10.14639/0392-100X-N1614
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous inflammatory condition of nasal mucosa and paranasal sinuses, predominantly mediated by type 2 inflammation and often associated with comorbid asthma and/or Exacerbated Respiratory Disease (N-ERD). The standard of care involves local and systemic corticosteroids and/or sinonasal surgery, although these options may be associated with recurrences and patients may require revision surgery. Difficult-to-treat patients, in fact, have a more severe disease requiring high systemic corticosteroid use and/or multiple sinonasal surgeries. Literature data suggests that biologic agents targeting specific key effectors of type 2 inflammation may offer supplemental therapy for patients with severe and uncontrolled CRSwNP, leading to significant improvement in several outcomes. For these reasons, over the years the endotyping of the disease has become increasingly important. Herein, we provide not only an update on the existing studies about the most promising biologics in CRSwNP, but also critical discussion on controversies about the use of biologics in severe uncontrolled CRSwNP. We finally provide consensus on strategic issues gathered among experts of the Joint Committee of Italian Society of Otorhinolaryngology on biologics in order to offer the best care for difficult to treat patients.
text/xml
1827-675X
1614
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Desiderio Passali
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ACTA Otorhinolaryngologica Italica
endotyping
Biologics for severe uncontrolled chronic rhinosinusitis with nasal polyps: a change management approach. Consensus of the Joint Committee of Italian Society of Otorhinolaryngology on biologics in rhinology
Text.Serial.Journal
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Position paper
2021-07-23
2021-04-14
2022-03-07
2022-03-07
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1
Desiderio Passali
2022
10.14639/0392-100X-N1614
1
IFOS Former President and Executive Board member, Rome, Italy
1827-675X
endotyping
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Biologics for severe uncontrolled chronic rhinosinusitis with nasal polyps: a change management approach. Consensus of the Joint Committee of Italian Society of Otorhinolaryngology on biologics in rhinology
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ACTA OTORHINOLARYNGOLOGICA ITALICA 2022;42:1-16; doi: 10.14639/0392-100X-N1614




Position Paper


Biologics for severe uncontrolled chronic
rhinosinusitis with nasal polyps: a change
management approach.
Consensus of the Joint Committee of Italian Society
of Otorhinolaryngology on biologics in rhinology
Biologici nel trattamento della poliposi naso-sinusale severa non controllata:
cambiamento nelle strategie terapeutiche.
Consensus dei membri della Commissione SIO sui farmaci biologici in rinologia
Eugenio De Corso1, Gianluca Bellocchi2, Michele De Benedetto3,
Nicola Lombardo4, Alberto Macchi5, Luca Malvezzi6, Gaetano Motta7,
Fabio Pagella8, Claudio Vicini9, Desiderio Passali10
1
 Fondazione Policlinico Universitario A. Gemelli IRCCS, Head and Neck Surgery –
Otorhinolaryngology, Rome, Italy; 2 ENT Department, San Camillo-Forlanini Hospital,
Roma, Italy; 3 ENT Unit, Vito Fazzi Hospital, ASL Lecce, Italy; 4 ENT Unit Department
of Medical and Surgical Sciences, University Magna Græcia Catanzaro, Italy; 5 ENT
University of Insubria, Varese, ASST Settelaghi, Italy; 6 IRCCS Humanitas Research
                                                                                                    Extract from the workshops of the Joint Committee
Hospital, Department of Otorhinolaryngology and Head and Neck Surgery, Rozzano,
                                                                                                    of Italian Society of Otorhinolaryngology on
Milan, Italy; 7 Otorhinolaryngology-Head and Neck Surgery, University of Campania                   biologics in rhinology in 2020.
L. Vanvitelli, Napoli, Italy; 8 ENT Department, I.R.C.C.S. Policlinico San Matteo-
University of Pavia, Italy; 9 Department of Head-Neck Surgery, Otolaryngology,                      Received: April 14, 2021
Head-Neck and Oral Surgery Unit, Morgagni Pierantoni Hospital, Forlì, Italy; 10 IFOS                Accepted: June 16, 2021
Former President and Executive Board member, Rome, Italy                                            Pubished online: July 23, 2021

                                                                                                    Correspondence
                                                                                                    Eugenio De Corso
SUMMARY                                                                                             Otorhinolaryngology - Head and Neck Surgery,
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous inflammatory condi-            Rhinology Unit, “A. Gemelli” Hospital Foundation
tion of nasal mucosa and paranasal sinuses, predominantly mediated by type 2 inflamma-              IRCCS, Catholic University of the Sacred Heart
tion and often associated with comorbid asthma and/or Exacerbated Respiratory Disease               largo A. Gemelli 8, 00168 Rome, Italy
                                                                                                    E-mail: eugenio.decorso@policlinicogemelli.it
(N-ERD). The standard of care involves local and systemic corticosteroids and/or sinonasal
surgery, although these options may be associated with recurrences and patients may require
revision surgery. Difficult-to-treat patients, in fact, have a more severe disease requiring high     How to cite this article: De Corso E, Bellocchi
systemic corticosteroid use and/or multiple sinonasal surgeries. Literature data suggests that        G, De Benedetto M, et al. Biologics for severe un-
biologic agents targeting specific key effectors of type 2 inflammation may offer supplemental        controlled chronic rhinosinusitis with nasal pol-
therapy for patients with severe and uncontrolled CRSwNP, leading to significant improve-             yps: a change management approach. Consensus
                                                                                                      of the Joint Committee of Italian Society of Oto-
ment in several outcomes. For these reasons, over the years the endotyping of the disease has
                                                                                                      rhinolaryngology on biologics in rhinology. Acta
become increasingly important. Herein, we provide not only an update on the existing studies          Otorhinolaryngol Ital 2022;42:1-16. https://
about the most promising biologics in CRSwNP, but also critical discussion on controversies           doi.org/10.14639/0392-100X-N1614
about the use of biologics in severe uncontrolled CRSwNP. We finally provide consensus on
strategic issues gathered among experts of the Joint Committee of Italian Society of Otorhino-      © Società Italiana di Otorinolaringoiatria
laryngology on biologics in order to offer the best care for difficult to treat patients.           e Chirurgia Cervico-Facciale

KEY WORDS: type 2 inflammation, chronic rhinosinusitis with nasal polyps, biologics,
                                                                                                                   OPEN ACCESS
endoscopic sinus surgery, endotyping
                                                                                                    This is an open access article distributed in accordance with
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RIASSUNTO                                                                                           Commercial-NoDerivatives 4.0 International) license. The
                                                                                                    article can be used by giving appropriate credit and mentio-
La rinosinusite cronica con poliposi naso sinusale è una condizione infiammatoria cronica
                                                                                                    ning the license, but only for non-commercial purposes and
della mucosa naso sinusale, sostenuta prevalentemente da infiammazione di tipo 2 che si             only in the original version. For further information: https://
associa frequentemente a comorbidità come asma e intolleranza ai FANS. I recenti studi              creativecommons.org/licenses/by-nc-nd/4.0/deed.en




                                                                                                                                                                1
E. De Corso et al.




sull’endotyping di malattia hanno rivelato il ruolo cruciale delle citochine dell’infiammazione di tipo 2 nella patogenesi delle forme più severe.
L’approccio terapeutico negli ultimi anni si è basato sull’uso di corticosteroidi locali/sistemici e chirurgia endoscopica naso-sinusale. I pazien-
ti con forme più severe, tuttavia, richiedono impiego di alte dosi di corticosteroidi sistemici e ripetuti interventi chirurgici. I dati della letteratu-
ra hanno confermato che i nuovi farmaci biologici, specifici per le citochine dell’infiammazione di tipo 2, possono rappresentare un approccio
supplementare offrendo un significativo miglioramento clinico nei pazienti affetti da poliposi naso sinusale severa e non controllata. In questo
lavoro riportiamo non solo i risultati di una revisione sistematica della letteratura sulle attuali evidenze dei più promettenti farmaci biologici in
poliposi naso-sinusale severa non controllata, ma anche i risultati di una consensus su alcuni degli argomenti più dibattuti estratti dai verbali
delle riunioni dei membri della Commissione della Società Italiana di Otorinolaringoiatria sui farmaci biologici in rinologia durante il 2020.
PAROLE CHIAVE: infiammazione di tipo 2, rinosinusite cronica con poliposi nasale, biologics, chirurgia endoscopica nasosinusale, endotyping



