MagneticResonanceImagingofaPopulationǦbasedCohortof PatientswithLongǦtermInflammatoryBowelDisease Primarysclerosingcholangitis,boweldamageandinflammation
By
AidaKapicLunder
FacultyofMedicine
DepartmentofRadiology,AkershusUniversityHospital
UNIVERSITETETIOSLO 2018
© Aida Kapic Lunder, 2018
Series of dissertations submitted to the Faculty of Medicine, University of Oslo
ISBN 978-82-8377-254-8
All rights reserved. No part of this publication may be
reproduced or transmitted, in any form or by any means, without permission.
Cover: Hanne Baadsgaard Utigard.
Print production: Reprosentralen, University of Oslo.
LLL
͞Youonlyseewhatyouknow”
JWvonGoethe
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ϯ͘WĂƚŝĞŶƚƐĂŶĚŵĞƚŚŽĚƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϴ ϯ͘ϭ^ƚƵĚLJĚĞƐŝŐŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϴ ϯ͘Ϯ^ƚƵĚLJƉŽƉƵůĂƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϴ ϯ͘Ϯ͘ϭWĂƉĞƌ/͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϭϵ ϯ͘Ϯ͘ϮWĂƉĞƌ//͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϭ ϯ͘Ϯ͘ϯWĂƉĞƌ///͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϮϮ ϯ͘ϯƐƐĞƐƐŵĞŶƚŽĨĐůŝŶŝĐĂůĚŝƐĞĂƐĞĂĐƚŝǀŝƚLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ϮϮ ϯ͘ϰ/ŵĂŐŝŶŐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϯ ϯ͘ϰ͘ϭDZ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϯ ϯ͘ϰ͘ϮDZ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϯ ϯ͘ϱ/ŵĂŐĞĞǀĂůƵĂƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϰ ϯ͘ϱ͘ϭĞƚĞĐƚŝŽŶŽĨW^ͲůŝŬĞůĞƐŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘Ϯϰ
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YLL ĐŬŶŽǁůĞĚŐĞŵĞŶƚƐ
Iamthankfulfortheopportunitygiventometoentertheworldofscientific research.Ithasbeenaninspiringandenlighteningprocess.Iwouldliketo expressmygratitudetonumberofpeople…
AnneNegård,mymaintutorandhighlyvaluedcolleagueforherkindness, professionalinsightandendlesssupportandgenerosity.Arne Borthne,my enthusiastic tutor for his unfailing support, generosity and confidence throughout the work of this thesis. Morten Vatn, my coǦtutor for his outstandingassistancewithresearchpracticeandforenthusiasticdiscussions.
JohannesRoksundHov,mycoǦtutorforhisenormous,neverǦendingenergyand competitivespiritineverythinghedoes.JørgenJahnsen,mysurrogateǦtutor andcoǦauthorforhisknowledgeableassistancethroughoutthisproject.
LindaTøftenBakstad,respectedcolleagueandcoǦauthorforlayingtheground formyresearch.Additionally,IthankmyothercoǦauthorsforsuccessfuland productivecooperationandmyworkmatesatAkershusUniversityHospitalfor creatingagreatatmosphereforwork.LadiesattheCDroom,MRtechnicians atthedepartment,statisticianJonasLindstøm,thankyou!Thankstothe formerandcurrentHeadoftheRadiologyDepartment,PetterHurlenand Hasan Banitalebi, and former Head of Resident Unit,Haseem Ashraffor offeringfacilitiestobringmyworktoaconclusion.
Finally,Iwanttoexpressmydeepestgratitudetomylovedones.Thisworkis dedicatedtoyou.Myparentsandmybrother,foralwaysencouragingmy studiesandforyourcontinuoussupportthroughlife.Mygirlfriendsandfellow researchersKristin,Elin,BanoandCamillaforinspiringtalksandsupport throughoutthisprocess.Mylittlegirls,whoIvaluemostinlife.
Helge,Iloveyou.
YLLL ďƐƚƌĂĐƚ
Background:
Inflammatoryboweldisease(IBD)isachronicdiseaseofthegutwithan unknown etiology and increasing incidence rates worldwide. Persistent inflammationcanleadtoseriouscomplicationsandpermanentboweldamage.
Additionally,IBDisoftencomplicatedbyextraintestinalmanifestations(EIMs), suchasprimarysclerosingcholangitis(PSC).PSCisachroniccholestaticliver diseasethatisusuallyprogressiveandultimatelyleadstoliverfailure.Thereis nosinglegoldstandardforthediagnosisoftheseconditions.Inrecentyears, crossǦsectional and magnetic resonance imaging (MRI) have emerged as reliable,consistentandwellǦtolerateddiagnosticmodalities.
Aims:
Theprimaryaimofthisthesiswastoassessthediseaseextentanddistribution ofintestinalandEIMsinapopulationǦbasedstudyofpatientswithlongǦterm IBDbymeansofMRI.Specifically,theaimwastoexaminetheprevalenceof PSC by magnetic resonance cholangiography (MRC) and to assess bowel damageandinflammationinpatientswithCrohn’sdisease(CD)20yearsafter thediagnosisbymagneticresonanceenterography(MRE).
Results:
TheaccumulatedprevalenceofPSCamongpatientswithIBDinSoutheast Norwaywas2.2%.InPaperI,MRCscreeningwasperformedin322patients;26 patients(8.1%)hadPSCǦlikelesions,outofwhich9(35%)hadknownPSC.
PatientswithsuspectedPSChadsignificantlymoreextensivecolitis,ahigher prevalenceofcolectomy,andmorechronicandcontinuoussymptomsofIBD thanpatientswithoutPSC(P=0.029,P=0.002,andP=0.012,respectively).The MRCprogressionscoreforPSCatbaseline(mean=0.94,SD=0.75)increased
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significantly(P=0.046)whenpatientswerereǦexaminedafteramedianof3.2 years(mean=1.18,SD=0.95).
