Eficácia e segurança da ciclesonida no tratamento da rinite alérgica perene: uma revisão sistemática e metanálise

www.bjorl.org

Brazilian

Journal

of

OTORHINOLARYNGOLOGY

REVIEW

ARTICLE

The

efficacy

and

safety

of

ciclesonide

for

the

treatment

of

perennial

allergic

rhinitis:

a

systematic

review

and

meta-analysis

夽

Qi

Yang

_,

_Fei

_Wang

_,

_Bin

_Li

_,

_Wenbin

_Wu

_,

_Dengpiao

_Xie

_,

_Li

_He

_,

Nan

Xiang

_,

_Yan

_Dong

a_{ChengduUniversityofTraditionalChineseMedicine,Chengdu,China} b_{SichuanCollegeofTraditionalChineseMedicine,Mianyang,China}

c_{HospitalofChengduUniversityofTraditionalChineseMedicine,Chengdu,China} d_{ChengduFirstPeople’sHospital,Chengdu,China}

Received19August2018;accepted24October2018 Availableonline22November2018

KEYWORDS Meta-analysis; Ciclesonide; Rhinitis; Allergic; Perennial Abstract

Introduction:Allergicrhinitisisachronicinflammatorydiseasewhichaffects1outof6 individ-uals.Perennialallergicrhinitisaccountsfor40%ofARcases.Ciclesonideisoneoftherelatively newintranasalsteroidforallergicrhinitis.

Objective: Thepurposeofthisstudywastoevaluatetheefficacyandsafetyofciclesonidein thetreatmentofperennialallergicrhinitis.

Methods:WesearchedPubmed,ScientificCitationIndex,Embase,ClinicalTrialRegistriesfor randomizedcontrolledtrialsandCochraneCentralRegisterofControlledTrialstofindoutthe randomizedcontrolledTrialcomparingciclesonidewithplaceboforPAR.

Results:Eightstudieswereincluded.Incomparisonwithplacebogroups,ciclesonidegroups sig-nificantlydecreasedReflectiveTotalNasalSymptomScore(MD=−0.56;95%CI−0.72to0.39, p<0.00001)withheterogeneity(p=0.19, I2_{=24%),InstantaneousTotalNasalSymptomScore}

(MD=−0.57;95%CI−0.75to−0.39,p<0.00001)withheterogeneity(p=0.34,I2_=11%).A

sig-nificanteffectforReflectiveNasalSymptomScoreSubtotal(MD=_−0.15;95%CI_−0.18to_−0.13, p<0.00001)withheterogeneity(p=0.12,I2_{=24%)wasalsodemonstrated.Rhinoconjunctivitis}

qualityoflifequestionnairescore(RQLQs)(MD=_−0.27;95%CI_−0.39to_−0.15,p<0.00001)with heterogeneity(p=0.58,I2_{=0%)inthetreatmentofciclesonidewasalsosignificantlyreduced.}

Inaddition,thedifferenceinTreatment-EmergentAdverseEventsbetweenthetwogroupswas notsignificant.

夽 _{Pleasecitethisarticleas:YangQ,WangF,LiB,WuW,XieD,HeL,etal.Theefficacyandsafetyofciclesonideforthetreatmentof}

perennialallergicrhinitis:asystematicreviewandmeta-analysis.BrazJOtorhinolaryngol.2019;85:371---8.

∗_{Correspondingauthor.}

E-mail:dongyancd@163.com(Y.Dong). https://doi.org/10.1016/j.bjorl.2018.10.008

1808-8694/©2018Associac¸˜aoBrasileiradeOtorrinolaringologiaeCirurgiaC´ervico-Facial.PublishedbyElsevierEditoraLtda.Thisisanopen accessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).

