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Mini-review

Biotherapy and treatment of adult primary chronic rhinosinusitis

with nasal polyps: Cellular and molecular bases
S. Bartier a,b,c,d,e,∗ , A. Coste a,b,c,d,e , E. Béquignon a,b,c,d,e
a
Service d’Oto-Rhino-Laryngologie et Chirurgie Cervico-Faciale, Centre Hospitalier Intercommunal de Créteil, 94000 Créteil, France
b
Service d’Oto-Rhino-Laryngologie et Chirurgie Cervico-Faciale, Hôpital Henri Mondor, 94000 Créteil, France
c
Université Paris-Est Créteil (UPEC), Faculté de Médecine, 94000 Créteil, France
d
INSERM U955, 94000 Créteil, France
e
CNRS, ERL 7240, 94000 Créteil, France

a r t i c l e i n f o a b s t r a c t

Keywords: The present article reviews the molecular and cellular mechanisms involved in the pathophysiology of
Chronic rhinosinusitis with nasal polyps chronic rhinosinusitis with nasal polyps (CRSwCRSwNP) and underlying the action mechanisms of bio-
Biotherapy therapies. Biotherapy uses substances naturally produced by the organism or their specific antagonists
Pathophysiology
targeting a proinflammatory mechanism. CRSwCRSwNP is a form of chronic rhinosinusitis (CRS), which
Endotypes
is classically subdivided in to 2 types according to the presence of polyps. In recent years, the concept
of endotypes emerged, with a more exhaustive definition of the types of CRS according to inflamma-
tory mechanism, with a view to developing personalized treatments. CRSwNP pathophysiology is poorly
understood. Polyps arise from a primary epithelial lesion in a context of chronic local inflammation,
mainly type 2 in Europe, implicating eosinophils, IgE, Th2 cytokines (IL-4/IL-13, IL-5) and T and B cells.
Biotherapy seems promising in CRSwNP. The present review details the various pathophysiological path-
ways underlying the action mechanisms of biotherapies, and the various published studies, assessing
efficacy and mode of action in the treatment of CRSwNP.
© 2020 Elsevier Masson SAS. All rights reserved.

1. Introduction 2 for eosinophilic CRS (tissue eosinophil rate > 10 eosinophils/field

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a chronic
inflammatory disease of the upper airway, characterized by
bilateral edematous fibroepithelial polyps [1,2], belonging to
the chronic rhinosinusitis (CRS) group [3]. It affects 1–4% of the
population, leading to morbidity and severely impaired qual-
ity of life [3–6]. The aim in recent years has been to improve
understanding of proinflammatory mechanisms and to identify
biomarkers enabling CRS to be classified according to endotype
[7–9]. Many studies showed the importance of eosinophils and
proinflammatory cytokines in the development and mainte-
nance of the local inflammatory reaction [10–12]. The 2020
European Position Paper (EPOS) on Rhinosinusitis and Nasal
Polyps proposed a new classification of CRS according to endotype
(https://www.rhinologyjournal.com/Documents/Supplements/
supplement 29.pdf), as previously described in asthma [13]: type-
(× 400), including CRSwNP and allergic fungal sinusitis) and
non-type-2 for non-eosinophilic CRS (tissue eosinophil rate
≤ 10 eosinophils/field (× 400)). The gold-standard treatment for
CRSwNP is local and systemic corticosteroids with not more than
4 courses per year, and surgery in case of failure [14,15]. Recur-
rence, however, is classical [16,17]. Biotherapies gave promising if
variable results in type-2 asthma, with an 18–25% non-response
rate [18,19].
The aim of the present review was, firstly, to present the var-
ious molecular and cellular pathways currently under study as
biotherapy targets and, secondly, to describe the various exist-
ing biotherapies, and their efficacy and indications. A literature
search on PubMed, with the search-terms “chronic rhinosinusi-
tis with nasal polyps” and “biologics” selected articles of interest,
focusing on those with high levels of evidence, meta-analyses and
international expert guidelines.

∗ Corresponding author. Service d’Oto-Rhino-Laryngologie et Chirurgie Cervico-

2. Pathophysiology
Faciale, CHU Henri Mondor, 51 Avenue du Maréchal De Lattre de Tassigny, 94000
Créteil, France. CRSwNP is a multifactorial condition, the pathophysiologi-
E-mail address: sophie.bartier@aphp.fr (S. Bartier). cal mechanisms of which are poorly understood. It originates in

https://doi.org/10.1016/j.anorl.2020.12.002
1879-7296/© 2020 Elsevier Masson SAS. All rights reserved.

