Pathophysiology Of ANCA-associated Vasculitis Research Articles

Prevalence of ANCA-associated vasculitis amid natural gas drilling sites in West Virginia

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.

Mass spectrometry-based proteomic exploration of the small urinary extracellular vesicles in ANCA-associated vasculitis in comparison with total urine

ANCA-associated vasculitis (AAV) is a rare, but potentially severe autoimmune disease, even nowadays displaying increased mortality and morbidity. Finding early biomarkers of activity and prognosis is thus very important. Small extracellular vesicles (EVs) isolated from urine can be considered as a non-invasive source of biomarkers. We evaluated several protocols for urinary EV isolation. To eliminate contaminating non-vesicular proteins due to AAV associated proteinuria we used proteinase K treatment. We investigated the differences in proteomes of small EVs of patients with AAV compared to healthy controls by label-free LC–MS/MS. In parallel, we performed an analogous proteomic analysis of urine samples from identical patients. The study results showed significant differences and similarities in both EV and urine proteome, the latter one being highly affected by proteinuria. Using bioinformatics tools we explored differentially changed proteins and their related pathways with a focus on the pathophysiology of AAV. Our findings indicate significant regulation of Golgi enzymes, such as MAN1A1, which can be involved in T cell activation by N-glycans glycosylation and may thus play a key role in pathogenesis and diagnosis of AAV. SignificanceThe present study explores for the first time the changes in proteomes of small extracellular vesicles and urine of patients with renal ANCA-associated vasculitis compared to healthy controls by label-free LC–MS/MS. Isolation of vesicles from proteinuric urine samples has been modified to minimize contamination by plasma proteins and to reduce co-isolation of extraluminal proteins. Differentially changed proteins and their related pathways with a role in the pathophysiology of AAV were described and discussed. The results could be helpful for the research of potential biomarkers in renal vasculitis associated with ANCA.

D-penicillamine-induced ANA (+) ANCA (+) vasculitis in pediatric patients with Wilson’s disease

Anti-neutrophil cytoplasmic antibodies (ANCA) are associated with systemic vasculitis. The pathophysiology of ANCA-associated vasculitis (AAV) has not been clearly proven, and drug-induced ANCA-associated vasculitis has been reported. Wilson's disease is an inborn error of copper metabolism caused by a mutation in the copper transporting gene ATP7B, and traditional treatment is based on copper chelation with agents such as D-penicillamine. There have been rare reports that prolonged D-penicillamine therapy might cause adverse renal events such as membranous nephropathy and minimal change disease, but it is questionable if D-penicillamine induces ANCA-associated vasculitis. We describe 2 patients with Wilson's disease treated with D-penicillamine who presented with ANCA (+) vasculitis and renal involvement. The 2 patients also showed positive results for antinuclear antibody (ANA). Their kidney biopsy findings were compatible with crescentic/necrotizing glomerulonephritis, pauci-immune type. After diagnosis of AAV, D-penicillamine was stopped. Patients were then treated with plasmapheresis and immunosuppressants, including methylprednisolone pulse therapy and intravenous cyclophosphamide. One patient progressed to end-stage renal disease and the other showed persistent proteinuria. These cases suggest that D-penicillamine may induce ANA (+) ANCA (+) vasculitis with severe renal involvement in pediatric patients, and plasmapheresis combined with immunosuppressant should be considered.