Eosinophilic Esophagitis

5/11/2015
www.medscape.com/viewarticle/850403_print
www.medscape.com
FromGeneticstoTreatmentof
EosinophilicEsophagitis
AntonellaCianferoniJonathanM.Spergel
CurrOpinAllergyClinImmunol.201515(5):417425.
AbstractandIntroduction
Abstract
PurposeofreviewEosinophilicEsophagitis(EoE)isanemergingchronicatopicdisease.Recentadvancesin
understandingitsgeneticandmolecularbiologypathogenesismayleadtoabettermanagementofthedisease
RecentfindingsEoEisanatopicdisease.MostofthepatientsaffectedbyEoEhaveotheratopicdiseasessuch
asallergicrhinitis,asthma,IgEmediatedfoodallergiesand/oratopicdermatitis.ThelocalinflammationisaT
helpertype2(Th2)flogosis,whichmostlikelyisdrivenbyamixedIgEandnIgEmediatedreactiontofoodand/or
environmentalallergens.EpidemiologicalstudiesshowthatEoEisanatopicdiseasewithastronggenetic
component.GeneticstudieshaveshownthatEoEisassociatedwithsinglenucleotidepolymorphismongenes,
whicharereleasedbytheepitheliumandimportantinatopicinflammationsuchasthymicstromallymphopoietin
located(TSLP)closetotheTh2cytokinecluster[interleukin(IL)4,IL5,IL13]onchromosome5q22,Calpain14,
EMSY,andEotaxin3.WhentheEoEdiagnosisismade,itisimperativetocontrolthelocaleosinophilic
inflammationnotonlytogivesymptomaticrelieftothepatient,butalsotopreventcomplicationssuchas
esophagealstrictureandfoodimpaction.
SummaryEoEistreatedlikemanyotheratopicdiseaseswithacombinationoftopicalsteroidsand/orfoodantigen
avoidance.ThenewunderstandingofEoEmayleadtomorespecificanddefinitivetreatmentsofEoE.
Introduction
EosinophilicEsophagitis(EoE)isachronicatopicclinicalpathologicdiseaseaffectingbothchildrenandadults. [1,2]
Itisdefinedbyasignificantpathologicaleosinophilinfiltrationlimitedtotheesophagusthatcausesesophageal
dysfunctionand,ifleftuntreated,fibrosis. [1,2]Astheesophagealgastroduodenalendoscopyhasbecomereadily
availableatthebeginningofthe21stcentury,EoEhasbeenexponentiallymorerecognizedinwesterncountries,
withayearlyincidencenowestimatedtobesimilartoCrohn'sdisease. [38]
Inthelastfewyear,usingtraditionalepidemiology,anovelgeneticsstudyapproachandtraditionalmolecular
biology,therehasbeengreatprogressinunderstandingEoEpathogenesis. [9]Thisprogresshasledtoestablisha
welldefinedgloballyacceptedmanagementoftheEoEandasearchformorespecifictreatmentsthatwill
hopefullyresultinthecureofthispuzzlingandevermoreprevalentdisease. [1013]
Epidemiology
Severalepidemiologicalstudies[57,1416]haverevealedthatEoEisahighlyhereditableatopicdiseasethataffect
mainlyCaucasianmenregardlessoftheirage.EoEaffectschildrenandadultsfromallcontinents [57,14,15,17]
however,thewesternworldhasahighestprevalence,withanorthsouthandwesteastgradientssimilartothe
onedescribedfortheincidenceofatopicdiseases. [57,14,15,16]InchildrenintheUniteStates,EoEhasprevalence
of50.5/10000,equivalenttopediatricinflammatoryboweldisease. [18]
TheepidemiologicaldatasuggestbothatopicandgeneticcomponentsinpatientswithEoE:
1. PatientswithEoEarehighlyatopic[19,20]().Themostcommoncomorbidityistheallergicrhinitis,butalso
therateofIgEmediatedfoodallergyis10timeshigherthanthegeneralpopulation. [1922]Unlikeclassic
foodallergythattypicallyinvolvesalimitedsetoffoods,EoEpatientsareoftensensitizedtoamyriadof
foods,oftenincludingfoodgroupsnottypicallyconsideredtoelicitIgEmediatedfoodallergy. [23]
http://www.medscape.com/viewarticle/850403_print
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Table1.Incidenceofotheratopicdiseasesineosinophilicesophagitis
Numberof
patientswith
EoE
IgE
Allergic Atopic
Atopy Asthma
specific
rhinitis dermatitis
forfoods
Anaphylaxis
tofoods
General
population
NA
30%
8.5%
25%
10%
10%
0.2%
Spergeletal.,
Philadelphia
620
NA
50%
61%
21%
50
10%
Assa'adetal.,
Cincinnati
89
79%
39%
30%
19%
75%
NA
Sugnanametal.,
45
Australia
NA
66%
93%
55%
NA
24%
Guajardoetal.,
Worldregistry
80%
38%
64%
26%
62%
23%
39
EoE,eosinophilicesophagitisNA,notavailable.
2. EoEaffectspredominantlymenwithamaletofemaleratioof3:1inbothchildrenandadults. [2,6,18]
3. Familyhistory,especiallyinmen,isveryfrequentwithnearly10%ofparentsofEoEpatientshavinga
historyofesophagealstricturesandabout8%havingbiopsyprovenEoE. [24]EoEalsoshowsasiblingrisk
ratioof80,meaningthathavingasiblingwiththediseaseincrease80timestheriskofdevelopingasimilar
diseaseinothersiblings.Thisisextremelyhighcomparedwiththeoneforrelatedatopicdiseasessuchas
asthmathathasasiblingriskratioofabout2. [4,25,26]
Alltogether,theepidemiologicaldatasuggestastrongatopicandgeneticcomponentinEoEdevelopment.
GeneticsBasisofEosinophilicEsophagitis
TheepidemiologicaldatashowthatEoEisanatopic,multifactorial,andcomplexdiseasewithastronggenetic
component,whoseinheritancedoesnotfollowtheclassicalMendelianpatterns. [2630]Itisbelievedthatmultiple
interactinggenes,somehavingaprotectiveeffectandotheracausativeone,acttogetherwitheachgenehaving
itsowntendencytobeinfluencedbytheenvironment. [2630]Twostudydesignsarecommonlyusedtodetermine
thegeneticcontributionsincomplexdiseasescandidategeneassociationstudiesandgenomewideassociation
studies(GWAS). [30]Genomewidelinkagestudydesigncanbealsousedinlargefamiliesaffectedbycomplex
multifactorialdiseases,butitwillnotbediscussedasthisapproachhasnotbeenusedtostudyEoE.
Thecandidategeneassociationstudiesallowtheidentificationofgenesandpathwayssuspectedofcontributingto
thediseasebasedonitsbiologicalplausibility,andtheincidenceofsmallgenevariationssuchassinglenucleotide
polymorphysim(SNP)inthesuspectedgeneorsetsofgenesarecomparedbetweenapopulationaffectedbythe
disease(cases)andagroupofcontrols. [30]Themainlimitationsofsuchadesignareitsinabilitytoidentifynovelor
unsuspectedgenesandpathwayscontributingtothepathogenesisofadisorder. [30]
Theavailabilityofmicroarraytechnologyhasmadepossiblethehighthroughputgenotypingofhundredsof
thousandsSNPsontheentiregenomeandhasallowedthedevelopmentoflikeGWAS. [30]Inthisdesignmany
SNPsarecomparedacrosstheentiregenomebetweencasesandcontrols.Asshowninthecandidategene
associationstudy, [30]thelargerthenumberofcasesandcontrolsforanalysis,thebetterthestatisticalpower.
