结缔组织病.ppt

结缔组织病,北京大学第三医院皮肤科谢志强,结缔组织病connectivetissuedisease是指与免疫有关侵犯多系统的组织、器官中疏松结缔组织胶原纤维和基质的一组疾病，属于自身免疫性疾病的范畴。患者病变组织中有淋巴细胞浸润，血清中可测出多种自身抗体。应用糖皮质激素免疫抑制剂治疗有效。主要包括：红斑狼疮、皮肌炎、硬皮病。,红斑狼疮,LupusErythematosus,一概念,红斑狼疮是一组以累及皮肤及多脏器损害为特点的自身免疫性结缔组织病，是一组病谱性疾病。LupuserythematosusrootdesignationLEasclinicalspectrum,分类,1.盘状红斑狼疮（DiscoidLupusErythematosus,DLE）2.亚急性皮肤型红斑狼疮（SubacuteCutaneouslupusErythematosus,SCLE）3.系统性红斑狼疮（SystemicLupusErythematosus.SLE）,LE-specificskindiseaseAcutecutaneousLE(ACLE)SubacutecutaneousLE(SCLE)ChroniccutaneousLE(CCLE)TheessenceofLEisinitsheterogeneityFocusonthecutaneousfeaturesEspeciallytheLE-specificskinlesions,HistoricaspectsCazenaveiscreditedforfirstusingthetermLupuserythemateausin1851todistinguishcutaneousLEfromcutaneoustuberculosis(lupusvulgaris)SkindiseaseisthesecondmostfrequentclinicalmanifestationofLEafterjointinflammation,二临床表现,1.盘状红斑狼疮,典型皮损：暗红斑，上覆粘着性鳞屑，其下有刺状毛囊角栓。皮损分布：头面（限局型），手、足、四肢躯干（播散型），好发于面部不对称。自觉症状：烧灼，微痒或无不适。,CCLE,ClasicDLE:localizedgeneralizedDLEred-purplemaculespapules,smallplaques,hyperkeratoticsurface.follicularinvolvementisaaprominetfeatureHypertrophicDLELEprofundus/LEpanniculitisMucosal;DLEChilblainsLE/pernioticLELupustumidus,发生过程：小丘疹或片状红斑-扩大圆形或不规则型色暗边缘凸中央萎淡界清盘状-继发色素脱失或沉着。有粘膜损害永久脱发日晒加重癌变。全身症状：无实验室检查：ANA+大多数皮损直接免疫荧光+,2.亚急性皮肤型红斑狼疮,典型皮损：丘疹鳞屑型环形红斑型皮损分布：面、耳、上胸、背、肩和手背发生过程：初小丘疹-斑-屑或水肿性丘疹-扩大环不留瘢痕。全身症状：有但肾、中枢神经少累及实验室检查：SSA/Ro+SSB/La+ANA+daDNASm抗体+部分皮损直接免疫荧光+,SCLE,HyperkeratoticpapulosquamousAnnular/polycyclicplaquesErythemamultiformeToxicepidermalnecrolysisExfoliativeerythroderma15-20%SCLEdevelopACLEorClassicDLE,50%SCLEmeettheAmericancriteriaSLE,3.系统性红斑狼疮,好发于中青年女性，临床表现复杂，皮损和多器官损害。早期仅侵犯1-2个器官-表现不典型误诊，以后侵犯多个器官-表现复杂，大多缓解与发作交替,典型皮损特征皮损即有意义的皮损：（1）面部蝶型红斑（2）盘状红斑（3）甲周红斑指尖红斑或出血点（4）狼疮发（5）光敏感,ACLE:localizedclassicbutterflyrashgeneralizedmorbilliform,exanthematuseruptionfocusedovertheextensormaculopapularrashofSLEExtremelyacuteformstoxicepidermalnecrolysis,全身症状发热乏力骨关节病变肌肉痛眼干燥综合征肾、心脏病变以及呼吸系统、中枢神经系统、消化系统、血液系统病变,实验室检查自身抗体,总抗核抗体与抗核抗体组分（1）ANA+反映多种抗核抗体组分敏感性95%SLE筛选试验特异性65%血清效价1：80（2）抗dsDNA抗体+特异性95%敏感性70%-SLE特异性疾病活动疗效指标,（3）抗Sm抗体+对SLE特异性强特异性99%-敏感性25%SLE不活动也可以回顾诊断（4）抗核糖核蛋白（RNP）抗体+40%雷诺现象肾损害少（5）SSA/Ro+30%-SLE伴干燥综合征或亚急性皮肤型红斑狼疮老人、新生儿狼疮（6）SSB/La抗体,（7）抗核糖体P蛋白抗体Rib-p(rRNP)阳性15%特异性较高，常有神经系统损害（8）抗心磷脂抗体+50%血栓血小板减少网状青斑小腿溃疡神经系统症状流产（9）血清总补体CH50C3C4低下80%+特异型较高活动,（10）狼疮带试验皮损和外观正常皮肤直接免疫荧光IgG沉着70%+（11）肾活检、CT,超声心动图等,三诊断,病史体格检查（典型皮损）实验室检查1.