IBD的生物學治療適應癥與處理

IBD的生物學治療適應癥與處理“TheTaleofTwoFamilies”大連醫(yī)科大學附屬第一醫(yī)院消化科FAMILY#1:TheAnti-TNF’sFDA-ApprovedTherapiesGeneric

Crohn’sDisease

UlcerativeColitisAdalimumab

阿達木

+

+Certolizumab賽妥珠

+Golimumab戈利木

+Infliximab英夫利昔

+

+Comparisonofanti-TNFAgentsChimericmonoclonalantibodyHumanizedmonoclonalantibodyHumanrecombinantantibody

HumanizedFab’fragmentHumanrecombinantreceptor/FcfusionproteinInfliximabCDP571AdalimumabGolimumabCertolizumabpegolEtanerceptPEGPEGMouseCDR=Complementarity-determiningregion（補償決定區(qū)）HumanPEG=Polyethyleneglycol（聚乙二醇）Hanauer,RevGastroenterolDisord2004;4(supp3):S18-24Benefitsvs.Drawbacks:Anti-TNF’s?Workfast.?Workverywellinmanypatients.?Dosedonlyevery2weeks–2months.?Containnosteroids;sohavenosteroidside-effects.?Long-termsafetyprofileexcellent.?

GivenIVorbyshotonly.?Maybecomeallergicorineffectiveifstopandthenrestartlater.?Internet-hypeoververyveryrarepotentialriskoflymphomaandpotentialincreasedriskofskincancersThebenefitsfaroutweightheextremelyrarerisksinthevastmajorityofpatients.?Benefits

?DrawbacksAdult&PediatricPatients?

Reducingsignsandsymptoms?Inducingandmaintainingclinicalremission?Moderatelytoseverelyactivediseasewhohavehadaninadequateresponsetoconventionaltherapy–Pediatrics:specifies“corticosteroidsorimmumodulatorssuchasazathioprine,6-mercaptopurine,ormethotrexate.”（咪唑硫嘌呤，6-巰基嘌呤甲氨喋呤）AdultPatients?ReducingsignsandsymptomsandinducingclinicalremissioninpatientsiftheyhavealsolostresponsetoorareintoleranttoinfliximabFDAIndication:AdalimumabinCrohn’sDisease/pdf/humira.pdfAccessed11/9/2014FDAIndication:Adalimumabin

UlcerativeColitisAdultPatientsInducingandmaintainingclinicalremissionModeratelytoseverelyactivediseasewhohavehadaninadequateresponsetoimmunosuppressants“suchascorticosteroids,azathioprine,or6-mercaptopurine(6-MP)”“TheeffectivenessofAdalimumabhasnotbeenestablishedinpatientswhohavelostresponsetoorwereintoleranttoTNFblockers.”/pdf/humira.pdfAccessed11/9/2014AdalimumabinUC:ULTRA2BaselineCharacteristics

Placebo

Adalimumab

Total

(n=246)

(n=245)(n=494)DiseaseLocationPan-colitis

48.8%

48.4%

48.6%Descending

39.0%

38.7%

38.9%Other

12.2%

12.9%

12.9%CRP

above

ULN

47.2%

45.7%

46.5%MayoScore,mean

8.9

8.9

8.9Concomitant

MedCorticosteroid

56.9%

60.5%

58.7%6MP/AZA

32.5%

37.5%

35.0%6MP/AZA+CS

18.3%

20.2%

19.2%PriorAnti-TNF

41.1%

39.1%

40.3%SandbornWJetal.Gastroenterology.2012;142:257-265.AdalimumabinUC:

ULTRA2Week8and52ResultsRemissionResponseMHRemissionResponseMHRemissionResponseMHPlacebo(n=246)

Adalimumab(n=248)Week8Week52Week8and529.316.534.650.431.741.18.517.318.330.215.425.04.18.523.812.210.618.51020304050600Patients(%)P=.03P=.02P=.004P<.01P<.001P<.01P<.05P<.01P<.001AdalimumabinUC:ULTRA2

ResultsByPriorInfliximabExposure1020304050600Week52,RemissionWeek52,ResponsePlacebo(n=246)Adalimumab(n=248)12.4Patients(%)P=.019P=.03822310.224.136.79.920.4Anti-TNFna?veAnti-TNFna?veAnti-TNFexperiencedAnti-TNFexperiencedSandbornWJetal.Gastroenterology.2014;142:257-265.AdalimumabinUC:ULTRA2

