10.14639/0392-100X-N1911
Herein we review the current literature on the adverse effects related to biological therapy with the monoclonal antibody dupilumab in patients with type 2 inflammation prevalent phenotype chronic rhinosinusitis with nasal polyps (CRSwNP). Our review shows that the side effects of dupilumab may be linked to the prevalent type 2 inflammation phenotype (asthma, dermatitis, CRSwNP). We also report the first case of cutaneous rash as a side effect of dupilumab in a patient with CRSwNP
text/xml
1827-675X
1911
en
Carlotta Pipolo
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
adverse effect
Adverse effects of dupilumab in chronic rhinosinusitis with nasal polyps. Case report and narrative review
Text.Serial.Journal
https://www.actaitalica.it/
42
Reviews
2022-06-30
2021-11-21
2022-07-26
2022-07-26
199-204
1
Carlotta Pipolo
2022/06/30
10.14639/0392-100X-N1911
199
Otolaryngology Unit, Santi Paolo e Carlo Hospital, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
1827-675X
adverse effect
en
204
Adverse effects of dupilumab in chronic rhinosinusitis with nasal polyps. Case report and narrative review
https://www.actaitalica.it/article/download/1911/812
42
ACTA OTORHINOLARYNGOLOGICA ITALICA 2022;42:199-204; doi: 10.14639/0392-100X-N1911




Review


Adverse effects of dupilumab in chronic rhinosinusitis
with nasal polyps. Case report and narrative review
Effetti avversi di dupilumab nel trattamento della rinosinusite cronica con poliposi nasale
Letizia Nitro, Antonio Mario Bulfamante, Cecilia Rosso, Alberto Maria Saibene, Flavio Arnone,
Giovanni Felisati, Carlotta Pipolo
Otolaryngology Unit, Santi Paolo e Carlo Hospital, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy


SUMMARY
Herein we review the current literature on the adverse effects related to biological therapy
with the monoclonal antibody dupilumab in patients with type 2 inflammation prevalent
phenotype chronic rhinosinusitis with nasal polyps (CRSwNP). Our review shows that the
side effects of dupilumab may be linked to the prevalent type 2 inflammation phenotype
(asthma, dermatitis, CRSwNP). We also report the first case of cutaneous rash as a side ef-
fect of dupilumab in a patient with CRSwNP.
KEY WORDS: dupilumab, chronic rhinosinusitis with nasal polyps, type 2 inflammation,
cutaneous rash, adverse effect

RIASSUNTO
La presente revisione della letteratura è incentrata sugli effetti collaterali correlati al trat-
tamento con l’anticorpo monoclonale dupilumab, con particolare riferimento alla rino-
sinusite cronica con polipi nasali. La revisione mostra come gli specifici effetti avversi
della terapia con dupilumab appaiano direttamente correlati con il fenotipo prevalente di
infiammazione di tipo 2. Si riporta inoltre il primo caso clinico di comparsa di rash cutaneo
a seguito di assunzione della prima dose di dupilumab in questa categoria di pazienti.
PAROLE CHIAVE: dupilumab, rinosinusite cronica con polipi nasali, infiammazione di
tipo 2, rash cutaneo, effetto avverso
                                                                                                    Received: November 10, 2021
                                                                                                    Accepted: February 18, 2022
Introduction
                                                                                                    Correspondence
The prevalence of chronic rhinosinusitis (CRS) in the world population is es-                       Letizia Nitro
                                                                                                    Santi Paolo e Carlo Hospital, via Antonio di Rudini
timated at 11-15% 1 with an average of 11% in European countries 2. CRS has                         8, 20142 Milan, Italy
significant impact on patients’ quality of life (QoL) and inevitably leads to a                     E-mail: letizia.nitro@unimi.it
burdensome effect on healthcare costs in addition to social-economic impact
by reducing individual productivity 3-5.                                                              How to cite this article: Nitro L, Bulfamante
The very recent introduction of targeted therapies based on the use of mono-                          AM, Rosso C, et al. Adverse effects of dupilum-
                                                                                                      ab in chronic rhinosinusitis with nasal polyps.
clonal antibodies has significantly modified and improved the outcomes of
                                                                                                      Case report and narrative review. Acta Otorhi-
these patients 6.                                                                                     nolaryngol Ital 2022;42:199-204. https://doi.
Dupixent® (dupilumab, Sanofi Genzyme) is a fully human monoclonal anti-                               org/10.14639/0392-100X-N1911
body that acts on the alpha subunit of the interleukin-4 receptor (IL 4Rα) 7,
                                                                                                    © Società Italiana di Otorinolaringoiatria
and is capable of inhibiting the action of both IL-4 and IL-13 8. Its adminis-                      e Chirurgia Cervico-Facciale
tration has been approved in the EU since October 2020 9 for the treatment
of severe CRS associated with nasal polyps (severe CRSwNP) 10,11. Previous                                         OPEN ACCESS
approval by the FDA for its use in severe asthma and atopic dermatitis date to                      This is an open access article distributed in accordance with
                                                                                                    the CC-BY-NC-ND (Creative Commons Attribution-Non-
2018, and there is now substantial data in the literature on the adverse effects                    Commercial-NoDerivatives 4.0 International) license. The
(AE) of subcutaneous treatment with dupilumab 8,12,13,14.                                           article can be used by giving appropriate credit and mentio-
                                                                                                    ning the license, but only for non-commercial purposes and
In CRSwNP, this therapeutic option is suitable for selected patients who have a                     only in the original version. For further information: https://
type 2 inflammation pattern-related endotype. Among the different criteria for in-                  creativecommons.org/licenses/by-nc-nd/4.0/deed.en




