Original Article

Mepolizumab Reduces Systemic Corticosteroid Use

in Chronic Rhinosinusitis With Nasal Polyps
Geoffrey Chupp, MDa, Isam Alobid, MD, PhDb,c,d,e, Njira L. Lugogo, MD, MSf, Harsha H. Kariyawasam, MD, PhDg,
Arnaud Bourdin, MD, PhDh,i, Adam M. Chaker, MDj, Steven G. Smith, PhDk, Ana R. Sousa, PhDl, Bhabita Mayer, MScm,
Robert H. Chan, MDl, and Andrea Matucci, MDn Conn; Barcelona, Spain; Ann Arbor, Mich; London and Middlesex, United
Kingdom; Montpellier, France; Munich, Germany; Durham, NC; and Florence, Italy

What is already known about this topic? In the phase III SYNAPSE trial, mepolizumab versus placebo significantly
reduced nasal polyp size and sinonasal symptoms, sinus surgery occurrence, and systemic corticosteroid (SCS) use in
patients with severe chronic rhinosinusitis with nasal polyps.

What does this article add to our knowledge? This article demonstrates that mepolizumab versus placebo is
associated with improved treatment responses irrespective of prior SCS use, and SCS-sparing capabilities, overall and in
patients with differing clinical characteristics.

How does this study impact current management guidelines? Given the adverse effects associated with SCS use,
mepolizumab could be used to reduce reliance on SCSs and the associated adverse effect burden of SCSs in patients
with recurrent, refractory, severe chronic rhinosinusitis with nasal polyps.

VISUAL SUMMARY

e
Unidad Alergo Rino, Centro Medico Teknon, Barcelona, Spain
a f
Department of Internal Medicine, Yale School of Medicine, New Haven, Conn Department of Medicine, University of Michigan, Ann Arbor, Mich
b g
Department of Otorhinolaryngology, Universitat de Barcelona, Barcelona, Spain Royal National ENT Hospital, UCLH London, London, United Kingdom
c h
Institut d Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Departement de Pneumologie et Addictologie, Hôpital Arnaud de Villeneuve, CHU
Spain Montpellier, Montpellier, France
d i
Centro de Investigacion Biomedica en Red de Enfermedades Respiratorias University of Montpellier, Montpellier, France
(CIBERES), Barcelona, Spain

3504
J ALLERGY CLIN IMMUNOL PRACT CHUPP ET AL 3505
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estimate [95% CI]) was lower with mepolizumab (25.4%

Abbreviations used [20.0-32.1]) versus placebo (37.5% [31.1-44.6]). In patients
CRSwNP- chronic rhinosinusitis with nasal polyps requiring 1 or more dose of SCSs, total (mean – SD mg/y)
NP- nasal polyp prednisolone-equivalent oral corticosteroid dose was lower with
OCS- oral corticosteroid mepolizumab (438.9 – 350.40) versus placebo (505.2 –
SCS- systemic corticosteroid
455.091), overall and irrespective of prior sinus surgeries, blood
SNOT-22- 22-item Sino-Nasal Outcome Test
VAS- visual analog scale
eosinophil count, or comorbidities.
CONCLUSIONS: Mepolizumab is associated with clinical
benefits in patients with severe chronic rhinosinusitis with nasal
polyps regardless of prior SCS use and has an SCS-sparing
BACKGROUND: Systemic corticosteroids (SCSs) are associated effect. Ó 2023 Published by Elsevier Inc. on behalf of the
with short- and long-term adverse effects. American Academy of Allergy, Asthma & Immunology. This is
OBJECTIVE: To assess mepolizumab efficacy according to prior an open access article under the CC BY license (http://
SCS use and characterize mepolizumab’s SCS-sparing capabil- creativecommons.org/licenses/by/4.0/). (J Allergy Clin Immunol
ities, in patients with severe chronic rhinosinusitis with nasal Pract 2023;11:3504-12)
polyps. Key words: Asthma; Mepolizumab; AERD; Aspirin-exacerbated
METHODS: In the randomized, double-blind, phase respiratory disease; Refractory disease; Severe chronic rhinosi-
III SYNAPSE trial (NCT03085797), adults with severe chronic nusitis with nasal polyps; Subgroup analysis; Systemic
rhinosinusitis with nasal polyps eligible for repeat sinus surgery corticosteroids
despite standard of care treatment received mepolizumab (100
mg subcutaneously) or placebo every 4 weeks for 52 weeks. The
impact of prior SCS courses (0/1/>1) on mepolizumab versus INTRODUCTION
placebo treatment responses (changes from baseline in total Chronic rhinosinusitis with nasal polyps (CRSwNP) is a
endoscopic nasal polyp [week 52], nasal obstruction visual subtype of CRS characterized by inflammation of the nose and
analog scale [weeks 49-52], and 22-item Sino-Nasal Outcome paranasal sinuses.1,2 Type 2, predominantly eosinophilic
Test total [week 52] scores) was analyzed post hoc. To charac- inflammation is a common feature of CRSwNP, with other
terize mepolizumab’s SCS-sparing capabilities, time-to-first SCS immunologic subtypes often present.3,4 For patients, CRSwNP
course for nasal polyps (prespecified) and total prednisolone- is often severe in nature and has a substantial negative impact on
equivalent oral corticosteroid dose by patient baseline charac- sleep5,6 along with health-related quality-of-life impairments
teristics (post hoc, in patients with ‡1 SCS course during similar to those of other chronic diseases such as diabetes, chronic
SYNAPSE) were assessed up to week 52. obstructive pulmonary disease, and asthma.7-9
RESULTS: Mepolizumab versus placebo improved treatment For patients with uncontrolled severe disease despite treatment
responses, irrespective of prior SCS use. By week 52, the with nasal lavage and intranasal corticosteroids, the standard
probability of requiring SCSs for nasal polyps (Kaplan-Meier treatment approach is administration of single or recurrent

