved productivity.
KEYWORDS
biologics, ENT (rhinitis, sinusitis, nasal polyps...), quality of life


BACHERT ET Al. | 149
GRAPHICAL ABSTRACT
Dupilumab improves HRQoL, with significantly greater improvement in SNOT‐22, SF‐36, and EQ‐5D VAS, and with the greatest improvement vs placebo in the SNOT‐22 items ‘sense of smell/taste’ and ‘nasal blockage’. Dupilumab reduces CRSwNP disease severity VAS, decreasing the proportion of patients with moderate‐to‐severe CRSwNP. Dupilumab improves productivity, with significantly lower annualized mean sick leave days vs placebo.
Abbreviations: CRSwNP, Chronic rhinosinusitis with nasal polyposis; EQ‐5D, 5‐dimension EuroQoL questionnaire; HRQoL, Health‐related quality of life; SF‐36, 36‐item short‐form health survey; SNOT‐22, 22‐item sino‐nasal outcome test; VAS, Visual analog scale
1 | INTRODUCTION
Chronic rhinosinusitis (CRS) is an inflammatory disease with an estimated prevalence of 12.1% in the United States and 10.9% in Europe.1,2 It can occur with or without nasal polyposis; if nasal polyps are present, patients are diagnosed with chronic rhinosinusitis with nasal polyposis (CRSwNP). CRSwNP has an estimated prevalence of 4.2% in the United States,3 between 2.1% and 4.3% in Europe,4,5 and between 2.1% and 8.4% in Asia.6 The prevalence of nasal polyps has been reported to increase with age.4,7
CRSwNP is a chronic disease often associated with type 2‐ mediated inflammation, which causes debilitating, uncontrolled, persistent symptoms despite systemic corticosteroid use and/or sur‐ gery.8 CRS is associated with two or more symptoms of either nasal blockage/obstruction/congestion or nasal discharge (anterior/poste‐ rior nasal drip), facial pain/pressure, and/or reduction/loss of smell. In addition, patients present with either endoscopic signs of nasal polyps/mucopurulent discharge in middle meatus, and/or mucosal changes within the ostiomeatal complex and/or sinuses that can be detected by CT scan.9 Disease relapse and persistent symptoms can occur even following postoperative medical treatment after endo‐ scopic sinus surgery (ESS).10,11
CRSwNP has a substantial negative effect on patient health‐ related quality of life (HRQoL).12 The nasal congestion and rhi‐ norrhea associated with the disease increase the likelihood of sleep disruption, resulting in fatigue and daytime somnolence.13
Emotional function, productivity, and the ability to perform daily activities are also affected,14 with patients often reporting feelings of sadness, embarrassment, and frustration.15 Considerable ab‐ senteeism and presenteeism affect work productivity in CRSwNP patients.12,16
Two current treatment options for patients with CRSwNP, nasal corticosteroids and nasal polyp surgery, are reported to signifi‐ cantly improve HRQoL as assessed by the 20‐ or 22‐item Sino‐Nasal Outcome Test (SNOT‐20 or SNOT‐22).17,18 Despite these reported improvements, many patients experience a relapse of symptoms or persistent sinus disease, thus necessitating new therapies for treatment.11,19
CRSwNP patients frequently suffer from other type 2 comor‐ bidities, characterized by type 2‐mediated inflammation, such as asthma, atopic dermatitis, and allergic rhinitis.20 The incidence of co‐ morbid asthma is as high as 66%, and it is even more common among patients with refractory CRSwNP.21 Suboptimal control of CRSwNP and the presence of nasal polyps have both been shown to reduce asthma control.22‐24 The severity of asthma correlates with sinus CT scan abnormalities, severe nasal obstruction, and hyposmia.25 Inflammatory endotype analyses demonstrate that CRSwNP pa‐ tients with comorbid asthma have high expression levels of interleu‐ kin (IL)‐5, eosinophil cationic protein, and total and specific IgE.26,27
Dupilumab, a fully human VelocImmune®‐derived28,29 mono‐ clonal antibody, blocks the shared receptor component for IL‐4 and IL‐13, thus inhibiting signaling of both IL‐4 and IL‐13, cytokines that


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BACHERT ET Al.
are key drivers of type 2 diseases such as atopic dermatitis (AD), asthma, allergic rhinitis, and food allergies, conditions often asso‐ ciated as comorbidities. Dupilumab is approved for the treatment of adults with moderate‐to‐severe atopic dermatitis (AD) inade‐ quately controlled with topical prescription therapies or when those therapies are not advisable, and for use in adults with inadequately controlled, moderate‐to‐severe AD who are candidates for systemic therapy.30‐32 Dupilumab has also been approved in the United States as an add‐on maintenance treatment in adult patients with inade‐ quately controlled CRSwNP and in patients with moderate‐to‐severe asthma aged ≥12 years with an eosinophilic phenotype or with oral corticosteroid‐dependent asthma.33,34 In all studies, dupilumab has been shown to be well tolerated, with nasopharyngitis, headache, and injection‐site reactions, the most common adverse events.35‐37
In a proof‐of‐concept phase 2a study in patients with CRSwNP refractory to intranasal corticosteroids (INCS), the use of add‐on subcutaneous dupilumab with mometasone furoate nasal spray (MFNS) significantly improved endoscopic, radiographic, and clin‐ ical endpoints and patient‐reported outcomes.35 Dupilumab treat‐ ment was associated with a reduction in the nasal polyp burden and disease severity as assessed by a visual analog scale (VAS); with improvements in nasal congestion or obstruction, anterior and posterior rhinorrhea, subjective sense of smell, and nocturnal awakenings; and with improved nasal inspiratory flow.9 In addition, a significant improvement was observed in HRQoL as assessed by the validated disease‐specific SNOT‐22.35 In patients with comor‐ bid asthma, dupilumab was associated with improved lung function and asthma control, as assessed by the 5‐item Asthma Control Questionnaire.38
The objective of this analysis was to examine the impact of 16 weeks of dupilumab treatment on HRQoL outcomes and produc‐ tivity, including absenteeism, in patients with CRSwNP refractory to INCS. This report adds to the data from the phase 2a trial previously described,35 with the aim of better understanding the impact of se‐ vere nasal polyposis on HRQoL.
