伴肺部損害的自身免疫?。鯂?guó)春

伴肺部損害的自身免疫病北京中日友好醫(yī)院

Evidence-BasedMedicineDeptofRheumatologyDeptofRheumatologyCTD-ILDILDinestablishedCTDCTDpresentingasILDILD

withfeatures

ofautoimmunityCTD-ILD有幾種類(lèi)型？1DeptofRheumatologyCTD-ILDILD

withfeatures

ofautoimmunity

UCTD-ILDLung-dominantCTDILDwithautoantibodiesA

formes-frustes

ofautoimmunerheumatic

diseaseDeptofRheumatologyCTD-ILDInterstitialpneumoniawithautoimmunefeatures

(IPAF)Presenceofaninterstitialpneumonia(byHRCTorsurgicallungbiopsy)and,Exclusionofalternativeaetiologies

and,DoesnotmeetcriteriaofadefinedCTDand,Atleastonefeaturefromatleasttwoofthesedomains:A.Clinicaldomain

B.Serologicdomain

C.MorphologicdomainDeptofRheumatologyCTD-ILDInterstitialpneumoniawithautoimmunefeatures

(IPAF)A.ClinicaldomainDistaldigitalfissuring(i.e.“mechanichands”)DistaldigitaltipulcerationInflammatoryarthritisorpolyarticularmorningjointstiffness?60minPalmartelangiectasiaRaynaud’sphenomenonUnexplaineddigitaloedema

Unexplainedfixedrashonthedigitalextensorsurfaces(Gottron’ssign)DeptofRheumatologyCTD-ILDInterstitialpneumoniawithautoimmunefeatures

(IPAF)B.SerologicdomainANA>1:320Rheumatoidfactor?2×upperlimitofnormalAnti-CCPAnti-dsDNAAnti-Ro(SS-A)Anti-La(SS-B)Anti-ribonucleoproteinAnti-SmithAnti-topoisomerase(Scl-70)Anti-tRNA

synthetase

Anti-PM-Scl

Anti-MDA-5DeptofRheumatologyCTD-ILDInterstitialpneumoniawithautoimmunefeatures

(IPAF)C.MorphologicdomainSuggestiveradiologypatternsbyHRCT:

a.NSIP;b.OP;c.NSIPwithOPoverlap;d.LIPHistopathologypatternsorfeaturesbysurgicallungbiopsy:

a.NSIP;b.OP;c.NSIPwithOPoverlap;d.LIP

e.Interstitiallymphoidaggregateswithgerminalcentres

f.Diffuselymphoplasmacytic

infiltrationMulti-compartmentinvolvement(inadditiontointerstitialpneumonia):

a.Unexplainedpleuraleffusionorthickening

b.Unexplainedpericardialeffusionorthickening

c.Unexplainedintrinsicairwaysdiseased.Unexplainedpulmonaryvasculopathy

RA-ILDSSc-ILDIIM-ILDOtherCTD-ILDCTD-ILDDeptofRheumatologyRA-ILDPrevalence:3.5%-41%inRA(方法,時(shí)間)Histopathologicaltypes:UIPandNSIParethemostcommontypes,OthersubtypesincludeOP,AIPorDAD,LIP,andDIPDeptofRheumatologyRFAnti-CCPSmokingGeneticfactors(HLA-B40,B54polymorphisms)RA-ILDBiomarkers/riskfactorsDeptofRheumatologyRA-ILDNoRCTsexisttoguidepharmacologicaltherapyspecificallyinRA-ILD.Steroidswereoftenusedasfirstlineagentswithhighlyvariableresults.NSIPandOP-ILDsubtypesaresteroidresponsive.NSIPsubtypecanbemanagedwithaggressivesteroidtherapyOtherregimenthatincludespulsedCTXivandsteroids.PtswhorespondwellaremaintainedonoralAZAandsteroidstreatmentDeptofRheumatologyRA-ILDThemanagementofasymptomaticILDinRAptsremainsunclear.ItisnotknownwhethertreatmentwillalterthecourseofthediseaseinthesecasesMTXhasbeenestablishedasasourceofpneumonitisin0.5%to14%oftreatedpts.ButMTXhasnotbeenconclusivelyshowntoworsenRA-ILDdirectlyLEF,anotherDMARD,hassimilarassociationswithILDreportedintheliterature.treatmentDeptofRheumatologyRA-ILD3例RA-ILD用MMF治療一年，ILD及關(guān)節(jié)炎均有改善