j
Technical University of Munich, TUM School of Medicine, Klinikum rechts der Isar, Novartis, LETI, Roche, Zeller, Federal German Ministry of Education and
Department of Otolaryngology and Center for Allergy and Environment, Munich, Research, and the European Institute of Technology; advisory board/speaker fees
Germany via Technical University Munich from Allegropharma, ALK-Abelló, AstraZeneca,
k
Clinical Sciences, GSK, Durham, NC Bencard/Allergen Therapeutics, GSK, Immunotech, Lofarma, Novartis, LETI,
l
Clinical Sciences, GSK R&D, Brentford, Middlesex, United Kingdom Sanofi Genzyme/Regeneron, and Zeller; is a Board Member for the European
m
Clinical Statistics, GSK, Brentford, Middlesex, United Kingdom Academy of Allergy and Clinical Immunology, European Forum of Research and
n
Immunoallergology Unit, University Careggi Hospital of Florence, Florence, Italy Education in Allergy and Airway Disease, and German Society of Allergy and
This study was funded by GSK (GSK ID: 205687; NCT03085797). Clinical Immunology; and is also Scientific Advisor for the German Society of
Conflicts of interest: G. Chupp has received advisory board fees, speaking fees, and Applied Allergy, and former Chair of the German Society of Otorhinolaryngology
research grants from GSK, AstraZeneca, Genentech, Sanofi Genzyme, Regeneron, and Head and Neck Surgery. S. G. Smith, A. R. Sousa, B. Mayer, and R. H. Chan
Teva, and Novartis. I. Alobid has received advisory board fees and consultation are employees of GSK and own stocks/shares. A. Matucci has received speaker’s
fees from Maylan, Menarini, GSK, MSD, Novartis, Sanofi, and Roche. N. L. honoraria from AstraZeneca, Novartis, and GSK, and honoraria for attending
Lugogo reports receiving non-speaker fees from Amgen, AstraZeneca, Avillion, advisory panels with Sanofi, AstraZeneca, GSK, Novartis, and Chiesi.
Genentech, GSK, Novartis, Regeneron, Sanofi, Teva; honoraria for nonspeaker Data sharing statement: GSK makes available anonymized individual participant data
bureau presentations from GSK and AstraZeneca; and travel support from Astra- and associated documents from interventional clinical studies that evaluate medi-
Zeneca; her institution has received research support from Amgen, AstraZeneca, cines, on approval of proposals submitted to https://www.gsk-studyregister.com/
Avillion, Evidera, Gossamer Bio, Genentech, GSK, Regeneron, Sanofi, Novartis, en/.
and Teva; and she is an honorary faculty member of the Observational and Received for publication March 8, 2023; revised July 28, 2023; accepted for publi-
Pragmatic Research Institute but does not receive compensation for this role. H. H. cation August 6, 2023.
Kariyawasam has received speaker fees and conference attendance support from Available online August 14, 2023.
GSK. A. Bourdin has received research grants and consulting fees from Astra- Corresponding author: Geoffrey Chupp, MD, TAC 441, 300 Cedar St, Department of
Zeneca-MedImmune, Boehringer Ingelheim, Cephalon/Teva, GSK, Novartis, and Internal Medicine, New Haven, CT 06520. E-mail: [email protected].
Sanofi-Regeneron; consulting fees from Med-in-Cell, Actelion, Merck, Roche, and 2213-2198
Chiesi; and is an investigator/coinvestigator for trials promoted by AstraZeneca- Ó 2023 Published by Elsevier Inc. on behalf of the American Academy of Allergy,
MedImmune, Boehringer Ingelheim, GSK, Novartis, Sanofi/Regeneron, Chiesi, Asthma & Immunology. This is an open access article under the CC BY license
Actelion, Merck, Roche, Vertex, and Galapagos. A. M. Chaker has received (http://creativecommons.org/licenses/by/4.0/).
research grants via Technical University Munich from Allegropharma, ALK- https://doi.org/10.1016/j.jaip.2023.08.015
Abelló, AstraZeneca, Bencard/Allergen Therapeutics, ASIT Biotech, GSK,
3506 CHUPP ET AL J ALLERGY CLIN IMMUNOL PRACT
NOVEMBER 2023

