mocetinostat and Anti-Neutrophil-Cytoplasmic-Antibody-Associated-Vasculitis

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

Relapse in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) is associated with significant morbidity and mortality. Utility of ANCA for prediction of relapses is still controversial. PubMed/MEDLINE, Scopus, and WebOfScience were searched, screened and confirmed for inclusion [PROSPERO No: CRD42020220308]. Studies measuring serial ANCA by ELISA or indirect immunofluorescence (IF), reporting relapses with sufficient data to calculate sensitivity and specificity were included. Diagnostic odds ratio (OR), sensitivity, specificity and likelihood ratios (LR) were synthesized using a bivariate mixed-effect regression model. Sub-group analysis included a comparison between ELISA and IIF, anti-myeloperoxidase (MPO) and -proteinase 3(PR3), and type of rise in ANCA. For meta-analysis of survival outcomes, hazard ratios were synthesized using a random-effect model. QUADAS-2 was used for assessing quality of studies, I

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Enzyme-Linked Immunosorbent Assay; Humans; Myeloblastin; Peroxidase; Recurrence

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

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a chronic relapsing condition with unknown etiology. To gain insight into the molecular processes underlying the disease, we examined biomarkers in blood samples collected prior to symptom onset.. The National Patient Register and Cause of Death register were searched for AAV-related International Classification of Diseases, Ninth Revision and Tenth Revision codes and linked to the registers from 5 biobanks. Eighty-five AAV patients with samples predating symptom onset of AAV were identified. For each case of AAV, 2 matched controls were included. Proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA expression levels were analyzed using enzyme-linked immunosorbent assays. Using an Olink Inflammation panel, 73 of 92 proteins were included after quality control. Data were replicated in a second cohort of 48 presymptomatic individuals and 96 controls.. Of the 20 proteins with the lowest P values in the original cohort, 7 were replicated in the second cohort and 5 proteins were found to be significant between the groups in a meta-analysis. Eleven different pathways were identified in network enrichment analyses and were found to be significant in both cohorts. Stratification of samples obtained ≤5 years before symptom onset showed significant levels of CCL23, vascular endothelial growth factor A, and hepatocyte growth factor, which were also increased at borderline significant levels in the replication cohort (interleukin-6 was found to be significantly increased in the replication cohort). In presymptomatic AAV patients, 6 proteins were associated with MPO-ANCA positivity, and 7 proteins were associated with PR3-ANCA positivity.. To our knowledge, this is the first study to identify protein markers preceding symptom onset in AAV patients. These findings set the stage for further research into the underlying cellular and molecular mechanisms in the pathogenesis of AAV and the diversification of patients into PR3-ANCA+ and MPO-ANCA+ subphenotypes.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Myeloblastin; Peroxidase; Vascular Endothelial Growth Factor A

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

Usually associated with autoimmune diseases, anti-neutrophil cytoplasmic antibodies are also detected in other conditions, such as infections, malignancies, and after intake of certain drugs. Even if the mechanisms of production and their pathogenic role have not been fully elucidated yet, ANCA are widely recognized as a clinically alarming finding due to their association with various disorders. While ANCA target several autoantigens, proteinase-3, and myeloperoxidase are the ones proved to be most frequently related to chronic inflammation and tissue damage in murine models. Albeit these autoantibodies could be present as an isolated observation without any implications, ANCA are frequently used in clinical practice to guide the diagnosis in a suspect of small vessel vasculitis. Conditions that should prompt the clinician to test ANCA status range from various forms of lung disease to renal or peripheral nervous system impairment. ANCA positivity in the presence of an autoimmune disease, especially rheumatoid arthritis, or connective tissue diseases, is frequently correlated with more clinical complications and treatment inefficacy, even in the absence of signs of vasculitis. For this reason, it has been postulated that ANCA could represent the final expression of an immune dysregulation rather than a pathogenic event responsible for organs damage. Recently, it has also been proposed that ANCA specificity (PR3 or MPO) could possibly define ANCA-associated vasculitides better than clinical phenotype. This review aims at summarizing the latest advancements in the field of ANCA study and clinical interpretation.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Autoantigens; Biomarkers; Humans; Mice; Myeloblastin; Peroxidase

Uncertainties exist about the use of mycophenolate mofetil (MMF) in anti-neutrophil cytoplasmatic antibody (ANCA)-associated vasculitis (AAV), particularly for remission maintenance.. Systematic review and meta-analysis of phase II and III trials assessing the use of MMF in AAV, granulomatosis with polyangiitis and microscopic polyangiitis (MPA). A comprehensive search of several databases (Medline, EMBASE, Cochrane, Web of Science, Scopus) from inception to 5 May 2020 has been conducted. Trial data were extracted to estimate odds ratios (ORs) and estimates (ES) for MMF efficacy (remission-induction and maintenance). Severe adverse effects (SAEs) were collected.. From 565 articles captured, 10 met the predefined criteria, 5 phase II and 5 III trials; 4 assessed remission-induction, 3 remission maintenance and 3 both. The pooled OR for remission-induction at 6 months was 1.06 (95% confidence interval 0.74, 1.52), with no significant difference by subgroup meta-analysis of trials stratified by different study-level features (i.e. kidney disease, MPA, myeloperoxidase-ANCA positivity, newly diagnosed disease) (P > 0.05). The overall ES for remission maintenance at the end of follow-up ranged between 51% and 91% (I2 = 74.8%). Subgroup meta-analysis identified kidney involvement as a possible source of heterogeneity, yielding a significantly higher rate of sustained remission in trials enrolling only patients with kidney involvement (92%, 76-100%) versus those enrolling patients with and without kidney involvement (56%, 45-66%). Results were similar in multiple sensitivity analyses. During follow-up, the frequency of SAEs in MMF-based treatment arms was 31.8%.. In AAV, MMF use was significantly associated with higher sustained remission rates in trials enrolling only patients with kidney involvement. These findings might influence clinical practice.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Immunosuppressive Agents; Microscopic Polyangiitis; Mycophenolic Acid; Peroxidase; Remission Induction

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) affects small blood vessels and causes severe systemic organ injury commonly affecting the lungs and kidney. However, gastrointestinal, especially pancreatic, lesions are rare. We report the case of a 67-year-old Japanese man diagnosed with myeloperoxidase (MPO) AAV who developed pancreatic lesions and diabetes mellitus. The patient was admitted to our hospital due to fever, cough, and weight loss. He developed progressive glomerulonephritis, lung nodules, and pancreatic swelling and mass. Additionally, laboratory examination revealed positive MPO-ANCA and elevated glycated hemoglobin A1c, which were suggestive of diabetes mellitus. Renal biopsy revealed necrotizing crescentic glomerulonephritis and vasculitis in the small arteries. Endoscopic ultrasound-guided fine needle aspiration of the pancreas was performed, and histological findings suggested the possibility of pancreatic vasculitis and parenchymal injury. The patient was diagnosed with AAV, which was managed with glucocorticoids. This improved the renal function and pancreatic lesions. Furthermore, blood glucose levels improved despite treatment with glucocorticoids. These findings suggest that AAV-related pancreatic lesions worsened glycemic control. However, glucocorticoid therapy improved vasculitis and pancreatic lesions, which resulted in improved glycemic control.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Diabetes Mellitus; Glomerulonephritis; Humans; Male; Pancreas; Pancreatic Neoplasms; 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

This review provides an update on recent advances in the diagnosis, pathogenesis, clinical presentation, histopathological findings, and treatment approaches for antineutrophil cytoplasmic antibody (ANCA) vasculitis-associated interstitial lung disease (AAV-ILD) with a focus on literature published in the last 3 years.. Although there is no validated definition of AAV-ILD, which contributes to some of the heterogeneity seen in study results, there has been an increasing number of publications in recent years on this topic. Most patients with AAV-ILD have MPO-ANCA vasculitis, and this association appears to reduce their 5-year-survival to 60-66% (Sun et al. BMC Pulm Med 21(1), 2021, Maillet et al. J Autoimmun 106, 2020). Median age of diagnosis ranges from mid-60 s to mid-70 s (Ando et al. Respir Med 107(4), 2013), Kagiyama et al. BMJ Open Respir Res 2(1):1-9, 2015, Hozumi et al. Lung 194(2):235-42, 2016, Liu et al. Chest 156(4):715-23, 2019, Maillet et al. J Autoimmun 106, 2020, Wurmann et al. Sarcoidosis Vasc Diffuse Lung Dis 37(1):37-42, 2020, Watanabe et al. BMC Pulm Med 19(1), 2019). Computed tomography (CT) chest imaging for patients with AAV-ILD often shows a usual interstitial pneumonia (UIP) or nonspecific interstitial pneumonia (NSIP) pattern (12-58% and 13-61%, respectively) (Sun et al. BMC Pulm Med 21(1), 2021, Maillet et al. J Autoimmun 106, 2020, Wurmann et al. Sarcoidosis Vasc Diffuse Lung Dis 37(1):37-42, 2020, Watanabe et al. BMC Pulm Med 19(1), 2019, Baqir at al. Sarcoidosis Vasc Diffuse Lung Dis Off J WASOG 36(3):195-201, 2019). Additionally, lung biopsies typically do not demonstrate active inflammation, or capillaritis, questioning whether these patients should be treated with either immunotherapy or anti-fibrotic therapy, or both (Hozumi et al. Lung 194(2):235-42, 2016, Liu et al. Chest 156(4):715-23, 2019, Kitching at al. Nat Rev Dis Prim 6(1):71, 2020, Tanaka et al. Respir Med 106(12):1765-70, 2012). Besides immunosuppressive treatments, recent advances in anti-fibrotic therapy may offer patients with progressive AAV-ILD an alternative and/or more effective and individualized treatment option.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Lung; Lung Diseases, Interstitial; Peroxidase; Sarcoidosis

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

Myeloperoxidase (MPO) anti-neutrophil cytoplasmic antibodies (ANCA) are often detected in association with a variety of lung pathologies, the most common being interstitial lung disease (ILD). A growing cohort of patients are being diagnosed with MPO-ANCA in the context of ILD without ANCA-associated vasculitis. Clinically and radiologically, there is little to differentiate this cohort from MPO-ANCA-negative ILD patients; however, the pathophysiology is likely different and different treatments are likely required. We present here a brief summary of the proposed pathophysiology of MPO-ANCA-positive ILD, and a more detailed review of the latest evidence on management, including monitoring for development of ANCA-associated vasculitis, immunosuppression, anti-fibrotics, and novel agents that have yet to be trialled in human experiments.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antifibrotic Agents; Humans; Immunosuppression Therapy; Lung Diseases, Interstitial; Peroxidase

The testing of anti-neutrophil cytoplasmic antibodies (ANCA) takes an important place in the diagnostic workup to ANCA-associated vasculitis (AAV). Nowadays, it is recommended to screen for the presence of PR3 and MPO specific antibodies first using immunoassay, without the need for ANCA measurement by indirect immunofluorescence (IIF). A literature search was performed to assess the diagnostic test value of ANCA IIF and PR3- and MPO-antibody immunoassay to diagnose AAV. This meta-analysis shows that the c-ANCA testing by IIF has a pooled sensitivity of 75.2% and a pooled specificity of 98.4%. For PR3-antibody immunoassay, the pooled sensitivity depended on the immunoassay method used, and ranged from 79.8% to 86.6%, whereas the pooled specificity ranged from 96.8% to 98.3%. For both p-ANCA IIF and MPO-antibody immunoassay (all methods) sensitivity varied considerably showing pooled values of respectively 46.3% and 58.1%, whereas respective pooled specificity was 91.4% and 95.6%. These findings support the 2017 international consensus that primary anti-PR3 and anti-MPO screening by immunoassay, based on superior immunoassay sensitivity without the need for IIF ANCA testing, improves the diagnostic workup of AAV.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique, Indirect; Humans; Immunoassay; Myeloblastin; Peroxidase

The incidence of venous thromboembolism (VTE) in ANCA-associated vasculitis patients varies in different populations. Moreover, the risk factors for VTE in these patients are poorly described due to the small number of events. Ovid MEDLINE, EMBASE, and the Cochrane Library were searched for eligible articles. The inclusion criteria included observational studies that enrolled patients age ≥ 18 years diagnosed with ANCA-associated vasculitis. The incidence of VTE is the outcome of interest. Of 1362 citations, a total of 21 studies (n = 4422) dated from 2006 to 2019 were included in the systematic review. The mean age was 54.2 ± 4.0 years. Most were male (52.0%) and Caucasian (80.9%). With a mean follow-up duration of 5.2 ± 2.8 years, the pooled incidence of VTE in ANCA-associated vasculitis patients was 12.4% (95% CI, 8.8-17.2). Of these, 63.4% (95% CI, 57.3-69.1) had deep vein thrombosis and 26.3% (95% CI, 17.6-37.4) had pulmonary embolism. Recurrent VTE occurred in 10.0% (95% CI, 5.2-18.6). From the metaregression adjusted for age, sex, and ethnicity; positive MPO-ANCA, increasing Birmingham Vasculitis Activity Score at time of vasculitis diagnosis, and presence of renal involvement were positively associated with increased VTE events. Positive PR3-ANCA profile was inversely associated with increased VTE events. Increasing follow-up duration was not associated with increased VTE events. VTE in ANCA-associated vasculitis is common. Positive MPO-ANCA, increasing vasculitis activity, and presence of renal involvement were significant risk factors for VTE while positive PR3-ANCA was inversely associated with increased VTE. Key Points • Venous thromboembolism (VTE) is common in ANCA-associated vasculitis with a pooled incidence of 12.4% • Deep vein thrombosis accounts for two-third of total VTE cases • Positive MPO-ANCA profile, higher disease activity at ANCA-associated vasculitis diagnosis, and renal involvement are risk factors for VTE • Positive PR3-ANCA profile is protective factor for VTE.

Topics: Adolescent; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Humans; Incidence; Male; Middle Aged; Myeloblastin; Peroxidase; Risk Factors; Venous Thromboembolism

Anti-neutrophil cytoplasmic antibodies (ANCA) are a group of autoantibodies, predominantly IgG, involved in the pathogenesis of several autoimmune disorders, detected either through indirect immunofluorescence or enzyme-linked immunosorbent assay. By means of indirect immunofluorescence, the main patterns are C-ANCA (cytoplasmic) and P-ANCA (perinuclear), while proteinase 3 (PR3) and myeloperoxidase (MPO) represent the main autoantigens in granulomatosis with polyangiitis and microscopic polyangiitis, both belonging to the family of ANCA-associated vasculitis (AAV). While several experiments established the pathogenicity of MPO-ANCA, evidence remains elusive for PR3-ANCA and an additional target antigen, i.e. LAMP2, has been postulated with specific clinical relevance. The presence of a subset of AAV without ANCA may be explained by the presence of further target antigens or the presence of molecules in blood which make ANCA undetectable. A rise in ANCA titers is not necessarily predictive of a flare of disease in AAV if not accompanied by clinical manifestations. ANCA may develop through variable mechanisms, such as autoantigen complementarity, apoptosis impairment, neutrophil extracellular traps dysfunction and molecular mimicry. We will provide herein a comprehensive review of the available evidence on the biological mechanisms, pathogenetic role, and clinical implications of ANCA testing and disease management. Further, we will address the remaining open challenges in the field, including the role of ANCA in inflammatory bowel disease and in cocaine-induced vasculitis.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biology; Humans; Myeloblastin; Peroxidase

Recent genome-wide association studies (GWAS) in populations of European ancestry have identified several susceptibility genes to anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The most significant association was observed in HLA-DP variants in granulomatosis with polyangiitis and proteinase 3 (PR3)-ANCA positive vasculitis, while HLA-DQ variants were strongly associated with microscopic polyangiitis (MPA) and myeloperoxidase (MPO)-ANCA positive vasculitis (MPO-AAV). In non-HLA genes, SERPINA1, PRTN3 and PTPN22 were identified as susceptibility genes to AAV. The observations in GWAS suggested the presence of shared and non-shared susceptibility genes among AAV subsets. Epidemiological features of AAV are strikingly different in the East Asian populations; the proportions of MPO-AAV among total AAV, MPO-ANCA positive patients among GPA, and patients with interstitial lung disease among total AAV are considerably higher in Japan as compared with Europe. Such population differences suggest the critical role for genetic background behind these conditions. Although no GWAS has been reported in the Asian populations so far, the association of HLA-class II alleles with MPA and MPO-AAV was identified. Future genomics studies on AAV, especially from Asian populations, will provide valuable information to elucidate the molecular mechanisms and to identify molecular targets for AAV.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Asia, Eastern; Genome-Wide Association Study; Genomics; Humans; Peroxidase; Protein Tyrosine Phosphatase, Non-Receptor Type 22

Our understanding of immune recognition and response to infection and non-infectious forms of cell damage and death is rapidly increasing. The major focus is on host immunity and microbiological invasion. However, it is also clear that these same pathways are important in the initiation and maintenance of autoimmunity and the damage caused to targeted organs. Understanding the involvement of cell death in autoimmune disease is likely to help define critical pathways in the immunopathogenesis of autoimmune disease and new therapeutic targets. An important immune responder cell population in host defense and autoimmunity is the neutrophil. One autoimmune disease where neutrophils play important roles is MPO-ANCA Microscopic Vasculitis. This a severe disease that results from inflammation to small blood vessels in the kidney, the glomeruli (high blood flow and pressure filters). One of the best studied ways in which neutrophils participate in this disease is by cell death through NETosis resulting in the discharge of proinflammatory enzymes and nuclear fragments. In host defense against infection this process helps neutralize pathogens however in auto immunity NETosis results in injury and death to the surrounding healthy tissues. The major autoimmune target in this disease is myeloperoxidase (MPO) which is found uniquely in the cytoplasm of neutrophils. Although the kidney is the major organ targeted in this disease MPO is not expressed in the kidney. Autoantibodies target surface MPO on activated circulating neutrophils resulting in their lodgment in glomerular capillaries where they NETose releasing extracellularly MPO and nuclear fragments initiating injury and planting the key autoantigen MPO. It is the cell death of neutrophils that changes the kidney from innocent bystander to major autoimmune target. Defining the immunopathogenesis of this autoimmune disease and recognizing critical injurious pathways will allow therapeutic intervention to block these pathways and attenuate autoimmune injury. The insights (regarding mechanisms of injury and potential therapeutic targets) are likely to be highly relevant to many other autoimmune diseases.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoimmunity; Extracellular Traps; Humans; Immunotherapy; Inflammation Mediators; Neutrophil Activation; Neutrophils; Peroxidase

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

IgG4-related disease is an immune-mediated systemic inflammatory condition characterized by tissue infiltration of IgG4-positive plasma cells and elevated serum IgG4 concentrations. Peripheral neuropathy is an atypical manifestation of this disease. We describe an unusual case of vasculitic neuropathy in a patient with IgG4-related kidney disease. A 55-year-old woman presented with right leg weakness progressing to bilateral leg weakness, pain and numbness of the legs, and impaired gait. She was previously evaluated for weight loss and anemia with a CT scan of the abdomen due to concern for malignancy. Abnormal enhancement of the kidneys was seen, and laboratory work-up and kidney biopsy were consistent with IgG4-related disease. Myeloperoxidase-antineutrophil cytoplasmic antibodies were also positive. In combination with the patient's asymmetric leg weakness and painful neuropathy, this raised concern for vasculitis. Sural nerve biopsy confirmed vasculitic neuropathy. Recent studies have demonstrated an overlap in the clinical characteristics of IgG4-related disease and the anti-neutrophil cytoplasmic antibody-associated vasculitides, which are known to cause vasculitic neuropathy. Clinicians should recognize this association, and IgG4-related disease should be considered in the differential diagnosis in patients with peripheral neuropathy in the right clinical context.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Female; Humans; Immunoglobulin G4-Related Disease; Kidney; Middle Aged; Peripheral Nervous System Diseases; Peroxidase

Anti-myeloperoxidase vasculitis (MPO-AAV) is a life-threatening autoimmune disease which causes severe inflammation of small blood vessels, mainly in the kidney. As for many other autoimmune diseases, current treatments, which consist of general immunosuppressants, are partially effective, toxic and broadly immunosuppressive, causing significant and serious adverse effects in many patients. Therefore, there is an urgent need for more targeted and less harmful therapies. Tolerogenic dendritic cells, regulatory T cells and stem cells have emerged as attractive, new and safer options for the treatment for various autoimmune diseases due to their unique and selective immunosuppressive capacity. In this review, we will discuss how these cellular therapies offer potential to become novel and safer treatments for MPO-AAV.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoimmune Diseases; Cell- and Tissue-Based Therapy; Humans; Peroxidase

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a rare and severe autoimmune multisystemic disease. Its pathogenesis involves multiple arms of the immune system, as well as complex interactions between immune cells and target organs. Experimental animal models of disease can provide the crucial link from human disease to translational research into new therapies. This is particularly true in AAV, due to low disease incidence and substantial disease heterogeneity. Animal models allow for controlled environments in which disease mechanisms can be defined, without the clinical confounders of environmental and lifestyle factors. To date, multiple animal models have been developed, each of which shed light on different disease pathways. Results from animal studies of AAV have played a crucial role in enhancing our understanding of disease mechanisms, and have provided direction toward newer targeted therapies. This review will summarize our understanding of AAV pathogenesis as has been gleaned from currently available animal models, as well as address their strengths and limitations. We will also discuss the potential for current and new animal models to further our understanding of this important condition.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoantibodies; Autoimmunity; Disease Models, Animal; Glomerulonephritis; Humans; Myeloblastin; Peroxidase; Translational Research, Biomedical

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

ANCA-associated vasculitis (AAV) is a group of chronic inflammatory diseases of small- and medium-sized vessels, which are broadly subdivided based on organ manifestations and disease-specific autoantibodies. The so called anti-neutrophil cytoplasmic antibodies (ANCA) mostly target one of the enzymes, proteinase 3 (PR3) or myeloperoxidase (MPO). Accumulating genetic data demonstrates that these two autoantibodies discriminate two distinct disease entities, more so than the clinical subdivision which is mainly criteria-based. Treatment of AAV includes heavy immunosuppression and is guided by which organs that are involved. Generally, patients with PR3-ANCA display higher risk for disease relapse than patients with MPO-ANCA. In this review, we will focus on the autoimmune features of PR3+ AAV and our current understanding of its triggers and the potential translation into clinical practice.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; HLA-DP beta-Chains; Humans; Inflammation; Models, Immunological; Myeloblastin; Peroxidase; T-Lymphocyte Subsets

Anti-neutrophil cytoplasmic autoantibody (ANCA)-positive retroperitoneal fibrosis (RPF) is extremely rare. This study aimed to clarify the clinical characteristics and prognosis of patients with ANCA-positive RPF.. We conducted a systematic literature review of articles reporting on ANCA-positive RPF from the database inception dates until March 8, 2020.. We identified 19 patients with ANCA-positive RPF with a mean age of 62 years; a male dominance (68.4%) was noted. Most patients presented with systemic symptoms and/or lower back or abdominal pain. Proteinase 3 (PR3) -ANCA positivity was predominant compared with myeloperoxidase (MPO)-ANCA (63.2% vs. 36.8%, respectively), and all patients showed elevated serum C-reactive protein levels. Of note, 26.7% of patients had isolated RPF without any other ANCA-associated systemic organ involvement. Regarding typical manifestations of ANCA- associated vasculitis, ear, nose, and throat involvement occurred in 26.3%, lung involvement in 36.8%, and kidney involvement (rapidly progressive glomerulonephritis) in 31.6% of patients. Necrosis and granulomatous inflammation, vasculitis, and multinucleated giant cells were pathologically observed in tissue sections of RPF, whereas tertiary lymphoid organ formation was not identified. Glucocorticoids with or without other immunosuppressive treatments were effective in most patients, but 4 patients experienced disease relapse during the clinical course. All relapsed patients were positive for PR3-ANCA.. Clinical features of ANCA-positive RPF are associated with systemic inflammatory components such as fever and elevated serum C-reactive protein levels. ANCA-. positive RPF presents as an "isolated" involved organ in one-third of patients. Immunosuppressive treatments are effective, but the disease can recur, particularly in PR3-ANCA-positive patients.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Male; Middle Aged; Myeloblastin; Peroxidase; Prognosis; Retroperitoneal Fibrosis; Retrospective Studies

The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are a group of disorders involving severe, systemic, small-vessel vasculitis and are characterized by the development of autoantibodies to the neutrophil proteins leukocyte proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA). The three AAV subgroups, namely granulomatosis with polyangiitis (GPA), microscopic polyangiitis and eosinophilic GPA (EGPA), are defined according to clinical features. However, genetic and other clinical findings suggest that these clinical syndromes may be better classified as PR3-positive AAV (PR3-AAV), MPO-positive AAV (MPO-AAV) and, for EGPA, by the presence or absence of ANCA (ANCA

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Diagnostic Imaging; Humans; Immunosuppressive Agents; Myeloblastin; Peroxidase; Prognosis; Risk Factors

We conducted a systematic review to identify cases of infection-induced anti-myeloperoxidase (MPO) antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).. PubMed/Medline databases were searched from inception to July of 2020, according to PRISMA guidelines.. Among the 618 abstracts identified, 18 articles describing 23 patients (60.9% female, mean age 50.5 years) were included. Median time between infection and vasculitis development was 3 months. Five (21.7%) patients expired during follow-up. Vasculitis regressed after the resolution of infection in 12/23 (52.2%). ANCA titers decreased significantly on follow-up in 14/16 patients and in all survivors in which they were measured. Pathogens reported included Mycobacterium spp., Coccidioides spp., Rickettsia rickettsii, Staphylococcus spp., EBV, CMV and Dengue virus.. MPO-AAV can occur after infection and may regress after its resolution. Infection should be considered in cases of MPO-AAV, as immunosuppressive treatment can have catastrophic results if the infection is not adequately treated.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Humans; Immunosuppressive Agents; Infections; 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

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small- to medium-vessel necrotizing vasculitis responsible for excess morbidity and mortality (1). The AAVs, which include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA), are among the most difficult types of vasculitis to treat. Although clinicopathologic disease definitions have been used traditionally to categorize patients into one of these three diagnoses, more recently ANCA specificity for either proteinase 3 (PR3) or myeloperoxidase (MPO) has been advocated for the purpose of disease classification (2). This is because differences in genetics, pathogenesis, risk factors, treatment responses, and outcomes align more closely with PR3- or MPO-ANCA type than with the clinocopathologic diagnosis. Moreover, classifying patients as GPA or MPA can be challenging because biopsies are not obtained routinely in most cases and existing classification systems can provide discrepant classification for the same patient (3). In this review, we address the recent literature supporting the use of ANCA specificity to study and personalize the care of AAV patients (Table 1). We focus particularly on patients with GPA or MPA.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antibody Specificity; Humans; Myeloblastin; Peroxidase; Precision Medicine

Testing for antineutrophil cytoplasmic antibodies (ANCA) is performed to diagnose or exclude small vessel vasculitis, and, in treated patients, to monitor disease activity. However testing is also undertaken to assist with the diagnosis of other autoimmune diseases and some infections. Most laboratories use the same assays for all sera regardless of the testing indications. The International Consensus Statement on ANCA Testing and Reporting recommended screening for ANCA by indirect immunofluorescence (IIF) and confirming IIF-positive sera in antigen-specific ELISAs for both proteinase 3 (PR3) and myeloperoxidase (MPO). These guidelines have been reviewed after many refinements of the assays, and the development of new testing methodologies. However the advances have focused largely on improving the diagnostic accuracy in new-onset vasculitis, and not on more accurately monitoring disease activity, nor increasing the diagnostic sensitivity for non-vasculitic conditions. The recently-revised guidelines for ANCA testing indicate that where new onset vasculitis is suspected, sera should be examined for both PR3- and MPO-ANCA using any highly sensitive and specific assay, rather than IIF. They further state that where sera are negative in one assay but the suspicion of vasculitis is high, that testing should be repeated using a different assay. The guidelines do not provide recommendations for treated vasculitis or non-vasculitic disease. However for a routine diagnostic laboratory where sera are tested for many different indications, or where the reasons are not known, IIF screening followed by confirmation of IIF-positive sera in antigen-specific assays remains a highly sensitive, specific and convenient method for detecting ANCA in "all-comers".

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Clinical Laboratory Services; Consensus; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique, Indirect; Humans; Myeloblastin; Peroxidase; Practice Guidelines as Topic; Sensitivity and Specificity; Treatment Outcome

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is characterized as inflammation of small-sized to medium-sized blood vessels and encompasses several clinicopathologic entities including granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and renal-limited ANCA-associated vasculitis. Over the past several decades, significant progress has been made in understanding the pathophysiology of ANCA-associated vasculitis. Although neutrophils contain a multitude of granular proteins, clinically significant autoantibodies are only recognized against myeloperoxidase and proteinase 3, both of which are present in the azurophilic granules. The propensity to develop these antibodies depends on a variety of predisposing factors such as microbial infection, genetic factors, environmental agents, and therapeutic drugs among others. These factors are usually associated with production of proinflammatory cytokines with capacity to prime the neutrophils. As a result a high proportion of neutrophils in circulation may be primed resulting in exposure of cytoplasmic proteins including myeloperoxidase and proteinase 3 on the surface of the neutrophils. Primed neutrophils are activated by interaction with ANCA in circulation. Activated neutrophils attach to and transmigrate through endothelium and accumulate within the vessel wall. These neutrophils degranulate and produce reactive oxygen radicals and ultimately die, causing tissue injury. Endothelial injury results in leakage of serum proteins and coagulation factors causing fibrinoid necrosis. B cells produce ANCAs, as well as neutrophil abnormalities and imbalances in different T-cell subtypes with excess of Th17, which perpetuate the inflammatory process.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Neutrophils; Peroxidase; T-Lymphocytes

Our understanding of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis has developed greatly since the discovery of ANCA, directed against neutrophil components, in 1982. Observations in human disease, and increasingly sophisticated studies in vitro and in rodent models in vivo, have allowed a nuanced understanding of many aspects of the immunopathogenesis of disease, including the significance of ANCA as a diagnostic and monitoring tool as well as a mediator of microvascular injury. The mechanisms of leukocyte recruitment and tissue injury, and the role of T cells increasingly are understood. Unexpected findings, such as the role of complement, also have been uncovered through experimental studies and human observations. This review focusses on the pathogenesis of ANCA-associated vasculitis, highlighting the challenges in finding new, less-toxic treatments and potential therapeutic targets in this disease. The current suite of rodent models is reviewed, and future directions in the study of this complex and fascinating disease are suggested.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoimmunity; Bone Marrow Transplantation; Disease Models, Animal; Humans; Peroxidase; T-Lymphocytes

The purpose of this review is to provide a critical analysis of the recent literature on this topic, with particular focus on the most relevant studies published over the last year.. Many studies are published every year on the diagnosis, pathogenesis and treatment of pulmonary involvement in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). The main subjects covered by this article are the pathogenesis, diagnosis and clinical aspects of lung involvement in ANCA-associated vasculitis and non-ANCA-associated vasculitis.. Lung involvement is a common feature in systemic vasculitis. The lungs are one of the most frequently involved organs in systemic vasculitis. In order to provide an update on the recent advances in the pathogenesis, clinical features and novel treatments of lung involvement in systemic vasculitis, a systematic MedLine search has been performed.Most of the data analyzed have confirmed that lung involvement seems to develop more frequently in patients with myeloperoxidase-ANCA-positive AAV, mainly in those with a diagnosis of microscopic polyangiitis (MPA), compared with patients with proteinase 3 ANCA-positive AAV. Moreover, among non-ANCA-associated vasculitis lung involvement may represent a worrying complication of the disease, mainly when associated with vascular involvement.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Lung Diseases; Myeloblastin; Peroxidase; Vasculitis

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

The anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) are a heterogeneous group of diseases causing inflammation in small blood vessels and linked by the presence of circulating ANCA specific for proteinase 3 (PR3) or myeloperoxidase (MPO). These antigens are present both in the cytoplasmic granules and on the surface of neutrophils, and the effect of ANCA on neutrophil biology has been extensively studied. In contrast, less attention has been paid to the role of monocytes in AAV. These cells contain PR3 and MPO in lysosomes and can also express them at the cell surface. Monocytes respond to ANCA by producing pro-inflammatory and chemotactic cytokines, reactive-oxygen-species and by up-regulating CD14. Moreover, soluble and cell surface markers of monocyte activation are raised in AAV patients, suggesting an activated phenotype that may persist even during disease remission. The presence of monocyte-derived macrophages and giant cells within damaged renal and vascular tissue in AAV also attests to their role in pathogenesis. In particular, their presence in the tertiary lymphoid organ-like granulomas of AAV patients may generate an environment predisposed to maintaining autoimmunity. Here we discuss the evidence for a pathogenic role of monocytes in AAV, their role in granuloma formation and tissue damage, and their potential to both direct and maintain autoimmunity. ANCA-activation of monocytes may therefore provide an explanation for the relapsing-remitting course of disease and its links with infections. Monocytes may thus represent a promising target for the treatment of this group of life-threatening diseases.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoimmunity; Humans; Kidney; Macrophages; Monocytes; Myeloblastin; Peroxidase

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

Antineutrophil cytoplasmic antibodies (ANCAs) remain central to our current understanding of the pathogenesis of ANCA-associated vasculitis (AAV), and this review considers recent developments in the context of four key questions: are there targets for ANCA beyond myeloperoxidase (MPO) and proteinase 3 (PR3); are all ANCA pathogenic; how are ANCAs generated; and how do ANCA cause disease?. B-cell epitope mapping raises the possibility that only a subset of ANCA may be pathogenic. Anti-lysosomal-associated membrane protein 2 autoantibodies have recently emerged as a novel form of ANCA and can be found in anti-MPO and anti-PR3 negative disease. These also provide recent evidence for molecular mimicry in the pathogenesis of AAV, but a definitive proof in human AAV remains elusive. Neutrophil extracellular traps may represent an important mechanism by which MPO and PR3 are taken up by dendritic cells for presentation to the adaptive immune system, and the role of the alternative pathway of complement in AAV has recently been emphasized, with therapeutic implications.. Our current understanding of the pathogenesis of AAV not only reinforces the central role of neutrophils but also provides a sound rationale for B-cell and complement-directed therapies.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomedical Research; Complement System Proteins; Extracellular Traps; Humans; Myeloblastin; Neutrophils; Peroxidase

In patients with GN or vasculitis, ANCAs are directed against proteinase 3 (PR3) or myeloperoxidase (MPO). The differences between PR3-ANCA-associated vasculitis (AAV) and MPO-AAV described in the past have been supplemented during the last decade. In this review, we discuss the differences between these two small-vessel vasculitides, focusing especially on possible etiologic and pathophysiologic differences. PR3-AAV is more common in northern parts of the world, whereas MPO-AAV is more common in southern regions of Europe, Asia, and the Pacific, with the exception of New Zealand and Australia. A genetic contribution has been extensively studied, and there is a high prevalence of the HLA-DPB1*04:01 allele in patients with PR3-AAV as opposed to patients with MPO-AAV and/or healthy controls. Histologically, MPO-AAV and PR3-AAV are similar but show qualitative differences when analyzed carefully. Clinically, both serotypes are difficult to distinguish, but quantitative differences are present. More organs are affected in PR3-AAV, whereas renal limited vasculitis occurs more often in patients with MPO-AAV. For future clinical trials, we advocate classifying patients by ANCA serotype as opposed to the traditional disease type classification.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Disease Models, Animal; Humans; Myeloblastin; Peroxidase

Since the discovery of anti-neutrophil cytoplasmic autoantibodies (ANCA), great strides have been made in elucidating the etiology and pathogenesis of disease. In this article, we review recent published key breakthroughs in understanding the pathogenesis of ANCA vasculitis, including some that may lead to novel therapeutics. These breakthroughs have occurred in multiple areas of investigation. A European genome-wide association study (GWAS) revealed the importance of the genetic contribution of proteinase 3 (PR3) and its endogenous inhibitor, alpha (1)-antitrypsin as well as HLA risk. Epigenetic modification of autoantigen genes appears to contribute to perpetuation of disease and possibly relapse risk. Autoantigen excision, a novel method to detect autoantibody epitopes using mass spectrometry, not only revealed pathogenic epitopes in myeloperoxidase (MPO)-ANCA vasculitis and identified unique MPO-ANCA responsible for the majority of ANCA-negative small vessel vasculitis, but has vast applicability to other autoantibody-mediated diseases. An explosion of biomarker studies has revealed circulating cytokines and alternative complement pathway products that may predict active disease. Interestingly, alternative complement pathway blockade in the murine model of disease is protective and a clinical trial in humans using an oral alternative complement pathway inhibitor is underway. Increasing clarity of the role of B and T cells in disease pathogenesis is ongoing. B cell depleting agents have shown great utility in remission induction and maintenance, and monitoring specific B cell subsets during the disease course may have predictive power for remission maintenance. Despite these substantial advances, more research is needed including, but not limited to, validation of existing discoveries. As additional novel discoveries emerge, so will novel therapies, and it is with great hope that these collective insights will ultimately lead to prevention and cure.

Topics: Alleles; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantigens; Biomarkers; Disease Models, Animal; Epigenesis, Genetic; Ethnicity; Forecasting; Genetic Predisposition to Disease; Genome-Wide Association Study; Histones; Humans; Jumonji Domain-Containing Histone Demethylases; Lymphocyte Subsets; Methylation; Myeloblastin; Peroxidase; Phenotype; Polymorphism, Single Nucleotide; Protein Processing, Post-Translational

Pathophysiological features and laboratory findings in patients with anti-neutrophil cytoplasmic antibody (ANCA) -associated vasculitis are described. In contrast to Western countries, MPO-ANCA-positive microscopic polyangiitis and renal-limited vasculitis is the most common form of ANCA-associated vasculitis in Japanese patients. Oral prednisolone in combination with immunosuppressive agents has improved patient survival in older Japanese patients. However, the recurrence rate has significantly increased in recent years Accumulative evidence supports a direct pathogenic role of ANCA in glomerulonephritis and vasculitis, in which inflammatory processes with the up-regulation of cytokines/chemokines and possible involvement of a neutrophil extracellular trap may play a role. However, whether or not the measurement of ANCA titers reflects disease activity and predicts the onset and/or relapse of ANCA-associated vasculitis remains controversial. Further studies will be required to determine the clinical significance of ANCA in more detail. In addition to ANCA, measurements of novel clinical test items, including anti-erythropoietin receptor antibody, may reveal the possibility of their application as useful biomarkers of the pathophysiology and clinical manifestations in patients with ANCA-associated vasculitis.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Biomarkers; Clinical Laboratory Techniques; Humans; Myeloblastin; Peroxidase; Receptors, Erythropoietin; Recurrence

The timely diagnosis of vasculopathies, such as granulomatosis with polyangiitis, has important implications for the favorable clinical outcome of these diseases. In the clinical setting, autoantibodies to proteinase 3 (Pr3) and myeloperoxidase (MPO) have been shown to be valuable adjuncts to an early and accurate diagnosis. The sensitive and specific detection of anti-Pr3 and anti-MPO was shown using a point of care device that employed rapid Lateral Flow Technologies. The validation of the lateral flow assay (LFA) was performed with serum samples collected in two Reference Laboratories and showed excellent results that were comparable to widely accepted and used ELISA. The advantage of the LFA is the flexibility to be used as an economical, point of care diagnostic device, features that are especially important for an early and accurate diagnosis and the prompt initiation of appropriate treatment so as to avoid inevitable development of undue complications of these diseases such as disseminated organ involvement, e.g. renal failure.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique, Indirect; Humans; Immunoassay; Immunoglobulin G; Luminescent Measurements; Myeloblastin; Peroxidase; Predictive Value of Tests; Reproducibility of Results

Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is strongly associated with autoantibodies against myeloperoxidase (MPO) and proteinase 3 (PR3). No clear consensus has been reached on the pathogenicity of these autoantibodies. Animal models for MPO-ANCA, in vitro data suggesting pathogenicity of ANCA, and one case of a neonate showing symptoms of vasculitis after transplacental transfer of MPO, argue in favour of a pathogenic role for ANCA. On the other hand, the presence of natural MPO and PR3 autoantibodies in healthy individuals, lack of a strong correlation between ANCA titres and disease activity, and the occurrence of ANCA-negative AAV patients argue against pathogenicity of ANCA. Recent papers have drawn attention to the possibility of epitope specificity defining ANCA pathogenicity. Certain MPO epitopes were found to be specific for active disease, and others remained present during remission or were also present in healthy individuals. One linear epitope, aa447-459, was not only exclusive for active disease, but also detected in the total Ig fraction of ANCA-negative patients, reactivity being masked in serum by ceruloplasmin. So, not all ANCA seems to be equal, some could be pathogenic while others are not. For development of an autoimmune response, a specific ANCA repertoire is required, which may occur through intra-molecular epitope spreading in patients.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoimmunity; Humans; Neutrophils; Peroxidase

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Autoimmunity; Bone Marrow Cells; Cytokines; Dendritic Cells; Deoxyribonuclease I; Humans; Inflammation Mediators; Microscopic Polyangiitis; Neutrophil Activation; Neutrophils; Peroxidase; Propylthiouracil; Rats

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Female; Glomerulonephritis; Humans; Kidney; Kidney Function Tests; Kidney Glomerulus; Peroxidase; Polyarteritis Nodosa; Vasculitis

Topics: Aged; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Disease Models, Animal; Drugs, Investigational; Endothelial Cells; Etanercept; Humans; Immunoglobulin G; Inflammation Mediators; Interleukin 1 Receptor Antagonist Protein; Mice; Myeloblastin; Neutrophil Activation; Neutrophils; p38 Mitogen-Activated Protein Kinases; Peroxidase; Rats; Reactive Oxygen Species; Receptors, Fc; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factor-alpha

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: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Disease Models, Animal; Glomerulonephritis; Humans; Mice; Mice, Inbred C57BL; Necrosis; Neutrophil Activation; Peroxidase; T-Lymphocyte Subsets

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; B-Lymphocytes, Regulatory; Disease Models, Animal; Disease Progression; Humans; Inflammation Mediators; Monocytes; Peroxidase; Prognosis; T-Lymphocytes, Regulatory

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; CD4-Positive T-Lymphocytes; Churg-Strauss Syndrome; Disease Models, Animal; Endothelium, Vascular; Humans; Interleukin-17; Interleukins; Leukocytes, Mononuclear; Mice; Mice, Inbred C57BL; Microscopic Polyangiitis; Peroxidase; T-Lymphocyte Subsets

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: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Churg-Strauss Syndrome; Disease Models, Animal; Humans; Mice; Mice, Transgenic; Myeloblastin; Peroxidase; Receptor, Anaphylatoxin C5a; Receptors, Complement

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Biopsy; Churg-Strauss Syndrome; Follow-Up Studies; Glomerulonephritis; Humans; Kidney Failure, Chronic; Kidney Glomerulus; Peroxidase; Prognosis; Survival Rate

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

It is well known that antineutrophil cytoplasmic antibodies (ANCAs) are pathogenic and have a diagnostic value for ANCA-associated vasculitis. We demonstrated that a rise in myeloperoxidase (MPO)-ANCA titers during remission is often predictive of a future relapse in MPO-ANCA-associated vasculitis. Pathological examination of renal biopsies indicated that not only MPO-ANCAs, but also extracellular MPO, an in situ immune complex composed of MPO and MPO antibodies, may play important roles in the pathogenesis of glomerular capillary injury in MPO-ANCA-associated vasculitis.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Capillaries; Cytokines; Glomerulonephritis; Humans; Kidney Glomerulus; Neutrophils; Peroxidase; Prognosis; Recurrence; Remission Induction

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

The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) comprise granulomatosis with polyangiitis (GPA), primarily associated with antibodies to proteinase 3 (PR3-ANCA); microscopic polyangiitis (MPA); and eosinophilic granulomatosis with polyangiitis (EGPA), both principally associated with antibodies to myeloperoxidase (MPO-ANCA). Genetic and environmental factors are involved in their etiopathogenesis, with a possible role for silica exposure in AAVs and Staphylococcus aureus infection in GPA. The distinct associations of PR3-ANCA and MPO-ANCA with different HLA class II antigens, which are stronger than those with the associated diseases, suggest a pathogenic role for those ANCAs and indicate that GPA and MPA are different diseases. Both in vitro and in vivo experimental data have shown that MPO-ANCA can induce necrotizing small-vessel vasculitis and glomerulonephritis. The additional role of the alternative pathway of complement activation has been demonstrated in human and experimental pathology. Also, T cells seem to be involved in lesion development, particularly in the kidney. Granuloma formation, as seen in PR3-ANCA-associated GPA, is not well explained by the presence of autoantibodies in experimental models. Here, T cells seem crucial. Recently obtained insights into the pathogenesis of AAVs have led to more targeted treatment of these life-threatening diseases.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Churg-Strauss Syndrome; Complement Pathway, Alternative; Gene-Environment Interaction; Genetic Predisposition to Disease; Glomerulonephritis; Histocompatibility Antigens Class II; Humans; Microscopic Polyangiitis; Myeloblastin; Peroxidase; Polyarteritis Nodosa; Silicon Dioxide; Staphylococcal Infections; T-Lymphocytes

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

Otitis media is one of the common organ injuries that appear during the course of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We experienced four patients with myeloperoxidase (MPO)-ANCA-positive AAV with otitis media. All were elderly Japanese women. MPO-ANCA in our patients was reminiscent of microscopic polyangiitis (MPA), although chest computed tomography (CT) scans revealed characteristics of both granulomatosis with polyangiitis (GPA), showing bronchial lesions and nodule formation, and MPA, showing interstitial changes. Whether our cases should be classified as GPA or MPA is a matter of discussion. We detail their profiles, and review previous literature on MPO-ANCA-positive AAV with otitis media.

Topics: Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Female; Humans; Immunosuppressive Agents; Middle Aged; Otitis Media; Peroxidase; Ribonucleosides; Treatment Outcome

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a common autoimmune disease in China. AAVs in the majority of Chinese patients are microscopic polyangiitis with antigenicity to myeloperoxidase. Propylthiouracil is the leading cause of drug-induced AAV. The genetic background and immunological characteristics of ANCA, such as the epitope, IgG subclass and avidity, might contribute to various clinical phenotypes of AAV.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Asian People; Biomarkers; China; Genetic Predisposition to Disease; Humans; Myeloblastin; Peroxidase; Phenotype; Prognosis; Propylthiouracil; Risk Factors

During the past 30 years, remarkable progress has been achieved in understanding the role of the antineutrophil cytoplasmic antibodies (ANCAs) directed against proteinase 3 (PR3) and myeloperoxidase (MPO) in so-called "ANCA-associated vasculitides". In the right clinical context, ANCAs are a good seromarker for these diseases, have improved nomenclature of systemic vasculitides and have contributed to new pathogenic concepts. However, problems with the clinical applications of ANCA testing in daily practice remain. They can be summarised as follows: assay standardisation and performance; the use of ANCA testing in a clinical setting with a low pretest probability; the relationship between ANCA titres and disease activity remains unclear. The solution to problems regarding the ANCA diagnosis is focussed on the fundamental methods, i.e., correct implementation of IFT and ELISA, the cautious use of commercial assays and restricting the use of the tests to clinical situations with a rather high pretest probability of AAV.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Enzyme-Linked Immunosorbent Assay; Humans; Myeloblastin; Peroxidase; Practice Guidelines as Topic; Predictive Value of Tests; Prognosis; Serologic Tests; Severity of Illness Index

Microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) are conditions classified under the general heading of antinuclear cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). Lung lesion is a very common and important clinical feature in AAV. In MPA, diffuse alveolar hemorrhage and pulmonary fibrosis (PF) are the most frequent manifestations. High-resolution computed tomography (HRCT) chest findings associated with MPA in PF patients demonstrate a high frequency of usual interstitial pneumonia (UIP), fibrotic-nonspecific interstitial pneumonia (F-NSIP), and combined PF and emphysema (CPFE) pattern with honeycombing, traction bronchiectasis, ground-glass opacity, and emphysema. In most of these cases, the histologic pattern of PF has been classified as UIP and/or fibrotic NSIP. In addition, a high incidence of histological findings, such as extensive interstitial fibrosis, lymphoid hyperplasia, and bronchiolitis, are characteristics observed in PF associated with collagen vascular diseases and which are not observed in idiopathic PF (IPF). In some cases, PF precedes the development of MPA. Indeed, there are some cases of pulmonary-limited MPA in this group. Therefore, clinicians should be aware of MPA as an underlying feature of PF in order to avoid overlooking and misdiagnosing this condition as IPF. The median survival time (MST) in UIP pattern/MPA is comparable with that of IPF. In GPA, almost all patients have either upper airway or lower respiratory tract lesions. Solitary or multiple nodules (frequently cavitated) and masses are the most common findings on chest images. Asthma is a cardinal symptom of Churg-Straus syndrome, often preceded by allergic rhinitis. To induce remission, a severity-based regimen was given to patients according to the appropriate protocol of the Japanese patients with myeloperoxidase (MPO)-ANCA-associated vasculitis (JMAAV) study group: low-dose corticosteroid and, if necessary, cyclophosphamide or azathioprine in patients with mild form; high-dose corticosteroid and cyclophosphamide in those with severe form; severe-form regimen plus plasmapheresis in those with the most severe form.

Topics: Adrenal Cortex Hormones; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Lung; Lung Diseases; Peroxidase; Predictive Value of Tests; Pulmonary Medicine; Respiratory Function Tests; Severity of Illness Index; Tomography, X-Ray Computed; Treatment Outcome

Neutrophil extracellular traps (NETs) are characterized by the presence of extracellular DNA fibers studded with antimicrobial proteins, including myeloperoxidase (MPO). Although NETs play an important role in the innate immune system, the scattered extracellular enzymes, such as MPO, pose risks to the host. Therefore, NETs are strictly regulated by DNase I in the serum, which prevents them from persisting. Recent studies have demonstrated that dysregulation of NETs could be involved in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus. In this review, we interpret the association of disordered NETs with autoimmune diseases, especially propylthiouracil-induced MPO-ANCA-associated vasculitis.