InPaperII,96patientswithCDwereexaminedbyMRE.TheLémannindex (LI),whichisameasureofaccumulatedboweldamage,wascalculated.The median LI was 4.6 (interquartile range (IQR): 17.5), and the score was associatedwithayoungerage(P=0.02),thecomplicatedileocolonicphenotype (P<0.001)andtheuseofbiological(P<0.001)orimmunosuppressivetreatments (P=0.045).SixtyǦfivepatients(67.7%)hadimagingfindingsindicatingCD,and thediseaseclassificationwaschangedfor8patients(8.3%)solelybasedon MREfindings.Complicateddisease,CǦreactiveprotein(CRP)andthrombocyte levelsandtheuseofmedicationduringthefollowǦupperiodwerepositively associatedwithLI,whileage,hemoglobinandalbuminlevelswerenegatively associatedwithLIatthe20ǦyearfollowǦup.
InPaperIII,theinflammatoryactivityin95patientswithCDwasassessedby the MRE Global Score (MEGS). ThirtyǦfive (36.8 %) patients had active inflammation,withamedianMEGSof5(IQR:18.5).TheinterobserverBlandǦ AltmanlimitsofagreementfortheMEGSwereto Ǧ9.53to6.77,andthe intraclasscorrelationcoefficientwas0.98(95%CI:0.97to0.99).TheMEGS associatedpositivelywiththeCRPlevel(P=0.01),elevatedfecalcalprotectin (P=0.001),mucosal ulceration on endoscopy (P=0.03), complicated disease (P=0.04),chronicdiseasepattern(P=0.006)anduseofmedication(P=0.007).
Conclusions:
MRCscreeningofpatientswithIBDrevealedaprevalencerateofPSC3Ǧfold higherthanthatdetectedbasedonsymptoms.SixtyǦfivepercentofthepatients hadsubclinicalPSCassociatedwithprogressiveIBD.
HalfofthepatientswithlongǦtermCDhadimagingfindingsofboweldamage thatwereassociatedwithayoungage,complicateddiseaseandongoingactive
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disease.Additionally,approximatelyoneǦthirdofpatientshadmoderateor severeinflammation20yearsafterthediagnosis.MREproveditsroleasan indispensable supplement in the clinical assessment of CD location and behavior.
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LunderAK,HovJR,BorthneA,GleditschJ,JohannesenG,TveitK,etal.
PrevalenceofSclerosingCholangitisDetectedbyMagneticResonance Cholangiography in Patients With LongǦterm Inflammatory Bowel Disease.Gastroenterology.2016;151(4):660Ǧ9.e4.
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LunderAK,JahnsenJ,BakstadLT,BorthneA,HovJR,VatnM,etal.Bowel Damage in Patients With LongǦterm Crohn's Disease, Assessed by Magnetic Resonance Enterography and the Lemann Index. Clinical gastroenterologyandhepatology:theofficialclinicalpracticejournalofthe AmericanGastroenterologicalAssociation.2018;16(1):75Ǧ82.e5.
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LunderAK,BakstadLT,JahnsenJ,BorthneA,HovJR,VatnM,NegårdAAND TheIBSENStudyGroup.AssessmentofBowelInflammationbyMagnetic ResonanceEnterographyinLongǦtermCrohn´sDisease.Submitted.
[LL ďďƌĞǀŝĂƚŝŽŶƐ
ADC–apparentdiffusioncoefficient ANOVAǦanalysisofvariance
5ǦASA–5Ǧaminosalicylate
ASCAǦanti–Saccharomycescerevisiaeantibodies bǦSSFPǦbalancedsteadystatefreeprecession CCCǦcholangiocellularcarcinoma
CD–Crohn´sdisease
CDAIǦCrohn'sdiseaseactivityindex
CDEISǦCrohn'sdiseaseendoscopicindexofseverity CRC–colorectalcancer
CRP–CǦreactiveprotein CT–computertomography
DWI–diffusionweightedimaging EIMs–extraintestinalmanifestations
ERCPǦendoscopicretrogradecholangiography FSE–fastspinecho
GADOǦGadoliniumenhancementafterintravenouscontrastmedium administration
GRE–gradientecho
HBI–HarveyBradshawindex IBD–inflammatoryboweldisease
IBSENǦInflammatoryBowelDiseaseSouthǦEastNorway ICCǦintraclasscorrelationcoefficients
IQR–interquartilerange LI–Lemannindex
MARIAǦmagneticresonanceindexofactivity
MEGSǦmagneticresonanceenterographyglobalscore MIPǦmaximumintensityprojection
[LLL MRCǦmagneticresonancecholangiography MRE–magneticresonanceenterography MRI–magneticresonanceimaging
PABAKǦprevalenceǦadjustedbiasǦadjustedkappa PACSǦpictureǦarchivingandcommunicationsystem
pANCAǦperinuclearanti–neutrophilcytoplasmicantibodies PSC–primarysclerosingcholangitis
RCEǦrelativecontrastenhancement
SCCAIǦSimpleClinicalColitisActivityIndex
SESǦCDǦSimpleEndoscopicScoreforCrohnDisease TǦTesla
TNFǦɄ–tumornecrosisfactorɄ TSE–turbospinecho
UC–ulcerativecolitis USǦultrasound
ϭ͘/ŶƚƌŽĚƵĐƚŝŽŶ
Overthelasttwodecades,radiologicalimaginghasbecomeanessentialpartof theassessmentofpatientswithknownorsuspectedinflammatoryboweldisease (IBD).Severalfactorshavecontributedtothisdevelopment.Therehasbeenan increasingunderstandingofIBDasacomplex,multifaceteddiseasethatcannotbe assessedfullybyclinical,laboratoryandendoscopicevaluations.Clinicalindices have shown poor correlations with inflammatory activity (1), and there is increasingevidencethatinflammation,structuralbowelchangesandbileduct affection have gone undetected in patients with IBD (2Ǧ4). In this setting, magneticresonanceimaging(MRI)isanimportant,noninvasivesupplemental modalitywithlittleornocomplications.Moreover,therapeuticadvancesinthe managementofIBDcallforthereproducible,objectivemonitoringofdisease activity.MRIhasshownahighsensitivityandspecificityfordetectingbowel inflammation, penetrating lesions, strictures and extraintestinal disease manifestations(5Ǧ7)andisincreasinglybeingusedtomonitormedicaltherapy(8Ǧ 10).Additionally,standardizedassessmentsareevolvingthroughnewscoring systems,whichwillhopefullyfacilitatepatientfollowǦupvisitsandtherapeutic decisionǦmaking.
