系统性小血管炎诊治及进展(2016-4-26)

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,*,*,上海交通大学医学院附属新华医院肾脏科,蒋更如,2016-4-26,系统性小血管炎,诊治及进展,系统性血管炎是指以血管壁坏死性炎症和,/,或纤维素样坏死为主要病理特征的一类自身免疫性疾病,病变血管局限于微小动脉、静脉和毛细血管时为,小血管炎,系统性小血管炎,原发性系统性小血管炎,显微镜下型多血管炎（,MPA,）,韦格纳肉芽肿病（,WG,）,变应性肉芽肿性血管炎（,CSS,）,过敏性紫癜,原发性冷球蛋白血症性血管炎,皮肤白细胞碎裂性血管炎,Jennette et al.,Arthritis Rheum,1994;37:187-192,ANCA,相关性血管炎（,AAV,）,1994,年,Chapel Hill,会议命名,2011 15,th,International vasculitis &ANCA worksho,European League Against Rheumatism(EULAR) EuropeanVasculitis Study Group (EUVAS),Microscopic polyangiitis,(MPA),Granulomatosis with polyangiitis,(GPA),Eosinophilic Granulomatosis with Polyangiitis,（,CSS,）,ANCA-associated Vasculitis,（,AAV,）,2012 Chapel Hill Consensus Conference Vasculitis Nomenclature,ANCA,阴性不能排除血管炎诊断,原发性系统性小血管炎,临床表现,-,小血管炎肾损害,常见，,7090%,血尿（,100%,）、蛋白尿、,RPGN,可隐袭起病,多为非少尿性，,易误诊为CRF,免疫荧光,寡免疫复合物沉积,光镜,局灶节段坏死性,GN,伴,/,不伴新月体形成,肾间质、小球病变不平行,临床表现,-,肺受累的表现,50,90%,肺受累,50%,肺出血,咳嗽、咯血、呼吸困难,胸片,阴影、结节和空洞,易误诊为感染、肿瘤和结核,弥漫性肺泡毛细血管炎,易误诊为感染、肺水肿,老年人可以肺间质纤维化首发，且全身小血管炎无明显活动,MPA,主要为肺部浸润影、肺间质纤维化、弥漫性肺泡出血,WG,肺结节性病变,临床表现,-,头颈部受累,多数病人可分别受累，,问诊,眼,:,“红眼病”、畏光流泪、视力下降,耳：,33%,首发,中耳受累多，中耳炎，耳鸣，听力下降（传导性、感音神经性）,很少外耳受累,鼻,:,鼻窦炎，鼻息肉，鼻甲肥大,咽喉,:,咽鼓管炎，声门下狭窄,临床表现,-,其他脏器受累,外周神经系统：约50%,多发性单神经炎,感觉过敏、迟钝,关节肌肉痛,皮肤-皮疹，溃疡，坏疽，结节，网状青斑,消化道-约2/3受累。食道炎，溃疡，出血,心血管系统：心绞痛、心包炎、心衰,血液系统,前列腺炎，睾丸炎,MPA 临床表现,好发年龄为,4060,岁，男女,11.8:1,大多数起病急，进展快，部分起病隐匿,同时或相继出现多系统受累表现，肺肾综合征,肾脏几乎,100%,受累，以,RPGN,为特点，少尿、血尿、肾功能不全,半数累及肺脏，弥漫性肺泡出血和肺间质纤维化，咯血、贫血和呼吸困难,可有发热、关节痛、肌痛、紫癜、肢体麻木和无力、眼炎和,ENT,受累表现,G,PA 临床表现（WG）,特征：反复发作的上、下呼吸道坏死性肉芽肿和肾小球肾炎及其他系统性小血管炎性损害,典型,WG,三联症：上呼吸道症状，肺病变，肾病变,另有患者以眼部病变首发，眼球突出最具特征性,eG,PA 临床表现,(,CSS,),典型病程为三期：,前驱期,:,多种过敏性疾病表现，如：变应性鼻炎、鼻息肉、哮喘（可持续,10,年左右）；,血管炎期：全身不适、,腓肠肌痛,，可急性发作，急剧恶化,血管炎后期：重症哮喘及系统性血管炎继发改变，如高血压、慢性心功能不全、外周神经损伤等,各期可见外周血嗜酸粒细胞增多及其在肺、胃肠道、心脏组织浸润。,84%,累及肾脏，多数轻度损害，少数发生肾梗死、高血压,实验室检查,一般指标,ESR多大于100mm/h，CRP升高,Hb低,(,与出血不相称,),，WBC和PLT高,球蛋白升高,C3正常或偏低,RF,可阳性,血尿、蛋白尿、,Cr,、,BUN,升高,特异性指标-ANCA,诊断，指导治疗，判断复发,，滴度与活动相关,ANCA,P-ANCA,核周型（MPA）,MPO (,髓过氧化物酶）,ANCA,滴度与病情活动相关,C-ANCA,胞浆型,（WG）,PR3,（丝氨酸蛋白酶,3,）,临床表现（症状体征）,不明原因的发热、难以解释的全身症状,多系统损害,进展迅速的脏器功能衰竭（肺肾综合征）,肾脏损害（特别是活动性肾小球肾炎）,肺部病变（浸润、出血、呼衰）,肌肉和关节疼痛,皮肤紫癜及结节性坏死性皮疹,突发神经系统病变，尤其是多发性单神经炎,实验室检查,ESR,、,CRP,、与肾功能下降不平行的贫血,ANCA,病理学证据：金标准,如何诊断ANCA相关小血管炎？,诊断流程,一元论,多系统性损害，尤其肺、肾损害,详细的病史及查体,血清学检查：,ANCA、,ESR,、,CRP,、自身抗体、,RF,、补体、蛋白电泳,治疗,确诊血管炎,组织活检,心、肺、肾、神经系统检查，明确系统损害的范围和程度,金标准,如何判断病情活动？,临床病理表现,BVAS,积分,高滴度的,ANCA,其它指标,ESR,，,CRP,（,+,）,BVAS（伯明翰血管炎评分系统）,分为,9,大类或系统（,63,）,全身非特异性表现（,3,）,皮肤（,6,）,粘膜（,6,）,耳鼻喉（,6,）,肺（,6,）,心血管（,6,）,胃肠道（,9,）,肾脏（,12,）,神经系统（,9,）,耳鼻喉,无,0,鼻分泌物,/,鼻堵,2,鼻窦炎,2,鼻出血,4,鼻痂,4,外耳道溢液,4,中耳炎,4,新发听力下降,/,耳聋,6,声嘶,/,喉炎,2,声门下受累,6,BVAS达到25即为高危,ANCA相关小血管炎的治疗策略,诱导缓解治疗,长期保护肾功能,减少复发,维持治疗,尽快控制炎症,争取完全缓解,治疗,目标,提高生存率、保存靶器官功能、减少副作用,复发治疗,尽快控制炎症,争取完全缓解,13.1:,Initial treatment,of,pauci,-immune focal and segmental necrotizing GN,13.1.1: We recommend that,cyclophosphamide,and corticosteroids,be used as initial