mocetinostat and Granulomatosis-with-Polyangiitis

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) compromise a rare group of necrotizing small to medium vessel vasculitides that constitute three distinct disorders: granulomatosis with polyangiitis (GPA) (formerly known as Wegener's granulomatosis), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA) (formerly known as Churg-Strauss syndrome). AAV is characterized by the usual presence of circulating autoantibodies to the neutrophil proteins leukocyte proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). These antibodies can activate neutrophils and the complement system resulting in vessel wall inflammation and damage. The clinical presentation of AAV varies from non-severe (non-life threatening) to severe often with potentially life-threatening multi-organ involvement. Early recognition and diagnosis are crucial. In the past two decades, advances in understanding the pathophysiology of AAV have led to development of new treatments and resulted in significant improvement in general outcomes and survival rates. This narrative review will focus on GPA and MPA. We will highlight clinical manifestations, diagnosis, disease monitoring, and treatment strategies in patients with AAV.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Granulomatosis with Polyangiitis; Humans; Microscopic Polyangiitis; Myeloblastin; Peroxidase

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a group of systemic vasculitis characterized by autoantibodies against neutrophil cytoplasmic antigens (proteinase 3 PR3-ANCA and myeloperoxidase MPO-ANCA) and inflammation of small vessels. AAV include the diagnosis Granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), which share many clinical and pathological features. Immunomodulatory therapies have significantly improved prognosis during the last decade. Nevertheless, especially in undiagnosed and thus uncontrolled AAV mortality due to renal impairment or pulmonary haemorrhages is still high. AAV are rare in fertile women, as the typical age of manifestation is above 50 years but there are women with AAV who are or want to become pregnant. This review focusses on how to manage patients with AAV planning to become pregnant and during their pregnancy.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Female; Granulomatosis with Polyangiitis; Humans; Male; Microscopic Polyangiitis; Middle Aged; Myeloblastin; Peroxidase; Pregnancy

Hypertrophic pachymeningitis (HP) is an inflammatory disorder characterized by intracranial and spinal thickened dura mater, leading to several neurological manifestations including headaches, cranial neuropathies, seizures, and sensorimotor disorders. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a crucial disease that is implicated in the development of immune-mediated HP. HP is observed throughout the clinical course of AAV, and 3%-4% of patients with AAV experience HP as the initial clinical episode. However, patients with ANCA-related HP are unclassifiable in the classification criteria of AAV when HP is the only manifestation, suggesting that ANCA-related HP can be identified as a central nervous system-limited type of AAV. Among patients with AAV, those who develop HP have predominantly been classified as having granulomatosis with polyangiitis (GPA). Myeloperoxidase-ANCA positivity has been more frequently demonstrated than proteinase 3-ANCA positivity in patients with ANCA-related HP. The ear, nose, and throat manifestations, such as otitis media, sinusitis, and mastoiditis, as well as mucous membranes/eyes manifestations including sudden visual loss, are robustly associated with HP in AAV. The histology of thickened dura mater tissues includes fibrotic changes and infiltration of several immunocompetent cells, but the typical findings of GPA, such as granulomatous inflammation with necrotizing vasculitis, are not observed in all patients with ANCA-related HP. Corticosteroids are the first-line therapy for ANCA-related HP, while the concomitant use of immunosuppressive agents including cyclophosphamide, methotrexate, and mycophenolate mofetil, is an ideal strategy for achieving remission. Rituximab is a useful agent in refractory ANCA-related HP.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Cyclophosphamide; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Meningitis; Peroxidase

To determine the impact of myeloperoxidase (MPO) and proteinase 3 (PR3) antigen-specific immunoassays in the stratification of patients at-risk for anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) at diagnosis.. A Medline search was conducted to identify diagnostic accuracy studies using PR3-ANCA or MPO-ANCA for the evaluation of granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Studies estimates were pooled using the bivariate method.. Diagnostic accuracy varied by analyte and AAV subtype. PR3-ANCA had greater sensitivity than MPO-ANCA for GPA (74% vs 11%, p < 0.001) and MPO-ANCA greater sensitivity for MPA (73% vs 7%, p < 0.001). Specificities of both MPO-ANCA and PR3-ANCA were consistently high (mean 97%, range: 93-99%) for both AAV subtypes. There was insufficient data to perform meta-analysis for the diagnostic accuracy of EPGA.. These results validate the use of high quality MPO-ANCA and PR3-ANCA immunoassays to screen patients at-risk for AAV as well as to categorize disease as GPA or MPA subtype. However, caution must be exercised in doing so, since some assays may not have optimal performance. Each laboratory should validate appropriate algorithms based on the tests used and testing population.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Granulomatosis with Polyangiitis; Humans; Immunoassay; Microscopic Polyangiitis; Myeloblastin; Peroxidase

Necrotizing sarcoid granulomatosis (NSG) is a rare disease that shares similarities with pulmonary vasculitides and sarcoidosis. This is a report of two cases of NSG with a review of literature. The first case is a 33-year-old black female with a one-year history of malaise and cough. Lung imaging revealed scattered pulmonary nodules. Histopathology showed multiple necrotizing granulomas without prominent neutrophilic infiltrates. The second case is a 58-year-old white female with a one-year history of fatigue, dyspnea, and ophthalmoplegia on the left eye. Imaging showed multiple pulmonary nodules. Lung biopsy was consistent with NSG. The challenge of the NSG diagnosis is to distinguish it from other mimickers. Pathology often shows necrotizing granulomatous vasculitis, distinguishing it from classical sarcoid. Laboratory markers for vasculitis like neutrophil cytoplasmic antibodies and antibodies against myeloperoxidase and proteinase 3 are negative or only low titers. NSG responds well to immune-suppression, most commonly with glucocorticoids.

Topics: Adult; Female; Glucocorticoids; Granulomatosis with Polyangiitis; Humans; Middle Aged; Multiple Pulmonary Nodules; Myeloblastin; Necrosis; Peroxidase; Sarcoidosis; Sarcoidosis, Pulmonary; Vasculitis, Central Nervous System

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), that share features of pauci-immune small-vessel vasculitis and the positivity of ANCA targeting proteinase-3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). AAV syndromes are rare, complex diseases and their aetio-pathogenesis is mainly driven by the interaction between environmental and genetic factors. In patients with GPA and MPA, the genetic associations are stronger with ANCA specificity (PR3- versus MPO-ANCA) than with the clinical diagnosis, which, in keeping with the known clinical and prognostic differences between PR3-ANCA-positive and MPO-ANCA-positive patients, supports an ANCA-based re-classification of these disorders. EGPA is also made up of genetically distinct subsets, which can be stratified on ANCA-status (MPO ANCA-positive versus ANCA-negative); these subsets differ in clinical phenotype and possibly in their response to treatment. Interestingly, MPO-ANCA-positive patients with either MPA or EGPA have overlapping genetic determinants, thus strengthening the concept that this EGPA subset is closely related to the other AAV syndromes. The genetics of AAV provides us with essential information to understand its varied phenotype. This Review discusses the main findings of genetic association studies in AAV, their pathogenic implications and their potential effect on classification, management and prognosis.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Granulomatosis with Polyangiitis; Humans; Microscopic Polyangiitis; Myeloblastin; Peroxidase

Granulomatosis with polyangiitis (GPA) is a rare but serious necrotizing auto-immune vasculitis. GPA is mostly associated with the presence of Anti-Neutrophil Cytoplasmic Antibody (ANCA) targeting proteinase 3 (PR3-ANCA), a serine protease contained in neutrophil granules but also exposed at the membrane. PR3-ANCAs have a proven fundamental role in GPA: they bind neutrophils allowing their auto-immune activation responsible for vasculitis lesions. PR3-ANCAs bind neutrophil surface on the one hand by their Fab binding PR3 and on the other by their Fc binding Fc gamma receptors. Despite current therapies, GPA is still a serious disease with an important mortality and a high risk of relapse. Furthermore, although PR3-ANCAs are a consistent biomarker for GPA diagnosis, relapse management currently based on their level is inconsistent. Indeed, PR3-ANCA level is not correlated with disease activity in 25% of patients suggesting that not all PR3-ANCAs are pathogenic. Therefore, the development of new biomarkers to evaluate disease activity and predict relapse and new therapies is necessary. Understanding factors influencing PR3-ANCA pathogenicity,

Topics: Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Granulomatosis with Polyangiitis; Humans; Myeloblastin; Neutrophils; Peroxidase; Protein Binding; Recurrence; Risk Factors

There is ongoing debate concerning the classification of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. That is, whether classification should be based on the serotype (proteinase 3 (PR3)- or myeloperoxidase (MPO)-ANCA) or on the clinical phenotype (granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA)). To add clarity, this review focused on integration of the most recent literature.. Large clinical trials have provided evidence that a serology-based risk assessment for relapses is more predictive than distinction based on the phenotype. Research conducted in the past decade indicated that a serology-based approach more closely resembles the genetic associations, the clinical presentation (i.e., lung involvement), biomarker biology, treatment response, and is also predicting comorbidities (such as cardiovascular death). Our review highlights that a serology-based approach could replace a phenotype-based approach to classify ANCA-associated vasculitides. In future, clinical trials and observational studies will presumably focus on this distinction and, as such, translate into a "personalized medicine."

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Granulomatosis with Polyangiitis; Humans; Microscopic Polyangiitis; Myeloblastin; Peroxidase; Phenotype

This document follows up on a 2017 revised international consensus on anti-neutrophil cytoplasm antibodies (ANCA) testing in granulomatosis with polyangiitis and microscopic polyangiitis and focuses on the clinical and diagnostic value of ANCA detection in patients with connective tissue diseases, idiopathic interstitial pneumonia, autoimmune liver diseases, inflammatory bowel diseases, anti-glomerular basement membrane (GBM) disease, infections, malignancy, and during drug treatment. Current evidence suggests that in certain settings beyond systemic vasculitis, ANCA may have clinical, pathogenic and/or diagnostic relevance. Antigen-specific ANCA targeting proteinase-3 and myeloperoxidase should be tested by solid phase immunoassays in any patient with clinical features suggesting ANCA-associated vasculitis and in all patients with anti-GBM disease, idiopathic interstitial pneumonia, and infective endocarditis associated with nephritis, whereas in patients with other aforementioned disorders routine ANCA testing is not recommended. Among patients with autoimmune liver diseases or inflammatory bowel diseases, ANCA testing may be justified in patients with suspected autoimmune hepatitis type 1 who do not have conventional autoantibodies or in case of diagnostic uncertainty to discriminate ulcerative colitis from Crohn's disease. In these cases, ANCA should be tested by indirect immunofluorescence as the target antigens are not yet well characterized. Many questions concerning the optimal use of ANCA testing in patients without ANCA-associated vasculitis remain to be answered.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Consensus; Granulomatosis with Polyangiitis; Hepatitis, Autoimmune; Humans; Myeloblastin; Peroxidase

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disorder which affects small- and, to a lesser degree, medium-sized vessels. ANCA-associated vasculitis encompasses three disease phenotypes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). This classification is largely based on clinical presentations and has several limitations. Recent research provided evidence that genetic background, risk of relapse, prognosis, and co-morbidities are more closely related to the ANCA serotype, proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA, compared to the disease phenotypes GPA or MPA. This finding has been extended to the investigation of biomarkers predicting disease activity, which again more closely relate to the ANCA serotype. Discoveries related to the immunopathogenesis translated into clinical practice as targeted therapies are on the rise. This review will summarize the current understanding of the immunopathogenesis of ANCA-associated vasculitis and the interplay between ANCA serotype and proposed disease biomarkers and illustrate how the extending knowledge of the immunopathogenesis will likely translate into development of a personalized medicine approach in the management of ANCA-associated vasculitis.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Churg-Strauss Syndrome; Granulomatosis with Polyangiitis; Humans; Microscopic Polyangiitis; Myeloblastin; Peroxidase; Prognosis; Serogroup

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of disorders characterized by inflammation and destruction of small- and medium-sized blood vessels and the presence of circulating ANCA. Clinical disease phenotypes include granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and renal-limited vasculitis. Serologic classification of AAV into proteinase 3-ANCA disease and myeloperoxidase-ANCA disease correlates with a number of disease characteristics. AAV has a predilection for the kidney, with >75% of patients having renal involvement characterized by rapidly progressive glomerulonephritis. The cause and pathogenesis of AAV are multifactorial and influenced by genetics, environmental factors, and responses of the innate and adaptive immune system. Randomized controlled trials in the past 2 decades have refined the therapy of AAV and transformed AAV from a fatal disease to a chronic illness with relapsing course and associated morbidity. This article in AJKD's Core Curriculum in Nephrology series provides a detailed review of the epidemiology, pathogenesis, diagnosis, and advances in the management of AAV.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Cyclophosphamide; Disease Progression; Glomerulonephritis; Glucocorticoids; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Kidney Transplantation; Microscopic Polyangiitis; Mycophenolic Acid; Myeloblastin; Peroxidase; Remission Induction; Renal Dialysis; Rituximab

Granulomatosis with Polyangiitis is a necrotising systemic vasculitis predominantly affecting small and medium sized vessels. It is predominantly associated with antibodies directed against proteinase 3, but a small number of individuals with this disease have antibodies directed against myeloperoxidase. The premise of this paper is to explore the possibility that these two serotypes maybe two separate diseases. There is evidence that the same single nucleotide polymorphisms in the TLR 9 gene is associated with increased risk for PR3 ANCA positivity but protects against MPO ANCA positivity. There is some evidence that MPO ANCA positive GPA disease may be 'limited' in its expression and be associated with the more indolent phenotype. The genotype may affect the serotype, and the serotype might affect the phenotype. There has been limited success in identifying how the difference in phenotype might affect outcomes. We are at a very early stage in our understanding of how these serotypes might be treated differently. This paper attempts to critically appraise the evidence available so far.

Topics: Autoantibodies; Biomarkers; Diagnosis, Differential; Genetic Predisposition to Disease; Granulomatosis with Polyangiitis; Humans; Myeloblastin; Peroxidase; Phenotype; Polymorphism, Single Nucleotide; Predictive Value of Tests; Prognosis; Risk Factors; Toll-Like Receptor 9

ANCA vasculitis has an associated autoimmune response that produces ANCAs that induce distinct pathologic lesions. Pauci-immune necrotizing and crescentic GN is a frequent component of ANCA vasculitis. ANCA vasculitis is associated with ANCA specific for myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA). A diagnosis of ANCA vasculitis should always specify the serotype as MPO-ANCA positive, PR3-ANCA positive, or ANCA-negative. To fully characterize a patient, the serotype also should be accompanied by the clinicopathologic variant if this can be determined: microscopic polyangiitis, granulomatosis with polyangiitis (Wegener), eosinophilic granulomatosis with polyangiitis (Churg-Strauss), or renal-limited vasculitis. ANCA vasculitis is most prevalent in individuals >50 years old. There are racial/ethnic and geographic influences on the prevalence, serotype frequencies, and clinicopathologic phenotypes. There is clinical,

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Female; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Male; Microscopic Polyangiitis; Middle Aged; Myeloblastin; Peroxidase; Prevalence; Recurrence; Remission Induction; Risk Factors; Treatment Outcome

Eosinophilic granulomatosis with polyangitis (EGPA) is a rare small- and medium-sized vessel vasculitis belonging to the group of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV). It is commonly divided into two phenotypes depending on the presence of ANCAs targeting myeloperoxidase (MPO). MPO-ANCAs are present in 31% to 38% of patients and are associated with a vasculitis phenotype of the disease, whereas patients without MPO-ANCA are at risk of cardiac involvement. Despite significant advances in understanding the overall pathogenesis of the disease, the explanation for this dichotomy is still unclear. In this review, we synthesize our knowledge of the pathogenesis of EGPA and attempt to i) distinguish EGPA from other diseases including other AAVs, asthma, allergy and hypereosinophilic-associated conditions and ii) speculate about the preponderant mechanisms, which could explain the two disease phenotypes.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Asthma; B-Lymphocytes; Eosinophils; Granulomatosis with Polyangiitis; Humans; Peroxidase

The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a heterogeneous group of rare syndromes characterized by necrotizing inflammation of small and medium-sized blood vessels and the presence of ANCAs. Several clinicopathological classification systems exist that aim to define homogeneous groups among patients with AAV, the main syndromes being microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic GPA (EGPA). Two main types of ANCA can be detected in patients with AAV. These ANCAs are defined according to their autoantigen target, namely leukocyte proteinase 3 (PR3) and myeloperoxidase (MPO). Patients with GPA are predominantly PR3-ANCA-positive, whereas those with MPA are predominantly MPO-ANCA-positive, although ANCA specificity overlaps only partially with these clinical syndromes. Accumulating evidence suggests that ANCA specificity could be better than clinical diagnosis for defining homogeneous groups of patients, as PR3-ANCA and MPO-ANCA are associated with different genetic backgrounds and epidemiology. ANCA specificity affects the phenotype of clinical disease, as well as the patient's initial response to remission-inducing therapy, relapse risk and long-term prognosis. Thus, the classification of AAV by ANCA specificity rather than by clinical diagnosis could convey clinically useful information at the time of diagnosis.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Churg-Strauss Syndrome; Granulomatosis with Polyangiitis; Humans; Immunologic Factors; Inflammation; Microscopic Polyangiitis; Myeloblastin; Peroxidase; Predictive Value of Tests; Prognosis; Sensitivity and Specificity

This article provides an update on the diagnosis and management of the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides, granulomatosis with polyangiitis (formerly Wegener), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss). Focus is on new schemes of classification and the importance of ANCAs in the diagnosis and prognosis of these systemic vasculitides. Current therapeutic strategies consisting of glucocorticoids in conjunction with conventional or biologic agents for both induction of remission and remission maintenance are outlined. Future research directions include investigation of the optimal duration and frequency of maintenance therapy and development of targeted therapeutic agents.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Churg-Strauss Syndrome; Enzyme-Linked Immunosorbent Assay; Glucocorticoids; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Maintenance Chemotherapy; Microscopic Polyangiitis; Myeloblastin; Peroxidase; Remission Induction

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Blotting, Western; Churg-Strauss Syndrome; Cohort Studies; Cross-Sectional Studies; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Epitopes; Granulomatosis with Polyangiitis; Humans; Lysosomal Membrane Proteins; Lysosomal-Associated Membrane Protein 2; Microscopic Polyangiitis; Myeloblastin; Peroxidase; Predictive Value of Tests; Rabbits; Rats

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Endothelium, Vascular; Epitopes; Granulomatosis with Polyangiitis; Humans; Immunogenetics; Immunomodulation; Microscopic Polyangiitis; Myeloblastin; Neutrophils; Peroxidase

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Churg-Strauss Syndrome; Diagnosis, Differential; Disease Progression; Epitopes; Genotype; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Lung Diseases; Microscopic Polyangiitis; Myeloblastin; Peroxidase; Phenotype; Prognosis; Risk Factors

Topics: Alleles; alpha 1-Antitrypsin; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Genetic Loci; Genome-Wide Association Study; Genotype; Granulomatosis with Polyangiitis; HLA-DP beta-Chains; HLA-DQ Antigens; Humans; Microscopic Polyangiitis; Myeloblastin; Peroxidase; Polymorphism, Single Nucleotide

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides are a heterogeneous group of diseases corresponding to necrotising inflammation of small vessels with a wide range of clinical presentations. At least two of the diseases are believed to exhibit a common ground of pathophysiological mechanisms. These are granulomatosis with polyangiitis (GPA, formerly known as Wegener's granulomatosis) and microscopic polyangiitis (MPA). ANCA directed against proteinase 3 (PR3) are preferentially associated with GPA, and anti-myeloperoxidase (MPO) ANCA are associated mainly with MPA and eosinophilic GPA (formerly known as Churg-Strauss syndrome). Anti-MPO and anti-PR3 antibodies can activate neutrophils in vitro. In vivo data are available for humans and mice on the pathogenicity of anti-MPO but it is more controversial for PR3-ANCA. A recent genome-wide association study of patients with ANCA-associated vasculitides confirmed the genetic contribution to the pathogenesis of these conditions, with significant association of PR3-ANCA and human leukocyte antigen-DP and the genes encoding α1-antitrypsin and PR3. MPO-ANCA were significantly associated with human leukocyte antigen-DQ. Thus, recent results from epidemiological studies, genome-wide association study and therapeutic trials have suggested that these entities are, in fact, distinct. We have summarised these results and discuss the idea that these two entities should be studied separately as the nature of the two auto-antigens suggests at a molecular level despite shared ANCA involvement.

Topics: alpha 1-Antitrypsin; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantigens; Churg-Strauss Syndrome; Genome-Wide Association Study; Granulomatosis with Polyangiitis; Humans; Mice; Microscopic Polyangiitis; Myeloblastin; Peroxidase; Terminology as Topic

A 75-year-old woman presented with rapidly progressive glomerulonephritis with positive results for anti-myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA). Corticosteroid therapy was successfully introduced. However, 7 months later, magnetic resonance imaging revealed marked swelling in the falx cerebri and high density regions were apparent on gallium scintigraphy, leading to diagnosis of hypertrophic cranial pachymeningitis (HCP). Symptoms improved with intensified corticosteroid therapy, but radiological examination 9 months later revealed right nasal sinus inflammation accompanied by osteolytic change. Granulomatosis with polyangiitis (Wegener's) was finally diagnosed. HCP is an important complication in MPO-ANCA-related vasculitis, and needs to be considered during the clinical course.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Female; Granulomatosis with Polyangiitis; Humans; Hypertrophy; Meningitis; Peroxidase

Abstract Wegener's granulomatosis is a rare autoimmune disease associated with granulomatous inflammation and anti-neutrophil cytoplasmic antibody (ANCA)-associated small vessel vasculitis. Following the discovery of ANCA, ANCA-associated vasculitis is established as a disease entity of Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. Clinical and experimental studies have provided evidences that myeloperoxidase (MPO) and proteinase 3 (PR3), which are major antigenic targets for ANCA in neutrophils, are not only disease markers but also involved in the pathogenesis. In addition, recent studies have revealed another potential antigen for ANCA, lysosomal-associated membrane protein-2 (LAMP-2). Though nervous system manifestations of Wegener's granulomatosis are less frequent than classical manifestations in the lungs and kidneys, 20-50% of patients demonstrate neurological involvements. Peripheral nervous system involvement (in generalized Wegener's granulomatosis) is more frequent than central nervous system (CNS) involvement. Multiple mononeuropathy and multiple cranial neuropathy are the most prevalent symptoms. CNS manifestations include cerebrovascular events, pachymeningitis, seizures, and reversible posterior leukoencephalopathy syndrome. Here we discuss the pathogenic mechanism of ANCA and review the literature regarding neurological involvement in Wegener's granulomatosis.

Topics: Antibodies, Antineutrophil Cytoplasmic; Central Nervous System Diseases; Granulomatosis with Polyangiitis; Humans; Myeloblastin; Peroxidase

Names influence how something is perceived. Diagnostic terms (diagnoses) are the names of diseases that are usually derived either from some distinctive characteristic of the disease or include an eponym recognizing someone who elucidated the disease. No matter how logical and appropriate a name may be, if it is not usable and used it is of no lasting value. This brief commentary focuses on the nomenclature of systemic vasculitides, and uses as a prime example Wegener's granulomatosis, which has been renamed recently 'granulomatosis with polyangiitis', in part because of concerns about the suitability of Friedrich Wegener as the source of an eponym. The most distinctive pathological feature of Wegener's granulomatosis is multi-focal necrotizing inflammation that has long been called granulomatosis. The systemic variant of Wegener's granulomatosis also is characterized by inflammation in many different vessels or different types, i.e. polyangiitis. Thus, granulomatosis with polyangiitis is a very appropriate alternative term for Wegener's granulomatosis. This term also is in accord with the name for a closely related vasculitis, i.e. microscopic polyangiitis. Terms that indicate aetiology and pathogenesis, when known, are useful to include in names for diseases (diagnoses). Anti-neutrophil cytoplasmic autoantibodies specific for myeloperoxidase (MPO-ANCA) or proteinase 3 (PR3-ANCA) are implicated in the cause of granulomatosis with polyangiitis and thus also should be specified in the diagnosis (e.g. PR3-ANCA-positive granulomatosis with polyangiitis or MPO-ANCA-positive microscopic polyangiitis). As our understanding of the clinical manifestations, pathogenesis and aetiology of vasculitides change over time, the names and approaches for diagnosing these diseases will change accordingly.

Topics: Antibodies, Antineutrophil Cytoplasmic; Granulomatosis with Polyangiitis; Humans; Microscopic Polyangiitis; Myeloblastin; Peroxidase; Vasculitis

One of the main characteristics of the vasculitis associated with antineutrophil cytoplasm autoantibodies (AASV) is the absence of immune complex deposition in biopsies of affected tissues as well as a lack of complement depletion. However, in early stages of disease induced in animal models, it has been observed that the complement system may be involved in the generation of these diseases. There are various animal models which have been developed with the aim of knowing which are the pathogenic mechanisms in granulomatosis with polyangiitis (Wegener) (GPA) and microscopic polyangiitis (MPA), the latter being explained using these approaches in a more satisfactory manner, as there is lack of a model which reproduces the changes leading to a granulomatous vasculitis associated with antibodies against proteinase-3, as in GPA. This short review presents recent evidence of the presence of complement in biopsies of patients with AASV and the most recent animal models, which show the participation of complement in their etiology.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal; Autoantigens; Biopsy; Complement Activation; Complement C5; Complement C5a; Complement System Proteins; DNA-Binding Proteins; Granulomatosis with Polyangiitis; Humans; Kidney; Mice; Mice, Inbred C57BL; Microscopic Polyangiitis; Myeloblastin; Peroxidase

The term pauci-immune glomerulonephritis with vasculitis encompasses a group of auto-immune disorders, which includes Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, and renal-limited vasculitis. Over the past few years, progress has been made in understanding the epidemiology and environmental and genetic risk factors of the role of antineutrophil cytoplasmic antibodies (ANCA) in kidney pathogenesis and the utilization of ANCA in diagnosis. However, certain aspects are still subject to debate including the classification and the place of ANCA in treatment.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Disease Models, Animal; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Kidney; Myeloblastin; Peroxidase; Risk Factors

Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome are idiopathic systemic vasculitides in which circulating anti-neutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3) or myeloperoxidase (MPO) are commonly found. Within the last 25 years, these antibodies were subject of intensive studies, and a growing body of evidence arose for a distinct role of ANCA in the pathogenesis of the ANCA-associated vasculitides (AAV). Yet, the evidence derived from clinical observations and in vitro studies remains circumstantial. The various animal models have provided substantial support for a pathogenic role of MPO-ANCA in vivo, but the debate if ANCA play a primary role in the pathogenesis of these diseases is still open. The aim of this review was to update current basic and clinical research on ANCA in the pathophysiology of AAV and to point out and discuss limitations and inconsistencies of the clinical and experimental evidence.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Apoptosis; B-Lymphocytes; Cell Differentiation; Dendritic Cells; Genetic Predisposition to Disease; Granulomatosis with Polyangiitis; Humans; Infections; Myeloblastin; Neutrophils; Peroxidase; Receptor, PAR-2; Vasculitis

Recent studies provided new insights into the pathogenesis of vasculitides associated with antineutrophil cytoplasm antibodies (ANCA). They yield more information about the pathogenic role of ANCA, the initiation of the immune response against proteinase 3, the expression of ANCA target antigens on neutrophil surfaces, endothelial damage and the mechanisms of vasculitis associated with propylthiouracil. The pathogenic role of antimyeloperoxidase antibodies has been established in vitro and in vivo in animal models and in human. A pathogenic role for antiproteinase 3 antibodies has not yet been clearly established in vivo although it is well documented in vitro.

Topics: Adult; Animals; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Chemokines; Churg-Strauss Syndrome; Dendritic Cells; Disease Models, Animal; Epitopes; Female; Granulomatosis with Polyangiitis; Humans; Infant, Newborn; Male; Mice; Myeloblastin; Peroxidase; Polymorphism, Genetic; Propylthiouracil; Rats; Rats, Inbred WKY; Risk; Vasculitis

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.

Topics: Adrenal Cortex Hormones; Antibodies, Antineutrophil Cytoplasmic; Azathioprine; Biological Products; Churg-Strauss Syndrome; Cyclophosphamide; Drug Therapy, Combination; Granulomatosis with Polyangiitis; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Immunosuppressive Agents; Methotrexate; Myeloblastin; Peroxidase; Remission Induction; Severity of Illness Index; Treatment Outcome; Vasculitis

Systemic vasculitis, although rare, is often diagnosed late and long after the onset of symptoms. The small vessel vasculitides are recognized clinically by their multisystem presentation, markers of inflammation and evidence for an acute glomerulonephritis (GN), with the most apparent organ involved directing referral to secondary care. Routine laboratory tests are usually non-specific in systemic vasculitis but the use of anti-neutrophil cytoplasmic antibodies (ANCAs) and glomerular basement membrane (GBM) antibodies can aid diagnosis, treatment and monitoring decisions. These antibodies are detected and quantified by indirect immunofluorescence (IIF) and antigen-specific enzyme-linked immunosorbent assay (ELISA), usually in combination for ANCA, and ELISA systems (or direct IIF on kidney biopsy) for GBM antibodies. The presence or absence of ANCA does not confirm or exclude the diagnosis of systemic vasculitis but negative and positive predictive values will be strongly influenced by clinical presentation. Various large studies have been unable to conclude that following serial ANCA titres has great clinical utility in each case but each patient must be considered on its own merits; for example the reappearance of ANCA in a patient who was rendered ANCA negative following treatment is more likely to indicate relapse. The adoption of consensus guidelines that direct testing towards patients with rapidly progressive GN, pulmonary haemorrhage, persistent and destructive ear, nose and upper airways problems, such as subglottic tracheal stenosis, a retro-orbital mass and cutaneous vasculitis with systemic features or peripheral neuropathy, will greatly increase the clinical utility and positive predictive value of these tests.

Topics: Algorithms; Anti-Glomerular Basement Membrane Disease; Antibodies, Antineutrophil Cytoplasmic; Basement Membrane; Biomarkers; Comorbidity; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique, Indirect; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Myeloblastin; Peroxidase; Sensitivity and Specificity; Vasculitis

Wegener's granulomatosis and microscopic polyangiitis are idiopathic systemic vasculitides strongly associated with antineutrophil cytoplasmic autoantibodies (ANCA). In Wegener's granulomatosis, ANCA are mostly directed against proteinase 3 (PR3), whereas in microscopic polyangiitis ANCA are directed against myeloperoxidase; increases in levels of these autoantibodies precede or coincide with clinical relapses in many cases. In vitro, ANCA can further activate primed neutrophils to release reactive oxygen species and lytic enzymes, and, in conjunction with neutrophils, can damage and lyse endothelial cells. Patients with Wegener's granulomatosis or microscopic polyangiitis have an increased percentage of neutrophils that constitutively express PR3 on their membrane. These neutrophils can be stimulated by ANCA, without priming. In vivo, transfer of splenocytes from myeloperoxidase-deficient mice immunized with mouse myeloperoxidase into wild-type mice resulted in pauci-immune systemic vasculitis. A similar experiment in PR3-deficient mice did not cause significant vasculitic lesions. Together, clinical, in vitro and in vivo experimental data support a pathogenic role for ANCA in Wegener's granulomatosis and microscopic polyangiitis, although this role is more evident for myeloperoxidase-specific ANCA than for PR3-specific ANCA. Several controlled trials have led to an evidence-based approach for the treatment of ANCA-associated vasculitis, and further studies, based on new insights into pathogenesis, are in progress.

Topics: Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Granulomatosis with Polyangiitis; Humans; Myeloblastin; Neutrophils; Peroxidase

Wegener's granulomatosis (WG) is a complex autoimmune syndrome that is characterised by upper/lower respiratory necrotising granulomatosis, glomerulonephritis and small-vessel vasculitis. Since Wegener's 1936 description, considerable advances in recognition and treatment have changed this disease from a rapidly and uniformly fatal illness to a chronic disease characterised by remissions and relapses. The serendipitous discovery of anti-neutrophil cytoplasmic antibodies (ANCAs) as a marker associated with WG focused attention on the potential pathogenic role of these antibodies and has recently led to the development of novel animal models that might facilitate our understanding of the disease pathogenesis. Future animal models of this disease will have to account for the role of both ANCA-mediated pathology and granulomatous inflammation to enable us to understand the chronic and persistent features of WG in humans.

Topics: Adolescent; Adult; Animals; Antibodies, Antineutrophil Cytoplasmic; Autoantigens; Autoimmune Diseases; Chemokines; Child; Cytokines; Female; Granulomatosis with Polyangiitis; Humans; Kidney; Lung; Male; Mice; Mice, Knockout; Myeloblastin; Peroxidase; Th1 Cells

Topics: Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Churg-Strauss Syndrome; Diagnosis, Differential; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique, Indirect; Granulomatosis with Polyangiitis; Humans; Myeloblastin; Peroxidase; Serine Endopeptidases; Vasculitis

The pathogenesis of different types of systemic vasculitis positive for antineutrophil cytoplasmic antibodies (ANCA) remains incompletely understood. ANCA constitute a heterogeneous group of antibodies that are associated with different types of small-vessel vasculitis, including Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CSS). Anti-proteinase 3 ANCA are present in more than 90% of patients with systemic WG, and anti-myeloperoxidase (MPO) ANCA in 50-75% of those with MPA and 40-60 % of those with CSS. The pathogenic role of ANCA has been well documented in vivo: passive transfer of anti-MPO ANCA in an MPO knockout mouse model immunized with MPO is sufficient to induce the disease. In vitro, mouse and human anti-proteinase 3 ANCA can activate neutrophils primed with TNF-a and contribute to vasculitic lesions. T-cells are also involved: type 1 helper cytokines have been detected in tissue lesions of limited forms of WG, while type 2 helper cytokines have been identified in its systemic forms. Eosinophils may play a key role in the development of vasculitic lesions in CSS, although this remains to be proved.

Topics: Adoptive Transfer; Animals; Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Cytokines; Disease Models, Animal; Eosinophils; Granulomatosis with Polyangiitis; Humans; Immunization; Mice; Mice, Inbred BALB C; Mice, Knockout; Monocytes; Neutrophils; Peroxidase; Prevalence; T-Lymphocytes; Vasculitis

Little is known about the etiologies of diseases associated with circulating antineutrophil cytoplasm autoantibodies (ANCA), such as primary vasculitides and inflammatory bowel diseases. However, the understanding of immune mechanisms supposedly involved in the pathogenesis of these diseases is still growing. In the present review, we first focus on the mechanisms triggering the development of ANCA, including the potential role of microbial superantigens and the possible defect(s) in the progression of apoptosis or in the removal of apoptotic cells. We next concentrate on the contribution of ANCA to the clinical symptoms and on the pathogenic role of ANCA, including the accessibility of ANCA antigens as targets for circulating antibodies and the mode of action of ANCA. Mechanisms of neutrophil activation by ANCA include the engagement of Fcgamma receptors, the possible mechanisms of neutrophil-mediated tissue damage, and the neutrophil-endothelial interaction.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Apoptosis; Autoantigens; Autoimmune Diseases; Churg-Strauss Syndrome; Endothelium, Vascular; Granulomatosis with Polyangiitis; Humans; Mice; Models, Animal; Myeloblastin; Neutrophils; Peroxidase; Serine Endopeptidases; Superantigens; T-Lymphocytes, Cytotoxic; Vasculitis

Wegener's granulomatosis (WG), microscopic polyangiitis, and Churg-Strauss syndrome belong to the group of ANCA-associated vasculitides. Numerous in vitro studies underscored the role of antineutrophil cytoplasmic antibodies (ANCA) in the pathogenesis of vasculitis. More recently, a mouse model provided in vivo evidence of the pathogenic role of ANCA by inducing a vasculitis after the transfer of splenocytes or MPO-ANCA. The target antigens of ANCA, myeloperoxidase (MPO) and proteinase 3 (PR3), are translocated onto the cell surface after priming of neutrophil granulocytes with cytokines. ANCA bind to target antigens and activate neutrophil granulocytes resulting in premature degranulation and endothelial cell damage (ANCA-cytokine sequence theory). Both the F(ab')2 end and the FcgammaR(eceptor) end of the ANCA are involved in activating neutrophil granulocytes. This mode of activation might account for differences to normal neutrophil activation via the FcgammaR. In addition, an expansion of T-cells lacking the co-stimulatory molecule CD28 is seen in WG suggesting an altered cellular immune response. Data from European multicenter studies demonstrated, among other things, that azathioprine can be used for the maintenance of remission after successful induction of remission with cyclophosphamide in ANCA-associated vasculitides.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Autoantigens; Azathioprine; CD28 Antigens; Churg-Strauss Syndrome; Cyclophosphamide; Disease Models, Animal; Granulomatosis with Polyangiitis; Humans; Immunoglobulin Fab Fragments; Immunosuppressive Agents; Mice; Multicenter Studies as Topic; Myeloblastin; Neutrophil Activation; Peroxidase; Randomized Controlled Trials as Topic; Receptors, IgG; Remission Induction; Serine Endopeptidases; T-Lymphocytes; Vasculitis

Anti-neutrophil cytoplasmic antibodies (ANCA) are a heterogenous group of autoantibodies with a broad spectrum of clinically associated diseases. ANCA testing has been established as a useful tool for the diagnosis of small vessel vasculitides, especially of 'ANCA-associated vasculitides' (AAV), such as Wegener's granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome, in which circulating ANCA are commonly found. Within the last 20 years these antibodies were subject of intensive studies and a growing body of evidence arose for a distinct role of ANCA in the pathogenesis of the AAV. Our current concept of whether ANCA directly or indirectly contribute to vascular damage (ANCA-cytokine-sequence-theory) was mainly developed from in vitro studies and is supported by data from clinical investigations as well as animal models. Recently a direct causal link between ANCA and the development of glomerulonephritis and vasculitis has been demonstrated. We now know that a passive transfer of ANCA is sufficient to induce disease, but it remains to be discovered how the autoantibodies to neutrophil antigens might triggered.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Granulomatosis with Polyangiitis; Humans; Myeloblastin; Peroxidase; Serine Endopeptidases; Vasculitis

Anti-Neutrophil Cytoplasmic Antibodies (ANCA) are a heterogenous group of autoantibodies with a broad spectrum of clinically associated diseases. The diagnostic value is established of Proteinase 3 (PR3)-ANCA for Wegener's granulomatosis (WG) as well as Myeloperoxidase (MPO)-ANCA for microscopic polyangiitis (MPA). Within the last 20 years these antibodies were subject of intensive studies and a growing body of evidence arose for a distinct role of ANCA in the pathogenesis of the ANCA associated vasculitides WG and MPA. Our current concept of whether ANCA directly or indirectly contribute to vascular damage (ANCA-Cytokine-Sequence-Theory) was mainly developed from in vitro studies. It is plausible and it is supported by data from clinical investigations as well as animal models. Nevertheless our knowledge of the etiological and pathogenetic pathways remains incomplete.

Topics: Antibodies, Antineutrophil Cytoplasmic; Enzyme-Linked Immunosorbent Assay; Epitopes; Fluorescent Antibody Technique; Granulomatosis with Polyangiitis; Humans; Myeloblastin; Peroxidase; Predictive Value of Tests; Serine Endopeptidases; Vasculitis

Antineutrophil cytoplasmic autoantibodies (ANCA) directed to proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA) are closely associated with the idiopathic systemic necrotizing vasculitides, in particular Wegener's granulomatosis, microscopic polyangiitis and its renal limited manifestation, and Churg Strauss Syndrome. Many in vitro studies show that those ANCA have phlogistic potential, particularly at the interface of neutrophils and endothelial cells. A limited number of studies in experimental animals support their pathogenetic role. However, ANCA alone are not sufficient, as based on clinical and experimental data, and other, probably exogenous factors, seem necessary for disease induction and (re)activation. Among those silica and particularly, the carriage of Staphylococcus aureus have been proposed. Besides, various genetic factors are involved in disease susceptibility. The ANCA-associated vasculitides are systemic autoimmune diseases in which the interplay of autoimmunity with environmental and genetic factors determines their clinical expression.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Endopeptidases; Genetic Predisposition to Disease; Granulomatosis with Polyangiitis; Humans; Peroxidase; Vasculitis

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantigens; Epitopes; Granulomatosis with Polyangiitis; Humans; Myeloblastin; Peroxidase; Serine Endopeptidases

Microscopic polyangiitis ("microscopic polyarteritis") is a form of necrotizing small vessel vasculitis that most often affects venules, capillaries, arterioles, and small arteries, although it occasionally involves medium-sized arteries. Microscopic polyangiitis is a more appropriate name than microscopic polyarteritis because some patients have no evidence for arterial involvement. The absence or paucity of immunoglobulin localization in vessel walls distinguishes microscopic polyangiitis from immune complex mediated small vessel vasculitis, such as Henoch-Schonlein purpura and cryoglobulinemic vasculitis. Clinical, epidemiological, and pathologic differences warrant the separation of microscopic polyangiitis from polyarteritis nodosa on the basis of involvement of capillaries and venules by the former but not the latter. Pauci-immune necrotizing and crescentic glomerulonephritis, and hemorrhagic pulmonary capillaritis are common in patients with microscopic polyangiitis. Microscopic polyangiitis is the most common cause for pulmonary-renal vasculitic syndrome. The vasculitis in patients with microscopic polyangiitis is pathologically indistinguishable from the vasculitis of Wegener's granulomatosis and Churg-Strauss syndrome. Granulomatous inflammation distinguishes Wegener's granulomatosis from microscopic polyangiitis. Asthma and eosinophilia distinguish Churg-Strauss syndrome from microscopic polyangiitis. Microscopic polyangiitis, Wegener's granulomatosis, and Churg-Strauss syndrome are all associated with circulating antineutrophil cytoplasmic autoantibodies.

