Original Article

Comparison of Different Biologics for Treating

Chronic Rhinosinusitis With Nasal Polyps: A
Network Analysis
Shiru Cai, BSa,b,*, Shenglong Xu, BSa,b,*, Hongfei Lou, MD, PhDa,b,c, and Luo Zhang, MD, PhDa,b,c,d Beijing, P.R. China

What is already known about this topic? Several type 2 biologics have been shown to be safe and more effective than
placebos in the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP). However, there are no existing direct
comparisons between these biologics.

What does this article add to our knowledge? The results indicate that dupilumab is the most effective and safe
treatment route for CRSwNP, when compared with omalizumab, mepolizumab, and benralizumab at 24 weeks of the
treatment and end of follow-up.

How does this study impact current management guidelines? Dupilumab may be the best choice when considering
the biological therapy for CRSwNP. Nevertheless, real-world evidence and head-to-head comparisons with longer follow-
up periods are necessary to confirm these findings.

BACKGROUND: Several promising clinical trials have
demonstrated the effects of type 2 biologics compared with
placebos in chronic rhinosinusitis with nasal polyps (CRSwNP).
However, there are no head-to-head randomized controlled trials
(RCTs) between the biologics.
OBJECTIVE: To compare the efficacy and safety of different
biologics used for the treatment of CRSwNP.
a
Department of Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospi-
tal, Capital Medical University, Beijing, P.R. China
b
Beijing Key Laboratory of Nasal Diseases and Beijing Laboratory of Allergic
Diseases, Beijing Institute of Otorhinolaryngology, Beijing, P.R. China
c
Research Unit of Diagnosis and Treatment of Chronic Nasal Diseases, Chinese
Academy of Medical Sciences, Beijing, P.R. China
d
Department of Allergy, Beijing TongRen Hospital, Capital Medical University,
Beijing, P.R. China
This work was supported by grants from the National Natural Science Foundation of
China (81970850, 81870698, and 82025010), CAMS Innovation Fund for Med-
ical Sciences (2019-I2M-5-022, 2021-I2M-C&T-B-098), National Key R&D
Program of China (2018YFC0116800), the Program for Changjiang Scholars and
Innovative Research Team (IRT13082), Beijing Municipal Science and Tech-
nology Project (Z181100001618002), Beijing Municipal Administration of Hos-
pitals’ Dengfeng Plan (DFL20190202), and Beijing DongCheng District
Distinguished Talent Project (2020-dchrcpyzz-31).
Conflicts of Interest: The authors declare that they have no relevant conflicts of
interest.
Received for publication September 21, 2021; revised February 13, 2022; accepted
for publication February 21, 2022.
Available online March 8, 2022.
Corresponding authors: Hongfei Lou, MD, PhD, Department of Otolaryngology,
Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University,
No. 1, DongJiaoMinXiang, DongCheng District, Beijing 100730, P.R. China. E-
mail: louhongfei@yahoo.com. Or: Luo Zhang, MD, PhD, Department of
Otolaryngology, Head and Neck Surgery, Beijing TongRen Hospital, Capital
Medical University, No. 1, DongJiaoMinXiang, DongCheng District, Beijing
100730, P.R. China. E-mail: dr.luozhang@139.com.
* These authors contributed equally to this article.
2213-2198
Ó 2022 American Academy of Allergy, Asthma & Immunology
https://doi.org/10.1016/j.jaip.2022.02.034
METHODS: We systematically identified RCTs investigating
the effects of biologics for CRSwNP. Primary outcomes were
nasal polyp score (NPS), nasal congestion severity, and serious
adverse events. Secondary outcomes included the 22-item Sino-
Nasal Outcome Test (SNOT-22) score, loss of smell severity, the
University of Pennsylvania Smell Identification Test score, and
the Lund-Mackay computed tomography score. Bucher indirect
treatment comparison (ITC) was used to compare the outcome
parameters.
RESULTS: Seven RCTs (Bachert 2017, OSTRO, POLYP 1,
POLYP 2, SINUS-24, SINUS-52, and SYNAPSE) involving 1913
patients and 4 biologics (benralizumab, dupilumab, mepolizu-
mab, and omalizumab) were included for ITC. Dupilumab
presented better effects in decreasing NPS and nasal congestion
severity compared with the other 3 biologics at 24 weeks of the
treatment and at the end of follow-up (more than 48 weeks).
Benralizumab was the least effective in reducing nasal congestion
severity and SNOT-22 score at 24 weeks. No significant differ-
ences were observed between the effects of the other biologics.
CONCLUSION: Our current findings suggest that dupilumab
exhibits the best efficacy and safety for the treatment of
CRSwNP. Ó 2022 Published by Elsevier Inc. on behalf of the
American Academy of Allergy, Asthma & Immunology (J Allergy
Clin Immunol Pract 2022;10:1876-86)
Key words: Biologics; Chronic rhinosinusitis with nasal polyps;
Dupilumab; Indirect treatment comparison; Omalizumab;
Mepolizumab; Benralizumab
Chronic rhinosinusitis with nasal polyps (CRSwNP) affects
1% to 2.6% of the general population,1 and its coexistence with
asthma and aspirin sensitivity makes it difficult to manage.2
Patients with CRSwNP may present symptoms including nasal
congestion, loss of smell, runny nose, postnasal drip, and head/
facial pressure,3 all of which significantly affect patients’ quality