Conclusion:Ciclesonide can improve perennial allergic rhinitis without increasing adverse events.Ciclesonidemaybeanothervaluablechoiceforperennialallergicrhinitisinthefuture. © 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/). PALAVRAS-CHAVE Metanálise; Ciclesonida; Rinite; Alérgica; Perene

Eficáciaeseguranc¸adaciclesonidanotratamentodarinitealérgicaperene:uma revisãosistemáticaemetanálise

Resumo

Introduc¸ão:Arinitealérgicaéumadoenc¸ainflamatóriacrônicaqueafetaumacadaseis indi-víduos.Arinitealérgicapereneéresponsávelpor40%doscasosderinitealérgica.Aciclesonida éumdoscorticosteroidesintranasaismaisnovosparaotratamentodessacondic¸ãoclínica. Objetivo:Avaliaraeficáciaeseguranc¸adaciclesonidanotratamentodarinitealérgicaperene. Método: UmabuscafoifeitanosbancosdedadosPubmed,ScientificCitationIndex,Embasee ClinicalTrialRegistriesporensaiosclínicosrandomizadoseCochraneCentralRegisterof Con-trolledTrialsporestudoscontroladosrandomizadosquecomparassemciclesonidacomplacebo notratamentodarinitealérgicaperene.

Resultados: Oitoestudosforamincluídos.Emcomparac¸ãocomosgruposplacebo,osgrupos ciclesonidamostraram diminuic¸ãosignificantenoescoredo ReflectiveTotalNasalSymptom Score(DM=−0,56;IC95%:−0,72a−0,39,p<0,00001)comheterogeneidade(p=0,19,I2_=24%),

doInstantaneousTotalNasalSymptomScore(DM=_−0,57;IC95%:_−0,75a_−0,39,p<0,00001) comheterogeneidade(p=0,34,I2_{=11%).UmefeitosignificantenoescoredoReflectiveNasal}

SymptomScoreSubtotal(DM=−0,15;IC95%:−0,18a−0,13,p<0,00001)comheterogeneidade (p=0,12,I2_{=24%)tambémfoidemonstrado.OescoredoRhinoconjunctivitisQualityofLife}

Questionnairescore(RQLQs)(DM=−0,27;IC95%:−0,39a−0,15,p<0,00001)com heterogenei-dade(p=0,58,I2_{=0%)tambémfoisignificantementereduzidonotratamentocomciclesonida.}

Alémdisso,adiferenc¸aemrelac¸ãoaoseventosadversosemergentesdotratamentoentreos doisgruposnãofoisignificante.

Conclusão:A ciclesonida pode melhorar arinite alérgica perene sem aumentaros eventos adversos.Essefármacopodeseroutraopc¸ãovaliosaparaarinitealérgicaperenenofuturo. © 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

Allergic Rhinitis (AR), a chronic inflammatory disease, is characterized by nasal itching, sneezing, runny nose and congestion.1 _{As ahighly prevalentcondition, ARaffects1}

outof6individuals.ThesymptomsofARinterferewithall aspectsofdailylifethatareassociatedwithdecreasedsleep qualityandperformanceatwork.2

Despitecurrentlyavailabletreatmentoptions,the inci-dence of AR is increasing. It remains the leading cause of morbidity,absenteeism andrestricted activities and is relatedto considerable cost pressures in the health care system.3,4 _{AR can be divided into seasonal and perennial}

forms. Perennial allergic rhinitis (PAR) accounts for 40% ofARcases.5 _{ARis aType1IgE-mediatedhypersensitivity}

reaction.6

Intranasal corticosteroids (INS) represent the standard treatment for AR of all severities owing to their anti-inflammatoryactivity.7,8_{Systematicreviewsand}

meta-analyses revealed topical corticosteroids are superior to

antihistamines in putting nasal symptoms of AR under control.9,10 _{CiclesonidewasapprovedbytheFDAasoneof}

therelativelynewINSadditionstotheARarmamentarium in2006.11

Ciclesonidein PARhave been evaluatedin several ran-domizedcontrolledtrials(RCT).However,theevidencefrom thecurrentlyavailableindividualrandomizedtrials concern-ingciclesonideinPARisnotconvincing.Whetherciclesonide has an effecton PAR and whether it plays a role in pre-vention and treatment remains tobe seen. To figure out theseissues,weengagedinasystematicreviewwith meta-analysisofrandomizedcontrolledtrialstoanalyzetheeffect ofciclesonideinthetreatmentofPAR.