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clusion in the treatment protocol, previous failure of therapy    lated to the use of dupilumab in patients with CRSwNP.
with topical nasal and systemic corticosteroids and/or recur-     Furthermore, a major risk in developing side effects is de-
rence of nasal polyposis after surgery should be present 15,16.   scribed in comparison to the control group treated with pla-
Clinical assessment and follow-up of patients is carried out      cebo 10,17,22. The most frequent are, respectively, nasophar-
through outpatient assessment using standardised ques-            yngitis, injection site reaction and headache 15,17,22-24. Less
tionnaires aimed at the evaluation of the patient’s QoL, e.g.     frequently epistaxis, lack of improvement, or worsening
the 22-item Sino-Nasal Outcome Test (SNOT-22) and the             of nasal polyps, arthralgia, asthma or worsening of asthma
Visual Analogue Scale (VAS), endoscopic criteria (Nasal           have been reported 21,25,26.
Polyp Score, NPS), functional testing (with Sniffin’ Sticks       To the best of our knowledge there are no reported cases
or University of Pennsylvania smell identification test, UP-      of increased eosinophilia or ophthalmological or dermato-
SIT) and radiological evaluation, such as the Lund-Mackay         logical manifestations in patients treated with dupilumab
computed tomography (CT) score 10,11,17,18.                       for exclusive CRSwNP 10,15,22,27,28.
The use of biological therapy has shown consistent ben-
efit on symptoms and QoL, in addition to improvement              Authors’ experience - Case report
in endoscopic and radiological markers in patients with
CRSwNP. However, its use is associated with several ad-           Among 20 patients treated in our institution with dupilumab
verse effects 17,19-21.                                           since January 2021, a single adverse event (AE) emerged.
Herein, we review the current literature on the different ad-     The patient reporting the AE was a 50-year-old male pa-
verse effects of dupilumab in patients suffering from differ-     tient, with a confirmed diagnosis of CRSwNP, who had un-
ent type 2 inflammatory diseases and highlight the variety        dergone multiple Endoscopic Sinus Surgeries (ESS) in the
of clinical presentations among the different pathologies         previous years (the last in 2011). The patient’s comorbidi-
such as atopic dermatitis, asthma and CRSwNP. We focus            ties included bronchial asthma (pulmonary function tests
on the current literature about adverse effects in patients       show a FEV1 59%, FVC 93%, positive bronchial revers-
with CRSwNP and report the first case of cutaneous rash           ibility test with salbutamol and a fraction of nitric oxide ex-
as a side effect of dupilumab localised on the caudal part of     halated (FeNO) of 63% with poorly controlled symptoms
the body in a patient with CRSwNP.                                by inhalation therapy, intolerance to acetylsalicylic acid
                                                                  (ASA), polyposis of the stomach and gastric body, prick
                                                                  tests negative for inhalant allergic diathesis and no prior
Materials and methods                                             episodes of dermatitis.
A review of the relevant international literature was carried     The patient underwent ENT evaluation in March 2021
out using the Medline® and Embase® databases with the             for recurrence of persistent hyposmia and chronic nasal
following search term:                                            bilateral obstruction that was non-responsive to oral and
“Dupilumab” [All Fields] AND (side effects [MeSH                  topical steroids. Endoscopic evaluation (OLYMPUS, EN-
Terms] OR adverse effects [MeSH Terms]). Subsequently             DOEYE™ LF-V) provided evidence of complete nasal
another search was performed using: ((“Dupilumab” [Title/         obstruction due to bilateral polypoid neoformations (NPS
Abstract] AND “side effects” [Title/Abstract] OR “adverse         average score of 8).
effects” [Title/Abstract]) AND (“nasal polyps” [Title/Ab-         During ENT evaluation, the SNOT-22 questionnaire was
stract] OR “rhinosinusitis” [Title/Abstract])).                   administered with a total score of 89/110; olfactometry us-
References of retrieved articles were scrutinised for ad-         ing identification Sniffin’ Sticks (Burghart®) scored 3/12
ditional articles. Articles and book chapters published in        and 4-Phase rhinomanometry values of 0.22 to the right
English and French were included. Abstracts of all articles       side and 0.72 on the left side were observed.
and book chapters were screened and selected according to         After evaluation of blood eosinophils (0.71 x 109/L, r.v.
relevance, followed by full reading of the papers.                0.00-0.50 x 109/L) and nasal cytology (presence of eosino-
AE events in the current case series of our institution           phils: 12/hpf,) that confirmed the presence of type 2 lead
were further reviewed. Furthermore, a literature review           inflammation, treatment with dupilumab (300 mg) was ini-
for dupilumab-related AE in atopic dermatitis and asthma          tiated in May 2021 and followed by one injection every two
treatment was also performed.                                     weeks.
                                                                  The first follow-up was performed after 1 month of treat-
                                                                  ment; the patient reported clear subjective clinical im-
Adverse effects in CRSwNP                                         provement (SNOT-22: 10 points), improvement of the en-
Several clinical studies have reported adverse effects re-        doscopic nasal findings with NPS of 4 (2 + 2), performance