1876

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J ALLERGY CLIN IMMUNOL PRACT
VOLUME 10, NUMBER 7
Abbreviations used
AE- Adverse event
CI- Confidence interval
CRSwNP- Chronic rhinosinusitis with nasal polyps
CT- Computed tomography
EOF- End of follow-up
IL-4Ra- IL-4 receptor alpha
ITC- Indirect treatment comparison
mAb- Monoclonal antibody
MD- Mean difference
MFNS- Mometasone furoate nasal spray
NP- Nasal polyps
NPS- Nasal polyp score
RCT- Randomized clinical trial
SCS- Systemic corticosteroids
SD- Standard deviation
SMD- Standardized mean difference
SNOT-22- 22-item Sino-Nasal Outcome Test
TSLP- Thymic stromal lymphopoietin
UPSIT- University of Pennsylvania Smell Identification Test
of life, ultimately leading to problems such as sleep disorders,
negative emotions, and poor performance in work, study, and
social settings.
Currently, both topical corticosteroids and nasal saline irri-
gations are recommended as initial maintenance therapies for
patients with CRSwNP. Systemic corticosteroids (SCS) are used
for acute exacerbations; however, their long-term use may result
in significant side effects.4 For patients with persistent symptoms
despite regular medical management, endoscopic surgery is
considered the alternative treatment. Although effective, the
recurrence rate after operation is as high as 40%.5 Therefore,
novel therapeutics targeting the specific mechanisms are urgently
needed.
In recent years, there have been several promising clinical
trials evaluating the efficacy and safety of biologics for the
treatment of CRSwNP. Most patients with CRSwNP show a
type 2 inflammatory signature with a high expression of IL-4,
IL-5, IL-13, and IgE. Dupilumab, an anti-IL-4 receptor alpha
(IL-4Ra) monoclonal antibody (mAb), targets IL-4 and IL-13
signaling simultaneously, whereas omalizumab, an anti-IgE
mAb, neutralizes IgE to prevent the downstream inflamma-
tion effects. Mepolizumab, an anti-IL-5 mAb, can bind free IL-
5 protein in circulation. These 3 biologics have already been
approved by European Medicines Agency and Food and Drug
Administration to enter the market for patients with CRSwNP.
In addition, the roles of other biologics are also being explored.
For example, benralizumab, an anti-IL-5Ra mAb, can directly
target the a-chain of the IL-5 receptor. A recent phase 3 clinical
trial demonstrated its potential in treating refractory nasal
polyps (NP).6 However, there are no head-to-head randomized
clinical trials (RCTs) directly comparing the efficacy and safety
of these mAb treatments. Therefore, as an alternative approach,
indirect treatment comparison (ITC) can examine the differ-
ences in the efficacy and safety between each treatment, by
analyzing the primary and secondary endpoints. This network
meta-analysis aims to provide a strategy for the selection of
biologics in patients with CRSwNP and identify directions for
further research.
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CAI ET AL 1877
METHODS
Literature search and study selection
We performed a literature search to identify RCTs evaluating the
effects of biologic therapy in CRSwNP. PubMed, EMBASE,
Cochrane Library, Web of Science, BIOSIS Previews, clinicaltrials.
gov, and clinicaltrialsregister.eu were consulted using a combina-
tion of medical subject headings and free-text terms (Table E1,
available in this article’s Online Repository at www.jaci-inpractice.
org) until November 8, 2021, with no language limitations.
Articles meeting the following criteria were selected: (1) popula-
tion: adult patients (
18 years old) diagnosed with CRSwNP
through computed tomography (CT) or endoscopy presenting
sinusitis symptoms despite steroid treatment or surgery; (2) study
design: RCTs with at least 24 weeks of follow-up; (3) intervention:
all types of mAbs for the treatment of CRSwNP; (4) comparison:
placebo, standard of care, or no treatment. Exclusion criteria
included patients with malignant polyps, allergic fungal sinusitis,
cystic fibrosis, or other diseases that may influence the outcome
measures.
Data extraction and outcome measurements
Data were collected by one author (SC) and checked by another
(SX). Disagreements were resolved through consensus. The
following data were collected: study design, potential sources of bias,
participants, intervention and control, follow-up period, inclusion
and exclusion criteria, baseline characteristics, outcome measure-
ments of interest, and results, which were obtained from texts, ta-
bles, figures, and supplementary materials in the published articles
and registry platforms.
The mean values, standard deviations (SDs), and number of
patients of each treatment group were collected. Effects were based
on their change from baseline by subtracting the baseline measure-
ment from the postintervention measurement. Missing SDs were
filled in by borrowing the SDs from other included studies that
analyzed the same mAb when none of the methods allowed the
calculation. For binary data, the number of participants experiencing
an event and the number of patients assessed were analyzed. Data
were pooled for studies with multiple arms and different dosing
schemes.
We selected nasal polyp score (NPS), nasal congestion severity,
and serious adverse events (AEs) as primary outcomes. Patients were
defined as “responders” if they had a
1 point improvement in
NPS.6-8 Secondary outcomes include the 22-item Sino-Nasal
Outcome Test (SNOT-22) score, loss of smell severity, the Uni-
versity of Pennsylvania Smell Identification Test (UPSIT) score, the
Lund-Mackay CT score, overall symptom visual analog scale score,
total symptoms severity, and nonserious AEs. See Table E2 in this
article’s Online Repository at www.jaci-inpractice.org for more de-
tails about these outcomes. Efficacy outcomes were measured at 24
weeks of the treatment and end of follow-up (EOF, more than 48
weeks). For AEs, we analyzed the data at EOF.
Quality assessment
Included records were assessed using the Cochrane Risk of Bias
Tool for methodologic quality. Two reviewers (SC and SX) inde-
pendently conducted the assessment, and disagreements were
resolved by consensus. Quality assessment was performed using
Review Manager (version 5.4, The Cochrane Collaboration, 2020).
1878 CAI ET AL
Statistical analysis
Efficacy was analyzed in the intent-to-treat population, whereas
safety was analyzed in the safety population. All results are expressed
as 95% confidence intervals (CIs). For continuous outcomes, we
expressed treatment effects as mean differences (MDs). If outcomes
were assessed by different rating systems (nasal congestion severity,
loss of smell severity, and total symptoms severity), we used stan-
dardized mean differences (SMDs) instead of MDs to resolve the
disparities among the scoring systems. For binary outcomes, odd
ratios were calculated.
ITCs were conducted using methods proposed by Glenny and
Bucher in 1997.9 Standard meta-analyses for the results of the same
biologic treatment were first performed using a random-effects
model to generate pooled effects. This model acknowledges the
potential heterogeneity across the RCTs derived from characteristics
of patients and study design, and provides the mean of the distri-
bution of true effect sizes.10 Then, the pooled effects were indirectly
compared using the common comparator under the frequentist
model. The underlying assumptions of ITCs, similarity and transi-
tivity, were verified by comparing the study designs and baseline
characteristics across the trials and between the mAbs (data sup-
porting transitivity shown in Table E3, available in this article’s
Online Repository at www.jaci-inpractice.org). ITCs were per-
formed using a network package in Stata MP 16.0 (Stata Corp LLC,
College Station, Tex). Sensitivity analyses regarding prior surgical
history and phases of clinical trials were employed to assess the
robustness of findings. Subgroup analyses (with vs without asthma)
were conducted, with interaction tests identifying the potential effect
modification of asthma toward the differences between treatments11
(z test was used to test the statistical significance). A P value <.05
was considered statistically significant.
RESULTS
Included trials
The literature search identified a total of 1812 records, of
which 1509 were left after removal of duplicates. We excluded
1426 records that did not meet the eligibility criteria by
screening the title and abstract. Other 49 publications were
excluded after full-text appraisal. Finally, 7 RCTs (Bachert
201712 [NCT01362244], OSTRO6 [NCT03401229], POLYP
17 [NCT03280550], POLYP 27 [NCT03280537], SINUS-248
[NCT02912468], SINUS-528 [NCT02898454], and SYN-
APSE13 [NCT03085797]) with 32 reports involving 1913 par-
ticipants were included in our network meta-analysis (Figure 1).
The included studies were phase 3 clinical trials, only excep-
tion being the study of Bachert 2017 that is a phase 2 trial. All
studies focused on adult patients with CRSwNP and the efficacy
of 4 mAbs, including benralizumab (anti-IL-5Ra), dupilumab
(anti-IL-4Ra), mepolizumab (anti-IL-5), and omalizumab (anti-
IgE).
We summarized the schemes of intervention and control of
these trials and their follow-up period ranging from 24 to 56
weeks (Table I). Selection criteria (Table E4, available in this
article’s Online Repository at www.jaci-inpractice.org) and
baseline characteristics (Table II) of the included RCTs were
provided. All participants showed nasal symptoms and were
required to have an NPS
5 and an NPS
2 in each nostril.
Comorbid asthma was found in over half of the patients. Two
mepolizumab studies (Bachert 2017 and SYNAPSE) only
recruited participants with a history of NP surgery. The extracted
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J ALLERGY CLIN IMMUNOL PRACT
JULY 2022
outcome data are shown in Tables E5 and E6, available in this
article’s Online Repository at www.jaci-inpractice.org.
Risk of bias
The risk-of-bias assessment demonstrated that the overall risk
was low, but there were concerns regarding incomplete outcome
data (Figure 2). Among the 3 studies considered to be at high
risk of attrition bias, the Bachert 2017 trial had high rates of
discontinuation, whereas the SINUS-52 and OSTRO studies
had disproportionally more discontinuations in the placebo arm.
ITCs of primary outcome measures
Dupilumab had better efficacy in reducing NPS and nasal
congestion severity compared with the other biologics at both eval-
uation points. In terms of NPS (Figure 3, A), dupilumab had a mean
1.06-point, 1.09-point, and 1.64-point greater improvement
compared with omalizumab (MD [95% CI], 1.06
[1.63 to 0.48]), mepolizumab (MD [95% CI], 1.09 [1.68
to 0.51]), and benralizumab (MD [95% CI], 1.64
[2.24 to 1.03]) at 24 weeks, respectively. Greater improvements
were also observed at EOF (MD [95% CI], dupilumab vs
mepolizumab, 1.50 [1.98 to 1.01]; dupilumab vs
benralizumab, 1.82 [2.31 to 1.33]). These results were
consistent with the responder analysis (Figure 3, C), showing the
proportion of patients achieving an NPS improvement of
1 point
being significantly larger in patients receiving dupilumab than the
other biologics.
Furthermore, for nasal congestion severity (Figure 3, B),
dupilumab was also superior to omalizumab (SMD [95%
CI], 0.37 [0.66 to 0.08] at 24 weeks), mepolizumab (SMD
[95% CI], 0.47 [0.71 to 0.24] at 24 weeks, and 0.59
[0.88 to 0.31] at EOF), and benralizumab (SMD [95%
CI], 0.90 [1.15 to 0.65] at 24 weeks, and 0.82, [1.10
to 0.53] at EOF). Benralizumab in the OSTRO trial was
found to be the least effective in alleviating nasal congestion at 24
weeks, with a mean 0.53 [95% CI, 0.21-0.84] higher than
omalizumab and 0.42 [95% CI, 0.16-0.68] higher than mepo-
lizumab. No other statistical differences in the treatment effects
were observed between the mAbs (Figure 3, A and B).
For safety, no significant differences in serious AEs were
observed between different mAb treatments (Figure 3, D).
ITCs of secondary outcome measures
For secondary outcomes (Figure 4; Figure E1, available in
this article’s Online Repository at www.jaci-inpractice.org),
dupilumab showed better efficacy versus omalizumab, mepo-
lizumab, and benralizumab in all shared secondary endpoints at
week 24 and/or EOF, except for SNOT-22 score and total
symptoms severity at 24 weeks in the dupilumab-omalizumab
comparison (differences in the treatment effects were not sta-
tistically significant). Benralizumab was found to be less
effective than the other 3 mAbs in reducing SNOT-22 score at
24 weeks (Figure 4, A). For nonserious AEs (Figure E1, C,
available in this article’s Online Repository at www.jaci-
inpractice.org), no statistical differences were found between
mAbs.
Sensitivity analysis in patients with prior surgery
Patients who had undergone nasal surgery for removing NP
were analyzed separately, as a history of surgery was required for
participant selection in both the SYNAPSE and the Bachert
2017 trial. The results (Figure 5) were in line with that of the
J ALLERGY CLIN IMMUNOL PRACT CAI ET AL 1879
VOLUME 10, NUMBER 7

