Does mucosal inflammation drive recurrence of primary sclerosing cholangitis in liver transplantion recipients with ulcerative colitis?

(1)

ContentslistsavailableatScienceDirect

Digestive

and

Liver

Disease

j o u r n a l ho me p a g e :w w w . e l s e v i e r . c o m / l o c a t e / d l d

Alimentary

Tract

Does

mucosal

inﬂammation

drive

recurrence

of

primary

sclerosing

cholangitis

in

liver

transplantion

recipients

with

ulcerative

colitis?

Nik

Dekkers

a,∗

_,

_Menso

_Westerouen

_van

_Meeteren

a

_,

_Ron

_Wolterbeek

b

_,

Arantza

Farina

Sarasqueta

c,d

_,

_Wim

_Laleman

e,f,g

_,

_Akin

_Inderson

a

_,

_Bruno

_Desschans

e

_,

Bart

van

Hoek

a

_,

_Kerem

_Sebib

_Korkmaz

a

_,

_Severine

_Vermeire

f,h

_,

_Jeroen

_Maljaars

a

a_Leiden_University_Medical_Centre,_Department_of_{Gastroenterology-hepatology,}_LUMC:_Albinusdreef_2,_2333ZA,_Leiden,_The_Netherlands b_Leiden_University_Medical_Centre,_Department_of_Medical_Statistics,_LUMC,_Leiden,_The_Netherlands

c_Leiden_University_Medical_Centre,_Department_of_Pathology,_LUMC,_Leiden,_The_Netherlands d_Amsterdam_University_Medical_Centre,_Department_of_Pathology,_AUMC,_Amsterdam,_The_Netherlands

e_University_Hospitals_Leuven,_Department_of_{Gastroenterology-Hepatology,}_Division_of_Liver_and_{Biliopancreatic}_Disorders,_KU_Leuven,_Leuven,_Belgium f_KU_Leuven,_Department_Chronic_Diseases,_Metabolism_&_Ageing_(CHROMETA),_Leuven,_Belgium

g_University_Hospitals_Leuven,_Department_of_Abdominal_Transplant_Surgery_&_Transplant_{Coordination,}_KU_Leuven,_Belgium h_University_Hospitals_Leuven,_Department_of_{Gastroenterology-Hepatology,}_KU_Leuven,_Belgium

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received18June2019 Accepted5February2020 Availableonline5March2020 Keywords: Geboes IBD Mucosalinﬂammation Riskfactors rPSC

a

b

s

t

r

a

c

t

Background:Livertransplantationremainstheonlyeffectiveevidencebasedtreatmentforadvanced primarysclerosingcholangitis.However,recurrenceofdiseaseoccursinapproximately18%.

Aims:Thisstudyaimedtoassessriskfactorsofrecurrenceofprimarysclerosingcholangitis.

Methods:Aretrospectivecohortstudywasperformedonpatientsundergoingtransplantationfor recur-renceofprimarysclerosingcholangitisintwo academiccenters(Leuven,BelgiumandLeiden,The Netherlands).Besidesotherriskfactors,thedegreeofmucosalinﬂammationwasassessedasapotential riskfactorusinghistologicalGeboesscores.

Results:81patientswereincluded,ofwhich62(76.5%)werediagnosedwithulcerativecolitis.Seventeen patients(21.0%)developedrPSCduringamedianfollow-uptimeof5.2years.Inasubsetof42patientsno associationwasfoundbetweenthedegreeofmucosalinﬂammationandrecurrence,usingbothoriginal Geboesscoresandmultiplecut-offpoints.Inthetotalcohort,cytomegaloviremiapost-transplantation (HR:4.576,95%CI1.688–12.403)andyoungerreceiverageattimeoflivertransplantation(HR:0.934, 95%CI0.881–0.990)wereindependentlyassociatedwithanincreasedriskofrecurrenceofdisease. Conclusion:Thisstudyfoundnoassociationbetweenthedegreeofmucosalinﬂammationandrecurrence ofprimarysclerosingcholangitis.Anassociationwithrecurrencewasfoundforcytomegaloviremia post-livertransplantationandyoungerageattimeoflivertransplantation.

1. Introduction

Primary sclerosing cholangitis (PSC) is a progressive

ﬁbro-inﬂammatorydiseaseofthe(intraand/orextra-hepatic)biliarytree

andcomprises awidespectrum ofpresentationsgoingfroman

asymptomaticstage,overtliverfunctiontestdisturbanceto

recur-rentcholangitis,hepatogenicpruritus,and/oraprogressiveformof

hepaticﬁbrosis,insomecasesultimatelyresultinginbiliary

cirrho-sis[1].Additionally,PSCpatientsalsohavea10–15%lifetimeriskof

∗ Correspondingauthorat:Albinusdreef2(StafsecretariaatMDL,C4-P),2333ZA Leiden,TheNetherlands.

E-mailaddress:n.dekkers@lumc.nl(N.Dekkers).

developingcholangiocarcinoma(CCA),ahighlymalignantand

dif-ﬁculttodetecttypeofprimarylivercancer[2].Theonlytreatment

provensuccessfultoimprovequalityoflifeandsurvivalin

evolv-ingandtherapy-refractoryPSCpatientsisalivertransplantation

(LT)[1].Regrettably,afterlivertransplantation,PSCisestimated

tore-occurinapproximately18%ofthepatients[3].Recurrenceof

PSCissuggestedtobeassociatedwithaworsepatientandgraft

survival[4,5].AveragepatientsurvivalafterthediagnosisofrPSC

variesbetween12and17years[1].