courses of systemic corticosteroids (SCSs).10 However, SCS use The trial was conducted in accordance with the ethical principles of
has several limitations. For example, both short- and long-term the Declaration of Helsinki, Good Clinical Practice guidelines from
SCS exposure is associated with adverse effects including the International Conference on Harmonisation, and any applicable
osteoporosis, pneumonia, cardiovascular/cerebrovascular effects, country-specific regulatory requirements. All patients provided written
cataract, and depression/anxiety,11-15 the management of which informed consent before study initiation. The study was approved by
can result in a substantial economic burden.16 A cumulative local ethics review boards at the participating sites. The protocol is
exposure of 500 mg to less than 1000 mg SCSs is also associated available at https://www.gsk-studyregister.com/.
with an increased risk for adverse effects compared with
exposures of more than 0 mg to less than 500 mg.17 Patients
Furthermore, some patients with CRSwNP fail to achieve Full inclusion and exclusion criteria have been published
adequate disease control with SCSs.8,18 For these patients, sinus previously.32 Eligible patients were 18 years or older with recurrent,
surgery may be indicated10; however, the long-term recurrence refractory, severe bilateral NPs (defined as nasal obstruction VAS
rate following sinus surgery is high, particularly in patients with symptom score of more than 5 [maximum 10]) who were eligible for
eosinophil-rich endotypes.19,20 In 2 studies of patients with repeat surgery, as evidenced by an overall VAS symptom score of
CRSwNP who had undergone sinus surgery, disease recurrence more than 7 (maximum 10) and endoscopic bilateral NP score of 5
was reported in 79% and 82% of patients within 12 years of or more (maximum 8), with a score of 2 or more in each nasal cavity,
follow-up.19,21 Given the substantial burden associated with SCS despite standard of care treatment. Patients had to have 1 or more
use, biologic therapies directly or indirectly targeting eosinophils sinus surgery (defined as any incision of the paranasal sinuses and
have the potential to reduce SCS use in dependent patients, as removal of polyp tissue from the nasal cavity [polypectomy] and the
has been demonstrated in other eosinophilic diseases.22-26 sinuses) in the previous 10 years. In addition, patients had received
Mepolizumab is a humanized monoclonal antibodies that tar- stable maintenance therapy with intranasal spray (mometasone
gets IL-5, thereby blocking the proliferation, differentiation, furoate) for 8 weeks or more before screening and displayed 2 or
activation, and survival of eosinophils.27 Mepolizumab is associ- more different sinonasal symptoms for 12 weeks or more before
ated with a range of clinical benefits in a number of eosinophilic screening (nasal blockage, obstruction or congestion, and/or nasal
diseases, including a reduced risk of exacerbations, improvement in discharge [anterior or posterior nasal drip], with 1 or more of the
symptom control and health-related quality of life, as well as having following: nasal discharge, facial pain or pressure, and/or a reduction
an SCS-sparing effect in severe eosinophilic asthma; increased time in or loss of smell). CS use was not permitted in the 4 weeks before
in remission and higher proportions of patients with remission in screening. Patients were not eligible for randomization if there were
eosinophilic granulomatosis with polyangiitis; and a reduced changes in their CRSwNP maintenance therapy during the run-in
occurrence of flares in hypereosinophilic syndrome.22,26,28-31 In period, including changes in or addition of an intranasal cortico-
the landmark randomized, placebo-controlled, phase III SYN- steroid, a short-burst course of an SCS, a leukotriene receptor
APSE trial, mepolizumab significantly improved nasal polyp (NP) antagonist, or allergen immunotherapy. Only short courses of SCSs
size (total endoscopic NP score) and nasal obstruction (nasal were permitted during the study. Patients were excluded if they had
obstruction visual analog scale [VAS] score10) compared with received biologic or immunosuppressive treatment within 5 terminal
placebo in patients with recurrent, refractory CRSwNP in need of phase half-lives of screening.
repeat surgery, as well as significantly reducing the occurrence of
sinus surgery and the use of SCSs, and improving health-related End points and assessments
quality of life as assessed with the 22-item Sino-Nasal Outcome To assess the impact of prior SCS use on treatment response and
Test (SNOT-22).32 As a result, mepolizumab is now approved for the need for surgery, changes from baseline in total endoscopic NP
the treatment of severe eosinophilic asthma, CRSwNP, eosino- score at week 52, nasal obstruction VAS score at weeks 49 to
philic granulomatosis with polyangiitis, and hypereosinophilic 52, SNOT-22 total score at week 52, and time-to-first sinus surgery
syndrome in multiple regions worldwide.33-35 The objective of this up to week 52 were analyzed post hoc by the number of SCS courses
analysis was to explore the relationship between prior SCS use and in the year before enrollment (0, 1, >1).
treatment response, and to characterize the SCS-sparing effect of To assess the SCS-sparing effect of mepolizumab, prespecified
mepolizumab in patients with CRSwNP. end points relating to SCS use during the study included the
proportion of patients requiring 1 or more course of SCSs for NPs,
the total number of SCS courses for NPs, and time-to-first SCS
METHODS course for NPs, all up to week 52 in the intent-to-treat popula-
Study design tion. Among patients with 1 or more SCS course during the study,
Full details of the SYNAPSE study have been described end points included the total dose (mg/y) of prednisolone-
previously.32 In brief, SYNAPSE was a phase III randomized, equivalent oral corticosteroid (OCS) for NPs (post hoc analysis),
double-blind, placebo-controlled, parallel-group, multicenter trial the proportion of patients receiving distinct dose categories of
(GSK ID: 205687; NCT03085797). Patients were randomized prednisolone-equivalent OCSs for NPs (prespecified analysis;
(1:1) to receive mepolizumab 100 mg or placebo subcutaneously categories: >0-100 mg/y, >100-200 mg/y, >200-300 mg/y,
every 4 weeks, for 52 weeks, in addition to standard of care >300-400 mg/y, >400-500 mg/y, >500-600 mg/y, and
(daily mometasone furoate nasal spray and, if required, saline nasal >600 mg/y) and the total number of days on SCSs for NPs
lavage, and short courses of high-dose SCSs and/or antibiotics). The (prespecified analysis), all up to week 52.
use of SCSs was based on the treating physician’s assessment of To assess the potential impact of patient clinical characteristics on
clinical need and driven by clinical guidance. Patients maintained the SCS-sparing effect of mepolizumab, prespecified analyses
standard of care throughout the study period, and SCS rescue included the proportion of patients requiring SCSs for NPs up to
medication use was permitted at any time during the study. week 52 by the number of prior sinus surgeries (1, 2, >2), blood
J ALLERGY CLIN IMMUNOL PRACT CHUPP ET AL 3507
VOLUME 11, NUMBER 11