GWASallowsalsoperformingahypothesisfreesearchforgenevariantsassociatedwithacertaindiseaseandthis
hasbeenapowerfultooltounveilnewtargetsforresearchers. [30]Moreover,independentreplicationofgenes
identifiedthroughGWASismuchmorecommonthanthoseidentifiedwiththesinglegeneapproachassociation.
[30]
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ThefirstcandidategeneforEoEidentifiedwasCCL26(Eotaxin3),afteragenomewideprofilingrevealedthat
CCL26wasoverexpressedabout50foldcomparedwithnormalcontrolsorpatientswithgastroesophagealacid
reflux. [31]ThisstudyhighlightedtheimportantroleofCCL26inEoEpathogenesis.Apotentialproposed
mechanismisthatThelpertype2(Th2)cellactivationleadstooverexpressionofCCL26fromtheesophageal
epithelialcells,especiallyifgeneticallypredisposed,andtothemigrationofeosinophilstotheesophagus. [29,3140]
Acevesetal. [4143]examinedhowSNPcouldinfluencetheresponsetotopicalcorticosteroidsinpatientswith
EoE.ThepatientswhorespondedtothetopicaltherapyweremorelikelytohaveaCCgenotypeatthe509
positionintheTGFpromoterthanwerenonresponders.Thesedatasuggestthatresponsetotherapymaybe
influencedbythegeneticbackground.
Morerecently,GWASanalysishasidentifiedthreegenesasimportantcandidategeneinthepathogenesisofEoE:
thethymicstromallymphopoietin(TSLP)gene,at5q22,theCalpain14oneonchr2p23.1,andthec11orf30/EMSY
geneoneonchr11q13.5[27,28,44,45]().
Table2.Eosinophilicesophagitisgeneticriskdescriptionofsinglenucleotidepolymorphysimsfoundineosinophilic
esophagitisgenomewideassociationstudies
Variant
(effect
allele)
chr:pos
hg19
rs1438673
(T)
chr5:
TSLP
110467499
rs55646091 chr11:
(A)
76299431
rs74732520 chr2:
(G)
31396392
Gene
Location Function
Effect
EoE
allele
OR
frequency
SE
PEoE
EoE
GWAS
GWAS
TSLPeSNP/ENCODE
Intergenic transcriptionfactorbinding
site
0.496
0.626
2.74x
0.063
1012
c11orf30 Intergenic
ENCODEtranscription
factorbindingsite
0.044
2.219
5.38x
0.157
1010
CAPN14 3'UTR
TranscribedandhighLD
withthreevariants
(rs77997242,rs113412973,
0.067
rs78464756)inENCODE
transcriptionfactorbinding
sites
1.782
1.69x
0.131
108
EoE,eosinophilicesophagitisCAPN14,Calpain14ENCODE,encyclopediaofDNAelementsGWAS,genome
wideassociationstudiesLD,linkagedisequilibriumSNP,singlenucleotidepolymorphysimTSLP,thymicstromal
lymphopoietin.
TSLPisacytokinethatbelongstotheinterleukin(IL)7family,itissecretedbyepithelialcellsinresponsedanger
stimuli(i.e.infectiousagent,stimulationoftolllikereceptor,allergens)anditiselevatedinEoEpatients. [27,46,47]
TSLPisamajordriverofatopicinflammationandtissueremodeling,asitstronglypromotesTh2inflammationby:
activatingprofessionalantigenpresentingcells(APCtoprimenaiveTcelltoinitiateTh2typeallergicresponses
inhibitingTregsdirectlypromotingTh2cytokinesecretionfromTcells,basophils,eosinophils,mastcells,and
invariantnaturalkillercells. [46,4859]ThefirsteverGWASconductedinEoEshowedanassociationbetweena
SNPinTSLPgeneandriskforEoEinarelativesmallpopulationof500EoEchildren,confirmingthestrong
influenceofgeneticsinEoE. [27]ThosewhowerehomozygousfortheEoEriskallele(AA)hadincreasedTSLP
expressionandbasophilinfiltrationintheesophagealepitheliumcomparedwiththosecarryingheterozygous(AG)
riskalleleandhomozygous(GG)protectiveminoralleles. [27]Inaddition,Sherrilletal. [45]notonlyconfirmedTSLP
protectiveSNPbutalsofoundthatmalepatientswithEoEhadmoreoftenaSNPintheTSLPreceptor(TSLPR)
gene,whichisencodedbyapseudoautosomalregiononXp22.3andYp11.3. [45]Thisfindingcouldexplainthe
epidemiologicaldatathatEoEismorecommoninmenbya3:1ratio. [15]
Subsequentmolecularbiologystudies[52,53,60]conductedbyourgroupwithcollaborationwithDrArtis'sgroup
showedthatTSLPmaypromoteTh2inflammationinEoEthroughbasophils.Basophilsareknowntosecrete
histamineandTh2cytokine(IL4andIL13)ifstimulatedthroughtheirhighaffinityreceptorforimmunoglobulin
[61]
(Ig)E(Fc[epsilon]RI). However,Siracusaetal.
[53]havedescribedthatTSLPmayactasanindependentgrowth
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(Ig)E(Fc[epsilon]RI). [61]However,Siracusaetal. [53]havedescribedthatTSLPmayactasanindependentgrowth

factorforasubpopulationofbasophils,whichisoverexpressedinEoEpatientsandisabletoproducesignificant
Th2cytokines(IL4,IL6,CCL3,CCL4,andCCL12).EvenmoreinterestinglyNotietal. [52]recentlydescribeda
novelmousemodelofEoEinwhichthedevelopmentofEoElikefeatureswasdependentuponbothTSLPand
basophils,butindependentofIgEresponses.Inhismousemodel,blockingofTSLPorbasophilbymonoclonal
antibodiespreventedthedevelopmentofEoE.
Together,thesestudiesshowhowaGWASidentifiedinTSLPandsubsequentstudiesconfirmeditsroleinEoE
makingitapromisingtherapeutictarget.
Th2cytokinesareresponsibleoftheinflammationobservedinEoE. [9]TheTh2cytokinesappeartoexertredundant
functions,astheyhavemanysimilarandoverlappingeffectstherefore,treatmentstrategiesthatarebasedon
abolishingasinglecytokineareprobablynotgoingtobesufficienttotreatEoE.Indeed,antiIL5administrationin
patientswithEoEhasresultedtopartialreductionofesophagealinflammationandminimalsymptomaticrelief.
[62,63]But,targetsagainstTSLPwouldmaybeabetteroption,astheywouldabolishmoregloballytheTh2
response.
BuildingonthesuccessofourfirstGWAS,weperformedanexpandedGWAS936casesand4312controlsto
identifyadditionaltargetsworthyoffurtherbiologicalstudy.Inadditiontoconfirmingtherelevanceofourpreviously
reportedTSLPlocus, [27]wediscoveredthreenovellocionc110rf30,Calpain14(CAPN14), [28]().Asummaryof
thefindingsisshownin.
