抗中性粒细胞胞浆抗体相关性小血管炎1例并文献复习

抗中性粒细胞胞浆抗体（anti-neutrophil cytoplasmic antibody,ANCA）相关性小血管炎（ANCA associated systemic vasculitis,AASV）是一组以ANCA阳性为突出临床特征,累及多个系统的血管炎性疾病。因其临床表现缺乏特异性,易被漏诊、误诊。现将我科收治的1例以呕吐为首发表现的AASV患者的临床特点进行总结和分析。     

肺脏受累的原发性抗中性粒细胞胞浆抗体相关性小血管炎43例临床分析

目的 探讨肺脏受累的原发性抗中性粒细胞胞浆抗体（ANCA）相关性小血管炎患者的临床特征,为肺部受累的原发性ANCA相关性小血管炎的诊断提供帮助.方法 回顾性分析2009年3月至2013年9月在湘雅二医院住院的符合2012年美国Chapel Hill会议关于系统性小血管炎诊断标准,并血清ANCA阳性的43例肺脏受累的的原发性ANCA相关性小血管炎患者的临床资料.结果 43例患者中,肺部症状首发就诊者22例,常见肺部症状依次为咳嗽咯痰、活动后气促、咯血、哮喘等,肺外受累器官依次为肾脏、神经系统、眼、鼻;肺外症状首发就诊者21例,肾脏为最常见受累器官;显微镜下多血管炎（MPA） 34例,其中抗髓过氧化物酶（MPO）抗体（P-ANCA）阳性率97.1％（33/34）,抗蛋白酶3（PR3）抗体（C-ANCA）阳性率2.9％ （1/34）;肉芽肿性多血管炎（GPA）（韦格纳肉芽肿）8例,抗蛋白酶3（PR3）抗体（C-ANCA）阳性率62.5％（5/8）,抗髓过氧化物酶（MPO）抗体（P-ANCA）阳性率为37.5％（3/8）;嗜酸细胞性肉芽肿性多血管炎（EGPA）1例,为抗髓过氧化物酶（MPO）抗体阳性;胸部影像学表现多为双肺间质病变,如双肺网格样改变、磨玻璃影、蜂窝肺、多发条索状及结节性病变等,或为条索或斑片状病变、支气管扩张、胸腔积液及肿块病变等.经激素和免疫抑制剂治疗多数患者病情可缓解,19例患者（44.2％）于住院及随访期间因血管炎活动并肺部感染、大咯血及肾功能衰竭等原因死亡.结论 肺脏受累的原发性ANCA相关性小血管炎临床表现无特异性,多数患者合并有肾脏受累,影像学多为肺间质病变,具有提示诊断价值,血清ANCA检查有特殊诊断价值,此类患者死亡率高,多为疾病活动并感染致死,应积极控制感染并合理采用抑制免疫治疗.     

肾脏受累为主的抗中性粒细胞胞质抗体相关性血管炎患者的预后及其相关危险因素分析

目的 探讨肾脏受累为主的抗中性粒细胞胞质抗体(ANCA)相关性血管炎患者的预后及其影响因素.方法 对2006-2008年我院诊断的64例肾脏受累为主的ANCA相关性血管炎患者进行回顾性分析,并对其进行前瞻性随访,使用Logistic回归、Cox回归等分析与患者肾脏预后有关的危险因素.结果 ①共入选64例患者,其中男性40例,女性24例,平均年龄(59.9±2.0)岁.随访21～55个月,平均(38±16)个月,期间34例(53％)患者出现死亡或进入长期肾脏替代治疗.②预后不同的2组患者起病时血肌酐[分别为(624±246)、(245±127) μmol/L,t=7.17,P=0.005]、红细胞沉降率(ESR)[分别为(112±24)、(76±48) mm/l h,t＝3.74,P＜0.01]、血浆白蛋白[分别为(294±31)、(316±42) g/L,t=-2.27,P=0.01]、血红蛋白[分别为(79±13)、(99±33) g/L,t=-3.23,P＜0.01 ]差异均有统计学意义.Logistic回归及Cox回归分析证实起病时血肌酐[β=1.004,95％可信区间(CI) 1.002～1.006,P＜0.01]及ESR[β=1.018,95％CI1.000～1.037,P=0.046]是预测患者预后的独立危险因素.③ROC曲线结果显示起病时血肌酐和ESR曲线下面积分别为0.95,0.80;敏感性均为94％,特异性分别为93％和70％.结论 以肾脏受累为主的ANCA相关性血管炎患者预后差,起病时血肌酐水平和ESR可能是判断患者预后的重要影响因素.     

