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.     

Pathogenesis of ANCA-Associated Vasculitis

Antineutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitides (AAV) are a group of systemic vasculitis syndromes characterized by inflammation and necrosis of blood vessel walls. Genetic, epigenetic, and environmental factors contribute to the etiology and pathogenesis of AAV. On the basis of currently available clinical and experimental evidence, it is reasonable to believe that, in predisposed patients, different triggers can lead to the production of autoantibodies (ANCA) that, in the context of an inflammatory environment, can cause tissue inflammation and vascular injury. Several different pathways and mechanisms in the pathogenesis of AAV are described in this contemporary review.     

Autoimmune hepatitis in diverse ethnic populations and geographical regions

Autoimmune hepatitis has diverse clinical phenotypes and outcomes in ethnic groups within a country and between countries, and these differences may reflect genetic predispositions, indigenous etiological agents, pharmacogenomic mechanisms and socioeconomic reasons. In the USA, African–American patients have cirrhosis more commonly, treatment failure more frequently and higher mortality than white American patients. Survival is poorest in Asian–American patients. Autoimmune hepatitis in other countries is frequently associated with genetic predispositions that may favor susceptibility to indigenous etiological agents. Cholestatic features influence treatment response; acute-on-chronic liver disease increases mortality and socioeconomic and cultural factors affect prognosis. Ethnic-based deviations from classical phenotypes and the frequency of late-stage disease can complicate the diagnosis and management of autoimmune hepatitis in non-white populations.     

Immunopathology of ANCA-associated vasculitis.

During the past few years remarkable progress has been achieved in the understanding of the pathogenic mechanisms leading to vascular inflammation and injury in ANCA-associated vasulitides (AAV): Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and Churg Strauss syndrome (CSS). In this paper we review the immunopathology of these diseases by describing the role of autoantibodies (ANCA), dysregulation and abnormalities at the cellular level, genetic background and environmental factors that predispose to autoimmune response.     

ANCA-associated vasculitis: diagnostic and therapeutic strategy.

Among small-vessel vasculitides, microscopic polyangiitis (MPA), Wegener's granulomatosis (WG), and allergic granulomatous angiitis (AGA) are known collectively as ANCA-associated vasculitis (AAV) because of the involvement of anti-neutrophil cytoplasmic antibodies (ANCA) as the common pathogenesis. Major target antigens of ANCA associated with vasculitis are myeloperoxidase (MPO) and proteinase 3 (PR3). MPO-ANCA is related to MPA and AGA, and PR3-ANCA is the marker antibody in WG. MPO-ANCA-associated vasculitis is more frequent in Japan, whereas PR3-ANCA-associated vasculitis is more common in Europe and USA. ANCA appears to induce vasculitis by directly activating neutrophils. Therefore, no immunoglobulins or complement components are detected in the vasculitis lesions; hence, AAV is called pauci-immune vasculitis (pauci = few/little). Untreated patients with severe AAV with multi-organ involvement have a poor prognosis, which is improved by combination therapy with cyclophosphamide and high-dose corticosteroid. Randomized controlled trials (RCT) regarding induction and maintenance of remission of AAV indicated that the rate of remission induction by the standard regimen is approximately 90% in 6 months, that maintenance of remission can be achieved with oral azathioprine as well as cyclophosphamide, and that methotrexate can be used only for non-renal mild AAV. As these data were obtained mostly in patients positive for PR3-ANCA, caution must be taken in applying these findings to Japanese patients, most of whom are positive for MPO-ANCA. A prospective study is now underway to clarify the effectiveness of the standard regimen in Japanese patients with MPO-ANCA-associated vasculitis. This article describes the diagnostic criteria and the recent evidence-based therapeutic strategy of AAV.     

Renal involvement in ANCA associated vasculitis

Kidney is involved in upto 75–80% of various ANCA associated vasculitis (AAV) and remains the major cause of mortality and morbidity. The classic clinical presentation is that of rapidly progressive renal failure with cresenteric glomerulonephritis being its pathologic correlate. ANCA positivity has been implicated in the pathogenesis and is useful for diagnosis.The treatment of renal AAV involves the use of steroids in combination with other immunosuppressive agents like cyclophosphamide to induce remission followed by maintenance therapy with a less potent agent like azathioprine. Plasmapharesis has a definite role especially in presence of renal failure while Rituximab is emerging as a promising alternative for remission induction.     

