炎癥性腸病的研究進展消化內科張文俊IBD

概述CD和UC是一種疾病的兩個階段或兩種疾病目前尚無定論inflammatoryboweldiseasesCrohndiseaseUlcerativecolitisUndeterminatedcolitis

CH/10/30炎癥性腸病的復雜性EpidemiologyofIBD1-2millionIBDpatientsintheU.S.EqualincidenceofulcerativecolitisandCrohn’sdiseaseApproximately10,000newcasesdiagnosedannually**HanauerS.InflammatoryBowelDisease.NEnglJMed.1996;334(13):841-8Variable FindingTimetrendsinincidence Increased1960s–80s

withrecentplateauIncidence(per100,000) 5-7Peakageatonset(y) 15-30Female-to-maleratio 1.1to1.8:1Racial/ethnicincidence Highinwhites,JewsEpidemiologyofIBD:OverviewAndresPGetal.GastroenterolClinNAm.1999;28:255.AgeandSexIncidenceofIBDIBD病因遺傳易感性環境促發因素精神因素免疫因素IBD識別的第一個IBD基因–CARD15/NOD2糖多肽CD14TLR4TRAF6NOD2NF-kBIkBNF-kB細胞核

炎癥單核細胞C-插入突變終止碼,NF-kB的異常激活IBD相關基因Bamias.AnnInternMed,2005,143(12):895-904基因型與IBD的關系不同基因型不同IBD分型疾病易感性不同對藥物治療的反應不同NocontributionofNOD2NOD2contributesNOD2majorfactorM.CROHNANDNOD2/CARD15CP/06/23EnvironmentalTriggersInfectionsNSAIDsStressSmokingDietAntibioticsIBD飲食因素

明確危險因素:過量攝入糖類，尤其是CD可能危險因素:巧克力和可樂類飲料,高脂可能保護因素:高纖維食物,水果和蔬菜其他：丁酸，硫化物，谷氨酸鹽Meta分析:吸煙者發病危險性為從不吸煙者的2倍吸煙增加CD復發可能性，女性多見（4倍）過量吸煙CD的危險因素，UC的保護因素對于CD：長期吸煙者發病危險性高戒煙者患病的危險性為從不吸煙者的1.7倍

戒煙者重新吸煙(45％)可改善癥狀尼古丁治療可增加活動期UC的癥狀緩解率對于UC：TheHumanGutFloraRapidlycolonisesgutafterbirthComprisesmorethan1014organismsWeighs1-2kgMorethan400speciesAnindividualsfloraisimmunologicallydistinctSymbioticrelationshipwithhostProbioticsBALANCEOFCOMMENSALBACTERIALCOMPONENTS麻疹病毒感染與IBD的相關研究EkbomA.Lancet1996;348.LawrensonR.BMJ1998;316.NielsenLLW.BMJ1998;316.AfzalMA.Lancet1998;351.HagaY.Gut1996;38.ChadwickN.JMedVirol1998:55.假說一：持續麻疹病毒感染與CD相關來自瑞士的研究:麻疹流行期出生者CD患病率高在CD病人腸道組織中發現麻疹病毒蛋白和DNA證據研究者Wakefield后續的研究不支持自己前期研究當時檢測麻疹病毒的技術不夠可靠

來自英、美、日等國的研究存在分歧血清中未檢測到抗麻疹病毒抗體反證據麻疹病毒感染與IBD的相關研究ThomsponNP.Lancet1995;345.GilatT.ScanJGastroenterology1987;22.PebodyRG.BMJ1998;316.FeeneyM.Lancet1997;350.假說二：麻疹疫苗(非MMR)接種與CD相關麻疹疫苗接種者IBD發病率較未接種者高證據來自歐洲的病例對照研究不支持上述觀點

英國和芬蘭的研究顯示CD與疫苗接種無關反證據大腸桿菌與IBD的相關研究假說：鞭毛蛋白在IBD中啟動獲得性免疫機制E.ColiFlagella大腸桿菌與IBD的相關研究假說：鞭毛蛋白在IBD中啟動獲得性免疫機制