treatment. (1A),13.1.2: We recommend that,rituximab,and corticosteroids,be used as an alternative initial treatment in patients without severe disease or in whom,cyclophosphamide,is contraindicated. (1B),KDIGO-AAV,治疗指南,-1,13.3:,Maintenance therapy,13.3.1: We recommend maintenance therapy in patients who have achieved remission. (1B),13.3.2: We suggest continuing maintenance therapy for at least 18 months in patients who remain in complete remission. (2D),13.3.3: We recommend no maintenance therapy in patients who are dialysis-dependent and have no,extrarenal,manifestations of disease. (1C),KDIGO-AAV,治疗指南,-2,13.4:,Choice of agent for maintenance therapy,13.4.1: We recommend,azathioprine,12 mg/kg/d,orally as maintenance therapy. (1B),13.4.2: We suggest that,MMF, up to 1 g twice daily, be used for maintenance therapy in patients who are allergic to, or intolerant of,azathioprine,. (2C),13.4.3: We suggest,trimethoprim-sulfamethoxazol,e,as an adjunct to maintenance therapy in patients with upper respiratory tract disease. (2B),13.4.4: We suggest,methotrexate,(initially 0.3 mg/kg/wk, maximum 25 mg/wk),for maintenance therapy in patients intolerant of,azathioprine,and MMF, but not if GFR is,60 ml/min per 1.73m2. (1C),13.4.5: We recommend,not using,etanercept,as adjunctive therapy. (1A),KDIGO-AAV,治疗指南,-3,13.5:,Treatment of relapse,13.5.1: We recommend treating patients with severe relapse of ANCA,vasculitis,(life- or organ-threatening) according to,the same guidelines as for the initial therapy,(see Section 13.1). (1C),13.5.2: We suggest treating other relapses of ANCA,vasculitis,by,reinstituting immunosuppressive therapy or increasing its intensity,with agents,other than,cyclophosphamide, including instituting or increasing dose of corticosteroids, with or without,azathioprine,or MMF. (2C),13.6:,Treatment of resistant disease,13.6.1: In ANCA GN resistant to induction therapy with,cyclophosphamide,and corticosteroids, we recommend the addition of,rituximab,(1C,), and suggest,.,immunoglobulin (2C,) or,plasmapheresis,(2D,) as alternatives.,KDIGO-AAV,治疗指南,-4,13.7:,Monitoring,13.7.1: We suggest not changing,immunosuppression,based on changes in ANCA titer alone. (2D),13.8:,Transplantation,13.8.1: We recommend,delaying transplantation,until patients are in complete,extrarenal,remission for 12 months. (1C),13.8.2: We recommend,not delaying transplantation,for patients who are in complete remission but are still ANCA-positive. (1C),KDIGO-AAV,治疗指南,-5,建议联合用,CTX,（静脉或口服）和糖皮质激素进行诱导缓解治疗；,建议对无危及生命或器官的,AAV,患者联合甲氨蝶呤和糖皮质激素替代,CTX,作为诱导缓解治疗；,建议对快速进展或重度肾损害者，加用血浆置换治疗（,1B,级证据，,A,级推荐）；,建议小剂量激素联合硫唑嘌呤或来氟米特或甲氨蝶呤作为维持缓解治疗。,EUVAS,治疗建议,预 后,影响因素,年龄,就诊时肌酐水平,有无肺出血,激素联合免疫抑制剂治疗后,1,年生存率可达,80100%,；,5,年生存率较未治疗的,10%,提高到,7080%,预 后,思 考,误漏诊多，如何解决？,提高认识，综合诊断思维,临床和病理表现,熟悉诊断标准,规范化ANCA检测（,IF,、,ELISA,）,THANKS FOR YOUR ATTENTION,！,