Topics: alpha-Defensins; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Deoxyribonuclease I; Disease Models, Animal; Humans; Neutrophils; Peroxidase; Propylthiouracil

We investigated the clinical features of Korean patients with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) by reviewing the literature. The characteristics of AAV in Korean patients were as follows: (1) granulomatous and limited disease is prevalent in granulomatosis with polyangiitis (Wegener's) (GPA), (2) ANCA positivity is lower in GPA (56.6-68.9%) and eosinophilic granulomatosis with polyangiitis (EGPA) (5.9-8.3%), whereas it is higher in microscopic polyangiitis (MPA) (69-94%), (3) C-ANCA/proteinase 3 (PR3)-ANCA positivity is 71.5-100% in GPA and P-ANCA/myeloperoxidase (MPO)-ANCA positivity reached 94-100% in patients with MPA, (4) renal involvement or progression to end-stage renal disease was lower in Korean patients with GPA and EGPA than in Caucasians with GPA and EGPA (according to data provided in reports). The data provided here may need to be confirmed in large-scale studies.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Asian People; Biomarkers; Humans; Myeloblastin; Peroxidase; Phenotype; Prevalence; Prognosis; Republic of Korea

To provide an update on animal models of antineutrophil cytoplasmic autoantibody (ANCA)-mediated vasculitis and highlight recent insights gained from studies in these models pertaining to immunopathogenesis.. Animal models support the pathogenic potential of myeloperoxidase (MPO)-ANCA. Alternative pathway complement activation has been identified as a novel inflammatory pathway in disease induction and a potential target for intervention. Interventions targeting B cells, antibodies, and signal transduction pathways may hold promise as well. The role of T cells is beginning to be explored, and studies indicate a prominent role for Th17 responses. The link between infection and ANCA vasculitis is well established. In animal models, Toll-like receptor (TLR)4 ligation is involved in disease induction. Ligation of TLRs contributes to the initiation of anti-MPO autoimmune responses in which TLR2 activation induces a Th17 response and TLR9 activation directs a Th1 response. An animal model for PR3-ANCA vasculitis is not available yet but models with a humanized immune system are being developed and show promising first results.. Animal models of MPO-ANCA vasculitis have contributed substantially to our understanding of disease immunopathogenesis and have illuminated novel targets for intervention. The development of PR3-ANCA animal models remains a challenge but recent observations in humanized model systems offer hope.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Complement Pathway, Alternative; Disease Models, Animal; Humans; Mice; Mice, Inbred C57BL; Peroxidase; Rats; Rats, Inbred WKY; Signal Transduction; Th17 Cells

We report a case of long-standing sinobronchial syndrome complicated by microscopic polyangiitis (MPA) during the clinical course. The patient showed a mild elevation of myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) 17 months prior to the diagnosis of MPA. Subsequently, her MPO-ANCA level gradually became more elevated, and finally her MPO-ANCA level peaked when purpura appeared. Histologic examination of the skin biopsy was consistent with leukocytoclastic vasculitis. Based on the pathological and clinical findings, a diagnosis of MPA was made. Corticosteroid therapy finally led to a remission of MPA with normalized MPO-ANCA titers.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Bronchiectasis; Female; Humans; Peroxidase; Sinusitis; Syndrome

We report a case of recurrent anti-cytoplasmic neutrophil antibody (ANCA)-associated vasculitis post kidney transplantation. A 60-year-old woman underwent uncomplicated deceased-donor kidney transplantation for end-stage renal disease (ESRD) secondary to myeloperoxidase-specific ANCA-associated vasculitis, after six years of haemodialysis, and clinical remission. Immunosuppression was with tacrolimus/mycophenolate and prednisolone after basiliximab induction therapy. Five weeks post-transplantation, an allograft biopsy, done for a rising creatinine and glomerular haematuria, revealed pauci-immune crescentic glomerulonephritis. This was treated with pulse methylprednisolone, increase in maintenance prednisolone, 7 sessions of plasma exchange, and replacement of mycophenolate with cyclophosphamide. Tacrolimus was continued throughout. After 3 months of therapy a repeat allograft biopsy showed quiescent vasculitis. The cyclophosphamide was then ceased, and mycophenolate reinstituted. The patient has maintained clinical and histological stability. Reported rates of ANCA-associated vasculitis recurrence post-kidney transplantation have varied but are low compared with other types of glomerulonephritis and seemed to have further declined in the era of modern immunosuppression. Given the low recurrence rate and excellent outcomes in suitable patients, kidney transplantation remains the optimal form of renal replacement therapy for ESRD due to ANCA-associated vasculitis. Whilst re-introduction of cyclophosphamide has been the mainstay of therapy, additional reported successful therapeutic strategies have included pulse methylprednisolone, plasma exchange and rituximab. Further study on the most effective and safest treatment options would be of use given the current paucity of data in this area.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoantibodies; Biopsy; Drug Administration Schedule; Drug Substitution; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Middle Aged; Peroxidase; Plasma Exchange; Recurrence; Time Factors; Treatment Outcome

Neutrophils are pivotal to host defence during infectious diseases. However, activated neutrophils may also cause undesired tissue damage. Ample examples include small-vessel inflammatory diseases (vasculitis) that are associated with anti-neutrophil cytoplasmic autoantibodies (ANCA) residing in the patients' plasma. In addition to being an important diagnostic tool, convincing evidence shows that ANCA are pathogenic. ANCA-neutrophil interactions induce important cellular responses that result in highly inflammatory necrotizing vascular damage. The interaction begins with ANCA binding to their target antigens on primed neutrophils, proceeds by recruiting transmembrane molecules to initiate intracellular signal transduction and culminates in activation of effector functions that ultimately mediate the tissue damage.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antigen-Antibody Reactions; Antigens, Surface; Autoantigens; Cell Membrane; Cytokines; GPI-Linked Proteins; Humans; Immunoglobulin Fc Fragments; Intracellular Membranes; Lysosomal Membrane Proteins; Lysosomal-Associated Membrane Protein 2; Myeloblastin; Neutrophil Activation; Neutrophils; Organelles; Peroxidase; Phosphatidylinositol 3-Kinases; Receptors, IgG; Signal Transduction

Antibodies against neutrophil proteins myeloperoxidase (MPO) and proteinase 3 are thought to cause disease in anti-neutrophil cytoplasmic antibody (ANCA) vasculitis. There have been a number of recent developments in the animal models of ANCA vasculitis in both mice and rats. These include models based on an immune response to MPO generated in MPO-deficient mice, with other models using MPO-sufficient mice and rats. In addition, there is a report of the use of humanized mice where immunodeficient mice have been engrafted with human haematopoietic stem cells and injected with patient ANCA. Antibodies to another protein lysosomal-associated protein-2 have been found in patients with ANCA vasculitis, and evidence from a rat model suggests that they are also pathogenic. These models all have advantages and disadvantages, which are discussed. We also consider what these models have taught us about the pathogenesis of ANCA vasculitis. Experiments using genetically modified mice and pharmacological inhibition have given insights into disease mechanisms and have identified potential therapeutic targets. Toll-like receptor stimulation modifies disease by acting both at the level of tissue injury and in the generation of the autoimmune response. Complement is also potentially important with data to support the role of the alternative pathway and C5a in particular. Intracellular pathways have been examined, with a role showing p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase γ. Serine proteases are now known to contribute to disease by release of interleukin-1β in ANCA-activated neutrophils and monocytes. Other potential therapies studied in these models include the use of bortezemib and strategies to modify antibody glycosylation.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoantigens; Glomerulonephritis; Humans; Immunoglobulin G; Lysosomal-Associated Membrane Protein 2; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Mutant Strains; Mice, SCID; Models, Animal; Molecular Mimicry; Myeloblastin; Peroxidase; Radiation Chimera; Rats; Rats, Inbred WKY; Signal Transduction; Species Specificity; Toll-Like Receptors

Clinical observations, including a report of neonatal vasculitis occurring in a child born from a mother with anti-neutrophil cytoplasmic antibody directed to myeloperoxidase (MPO-ANCA)-associated vasculitis, suggest a pathogenic role for ANCA. Such a role is supported by in vitro experimental data showing that ANCA can activate primed neutrophils to the production of reactive oxygen species and lytic enzymes resulting in lysis of endothelial cells. An interplay between neutrophils, the alternative pathway of complement, and MPO-ANCA resulting in systemic vasculitis including necrotizing glomerulonephritis has clearly been demonstrated in animal models. An in vivo pathogenic role of ANCA directed to proteinase 3 (PR3-ANCA) has, however, not been substantiated. In PR3-ANCA-associated vasculitis, granulomatous inflammation points to involvement of cell-mediated immunity. In vitro studies, indeed, suggest that PR3-specific Th17 CD4-positive lymphocytes are operative in lesion development. The triggering role of microbial factors is becoming more clear. In particular Staphylococcus aureus carriage and infection with Gram-negative bacteria could contribute to induction and persistence of ANCA-associated vasculitis (AAV). Insight into the pathogenic pathways involved in AAV have opened and will further open new ways to targeted treatment.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoantibodies; Complement Pathway, Alternative; Disease Models, Animal; Endothelium, Vascular; Humans; Immunity, Cellular; Myeloblastin; Neutrophils; Peroxidase; Reactive Oxygen Species; Staphylococcal Infections; Staphylococcus aureus; Th17 Cells

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides are characterised by necrotising inflammation of small vessels in conjunction with ANCA directed to either proteinase 3 (PR3) or myeloperoxidase (MPO). The aetiopathogenesis of these disorders is still not fully elucidated but clinical as well as in vitro and in vivo experimental data strongly suggest a role for the autoimmune responses to PR3 and MPO in disease development. Clinically, PR3-ANCA are strongly associated with granulomatous vasculitis as in Wegener's granulomatosis, and MPO-ANCA with necrotising small vessel vasculitis as in microscopic polyangiitis. Levels of PR3-ANCA and MPO-ANCA do, however, not fully reflect disease activity. In vitro, ANCA activate primed neutrophils to release lytic enzymes and reactive oxygen species, a process reinforced by the alternative pathway of complement. In the context of endothelial cells, this process leads to endothelial detachment and lysis. In vivo experimental studies have clearly demonstrated the pathogenic potential of MPO-ANCA for necrotising glomerulonephritis and pulmonary capillaritis. For PR3-ANCA-associated granulomatous vasculitis, an animal model is lacking. Here, effector T cells, in particular Th17 cells, appear to have a major pathogenic role in addition to ANCA. Finally, microbial factors, derived in particular from S aureus and Gram-negative bacteria, could play a part in disease induction and expression. These new insights into the pathogenesis of ANCA-associated vasculitides have opened new ways for targeted treatment.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Disease Models, Animal; Humans; Mice; Myeloblastin; Peroxidase; Rats

Enormous progress has been made during the last 25 years in our understanding of the aetiopathogenesis of the anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV). This has led to improvements in early diagnosis, treatment and secondary prevention of these diseases. Nevertheless, there are still unmet needs in the AAV. With respect to diagnosis and follow-up, sensitive biomarkers that reflect disease activity, also during smouldering disease, are needed. In the field of aetiopathogenesis, genetic and epigenetic studies are being performed not only directed at the autoimmune response but also at the expression of, possibly modified, autoantigens. Environmental factors, in particular microbial factors, are also being explored. This will enable analysis of gene-environment interactions in the AAV, so elucidating further their aetiopathogenesis. Explaining the differences in clinical presentation between proteinase 3 (PR3)-associated AAV and myeloperoxidase (MPO)-associated AAV requires an adequate animal model for PR3-ANCA disease, which is currently lacking. Although many large randomized controlled trials have built a base for a rational therapeutic approach in the AAV, late morbidity and mortality is still significant. The availability of new biologicals and the development of sensitive biomarkers for disease activity could further improve prognosis for patients suffering from AAV.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Humans; Myeloblastin; Peroxidase; Randomized Controlled Trials as Topic

Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis is an autoimmune disease in which the contributions of genetic, epigenetic and environmental factors to aetiology and pathogenesis are being unravelled. The ANCA immunoglobulin G targeting proteinase 3 and myeloperoxidase affects several neutrophil functions, usually to augment or dysregulate these, promoting a proinflammatory phenotype whereby neutrophils have enhanced capabilities of causing collateral damage to endothelial and other cells. In addition, B cells are intimately involved in pathogenesis as anti-B cell therapies are highly effective, but the manner of this involvement still needs to be delineated. Similarly, the T cell compartment is disturbed in ANCA vasculitis and numerous alterations in T cell subsets have been described, but recognition of a novel CD8(+) T cell transcription signature which can predict likelihood of relapse in ANCA vasculitis indicates that more needs to be learnt about the influence of T cells in the disease process. Finally, the role of the alternative complement pathway and the potential therapeutic value of its neutralization is under active investigation after compelling studies in murine models have demonstrated that C5 and factor-B knock-out mice are protected.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; B-Lymphocytes; Complement C5; Complement Pathway, Alternative; Endothelium, Vascular; Epigenomics; Humans; Macrophages; Mice; Myeloblastin; Neutrophils; Peroxidase; T-Lymphocytes

The possible link between pulmonary fibrosis, anti-neutrophil cytoplasmic autoantibody (ANCA) positivity, and vasculitis is poorly understood. During the past 6 years, five retrospective case-control studies have been published. These studies suggest that pulmonary fibrosis (PF) is an underestimated manifestation of ANCA-associated vasculitis. Common clinical characteristics include older age (around 70 years), constant positivity of myeloperoxidase (MPO)-ANCA and the poor prognosis of the pulmonary disease. The diagnosis of PF often predates the development of vasculitis. There are no significant differences of pulmonary function parameters, bronchoalveolar lavage analysis, or high-resolution computed tomographic (HRCT) findings between ANCA-associated PF and idiopathic pulmonary fibrosis (IPF). The high mortality rate of ANCA-associated PF indicates that a search for ANCAs should be performed at diagnosis in every patient with PF because the presence of ANCAs increases the risk of development of vasculitis and should promote specific monitoring of patients with positive MPO-ANCA.

Topics: Age Factors; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Comorbidity; Diagnosis, Differential; Female; Humans; Immunosuppressive Agents; Male; Peroxidase; Prognosis; Pulmonary Fibrosis; Sex Factors

This review provides a summary of recent advances in the understanding of crescentic glomerulonephritis, focusing on antineutrophil cytoplasm antibody (ANCA)-associated vasculitis and anti-glomerular basement membrane (anti-GBM) antibody disease. In ANCA-associated vasculitis (AAV), four main conceptual advances are discussed as follows: (1) evidence for the pathogenicity of ANCA, (2) molecular mimicry and the role of infection in AAV, (3) evidence for aberrant T-cell responses and T-cell regulation in AAV, and (4) advances in understanding of genetic predisposition to AAV. In relation to anti-GBM disease we discuss the following: (1) the nature of the Goodpasture autoantigens, (2) T-cell responses and regulation in anti-GBM disease, and (3) human leukocyte antigen and non-human leukocyte antigen genetic associations.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Glomerulonephritis; Humans; Lymphocyte Activation; Lysosomal Membrane Proteins; Lysosomal-Associated Membrane Protein 2; Peroxidase; T-Lymphocytes

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

We report a 63-year-old man with a 35-year history of slowly progressive type 1 diabetes mellitus (SPIDDM), complicated with myeloperoxidase-specific anti-neutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis presenting alveolar hemorrhage and pachymeningitis. The patient was first diagnosed as having DM at age of 28 years old and deteriorated secretion of insulin and the typical clinical course led us to the diagnosis of SPIDDM. When he was 58 years old, he suffered from fever, headache, and alveolar hemorrhage. He was diagnosed as having MPO-ANCA associated vasculitis based on a high titer of MPO-ANCA and histological findings of lung biopsy. Treatment with steroid pulse therapy, followed by oral prednisolone and oral cyclophosohamide, resulted in clinical improvement. Five years later, he complained of double vision. A gadolinium-enhanced magnetic resonance imaging (MRI) study of the brain showed normal. Two months later, he developed right cranial nerve V~XII palsy. A second MRI study revealed thickening of the right temporal region and cerebellar dura mater, leading us to the diagnosis of hypertrophic pachymeningitis. He responded well to oral prednisolone (50 mg/day) and intravenous cyclophosohamide (500 mg). This is the first case report of SPIDDM complicated with MPO-ANCA-associated vasculitis, manifesting as alveolar hemorrhage and hypertrophic pachymeningitis.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies; Biopsy; Cranial Nerve Diseases; Diabetes Mellitus, Type 1; Hemorrhage; Humans; Male; Meningitis; Middle Aged; Peroxidase

Drugs and infections may induce antineutrophil cytoplasmic antibodies (ANCA) and vasculitic manifestations mimicking ANCA-associated vasculitides (AAV) and mechanisms relevant in their pathogenesis. This review summarizes the most recent findings in this field.. Drug-induced and infection-induced proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA may be associated with a vasculitis clinically resembling AAV. Mechanisms relevant for the break of tolerance and induction of ANCA (e.g. danger signals, superantigens, neutrophil extracellular traps, protease-activated receptor-2, IL-17 cells) may be shared to some extent between drug-induced and infection-induced ANCA-positive vasculitis and AAV, especially with regard to the potential role of infection in Wegener's granulomatosis. Differences in immunopathology, clinical presentation, and functional aspects of ANCA help to distinguish drug-induced and infection-induced ANCA-positive vasculitis from AAV, and present new avenues for future research in this field.. Medications and infections, which induce PR3-ANCA and MPO-ANCA, have to be considered in the differential diagnosis of primary AAV. Moreover, there is clinical and experimental evidence for an association between certain drugs and infections with ANCA-production. Analysis of ANCA-induction in such conditions also sheds new light on our understanding of immune mechanisms relevant in the break of tolerance and ANCA-production in AAV.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Bacterial Infections; Cocaine-Related Disorders; Diagnosis, Differential; Humans; Immunologic Factors; Myeloblastin; Peroxidase

Palpable purpura tends to indicate involvement of small vessel vasculitis in the upper dermis. Livedo racemosa, nodular lesion and skin ulceration are indicative of involvement of small to medium-sized vessel vasculitis in the lower dermis to subcutaneous fat. We set out to establish a new algorithm (KAWAKAMI algorithm) for primary cutaneous vasculitis based on the Chapel Hill Consensus Conference classification and our research results, and apply to the diagnosis. The first step is to measure serum antineutrophil cytoplasmic antibodies (ANCA) levels. If myeloperoxidase-ANCA is positive, Churg-Strauss syndrome or microscopic polyangiitis can be suspected, and if the patient is positive for proteinase 3-ANCA, Wegener's granulomatosis is most likely. Next, if cryoglobulin is positive, cryoglobulinemic vasculitis should be suspected. Third, if direct immunofluorescence of the skin biopsy specimen reveals immunoglobulin A deposition within the affected vessels, Henoch-Schönlein purpura is indicated. Finally, the presence of anti-phosphatidylserine-prothrombin complex antibodies and/or lupus anticoagulant and histopathological necrotizing vasculitis in the upper to middle dermis (leukocytoclastic vasculitis) indicates cutaneous leukocytoclastic angiitis, whereas if necrotizing vasculitis exists in the lower dermis and/or is associated with the subcutaneous fat, cutaneous polyarteritis nodosa is indicated. The KAWAKAMI algorithm may allow us to refine our earlier diagnostic strategies and allow for efficacious treatment of primary cutaneous vasculitis. In cutaneous polyarteritis nodosa, warfarin or clopidogrel therapies should be administrated, and in cases that have associated active inflammatory lesions, corticosteroids or mizoribine (mycophenolate mofetil) therapy should be added. We further propose prophylactic treatment of renal complications in patients with Henoch-Schönlein purpura.

Topics: Adrenal Cortex Hormones; Algorithms; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Clopidogrel; Cryoglobulinemia; Diagnosis, Differential; Humans; IgA Vasculitis; Immunoglobulin A; Myeloblastin; Peroxidase; Polyarteritis Nodosa; Ribonucleosides; Ticlopidine; Vasculitis, Leukocytoclastic, Cutaneous; Warfarin

Several cases of rheumatoid arthritis (RA) with myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-associated crescentic glomerulonephritis (CrGN) have been reported. However, its clinical characteristics are not clear.. We summarized 3 patients of concurrent RA and MPO-ANCA-associated CrGN, diagnosed in our hospital from 1992 to 2006, and compared their clinicopathological data with those of 10 MPO-ANCA-associated CrGN patients without RA in the same period.. All three RA patients were middle-aged or young adult women with 7-14 years of RA history. The initial clinical symptom was microhematuria, and mean duration from hematuria onset to histological confirmation of CrGN was 17 months. At renal biopsy, serum creatinine concentration (sCr) was modestly elevated, with the mean value of 3.4 mg/dl. Crescents were detected in 30% of glomeruli, whereas advanced glomerular sclerosis, tubular atrophy, and interstitial fibrosis were also observed. In comparison with patients without RA, patients with RA were significantly younger and showed a longer duration from the onset to histological confirmation of CrGN. Serum creatinine concentration at referral was significantly lower; however, estimated glomerular filtration rate (eGFR) was comparable. The Birmingham Vasculitis Activity Score and the Disease Extent Index were significantly lower, and pathological examination showed less crescent formation and a tendency to advanced glomerular sclerosis in patients with RA.. In patients with RA, MPO-ANCA-associated CrGN appeared to develop at younger ages and often showed a slowly progressive deterioration of the renal function with slight extrarenal manifestations. These smoldering clinical features may result in late referral from rheumatologists to nephrologists and therefore poor prognosis.

Topics: Adult; Age of Onset; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Arthritis, Rheumatoid; Biomarkers; Biopsy; Case-Control Studies; Creatinine; Disease Progression; Female; Glomerular Filtration Rate; Glomerulonephritis; Hematuria; Humans; Kidney; Middle Aged; Peroxidase; Prognosis; Proteinuria; Referral and Consultation; Retrospective Studies; Severity of Illness Index; Time Factors

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

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Cytoplasm; Humans; Myeloblastin; Neutrophils; Pancreatic Elastase; Peroxidase

We aimed to validate and modify the renal risk score for antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (AAGN) in a Chinese cohort with a majority of myeloperoxidase (MPO)-positive patients.. A total of 285 patients with biopsy-proven AAGN in our center were retrospectively included. Patients were randomly assigned to the development set (n = 201) and the validation set (n = 84). We calculated the renal risk score and analyzed the clinicopathological characteristics and follow-up data. The nomogram was constructed based on the independent prognostic factors identified by the multivariable Cox regression and then compared with the renal risk score.. Over a median follow-up period of 41.3 (range 20.0-63.8) months, 84 (29.5%) patients reached end-stage kidney disease (ESKD). In the development set, hypertension (hazard ratio [HR] 2.16, 95% CI 1.08-4.32,. We present a nomogram as a practical tool to predict renal outcomes in Chinese patients with MPO-ANCA glomerulonephritis.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; East Asian People; Glomerulonephritis; Humans; Kidney Failure, Chronic; Peroxidase; Prognosis; Retrospective Studies; Risk Factors

The life prognosis of elderly patients with myeloperoxidase-anti-neutrophil cytoplasmic antibodies-associated vasculitis (MPO-AAV) has been improved by reducing the corticosteroid or cyclophosphamide dose to avoid opportunistic infection. However, many elderly MPO-AAV patients experience recurrence and renal death. An effective and safer maintenance treatment method is necessary to improve the renal prognosis of MPO-AAV.. Patients with MPO-AAV who reached complete or incomplete remission after induction therapy were prospectively and randomly divided into mizoribine (MZR; n = 25) and control (n = 28) groups. The primary endpoint was relapse of MPO-AAV. The patients' serum MZR concentration was measured before (C0) and 3 h after taking the MZR. The maximum drug concentration (Cmax) and the serum MZR concentration curves were determined using population pharmacokinetics parameters. We also assessed the relationship between the MZR concentrations and adverse events. The observation period was 12 months.. Fifty-eight MPO-AAV patients from 16 hospitals in Japan were enrolled. Ten patients relapsed (MZR group, n = 6; control group, n = 4; a nonsignificant between-group difference). Changes in the serum MZR concentration could be estimated for 22 of the 25 MZR-treated patients: 2 of the 11 patients who reached a Cmax of 3 μg/mL relapsed, whereas 4 of the 11 patients who did not reach this Cmax relapsed. The treatment of one patient with C0 > 1 μg/mL was discontinued due to adverse events. No serious adverse events occurred.. There was no significant difference in the recurrence rate of MPO-AAV between treatment with versus without MZR.

Topics: Adrenal Cortex Hormones; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Cyclophosphamide; Humans; Immunosuppressive Agents; Peroxidase; Ribonucleosides

Anti-neutrophil cytoplasm antibody-associated vasculitis is a multisystem, autoimmune disease that causes organ failure and death. Physical removal of pathogenic autoantibodies by plasma exchange is recommended for severe presentations, along with high-dose glucocorticoids, but glucocorticoid toxicity contributes to morbidity and mortality. The lack of a robust evidence base to guide the use of plasma exchange and glucocorticoid dosing contributes to variation in practice and suboptimal outcomes.. We aimed to determine the clinical efficacy of plasma exchange in addition to immunosuppressive therapy and glucocorticoids with respect to death and end-stage renal disease in patients with severe anti-neutrophil cytoplasm antibody-associated vasculitis. We also aimed to determine whether or not a reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen with respect to death and end-stage renal disease.. This was an international, multicentre, open-label, randomised controlled trial. Patients were randomised in a two-by-two factorial design to receive either adjunctive plasma exchange or no plasma exchange, and either a reduced or a standard glucocorticoid dosing regimen. All patients received immunosuppressive induction therapy with cyclophosphamide or rituximab.. Ninety-five hospitals in Europe, North America, Australia/New Zealand and Japan participated.. Participants were aged ≥ 16 years with a diagnosis of granulomatosis with polyangiitis or microscopic polyangiitis, and either proteinase 3 anti-neutrophil cytoplasm antibody or myeloperoxidase anti-neutrophil cytoplasm antibody positivity, and a glomerular filtration rate of < 50 ml/minute/1.73 m. Participants received seven sessions of plasma exchange within 14 days or no plasma exchange. Oral glucocorticoids commenced with prednisolone 1 mg/kg/day and were reduced over different lengths of time to 5 mg/kg/day, such that cumulative oral glucocorticoid exposure in the first 6 months was 50% lower in patients allocated to the reduced-dose regimen than in those allocated to the standard-dose regimen. All patients received the same glucocorticoid dosing from 6 to 12 months. Subsequent dosing was at the discretion of the treating physician.. The primary outcome was a composite of all-cause mortality and end-stage renal disease at a common close-out when the last patient had completed 10 months in the trial.. Plasma exchange did not prolong the time to death and/or end-stage renal disease in patients with anti-neutrophil cytoplasm antibody-associated vasculitis with severe renal or pulmonary involvement. A reduced-dose glucocorticoid regimen was non-inferior to a standard-dose regimen and was associated with fewer serious infections.. A meta-analysis examining the effects of plasma exchange on kidney outcomes in anti-neutrophil cytoplasm antibody-associated vasculitis is planned. A health-economic analysis of data collected in this study to examine the impact of both plasma exchange and reduced glucocorticoid dosing is planned to address the utility of plasma exchange for reducing early end-stage renal disease rates. Blood and tissue samples collected in the study will be examined to identify predictors of response to plasma exchange in anti-neutrophil cytoplasm in antibody-associated vasculitis. The benefits associated with reduced glucocorticoid dosing will inform future studies of newer therapies to permit further reduction in glucocorticoid exposure. Data from this study will contribute to updated management recommendations for anti-neutrophil cytoplasm antibody-associated vasculitis.. This study had an open-label design which may have permitted observer bias; however, the nature of the end points, end-stage renal disease and death, would have minimised this risk. Despite being, to our knowledge, the largest ever trial in anti-neutrophil cytoplasm antibody-associated vasculitis, there was an insufficient sample size to assess clinically useful benefits on the separate components of the primary end-point: end-stage renal disease and death. Use of a fixed-dose plasma exchange regimen determined by consensus rather than data-driven dose ranging meant that some patients may have been underdosed, thus reducing the therapeutic impact. In particular, no biomarkers have been identified to help determine dosing in a particular patient, although this is one of the goals of the biomarker plan of this study.. This trial is registered as ISRCTN07757494, EudraCT 2009-013220-24 and Clinicaltrials.gov NCT00987389.. This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in. Anti-neutrophil cytoplasm antibody vasculitis is a rare and severe disease in which the patient makes antibodies that damage their blood vessels. It can cause lung damage, kidney failure and early death. Treatment aims to suppress the harmful effects of the antibodies and associated inflammation. In particular: Plasma exchange aims to remove the antibodies from the bloodstream.Steroids aim to reduce the harmful activity of the antibodies. Unfortunately, plasma exchange is expensive and time-consuming, and we do not know if it really works long term to reduce kidney damage or the risk of death. We know steroids work, but they have many severe side effects that are related to higher doses. Again, we do not know if lower doses are equally effective. We conducted a randomised trial, PEXIVAS (Plasma Exchange In VASculitis), to measure the clinical effectiveness of plasma exchange and of reduced steroid doses. Anti-neutrophil cytoplasm antibody vasculitis patients with severe kidney or lung disease were allocated randomly to either plasma exchange or no plasma exchange. The same patients were then randomly allocated to a ‘reduced’ or ‘standard’ steroid dose. All patients received an immunosuppressive drug: cyclophosphamide or rituximab. The primary end point for both trials was the occurrence of either kidney failure or death. A total of 704 patients were recruited between 2010 and 2016, and they were followed up until the end of the trial in July 2017. Ninety-nine patients died and 138 developed kidney failure. Plasma exchange did not reduce the chances of death or kidney failure. There was also no difference between the two steroid dose groups in the number of deaths or patients developing kidney failure. However, there were fewer serious infections in the reduced steroid dose group. These results do not support the routine use of plasma exchange for all patients with severe vasculitis. They do show that the reduced-dose steroid regimen is just as effective as, and safer than, a ‘standard’-dose steroid regimen. These results have the potential to save money and make the treatment of vasculitis patients safer in the future.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoantibodies; Cost-Benefit Analysis; Cyclophosphamide; Cytoplasm; Glucocorticoids; Humans; Kidney Failure, Chronic; Myeloblastin; Peroxidase; Prednisolone; Rituximab

Rituximab is approved in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and leads to a decrease of ANCA levels. The objectives of this study were to investigate the non-linear pharmacokinetics of rituximab and the relationship between its concentrations and ANCA levels in AAV patients.. Ninety-two AAV patients from the RAVE (Rituximab in ANCA-Associated Vasculitis) trial were assessed. Both ANCA anti-myeloperoxidase (MPO-ANCA) and anti-proteinase 3 (PR3-ANCA) levels were used as biomarkers. The pharmacokinetics of rituximab were described using a semi-mechanistic two-compartment model that included a latent target antigen turnover and allowed the estimation of specific target-mediated elimination in addition to its non-specific elimination of rituximab. The effect of rituximab on the ANCA level was described using a semi-mechanistic compartment model with a negative feedback (Friberg) model with no transit compartment. A population modeling approach was used.. A non-linear target-mediated elimination of rituximab was detected in AAV patients. Our PK-PD model allowed quantification of the association between rituximab concentrations and ANCA levels. This decrease was deep but delayed, and more sustained in patients with MPO-ANCA than in those with PR3-ANCA. Our results suggest that repeating courses of rituximab might improve the clinical response to rituximab.

Topics: Adult; Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antineoplastic Agents, Immunological; Biomarkers; Double-Blind Method; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Models, Biological; Myeloblastin; Nonlinear Dynamics; Peroxidase; Remission Induction; Rituximab

To investigate serum IL-6 (sIL-6) levels during active disease, complete remission (CR), and relapse in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), and to explore the association of changes in sIL-6 with clinical outcomes.. sIL-6 levels were measured at baseline and longitudinally over 18 months, in 78 patients with AAV enrolled in a randomized controlled trial comparing treatment with either rituximab (RTX) or cyclophosphamide (CYC)/azathioprine (AZA). Outcome variables included baseline clinical features, ANCA specificity, disease activity (active disease versus CR), time to relapse events, B cell repopulation, and ANCA titer increases.. At baseline, sIL-6 concentrations correlate with PR3-ANCA titers and are associated with specific clinical manifestations of AAV. Baseline sIL6 concentrations do not predict CR at 6 months, but the increase in sIL-6 concentrations during CR is associated with subsequent severe relapse among RTX-treated patients. Further investigation into the mechanistic role of IL6 in AAV might lead to identifying this pathway as a potential therapeutic target in this disease.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Azathioprine; B-Lymphocytes; Cyclophosphamide; Cytoplasm; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Interleukin-6; Longitudinal Studies; Male; Middle Aged; Myeloblastin; Neutrophils; Peroxidase; Remission Induction; Rituximab

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

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of life-threatening disorders, and frequently affects the kidneys. This study investigated whether the circulating neutrophil extracellular traps (NETs) levels were associated with disease activity of AAV. We collected serum samples from 34 patients with AAV in active stage and 62 patients with AAV in remission. Cell free DNA in serum was quantified using the Quant-iT PicoGreen assay. NETs associated MPO-DNA complexes, citrullinated-histone H3-DNA (cit-H3-DNA) complexes and the concentration of deoxyribonuclease I (DNase I) were quantified using ELISA. The activity of DNase I was quantified using radial enzyme-diffusion method. Associations between circulating levels of NETs with clinico-pathological parameters were analyzed. Serum levels of NETs in active AAV patients were significantly higher than those in healthy controls, and the level of cell free DNA correlated with C-reactive protein (CRP). However, no correlation was found between MPO-DNA complexes or cit-H3-DNA complexes level and CRP. Also there was no significant correlation between NETs level and initial serum creatinine, estimated glomerular filtration rate (eGFR), crescents formation or Birmingham Vasculitis Activity Score (BVAS). Furthermore, there was no significant difference of serum levels of cell free DNA or MPO-DNA complexes between active stage and remission of AAV. In conclusion, circulating levels of NETs cannot be used as a biomarker to assess disease activity in AAV patients.

Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Biomarkers; DNA; Extracellular Traps; Female; Humans; Male; Peroxidase

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

In view of the marked difference in epidemiology of myeloperoxidase/proteinase 3 anti-neutrophil cytoplasmic antibody (MPO/PR3-ANCA)-associated vasculitis between Japan and Western countries, a prospective, open-label, multi-center trial (Japanese Patients with MPO-ANCA-Associated Vasculitis; JMAAV) was performed to evaluate the usefulness of severity-based treatment in Japanese patients with newly diagnosed MPO-ANCA-associated vasculitis. Among the 47 patients enrolled and prescribed predefined therapies, 42 achieved remission within 6 months (89%), 5 died (11%), and 1 developed end-stage renal disease (2%). Disease relapsed in 8 of the 42 patients with remission during the 18-month follow-up period (19%). The remission and death rates were comparable to several previous clinical trials performed in Western counties. Relapse and severe infection, however, appeared to be more frequent than in previous trials, and therefore should be investigated further in future trials. Subsidiary analysis was also performed using samples from these patients, and a new serum biomarker for microscopic polyangiitis and a novel gene expression profile of peripheral blood to predict response to treatment were found by proteomic and transcriptomic analysis, respectively.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Disease Progression; Humans; Immunosuppressive Agents; Japan; Kidney Failure, Chronic; Peroxidase; Prospective Studies; Recurrence; Remission Induction; Respiratory Tract Infections; Severity of Illness Index; Time Factors; Treatment Outcome

We (JMAAV [Japanese patients with MPO-ANCA-associated vasculitis] Study Group) performed a prospective, open-label, multi-center trial to evaluate the usefulness of severity-based treatment in Japanese patients with myeloperoxidase-anti-neutrophil cytoplasmic antibodies (MPO-ANCA)-associated vasculitis. Patients with MPO-ANCA-associated vasculitis received a severity-based regimen according to the appropriate protocol: low-dose corticosteroid and, if necessary, cyclophosphamide or azathioprine in patients with mild form; high-dose corticosteroid and cyclophosphamide in those with severe form; and the severe-form regimen plus plasmapheresis in those with the most severe form. We followed up the patients for 18 months. The primary end points were the induction of remission, death, and end-stage renal disease (ESRD). Fifty-two patients were registered, and 48 patients were enrolled in this study (mild form, n = 23; severe form, n = 23; most severe form, n = 2). Among the 47 patients who received the predefined therapies, 42 achieved remission within 6 months, 5 died, and 1 developed ESRD. Disease flared up in 8 of the 42 patients with remission during the 18-month follow-up period. The JMAAV trial is the first prospective trial for MPO-ANCA-associated vasculitis to be performed in Japan. The remission and death rates were comparable to those in several previous clinical trials performed in western counties. The regimen employed in this trial was tailor-made based on patients' disease severity and disease type, and it seems that standardization can be consistent with treatment choices made according to severity.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Asian People; Cyclophosphamide; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Japan; Male; Middle Aged; Peroxidase; Prednisolone; Remission Induction; Severity of Illness Index; Treatment Outcome

To examine the improvement in health-related quality of life (HRQOL) in association with disease activity in myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis patients treated with cyclophosphamide plus prednisolone.. According to the Japanese Patients with MPO-ANCA-Associated Vasculitis (JMAAV) study protocol, a total of 48 patients with newly diagnosed MPO-ANCA-associated vasculitis received a standardized cyclophosphamide plus prednisolone regimen, and their clinical courses were followed for 18 months following their entry into the study. Disease activity was assessed using the Birmingham Vasculitis Activity Score (BVAS) 2003. HRQOL was assessed using MOS Short-Form 36 (SF-36) v2. BVAS new/worse, BVAS persistent, and SF-36 domain scores (norm-based) were calculated for the 32 eligible patients.. The mean SF-36 domain scores were significantly lower than the Japanese general population norm. Stepwise multiple linear regression analysis showed that the presence of new or worsening features of the nervous system was significantly associated with a deterioration in physical function. During the 18 months of follow-up, there were significant improvements in BVAS new/worse and all SF-36 domains except for general health and role emotional.. MPO-ANCA-associated vasculitis patients experienced a considerable deterioration in HRQOL. The standardized cyclophosphamide plus prednisolone regimen of the JMAAV study induced remission in the majority of patients, and the induction of remission accompanied a recovery in HRQOL.

Topics: Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Asian People; Autoantibodies; Cyclophosphamide; Drug Therapy, Combination; Female; Health Status; Humans; Immunosuppressive Agents; Japan; Male; Middle Aged; Peroxidase; Prednisolone; Quality of Life; Remission Induction; Treatment Outcome

There is a consensus that maintenance therapy should be used to prevent relapse of myeloperoxidase-anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (MPO-AAV), but there is a debate about the optimal duration of maintenance therapy. Therefore, the purpose of this study was to determine whether discontinuation of maintenance therapy in MPO-AAV patients who were in long-term stable remission affects relapse, renal survival and patient survival. Seventy-nine patients with MPO-AAV diagnosed at Xiangya hospital from June 2010 to June 2019 who were in stable remission for at least 18 months following maintenance therapy were included. Patient records were retrospectively reviewed, and based on whether patients discontinued maintenance therapy 18 months after commencing maintenance therapy, patients were assigned into either the withdrawal group (n = 26) or maintenance group (n = 53). The endpoint was the percentage of relapse, relapse-free survival, renal survival and patient survival during follow-up. Ten relapses (38.5%) occurred in the withdrawal group (n = 26) and 8 relapses (15.1%) occurred in the maintenance group (n = 53) (p = 0.020). Compared to the withdrawal group, the maintenance group had similar relapse-free survival (log-rank test p = 0.099). But maintenance group had a better renal survival (p = 0.035), with no difference in patient survival or adverse events. This study suggests that discontinuing maintenance therapy at 18 months following induction of sustained remission leads to a significant increase in the percentage of relapse, and decreases renal survival in patients with MPO-AAV, but does not decrease relapse-free survival or patient survival.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; East Asian People; Humans; Peroxidase; Recurrence; Retrospective Studies

Several case reports have indicated that nontuberculous mycobacterial pulmonary disease is associated with anti-neutrophil cytoplasmic antibody-associated vasculitides. However, the effect of the treatment for nontuberculous mycobacterial pulmonary disease on anti-neutrophil cytoplasmic antibody-associated vasculitides remains unclear. An asymptomatic 80-year-old woman presented with nodular bronchiectasis. After 1 year, she developed a productive cough. Mycobacterial culture of the respiratory specimen revealed Mycobacterium avium. She was diagnosed with nontuberculous mycobacterial pulmonary disease based on the criteria proposed by the American Thoracic Society. Concurrently, she had hearing loss, tinnitus, and weight loss. A blood test showed an elevated level of myeloperoxidase-anti-neutrophil cytoplasmic antibody (107 IU/mL, normal level: <3.5 IU/mL). Bilateral otitis media with anti-neutrophil cytoplasmic antibody-associated vasculitis was diagnosed based on the diagnostic criteria proposed by the Japan Otological Society. After starting antimicrobial agents for the nontuberculous mycobacterial pulmonary disease, her pulmonary symptoms and hearing loss improved, and the level of myeloperoxidase-anti-neutrophil cytoplasmic antibody normalized. No immunosuppressive treatment was administered. The present case suggests that nontuberculous mycobacterial pulmonary disease can cause otitis media with anti-neutrophil cytoplasmic antibody-associated vasculitides, and antimicrobial treatment for the nontuberculous mycobacterial pulmonary disease may resolve otitis media with anti-neutrophil cytoplasmic antibody-associated vasculitides.

Topics: Aged, 80 and over; Anti-Infective Agents; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Hearing Loss; Humans; Lung Diseases; Mycobacterium Infections, Nontuberculous; Otitis Media; Peroxidase

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

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biopsy; Humans; Muscles; Peroxidase

To evaluate the prevalence, clinical and radiographic features, and long-term outcomes of interstitial lung disease (ILD) in a United States-based ANCA-associated vasculitis (AAV) cohort.. In this retrospective cohort study, we identified cases of ILD within the 2002-2019 Mass General Brigham AAV Cohort, a consecutive inception cohort of PR3- or MPO-ANCA+ AAV patients. ILD diagnosis and classification as fibrotic or non-fibrotic were confirmed by review of available chest imaging by two board-certified radiologists. Cox proportional hazard models, with age as the time scale, were used to estimate the association of AAV-ILD with all-cause mortality.. Of 684 patients in the MGB AAV Cohort, 91 (13%) had ILD which preceded the diagnosis of AAV by a mean of 2.2 years. AAV-ILD patients were older (67 vs 60 years, P < 0.001) than patients without ILD but the distribution of sex and race was similar. AAV-ILD patients were more often MPO-ANCA+ (93% vs 65%, P < 0.001); among MPO-ANCA+ patients (n = 470), 85 (18%) had ILD. The majority of ILD was fibrotic (76%) and UIP was the most common ILD pattern (42%). The baseline forced vital capacity (FVC) % predicted among ILD patients was 81 ± 20%. Fibrotic AAV-ILD was associated with a 58% higher risk of death (aHR 1.58, 95% CI 1.06, 2.37) compared with AAV patients without ILD.. ILD is a frequent complication of AAV, especially MPO-ANCA+ AAV, often preceding recognition of AAV. Fibrotic AAV-ILD is associated with a higher risk of death than AAV without ILD.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Lung Diseases, Interstitial; Peroxidase; Retrospective Studies

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

Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a systemic autoimmune disease in which glomerulonephritis is an important manifestation. Antibodies against myeloperoxidase (MPO) or proteinase 3 are thought to be important in pathogenesis. Phosphoinositide 3-kinase δ (PI3Kδ) mediates a number of effects in lymphocytes, but its role in myeloid cell responses is less clear. Therefore, this study was undertaken to assess this in a preclinical model of glomerulonephritis induced by the transfer of antibodies to MPO.. D910A mice with inactive PI3Kδ were compared with wild-type controls. Disease protocols allowed for a comparison of experimental groups in the setting of both mild and more severe disease. Adoptive transfer experiments were performed, with flow cytometric analysis of digested kidneys taken at the end of the experiment.. With mild disease, D910A mice had fewer glomerular macrophages, fewer glomerular neutrophils, and reduced albuminuria compared with wild-type controls. With more severe disease, they also had fewer glomerular crescents and lower serum creatinine levels, indicating protection from acute kidney injury. Adoptive transfer experiments showed a defect in the recruitment of D910A monocytes to the diseased kidney.. Mice with inactive PI3Kδ were protected from anti-MPO vasculitis. This is due to cell intrinsic defect in the recruitment of monocytes to the kidney. These findings suggest that PI3Kδ is a potential therapeutic target in AAV.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Glomerulonephritis; Mice; Peroxidase; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases

Anti-neutrophil cytoplasmic antibody (ANCA) kinetic in ANCA-associated vasculitis with glomerulonephritis (AAV-GN) has been suggested to be associated with AAV relapse. Few studies have focused on its association with renal prognosis. Thus we aimed to investigate the relationship between ANCA specificity and the evolutive profile and renal outcomes.. This multicentric retrospective study included patients diagnosed with ANCA-GN since 1 January 2000. Patients without ANCA at diagnosis and with fewer than three ANCA determinations during follow-up were excluded. We analysed estimated glomerular filtration rate (eGFR) variation, renal-free survival and relapse-free survival according to three ANCA profiles (negative, recurrent and persistent) and to ANCA specificity [myeloperoxidase (MPO) or proteinase 3 (PR3)].. Over a follow-up of 56 months [interquartile range (IQR) 34-101], a median of 19 (IQR 13-25) ANCA determinations were performed for the 134 included patients. Patients with a recurrent/persistent ANCA profile had a lower relapse-free survival (P = .019) and tended to have a lower renal survival (P = .053) compared with those with a negative ANCA profile. Patients with a recurrent/persistent MPO-ANCA profile had the shortest renal survival (P = .015) and those with a recurrent/persistent PR3-ANCA profile had the worst relapse-free survival (P = .013) compared with other profiles. The negative ANCA profile was associated with a greater eGFR recovery. In multivariate regression analysis, it was an independent predictor of a 2-fold increase in eGFR at 2 years [odds ratio 6.79 (95% confidence interval 1.78-31.4), P = .008]).. ANCA kinetic after an ANCA-GN diagnosis is associated with outcomes. MPO-ANCA recurrence/persistence identifies patients with a lower potential of renal recovery and a higher risk of kidney failure, while PR3-ANCA recurrence/persistence identifies patients with a greater relapse risk. Thus ANCA kinetics may help identify patients with a smouldering disease.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Chronic Disease; Glomerulonephritis; Humans; Kidney; Myeloblastin; Peroxidase; Retrospective Studies

Antibodies to neutrophil and monocyte myeloperoxidase and proteinase 3 are a feature of anti-neutrophil cytoplasmic antibody vasculitis, a disease with significant morbidity for which new treatments are needed. Mice with a myeloid-specific deletion of the anti-apoptotic protein Mcl1 have reduced numbers of circulating neutrophils. Here, we assessed if myeloid-specific Mcl1 was required in murine anti-myeloperoxidase vasculitis and whether inhibition of myeloperoxidase was protective. In a murine model of anti-neutrophil cytoplasmic antibody vasculitis, induced by anti-myeloperoxidase antibody, mice with a myeloid-specific deletion of Mcl1 were protected from disease. They had fewer crescents, neutrophils, and macrophages in the glomeruli, lower serum creatinine levels and reduced albuminuria compared with controls. At baseline and day six after disease induction they had fewer circulating neutrophils than controls. At day six there were also fewer circulating monocytes. Myeloperoxidase inhibition with AZD5904 had no effect on histological or biochemical parameters of disease, and there was also no reduction in albuminuria at day one, two, five or seven after disease induction. These findings persisted when disease was induced without granulocyte-colony stimulating factor, which increases disease severity. A second myeloperoxidase inhibitor, AZM198, also showed no evidence of an effect, although both AZD5904 and AZM198 inhibited human neutrophil extracellular trap formation in vitro. Thus, our results show that while myeloid-specific Mcl1 is required in this model of anti-myeloperoxidase vasculitis, myeloperoxidase inhibition is not protective.

Topics: Albuminuria; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Apoptosis Regulatory Proteins; Glomerulonephritis; Humans; Mice; Myeloid Cell Leukemia Sequence 1 Protein; Neutrophils; Peroxidase; Vasculitis

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Child; Humans; Peroxidase

Patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and idiopathic interstitial lung diseases (IIPs) are positive for myeloperoxidase (MPO)-ANCA. MPO-ANCA-positive vasculitis mainly comprises microscopic polyangiitis (MPA) and unclassifiable vasculitis. These diseases are frequently complicated by interstitial lung disease (ILD). Few studies have reported the clinical differences between the subtypes of MPO-ANCA-positive ILD. Therefore, this study aimed to examine the clinical findings and courses of MPO-ANCA-positive ILD.. This retrospective study enrolled 100 patients with MPO-ANCA-positive ILD who were categorized into three groups: MPA (n = 44), unclassifiable vasculitis (n = 29), and IIP (n = 27). Our study compared the clinical findings and prognosis of these patients and analyzed the poor prognostic factors. Furthermore, we assessed the association between the patients with and without acute exacerbation of ILD (AE-ILD).. Our study found clinical differences in serum markers, clinical symptoms, and treatment regimens among the three groups. ILD complications, as the main cause of death, differed among the three groups (P = 0.04). Patients with unclassifiable vasculitis showed higher survival rates than those with IIP (P = 0.046). Patients with AE-ILD showed fewer general symptoms (P = 0.02) and lower survival rates (P < 0.01) than those without AE-ILD. In multivariate analysis, AE-ILD development was a strong poor prognostic factor for MPO-ANCA-positive ILD.. The subtypes of MPO-ANCA-positive ILD have different clinical features and prognoses. Patients who develop AE-ILD require careful evaluation of clinical courses. Key Points • In myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-positive interstitial lung disease (ILD), patients with unclassifiable vasculitis showed a better prognosis than those with idiopathic ILD.. • Development of acute exacerbation in ILD was a strong poor prognostic factor in patients with MPO-ANCA-positive ILD..

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Lung Diseases, Interstitial; Microscopic Polyangiitis; Peroxidase; Retrospective Studies

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

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of life-threatening autoimmune diseases. Inhibitors of apoptosis proteins (IAPs) are a class of molecules engaged in cell death and inflammation, interventions of which are proven effective in a number of inflammatory diseases. Here we tested whether targeting IAPs could ameliorate AAV and explored the potential mechanism.. We collected 19 kidney specimens from patients with myeloperoxidase (MPO)-AAV to investigate the expression of IAPs. The IAP pan-inhibitor SM164 was used to treat the experimental autoimmune vasculitis (EAV) rat model of AAV. RNA sequencing of renal cortex and enrichment analysis were developed to interpret gene expression. Functional experiments were performed to investigate the role of SM164 on neutrophils and endothelial cells.. The expression of three IAPs (cIAP1, cIAP2 and XIAP) was upregulated in kidneys of AAV patients compared with normal controls. SM164 dramatically reduced renal injury in EAV rats. Transcriptomic analysis revealed prominent alterations in fatty acid oxidation and respiratory burst following SM164 treatment. Functional studies demonstrated that SM164 inhibited neutrophil activation induced by MPO-ANCA positive IgG or serum from MPO-AAV patients, and such inhibitory effect was abolished by gene silencing or pharmacological inhibition of fatty acid oxidation. SM164 also inhibited the adhesion of neutrophils to endothelial cells with little effect on the endothelial injury induced by serum from MPO-AAV patients.. Inhibition of IAPs with SM164 played a protective role in AAV through enhancing intracellular fatty acid oxidation in neutrophils.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Endothelial Cells; Fatty Acids; Inhibitor of Apoptosis Proteins; Neutrophils; Peroxidase; Rats

A 71-year-old man with hyperthyroidism complained of headache lasting two months. He had been using propylthiouracil (PTU) for 14 years. Treatment intensification did not improve the symptoms. Blood tests detected a positive myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA). Diffuse dural thickening was identified by magnetic resonance imaging. The patient was diagnosed with hypertrophic pachymeningitis (HP) due to ANCA-associated vasculitis (AAV). He received methylprednisolone pulse therapy followed by prednisolone and methotrexate, which improved his headache. PTU-induced AAV-related HP is a rare and indiscernible disease. Therefore, the possibility of the disease should be proactively considered when a PTU user experiences refractory headaches.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Headache; Humans; Hypertrophy; Male; Meningitis; Peroxidase; Propylthiouracil

We encountered an 86-year-old Japanese woman who presented with proteinuria (0.4 g/day) and hematuria (red blood cell sediment >100/high-power field), a decreased renal function (serum creatinine, 1.51 mg/dL), and elevated myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) levels (231 IU/mL) during treatment of rheumatoid arthritis with abatacept (a cytotoxic T-lymphocyte-associated antigen 4 agent) and adalimumab (a tumor necrosis factor-α agent). A kidney biopsy showed pauci-immune necrotizing glomerulonephritis, and ANCA-associated vasculitis was diagnosed. Treatment with tocilizumab (an interleukin 6 receptor antibody) monotherapy resulted in the improvement of renal findings and normalization of rheumatoid arthritis disease activity and serum ANCA levels. Tocilizumab can also suppress ANCA-associated vasculitis.

Topics: Abatacept; Adalimumab; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Arthritis, Rheumatoid; Female; Glomerulonephritis; Humans; Nephritis; Peroxidase

Syk is a cytoplasmic protein tyrosine kinase that plays a role in signaling via B cell and Fc receptors (FcR). FcR engagement and signaling via Syk is thought to be important in antineutrophil cytoplasm antibody (ANCA) IgG-mediated neutrophil activation. This study was undertaken to investigate the role of Syk in ANCA-induced myeloid cell activation and vasculitis pathogenesis.. Phosphorylation of Syk in myeloid cells from healthy controls and ANCA-associated vasculitis (AAV) patients was analyzed using flow cytometry. The effect of Syk inhibition on myeloperoxidase (MPO)-ANCA IgG activation of cells was investigated using functional assays (interleukin-8 and reactive oxygen species production) and targeted gene analysis with NanoString. Total and phosphorylated Syk at sites of tissue inflammation in patients with AAV was assessed using immunohistochemistry and RNAscope in situ hybridization.. We identified increased phosphorylated Syk at critical activatory tyrosine residues in blood neutrophils and monocytes from patients with active AAV compared to patients with disease in remission or healthy controls. Syk was phosphorylated in vitro following MPO-ANCA IgG stimulation, and Syk inhibition was able to prevent ANCA-mediated cellular responses. Using targeted gene expression analysis, we identified up-regulation of FcR- and Syk-dependent signaling pathways following MPO-ANCA IgG stimulation. Finally, we showed that Syk is expressed and phosphorylated in tissue leukocytes at sites of organ inflammation in AAV.. These findings indicate that Syk plays a critical role in MPO-ANCA IgG-induced myeloid cell responses and that Syk is activated in circulating immune cells and tissue immune cells in AAV; therefore, Syk inhibition may be a potential therapeutic option.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Immunity, Innate; Immunoglobulin G; Inflammation; Peroxidase; Receptors, Fc; Syk Kinase

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Peroxidase

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

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare, life-threatening inflammation of blood vessels that can affect both adults and children. Compared to adult-onset disease, AAV is especially rare in children, with an annual prevalence of 0.5-6.4 cases per million children. The etiology of AAV remains largely unknown, and both environmental and genetic factors are likely involved. The present study was undertaken to explore the genetic susceptibility factors recently identified in adult patients, including HLA-DP and HLA-DQ, in pediatric patients.. We performed a genome-wide association study of pediatric AAV in patients of European ancestry (n = 63 AAV cases, n = 315 population-matched controls).. We identified a significant genetic association between pediatric AAV and the HLA-DPB1*04:01 allele (P = 1.5 × 10. The HLA-DPB1 locus showed an association with pediatric AAV, as similarly shown previously in adult AAV. Despite the difference in the age of onset, these findings suggest that childhood- and adult-onset vasculitis share a common genetic predisposition. The identification of genetic variants contributing to AAV is an important step to improved classification tools and treatment strategies.

Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Child; Genetic Predisposition to Disease; Genome-Wide Association Study; HLA-DP beta-Chains; Humans; Peroxidase

In anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV), relapses are cause of concern as they are unpredictable and predictors of poor prognosis. We aimed to assess the characteristic and predictors of clinical relapse in AAV.. This retrospective study included 132 cases of AAV newly diagnosed from January 2016 through November 2021 in the Affiliated Hospital of Qingdao University. We reviewed clinical data of patients and analysed the risk factors for clinical relapse of overall population and subgroups by univariate and multivariate regression models and the K-M survival curve was plotted.. The rate of relapse was highest in the positive conversion group than the others significantly (p<0.001). In overall population, ANCA patterns (p<0.001; persistent positive pattern: HR=3.352, 95%CI 1.463~7.678, p=0.004; positive conversion pattern: HR=4.760, 95%CI 2.094~10.820, p<0.001) and infections (HR =4.684, 95%CI 1.980~11.079, p<0.001) were significantly associated with clinical relapse. In myeloperoxidase (MPO)-AAV patients, ANCA patterns (p=0.001; persistent positive pattern: HR=4.495, 95%CI 1.508~13.396, p=0.007; positive conversion pattern: HR=7.404, 95%CI 2.652~20.671, p<0.001) and infections (HR=3.594, 95%CI 1.511~8.547, p=0.004) were significantly associated with clinical relapse. In renal involvement patients, ANCA patterns (p=0.004; persistent positive pattern: HR=3.618, 95%CI 1.364~9.592, p=0.01; positive conversion pattern: HR=4.492, 95%CI 1.778~11.352, p<0.001) and infections (HR=7.791, 95%CI 2.511~24.174, p<0.001) were significantly associated with clinical relapse, but were not in patients without renal involvement.. Persistently positive and re-positive ANCA and infections predict clinical relapse in AAV, especially in patients with MPO-AAV and renal involvement. Regular ANCA monitoring should be carried out in high-risk populations.

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

We describe an unusual presentation of myeloperoxidase positive antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis managed by a multidisciplinary approach. A 75-year-old man gave a 3-week history of proximal lower limb weakness and exertional myalgia. His serum creatine kinase was normal and many of his non-specific symptoms suggested small vessel vasculitis. His investigations for common causes of muscle weakness were normal, and renal biopsy was normal despite haemoproteinuria. CT scan of the chest identified a pulmonary nodule of uncertain significance, not amenable to biopsy. MR scan of the thighs showed muscle oedema, and muscle biopsy confirmed typical features of vasculitis. Following high-dose corticosteroids his exertional myalgia quickly resolved and his normal mobility returned. Early immunosuppression is essential to improving clinical outcomes in ANCA-associated vasculitis, but diagnostic investigations often lack sensitivity.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Male; Myalgia; Peroxidase

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents with severe pneumonia and fatal systemic complications. Currently, SARS-CoV-2 vaccines are effective in reducing the risk of new onset and getting worse of the disease. However, autoimmune diseases such as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have been reported to develop after COVID-19 vaccine administration. A 71-year-old woman presented with fever, malaise, urinary abnormalities, and renal dysfunction after receiving the COVID-19 vaccine (Pfizer-BioNTech). We clinically diagnosed AAV with her manifestations and serological test (myeloperoxidase-ANCA-positive). Her clinical findings were improved after immunosuppressive therapy. We examined her genetic susceptibility to AAV, and we found that her allele was HLA-DRB1*09:01, which is a risk allele of myeloperoxidase-AAV. Mechanistically, SARS-CoV-2 vaccines would activate immunity, including neutrophils, and trigger AAV onset in this patient with a genetic risk to develop AAV. The pathophysiology of this case would share with that of autoimmune/inflammatory syndrome induced by adjuvants in the absence of external adjuvants.