DiscontinuationofCorticosteroids81216202632384452450510154030352520P<0.05WeekPlaceboAdalimumabPatientswhodiscontinuecorticosteroids%AdalimumabDosing(CDandUC)Load–Week0:160mgsc(syringeorpen)–Week2:80mgsc(syringeorpen)Maintenance–Starting@Week4:40mgsceveryotherweek.Ifloseresponse:–Increasetoqweeklydosing.SCONLY?Moreconvenient?Lesscompliant??Self-Medicating?Adalimumab:DosingIssues1.Useoftroughlevelstooptimizetherapy2.Increasedose:40mgqweekor80mgq2weeks3.Bestoutcomeswithcombinationtherapy4.?Ifdosesover80mgshouldbeused.5.Highdoseloadinginseveredisease?FDAIndication:CertolizumabinCrohn’sDiseaseAdultPatientsReducingsignsandsymptomsMaintainingclinicalresponseModeratelytoseverelyactivediseasewhohavehadaninadequateresponsetoconventionaltherapy/assets/pdf/Prescribing_Information.pdfAccessed11/9/2014CertolizumabPegolDosing(CD)LoadWeek0:400mgscWeek2:400mgscMaintenanceStarting@Week4:400mgscevery4weeksIfloseresponse:–Giveanextradoseof400mg2weeksafterlastdose

SCONLY1.Lyophylizeddrug:MixedandAdministeredbyhealthcareprofessional?+/-convenient?Morecompliant??LessSelf-Medicating??PreferredifMedicare2.Prefilledsyringe:?MoreconvenientCertolizumabPegol:DosingIssues1.Useoftroughlevelstooptimizetherapy?(N/A)2.Increasedoseto400mgq2weeks:effective?3.Bestoutcomeswithcombinationtherapy4.Highdoseloadinginseveredisease?5.ChoosethelyophilizedversionforMedicarepatients(Medicarepaysforinjectablesifadministeredbyahealthcareprofessional)FDAIndication:GolimumabinUCAdultPatientsInducingandmaintainingclinicalresponseInducingclinicalremissionAchievingandsustainingclinicalremissionininductionrespondersImprovingendoscopicappearanceofthemucosaduringinductionModeratetosevereulcerativecolitiswithaninadequateresponseorintoleranttopriortreatmentorrequiringcontinuoussteroidtherapy/shared/product/simponi/prescribing-information.pdfAccessed11/9/2014PURSUIT:GolimumabfortheInductionofModeratetoSevereUC33.3102030405060

0Patients(%)6.442.355.017.820.4Phase3:ClinicalResponse,ClinicalRemissionandMucosalHealingatWeek6Placebo(n=251)200mg→100mg(n=253)400mg→200mg(n=257)28.751.818.745.1SandbornWJ,etal.Gastroenterology.2014;146:85–95.ResponseRemissionMH*P<.0001vsplacebo§P=0.0014vs.placebo*****§PURSUIT:GolimumabfortheMaintenanceof

ModeratetoSevereUC31.2102030405060

0Patients(%)15.649.727.8Placebo(n=154)50mg(n=151)100mg(n=15147.023.2SandbornWJ,etal.Gastroenterology.2014;146:85–95.**§*P=0.01vsplacebo§P<0.001vs.placebo?P=0.004vs.placeboContinuousClinicalResponseRemissionWk30&50PURSUIT:Corticosteroid-FreeRemissionatWk54withGolimumabinUC18.4102030405060

0Patients(%)P=.42323.2Placebo(n=87)Golimumab50mg(n=78)Golimumab100mg(n=82)28.2SandbornWJ,etal.Gastroenterology.2014;146:96–109P=.279*Amongthosepatientswhowereinitiallyreceivingcorticosteroids.*GolimumabDosing(UC)Load–Week0:200mgsc(syringeorpen)–Week2:100mgsc(syringeorpen)Maintenance–Starting@Week4:100mgscevery4weeks.SCONLY?Moreconvenient?Lesscompliant??Self-Medicating?Golimumab:DosingIssues1.