Variant
(effect
allele)
chr:pos
hg19
rs1438673
(T)
chr5:
TSLP
110467499
rs55646091 chr11:
(A)
76299431
rs74732520 chr2:
(G)
31396392
Gene
Location Function
Effect
EoE
allele
OR
frequency
SE
PEoE
EoE
GWAS
GWAS
TSLPeSNP/ENCODE
site
0.496
0.626
2.74x
0.063
1012
c11orf30 Intergenic
ENCODEtranscription
factorbindingsite
0.044
2.219
5.38x
0.157
1010
CAPN14 3'UTR
withthreevariants
(rs77997242,rs113412973,
0.067
rs78464756)inENCODE
sites
1.782
1.69x
0.131
108
lymphopoietin.
Variant
(effect
allele)
chr:pos
hg19
rs1438673
(T)
chr5:
TSLP
110467499
Gene
Location Function
Effect
EoE
allele
OR
frequency
SE
PEoE
EoE
GWAS
GWAS
TSLPeSNP/ENCODE
site
0.496
2.74x
0.063
1012
0.626
4/18
5/11/2015
rs55646091 chr11:
(A)
76299431
rs74732520 chr2:
(G)
31396392
c11orf30 Intergenic ENCODEtranscription

factorbindingsite
CAPN14 3'UTR
0.044
withthreevariants
(rs77997242,rs113412973,
0.067
rs78464756)inENCODE
sites
2.219 5.38x 0.157

1010
1.782
1.69x
0.131
108
lymphopoietin.
Variantsatthec11orf30locus(EMSY)havebeenassociatedwithseasonalallergicrhinitis, [64]ulcerativecolitis, [65]
Crohn'sdisease, [66]atopicdermatitis, [67,68]asthma, [69]andallergicsensitization, [70]albeitwithmuchlowerodds
ratios(range1.09inasthmato1.22inatopicdermatitis).EMSYhasbeenidentifiedasacentralcomponentina
novelAktdependentmechanismbywhichinterferonandothergrowthfactorsregulatetheexpressionofinterferon
stimulatedgenes(ISGs). [71]InterferonandISGsplayacentralroleinTh1inflammationandTh2suppression
consequently,adysregulationinEMSYexpressioncouldleadtoallergicdiseases. [7173]
SNPsinCAPN14hasbeenshownasariskfactorforEoEindependentlybyKottyanetal., [44]henceitisthe
secondlocusthathasbeenreplicatedlinkedtoEoEtodate.CAPN14belongstothecalpainfamilyofintracellular
Ca2+regulatedcysteineproteasesknowntofunctionindiversebiologicalprocessesincludingthecellcycle,tight
junctionprotein,cytokineregulation,andhumanfibroblastbiology. [7478]Calpainsincludebothubiquitousand
tissuespecificmembers.TheGenotypeTissueExpressionproject, [79]theHumanProteinAtlas, [80]andKottyanet
al. [44]demonstratedthatCAPN14ishighlyandselectivelyexpressedintheesophagus.Moreover,weandothers
alsodemonstratedthatCAPN14isoverexpressedinEoEesophagealepithelialcellscomparedwithcontrols[28,44]
andisdynamicallyupregulatedafterexposureofepithelialcellstoTh2cytokines(i.e.IL13[44]andIL4[81]).
TheroleofCAPN14inesophagealbiologyorinEoEisnotknownbutisageneselectiveexpressedinthe
epiheliumandlikeTSLPpointstoanepithelialdysfunctionasadrivingforceoflocalimmuneTh2responsein
geneticallypredisposedpatients.Othermolecularbiologystudieshavealsoshownanimpairedepithelialbarrier
function,usinggeneexpressionprofiling[82]andimmunolocalizationstudies, [83]whichmaycontributeenhanced
permeabilityoftheepitheliumtolocalfoodandenvironmentalallergensandsubsequentlocalinflammation. [84]
PotentialPathwaysforTreatment
ThecurrentunderstandingofthepathobiologyofEoEisincomplete,butevolvingitseemstopointtothreefactors
leadingtothedevelopmentofEoE:atopy,geneticpredisposition,andalocalTh2inflammationdrivenbya
dysfunctionalesophagealepithelium.
CurrentEoEmanagementisbasedoncurrentknowledgeofthediseaseandismainlybasedontwomainclinically
acceptedclinicaltreatmentstrategieslikeanyotheratopicdisease:allergenavoidanceandcorticosteroidtreatment
().
Table3.Eosinophilicesophagitistherapy
Elementaldiet
Description
Use
Dietisbasedonelementalformula
CurrentlyusedforshorttermtreatmentofEoEto
1)inducerapidresolutionofEoEinalmostallpatients
(adultandchildren)
2)toestablishfoodallergy
Sixfood
Mostallergenicfoods(milk,soy,
eliminationdiet egg,wheat,treenuts,peanuts,fish, Effectiveinabout70%ofadultanpediatricpatients
5/18
5/11/2015
(SFED)
shellfish)areeliminated
Targeteddiet
withallergy
tests
Foodeliminatedbasedonskintests
andmilk(oftenonly12foodsare
Effectivein80%ofchildren,limitedstudiesinadults
eliminated)
Protonpump
1mg/kg(2040mgmaxdose)12
inhibitors(PPI) timesaday
Giventoeverybody8weekspriortodiagnosticEGD
MayworkasastandalonetherapyinPPIresponsive
EoE
Oralsteroids
Veryeffectiveshorttermtreatmentusedforemergency
1mg/kgtwiceadayfor1015days therapyoffoodimpactionordebilitatingsymptoms
(failuretothrive,protractedvomiting)
Swallowed
steroids
Fluticasone110220mcgtwopuffs
twiceaday,Budesonide0.52mga Effective5070%ofpatients
day
AntiIL5
ReslizumabMepolizumab
Significantlyreduceeosinophilicinfiltrationinthe
esophagus,noeffectsonsymptoms
AntiIgE
omalizumab
Noteffective
Antitumor
necrosisfactor Infliximab
(TNF)
Noteffective
AntiCRTH2
OC000459
Partiallyeffective
AntiIL13
QAX576
Partiallyeffective
AntiTSLP
AMG157
FutureforEoEeffectiveonasthma
Foodallergy
EPIT
immunotherapy
FutureforEoEeffectiveforIgEmediatedfoodallergy
(peanut)
EGD,esophagealgastroduodenalendoscopyEoE,eosinophilicesophagitisEPIT,epicutaneousimmunotherapy
TSLP,thymicstromallymphopoietin.
Thenewgeneticstudiesthatarepointingtotheesophagealdysfunctionareshapingthetreatmentfortomorrow
thatwillbebasedonantigentoleranceinductionandspecificbiologicaltreatments.
SteroidTreatment
SteroidsareaveryeffectivetreatmentofEoE.Oralsteroidsareveryeffective,butnotrecommendedasalong
termtherapyforthewellknownsideeffects[85]().Swallowedinhaledcorticosteroidsareeffectivein5080%of
patientsandcanbeconsideredasfirstlinetherapiesforinitialandmaintenancemanagementofEoE,astheyhave
lowbioavailabilityandfewersystemicsideeffects.Fluticasoneisadministeredbysprayinginthemouthwitha
metereddoseinhalerwithoutaspacer,andswallowedtwicedaily. [86,87]Budesonideisusedasanoralviscous
slurryonceortwicedaily. [88,89]Swallowedinhaledcorticosteroidsappeartobewelltoleratedwhenusedinthe
shortterm,buttheycanleadtoincreasedriskoflocalizedyeastinfectionsandhavepotentiallongtermside
effects,includinggrowthsuppressionandosteopenia(lowbonedensity). [87,89]Althoughsteroidsareeffectivefor
treatment,clinical,andhistologicfeaturesofEoEreturnupondiscontinuation. [1,2]Steroidsmayreversethe
esophagealfibrosisinchildren[9092]butnotinadults[93]withEoE.