Topics: Aged; Alleles; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; COVID-19; COVID-19 Vaccines; Female; HLA-DRB1 Chains; Humans; Peroxidase; SARS-CoV-2; Vaccination

A GWAS of patients with anti-neutrophil cytoplasmic antibodies (ANCAs) found an association between proteinase-3 ANCA (PR3-ANCA) and a single nucleotide polymorphism (rs62132293) upstream of PRTN3, encoding PR3. The variant (G allele) was shown to be an expression quantitative trait locus in healthy controls, but the clinical impact remains unknown. Longitudinally followed patients with ANCA and healthy controls were genotyped. Gene expression was quantified by real-time quantitative PCR from leukocyte RNA. Plasma PR3 was quantified by ELISA. Among patients, variant carriers had elevated leukocyte PRTN3 expression compared with noncarriers (C/G vs. C/C and G/G vs. C/C). Healthy controls had low PRTN3 regardless of genotype. Myeloperoxidase (MPO) expression did not differ by genotype. PRTN3 expression correlated with circulating PR3, and variant carriers had higher plasma PR3 compared with noncarriers. Among variant carriers, there was an increased risk of relapse in patients with PR3-ANCA versus MPO-ANCA. The risk allele marked by rs62132293 is clinically significant as it is associated with increased autoantigen and may, in part, explain increased relapse in PR3-ANCA. Our results underscore the role of autoantigen availability in ANCA vasculitis.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantigens; Humans; Myeloblastin; Peroxidase; Recurrence

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease that is prone to respiratory and renal failures. Its major target antigens are serine protease 3 (PR3) and myeloperoxidase (MPO), but the determinants of PR3 and MPO subtypes are still unclear. Uncoupling protein-1 (UCP-1) and adropin (Adr) regulate mutually and play an important role in endothelial cell injury. In this study, adropin and UCP-1 knockout (AdrKO and UCP-1-KO) models were established on the basis of C57BL/6 J mice. The results showed that UCP-1-KO and AdrKO mice similar to AAV: significant inflammatory cell infiltration, vascular wall damage, and erythrocyte extravasation. The pathological basis of AdrKO was that endothelial cells adhered and activated neutrophils to release MPO, and the core gene was peroxisome proliferator-activated receptor gamma (PPARG). However, UCP-1-KO induced PR3 release, and the accumulation and expression of tissue factor on the vascular wall, and the core gene was peroxisome proliferator-activated receptor delta (PPARD). The present study verified that the subtypes of AAV may be genetically different diseases and it also provide novel experimental evidence for clinical differentiation of the two subtypes.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Endothelial Cells; Mice; Mice, Inbred C57BL; Myeloblastin; Peroxidase

ANCA-associated vasculitis (AAV) is intricately linked with infections. Toll-like receptors (TLR) provide a potential link between infection and anti-myeloperoxidase (MPO) autoimmunity. TLR9 ligation has been shown to promote anti-MPO autoimmunity and glomerular vasculitis in murine MPO-AAV. This study investigates dendritic cell TLR9 ligation in murine experimental anti-MPO glomerulonephritis. We analyzed autoimmune responses to MPO following transfer of TLR9 stimulated, MPO pulsed dendritic cells and kidney injury following a sub-nephritogenic dose of sheep anti-mouse glomerular basement membrane globulin. TLR9 ligation enhanced dendritic cell activation upregulating CD40 and CD80 expression, promoting systemic anti-MPO autoimmunity and T cell recall responses and exacerbating kidney injury. CD40 upregulation by TLR9 was critical for the induction of nephritogenic autoimmunity. The presence of DEC205, which transports the TLR9 ligand to TLR9 located in the endosome, also promoted kidney injury. This confirms TLR9 mediated dendritic cell activation as a mechanism of anti-MPO autoimmunity in AAV and further defines the link between infection and the generation of MPO specific autoimmune inflammation.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoimmunity; Dendritic Cells; Glomerulonephritis; Mice; Peroxidase; Sheep; Toll-Like Receptor 9

This study aims to compare the prognostic values of two histopathological classification, Berden's classification versus renal risk score (RRS) by Brix et al. for predicting renal survival in Chinese patients with myeloperoxidase-anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (MPO-AAGN).. The medical records of 225 patients with MPO-AAGN diagnosed in our centre between February 2004 and December 2020 were retrospectively analysed. The predictive model of Berden's classification or RRS was established by Cox regression, respectively. The above two models were compared on aspects of discrimination, calibration, and decision curve analysis for predicting the 0.5-, 1-, 3-, and 5-year renal survival.. After a median follow up of 38.99 months, 32.44% of patients developed end-stage renal disease (ESRD). In the Kaplan-Meier analysis, there were significant differences in renal survival among groups according to Berden's classification or RRS (both log-rank p<0.001). According to time-dependent receiver operating characteristic (ROC) curve analysis, the model based on RRS showed better discrimination ability than the model based on Berden's classification for predicting 0.5-, 1-, and 3-year renal survival. For calibration analysis, the model based on RRS showed worse calibration than the model based on Berden's classification for predicting 1- and 3-year renal survival. According to the decision curve analysis, the clinical decisions based on RRS could achieve more clinical benefits than those based on Berden's classification in predicting 0.5-, 1-, and 3-year renal survival.. The model based on RRS has better predictive value for renal survival than Berden's classification in aspect of discrimination and clinical decision from 0.5- to 3-year renal survival.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; East Asian People; Glomerulonephritis; Humans; Kidney Failure, Chronic; Peroxidase; Retrospective Studies; Risk Factors

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease involving autoreactivity to proteinase 3 (PR3) as demonstrated by presence of ANCAs. While autoantibodies are screened for diagnosis, autoreactive T cells and their features are less well-studied. Here, we investigated PR3-specific CD4+T cell responses and features of autoreactive T cells in patients with PR3-AAV, using a cohort of 72 patients with either active or inactive disease. Autoreactive PR3-specific CD4+T cells producing interferon γ in response to protein stimulation were found to express the G-protein coupled receptor 56 (GPR56), a cell surface marker that distinguishes T cells with cytotoxic capacity. GPR56+CD4+T cells were significantly more prominent in the blood of patients with inactive as compared to active disease, suggesting that these cells were affected by immunosuppression and/or that they migrated from the circulation to sites of organ involvement. Indeed, GPR56+CD4+T cells were identified in T-cell infiltrates of affected kidneys and an association with immunosuppressive therapy was found. Moreover, distinct TCR gene segment usage and shared (public) T cell clones were found for the PR3-reactive TCRs. Shared T cell clones were found in different patients with AAV carrying the disease-associated HLA-DP allele, demonstrating convergence of the autoreactive T cell repertoire. Thus, we identified a CD4+T cell signature in blood and in affected kidneys that display PR3 autoreactivity and associates with T cell cytotoxicity. Our data provide a basis for novel rationales for both immune monitoring and future therapeutic intervention in PR3-AAV.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; CD4-Positive T-Lymphocytes; Humans; Myeloblastin; Peroxidase; Receptors, Antigen, T-Cell

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a potentially life-threatening systemic small-vessel vasculitis that is characterized by pauci-immune glomerulonephritis in case of kidney involvement, representing a major denominator of AAV mortality. Innate immunity with complement system activation is increasingly recognized in the pathogenesis of AAV and as an attractive therapeutic target. Although C-reactive protein (CRP) was thought to be a passive, nonspecific marker of inflammation, recent studies indicate that CRP plays a key role in the innate immune system by recognizing pathogens and altered self-determinants. Elevated baseline CRP at disease onset of AAV has already been described as a determinant of poor long-term outcomes. However, its clinical implications at disease onset of AAV, with respect to vasculitis manifestations and complement system activation that might also affect long-term outcomes, remain elusive. CRP levels were retrospectively analyzed in 53 kidney-biopsy-confirmed cases of ANCA-associated renal vasculitis; a total of 138 disease controls were also evaluated. Univariate and multivariate regression analysis was performed on clinicopathological parameters associated with CRP levels in ANCA-associated renal vasculitis. Results: Compared to disease controls, CRP elevation was common in ANCA-associated renal vasculitis and associated with de novo disease (

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Arteritis; C-Reactive Protein; Complement C4; Humans; Kidney; Peroxidase; Retrospective Studies

Disease relapse remains a major problem in the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In European populations,. First, the association of. The association of

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; East Asian People; Humans; Microscopic Polyangiitis; Myeloblastin; Peroxidase

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 identify and genetically characterize subgroups of patients with ANCA-associated vasculitides (AAV) based on sex and ANCA subtype.. A previously established SNP dataset derived from DNA sequencing of 1853 genes and genotyping of 1088 Scandinavian cases with AAV and 1589 controls was stratified for sex and ANCA subtype and analysed for association with five top AAV SNPs. rs9274619, a lead variant at the HLA-DQB1/HLA-DQA2 locus previously associated with AAV positive for myeloperoxidase (MPO)-ANCA, was analysed for association with the cumulative disease involvement of ten different organ systems.. rs9274619 showed a significantly stronger association to MPO-ANCA-positive females than males [P = 2.0 × 10-4, OR = 2.3 (95% CI 1.5, 3.5)], whereas proteinase 3 (PR3)-ANCA-associated variants rs1042335, rs9277341 (HLA-DPB1/A1) and rs28929474 (SERPINA1) were equally associated with females and males with PR3-ANCA. In MPO-ANCA-positive cases, carriers of the rs9274619 risk allele were more prone to disease engagement of eyes [P = 0.021, OR = 11 (95% CI 2.2, 205)] but less prone to pulmonary involvement [P = 0.026, OR = 0.52 (95% CI 0.30, 0.92)]. Moreover, AAV with both MPO-ANCA and PR3-ANCA was associated with the PR3-ANCA lead SNP rs1042335 [P = 0.0015, OR = 0.091 (95% CI 0.0022, 0.55)] but not with rs9274619.. Females and males with MPO-ANCA-positive AAV differ in genetic predisposition to disease, suggesting at least partially distinct disease mechanisms between the sexes. Double ANCA-positive AAV cases are genetically similar to PR3-ANCA-positive cases, providing clues to the clinical follow-up and treatment of these patients.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Humans; Male; Myeloblastin; Peroxidase; Sex Characteristics

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

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

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Corneal Ulcer; Humans; Peroxidase

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune vasculitis characterized by the production of antibodies against ANCA, with unclear pathogenesis. With the ongoing COVID-19 pandemic, COVID-19 mRNA vaccination has been available in Japan since February 2021. Although autoimmune symptoms have been reported after COVID-19 vaccinations, there have been no clinical investigations regarding the relationship between COVID-19 mRNA vaccines and the pathogenesis of AAV. Thus, the present study aimed to investigate whether the administration of COVID-19 mRNA vaccines affects the development of AAV. The study identified patients with new-onset AAV who were MPO-ANCA or PR3-ANCA positive and met the entry criteria of the AAV EMA classification algorithm. The study compared the number of new AAV cases per year before and after the start of the COVID-19 mRNA vaccine program in Japan. The study found that the annual number of new cases of AAV in Japan's Nagasaki Prefecture increased by approximately 1.5-fold since the COVID-19 vaccine program was initiated, suggesting a possible link between the COVID-19 mRNA vaccines and the development of AAV. Although the study provides insight into the clinical evaluation and management of autoimmune symptoms following COVID-19 vaccination, further investigation of the possible association between COVID-19 mRNA vaccines and the pathogenesis of AAV is required.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; COVID-19; COVID-19 Vaccines; Humans; Myeloblastin; Pandemics; Peroxidase

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

Antimyeloperoxidase (anti-MPO) and antiproteinase 3 (anti-PR3) antibodies are found in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). We investigated the effect of both anti-MPO and anti-PR3 IgG on human monocytes. Peripheral blood monocytes were cultured under a range of conditions that included TLR agonists, anti-MPO IgG and anti-PR3 IgG with appropriate controls. Experiments included whole transcriptome profiling and an assessment of the role of Fc receptors. When monocytes were stimulated with LPS or R848, anti-MPO but not anti-PR3 IgG, caused a reduction in IL-10 secretion and had a profound effect on cell-surface marker expression. Anti-MPO but not anti-PR3 IgG enhanced monocyte survival in the absence of TLR stimulation. These effects depended on the Fc receptor CD32a. With TLR stimulation, the effect of anti-MPO but not anti-PR3 IgG on the transcriptional response at 6 h was variable, but we identified a core set of transcripts likely to be important. Without TLR stimulation, there was a robust effect of anti-MPO but not anti-PR3 IgG on the transcriptional response at 24 h, and there was a highly significant enrichment of genes encoding extracellular matrix and extracellular matrix-associated proteins. Analysis with nCounter confirmed many of the differentially expressed transcripts and supported a role for CD32a. These data show that anti-MPO, but not anti-PR3 IgG, from patients with AAV has wide-ranging effects on monocytes which depend on CD32a. The activation of a profibrotic transcriptional response by anti-MPO but not anti-PR3 IgG may give insights into the differences in disease phenotype.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Immunoglobulin G; Monocytes; Myeloblastin; Peroxidase; Receptors, Fc

Hematuria is common in myeloperoxidase anti-neutrophil cytoplasmic antibody associated vasculitis (ANCA-MPO). Previous studies have mainly focused on urinary dysmorphic red blood cells and few have reported the clinical significance of isomorphic urinary red blood cells. Therefore, the main aim of this study was to assess the predictive yield  of urinary isomorphic red blood cells for disease severity and renal outcomes in patients with ANCA-MPO associated vasculitis.. A total of 191 patients with ANCA-MPO associated vasculitis with hematuria were retrospectively selected and were divided into two groups (with isomorphic red blood cells versus dysmorphic red blood cells) according to the percentage of isomorphic red blood cells on urinary sediment analysis. Clinical, biological and pathological data at diagnosis were compared. Patients were followed up for a median of 25 months and progression to end-stage kidney disease and death were regarded as main outcome events. Additionally, univariate and multivariate Cox regression models were used to estimate the risk factors for end-stage kidney disease.. Out of 191 patients, 115 (60%) had ≥ 70% and 76 (40%) had < 30% urine isomorphic red blood cells. Compared with patients in the dysmorphic red blood cell group, patients in the isomorphic red blood cell group had a significantly lower estimated glomerular filtration rate (eGFR) [10.41 mL/min (IQR 5.84-17.06) versus 12.53 (6.81-29.26); P = 0.026], higher Birmingham Vasculitis Activity Score [16 (IQR 12-18) versus 14 (10-18); P = 0.005] and more often received plasma exchange [40.0% versus 23.7% (P = 0.019)] at diagnosis. Kidney biopsies revealed a higher proportion of patients with glomerular basement membrane fracture in the isomorphic red blood cell group [46.3% versus 22.9% (P = 0.033)]. Furthermore, patients with predominant urinary isomorphic red blood cells were more likely to progress to end-stage kidney disease [63.5% versus 47.4% (P = 0.028)] and had a higher risk of death [31.3% versus 19.7% (P = 0.077)]. The end-stage kidney disease-free survival was lower in patients in the isomorphic red blood cell group (P = 0.024). However, urine isomorphic red blood cells ≥ 70% could not predict the presence of end-stage kidney disease in multivariate Cox analysis.. Myeloperoxidase-anti-neutrophil cytoplasmic antibody associated vasculitis patients with predominant urinary isomorphic red blood cells at diagnosis had more severe clinical manifestations and a higher risk of poor renal outcomes. In this respect, urinary isomorphic red blood cells could be viewed as a promising biomarker of ANCA_MPO vasculitis severity and progression.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Hematuria; Humans; Kidney; Kidney Failure, Chronic; Patient Acuity; Peroxidase; Retrospective Studies

There are a few studies that reported sex disparities in clinical features, pathological features and outcomes among ANCA-associated vasculitis (AAV) patients, but studies focusing on sex-specific differences of myeloperoxidase (MPO)-AAV patients are scarce. Therefore, the purpose of this study was to analyze sex differences in clinicopathological features and outcomes of MPO-AAV. Patients diagnosed with MPO-AAV in Xiangya Hospital from January 2010 to June 2021 were included in the study and separated into female and male groups. The differences in clinical manifestations, laboratory parameters, pathological features and prognosis between the two groups were retrospectively analyzed. Three hundred and sixty-six patients were included and divided into female group (n = 176) and male group (n = 190). The age of the male group was 62.41 ± 10.49 years, significantly higher than that of the female group (58.69 ± 16.39, p = 0.011). Compared with the female group, the male group had a shorter duration of disease, higher levels of hemoglobin, eosinophil count, proteinuria, serum C4, and lower levels of serum globulin, serum IgG and serum IgM (p < 0.05). No significant differences in kidney pathological features were observed between the two groups. During a median follow-up of 37.6 months, there was no significant difference in renal survival and patient survival between the two groups, but male patients had a worse composite outcome of renal and patient survival compared with the female patients (p = 0.044). This study found that male patients with MPO-AAV had a higher age of onset, shorter duration of disease, higher levels of hemoglobin, eosinophil count, proteinuria, serum C4, and lower levels of serum globulin, serum IgG and serum IgM. Male patients fared worse than female patients in terms of the composite outcome of renal and patient survival.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; East Asian People; Female; Hemoglobins; Humans; Immunoglobulin G; Immunoglobulin M; Male; Middle Aged; Peroxidase; Proteinuria; Retrospective Studies

Severe renal impairment is a common complication of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and is associated with poor prognosis and shorter survival. It is urgent to find effective treatments to improve the prognosis of AAV patients. This study was designed to assess the efficacy and safety of protein A immunoadsorption (PAIA) and therapeutic plasma exchange (TPE) for AAV with severe renal involvement.. A total of 48 AAV patients with renal involvement admitted to the Second Xiangya Hospital from January 2018 to February 2021 were selected. Clinical data, myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA), remission at 6 months, and outcomes were evaluated. The primary outcomes of interest were death and renal survival as defined by the occurrence of end-stage renal disease (ESRD).. PAIA was effective in the removal of MPO-ANCA and IgG, and showed superior over TPE in the clearance of MPO-ANCA within 1 month after treatment. After a median follow-up of 14.5 months, PAIA therapy showed an advantage in reducing mortality over TPE. There was no difference in the development of ESRD between the two groups. Multivariate Cox regression analysis indicated that higher serum creatinine (SCr) and lower haemoglobin level were independent risks of ESRD. Age > 60, lower serum albumin (ALB), and failure to achieve remission at 6 months were independent risks of death.. PAIA treatment reduces MPO-ANCA and IgG as well as mortality in AAV patients, and may be beneficial for severe AAV in clinical practice. Higher SCr, lower serum ALB or haemoglobin levels, age > 60, and failure to achieve remission at 6 months independently predict the ESRD or death of AAV patients with severe renal involvement.KEY MESSAGESCompared with therapeutic plasma exchange, protein A immunoadsorption treatment eliminates myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA) and IgG better and reduces mortality in ANCA-associated vasculitis (AAV) patients with severe renal involvement.Higher serum creatinine, lower serum albumin or haemoglobin levels, age > 60, and failure to achieve remission at 6 months independently predict the end-stage renal disease (ESRD) or death of AAV patients with severe renal involvement.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Child, Preschool; Creatinine; Hemoglobins; Humans; Immunoglobulin G; Kidney Failure, Chronic; Peroxidase; Plasma Exchange; Retrospective Studies

Previous studies from our group and other investigators have shown that lung involvement is one of the independent predictors for treatment resistance in patients with myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (MPO-AAV). However, it is unclear which image features of lung involvement can predict the therapeutic response in MPO-AAV patients, which is vital in decision-making for these patients. Our aim was to develop and validate a radiomics nomogram to predict treatment resistance of Chinese MPO-AAV patients based on low-dose multiple slices computed tomography (MSCT) of the involved lung with cohorts from two centers.. A total of 151 MPO-AAV patients with lung involvement (MPO-AAV-LI) from two centers were enrolled. Two different models (Model 1: radiomics signature; Model 2: radiomics nomogram) were built based on the clinical and MSCT data to predict the treatment resistance of MPO-AAV with lung involvement in training and test cohorts. The performance of the models was assessed using the area under the curve (AUC). The better model was further validated. A nomogram was constructed and evaluated by DCA and calibration curves, which further tested in all enrolled data and compared with the other model.. Model 2 had a higher predicting ability than Model 1 both in training (AUC: 0.948 vs. 0.824;. The radiomics nomogram (Model 2) is a useful, non-invasive tool for predicting the treatment resistance of MPO-AAV patients with lung involvement, which might aid in individualizing treatment decisions.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; East Asian People; Humans; Lung Diseases; Nomograms; Peroxidase

BACKGROUND Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a form of vasculitis predominantly affecting small blood vessels and systemic organs, including the lungs and kidneys. The serum ANCA is an important diagnostic marker for AAV. However, ANCA levels can be nonspecifically elevated in autoimmune diseases like rheumatoid arthritis (RA) and some infectious diseases. Furthermore, RA and AAV can occur together. Therefore, when ANCA is detected in patients with RA, interpretation of the results is often difficult. CASE REPORT A 71-year-old woman with a 15-year history of RA was admitted to our hospital with a fever and anorexia. She was treated with prednisolone 5 mg/day and iguratimod 50 mg/day for the RA. She presented with bilateral frosted glass shadows in the lungs, acute kidney injury, positive myeloperoxidase (MPO)-ANCA results, and elevated ß-D-glucan levels, suggesting AAV or pneumocystis pneumonia. A renal biopsy and bronchoalveolar lavage ruled out AAV. A polymerase chain reaction of the bronchoalveolar lavage fluid was positive for Pneumocystis jirovecii DNA, leading to a diagnosis of pneumocystis pneumonia. After admission, the patient continued to receive intravenous supplemental fluids, and renal function improved. Based on her pathological test results and clinical course, acute kidney injury was diagnosed as prerenal failure due to dehydration in the background of chronic kidney disease. CONCLUSIONS Even if MPO-ANCA is positive in patients with RA, it is important to consider the possibility of a false-positive result and perform a thorough and aggressive examination.

Topics: Acute Kidney Injury; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Arthritis, Rheumatoid; Female; Humans; Peroxidase; Pneumonia, Pneumocystis

This study examined whether plasma FXII levels reflect disease activity in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Plasma FXII levels were detected by ELISA in 127 patients with AAV, and their associations with disease activity and plasma myeloperoxidase (MPO)-ANCA titre were examined. Immunofluorescent co-staining of FXII and neutrophils was performed on the renal tissues of patients with AAV. MPO expression in renal biopsy tissues was determined by immunohistochemical staining. The association between plasma FXII levels and histological activity was assessed in 82 patients who underwent kidney biopsy. Plasma FXII levels were considerably increased in patients with clinically active AAV compared to those in clinical remission and healthy individuals. Plasma FXII levels correlated positively with creatinine (r = 0.377), CRP (r = 0.222), urine red blood cell (r = 0.203), serum MPO-ANCA titer (r = 0.353), white blood cell (r = 0.194), percentage of glomeruli with crescents (P = 0.001), capillary breaks (P = 0.001), interstitial inflammation (P < 0.001) and fibrinoid necrosis (p < 0.001) on kidney biopsy. The plasma FXII optimal cut-off value for evaluating AAV activity was 24.5 μg/mL (sensitivity = 0.81, specificity = 0.82, P = 0.0001), which was superior to that achieved using conventional serologic biomarkers. Co-expression of FXII and neutrophils was higher, with increased MPO expression, in renal tissue with pathologically active AAV than that observed in pathologically inactive tissues. In conclusion, elevated plasma FXII levels reflect AAV clinical and histologic activity, and can serve as markers of active AAV.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Cross-Sectional Studies; Humans; Peroxidase; Retrospective Studies

A 68-year-old male, who was undergoing XELOX plus trastuzumab therapy for gastric cancer, developed proteinuria, hematuria, and progressive increase in creatinine after 3 months. Subsequently, the patient also experienced hemoptysis, nasal bleeding. Chest CT examination shown pulmonary hemorrhage. The MRI of the nasopharynx ruled out nasopharyngeal cancer recurrence. The MPO and PR3 were elevated, and renal biopsy confirmed ANCA-related vasculitis, which affected the lungs, kidneys, and nasopharynx. Based on the review of the patient''s medical history and medication, it is believed that ANCA-related vasculitis was caused by XELOX plus trastuzumab chemotherapy, but it is difficult to confirm which specific drug caused it. After stopping XELOX plus trastuzumab chemotherapy, glucocorticoids and cyclophosphamide was given, the patient''s pulmonary hemorrhage and nasal bleeding stopped, and the lung lesions were absorbed. The renal function also improved. The patient later experienced pulmonary infection again, and tNGS indicated Legionella pneumophila and pulmonary tuberculosis infection. Despite anti-infection treatment, steroid dose was rapidly reduced. Ultimately, the patient gave up on treatment and eventually died.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Capecitabine; Epistaxis; Humans; Kidney Diseases; Lung Diseases; Male; Nasopharyngeal Neoplasms; Neoplasm Recurrence, Local; Oxaliplatin; Peroxidase; Trastuzumab

To investigate the clinical features and long-term outcomes of Chinese anti-neutrophil cytoplasmic antibodies (ANCAs)-associated vasculitis (AAV) patients with different ANCA serotypes.. Two hundred and twenty-four AAV patients from January 2010 to June 2021 were divided into myeloperoxidase (MPO)-ANCA and proteinase 3 (PR3)-ANCA groups. Clinical and long-term outcomes were compared.. In this study, the average follow-up was 46.4 months (range 0.3-188.4 months). One hundred and seventy-seven (79.0%) patients were MPO-ANCA-positive and 47 were PR3-ANCA-positive; the mean age of MPO-ANCA positive patients at diagnosis was elder than that of PR3-ANCA positive patients (67.0 vs. 60.0 years,. The likelihood of induced remission, patient survival or disease recurrence is all unaffected by ANCA serotypes. A better prognosis is seen in younger patients with milder kidney involvement and lower BVAS/FFS scores.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Myeloblastin; Peroxidase; Prognosis; Retrospective Studies; Serogroup

ANCA-associated vasculitis (AAV) is an autoimmune disease characterized by small blood vessel inflammation, commonly affecting the kidneys and respiratory tract. It is unclear why the incidence of this condition increases with age. Previous studies in a passive antibody transfer system in aged mice have implicated innate effectors. To test the hypothesis that autoimmunity to myeloperoxidase (MPO), an autoantigen responsible for AAV, increases with age, anti-MPO autoimmunity was studied in murine models of active autoimmunity and disease induced by cellular immunity.. Young (8 weeks) and aged (either 15 or 22 months) mice were immunized with whole proteins or peptides from ovalbumin, as a model foreign antigen, or MPO protein or peptides. Mice were subjected to a model of active anti-MPO glomerulonephritis. Cellular and humoral immune responses, and tissue inflammation were assessed.. While cellular immunity to ovalbumin was diminished in aged mice, cellular autoimmunity to MPO and its immunodominant CD4+ and CD8+ T cell epitopes was increased after immunization with either MPO peptides or whole MPO protein, assessed by peptide and antigen-specific production of the pro-inflammatory cytokines IFN-γ and IL-17A. MPO-ANCA titres were not increased in aged mice compared with young mice. In experimental anti-MPO glomerulonephritis, cell-mediated injury was increased, likely due to CD4+ and CD8+ T cells, innate immunity and the increased vulnerability of aged kidneys.. Heightened cellular immunity to MPO develops with ageing in mice and may contribute to the increased incidence and severity of AAV in older people.

Topics: Aged; Aging; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; CD4-Positive T-Lymphocytes; Female; Glomerulonephritis; Humans; Immunity, Cellular; Inflammation; Male; Mice; Ovalbumin; Peroxidase

Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a systemic disease that causes vasculitis in various organs. Although the cause of the onset is unknown, infection has been reported to be a causative factor. The subsequent cytokine storm triggered by the immune response against SARS-CoV-2 infection has been reported to lead to symptoms being more severe. We herein report our experience with the onset of AAV following COVID-19 infection. We also report the course of anti-SARS-CoV-2 serum antibody titers following induction therapy, which suggests that vaccination and education concerning standard precautions are necessary in patients who require immunosuppressive therapy, even after COVID-19 infection.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; COVID-19; Humans; Microscopic Polyangiitis; Peroxidase; SARS-CoV-2

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

Otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV) is a new category of otitis media in which cases of otitis media due to ANCA-associated vasculitis (AAV) are classified, regardless of ANCA variant or ANCA serotype. We aimed to describe the clinical features and course of patients with OMAAV and identify factors associated with hearing outcomes.. We retrospectively analysed 30 patients with OMAAV, classified based on the criteria proposed by the Japan Otological Society in 2016.. Single-positive myeloperoxidase-ANCA, single-positive proteinase 3-ANCA, double-positive ANCA, and double-negative ANCA were identified in 47%, 33%, 7%, and 13% of the patients, respectively. All patients subjected to audiometry showed hearing impairments, and 85% were affected bilaterally. Mixed- and sensorineural-type hearing impairments were identified in 80% and 20% of impaired ears, respectively. Hypertrophic pachymeningitis (HPM) was identified in 37% of the patients. Immunosuppressive therapy was administered to 93% of patients, and the median air conduction hearing levels at pre- and post-treatment were 66.1 dB and 43.4 dB, respectively, indicating significant hearing improvements. HPM and a long interval between disease onset and treatment initiation were significantly correlated with poor hearing prognosis.. OMAAV develops under any type of ANCA-serology and typically causes mixed or sensorineural bilateral hearing loss. The early initiation of immunosuppressive therapy and the absence of HPM were associated with good hearing outcomes.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Meningitis; Myeloblastin; Otitis Media; Peroxidase; Retrospective Studies

The epidemiology of ANCA-associated vasculitis (AAV) varies by ethnicity and region. Environmental exposure has been implicated in the pathophysiology of MPO-AAV. The aim of this study was to evaluate the epidemiology of AAV and explore a potential relationship with environmental factors in north central West Virginia.. This is a retrospective cohort study of 212 patients diagnosed with AAV at West Virginia University and its affiliated hospitals from January 1, 1990 to December 31, 2019. We assessed prevalence of AAV over time according to patient's zip codes and counties. Silica exposure through natural gas extraction was considered as a possible environmental factor.. The proportion of patients with MPO-ANCA increased after 2010 (37.5% before 2010 vs 61% after 2010, p = 0.008). At the same time, the prevalence of AAV in Monongalia and surrounding counties has increased significantly after 2010 from 64.8 to 141.9 cases per million (p = 0.001). The increase in prevalence of AAV was primarily due to an increase in MPO-AAV (43 vs 101.7 cases per million before and after 2010, respectively, p = 0.028). During this time, the production of natural gas through fracking increased, rising more than tenfold after 2010 (p-value < 0.001). Heat mapping reveals that the increase in cases of AAV occurred in areas of increased fracking activity.. There was an increase in the prevalence of patients who were newly diagnosed with AAV over time in north central West Virginia. Further studies are required to ascertain the potential role of environmental exposure in the pathophysiology of AAV.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Natural Gas; Peroxidase; Prevalence; Retrospective Studies; West Virginia

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are severe inflammatory disorders that often involve focal necrotizing glomerulonephritis (FNGN) and consequent glomerular scarring, interstitial fibrosis, and chronic kidney disease. Robust murine models of scarring in FNGN that may help to further our understanding of deleterious processes are still lacking. Here, we present a murine model of severe FNGN based on combined administration of antibodies against the glomerular basement membrane (GBM) and myeloperoxidase (MPO), and bacterial lipopolysaccharides (LPS), that recapitulates acute injury and was adapted to investigate subsequent glomerular and interstitial scarring. Hematuria without involvement of other organs occurs consistently and rapidly, glomerular necrosis and crescent formation are evident at 12 days, and consequent glomerular and interstitial scarring at 29 days after initial treatment. Using mass-spectrometric proteome analysis, we provide a detailed overview of matrisomal and cellular changes in our model. We observed increased expression of the matrisome including collagens, fibronectin, tenascin-C, in accordance with human AAV as deduced from analysis of gene expression microarrays and tissue staining. Moreover, we observed tissue infiltration by neutrophils, macrophages, T cells and myofibroblasts upon injury. Experimental inhibition of CXCR4 using AMD3100 led to a sustained histological presence of fibrin extravasate, reduced chemokine expression and leukocyte activation, but did not markedly affect ECM composition. Altogether, we demonstrate an adapted FNGN model that enables the study of matrisomal changes both in disease and upon intervention, as exemplified via CXCR4 inhibition.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Glomerular Basement Membrane; Glomerulonephritis; Humans; Mice; Peroxidase; Receptors, CXCR4

Increased soluble levels of complement effectors have been demonstrated in active anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but the timing of complement activation in the autoimmune inflammation remains elusive. This study investigated whether the complement system is activated before onset of symptoms in AAV.. The Swedish National Patient Register and Cause of Death register were linked to registers of five biobanks to identify individuals sampled before AAV symptom onset. Diagnosis of AAV and time-point for symptom onset were confirmed by reviewing medical records. We identified 64 presymptomatic individuals with serum samples > 1 month < 10 years from AAV symptom onset and 122 matched controls. Complement factors (C2, C5) and activation markers (C5a, C4b) were measured using Luminex technology.. Activation of the complement system is an early event in the pathogenesis of AAV and is mainly associated with MPO-ANCA

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biological Specimen Banks; Complement Activation; Humans; Microscopic Polyangiitis; Myeloblastin; Peroxidase; Sweden

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Kidney; Kidney Failure, Chronic; Matrix Metalloproteinase 7; Oxidative Stress; Peroxidase; Prognosis; Prospective Studies

A 44-year-old woman was admitted due to gross hematuria and progressive renal dysfunction. Poststreptococcal acute glomerulonephritis (PSAGN) was suspected due to her elevated anti-streptolysin O and anti-streptokinase titers and hypocomplementemia. A renal biopsy showed crescent formation and endocapillary hypercellularity with neutrophil infiltrate. An immunofluorescence analysis showed granular immunoglobulin G and C3 deposition, suggesting immune-complex-type glomerulonephritis. However, myeloperoxidase anti-neutrophil cytoplasmic antibody (ANCA) was positive, and peritubular capillaritis was observed. Furthermore, citrullinated histone H3-positive neutrophils were detected as markers for neutrophil extracellular trap formation. Therefore, she was diagnosed with ANCA-associated vasculitis superimposed on PSAGN that was the main contributor to her progressive renal injury.

Topics: Acute Disease; Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Glomerulonephritis; Histones; Humans; Immunoglobulin G; 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 ANCA autoantigens proteinase 3 (PR3) and myeloperoxidase (MPO) are exclusively expressed by neutrophils and monocytes. ANCA-mediated activation of these cells is the key driver of the vascular injury process in ANCA-associated vasculitis (AAV), and neutrophil serine proteases (NSPs) are disease mediators. Cathepsin C (CatC) from zymogens activates the proteolytic function of NSPs, including PR3. Lack of NSP zymogen activation results in neutrophils with strongly reduced NSP proteins.. To explore AAV-relevant consequences of blocking NSP zymogen activation by CatC, we used myeloid cells from patients with Papillon-Lefèvre syndrome, a genetic deficiency of CatC, to assess NSPs and NSP-mediated endothelial cell injury. We also examined pharmacologic CatC inhibition in neutrophil-differentiated human hematopoietic stem cells, primary human umbilical vein cells, and primary glomerular microvascular endothelial cells.. Patients with Papillon-Lefèvre syndrome showed strongly reduced NSPs in neutrophils and monocytes. Neutrophils from these patients produced a negative PR3-ANCA test, presented less PR3 on the surface of viable and apoptotic cells, and caused significantly less damage in human umbilical vein cells. These findings were recapitulated in human stem cells, in which a highly specific CatC inhibitor, but not prednisolone, reduced NSPs without affecting neutrophil differentiation, reduced membrane PR3, and diminished neutrophil activation upon PR3-ANCA but not MPO-ANCA stimulation. Compared with healthy controls, neutrophils from patients with Papillon-Lefèvre syndrome transferred less proteolytically active NSPs to glomerular microvascular endothelial cells, the cell type targeted in ANCA-induced necrotizing crescentic glomerulonephritis. Finally, both genetic CatC deficiency and pharmacologic inhibition, but not prednisolone, reduced neutrophil-induced glomerular microvascular endothelial cell damage.. These findings may offer encouragement for clinical studies of adjunctive CatC inhibitor in patients with PR3-AAV.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Cathepsin C; Endothelial Cells; Enzyme Precursors; Humans; Myeloblastin; Neutrophils; Papillon-Lefevre Disease; Peroxidase

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Cathepsin C; Humans; Myeloblastin; Peroxidase

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Esthetics; Humans; Mammaplasty; Myeloblastin; Peroxidase; Vasculitis

Platelet-to-lymphocyte ratio (PLR) has recently been investigated as a new inflammatory marker in many inflammatory diseases, including systemic lupus erythematosus and immunoglobulin A vasculitis. However, there were very few reports regarding the clinical role of PLR in patients with anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis. This study was thus undertaken to investigate the relationship between inflammatory response and disease activity in Chinese patients with myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA) associated vasculitis. Furthermore, we evaluated whether PLR predicts the progression of end stage of renal disease (ESRD) and all-cause mortality.. The clinical, laboratory and pathological data, and the outcomes of MPO-ANCA associated vasculitis patients were collected. The Spearman correlation coefficient was computed to examine the association between 2 continuous variables. Cox regression analysis was used to estimate the association between PLR and ESRD or all-cause mortality.. PLR is positively correlated with CRP and ESR. Furthermore, PLR may independently predict the risk of ESRD.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; China; Humans; Kidney Failure, Chronic; Lymphocytes; Peroxidase; Retrospective Studies

Bronchiectasis was reported in 2%-40% of patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV), but there were no studies on the prevalence, risk factors and impact of AAV-associated bronchiectasis in Chinese patients.. AAV patients were retrospectively enrolled. The clinical, laboratory and imaging features and the prognosis were analyzed and compared between those with and without bronchiectasis.. Bronchiectasis was present in 48/212 (22.6%) of our AAV patients, among whom 41 were confirmed in 210 patients (19.5%) who received chest HRCT at the initial diagnosis of AAV. There were more women and fewer smokers in those with bronchiectasis as compared to those without. Cases with positive anti-MPO were more likely to have bronchiectasis (26.2%), and those with bronchiectasis were more likely to be anti-MPO positive (93.8%). Patients who had a diagnosis of bronchiectasis before AAV were more likely to have nervous system involvement, while patients without bronchiectasis had higher 24h proteinuria. The presence of bronchiectasis showed no significant effect on the 1, 3, 5-year survival.. Nearly 20% of patients showed bronchiectasis on chest HRCT at the initial diagnosis of AAV, and positivity of anti-MPO was associated with bronchiectasis in a Chinese cohort of AAV patients.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Bronchiectasis; Case-Control Studies; Female; Humans; Peroxidase; Prognosis; Retrospective Studies

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Glomerulonephritis; Humans; Peroxidase; T-Lymphocytes

Patients with infective endocarditis (IE) may present rheumatic manifestations concurrent with various autoantibodies and thus mimic antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This study aims to characterize the specific features in a long-term cohort of ANCA-positive IE patients and to perform comparative analysis with primary AAV patients.. We performed a retrospective thorough review of 475 consecutive IE patients over 23 years, identifying 22 patients positive for proteinase 3 and/or myeloperoxidase and 36 treatment-naïve AAV patients. The clinical, laboratory, and follow-up data were collected to perform comparative analysis.. Our study illustrated that ANCA-positive IE patients were younger and had a shorter duration than AAV patients. Pulmonary lesions, ENT signs, peripheral neuropath, and proteinuria were more commonly seen in AAV patients, while heart valve involvement, spleen enlargement, and cerebral hemorrhage were more typical for IE patients (all p < 0.05). Besides, ANCA-positive IE patients presented a higher level of PR3-ANCA but lower C3 (both p < 0.05). Hyperleukocytosis and thrombocytopenia were more frequently found in AAV patients (both p < 0.05). No significant difference was noticed in the survival rate.. Our study urges the early differential diagnosis of IE in ANCA-positive patients. It supports the claim that ANCA-positive IE patients and AAV patients do not share the same clinical spectrum. Echocardiography, serological profiles, and evaluation of multi-organ involvement might be required to improve diagnostic accuracy. Key Points •Early differential diagnosis of ANCA-positive IE from AAV is challenging even for expert rheumatologists. •Our study is so far one of the largest to include 22 ANCA-positive IE patients in one single center and spanning over 23 years. It is also the first study to include both ANCA-positive IE patients and AAV patients in one center. •Our study aides to identify a clinical picture to differentiate ANCA-Positive IE Patients from AAV Patients.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Endocarditis; Follow-Up Studies; Humans; Myeloblastin; Peroxidase; Retrospective Studies

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

The association of bronchiectasis with myeloperoxidase (MPO) antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (MPO-AAV) has been widely described in recent studies. However, the clinical features and outcomes of MPO-ANCA-associated glomerulonephritis (MPO-ANCA GN) patients with bronchiectasis remain enigmatic.. MPO-ANCA GN patients with bronchiectasis were compared to MPO-ANCA GN patients alone. Clinical imaging, pathological tests, and follow-up examination data of patients were collected retrospectively. Progression to end-stage renal disease (ESRD) and death was treated as endpoint events.. 153 cases (52 patients with bronchiectasis) were included in this study. Compared to MPO-ANCA GN patients alone, MPO-ANCA GN patients with bronchiectasis exhibited a lower level of proteinuria (p = 0.019) and relatively higher eGFR level. MPO-ANCA GN patients with bronchiectasis had less frequent incidences of interstitial lung disease (ILD) and emphysema (p<0.001, p = 0.016, respectively) but with higher rates of pulmonary infection (p<0.001). Bronchiectasis severity (the modified Reiff score) was positively correlated with MPO antibody titers (ρ=0.480, p<0.001), but not with shorter renal survival. A relatively higher remission rate was been seen in MPO-ANCA GN patients with bronchiectasis, who showed reduced susceptibility in progressing to ESRD in multivariate analysis (p = 0.043, HR=0.542, 95% CI 0.299-0.982). One-and three-year overall survival rates were 88.2% and 77.3% for MPO-ANCA GN with bronchiectasis cases versus 83.7% and 67.2% for MPO-ANCA GN patients alone (p = 0.431, p = 0.241, respectively).. The severity of bronchiectasis was correlated with anti-MPO antibody titers in MPO-ANCA GN patients. For MPO-ANCA GN patients, bronchiectasis associated with good renal prognosis, but it did not improve overall survival.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Bronchiectasis; Case-Control Studies; Glomerulonephritis; Humans; Kidney Failure, Chronic; Peroxidase; Retrospective Studies

Monocytes are involved in the pathogenesis of ANCA-associated vasculitis (AAV). Monocyte/macrophages are the dominant infiltrating cells in the glomeruli of patients with myeloperoxidase-AAV (MPO-AAV). However, how human monocyte subsets extravasate to the kidney in MPO-AAV with renal damage is unclear.. 30 MPO-AAV patients with renal damage and 22 healthy controls were enrolled in this study. Monocyte subsets and monocyte-related chemokines in the blood and kidneys of MPO-AAV patients were detected. The chemoattractant activity of the CX3CL1-CX3CR1 axis on CD16. Compared with controls, CD16. Enhanced extravasation of CD16

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Chemokine CX3CL1; Creatinine; Endothelial Cells; Humans; Kidney; Monocytes; Peroxidase

The significance of S100A8/A9 and S100A12 in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) has not been clarified. This study was dedicated to exploring the potential pathogenic roles of S100A8/A9 and S100A12 in patients with myeloperoxidase (MPO)-ANCA-positive vasculitis.. Serum and urine concentrations of S100A8/A9 and S100A12 of forty-two AAV patients were evaluated. The influence of S100A8/A9 and S100A12 on the chemotaxis, the apoptosis, the release of IL-1β, the complement activation, the respiratory burst, as well as the neutrophil extracellular traps (NETs) formation of MPO-ANCA-activated neutrophils was investigated.. The serum and urine S100A8/A9 and S100A12 of active MPO-AAV significantly increased (compared with inactive AAV and healthy controls, p < 0.001) and were correlated with the severity of the disease. In vitro study showed that S100A8/A9 and S100A12 activated the p38 MAPK/NF-κB p65 pathway, increased the chemotaxis index (CI) and the release of IL-1β, extended the life span, and enhanced the complement activation ability of MPO-ANCA-activated neutrophils. The Blockade of TLR4 and RAGE inhibited the effects of S100A8/A9 and S100A12. All above-mentioned effects of S100A8/A9 and S100A12 were ROS-independent because neither S100A8/A9 nor S100A12 enhanced the ROS formation and NETs formation of MPO-ANCA-activated neutrophils.. S100A8/A9 and S100A12 serve as markers for assessing the disease severity, and they may also play a role in MPO-AAV pathogenesis.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Calgranulin A; Humans; Peroxidase; Reactive Oxygen Species; S100A12 Protein

BackgroundAntineutrophil cytoplasmic autoantibody-associated (ANCA-associated) vasculitidies (AAV) are life-threatening systemic autoimmune conditions. ANCAs directed against proteinase 3 (PR3) or myeloperoxidase (MPO) bind their cell surface-presented antigen, activate neutrophils, and cause vasculitis. An imbalance between PR3 and its major inhibitor α1-antitrypsin (AAT) was proposed to underlie PR3- but not MPO-AAV. We measured AAT and PR3 in healthy individuals and patients with AAV and studied protective AAT effects pertaining to PR3- and MPO-ANCA.MethodsPlasma and blood neutrophils were assessed for PR3 and AAT. WT, mutant, and oxidation-resistant AAT species were produced to characterize AAT-PR3 interactions by flow cytometry, immunoblotting, fluorescence resonance energy transfer assays, and surface plasmon resonance measurements. Neutrophil activation was measured using the ferricytochrome C assay and AAT methionine-oxidation by Parallel Reaction Monitoring.ResultsWe found significantly increased PR3 and AAT pools in patients with both PR3- and MPO-AAV; however, only in PR3-AAV did the PR3 pool correlate with the ANCA titer, inflammatory response, and disease severity. Mechanistically, AAT prevented PR3 from binding to CD177, thereby reducing neutrophil surface antigen for ligation by PR3-ANCA. Active patients with PR3-AAV showed critical methionine-oxidation in plasma AAT that was recapitulated by ANCA-activated neutrophils. The protective PR3-related AAT effects were compromised by methionine-oxidation in the AAT reactive center loop but preserved when 2 critical methionines were substituted with valine and leucine.ConclusionPathogenic differences between PR3- and MPO-AAV are related to AAT regulation of membrane-PR3, attenuating neutrophil activation by PR3-ANCA rather than MPO-ANCA. Oxidation-resistant AAT could serve as adjunctive therapy in PR3-AAV.FUNDINGThis work was supported by KE 576/10-1 from the Deutsche Forschungsgemeinschaft, SCHR 771/8-1 from the Deutsche Forschungsgemeinschaft, grant 394046635 - SFB 1365 from the Deutsche Forschungsgemeinschaft, and ECRC grants.

Topics: alpha 1-Antitrypsin; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Giant Cell Arteritis; Humans; Methionine; Mucocutaneous Lymph Node Syndrome; Myeloblastin; Neutrophil Activation; Peroxidase

The extent of rare side effects of mRNA vaccines for coronavirus disease 2019 (COVID-19) remains unclear. Several cases of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) following COVID-19 vaccination have been reported. We herein report a 72-year-old man who presented with a fever after receiving the second dose of the Pfizer-BioNTech COVID-19 vaccine. He was diagnosed with acute kidney injury due to myeloperoxidase-ANCA-associated vasculitis and was treated with intermittent hemodialysis, high-dose prednisolone, and intravenous rituximab. His general symptoms and renal impairment subsequently improved. When systemic symptoms are prolonged or renal abnormalities appear after COVID-19 vaccination, the possibility of AAV should be considered.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; BNT162 Vaccine; COVID-19; COVID-19 Vaccines; Humans; Male; Peroxidase; Prednisolone; Rituximab; Vaccination

Several lines of evidence implicate that there are distinct differences between patients with myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA) and anti-glomerular basement membrane (GBM) antibody double-seropositive patients (DPPs) and single-positive patients. Hence, we conducted a retrospective study from a single center in China to analyze the clinical and pathological features, and prognosis of DPPs.. 109 patients with MPO-ANCA-associated vasculitis (MPO-AAV), 20 DPPs and 23 patients diagnosed with anti-GBM disease from a large center in China were included in this study. The ratio of patients with renal biopsy in three groups were 100%, 50% and 100%, respectively. Their clinical and pathological characteristics, and outcomes were analyzed. The intensity of immune deposits in the kidney at diagnosis was detected by immunofluorescence (IF). Furthermore, multivariate Cox hazard model analysis was used to assess the clinical and histological predictors of end-stage renal disease (ESRD) and death for DPPs.. In our study, we found that patients in the DPPs group were older than the other two groups (. In summary, compared with anti-GBM disease, DPPs tended to involve multi-organ damage rather than limited to the kidney. It is highlighted that serologic DPPs have a worse renal and patient prognosis than MPO-AAV. Moreover, we found that the risk factors of renal survival of DPPs include low lymphocyte count, elevated serum creatinine and reduced eGFR, and serum creatinine can predict patient survival.