2 | METHODS 2.1 | Study design
This was a randomized, double‐blind, placebo‐controlled, paral‐ lel‐group study that included a 4‐week run‐in period followed by 16 weeks of blinded treatment on a background of treatment with INCS.
2.1.1 | Inclusion criteria
The study enrolled adults aged 18‐65 years with bilateral nasal poly‐ posis and symptoms of chronic rhinosinusitis despite use of INCS for at least 2 months. Patients had a minimum bilateral nasal polyp score of 5 of a maximum of 8 for both nostrils (with a score of at least 2 for each nostril) and at least 2 of the following symptoms before screening: nasal obstruction or nasal discharge and/or facial pain or
pressure and a reduction/loss of smell. The nasal polyp score is the sum of the right and left nasal cavities, as evaluated by means of nasal endoscopy. Nasal polyps are graded based on location and size of the polyps.39
2.1.2 | Exclusion criteria
Patients were excluded if they had used oral or intranasal corticos‐ teroid drops or received monoclonal antibody treatment, immu‐ nosuppressive treatment, or anti‐IgE therapy during the 2 months before screening, or if they had undergone any nasal surgery within 6 months before screening or more than 2 surgical procedures for nasal polyposis in the past. The full inclusion and exclusion criteria have been published.35
Protocol approval was provided by the institutional review board at each study site or by a centralized institutional review board.
2.2 | Study treatments
Following a 4‐week run‐in period of treatment with MFNS (100 μg in each nostril; twice daily or one time daily if they cannot tolerate), patients were randomly assigned (1:1) to add‐on therapy with sub‐ cutaneous dupilumab (a 600 mg loading dose followed by 300 mg once weekly for 15 weeks) or subcutaneous matched placebo. Patients were randomized using a centralized, computer‐generated, permuted‐block schedule with a block size of 4 and stratified by medical history of asthma (with comorbid asthma and without co‐ morbid asthma) and by V2 nasal biopsy (biopsy performed at Visit 2 prior to administration of dupilumab/placebo: Yes/No). Dupilumab and placebo were provided in identical, indistinguishable treatment kits. Study patients, investigators, and site personnel were blinded to study treatment.
2.3 | Outcomes
Patient‐reported secondary outcomes, including scores on the CRS disease severity VAS9; SNOT‐22,18 5‐dimension EuroQoL (EQ‐5D‐3L) general health status VAS,40 and 36‐item Short‐Form Health Survey (SF‐36)41,42 for HRQoL; and the nasal polyp‐related healthcare resource use (HCRU) questionnaires, were obtained at baseline and Weeks 4, 8, 12, and 16.43
CRS disease severity VAS allows patients to evaluate the se‐ verity of their disease (can be used in CRS with and without NP), on a scale from 0 cm (not troublesome) to 10 cm (worst thinkable troublesome). SNOT‐22 assesses the symptoms, sleep, and func‐ tional and emotional consequences of CRS, where patients respond to 22 items by using a 6‐category scale from 0 (no problem) to 5 (problem as bad as it can be). EQ‐5D VAS is a standardized HRQoL questionnaire that provides a simple generic measure of health by recording the respondent's self‐rated current health on a vertical VAS with endpoints of 100 mm (best imaginable health state) at the top and 0 mm (worst imaginable health state) at the bottom. SF‐36 is a generic HRQoL scale used to assess health status using a 36‐item


BACHERT ET Al.