Description
Use
6/18
5/11/2015
Elementaldiet
(adultandchildren)
Sixfood
(SFED)
Targeteddiet
withallergy
tests
eliminated)
Protonpump
EoE
Oralsteroids
Swallowed
steroids
day
AntiIL5
AntiIgE
omalizumab
Noteffective
Antitumor
(TNF)
Noteffective
AntiCRTH2
OC000459
Partiallyeffective
AntiIL13
QAX576
Partiallyeffective
AntiTSLP
AMG157
Foodallergy
EPIT
immunotherapy
(peanut)
DietaryIntervention
ThemajorityofpatientswithEoEareallergictofoodallergensandaeroallergens[1,2]().Dietaryeliminationtherapy
shouldbeconsideredinallchildrenandmotivatedadultsdiagnosedwithEoE.Dietaryeliminationapproaches
includeastrictlyelementaldiet,specificantigenavoidancebasedonallergytesting,andempiricfoodelimination
basedonthemostcommonfoodantigens. [1,2]Allthreemethodshavebeenproventobeeffectivewithimproved
clinicalsymptomsandpathology[85,94,95]andtheregimenchosenshouldbebasedontheindividualpatient. [96]
Treatmentwithfoodavoidanceishighlysuccessful,withratescloseto100%withelementaldiets(aminoacid
formulas)andupto80%foreliminationdiet.However,aminoacidformulasareunpalatableandleadtolowquality
oflife.Eliminationdietonthebasisofallergytestingorempiricaleliminationmaybesustainableinthelongterm
albeitwithsomedifficulties,andmanypatientsrefusetocontinuethem.Foradditionaldetailsofdietary
management,pleaseseerecentreview. [97]
Description
Use
7/18
5/11/2015
Elementaldiet
(adultandchildren)
Sixfood
(SFED)
Targeteddiet
withallergy
tests
eliminated)
Protonpump
EoE
Oralsteroids
Swallowed
steroids
day
AntiIL5
AntiIgE
omalizumab
Noteffective
Antitumor
(TNF)
Noteffective
AntiCRTH2
OC000459
Partiallyeffective
AntiIL13
QAX576
Partiallyeffective
AntiTSLP
AMG157
Foodallergy
EPIT
immunotherapy
(peanut)
EsophagealDilation
EsophagealfibrosisandesophagealstricturesareknowncomplicationsofEoE.Endoscopicstricturedilationis
sometimesnecessaryforshorttermsymptomaticreliefbutshouldbeconsideredasatreatmentoptiononlyif
patientshavefaileddietaryandmedicaltherapy. [1,2]
OtherBiologicalTreatment
OthertreatmentsthathavebeeninvestigatedincludeantiIL5[62,63]andchemoattractanthomologousreceptor
expressedonTh2cells(CRTH2)antagonist().Bothstrategieshaveshownlimitedornoefficacyincontrollingthe
disease,suggestingthatabroaderinhibitionofTh2inflammationmaybeneededduetotheredundancyofits
mediators.
Description
Use
8/18
5/11/2015
Elementaldiet
(adultandchildren)
Sixfood
(SFED)
Targeteddiet
withallergy
tests
eliminated)
Protonpump
EoE
Oralsteroids
Swallowed
steroids
day
AntiIL5
AntiIgE
omalizumab
Noteffective
Antitumor
(TNF)
Noteffective
AntiCRTH2
OC000459
Partiallyeffective
AntiIL13
QAX576
Partiallyeffective
AntiTSLP
AMG157
Foodallergy
EPIT
immunotherapy
(peanut)
Antiinterleukin5
IL5isthemajorsurvivalfactorforeosinophilsandisindispensableforthedifferentiation,recruitment,and
activationoftheeosinophils. [98]Therefore,humanizedmonoclonalantibodiesagainstIL5Mepolizumab
(SB240563)andReslizumab(Sch55700)havebeenusedinclinicaltrialsforEoEtreatment. [62,63]Bothantibodies
inpediatricsandadulttrialshavefailedtoshowsymptomaticimprovementbeyondtheplaceboeffect.However,
bothReslizumabandMepolizumabhadagoodsafetyprofileandsignificantlydecreasedeosinophilsnumbersin
theesophagealbiopsiesinadultsandchildrenwithEoE,evenifonlyfewpatientsachievednormalbiopsies.These
dataconfirmthateosinophilsarelikelyonlyoneoftheplayersinEoEinflammationandtheimportanceofother
cellsandmediatorsinthepathogenesisofEoEthatcanbeatargetforimmunologicaltherapy.
OtherbiologicaltreatmentsuchasantiTNF(Infliximab), [99]antiIgE(omalizumab)[100]havebeentriedinsmall
groupsofpatientswithoutshowinganyefficacy.
ArecentstudyhasbeenpublishedontheefficacyofantiCRTHintreatmentofEoEandshowedpromisingalbeit
9/18
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smallresults.OC000459isapotent,selective,andorallybioavailableCRTH2antagonist,whichblocks
prostaglandin2mediatedchemotaxisandactivationofCRTH2expressingcells.Inasmallgroupofpatientswith
severeEoEdependentorresistanttocorticosteroidsantiCRTH2hadamodest,butsignificant,antibeneficial
clinicaleffect. [101]
AntiIL13antibodieshavealsobeentriedinasthmaandmorerecentlyinthetreatmentofEoE. [102107]Giventhe
importanceofTh2inflammationandIL13inparticularinEoEpathogenesis[102105]Rothenbergetal. [108]tried
antiIL13(QAX576)inadoubleblindplacebocontrolledclinicaltrialforEoEtreatment.Thetreatedgrouphada
significantreductionofesophagealeosinophiliaandothermarkersofTh2inflammationandepithelialdysfunction
comparedwiththosetreatedwithplacebo.However,eveniftherewasatrendforimprovedsymptoms,particularly
dysphagia,thisdidnotreachstatisticalsignificance.QAX576waswelltolerated.Therefore,theauthorsconcluded
thatQAX576significantlyimprovedintraepithelialesophagealeosinophilcountsanddysregulatedesophageal
diseaserelatedtranscriptsinadultswithEoEbuttheclinicalsignificanceofsuchtreatmentremainstobe
established.
AntithymicStromalLymphopoietin
TherecentidentificationofTSLPanditsreceptoraskeycomponentsintheEoEpathogenesissuggeststhat
blockageoftheTSLPTSLPRactivationcouldprovideanattractiveapproachtotreatingthecauseofEoE. [109]
ThishasbeenconfirmedinanimalstudieswhereinblockageofNotietal. [52]recentlydescribedanovelmouse
modelofEoEinwhichthedevelopmentofEoElikefeatureswasdependentuponTSLP.InsuchamodelTSLP
blockingantibodiesamelioratedtheEoElikediseaseincludingthedevelopmentoffoodimpaction,when
administeredaftertheonsetofdisease.ThisisnotsurprisingasantiTSLPantibodieshavebeenshowntobe
beneficialinvariousmurinemodelsofatopy. [110114]
AhumanizedantiTSLPmonoclonalantibody(AMG157)thatspecificallybindshumanTSLPandpreventsits
interactionwithTSLPRhasbeentestedinadultasthmaticpatientsinadoubleblind,placebocontrolledstudy.In
thegroupreceivingtheantibodytherewere:attenuatedallergeninducedbronchoconstrictioninbothearlyandlate
asthmaticresponsesreducedmarkersofsystemicandairwayinflammation.Althoughthiswasonlyaproofof
conceptstudy, [115]whichdidnotdeterminewhetherantiTSLPtherapeuticswillhaveclinicalimpact,thesefindings
confirmthatTSLPhasakeyroleinallergicasthma.TSLPantibodieshavenotbeentestedinEoEyet.
