结--缔--组--织--病

,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,2020/11/3,*,结 缔 组 织 病,北京大学第三医院皮肤科,谢志强,2020/11/3,1,结缔组织病 connective tissue disease,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。,2020/11/3,2,红 斑 狼 疮,Lupus Erythematosus,2020/11/3,3,一 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。,Lupus erythematosus,root designation,LE as clinical spectrum,2020/11/3,4,分 类,1.盘状红斑狼疮（Discoid Lupus Erythematosus ,DLE）,2.亚急性皮肤型红斑狼疮,（Subacute Cutaneous lupus Erythematosus,SCLE）,3.系统性红斑狼疮（Systemic Lupus Erythematosus.SLE）,2020/11/3,5,LE-specific skin disease,Acute cutaneous LE(ACLE),Subacute cutaneous LE(SCLE),Chronic cutaneous LE(CCLE),The essence of LE is in its heterogeneity,Focus on the cutaneous features,Especially the LE-specific skin lesions,2020/11/3,6,Historic aspects,Cazenave is credited for first using the term Lupus erythemateaus in 1851 to distinguish cutaneous LE from cutaneous tuberculosis(lupus vulgaris),Skin disease is the second most frequent clinical manifestation of LE after joint inflammation,2020/11/3,7,二 临床表现,2020/11/3,8,1.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。,2020/11/3,9,CCLE,Clasic DLE: localized generalized DLE red-purple macules papules,small plaques,hyperkeratotic surface.follicular involvement is aa prominet feature,Hyper trophic DLE,LE profundus/LE panniculitis,Mucosal; DLE,Chilblains LE/perniotic LE,Lupus tumidus,2020/11/3,10,2020/11/3,11,2020/11/3,12,2020/11/3,13,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+,2020/11/3,14,2. 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+,daDNA Sm,抗体+ 部分皮损直接免疫荧光+,2020/11/3,15,SCLE,Hyperkeratotic papulosquamous,Annular/polycyclic plaques,Erythema multiforme,Toxic epidermal necrolysis,Exfoliative erythroderma,15-20%SCLE develop ACLE or Classic DLE,50%SCLE meet the American criteria SLE,2020/11/3,16,2020/11/3,17,2020/11/3,18,2020/11/3,19,3. 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,2020/11/3,20,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,2020/11/3,21,ACLE:localized classic butterfly rash,generalized morbilliform,exanthematus eruption focused over the extensor maculopapular rash of SLE,Extremely acute forms toxic epidermal necrolysis,2020/11/3,22,2020/11/3,23,2020/11/3,24,2020/11/3,25,2020/11/3,26,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,2020/11/3,27,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,2020/11/3,28,（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,2020/11/3,29,（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 CH50 C3 C4 低下,80%+ 特异型较高 活动,2020/11/3,30,（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,2020/11/3,31,三 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）,2020/11/3,32,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0.5,g/d,或细胞管型）,2020/11/3,33,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,2020/11/3,34,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,2020/11/3,35,Camparison of the major types of LE-specific skin disease,Clinical features ACLE SCLE C- DLE,Induration 0 0 +,Dermal atrophy 0 0 +,Pigment change + + +,Follicular plugging 0 0 +,Hyperkeratosis + + +,2020/11/3,36,histopathology,ACLE SCLE C-DLE,Thickened basement 0 + +,membran,Lichenoid infiltrate + + +,Periappendageal,Inflammation 0 + +,2020/11/3,37,Lupus band ACLE SCLE C-DLE,Lesions + + +,Nonlesional + + 0,ANA + + +,SSA/RO Ab + + 0,Ds-DNA Ab + + 0,C3 + + +,Risk for developing,SLE + + +,2020/11/3,38,四 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,2020/11/3,39,2020/11/3,40,Etiology,Genetic associations,ACLE isusually encountered in patients having overt SLE,SLE-HLA-DR2,DR3,SCLE: HLA-B8,DR3,haplotype,DLE: HLA-B7,B8,Cw7,DR2,DR3,DQw1,2020/11/3,41,Envirnmental factors,UV radiation UVA,UVB,Drugs :procainamide,Infections of all types;viral infection,2020/11/3,42,Passible pathogenetic machanisms,Environmental stimulis,genetic susceptible indivdialneoantigen formation,autoantigen modulationcross-reactive with homologous auoantigensautoimmune responsesdeposition of Ig and Ctissue injury(C-mediated lysis,ADCC),2020/11/3,43,Autoantigen-specific T cell play a role in the pathogenesis of forms of cutaneous LE, type hypersensitivity,2020/11/3,44,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,2020/11/3,45,五 