BrazJOtorhinolaryngol.2020;86(1):99---104
www.bjorl.org
Brazilian
Journal
of
OTORHINOLARYNGOLOGY
ORIGINAL
ARTICLE
Effects
of
oral
isotretinoin
therapy
on
the
nasal
cavities
夽,夽夽
Hamdi
Tasli
a,∗,
Aslan
Yurekli
b,
Mert
Cemal
Gokgoz
c,
Omer
Karakoc
daBirecikStateHospital,DepartmentofOtolaryngology,HeadandNeckSurgery,Sanliurfa,Turkey bBayburtStateHospital,DepartmentofDermatology,Bayburt,Turkey
cSiirtStateHospital,DepartmentofOtolaryngology,HeadandNeckSurgery,Siirt,Turkey dGulhaneMedicalSchool,DepartmentofOtolaryngology,HeadandNeckSurgery,Ankara,Turkey
Received13May2018;accepted20October2018 Availableonline12November2018
KEYWORDS Isotretinoin; Rhinomanometry; Acne; Saccharinetest Abstract
Introduction:Isotretinoin(13cis-retinoicacid)isthemosteffectivetreatmentforacnevulgaris andistheonlytreatmentoptionthatcanprovideeitherremissionorapermanentcure.
Objective: Theaimofthisstudywastousebothsubjectiveandobjectivemethodstoassess thenasalcomplaintsofpatientswithsevereacnewhoreceivedoralisotretinointherapy.
Methods:Fifty-foursubjectswere enrolledinthestudy.Allthesubjectswereassessedwith subjective(NOSEandVASquestionnaires)andobjective(rhinomanometryandsaccharine)tests todeterminetheseverityoftheirnasalcomplaints.
Results:Themeanseverityscores(min:0;max:100)fornasaldryness/crustingandepistaxis were0.47±1.48(0---5);0.35±1.30(0---5)atadmission,3.57±4.45(0---10);2.26±4.71(0---20) atthefirst month,and4.28±6(0---20);2.26±4.71(0---20)atthethirdmonthofthe treat-mentrespectively.Totalnasalresistanceof0.195±0.079(0.12---0.56)Pa/cm3/satadmission,
0.21±0.084(0.12---0.54)Pa/cm3/satthefirstmonth,and0.216±0.081(0.14---0.54)Pa/cm3/s
atthethirdmonth.
Conclusion: Oralisotretinointherapycancausethecomplaintofnasalobstruction.Inaddition, nasalcomplaints,suchasdryness/crustingandepistaxis,significantlyincreaseinpatientsduring thetherapyschedule.
© 2018 Associac¸˜ao Brasileira de Otorrinolaringologia e Cirurgia C´ervico-Facial. Published by Elsevier Editora Ltda. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).
夽 Pleasecitethisarticleas:TasliH,YurekliA,GokgozMC,KarakocO.Effectsoforalisotretinointherapyonthenasalcavities.BrazJ Otorhinolaryngol.2020;86:99---104.
夽夽ThisworkwasdoneinGulhaneMedicalSchool,DepartmentofOtolaryngology,HeadandNeckSurgery,Ankara,Turkey. ∗Correspondingauthor.
E-mail:hamditasli@gmail.com(H.Tasli).
PeerReviewundertheresponsibilityofAssociac¸ãoBrasileiradeOtorrinolaringologiaeCirurgiaCérvico-Facial. https://doi.org/10.1016/j.bjorl.2018.10.004
1808-8694/©2018Associac¸˜aoBrasileiradeOtorrinolaringologiaeCirurgiaC´ervico-Facial.PublishedbyElsevierEditoraLtda.Thisisanopen accessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).
PALAVRAS-CHAVE
Isotretinoína; Rinomanometria; Acne;
Testedesacarina
Efeitosnasaisdaterapiacomisotretinoínaoral
Resumo
Introduc¸ão:Aisotretinoína(ácido-13cis-retinóico)éotratamentoporviaoralmaiseficazpara acnevulgareéaúnicaopc¸ãodetratamentoquepodeproduzirremissãooucurapermanente.
Objetivo:Usarmétodossubjetivoseobjetivosparaavaliarasqueixasnasaisdepacientescom acnegravequereceberamterapiacomisotretinoínaoral.