Randomized controlled trials in vasculitis associated with anti-neutrophil cytoplasmic antibodies

PURPOSE OF REVIEW: To review three major randomized clinical trials in forms of vasculitis associated with anti-neutrophil cytoplasmic antibodies. RECENT FINDINGS: The design features, results, and context of the Cyclophosphamide versus Azathioprine for the Remission Phase of Vasculitis, Non-renal AAV alternatively treated with Methotrexate, and Wegener Granulomatosis Etanercept Trial are reviewed. SUMMARY: Until recently, therapies for Wegener granulomatosis and microscopic polyangiitis have been based primarily on a relatively small number of nonrandomized studies. During the past 18 months, three randomized, controlled trials (one double-blinded) have been performed in vasculitis associated with anti-neutrophil cytoplasmic antibodies. Careful comparisons of the results of these trials yield insights into new standards of care for vasculitis associated with anti-neutrophil cytoplasmic antibodies. This paper summarizes the designs of these three trials; highlights their principal conclusions, strengths, and shortcomings; and distills from their results several recommendations on major questions related to the therapy of vasculitis associated with anti-neutrophil cytoplasmic antibodies.     

Utility of the neutrophil-to-lymphocyte ratio in the prediction of anti-neutrophil cytoplasmic antibody–associated vasculitis with infection

Clinical Rheumatology - This study aimed to evaluate the predictive value of the neutrophil-to-lymphocyte ratio (NLR) for infection in patients with anti-neutrophil cytoplasmic antibody...     

丙基硫氧嘧啶与抗中性粒细胞胞浆抗体相关小血管炎

抗中性粒细胞胞浆抗体 (ａｎｔｉｎｅｕｔｒｏｐｈｉｌｃｙｔｏｐｌａｓｍｉｃａｎｔｉｂｏｄｉｅｓ,ＡＮＣＡ)是一种以中性粒细胞和单核细胞为靶抗原的自身抗体 ,是近 10年来发展起来的一种用于原发性小血管炎的特异性血清学诊断工具。ＡＮＣＡ相关的原发性小血管炎主要指韦格纳肉芽肿病、显微镜下型多血管炎、变应性肉芽肿血管炎和原发性局灶坏死性肾小球肾炎〔1〕。间接免疫荧光法 (ＩＩＦ)可将ＡＮＣＡ分为二种类型 :核周型称为ｐ ＡＮＣＡ ,胞浆型称为ｃ ＡＮＣＡ。ｃ ＡＮＣＡ和韦格纳肉芽肿病密切相关 ,其特异性靶抗原是蛋白酶 3(Ｐ…     

Clinical course of anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and systemic vasculitis. The Glomerular Disease Collaborative Network

OBJECTIVES: To determine the spectrum of clinical manifestations in patients with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis; to determine renal and patient survival in these patients; to compare survival among patients treated with corticosteroids alone, corticosteroids plus intravenous cyclophosphamide or corticosteroids plus oral cyclophosphamide; and to assess the correlation of disease manifestations and treatment response with ANCA subtypes and serial autoantibody titers. DESIGN: Inception cohort study; mean follow-up of 24 months. SETTING: Collaborative network of 120 university and private practice nephrologists (The Glomerular Disease Collaborative Network). PARTICIPANTS: Seventy patients with ANCA and pauci-immune necrotizing and crescentic glomerulonephritis, of whom 59 were treated with either corticosteroids alone (14 patients), corticosteroids plus oral cyclophosphamide (30 patients), or corticosteroids plus intravenous cyclophosphamide (15 patients). MAIN RESULTS: Of the 70 patients, 18 had renal-limited disease (idiopathic crescentic glomerulonephritis); 15, nonpulmonary extrarenal disease consistent with polyarteritis nodosa; and 37, pulmonary disease consistent with Wegener granulomatosis or alveolar capillaritis. There were overlapping manifestations of disease between patients with autoantibodies producing a cytoplasmic pattern and patients with autoantibodies producing a perinuclear pattern; however, the perinuclear pattern occurred more frequently in patients with renal-limited disease. Renal and patient survival was 75% at 24 months, and no difference in survival was seen between patients with renal-limited disease and those with systemic disease. No differences in survival were seen between patients treated with oral cyclophosphamide and those treated with intravenous cyclophosphamide; however, the comparative data from patients treated with corticosteroids alone were inconclusive. In general, autoantibody titers correlated with response to treatment and disease activity, but there were exceptions. CONCLUSIONS: Patients with ANCA have various forms of necrotizing vascular inflammation, ranging from renal-limited disease to widespread systemic vasculitis, including polyarteritis nodosa and Wegener granulomatosis. Oral corticosteroids with either oral or intravenous cyclophosphamide appear to be equally effective therapy for ANCA-associated glomerulonephritis.     