常規革蘭染色陰性的鞭毛蛋白單體（如大腸桿菌）在CD中可作為抗原激發獲得性免疫反應這種獲得性免疫反應受TLR5介導的先天性免疫調節粘膜組織中可檢測到非造血細胞產生的細胞因子（如IL-6和TNFa)獲得性免疫與CD發生發展相關大腸桿菌與IBD的相關研究依據：應激增強動物模型腸粘膜炎癥反應Qui.NatureMed.1999.依據：無癥狀UC中應激與直腸炎癥有關LevensteinS,etal.AmJGastroenterol1994;89:1219-25.依據：應激對UC病情影響與持續時間有關LevensteinS,etal.AmJGastroenterol2000;95(5):1213-20.LevensteinS,etal.AmJGastroenterol2000;95(5):1213-20.依據：應激對UC病情影響與應激程度有關不同IBD分型應激的影響不同MaunderR.DigDisSci2000;45(11):2127-32.機制：應激與循環遞質機制：應激與腸壁通透性WilsonLM.Microcirculation1999;6:189..MeddingsJB.Gastroent2000;119:1019.機制：應激與腸道局部介質SoderholmJD.AmJPhysiolGastrointestLiverPhysiol2001;280:G7–G13.MawdsleyJE.Gut.2005,54(10):1481-91.應激對胃腸道影響的多通路機制MawdsleyJE.Gut.2005,54(10):1481-91.應激與IBD精神神經免疫學機制

IBD處于血栓前狀態凝血參數大多增高血栓栓塞發生時給予抗凝治療可同時改善IBD病情血栓栓塞是IBD的嚴重并發癥多發生于年輕患者急性期；深靜脈血栓和肺栓塞常見；動脈栓塞和其他則少見凝血和抗凝平衡紊亂SchapiraM.ActaGastroenterolBelg.1999,62:182.AlfredoGuglielmi.WorldJGastroenterol,2005,7;11:2035.凝血狀態異常是IBD的病因還是結果尚不確定UC患者腸系膜靜脈和門靜脈血栓形成IBD發病機制(Pathogenesis)

損傷機理：粘膜屏障受損粘膜免疫異常系統免疫失衡IBD發病機制研究進展：先天性免疫在IBD中的作用IBD免疫效應分型－－Th1/Th2CD是免疫亢進或免疫缺陷細胞因子及免疫遞質研究進展ETIOLOGICHYPOTHESESPathogenesisofIBDNSAIDsAntibioticsInfections

Viral

Bacterial

ParasiticLuminalantigensFoodantigensBacteriaBacterialproducts

FMLP

LPS

PGPSIL-2IFN-IL-12TNF-IL-1TGF-

IL-4IL-5IL-10etc.TranslocationofluminalcontentsInitiatingEventsMucosalDamageAbnormalImmuneResponseChronicInflammationCourtesyofRBaldassano,2000.ChronicInflammation:

ImbalanceBetweenMediatorsPro-inflammatoryAnti-inflammatoryTNF-aIL-1bIL-8IL-12IFN-gTGF-bIL-10IL-1raIL-4/IL-13"Target“

PGLTBPAFH2O2IndirectdestructionInterleukinschemokinesTNFaReleaseoffactorsVirusBac-

teriaProteinLymphocytesUncontrolledreaction

toantigenMacrophagesPMN′sRecruitmentofcellsMHC4CP/03/48PRINCIPLESOFPATHOPHYSIOLOGYOFIBDAPCEffectorT-cellUncontrolledT-CellResponsesInduceChronicGutInflammation

正常腸壁有生理性抗炎功能

IBD腸壁滲透性增加損害腸粘膜屏障的因素：遺傳易感性環境促發因素機制一：粘膜屏障受損MucosalImmuneSystem機制二：粘膜免疫失衡

腔內抗原浸潤并激活MC

效應細胞產生促炎細胞因子減少調節性細胞因子產生級聯反應促使炎癥反應擴大粘膜免疫中的腸道微環境和相關基因機制三：系統免疫失衡遺傳、環境及社會心理等因素共同作用于免疫系統

先天性免疫是非特異性防御病原體的機制——是機體的第一道防線主要針對抗原產生的化學物質(而非抗原本身)針對抗原的某種免疫細胞選擇性增殖TheRoleoftheInnateImmuneSysteminIBD