InAmericaandNorthernEurope,70–80%ofPSCpatientshave

beenorwillbediagnosedwithinﬂammatoryboweldisease(IBD),

mostlyulcerativecolitis[6].Viceversa,2.4–4%ofIBDpatientswill

developPSC[1].ThephenotypeofUCisdifferentinPSCcompared

tonon-PSCpatients.InPSCpatients,theUCismoreoftenclinically

https://doi.org/10.1016/j.dld.2020.02.006

(2)

quiescentpre-transplant,buttheinﬂammationmostlyinvolvesthe

entirecolonwithpredominantright-sidedactivityincomparison

toUCpatientswithoutPSC[7].Aftertransplantation,thenumber

andseverityofUCﬂaresmayincrease[8]and30%ofthepatients

willexperienceanincreaseindiseaseactivity.OfPSCpatients

with-outadiagnosisofIBDatthetimeofthetransplantation,14–30%will

developIBDpost-transplant.Itshouldbekeptinmindthat,even

afterLT,IBD-PSCpatientshavea10-foldhigherriskofColorectal

cancers(CRCs)comparedtoIBD-patientsundergoingaLTforother

indicationsthanPSC[9–11].TheriskofCRCdevelopmentisashigh

as30%,at20yearsaftertheconcurrentdiagnosisofIBDandPSC

[12].

TheriskfactorsassociatedwithrPSCremainatopicoflively

scientiﬁcdiscussion. Severalassociationshavebeenfound, such

asmalegender,youngerageatthetime oftheLT,intercurring

acutecellularrejection,co-incidingCMV-viremiapost-LT,donor

relatedfactors(age,gender-mismatch),internationalnormalized

ratio(INR)atLTandCCApre-transplant[5,7,13–15].

Thelargeststudyonthistopic,publishedin2015,concluded

that thepresence of UC afterLT wasassociated witha

signiﬁ-cantlyincreasedriskofrPSC[7].Intriguingly,acolectomybefore

or during LT protected for rPSC [14,15]. This suggeststhat UC

mightincreasetheriskofdevelopingrPSC.AGerman

retrospec-tivemulticentreanalysis,concludedin2016thattherateofrPSC

wassigniﬁcantlyhigherinpatientswithanactivecolitisafterLT

comparedtopatientswithoutIBD,inactive IBDorpatientswho

underwentacolectomybeforeorduringLT[5].Ameta-analysisby

Steenstratenetal.alsoconcludedin2019thatacolectomybefore

livertransplantationreducedtheriskofrecurrence[3].

ThesuggestionthatactivecolitisafterLTmightbeariskfactor

forrPSCimpliesthatrecurrenceofPSCcouldbedrivenby

intesti-nalmucosalinﬂammationviatheconceptofthegut-liveraxis.This

studyaimstoretrospectivelyassessthislatterandprevious

men-tionedfactorsintherecurrenceofPSCafterlivertransplantationin

DutchandBelgianLTrecipientswithUC.

2. Materialsandmethods

2.1. Designandpopulation

WeperformedaretrospectivecohortstudyintheLeiden

Univer-sityMedicalCentre(LUMC)intheNetherlandsandtheUniversity

HospitalsLeuven(UZLeuven)inBelgium.

Theinclusioncriteriaare:UCandnon-IBDpatientsreceiving

theirﬁrstLTduetoPSCbetweenJuly1994–August2–15(LUMC)

andFebruary1992–July2015(Leuven).Theexclusioncriteriumis

afollow-upperiodshorterthan6months.Thefollowingdatawere

systematicallyobtainedfromtheelectronicpatientrecords:

1Standarddemographicpatientcharacteristics.

2PSCdata: Dateofdiagnosis,occurrenceof rPSCand presence

and/or occurrenceof: CCA,co-inciding autoimmune hepatitis

(AIH)and/orCMVinfections;deﬁnedasapositivePolymerase

chainreaction(PCR)forCMV.

3Transplantationdata:Dateandindicationofliver

transplanta-tion, demographic donor data, internationalnormalized ratio

(INR),eventsofrejectionandtypeofimmunosuppression.

4Colitisdata: Presenceof colitis and dateof diagnosis,steroid

usage,timingandtypeofcolectomyandadoptedmedical

treat-ment.

5Pathologyreports;assessmentofinﬂammationanddysplasia.

Ethicalapproval wasobtainedfromtheethicscommitteesof

boththeLUMCandUZLeuven.Iffollow-updurationwaslessthan

6months,patientswereexcluded.However,patientsundergoing

are-transplantationwithin6monthswereincludedinanalysis.

Timezerowasconsidereddataofindextransplantation.Follow-up

startedattimeoftransplantationandendedatdeath,recurrence

ofPSCorgraftfailureduetoothercauses.

2.2. DiagnosisofrPSC

Patients receivedroutine annual check-ups after their liver

transplantation.Morethoroughdiagnostictests(e.g.MRCP,ERCP

or biopsies)wereperformedif eitherlab resultsand/or clinical

signssuggestedcholestasis.RecurrenceofPSCwasdiagnosedin

allcasesaccordingtotheacceptedGraziadeiorMayocriteria[6].

