CommonErrorsintheTreatmentofIBD:CaseStudiesGaryR.Lichtenstein,MDDavidT.Rubin,MDGaryLichtenstein,MD

Disclosures

AbbottAlavenBristol-MyersSquibbElanFerringHospiraMedaLuitpold/AmericanRegentMillenium

OnoPfizerPrometheusSalixSantarusSchering-PloughShireTakedaUCBWarnerChilcottResearch,Advisory,and/orHonorariumSomeCommonErrorsinIBDManagementDelayindiagnosis!Thisisnotusuallyagastroenterologist’serror.SteroidsasinitialtherapyformildtomoderateUC-trusttheevidence!Usinganti-TNFtherapyasmonotherapy-concomitantisfavoredformostpatientsatleastforinduction.Avoidingsurgerywhenitisneeded.Underdosingtherapies:5-ASA–focusondeliveryThiopurines–understandmetabolismandshuntersTNF–insomepatients(maybelessthanwewouldliketothink)NotvaccinatingIgnoringvitaminDRelyingon“crisismanagement”ratherthanproactivemonitoringandcontrolDismissingpatientinterestsindietorcomplementarytherapiesratherthanworkingwiththemNotreferringtomentalhealthprofessionalsWhyDoPatientsWithIBDNotRespondToTheirMedications?PrimaryNonresponseDrug/mechanismjustdoesn’tworkWrongdiagnosisInfectionIschemiaCrohn’sdiseaseWrongdoseNotenoughToomuch?pKissuesWrongdeliveryRationaleAllergy/intoleranceSecondaryNonresponseChangeindose(byyou)ChangeindeliveryChangeinphysiologyDoesdiseasechange

overtime?IntentionalnonadherenceEpisodicdosingstrategyDenialFearoftherapyUnintentionalnonadherenceCan’taffordmedicationInconvenientdosingregimenPatientCase1DiagnosticEvaluationFemale,age23yr;

welluntil5moagoSymptomsPainDiarrhea(4–6loosestools/day)5-lbweightlossPhysicalexaminationTenderRLQNomassSocialHistoryCigs:1ppdx5yrsLaboratoryvaluesWBC:4,500cells/μLHgb:10.5g/dLCRP:5.5mg/dLAlbumin:3.5g/dLColonoscopyTerminalileumandcecumwithnumerousaphthousulcerationsBiopsiesc/wCrohn’sSBFTMildbowel-wallthickeningwithslightnarrowinginterminalileumonlyCRP=C-reactiveprotein;RLQ=rightlowerquadrant.InitialTreatmentDiagnosisMild-to-moderateileocecalCDTreatmentgoalsInducerapid,completeremissionMinimizethepotentialforsideeffectsTreatmentprescribedMesalamine1.2gTIDResponseNoclinicalimprovementafter3weeksMesalamineisnotFDAapprovedforthetreatmentofCrohn’sdiseaseintheUnitedStates.

Whatisthemostappropriatetreatmentoptioninthispatient?ContinuemesalamineatahigherdoseChangetoanother5-ASAderivativeAddasystemiccorticosteroid–prednisone40mgorallydailySwitchtoECbudesonideat9mgadayInductionNonresponderTreatmentOptionsforMild-ModerateCrohn’sDiseaseStep-UpaccordingtoseverityatpresentationorfailureatpriorstepAminosalicylateBudesonide

CorticosteroidAnti-TNFDiseaseSeverityatPresentationSevereModerateMildNatalizumabThiopurine/MTXAminosalicylateBudesonide/ThiopurineAnti-TNF+/-Thiopurine/MTX

InductionMaintenanceSequentialTherapiesforCrohn’sDiseaseMildModerateSevereAminosalicylatesTNFantagonists(IFX,ADA,CZP)ParentalCorticosteroidsAntibioticsOralCorticosteroids

BowelRestNatalizumabLocallyActiveOralCorticosteroidsAntimetabolites(AZA,6-MP,MTX)SurgeryConventionalCDTherapyisSequentialTreatmentofIBDI.EstablishtheCorrectDiagnosis,SeverityofDisease&ExtentofDisease UlcerativeColitisversusCrohn’sDisease DiseaseDistribution SeverityofDiseaseACGGuidelines