TheetiopathogenesisofIBDiselusive.Goodepidemiologicalstudiesarecrucial forprovidingcluestotheetiologyofthediseaseandidentifyingareasthatwarrant furtherstudy.However,reliableepidemiologydataaredependentonaccurate diseaseassessment.Todate,therearerelativelyfewdataontheradiologicallongǦ termoutcomesofIBD.ThisthesisproceedsfromapopulationǦbasedcohortstudy ofpatientswithIBDinSoutheastprovincesofNorway.Itexaminestheintestinal and extraintestinal MRI findings of patients who have had the disease for approximatelytwodecades.Inthelongterm,acquiringdetailedknowledgeonthe naturalextentandbehaviorofIBDwillhelpimproveourunderstandingofthis challengingdisease.
First,abriefintroductiontoIBD,primarysclerosingcholangitis(PSC)andthe diagnosticworkǦup,whichisrelevanttotheresultsandinterpretationofthe studies,ispresented.Studyaimsarethenpresented,followedbyareviewofthe appliedmethodsandsummarizedresults.Finally,findingsandmethodological considerationsarediscussed.
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IBDinvolveschronicinflammationofthedigestivetractandprimarilyincludes ulcerativecolitis(UC)andCrohn’sdisease(CD).Bothconditionsusuallyinvolve suchclinicalsymptomsasdiarrhea,abdominalpainandfatigue.Seriouslocaland systemicdiseasecomplicationscanbedebilitatingforthepatient.IBDaffects mostlyyoungpeople,usuallyinlateadolescenceandearlyadulthood(11,12).The prevalenceof IBDvariesgreatly in different partsof the worldand among differentethnicities(13).Caucasiansinnorthernpartsoftheworldareatthe greatestrisk,andprevalenceashighas0.5%hasbeenreportedintheWestern world(13).Itisestimatedthatapproximately3millionpeopleinEuropesuffer from IBD (14). Additionally, both the prevalence and incidence of IBD are increasingworldwide(13)(Figure1).
Figure1.IncreasingtrendofIBDintheworld.TheinteractivemapofIBD
incidenceandprevalencecanbefoundat:
https://people.ucalgary.ca/ggkaplan/IBDG2016.html.
ReprintedfromKaplanGGetal.(15)withpermissionfromElsevier.
IBDisacomplexdiseasethatarisesasaresultoftheinteractionofenvironmental andgeneticfactorsleadingtoimmunologicalresponsesandinflammationinthe intestine(16).Theexactetiologyisunknown.Itissuspectedthatthedisrupted interplayofgeneticandepigeneticfactorsandadefectiveimmuneresponseina dysbioticgutcombinedwithseveralenvironmentalandpsychologicalfactors resultsinchronicinflammationofthegut.UCcausesinflammationandulcersin theinnermostliningofthecolonandrectum,whileCDcausesdeep,transmural inflammationthatcaninvolveallareasofthedigestivetract–frommouthto anus.PatientswithIBDoftenexperienceextraintestinalmanifestations(EIMs), such as arthritis,dermatological and ocularcomplications and PSC (17, 18).
Additionally,thesepatientsareatahigherriskthanthegeneralpopulationof developing serious complications, including colorectal cancer (CRC) and cholangiocellularcarcinoma(CCC)(19,20).
ϭ͘ϭ͘ϭ h
UCisconfinedtothecolon,typicallystartingintherectumandextending proximallyinacontinuouspattern.ItisthemostprevalentoftheIBDdisorders, affecting505/105personsinNorway(13).TheclassificationofUCisbasedonthe colonicdiseaseextension,asfollows:proctitis(limitedtotherectum,extending ϐ15cm);leftǦsidedcolitis(extensiondistaltothesplenicflexure);andextensive colitis(extensionproximaltothesplenicflexure)(21),withapproximatelyathird ofpatientsfallingintoeachgroupatdiagnosis(22Ǧ24).However,thedisease extendsfromproctitistopancolitisinmanypatientsovertime(12).Reported longǦtermcumulativerelapseratesrangefrom67–83%(22,25),andaccordingto the10ǦyearfollowǦupofpatientsfromtheIBSENstudycohort,40%ofpatients reportchronicsymptoms(22).
Currentmedicaltreatments,suchas5Ǧaminosalicylate(5ǦASA),corticosteroids, immunosuppressantsandbiologicaltreatments,eitheraloneorincombination, aimtoinduceandmaintainremission.Inpatientswhoareunresponsiveto medicaltherapy,resectivesurgeryisrecommended.Thereportedcumulative colectomyratesvaryfrom3%to17%indifferentcohorts(26),andtherateshave been decreasing gradually over time (27, 28). Patients with extensive, longstandingactivediseaseareatahigherriskofdevelopingCRC(20),andthey areofferedregularsurveillancecolonoscopies(29).Currently,themortalityrates ofpatientswithUCarecomparabletothoseofthegeneralpopulation(30,31).
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CD is a chronic inflammatory disease that can affect any part of the gastrointestinaltract.ThereportedprevalenceinNorwayis262/100,000persons (32). The disease varies in extent and presentation. Most patients have an intermittentdiseasecourse,butupto20%exhibitcontinuoussymptoms(33).
TheclassificationofCDisbasedonageatdiagnosis,diseaselocationanddisease
behavior.TheViennaclassification(34),usedinthiscohortstudy,wasdeveloped in1998andlaterevolvedintotheMontrealclassification(21).Modifications includedanadditionalagecategory,andamodifierforproximaldiseaselocation (L4)andperianaldisease(P)(Table1).
Table 1. The Vienna and the Montreal classification for Crohn´s disease.
1added to L1-L3; 2added to B1-B3
Atthetimeofdiagnosis,roughlyoneǦthirdofpatientspresentswithileal, colonicorileocolonicaffection(35).Ithasbeenreportedthatsome1–2%of patientspresentwithuppergastrointestinaltractaffectiononly(36,37).Most patientshaveaninflammatorydiseasetypetobeginwith,butovertime,they developstricturingand/orpenetratingdisease,i.e.,complicateddiseasethat eventuallyaffectsover50%ofpatients(33,38Ǧ41).Additionally,populationǦ basedstudiespreǦdatingbiologicaltherapieshavedescribedhighlongǦterm relapseratesrangingfrom75–90%(38,42,43).
