BrazJOtorhinolaryngol.2016;82(3):251---252
www.bjorl.org
Brazilian
Journal
of
OTORHINOLARYNGOLOGY
EDITORIAL
Innovative
therapeutic
targets
in
chronic
sinusitis
with
nasal
polyps
夽
Alvos
terapêuticos
inovadores
na
sinusite
crônica
com
pólipos
nasais
Ourcurrent therapeutic options for patients withchronic sinusitis andnasal polyps consist of topical glucocorticos-teroids(GCS),carefullyindicatedshortepisodesoforalGCS, coursesoflong termantibiotics (specificallydoxyxycline1)
and sinus surgery. Even with thisarmamentarium usedin combinationwithpre-andpostoperativeGCS,studiesshow high recurrence rates of nasal polyps, withabout 80% of regrowth over 12 years. About half of these patients will requiresurgeryagain,someofthemmorethan4surgeries. Thereisaclearunmetneedforasubgroupofchronic sinus-itispatients.
In Europe,the US andcertainly Australia, andpossibly in other regions, most polyps arecharacterized by a Th2 inflammatorypattern, withcytokinesinterleukins(IL)-4, -5,and-13,eosinophilsandIgEinvolved.Infact,this‘‘type 2inflammation’’isassociatedwithseverepolypdiseaseall overtheworld,andhasbeendemonstratedtopredict recur-rence of disease and asthma comorbidity, different from eosinophil-poor primarilyneutrophilic polyps.2 This makes
Th2 cytokines and the associated inflammatory cells and their products perfect targets for innovative therapeutic interventions.Verysimilarmechanismsarealsoinvolvedin severeasthmaandatopicdermatitis,andthuswemayhope thattreatmentapproachesthataredevelopedforthose dis-easeswillalsoonedaybeavailableforseverenasalpolyps. So far, therehave been several proof-of-concept stud-iesperformedinnasalpolypdisease,allinGhent,involving theantibodies reslizumab,mepolizumab andomalizumab. These studies have shown that indeed the type2 inflam-mation does play a major role in nasal polyps; all three humanizedmonoclonalanti-bodiestargetingIL-5orIgEhave beensuccessfultoacertainextent.3Althoughrathersmall,
thestudiesdemonstratedthatpolypsshrinkover2---3months
夽
Pleasecitethisarticleas:BachertC.Innovativetherapeutic tar-getsinchronicsinusitiswithnasalpolyps.BrazJOtorhinolaryngol. 2016;82:251---2.
and remain under control for several months thereafter, althoughtreatmentapproacheswereratherlimitedintime andnumberofinjections.Thisstimulatedhopeforfurther achievements in the future, when nasal polyps would be accepted as targets for registration for major ‘‘players’’ (suchasGSK,Sanofi,Novartisetc.),andlargerstudieswould beperformedwiththeaimofachievingregistrationforthe indicationofnasalpolyps.
This time has now come. On February 2nd, 2016, a firstproof-of-conceptstudywithdupilumab,afullyhuman biologicstargeting theIL-4receptoralphaand interfering withboth IL-4and IL-13pathways, hasbeen publishedin JAMA.4 IL-4andIL-13signal through2 differentreceptors
thatpartlyoverlap in theirfunctions, and theyboth con-tainthe␣subunitoftheIL-4receptor.Viathosereceptors,
IL-4andIL-13orchestrateIgEformation,eosinophil recruit-ment,mucussecretionand manyother ‘‘typical’’events. As both cytokines are prominent representatives of type 2 inflammatory reactions, we performed a double-blind, placebo-controlledrandomizedstudy ontheeffectiveness andsafety ofdupilumab in patients withchronic sinusitis withnasalpolypswithorwithoutconcomitantasthma.Polyp scoreshadtobeatleast5of8bilaterally,andpolypshad toberefractorytotopicalGCSs.Sixtypatientswith bilat-eralnasalpolyposiswereincludedandobservedfor4weeks duringtopicalGCStreatment andthentreatedeitherwith 300mgofsubcutaneous dupilumabperweek(loadingdose 600mg)orplacebofor16weeks;bothgroupswerereceiving dailymometasonefuroatenasalspray.