FIGURE 1. PRISMA flow diagram. CRS, Chronic rhinosinusitis; CRSwNP, chronic rhinosinusitis with nasal polyps.

whole population analyzed above, demonstrating that dupilu-
mab was more effective in reducing NPS and nasal congestion
severity than mepolizumab at 24 weeks and EOF. Comparisons
between other mAbs were not feasible as no relevant data were
reported.
Sensitivity analysis in phase 3 clinical trials
Because all included studies except Bachert 2017 were phase 3
clinical trials, we performed a sensitivity analysis excluding it.
The results were consistent with our previous findings
(Figure E2, available in this article’s Online Repository at www.
jaci-inpractice.org), indicating that dupilumab had better efficacy
than the other mAbs.
Subgroup analysis in patients with and without
comorbid asthma
Subgroup analysis was performed among patients with and
without comorbid asthma at week 24 and EOF. Compared with
omalizumab at week 24 and mepolizumab at EOF, patients in
both subgroups benefited more from dupilumab in reducing

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1880 CAI ET AL J ALLERGY CLIN IMMUNOL PRACT
JULY 2022

TABLE I. Intervention, control, and follow-up period

Study Intervention and control Follow-up period (wk)
SINUS-24 Dupilumab or placebo, 300 mg, SC injection, q2w for 24 wk. Background therapy: intranasal 24
MFNS at stable dose.
SINUS-52 Interventions: 52
(A) Dupilumab, 300 mg, SC injection, q2w for 52 wk.
(B) Dupilumab, 300 mg, SC injection, q2w for 24 wk þ q4w until 52 wk (alternated with
placebo injection every other week up to 50 wk).
Control: placebo, 1 SC injection, q2w for 52 wk.
Background therapy: intranasal MFNS at stable dose.
Bachert 2017 Mepolizumab or placebo, 750 mg, intravenous injection, q4w for 24 wk. 25
INS was continued throughout the study.
POLYP 1 and 2 Omalizumab or placebo, SC injections, for 24 wk. The dose (75-600 mg) and dosing frequency 28*
(q2w or q4w) were determined by the serum total IgE level and body weight.
Background therapy: intranasal MFNS.
SYNAPSE Mepolizumab or placebo, 100 mg, SC injections, q4w for 48 wk. 52
Standard of care, including daily intranasal MFNS.
OSTRO Benralizumab or placebo, 30 mg, SC injections, q4w for 8 wk þ q8w until 48 wk 56
Background therapy: intranasal MFNS at stable dose.
INS, Intranasal steroids; MFNS, mometasone furoate nasal spray; q2w, every 2 weeks; q4w, every 4 weeks; SC, subcutaneous.
*Most outcomes assessed after 24 weeks.

