Maintenance of Remission in antineutrophil cytoplasm antibody‐associated vasculitides

The classification of the systemic vasculitides has been controversial for several decades. The Chapel Hill consensus Conference definitions originally developed in 1994, but revised and extended in 2012 are now widely accepted. The American College of Rheumatology (ACR) criteria were first published in 1990, are now generally accepted to be out of date and new criteria are needed. More recently the classical division of the ANCA vasculitides using clinical phenotype has come under scrutiny with evidence from epidemiological, genetic and outcome studies that perhaps these conditions should be classified on the basis of ANCA specificity into PR3‐ANCA positive and MPO‐ANCA positive groups. The traditional distinction between giant cell arteritis and Takayasu arteritis has been questioned and some recent studies of GCA have included patients with only extra‐cranial disease. The Diagnostic and Classification Criteria of Vasculitis study (DCVAS) will provide new validated classification criteria for the systemic vasculitides.     

Evolving concepts in classification of systemic vasculitis: where are we and what is the way forward?

The classification of the systemic vasculitides has been controversial for several decades. The Chapel Hill consensus Conference definitions originally developed in 1994, but revised and extended in 2012 are now widely accepted. The American College of Rheumatology (ACR) criteria were first published in 1990, are now generally accepted to be out of date and new criteria are needed. More recently the classical division of the ANCA vasculitides using clinical phenotype has come under scrutiny with evidence from epidemiological, genetic and outcome studies that perhaps these conditions should be classified on the basis of ANCA specificity into PR3‐ANCA positive and MPO‐ANCA positive groups. The traditional distinction between giant cell arteritis and Takayasu arteritis has been questioned and some recent studies of GCA have included patients with only extra‐cranial disease. The Diagnostic and Classification Criteria of Vasculitis study (DCVAS) will provide new validated classification criteria for the systemic vasculitides.     

新分类标准对结节性多动脉炎诊断影响的研究初探

随着对抗中性粒细胞胞质抗体（ANCA）相关性血管炎的认识及乙型病毒性肝炎疫苗的广泛接种,结节性多动脉炎（PAN）的诊断发生了很大变化。本研究结合2012年Chapel Hill共识会议（CHCC）对PAN的定义和2007年欧洲药品管理局 （EMA）对中小血管炎分类法则,对2002年1月至2018年12月在北京协和医院住...     

Update on the epidemiology,risk factors,and outcomes of systemic vasculitides

Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) and giant cell arteritis (GCA) are the most common primary systemic vasculitides of the adult population, while polymyalgia rheumatica (PMR) is a clinical syndrome often associated with GCA.Incidence and prevalence rates of AAV have been increasing in the last decades, whereas those of GCA and PMR have remained stable. The mutual interplay between environmental and genetic risk factors leading to the development of these diseases has been further analyzed in the last years. The role of infectious agents has repeatedly been studied with regard to Staphylococcus aureus, associated with relapse in granulomatosis with polyangiitis, and Herpes zoster, potentially contributing to GCA development.Remission of disease and prevention of disease-related complications are the most important outcomes for all systemic vasculitides. Although these goals are achieved in the majority of patients receiving modern therapies, the prevention of treatment-related complications, especially glucocorticoid side effects, is still an unmet need that is common to AAV, GCA, and PMR.     

Classification,diagnosis and treatment of ANCA-associated vasculitis

Diagnosis of anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis is usually not difficult in patient with systemic disease, including lung and kidneys involvement, and laboratory signs of inflammation. The presence of ANCA and the results of histological investigation confirm diagnosis of ANCA-associated vasculitis. Cyclophosphamide/azathioprine in combination with high dose steroids are used to induce and maintain remission of systemic vasculitis. The clinical trials also showed efficacy of rituximab that induces depletion of B-cells. Our understanding and management of ANCA-associated vasculitis improved significantly over the last decades but there is still a lot of debate over its classification, diagnostic criteria, assessment of activity and optimum treatment.     