eosinophil count (
300, 300-
500, >500-
700, >700 cells/ Figure 1 shows the time-to-first course of SCSs for NPs over
mL), comorbid asthma (yes, no), and comorbid AERD (yes, no). Post the 52-week treatment period; the probability of requiring an
hoc analyses included total dose (mg/y) of prednisone-equivalent initial course of SCSs for NPs by week 52 was lower in the
OCSs for NPs up to week 52 by the number of prior sinus mepolizumab group (25.4%; 95% CI, 20.0-32.1) than in the
surgeries (1, 2, >2), blood eosinophil count (<150 cells/mL, 150 placebo group (37.5%; 95% CI, 31.1-44.6).
cells/mL, <300 cells/mL, 300 cells/mL; different thresholds used vs Among patients with 1 or more SCS course for NPs during
prespecified analyses, owing to small patient numbers), comorbid the study, mepolizumab treatment reduced the mean  SD
asthma (yes, no), and comorbid AERD (yes, no). Safety data during total prednisolone-equivalent OCS dose for NPs (438.9 
SYNAPSE have been previously published.32 350.4 mg/y) versus placebo (505.2  455.1 mg/y). Furthermore,
smaller proportions of patients treated with mepolizumab versus
Sample size and statistical analysis placebo received more than 200 mg/y (Figure 2), and more than
All data reported up to week 52 were included in the analysis, 200 to 300 mg/y and more than 400 to 500 mg/y of
regardless of treatment discontinuation. Sample size calculations and prednisolone-equivalent OCSs for NPs (see Table E1 in this
the hierarchical testing of secondary end points have been described article’s Online Repository at www.jaci-inpractice.org). Patients
previously.32 For the purposes of this study, courses of SCSs less receiving mepolizumab spent a similar number of days on SCSs
than 7 days apart were considered as 1 course. Within a subgroup, to those receiving placebo (mean  SD, 15.7  11.9 vs 19.0 
total endoscopic NP score, nasal obstruction VAS score, SNOT-22 18.5 days). One patient receiving mepolizumab with reported
total score, and estimates of the treatment effect accounting for SCS use for 335 days was considered an outlier and was excluded
covariates of treatment group, geographical region, baseline score, from this analysis, because all other mepolizumab-treated
and loge baseline blood eosinophil count (if applicable) were patients had used SCSs for 51 days or less.
presented as a difference in medians based on a quantile regression
model.36,37 Within a subgroup, the proportion of patients requiring Impact of baseline characteristics on the
SCSs for NPs was analyzed using a logistic regression model with SCS-sparing effect of mepolizumab
covariates of treatment group, baseline NP score (centrally read), The proportion of patients receiving 1 or more SCS course
baseline nasal obstruction VAS score, loge baseline blood eosinophil during the 52-week study period was lower with mepolizumab
count (if applicable), number of SCS courses in the previous than with placebo in patients with blood eosinophil counts less
12 months (0, 1, >1; ordinal), and geographic region. Time-to-first than or equal to 300 cells/mL, more than 300 to less than or
SCS course was determined using Kaplan-Meier estimates. All data equal to 500, and more than or equal to 700 cells/mL, in patients
were analyzed using SAS v 9.4 (SAS Institute, Inc, Cary, NC). with 1 or more than 2 previous surgeries, and in patients with or
without comorbid asthma and in patients with or without
comorbid AERD (Figure 3). The total prednisolone-equivalent
RESULTS
OCS dose during the study was reduced with mepolizumab
Patient population
versus placebo in patients with 1 or more than 2 previous
A total of 407 patients were included in the SYNAPSE intent-
surgeries and baseline blood eosinophil counts of less than 150
to-treat population; 206 received mepolizumab and 201 received
cells/mL, more than or equal to 150 cells/mL, and more than or
placebo. The demographic and clinical characteristics of these
equal to 300 cells/mL, and in patients with and without
patients have been previously reported.32 In the year before the
comorbid asthma and comorbid AERD (Table II).
study, 52% (n ¼ 210) of patients had not received a course of
SCSs for NPs, with 27% (n ¼ 111) receiving 1 course and 21%
(n ¼ 86) more than 1 course. DISCUSSION
The phase III SYNAPSE study demonstrated the efficacy and
Treatment response by prior SCS use safety of mepolizumab versus placebo among patients with
Improvements in total endoscopic NP score at week 52, nasal recurrent, refractory, severe, bilateral CRSwNP eligible for repeat
obstruction VAS score at weeks 49 to 52, and SNOT-22 total surgery.32 SYNAPSE patients receiving mepolizumab experienced
score at week 52 with mepolizumab versus placebo were largest a range of clinical benefits including reduced polyp size, improved
in the subgroup of patients with 1 SCS course in the year before nasal obstruction, and a reduced need for sinus surgery and
the study (Table I; see Figure E1 in this article’s Online SCSs.32 This analysis demonstrated that clinical improvements
Repository at www.jaci-inpractice.org). The proportion of were consistently observed with mepolizumab versus placebo in
patients requiring sinus surgery up to week 52 was consistently SYNAPSE patients, irrespective of baseline SCS use. In addition,
lower with mepolizumab than with placebo across all baseline the reduction in SCS use previously shown with mepolizumab
SCS use subgroups, with the largest benefit in patients with more during SYNAPSE was further characterized; mepolizumab versus
than 1 SCS course in the year before the study (Table I). placebo treatment was associated with a reduced probability of
requiring SCSs for NPs during the study. In patients with 1 or
SCS-sparing effect of mepolizumab more SCS course, the prednisolone-equivalent OCS dose was also
As previously reported, the proportion of patients requiring reduced with mepolizumab versus placebo treatment. These data
1 or more course of SCSs for NPs during the study was also show consistent reductions in SCS use across patients with
lower with mepolizumab (n ¼ 52 of 206 [25%]) versus placebo varying clinical characteristics, including differing numbers of
(n ¼ 74 of 201 [37%]).32 Mepolizumab significantly reduced previous surgeries, a range of baseline blood eosinophil counts,
the odds of patients requiring 1 or more SCS course for NPs and those with and without comorbid asthma or comorbid
(odds ratio, 0.58; 95% CI, 0.36-0.92; P ¼ .02), with AERD. Together, these data demonstrate a range of clinical
mepolizumab-treated patients receiving a total of 82 courses benefits with mepolizumab regardless of prior SCS use and pro-
compared with a total of 124 courses in the placebo group.32 vide support for the SCS-sparing effects of mepolizumab in
3508 CHUPP ET AL J ALLERGY CLIN IMMUNOL PRACT
NOVEMBER 2023