A historical study of American patients with anti-neutrophil cytoplasmic antibody negative pauci-immune glomerulonephritis

Anti-neutrophil cytoplasmic antibodies (ANCA) play an important role in the pathogenesis of ANCA-associated vasculitis. The lack of ANCA antibodies may indicate a variation in clinical presentation and outcomes of this disease. We identified 74 adult patients between 1995 and 2009 with the diagnosis of pauci-immune glomerulonephritis. Demographics, histological features, and treatment outcomes were compared between ANCA-positive and ANCA-negative patients. These factors were correlated with renal function at presentation and follow-up. Of the 74 patients, 57 were ANCA-positive, and 17 were ANCA-negative. Demographics and mean Birmingham Vasculitis Activity Score were similar between ANCA-negative and ANCA-positive patients at presentation. Renal function was significantly worse at presentation in the ANCA-negative patients (eGFR 16.59 vs. 31.89 ml/min/1.73 m², p?=?0.03). Patients in the ANCA-negative group had a significantly higher interstitial fibrosis score compared to the ANCA-positive group (2.1 vs.1.6, p?=?0.04). The median time to remission was shorter in the ANCA-negative patients (51 vs. 78 days, p?=?0.01). Long-term renal function and 1-year patient and renal survival were similar between ANCA-negative and ANCA-positive patients. Baseline eGFR, percentage of normal glomeruli, glomerular sclerosis, and tubulointerstitial scarring predicted eGFR at 1 year in both groups similarly. This is the first historical review of American patients with pauci-immune glomerulonephritis, comparing patients with ANCA-negative and ANCA-positive serology. Although ANCA-negative patients present with lower eGFR and more interstitial fibrosis, 1-year and long-term outcomes in both groups are similar.     

Perinuclear anti-neutrophil cytoplasmic antibody and refractory pouchitis

Refractory pouchitis (RP) is a debilitating complication of ileal pouch reservoirs that affects hypothesized that it reflects underlying Crohn's disease. Since perinuclear anti-neutrophil cytoplasmic antibody (pANCA) is found in approximately 70% of ulcerative colitis patients but only rarely in Crohn's disease patients, it may help distinguish Crohn's disease from ulcerative colitis. Therefore, to test whether RP reflects missed Crohn's disease, we determined the ANCA status of 26 patients with RP. The pANCA was positive in 42% of cases [50% of Kock pouch cases and 33% of ileoanal pull-through (IAPT) cases] and 57% of matched control subjects without pouchitis (N=42,P=NS). Moreover, 3/6 (50%) of IAPT RP subjects whose signs and symptoms most suggested Crohn's disease tested positive for pANCA. When compared to controls, IAPT cases exhibited significantly more preoperative extraintestinal manifestations (EIMs) of inflammatory bowel disease (P<0.05). The presence of preoperative EIMs was 100% predictive of postoperative EIMs (P<0.05). Review of pouch biopsies from cases of RP revealed no pathognomonic histologic features of Crohn's disease. These data confirm our previous suggestion that RP does not reflect underlying Crohn's disease but may be associated with the EIMs of inflammatory bowel disease.     

Disease associations and pathogenic role of antineutrophil cytoplasmic autoantibodies in vasculitis.

Antineutrophil cytoplasmic autoantibodies are a useful diagnostic serologic marker for a variety of well-known vasculitic syndromes, including Wegener's granulomatosis, polyarteritis nodosa (especially microscopic polyarteritis nodosa), Churg-Strauss syndrome, and pulmonary-renal syndrome with alveolar capillaritis. Although most patients with antineutrophil cytoplasmic autoantibody-associated disease have systemic disease, disease limited to one organ does occur, eg, isolated necrotizing glomerulonephritis, isolated respiratory tract disease, or isolated orbital disease. Antineutrophil cytoplasmic autoantibody titers may be useful in modulating treatment regimens. There is in vitro evidence that antineutrophil cytoplasmic autoantibodies are directly involved in the pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitides.     