Topics: Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Cryoglobulinemia; Diagnosis, Differential; Granulomatosis with Polyangiitis; Humans; IgA Vasculitis; Microcirculation; Myeloblastin; Peroxidase; Polyarteritis Nodosa; Serine Endopeptidases; Vasculitis

The diagnostic value of tests for antimyeloperoxidase antibodies (anti-MPO) for systemic vasculitis is less established than that for cytoplasmic antineutrophil cytoplasmic antibody (cANCA)/antiproteinase 3 antibodies (anti-PR3). Controversy exists regarding the optimal utilization of indirect immunofluorescence (IIF) ANCA testing versus antigen-specific ANCA testing. To summarize the pertinent data, we conducted a metaanalysis examining the diagnostic value of ANCA testing systems that include assays for anti-MPO.. We performed a structured Medline search and reference list review. Target articles in the search strategy were those reporting the diagnostic value of immunoassays for anti-MPO for the spectrum of systemic necrotizing vasculitides that includes Wegener's granulomatosis, microscopic polyangiitis, the Churg-Strauss syndrome, and isolated pauci-immune necrotizing or crescentic glomerulonephritis, regardless of other types of ANCA tests. Inclusion criteria required specification of a consecutive or random patient selection method and the use of acceptable criteria for the diagnosis of vasculitis exclusive of ANCA test results. Weighted pooled summary estimates of sensitivity and specificity were calculated for anti-MPO alone, anti-MPO + perinuclear ANCA (pANCA), and anti-MPO/pANCA + anti-PR3/cANCA.. Of 457 articles reviewed, only 7 met the selection criteria. Summary estimates of sensitivity and specificity (against disease controls only) of assays for anti-MPO for the diagnosis of systemic necrotizing vasculitides were 37.1% (confidence interval 26.6% to 47.6%) and 96.3% (CI 94.1% to 98.5%), respectively. When the pANCA pattern by IIF was combined with anti-MPO testing, the specificity improved to 99.4%, with a lower sensitivity, 31.5%. The combined ANCA testing system (anti-PR3/cANCA + anti-MPO/pANCA) increased the sensitivity to 85.5% with a specificity of 98.6%.. These results suggest that while anti-MPO is relatively specific for the diagnosis of systemic vasculitis, the combination system of immunoassays for anti-MPO and IIF for pANCA is highly specific and both tests should be used together given the high diagnostic precision required for these conditions. Because patients with ANCA associated vasculitis have either anti-MPO with pANCA or anti-PR3 with cANCA, and rarely both, a combined ANCA testing system including anti-PR3/cANCA and anti-MPO/pANCA is recommended to optimize the diagnostic performance of ANCA testing.

Topics: Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Myeloblastin; Peroxidase; Serine Endopeptidases

Antineutrophil cytoplasmic antibody (ANCA) tests are used to diagnose and monitor inflammatory activity in the primary systemic small vessel vasculitides. ANCA is best demonstrated in these diseases by using a combination of indirect immunofluorescence (IIF) of normal peripheral blood neutrophils and enzyme-linked immunosorbent assays (ELISAs) that detect ANCA specific for proteinase 3 (PR3) or myeloperoxidase (MPO). For ANCA testing in "new" patients, IIF must be performed on all serum samples. Serum samples containing ANCA, any other cytoplasmic fluorescence, or an antinuclear antibody (ANA) that results in homogeneous or peripheral nuclear fluorescence then should be tested in ELISAs for PR3-ANCA and MPO-ANCA. Optimally, ELISAs for PR3-ANCA and MPO-ANCA should be performed on all serum samples. Inclusion of the most recent positive sample in the IIF or ELISA may help demonstrate a change in antibody level. Reports should use recommended terms. Any report of positive neutrophil fluorescence issued before the ELISA results are available should indicate that positive fluorescence alone is not specific for the diagnosis of Wegener granulomatosis or microscopic polyangiitis and that decisions about treatment should not be based solely on the ANCA results.

Topics: Antibodies, Antineutrophil Cytoplasmic; Antibodies, Antinuclear; Churg-Strauss Syndrome; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique, Indirect; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Myeloblastin; Neutrophils; Peroxidase; Quality Control; Reference Values; Sensitivity and Specificity; Serine Endopeptidases; Terminology as Topic; Vascular Diseases; Vasculitis

Anti-neutrophil cytoplasmic antibodies, as detected by indirect immunofluorescence, have limited diagnostic significance as they occur in a variety of inflammatory disorders. The presence of antibodies to defined target antigens of anti-neutrophil cytoplasmic antibodies, that is proteinase 3 and myeloperoxidase, is, however, highly specific for one of the systemic vasculitides, in particular Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, and idiopathic pauci-immune necrotizing crescentic glomerulonephritis. In general, anti-proteinase-3-positive patients show more widespread organ involvement, more granuloma formation, and a more severe initial course of their renal lesions than anti-myeloperoxidase-positive patients; however, there is considerable overlap, and either antibody specificity may be found in the different clinical syndromes. In vitro, anti-neutrophil cytoplasmic antibodies are able further to activate pre-activated neutrophils and monocytes, which can result in endothelial damage. A direct activating effect of anti-neutrophil cytoplasmic antibodies on endothelial cells has been suggested, but those studies should be confirmed. In vivo, experimental data support a pathogenetic role for anti-neutrophil cytoplasmic antibodies, particularly anti-myeloperoxidase, but besides anti-neutrophil cytoplasmic antibodies a second pro-inflammatory stimulus seems to be required to induce lesions. Whether anti-neutrophil cytoplasmic antibodies can be a direct target for treatment has still to be proved. Current immunosuppressive treatment regimens for the anti-neutrophil cytoplasmic antibody-associated vasculitides are, however, unsatisfactory because of side-effects, that is opportunistic infections and malignancies. New treatment regimens, based on new pathogenetic concepts, are currently being tested.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Cytoplasm; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Models, Biological; Myeloblastin; Neutrophils; Peroxidase; Serine Endopeptidases; Vasculitis

Anti-neutrophil cytoplasm antibodies (ANCA) are a group of autoantibodies primarily associated with systemic vasculitis. Hitherto, the method of choice for ANCA detection has been indirect immunofluorescence (IIF). By this method two major patterns can be seen: a cytoplasmic pattern (cANCA) or a perinuclear pattern (pANCA). The cANCA pattern is most often caused by antibodies directed against proteinase-3 (PR3) and in rare cases it is caused by anti-myeloperoixdase (MPO) antibodies. The pANCA pattern can de caused by antibodies directed against a large group of proteins i.e. MPO, lactofenin and bactericidal/permeability-increasing protein. Often there is a discrepancy between the results obtained by IIF and those reported from the use of assays with purified antigens. This causes confusion. Until now only anti-PR3 and anti-MPO have been found of any clinical value. Therefore, it would be more proper to use assays with these highly purified antigens instead of an unspecific method like IIF.

Topics: Antibodies, Antineutrophil Cytoplasmic; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique, Indirect; Granulomatosis with Polyangiitis; Humans; Immunologic Tests; Peroxidase; Sensitivity and Specificity; Serine Endopeptidases; Vasculitis

We report the results of a meta-analysis of 349 patients with Wegener's granulomatosis (WG) that were described in the literature from 1979 onward. We describe the patients in terms of diagnosis (granulomas present or absent in biopsy samples from various organs, results of the anti-neutrophil cytoplasmic antibody [ANCA) test) and of the clinical impact of renal involvement. Furthermore, we report the incidence of histopathologic lesions that were found in 134 renal biopsy samples. Before and after the development of the ANCA test, the percentage of patients in whom WG was diagnosed with histologically proven granulomas is the same. However, after 1987 the diagnosis of the group without granulomas is frequently supported by a positive ANCA test result. For the entire group we found that patients without renal involvement (N = 82) were reported to have lower erythrocyte sedimentation rate (ESR), lower white blood cell count (WBC), less anemia, less hypertension, less occurrence of joint symptoms, and less multi-organ involvement than patients with renal involvement (N = 267). The most frequently reported lesion in the renal biopsy samples was extracapillary proliferation (70%), followed by fibrinoid necrosis of the glomerular tuft (54%). Renal granulomas were reported in only 7 biopsy samples.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Biopsy; Child; Clinical Protocols; Female; Granuloma; Granulomatosis with Polyangiitis; Humans; Kidney; Kidney Diseases; Lung Diseases; Male; Middle Aged; Myeloblastin; Peroxidase; Serine Endopeptidases

Antineutrophil cytoplasmic antibodies (ANCA) are a heterogeneous group of autoantibodies with a wide and diverse range of clinical associations. In vasculitis, the diagnostic utility of proteinase 3 (PR3)-ANCA and myeloperoxidase-ANCA for Wegener's granulomatosis and microscopic polyangiitis, respectively, is now well established. Because of their significance as tools for diagnosis and prognosis, these autoantibodies have been analyzed extensively as markers for underlying immunopathogenic disturbances. In this review, we consider recent advances in the understanding of ANCA, focusing on their detection, diagnostic value, and role in the pathogenesis of vasculitis. In addition, promising new ways have been developed to elucidate the pathophysiologic and diagnostic relevance of the ANCA target antigens PR3 and myeloperoxidase. A great deal of attention and controversy has focused on the possible mechanisms underlying the ANCA-related immune response, such as antigenic cross-reactivity between human polymorphonuclear leukocyte proteins and extrinsic antigens by molecular mimicry, idiotype network regulation, and T cell reactivity to PR3 and myeloperoxidase.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Autoimmunity; Granulomatosis with Polyangiitis; Humans; Immunologic Tests; Myeloblastin; Neutrophils; Peroxidase; Serine Endopeptidases; Vasculitis

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Autoantigens; Autoimmune Diseases; Biomarkers; Fluorescent Antibody Technique; Granulomatosis with Polyangiitis; Humans; Myeloblastin; Peroxidase; Serine Endopeptidases; Vasculitis

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Biomarkers; Churg-Strauss Syndrome; Granulomatosis with Polyangiitis; Humans; Myeloblastin; Peroxidase; Polyarteritis Nodosa; Serine Endopeptidases

Wegener's autoantigen (WA), a 29 kD multifunctional protein, is the principal target antigen of autoantibodies associated with Wegener's granulomatosis (WG). WA was first identified as proteinase 3 (PR3), which is now known to be identical with myeloblastin and AGP7. Like other lysosomal proteins, WA/PR3 displays enzymatic activity, differentiation factor activity for myeloid precursor cells, and antimicrobial functions. Neutrophilic polymorphonuclear leukocytes (PMN) and a subpopulation of monocytes contain high levels of WA/PR3 in their myeloperoxidase-positive granules. The autoantibodies from WG sera produce a finely granular, centrally accentuated fluorescence pattern on PMN and monocytes and have been designated 'classic' pattern antineutrophil cytoplasmic autoantibodies (cANCA). However, PMN/monocyte activation (in vitro/ex vivo) is associated with the translocation of WA/PR3 on the cytoplasm membrane. WA/PR3 is accessible to the WG-associated autoantibody: cANCA stimulate cytokine-preactivated PMN to produce oxygen radicals and to degranulate. Furthermore, cANCA interfere with the biological functions of WA/PR3 (e.g. inhibition of elastinolytic activity). Hence, cANCA represents not only the best seromarker for WG so far available, but several lines of evidence indicate that the autoantibodies against WA/PR3 play a major role in the pathogenesis of this enigmatic disease.

Topics: Amino Acid Sequence; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Autoantigens; Autoimmune Diseases; Base Sequence; Cytoplasm; Fluorescent Antibody Technique; Granulomatosis with Polyangiitis; Humans; Molecular Sequence Data; Myeloblastin; Neutrophils; Peroxidase; Serine Endopeptidases; Vasculitis

The identification of ANCA and their association with systemic vascular inflammation has become quite useful in both the diagnosis and management of patients with necrotizing vasculitic conditions. Primary autoantibody specificities have been identified, and many more await further characterization. As with ANA, it is highly probable that ANCA will not only complement patient care, but will provide means helpful in exploring the molecular structures and biochemical pathways within granulocytic phagocytes.

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Autoantigens; Cytoplasm; Granulomatosis with Polyangiitis; Humans; Neutrophils; Peroxidase

The demonstration of autoantibodies to neutrophil cytoplasmic antigens (ANCA) in (1) systemic vasculitides such as Wegener's granulomatosis, classic polyarteritis nodosa and the Churg Strauss syndrome and (2) idiopathic crescentic glomerulonephritis has placed these disorders within the spectrum of autoimmune diseases. The target antigens have been identified as myeloid lysosomal enzymes that are involved in tissue destruction by neutrophils. Recent data suggest a pathogenetic role for these autoimmune responses. The autoantibodies may activate neutrophils, resulting in extensive tissue necrosis. Alternatively, T-cell-mediated immunity to these positively-charged enzymes that localize to polyanionic basement membranes may, in concert with the presence of autoantibodies, result in glomerulonephritis and vasculitis.

Topics: Animals; Autoantibodies; Autoantigens; Autoimmune Diseases; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Immune Complex Diseases; Lysosomes; Myeloblastin; Necrosis; Neutrophils; Peroxidase; Rats; Serine Endopeptidases; T-Lymphocytes; Vasculitis

Antineutrophil cytoplasmic autoantibodies (ANCA) are found in the sera of patients with systemic necrotizing vasculitis and glomerulonephritis. Their role in the pathogenesis of these diseases is not clearly understood; however, there is a growing body of data that supports a pathogenic function for these antibodies. In vitro they can activate neutrophils and monocytes to produce reactive oxygen species (ROS), degranulate, and damage target cells. The antigens to which they are directed stimulate T lymphocytes from patients with these diseases. The ANCA directed against proteinase 3 (PR3) may also play a role in growth regulation of monocytes by inactivating the enzymatic function of its antigen. The proposed model of ANCA-induced disease takes into account both the in vitro data and the natural history of these diseases.

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Autoantigens; Cytoplasmic Granules; Granulomatosis with Polyangiitis; Humans; Models, Molecular; Neutrophils; Peroxidase; Signal Transduction; T-Lymphocytes; Vasculitis

Topics: Autoantibodies; Autoimmune Diseases; Churg-Strauss Syndrome; Cytoplasm; Cytoplasmic Granules; Glomerulonephritis; Glucuronidase; Granulomatosis with Polyangiitis; Hexosaminidases; Humans; Luminescent Measurements; Microscopy, Fluorescence; Necrosis; Neutrophils; Oxidation-Reduction; Oxygen; Peroxidase; Polyarteritis Nodosa; Superoxides

To investigate the possible association of crescentic glomerulonephritis (CGN) with autoantibodies to myeloid lysosomal enzymes, we tested sera from 35 consecutive patients with CGN without diagnostic immunohistological findings in their renal biopsy for the presence of antineutrophil cytoplasmic antibodies directed against a 29 kD antigen from azurophilic granules (29 kD-ANCA), against myeloperoxidase (MPO-ANCA) and against elastase (elastase-ANCA), using antigen-catching ELISAs with well-defined monoclonal antibodies. 29 kD-ANCA were present in the sera of all nine patients with CGN as part of biopsy-proven Wegner's granulomatosis (WG), of ten patients with CGN and clinically suspected WG, and of two patients with idiopathic CGN. Sera from the remaining patients with clinically suspected WG (N = 5) or idiopathic CGN (N = 6) were negative for 29 kD-ANCA, but invariably positive for MPO-ANCA. Neither of these antibodies could be detected in sera from patients with CGN of infectious origin (N = 3), different forms of CGN (N = 7), other renal lesions (N = 34), or normal controls (N = 52). None of the sera tested were positive for elastase-ANCA. Our results indicate that both vasculitis-associated CGN and idiopathic CGN are associated with autoantibodies against myeloid lysosomal enzymes. This finding places these disorders within one spectrum of diseases.

Topics: Autoantibodies; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Male; Middle Aged; Pancreatic Elastase; Peroxidase

Topics: Antibodies; Autoantibodies; Cytoplasm; Granulomatosis with Polyangiitis; Humans; Lysosomes; Neutrophils; Pancreatic Elastase; Peroxidase; Vasculitis

To evaluate whether the classification of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) according to ANCA type (anti-proteinase 3 (PR3) or anti-myeloperoxidase (MPO) antibodies) predicts treatment response.. Treatment responses were assessed among patients enrolled in the Rituximab in ANCA-associated Vasculitis trial according to both AAV diagnosis (granulomatosis with polyangiitis (GPA)/microscopic polyangiitis (MPA)) and ANCA type (PR3-AAV/MPO-AAV). Complete remission (CR) was defined as disease activity score of 0 and successful completion of the prednisone taper.. PR3-AAV patients treated with rituximab (RTX) achieved CR at 6 months more frequently than did those randomised to cyclophosphamide (CYC)/azathioprine (AZA) (65% vs 48%; p=0.04). The OR for CR at 6 months among PR3-AAV patients treated with RTX as opposed to CYC/AZA was 2.11 (95% CI 1.04 to 4.30) in analyses adjusted for age, sex and new-onset versus relapsing disease at baseline. PR3-AAV patients with relapsing disease achieved CR more often following RTX treatment at 6 months (OR 3.57; 95% CI 1.43 to 8.93), 12 months (OR 4.32; 95% CI 1.53 to 12.15) and 18 months (OR 3.06; 95% CI 1.05 to 8.97). No association between treatment and CR was observed in the MPO-AAV patient subset or in groups divided according to AAV diagnosis.. Patients with PR3-AAV respond better to RTX than to CYC/AZA. An ANCA type-based classification may guide immunosuppression in AAV.. NCT00104299; post-results.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Azathioprine; Biomarkers; Cyclophosphamide; Double-Blind Method; Drug Therapy, Combination; Female; Granulomatosis with Polyangiitis; Humans; Male; Microscopic Polyangiitis; Middle Aged; Myeloblastin; Peroxidase; Prognosis; Remission Induction; Rituximab; Treatment Outcome

Nonsevere relapses are more common than severe relapses in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but their clinical course and treatment outcomes remain largely unexamined. We undertook this study to analyze the outcomes of patients with nonsevere relapses in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial who were treated with prednisone according to a prespecified protocol.. RAVE was a randomized, double-blind, placebo-controlled trial comparing rituximab (RTX) to cyclophosphamide (CYC) followed by azathioprine (AZA) for induction of remission. Patients who experienced nonsevere relapses between months 1 and 18 were treated with a prednisone increase without a concomitant change in their nonglucocorticoid immunosuppressants, followed by a taper.. Forty-four patients with a first nonsevere relapse were analyzed. In comparison to the 71 patients who maintained relapse-free remission over 18 months, these patients were more likely to have proteinase 3-ANCAs, diagnoses of granulomatosis with polyangiitis (Wegener's), and a history of relapsing disease at baseline. A prednisone increase led to remission in 35 patients (80%). However, only 13 patients (30%) were able to maintain second remissions through the followup period (mean 12.5 months); 31 patients (70%) had a second disease relapse, 14 of them with severe disease. The mean time to second relapse was 9.4 months (4.7 months in the group treated with RTX versus 13.7 months in the group treated with CYC/AZA; P < 0.01). Patients who experienced nonsevere relapses received more glucocorticoids than those who maintained remission (6.7 grams versus 3.8 grams; P < 0.01).. Treatment of nonsevere relapses in AAV with an increase in glucocorticoids is effective in restoring temporary remission in the majority of patients, but recurrent relapses within a relatively short interval remain common. Alternative treatment approaches are needed for this important subset of patients.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Monoclonal, Murine-Derived; Autoantibodies; Azathioprine; Cyclophosphamide; Double-Blind Method; Female; Glucocorticoids; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Maintenance Chemotherapy; Male; Microscopic Polyangiitis; Myeloblastin; Peroxidase; Prednisone; Recurrence; Remission Induction; Rituximab; Severity of Illness Index; Treatment Outcome

This study applied the 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology (the 2022 ACR/EULAR) criteria for microscopic polyangiitis (MPA) to patients with previously diagnosed MPA as per the 2007 European Medicines Agency algorithm (the 2007 EMA algorithm) and the 2012 revised International Chapel Hill Consensus Conference nomenclature of vasculitides (the 2012 CHCC definitions) The concordance rate between the new and old criteria was investigated.. This study included 117 patients with MPA, and the new criteria were applied to these patients. MPA could be classified when the total score is ≥5.. The median age was 64.0 years. The concordance rate between the new and old criteria reached 96.6%. Four patients with previously diagnosed MPA were unclassified. Of these, three patients without myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA) (or perinuclear [P]-ANCA) were not reclassified as having MPA according to the new criteria, despite histopathological findings that were suggestive of MPA based on both the 2007 EMA algorithm and the 2012 CHCC definitions. Conversely, three of four patients with both MPO-ANCA (or P-ANCA) and proteinase 3 (PR3)- ANCA (or cytoplasmic [C]-ANCA) were reclassified as having both MPA and granulomatosis with polyangiitis (GPA) simultaneously according to the 2022 ACR/EULAR criteria for MPA and GPA.. In the new criteria, excessively high score was assigned to MPO-ANCA (or P-ANCA) and MPA-specific histopathological findings were not considered. Hence, the 2007 EMA algorithm and the 2012 CHCC definitions can be applied as additional criteria to complex cases.

Topics: Algorithms; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Granulomatosis with Polyangiitis; Humans; Microscopic Polyangiitis; Middle Aged; Myeloblastin; Peroxidase

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a systemic autoimmune disease characterized by necrotizing inflammation of the small blood vessels. ANCA-associated vasculitis is subclassified into three variants: granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and microscopic polyangiitis (MPA). Myeloperoxidase (MPO) ANCA is a marker antibody for MPA. Interstitial pneumonia (IP) is occasionally complicated with MPA. However, only a few cases of idiopathic IP develop MPO-ANCA-positive conversion and MPA. Therefore, we present a case of a 70-year-old Japanese man with idiopathic IP who developed MPO-ANCA-positive conversion and MPA. We performed renal biopsy, which revealed pauci-immune crescentic glomerulonephritis. The patient was treated with intravenous methylprednisolone pulse therapy and oral prednisone, and the patient's laboratory data gradually improved with steroid therapy. The association between the production of MPO-ANCA and IP remains unclear, and the present case suggests that IP plays a role in inducing MPO-ANCA production. Patients with idiopathic IP should be followed-up carefully for an examination of increased MPO-ANCA levels and MPA development. In addition, early gastric cancer was detected during upper gastrointestinal endoscopy in our case, and it could also be important not to miss malignancy in patients with ANCA-associated vasculitis.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Granulomatosis with Polyangiitis; Humans; Idiopathic Interstitial Pneumonias; Male; Microscopic Polyangiitis; Peroxidase

Interstitial lung disease (ILD) has been described as a possible pulmonary involvement in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV), mainly granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Aim of this cross-sectional Italian national study was to describe demographic, clinical and serological profile of ILD related to MPA and GPA and investigate possible correlations between radiologic patterns of ILD and vasculitis features.. We enrolled 95 consecutive patients with AAV-ILD, 56 affected by MPA (58.9%) and 39 by GPA (41.1%).. NSIP was the most frequently detected ILD pattern, observed in c-ANCA patients in 60.9% of cases, followed by UIP pattern mainly observed in p-ANCA patients (47.7%, p=0.03). ILD represented the first clinical manifestation, preceding vasculitis diagnosis in 22.1% of cases and, globally, ILD was already detectable at AAV diagnosis in 66.3% of patients. The diagnosis of ILD preceded that of AAV in 85.7% of p-ANCA positive-patients, while only one patient with c-ANCA developed ILD before AAV (p= 0.039). Multivariate analysis confirmed the correlation of UIP pattern with p-ANCA-positivity and a diagnosis of ILD before AAV, also when adjusted for age and sex.. Our study confirms that UIP is a frequent pattern of lung disease in AAVILD patients. Our results also suggest that ILD can represent an early complication of AAV but also occur in the course of the disease, suggesting the need of a careful evaluation by both pulmonologist and rheumatologist to achieve an early diagnosis. Further prospective studies are needed to define ILD prevalence and evolution in AAV patients.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Cross-Sectional Studies; Demography; Granulomatosis with Polyangiitis; Humans; Lung Diseases, Interstitial; Microscopic Polyangiitis; Myeloblastin; Peroxidase; Rheumatology

The optimal strategy for remission-maintenance therapy in patients with myeloperoxidase-ANCA (MPO-ANCA)-associated vasculitis is not established. Defining parameters to guide maintenance therapy is required.. This was a retrospective cohort study of all patients with MPO-ANCA-associated vasculitis (microscopic with polyangiitis and granulomatosis with polyangiitis) and GN followed at the Mayo Clinic between 1996 and 2015. Relapse rate, MPO-ANCA status, and remission-maintenance therapies were reviewed. Logistic regression models, Kaplan-Meier method, and Cox proportional hazards regression models were applied.. We analyzed 159 patients with active MPO-ANCA-associated vasculitis with GN. Sixty-six (42%) patients had at least one relapse, and 52 (33%) relapsed before 60 months. Patients with MPO-ANCA who became persistently negative did not relapse (hazard ratio [HR], 0.03; 95% confidence interval [95% CI], 0.002 to 0.431; P =0.01). The reappearance of MPO-ANCA was associated with a higher risk of relapse (HR, 1.91; 95% CI, 1.109 to 3.293; P =0.02). Immunosuppression was withdrawn in 80 (50%) patients, and this was less likely in those who received cyclophosphamide for remission induction or in patients with persistently positive MPO-ANCA (odds ratio [OR], 0.44; 95% CI, 0.228 to 0.861; P =0.02 and OR, 0.42; 95% CI, 0.213 to 0.820; P =0.01, respectively). Relapse frequency was not different between patients with persistently positive MPO-ANCA and patients with MPO-ANCA reappearance (44% versus 39%, P =0.49), irrespective of remission-maintenance treatment. Ear, nose, and throat involvement (OR, 6.10; 95% CI, 1.280 to 29.010; P =0.02) and MPO-ANCA reappearance (OR, 9.25; 95% CI, 3.126 to 27.361; P <0.001) were independently associated with relapse after treatment withdrawal.. Patients persistently MPO-ANCA negative are at low risk for relapse even without remission-maintenance therapy. Persistence or subsequent reappearance of MPO-ANCA is associated with a higher risk of relapse.. This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast.aspx?p=CJASN&e=2023_01_10_CJN06460622.mp3.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Chronic Disease; Granulomatosis with Polyangiitis; Humans; Kidney; Peroxidase; Recurrence; Retrospective Studies

Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are autoimmune vasculitides associated with antineutrophil cytoplasm antibodies that target proteinase 3 (PR3) or myeloperoxidase (MPO) found within neutrophils and monocytes. Granulomas are exclusively found in GPA and form around multinucleated giant cells (MGCs), at sites of microabscesses, containing apoptotic and necrotic neutrophils. Since patients with GPA have augmented neutrophil PR3 expression, and PR3-expressing apoptotic cells frustrate macrophage phagocytosis and cellular clearance, we investigated the role of PR3 in stimulating giant cell and granuloma formation.. We stimulated purified monocytes and whole peripheral blood mononuclear cells (PBMCs) from patients with GPA, patients with MPA or healthy controls with PR3 or MPO and visualised MGC and granuloma-like structure formation using light, confocal and electron microscopy, as well as measuring the cell cytokine production. We investigated the expression of PR3 binding partners on monocytes and tested the impact of their inhibition. Finally, we injected zebrafish with PR3 and characterised granuloma formation in a novel animal model.. In vitro, PR3 promoted monocyte-derived MGC formation using cells from patients with GPA but not from patients with MPA, and this was dependent on soluble interleukin 6 (IL-6), as well as monocyte MAC-1 and protease-activated receptor-2, found to be overexpressed in the cells of patients with GPA. PBMCs stimulated by PR3 formed granuloma-like structures with central MGC surrounded by T cells. This effect of PR3 was confirmed in vivo using zebrafish and was inhibited by niclosamide, a IL-6-STAT3 pathway inhibitor.. These data provide a mechanistic basis for granuloma formation in GPA and a rationale for novel therapeutic approaches.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Giant Cells; Granuloma; Granulomatosis with Polyangiitis; Interleukin-6; Leukocytes, Mononuclear; Microscopic Polyangiitis; Myeloblastin; Peroxidase; Zebrafish

Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory condition that was first recognized as a unique disease entity in the early 2000s. Its diagnosis is based on specific pathologic, serologic, and clinical features, and the exclusion of several differential diagnoses, such antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, emerging evidence suggests that these 2 conditions may overlap in some cases. Here, we report a new case of overlapping IgG4-RD and AAV. The patient was diagnosed with IgG4-RD owing to the presence of periaortitis and IgG4 positive tubulointerstitial nephritis. Myeloperoxidase (MPO)-ANCA positivity, chronic paranasal sinusitis, and glomerulonephritis with granuloma led to a concurrent diagnosis of MPO-ANCA-positive granulomatosis with polyangiitis. Our case supports the hypothesis that diagnoses of IgG4-RD and AAV are not mutually exclusive but can overlap. It can be assumed that an overlap with IgG4-RD typically affects the granulomatous form of AAV, suggesting a common pathophysiological pathway for these 2 conditions.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoimmune Diseases; Connective Tissue Diseases; Granulomatosis with Polyangiitis; Humans; Immunoglobulin G4-Related Disease; Nephritis, Interstitial; Peroxidase

To determine the spectrum of anti-neutrophil cytoplasmic antibody (ANCA) antigen-specificities in eosinophilic granulomatosis with polyangiitis (EGPA), an ANCA-associated vasculitis (AAV) entity.. We conducted a retrospective analysis of 73 EGPA patients from three German tertiary referral centres for vasculitis. In addition to in-house ANCA testing, pentraxin 3 (PTX3)- and olfactomedin 4 (OLM4)-ANCA were determined using a prototype cell-based assay for research (EUROIMMUN, Lübeck, Germany). Patient characteristics and clinical manifestations were evaluated and compared based on ANCA status.. Myeloperoxidase (MPO)-ANCA positive patients (n=8; 11%) significantly more frequently displayed peripheral nervous system (PNS) and pulmonary involvement and less frequently heart involvement compared to MPO-ANCA negative patients. PTX3-ANCA positive patients (n=5; 6.8%) had a significantly higher prevalence of ear, nose and throat, pulmonary, gastrointestinal and PNS involvement, and a lower prevalence of renal and central nervous system involvement compared to PTX3-ANCA negative patients. Proteinase 3 (PR3)-ANCA and OLM4-ANCA were detected in 2 patients (2.7%) each with multiorgan involvement. One PR3-ANCA positive patient was also positive for bactericidal permeability increasing protein (BPI)-ANCA.. In addition to MPO, the spectrum of ANCA antigen specificities includes various other target antigens such as PR3, BPI, PTX3, and OLM4, potentially segregating further EGPA subgroups. A lower prevalence of MPO-ANCA was detected in this study compared with other studies. OLM4 is reported as novel ANCA antigen-specificity in EGPA, and thus AAV.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Granulomatosis with Polyangiitis; Humans; Myeloblastin; Peroxidase; Retrospective Studies

Topics: Antibodies, Antineutrophil Cytoplasmic; Granulomatosis with Polyangiitis; Humans; Peroxidase

To understand the most common type and clinical manifestations of associated vasculitis (AAV) in the Saudi Arabia.. This retrospective study was conducted at King Fahad Medical City and the Security Forces Hospital Program, Riyadh, Saudi Arabia, between January 2014 and May 2022. Patients aged ≥18 years were included in the study and diagnosed based on clinical manifestations, serology, or histopathology according to the EMA algorithm. Univariate analysis was carried out to compare different groups; a series of independent samples t-tests was applied for continuous data.. A total of 53 patients were enrolled: eosinophilic granulomatosis with polyangiitis (EGPA), granulomatosis with polyangiitis (GPA), and microscopic polyangiitis (MPA). Overall, proteinase-3 was the most prevalent (52.8%), and myeloperoxidase, myeloperoxidase MPO was the least prevalent antineutrophil cytoplasmic antibody (ANCA)-type (18.9%) among patients; other patients showed negative ANCA test results. The clinical manifestations differed significantly between EGPA and GPA groups in pulmonary, neurological, cardiological, and renal signs and symptoms (. This study validated international reports on AAV clinical manifestations in the Saudi population. The GPA was associated with more upper airway and pulmonary signs and symptoms. Further investigation is needed to understand the treatments and quality of life of patients with AAV.

Topics: Adolescent; Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Granulomatosis with Polyangiitis; Humans; Peroxidase; Quality of Life; Retrospective Studies; Saudi Arabia

To clarify seasonal and other environmental effects on the onset of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).. We enrolled patients with new-onset eosinophilic granulomatosis with polyangiitis (EGPA), microscopic polyangiitis (MPA), and granulomatosis with polyangiitis (GPA) registered in the database of a Japanese multicenter cohort study. We investigated the relationship between environmental factors and clinical characteristics. Seasons were divided into 4 (spring, summer, autumn, and winter), and the seasonal differences in AAV onset were analyzed using Pearson chi-square test, with an expected probability of 25% for each season.. A total of 454 patients were enrolled, with a mean age of 70.9 years and a female proportion of 55.5%. Overall, 74, 291, and 89 patients were classified as having EGPA, MPA, and GPA, respectively. Positivity for myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA was observed in 355 and 46 patients, respectively. Overall, the seasonality of AAV onset significantly deviated from the expected 25% for each season (. The onset of AAV was influenced by seasonal variations and was less frequently observed in autumn. In contrast, the occurrence of PR3-ANCA was triggered, not by season, but by rural residency.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Cohort Studies; Female; Granulomatosis with Polyangiitis; Humans; Japan; Microscopic Polyangiitis; Myeloblastin; Peroxidase; Retrospective Studies; Seasons

ANCA vasculitides (AAV) are autoimmune diseases responsible for damage to small-size vessels. Three entities are distinguished from clinical, histological and biological criteria: micropolyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (EGPA). The neutrophil-ANCA couple is central to the pathophysiology of AAV. The mechanisms that lead to the breakdown of tolerance to myeloperoxidase or proteinase-3 remain hypothetical, however, probably multifactorial, occurring on a predisposing genetic background. The understanding of the injury mechanisms involved in AAV has made great progress thanks to the study of a murine model of immunization against myeloperoxidase. This work has made it possible to show the central role of the PNN in vivo, which are activated under sterile conditions, under the effect of the ANCAs which recognize the self-antigen expressed on their surface. Understanding the role of the alternative complement pathway and in particular that of C5a, a powerful anaphylatoxin, was a major advance. C5a acts as an amplifying factor for PNN activation and blocking its receptor (C5aR) prevents the occurrence of vasculitis lesions in the mouse model. These discoveries led to therapeutic trials in humans highlighting the interest of blocking C5aR and validating this therapeutic strategy. It should be emphasized that the AAV study model is, above all, an anti-MPO model and that the mechanisms involved in anti-PR3 ANCA or ANCA negative vasculitis remain very hypothetical. Finally, the mechanisms that account for the heterogeneity relating to the presentation or severity of AAV remain poorly understood.. Les vascularites à ANCA (anticorps anticytoplasmes des polynucléaires neutrophiles) ou VAA sont des maladies auto-immunes responsables d’une atteinte des vaisseaux de petit calibre. Trois entités sont distinguées à partir de critères cliniques, histologiques et biologiques : la micropolyangéite (MPA), la granulomatose avec polyangéite (GPA) et la granulomatose éosinophilique avec polyangéite (EGPA). Le couple polynucléaire neutrophile (PNN)-ANCA est au centre de la physiopathologie des VAA. Les mécanismes qui mènent à la rupture de tolérance vis-à-vis de la myéloperoxydase (MPO) ou de la protéinase 3 (PR3) restent toutefois hypothétiques, probablement multifactoriels, survenant sur un terrain génétique prédisposant. La compréhension des mécanismes lésionnels mis en jeu au cours des VAA a beaucoup progressé grâce à l’étude d’un modèle murin d’immunisation contre la myéloperoxydase. Ces travaux ont permis de montrer le rôle central des PNN in vivo qui s’activent en condition stérile, sous l’effet des ANCA qui reconnaissent l’auto-antigène exprimé à leur surface. La compréhension du rôle de la voie alterne du complément et notamment celui du C5a, puissante anaphylatoxine, est une avancée majeure. Le C5a agit comme un facteur d’amplification de l’activation du PNN et le blocage de son récepteur (C5aR) prévient la survenue des lésions de vascularite dans le modèle murin. Ces découvertes ont abouti à des essais thérapeutiques chez l’homme, soulignant l’intérêt du blocage du C5aR et validant ce traitement. Il convient de souligner que le modèle d’étude des VAA est avant tout un modèle de VAA anti-MPO et que les mécanismes impliqués dans les vascularites anti-PR3 ou ANCA négatives restent très hypothétiques. Enfin, les mécanismes qui rendent compte de l’hétérogénéité relative à la présentation ou à la sévérité des VAA restent mal compris.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Autoantigens; Churg-Strauss Syndrome; Granulomatosis with Polyangiitis; Humans; Mice; Peroxidase

To identify and characterize genetic loci associated with the risk of developing ANCA-associated vasculitides (AAV).. Genetic association analyses were performed after Illumina sequencing of 1853 genes and subsequent replication with genotyping of selected single nucleotide polymorphisms in a total cohort of 1110 Scandinavian cases with granulomatosis with polyangiitis or microscopic polyangiitis, and 1589 controls. A novel AAV-associated single nucleotide polymorphism was analysed for allele-specific effects on gene expression using luciferase reporter assay.. PR3-ANCA+ AAV was significantly associated with two independent loci in the HLA-DPB1/HLA-DPA1 region [rs1042335, P = 6.3 × 10-61, odds ratio (OR) 0.10; rs9277341, P = 1.5 × 10-44, OR 0.22] and with rs28929474 in the SERPINA1 gene (P = 2.7 × 10-10, OR 2.9). MPO-ANCA+ AAV was significantly associated with the HLA-DQB1/HLA-DQA2 locus (rs9274619, P = 5.4 × 10-25, OR 3.7) and with a rare variant in the BACH2 gene (rs78275221, P = 7.9 × 10-7, OR 3.0), the latter a novel susceptibility locus for MPO-ANCA+ granulomatosis with polyangiitis/microscopic polyangiitis. The rs78275221-A risk allele reduced luciferase gene expression in endothelial cells, specifically, as compared with the non-risk allele.. We identified a novel susceptibility locus for MPO-ANCA+ AAV and propose that the associated variant is of mechanistic importance, exerting a regulatory function on gene expression in specific cell types.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Endothelial Cells; Granulomatosis with Polyangiitis; Humans; Microscopic Polyangiitis; Myeloblastin; Peroxidase

To determine whether development of ANCA-associated vasculitis (AAV) shows a relationship with a prior infection and if prior infection affects disease characteristics and outcome.. All incident cases of AAV diagnosed in a defined region of Sweden from 2000 through 2016 were identified. For each case, 10 individuals from the general population, matched for age, sex and area of residence, were selected. Infections occurring in AAV patients and controls prior to the date of AAV diagnosis (index date for respective controls) were identified using an administrative database. Conditional logistic regression models were used to calculate odds ratios (OR) of developing AAV. Occurrence, clinical characteristics and outcome of AAV were analysed with respect to prior infection.. Two-hundred and seventy patients with AAV (48% female) and 2687 controls were included. Prior to diagnosis/index date, 146 (54%) AAV patients had been diagnosed with infection vs 1282 (48%) controls, with OR for AAV 1.57 (95% CI 1.18, 2.19) in those with infections of the upper respiratory tract and 1.68 (1.02, 2.77) in those with pneumonia. Difference from controls was significant in patients with MPO-ANCA 1.99 (95% CI 1.25, 3.1) but not in those with PR3-ANCA 1.0 (0.61, 1.52). Patients with prior infection showed higher disease activity at AAV diagnosis. No differences in disease characteristics, comorbidities or outcome in those with and without prior infections were observed.. Respiratory tract infections are positively associated with development of MPO- but not PR3-ANCA vasculitis. Prior infection is associated with higher disease activity at AAV diagnosis.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Granulomatosis with Polyangiitis; Humans; Male; Myeloblastin; Odds Ratio; Peroxidase

The aim of this study is to investigate the clinical significance of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA) on eosinophilic granulomatosis with polyangiitis (EGPA) from a longitudinal Chinese cohort.. A total of 120 patients with EGPA were consecutively enrolled and followed up. Two patients with PR3 ANCA was excluded and our analysis focused on the 118 patients with EGPA. On the basis of MPO-ANCA status, baseline clinical manifestations, treatment, and outcomes were analyzed. Logistic regression analysis was performed to analyze the independently associated factors for renal involvement.. ANCA positivity was observed in 24.2% of patients with EGPA. Patients with MPO-ANCA accounted for 20.8%. Patients with positive MPO-ANCA had higher levels of erythrocyte sedimentation rate (ESR), C-reactive protein, Birmingham Vasculitis Activity Score (BVAS), higher ratios of fever, myalgia, renal involvement, and biopsy-proven vasculitis. Heart manifestations and asthma were more common in patients with negative ANCA. Baseline MPO-ANCA titers positively correlated with ESR, eosinophil count, and BVAS and were higher in patients with methylprednisolone pulse. Among patients with renal involvement, patients with positive MPO-ANCA had higher proportions of female, fever, biopsy-proven vasculitis, and faster ESR; patients with negative ANCA developed more skin and cardiac involvement. MPO-ANCA positivity, male, and ear involvement were the independent factors associated with renal involvement. Intravenous cyclophosphamide and immunoglobulins were prescribed more frequently in patients with positive MPO-ANCA.. In this cohort, patients with positive MPO-ANCA and negative ANCA displayed distinct clinical features, suggesting that MPO-ANCA might be a valuable biomarker for EGPA stratification. Baseline MPO-ANCA level correlated positively with disease activity of EGPA. MPO-ANCA was a significant independent factor associated with renal involvement.