DeterminingSeverityofCrohn’sDiseaseLichtensteinGR,HanauerSB,SandbornWJ.AmJGastroenterol.2009;104(2):465-83.MildtoModerateAmbulatorywithouttoxicity,no

abdominaltenderness,painfulmass,orobstructionModeratetoSevereUnresponsivetotreatmentformild-to-moderatestageorwithprominentfever,weightloss,anemia,abdominalpainandtenderness,orintermittentnauseaorvomitingSeveretoFulminantPersistentsymptomsoncorticosteroidsorwithhighfever,reboundtenderness,cachexia,orabscessRemissionAsymptomatic,noinflammatorysequelae,responsivetomedicationorsurgery,ornotrequiringsystemiccorticosteroidsMesalamineDeliverySystemsMesalamineControlled-releaseCapsules(Pentasa)5-ASA5-ASAN=N5-ASANNN=NSulfasalazine(Azulfidine)NHSO2SulfapyridineCOOHCHOlsalazine(Dipentum)5-ASA5-ASABalsalazideDisodiumCapsules(Colazal)(ABA)inertcarrierNaOOCOHEthylcelluloseMicrospheresEudragitS/L5-ASAMMXtechnologyMesalamineGastro-resistant/pH(Lialda)MesalamineDelayed-releaseCapsules

(Asacol)MesalamineGranulatedformulation

(Apriso)MesalamineRectalsuspension

enema/suppository(Rowasa,Canasa)5-ASA5-ASANCCDS:ResponsetoTherapyfor

ActiveCrohn’sDiseaseNCCDS,NationalCooperativeCrohn’sDiseaseStudy.SummersRWetal.Gastroenterology1979;77:847-869Patients

(%)WeeksafterRandomization051015Sulfasalazine1g/15kg(5g)Placebo60504030201007013%Meta-Analysis:Mesalamine

inActiveCrohn’sDiseaseP=0.005P=0.7P=0.5P=0.04Hanauer,Stromberg.ClinicalGastroenterology&Hepatology2004P=0.005P=0.7P=0.05P=0.04-80-70-60-50-40-30-20-100Crohn'sIn=155Crohn’sIIn=150Crohn'sIIIn=310Overalln=615ChangefrombaselineinCDAIscorePentasa?4gPlacebo-60-50-40-30-20-100Crohn'sIn=155Crohn'sIIn=150Crohn'sIIIn=310Overalln=615Pentasa?4gminusPlaceboRoleofAntibioticsinCrohn’sDiseaseWidespreadusedespiteinsufficientevidenceInadequatedataformetronidazoleandciprofloxacinasfirst-linetherapyMaybeusefulinthemanagementofComplicationsPerianaldiseaseSmallIntestinalBacterialOvergrowthPostoperativeprophylaxisLittle,ifany,effectonsmallboweldiseasePotentialforresistanceandselectiveovergrowthandClostridiumDifficileinfectionSteroid

Dependent28%(n=21)Prolonged

Response32%(n=24)Surgery38%(n=28)CorticosteroidTherapyfor

Crohn’sDiseaseImmediateOutcome*(n=74)1-YearOutcome(n=74)CompleteRemission58%(n=43)PartialRemission26%(n=19)NoResponse16%(n=12)*30daysafterinitiatingcorticosteroidtherapy.FaubionW,etal.Gastroenterology.

2001;121:225-260.BudesonideinActiveIleal/

RightColonicCrohn’sDisease0102030405060708053%66%51%20%62%36%10Weeks116Weeks38Weeks2PatientsinRemission(%)CIR=controlledilealrelease.*Mesalaminecontrolled-releasecapsules(Pentasa).1.RutgeertsP,etal.NEnglJMed.1994;331:842-845.2.GreenbergGR,etal.NEnglJMed.1994;331:836-841.3.ThomsenOO,etal.NEnglJMed.1998;339:370-374.PlaceboPrednisolone40mgMesalamine*4gBudesonideCIR9mgCorticosteroidsinCrohn’sdisease Budesonideisfirst-linetherapyformild-moderateilealorrightcolondiseaseMaintenancetherapy?Systemicsteroidsformoderate-severediseaseHighriskofsteroid-dependenceGreatestriskoflong-termsideeffectsAGAQualityguidanceAttemptsteroidweaningMonitorforosteoporosis