| 151
TABLE 1 Baseline clinical characteristics and patient‐reported outcomes
Placebo/MFNS (n = 30)
Dupilumab/MFNS (n = 30)
Baseline clinical characteristics
Male, n (%)
Nasal polyp score, mean (SD)
Nasal congestion/obstruction score, mean (SD); range 0‐3 Anterior/posterior rhinorrhea score, mean (SD); range 0‐3 Patients with previous surgery for nasal polyposis, n (%) Duration of asthma, mean (SD), years
Total serum IgE, IU/mL mean (SD) Patient‐reported outcomes
EQ‐5D health status VAS, mean (SD); range 0‐100 SF‐36 mental component score, mean (SD); range 0‐100 Patients employed, n (%)
16 (53.3) 5.67 (0.88) 1.69 (0.69) 1.27 (0.73)
19 (63.3) 20.2 (17.4)
195.3 (251.5)
72.4 (15.2) 51.6 (7.7)
26 (86.7)
18 (60.0) 5.87 (1.01) 1.66 (0.73) 1.04 (0.83)
16 (53.3) 15.5 (12.1)
139.7 (136.3)
70.3 (19.8) 48.7 (10.8) 25 (83.3)
Age, mean (SD), years
49.3 (9.1)
47.4 (9.8)
BMI, mean (SD)
26.8 (39.0)
28.1 (4.2)
CT scan Lund‐Mackay total score, mean (SD)
18.73 (5.52)
18.62 (5.00)
Loss of smell score, mean (SD); range 0‐3
2.82 (0.49)
2.41 (0.91)
Duration of nasal polyposis, mean (SD), years
11.5 (8.7)
7.6 (6.1)
Asthma, n (%)
19 (63.3)
16 (53.3)
NSAID sensitivity, n (%)
10 (33.3)
7 (23.3)
Blood eosinophil count, ×109/L, mean (SD)
0.45 (0.67)
0.41 (0.24)
CRSwNP VAS, mean (SD); range 0‐10
6.4 (2.7)
6.4 (2.7)
SNOT‐22 total score, mean (SD); range 0‐110
40.6 (19.9)
41.4 (18.2)
SF‐36 physical component score, mean (SD); range 0‐100
48.5 (7.6)
46.7 (8.4)
Abbreviations: BMI, body mass index; CRSwNP, chronic rhinosinusitis with nasal polyposis; CT, computerized tomography; EQ‐5D, 5‐dimension EuroQoL questionnaire; MFNS, mometasone furoate nasal spray; NSAID, nonsteroidal anti‐inflammatory drug; SD, standard deviation; SF‐36, 36‐ item Short‐Form Health Survey; SNOT‐22, 22‐item Sino‐Nasal Outcome Test; VAS, visual analog scale.
questionnaire, which comprises 8 domains measuring physical func‐ tioning, social functioning, role limitations due to physical problems, role limitations due to emotional problems, mental health, energy or vitality, bodily pain, and general health perception. The nasal polyp‐ related HCRU questionnaire was used to evaluate HCRU for nasal polyposis, including days missed from work (defined as sick leaves from work during the on‐treatment period).
2.4 | Statistical analysis
Analyses of patient‐reported outcomes were performed using the intent‐to‐treat (ITT) population, which was predefined as all rand‐ omized patients. Data were analyzed at the group and individual levels.
Within‐group changes and between‐group changes from base‐ line to Week 16 were analyzed using a mixed‐effect model with re‐ peated measures (MMRM) approach for the CRSwNP VAS, SNOT‐22 (both total and individual item scores), SF‐36 domains and summary scores, and EQ‐5D VAS. The model included fixed‐effect factors for treatment, stratification factors (comorbid asthma [yes/no], biopsy
performed [yes/no]), visit, treatment‐by‐visit interaction, baseline value, and baseline‐by‐visit interaction. Missing data were not im‐ puted in this model. An unstructured correlation matrix was used to model the within‐patient errors. Parameters were estimated using the restricted maximum likelihood method with the Newton‐ Raphson algorithm. Differences in least squares means (LS means), the corresponding 95% CIs, and P values were provided for compar‐ isons of dupilumab vs placebo.
An individual‐level analysis was a “responder analysis” based on the minimal clinically important difference (MCID)44 established for individual patient‐reported outcomes. The MCID threshold is 8.9 for the SNOT‐22 global score45; 3.8 and 4.6 for the SF‐36 PCS and MCS summary scores, respectively42; and 8.45 for the EQ‐5D VAS.46 The MCID thresholds for the SF‐36 domains are 5.5 for bodily pain, 7.0 for general health perceptions, 6.7 for mental health, 4.3 for physical functioning, 4.6 for role—emotional, 4 for role—physical, 6.2 for so‐ cial functioning, and 6.7 for vitality.42
The nasal polyp‐related HCRU questionnaire was analyzed using Poisson regression modeling with robust error variance, with the total number of events as response variable, treatment and


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stratification factors (asthma, nasal polyp biopsy) as covariates, and log‐transformed treatment duration as an offset variable.
3 | RESULTS 3.1 | Baseline characteristics
Overall, 60 patients were randomized in a 1:1 ratio to the dupilumab and placebo arms, and 51 completed the study (Figure S1).35 Patient baseline demographic and disease characteristics were similar be‐ tween groups (Table 1). For the randomized patients, mean (SD) age was 48.4 (9.4) years, 34 patients were men, and more than half had asthma (63% of the placebo group and 53% of the dupilumab group). Sensitivity to nonsteroidal anti‐inflammatory drugs (NSAIDs; mainly aspirin) was reported in 33.3% of patients in the placebo group and 23.3% of the dupilumab group. At baseline, most patients had mod‐ erate‐to‐severe disease, with a high symptom burden and a poor HRQoL, according to generic and disease‐specific scales.
3.2 | Patient‐reported outcomes, including HRQoL 3.2.1 | CRS disease severity VAS
The change in CRS disease severity VAS status in each category (mild, moderate, and severe) in the placebo and dupilumab groups is shown in Figure 1. At baseline, in the dupilumab arm 9 (31%) patients had moderate VAS scores and 16 (55.2%) had severe scores for rhinosi‐ nusitis, while in the placebo arm 9 (36%) patients had moderate scores and 13 (52%) had severe scores. After 16 weeks of treatment, 78.6%, 14.3%, and 7.1% of 28 dupilumab patients and 15.8%, 42.1%, and 42.1% of 19 placebo patients reported mild, moderate, and severe CRSwNP disease, respectively.