TABLE I. Study outcomes by number of SCS courses received in the year before study entry
0 SCS course in the 1 SCS course in the >1 SCS course in the
year before the study year before the study year before the study
Placebo Mepolizumab Placebo Mepolizumab Placebo Mepolizumab
Outcome (N [ 201) (N [ 206) (N [ 201) (N [ 206) (N [ 201) (N [ 206)
Change from baseline in total endoscopic NP score at week 52*
n 110 100 47 64 44 42
5-point improvement, n (%) 1 (<1) 3 (3) 0 2 (3) 1 (2) 1 (2)
4-point improvement, n (%) 2 (2) 7 (7) 1 (2) 4 (6) 2 (5) 5 (12)
3-point improvement, n (%) 7 (6) 15 (15) 3 (6) 6 (9) 1 (2) 2 (5)
2-point improvement, n (%) 5 (5) 11 (11) 1 (2) 12 (19) 2 (5) 6 (14)
1-point improvement, n (%) 19 (17) 11 (11) 7 (15) 14 (22) 5 (11) 5 (12)
No change, n (%) 41 (37) 30 (30) 21 (45) 17 (27) 21 (48) 10 (24)
Worsening, n (%) 35 (32) 23 (23) 14 (30) 9 (14) 12 (27) 13 (31)
Median change from baseline 0.0 0.0 0.0 1.0 0.0 0.0
Difference in medians (95% CI) 0.52 (1.01 to 0.04) 1.00 (1.51 to 0.49) 0.43 (1.25 to 0.39)
Change from baseline in nasal obstruction VAS score at weeks 49-52*
n 110 100 47 64 44 42
>5-point improvement 25 (23) 46 (46) 11 (23) 31 (48) 10 (23) 14 (33)
>3- to 5-point improvement 19 (17) 13 (13) 4 (9) 9 (14) 4 (9) 11 (26)
>1- to 3-point improvement 20 (18) 10 (10) 4 (9) 5 (8) 3 (7) 7 (17)

1-point improvement to
1-point worsening 44 (40) 29 (29) 25 (53) 18 (28) 26 (59) 10 (24)
>1-point worsening 2 (2) 2 (2) 3 (6) 1 (2) 1 (2) 0
Median change from baseline 1.75 4.55 0.04 4.83 0.03 3.80
Difference in medians (95% CI) 2.55 (4.17 to 0.92) 3.72 (5.49 to 1.95) 3.55 (5.18 to 1.92)
Change from baseline in SNOT-22 total score at week 52* (MCID, 8.9-point improvement)38
n 110 100 47 64 44 42
45-point improvement 17 (16) 29 (29) 4 (9) 21 (33) 5 (11) 6 (15)
36- to 44-point improvement 6 (6) 16 (16) 3 (7) 7 (11) 1 (2) 7 (17)
27- to 35-point improvement 15 (14) 10 (10) 10 (22) 13 (20) 5 (11) 5 (12)
18- to 26-point improvement 15 (14) 11 (11) 2 (4) 5 (8) 5 (11) 6 (15)
9- to 17-point improvement 10 (9) 7 (7) 5 (11) 2 (3) 3 (7) 5 (12)
1- to 8-point improvement 8 (7) 3 (3) 2 (4) 3 (5) 3 (7) 2 (5)
No change 16 (15) 16 (16) 7 (15) 7 (11) 11 (25) 7 (17)
Worsening 21 (19) 8 (8) 13 (28) 6 (9) 11 (25) 3 (7)
Median change from baseline 16.50 31.00 10.00 32.00 1.50 22.00
Difference in medians (95% CI) 17.02 (26.16 to 7.88) 22.57 (39.16 to 5.98) 16.16 (27.67 to 4.65)
Time to first sinus surgery
Sinus surgery up to week 52, n (%) 21 (19) 9 (9) 13 (28) 6 (9) 12 (27) 3 (7)
Hazard ratio,† mepolizumab/placebo (95% CI) 0.62 (0.27 to 1.39) 0.30 (0.10 to 0.86) 0.17 (0.04 to 0.68)

CI, Confidence interval; MCID, minimal clinically important difference; NP, nasal polyps; SCS, systemic corticosteroid; SNOT-22, sino-nasal outcomes test-22; VAS, visual
analog scale.
*Patients with sinus surgery before time period are assigned their worst observed score before sinus surgery; patients with no sinus surgery who withdrew from study before visit
are assigned their worst observed score before study withdrawal; patients with missing visit data are assigned their worst observed score before the missing visit; Quantile
regression with covariates of treatment group, geographic region, baseline score, and log(e) baseline blood eosinophil count.
†Estimated from a Cox proportional hazards model with covariates of treatment group, geographic region, baseline total endoscopic score (centrally read), baseline nasal
obstruction VAS score, log(e) baseline blood eosinophil count, and number of previous surgeries (1, 2, >2 as ordinal).

patients with recurrent, refractory CRSwNP. These findings are previous year than in those who did not receive SCS in the year
consistent with the clinical benefits and SCS-sparing effects of before the study, possibly reflecting greater disease severity in
mepolizumab previously demonstrated in patients with severe the patients requiring SCSs and therefore greater room for
eosinophilic asthma.22,30 clinical improvement. However, this upward trend did not
This analysis assessed the impact of SCS use in the year continue in those with more than 1 SCS course in the previous
before SYNAPSE on several study outcomes. Mepolizumab year, which may be due to the low number of patients in this
improved total endoscopic NP score, nasal obstruction VAS subgroup. The reduction in occurrence of sinus surgery with
score, and SNOT-22 total score versus placebo across sub- mepolizumab versus placebo increased with increasing number
groups of patients with 0, 1, and more than 1 SCS courses in of SCS courses in the year before the study, again likely
the year before the study. Between-group differences were reflecting disease severity in the subgroups with greater SCS
consistently higher in patients with 1 SCS course during the dependence.
J ALLERGY CLIN IMMUNOL PRACT CHUPP ET AL 3509
VOLUME 11, NUMBER 11

FIGURE 1. Time to first course of SCSs for NPs up to week 52 (ITT population). Vertical bars represent 95% CI. CI, Confidence interval;
ITT, intent-to-treat; NP, nasal polyps; SC, subcutaneous; SCS, systemic corticosteroids.

FIGURE 2. Prednisolone-equivalent OCS dose category for NPs during the 52-week treatment period in patients receiving 1 or more
course of SCSs during the study. *Percentages calculated on the basis of 71 patients in the placebo group and 51 patients in the
mepolizumab group with 1 or more course of SCSs during the study and with available OCS-dose data. NP, Nasal polyps; OCS, oral
corticosteroid; SC, subcutaneous; SCS, systemic corticosteroid.