Introduction                                                                   As some biologics have received regulatory approval in Italy,
                                                                               the Joint Committee of Italian Society of Otorhinolaryngol-
Chronic rhinosinusitis with nasal polyposis (CRSwNP)
                                                                               ogy on biologics in rhinology became interested in how to
is a complex inflammatory disorder including multiple
                                                                               incorporate these new agents into the treatment paradigm for
phenotypes. It is a debilitating disease that has a substan-
                                                                               CRSwNP. In this report we summarise the substantial litera-
tial impact on the patient’s quality of life with significant
                                                                               ture evidence about the most promising biologics in CRSwNP
healthcare-related costs. Over the years, management strat-
                                                                               presenting a consensus on the most critical issues that emerged
egies have been focused mainly on symptom relief includ-
                                                                               from the workshops of the commission in 2020. We aimed to
ing intranasal corticosteroid (INCS), saline irrigations and
                                                                               provide consensus on strategic issues to offer the best care for
a brief courses of systemic corticosteroids (SCS) with or
                                                                               patients with severe uncontrolled CRSwNP. It is hoped that
without antibiotics to manage acute exacerbations that
                                                                               this report will be used by researchers and clinicians who will
may be associated with significant quantitative changes in
                                                                               address the incorporation of these new therapeutic modalities
inflammatory biomarkers 1-4. Optional treatments include
                                                                               into the CRSwNP treatment algorithm.
macrolide, anti-leukotrienes, anti-histamine and aspirin de-
sensitisation only for patients with NSAIDs Exacerbated
Respiratory Disease (N-ERD). If maximal medical therapy                        Materials and methods
does not lead to adequate control of symptoms, endoscopic                      We used the RAND indication for standard Delphi method-
sinus surgery (ESS) is considered to remove inflammatory                       ology with a multi-step process. Specific statements were
tissue alleviating nasal obstruction and expediting delivery                   formulated basing on an extensive review of existing litera-
of topical therapies. Surgery is not curative but is crucial in                ture about the use of biologics in CRSwNP. Manuscript were
improving access for future topical medical therapy 5.                         screened primarily by Ovid Medline and EMBASE and from
Unfortunately, a significant percentage of patients do not find                other sources (PubMed Central, Cochrane review, Web of
relief from current standard of care medications and surgery                   Science, and Google Scholar). Our expert panel undertook
having residual symptoms or recurrence of polyposis even cy-                   a modified 2-round Delphi process and members were asked
cles of systemic corticosteroids and/or surgery. “Difficult-to-                to independently vote on statements, which were formulated
treat” patients are considered as those in whom an acceptable                  based on strategic discussion during 2020. We used a 4-point
level of control is not achieved despite appropriate medical and               Likert scale (‘strongly agree’, ‘agree’, ‘disagree’, ‘strongly
surgical treatment. For these patients, the only chance in recent              disagree’). Free text comments were encouraged if greater
years was to repeat multiple ESS with an increasingly high                     context was required or if the statements were ambiguous.
risk of perioperative complications and a progressively shorter                Consensus was defined as > 70% of participants agreeing/
time of symptom control between surgeries 6,7. The success in                  strongly agreeing. The document was written and submitted
targeting specific immunologic mediators in asthma with bio-                   for review and approval to all the members of the committee.
logics has led to an interest in the use of a similar therapeutic              All changes made were discussed and refined until unani-
approach for CRSwNP 8. Several trials 9 have shown subjec-                     mous approval was obtained. Statements receiving consen-
tive and objective improvements in patients with CRSwNP                        sus are summarised at the end of each paragraph.
with or without asthma as well as a good safety profile. For
this reason, biologic agents have been proposed as an adjunct
treatment for CRSwNP patients and in the next months, the
                                                                               Results and discussion
therapeutic opportunity may change quickly because several                     Management based on phenotyping and endotyping
monoclonal antibodies (MAbs) will be available within a short                  of the disease
time in many countries for uncontrolled severe CRSwNP.                         Chronic rhinosinusitis (CRS) comprises a spectrum of



2
                                                                               Biologics in the treatment of severe uncontrolled CRSwNP




conditions with distinct clinical presentations and patho-       achieved by analysing at least three of the most dense col-
genic mechanisms 1,10,11. For years it has been adopted          lections of eosinophils (very rich fields) in the samples
clinical dichotomisation of CRS without NP (CRSsNP)              counted at hpf (~400x). The EPOS steering group 1 speci-
and CRSwNP assuming that it was determined by predom-            fied that the minimal cut-off to achieve evidence of Type 2
inantly T-helper 1 cells in the former and T-helper 2 cells      inflammation on tissue samples was eosinophils > 10/hpf.
in the latter. However, further research demonstrated that       The cut-offs for the other procedures had not be established
immunologic profile is much more complex, demonstrat-            and specific studies are required to determine it. Other bio-
ing that there is some overlap and endotypes may coexist         markers used at the moment to define type 2 disease are
in the same patient. In fact, non-eosinophilic inflammation      blood eosinophilia, IgE levels and, in some specialised
dominated by Th1/Th17 pathways may be associated with            centers, periostin. EPOS group suggests as specific cut offs
CRSwNP and CRSsNP patients may express a Type 2 cy-              for this biomarker: > 250/microliter for blood eosinophilia
tokine profile 12-15. Because studies on endotyping provided     and > 100 kU/l for total IgE. Other biomarkers are cur-
full insight into the underlying cellular and molecular in-      rently under investigation and may provide further guid-
flammatory mechanisms associated with CRS 16, the EPOS           ance in the future.
2020 group 1 came into the decision to change the man-           The combination of phenotyping (responsiveness to differ-
agement approach to CRS. The authors recognised the im-          ent treatments, including systemic or intranasal corticoster-
portance to move away from differentiating management            oids, surgical interventions, comorbid asthma, N-ERD, etc.)
basing on phenotypical classification between CRSsNP             and endotyping [blood/local eosinophils or neutrophils, TH-
and CRSwNP towards a new classification based on the             cell populations, levels of cytokines (IL-4, IL-5, or IL-13,
disease being localised (often unilateral) or diffuse (always    etc.), IgE either in blood or tissue, anti-staphylococcal IgE,
bilateral). Both these groups are further divided basing the     periostin and other future potential biomarkers] are at the
endotype into type 2 or non-type 2 disease. In case of more      moment the best way to predict the likely natural course of
endotypes coexisting in the same patient, the authors sug-       disease and prognosis in terms of disease control after sur-
gested to identify the dominant one in order to establish the    gery. Based on this concept, many authors 21,28,30-34 have tried
best personalised therapeutic approach.                          to identify the best way to predict the natural history of the
Approximately 80% of diffuse CRS in Western countries            disease, facilitating counseling the patient on the expected
are characterised by a dominant Type 2 response driven           outcome of the surgery and helping to establish the best post-
mainly by key Type 2 cytokines (IL4, IL5, IL13 etc) and          operative medical management that can offer the best chance
circulating/local IgE, with eosinophilia as a typical signa-     to control patient’s symptoms. Finally, identification of en-
ture 16-18. Currently, both an allergic (IgE-mediated) and       dotypes is essential for individualisation of therapy.
non-allergic pathway are understood to play a role in the
pathophysiology of the underlying eosinophilia, represent-          Adequate endotyping and phenotyping of the disease
                                                                         should be refined in an additional work-up
ing the ideal immune profile of severe CRSwNP potentially
                                                                        in all severe uncontrolled CRSwNP patients.
candidates for biologics. For this reason, recent position
papers 1,19 suggested to provide confirmatory evidence of          ENT physicians involved in prescription of biologics in
Type 2 inflammation in these patients using systemic eo-            rhinology centers should standardise the diagnostic
sinophil and IgE count. It has also demonstrated that the         work-up for severe uncontrolled CRSwNP strengthening
                                                                  multidisciplinary cooperation to define endotype of the
amount of local eosinophilic infiltration and the overall in-
                                                                            disease and eligibility for biologics.
tensity of the inflammatory response are closely related to
the prognosis and severity of disease 20. For this reason, de-    Rhinologic centers should develop institutional protocols
velopment of institutional protocols for sampling, storing        for determination of type 2 inflammation associated with
and processing sino-nasal mucosa samples, sometimes in                         severe uncontrolled CRSwNP.
close collaboration with histopathologists is increasing 21.
                                                                   Clinical predictors of treatment outcomes are useful to
Actually, authors discuss on the best procedure to define         foresee the likely natural course of disease and facilitate
local inflammation and the most common used techniques           counseling of patients on expected outcomes of standard
include: nasal biopsy, nasal brushing or scraping (nasal cy-                          of care treatments.
tology), nasal lavage fluid and nasal suctioning of secre-
tions 22-26. Authors 27-29 have suggested that diagnosis of      The new age of biologics in CRS: from scientific evidence
eosinophilic CRS requires quantification of the numbers          to approval of new treatment options
of eosinophils, i.e. number/high powered field (hpf), which      Monoclonal antibodies have been demonstrated to be very
may vary in the literature (8-12/hpf) and which should be        useful in the management of chronic eosinophilic diseases