Please cite this article as: Bartier S, et al, Biotherapy and treatment of adult primary chronic rhinosinusitis with nasal polyps: Cellular
and molecular bases, European Annals of Otorhinolaryngology, Head and Neck diseases, https://doi.org/10.1016/j.anorl.2020.12.002
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ANORL-1174; No. of Pages 8 ARTICLE IN PRESS
S. Bartier et al.
Fig. 1. Molecular and cellular pathways of Th2 epithelial inflammation, adapted
from Gubernatorova et al., 2018 [48]. IgE: Immunoglobulin E; IL: Interleukin; ILC2:
type-2 Innate Lymphoid Cells).
epithelial aggression. Historically, an experimental model of polyp
formation was described by Norlander in 1996 [20]. The epithelial
aggression leads to rupture of the basal membrane, followed by
dysregulation of the repair process with creation of a conjunctive
hernia containing neovessels, inflammatory cells and fibroblasts.
Finally, there is re-epithelialization of the hernia starting from the
edges, with secondary autonomization of polyps accompanied by
epithelial remodeling in a context of chronic nasal inflammation
[21,22]. Numerous local, systemic, microbial, environmental, aller-
gic, genetic and iatrogenic factors seem to be involved [23]. Here
we shall focus exclusively on pathophysiological mechanisms tar-
geted by the new biotherapies. Classically, in Europe CRSwNP is
described as a type-2 inflammatory disease, involving eosinophils,
IgE and cytokines (principally, IL-5 and IL-4/IL-13), as distinct from
type-1 (involving neutrophils and IL-17) [11]. Type-2 inflamma-
tion mediator levels are higher than in healthy subjects: blood
eosinophils > 150/mL, total IgE > 150 IU/L, Th2 (T-helper 2), IL-5
and IL-13 cytokines, eotaxin-2 and chemokine ligand 13 (CCL-13)
[24–29]. Fig. 1 shows the molecular and cellular pathways of type-2
inflammation.
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3. Infectious factor and Staphylococcus Aureus
Infectious factors (fungal, viral and bacterial) in eosinophil
recruitment and activation were highlighted in several studies
[30,31]. The implication of Staphylococcus aureus as producer of
enterotoxins has been explored for several years. Staphylococcus
aureus colonization is seen in 63% of CRSwNP patients, versus
less than a third of those with CRS without nasal polyps and 20%
of healthy controls [32]. Enterotoxins (or superantigens) are the
target of specific IgEs. They are seen in CRSwNP tissue and are
involved in a molecular cascade leading to IgE synthesis and pre-
dominantly eosinophilic inflammation [32,33]. Superantigens are
microbial toxins, triggering polyclonal proliferation of T cells that,
once activated, massively release cytokines. Massive B-cell activa-
tion by superantigens is also known to upregulate IL-4, Il-5 and
IL-13, leading to production of polyclonal IgE and histamine release
[34].
4. Eosinophils
More than 20 years ago, Bachert et al. demonstrated the key role
of eosinophils in polyp formation and growth in type-2 inflam-
mation [11,35]. The analogy with type-2 asthma, also featuring
eosinophilic inflammation, shed light on the pathophysiology of
CRSwNP. After adhesion to the epithelium by ICAM-1, eosinophils
contribute to fibrosis and edema by secretion of Transforming
Growth Factor ␤ (TGF-␤1), inducing production of fibroblasts
and expression of Vascular Endothelial Growth Factor, which are
both elevated in polyps [12,36]. Once recruited and activated,
eosinophils release toxic mediators underlying epithelial lesions
and tissue remodeling [37].
5. Interleukins
5.1. IL-4 and IL-13
Levels of IL-4 and IL-13, two cytokines with structural similari-
ties in their receptor (shared subunit), are higher in polyps than in
CRS without polyps or healthy tissue [38]. In response to epithelial
aggression, type-2 inflammation leads to epithelial cell production
of thymic stromal lymphopoietin, activating type-2 innate lym-
phoid cells. This results in production of type-2 cytokines, including
IL-4 and IL-13. IL-4 induces naïve T-cell differentiation into Th2
and stimulates activation of B cells and thus production of IgE.
In IL-4 knockout mice, IgE levels collapse, as does local inflam-
mation [39]. IL-4 and IL-13 also exert feedback on epithelial cells
by reducing expression of tight junctions and increasing mucus
production. IL-13 induces increased expression of vascular cell
adhesion molecules, thereby facilitating recruitment and transmi-
gration of eosinophils, basophils and mast cells in the epithelium
[37].
5.2. IL-5
IL-5 is another glycoprotein produced by activated Th2 T cells,
mast cells, type-2 innate lymphoid cells and eosinophils them-
selves. IL-5 has two particular cell targets, triggering differentiation
and activation: B cells, and eosinophils. The activated B cells syn-
thesize IgE and induce proliferation of eosinophils [40]. The IL-5
receptor comprises a subunit specific to IL5␣ (IL-5R␣) and another
non-specific subunit, ␤c. Interaction between IL-5 and its recep-
tor activates an intracellular transduction pathway including Janus
kinases (JAK 1 and JAK 2), which in return activate signal trans-
ducers and activators of transcription (STAT) 1, 3 and 5, involved
in eosinophil proliferation (Fig. 2). IL-5 elevation in polyps is
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Fig. 2. Signaling pathways activated by IL-5 in eosinophils, adapted from Pelaia et al., 2016 [40]. IL-5 binding to its receptor induces dimeric assembly of 2 subunits of the
IL-5 receptor (subunits ␣ and ␤c). Activated signaling pathways include JAK/STAT, MAPK, PI3K and NF-KB and are involved in transcription of genes involved in eosinophil
differentiation, degranulation, survival, proliferation and adhesion. IL-5: interleukin 5; JAK: Janus Kinases; STAT: signal transducer and activators of transcription; PI3K
phosphoinositide-3-kinase; MAPK: mitogen-activated protein kinases.

associated with a more severe form of CRSwNP and concomitant 6. IgEs

asthma, while low IL-5 levels are associated with CRSwNP without
asthma [8,41]. IL-5 is also elevated in mucosa in recurrent compared
to non-recurrent forms of CRSwNP [42].
5.3. IL-9
IL-9 is a glycoprotein produced by Th2 cells, mast cells and
eosinophils [43]. Mortuaire et al. showed that IL-9 is involved in
IL-5 receptor expression and acts synergically with IL-5 to reduce
eosinophil apoptosis in asthma [44–46].
In rhinitis and allergic asthma, IgE-dependent sensitization to
allergens induces eosinophilic inflammation in the epithelium and
respiratory mucosa. In CRSwNP, total non-specific IgEs, without
obvious link to allergy, are elevated in polyp tissue, as is blood
eosinophil level [52]. Antibacterial IgEs specific to Staphylococcus
aureus endotoxins play a major role by activating B and T cells then
releasing IL-4/-5/-13 and finally polyclonal IgE [52]. B cells activated
by other proinflammatory factors such as IL-5 also induce IgEs and
thus eosinophil proliferation [40]. IgEs thus seem to amplify the
eosinophilic inflammatory reaction in CRSwNP [52].

7. Biotherapies: mode of action and results

5.4. IL-6
The pathophysiology of asthma is very close to that of CRSwNP,
and shows 2 endotypes: type 2 (eosinophilic and allergic) and type
IL-6 is a proinflammatory cytokine produced by T and B cells,
1 [53]. Therapies targeting type-2 inflammation give good results
monocytes, macrophages, fibroblasts, keratinocytes, endothelial
in severe allergic asthma. Hypothesizing comparable pathophysi-
cells, mesenchymal cells and adipocytes, activating T cells and
ology, as suggested by many studies, biotherapies have been tested
immunoglobulin secretion by B cells. IL-6 expression is ele-
in CRSwNP, with promising results [54]. Four monoclonal antibod-
vated in polyps compared to healthy tissue [47]. In asthma,
ies are being investigated [55]. Two lack market authorization in
IL-6 contributes to type-2 eosinophilic or neutrophilic allergic
France for CRSwNP alone, but can be prescribed by pneumologists
inflammatory response, depending on whether it is produced by
for severe allergic asthma (anti-IgE: omalizumab) and eosinophilic
macrophages or by dendritic cells [48]. Bequignon et al., in an in-
asthma (anti-IL5: reslizumab, mepolizumab and benralizumab).
vitro model of primary culture of human nasal epithelial cells taken
Dupilumab, a human monoclonal antibody specifically inhibiting
from polyps, showed the influence of IL-6 on epithelial repair, with
IL-4 and IL-13 signaling, recently obtained European market autho-
accelerated wound closure and increased cellularity only in case of
rization (with French authorization expected) for severe CRSwNP.
epithelial lesion, which may make it a major cytokine in CRSwNP
Anti-IL5 antibodies were the first to be studied in CRSwNP, followed
pathophysiology and in particular in the dysregulation of epithelial
by anti-IgEs and then anti-IL-4 and anti-IL-13 (Fig. 3). Fig. 4 presents
repair following the initial epithelial wound [49].
the molecular and cellular targets. They require initial hospital pre-
scription, with 1 or 2 subcutaneous injections per month. Their high
cost, subcutaneous route and risk of anaphylactic shock limit use.
5.5. IL-10 Tables 1, 2 and 3 show the main phase 2 and 3 studies of anti-IgEs,
anti-IL-5s and anti-IL-4 and anti-IL-13 for CRSwNP.
IL-10 is produced by several types of cell: Th1 and Th2 cells, T
regulatory cells, monocytes, and macrophages; it is overexpressed 8. Anti-IgE (Table 1)
in CRSwNP [50]. It has anti-inflammatory action by inhibiting
proinflammatory cytokine production by Th1 cells, but also a Omalizumab is an anti-IgE IgG1 monoclonal antibody. For more
reversible proinflammatory effect in case of IL-10 overproduction than 10 years, it has shown efficacy against resistant allergic
[51]. asthma [56], by fixing to IgEs and competition with high-affinity IgE

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Fig. 3. Chronology of emergence of biotherapies and major studies. FDA: Food and Drug Administration; PoC: proof of concept; EU: European Union.