獲得性免疫與先天性免疫在IBD中的作用傳統觀點認為

Acquiredimmunesystem

IBD是獲得性免疫系統細胞介導的炎癥反應主要識別抗原本身效應T細胞(Teff)和調節T細胞(Treg)Defectsintheinnateimmunesystemmayplay

anequalorevenmoreimportantroleinIBDIBD可有原發性的調節性淋巴細胞和細胞因子功能失調，如:IL-10、TGF-β,導致炎癥控制失靈CD中存在激活的T細胞調亡抵抗這些現象無法用現有的獲得性免疫機制解釋先天性免疫缺陷可能在IBD中起更重要的作用進一步研究提示AnnInternMed,Volume143(12).December20,2005.895-904NOD2蛋白是細胞內受體主要識別細菌胞壁成分在先天免疫中起作用被認為是IBD的易感基因NOD2突變見于1/3的CD而在UC不是危險因素支持先天性免疫的證據先天性免疫中介導微生物-宿主反應的信號通路基因

膜耦聯受體TLRs（toll-likereceptors）識別脂多糖等微生物結構組分細胞質蛋白家族成員：NBS/LRR(Nod1andNod2)特異性識別肽聚糖MediatesInnateImmuneDefensePro-InflammatoryCytokinesNFkBIBD免疫效應分型－－Th1/Th2paradigm傳統觀點認為:CD為Th1優勢反應

IL-12和IFN-γ等分泌增多抗IL-12治療可減少固有層MC分泌細胞因子傳統觀點認為:UC為Th2優勢反應

IL-5和IL-13等分泌增多抗IL-13治療有助于改善結腸炎癥Th1Th2

Crohn’sDisease

BACTERIAThiswillmeansomethinguniquetoeveryone.Thebottomlineisthis:We’resurethatyou’llhaveapositiveexperiencewithDanActiveandthatyou’llbecompletelysatisfiedwithit.We’realsoconfidentthatyou’llwanttomakeDanActiveapartofyourfamily’sdailywellnessroutine.Th1/Th2新觀點的提出

UC和CD的研究發現Th1,Th2免疫分型界限不明顯各種細胞因子表達與原有分型差異甚至完全相反基于傳統Th1/Th2觀點提出抗TNF單克隆抗體(Infliximab)用于CD治療；

目前的研究發現Infliximab對重癥UC同樣有效；而對部分CD不能誘導緩解抗IL-10的制劑不能誘導CD患者緩解IBD存在免疫反應差異性這些現象無法用傳統的Th1/Th2模式解釋其他T細胞免疫效應途徑AmJGastroenterol.2002,97:2820.NEnglJMed,2002,347:417.NatRevImmunol,2003,3:521.JExpMed,2002,195:1129.JClinInvest.2004;113:1490.Th3/Tr1與口服耐受相關IBD病程不同免疫分型不同急性期Th1為主慢性期Th1/Th2混合型自身免疫機制是CD發病的關鍵遺傳易感的宿主對細菌抗原的免疫耐受終止免疫過度激活導致慢性透壁性炎癥CD是免疫亢進或免疫缺陷Sands,BE.InflammBowelDis,

2006,12(2),S2:pS1傳統觀點:IBD包括CD免疫亢進是其主要機制

細菌與腸粘膜粘附性增強defensins表達降低defensins治療有效IBD存在體液,細胞免疫缺陷NOD2/CARD15基因突變損害細胞因子的轉錄表達GM-CSF治療有效支持CD存在免疫缺陷的證據ChristianF.EurJGastroenterolHepatol200315:621–626集落刺激因子改善粒細胞功能缺陷KORZENIKJR.DigDisSci,2000,45,6:1121.G-CSFandGM-CSFKORZENIKJR.NewEnglJMed,2005,352,21:2193.Sargramostim作為一種GM-CSF刺激腸道先天性免疫系統細胞過氧化物酶增殖活化受體PPAR-Lewis,AJG2001.Dubuquoy,Gastro2003NFkBPPARX治療應用

外源物質代謝與IBD密切相關PregnaneXreceptor(PXR)是配體激活的轉錄因子家族成員PXR可啟動外源物質代謝PXR可被多種內源性或外源性物質激活，如:激素，膽汁酸，抗生素PXR編碼基因NR1I2多態性與IBD相關PregnaneXreceptorandIBDDringMM.Gastrol,2006,130:341–348.VitaminD和IBDLimWC.JGastro&Hepatol,2005,2:308.ClinicalFindingsCD/05/105STRICTURINGSTENOSIS

ATTHEILEOCECALBORDER

PresentationofUCDiarrheaBleedingNOabdominalpain(cramps)ExtraintestinalmanifestationsUlcerativeColitis:Bleeding101402.7Lindenbaum-On-screen80ComplicationsofUCToxicMegacolonColonicPerforationDysplasiaorCancerGrowthfailure(pediatrics)Extraintestinaldisorders

(eg,arthritis,anddermatologic,musculoskeletal,ocular,renal,andhepaticdisorders)ClinicalVignette:UlcerativeColitis22yomalepresentswith15-20bloodyliquidbowelmovementsaday.HerecentlyquitcigarettesmokingHismotherhasCrohn’sdiseaseHetakesibuprofenforleftkneearthritisStoolculturesarenegativeandcolonoscopyrevealscolitisfromtherectumtocecum.