200
                                                                                    Adverse effects of dupilumab in CRSwNP and case report




at the Sniffin’ Stick test (Burghart®) with recognition of 14        that are resistant to treatments such as phototherapy, oral
of 16 items and rhinomanometry values of 1.06 cm H2O/l/s             corticosteroids and immunosuppressants 29,30. In addition,
on the right and 1.18 cm H2O/l/s on the left.                        dupilumab allows a substantial reduction of toxic effects in
However, the appearance of pruritus accompanied by a skin            comparison with other therapies 29.
rash localised on the caudal surfaces of the body (mainly            Treatment-emergent AEs of dupilumab therapy are defined
localised on the lower limbs and groin) appeared at 2 weeks          according to the Medical Dictionary for Regulatory Activi-
after the first administration, 1 day after the second admin-        ties (MedDRA).
istration of dupilumab (Figs. 1A-C, 2). After administra-            The most frequently observed AEs can be divided into
tion of antihistamine therapy (bilastine, 20 mg BID) with            infectious and non-infectious. Among infectious AEs, na-
only transient benefit, the patient was sent for dermatologi-        sopharyngitis, upper respiratory tract infections, conjunc-
cal evaluation with diagnosis of irritative dermatitis and           tivitis and Herpes virus skin infections have been reported.
confirmation of the current therapy with addition of topi-           Injection-site reactions, exacerbation of AD, headache and
cal skin therapy with emollients. No other adverse effects           allergic conjunctivitis are the main non-infectious side ef-
(conjunctival inflammation, nasopharyngitis, or injection            fects reported in the literature 29,31-33. Moreover, rare AEs
site inflammation were present). Blood work showed an in-            such as facial redness, alopecia, arthralgia 12,13,33,34, itching
crease of eosinophilia (0.90 x 109/L, r.v. 0.00-0.50 x 109/L).       and urticarial-like rash typically localised in head and neck
Adverse event reporting to the national authorities was              region have been described 35,36.
promptly undertaken.                                                 According to many studies, conjunctivitis seems to be the
In July 2021 (after 3 months of dupilumab therapy), due              only specific side effect related to dupilumab in patients
to the persistence of cutaneous rash and worsening of pru-           with AD 31,37. According to Wollemberg et al. 37, bilateral
ritus, and despite the current local and systemic therapy,           conjunctivitis occurred in 25-50% of their patients with AD
treatment with dupilumab was interrupted.                            treated with dupilumab. However, the pathological mecha-
After discontinuation, the patient reported rapid disappear-         nism is not fully understood. Indeed, prescription of bio-
ance of the cutaneous manifestation and resolution of pru-           logical therapy and ocular manifestations show a temporal
ritus at one month after treatment discontinuation.                  but not causal relation 37.
                                                                     Cutaneous manifestations have been reported as side ef-
Adverse effects in atopic dermatitis (AD)                            fects during the use of dupilumab in patients with AD.
Atopic dermatitis is a relapsing inflammatory chronic dis-           These include, rash-like forms which have been described
ease 29. It affects 3 to 10% of adults and 10 to 20% of chil-        exclusively on the acral portions of the body (mainly face
dren 30. Dupilumab has shown encouraging results in the              and upper limbs) 35. No patient has shown involvement of
treatment of controlled moderate-to-severe forms of AD               caudal portions 35.




 A                                                    B                                       C

Figure 1A, B, C. Skin rash localised on the lower limbs and groin.



                                                                                                                                     201
L. Nitro et al.




                                                                in the injection site reactions) in dupilumab-treated asthma
                                                                patients has not been reported.

                                                                Discussion
                                                                Biological therapies based on the use of monoclonal anti-
                                                                bodies such as dupilumab show encouraging results in the
                                                                treatment of comorbidities related to type 2 inflammation 21.
                                                                In patients with CRSwNP, dupilumab has been shown to