ThetreatmentofCDoftenrequiresamultidisciplinaryapproach.Simplified inflammation is treated with medical therapy, such as corticosteroids, immunosuppressants (methotrexate and thiopurines), biological therapy (mainlyantiǦTNFagents)andoccasionallyantibioticsorsulfasalazine.The
Variable Vienna Classification Montreal Classification Age at diagnosis (A) A1: < 40 years A1: 16 years
A2: 40 years A2: 17-40 years A3: > 40 years Disease location (L) L1: ileal L1: ileal
L2: colonic L2: colonic
L3: ileocolonic L3: ileocolonic
L4: upper GI tract L4: isolated upper GI tract1 Disease behavior (B) B1: inflammatory B1: inflammatory
B2: stricturing B2: stricturing B3: penetrating B3: penetrating
P: perianal disease2
mainindicationsforsurgeryarecomplicatingstrictures,abscessesandfistulas.
Withintenyearsofonset,approximately50%ofpatientsundergointestinal resection,andoneinthreeofthesewillsubsequentlyneedasecondsurgical interventionwithin10years(44).Studieshaveshownthatilealaffection, complicateddisease,andyoungageatonset,amongotherfactors,predict surgicalresection(33,38,40,45,46).Moststudieshaveindicatedamodest increaseinthemortalityofpatientswithCD,mainlyduetomalignanciesinthe gastrointestinaltractandinthelungs(47,48).
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IBDisasystemicdiseasethataffectsorgansotherthanthegut(49,50),suchas joints (51, 52), skin, eyes (53) and the hepatobiliary system (54). These conditions presumably share an immunological pathogenesis with the coexistingIBD.SomeEIMsaresecondarytotheboweldiseaseandcausedby metabolicprocesses,malnutritionanddrugǦrelatedsideeffects.Theseinclude metabolicbonediseaseandvariousurogenital,pulmonaryandcardiovascular manifestations(55).TheEIMsofIBDhavereportedprevalenceratesthatvary from6%to38%indifferentstudies(56,57).Thereportedaccumulated prevalenceofEIMsinNorwayis16.9%(58).
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PSCisachronicinflammationoftheintraǦandextraǦhepaticbileductscausing biliarystricturesandrecurrentcholangitisthatcanultimatelyleadtoendǦstage liverdiseaseandcancer(Figure2).
Figure2.IllustrationofbileductpathologyinPSC.Chronicinflammationand fibrosisleadtomultifocalbiliarystricturesanddilatationsbothinsideandoutsideof theliver.Reprintedwithpermission©KariC.Toverud,CMI.
PSCmostlyaffectsyoungmaleadults(59,60),andupto80%ofPSCpatients inNorthernEuropehaveconcomitantIBD(61).PSChasoftenbeenconsidered anEIMofIBD,butthecausativerelationshipbetweenthesediseasesisstill uncertain.PSCǦIBDisadistinctphenotypethatisgenerallycolonic,witha rightǦsidedpredominance, highfrequency of“backwash” ileitis,and rectal sparing(62).Genetically,thereisalsosubstantialevidencesuggestingthatPSC isaconditionseparatefromoronlypartlyoverlappingwithIBD(63).The reportedprevalenceofPSCinIBDrangesfrom0.8%to7.5%inpatientswith UCandfrom0to6.4%inpatientswithCD,withthehighestprevalences reportedbynonǦpopulationǦbasedstudies(Table2).Thesediscrepanciesmay beduetodifferentpatientpopulationsandothermethodologicaldifferences;
thus,thetrueprevalenceofPSCinIBDremainsunclear.
Table2.SummaryofstudiesreportingprevalenceofPSCinIBD.
Reference Region Studyperiod No.ofpatients No.(%)ofPSC patients Populationbasedstudies
MonsenU.(Ͷʹ) Sweden ͱ͵͵Ǧͷ ͱͲͷʹUC ͱͳ(ͱ)
OlssonR.(Ͷ͵) Sweden ͱ ͱ͵ͰͰUC ͵͵(ͳ.ͷ)
AitolaP.(ͶͶ) Finland ͱʹ ͵ͳʹUC ͱͱ(Ͳ)
BroomeU.(Ͷͷ) Sweden ͱ͵͵Ǧͷ ͱͲͷʹUC Ͳ(Ͳ.ͳ)
BernsteinC.N.(͵Ͷ) Canada ͱʹǦͶ ʹʹ͵ʹIBD ͰUC(Ͳ)
ͱCD(Ͱ.ʹ)
MendesF.D.(Ͷ) US ͲͰͰͰǦͰͱ ͵ʹʹIBD Ͳ͵(ʹ.Ͷ)
IseneR.(͵) EU+Israel ͱͱǦͲͰͰʹ ͱͱʹ͵IBD (Ͱ.)
RönnblomA.(Ͷ) Sweden ͲͰͰ͵ǦͰ ͵ͲͶUC
ͲͶʹCD
(ͱ.ͷ)
(ͳ) FragaM.(ͷͰ) Switzerland ͲͰͰͶǦͲͰͱͳ ͱͱUC
ͱ͵͵ͶCD
ʹ(ʹ.Ͱ)
(Ͱ.Ͷ) NonǦpopulationbasedstudies
LupinettiM.(ͷͱ) US ͱͶͶǦͷͷ ͲͰͲIBD Ͳ(ͱ.Ͱ)
SchrumpfE.(ͷͲ) Norway ͱͷʹǦͷ ͳͳͶUC ͱʹ(ʹ.Ͳ)/Ͳ͵(ͷ.͵)*
ShepherdHA.(ͷͳ) UK NR ͶͱUC ͱͷ(Ͳ.͵)
TobiasR.(ͷʹ) South Africa
ͱͷ͵Ǧͱ Ͳ͵ͰUC ͱͶʹCD
(ͳ.Ͳ) Ͳ(ͱ.Ͳ)
McGarityB.(ͷ͵) UK ͱͶǦͷ ͱͲ͵CD (Ͷ.ʹ)
WewerV.(ͷͶ) Denmark NR ͳͶUC
ͱͲ͵CD
ͳ(Ͱ.) Ͱ
HashimotoE.(ͷͷ) Japan ͱʹǦͰ ͱͶͳUC ͵(ͳ.ͱ)
RasmussenH.H.