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%,2020/11/3,46,treatment,Protection from sunlight and artificial sources of UV radiation,Avoid photosensitizing drugs,Local therapy;local glucocorticoids,intralesional glucocorticoids,Systemic therapy:antimalarials,nonimmunosuppressive options for antimalarials refractory disease,systemic glucocorticoids,other immunosuppressives,2020/11/3,47,Option for systemic therapy in cutaneous LE,First line,hydroxychloroquin,hydroxychloroquin+quinacrine,chloroquin+quinacine,Second line,dapsone,retinoids,thalidomide,Third line,Clofazimine,gold,2020/11/3,48,Fourth line,Systemic glucocorticoids,Oral prednisone,Pulse intravenous methylprednisolone,Azathioprine,Methotrexate,Cyclophosphamide,Evolving/experiment: Cyclosporine,high dose IV gamma globulin,CD4+cell-depleting McAb,phototherapy(UVA1),2020/11/3,49,prognosis,ACLE:hypertension,nephritis,systemic vasculitis,central nervous system disease,SCLE;15%,SLE,CCLE:cutaneous dystrophy ,scaring alopecia,2020/11/3,50,皮 肌 炎,Dermatomyositis,2020/11/3,51,一 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）,2020/11/3,52,Dernatomyositis is a disease in which characteristic patterns of autoimmunue injury occue in striated muscle and skin,2020/11/3,53,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,2020/11/3,54,二 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。,2020/11/3,55,Systemic manifestations/associations of dermatomyositis/polymyositis,Musculoskeletal,Myositis with proximal weakness,Muscle atrophy and contracture,Muscle calcification,Cardiac,cardiomyopathy,canduttion defects,2020/11/3,56,Respiratory,Dysphonia,Diffuse intersstitial pneumonitis/fibrosis,Aspiration pneumonia,Respiratory failure,Gastrointestinal,Proximal dysphagia,Large bowel infarction/perforation secondary to vasculopathy,Ophthalmologic,Retinopathy,Internal malignancy,2020/11/3,57,2020/11/3,58,2020/11/3,59,2020/11/3,60,2020/11/3,61,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,2020/11/3,62,（3）抗Mi-2抗体 对DM特异，阳性，95%皮疹，肺间质病变少,The histopathology of cutaneous dermatomyositis include is similar to that of certain forms of cutaneous lupus erythematosus,Immunopathology of cutaneous dermatomyositis includes a variable degree of Ig and C deposition at dermal-epidermal junction and within the dermal microvasculature,membrane attack complex(c5-9),2020/11/3,63,三 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,2020/11/3,64,5=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,2020/11/3,65,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,2020/11/3,66,etiology,Polymyositis and dermatomyositis:HLA-B8,DR3,DRw52,Environmental factors:seasonality,infectious etiology,coxsackievirus,echovirus,T-cell leukemia virus type ,HIV,toxoplasma gondii,drugs;silicone breast implants,silicon,2020/11/3,67,pathogenesis,Cell-mediated immunity against muscle autoantigens is thought to be responsible for the mucle injury that occurs in polymyositis,whereas humoral autoimmune mechanisms have been implicated in the pathogenesis of muscle and skin injury in dermatomyositis,2020/11/3,68,五 治 疗,首选激素，+细胞毒药物,Local,systemic,2020/11/3,69,硬皮病,Scleroderma,2020/11/3,70,一 概 念,硬皮病（Scleroderma）新称系统性硬化症（systemic sclerosis,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。,2020/11/3,71,二 临床表现,局限性硬皮病（硬斑病）,分为斑块状、线状及泛发性硬斑病,系统行硬斑病,肢端型、弥漫硬化型，CREST综合征,2020/11/3,72,早期，隐，雷诺现象，手指肿，僵，关节痛,皮肤病变双手指及面；躯干至面,水肿期硬化期- 萎缩期,面部典型表现为假面具样改变,2020/11/3,73,2020/11/3,74,2020/11/3,75,2020/11/3,76,2020/11/3,77,2020/11/3,78,关节肌肉痛,胃肠道，吞，噎感，腹胀,肺，胸膜炎，肺间质纤维化,心包积液,肾,抗Scl-70抗体弥漫性系统性硬化病标志性抗体，肺受累,抗着丝点抗体（ACA）局限性系统性标志性抗体，不易发生肾肺损害,2020/11/3,79,三 诊 断,雷诺现象，皮肤表现（皮肤硬化），内脏受累，特异性抗核抗体,2020/11/3,80,四 病因分析与发病机制,遗传+环境因素,2020/11/3,81,五 治 疗,缺乏特效治疗药物,2020/11/3,82,参考书,1.Wallace DJ et al . Dubois lupus Erythematosus(97),2.Wilkinson DS et al . Textbook of Dermatoloty(98),3.Fitzpatrick TB et al .Dermatoloty in General Medicine.(99),4.陈敏章 中华内科学（99）,5.陈灏珠 实用内科学（97）,6.杨国亮 现代皮肤病学（96）,7.赵辩 临床皮肤病学（2001）,2020/11/3,83,病例一：一位23岁青年女性，向你主诉她患严重的面部晒伤，她刚从海南岛度蜜月回来，在那她曾暴露于强光下。早在三个月前她开始服用避孕药，问及病史她还有疲劳和关节痛。,问题：你在诊断中考虑何种疾病？你将作什么实验室检查？处理计划如何？,2020/11/3,84,病例2：一位70岁男性向你主诉严重疲乏和软弱无力，在他的指背和手背上有红色斑疹。,问题：这些描述提示什么诊断？你将如何证实？如何处理？有什么合适的检查项目？,2020/11/3,85,