SaketkooLA,etal.RA-ILD:MMFasanantifibroticandDMARD.ArchInternMed2008:168:1718.ChangHK,ParkW,RyuDS.SuccessfultreatmentofprogressiverheumatoidILDwithcyclosporine:acasereport.J.KoreanMed.Sci.17,270–273(2002).CohenJM,etal.InterstitialpneumonitiscomplicatingRA.Sustainedremissionwithazathioprinetherapy.Chest72,521–524(1977).MMF,CosA,AZADeptofRheumatologytreatmentSSc-ILDCTD-ILDDeptofRheumatologySSc-ILDPrevalence:occurringtosomedegreeinabout80%ofpatientswithdiffusecutaneoussclerodermaandin20%ofpatientswithlimitedskindisease.Histopathologicaltypes:Themostcommonpatternisnonspecificinterstitialpneumonia(NSIP),theothersarerare.DeptofRheumatologyDiffuseskininvolvementEsophagealinvolvementAnti-SCL-70vsanti-RNPSSc-ILDBiomarkers/riskfactorsDeptofRheumatologySSc-ILDNEnglJMed2006;354:2655-66(USA).Treatment:CTXAt13clinicalcenters,enrolled158patientswithSSc.PatientsreceivedoralCTX(≤2mg/kg/D)ormatchingplaceboforoneyearandwerefollowedforanadditionalyear.Theprimaryendpointwastheforcedvitalcapacity(FVC)at12months,afteradjustmentforthebaselineFVC.DeptofRheumatologySSc-ILDDeptofRheumatologySSc-ILDDeptofRheumatologySSc-ILDCONCLUSIONSOneyearoforalCTXinsymptomaticSSc-ILDhad

asignificantbutmodestbeneficialeffecton：

lungfunction,Dyspnea,Thickeningoftheskin,Health-relatedqualityoflife.Theeffectsonlungfunctionweremaintainedthroughthe24monthsofthestudyDeptofRheumatologySSc-ILDHoylesRK,etal.Amulticenter,prospective,randomized,double-blind,placebo-controlledtrialofcorticosteroidsandintravenouscyclophosphamidefollowedbyoralazathioprineforthetreatmentofpulmonaryfibrosisinscleroderma.ArthritisRheum.54,3962(2006)UK.45patientswithSSc-ILDwhowererandomizedtoreceiveprednisoloneandsixCTXinfusionsorplacebo.Theestimatedrelativetreatmenteffectinthisstudyrevealedameanimprovementof4.19%ofFVC,butDLCOwasnotimproved.