盘状红斑狼疮2.亚急性皮肤型红斑疮3.系统性红斑狼疮（82美国风湿学会分类标准）,颧部红斑（平高固定）盘状红斑光过敏口腔溃疡关节炎（非2上）浆膜炎（胸心）肾病变（蛋白尿0.5g/d或细胞管型）,神经病变（癫痫）血液系统异常免疫学异常（抗dsDNA抗体，抗Sm抗体，抗心磷脂抗体抗核抗体）11条，病程中任何时候4条以上可诊断，特异型98%敏感性97%-SLE,上海风湿学会标准（1987）,C3狼疮带试验（非皮损），肾病理美国标准11早期病例敏感性高,CamparisonofthemajortypesofLE-specificskindisease,ClinicalfeaturesACLESCLEC-DLEInduration00+Dermalatrophy00+Pigmentchange+Follicularplugging00+Hyperkeratosis+,histopathology,ACLESCLEC-DLEThickenedbasement0+membranLichenoidinfiltrate+PeriappendagealInflammation0+,LupusbandACLESCLEC-DLELesions+Nonlesional+0ANA+SSA/ROAb+0Ds-DNAAb+0C3+RiskfordevelopingSLE+,四病因和发病机制,病因内因遗传因素外因物理感染药物性激素（雌）精神因素,Etiology,GeneticassociationsACLEisusuallyencounteredinpatientshavingovertSLESLE-HLA-DR2,DR3SCLE:HLA-B8,DR3,haplotypeDLE:HLA-B7,B8,Cw7,DR2,DR3,DQw1,Envirnmentalfactors,UVradiationUVA,UVBDrugs:procainamideInfectionsofalltypes;viralinfection,Passiblepathogeneticmachanisms,Environmentalstimulisgeneticsusceptibleindivdialneoantigenformation,autoantigenmodulationcross-reactivewithhomologousauoantigensautoimmuneresponsesdepositionofIgandCtissueinjury(C-mediatedlysis,ADCC),Autoantigen-specificTcellplayaroleinthepathogenesisofformsofcutaneousLE,typehypersensitivity,发病机制遗传因素外因作用免疫功能紊乱（细胞、体液）细胞凋亡异常自身致敏T淋巴细胞B细胞多克隆活化大量自身抗体细胞因子，型变态反应皮肤多器官损害,五治疗,治疗原则个体化权衡治疗效果/药物严重反应风险比激素细胞毒药物环孢菌素丙种球蛋白雷公藤中药10年存活率75%,treatment,ProtectionfromsunlightandartificialsourcesofUVradiationAvoidphotosensitizingdrugsLocaltherapy;localglucocorticoids,intralesionalglucocorticoidsSystemictherapy:antimalarials,nonimmunosuppressiveoptionsforantimalarialsrefractorydisease,systemicglucocorticoids,otherimmunosuppressives,OptionforsystemictherapyincutaneousLE,Firstlinehydroxychloroquinhydroxychloroquin+quinacrinechloroquin+quinacineSecondlinedapsone,retinoids,thalidomideThirdlineClofazimine,gold,FourthlineSystemicglucocorticoidsOralprednisonePulseintravenousmethylprednisoloneAzathioprineMethotrexateCyclophosphamideEvolving/experiment:Cyclosporine,highdoseIVgammaglobulin,CD4+cell-depletingMcAb,phototherapy(UVA1),prognosis,ACLE:hypertension,nephritis,systemicvasculitis,centralnervoussystemdiseaseSCLE;15%SLECCLE:cutaneousdystrophy,scaringalopecia,皮肌炎,Dermatomyositis,一概念,皮肌炎（Dermatomyositis,DM）（特发性炎症性肌病）是一种主要累及皮肤肌肉的非感染性炎症性疾病，为自身免疫性结缔组织病之一。