Topics: Antibodies, Antineutrophil Cytoplasmic; China; Churg-Strauss Syndrome; Female; Granulomatosis with Polyangiitis; Humans; Male; Peroxidase

Topics: Antibodies, Antineutrophil Cytoplasmic; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Inflammation; Peroxidase

This study investigated the characteristics of hypertrophic pachymeningitis (HP) in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), using information from a multicenter study in Japan.. We analyzed the clinical information of 663 Asian patients with AAV (total AAV), including 558 patients with newly diagnosed AAV and 105 with relapsed AAV. Clinical findings were compared between patients with and without HP. To elucidate the relevant manifestations for HP development, multivariable logistic regression analyses were additionally performed.. Of the patients with AAV (mean age, 70.2 ± 13.5 years), HP was noted in 30 (4.52%), including 20 (3.58%) with newly diagnosed AAV and 10 (9.52%) with relapsed AAV. Granulomatosis with polyangiitis (GPA) was classified in 50% of patients with HP. A higher prevalence of GPA was significantly observed in patients with HP than in those without HP in total AAV and newly diagnosed AAV (p < 0.001). In newly diagnosed AAV, serum proteinase 3 (PR3)-ANCA positivity was significantly higher in patients with HP than in those without HP (p = 0.030). Patients with HP significantly had ear, nose, and throat (ENT) (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.03-2.14, p = 0.033) and mucous membrane/eye manifestations (OR 5.99, 95% CI 2.59-13.86, p < 0.0001) in total AAV. Moreover, they significantly had conductive hearing loss (OR 11.6, 95% CI 4.51-29.57, p < 0.0001) and sudden visual loss (OR 20.9, 95% CI 5.24-85.03, p < 0.0001).. GPA was predominantly observed in patients with HP. Furthermore, in newly diagnosed AAV, patients with HP showed significantly higher PR3-ANCA positivity than those without HP. The ear and eye manifestations may be implicated in HP development.

Topics: Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Cross-Sectional Studies; Granulomatosis with Polyangiitis; Humans; Hypertrophy; Japan; Meningitis; Middle Aged; Myeloblastin; Peroxidase; Retrospective Studies

Torasemide is a loop diuretic with a molecule that is chemically similar to the sulphonamides described as eosinophilic granulomatosis with polyangiitis (EGPA) triggering drugs. The presented case is probably the first description of torasemide-induced vascular purpura in the course of EGPA. Any diagnosis of vasculitis should be followed by an identification of drugs that may aggravate the disease. A 74-year-old patient was admitted to the Department of Dermatology with purpura-like skin lesions on the upper, and lower extremities, including the buttocks. The lesions had appeared around the ankles 7 days before admission to the hospital and then started to progress upwards. The patient complained on lower limb paresthesia and pain. Other comorbidities included bronchial asthma, chronic sinusitis, ischemic heart disease, mild aortic stenosis, arterial hypertension, and degenerative thoracic spine disease. The woman had previously undergone nasal polypectomy twice. She was on a constant regimen of oral rosuvastatin 5 mg per day, spironolactone 50 mg per day, metoprolol 150 mg per day, inhaled formoterol 12 μg per day, and ipratropium bromide 20 μg per day. Ten days prior to admission, she was commenced on torasemide at a dose of 50 mg per day prescribed by a general practitioner due to high blood pressure. Doppler ultrasound upon admission to the hospital excluded deep venal thrombosis. The laboratory tests revealed leukocytosis (17.1 thousand per mm3) with eosinophilia (38.6%), elevated plasma level of C-reactive protein (119 mg per L) and D-dimers (2657 ng per mm3). Indirect immunofluorescent test identified a low titer (1:80) of antinuclear antibodies, but elevated (1:160) antineutrophil cytoplasmic antibodies (ANCA) in the patient's serum. Immunoblot found them to be aimed against myeloperoxidase (pANCA). A chest X-ray showed increased vascular lung markings, while high-resolution computed tomography revealed peribronchial glass-ground opacities. Microscopic evaluation of skin biopsy taken from the lower limbs showed perivascular infiltrates consisting of eosinophils and neutrophils, fragments of neutrophil nuclei, and fibrinous necrosis of small vessels. Electromyography performed in the lower limbs because of their weakness highlighted a loss of response from both sural nerves, as well as slowed conduction velocity of the right tibial nerve and in both common peroneal nerves. Both clinical characteristics of skin lesions and histopathology suggested a

Topics: Adolescent; Aged; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Antinuclear; Antihypertensive Agents; Asthma; C-Reactive Protein; Churg-Strauss Syndrome; Eosinophilia; Female; Formoterol Fumarate; Granulomatosis with Polyangiitis; Humans; IgA Vasculitis; Inflammation; Ipratropium; Leukotriene Antagonists; Metoprolol; Mycophenolic Acid; Peroxidase; Prednisone; Purpura; Receptors, Fc; Rosuvastatin Calcium; Sodium Potassium Chloride Symporter Inhibitors; Spironolactone; Sulfanilamides; Torsemide

Results of randomized clinical trials have demonstrated rituximab's noninferiority to cyclophosphamide as induction therapy for antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV), with neither treatment having a specific advantage for granulomatosis with polyangiitis (GPA). However, post hoc analysis results have suggested that rituximab might be more effective than cyclophosphamide in inducing remission in patients with proteinase 3-positive AAV.. To compare the effectiveness of rituximab and cyclophosphamide in inducing GPA remission in a large population of unselected patients.. This comparative effectiveness study used multicenter target trial emulation observational data from 32 French hospitals in the French Vasculitis Study Group Registry. Groups were determined according to treatments received, without any intervention from the investigators. Inverse probability of treatment weighting was used to correct for baseline imbalance between groups. Participants included patients with newly diagnosed or relapsing GPA who satisfied American College of Rheumatology classification criteria and/or Chapel Hill Consensus Conference nomenclature. Data were analyzed from October 1, 2021, to May 31, 2022.. At least 1 infusion of rituximab or cyclophosphamide for induction therapy between April 1, 2008, and April 1, 2018.. The primary outcome was remission rate at month 6 (±2 months), with remission defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 and prednisone dose of 10 mg/d or less. The BVAS is a validated tool for small-vessel vasculitis and used to assess the level of disease activity, with a numerical weight attached to each involved organ system. The BVAS has a range of 0 to 63 points; a score of 0 indicates no disease activity. Subgroup analyses included the primary outcome for patients with a new diagnosis, for most recently treated patients, and for patients with myeloperoxidase-ANCA positivity.. Among 194 patients with GPA included in the analysis (mean [SD] age, 54 [15] years; 110 men [56.7%]), 165 (85.1%) had a new diagnosis, and 147 of 182 with data available (80.8%) had proteinase 3-ANCA positivity. Sixty-one patients received rituximab and 133 received cyclophosphamide for induction therapy. In the weighted analysis, the primary outcome was reached for 73.1% of patients receiving rituximab vs 40.1% receiving cyclophosphamide (relative risk [RR], 1.82 [95% CI, 1.22-2.73]; risk difference, 33.0% [95% CI, 12.2%-53.8%]; E value for RR, 3.05). Similar results were observed in the subgroup of patients with newly diagnosed GPA and those with a more recent treatment. In the subset of 27 patients with myeloperoxidase-ANCA-positive GPA, 8 of 10 rituximab recipients and 8 of 17 cyclophosphamide recipients met the primary end point (unweighted RR, 1.73 [95% CI, 0.96-3.11]).. In this comparativeness effectiveness study using clinical data, rituximab induction therapy for GPA was more frequently associated with remission than cyclophosphamide. These results inform clinical decision-making concerning the choice of remission induction therapy for this subset of patients with AAV.

Topics: Adult; Aged; Antibodies, Antineutrophil Cytoplasmic; Coloring Agents; Cyclophosphamide; Female; Granulomatosis with Polyangiitis; Humans; Induction Chemotherapy; Male; Middle Aged; Myeloblastin; Peroxidase; Rituximab

We investigated the association of airway comorbidities with the clinical phenotypes and outcomes of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibodies (ANCA)-positive ANCA-associated vasculitis (AAV).. An AAV patient multicenter cohort trial was established in 13 hospitals in western Japan between 2012 and 2018. We examined 143 of the new-onset MPO-ANCA-positive AAV patients. Their clinical characteristics and comorbidities at disease onset were compared based on clinical phenotypes. Multivariate analysis was performed to identify factors predictive of remission and death.. Twenty-seven cases with granulomatosis with polyangiitis (GPA), 10 with eosinophilic GPA (EGPA), 81 with microscopic polyangiitis (MPA), and 25 with unclassified AAV were identified. The average age of MPO-ANCA-positive patients was 71.4 years. Comorbidity (87.4%) and airway comorbidity (70.6%) were frequently observed in these patients. Examination of the clinical phenotypes revealed that the cases of GPA were frequently accompanied by infectious airway comorbidity (upper airway disease, bronchiectasis, pulmonary infections), and most of the cases of MPA and unclassified AAV were accompanied by fibrotic interstitial lung disease (fILD) or emphysema. Among MPO-ANCA-positive patients, infectious airway comorbidity was predictive of both remission (HR 1.58,. MPO-ANCA-positive AAV was frequently accompanied by airway comorbidities. In addition to fILD, infectious airway comorbidities were closely associated with those clinical phenotypes and outcomes.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Comorbidity; Granulomatosis with Polyangiitis; Humans; Myeloblastin; Peroxidase; Phenotype

Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Churg-Strauss Syndrome; Female; Granulomatosis with Polyangiitis; Humans; Microscopic Polyangiitis; Peroxidase

Long-term observation of patients with ANCA-associated vasculitis (AAV) allows the identification of different longitudinal patterns of ANCA levels during follow-up. This study aimed to characterize these patterns and to determine their prognostic significance. All ANCA determinations performed in two university hospitals during a 2-year period were retrospectively reviewed. Patients were included in the analysis if they had high titers of anti-myeloperoxidase (anti-MPO) or anti-proteinase 3 (anti-PR3) antibodies at least once, ≥ 5 serial ANCA determinations and AAV diagnosed by biopsy or American College of Rheumatology (ACR) classification criteria. Patients' time-course ANCA patterns were classified as monophasic, remitting, recurrent or persistent. Associations between ANCA patterns and prognostic variables (relapse rate and renal outcome) were analysed by univariate and multivariate statistics. A total of 99 patients [55 with microscopic polyangiitis (MPA), 36 with granulomatosis with polyangiitis (GPA) and eight with eosinophilic granulomatosis with polyangiitis (EGPA)] were included. Median follow-up was 9 years. Among patients diagnosed with MPA or GPA, recurrent or persistent ANCA patterns were associated with a higher risk of clinical relapse [hazard ratio (HR) = 3·7, 95% confidence interval (CI) = 1·5-9·1 and HR = 2·9, 95% CI = 1·1-8·0, respectively], independently of clinical diagnosis or ANCA specificity. In patients with anti-MPO antibodies, the recurrent ANCA pattern was associated with worsening renal function [odds ratio (OR) = 5·7, 95% CI = 1·2-26·0]. Recurrent or persistent ANCA patterns are associated with a higher risk of clinical relapse. A recurrent ANCA pattern was associated with worsening renal function in anti-MPO-associated vasculitis.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biopsy; Chronic Disease; Churg-Strauss Syndrome; Female; Follow-Up Studies; Granulomatosis with Polyangiitis; Humans; Kidney; Male; Microscopic Polyangiitis; Middle Aged; Myeloblastin; Peroxidase; Prognosis; Recurrence; Retrospective Studies

Enzyme-linked immunosorbent assay (ELISA) has traditionally been used to detect myeloperoxidase (MPO) and proteinase 3 (PR3) antibodies, although it is time-consuming and physically demanding. As a novel and highly effective immunoassay, we compared chemiluminescent immunoassay (CIA) with ELISA to verify the application value of CIA in MPO and PR3 antibodies detection.. By ELISA and CIA, serum levels of anti-MPO and anti-PR3 antibodies were measured in 63 anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patients (AAV group), including 47 microscopic polyangiitis (MPA) patients and 16 granulomatosis with polyangiitis (GPA) patients, in addition, 68 patients in interference control group (IC group), 19 healthy subjects in healthy control group (HC group). We compared MPO and PR3 antibodies levels and positive rates measured by these two methods among groups. Relationship and coincidence rate between ELISA and CIA were investigated. Diagnostic values for clinical outcomes for MPO and PR3 antibodies were assessed by receiver operator characteristic (ROC) curve.. In AAV patients, when detecting anti-MPO (r = .90) and anti-PR3 (r = .81), CIA was highly correlated with ELISA, companying with highly total (88.89%, 92.06%, respectively) and positive coincidence rates (84.78%, 77.27%, respectively). In HC group, anti-PR3 positive rate detected by both immunoassay were 0, anti-MPO almost were 0, which without statistically significant difference (P = .32). In IC group, the total (76.47%, 58.82, respectively) and positive coincidence rates (48.38%, 30.00%, respectively) of anti-MPO and anti-PR3 were the lowest, but the negative coincidence rates reached 100%. By CIA, similar to ELISA, the levels of anti-MPO were significantly higher both in AAV patients (56.00; [4.40-235.30]) and MPA patients (98.00; [27.90-324.70]) compared with either IC group (3.20; [3.20-18.55) (P < .0001) or HC group (3.20; [3.20-3.20]) (P < .0001), yielded an area under curve (AUC) of 0.76 for AAV and 0.89 for MPA, the concentration of anti-PR3 in GPA group (66.65; [24.43-150.00]) was significantly higher than that in IC group (2.3; [2.3-10.95]) (P < .0001) and HC group (2.3; [2.3-2.3]) (P < .0001), with an AUC of 0.92.. Similar to ELISA, CIA was competent to detect MPO and PR3 antibodies in AAV patients and healthy population, thus distinguish AAV patients from IC group and HC group and effectively diagnose MPA and GPA.

Topics: Adult; Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Granulomatosis with Polyangiitis; Humans; Immunoassay; Luminescent Measurements; Male; Middle Aged; Myeloblastin; Peroxidase; ROC Curve; Young Adult

We herein report a case of granulomatosis with polyangiitis in a 73-year-old man. He had experienced bilateral ptosis, redness of both eyes, right facial weakness, and hearing loss in the right ear for two months. Myeloperoxidase anti-neutrophil cytoplasmic antibody was positive. Corticosteroids and intravenous cyclophosphamide pulse therapy yielded a response. After the fourth pulse of cyclophosphamide, he developed headache, diplopia, restricted left eye movement, right facial palsy, and hearing loss in the right ear. A one-year remission period was achieved by increasing the steroid and rituximab doses. Rituximab was effective against the relapse of granulomatosis with polyangiitis and cranial neuropathy.

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Cranial Nerve Diseases; Granulomatosis with Polyangiitis; Humans; Male; Peroxidase; Rituximab

ANCA-associated vasculitis (AAV) usually involves the renal and respiratory systems, but the paediatric literature on pulmonary manifestations and outcomes is limited. We aimed to describe pulmonary manifestations and outcomes after therapy in a cohort of paediatric AAV (pAAV) patients.. A retrospective chart review of all patients <19 years presenting to our institution with AAV between 1/2008 and 2/2018 was conducted. Patient demographics, clinical presentation, diagnostic testing, therapy and pulmonary outcomes over the first 3 years after presentation were evaluated.. A total of 38 patients were included; all had ANCA positivity by immunofluorescence. A total of 23 had microscopic polyangiitis (MPA), 13 had granulomatosis with polyangiitis and 2 had eosinophilic granulomatosis with polyangiitis. A total of 30 (79%) had pulmonary manifestations, with cough (73%) and pulmonary haemorrhage (67%) being the most common. Abnormalities were noted in 82% of chest CT scans reviewed, with nodules and ground-glass opacities being the most common. At 6, 12 and 36 months follow-up, respectively, 61.8%, 39.4% and 29% of patients continued to show pulmonary manifestations. Five MPA patients with re-haemorrhage are described in detail.. MPA was more common than granulomatosis with polyangiitis, with pulmonary involvement being common in both. MPA patients had more severe pulmonary manifestations. Chest CT revealed abnormal findings in a majority of cases. A subgroup of young MPA patients experienced repeat pulmonary haemorrhage. Treatment modality and response were comparable in different subtypes of AAV, except for this young MPA group. Additional prospective studies are needed to better understand the different phenotypes of pAAV.

Topics: Adolescent; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoantibodies; Child; Child, Preschool; Churg-Strauss Syndrome; Cohort Studies; Cough; Disease Progression; Female; Granulomatosis with Polyangiitis; Hemoptysis; Hemorrhage; Humans; Infant; Lung Diseases; Male; Microscopic Polyangiitis; Multiple Pulmonary Nodules; Myeloblastin; Peroxidase; Recurrence; Retrospective Studies; Tomography, X-Ray Computed

A 26-year-old woman presented with abdominal pain, diarrhoea, vomiting, fever, and progressive paralysis in the lower limbs. She had a history of bronchial asthma and experienced sinusitis, progressive peripheral neuropathy, polyarthritis, and leukocytosis with prominent eosinophilia. The patient was diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA). Abdominal pain was considered to be an ischaemic enteritis associated with EGPA. She was administered 1,000 mg/day of methylprednisolone for 3 days and intravenous immunoglobulin (400 mg/kg/day of γ-globulin for 5 days) followed by 50 mg (1 mg/kg)/day of oral prednisolone due to rapidly progressing peripheral neuropathy. Her symptoms temporarily improved; however, peripheral neuropathy recurred after a week, and the eosinophil count increased. Eighteen days after following the resumed treatment, 300 mg of mepolizumab, a humanised monoclonal antibody, was administered. Subjective symptoms, nerve conduction velocity, and skin perfusion pressure (an index of peripheral circulation in the lower extremities) improved after 4 weeks. Although mepolizumab has been approved for EGPA, there is no evidence of its efficacy against peripheral neuropathy. Early introduction of mepolizumab may contribute to an the early improved progressive peripheral neuropathy with eosinophilia.

Topics: Adult; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Churg-Strauss Syndrome; Female; Granulomatosis with Polyangiitis; Humans; Peripheral Nervous System Diseases; Peroxidase; Treatment Outcome

Although cyclophosphamide (CPA) is the key drug for the treatment of autoimmune diseases including vasculitides, it has some well-known adverse effects, such as myelosuppression, hemorrhagic cystitis, infertility, and infection. However, CPA-associated severe enteritis is a rare adverse effect, and only one case with a lethal clinical course has been reported. Therefore, the appropriate management of patients with CPA-associated severe enteritis is unclear.. We present the case of a 61-year-old woman diagnosed with granulomatosis with polyangiitis based on the presence of symptoms in ear, lung, and, kidney with positive myeloperoxidase-antineutrophil cytoplasmic antibody. She received pulsed methylprednisolone followed by prednisolone 55 mg/d and intravenous CPA at a dose of 500 mg/mo. Ten days after the second course of intravenous CPA, she developed nausea, vomiting, and diarrhea, and was admitted to the hospital. Laboratory testing revealed hypoalbuminemia, suggesting protein-losing enteropathy. Computed tomography revealed wall thickening of the stomach, small intestine, and colon with contrast enhancement on the lumen side. Antibiotics and immunosuppressive therapy were not effective, and the patient's enteritis did not improve for > 4 mo. Because her condition became seriously exhausted, corticosteroids were tapered and supportive therapies including intravenous hyperalimentation, replenishment of albumin and gamma globulin, plasma exchange, and infection control were continued. These supportive therapies improved her condition, and her enteritis gradually regressed. She was finally discharged 7 mo later.. Immediate discontinuation of CPA and intensive supportive therapy are crucial for the survival of patients with CPA-associated severe enteritis.

Topics: Cyclophosphamide; Enteritis; Female; Granulomatosis with Polyangiitis; Humans; Middle Aged; Peroxidase; Protein-Losing Enteropathies

To report on a large series of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and bronchiectasis, with a specific focus on the timeline of occurrence of both features.. Retrospective nationwide multicenter study of patients diagnosed with both AAV and bronchiectasis.. Sixty-one patients were included, among whom 27 (44.25%) had microscopic polyangiitis (MPA), 27 (44.25%) had granulomatosis with polyangiitis (GPA), and 7 (11.5%) had eosinophilic GPA. Thirty-nine (64%) had myeloperoxidase (MPO)-ANCA and 13 (21%) had proteinase 3-ANCA. The diagnosis of bronchiectasis either preceded (n = 25; median time between both diagnoses: 16 yrs, IQR 4-54 yrs), was concomitant to (n = 12), or followed (n = 24; median time between both diagnoses: 1, IQR 0-6 yrs) that of AAV. Patients in whom bronchiectasis precedes the onset of AAV (B-AAV group) have more frequent mononeuritis multiplex, MPA, MPO-ANCA, and a 5-fold increase of death. The occurrence of an AAV relapse tended to be protective against bronchiectasis worsening (HR 0.6, 95% CI 0.4-0.99,. The association of bronchiectasis with AAV is likely not accidental and is mostly associated with MPO-ANCA. Patients in whom bronchiectasis precedes the onset of AAV tend to have distinct clinical and biological features and could carry a worse prognosis.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Bronchiectasis; Granulomatosis with Polyangiitis; Humans; Peroxidase; Prognosis; Retrospective Studies

Current evidence suggests that high uric acid levels are associated with accelerated renal damage. However, the clinical impact of serum uric acid level on patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) is unknown. We aimed to evaluate the impact of hyperuricemia on such patients. A retrospective study was performed to obtain patients' demographic, clinical, and laboratory data from when they were diagnosed with MPA and GPA. Multivariable logistic regression and Cox hazard model analyses were performed to evaluate factors associated with hyperuricemia at diagnosis and predictive factors of end-stage renal disease (ESRD) development. Among 156 patients, 35 (22.4%) had hyperuricemia at baseline. Hyperuricemic patients had renal manifestation and impaired renal function more frequently than non-hyperuricemic patients. Logistic regression analysis revealed that serum creatinine was significantly associated with hyperuricemia at diagnosis [odds ratio 1.995; 95% confidence interval (CI), 1.503-2.648; P < 0.001]. Cox hazard model analysis revealed that body mass index and serum creatinine were significantly associated with ESRD when all variables were included, but hyperuricemia was independently associated with ESRD [hazard ratio (HR), 3.799; 95% CI 1.719-8.222; P < 0.001) when serum creatinine was excluded. Additionally, in a subgroup analysis of patients with decreased glomerular filtration rates (GFRs), serum uric acid was the sole predictor of ESRD (HR, 1.243; 95% CI 1.048-1.475; P = 0.013). Hyperuricemia is associated with renal damage and ESRD occurrence in MPA and GPA patients. Serum uric acid level is associated with ESRD occurrence in patients with decreased GFRs.

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Case-Control Studies; Female; Glomerular Filtration Rate; Granulomatosis with Polyangiitis; Humans; Hyperuricemia; Kidney Failure, Chronic; Logistic Models; Male; Microscopic Polyangiitis; Middle Aged; Myeloblastin; Peroxidase; Proportional Hazards Models; Renal Insufficiency, Chronic; Retrospective Studies; Risk Factors

Topics: Antirheumatic Agents; Cyclophosphamide; Diagnosis, Differential; Female; Granulomatosis with Polyangiitis; Humans; Immunologic Tests; Middle Aged; Myeloblastin; Orbit; Peroxidase; Scleritis; Steroids; Tomography, X-Ray Computed; Treatment Outcome

Topics: Antibodies, Antineutrophil Cytoplasmic; Azathioprine; Cyclophosphamide; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Kidney Diseases; Maintenance Chemotherapy; Microscopic Polyangiitis; Myeloblastin; Peroxidase; Recurrence; Rituximab

A 66-year-old woman presented with dysesthesia over the right side of her face, hypoglossal nerve dysfunction, dysphagia, and dysgeusia of the right side. A MRI scan of the brain revealed cerebral dural thickening on the right side of the skull base, and histopathological examination revealed granulomatous inflammation of the dura. Based on paranasal sinusitis, bronchodilatation, laboratory tests showing weakly positive MPO-ANCA, intact renal function, and the patient's favorable response to steroids, we diagnosed the patient with limited granulomatosis with polyangiitis (GPA). Reportedly, autoimmune disease might occur in patients with exacerbation of monoclonal gammopathy of undetermined significance, which was observed in this case. This suggests the utility of immunoelectrophoresis.

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Brain; Disease Progression; Female; Granulomatosis with Polyangiitis; Humans; Hypertrophy; Meningitis; Methylprednisolone; Monoclonal Gammopathy of Undetermined Significance; Peroxidase; Prednisolone; Treatment Outcome

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantigens; Granulomatosis with Polyangiitis; Humans; Immunoassay; Myeloblastin; Peroxidase; Reference Standards

To investigate clinical features, independent associated factors, treatment, and outcome of patients with peripheral neuropathy (PN) in eosinophilic granulomatosis with polyangiitis (EGPA).. We retrospectively analyzed clinical data of 110 EGPA patients from 2007 to 2019 in Peking Union Medical College Hospital. The independent factors associated with PN in EGPA were analyzed with univariate and multivariate logistic regressions.. In EGPA with PN, paresthesia and muscle weakness were observed in 82% and 33% of patients, respectively. Both the upper and lower limbs were involved in 51% of patients. 30% of EGPA patients had symmetrical multiple peripheral neuropathy, whereas only 16.4% presented with mononeuritis multiplex. Compared to patients without PN, patients with PN had a higher erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, Birmingham vasculitis activity score (BVAS), and positivity of myeloperoxidase-antineutrophil cytoplasmic antibodies (MPO-ANCA). Regarding manifestations, patients with PN tended to develop weight loss and arthritis or joint pain. Notably, ANCA positivity, arthritis or joint pain, and higher BVAS were found to be independent associated factors for PN in EGPA. Patients with PN more frequently need glucocorticoid pulses and intravenous infusion of cyclophosphamide. With the longest follow-up of 11.0 years, we found that age and cardiac involvement were risk factors for survival, and female was the protective factor.. PN in EGPA frequently displays with symmetrical multiple peripheral neuropathy in China. Positive ANCA, arthritis or joint pain, and higher BVAS are the independent associated factors of PN in EGPA. Glucocorticoids with immunosuppressants are vital therapeutic strategy.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Arthralgia; Arthritis; C-Reactive Protein; China; Cyclophosphamide; Erythrocytes; Female; Glucocorticoids; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Male; Middle Aged; Peripheral Nervous System Diseases; Peroxidase; Retrospective Studies; Young Adult

Granulomatosis with polyangiitis (GPA) is an autoimmune disease which is a type of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis that frequently affects the lungs and kidneys. However, GPA limited to a single organ has also been reported. A 71-year-old man was admitted for back pain and fever. We detected elevated levels of inflammatory markers and myeloperoxidase-ANCA. Magnetic resonance imaging indicated diffuse inflammation of the back and psoas muscles. Histology showed degenerated muscle fibers and granulomatosis vasculitis with mixed lymphoplasma cell infiltration. High-dose methylprednisolone therapy improved his symptoms. A final diagnosis of GPA limited to the muscles was made.

Topics: Aged; Anti-Inflammatory Agents; Antibodies, Antineutrophil Cytoplasmic; Back Muscles; Biomarkers; Granulomatosis with Polyangiitis; Humans; Male; Methylprednisolone; Peroxidase; Psoas Muscles

Topics: Antirheumatic Agents; Betacoronavirus; Clinical Laboratory Techniques; Comorbidity; Coronavirus Infections; COVID-19; COVID-19 Testing; Granulomatosis with Polyangiitis; Humans; Immunocompromised Host; Male; Middle Aged; Monitoring, Immunologic; Pandemics; Patient Acuity; Patient Care Management; Peroxidase; Pneumonia, Viral; Recurrence; Rituximab; SARS-CoV-2; Symptom Assessment; Treatment Outcome

Previous studies have evaluated the risk factors for relapse of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and the biomarkers of AAV for predicting relapse. However, little is known about the association between the presence of sinusitis and relapse and changes in the ANCA levels in AAV. This single-center, retrospective cohort study included 104 consecutive patients who were newly diagnosed with myeloperoxidase (MPO)-ANCA-positive microscopic polyangiitis (MPA) between 2006 and 2018 and were treated at the Aichi Medical University Hospital in Japan. The relationships between sinusitis and relapse of vasculitis and elevated MPO-ANCA levels were assessed using multivariate Cox proportional hazards models that were adjusted for clinically relevant factors. During the entire follow-up period (median, 24 months; interquartile range, 7-54 months), 93 (89.4%) patients achieved remission. After achieving remission, 38 (40.9%) patients experienced at least one relapse (13 [65.0%] in the sinusitis group; 25 [34.3%] in the non-sinusitis group). Sinusitis was identified as a significant predictor of relapse (adjusted hazard ratio: 2.41, 95% confidence interval [CI]: 1.19-4.88; P = 0.015). Furthermore, sinusitis was more likely to be associated with elevated MPO-ANCA levels (adjusted hazard ratio: 2.59, 95% CI: 1.14-5.92; P = 0.024). In conclusion, sinusitis was associated with a higher risk of relapse and elevated MPO-ANCA levels in MPA patients, suggesting that careful management may be required to reduce the risk of relapse in patients with sinusitis. Further studies are needed to elucidate the optimal treatment strategy for these patients.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Chronic Disease; Cohort Studies; Female; Granulomatosis with Polyangiitis; Humans; Japan; Male; Microscopic Polyangiitis; Middle Aged; Myeloblastin; Peroxidase; Proportional Hazards Models; Recurrence; Retrospective Studies; Risk Factors; Sinusitis

Cumulative survival in patients with anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitis (VAA) is 88 and 78% at 1 and 5 years, respectively. Despite this, mortality continues to be 2.7 times higher than the general population. Differences in the clinical profile of VAA in different ethnicities have been observed.. To identify factors at the time of diagnosis, associated with mortality at one year of follow-up and to describe the clinical characteristics of these patients.. We identified in local databases and reviewed clinical records of patients with VAA with at least one year of follow up in a clinical hospital. Demographic and laboratory parameters and clinical activity scores were analyzed.. Of 103 patients with VAA identified, 65 met the inclusion criteria and were analyzed. Their age ranged from 45 to 63 years and 56% were women. Thirty-five patients (54%) were diagnosed as granulomatosis with Polyangiitis (GPA) and 30 patients (46%) with Microscopic Polyangiitis (MPA). The frequency of renal disease was 53% and pulmonary involvement occurred in 72%. At one year of follow-up 11 patients died resulting in a mortality of 17%. Seven patients died within three months after diagnosis. MPO ANCA were more common than PR3 ANCA. In the multivariate analysis, the presence of ophthalmological involvement, lung kidney syndrome and a Five Factor Score (FFS) of 1 or more were independent factors associated with mortality at one year.. In these patients, pulmonary manifestations predominate. Lung kidney syndrome, ophthalmological involvement and a FFS score ≥ 1 were associated with mortality.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Granulomatosis with Polyangiitis; Humans; Male; Middle Aged; Myeloblastin; Peroxidase; Retrospective Studies

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Belgium; Cohort Studies; Female; Glucocorticoids; Granulomatosis with Polyangiitis; Hospitals, University; Humans; Immunologic Factors; Kidney Diseases; Lung Diseases; Male; Microscopic Polyangiitis; Middle Aged; Myeloblastin; Otorhinolaryngologic Diseases; Peroxidase; Practice Patterns, Physicians'; Prednisone; Remission Induction; Retrospective Studies; Rituximab; Treatment Outcome

Age is a risk factor for organ damage, adverse events, and mortality in microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). However, the relationship between treatment and damage, hospitalizations, and causes of death in elderly patients is largely unknown.. Consecutive patients from Sweden, the United Kingdom, and the Czech Republic diagnosed between 1997 and 2013 were included. Inclusion criteria were a diagnosis of MPA or GPA and age 75 years or more at diagnosis. Treatment with cyclophosphamide (CYC), rituximab (RTX), and corticosteroids the first 3 months was registered. Outcomes up to 2 years from diagnosis included Vasculitis Damage Index (VDI), hospitalization, and cause of death.. Treatment data were available for 167 of 202 patients. At 2 years, 4% had no items of damage. There was a positive association between VDI score at 2 years and Birmingham Vasculitis Activity Score at onset, and a negative association with treatment using CYC or RTX. Intravenous methylprednisolone dose was associated with treatment-related damage. During the first year, 69% of patients were readmitted to hospital. Myeloperoxidase-antineutrophil cytoplasmic antibody positivity and lower creatinine levels decreased the odds of readmission. The most common cause of death was infection, and this was associated with cumulative oral prednisolone dose.. Immunosuppressive treatment with CYC or RTX in elderly patients with MPA and GPA was associated with development of less permanent organ damage and was not associated with hospitalization. However, higher doses of corticosteroids during the first 3 months was associated with treatment-related damage and fatal infections.

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Granulomatosis with Polyangiitis; Hospitalization; Humans; Microscopic Polyangiitis; Peroxidase

The different sets of criteria for diagnosis or classification of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) lead to numerous overlapping and reclassified diagnoses in clinical practice. We designed this study to assess the difficulties in classifying patients with AAV. As a secondary objective, different variables were tested to predict prognosis. We conducted a retrospective chart review in a Western Spain multicentre survey. A total of 115 adult patients diagnosed with AAV from 2002 to 2013 and followed for at least 3 years were included. They were classified according to (1) Chapel Hill Consensus Conference (CHCC), (2) European Medicines Agency algorithm and (3) French Vasculitis Study Group/European Vasculitis Society phenotypes. Fifty-three patients (46%) had neither distinctive histopathological data of a single AAV definition nor any surrogate markers for granulomatous inflammation and thus did not fulfill any diagnostic criteria. Ocular, ear, nose, throat, skin, and lung involvement were more frequent with proteinase 3 (PR3) antibodies, whereas peripheral neuropathy was more frequent with myeloperoxidase (MPO) antibodies. When the disease was severe at diagnosis, the HR for mortality was 10.44. When induction treatment was not given in accordance with the guidelines, the HR for mortality was 4.00. For maintenance treatment, the HR was 5.49 for mortality and 2.48 for relapse. AAV classification is difficult because many patients had neither specific clinical data nor distinctive histological features of a single CHCC definition. A structured clinical assessment of patient severity is the best tool to guide the management of AAV.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Epistaxis; Eye Diseases; Female; Gastrointestinal Diseases; Granulomatosis with Polyangiitis; Humans; Hypertension; Kidney Diseases; Kidney Failure, Chronic; Lung Diseases; Male; Microscopic Polyangiitis; Middle Aged; Mortality; Myeloblastin; Peripheral Nervous System Diseases; Peroxidase; Primary Prevention; Prognosis; Proportional Hazards Models; Recurrence; Retrospective Studies; Severity of Illness Index; Sinusitis; Skin Diseases

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disorder of unknown etiology with dysregulated cytokines levels.. The main aim of this study was to assess the clinical correlation between antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, granulomatosis with polyangiitis (GPA) serum levels of the microscopic polyangiitis (MPA), serum levels of the proinflammatory cytokines, interleukin (IL)-32 and interleukin-6.. Study included 71 patients, 47 with GPA and 24 with MPA. Serum IL-32 and IL-6 concentrations were analyzed in all patients, and compared with levels observed in 10 controls. IL-32 and IL-6 were evaluated using DuoSet and Quantikine HS ELISA, respectively. IL-32 and IL-6 concentrations were correlated with disease-related clinical and laboratory findings.. IL-32 and IL-6 levels were significantly higher in GPA and MPA than in controls, especially IL-32 levels in GPA were elevated. IL-32 concentrations correlated positively with anti-proteinase 3 - ANCA (PR3-ANCA) levels in GPA (P < 0.0001), and with anti-myeloperoxidase ANCA (MPO-ANCA) in MPA (P = 0.049). IL-32 levels correlated positively with disease activity in GPA and MPA (P < 0.0001). GPA patients with pulmonary, cutaneous, and musculoskeletal involvement presented the highest IL-6 serum levels. Cutaneous manifestations correlated positively with IL-6 levels in MPA patients (P = 0.05). ANCA-positive patients with GPA expressed significantly high IL-6 levels (P = 0.036). No significant difference in IL-32 values was observed between ANCA-positive and ANCA-negative patients.. Patients with GPA and MPA present higher serum IL-32 and IL-6 levels than controls. IL-32 levels correlate positively with disease activity.

Topics: Adult; Aged; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Case-Control Studies; Diagnosis, Differential; Female; Gene Expression; Granulomatosis with Polyangiitis; Humans; Interleukin-6; Interleukins; Male; Microscopic Polyangiitis; Middle Aged; Myeloblastin; Peroxidase; Severity of Illness Index

Antineutrophil cytoplasmic antibody (ANCA) directed to proteinase 3 (PR3) used to be considered the serologic marker for granulomatosis with polyangiitis (GPA). However, patients with myeloperoxidase (MPO)-ANCA positive GPA have been increasingly reported. The aim of this study was to analyze the clinical and pathological characteristics and outcome of Chinese patients with MPO-ANCA positive GPA.. The clinical and renal histology data, renal outcomes, response to treatment, relapse and mortality were compared between patients with MPO-ANCA positive GPA and MPO-ANCA positive microscopic polyangiitis (MPA) as well as proteinase 3 (PR3)-ANCA positive GPA.. 455 patients with ANCA-associated vasculitis (AAV) were recruited in this study. 276/455 patients were classified as MPO-ANCA positive MPA, 4/455 patients were classified as PR3-ANCA positive MPA, 124/455 were MPO-ANCA positive GPA and 51/455 were PR3-ANCA positive GPA. Compared with MPO-ANCA positive MPA patients, MPO-ANCA positive GPA patients had significantly higher level of BVAS and milder renal lesion at diagnosis. The probability of developing ESRD was significantly higher in patients with MPO-ANCA positive MPA than MPO-ANCA positive GPA. MPO-ANCA positive GPA patients were likely to have relapse than MPO-ANCA positive MPA patients. Compared with PR3-ANCA positive GPA patients, MPO-ANCA positive GPA patients had significantly higher proportion of female, less constitutional symptoms and milder renal lesion at diagnosis.. Patients with MPO-ANCA positive GPA should be regarded as a unique subset of AAV. This subset of AAV patients had relatively milder renal injury. Although ANCA specificities play an important role in differentiating AAV, taking the disease type together to classify AAV may be more rational.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; China; Female; Granulomatosis with Polyangiitis; Humans; Male; Middle Aged; Peroxidase; Retrospective Studies

In ANCA-associated vasculitis (AAV), classifications have emerged to individualize homogeneous clinical and outcomes patterns, including the recently defined anti-MPO granulomatosis with polyangiitis (GPA) subgroup. This study aimed to retrospectively evaluate the impacts of re-classification based on clinicopathological criteria and/or ANCA specificity.. A retrospective monocentric study conducted at Caen University Hospital led to the identification of PR3 or MPO-ANCA AAV patients from January 2000 or September 2011, respectively, to June 2016. Eosinophilic GPA patients were excluded. AAVs were thereby also classified either as GPA or microscopic polyangiitis (MPA) according to the European Medicines Agency vasculitis algorithm.. A total of 150 AAV patients were included (94 GPA, 56 MPA; 87 anti-PR3 and 63 anti-MPO patients). GPA patients exhibited a worse relapse-free survival but a better renal survival (P < 0.001 and P = 0.021, respectively) than MPA patients. Overall, relapse-free and renal survival rates were similar between anti-PR3 and anti-MPO patients (P = 0.35, 0.17 and 0.15, respectively). Similarly, the prognosis was identical between anti-MPO MPA patients and anti-PR3 MPA patients (P = 0.33, 0.19 and 0.65, respectively), and between anti-MPO GPA patients and anti-PR3 GPA patients (P = 0.06, 0.99 and 0.64, respectively). Moreover, anti-PR3 GPA and anti-MPO GPA patients exhibited no differences in clinical manifestations or BVAS score.. Clinicopathological classification appeared to be the strongest criterion for distinguishing among homogeneous prognoses of AAV. Individualizing the anti-MPO GPA subgroup does not appear to bring additional value to clinical practice, but multicentre studies are required to confirm this trend.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antibody Specificity; Female; Granulomatosis with Polyangiitis; Humans; Kidney; Male; Microscopic Polyangiitis; Middle Aged; Peroxidase; Prognosis; Retrospective Studies; Survival Rate

Deficiency in alpha-1 antitrypsin (AAT) is a possible pathogenic cofactor in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, the clinical effect of AAT deficiency remains poorly established in this setting. This study aimed to describe the clinical phenotypes and outcomes of AAV according to AAT phenotypes.. This study was conducted retrospectively at Caen University Hospital and included all consecutive granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) patients with positive proteinase 3-ANCA or myeloperoxidase-ANCA, from January 2000 or September 2011, respectively, to June 2016. AAT dosage (nephelometry) and phenotyping (isoelectric focusing in agarose gel) were performed.. Among the 142 patients with AAV, including 88 GPA and 54 MPA, 102 (72%) had the MM phenotype, 5 (4%) had a nonpolymerogenic M-variant phenotype, 18 (13%) had the deficient allele MZ, 12 (8%) had MS, 2 (1%) had ZZ, 2 (1%) had SZ, and 1 (1%) had SS. M, Z, and S allele frequencies were 84%, 8%, and 6%, respectively. No association was observed between AAT deficiency and ANCA subtype or AAV phenotype, except for intraalveolar hemorrhage (IAH), which was more frequent in patients harboring at least 1 of the deficient Z or S alleles than in those without any deficient alleles (p < 0.01). Global, renal, or relapse-free survival rates were similar for all subgroups.. This study shows that AAT deficiency confers, independently of ANCA subtype, a higher risk of IAH. Prospective studies are required to refine these data and to assess the need for replacement therapy in AAT-deficient patients with AAV.