Withtypicalﬁndingsofbileductirregularitieson

cholangiogra-phyand/orhistologicalﬁndingsinabsenceofdeﬁned causesof

secondarysclerosingcholangitis(Establishedductopenicrejection,

hepaticarterythrombosis/stenosis,anastomoticbiliarystrictures

alone, ABO incompatibility between donor and recipient and

non-anastomotic stricturesoccurring within90 days after liver

transplantation)[6].Todiscriminatefromischemic

cholangiopa-thy,histologicaland/orradiological ﬁndingsoccurring>90days

aftertransplantationwereconsideredasrPSC,asproposedinan

earlierpublishedreportonthismatter[6].

2.3. Assessmentofmucosalinﬂammation

BecauseoftheincreasedriskofCRC,guidelinessuggest

perform-ingacolonoscopyyearlyoreverytwoyearsinPSCpatientswith

UC.Duringmostofthesecolonoscopies,biopsiesaretaken.These

biopsieswereusedfortheassessmentofmucosalinﬂammation;all

pathologyreportswerere-examinedbyonepathologistspecialised

inGastro-intestinalpathologyandscored, usingthe0–5Geboes

score[16].A-1scorewasaddedtoscorebiopsiesthatshowedno

histologicalalterations.ThecompleteGeboesscoreusedforthisstudy

isshowninsupplementarydata(A).Histologicalactivediseaseis

deﬁnedasaGeboesscore_≥3[17].Foreverybiopsytheworst

right-sided(Cecum-FlexuraLienalis)andtheworstleft-sided(Flexura

Lienalis-proximalRectum)scorewasnoted.Ifareportwas

insufﬁ-cientforscoring,archivedslideswererequestedforreassessment

andscoredbythesamepathologist.

2.4. Statisticalanalysis

Data werecollectedand analysedusing SPSS23.0.

Categori-calparametersareexpressedasn(%),continuousvariables,when

normallydistributed,asmean±standard deviationandifnotas

median±interquartilerange(IQR).Follow-upwascalculatedfrom

date of ﬁrst LT (or second LT if patients were re-transplanted

within 6 months) to recurrence of PSC and censored at: graft

loss(i.e.regraft>6monthsafterinitialLTforotherreasonsthan

recurrenceofdisease),deathorendoffollow-up(July5th_2016).

Univariateanalysisof allriskfactors,except inﬂammation,was

performedusingCoxproportionalhazardsregressionmodels.All

variablesclosetoorundersigniﬁcancelevel(p<0.1)wereincluded

in multivariate analysis, performed by Cox regression analysis.

Aftermultivariateanalysis,riskfactorswithap-value<0.05were

consideredstatisticallysigniﬁcant.

A time-dependent covariate in theCox proportional hazard

regressionmodelwasusedforthestatisticalanalysisoftherisk

fac-torinﬂammation.Thetimedependentcovariatetakesintoaccount

theamountoftimeapatientisexposedtothedifferentriskscores;

inthiscasethedegreeofintestinalinﬂammationasdeﬁnedbythe

Geboesscores.Theproportionalityrequirementwillbeveriﬁedby

plottinglog[-log(survivalfunction)]bytimeandbyverifyingthat

therearenolinescrossing.

First,alloriginalGeboesscores(−1to5)wereanalysedforboth

(3)

Fig.1. Timedependentcovariate.

minimumandmaximumscoreswereusedforanalysis(i.e.the

low-est/highestscore;soeithertheleft-sidedorright-sidedscorefor

eachofthe13scoringmoments).Lastly,allGeboesscoreswere

dividedintotwogroups,usingcut-offpoints:startingwithacut-off

pointofGeboes4(i.e.allGeboesscores<4weretransformedto0,all

Geboesscores4or5weretransformedto1).Inthetimedependent

covariatedateofLTwasstatedast0,appointingeverypatientazero

riskfromthispointonuntilthedateoftheirﬁrstbiopsy;labelling

theLTaresetforthePSCrisk.TheﬁrstGeboesscorewasappliedas

theriskfactorfortheintervalbetweenﬁrst(t1)andsecondbiopsy

date(t2).Fromt2untilthedateofthepatient’sthirdbiopsy(t3),the

secondGeboesscorewasappliedasriskfactor.Thesameappliesfor

Geboesscore3toGeboesscore13(Fig.1).Fortheanalysis,usingthe

timedependentcovariate,itwasnecessarythateverypatienthad

thesamenumberofGeboesscores.Therefore,wecomplemented

thescorestothepointwhereeverypatienthadthesameamount

ofGeboesscores.Forcomplementingweusedthe“lastobservation

carriedforward”method,withtheexceptionofpatients

undergo-ingcolectomiesduringfollow-up.Aftera(sub)totalcolectomywe

renderedtheGeboesscore,forbothright-andleft-sidedcolon,−1.

Onlypatientswithatleasttwobiopsieswereincludedin

analy-sis.Whenpatientshadmissingscores,thatsideofthecolonwas

excludedfromanalysisforthatspeciﬁctimepoint.

3. Results

3.1. Overallstudypopulationandoutcome

Atotalof93livertransplantswereperformedforPSCinUCand

non-IBDpatients.Elevenpatientsdiedwithin6monthsofLTand

werethereforeexcludedfromﬁnalanalysis;theleadingcausesof

deathweresepsisandmulti-organfailure.Inaddition,onepatient

wasexcludedbecauseofmissingdataregardingtheIBD-diagnosis.