                                                                                                                                     3
E. De Corso et al.




such as asthma and atopic dermatitis; the experience in                                        evidence about their significative steps in the approval pro-
these fields encouraged researchers to investigate efficacy                                    cess (Tab. II).
of these drugs in CRSwNP. Proof-of- concept studies 35-40
                                                                                               Anti-IL-4/IL-13: Dupilumab
were performed mainly in patients with severe asthma and
                                                                                               Dupilumab is a fully human monoclonal antibody targeting
nasal polyps, generating promising results and building
upon successful phase 3 studies 41.                                                            the α-chain subunit of IL-4 receptors (Type 1 and type 2
The pathophysiology of CRSwNP includes eosinophilia,                                           IL-4Rα) and inhibiting IL-4/IL-13 signaling 35. Literature
T-helper cell 2 cytokines and IgE formation, and for this                                      data 42-44 have demonstrated that the dual inhibition of IL-4
reason three main strategies may be undertaken with mon-                                       and IL-13 signaling may represent an important strategy
oclonal antibodies: anti-IL-4/IL-13 signaling (dupilumab),                                     for the treatment of type 2 CRSwNP. Bachert et al. 35 in
anti-IL-5 pathways (mepolizumab, benralizumab) and an-                                         a phase II, randomised, double-blind, placebo-controlled
ti-IgE antibodies (omalizumab). In Table I we summarise                                        study evaluated dupilumab in patients with CRSwNP re-
mechanism of action, possible side effects, dose, and ad-                                      fractory to INCS. Patients (n = 60) were randomised to 2
ministration modalities of most promising biologics in the                                     weekly subcutaneous dupilumab injections or placebo, and
treatment of CRSwNP. Furthermore, we reviewed literature                                       51 patients completed the study. The group treated with


Table I. Mechanism of action, possible side effects, dose, and administration modalities of the most promising MAbs in the treatment of severe uncontrolled
CRSwNP.
 Generic name       Brand name            Key mediator target                Mode of action            Dose and route of      Most common side effects
                                                                                                        administration
 Dupilumab                   Dupixent                   IL-4 and IL-13R:         Anti–IL-4 MAb; targets the Subcutaneous injection,                Injection site reaction,
                                               involved in Th2 differentiation;     IL-4 receptor α subunit       300 mg every 2 week                   conjunctivitis,
                                                   class switching of B cells      to inhibit IL-4 and IL-13        Device auto-injector.          eosinophilia transitory
                                                    to plasma cells and IgE        cytokines central to Th2             Allowed home                  (< 2% of cases)
                                             production; barrier disruption and mediated inflammation                   administration
                                               microbiome imbalance; tissue
                                             remodelling and polyp formation;
                                              eosinophils trafficking to tissues
 Omalizumab                    Xolair                           IgE:              Anti-IgE MAb; it binds Fc Subcutaneous injection                  Headache, dizziness,
                                                 involved in T2 inflammatory         region of IgE, reducing          every 2-4 weeks            arthralgia, abdominal pain
                                                  cascade. Activating type 2          circulating IgE; down-       Dosing and frequency           upper and injection site
                                             inflammatory cells such as mast           regulating FcεRI and        level is determined by                 reactions
                                              cells, basophils, and eosinophils      FcεRII in inflammatory      serum total IgE level and
                                                                                    cells. It is able to inhibit         body weight
                                                                                        type 2 inflammation
                                                                                          through several
                                                                                      mechanisms of action
 Mepolizumab                  Nucala                           IL-5:                 Anti–IL-5 MAb; blocks            100 mg monthly                  Nasopharyngitis
                                                 key mediator in chemotaxis,           the binding of IL-5 to    subcutaneous injections                 headache,
                                                differentiation, activation, and      the alpha chain of the        regardless of weight           injection site reaction
                                                     survival of eosinophil           IL-5 receptor complex
                                                                                  expressed on the surface
                                                                                 of eosinophil cells, inhibits
                                                                                 IL-5 signaling and reduces
                                                                                       eosinophil activation,
                                                                                  proliferation, recruitment,
                                                                                   maturation, and survival
 Benralizumab                 Fasenra                 Eosinophils IL-5Rα:              Anti-eosinophil MAb;       Subcutaneous injection         Asthma, pharyngitis, URTI,
                                                  key effector cells in Type 2          specifically binds to        30 mg once every             headache, Injection site
                                                          inflammation                   eosinophils IL-5Rα            4 weeks for the                   reaction
                                                                                        interfering with IL-5        first 3 doses, then
                                                                                     inflammatory signaling          subsequently once
                                                                                  and inducing eosinophils              every 8 weeks
                                                                                         apoptosis through
                                                                                   interaction with FcγRIIIα
                                                                                             on NK cells
IgE: immunoglobulin E; IL: interleukin; ILC: innate lymphoid cell; MAb: monoclonal antibody; Th: T helper; URTI: upper airway tract infection.




4
                                                                                                                  Biologics in the treatment of severe uncontrolled CRSwNP




Table II. Literature evidence and approval of MAbs in the treatment of severe uncontrolled CRSwNP.
 Generic name Brand                     Phase II trials                     Phase III trials                                Demonstrated                  Development status
                    name                                                  inclusion criteria                              therapeutic effects                and approval
 Dupilumab           Dupixent     Bachert, et al. JAMA 2016;315:469-             Bachert C, SINUS-24 and            Rapid and sustained Reduction    Phase 3 trials pub-
                                    479. https://doi.org/10.1001/ja-             SINUS-52. Lancet 2019 41                 in nasal polyp and CT   lished, FDA approval on
                                           ma.2015.19330 35                                                                       scores.           June 26th 2019, EMA
                                                                                Prior SCS in past 2 years OR            Improvement in olfaction,    approval on October
                                                                                       prior NP surgery                    in nasal congestion       26th, 2019 and AIFA
                                                                                           NPS ≥ 5                    scores, symptoms, and QOL approval 9th December
                                                                                Nasal congestion/blockage/          (SNOT-22), pulmonary function            2020
                                                                                   obstruction or symptom              (FEV1), and asthma control
                                                                                        severity = 2/3                      test score (ACQ6).
                                                                                                                     Reduction of the need of SCS
                                                                                                                              and of surgery.

 Omalizumab            Xolair         Gevaert. J Allergy Clin Immu-                Gevaert P POLYP 1 and      Rapid and sustained improve- Phase 3 trials conduct-
                                    nol 2013;131:110-6. https://doi.                    POLYP 2 50            ments in mean NPS and daily      ed published,
                                   org/10.1016/j.jaci.2012.07.047 36                                                 NCS at Week 24.         FDA approval in De-
                                                                                No requirement for prior SCS Improvements in SNOT-22 and       cember 2020
                                                                                      OR NP surgery          patient-reported health-related EMA approval in July
                                                                                          NPS ≥ 5              QoL (HRQoL), sense of smell         2020
                                                                                      SNOT 22 ≥ 20              score, total nasal symptom
                                                                                   NCS ≥ 2 at screening                score (TNSS).
                                                                                                                    Reduction in need
                                                                                                                        for surgery.

 Mepolizumab          Nucala      Gevaert, et al. J Allergy Clin Immunol         SYNAPSE study (GSK Study            Improvement in nasal polyp            Phase 3 concluded in
                                          2011;128:989-995.                     ID: 205687; NCT03085797)                 score and VAS score.                      2020
                                     https://doi.org/10.1016/j.ja-                  Concluded in 2020 51               Improvement in SNOT-22,             FDA accepted GSK fil-
                                           ci.2011.07.056 37                                                               overall VAS score              ing in 2020 – approval
                                                                                 Prior NP surgery in past 10            and VAS symptom score                     ongoing
                                  Bachert, et al. J Allergy Clin Immunol                    years                          for loss of smell.             EMA accepted GSK fil-
                                        2017;140:1024-1103.                               NPS ≥ 5                    Reduction in required sinus                ing in 2020
                                     https://doi.org/10.1016/j.ja-                VAS symptom score > 7                         surgery.
                                           ci.2017.05.044 38                                                           Reduction of proportion of            Approval ongoing
                                                                                                                                subjects
                                                                                                                      requiring systemic steroids
                                                                                                                           for nasal polyps.
                                                                                                                    Reduction of blood eosinophils
                                                                                                                     without complete depletion.