Opportunistic infections are preceded by a rapid fall in antineutrophil cytoplasmic antibody (ANCA) titer in patients with ANCA associated vasculitis

OBJECTIVE: To study the clinical course and changes in antineutrophil cytoplasmic antibody (ANCA) titers in patients with ANCA associated vasculitis (AAV) who developed opportunistic infections. METHODS: Among the patients with AAV tested in the Immunopathology Laboratory at the Massachusetts General Hospital between 1989 and 1998, all patients who experienced opportunistic infections (n = 16) were included. We retrospectively studied their clinical features and examined the relationship between changes in ANCA titer and the onset of the opportunistic infections. ANCA titers were measured by antigen-specific ELISA. RESULTS: Of the 16 AAV patients with opportunistic infection, 15 had no evidence for active vasculitis at the time of the infection. Among these 15 patients, opportunistic infections were associated with a steep fall in ANCA titers. There was no consistent pattern of change in C-reactive protein levels. In 7 patients, the immunosuppressive regimen was increased for new clinical findings shortly before the diagnosis of an opportunistic infection, despite the absence of histologic documentation of active vasculitis. Three of these 7 patients died. One patient, who did not experience a significant fall in ANCA titer. i.e., less than 4-fold from his prior peak, was simultaneously found to have Pneumocystis carinii pneumonia and biopsy proven active vasculitis. CONCLUSION: Our data strongly suggest that opportunistic infections in patients with AAV are associated with negative or rapidly falling ANCA titers. Therefore, changes in ANCA titer can help distinguish opportunistic infections from vasculitis flares when patients with AAV present with indeterminate clinical findings.     

Classification of antineutrophil cytoplasmic autoantibody vasculitides: The role of antineutrophil cytoplasmic autoantibody specificity for myeloperoxidase or proteinase 3 in disease recognition and prognosis

Objective

To compare the usefulness of 3 currently used classification systems in predicting the outcomes of treatment resistance, disease relapse, end‐stage renal disease (ESRD), and death in patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV).

Methods

Three classification systems were applied to 502 patients with biopsy‐proven AAV: 1) the Chapel Hill Consensus Conference (CHCC) definition with categories for granulomatosis with polyangiitis (GPA) (Wegener's), microscopic polyangiitis (MPA), and kidney‐limited disease; 2) the European Medicines Agency (EMA) system with categories for GPA and MPA; and 3) classification based on ANCA with specificity for myeloperoxidase (MPO ANCA) versus ANCA with specificity for proteinase 3 (PR3 ANCA). Outcomes included treatment resistance, relapse, ESRD, and death. Proportional hazards models were compared between systems using an information‐theoretic approach to rank models by predictive fit. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) and P values are reported.

Results

ANCA specificity was predictive of relapse, with PR3 ANCA–positive patients almost twice as likely to relapse as those with MPO ANCA (HR 1.89 [95% CI 1.33–2.69], P = 0.0004), and ANCA specificity had the best predictive model fit (model rank 1) compared to the CHCC and EMA systems. The CHCC and EMA systems did not predict relapse. By ANCA specificity, categories of GPA, MPA, and kidney‐limited disease did not distinguish differences in probability of relapse‐free survival. None of the systems predicted treatment resistance, ESRD, or death.

Conclusion

ANCA specificity independently predicts relapse among patients with AAV with renal disease. Classification and diagnostic systems that incorporate ANCA specificity, such as PR3 ANCA–positive MPA and MPO ANCA–positive MPA, provide a more useful tool than the clinical pathologic category alone for predicting relapse.

     

Biomarkers in ANCA-Associated Vasculitis

Despite recent advances in the treatment of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV), relapse remains common and patients often experience a variable clinical course after initial treatment. New biomarkers are needed to aid the management of these complex diseases. Discoveries regarding the pathogenesis of AAV, from the importance both of activated B and T cells and the alternative complement pathway to genomic data, may lay the groundwork for identification of novel biomarkers.     

Pathogenic role and clinical relevance of antineutrophil cytoplasmic antibodies in vasculitides

Within the last year, a growing body of evidence for a distinct role of antineutrophil cytoplasmic antibodies (ANCA) in the pathogenesis of ANCA-associated vasculitides (AAV) has developed. An experimental model of myeloperoxidase (MPO)-ANCA-associated vasculitis provided direct and convincing in vivo evidence that MPO-ANCA are primary pathogenic factors in small-vessel vasculitis by augmenting of leukocyte-vessel wall interaction and leukocyte-mediated vascular injury. Determination of bacterial lipopolysaccharide (LPS) effects on disease severity in a mouse model of anti-MPO-induced glomerulonephritis showed that ANCA and other proinflammatory stimuli of infectious origin acted in synergism in the development of destructive inflammation.     