Fig. 4. Cells and Th2 inflammation mediators and corresponding biotherapies, adapted from Bachert et al., 2020 [55]. IgE: Immunoglobulin E; IL: interleukin; R␣: receptor
subunit ␣; FcR: Fc epsilon RI (IgE high-affinity receptor).

Table 1
Studies of anti-IgE in CRSwNP.

Study Method Participants Interventions Endpoints Results

Pinto et al., 2010 [58] Controlled randomized 14 patients with CRS, 7 patients with SNOT 20 at 1, 2, 3, 4, 5, 6 Omalizumab compared to
study, double blind, versus including 12 with CRSwNP omalizumab (0.016 mg/kg months placebo:
placebo subcutaneous) vs injection SF-36 at 6 months − No significant difference
of placebo At 6 months: nasal in SNOT-20 or SF-36
symptoms score, UPSIT, − Improved opacity on
radiology score, peak nasal coronal slice CT
inspiratory flow, use of − Less corticotherapy
other drugs, during trial (median 0 vs 1,
eosinophils in lavage, side p < 0.043)
-effects at 6 months − Less antibiotics (0 vs 1,
p < 0.32)
− No side-effects or
adverse events in either
group
Gevaert et al., 2013 Controlled randomized 24 patients with CRSwNP Omalizumab every 2 At 16 weeks: Anti-IgE vs placebo:
[59] study, double blind, versus weeks/8 injections in all, or − Quality of life (RSOM-31, − No significant difference
placebo every 4 weeks/4 injections AQLQ, SF-36) in quality of life, but
in all according to total − Symptoms score significant improvement
serum IgE and body weight − Endoscopy score over baseline with anti-IgE
(max. dose 375 mg) (n = 16) − Lund-Mackay CT score on AQLQ, SF-36 physical
or placebo (n = 8) − Spirometry domain and some
− Adverse effects RSOM-31 subdomains
− Symptoms scores lower
with anti-IgE
− Reduced polyps size on
endoscopy
− Improved Lund-MacKay
score
− More colds (p = 0.02)
− 1 fatal lymphoblastic
lymphoma within 1 year of
study

AQLQ: Asthma Quality of Life Questionnaire; IgE: Immunoglobulin E; CRSwNP: Chronic rhinosinusitis with nasal polyps; CRS: chronic rhinosinusitis; RSOM-31: Rhinosinusitis
Outcome Measure-31; SNOT: Sino-Nasal Outcome Test; SF-36: Short Form 36; UPSIT: University of Pennsylvania Smell Identification Test.

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Table 2
Studies of anti-IL-5 in CRSwNP.

Study Method Participants Interventions Endpoints Results

Gevaert et al., 2006 Controlled, double blind, 24 CRSwNP patients Reslizumab 3 mg/kg (n = 8) At 4 weeks: − No significant
[64] versus placebo or 1 mg/kg (n = 8) × 1 dose − Endoscopy score (0–8) improvement in symptoms
vs placebo (n = 8) − Symptoms or peak nasal inspiratory
− Peak nasal inspiratory flow
flow − Endoscopy score
− Biomarkers: eosinophils, significantly reduced (to 1)
ECP, eotaxin, IL5 in 1 mg/kg group
− Significant reduction in
blood eosinophils, serum
ECP and IL5R␣
Gevaert et al., 2011 Controlled, double blind, 30 severe CRSwNP patients Mepolizumab 750 mg IV/4 At 8 weeks: − No change in symptoms
[67] versus placebo week × 2 doses (n = 20) vs − Endoscopy score score
placebo/4 week × 2 doses − CT − Significantly improved
(n = 10) − Peak nasal inspiratory endoscopy score
flow − Improved variation in
− Symptoms peak nasal inspiratory flow
− Biomarkers: blood − Significant reduction in
eosinophils, serum and blood eosinophils, serum
local ECP, IL5R␣, IL5, IgE ECP and IL5R␣ in
mepolizumab group
Bachert et al., 2017 Controlled, double blind, 105 CRSwNP patients Mepolizumab 750 mg IV/4 At 25 weeks: − Less surgery in Mepo vs
[68] versus placebo week × 6 months (n = 54) − No revision surgery placebo
vs placebo/4 week × 6 − Severity VAS − Significant improvement
months (n = 53) − Endoscopy score with Mepo for VAS,
− Symptoms score: SNOT22 and peak nasal
symptoms VAS, SNOT22, inspiratory flow
EQ-5D, peak nasal − Reduction in blood
inspiratory flow, olfaction eosinophils in Mepo, but
− Eosinophils not placebo
− Respiratory EFR − No difference in EQ-5D,
olfaction scores or lung
function

ECP: pour eosinophil cationic protein; EQ-5D: EuroQol 5 Dimensions; IL: Interleukin; CRSwNP: chronic rhinosinusitis with nasal polyps; CRS: chronic rhinosinusitis; SNOT:
Sino-Nasal Outcome Test; SF-36: Short Form 36; UPSIT: University of Pennsylvania Smell Identification Test.

Table 3
Studies of anti-IL-4 and anti-IL-13 in CRSwNP.

