儿童消化性疾病和内镜诊治技术进展交流课件：炎症性肠病：新概念,新策略,新药物

炎症性肠病：新概念,新策略,新药物Crohn’sDisease:

1960’shistoricalperspectiveWhatisCrohn’sdisease?IBDImmunology101MucosaSubmucosaBloodVesselsIBDImmunology101MucosaSubmucosaBloodVesselsIBDImmunology101IBDImmunology101MucosaSubmucosaBloodVesselsMainRoleinAdaptiveImmunityActivateinfectedmacrophagesProvidehelpforBcellAbproduction;switchingtoIgEIncreaseneutrophilresponseSuppressorTcells/app/template/Article.vm/article/2177ThereisanapparentincreaseinIL-17productioninpatientswithIBD(Fujino,etal.),meaningtheremustbeanincreaseinTh17cells/doi/10.1002/ibd.20894/pdfIL-23hasbeenshowntopromotethesurvivalofTh17cellsLeesCWetal.Gut2011;60:1739-1753InflammatoryBowelDisease

morethan200SusceptibleLociKeypathwaysarisingfromgenediscoveryinCrohn'sdiseaseandulcerativecolitis.LeesCWetal.Gut2011;60:1739-1753大隅良典

ŌsumiYoshinori,Nobelprize,2016慢性炎症反应：炎症介质间失平衡IBDinearlyinfancy

IL10signalingdefectsDeficiencyofIL10associatedwithVEO-IBDMutationsinthegenesencodingthetwopolypeptidechainsoftheinterleukin-10receptorabrogateinterleukin-10–mediatedimmunomodulatorysignalingandarestronglyassociatedwithhyper-inflammationoftheintestineHSCTeffectiveinmanagingthehyper-inflammatoryconditionBeforeHSCTAfterHSCTCASE2ChronicGranulomatousDiseaseShortarmoftheXchromosomeNBT(nitrobluetetrazoleum):feedtoPMN’swithaparticle(bacteria,latex).

Ifthehexosemonophosphatepathisnl,thedyeisreduced(turnspurple).

Heparininterferes.Highfalse(-)rate.Respiratoryburstassay:non-fluorescingdyetoPMN’s;additionofparticlemakesitfluoresce.Aquantitativetest–canpickupcarriers.Poorphagocytosis;poorperoxidaseproductionInfectionswithnon-peroxidase-producingorg’s:staph,serratiaAbscessesoflung,LN;alsoinfxofskin,liver,boneNFKBrelatedIBDNF-KBpathwayX-linkedgenodermatosis,associatedwithmutationsintheNEMO

gene

(NFkBessentialmodulator,Xq28)Affectsalmostexclusivelyfemales(malesdieinuterobeforethesecondtrimester)HighlyvariableinclinicalmanifestationsbutalwaysassociatedwithskindefectsIncontinentiapigmenti(IP)现在最佳的抗炎治疗

和免疫调节治疗We’vecomealongway…Crohn’sandUCaredescribedIBDisrecognizedPrednisoneMesalamineRemicadeAzathioprineMethotrexateHumiraCimziaTysabri1700-19001930194019501960197019801990200020102020IBDStepUpTherapySurgeryASA(aspirin-like)SulfasalazineMesalamine:Asacol,Delzicol,PentasaAntibioticsFlagyl,CiproSteroidsBridgeImmuneModulatorsBiologicalsInfliximab(Remicade)Adalimumab(Humira)Vedolizumab(Entyvio)Ustekinumab(Stelera)Azathioprine6MPMethotrexate难治性克罗恩病的治疗方案

合并结核的CD患儿的治疗方案治疗前后PCDAI的变化治疗6月后随访肠镜：黏膜愈合ZhengCF,XuJH,HuangY,LeungYK.TreatmentofCrohn’sdiseasewiththalidomideAnti-adhesiontherapiesChemokineAntagonistsAnti-IntegrinblockadeInterleukinandCytokineAntagonistsIL-12/23pathwaysBlockadeofIntracellularInflammationControlJAK-STATKinasePathwaysTargetsforTherapyBlockWBCBindingtoIntegrinsAnti-IntegrinCoatingBlockadeofAdhesionMolecules:VedolizumabSelectiveAdhesionMolecules(SAM)andSAMInhibitors