FoodImmunotherapy
Weandothershavereportedthatinbothadultsandchildren,milkisthemostcommontriggerofEoE, [116119]
initiatinginflammationinageneticallysusceptibleindividualviaadisruptedepithelialbarrier. [27,83]Epicutaneous
immunotherapy(EPIT)hasrecentlybeenproposedasawaytobypassthedysfunctionalandTSLPproducing
esophagealepithelium,andinducelastingfoodtoleranceinEoE. [120]InmurinemodelsofEoE,EPITinducesa
persistentresolutionofesophagealeosinophilia. [121]Inhumans,EPIThasbeenshowntobeawelltolerated
methodtodesensitizeIgEfoodallergicpatients. [122]EPIT,therefore,couldbeapromisingstrategytocurefood
allergyandtheconsequentdevelopmentofEoEinchildrenwithEoEduetofoodallergy.
Conclusion
Insummary,todate,thereisnovalidprimarypreventionstrategynorpharmacologicalcureforEoE.Longterm
immunotherapeuticapproachestoEoEareclearlyneeded.Recentadvancesinourunderstandingofgeneticsand
pathophyisologyofEoEwillhopefullyleadtosuchnewtreatmentsinanotdistantfuture.
Sidebar
KeyPoints
EosinophilicEsophagitis(EoE)isaclinicalpathologicdiseasecharacterizedbysymptomsofesophageal
dysfunctionandeosinophilialimitedtheesophagus,inabsenceofgastroesophagealacidreflux.
EpidemiologicalstudieshaveshownthatEoEisanatopicdiseasesthatmostlikelyduetoaninteraction
10/18
5/11/2015
betweenenvironmentalandgeneticpredispositionfactors.
SpecificgeneticassociationhavebeenfoundbetweenEoEandepithelialrelatedgenessuchasthymic
stromallymphopoietin(TSLP),CAPN14,Eotaxin3,andothergenesinvolvedinThelpertype2(Th2)
inflammationsuchasTGFbandEMSY.RecentadvancesinresearchhaveshownthatTSLPmayplaya
pivotalroleindrivingTh2inflammationtypicalofEoE.
EoEmanagement:EoEisknowntobeafoodantigendriven,chronicallergicdisease.Therearetwomain
clinicallyacceptedclinicaltreatmentstrategiesforEoE:dietaryeliminationandcorticosteroidtreatment.
WiththeincreaseinourunderstandingofEoEpathogenesis,itislogicaltoanticipatethatinthefuturethere
willbemorespecifictreatmentoptionsforthisrapidlyincreasingdisease.Inparticular,TSLPappearstobe
averypromisingEpicutaneousimmunotherapythatmaybecomeaviabletreatmentiftherewillbestudies
toprovethatthisaneffectivestrategytoinducefoodtoleranceinEoE.
References
1. FurutaGT,LiacourasCA,CollinsMH,etal.Eosinophilicesophagitisinchildrenandadults:asystematic
reviewandconsensusrecommendationsfordiagnosisandtreatment.Gastroenterology2007133:1342
1363.
2. LiacourasCA,FurutaGT,HiranoI,etal.Eosinophilicesophagitis:updatedconsensusrecommendationsfor
childrenandadults.JAllergyClinImmunol2011128:320.e26.
3. PrasadGA,AlexanderJA,SchleckCD,etal.Epidemiologyofeosinophilicesophagitisoverthreedecades
inOlmstedCounty,Minnesota.ClinGastroenterolHepatol20097:10551061.
4. NoelRJ,PutnamPE,RothenbergME.Eosinophilicesophagitis.NEnglJMed2004351:940941.
5. StraumannA,SimonHU.Eosinophilicesophagitis:escalatingepidemiology?JAllergyClinImmunol2005
115:418419.
6. HruzP,StraumannA,BussmannC,etal.Escalatingincidenceofeosinophilicesophagitis:a20year
prospective,populationbasedstudyinOltenCounty,Switzerland.JAllergyClinImmunol2011128:1349
1350.e1345.
7. CherianS,SmithNM,ForbesDA.RapidlyincreasingprevalenceofeosinophilicoesophagitisinWestern
Australia.ArchDisChild200691:10001004.
8. vanRhijnBD,VerheijJ,SmoutAJ,BredenoordAJ.Rapidlyincreasingincidenceofeosinophilicesophagitis
inalargecohort.NeurogastroenterolMotil201325:4752.e5.
9. MervesJ,MuirA,ModayurChandramouleeswaranP,etal.Eosinophilicesophagitis.AnnAllergyAsthma
Immunol2014112:397403.
*RecentreviewofEoEpathogenesis.
10. GonsalvesN.Eosinophilicesophagitis:history,nomenclature,anddiagnosticguidelines.Gastrointest
EndoscClinNAm200818:19.vii.
11. LipkaS,BoyceHW,KumarA,RichterJE.Thechangingfacesofeosinophilicesophagitis:theimpactof
consensusguidelinesattheUniversityofSouthFlorida.DigDisSci201560:15721578.
12. PapadopoulouA,KoletzkoS,HeuschkelR,etal.Managementguidelinesofeosinophilicesophagitisin
childhood.JPediatrGastroenterolNutr201458:107118.
13. SperrySL,ShaheenNJ,DellonES.Towarduniformityinthediagnosisofeosinophilicesophagitis(EoE):
theeffectofguidelinesonvariabilityofdiagnosticcriteriaforEoE.AmJGastroenterol2011106:824
11/18
5/11/2015
832.quiz833.
14. DellonES.Epidemiologyofeosinophilicesophagitis.GastroenterolClinNorthAm201443:201218.
*ComprehensivereviewofEoEepidemiology.
15. FranciosiJP,TamV,LiacourasCA,SpergelJM.Acasecontrolstudyofsociodemographicandgeographic
characteristicsof335childrenwitheosinophilicesophagitis.ClinGastroenterolHepatol20097:415419.
16. RonkainenJ,TalleyNJ,AroP,etal.Prevalenceofoesophagealeosinophilsandeosinophilicoesophagitis
inadults:thepopulationbasedKalixandastudy.Gut200756:615620.
17. LevinM,MotalaC.EosinophilicoesophagitisinCapeTown,SouthAfrica(abstract).ClinTranslational
Allergy20111(Suppl1):26.
18. DellonES,JensenET,MartinCF,etal.PrevalenceofEosinophilicEsophagitisintheUnitedStates.Clin
GastroenterolHepatol201412:589596.e1.
19. SugnanamKK,CollinsJT,SmithPK,etal.Dichotomyoffoodandinhalantallergensensitizationin
eosinophilicesophagitis.Allergy200762:12571260.
20. Assa'adAH,PutnamPE,CollinsMH,etal.Pediatricpatientswitheosinophilicesophagitis:an8year
followup.JAllergyClinImmunol2007119:731738.