Fromthestudycohortof81,13patientswerecensoredatdeathand

threewerere-transplantedaftersixmonthsforotherindications

thanrPSC.ApatientﬂowdiagramisshowninFig.2.

BaselinepatientcharacteristicsaregiveninTable1.Themedian

follow-up was 5.2 years (IQR 6.9); there were529.16

cumula-tivefollow-upyears,70.4%ofthecohortconsistedofmen(n=57)

andthemeanageatlivertransplantationwas41.9years(±12.7).

Pre-transplant,57 patientswere diagnosed withUC (70.4%), of

whom7(12.3%) underwent a colectomypre-LT and 10 (17.5%)

post-LT.Threepatients(5.3%)were diagnosedwithcolitis after

livertransplantation.Nineteenpatients(23.5%)werenotdiagnosed

withIBDpriortotransplantationorduringfollow-up.Atotalof3

(3.7%)patientsdevelopedCRCduringfollow-upand9(11.1%)other

patientshadbiopsieswithdeﬁnitedysplasia.Inaddition,2other

patientshadbiopsiesscoredasindeﬁnitefordysplasia.

Fig.2.Patientﬂowdiagram.

Table1

Patientbaselinecharacteristics.

Patientcharacteristics NL,n=37 BE,n=44 Cohortn=81

AgeatLT,mean±SD 43.2±11.2 40.8±13.8 41.9±12.7

AgeatPSCdiagnosis,mean±SD 33.9±11.0 32.8±14.8 33.3±13.0 Gender

Male,n(%) 25(67.6%) 32(72.7%) 57(70.4%)

Female,n(%) 12(32.4%) 12(27.3%) 24(29.6%)

Follow-up,median(IQR) 4.7(6.2) 5.4(8.5) 5.2(6.9)

UCdiagnosedpre-LT,n(%) 32(86.5%) 25(56.8%) 57(70.4%) Colectomypre/duringLT,n(%) 4(10.8%) 3(6.8%) 7(8.6%) ColectomyafterLT,n(%) 4(10.8%) 6(13.6%) 10(12.3%) UCdiagnosedpost-LT,n(%) 1(2.7%) 4(9.1%) 5(6.2%) Colectomypre/duringLT,n(%) – 1(2.2%) 1(1.2%) ColectomyafterLT,n(%) – 2(4.5%) 1(1.2%) No-IBD 4(10.8%) 15(34.1%) 19(23.5%) Colectomypre-LT,n(%) 1(2.7%) – 1(1.3%) Colectomypost-LT 1(2.7%) – 1(1.3%) CCApre-LT,n(%) 5(13.5%) 4(9.3%) 9(11.1%)

Donorage,mean±SD 44.2±13.5 46.1±15.3 45.3±1.7

CMV

Pre,n(%) 9(24.3%) 15(34.1%) 24(29.6%)

Post,n(%) 7(18.9%) 8(18.2%) 15(18.5%)

Gendermismatch,n(%) 13(35.1%) 14(31.8%) 27(33.3%)

LTlivertransplantation,SDstandarddeviation,IQRinterquartilerange,PSCprimary sclerosingcholangitis,UCulcerativecolitis,IBDinﬂammatoryboweldisease,CCA cholangiocarcinoma,CMVcytomegalovirus.

3.2. rPSC,graftfailureandsurvival

In this cohort,rPSC wasidentiﬁed in17 patients(21.0%), of

whom14hadadiagnosisofUC.TenrPSCpatientsexperiencedgraft

failure(58.8%)ofwhich2patientsdiedand8werere-graftedafter

amedianof6.1(IQR9.1)years.The1,5and10yearsgraftsurvival

was94%,61%and35%respectively.

Graftfailurewaslesscommoninthe64patientsnot

experi-encing recurrenceof PSC,namely inﬁve patients(7.8%). These

patientswere re-transplantedfor autoimmune hepatitis (n=1),

hepaticarterythrombosis(n=1),chronicrejection(n=1),ischemic

typebiliarylesions(n=1).Inonepatientgraftfailureoccurredafter

asuicideattempt.The1,5and10yearsurvivalwas100%,89%and

(4)

10yearpatients’survivalwasrespectively97.5%,87.4%and58.8%

inthisstudycohort(n=81).The1,5and 10yearsurvivalforall

patients(n=91),thusincludingthosewhohadafollow-uptime

lessthan6months,was87.8%,78.7%and52.9%respectively.No

statisticaldifferencewasseenbetween10yearsurvival inrPSC

patientsvs.non-rPSC patientsforthestudycohort (p=0.15)or

whenpatientswithafollow-uptimeshorterthan6monthswere

included(p=0.06).

3.3. InﬂammationasariskfactorforrPSC

Intotal,42patientshadasufﬁcientnumberofbiopsiestaken

fromeitherleft,rightorbothsidesoftheircolonandwereincluded

intoanalysis.Recurrenceofdiseaseoccurredin10patients(23.8%).