TABLE II. Baseline demographics and patient characteristics of the analyzed studies
SINUS-24 SINUS-52 POLY 1 POLY 2 SYNAPSE Bachert 2017 OSTRO
Variable (n [ 276) (n [ 448) (n [ 138) (n [ 127) (n [ 407) (n [ 105) (n [ 410)
Baseline demographics
Age (y) 50.5 52.0 51.0 50.1 48.7 50.5 50.1
Female (%) 42.8 37.7 36.3 34.7 35.0 28.6 35.9
Body mass index (kg/m2) 27.9 27.9 27.5 27.5 28.2 25.6 27.9
Duration of nasal polyps (y) 11.1 10.9 NA NA 11.4 NA NA
Previous nasal surgery (%) 71.7 58.3 57.2 62.2 100.0 100.0 73.2
Time since previous nasal polyp 5.7 8.2 NA NA 4.0 NA 6.9
surgery (y)
Prior systematic corticosteroids within 53.6 64.5 18.8 26.0 48.4 NA NA
1 y (%)
Comorbid asthma (%) 58.3 59.6 53.6 60.6 71.0 78.1 67.8
Clinical characteristics
Nasal polyp score (scale, 0-8) 5.8 6.1 6.2 6.3 5.4 6.3 6.1
Nasal congestion severity* 2.4 2.4 2.4 2.3 8.9 8.0 2.6
SNOT-22 score (scale, 0-110) 49.4 51.9 60.1 59.5 64.0 50.5 69.2
Loss of smell severity* 2.7 2.8 2.6 2.7 9.6 9.1 NA
Overall symptom VAS score (scale, 0- 7.7 8.0 NA NA 9.0 NA NA
10)
Lund-Mackay CT score (scale, 0-24) 19 18 NA NA NA NA NA
UPSIT score (scale, 0-40) 14.6 13.6 13.3 13.0 NA NA NA
Peripheral blood and serum
Blood eosinophil count (cells/mL) 440 430 350 330 395 NA 447
Serum total IgE (IU/mL) 212.0 239.8 160.9 190.2 NA NA 232.4
Data are n (%) or mean.
CT, Computed tomography; NA, not available; SNOT-22, 22-item Sino-Nasal Outcome Test; UPSIT, University of Pennsylvania Smell Identification Test; VAS, visual analog
scale.
*The SINUS-24 and -52, POLYP 1 and 2, and OSTRO trials used a 0 to 3 categorical scale; the SYNAPSE and Bachert 2017 trials used a 0 to 10 VAS score.

NPS (Figure 6, A and B). Dupilumab also showed greater
improvement in nasal congestion severity in patients with co-
morbid asthma (Figure 6, C), whereas the differences regarding
SMD were not significant in patients without asthma (Figure 6,
D). Nevertheless, interaction tests showed no statistical differ-
ences in MD or SMD between the asthma group and the
nonasthma group for each outcome and follow-up period (P
values all >.05), indicating that asthma was not a modifier of the
differences in treatment effect.
DISCUSSION
Biologics, mainly targeting type 2 inflammation, are a new
direction for the treatment of serious and uncontrolled
CRSwNP. This network meta-analysis aimed to compare the

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J ALLERGY CLIN IMMUNOL PRACT CAI ET AL 1881
VOLUME 10, NUMBER 7

FIGURE 2. Risk of bias. (A) Quality assessment graph of risk of bias; (B) risk of bias summary.

efficacy and safety of different mAbs for the treatment of
CRSwNP. Seven RCTs with a total of 1913 participants were
analyzed. Despite the small number of studies, the quality of the
trials is relatively high, and the number of patients is large. We
showed that dupilumab is safe and has the best efficacy for
CRSwNP among the 4 included biologics, although
omalizumab, mepolizumab, and benralizumab are also safe and
effective when compared with placebo.
The outcome measurement efficacy was analyzed at 24 weeks
and EOF (more than 48 weeks) separately to explore the dura-
bility of efficacy. According to the documents provided by the
European Forum for Research and Education in Allergy and

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1882 CAI ET AL J ALLERGY CLIN IMMUNOL PRACT
JULY 2022

FIGURE 3. Indirect comparison of primary outcome measures. (A) Mean difference in NPS change from baseline to 24 weeks and EOF;
(B) standardized mean difference in nasal congestion severity change from baseline to 24 weeks and EOF; (C) responder analysis for
patients with NPS improvement of
1 from baseline to 24 weeks and EOF, odds ratio; (D) odd ratio of serious AEs at EOF. AEs, Adverse
events; CI, confidence interval; EOF, end of follow-up; MD, mean difference; NPS, nasal polyp score; SMD, standardized mean
difference.

Airway Diseases Expert Board Meeting,14 it is recommended to
evaluate the clinical response to a biologic within 6 months of
treatment and then provide “continue or stop” suggestions. If the
degree of partial response is considered acceptable, continuation
of the drug over another 6 months is advised and a follow-up at
12 months is planned. Otherwise, the management strategy
should be changed accordingly. In our ITC, the comparisons
between dupilumab and other biologics drew similar conclusions
at both evaluation points, demonstrating that dupilumab was
superior to the other 3 biologics in nearly all primary and sec-
ondary outcomes.
Before our analysis, there was a meta-analysis (Oykhman
202115) comparing different mAbs and aspirin desensitization
for CRSwNP. The main difference between our study and
Oykhman 2021 is that we evaluated the efficacy of the mAbs at 2
time points instead of comparing the results at the primary
endpoint of each study (which were not consistent) directly. In
addition, we compared the changes of nasal congestion severity,
loss of smell severity, and total symptoms severity, as well as the
number of patients with
1 point improvement in NPS to
further assess the treatment efficacy. We also performed sub-
group analyses to assess the treatment effects in patients with and