Introduction,epidemiology and classification of vasculitis

Classification of the vasculitides has been traditionally based on vessel size. The American College of Rheumatology (ACR) criteria were developed in the 1980s and published in 1990 before the development of ANCA testing and modern imaging techniques such as MRI and PET scanning, and therefore, these criteria are not fit for use in 2010s. The Chapel Hill Consensus Conference provided a framework for defining various types of vasculitis. In the next two years, new classification criteria will be published from the DCVAS study, which will provide a modern system for the classification of vasculitis for clinical studies.The epidemiology of vasculitides is increasingly well studied; however, there remain gaps in our knowledge of the occurrence of vasculitis in many populations, especially from the third world or those with health care systems that do not permit ready collection of accurate epidemiological data. Giant cell arteritis presents in the elderly and those of Northern European ancestry; ANCA-associated vasculitis appears to have a consistent overall occurrence, but there are differences in the occurrence of MPO and PR3 vasculitis between populations. Kawasaki disease occurs most commonly in Asian populations, especially Japanese, and in those aged less than 5 years. It is currently the most common cause of acquired cardiac disease in those populations.     

Clinical value of antineutrophil cytoplasmic antibodies

This article presents a brief review of the clinical value of antineutrophil cytoplasmic antibodies (ANCA) in the diagnosis and management of patients with various forms of vasculitis. ANCA assay methodology and testing recommendations are reviewed. The patterns of reactivity of ANCA observed by indirect immunofluorescence, the antigens recognized by ANCA, and the sensitivity, specificity, and positive predictive value of ANCA for diagnosis of different vasculitides are described. In addition, the spectrum of drugs and nonvasculitic diseases that are associated with ANCA and need to be differentiated from true ANCA-positive vasculitides are reviewed. When properly utilized and cautiously interpreted, ANCA are a useful, noninvasive diagnostic tool in the differential diagnosis of vasculitis.     

Role of plasmapheresis performed in hemodialysis units for the treatment of anti-neutrophilic cytoplasmic antibody-associated systemic vasculitides

Anti‐neutrophilic cytoplasmic antibody (ANCA) positivity is seen in some systemic necrotizing vasculitides. Wegener's granulomatosis and microscopic polyangiitis are among the ANCA‐associated systemic vasculitides (AASV) and mortality is very high when renal failure occurs together with alveolar hemorrhage. The role of plasmapheresis in the treatment of these diseases has been studied retrospectively. Twelve patients with AASV who had plasmapheresis together with immunosuppressive medications have been involved. Primary diseases, immunosuppressive protocols, the number of plasmapheresis sessions, the amount of plasma that has been exchanged, urea and creatinine levels before and after treatment, pulmonary findings, the need for hemodialysis, and the outcome of patients were recorded. The mean age of patients was 52.9 ± 18.2 years. Wegener's granulomatosis was diagnosed in seven (58.3%) and microscopic polyangiitis in five (41.7%) patients. All patients had pulse cyclophosphamide and methylprednisolone followed by maintenance doses and plasmapheresis. Seven patients had hemodialysis at the beginning, and hemodialysis needed to be continued in three patients. Partial and complete remission was seen in 6 (50%) and 3 (25%) patients, respectively, and pulmonary findings regressed in all patients. End‐stage renal disease develops generally in AASV due to rapidly progressive glomerulonephritis causing severe irreversible glomerular damage. The mortality rate rises to 50% in cases of renal failure with diffuse alveolar hemorrhage; therefore, pulse immunosuppressive treatment with plasmapheresis may be life‐saving, as shown in our study.     

Anti-MPO-ANCA-Positive Microscopic Polyangiitis following Subacute Bacterial Endocarditis

Although infectious agents such as Staphylococcus aureus have been implicated in the pathogenesis of Wegener’s granulomatosis, the role of bacterial infections in the pathogenesis of other types of small-vessel vasculitides associated with antineutrophil cytoplasmic antibodies (ANCA) is less clear. We describe a patient who developed a non-granulomatous necrotising small vessel vasculitis and perinuclear ANCA (p-ANCA) directed against myeloperoxidase (MPO) after recurrent episodes of bacterial endocarditis due to Staph. aureus. Although cytoplasmic ANCA (c-ANCA) directed against proteinase 3 have been reported in single patients with bacterial endocarditis, to our knowledge this patient is the first reported case of an anti-MPO-ANCA positive systemic vasculitis following bacterial endocarditis. Received: 2 February 2001 / Accepted: 6 June 2001     

Churg-Strauss syndrome: clinical presentation,antineutrophil cytoplasmic antibodies,and leukotriene receptor antagonists