Systemic antineutrophil cytoplasmic antibody vasculitis associated with lymphoid neoplasia

Two cases of systemic antineutrophil cytoplasmic antibody (ANCA) vasculitis in the setting of chronic lymphocytic leukaemia and angioimmunoblastic lymphadenopathy type T cell lymphoma are reported. The two patients had fever of unknown origin associated with cutaneous vasculitis and "pulmonary-renal syndrome" with alveolar haemorrhage. Despite anti-infectious treatments, steroids, and chemotherapy, the vasculitis had a fatal paraneoplastic course in several weeks. When infection is excluded in patients with malignancy, atypical features should be promptly investigated for systemic vasculitis, and an ANCA test performed.     

Relapses in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis: a retrospective study

Clinical Rheumatology - To investigate the activity of relapsing events (RE) and their mode of presentation in patients with anti-neutrophil cytoplasmic (ANCA)-associated vasculitis (AAV). Patients...     

抗中性粒细胞胞浆抗体相关血管炎致弥漫性肺泡出血

目的 提高对抗中性粒细胞胞浆抗体(antineutrophil cytoplasmic antibody,ANCA)相关血管炎致弥漫性肺泡出血的认识,提高其预防和治疗水平.方法 回顾分析我院治疗的1例血管炎致肺泡出血的病例,进行相关文献的复习.结果 该患者尿检异常7年,咳嗽、咳血痰,出现多器官功能衰竭,给予呼吸机支持治疗,连续血浆置换、血液净化、透析及抗感染后最终好转出院.结论 ANCA相关血管炎致弥漫性肺泡出血病情发展较快,及时诊断及治疗对患者预后有极大意义.     

Clinical and pathophysiological significance of anti-neutrophil cytoplasmic autoantibodies in vasculitis syndromes

Abstract

Necrotizing vasculitis of small blood vessels is a rare condition, but when it affects important organs it can lead to life-threatening organ damage and death. Thus, recognizing these conditions at an early stage before they spread to become systemic is a constant challenge to clinical medicine. The objectives of this review are: to give advice on clinical indications for ANCA diagnostics and laboratory procedures for highly specifically detecting the most important ANCA; to provide some data on the autoantigens involved in ANCA reactivity in small vessel vasculitides; and to discuss at the occurrence of ANCA in different vasculitic populations and at different stages of disease. One important task for the near future will be to standardize the assays used for ANCA detection/quantification and to harmonize the results given to clinicians by ensuring that international reference reagents are used by laboratories and the diagnostic industry. Finally, the author has attempted to summarize the role that ANCA are currently believed to play in the immuno-inflammatory events that take place in tissues and that affect small vessels in idiopathic vasculitis. The review concludes that the presence of ANCA is likely to become an important criterion for diagnosing idiopathic small vessel vasculitis.     