Study Method Participants Interventions Endpoints Results

Bachert et al., 2016 Controlled 60 CRSwNP patients Subcutaneous At 16 weeks: − Significantly improved
[73] randomized, double dupilumab 600 mg or − Endoscopy score (0–8) endoscopy score
blind, versus placebo placebo loading doses − Lund-Mackay score − Significantly improved
then 15 daily doses of (0–24) Lund-Mackay score with
300 mg dupilumab − SNOT-22 dupilumab
(n = 30) or placebo − Olfaction (UPSIT) (0–40) − Significantly improved
(n = 30) − Symptoms VAS SNOT-22
− Biomarkers: − Significantly improved
eosinophiles, IgE, eotaxin. olfaction
− Side-effects − Side-effects:
rhinopharyngitis, injection
site reaction, headache
Bachert et al., 2019 Two phase-3 SINUS-24 276 and − SINUS-24: At 24 weeks: − Significantly improved
[74] controlled randomized, SINUS-52 448 severe dupilumab 300 mg − Endoscopy score endoscopy score with
double blind studies, CRSwNP patients or (n = 143) or placebo/2 − Nasal congestion score dupilumab
versus placebo: with prior surgery weeks (n = 133) for 24 − Lund-Mackay score − Significantly improved
LIBERTY CRSwNP weeks (0–24) nasal congestion score
SINUS-24 and LIBERTY − SINUS-52: − SNOT-22 with dupilumab
CRSwNP SINUS-52 dupilumab 300 mg/2 − Olfaction (UPSIT) (0–40) − Significantly improved
weeks for 52 weeks − Symptoms VAS Lund Mackay score with
(n = 150), or (congestion, anterior and dupilumab
dupilumab/2 weeks for posterior rhinorrhea, ON, − Significantly improved
24 weeks the/4 weeks impaired olfaction) SNOT-22, olfaction, use of
for the other 28 weeks − Biomarkers: eosinophils, systemic corticosteroids
(n = 145), or placebo/2 IgE, eotaxin, ECP, IL-5 (−74%) and surgery (−83%)
weeks for 52 weeks − Side-effects with dupilumab vs placebo
(n = 153). at 52 weeks
− Side-effects more
frequent with placebo

ECP: eosinophil cationic protein; IgE: Immunoglobulin E; IL: Interleukin; CRSwNP: chronic rhinosinusitis with nasal polyps; CRS: chronic rhinosinusitis; SNOT: Sino-Nasal
Outcome Test; SF-36: Short Form 36; UPSIT: University of Pennsylvania Smell Identification Test.