3.2.2 | SNOT‐22 total score and individual items
At baseline, mean total SNOT‐22 scores were similar in the dupilumab (41.4) and placebo (40.6) groups (Table 1). At Week 16, dupilumab‐ treated patients showed significant improvement, with an LS mean difference in change from baseline vs placebo of −18.1 (95% confi‐ dence interval [CI] −25.6, −10.6; P < .001; Figure 2). More patients in the dupilumab group (93.3%) than the placebo group (26.7%) had a clinically meaningful improvement (change in score ≥ MCID).
Patients indicated that the most important items affecting their health were decreased sense of smell/taste (90% of patients), nasal blockage (77% of patients), thick nasal discharge (33.3%), postnasal discharge (26.7%), and reduced concentration (26.7%) (Figure 3). Of the five individual items with the greatest improvements in change from baseline to Week 16 in the dupilumab group vs the placebo group—sense of smell or taste (−2.06), nasal blockage (−1.38), thick nasal discharge (−1.22), wake up tired (−1.16), and fatigue (−1.05)— 3 were items that patients had indicated were the most important to them (Figure 3).
3.2.3 | SF‐36
At Week 16, in the dupilumab arm, the mean change from baseline was statistically significant (P < .05) in 7 domains (general health per‐ ception, mental health, physical functioning, role—emotional, role— physical, social functioning, and vitality) (Table S1; Figure 4). In the placebo arm, the change from baseline was statistically significant (P < .05) in 3 domains (general health perception, role‐physical, and social functioning). Significant changes from baseline were observed in both PCS (P = .007) and MCS scores (P = .0002) in the dupilumab arm but only in PCS score in the placebo arm (P = .006).
At Week 16, the dupilumab group had a significantly greater im‐ provement in vitality (LS mean difference 5.66; 95% CI 0.95‐10.37; P = .0196) and mental health (LS mean difference 5.26; 95% CI 1.69‐8.82; P = .0047) compared with the placebo group. The differ‐ ence between treatment groups at Week 16 was also statistically significant for MCS (LS mean difference 5.45; 95% CI 1.42‐9.48; P = .0091) but not for PCS score.
All SF‐36 response rates were numerically greater in the dupi‐ lumab group than the placebo group. The SF‐36 MCS response rate at Week 16 was 46.7% for dupilumab vs 6.7% for placebo, and the PCS response rate was 46.7% for dupilumab vs 26.7% for placebo.
3.2.4 | EQ ‐5D‐VAS
At the end of treatment, the dupilumab group had a significantly greater improvement in EQ‐5D VAS self‐rated health state than did the placebo group, with an LS mean difference in change from base‐ line at Week 16 of 7.72 (P = .02; Figure 5).
The EQ‐5D‐VAS response rate was 50% for dupilumab vs 20% for placebo.
F I G U R E 1 Box‐whisker plot of patient‐reported CRS disease severity VAS score by treatment and visit—ITT population. CRS, chronic rhinosinusitis; ITT, intent‐to‐treat; MFNS, mometasone furoate nasal spray; VAS, visual analog scale. *Indicates outliers, values that lie more than one and a half times the length of the box from either end of the box


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FIGURE 2 LS mean change from baseline in SNOT‐22 total score by treatment group. LS, least squares; MCID, minimally clinically important difference; MFNS, mometasone furoate nasal spray; SE, standard error; SNOT‐22, 22‐item Sino‐Nasal Outcome Test
Decreased
F I G U R E 3 LS mean difference in dupilumab vs placebo at Week 16 in SNOT‐22 individual items score. LS, least squares; MFNS, mometasone furoate nasal spray; SNOT‐22, 22‐item Sino‐Nasal Outcome Test. The percentages of patients who considered the item as one of the 5 most important items affecting health at baseline are in orange boxes (the 5 most frequent items are highlighted in orange)
3.2.5 | Absenteeism and SNOT‐22 productivity‐ related items
Productivity was determined using data from the HCRU question‐ naire on days missed from work. At baseline, 45 patients (75%) were employed full time, and 6 (10%) were employed part time. Employed patients in the dupilumab group had a significantly lower (relative risk reduction 98%) adjusted annualized mean number of sick leave days (0.09 vs 4.18 in the placebo group, P = .0145) (Figure S1). The adjusted annualized mean number of usual activities days lost, for all patients, was lower in the dupilumab group (2.6) than in the placebo group (6.6, P = .3293; relative risk reduction 61%).
At the end of treatment (Week 16), dupilumab‐treated patients had a significantly reduced loss of productivity compared with placebo‐ treated patients, as shown by scores on item 18 of SNOT‐22, “reduced productivity”, with an LS mean treatment group difference in change from baseline of −0.62 in favor of dupilumab (P = .026).
4 | DISCUSSION
The current analysis provides further details on secondary out‐ comes from the previously described phase 2a clinical trial inves‐ tigating the effect of dupilumab in patients with CRSwNP. In this


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(A) (B)
F I G U R E 4 Mean change from baseline to Week 16 in SF‐36 individual domain scores in (A) placebo and (B) dupilumab groups. BP, bodily pain; GH, general health; MCS, mental component summary; MFNS, mometasone furoate nasal spray; MH, mental health; PCS, physical component summary; PF, physical functioning; RE, role—emotional; RP, role—physical; SF, social functioning; SF‐36, 36‐item Short‐Form Health Survey; VT, vitality. *Indicates statistically significant improvement in change from baseline within each treatment group (P < .05)
FIGURE 5 LS mean change from baseline in self‐rated health (EQ‐5D VAS) at Week 16 by treatment group. EQ‐5D, 5‐dimension EuroQoL questionnaire; LS, least squares; MCID, minimal clinically important difference; MFNS, mometasone furoate nasal spray; SE, standard error; VAS, visual analog scale. Score range 0‐100
proof‐of‐concept study, the addition of dupilumab to INCS in pa‐ tients with CRSwNP was associated with significant improvements in several patient‐reported outcomes, including CRS disease severity VAS and HRQoL as measured by disease‐specific (SNOT‐22) and ge‐ neric (SF‐36, EQ‐5D VAS) tools, productivity as measured by scores on item 18 of the SNOT‐22, and absenteeism as measured by HCRU.