(ͷ)
Denmark ͱͷͶǦͷ ͳͰ͵UC ͱͱ(ͳ.Ͷ)
VelosoF.T.(ͷ) Portugal ͱͷ͵Ǧʹ ʹʹUC
ͳʹͳCD
(Ͳ) Ͳ(Ͱ.ͷ) RasmussenH.H.
(Ͱ)
Denmark ͱͷͶǦͱ ͲͶͲCD (ͳ.ʹ)
ParlakE.(ͱ) Turkey ͱͳǦͲͰͰͰ ͳͶUC
ͱͱͰCD
(Ͳ.ʹ) ʹ(ͳ.Ͷ) LakatosL.(Ͳ) Hungary NR,Ͳ͵y
followǦup
ͶͱUC Ͳ͵ʹCD
ͱͰ(ͱ.Ͷ) Ͳ(Ͱ.)
YeB.D.(ͳ) Korea ͱͷͷǦͲͰͰ ͱʹUC Ͳͱ(ͱ.ͱ)
RobertsH.(ʹ) Kentucky, US
ͱͶǦͲͰͱͳ ͲͶUC ʹCD
(ͳ) ͷ(ͱ.ʹ)
*laterfollowǦup(͵)
ThediagnosisofPSCcanbeachallenge.Somepatientshaveclinicaland biochemicalsignsofcholestasis,butthismayfluctuateovertime(86,87).The diagnosisofPSCisbasedonfindingscompatiblewithsclerosingcholangitis and the exclusion of secondary causes, such as cholelithiasis, cholangiocarcinoma,iatrogenicbileductstricturesandcirrhosiscausedby otherliverdiseases.Magneticresonancecholangiography(MRC)iscurrently the primary modality for diagnosing PSC (88). Endoscopic retrograde cholangiography(ERCP)issometimesperformedwhenthereareuncertain MRCfindingsorfortherapeuticpurposes.Therearenohistologicalfeatures pathognomonicforPSC,andliverbiopsyisusuallyonlyperformedwhenthere isdoubtaboutthediagnosisorsuspicionofanoverlappingconditionwith autoimmunehepatitis.Somepatientshavehepatichistologycompatiblewitha diagnosisofPSCbutnormalcholangiographyresults.Thisconditionhasa slightlybetterlongǦtermoutcome(89,90),anditistermedsmallǦductPSC(91, 92).
PSChasavariablediseasecoursethatgenerallyprogressestoliverfailureafter amedianof12to21years(93,94).Currently,therearenoestablishedmedical treatments,andlivertransplantationistheonlypotentiallycurativetherapy.
PSCistheleadingindicationforlivertransplantationinNorway,accountingfor 18%ofallfirstlivertransplantationsperformedfrom 2004to2013(95).
Additionally,patientswithPSChaveanincreasedriskofcholangiocarcinoma, hepatocellularcarcinoma,andgallbladdercancer(96Ǧ99),aswellasCRCin patientswithcolitis(19,100).
ϭ͘ϯƐƐĞƐƐŵĞŶƚŽĨĚŝƐĞĂƐĞĂĐƚŝǀŝƚLJŝŶ/
IBDisaheterogeneousdiseaseentitythatvariesinextension,severityand activityovertimeinthesamepatientaswellasamongpatients.Thereisno singlegoldstandardforthediagnosisofIBD.Thediagnosisisbasedonclinical presentation, laboratory tests, endoscopy findings with histopathological
evaluationandradiologicalimaging(101,102).However,discrepanciesbetween clinicalsymptomsandinflammatorylesionshavebeenreported,moresoinCD thanUC(103,104).Althoughileocolonoscopyisconsideredthegoldstandard forassessingdiseaseactivityinpatientswithIBD,theprocedureisinvasiveand associated with patient discomfort and the risk of bowel perforation.
Furthermore,themethodevaluatesthesuperficialmucosaonly,itcanbe incomplete(105),anditdoesnotassessthewholesmallbowel.Still,thesmall bowelmucosacanbeassessedbycapsuleendoscopy.Thetechniquehasbeen improvinginrecent yearswith highsensitivity fordetectingsmallbowel inflammationthatiscomparabletothatofMRE(106,107).However,itisa logisticallydemandingandinvasiveprocedurewhoseuseislimitedbylow specificity(108)andpotentialcapsuleretention(109).
Themost commonlyusedbiomarkersfor evaluatinginflammation areCǦ reactiveprotein(CRP)andfecalcalprotectin.CRPisanacuteǦphaseprotein thatincreasesrapidlyinresponsetosystemicinflammation.Calprotectinisa cytosolicproteinfoundintheinflammatorycellsofthegut.Itisreleased duringinflammationandreflectsthelevelofinflammatoryactivityinthe intestinalmucosa(110).Fecalcalprotectinscreeninginpatientswithsuspected IBDhasshownhighsensitivityandspecificityrates(111,112).BothCRPandfecal calprotectincorrelate toendoscopicactivityand mucosal healing (113Ǧ115).
Unfortunately, these markers can be influenced by other inflammatory activities,geneticfactorsandnutritionalstatus.CRPlevelscanbelowin patientswithactivedisease(116,117),andpatientswithCDhavehigherCRP levels than patients with UC (118). Additionally, fecal calprotectin levels correlatebetterwithcolonicdiseasethanilealdisease(119).
The comprehensive diagnostics and disease monitoring methods are supplementedbyradiologicalimaging.Thechoiceofimagingmodalityisbased
onpatients’symptomsandpresentation,butitusuallyencompassestransǦ abdominalultrasound(US),computedtomography(CT)orMRI.
Thedemandsforquantifyingdiseaseactivityinrecentyears,especiallyin clinicaltrials,haveledtoanintroductionofclinicalindices.Thereareavariety of clinical scores, which can be symptomǦbased, patientǦreported or endoscopic.Thepurposeofthesescoresistoimprovetheobjectivityofclinical assessments,facilitatethefollowǦupexaminationsandevaluatethetreatment response.ThemostcommonlyusedindicesaresummarizedinTable3.Still, therearenovalidateddefinitionsofoveralldiseaseseverity.Additionally,we have limitedability topredictdiseasecourse and treatment responsefor individualpatients.