Método: Foramincluídosnoestudo54indivíduos.Todososindivíduosforamavaliadospormeio detestessubjetivos(questionáriosNOSEeescalaEVA)eobjetivos(rinomanometriaetestede sacarina)paradeterminaragravidadedesuasqueixasnasais.
Resultados: Osescores médiosde gravidade(min: 0; max: 100)para ressecamento/crostas e epistaxenasal foram de0,47±1,48(0-5); 0,35±1,30(0-5) no início,3,57±4,45(0-10); 2,26±4,71(0-20)noprimeiromêse4,28±6(0-20);2,26±4,71(0-20)noterceiromêsdo trata-mento,respectivamente.Aresistêncianasaltotalfoide0,195±0,079(0,12a0,56)Pa/cm3/s
no início, 0,21±0,084 (0,12 a 0,54)Pa/cm3/s no primeiro mês e 0,216±0,081 (0,14 a
0,54)Pa/cm3/snoterceiromês.
Conclusão:Aterapiacomisotretinoínaporviaoralpoderesultaremqueixadeobstruc¸ãonasal. Alémdisso,queixasnasaistaiscomoressecamento/formac¸ãodecrostaseepistaxe,aumentam significativamentenospacientesduranteoesquematerapêutico.
© 2018 Associac¸˜ao Brasileira de Otorrinolaringologia e Cirurgia C´ervico-Facial. Publicado por Elsevier Editora Ltda. Este ´e um artigo Open Access sob uma licenc¸a CC BY (http:// creativecommons.org/licenses/by/4.0/).
Introduction
Acne is a chronic dermatologic disease characterized by lesions and scarring that last a lifetime.1 This
disor-der is more common and more severe in adolescence (70%---87% of the adolescent population) and its inci-dence gradually decreases in the adult years.2 It has a
complex pathophysiology, involving abnormal keratiniza-tion,hormonaldysfunction,bacterialgrowth,andimmune hypersensitivity.3Itcan bedivided traditionallyintothree
categories according to the lesion type and the symp-tompresentations:mild, moderate,andsevere.The most widelyacceptedformof treatmentforsevereacne isoral isotretinoin(13cis-retinoicacid).
Oralisotretinoinwasfirstapprovedforthemanagement of acne vulgaris in 1982.4 It was originally indicated for
treatmentatadoseof1---2mg/kg/daytoacumulativedose of120---150mg/kg,usuallyadministeredover4---5months.5
Although it hasa favorable safetyprofile, the major lim-itationofisotretinoin isitswell-describedadverse effect. Themostcommonadverseeffectismucocutaneousdryness ofthe epidermalsurfaces, givingrisetocheilitis,xerosis, anddermatitis.6Despitethewiderangeofadverseeffects
includingnasalcomplaintsasepistaxis,noneofthestudies have mentioned the feelingof nasal obstruction and dry-ness/crusting.
The aim of this study was to use both subjective and objectivemethodstoassessthenasalcomplaintsofpatients withsevereacnewhoreceivedoralisotretinointherapy.
Methods
Patients with severe acne who were treated with oral isotretinoinwereenrolledinthisstudybetweenAugust10,
2014andMay10,2016.Thestudywascarriedout accord-ingtotheDeclarationofHelsinkiandhadbeen previously approved by the local review board (2015---269). All data werecollectedprospectively,andeachsubjectwasenrolled in thestudy afterprovidingwritten informedconsent.All the subjects filled out the NOSE and VAS questionnaires to determine the severity of their nasal complaints. Two objectivemethods---anteriorrhinomanometryand saccha-rine tests--- werealso performed for each patient. These questionnaires and tests were conducted for all patients at admissionand inthe firstandthird monthsof theoral isotretinoin therapy schedule, and the results were com-paredstatisticallytorevealchangesinthenasalcomplaints during the treatment process. The cumulative treatment dose, which wasmore reproducibleand reliable than the daily dose, was used asthe measurement in the present study. The isotretinoin treatment was administered at a cumulativedoseof120mg/kgfor6months.