ChangeofTherapyTreatmentECbudesonide9mgQDfor8weeksOutcomeRemissionattainedat5weeksHgb:11.2g/dLMildfacialacneECBudesonidesuccessfullytaperedtocompletecessationafter8weeksPlanWatchfulwaiting

FollowupFollowup2weeksaftercessationofECBudesonidesymptomaticrecurrenceisnoted6BM/daywithRLQabdominalpainPerianaldrainagefromasmallfistulawasnotedLabs:WBC-13.0x109/LHgb:8.7g/dLESR-45mm/hrCRP-22mg/L

RecommendationsWhichofthefollowingareappropriateatthistime1.)MRIenterography2.)CTenterography3.)StoolforCdiff4.)Askpatienttostopsmoking5.)1and46.)1,3and4RefractoryIBDEstablishtheCorrectDiagnosis,SeverityofDisease&ExtentofDiseaseEvaluateforDiseaseComplicationsEvaluateforEntericInfectionsUseOptimalMedicationDosesMiscellaneous NonAdherenceParadoxicalResponsesNSAIDsCigarettesDiseaseComplications

Abdominal/PelvicAbscessCTabdomenandpelviswithoralandivcontrastMRIpelviswithgadoliniumMesentericVenousThrombosisCTabdomenandpelviswithoralandivcontrastMRIpelviswithgadoliniumEntericInfectionsBacterialInfectionsCMVClostridiumDifficileParasiticDiseases“Pseudointractibility”ofIBDCMVClostridiumDifficileNSAIDsCigaretteCessationinUCUseinCDMRIEnterography:ActiveCrohn’sDiseaseT2andPost-gadimagesdemonstratingmarkedthickeningandenhancementofTI.NoteelevatedT2signalwithinandadjacenttoTI(arrows)indicatingactivedisease.

FollowupFollowupTherapywasinitiatedwithinfliximab5mg/kgat0,2,and6weekstheevery8weeksandalsoAZA2.5mg/kgwasgiven(TPMTenzymeactivitywasnormal).OralIronwasgiven(Ferritincheckedwas10ng/mL).Withinaperiodof3monthssymptomaticremissionwasnoted.Hgb-11.0gramsWBC-9.9g/dLESR-12mm/hrCRP-3.8mg/LCASE2:ThePatientFailingThiopurineTherapyTwoBrotherswithUlcerativeColitisPatient#1:18yowithpancolitis,steroidresponsivebutsteroiddependent.TPMTnormal6-MPstartedat1.5mg/kgUnabletoweansteroidsbelow15mgPatient#2:15yobrotherofpatient#1,ulcerativeproctitis,steroidresistantTPMTnormal6-MPstartedat1.5mg/kgNotrespondingMetabolismofAzathioprine

and6-MercaptopurineAzathioprine6-Methyl-

mercaptopurine6-MercaptopurineThioinosinic

acid6-Thioguainine

nucleotides6-Thiouric

acidTPMTHPRTXOChanGLetal.JClinPharmacol.1990;30:358.AssociationBetweenClinicalResponseand

Both6-TGNandIntermediateActivityTPMTGenotypeinPediatricPatientsWithIBDTherapeuticEfficacyFrequencyof6-TGlevel>235