Methods

Datasources

We searched Pubmed, Scientific Citation Index, Embase, ClinicalTrialRegistriesforrandomizedcontrolledtrialsand

Records identified through datebase searching (n=53) Pubmed:11 Embase:28 Cochrane library:0 Web of Science:10 ClinicalTrials.gov:4 Records after duplicates removed (n=39)

Records screened (n=39)

with reasons -review(0) -intervention was not

eligible(1) -control group was not

eligible(1) -in vitro study(0) Excluded after evaluation of

title or abstract(29)

Full texts assesed for eligibility

(n=10)

Studies included in quantitative synthesis (n=8)

Figure1 Selectionofstudies.

CochraneCentralRegisterofControlledTrials,withasearch deadline of July 2018. We used the following keywords: ‘‘Rhinitis, Allergic, Perennial’’, ‘‘Rhinitis, Allergic, Non-seasonal’’,‘‘Ciclesonide’’and‘‘random*controlledtrial’’ (Fig.1).Inordertoidentifypotentially pertinentstudies, wescannedthecitationsoftheincludedstudies.

Studyselection

Twoindependentreviewersassessedthetitleandabstract of relevant papers. If the study was randomized trials andcontrasted ciclesonide withplacebo forpatients with ‘‘perennialallergicrhinitis’’,thestudywasincluded.

Dataextractionandqualityassessment

The data information of characteristics of methods, participants,interventionsandresultswereextracted inde-pendently by two reviewers. The Cochrane Handbook for Systematic Reviews of Interventions12 _{was used to}

assess the quality of included studies by evaluating the risk of bias. Any discrepancy was resolved by the third author.

Outcomedefinition

TheprimaryoutcomewasthechangeinaverageA.M. and P.M. reflective Total Nasal Symptom Score (rTNSS), A.M. instantaneous Total NasalSymptom Score(iTNSS) and the

secondoutcomeincludedchangesinaverageA.M.andP.M. reflectiveNasalSymptomScore(rNSS),Rhinoconjunctivitis Quality of Life Questionnaire score (RQLQs). Treatment-EmergentAdverseEvents(TEAEs)wereusedtomonitorthe safety.

Datasynthesisandanalysis

The effect size of continuous outcomes was evalu-ated by weighted mean difference (WMD) and dichoto-mous outcomes assessed by Risk Ratio (RR) with 95% Confidence Interval (CI). Heterogeneity was evaluated with I2 _{statistics. A random-effects model was applied} regardless of the heterogeneity of the results. Statisti-cal assessments were performed using Review Manager, version5.3.

Results

Studyselectionandstudycharacteristics

In the initial search 53 related publications were identi-fied in total. 14 duplicates were removed afterward. 29 studies were excluded by reading the title or abstract. The remaining 10 full-text articles were reviewed and 2 studieswereexcluded.Finally,8 trials13---17 _{(NCT01451541,}

NCT01033825,NCT01378429)enrolling4039 patientswere included (Table 1). The selection process of studies

Table1 Summaryoftrialsincludedinthemeta-analysis.