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receptors, thus reducing the amount of circulating IgE and sub-
sequent activation of mast cells and basophils [57]. After an
initial negative study [58], in 2012 Gevaert et al. provided first
proof of efficacy in a double-blind randomized controlled study in
patients with CRSwNP and asthma, both allergic and non-allergic
[59]. Subcutaneous omalizumab significantly improved clinical
and endoscopic CRSwNP scores, respiratory symptoms (nasal con-
gestion, anterior rhinorrhea, olfactory impairment, wheezing and
dyspnea) and quality of life. Other studies reported benefit in terms
of reduced nasal polyp size and symptom improvement compared
to placebo in corticoresistant CRSwNP or after failure of surgery,
with or without asthma [60,61]. Two phase 3 studies are under-
way, to assess safety and efficacy against placebo for 24 weeks in a
cohort with failure of local corticosteroids [62].
9. Anti-IL-5 (Table 2)
9.1. Reslizumab
Reslizumab is a humanized monoclonal antibody (IgG4, ␬)
targeting IL-5, prescribed for asthma with hypereosinophilia. It
neutralizes the action of IL-5 by high-affinity binding to the sub-
unit of IL-5R␣ binding to IL-5, thus preventing binding to the cell
surface receptor and blocking its biological function and reduc-
ing eosinophil survival and activation [63]. In a 2006 study against
placebo, Gevaert et al. demonstrated efficacy in reducing polyp size
with a single injection in half of the 12 patients, with blood IL-5
levels predictive of efficacy in respondents [64].
9.2. Mepolizumab
Mepolizumab is a humanized monoclonal antibody (IgG1, ␬)
likewise blocking IL-5 binding to IL-5R␣ by itself binding to IL-5
[65]. It is prescribed for resistant asthma with hypereosinophilia
(> 300/mm3 ) [66]. The first study against placebo in CRSwNP in
2011 found significant improvement in clinical and radiologi-
cal scores after a single injection [67]. In 2017, Bachert et al.
reported a double-blind randomized controlled study comparing
efficacy between mepolizumab in monthly intravenous injec-
tion versus placebo [68]. At 25 weeks, surgical intervention was
less frequent in the mepolizumab than the placebo group (n = 5
[10%] vs n = 16 [30%]; p = 0.006), with significant improvement in
rhinologic symptoms and endoscopic and radiologic scores. Inter-
estingly, pre-treatment blood eosinophil level was not predictive
of mepolizumab efficacy.
9.3. Benralizumab
Benralizumab, which recently received market authoriza-
tion for eosinophilic asthma, is an afucosylated humanized
monoclonal antibody (IgG1, ␬) binding to IL-5R␣. It induces
recruitment of natural killer cells, leading to apoptosis and
depletion of eosinophils and basophils within 24 h [69]. At
present, just 1 case report demonstrated efficacy, in an
asthma patient with hypereosinophilic CRSwNP, with signifi-
cant alleviation of CRSwNP [70]. Two other phase 3 studies
are underway (https://clinicaltrials.gov/ct2/show/NCT03401229,
https://clinicaltrials.gov/ct2/show/NCT04157335).
10. Anti-IL-4 and anti-IL-13 (Table 3)
Dupilumab is an IgG4 human monoclonal antibody blocking the
IL-4 receptor alpha subunit. Initially developed and indicated for
atopic dermatitis, it inhibits IL-4 signaling via the type-1 receptor
(IL-4R␣/␥c) and both IL-4 and IL-13 signaling via the type-2 recep-
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tor (IL-4R␣/IL-13R␣). In 2016, Bachert et al. demonstrated efficacy
with significant improvement in endoscopic and radiologic scores,
symptoms and quality of life in CRSwNP refractory to medical and
surgical treatment [71]. Two phase-3 randomized controlled stud-
ies versus placebo were recently published, assessing efficacy at
24 and 52 weeks’ treatment with 1 subcutaneous injection twice
monthly in corticoresistant CRSwNP or recurrent CRSwNP within
2 years of surgery. Bachert et al. reported significant improve-
ment in endoscopic, radiologic, symptomatic and quality-of-life
scores compared to placebo; they also found decreased serum
biomarkers (total IgE, periostin, eotaxin 3) [72]. Dupilumab was
the first biotherapy to receive FDA and EU approval in 2019 for
CRSwNP resistant to oral corticosteroids and in case of failure of
surgery.
11. Therapeutic perspectives
Other cytokines used against asthma are potential biotherapy
candidates. MEDI-528, an anti-IL-9 antibody, is being studied in
asthma, and tocilizumab, an anti-IL-6 antibody, has been used
against rheumatoid arthritis and systemic juvenile idiopathic
arthritis for several years [73,74].
12. Therapeutic indications
The 2020 EPOS set a framework for indications for biotherapies
in CRSwNP. They are indicated in second line after failure of medical
and surgical treatment, defined by bilateral post-ethmoidectomy
polyps associated to 3 of the following:
• Th2 inflammation: tissue eosinophils > 10/field or blood
eosinophils > 250/mm3 or blood IgE > 100 IU/mL;
• requirement for > 2 courses of general corticosteroids per year,
contraindication to corticosteroids or > 3 months’ low-dose treat-
ment;
• significant deterioration in quality of life (22-item Sino-Nasal
Outcome Test (SNOT-22) ≥ 40);
• significant hyposmia: anosmia on olfactory tests;
• diagnosis of comorbid asthma: asthma requiring iterative corti-
costeroid inhalation.
In April 2019, the EUFOREA expert panel (European Forum for
Research and Education in Allergy) reported broader indications
than in the EPOS, without the requirement for prior surgery [75].
Biotherapy for CRSwNP must meet 3 or 4 of the following criteria
(depending on prior ethmoidectomy):
• type 2 inflammation (biomarkers);
• requirement for general corticosteroid therapy (2 course during
the previous year);
• significant deterioration in quality of life;
• significant olfactory impairment;
• associated comorbid asthma.
The authors justified extending indications to patients without
prior ethmoidectomy as iterative surgery in Th2 CRSwNP fails to
prevent recurrence of polyps, suggesting biotherapy as first-line
alternative to surgery. Although they also stressed that biotherapies
reduce polyp size only slightly, rarely rendering surgery unneces-
sary [76], their recommendation was reinforced by Bidder et al.
[61], who found comparable results for quality of life on SNOT-22
in patients with grade 3 CRSwNP and asthma between the omal-
izumab and surgery groups, although the two were not perfectly
comparable, with a higher rate of pneumo-allergen sensitization
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in the omalizumab group, and follow-up was short and variable
according to group.
Whether the criteria are those of EPOS 2020 or EUFOREA, it is
noteworthy that the concept of “comorbid asthma” involves no
clinical severity criteria but is at the prescriber’s discretion. These