(pmol/8×108RBC)(%)6-TGQuartilesFrequencyofresponse(pmol/8×108RBC)(%)41%78%DubinskyMCetal.Gastroenterology2000;118:705.0204060801000–173174–235236–367368–1,2036527020406080100ResponseFailuren=44n=42n=43n=44FrequencyofResponseFrequencyof6-TGlevelThePatientnotRespondingtoThiopurineConfirmadherence,considermetabolites:6-TG6-MMPPossiblecauseRecommendationundetectableundetectableNon-adherentorunderdosedUnderstandwhyptnottakingmedorincreasedoseDubinsky.CurrGastroenterolRep.2003;5(6):506-11.ThePatientnotRespondingtoThiopurineConfirmadherence,considermetabolites:6-TG6-MMPPossiblecauseRecommendationundetectableundetectableNon-adherentorunderdosedUnderstandwhyptnottakingmedorincreasedoseLow(<230)LoworundetectableNon-adherentorunderdosedDiscussadherence,increasedoseDubinsky.CurrGastroenterolRep.2003;5(6):506-11.ThePatientnotRespondingtoThiopurineConfirmadherence,considermetabolites:6-TG6-MMPPossiblecauseRecommendationundetectableundetectableNon-adherentorunderdosedUnderstandwhyptnottakingmedorincreasedoseLow(<230)LoworundetectableNon-adherentorunderdosedDiscussadherence,increasedoseLow(<230)High(>5700)6-MMPshunterIncreasethiopurine,orConsiderallopurinol,orSwitchagentsDubinsky.CurrGastroenterolRep.2003;5(6):506-11.ThePatientnotRespondingtoThiopurineConfirmadherence,considermetabolites:6-TG6-MMPPossiblecauseRecommendationundetectableundetectableNon-adherentorunderdosedUnderstandwhyptnottakingmedorincreasedoseLow(<230)LoworundetectableNon-adherentorunderdosedDiscussadherence,increasedoseLow(<230)High(>5700)6-MMPshunterIncreasethiopurine,orConsiderallopurinol,orSwitchagents“Therapeutic”(>230-<400)orHigh(>400)NormalrangeorhighPrimarynon-responderAssessdiseaseSwitchtodifferentmechanismDubinsky.CurrGastroenterolRep.2003;5(6):506-11.BrotherswithShunting6-MPmonotherapyPtTPMT6-TGN6-MMPALT123.013713,477114219.730112,796141ThePatientnotRespondingtoThiopurineConfirmadherence,considermetabolites:6-TG6-MMPPossiblecauseRecommendationundetectableundetectableNon-adherentorunderdosedUnderstandwhyptnottakingmedorincreasedoseLow(<230)LoworundetectableNon-adherentorunderdosedDiscussadherence,increasedoseLow(<230)High(>5700)6-MMPshunterIncreasethiopurine,orConsiderallopurinol,orSwitchagents“Therapeutic”(>230-<400)orHigh(>400)NormalrangeorhighPrimarynon-responderAssessdiseaseSwitchtodifferentmechanismDubinsky.CurrGastroenterolRep.2003;5(6):506-11.PracticalApproachtoAllopurinolandThiopurineCombinationTherapyNotforeveryone!Beawareofsafetyconcerns.Choosepatient(andMD)wisely:ActivediseaseAdherencewiththiopurinesSubtherapeutic6-TGn,supratherapeutic6-MMPElevatedLFTsornauseamaybepresentbutnotnecessarytoconsiderthisapproachDropthiopurineto25mg(6-MP)or50mg(AZA)Allopurinol100mgNotifypharmacist!CBCweeklyforonemonth,thenmonthly…Metabolitesatweek3DoseadjustmentifnecessarybutinsmallincrementsGovaniandHiggins.JCrohnsColitis2010;4(4):444-9.Sparrow,etal.JCrohnsColitis2009;3(3):162-7.BrotherswithShuntingBothpatientsrespondedquickly(within2-3weeks),havebeeninstablesteroid-freeremissionfor>2years.6-MPmonotherapy6-MP/allopurinolPtTPMT6-TGN6-MMPALT6-TGN6-MMPALT123.013713,477114422--21219.730112,796141351--2521yearoldmalewitha4yearhistoryofextensivesmallbowelCDtreatedwithinfliximabforthepast3yearspresentswithincreasingcrampingabdominalpain,12poundweightlossanddiarrheaNorecenttravelorantibioticsNopreviousabdominalsurgerySH:DoesnotsmokeFH:NoFHofIBDOninfliximab10mg/kgq6wkCase3PEshowsawellappearingmaleinNADwithfullnessintheRLQStoolsamplesforentericpathogensandC.diffnegativeMRE-5cmsegmentofsmallboweldiseasewithsmallboweldilationproximaltotheareaofinvolvementbutw/oinflammationIFXlevel(trough:9.0mcg/ml)ATInegativeLABS:

WBC–8.6K Hgb–12 Ptlt-334K CRP-3.3(Normal<4mg/dl)Case3PleasechoosethebestmanagementstrategyIncreaseinfliximabAddanantimetabolite(AZA/6MP/MTX)andcontinueinfliximabSwitchtoadalimumaborcertolizumabSwitchtonatalizumabContinueinfliximabbutevaluateforsmallbowelintestinalovergrowth,irritablebowelsyndromeandconsidersurgicaloptionsSendforileocecectomyCase3FactorsthatInfluencethePKofTNFAntagonistsImpactonTNFantagonistPKPresenceofADAsDecreasesdrugconcentration