Topics: Aged; Alleles; alpha 1-Antitrypsin; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Follow-Up Studies; France; Gene Frequency; Granulomatosis with Polyangiitis; Hospitals, University; Humans; Male; Microscopic Polyangiitis; Middle Aged; Myeloblastin; Peroxidase; Phenotype; Retrospective Studies; Survival Rate

Topics: Anti-Asthmatic Agents; Antibodies; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal, Humanized; Eosinophilia; Granulomatosis with Polyangiitis; Humans; Male; Middle Aged; Peroxidase

To describe tracheobronchial disease in patients with granulomatosis with polyangiitis (GPA) and evaluate the utility of dynamic expiratory CT to detect large-airway disease.. Demographic and clinical features associated with the presence of subglottic stenosis (SGS) or endobronchial involvement were assessed in a multicentre, observational cohort of patients with GPA. A subset of patients with GPA from a single-centre cohort underwent dynamic chest CT to evaluate the airways.. Among 962 patients with GPA, SGS and endobronchial disease were identified in 95 (10%) and 59 (6%) patients, respectively. Patients with SGS were more likely to be female (72% vs 53%, P < 0.01), younger at time of diagnosis (36 vs 49 years, P < 0.01), and have saddle-nose deformities (28% vs 10%, P < 0.01), but were less likely to have renal involvement (39% vs 62%, P < 0.01). Patients with endobronchial disease were more likely to be PR3-ANCA positive (85% vs 66%, P < 0.01), with more ENT involvement (97% vs 77%, P < 0.01) and less renal involvement (42% vs 62%, P < 0.01). Disease activity in patients with large-airway disease was commonly isolated to the subglottis/upper airway (57%) or bronchi (32%). Seven of 23 patients screened by dynamic chest CT had large-airway pathology, including four patients with chronic, unexplained cough, discovered to have tracheobronchomalacia.. SGS and endobronchial disease occur in 10% and 6% of patients with GPA, respectively, and may occur without disease activity in other organs. Dynamic expiratory chest CT is a potential non-invasive screening test for large-airway involvement in GPA.

Topics: Adult; Aged; Bronchial Diseases; Female; Granulomatosis with Polyangiitis; Humans; Laryngostenosis; Male; Middle Aged; Myeloblastin; Peroxidase; Tomography, X-Ray Computed; Tracheal Stenosis; Tracheobronchomalacia

To assess the frequency of venous thromboembolism (VTE) events in the Rituximab in Antineutrophil Cytoplasmic Antibody (ANCA)-Associated Vasculitis (RAVE) trial and identify novel potential risk factors.. VTE events in 197 patients enrolled in the RAVE trial were analyzed. Baseline demographic and clinical characteristics were recorded, and univariate and multivariate analyses were performed to identify factors associated with VTE in ANCA-associated vasculitis (AAV).. VTE occurred in 16 patients (8.1%) with an overall average time to event of 1.5 months (range 1.0-2.75). In univariate analyses with calculation of hazard ratios (HRs) and 95% confidence intervals (95% CIs), heart involvement (HR 17.408 [95% CI 2.247-134.842]; P = 0.006), positive proteinase 3 (PR3)-ANCA (HR 7.731 [95% CI 1.021-58.545]; P = 0.048), pulmonary hemorrhage (HR 3.889 [95% CI 1.448-10.448]; P = 0.008), and the presence of red blood cell casts (HR 15.617 [95% CI 3.491-69.854]; P < 0.001) were associated with the onset of VTE. In multivariate models adjusted for age and sex, the significant associations between VTE events and heart involvement (HR 21.836 [95% CI 2.566-185.805]; P = 0.005), PR3-ANCA (HR 9.12 [95% CI 1.158-71.839]; P = 0.036), pulmonary hemorrhage (HR 3.91 [95% CI 1.453-10.522]; P = 0.007), and urinary red blood cell casts (HR 16.455 [95% CI 3.607-75.075]; P < 0.001) remained.. Patients diagnosed as having AAV with pulmonary hemorrhage, positive PR3-ANCA, heart involvement, and the presence of red blood cell casts are at an increased risk to develop VTE. Further studies are needed to confirm and expand these findings and to explore the mechanisms of hypercoagulability in these patients with the aim of informing potential targets for therapeutic intervention.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Erythrocytes; Female; Granulomatosis with Polyangiitis; Hemorrhage; Humans; Lung Diseases; Male; Microscopic Polyangiitis; Middle Aged; Myeloblastin; Peroxidase; Proportional Hazards Models; Pulmonary Embolism; Risk Factors; Urine; Venous Thromboembolism; Venous Thrombosis

Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystemic small-vessel vasculitic disease that can present with positive MPO-P-ANCA (myeloperoxidase-perinuclear-anti-neutrophil cytoplasmic antibody). It is a rare condition that is difficult to diagnose. We present the case of a 64-year-old man with late-onset adult asthma and treated nasopharyngeal carcinoma who initially presented to us with proximal myopathy. Thereafter, he developed a constellation of fleeting symptoms which included rhinosinusitis, mononeuritis multiplex, skin vasculitis and arthritis. Blood investigations showed that he had eosinophilia, and skin biopsy demonstrated dermal vasculitis with eosinophils. He was found to be MPO-C-ANCA positive, and although initially thought to have granulomatosis with polyangiitis, the diagnosis was later revised to EGPA. This case highlights the diagnostic challenges with atypical presentations of EGPA and also presents a rare case of positive MPO-C-ANCA that has never been described in EGPA before.

Topics: Antibodies, Antineutrophil Cytoplasmic; Asthma; Churg-Strauss Syndrome; Diagnosis, Differential; Granulomatosis with Polyangiitis; Humans; Male; Middle Aged; Peroxidase

Topics: Antibodies, Antineutrophil Cytoplasmic; Diagnostic Errors; Granulomatosis with Polyangiitis; Humans; Immunoassay; Myeloblastin; Peroxidase

To assess the prevalence of bronchiectasis in a Western cohort with ANCA-positive granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) and its correlations with disease presentation and outcome.. Retrospective study of ANCA-associated vasculitis (AAV) patients followed at Nantes University Hospital (2005-2015). Clinical, biological, and follow-up data were collected through chart review. Two experienced radiologists blinded to the clinical data interpreted chest high-resolution CTs according to the Feischner Society criteria.. Fifty-eight patients were included: 30 had MPA (51.7%) and 28 had GPA (48.3%). The median age at AAV diagnosis was 65.5 years. Anti-MPO-ANCA and anti-PR3-ANCA were present in 39 (67.2%) and 19 (32.8%) patients, respectively. Overall, bronchiectasis was found in 22 patients (37.9%), all of whom had anti-MPO ANCA. In multivariate analysis, bronchiectasis was independently associated with anti-MPO-ANCA, female gender and age at AAV diagnosis. Furthermore, anti-MPO ANCA patients with bronchiectasis had more frequent peripheral nerve involvement (54.5 vs. 17.6%, p = 0.019) and less frequent renal involvement than those without bronchiectasis (40.9% vs. 82.3%, p = 0.009). Disease course, survival and risk of severe pulmonary infection were similar in patients with and without bronchiectasis on chest CT.. This study shows that bronchiectasis is a highly prevalent pre-existing respiratory condition in Caucasian patients with anti-MPO AAV. This subset of patients exhibits a distinct presentation. Further studies are needed to confirm these findings and clarify the clinical implications of this association. Whether the respiratory tract could be the site of initiation of anti-MPO auto-immunity remains to be investigated.

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Bronchiectasis; Comorbidity; Female; Granulomatosis with Polyangiitis; Humans; Lung; Male; Microscopic Polyangiitis; Middle Aged; Peroxidase; Prevalence; Retrospective Studies; Sex Factors

The small vessel vasculitides granulomatosis with polyangiitis (GPA) and microscopic polyangiitis are associated with autoantibodies to neutrophil cytoplasm antigens (ANCA), principally proteinase-3 (PR3) and myeloperoxidase (MPO). There is an association between GPA and nasal carriage of Staphylococcus aureus. The recent finding that S. aureus produces proteins that bind tightly to and block the function of both PR3 and MPO suggests a mechanism for ANCA formation. The bacterial protein-autoantigen conjugate is recognised by B cells with ANCA specificity, internalised, and the bacterial protein processed and presented to T cells with specificity for bacterial peptides. The T cell can then provide help to the B cell, allowing class switching, affinity maturation and the production of pathogenic ANCA. This mechanism predicts that T cells with this specificity will be found in patients, and that the bacterial protein-autoantigen conjugate will be particularly efficient at eliciting ANCA production.

Topics: Antibodies, Antineutrophil Cytoplasmic; Antibody Specificity; Antigen Presentation; Antigen-Antibody Reactions; Autoantigens; B-Lymphocytes; Bacterial Proteins; Carrier State; Granulomatosis with Polyangiitis; Immunoglobulin Class Switching; Lymphocyte Cooperation; Microscopic Polyangiitis; Models, Immunological; Myeloblastin; Peroxidase; Protein Binding; Receptors, Antigen, B-Cell; RNA-Binding Proteins; Staphylococcal Infections; Staphylococcus aureus; T-Lymphocyte Subsets

To evaluate circulating cytokine profiles in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV), classified by antineutrophil cytoplasmic antibody (ANCA) specificity (proteinase 3 ANCA [PR3-ANCA] versus myeloperoxidase ANCA [MPO-ANCA]) or by clinical diagnosis (granulomatosis with polyangiitis [GPA] versus microscopic polyangiitis [MPA]).. A panel of 29 cytokines was tested in 186 patients with active AAV at inclusion into the Rituximab in AAV trial. Cytokine concentrations were compared between groups within each classification system. Multivariable analyses adjusted for age, sex, and renal insufficiency were performed, with each biomarker as a dependent variable and ANCA specificity and clinical diagnosis as explanatory variables of interest.. Levels of 9 circulating cytokines (interleukin-6 [IL-6], granulocyte-macrophage colony-stimulating factor [GM-CSF], IL-15, IL-18, CXCL8/IL-8, CCL-17/thymus and activation-regulated chemokine [TARC], IL-18 binding protein [IL-18 BP], soluble IL-2 receptor α [sIL-2Rα], and nerve growth factor β [NGFβ]) were significantly higher in PR3-AAV than MPO-AAV, 4 cytokines (sIL6R, soluble tumor necrosis factor receptor type II [sTNFRII], neutrophil gelatinase-associated lipocalin [NGAL], and soluble intercellular adhesion molecule 1 [sICAM-1]) were higher in MPO-AAV than in PR3-AAV, 6 cytokines (IL-6, GM-CSF, IL-15, IL-18, sIL-2Rα, and NGFβ) were higher in GPA than in MPA, and 3 cytokines (osteopontin, sTNFRII, and NGAL) were higher in MPA than in GPA (all P < 0.05). For nearly all cytokines, the difference between PR3-AAV and MPO-AAV was larger than that between GPA and MPA. The multivariate analysis showed that 8 cytokines (IL-15, IL-8, IL-18 BP, NGF-β, sICAM-1, TARC, osteopontin, and kidney injury molecule 1 (P < 0.05) distinguished patients with AAV better (lower P values and larger effect sizes) when grouped by ANCA specificity than by clinical diagnosis.. Distinct cytokine profiles were identified for PR3-AAV versus MPO-AAV and for GPA versus MPA. Differences in these circulating immune mediators are more strongly associated with ANCA specificity than with clinical diagnosis, suggesting that heterogeneity in the AAV subtypes extends beyond clinical phenotypes.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Cytokines; Double-Blind Method; Female; Granulomatosis with Polyangiitis; Humans; Male; Microscopic Polyangiitis; Middle Aged; Myeloblastin; Peroxidase; Prospective Studies; Randomized Controlled Trials as Topic; Sensitivity and Specificity; Young Adult

To evaluate clinical links between levels of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA) and relapse in patients with ANCA-associated vasculitis (AAV) using a data set from 2 nationwide prospective cohort studies.. From the cohort studies, MPO-ANCA-positive patients who achieved remission during the 6 months after remission induction therapy were enrolled. We measured MPO-ANCA levels at months 0, 3, 6, 12, 18, 24, and at the time of relapse. The primary outcome measure was relapse. A nested case-control analysis and multivariable analysis were performed to investigate the relationship between ANCA reappearance and relapse.. Of 271 patients, 183 were classified as having microscopic polyangiitis, 34 as having granulomatosis with polyangiitis, 15 as having eosinophilic granulomatosis with polyangiitis, and 39 were unclassifiable. The median age was 73 years, and 165 (61%) were female. In 195 patients (72%), MPO-ANCA levels decreased to normal levels within 6 months after commencement of treatment, and MPO-ANCA reappeared in 73 of 181 patients (40%) with complete follow-up data. Reappearance of MPO-ANCA was more frequent in patients with relapse than in 75 age- and sex-matched control patients without relapse (odds ratio 26.2 [95% confidence interval 8.2-101], P < 0.0001) after adjustment for confounding factors.. Reappearance of MPO-ANCA could be a clinically useful biomarker for predicting relapse in patients with MPO-ANCA-positive AAV in remission. This suggests that routine MPO-ANCA monitoring should be implemented in this patient population.

Topics: Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Case-Control Studies; Female; Granulomatosis with Polyangiitis; Humans; Male; Microscopic Polyangiitis; Multivariate Analysis; Peroxidase; Prospective Studies; Recurrence; Risk Factors; Time Factors

Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) are rare autoimmune disorders and characterized by severe multiple organ lesions with a potential fatal outcome. AAV comprises granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). Early diagnosis and treatment can significantly improve the AAV prognosis, but there are can be difficult, largely due to the lack of criteria for the classification MPA, whose main difference is the absence of granulomatous inflammation. The presented paper deals with the results of the analysis of 251 patients with AAV (mean age 43.1 ± 15.9 years, men 40%, disease duration 3 (0,2-28,5) years, ANCA 100%), based on which the diagnostic algorithm was developed. The algorithm steps include classification criteria of EGPA as well as surrogate markers for granulomatous inflammation (SG) and vasculitis (SV). MPA confirmed by the absence of criteria for EGPA, the presence of SV and the absence of SG. Due to the algorithm usage, nosological affiliation of AAV was determined in 99% patients. Both GPA and MPA were the most common (53% and 37%), while EGPA was rare (9%). In MPA group the overall mortality was higher (18%) than GPA and EGPA (7-5%), p=0.003. In MPA with anti- proteinase 3 antibody the two-year survival rate was lower than those with anti-myeloperoxidase antibody (p=0.04), mainly because of the high risk for alveolar hemorrhage and rapidly progressive glomerulonephritis. Relapses occurred more frequently in EGPA (80%) and in GPA (64%) and less frequently in MPA (49%). The group differences confirm diagnostic value of the algorithm. In conclusion, the proposed algorithm will help to improve the diagnosis of AAV. It is important that crucial in the AAV diagnosis belongs focused and systematic clinical examination of patients.

Topics: Adult; Algorithms; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Granulomatosis with Polyangiitis; Humans; Male; Microscopic Polyangiitis; Middle Aged; Peroxidase

Recent findings have indicated a close relationship between myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-positive hypertrophic pachymeningitis and the limited form of granulomatosis with polyangiitis (GPA). In Japan, MPO-ANCA-positive hypertrophic pachymeningitis predominantly occurs in elderly individuals. We herein describe the cases of two patients with MPO-ANCA-positive hypertrophic pachymeningitis associated with the limited form of GPA who were successfully treated with a combination of corticosteroids and methotrexate. Although methotrexate has been shown to be less effective than cyclophosphamide for inducing the remission of GPA in patients with organ-threatening diseases, its safety and efficacy may make it a useful alternative treatment modality for patients with the limited form of GPA who show meningeal involvement.

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Female; Granulomatosis with Polyangiitis; Humans; Hypertrophy; Immunosuppressive Agents; Meningitis; Methotrexate; Middle Aged; Peroxidase

Granulomatosis with polyangiitis (GPA) that is localized to the upper airway presents a diagnostic challenge because of a tendency towards anti-neutrophil cytoplasmic antibody (ANCA)-negativity. The purpose of this study was to investigate whether positivity of ANCA detection might be elicited with combined use of enzyme-linked immunosorbent assay (ELISA) kits.. Twenty-nine serum samples obtained from GPA patients were used in this study. In addition to routine biochemical investigation for ANCA, tests for detecting PR3-, MPO-ANCAs, and minor ANCAs were performed with commercially available ELISA kits. Cytoplasmic (C)-ANCA and perinuclear (P)-ANCA were evaluated using the indirect immunofluorescence (IIF) technique.. Twelve patients were positive for PR3- or MPO-ANCA in the clinical laboratory test, and 17 patients were negative for both ANCAs. Of the 17 ANCA-negative patients, four were positive for PR3- or MPO-ANCA, and three were positive for minor ANCA according to results obtained from six different ELISA kits. These findings indicated that performing detection tests with six different ELISA kits might improve the positivity of ANCA and might contribute to establishing the diagnosis of ANCA-associated vasculitis. Together with results from IIF, the samples of eight patients with clinically ANCA-negative results (8/17, 47.1%) were converted to ANCA-positive results, and the ANCA detection rate was significantly improved from 12/29 (41.4%) to 20/29 (69.0%, p=0.03).. Additional detection techniques should be used to confirm the results of clinically ANCA-negative samples, particularly when vasculitis is suspected. Minor ANCAs should also be evaluated with detection tests when PR3- and MPO-ANCA are negative.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique, Indirect; Granulomatosis with Polyangiitis; Humans; Male; Middle Aged; Myeloblastin; Peroxidase

To estimate the annual incidence, prevalence, and mortality of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) and its subsets, granulomatosis with polyangiitis (Wegener's) (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA), in a US-based adult population.. All medical records of patients with a diagnosis of, or suspicion of having, AAV in Olmsted County, Minnesota from January 1, 1996 to December 31, 2015 were reviewed. AAV incidence rates were age- and sex-adjusted to the 2010 US white population. Age- and sex-adjusted prevalence of AAV was calculated on January 1, 2015. Survival rates observed in the study cohort were compared with expected rates in the Minnesota population.. Of the 58 incident cases of AAV in Olmsted County during the study period, 23 (40%) were cases of GPA, 28 (48%) were cases of MPA, and 7 (12%) were cases of EGPA. Overall, 28 (48%) of the patients with AAV were women and 57 (98%) were white. The mean ± SD age at diagnosis was 61.1 ± 16.5 years. Thirty-four patients (61%) had myeloperoxidase (MPO)-ANCAs, and 17 (30%) were positive for proteinase 3 (PR3)-ANCAs; 5 (9%) were ANCA-negative. The annual incidence of AAV was 3.3 per 100,000 population (95% confidence interval [95% CI] 2.4-4.1). The incidence rates of GPA, MPA, and EGPA were 1.3 (95% CI 0.8-1.8), 1.6 (95% CI 1.0-2.2), and 0.4 (95% CI 0.1-0.6), respectively. The overall prevalence of AAV was 42.1 per 100,000 (95% CI 29.6-54.6). The mortality rate among AAV patients overall, and among patients with EGPA, those with MPA, and those with MPO-ANCAs, was increased in comparison to the Minnesota general population (each P < 0.05), whereas mortality rates among patients with GPA, those with PR3-ANCAs, and ANCA-negative patients did not differ from that in the general population.. The annual incidence of AAV in Olmsted County, Minnesota over the 20 years of the study was 3.3 per 100,000, with a prevalence of 42.1 per 100,000, which is substantially higher than the rates reported in other areas worldwide. The incidence of GPA was similar to that of MPA. Patients with MPA and those with EGPA, but not patients with GPA, experienced higher rates of mortality than that in the Minnesota general population. MPO-ANCAs were a marker of poor survival in this population of patients with AAV.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Cohort Studies; Female; Granulomatosis with Polyangiitis; Humans; Incidence; Male; Microscopic Polyangiitis; Middle Aged; Minnesota; Myeloblastin; Peroxidase; Prevalence; Survival Rate; Time Factors

The proteinase 3 (PR3)-positive anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) granulomatosis with polyangiitis (GPA) has been associated with chronic nasal S. aureus carriage, which is a risk factor for disease relapse. The present study was aimed at comparing the genetic make-up of S. aureus isolates from PR3-ANCA-positive GPA patients with that of isolates from patients suffering from myeloperoxidase (MPO)-ANCA-positive AAV, and isolates from healthy controls. Based on a DNA microarray-based approach, we show that not only PR3-ANCA-positive GPA patients, but also MPO-ANCA-positive AAV patients mainly carried S. aureus types that are prevalent in the general population. Nonetheless, our data suggests that MPO-ANCA-associated S. aureus isolates may be distinct from healthy control- and PR3-ANCA-associated isolates. Furthermore, several genetic loci of S. aureus are associated with either PR3-ANCA- or MPO-ANCA-positive AAV, indicating a possible role for pore-forming toxins, such as leukocidins, in PR3-ANCA-positive GPA. Contrary to previous studies, no association between AAV and superantigens was detected. Our findings also show that a lowered humoral immune response to S. aureus is common for PR3-ANCA- and MPO-ANCA-positive AAV. Altogether, our observations imply that the presence or absence of particular virulence genes of S. aureus isolates from AAV patients contributes to disease progression and/or relapse.

Topics: Adult; Aged; Antibodies, Antineutrophil Cytoplasmic; Carrier State; Female; Genetic Loci; Granulomatosis with Polyangiitis; Host-Pathogen Interactions; Humans; Male; Middle Aged; Myeloblastin; Peroxidase; Recurrence; Retrospective Studies; Staphylococcal Infections; Staphylococcus aureus; Young Adult

We studied whether in ANCA-associated vasculitis patients, duration of AZA maintenance influenced relapse rate during long-term follow-up.. Three hundred and eighty newly diagnosed ANCA-associated vasculitis patients from six European multicentre studies treated with AZA maintenance were included; 58% were male, median age at diagnosis 59.4 years (interquartile range: 48.3-68.2 years); granulomatosis with polyangiitis, n = 236; microscopic polyangiitis, n = 132; or renal limited vasculitis, n = 12. Patients were grouped according to the duration of AZA maintenance after remission induction: ⩽18 months, ⩽24 months, ⩽36 months, ⩽48 months or > 48 months. Primary outcome was relapse-free survival at 60 months.. During follow-up, 84 first relapses occurred during AZA-maintenance therapy (1 relapse per 117 patient months) and 71 after withdrawal of AZA (1 relapse/113 months). During the first 12 months after withdrawal, 20 relapses occurred (1 relapse/119 months) and 29 relapses >12 months after withdrawal (1 relapse/186 months). Relapse-free survival at 60 months was 65.3% for patients receiving AZA maintenance >18 months after diagnosis vs 55% for those who discontinued maintenance ⩽18 months (P = 0.11). Relapse-free survival was associated with induction therapy (i.v. vs oral) and ANCA specificity (PR3-ANCA vs MPO-ANCA/negative).. Post hoc analysis of combined trial data suggest that stopping AZA maintenance therapy does not lead to a significant increase in relapse rate and AZA maintenance for more than 18 months after diagnosis does not significantly influence relapse-free survival. ANCA specificity has more effect on relapse-free survival than duration of maintenance therapy and should be used to tailor therapy individually.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Azathioprine; Disease-Free Survival; Female; Follow-Up Studies; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Kidney Diseases; Maintenance Chemotherapy; Male; Microscopic Polyangiitis; Middle Aged; Myeloblastin; Peroxidase; Recurrence; Time Factors; Young Adult

Topics: Antibodies, Antineutrophil Cytoplasmic; Cough; Diagnosis, Differential; Dyspnea; Eosinophilia; Fibromyalgia; Granulomatosis with Polyangiitis; Headache; Humans; Immunosuppressive Agents; Lung; Male; Middle Aged; Peroxidase; Respiratory Sounds; Sweating; Tomography, X-Ray Computed

To identify risk alleles relevant to the causal and biologic mechanisms of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).. A genome-wide association study and subsequent replication study were conducted in a total cohort of 1,986 cases of AAV (patients with granulomatosis with polyangiitis [Wegener's] [GPA] or microscopic polyangiitis [MPA]) and 4,723 healthy controls. Meta-analysis of these data sets and functional annotation of identified risk loci were performed, and candidate disease variants with unknown functional effects were investigated for their impact on gene expression and/or protein function.. Among the genome-wide significant associations identified, the largest effect on risk of AAV came from the single-nucleotide polymorphism variants rs141530233 and rs1042169 at the HLA-DPB1 locus (odds ratio [OR] 2.99 and OR 2.82, respectively) which, together with a third variant, rs386699872, constitute a triallelic risk haplotype associated with reduced expression of the HLA-DPB1 gene and HLA-DP protein in B cells and monocytes and with increased frequency of complementary proteinase 3 (PR3)-reactive T cells relative to that in carriers of the protective haplotype. Significant associations were also observed at the SERPINA1 and PTPN22 loci, the peak signals arising from functionally relevant missense variants, and at PRTN3, in which the top-scoring variant correlated with increased PRTN3 expression in neutrophils. Effects of individual loci on AAV risk differed between patients with GPA and those with MPA or between patients with PR3-ANCAs and those with myeloperoxidase-ANCAs, but the collective population attributable fraction for these variants was substantive, at 77%.. This study reveals the association of susceptibility to GPA and MPA with functional gene variants that explain much of the genetic etiology of AAV, could influence and possibly be predictors of the clinical presentation, and appear to alter immune cell proteins and responses likely to be key factors in the pathogenesis of AAV.

Topics: Adult; alpha 1-Antitrypsin; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoantigens; B-Lymphocytes; Case-Control Studies; Female; Gene Expression; Genetic Predisposition to Disease; Genome-Wide Association Study; Granulomatosis with Polyangiitis; Haplotypes; HLA-DP Antigens; HLA-DP beta-Chains; Humans; Male; Microscopic Polyangiitis; Middle Aged; Monocytes; Myeloblastin; Neutrophils; Odds Ratio; Peroxidase; Polymorphism, Single Nucleotide; Protein Tyrosine Phosphatase, Non-Receptor Type 22; T-Lymphocytes

We investigated what variables at diagnosis might be associated with the relapse of eosinophilic granulomatosis with polyangiitis (EGPA) and whether five factor score (FFS) at diagnosis might predict it.. We reviewed the medical records of 30 patients with EGPA having results of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibodies (ANCA) and proteinase 3 (PR3)-ANCA and having achieved remission during the first therapeutic regimen administration within follow-up duration for at least more than 2 years. Clinical manifestations, the presence of relapse and items for FFS at diagnosis were collected and compared among groups.. The mean age of patients (18 women) was 50.3 years and the mean follow-up duration was 2175 days. EGPA patients having MPO-ANCA had shown higher frequency of skin involvement and proteinuria over 1 g/day than those having PR3-ANCA and no ANCA. EGPA patients with relapse had more frequent baseline MPO-ANCA and kidney involvement,including proteinuria over 1 g/day and renal insufficiency and higher FFS at diagnosis than those without. However, only FFS showed the predictive significance for relapse (Exp(B) 2.624, P = 0.014) on Cox Hazard model analysis. When the cutoff of FFS for the relapse was set as 1, relapse was identified more frequently in patients with FFS ≥ 1 than those with FFS <1 (68.8% vs. 7.1%, P = 0.001; relative risk 28.6).. In this study, FFS at diagnosis was associated with relapse and FFS ≥ 1 was the independent predictor of relapse during follow-up for more than 2 years.

Topics: Adult; Aged; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Chi-Square Distribution; Churg-Strauss Syndrome; Decision Support Techniques; Female; Follow-Up Studies; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Male; Middle Aged; Myeloblastin; Peroxidase; Predictive Value of Tests; Proportional Hazards Models; Recurrence; Retrospective Studies; Risk Factors; Time Factors; Treatment Outcome

To compare the phenotype, clinical course, and outcome of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-positive granulomatosis with polyangiitis (Wegener's) (GPA) to proteinase 3 (PR3)-ANCA-positive GPA and to MPO-ANCA-positive microscopic polyangiitis (MPA).. We characterized all MPO-ANCA-positive patients classified as having GPA by the European Medicines Agency algorithm who attended our center, in a retrospective chart review. A second cohort of patients with PR3-ANCA-positive GPA matched for age and sex was characterized. Patients with MPO-ANCA-positive MPA from a recently published cohort were also included in the analysis. All patients were diagnosed and treated according to a standardized interdisciplinary approach at a vasculitis referral center.. Comprehensive data were available for 59 patients with MPO-ANCA-positive GPA, and they were compared to 118 patients with PR3-ANCA-positive GPA and 138 patients with MPO-ANCA-positive MPA. We observed a distinct phenotype in MPO-ANCA-positive GPA as compared to the other 2 cohorts. Patients with MPO-ANCA-positive GPA frequently had limited disease without severe organ involvement, had a high prevalence of subglottic stenosis, and had less need for aggressive immunosuppressive therapy (cyclophosphamide/rituximab). The patients with MPO-ANCA-positive GPA were also younger than the MPA patients and were predominantly female (significantly different than the MPA cohort). While GPA patients had higher survival rates compared to MPA patients (due to a high prevalence of pulmonary fibrosis in MPA), patients with MPO-ANCA had significantly lower relapse rates than those with PR3-ANCA.. Patients with MPO-ANCA-positive GPA show significantly different clinical courses compared to those with PR3-ANCA-positive GPA or MPO-ANCA-positive MPA, which should be considered in their clinical management. Classification according to ANCA specificity may improve the evaluation of relapse risk.

Topics: Adolescent; Adult; Age Distribution; Aged; Antibodies, Antineutrophil Cytoplasmic; Case-Control Studies; Cyclophosphamide; Eye Diseases; Female; Germany; Granulomatosis with Polyangiitis; Humans; Immunologic Factors; Immunosuppressive Agents; Kidney Diseases; Laryngostenosis; Male; Middle Aged; Myeloblastin; Otorhinolaryngologic Diseases; Peripheral Nervous System Diseases; Peroxidase; Proportional Hazards Models; Recurrence; Retrospective Studies; Rituximab; Survival Rate; Young Adult

To examine the relationship of antineutrophil cytoplasmic antibody (ANCA) type and ANCA-associated vasculitis (AAV) diagnosis with demographic features, disease manifestations, and clinical outcomes. We focused on patients who account for the differences between ANCA type and disease type classifications: anti-myeloperoxidase (MPO)-ANCA-positive and ANCA-negative patients with granulomatosis with polyangiitis (Wegener's) (GPA).. We performed a pooled analysis of the Wegener's Granulomatosis Etanercept Trial and the Rituximab in ANCA-Associated Vasculitis trial comparing patients with MPO-ANCA-positive GPA and patients with ANCA-negative GPA to patients with proteinase 3 (PR3)-ANCA-positive GPA and patients with MPO-ANCA-positive microscopic polyangiitis (MPA).. Of the 365 patients analyzed, 273 (75%) had PR3-ANCA-positive GPA, 33 (9%) had MPO-ANCA-positive GPA, 15 (4%) had ANCA-negative GPA, and 44 (12%) had MPO-ANCA-positive MPA. MPO-ANCA-positive GPA patients were younger at diagnosis compared to MPO-ANCA-positive MPA patients (53 versus 61 years; P = 0.02). Their disease manifestations and rates of relapse were similar to those of PR3-ANCA-positive GPA patients. Relapse was more frequent in MPO-ANCA-positive GPA patients than in patients with MPO-ANCA-positive MPA at trial entry as well as at 12 and 18 months. ANCA-negative patients with GPA had lower Birmingham Vasculitis Activity Score for Wegener's Granulomatosis scores at trial entry than PR3-ANCA-positive patients with GPA (4.5 versus 7.7; P < 0.01), primarily because of a lower prevalence of renal involvement.. We were unable to demonstrate important clinical differences between MPO-ANCA-positive and PR3-ANCA-positive patients with GPA. The risk of relapse was associated more closely with disease type than with ANCA type in this patient cohort. These findings deserve consideration in the assessment of relapse risk in patients with AAV.

Topics: Antibodies, Antineutrophil Cytoplasmic; Antirheumatic Agents; Etanercept; Eye Diseases; Female; Granulomatosis with Polyangiitis; Humans; Kidney Diseases; Lung Diseases; Male; Middle Aged; Myeloblastin; Nervous System Diseases; Otorhinolaryngologic Diseases; Peroxidase; Recurrence; Rituximab; Severity of Illness Index

Granulomatosis with polyangiitis (GPA) is a rare systemic vasculitis that often involves the lung. However, interstitial pneumonia (IP) is rarely seen in GPA patients. We herein report 3 cases of IP associated with GPA diagnosed by surgical lung biopsy. High-resolution CT showed uniform subpleural reticular opacity with traction bronchiectasis. Biopsies from all 3 patients revealed neutrophilic capillaritis, microabscesses with giant cells, and coexisting histological findings of usual IP pattern or fibrosing nonspecific IP pattern. All 3 patients had elevated levels of serum myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA), but not proteinase 3-ANCA. We diagnosed GPA and treated with corticosteroid and cyclophosphamide. Follow-up CT showed improvement of the lesions in all patients. Surgical lung biopsy specimens which revealed GPA enabled us to conduct the most suitable therapy. This report indicates the importance of surgical lung biopsy for differentiating idiopathic IPs from GPA-associated IP and suggests a relationship between MPO-ANCA and IP in GPA.

Topics: Adrenal Cortex Hormones; Aged; Antibodies, Antineutrophil Cytoplasmic; Biopsy; Cyclophosphamide; Female; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Lung; Lung Diseases, Interstitial; Middle Aged; Peroxidase; Tomography, X-Ray Computed

We studied the clinico-pathological differences among PR3-ANCA-positive granulomatosis with polyangiitis (PR3-GPA), MPO-ANCA-positive GPA (MPO-GPA) and microscopic polyangiitis (MPA). ANCA-associated vasculitis (AAV) was classified using the European Medicines Agency classification. We retrospectively analyzed 38 patients with GPA and 41 with MPA treated in eight hospitals in Japan. Of the patients with GPA, 17 were positive for MPO-ANCA, and 15 for PR3-ANCA. All patients with MPA were MPO-ANCA positive. The mean ages of those with MPO-GPA were 69.6 years old, 10 years older than those with PR3-GPA. The majority (82 %) of patients with MPO-GPA were woman, a significantly greater proportion than for PR3-GPA. We also found that ear, nose and throat (ENT), nervous system involvement were significantly more common in MPO-GPA, but renal function was less impaired than those with MPA. Both PR3-GPA and MPO-GPA relapsed more frequently than MPA, but overall survival was significantly better (P < 0.01 and P < 0.05, respectively). Univariate analysis identified the following factors as predictors of a poor prognosis: MPA (P < 0.01), pulmonary UIP pattern (P < 0.005) Cr ≥ 1.7 mg/dl (P < 0.01) and absence of ENT involvement (P < 0.05), which were characteristics of MPA. In our cohort, MPO-GPA was most likely to affect older women and was associated with otitis media, nervous system involvement, mild renal impairment and more favorable outcome. It is clinically useful to differentiate MPO-GPA from MPA and PR3-GPA in patients with AAV.

Topics: Age Factors; Aged; Antibodies, Antineutrophil Cytoplasmic; Female; Granulomatosis with Polyangiitis; Humans; Japan; Lung Diseases, Interstitial; Male; Middle Aged; Myeloblastin; Otitis Media; Peroxidase; Recurrence; Retrospective Studies; Sex Factors; Vasculitis, Central Nervous System

Rituximab and glucocorticoids are a non-inferior alternative to cyclophosphamide and glucocorticoid therapy for induction of remission in antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) patients with moderate renal disease. The efficacy and safety of this approach in patients with severe renal impairment are unknown. We report the outcomes and safety profile of rituximab and glucocorticoid therapy for induction of remission in patients with AAV and ANCA-negative vasculitis presenting with severe renal disease.. A multicenter, retrospective, cohort study was conducted between 2005 and 2014. Patients with new or relapsing disease with an estimated glomerular filtration rate (eGFR) of ≤20 ml/min/1.73 m(2) treated with rituximab and glucocorticoid induction with or without plasmapheresis were included. Fourteen patients met the inclusion criteria. The primary outcomes were rate of remission and dialysis independence at 6 months. The secondary outcomes were eGFR at 6 months, end-stage renal disease (ESRD), survival rates and adverse events.. All patients were Caucasian, and 57% were male. The mean eGFR was 12 ml/min/1.73 m(2) at diagnosis. All patients achieved remission with a median time to remission of 55 days. Seven patients required dialysis at presentation of which 5 patients recovered renal function and discontinued dialysis by 6-month follow-up. The mean eGFR for the 11 patients without ESRD who completed 6-month follow-up was 33 ml/min/1.73 m(2). Four patients ultimately developed ESRD, and one died during the follow-up period.. Patients with AAV and severe renal disease achieve high rates of remission and dialysis independence when treated with rituximab and glucocorticoids without cyclophosphamide.

Topics: Adult; Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Cohort Studies; Disease Progression; Drug Therapy, Combination; Female; Glucocorticoids; Granulomatosis with Polyangiitis; Humans; Immunologic Factors; Kidney Failure, Chronic; Male; Microscopic Polyangiitis; Middle Aged; Myeloblastin; Peroxidase; Plasmapheresis; Remission Induction; Renal Insufficiency, Chronic; Retrospective Studies; Rituximab; Severity of Illness Index; Treatment Outcome; Vasculitis

A 69-year-old man was diagnosed with granulomatosis with polyangiitis (GPA) based on the presence of skin granuloma, refractory otitis media, renal insufficiency and myeloperoxidase-antineutrophil cytoplasmic antibody positivity and slight lung opacity. He was treated with high-dose corticosteroid therapy. Despite the initial improvement of his renal function and a decrease in his C-reactive protein level, he suffered from an alveolar hemorrhage one week after the start of corticosteroid therapy. An anti-dsDNA antibody test was positive and the patient had hypocomplementemia. Elements of both GPA and systemic lupus erythematosus were thought to have affected his clinical course.