A significant reduction in CRS disease severity VAS score with dupilumab (vs placebo) has already been reported.35 In agreement, the current analysis demonstrated that most patients (approximately 85%) in both groups had moderate (a score of 3‐7) or severe CRSwNP disease (a score >7) at baseline. After 16 weeks of treatment, disease
severity decreased to mild in most patients in the dupilumab group who had severe disease at baseline, while most patients in the placebo group continued to have moderate‐to‐severe disease.
Bachert et al reported that compared with placebo, dupilumab treatment is associated with a significantly greater improvement in scores on the SNOT‐22, a HRQoL instrument specific to CRS.35 The current analysis expanded upon these findings by demonstrating that a total of 93.3% of patients treated with dupilumab had a re‐ sponse to treatment, compared with only 26.7% of those who re‐ ceived placebo with MFNS, based on an improvement in SNOT‐22 score with MCID threshold of at least 8.9.


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Of the 22 items comprising the SNOT‐22, a decreased sense of smell or taste was the item that improved most from baseline. This item was also frequently rated by patients as being one of the most important items affecting their health. This finding is consistent with the previously reported dupilumab‐associated improvement in the University of Pennsylvania Smell Identification Test.35 Olfactory dys‐ function is common in patients with CRSwNP and has been reported to negatively affect HRQoL47,48; at baseline, 90% of patients in the current study rated decreased sense of smell/taste as one of the top 5 most important items on the SNOT‐22. Individuals with olfactory disorders have reported difficulties in cooking and enjoying food and maintaining personal hygiene and problems with personal and profes‐ sional life due to social difficulties.49,50 As olfactory loss is commonly associated with depression,51 improvements in olfactory deficits may greatly improve patients’ HRQoL. Furthermore, CRS‐associated nasal blockage and discharge have been reported to negatively affect HRQoL as well as breathing and sleep.47,52 In the current study, these SNOT‐22 items, which patients frequently rated as important items affecting their health, also were substantially improved from baseline.
Corticosteroid and surgical treatments have previously resulted in improvement in HRQoL measures. In patients who received 6 months of corticosteroid treatment after endoscopic sinus sur‐ gery for CRSwNP, fluticasone nasal spray was associated with a decrease in SNOT‐22 score of 27.4 from baseline.17 Surgery alone has also been shown to improve CRS‐specific outcomes, with a recent meta‐analysis demonstrating a mean decrease in SNOT‐22 score of 23.0 points after endoscopic sinus surgery for CRSwNP.18 Patients included in the current study had uncontrolled nasal polyp disease despite use of INCS for ≥2 months, and in over half of the patients, despite any nasal surgery (including polypectomy) (58%). The fact that dupilumab plus MFNS treatment was associated with a decrease in SNOT‐22 score from baseline of 27.3 points is notable and similar to that of sinus surgery plus 6 months of corticosteroid treatment.17 In contrast, we found that placebo plus MFNS led to a reduction of 9.2 points from baseline. Although this reduction, which is greater than the SNOT‐22 MCID of 8.9, may be due to the standardized use of background MFNS, there was no change in the nasal polyp score in the placebo group over time. Therefore, these changes in patient‐reported outcomes may also be related to the placebo effect. Furthermore, dupilumab treatment was associated with meaningful improvements in the individual components of the SNOT‐22 that were regarded as most important to patients.53
Generic measures of HRQoL, including mental health, physical functioning, role—emotional, and vitality, as measured by the SF‐36, also indicated improvements with dupilumab treatment, but not with placebo. It is important that patients treated with dupilumab had an improvement in role limitations due to emotional problems, because others have reported that emotional function is affected by the nasal congestion and rhinorrhea associated with CRSwNP.14,15 As many pa‐ tients with CRSwNP complain of fatigue, it is also noteworthy that patients treated with dupilumab had a greater clinically relevant im‐ provement in vitality than those treated with placebo. Compared with the placebo group, the dupilumab group had a significantly greater
improvement from baseline in the SF‐36 MCS score. The improvement in PCS score was not different between groups; this lack of difference can be attributed to the PCS scoring not being disease‐specific.
Dupilumab patients had significantly reduced loss of produc‐ tivity compared with placebo patients, based on the “reduced pro‐ ductivity” SNOT‐22 item. For the 54 employed patients, dupilumab treatment resulted in a significantly lower annualized number of sick leave days, with a relative risk reduction of 98%. These improve‐ ments in HRQoL and productivity were observed in a population that included patients with asthma and prior surgery, a group with a greater disease burden. The positive effect of dupilumab on pro‐ ductivity in this population is important, because even diseases such as allergic rhinitis are associated with a significant decline in work productivity, a decline that is even greater than that observed with diabetes mellitus and hypertension.54 The observed improvement in productivity may be linked to the observed improvement in vital‐ ity, as fatigue has been associated with lost productive work time.55 In addition, the improvement in work productivity may translate to savings in indirect costs and potentially increase the cost‐effective‐ ness of dupilumab in treating patients with CRSwNP.