Topics: Anti-Glomerular Basement Membrane Disease; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Creatinine; Humans; Kidney Failure, Chronic; Peroxidase; Prognosis; Retrospective Studies

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a potentially life-threatening systemic small-vessel vasculitis that is characterized by pauci-immune glomerulonephritis, depicting in turn a major denominator of AAV mortality. It is well established that AAV patients feature an increased risk of developing thrombotic events, and platelets are activated in AAV patients being triggered by the alternative complement pathway. Platelets guard vessels integrity and initiate thrombus formation in response to endothelial damage, further constituting a triangular interconnection with the activation of neutrophils and the complement system. We here aimed to systematically assess the relevance of platelet counts and systemic complement system activation regarding distinct histopathological lesions in ANCA-associated renal vasculitis.. A cohort of 53 biopsy-proven cases of ANCA-associated renal vasculitis were retrospectively enrolled in a single-center observational study. Univariate and multivariate regression analysis was performed to identify parameters associated with platelet counts in ANCA-associated renal vasculitis compared to disease controls. Finally, the relevance of platelets for disease course and recovery was assessed by survival analysis.. Lower platelet counts correlated with markers of kidney injury including eGFR loss (. Based on our observation that an association between platelets and complement system activation is only observed in the MPO-ANCA subgroup, this could implicate that platelets and complement C3 link innate immunity to tubulointerstitial injury in the presence of MPO-ANCA autoantibodies.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Atrophy; Complement C3; Fibrosis; Humans; Immunity, Innate; Kidney Diseases; Peroxidase; Retrospective Studies

The value of myeloperoxidase (MPO) and proteinase 3 (PR3) antibody titres in the assessment of renal disease activity and flare prediction in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is not well known.. We performed a retrospective study including 113 AVV patients with renal biopsy-proven pauci-immune necrotizing glomerulonephritis from seven Spanish hospitals. The main inclusion criteria were assessment of MPO antibodies using multiplex flow immunoassay and PR3 antibody measurements using immunoassay chemiluminescence with an identical range of values for all participating centres.. Serum MPO antibodies 3 ± 1.2 months before relapse were higher in patients who relapsed [19.2 ± 12.2 versus 3.2 ± 5.1 antibody index (AI); P < 0.001]. The discrimination value of MPO antibodies 3 months before renal relapse had an area under the receiver operating characteristics curve (AUC) of 0.82 [95% confidence interval (CI) 0.73-0.92; P < 0.001]. ΔMPO antibodies (change in antibodies titration 6 months before relapse) were higher in patients who relapsed (8.3 ± 12 versus 0.9 ± 3.1 AI; P = 0.001). The discrimination value of ΔMPO had an AUC of 0.76 (95% CI 0.63-0.88; P < 0.001). The positive predictive value of renal relapse in PR3 patients is 100% and the negative predictive value of renal relapse in patients with PR3-positive titres is 57.1%. Serum PR3 antibodies were higher in patients who relapsed 2.8 ± 1.4 months before relapse (58.6 ± 24.6 versus 2.0 ± 0.6 AI; P < 0.001).. MPO level monitoring using multiplex flow immunoassay and PR3 measurements using immunoassay chemiluminescence are useful and sensitive tools for the prediction of renal relapse in the follow-up of AAV patients with renal disease and relevant surrogate markers of renal disease activity.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Humans; Kidney Diseases; Male; Myeloblastin; Nephritis; Peroxidase; Recurrence; Retrospective Studies

Kidney biopsy is valuable for prognostic assessment of renal outcomes in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) with glomerulonephritis (AAV-GN) but the impact of chronic changes is not determined.. We conducted a retrospective cohort study of myeloperoxidase (MPO)- or proteinase 3 (PR3)-ANCA-positive patients with AAV and active renal disease. We applied the Mayo Clinic Chronicity Score (MCCS) and validated and evaluated its implications on outcome prediction in AAV-GN.. We analyzed 329 patients with kidney biopsies available to score. The extent of chronicity was graded by MCCS as minimal [102 (31.0%)], mild [106 (32.2%)], moderate [86 (26.1%)] and severe [35 (10.6%)]. The MCCS grades correlated with the degree of renal function impairment at presentation [mean estimated glomerular filtration rate (eGFR) 48.3 versus 29.2 versus 23.7 versus 18.5 mL/min/1.73 m2, respectively; P < 0.0001]. Higher degrees of the individual components of the MCCS (glomerulosclerosis, interstitial fibrosis, tubular atrophy and arteriosclerosis) were associated with lower median eGFR (P < 0.0001) and decreased event-free [kidney failure (KF) and death] survival (P = 0.002, P < 0.0001, P < 0.0001 and P = 0.017, respectively). Patients with lower MCCS grades recovered renal function more frequently (P < 0.0001). Increasing MCCS grades were associated with decreased renal recovery (P = 0.001), more frequent events and shorter time to KF (P < 0.0001), KF and death (P < 0.0001) and death (P = 0.042), independent of the remission induction treatment used (cyclophosphamide or rituximab). The MCCS stratified renal outcomes for each MCCS grade and can be used in clinical practice as a cutoff for KF prediction (MCCS ≥4).. Chronic changes on kidney histology independently predict renal function, outcomes and response to treatment in AAV-GN.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biopsy; Glomerulonephritis; Humans; Kidney; Kidney Diseases; Peroxidase; Retrospective Studies

The antineutrophil cytoplasmic antibody (ANCA) vasculitides include several closely related, often severe, multisystem autoimmune diseases characterized by antibodies against serine proteinase 3 (PR3) or myeloperoxidase. Loss of tolerance to these antigens triggers a cascade of events, beginning with the priming of neutrophils by proinflammatory cytokines and complement activation, translocation of ANCA-specific antigens to the plasma membrane, neutrophil hyperactivation, and further activation of the alternative complement pathway, leading to tissue damage and the clinical manifestations of ANCA vasculitis. Due to the heterogeneity in presentation of these diseases, diagnosis is often substantially delayed, leading to poor outcomes. The current treatment pathway for most patients involves induction with cyclophosphamide or rituximab in combination with glucocorticoids, followed by a maintenance phase with rituximab, azathioprine, or methotrexate, during which time glucocorticoids are tapered. Current therapies are often effective in inducing and maintaining remission but are associated with a range of toxicities. Several new therapies are in development for ANCA vasculitis. Avacopan, an orally administered inhibitor of the complement fragment 5a (C5a) receptor, has been assessed in a phase 3 clinical trial and may play a role in reducing the cumulative glucocorticoid dose. Preliminary data suggest that cluster of differentiation (CD) 80 and CD86 blockade with abatacept may also have a role in the management of ANCA vasculitis. There is an unmet need for additional therapeutic options for patients with these diseases.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Peroxidase

We present a patient with systemic symptoms including 4 months of dyspnoea worsened with exertion, fatigue, rhinorrhoea, intermittent facial swelling, generalised lymphadenopathy and weight loss. Laboratory studies demonstrated proteinuria and eosinophilia. His serology was consistent with Epstein-Barr Virus (EBV) reactivation. A lymph node biopsy was consistent with EBV-associated reactive lymphoid hyperplasia. He was told to continue symptomatic treatment for EBV infection. After several admissions, vasculitis workup and myeloperoxidase-antineutrophil cytoplasmic autoantibody (ANCA) studies were positive. Evolution of clinical symptoms, laboratory parameters and our literature review suggested the diagnosis of EBV-associated ANCA vasculitis. Steroids were started after the patient continued to deteriorate; the viral load started increasing, so we added valganciclovir with favourable clinical response and no relapse during the follow-up for 6 months. This suggests that with evidence of viraemia (primary or reactivation), antiviral treatment likely has clinical benefit while immunosuppression is being considered.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Male; Peroxidase

Acute kidney injury (AKI) is a common and severe complication of anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), potentially leading to chronic kidney disease (CKD), end-stage renal disease (ESRD), or death. Pathogenic ANCAs, in particular proteinase 3 (PR3) and myeloperoxidase (MPO), trigger a deleterious immune response with intrarenal immune cell infiltration resulting in a pauci-immune necrotizing and crescentic glomerulonephritis (GN). However, a systematic analysis of intrarenal immune cell subtypes concerning neutrophils, eosinophils, plasma cells, and mononuclear cell infiltrates (macrophages, lymphocytes) in ANCA GN remains elusive. Therefore, we aimed to compare distinct immune cell infiltrates in association with clinicopathological findings in ANCA GN.. A total of 53 kidney biopsies with ANCA GN at the University Medical Center Göttingen were retrospectively analyzed. Histological infiltrates of neutrophils, eosinophils, plasma cells, and mononucleated cells (macrophages, lymphocytes) were quantified as a fraction of the total area of inflammation.. Neutrophilic infiltrates were associated with glomerular necrosis and severe kidney injury in ANCA GN. Among tubulointerstitial lesions, intrarenal neutrophils correlated with interstitial inflammation, tubulitis, and inflammation in areas of interstitial fibrosis/tubular atrophy (IFTA), representing active inflammatory lesions. Concerning eosinophils, infiltrates were associated with severe kidney injury, interstitial inflammation, and cellular casts independent of glomerular lesions, implicating a distinct role in inflammation and damage in ANCA GN. Plasma cell infiltrates correlated with tubulitis and interstitial fibrosis and were associated with renal replacement therapy during the short-term disease course. Finally, mononuclear cell infiltrates correlated with severe kidney injury and active histopathological lesions (glomerular crescents, interstitial inflammation, tubulitis, inflammation, and tubulitis in areas of IFTA) besides chronic lesions (interstitial fibrosis and tubular atrophy) in ANCA GN. Interestingly, intrarenal subtypes of immune cell infiltrates differed in MPO-ANCA versus PR3-ANCA GN and were associated with distinct glomerular and tubulointerstitial lesions, implicating different pathogenic mechanisms of kidney injury in ANCA subtypes.. Our observations imply distinct pathomechanisms contributing to inflammation and renal injury in MPO vs. PR3-associated ANCA GN and potentially contribute to new therapeutic targets in specific ANCA subtypes.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biopsy; Chemotaxis, Leukocyte; Female; Glomerulonephritis; Humans; Kidney; Leukocytes; Macrophages; Male; Middle Aged; Myeloblastin; Neutrophil Infiltration; Peroxidase; Retrospective Studies

Myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) associated vasculitis is an autoimmune disease usually with severe multiple dysfunction syndrome, especially prominent acute renal failure. A 65-year-old woman was admitted with progressive dyspnoea for six months and fever, sputum with blood, pain of the lower extremities and intermittent claudication for two days, indicating multiple organ involvement (respiratory system, blood vessels). The renal involvement was relatively mild, presenting with microscopic haematuria. The chest computed tomography demonstrated multiple pulmonary embolisms. Ultrasound and computed tomography angiography for the lower extremity vessels showed venous and arterial thrombosis. Exclusion of other diseases that can cause multiple organ damage and thrombosis, the positive perinuclear ANCA and MPO-ANCA strongly support the diagnosis of MPO-ANAC-associated vasculitis. The patient's physical condition has been greatly improved by treatment with corticosteroids and anticoagulation.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Female; Humans; Lower Extremity; Peroxidase; Pulmonary Embolism; Thrombosis

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Humans; Male; Peroxidase; Skin

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

We evaluated the effectiveness of cyclophosphamide for patients with microscopic polyangiitis and granulomatosis with polyangiitis.. Patients treated with cyclophosphamide and glucocorticoid (cyclophosphamide group) or glucocorticoid alone (non-cyclophosphamide group) for remission-induction were enrolled from two Japanese nationwide prospective inception cohort studies. The effectiveness and safety outcomes were compared before and after propensity score (PS)- matching.. Proportion of patients achieving Birmingham Vasculitis Activity Score (BVAS)-remission and BVAS-remission plus a daily prednisolone dosage of ≤10 mg (GC-remission) by Month 6 were not significantly different between cyclophosphamide and non-cyclophosphamide groups before (. Concomitant cyclophosphamide use may improve GC-remission by Month 6 in MPO-ANCA-positive patients and could exert glucocorticoid sparing effect.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Cyclophosphamide; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Male; Microscopic Polyangiitis; Middle Aged; Peroxidase; Prednisolone; Remission Induction

Topics: Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Aortic Valve; Aortic Valve Insufficiency; Atrioventricular Block; Female; Heart Valve Diseases; Humans; Mitral Valve; Mitral Valve Insufficiency; Peroxidase

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

The primary challenge of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patient care is the early detection of relapses to prevent organ damage and increase survival. Potential biomarkers for relapses are ANCA and B cells, but their predictive value is a matter of debate. Therefore this study investigated how ANCA and B-cell status related to relapses in AAV patients treated with rituximab (RTX) as remission induction (RI).. This single-centre cohort study identified 110 ANCA-positive AAV patients treated with RTX between 2006 and 2018. Serial ANCA, CD19+ B-cell status and relapses were assessed >2 years.. Patients (31/110) relapsed within 2 years after RTX RI treatment. Patients who achieved and maintained PR3-ANCA negativity (n = 29) had few relapses (3%), while persistent proteinase 3 (PR3)-ANCA positivity (n = 49) and reappearance of PR3-ANCAs (n = 10) associated significantly with more relapses (37%, P = 0.002 and 50%, P = 0.002). Patients with incomplete B-cell depletion (n = 11) had significantly more relapses (54%) as compared with patients with B-cell depletion [n = 76 (26%), P = 0.02]. Also, patients with repopulation of B cells (n = 58) had significantly more relapses (41%) as compared with patients without B-cell repopulation [n = 27 (15%), P = 0.03]. Overall, the absence of PR3- or myeloperoxidase (MPO)-ANCA positivity was highly predictive for remaining relapse-free. In PR3-ANCA-positive patients, 96% of the relapses occurred with persistent or reappearance of PR3-ANCAs and 81% with B-cell repopulation. In MPO-ANCA-positive patients, all relapses were restricted to patients with persistent MPO-ANCAs and B-cell repopulation.. Upon RI treatment with RTX in AAV patients, ANCA and B-cell status were predictive of the majority of relapses and specifically their absence strongly predicted a relapse-free status. Therefore the implementation of ANCA and B-cell monitoring could guide therapeutic decision-making to prevent relapses in AAV patients treated with RTX.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Cohort Studies; Humans; Myeloblastin; Peroxidase; Recurrence; Rituximab

Membranous nephropathy (MN) with anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (ANCA-GN) is seen infrequently. Previous reports of patients with ANCA-GN with MN showed that the most frequent ANCA subtype was myeloperoxidase-ANCA. We herein present a 73-year-old woman with scleritis, hematuria, proteinuria, and positive serum proteinase 3 (PR3)-ANCA. She underwent a renal biopsy and was diagnosed with MN and ANCA-GN. Immunofluorescence staining for PR3 colocalized with IgG along the glomerular basement membrane were observed. Oral prednisolone and intravenous rituximab therapy immediately improved her symptoms and urinalysis abnormalities. PR3-ANCA may be involved in the pathogenesis of MN via the formation of immune complexes.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Glomerulonephritis; Glomerulonephritis, Membranous; Humans; Myeloblastin; Peroxidase; Rituximab

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

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Giant Cell Arteritis; Humans; Peroxidase; Sjogren's Syndrome

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

The prognosis of microscopic polyangiitis (MPA) with interstitial lung disease (ILD) is significantly worse than that of MPA without ILD. However, the clinical characteristics in MPA-ILD, especially poor prognostic factors, are not elucidated. We evaluated demographic, clinical, laboratory, and radiological findings, treatments, and outcomes of 80 patients with MPA, and investigated prognostic factors of respiratory-related death in patients with myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA) positive MPA-ILD. Ground-glass opacity and fibrosis were evaluated as scores on high-resolution computed tomography (HRCT). The presence of ILD was consistent with a high risk of respiratory-related death (hazard ratio, 4.8; P = 0.04). Multivariable logistic regression analyses using propensity scoring showed right or left lower lobe fibrosis score to be significantly associated with respiratory-related death (P = 0.0005 and 0.0045, respectively). A right or left lower lobe fibrosis score ≥ 2, indicating the presence of honeycombing at 1 cm above the diaphragm, was determined to be the best cut-off value indicating a poor prognosis. The 5-year survival rate was significantly lower in patients with right or left lower lobe fibrosis score ≥ 2 (survival rates: 37% and 19%, respectively) than those with a score < 2 (71% and 68%, respectively) (P = 0.002 and 0.0007, respectively). These findings suggest that the presence of honeycomb lesions in bilateral lower lobes on chest HRCT was associated with respiratory-related death in patients with MPO-ANCA positive MPA-ILD.

Topics: Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Humans; Japan; Lung; Lung Diseases, Interstitial; Male; Microscopic Polyangiitis; Peroxidase; Prognosis; Proportional Hazards Models; Retrospective Studies; Survival Rate; Tomography, X-Ray Computed

Degenerative aortic valve stenosis (AS) is a chronic progressive disease that resembles atherosclerosis development. Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is reportedly associated with accelerated atherosclerosis. This study aimed to examine the development of AS in patients with myeloperoxidase-AAV (MPO-AAV) with renal involvement at more than 1 year after the onset of vasculitis.. We performed a retrospective review of clinical records of MPO-AAV patients with renal involvement without AS at the onset of vasculitis who were treated in three hospitals and three dialysis clinics.. The study included 97 MPO-AAV patients with renal involvement and 230 control patients with chronic kidney disease (CKD). Among them, 64 patients had AS. The prevalence rates of AS were 28.9% and 15.7% in MPO-AAV and control patients, respectively (p = 0.006). The multivariable logistic regression analysis showed that MPO-AAV, dialysis dependence, and hypertension were independently associated factors for AS. In MPO-AAV patients, systolic blood pressure was positively significantly associated with AS, whereas glucocorticoid dose of induction therapy was negatively significantly associated. The use of cyclophosphamide tended to be negatively associated with AS. The survival rate was significantly lower for patients with AS than for those without AS.. The AS prevalence rate was significantly higher in MPO-AAV patients at more than 1 year after the onset of vasculitis than in control CKD patients. Therefore, regular monitoring of echocardiography during MPO-AAV treatment is suggested.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Aortic Valve Stenosis; Female; Humans; Kidney; Male; Peroxidase; Retrospective Studies; Survival Analysis

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Panniculitis; Peroxidase

The objective of this study is to evaluate the association between antineutrophil cytoplasmic autoantibody (ANCA) subtype and ANCA titers on clinical outcomes and disease activity among a cohort of patients from Central Appalachia diagnosed with ANCA-associated vasculitis (AAV) over a 3-decade period. This is a retrospective chart review of all patients diagnosed with AAV. ANCA subtypes (myeloperoxidase (MPO) and proteinase 3 (PR3)) and titers at the time of diagnosis and at the time of relapse or last follow-up were evaluated along with patient outcomes. Outcomes of interest included relapse, development of end-stage renal disease (ESRD) and mortality. Sensitivity analysis and multivariable analysis were performed. Of the 202 patients, 111 patients were MPO-ANCA positive and 91 patients were PR3-ANCA positive. Relapse was more frequent among patients with PR3-ANCA compared to MPO-ANCA (35% vs 12%, p < 0.001). In both ANCA subgroups, the strongest predictor of relapse was an increase in titers prior to relapse, HR 8.1 (95% CI 1.6-40), p 0.009. Patients who achieved serological remission had a lower risk of ESRD [sub-HR 0.31 (95% CI 0.11-0.89)] and mortality [HR (95% CI) 0.24 (0.07-0.7)]. PR3-ANCA was associated with higher risk of ESRD [sub-HR 3.1 (95% CI 1.1-8.5)]. There was no difference in mortality between patients with MPO-ANCA and PR3-ANCA. Our study supports the use of both ANCA subtypes and titer levels for predicting clinical outcomes in patients receiving treatment for AAV. Monitoring of ANCA antibody titers may be useful since both serological remission and increase in titers provide prognostic information.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Disease Progression; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Myeloblastin; Peroxidase; Recurrence; Retrospective Studies

The concept of otitis media with ANCA-associated vasculitis (OMAAV) was recently proposed by the study group of the Japan Otological Society. However, little is known about the effect of ear involvement on the clinical features and prognosis of AAV. We investigate this issue in this study.. We retrospectively examined 36 patients diagnosed with OMAAV and 44 patients diagnosed with AAV without ear involvement (non-OMAAV) at Ehime University Hospital from 2013 to 2018. We collected serological findings including ANCA type and titer, C-reactive protein (CRP), serum creatinine level, organ involved at initial diagnosis, treatment, remission, disease relapse, and mortality from medical records. We investigated whether clinical features and outcomes differed between the OMAAV and non-OMAAV groups.. Age, ANCA titer, and CRP at initial diagnosis were not significantly different between the two groups, and the rate of intravenous cyclophosphamide (IVCY) use also did not differ. The proportions of patients with concurrent eye involvement, facial palsy (FP), and hypertrophic pachymeningitis (HCP) were significantly higher in the OMAAV than in the non-OMAAV group (p = 0.005, 0.005 and 0.049, respectively), while both renal and peripheral nerve involvement were significantly less common in OMAAV patients (p = 0.04). Among the 30 patients with renal involvement, serum creatinine level at diagnosis was significantly lower in the OMAAV group (p = 0.04). The mortality rate was 8.3% in OMAAV and 6.8% in non-OMAAV cases, but this difference was not significant. The rate of relapse was 33.3% in OMAAV and 13.6% in non-OMAAV cases; this difference was significant (p = 0.04).. Serological measurements of disease activity did not differ between the groups. Eye involvement, FP, and HCP, however, were significantly more common in AAV with ear involvement. In addition, renal involvement was less common and renal impairment was milder in AAV with ear involvement. These findings can be considered clinical features. The relapse rate was significantly higher in AAV with ear involvement.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; C-Reactive Protein; Cyclophosphamide; Eye Diseases; Facial Paralysis; Female; Glucocorticoids; Humans; Immunologic Factors; Immunosuppressive Agents; Kidney Diseases; Lung Diseases, Interstitial; Male; Meningitis; Methylprednisolone; Myeloblastin; Otitis Media; Peripheral Nervous System Diseases; Peroxidase; Prognosis; Rituximab

A novel patient cluster in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) may be identified in Japan. We performed multiple correspondence and cluster analysis regarding 427 clinically diagnosed AAV patients excluding eosinophilic granulomatosis with polyangiitis. Model 1 included the ANCA phenotype, items of the Birmingham Vasculitis Activity Score, and interstitial lung disease; model 2 included serum creatinine (s-Cr) and C-reactive protein (CRP) levels with model 1 components. In seven clusters determined in model 1, the ANCA-negative (n = 8) and proteinase 3-ANCA-positive (n = 41) groups emerged as two distinct clusters. The other five myeloperoxidase-ANCA-positive clusters were characterized by ear, nose, and throat (ENT) (n = 47); cutaneous (n = 36); renal (n = 256), non-renal (n = 33); and both ENT and cutaneous symptoms (n = 6). Four clusters in model 2 were characterized by myeloperoxidase-ANCA negativity (n = 42), without s-Cr elevation (< 1.3 mg/dL) (n = 157), s-Cr elevation (≥ 1.3 mg/dL) with high CRP (> 10 mg/dL) (n = 71), or s-Cr elevation (≥ 1.3 mg/dL) without high CRP (≤ 10 mg/dL) (n = 157). Overall, renal, and relapse-free survival rates were significantly different across the four clusters in model 2. ENT, cutaneous, and renal symptoms may be useful in characterization of Japanese AAV patients with myeloperoxidase-ANCA. The combination of s-Cr and CRP levels may be predictive of prognosis.

Topics: Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; C-Reactive Protein; Creatinine; Disease-Free Survival; Female; Humans; Japan; Kidney Diseases; Male; Middle Aged; Peroxidase; Phenotype; Skin Abnormalities

A 21-year-old woman was admitted to our hospital because of massive intestinal bleeding. She started hemodialysis due to myeloperoxidase antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) at 18 years of age. Her ANCA titers remained stable; however, her C-reactive protein increased on 5 mg/day prednisolone before admission. Computed tomography angiography revealed a ruptured jejunal arterial aneurysm. Transcatheter arterial embolization, blood transfusion and the reinforcement of steroid therapy resolved her symptoms of AAV. Our case of a young patient with AAV and medium-sized arterial vasculitis is rare and emphasizes that the ANCA titer does not always rise, especially in patients with nonrenal vasculitis flare-ups.

Topics: Aneurysm; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Gastrointestinal Hemorrhage; Humans; Peroxidase; Renal Dialysis; Young Adult

Myeloperoxidase ANCA-associated vasculitis is a major cause of ESKD. Efficacy of anti-CD20 mAb treatment was tested in a mouse model of the disease.. MPO immunization induced anti-MPO autoimmunity, and a subnephritogenic dose of sheep anti-mouse GBM globulin triggered GN.. Anti-CD20 mAb treatment increased the numbers and immunomodulatory capacity of MPO-specific T regulatory cells (Tregs) and attenuated T cell-mediated and humoral anti-MPO autoimmunity and GN. Disabling of Tregs negated the therapeutic benefit of anti-CD20 treatment. The mechanism of enhancement of Treg activity could be attributed to anti-CD20 mAb effects on inducing B cell apoptosis. Administering anti-CD20 mAb-induced apoptotic splenocytes to mice developing anti-MPO GN was as effective as anti-CD20 mAb treatment in inducing Tregs and attenuating both anti-MPO autoimmunity and GN. A nonredundant role for splenic macrophages in mediating the anti-CD20 mAb-induced immunomodulation was demonstrated by showing that administration of anti-CD20 mAb. Collectively, these data suggest that, as well as reducing humoral autoimmunity, anti-CD20 mAb more rapidly induces protective anti-MPO Treg-mediated immunomodulation by splenic processing of anti-CD20-induced apoptotic B cells.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Apoptosis; B-Lymphocytes; Disease Models, Animal; Immunologic Factors; Male; Mice; Peroxidase; Rituximab; T-Lymphocytes, Regulatory

Rapidly progressive glomerulonephritis caused by antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is typically characterized as pauci-immune glomerulonephritis. However, immune complex (IC) deposition in the glomerulus has been reported in a growing number of studies. Here, we assess the presence of glomerular immune deposits alongside renal outcome in myeloperoxidase (MPO)-ANCA associated glomerulonephritis (MPO-ANCA GN).. Clinical and histopathologic characteristics of 97 patients with MPO-ANCA GN classified by renal biopsy from January 2008 to December 2019 were extracted retrospectively from electronic medical records. The extent of immune deposits in the kidney (C3, C4, C1q, IgA, IgG, IgM) at diagnosis were analyzed by immunofluorescence (IF). Patients were followed up for a median period of 15 months. The response to treatment and outcomes of renal and histological lesion changes were also assessed.. In our study, 41% (40/97) of patients showed positive IF (≥2+) for at least one of the six immunoglobulin or complement components tested. Patients with IC deposits showed higher levels of serum creatinine (p=0.025), lower platelet counts (p=0.009), lower serum complement C3 (sC3) (≤790 ml/L) (p=0.013) and serum IgG (p=0.018) than patients with pauci-immune (PI) deposition at diagnosis. End-stage renal disease was negatively associated with eGFR (HR 0.885, 95% CI 0.837 to 0.935, p<0.0001), platelet count (HR 0.996, 95% CI 0.992 to 1.000, p=0.046) and serum globulin (HR 0.905, 95% CI 0.854 to 0.959, p=0.001). Patients with lower sC3 levels showed a worse renal outcome than the patients with normal sC3 at diagnosis (p=0.003). Analysis of the components of the renal deposits found that patients with IgG deposits exhibited a poorer renal outcome compared to patients that were IgG negative (p=0.028). Moreover, Bowman's capsule rupture occurred less frequently in patients with IgM deposition compared with IgM negative counterparts (p=0.028). Vascular lesions and granuloma-like lesions had been seen more frequently in cases with IgA deposition than those without IgA deposition (p=0.03 and 0.015, respectively).. In conclusion, patients with immune complex deposits in the kidney showed less platelet count, lower sC3 and sIgG levels, and higher serum creatinine levels. Patients with low sC3 at initial and with continued low sC3 during the treatment displayed a trend toward poorer kidney survival. Moreover, the IC group showed a worse renal outcome than the PI group, further enforcing the present strategy of introducing complement targeted therapies in AAV.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biopsy; Complement System Proteins; Cyclophosphamide; Disease Progression; Drug Therapy, Combination; Female; Fluorescent Antibody Technique; Glomerulonephritis; Glucocorticoids; Humans; Immunoglobulin Isotypes; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Glomerulus; Male; Middle Aged; Peroxidase; Retrospective Studies; Risk Assessment; Risk Factors; Time Factors; Treatment Outcome

Hydralazine, a widely used therapy for hypertension and heart failure, can elicit autoimmune disease, including anti-neutrophil cytoplasmic antibody associated glomerulonephritis (ANCA-GN). We identified 80 cases of ANCA-GN complicating treatment with hydralazine, accounting for 4.3% (80/1858 biopsies) of ANCA-GN diagnosed between 2006 and 2019. Over three-fourths of patients were on hydralazine for at least one year, with mean daily dose of approximately 250 mg/day. ANCA testing revealed p-ANCA/myeloperoxidase-ANCA seropositivity in 98%, including 39% with dual p-ANCA/myeloperoxidase-ANCA and cANCA/anti-protinase 3-ANCA positivity, often accompanied by anti-nuclear antibody (89%), anti-histone antibody (98%), and hypocomplementemia (58%). Kidney biopsy revealed necrotizing and crescentic glomerulonephritis, similar to primary ANCA-GN, but significantly less frequently pauci-immune (77 vs. 100%) and more commonly associated with mesangial hypercellularity (30 vs. 5%), electron dense deposits (62 vs. 20%), and endothelial tubuloreticular inclusions (11 vs. 0%); all significant differences. On follow-up, 42 of 51 patients received induction immunosuppression: 19 reached the combined end-points of kidney failure or death and 32 had mean creatinine of 1.49 mg/dL at last follow-up. Thus, hydralazine-associated ANCA-GN often exhibits overlapping clinical and pathologic features of mild immune complex glomerulonephritis resembling lupus nephritis. With discontinuation of hydralazine and immunosuppression, outcomes are similar to primary ANCA-GN.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Glomerulonephritis; Humans; Hydralazine; Hypertension; Peroxidase

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Humans; Mutation; Peroxidase; Ubiquitin-Activating Enzymes

Experimental autoimmune vasculitis (EAV) is a model of antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) induced by immunisation of susceptible rat strains with myeloperoxidase (MPO). Animals develop circulating MPO-ANCA, pulmonary haemorrhage, and glomerulonephritis, although renal injury is mild and recovers spontaneously without treatment. In this study we aimed to augment the severity of glomerulonephritis. Following induction of EAV on day 0, a sub-nephritogenic dose of nephrotoxic serum (NTS) containing heterologous antibodies to glomerular basement membrane was administered on day 14. This resulted in a significant increase in disease severity at day 28 compared to MPO immunisation alone - with more urinary abnormalities, infiltrating glomerular leucocytes, and crescent formation that progressed to glomerular and tubulointerstitial scarring by day 56, recapitulating important features of human disease. Importantly, the glomerulonephritis remained pauci-immune, and was strictly dependent on the presence of autoimmunity to MPO, as there was no evidence of renal disease following administration of sub-nephritogenic NTS alone or after immunisation with a control protein in place of MPO. Detailed phenotyping of glomerular leucocytes identified an early infiltrate of non-classical monocytes following NTS administration that, in the presence of autoimmunity to MPO, may initiate the subsequent influx of classical monocytes which augment glomerular injury. We also showed that this model can be used to test novel therapeutics by using a small molecule kinase inhibitor (fostamatinib) that rapidly attenuated both glomerular and pulmonary injury over a 4-day treatment period. We believe that this enhanced model of MPO-AAV will prove useful for the study of glomerular leucocyte behaviour and novel therapeutics in AAV in the future. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoantibodies; Autoantigens; Disease Models, Animal; Glomerular Basement Membrane; Glomerulonephritis; Male; Peroxidase; Rats

We present a case of antineutrophil cytoplasmic antibodies (ANCA)-associated rapidly progressive glomerulonephritis in the context of treatment of pulmonary tuberculosis (TB). A 42-year-old woman was treated for drug-susceptible pulmonary TB and represented with paradoxical worsening of symptoms and radiological features. She was HIV negative. A severe acute kidney injury with features of glomerulonephritis was evident on admission. Perinuclear ANCA and antimyeloperoxidase antibodies were present in serum and renal biopsy was consistent with ANCA-associated vasculitis. The patient was successfully treated with both antituberculous therapy and immunosuppression (corticosteroids and mycophenolate mofetil) with subsequent clinical improvement and amelioration of renal function. We propose this is the first case that describes the association between paradoxical reactions during TB treatment and ANCA-associated glomerulonephritis.

Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Glomerulonephritis; Humans; Peroxidase; Tuberculosis

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biopsy; Glomerulonephritis; Humans; Peroxidase

Effector memory T cells are pivotal effectors of adaptive immunity with enhanced migration characteristics and are involved in the pathogenesis of ANCA-associated vasculitis (AAV). The diversity of effector memory T cells in chemokine receptor expression has been well studied in proteinase 3 (PR3)-AAV. However, few studies have been conducted in myeloperoxidase (MPO)-AAV. Here, we characterized chemokine receptor expression on effector memory T cells from patients with active MPO-AAV.. Clinical data from newly diagnosed MPO-AAV patients and healthy subjects were collected and analyzed. Human peripheral blood mononuclear cells (PBMCs) isolated from patients with active MPO-AAV were analyzed by flow cytometry. The production of effector memory T cell-related chemokines in serum was assessed by ELISA.. We observed decreased percentages of CD4. Our data indicate that dysregulated chemokine receptor expression on CD4

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; CD8-Positive T-Lymphocytes; Humans; Kidney; Leukocytes, Mononuclear; Peroxidase; Prognosis; Receptors, CCR6; Receptors, CXCR3; T-Lymphocyte Subsets

Antineutrophil cytoplasmic antibodies (ANCA) serology can aid in the diagnosis and classification of ANCA-associated vasculitides (AAV). However, it is often ordered in patients without clinical manifestations of vasculitis. In this retrospective chart review, we aim to better understand the clinical practices on ANCA testing.. We retrospectively reviewed patients' charts for the indications and diagnostic outcomes of ANCA tests. All ANCA tests ordered at two Canadian hospitals (a community hospital and an academic tertiary hospital) between January and December 2016 were included in the study. Descriptive statistics are used.. A total of 302 ANCA tests were included. The majority (n = 198, 65.6%) were ordered without an indication for testing. For those patients with at least 1 clinical manifestation of AAV (n = 104), 25% were ANCA positive and 18.3% resulted in a diagnosis of AAV. In comparison, among those without a clinical manifestation of AAV (n = 198), only 1.5% were ANCA positive and none was diagnosed with AAV. All patients diagnosed with AAV had at least 1 indication for ANCA testing. The three most common clinical presentations in patients with a final diagnosis of AAV were glomerulonephritis (81.8%), pulmonary hemorrhage (45.5%), and multiple lung nodules (31.8%).. To our knowledge, this is the first study that evaluates patients with both positive and negative ANCA test results in an inpatient setting. We demonstrated a low rate of ANCA positivity and AAV diagnosis in patients without clinical manifestations of AAV. Overall, there is a high rate of ANCA testing without an indication at our academic institution. This over-testing may be curbed by strategies such as a gating policy, culture changes, and clinician education. Key Points • AAV is a clinical-pathological diagnosis, and despite the usefulness of ANCA testing, it does not confirm nor rule out AAV. • ANCA testing for the diagnosis of AAV is generally only indicated when there is a clear manifestation of AAV. • Although patients with AAV may occasionally present without classic signs and symptoms, the diagnostic utility of ANCA serology in this setting is low, and testing is more likely to result in a false-positive or false-negative test. • If clinical suspicion remains high despite negative ANCA testing, clinicians should seek consultation with a rheumatologist.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Canada; Hospital Medicine; Humans; Peroxidase; Retrospective Studies

Perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA) are associated with a multisystem vasculitis affecting small blood vessels in the body. A handful of adult patients who developed vasculitis post-COVID-19 have been reported. Although SARS-CoV-2 has been shown to drive an exaggerated immune response in the pediatric population, such as in Multisystem Inflammatory Syndrome in Children (MIS-C), only one case of vasculitis following COVID-19 has been reported previously in children.. Seventeen-year-old male with a past medical history of COVID-19 pneumonia two months prior presented with acute kidney injury and diffuse alveolar hemorrhage. Rheumatologic workup revealed P-ANCA and Myeloperoxidase (MPO) positivity. Kidney biopsy showed necrotizing glomerulonephritis with limited immune complex deposition. Subsequently, he was treated with steroids and plasmapheresis, and ultimately started on cyclophosphamide.. To our knowledge, this report presents the second reported pediatric case of P-ANCA/MPO vasculitis following COVID-19.

Topics: Adolescent; Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Child; COVID-19; Humans; Male; Peroxidase; SARS-CoV-2; Systemic Inflammatory Response Syndrome; Treatment Outcome; Vasculitis

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; COVID-19; COVID-19 Vaccines; Humans; Peroxidase; RNA, Messenger; SARS-CoV-2

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Clonal Hematopoiesis; Humans; Peroxidase

A 60-year-old woman with a 20-year history of myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis visited our hospital due to productive cough and a low-grade fever for several weeks. Thoracic computed tomography demonstrated scattered tiny nodules, patchy consolidation, ground glass opacities, and thickening interlobular septa. On video-assisted thoracic surgery, those abnormalities were found to correspond to the accumulation of hemosiderin-laden alveolar macrophages (AMs) in the alveolar spaces and alveolar septa due to MPO-ANCA vasculitis. The radiological findings persisted for a further two years, indicating the possibility of persistent vasculitis in the lung or evidence of incomplete clearance of hemosiderin-laden AMs.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Hemosiderosis; Humans; Lung Diseases; Middle Aged; Peroxidase; Radiography; Tomography, X-Ray Computed

We herein report the case of myeloperoxidase (MPO) anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis with anti-glomerular basement membrane (anti-GBM) antibody positivity that successfully treated with mizoribine (MZR) as an immunosuppressive drug for remission maintenance therapy after the initiation of dialysis in addition to plasma exchange (PE) and glucocorticoid treatment to control the disease condition. A 79-year-old woman developed serious renal dysfunction and pulmonary alveolar hemorrhaging due to MPO-ANCA and anti-GBM antibody double-positive vasculitis. She was started on hemodialysis and was treated with methylprednisolone (m-PSL) pulse therapy with PE, followed by oral prednisolone (PSL). The pulmonary alveolar hemorrhaging disappeared, and both antibody titers immediately decreased but then rose again. Thus, m-PSL pulse therapy performed again in combination with combined with MZR treatment. Her poor renal function was irreversible; however, this therapy decreased both antibody titers, and they did not increase again. The patient developed pancytopenia and hyperuricemia. It was considered likely that these conditions developed in association with MZR treatment. We, therefore, measured the patient's blood concentration of MZR, and the maintenance dose was finally set at 50 mg after each dialysis session. The patient's pancytopenia and hyperuricemia improved and PSL could be smoothly tapered. This is the first case report of the use of MZR for remission maintenance therapy in a patient on hemodialysis who was positive for both ANCA and anti-GBM antibodies. The findings suggest that MZR can be used safely and effectively in such cases.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Asian People; Autoantibodies; Combined Modality Therapy; Female; Glucocorticoids; Hemorrhage; Humans; Immunosuppressive Agents; Lung Diseases; Peroxidase; Plasma Exchange; Prednisolone; Remission Induction; Renal Dialysis; Ribonucleosides; Treatment Outcome

The value of urinary mitochondrial DNA (mtDNA) for assessing kidney injury of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) was investigated.. Thirty-nine kidney biopsy-proved myeloperoxidase (MPO)-ANCA associated AAV patients were enrolled and analyzed.. The average urinary mtDNA of patients was significantly higher than that of normal controls (3372.74 ± 1859.72 vs. 474.90 ± 123.59 copy/nmol creatinine, p < 0.001). The patients who needed dialysis at disease onset had the highest levels of urinary mtDNA (5072.23 ± 1302.87 copy/nmol creatinine). Urinary mtDNA positively correlated with urinary neutrophil gelatinase-associated lipocalin (R = 0.661, P < 0.001) and negatively correlated with estimated glomerular filtration rate (R = -0.515, P = 0.001). The urinary mtDNA level of crescentic class (4703.08 ± 1744.31 copy/nmol creatinine) was higher than that of mixed class (3258.14 ± 1158.99 copy/nmol creatinine) and focal class (2268.15 ± 1897.63 copy/nmol creatinine). Univariate correlation analysis showed urinary mtDNA positively correlated with interstitial neutrophils (R = 0.471, P = 0.048) and glomerular neutrophils (R = 0.673, P = 0.002) in kidney biopsy. Among 13 patients who needed hemodialysis at disease onset, 10 patients who got renal recovery had higher urinary mtDNA than 3 patients who remained dialysis dependent (5455.20 ± 1174.64 vs. 3795.67 ± 893.34 copy/nmol creatinine, p = 0.047).. Urinary mtDNA increases in AAV with kidney injury, and its levels correlate with the severity of kidney injury and neutrophils infiltration in pathology.

Topics: Acute Kidney Injury; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Biomarkers; DNA, Mitochondrial; Female; Glomerular Filtration Rate; Humans; Lipocalin-2; Male; Middle Aged; Peroxidase

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

High mobility group box 1 (HMGB1) played pathogenic role in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Recent findings demonstrated that Toll-like receptor 9 (TLR9) was involved in B cell tolerance breaking of autoimmune disease, including AAV. Here, we investigated the effect of HMGB1 on TLR9 in B cells of AAV. In the present work, patients with myeloperoxidase (MPO)-AAV in active stage were recruited. Intracellular TLR9 expression in various B cell subpopulations of the whole blood was detected by flow cytometry and the correlation with clinical data was analysed. Our results showed that intracellular TLR9 expression in B cells, memory B cells and plasmablasts correlated with erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). In particular, TLR9 expression in plasma cells correlated with ESR, CRP, serum creatinine, eGFR, and Birmingham Vasculitis Activity Score. To further explore the effect of HMGB1 on B cell, peripheral blood mononuclear cells (PBMCs) from AAV patients were isolated. After stimulated with HMGB1, TLR9 expression in various B cell subpopulations and proliferation ratio of live B cells were analysed by flow cytometry. We found that TLR9 expression in plasma cells and the proliferation ratio of live B cells by HMGB1 stimulation were significantly upregulated compared with the control group. Therefore, TLR9 expression in plasma cells was associated with disease activity of MPO-AAV. HMGB1 could enhance TLR9 expression in plasma cells and B cell proliferation. These indicated a role of HMGB1 on TLR9 in B cells in MPO-AAV, which would provide potential clues for intervention strategies.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoimmune Diseases; Autoimmunity; B-Lymphocyte Subsets; B-Lymphocytes; Biomarkers; HMGB1 Protein; Humans; Immunophenotyping; Leukocytes, Mononuclear; Lymphocyte Activation; Peroxidase; Toll-Like Receptor 9

The objective of this study was to evaluate causes of death in a contemporary inception cohort of ANCA-associated vasculitis patients, stratifying the analysis according to ANCA type.. We identified a consecutive inception cohort of patients newly diagnosed with ANCA-associated vasculitis from 2002 to 2017 in the Partners HealthCare System and determined vital status through the National Death Index. We determined cumulative mortality incidence and standardized mortality ratios (SMRs) compared with the general population. We compared MPO- and PR3-ANCA+ cases using Cox regression models.. The cohort included 484 patients with a mean diagnosis age of 58 years; 40% were male, 65% were MPO-ANCA+, and 65% had renal involvement. During 3385 person-years (PY) of follow-up, 130 patients died, yielding a mortality rate of 38.4/1000 PY and a SMR of 2.3 (95% CI: 1.9, 2.8). The most common causes of death were cardiovascular disease (CVD; cumulative incidence 7.1%), malignancy (5.9%) and infection (4.1%). The SMR for infection was greatest for both MPO- and PR3-ANCA+ patients (16.4 and 6.5). MPO-ANCA+ patients had an elevated SMR for CVD (3.0), respiratory disease (2.4) and renal disease (4.5). PR3- and MPO-ANCA+ patients had an elevated SMR for malignancy (3.7 and 2.7). Compared with PR3-ANCA+ patients, MPO-ANCA+ patients had a higher risk of CVD death [hazard ratio 5.0 (95% CI: 1.2, 21.2]; P = 0.03].. Premature ANCA-associated vasculitis mortality is explained by CVD, infection, malignancy, and renal death. CVD is the most common cause of death, but the largest excess mortality risk in PR3- and MPO-ANCA+ patients is associated with infection. MPO-ANCA+ patients are at higher risk of CVD death than PR3-ANCA+ patients.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Cardiovascular Diseases; Cause of Death; Female; Humans; Kidney Diseases; Male; Middle Aged; Mortality, Premature; Neoplasms; Peroxidase; Proportional Hazards Models; Retrospective Studies

Myeloperoxidase released after neutrophil and monocyte activation can generate reactive oxygen species, leading to host tissue damage. Extracellular glomerular myeloperoxidase deposition, seen in ANCA-associated vasculitis, may enhance crescentic GN through antigen-specific T and B cell activation. Myeloperoxidase-deficient animals have attenuated GN early on, but augmented T cell responses. We investigated the effect of myeloperoxidase inhibition, using the myeloperoxidase inhibitor AZM198, to understand its potential role in treating crescentic GN.. We evaluated renal biopsy samples from patients with various forms of crescentic GN for myeloperoxidase and neutrophils, measured serum myeloperoxidase concentration in patients with ANCA-associated vasculitis and controls, and assessed neutrophil extracellular trap formation, reactive oxygen species production, and neutrophil degranulation in ANCA-stimulated neutrophils in the absence and presence of AZM198. We also tested the effect of AZM198 on ANCA-stimulated neutrophil-mediated endothelial cell damage. All biopsy specimens with crescentic GN had extracellular glomerular myeloperoxidase deposition that correlated significantly with eGFR and crescent formation.. Myeloperoxidase inhibition reduced neutrophil degranulation and neutrophil-mediated endothelial cell damage in patients with ANCA-associated vasculitis. In preclinical crescentic GN, delayed myeloperoxidase inhibition suppressed kidney damage without augmenting adaptive immune responses, suggesting it might offer a novel adjunctive therapeutic approach in crescentic GN.

Topics: Adaptive Immunity; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Cell Degranulation; Endothelial Cells; Extracellular Traps; Glomerulonephritis; Humans; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neutrophil Activation; Peroxidase

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Humans; Peroxidase

Identification of risk factors for treatment resistance and relapse would be crucial to personalization therapy in patients with myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (MPO-AAV). Current evidence with regard to the risk factors for treatment resistance and relapse remains limited and inconclusive. We aimed to assess the predictors for treatment resistance and relapse in a single-center cohort of Chinese patients with MPO-AAV in this study. In total, 184 patients with MPO-AAV were included. Treatment resistance occurred in 64 (34.9%) of 184 patients and was positively associated with lung involvement (odds ratio [OR] 3.581, 95% CI 1.137-11.278, p = 0.029) and the initial serum creatinine level (OR 1.004, 95% CI 1.001-1.007, p = 0.010) and was negatively associated with platelet (OR 0.992, 95% CI 0.987-0.998, p = 0.007) and serum C3 levels (OR 0.998, 95% CI 0.996-0.999, p = 0.004). Relapse occurred in 29 (24.17%) of 120 patients in whom remission was achieved and was independently associated with lung involvement (hazard ratio [HR] 4.595, 95% CI 1.272-16.599, p = 0.020) and cardiovascular involvement (HR 3.689, 95% CI 1.237-11, p = 0.019,). The serum globulin was demonstrated to be negatively associated with relapse independently (HR 0.876; 95% CI 0.806-0.953; p = 0.002). This retrospective study of MPO-AAV patients in a single Chinese center suggests that treatment resistance was positively associated with lung involvement and the initial serum creatinine level and was negatively associated with platelet and serum C3 levels. Lung involvement and cardiovascular involvement were associated with an increased risk of relapse, while the higher serum globulin was demonstrated to be in association with a decreased risk of relapse.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Creatinine; Cyclophosphamide; Female; Humans; Kidney; Male; Middle Aged; Peroxidase; Prednisolone; Recurrence; Retrospective Studies; Risk Factors; Treatment Outcome

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic small vessel vasculitis characterized by circulating ANCAs targeting proteinase 3 (PR3) or myeloperoxidase (MPO) and associated with excess morbidity and mortality. Myeloperoxidase-ANCA-positive AAV and PR3-ANCA-positive AAV are increasingly recognized to have differences in genetic risk, pathogenesis, and response to treatment. Risk factors for AAV, including cigarette smoking, are poorly understood.. To examine the association between cigarette smoking and AAV.. This case-control study included a consecutive inception cohort of 484 patients with AAV diagnosed from 2002 to 2017 compared with a cohort of sex-, race-, and age-matched controls. Eleven cases were excluded owing to discordant smoking information in the electronic health record. Controls were randomly selected from participants recruited to the Partners HealthCare Biobank between its inception in 2010 and 2018 and who completed a smoking questionnaire and were not diagnosed with AAV (n = 30 536).. Smoking status (current, former, never) and pack-years of cigarette smoking were determined from review of the electronic medical record and smoking questionnaires.. Patients with AAV were individually matched with 3 randomly-selected controls based on sex, race, and age (within 2 years difference). Conditional logistic regression was performed to examine the association between cigarette smoking and AAV using odds ratios (OR) and 95% confidence intervals (CIs).. Overall, 473 cases were matched with 1419 controls (mean [SD] age, 59 [16] years; 281 women [59%], 396 white [84%]). Patients with AAV were more likely to be former (OR, 1.6; 95% CI, 1.3-2.0) or current smokers (OR, 2.7; 95% CI, 1.8-4.1); there was a dose-response relationship according to pack-years of exposure (P < .001). These associations were especially strong among participants with MPO-ANCA-positive disease (former smokers: OR, 1.7; 95% CI, 1.3-2.3; current smokers: OR, 3.5; 95% CI, 2.1-6.1) but not in participants with PR3-ANCA-positive AAV (former smokers: OR, 1.3; 95% CI, 0.9-2.0; current smokers: OR, 1.7; 95% CI, 0.8-3.5). After stratifying by selected demographics and disease manifestations, these associations remained strong.. Cigarette smoking was associated with AAV, especially MPO-ANCA-positive AAV. Further studies are needed to investigate a potential pathogenic mechanism.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoantibodies; Cigarette Smoking; Female; Follow-Up Studies; Humans; Male; Middle Aged; Peroxidase; Retrospective Studies; Risk Factors

Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is an autoimmune disease characterized by necrotizing small vessel vasculitis that can affect various organs and present multiple symptoms. Susceptibility to AAV is multifactorial and most likely caused by an amalgamation of genetic and environmental factors. The aim of the present study was to explore the distribution of human leukocyte antigen (HLA)-DRB1/DQB1, protein tyrosine phosphatase non-receptor type 22 (PTPN22) and cytotoxic T-Lymphocyte-associated protein 4 (CTLA-4) polymorphisms in North Indian AAV patients and their associations with clinical and pathological characteristics associated with the disease.. A total of 150 AAV patients and 150 healthy controls were recruited. The clinical classification showed 128 as granulomatosis with polyangiitis (GPA) and 21 as microscopic polyangiitis. Only 1 case of eosinophilic granulomatosis with polyangiitis was encountered, which was excluded from analysis. HLA-DRB1/DQB1 alleles were determined by polymerase chain reaction-sequence-specific primer (PCR-SSP) method and single nucleotide variant genotyping for CTLA-4 and PTPN22 was done by simple probe-based SNP arrays.. A significant predispositional association of DRB1*03 and DQB1*02 alleles, were confirmed in proteinase 3 (PR3)-AAV patients, whereas DRB1*10, DRB1*14 and DQB1*05 were protective alleles in AAV, PR3-AAV and GPA patients. GG genotype of CTLA-4 + 49A/G was increased in patients as compared to controls and showed an association with AAV, PR3-AAV and GPA patients.. The study indicated strong genetic associations were linked with PR3 antineutrophil cytoplasmic antibody specificity and it appears that PR3-AAV and MPO-AAV have distinct genetic backgrounds.

Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Case-Control Studies; CTLA-4 Antigen; Female; Genetic Association Studies; Genetic Predisposition to Disease; HLA-DQ beta-Chains; HLA-DRB1 Chains; Humans; India; Male; Middle Aged; Myeloblastin; Peroxidase; Phenotype; Polymorphism, Single Nucleotide; Protein Tyrosine Phosphatase, Non-Receptor Type 22

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Glomerulonephritis; Humans; Peroxidase; Rats; Syk Kinase

Neutrophil-to-lymphocyte ratio (NLR) has been recently reported to be a promising inflammatory marker to assess systemic inflammation in many disorders. However, there are only a few studies looking at NLR in patients with myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This study was thus undertaken to explore the relationship between NLR at diagnosis with inflammatory response and disease activity among MPO-AAV patients in a single Chinese center. Furthermore, we evaluated whether NLR could predict the renal prognosis and patient outcome. 188 patients with MPO-AAV were included in this study. Baseline NLR was positively correlated with CRP (r = 0.404, P < 0.001) and negatively with serum levels of C3 (r =  - 0.163, P = 0.035), but it had no obvious correlation with Birmingham Vasculitis Activity Score (BVAS). Patients with MPO-AAV having NLR ≥ 9.53 exhibited higher risk for all-cause mortality than those having NLR < 9.53 (P < 0.0001). However, no significant difference was found in the kidney survival between patients having NLR ≥ 9.53 and those NLR < 9.53 at diagnosis. In multivariate analysis, NLR was positively associated with all-cause mortality (P = 0.037, HR = 1.98, 95% CI 1.04-3.78). There was no association between NLR with ESRD observed using univariate analysis or multivariate analysis. This large retrospective study of MPO-AAV patients in a single Chinese center demonstrates that NLR positively correlates with CRP and negatively correlates with serum levels of C3 in Chinese patients with MPO-AAV. Importantly, higher NLR predicts increased mortality and is, therefore, a useful independent prognostic in MPO-AAV.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Complement C3; Female; Glomerular Filtration Rate; Humans; Kidney; Lymphocyte Count; Male; Middle Aged; Neutrophils; Peroxidase; Prognosis; Receptors, Immunologic; Retrospective Studies; Severity of Illness Index; Survival Analysis

an 80-year-old woman presented with rapidly progressive glomerulonephritis and was admitted to our hospital. Myeloperoxidase-specific antineutrophil cytoplasmic antibody (MPO-ANCA) was positive. We diagnosed ANCA-associated renal vasculitis (ANCA-RV). Treatment was initiated with intravenous methylprednisolone pulse therapy, followed by prednisolone (PSL) at 30 mg/day. We gradually reduced the PSL dose to 7.5 mg/day over 6 months. At that time, the patient developed disturbances of consciousness which progressed subacutely. MRI revealed regions of patchy white matter with an increased signal on T2-weighted, fluid attenuated inversion recovery (FLAIR) sequences and diffusion-weighted sequences. JC virus DNA was detected in the cerebrospinal fluid (CSF) by polymerase chain reaction (PCR), leading to a diagnosis of progressive multifocal leukoencephalopathy (PML). PML is a rare infectious demyelinating disease of the central nervous system caused by JC virus infection, occurring in highly immunosuppressed individuals such as HIV-infected patients and patients using some biological agents, and having a very poor prognosis. In the present case, PML may have been associated with steroid use, although there are very few case reports of PML in patients taking only steroids. We report progressive multifocal leukoencephalopathy during steroid treatment of ANCA-RV. When patients show progressive disturbance of consciousness during treatment for ANCA-RV, we need to take PML into consideration for differential diagnosis.

Topics: Administration, Intravenous; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Diagnosis, Differential; Fatal Outcome; Female; Glomerulonephritis; Humans; Immunocompromised Host; JC Virus; Leukoencephalopathy, Progressive Multifocal; Magnetic Resonance Imaging; Peroxidase; Severity of Illness Index; Steroids

Topics: alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiency; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Cohort Studies; Female; France; Genetic Testing; Humans; Male; Middle Aged; Myeloblastin; Peroxidase; Prevalence; Pulmonary Disease, Chronic Obstructive; Serologic Tests; Symptom Assessment

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Child; Corneal Ulcer; Humans; Peroxidase

Neutrophil gelatinase-associated lipocalin (NGAL) is a diagnostic marker of intrinsic kidney injury produced by damaged renal cells and by neutrophils. ANCA-associated vasculitis features necrotizing crescentic GN (NCGN), and ANCA-activated neutrophils contribute to NCGN. Whether NGAL plays a mechanistic role in ANCA-associated vasculitis is unknown.. Our findings support that bone marrow-derived, presumably neutrophil, NGAL protects from ANCA-induced NCGN by downregulating T

Topics: Adult; Aged; Aged, 80 and over; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; CD28 Antigens; CD3 Complex; CD4-Positive T-Lymphocytes; Cell Proliferation; Chimera; Disease Models, Animal; Female; Glomerulonephritis; Humans; Immunity, Cellular; Interleukin-17; Kidney; Lipocalin-2; Male; Mice; Middle Aged; Neutrophils; Peroxidase; Siderophores; Spleen; Th17 Cells

The cornerstone of the laboratory diagnostics of small vessel vasculitis is the detection of antineutrophil cytoplasmic antibodies (ANCA). The current international consensus recommendations suggest that proteinase 3 (PR3) and myeloperoxidase (MPO) ANCA immunoassays should be used as a first-line test if there is a justified suspicion of ANCA-associated vasculitis (AAV). A second method is only recommendable when the immunoassay shows a negative or borderline result. The precise identification of all patients with active AAV and avoidance of misdiagnoses due to false positive ANCA measurements is achieved when the ANCA determination is limited to defined clinical situations, which are indicative for AAV. There is increasing evidence that the specificity of ANCA to define homogeneous groups of patients could be better with respect to the prognosis than the clinical subtype.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Immunoassay; Myeloblastin; Peroxidase

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Female; Humans; Lupus Erythematosus, Systemic; Myeloblastin; Peroxidase

Sphingosine-1-phosphate (S1P) is a pleiotropic lysosphingolipid derived from the metabolism of plasma membrane lipids. The interaction between S1P and its ubiquitously expressed G-protein-coupled receptors (S1PR1-5) is crucial in many pathophysiological processes. Emerging evidence suggested a potential role for S1P receptors in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In the present study, we investigated the effects of three different S1P receptors modulators (FTY720, SEW2871 and TY52156) in a recognized rat model of experimental autoimmune vasculitis (EAV). The effects of treatments were evaluated with clinico-pathological parameters including hematuria, proteinuria, crescent formation, pulmonary hemorrhage, etc. In vitro functional studies were performed in a Jurkat T-cell line following stimulations of serum from myeloperoxidase-AAV patients. We found that only the FTY720 treatment significantly alleviated hematuria and proteinuria, and diminished glomerular crescent formation, renal tubulointerstitial lesions and pulmonary hemorrhage in EAV. The attenuation was accompanied by less renal T-cell infiltration, up-regulated mRNA of S1PR1 and down-regulated IL-1β in kidneys, but not altered circulating ANCA levels, suggesting that the therapeutic effects of FTY720 were B-cell independent. Further in vitro studies demonstrated that FTY720 incubation could significantly inhibit the proliferation, adhesion, and migration, and increase apoptosis of T cells. In conclusion, the S1P modulator FTY720 could attenuate EAV through the reduction and inhibition of T cells, which might become a novel treatment of ANCA-associated vasculitis.