Topics: Adrenal Cortex Hormones; Aged; C-Reactive Protein; Dose-Response Relationship, Drug; Granulomatosis with Polyangiitis; Hemorrhage; Humans; Kidney Function Tests; Lupus Erythematosus, Systemic; Male; Peroxidase; Pulmonary Alveoli

Idiopathic hypertrophic pachymeningitis is a fibroinflammatory immune-mediated disease of the dura mater. Its diagnosis requires the preclusion of infectious, tumoral and other inflammatory diseases. In recent years new entities have been reported that can present with hypertrophic pachymeningitis, such as IgG4-associated disease and MPO-ANCA+ pachymeningitis, as a form of vasculitis limited to the central nervous system.. We describe the case of a 64 years-old male with headaches and cervicalgia, predominantly at night, and clinical signs and symptoms of spinal cord compression. Following the diagnosis of craniocervical hypertrophic pachymeningitis provided by the magnetic resonance imaging study, an aetiological study was conducted. Infectious and tumoral diseases were precluded. The clinical features did not show any systemic involvement and high levels of IgG4 and MPO-ANCA+ were found in the results of the analyses. The clinical signs and symptoms quickly improved following treatment with corticoids.. IgG4-related disease and MPO-ANCA-associated vasculitis limited to the central nervous system can account for a high percentage of the cases of hypertrophic pachymeningitis that were considered idiopathic, and their diagnosis requires a biopsy and a histological study.. Paquimeningitis hipertrofica relacionada con IgG4 y MPO-ANCA.. Introduccion. La paquimeningitis hipertrofica idiopatica es una enfermedad fibroinflamatoria de la duramadre. Su diagnostico requiere la exclusion de enfermedades infecciosas, tumorales y otras enfermedades inflamatorias. En los ultimos años se han descrito nuevas entidades que pueden presentarse con paquimeningitis hipertrofica: la enfermedad relacionada con IgG4 y la paquimeningitis MPO-ANCA+ como forma de vasculitis limitada al sistema nervioso central. Caso clinico. Varon de 64 años con cefalea y cervicalgia de predominio nocturno y clinica de compresion medular. Tras el diagnostico de paquimeningitis hipertrofica craneocervical facilitado por el estudio de resonancia magnetica, se realizo un estudio etiologico. Se descartaron enfermedades infecciosas y tumorales. La clinica no mostraba afectacion sistemica y en la analitica presentaba IgG4 elevada y MPO-ANCA+. Tras tratamiento con corticoides presento una rapida mejoria de la clinica. Conclusiones. La enfermedad relacionada con IgG4 y la vasculitis asociada a MPO-ANCA limitada al sistema nervioso central pueden representar un alto porcentaje de las paquimeningitis hipertroficas que se consideraban idiopaticas, y su diagnostico requiere biopsia y estudio histologico.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoantigens; Dura Mater; Evoked Potentials, Somatosensory; Granulomatosis with Polyangiitis; Headache; Humans; Hypertrophy; Immunoglobulin G; Magnetic Resonance Imaging; Male; Meningitis; Middle Aged; Neck Pain; Organ Specificity; Peroxidase; Prednisone

This report describes a 72-year-old woman presenting MPO-ANCA-associated hypertrophic pachymeningitis and venous thrombosis. Five years prior, positive MPO-ANCA and renal dysfunction had been indicated. At that time, oral steroids and tacrolimus were given to treat systemic vasculitis. During the course of the disease, she repeated otitis media. Saddle nose appeared. She was suspected of having localized type granulomatosis with polyangiitis (GPA). She was hospitalized because of consciousness disturbance and was diagnosed as having MPO-ANCA-associated hypertrophic pachymenigitis and venous thrombosis. Brain MRI detected thick dura mater with abnormal enhancement, predominantly on the right cerebral hemisphere, and tentorium cerebella partially along with the cerebral sulci. MRI revealed vasogenic brain edema lesions in the right occipital, parietal, and temporal lobes and cytotoxic edema lesions in the right parietal lobe and centrum semiovale. MR venography revealed stenosis of the venous sinus including confluence of sinuses, straight sinus, and right transverse sinus. Subsequent treatment with corticosteroids, an immunosuppressant, and an anticoagulant led to recovery. No patient with MPO-ANCA-associated hypertrophic pachymenigitis and venous thrombosis that developed alternation of consciousness has ever been reported. This is therefore regarded as a rare case.

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Cerebral Veins; Consciousness Disorders; Female; Granulomatosis with Polyangiitis; Humans; Intracranial Thrombosis; Magnetic Resonance Imaging; Meningitis; Peroxidase; Tomography, X-Ray Computed; Venous Thrombosis

Topics: Age Factors; Anti-Inflammatory Agents; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Disease Progression; Drug Therapy, Combination; Glucocorticoids; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Microscopic Polyangiitis; Myeloblastin; Peroxidase; Prognosis; Sex Factors

We studied 91 patients with granulomatosis with polyangiitis (GPA; Wegener's granulomatosis) who were dealt with by otolaryngologists in Japan. The upper respiratory tract (URT) alone was involved in 56%. Regarding findings of PR3-ANCA, histology and initial diagnosis, of the 40 patients in whom sites other than the URT were involved, 64 and 73% were positive for PR3-ANCA and histology, respectively. On the other hand, of 51 patients in whom only the URT was involved, only 49 and 31% were positive for PR3-ANCA and histology, respectively. With regard to diagnosis, definitive and probable diagnoses were made in 78 and 20%, respectively, of patients involving sites other than the URT. On the other hand, definitive and probable diagnoses were made in only 22 and 37%, respectively, of patients involving the URT alone; the Japanese diagnostic criteria were inapplicable to 41%. Of the 21 patients to whom the diagnostic criteria were inapplicable, 13 (62%) developed additional symptoms and signs during the observation period, and they then fulfilled the Japanese diagnostic criteria. Among these patients, 8 were MPO-ANCA-positive and 3 patients had 2 or more sub-lesions in the URT. If the diagnostic criteria included cases with MPO-ANCA (±) and 2 lesions in the URT, the diagnostic rates increased from 59 to 86% even though they were of limited form. Thus, about 60% of the patients with URT symptoms alone did not satisfy the Japanese diagnostic criteria at the initial visit.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Female; Granulomatosis with Polyangiitis; Health Care Surveys; Humans; Japan; Male; Middle Aged; Myeloblastin; Neutrophils; Otolaryngology; Peroxidase; Predictive Value of Tests; Respiratory System; Retrospective Studies; Surveys and Questionnaires; Young Adult

Antimyeloperoxidase antibodies are a variety of antineutrophil cytoplasm antibodies (Anca), which can be detected in systemic small-sized vessel vasculitides such as microscopic polyangiitis, Wegener's granulomatosis and Churg-Strauss syndrome. Antimyeloperoxidase antibodies have been also associated with the development of lung fibrosis. Their pathogenic role has been well established, both in vitro and in vivo. These autoantibodies can activate neutrophils and trigger their oxidative burst leading to the release of free oxygen species and cytotoxic proteins. The oxidative burst is deleterious for the endothelium. Another mechanism by which antimyeloperoxidase may act is the activation of myeloperoxydase leading to an increased production of hypochlorous acid, which is highly toxic for the endothelial cells. These mechanisms contribute to the development of vasculitis.

Topics: Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Granulomatosis with Polyangiitis; Humans; Neutrophils; Peroxidase; Pulmonary Fibrosis; Vasculitis

Topics: Acute Disease; Acute Kidney Injury; Antibodies, Antineutrophil Cytoplasmic; Autoantigens; Chemical and Drug Induced Liver Injury; Cholelithiasis; Combined Modality Therapy; Cyclophosphamide; Drug Therapy, Combination; Glomerulosclerosis, Focal Segmental; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Male; Middle Aged; Pancreatitis; Peroxidase; Plasmapheresis; Renal Dialysis

A 77-year-old Japanese man was referred to our hospital because of the progression of renal dysfunction. Two months prior to the admission he had been diagnosed with otitis media. Urinalysis showed proteinuria and microscopic hematuria. Blood examination revealed renal dysfunction, hepatitis C virus (HCV)infection and positive myeloperoxidase (MPO)-ANCA. A chest CT revealed small infiltrates in the right middle lobe. The renal biopsy demonstrated crescentic glomerulonephritis with tubulitis. He was diagnosed as having Wegener's granulomatosis according to the American College of Rheumatology classification criteria. Methylprednisolone pulse therapy followed by oral prednisolone improved all of the otitis media, lung infiltrates and renal function. Recently, a high prevalence of ANCA has been reported in patients with HCV. It has also been reported that the prevalence of HCV infection is high in patients with Wegener's granulomatosis. Therefore, our case points to the clinical significance of HCV infection in ANCA-associated systemic vasculitis including Wegener's granulomatosis.

Topics: Aged; Antibodies, Antinuclear; Glomerulonephritis; Granulomatosis with Polyangiitis; Hepatitis C; Humans; Male; Methylprednisolone; Otitis Media; Peroxidase; Prednisolone; Pulse Therapy, Drug; Treatment Outcome

Wegener's granulomatosis (WG) is a rare systemic necrotizing granulomatous vasculitis affecting small- to medium-sized vessels, associated with antineutrophil cytoplasm antibodies (ANCA), mainly anti-proteinase 3. Rarely, ANCA may be directed against myeloperoxidase. We report a 58-year-old woman who developed an uveitis as the presenting manifestation of Wegener's granulomatosis who highlight the usefulness of internist and ophthalmologist collaboration.

Topics: Antibodies, Antineutrophil Cytoplasmic; Female; Granulomatosis with Polyangiitis; Humans; Middle Aged; Peroxidase; Uveitis

Topics: Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Churg-Strauss Syndrome; Enzyme-Linked Immunosorbent Assay; Granulomatosis with Polyangiitis; Humans; Microscopic Polyangiitis; Myeloblastin; Peroxidase; Reference Values; Specimen Handling

Our previous study suggested that patients with MPO-ANCA (myeloperoxidase antineutrophil cytoplasmic autoantibodies)-positive Wegener's granulomatosis (WG) were common in Chinese, indicating that patients with MPO-ANCA could manifest as either WG or microscopic polyangiitis (MPA). The aim of this study was to compare the immunological characteristics of MPO-ANCA in patients with WG and MPA.. Fifteen patients with WG and 21 patients with MPA were enrolled in the current study. Anti-MPO IgG subclasses and their titres were detected by antigen-specific enzyme-linked immunosorbent assays (ELISA); affinity was assessed by antigen-inhibition ELISAs. The sera from all patients were employed to inhibit biotin conjugated affinity-purified human anti-MPO antibodies (Probe-biotin), from plasma exchange of a patient with MPA, in a competitive inhibition ELISAs system.. All four anti-MPO subclasses could be detected in sera from patients with WG and MPA. The titres of anti-MPO IgG4 subclass in patients with WG were significantly higher than those with MPA (1:1878 vs 1:218, P < 0.005). The affinity constants of MPO-ANCA were comparable between patients with WG and MPA (0.3-70/M vs 0.3-140/M respectively). Eleven out of the 15 sera and 18 out of the 21 sera could inhibit the binding of the Probe-biotin in patients with WG and MPA respectively. The average inhibition rate was 47.7% +/- 11.5% and 61.7% +/- 14.5% respectively (P < 0.05).. MPO-ANCA IgG4 subclass might play a role in the development of WG. The MPO-ANCA in WG and MPA might recognize overlapping but different epitopes on native MPO molecule. The difference in immunological characteristics of MPO-ANCA might contribute to different disease entities.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Antibody Affinity; Enzyme-Linked Immunosorbent Assay; Female; Granulomatosis with Polyangiitis; Humans; Immunoglobulin G; Male; Middle Aged; Peroxidase; Vasculitis

This study evaluated the performance of 12 assays for antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3) and myeloperoxidase (MPO) in 55 active and 68 treated cases of vasculitis and in nonvasculitic disease. It examined within- and between-assay precision; binding curves, binding levels, and interassay consistency; and sensitivity, specificity, and receiver operating characteristic analysis. All assays were highly sensitive for active vasculitis (median, 94%; range, 91%-96%), but sensitivities were more varied in treated disease (median, 69%; range, 57%-82%). Binding curves and binding levels were also very variable in PR3-ANCA and MPO-ANCA assays. This has implications for studies correlating ANCA levels with disease activity and in developing ANCA-based treatment guidelines. PR3-ANCA and MPO-ANCA assays need to be standardized as a matter of urgency, but in the meantime, individual laboratories must understand the limitations of the assays used, especially with low-level ANCA in treated vasculitis and nonvasculitic disease.

Topics: Antibodies, Antineutrophil Cytoplasmic; Enzyme-Linked Immunosorbent Assay; Epitopes; Fluorescent Antibody Technique, Indirect; Granulomatosis with Polyangiitis; Humans; Myeloblastin; Neutrophils; Peroxidase; Prognosis; Reproducibility of Results; ROC Curve; Sensitivity and Specificity

Proteinase-3 antineutrophil cytoplasmic antibody (PR3-ANCA) was the serological marker for Wegener's granulomatosis (WG), while myeloperoxidase (MPO)-ANCA was the serological marker for microscopic polyangiitis (MPA). However, our previous study suggested that patients with MPO-ANCA positive WG were common in Chinese. This study aimed to analyse the renal histology of patients with MPO-ANCA positive WG.. Patients in our centre with WG were selected according to both the Chapel Hill Consensus Conference (CHCC) definition and American College of Rheumatology classification criteria. Patients with MPA were selected according to the CHCC definition. The renal histology was compared between patients with MPO-ANCA positive WG and with PR3-ANCA positive WG as well as patients with MPO-ANCA positive MPA.. Sixty-one patients with WG had complete renal histological data, 39/61 with positive MPO-ANCA and 22/61 with positive PR3-ANCA. Among patients with crescents in glomeruli, those with MPO-ANCA had fewer cellular crescents and more fibrous crescents than those with PR3-ANCA (P < 0.01 and P < 0.05, respectively). Interstitial fibrosis and tubular atrophy were more prevalent and severe in patients with MPO-ANCA than in those with PR3-ANCA (P < 0.01 and P < 0.05, respectively). Compared with 44 patients with MPO-ANCA positive MPA, patients with MPO-ANCA positive WG had fewer glomeruli with crescents and more normal glomeruli (P < 0.01 and P < 0.01, respectively).. Patients with MPO-ANCA positive WG are common in Chinese. In renal histology, chronic lesions were more severe and prevalent in patients with MPO-ANCA positive WG than in patients with PR3-ANCA positive WG. Glomerular lesions were less severe and less prevalent in patients with MPO-ANCA positive WG than in those with MPO-ANCA positive MPA.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; China; Female; Fluorescent Antibody Technique, Indirect; Granulomatosis with Polyangiitis; Humans; Kidney; Male; Middle Aged; Myeloblastin; Peroxidase

Propylthiouracil (PTU) could induce antineutrophil cytoplasmic antibody (ANCA) associated vasculitis. This study aimed to investigate the inhibitory effects on MPO oxidation activity by PTU and MPO-ANCA from patients with primary microscopic polyangiitis (MPA) and PTU-induced vasculitis. IgG preparations were purified from MPO-ANCA-positive sera from seven patients with PTU-induced vasculitis and ten patients with primary MPA. The oxidation activity of MPO was measured in the presence of PTU and MPO-ANCA-positive IgG preparations from patients with PTU-induced vasculitis and primary MPA respectively. PTU could competitively inhibit the oxidation activity of MPO dose dependently. MPO-ANCA-positive IgG preparations from 6/7 patients with PTU-induced vasculitis and only 3/10 from patients with primary MPA could inhibit the MPO activity in a dose-dependent manner. In conclusions, the oxidation activity of MPO could be inhibited by PTU and PTU-induced MPO-ANCA in a dose-dependent manner, which might be involved in the pathogenesis PTU-induced vasculitis.

Topics: Adult; Aged; Animals; Antibodies, Antineutrophil Cytoplasmic; Antimetabolites; Female; Granulomatosis with Polyangiitis; Haplorhini; Humans; Male; Middle Aged; Myeloblastin; Oxidation-Reduction; Peroxidase; Propylthiouracil; Vasculitis, Leukocytoclastic, Cutaneous

Clinical and experimental data indicate that anti-neutrophil cytoplasmic autoantibodies (ANCAs) cause glomerulonephritis and vasculitis. Here we report the first evidence that complement is an important mediator of ANCA disease. Transfer of anti-myeloperoxidase (MPO) IgG into wild-type mice or anti-MPO splenocytes into immune-deficient mice caused crescentic glomerulonephritis that could be completely blocked by complement depletion. The role of specific complement activation pathways was investigated using mice with knockout of the common pathway component C5, classic and lectin binding pathway component C4, and alternative pathway component factor B. After injection of anti-MPO IgG, C4-/- mice developed disease comparable with wild-type disease; however, C5-/- and factor B-/- mice developed no disease. To substantiate a role for complement in human ANCA disease, IgG was isolated from patients with myeloperoxidase ANCA (MPO-ANCA) or proteinase 3 ANCA (PR3-ANCA) and from controls. Incubation of MPO-ANCA or PR3-ANCA IgG with human neutrophils caused release of factors that activated complement. IgG from healthy controls did not produce this effect. The findings suggest that stimulation of neutrophils by ANCA causes release of factors that activate complement via the alternative pathway, thus initiating an inflammatory amplification loop that mediates the severe necrotizing inflammation of ANCA disease.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Cells, Cultured; Complement Pathway, Alternative; Disease Models, Animal; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Immunoglobulin G; Kidney; Mice; Mice, Knockout; Myeloblastin; Neutrophil Activation; Peroxidase

There are only a few reported cases about spinal cord involvement with Wegener's granulomatosis (WG) in the literature. In these cases, the spinal cord is usually indented or compressed by dural and meningeal masses which are characterized by necrotizing granuloma formation and vasculitis. And, it usually cannot be correctly diagnosed. A 53-year-old woman suffered from Wegener's granulomatosis, in whom the upper thoracic spinal cord compression is the initial manifestation. The surgical biopsy and thoracic laminectomy were performed and the histologic examination was done. This patient was finally diagnosed as WG when the pathologic examination revealed as Wegener's granulomatosis and the serum antineutrophil cytoplasmic antibodies (ANCA) were reported positive; titers of antimyeloperoxidase (MPO) antibodies were markedly elevated. After treatment with cyclophosphamide and corticosteroids this patient partially recovered from neurological involvement. In a case such as this, careful monitoring of clinical parameters is essential for assessing disease activity with repeated MRI if neurologic status changes. Serial measurement of ANCA titers may also be helpful to establish the diagnosis. Cyclophosphamide and corticosteroids are the agents of choice for induction of remission of WG.

Topics: Adrenal Cortex Hormones; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Biopsy; Cyclophosphamide; Dura Mater; Female; Fever; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Middle Aged; Paraparesis; Peroxidase; Spinal Cord; Spinal Cord Compression; Subdural Space; Thoracic Vertebrae; Treatment Outcome

In patients with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis, indirect immunofluorescence (IF) distinguishes between cytoplasmic (C-ANCA) and perinuclear (P-ANCA) neutrophil staining patterns. In patients with primary systemic vasculitis such as Wegener's granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome, these IF staining patterns correspond broadly with antibodies to the two major antigens: the C-ANCA pattern is associated generally with antibodies to serine protease 3 (PR3) and the P-ANCA pattern with antibodies to myeloperoxidase (MPO). However, some sera positive for ANCA by IF are negative for anti-PR3 and anti-MPO antibodies, suggesting the presence of antibodies to minor antigens of PMN granules. We tested sera from a previously well-defined clinical cohort of patients for antibodies to four possible minor antigens: bactericidal permeability increasing protein, elastase, cathepsin G and lactoferrin. IF-positive (+) sera had significantly higher antibody frequencies to the minor antigens than did the IF-negative (-) sera (P < 0.01). Patients with IF(+) PR3(-)MPO(-) sera showed the most varied reactivity to the minor antigens. Among the IF(+) groups, the IF(+) PR3(+)/MPO(-) sera showed the lowest reactivity to the minor antigens. Patients with well-defined ANCA specificities, e.g. the PR3-ANCA response associated with Wegener's granulomatosis, are less likely than are other patient subsets to have antibodies to minor antigen targets. Autoantibodies to these minor antigens contribute to the overall pattern of ANCA identified by IF and help to explain why the correlation between IF and enzyme immunoassays show discrepancies. While the pathophysiological significance of antibodies to minor target antigens needs further evaluation, they may be markers of inflammation associated with disease processes.

Topics: Antibodies, Antineutrophil Cytoplasmic; Antimicrobial Cationic Peptides; Autoantibodies; Autoantigens; Blood Proteins; Cathepsin G; Cathepsins; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique, Indirect; Granulomatosis with Polyangiitis; Humans; Membrane Proteins; Neoplasm Proteins; Peroxidase; Serine Endopeptidases; Vasculitis

Proteinase 3 (PR3), a serine proteinase contained in neutrophil azurophilic granules, is considered a risk factor for vasculitides and rheumatoid arthritis when expressed on the outer leaflet of neutrophil plasma membrane and is the preferred target of antineutrophil cytoplasm autoantibodies (ANCA) in Wegener granulomatosis. ANCA binding to PR3 expressed at the surface of neutrophils activates them. Evidence is provided that neutrophil apoptosis induced significantly more membrane PR3 expression without degranulation (but no enhanced membrane CD35, CD66b, CD63, myeloperoxidase, or elastase expression). This observation was confirmed on cytoplasts, a model of granule-free neutrophils. We hypothesized that PR3 could interact with proteins involved in membrane flip-flop (eg, phospholipid scramblase 1 [PLSCR1]). PR3-PLSCR1 interaction in neutrophils was demonstrated by confocal microscopy and coimmunoprecipitation. In the RBL-2H3 rat mast-cell line stably transfected with PR3 or its inactive mutant (PR3S203A), PR3 externalization depended on PLSCR1, as shown by less PR3 externalization in the presence of rPLSCR1 siRNA, but independently of its serine-proteinase activity. Finally, apoptosis-externalized PR3 decreased the human macrophage-phagocytosis rate of apoptotic PR3 transfectants. Therefore, in addition to ANCA binding in vasculitis, the proinflammatory role of membrane PR3 expression may involve interference with macrophage clearance of apoptotic neutrophils.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Antigens, CD; Apoptosis; Arthritis, Rheumatoid; Cell Line; Cell Membrane; Gene Expression Regulation, Enzymologic; Granulomatosis with Polyangiitis; Humans; Macrophages; Mast Cells; Mutation; Myeloblastin; Neutrophil Activation; Neutrophils; Pancreatic Elastase; Peroxidase; Phagocytosis; Phospholipid Transfer Proteins; Protein Transport; Rats; Risk Factors; RNA, Small Interfering; Secretory Vesicles; Vasculitis

Pulmonary-renal syndrome (PRS) is defined as a diffuse alveolar hemorrhage and rapidly progressive glomerulonephritis. We present a retrospective study of 22 consecutive patients with Wegener's granulomatosis (WG). Logistic regression analysis and a Wilcoxon test were included in the statistics. Survival time death risk were assessed using the Kaplan-Meier estimator and the Cox proportional hazard model. At recognition, the median Birmingham Vasculitis Activity Score for Wegener's Granulomatosis (BVAS/WG) was 30.0 (23.0-32.5), PO2 on air was 5.8+/-0.5 kPa, creatinine level was 7.2+/-1.4 mg/dl. Fifteen patients were PR3 positive, among them 4 patients were also positive for anti-glomerular basement membrane antibodies (anti-GBM). Renal biopsy was performed in 16 patients. Histological examination reviled segmental necrotizing crescentic GN in 15 patients. Thirteen patients were initially dialysis-dependent, and 7 required ventilatory support. All patients were treated with methylprednisolone and cyclophosphamide (pulses). The patients were followed up for 24+/-8 months. Of the survivors, 55% and 31% were alive after 1 and 2 years. Early recognition and proper treatment may improve outcome in PRS.

Topics: Adrenal Cortex Hormones; Adult; Aged; Anti-Glomerular Basement Membrane Disease; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Female; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Kidney Diseases; Lung Diseases; Male; Middle Aged; Myeloblastin; Peroxidase; Renal Dialysis; Survival Analysis

Macrophage migration inhibitory factor (MIF) is a central proinflammatory cytokine that regulates innate and adaptive immune responses. To evaluate its role in primary vasculitides, we determined MIF by enzyme-linked immunoassay in the sera of patients with Wegener's granulomatosis (WG; n=26), microscopic polyangiitis (MPA; n=10), polyarteritis nodosa (PAN; n=9) and giant cell arteritis (GCA; n=11). Healthy controls (n=26) and patients with sarcoidosis (n=14) were studied in parallel. Serum levels of MIF were significantly higher in patients with WG (median 41.1, range 3.2-120 ng/ml) than those in healthy controls (6.0, 0.015-36.5 ng/ml; P<0.001) and in patients with sarcoidosis (13.8, 0.015-67.1 ng/ml; P<0.05). MIF values were higher in MPA patients (29.5, 9.9-69.4 ng/ml; P<0.01) in comparison with those in healthy controls. In particular, increased levels of MIF were associated with active disease as assessed by the Birmingham Vasculitis Activity Score. Sequential studies showed decreased levels of MIF after initiation of immunosuppressive therapy, with clinical improvement in WG and MPA patients. In contrast, serum levels of MIF were not significantly elevated in patients with PAN and GCA. The results suggest that MIF contributes to the inflammatory process and correlates with disease activity in antineutrophil cytoplasmic antibody-associated vasculitides.

Topics: Adult; Aged; Antibodies, Antineutrophil Cytoplasmic; Giant Cell Arteritis; Granulomatosis with Polyangiitis; Humans; Macrophage Migration-Inhibitory Factors; Middle Aged; Myeloblastin; Peroxidase; Polyarteritis Nodosa; Reference Values; Sarcoidosis; Serine Endopeptidases; Vasculitis

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Creatinine; Granulomatosis with Polyangiitis; Humans; Peroxidase

Topics: Antibodies, Antineutrophil Cytoplasmic; Female; Granulomatosis with Polyangiitis; Humans; Incidence; Male; Myeloblastin; Pancreatic Elastase; Peroxidase; Sweden

Previous studies have shown considerable variation in diagnostic performance of enzyme linked immunosorbent assays (ELISAs) for measuring antineutrophil cytoplasmic antibodies (ANCA) specific for proteinase 3 (PR3) and myeloperoxidase (MPO).. To analyse the performance characteristics of different commercially available direct ANCA ELISA kits.. ELISA kits for detecting PR3-ANCA and MPO-ANCA from 11 manufacturers were evaluated. Serum samples were taken from patients with Wegener's granulomatosis (15), microscopic polyangiitis (15), other vasculitides (10), and controls (40).. were compared with data obtained by indirect immunofluorescence (IFT). The diagnostic performance of the tests was analysed and compared by receiver operating characteristic (ROC) curve analysis.Results: Applying the manufacturers' cut off resulted in great variation in sensitivity of the commercial PR3-ANCA kits for diagnosing Wegener's granulomatosis (ranging from 13.3% to 66.7%), and of the MPO-ANCA kits for diagnosing microscopic polyangiitis (ranging from 26.7% to 66.7%). Specificities were relatively constant (from 96.0% to 100%). IFT was superior to all ELISAs (C-ANCA for Wegener's granulomatosis: sensitivity 73.3%, specificity 98%; P-ANCA for microscopic polyangiitis: sensitivity 86.7%, specificity 98%). The sensitivities of PR3-ANCA and MPO-ANCA ELISA kits were increased by lowering the cut off values. This reduced specificity but increased overall diagnostic performance.. The low sensitivity of some commercial kits reflects the high cut off levels recommended rather than methodological problems with the assays. Comparative analyses using sera from well characterised patients may help identify optimum cut off levels of commercial ANCA ELISA tests, resulting in better comparability of results among assays from different manufacturers.

Topics: Adult; Aged; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Enzyme-Linked Immunosorbent Assay; Epidemiologic Methods; Female; Fluorescent Antibody Technique, Direct; Granulomatosis with Polyangiitis; Humans; Male; Middle Aged; Myeloblastin; Peroxidase; Reagent Kits, Diagnostic; Serine Endopeptidases; Vasculitis

In this study we have evaluated a new, fully automated fluorescent-enzyme immuno-assay (FEIA) for detection and quantification of anti-PR3 and anti-MPO ANCA in diagnosis and follow-up of ANCA-associated small vessel vasculitis (AAV). PR3- and MPO-ANCA were determined by FEIA technology in (1) sera of 87 consecutive patients with biopsy-proven, pauci-immune necrotizing crescentic glomerulonephritis (NCGN) and 72 controls; (2) 120 sera (60 patients with Wegener's granulomatosis and 60 controls) that were previously used in a multicentre comparison of direct and capture ELISAs for PR3-ANCA; (3) in samples preceding relapse in 23 PR3-AAV patients with and 23 matched PR3-AAV patients without relapse for prediction of relapses. PR3- and/or MPO-ANCA detection in pauci-immune NCGN by FEIA revealed an overall sensitivity of 82.8%. The FEIA specificity was 96% and 100% for PR3- and MPO-ANCA, respectively. The overall sensitivity of MPO- and PR3-ANCA could be increased to 88.5% by lowering the cut-off values without affecting the specificity (ROC-curve analysis), which is similar to a multistep ANCA procedure that combines indirect immunofluorescence with direct and capture ELISAs. The sensitivity for Wegener's granulomatosis (WG) of the PR3-ANCA FEIA (60%) was more comparable to direct ELISAs (64%) than to capture ELISAs (74%). A rise of 100% in ANCA level as measured by FEIA appeared optimal (ROC-curve) for prediction of relapses and such a rise was observed in 26 patients. In 18 of these 26 patients the rise was followed by a relapse (PPV 69%), whereas in 15 of the 20 patients without a rise no relapse was observed (NPV 75%). In conclusion, detection of PR3- and MPO-ANCA by FEIA has excellent performance in terms of diagnosis of AAV patients. Furthermore, detection of rises in PR3-ANCA by FEIA for prediction of relapses gives results comparable to other techniques.

Topics: Adult; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Male; Middle Aged; Myeloblastin; Peroxidase; Predictive Value of Tests; Recurrence; Sensitivity and Specificity; Serine Endopeptidases; Vasculitis

The value of anti-neutrophil cytoplasmic antibody (ANCA) detection for monitoring disease activity in ANCA-associated systemic vasculitis (AASV) remains controversial. The aim of our work was to rate the performance of a new automated fluorescence PR3 and MPO-ANCA immunoassay (EliA) for monitoring disease activity in AASV. We evaluated 100 serum samples from 71 AASV patients (with Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome) as well as sera from 58 pathological and 35 normal controls. In addition to PR3 and MPO-ANCA EliA, we performed indirect immunofluorescence and "homemade" PR3 and MPO-ANCA ELISA tests. In AASV patients, ANCA levels were correlated with disease activity, according to the Birmingham Vasculitis Activity Score (BVAS). We derived cutoff limits from receiver operating characteristic (ROC) curve analysis comparing AASV with pathological controls. Our results showed that EliA and ELISA had comparable sensitivity (76%) and specificity (95%). The analysis of active versus inactive status and correlation with ANCA levels showed a clear difference between BVAS Group I (score < or = 4) and BVAS Group II (scores > 4) (AUC = 0.86 vs. 0.72; relative risk [RR] = 2.4; P < 0.0001) for PR3-ANCA, but not for MPO-ANCA (AUC = 0.94 vs. 0.87; RR = 1.48; P = 0.46). Serial serum samples from 16 patients were examined in detail. For the majority of patients, for both PR3 and MPO-ANCA, change in titer was strongly associated with change in BVAS score. Our data showed a good correlation between ANCA titer (especially for PR3) and AASV disease activity. We recommend that ANCA titer be used to monitor AASV disease activity with the caveat that a few exceptions, in particular with MPO-ANCA, are possible.

Topics: Antibodies, Antineutrophil Cytoplasmic; Case-Control Studies; Churg-Strauss Syndrome; Enzyme-Linked Immunosorbent Assay; Evaluation Studies as Topic; Fluoroimmunoassay; Granulomatosis with Polyangiitis; Humans; Peroxidase; Predictive Value of Tests; Reagent Kits, Diagnostic; Retrospective Studies; Risk; ROC Curve; Sensitivity and Specificity; Vasculitis

Wegener's granulomatosis (WG) is being increasingly diagnosed in India, which exists in two forms, the 'limited Wegener's granulomatosis' (LWG) having upper respiratory tract (URT) and lower respiratory tract (LRT) involvement and the 'classical Wegener's granulomatosis' (CWG), with the triad of URT, LRT involvement along with kidney involvement. Cytoplasmic ANCA (C-ANCA) or anti-Proteinase3 (anti-PR3), which is highly diagnostic for WG, rarely perinuclear ANCA (P-ANCA) may exist.. To detect anti-neutrophil cytoplasmic antibodies (ANCA) and correlate it with serological, hematological parameters, and the Birmingham Vasculitis Activity Score (BVAS).. Twenty-three clinically and histopathologically proven WG (16 CWG, 7 LWG) were studied.. C-ANCA and P-ANCA patterns were identified by immunofluorescence and specificities were confirmed by 'alpha granule' enzyme linked immunosorbent assay (ELISA), anti-PR3, anti-MPO (myeloperoxidase) and anti-Lactoferrin (anti-LF) by ELISA.. LRT involvement was seen in 91.3%, URT in 78.3%, and renal manifestations in 69.6% cases. The BVAS in CWG was significantly higher than BVAS in the LWG. Decreased hemoglobin, increased WBC counts, ESR, CRP and Creatinine were seen in CWG as compared to LWG. The C-ANCA was present in 65.2% patients and P-ANCA in 13% cases. Anti-PR3 was seen in 69.6% patients and anti-LF in 17.4% cases. Severity of disease and ANCA was higher in CWG than in LWG.. Vasculitis syndromes are known to overlap and many go undetected; therefore ANCA testing, along with the clinical and histopathological observations may be helpful in early detection and management of WG cases.

Topics: Antibodies, Antineutrophil Cytoplasmic; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique, Indirect; Granulomatosis with Polyangiitis; Humans; Lactoferrin; Male; Myeloblastin; Peroxidase; Serine Endopeptidases

Clinical and serological profiles of idiopathic and drug-induced autoimmune diseases can be very similar. We compared data from idiopathic and antithyroid drug (ATD)-induced antineutrophil cytoplasmic antibody (ANCA)-positive patients. From 1993 to 2003, 2474 patients were tested for ANCA in the Laboratory for Allergy and Clinical Immunology in Belgrade. Out of 2474 patients, 72 (2.9%) were anti-proteinase 3 (PR3)- or anti-myeloperoxidase (MPO)-positive and their clinical and serological data were analyzed. The first group consisted of ANCA-associated idiopathic systemic vasculitis (ISV) diagnosed in 56/72 patients: 29 Wegener's granulomatosis (WG), 23 microscopic polyangiitis (MPA) and four Churg-Strauss syndrome. The second group consisted of 16/72 patients who became ANCA-positive during ATD therapy (12 receiving propylthiouracil and four receiving methimazole). We determined ANCA and antinuclear (ANA) antibodies by indirect immunofluorescence; PR3-ANCA, MPO-ANCA, anticardiolipin (aCL) and antihistone antibodies (AHA) by ELISA; and cryoglobulins by precipitation. Complement components C3 and C4, alpha-1 antitrypsin (alpha1 AT) and C reactive protein (CR-P) were measured by nephelometry. Renal lesions were present in 3/16 (18.8%) ATD-treated patients and in 42/56 (75%) ISV patients (p <0.001). Skin lesions occurred in 10/16 (62.5%) ATD-treated patients and 14/56 (25%) ISV patients (p <0.01). ATD-treated patients more frequently had MPO-ANCA, ANA, AHA, aCL, cryoglobulins and low C4 (p <0.01). ISV patients more frequently had low alpha1 AT (p = 0.059) and high CR-P (p <0.001). Of 16 ATD-treated patients, four had drug-induced ANCA vasculitis (three MPA and one WG), while 12 had lupus-like disease (LLD). Of 56 ISV patients, 13 died and eight developed terminal renal failure (TRF). There was no lethality in the ATD-treated group, but 1/16 with methimazole-induced MPA developed pulmonary-renal syndrome with progression to TRF. ANCA-positive ISV had a more severe course in comparison with ATD-induced ANCA-positive diseases. Clinically and serologically ANCA-positive ATD-treated patients can be divided into two groups: the first consisting of patients with drug-induced WG or MPA which resemble ISV and the second consisting of patients with LLD. Different serological profiles could help in the differential diagnosis and adequate therapeutic approach to ANCA-positive ATD-treated patients with symptoms of systemic disease.

Topics: Adolescent; Adult; Aged; Antibodies, Antineutrophil Cytoplasmic; Antibody Specificity; Antithyroid Agents; Autoantigens; Autoimmune Diseases; Churg-Strauss Syndrome; Cyclophosphamide; Female; Fluorescent Antibody Technique, Indirect; Follow-Up Studies; Granulomatosis with Polyangiitis; Graves Disease; Hashimoto Disease; Humans; Hyperthyroidism; Immunoprecipitation; Kidney; Lung; Male; Methimazole; Middle Aged; Myeloblastin; Nephelometry and Turbidimetry; Peroxidase; Polyarteritis Nodosa; Prednisone; Pregnancy; Pregnancy Complications; Propylthiouracil; Retrospective Studies; Serine Endopeptidases; Skin; Vasculitis; Vasculitis, Leukocytoclastic, Cutaneous

Cytoplasmic antineutrophil cytoplasmic autoantibodies (cANCA)/proteinase-3(PR3)-ANCA was considered the serologic diagnostic marker for Wegener's granulomatosis (WG). However, Chinese patients with MPO-ANCA positive WG were frequently diagnosed. We now analyze the characteristics of patients with MPO-ANCA positive WG and investigate the difference between patients with MPO-ANCA and PR3-ANCA.. Patients with WG were selected according to both Chapel Hill Consensus Conference definition and American College of Rheumatology (ACR) classification criteria in 500 Chinese patients with ANCA-associated systemic vasculitides. The clinical manifestions were compared between patients with MPO-ANCA and with PR3-ANCA.. Eight-nine patients fulfilled the diagnostic criteria of WG: 54/89(60.7%) were MPO-ANCA positive, 34/89(38.2%) were PR3-ANCA positive. Patients with MPO-ANCA were predominantly female compared with patients with PR3-ANCA. Patients with MPO-ANCA also had multisystem involvement. However, the prevalences of arthagia, skin rash, ophthalmic and ear involvement were significantly lower in patients with MPO-ANCA than those in patients with PR3-ANCA (46.3% vs. 70.6%, P < 0.05; 20.4% vs. 44.1%, P < 0.05; 27.8% vs. 58.8%, P < 0.01; 40.7% vs. 67.6%, P < 0.05, respectively). The prevalence of elevated initial serum creatinine was significantly higher in patients with MPO-ANCA than that in patients with PR3-ANCA (81.5% vs. 61.8%, chi(2) = 4.20, P < 0.05).. Patients with MPO-ANCA positive WG were not rare in Chinese.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Asian People; Child; Child, Preschool; Ear Diseases; Eye Diseases; Female; Granulomatosis with Polyangiitis; Humans; Kidney Diseases; Male; Middle Aged; Myeloblastin; Peroxidase; Pulmonary Fibrosis; Retrospective Studies; Serine Endopeptidases; Seroepidemiologic Studies; Sinusitis

Autoantibodies against proteinase 3 (PR3) and myeloperoxidase (MPO) (ANCA = anti-neutrophil cytoplasmic antibodies) are used as diagnostic tools for patients with small vessel vasculitis. ANCA are detected by different assays, but the correlation between the results of these assays is generally poor. The overall aim of the study was to provide a framework for the future development of new assays with an increased diagnostic yield. In order to express discrete epitopes of human PR3 (hPR3), the nonantigenic molecules murine PR3 (mPR3) and human leucocyte elastase (HLE) were used as a framework. We constructed recombinant chimeric vectors and were able to produce 6 hPR3/mPR3 proteins and 3 hPR3/HLE proteins. Anti-PR3 monoclonal antibodies differed in their binding pattern to the chimeras, but no distinct binding region could be identified for any monoclonal antibody. The recombinant hPR3/mPR3 were also tested in ELISA with sera from patients with Wegener's granulomatosis with renal involvement. The results show that patients have antibodies to different constructs, indicating that the patients vary in their antibody repertoire from the beginning of the disease, and that patients may have antibodies from a broad range of clones early in the course of the disease. Recombinant hPR3/mPR3 chimeric proteins have a potential to be used as antigens in future ANCA assays.

Topics: Amino Acid Sequence; Animals; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal; Autoantibodies; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Epitope Mapping; Genetic Vectors; Granulomatosis with Polyangiitis; Humans; Leukocyte Elastase; Mice; Molecular Sequence Data; Myeloblastin; Peroxidase; Recombinant Fusion Proteins; Recombinant Proteins; Serine Endopeptidases; Transfection

The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides are a group of heterogeneous diseases. This study was undertaken to investigate the outcome of Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and renal-limited vasculitis (RLV). Furthermore, we analysed the differences in patients with proteinase 3-ANCA (PR3-ANCA) and those with myeloperoxidase-ANCA (MPO-ANCA), which have not been assessed in a homogeneously treated group of patients with renal involvement.. In this retrospective analysis, 80 patients with a new diagnosis of WG, MPA or RLV with biopsy-proven renal involvement were followed over a median of 46.7 months (range: 0.8-181.9 months). All patients had induction treatment with cyclophosphamide and oral corticosteroids.. At the end of follow-up, 23% were dependent on dialysis. Renal survival was significantly worse in patients with WG compared with patients with MPA or RLV (P = 0.04). A higher rate of end-stage renal disease (ESRD) was noticed in PR3-ANCA- vs MPO-ANCA-positive patients. A total of 21 patients (26%) died. Predictors of patient mortality were development of ESRD, older age and the maximum creatinine in the first month. Mortality was found to be higher in patients with WG and was significantly higher in PR3-ANCA-positive cases (P = 0.02). The relative risk of death was 9.32 times higher in PR3-ANCA- vs MPO-ANCA-positive patients.. Our data underscore the pathogenetic potential of ANCA by demonstrating a more aggressive disease state and a poorer outcome in patients with PR3-ANCA.