抗中性粒细胞胞浆抗体相关性血管炎感染患者淋巴细胞及CD4^+T细胞减少与死亡的相关性

目的探讨使用激素和(或)环磷酰胺(cyclophosphamide,CTX)发生感染的抗中性粒细胞胞浆抗体(antineutrophil cytoplasmic antibody,ANCA)相关性血管炎(ANCA associated vasculitis,AAV)患者,住院期间淋巴细胞及CD4^+T细胞减少程度与死亡的相关性。方法回顾性分析2010至2013年北京协和医院治疗期间发生感染住院AAV患者的临床资料,按照淋巴细胞最低值连续两次符合≥0.8×10^9/L、0.5~0.79×10^9/L、0.3~0.49×10^9/L、<0.3×10^9/L分为无减少、轻度、中度和重度减少,CD4^+T细胞计数按照符合≥500×10^6/L、200~499×10^6/L、<200×10^6/L分为无减少、轻度和重度减少,并收集患者诊断、年龄、病程、住院时间、伯明翰系统性血管炎活动评分(BVAS)、CTX累计剂量、激素使用时间、感染部位和病原学,按转归分组行相关性及风险分析。结果共纳入67例患者,存活组与死亡组相比,年龄、病程、住院时间、BVAS、起病时肌酐水平及尿蛋白定量、CTX累计剂量、激素使用时间均无差异,淋巴细胞减少有统计学差异(P<0.001)。38例检测T细胞亚群,发现死亡组与存活组间CD4^+T细胞减少有统计学差异(P=0.003)。死亡组中,患者感染病原学以巨细胞病毒(cytomegalovirus,CMV)最常见,淋巴细胞重度下降组中最常见为鲍曼不动杆菌,其次分别为CMV、肺炎克雷伯菌、白色念珠菌;中度和轻度下降组最常见为CMV感染。多因素COX模型校正年龄和性别后的死亡风险预测分析发现,重度淋巴细胞减少HR为5.23(95%CI:1.68~16.31,P=0.004),中度下降HR为3.87(95%CI:1.03~14.54,P=0.045)。结论AAV患者感染后住院期间淋巴细胞及CD4^+T细胞减少与死亡相关,淋巴细胞中重度减少是死亡的风险因素,死亡患者主要感染病原体为CMV、鲍曼不动杆菌及肺炎克雷伯菌。     

Clinical and pathophysiological significance of anti-neutrophil cytoplasmic autoantibodies in vasculitis syndromes

Necrotizing vasculitis of small blood vessels is a rare condition, but when it affects important organs it can lead to life-threatening organ damage and death. Thus, recognizing these conditions at an early stage before they spread to become systemic is a constant challenge to clinical medicine. The objectives of this review are: to give advice on clinical indications for ANCA diagnostics and laboratory procedures for highly specifically detecting the most important ANCA; to provide some data on the autoantigens involved in ANCA reactivity in small vessel vasculitides; and to discuss at the occurrence of ANCA in different vasculitic populations and at different stages of disease. One important task for the near future will be to standardize the assays used for ANCA detection/quantification and to harmonize the results given to clinicians by ensuring that international reference reagents are used by laboratories and the diagnostic industry. Finally, the author has attempted to summarize the role that ANCA are currently believed to play in the immuno-inflammatory events that take place in tissues and that affect small vessels in idiopathic vasculitis. The review concludes that the presence of ANCA is likely to become an important criterion for diagnosing idiopathic small vessel vasculitis.     

The impact of intravenous methylprednisolone pulses on renal survival in anti-neutrophil cytoplasmic antibody associated vasculitis with severe renal injury patients: a retrospective study

Background

High-dose methylprednisolone pulses were one of the main treatments for anti-neutrophil cytoplasmic autoantibody (ANCA) associated vasculitides (AAV) but had obvious side effects. We aimed to know the impact on renal survival and identify the prognostic factors of this treatment in Chinese AAV patients with severe renal involvement.

Methods

One hundred and eleven AAV patients with an estimated glomerular filtration rate (eGFR) of 10ml/min/1.73 m² or less at admission were included. The MP group (n?=?57) received intravenous methylprednisolone 500 mg/d for 3 days, while the control group (n?=?54) had not. The outcomes and adverse events between two groups were compared. Besides, predictors for dialysis independence and good response of intravenous methylprednisolone were analyzed using Cox regression analysis and ROC curves respectively.

Results

Their median duration of follow-up was 31 (range 3 to 134) months. Eleven patients in MP group and 20 patients in control group were died (P?=?0.056). Twenty-one patients (36.8%) in MP group and 29 patients (53.7%) in control group were on maintaining dialysis (P = 0.088). Twenty-one patients in MP group remained dialysis independent, more than those in control group (4 patients, P?<0.01). Urine protein creatinine ratio (hazard ratio 1.730, 95% confidence interval 1.029 to 2.909, P?=?0.039) and the treatment of intravenous methylprednisolone pulses (hazard ratio 0.362, 95% confidence interval 0.190 to 0.690, P?=?0.002) were the independent risk factors for dialysis independence. Those patients with serum creatinine≥855μmol/L and urine protein ≥3.7g/24h at admission may have worse responses to intravenous methylprednisolone pulses (sensibility 56.7%, specificity 85.0%, PPV 100.0% and NPV57.1%).

Conclusions

Intravenous methylprednisolone pulses could improve the long-term outcome in term of dialysis independence and tend to decrease mortality for Chinese AAV patients with severe renal involvement.