                                                                improve symptom scores 17,42, eosinophilic and IgE blood
                                                                counts 7, and endoscopic/radiological findings 17,21. The re-
                                                                cent introduction of biological therapy with dupilumab for
                                                                CRSwNP was accompanied by different types of side ef-
                                                                fects in type 2 inflammation-related diseases. At present,
                                                                the effort of several authors to standardise those AEs and
                                                                assess the safety of dupilumab seems to show some short-
                                                                comings in terms of concordance and identification of spe-
                                                                cific AEs in patients with CRSwNP. The safety and efficacy
                                                                of this therapy have been confirmed by many studies, but
                                                                side effects in patients with CRSwNP are nonetheless
                                                                poorly described in the literature. In the LIBERTY NP SI-
                                                                NUS-24 and LIBERTY NP SINUS-52 multicentre studies,
                                                                the most commonly reported AEs were nasopharyngitis,
                                                                lack of improvement of nasal polyps and asthma, head-
                                                                ache, epistaxis and injection-site reactions 21. Likewise, ac-
                                                                cording to a meta-analysis by Chong et al. in patients with
Figure 2. Urticarial-like rash localised on the lower limb.
                                                                CRSwNP, there is a low and uncertain increase of the risk
                                                                of developing nasopharyngitis compared to the placebo
Adverse effects in asthma                                       group 22. The randomised, double-blind, placebo-controlled
                                                                parallel-group study by Bachert et al. in 2016 was one of
The efficacy and safety of dupilumab in treatment of asth-      the few which investigated the side effects of dupilumab in
ma has been assessed by several studies 14,27,38-40. Approxi-   CRSwNP with and without other comorbidities (50% of
mately 20% of patients with moderate-to-severe disease          the sample suffered from asthma) with evidence of AEs in
show uncontrolled symptoms with maximal standardised            25 of 30 patients in the placebo group and in all 30 patients
therapies 27.                                                   in the dupilumab group. The most frequent AEs described
The most frequent side effects, occurring in variable per-      were nasopharyngitis, injection site reactions (7 and 40%,
centage of 5-13% in patients with asthma treated with           respectively), and headache 17.
dupilumab are injection-site reactions 14,27,38. The appear-    Although there is agreement about dupilumab-related AEs
ance of blood eosinophilia may also be related to dupilum-      in patients with CRSwNP; there is a lack of studies focus-
ab therapy and is associated with an augmented risk of          ing on the main side effects of therapy with dupilumab in
worsening of pre-existing hypereosinophilia symptoms            patients with CRS with or without other comorbidities. No-
(e.g. chronic eosinophilic pneumonia) 8,27,41.                  ticeably, different expressions of type 2 inflammation pat-
In many studies upper respiratory tract (such as nasophar-      terns seem to show distinct side effects, and in fact most
yngitis and sinusitis) and urinary infections are reported      of the cutaneous adverse effects described in the literature
more frequently with dupilumab compared to placebo 27,38.       have been reported in patients with AD or other cutaneous
Influenza, headache and back pain are also mentioned as side    type 2 inflammation manifestations 33. The description of
effects of dupilumab therapy in asthmatic patients 14,27,38.    itching and urticarial-like rash is only referred in literature
Conjunctivitis is rarely mentioned as an adverse effect in      to patients with AD, as a side effect of dupilumab adminis-
patients with asthma and no cause-effect relation has been      tration 33,36,43. Deleuran et al. in their clinical trial stated that
established 27,38. To the best of our knowledge, the appear-    cutaneous side effects, such AD, should be included in the
ance of skin manifestations (except for erythema localised      most common AEs in those patients 44.