Useoftroughlevelstooptimizetherapy?(N/A)2.Increasedose?3.Bestoutcomeswithcombinationtherapy(anticipated)4.?Ifdosesover200mgshouldbeused.5.Highdoseloadinginseveredisease?FDAIndication:InfliximabinCrohn’sDiseaseAdult&PediatricPatients?

Reducingsignsandsymptoms?Inducingandmaintainingclinicalremission?ModeratelytoseverelyactivediseasewhohavehadaninadequateresponsetoconventionaltherapyAdultPatients?Reducingthenumberofdrainingenterocutaneousandrectovaginalfistulas?Maintainingfistulaclosure/shared/product/remicade/prescribing-informationFDAIndication:InfliximabinUlcerativeColitisAdult&PediatricPatients?Reducingsignsandsymptoms?Inducingandmaintainingclinicalremission?ModeratelytoseverelyactivediseasewhohavehadaninadequateresponsetoconventionaltherapyAdultPatients?Inducingandmaintainingmucosalhealing?EliminatingcorticosteroiduseInfliximab:Dosing(Crohn’sandUC)?Load:

?

Week0:5mg/kgIV

?Week2:5mg/kgIV

?Week6:5mg/kgIV?Maintenance:

?

Starting@Week14:5mg/kgIVq8weeks.?Ifloseresponse:

?Increasedoseupto10mg/kgordecreasedosinginterval.

IVONLY?Lessconvenient?MorecompliantInfliximab:DosingIssues1.Useoftroughlevelstooptimizetherapy2.?Ifshouldincreasedoseordecreasedurationbetweeninfusions3.Bestoutcomeswithcombinationtherapy4.?Ifdosesover10mg/kgshouldbeused5.Aggressiveloadinginseveredisease?CombinationTherapy:SuperiorEfficacyinCrohn’s100%0%60%40%20%80%SteroidfreeremissionMucosalhealing30.6%44.4%56.8%43.9%30.1%16.5%SonicTrial:Crohn'sDiseaseOutcomesatWeek26azaInfComboP<0.001vsazaP=0.022vsifxP<0.001vsazaP=0.055vsifxAnti-InfliximabAntibodies:Mono:14%Combo:1%ColumbelJFetal.NEnglJMed2010;362:1383-95.CombinationTherapy:SuperiorEfficacyinUlcerativeColitis100%0%60%40%20%80%24%22%40%UC-SUCCESSTrial:UlcerativecolitisWeek16corticosteroid-freeremissionazaInfComboP<0.032vsazaP=0.0017vsifxAnti-InfliximabAntibodies:Mono:14%Combo:1%Panaccioneetal.Gastroenterology2014;146:392-400e3BestOutcomesWithCombinationTherapy(Biologics+Immunosuppressant)Infliximab+Azathioprine:Crohn’sDisease(SONICTrial)1UlcerativeColitis(UC-SUCCESSTrial)2Ongoingquestions:Isthesametrueforadalimumab?Whenshouldthiopurinebestarted?Shouldthiopurinesbeattherapeuticdoses?Shouldbiologicsbeattherapeuticdoses?1ColumbelJFetal.NEnglJMed2010;362:1383-95.2Panaccioneetal.Gastroenterology2014;146:392-400.FAMILY#2:TheAnti-IntegrinAntibodiesFDA-ApprovedTherapiesGeneric

Crohn’sDisease

UlcerativeColitisNatalizumab那他珠

+Vedolizumab

維多珠+

+FDAIndication:NatalizumabinCrohn’sDiseaseAdultCrohn’sDisease:I.

InducingandMaintainingClinicalResponseII.InducingandMaintainingClinicalRemissionIII.Moderate-to-SevereactiveCrohn’sDiseasewithevidenceofinflammationIV.Inadequateresponseto,orareunabletotolerateconventionalCDtherapiesandinhibitorsofTNF-α.V.InCD,shouldnotbeusedincombinationwithimmunosuppressantsorinhibitorsofTNF-αFDAPrescribingInformation:v05/2014Natalizumab:Dosing(CD)?