PURPOSE: To determine the association of antineutrophil cytoplasmic antibodies (ANCA) and leukotriene receptor antagonists with disease activity in a large series of patients with Churg-Strauss syndrome. METHODS: Potential subjects were identified by a computerized search of the Mayo Clinic Rochester database for the years 1990 to 2000. Patients meeting one of three classification schemes for Churg-Strauss syndrome were included. RESULTS: Ninety-one patients met the inclusion criteria. Clinical manifestations were similar to those in previous reports. Mortality was similar to that in the general population. ANCA testing was performed in 74 patients. Seventy-three percent (n = 22) of the 30 patients tested before therapy were ANCA positive, as were 75% (n = 12) of the 16 patients tested during a disease flare. In comparison, 16% (n = 8) of the 49 tested during remission were ANCA positive. Serial measurements indicated a correlation of ANCA levels with disease activity. Central nervous system involvement was the only clinical manifestation that correlated with ANCA status (P = 0.05). Twenty-three patients received leukotriene receptor antagonists, of whom 16 (70%) began treatment before diagnosis and 6 (27%) began during remission. Two of those treated after diagnosis relapsed. In 1 patient the relation between disease and leukotriene receptor antagonist use could not be determined. Use of leukotriene receptor antagonists did not affect the time between onset of asthma and manifestations of vasculitis, and was not correlated with organ manifestations, except sinus disease. CONCLUSION: No one classification scheme identified all patients. Churg-Strauss syndrome has a better prognosis than other ANCA-associated vasculitides. ANCA status correlates with disease activity, whereas a pathogenic role for leukotriene receptor antagonists in the development of Churg-Strauss syndrome was not noted.     

Is granulomatosis with polyangiitis in Asia different from the West?

The incidence and clinical features of antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) have been shown to vary according to geographical areas, with granulomatosis with polyangiitis (GPA) being more common in northern Europe and microscopic polyangiitis (MPA) being more common in Asian countries. The annual incidence of GPA among Asians varies between 0.37/million to 2.1/million population. The prevalence of GPA has been estimated to be 1.94/100 000 in a Chinese population. Polymorphisms in class II major histocompatibility genes and ETS1 proto‐oncogene has been shown in Asian patients with GPA. There is a difference in mean age at onset and proteinase 3 (PR3) or myeloperoxidase (MPO) positivity in GPA patients from different Asian countries. Those from India had mean age of 40 years and those from Japan had mean age of 65 years. Sixty percent of GPA patients from China and Japan were MPO ANCA positive while the majority of patients from India and Korea were PR3 positive. Geographical variation with lower frequency of renal involvement in Indian studies and higher frequency in Chinese patients has also been noted. Treatment outcomes have been similar to those reported from other parts of the world. Remission was achieved in about two‐thirds of patients while relapses were noted in one‐third to half of the patients. Apart from minor differences in the organ systems involved, MPO‐ANCA GPA and PR3‐ANCA GPA had similar rates of remission and relapses.     

Current Concept and Epidemiology of Systemic Vasculitides

Although a new classification algorithm for systemic vasculitides was proposed by Watts et al. and the Chapel Hill Consensus Conference (CHCC) was updated in 2012, there are currently no validated diagnostic criteria for systemic vasculitides. The Diagnostic and Classification Criteria for Vasculitis study (DCVAS) is a global study to develop and improve the diagnostic criteria for systemic vasculitides. The epidemiology of systemic vasculitides differs widely among countries. For example, in the case of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, patients with microscopic polyangiitis (MPA) and with positivity for MPO-ANCA are predominant in Asian countries, whereas patients with granulomatosis with polyangiitis (GPA) and with positivity for PR3-ANCA are predominant in northern Europe and the United States. Interstitial lung disease (ILD) occurs more frequently in Asian patients compared with patients in Europe. The incidence and the prevalence of large-vessel vasculitis also differ significantly. Giant cell arteritis (GCA) occurs frequently in northern Europe, unlike Takayasu arteritis (TAK). The ethnic and regional differences in the incidence, prevalence and clinical characteristics of patients with vasculitis should be recognized when we diagnose and treat patients with vasculitis using criteria, and should also be considered when interpreting the results from clinical studies.     

Cytomegalovirus infection in systemic necrotizing vasculitis: causative agent or opportunistic infection?