Topics: Adolescent; Adult; Aged; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies; Apoptosis; Female; Fingolimod Hydrochloride; Hematuria; Humans; Jurkat Cells; Kidney; Lung; Male; Middle Aged; Models, Biological; Peroxidase; Proteinuria; Rats, Inbred WKY; Signal Transduction; Sphingosine-1-Phosphate Receptors; T-Lymphocytes

Glomerular cell death is a pathological feature of myeloperoxidase anti neutrophil cytoplasmic antibody associated vasculitis (MPO-AAV). Extracellular deoxyribonucleic acid (ecDNA) is released during different forms of cell death including apoptosis, necrosis, necroptosis, neutrophil extracellular traps (NETs) and pyroptosis. Measurement of this cell death is time consuming with several different biomarkers required to identify the different biochemical forms of cell death. Measurement of ecDNA is generally conducted in serum and urine as a surrogate for renal damage, not in the actual target organ where the pathological injury occurs. The current difficulty in investigating ecDNA in the kidney is the lack of methods for formalin fixed paraffin embedded tissue (FFPE) both experimentally and in archived human kidney biopsies. This protocol provides a summary of the steps required to stain for ecDNA in FFPE tissue (both human and murine), quench autofluorescence and measure the ecDNA in the resulting images using a machine learning tool from the publicly available open source ImageJ plugin trainable Weka segmentation. Trainable Weka segmentation is applied to ecDNA within the glomeruli where the program learns to classify ecDNA. This classifier is applied to subsequent acquired kidney images, reducing the need for manual annotations of each individual image. The adaptability of the trainable Weka segmentation is demonstrated further in kidney tissue from experimental murine anti-MPO glomerulonephritis (GN), to identify NETs and ecMPO, common pathological contributors to anti-MPO GN. This method provides objective analysis of ecDNA in kidney tissue that demonstrates clearly the efficacy in which the trainable Weka segmentation program can distinguish ecDNA between healthy normal kidney tissue and diseased kidney tissue. This protocol can easily be adapted to identify ecDNA, NETs and ecMPO in other organs.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Biopsy; DNA; Extracellular Space; Extracellular Traps; Glomerulonephritis; Humans; Image Processing, Computer-Assisted; Kidney Glomerulus; Male; Mice, Inbred C57BL; Models, Biological; Peroxidase; Supervised Machine Learning

A number of disease processes can culminate in rapidly progressive glomerulonephritis, including pauci-immune focal segmental necrotising glomerulonephritis, usually seen with positive serum antineutrophil cytoplasmic antibodies (ANCA). Propylthiouracil (PTU) has been associated with drug-induced ANCA-associated vasculitis (AAV), with antibodies against myeloperoxidase (MPO) and proteinase 3 (PR3) present individually and together having been recognised. 'Double-positive' vasculitis with ANCA and anti-glomerular basement membrane (GBM) antibodies has also been reported in association with PTU treatment. We present a case of PTU-induced anti-MPO and PR3 positive ANCA vasculitis with associated anti-GBM antibodies, IgA nephropathy and an IgG4 interstitial infiltrate.. A 51-year-old man presented 2 weeks after re-commencing propylthiouracil (PTU) treatment for Graves' disease, with a severe acute kidney injury and haemato-proteinuria. He demonstrated positive titres for autoantibodies to PR3 (76.9 IU/mL), MPO (28.8 IU/mL) and GBM (94 IU/mL). Renal biopsy demonstrated numerous glomerular crescents, widespread IgG4-positive lymphoplasmacytic infiltrate and mesangial positivity for IgA. PTU was stopped and he was treated with steroids, plasma exchange and cyclophosphamide with sustained improvement in his renal function.. This case of drug-induced AAV presented a unique and intriguing collection of serological and histological features. We propose that the PTU-induced AAV resulted in epiphenomena of anti-GBM antibody production and an IgG4-cell-rich tubulointerstitial infiltrate. It is uncertain whether the mesangial IgA deposition preceded or resulted from the AAV.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Glomerulonephritis, IGA; Humans; Immunoglobulin G; Male; Middle Aged; Myeloblastin; Peroxidase; Propylthiouracil

To investigate presence of circulating myeloperoxidase-positive microparticles (MPO

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Cell-Derived Microparticles; Cross-Sectional Studies; Disease Susceptibility; Female; Flow Cytometry; Humans; Male; Peroxidase; Severity of Illness Index

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Diagnostic Imaging; Humans; Immunosuppressive Agents; Myeloblastin; Peroxidase; Prognosis; Risk Factors

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Calibration; Data Interpretation, Statistical; Diagnosis, Differential; Humans; Immunoassay; Likelihood Functions; Myeloblastin; Peroxidase; Reference Standards; Sensitivity and Specificity

It is not elucidated that there is treatment-related damage in elderly patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).. Elderly (≥ 75 years of age) patients were enrolled from two nationwide prospective inception cohort studies. The primary outcome was 12-month treatment-related Vasculitis Damage Index (VDI) score. Secondary outcomes included serious infections within 6 months, total VDI score, remission, and relapse. Patient characteristics and outcomes were compared across three different initial glucocorticoid (GC) dose groups: high-dose, prednisolone (PSL) ≥ 0.8 mg/kg/day; medium-dose, 0.6 ≤ PSL < 0.8 mg/kg/day; and low-dose, PSL < 0.6 mg/kg/day.. Of the 179 eligible patients, the mean age was 80.0 years; 111 (62%) were female. The mean Birmingham Vasculitis Activity Score was 16.1. Myeloperoxidase-ANCA findings were positive in 168 (94%) patients, while proteinase 3-ANCA findings were positive in 11 (6%). The low-dose group was older and had higher serum creatinine levels than the other groups. There were no statistically significant intergroup differences in remission or relapse, whereas serious infection developed more frequently in the high-dose (29 patients [43%]) than the low-dose (13 patients [22%]) or medium-dose (10 patients [19%]) groups (p = 0.0007). Frequent VDI items at 12 months included hypertension (19%), diabetes (13%), atrophy and weakness (13%), osteoporosis (8%), and cataracts (8%). Logistic regression analysis revealed that GC dose at 12 months (odds ratio, 1.14; 95% confidence interval, 1.00-1.35) was a predictor for diabetes.. A reduced initial GC dose with rapid reduction might be required to ensure the safe treatment of elderly AAV patients.

Topics: Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Humans; Male; Myeloblastin; Peroxidase; Prospective Studies

Interstitial lung disease (ILD) is a severe complication with poor prognosis in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Prevalence of AAV-associated ILD (AAV-ILD) in Japan is considerably higher than that in Europe. Recently, we reported that a MUC5B variant rs35705950, the strongest susceptibility variant to idiopathic pulmonary fibrosis (IPF), was strikingly increased in AAV-ILD patients but not in AAV patients without ILD; however, due to the low allele frequency in the Japanese population, the MUC5B variant alone cannot account for the high prevalence of AAV-ILD in Japan. In this study, we examined whether other IPF susceptibility alleles in TERT and DSP genes are associated with susceptibility to AAV subsets and AAV-ILD.. Five hundred and forty-four Japanese patients with AAV and 5558 controls were analyzed. Among the AAV patients, 432 were positive for myeloperoxidase (MPO)-ANCA (MPO-AAV). A total of 176 MPO-AAV patients were positive and 216 were negative for ILD based on CT or high-resolution CT. Genotypes of TERT and DSP variants were determined by TaqMan SNP Genotyping Assay, and their association was tested by chi-square test.. When the frequencies of the IPF risk alleles TERT rs2736100A and DSP rs2076295G were compared between AAV subsets and healthy controls, both alleles were significantly increased in microscopic polyangiitis (MPA) (TERT P = 2.3 × 10. Unexpectedly, TERT and DSP IPF risk alleles were found to be associated with MPA and MPO-AAV, regardless of the presence of ILD. These findings suggest that TERT and DSP may be novel susceptibility genes to MPA/MPO-AAV and also that some susceptibility genes may be shared between IPF and MPA/MPO-AAV.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Europe; Genetic Association Studies; Humans; Japan; Microscopic Polyangiitis; Peroxidase; Telomerase

Topics: Acute Coronary Syndrome; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Peroxidase; Treatment Outcome

Vasculitis can also present with GI or solid organ involvement. IgA and ANCA associated vasculitis are more likely to have GI involvement. A 56-year-old female was admitted to the ER due to nausea, vomiting, epigastric pain and fever. The patient had a medical history of acromegaly and chronic kidney disease of an undetermined etiology, elevated C-reactive protein and renal dysfunction. Abdominal-CT revealed duodenal parietal thickening and pancreatic head edema. On esophagogastroduodenoscopy (EGD), duodenal mucosa had a diffusely nodular aspect with ulcerated areas. The following differential diagnosis were made, infectious enteritis, Whipple disease, infiltrative disorder and GI vasculitis. After discussion between a multidisciplinary team of Gastroenterology and Nephrology, they decided to initiate oral glucocorticoids due to worsening of the renal function, which lead to the resolution of digestive symptoms and renal function stabilization. Myeloperoxidase antineutrophilic-cytoplasmic antibodies (MPO-ANCA) were subsequently positive and histology confirmed duodenal involvement by vasculitis. The patient was asymptomatic after 4-weeks, with endoscopic healing and renal function stabilization. GI involvement limited to the duodenum in the setting of ANCA-MPO vasculitis is a rare condition. Moreover, histopathologic confirmation of vasculitis in endoscopic biopsy samples is exceptional.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Gastrointestinal Tract; Humans; Middle Aged; Peroxidase; Renal Insufficiency, Chronic

BACKGROUND Drug-induced anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) should be suspected in patients on certain medications who present with inflammatory ocular, constitutional, pulmonary, and/or renal manifestations. Here, we present a case of propylthiouracil (PTU)-induced AAV presenting initially with red eye, and review important diagnostic and management considerations for this uncommon disorder. CASE REPORT A 34-year-old woman with hyperthyroidism taking PTU presented with red eye, later followed by fevers and hemoptysis. She was found to have episcleritis, diffuse alveolar hemorrhage, and microhematuria. The infectious diseases workup was unrevealing. Laboratory evaluations were notable for a high-titer perinuclear ANCA and elevated anti-myeloperoxidase antibodies. Renal function was normal. She was ultimately diagnosed with PTU-induced AAV. PTU was promptly discontinued and she was treated with pulse-dose methylprednisolone for 3 days, followed by prednisone 60 mg daily. A kidney biopsy revealed pauci-immune focal segmental necrotizing and crescentic glomerulonephritis. Given an allergy to methimazole, she underwent thyroidectomy and was ultimately treated with rituximab. Her steroid doses are progressively being tapered and she has complete resolution of symptoms. CONCLUSIONS PTU-induced AAV is a rare and serious condition. Our patient presented with ocular symptoms prior to more commonly recognized pulmonary and renal manifestations. Patients may have favorable outcomes if PTU is discontinued promptly, but patients with vital-organ involvement may require treatment with steroids and may need additional immunosuppression.

Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Female; Humans; Peroxidase; Propylthiouracil

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: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Humans; Inflammation; Peroxidase

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

Antineutrophil cytoplasm antibody-associated vasculitides encompass a diverse spectrum of autoimmune diseases characterized by necrotizing small vessel vasculitis. Ocular manifestations may be the presenting findings of antineutrophil cytoplasm antibody-associated vasculitides.. Single, retrospective case study.. We report the rare case of a 55-year-old woman with a cilioretinal artery occlusion as the presenting feature of perinuclear antineutrophil cytoplasm antibody-associated microscopic polyangiitis.. Although rare, antineutrophil cytoplasm antibody-related vasculitis should be considered in any retinal vascular occlusion, particularly in the setting of patients with new vague headaches and a paucity of vasculopathic risk factors.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Arterial Occlusive Diseases; Blood Sedimentation; C-Reactive Protein; Ciliary Arteries; Female; Fluorescein Angiography; Humans; Middle Aged; Peroxidase; Retinal Artery; Retrospective Studies

To investigate expression of terminal complement components C3a and C5a on circulating myeloperoxidase (MPO)-positive microparticles (MPO+MP) in relation to disease activity and renal involvement in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).. Forty-six clinically well-characterized patients with AAV and 23 age- and sex-matched healthy controls were included. The concentration of MPO+MP expressing C3a and C5a was analyzed from citrate plasma by flow cytometry. Serum levels of C3a and C5a were determined using commercial ELISA. The assessment of vasculitis disease activity was performed using the Birmingham Vasculitis Activity Score (BVAS). Among patients, 23 had active disease with BVAS ≥ 2 and 14 patients had active renal flares.. AAV patients had significantly increased expression of C3a and C5a on MPO+MP compared to controls (both p < 0.0001). When the group of patients with active AAV was divided according to the presence of renal activity, the concentration of MPO+MP expressing C3a and C5a was significantly higher in patients with renal involvement compared to patients with nonrenal disease and controls (p < 0.05 and p < 0.01, respectively). The serum levels of C3a were significantly decreased (p < 0.01) in the renal subgroup, while there were no changes in serum levels of C5a comparing the renal and nonrenal groups. There was significant correlation between the disease activity measured by BVAS and the levels of C3a and C5a expressed on MPO+MP.. Determination of C3a and C5a on MPO+MP might be considered as a novel biomarker of renal involvement in patients with AAV and may be of importance in the pathogenetic process.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Complement C3a; Humans; Kidney Diseases; 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

A genome-wide association study (GWAS) indicated that myeloperoxidase-ANCA associated vasculitis (AAV) is associated with HLA-DQ. However, susceptibility alleles in these loci have been under-investigated. Here we genotyped 258 Chinese patients with myeloperoxidase-AAV and 597 healthy control individuals at HLA DRB1, DQA1, DQB1 and DPB1, and extracted the encoded amino acid sequences from the IMGT/HLA database. The replication cohort included 97 cases and 107 controls. T cell epitopes of myeloperoxidase were predicted and docked to the HLA molecules. We found DQA1∗0302 (odds ratio 2.34 (95% confidence interval 1.75-3.14)) and DQB1∗0303 (odds ratio 1.89 (1.45-2.48)) were risk alleles for myeloperoxidase-AAV. They are in overt linkage disequilibrium (r

Topics: Adult; Aged; Alleles; Amino Acids; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Case-Control Studies; Epitopes, T-Lymphocyte; Female; Genome-Wide Association Study; HLA-DQ alpha-Chains; HLA-DQ beta-Chains; Humans; Linkage Disequilibrium; Male; Middle Aged; Peroxidase

Pulse methylprednisolone (MP) was routinely used before commencing standard immunosuppressive therapy for induction of remission in patients with dialysis-dependent anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in spite of the paucity of evidence of benefit. The aim of this study was thus to determine whether the addition of pulse MP to standard induction immunosuppressive therapy in severe myeloperoxidase (MPO) -AAV patients who were on dialysis at onset is associated with an improvement in kidney recovery and patient survival. Furthermore, we analyzed the factors associated with restoration of kidney function and mortality in a single Chinese cohort.. 69 MPO-AAV patients who were on dialysis at the time of diagnosis were included in this study. The MP group (n = 30) received pulse MP (5-10 mg/kg/day) for 3 days before the standard immunosuppressive therapy. The Non-MP group (n = 39) had no MP pulses. The outcomes and adverse events between the two groups were compared. In addition, the predictive value of the clinical and histological parameters for kidney and patient survival was assessed using univariate and multivariate logistic regression analysis.. There was no difference in patient survival, kidney recovery and the rates of adverse events between the two groups. A higher Birmingham Vasculitis Activity Score (BVAS) was shown to be a negative prognostic factor for kidney function restoration (p = 0.046, OR 0.811, 95% CI 0.660-0.997). BVAS was also demonstrated to be an independent predictor for both all-cause death (p = 0.007, OR 1.324, 95% CI 1.079-1.624) and therapy-related death (p = 0.003, OR 1.574, 95% CI 1.171-2.115). Patients' eGFR at the presentation of the disease was shown to be an independent predictor for therapy-related death (p = 0.027, OR 2.535, 95% CI 1.112-5.779).. This retrospective study of MPO-AAV patients who required dialysis at presentation in a single Chinese center suggests that the addition of pulse MP to standard immunosuppressive induction therapy for remission appears to confer no benefit in terms of improving patient outcomes. Further research is required to determine the role of pulse MP in severe MPO-AAV.

Topics: Adult; Aged; Anti-Inflammatory Agents; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Asian People; Female; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kidney; Male; Methylprednisolone; Middle Aged; Peroxidase; Renal Dialysis; Treatment Outcome

Anti-neutrophil cytoplasmic antibody (ANCA) may target proteinase 3 (PR3) or myeloperoxidase (MPO). Although a few patients with vasculitis have both MPO- and PR3-ANCA, the details of their clinical characteristics are not known. The objective of this study was to analyze the characteristics of patients with dual MPO- and PR3-ANCA-positive vasculitis. The medical records of patients with ANCA and vasculitis confirmed by biopsy were reviewed. The age at diagnosis, sex, and data on organ involvement of the kidney, lung, upper airways, skin, nervous system, and gastrointestinal tract were collected. Clinical variables were analyzed according to ANCA specificity. Of 85 patients with ANCA and vasculitis included in this study, 67 (78.8%) had MPO-ANCA, 10 (11.8%) had PR3-ANCA, and 8 (9.4%) had both MPO- and PR3-ANCA. Patients with MPO- PR3 + ANCA-associated vasculitis (AAV) were younger at diagnosis (median, 54.4 years; p < 0.05) than patients with MPO + PR3- AAV (67.0 years) or dual-ANCA AAV (MPO + PR3 + , 68.5 years). The initial glomerular filtration rate in patients with MPO + PR3- AAV (22.0 ml/min) was significantly lower than that in patients with MPO- PR3 + AAV (108.6 ml/min, p < 0.05), but was not different from that in dual-ANCA AAV patients (16.5 ml/min). Upper airway involvement also differed with ANCA type (MPO+ PR3- , 35.8% vs. MPO- PR3 + , 70.0% vs. MPO + PR3+ , 75.0%, p < 0.05). The involvement of other organs did not differ according to ANCA type. Age at diagnosis, kidney involvement, and upper airway involvement were associated with ANCA type. Patients with dual-ANCA-positive vasculitis had considerably more kidney dysfunction than patients with MPO- PR3+ AAV. They also had more upper airway involvement than patients with MPO+ PR3- AAV.

Topics: Adult; Age of Onset; Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Female; Glomerular Filtration Rate; Humans; Kidney; Lung; Male; Middle Aged; Myeloblastin; Peroxidase; Retrospective Studies; Young Adult

The characteristics and the pathogenesis of the concomitant antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) and immunoglobulin G4-related disease (IgG4-RD) have not been elucidated.. We included 92 AAV patients with renal biopsy results. Among them, 10 patients met both AAV and IgG4-RD criteria (concomitant group). The IgG subclasses of myeloperoxidase (MPO)-ANCA in both serum and renal tissue were measured and complement activation components were detected in serum.. Patients in the concomitant group had both elevated serum IgG4 levels and positive MPO-ANCA. They had higher levels of eosinophil counts, serum globulin, IgG, IgE and C-reactive protein than patients in the AAV alone group. All 10 patients had glomerulonephritis with crescents and seven patients also had segmental necrosis of the glomerular capillary wall. Most of them also presented with storiform fibrosis and lymphoplasmacytic infiltration in renal interstitium with IgG4 positive plasma cells more than 10/high-power field. Eight patients achieved remission with improved renal function, the other two patients were on maintenance dialysis. The IgG4 subclass of MPO-ANCA was higher in the concomitant group than that in AAV alone group. A merge of IgG4 and MPO immunofluorescence was observed in parts of the mesangium of concomitant AAV and IgG4-RD patients. For complement components, Bb and mannose-binding lectin were elevated in serum of concomitant AAV and IgG4-RD patients.. We showed a new overlap syndrome of AAV and IgG4-RD, in which the IgG4 subclass of ANCA may be a pathogenic factor.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; C-Reactive Protein; Case-Control Studies; Complement Activation; Complement System Proteins; Female; Humans; Immunoglobulin E; Immunoglobulin G; Immunoglobulin G4-Related Disease; Kidney; Kidney Diseases; Male; Middle Aged; Peroxidase; Prognosis

Myeloperoxidase anti-neutrophil cytoplasmic antibody-related nephritis (MPO-ANCA nephritis) is occasionally accompanied by lung abnormalities such as pulmonary fibrosis. However, the clinical features of pulmonary fibrosis in patients with MPO-ANCA nephritis have not been well documented. This study was performed to compare the prognosis of a usual interstitial pneumonia (UIP) pattern of lung fibrosis in patients with MPO-ANCA nephritis with the prognosis of idiopathic pulmonary fibrosis (IPF).. We retrospectively reviewed the medical records of 126 patients with MPO-ANCA nephritis and identified 31 with a UIP pattern of lung fibrosis on high-resolution or thin-slice computed tomography (CT). We compared the characteristics and prognosis of these patients with those of 32 patients with IPF. In 18 patients from both groups, we assessed and compared the decline in lung volume over time using three-dimensional (3D) CT images reconstructed from thin-section CT data.. The numbers of male and female patients were nearly equal among patients with MPO-ANCA nephritis exhibiting a UIP pattern; in contrast, significant male dominancy was observed among patients with IPF (p = 0.0021). Significantly fewer smokers were present among the patients with MPO-ANCA nephritis with a UIP pattern than among those with IPF (p = 0.0062). There was no significant difference in the median survival time between patients with MPO-ANCA nephritis with a UIP pattern (50.8 months) and IPF (55.8 months; p = 0.65). All patients with IPF in this cohort received antifibrotic therapy (pirfenidone or nintedanib). Almost half of the deaths that occurred in patients with MPO-ANCA nephritis with a UIP pattern were caused by non-respiratory-related events, whereas most deaths in patients with IPF were caused by respiratory failure such as acute exacerbation. In the 3D CT lung volume analyses, the rate of decline in lung volume was equivalent in both groups.. MPO-ANCA nephritis with a UIP pattern on CT may have an unfavorable prognosis equivalent to that of IPF with a UIP pattern treated with antifibrotic agents.

Topics: Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Cause of Death; Female; Humans; Idiopathic Pulmonary Fibrosis; Imaging, Three-Dimensional; Lung; Male; Middle Aged; Nephritis; Peroxidase; Prognosis; Pulmonary Fibrosis; Respiratory Insufficiency; Retrospective Studies; Survival Rate; Tomography, X-Ray Computed

Low Density Granulocytes (LDGs), which appear in the peripheral blood mononuclear cell layer of density-separated blood, are seen in cancer, sepsis, autoimmunity, and pregnancy. Their significance in ANCA vasculitis (AAV) is little understood. As these cells bear the autoantigens associated with this condition and have been found to undergo spontaneous NETosis in other diseases, we hypothesized that they were key drivers of vascular inflammation. We found that LDGs comprise a 3-fold higher fraction of total granulocytes in active vs. remission AAV and disease controls. They are heterogeneous, split between cells displaying mature (75%), and immature (25%) phenotypes. Surprisingly, LDGs (unlike normal density granulocytes) are hyporesponsive to anti-myeloperoxidase antibody stimulation, despite expressing myeloperoxidase on their surface. They are characterized by reduced CD16, CD88, and CD10 expression, higher LOX-1 expression and immature nuclear morphology. Reduced CD16 expression is like that observed in the LDG population in umbilical cord blood and in granulocytes of humanized mice treated with G-CSF. LDGs in AAV are thus a mixed population of mature and immature neutrophils. Their poor response to anti-MPO stimulation suggests that, rather than being a primary driver of AAV pathogenesis, LDGs display characteristics consistent with generic emergency granulopoiesis responders in the context of acute inflammation.

Topics: Adult; Aged; Aged, 80 and over; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antigens, Surface; Autoantibodies; Cell Count; Female; Flow Cytometry; GPI-Linked Proteins; Granulocytes; Humans; Male; Mice; Middle Aged; Myelopoiesis; Peroxidase; Phenotype; Receptors, IgG

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies; Antibodies, Antineutrophil Cytoplasmic; Epitopes; Flow Cytometry; Humans; Immunization; Neutrophils; Peroxidase; Rats, Inbred WKY; Recombinant Proteins

In anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, antigen specificity varies between myeloperoxidase (MPO) and proteinase 3 (PR3). This has been reported to vary in relation to age, gender, geography and extrarenal manifestations. However, studies are difficult to compare as criteria for inclusion vary. The aim of this study was to investigate the relationship between ANCA serotype, latitude, ultraviolet (UV) radiation levels, age, gender and renal function at diagnosis in a large study with uniform inclusion criteria.. Patients with biopsy-proven ANCA-associated glomerulonephritis were identified from regional or nationwide registries in 14 centres in Norway, Sweden, the UK, the Czech Republic, Croatia, Italy and the USA during the period 2000-13. UV radiation levels for 2000-13 in Europe were obtained from the Swedish Meteorological and Hydrological Institute.. A total of 1408 patients (45.2% PR3-ANCA) were included in the study. In univariable analysis, PR3-ANCA was significantly associated with male gender {odds ratio [OR] 2.12 [95% confidence interval (CI) 1.71-2.62]}, younger age [OR per year 0.97 (95% CI 0.96-0.98)] and higher glomerular filtration rate [OR per mL/min 1.01 (95% CI 1.01-1.02); P < 0.001] at diagnosis but not with latitude or UV radiation. In multivariable logistic regression analysis, latitude and UV radiation also became significant, with higher odds for PR3-ANCA positivity at northern latitudes/lower UV radiation levels. However, the latitudinal difference in MPO:PR3 ratio is smaller than differences previously reported concerning microscopic polyangiitis and granulomatosis with polyangiitis.. The ratio between PR3-ANCA and MPO-ANCA varies in glomerulonephritis with respect to age, gender, renal function and geographic latitude/UV radiation levels.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antibody Specificity; Biopsy; Czech Republic; Demography; Female; Geography; Glomerulonephritis; Humans; Italy; Male; Middle Aged; Myeloblastin; Norway; Peroxidase; Registries; Serogroup; Sweden; United Kingdom; United States

To investigate treatment outcomes, hearing outcomes, and adverse effects of rituximab (RTX) for intractable otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV).. Twenty-three patients who met the criteria proposed by the OMAAV study group were included. RTX was used for patients who had difficulty achieving induction of remission using glucocorticoids (GC) and intravenous cyclophosphamide (IVCY).. Six patients were treated with RTX (RTX group), while 17 patients did not require RTX for induction of remission (non-RTX group). All six patients in the RTX group achieved remission. Age, sex, and months from onset to diagnosis did not differ significantly between the groups. The air-conduction hearing thresholds at diagnosis and remission were 71.7±6.3dB and 50.1±5.1dB in the RTX group, and 56.8±4.8dB and 35.8±4.8dB in the non-RTX group, respectively. Hearing level at remission was significantly better in the non-RTX group (p<0.05), while hearing gain did not differ significantly between the groups. Infectious complications were similar between the groups.. Our findings suggest that RTX is effective and safe for intractable OMAAV patients who have a poor response to GC and IVCY.

Topics: Adult; Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Hearing; Humans; Immunologic Factors; Male; Middle Aged; Myeloblastin; Otitis Media; Peroxidase; Rituximab; Treatment Outcome

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

True population-based clinical and outcomes data are lacking for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis (AAGN). Therefore we aimed to estimate the incidence, prevalence and mortality of AAGN, as well as the relationship between the grade of chronic renal damage at presentation and renal and non-renal outcomes.. Patients with AAGN were identified among a population-based incident cohort of 57 Olmsted County residents diagnosed with ANCA-associated vasculitis (AAV) in 1996-2015. Incidence rates were age and sex adjusted to the 2010 US white population. Age- and sex-adjusted prevalence was calculated for 1 January 2015. Survival rates were compared with expected rates in the Minnesota population. Chronic renal damage was assessed by chronicity score (CS) on biopsies performed at diagnosis.. Thirty-four (60%) patients had AAGN. Of these, 65% had microscopic polyangiitis (MPA) and 74% were myeloperoxidase (MPO)-ANCA positive. The annual incidence of AAGN was 2.0/100 000 population [95% confidence interval (CI) 1.3-2.7] and the overall prevalence was 35/100 000 (95% CI 24-47). Mortality for AAGN was increased (P < 0.001), whereas mortality for AAV without glomerulonephritis did not differ from the general population. Minimal to mild CS predicted recovery of renal function at 1 year; clinical diagnosis (granulomatosis with polyangiitis versus MPA) and ANCA specificity (proteinase 3 versus MPO) did not. This observation was replicated in an independent cohort of 38 newly diagnosed AAGN patients seen at our centre over the 1999-2014 period.. The annual incidence and prevalence of AAGN in Minnesota are 2.0/100 000 and 35/100 000, respectively. Mortality is worse compared with AAV patients without glomerulonephritis. More advanced renal damage at diagnosis predicts less renal recovery.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Cohort Studies; Female; Glomerulonephritis; Humans; Incidence; Male; Middle Aged; Minnesota; Myeloblastin; Peroxidase; Prevalence; Prognosis; Survival Rate

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Mice; Myeloblastin; Neutrophil Activation; Neutrophils; Peroxidase

This prospective study aimed to evaluate the diagnostic and clinical utility of the myeloperoxidase (MPO)-DNA complex as a NETosis-derived product in the middle ear fluid of patients with otitis media with antineutrophil cytoplasmic antibody-associated vasculitis (OMAAV).. Prospective study.. Tertiary referral center.. Twenty-two patients diagnosed with OMAAV.. Collection of the fluid samples from middle ear.. The levels of the MPO-DNA complex in the fluid samples were quantified using an enzyme-linked immunosorbent assay.. Patients with both systemic and localized forms of OMAAV showed significantly higher levels of the MPO-DNA complex compared to the controls (p < 0.001 and p = 0.002, respectively). In particular, they showed significantly higher levels of MPO-DNA complex compared to the controls, regardless of serum antineutrophil cytoplasmic antibody status (p < 0.001 and p < 0.001, respectively) or immunosuppressive therapy (p < 0.001 and p < 0.001, respectively) at the time of sampling. An optical density cutoff value of 0.16 at 405 nm according to the receiver operating characteristic curve showed a sensitivity of 86.4%, specificity of 95.5%, positive predictive value of 95.0% and negative predictive value of 87.5% for the diagnosis of OMAAV. Significant positive correlations were observed between the levels of MPO-DNA complex and the values for air conduction - (r = 0.49, p = 0.022) and bone conduction - pure tone average thresholds (r = 0.45, p = 0.035).. The detection and quantification of the MPO-DNA complex in the otitis media fluid may aid in providing a definite diagnosis as well as predicting the activity and severity of OMAAV.

Topics: Adult; Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Biomarkers; Body Fluids; DNA; Enzyme-Linked Immunosorbent Assay; Extracellular Traps; Female; Humans; Male; Middle Aged; Otitis Media; Peroxidase; Prospective Studies

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are very rare in childhood with an increased risk of morbidity and mortality. We aimed to evaluate renal prognostic factors in childhood AAV from the perspective of ANCA serotype, histopathological classification, and five-factor score (FFS).. Pediatric AAV patients from 11 referral centers in Turkey had been included to the study. The demographics, clinical findings, AAV subtypes, outcomes, and FFS were evaluated retrospectively. Kidney biopsies were classified histopathologically.. Totally, 39 patients were enrolled in the study. Among all patients, 74.4% had renal involvement, 56.4% ear-throat-nose involvement, and 51.3% had musculoskeletal involvement. Proteinase 3 (PR3)-ANCA was positive in 48.7%, and myeloperoxidase (MPO)-ANCA was positive in 30.8%. 69.2% of patients had impaired renal function, and 28.2% had progressed to end-stage renal disease (ESRD) during the follow-up. At the time of diagnosis, FFS was ≥ 2 in 53.8%. The most common histopathologic classifications were as follows: crescentic type in 40.7% and sclerotic type in 25.9%. Gastrointestinal and renal involvement, MPO-ANCA positivity, serum creatinine levels, and impaired renal function during the follow-up were significantly higher in patients with FFS ≥ 2, compared to patients with FFS < 2. Patients with FFS ≥ 2 had more common crescentic, mixed and sclerotic histopathologic findings in biopsies. By logistic regression analysis forward method, the strongest single-risk factor among all the parameters was the initial level of creatinine in patients with ESRD, compared to the other patients (p = 0,007).. Evaluation of the FFS, ANCA serology, and the creatinine levels may help to predict renal prognosis.

Topics: Adolescent; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biopsy; Child; Creatinine; Disease Progression; Female; Follow-Up Studies; Glomerulonephritis; Humans; Kidney Failure, Chronic; Kidney Glomerulus; Male; Myeloblastin; Peroxidase; Prognosis; Retrospective Studies; Risk Factors; Turkey; Young Adult

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Female; Headache; Humans; Intracranial Thrombosis; Magnetic Resonance Imaging; Meningitis; Middle Aged; Peroxidase; Prednisolone; Treatment Outcome

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Immunosuppressive Agents; Myeloblastin; Peroxidase

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Immunosuppressive Agents; Myeloblastin; Peroxidase

Anti-neutrophil cytoplasmic antibodies (ANCA) have a role in the diagnostic workup of ANCA-associated vasculitis. However, the clinical significance of positive ANCA in the absence of vasculitis is yet to be determined. Therefore, we sought to investigate the clinical spectrum and rate of patients with a positive ANCA without evidence of vasculitis.. Retrospective analysis of patients positive for cytoplasmic ANCA (C-ANCA) and proteinase 3 (PR3) or P-ANCA and myeloperoxidase (MPO) between 2007 and 2016 in the Chaim Sheba Medical Center, Israel. The proportion of patients who had no evidence of vasculitis among all patients with a positive C-ANCA/PR3 or P-ANCA/MPO was calculated according to tertiles of enzyme-linked immunosorbent assay (ELISA) antibody levels.. Among 113 patients who tested positive for C-ANCA/PR3 or P-ANCA/MPO, 68 (60.1%) had no evidence of vasculitis. ELISA antibody titers were significantly higher among patients with vasculitis than those without (6.2 vs 3.2, for C-ANCA/PR3 and 5.4 vs 2.6 for P-ANCA/MPO, P < 0.05). The proportion of patients without vasculitis among all patients with a positive C-ANCA/PR3 and among all patients with a positive P-ANCA/MPO declined in parallel to the increases in ELISA antibody level tertiles (96%, 57% and 22% in the 1st, 2nd and highest tertiles, respectively, for patients with C-ANCA/PR3 patients and 100%, 66% and 20% in the 1st, 2nd and highest tertiles, respectively, for patients with P-ANCA/MPO).. A significant proportion of patients with a positive C-ANCA/PR3 or P-ANCA/MPO do not have evidence of vasculitis, particularly those with low-medium ELISA antibody titers. Using a higher threshold of ANCA titers may be required to improve specificity.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Enzyme-Linked Immunosorbent Assay; Female; Humans; Israel; Male; Middle Aged; Myeloblastin; Peroxidase; Predictive Value of Tests; Reproducibility of Results; Retrospective Studies

To retrospectively investigate the clinical and histological features and outcomes of ANCA-associated glomerulonephritis (AAGN) with different ANCA serotypes.. A total of 467 AAGN patients were divided into MPO-AAGN (MPO) and PR3-AAGN (PR3) groups according to ANCA serotype. Clinical and histological features and renal outcomes were compared.. In this study, 429 (91.9%) patients tested positive for MPO-ANCA, and 38 (8.1%) for PR3-ANCA. The median age at diagnosis (P = 0.017) and proportion of females (P = 0.003) were higher in the MPO group. Joint (P < 0.001), ENT (P = 0.000), skin (P = 0.007), and eye (P = 0.014) involvements were more common in the PR3 group. Compared with that in the PR3-group, a higher proportion of patients in the MPO group had microscopic polyangiitis (P = 0.000), and a lower proportion of exhibited granulomatosis with polyangiitis (P = 0.000). Patients in the MPO group also exhibited lower BVAS scores (P = 0.003) and higher serum albumin levels (P = 0.009). Histologically, a lower proportion of MPO patients had crescentic glomerulonephritis (P = 0.028) and acute tubule-interstitial lesion scores (P = 0.007), but a higher proportion of these patients exhibited mixed class glomerulonephritis (P = 0.032) than in the PR3 group. The relapse rate was lower (P = 0.020), and the 5-year relapse-free survival rate (P = 0.003) was higher in the MPO group than in the PR3 group. However, the 5-year renal survival rates (P = 0.106) were not significantly different.. MPO-ANCA was predominant in Chinese patients with ANCA-associated vasculitis and renal disease. The epidemiological characteristics, extra-renal involvement, and histopathological classes and outcomes were different between MPO-positive and PR3-positive patients, implying that they might be two different disease entities.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Fluorescent Antibody Technique, Indirect; Glomerulonephritis; Humans; Kidney; Male; Middle Aged; Myeloblastin; Peroxidase; Recurrence; 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

Anti-neutrophil cytoplasmic autoantibodies (ANCA) directed against myeloperoxidase (MPO) and proteinase 3 (PR3) are pathogenic in ANCA-associated vasculitis (AAV). The respective role of IgG Fc and Fab glycosylation in mediating ANCA pathogenicity is incompletely understood. Herein we investigate in detail the changes in Fc and Fab glycosylation in MPO-ANCA and Pr3-ANCA and examine the association of glycosylation aberrancies with disease activity.. Total IgG was isolated from serum or plasma of a cohort of 30 patients with AAV (14 MPO-ANCA; 16 PR3-ANCA), and 19 healthy control subjects. Anti-MPO specific IgG was affinity-purified from plasma of an additional cohort of 18 MPO-ANCA patients undergoing plasmapheresis. We used lectin binding assays, liquid chromatography, and mass spectrometry-based methods to analyze Fc and Fab glycosylation, the degree of sialylation of Fc and Fab fragments and to determine the exact localization of N-glycans on Fc and Fab fragments.. IgG1 Fc glycosylation of total IgG was significantly reduced in patients with active AAV compared to controls. Clinical remission was associated with complete glycan normalization for PR3-ANCA patients but not for MPO-ANCA patients. Fc-glycosylation of anti-MPO specific IgG was similar to total IgG purified from plasma. A major fraction of anti-MPO specific IgG harbor extensive glycosylation within the variable domain on the Fab portion.. Significant differences exist between MPO and PR3-ANCA regarding the changes in amounts and types of glycans on Fc fragment and the association with disease activity. These differences may contribute to significant clinical difference in the disease course observed between the two diseases.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antibody Specificity; Carbohydrate Conformation; Carbohydrate Sequence; Cohort Studies; Female; Glycosylation; Humans; Immunoglobulin Fab Fragments; Immunoglobulin Fc Fragments; Immunoglobulin G; Male; Middle Aged; Myeloblastin; Peroxidase; Polysaccharides; Young Adult

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-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Myeloblastin; Peroxidase

The etiology of anemia in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) has not been elucidated. In this cross-sectional study, we tried to investigate the relationship between serum hepcidin and anemia in myeloperoxidase (MPO)-ANCA-AAV. Data of 64 newly diagnosed AAV patients who did not have kidney dysfunction or hemorrhage were analyzed. Serum hepcidin was measured with enzyme linked immunosorbent assay. Twenty-three of 64 patients had anemia. Compared with patients without anemia, patients with anemia had higher Birmingham vasculitis activity score [10 (3, 23) vs. 5 (3, 17), p = 0.020], lower levels of serum iron (5.83 ± 1.63 vs. 9.76 ± 1.54, p < 0.001) and higher levels of ferrtin [358.00 (59.85, 1314.10) vs. 151.05 (43.00, 645.30), p = 0.006]. All 64 patients had increased levels of serum hepcidin compared with normal controls, while patients with anemia had higher serum hepcidin than patients without anemia (85.30 ± 16.92 ng/mL vs. 53.48 ± 13.32 ng/mL, p < 0.001). In the multivariable analysis, the level of hemoglobin correlated with the levels of serum iron (r = 0.344, p = 0.026) and hepcidin (r = - 0.353, p = 0.022). Low level of serum iron was related to high level of serum hepcidin (r = - 0.472, p = 0.001). Immunosuppressive treatment induced rapid decrease of hepcidin and increase of serum iron on the 1st month, while the recovery of hemoglobin was relatively slow. This study indicated that in MPO-AAV without kidney dysfunction or hemorrhage, the existence of anemia is associated with high level of hepcidin which induces low serum iron and the abnormality of iron utilization.

Topics: Aged; Aged, 80 and over; Anemia; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Cross-Sectional Studies; Female; Hepcidins; Humans; Male; Middle Aged; Peroxidase

This study aimed to characterize the association between HLA alleles and ANCA-associated vasculitis (AAV) in a genetically homogeneous population, and to analyse the contribution of specific HLA molecule amino acid sequences to the risk of AAV.. We included 187 Danish patients with AAV and 1070 healthy controls. All were HLA typed at two-field resolution. The association of HLA alleles to PR3- or MPO-AAV was analysed. The contribution of the dominant molecular motifs of the HLA-DPB1 molecule to the risk of AAV was investigated by association studies that included specific amino acid sequences of the hypervariable regions in exon 2.. Ninety-four percent of patients with PR3-AAV were carriers of HLA-DPB1*04:01 while all patients with PR3-AAV were carriers of an HLA-DPB1*04 allele, and 85% were homozygous. This was significantly more than in the control group (P < 0.0001). The association was even stronger when HLA-DPB1*04:02 and -DPB1*23:01 were included. HLA-DPB1*04:01, -DPB1*04:02 and -DPB1*23:01 share amino acids in positions 8-9, 69, 76 and 84-87 within the hypervariable regions, but only positions 69 and 84-87 contributed significantly to the disease risk. HLA-DRB1*15 was associated with an increased risk of developing PR3-AAV, while HLA-DRB1*04, -DRB1*07 and -DQB1*03 were associated with a reduced risk of kidney involvement in PR3-AAV. MPO-AAV was only weakly associated with HLA class I alleles.. PR3-AAV is strongly associated with the HLA-DPB1 alleles HLA-DPB1*04:01, -DPB1*04:02 and -DPB1*23:01, which share amino acid sequences crucial for the peptide-binding groove.

Topics: Adult; Aged; Alleles; Amino Acid Motifs; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Case-Control Studies; Denmark; Exons; Female; Genetic Predisposition to Disease; Genotype; HLA-DP Antigens; HLA-DRB1 Chains; Homozygote; Humans; Male; Middle Aged; Myeloblastin; Peroxidase; Registries; Retrospective Studies; Risk Factors; White People

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) often causes peripheral nervous system impairments. However, little is known about subclinical involvements of the central nervous system in AAV. We investigated the frequency and progression of cerebral small vessel disease (SVD) in patients with AAV.. This single-center, case-control study comprised 56 patients with myeloperoxidase (MPO)-ANCA-positive AAV. Cerebral SVD presenting periventricular and deep white matter hyperintensities was assessed using brain magnetic resonance imaging (MRI). Seventy-five patients with non-stroke-associated neurological diseases were employed as controls.. At clinical diagnosis of MPO-ANCA-positive AAV, the frequency of periventricular hyperintensities in the AAV group was significantly higher than that in the control group (P = 0.014). Shinohara and Fazekas grades of periventricular hyperintensities in the AAV group were significantly higher than those in the control group (P = 0.019 and 0.020, respectively). In the AAV group, atherosclerosis-related factors, such as age and hypertension, were not associated with the Shinohara grades of periventricular hyperintensities, whereas serum CRP levels were significantly associated (odds ratio = 6.000, 95% confidence interval 1.648-21.840, P = 0.004). MRI changes were followed in 23 patients with AAV until 2 years after 6 months of diagnosis. Six of these patients worsened the grades of periventricular hyperintensities, while two of 27 in the control group worsened the grades (P = 0.013).. Inflammatory events are associated with the occurrence of cerebral SVD before clinical diagnosis of MPO-ANCA-positive AAV. The patients may be continuously exposed to the risk of cerebral SVD after immunosuppressive therapy.

Topics: Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Case-Control Studies; Cerebral Small Vessel Diseases; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Peroxidase

A reliable noninvasive prognostic factor of ANCA-associated vasculitis (AAV) is still lacking, but little research has focused on the value of MPO-ANCA titers in patients with active vasculitis. This study explored the prognostic significance of MPO-ANCA titer in active AAV patients.. Ninety-seven inpatients diagnosed with MPO-ANCA associated vasculitis at Linkou Chang Gung Memorial hospital and Keelung Chang Gung Memorial hospital from January 2005 to December 2016 were enrolled. Serum ANCA titers and basic characteristics of these patients at diagnosis were collected completely Medical records since AAV diagnosis were reviewed to evaluate two years renal and patient outcome.. This study demonstrated that higher MPO-ANCA titers at diagnosis was associated with poor initial renal function and 2-year renal outcomes.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Peroxidase; Prognosis; Proportional Hazards Models; Renal Dialysis; Retrospective Studies; Severity of Illness Index; Survival Rate

Patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have an elevated risk of cardiovascular disease (CVD). This study was undertaken to develop a clearer understanding of the association between changes in disease activity and lipid levels in AAV, which may inform CVD risk stratification in this population.. Lipid levels were assessed in stored serum samples (obtained at baseline and month 6) from the Rituximab for ANCA-Associated Vasculitis (RAVE) trial, which randomized patients to receive either rituximab or cyclophosphamide followed by azathioprine. Paired t-tests and multivariable linear regression were used to assess changes in lipid levels.. Of the 142 patients with serum samples available, the mean ± SD age was 52.3 ± 14.7 years, 72 (51%) were male, 95 (67%) were proteinase 3 (PR3)-ANCA positive, 72 (51%) had received a new diagnosis of AAV, and 75 (53%) were treated with rituximab. Several lipid levels increased between baseline and month 6, including total cholesterol (+12.4 mg/dl [95% confidence interval (95% CI) +7.1, +21.0]), low-density lipoprotein (+10.3 mg/dl [95% CI +6.1, +17.1]), and apolipoprotein B (+3.5 mg/dl [95% CI +1.0, +8.3]). These changes were observed among newly diagnosed and PR3-ANCA-positive patients but not among those with relapsing disease or myeloperoxidase-ANCA-positive patients. There was no difference in change in lipid levels between rituximab-treated patients and cyclophosphamide-treated patients. Changes in lipid levels correlated with changes in erythrocyte sedimentation rate but not with other inflammatory markers or glucocorticoid exposure.. Lipid levels increased during remission induction among patients with newly diagnosed AAV and those who were PR3-ANCA positive. Disease activity and ANCA type should be considered when assessing lipid profiles to stratify CVD risk in patients with AAV.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antirheumatic Agents; Apolipoprotein A-I; Apolipoproteins B; Azathioprine; Blood Sedimentation; Cardiovascular Diseases; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cyclophosphamide; Female; Humans; Lipid Metabolism; Male; Middle Aged; Myeloblastin; Peroxidase; Randomized Controlled Trials as Topic; Rituximab; Severity of Illness Index

There is accumulating evidence that complement activation is important in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) pathogenesis. This study was undertaken to investigate complement activation in AAV with myeloperoxidase (MPO) positivity and AAV with proteinase 3 (PR3) positivity after determining optimal methods for measuring activated complement factors in circulation.. Participants included 98 patients with AAV (45 MPO-ANCA positive, 53 PR3-ANCA positive) and 35 healthy controls. Plasma was obtained from blood collected using EDTA tubes, with or without 100 μg/ml Futhan. Levels of Bb, C3a, C5a, soluble C5b-9 (sC5b-9), properdin, and C4d were measured by enzyme-linked immunosorbent assay. Group comparisons were made using Wilcoxon's 2-sample test. Paired data were analyzed using a matched pairs signed rank test.. Compared to healthy controls, certain complement analyte levels were high in patients with active AAV with MPO positivity, including C3a (P < 0.0001), C5a (P = 0.0004), and sC5b-9 (P = 0.0007). During remission, levels of Bb (P = 0.001), C3a (P < 0.0001), and sC5b-9 (P = 0.003) were higher. Compared to healthy controls, C3a (P < 0.0001), C5a (P = 0.002), sC5b-9 (P = 0.0001), and C4d (P = 0.005) levels were higher in patients with active AAV with PR3 positivity; levels of C3a (P < 0.0001) and C4d (P = 0.007) were also higher duriing remission. There were no significant differences in any complement analyte for either ANCA serotype between patients with active disease and those with disease in remission. Among patients with paired samples, sC5-9 levels were significantly lower during disease remission compared to active disease. C5a was significantly lower among patients with disease in long-term remission who were not receiving therapy. For Bb, C5a, and sC5b-9, median levels and individual values were considerably higher in control and patient samples processed without Futhan compared to those processed with Futhan.. Complement activation occurs in both MPO-positive AAV and PR3-positive AAV. The complement activation profile differs according to disease activity and possibly ANCA serotype. Futhan reduces in vitro complement activation and provides a more accurate measurement.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Case-Control Studies; Complement C3a; Complement C4; Complement C5a; Complement Factor B; Complement Membrane Attack Complex; Female; Humans; Male; Middle Aged; Myeloblastin; Peroxidase; Properdin; Severity of Illness Index

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

Autoreactivity to myeloperoxidase (MPO) causes anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), with rapidly progressive glomerulonephritis. Here, we show that a Staphylococcus aureus peptide, homologous to an immunodominant MPO T-cell epitope (MPO

Topics: Amino Acid Sequence; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoimmunity; Bacterial Proteins; Epitopes, T-Lymphocyte; Glomerulonephritis; Heymann Nephritis Antigenic Complex; Humans; Male; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Peptides; Peroxidase; Plasmids; Staphylococcus aureus

Many patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) need dialysis at disease onset due to severe kidney injury. Determining whether they can become dialysis independent is an important clinical assessment.. Forty kidney biopsy-proved myeloperoxidase (MPO)-ANCA associated AAV patients who required dialysis at disease onset were enrolled. Relationships between laboratory and pathological characteristics and prognoses were analyzed.. Twenty-five patients obtained dialysis independence within 3 months, while the other 15 patients remained dialysis dependent. No sclerotic class was identified among the 40 patients. Only two biopsies exhibited focal class diagnoses and both these patients recovered their renal function. The renal recovery rate of the 20 patients with mixed class was significantly lower than that of the 18 patients with crescentic class (40.0% vs. 83.3%, p = 0.006). Receiver operating characteristics (ROC) curves showed fibrous crescent+global glomerulosclerosis greater than 32.6% was a strong predictor of dialysis dependence with a sensitivity of 93.3% and specificity of 88.0%. When the percentage of fibrous crescent+global glomerulosclerosis exceeded 47.9%, dialysis independence was not possible. Correlation analysis indicated that platelet counts were negatively correlated with the percentage of fibrous crescent+global glomerulosclerosis (R = -0.448, p = 0.004). Most patients with increased platelets (84.62%) obtained renal recovery. Compared with methylprednisolone pulse therapy, plasma exchange accelerated renal recovery (29.4 ± 15.6 vs. 41.4 ± 11.7 days, p = 0.039).. For MPO-ANCA AAV who required dialysis at disease onset, crescentic and mixed classes accounted for the majority of patients in our cohort. The renal outcome of mixed class patients was worse than that of crescentic class. A high proportion of fibrous crescent+global glomerulosclerosis is a predictor of dialysis dependence. Increased platelet count is associated with active and reversible renal lesions.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Female; Humans; Kidney Diseases; Male; Middle Aged; Peroxidase; Renal Dialysis; Retrospective Studies; Severity of Illness Index; Treatment Outcome

Topics: Algorithms; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Europe; Fluorescent Antibody Technique, Indirect; Humans; Laboratories; Myeloblastin; Peroxidase; Societies, Scientific; Surveys and Questionnaires

Cumulating evidences suggested an important role of sphingosine-1-phosphate (S1P) and its receptors in regulating endothelial barrier integrity. Our previous study revealed that the circulating S1P levels and renal expression of S1PRs correlated with disease activity and renal damage in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This study investigated the role of S1P and its receptors in myeloperoxidase (MPO)-ANCA-positive IgG-mediated glomerular endothelial cell (GEnC) activation. The effect of S1P on morphological alteration of GEnCs in the presence of MPO-ANCA-positive IgG was observed. Permeability assay was performed to determine endothelial monolayer activation in quantity. Both membrane-bound and soluble ICAM-1 and VCAM-1 levels were measured. Furthermore, antagonists and/or agonists of various S1PRs were employed to determine the role of different S1PRs. S1P enhanced MPO-ANCA-positive IgG-induced disruption of tight junction and disorganization of cytoskeleton in GEnCs. S1P induced further increase in monolayer permeability of GEnC monolayers in the presence of MPO-ANCA-positive IgG. S1P enhanced MPO-ANCA-positive IgG-induced membrane-bound and soluble ICAM-1/VCAM-1 up-regulation of GEnCs. Soluble ICAM-1 levels in the supernatants of GEnCs stimulated by S1P and MPO-ANCA-positive IgG increased upon pre-incubation of S1PR1 antagonist, while pre-incubation of GEnCs with the S1PR1 agonist down-regulated sICAM-1 level. Blocking S1PR2-4 reduced sICAM-1 levels in the supernatants of GEnCs stimulated by S1P and MPO-ANCA-positive IgG. Pre-incubation with S1PR5 agonist could increase sICAM-1 level in the supernatants of GEnC stimulated by S1P and MPO-ANCA-positive IgG. S1P can enhance MPO-ANCA-positive IgG-mediated GEnC activation through S1PR2-5.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Cells, Cultured; Culture Media, Conditioned; Endothelial Cells; Gene Expression Regulation; Humans; Immunoglobulin G; Intercellular Adhesion Molecule-1; Kidney Glomerulus; Lysophospholipids; Peroxidase; Protein Isoforms; Receptors, Lysosphingolipid; Sphingosine; Sphingosine-1-Phosphate Receptors

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Neutrophils; Peroxidase

A previously healthy 58-year-old man was admitted for muscle pain and weakness [manual muscle testing (MMT) of 4/4 for upper and lower limbs]. We detected elevated levels of inflammatory makers and PR3-anti-neutrophil cytoplasmic antibody (ANCA). Subsequently, the muscle weakness rapidly progressed to an MMT of 2 for all limbs. Magnetic resonance imaging indicated muscle edema, and the creatine kinase (CK) level increased to 29,998 U/L. Methylprednisolone (mPSL) and cyclophosphamide pulse therapy improved the patient symptoms. MMT recovered to 4 for all limbs. A muscle biopsy showed degenerated muscle fibers surrounded by neutrophil-predominant infiltration. In addition, lamina elastic breakdown and fibrinoid necrosis of arterioles were observed. A final diagnosis of microscopic polyangiitis (MPA) limited to the muscles was made.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Asian People; Biomarkers; Cyclophosphamide; Humans; Inflammation; Lower Extremity; Male; Microscopic Polyangiitis; Middle Aged; Muscle Weakness; Myeloblastin; Peroxidase; Prednisolone; Treatment Outcome; Upper Extremity

The interaction between neutrophils and activation of alternative complement pathway plays a critical role in the pathogenesis of ANCA-associated vasculitis (AAV). MPO, which can be released from ANCA-stimulated neutrophils, was recently demonstrated to be capable of activating the alternative complement pathway. Here we aimed to investigate the interaction between MPO and factor H (FH), a key regulator of the alternative pathway, and its effect on the functional activities of FH.. Detection of FH and MPO on neutrophil extracellular traps (NETs) induced by serum from AAV patients and in kidney biopsies of AAV patients was performed by immunostaining. In vitro binding between MPO and FH was examined by ELISA and surface plasmon resonance. The influence of MPO on the complement regulatory activity of FH was further assessed.. FH deposited and co-localized with MPO in NETs. In kidney biopsies from AAV patients, MPO was closely adjacent to FH in glomerular capillaries. We demonstrated that MPO binds to FH with an apparent nanomolar affinity and identified short consensus repeats 1-4 of FH as the major binding sites. In terms of functional analysis, MPO inhibited the interaction between FH and C3b and the decay-accelerating activity of FH. The fluid phase and surface cofactor activities of FH upon C3b inactivation were inhibited by MPO.. Our findings indicate that MPO binds to FH and influences the complement regulatory activity of FH. MPO-FH interaction may participate in the pathogenesis of AAV by contributing to activation of the alternative complement pathway.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Biopsy; Complement Factor H; Extracellular Traps; Humans; Kidney; Neutrophil Activation; Neutrophils; Peroxidase

Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) has been linked with thyroid disease as a result of antithyroid medications. We assessed the prevalence of thyroid disease in our patients with AAV.. Clinical records of 279 patients with AAV diagnosed between 1991 and 2014 were analyzed.. Thyroid disease was identified in 21.5% of patients, but only 2 had previously received propylthiouracil. There was a greater proportion of female patients, patients with antimyeloperoxidase antibodies, and patients with renal disease in the group with thyroid disease.. Our data show a higher prevalence of thyroid disease in patients with AAV than the general population. This was not attributable to antithyroid drugs.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies; Antithyroid Agents; Chi-Square Distribution; Female; Follow-Up Studies; Humans; Kidney Diseases; Logistic Models; Male; Multivariate Analysis; Peroxidase; Prevalence; Propylthiouracil; Retrospective Studies; Risk Factors; Sex Factors; Statistics, Nonparametric; Thyroid Diseases

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

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and cryoglobulinemic vasculitis (CV) rarely coexist. An 83-year-old woman was admitted with rapidly progressive renal failure, gastrointestinal hemorrhage and purpura with myeloperoxidase (MPO)-ANCA positivity and cryoglobulinemia. Despite intensive immunosuppressive treatment, she died of aspergillus pneumonia. Autopsy revealed necrotizing crescentic glomerulitis in the majority of the glomeruli, accompanied by partially membranoproliferative-like glomerular changes. Immunofluorescence staining revealed the presence of neutrophil extracellular trap (NET) formation in the glomeruli and cutaneous arteries. These pathological findings suggested that MPO-AAV and/or CV caused NET formation, leading to lethal systemic vasculitis.

