maintenance therapy for fistulating crohns disease英夫利昔单抗为fistulating克罗恩病维持治疗课件

InfliximabMaintenanceTherapyforFistulatingCrohn sDisease NewEnglandjournalofMedicineFeb 26 2004Directedby Dr A HAMAMPresentedBy Dr Y Abu Zanouna Crohn sDisease Itisanidiopathic chronic transmuralinflammatoryprocessofthebowel thatcanaffectanypartoftheGItract mostcasesinvolveterminalileum Itisbelievedtobearesultofanimbalancebetweenproinflammatoryandanti inflammatorymediators Unpredictableflares remissions Pathophysiology TheexactcauseremainsunknownTheories geneticmicrobial immunologic environmental dietary vascular psychosocial Microscopically inflammationaroundthecrypts ulceration granuloma mesentery lymphnodes Macroscopically Hyperemia edema ulcers cobblestone segmentallesions Genetics 1stdegreerelativeshavea5 25 higherriskthannormalpopulation FamilymembersofpatientswithCrohn sDiseasehaveincreasedriskforbothCD UC Offspringhavean8 9 siblingsan8 6 riskfordevelopingIBDSusceptibilityregionsdetectedondifferentchromosomes 6 12 16 Epidemiology Incidencerateinchildren3 5 100 000inNA10 19yrolds Morethan1 3ofpatientspresentinchildhoodoradolescence Familyhistoryispresentin30 youngerthan30 Males Femalesinadulthood Males femalesinchildhood HighestincidenceinCaucasians ClinicalPresentation Weightloss85 Diarrhea80 Abdominalpain85 Rectalbleeding50 Growthfailure35 Fever40 Rectaldisease25 Extraintestinalsigns25 Perianaldisease25 Nausea vomiting25 Clinicalpresentation Physicalexamination GrowthDelay wtloss delayedpubertyRLQmass tendernessPalpablethickenedloopofintestineHyperactivebowelsoundsPerianal rectalexamination skintag fissure fistula hemorrhoidsorabscess LaboratoryAids Anemia ChronicinflammationMalabsorption B12 folate ChronicbloodlossLeukocytosis ChronicinflammationAbscessSteroidtreatment Lab s HypoalbuminemiaHypocholestrolemiaHypocalcaemiaHypomagnesaemiaHighCRPCD60 ImagingStudies PlainAbdominalradiographBariumcontraststudiesCTscanMRIU SRadionucleotideScans Procedures Colonoscopy Obtainingmultiplebiopsies diagnosticDilatationoffibroticstricturesUpperendoscopy DifferentiatingCrohn sfromotherdiseaseERCP diagnostic therapeutic DifferentialDiagnosis UCAppendicitisInfectionHUSHSPIrritableBowelSyndrome ImmunedeficiencyPUDTBLactoseintoleranceSILymphomaPsychosocialdisturbance Complications Obstruction 8 40 Transient strictureformationFistulization Enteroenteral entervesical enterovaginal enterocutaneosAbscessformationPerianalDisease 25 50 AdhesionsMalabsorptionGrowthFailure Treatment MedicalCare DiarrheaAbdominalpainDiet nutritionaltherapy Balanced highFiberLowfat MCTGEnteraltherapy elementaldietinacutediseaseTPN MedicalTreatment 5 ASApreparationsSteroidsImmunosuppressants Azathioprine 6MP AntibioticsIfmedicaltreatmentfails surgicalresectionoftheinvolvedpartofbowelisresected Fistulae FistulaebetweenBowelloopsareusuallybenign maynotproducemajorproblemsEnterovesical enterocutaneous cologastric coloduedenalaremoreserious Surgery progressiveobstruction abscess malabsorption Medically Metronidazole Ciprofloxacin NewMedicalTherapies Immunosupressiveagents TacrolimusMycophenolatemofetilAntiinflammatoryCytokines IL10 IL11 INFLIXIMAB MonoclonalAntibodyagainstTNFItblocksTNFintheserum atthecellsurface leadingtolysisofTNF producingmacrophages T cells Inonestudy 65 ofrefractorycasesofCDrespondedwelltoRxwithinfliximab 1 3wentintoremission Patientswhorelapsed respondedagaintofurtherinfusions EffectiveinpatientswithFistulae mediandurationofresponse12wks INFLIXIMAB Beforestartingtreatment Allergies Infliximab rodentsPregnancy Studieshavenotbeenconducted BreastFeeding NotknownwhetheritisexcretedinbreastmilkornotMedicalproblems CongestiveHeartFailureActiveinfectionsTuberculosisinfection PPD InfliximabinChildren StudiesonthismedicinehavebeendoneONLYinadultpatients thereisnospecificinformationcomparinguseofinfliximabinchildrenwithuseinotheragegroups