Subjectiveassessmentofthenasalairway
The NOSE scale consists of five obstruction-related items (nasalcongestion or stuffiness, nasal blockageor obstruc-tion,troublebreathingthroughthenose,troublesleeping, inability to get air throughthe nose during exercise) and isaneasymethodfordeterminationoftheseverityofthe complaints. Two questions regarding theseverity of nasal dryness/crustingandepistaxiswerealsoaskedandscored inadditiontotheNOSE scale.Allitemswerescoredusing a5pointLikertscaleandscaledtoatotalscoreof0---100. Higherscoresindicatedgreaternasalobstructionandmore severe symptoms of nasal dryness/crusting and epistaxis. TheVASallowspatientstoratetheirsymptomsona10cm linearscale,where0correspondstosymptomsthatarenot
Effectsofisotretinoinonthenasalcavities 101 troublesomeatalland10isthemosttroublesomesymptoms
imaginable.7
Objectiveassessmentofthenasalairway
Anterior rhinomanometry was used for objective evalua-tionofnasalobstruction.Duringthetest,thepatientwas instructedtositinanuprightpositionandtobreathequietly for20---30minwithaminimumairflowof 300cm3/s. With
thismethod,nasalairflowwasmeasuredfromonenostrilat atimeandthepressure-sensingtubewasswappedfromone sidetotheother.Therefore,thepressure/flowcurvesand nasalresistanceorconductancemeasurementswere deter-minedseparatelyforeachnasalpassage,andthetotalwas thencalculated.8
The saccharinetest wasusedtodeterminemucociliary clearance(MCC). Each subject wasseatedand positioned withtheheadslightlyextended. Asaccharinegranulewas 2 to 3mm in diameter and placed by the tester, under visualcontrol,2cminsidetherightnostril.Eachsubjectwas instructedtoswallowevery30seconds,determinedwitha chronometer.Thesubjectusedastopwatchtoindicatethe timeforthefirstperceptionofthesweettasteofthe sac-charineandrecordedthetimeinminutes.NormalnasalMCC shouldrangebetween9and17min.9
Inclusion/exclusioncriteria
Only adult patients with severe acne were recruited. After taking a detailed medical history, a complete otorhinolaryngologicexaminationwasperformed,including nasalendoscopyafterdecongestion.The exclusioncriteria includedagebelow18years,anymedicaltherapywithin6 months,chronicrhinosinusitisaccordingtoEPOScriteria,10
inflammatory or infectious sinus disease, allergicrhinitis, headandneckradiotherapyhistory,sino-nasalmalignancy, historyorclinicalevidenceofanynasalsurgery.
Statisticalanalysis
The responsiveness of the questionnaire was assessed by comparing the NOSE scores at admission and during a 3 month oral isotretinoin treatment. The Wilcoxon signed-rank test was applied to measure the magnitude of the effectforthestatisticalevaluationandtocomparethe sub-jectiveandobjectivetestresults.Statisticalanalyseswere performedusingtheStatisticalPackageforSocialSciences software(SPSS17.0forWindows;SPSSInc.,IL,USA).Values ofp<0.05wereconsideredstatisticallysignificant.
Results
Fifty-four subjects were enrolled in the study. The mean age was 21±3 (18---33 years). The treatment with oral isotretinoin was stopped because of adverse side effects in12ofthe54patients.Threepatientscouldnottolerate theobjectivetests,buttheyperformedthesubjectivetests andsevenpatientsdidnotattendregularfollow-up,butwe questionedthesepatientsbyphoneandreceivedtheir sub-jectiveresponses.Wecompletedthestudywithsubjective
testsadministeredto42of54patientsandobjectivetests administeredto32of54patientsatadmissionandatthefirst andthirdmonthsoftheoralisotretinointherapyschedule.