Topics: Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autopsy; Cryoglobulinemia; Extracellular Traps; Fatal Outcome; Female; Gastrointestinal Tract; Glomerulonephritis; Humans; Kidney; Kidney Glomerulus; Peroxidase; Skin; Systemic Vasculitis

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Complement Factor H; Complement System Proteins; Humans; Peroxidase

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

In antineutrophil cytoplasmic antibody-associated vasculitis (AAV), Toll-like receptors (TLRs) may be engaged by infection-associated patterns and by endogenous danger signals, linking infection and innate inflammation with this autoimmune disease. This study examined intrarenal TLR2, TLR4, and TLR9 expression and renal injury in AAV, testing the hypothesis that increased TLR expression correlates with renal injury. Patients with AAV exhibited both glomerular and tubulointerstitial expression of TLR2, TLR4, and TLR9, with TLR4 being the most prominent in both compartments. Glomerular TLR4 expression correlated with glomerular segmental necrosis and cellular crescents, with TLR2 expression correlating with glomerular segmental necrosis. The extent and intensity of glomerular and tubulointerstitial TLR4 expression and the intensity of glomerular TLR2 expression inversely correlated with the presenting estimated glomerular filtration rate. Although myeloid cells within the kidney expressed TLR2, TLR4, and TLR9, TLR2 and TLR4 colocalized with endothelial cells and podocytes, whereas TLR9 was expressed predominantly by podocytes. The functional relevance of intrarenal TLR expression was further supported by the colocalization of TLRs with their endogenous ligands high-mobility group box 1 and fibrinogen. Therefore, in AAV, the extent of intrarenal TLR4 and TLR2 expression and their correlation with renal injury indicates that TLR4, and to a lesser degree TLR2, may be potential therapeutic targets in this disease.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Fibrinogen; Glomerular Filtration Rate; Glomerulonephritis; HMGB1 Protein; Humans; Kidney Glomerulus; Male; Middle Aged; Peroxidase; Receptor, PAR-1; Severity of Illness Index; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptor 9

Overlap syndrome of ANCA-associated vasculitis (AAV) and scleroderma (SSc) is rare with conflicting data on renal outcomes. We describe the clinical characteristics and treatment outcome of ANCA-associated glomerulonephritis (AAG) in SSc patients followed at a single center.. We conducted a retrospective study of 3,570 patients in our SSc database to identify SSc patients who subsequently developed AAV with renal involvement. Patient demographics, serology, renal function, renal histology, and treatment outcomes were assessed.. Of the 3,570 patients, we identified 7 patients who developed acute glomerulonephritis, and all were ANCA positive. The mean age at SSc diagnosis was 47 years, 4 patients were female, and 6 had diffuse SSc. Anti-nuclear antibody (ANA) was positive in all. Mean time of onset of AAV from time of diagnosis of SSc was 6 years, and all were myeloperoxidase (MPO) positive. Patients presented with hematuria, proteinuria, with or without rise in serum creatinine, and all patients had biopsy-proven crescentic glomerulonephritis. One patient required dialysis at presentation. Five patients were treated with cyclophosphamide and steroids, and 2 were treated with rituximab and steroids. Of the 7 patients, 4 did not receive maintenance immunosuppression. Three patients died, and 1 of them experienced relapse with fulminant alveolar hemorrhage.. AAG in SSc is rare, with disease manifestation and course similar to that of AAV. This case series demonstrates that disease remission can be achieved with standard induction therapy. Vasculitis relapse can occur, and similar to idiopathic AAV, maintenance immunosuppression should be initiated to maintain remission.
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Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Creatinine; Cyclophosphamide; Female; Glomerulonephritis; Hematuria; Humans; Immunologic Factors; Immunosuppressive Agents; Male; Middle Aged; Peroxidase; Proteinuria; Recurrence; Renal Dialysis; Retrospective Studies; Rituximab; Scleroderma, Diffuse; Steroids; Treatment Outcome; Young Adult

Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antinuclear; Antithyroid Agents; Female; Graves Disease; Humans; Myeloblastin; Peroxidase; Propylthiouracil; Skin; Skin Diseases

Current therapies for treating antineutrophil cytoplasm autoantibody (ANCA)-associated vasculitis include cyclophosphamide and corticosteroids. Unfortunately, these agents are associated with severe adverse effects, despite inducing remission in most patients. Histone deacetylase inhibitors are effective in rodent models of inflammation and act synergistically with many pharmacological agents, including alkylating agents like cyclophosphamide. EDO-S101 is an alkylating fusion histone deacetylase inhibitor molecule combining the DNA alkylating effect of Bendamustine with a pan-histone deacetylase inhibitor, Vorinostat. Here we studied the effects of EDO-S101 in two established rodent models of ANCA-associated vasculitis: a passive mouse model of anti-myeloperoxidase IgG-induced glomerulonephritis and an active rat model of myeloperoxidase-ANCA microscopic polyangiitis. Although pretreatment with EDO-S101 reduced circulating leukocytes, it did not prevent the development of passive IgG-induced glomerulonephritis in mice. On the other hand, treatment in rats significantly reduced glomerulonephritis and lung hemorrhage. EDO-S101 also significantly depleted rat B and T cells, and induced DNA damage and apoptosis in proliferating human B cells, suggesting a selective effect on the adaptive immune response. Thus, EDO-S101 may have a role in treatment of ANCA-associated vasculitis, operating primarily through its effects on the adaptive immune response to the autoantigen myeloperoxidase.

Topics: Adaptive Immunity; Alkylation; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Apoptosis; Benzimidazoles; DNA Repair; Female; Histone Deacetylase Inhibitors; HL-60 Cells; Humans; Male; Mice; Mice, Inbred C57BL; Peroxidase; Rats; Rats, Inbred WKY

Glomerulonephritis is a severe complication of microscopic polyangiitis (MPA), a small-vessel vasculitis associated with anti-myeloperoxidase antibodies (MPO-ANCA). We previously showed the pathogenic effects of MPO-ANCA that activate MPO to trigger an oxidative burst mainly through HOCl production, contributing to endothelial injury and lung fibrosis. The aim of this study was to investigate the relationship between MPO-induced oxidative stress, anti-oxidant defenses and renal histological lesions in MPA patients. We therefore analyzed histological data from a prospective cohort of ANCA-associated glomerulonephritis. Serum-mediated HOCl production, advanced oxidation protein products (AOPP), and thiol concentration in sera were determined. From 38 patients included, histological classification noted 50% focal glomerulonephritis, 15.8% crescentic-glomerulonephritis, and 34.2% mixed-glomerulonephritis. MPA patients' sera displayed higher HOCl production by MPO ( P < 0.001), higher AOPP ( P < 0.001) and thiol ( P < 0.01) levels, compared with healthy subjects. The presence of cellular crescents was associated with higher serum-mediated HOCl production ( P = 0.049) and lower thiol levels ( P = 0.022) at disease onset. Higher thiol concentrations were associated with focal glomerulonephritis ( P = 0.042), less interstitial fibrosis ( P = 0.039) and hyalinosis ( P = 0.066). In remission, HOCl production was decreased ( P < 0.01), and thiol concentration remained high ( P = 0.39). Our findings suggest that HOCl production by activated MPO could contribute to the very early stage of glomerulonephritis, whereas thiol may exert a protective effect against the development of renal vasculitis and glomerulosclerosis. This study highlights the importance of oxidative defenses to counteract the process of MPO-ANCA associated glomerulonephritis.

Topics: Advanced Oxidation Protein Products; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Enzyme Activation; Female; Fibrosis; Glomerulonephritis; Humans; Hypochlorous Acid; Kidney; Kidney Diseases; Male; Middle Aged; Oxidative Stress; Peroxidase; Prospective Studies; Registries; Sulfhydryl Compounds

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Humans; Interleukin-2; Neutrophils; Peroxidase; T-Lymphocytes, Helper-Inducer

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

Complement activation plays an important role in the pathophysiology of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), although it remains unclear which pathway is activated. Whether pauci-immune necrotizing crescentic glomerulonephritis (pauci-immune GN) with negative ANCA serology is part of the spectrum of AAV or a different disease entity is essentially unknown.. We used proteomic analysis to delineate the complement profile in a series of 13 kidney biopsies of patients with pauci-immune GN, with either proteinase 3 (PR3) (five patients) or myeloperoxidase (MPO) antibodies (four patients) or with consistently negative ANCA serology (four patients). Immunofluorescence staining of glomeruli was essentially negative in the PR3-ANCA and MPO-ANCA groups, while a mild staining for C3 was seen in the ANCA-negative cases. No electron-dense deposits were found in the PR3-ANCA and MPO-ANCA groups, but mesangial and few subepithelial deposits were clearly present in the ANCA-negative specimens.. Mass spectrometry revealed low spectra numbers for C3 and immunoglobulins in both PR3-positive and MPO-positive patients with minimal or no C4 and C9. In contrast, larger spectra numbers for C3, moderate spectra numbers for C9, complement factor H-related protein-1 and low spectra numbers for C4, C5 and immunoglobulins were found in the ANCA-negative cases.. While complement activation is noted in AAV, the complement activation appears to be more prominent in the ANCA-negative glomerulonephritis. The larger amount of C3 and moderate amount of C9 in the ANCA-negative glomerulonephritis implies activation of the alternate and terminal pathway of complement, suggesting that this entity may be caused or promoted by a genetic or acquired defect in the alternative pathway.

Topics: Adolescent; Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Biomarkers; Complement Activation; Female; Glomerulonephritis; Humans; Male; Middle Aged; Myeloblastin; Peroxidase; Proteome; Proteomics; Young Adult

The objective of this multicentre study was to improve the clinical interpretation of PR3- and MPO-ANCAs as an adjunct for the diagnosis of ANCA-associated vasculitis (AAV) by defining thresholds and test result intervals based on predefined specificities and by calculating test result interval-specific likelihood ratios (LRs).. Eight different PR3- and MPO-ANCA immunoassays from seven companies were evaluated using 251 diagnostic samples from AAV patients and 924 diseased controls.. Thresholds for antibody levels were determined based on predefined specificities (95, 97.5, 99 and 100%) and used to delimit test result intervals. Test result interval-specific LRs were determined. For all assays, the LR for AAV increased with increasing antibody level. For all but one immunoassay, high antibodies levels (associated with LR >55) were found in a substantial fraction (>65%) of patients. The area under the curve (AUC) of receiver operating characteristics analysis of a diagnostic approach in which positive results were confirmed by IIF or another immunoassay was not substantially higher than the AUC of performing immunoassay only. The highest AUC was found when immunoassay was combined with another immunoassay or with IIF.. To diagnose AAV based on PR3- and MPO-ANCA, it is useful to define thresholds for antibody levels and to assign test result interval-specific LRs. Higher antibody levels are associated with a higher likelihood for disease. Such information improves clinical interpretation.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Case-Control Studies; Humans; Immunoassay; Likelihood Functions; Myeloblastin; Peroxidase; Sensitivity and Specificity

Antineutrophil cytoplasmic antibody (ANCA) has been known to cause pauci-immune crescentic glomerulonephritis. In addition, several reports described membranous glomerulonephritis (MN) concurrent with ANCA-associated glomerulonephritis. Because the two glomerular diseases simultaneously appear in an ANCA-positive patient, the mechanisms whereby ANCA causes the two different glomerular diseases remain ambiguous. Herein, we report a case of 19-year-old man who presented with hematuria, pre-nephrotic proteinuria, and high titer of myeloperoxidase (MPO)-ANCA. The first renal biopsy revealed MN with chronic glomerular scar lesions of unknown etiology. Predominant immunoglobulin (Ig) G1 subclass and negative phospholipase-A2 receptor staining, together with granular-positive glomerular capillary co-localization of MPO and IgG staining, suggested secondary MN due to MPO-MPO-ANCA immune-complex. Five years later, the patient presented with fever, severe renal dysfunction, and alveolar hemorrhage with high titer of MPO-ANCA that indicated pulmonary renal syndrome due to ANCA-associated vasculitis. The second renal biopsy revealed pauci-immune crescentic glomerulonephritis without either apparent MN-lesion or glomerular IgG staining. This is the first reported case showing that MPO-ANCA caused two different glomerular diseases, MN and pauci-immune crescentic glomerulonephritis, in the same patient at the different time points. Our case indicated that common MPO-ANCA might cause different glomerular diseases by different immune mechanisms.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antigen-Antibody Complex; Glomerulonephritis; Glomerulonephritis, Membranous; Hemorrhage; Humans; Lung Diseases; Male; Peroxidase; Young Adult

Our previous study found that circulating and urinary levels of high mobility group box-1 (HMGB1) were closely associated with disease activity in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Moreover, HMGB1 participates in ANCA-induced neutrophil activation. Cross-reactivity between moesin and anti-myeloperoxidase (MPO) antibody has been reported in both human and mouse. The current study investigated whether HMGB1 participated in MPO-ANCA-induced glomerular endothelial cell (GEnC) injury, which is one of the most important aspects in the pathogenesis of AAV.. The effects of HMGB1 on expression of moesin on GEnCs and anti-MPO antibody binding to GEnCs were measured. MPO expression on GEnCs was explored. The effects of HMGB1 in MPO-ANCA induced GEnC injury were measured, during which the role of moesin was explored. Antagonists for various relevant receptors were employed.. Sera from AAV patients at the active stage could mediate GEnC injury, while this effect could be attenuated by preblocking HMGB1. HMGB1 could increase the expression of moesin on GEnCs and the binding of anti-MPO antibody to moesin. The colocalization of moesin expression and anti-MPO antibody binding can be detected. Little, if any, MPO was expressed in GEnCs. HMGB1 increased GEnC activation and injury in the presence of patient-derived MPO-ANCA-positive IgGs through moesin. The effects of HMGB1 on expression of moesin on GEnCs, anti-MPO antibody binding to GEnCs, GEnC activation and injury were mainly toll like receptor 4 (TLR4) dependent.. HMGB1 can increase the expression of moesin but not MPO on GEnCs, and can further participate in MPO-ANCA-induced GEnC activation and injury by cross-reactivity between moesin and anti-MPO antibody.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoantibodies; Cell Survival; Cells, Cultured; Endothelial Cells; Female; HMGB1 Protein; Humans; Immunoglobulin G; Kidney Glomerulus; Male; Microfilament Proteins; Middle Aged; Peroxidase; Protein Binding

To describe pulmonary involvement at time of diagnosis in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), as defined by computed tomography (CT).. Patients with thoracic CT performed on or after the onset of AAV (n = 140; 75 women; granulomatosis with polyangiitis, n = 79; microscopic polyangiitis MPA, n = 61) followed at a tertiary referral center vasculitis clinic were studied. Radiological patterns of pulmonary involvement were evaluated from the CT studies using a predefined protocol, and compared to proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA specificity.. Of the patients, 77% had an abnormal thoracic CT study. The most common abnormality was nodular disease (24%), of which the majority were peribronchial nodules, followed by bronchiectasis and pleural effusion (19%, each), pulmonary hemorrhage and lymph node enlargement (14%, each), emphysema (13%), and cavitating lesions (11%). Central airways disease and a nodular pattern of pulmonary involvement were more common in PR3-ANCA-positive patients (p < 0.05). Usual interstitial pneumonitis (UIP) and bronchiectasis were more prevalent in MPO-ANCA-positive patients (p < 0.05). Alveolar hemorrhage, pleural effusion, lymph node enlargement, and pulmonary venous congestion were more frequent in MPO-ANCA-positive patients.. Pulmonary involvement is frequent and among 140 patients with AAV who underwent a thoracic CT study, almost 80% have pulmonary abnormalities on thoracic CT. Central airway disease occurs exclusively among patients with PR3-ANCA while UIP were mainly seen in those with MPO-ANCA. These findings may have important implications for the investigation, management, and pathogenesis of AAV.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Humans; Lung; Male; Middle Aged; Myeloblastin; Peroxidase; Radiography, Thoracic; Tomography, X-Ray Computed

Medial medullary infarction accounts for less than 1% of brain infarctions, and medial medullary infarctions is very rarely caused by antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.. We report the case of a 76-year-old man at low risk of arteriosclerosis who presented with disorders on the left side including gaze-evoked nystagmus, paralysis of the extremities, pyramidal signs, sensory disturbance, and dysesthesia. Brain magnetic resonance imaging also showed right medial medullary infarction.. Medial medullary infarction caused by ANCA-related vasculitis was diagnosed based on mild renal dysfunction and high levels of blood leukocytes, C-reactive protein (CRP), and myeloperoxidase (MPO)-ANCA.. He underwent two 3-day courses of steroid pulse therapy involving daily 1000 mg doses of methylpredonine. He then received 30 mg/day (0.5 mg/kg/day) of prednisolone (PSL) without other immunosuppressants. Levels of MPO-ANCA and the inflammatory marker CRP decreased rapidly a month after admission. Once MPO-ANCA became undetectable, the PSL dose was carefully reduced to 10 mg/day. To treat his paralysis, we provided rehabilitation with a Hybrid Assistive Limb five times starting at a month post-onset. His Barthel index score rose from 45 to 70 points.. Medullary infarction is mostly caused by arteriosclerosis and vertebral arterial dissection. When systemic inflammatory findings are obtained, ANCA-associated vasculitis should be considered a potential cause, and steroid pulse therapy should be promptly administered.

Topics: Adrenal Cortex Hormones; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Brain Infarction; C-Reactive Protein; Humans; Immunosuppressive Agents; Leukocyte Count; Magnetic Resonance Imaging; Male; Medulla Oblongata; 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

Myeloperoxidase (MPO) anti-neutrophil cytoplasmic Ab (ANCA)-associated vasculitis results from autoimmunity to MPO. IL-17A plays a critical role in generating this form of autoimmune injury but its cell of origin is uncertain. We addressed the hypothesis that IL-17A-producing γδ T cells are a nonredundant requisite in the development of MPO autoimmunity and glomerulonephritis (GN). We studied MPO-ANCA GN in wild type, αβ, or γδ T cell-deficient (C57BL/6,

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoantibodies; Autoimmune Diseases; CD4-Positive T-Lymphocytes; Glomerulonephritis; Interleukin-17; Mice; Mice, Knockout; Peroxidase; Receptors, Antigen, T-Cell, alpha-beta; Receptors, Antigen, T-Cell, gamma-delta

There are few data on clinical profiles of ANCA-associated vasculitis (AAV) in different ethnic populations. The aim of this study was to examine the differences in the ANCA type and clinical features of AAV between populations using the Diagnostic and Classification Criteria in Vasculitis Study (DCVAS) dataset.. The DCVAS is an international, multicentre, observational study recruiting in 133 sites. Eight ethnic categories were analysed: Northern European, Caucasian American, Southern European, Middle Eastern/Turkish, Chinese, Japanese, Indian subcontinent and other. ANCA type was categorized as myeloperoxidase (MPO), PR3 and ANCA negative. Organ system involvement was recorded using a standard dataset. Differences were analysed by chi-squared tests using a Bonferroni correction and logistic regression (adjusting for age and sex). Northern European was the reference population.. Data from 1217 patients with AAV were available and the 967 (79.5%) patients recruited by rheumatology departments were analysed to reduce confounding by recruitment specialty. There were differences in ANCA type between ethnic categories (P < 0.001): MPO-ANCA was more common than PR3-ANCA in Japanese, Chinese and Southern Europeans; PR3-ANCA was more common in the other groups. Compared with Northern Europeans, Japanese had a nearly 60-fold increased chance of having MPO-ANCA (vs PR3-ANCA) [odds ratio (OR) 59.2 (95% CI 8.0, 440.7), P < 0.001] and Chinese had a nearly 7-times increased chance [OR 6.8 (95% CI 2.6, 17.8), P < 0.001]. Ophthalmologic and otorhinolaryngologic involvement were less common in Japanese and Chinese populations than Northern Europeans; otherwise, there were few differences in organ involvement between ethnic groups.. This study confirms the previously observed differential occurrence of MPO-AAV and PR3-AAV between different ethnic groups.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Arabs; Asian People; China; Europe; Eye Diseases; Female; Female Urogenital Diseases; Heart Diseases; Humans; India; Japan; Kidney Diseases; Male; Male Urogenital Diseases; Middle Aged; Middle East; Myeloblastin; Nervous System Diseases; Odds Ratio; Otorhinolaryngologic Diseases; Peroxidase; Respiratory Tract Diseases; Skin Diseases; Turkey; United States; White People

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

A previously healthy 77-year-old Japanese man presented with a 2-week history of daily fevers peaking at 38°C, chills, hearing loss, and almost 10 kg of unintentional weight loss over 2 months. Pure tone audiometry showed mixed conductive-sensorineural hearing loss: right, 63.6 dB, left, 80.0 dB. Blood tests after admission showed a high myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) level (>300 U/mL), so we suspected ANCA-related vasculitis. The Japanese Otorhinolaryngology Society has recently been advocating the concept of otitis media with ANCA-associated vasculitis (OMAAV). Our case met the criteria proposed, leading to our diagnosis.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Hearing Loss; Humans; Male; Otitis Media; Peroxidase

The relationship between antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) and ANCA-negative vasculitis has not been elucidated.. A 64-year-old female with edema and proteinuria was admitted. A kidney biopsy indicated focal proliferative nephritis with crescents in 25% of glomeruli. Serum ANCA was negative. Eighteen months later, systemic symptoms emerged and acute kidney injury occurred. Serum ANCA against myeloperoxidase (MPO) turned positive. Repeated kidney biopsy showed more severe lesion than last time. Immunoglobulin (Ig)G was purified from serum obtained before the first kidney biopsy. Weak ANCA which could not be detected in serum was found in IgG.. MPO-ANCA-associated AAV developed from ANCA-negative renal-limited AAV.. The patient was treated with glucocorticoid.. The serum creatinine decreased to 2.17 mg/dL a week later. MPO-ANCA turned negative when re-examined 3 weeks later. No relapse has been observed during follow-up for 6 months.. This is the first reported case about the spontaneous transformation from ANCA-negative renal-limited AAV to ANCA-positive systemic vasculitis. There might be a slow process of epitope spreading in the pathogenesis of disease. Physicians should try their best to detect the ANCA in the diagnose and treatment of ANCA-negative AAV.

Topics: Acute Kidney Injury; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Glomerulonephritis; Humans; Middle Aged; Peroxidase; Proteinuria

Anti-neutrophil cytoplasmic antibodies (ANCA) are found in pauci-immune necrotizing crescentic glomerulonephritis. In the past, the role of complement in ANCA-associated vasculitis (AAV) was assumed to be minimal. More recently, however, it was found that blocking the complement cascade in a mouse model of AAV reduces glomerular damage. Immune complex deposits have been found in biopsies from AAV patients. In this study, we questioned whether immune complex formation or deposition may result in complement activation in ANCA-associated glomerulonephritis.. ANCA-positive patients from the Limburg Renal Registry were included between 1979 and 2011. Renal histology was documented together with immunoglobulin and complement immunofluorescence. In addition, C3d, properdin, C4d and mannose-binding lectin (MBL) were stained. Electron microscopy was performed. Circulating immune complexes were determined in a subset of patients, as well as C3 allotypes.. C3c was found in 78 of 187 renal biopsies (41.7%) divided over 32.3% of proteinase-3 (PR3)-AAV patients and 52.3% of myeloperoxidase (MPO)-AAV patients (P = 0.006), whereas C3d was found positive in 51.1% of PR3-AAV patients and 70.4% of MPO-AAV patients (P = 0.105). C4d was found positive in 70.8%, properdin in 38.7% and MBL in 30.4% of patients. Whereas C4d and MBL positivity was similar between the AGN groups, properdin was more common in biopsies classified as crescentic compared with biopsies classified as focal or mixed. Renal biopsies positive for C3d and/or properdin showed more cellular crescents and less normal glomeruli compared with biopsies negative for C3d and/or properdin (P < 0.05). In 3 out of 43 renal biopsies analysed by electron microscopy, small electron dense deposits were found. In 14 of 46 patients analysed, circulating immune complexes were detectable. No association between histological findings and C3 allotypes was found.. In the majority of AAV patients, no immune complex deposits were found in their renal biopsies. C3d, C4d and C5b-9 staining, however, was found to be positive in a majority of analysed renal biopsies. Importantly, C3d and properdin staining was associated with cellular crescents. We hypothesize that local immune complexes are quickly degraded in AAV and therefore not visible by electron microscopy. Our findings are compatible with the hypothesis that complement activation in AAV occurs predominantly via alternative pathway activation.

Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Complement Activation; Complement C3; Complement Membrane Attack Complex; Female; Fluorescent Antibody Technique; Glomerulonephritis; Humans; Immunologic Factors; Male; Microscopy, Electron; Middle Aged; Peroxidase

We aimed to analyze clinical features and treatment outcomes of otitis media caused by antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), i.e. otitis media with AAV (OMAAV).. This survey was performed between December 2013 and February 2014. The study began with a preliminary survey to 123 otolaryngology institutions in Japan to inquire about their experiences with OMAAV patients during the past 10 years, and was followed by a questionnaire survey to investigate clinical and laboratory findings. OMAAV was defined using the criteria described in the text.. Two hundred and thirty-five patients classified as OMAAV were enrolled in this study. They were characterized as follows: (1) disease onset with initial signs/symptoms due to intractable otitis media with effusion or granulation, which did not respond to ordinary treatments such as antibiotics and insertion of tympanic ventilation tubes, followed by progressive hearing loss; (2) predominantly female (73%) and older (median age: 68 years); (3) predominantly myeloperoxidase (MPO)-ANCA-positive (60%), followed by proteinase 3 (PR3)-ANCA-positive (19%) and both ANCAs-negative (16%); (4) frequently observed accompanying facial palsy (36%) and hypertrophic pachymeningitis (28%); and (5) disease often involving lung (35%) and kidney (26%) lesions. Four factors associated with OMAAV were found to be related to an unfavorable clinical course threatening the patient's hearing and/or lives, namely facial palsy, hypertrophic pachymeningitis, both ANCAs-negative phenotype, and disease relapse. The occurrence of hypertrophic pachymeningitis was associated with facial palsy (p < 0.05), both ANCAs-negative phenotype (p < 0.001), and headache (p < 0.001). The administration of corticosteroid together with an immunosuppressant was an independent predicting factor for lack of disease relapse (odds ratio [OR] = 1.90, p = 0.03) and an improvement in hearing loss (OR =2.58, p = 0.0002).. Since OMAAV has novel clinical features, the disease may be categorized as a subentity for the classification of AAV.

Topics: Adult; Age Factors; Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Female; Health Surveys; Humans; Japan; Male; Middle Aged; Myeloblastin; Otitis Media; Peroxidase; Retrospective Studies; Sex Factors; Treatment Outcome

Observations in patients with ANCA-associated vasculitis suggest that CD8

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoantigens; CD8-Positive T-Lymphocytes; Glomerulonephritis; Kidney Glomerulus; Male; Mice; Mice, Inbred C57BL; Peroxidase

To correlate the serotype specificity to myeloperoxidase (MPO) and proteinase-3 (PR3) with clinical characteristics in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).. Clinical characteristics and outcomes of patients with AAV in our division from 2005 to 2014 were retrospectively compared on the basis of ANCA subtype.. We collected the data from 88 patients with MPO-ANCA vasculitis, and 17 with PR3-ANCA vasculitis. Patients with PR3-ANCA vasculitis were younger, and had higher involvement-rates in the eye, nose, and ear. In both MPO- and PR3-ANCA vasculitis, the most frequently involved organ was the respiratory system. Interstitial pneumonia was more frequent in MPO-ANCA vasculitis (52.3% versus 5.9%, p < 0.01), whereas nodular shadow was more frequent in PR3-ANCA vasculitis (9.1% versus 58.8%, p < 0.01). Multivariable Cox proportional hazard regression analysis showed that the hazard ratio of PR3-ANCA for relapse was 2.48 (95% confidence interval 1.14-5.42, p = 0.02). There was no difference in the survival and the progression to end-stage kidney disease and respiratory failure between the two vasculitides.. MPO-ANCA vasculitis was a predominant form of AAV in Japan. Classification based on ANCA subtype would be clinically relevant in the prediction of organ involvement and relapse.

Topics: Adult; Age Factors; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Chronic Disease; Female; Humans; Japan; Male; Middle Aged; Myeloblastin; Peroxidase; Phenotype; Recurrence; Retrospective Studies; Risk Factors; Sex Factors

This multicentre study was performed to evaluate the diagnostic accuracy of a wide spectrum of novel technologies nowadays available for detection of myeloperoxidase (MPO) and proteinase 3 (PR3)-antineutrophil cytoplasmic antibodies (ANCAs).. Sera (obtained at the time of diagnosis) from 251 patients with ANCA-associated vasculitis (AAV), including granulomatosis with polyangiitis and microscopic polyangiitis, and from 924 disease controls were tested for the presence of cytoplasmic pattern/perinuclear pattern and atypical ANCA (A-ANCA) by indirect immunofluorescence (IIF) (at two sites) and for the presence of PR3-ANCA and MPO-ANCA by eight different immunoassays.. The area under the curve (AUC) of the receiver operating characteristic curve to discriminate AAV from controls was 0.923 (95% CI 0.902 to 0.944) and 0.843 (95% CI 0.814 to 0.871) for the two IIF methods. For the antigen-specific immunoassays, the AUC varied between 0.936 (95% CI 0.912 to 0.960) and 0.959 (95% CI 0.941 to 0.976), except for one immunoassay for which the AUC was 0.919 (95% CI 0.892 to 0.945).. Our comparison of various ANCA detection methods showed (i) large variability between the two IIF methods tested and (ii) a high diagnostic performance of PR3-ANCA and MPO-ANCA by immunoassay to discriminate AAV from disease controls. Consequently, dual IIF/antigen-specific immunoassay testing of each sample is not necessary for maximal diagnostic accuracy. These results indicate that the current international consensus on ANCA testing for AAV needs revision.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Area Under Curve; Case-Control Studies; Fluorescent Antibody Technique, Indirect; Immunoassay; Myeloblastin; Peroxidase; ROC Curve

Topics: Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antihypertensive Agents; Drug Eruptions; Extracellular Traps; Humans; Hydralazine; Immunoglobulin G; Peroxidase

ANCA-associated vasculitis is an autoimmune condition characterized by vascular inflammation and organ damage. Pharmacologically induced remission of this condition is complicated by relapses. Potential triggers of relapse are immunologic challenges and environmental insults, both of which associate with changes in epigenetic silencing modifications. Altered histone modifications implicated in gene silencing associate with aberrant autoantigen expression. To establish a link between DNA methylation, a model epigenetic gene silencing modification, and autoantigen gene expression and disease status in ANCA-associated vasculitis, we measured gene-specific DNA methylation of the autoantigen genes myeloperoxidase (

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoantigens; DNA Methylation; Female; Gene Expression Regulation; Humans; Male; Middle Aged; Myeloblastin; Peroxidase; Prognosis; Remission Induction

To evaluate the effect of rituximab on pathogenic autoantibodies and total Ig levels, and to identify serious adverse events in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with continuous B cell depletion.. We conducted a retrospective analysis of 239 patients with AAV treated with rituximab-induced continuous B cell depletion. Two treatment cohorts were analyzed: an induction group (n = 52) and a maintenance group (n = 237). Changes in ANCA titers and total Ig levels over time were evaluated using mixed-effects models. Risk factors for serious infections during maintenance treatment were evaluated using Poisson regression.. During induction, IgG levels fell at a mean rate of 6% per month (95% confidence interval [95% CI] 4, 8%), while ANCA levels declined at a mean rate of 47% per month (95% CI 42, 52%) and 48% per month (95% CI 42, 54%) for patients with antimyeloperoxidase (anti-MPO) antibodies and those with anti-proteinase 3 (anti-PR3) antibodies, respectively. During maintenance treatment, with a median duration of 2.4 years (interquartile range 1.5, 4.0 years), IgG levels declined a mean of 0.6% per year (95% CI -0.2, 1.4%). New significant hypogammaglobulinemia (IgG level of <400 mg/dl) during maintenance treatment occurred in 4.6% of the patients, all of whom were in the lowest baseline IgG quartile. Serious infections during maintenance therapy occurred at a rate of 0.85 per 10 patient-years (95% CI 0.66, 1.1) and were independently associated with an IgG level of <400 mg/dl.. B cell-targeted therapy causes a preferential decline in ANCA titers relative to total IgG levels. Despite prolonged maintenance therapy with rituximab, IgG levels remain essentially constant. Serious infections were rare.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antirheumatic Agents; Autoantibodies; Female; Humans; Immunoglobulin G; Immunologic Deficiency Syndromes; Infections; Maintenance Chemotherapy; Male; Middle Aged; Myeloblastin; Peroxidase; Remission Induction; Retrospective Studies; Rituximab

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

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; DNA; DNA Methylation; Epigenesis, Genetic; Glomerulonephritis; Humans; Peroxidase

To clarify the roles of neutrophils in anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitic neuropathy, we studied neutrophil extracellular traps (NETs) in peripheral nerve vasculitis. Stored nerve samples from 17 patients with microscopic polyangiitis (MPA) were immunohistochemically analyzed using antibodies for citrullinated histone H3 (citH3) and various neutrophil enzymes. We defined merged citH3 and extracellularly released myeloperoxidase (MPO) as NET formation. We also compared NET formation between MPO-ANCA-positive/negative MPA and rheumatoid arthritis (RA)-associated vasculitic neuropathy. NETs were identified mostly in vasculitic small arterioles of 6 of 12 MPO-ANCA-positive MPA patients, and their frequency was higher (p < 0.05) than in ANCA-negative patients. NETs were not found in vasculitic neuropathy with RA or patients with chronic inflammatory demyelinating polyradiculoneuropathy. NETs were also observed in the peripheral nervous system of MPA patients as well as in the lung and kidney. These results suggest that NETs may be involved in the pathogenesis of MPA neuropathy.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Arthritis, Rheumatoid; Extracellular Traps; Female; Humans; Japan; Kidney; Male; Microscopic Polyangiitis; Middle Aged; Neutrophils; Peripheral Nerves; Peripheral Nervous System Diseases; Peroxidase; Retrospective Studies

Anti-neutrophil cytoplasmic antibody (ANCA) vasculitis is characterized by the presence of autoantibodies to myeloperoxidase and proteinase-3, which bind monocytes in addition to neutrophils. While a pathological effect on neutrophils is acknowledged, the impact of ANCA on monocyte function is less well understood. Using IgG from patients we investigated the effect of these autoantibodies on monocytes and found that anti-myeloperoxidase antibodies (MPO-ANCA) reduced both IL-10 and IL-6 secretion in response to LPS. This reduction in IL-10 and IL-6 depended on Fc receptors and enzymatic myeloperoxidase and was accompanied by a significant reduction in TLR-driven signaling pathways. Aligning with changes in TLR signals, oxidized phospholipids, which function as TLR4 antagonists, were increased in monocytes in the presence of MPO-ANCA. We further observed that MPO-ANCA increased monocyte survival and differentiation to macrophages by stimulating CSF-1 production. However, this was independent of myeloperoxidase enzymatic activity and TLR signaling. Macrophages differentiated in the presence of MPO-ANCA secreted more TGF-β and further promoted the development of IL-10- and TGF-β-secreting CD4

Topics: Adult; Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; CD4-Positive T-Lymphocytes; Cell Survival; Cells, Cultured; Female; Humans; Immunoglobulin G; Interleukin-10; Interleukin-6; Lipopolysaccharides; Lymphopoiesis; Macrophage Colony-Stimulating Factor; Macrophages; Male; Middle Aged; Monocytes; Oxidation-Reduction; Peroxidase; Phospholipids; Receptors, Fc; Toll-Like Receptors; Transforming Growth Factor beta

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antihypertensive Agents; Biomarkers; Dyspnea; Fatigue; Glomerulonephritis; Humans; Hydralazine; Immunosuppressive Agents; Male; Peroxidase; Plasmapheresis; Pulse Therapy, Drug; Renal Insufficiency; Steroids

A 14-year-old Japanese girl was admitted to our institution for the evaluation of renal dysfunction. Her serum creatinine was 1.1 mg/dL, proteinuria was 1.5 g/day, the urine sediment contained numerous erythrocytes per high-power field, and she was positive for myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA). Proteinuria was first noted at the age of 12 years. Renal biopsy showed crescentic glomerulonephritis with slight immunoglobulin A (IgA) deposition. A diagnosis of ANCA-associated vasculitis was made. Immunosuppressive therapy was initiated, including steroid pulse therapy and intravenous cyclophosphamide pulse therapy, but hemodialysis was required after 6 years. Eight months after the patient became anuric and her MPO-ANCA titer became negative, living-related donor kidney transplantation was done from her mother. ANCA became slightly positive 2 years later, but the patient remains stable without proteinuria or hematuria at 4 years after surgery. This case suggests that kidney transplantation can be performed successfully for a patient with refractory childhood-onset ANCA-associated vasculitis, and that remission of vasculitis associated with ANCA negativity at transplantation may contribute to a better renal prognosis in this patient.

Topics: Adolescent; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Humans; Kidney Function Tests; Kidney Transplantation; Peroxidase; Proteinuria; Treatment Outcome

This study investigated the clinical course of myeloperoxidase-antineutrophil cytoplasm autoantibody (MPO-ANCA)-associated vasculitis after starting dialysis.. A retrospective review was conducted of the clinical charts of dialysis-dependent patients with MPO-ANCA-associated vasculitis who attended one of 8 associated clinics over the past 21 years.. Eighty-nine patients were included in the study; 88 had microscopic polyangiitis (MPA) and 1 had granulomatosis with polyangiitis. Of the 88 patients with MPA, 18 had renal-limited vasculitis. Twenty-one relapses occurred among 13 patients (frequency, 0.05 relapses/person-year; 95% confidence interval, 0.03-0.08). Mean time from start of dialysis to relapse was 65 ± 59 months. Cox multivariate analysis showed that pulmonary involvement was a predictor of relapse (hazard ratio [HR], 21.4) and mortality (HR, 4.60), and that patient age (HR, 1.10) and cyclophosphamide use (HR, 0.20) were significant predictors of mortality. Postdialysis 1- and 5-year survival rates were 83.0% and 65.6%, respectively; infection was the most frequent cause of death.. Pulmonary involvement was a predictor of relapse and mortality. Although relapse can occur long after the start of dialysis, incidence was low among dialysis-dependent patients. Prolonged maintenance immunosuppressive therapy might be limited to patients with pulmonary involvement in dialysis-dependent ANCA-associated vasculitis.

Topics: Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Cyclophosphamide; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Multivariate Analysis; Peroxidase; Recurrence; Renal Dialysis; Retrospective Studies; Survival Rate

Observations in experimental murine myeloperoxidase (MPO)-ANCA-associated vasculitis (AAV) show mast cells degranulate, thus enhancing injury as well as producing immunomodulatory IL-10. Here we report that, compared with biopsy specimens from control patients, renal biopsy specimens from 44 patients with acute AAV had more mast cells in the interstitium, which correlated with the severity of tubulointerstitial injury. Furthermore, most of the mast cells were degranulated and spindle-shaped in patients with acute AAV, indicating an activated phenotype. We hypothesized that the mast cell stabilizer disodium cromoglycate would attenuate mast cell degranulation without affecting IL-10 production. We induced anti-MPO GN by immunizing mice with MPO and a low dose of anti-glomerular basement membrane antibody. When administered before or after induction of MPO autoimmunity in these mice, disodium cromoglycate attenuated mast cell degranulation, development of autoimmunity, and development of GN, without diminishing IL-10 production. In contrast, administration of disodium cromoglycate to mast cell-deficient mice had no effect on the development of MPO autoimmunity or GN. MPO-specific CD4(+) effector T cell proliferation was enhanced by co-culture with mast cells, but in the presence of disodium cromoglycate, proliferation was inhibited and IL-10 production was enhanced. These results indicate that disodium cromoglycate blocks injurious mast cell degranulation specifically without affecting the immunomodulatory role of these cells. Thus as a therapeutic, disodium cromoglycate may substantially enhance the regulatory role of mast cells in MPO-AAV.

Topics: Aged; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoimmune Diseases; Cromolyn Sodium; Female; Glomerulonephritis; Humans; Male; Mast Cells; Mice; Peroxidase

Antineutrophil cytoplasmic antibody (ANCA) and neutrophil interactions play important roles in ANCA-associated vasculitis (AAV) pathogenesis. However, mechanisms underlying the pathogenesis of crescent formation in ANCA-associated vasculitis have not been completely elucidated. To ascertain the involvement of these interactions in necrotizing crescentic glomerulonephritis (NCGN), we used an AAV rat model and investigated the effects of the anti-myeloperoxidase (MPO) antibody (Ab) titer, tumor necrosis factor α (TNF-α), granulocyte colony-stimulating factor (G-CSF) and subnephritogenic anti-glomerular basement membrane (GBM) Abs, as proinflammatory stimuli.. NCGN was induced in Wistar Kyoto rats by human MPO (hMPO) immunization. Renal function, pathology, and glomerular cytokine and chemokine expression were evaluated in hMPO-immunized rats with/without several co-treatments (TNF-α, G-CSF or subnephritogenic anti-GBM Abs). Rat neutrophils activation by IgG purified from rat serum in each group was examined in vitro.. The hMPO-immunized rats had significantly higher level of anti-hMPO Ab production. The induced anti-hMPO Abs cross-reacted with TNF-α- or G-CSF-primed rat neutrophils secreting TNF-α and interleukin-1β in vitro. The reactivity of anti-MPO Abs against rat MPO, crescent formation with neutrophil extracellular traps and glomerular-activated neutrophil infiltration in the rat model were significantly enhanced by subnephritogenic anti-GBM Ab but not by TNF-α or G-CSF administration. The model rats injected with the subnephritogenic anti-GBM Abs showed increased urinary albumin excretion and serum TNF-α, chemokine (C-X-C) ligand 1 (CXCL1) and CXCL2 levels. TNF-α, CXCL1, CXCL2 and CXCL8 increased in the glomeruli with significant amounts of crescent formation. In addition, in vitro activated neutrophils decreased CXC chemokine receptor 1 (CXCR1) and CXCR2 expressions.. The coexistence of subnephritogenic anti-GBM Abs leads to the inflammatory environment in glomeruli that is amplified by the interaction of ANCA and neutrophils. Development of NCGN in MPO-AAV may be necessary for not only the accumulation of neutrophils in glomeruli, but also the aberrant neutrophil activation on glomerulonephritis.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Chemokine CXCL1; Chemokines; Glomerular Basement Membrane; Glomerulonephritis; Granulocyte Colony-Stimulating Factor; Humans; Interleukin-1beta; Male; Neutrophil Activation; Neutrophils; Peroxidase; Rats; Rats, Inbred WKY; Tumor Necrosis Factor-alpha

Anti-neutrophil cytoplasmic antibody (ANCA) is associated with small-vessel vasculitis particularly in the kidneys and can induce the formation of neutrophil extracellular traps (NETs) from primed neutrophils. Recently we have reported that the induction of NETs correlates with ANCA affinity for myeloperoxidase (MPO) and disease activity in patients with MPO-ANCA-associated microscopic polyangiitis. To investigate whether MPO-ANCA affinity is associated with the formation of NETs in vivo, we examined the occurrence of NETs in the renal tissues of patients with MPO-ANCA-associated microscopic polyangiitis and ANCA affinity by double immunofluorescence staining for NET components of citrullinated histone, MPO and PAD4 and by ELISA competition with MPO, respectively. We divided 30 MPO-ANCA-associated microscopic polyangiitis patients into 2 groups based on their ANCA affinity levels (IC50 for the high: 0.11 ± 0.04 µg/mL (Group1) and IC50 for the low: 0.66 ± 0.24 µg/mL (Group2)). Group1 showed a higher Birmingham vasculitis activity score (15.6 ± 5.7) and 73% of the patients presented clinically with rapidly progressive glomerulonephritis and histologically with focal/crescentic glomerulonephritis (GN). Group 2 showed a lower Birmingham vasculitis activity score (9.2 ± 4.9) and 73% of the patients presented clinically with chronic renal failure and histologically with mixed/sclerotic GN. Group 1 showed a much higher occurrence of NETs than Group 2. Our findings indicate that ANCA affinity was associated with the in vivo formation of NETs, which might be involved in the pathophysiology of patients with MPO-ANCA-associated microscopic polyangiitis.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Biopsy; Citrulline; Enzyme-Linked Immunosorbent Assay; Extracellular Traps; Female; Fluorescent Antibody Technique; Histones; Humans; Hydrolases; Kidney; Male; Microscopic Polyangiitis; Middle Aged; Neutrophils; Peroxidase; Predictive Value of Tests; Protein-Arginine Deiminase Type 4; Protein-Arginine Deiminases

The contribution of infections to the mortality of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is important, and early and careful infection control is necessary. We investigated the usefulness of the serum-soluble haemoglobin scavenger receptor CD163 for detecting the presence of infectious complications regardless of disease activity.. Soluble CD163 in serum obtained from 45 Japanese patients with myeloperoxidase (MPO)-AAV was measured by an enzyme-linked immunosorbent assay (ELISA). We evaluated 36 samples from active-vasculitis patients, 36 samples from inactive-vasculitis patients without infection, and 19 samples from inactive-vasculitis patients with infectious complications. Serum-soluble CD163 was also measured in 15 infectious patients without vasculitis and in 30 normal controls.. The mean serum-soluble CD163 level was higher in the patients with infectious complications than in the active-vasculitis patients, inactive-vasculitis patients, and normal controls. There were significant positive correlations between serum-soluble CD163 levels and white blood cell (WBC) count, serum C-reactive protein (CRP) levels, and serum albumin levels, but only serum CRP levels were correlated with serum-soluble CD163 levels in a multiple regression analysis. On the receiver-operating characteristic (ROC) curve, serum-soluble CD163 levels had 80.6% sensitivity and 86.7% specificity for differentiating patients with infection from those without infection. Among the active-vasculitis patients, the mean serum-soluble CD163 level of the patients with alveolar haemorrhage was significantly lower than that of the patients with interstitial lung diseases and that of the patients without pulmonary lesions.. The serum-soluble CD163 level may be a useful marker for the detection of infectious complications in MPO-AAV patients.

Topics: Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Bacterial Infections; Bronchitis; C-Reactive Protein; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Female; Humans; Kidney Diseases; Leukocyte Count; Male; Microscopic Polyangiitis; Middle Aged; Peroxidase; Pleurisy; Pneumonia, Bacterial; Pyelonephritis; Receptors, Cell Surface; Regression Analysis; Renal Insufficiency, Chronic; ROC Curve; Sensitivity and Specificity; Serum Albumin; Tuberculosis, Pulmonary

Among antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), granulomatosis with polyangiitis (GPA) and proteinase 3-ANCA-positive AAV (PR3-AAV) are prevalent in European populations, while microscopic polyangiitis (MPA) and myeloperoxidase-ANCA-positive AAV (MPO-AAV) are predominant in the Japanese. We previously demonstrated association of DRB1*09:01-DQB1*03:03 haplotype, a haplotype common in East Asians but rare in the European populations, with MPA/MPO-AAV, suggesting that a population difference in HLA-class II plays a role in the epidemiology of this disease. To gain further insights, we increased the sample size and performed an extended association study of DRB1 and DPB1 with AAV subsets in 468 Japanese patients with AAV classified according to the European Medicines Agency algorithm (MPA: 285, GPA: 92, eosinophilic GPA [EGPA]: 56, unclassifiable: 35) and 596 healthy controls. Among these patients, 377 were positive for MPO-ANCA and 62 for PR3-ANCA. The significance level was set at α = 3.3x10-4 by applying Bonferroni correction. The association of DRB1*09:01 with MPO-AAV was confirmed (allele model, P = 2.1x10-4, odds ratio [OR] = 1.57). Protective association of DRB1*13:02 was detected against MPO-AAV (allele model, P = 2.3x10-5, OR = 0.42) and MPA (dominant model, P = 2.7x10-4, OR = 0.43). A trend toward increased frequency of DPB1*04:01, the risk allele for GPA in European populations, was observed among Japanese patients with PR3-AAV when conditioned on DRB1*13:02 (Padjusted = 0.0021, ORadjusted = 3.48). In contrast, the frequency of DPB1*04:01 was decreased among Japanese patients with MPO-AAV, and this effect lost significance when conditioned on DRB1*13:02 (Padjusted = 0.16), suggesting that DRB1*13:02 or other allele(s) in linkage disequilibrium may be responsible for the protection. The differential association of DPB1*04:01 with PR3-AAV and MPO-AAV and difference in DPB1*04:01 allele frequencies between populations supported the hypothesis that the HLA-class II population difference may account in part for these epidemiologic characteristics. Furthermore, taken together with our previous observations, the haplotype carrying DRB1*13:02 was suggested to be a shared protective factor against multiple autoimmune diseases.

Topics: Adult; Aged; Alleles; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Case-Control Studies; Female; Gene Expression; Gene Frequency; Haplotypes; HLA-DRB1 Chains; Humans; Japan; Linkage Disequilibrium; Male; Microscopic Polyangiitis; Middle Aged; Odds Ratio; Peroxidase; Protective Factors

Anti-neutrophil cytoplasmic antibody vasculitis is a systemic autoimmune disease with glomerulonephritis and pulmonary haemorrhage as major clinical manifestations. The name reflects the presence of autoantibodies to myeloperoxidase and proteinase-3, which bind to both neutrophils and monocytes. Evidence of the pathogenicity of these autoantibodies is provided by the observation that injection of anti-myeloperoxidase antibodies into mice causes a pauci-immune focal segmental necrotizing glomerulonephritis which is histologically similar to the changes seen on renal biopsy in patients. Previous studies in this model have implicated the alternative pathway of complement activation and the anaphylatoxin C5a. Despite this progress, the factors that initiate complement activation have not been defined. In addition, the relative importance of bone marrow-derived and circulating C5 is not known. This is of interest given the recently identified roles for complement within leukocytes. We induced anti-myeloperoxidase vasculitis in mice and confirmed a role for complement activation by demonstrating protection in C3-deficient mice. We showed that neither MASP-2- nor properdin-deficient mice were protected, suggesting that alternative pathway activation does not require properdin or the lectin pathway. We induced disease in bone marrow chimaeric mice and found that circulating and not bone marrow-derived C5 was required for disease. We have therefore excluded properdin and the lectin pathway as initiators of complement activation and this means that future work should be directed at other potential factors within diseased tissue. In addition, in view of our finding that circulating and not bone marrow-derived C5 mediates disease, therapies that decrease hepatic C5 secretion may be considered as an alternative to those that target C5 and C5a. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Bone Marrow; Complement C3; Complement C5; Disease Models, Animal; Mannose-Binding Protein-Associated Serine Proteases; Mice; Mice, Knockout; Peroxidase; Properdin

Detection of antineutrophil cytoplasmic antibodies (ANCA) for ANCA-associated vasculitides (AAV) is based on indirect immunofluorescence (IIF) on ethanol-fixed neutrophils and reactivity toward myeloperoxidase (MPO) and proteinase 3 (PR3). According to the international consensus for ANCA testing, presence of ANCA should at least be screened for by IIF and, if positive, followed by antigen-specific immunoassays. Optimally, all samples are analyzed by both IIF and quantitative antigen-specific immunoassays. Since the establishment of this consensus many new technologies have become available and this has challenged the positioning of IIF in the testing algorithm for AAV. In the current paper, we summarize the novelties in ANCA diagnostics and discuss the possible implications of these developments for the different ANCA algorithms that are currently applied in routine diagnostic laboratories. Possible consequences of replacing ANCA assays by novel methods are illustrated by our data obtained in daily clinical practice. Eventually, it is questioned if there is a need to change the consensus, and if so, whether IIF can be discarded completely, or be used as a confirmation assay instead of a screening assay. Both alternative options require that ANCA requests for AAV can be separated from ANCA requests for gastrointestinal autoimmune diseases.