PresentationofCDDiarrheaChronicabdominalpainandtendernessLossofappetiteandweightlossFeverPerianaldiseaseComplicationssuchasfistulasExtraintestinalmanifestationsComplicationsofCDFistulasAbscessesStricturesGrowthfailure(pediatrics)MalnutritionExtraintestinaldisorders

Crohn’sDisease

Complications:FistulasAtunnelbetweentwosectionsof

theintestinesorbetweentheintestinesand

otherorgans,includingtheskinSmallIntestineLargeIntestine(Colon)FistulaFistulaCrohn’sDisease

Complications:AbscessesAlocalizedcollection

ofpuswithinthetissueoftheGItractStomachSmallIntestineLargeIntestine(Colon)Abscessfrom

afissureinthe

smallintestine

intothe

peritonealcavityComplicationsofCD:Fistulas AbdominalFistulaPerianalFistula

DifferentialDiagnosisofIBDLymphomaInfectiousetiologiesAppendicitisDiverticulitisCarcinomaIschemicColitisCeliacdiseaseSignificantfactors UC CDAnatomiclocation Colon/rectum AnypartofGItractDistribution Diffuse Focalwith“skip”areasFistulaorabscess Rare CommonStrictures Uncommon CommonCurrentsmoker Rare CommonBloodydiarrhea Common RareAdaptedfromSurawiczCM.ContempInternMed.1991;3:17.DifferentialDiagnosisSevereCrohn’sColitis

ReprintedbypermissionofBlackwellScience,Inc.MarionJFetal.In:DiMarinoAJ,

BenjaminSB(eds).GastrointestinalDisease:AnEndoscopicApproach.1997:511.PseudopolypsinCD

ReprintedbypermissionofBlackwellScience,Inc.MarionJFetal.In:DiMarinoAJ,

BenjaminSB(eds).GastrointestinalDisease:AnEndoscopicApproach.1997:511.FibrostenosisinCD

CourtesyofJ-FColombel,MD.IntestinalComplicationsofUlcerativeColitisToxicity101402.7Lindenbaum-On-screen95GranulomaoftheIleuminCDCourtesyofJ-FColombel,MDandKGeboes,MD.CryptAbscessesinIBD

CourtesyofJ-FColombel,MD.Extraintestinal

ManifestationsExtraintestinalManifestationsofIBDSkindisordersErythemanodosumPyodermagangrenosumJointdisordersPeripheralarthritisSacroiliitisAnkylosingspondylitisOculardisordersIritis,uveitis,andepiscleritisExtraintestinalManifestationsofIBDHepatobiliaryGallstonesSclerosingcholangitisCholangiocarcinomaRenalRenalstonesAmyloidosisOthermanifestationsAphthousstomatitisHypercoagulablestateErythemaNodosuminIBD

CourtesyofJ-FColombel,MD.PyodermaGangrenosuminIBD

CourtesyofJ-FColombel,MD.PyodermaGangrenosuminCDSacroiliitisinIBD

CourtesyofJ-FColombel,MD.ReprintedfromtheClinicalSlideCollectionontheRheumaticDiseases,copyright1991,1995,1997.UsedbypermissionoftheAmericanCollegeofRheumatology.AnkylosingSpondylitisScleritisinIBD

CourtesyofJ-FColombel,MD.AphthousStomatitisinIBD

CourtesyofJ-FColombel,MD.SclerosingCholangitisinIBD

CourtesyofJ-FColombel,MD.CD/05/76SMALLLESIONSINTHECOLONINCD–INVISIBLEINMRICD/05/62WCE