Asstatedabove,scoresofallpatientswerecomplementedtothe

amountof13Geboesscores.Insomepatientsonlybiopsieswere

takenfromthesigmoidcolon,thereforedatafromtherightsideof

thecolonweremissing.Thesepatientswereexcludedfromanalysis

oftherightside,leaving 32patientsfor analysis.Complemented

originalscoresareshowninsupplementarydata(B.1).

Noassociationwasfoundbetweenhistologicalinﬂammation

and rPSC in this cohort (Table 2).When using original Geboes

scores,usingvalues−1to5,left-sidedinﬂammationappearedto

increasetheriskofrPSCwith19.6%(HR:1.196,95%CI0.885–1.616),

whereasright-sidedinﬂammationreducedtherateofrecurrence

(HR0.557,95%CI0.254–1.219).Neitherreachedstatistical

signiﬁ-cance(respectivelyp=0.41,p=0.14).Therewasalsonoassociation

foundwhenusingthemaximumscoresorjusttheminimumofthe

Geboesscoresforeachofthe13scoringmoments.Furthermore

noassociationwasfoundinthiscohortwhenusingdifferent

cut-offpoints;forinstancelookingatmicroscopicactivedisease(i.e.

Geboesscore≥3).Alsothecumulativeright-sidedscore,(p0.274,

HR0.964,95%CI0.902–1.030)thecumulativeleft-sidedscore(p

0.432,HR1.011,95%CI0.984–1.039)andtotalcumulativescore(p

0.228,HR0.976,95%CI0.937–1.016)showednoassociationwith

recurrenceofdisease.Scoresrecodedforhistologicalactivecolitisare

showninsupplementarydata(B.2).

3.4. RiskfactorsforrPSC

ThestrongestpredictorforrPSCwasintercurrentCMVviremia

post-LT(Table3).Interestingly,olderrecipientagewasfoundto

beaprotectivefactoragainstrPSC;witheach10yearincrementin

agetherewasariskreduction forrPSCof6.5%(HR:0.935,95%

CI0.890–0.982). UnivariateanalysisshowedageatPSC

diagno-sistobeprotectiveforrPSC.Similartorecipientageitdecreases

therecurrenceriskwithanincrementofage(HR:0.94295%CI

0.893–0.993,p=0.03).However,ageatPSCdiagnosisappearedto

bedependentoftheriskfactorrecipientageatLT(r0.86)andwas

thereforeleftoutofmultivariateanalysis.Anassociationwas

fur-thermoreobservedfornon-heart-beating(NHB)donors;showing

anincreasedriskof265%ofrPSC(HR:3.653,95%CI0.914–14.60),

althoughdidnotreachstatisticalsigniﬁcance(p=0.07).No

associa-tionwasfoundbetweenrPSCandtheintervalbetweendateofPSC

diagnosisandLT(p=0.77)ortheintervalbetweenIBDdiagnosis

andLT(p=0.29).

Multivariate analysis showed an independent association

betweenrecipientageatLTandpost-LTCMVviremiawithrPSC

(Table4).Every10yearincrementoftherecipientageshowedarisk

reductionof6.6%forrPSC(HR:0.934,95%CI0.881–0.990).Patients

sufferingfromapost-LTCMVviremiashowedanincreasedriskof

357%inmultivariateanalysis(HR:4.576,95%CI1.688–12.403).An

increasedriskwasfurthermoreseenfornon-heart-beatingdonors

(HR:4.258,95%CI0.989–18.329),thishoweverdidnotreach

sta-tisticalsigniﬁcance(p=0.05).

4. Discussion

InUCandnon-IBDpatientstransplantedforPSC,this

multicen-treretrospectivecohortstudyidentiﬁedCMVviremiapost-LTand

ayoungerrecipientageattimeofLTasindependentriskfactors

forrecurrenceofPSCafterlivertransplantation.Theextentand

severityofmucosalinﬂammationwasnotfoundrelatedtorPSC.

Tothebestofourknowledge,thisstudyistheﬁrsttoassess

theassociationofthehistologicaldegreeofmucosalinﬂammation

withrPSC. We usedthevalidated Geboesscore [16] as a

mea-sureofmucosalinﬂammation.EitherwhenusingtheGeboesscore

value,orwhenusingcut-offpointsofactivemucosalinﬂammation

(Geboesscoreofthreeorhigher),orwhenusingcumulativescores,

no relationwas observed withPSC recurrence, which opposed

our initialhypothesis. Also when theGeboes scoreswere

ren-dered5afteracolectomy(Insteadofthepreviouslydescribed−1

after),becauseyoucouldarguethesepatientsareexposedtothe

maximuminﬂammatoryamount,noassociationwasfound.

Inter-estingly,Hildebrandetal.alsodidnotﬁndanassociationbetween

(merelyclinically-endoscopicallydeﬁned)activeIBDdiseaseand

recurrenceofPSCinmultivariateanalysis.Inthestudyof

Hilde-brandonlyendoscopic(andclinical)activitywerereportedwithout

histologicalconﬁrmation[5].Theseﬁndingsarealsoinlinewith

theresultsfromLindströmetal.wherealsonoassociationwas

foundbetweenIBD-activityandrecurrenceofPSC[18].Lindström

etal.statedtheIBDactivitywasmeasuredbythenumberofIBD

ﬂares,endoscopicactivityandmicroscopicactivity.Theassessment

ofmicroscopicactivitywashowever,notexplained.Wechoseto

excludepatientswithCrohn’sdiseasebecausetheGeboesscore

isn’tvalidatedforthisdisease.

