Recent advances in anti-neutrophil cytoplasmic antibody-associated vasculitis.
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ABSTRACT:
SUBMITTER: Lazarus B
PROVIDER: S-EPMC4795442 | biostudies-literature | 2016 Mar-Apr
REPOSITORIES: biostudies-literature
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Recent advances in anti-neutrophil cytoplasmic antibody-associated vasculitis.
Lazarus B B John G T GT O'Callaghan C C Ranganathan D D
Indian journal of nephrology 20160301 2
Anti-neutrophil cytoplasmic antibody-associated vasculitis is an uncommon inflammatory disease of small to medium-sized vessels that frequently presents with rapidly progressive glomerulonephritis and renal failure though it can affect any organ system. If untreated, the vast majority of patients will die within a year. Current treatments improve prognosis but affected patients remain at a substantially higher risk of death and adverse outcomes. We review the classification of the disease, our u ...[more]
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Project description:BackgroundAnti-neutrophil cytoplasmic antibodies associated vasculitides (AAV) are characterized by autoimmune small vessel inflammation. Eosinophils are multifunctional cells with both pro-inflammatory and immunoregulatory properties. Tissue activated eosinophils secrete cyto- and chemokines and form extracellular traps (EETs), they release free granules and produce reactive oxygen species. The role of eosinophils is well established in eosinophilic granulomatosis with polyangiitis (EGPA) but very little is known about their role in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).MethodsThe expression of surface markers CD11c, CD11b, CD16, CD35, CD62L, CD64, CD88, Siglec-8 and CD193 and reactive oxygen species production by peripheral blood eosinophils were studied using flow cytometry. Fluorescence microscopy was used to visualize the release of eosinophil extracellular DNA traps (EETs). 98 GPA and MPA patients and 121 healthy controls were included in the study.ResultsBoth GPA and MPA patients had decreased frequency of eosinophils in peripheral blood compared with healthy controls (p < 0.0001), which could not solely be explained by corticosteroid treatment. The patient's eosinophils showed increased surface expression of the Fc receptors CD16 (p < 0.0001) and CD64 (p = 0.0035) as well as CCR3 (CD193) (p = 0.0022). Decreased expression was found of the complement receptors CD35 (p = 0.0022), CD88 (p < 0,0001) as well as CD11c (p < 0,0001), CD11b (p = 0.0061) and Siglec-8 (p = 0,0015). Moreover, GPA and MPA eosinophils, showed decreased capacity to produce ROS (p < 0.0001). ANCA stimulation of eosinophils from GPA and MPA patients after C5a priming enhanced EETosis (p = 0,0088).ConclusionsThe percentage of eosinophils were decreased in peripheral blood in GPA and MPA patients and showed altered surface marker expression and function. The enhanced EETosis after ANCA stimulation, suggests that eosinophil can contribute to the autoantibody driven inflammatory process.
| S-EPMC6408823 | biostudies-literature
Project description:Two patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and rapid onset of high fever, tachycardia and systemic hypotension accompanied by elevated laboratory markers of infection were diagnosed with azathioprine hypersensitivity syndrome only after repeat exposure. Azathioprine hypersensitivity can closely mimic sepsis and/or vasculitis activity and should be considered in AAV, a condition with frequent use of this drug. We discuss the pitfalls in diagnosis and the possible pathophysiologic background.
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Project description:•AAV is characterized by necrotizing small vessel vasculitis with positive serum ANCA.•MPO/PR3-ANCA and neutrophils play central roles in AAV pathogenicity.•Dysregulated complement system primes neutrophils.•MPO-ANCA directly activates neutrophils to induce NETosis followed by releasing NETs.•B cells, T cells, and dendritic cells also contribute to the pathogenicity of AAV.
| S-EPMC8063861 | biostudies-literature
Project description:BACKGROUND:Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic GPA (EGPA). Myeloperoxidase (MPO) and proteinase 3 (PR3) are the main antigens for ANCA. AAV is a common multisystem autoimmune disease and most of the studies on AAV have been conducted in Western countries. Nowadays in China many efforts are made to investigate this disease. SUMMARY:This review highlights the progress in the prevalence, management and outcomes of AAV in Chinese patients. With respect to the prevalence of AAV, though there are no precise data, AAV is not rare in the Chinese population. In Chinese patients with AAV there is a striking preponderance of MPA, and MPO-ANCA is much more common than PR3-ANCA. Even in patients with GPA there is a predominance of MPO-ANCA over PR3-ANCA. Propylthiouracil-induced AAV and ANCA-negative pauci-immune glomerulonephritis are stated in this review as well. With respect to the management of AAV, glucocorticoids in combination with cyclophosphamide remain the mainstay of induction therapy. Besides, we describe predictors of different outcomes in Chinese patients, including mortality, relapse, treatment resistance and end-stage renal disease. KEY MESSAGES:AAV is not rare in the Chinese population. The disease spectrum and subtypes of ANCA are different between patients with AAV in China and Western countries. The treatment strategy for AAV in China is in consistency with that in Western countries. Predictors of different clinical outcomes are provided. FACTS FROM EAST AND WEST:Treatment options for AAV are shared between the East and West, with corticosteroid combined with cyclophosphamide being the standard regimen for inductive therapy and switching to azathioprine after remission. The major cause of death in treated patients is infection related to immunosuppressive therapy within the first year after diagnosis, and this rate might be higher in China than in Western countries. Western studies demonstrated the efficacy and safety of rituximab for induction of remission in cases with relatively mild disease and maintenance therapy, but this agent is rarely used in China.