  Benralizumab       Fasenra             Chitguppi. Am J Rhinol                  OSTRO (NCT03401229) 62               Improvement in NPS, nasal    Phase 3 trials on-going
                                        Allergy 2020. https://doi.                                                  blockage score, Lund-Mackey FDA to be determined
                                  org/10.1177/1945892420978351 39               Prior SCS use or NP surgery         CT score, SNOT-22, NRS, AER, EMA to be determined
                                                                                          NPS ≥ 5                     pulmonary function (FEV1),   AIFA to be determined
                                               Lombardo.                                NCS = 2/3                      OCS daily use in real-life
                                   Int J Immunopathol Pharmacol 2020.                  SNOT 22 ≥ 30                   SEA patients with comorbid
                                               https://doi.                                                                    CRSwNP.
                                   org/10.1177/2058738420950851 40               ORCHID (NCT04157335) 63              Improvement in NPS, NBS,
                                                                                      (trial ongoing).                SNOT-22, Lund-Mackey CT
                                   Tversky, et al. Clin Exp Allergy 2021.                 NPS ≥ 5                    score, UPSIT score in patient
                                  https://doi.org/10.1111/cea.13852 61                   NCS ≥ 2%                        with severe CRSwNP.
                                                                                      SNOT-22 ≥ 20
                                                                                     Comorbid asthma
                                                                                 Eosinophils ≥ 150 cells or
                                                                                            > 2%
SCS: systemic corticosteroids; OCS: oral corticosteroids; NPS: nasal polyps score; NCS: nasal congestion score; SNOT: sino nasal outcomes test; VAS visual analogical scale; FDA:
Food and Drug Administration; EMA: European Medicines Agency; AIFA: Italian Agency of Drugs.
UPSIT: University of Pennsylvania smell identification test; CRSwNP chronic rhinosinusitis with nasal polyps; SEA: severe eosinophilic asthma; QoL: quality of life; TNSS: total nasal
symtpoms score; NRS: numerical rating scale; AER: asthma exacerbation rate.




                                                                                                                                                                                   5
E. De Corso et al.




dupilumab had a significant reduction in polyp size (pri-        Omalizumab (anti-IgE antibody)
mary endpoint), which was clinically observable from the         Omalizumab is the longest-lived monoclonal antibody ap-
4th week of treatment. Later, the SINUS-24 and SINUS-52          proved since 2003 for the treatment of moderate to severe
phase 3 studies 41 demonstrated the efficacy and safety of       persistent allergic asthma in more than 90 countries 45. It was
subcutaneous dupilumab 300 mg administered every 2               designed to treat IgE-mediated disease by reducing the con-
weeks versus placebo in severe CRSwNP not controlled             centration of free IgE in blood and tissue 47-49. Given multi-
with standard of care (INC, previous SCS and/or surgery).        ple potential mechanisms by which omalizumab may limit
Patients obtained significant improvements in all primary        Type 2 inflammation it was investigated not only in asthma
and secondary endpoints at week 24 and 52. A significant         but also in CRSwNP. Phase III trials (POLYP 1 and POLYP
improvement was observed in treated patients compared            2) 50 were conducted in parallel to evaluate the efficacy and
to placebo in terms of nasal congestion/obstruction sever-       safety of omalizumab in adults with severe uncontrolled
ity, nasal polyps score (NPS), sinus opacification and loss      CRSwNP refractory to treatment with INCS. The trials com-
of smell. For the two primary endpoints, NPS and NCS,            pared the effects of omalizumab (75-600 mg s.c. every 2 or
significant improvement was observed as early as week 4          4 weeks, adjusted according to pre-treatment serum IgE and
of treatment. For UPSIT score, significant improvement           body weight) to placebo in patients with severe CRSwNP
was observed at week 2 of observation, with continued im-        not controlled with standard of care background therapy by
provement evident up to the end of treatment in both studies     INCS. Both POLYP-1 (n = 138) and POLYP-2 (n = 127)
for all endpoints. For loss of smell, 62% of patients treated    met their co-primary endpoints: omalizumab-treated patients
with dupilumab changed their smell status from anosmic           achieved statistically significant improvements in mean NPS
to non-anosmic. Lastly, dupilumab treatment resulted in a        and daily NCS at Week 24 versus placebo. Moreover, the im-
significant reduction of SCS use and the need for revision       provements were observed as early as week 4 in both stud-
                                                                 ies, demonstrating a rapid effect and maintained in time. Key
surgery compared to placebo.
                                                                 secondary endpoints were also met including SNOT-22, total
Supporting dupilumab’s mechanism of action, analyses of
                                                                 nasal symptom score (TNSS), sense of smell (assessed by
biomarkers in patients treated with dupilumab in SINUS-52
                                                                 UPSIT), posterior and anterior rhinorrhea scores for post-na-
showed a consistent decrease in concentrations of serum
                                                                 sal drip and runny nose. Improvements above placebo were
total IgE, periostin, TARC and plasma eotaxin-3 at weeks
                                                                 observed for most secondary endpoints as early as Week 4
24 and 52 and in concentrations of ECP, total IgE, eotax-
                                                                 (Week 8 for UPSIT) and were maintained over the 24-week
in-3, and IL-5 in nasal secretions at week 24. Furthermore,
                                                                 treatment period. In addition, reduced need for surgery by
in SINUS-24, the suspension of dupilumab vs placebo at
                                                                 Week 24 (NPS of ≤ 4 and MCID improvement in SNOT-22)
week 24 led to loss of efficacy on all endpoints observed        was observed in 19% of omalizumab-treated patients versus
up to week 48.                                                   3% of placebo-treated patients in POLYP-1 and 17% versus
Finally, literature data supports the benefits of add-           3% in POLYP-2 50.
ing dupilumab to daily standard of care in patients with         An open-label extension study 50 for participants in POL-
CRSwNP as a novel approach in treating the entire spectrum       YP-1 and POLYP-2 studies was conducted to evaluate the
of clinical manifestations of the disease, as well as the fre-   safety, efficacy and durability of response of omalizumab
quently associated type 2 lower airway comorbidities 42-44.      in adult patients with CRSwNP and inadequate respond-
Dupilumab was the first biologic approved by the Food and        ers to INCS. Patients who completed either POLYP-1 or
Drug Administration (FDA) on June 26th, 2019 to treat in         POLYP-2 were eligible for this study (n = 249). All pa-
adults with CRSwNP not adequately controlled. The Euro-          tients received treatment with omalizumab for 28 weeks,
pean Medicines Agency (EMA) released a favourable opin-          followed by a 24-week period off treatment to assess the
ion on dupilumab on October 26th, 2019 as add-on therapy         recurrence of nasal polyposis. The extension study results
with INCS for the treatment of adults with severe CRSwNP         show that omalizumab treated patients improved in term of
for whom therapy with systemic cosrticosteroids and/or           NPS and SNOT-22 scores. On the other hand, when ceas-
surgery do not provide adequate disease control. In Italy,       ing the treatment NPS, NCS and SNOT-22 progressively
dupilumab was approved by the Italian Agency of Drugs            worsened, although they never returned to pre-treatment
(AIFA) on December 9th, 2020 for adult patients with se-         levels. Therefore, long-term benefits of the therapy have
vere CRSwNP (assessed by an NPS score ≥ 5 or a SNOT-22           been demonstrated. Omalizumab was generally well toler-
score ≥ 50) for whom therapy with SCS and/or surgery do          ated with overall rates of adverse events (AE) comparable
not provide adequate disease control, in addition to back-       to those observed in previous Phase III trials 48. No new or
ground therapy with INCS.                                        unexpected AEs were observed.