broader indications, backed by insufficient evidence, are bound
to run up against medicoeconomic realities, depending on health
system funding in different countries where biotherapy might
be prescribed for CRSwNP. Surgery is effective and cheaper, and
will remain an option of choice in many countries [77]. Biother-
apies will also run up against the “surgical culture” prevailing in
some countries, depending on surgeons’ habits, which vary greatly
between countries and even regions [78]. It is also to be borne in
mind that ENT physicians are necessarily interacting with pneu-
mologists, allergologists and pediatricians for these indications
and prescriptions, given the frequent association of asthma and
CRSwNP and the respective indications for different molecules in
the two.
13. Conclusion
Although benign, CRSwNP is frequent and disabling. The patho-
physiology is complex, and still imperfectly understood. Making
the parallel with asthma shed light on the molecular and cellu-
lar mechanisms involved: a major role for tissue remodeling, but
also for eosinophils and proinflammatory cytokines, which are
at the heart of Th2 inflammation. This has allowed therapeutic
targets to be identified and the advent of anti-IgE, anti-IL-5 and
anti-IL-4/13 biotherapies, for which phase-3 clinical trials are giv-
ing promising results in patients with severe CRSwNP resistant to
medical and surgical treatment. Even so, many questions remain
in suspense, including new therapeutic targets, factors for success
(enabling appropriate selection), optimal treatment duration, risk
of failure, and development of administration routes other than
subcutaneous or intravenous.
Disclosure of interest
The authors declare that they have no competing interest.
References
[1] Jankowski R, Rumeau C, Gallet P, Nguyen DT. Nasal polyposis (or chronic
olfactory rhinitis). Eur Ann Otorhinolaryngol Head Neck Dis 2018;135:191–6,
http://dx.doi.org/10.1016/j.anorl.2018.03.004.
[2] Jankowski R, Nguyen DT, Russel A, Toussaint B, Gallet P, Rumeau C. Chronic
nasal dysfunction. Eur Ann Otorhinolaryngol Head Neck Dis 2018;135:41–9,
http://dx.doi.org/10.1016/j.anorl.2017.11.006.
[3] Fokkens WJ, Lund VJ, Mullol J, Bachert C, Alobid I, Baroody F, et al. EPOS 2012:
European position paper on rhinosinusitis and nasal polyps 2012. Rhinology
2012;50:1–12, http://dx.doi.org/10.4193/Rhino50E2.
[4] Grigoreas C, Vourdas D, Petalas K, Simeonidis G, Demeroutis I, Tsioulos
T. Nasal polyps in patients with rhinitis and asthma. Allergy Asthma Proc
2002;23:169–74.
[5] Hedman J, Kaprio J, Poussa T, Nieminen MM. Prevalence of asthma,
aspirin intolerance, nasal polyposis and chronic obstructive pulmonary
disease in a population-based study. Int J Epidemiol 1999;28:717–22,
http://dx.doi.org/10.1093/ije/28.4.717.
[6] Klossek JM, Neukirch F, Pribil C, Jankowski R, Serrano E, Chanal I, et al. Preva-
lence of nasal polyposis in France: a cross-sectional, case-control study. Allergy
2005;60:233–7, http://dx.doi.org/10.1111/j.1398-9995.2005.00688.x.
[7] Bachert C, Akdis CA. Phenotypes and emerging endotypes of
chronic rhinosinusitis. J Allergy Clin Immunol Pract 2016;4:621–8,
http://dx.doi.org/10.1016/j.jaip.2016.05.004.
[8] Tomassen P, Vandeplas G, Van Zele T, Cardell L-O, Arebro J, Olze
H, et al. Inflammatory endotypes of chronic rhinosinusitis based
on cluster analysis of biomarkers. J Allergy Clin Immunol 2016;137,
http://dx.doi.org/10.1016/j.jaci.2015.12.1324, 1449-1456.e4.
[9] Akdis CA, Bachert C, Cingi C, Dykewicz MS, Hellings PW, Naclerio RM, et al.
Endotypes and phenotypes of chronic rhinosinusitis: a PRACTALL document
of the European Academy of Allergy and Clinical Immunology and the Amer-
7
European Annals of Otorhinolaryngology, Head and Neck diseases xxx (xxxx) xxx–xxx
ican Academy of Allergy, Asthma & Immunology. J Allergy Clin Immunol
2013;131:1479–90, http://dx.doi.org/10.1016/j.jaci.2013.02.036.
[10] Kountakis SE, Arango P, Bradley D, Wade ZK, Borish L. Molecular and cel-
lular staging for the severity of chronic rhinosinusitis. The Laryngoscope
2004;114:1895–905, http://dx.doi.org/10.1097/01.mlg.0000147917.43615.c0.
[11] Bachert C, Wagenmann M, Rudack C, Höpken K, Hillebrandt M, Wang D,
et al. The role of cytokines in infectious sinusitis and nasal polyposis. Allergy
1998;53:2–13, http://dx.doi.org/10.1111/j.1398-9995.1998.tb03767.x.
[12] Coste A, Brugel L, Maître B, Boussat S, Papon JF, Wingerstmann L,
et al. Inflammatory cells as well as epithelial cells in nasal polyps
express vascular endothelial growth factor. Eur Respir J 2000;15:367–72,
http://dx.doi.org/10.1034/j.1399-3003.2000.15b24.x.
[13] Kuruvilla ME, Lee FE-H, Lee GB. Understanding asthma phenotypes, endo-
types, and mechanisms of disease. Clin Rev Allergy Immunol 2019;56:219–33,
http://dx.doi.org/10.1007/s12016-018-8712-1.
[14] Rudmik L, Schlosser RJ, Smith TL, Soler ZM. Impact of topical nasal steroid
therapy on symptoms of nasal polyposis: a meta-analysis. The Laryngoscope
2012;122:1431–7, http://dx.doi.org/10.1002/lary.23259.
[15] Lund VJ, Flood J, Sykes AP, Richards DH. Effect of fluticasone in
severe polyposis. Arch Otolaryngol Head Neck Surg 1998;124:513–8,
http://dx.doi.org/10.1001/archotol.124.5.513.
[16] Liao B, Liu J-X, Li Z-Y, Zhen Z, Cao P-P, Yao Y, et al. Multidimensional endotypes of
chronic rhinosinusitis and their association with treatment outcomes. Allergy
2018;73:1459–69, http://dx.doi.org/10.1111/all.13411.
[17] DeConde AS, Soler ZM. Chronic rhinosinusitis: epidemiology
and burden of disease. Am J Rhinol Allergy 2016;30:134–9,
http://dx.doi.org/10.2500/ajra.2016.30.4297.
[18] Niven RM, Saralaya D, Chaudhuri R, Masoli M, Clifton I, Mansur AH, et al.
Impact of omalizumab on treatment of severe allergic asthma in UK clinical
practice: a UK multicentre observational study (the APEX II study). BMJ Open
2016;6:e011857, http://dx.doi.org/10.1136/bmjopen-2016-011857.
[19] Drick N, Seeliger B, Welte T, Fuge J, Suhling H. Anti-IL-5 therapy in
patients with severe eosinophilic asthma - clinical efficacy and pos-
sible criteria for treatment response. BMC Pulm Med 2018;18:119,
http://dx.doi.org/10.1186/s12890-018-0689-2.
[20] Norlander T, Westrin KM, Fukami M, Stierna P, Carlsöö B. Exper-
imentally induced polyps in the sinus mucosa: a structural
analysis of the initial stages. The Laryngoscope 1996;106:196–203,
http://dx.doi.org/10.1097/00005537-199602000-00017.
[21] Stevens WW, Lee RJ, Schleimer RP, Cohen NA. Chronic rhinosi-
nusitis pathogenesis. J Allergy Clin Immunol 2015;136:1442–53,
http://dx.doi.org/10.1016/j.jaci.2015.10.009.
[22] Lazard DS, Prulière-Escabasse V, Papon J-F, Escudier E, Coste A. Injury
and epithelial wound healing: a pathophysiologic hypothesis for
nasal and sinus polyposis. Presse Medicale Paris Fr 2007;36:1104–8,
http://dx.doi.org/10.1016/j.lpm.2007.01.021.