Treatment:CTXDeptofRheumatologySSc-ILDZamoraevaluated17ptswithSSc-ILDtreatedwithMMFforupto24months.At12months,FVCandDLCOhadimprovedby2.6and1.4%,respectively,whileat24monthstheincreaseinFVCwas2.4%.Gerbinoetal.evaluatedMMFin13patientswithearlySSc-ILDandfoundthatasignificantimprovementinFVCwasnotedafter12monthsoftreatmentZamoraAC,etal.Respir.Med.102,150–155(2008).GerbinoAJ,etal.Chest133,455–460(2008).Treatment:MMF兩相回顧性分析研究證明MMF治療12個(gè)月改善FVCDeptofRheumatologySSc-ILDMMForCTX,Whichisbetter?treatmentConclusion：MMFpresentsasafetherapeuticalternativeforthiscondition.Asfarasdrugefficacyisconcerned,ourdatacannotsupportanyclearsuperiorityofMMFoverCTX.WeproposeMMFcouldbeusedforpatientsforwhomCTXisintolerableorcontraindicated.GREECEDeptofRheumatologySSc-ILDAzathioprineappearstobelessefficaciousinSSc-ILDthanoraldailyCTX.Aretrospectiveseriesof27ptswithSSc-ILDfoundimprovementsinpulmonaryfunctiontestsafteracombinationof6monthsofmonthlyCTXIVfollowedby18monthsofAZANadashkevichO,etal.Clin.Rheumatol.25,205–212(2006).BéreznéA,etal.J.Rheumatol.35,1064–1072(2008).Treatment:AZADeptofRheumatologySSc-ILDTworetrospectivestudieshavedemonstratedclinicalbenefits,includinganimprovedskinscore,lessneworganinvolvementandimprovedsurvival.Aprospectivedouble-blindstudyrevealedthattherewasnodifferenceintheextentofskininvolvementorsurvivalwithd-penicillamineuse.ClementsPJ,etal.ArthritisRheum.42,1194–1203(1999).deClerckLS,etal.ArthritisRheum.30,643–650(1987).SteenVD,etal.ArthritisRheum.28,882–888(1985).Treatment:D-penicillamineDeptofRheumatologySSc-ILDColchicineusedfortreatingSSc-ILDdemonstratednoimprovementinlungfunction.GuttadauriaMetal..J.Rheumatol.4,272–276(1977).Treatment:ColchicineDeptofRheumatologyIIM-ILD的發(fā)病率IIM-ILD的發(fā)病機(jī)制IIM-ILD的臨床特征IIM-ILD的血清生物標(biāo)記物IIM-ILD的治療進(jìn)展及預(yù)后DeptofRheumatologyIIM-ILDIIM-ILD的發(fā)病率DeptofRheumatologyShuX,GWang,etal.BMCNeurology2011,11:143IIM-ILDEmergingdatahighlighttheimportanceofautoantigenexpressionandconformationinthetargettissue(lungandmuscle,inthiscase),aswellasidentifyingrelevantamplifyingpathways(suchasregeneration).DeptofRheumatologyGWick,201331,AnnuRevImmunolIIM-ILD的發(fā)病機(jī)制DeptofRheumatologyDeptofRheumatology天然免疫:Nets在PM/DM中的作用SigongZhang,GuochunWang,etal.ClinExpImmunol.2014;177(1):134-41DeptofRheumatology天然免疫:Nets在PM/DM中的作用PM/DM患者Nets形成增加以及DNA酶I活力降低導(dǎo)致的Nets降解減少,參與PM/DM的發(fā)病機(jī)制,尤其是在誘發(fā)ILD中起重要作用。SigongZhang,GuochunWang,etal.ClinExpImmunol.2014;177(1):134-41IIM-ILD的臨床特征ILD可以是PM/DM的首發(fā)癥狀.約18-20%發(fā)生在肌炎之前.大部分患者與肌病其他癥狀同時(shí)出現(xiàn)或之后出現(xiàn).咳嗽和呼吸困難是最常見(jiàn)的癥狀.DeptofRheumatologyIIM-ILD的臨床特征ILDoccurringinoneofthreepatternsbasedonsymptomsatpresentation:rapidlyprogressiveformwithacuteonsetsymptoms,subacuteformwithslowlyprogressivesymptoms,andasymptomaticorsubclinicalformwithanabnormalchestradiographoranabnormalpulmonaryfunctiontestbutwithoutanypulmonarycomplaints.ILDthatinitiallypresentsasaslowlyprogressiveorasymptomaticpatternalsocantransformintotherapidlyprogressivepatternduringthelatercourseofthediseaseDeptofRheumatologyIIM-ILD的臨床特征Theacuteformsoccur<20%ofPM/DM-ILD.RapidlyprogressiveILDwasnotedinpatientswithADM.ILDinthesepatientscharacteristicallyrespondspoorlytoevenaggressivetreatmentandprogressesrapidlytorespiratoryfailure.Upto30%ofPMandDMpatientsseemtohavesubclinicalorasymptomaticILD.Complaintsassociatedwithanotherorgandiseasemayoverwhelmsubtlepulmonarydiscomfortsinthesepatients.Thislackofovertsymptomsemphasizestheneedforpulmonaryscreeninginallmyositispatients,especiallythosewithMSAsDeptofRheumatology缺乏RCT研究異質(zhì)性大,治療反應(yīng)不一IIM-ILD的治療DeptofRheumatology糖皮質(zhì)激素是首選用藥免疫抑制劑(CYC,AZA,MMF,CSA,TAC)靜脈注射免疫球蛋白(IVIg)早期聯(lián)合GC+IS可能改善預(yù)后IIM-ILD的治療傳統(tǒng)治療多數(shù)是經(jīng)驗(yàn)性治療，無(wú)大樣本的隨機(jī),對(duì)照試驗(yàn)證實(shí)藥物的確切療效DeptofRheumatologyIIM-ILDTreatment:CTXDeptofRheumatologyIVCYCpulsesof0.3–1.0g/m2or10–30mg/kgwereappliedatweeklytomonthlyintervalsfor6–12monthstogetherwith

glucocorticoids.FVCandDLCOimprovedin57.6%and64.3%ofpatients.HRCTfindingsimprovedin67.3%ofpatients.IVCYCtreatmentallowed58.1%ofacute/subacuteIIM-ILDpatientstosurvive.DM-ILD3ptswithatleast1yearoffollowupreceivingMMFexperiencedcompletenormalizationofpulmonaryfunctiontests(includingDLCO)andresolutionofdyspnea.Theywerealsoabletoreducetheirpreddoses.Theonlyptwithpre-andposttreatmentchestCThadtotalresolutionofherinterstitialopacities.Thepatientwithonly5monthsofposttreatmentfollowupexperiencedanimprovementinDLCOfrom44%to77%predicted,butnochangeindyspnea.USAConclusion.ThesepromisingdataindicatethatMMFmaybeausefultherapyforILDinpatientswithDM,butlargerstudiesareneededtomoredefinitivelyevaluatetheroleofthismedicationintherapy.Treatment:MMFDeptofRheumatologyIIM-ILDCASEREPORTTreatment:MMFDeptofRheumatologyIIM-ILDUSATreatment:CTXMMFAZAIIM-ILDAmong46pts,24weretreatedwithCYC,13AZA,9MMF.Therewerenobaselinedifferencesbetweenthethreetreatmentgroupsforanyofthedemographicorphysiologicvariables,d