6
                                                                               Biologics in the treatment of severe uncontrolled CRSwNP




On November 30th, 2019, the FDA approved omalizumab              sults were presented firstly at the congress of the European
for the treatment of CRSwNP. Furthermore, the EMA gave           Respiratory Society, September 7-9, 2020 55. Mepolizumab
a favourable opinion of omalizumab on July 7th, 2020 in          100 mg administered subcutaneously demonstrated signifi-
Europe.                                                          cant improvement in terms of size of nasal polyps and nasal
                                                                 obstruction at week 52 compared with placebo.
Biologics Targeting IL-5 pathways
                                                                 Based on these data, in October 2020, EMA accepted regu-
(Mepolizumab, Benralizumab)
                                                                 latory submissions seeking approval for the use mepoli-
Mepolizumab                                                      zumab in CRWwNP. Mepolizumab is currently not indi-
The clinical development programme of mepolizumab in             cated for the treatment of CRSwNP.
CRWwNP was composed of two phase 2 placebo-con-
trolled studies that evaluated intravenous mepolizumab           Benralizumab
750 mg in patients with severe nasal polyps 37,38, and by the    Benralizumab is a humanised monoclonal antibody that
phase 3 SYNAPSE study which investigated the efficacy            binds to the alpha subunit of the IL-5 receptor (IL-5R or
and safety of subcutaneous mepolizumab 100 mg adminis-           CD125) which is expressed on different cells like eosino-
tered via pre-filled syringe in adult CRWwNP 51.                 phils, basophils and type-2 innate lymphoid cells (ILC2).
Bachert et al. 38 in the phase II study evaluated intravenous    The mechanism of action of benralizumab, different from
mepolizumab 750 mg every 4 weeks in 105 patients with            other monoclonal antibodies binding IL-5, is not limited
severe bilateral CRSwNP requiring surgery according to           to interference with IL-5 inflammatory pathways. Indeed,
predefined criteria (NPS > 3 or more in 1 nostril and a VAS      benralizumab is able to induce an antibody-dependent cel-
> 7). The authors demonstrated that mepolizumab led to a         lular cytotoxicity (ADCC) by binding to the FcγRIIIα re-
significant reduction in the need for surgery and a signifi-     ceptor expressed on natural killer (NK) cells. This second
cant improvement of symptoms vs placebo. Gevaert et al. 37       mechanism of action produces a direct, rapid and nearly
evaluated intravenous mepolizumab 750 mg every 4 weeks           complete eosinophil depletion both in peripheral blood
in 30 adults with severe uncontrolled CRSwNP. Mean to-           and bronchial tissue 56. The Phase III studies, SIROCCO
tal nasal polyp score was significantly improved in 60%          and CALIMA 57,58, demonstrated the efficacy and safety of
of mepolizumab-treated patients compared to 10% of the           benralizumab in significantly reducing annualised exacer-
placebo group.                                                   bations rates, improving lung function and disease control
Howarth et al. 51 described results of a post hoc analysis of    vs placebo as add-on therapy to high-dosage ICS/LABA in
the MUSCA study 52 and a meta-analysis of MUSCA and              patients with SEA and blood eosinophil counts ≥ 300 cells/
MENSA 53; their combined objective was to determine              microliter.
the change in HRQOL in mepolizumab-treated patients              A growing body of evidence suggests that benralizumab
with severe eosinophilic asthma (SEA) with or without            may exert a rapid and effective therapeutic action in pa-
NP. For the MUSCA post hoc analysis, 422 patients com-           tients with SEA and concomitant relapsing nasal polypo-
pleted the SNOT-22 questionnaire at baseline and were            sis 39. Canonica et al. 59 presented the results of a sub-study
included. Overall, 19% of patients (n = 80) had NP; in           of ANDHI phase III-b trial at EAACI congress in 2020,
these patients mepolizumab and placebo significantly             involving 153 patients with SEA and CRSwNP as comor-
reduced the mean SNOT-22 from baseline to week 24.               bidity, demonstrating the efficacy of benralizumab in im-
For the meta-analysis of MENSA/MUSCA, 166 of 936                 proving SNOT-22 scores. Clinically relevant improvements
patients (18%) had NP at screening. Patients with SEA            in CRSwNP symptoms were observed following the first
and concomitant NP had a phenotype that showed greater           dose and maintained over time.
benefit with mepolizumab compared with patients with             Real world studies and case reports have confirmed the
SEA in the absence of NP.                                        efficacy and safety of benralizumab in this population in
The phase 3 SYNAPSE study 54 was a 52-week, randomised,          clinical practice. Lombardo et al. 40 assessed a cohort of
double-blind, placebo-controlled, parallel group study of        10 SEA patients with CRSwNP treated with benralizumab,
subcutaneous mepolizumab 100 mg in 407 adult patients            demonstrating significant reduction of endoscopic Nasal
with highly symptomatic CRSwNP uncontrolled by previ-            Polyp Score (NPS), Lund-Mackay Score and SNOT-22 af-
ous surgery and treated with INCS. Eligible patients had         ter 24 weeks. Bagnasco et al. 60 in a real-world evaluation
at least 1 prior surgery in the past 10 years, recurrent nasal   in 34 patients with SEA and CRSwNP, confirmed the effec-
polyps despite treatment with standard of care and in need       tiveness of benralizumab on SNOT-22 reduction, with 8/26
of nasal polyp surgery (overall VAS > 7 and an NPS of at         patients (31%) recovering from anosmia after 6 months of
least 5 with a minimum score of 2 in each side). The re-         treatment.



                                                                                                                                     7
E. De Corso et al.




In a phase II randomised, double-blind, placebo-controlled      ≥ 250/microliter or total IgE ≥ 100), need for at least two
20-week trial 61, benralizumab led to significant improve-      courses of SCS per year or long term (> 3 months) low dose
ment in endoscopic NPS, CT score, SNOT-22 and UPSIT             steroids or contraindication to systemic steroids, signifi-
score vs baseline in severe CRSwNP patients refractory to       cantly impaired quality of life (SNOT-22 ≥ 40), anosmic
standard therapies with at least one previous polypectomy.      on smell test and/or comorbid asthma needing regular in-
These results suggested that benralizumab, which targets        haled corticorsteroid. EPOS 2020 1 concluded that biolog-
eosinophils directly, may have a role in the treatment of       ics are indicated in patients with bilateral nasal polyps,
patients with severe uncontrolled CRSwNP.                       who had sinus surgery or were not fit for surgery and who
Currently, a Phase III development programme which in-          had three of the listed criteria. The authors were involved
cludes the completed OSTRO study 62 and the ongoing             in an extensive discussion of whether there was a role for
ORCHID trial 63 is assessing the efficacy and safety of ben-    biologics in patients without previous sinus surgery ac-
ralizumab in patients with severe CRSwNP with or without        cepting that it was possible in exceptional circumstances.
asthma. On September 2020, a press release revealed that        Criteria established by current guidelines 1,19 refers use
the OSTRO study Benralizumab met both its co-primary            of biologics in patients with severe and uncontrolled
endpoints of reduced nasal polyp size and nasal congestion      CRSwNP bringing to light the increasing necessity of
score (NCS) vs placebo as add-on therapy to standard of         identifying subgroups of patients who are eligible for
care in patients with severe bilateral nasal polyposis. Ben-    biologics and of a clear definition of severe uncontrolled
ralizumab for use in CRSwNP is expected to be approved          CRSwNP.
in the next few years.                                          The concept of disease control has been a major critical
                                                                point to optimise CRS management and was introduced
Basing on the data of phase 3 studies, biologics approved       for the first time at EPOS 2012 5 combining the following
 and oncoming in the next future should be considered as        parameters: control of the four major sino-nasal symp-
add-on therapy to local corticosteroids when control of the     toms (nasal blockage, rhinorrhoea/postnasal drip, facial
                  disease is not achieved
      even after oral corticosteroids and/or surgery.
                                                                pain/pressure, smell), sleep disturbance and/or fatigue,
                                                                endoscopic aspect of nasal mucosa and medical intake.
All the members of the committee agree that biologics are       EPOS2020 1 criteria specified that the 4 major symptoms
recommended when Type 2 inflammation is highly likely to        should be specifically related to CRS and not to other rea-
be the dominant endotype of severe uncontrolled CRSwNP.         sons 65. EPOS 2020 1 assumed as “difficult-to- treat” those
                                                                in whom an acceptable level of control was not achieved
 ENT physicians involved in the prescriptions of biologics
  should have a clear understanding not only about sino-        despite appropriate surgery, INCS, and up to 2 brief cours-
 nasal inflammatory patterns driving diffuse CRSwNP, but        es of antibiotics or SCS in the last year, or long term (> 3
also about the mechanism of action, possible side effects,      months) low dose steroids. The EPOS 2020 panel defined
     dose and administration modalities of biologics.           “short” courses of SCS as at least 7-21 days.
                                                                In the latest EUFOREA 2020 19, “uncontrolled CRSwNP”
Recommendations for biologics in uncontrolled severe            was defined as “persistent or recurring despite long-term
CRSwNP                                                          INCS and having received at least one course of SCS in
Several trials have investigated the efficacy of biologics in   the preceding 2 years (or having a medical contraindica-
the treatment of CRSwNP with encouraging results. The           tion or intolerance to SCS) and/or previous sinonasal sur-
approval of some biologics by the FDA in the treatment          gery (unless having a medical contraindication or being
of severe uncontrolled CRSwNP even without asthma has           unwilling to undergo surgery)”. The EUFOREA group 19
stimulated discussion in the medical community, expect-         suggested that a short course of oral corticosteroids should
ing a quick entry in the market not only for dupilumab,         be of a minimum of 5 days at a dose of 0.5-1 mg/kg/day
but also for other monoclonal antibodies. For this reason,      or more. In this last definition, the need for corticosteroids
recent guidelines 1,64 gave full consideration about selec-     was lowered based on evaluation of baseline criteria of
tion criteria of the ideal candidate for biologics and their    subjects included in the Phase 3 studies. The EUFOREA
place in current care pathways. In 2019, the EUFOREA            group further confirmed that long term low does SCS are
team 64 suggested for the first time five criteria as crucial   not recommended for CRSwNP. This panel believes that a
to select CRSwNP patients who are eligible for biologics.       specific discussion should be opened by the medical com-
In February 2020, EPOS guidelines 1 further defined these       munity on the right dose of SCS to consider as maximal
criteria introducing specific cut-offs: evidence of type 2      per year. Given the considerable variability of ENT physi-
disease (tissue eosinophils ≥ 10/hpf or blood eosinophils       cians in prescribing SCS in terms of daily dose and length