Increasesclearance

WorseclinicaloutcomesConcomitantuseofimmunosuppressivesReducesADAformation

IncreasesdrugconcentrationDecreasesdrugclearance

BetterclinicaloutcomesLowserumalbuminconcentrationIncreasesdrugclearance

WorseclinicaloutcomeHighbaselineCRPconcentrationIncreasedrugclearanceHighbaselineTNFconcentrationMaydecreasedrugconcentrationbyincreasingclearanceHighbodysizeMayincreasedrugclearanceSexMaleshavehigherclearanceOrdasIet.al.ClinGastroenterolHepatol.2012;10:1079-1087.ClinicalOutcomesofPatientsWithDetectableHumanAnti-ChimericAntibodiesorSubtherapeuticIFXConcentrationsResponsetotestComplete/partialresponse(%)PvalueDetectableHACAIncreaseIFX1/6(17)<0.004Changeanti-TNF11/12(92)SubtherapeuticconcentrationsIncreaseIFX25/29(86)<0.016Changeanti-TNF2/6(33)AfifW,etal.AmJGastroenterol.2010;105:1133-1139.HACAandIFXconcentrationtestingimpactedtreatmentdecisionsin73%ofpatientsandwereausefuladjuncttoclinicalandendoscopic/radiologicassessmentAimExaminetheutilityofmeasuringHACAandIFXconcentrationsandcomparesubsequentclinicalmanagementandresponseTherapeuticinfliximabtroughlevel(7μg/mL)andshortsegmentoffixednon-inflammatorydiseaseSendtosurgeryandlaparoscopicileocecectomyperformedTreatedpostopwithmetronidazole500mgpobidfor3monthsaswellas6MPDoingwell10monthspostopwithcolonoscopydemonstrating2isolatedaphthouserosionsintheneoterminalileumFollowup:Case3P<0.001P<0.001P=nsVermeireetal.Gut2007;56;1226-1231“anIFXlevelof<4μg/mlmeasured4weeksafterthefirstinfusionhadaPPVof81%todetectthedevelopmentofhighATIsduringthelatercourseoftreatment”“anIFXlevelof>15μg/mlmeasured4weeksafterthefirstinfusionwas80%predictivefortheabsenceofATIsduringlaterfollow-up.”Week4serumlevelandsubsequentATItitre

“Therefore,IFXlevelsmeasuredearlyafterthefirstinfusionofIFX(at4weeks)areagoodprognosticparameterfordevelopmentofimmunogenicity.”DrugLevelsPredictImmunogenicity:

SerumIFXatWeek4AfteranInfusionPredictsEventualAppearanceofATI’sinEpisodicDosingPatientsWithSustainedATIAssociatedWithLORVandeCasteeleN,etal.AmJGastroenterol.2013.DOI:10.1038/ajg.2013.12.PatientswhodiscontinuedIFXtreatmentduetoLOR/hypersensitivity(%)P<0.001TimetoIFXDiscontinuationDuetoLORVandeCasteeleN,etal.AmJGastroenterol.2013.DOI:10.1038/ajg.2013.12.PatientswhodiscontinuedIFXtreatmentduetoLOR/hypersensitivity(%)Log-rankP=0.006TransientATI(n=12)SustainedATI(n=35)YearsofIFXfollow-upAAAFormationLowersAdalimumabTroughSerumLevels92%ofthepatientswithatroughserumconcentrationmeasuredbelowthethresholdfordetectionwerepositiveforAAAMedianADATR

(μg/mL)02681242.1(n=9)Week4106.1(n=58)0.6(n=8)8.9(n=53)Week120.1(n=8)Week248.8(n=37)0.02(n=3)11.1(n=46)Week540.05(n=10)5.8(n=30)Therapy