202
                                                                                              Adverse effects of dupilumab in CRSwNP and case report




The Food Drug Administration (FDA) 45 and Kim et al. 43                         nolaryngologists. Rhinology 2012;50:1-12. https://doi.org/10.4193/
                                                                                Rhino12.000
reported that the appearance of generalised urticaria is seen
                                                                           2
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in < 1% of patients who received dupilumab and only in                          tion with chronic rhinosinusitis: the GA2LEN survey in Europe. Aller-
clinical trials on AD. Furthermore, it is interesting that these                gy 2012;67:91-98. https://doi.org/10.1111/j.1398-9995.2011.02709.x
clinical features tend to appear exclusively on the acral por-             3
                                                                                Hastan D, Fokkens WJ, Bachert C, et al. Chronic rhi-
tions of the body (trunk, upper limbs, face and neck), while                    nosinusitis in Europe-an underestimated disease. A GA-
in the literature no forms localised to the lower limbs and                     2LEN        study.    Allergy      2011;66:1216-1223.      https://doi.
                                                                                org/10.1111/j.1398-9995.2011.02646.x
inguinal region have been described 35.                                    4
                                                                                Chung JH, Lee YJ, Kang TW, et al. Altered quality of life and psycho-
Our clinical case is the first to describe a lower limb derma-                  logical health (SCL-90-R) in patients with chronic rhinosinusitis with
titis in a patient after the administration of dupilumab for                    nasal polyps. Ann Otol Rhinol Laryngol 2015;124:663-670. https://
CRSwNP. In our experience, only interruption of dupilum-                        doi.org/10.1177/000348941557618
ab therapy allowed for resolution of pruritus and skin rash,
                                                                           5
                                                                                Bhattacharyya N, Villeneuve S, Joish VN, et al. Cost burden and re-
                                                                                source utilization in patients with chronic rhinosinusitis and nasal
despite antihistamine treatment. It has to be noted that this                   polyps. Laryngoscope 2019;129:1969-1975. https://doi.org/10.1002/
single report of a patient with a skin AE in the context of                     lary.27852
CRSwNP is an exception to the general trend linking AE to                  6
                                                                                Bachert C, Bhattacharyya N, Desrosiers M, et al. Burden of dis-
the specific type 2 inflammation-related disease.                               ease in chronic rhinosinusitis with nasal polyps. J Asthma Allergy
                                                                                2021;14:127-134. https://doi.org/10.2147/JAA.S290424
This review of the current literature on the safety of                     7
                                                                                Jonstam K, Swanson BN, Mannent LP, et al. Dupilumab reduces lo-
dupilumab highlights that different type 2 inflammation-                        cal type 2 pro-inflammatory biomarkers in chronic rhinosinusitis with
related diseases seem to show different adverse effects. In                     nasal polyposis. Allergy 2019;74:743-752. https://doi.org/10.1111/
addition, our review has shown that different studies focus-                    all.13685
ing on the same phenotype of type 2 inflammation show no                   8
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                                                                                with elevated eosinophil levels. N Engl J Med 2013;368:2455-2466.
concordance in terms of AE reported.                                            https://doi.org/10.1056/NEJMoa1304048
                                                                           9
                                                                                European Medicines Agency. Annex I. Summary of product char-