Topics: Antibodies, Antineutrophil Cytoplasmic; Cyclophosphamide; Glucocorticoids; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Multivariate Analysis; Myeloblastin; Peroxidase; Prognosis; Retrospective Studies; Serine Endopeptidases; Survival Analysis; Treatment Outcome; Vasculitis

The detection rate of antineutrophil cytoplasmic antibodies (ANCA) in Chinese patients with clinically suspected small vessel vasculitis was investigated, and their antigen specificity and demographic features were analyzed. A number of sera (n = 5,604) sent to our referral laboratory for ANCA screening were tested by indirect immunofluorescence (IIF), enzyme-linked immunosorbent assays (ELISAs) for myeloperoxidase (MPO)- and proteinase 3 (PR3)-ANCA. Then the IIF-ANCA-positive sera that were negative for MPO- and PR3-ANCA were further tested by antigen-specific ELISA by using other five highly purified known ANCA antigens as solid-phase ligands. The known antigens included bactericidal/permeability-increasing protein (BPI), human leukocyte elastase (HLE), lactoferrin, cathepsin G, and azurocidins. Of the 5,604 sera, 267 (4.76%) sera were IIF-ANCA positive and 390 (7%) were antinuclear antibody (ANA) positive in the IIF assay. Of the IIF-positive samples, 213 were anti-MPO positive, 32 were anti-PR3 positive, and five cases were positive for both. Of the 48 sera positive for IIF-ANCA but negative for MPO- and PR3-ANCA, 13 sera (27%) recognized other target antigens, 7 sera recognized BPI, 5 recognized HLE, 1 recognize cathepsin G, and 1 recognized azurocidin. None of the sera recognized lactoferrin, and one serum sample recognized both BPI and HLE. The majority of ANCA-positive patients presented in summer or winter. There was no difference in gender (male/female ratio, 1:1.12) in ANCA-positive patients with a mean age of 53.1 years. The male/female ratio was 1.17:1 for patients over 60 years of age; however, it was 1:4 for patients under 20 years of age. We conclude that ANCA-related diseases are not rare in China, and the major antigens are MPO and PR3. When the IIF technique is used to detect ANCA, ANA should be carefully distinguished.

Topics: Adolescent; Adult; Aged; Anemia, Hemolytic; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Antinuclear; Antibody Specificity; Antimicrobial Cationic Peptides; Autoantibodies; Blood Proteins; Cathepsin G; Cathepsins; Child; China; Colitis, Ulcerative; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique, Indirect; Granulomatosis with Polyangiitis; Humans; Lactoferrin; Leukocyte Elastase; Male; Membrane Proteins; Middle Aged; Myeloblastin; Peroxidase; Seasons; Serine Endopeptidases; Sex Factors; Vasculitis

A characteristic feature of Wegener's granulomatosis is the presence of antineutrophil cytoplasm antibodies (ANCA) to proteinase 3 (PR3). In vitro, ANCA activate neutrophils by co-ligating PR3 and FcgammaRIIa/IIIb receptors. ANCA are predominantly of the IgG isotype, and IgG1, IgG3 and IgG4 subclasses are particularly represented. To address the pathogenic role of individual ANCA-IgG subclass antibodies, patients' sera were screened using indirect immunofluorescence, enzyme-linked immunosorbent assay (ELISA) and subclass PR3-ELISA to identify patients with high titres of PR3-ANCA within the IgG1, IgG3 or IgG4 subclasses. Unfractionated ANCA-IgG and subclass fractions were isolated by affinity chromatography and compared for their capacities to stimulate superoxide production by primed human neutrophils. Donor neutrophils were analysed for constitutive and induced FcgammaRI expression by flow cytometry. The IgG1, IgG3 and IgG4 subclass fractions, isolated from three different ANCA sera, each stimulated superoxide production from neutrophils derived from multiple donors. Subsequently, IgG4 subclass fractions isolated from a further four ANCA positive sera demonstrated varying abilities to stimulate release of superoxide; unrelated to PR3-ANCA titre, neutrophil donor, or neutrophil FcgammaRI expression. The stimulation of superoxide release by IgG1- and IgG3-ANCA subclass fractions is consistent with the proposed mechanism of co-ligation of PR3 antigen and FcgammaRIIa/IIIb receptors. However, the demonstration of similar activity for the IgG4-ANCA subclass fractions isolated from some sera was unexpected. This activity was independent of neutrophil donor and expression of FcgammaRI, suggesting it was capable of activating neutrophils via constitutively expressed FcgammaRIIa/IIIb or co-ligation of other, unidentified, cell surface molecules.

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Antibody Affinity; Autoantigens; Cells, Cultured; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique, Indirect; Granulomatosis with Polyangiitis; Humans; Immunoglobulin G; Interferon-gamma; Male; Middle Aged; Myeloblastin; Neutrophil Activation; Neutrophils; Peroxidase; Receptors, IgG; Serine Endopeptidases

Anti-proteinase 3 antineutrophil cytoplasmic antibodies (PR3-ANCA) and anti-myeloperoxidase antibodies (MPO-ANCA) are considered important serological markers for several forms of idiopathic systemic vasculitis. The aim of the study was to verify the analytical and clinical performance of a new automated enzyme fluoroimmunoassay, the EliA system, for PR3-ANCA and MPO-ANCA detection. For this purpose the sera of 52 consecutive well-defined patients with a clinical diagnosis of Wegener's granulomatosis (WG) (n=29) or microscopic polyangiitis (MPA) (n=23), and 70 controls suffering from connective tissue disease (25 systemic lupus erythematosus, 25 Sjögren's syndrome and 20 rheumatoid arthritis) were tested for PR3-ANCA and MPO-ANCA with the EliA assay (Pharmacia Diagnostics, Freiburg, Germany). For comparison purposes, the same sera were also tested by indirect immunofluorescence, another direct immunometric assay (Varelisa, Pharmacia Diagnostics) and a capture PR3-ANCA (Wieslab AB, Lund, Sweden) method. Both the EliA PR3-ANCA and MPO-ANCA assays showed between- and within-assay precision of <10%. The dilution test gave straight lines (r2=0.998) for both antibody assays. The recovery ranged from 97.9% to 102.7% for PR3-ANCA and from 84.9% to 91.4% for MPO-ANCA. There was a high positive correlation between the EliA and Varelisa methods for quantitative detection of MPO-ANCA levels (r2=0.949) and a lower correlation for PR3-ANCA (r2=0.771). Conversely, poor correlation was observed between EliA PR3-ANCA and capture PR3-ANCA (r2=0.537). The overall sensitivity and specificity of EliA PR3-ANCA and MPO-ANCA for the vasculitides considered in this study were 82.7% and 97.2%, respectively, with a positive predictive value of 96.6% and a negative predictive value of 84.9%. Comparison of the results obtained with the indirect immunofluorescence, Varelisa and capture PR3-ANCA methods showed that the indirect immunofluorescence assay is the most sensitive method for the diagnosis of vasculitis (88.5%), but the least specific (94.3%); the EliA method is slightly more specific (97.2%) than the Varelisa method (95.7%), and also slightly more sensitive (82.7% vs. 80.8%). Capture PR3-ANCA proved to be the most sensitive method for detection of anti-proteinase 3 antibodies in WG (89.7% vs. 86.2% EliA and 79.3% Varelisa). In conclusion, the EliA MPO-ANCA and PR3-ANCA methods provide good diagnostic accuracy and excellent analytical accuracy, which, in association with the p

Topics: Adult; Aged; Antibodies, Antineutrophil Cytoplasmic; Connective Tissue Diseases; Diagnosis, Differential; Enzyme-Linked Immunosorbent Assay; Female; Fluoroimmunoassay; Granulomatosis with Polyangiitis; Humans; Male; Middle Aged; Peroxidase; Reagent Kits, Diagnostic; Sensitivity and Specificity; Vasculitis

Anti-neutrophil cytoplasmic antibodies (ANCA) are the immunodiagnostic markers for idiopathic necrotizing crescentic glomerulonephritis affecting mainly medium to small sized blood vessels. The diagnosis of ANCA associated vasculitis (AAV) is mainly based on clinical and histopathological characteristics along with the serological evidence. Immunofluorescence microscopy (IIF) is considered as the "gold standard" for ANCA detection, and ANCA showing two major patterns ie, cytoplasmic (c-ANCA) and perinuclear (p-ANCA) react with different antigenic targets of neutrophils like Proteinase3 (PR3) and Myeloperoxidase (MPO). A third unusual and rare immunofluorescence pattern called as "X- ANCA" or atypical ANCA is also sometimes seen. The difficulty in identification of ANCA immunofluorescence patterns is mainly seen due to the rare dual patterns seen in the same sera and also the additional nuclear immunofluorescence seen due to presence of anti-nuclear antibodies. ANCA testing by immunofluorescence and Confocal Laser scanning microscopy, as well as by specific ELISAs for detection of anti-PR3 and anti-MPO antibodies have helped in improving the diagnosis. Patients having dual specificities to MPO and PR3 in a patient is a rare finding. Among 425 clinically and histopathologically proven cases of AAV, eight patients (1.9%) had dual specificities, of which five patients showed mixed immunofluorescence pattern and 3 patients showed X-ANCA pattern which was confirmed by both immunofluorescence and Confocal Laser scanning microscopy and the dual specificities to MPO and PR3 were detected by individual ELISAs.

Topics: Adolescent; Adult; Aged; Anti-Glomerular Basement Membrane Disease; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Antinuclear; Antibody Specificity; Binding, Competitive; DNA; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Granulomatosis with Polyangiitis; Humans; Lupus Nephritis; Male; Microscopy, Confocal; Middle Aged; Myeloblastin; Neutrophils; Peroxidase; Serine Endopeptidases; Vasculitis

The major antigen specificities of antineutrophil cytoplasmic antibodies (ANCA) are for proteinase 3 (PR3) and myeloperoxidase (MPO). Only a limited number of studies have systematically assessed renal pathology with respect to ANCA antigen specificity.. The authors evaluated renal biopsy light microscopy and immunofluorescence findings, clinical presentation, and outcome in 135 patients with ANCA-associated vasculitides.. Patients were divided into 3 groups: PR3-ANCA (n = 55), MPO-ANCA (n = 74), and ANCA of other specificities (n = 6). The mean duration of renal disease at biopsy was significantly longer in patients with MPO-ANCA than in those with PR3-ANCA (6.9 v 3.0 months). Immunofluorescence results showed mostly pauci-immune glomerulonephritis (n = 129) and rarely diffuse granular glomerular immune deposits suggesting immune complex deposition (n = 6). A focal form of crescentic glomerulonephritis was more frequent (P < 0.001), and glomerular necrosis was more prominent (P = 0.013) in the PR3-ANCA group, whereas diffuse crescentic glomerulonephritis, glomerulosclerosis, and interstitial fibrosis predominated in the MPO-ANCA group (P < 0.001). Extraglomerular vasculitis, present in 22.2%, and chronic vascular lesions indicative of previous vasculitis, present in 11.9% of patients, correlated with systemic involvement.. The evolution of the pathologic lesions of PR3-ANCA and MPO-ANCA-associated glomerulonephritis seems to be similar. Differences in histopathology could be explained by the observation that in patients with PR3-ANCA, kidney biopsy was performed soon after renal involvement appeared, and focal active lesions were prevalent, whereas in patients with MPO-ANCA, kidney biopsy was done late in the course of the disease, and diffuse chronic sclerotic lesions predominated. Renal extraglomerular small vessel vasculitis appeared to be predictive of systemic involvement.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Antibody Specificity; Autoantibodies; Child; Churg-Strauss Syndrome; Female; Fluorescent Antibody Technique, Indirect; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Immunohistochemistry; Kidney; Kidney Diseases; Male; Middle Aged; Myeloblastin; Peroxidase; Serine Endopeptidases; Treatment Outcome; Vasculitis

A 49 year old woman was admitted because of general poor health condition having lasted for 15 days and been associated for 6 months with sinusitis. During hospitalisation, she developed thrombosis of the retina central artery and signs of cerebral vasculitis. A diagnosis of Wegener disease was suggested based on one side on the presence of multiple excavated pulmonary macronodules and, on the other side, on the signs of cerebral vasculitis. No renal dysfunction was documented in our patient. The detection of serum antineutrophil antibodies (c-ANCA and anti-PR3) confirmed the diagnosis of Wegener disease without the need of surgical pulmonary biopsy. In addition to the typical ENT and pulmonary symptoms, this particular clinical presentation of unusual ocular and cerebral symptoms, reminds us that Wegener disease is a vasculitis that can give multisystemic disorders.

Topics: Antibodies, Antineutrophil Cytoplasmic; Female; Granulomatosis with Polyangiitis; Humans; Lung; Middle Aged; Peroxidase; Retinal Artery Occlusion; Vasculitis, Central Nervous System

Antineutrophil cytoplasmic Abs (ANCA) can activate neutrophils in an FcgammaR-dependent manner, but the link between this ANCA-induced effect and mononuclear cell activation with the characteristic granuloma formation of Wegener's granulomatosis is unclear. Human alpha-defensins, small cationic antimicrobial peptides, are found in neutrophils and have chemotactic activity for T cells, dendritic cells, and monocytes. In this study, we quantitated the release of alpha-defensins (human neutrophil peptides 1-3) from human neutrophils after targeted FcgammaR cross-linking (XL). Homotypic XL of FcgammaRIIa, FcgammaRIIIb, or heterotypic XL of both receptors resulted in significant release of alpha-defensins, an effect also induced by both human polyclonal and murine monoclonal cytoplasmic staining ANCA (anti-proteinase 3). This release of alpha-defensins, as well as of other granule constituents (ANCA targets anti-proteinase 3 and myeloperoxidase and elastase), was significantly greater in donors homozygous for the NA1 allele of FcgammaRIIIb than in donors homozygous for NA2. Interestingly, the ANCA-induced release was completely inhibited by the IgG Fc-binding peptide TG19320, which blocks the IgG-Fc region from binding to FcgammaR. Based on their chemotactic properties, alpha-defensins and their release by ANCA may contribute to modulation of the acquired immune response and to granuloma formation. The greater activity of the FcgammaRIIIB-NA1 genotype may also explain the greater severity of disease and its flare-ups in patients with this allele.

Topics: Alleles; alpha-Defensins; Antibodies, Antineutrophil Cytoplasmic; Antigens, CD; Chemotactic Factors; Cross-Linking Reagents; Cytoplasmic Granules; GPI-Linked Proteins; Granulomatosis with Polyangiitis; Humans; Myeloblastin; Neutrophils; Pancreatic Elastase; Peroxidase; Receptors, IgG; Serine Endopeptidases

To evaluate the performance of 11 commercial enzyme-linked immunosorbent assay (ELISA) kits for the detection of antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3) and myeloperoxidase (MPO) in patients with Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA).. Serum samples were taken from 92 patients with a histological and clinical diagnosis of WG (n=50) or MPA (n=42) and from 30 disease controls (systemic lupus erythematosus, n=15; rheumatoid arthritis, n=15) and 30 healthy controls. Each of the sera was tested for the presence of ANCA directed against PR3 and MPO using 11 commercially available direct ELISA kits, our in-house PR3- and MPO-ANCA capture ELISAs, and the indirect immunofluorescence technique (IFT).. In tests for WG using PR3-ANCA, the commercial direct ELISA kits differed widely in their sensitivity (from 22 to 70%) and negative predictive value (NPV) (from 43 to 70%), but only moderately in their specificity (from 93 to 100%) and positive predictive value (PPV) (from 93 to 100%). The highest sensitivity (74%) and specificity (100%) for PR3-ANCA were obtained with the in-house capture ELISA. Similar differences and trends were noted for MPO-ANCA assays. Diagnostic sensitivity was more than 60% for four and at least 50% for six of the 11 ELISA kits. The PPV varied from 84 to 100% and the NPV from 58 to 70%. In tests for MPA, the MPO-ANCA ELISA kit designated F and the in-house capture ELISA were best (both had sensitivity 62% and specificity 100%). For both WG and MPA, maximum sensitivity for ANCA was obtained with IFT (80 and 70% respectively).. Determination of PR3-ANCA and MPO-ANCA with the commercial direct ELISA kits achieved poor sensitivity for both WG and MPA. The in-house PR3 and MPO-ANCA capture ELISAs performed better than the commercial ELISAs, combining higher specificity with similar sensitivity. IFT remains the best method for ANCA detection in both diseases.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique, Indirect; Granulomatosis with Polyangiitis; Humans; Male; Middle Aged; Myeloblastin; Peroxidase; Predictive Value of Tests; Reagent Kits, Diagnostic; Reference Values; ROC Curve; Sensitivity and Specificity; Serine Endopeptidases; Vasculitis

To compare the clinical and pathological manifestations of patients with antineutrophil cytoplasmic autoantibodies (ANCA) directed against proteinase 3 (anti-PR3) or myeloperoxidase (anti-MPO).. One hundred and forty patients with ANCA were detected for anti-PR3 and anti-MPO by ELISA. The clinical features at presentation, histopathological characteristics and outcome of all patients who were tested positive for anti-PR3 or anti-MPO were analysed.. In anti-PR3 group (n = 21), 16 cases (76.2%) had systemic vasculitis, in which Wegener's granulomatosis prevailed (13 cases, 61.9%). In anti-MPO group (n = 31), 19 cases (61.3%) were diagnosed as systemic vasculitis and 12 cases (38.7%) as microscopic angiitis. For vasculitic patients with anti-PR3 and anti-MPO, the disease duration at diagnosis was 9.6 +/- 2.0 m and 4.4 +/- 0.9 m respectively, P < 0.05; vasculitis activity index (BVAS) and mean number of affected organ were 22.5 +/- 2.1, 5.0 +/- 0.4 and 25.1 +/- 1.7, 4.8 +/- 0.4 respectively, P > 0.05; upper respiratory tract, eye and joint involvements were 11(68.8%), 7(43.8%), 11(68.8%) and 7(36.8%), 2(10.5%), 5(26.3%) respectively, P < 0.05. Although there was no statistical difference in renal involvement between these two groups, patients with serum creatine > 500 micromol/L were more commonly seen in anti-MPO group than in anti-PR3 group, which were 8(42.1%) and 2(12.5%) respectively, P < 0.05. Ten relapses were seen in anti-PR3 group and only 2 in anti-MPO group, but the acute mortality rate in anti-MPO group (5/19, 27.4%) was much higher than that in anti-PR3 group (1/16, 6.3%).. Anti-PR3 and anti-MPO occurred mainly in systemic vasculitis. A large divergence was seen in the disease spectrum between patients with anti-PR3 and those with anti-MPO. In particular, upper respiratory tract, eye and joint involvements, granuloma formation and relapse were more prominent in anti-PR3 patients. By contrast, the anti-MPO patients had a more acute disease onset, more rapid progressive renal involvement and a higher acute mortality rate.

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Follow-Up Studies; Granulomatosis with Polyangiitis; Humans; Immunosuppressive Agents; Kidney; Myeloblastin; Peroxidase; Respiratory System; Serine Endopeptidases; Vasculitis

Differences in renal histopathology between microscopic polyangiitis (MPA) and Wegener's granulomatosis (WG), and between anti-neutrophil cytoplasm autoantibody (ANCA) test results in patients with ANCA-associated vasculitis may provide insight into the differences in pathogenesis and raise the opportunity of classifying the vasculitides more accurately. The possible differences in histopathology are investigated in this study.. We report an analysis of 173 patients with renal disease in microscopic polyangiitis or Wegener's granulomatosis. A total of 173 renal biopsies, performed at diagnosis, were scored by two observers separately, using a previously standardized protocol. Consensus on each biopsy was achieved during a central review.. Normal glomeruli were more common in WG than in MPA (P < 0.001). Glomerulosclerosis was more prominent in MPA than in WG (P=0.003). Interstitial fibrosis (P < 0.001), tubular atrophy (P < 0.001), and tubular casts (P=0.005) were more frequently present and more severe in MPA than in WG. Presence of glomerulosclerosis was more extensive in patients with myeloperoxidase (MPO)-ANCA than with proteinase 3 (PR3)-ANCA (P=0.022). Interstitial fibrosis (P=0.008), tubular necrosis (P=0.030), tubular atrophy (P=0.013), and intra-epithelial infiltrates (P=0.006) were more frequently present and more severe in MPO-ANCA than in PR3-ANCA.. Glomerulonephritis in relation to MPA has more characteristics of chronic injury at the time of presentation than glomerulonephritis in relation to WG. This difference may be due to a delayed establishment of diagnosis in patients with MPA compared to patients with WG. Both active and chronic lesions are more abundantly present in MPO-ANCA-positive patients than in patients with PR3-ANCA-positivity, which suggests that the pathogenesis of renal disease in these ANCA subsets could be different. Our results also suggest that ANCA test results may be useful in classifying ANCA-associated vasculitides.

Topics: Antibodies, Antineutrophil Cytoplasmic; Antibody Specificity; Biopsy; Diagnosis, Differential; Enzyme-Linked Immunosorbent Assay; Granulomatosis with Polyangiitis; Humans; Kidney; Myeloblastin; Peroxidase; Sample Size; Serine Endopeptidases; Serologic Tests

Wegener's granulomatosis, microscopic polyangiitis, and Churg Strauss syndrome are forms of systemic vasculitides in which neutrophils and monocyte macrophages infiltrate the walls of small blood vessels, leading to destruction and occlusion. These diseases are associated with autoantibodies directed against granular components of neutrophils and monocytes, i.e., antineutrophil cytoplasmic antibodies (ANCA). The most common target antigens of ANCA in these vasculitides are myeloperoxidase (MPO) and proteinase 3 (PR3). ANCA-stimulated neutrophils injure endothelial cells, a process that is dependent upon the production of reactive oxygen radicals and the release of granular components such as MPO and PR3. Here we investigate whether a common functional MPO promoter polymorphism (-463 G/A) is associated with increased incidence and clinical aspects of ANCA-associated small vessel vasculitis. Genotyping was carried out for 142 patients with ANCA-associated small vessel vasculitis and 129 ethnically matched controls. The GG genotype was found to be associated with an increased risk for MPO-ANCA-associated vasculitis in females (86% GG, P = 0.045), but not males (64% GG, P = 1.0). Interestingly, the MPO A allele is associated with an increased incidence of relapses (P = 0.012) and an earlier age at diagnosis (P = 0.03) of MPO-ANCA-associated vasculitis. Both these associations are specific for MPO-ANCA and are not observed in patients with PR3-ANCA-associated vasculitis. These findings suggest that MPO expression levels influence the disease course of MPO-ANCA-associated vasculitis and further support the view that genetic factors are involved in the pathophysiology of this autoimmune disease.

Topics: Antibodies, Antineutrophil Cytoplasmic; Churg-Strauss Syndrome; Genotype; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Monocytes; Neutrophils; Peroxidase; Phenotype; Polymorphism, Genetic; Vasculitis

The triad of small vessel vasculitides (SVV) comprise Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CS). All three are associated with presence of circulating IgG antineutrophil cytoplasm antibodies (ANCA) which target autoantigens contained, primarily, within neutrophil azurophilic granules. The widely accepted model of pathogenesis suggests that ANCA activate cytokine-primed neutrophils within the microvasculature, leading to by-stander damage to endothelial cells, and rapid escalation of inflammation with recruitment of mononuclear cells. Activation may be initiated, in vitro, by the coligation of the PR3 or MPO antigen, translocated to the cell surface, and FcgammaRIIa/FcgammaRIIIb receptors. This suggests that the IgG subclass profile of ANCA and, possibly, its glycosylation status could influence the inflammatory mechanisms activated. The glycosylation status of total IgG isolated from the sera of patients with WG (13), MPA (6) and CSS (1) was determined by analysis of the released oligosaccharides. A deficit in IgG galactosylation is demonstrated for all patient samples, compared to controls. The mean percentage values for the agalactosylated (G0) oligosaccharides were 57% (SD +/- 9.71), 47% (SD +/- 4.25) and 28% (SD +/- 4.09) for WG, MPO and control samples, respectively. The G0 levels for polyclonal IgG isolated from the sera of both WG and MPA patients were significantly increased compared to controls (P < 0.0001). The major glycoform present therefore is agalactosylated (G0) IgG. In previous studies the G0 glycoform of IgG has been shown to bind and activate mannan binding lectin, and hence to activate the complement cascade, and to facilitate mannose receptor binding and the uptake of IgG complexes by macrophages and dendritic cells. Both of these activities could impact on the processing and presentation of self-antigens in autoimmune disease.

Topics: Adolescent; Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Antibody Specificity; Antigen Presentation; Autoantibodies; Autoantigens; Autoimmune Diseases; Churg-Strauss Syndrome; Female; Galactose; Glycosylation; Granulomatosis with Polyangiitis; Humans; Immunoglobulin G; Male; Middle Aged; Myeloblastin; Neutrophils; Peroxidase; Polysaccharides; Protein Processing, Post-Translational; Serine Endopeptidases; Vasculitis

Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) have been reported to be pathologically and clinically different. The aim of this study was to assess whether these differences could be explained by differing abilities of proteinase 3-antineutrophil cytoplasmic antibody (PR3-ANCA)-positive IgG preparations or myeloperoxidase-ANCA (MPO-ANCA)-positive IgG preparations to activate neutrophils (polymorphonuclear cells [PMN]) in vitro.. Using Percoll density gradients, PMN were isolated (concentration 2 x 10(6)/ml) and primed with cytochalasin B (1 ng/ml) and tumor necrosis factor alpha (TNFalpha; 2 ng/ml). The PMN were activated with 200 microg/ml of normal IgG or ANCA. Activation was determined by 1) superoxide anion generation as determined by the superoxide dismutase-inhibitable reduction of ferricytochrome c, 2) monitoring fluxes in Ca2+ concentration using Fura 2-AM-loaded PMN, and 3) degranulation using an MPO assay. Surface expression of PR3 and MPO was determined by fluorescence-activated cell sorter analysis. ANCA isotypes were investigated by enzyme-linked immunosorbent assay.. Activation of PMN by MPO-ANCA-positive IgG preparations compared with PR3-ANCA-positive IgG preparations resulted in greater generation of superoxide anions (MPO-ANCA-positive IgG preparations 9.13 +/- 0.39 nmoles [mean +/- SEM], PR3-ANCA-positive IgG preparations 6.32 +/- 0.35 nmoles; P < 0.001), Ca2+ fluxes (MPO-ANCA-positive IgG preparations 0.735 +/- 0.10, PR3-ANCA-positive IgG preparations 0.33 +/- 0.098; P < 0.01), and MPO degranulation (MPO-ANCA-positive IgG preparations 251.98 +/- 26.7 ng, PR3-ANCA-positive IgG preparations 145.19 +/- 19.4 ng; P < 0.001). The increased activation seen with MPO-ANCA-positive IgG preparations was not due to increased expression of MPO on the cell surface, because following TNFalpha priming PR3 was expressed on significantly more cells than was MPO (PR3 expression 54.2 +/- 5.18%, MPO 31.6 +/- 3.55%; P < 0.001). IgG1 and IgG4 were the predominant isotypes in both MPO-ANCA-positive IgG preparations and PR3-ANCA. MPO-ANCA contained significantly more IgG1 than did PR3-ANCA, and PR3-ANCA-positive IgG preparations contained significantly more IgG3.. In vitro MPO-ANCA-positive IgG preparations are more activating than PR3-ANCA-positive IgG preparations. The increased activation cannot be explained by increased MPO expression on the cell surface or greater IgG3 present in MPO-ANCA-positive IgG preparations. Differences in activation of PMN by these antibodies may determine some differences between WG and MPA.

Topics: Adult; Aged; Antibodies, Antineutrophil Cytoplasmic; Cells, Cultured; Cytochalasin B; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Granulomatosis with Polyangiitis; Humans; Immunoglobulin G; Male; Microcirculation; Middle Aged; Myeloblastin; Neutrophil Activation; Neutrophils; Peroxidase; Serine Endopeptidases; Tumor Necrosis Factor-alpha; Vasculitis

Interactions between anti-neutrophil cytoplasmic autoantibody (ANCA) and primed neutrophils (PMNs) may be central to the pathogenesis of primary small vessel vasculitis. PMNs from patients are primed, expressing proteinase 3 (PR3) on the cell surface, which permits interaction with ANCA. In vitro ANCA activates primed PMN to degranulate and generate a respiratory burst. Resultant reactive oxygen species are important in triggering apoptosis, but the fate of PMN in ANCA-associated vasculitis is unknown. Failure to remove apoptotic PMN in a nonphlogistic manner may sustain the inflammatory response.. PMNs from patients or controls were isolated, and the basal production of superoxide was measured by the superoxide dismutase-inhibitable reduction of ferricytochrome C. ANCA antigen expression on apoptotic PMN was assessed at 0, 12, and 18 hours by flow cytometry using dual staining with FITC-conjugated annexin V and PE-conjugated anti-murine IgG against monoclonal ANCA. Apoptosis was also assessed by morphology. In further studies, apoptotic PMNs were opsonized with monoclonal anti-myeloperoxidase (MPO) or anti-proteinase-3 (PR3) or irrelevant isotype-matched IgG (N IgG) and phagocytosis by macrophages was measured using interaction assays. Cytokines interleukin-8 (IL-8) and interleukin-1 were measured by enzyme-linked immunosorbent assay (ELISA).. Proteinase-3 expression (active 63.04 +/- 5.6% of total number of cells, remission 51.47 +/- 7.9% of total number of cells, control 17.7 +/- 4.7% of total number of cells, P < 0.05) and basal superoxide production (active 6.9 +/- 0.8 nmol/L x 10(6) cells, remission 5.15 +/- 0.4 nmol/L/10(6) cells, control 3.63 +/- 0.3 nmol/L/10(6) cells, P < 0.001) were significantly greater with freshly isolated PMN from patients than controls. PR3 expression and superoxide generation were positively correlated. PMN from patients with active disease became apoptotic at a greater rate than those of controls (at 18 hours, patients 72.3 +/- 3.9% apoptosis, controls 53.2 +/- 2.7% apoptosis, P < 0.05). PR3 and MPO expression were significantly greater on PMN isolated from patients at 12 and 18 hours. Opsonization of apoptotic PMN with ANCA significantly enhanced recognition and phagocytosis by scavenger macrophages (anti-MPO 88.95 +/- 6.27, anti-PR3 93.98 +/- 4.90, N IgG 44.89 +/- 3.44, P < 0.01) with increased secretion of IL-1 (anti-PR3 34.73 +/- 6.8 pg/mL, anti-MPO 42.01 +/- 12.3 pg/mL, N IgG 8.04 +/- 6.3 pg/mL, P < 0.05) and IL-8 (anti-PR3 8.97 +/- 0.93 ng/mL, anti-MPO 8.45 +/- 1.46 ng/mL, N IgG 0.96 +/- 0.15 ng/mL, P < 0.01).. In vivo circulating PMNs are primed as assessed by PR3 expression and basal superoxide production, thereby enhancing their inflammatory potential. These PMNs undergo apoptosis more readily, at which times they express PR3 and MPO on their surface. These antigens may then provide targets for ANCA. Opsonization of apoptotic PMN will enhance clearance by macrophages but will also trigger the release of pro-inflammatory cytokines that may contribute to chronic inflammation.

Topics: Antibodies, Antineutrophil Cytoplasmic; Apoptosis; Case-Control Studies; Cell Membrane; Cytokines; Granulomatosis with Polyangiitis; Humans; In Vitro Techniques; Inflammation Mediators; Myeloblastin; Neutrophils; Opsonin Proteins; Peroxidase; Serine Endopeptidases; Superoxides; Vasculitis

The initial presentation of a patient with Wegener's granulomatosis was indistinguishable from that of Henoch-Schönlein purpura. The patient presented with skin purpura and pulmonary hemorrhage followed by purpura in the colon. The diagnosis of this patient at that time was Henoch-Schönlein purpura. With time, massive lesions in the sinus and those with cavities in the lung became apparent, and a specimen obtained from the sinus massive lesion was disclosed to be granulomatous inflammation. Retrospectively, the proteinase 3 antineutrophil cytoplasmic antibody turned out to be strongly positive in her stored serum from the time of the initial presentation.

Topics: Adult; Antibodies, Antineutrophil Cytoplasmic; Autoantigens; Diagnosis, Differential; Female; Granulomatosis with Polyangiitis; Humans; IgA Vasculitis; Myeloblastin; Peroxidase; Serine Endopeptidases; Time Factors

Endothelial cell damage occurs during vasculitic processes in vivo. With the alteration of the endothelium, exposure to basement membrane components may occur with induction of humoral immunity.. In the present study, we evaluated the prevalence of antibodies against the basement membrane antigen laminin (LMN) in patients with ANCA-associated systemic vasculitis (AASV), pathologic controls (systemic lupus erythematosus, mixed cryoglobulinaemia, Henoch-Schönlein purpura, primary glomerulonephritis) and normal individuals.. By ELISA, 21.6% of AASV (16/74) and 10% of pathologic controls (3/30), but only one of the normal controls (2. 8%) had these antibodies (P=0.02). When AASV patients were divided into two groups according to diagnosis and ANCA antigen specificity, antibodies to LMN were found in 27.5% of MPO-ANCA positive microscopic polyangiitis patients (11/40) vs. only 14.7% of PR3-ANCA positive Wegener granulomatosis patients (5/34). There was no correlation between the presence or titre of anti-LMN antibodies and the main clinical and laboratory parameters.. These results indicate that basement membrane antigens may become immunogenic in patients with AASV, especially in those with MPO-ANCA positivity. These antibodies are most likely the result of endothelial damage secondary to the initial inflammatory process but may well perpetuate further vascular damage in some patients.

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Enzyme-Linked Immunosorbent Assay; Epitopes; Granulomatosis with Polyangiitis; Humans; Laminin; Myeloblastin; Peroxidase; Reference Values; Serine Endopeptidases; Vasculitis

Prediction of relapses in Wegener's granulomatosis (WG) by measuring levels of antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3) or myeloperoxidase (MPO) remains a controversial issue. To assess the value of serial quantification of ANCA by indirect immunofluorescence (IIF) and antigen-specific enzyme-linked immunosorbent assay (ELISA) for monitoring disease activity in patients with WG, a prospective observational study was conducted in patients with WG attending an outpatient clinic in the Netherlands.. One hundred patients with WG (85 with PR3-ANCA, 15 with MPO-ANCA) were studied prospectively from 1996 to 1998. Serum samples were obtained and analyzed every 2 months for ANCA levels. Disease activity was prospectively assessed without knowledge of the ANCA levels.. Relapses occurred in 37 of 100 patients (37%). Thirty-four (92%) of the 37 patients showed a rise in the level of ANCA preceding their relapse, as detected by ELISA or IIF. The predictive value of an increase in ANCA titers for relapse was 57% (17 of 30) for cytoplasmic/classic ANCA (cANCA; by IIF), 71% (27 of 38) for PR3-ANCA (by ELISA), and 100% (3 of 3) for MPO-ANCA (by ELISA). The predictive value of a rise in ANCA as measured by ELISA or IIF did not substantially improve following concomitant measurement of the IgG3 subclass of PR3-ANCA. Forty-three percent of patients who showed a rise in cANCA (by IIF) and 29% with a rise in PR3-ANCA (by ELISA) did not subsequently experience a relapse.. Serial measurement of ANCA levels is valuable for the early prediction of relapses in patients with WG.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Antibody Specificity; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Granulomatosis with Polyangiitis; Humans; Male; Middle Aged; Peroxidase; Recurrence; ROC Curve

Anti-neutrophil cytoplasm autoantibodies (ANCA) directed against proteinase 3 (PR3) are highly sensitive and specific markers for Wegener's granulomatosis (WG). Consequently, antigen-specific assays for detection of PR3-ANCA are helpful for the diagnosis and follow-up of patients with WG. Purification of PR3 is laborious and requires large amounts of granulocytes. Therefore, several attempts have been made to produce recombinant PR3 that is recognized by PR3-ANCA. The purpose of this study was to compare the recognition of different recombinant forms of PR3 (rPR3) by anti-PR3 antibodies. Recombinant PR3 produced in E. coli (rcPR3), P. pastoris (rpPR3), insect cells using the baculovirus system (rbPR3), the human mast cell line, HMC-1 (HMC-1/PR3-S176A), or the human epithelial cell line, 293 (Delta-rPR3-S176A) as well as purified neutrophil PR3 (nPR3) were used. Recognition of these rPR3s by anti-PR3 antibodies was determined by direct and capture ELISA with 19 PR3-ANCA sera, 13 anti-PR3 mAbs and a rabbit serum raised against human PR3. In the capture ELISA rabbit anti-PR3 strongly bound nPR3 and all rPR3 products. By capture ELISA rcPR3 and rpPR3 were recognized by 11 (57%) and 13 (68%) of the 19 PR3-ANCA sera, respectively, whereas rbPR3, HMC-1/PR3-S176A, Delta-rPR3-S176A and nPR3 were recognized by all PR3-ANCA sera. By direct ELISA rabbit anti-PR3 strongly bound nPR3 and all tested rPR3 products. Using the direct ELISA none of the PR3-ANCA sera recognized rcPR3, whereas rpPR3 and rbPR3 were recognized by two (11%) and 17 (89%) of the 19 PR3-ANCA sera, respectively. All 13 anti-PR3 mAbs recognized nPR3 in the direct as well as in the capture ELISA. The rcPR3 was recognized by two mAbs in the capture ELISA but by none of the mAbs in the direct ELISA. The rpPR3 was recognized by seven mAbs in the capture ELISA and only by two mAbs in the direct ELISA. All but one of the anti-PR3 mAbs recognized rbPR3, whereas HMC-1/PR3-S176A and Delta-rPR3-S176A were recognized by all anti-PR3 mAbs. In conclusion, rPR3 expressed in insect cells, HMC-1 and 293 cells is recognized by anti-PR3 antibodies, whereas conformational epitopes recognized by anti-PR3 mAbs and PR3-ANCA are not well preserved on rPR3 expressed in E. coli or P. pastoris.

Topics: Adult; Aged; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal; Antibody Specificity; Baculoviridae; Enzyme-Linked Immunosorbent Assay; Epitopes; Escherichia coli; Female; Granulomatosis with Polyangiitis; Humans; Immunoblotting; Male; Mast Cells; Middle Aged; Myeloblastin; Neutrophils; Peroxidase; Pichia; Recombinant Proteins; Serine Endopeptidases

The association of lung emphysema with severe systemic antineutrophil cytoplasm antibodies (ANCA)-positive vasculitis, such as Wegener's granulomatosis is unusual since only four cases have been described previously. We report the first case of a 30 year-old smoker man presenting with biopsy-proven Wegener's granulomatosis, who developed a bullous emphysema during severe active lung vasculitis, in association with positive ANCA disclosing an anti-myeloperoxydase pattern. Alpha 1-antitrypsin deficiency, a known risk factor of lung emphysema recently found to be associated with anti-proteinase 3-positive vasculitis, was not present in this patient. Cigarette smoking, in association with severe lung vasculitis, might have contributed to the development of this emphysematous lesion.

Topics: Adult; Antibodies, Antineutrophil Cytoplasmic; Granulomatosis with Polyangiitis; Humans; Male; Peroxidase; Pulmonary Emphysema; Smoking

T cell-mediated immunity is thought to play an important role in the pathogenesis of WG. In previous studies a minority of WG patients as well as some healthy controls showed in vitro proliferation of their peripheral blood mononuclear cells (PBMC) to PR3, the main autoantigen in WG. The relevant peptides responsible for this in vitro proliferation have not been identified. In order to define immunogenic peptides, PBMC of 13 WG patients in remission and 10 healthy controls were tested for proliferation to linear peptides of PR3 and to whole PR3. Fifty overlapping peptides spanning the whole PR3 sequence were synthesized. Peptides were tested in pools of five peptides and as single peptide. PBMC of two WG patients and one healthy control proliferated to whole PR3 and to peptide pools. In addition, 10 WG patients and eight healthy controls that did not proliferate to whole PR3 did proliferate to pools of PR3 peptides. Although more WG patients tended to react to particular peptide pools, no significant difference was seen between lymphocyte proliferation to PR3 peptides of WG patients and that of healthy controls. The pools of peptides recognized were mainly located at the N- and C-terminus of PR3. No correlation was observed between HLA type and proliferation on particular peptide pools. No proliferation of PBMC was observed to single peptides. In conclusion, T cells of WG patients proliferate in vitro more frequently to PR3 peptides than to the whole PR3 protein. Peptides derived from the signal sequence, the propeptide or peptides located at the C-terminus of PR3 induce highest levels of proliferation. No specific PR3 sequence could be identified that was preferentially recognized by PBMC of WG patients compared with controls.

Topics: Adult; Aged; Amino Acid Sequence; Animals; Antibodies, Antineutrophil Cytoplasmic; Autoantigens; CD28 Antigens; CD3 Complex; Cell Division; Female; Granulomatosis with Polyangiitis; HLA-A Antigens; HLA-B Antigens; HLA-DQ Antigens; HLA-DR Antigens; Humans; Male; Middle Aged; Molecular Sequence Data; Myeloblastin; Oligopeptides; Peroxidase; Rabbits; Serine Endopeptidases; T-Lymphocytes

We describe a patient who presented with Wegener's granulomatosis associated with antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3) with a cytoplasmic immunofluorescence pattern (cANCA), whose ANCA type changed to antimyeloperoxidase antibodies with a perinuclear immunofluorescence pattern (pANCA) when treated with propylthiouracil, and changed back to anti-PR3 antibodies with cANCA after the medication was discontinued. The patient developed flares of vasculitis symptoms associated with rises in either type of ANCA. Tests for antimyeloperoxidase ANCA were repeatedly negative before the drug was started, strongly implicating the drug as the cause of the episode. This case demonstrates that patients with idiopathic ANCA-positive vasculitis may quickly develop a superimposed drug-associated ANCA-positive vasculitis. Iatrogenic vasculitis should be suspected when a patient with idiopathic vasculitis with one type of ANCA develops the other type of ANCA.