Approximately half the patients enrolled in SYNAPSE need for SCS use during the study. Notably, the response to
required at least 1 course of SCSs and more than 20% needed at mepolizumab was variable, with most but not all patients in the
least 2 courses of SCSs in the year before the study, highlighting mepolizumab group completing the study without the need for
that many were failing to achieve adequate disease control with SCSs. Given the multiple inflammatory subtypes known to be
standard of care therapy. During SYNAPSE, 75% of patients present among patients with CRSwNP,4 it is tempting to
treated with mepolizumab received no courses of SCSs, speculate that patients who required SCSs during the study had a
compared with 63% of patients receiving placebo. For these complex mix of inflammatory pathways contributing to their
patients, the reduced risk of SCS-associated adverse effects is an disease, including high levels of inflammation also driven by IgE,
important benefit, given the high burden they bear.11-15 More- for example. All SYNAPSE patients had eosinophilic CRSwNP
over, completing the 52-week study period with no SCS use is in based on their baseline blood eosinophil counts; however, further
line with treatment goals recommended in the most recent Eu- research is needed to understand the relationship between blood
ropean Position Paper on Rhinosinusitis and Nasal Polyps, which and tissue levels of eosinophils and IL-5 in patients with
include minimizing SCS courses to 2 or fewer per year in patients CRSwNP. Investigation of other outcomes, such as olfaction, in
with partially controlled or uncontrolled NP.10 the subset of patients who required SCSs despite mepolizumab
The baseline characteristics subgroup analysis presented here treatment would be of interest, to determine whether improve-
did not find any clinical characteristics that were predictive of the ments in other clinical outcomes were still observed. The present
3510 CHUPP ET AL J ALLERGY CLIN IMMUNOL PRACT
NOVEMBER 2023

Favors mepolizumab Favors placebo

Odds ratio Patients (%)
(95% CI)
Mepolizumab Placebo
Blood eosinophil
count (cells/μL)
≤300 0.78 (0.33-1.84) 15 18

>300-≤500 0.47 (0.19-1.16) 14 21

>500-≤700 1.04 (0.30-3.58) 9 8

≥700 0.34 (0.12-0.95) 14 27

Prior surgeries

1 0.37 (0.18-0.76) 19 36

2 1.77 (0.60-5.19) 30 30

>2 0.55 (0.22-1.37) 35 42

Comorbid asthma

Yes 0.56 (0.32-0.98) 26 38

No 0.64 (0.26-1.56) 23 35

Comorbid AERD

Yes 0.39 (0.15-0.97) 29 46

No 0.68 (0.39-1.18) 24 33

0.0625 0.125 0.25 0.5 1 2 4 8

Odds ratio (95% CI) (mepolizumab/placebo)

FIGURE 3. Proportion of patients requiring SCSs for NPs up to week 52 by baseline characteristic subgroups. Analysis using logistic
regression model with covariates of treatment group, geographic region, number of SCS courses for NPs in last 12 months (0, 1, >1 as
ordinal), baseline total endoscopic score (centrally read), baseline nasal obstruction VAS score, and log(e) baseline blood eosinophil count.
Courses of systemic steroids separated by less than 7 days are considered a continuation of the same course. AERD, Aspirin-exacerbated
respiratory disease; CI, confidence interval; NP, nasal polyps; SCS, systemic corticosteroid; VAS, visual analog scale.

TABLE II. Prednisolone-equivalent OCS dose by baseline charac- treatment, to identify potential therapeutic targets and predict
teristic subgroups response to treatment.10 For example, measurement of IL-5 to
Total prednisolone-equivalent OCS dose for NPs categorize patients on the basis of high or low IL-5 levels would
up to week 52 (mg/y), mean – SD be beneficial for predicting treatment response to mepolizumab
Baseline
characteristic Placebo Mepolizumab and could potentially be carried out in a clinical laboratory
Prior surgery
setting. Interestingly, an analysis of the effect of blood eosinophil
1 151.7  334.8 n ¼ 80 61.5  175.1 n ¼ 108
count on the response to mepolizumab in SYNAPSE suggested
that higher counts were predictive of improvements in nasal
2 149.0  349.9 n ¼ 46 160.4  329.7 n ¼ 47
obstruction VAS score but not total endoscopic NP score.32
>2 234.5  401.4 n ¼ 72 164.2  310.3 n ¼ 50
However, patient numbers in the subgroups were low; thus,
Baseline blood
further investigation of blood eosinophil count as a potential
eosinophil count
biomarker of response to mepolizumab is warranted.
<150 cells/mL 147.4  380.4 n ¼ 15 68.5  176.8 n ¼ 20
In addition to reducing the proportion of patients requiring
150 cells/mL 183.9  363.7 n ¼ 183 113.6  264.7 n ¼ 185
SCSs during SYNAPSE, mepolizumab reduced the mean dose of
<300 cells/mL 86.6  225.7 n ¼ 61 94.7  238.8 n ¼ 67
prednisolone-equivalent OCSs over the year compared with pla-
300 cells/mL 223.3  404.7 n ¼ 137 116.2  266.6 n ¼ 138
cebo in those receiving SCSs. The mean total
Comorbid asthma prednisolone-equivalent dose of 438.9 mg/y in the mepolizumab
Yes 202.2  399.3 n ¼ 146 119.3  277.8 n ¼ 139 group (compared with 505.2 mg/y in the placebo group) was of
No 122.0  232.3 n ¼ 52 87.8  208.6 n ¼ 66 particular clinical relevance given the results of a previous study in
Comorbid AERD 2018. Price et al17 demonstrated a lower risk of several SCS-related
Yes 231.5  409.4 n ¼ 61 90.1  206.0 n ¼ 44 adverse effects in patients with a cumulative SCS exposure of more
No 158.8  341.3 n ¼ 137 114.4  270.1 n ¼ 161 than 0 mg to less than 500 mg, compared with those with ex-
posures of 500 mg to less than 1000 mg.17 Furthermore, among
AERD, Aspirin-exacerbated respiratory disease; NP, nasal polyps; OCS, oral
corticosteroid those receiving at least 1 course of SCSs in the current SYNAPSE
analysis, the proportion of patients receiving more than 200 mg
findings highlight the need for understanding of how symptoms prednisolone-equivalent OCSs per year was lower with mepoli-
relate to the underlying inflammatory processes in CRSwNP and zumab than with placebo (75% vs 86%). This is important
for endotyping of those patients who are eligible for biologic because a dose of 200 mg possibly reflects the typical treatment
J ALLERGY CLIN IMMUNOL PRACT CHUPP ET AL 3511
VOLUME 11, NUMBER 11