Inourstudy,bothintercurringCMVviremiapost-transplantand

ayoungerageatlivertransplantationwereidentiﬁedasrisk

fac-torsforPSCrecurrence.Bothfactorshavebeenidentiﬁedbefore.In

thelargeststudypublishedsofaronthissubject,Ravikumaretal.

[7]explainedtheassociationbetweenyoungerreceiverageatLT

andrPSCbythefactthatbeinginneedofaLTatayoungerage

reﬂectsamoreaggressive/relentlesscourseofdiseaseatthatpoint

thatmightresurfacebyreactivationof“residualimmunememory”

aftertransplantation(inaccordancewiththehominglymphocyte

hypothesis[19]).

ACMVviremiawithin3monthsafterLThasalsobeendescribed

earlierasariskfactorforrPSCinasmallsinglecentrecohortstudy

(n=20)[13].Noexplanationwasgivenfortheirﬁndings.Purely

hypothetical,onecouldconsidertheinitialhepatobiliary

inﬂam-mationanddamagecausedbytheacuteCMVviremiatoinstigate

recurrenceofthechronicﬁbro-inﬂammatorycascadeleadingto

PSC[20,21].Adifferentexplanationforthisassociationmightbe

thatthedosageofimmunesuppressivetherapyisincreasedwhen

thereissuspicionofrejectionbecauseofelevatedliverenzymes,

increasingtheriskofaCMVviremia.Arecentmeta-analysisonrisk

factorsofrPSCdidnotﬁndarelationbetweenCMVinfectionand

rPSC[3].Thismayalsohavebeentheconsequenceofthedifferent

deﬁnitionsforCMV-infectioninthereviewedpapers.

Finally,wealsoevaluatedwhetherthepresenceofIBDincreased

theriskofdevelopingrPSC.Inourstudy,althoughrecurrenceof

PSCwasnumericallyhigherinIBDpatients(22%DiagnosisofIBD

pre-transplantvs.15%ofpatientswithoutUC),nosigniﬁcant

rela-tionwasfoundbetweenpresenceand/oractivityofUCpresence

and rPSC recurrence. A previous systematic review by Gautam

etal.,alsofoundnorelationbetweenrPSCandIBDpresence[4]

whereotherstudiesdid[5,7]. Ameta-analysisbyourgroupdid

ﬁnda relation betweenpresence ofIBD and recurrence ofPSC

[3].

Thelimitationsofourstudyareinlinewiththenatureofall

ret-rospectivestudies,namelythatselectionbiascannotbeexcluded

(5)

Table2

RiskassessmentofGeboesscoresusingthetimedependentcovariate.

Scoringusedforanalysis Right-sided(n=32) Left-sided(n=42)

Hazardratio(95%CI) p-Value Hazardratio(95%CI) p-Value

OriginalGeboes 0.669(0.340–1.314) 0.243 1.196(0.885–1.616) 0.24 Geboes≥0 0.459(0.084–2.510) 0.369 2.137(0.619–7.373) 0.23 Geboes≥1 0.486(0.088–2.682) 0.408 1.776(0.534–5.909) 0.35 Geboes≥2 0.026(0.000–36.777) 0.325 1.283(0.339–4.855) 0.71 Geboes≥3 0.606(0.069–5.306) 0.651 2.309(0.603–8.845) 0.22 Geboes≥4 0.042(0.000−182×104₎ _0.723 _1.219_{(0.150–9.888)} _0.85

Right-sidedandleft-sided(n=32)

Hazardratio(95%CI) p-Value

Minimumscore 0.632(0.325–1.231) 0.18

Maximalscore 0.719(0.346–1.497) 0.38

CIconﬁdenceinterval. Table3

UnivariateanalysisusingCoxproportionalhazardsmodel.

Studyvariable n(missing) Recurrenceofdisease Hazardratio(95%CI) p-Value

rPSC,%(n=17,21%) norPSC,%(n=64,79%) Gender

Male,n(%) 57 14(82.3%) 43(67.2%) 1.844(0.528–6.441) 0.34

Female,n(%) 24 3(17.6%) 21(32.8%) 1.0

AgeatLTinyears,median(IQR) 81 34.6(11.2) 43.0(16.0) 0.935(0.890–0.982) 0.01

AgeatPSCdiagnosis,mean±SD 77(4) 26.9±11.50 34.87±13.03 0.942(0.893–0.99) 0.03

CMVTotal 80(1) 12(70.6%) 27(42.2%) 3.111(1.090–8.880) 0.03

Pre-LT,n(%) 24 3(17.6%) 21(32.8%) 0.586(0.168–2.043) 0.40

Post-LT,n(%) 15 9(52.9%) 6(9.4%) 5.535(2.122–14.437) <0.001

Donorage,mean±SD 76(5) 42.437±17.0 46.03±13.8 0.989(0.954–1.025) 0.55

INR,median(IQR) 59(22) 12(4.75) 12(3.00) 0.965(0.795–1.172) 0.72

NHB,n(%) 81 3(17.6%) 8(12.5%) 3.653(0.914–14.60) 0.07 CCApre-LT 81 – 9(14.1%) 0.044(0.000–109.93) 0.43 Gendermismatch 72(9) 6(40%) 21(36.8%) 0.983(0.349–2.770) 0.97 Acuterejection 81 9(52.9%) 31(48.4%) 1.273(0.488–3.322) 0.62 Timingcolectomy 81 Nocolectomy 57 12(21%) 45(79.4%) 1.0 Pre-LT,n(%) 9 1(11%) 8(89%) 0.719(0.092–5.595) 0.75 Post-LT,n(%) 13 2(16.4%) 11(84.6%) 0.411(0.093–1.824) 0.24 UCdiagnosed 81 Never,n(%) 19 3(15.8%) 16(84.2%) 1.0 Pre-LT,n(%) 57 13(22.8%) 44(77.2%) 1.509(0.430–5.301) 0.52 Post-LT,n(%) 5 1(5.9%) 4(80%) 0.903(0.094–8.700) 0.93