VerifyJCvirus“-”?JCvirus:ahumanpolyomavirus,causingprogressivemultifocalleukoencephaopathy(PML).?NoLoad?StandardDosingRegimen

?300mgIVevery4weeks

?Nootherimmunomodulatorsallowed;taperprednisone?Ifnoresponseorloseresponse:

?Stoptherapy

IVONLY“CD-TOUCH”Program?Lessconvenient?Morecompliant?Natalizumab:DosingIssues1.VerifyJCvirus“-”priortostarting2.RecheckJCvirusq6-12months-StoptherapyifconvertstoJC“+”3.Verifydrugworkingbymonth6;otherwisestop.4.Cancheckdruglevelif?oflowlevel/likelyantibodies5.IfJCvirusstatus“-”shouldonebe“allowedto”:Useconcomitantimmunomodulators?Doseincrease?FDAIndication:VedolizumabinCrohn’sDiseaseAdultCrohn’sDisease:I.Moderate–to–SevereactiveCrohn’sDiseaseII.Inadequateresponsewith,lostresponseto,orintoleranttoeithera.Anti-TNFblockerb.Immunomodulatorc.Corticosteroids(ordependent)III.Outcomes:a.Achievingclinicalresponseb.Achievingclinicalremissionc.Achievingcorticosteroid-freeremissionFDAIndication:Vedolizumabin

UlcerativeColitisAdultUlcerativeColitis:I.Moderate–to–SevereactiveUCII.Inadequateresponsewith,lostresponseto,orintoleranttoeithera.Anti-TNFblockerb.Immunomodulatorc.Corticosteroids(ordependent)III.Outcomes:a.Inducingandmaintainingclinicalresponseb.Inducingandmaintainingclinicalremissionc.Improvingendoscopicappearanceofthemucosad.Achievingcorticosteroid-freeremissionFDAPrescribingInformation:v05/2014VedolizumabBlocksα4β7IntegrinAnti-α4MAdCAM-1Tcellα4β1α4β7InflammatoryCytokines細胞黏附分子-1Vedolizumab:α4β7integrinhumanizedIgG4monoantibody,selectivelyblockingsignaltransferbetweenα4β7andMAdCAM-1,α4β1andVCAM-1,inhibingmigrationofWBCtotheinflammatorymucosa.Vedolizumab:Dosing(Crohn’sandUC)?

Load:?Week0:300mgIV?Week2:300mgIV?Week6:300mgIV?Maintenance:?Starting@Week14:300mgIVq8weeks

IVONLY?Lessconvenient?MorecompliantVedolizumab:InductioninUC

ClinicalResponseClinicalRemissionMucosalHealingVedolizumabPlaceboPrimaryAnalysis:Week6GEMINIIP<0.001P=0.00147.1%25.5%16.9%5.4%40.9%24.8%P=0.001100%75%50%25%0%FeaganBGetal.NEnglJMed2013;369(8):699-710),Patients%Vedolizumab:MaintenanceinUCClinicalResponseClinicalRemissionSteroid-FreeRemisionMucosalHealingPrimaryAnalysis:Week52GEMINII52.0%56.6%100%75%50%25%0%FeaganBGetal.NEnglJMed2013;369(8):699-710),23.8%44.8%41.8%15.9%45.2%31.4%13.9%56.0%51.6%19.8%Vedolizumabq4wVedolizumabq8wPlaceboP<0.001foreitherdruggroupvs.placeboP=0.01vs.placeboPatients%Vedolizumab:InductioninCrohn's

ClinicalResponseClinicalRemission

VedolizumabPlaceboPrimaryAnalysis:Week6GEMINIIIP=0.2331.4%25.7%14.5%6.6%P=0.02100%75%50%25%0%Sandbornetal.NEnglJMed2013;369(8):711-721.Patients%Vedolizumab:MaintenanceinCrohn'sClinicalResponseClinicalRemissionSteroid-FreeRemisionPrimaryAnalysis:Week52GEMINIII45.5%43.5%100%75%50%25%0%FeaganBGetal.NEnglJMed2013;369(8):699-710),31.0%36.4%39.0%21.6%28.8%31.7%15.9%Vedolizumabq4wVedolizumabq8wPlaceboPvaluesvs.placeboP=0.005P=0.004P=0.04P=0.02P<0.001Patients%VedolizumabinUC:

MeanPartialMayoScorethroughWeek61265430FeaganBG.NEnglJ