8
                                                                              Biologics in the treatment of severe uncontrolled CRSwNP




of short courses, we believe that it may be more appropri-         The members of the committee agree that given the
ate to refer to the yearly cumulative dose in the last year        importance of measuring the severity of the disease,
                                                                particular attention should be paid to this aspect. The ENT
as for asthma patients. Bourdin et al. 66 in fact suggested
                                                                should always be familiar with the most common severity
that “a yearly cumulative OCS dose above 1 gram should            indicators that should routinely be adopted in clinical
be considered unacceptable in severe asthma and should                                    practice.
make the case for referral”.
The concept of severity of disease over the years has been         Future debates should be opened about the maximal
mainly based on the impact of disease on quality of life and     yearly SCS dose and specific cut offs for the definition of
                                                                              severe uncontrolled CRwNP.
its local extension. Because CRSwNP has a wide variabil-
ity of presentation and the severity may vary significantly
between individuals, several authors investigated how to        Multidisciplinary approach
measure it and its definition is becoming increasingly im-      The recent scientific evidence clearly underlines the link
portant. Validated QOL markers have been utilised to iden-      between Type 2 diseases, leading to implement multidisci-
tify eligible CRSwNP patients for Phase 3 studies with bio-     plinary evaluation in Type 2 inflammatory conditions. CRS
logics, with VAS and SNOT-22 being the most commonly            healthcare often requires support from other specialists es-
used; for this reason, they are currently adopted to define     pecially in severe cases. The collaboration with an aller-
severe CRSwNP 67,68. Several nasal polyp endoscopic scor-       gologist, pneumologist, immunologist and rheumatologist
ing systems have been described over the years 69,70 until a    is crucial to define endotype of the disease and coexisting
total NPS was recently developed and standardised 71. It has    Type 2 comorbidities such as atopic dermatitis, eosinophil-
served as a co-primary outcome in clinical trials of biolog-    ic esophagitis or gastroenteritis, N-ERD, allergic fungal
ics, the results are reproducible and responsive to change      rhinosinusitis, Churg Struss Syndrome etc. 76,77.
in severe disease and it is the most common used to evalu-      In the context of a multidisciplinary approach, the central
ate the size of nasal polyps. Equally, the Lund-Mackay ra-      role of the ENT in the management of CRSwNP should
diological score allows reliable assessment of the extent of    be underlined. The ENT has a crucial role firstly in the
disease, and like endoscopy is easily repeatable 71. Evalu-     confirmation of the disease, in evaluating previous surgi-
ation of olfaction is always important to define severity of    cal treatment and measuring severity of the disease. En-
the disease. UPSIT 72 is the standard clinical test used in     doscopy should be considered a mainstay in the diagnosis
United States, whereas the Sniffin’ Sticks in Europe 73,74.     of CRSwNP to perform an adequate phenotyping, accurate
Both have high test-retest reliability, normative values by     staging of the disease and adequate differential diagnosis.
age and sex, and are widely used in research and clinical       It should be noted that the possible coexistence of inverted
practice. Nasal airflow may easily be measured by peak na-      papilloma and diffuse CRS with nasal polyps should be al-
sal inspiratory flow (PNIF) that is an objective measure of     ways excluded even if rare 68-71.
airflow and closely correlated with nasal airway resistance.
                                                                CT scan without endoscopy is not sufficient to confirm the
PNIF is simple to obtain, and the devices are inexpensive
                                                                                 diagnosis of CRSwNP.
and can be used for repeated measurements 75.
The EPOS steering group 1 identified as cut offs for severe      Particular attention should be paid in the definition of the
CRSwNP a VAS > 7, SNOT-22 > 40 and NPS > 5. Further-                              severity of comorbidities.
more, the EPOS guidelines suggested that also olfaction
evaluation was an important parameter to take into con-           Biologics for CRSwNP and concomitant severe asthma
                                                                  should be mainly managed by asthma specialists, while
sideration suggesting as cut-offs the specific ones for the       on the other hand for patients with severe uncontrolled
test used and indicating a picture of anosmia. Recently, the    CRSwNP without asthma/mild moderate asthma the role of
expert EUFOREA panel 19 lowered this parameter as fol-          the ENT specialist should be central. Close collaboration is
lows: SNOT-22 > 35, loss of smell score (0-3) > 2 points or        always recommended to manage comorbid patients.
VAS ≥ 5 and NPS ≥ 4. The members of this committee be-
lieve that particular attention should be paid about cut offs   Surgery and biologics
of severe CRSwNP. Some concerns have been raised about          The commission believes that the role of surgery should not
this new proposed endoscopic score cut-off (NPS > 4)            be underestimated, but rather that its role should be recon-
which seems to more properly reflect a moderate picture.        sidered in the light of new therapeutic opportunities. ESS
Considering the fact that quality of life parameters were       usually leads to a very quick relief of symptoms and in par-
also lowered, we believe that future considerations should      ticular of nasal obstruction, and it further improves control
be made about this topic.                                       of the disease obtained by long term local corticosteroids.