schedule of 40 mg OCSs for 5 days. Of note, analyses of total 11. Price D, Castro M, Bourdin A, Fucile S, Altman P. Short-course systemic
corticosteroids in asthma: striking the balance between efficacy and safety. Eur
prednisolone-equivalent OCS dose per year and proportions of
Respir Rev 2020;29:190151.
patients receiving different category levels of OCSs were restricted 12. Winblad L, Larsen CG, Hakansson K, Abrahamsen B, von Buchwald C. The
to patients receiving at least 1 SCS course during the study. risk of osteoporosis in oral steroid treatment for nasal polyposis: a systematic
The SYNAPSE study has a number of strengths, including review. Rhinology 2017;55:195-201.
allowing patients to continue to receive SCS rescue medication in 13. Bleecker ER, Menzies-Gow AN, Price DB, Bourdin A, Sweet S, Martin AL,
et al. Systematic literature review of systemic corticosteroid use for asthma
the study; this may be more representative of real-world clinical management. Am J Respir Crit Care Med 2020;201:276-93.
practice than other phase III CRSwNP studies, such as the 14. Sweeney J, Patterson CC, Menzies-Gow A, Niven RM, Mansur AH, Bucknall C,
dupilumab LIBERTY NP SINUS studies in which patients who et al. Comorbidity in severe asthma requiring systemic corticosteroid therapy:
received SCSs had their worst pre-SCS end-point values used for cross-sectional data from the Optimum Patient Care Research Database and the
analysis.39 Study limitations include the post hoc nature of the British Thoracic Difficult Asthma Registry. Thorax 2016;71:339-46.
15. Hox V, Lourijsen E, Jordens A, Aasbjerg K, Agache I, Alobid I, et al.
subgroup analyses presented here as well as the low number of Benefits and harm of systemic steroids for short- and long-term use in
patients in some of the subgroups. Despite these limitations, rhinitis and rhinosinusitis: an EAACI position paper. Clin Transl Allergy
these data provide a comprehensive picture of the SCS-sparing 2020;10:1.
capabilities of mepolizumab in a population of adults with se- 16. Manson SC, Brown RE, Cerulli A, Vidaurre CF. The cumulative burden of oral
corticosteroid side effects and the economic implications of steroid use. Respir
vere CRSwNP and highlights the potential for mepolizumab as Med 2009;103:975-94.
an SCS-sparing agent in CRSwNP. 17. Price DB, Trudo F, Voorham J, Xu X, Kerkhof M, Ling Zhi Jie J, et al. Adverse
outcomes from initiation of systemic corticosteroids for asthma: long-term
observational study. J Asthma Allergy 2018;11:193-204.
CONCLUSIONS 18. Khan A, Vandeplas G, Huynh TMT, Joish VN, Mannent L, Tomassen P, et al.
This analysis of the SYNAPSE study found that mepolizumab The Global Allergy and Asthma European Network (GALEN) rhinosinusitis
was associated with clinical benefits regardless of prior SCS use in cohort: a large European cross-sectional study of chronic rhinosinusitis patients
patients with severe CRSwNP in need of repeat surgery and that with and without nasal polyps. Rhinology 2019;57:32-42.
19. Calus L, Van Bruaene N, Bosteels C, Dejonckheere S, Van Zele T,
mepolizumab is associated with an SCS-sparing effect in this pa- Holtappels G, et al. Twelve-year follow-up study after endoscopic sinus surgery
tient population. These data support the use of mepolizumab as a in patients with chronic rhinosinusitis with nasal polyposis. Clin Transl Allergy
valuable add-on treatment to standard-of-care CRSwNP therapy 2019;9:30.
with an SCS-sparing effect that can both improve efficacy out- 20. Tosun F, Arslan HH, Karslioglu Y, Deveci MS, Durmaz A. Relationship be-
comes and reduce the adverse effect burden associated with SCS tween postoperative recurrence rate and eosinophil density of nasal polyps. Ann
Otol Rhinol Laryngol 2010;119:455-9.
use in patients with recurrent, refractory, severe CRSwNP. 21. Arancibia C, Langdon C, Mullol J, Alobid I. Twelve-year long-term post-
operative outcomes in patients with chronic rhinosinusitis with nasal polyps.
Rhinology 2022;60:109-17.
Acknowledgment 22. Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, et al.
Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma.
Editorial support (in the form of writing assistance, including N Engl J Med 2014;371:1189-97.
preparation of the draft manuscript under the direction and 23. Nair P, Wenzel S, Rabe KF, Bourdin A, Lugogo NL, Kuna P, et al. Oral
guidance of the authors, collating and incorporating authors’ glucocorticoid-sparing effect of benralizumab in severe asthma. N Engl J Med
comments for each draft, assembling tables and figures, and 2017;376:2448-58.
24. Rabe KF, Nair P, Brusselle G, Maspero JF, Castro M, Sher L, et al. Efficacy and
grammatical editing and referencing) was provided by Ciara
safety of dupilumab in glucocorticoid-dependent severe asthma. N Engl J Med
Keogh, PhD, at Fishawack Indicia Ltd, UK, part of Fishawack 2018;378:2475-85.
Health, and was funded by GSK. 25. Solèr M, Matz J, Townley R, Buhl R, O’Brien J, Fox H, et al. The anti-IgE
antibody omalizumab reduces exacerbations and steroid requirement in
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osis. Annu Rev Pathol 2017;12:331-57. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis.
2. Stevens WW, Schleimer RP, Kern RC. Chronic rhinosinusitis with nasal polyps. N Engl J Med 2017;376:1921-32.
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3. Stoop AE, van der Heijden HA, Biewenga J, van der Baan S. Eosinophils in mAb mepolizumab in the treatment of severe refractory asthma and hyper-
nasal polyps and nasal mucosa: an immunohistochemical study. J Allergy Clin eosinophilic diseases. J Asthma Allergy 2015;8:105-14.
Immunol 1993;91:616-22. 28. Chupp GL, Bradford ES, Albers FC, Bratton DJ, Wang-Jairaj J, Nelsen LM,
4. Tomassen P, Vandeplas G, Van Zele T, Cardell LO, Arebro J, Olze H, et al. et al. Efficacy of mepolizumab add-on therapy on health-related quality of life
Inflammatory endotypes of chronic rhinosinusitis based on cluster analysis of and markers of asthma control in severe eosinophilic asthma (MUSCA): a
biomarkers. J Allergy Clin Immunol 2016;137:1449-1456.e4. randomised, double-blind, placebo-controlled, parallel-group, multicentre,
5. Varendh M, Johannisson A, Hrubos-Strom H, Andersson M. Sleep quality phase 3b trial. Lancet Respir Med 2017;5:390-400.
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and nasal polyposis. Rhinology 2017;55:45-52. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J
6. Vennik J, Eyles C, Thomas M, Hopkins C, Little P, Blackshaw H, et al. Chronic Med 2014;371:1198-207.
rhinosinusitis: a qualitative study of patient views and experiences of current 30. Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al.
management in primary and secondary care. BMJ Open 2019;9:e022644. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-
7. Soler ZM, Wittenberg E, Schlosser RJ, Mace JC, Smith TL. Health state utility values blind, placebo-controlled trial. Lancet 2012;380:651-9.
in patients undergoing endoscopic sinus surgery. Laryngoscope 2011;121:2672-8. 31. Roufosse F, Kahn JE, Rothenberg ME, Wardlaw AJ, Klion AD, Kirby SY, et al.
8. Bachert C, Bhattacharyya N, Desrosiers M, Khan AH. Burden of disease in Efficacy and safety of mepolizumab in hypereosinophilic syndrome: a phase III,
chronic rhinosinusitis with nasal polyps. J Asthma Allergy 2021;14:127-34. randomized, placebo-controlled trial. J Allergy Clin Immunol 2020;146:
9. Wensing M, Vingerhoets E, Grol R. Functional status, health problems, age and 1397-405.
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10. Fokkens WJ, Lund VJ, Hopkins C, Hellings PW, Kern R, Reitsma S, et al. Mepolizumab for chronic rhinosinusitis with nasal polyps (SYNAPSE): a
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J ALLERGY CLIN IMMUNOL PRACT CHUPP ET AL 3512.e1
VOLUME 11, NUMBER 11