INSMALLBOWELCROHN′SDISEASECD/05/97CT-ENTEROCLYSIS–CROHN′SDISEASEWITHSTENOSISANDPRESTENOTICDILATATIONn=41WCECTELargelesions85Smalllesions23*10*p<0.007CD/05/73COMPARISONOFWIRELESSCAPSULEENDOS-COPY(WCE)–CT-ENTEROCLYSIS(CTE)INIBDVoderholzer,2005CD/06/22DIAGNOSTICALGORITHMINIBDLabtest(bloodcount,CRP,lipase),

microbiology,abdominalultrasoundInflammatoryconstellation

persistenceofcomplaintsIleocolonoscopy

smallbowelX-ray/MRE/CTEAbdominalpain(Bloody)diarrheaCrohn’sdiseaseUlcerativecolitisEsophagogastroduodenoscopyGoalsofTreatmentInduceresponse/remissionMaintainresponse/remissionHealmucosalliningPreventorcurecomplications(eg,fistulas)ImprovequalityoflifeRestoreandmaintainnutritionLimitsurgeryConventionalTreatmentsforIBDAminosalicylates(5-ASA)Glucocorticosteroids(GCS)ImmunosuppressantsAntibiotics(CiproandFlagyl)TraditionalTreatmentPyramidBasedonSeverityofCDSurgery

Bowelrest

Cyclosporine

Corticosteroids

Azathioprine

6-mercaptopurine

Methotrexate

Corticosteroids

Antibiotics

AminosalicylatesDiseaseSeverityMildModerateSevereInitialTreatment:Oral5-ASAtherapyTopicalTherapyDiseaseFlareorProgression:Oral5-ASAathigherdose(>4g/d)CorticosteroidsImmunomodulatorsSteroidDependentorRefractoryorSevereColitis:CyclosporineSurgery

ApproachtoMedicalTreatmentofUCEarlyorMildDisease:

5-ASAagents

Antibiotics(FlagylorCipro)ModeratetoSevereDisease:Corticosteroids

ImmunomodulatorsBiologicResponseModifiers:Remicade

Fistulizing

Crohn’sDisease:Antibiotics:Flagyl,Cipro

Immunomodulators:6-MP/Imuran

RemicadeApproachtoMedicalTreatmentofCrohn’sdiseaseSASP5-ASAtop.SASP/ASAPrednisoloneSteroidEnema020406080100%SuccessDrugPlaceboTA39%TA41%TA56%TA56%TA45%CUT/03/21META-ANALYSISOFDRUGTREATMENT

OFULCERATIVECOLITISKornbluth,1993CUT/01/11DOSEFINDINGFOR5-ASA

INACTIVEULCERATIVECOLITISKruis,AGA20008weeks 3x0.5g 3x1.0g 3x1.5g

(n=104) (n=104) (n=104)Remission(CAI<4) 50 66* 55Timetoresponse 27.5 26.5 21.6

(days,mean)Endoscopicremission(%) 28 48* 49Histologicalimprovement(%) 42 56* 63Stopduetosideeffects(n) 11 7 9 CUT/05/17COMBINEDORALANDENEMA5-ASAFOREXTENSIVEACTIVEULCERATIVECOLITISP.Marteau,2005

Oral5-ASA,2x2g/d

8weeks +Placebo +Enema,1g/d

(4weeks)

Remission 4weeks(%) 34 44

8weeks(%) 43 64*Improvement 4weeks(%) 62 89*

8weeks(%) 68 86**=significantCUT/03/07DOSEFINDINGFORCYCLOSPORININSEVEREULCERATIVECOLITISG.VanAssche,AGA2002PatientswithCAI>10,8daystherapy,followedbyNeoral?

2mg/kg 4mg/kg

(n=35) (n=35)

Plasmalevel(corrected,ng/ml) 150-250 250-350CAI>3and<10(%) 83 82Colectomy(2months,n) 3 5CAI(median) 7 7CUT/03/42REMISSIONMAINTENANCEINULCERATIVECOLITISRiley,1988

Mesalazine SASP

0.8g 2g

(n=48) (n=44)

Relapserate(%) 38 39Sideeffects

Headache(%) 8 27

abdominaldiscomfort(%) 12 32CA/02/15STEROIDSFORIBD-

POPULATIONRELATEDDATACDn=173Steroidsn=74(43%)CR:43 PR:19 NR:12

(58%) (26%) (16%)UCn=185Steroidsn=63(34%)CR:34 PR:19 NR:10

(54%) (30%) (16%)1970-19931YearSurgery 28(38%)Remission 24(32%)Steroiddependent 21(28%)Surgery 18(29%)Remission 31(49%)Steroiddependent 14(22%)Faubion,2001~10%BudesonideLiver~90%metabolismintheliverBudesonideenemaCA/03/85BUDESONIDE-METABOLISM