[23] Watelet J-B, Dogne J-M, Mullier F. Remodeling and repair
in rhinosinusitis. Curr Allergy Asthma Rep 2015;15:34,
http://dx.doi.org/10.1007/s11882-015-0531-3.
[24] Olze H, Förster U, Zuberbier T, Morawietz L, Luger EO. Eosinophilic nasal
polyps are a rich source of eotaxin, eotaxin-2 and eotaxin-3. Rhinology
2006;44:145–50.
[25] Yao T, Kojima Y, Koyanagi A, Yokoi H, Saito T, Kawano K, et al. Eotaxin-
1, -2, and -3 immunoreactivity and protein concentration in the nasal
polyps of eosinophilic chronic rhinosinusitis patients. The Laryngoscope
2009;119:1053–9, http://dx.doi.org/10.1002/lary.20191.
[26] Van Bruaene N, Pérez-Novo CA, Basinski TM, Van Zele T, Holtappels G, De
Ruyck N, et al. T-cell regulation in chronic paranasal sinus disease. J Allergy
Clin Immunol 2008;121, http://dx.doi.org/10.1016/j.jaci.2008.02.018, 1435-
41, 1441.e1-3.
[27] Van Zele T, Claeys S, Gevaert P, Van Maele G, Holtappels G, Van
Cauwenberge P, et al. Differentiation of chronic sinus diseases by
measurement of inflammatory mediators. Allergy 2006;61:1280–9,
http://dx.doi.org/10.1111/j.1398-9995.2006.01225.x.
[28] Stevens WW, Ocampo CJ, Berdnikovs S, Sakashita M, Mahdavinia M, Suh L,
et al. Cytokines in chronic rhinosinusitis, role in eosinophilia and aspirin-
exacerbated respiratory disease. Am J Respir Crit Care Med 2015;192:682–94,
http://dx.doi.org/10.1164/rccm.201412-2278OC.
[29] Derycke L, Eyerich S, Van Crombruggen K, Pérez-Novo C, Holtap-
pels G, Deruyck N, et al. Mixed T helper cell signatures in chronic
rhinosinusitis with and without polyps. PloS One 2014;9:e97581,
http://dx.doi.org/10.1371/journal.pone.0097581.
[30] Sharma R, Lakhani R, Rimmer J, Hopkins C. Surgical interventions for
chronic rhinosinusitis with nasal polyps. Cochrane Database Syst Rev 2014,
http://dx.doi.org/10.1002/14651858.CD006990.pub2. CD006990.
[31] Gendre A, Rives P, Michel G, Boutoille D, Espitalier F, Malard O.
Intraoperative bacterial analysis in nasal polyposis: clinical and func-
tional impact. Eur Ann Otorhinolaryngol Head Neck Dis 2019;136:155–60,
http://dx.doi.org/10.1016/j.anorl.2019.02.013.
[32] Van Zele T, Gevaert P, Watelet J-B, Claeys G, Holtappels G, Claeys C, et al.
Staphylococcus aureus colonization and IgE antibody formation to enterotox-
ins is increased in nasal polyposis. J Allergy Clin Immunol 2004;114:981–3,
http://dx.doi.org/10.1016/j.jaci.2004.07.013.
[33] Malik Z, Roscioli E, Murphy J, Ou J, Bassiouni A, Wormald P-J, et al. Staphylo-
coccus aureus impairs the airway epithelial barrier in vitro. Int Forum Allergy
Rhinol 2015;5:551–6, http://dx.doi.org/10.1002/alr.21517.
G Model
ANORL-1174; No. of Pages 8 ARTICLE IN PRESS
S. Bartier et al.
[34] Vickery TW, Ramakrishnan VR, Suh JD. The role of Staphylococcus aureus in
patients with chronic sinusitis and nasal polyposis. Curr Allergy Asthma Rep
2019;19:21, http://dx.doi.org/10.1007/s11882-019-0853-7.
[35] Bachert C, Geveart P. Effect of intranasal corticosteroids on release of
cytokines and inflammatory mediators. Allergy 1999;54(Suppl. 57):116–23,
http://dx.doi.org/10.1111/j.1398-9995.1999.tb04413.x.
[36] Coste A, Lefaucheur JP, Wang QP, Lesprit E, Poron F, Peynegre R, et al.
Expression of the transforming growth factor beta isoforms in inflammatory
cells of nasal polyps. Arch Otolaryngol Head Neck Surg 1998;124:1361–6,
http://dx.doi.org/10.1001/archotol.124.12.1361.
[37] Nakagome K, Nagata M. Involvement and possible role of
eosinophils in asthma exacerbation. Front Immunol 2018;9:2220,
http://dx.doi.org/10.3389/fimmu.2018.02220.
[38] Milonski J, Zielinska-Blizniewska H, Majsterek I, Przybyłowska-Sygut K, Sitarek
P, Korzycka-Zaborowska B, et al. Expression of POSTN, IL-4, and IL-13
in chronic rhinosinusitis with nasal polyps. DNA Cell Biol 2015;34:342–9,
http://dx.doi.org/10.1089/dna.2014.2712.
[39] Coyle AJ, Le Gros G, Bertrand C, Tsuyuki S, Heusser CH, Kopf M, et al. Interleukin-
4 is required for the induction of lung Th2 mucosal immunity. Am J Respir Cell
Mol Biol 1995;13:54–9, http://dx.doi.org/10.1165/ajrcmb.13.1.7598937.
[40] Pelaia G, Vatrella A, Busceti MT, Gallelli L, Preianò M, Lombardo N, et al. Role
of biologics in severe eosinophilic asthma - focus on reslizumab. Ther Clin Risk
Manag 2016;12:1075–82, http://dx.doi.org/10.2147/TCRM.S111862.
[41] Bachert C, Zhang N, Holtappels G, De Lobel L, van Cauwenberge P, Liu S, et al.
Presence of IL-5 protein and IgE antibodies to staphylococcal enterotoxins
in nasal polyps is associated with comorbid asthma. J Allergy Clin Immunol
2010;126, http://dx.doi.org/10.1016/j.jaci.2010.07.007, 962-8, 968.e1-6.
[42] Huriyati E, Darwin E, Yanwirasti Y, Wahid I. Association of inflam-
mation mediator in mucosal and tissue of chronic rhinosinusitis with
recurrent nasal polyp. Open Access Maced J Med Sci 2019;7:1635–40,
http://dx.doi.org/10.3889/oamjms.2019.327.
[43] Goswami R, Kaplan MH. A brief history of IL-9. J Immunol Baltim Md
2011;186:3283–8, http://dx.doi.org/10.4049/jimmunol.1003049.
[44] Gounni AS, Gregory B, Nutku E, Aris F, Latifa K, Minshall E, et al. Interleukin-
9 enhances interleukin-5 receptor expression, differentiation, and survival of
human eosinophils. Blood 2000;96:2163–71.
[45] Bhathena PR, Comhair SA, Holroyd KJ, Erzurum SC. Interleukin-9 recep-
tor expression in asthmatic airways In vivo. Lung 2000;178:149–60,
http://dx.doi.org/10.1007/s004080000018.
[46] Mortuaire G, Gengler I, Vandenhende-Szymanski C, Delbeke M, Gatault S,
Chevalier D, et al. Immune profile modulation of blood and mucosal eosinophils
in nasal polyposis with concomitant asthma. Ann Allergy Asthma Immunol
2015;114, http://dx.doi.org/10.1016/j.anai.2015.01.012, 299-307.e2.
[47] Danielsen A, Tynning T, Brokstad KA, Olofsson J, Davidsson A. Interleukin
5, IL6, IL12, IFN-gamma, RANTES and Fractalkine in human nasal polyps,
turbinate mucosa and serum. Eur Arch Oto-Rhino-Laryngol 2006;263:282–9,
http://dx.doi.org/10.1007/s00405-005-1031-1.
[48] Gubernatorova EO, Gorshkova EA, Namakanova OA, Zvartsev RV, Hidalgo
J, Drutskaya MS, et al. Non-redundant functions of IL-6 produced by
macrophages and dendritic cells in allergic airway inflammation. Front
Immunol 2018;9:2718, http://dx.doi.org/10.3389/fimmu.2018.02718.
[49] Bequignon E, Mangin D, Bécaud J, Pasquier J, Angely C, Bottier M,
et al. Pathogenesis of chronic rhinosinusitis with nasal polyps: role of
IL-6 in airway epithelial cell dysfunction. J Transl Med 2020;18:136,
http://dx.doi.org/10.1186/s12967-020-02309-9.
[50] Mosser DM, Zhang X. Interleukin-10: new perspec-
tives on an old cytokine. Immunol Rev 2008;226:205–18,
http://dx.doi.org/10.1111/j.1600-065X. 2008.00706.x.
[51] Xu M, Chen D, Zhou H, Zhang W, Xu J, Chen L. The role of periostin in the
occurrence and progression of eosinophilic chronic sinusitis with nasal polyps.