Topics: Algorithms; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Fluorescent Antibody Technique, Indirect; Humans; Immunoassay; Myeloblastin; Neutrophils; Peroxidase

To investigate the clinical features of patients with antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV), and to explore the disease activity of AAV patients and the relationship with prognosis.. The clinical data of 46 cases of AAV patients in the First Affiliated Hospital of PLA General Hospital were analyzed retrospectively.The clinical and laboratory features of each clinical subtype were compared.The disease activity of AAV and the relationship between disease activity and prognosis were evaluated.. Among the 46 patients with AAV, 24 were male, and 22 were female, with the average age of 56±18.Among the subtypes of AAV, the number of granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA) were 22, 17 and 4 respectively, while the positive rate of ANCA are 72.7%, 88.2% and 50.0% respectively.For GPA, the results of ANCA were mainly C-ANCA or ANCA directed toward proteinase-3 (PR3), and for MPA, the results of ANCA were mainly P-ANCA or ANCA directed toward myeloperoxidase (MPO). Upper and lower respiratory disease, renal involvement and non-deformity arthropathy were the common clinical manifestations of all primary AAV subtypes.Epistaxis, nasal blood scab, saddle nose, pulmonary nodule and intrapulmonary cavities were the characteristic manifestations of GPA, while rapid progress of renal failure was prominent in MPA.Whatever their ANCA results, there were no significant differences between each other as to system-organ involvements and laboratory indexes.Seven patients (15.2%) died during hospitalization or in follow-up visits.Serious involvements of heart, lung, kidney, and complicated with infections were the main risk factors of death in AAV patients.. Upper and lower respiratory involvements and kidney diseases are the primary manifestations of AAV patients.ANCA results are irrelevant with disease activity and system-organ involvements.Serious involvements of heart, lung, kidney, and complicated with infections are the main risk factors of death in AAV patients.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Humans; Kidney; Kidney Diseases; Lung; Male; Middle Aged; Myeloblastin; Peroxidase; Retrospective Studies

Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease characterized by destructive vascular inflammation. Two prominent ANCA autoantigens are myeloperoxidase (MPO) and proteinase 3 (PR3), and transcription of. We identified a network of genes regulating histone modifications that were differentially expressed in AAV patients compared to healthy controls. We focused on four genes (

Topics: Acylation; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Epigenesis, Genetic; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Histones; Humans; Methylation; Myeloblastin; Oligonucleotide Array Sequence Analysis; Peroxidase

Current biomarkers of renal disease in systemic vasculitis lack predictive value and are insensitive to early damage. To identify novel biomarkers of renal vasculitis flare, we analysed the longitudinal urinary metabolomic profile of a rat model of anti-neutrophil cytoplasmic antibody (ANCA) vasculitis. Wistar-Kyoto (WKY) rats were immunised with human myeloperoxidase (MPO). Urine was obtained at regular intervals for 181 days, after which relapse was induced by re-challenge with MPO. Urinary metabolites were assessed in an unbiased fashion using nuclear magnetic resonance (NMR) spectroscopy, and analysed using partial least squares discriminant analysis (PLS-DA) and partial least squares regression (PLS-R). At 56 days post-immunisation, we found that rats with vasculitis had a significantly different urinary metabolite profile than control animals; the observed PLS-DA clusters dissipated between 56 and 181 days, and re-emerged with relapse. The metabolites most altered in rats with active or relapsing vasculitis were trimethylamine N-oxide (TMAO), citrate and 2-oxoglutarate. Myo-inositol was also moderately predictive. The key urine metabolites identified in rats were confirmed in a large cohort of patients using liquid chromatography-mass spectrometry (LC-MS). Hypocitraturia and elevated urinary myo-inositol remained associated with active disease, with the urine myo-inositol:citrate ratio being tightly correlated with active renal vasculitis.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Citric Acid; Disease Models, Animal; Female; Humans; Immunization; Ketoglutaric Acids; Kidney Diseases; Least-Squares Analysis; Male; Metabolomics; Methylamines; Peroxidase; Rats; Rats, Inbred WKY; Recurrence

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Granuloma; Humans; Lung Diseases; Middle Aged; Peroxidase; Sjogren's Syndrome

Proteinase 3 (PR3) and myeloperoxidase (MPO) are two major autoantigens in patients with vasculitis with ANCA. The genes encoding these autoantigens are abnormally expressed in peripheral granulocytes of patients with active ANCA-associated vasculitis. This study provides evidence that this transcriptional dysregulation results in a variety of mRNA processing events from the PRTN3 gene locus. In addition to elevated levels of PR3 message, leukocyte RNA from patients contained PR3 transcripts with an alternative 3' untranslated region. Furthermore, we detected usage of an alternative transcription start site within intron 1 of the PRTN3 gene locus that coincided with active disease (odds ratio, 3.3; 95% confidence interval, 1.3 to 8.4; P=0.01). This promoter may be developmentally regulated, because it was active in normal human bone marrow, multiple leukemia cell lines, MCF-7 cells, and subjects after GM-CSF treatment but not subjects with a neutrophil left shift. This transcript, which lacks exon 1 of PRTN3, encodes a 24-kD protein (p24(PR3/MBN)) with a sequence similar to that previously described for myeloblastin. Notably, PR3, p24(PR3/MBN), and MPO were synthesized in cultured neutrophils from patients with active ANCA-associated vasculitis, indicating that increased transcription results in newly synthesized autoantigens in peripheral neutrophils of patients. The synthesis of p24(PR3/MBN) seems to expand the autoantigen repertoire, because immunoblots showed that sera from patients recognized p24(PR3/MBN). These findings emphasize the importance of transcriptional dysregulation of the autoantigen in autoimmune disease.

Topics: Adult; Aged; Aged, 80 and over; Amino Acid Sequence; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoantigens; Base Sequence; Case-Control Studies; Cells, Cultured; Exons; Female; Humans; Male; Middle Aged; Molecular Sequence Data; Myeloblastin; Neutrophils; Peroxidase; Protein Biosynthesis; Transcription, Genetic

Myeloperoxidase (MPO) anti-neutrophil cytoplasmic antibody (ANCA) represents the serological hallmark of ANCA-associated vasculitis (AAV). We evaluated the analytical and diagnostic accuracy of chemiluminescence enzyme immunoassay (CLEIA) versus enzyme-linked immunosorbent assay (ELISA) for the detection of MPO-ANCA.. A total of 242 sera obtained from 51 patients with AAV and 103 patients without AAV were tested for MPO-ANCA by ELISA (NephroScholor MPOANC II) and CLEIA (the STACIA MEBLux test). Disease activity in the patients with AAV was determined based on the Birmingham Vasculitis Activity Score. We analyzed the correlations between the MPO-ANCA titers determined by the CLEIA and those determined by the ELISA, and also between the MPO-ANCA titers and the disease activity.. The MPO-ANCA titers determined by the CLEIA (x) were strongly correlated with those determined by the ELISA (y). The correlation could be expressed by the following equation in this study: y = 1.8x + 7.7 (r = 0.96; p < 0.0001). At the cutoff value of 3.5 U/ml, the CLEIA yielded positive test results for MPO-ANCA in 73 of the 242 sera (30.2%), while at the cutoff value of 20 U/ml, ELISA yielded positive test results in 57 of the 242 sera (23.6%). The CLEIA yielded false-positive test results in 4 of the 120 sera obtained from the non-AAV patients (3.3%), whereas the ELISA yielded a false-positive result in only 1 of the 120 sera obtained from the non-AAV patients (0.8%). The sensitivity and specificity of the CLEIA for the diagnosis of AAV were 100% and 96.7%, respectively, while those of the ELISA were 94.3% and 99.2%, respectively. The sensitivity and specificity of the CLEIA for the prediction of active disease were 100% and 64.4%, respectively, while those of the ELISA were 94.3% and 73.6%, respectively.. The false positivity rate of the CLEIA for MPO-ANCA tended to be high as compared with that of the ELISA. Also, according to the correlation coefficient between the results of the CLEIA and the ELISA calculated in this study, it is necessary to pay attention to the differences in the sensitivity and specificity between CLEIA and ELISA.

Topics: Adult; Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Enzyme-Linked Immunosorbent Assay; Female; Humans; Luminescent Measurements; Male; Middle Aged; Peroxidase; Reproducibility of Results; Sensitivity and Specificity; Young Adult

Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis affects small vessels in the kidney (i.e., arterioles, glomerular or peritubular capillaries, or venules). Although crescentic glomerulonephritis is a common histological finding, the incidence of peritubular capillaritis (PTC) or arteriolitis is unclear. Moreover, the laboratory data that reflect the degree of renal histological damage and distinguish between PTC and arteriolitis have not yet been clarified.. We investigated laboratory data and histological findings from 11 patients diagnosed with ANCA-associated vasculitis (2 men and 9 women, mean age 70.3 ± 3.3 years) whose renal biopsies were performed between 2009 and 2014.. All patients were positive for myeloperoxidase (MPO)-ANCA. PTC or arteriolitis was detected in six patients (54.5 %), respectively. The only significant positive relationship between laboratory data and histological findings observed was that between levels of urinary α1 microglobulin (u-α1MG) excretion and the percentage of tubular atrophy and interstitial fibrosis (r = 0.67, p = 0.035). No significant differences in laboratory data were found between patients with or without arteriolitis. However, the levels of u-α1MG excretion were significantly higher in patients with PTC than in those without PTC (75.2 ± 19.5 vs. 15.0 ± 3.6 mg/dl, p = 0.035).. PTC or arteriolitis occurs at a high rate independently of crescentic glomerulonephritis in ANCA-associated vasculitis patients. The levels of u-α1MG excretion reflect the degrees of tubular atrophy and interstitial fibrosis. Moreover, high levels of u-α1MG excretion suggest that PTC is more likely than arteriolitis in ANCA-associated vasculitis patients.

Topics: Aged; Aged, 80 and over; Alpha-Globulins; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Capillaries; Female; Glomerulonephritis; Humans; Kidney; Kidney Glomerulus; Male; Middle Aged; Peroxidase; Retrospective Studies

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Male; Peroxidase; Plasmapheresis

Monocyte subsets with differing functional properties have been defined by their expression of CD14 and CD16. We investigated these subsets in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) and determined their surface expression of ANCA autoantigens. Flow cytometry was performed on blood from 14 patients with active AAV, 46 patients with AAV in remission and 21 controls. The proportion of classical (CD14(high) CD16(neg/low)), intermediate (CD14(high) CD16(high)) and non-classical (CD14(low) CD16(high)) monocytes and surface expression levels of CD14 and CD16 were determined, as well as surface expression of proteinase 3 (PR3) and myeloperoxidase (MPO) on monocyte subsets. There was no change in the proportion of monocytes in each subset in patients with AAV compared with healthy controls. The expression of CD14 on monocytes from patients with active AAV was increased, compared with patients in remission and healthy controls (P < 0.01). Patients with PR3-ANCA disease in remission also had increased monocyte expression of CD14 compared with controls (P < 0.01); however, levels in patients with MPO-ANCA disease in remission were lower than active MPO-ANCA patients, and not significantly different from controls. There was a correlation between CD14 and both PR3 and MPO expression on classical monocytes in AAV patients (r = 0.79, P < 0.0001 and r = 0.42, P < 0.005, respectively). In conclusion, there was an increase in monocyte CD14 expression in active AAV and PR3-ANCA disease in remission. The correlation of CD14 expression with ANCA autoantigen expression in AAV may reflect cell activation, and warrants further investigation into the potential for increased CD14 expression to trigger disease induction or relapse.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Flow Cytometry; GPI-Linked Proteins; Humans; Lipopolysaccharide Receptors; Male; Middle Aged; Monocytes; Myeloblastin; Peroxidase; Receptors, IgG

Disease control in anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) with immunosuppression is effective but burdened by adverse events, especially infections. The study goal was to evaluate risks and types of infections in patients with AAV.. Biopsy-proven AAV patients (diagnosed 1/1991-6/2011) followed in an inception cohort were evaluated for adverse events. Severe infections (requiring intravenous antibiotics, intensive care unit, or causing death) were recorded. Infection number was grouped as none, 1-2 or ≥3. Cox regression was used to estimate hazard ratios with 95% confidence intervals.. A total of 489 patients (median age 59; 47% female, 55% myeloperoxidase-ANCA) were followed for 2.8 years (median). At 1, 2 and 5 years cumulative incidence of infection was 51, 58 and 65% and severe infection was 22, 23 and 26%. Pulmonary and upper respiratory infections were most common (42 and 30% ever experienced each, respectively), highest in the first 3 months. Staphylococcus aureus was most frequently seen among positive cultures (41%, 78 S. aureus/192 total positive cultures), and only one Pneumocystis jiroveci pneumonia (6 weeks into treatment). All-cause death in 12 months was associated with infections (% deaths: 0 infections 3%; 1-2 infections 10%, ≥3 infections 13%, P = 0.002). Controlling for age, sex and kidney function, patients with severe infections were 4.2 times more likely to die within 12 months (95% CI 2.0-8.7; P = 0.001).. More infections increase the risk of a severe infection which increases risk of all-cause mortality. Respiratory and S. aureus infections are dominant. Targeted prophylactic therapy could decrease morbidity.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Immunosuppressive Agents; Incidence; Kidney; Longitudinal Studies; Male; Middle Aged; North Carolina; Peroxidase; Prognosis; Staphylococcal Infections; Staphylococcus aureus; Survival Rate

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Female; Granulocytes; Humans; Leukocyte Elastase; Male; Myeloblastin; Peroxidase

To discover biomarkers involved in the pathophysiology of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and to determine whether low-density granulocytes (LDGs) contribute to gene expression signatures in AAV.. The source of clinical data and linked biologic specimens was a randomized controlled treatment trial in AAV. RNA sequencing of whole blood from patients with AAV was performed during active disease at the baseline visit and during remission 6 months later. Gene expression was compared between patients who met versus those who did not meet the primary trial outcome of clinical remission at 6 months (responders versus nonresponders). Measurement of neutrophil-related gene expression was confirmed in peripheral blood mononuclear cells (PBMCs) to validate the findings in whole blood. A negative-selection strategy isolated LDGs from PBMC fractions.. Differential expression between responders (n = 77) and nonresponders (n = 35) was detected in 2,346 transcripts at the baseline visit (P < 0.05). Unsupervised hierarchical clustering demonstrated a cluster of granulocyte-related genes, including myeloperoxidase (MPO) and proteinase 3 (PR3). A granulocyte multigene composite score was significantly higher in nonresponders than in responders (P < 0.01) and during active disease than during remission (P < 0.01). This signature strongly overlapped an LDG signature identified previously in lupus (false discovery rate by gene set enrichment analysis <0.01). Transcription of PR3 measured in PBMCs was associated with active disease and treatment response (P < 0.01). LDGs isolated from patients with AAV spontaneously formed neutrophil extracellular traps containing PR3 and MPO.. In AAV, increased expression of a granulocyte gene signature is associated with disease activity and decreased response to treatment. The source of this signature is likely LDGs, a potentially pathogenic cell type in AAV.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Biomarkers; Extracellular Traps; Female; Gene Expression Regulation; Glucocorticoids; Granulocytes; Humans; Leukocyte Elastase; Leukocytes, Mononuclear; Male; Middle Aged; Myeloblastin; Peroxidase; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome

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

The recently suggested distinct pathogenic pathways for myeloperoxidase (MPO) and proteinase 3 (PR3) anti-neutrophilic cytoplasmic antibodies (ANCA) associated vasculitis could result in different modes of presentation and outcome. Moreover, kidney outcome was related to a new histopathologic classification of pauci-immune glomerulonephritis. As reports were not always concordant, possible because differences in severity of organ lesions and ethnicity, we evaluated the outcome of a cohort of Central-East European patients with crescentic glomerulonephritis in relation with ANCA specificity and histopathological classification.. Seventy-five patients were consecutively diagnosed by kidney biopsy (76 % MPO-ANCA specificity, 52 % crescentic) and followed for a median period of 3.2 years. Study end-points were response to therapy, end stage renal disease (ESRD) and death.. PR3-ANCA patients were younger, in higher proportion male and had higher Birmingham Vasculitis Activity Scores (BVAS). The kidney disease was severe at presentation (median creatinine 5 mg/dL; 27 % required temporary dialysis) and worst in PR3-ANCA positive patients (50 % patients needed temporary dialysis vs. 19 %). The lung was the second most affected organ (31 % severe lung hemorrhage). Lung and kidney damage were related; the odds of hemorrhagic alveolitis in patients needing dialysis at presentation were 4 (95 % CI 1-13; p = 0.006) times higher than in those who did not. The rate of response to therapy (without signs of active vasculitis and stable or declining serum creatinine) was 60 % and was associated with dialysis independency, older age and higher platelet number at presentation. The probabilities to survival 1 and 5 years for kidney and patient were 93 and 64 %, and respectively 88 and 67 %. Kidney survival was predicted by response to therapy and dialysis independency at presentation. Patients with BVAS < 15 and responding to induction therapy had better chances of survival. Neither response to therapy nor outcome was influenced by ANCA specificity or by the histopathological class.. When kidney damage is severe in ANCA vasculitis, the need of dialysis at presentation and the response to induction therapy overcome the prognostic utility of both ANCA specificity and histopathological class.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Cohort Studies; Cyclophosphamide; Disease Progression; Female; Glomerulonephritis; Hemorrhage; Humans; Immunosuppressive Agents; Induction Chemotherapy; Kidney Failure, Chronic; Logistic Models; Lung Diseases; Maintenance Chemotherapy; Male; Methylprednisolone; Middle Aged; Myeloblastin; Peroxidase; Prednisone; Renal Dialysis; Retrospective Studies

This prospective study analyzed the clinical characteristics of myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis and explored the relationship between MPO-ANCA and clinical manifestations of the associated vasculitis in 132 p-ANCA and MPO-ANCA-positive patients (average age, 62.3 ± 14.8 years) who were initially diagnosed with ANCA-associated vasculitis. The p-ANCA and MPO-ANCA levels in peripheral blood were detected in all patients. Among these, 128 (97%) had microscopic polyangiitis (MPA), 3 (2.3%) had granulomatous polyangiitis, and 1 (0.7%) had eosinophilic granulomatous vasculitis. The average time of diagnosis was 10.2 ± 18 months; only 14 (10.6%) patients were diagnosed within 1 month. The main organs involved and the corresponding number of patients were: renal, 95 (72%); lung, 89 (67.4%); joints, 35 (26.5%); heart, 26 (19.7%); peripheral nerve, 23 (17.4%); skin rash, 14 (10.6%); and CNS, 13 (9.8%). Older patients were more likely to show lung involvement in the early disease stage, whereas the joints were involved mostly in the younger patients. The p-ANCA levels (mean titers, 1:60) were not correlated with disease activity and extent of organ involvement, and the MPO-ANCA levels were positively correlated with disease activity, but had no correlation with the extent of organ involvement. MPO-ANCA vasculitis is a common occurrence in China; it mainly involves the elderly and presents as clinical manifestations of MPA. However, the multiple organ damage is not specific leading to delay in diagnosis. MPO-ANCA may play a pathogenic role in the associated vasculitis, and the diverse clinical manifestations might be related with the different characteristics of MPO-ANCA.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Child; Child, Preschool; China; Female; Humans; Male; Middle Aged; Neutrophils; Peroxidase; Prospective Studies

To investigate the incidence of malignancies during longitudinal followup of patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV), and to examine the effect of immunosuppressive therapy on malignancy risk in these patients.. The study population consisted of patients with histopathologically confirmed AAV, diagnosed between 1991 and 2013 at a large university hospital. The mean duration of followup was 10 years. Malignancy incidence was assessed using the Dutch National Pathology Database. Incidence rates from the Netherlands Cancer Registry were used to compare malignancy incidence in the AAV cohort to that in the general Dutch population.. Thirty-six of 138 patients with AAV developed a total of 85 malignancies during a mean followup of 9.7 years. The sex-, age-, and calendar year-adjusted malignancy risk was 2.21-fold higher (95% confidence interval [95% CI] 1.64-2.92) than that in the general population. Non-melanoma skin cancers occurred most frequently (standardized incidence ratio 4.23 [95% CI 2.76-6.19]). The incidence rates of other malignancies were not significantly increased. Malignancy risk was associated with the duration of cyclophosphamide (CYC) therapy and, interestingly, was not increased in patients who had received CYC for <1 year.. Patients with AAV have a higher risk of malignancy than the general population, but this risk is accounted for solely by non-melanoma skin cancers. Over the years, the risk of other malignancies-specifically bladder and hematologic malignancies-has decreased in patients with AAV. This finding reflects ongoing efforts to reduce CYC exposure by developing new treatment regimens.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Breast Neoplasms; Carcinoma; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Case-Control Studies; Cohort Studies; Cyclophosphamide; Female; Humans; Immunosuppressive Agents; Incidence; Lung Neoplasms; Male; Middle Aged; Myeloblastin; Neoplasms; Neoplasms, Unknown Primary; Netherlands; Peroxidase; Retrospective Studies; Risk Factors; Sarcoma; Skin Neoplasms; Time Factors

To investigate the clinical characteristics of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (MPO-AAV) with pulmonary injury and the relationship between pulmonary injury and ANCA against light chain of MPO (LCMPO-ANCA).. A total of 195 patients with newly diagnosed primary active MPO-AAV were recruited in this prospective study. Indirect immunofluorescence assay was used to detect peri-nuclear ANCA (p-ANCA). Immunoblotting and ELISA were used to detect myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA). Clinical features of patients with both positive p-ANCA and MPO-ANCA were collected. Disease activity was evaluated by Birmingham Vasculitis Activity Score- version 3 (BVAS-V3) Recombinant light chain of MPO was used to coat substrate of LCMPO-ANCA by ELISA. The clinical characteristics of pulmonary injury and its correlation with serum levels of p-ANCA, MPO-ANCA and LCMPO-ANCA were explored.. All 195 patients (64 male and 131 female), consisted of 191 patients (98.0%) with microscopic polyangiitis, 3 patients (1.5%) with granulomatosis with polyangiitis, and 1(0.5%) with eosinophilic granulomatosis with polyangiitis including 64 men and 131 women. Their mean age was (63.2 ± 13.5) years old. The level of MPO-ANCA had a positive correlation with general BVAS-V3 (r=0.193, P=0.007) in all patients, and the level of LCMPO-ANCA was positively related with the pulmonary BVAS-V3 (r=0.228, P=0.001). As for multiple systemic damages, the incidence of lung involvement was 60.51% (118/195), which ranked second to renal involvement (71.80%, 140/195). The most common pulmonary injuries represented as pulmonary infiltration of 80.51% (95/118), pleural effusion / pleurisy of 41.53% (49/118), pulmonary nodule or cavity of 22.03% (26/118). Compared with those without lung involvement, the patients with pulmonary injuries were older [(66.39 ± 10.70) years old vs (58.30 ± 15.72) years old; t=4.277, P=0.001], had a shorter course of disease [2.00(1.00,10.50) months vs 3.00(1.00,3.50) months; t=-2.283, P=0.024], and higher scores of general BVAS-V3 (18.21 ± 6.08 vs 15.18 ± 5.64; t=3.501, P=0.001). Also, in the patients with pulmonary lesions, the positive rate of LCMPO-ANCA was significantly higher (35.59% vs 6.49%; χ² =21.569, P<0.001), and the level of LCMPO-ANCA was significantly higher (0.377 ± 0.229 vs 0.285 ± 0.079; t=3.399, P=0.001) than those without lung involvement. The pulmonary BVAS-V3 in the patients with LCMPO-ANCA was significantly higher than that in the patients without LCMPO-ANCA (4.34 ± 2.10 vs 2.59 ± 2.52; t=4.301, P<0.001), whereas the pulmonary BVAS-V3 was not correlated with LCMPO-ANCA (r=0.035, P=0.708) in patients with lung injuries.. Pulmonary injury was relatively common and insidious in patients with MPO-AAV. To monitor ANCA level is necessary in patients with pulmonary injury. LCMPO-ANCA might play an important role in the pathogenesis of pulmonary lesions in AAV.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Enzyme-Linked Immunosorbent Assay; Female; Fluorescent Antibody Technique, Indirect; Humans; Kidney; Lung; Male; Peroxidase; Prospective Studies; Vasculitis

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Blindness; Brain; Diagnosis, Differential; Female; Humans; Magnetic Resonance Imaging; Meningitis; Peroxidase

Although anti-neutrophil cytoplasmic antibodies [ANCA] are frequently found in patients diagnosed with idiopathic pulmonary fibrosis [IPF], current guidance does not recommend serologic testing for vasculitis.. A 71-year old Caucasian male, diagnosed with IPF three years earlier, presented with rapidly progressive glomerulonephritis. ANCA were found both in current and historical sera. A kidney biopsy sample was taken, which revealed a pauci-immune glomerulonephritis, but also areas of glomerular fibrosis, hence strongly suggesting unrecognized flares of an indolent vasculitis in his past. This made the diagnosis of "idiopathic" pulmonary fibrosis very unlikely.. As nephrologists, we argue that testing for ANCA should be performed on a systematic basis, at least in elderly patients, even in the absence of extra-pulmonary signs of vasculitis at presentation.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Diagnosis, Differential; Glomerulonephritis; Humans; Idiopathic Pulmonary Fibrosis; Male; Peroxidase; Tomography, X-Ray Computed

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

O'Sullivan et al. describe glomerular localization of myeloperoxidase (MPO) in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and correlate the amount of deposition with severity of injury. MPO is the antigen against which anti-MPO ANCAs are directed, the antigen to which pathogenic T cells that can induce antibody-independent AAV are directed, and MPO can induce glomerular injury directly by interacting with H2O2 and a halide to halogenate glomerular structures. All three of these roles are likely involved in human disease.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Glomerulonephritis; Humans; Hydrogen Peroxide; Peroxidase

To describe lung manifestations in MPO-ANCA associated vasculitides in children.. We retrospectively reviewed the medical records of patients with MPO-ANCA associated vasculitis, who were followed in two pediatric nephrology departments from January 2000 to December 2010.. Twelve patients were identified with MPO-ANCA over the study period. Their median age (IQR) at diagnosis was 10.5 (6.3-12.0) years, and their median duration of follow-up was 4.8 (1.2-7.5) years. Only five of them had pulmonary involvement with diffuse alveolar hemorrhage. Lung involvement was inaugural for four of five children. One child with severe chronic respiratory disease and renal failure died after 6 years of disease progression. Pulmonary function tests were available for 10 children. They were within normal ranges in four of five patients without clinical lung manifestations, and no significant impairment was observed in children with pulmonary complications.. Diffuse alveolar hemorrhage complicates 40% of cases of MPO-ANCA associated vasculitides in children with renal involvement. After an acute potentially severe phase, a complete recovery without significant functional impairment was observed in four of five affected children.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Child; Child, Preschool; Female; Hemorrhage; Humans; Kidney Diseases; Lung; Lung Diseases; Male; Peroxidase; Radiography; Retrospective Studies

Necrotizing and crescentic GN (NCGN) with a paucity of glomerular immunoglobulin deposits is associated with ANCA. The most common ANCA target antigens are myeloperoxidase (MPO) and proteinase 3. In a manner that requires activation of the alternative complement pathway, passive transfer of antibodies to mouse MPO (anti-MPO) induces a mouse model of ANCA NCGN that closely mimics human disease. Here, we confirm the importance of C5aR/CD88 in the mediation of anti-MPO-induced NCGN and report that C6 is not required. We further demonstrate that deficiency of C5a-like receptor (C5L2) has the reverse effect of C5aR/CD88 deficiency and results in more severe disease, indicating that C5aR/CD88 engagement enhances inflammation and C5L2 engagement suppresses inflammation. Oral administration of CCX168, a small molecule antagonist of human C5aR/CD88, ameliorated anti-MPO-induced NCGN in mice expressing human C5aR/CD88. These observations suggest that blockade of C5aR/CD88 might have therapeutic benefit in patients with ANCA-associated vasculitis and GN.

Topics: Administration, Oral; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoantigens; Complement C6; Complement Pathway, Alternative; Dose-Response Relationship, Drug; Gene Knock-In Techniques; Glomerulonephritis; Hematuria; Humans; Immunization, Passive; Leukocytes; Metabolism, Inborn Errors; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Knockout; Peroxidase; Proteinuria; Receptor, Anaphylatoxin C5a; Receptors, Chemokine; Recombinant Fusion Proteins; Urine

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoantigens; Glomerulonephritis; Humans; Peroxidase; Receptor, Anaphylatoxin C5a

In patients with active anti-neutrophil cytoplasmic Ab (ANCA)-associated vasculitis (AAV), there are high levels of circulating C-reactive protein (CRP), which can inhibit the alternative complement pathway by binding factor H and triggering the classical complement pathway by binding C1q. However, the alternative, not the classical, complement pathway has been proven to play an important role in AAV. We found that both purified myeloperoxidase (MPO) and MPO released from ANCA-stimulated neutrophils could bind modified CRP (mCRP), but not pentameric CRP. Furthermore, MPO could block the binding between mCRP and factor H, as well as the binding between mCRP and C1q. Binding with mCRP did not influence the enzymatic activity of MPO. Binding with mCRP also did not influence the binding between MPO and its physical inhibitor, ceruloplasmin, as well as the binding between MPO and MPO-ANCA. The results indicated that MPO might be a complement regulator and inhibit the negative regulatory effect of CRP on the alternative complement pathway.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; C-Reactive Protein; Ceruloplasmin; Complement C1q; Complement Factor H; Complement Pathway, Alternative; Complement Pathway, Classical; Complement System Proteins; Humans; Immunomodulation; Neutrophils; Peroxidase; Protein Binding

A myelopoiesis gene signature in circulating leucocytes, exemplified by increased myeloperoxidase (MPO) and proteinase 3 (PR3) mRNA levels, has been reported in patients with active anti-neutrophil cytoplasm antibody-associated vasculitis (AAV), and to a lesser extent during remission. We hypothesized that this signature could predict disease relapse. mRNA levels of PR3, MPO, selected myelopoiesis transcription factors [CCAAT/enhancer binding protein α (CEBP-α), CCAAT/enhancer binding protein β (CEBP-β), SPI1/PU.1-related transcription factor (SPIB), spleen focus forming virus proviral integration oncogene, PU.1 homologue (SPI1)] and microRNAs (miRNAs) from patient and control peripheral blood mononuclear cells (PBMC) and polymorphonuclear cells (PMN) were analysed and associated with clinical data. Patients in stable remission had higher mRNA levels for PR3 (PBMC, PMN) and MPO (PBMC). PR3 and SPIB mRNA correlated positively in controls but negatively in patient PBMC. Statistically significant correlations existed between PR3 mRNA and several miRNAs in controls, but not in patients. PR3/MPO mRNA levels were not associated with previous or future relapses, but correlated with steroid treatment. Prednisolone doses were negatively linked to SPIB and miR-155-5p, miR-339-5p (PBMC) and to miR-221, miR-361 and miR-505 (PMN). PR3 mRNA in PBMC correlated with time since last flare, blood leucocyte count and estimated glomerular filtration rate. Our results show that elevated leucocyte PR3 mRNA levels in AAV patients in remission do not predict relapse. The origin seems multi-factorial, but to an important extent explainable by prednisolone action. Gene signatures in patients with AAV undergoing steroid treatment should therefore be interpreted accordingly.

Topics: Aged; Anti-Inflammatory Agents; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Glomerular Filtration Rate; Humans; Immunologic Factors; Leukocyte Count; Male; MicroRNAs; Microscopic Polyangiitis; Middle Aged; Myeloblastin; Myelopoiesis; Peroxidase; Prednisolone; Recurrence; RNA, Messenger; Transcription Factors; Transcriptome

Antineutrophil cytoplasmic autoantibody (ANCA) directed against myeloperoxidase (MPO), a diagnostic criterion in MPO-ANCA-associated vasculitis (MPO-AAV), does not always correlate with disease activity. Here, we detected autoantibodies against moesin, which was located on the surface of stimulated endothelial cells, in the serum of patients.. The anti-moesin autoantibody titer was evaluated by ELISA. Seventeen kinds of cytokines/chemokines were measured by a Bio-Plex system.. Serum creatinine in the anti-moesin autoantibody-positive group was higher than that in the negative group. Additionally, interferon (IFN)-γ, macrophage chemotactic peptide-1 (MCP-1), interleukin (IL)-2, IL-7, IL-12p70, IL-13, granulocyte/macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor were significantly higher in the positive group. Furthermore, IL-7 and IL-12p70 levels correlated with the anti-moesin autoantibody titer. Based on these findings and the binding of anti-moesin IgG to neutrophils and monocytes, we detected the secretion of cytokines/chemokines such as IFN-γ, MCP-1 and GM-CSF from these cells.. The anti-moesin autoantibody existed in the serum of patients with MPO-AAV and was associated with the production of inflammatory cytokines/chemokines targeting neutrophils with a cytoplasmic profile, which suggests that the anti-moesin autoantibody has the possibility to be a novel autoantibody developing vasculitis via neutrophil and endothelial cell activation.

Topics: Adult; Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoantibodies; Chemokines; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Granulocyte Colony-Stimulating Factor; Humans; Interleukins; Macrophage Inflammatory Proteins; Male; Microfilament Proteins; Middle Aged; Peroxidase

Neutrophils and complement are key members of innate immunity. The alternative pathway (AP) of complement consists of C3, factor B, factor D and properdin, which amplifies AP activation. AP has been implicated in many neutrophil-mediated diseases, such as anti-neutrophil cytoplasmic antibody-associated vasculitis. The exact mechanism by which the AP and neutrophils interact remains largely unstudied. We investigated the ability of the AP to interact with neutrophil components which can be exposed and released upon activation. Our studies focused on neutrophil enzymes, including myeloperoxidase (MPO), proteinase 3 (PR3), azurocidin, elastase, lysozyme and cathepsin G. All enzymes except for azurocidin were able to bind properdin. However, only MPO could induce C3 activation. MPO mediated AP complement activation in the presence of MgEGTA compared to the EDTA control. This activation resulted in C3 deposition and required properdin to occur. Furthermore, we could show that MPO binds properdin directly, which then serves as a focus for AP activation. In summary, properdin can directly interact with neutrophil components. MPO demonstrates the ability to activate the AP which is dependent on properdin. Finally, MPO is capable of inducing properdin-initiated C3 and C5b-9 deposition in vitro.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antimicrobial Cationic Peptides; Blood Proteins; Carrier Proteins; Cathepsin G; Complement C3; Complement Membrane Attack Complex; Complement Pathway, Alternative; Humans; Immunity, Innate; Muramidase; Myeloblastin; Neutrophils; Pancreatic Elastase; Peroxidase; Properdin; Protein Binding

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoantibodies; Humans; Microfilament Proteins; Peroxidase; Vasculitis

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoantibodies; Female; Humans; Male; Microfilament Proteins; Peroxidase

This study aimed to determine the value of hypocomplementemia in predicting the renal and patient survival of patients with antineutrophil cytoplasmatic antibody-associated vasculitis (AAV).. A retrospective analysis of 30 consecutive patients who were diagnosed with AAV and followed at our hospital from 1996 to 2011 was performed. Renal outcome was determined by the Modification of Diet in Renal Disease equation. Disease outcome measures included patient survival and accrual of chronic kidney disease (CKD) defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2) from the date of diagnosis. Logistic regression analysis was used to identify predictors of survival.. At presentation, 6 (20%) patients had a low C3 level, which was significantly associated with older age (p = 0.009), higher C-reactive protein (p = 0.02), a lower eGFR (p = 0.03), and anti-MPO antibody positivity (p = 0.03). A low C3 level at presentation was significantly associated with a reduced eGFR at the last study visit (p = 0.015, OR = 11; 95% CI 1.27-95.15). During a mean follow-up of 9.0 ± 6.2 years, 8 (26.6%) patients had accrued CKD that was significantly associated with low C3 levels at presentation (p = 0.002, OR = 22; 95% CI 2.36-204.7). Mortality was significantly associated with low serum C3 levels at presentation (p = 0.02).. We found that a low serum C3 level at the time of diagnosis was significantly associated with reduced renal and patient survival in patients with anti-MPO AAV. Our results suggest a role for complement activation in the pathogenesis of AAV.

Topics: Adolescent; Adult; Age Factors; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies; C-Reactive Protein; Complement C3; Creatinine; Disease Progression; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Male; Middle Aged; Peroxidase; Renal Insufficiency, Chronic; Retrospective Studies; Survival Rate; Young Adult

The prevalence and significance of treatment resistance and relapse in patients from China with antineutrophil cytoplasmic antibody-associated (ANCA) disease are poorly understood.. A total of 98 patients with ANCA vasculitis, diagnosed between January 2003 and December 2009 in the China-Japan Friendship Hospital, were enrolled in this retrospective study.. Fifteen patients (15.3%) were categorized as having cytoplasmic and/or proteinase 3 (PR3) ANCA and 83 patients (84.7%) had perinuclear and/or myeloperoxidase (MPO) ANCA. After the induction phase treatment, the disease was resistant to therapy in 24 (25%) of the patients. A response to initial treatment occurred in 74 patients (75%). Of these 74 patients, remission was achieved and sustained with or without maintenance therapy in 41 patients (55%). Multivariable logistic regression models revealed that female sex was a statistically significant predictor of treatment resistance (OR 2.85; 95% CI: 1.06-2.86; p = 0.036). Additionally, elevated serum creatinine level, with each increment of 150 μmol/l, predicted resistance (p = 0.002). Among the 74 patients where remission was achieved, Cox proportional hazards models detected that those with PR3 ANCA were 1.31 times more likely to experience a relapse than were patients with MPO ANCA (95% CI: 1.01-5.35; p = 0.0001). Lung involvement was associated with an increased risk of relapse (HR 1.87; 95% CI: 1.12-4.35; p = 0.014). Although not significant, advanced age tended to be associated with relapse (p = 0.08).. Our findings highlight the important effect of female sex and severity of renal disease at presentation as predictors of treatment resistance, and PR3 ANCA and lung involvement as predictors of relapse.

Topics: Adult; Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Asian People; Drug Resistance; Female; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Logistic Models; Male; Middle Aged; Myeloblastin; Peroxidase; Predictive Value of Tests; Recurrence; Retrospective Studies; Seroepidemiologic Studies; Young Adult

We herein report the case of a 72-year-old woman with diffuse cutaneous systemic sclerosis (SSc) complicated by antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis who exhibited honeycomb lung without volume loss. On admission, chest computed tomography (CT) revealed honeycomb lung without volume loss in addition to increased density of the partition walls. A renal biopsy revealed global sclerosis and cellular crescent formation. Mononeuritis multiple subsequently occurred, and steroid pulse therapy with cyclophosphamide was administered. Repeat chest CT showed that the honeycomb lung was unchanged; however, overall reduced density of the partition walls was observed. It is necessary to recognise that vasculitis may develop in SSc patients who exhibit honeycomb lung without volume loss.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Diagnosis, Differential; Fatal Outcome; Female; Humans; Lung Diseases; Peroxidase; Scleroderma, Diffuse; Tomography, X-Ray Computed

The phenotype of renal involvement in anti-neutrophil cytoplasmic antibodies (ANCA) vasculitis has a major influence on survival, and histological subgrouping of diagnostic renal biopsies has been proposed to aid in the prediction of renal outcome. We aimed to validate this histological subgrouping and to investigate the additional value of ANCA serotype in the prediction of renal outcome.. Data were retrospectively collected from the time of diagnosis by systematic review of medical records from 136 patients with renal biopsies recruited to cohorts from the UK and Spain, over 15 years. The end point, renal survival, was the composite of end-stage renal disease (ESRD) or death from any cause. The occurrence of ESRD, Stage 4 Kidney Disease Outcomes Quality Initiative-Chronic Kidney Disease, was assessed separately, in order to establish a severity index risk of chronic kidney disease.. Renal survival at 5 years was 96% in the focal, 86% in the crescentic, 81% in the mixed and 61% in the sclerotic subgroups (P = 0.03). Myeloperoxidase (MPO)-ANCA was associated with more severe disease when compared with PR3-ANCA, as demonstrated by a lower frequency of focal and higher frequency of sclerotic subgroups, by more advanced interstitial fibrotic change and by lower glomerular filtration rate at diagnosis and worse renal function at 1 and 2 years.. We have confirmed the predictive value for renal survival of the ANCA vasculitis histology classification in a multi-centre study. We found a worse renal outcome in patients with tubulointerstitial fibrosis and atrophy. MPO-ANCA positive patients had a worse renal prognosis due to more severe glomerular injury. These results contribute to patient stratification in renal vasculitis for therapeutic, epidemiological and basic research.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Glomerulonephritis; Humans; Kidney Failure, Chronic; Kidney Glomerulus; Male; Middle Aged; Peroxidase; Retrospective Studies; Serogroup; Severity of Illness Index

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Churg-Strauss Syndrome; Gene-Environment Interaction; Humans; Microscopic Polyangiitis; Peroxidase

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Churg-Strauss Syndrome; Gene-Environment Interaction; Humans; Microscopic Polyangiitis; Peroxidase

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is usually differentiated based on clinical phenotypes, but recent data indicate that myeloperoxidase (MPO)-AAV is genetically distinct from proteinase 3 (PR3)-AAV. We reviewed a population-based cohort of AAV, focusing on differences in clinical and laboratory characteristics and to compare renal outcome between MPO-ANCA and PR3-ANCA nephritis.. All new cases of AAV diagnosed between 1997 and 2009 in a geographically defined area in southern Sweden were retrieved using a validated search algorithm. Data were collected from time of diagnosis and end of followup. Renal and patient survival were analyzed according to ANCA serotype.. During the study period, 201 patients were diagnosed with AAV, 98 tested positive for PR3-ANCA, and 85 for MPO-ANCA. Patients with PR3-ANCA were younger, had significantly higher inflammatory activity, and had a larger number of organs involved at diagnosis, but nephritis was more prevalent among patients with MPO-associated (72/85; 85%) versus PR3-associated disease (67/98, 68%). When comparing only patients with ANCA-associated nephritis, those with MPO-ANCA were more likely to develop endstage renal disease (n = 27, 38%) than those with PR3-ANCA (n = 10, 15%), p = 0.003. The risk remained significantly elevated after adjusting for sex, age, and s-creatinine level at diagnosis (HR 2.64; 95% CI 1.25-5.58; p = 0.003). There were no significant differences in mortality rates between the 2 groups.. The outcome in this population-based cohort indicates that among AAV patients with nephritis, renal prognosis is better in the PR3-ANCA group, even after adjustment for sex, age, and renal function at diagnosis.

Topics: Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Female; Humans; Kidney; Male; Middle Aged; Myeloblastin; Nephritis; Peroxidase; Prognosis

A 73-year-old man was admitted to our hospital because of a decrease in spontaneity. His medical history included two stroke episodes, probably related to hypertension. Brain MRI on admission demonstrated acute infarction in the right caudate nucleus and left putamen. Intravenous infusion of a low molecular-weight heparin added to oral antiplatelets was started. Following admission, he developed a low grade fever and severe inflammatory reaction. The focus of infection was not evident, and none of the antibiotics tried were effective. Ten days after admission, he developed right hemiparesis, and an additional brain MRI showed new multiple infarctions. We also determined the presence of a high MPO-ANCA titer (57 EU), and we diagnosed the patient's condition to be ANCA-associated vasculitis (AAV). Steroid therapy improved his inflammatory reaction and stroke recurrence was not observed. We suggest that vasculitis should be considered as a potential risk factor for repeated small infarctions with fever of unknown origin, especially those of perforating artery territories.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Anticoagulants; Biomarkers; Fever of Unknown Origin; Heparin; Humans; Magnetic Resonance Imaging; Male; Methylprednisolone; Peroxidase; Prednisolone; Pulse Therapy, Drug; Recurrence; Risk Factors; Stroke; Warfarin

The aim of the study was to characterize the expression of TLR2, TLR4 and TLR9 in PMNs of patients with granulomatosis with polyangiitis (GPA) and to elucidate the role of these receptors in GPA with respect to neutrophil activation.. The expression of TLR2, TLR4 and TLR9 was determined on ex vivo PMNs in whole blood samples of GPA patients (n = 35) and healthy controls (HCs) (n = 24). Isolated PMNs were stimulated in vitro with TLR agonists and assessed for degranulation, membrane proteinase 3 (mPR3) expression, soluble l-selectin shedding and cytokine production (IL-8) in five GPA patients and five HCs. The priming effects of TLR2 and TLR9 ligation were assessed by measurement of serine protease activity after stimulation with PR3-ANCA.. There were no significant differences in the ex vivo expression of TLRs on PMNs in HCs and GPA patients. Stimulation of TLR4 and TLR9 induced MPO release, stimulation with TLR2, TLR4 and TLR9 ligands elicited IL-8 production and stimulation of TLR2 and TLR9 led to an upregulation in mPR3 expression on PMNs with no significant differences between GPA and HC after 1 or 24 h stimulation. Priming of PMNs with TLR2 and TLR9 ligands induced degranulation after subsequent stimulation with PR3-ANCA, which was comparable to priming with TNF-α.. Expression of TLR2, TLR4 and TLR9 in PMNs and the TLR-induced activation of PMNs was comparable in GPA and HC. mPR3 upregulation by TLR2 and TLR9 stimulation and the priming effect of TLR ligands on PMNs may have a potential implication for triggering disease activity during infection in GPA.

Topics: Adult; Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Case-Control Studies; Cohort Studies; Female; Humans; Interleukin-8; Male; Matrix Metalloproteinase 16; Middle Aged; Neutrophil Activation; Neutrophils; Peroxidase; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptor 9; Up-Regulation; Young Adult

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Cohort Studies; Epitopes; Genetic Loci; Genetic Predisposition to Disease; Genotype; HLA-DP Antigens; HLA-DQ Antigens; Humans; Myeloblastin; Peroxidase; Phenotype; Prognosis; Risk Factors; Serpins; T-Lymphocyte Subsets

Topics: Alleles; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Disease Models, Animal; Genotype; Glomerulonephritis; Humans; Immunoglobulin G; Mice; Mice, Inbred Strains; Myeloblastin; Neutrophils; Peroxidase; Quantitative Trait Loci; Rats; Rats, Inbred WKY

ANCA are a good serologic marker for AAV, especially for GPA and MPA. Today, the best diagnostic performance is obtained when indirect immunofluorescence test is combined with antigen-specific assay. The new developed more sensitive and specific methods for ANCA detection in AAV, which may replace the need for a combined analysis with IFT and ELISA in the future, should be evaluated in multicentre studies. ANCA testing can be improved by restricting the use of the tests to clinical situations with a rather high pretest probability for AAV, and carefully searching for conditions such as drug exposures and infections that are known to be associated with the occurrence of ANCA, whether the vasculitis is present or not. Therefore, a rational strategy for ANCA testing is needed and the International consensus statement on testing of ANCA should urgently be revised.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biopsy; Cross-Sectional Studies; Enzyme-Linked Immunosorbent Assay; Epitopes; Fluorescent Antibody Technique, Indirect; Humans; Mass Screening; Myeloblastin; Peroxidase; Predictive Value of Tests

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

Anti-neutrophil cytoplasmic antibody-associated (ANCA-associated) small vessel necrotizing vasculitis is caused by immune-mediated inflammation of the vessel wall and is diagnosed in some cases by the presence of myeloperoxidase-specific antibodies (MPO-ANCA). This multicenter study sought to determine whether differences in ANCA epitope specificity explain why, in some cases, conventional serologic assays do not correlate with disease activity, why naturally occurring anti-MPO autoantibodies can exist in disease-free individuals, and why ANCA are undetected in patients with ANCA-negative disease. Autoantibodies from human and murine samples were epitope mapped using a highly sensitive epitope excision/mass spectrometry approach. Data indicated that MPO autoantibodies from healthy individuals had epitope specificities different from those present in ANCA disease. Importantly, this methodology led to the discovery of MPO-ANCA in ANCA-negative disease that reacted against a sole linear sequence. Autoantibodies against this epitope had pathogenic properties, as demonstrated by their capacity to activate neutrophils in vitro and to induce nephritis in mice. The confounder for serological detection of these autoantibodies was the presence of a fragment of ceruloplasmin in serum, which was eliminated in purified IgG, allowing detection. These findings implicate immunodominant epitopes in the pathology of ANCA-associated vasculitis and suggest that autoantibody diversity may be common to other autoimmune diseases.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amino Acid Sequence; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibody Specificity; Autoantibodies; Case-Control Studies; Ceruloplasmin; Child; Epitopes; Female; Humans; Male; Mice; Mice, Transgenic; Middle Aged; Molecular Sequence Data; Peptide Fragments; Peroxidase; Young Adult

Increasing evidences have suggested the pathogenic role of anti-neutrophil cytoplasmic antibodies (ANCA) directing myeloperoxidase (MPO) in ANCA-associated vasculitis (AAV). The current study aimed to analyze the association between the linear epitopes of MPO-ANCA and clinicopathological features of patients with AAV.. Six recombinant linear fragments, covering the whole length amino acid sequence of a single chain of MPO, were produced from E.coli. Sera from 77 patients with AAV were collected at presentation. 13 out of the 77 patients had co-existence of serum anti-GBM antibodies. Ten patients also had sequential sera during follow up. The epitope specificities were detected by enzyme-linked immunosorbent assay using the recombinant fragments as solid phase ligands.. Sera from 45 of the 77 (58.4%) patients with AAV showed a positive reaction to one or more linear fragments of the MPO chain. The Birmingham Vasculitis Activity Scores and the sera creatinine were significantly higher in patients with positive binding to the light chain fragment than that in patients without the binding. The epitopes recognized by MPO-ANCA from patients with co-existence of serum anti-GBM antibodies were mainly located in the N-terminus of the heavy chain. In 5 out of the 6 patients, whose sera in relapse recognize linear fragments, the reactivity to linear fragments in relapse was similar to that of initial onset.. The epitope specificities of MPO-ANCA were associated with disease activity and some clinicopathological features in patients with ANCA-associated vasculitis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies; Cross Reactions; Epitope Mapping; Female; Humans; Male; Middle Aged; Peptide Fragments; Peroxidase; Recombinant Proteins; Recurrence; Sequence Deletion; Young Adult

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies; Antibodies, Antineutrophil Cytoplasmic; Female; Humans; IgA Vasculitis; Peroxidase; Scleroderma, Systemic

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antithyroid Agents; Diagnosis, Differential; Glomerulonephritis, IGA; Humans; Hyperthyroidism; Male; Middle Aged; Peroxidase; Propylthiouracil

To define the clinical, serological, histological and immunogenetic features of patients with scleroderma and ANCA-associated vasculitis (AAV).. We examined a clinical database of 2,200 patients with either limited or diffuse cutaneous systemic sclerosis (SSc). Patients with a confirmed diagnosis of vasculitis who were ANCA positive with either MPO or PR3 reactivity had their clinical features, serology, histology and HLA haplotypes examined in detail.. From this SSc cohort, 35 patients (1.6%) had evidence of vasculitis, and the SSc autoantibody profiles in this group were comparable to those previously published from the whole cohort. Of these 35 patients, 8 (0.4% of whole SSc cohort) had either anti-MPO or anti-PR3 antibodies and two further patients were ANCA positive without defined specificities. Of the eight ANCA-positive patients, seven had limited cutaneous SSc and anti-MPO antibodies and only one had anti-PR3 antibodies, associated with diffuse cutaneous SSc. Two ANCA-positive patients had anti-U3RNP antibodies, usually associated with overlap disease. None of the patients had granulomatous disease. The majority had glomerulonephritis, renal arteritis and pulmonary fibrosis. There were several shared HLA haplotypes from the DP and DQ loci in these overlap patients.. SSc in overlap with ANCA-associated vasculitis is rare, and clinical features are more mixed than when either of these two conditions occurs separately. From our database, U3RNP antibodies may be more associated with overlap AAV than the other scleroderma-specific antibodies.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Autoantibodies; Biopsy; Female; Genetic Predisposition to Disease; Haplotypes; Histocompatibility Testing; HLA-D Antigens; Humans; Kidney; Male; Middle Aged; Myeloblastin; Peroxidase; Retrospective Studies; Ribonucleoproteins, Small Nucleolar; Scleroderma, Systemic; Skin

This study evaluated predictors for patient and renal survival in patients with ANCA-associated vasculitis (AAV) with and without renal involvement.. There were 273 consecutive AAV patients from January 1990 until December 2007 who were followed until death, loss to follow-up, or December 2010. Based on organ involvement, patients were divided into renal (n=212) and nonrenal groups (n=61). The primary end point was ESRD requiring renal replacement therapy (RRT) or renal transplantation or death.. Patient survival was significantly better in the nonrenal group compared with the renal group (hazard ratio, 0.55; 95% confidence interval, 0.33 to 0.92; P=0.02). In the renal group, renal survival was significantly worse in MPO-ANCA-positive patients (n=65) compared with PR3-ANCA-positive patients (n=138) (hazard ratio, 2.1; 95% confidence interval, 1.11 to 3.8; P=0.01). Of 48 patients who needed RRT at diagnosis, 11 patients (23%) died within 6 months and 14 patients (29%) did not regain renal function. Of all 23 patients who regained renal function after RRT, 7 patients (30%) were temporarily dialysis independent and needed dialysis later (range, 13-63 months). Five patients had a renal relapse in the 6 months before restart of RRT. Of all 203 PR3-ANCA-positive and MPO-ANCA-positive patients with renal involvement, 12 patients (6%) developed ESRD during follow-up. These patients were classified as CKD stage 4 or 5 after initial treatment and eight patients had a renal relapse before becoming dialysis dependent.. AAV patients with renal involvement who needed RRT had the worst survival probability. In multivariate analysis, the only major determinants for long-term renal survival were renal function at 6 months and renal relapses.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Myeloblastin; Peroxidase; Renal Replacement Therapy

Interferon regulatory factor 5 (IRF5) and signal transducer and activator of transcription 4 (STAT4) are shared susceptibility genes for various autoimmune diseases. In this study, we investigated whether these genes also contribute to susceptibility to anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in a Japanese population. A case-control study was carried out on IRF5 rs10954213 and STAT4 rs7574865 in 232 Japanese myeloperoxidase (MPO)-ANCA-positive AAV patients, including 177 microscopic polyangiitis and 710 healthy controls. IRF5 rs10954213G was significantly increased in MPO-ANCA-positive AAV (additive model, P=0.023, odds ratio=1.27, 95% confidence interval=1.03-1.57). The risk allele was previously shown to be associated with lower mRNA level of IRF5. On the other hand, significant association of STAT4 rs7574865T with AAV was not detected. These observations suggested that IRF5 may contribute to susceptibility to MPO-ANCA-positive AAV in a Japanese population.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Case-Control Studies; Female; Humans; Interferon Regulatory Factors; Japan; Male; Microscopic Polyangiitis; Middle Aged; Peroxidase; Polymorphism, Single Nucleotide; STAT4 Transcription Factor

Increasing evidence has suggested that linear epitopes of antineutrophil cytoplasmic antibody (ANCA) directed to myeloperoxidase (MPO) might provide clues to the pathogenesis of propylthiouracil (PTU)-induced ANCA-associated vasculitis (AAV). This study mapped epitopes of MPO-ANCA in sera from patients with PTU-induced MPO-ANCA (with or without vasculitis) and primary AAV, aiming to analyze certain epitopes associated with the development of PTU-induced AAV.. Six recombinant linear fragments, covering the whole amino acid sequence of a single chain of MPO, were produced from Escherichia coli. Sera from 17 patients with PTU-induced AAV, 17 patients with PTU-induced MPO-ANCA but without clinical evidence of vasculitis, and 64 patients with primary AAV were collected at presentation. Of the 17 patients with PTU-induced AAV, 12 also had sera at remission. The epitope specificities were detected by enzyme-linked immunosorbent assay by using the recombinant fragments as solid-phase ligands.. Compared with patients with PTU-induced MPO-ANCA but without clinical vasculitis, sera from PTU-induced AAV patients showed significantly higher reactivity against the H1 fragment of MPO (optical density values: 0.17 (0.10 to 0.35) versus 0.10 (0.04 to 0.21), P = 0.038) and could recognize a significantly higher number of fragments (two (none to four) versus one (none to two), P = 0.026). Compared with sera from primary AAV patients, sera from PTU-induced AAV patients had significantly higher reactivity to the P fragment and the H4 fragment (47.1% versus 14.1% P < 0.001; 41.2% versus 14.1%, P = 0.034, respectively), and could recognize a significantly higher number of fragments (two (none to four) versus one (none to two), P = 0.013]. Among the 12 PTU-induced AAV patients with sequential samples, the number of fragments recognized in remission was significantly less than that in initial onset (two (none to four) versus none (none to 0.75), P < 0.001].. Linear epitopes of MPO molecules might be associated closely with PTU-induced AAV. In particular, the P and H4 fragments may be important epitopes in PTU-induced AAV.