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VOLUME 10, NUMBER 7

FIGURE 4. Indirect comparison of secondary outcome measures. (A) Mean difference in SNOT-22 score change from baseline to 24
weeks and EOF; (B) standardized mean difference in loss of smell severity change from baseline to 24 weeks and EOF; (C) mean dif-
ference in UPSIT score change from baseline to 24 weeks and EOF; (D) mean difference in the Lund-Mackay CT score change from
baseline to EOF. CI, Confidence interval; CT, computed tomography; EOF, end of follow-up; MD, mean difference; SMD, standardized
mean difference; SNOT-22, 22-item Sino-Nasal Outcome Test; UPSIT, University of Pennsylvania Smell Identification Test.

without asthma and sensitivity analyses in patients with prior
nasal surgery. Apart from Oykhman 2021, similar ITCs were
published by Peter16 and Wu17; however, they compared no
more than 3 biologics. Lipworth18 performed a simple indirect
comparison of dupilumab, omalizumab, and mepolizumab
without meta-analyses, whereas Chong19 conducted meta-
analyses on each biologic without performing an indirect com-
parison. Overall, our conclusion is consistent with these reviews,
showing that dupilumab might be more effective than other
evaluated mAbs.
Patients who have previously undergone surgical therapies
may respond differently to the biologics due to differences in
NP characteristics20 and severity of their symptoms.21 It seems
that patients with previous sinus surgery may present milder
symptoms.21 In the 2 mepolizumab studies (Bachert 2017 and
SYNAPSE), participants were required to have at least 1 prior
nasal surgery, although this was not a selection criterion for the
other studies. To explore the potential heterogeneity within
the population, we conducted a sensitivity analysis in subjects
with previous surgeries. The results were consistent with that
of the whole population, indicating that dupilumab was su-
perior to mepolizumab in improving NPS and nasal congestion
severity.
The biologics that might be effective in the treatment of NP
were first discovered in studies investigating their effects on
asthma. The underlying inflammatory bidirectional link between
CRSwNP and asthma has important implications for systemic
treatment with novel biologics targeting the shared type 2 in-
flammatory pathways. It was reported that anti-IL-5 agents were
associated with improved CT and SNOT-22 scores in asthma
patients with coexistent CRSwNP in the real-world setting.22 In
our meta-analysis, a subgroup analysis was conducted to assess
the treatment efficacy among CRSwNP patients with or without
asthma. Dupilumab showed an increased ability to reduce the

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1884 CAI ET AL J ALLERGY CLIN IMMUNOL PRACT
JULY 2022

FIGURE 5. Sensitivity analysis of primary efficacy outcome measures in patients with prior surgery. (A) Mean difference in NPS change
from baseline to 24 weeks and EOF; (B) standardized mean differences in nasal congestion severity change from baseline to 24 weeks
and EOF. CI, Confidence interval; EOF, end of follow-up; MD, mean difference; NPS, nasal polyp score; SMD, standardized mean
difference.

FIGURE 6. Subgroup analysis of primary efficacy outcome measures in patients with and without asthma. (A) Mean difference in NPS
change from baseline to 24 weeks and EOF in patients with asthma; (B) mean difference in NPS change from baseline to 24 weeks and
EOF in patients without asthma. (C) Standardized mean difference in nasal congestion severity change from baseline to 24 weeks and
EOF in patients with asthma. (D) Standardized mean difference in nasal congestion severity change from baseline to 24 weeks and EOF in
patients without asthma. CI, Confidence interval; EOF, end of follow-up; MD, mean difference; NPS, nasal polyp score; SMD, stan-
dardized mean difference.

NP size when compared with omalizumab and mepolizumab dupilumab was the superior treatment for controlling nasal
regardless of population. This observation is in line with previous congestion when asthma comorbidity was present, whereas in
studies investigating the effects of dupilumab on severe asthma patients without asthma, dupilumab did not show a significantly
patients.23,24 Meanwhile, compared with the other mAbs, different effect. However, interaction tests showed that there

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J ALLERGY CLIN IMMUNOL PRACT
VOLUME 10, NUMBER 7
were no significant differences between these 2 subgroups for
either dupilumab versus omalizumab or dupilumab versus
mepolizumab, which means that comorbid asthma had no
impact on the differences in treatment effect. Nevertheless, the
efficacy of different biologics in these subgroups should be
further explored.
Based on our current findings, dupilumab would represent the
best choice for patients with CRSwNP. However, there were
concerns that its efficacy might have been exaggerated. In the
SINUS and POLYP trials, dupilumab or omalizumab and their
matching placebos were given with background therapy (intra-
nasal mometasone furoate nasal spray [MFNS] at a stable dose),
whereas mepolizumab was given in addition to the standard of
care (intranasal MFNS and SCS were given as needed) in the
SYNAPSE trial. Therefore, the therapeutic effect of mepolizu-
mab might have been underestimated, as the placebo group used
more corticosteroids than the treatment group in the SYNAPSE
trial. Another concern is that there were insufficient data in terms
of recurrence and CRSwNP worsening after treatment discon-
tinuation. Previous studies reported that the improvements in
NPS and nasal symptoms soon diminished after participants
finished dupilumab or omalizumab treatment.8,25 In the future,
clinical trials with a longer follow-up period should be conducted
to examine the long-term efficacy of these biologics.
In terms of safety, it has been previously shown that all mAbs
were safe at EOF when compared with placebos. However, their
long-term adverse effects were not assessed in our analysis due to
insufficient follow-up period. Dupilumab and mepolizumab
showed no serious safety concerns for more than 3 years in the
treatment for other diseases.26,27 However, a recent analysis
based on real-world data reported that omalizumab may be
associated with a significantly increased risk of malignant tu-
mors.28 Therefore, the use of biologics for long-term treatment
should be carefully considered until further studies confirm their
long-term safety.
Although the designs of the included studies were generally
the same, there were some underlying differences that might
hinder the comparisons. In the SINUS and OSTRO trials, NPs
were assessed through nasal endoscopy combined with CT,
whereas other studies used nasal endoscopy alone. The value of
CT in NP assessment should not be ignored. CT has a better
ability to display the soft tissue and the paranasal sinuses and
allows more rigorous assessment when referenced to a grading
system such as the Lund-Mackay score. Endoscopy and CT are
complementary in the evaluation of NP, especially after medical
treatment failure. Another issue was that, although most studies
reported the number of patients who had surgery as a rescue
treatment or were still meeting criteria for surgery at EOF, the
criteria for surgery avoidance were different across these studies.
Thus, we believed to be of limited value to pool the results
regarding the need for surgery in this network analysis. Thirdly,
the Bachert 2017 trial only reported the final means and SDs of
nasal congestion severity, SNOT-22 score, and loss of smell
severity rather than the mean change from the baseline. There-
fore, we borrowed the SDs from the SYNAPSE trial. This
method has been proven safe,29 and the sensitivity analysis by
excluding Bachert 2017 also showed results consistent with
previous findings.
In addition, it is possible that some biologics may perform
better, in particular, endotypes, which addresses the importance
of patient selection and individualized treatment. However, this
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CAI ET AL 1885
cannot be interpreted from the RCTs analyzed here, which
included all-comers with CRSwNP, except POLY 1 and 2
selecting participants with high levels of IgE. One article based
on the SINUS-52 trial reported that the eosinophilic status did
not affect the efficacy of dupilumab.30 Nevertheless, it is neces-
sary to identify potential biomarkers that might correlate with
the efficacy of the biologics.
Besides these 4 mAbs, other biologics may also be effective for
the treatment of NP, such as antiethymic stromal lympho-
poietin (TSLP) mAb, anti-IL-33 mAb, and reslizumab31 (an
anti-IL-5 mAb). Although there are several studies supporting
the role of TSLP and IL-33 in the pathogenesis of CRSwNP,
there are no published RCTs examining the effects of anti-TSLP
and anti-IL-33 in patients with CRSwNP.32 These biologics
might benefit patients with CRSwNP of different endotypes,
provided that they are proven efficacious and safe.
In terms of clinical application, Scadding et al33 suggested
several criteria on beginning and continuing biologic treatment
in CRSwNP. However, multiple outstanding questions remain
unanswered. How to select the best biologic for an individual
patient? How to integrate these biologic treatments into the
standard care? In addition, these agents are extremely expensive
compared with the standard-of-care treatment, including surgery
that was reported more cost-effective than dupilumab for upfront
treatment of CRSwNP.34 Frequent visits to the hospitals and
injections may also reduce patients’ compliance. All these factors
require careful consideration before deciding to choose 1 treat-
ment over another.
Overall, our current findings suggest that dupilumab is safe
and exhibits the best efficacy among the 4 biologics used for the
treatment of patients with CRSwNP. Head-to-head comparisons
with longer follow-up and real-world evidence are necessary to
confirm these findings and determine how these biologics fare in
the long run. Future research on subgroups will further facilitate
personalized treatment of patients with CRSwNP.
Acknowledgments
S. Cai, S. Xu, H. Lou, and L. Zhang contributed to the design
of the research. S. Cai, S. Xu, and L. Lou performed the data
collection and analysis, and wrote the manuscript. H. Lou and L.
Zhang contributed amendments to the manuscript and revised it
critically. All authors approved the final version to be published.
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J ALLERGY CLIN IMMUNOL PRACT CAI ET AL 1886.e1
VOLUME 10, NUMBER 7