It should be noted that in the subpopulation of patients who also had asthma, patient‐reported asthma control also improved during dupilumab treatment.35 Given that asthma is common in patients with CRSwNP (58% of patients in the current study had asthma) and can further worsen HRQoL,47,56,57 the effects of dupilumab on asthma control may have contributed to the positive effect on HRQoL.
A limitation of this study was the small cohort of patients avail‐ able. Similar analyses, with a larger cohort and longer duration, will allow for the assessment of the long‐term effects of dupilumab treatment over time.
5 | CONCLUSIONS
CRSwNP has a significant adverse impact on patients’ HRQoL. Beyond sino‐nasal symptoms, the disease affects overall HRQoL, physical and mental health, and productivity, including absenteeism. In this study, dupilumab added to INCS resulted in an overall improve‐ ment in patients’ HRQoL (based on both disease‐specific and generic scales), reduced sick leave days, and improved work productivity.
ACKNOWLEDGMENTS
Research was sponsored by Sanofi and Regeneron Pharmaceuticals Inc. Clinical Trials.gov Identifier: NCT01920893. Medical writing/ editorial assistance was provided by Adam J. Beech, PhD, and Bilge Yoruk, PhD, of Excerpta Medica and funded by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc.
CONFLICT OF INTEREST
Bachert C: principal investigator of the study and consultant for Sanofi. Hellings PW: No conflicts of interest to disclose. Mullol J:


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present or past member of national and international scientific ad‐ visory boards (consulting) and received fees for lectures and grants for research projects from Allakos, ALK‐Abelló, FAES, Genentech, GlaxoSmithKline, Hartington Pharmaceuticals, MYLAN/MEDA Pharma, Menarini, Merck Sharp and Dohme, Novartis, Sanofi‐ Genzyme, Regeneron Pharmaceuticals, Inc., UCB, and Uriach Group. Hamilos DL: provided consultancy for use of biolog‐ ics for chronic rhinosinusitis and nasal polyposis in Genentech, Regeneron Pharmaceuticals, Inc., and Sanofi; received grant sup‐ port for bench research from Merck and royalties from UpToDate. Gevaert P: received grant support from Sanofi. Naclerio R: member of advisory board of Genentech, Novartis, Sanofi, and ActoBiotics, and member of speaker's bureau of Optinose. Joish VN: former employee and shareholder of Regeneron Pharmaceuticals, Inc. Abbe A: former employee and shareholder of Sanofi. Taniou C: employee of Altran Technologies and contractor of Sanofi. Chao J, Amin N, and Graham NMH: employees and shareholders of Regeneron Pharmaceuticals, Inc. Mannent L, Fan C, Pirozzi G, Mahajan P, Staudinger H, and Khan A: employees and sharehold‐ ers of Sanofi.
AUTHOR CONTRIBUTIONS
CB, PH, JM, DLH, PG, and RN contributed to the study concept and design; assisted with acquisition, analysis, and interpretation of data; reviewed and provided direction for manuscript development; and provided critical feedback and final approval for submission. VNJ, JC, LM, NA, AA, CT, CF, GP, NMHG, PM, HS, and AK contributed to the study concept and design; assisted with analysis and inter‐ pretation of data; reviewed and provided direction for manuscript development; and provided critical feedback and final approval for submission.
7. Bohman A, Oscarsson M, Holmberg K, et al. Relative frequencies of symptoms and risk factors among patients with chronic rhinosinus‐ itis with nasal polyps using a case‐control study. Acta Otolaryngol. 2018;138:46‐49.
8. Van Zele T, Claeys S, Gevaert P, et al. Differentiation of chronic sinus diseases by measurement of inflammatory mediators. Allergy. 2006;61:1280‐1289.
9. Fokkens WJ, Lund VJ, Mullol J, et al. European position paper on rhinosinusitis and nasal polyps 2012. Rhinol Suppl. 2012;23:1‐299.
10. Deal RT, Kountakis SE. Significance of nasal polyps in chronic rhinosinusitis: symptoms and surgical outcomes. Laryngoscope. 2004;114:1932‐1935.
11. van der Veen J, Seys SF, Timmermans M, et al. Real‐life study show‐ ing uncontrolled rhinosinusitis after sinus surgery in a tertiary refer‐ ral centre. Allergy. 2017;72:282‐290.
12. Sahlstrand‐Johnson P, Ohlsson B, von Buchwald C, Jannert M, Ahlner‐Elmqvist M. A multi‐center study on quality of life and ab‐ senteeism in patients with CRS referred for endoscopic surgery. Rhinology. 2011;49:420‐428.
13. Stull DE, Roberts L, Frank L, Heithoff K. Relationship of nasal con‐ gestion with sleep, mood, and productivity. Curr Med Res Opin. 2007;23:811‐819.
14. Shedden A. Impact of nasal congestion on quality of life and work productivity in allergic rhinitis: findings from a large online survey. Treat Respir Med. 2005;4:439‐446.
15. Dietz de Loos D, Hopkins C, Fokkens WJ. Symptoms in chronic rhinosi‐ nusitis with and without nasal polyps. Laryngoscope. 2013;123:57‐63. 16. Rudmik L, Soler ZM, Smith TL, Mace JC, Schlosser RJ, DeConde AS. Effect of continued medical therapy on productivity costs for refractory chronic rhinosinusitis. JAMA Otolaryngol Head Neck Surg.