                                                                                                                                    9
E. De Corso et al.




Sinuses are, in fact, better accessible to local treatments af-   this situation, the ENT specialist has a central role in
ter surgery increasing disease control by long term use of        clarifying if surgery was appropriate or not by a care-
INCS (in 60%-70% of cases, disease does not recur within          ful evaluation of CT and endoscopic findings. It is very
5 years) 35,78. For this reason, it is very important to dis-     important to consider the surgical technique used in the
tinguish between first-time and revision surgery. Another         previous treatments. Unfortunately, literature data about
crucial factor that may influence the decision-making al-         rate of success surgical management of CRSwNP varies
gorithm is the coexistence of other Type 2 comorbidities          significantly mainly because authors have not differen-
and in particular asthma (the one most associated with            tiated patients based on their phenotypes and because
CRSwNP). The severity of comorbidities should be estab-           they adopted different criteria to define recurrence and
lished because different scenarios may be faced that need         disease control 82. In addition, revision ESS rates have
to be assessed separately 16,17.                                  changed over the last decade tailoring the extent of sur-
Patients with severe uncontrolled CRSwNP mainly man-              gery and optimising adjuvant post-operative therapy 83.
aged by medical treatment and never treated by surgery            Recurrence after a simple polypectomy should be under-
with or without mild moderate asthma                              stood in a different way compared to a patient who un-
If a patient has never undergone surgery, ESS should be           derwent a more extended approach. It should be careful
taken into consideration because it improves control of the       evaluated if surgery was commensurate to the severity of
disease by INCS spreading their distribution to all sinona-       the phenotype.
sal mucosa. Based on this assumption one could infer that
                                                                  In case of uncontrolled disease after previous appropriate
if patients never received surgery probably control by INCS       surgery and good adherence to INCS the shift to a biologic
may not be fully achieved 78,79.                                   should be advised. On the other hand, especially in cases
                                                                     in which a simple polypectomy was performed and the
  The members of the commission believe that in a patient              ethmoidal labyrinth was not adequately opened, the
with uncontrolled severe CRSwNP treated mainly with long          possibility of revision surgery should be discussed with the
term INCS and brief cycles of SCS and who never received            patient. The commission agreed that in this situation the
   surgery, ESS should be taken into consideration as first       ENT specialist should have a clear idea of which additional
    line treatment, although the following circumstances              surgical goals may be achieved to improve access to
  should be considered as limitations: contraindications to           sinus cavities including, for example, a partial middle
   surgery because of patient’s general condition (severe                   turbinectomy if not performed previously.
    cardiopathy, severe haemorrhagic risk, high risks for
  general anaesthesia etc.); patients refusing treatment by
                                                                  Another important factor to take into consideration is the
 surgery; relevant side effects using INCS and SCS; patient
  preferences after adequate counseling on all therapeutic        timing of recurrence and control of symptoms that patients
                           options.                               experienced over the years after surgery. Recently, some
                                                                  authors 84 have demonstrated that patients presenting with
Finally, one last matter should be covered in the near fu-        a symptomatic recurrence within 3 years of surgery have a
ture. Taking into consideration that some authors 34,80,81        high risk of treatment failure, defined as the need for fur-
have demonstrated that disease control by ESS plus long-          ther surgery. Surgeons should distinguish between revision
term local corticosteroids is very difficult to achieve in        surgery that is required within a short period from the first
the presence of negative predictors of surgical outcomes          procedure and a revision that is required after several years
(asthma, allergy, blood eosinophilia, ASA triad, high load        with good control of the disease. In these cases, we believe
local inflammation, specific preoperative inflammatory            that the patient should be involved into the decision to re-
patterns) 34, some speculate that in this subgroup of pa-         peat surgery or to shift towards treatment with biologics. If
tients biologics should be taken into consideration even          patients experience a long period of symptoms controlled
as first line treatment. Nevertheless, at the moment, there       by surgery and INCS, a revision surgery can be discussed
is insufficient literature evidence to support this statement     with the patient. In this context, the presence of clinical
and specific trials should be properly designed to verify         predictors of poor surgical outcomes may help the patient
this hypothesis.                                                  and the surgeon towards the choice of biologics. Other fac-
                                                                  tors may influence the choice such age of the patient and
Patients with severe CRSwNP uncontrolled after medical
                                                                  his/her preferences.
and surgical treatments with or without mild moderate
asthma                                                            In case of patients who underwent multiple surgeries with
This may be a different scenario if CRSwNP patients                a severe impact on quality of life and who experienced a
already underwent at least one previous surgery. In               short interval of symptoms control between interventions,



10
                                                                                 Biologics in the treatment of severe uncontrolled CRSwNP




    the use of biologic is recommended whatever the               Criteria to evaluate response to biologics
  endoscopic nasal polyps score at the moment of the              EUFOREA expert panel on 2019 64 first described criteria
evaluation. Similarly, in patients already treated by surgery
                                                                  to evaluate response to biologics and specifically: reduced
and who reported major complications after ESS, the shift
              to biologics is recommended.                        nasal polyps size, reduced need for SCS, improved qual-
                                                                  ity of life, improved sense of smell and reduced impact of
    This committee believes that adequate counselling             comorbidities. The same criteria were adopted by EPOS
     is always recommended in order to discuss all the            2020 1. Initially authors 86 agreed that the first evaluation
  alternative treatments and possibilities with the patient       should be set at 4 months to consider an early stopping
    based on control and severity of disease. Based on
                                                                  point if treatment response is lacking, due to the high cost
   the new personalised medicine requirement, patients
 should participate in the decision to start with a specific      of these medications. More recently, the EUFOREA ex-
                         treatment.                               pert panel in 2020 19 prolonged the first evaluation to 6
                                                                  months of treatment and specified cut-offs for each cri-
We believe that surgery still plays an important role not         terion. The authors specified that the treatment should be
only in order to optimise control of the disease, but also for    followed when a clear change for at least one of the fol-
the dynamics between forces that range from international         lowing criteria have been met: smell score increase > 0.5,
recommendations and payer policies to patient and physi-          NCS decrease > 0.5, NPS decrease by 1 point, SNOT-22
cian preferences. Discussion should be opened about the           reduction > 8.9; VAS reduction > 2 cm. In addition, the
possibility to use biologics as first line with surgery in case   authors recommended to discuss improvement with the
of very high polyps score to offer a better starting point        patient. If patients do not accept improvement, a salvage
to patients, even if there is insufficient evidence to support    treatment by SCS or surgery should be considered. A pro-
this hypothesis considering that there are no data compar-        portion of patients, in fact, might need surgery that the
ing surgery in combination with biologics. In addition, the       authors 19 defined as “salvage surgery under biologic pro-
following recommendation of EUFOREA 2021 should be                tection”, although there is limited data about long term
taken into consideration: “A fixed combination plan with          benefit of this kind of approach. Otherwise, if the patients
surgery and biologic treatment starting in parallel or within     accept improvement even in case of a minimal response
a short time of one another is not advised, as the response       the treatment should be prolonged until 12 months when
of the individual patient to surgery or the biologic would be     efficacy should be re-evaluated, and all the following defi-
impossible to evaluate” 19.                                       nitions should be satisfied to follow treatment: NPS < 4;
                                                                  NCS < 2; VAS < 5; SNOT-22 < 30. If the criteria are not
Patients with severe uncontrolled CRSwNP and comor-               met, surgery should be performed, or a different biologic
bid uncontrolled severe asthma                                    should be considered.
A proportion of patients with severe uncontrolled CRSwNP          The EUFOREA group 19 tried to standardise the evaluation
may also have a coexisting, highly disabling Type 2 dis-          of biologic efficacy and the decision to adopt based on the
ease such as severe asthma 85. In this situation, multidisci-     results and the patient’s comfort and preferences. We be-
plinary discussion with an allergologist and pneumologist         lieve that future considerations will probably be required to
is essential and treatment with biologics should be mainly        confirm these criteria or to confirm more or less stringent
managed by them. In these patients, surgery may offer a           indications. Real-life experience will be crucial to support
better starting point to achieve quick relief of sino-nasal       this shared decision-making model.
symptoms and asthma control as soon as possible, even if
surgery should be delayed while verifying the efficacy of            The commission believes that evaluation to consider
biologics on sino-nasal symptoms and reducing the nasal              response to biologics is extremely important. All the
polyp score. Close cooperation is recommended during                 members of the committee agree that the rhinology
                                                                      centres involved in the prescription of the biologics
treatment to evaluate both efficacy on asthma and CRwNP.
                                                                   should organise the right setting for proper follow-up and
Surgery or shift to another biologic may be indicated if                     assessment of response to biologics.
poor control of CRSwNP is observed after 4-6 months of
treatment with biologics.                                         Prediction of response to biologics and biomarkers
                                                                  Biomarkers can serve as predictors of which patients will
  The commission agrees that if severe asthma co-exists
                                                                  respond best to therapy and as outcome parameters during
 close cooperation with a pneumologist and allergologist
 is highly recommended to evaluate in a multidisciplinary         treatment in order to establish efficacy of treatment. Actu-
  fashion the best way forward in term of indications and         ally, prediction of response to biologics in an individual pa-
                   selection of biologics.                        tient is not possible. In fact, we currently lack reliable clini-