VCAMvascularcellularadhesivemolecules

黏附分子蛋白抗体

MAdCAMmucosaladdressincellularmolecules

黏膜地址素细胞分子

即将用于

IBD的免疫调节治疗方法1、抗粘附分子EndothelialandLeukocyteAdhesion:Alpha-4IntegrinsBlockWBCBindingtoIntegrinsAnti-IntegrinCoatingBlockadeofAdhesionMolecules:VedolizumabVedolizumabrhuMAbBeta7PF-00547659(MAdCAM-1Antagonist)LeadingAnti-IntegrinsInDevelopmentBlockadeofAdhesionMolecules:Vedolizumab抗粘附分子维多珠单抗Vedolizumab是一种单克隆抗体，在

2014年

5月美国

FDA批准其用于

UC和

CDα4-β7是淋巴细胞表面的一种整合素，其作用是将淋巴细胞转运到肠道以及将淋巴细胞结合到肠道特异性配体（如粘膜地址素细胞粘附分子

-1）维多珠单抗阻断了这种整合素的作用。抗粘附分子维多珠单抗Vedolizumab它不会影响淋巴细胞转运到其他位点这将限制系统毒性和见于那他珠单抗natalizumab的中枢神经系统毒性（和

JC病毒相关的进展多发脑白质病变）依托珠单抗Etrolizumab

特异性针对β7亚基的单克隆抗体皮下给药的依托珠单抗以两种不同剂量给药方法给药大于

8周后，在第

10周达到缓解。在一个剂量组，21%达到缓解。该药正准备进行三期临床试验IL-12/23LigandIL-12ReceptorBlockadeofCell-ActivatingSignalsT-cellT-cellsACTIVATEDDendriticcellIL-17Interferon优斯它单抗Ustekinumab

是

IL-12/23的抗体，FDA批准其用于银屑病和银屑病关节炎的临床应用直到最近才用于

CD治疗的研究在一个由使用优斯它单抗治疗的

38例患者组成的开放病案系列中，3个月时的应答率达到

75%，且其应答可以维持超过一年BlockadeofCellularInflammationControlsT-cellJAKInterleukinsInterleukinsAttachtoReceptorsJAKBindstoActivatedReceptorsJAKthenSignalsDNACellproducesmediatorsofinflammationJAK抑制剂托法替尼Tofacitinib是一种口服的

JAK抑制剂，它可通过和一些细胞因子受体相互作用而抑制炎症在一项

UC研究中，患者以

30mg每天的剂量给药，接受托法替尼的患者中有

78%在第

8周达到了有意义的临床应答接受托法替尼

30mg/day的患者中有

41%达到了临床缓解。Anti-adhesiontherapiesChemokineAntagonistsAnti-IntegrinblockadeInterleukinandCytokineAntagonistsIL-12/23pathwaysBlockadeofIntracellularInflammationControlJAK-STATKinasePathwaysTargetsforTherapyCCL-25LigandCCR9ReceptorBlockadeofCellAdhesionandHomingCytokinesChemokineCCR-9ChemokinesareselectivelyreleasedtoactivateelementsofinflammatoryresponseChemokineCCR9hasmanyfunctioninintestinalinflammationAttractsTandB-cellstothesiteofinflammationCCR9BindstointestinalendotheliumtohelppullT-cellsintotheintestineAlsoactivatesendothelialIntegrins,permittingotherinflammatorycellstoenterthegut.BlockadeofCellAdhesionandHomingCytokinesCompoundCCX282-BAnti-chemokineCCR9medicationInPhaseIIITestinginLargeCrohn’sPopulationTakeninpillformtwiceada