Sci Rep 2017;7:9479, http://dx.doi.org/10.1038/s41598-017-08375-2.
[52] Bachert C, Gevaert P, Holtappels G, Johansson SG, van Cauwen-
berge P. Total and specific IgE in nasal polyps is related to local
eosinophilic inflammation. J Allergy Clin Immunol 2001;107:607–14,
http://dx.doi.org/10.1067/mai.2001.112374.
[53] Brussino L, Heffler E, Bucca C, Nicola S, Rolla G. Eosinophils target ther-
apy for severe asthma: critical points. BioMed Res Int 2018;2018:7582057,
http://dx.doi.org/10.1155/2018/7582057.
[54] Bachert C, Gevaert P, Hellings P. Biotherapeutics in chronic rhinosinusitis
with and without nasal polyps. J Allergy Clin Immunol Pract 2017;5:1512–6,
http://dx.doi.org/10.1016/j.jaip.2017.04.024.
[55] Bachert C, Zhang N, Cavaliere C, Weiping W, Gevaert E, Krysko O. Bio-
logics for chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol
2020;145:725–39, http://dx.doi.org/10.1016/j.jaci.2020.01.020.
[56] Tsabouri S, Tseretopoulou X, Priftis K, Ntzani EE. Omalizumab for the treatment
of inadequately controlled allergic rhinitis: a systematic review and meta-
analysis of randomized clinical trials. J Allergy Clin Immunol Pract 2014;2,
http://dx.doi.org/10.1016/j.jaip.2014.02.001, 332-340.e1.
[57] Wright JD, Chu H-M, Huang C-H, Ma C, Chang TW, Lim C. Struc-
tural and physical basis for Anti-IgE therapy. Sci Rep 2015;5:11581,
http://dx.doi.org/10.1038/srep11581.
European Annals of Otorhinolaryngology, Head and Neck diseases xxx (xxxx) xxx–xxx
[58] Pinto JM, Mehta N, DiTineo M, Wang J, Baroody FM, Naclerio RM. A randomized,
double-blind, placebo-controlled trial of anti-IgE for chronic rhinosinusitis.
Rhinology 2010;48:318–24, http://dx.doi.org/10.4193/Rhin09.144.
[59] Gevaert P, Calus L, Van Zele T, Blomme K, De Ruyck N, Bauters W,
et al. Omalizumab is effective in allergic and nonallergic patients
with nasal polyps and asthma. J Allergy Clin Immunol 2013;131,
http://dx.doi.org/10.1016/j.jaci.2012.07.047, 110-116.e1.
[60] Tiotiu A, Oster JP, Roux PR, Nguyen Thi PL, Peiffer G, Bonniaud P, et al.
Effectiveness of omalizumab in severe allergic asthma and nasal poly-
posis: a real-life study. J Investig Allergol Clin Immunol 2020;30:49–57,
http://dx.doi.org/10.18176/jiaci.0391.
[61] Bidder T, Sahota J, Rennie C, Lund VJ, Robinson DS, Kariyawasam HH.
Omalizumab treats chronic rhinosinusitis with nasal polyps and asthma
together-a real life study. Rhinology 2018;56:42–5, http://dx.doi.org/10.4193/
Rhin17.139.
[62] Gevaert P, Omachi TA, Corren J, Mullol J, Han J, Lee SE, et al. Efficacy and
safety of omalizumab in patients with chronic rhinosinusitis with nasal
polyps: results from two, multicenter, randomized, double-blind, placebo-
controlled phase III trials (POLYP 1 and POLYP 2). J Allergy Clin Immunol 2020
[in press].
[63] Egan RW, Athwal D, Bodmer MW, Carter JM, Chapman RW, Chou CC, et al. Effect
of Sch 55700, a humanized monoclonal antibody to human interleukin-5, on
eosinophilic responses and bronchial hyperreactivity. Arzneimittelforschung
1999;49:779–90, http://dx.doi.org/10.1055/s-0031-1300502.
[64] Gevaert P, Lang-Loidolt D, Lackner A, Stammberger H, Staudinger H, Van
Zele T, et al. Nasal IL-5 levels determine the response to anti-IL-5 treatment
in patients with nasal polyps. J Allergy Clin Immunol 2006;118:1133–41,
http://dx.doi.org/10.1016/j.jaci.2006.05.031.
[65] Tsukamoto N, Takahashi N, Itoh H, Pouliquen I. Pharmacokinetics and phar-
macodynamics of mepolizumab, an anti-interleukin 5 monoclonal antibody,
in healthy Japanese male subjects. Clin Pharmacol Drug Dev 2016;5:102–8,
http://dx.doi.org/10.1002/cpdd.205.
[66] Robinson DS, Kariyawasam HH. Mepolizumab for eosinophilic severe
asthma: recent studies. Expert Opin Biol Ther 2015;15:909–14,
http://dx.doi.org/10.1517/14712598.2015.1041911.
[67] Gevaert P, Van Bruaene N, Cattaert T, Van Steen K, Van Zele T, Acke
F, et al. Mepolizumab, a humanized anti-IL-5 mAb, as a treatment
option for severe nasal polyposis. J Allergy Clin Immunol 2011;128,
http://dx.doi.org/10.1016/j.jaci.2011.07.056, 989-995.e1-8.
[68] Bachert C, Sousa AR, Lund VJ, Scadding GK, Gevaert P, Nasser S, et al. Reduced
need for surgery in severe nasal polyposis with mepolizumab: randomized trial.
J Allergy Clin Immunol 2017;140, http://dx.doi.org/10.1016/j.jaci.2017.05.044,
1024-1031.e14.
[69] Kolbeck R, Kozhich A, Koike M, Peng L, Andersson CK, Damschroder MM, et al.
MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-
dependent cell-mediated cytotoxicity function. J Allergy Clin Immunol
2010;125, http://dx.doi.org/10.1016/j.jaci.2010.04.004, 1344-1353.e2.
[70] Tsurumaki H, Matsuyama T, Ezawa K, Koga Y, Yatomi M, Aoki-Saito H,
et al. Rapid effect of benralizumab for hypereosinophilia in a case of severe
asthma with eosinophilic chronic rhinosinusitis. Med Kaunas Lith 2019:55,
http://dx.doi.org/10.3390/medicina55070336.
[71] Bachert C, Mannent L, Naclerio RM, Mullol J, Ferguson BJ, Gevaert P, et al.
Effect of subcutaneous dupilumab on nasal polyp burden in patients with
chronic sinusitis and nasal polyposis: a randomized clinical trial. JAMA
2016;315:469–79, http://dx.doi.org/10.1001/jama.2015.19330.
[72] Bachert C, Han JK, Desrosiers M, Hellings PW, Amin N, Lee SE, et al.
Efficacy and safety of dupilumab in patients with severe chronic rhinosi-
nusitis with nasal polyps (LIBERTY CRSwNP SINUS-24 and LIBERTY CRSwNP
SINUS-52): results from two multicentre, randomised, double-blind, placebo-
controlled, parallel-group phase 3 trials. Lancet Lond Engl 2019;394:1638–50,
http://dx.doi.org/10.1016/S0140-6736(19)31881-1.
[73] Biggioggero M, Crotti C, Becciolini A, Favalli EG. Tocilizumab in the treatment
of rheumatoid arthritis: an evidence-based review and patient selection. Drug
Des Devel Ther 2019;13:57–70, http://dx.doi.org/10.2147/DDDT.S150580.
[74] Gong F, Pan Y-H, Huang X, Zhu H-Y, Jiang D-L. From bench to bedside: ther-
apeutic potential of interleukin-9 in the treatment of asthma. Exp Ther Med
2017;13:389–94, http://dx.doi.org/10.3892/etm.2017.4024.
[75] Fokkens WJ, Lund V, Bachert C, Mullol J, Bjermer L, Bousquet J, et al. EUFOREA
consensus on biologics for CRSwCRSwNP with or without asthma. Allergy
2019;74:2312–9, http://dx.doi.org/10.1111/all.13875.
[76] Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, et al. Dupilumab
efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med
2018;378:2486–96, http://dx.doi.org/10.1056/NEJMoa1804092.
[77] Jankowski R, Rumeau C, Nguyen DT, Gallet P. Updating nasalisation: from
concept to technique and results. Eur Ann Otorhinolaryngol Head Neck Dis
2018;135:327–34, http://dx.doi.org/10.1016/j.anorl.2018.05.006.
[78] Scangas GA, Wu AW, Ting JY, Metson R, Walgama E, Shrime MG, et al.
Cost utility analysis of dupilumab versus endoscopic sinus surgery
for chronic rhinosinusitis with nasal polyps. Laryngoscope 2020,
http://dx.doi.org/10.1002/lary.28648.