                                                                                                                                     11
E. De Corso et al.




cal biomarkers to differentiate among CRSwNP endotypes            patients will probably be burdened with lifelong disease.
that may differ in their response to specific biologics 87. In    Therefore, as with any chronic condition, we cannot just
this context, specific biomarkers should be investigated; to      focus cost estimations on short time intervals, even if long-
be clinically useful, as a predictor of the response to treat-    term cost calculations and modeling are unfortunately very
ment, a biomarker must be highly predictive; it is also pos-      difficult to estimate.
sible that clusters of biomarkers may be able to attain high
levels of predictability, but extensive work is required to          The commission agrees that future studies should be
advance this field especially to be ready in the near future          planned about the cost effectiveness of new drugs.
when more biologics will be available for severe uncon-
trolled CRSwNP. There is no experience on the best choice         Conclusions
of a first biologic or a second, and there are no known limi-
                                                                  In a patient with uncontrolled severe type 2 CRSwNP, if
tations for blood or serum parameters for CRSwNP. Final-
                                                                  non-effective systemic medical treatment or surgery has
ly, no head-to-head comparisons between biologics have
                                                                  been performed, a long-term plan using a biologic should
been performed. Future work on biomarkers may yield bet-
                                                                  be contemplated together with an informed patient. This
ter tests for selecting the first drug to start with.
                                                                  plan needs to consider the endotype, comorbidities and
  Prediction of response to biologics basing on validated         former treatment history (long term INCS, surgeries,
            biomarkers actually is not possible.                  SCS and their efficacy, duration of effect, and adverse
                                                                  events). We believe that patients who are still sympto-
Costs of biologics in CRSwNP                                      matic despite current maximal medical therapy and sur-
Although multiple studies have confirmed the efficacy of          gical intervention are the main focus of treatment with
biologics for treatment of CRSwNP, very limited data are          biologics. Based on the new developments, the physician
currently available about cost analyses of biologics com-         should properly inform the patient about available alter-
pared with the current standard of care. Brown et al. 88 criti-   natives involving him/her in the clinical decisions in line
cally looked at the efficacy and costs of biologic therapy        with the principles of precision medicine that patients
for CRSwNP. They found few studies addressing this topic,         will also share in decision making.
reporting a more robust literature in asthma compared to          The clinical scenario may further evolve in the next
CRwNP. They concluded that cost-efficacy studies are am-          months/years because other biologic will receive approv-
bivalent when evaluating biologics. In fact, some authors 88      al for severe CRSwNP, others are currently in the pipe-
demonstrated that biologics tended to be cost-efficient,          line and even more targets are being identified. Future
especially in patients who are poorly controlled with the         study should be oriented to characterise in which patients
standard of care, while several studies 89-91 have under-         the single biologic may have greatest clinical efficacy. In
lined that costs might be better justified if pharmaceutical      fact, the general biomarkers of Type 2 inflammation cur-
companies lowered prices and if clinicians focused more           rently adopted may help to broadly identify patients who
on subgroups such as clear responders and those requiring         may benefit from biologics, while ongoing research may
more frequent SCS prescriptions.                                  lead to identification of new biomarkers that are useful
We agree on the extreme need to plan cost-efficacy studies        in the selection of the right patient. For these reasons,
evaluating the long-term use of biologics compared with           we expect in the future that clinical algorithm and care
the current standard of care for CRSwNP. Total costs of the       pathways may be implemented based on improving se-
disease account for direct and indirect costs, where direct       lection criteria. Future clinical trials are needed to im-
costs refer to health care costs and indirect costs refer to      plement recommendations for initiation of biologics, and
lost productivity. As demonstrated in other chronic diseas-       to compare biologics to the current standard of care and
es, the indirect costs of CRSwNP are much greater than the        between biologic medication options.
direct costs because patients are usually of working age 92.      A multidisciplinary shared airway approach can possibly
Recently, some authors 93-97 have demonstrated significant        identify patients who may require treatment with biologics
improvement in productivity after treatment of CRS and            at an earlier stage in the disease process. This may have an
reduction of indirect costs. Likewise, if biologics are ef-       overall positive impact on the psychological burden of the
fective, they may reduce the costs related to the burden of       disease on patients and healthcare service. Nevertheless,
CRSwNP.                                                           current literature data do not support use of biologics at an
Finally, the cost of disease needs to consider the disease        earlier stage in the disease process of CRS, although this
time horizon and in particular the interval time in which the     scenario might change in the future.



12
                                                                                               Biologics in the treatment of severe uncontrolled CRSwNP




At present, biologics are mainly considered only as adjunct                 5
                                                                                 Fokkens WJ, Lund VJ, Mullol J, et al. EPOS 2012: European position
                                                                                 paper on rhinosinusitis and nasal polyps 2012. A summary for otorhi-
therapy in patients with severe uncontrolled CRSwNP and
                                                                                 nolaryngologists. Rhinology 2012;50:1-12. https://doi.org/10.4193/
evidence of Type 2 disease. The exact application of bio-                        Rhino50E2
logics will continue to evolve. Combinations of biologic                    6
                                                                                 Bachert C, Bhattacharyya N, Desrosiers M, et al. Burden of dis-
therapies with surgery will be probably explored. Further                        ease in chronic rhinosinusitis with nasal polyps. J Asthma Allergy
research into biologics vs surgery as well as long-term dis-                     2021;14:127-134. https://doi.org/10.2147/JAA.S290424
ease control is required. It is likely that biologics will in
                                                                            7
                                                                                 Vlaminck S, Acke F, Prokopakis E, et al. Surgery in nasal polyp patients:
                                                                                 outcome after a minimum observation of 10 years. Am J Rhinol Al-
time become an alternative for sinus surgery as currently                        lergy 2021;35:449-457. https://doi.org/10.1177/1945892420961964
performed. We believe that the role of biologics in conjunc-                8
                                                                                 Vanderhaegen T, Gengler I, Dendooven A, et al. Eosinophils in
tion with surgery, after surgery, or as an alternative to it,                    the field of nasal polyposis: towards a better understanding of bio-
needs to be investigated further.                                                logic therapies. Clin Rev Allergy Immunol 2021 Jan 26. https://doi.
                                                                                 org/10.1007/s12016-021-08844-7. Online ahead of print.
While MAbs are well tolerated with no severe adverse ef-                    9
                                                                                 Peters AT, Han JK, Hellings P, et al. Indirect treatment compari-
fects, further research is required to determine their long-                     son of biologics in chronic rhinosinusitis with nasal polyps. J Al-
term benefits, comparability to other medical treatments                         lergy Clin Immunol Pract 2021;3:S2213-219800159-8. https://doi.
and potential side effects.                                                      org/10.1016/j.jaip.2021.01.031.
Physicians, patients, insurers and government payers
                                                                            10
                                                                                 Stevens WW, Lee RJ, Schleimer RP, et al. Chronic rhinosinusitis
                                                                                 pathogenesis. J Allergy Clin Immunol 2015;136:1442-1453. https://
should not ignore considerations about costs. At this time,                      doi.org/10.1016/j.jaci.2015.10.009
there is minimal data examining the cost-efficacy and long-                 11
                                                                                 Mahdavinia M, Keshavarzian A, Tobin MC, et al. A comprehensive
term side effects. To better understand costs, studies should                    review of the nasal microbiome in chronic rhinosinusitis (CRS). Clin
be designed to evaluate if biologics may decrease costs re-                      Exp Allergy 2016;46:21-41. https://doi.org/10.1111/cea.12666
lated to severe uncontrolled CRSwNP.                                        12
                                                                                 Schleimer RP. Immunopathogenesis of chronic rhinosinusitis and
                                                                                 nasal polyposis. Annu Rev Pathol 2017;24;12:331-357. https://doi.
                                                                                 org/10.1146/annurev-pathol-052016-100401
Acknowledgements                                                            13
                                                                                 Stevens WW, Ocampo CJ, Berdnikovs S, et al. Cytokines in chronic
We would like to thank Professor Gaetano Paludetti that                          rhinosinusitis. role in eosinophilia and aspirin-exacerbated respiratory
encouraged and stimulated discussion of the commission                           disease. Am J Respir Crit Care Med 2015;192:682-694. https://doi.
                                                                                 org/10.1164/rccm.201412-2278OC
about the important fields of Biologics in severe uncon-                    14
                                                                                 Lee K, Tai J, Lee SH, et al. Advances in the knowledge of the under-
trolled CRSwNP when he was President of Italian Society                          lying airway remodeling mechanisms in chronic rhinosinusitis based
of Otorhinolaryngology. We finally thank Professor Palu-                         on the endotypes: a review. Int J Mol Sci 2021;22:910. https://doi.
detti for final critical revision of the manuscript.                             org/10.3390/ijms22020910
                                                                            15
                                                                                 Akdis CA, Bachert C, Cingi C, et al. Endotypes and phenotypes
                                                                                 of chronic rhinosinusitis: a PRACTALL document of the Eu-
Conflict of interest statement
                                                                                 ropean Academy of Allergy and Clinical Immunology and the
The authors declare no conflict of interest.                                     American Academy of Allergy, Asthma & Immunology. J Allergy
                                                                                 Clin Immunol 2013;131:1479-1490. https://doi.org/10.1016/j.
Funding                                                                          jaci.2013.02.036
This research did not receive any specific grant from funding
                                                                            16
                                                                                 Wang M, Bu X, Luan G, et al. Distinct type 2-high inflammation as-
                                                                                 sociated molecular signatures of chronic rhinosinusitis with nasal pol-
agencies in the public, commercial, or not-for-profit sectors.                   yps with comorbid asthma. Clin Transl Allergy 2020;3:10-26. https://
                                                                                 doi.org/10.1186/s13601-020-00332-z
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