ONLINE REPOSITORY

0 SCS courses 1 SCS course >1 SCS course 0 SCS courses 1 SCS course >1 SCS course
0 0
0 0 0 0 0 −0.04 −0.03
−0.2 −1

Median change from baseline

Median change from baseline

−0.4 −2 −1.75

−0.6 −3

−0.8 −4 −3.80

−1 −5 −4.55
−4.83
−1.00
−1.2 −6
Difference Difference
in medians ─0.52 ─1.00 ─0.43 in medians ─2.55 ─3.72 ─3.55
(95% CI): (─1.01, ─0.04) (─1.51, ─0.49) (─1.25, 0.39) (95% CI): (─4.17, ─0.92) (─5.49, ─1.95) (─5.18, ─1.92)
A B
0 SCS courses 1 SCS course >1 SCS course
0
−1.50
−5
Median change from baseline

−10
−10.00
−15
−16.50
−20
−22.00
−25

−30
−31.00
−32.00
−35
Difference
in medians ─17.02 ─22.57 ─16.16
(95% CI): (─26.16, ─7.88) (─39.16, ─5.98) (─27.67, ─4.65)

C Placebo Mepolizumab 100 mg

FIGURE E1. Study outcomes by number of SCS courses received in the year before study entry: (A) Change from baseline in total
endoscopic NP score at week 52. (B) Change from baseline in nasal obstruction VAS score at weeks 49 to 52. (C) Change from baseline
in SNOT-22 total score at week 52* (MCID, 8.9-point improvement).E1 *Patients with sinus surgery before time period are assigned
their worst observed score before sinus surgery; patients with no sinus surgery who withdrew from study before visit are assigned their
worst observed score before study withdrawal; patients with missing visit data are assigned their worst observed score before the
missing visit. MCID, Minimal clinically important difference; NP, nasal polyp; SCS, systemic corticosteroid; SNOT-22, Sino-Nasal Out-
comes Test-22; VAS, visual analog scale.
3512.e2 CHUPP ET AL J ALLERGY CLIN IMMUNOL PRACT
NOVEMBER 2023

TABLE E1. Prednisolone-equivalent OCS dose category for NPs during the 52-wk treatment period in patients receiving 1 course of
SCSs for NPs during the study
Patients, n (%)*
Prednisolone-equivalent
OCS dose for NP (mg/y) Placebo (N [ 74) Mepolizumab (N [ 52)
>0-100 5 (7) 9 (18)
>100-200 5 (7) 4 (8)
>200-300 18 (25) 9 (18)
>300-400 10 (14) 9 (18)
>400-500 12 (17) 2 (4)
>500-600 2 (3) 3 (6)
>600 19 (27) 15 (29)

NP, Nasal polyps; OCS, oral corticosteroid; SCS, systemic corticosteroid.

*Percentages calculated on the basis of 71 patients in the placebo group and 51 patients in the mepolizumab group with 1 course of SCSs during the study and with available
OCS-dose data.

REFERENCE medically managed patients with chronic rhinosinusitis. Clin Otolaryngol

E1. Phillips KM, Hoehle LP, Caradonna DS, Gray ST, Sedaghat AR. Minimal 2018;43:1328-34.
clinically important difference for the 22-item Sinonasal Outcome Test in