21. GuajardoJR,PlotnickLM,FendeJM,etal.Eosinophilassociatedgastrointestinaldisorders:aworldwide
webbasedregistry.JPediatr2002141:576581.
22. SpergelJM,BookWM,MaysE,etal.Variationinprevalence,diagnosticcriteria,andinitialmanagement
optionsforeosinophilicgastrointestinaldiseasesintheUnitedStates.JPediatrGastroenterolNutr2011
52:300306.
23. JyonouchiS,BrownWhitehornTA,SpergelJM.Associationofeosinophilicgastrointestinaldisorderswith
otheratopicdisorders.ImmunolAllergyClinNorthAm200929:8597.x.
24. BlanchardC,RothenbergME.Basicpathogenesisofeosinophilicesophagitis.GastrointestEndoscClinN
Am200818:133143.
25. MalerbaG,LaucielloMC,ScherpbierT,etal.Linkageanalysisofchromosome12markersinItalianfamilies
withatopicasthmaticchildren.AmJRespirCritCareMed2000162:15871590.
26. SpergelJM.Newgeneticlinksineosinophilicesophagitis.GenomeMed20102:60.
27. RothenbergME,SpergelJM,SherrillJD,etal.Commonvariantsat5q22associatewithpediatric
eosinophilicesophagitis.NatGenet201042:289291.
28. SleimanPM,WangML,CianferoniA,etal.GWASidentifiesfournoveleosinophilicesophagitisloci.Nat
Commun20145:5593.
**FirstGWASstudytoindicateassociationbetweenEMSYandEoEandoneofthetwoindependent
studiesthathaveshowntheimplicationofCAPN14inEoEpathogenesis.
29. BlanchardC,WangN,RothenbergME.Eosinophilicesophagitis:pathogenesis,genetics,andtherapy.J
AllergyClinImmunol2006118:10541059.
30. MarchME,SleimanPM,HakonarsonH.Thegeneticsofasthmaandallergicdisorders.DiscovMed2011
11:3545.
31. BlanchardC,WangN,StringerKF,etal.Eotaxin3andauniquelyconservedgeneexpressionprofilein
eosinophilicesophagitis.JClinInvest2006116:536547.
12/18
5/11/2015
32. GuptaSK,FitzgeraldJF,KondratyukT,HogenEschH.Cytokineexpressioninnormalandinflamed
esophagealmucosa:astudyintothepathogenesisofallergiceosinophilicesophagitis.JPediatr
GastroenterolNutr200642:2226.
33. StraumannA,BauerM,FischerB,etal.IdiopathiceosinophilicesophagitisisassociatedwithaT(H)2type
allergicinflammatoryresponse.JAllergyClinImmunol2001108:954961.
34. StraumannA,KristlJ,ConusS,etal.Cytokineexpressioninhealthyandinflamedmucosa:probingtherole
ofeosinophilsinthedigestivetract.InflammBowelDis200511:720726.
35. BlanchardC,MinglerMK,VicarioM,etal.IL13involvementineosinophilicesophagitis:transcriptome
analysisandreversibilitywithglucocorticoids.JAllergyClinImmunol2007120:12921300.
36. BlanchardC,MishraA,SaitoAkeiH,etal.Inhibitionofhumaninterleukin13inducedrespiratoryand
oesophagealinflammationbyantihumaninterleukin13antibody(CAT354).ClinExpAllergy2005
35:10961103.
37. BlanchardC,StuckeEM,BurwinkelK,etal.CoordinateinteractionbetweenIL13andepithelial
differentiationclustergenesineosinophilicesophagitis.JImmunol2010184:40334041.
38. MishraA,HoganSP,BrandtEB,RothenbergME.IL5promoteseosinophiltraffickingtotheesophagus.J
Immunol2002168:24642469.
39. MishraA,RothenbergME.IntratrachealIL13induceseosinophilicesophagitisbyanIL5,eotaxin1,and
STAT6dependentmechanism.Gastroenterology2003125:14191427.
40. SchmidGrendelmeierP,AltznauerF,FischerB,etal.EosinophilsexpressfunctionalIL13ineosinophilic
inflammatorydiseases.JImmunol2002169:10211027.
41. AcevesS,HiranoI,FurutaGT,CollinsMH.Eosinophilicgastrointestinaldiseases:clinicallydiverseand
histopathologicallyconfounding.SeminImmunopathol201234:715731.
42. AcevesSS,AckermanSJ.Relationshipsbetweeneosinophilicinflammation,tissueremodeling,andfibrosis
ineosinophilicesophagitis.ImmunolAllergyClinNorthAm200929:197211.xiiixiv.
43. AcevesSS,BroideDH.Airwayfibrosisandangiogenesisduetoeosinophiltraffickinginchronicasthma.
CurrMolMed20088:350358.
44. KottyanLC,DavisBP,SherrillJD,etal.Genomewideassociationanalysisofeosinophilicesophagitis
providesinsightintothetissuespecificityofthisallergicdisease.NatGenet201446:895900.
**OneofthetwoindependentstudiesthathaveshowntheimplicationofCAPN14inEoEpathogenesis.
45. SherrillJD,GaoPS,StuckeEM,etal.Variantsofthymicstromallymphopoietinanditsreceptorassociate
witheosinophilicesophagitis.JAllergyClinImmunol2010126:160165.e163.
46. JyonouchiS,SmithCL,SarettaF,etal.InvariantnaturalkillerTcellsinchildrenwitheosinophilic
esophagitis.ClinExpAllergy201444:5868.
47. LimDM,NarasimhanS,MichayliraCZ,WangML.TLR3mediatedNF{kappa}Bsignalinginhuman
esophagealepithelialcells.AmJPhysiolGastrointestLiverPhysiol2009297:G1172G1180.
48. WangYH,AngkasekwinaiP,LuN,etal.IL25augmentstype2immuneresponsesbyenhancingthe
expansionandfunctionsofTSLPDCactivatedTh2memorycells.JExpMed2007204:18371847.
49. ObokiK,OhnoT,KajiwaraN,etal.IL33isacrucialamplifierofinnateratherthanacquiredimmunity.Proc
NatlAcadSciUSA2010107:1858118586.
13/18
5/11/2015
50. TogbeD,FauconnierL,MadouriF,etal.ThymicStromalLymphopoietinEnhancesTh2/Th22andReduces
IL17AinProteaseAllergenInducedAirwaysInflammation.ISRNAllergy2013971036.
51. GregoryLG,JonesCP,WalkerSA,etal.IL25drivesremodellinginallergicairwaysdiseaseinducedby
housedustmite.Thorax201368:8290.
52. NotiM,WojnoED,KimBS,etal.Thymicstromallymphopoietinelicitedbasophilresponsespromote
eosinophilicesophagitis.NatMed201319:10051013.
53. SiracusaMC,SaenzSA,HillDA,etal.TSLPpromotesinterleukin3independentbasophilhaematopoiesis
andtype2inflammation.Nature2011477:229233.
54. LinJ,ZhaoGQ,WangQ,etal.Regulationofinterleukin33/ST2signalingofhumancornealepitheliumin
allergicdiseases.IntJOphthalmol20136:2329.
55. HalimTY,KraussRH,SunAC,TakeiF.LungnaturalhelpercellsareacriticalsourceofTh2celltype
cytokinesinproteaseallergeninducedairwayinflammation.Immunity201236:451463.
56. SimonD,AeberhardC,ErdemogluY,SimonHU.Th17cellsandtissueremodelinginatopicandcontact
dermatitis.Allergy201469:125131.