Conclusions                                                                     acteristics [dupilumab]. https://www.ema.europa.eu/en/documents/
                                                                                product-information/dupixent-epar-product-information_en.pdf. Ac-
Herein, we presented the first case report of a lower limb                      cessed on 19 September 2019.
cutaneous side effect related to therapy with dupilumab for                10
                                                                                Bachert C, Zhang N, Cavaliere C, et al. Biologics for chronic rhinosi-
                                                                                nusitis with nasal polyps. J Allergy Clin Immunol 2020;145:725-739.
CRSwNP. Narrative review of the literature showed that                          https://doi.org/10.1016/j.jaci.2020.01.020
the side effects of dupilumab may be specific to the preva-                11
                                                                                Bachert C, Zhang L, Gevaert P. Current and future treatment op-
lent phenotype of type 2 inflammation (asthma, dermatitis,                      tions for adult chronic rhinosinusitis: focus on nasal polyposis. J Al-
CRSwNP) and further studies will be needed to establish                         lergy Clin Immunol 2015;136:1431-1440. https://doi.org/10.1016/j.
                                                                                jaci.2015.10.010
which AEs are more likely in each subgroup and define                      12
                                                                                Halling A-S, Loft N, Silverberg JI, et al. Real-world evidence of
their pathogenetic mechanisms.                                                  dupilumab efficacy and risk of adverse events: a systematic review
                                                                                and meta-analysis. J Am Acad Dermatol 2021;84:139-147. https://
Conflict of interest statement                                                  doi.org/10.1016/j.jaad.2020.08.051
The authors declare no conflict of interest.                               13
                                                                                Blauvelt A, de Bruin-Weller M, Gooderham M, et al. Long-term
                                                                                management of moderate-to-severe atopic dermatitis with dupilumab
                                                                                and concomitant topical corticosteroids (LIBERTY AD CHRONOS):
Funding                                                                         a 1-year, randomised, double-blinded, placebo-controlled, phase
This research did not receive any specific grant from fund-                     3 trial. Lancet 2017;389:2287-2303. https://doi.org/10.1016/
ing agencies in the public, commercial, or not-for-profit                       S0140-6736(17)31191-1
sectors.
                                                                           14
                                                                                Wenzel S, Castro M, Corren J, et al. Dupilumab efficacy and safety
                                                                                in adults with uncontrolled persistent asthma despite use of medi-
                                                                                um-to-high-dose inhaled corticosteroids plus a long-acting β2 ago-
Authors’ contributions                                                          nist: a randomised double-blind placebo-controlled pivotal phase 2b
LN: study design, article search and selection, data extrac-                    dose-ranging trial. Lancet 2016;388:31-44. https://doi.org/10.1016/
                                                                                S0140-6736(16)30307-5
tion and drafting of the article. CR, FA and AMB: drafting                 15
                                                                                Kartush AG, Schumacher JK, Shah R, et al. Biologic agents for the
of the article. AMS and CP: study design, critical revision                     treatment of chronic rhinosinusitis with nasal polyps. Am J Rhinol Al-
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                                                                           16
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