Study Year No.ofpatients

(ciclesonide/placebo) Interventions Duration (weeks) Outcomes NCT01451541 2014 758(511/247) Ciclesonide37␮g 12 rTNSSiTNSS Ciclesonide74␮g TEAE NCT01033825 2012 160(105/55) Ciclesonide160_␮g 6 rTNSSiTNSS Ciclesonide200␮g rNSS Ciclesonide320_␮g Eli(13) 2007 471(238/233) Ciclesonide200␮g 6 rTNSSrNSS RQLQTEAE Paul(14) 2007 663 (441/222) Ciclesonide200_␮g 52 rTNSSrNSS RQLQTEAE

William(15) 2012 1110(803/307) Ciclesonide74␮g 26 rTNSSiTNSS

Ciclesonide148␮g rNSSRQLQ

TEAE

Kenneth(16) 2007 123(81/42) Ciclesonide200␮g 12 rTNSSrNSS

TEAE

NCT01378429 2014 89(47/42) Ciclesonide74␮g 6 rTNSS

William(17) 2008 665(500/165) Ciclesonide25␮g 12 rTNSSTEAE

Ciclesonide100␮g Ciclesonide200␮g

was showed in Fig. 1. Duration of treatment was 6---52 weeks.

Qualityassessmentofincludedstudies

All 8 studies13---17 _{(NCT01451541, NCT01033825,}

NCT01378429) were randomized and double-blind. Seven studies13---15,17 _{(NCT01451541,NCT01033825,NCT01378429)}

were multicentre trials. However, all studies did not provide concrete randomization methods. All studies13---17

(NCT01451541, NCT01033825, NCT01378429) reported blindingof participantsand personnel.Allstudies didnot havereportingbias.Fivestudiesreportedwithdrawalsand one study15 _{was analyzed on an intention-to-treat basis}

(Fig.2).

EffectsonrTNSS

EightstudiesincludedthecomparisonofthechangeinrTNSS between eight groups13---17 _{(NCT01451541, NCT01033825,}

NCT01378429).Thepooledresultshowedthattherewas sig-nificantdifferencebetweenthetwogroups(MD=−0.56;95% CI−0.72to−0.39,p<0.00001)(Fig.3)withheterogeneity (p=0.19,I2_{=24%)(Fig.3).}

EffectsoniTNSS

Three studies included comparison of iTNSS between threegroups15_{(NCT01451541,NCT01033825).Pooledresults}

showed that there was a significant difference between the two groups (MD=−0.57; 95% CI −0.75 to −0.39,

p<0.00001)(Fig. 4)with heterogeneity (p=0.34,I2_=11%) (Fig.4).

EffectsonrNSS

WecomparedrNSSinfivetrials14---17 _{(NCT01033825).There}

wassignificantdifferencebetweenthetwogroups, sneez-ing (MD=−0.15; 95% CI −0.21 to −0.10, p<0.00001) withheterogeneity (p=0.29, I2_{=18%)(Fig.5), runnynose} (MD=−0.16; 95% CI −0.22 to −0.10, p<0.00001) with heterogeneity (p=0.28, I2_{=19%) (Fig. 5), nasal itching} (MD=−0.14; 95% CI −0.20 to −0.09, p<0.00001) with heterogeneity (p=0.37, I2_{=8%) (Fig. 5), nasal congestion} (MD=−0.17;95%CI−0.25to−0.09,p<0.0001)with hetero-geneity(p=0.03,I2_{=55%)(Fig.5),Subtotal(MD=−0.15;95%} CI−0.18to−0.13,p<0.00001)withheterogeneity(p=0.12,

I2_{=24%)(Fig.5).}

EffectsonRQLQs

RQLQs was compared in the three trials.13---15 _Compared

with placebo, ciclesonide significantly reduced RQLQs (MD=−0.27;95%CI−0.39to−0.15,p<0.00001)with het-erogeneity(p=0.58,I2_=0%)(Fig.6).

Safety

Safety was assessed by monitoring TEAEs. For TEAEs, six trials13---17 _{(NCT01451541) reported complete data. There}

was no significant difference between the two groups (RR=1.02; 95% CI 0.94---1.10, p=0.61) withheterogeneity (p=0.17,I2_{=36%)(Fig.7).}

Publicationbiasandsensitivityanalysis

There was no evidence of significant publication bias by Egger’stestforrTNSS(t=−0.52,p=0.609).

Figure2 Riskofbiasgraphaccording torecommendations fromtheCochranecollaboration.