Interval:PSCdiagnosisandLT,median(IQR) 77(4) 6.522(7.94) 6.337(8.7) 0.989(0.919–1.065) 0.77

Interval:IBDdiagnosisandLT,median(IQR) 54(27) 11.2(11.7) 17.2(18.8) 0.975(0.931–1.022) 0.29

rPSCrecurrenceofprimarysclerosingcholangitis,CIconﬁdenceinterval,LTlivertransplantation,IQRinterquartilerange,SDstandarddeviation,CMVcytomegalovirus,INR internationalnormalizedratio,NHBnon-heart-beating,CCAcholangiocarcinoma,UCulcerativecolitis.

Table4

MultivariateanalysisusingCoxproportionalhazardsmodel.

Patientcharacteristics Hazardratio(95%CI) p-Value

CMVviremiapost-LT 4.576(1.688–12.403) 0.01

AgeatLT 0.934(0.881–0.990) 0.02

NHBprocedure 4.258(0.989–18.329) 0.05

CIconﬁdenceinterval,CMVcytomegalovirus,LTlivertransplantation,NHB non-heart-beating.

in accordance withother reportedcohorts of transplanted PSC

patients. Othershortcomingsrelate tothesize and duration of

follow-up. Dueto thelimited sample size (numbersof events)

thestudymaysufferfromlackofpower.However,ourcohortof

81patientssurpassedthenumbersofmostpreviouslyreported

cohorts[13,22–25] and reporteda rPSC rateof 21.0% in

accor-dance with larger cohort studies [6,7,15]. In analogy with the

latter,ourcohortalsohadacomparablemedianfollow-uptimeof

5.2yearsandamaximumfollow-uptimeof17.1years.Anitem

applicabletoallrPSCstudiesatpresent isthedeﬁnitionofPSC

recurrence.AlthoughthecriteriabyGraziadeietal.[6]are

gen-erallyacceptedand werealsousedtodeﬁnerecurrencein this

study,thesecriteriastillleavesomeuncertaintywithregardsto

distinguishingbetweenischemictype biliarylesions (ITBL)and

rPSC given thelack of diagnostic tools to distinguish between

theseentitiesexceptfortimingofarisalpost-transplantation.The

medical treatmentspatients wereexposed towas oftenpoorly

reported.Sincetheassessmentofdrugexposurewouldnotbe

reli-ableduetotheverysmallsamplesizewechosenottoanalysethese

data.

In conclusion, this multicentre cohort study is the ﬁrst to

haveassessedthehistologicalextentofmucosalinﬂammationas

potentialriskfactorfor rPSCandfoundnoassociationbetween

the two. Anassociation between younger receiver age at time

ofLTand CMVviremiapost-LTand theriskforpost-transplant

PSC recurrencewas foundadding weight tothe awareness for

andclinicalsuspicionofthisentitybytransplantclinicianswhen

facingrecurrentcholestasisand/orbiliarytreeabnormalities.

Fur-ther studies, designed to optimally analyse these risk factors

in a prospective setting, are necessary to conﬁrm our

ﬁnd-ings.

Conﬂictsofinterest

(6)

Acknowledgements

Noacknowledgments,allcolleagueswhohaveassistedmetthe

fullauthorshipcriteria.

AppendixA. Supplementarydata

Supplementarymaterial relatedto thisarticle canbe found,

intheonlineversion,atdoi:https://doi.org/10.1016/j.dld.2020.02.

006.

References

[1]LaRussoNF,ShneiderBL,BlackD,GoresGJ,JamesSP,DooE,etal.Primary sclerosingcholangitis:summaryofaworkshop.Hepatology(Baltimore,Md) 2006;44(3):746–64.

[2]BoonstraK,WeersmaRK,vanErpecumKJ,RauwsEA,SpanierBWM,Poen AC, et al. Population-based epidemiology,malignancy risk, and outcome ofprimarysclerosingcholangitis.Hepatology(Baltimore,Md)2013;58(6): 2045–55.

[3]SteenstratenIC,SebibKorkmazK,TrivediPJ,IndersonA,vanHoekB,Rodriguez GirondoMDM,etal.Systematicreviewwithmeta-analysis:riskfactorsfor recurrentprimarysclerosingcholangitisafterlivertransplantation.Aliment PharmacolTher2019;49(6):636–43.

[4]Gautam M, Cheruvattath R, Balan V. Recurrence of autoimmune liver disease after liver transplantation: a systematic review. Liver Transpl 2006;12(12):1813–24.