DiscontinuationAAA(+)AAA(-)ReprintedfromGastroenterology137(5),KarminisK,etal.Influenceoftroughserumlevelsandimmunogenicityonlong-termoutcomeofadalimumabtherapyinCrohn'sdisease,1628-1640.Copyright2009,withpermissiontheAGAInstitute.ProposedTreatmentAlgorithmintheSettingofLossofResponseOrdasIet.al.ClinGastroenterolHepatol.2012;10:1079-1087.HightitersLowtitersDe-escalationChangedrugclass

(nobenefitfromdoseescalation)DrugescalationSwitchwithinclassHigh

ClearanceDrugescalationorswitchImpact

ClearanceSwitchHigh

ClearanceDrugescalationorswitchImpact

ClearanceHightitersLowtitersSubtherapeuticTherapeuticSubtherapeutic&normalCRPNegative&ADAs(+)PositiveDrugADAsLORCanAntibodiestoBiologicTherapiesBeOvercome?5patientswithlossofresponsetoinfliximab,undetectableinfliximabtroughlevels,andpositiveantibodiestoinfliximabon2occasionsAntimetabolitetherapyaddedwithoutchangingdoseofinfliximabMethotrexate(2);Thiopurine(3)ATItiterdecreasedandtroughIFXlevelsroseover1-5monthsClinicalresponsereestablishedBen-HorinS.CGH2013;11:444-7ConclusionReactiveTherapeuticDrugMonitoringeffectiveforoptimizationofAntiTNFtherapyinNonRespondersMostdatastudiedwithInfliximab-butlikelyappliestootherantiTNFagentsAdalimumabCertolizumabPegolFutureprospectivetrialneededtodefineProactiveDrugmonitoringCASE424yearoldwomanwithnewlydiagnosedCrohn’sdiseaseofthecolon,ileumandperianalskintagswithasmallsimplefistulaAnemicElevatedCRPTreatedwithinfliximabandazathioprineExcellentresponseandclinicalremissionLaboratoryvaluesreturntonormalCASE4-continuedAfter6monthsofcontinuoustherapy,requeststostopazathioprine6weekslater,hasbloodperrectum,loosestoolsSteroidsstartedInfliximabgivenearlyathigherdoseNoimprovementCASE4-continuedWhathappenedhere?Colonoscopyperformed:completemucosalhealingSmallirritatedskintagwithfriabilityFistulanotdrainingCASE4–continued-oops4monthslaterDiarrhea,frankhematocheziaAnemicCRPelevatedagainC.diffnegativeTherapeuticassessmentInfliximablevelelevated(16ug/ml)NoantibodiestoinfliximabInterpretationofInfliximabLevelsandAntibodiestoInfliximabinaPatientLosingResponseInfliximabLevelAntibodiestoInfliximabTreatmentrecommendationElevatedAbsentSwitchtreatmentmechanismElevatedPresentUnclear,considerswitchingtoanotherTNF-inhibitorNotelevatedAbsentAdjustdose,intervalofinfliximabNotelevatedPresentSwitchtoanotherTNF-inhibitorAfif,etal.AmJGastroenterol.2010;105(5):1133-9.Whoisatriskforanti-drugantibodies?ThepatientreceivingepisodictherapyIntentionalUnintentional:breakintherapyduetocoverageissuesorcomplication“Pseudo-episodictherapy”Sub-therapeuticserumdruglevels1ThepatientwithdrugclearancebetweendosesThepatientwhodevelopedanti-drugantibodiespreviously1VermeireSetal.Gut.2007;56(9);1226.SwitchingtoAnotherBiologicTherapy

Whattochooseandwhentochooseit?Evidenceonlyexistsinonedirection(infliximabfirst),assumptionistheoppositeistruePrimarynon-responder:anti-TNFαloadingdosewithnoresponse:Whereisthedruggoing?tryadifferentmechanism(notadifferentanti-TNFαtherapy!)PrimaryrespondernowrelapsingAssessforinflammationIfsuspectimmunogenicity,switchingtosecondanti-TNFisreasonable1-3Ifnotimmunogenicity,consideradifferentmechanismoftreatment1.Sandborn,etal.AnnIntMed,20072.PanaccioneR,etal.DDW2008:#9203.RutgeertsPJ,etal.DDW2008:#494SwitchingBetweenTNFInhibitors:RheumatoidArthritisExperienceResponsetoasecondinhibitorislowerrelativetofirst1Responsetoasecondinhibitorwillbecomparableifinitialdiscontinuationwasduetoadverse