We report on a 69-year-old woman who presented with myalgia, hearing impairment, fever, night sweats, weight loss, muscular weakness, paresthesia, hypesthesia, and hypalgesia. Sural nerve biopsy showed demyelinative and axonal polyneuropathy due to necrotizing vasculitis with fibrinoid necrosis. A positive test for antineutrophil cytoplasmic antibodies (ANCA) with a perinuclear immunofluorescence pattern directed against myeloperoxidase was more suggestive of microscopic polyangiitis (MPA) than of polyarteritis nodosa (PAN), the possible differential diagnoses. In addition, positive tests for cytomegalovirus (CMV) antibodies (immunoglobulin (Ig)M and IgG) and the detection of CMV-DNA in sputum specimens by polymerase chain reaction (PCR) were indicative of active CMV infection. Treatment with ganciclovir and anti-CMV immunoglobulin in addition to prednisolone medication for 6 months resulted in rapid improvement of the clinical symptoms without relapse. CMV infection has been described to be related to ANCA-associated vasculitis in non-immunocompromized patients and may be either a causative agent or an opportunistic infection. Identification of a viral etiology in patients with atypical ANCA-associated vasculitides may lead to different, less aggressive treatment approaches, including antiviral therapy. Received: 5 April 2000 / Accepted: 16 June 2000     

Laboratory diagnostics of systemic autoimmune diseases. Part II: rheumatoid arthritis and vasculopathies

This is the second part in a series of articles on the laboratory diagnostics of rheumatic diseases. It addresses rheumatoid arthritis, systemic, anti-neutrophil cytoplasmatic antibody (ANCA) positive vasculitides and antiphospholipid-syndrome. The diagnostics of rheumatoid arthritis has been substantially improved by the recently introduced assay for antibodies against citrullinated peptides. In addition, a number of vasculitides can be differentiated by the presence of ANCA. Beta2-glycoprotein I antibodies and lupus anticoagulants are at present the most specific markers for antiphospholipid syndrome. Inflammatory activity can be monitored by determining the levels of acute phase proteins and erythrocyte sedimentation rate, but only in some situations by measuring immunoglobulins and interleukins.     

Labordiagnostik der systemischen Autoimmunerkrankungen

This is the second part in a series of articles on the laboratory diagnostics of rheumatic diseases. It addresses rheumatoid arthritis, systemic, anti-neutrophil cytoplasmatic antibody (ANCA) positive vasculitides and antiphospholipid-syndrome. The diagnostics of rheumatoid arthritis has been substantially improved by the recently introduced assay for antibodies against citrullinated peptides. In addition, a number of vasculitides can be differentiated by the presence of ANCA. β2-glycoprotein I antibodies and lupus anticoagulants are at present the most specific markers for antiphospholipid syndrome. Inflammatory activity can be monitored by determining the levels of acute phase proteins and erythrocyte sedimentation rate, but only in some situations by measuring immunoglobulins and interleukins.     

肾脏病抗中性粒细胞胞浆抗体检测的临床意义

本文通过分析２６例抗中性粒细胞胞浆抗体（ＡＮＣＡ）阳性肾脏病例的临床病理特点，探讨了ＡＮＣＡ在肾脏病中的临床意义。结果显示，ＡＮＣＡ阳性不仅可见于结节性多动脉炎（４例）、紫癜性肾炎（８例），还可见于Ⅲ型新月体肾炎（２例）及ＩｇＡ肾病（１２例）．ＡＮＣＡ阳性的肾脏病例具有某些共同的临床病理特征，提示可能具有相同的发病机理。ＡＮＣＡ阳性的ＩｇＡ肾病及Ⅲ型新月体肾炎可能是特殊类型的血管炎。     

Roadmap to vasculitis: a rheumatological treasure hunt: Part II. Classification,features of individual vasculitides and differential diagnosis against pseudovasculitis