2015;141:969‐973.
17. Neubauer PD, Schwam AG, Manes RP. Comparison of intranasal
fluticasone spray, budesonide atomizer, and budesonide respules in patients with chronic rhinosinusitis with polyposis after endoscopic sinus surgery. Int Forum Allergy Rhinol. 2016;6:233‐237.
18. Le PT, Soler ZM, Jones R, Mattos JL, Nguyen SA, Schlosser RJ. Systematic review and meta‐analysis of SNOT‐22 outcomes after surgery for chronic rhinosinusitis with nasal polyposis. Otolaryngol Head Neck Surg. 2018;159(3):414‐423.
19. Li N, Peters AT. Chronic rhinosinusitis management beyond intra‐ nasal steroids and saline solution irrigations. Allergy Asthma Proc. 2015;36:339‐343.
20. Schlosser RJ, Smith TL, Mace J, Soler ZM. Asthma quality of life and control after sinus surgery in patients with chronic rhinosinusitis. Allergy. 2017;72:483‐491.
21. Dávila I, Rondón C, Navarro A, et al. Aeroallergen sensitization in‐ fluences quality of life and comorbidities in patients with nasal pol‐ yposis. Am J Rhinol Allergy. 2012;26.
22. Bilodeau L, Boulay ME, Prince P, Boisvert P, Boule LP. Comparative clinical and airway inflammatory features of asthma with or without nasal polyposis. Rhinology. 2010;48:420‐425.
23. Akarcay M, Ekici N, Miman MC, Firat Y, Bayindir T, Selimoglu E. Do comorbidities influence objective and subjective recovery rates of nasal polyposis? J Craniofac Surg. 2010;21:71‐74.
24. Seybt MW, McMains KC, Kountakis SE. The prevalence and effect of asthma in adults with chronic rhinosinusitis. Ear Nose Throat J. 2007;86:409‐411.
25. Matsuno O, Ono E, Takenaka R, et al. Asthma and sinusitis: associa‐ tion and implication. Int Arch Allergy Immunol. 2008;147:52‐58.
26. Tomassen P, Vandeplas G, Van Zele T, et al. Inflammatory endotypes
of chronic rhinosinusitis based on cluster analysis of biomarkers. J
Allergy Clin Immunol. 2016;137:1449‐1456.
27. Bachert C, Zhang N. Chronic rhinosinusitis and asthma: novel
understanding of the role of IgE ‘above atopy’. J Intern Med. 2012;272:133‐143.
ORCID
Claus Bachert
REFERENCES
https://orcid.org/0000‐0003‐4742‐1665
1. Blackwell DL, Lucas JW, Clarke TC. Summary health statistics for U.S. adults: national health interview survey, 2012. Vital Health Stat. 2014;10:1‐161.
2. Hastan D, Fokkens WJ, Bachert C, et al. Chronic rhinosinusitis in Europe—an underestimated disease. A GALEN study. Allergy. 2011;66:1216‐1223.
3. Settipane GA, Chafee FH. Nasal polyps in asthma and rhinitis. A review of 6,037 patients. J Allergy Clin Immunol. 1977;59:17‐21.
4. Klossek JM, Neukirch F, Pribil C, et al. Prevalence of nasal pol‐
yposis in France: a cross‐sectional case‐control study. Allergy.
2005;60:233‐237.
5. Hedman J, Kaprio J, Poussa T, Nieminen MM. Prevalence of
asthma, aspirin intolerance, nasal polyposis and chronic obstruc‐ tive pulmonary disease in a population‐based study. Int J Epidemiol. 1999;28:717‐722.
6. Zhang Y, Gevaert E, Lou H, et al. Chronic rhinosinusitis in Asia. J Allergy Clin Immunol. 2017;140:1230‐1239.


BACHERT ET Al.
| 157
28. Macdonald LE, Karow M, Stevens S, et al. Precise and in situ ge‐ netic humanization of 6 Mb of mouse immunoglobulin genes. PNAS. 2014;111:5147‐5152.
29. Murphy AJ, Macdonald LE, Stevens S, et al. Mice with megabase humanization of their immunoglobulin genes generate antibodies as efficiently as normal mice. PNAS. 2014;111:5153‐5158.
30. Blauvelt A, de Bruin‐Weller M, Gooderham M, et al. Long‐term man‐ agement of moderate‐to‐severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1‐year, randomised, double‐blinded, placebo‐controlled, phase 3 trial. Lancet. 2017;389:2287‐2303.
31. Simpson EL, Bieber T, Guttman‐Yassky E, et al. Two phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med. 2016;375:2335‐2348.
32. Thaçi D, Simpson EL, Beck LA, et al. Efficacy and safety of dupilumab in adults with moderate‐to‐severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo‐controlled, dose‐ranging phase 2b trial. Lancet. 2016;387:40‐52.
33. Castro M, Corren J, Pavord ID, et al. Dupilumab efficacy and safety in moderate‐to‐severe uncontrolled asthma. N Engl J Med. 2018;378:2486‐2496.
34. Rabe KF, Nair P, Brusselle G, et al. Efficacy and safety of dupi‐ lumab in glucocorticoid‐dependent severe asthma. N Engl J Med. 2018;378:2475‐2485.
