系统性小血管炎诊治及进展

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 15th 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,5090%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,GPA 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,eGPA 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 GN13.1.1: 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 therapy13.3.1: 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 therapy13.4.1: 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-sulfamethoxazole 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 relapse13.5.1: 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 disease13.6.1: In ANCA GN resistant to induction therapy with cyclophosphamide and corticosteroids, we recommend the addition of rituximab (1C), and suggest i.v. immunoglobulin (2C) or plasmapheresis (2D) as alternatives.,KDIGO-AAV治疗指南-4,13.7: Monitoring13.7.1: We suggest not changing immunosuppression based on changes in ANCA titer alone. (2D)13.8: Transplantation13.8.1: 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