Topics: Adult; Antibodies, Antineutrophil Cytoplasmic; Antibody Specificity; Antithyroid Agents; Enzyme-Linked Immunosorbent Assay; Granulomatosis with Polyangiitis; Humans; Iatrogenic Disease; Male; Myeloblastin; Peroxidase; Propylthiouracil; Serine Endopeptidases; Vasculitis, Leukocytoclastic, Cutaneous

Proteinase 3 (PR3), the major target autoantigen in Wegener's granulomatosis is a serine proteinase that is normally stored intracellularly in the primary granules of quiescent neutrophils and monocytes. Upon cell activation, a significant portion of this antigen is detected on the cell surface membrane. The nature of the association of PR3 with the membrane and its functional significance are unknown. We investigated the interaction of purified human PR3 with mixtures of zwitterionic (dimyristoyl-L-alpha-phosphatidylcholine, DMPC) and anionic (dimyristoyl-L-alpha-phosphatidylglycerol, DMPG) phospholipids in reconstituted lipid bilayers using differential scanning calorimetry and lipid photolabeling, and measured the affinity of this interaction using spectrophotometry. Two other primary granule constituents, human neutrophil elastase (HNE) and myeloperoxidase (MPO) were investigated for comparison. In calorimetric assays, using lipid vesicles of mixed DMPC/DMPG, increasing PR3 concentrations (protein/lipid molar ratio from 0 to 1 : 110) induced a significant decrease of the main chain transition enthalpy and a shift in chain melting temperatures which is indicative of partial insertion of PR3 into the hydrophobic region of the lipid membranes. This was confirmed by hydrophobic photolabeling using liposomes containing trace amounts of the photoactivable [125I]-labeled phosphatidylcholine analog TID-PC/16. The molar affinity of PR3, HNE, and MPO to lipid vesicles of different DMPC/DMPG ratios was then determined by spectrophotometry. At a DMPC/DMPG ratio of 1 : 1, molar affinities of PR3, Kd = 4.5 +/- 0.3 microm; HNE, 14.5 +/- 1.2 microm; and MPO, 50 +/- 5 microm (n = 3) were estimated. The lipid-associated PR3 exhibited two-fold lower Vmax and Km values, and its enzyme activity was slightly more inhibited (Ki) by the natural alpha1-proteinase inhibitor (alpha1-PI) or an autoantibody to PR3.

Topics: Affinity Labels; Autoantigens; Calorimetry, Differential Scanning; Granulomatosis with Polyangiitis; Humans; In Vitro Techniques; Leukocyte Elastase; Lipid Bilayers; Models, Molecular; Myeloblastin; Peroxidase; Protein Conformation; Serine Endopeptidases; Spectrophotometry

To assess the value of serial determinations of antineutrophil cytoplasmic autoantibodies (ANCA) for monitoring disease activity in patients with systemic vasculitis.. Forty-three patients with histologically proven vasculitis (21 with Wegener's granulomatosis, 17 with microscopic polyangiitis, and 5 with renal-limited vasculitis) were studied for a median follow-up of 22 months. Disease activity was prospectively assessed and quantified by the Birmingham Vasculitis Activity Score. A total of 347 sera were analyzed for ANCA determination.. Relapses occurred in 23 (54%) of 43 patients. Diagnostic category (Wegener's granulomatosis vs micropolyangiitis and renal-limited vasculitis), severity of initial symptoms (mean vasculitis activity score, mean number of organs involved), and ANCA pattern [cytoplasmic-ANCA (c-ANCA) vs perinuclear-ANCA (p-ANCA)] did not significantly differ between relapsers and nonrelapsers. Lung involvement was more frequent at onset among relapsers [16 of 23 (70%) vs 6 of 20 (30%); P = 0.02]. Relapses were slightly, but not significantly, more frequent in patients with Wegener's granulomatosis or a c-ANCA pattern. The percentage of relapsers was greater in patients with persistently positive ANCA than in patients with negative or decreasing ANCA titers (86% vs 20%, P = 0.0001). However, the predictive value of an increase in ANCA titers for the occurrence of a subsequent relapse was only 28% (4 of 14) for c-ANCA, 12% (2 of 17) for anti-proteinase 3-ANCA, and 43% (6 of 14) for anti-myeloperoxidase-ANCA. An increase in ANCA occurred before or during relapse in 33% (10 of 30) of cases for c-ANCA/anti-proteinase 3 antibodies, and 73% (11 of 15) of cases for anti-myeloperoxidase antibodies.. The persistence of ANCA positivity is strongly associated with relapses. However, an increase in ANCA titers has a poor value for the early prediction of a subsequent relapse and should not be used as a sole parameter for therapeutic intervention. In addition, our results suggest that serial anti-myeloperoxidase determination may be useful as a prognostic marker in patients who are p-ANCA positive.

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Arteritis; Endopeptidases; Female; Granulomatosis with Polyangiitis; Humans; Male; Middle Aged; Peroxidase; Predictive Value of Tests; Recurrence; Vasculitis

Haemosiderin-laden alveolar macrophages are a common finding in patients with alveolar bleeding. Iron-positive macrophages, suggestive of subclinical alveolar bleeding, were found to be fairly common in bronchoalveolar lavage (BAL) fluid in primary systemic vasculitis but uncommon in collagen vascular diseases (CVDs) and rheumatoid arthritis (RA). To substantiate the impression that subclinical alveolar bleeding may be a feature distinguishing between these disorders, fibreoptic bronchoscopy and BAL were performed in 49 patients with active Wegener's granulomatosis or Churg-Strauss syndrome and 44 patients with CVDs or RA, all of them without clinically manifest alveolar bleeding. The percentage of iron-positive cells was compared with clinical and radiological findings. Only a minority of the CVD and RA patients had iron-positive alveolar macrophages; the 95th percentile of the median number of such cells was 5%. Fifty-three per cent of the patients in the vasculitis group had >5% iron-positive cells, with individual counts ranging up to 95%. Patients with iron-positive macrophages had more extensive disease, more frequent microhaematuria, a higher antineutrophil cytoplasmic antibody titre, a higher myeloperoxidase concentration in the BAL fluid and somewhat more frequent low-attenuation opacities in pulmonary high-resolution computed tomography than the patients with a low iron-positive cell count. In conclusion, subclinical alveolar bleeding was, indeed, a common finding in antineutrophil cytoplasmic antibody-associated vasculitis, which distinguished these disorders from lung disease due to collagen vascular diseases or rheumatoid arthritis. Its association with indices of disease activity, although weak in this cross-sectional study, merits a longitudinal study of its value for the long-term monitoring of vasculitis patients.

Topics: Aged; Antibodies, Antineutrophil Cytoplasmic; Arthritis, Rheumatoid; Bronchoalveolar Lavage Fluid; Bronchoscopy; Cell Count; Churg-Strauss Syndrome; Collagen; Female; Granulomatosis with Polyangiitis; Hemorrhage; Humans; Iron; Lung Diseases; Macrophages, Alveolar; Male; Middle Aged; Peroxidase; Pulmonary Alveoli; Retrospective Studies; Severity of Illness Index; Tomography, X-Ray Computed

Proteinase 3 (PR3), which is also called myeloblastin, the target autoantigen for antineutrophil cytoplasmic antibodies (ANCA) in Wegener's granulomatosis, is a serine proteinase stored in azurophil granules of human neutrophils. We have previously shown that, in contrast to elastase or myeloperoxidase, PR3 is also expressed at the plasma membrane of a subset of unactivated neutrophils and that a high proportion of neutrophils expressing membrane PR3 is a risk factor for vasculitis. The present study demonstrates that the association of PR3 with the plasma membrane is not an ionic interaction and seems to be covalent. Fractionation of neutrophils shows that, besides the azurophil granules, PR3 could be detected both in specific granules and in the plasma membrane-enriched fraction containing secretory vesicles, whereas elastase and myeloperoxidase were exclusively located in azurophil granules. Electron microscopy confirms that PR3 is present along with CR1 in secretory vesicles as well as in some specific granules. In neutrophils stimulated with an increasing dose of FMLP, membrane PR3 expression increased with the degranulation of secretory vesicles, followed by specific granules, and culminated after azurophil granules mobilization. The presence of a readily plasma membrane-mobilizable pool of PR3 contained in the secretory vesicles might play a relevant role in the pathophysiological mechanisms of ANCA-associated vasculitis.

Topics: Autoantigens; Cell Fractionation; Cell Membrane; Cells, Cultured; Cytochalasin B; Cytoplasmic Granules; Gene Expression Regulation, Enzymologic; Granulomatosis with Polyangiitis; Humans; Microscopy, Electron; Myeloblastin; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Peroxidase; Serine Endopeptidases; Vasculitis

Topics: Antibodies, Antineutrophil Cytoplasmic; Cranial Nerves; Diagnosis, Differential; Facial Paralysis; Granulomatosis with Polyangiitis; Hearing Loss, Sensorineural; Humans; Male; Maxillary Sinus; Middle Aged; Nasal Mucosa; Peroxidase; Radiography; Temporal Bone

To describe the neutrophil fluorescent patterns produced by antineutrophil cytoplasmic antibodies (ANCA) with different antigen specificities, and by other auto- and alloantibodies.. Most sera from patients with active generalised Wegener's granulomatosis result in diffusely granular cytoplasmic neutrophil fluorescence with internuclear accentuation (cANCA) and proteinase 3 (PR3) specificity. About 80% of the sera from patients with microscopic polyangiitis result in perinuclear neutrophil fluorescence with nuclear extension (pANCA) and myeloperoxidase (MPO) specificity, or a cANCA pattern with PR3 specificity. However, many different neutrophil fluorescence patterns are noted on testing for ANCA in routine immunodiagnostic laboratories.. Sera sent for ANCA testing, or containing a variety of auto- and alloantibodies, were studied. They were examined by indirect immunofluorescence according to the recommendations of the first international ANCA workshop, and for PR3 and MPO specificity in commercial and in-house enzyme linked immunosorbent assays (ELISA).. Sera with typical cANCA accounted for only half of all neutrophil cytoplasmic fluorescence. Other sera had "flatter" fluorescence without internuclear accentuation, and the corresponding antigens included MPO and bactericidal/permeability increasing protein (BPI), but were usually unknown. Peripheral nuclear fluorescence without nuclear extension occurred typically when the antigens were BPI, lactoferrin, lysozyme, elastase, or cathepsin G. Most types of ANA were evident on ethanol fixed neutrophil nuclei. AntidsDNA, antiRo, and antilamin antibodies resembled pANCA. Antimicrobial and antiribosomal antibodies produced cytoplasmic fluorescence, and antiGolgi antibodies, a pANCA. Sera from patients with anti-smooth muscle antibodies were associated with cytoplasmic fluorescence. There was no neutrophil fluorescence with anti-skeletal muscle and anti-heart muscle antibodies, anti-liver/kidney microsomal, antithyroid microsomal, or antiadrenal antibodies. Alloantibodies such as antiNB1 typically resulted in cytoplasmic fluorescence of only a subpopulation of the neutrophils.. The ability to distinguish between different neutrophil fluorescence patterns, and the patterns seen with other auto- and alloantibodies is helpful diagnostically. However, the demonstration of MPO or PR3 specificity by ELISA will indicate that the neutrophil fluorescence is probably clinically significant, and that the diagnosis is likely to be Wegener's granulomatosis or microscopic polyangiitis.

Topics: Antibodies, Antineutrophil Cytoplasmic; Antibody Specificity; Autoantibodies; Biomarkers; Cytoplasm; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique, Indirect; Granulomatosis with Polyangiitis; Humans; Isoantibodies; Muscle, Smooth; Myeloblastin; Peroxidase; Serine Endopeptidases; Vasculitis

The prevalence of antineutrophil cytoplasmic antibodies (ANCA) was studied in 12 children with Wegener's granulomatosis. The serum samples were taken in the active phase of disease and were screened for ANCA by indirect immunofluorescence with normal neutrophils and enzyme linked immunosorbent assay (ELISA) using crude neutrophil extract, proteinase 3, myeloperoxidase, cathepsin G, lactoferrin, and elastase as antigens. Of these 12 patients, 10 wre positive for ANCA in the active phase of their illness, and they showed a predominantly cytoplasmic ANCA staining pattern on indirect immunofluorescence. There were high titres of ANCA directed against crude neutrophil extract, proteinase 3, myeloperoxidase, and cathepsin G. IgM isotypes occurred as commonly as IgG isotypes. Therefore, screening for ANCA is usually but not invariably positive in children with Wegener's granulomatosis. Specific diagnosis still relies on clinical and pathological features, and the value of ANCA in the diagnosis of paediatric Wegener's granulomatosis requires further study.

Topics: Adolescent; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Cathepsin G; Cathepsins; Child; Child, Preschool; Endopeptidases; Enzyme-Linked Immunosorbent Assay; Epitopes; Female; Fluorescent Antibody Technique, Indirect; Granulomatosis with Polyangiitis; Humans; Immunoglobulin G; Immunoglobulin M; Infant; Male; Peroxidase; Serine Endopeptidases

Fifty-six sera from patients with autoimmune thyroiditis and 33 sera from patients with MPO-ANCA were examined in order to ascertain whether a cross reactivity between MPO-ANCA and anti-thyroperoxidase (aTPO) was present. Sera from 20 healthy donors aTPO and aMPO negative were used as control. About 95% of heat inactivated sera from patients with autoimmune thyroiditis and from controls gave positive results (atypical pANCA pattern) on ethanol-fixed neutrophils. The prevalence of positive results was significantly lower when unheated aTPO positive sera were used (17.8%). On the other hand, only 9% of sera with MPO-ANCA were positive on cryostatic sections of human thyroid. Indirect immunofluorescence tests (IF) on human neutrophils with MPO defect were negative with sera from patients with MPO-ANCA, but uninactivated sera with aTPO and positive for pANCA on normal neutrophils showed a very high prevalence of positive results (90%). According to our data only few sera positive for aTPO recognize "normal" MPO, but the majority of sera from patients with autoimmune thyroiditis and positive for pANCA on normal neutrophils recognize also an "abnormal" MPO. On the other hand MPO-ANCA usually recognize epitopes presently only on the normal enzyme, a small proportion of these autoantibodies can react with TPO. Heat inactivated sera give false positive results for pANCA on ethanol fixed human neutrophils.

Topics: Antibodies, Antineutrophil Cytoplasmic; Connective Tissue Diseases; Cross Reactions; Cryoultramicrotomy; Enzyme-Linked Immunosorbent Assay; Ethanol; False Positive Reactions; Fixatives; Fluorescent Antibody Technique, Indirect; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Iodide Peroxidase; Neutrophils; Peroxidase; Radioimmunoassay; Thyroid Gland; Thyroiditis, Autoimmune

Neutrophils accumulate in the acute blood vessel lesions of patients with autoimmune systemic vasculitis. They have been shown previously to produce the cytokine IL-1 beta in response to stimulation with TNF. This study demonstrates that neutrophils can be stimulated by anti-neutrophil cytoplasmic antibodies (ANCA), which are present in patients with systemic vasculitis, to express mRNA and protein for IL-1 beta. Both human ANCA and MoAbs to a variety of autoantigens recognized by ANCA, including proteinase 3, myeloperoxidase, bactericidal/permeability increasing protein and elastase, are effective. This response can be inhibited by actinomycin and cycloheximide, suggesting a requirement for de novo protein synthesis. IL-1 beta production can be inhibited by pooled human intravenous immunoglobulins but not by FK506 or cyclosporin A. These data suggest that ANCA in patients with active vasculitis may stimulate neutrophils to produce cytokines. It is hypothesized that cytokine production from neutrophils that accumulate in significant numbers in vasculitic lesions contribute to and augment the local inflammatory response by the activation of vascular endothelial cells and infiltrating leucocytes.

Topics: Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal; Antimicrobial Cationic Peptides; Arteritis; Autoantigens; Blood Proteins; Cycloheximide; Dactinomycin; Granulomatosis with Polyangiitis; Humans; Immunoglobulins, Intravenous; Interleukin-1; Leukocyte Elastase; Membrane Proteins; Myeloblastin; Neutrophil Activation; Neutrophils; Peroxidase; Protein Synthesis Inhibitors; RNA, Messenger; Serine Endopeptidases

Anti-proteinase 3 (PR3) and anti-myeloperoxidase (MPO) autoantibodies are present in many patients with Wegener's granulomatosis (WG) and microscopic polyarteritis. The aim of this study was to determine whether these antibodies bound to linear peptide sequences on their target antigens. If common linear epitopes were demonstrated, then these could be manufactured and used in diagnostic ELISAs for anti-PR3 and anti-MPO antibodies. In addition, any homology between these epitopes and bacterial or viral sequences might implicate those microorganisms in the development of these antibodies and the pathogenesis of the associated diseases. The presence of linear epitopes on PR3 and MPO was suggested by the binding of the corresponding autoantibodies to these proteins after they had been reduced with beta-mercaptoethanol (beta-ME) and denatured with SDS or boiling, and digested with proteases. Four of the 22 sera with anti-PR3 antibodies bound to PR3 in Western blots after treatment with SDS, beta-ME and boiling for 5 min. Thermal denaturation reduced the amount of binding more than other forms of denaturation. One serum with anti-PR3 antibodies bound to Lys-C and Glu-C-digested PR3 in dot blots. Linear epitopes could not be further defined by their binding in an ELISA using overlapping peptides corresponding to the PR3 molecule because of non-specific binding. Three of the five sera with anti-MPO antibodies bound to MPO in Western blots after treatment with SDS, beta-ME and boiling for 5 min. One serum with anti-MPO antibodies bound to Lys-C and Glu-C-digested MPO in dot blots. Again, linear epitopes could not be further defined using an ELISA with overlapping peptides because of non-specific binding. Some anti-PR3 and anti-MPO antibodies are likely to recognize linear epitopes, but these cannot be defined by use of a PIN ELISA system.

Topics: Amino Acid Sequence; Autoantigens; Enzyme-Linked Immunosorbent Assay; Epitope Mapping; Granulomatosis with Polyangiitis; Humans; Molecular Sequence Data; Myeloblastin; Peroxidase; Serine Endopeptidases

Antineutrophil cytoplasmic autoantibodies (ANCA) have been described in sera of patients with several forms of systemic vasculitis, including Wegener's granulomatosis and microscopic polyarteritis. The two main targets of ANCA in vasculitis are proteinase 3 (PR3) and myeloperoxidase (MPO). ANCA are capable of activating neutrophils primed by tumor necrosis factor-alpha (TNF-alpha) in vitro, which may be relevant for the induction of the vascular inflammation observed in vivo. Recently, it has been suggested that engagement of Fc gamma receptor IIa (Fc gamma RIIa) on the neutrophils is involved in the activation by ANCA. In the present study, we show that activation of the neutrophil respiratory burst by anti-PR3 and anti-MPO is strongly enhanced after TNF priming and lost on removal of the Fc parts of the antibodies. Similar results were obtained when the neutrophils were activated with antibodies against known membrane antigens without major changes in the expression of the target antigens. The TNF-induced enhancement of the neutrophil activation was not observed when adherence of the cells was prevented by continuous stirring of the suspension or by the addition of CD18 antibodies before TNF exposure. Hence, our results indicate that engagement of both Fc gamma RIIa and beta 2 integrins is instrumental in neutrophil activation induced by ANCA.

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Autoimmune Diseases; CD18 Antigens; Cell Adhesion; Granulomatosis with Polyangiitis; Humans; Immunoglobulin Fc Fragments; Myeloblastin; Neutrophils; Peroxidase; Receptors, IgG; Respiratory Burst; Serine Endopeptidases; Signal Transduction; Tumor Necrosis Factor-alpha; Vasculitis

Anti-neutrophil cytoplasmic autoantibodies (ANCA) occur in a subset of patients with systemic small vessel vasculitis, including patients with Wegener's granulomatosis, microscopic polyangiitis (microscopic polyarteritis), and Churg-Strauss syndrome. Pulmonary disease appears at some time during the course in many patients with ANCA-associated vasculitis. The histologic features of 25 open lung biopsies and two autopsy cases were studied from 27 patients with ANCA. Patients' ages ranged from 8 to 79 years with a mean of 52.6 years. There were 12 females and 15 males. Autoantibodies were characterized as C-ANCA in 13 patients and as P-ANCA in 14 patients. Anti-proteinase 3 antibodies were documented in 12 of 13 patients with C-ANCA. Anti-myeloperoxidase antibodies were documented in all 14 patients with P-ANCA. Vascular lesions were present in 21 patients (78%) and 11 patients (41%) had bronchial lesions. Capillaritis was the most common vascular lesion (17 patients, 63%), and was found with similar frequency in patients with C-ANCA and those with P-ANCA. Extravascular structures were a common site of tissue injury. Airway lesions including bronchiolitis obliterans organizing pneumonia (4 patients, 19%), necrotizing granulomatous inflammation (4 patients, 15%), and non-granulomatous inflammation (3 patients, 11%) were more commonly associated with patients with C-ANCA. Interstitial lesions were found in 20 patients (74%), and included necrotizing granulomatous inflammation (8 patients, 30%), fibrosis (13 patients, 48%), and chronic inflammation (12 patients, 44%). No histologic lesion were found that were specific for C-ANCA or P-ANCA. This series demonstrates the wide variety of pulmonary lesions found in patients with ANCA-associated pulmonary disease, and shows that extravascular structures are a common site of injury in ANCA-associated vasculitis.

Topics: Adolescent; Adult; Aged; Antibodies, Antineutrophil Cytoplasmic; Antibody Specificity; Autoantibodies; Biopsy; Child; Churg-Strauss Syndrome; Cryptogenic Organizing Pneumonia; Female; Fluorescent Antibody Technique; Granulomatosis with Polyangiitis; Humans; Lung; Male; Middle Aged; Myeloblastin; Peroxidase; Pulmonary Fibrosis; Serine Endopeptidases; Vasculitis

A retrospective analysis of the authors' own findings and foreign authors' data has demonstrated that neutrophilic cytoplasm antibodies (NCAs) play a definite pathogenetic role in the activation of neutrophils, a central link in the pathogenesis of vascular wall damage in necrotizing vasculitides. The clinical value of NCAs varies with their specificity. Proteinase 3 antibodies whose detection allows one to suppose Wegener's granulomatosis are of greater diagnostic value. Myeloperoxidase antibodies are revealed in various necrotizing vasculitides and promptly progressive glomerulonephritis and more infrequently in other diseases. Thus, the detection of antibodies to proteinase-3 and myeloperoxidase in the presence of appropriate clinical signs is most likely to diagnose primary necrotizing vasculitis. The changes in the levels of NCA reflect the activity of a renal processes and the progression of the whole disease.

Topics: Autoantibodies; Cytoplasm; Diagnosis, Differential; Endopeptidases; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Kidney Diseases; Neutrophils; Peroxidase; Polyarteritis Nodosa

We performed a retrospective study of the clinical features, the pattern of the pre-treatment renal function loss, the renal morphology and the outcome in 92 patients with anti-neutrophil cytoplasmic autoantibodies directed against proteinase 3 (aPR3; N = 46) or myeloperoxidase (aMPO; N = 46). Patients with aMPO had a higher median age than patients with a PR3 (63 and 56 years; P < 0.05). The mean (+/- SD) number of affected organs in the aPR3 group exceeded that of the aMPO group (3.9 +/- 1.4 and 2.2 +/- 1.1; P < 0.01). The prevalence of renal involvement did not differ between patients with aPR3 and aMPO (83% and 67%, respectively; NS). Pre-treatment renal function deteriorated significantly faster in aPR3- than in aMPO-associated renal disease. The kidney biopsies from patients with aPR3 showed a higher activity index (10.2 +/- 3.8 and 7.3 +/- 3.2; P < 0.03) and a lower chronicity index (4.5 +/- 2.6 and 7.0 +/- 3.1; P < 0.02) than biopsies from patients with aMPO. The kidney survival at two years was 73% in patients with aPR3- and 61% in patients with aMPO-associated renal disease (NS). We conclude that renal function generally deteriorates faster in aPR3- than in aMPO-associated renal disease. This goes together with more active renal lesions in patients with aPR3 and more chronic renal lesions in patients with aMPO. Despite these differences, there is no difference in outcomes between both antibody groups.

Topics: Adult; Aged; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Autoantigens; Female; Granulomatosis with Polyangiitis; Humans; Male; Middle Aged; Myeloblastin; Peroxidase; Polyarteritis Nodosa; Retrospective Studies; Serine Endopeptidases; Survival Analysis

Previous studies have shown a number of different associations between major histocompatibility complex (MHC) alleles and primary systemic vasculitis. Disease heterogeneity and the lack of specificity of certain MHC typing techniques may have contributed to the lack of consistency in those studies. We therefore studied a relatively homogeneous group of 94 patients with Wegener's granulomatosis, microscopic polyangiitis, or renal-limited vasculitis using molecular techniques that allow more precise assignment of MHC genotype. DNA was prepared from peripheral blood and DRB1 genotype determined by Taq restriction fragment length polymorphism. DQB1 and DPB1 genotype were assigned by polymerase chain reaction amplification followed by probing with allele-specific oligonucleotides. Specificity of associated anti-neutrophil cytoplasm antibodies (ANCA) was determined where possible by solid phase immunoassays using purified proteinase 3 (PR3) and myeloperoxidase (MPO). After correction for multiple comparisons there were no significant differences in the distribution of DRB1, DQB1 and DPB1 alleles between a local control group (N = 90 for DRB1, N = 50 for DQB1 and DPB1) and the patient group as a whole (N = 94) or two a priori defined subgroups (anti-PR3 positive, N = 35; anti-MPO positive, N = 22). We have therefore found no significant association between primary systemic vasculitis and any MHC class II allele. This, together with the fact that previous smaller studies have shown no consistent association, suggests that any such association is very weak, if it exists at all.

Topics: Alleles; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; DNA; DNA Probes; Gene Frequency; Genes, MHC Class II; Genotype; Granulomatosis with Polyangiitis; Histocompatibility Antigens Class II; Humans; Myeloblastin; Peroxidase; Polyarteritis Nodosa; Polymerase Chain Reaction; Polymorphism, Restriction Fragment Length; Serine Endopeptidases

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Granulomatosis with Polyangiitis; Humans; Male; Middle Aged; Myeloblastin; Peroxidase; Serine Endopeptidases

The objective of this study was to determine the significance of the antineutrophil cytoplasmic autoantibodies (ANCAs) from the clinicopathologic viewpoint of pulmonary hemorrhage occurring as a prominent event of disease. Forty-three consecutive patients with both pulmonary hemorrhage as a prominent clinical manifestation and a positive test for antineutrophil cytoplasmic autoantibodies were studied. Thirty-six patients underwent open lung biopsy, including histologic, tissue immunofluorescence, and microbiologic studies. Immunoassays were performed to investigate the antigenic specificities of antineutrophil cytoplasmic autoantibodies in the patients studied. All patients with lung biopsy confirmation had pauci-immune hemorrhagic alveolar capillaritis as the main morphologic substrate. In addition, renal involvement in the form of pauci-immune crescentic glomerulonephritis was a common finding. Serum samples from the 43 study patients contained antibodies that were monospecific for proteinase 3 (n = 13) or myeloperoxidase (n = 30). In our study, whereas anti-proteinase 3 antibodies were mainly detected in patients with alveolar capillaritis and a well-established diagnosis of Wegener's granulomatosis, antimyeloperoxidase antibodies were principally found in those patients who had alveolar capillaritis and polyarteritis nodosa not only as a primary finding but also accompanying other diseases. However, a significant number of patients with alveolar capillaritis and antimyeloperoxidase antibodies showed no evidence of polyarteritis nodosa (idiopathic pulmonary-renal syndrome and isolated forms of pulmonary hemorrhage). We conclude that in patients presenting with pulmonary hemorrhage as a prominent event of disease, antineutrophil cytoplasmic autoantibodies are a new clue strongly supportive of a pulmonary capillary vasculitis, irrespective of the primary underlying disease. Moreover, the antigenic subtype of antineutrophil cytoplasmic autoantibodies helps in recognizing the type of vasculitic disorder involved.

Topics: Antibodies; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Capillaries; Granulomatosis with Polyangiitis; Hemorrhage; Humans; Lung; Lung Diseases; Peroxidase; Polyarteritis Nodosa; Pulmonary Alveoli; Vasculitis

Antineutrophil cytoplasmic autoantibodies (ANCA) have been used as markers of systemic vasculitides, including microscopic polyarteritis (MPA) and Wegener's granulomatosis. The diagnostic potential of ANCA assays together with antibodies against the neutrophil enzymes myeloperoxidase (MPO) and proteinase 3 for detecting a systemic vasculitis was tested in a Chinese patient population. 672 sera were received for ANCA assay, and ANCA detected by indirect immunofluorescence was positive in 73 sera from 42 patients. Of the 42 patients, 3 had cytoplasmic ANCA, while 39 had a perinuclear pattern. There was no patient with Wegener's granulomatosis. Two cytoplasmic ANCA positive patients suffered from ulcerative colitis. Another cytoplasmic ANCA positive patient was a carrier of human immunodeficiency virus. Of the 39 perinuclear ANCA positive patients, 10 had MPA. Eight of them were tested for anti-MPO antibody, and all were positive. Other immune disorders that were perinuclear ANCA positive included: 13 patients with systemic lupus erythematosus, 3 with mixed connective tissue disease, 1 with Goodpasture's syndrome, 2 with inflammatory bowel disease, and 2 patients with IgA nephropathy. Anti-MPO antibody was not specific for MPA, and 7 out of the 13 patients with systemic lupus erythematosus were anti-MPO antibody positive. Our study suggests that ANCA and anti-MPO antibody are not specific for MPA in a Chinese population. They would alert the clinician of the possibility of vasculitis, but a clinicopathological correlation is essential in making the diagnosis.

Topics: Adolescent; Adult; Aged; Anti-Glomerular Basement Membrane Disease; Autoantibodies; Biomarkers; China; Colitis, Ulcerative; Cytoplasm; Female; Fluorescent Antibody Technique; Glomerulonephritis, IGA; Granulomatosis with Polyangiitis; HIV Infections; Humans; Inflammatory Bowel Diseases; Lupus Erythematosus, Systemic; Male; Middle Aged; Mixed Connective Tissue Disease; Myeloblastin; Neutrophils; Peroxidase; Polyarteritis Nodosa; Predictive Value of Tests; Serine Endopeptidases; Vasculitis

Wegener's granulomatosis (WG) and microscopic polyangiitis (MP) are "small vessel" vasculitides which can serologically be discriminated measuring autoantibodies directed towards different target antigens (ANCA). In the present study we can demonstrate increased autoimmunity in patients with MP, as evaluated by measurement of thyroid microsomal and cardiolipin antibodies. Neither thyroid microsomal- nor myeloperoxidase-, nor cardiolipin antibodies were correlated to each other.

Topics: Adult; Aged; Autoantibodies; Autoantigens; Cardiolipins; Female; Granulomatosis with Polyangiitis; Humans; Iodide Peroxidase; Male; Middle Aged; Peroxidase; Vasculitis

The role of immunoglobulin (Ig) isotype and affinity of antimyeloperoxidase (MPO) antibodies in the clinical expression of vasculitis (organ involvement, severity and evolution) remains incompletely defined. We have determined the anti-MPO antibody isotypes, as well as the apparent affinity constant (aK) of anti-MPO IgG by using fluid phase MPO inhibition of IgG binding in an MPO specific ELISA. Twenty-eight patients with anti-MPO antibodies and necrotic and crescentic glomerulonephritis, either isolated or associated to various other organ localizations, were analyzed. Serum samples were obtained before treatment and during follow-up. No association was observed between the isotype, the level or apparent affinity of anti-MPO antibodies and the clinical symptoms, severity, and organ distribution of vasculitis, including alveolar hemorrhage. No significant correlation was found between the apparent affinity and the level of anti-MPO IgG. However, the presence of anti-MPO IgM was clearly associated with low affinity anti-MPO IgG and vice versa. Furthermore, in a longitudinal study, high levels of anti-MPO IgM, when present, were observed early in the course of the disease and in some cases preceded the reappearance of anti-MPO IgG during relapses. High affinity anti-MPO IgG were usually present before treatment. Immunosuppressive therapy resulted in decreased apparent affinity and level of anti-MPO IgG. Importantly, anti-MPO IgG level increased during relapses but the affinity of these IgG autoantibodies remained low.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibody Affinity; Autoantibodies; Biomarkers; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Immunoglobulin G; Immunoglobulin Isotypes; Immunoglobulin M; Male; Middle Aged; Peroxidase

T cell-mediated immunity is hypothesized to play an important role in the pathogenesis of granulomatous inflammation and vasculitis as found in patients with WG. The antigenic specificities of those T cells remain, however, unknown. Anti-neutrophil cytoplasmic antibodies (ANCA) present in patients with WG are directed to proteinase 3 (PR3) and myeloperoxidase (MPO). In the present study we investigated the proliferative capacity of peripheral blood mononuclear cells (PBMC) from patients with WG and age- and sex-matched controls in response to the WG autoantigens PR3 and MPO. Possible mitogenic effects of active PR3 and toxic effects of active MPO were excluded by using heat-inactivated PR3 and MPO. Antigen-specific stimulation induced by these autoantigens was studied by using processed PR3 and MPO in the lymphocyte stimulation test (LST). Proliferation induced by processed antigen correlated with that by heat-inactivated free antigen. The general capacity to proliferate in response to mitogens and recall antigens did not differ between patients and controls. However, patients with WG who were or had been positive for PR3-ANCA (n = 17) responded more strongly to PR3 than to MPO and showed higher responses to PR3 compared with controls (n = 13). Within the PR3-ANCA group T cell proliferation did not correlate with ANCA titre. In a small group of patients with MPO-ANCA (n = 5) no differences were observed compared with controls for MPO-specific proliferation. The data presented demonstrate that autoreactive PR3-specific T cells are present in patients with WG. Their fine specificity and possible role in the pathogenesis of WG have to be defined in further studies.

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Antibody Specificity; Antigen-Presenting Cells; Antigens; Autoantibodies; Female; Granulomatosis with Polyangiitis; Histocompatibility Antigens Class II; Humans; Leukocytes, Mononuclear; Lymphocyte Activation; Male; Middle Aged; Mitogens; Myeloblastin; Peroxidase; Receptors, Antigen, T-Cell; Serine Endopeptidases; Stimulation, Chemical; T-Lymphocytes

The mechanisms underlying glomerular capillary wall injury in Wegener's granulomatosis (WG) are not well understood. Anti-neutrophil cytoplasmic antibodies (ANCA), present in sera from patients with WG, are known to stimulate respiratory burst and degranulation of primed polymorphonuclear neutrophils (PMN) in vitro. Experimental studies have shown that oxygen radical production and lysosomal enzymes are important mediators of glomerular capillary wall injury. In the present study we investigated the presence of activated PMN and the extracellular localization of lysosomal enzymes in 28 consecutive renal biopsies from patients with WG. The presence of activated PMN within the renal biopsies was compared with the capacity of ANCA, isolated from simultaneously drawn serum samples, to activate primed PMN obtained from a normal donor. Both parameters were also related to renal function. Renal biopsies were obtained from newly diagnosed WG patients before therapy had started. Activation of PMN in the biopsies was assessed by measuring hydrogen peroxide production in situ. The number of activated PMN in the biopsy correlated with the extent of impairment of renal function. Proteinase 3, myeloperoxidase, and elastase, all targets of ANCA, were localized extracellularly in renal tissue and were also found within tubular epithelial cells. All ANCA positive samples were capable of activating primed PMN. The amount of activation correlated with the ANCA titer in those samples. No correlation, however, was found between the in vitro capacity of ANCA-positive IgG fractions to activate primed PMN and the number of activated PMN present in the renal biopsy. We conclude that activated PMN producing toxic oxygen metabolites and releasing lysosomal enzymes, are present in renal biopsies from patients with WG. The amount of activated PMN present within the kidney, and not the capacity of the corresponding ANCA to activate PMN, correlates with renal tissue damage as assessed by serum creatinine levels.

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Autoantigens; Biomarkers; Complement System Proteins; Granulomatosis with Polyangiitis; Humans; Immunoglobulin G; Kidney; Myeloblastin; Neutrophils; Pancreatic Elastase; Peroxidase; Reactive Oxygen Species; Serine Endopeptidases; Superoxides

Binding of both proteinase 3 (PR3) and myeloperoxidase (MPO) to endothelial cells (EC) has been suggested to be involved in the vascular damage seen in patients with Wegener's granulomatosis or microscopic polyangiitis. In the present study we investigated in detail the interaction of MPO and PR3 with cultured human umbilical vein endothelial cells (HUVEC) and its matrix products. In addition, we investigated whether interaction of PR3 or MPO with HUVEC monolayers also resulted in antibody-dependent cell-mediated cytotoxicity (ADCC) mediated by anti-neutrophil cytoplasmic antibody (ANCA)-positive patient sera or rabbit IgG anti-PR3 or anti-MPO. Preincubation of HUVEC monolayers with PR3 or MPO resulted in a dose-dependent binding of both PR3 and MPO. However, HUVEC, preincubated with PR3 or MPO, followed by ANCA or by rabbit anti-PR3 or anti-MPO, were not susceptible to ADCC. Detailed analysis of the binding of PR3 to HUVEC monolayers showed that PR3 binds primarily to the extracellular matrix of endothelial cells, and to a very limited extent to the cells themselves. For MPO it was shown that it binds both to the extracellular matrix and to the endothelial cells themselves. However, after binding to HUVEC cultures, MPO was not detectable by polyclonal rabbit or human antibodies specific for MPO, probably because MPO is bound to sites not accessible for immunoglobulins. Binding of PR3 to HUVEC cultures (cells + matrix) was inhibited by fetal calf serum and by alpha 1-antitrypsin, but inactivation of enzymatic activity of PR3 by PMSF did not influence binding of PR3 to HUVEC cultures. Binding of MPO to HUVEC cultures was not influenced by fetal calf serum.

Topics: Animals; Antibodies, Antineutrophil Cytoplasmic; Antibody-Dependent Cell Cytotoxicity; Autoantibodies; Autoantigens; Blood Proteins; Cells, Cultured; Endothelium, Vascular; Extracellular Matrix; Granulomatosis with Polyangiitis; Humans; In Vitro Techniques; Myeloblastin; Peroxidase; Protein Binding; Rabbits; Serine Endopeptidases

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Autoantigens; Biomarkers; Granulomatosis with Polyangiitis; Humans; Myeloblastin; Peroxidase; Serine Endopeptidases

In systemic vasculitis reliable detection of myeloperoxidase antibodies (MPO-Abs) is of great clinical importance in the diagnosis and follow-up of patients. We have studied whether circulating myeloperoxidase (MPO) could have an effect on MPO-Ab findings. Serum MPO and MPO-Abs were measured in 50 healthy individuals, 35 patients and in the follow-up samples from two patients with Wegener's granulomatosis. Heating the sera at 56 degrees C for 30 min reduced the concentration of immunoreactive MPO both in control and patient sera. In 71% of the patient sera heating made initially negative MPO-Abs detectable. In a few cases with severe vasculitis the antibody findings remained totally negative. These results, together with the data from the follow-up samples from two patients with Wegener's granulomatosis, revealed that the serological diagnosis of vasculitis may be considerably delayed if only native samples are analysed for MPO-Abs. These findings are of considerable clinical significance for the interpretation of MPO-Ab results. Circulating myeloperoxidase affects MPO-Ab measurements, causing false negative findings in MPO-Ab assays. Therefore, it is recommended to denaturate circulating MPO by heating the sera before the analysis of MPO-Abs and to re-evaluate the cut off-values.

Topics: Adult; Aged; Aged, 80 and over; Autoantibodies; False Negative Reactions; Female; Follow-Up Studies; Granulomatosis with Polyangiitis; Hot Temperature; Humans; Male; Middle Aged; Peroxidase; Vasculitis

Proteinase 3/myeloblastin (Pr3/MBN) is a serine protease found in primary granules of neutrophilic granulocytes and monocytes in man. This enzyme has been identified as the main autoantigen in Wegener's granulomatosis. Pr3/MBN was earlier identified in the promyelocytic cell line HL-60 and was assumed to be at least partly responsible for controlling proliferation and differentiation within the granulocytic-monocytic system. We have investigated 98 leukemic cell lines representing all lineages of the hemopoietic system. Pr3/MBN was found to appear in mature myeloblastic precursors and in CD34+ immature monoblastic cells and was restricted to the granulocytic and monocytic lineage. Myeloperoxidase (MPO) was found to be expressed earlier in development in the granulocytic lineage, but appeared later than Pr3/MBN in the monocytic lineage. The identification of cell lines which contained Pr3 only or MPO only may make them useful for demonstration of anti-neutrophil cytoplasmic antibodies in primary vasculitides.

Topics: Autoantigens; Granulomatosis with Polyangiitis; Humans; Immunohistochemistry; Leukemia; Myeloblastin; Peroxidase; Phylogeny; Serine Endopeptidases; Tumor Cells, Cultured

Sera from 76 patients with diverse vasculitis, systemic lupus erythematosus (SLE) and hydralazine-induced lupus (HiL) were analysed by ELISA for their reactivity with native, reduced or urea-denatured MPO, respectively, as well as with bacterially expressed heavy and light subunits of MPO. All sera (n = 20) recognizing native MPO showed a positive reaction with reduced MPO, while 12 recognized the denatured protein. Most of the linear epitopes are located in the light subunit, since 9 MPO-positive sera recognized significantly the bacterially expressed, denatured light subunit, while only one serum recognized the bacterially expressed heavy subunit purified under denaturing conditions.