ϭ͘ϰƌŽƐƐͲƐĞĐƚŝŽŶĂůŝŵĂŐŝŶŐ
Thefieldofgastrointestinalradiologyhasadvancedandexpandedconsiderably duringthelastfourdecades,fromsinglebariumradiographystudiestofast imagingMRIsequencesofthebowel.CrossǦsectionalimagingtechniquesoffer an accurate and reliable overview of the intestinal, extramural and extraintestinalsignsofthedisease.CTisrapidandavailable,makingita preferredmodalityinacuteclinicalsettings.Sensitivityandspecificityratesof approximately90%havebeenreportedforCTenterography(120Ǧ123).The diagnosticaccuracyofUSiscomparabletothatofCTandMRE(124),butitis highlyoperatorǦdependentandsensitivetodisturbancesduetobowelgasora largebodyhabitus.However,itcanplayaroleinthefollowǦupexaminationof knownlesions(125,126)andininterventionalprocedures(127).SincethemidǦ 1990s,MRIhasgraduallybecomethepreferredmodalityforimagingthesmall bowel.Itexhibitsexcellentimagecontrastcombinedwithdynamicsequences, multiplanarpossibilitiesandalackofionizingradiation.MRIexaminations usedinthisthesiswillbediscussedinmoredetailbelow.
Table3.SymptombasedandendoscopicscoringsystemsinUCandCDforassessmentofdiseaseactivity.
Symptom baseddisease activityscores
UlcerativecolitisCrohn´sDisease ScoreDescriptionThresholdsScoreDescriptionThresholds SCCAI(128)Stoolfrequency, urgency,bloodin stool,generalhealth andother manifestations.
ϐ2(129)or <2.5(130)=remissionCDAI(131)Clinicalandlaboratoryvariables: stoolfrequency,pain,general wellǦbeing,medicationuseand complicationsinthepastweek, adjustedwithaweightingfactor.
<150=remission 150Ǧ450=mild/moderate >450=severedisease(132) Partial MayoScore (133)
Stoolfrequency, rectalbleeding, physicians’global assessment.
<2=remission 3Ǧ8=mild/moderate disease 9Ǧ12=severedisease (134) HBI(135)GeneralwellǦbeing,abdominalpain andstoolfrequencypreviousday. ComplicationsandEIMs.
<8=mild 8Ǧ16=mild/moderate >16=severe(1) Endoscopy scores
Rutgeerts Score(136)AssessespostǦsurgicalrecurrenceatileocolicanastomosislevel. <5aphtouslesions=remission,>5confinedaphtouslesions=substantialrecurrence,diffuseaphtousileitisandulcerations= advancedrecurrence. Mayo Endoscopic subscore (134) Assessesvascular pattern,bleedingand ulcers.
0=normal 1=mildactivity (erythema) 2=moderateactivity (markederythema, erosions) 3=severeactivity (bleeding,large ulcerations)(134).
CDEIS(137)Typeandextentofulcerationand stenosisinupto5preǦdefinedcolon segments.
<3=remission 3Ǧ12=mild/moderate ϑ12=severe(138) SESǦCD (139)SimplifiedCDEIS.Extentof ulcerationandthepresenceof stenosis.
ϐ2=remission 3Ǧ15=mild/moderate ϑ15=severe(140) Abbreviations: SCCAIǦSimpleClinicalColitisActivityIndex CDAIǦCrohn'sDiseaseActivityIndex HBI–HarveyǦBradshawIndex CDEISǦCrohn'sDiseaseEndoscopicIndexofSeverity SESǦCDǦSimpleEndoscopicScoreforCrohnDisease
ϭ͘ϰ͘ϭDZ
ThefirstreportofMRIofthesmallbowelcameinthemidǦnineties(141).Since then,severalsystematicreviewshaveshownhighdiagnosticaccuracyand reliabilityforthedetectionofsmallbowelpathologies(124,142,143).MetaǦ analyseshavereportedpooledsensitivitiesandspecificitiesrangingfrom88–93
%and88–90%,respectively(124,144).TheinterǦreaderagreementisalsogood (145Ǧ147).StudieshaveshownthatMREfindingscorrelatewellwithendoscopic and histological findings and surgical specimens (123, 145, 148Ǧ153).
Additionally, MRE can provide valuable information on colonic disease.
Sensitivityandspecificityratesrangingfrom78%to100%and46%to100%
havebeenreportedbyaperǦpatientanalysis(127).However,mildcolonic diseaseiseasilyoverlooked(154),althoughdiagnosticaccuracyinthecoloncan beimprovedwithbowelpreparationandadequateluminaldistention(155).
SeveralMREparametershavebeenconnectedwithbowelinflammationand damage.Studieshaveshownthatbowelwallthicknessisoneofthemost sensitiveindicatorsofbowelinflammation(5,156).AT2Ǧweightedsequenceis usuallyincludedintheMREprotocoltovisualizebowelwalledema,another goodmarkerofbowelinflammation(142,157).T2hyperintensityandmucosal lesionsarethemostspecificsignsofinflammationonMRE,withspecificity estimatessurpassing90%atthepatientlevel(7).Finally,increasedsignal intensityofthebowelwallonpostǦcontrastT1sequencesisasensitivesignof bowelinflammation(158,159)andfibrosis(6).Additionally,thepatternof contrastenhancementcanprovidevaluableinformation.Threepatternshave beendescribed: homogeneous enhancement of the entirethicknessofthe bowel;stratifiedenhancementofthemucosaandmuscularis/serosa,butnotthe submucosa;andmucosalenhancementwithsuperficialmucosalenhancement only.Layeredpatternshavebeencorrelatedwithseverediseaseactivity,while
mucosalandhomogeneousenhancementpatternsareconsidereddecreasingly lesssevereinthatorder(5,6,149,160).AmetaǦanalysisfrom2015concluded thatthemostconsistentlyaccuratesignsofdamagewereabscessandfistula (7).