Discussion

and

conclusions

Antihistaminesandcorticosteroids arecurrent treatments for controlling AR symptoms. INS are the most effec-tiveavailabledrugsuppressingallrhinitissymptomswhich includenasal blockage.18 _{However,although widely used,}

ciclesonideforARstillislackinginclearevidencetomake decisiverecommendationsforatherapeuticoption.Inthe presentstudy,weperformedasearchtoevaluatethe effi-cacy and safety of ciclesonide in patients with PAR. In thisreview, we found that the ciclesonide might beable todecrease rTNSS,iTNSS, rNSS,RQLQs withoutincreasing TEAEsintheshortterm.

Ciclesonide is the latest inhaled glucocorticosteroid to treatsymptomsofasthmaandAR.19_{Theanti-inflammatory}

effectofciclesonide isseen solelyat thebronchial level, onlyafractionofthedrugreachingthegastrointestinaltract andbecominginactive.14,20

Inourreview,ciclesonide producedsignificant reliefin rTNSSandiTNSS.InthestudybyEli,13_{itwassuggestedthat}

improvementintherTNSScontinuedtoincreasethroughout the6weeksoftreatment.Thesecontinuedimprovementsin nasalsymptomsareassociatedwithARandmayencourage patientstosticktotreatment.

AllindividualrNSSdeclined inallpatients treatedwith ciclesonide,especiallynasalcongestion,whichisthemost difficultsymptomtotreat.TheoverallchangeinrTNSSwas drivenbyallfournasalsymptoms,suggestingthatall individ-ualrNSScontributedtotheoveralldifferencebetweentwo groups.Owingtoavariabledegreeofheterogeneityinthese studies,weperformedsensitivityanalysis.Weshouldtreat theresultscautiously,althoughtheresultsdidnotchange.

Ciclesonideproducedastatisticallysignificantreduction inRQLQs.However,studiesontheclinicalrelevanceof ques-tionnairesshowedthatonly0.5ormoreofthechangeswere clinicallyrelevant.21

ForTEAEs,therewerenosignificantdifferencesbetween thetwo groups. In ourreview, most of adverse events of ciclesonideweremildormoderateandwelltolerated.Rates ofdiscontinuationwere similartoplacebo. Typicallyseen AdverseEvents(AEs)withINSareusuallytopicalinnature andincludenasaldiscomfortandnosebleeds.22_Inthestudy

byWilliam,15_{epistaxisandupperrespiratorytractinfection}

werethemostcommonlyreportedAEs.Itmaybeasa con-sequenceofnegligibleoralbioavailability(1%),highprotein

Figure4 ForestplotsofiTNSSofpatientstreatedwithciclesonide.

Figure6 ForestplotsofRQLQsofpatientstreatedwithciclesonide.

Figure7 ForestplotsofTEAEsofpatientstreatedwithciclesonide.

binding(99%)ofciclesonideandtheactivemetabolite,with negligible impact on the hypothalamic---pituitary---adrenal axis.23---25

There were several limitations in our meta-analysis. First, several notable areas of variability existed in the data. The duration of intervention variedbetween 2 and 52weeksandthebaselineseverityofthediseasehadsome differences. Second, there is a possibilityof study selec-tionbias.Third,fouroftheeightstudies15 _{(NCT01451541,}

NCT01033825, NCT01378429) were sponsored by pharma-ceutical companies. We conduct a subgroup analysis by excludingthesedataandtheresultsdidnotchange.

In conclusion, ciclesonide can improve PAR without increasingadverseevents.Ciclesonidemaybeanother valu-ablechoiceforpatientswithPARinthefuture.

Ethical

approval

Thisarticledoesnotcontainanystudieswithhuman partic-ipantsoranimalsperformedbyanyoftheauthors.

Informed

consent

Informedconsentwasobtainedfromallindividual partici-pantsincludedthestudy.

Conflicts

of

interest

Theauthorsdeclarenoconflictsofinterest.

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