Subjectivetests
The mean NOSE scores were 14.04±16.49 (0---50) at admission, 20.11±20.34 (0---75) at the first month, and 19.04±19.63(0---75)atthethirdmonth ofthetreatment. ThemeanVASscoreswere1.59±1.43(1---3)atfirst admis-sion,2.14±1.8 (2---3) at the first month, and 2.21±1.91 (2---3)atthethirdmonthofthetreatment(Table1).Only4 (9.5%)ofthe42patientshadcomplaintsofdryness/crusting atadmission.Atthefirstandthirdmonths,18(43%)patients had this complaint. The mean severity scores (min: 0; max:100)fornasaldryness/crustingwere0.47±1.48(0---5) at admission, 3.57±4.45 (0---10) at the first month, and 4.28±6(0---20)atthethird monthof thetreatment.Only 3(7%)ofthe42patientsdescribedacomplaintofepistaxis atadmission.Atthefirstandthirdmonths,13(31%)and11 (26.2%)patientsdescribedthiscomplaint.Themean sever-ityscoresofepistaxis(min:0;max:100)were0.35±1.30 (0---5)at admission,2.61±4.45(0---15) at thefirst month, and2.26±4.71(0---20)atthethirdmonthofthetreatment (Table2).
Thedifferencesbetweenscoresatadmissionandduring therapywerestatisticallysignificant(p<0.05),butthefirst andthethirdmonthswerenotstatisticallysignificanteither forNOSEandVASscales,severityofnasaldryness/crusting orforepistaxis(p=0.7;0.8;0.8;1).
Objectivetests
The mean score for the total nasal resistance was 0.195±0.079 (0.12---0.56)Pa/cm3/s at admission,
0.21±0.084 (0.12---0.54)Pa/cm3/s at the first month,
and 0.216±0.081 (0.14---0.54)Pa/cm3/s at the third
month. The meanscore of totalnasal flow was834±200 (247---1256)cm3/satadmission,803±188(383---1211)cm3/s
atthefirst month,and773±203 (322---1201)cm3/sat the
thirdmonthoftherapy.Thedifferencesbetweenthemean scoresatadmissionandatthefirstmonth;andthefirstand thethirdmonthswerenotstatisticallysignificantforeither totalnasalresistance(p=0.26---1)ornasalflow(p=0.54---1) (Table1).
The timing of nasal mucociliary activity, determined by the saccharine test, was 9.03±2.11min (5---15) at admission, 9.9±2.06min (7---15) at the first month, and 9.68±1.94min (6---14) at the third month (Table 1). The differences between the scores at admission and during therapywerestatisticallysignificant(p<0.05),butthe dif-ference between the first and the third months was not statisticallysignificant(p=0.1).
Discussion
Isotretinoin is themost effective treatment for acne vul-garis and is the only treatment option that can provide eitherremissionorapermanentcure.11 Themostcommon
Tasli
H
et
al.
Table1 Subjectiveandobjectivetestresultsofpatientswithsevereacnewhoreceivedoralisotretinointherapy.
Subjectivetest Objectivetests
NOSEscale VASscale Rhinomanometry Saccharinetest(min) Score±SD p Score±SD p Nasalresistance(Pa/cm3/s) Nasalflow(cm3/s) Score±SD p
Score±SD p Score±SD p
Admission 14.04±16.49 <0.05 1.59±1.43 <0.05 0.195±0.0790.26 834±200 0.54 9.03±2.11 <0.05 1month 20.11±20.34 0.7 2.14±1.8 0.8 0.21±0.0841 803±188 1 9.9±2.06 0.1 3month 19.04±19.63 2.21±1.91 0.216±0.081 773±203 9.68±1.94
Effectsofisotretinoinonthenasalcavities 103
Table2 Severityscoresofnasaldryness/crustingandepistaxis.
Admission 1month 3month p
n % MS±SD p n % MS±SD n % MS±SD
Dryness/crusting 4/42 10 0.47±1.48 <0.05 18/42 43 3.57±4.45 18/42 43 4.28±6 0.8
Epistaxis 3/42 7 0.35±1.30 <0.05 13/42 31 2.61±4.45 11/42 26 2.26±4.71 1
MS,meanscore;SD,standarddeviation.
surfacesassociatedwithcheilitis,xerosis,anddermatitis.6
In addition to these side effects, nasal complaints, such as the feeling of nasal obstruction and dryness/crusting, wereevaluatedin thisstudyasthesehadnotbeen exam-inedpreviously.Accordingtothisstudy,itisrevealed that oralisotretinointherapycausedthefeelingofnasal obstruc-tion,epistaxisanddryness/crustingduringthethreemonth follow-up.