Since the triggering factors causing primary vasculitides are by definition not (yet) known, we have to classify them to clinical syndromes based on the size, site, type and effect of the blood vessel involvement. ACR classification criteria and Chapel Hill nomenclature are useful tools to familiarize with the primary vasculitides, although a lot of criticism has been voiced in the literature indicating that they only represent the best available consensus. The present text takes advantage of the recent developments such as introduction of the anti-neutrophilic cytoplasmic auto (ANCA) antibodies, and divides the vasculitides to those affecting typically the large, medium and small arteries or only small blood vessels. In addition, some vasculitides, which are still difficult to place to the vasculitis map, like Bürger's disease, Goodpasture's syndrome, primary angiitin of the central nervous system (PACNS) and panniculitis, are dealt with. As it is a long and winding road, attention has to be paid to the clinical details to follow the road sign to “pseudovasculitis”, when that is the right way to go. They represent a bunch of non-vasculitic conditions, which lead to structural or vasospastic impairment of the blood flow, bleeding or thromboembolism and hyperviscosity. These imitators have to some extent, similar clinical symptoms and signs as well as laboratory and radiological findings to those found in true systemic vasculitides. This also emphasizes the importance of internal medicine as the intellectual (albeit not necessarily organizational) home of rheumatology and rheumatologists as we deal with conditions like atherosclerosis, antiphospholipid antibody syndrome, infectious endocarditic, myxoma of the heart and cholesterol embolism.     

Update on eosinophilic granulomatosis with polyangiitis

Eosinophilic granulomatosis with polyangiitis (EGPA) (formerly Churg-Strauss syndrome) is a rare form of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis characterized by eosinophil-rich granulomatous inflammation and small to medium-size vessel vasculitis associated with bronchial asthma and eosinophilia. Its rarity and unique features such as eosinophilic inflammation have delayed progress of research regarding EGPA for several years, compared to other forms of ANCA-associated vasculitis. However, recently, attention to EGPA as a research subject has been gradually increasing. To resolve problems in existing criteria for EGPA, new classification criteria for EGPA generated by a large international cohort will be launched and is being expected to accelerate future studies. Pathogenesis and roles of ANCA in EGPA are still largely unknown; however, it has been reported that glomerulonephritis is more frequent in ANCA-positive patients than in ANCA-negative patients, while heart failure is more frequent in ANCA-negative patients than in ANCA-positive patients. In addition, a recent genome-wide association study has suggested the presence of two genetically distinct subgroups of EGPA, which correspond to ANCA-positive and -negative subgroups. Although responses to glucocorticoids in EGPA are generally good, patients with EGPA often experience a relapse. Currently, there is no standard therapy for EGPA based on accumulation of clinical trial results. Recently, clinical benefits of mepolizumab for EGPA were proved by a randomized controlled trial and mepolizumab was approved for EGPA. In addition, various new drugs are under evaluation. To find optimal use of these drugs and to resolve unmet needs, such as relapse prevention, will be needed in future.     

酶联免疫吸附测定法检测抗髓过氧化物酶IgG亚型分布及其临床意义

目的：观察抗髓过氧化物酶（MPO）IgG各亚型（IgG1、IgG2、IgG3、IgG4)在小血管炎患者的分布及其与临床病情的关系,以探讨IgG亚型是否能更准确地反映病情变化。方法：选取30例抗MPO抗体阳性的原发性小血管炎患者,对其活动期和缓解期血清采用抗原特异性ELISA法分别测定活动期抗MPO IgG各亚型的阳性率及缓解期的转阴率,并与抗中性粒细胞胞质抗体（ANCA）总IgG的变化进行对比。结果：临床活动期抗MPO－ANCA IgG的4种亚型均为阳性,以IgG4最高;而缓解期以IgG1和IgG3下降为著,其中IgG3的转阴率最高,且显著高于总IgG。结论：IgG3的变化与病情活动密切相关,在一定程度上可以代替总IgG监测病情的发展。IgG4在疾病的活动期与缓解期都显著增高,可能与反复的抗原刺激和慢性的免疫反应有关。     

Genetics of ANCA-associated Vasculitides

The distribution of the anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) is not uniform across geographical regions and ethnic and racial groups, suggesting that genetic and environmental factors affect the pathogenesis of these diseases. In addition, genetic factors affect not only the clinical syndrome phenotypes and their prognosis, but also ANCA specificity; these data suggest that AAV may need reclassification. Several genes have been evaluated, including ANCA targets and those of the immune system, for example co-stimulatory molecules, signaling regulators, cytokines, Fc and other receptors, and other proteins. This article provides a review of genetic factors affecting the pathogenesis and prognosis of AAV. Further studies to determine the effect of genetic factors on the clinical syndrome phenotypes and ANCA specificity need to be performed across different ethnic groups.