ONLINE REPOSITORY

TABLE E1. Full search terms for PubMed

11 #6 AND #9 AND #10
10 ((randomized controlled trial[Publication Type]) OR (controlled
clinical trial[Publication Type]) OR (randomized[Title/
Abstract]) OR (placebo[Title/Abstract]) OR (randomly[Title/
Abstract]) OR (trial[Title/Abstract]) OR (groups[Title/
Abstract])) NOT ((animals[MeSH Terms]) NOT (humans
[MeSH Terms]))
9 #7 OR #8
8 ((biologic*[Title/Abstract]) OR (biotherap*[Title/Abstract]) OR
(monoclonal antibod*[Title/Abstract]) OR (lebrikizumab
[Title/Abstract]) OR (tralokinumab[Title/Abstract]) OR
(reslizumab[Title/Abstract]) OR (benralizumab[Title/
Abstract]) OR (mepolizumab[Title/Abstract]) OR
(omalizumab[Title/Abstract]) OR (tezepelumab[Title/
Abstract]) OR (anti-IL-4[Title/Abstract]) OR (anti-IL-5[Title/
Abstract]) OR (anti-IL-13[Title/Abstract]) OR (anti-IgE[Title/
Abstract]) OR (anti-IL-33[Title/Abstract])) OR (anti-TSLP
[Title/Abstract])
7 (antibodies, monoclonal[MeSH Terms]) OR (biological therapy
[MeSH Terms])
6 #1 OR #2 OR #3 OR #4 OR #5
5 ((nasal[Title/Abstract]) OR (rhin*[Title/Abstract]) OR (nose
[Title/Abstract])) AND ((polyps[Title/Abstract]) OR (polyp
[Title/Abstract]) OR (polyposis[Title/Abstract]))
4 (nasal polyp*[Title/Abstract]) OR (rhinopolyp*[Title/Abstract])
3 nasal polyps[MeSH Terms]
2 ((chronic rhinosinusitis[Title/Abstract]) OR (chronic sinusitis
[Title/Abstract])) OR (CRSwNP[Title/Abstract])
1 sinusitis[MeSH Terms]

CRSwNP, Chronic rhinosinusitis with nasal polyps; MeSH, Medical Subject Head-
ings; TSLP, antiethymic stromal lymphopoietin.

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1886.e2 CAI ET AL J ALLERGY CLIN IMMUNOL PRACT
JULY 2022

TABLE E2. Description of outcomes

Outcomes Grading method
NPS NPS was graded as 0 to 4 for each nostril (total ranges from 0 to 8), with higher scores indicating greater size of
polyps.
Nasal congestion severity Nasal congestion severity was defined as the scores reflecting the severity of nasal congestion, obstruction, or
blockage, with higher scores indicating greater symptom severity.
 The SINUS-24 and -52, POLYP 1 and 2, and OSTRO trials used a 0 to 3 categorical scale, where 0 ¼ no
symptoms, 1 ¼ mild symptoms, 2 ¼ moderate symptoms, and 3 ¼ severe symptoms.
 The SYNAPSE and Bachert 2017 trials used a 0 to 10 VAS score, with higher scores indicating greater severity.
SNOT-22 score The SNOT-22 score ranges from 0 to 110, with higher scores representing worse quality of life.
Loss of smell severity Loss of smell severity was defined as the scores reflecting the severity of decreased or loss of smell, with higher
scores indicating greater symptom severity.
 The SINUS-24 and -52, POLYP 1 and 2, and OSTRO trials used a 0 to 3 categorical scale, where 0 ¼ no
symptoms, 1 ¼ mild symptoms, 2 ¼ moderate symptoms, and 3 ¼ severe symptoms.
 The SYNAPSE and Bachert 2017 trials used a 0 to 10 VAS score, with higher scores indicating greater severity.
UPSIT score The UPSIT score ranges from 0 to 40, with higher scores reflecting improved smell.
Lund-Mackay CT score The Lund-Mackay CT score ranges from 0 to 24 reflecting the degree of sinus opacification.
Overall symptom VAS score The overall symptom VAS score was from 0 (not troublesome) to 10 (worse thinkable troublesome) to evaluate the
total disease severity.
Total symptoms severity Total symptoms severity was defined as the sum of participant-assessed nasal symptom scores, with higher scores
indicating greater symptom severity.
 The SINUS-24 and -52 trials used the sum of scores (ranging from 0 to 9) for nasal congestion/obstruction,
decreased or loss of sense of smell, and rhinorrhea (anterior or posterior nasal discharge), each accessed on
0 to 3 categorical scale.
 The POLYP 1 and 2 trials used the sum of nasal congestion score, anterior rhinorrhea score, posterior rhinorrhea
score, and sense of smell score. Total score ranged from 0 to 12.
 The SYNAPSE trial used a composite VAS score (ranging from 0 to 10), calculated as the average of individual
scores of nasal obstructions, nasal discharge, mucus in the throat, and loss of smell.
Serious AEs The number of patients with at least 1 serious AE.
Nonserious AEs The number of patients with at least 1 nonserious AE.
AEs, Adverse events; CT, computed tomography; NPS, nasal polyp score; SNOT-22, 22-item Sino-Nasal Outcome Test; UPSIT, University of Pennsylvania Smell Identification
Test; VAS, visual analog scale.