However,isolatedfindingsareprobablytooinaccurateforassessingdisease activity,andcombiningthemmayimprovetheaccuracyofMRE.Therehave beenseveralattemptstocreateacompositeMREǦbasedscoringsystemfor diseaseassessmentinrecentyears(Table4).Thepurposeistocreateagood surrogatemarkerofthediseaseactivityinCD.Themostappliedscoresbased onconventionalMREtechniquesarethemagneticresonanceindexofactivity (MaRIA)score(161)andthemagneticresonanceenterographyglobalscore (MEGS). The MEGS combines seven imaging variables in addition to extramuralfindingsintoaglobalinflammatoryscore.TheMaRIAscoreisalsoa multiǦitem measure of mural inflammation based on an extensive MRE protocolwithbowelcleansingandarectalenema.Bothscoreshaveshown goodcorrelationtoendoscopicandbiologicalinflammationmarkers(162Ǧ164).
Althoughinflammationisacrucialelementthatneedstobeassessedand controlled,theresultingstructuralboweldamageisequallyimportant.CDis usuallyintermittent,andimmediatemeasuresofactivityfailtoassessthe overallimpactofthedisease.TheLémannindex(LI)wasdevelopedtoassess boweldamageinCDbyincorporatingresectivesurgeryburdenandendoscopic and imaging findings from all segments of the digestive tract into one compositescore(165).Thegoalistoassessthebroadereffectsofthediseaseon thepatientinasystemizedmanner.
Table4.MRIbasedscoresofCrohn´sdiseaseactivity.
Type Score Description Thresholds
Protocol Segments Imagingvariables Reference exams
Conventional
MARIA (161)
Bowel cleansing.
Oralandrectal preparation.
Contrastdelay:
1,2,5,7min.
Distalileum, ascending, transverse, descending, sigmoidcolon, andrectum.
Wallthickness, relativecontrast enhancement (RCE),edema, ulceration.
CDEIS, HBI,CRP.
ϑ7=active disease
Formula:1.5xwallthickness(mm)+0.02xRCE+5xedema+10xulceration MEGS
(162,166)
Nobowel cleansing.
Oral
preparation.
Contrastdelay:
70s.
Jejunum,ileum, terminalileum, caecum, ascending transverse, descending, sigmoidcolon andrectum.
Extraintestinal structures.
Wallthickness, muraland perimuraledema, contrast
enhancementand pattern,haustral loss,extramural features.
Surgical resection specimens, endoscopic biopsy, calprotectin ,CRP,HBI.
Smallbowel:
ϑ10=
moderate inflammation
Largebowel:
ϑ12=
moderate inflammation
Formula:Totalscore=(ȳ(Segmentalscorexlengthscore))+extraintestinalscore
DWI based
Nancy score(155)
Nobowel cleansingor oral/rectal preparation.
Contrastdelay:
25sek,70sek, 2,3,5min.
Diffusion:
b=600s/mm2
Ileum,right, transverse,left colon,sigmoid, rectum.
DWI
hyperintensity, GADO, differentiation betweenbowel layers,bowelwall thickening, edema, ulceration.
Endoscopy (SESǦCD) andCDAI.
UC:
>1=
inflammation Totalscore<7
=mucosal healing(167)
CD:>2=
inflammation Formula:
Totalscore=ȳSegmentalscores(1pointperpositiveimagingvariablepersegment) Clermont
score (168)
Nobowel cleansing.
Oral
preparation.
Nocontrast.
Diffusion:
b=800s/mm2
Jejunum, proximalileum, distalileum, right,
transverse,left, sigmoidcolon, rectum.
Bowelthickness, ADC,edema, ulcers.
MARIA scorebased.
Ilealscore
>8.4:active disease Ilealscore
>12.5:severe disease(169)
Formula:1.646xbowelthicknessǦ1.321xADC+5.613xedema+8.306xulcers+5.039 Abbreviations:
DWI–DiffusionWeightedImaging
GADO–Gadoliniumenhancementafterintravenouscontrastmediumadministration ADC–ApparentDiffusionCoefficient
ϭ͘ϰ͘ϮDZ
MRCisthefirstǦchoicemodalityintheinitialdiagnosisofPSC(88,170).Ithas replacedERCPbecauseitisanoninvasive,comparablyaccurate,andless expensivemethod(171).ERCPisaninvasivemethodassociatedwithserious complicationsandmostlyreservedforinterventionalprocedures.CurrentMRC techniques are based on heavily T2Ǧweighted fast spin echo (FSE) pulse sequences,whichproduceahighǦintensitysignalinfluidǦfilledstructures,such asbileductsandthegallbladder.TheT2Ǧweightedhyperintensityofbile outlinesthebiliarytreeagainstahypointensebackground,demonstratingthe biliarytreeoptimally.ThefirstMRCresults,obtainedinthebeginningofthe 1990s, were produced by twoǦdimensional (2D) acquisitions. 3D imaging techniquesprovidebetterimagequalitythan2Dsequences,andtheyare usually acquired in the coronal orientation (172). Maximum intensity projections(MIPs)canthenbeobtainedinanyplane,providinghighresolution inallthreespatialplanes.TheperformanceofMRC in detectingPSCis comparabletothatofconventionalcholangiography,withasensitivityof86%
andaspecificityof94%(171).MRCisusuallycomplementedwithotherMRI sequences that provide additional information on both PSC and its complications(173).
Radiographical features of PSC are mural irregularities, multiple short segmentalstrictures,biliarydilatation,aprunedǦtreeappearance,alternating strictures and bile duct dilatations orbeading (174). The developed MRI progressionriskscoreisbasedonthecombinationofpredictiveradiological features,suchasdilatationofintrahepaticbileducts,liverdysmorphyand portalhypertension(175).ThescoreisassociatedwithPSCprogression,butitis notpresentlyusedasaprognosticmarker.AnnualPSCsurveillanceisusually performedduetotheincreasedriskofcholangiocarcinoma(176Ǧ178),butthe scientificevidenceforthispracticeislacking.
Ϯ͘^ƚƵĚLJĂŝŵƐ
Ϯ͘ϭWƌŝŵĂƌLJĂŝŵ
TheprincipalaimofthisthesisistheMRIassessmentoflongǦtermIBDandits complicationsinaNorwegianpopulationǦbasedcohortofIBDpatients–the IBSEN(InflammatoryBowelDiseaseSouthǦEastNorway)study.