SideEffects Common chestpain fever flushing S O B Abdominalpain N V headache fainting musclepain sorethroat nasalcongestionLesscommon Backpain hematuria dysuria urgency stomatitis Rare Weightloss thrombocytopenia Otheruses AnkylosingSpondylitisPsoriasisReactivearthritisRheumatoidArthritisInflammatoryboweldiseasearthritis InfliximabMaintenanceTherapyforFistulizingCrohn sDisease Background Infliximab iseffectiveinmaintenancetherapyforCDwithnofistulaeItisnotknownwhetheritiseffectiveasmaintenancetherapyforpatientswithfistulae Methods Multicenter doubleblind randomized placebo controlledtrialtoevaluatetheefficacyofinfliximabmaintenancetherapyin306adultpatientswithCD 1or drainingabdominalorperianalfistulasofatleast3monthsduration Cont Patientsreceived5mg kg IVonweeks 0 2 6 Atotalof195patientswhohadaresponseatweeks10 14 and87patientswhohadnoresponsewerethenrandomlyassignedtoreceiveplaceboorinfliximab5mg kgevery8weeks tobefollowedtoweek54 Theprimaryanalysiswasthetimetolossofresponseamongpatientswhohadaresponseatweek14andunderwentrandomization Results Thetimetolossofresponsewassignificantlylongerforpatientswhoreceivedinfliximabmaintenancetherapythanforthosewhoreceivedplacebo morethan0wksvs 14wks P 0 001Atweek54 19 ofpatientsintheplacebogrouphadacompleteabsenceofdrainingfistulas ascomparedwithwith36 ofpatientsintheinfliximabmaintenancegroup P 0 009 Conclusion PatientswithfistulizingCDwhohavearesponseatinductiontherapywithinfliximabhaveanincreasedlikelihoodofasustainedresponseover54 weekperiodifinfliximabtreatmentiscontinuedevery8weeks Methods Patients Men women 18yrs withCD 1or fistula ConcurrenttherapiesforCDwerepermitted Excluded abscessorstricturerequiringsurgeryPreviouslyreceivedinfliximab Methods Studydesign Patientswerescreenedforeligibility2weeksbeforeenrollment AlleligiblepatientsreceivedIvinfusions0 2 6weeksResponse reductionofatleast50 frombaselinenumberofdrainingfistulasatconsecutivevisits4or Wksapart Patienthadaresponseifitwasobservedatboth10 14wks Cont Lossofresponse Recrudescenceofdrainingfistulas NeedtochangemedicationsforCDNeedforadditionaltherapyforpersistentorworseningluminaldiseaseactivity Discontinuationofstudymedicationduetolackofefficacy Completeresponse absenceoffistulas Followup safety efficacyevaluation Physicalexaminationat 0 2 6 10 14 22 30 38 46 54wks CDActivityIndex 0 600 InflammatoryBowelDiseaseQuestionnaire healthrelatedqualityoflife 32 224 Adverseeventswereascertained labtestsobtained EfficacyPatientswithresponse Timetolossofresponse 14wksvs 40wksLossofresponse 62 vs 40 DiseaseActivity 6 vs 36 IBDquestionnaireat30 54wks 4 5 vs 14 10 Efficacy PatientswithNoResponse Subsequentresponse 16 vs 21 Crossovertreatment Amongrandomizedpatientswitharesponseduringinductiontherapywhosubsequentlylosttheirresponse 61 whowereallowedtocrossoverfromplacebotoinfliximab reestablishedaresponse 57 reestablishedaresponseaftercrossingoverfrominfliximabdoseof5mg kgto10mg kg AntibodiesagainstInfliximab ResponseratesamongpatientswithantibodiesagainstInfliximab 32 thosewithoutantibodies 31 thosewithinconclusiveresults 29 weresimilar Thosewithantibodieswere2 3Xmorelikelytohaveinfusionreactions Administrationofsteroids immunomodulatorsatbaselineappearedtopreventdevelopmentofABagainstinfliximab Safety Adverseeventsoccurredin92 ofpt sinplacebogroupvs 89 ininfliximabgroup DiscontinuationduetoS E 8 vs 4 Mostcommon worseningofCD6 Nodeathsorcancersoccurredduringthestudy Infectionsrequiringantimicrobialtherapy 1 3ofpt s Seriousinfections 5 Abscess Opportunisticinfections CMV cutaneousnocardia Safety Infusionreactions morewithinfliximab1 vs 4 Thereactionswerenotsevereenoughtowarrantdiscontinuationofinfusion onlyonereactionwassevere PatientsassignedtoinfliximabtwiceaslikelytohaveANA 4timestohaveantids DNAab s OnepatientdevelopedLupuslikesyndrome yethehad veAN