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J ALLERGY CLIN IMMUNOL PRACT CAI ET AL 1886.e3
VOLUME 10, NUMBER 7

TABLE E3. Trial transitivity

Omalizumab
Variable Dupilumab (n [ 724) (n[ 265) Mepolizumab (n [ 512) Benralizumab (n [ 410)
Age (y) 51.5 50.6 49.1 50.2
Female (%) 39.7 35.5 33.7 35.9
Body mass index (kg/m2) 27.9 27.5 27.7 27.9
Previous nasal surgery (%) 63.5 59.6 100 73.2
Time since previous nasal polyp surgery (y) 7.3 NA NA 6.9
Prior systematic corticosteroids within 1 y (%) 60.4 22.3 NA NA
Comorbid asthma (%) 59.2 57.0 72.5 67.8
Nasal polyp score (scale: 0-8) 6.0 6.2 5.6 6.1
Nasal congestion severity* 2.4 2.4 8.7 2.6
SNOT-22 score (scale: 0-110) 51.0 59.8 61.2 69.2
Loss of smell severity* 2.8 2.6 9.5 NA
UPSIT score (scale: 0-40) 14.0 13.2 NA NA
Blood eosinophil count (cells/mL) 434.2 340.4 NA 447
Serum total IgE (IU/mL) 229.4 175.0 NA 232.3
Data are represented as percentages (%) or means.
NA, Not available; SNOT-22, 22-item Sino-Nasal Outcome Test; UPSIT, University of Pennsylvania Smell Identification Test; VAS, visual analog scale.
*The data for dupilumab, omalizumab, and benralizumab used a 0 to 3 categorical scale; the data for mepolizumab used a 0 to 10 VAS score.

TABLE E4. Selection criteria of the included studies*

Selection criteria SINUS-24 and -52 POLYP 1 and 2 SYNAPSE Bachert 2017 OSTRO
Age
18 18-75
18 18-70 18-75
Weight or BMI No restriction No restriction Body weight
40 kg BMI 19.0-31.0 Body weight
40 kg
Diagnosis: CRS with Yes Yes Yes Yes Yes
bilateral NP
NPS
5 and
2 for Yes Yes Yes Yes Yes
each nostril
SNOT-22 score No restriction
20 No restriction No restriction
30
Nasal congestion
2 out of 3 at V1 $
2 out of 3 at V1 >5 out of 10 No restriction
2 out of 3 over 2
severity A weekly mean >1 out of $A weekly mean >1 weeks before V1
3 at randomization out of 3 at A biweekly mean
randomization
1.5 out of 3 at
randomization
Other symptoms At least 1 other associated At least 1 other $At least 1 other An overall VAS No restriction
symptom associated associated symptom score >7
symptom symptom
$An overall VAS
symptom score >7
Prior NP treatments SCS treatment within the INCS for at least 4 wk $INCS for at least 8 $INCS for at least 3 $INCS for at least 4
last 2 y, prior surgery, before screening wk before mo and/or a prior wk before
or both screening short course of SCS screening
$Surgery in the $Previous surgery $Prior SCS treatment
previous 10 y or surgery
Concomitant asthma Stable in the previous 6 No restriction An exacerbation Maintained on no An exacerbation
wk using their regular requiring more than 10 mg/ requiring SCS
asthma treatment hospitalization d of prednisolone or treatment or
within 4 wk of the equivalent hospitalization
screening was (>24 h) within 4
excluded wk of screening
was excluded

BMI, Body mass index; CRS, chronic rhinosinusitis; INCS, intranasal corticosteroids; NP, nasal polyps; NPS, nasal polyp score; SCS, systemic corticosteroids; SNOT-22, 22-
item Sino-Nasal Outcome Test; V1, the first visit; VAS, visual analog scale.
*Scale 0 to 3 was used.

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 1886.e4
TABLE E5. Efficacy outcome measurements extracted from the publications