Intheverumtreatedgroup,theendoscopicnasalpolyp score,theCTscoreaccordingtoLundandMackay,andeach ofthetypicalsymptomsaswellasnasalflowmeasurements improved significantly compared to the placebo treated group. Furthermore, the Sino-Nasal Outcome Test (SNOT-22)andthe UniversityofPennsylvaniaSmellIdentification Testrevealed clinicallyand statisticallysignificant effects compared with placebo. More than half of the patients respondedwitha reductionof thepolypscore ofat least
http://dx.doi.org/10.1016/j.bjorl.2016.03.001
252 EDITORIAL
2points,whichisthesamelevelofresponseas3weeksof oralapplicationofGCSs.Thedrugwaswelltolerated,with the most frequently reported adverse events being naso-pharyngitis, injection-site reactions, and headache (not significant).
Asthmatic patients additionally achieved significantly improved pulmonary function and asthma control test results in comparison with placebo. Concen-trations of biomarkers of eosinophilic inflammation, including serum IgEandchemokinesfor eosinophils,werealsosignificantly reduced in serum. The results of this study were consis-tent with previous investigations in patients with severe asthmaandatopicdermatitisand confirmedthepotential ofdupilumabtoinhibitTH2-inducedinflammationand con-secutivesymptomsandcomplaints.
Withthisstudy,anewdimensioninthemanagementof nasalpolyps includingcomorbidasthma may berevealed. Of course, studies with greater populations anddifferent dosingregimens havetobeperformed,andregistrationof thedrugmaystilltaketwoyearsormore;butforthefirst time,aregistrationfortheindicationofnasalpolypscould beachieved.Itwillthenbeourtasktodefine thepatient groupsandthetimingofthisinterventionintheflowofGCS treatmentandsurgery.Biomarkersmightallowustoselect patientsandpredict theirresponsetothetreatment,and thuswill haveimpactonourmanagementof thedisease. Andfinally, other biologics willlikely come tofollow this example.
Thefuturehasarrivedforinnovativetreatmentofsevere nasalpolyposis.Thisimpliesofcoursenotonlynew perspec-tivesforusandourpatients,butalsotheneedformaking us knowledgeable in the immunology of the disease, the
intervention andthepossible adverse events. Weneed to becomewellversedinthisarea,ifwewanttomaintainthe diseasewithinourspeciality.
Conflicts
of
interest
The authorwas principal investigator of the studies with biologicsforGSK,NovartisandSanofi-Aventis.
References
1.FokkensWJ,LundVJ,MullolJ,BachertC,AlobidI,BaroodyF, etal.Europeanpositionpaperonrhinosinusitisandnasalpolyps 2012.RhinolSuppl.2012;23:1---298.
2.TomassenP,VandeplasG,vanZeleT,CardellLO,ArebroJ,Olze H,etal.Inflammatoryendotypesofchronicrhino-sinusitisbased onclusteranalysisofbiomarkers.JAllergyClinImmunol.2016. 3.Bachert C,ZhangL, GevaertP.Currentand future treatment
optionsforadultchronicrhinosinusitis:focusonnasalpolyposis. JAllergyClinImmunol.2015;136:1431---40.
4.Bachert C, Mannent L, Naclerio RM, Mullol J, Ferguson BJ, GevaertP,etal.Effectofsubcutaneousdupilumabonnasalpolyp burdeninpatientswithchronicsinusitiswithnasalpolyposis---a randomizedclinicaltrial.JAMA.2016;315:469---79.
ClausBacherta,b
aUpperAirwaysResearchLaboratoryandENTDepartment,
GhentUniversityHospital,Ghent,Belgium
bDivisionofENTDiseases,CLINTEC,KarolinskaInstitute,