AFTERRECTALAPPLICATIONBrattsand,1990CDT/03/62BUDESONIDE(pH-DEPENDENT)vsPREDNISONEINACTIVECDBarMeir,AGA19988weeks BUD,3x3mg Pred.(40mg,

(ITT/PP) 30mg,5mgtaper)

(n=100) (n=101)

Remission(%) 51.0/56.0 52.5/55.2RemissionwithoutSE(%) 30.0/33.3 13.9/13.8*SE(n)** 39 80

*p=0.004**Moonface,acne,buffalohump,hirsutismCDT/04/16AZATHIOPRINEINACTIVECROHN′SDISEASE–SHORTANDLONG-TERMEFFECTSCandy,1995 Prednisolone

(12weeks,tapered)

+ +

Placebo Azathioprine,2.5mg/kg

(n=30) (n=33)

Remission12weeks(%) 63 73Remission15months(%) 7 42*

*=significantFrom12weeksononlyAZA!CDT/03/03INFLUENCEOFSMOKINGONTHECOURSEOFCD-INTERVENTIONSTUDYmonthsafterinclusionriskofaflare(%)ex-smokers (n=59)smokers (n=59)non-smokers (n=59)Cosnes,2001WHYDOWENEED

NEWTREATMENTSFORIBD?CA/02/16Lifeexpectancynormalized,socialintegrationpreserved>90%,acutediseasetreatedeffectively

inmostcasesProblems: - Somerefractoryandmoresteroid

dependentcases

- Sideeffectsofsteroidsandotherdrugs

- Highrelapseratein50%ofpatients

- Nomucosalhealing

Healingandnormallifequalityare

predominantgoals!ImmuneInterventionalTherapyforIBDAgPresentationTCellsTHCellsMastCellsMacrophagesBCellsIL2IFNgO2-CYCLOSPORINEANTI-METABOLITESO2-

SCAVENGERSINHIBITORSHYDROXY-CHLOROQUINETherapeuticUsesof

MonoclonalAntibodiesAntibodiescanbe

designedtotarget

anysubstancethat

isimmunogenicEnzymesCellular

structureProteinsAntibodyNeutralizationofTNF-TNFTNFTNF-ABcAMPIL-10ThalidomideMetalloproteinase

inhibitorTNF-TrimerTNF-ABApoptosisTNFCA/03/42EFFECTSOFANTITNF-STRATEGIESHealingofColonicUlceration

WithInfliximabReprintedwithpermissionofvanDullemenHMetal.Gastroenterology.1995;109:129.Pretreatment4Weeks

posttreatmentMucosalHealingWithInfliximab:HistologicH&EStaining

CourtesyofK.Geboes,MD.Pre-treatment4Weeks

Post-treatmentInfliximabinPatients

WithFistulizingCDPerianalFistulaCaseStudyPretreatment2Weeks10Weeks18WeeksPresentDHetal.NEnglJMed.1999;340:1398.TheFutureofBiologicTherapyinIBDMappingofIBDgenesmatchedwithphenotypeA“glimpse”intothefuture:extractDNAfrompttodefineimmunemediatedinflammatorydisease.administerbiologicresponsemodifierbasedongeneticallydeterminedcytokineprofile.maintainremissionwithbiologicresponsemodifierorcyclingofagents.CA/02/22Substance CD UCIL-1RA (–) ?

TNF-AB + +

RNF-R75and55 – ?

MAP-kinase-inhibitor – ?NFkBp65antisense (+) (+)Anti-CD4() + ?(SE)

Anti-CD3 (+) (+)Anti-IL-12() (+) ?

Anti-INFg – ?

Anti-Il-2R ? (+)

IL-10 (+) ?

AntiCD40L – –(SE)Antia4integrin() (+) ?

Antia4b7integrin (–) (+)

AntiICAM-1 – (+)EGF ? (+)

KGF ? –INFa (–) –

INFb (–) (+)

GCSF/GMCSF (+) ?

Growthhormone (+) ?

DHEA (+) (+)

IL-11 (–) ??BIOLOGICTREATMENTS“

FORIBD

STATEOFDEVELOPMENT07/2006CDT/05/24TOPDOWNvsSTEPUPTHERAPYINCROHN′SDISEASE129patientswithactiveandnewlydiagnosed(?)

Crohn′sdisease

Infliximab GCS

5mg/kg 40mg/d

0,2,6weeks tapered

+AZA2.5mg/kg/d over8weeks

Endpoint*reached6months (%) 74.5 48.1**CDAI