Themechanismofthenasalcomplaintscanbeexplained by the histopathological changes that occur in response to oral isotretinoin treatment. Isotretinoin is a vitamin A derivativethatdecreasestheproliferation,differentiation, andactivityofsebaceouscystsbyarrestingtheircellcycle.11
Thesecretionsofthesebaceouscystsmoisturizethenasal passageand determine theviscosity and elasticity of the mucusthatliesatopthecilialayerofthemucosa.They pro-tectthemucosa fromdrynessandprovide an appropriate nasal physiology. Isotretinoin also inhibits sebaceous lipid synthesis and reduces the sebum excretion rate.12 These
mechanismsblockthedevelopmentofacne,buttheyalso causemucocutaneousdryness,oneofthecommonadverse effects already mentioned.6 The mucocutaneous dryness
couldleadtocrusting,whichcouldeasilyobstructthenasal passageandcreatethecomplaintofnasalobstruction.
Several previous studies have evaluated epistaxis due to isotretinoin treatment. Blasiak et al. found epistaxis in 37.9% of the 116 patients with acne who used oral isotretinoinfor12monthsanddescribedepistaxisasoneof themostcommonsymptomsduringthetreatment.13 Ertam
etal.,14Gorpeliogluetal.,15andAlzoubietal.16alsofound
epistaxis in 23.1%, 40%, and 55.4%, respectively, of their patientstudy cohorts, while wenoted itin 19% ofour 42 patients. Epistaxis is a commonly accepted side effectof isotretinointreatment,anditwasblamedonthe mucocu-taneousdrynessobservedinallthesestudies;however,the mechanism leading to epistaxisstill remains unclear. The mucocutaneous dryness and resultingcrusting, which was seenin33%ofourpatients,coulddamagethenasalmucosa witha traumatic effect, and this waslikely the causeof epistaxis.Inanycase,themucocutaneousdrynesswas fol-lowedbyaviciouscycleofcrustingandepistaxisduringthe therapy.
Themucociliaryclearance(MCC)ensurestheremovalof foreignparticles,pathogens,andtoxinsfromthenasal pas-sage,anditisagoodindicatorofanormalnasalphysiology. Manyrecentstudies haveconfirmedthattheMCCiseasily disturbedbytoxins,drugs,smoking,sinonasalpathologies, andsurgery,9aswellasbyisotretinointreatment.15
Gorpe-liogluetal.evaluated40acnepatientswiththesaccharine
testandfoundthatthesaccharinetime(ST)wasprolonged duringan isotretinoin therapy appliedfor 3 monthsas in this study. It is concluded that the mucocutaneous dry-nessduetoisotretinointreatmentmayincreasethemucus viscosity in the nasal passage by altering the water and electrolytebalance,andtheyblamedthesechangesforthe pathogenesis.15
Unliketheresultsofsubjectivetests,the rhinomanom-etrymeasurementsrevealed thattherewasnodifference between the mean scores at admission and at the first month;andthefirstandthe thirdmonthsfor eithertotal nasalresistanceandflow.Thiscontroversycanbeexplained by the limited number of patients. Although the differ-encesbetweenthescoreswerenotstatisticallysignificant, theoralisotretinointreatmentclearlyhadadverseclinical effectsinthepatientsprovenwiththesubjectivetestsand theprolongedmucociliaryactivitycouldalsocontributeto thisresult.
Themajorlimitationsofthisstudywerethelimited num-berof patients andthe shortfollow-up period.Twelve of theinitial54patientsenrolledinthestudywereexcluded becauseof adverse side effects. The objective testsalso requireasubstantialeffortonthepartofboththepatient and the physician, and 7 patients failed to attend their regularfollow-ups.Ourfindingssuggest aneedforfurther studiesaimedatrevealingthelong-termnasalsideeffects duetooralisotretinointherapyforacnetreatmentandthe reversibilityofthesenasalcomplaints.
Conclusion
Oralisotretinointherapycancausethecomplaintofnasal obstruction. In addition, nasal complaints, such as dry-ness/crustingandepistaxis,significantlyincreaseinpatients duringthetherapyschedule.
Informed
consent
Allprocedures performed in studies involving human par-ticipantswereinaccordancewiththeethicalstandardsof the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amend-mentsor comparableethicalstandards.Informed consent wasobtainedfromallindividualparticipantsincludedinthe study
Conflicts
of
interest
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