Topics: Adolescent; Adult; Amino Acid Sequence; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antithyroid Agents; Autoantibodies; Autoantigens; Child; Enzyme-Linked Immunosorbent Assay; Epitope Mapping; Epitopes, B-Lymphocyte; Female; Humans; Male; Middle Aged; Molecular Sequence Data; Peroxidase; Propylthiouracil; Young Adult

Patients with MPO-ANCA related angitis sometimes experience the onset of sonsorineural hearing loss and facial palsy. The main aim of this study was to investigate the relationship between the inflammation in the inner ear and sensorineural hearing loss, or between the inflammation of the facial nerve and facial nerve palsy in patients with MPO-ANCA related angitis. From 2007 to 2011, the inner ear was evaluated in 16 ears from 8 patients with MPO-ANCA related angitis with 3D-FLAIR MRI. In 12 ears of the 16 ears the onset of sensorineural hearing loss was noted, and the signal intensity ratio (SIR) in the cochlea was 0.62 +/- 0.15 on pre-enhancement 3D-FLAIR MRI, and 0.97 +/- 0.5 on post-enhancement. These SIR values were significantly higher than the SIR of non-sensorineural hearing loss patients. The onset of facial palsy was noted in 9 of 16 sides and the facial nerve SIR was 0.83 +/- 0.23 on post-contrast 3D-FLAIR MRI. The SIR in the facial nerve of facial nerve palsy patients was higher than non-facial palsy patients. The conclusion is that sensorineural hearing loss and facial palsy in patients with MPO-ANCA related angitis occurred due to strong inflammation in the cochlea or facial nerve. 3D-FLAIR MRI made this pathology clear.

Topics: Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Female; Hearing Loss, Sensorineural; Humans; Imaging, Three-Dimensional; Magnetic Resonance Imaging; Male; Middle Aged; Peroxidase

We here report a rare case of dual antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in a 38-year-old Japanese woman previously diagnosed with mixed connective tissue disease. The patient was found to be positive for myeloperoxidase- and proteinase 3-ANCA, and was diagnosed with AAV following admission to hospital with fervescence, polyarthralgia, purpura, and asymmetric numbness of the extremities. Examination of her genetic background revealed that she carried HLA-DR9, which confers risk of both diseases in Japanese populations.

Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Azathioprine; Drug Therapy, Combination; Female; Genetic Predisposition to Disease; Glucocorticoids; HLA-DR Serological Subtypes; Humans; Immunosuppressive Agents; Methylprednisolone; Mixed Connective Tissue Disease; Myeloblastin; Peroxidase; Prednisolone; Pulse Therapy, Drug; Risk Factors; Treatment Outcome

Anti-neutrophil cytoplasmic autoantibodies (ANCA) are useful diagnostic markers in systemic vasculitic disorders with small-vessel involvement, but depending on the particular test used, the myeloperoxidase (MPO)-ANCA results are variable. In the present study, we performed a comparative analysis between our originally developed nMPO-ANCA assay that targets the native MPO antigen and other commercially available assays using sera of patients with clinical features of ANCA-associated vasculitis (AAV).. Sera of 24 patients strongly suspected of having AAV were examined for the presence of MPO-ANCAs by our nMPO-ANCA assay and by other commercial-based MPO-ANCA assays. These results were correlated to indirect immunofluorescence microscopy staining patterns and patient clinical parameters.. Eighteen out of 24 patients (75 %) were positive for nMPO-ANCA, compared with 13 out of 24 patients (54 %) by one of the most frequently used commercial-based MPO-ANCA enzyme-linked immunosorbent assays (ELISAs) in Japan. Interestingly, the patients who tested positive with our nMPO-ANCA assay alone showed clinical features of AAV marked by continuous fever, polyarthritis, and mild nephritis. The titers of nMPO-ANCA decreased in association with clinical improvement after treatment.. Our data suggest that a positive nMPO-ANCA result, which identifies antibodies to human native MPO antigen, correlates with AAV disease activity. Moreover, the nMPO-ANCA test has clinical utility in detecting AAV-affected patients who have tested negative using commercially available assays.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Enzyme-Linked Immunosorbent Assay; Ferrous Compounds; Humans; Maleimides; Metallocenes; Peroxidase; Sensitivity and Specificity

Granulocyte colony stimulating factor (GCSF) is important in mobilising neutrophils from the bone marrow but also has a range of proinflammatory effects. We therefore decided to investigate the role of GCSF in antineutrophil cytoplasmic antibody (ANCA) vasculitis.. We measured GCSF levels in the serum of 38 patients with active ANCA vasculitis compared with 31 age-matched controls, and assessed the effect of GCSF priming on the response of human neutrophils to ANCA. We also examined the effect of exogenous GCSF administration in a murine model of antimyeloperoxidase (anti-MPO) vasculitis, and the effect of GCSF on murine neutrophil activation.. The serum levels of GCSF in patients with active ANCA vasculitis were significantly higher than those of age matched healthy controls (mean 38.04 vs 18.35 pg/ml, p<0.001). Furthermore, we demonstrated that GCSF primed human neutrophils in vitro for a respiratory burst in response to anti-MPO ANCA. In an anti-MPO antibody transfer model, mice given GCSF had more crescents (mean 29.1% vs 5.8% per glomerular cross section, p<0.05), more macrophages (mean 3.2 vs 1.2 per glomerular cross-section, p<0.01), higher serum creatines (mean 13.6 vs 8.3 μmol/l, p<0.05) and more haematuria (p<0.05) compared with controls. In vivo administration of GCSF with lipopolysaccharide (LPS), but not LPS alone, led to upregulation of CD11c on murine neutrophils.. These data suggest that GCSF, which is raised in patient serum, may play an important role in exacerbating disease in ANCA vasculitis. In addition, GCSF therapy for neutropenia should be used with caution in these patients.

Topics: Aged; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Case-Control Studies; Disease Models, Animal; Disease Progression; Female; Glomerulonephritis; Granulocyte Colony-Stimulating Factor; Humans; Male; Mice; Neutrophil Activation; Neutrophils; Peroxidase

Propylthiouracil (PTU) is recommended as a first-line antithyroid drug (ATD) during first trimester organogenesis in pregnancy because recent evidence suggests that methimazole (MMI) may be associated with congenital anomalies. However, PTU more commonly causes myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, which usually occurs during prolonged treatment, compared with MMI. We report a case of MPO-ANCA-associated vasculitis in a 35-year-old woman with Graves'disease. Although her thyroid function could be maintained euthyroid by MMI, her ATD was switched to PTU because she wished to become pregnant. The patient presented with flu-like symptoms 8 days after starting PTU and developed hemoptysis and dyspnea at 22 days. Her MPO-ANCA titer was 21 ELISA units (EUs) before PTU treatment but increased to 259 EUs at 22 days after PTU treatment. Her clinical condition improved with the discontinuation of PTU and with immunosuppressive therapy. This case indicated that MPO-ANCA vasculitis occurred within several weeks after the initiation of PTU and that this side effect could be caused by the change from MMI to PTU. Thus, our clinical observation suggests that patients treated with PTU should be carefully monitored for MPO-ANCA titers and variable manifestations of MPO-ANCA-associated vasculitis regardless of the period of administration.

Topics: Abnormalities, Drug-Induced; Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Female; Graves Disease; Humans; Methimazole; Peroxidase; Pregnancy; Pregnancy Complications; Propylthiouracil

The prognostic value of renal biopsy in anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis is widely recognized; however, there is no consensus regarding its pathological classification. Berden et al. proposed a new classification of glomerulonephritis in ANCA-associated vasculitis (AAV) categorized into focal, crescentic, mixed, and sclerotic classes and showed its prognostic value in 100 international multicenter cohorts for 1- and 5-year renal outcomes. In order to evaluate whether this new classification has predictive value and reproducibility in Japanese AAV cases, 87 cohorts with only microscopic polyangiitis in 3 limited centers in Japan were analyzed. In addition, those from Japan, Europe (Berden's cohorts) and China were compared in a recent report.

Topics: Adult; Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Biopsy; China; Disease Progression; Europe; Female; Glomerulonephritis; Humans; Japan; Kidney Failure, Chronic; Kidney Glomerulus; Male; Middle Aged; Peroxidase; Predictive Value of Tests; Prognosis; Terminology as Topic; Time Factors; Young Adult

Our aim was to investigate the removal of myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA) from the circulation of patients with vasculitides by double-filtration plasmapheresis (DFPP) using various primary separator and secondary separator combinations. Nineteen patients diagnosed with vasculitides positive for serum MPO-ANCA were enrolled and received 56 sessions of DFPP. One patient received three sessions of DFPP using MPS07 (the primary filter)/EC50W (the secondary filter), nine patients received 27 sessions of DFPP using MPS07/EC20W, and the other nine patients received 26 sessions of DFPP using EC50W/EC20W. The sieving coefficients (SC) of albumin, immunoglobulin (Ig)A, IgG and IgM were measured, as well as the reduction ratio in plasma protein concentrations and MPO-ANCA titer after a single session of DFPP. The MPS07 filter was well permeable for all the above-mentioned plasma proteins; the EC50W and EC20W filters were permeable for albumin and IgG, less for IgA and IgM. During DFPP using MPS07/EC50W, the reduction ratio of IgG was much lower than IgM and IgA (30.5 ± 9.0% vs. 89.7 ± 5.4% and 61.7 ± 14.8%). During DFPP using MPS07/EC20W, the decline in IgM, IgA, and IgG was 94.2 ± 3.1%, 96.2 ± 2.3%, and 64.7 ± 21.0%, respectively. During DFPP using EC50W/EC20W, the decline in IgM, IgA, and IgG was 2.8 ± 12.9%, 90.9 ± 4.4%, and 43.5 ± 13.8%, respectively. The percentage reduction in MPO-ANCA titer after a single session of DFPP using EC50W/EC20W was 34.6 ± 14.3%. DFPP using EC50W/EC20W filters may be more selective for the removal of pathogens such as IgG, with subsequently effective reduction of serum ANCA titer.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Filtration; Humans; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Male; Middle Aged; Peroxidase; Pilot Projects; Plasmapheresis; Prospective Studies

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antibody Specificity; Female; Humans; Male; Myeloblastin; Peroxidase

A 12-year-old girl presented with a sudden decrease in her right visual acuity and homonymous hemianopsia. An angiography of the retinal arteries demonstrated recanalized occlusion of the right retinal artery. Cerebral angiography showed bilateral internal carotid artery stenosis associated with the development of collateral circulation. Laboratory evaluations revealed dual antineutrophil cytoplasmic antibodies (ANCA) positivity [anti-proteinase (anti-PR3) ANCA and anti-myeloperoxidase (anti-MPO) ANCA], anticardiolipin (aCL) antibodies, and low titers of antinuclear antibodies (ANA). There was no evidence of active systemic lupus erythematosus (SLE), ANCA-related vasculitis, or other risk factors for cerebral occlusion, such as antiphospholipid syndrome (APS). Dual positivity for both cytoplasmic (c-ANCA) and perinuclear (p-ANCA) antineutrophil antibodies has been found previously in a small number of reports, but to our knowledge, this case represents the first case of moyamoya disease associated with dual ANCA positivity.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Anticardiolipin; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Antinuclear; Biomarkers; Cerebral Angiography; Child; Female; Hemianopsia; Humans; Magnetic Resonance Imaging; Moyamoya Disease; Myeloblastin; Peroxidase; Visual Acuity

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is characterized by systemic necrotizing vasculitis, and patients fall into 2 groups: those with proteinase 3-ANCA and those with myeloperoxidase-ANCA. As infections are a trigger of ANCA-associated vasculitis, this disease tends to localize in areas around the upper airway. In this study, the authors compared ear and nasal symptoms between patients with proteinase 3-ANCA and those with myeloperoxidase-ANCA. We undertook a retrospective case series study of 34 patients diagnosed with ANCA-associated vasculitis. The otologic symptoms were divided into 3 types: chronic otitis media, secretory otitis media, and sensorineural hearing loss. Chronic otitis media was more common in patients with proteinase 3-ANCA (P = .001), whereas secretory otitis media was more frequently found in patients with myeloperoxidase-ANCA (P = .007). Crust formation (P = .001), saddle nose (P = .024), and sinusitis (P = .001) were more common in patients with proteinase 3-ANCA than in those with myeloperoxidase-ANCA. Marked differences were observed in the disease spectrum between the 2 ANCA groups.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Chronic Disease; Disease Progression; Follow-Up Studies; Hearing Loss, Sensorineural; Humans; Myeloblastin; Otitis Media; Peroxidase; Prognosis; Retrospective Studies

The mechanisms by which anti-neutrophil cytoplasmic antibodies (ANCAs) may contribute to the pathogenesis of ANCA-associated vasculitis are not well understood. In this study, both polyclonal ANCAs isolated from patients and chimeric proteinase 3-ANCA induced the release of neutrophil microparticles from primed neutrophils. These microparticles expressed a variety of markers, including the ANCA autoantigens proteinase 3 and myeloperoxidase. They bound endothelial cells via a CD18-mediated mechanism and induced an increase in endothelial intercellular adhesion molecule-1 expression, production of endothelial reactive oxygen species, and release of endothelial IL-6 and IL-8. Removal of the neutrophil microparticles by filtration or inhibition of reactive oxygen species production with antioxidants abolished microparticle-mediated endothelial activation. In addition, these microparticles promoted the generation of thrombin. In vivo, we detected more neutrophil microparticles in the plasma of children with ANCA-associated vasculitis compared with that in healthy controls or those with inactive vasculitis. Taken together, these results support a role for neutrophil microparticles in the pathogenesis of ANCA-associated vasculitis, potentially providing a target for future therapeutics.

Topics: Adolescent; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantigens; Case-Control Studies; CD18 Antigens; Cell-Derived Microparticles; Cells, Cultured; Child; Child, Preschool; Endothelial Cells; Endothelium, Vascular; Female; Humans; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; Male; Mice; Myeloblastin; Neutrophil Activation; Peroxidase; Reactive Oxygen Species; Thrombin

Myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-positive microscopic polyangiitis patients with renal involvement have been shown to have a progressive clinical course. In this study, we compared the clinical utility of the Japanese Vasculitis Activity Score (JVAS) with the Birmingham Vasculitis Activity Score (BVAS) for predicting death in patients with MPO-ANCA-associated renal involvement.. Sixty-nine patients with MPO-ANCA-associated vasculitis with renal involvement (22 males and 47 females, age 69.8 ± 8.7 years) were enrolled in this study. We retrospectively investigated which score was better for predicting the poor prognosis of patients.. The mortality rate of the patients within 2 years after disease onset was 33% (23/69). JVAS was not correlated with BVAS. Univariate logistic regression analysis for death showed that the odds ratio (OR) of JVAS was statistically significant (OR 1.76, 95% confidence interval, CI, 1.29-2.41, p < 0.001), while that of BVAS was not (OR 1.07, 95% CI 0.98-1.16, p = 0.14). Moreover, a multivariate model showed that JVAS was an independent determinant of death (OR 1.59, 95% CI 1.12-2.25, p = 0.009). The area under the receiver operating characteristic curve for JVAS was 0.778, which was significantly larger (p = 0.02) than that for BVAS (0.586). The estimated optimal cut-off point of JVAS for the prediction of death was 5. At this point, the sensitivity was 82.6% and the specificity was 60.9%.. We demonstrated that compared with BVAS, JVAS was a simpler and more reliable measure for predicting death in patients with MPO-ANCA-associated vasculitis with renal involvement.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Cardiology; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Models, Statistical; Odds Ratio; Peroxidase; Retrospective Studies; ROC Curve; Sensitivity and Specificity; Time Factors; Treatment Outcome; Vasculitis

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antirheumatic Agents; Chronic Disease; Cyclophosphamide; Dermatitis, Atopic; Eosinophilia; Female; Glomerulonephritis; Glucocorticoids; Heart Failure; Hemorrhage; Humans; Lung Diseases; Methylprednisolone; Peroxidase; Prednisone; Tomography, X-Ray Computed

The involvement of autoantibodies to human lysosome-associated membrane protein-2 (hLAMP-2) in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is controversial because of the absence of confirmatory data subsequent to the initial reports of their high prevalence in this disease. We characterized three assays for anti-hLAMP-2 antibodies: ELISA and Western blotting assays using unglycosylated recombinant hLAMP-2 expressed in Escherichia coli, and an indirect immunofluorescence assay using stably transfected ldlD cells that expressed glycosylated full-length hLAMP-2 on the plasma membrane. The assays detected autoantibodies to hLAMP-2 in human sera reproducibly and with comparable sensitivity and the assays gave the same results in 80.5% of the test panel of 40 selected positive and negative sera. In untreated patients at presentation, the frequencies of autoantibodies to LAMP-2 were 89%, 91%, and 80%, respectively, among three groups of patients with ANCA-associated vasculitis from Vienna, Austria (n=19); Groningen, the Netherlands (n=50) and Cambridge, United Kingdom (n=53). Prevalence of LAMP-2 autoantibodies was similar in both those with myeloperoxidase-ANCA and proteinase 3-ANCA. Furthermore, we detected LAMP-2 autoantibodies in two ANCA-negative patients. LAMP-2 autoantibodies rapidly became undetectable after the initiation of immunosuppressive treatment and frequently became detectable again during clinical relapse. We conclude that when robust assays are used, circulating autoantibodies to hLAMP-2 can be detected in most European patients with ANCA-associated vasculitis. Large-scale prospective studies are now needed to determine whether they are pathogenic or merely an epiphenomenon.

Topics: Adult; Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Austria; Autoantibodies; Blotting, Western; Case-Control Studies; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique, Indirect; Humans; Lysosomal Membrane Proteins; Lysosomal-Associated Membrane Protein 2; Middle Aged; Myeloblastin; Netherlands; Peroxidase; Prevalence; Sensitivity and Specificity; United Kingdom

We report a 79-year-old man presenting MPO-ANCA associated hypertrophic pachymeningitis and bilateral visual impairment. Two years before, microscopic hematuria and positive MPO-ANCA were indicated, then oral steroids and cyclophosphamide were given as systemic vasculitis. On admission, lateral hemianopsia in the right visual field was documented. Some weeks after admission, he complained of a left-hand side headache, and the visual impairment of a right eye. Brain MRI detected thick dura matter with abnormal enhancement predominantly on the left side of the basal temporal lobe and a tumor-like lesion at the sphenoid sinus near the right cavernous sinus. Multiple scotomas in the left visual field were compatible with ischemic changes caused by MPO-ANCA related vasculitis. On the other hand, the hemianopsia in his right eye was related with a tumor-like lesion. The visual problems showed a favorable response to the steroid pulse therapy. ANCA-positive cases can demonstrate various symptoms including intra-/extra-cranial involvement. Thus, thorough clinical workup is needed to determine the actual site of the lesion when cranial nerve involvement is observed in MPO-ANCA positive hypertrophic pachymeningitis.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Hypertrophy; Male; Meningitis; Peroxidase; Vision Disorders

Several authors have reported cases of anti-neutrophil cytoplasmic antibody (ANCA)-associated crescentic glomerulonephritis (CGN) with definite immune complex (IC) deposits, however, the clinical and pathological significance of IC deposits in patients with ANCA-associated CGN remains unclear.. Renal biopsy specimens from 28 patients with a diagnosis of CGN and positivity for anti-myeloperoxidase (MPO)-ANCA were retrospectively evaluated. Clinical data were compared between patients with IC deposits (Group A) and patients without IC deposits (Group B).. In 12 patients (43%; Group A), IC deposits were detected in the mesangium and/or along the glomerular capillary walls, while typical pauci-immune CGN without IC deposits was found in 16 patients (57%; Group B). Compared with Group B, Group A had lower levels of MPO-ANCA (171 ± 156 vs. 352 ± 299 EU) and C-reactive protein (CRP) (0.63 ± 1.04 vs. 4.45 ± 4.00 mg/dl), as well as less pulmonary involvement (8.3% vs. 56.3%) at diagnosis. However, Group A had significantly heavier proteinuria (2.46 ± 1.67 vs. 0.76 ± 0.52 g/d). Group A was classified into three subgroups: Group A1 with mesangial IgA and C3 deposits, A2 with mesangial IgG and C3 deposits, and A3 with IgG and C3 deposits mainly in the capillary walls.. ANCA-associated CGN causes two types of renal involvement, which are the pauci-immune type without IC deposits and the IC deposition type that involves three patterns of IC deposition in the glomeruli. The reason why IC deposits are associated with renal-limited vasculitis and not systemic vasculitis remains unclear.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antigen-Antibody Complex; Biopsy; C-Reactive Protein; Capillaries; Female; Glomerulonephritis; Humans; Japan; Kidney; Male; Mesangial Cells; Microscopy, Electron; Microscopy, Fluorescence; Middle Aged; Peroxidase; Retrospective Studies

Serum C-reactive protein (CRP) was one of the useful biomarkers for evaluating the disease activity in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Cumulating studies proved that CRP was pathogenic in a variety of diseases. In the current study, the in vitro effects of CRP to prime neutrophils for ANCA-induced respiratory burst were investigated with flow cytometry. Without TNF-α in the reactive system, ANCA could only induce a slight level of respiratory burst of neutrophils. CRP could enhance the respiratory burst of neutrophils induced by ANCA against myeloperoxidse [mean fluorescence intensity (MFI, 68.45 ± 16.87 vs. 58.65 ± 15.09, P < 0.05) or by ANCA against proteinase 3 (MFI, 79.51 ± 15.90 vs. 61.73 ± 14.89, P < 0.05). Although CRP (50 μg/mL, incubating for 30 min) could not active neutrophils alone, after incubation with neutrophils for 10 min, CRP (50 μg/mL) could increase the expression of membrane proteinase 3 of neutrophils (MFI, 365.27 ± 143.50 vs. 235.32 ± 124.65, P < 0.05). Heat-treated CRP could not enhance the levels of neutrophils respiratory burst induced by ANCA or increase the expression of membrane proteinase 3 of neutrophils. So CRP can prime neutrophils and enhance the respiratory burst induced by ANCA and might be pathogenic in AAV.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; C-Reactive Protein; Female; Humans; Interleukin-8; Male; Middle Aged; Myeloblastin; Neutrophils; Peroxidase; Respiratory Burst; Tumor Necrosis Factor-alpha; Young Adult

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Antinuclear; Autoantigens; Comorbidity; Humans; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Peroxidase; Polyarteritis Nodosa; Prevalence; Sjogren's Syndrome

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Humans; Neutrophils; Peroxidase; Propylthiouracil

Neutrophil extracellular traps (NETs) are composed of DNA and antimicrobial proteins, including myeloperoxidase (MPO). Recent studies have demonstrated that impaired regulation of NETs could trigger an autoimmune response. Propylthiouracil (PTU), an antithyroid drug, is associated with a risk of MPO antineutrophil cytoplasmic antibody (ANCA) production and MPO ANCA-associated vasculitis (MPO AAV). This study was undertaken to clarify the mechanism of MPO ANCA production, using the PTU-induced model of MPO AAV.. NETs were induced by treating human neutrophils with phorbol myristate acetate (PMA) in vitro. We examined whether the addition of PTU influenced the NET formation induced by PMA and the degradation of NETs by DNase I, which is regarded as a regulator of NETs. Furthermore, we examined whether NETs generated by the combination of PMA and PTU induced MPO ANCA and MPO AAV in vivo in rats.. When NETs were induced by PMA with PTU using human neutrophils in vitro, abnormal conformation of NETs was observed. Interestingly, the abnormal NETs were hardly digested by DNase I. Moreover, rats immunized with the abnormal NETs, which had been induced by PMA with PTU using rat neutrophils, produced MPO ANCA and developed pulmonary capillaritis. When rats were given oral PTU with intraperitoneal injection of PMA, pauci-immune glomerulonephritis and pulmonary capillaritis occurred with MPO ANCA production in the serum.. Our findings indicate that abnormal conformation and impaired degradation of NETs induced by PTU are involved in the pathogenesis of PTU-induced MPO ANCA production and MPO AAV. These findings suggest that disordered NETs can be critically implicated in the pathogenesis of MPO AAV.

Topics: alpha-Defensins; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antimetabolites; Carcinogens; Deoxyribonuclease I; Disease Models, Animal; DNA; Humans; Neutrophils; Nucleic Acid Conformation; Peroxidase; Propylthiouracil; Rats; Rats, Inbred WKY; Tetradecanoylphorbol Acetate

Anti-myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA)- related nephritis constitutes 60% of rapidly progressive glomerulonephritis (RPGN) in Japan. The reported 1-year survival rate is over 80%, however, the long-term prognosis remains unknown. We therefore investigated the prognosis and factors affecting the clinical course of patients.. We retrospectively investigated 74 patients (female, n=42; median age, 73.0 years) with MPO-ANCA-related nephritis. The patients were admitted to Fukushima Medical University and two affiliated hospitals between 2000 and 2010.. Median estimated GFR (eGFR) was 12.1 mL/min/1.73 m2 at admission. The Birmingham Vasculitis Activity Score (BVAS version 3: max 63 points) at diagnosis and at 4 weeks after start of treatment were 15.0 and 5.0, respectively. Twenty-three patients (31%) died during a median observation period of 30.5 months. Sixteen patients (22%) presented with end-stage renal disease (ESRD) at the initial phase, and needed regular dialysis therapy. Multivariate Cox proportional hazards model analysis revealed that renal death at the initial phase was a significant risk factor for all-cause death (Hazard ratio, 5.72; 95% confidence interval, 2.49-13.09; p<0.001). Furthermore, BVAS>6, evaluated 4 weeks after start of treatment, is an independent risk factor for ESRD and patient survival.. This is the first investigation to demonstrate clinical features focusing on MPO-ANCA-related nephritis. Renal death at the initial phase of treatment is a powerful risk factor for all-cause death in patients with MPO-ANCA-related nephritis. Patients at high risk of death and ESRD could be stratified according to BVAS.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Female; Glomerular Filtration Rate; Glomerulonephritis; Humans; Japan; Kaplan-Meier Estimate; Kidney Failure, Chronic; Male; Peroxidase; Prognosis; Retrospective Studies; Risk Factors

To compare the usefulness of 3 currently used classification systems in predicting the outcomes of treatment resistance, disease relapse, end-stage renal disease (ESRD), and death in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).. Three classification systems were applied to 502 patients with biopsy-proven AAV: 1) the Chapel Hill Consensus Conference (CHCC) definition with categories for granulomatosis with polyangiitis (GPA) (Wegener's), microscopic polyangiitis (MPA), and kidney-limited disease; 2) the European Medicines Agency (EMA) system with categories for GPA and MPA; and 3) classification based on ANCA with specificity for myeloperoxidase (MPO ANCA) versus ANCA with specificity for proteinase 3 (PR3 ANCA). Outcomes included treatment resistance, relapse, ESRD, and death. Proportional hazards models were compared between systems using an information-theoretic approach to rank models by predictive fit. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) and P values are reported.. ANCA specificity was predictive of relapse, with PR3 ANCA-positive patients almost twice as likely to relapse as those with MPO ANCA (HR 1.89 [95% CI 1.33-2.69], P = 0.0004), and ANCA specificity had the best predictive model fit (model rank 1) compared to the CHCC and EMA systems. The CHCC and EMA systems did not predict relapse. By ANCA specificity, categories of GPA, MPA, and kidney-limited disease did not distinguish differences in probability of relapse-free survival. None of the systems predicted treatment resistance, ESRD, or death.. ANCA specificity independently predicts relapse among patients with AAV with renal disease. Classification and diagnostic systems that incorporate ANCA specificity, such as PR3 ANCA-positive MPA and MPO ANCA-positive MPA, provide a more useful tool than the clinical pathologic category alone for predicting relapse.

Topics: Adult; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antibody Specificity; Female; Humans; Male; Middle Aged; Myeloblastin; Peroxidase; Prognosis

Mast cells contribute to the modulation of the immune response, but their role in autoimmune renal disease is not well understood. Here, we induced autoimmunity resulting in focal necrotizing GN by immunizing wild-type or mast cell-deficient (Kit(W-sh/W-sh)) mice with myeloperoxidase. Mast cell-deficient mice exhibited more antimyeloperoxidase CD4+ T cells, enhanced dermal delayed-type hypersensitivity responses to myeloperoxidase, and more severe focal necrotizing GN. Furthermore, the lymph nodes draining the sites of immunization had fewer Tregs and reduced production of IL-10 in mice lacking mast cells. Reconstituting these mice with mast cells significantly increased the numbers of Tregs in the lymph nodes and attenuated both autoimmunity and severity of disease. After immunization with myeloperoxidase, mast cells migrated from the skin to the lymph nodes to contact Tregs. In an ex vivo assay, mast cells enhanced Treg suppression through IL-10. Reconstitution of mast cell-deficient mice with IL-10-deficient mast cells led to enhanced autoimmunity to myeloperoxidase and greater disease severity compared with reconstitution with IL-10-intact mast cells. Taken together, these studies establish a role for mast cells in mediating peripheral tolerance to myeloperoxidase, protecting them from the development of focal necrotizing GN in ANCA-associated vasculitis.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Cells, Cultured; Glomerulonephritis; Humans; Immunomodulation; Interleukin-10; Lymph Nodes; Male; Mast Cells; Mice; Mice, Inbred C57BL; Peripheral Tolerance; Peroxidase; T-Lymphocytes, Regulatory

The contribution of infections to the mortality of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis patients is important and should induce early and careful control of these events. However, the differentiation of infection from active vasculitis is often difficult. The usefulness of serum-soluble triggering receptor expressed on myeloid cells-1 (TREM-1) for detecting the presence of infectious complications regardless of disease activity was investigated.. Soluble TREM-1 in serum obtained from 41 patients with myeloperoxidase (MPO)-ANCA-associated vasculitis was measured by an enzyme-linked immunosorbent assay. Twenty-nine samples were from active vasculitis patients, 27 samples from inactive vasculitis patients without infection and 17 samples from inactive vasculitis patients with infectious complications. Serum-soluble TREM-1 was also measured in 10 patients with acute pyelonephritis and 30 patients with chronic kidney disease (CKD).. There was a significant correlation between serum levels of soluble TREM-1 and serum creatinine levels among all patients (r = 0.554, P < 0.0001). The serum-soluble TREM-1/creatinine ratio was higher in inactive vasculitis patients with infectious complications than in active vasculitis, inactive vasculitis without infection and CKD patients (P = 0.0005, P < 0.0001 and P < 0.0001, respectively), but not significantly different to that in acute pyelonephritis patients. On receiver-operating-characteristic curve analysis, a lower-limit value of 9.40 ng/mg for this ratio had a sensitivity of 84.6% and a specificity of 90.8% in differentiating patients with infection from those without infection.. The serum ratio of soluble TREM-1 to creatinine may be a useful marker for detection of infectious complications in MPO-ANCA-associated vasculitis.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Bacterial Infections; Biomarkers; Chronic Disease; Creatinine; Enzyme-Linked Immunosorbent Assay; Humans; Kidney Diseases; Kidney Failure, Chronic; Membrane Glycoproteins; Peroxidase; Receptors, Immunologic; ROC Curve; Sensitivity and Specificity; Triggering Receptor Expressed on Myeloid Cells-1

To determine whether inhibition of p38 mitogen-activated protein kinase (p38MAPK) reduces the pathogenicity of anti-neutrophil cytoplasmic autoantibodies (ANCAs) in vitro and in vivo.. The effects of the p38MAPK-specific inhibitor AR-447 were studied in vitro using neutrophil respiratory burst and degranulation assays, and in lipopolysaccharide (LPS)-stimulated human glomerular endothelial cells. In vivo, p38MAPK inhibition was investigated in a mouse anti-myeloperoxidase (MPO) IgG/LPS glomerulonephritis model. Mice were treated orally with AR-447 daily, starting before (pretreatment group) or 24 h after disease onset (treatment group), and killed after 1 or 7 day(s).. In vitro, AR-447 diminished neutrophil respiratory burst and degranulation induced by patient-derived MPO-ANCA and proteinase 3 (Pr3)-ANCA. In glomerular endothelial cells, AR-447 reduced LPS-induced secretion of IL-6 and IL-8, but not of MCP-1. In mice, pretreatment with AR-447 reduced albuminuria 1 day after induction of glomerulonephritis. After 7 days, no effects on urinary abnormalities were observed upon AR-447 pretreatment or treatment. Also, glomerular neutrophil accumulation was not diminished. In contrast, glomerular macrophage accumulation and the formation of glomerular crescents was significantly reduced by AR-447 pretreatment (vehicle: 12.5 ± 5.6% crescentic glomeruli; AR-447: 7.7 ± 2.7%) and treatment (vehicle 14.6 ± 1.8%; AR-447 6.0 ± 3.4%) at 7 days.. This study shows that p38MAPK inhibition markedly reduces ANCA-induced neutrophil activation in vitro. In vivo, p38MAPK inhibition partly reduced crescent formation when the drug was administered prior to disease induction and after disease onset, suggesting that besides p38MAPK activity other signalling pathways contribute to the disease activity.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Cells, Cultured; Cytokines; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Glomerulonephritis; Humans; Immunoglobulin G; Kidney Glomerulus; Lipopolysaccharides; MAP Kinase Signaling System; Mice; Mice, Knockout; Neutrophil Activation; p38 Mitogen-Activated Protein Kinases; Peroxidase; Protein Kinase Inhibitors; Respiratory Burst

Autoantibodies constitute the hallmark of antineutrophil cytoplasmic antibody-associated vasculitis (AAV); however, CD4+ T cells play an essential role in the development of autoimmunity. Infection is associated with vasculitis, with Toll-like receptors (TLRs) a potential link between infection and autoimmunity. This study was undertaken to investigate the role of TLR ligation on cellular and humoral autoimmunity and glomerular injury in experimental myeloperoxidase (MPO)-induced AAV.. We analyzed autoimmune responses in wild-type mice immunized with MPO alone or coimmunized with MPO and a TLR-2 or TLR-9 ligand. The major vascular injury found in human disease, glomerulonephritis with focal necrosis, was triggered by administering a subnephritogenic dose of nephrotoxic serum.. MPO alone induced low-titer antineutrophil cytoplasmic antibodies (ANCAs) without delayed-type hypersensitivity or CD4 cytokine responses. However, when MPO was given with either TLR ligand, cellular and humoral autoimmunity was enhanced, but with distinctly different CD4 subsets and IgG ANCA isotypes. TLR-2 ligand induced Th17 autoimmunity, with retinoic acid receptor-related orphan nuclear receptor γt-dependent interleukin-17A (IL-17A) production. TLR-9 ligand promoted Th1 autoimmunity, with enhanced production of interferon-γ (IFNγ) and Th1-associated IgG subclasses. Glomerular vasculitis developed only after the administration of nephrotoxic serum in mice immunized with either TLR ligand and MPO. Glomerulonephritis directed by MPO and TLR-2 ligation was attenuated when IL-17A was neutralized, while glomerulonephritis induced by MPO and TLR-9 ligation was attenuated when IFNγ was neutralized.. Our findings indicate a pathogenic role of TLRs in initiating autoimmune AAV. TLR-2 induces Th17 CD4 cells while TLR-9 can also direct vasculitis, by directing Th1 autoimmunity.

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Monoclonal; Autoimmunity; CD4-Positive T-Lymphocytes; Disease Models, Animal; Glomerulonephritis; Immunity, Humoral; Interferon-gamma; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Peroxidase; Th1 Cells; Th17 Cells; Toll-Like Receptor 2; Toll-Like Receptor 9

A proliferation-inducing ligand (APRIL) and the B cell activation factor belonging to the tumor necrosis factor family (BAFF) have proven to be key factors in the selection and survival of B cells, and a higher concentration of BAFF has been shown to contribute to autoreactive B cell survival and elevated autoantibody production. Here, serum BAFF and APRIL levels were investigated to analyze their association with disease activity in myeloperoxidase anti-neutrophil cytoplasmic autoantibody (MPO-ANCA)-associated renal vasculitis.. APRIL and BAFF levels in serum obtained from 37 patients with MPO-ANCA-associated vasculitis were measured by ELISA. Samples were taken from active vasculitis patients, inactive vasculitis patients and inactive vasculitis patients with infectious complications.. Although there was no difference in serum APRIL among the active vasculitis, inactive vasculitis and infectious complication patients, serum BAFF was higher in active vasculitis patients than in inactive vasculitis, infectious complication and control patients (for all, p < 0.001). There was no significant correlation between serum APRIL and ANCA titers, but there was a significant correlation between serum BAFF and ANCA titers (r = 0.465, p < 0.001).. Excessive BAFF production in MPO-ANCA-associated vasculitis may be one of the factors for autoimmune B cell tolerance, resulting in MPO-ANCA production.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; B-Cell Activating Factor; Biomarkers; Humans; Infections; Kidney Diseases; Peroxidase; Tumor Necrosis Factor Ligand Superfamily Member 13

Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Anti-Idiotypic; Creatinine; Disease Models, Animal; Glomerular Filtration Rate; Glomerulonephritis; Humans; Mice; Mice, Knockout; Peroxidase; Plasma Exchange; Severity of Illness Index; Treatment Outcome

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Arthritis, Rheumatoid; Drug Substitution; Female; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Injections, Intravenous; Kidney Glomerulus; Peroxidase; Remission Induction; Treatment Outcome

The authors report the case of a 72-year-old man presenting with chronic dyspnoea and pyrexia of unknown origin (PUO). After extensive investigation, he was found to have pulmonary fibrosis with usual interstitial pneumonia pattern on high-resolution CT imaging and positive myeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA) with no infectious cause or other evidence of vasculitis organ involvement. His pyrexia and symptoms settled with oral systemic corticosteroid treatment. To the authors' knowledge this is the first case of MPO-ANCA positive vasculitis presenting as PUO and pulmonary fibrosis alone. The authors review the recent literature regarding the association of pulmonary fibrosis with ANCA-positive vasculitides with regards to pathogenesis, prognosis and treatment.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biomarkers; Dyspnea; Fever of Unknown Origin; Humans; Male; Peroxidase; Pulmonary Fibrosis

We report a case of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis in a 62-year-old patient with gastric cancer. The myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA) level was threefold above normal preoperatively. Vasculitis was seen on renal biopsy. Gastric resection revealed well-differentiated adenocarcinoma and vasculitis. The MPO-ANCA level returned to normal post-operatively. Although ANCA-associated vasculitis occasionally accompanies malignant tumors, this is the first documented case of concurrent gastric cancer-associated and ANCA-associated vasculitis, with post-operative resolution of the vasculitis.

Topics: Adenocarcinoma; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Humans; Male; Middle Aged; Peroxidase; Remission, Spontaneous; Stomach Neoplasms

Antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitides are major causes of rapidly progressive glomerulonephritis (RPGN). Although recent papers suggest differences in clinicoepidemiological manifestations of ANCA-associated vasculitis between Japan [microscopic polyangiitis (MPA) " Wegener's granulomatosis (WG)] and Europe (WG"MPA), little is known about the prevalence and serological pattern. We retrospectively analyzed 27 RPGN patients who were admitted in our hospital over the past 11 years and who could be basically followed for more than 1 year, concerning the incidence of ANCA-related vasculitis, the presence of (MPO)/proteinase 3 (PR3)-ANCA and their clinical outcomes. As there were no PR3-ANCA single positive and/or WG patients, all patients were serologically divided into four groups; Groups I: MPO-ANCA single-positive patients (N = 11), II: MPO-ANCA and PR3-ANCA double-positive patients (N = 3), III: antiglomerular basement membrane antibody (anti-GBM Ab)-positive patients (N = 6), and IV: all negative patients (N = 7). Patients in Groups II/III showed more severe manifestation at admission. However, in Group I, only 36.3% patients avoided death and/or dialysis-dependent end-stage renal disease. Most patients in Group IV were women (85.7%), and 50% of these patients was diagnosed as having rheumatic diseases. Every patient in Groups I-III was treated with oral corticosteroid and/or methylprednisolone pulse therapy. Most patients treated with immunosuppressants showed severe prognosis because of frequent recurrences of vasculitis and infectious episodes after repeated and prolonged treatments with immunosuppressants. Present analysis further confirms the epidemiological and serological differences in ANCA-related RPGN between Japan and Europe, and reinforced the fact that ANCA-associated vasculitis is the most serious causal disease for RPGN.

Topics: Administration, Oral; Age of Onset; Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Comorbidity; Female; Glomerulonephritis; Glucocorticoids; Hospitals, University; Humans; Incidence; Japan; Male; Methylprednisolone; Middle Aged; Myeloblastin; Peroxidase; Pulse Therapy, Drug; Retrospective Studies

The patient was a 57-year-old male, who developed bloody stool around May 2006. He was examined by another physician in the department of gastroenterology in our hospital. Gastrointestinal (GI) endoscopy showed a duodenal ulcer, and the biopsy specimen revealed angiitis of the duodenum. He was admitted to our hospital on June 2006. Serum level of creatinine (Cr) was rapidly increased with hematuria and proteinuria. The titer of MPO-ANCA was elevated, and he was diagnosed with microscopic polyangiitis. Steroid pulse therapy was initiated, followed by the administration of prednisolone (PSL : 1 mg/kg/day) and intravenous cyclophosphamide (IVCY). Serum Cr was gradually decreased, but bloody stool was observed from the 10th hospital day. GI endoscopy showed bleeding from the duodenal ulcer. Steroid pulse therapy was performed, and the dose of PSL was increased to 1.5 mg/kg. Endoscopic hemostatic therapy was repeatedly performed without clinical improvement. Pancreatoduodenectomy was performed on the 15th hospital day. However, bleeding from the small intestine was observed repeatedly and the computed tomography of the chest showed cavity-forming nodules, which were diagnosed with angiitis by the biopsy specimen. The additional treatments of steroid pulse therapy, intravenous immunoglobulin therapy, IVCY and Rituximab did not result in favorable response. We report a refractory case of ANCA-related angiitis presented with gastrointestinal ulcer, rapidly progressive nephritis and multiple lung nodules.

Topics: Adult; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Disease Progression; Duodenal Ulcer; Glomerulonephritis; Humans; Male; Multiple Pulmonary Nodules; Peroxidase

Chronic infections may mimic antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV). We investigated which markers may help in the diagnosis and the prognosis of infections associated with proteinase 3 (PR3) and myeloperoxidase (MPO)-ANCA. In this study (1993-2008)--with an average follow-up of 5.1 years--we compared 66 AAV patients with 17 PR3 and/or MPO-ANCA-positive patients with protracted bacterial (11/17) or viral (6/17) infections. Seven of 17 patients had subacute bacterial endocarditis (SBE), while six of 17 patients had various autoimmune manifestations of chronic hepatitis C virus (HCV) infection. We determined ANCA, antinuclear antibodies, anti-PR3, anti-MPO, anticardiolipin (aCL), antibeta 2 glycoprotein I (beta2-GP I), cryoglobulins, C3, and C4. Patients with infections were younger than AAV patients (p < 0.01). There was no difference in frequency of renal and skin lesions. AAV patients more frequently had pulmonary and nervous system manifestations (p < 0.01). Patients with infections more frequently had dual ANCA (high PR3, low MPO), aCL, anti-beta2-GP I, cryoglobulins, and hypocomplementemia (p < 0.001). Immunosuppressive therapy (IST) was used in five 17 patients who had persistently high ANCA, cryoglobulinemia, and hypocomplementemia. There was no difference in frequency of lethality and renal failure in the two study groups. In patients who are PR3- and/or MPO-ANCA positive, SBE and HCV infection should be excluded. Although similar in renal and skin manifestations in comparison to AAV, only patients with infections developed multiple serological abnormalities. In patients with infections, concomitant presence of ANCA, cryoglobulins, and hypocomplementemia was associated with severe glomerulonephritis. The serological profile should be repeated after specific antimicrobial or surgical therapy, since some cases might require IST.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Child; Endocarditis, Bacterial; Female; Follow-Up Studies; Glomerulonephritis, Membranoproliferative; Hepatitis C; Humans; Male; Middle Aged; Mycobacterium Infections; Myeloblastin; Peroxidase; Retrospective Studies; Staphylococcal Infections; Streptococcal Infections; Young Adult

A 56-year-old-woman presented a local otolaryngologist with a complaint of hearing loss. She was treated with antibiotics as acute otitis media, however her symptom did not improved. She admitted to our hospital because of hearing loss on both sides, fever, otorrhea and vertigo. On admission, an audiogram showed bilateral mixed conductive-sensorineural hearing loss, and CT image revealed the exudates in bilateral middle ear cavities and mastoid air cells. Moreover, serum level of myeloperoxidase anti-neutrophil cytoplasmic autoantibody (MPO-ANCA) elevated (133EU). Although pulmonary, renal and cutaneous involvements were not noted and the histopathological examination of operated specimen taken from otitis media revealed non-specific inflammatory changes, in the absence of any other obvious causes of otitis media, these findings might be associated with positive serum MPO-ANCA value itself. After the initiation of therapy with methylprednisolone and azathioprine, her symptoms and hearing ability ameliorated and both CRP value and the titer of ANCA became normalized. But, after the improvement by the immunosuppressive treatment, MRSA in the otorrhea persisted. This case suggests that otitis media may be one of the symptoms of vasculitis, and some previous cases described otitis media or hearing loss as rare manifestations of vasculitis. It is important to make an early diagnosis for good prognosis of hearing ability, and we have to consider the differential diagnosis including of ANCA-related vasculitis.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Azathioprine; Biomarkers; Drug Therapy, Combination; Female; Hearing Loss; Humans; Methicillin-Resistant Staphylococcus aureus; Methylprednisolone; Middle Aged; Otitis Media with Effusion; Peroxidase; Treatment Outcome

Leucocyte transendothelial migration is strictly regulated to prevent undesired inflammation and collateral damage of endothelial cells by activated neutrophils/monocytes. We hypothesized that in anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis (AAV) patients' dysregulation of this process might underlie vascular inflammation. Peripheral blood mononuclear cells (PBMC) and neutrophils from AAV patients (n = 12) and healthy controls (HC, n = 12) were isolated. The influence of human umbilical vein endothelial cells (HUVEC) on neutrophil/monocytes function was tested by N-formyl-methionyl-leucyl-phenyl-alanine (fMLP)- and phorbol 12-myristate 13-acetate (PMA)-mediated ROS production, degranulation and interleukin (IL)-8 production. In addition, the ability of lipopolysaccharide (LPS)-stimulated PBMC to produce tumour necrosis factor (TNF)-alpha in the presence or absence of HUVEC was tested. HUVEC inhibited ROS production dose-dependently by fMLP-stimulated neutrophils but did not influence degranulation. No differences between neutrophils from HC and AAV were found. However, in only one active patient was degranulation inhibited significantly by HUVEC only before cyclophosphamide treatment, but not 6 weeks later. Co-cultures of HUVEC with LPS-stimulated neutrophils/monocytes increased IL-8 production while TNF-alpha production was inhibited significantly. There was no apparent difference between AAV patients and HC in this respect. Our findings demonstrate that HUVEC are able to inhibit ROS and modulate cytokine production upon stimulation of neutrophils or monocytes. Our data do not support the hypothesis that endothelial cells inhibit ROS production of neutrophils from AAV patients inadequately. Impaired neutrophil degranulation may exist in active patients, but this finding needs to be confirmed.

Topics: Adenosine Deaminase; Adenosine-5'-(N-ethylcarboxamide); Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Cell Communication; Cell Degranulation; Cells, Cultured; Coculture Techniques; Endothelial Cells; Humans; Interleukin-8; Leukocytes, Mononuclear; Lipopolysaccharides; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Peroxidase; Reactive Oxygen Species; Respiratory Burst; Tetradecanoylphorbol Acetate; Tumor Necrosis Factor-alpha

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides are systemic or more limited conditions characterized by necrotizing destruction of small and medium-sized vessels (eg, capillaries, venules, and arterioles). ANCAs are the most predominant autoantibodies in patients affected by vasculitis, but other autoantibodies may also occur, probably reflecting pathogenetic events in affected tissue. These autoantibodies are assumed to play a role in the initiation and propagation of chronic inflammation. ANCAs are valuable for clinical diagnosis, follow-up, and guidance in therapy.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Endothelium, Vascular; Humans; Myeloblastin; Peroxidase

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) include Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. Given their rarity, protean clinical manifestations, imperfect diagnostic tests, and wide differential diagnosis, they pose a diagnostic challenge even to experienced clinicians. This article describes diagnostic approaches for patients suspected of having one of the ANCA-associated vasculitides. The clinical findings at presentation, the role of laboratory and imaging tests, and the importance of tissue diagnosis are presented. In each section, issues relevant to the differential diagnosis of AAV are discussed.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Biopsy; Electromyography; Humans; Lung; Magnetic Resonance Imaging; Myeloblastin; Peroxidase; Tomography, X-Ray Computed

Although autoimmune syndromes such as systemic lupus erythematosus and dermatomyositis have been previously reported in association with statin use, vasculitis has not been well described. We present a patient with an antineutrophil cytoplasmic antibody-positive, predominantly cutaneous vasculitis, the temporal course of which was associated with simvastatin/ezetimibe use. The patient's serologic findings were consistent with drug-induced disease, with high titer antimyeloperoxidase, in addition to antinuclear and anti-Ro (SSA) antibodies. The patient demonstrated complete resolution of symptoms simply by withdrawing the drug.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Anticholesteremic Agents; Autoimmunity; Azetidines; Biomarkers; Drug Combinations; Ezetimibe, Simvastatin Drug Combination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Peroxidase; Ribonucleoproteins; Simvastatin

We present a case of a middle-aged woman with myeloperoxidase anti-neutrophil cytoplasmic autoantibody (MPO-ANCA)-associated vasculitis that demonstrated immunohistochemically positive MPO capillaries of the pleura. The patient initially presented with proteinuria and microscopic hematuria at the age of 38. Acute progressive glomerulonephritis and pulmonary hemorrhage occurred 4 years later, and a high serum titer of MPO-ANCA was detected therefore a diagnosis of microscopic polyangiitis was made. Steroid-pulse therapy was performed and the pulmonary shadow improved, but the renal failure did not improve, thus, hemodialysis was initiated. Thereafter, an 18-year asymptomatic phase followed, but high serum levels of MPO-ANCA persisted during this period. Chronic pulmonary hemorrhage was discovered at the age of 60, and video-assisted thoracoscopic surgery was performed. Resected tissue revealed diffuse aloveolar hemorrhage accompanied by marked hemosiderin deposition, whereas MPO-immunopositive capillaries were identified only in the pleura. To our knowledge, this is the first report demonstrating MPO-positive capillaries in a disease other than glomerulonephritis. Judging from this unique case, MPO-positive endothelial cells may appear only during the hyperacute stage before hemorrhage, and may diminish thereafter, thus, may be associated with the trigger of microscopic polyangiitis.

Topics: Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Capillaries; Female; Humans; Immunohistochemistry; Middle Aged; Peroxidase; Pleura

Myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-associated vasculitis frequently induces crescentic glomerulonephritis. However, a few cases have so far been reported to have only tubulointerstitial (TI) nephritis without any apparent glomerular lesions. We recently treated three similar cases. Therefore, their pathological features as well as clinical manifestations were studied in detail.. The pathological study was performed with immunohistochemical staining using various antibodies to the vascular endothelial cell surface markers, von Willebrand factor, type IV collagen, cytokeratin, E-cadherin, and MPO in addition to the routine histochemical examination.. The study disclosed the loss of CD34 endothelial cell surface markers with and without the destruction of type IV collagen (capillary basement membrane) in the peritubular capillaries, even though the glomeruli showed good staining of these factors. Electron microscopy showed breaks in the capillary basement membrane. The loss of CD34 staining was associated with the infiltration of a few mononuclear cells and neutrophils in the lumen of peritubular capillaries and the surrounding interstitial tissues. The cytokeratin staining in the tubular epithelial cells was also diminished around these areas. Tubulitis was demonstrated with or without the destruction of the tubular basement membrane. The clinical manifestations of these three cases were only a few red blood cells and granular casts in the urinary sediment as well as slightly increased beta2-microglobulin in the urine, but no proteinuria.. Based on these findings, the loss of CD34 vascular endothelial markers occurs in the early phase of the disease because of the MPO, which is presumed to have burst out from the infiltrated, activated neutrophils. This MPO, which releases proteolytic enzymes and radical oxygen species, acts on tissue destruction, namely the lysis of endothelial cell membranes as well as vascular basement membranes in the peritubular capillary. This mechanism eventually proceeds to the destruction of the peritubular capillary walls (vasculitis). This pathogenesis is thought to play an important role in the pathogenesis of TI nephritis, which is associated with MPO-ANCA vasculitis.

Topics: Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antigens, CD34; Collagen Type IV; Female; Humans; Immunohistochemistry; Kidney Glomerulus; Male; Middle Aged; Nephritis, Interstitial; Peroxidase

To clarify the clinical significance of tumor necrosis factor (TNF) receptors in patients with myeloperoxidase (MPO)-anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, we evaluated the cell surface expression of TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2).. 43 patients with MPO-ANCA-associated vasculitis, 16 patients with chronic renal failure, 10 patients with sepsis, 15 patients with systemic lupus erythematosus, and 18 healthy controls were enrolled in this study, and the surface expression levels of TNFR1, TNFR2, CD63, and CD64 on granulocytes were assessed. In 21 patients with MPO-ANCA-associated vasculitis, soluble TNFR1 (sTNFR1), soluble TNFR2(sTNFR2), and TNF-alpha in the serum were also measured.. The surface expression levels of TNFR1 and TNFR2 on granulocytes were significantly higher in patients with MPO-ANCA-associated vasculitis than in the healthy controls, and positively correlated with the Birmingham Vasculitis Activity Score (BVAS). The levels of sTNFR1, sTNFR2, and TNF-alpha in the serum were also significantly higher in patients with MPO-ANCA-associated vasculitis than in the healthy controls. Serum levels of sTNFR1 and sTNFR2 correlated with serum creatinine, while the surface expression of TNFR1 and TNFR2 on the granulocytes did not. There was no significant correlation between the BVAS and CD63 or BVAS and CD64.. The surface expression levels of TNFR1 and TNFR2 on granulocytes were upregulated in patients with MPO-ANCA-associated vasculitis and reflected disease activity.

Topics: Adult; Aged; Aged, 80 and over; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Autoantibodies; Biomarkers; Female; Gene Expression Regulation; Granulocytes; Humans; Male; Middle Aged; Peroxidase; Receptors, Tumor Necrosis Factor; Young Adult