CAI ET AL
No. of patients
Nasal Overall Total with ‡1
congestion symptom VAS Loss of smell symptoms Lund-Mackay improvement in
Studies Groups NPS severity* SNOT-22 score score severity* severity† UPSIT score CT score NPS
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24 wk
SINUS-24 Placebo (n ¼ 133) 0.17 (1.73) 0.45 (0.81) 9.31 (18.68) 1.34 (2.77) 0.29 (0.81) 1.17 (1.96) 0.70 (8.19) NA 23
Dupilumab (n ¼ 143) 1.89 (1.67) 1.34 (0.84) 30.43 (18.42) 4.54 (2.75) 1.41 (0.84) 3.77 (1.91) 11.26 (8.01) NA 93
SINUS-52 Placebo (n ¼ 153) 0.10 (1.73) 0.38 (0.87) 10.40 (19.91) 1.39 (2.97) 0.23 (0.99) 1.00 (2.47) 0.81 (8.78) NA 16
Dupilumab (n ¼ 295) 1.71 (1.89) 1.25 (1.03) 27.77 (21.64) 4.32 (3.26) 1.21 (1.03) 3.45 (2.58) 9.71 (9.62) NA 183
POLYP 1 Placebo (n ¼ 66) 0.06 (1.30) 0.35 (0.89) 8.58 (16.90) NA 0.23 (0.81) 1.06 (2.76) 0.63 (7.31) NA
Omalizumab (n ¼ 72) 1.08 (1.36) 0.89 (0.85) 24.7 (17.06) NA 0.56 (0.76) 2.97 (2.80) 4.44 (7.13) NA Placebo: 38 (n ¼
131)z
POLYP 2 Placebo (n ¼ 65) 0.31 (1.29) 0.20 (0.89) 6.55 (17.66) NA 0.13 (0.81) 0.44 (2.58) 0.44 (6.53) NA
Omalizumab (n ¼ 62) 0.90 (1.34) 0.70 (0.87) 21.59 (17.72) NA 0.58 (0.79) 2.53 (2.60) 4.31 (6.54) NA Omalizumab: 75
(n ¼ 134)z
SYNAPSE Placebo (n ¼ 201) 0.12 (1.51) 2.22 (3.02) 16.06 (22.83) 1.34 (4.53) 0.01 (0.01) 1.21 (3.99) NA NA 14
Mepolizumab (n ¼ 206) 0.57 (1.53) 3.66 (3.06) 26.44 (34.29) 2.96 (5.68) 0.51 (2.11) 2.59 (5.35) NA NA 27
Bachert 2017 Placebo (n ¼ 51) 0.70 (1.78) 2.20 (3.06x) 9.14 (34.29x) NA 1.10 (2.11x) NA NA NA 53
Mepolizumab (n ¼ 54) 1.90 (1.83) 3.90 (3.06x) 24.37 (34.29x) NA 3.00 (2.11x) NA NA NA 88
OSTRO Placebo (n ¼ 203) 0.03 (1.29) 0.54 (0.90) 16.46 (24.68) NA 0.21 (0.64) NA NA NA 44
Benralizumab (n ¼ 207) 0.32 (1.27) 0.59 (0.88) 18.63 (24.59) NA 0.30 (0.63) NA NA NA 65
End of follow-up
SINUS-52 Placebo (n ¼ 153) 0.15 (1.86) 0.37 (0.99) 8.88 (19.91) 0.93 (3.22) 0.18 (1.11) 0.93 (2.47) 0.78 (8.78) 0.11 (4.58) NA
Dupilumab (n ¼ 295) 2.15 (1.82) 1.41 (0.91) 30.13 (19.89) 4.57 (3.16) 1.39 (1.04) 3.98 (2.43) 9.76 (8.79) 6.23 (4.53) NA
SYNAPSE Placebo (n ¼ 201) 0.10 (1.46) 2.50 (3.15) 15.70 (23.93) 2.50 (3.08) 1.40 (2.65) 2.20 (2.82) 0.40 (8.60) NA 57
n ¼ 54
Mepolizumab (n ¼ 206) 0.90 (1.90) 4.20 (3.42) 29.40 (24.67) 4.30 (3.43) 2.80 (3.61) 3.80 (3.19) 1.70 (10.80) NA 104
n ¼ 54
OSTROǁ Placebo (n ¼ 203) 0.11 (1.73) 0.42 (0.99) 8.75 (32.33) NA 0.19 (0.79) NA NA 0.14 (4.90) 30
n ¼ 90
Benralizumab (n ¼ 207) 0.36 (1.73) 0.70 (0.99) 16.25 (32.33) NA 0.42 (0.79) NA NA 0.99 (4.90) 52
n ¼ 92

J ALLERGY CLIN IMMUNOL PRACT

Data are represented as mean (SD) or n without manipulation.
CT, Computed tomography; NA, not available; NPS, nasal polyp score; SD, standard deviation; SNOT-22, 22-item Sino-Nasal Outcome Test; UPSIT, University of Pennsylvania Smell Identification Test; VAS, visual analog scale.
*The SINUS-24 and -52, POLYP 1 and 2, and OSTRO trials used a 0 to 3 categorical scale; the SYNAPSE and Bachert 2017 trials used a 0 to 10 VAS score.
†The SINUS-24 and -52, POLYP 1 and 2, and SYNAPSE trials used 0 to 9, 0 to 12, and VAS (0 to 10) scales, respectively.
zPooled results of POLYP 1 and 2.
xSDs were borrowed from the experimental group of the SYNAPSE trial.
ǁSDs were calculated using experimental n and mean, control n and mean, and mean difference (95% confidence interval) of between-group comparison.

JULY 2022
J ALLERGY CLIN IMMUNOL PRACT CAI ET AL 1886.e5
VOLUME 10, NUMBER 7

TABLE E6. Safety outcome measurements extracted from the publications

No. of patients with at least No. of patients with at least
Studies Groups 1 serious AE (n) 1 nonserious AE (n)
SINUS-24 Placebo (n ¼ 132) 19 61
Dupilumab (n ¼ 143) 6 55
SINUS-52 Placebo (n ¼ 150) 16 111
Dupilumab (n ¼ 297) 20 185
POLYP 1 Placebo (n ¼ 66) 1 16
Omalizumab (n ¼ 72) 0 12
POLYP 2 Placebo (n ¼ 64) 1 20
Omalizumab (n ¼ 63) 3 17
SYNAPSE Placebo (n ¼ 201) 14 141
Mepolizumab (n ¼ 206) 12 139
Bachert 2017 Placebo (n ¼ 52) 0 39
Mepolizumab (n ¼ 53) 0 35
OSTRO Placebo (n ¼ 203) 17 143
Benralizumab (n ¼ 207) 23 137
AE, Adverse event.

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1886.e6 CAI ET AL J ALLERGY CLIN IMMUNOL PRACT
JULY 2022

FIGURE E1. Indirect comparison of secondary outcome mea-

sures. (A) Mean difference in overall symptom VAS score change
from baseline to 24 weeks and EOF; (B) standardized mean dif-
ference in total symptoms severity change from baseline to 24
weeks and EOF; and (C) odd ratio of nonserious AEs at EOF. AEs,
Adverse events; CI, confidence interval; MD, mean difference;
SMD, standardized mean difference; VAS, visual analog scale.

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J ALLERGY CLIN IMMUNOL PRACT CAI ET AL 1886.e7
VOLUME 10, NUMBER 7

FIGURE E2. Sensitivity analysis in phase 3 trials. (A) Mean difference in NPS change from baseline to 24 weeks; (B) standardized mean
difference in nasal congestion severity change from baseline to 24 weeks; (C) mean difference in SNOT-22 score change from baseline to
24 weeks; and (D) standardized mean difference in loss of smell severity change from baseline to 24 weeks. CI, Confidence interval; MD,
mean difference; NPS, nasal polyp score; RCTs, randomized controlled trials; SMD, standardized mean difference; SNOT-22, 22-item
Sino-Nasal Outcome Test.

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