57. TanakaJ,WatanabeN,KidoM,etal.HumanTSLPandTLR3ligandspromotedifferentiationofTh17cells
withacentralmemoryphenotypeunderTh2polarizingconditions.ClinExpAllergy200939:89100.
58. SoumelisV,RechePA,KanzlerH,etal.Humanepithelialcellstriggerdendriticcellmediatedallergic
inflammationbyproducingTSLP.NatImmunol20023:673680.
59. SiracusaMC,SaenzSA,WojnoED,etal.Thymicstromallymphopoietinmediatedextramedullary
hematopoiesispromotesallergicinflammation.Immunity201339:11581170.
60. NotiM,KimBS,SiracusaMC,etal.Exposuretofoodallergensthroughinflamedskinpromotesintestinal
foodallergythroughthethymicstromallymphopoietinbasophilaxis.JAllergyClinImmunol2014
133:13901399.1399e13911396.
61. SiracusaMC,KimBS,SpergelJM,ArtisD.Basophilsandallergicinflammation.JAllergyClinImmunol
2013132:789801.quiz788.
62. SpergelJM,RothenbergME,CollinsMH,etal.Reslizumabinchildrenandadolescentswitheosinophilic
esophagitis:resultsofadoubleblind,randomized,placebocontrolledtrial.JAllergyClinImmunol2012
129:456463.463e451453.
63. Assa'adAH,GuptaSK,CollinsMH,etal.AnantibodyagainstIL5reducesnumbersofesophageal
intraepithelialeosinophilsinchildrenwitheosinophilicesophagitis.Gastroenterol2011141:15931604.
64. RamasamyA,CurjuricI,CoinLJ,etal.Agenomewidemetaanalysisofgeneticvariantsassociatedwith
allergicrhinitisandgrasssensitizationandtheirinteractionwithbirthorder.JAllergyClinImmunol2011
128:9961005.
65. AndersonCA,BoucherG,LeesCW,etal.Metaanalysisidentifies29additionalulcerativecolitisriskloci,
increasingthenumberofconfirmedassociationsto47.NatGenet201143:246252.
66. BarrettJC,HansoulS,NicolaeDL,etal.Genomewideassociationdefinesmorethan30distinct
susceptibilitylociforCrohn'sdisease.NatGenet200840:955962.
67. EsparzaGordilloJ,WeidingerS,FolsterHolstR,etal.Acommonvariantonchromosome11q13is
associatedwithatopicdermatitis.NatGenet200941:596601.
14/18
5/11/2015
68. HirotaT,TakahashiA,KuboM,etal.Genomewideassociationstudyidentifieseightnewsusceptibilityloci
foratopicdermatitisintheJapanesepopulation.NatGenet201244:12221226.
69. FerreiraMA,MathesonMC,DuffyDL,etal.IdentificationofIL6Randchromosome11q13.5asrisklocifor
asthma.Lancet2011378:10061014.
70. BonnelykkeK,MathesonMC,PersTH,etal.Metaanalysisofgenomewideassociationstudiesidentifies
tenlociinfluencingallergicsensitization.NatGenet201345:902906.
71. EzellSA,PolytarchouC,HatziapostolouM,etal.TheproteinkinaseAkt1regulatestheinterferonresponse
throughphosphorylationofthetranscriptionalrepressorEMSY.ProcNatlAcadSciUSA2012109:E613
E621.
72. MitchellC,ProvostK,NiuN,etal.IFNgammaactsontheairwayepitheliumtoinhibitlocalandsystemic
pathologyinallergicairwaydisease.JImmunol2011187:38153820.
73. CohnL,HomerRJ,NiuN,BottomlyK.Thelper1cellsandinterferongammaregulateallergicairway
inflammationandmucusproduction.JExpMed1999190:13091318.
74. MeephansanJ,TsudaH,KomineM,etal.RegulationofIL33expressionbyIFNgammaandtumor
necrosisfactoralphainnormalhumanepidermalkeratinocytes.JInvestDermatol2012132:25932600.
75. HsuCY,HenryJ,RaymondAA,etal.Deiminationofhumanfilaggrin2promotesitsproteolysisbycalpain
1.JBiolChem2011286:2322223233.
76. NassarD,LetavernierE,BaudL,etal.Calpainactivityisessentialinskinwoundhealingandcontributesto
scarformation.PLoSOne20127:e37084.
77. ChunJ,PrinceA.TLR2inducedcalpaincleavageofepithelialjunctionalproteinsfacilitatesleukocyte
transmigration.CellHostMicrobe20095:4758.
78. AichJ,MabalirajanU,AhmadT,etal.Lossoffunctionofinositolpolyphosphate4phosphatasereversibly
increasestheseverityofallergicairwayinflammation.NatCommun20123:877.
79. ConsortiumGT.TheGenotypeTissueExpression(GTEx)project.NatGenet201345:580585.
80. UhlenM,OksvoldP,FagerbergL,etal.Towardsaknowledgebasedhumanproteinatlas.NatBiotechnol
201028:12481250.
81. UetaM,SotozonoC,KinoshitaS.Expressionofinterleukin4receptoralphainhumancornealepithelial
cells.JpnJOphthalmol201155:405410.
82. WenT,StuckeEM,GrotjanTM,etal.Moleculardiagnosisofeosinophilicesophagitisbygeneexpression
profiling.Gastroenterol2013145:12891299.
83. SherrillJD,KcK,WuD,etal.Desmoglein1regulatesesophagealepithelialbarrierfunctionandimmune
responsesineosinophilicesophagitis.MucosalImmunol20147:718729.
84. YenEH,HornickJL,DehlinkE,etal.ComparativeanalysisofFcepsilonRIexpressionpatternsinpatients
witheosinophilicandrefluxesophagitis.JPediatrGastroenterolNutr201051:584592.
85. LiacourasCA,SpergelJM,RuchelliE,etal.Eosinophilicesophagitis:a10yearexperiencein381children.
ClinGastroenterolHepatol20053:11981206.
86. KonikoffMR,NoelRJ,BlanchardC,etal.Arandomized,doubleblind,placebocontrolledtrialoffluticasone
propionateforpediatriceosinophilicesophagitis.Gastroenterol2006131:13811391.
15/18
5/11/2015
87. SchaeferET,FitzgeraldJF,MollestonJP,etal.Comparisonoforalprednisoneandtopicalfluticasonein
thetreatmentofeosinophilicesophagitis:arandomizedtrialinchildren.ClinGastroenterolHepatol2008
6:165173.
88. DohilR,NewburyR,FoxL,etal.Oralviscousbudesonideiseffectiveinchildrenwitheosinophilic
esophagitisinarandomized,placebocontrolledtrial.Gastroenterol2010139:418429.
89. StraumannA,ConusS,DegenL,etal.Budesonideiseffectiveinadolescentandadultpatientswithactive
eosinophilicesophagitis.Gastroenterol2010139:15261537.1537e1521.
90. AcevesSS,BastianJF,NewburyRO,DohilR.Oralviscousbudesonide:apotentialnewtherapyfor
eosinophilicesophagitisinchildren.AmJGastroenterol2007102:22712279.quiz2280.
91. DohilR,AcevesSS,DohilMA.Oralviscousbudesonidetherapyinchildrenwithepidermolysisbullosaand
proximalesophagealstrictures.JPediatrGastroenterolNutr201152:776777.