[5]HildebrandT,PannickeN,DecheneA,GotthardtDN,KirchnerG,ReiterFP, et al.Biliarystrictures andrecurrence after livertransplantationfor pri-marysclerosingcholangitis:aretrospectivemulticenteranalysis.LiverTranspl 2016;22(1):42–52.

[6]GraziadeiIW,WiesnerRH,BattsKP,MarottaPJ,LaRussoNF,PoraykoMK,etal. Recurrenceofprimarysclerosingcholangitisfollowinglivertransplantation. Hepatology(Baltimore,Md)1999;29(4):1050–6.

[7]RavikumarR,TsochatzisE,JoseS,AllisonM,AthaleA,CreamerF,etal.Risk factorsforrecurrentprimarysclerosingcholangitisafterlivertransplantation. JHepatol2015;63(5):1139–46.

[8]PapatheodoridisGV,HamiltonM,MistryPK,DavidsonB,RollesK,Burroughs AK.Ulcerativecolitishasanaggressivecourseafterorthotopicliver transplan-tationforprimarysclerosingcholangitis.Gut1998;43(5):639–44.

[9]SinghS,TalwalkarJA.Primarysclerosingcholangitis–diagnosis,prognosisand management.ClinGastroenterolHepatol2013;11(8):898–907.

[10]HaagsmaEB,VanDenBergAP,KleibeukerJH,SlooffMJ,DijkstraG. Inﬂam-matory bowel disease after liver transplantation: the effectof different immunosuppressiveregimens.AlimentPharmacolTher2003;18(1):33–44.

[11]VerdonkRC,DijkstraG,HaagsmaEB,ShostromVK,VandenBergAP,Kleibeuker JH,etal.Inﬂammatoryboweldiseaseafterlivertransplantation:riskfactorsfor recurrenceanddenovodisease.AmJTransplant2006;6(6):1422–9.

[12]WangR,LeongRW.Primarysclerosingcholangitisasanindependentriskfactor forcolorectalcancerinthecontextofinﬂammatoryboweldisease:areviewof theliterature.WorldJGastroenterol2014;20(27):8783–9.

[13]EgawaH,TairaK,TeramukaiS,HagaH,UedaY,YonezawaA,etal.Risk fac-torsforrecurrenceofprimarysclerosingcholangitisafterlivingdonorliver transplantation:asinglecenterexperience.DigDisSci2009;54(6):1347–54.

[14]VeraA,MoledinaS,GunsonB,HubscherS,MirzaD,OlliffS,etal.Risk fac-torsforrecurrenceofprimarysclerosingcholangitisofliverallograft.Lancet 2002;360(9349):1943–4.

[15]AlabrabaE,NightingaleP,GunsonB,HubscherS,OlliffS,MirzaD,etal.A re-evaluationoftheriskfactorsfortherecurrenceofprimarysclerosing cholan-gitisinliverallografts.LiverTranspl2009;15(3):330–40.

[16]GeboesK,RiddellR,OstA,JensfeltB,PerssonT,LofbergR.Areproducible grad-ingscaleforhistologicalassessmentofinﬂammationinulcerativecolitis.Gut 2000;47(3):404–9.

[17]Jauregui-AmezagaA,GeeritsA,DasY, Lemmens B, SagaertX,Bessissow T,etal. Asimpliﬁed Geboesscore forulcerative colitis. JCrohns Colitis 2017;11(3):305–13.

[18]LindströmL,JørgensenKK,BobergKM,CastedalM,RasmussenA,RostvedAA, etal.Riskfactorsandprognosisforrecurrentprimarysclerosingcholangitis afterlivertransplantation:aNordicmulticentrestudy.ScandJGastroenterol 2018;53(3):297–304.

[19]EksteenB,MoraJR,HaughtonEL,HendersonNC,Lee-TurnerL,Villablanca EJ,et al. Guthoming receptorsonCD8 Tcells are retinoic acid depen-dentandnotmaintainedbyliverdendriticorstellatecells.Gastroenterology 2009;137(1):320–9.

[20]PakCY,EunHM,McArthurRG,YoonJW.Associationofcytomegalovirus infec-tionwithautoimmunetype1diabetes.Lancet1988;2(8601):1–4.

[21]HjelmesaethJ,MullerF,JenssenT,RollagH,SagedalS,HartmannA.Isthere alinkbetweencytomegalovirusinfectionandnew-onsetposttransplantation diabetesmellitus?Potentialmechanismsofvirusinducedbeta-celldamage. NephrolDialTransplant2005;20(11):2311–5.

[22]AlexanderJ,LordJD,YehMM,CuevasC,BakthavatsalamR,KowdleyKV.Risk factorsforrecurrenceofprimarysclerosingcholangitisafterliver transplanta-tion.LiverTranspl2008;14(2):245–51.

[23]KhettryU,KeavenyA,Goldar-NajaﬁA,LewisWD,PomfretEA,PomposelliJJ, etal.Livertransplantationforprimarysclerosingcholangitis:along-term clin-icopathologicstudy.HumPathol2003;34(11):1127–36.

[24]BrandsaeterB,SchrumpfE,BentdalO,BrabrandK,SmithHJ,AbildgaardA, etal.Recurrentprimarysclerosingcholangitisafterlivertransplantation:a magneticresonancecholangiographystudywithanalysesofpredictivefactors. LiverTransplant2005;11(11):1361–9.