Update Churg-Strauss-Syndrom

The Churg-Strauss syndrome (CSS) is the rarest subtype of the so-called anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) and has the lowest frequency of ANCA-positivity (around 30%). In addition to asthma and blood eosinophilia, CSS is characterized by end-organ damage, which can be caused by either vasculitis and/or tissue infiltration of eosinophilic granulocytes. The CSS shares many etiological and clinical features of other hypereosinophilic syndromes. Recently, a distinct genetic background could be demonstrated for both the ANCA-positive and ANCA-negative subtypes of CSS as compared to the other two forms of AAV. Among other cytokines, interleukin-5 (IL-5) could be identified as a key mediator of eosinophilia. Therefore, recent clinical trials in CSS aimed to target IL-5. Outside of clinical trials, treatment of CSS is adapted to disease stage and activity, as recommended for other types of AAV.     

Ethnic differences in genetic polymorphism associated with irritable bowel syndrome

Genetic polymorphism is associated with irritable bowel syndrome(IBS) in terms of susceptibility and clinical manifestations. Previous studies have shown that genetic polymorphism might play a key role in the onset and progression of IBS by modulating components of its pathogenesis such as the gut-brain axis,gastrointestinal motility, inflammatory activity, and immune status. Although underlying pathophysiological mechanisms have not been fully clarified, the potential ethnic differences that are present in worldwide genetic studies of IBS deserve attention. This review surveyed numerous studies focusing on IBSassociated single nucleotide polymorphisms, and investigated the ethnic disparities revealed by them. The results demonstrate the need for more attention on ethnic factors in IBS-related genetic studies. Taking ethnic backgrounds into accounts and placing emphasis on disparities potentially ascribed to ethnicity could help lay a solid and generalized foundation for transcultural, multi-ethnic,or secondary analyses in IBS, for example, a meta-analysis. Broader genetic studies considering ethnic factors are greatly needed to obtain a better understanding of the pathophysiological mechanisms of IBS and to improve the prevention, intervention, and treatment of this disease.     

Using antineutrophil cytoplasmic antibody testing to diagnose vasculitis: can test-ordering guidelines improve diagnostic accuracy?

BACKGROUND: Antineutrophil cytoplasmic antibodies (ANCAs) are strongly associated with Wegener granulomatosis, Churg-Strauss angiitis, microscopic polyangiitis, and pauci-immune glomerulonephritis, referred to collectively as ANCA-associated vasculitis (AAVs). It is unclear how accurate ANCA measurement is for diagnosing AAV in diverse populations or whether proposed ANCA test-ordering guidelines improve test performance. METHODS: We assembled a retrospective case series of hospitalized and ambulatory patients from 2 academic medical centers to assess the diagnostic accuracy of ANCA measurement by enzyme-linked immunosorbent assay in identifying cases of AAV. In addition, we assessed the effect of applying proposed ANCA test-ordering guidelines on test performance. RESULTS: For ANCA testing, sensitivity was 81%; specificity, 98%; positive predictive value, 54%; and negative predictive value, 99%. There were no significant changes in operating characteristics after applying the guideline criteria. Using guidelines would have decreased ANCA test ordering by 23% and would have decreased the false-positive rate by 27%. No cases of AAV would have been missed if only patients fulfilling the guidelines were ANCA tested. CONCLUSION: A positive result on an enzyme-linked immunosorbent assay ANCA test, as it is currently ordered, is not a definitive diagnostic indicator of AAV. Compliance with guidelines for ANCA testing would decrease the number of false-positive results and has the potential to reduce total test expenditures.     

Propylthiouracil-induced antineutrophil cytoplasmic antibody-associated vasculitis

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) refers to a group of potentially life-threatening autoimmune diseases. A recent development in this field is the recognition that certain drugs can induce AAV. Among these agents, the drug most often implicated in causing disease is the commonly used antithyroid agent propylthiouracil (PTU). This Review provides an update on PTU-induced AAV. Clinical characteristics of PTU-induced AAV are similar to that of primary AAV, but usually have a milder course and better prognosis, provided early cessation of the disease-causing drug. PTU-induced ANCAs usually react to several components of myeloid granules, which is helpful in differentiating PTU-induced AAV from primary AAV. Early cessation of PTU is crucial in the treatment of PTU-induced AAV. The duration of immunosuppressive therapy might be shorter than in primary AAV, depending on the severity of organ damage, and maintenance therapy is not always necessary.     