35. Bachert C, Mannent L, Naclerio RM, et al. Effect of subcutane‐ ous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: a randomized clinical trial. JAMA. 2016;315:469‐479.
36. Beck LA, Thaçi D, Hamilton JD, et al. Dupilumab treatment in adults with moderate‐to‐severe atopic dermatitis. N Engl J Med. 2014;371:130‐139.
37. Wenzel S, Castro M, Corren J, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of me‐ dium‐to‐high‐dose inhaled corticosteroids plus a long‐acting β2 ag‐ onist: a randomized double‐blind placebo‐controlled pivotal phase 2b dose‐ranging trial. Lancet. 2016;388:31‐44.
38. Juniper EF, Svensson K, Mörk AC, Ståhl E. Measurement properties and interpretation of three shortened versions of the asthma con‐ trol questionnaire. Respir Med. 2005;99:553‐558.
39. Gevaert P, Van Bruaene N, Cattaert T, et al. Mepolizumab, a human‐ ized anti‐IL‐5 mAb, as a treatment option for severe nasal polyposis. J Allergy Clin Immunol. 2011;128:989‐995.
40. EuroQol Group. EuroQol–a new facility for the measurement of health‐related quality of life. Health Policy. 1990;16:199‐208.
41. Ware JE Jr. Sherbourne CD. The MOS 36‐item short‐form health survey (SF‐36). I. Conceptual framework and item selection. Med Care. 1992;30:473‐483.
42. Maruish ME ed. User's Manual for the SF‐36v2 Health Survey (3rd ed). Lincoln, RI: QualityMetric Incorporated; 2011.
43. Bachert C, Hellings P, Mullol J, et al. Dupilumab improves health‐ related quality of life and absenteeism in nasal polyposis patients: results from a phase 2a trial. Allergy. 2016;71(Suppl 102):1‐665.
44. Coon CD, Cappelleri JC. Interpreting change in scores on pa‐ tient‐reported outcome instruments. Therapeutic Innov Regul Sci. 2016;50:22‐29.
45. Hopkins C, Gillett S, Slack R, Lund VJ, Browne JP. Psychometric validity of the 22‐item SinoNasal Outcome Test. Clin Otolaryngol. 2009;34:447‐454.
46. Remenschneider AK, D'Amico L, Gray ST, Holbrook EH, Gliklich RE, Metson R. The EQ‐5D: a new tool for studying clinical outcomes in chronic rhinosinusitis. Laryngoscope. 2015;125:7‐15.
47. Rudmik L, Smith TL. Quality of life in patients with chronic rhinosi‐ nusitis. Curr Allergy Asthma Rep. 2011;11:247‐252.
48. Banglawala SM, Oyer SL, Lohia S, Psaltis AJ, Soler ZM, Schlosser RJ. Olfactory outcomes in chronic rhinosinusitis with nasal polyposis after medical treatments: a systematic review and meta‐analysis. Int Forum Allergy Rhinol. 2014;4:986‐994.
49. Croy I, Nordin S, Hummel T. Olfactory disorders and quality of life— an updated review. Chem Senses. 2014;39:185‐194.
50. Nordin S, Hedén Blomqvist E, Olsson P, Stjärne P, Ehnhage A; NAF2S2 Study Group. Effects of smell loss on daily life and adopted coping strategies in patients with nasal polyposis with asthma. Acta Otolaryngol. 2011;131:826‐832.
51. Simopoulos E, Katotomichelakis M, Gouveris H, Tripsianis G, Livaditis M, Danielides V. Olfaction‐associated quality of life in chronic rhinosinusitis: adaptation and validation of an olfaction‐ specific questionnaire. Laryngoscope. 2012;122:1450‐1454.
52. Alt JA, Smith TL, Mace JC, Soler ZM. Sleep quality and disease severity in patients with chronic rhinosinusitis. Laryngoscope. 2013;123:2364‐2370.
53. Hopkins C, Philpott C, Crowe S, et al. Identifying the most import‐ ant outcomes for systematic reviews of interventions for rhinosi‐ nusitis in adults: working with patients, public and practitioners. Rhinology. 2016;54:20‐26.
54. de la Hoz CB, Rodríguez M, Fraj J, Cerecedo I, Antolín‐Amérigo D, Colás C. Allergic rhinitis and its impact on work productivity in pri‐ mary care practice and a comparison with other common diseases: the cross‐sectional study to evaluate work productivity in allergic rhinitis compared with other common diseases (CAPRI) study. Am J Rhinol Allergy. 2012;26:390‐394.
55. Ricci JA, Chee E, Lorandeau AL, Berger J. Fatigue in the U.S. work‐ force: prevalence and implications for lost productive work time. J Occup Environ Med. 2007;49:1‐10.
56. Mullol J, Picado C. Rhinosinusitis and nasal polyps in aspirin‐ exacerbated respiratory disease. Immunol Allergy Clin N Am. 2013;33:163‐176.
57. Alobid I, Benitez P, Bernal‐Sprekelsen M, Guilemany JM, Picado C, Mullol J. The impact of asthma and aspirin sensitivity on quality of life of patients with nasal polyposis. Qual Life Res. 2005;14:789‐793.
SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting Information section at the end of the article.
How to cite this article: Bachert C, Hellings PW, Mullol J, et al. Dupilumab improves health‐related quality of life in patients with chronic rhinosinusitis with nasal polyposis. Allergy. 2020;75:148–157. https://doi.org/10.1111/all.13984