92. DohilR,NewburyR,FoxL,etal.Oralviscousbudesonideiseffectiveinchildrenwitheosinophilic
esophagitisinarandomized,placebocontrolledtrial.Gastroenterology2010139:418429.
93. LucendoAJ,AriasA,DeRezendeLC,etal.Subepithelialcollagendeposition,profibrogeniccytokinegene
expression,andchangesafterprolongedfluticasonepropionatetreatmentinadulteosinophilicesophagitis:a
prospectivestudy.JAllergyClinImmunol2011128:10371046.
94. RothenbergME,AcevesS,BonisPA,etal.WorkingwiththeUSFoodandDrugAdministration:progress
andtimelinesinunderstandingandtreatingpatientswitheosinophilicesophagitis.JAllergyClinImmunol
2012130:617619.
95. KagalwallaAF,SentongoTA,RitzS,etal.Effectofsixfoodeliminationdietonclinicalandhistologic
outcomesineosinophilicesophagitis.ClinGastroenterolHepatol20064:10971102.
96. DellonES,GonsalvesN,HiranoI,etal.ACGclinicalguideline:Evidencedbasedapproachtothediagnosis
andmanagementofesophagealeosinophiliaandeosinophilicesophagitis(EoE).AmJGastroenterol2013
108:679692.quiz693.
97. GreenhawtMJ,AcevesS,SpergelJM,RothenbergME.Themanagementofeosinophilicesophagitis.J
AllergyClinImmunol20131:332340.
98. WenzelSE,SchwartzLB,LangmackEL,etal.Evidencethatsevereasthmacanbedividedpathologically
intotwoinflammatorysubtypeswithdistinctphysiologicandclinicalcharacteristics.AmJRespirCritCare
Med1999160:10011008.
99. StraumannA,BussmannC,ConusS,etal.AntiTNFalpha(infliximab)therapyforsevereadulteosinophilic
esophagitis.JAllergyClinImmunol2008122:425427.
100. RochaR,VitorAB,TrindadeE,etal.Omalizumabinthetreatmentofeosinophilicesophagitisandfood
allergy.EurJPediatr2011170:14711474.
101. StraumannA,HoesliS,BussmannC,etal.AntieosinophilactivityandclinicalefficacyoftheCRTH2
antagonistOC000459ineosinophilicesophagitis.Allergy201368:375385.
102. ScheerensH,ArronJR,ZhengY,etal.Theeffectsoflebrikizumabinpatientswithmildasthmafollowing
wholelungallergenchallenge.ClinExpAllergy201444:3846.
103. NoonanM,KorenblatP,MosesovaS,etal.Doserangingstudyoflebrikizumabinasthmaticpatientsnot
receivinginhaledsteroids.JAllergyClinImmunol2013132:567574.e512.
104. UltschM,BeversJ,NakamuraG,etal.StructuralbasisofsignalingblockadebyantiIL13antibody
16/18
5/11/2015
Lebrikizumab.JMolBiol2013425:13301339.
105. SongCH,LeeJK.Lebrikizumabtreatmentinadultswithasthma.NEnglJMed2011365:2433authorreply
24332434.
106. HuaF,RibbingJ,ReinischW,etal.ApharmacokineticcomparisonofAnrukinzumab,anantiIL13
monoclonalantibody,amonghealthyvolunteers,asthmaandulcerativecolitispatients.BrJClinPharmacol
201580:101109.
107. ReinischW,PanesJ,KhuranaS,etal.Anrukinzumab,anantiinterleukin13monoclonalantibody,inactive
UC:efficacyandsafetyfromaphaseIIarandomisedmulticentrestudy.Gut201564:894900.
108. RothenbergME,WenT,GreenbergA,etal.IntravenousantiIL13mAbQAX576forthetreatmentof
eosinophilicesophagitis.JAllergyClinImmunol2015135:500507.
109. CianferoniA,SpergelJ.TheimportanceofTSLPinallergicdiseaseanditsroleasapotentialtherapeutic
target.ExpertRevClinImmunol201410:14631474.
110. AlShamiA,SpolskiR,KellyJ,etal.AroleforTSLPinthedevelopmentofinflammationinanasthma
model.JExpMed2005202:829839.
111. LiYL,LiHJ,JiF,etal.Thymicstromallymphopoietinpromoteslunginflammationthroughactivationof
dendriticcells.JAsthma201047:117123.
112. ShiL,LeuSW,XuF,etal.LocalblockadeofTSLPreceptoralleviatedallergicdiseasebyregulatingairway
dendriticcells.ClinImmunol2008129:202210.
113. ZhangF,HuangG,HuB,etal.Asolublethymicstromallymphopoietin(TSLP)antagonist,TSLPR
immunoglobulin,reducestheseverityofallergicdiseasebyregulatingpulmonarydendriticcells.ClinExp
Immunol2011164:256264.
114. ZhouB,ComeauMR,DeSmedtT,etal.Thymicstromallymphopoietinasakeyinitiatorofallergicairway
inflammationinmice.NatImmunol20056:10471053.
115. GauvreauGM,O'ByrnePM,BouletLP,etal.EffectsofanantiTSLPantibodyonallergeninduced
asthmaticresponses.NEnglJMed2014370:21022110.
*FirststudyonantiTSLPthatshowsafetyandefficacyinanatopicdisease.
116. GonsalvesN.Foodallergiesandeosinophilicgastrointestinalillness.GastroenterolClinNorthAm2007
36:7591.vi.
117. HendersonCJ,AboniaJP,KingEC,etal.Comparativedietarytherapyeffectivenessinremissionof
pediatriceosinophilicesophagitis.JAllergyClinImmunol2012129:15701578.
118. LucendoAJ,AriasA,GonzalezCerveraJ,etal.Empiric6foodeliminationdietinducedandmaintained
prolongedremissioninpatientswithadulteosinophilicesophagitis:aprospectivestudyonthefoodcauseof
thedisease.JAllergyClinImmunol2013131:797804.
119. SpergelJM,BrownWhitehornTF,CianferoniA,etal.Identificationofcausativefoodsinchildrenwith
eosinophilicesophagitistreatedwithaneliminationdiet.JAllergyClinImmunol2012130:461467.e465.
120. DupontC,KalachN,SoulainesP,etal.Cow'smilkepicutaneousimmunotherapyinchildren:apilottrialof
safety,acceptability,andimpactonallergicreactivity.JAllergyClinImmunol2010125:11651167.
121. MondouletL,DioszeghyV,LarcherT,etal.Epicutaneousimmunotherapy(EPIT)blockstheallergic
esophagogastroenteropathyinducedbysustainedoralexposuretopeanutsinsensitizedmice.PLoSOne
20127:e31967.
17/18
5/11/2015
122. DioszeghyV,MondouletL,DhelftV,etal.TheregulatoryTcellsinductionbyepicutaneousimmunotherapy
issustainedandmediateslongtermprotectionfromeosinophilicdisordersinpeanutsensitizedmice.Clin
ExpAllergy201444:867881.
Acknowledgements
None.
CurrOpinAllergyClinImmunol.201515(5):417425.2015LippincottWilliams&Wilkins
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Eosinophilic Esophagitis

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Eosinophilic Esophagitis

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5/11/2015

(Ig)E(Fc[epsilon]RI). [61]However,Siracusaetal. [53]havedescribedthatTSLPmayactasanindependentgrowth

c11orf30 Intergenic ENCODEtranscription

2.219 5.38x 0.157

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