Management of alveolar hemorrhage in lung vasculitides

Alveolar hemorrhage (AH) is an important pulmonary manifestation of small vessel vasculitis because severe presentations are the most common vasculitic cause of early death. Renal vasculitis is usually present with AH; the combination is known as pulmonary-renal syndrome. Early diagnosis and intensive therapy are of particular importance to reduce early mortality and improve longer-term outcomes. The commonest immune-mediated cause of AH is anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) (80%), with other vasculitides, including systemic lupus erythematosus and anti-glomerular basement membrane disease accounting for 20%. One quarter of AAV patients develop AH, which when mild is associated with a good outcome, but mortality rises to 50% for cases with respiratory failure requiring ventilator support. The prognosis of AH in the other vasculitides is generally favorable, but cases are rare and experience is limited. Treatment follows similar regimens to those for other AAV presentations, although when severe there is widespread use of parenteral glucocorticoids together with plasma exchange. These interventions have developed empirically supported by a theoretical rationale but have not been validated by randomized clinical trials. Sepsis and cardiovascular and thromboembolic events are important early complications. and long-term follow-up is required to monitor for and prevent relapse and manage disease-related damage. A minority of cases develop on a background of pulmonary fibrosis, or progressive pulmonary fibrosis develops after vasculitis has gone into remission.     

抗中性粒细胞胞质抗体相关性肾炎诊治进展

摘要 抗中性粒细胞胞质抗体（ANCA）相关性血管炎（AAV）常出现肾脏受累，称为ANCA相关性肾炎（AAGN）。AAGN对患者的生存和长期预后有重要影响，早期诊断和及时适当的治疗至关重要。近年来，国内外大量临床试验的开展以及多部指南的发布为AAGN患者的临床管理决策提供了重要依据和宝贵指导意见。本文就此对AAGN的诊治进展进行简要概述。     

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.     

抗中性粒细胞胞浆抗体相关血管炎伴非呼吸道出血的临床分析

目的:探讨抗中性粒细胞胞浆抗体(ANCA)相关血管炎(AAV)伴非呼吸道出血的临床特征、诊疗及预后。方法:回顾性整理我院近5年诊治的47例AAV患者的临床病历资料,分析其中合并非呼吸道出血者的诊治过程。结果:47例AAV中合并非呼吸道出血6例(12.7%),中位年龄58岁。2例发生2处出血,共8处出血;消化道出血2例(4.2%),脑出血3例(6.4%),肾出血1例,腹膜后血肿1例,肌肉血肿1例。6例AAV临床表型为显微镜下多血管炎(MPA)4例,肉芽肿性多血管炎(GPA)2例(脑出血2例,肾出血1例)。6例中5例出血是AAV初诊活动期发生,同时伴急进性肾炎;胸部CT多提示双肺间质改变,但无咯血。1例肌肉血肿发生在血管炎复发期。4例MPOANCA强阳性,1例MPO-ANCA中阳性,1例PR3-ANCA强阳性。5例出血发作前已予激素治疗,临床表现较急骤危重,如头痛、腹痛、血便,常伴血红蛋白快速下降,3例休克血压;血小板计数及凝血指标均正常,仅1例血钙偏低。6例继续激素、环磷酰胺治疗,3例并用静脉免疫球蛋白、血浆置换和血液透析,辅以输血、止血(血管介入栓塞或手术)。6例中2例死亡(脑出血1例,消化道出血1例),4例存活者使用激素、免疫抑制剂诱导缓解,2例并用血浆置换治疗好转、脱离血液透析。结论:AAV合并非呼吸道出血的比例达12.7%;以脑出血和消化道出血为主,与本病导致血管损害相关,也是致命性的并发症。早期识别,积极免疫抑制剂治疗联合血浆置换、静脉免疫球蛋白,并止血处理(血管介入栓塞或手术),部分患者经救治可缓解。     

Classification of vasculitis: From historical controversies to present day pragmatic consensus

The classification of the systemic vasculitides has been controversial for several decades. However, over the past twenty years there have been several major developments, which means that there is pragmatic consensus regarding classification. These include the American College of Rheumatology criteria first published in 1990, and the Chapel Hill Consensus Conference definitions originally promulgated in 1994, but revised and extended in 2012. 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. There remains, however, a major need for validated classification and diagnostic criteria, a need which hopefully the DCVAS project will address.