皮肤未累及或仅有肌肉症状时称为多发性肌炎（Polymyositis,PM）,Dernatomyositisisadiseaseinwhichcharacteristicpatternsofautoimmunueinjuryoccueinstriatedmuscleandskin,分类,1.皮肌炎2.多发性肌炎3.合并或重叠其他结缔组织疾病的皮肌炎或多发性肌炎4.合并恶性肿瘤的皮肌炎或多发性肌炎5.儿童皮肌炎6.无肌病性皮肌炎高峰5-14岁，45-64岁,二临床表现,1皮肤表现典型皮损上眼睑紫红斑Gottron征颈前及上胸V字型红皮疹2肌肉症状四肢近端肌（髋，臀，肩胛带）痛无力3其他发热，消瘦，间质肺炎，关节炎等，肾损害少。,Systemicmanifestations/associationsofdermatomyositis/polymyositis,MusculoskeletalMyositiswithproximalweaknessMuscleatrophyandcontractureMusclecalcificationCardiaccardiomyopathycanduttiondefects,RespiratoryDysphoniaDiffuseintersstitialpneumonitis/fibrosisAspirationpneumoniaRespiratoryfailureGastrointestinalProximaldysphagiaLargebowelinfarction/perforationsecondarytovasculopathyOphthalmologicRetinopathyInternalmalignancy,肌酶肌红蛋白，尿肌酸，肌电图，肌活检自身抗体（1）抗氨酰tRNA合成酶抗体（胞浆蛋白）（抗Jo-1,EJ,PL-12,7）抗Jo-1阳性肺间质病变，多关节炎，雷诺现象，机工手称抗合成酶综合征或抗Jo-1综合征（2）抗SRP抗体与抗Jo-1综合征不同，急重心肌损害，对激素反应差。对PM特异,（3）抗Mi-2抗体对DM特异，阳性，95%皮疹，肺间质病变少ThehistopathologyofcutaneousdermatomyositisincludeissimilartothatofcertainformsofcutaneouslupuserythematosusImmunopathologyofcutaneousdermatomyositisincludesavariabledegreeofIgandCdepositionatdermal-epidermaljunctionandwithinthedermalmicrovasculature,membraneattackcomplex(c5-9),三诊断,（1）四肢近端肌无力（2）肌酶谱升高（3）肌电图肌源性改变（4）肌活检异常（5）皮肤特征性改变,5=DM前4=PM前2/4+皮疹=很可能DM前3/4=很可能PM前1/4+皮疹=可能DM前2/4=可能PM注意合并其他CT及肿瘤,病因,在遗传易感个体，感染及非感染因素下诱发一组疾病。皮肌炎与体液免疫紊乱有关，多发性肌炎与细胞介导的免疫紊乱有关,etiology,Polymyositisanddermatomyositis:HLA-B8,DR3,DRw52Environmentalfactors:seasonality,infectiousetiology,coxsackievirus,echovirus,T-cellleukemiavirustype,HIV,toxoplasmagondiidrugs;siliconebreastimplants,silicon,pathogenesis,Cell-mediatedimmunityagainstmuscleautoantigensisthoughttoberesponsibleforthemucleinjurythatoccursinpolymyositiswhereashumoralautoimmunemechanismshavebeenimplicatedinthepathogenesisofmuscleandskininjuryindermatomyositis,五治疗,首选激素，+细胞毒药物Localsystemic,硬皮病,Scleroderma,一概念,硬皮病（Scleroderma）新称系统性硬化症（systemicsclerosis,SSc）是一种以皮肤及各系统胶原纤维进行性硬化为特征的自身免疫性疾病，也是一组病谱性疾病。临床上分局限性和系统性两大类。高峰30-50岁。,二临床表现,局限