Topics: Antibodies, Antineutrophil Cytoplasmic; Antibody Specificity; Autoantibodies; Enzyme-Linked Immunosorbent Assay; Epitopes; Granulomatosis with Polyangiitis; Humans; Lupus Erythematosus, Systemic; Peroxidase; Protein Denaturation; Recombinant Proteins; Urea; Vasculitis

From 1987 to 1991, 2500 sera were tested for presence of anti-neutrophil cytoplasmic antibodies (ANCA) by standard indirect immunofluorescence (IIF) and specific proteinase 3 (PR3) and myeloperoxydase (MPO) ELISA. Clinical and histological data leading to precise diagnosis were retrospectively obtained in 98 patients with ANCA positivity by IIF and then a comparative study based on ANCA specificity was performed. Vasculitis was present in all cases. Among patients with anti-PR3 (n = 38), 19 had Wegener's granulomatosis (WG), 15 microscopic polyarteritis (mPA), 2 idiopathic necrotizing and crescentic glomerulonephritis (NCGN) and 2 relapsing polychondritis (RP). Among patients with anti-MPO (n = 45), 26 had mPA, 3 classical polyarteritis nodosa (PAN), 5 WG, 8 NCGN, 2 systemic lupus erythematosus (SLE) and one Churg-Strauss syndrome (CSS). Negative MPO and PR3 specific ELISA despite positive IIF were observed in 15 patients (13 WG, 1 mPA, 1 PAN). In the PR3 group, males predominated (66%) and the mean age was 49 years (range 13-85); in the MPO group, females predominated (62%) and the mean age was 57 years (range 13-85). These differences were statistically significant (p < 0.05). Renal involvement was present in 92% of patients and renal biopsy showed pauci-immune necrotizing and crescentic glomerulonephritis in nearly all cases. PR3 specificity was associated with frequent eye involvement (32%) and presence of granulomas (45%), but was not associated with other autoantibodies. MPO specificity was associated with a higher prevalence of pulmonary hemorrhage (40%) and various autoimmune disorders, especially antinuclear antibodies. Cholestasis was observed in 50% of WG with negative MPO and PR3 ELISA. Renal and patient survival at the 75th percentile was 15 months with MPO-ANCA and 16 months with PR3, and was similar for patients with WG and mPA. Relapses occurred in 20% of patients with anti-MPO and 36% of patients with anti-PR3. Serological follow-up was obtained in 44 patients. With immunosuppressive treatment, ANCA disappeared in 66% of cases and this disappearance was always associated with absence of disease activity.. 1. This study confirms that the presence of ANCA is a good marker of vasculitis. 2. Despite some clinical differences, MPO and PR3-associated vasculitis have a similar prognosis. 3. The titer of ANCA determined by ELISA is not correlated with the severity of vasculitis but disappearance of ANCA is always associated with absence of disease activity.

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Biomarkers; Enzyme-Linked Immunosorbent Assay; Epitopes; Female; Fluorescent Antibody Technique; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Immunoglobulin G; Male; Middle Aged; Myeloblastin; Peroxidase; Polyarteritis Nodosa; Serine Endopeptidases

Clinical and histological data leading to precise diagnosis were retrospectively obtained in 98 patients with antineutrophil cytoplasmic antibodies (ANCA) detected by indirect immunofluorescence (IIF). Specificity was determined by myeloperoxidase (MPO) and proteinase 3 (PR3) specific ELISA in all and a comparative study based on ANCA specificity was performed. Vasculitis was present in all cases. PR3-ANCA occurred predominantly in males (25/38) with WG (19/38). MPO-ANCA occurred predominantly in older women and were often associated with various autoimmune disorders. There was a high prevalence of lung hemorrhage (18/45) and mPA (26/45) in this group. Patients with negative MPO and PR3 specific ELISA despite positive IIF (n = 15) were almost exclusively WG (13/15) and were characterized by a high prevalence of hepatic and digestive manifestations. Renal and patient survival at the 75th percentile was 15 months with MPO-ANCA and 16 months with PR3, and was similar for patients with WG and mPA. With immunosuppressive treatment, ANCA disappeared in 66% of cases and this disappearance was always associated with absence of disease activity.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Antibody Specificity; Autoantibodies; Autoimmune Diseases; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Lung Diseases; Male; Middle Aged; Myeloblastin; Peroxidase; Polyarteritis Nodosa; Retrospective Studies; Serine Endopeptidases; Vasculitis

We studied sera from patients with vasculitis and controls for the presence of anti-endothelial cell antibodies (AECA) and correlated these with disease type, anti-neutrophil cytoplasmic antibodies (ANCA) and anti-myeloperoxidase (MPO) antibodies. AECA were detected by a cellular ELISA on cultured human umbilical vein endothelium. AECA were found in the sera of one of 43 patients with microscopic polyarteritis (2%), five of 27 patients with Wegener's granulomatosis (19%), three of 23 patients with an idiopathic glomerulonephritis (13%), none of eight patients with rheumatoid arthritis and three of 12 patients with rheumatoid vasculitis (25%). In patients with a vasculitis AECA titres were higher in sera with a positive ANCA as compared with ANCA negative sera although the difference was not significant (P = 0.0702) and there was no correlation between AECA and anti-MPO titres (r = 0.1171 P = 0.114). AECA binding was not enhanced following upregulation of endothelial ICAM-1 and ELAM-1 by TNF alpha. This study shows that AECA occur infrequently in microscopic polyarteritis and Wegener's granulomatosis, and are not a major antibody system in these vasculitides.

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Endothelium, Vascular; Granulomatosis with Polyangiitis; Humans; Immunoglobulin G; Peroxidase; Polyarteritis Nodosa; Tumor Necrosis Factor-alpha

The prevalence of positive ANCA as well as the prevalence of PR-3 and MPO antibodies were examined in a cross-sectional sample of 1277 haemodialysis patients from 16 German haemodialysis centres. We found 32 patients positive for c-ANCA (median titre 1:40; range 1:20-1:320) and 65 for p-ANCA (1:80; 1:20-1:1280). Twenty-two percent of the c-ANCA-positive and 31% of the p-ANCA-positive patients had PR-3 and MPO antibodies by ELISA respectively. Clinical evidence of vasculitis was found in 11 of 32 c-ANCA-positive and 19 of 65 p-ANCA-positive patients. Of the 11 c-ANCA-positive, four had a known diagnosis of Wegener's granulomatosis (WG); WG was recognized after the test in a further five patients and two had renal limited RPGN. Of the 19 p-ANCA-positive patients, three had a clinical diagnosis of microscopic polyarteritis (MP), MP was newly diagnosed in a further 12, WG in one and renal limited RPGN in three. The patients had not received cyclophosphamide (the diagnosis had been non-specified 'systemic disease'). Thus false-positive ANCA, as defined by absence of vasculitis, was found in 5% of dialysis patients versus 0% in patients with preterminal renal failure (n = 152) or blood donors (n = 150). Patients with vasculitis tended to have higher c-ANCA and p-ANCA titres respectively, but there was a considerable overlap. Titres were not higher in patients symptomatic at the time of examination (6 of 11 c-ANCA and 10 of 19 p-ANCA), but PR-3 and MPO ELISA were positive in all but two.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Cross-Sectional Studies; Female; Granulomatosis with Polyangiitis; Humans; Male; Middle Aged; Myeloblastin; Neutrophils; Peroxidase; Renal Dialysis; Serine Endopeptidases; Vasculitis

It was the aim of this study to reevaluate the diagnostic significance and clinical implication of ANCA after testing sera from 13,606 patients for the presence of ANCA. Our data confirm the high specificity (97%) and sensitivity (80%) of cANCA for Wegener's granulomatosis. pANCA were found in renal vasculitides (60%), collagen vascular diseases (SLE 20%, Sjögren's syndrome 26%, polymyositis 16%) and rheumatic disorders (Felty's syndrome 50%, rheumatoid arthritis 20%). A third fluorescence pattern in sera of patients with inflammatory bowel disease (ulcerative colitis 28/72, Crohn's disease 6/84), here called xANCA, was seen. Target antigens of granule proteins from PMN and monocytes (proteinase 3, myeloperoxidase, elastase, cathepsin G, lactoferrin, lysozyme) were identified.

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Autoantigens; Collagen Diseases; Granulomatosis with Polyangiitis; Humans; Inflammatory Bowel Diseases; Myeloblastin; Peroxidase; Rheumatic Diseases; Serine Endopeptidases; Vasculitis

Thirty five (41%) sera presented anti MPO specificity, 26 of them (74%) having a p-ANCA pattern. They were present in patients with vasculitis and isolated or predominant renal involvement, but also in 24% of Wegener patients.

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Peroxidase; Vasculitis

In a prospective study of 27 months duration p-ANCA were found in 120 patients. 35% of these patients had vasculitis and/or glomerulonephritis. 28% of the p-ANCA positive sera reacted with myeloid lysosomal enzymes.

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Fluorescent Antibody Technique; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Lysosomes; Myeloblastin; Neutrophils; Pancreatic Elastase; Peroxidase; Prospective Studies; Serine Endopeptidases; Vasculitis

We have conducted a prospective study of 372 patients with well-defined forms of systemic vasculitis and connective tissue diseases to determine the prevalence, the antigenic specificities and the clinical associations of ANCA in such cases. These antibodies were detected by indirect immunofluorescence on ethanol-fixed neutrophils and also by enzyme-linked immunosorbent assay using myeloperoxidase (MPO) as a substrate. In our study, ANCA with a cytoplasmic immunostaining pattern were mainly found in patients with biopsy-proven Wegener's granulomatosis with or without renal involvement and pulmonary hemorrhage. Furthermore, MPO-ANCA strongly correlated with necrotizing glomerular and alveolar capillaritis, mostly in patients having a well-established diagnosis of polyarteritis nodosa.

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Autoantigens; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Glomerulonephritis; Granulomatosis with Polyangiitis; Hemorrhage; Humans; Immunoglobulin G; Lung Diseases; Peroxidase; Prospective Studies; Vasculitis

Sera from patients with a vasculitis and controls were investigated for the presence of anti-endothelial cell antibodies(AECA), anti- neutrophil cytoplasmic antibodies(ANCA) and anti-myeloperoxidase (MPO) antibodies. Only 19% of patients with Wegener's granulomatosis and 2% of patients with microscopic polyarteritis had AECA. Our data suggests that AECA are a minor antibody system in vasculitis.

Topics: Antibodies, Antineutrophil Cytoplasmic; Arteritis; Autoantibodies; Autoantigens; Endothelium, Vascular; Granulomatosis with Polyangiitis; Humans; Immunoglobulin G; Immunoglobulin M; Peroxidase

We studied the presence of proteinase 3 (PR3), myeloperoxidase (MPO) and elastase (HLE) on the plasma membrane of neutrophils in patients with biopsy-proven Wegener's disease (WG), pANCA-positive vasculitis, control patients (SLE, rheumatoid arthritis, ankylosing spondylitis), sepsis patients and healthy donors. We found an overexpression of PR3 on the cell surface of neutrophils in WG, ANCA-associated vasculitis and during infection (sepsis). Thus PR3 becomes accessible to ANCA. Furthermore we detected intracytoplasmic IgG antibodies in PMN from patients with WG by immunoelectron microscopy and direct immunofluorescence. Our findings support the pathophysiological role of ANCA.

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Cell Membrane; Granulomatosis with Polyangiitis; Humans; Immunoglobulin G; Myeloblastin; Neutrophils; Pancreatic Elastase; Peroxidase; Serine Endopeptidases; Vasculitis

Sera of 108 patients with chronic inflammatory bowel disease (IBD) and 13 sera from patients with other gastrointestinal diseases were screened for antibodies against neutrophil cytoplasmic antigens (ANCA) by an indirect immunofluorescence test. 37 out of 64 sera (58%) from patients with ulcerative colitis (UC) produced a fine granular and perinuclear ANCA staining pattern ("snowdrift-like" p-ANCA) clearly different from the cytoplasmic ANCA fluorescence (c-ANCA) seen in active Wegener's granulomatosis (WG) and the typical p-ANCA pattern produced by anti-myeloperoxidase (MPO) autoantibodies. Only 1 of 44 sera from patients with Crohn's disease (CD) and none of the control sera showed positive "snowdrift-like" p- ANCA reactions. 31 out of the 37 p-ANCA positive sera (84%) were obtained from patients with high disease activity with and without longterm high dose steroids. p-ANCA titers became negative after longterm steroid therapy and following complete colectomy.

Topics: Adult; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Colitis, Ulcerative; Crohn Disease; Female; Fluorescent Antibody Technique; Gastrointestinal Diseases; Granulomatosis with Polyangiitis; Humans; Immunoglobulin G; Male; Myeloblastin; Peroxidase; Serine Endopeptidases

We studied the histologic findings from extrarenal biopsies (especially of the lung or upper respiratory tract) or autopsies of 68 patients who were tested for serum antineutrophil cytoplasmic antibodies (ANCAs). We used antigen-specific assays to detect antibodies against proteinase 3 (PR3) and myeloperoxidase (MPO), the two types of ANCAs of proven diagnostic value for the spectrum of diseases that includes Wegener's (pathergic) granulomatosis, microscopic polyarteritis (microscopic polyangiitis), Churg-Strauss syndrome, idiopathic necrotizing and crescentic glomerulonephritis, and their variants. Twenty-eight patients had antibodies to PR3 and 16 had antibodies to MPO; no patient had antibodies to both. All 44 patients with ANCAs had histologic evidence of this spectrum of diseases. Thirteen patients without histologic evidence of this spectrum of diseases had negative tests for ANCAs. There were no pathologic features that reliably identified patients with one or the other type of ANCA. Eighteen of 31 patients with lesions of Wegener's granulomatosis had antibodies to PR3, seven had antibodies to MPO, and six had neither. Three of four patients with necrotizing arteries without granulomas had anti-MPO antibodies, but similar lesions were seen, together with extravascular granulomas, in three patients with anti-PR3 antibodies. Of 16 patients with alveolar hemorrhage, nine had anti-PR3 and five had anti-MPO antibodies. Two patients diagnosed clinically as having Churg-Strauss syndrome had anti-MPO antibodies. In 16 of the 25 patients with ANCAs and a histologic diagnosis of Wegener's granulomatosis the diagnosis was made on the basis of extravascular granulomatous lesions alone, which argues against the requirement for vasculitis. Of six patients with negative tests for ANCAs and histologically diagnosed Wegener's granulomatosis, none had evidence of renal involvement. We conclude that in the appropriate clinical setting the presence of anti-PR3 or anti-MPO antibodies provides reliable evidence of the above spectrum of diseases, but that subclassification (to the extent this is possible) depends on the presence of distinctive clinical or pathologic features. In patients with negative tests for ANCAs, interpretation of clinical and histologic findings remains the only definitive method of diagnosis.

Topics: Antibodies, Antineutrophil Cytoplasmic; Arteritis; Autoantibodies; Churg-Strauss Syndrome; Enzyme-Linked Immunosorbent Assay; Female; Granulomatosis with Polyangiitis; Hemorrhage; Humans; Immunoglobulin G; Immunohistochemistry; Lung Diseases; Male; Myeloblastin; Peroxidase; Pulmonary Alveoli; Serine Endopeptidases; Vasculitis

Antineutrophil cytoplasmic antibodies (ANCAs) constitute a new class of autoantibodies that seem to recognise myeloid lysosomal enzymes. The occurrence of ANCAs with specificity for human leucocyte elastase (HLE) was assessed in serum samples that were routinely submitted for ANCA determination. During a study period of more than six years anti-HLE was found in only six out of 1102 serum samples that produced a perinuclear or an atypical cytoplasmic staining pattern on ethanol fixed granulocytes. These six serum samples were from four patients with a clinical diagnosis of Wegener's granulomatosis but without a definite histological diagnosis, one patient with systemic vasculitis, and one patient with Cogan's syndrome. To further evaluate the prevalence of anti-HLE we tested 315 serum samples from patients with different forms of vasculitis and related disorders. Anti-HLE was detected in two patients only. Thus autoantibodies to HLE are rarely found in serum samples from patients with vasculitic or related disorders.

Topics: Aged; Aged, 80 and over; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Enzyme-Linked Immunosorbent Assay; Female; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Immunoglobulin G; Leukocyte Elastase; Male; Middle Aged; Myeloblastin; Pancreatic Elastase; Peroxidase; Serine Endopeptidases; Vasculitis

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Granulomatosis with Polyangiitis; Humans; Kidney Diseases; Peroxidase

ANCA positive sera, detected by the standard immunofluorescence method, derived from 37 patients with vasculitis were studied using formalin-acetone fixed chronic myelocytic leukemia cells (CML). All 37 sera were positive on CML cell smears. Furthermore formalin-actone fixation selectively impaired antinuclear antibody binding without reducing ANCA staining and thus facilitated differentiation of these autoantibodies which is often difficult with the standard immunofluorescence method. Two unequivocal and mutually exclusive ANCA binding patterns were identified using the CML smears: (1) type I with diffuse granular binding confined to the polymorphonuclear (PMN) cell lineage and preferentially staining immature cells; (2) type II with similar binding to the PMN cell lineage and, in addition, granular staining of the basophils. All type I antibodies were associated with a c-ANCA pattern suggesting that the major antigen recognized by these antibodies, recently identified as proteinase 3, is not detectable in basophils. The type II pattern was detected in both p-ANCA (84%) and c-ANCA (16%) positive sera. The type I sera remained positive on PMN cells from a myeloperoxidase (MPO) deficient subject and anti-MPO antibodies could not be detected in this group by ELISA. Conversely the type II pattern occurred in the presence of anti-MPO antibodies identified by immunofluorescence, ELISA and dot-blot with the exception of a single serum with antilactoferrin antibody. Type I binding only was observed in Wegener's granulomatosis (WG) but both patterns were found in microscopic polyarteritis (MPA) and rapidly progressive glomerulonephritis (RPGN).

Topics: Antibodies, Antineutrophil Cytoplasmic; Antibodies, Antinuclear; Antibody Specificity; Autoantibodies; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Granulomatosis with Polyangiitis; Humans; Immunoglobulin G; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Neutrophils; Peroxidase

Topics: Adrenal Cortex Hormones; Antibodies; Asthma; Churg-Strauss Syndrome; Diagnosis, Differential; Eosinophilia; Granulomatosis with Polyangiitis; Humans; Male; Middle Aged; Peroxidase

The antigen specificity of autoantibodies causing perinuclear staining of granulocytes and monocytes (pANCA) was evaluated by analyzing 3000 sera, which were sent to us for screening of anticytoplasmic antibodies (ACPA, synonym: cANCA, anti-proteinase 3). In 620 sera, perinuclear staining was found. Antigen specificity was investigated by a myeloperoxidase ELISA and indirect immunofluorescence with Hep2 cells specific for antinuclear antibodies (ANA). Only 9.8% of the 620 sera showed reactivity with myeloperoxidase (AMPO), while 85.6% contained ANA which induced a pANCA-like staining. A further 4.6% of the 620 sera were neither ANA nor AMPO positive. Therefore, pANCA in general is only an indication that one should look for AMPO or other antilysosomal autoantibodies, when ANA have been excluded. To investigate the disease specificity of AMPO, we examined sera from patients with several well-defined autoimmune diseases. There were only very few positive results in collagen vascular diseases (3/114) (positive/total), primary systemic vasculitis (1/116) and clinically and histologically proven Wegener's granulomatosis (2/213). On the other hand, AMPO were present in patients with different forms of glomerulonephritis (45/192), especially crescentic glomerulonephritis (CGN) (34/79) without immune deposits in their biopsy specimen (3/30 showed trace deposits of IgM). There were, however, additionally 11 patients with symptoms resembling WG (who were cANCA negative, w/o characteristic WG biopsy), who had no obvious renal symptoms. These findings indicate that AMPO are primarily associated with idiopathic GN, especially CGN. Together with anti-proteinase-3 antibodies and anti-glomerular basement membrane antibodies they are an essential serologic parameter in the diagnosis of unclear systemic diseases with renal involvement.

Topics: Antibodies, Antineutrophil Cytoplasmic; Antibodies, Antinuclear; Autoantibodies; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Myeloblastin; Peroxidase; Prospective Studies; Serine Endopeptidases; Vasculitis

Antiglomerular basement membrane (anti-GBM) diseases-including Goodpasture's (GP) syndrome-and Wegener's granulomatosis (WG) are systemic diseases, which may be diagnosed by means of circulating autoantibodies. Possible overlap syndromes may exist; however, they remain imperfectly defined. We analyzed sera from 31 patients with WG and from 23 patients with anti-GBM disease. All underwent biopsy. Anti-cytoplasmic antibodies (ANCA) were demonstrated by indirect immunofluorescence (IIF); a perinuclear (P-ANCA) or diffuse-cytoplasmic (C-ANCA) staining was discerned. In addition, myeloperoxidase (MPO) antibodies (P-ANCA) and protein 3 (SP3) antibodies (C-ANCA) were analyzed by specific ELISA systems. Anti-GBM antibodies (anti-NC1 antibodies) were detected by ELISA and immunoblotting; the globular domain NC1 of collagen IV was employed as antigen. All 31 WG patients, as defined by clinical and histological criteria, showed ANCA by IIF. Twenty-nine of 31 showed a C-ANCA pattern; all were also positive for SP3 antibodies by ELISA. Three of 31 WG patients were P-ANCA positive by IIF and also had anti-MPO antibodies by ELISA. In one of these patients, SP3 antibodies were additionally found by IIF and by ELISA (double positive). No patient with WG had anti-NC1 antibodies. All 23 serum samples from patients with GP syndrome (N = 19) or anti-GBM glomerulonephritis (N = 4) had anti-NC1 antibodies. In seven of these patients, low titers of anti-MPO antibodies were detected by ELISA; however, the IIF for ANCA was negative. None of these seven patients had extraglomerular vasculities. In addition, the clinical prognosis of these patients was similar to that of those patients who lacked these antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Anti-Glomerular Basement Membrane Disease; Autoantibodies; Autoimmune Diseases; Basement Membrane; Creatinine; Cytoplasm; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique; Granulomatosis with Polyangiitis; Humans; Kidney Glomerulus; Male; Middle Aged; Neutrophils; Peroxidase

We conducted a prospective study of 651 Mediterranean patients from Catalonia (Spain) with well-defined forms of systemic vasculitis, connective tissue diseases, and renal and pulmonary disorders to determine the prevalence and clinical value of antineutrophil cytoplasmic autoantibodies (ANCA) with myeloperoxidase (MPO) specificity (MPO-ANCA). ANCA were first tested by indirect immunofluorescence on ethanol-fixed neutrophils. When a positive result was obtained, then MPO-ANCA were identified by performing the immunofluorescence assay again on neutrophils from a voluntary donor known to have a complete and selective deficiency of MPO. This disorder was detected by automated flow cytochemistry with the Technicon system and was further verified by cytochemical and biochemical studies. We detected MPO-ANCA in 61 of 70 (87%) patients with a perinuclear pattern (p-ANCA), but in none of 25 with a cytoplasmic pattern (c-ANCA). These results were corroborated by enzyme-linked immunosorbent assay (ELISA) using human purified MPO as a substrate. On immunofluorescence microscopy, all patients with MPO-ANCA were found to have a typical and restrictive immunostaining pattern. In our study, while c-ANCA were mainly found in patients with biopsy-proven Wegener's granulomatosis, MPO-ANCA identified those with idiopathic and polyarteritis nodosa-associated necrotizing and crescentic glomerulonephritis. In addition, pulmonary hemorrhage with necrotizing alveolar capillaritis as the main morphologic substrate occurred frequently among patients with MPO-ANCA, including three affected by polyarteritis nodosa and three who had pulmonary hemorrhage as the only clinical finding. On the other hand, these antibodies could be also detected in 30% of patients with a proven diagnosis of anti-glomerular basement membrane (GBM) disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Glomerulonephritis; Granulomatosis with Polyangiitis; Hemorrhage; Humans; Immunoglobulin G; Lung Diseases; Peroxidase; Prevalence; Prospective Studies; Spain

ANCA are markers for systemic vasculitis such as Wegener's granulomatosis (WG) and microscopic polyarteritis (MPA) and are usually of the IgG isotype. However, IgM ANCA may rarely occur in isolation, and in these circumstances, we have found that they are associated clinically with a syndrome of pulmonary hemorrhage and systemic vasculitis. How frequently IgM ANCA may occur in conjunction with IgG has not previously been investigated. We report here a study of 24 consecutive patients with IgG ANCA-positive systemic vasculitis (14 WG, 10 MPA) in whom we determined whether IgM ANCA occurred in association with IgG ANCA, and if so, whether this had clinical importance. Eight patients were found to have IgM ANCA as well as IgG ANCA, and of these, seven presented with severe pulmonary hemorrhage. None of the IgM ANCA-negative patients presented with pulmonary hemorrhage. Although the occurrence of pulmonary hemorrhage in ANCA positive vasculitis was closely correlated with the presence of IgM ANCA, the antigen specificity of these IgM autoantibodies was variable, since both myeloperoxidase (4 patients), PR3 (3 patients), and an unknown ANCA antigen (1 patient) were found to be targets. We conclude that knowledge of ANCA isotype may have important clinical and therapeutic implications for the management of patients with systemic vasculitis.

Topics: Adolescent; Adult; Aged; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Biomarkers; Female; Granulomatosis with Polyangiitis; Hemorrhage; Humans; Immunoglobulin G; Immunoglobulin Isotypes; Immunoglobulin M; Lung Diseases; Male; Middle Aged; Peroxidase; Polyarteritis Nodosa; Syndrome

Although proteinase 3 (PR3) has been identified as a major autoantigen in Wegener's granulomatosis, the precise antibody specificity(ies) and requirements for epitope recognition have not been characterized. We analyzed 11 sera containing antineutrophil cytoplasmic antibodies (cANCA) for binding to azurophilic granule proteins extracted from neutrophils under various conditions and for binding to native or rPR3. Ten of 11 (91%) of the cANCA sera bound to PR3 extracted by nonionic detergents when tested by immunoprecipitation or by IEF followed by capillary immunoblotting. Antibody binding to PR3 was retained when IEF was performed under dissociating conditions (8 M urea) indicating that PR3 is the major autoantigen in azurophilic granules and that association with other proteins is not required for antigenicity. In contrast, antigenicity was totally destroyed by exposure of PR3 to reducing agents or to low pH (less than 3.0) and was either lost or considerably diminished after boiling in SDS. cANCA sera also showed little or no binding to rPR3 expressed as a fusion protein in Escherichia coli or synthesized by wheat germ ribosomes in vitro. Inasmuch as PR3 enzymatic activity was partially retained after acid extraction, these findings indicate that cANCA bind to a limited number of conformational epitopes on PR3. In addition, IEF followed by capillary immunoblotting appears to be a sensitive and specific method to detect anti-PR3 antibodies in Wegener's granulomatosis.

Topics: Antibody Specificity; Autoantibodies; Autoantigens; Blotting, Western; Cytoplasm; Enzyme-Linked Immunosorbent Assay; Epitopes; Granulomatosis with Polyangiitis; Humans; Hydrogen-Ion Concentration; Mercaptoethanol; Myeloblastin; Neutrophils; Peroxidase; Precipitin Tests; Protein Conformation; Protein Denaturation; Recombinant Fusion Proteins; Serine Endopeptidases; Sodium Dodecyl Sulfate

Antibodies directed against myeloperoxidase (anti-MPO) were detected, using a solid-phase ELISA and purified sputum myeloperoxidase as the substrate, in 54 sera from 22 patients. Anti-MPO were present in 17 patients with crescentic glomerulonephritis (CGN), Wegener's granulomatosis (WG) and microscopic polyarteritis (MPA), and thus are associated with different forms of vasculitis. Anti-MPO were also present in five out of 20 patients with systemic lupus erythematosus (SLE). Anti-MPO activity in SLE sera was low, in contrast to the high titers observed in patients with vasculitis. All positive sera had IgG anti-MPO (except two SLE sera) and most of them also contained low-titered IgM anti-MPO. Only three patients had high IgM anti-MPO activities, the significance of which remains to be determined. In patients with CGN, WG or MPA, the anti-MPO titer decreased following therapy and paralleled the disease activity. Thus, anti-MPO constitute a useful diagnostic tool and a sensitive marker of disease activity in this group of patients with vasculitis.

Topics: Arteritis; Autoantibodies; Enzyme-Linked Immunosorbent Assay; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Immunoglobulin G; Immunoglobulin M; Lupus Erythematosus, Systemic; Neutrophils; Peroxidase

Proteinase 3 was identified as the target antigen of anticytoplasmic antibodies (ACPA/c-ANCA) in Wegener's granulomatosis (WG). Using the murine monoclonal antibody (MAb) WGM2, the authors localized proteinase 3 on normal and pathologic tissue and in various human cell lines. Proteinase 3 was found in all granulocytes, mast cells, and a subset of monocytes (2-10% of peripheral blood monocytes). No crossreactivity of the MAb with other cells or tissue components was observed. Comparing various vasculitic and granulomatous tissues, WG granulomas contained more granulocytes. In tissue of WG, no crossreactivity of the MAb with tissue components such as blood vessel wall or endothelium was seen. The monocytic line THP-1 and the promyelocytic line HL 60 contained proteinase 3. Since proteinase 3 was only found in neutrophil granulocytes, mast cells, and a subset of monocytes, the presented data provide further evidence that granulocytes play a central role in the pathogenesis of WG.

Topics: Antibodies; Antibodies, Monoclonal; Antigens; Cell Line; Cytoplasm; Cytoplasmic Granules; Fluorescent Antibody Technique; Granulocytes; Granulomatosis with Polyangiitis; Humans; Immunohistochemistry; Macrophages; Mast Cells; Microscopy, Electron; Monocytes; Myeloblastin; Neutrophils; Peroxidase; Serine Endopeptidases

Classic anti-neutrophil cytoplasm antibodies (cANCA), perinuclear ANCA (pANCA) and antibodies directed against myeloperoxidase (MPO-Ab) were evaluated in 25 patients with either idiopathic or secondary rapidly progressive glomerulonephritis (RPGN). While cANCA were found almost exclusively in Wegener's granulomatosis, pANCA were detectable in several disorders, including microscopic polyarteritis (mPA), but also idiopathic RPGN. MPO-Ab were frequently found in sera from patients with all types of idiopathic but not of secondary RPGN. These results support the hypothesis that some cases of RPGN are early or limited forms of systematic vasculitis. We then looked for the presence of IgA-ANCA in Henoch-Schoenlein purpura (HSP): we found IgA-ANCA with immunoenzymatic assay but not with immunofluorescence in HSP, in primary IgA-GN and in membranous GN as well, thus suggesting the poor specificity of this type of ANCA. The possible pathologic implications of ANCA were examined in vitro. Serum samples from several patients with ANCA were assessed for their capacity to enhance chemiluminescence generation from resting or PMA-stimulated macrophages. Sera from RPGN and mPA patients displaying anti-MPO activity induced granulocytes to enhance the production of oxygen free radicals, thus suggesting a phlogistic effect of MPO-Ab positive sera.

Topics: Adult; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Biomarkers; Fluorescent Antibody Technique; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; IgA Vasculitis; Immunoglobulin G; Luminescent Measurements; Middle Aged; Peroxidase

Topics: Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Immunoglobulin G; Peroxidase; Polyarteritis Nodosa

In view of the supposed hypersensitivity, the elevated levels of IgE, and the occurrence of eosinophilia reported in Wegener's granulomatosis and related conditions, we studied the IgG subclass distribution of ANCA directed against a 29-kD serine protease and myeloperoxidase (MPO) in 41 untreated ANCA-positive patients with several forms of active vasculitis and/or glomerulonephritis. We found that both 29-kD ANCA and MPO ANCA were predominantly of the IgG1 and IgG4 subclass in all groups of patients. The additional presence of IgG3 subclass was associated with renal involvement. We compared the subclass distribution of ANCA with that of total IgG subclass levels, and with the IgG subclass distribution of antibodies to cytomegalovirus (CMV) as a persistent endogenous antigen and antibodies to tetanus toxoid (TT) as an exogenous recall antigen. Total levels of IgG4 were elevated in the majority of the patients together with elevated IgG1 levels. Antibodies to CMV and TT, however, had the same subclass distribution as found in normals and did not show enhanced IgG4 expression. ANCA belong predominantly to the IgG1 and IgG4 subclass, which may suggest that the production of ANCA is related to recurrent exposition to the antigen(s) involved, possibly as part of a hypersensitivity reaction.

Topics: Adult; Aged; Autoantibodies; Cytomegalovirus; Female; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Immunoglobulin E; Immunoglobulin G; Male; Middle Aged; Molecular Weight; Neutrophils; Peroxidase; Serine Endopeptidases; Tetanus Toxoid; Vasculitis

Antibodies that are directed against cytoplasmic constituents of neutrophils and monocytes (anti-neutrophil cytoplasm antibodies, ANCA) have been described in Wegener's granulomatosis, microscopic polyarteritis (MPA) and some cases of segmental necrotizing glomerulonephritis (SNGN). Other antibodies occasionally described in Wegener's granulomatosis and MPA include anti-nuclear antibodies (ANA) and anti-glomerular basement membrane (GBM) antibodies. We have studied the diversity of the corresponding antigens in ANCA-associated renal diseases. Sera from 46 patients with active histologically proven Wegener's granulomatosis, MPA and SNGN were tested for ANCA by indirect immunofluorescent examination of normal peripheral blood neutrophils. Thirty-four sera (74%) were positive; 16 were associated with diffuse cytoplasmic staining (cANCA) and 18 with perinuclear staining (pANCA). In addition, five demonstrated antineutrophil-specific nuclear staining (ANNA). On Western blotting of the neutrophil extract, five sera recognized a 29-kD molecule recently identified as neutrophil proteinase 3. Two sera with typical cANCA bound to molecules of 36, 38 and 116 kD and another to a molecule of 22 kD. The final serum associated with pANCA bound to a molecule of about 12 kD. Thirteen sera out of 46 (28%) tested in an ELISA contained anti-myeloperoxidase antibodies; 10 of these were associated with pANCA and two others with ANNA. Three sera of 17 (18%) tested contained anti-elastase antibodies; these also contained anti-myeloperoxidase antibodies and were associated with pANCA. However, eight sera with pANCA were negative for anti-myeloperoxidase antibodies and three of these were also negative for anti-elastase antibodies, suggesting further unidentified target antigen or antigens associated with the pANCA. Fifteen of the 34 sera positive for ANCA also demonstrated anti-nuclear staining on Hep-2 cells (53%) in a speckled, homogeneous, or nucleolar pattern. ANA were significantly associated with the presence of pANCA (P less than 0.01), and levels of ANA and ANCA fell in parallel after treatment. One serum with a pANCA was also positive for anti-GBM antibodies. Inhibition studies using ELISAs for anti-GBM antibodies indicated that there was no cross-reactivity between target molecules recognized by these antibodies. The diversity of target molecules recognized by ANCA suggests that cross-reactivity with bacterial structures is less likely as the primary aetiological event

Topics: Antibodies, Antinuclear; Antibody Diversity; Autoantibodies; Autoantigens; Basement Membrane; Cytoplasm; Granulomatosis with Polyangiitis; Humans; Kidney Diseases; Kidney Glomerulus; Neutrophils; Pancreatic Elastase; Peroxidase; Polyarteritis Nodosa; Vasculitis

Anti-neutrophil cytoplasmic autoantibodies (ANCA) associated with active Wegener's granulomatosis are directed against a soluble 29-Kd protein present in human neutrophils and monocytes. Affinity labeling with tritiated diisopropylfluorophosphate (3H-DFP) suggested that ANCA-antigen is a serine protease. We used immunoelectron microscopy to study the in situ localization of the ANCA-antigen in normal human neutrophils and monocytes using immunoglobulin G (IgG) from ANCA-positive patients and a mouse monoclonal antibody against the ANCA-antigen. Label was observed on the large granules of the neutrophils and in granules of monocytes. Double-labeling, using anti-myeloperoxidase or the peroxidase reaction as markers for azurophil granules and anti-lactoferrin as marker for specific granules, showed that ANCA is colocalized with markers of azurophil granules but not with lactoferrin. Furthermore, elastase and cathepsin G were found in the azurophil granules of neutrophils and in the peroxidase-positive granules of monocytes, colocalized with ANCA-antigen. Cytochalasin-B-treated neutrophils stimulated with N-formyl-methionyl-leucyl-phenylalanine (fMLP) formed large intracellular vacuoles and were partially degranulated. Some vacuoles contained ANCA-antigen, as well as myeloperoxidase, elastase, and cathepsin G, demonstrating release of these enzymes from the azurophil granules into vacuoles. Our results demonstrate that ANCA-antigen is located in myeloperoxidase-containing granules of neutrophils and monocytes, and is packaged in the same granules as elastase and cathepsin G, the two previously identified serine proteases of myeloid leukocytes.

Topics: Autoantibodies; Autoantigens; Cathepsin G; Cathepsins; Cell Compartmentation; Cytochalasin B; Granulomatosis with Polyangiitis; Humans; Immunoenzyme Techniques; Immunohistochemistry; Lysosomes; Microscopy, Electron; Monocytes; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Pancreatic Elastase; Peroxidase; Serine Endopeptidases; Subcellular Fractions

Topics: Antibodies, Monoclonal; Autoantibodies; Cytoplasm; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique; Granulomatosis with Polyangiitis; Humans; Neutrophils; Peroxidase; Radioimmunoassay

Antineutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase (MPO) were found in 53 patient sera that were routinely submitted for antineutrophil cytoplasmic antibody determination. Based on clinical and histologic criteria, 15 of these 53 patients were classified as having systemic necrotizing vasculitis of the polyarteritis group, 11 patients were classified as having Wegener's granulomatosis (WG), and 14 were classified as having idiopathic crescentic glomerulonephritis. The remaining 13 patients did not fulfill the diagnostic criteria for these disorders, although most of these patients had clinical symptoms compatible with these disorders. While all patients with WG had renal involvement, only 4 of the 15 patients with systemic necrotizing vasculitis of the polyarteritis group had glomerulonephritis. The sensitivity of autoantibodies to MPO for either systemic necrotizing vasculitis of the polyarteritis group, WG, or idiopathic crescentic glomerulonephritis was further tested in all our patients with these disorders (n = 104). Twenty-seven of 104 patients had autoantibodies to MPO. Furthermore, 69 of the remaining 77 patients had autoantibodies specific for the 29-kd serine protease, which has been reported to be specifically associated with WG. Sera from 8 patients were negative for either of these antibodies (92% sensitivity of autoantibodies to MPO and/or the 29-kd serine protease). The specificity of autoantibodies to MPO for either systemic necrotizing vasculitis of the polyarteritis group, WG, or idiopathic crescentic glomerulonephritis was also tested in selected groups of patients who had closely related diseases. Two of 144 patients had autoantibodies to MPO (specificity 99%).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aged, 80 and over; Arteritis; Autoantibodies; Enzyme-Linked Immunosorbent Assay; Female; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Male; Middle Aged; Peroxidase; Sensitivity and Specificity; Vasculitis

Topics: Autoantibodies; Diagnosis, Differential; Female; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Immune Complex Diseases; Male; Peroxidase; Sex Factors; Vasculitis

Topics: Autoantibodies; Crohn Disease; Enzyme-Linked Immunosorbent Assay; Granulocytes; Granulomatosis with Polyangiitis; Humans; Peroxidase

Topics: Antibodies, Antineutrophil Cytoplasmic; Arteritis; Autoantibodies; Churg-Strauss Syndrome; Granulomatosis with Polyangiitis; Humans; Immunoglobulin G; Molecular Weight; Peroxidase

Anti-neutrophil cytoplasmic autoantibodies have been found in patients with systemic arteritis and glomerulonephritis. We studied the disease distribution and antigen specificity of these autoantibodies. Anti-neutrophil cytoplasmic autoantibodies were identified by indirect immunofluorescence microscopy in 27 of 35 patients with idiopathic necrotizing and crescentic glomerulonephritis, in whom the manifestations of disease ranged from injury limited to the kidney to systemic arteritis. The incidence and titers of the autoantibodies did not differ between patients with disease limited to the kidney and those with systemic disease. Anti-neutrophil immunostaining was detected in 5 of 11 patients with lupus nephritis, 4 of 71 patients with other renal diseases, and none of 50 normal controls. This distribution of autoantibodies was confirmed by an enzyme-linked immunosorbent assay (ELISA) using neutrophil lysate as antigen. According to ELISA, anti-neutrophil cytoplasmic autoantibodies were found to be specific for constituents of primary granules. Two types of autoantibodies were identified; one with reactivity with myeloperoxidase on ELISA produced an artifactual perinuclear immunostaining of alcohol-fixed neutrophils, and another with no reactivity with myeloperoxidase on ELISA produced diffuse cytoplasmic immunostaining. The presence of the same serologic marker in patients with kidney-limited and arteritis-associated necrotizing and crescentic glomerulonephritis, including Wegener's granulomatosis and polyarteritis nodosa, suggests that these clinically diverse diseases may have a similar pathogenesis, initiated by autoantibody-mediated activation of neutrophils.

Topics: Arteritis; Autoantibodies; Cytoplasm; Enzyme-Linked Immunosorbent Assay; Epitopes; Glomerulonephritis; Granulomatosis with Polyangiitis; Humans; Lupus Nephritis; Microscopy, Fluorescence; Neutrophils; Peroxidase; Polyarteritis Nodosa