Ϯ͘Ϯ^ĞĐŽŶĚĂƌLJĂŝŵƐ
i. ToestimatethefrequencyanddistributionofMRClesionsindicating PSCinpatientswithIBD20yearsaftertheinitialdiagnosisandto identifyclinicalcharacteristicsassociatedwiththesefindings.
ii. ToinvestigatetheextentandbehavioroflongǦtermCDbyMRI.
iii. ToevaluatetheaccumulatedboweldamagebyMRIinpatientswith longǦtermCDandsearchforpredictorsofthelatter.
iv. ToassessbowelinflammationbyMRIinpatientswithCDandrelatethe radiologicalfindingstoclinicaldata.
ϯ͘WĂƚŝĞŶƚƐĂŶĚŵĞƚŚŽĚƐ
ϯ͘ϭ^ƚƵĚLJĚĞƐŝŐŶ
AllpatientsinthisthesiscamefromtheIBSENstudy.TheIBSENstudyisa prospective,populationǦbasedinceptionstudyinitiatedintheearlynineties.
FromJanuary1990toDecember1993,allnewlydiagnosedIBDpatientsfrom fourSoutheasternNorwegiancounties(Oslo,Østfold,TelemarkandAustǦ Agder)wererecruitedbylocalphysicians(179).Patientswerediagnosedwith IBDaccordingtotheLennardǦJonescriteria(180).Thestudyincluded519 patientswithUCand237patientswithCDinacatchmentareaofnearly1 millionpeople.TheincludedpatientswereofferedprescheduledfollowǦup examinationsat1,5, 10 and20years, whichconsistedofastandardized interview, clinical examination, colonoscopy and blood tests. Additional procedureswereperformedifclinicallyindicated.Atthe10ǦyearfollowǦup,the finaldiagnosiswasmade,andthepatientswithCDwerecategorizedaccording totheViennaclassification(Table1).
The20ǦyearfollowǦupexaminationwasperformedbetweenFebruary2011and October2014.AllpatientswereofferedMRC,andpatientswithCDwere offeredMRE.Thedatawererecordedonpaperandsubsequentlyenteredintoa centraldatabase.Tenpercentofalltherecordswerechecked;theproportionof incorrectdatawasacceptable(<0.5%).
ϯ͘Ϯ^ƚƵĚLJƉŽƉƵůĂƚŝŽŶ
Threedifferentpatientcohortswerestudied,aspresentedinthethreepapers thatconstitutethisthesis(Table5).Allpatientswereprospectivelyincluded fromtheIBSENcohort.Theexclusioncriteriaincludedpregnancy,thepresence
of foreign bodies that were incompatible with a magnetic field, severe claustrophobiaandpatientnoncompliance.
Table5.Overviewofthepapers.
ϯ͘Ϯ͘ϭWĂƉĞƌ/
AllpatientsfromtheIBSENstudy,withaconfirmeddiagnosisofIBD,were invitedtoanMRCscreeningforPSCatthe20ǦyearfollowǦupvisit.Of470 patientswhoattendedthe20ǦyearfollowǦupvisit,327(69.6%)completedthe study(Figure3).Fourpatientswereexcludedduetothepresenceofforeign bodies(n=2),pregnancy(n=1)ornoncompliance(n=1),and5MRCresultswere discardedduetopoorimagequality.Additionally,earlierMRCresultswere collectedretrospectively(n=3)forpatientswithknownPSCinwhomanMRC hadnotbeenperformedaspartofthestudy.
PaperI PaperII PaperIII
No.ofpatients 322 96 95
Population IBD CD CD
Mainimagingmode MRC MRE MRE
Studyobjectives ScreeningforPSC Accumulatedbowel
damage Bowelinflammation
Figure3.FlowchartofpatientsinPaperI.
ϯ͘Ϯ͘ϮWĂƉĞƌ//
AlleligiblepatientsfromtheIBSENcohort,withaconfirmeddiagnosisofCD, wereinvitedtoundergoMREatthetimeofthe20ǦyearfollowǦupvisit.Of156 patients who completed the 20Ǧyear followǦup visit, MRE was performed successfullyin96patients(Figure4).Alsoupperendoscopyresultsperformed aspartoftheclinicalfollowǦupwerecollectedfromlocalhospitals(n=1).
Figure4.FlowchartofpatientsinPaperII.
ϯ͘Ϯ͘ϯWĂƉĞƌ///
Thestudypopulationinthethirdpaperwassimilartotheoneinthesecond paper.Outof96patientswhosuccessfullyunderwentMRE,onepatienthadan examinationthatlackedcontrastǦenhancedimages.Forthatreason,thepatient wasexcluded,andthefinalstudypopulationincluded95patients.
ϯ͘ϯƐƐĞƐƐŵĞŶƚŽĨĐůŝŶŝĐĂůĚŝƐĞĂƐĞĂĐƚŝǀŝƚLJ
Basic demographic data, blood tests, medication use, endoscopic and histologicalfindingsandsurgicalinterventionswererecordedatallfollowǦup timepoints.Clinicalcoursewasassessedusingvisualcurves,eachreflectinga differentpredefineddiseasepattern(Appendix1)(33).Medicationusewas recordedretrospectivelyateachprescheduledvisit.Theendoscopicevaluation didnotfollowanyscoringsystem,andtheendoscopistsrecordedthepresence andtheextentofmucosalinflammationandulceration.Surgerywasdefinedas anyresective,intraǦabdominalprocedureforactiveCDduringthefollowǦup period.Theresultsoftheserologicalanalysisforthepresenceofperinuclear antiǦneutrophil cytoplasmic antibodies (pANCAs) and anti–Saccharomyces cerevisiaeantibodies(ASCAs)performedatthe10ǦyearfollowǦupvisitwere availableforanalysis.
Additionaldatawerecollectedatthe20ǦyearfollowǦupvisit.TheHarveyǦ Bradshaw Index (HBI) was calculated, and values ϑ8 were consideredto represent moderate/severe disease (1). Fecal samples were collected and investigated for calprotectin by ELISA (Bühlmann fCALTM, Bühlmann Laboratories AG,Schönenbuch, Switzerland). Anoverview of all recorded variablesthatwereusedinthisthesisispresentedinAppendix2.