| S-EPMC4934806 | biostudies-literature
Project description:IntroductionThe complement system is crucial for the development of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In particular, C5a plays a central role. In this study, plasma and urinary levels of C5a as well as renal C5a receptors (CD88 and C5L2) expression were investigated in patients with AAV.MethodsTwenty-four patients with AAV in the active phase, 19 patients with AAV in the remission phase, and 20 patients with lupus nephritis (LN) were included. Plasma and urinary levels of C5a were measured with enzyme-linked immunosorbent assay (ELISA). The staining of CD88 and C5L2 in renal specimens was detected with immunohistochemistry.ResultsThe level of plasma C5a was significantly higher in patients with AAV in the active phase than that in patients in remission, that in patients with LN, and that in normal controls. The urinary C5a level was significantly higher in patients with AAV in the active phase than that in patients in remission and that in normal controls, but not significantly different between patients with active AAV and patients with LN. The mean optical density of CD88 staining in the tubulointerstitium was significantly lower in AAV patients than that in normal controls (0.0052 ± 0.0011 versus 0.029 ± 0.0042; P = 0.005). The mean optical density of C5L2 in glomeruli was significantly higher in AAV patients than that in normal controls (0.013 ± 0.0027 versus 0.0032 ± 0.0006; P < 0.001). The mean optical density of CD88 staining closely correlated with the initial eGFR (r = 0.835; P < 0.001) in AAV patients. Double-labeling immunofluorescence assay suggested that CD88 did not express on neutrophils, monocytes, or macrophages, but C5L2 expressed on neutrophils (or monocytes) and macrophages.ConclusionThe elevated plasma and urinary C5a levels indicated complement activation in human AAV. The level of renal CD88 expression could reflect the disease severity of ANCA-associated glomerulonephritis. CD88 expression was downregulated, and C5L2 was upregulated in ANCA-associated glomerulonephritis.
| S-EPMC3446523 | biostudies-literature
Project description:The anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a group of disorders characterized by necrotizing inflammation of the small to medium vessels in association with autoantibodies against the cytoplasmic region of the neutrophil. Included in this definition are granulomatosis with polyangiitis (GPA, formerly known as Wegener's granulomatosis), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome). AAV are chronic, often relapsing diseases that can be organ or life threatening. Despite immunosuppression, the morbidity and mortality remain high. Renal involvement contributes significantly to the morbidity with high numbers of patients progressing to end-stage kidney disease. Current therapies have enabled improvements in renal function in the short term, but evidence for long-term protection is lacking. In MPA, renal involvement is common at presentation (90%) and often follows a more severe course than that seen in paediatric GPA. Renal biopsy remains the 'gold standard' in diagnosing ANCA-associated glomerulonephritis. While GPA and MPA are considered separate entities, the two are managed identically. Current treatment regimens are extrapolated from adult studies, although it is encouraging to see recruitment of paediatric patients to recent vasculitis trials. Traditionally more severe disease has been managed with the 'gold standard' treatment of glucocorticoids and cyclophosphamide, with remission rates achieved of between 70 and 100%. Other agents employed in remission induction include anti-tumor necrosis factor-alpha therapy and mycophenolate mofetil. Recently, however, increasing consideration is being given to rituximab as a therapy for children in severe or relapsing disease, particularly for those at risk for glucocorticoid or cyclophosphamide toxicity. Removal of circulating ANCA through plasma exchange is a short-term measure reserved for severe or refractory disease. Maintenance therapy usually involves azathioprine. The aim of this article is to provide a comprehensive review of paediatric AAV, with a focus on renal manifestations, and to highlight the recent advances made in therapeutic management.
| S-EPMC5700225 | biostudies-literature
Project description: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.
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Project description:BackgroundAlthough rapidly progressive glomerulonephritis is the main renal phenotype of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), slow renal disease progression is sometimes observed. These forms have been rarely discussed; we analysed their prevalence, clinico-pathological characteristics and outcome.MethodsWe screened patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis followed at seven referral centres and selected those with estimated glomerular filtration rate (eGFR) reduction <50% over a 6-month period preceding diagnosis. Data regarding patient features and response to treatment were retrieved.ResultsOf 856 patients, 41 (5%) had slowly progressive renal AAV. All had MPA and all but one was P-ANCA/myeloperoxidase (MPO) ANCA-positive. At diagnosis, the median age was 70 years [interquartile range (IQR) 64-78] and extra-renal manifestations were absent or subclinical (interstitial lung lesions in 10, 24%). The median (IQR) eGFR was 23 mL/min/1.73 m2 (15-35); six patients (15%) had started renal replacement therapy (RRT). All had proteinuria (median 1180 mg/24 h, IQR 670-2600) and micro-haematuria. Main histologic findings were extracapillary proliferation at chronic stages and glomerulosclerosis; following Berden's classification, 6/28 biopsies (21%) were 'focal', 1/28 (4%) 'crescentic', 9/28 (32%) 'mixed' and 12/28 (43%) 'sclerotic'. At last follow-up (median 32 months, IQR 12-52), 20/34 patients (59%) treated with immunosuppression had eGFR improvement >25% as compared with diagnosis, while 4/34 (12%) had started RRT.ConclusionsAAV may present with slow renal disease progression; this subset is hallmarked by advanced age at diagnosis, positive MPO-ANCA, subclinical interstitial lung lesions and chronic damage at kidney biopsy. Partial renal recovery may occur following immunosuppression.
| S-EPMC7857823 | biostudies-literature
Project description:Objectives:To study the determinants of the pharmacokinetics (PK) of rituximab (RTX) in patients with ANCA-associated vasculitis (AAV) and its association with clinical outcomes. Methods:This study included data from 89 patients from the RTX in AAV trial who received the full dose of RTX (four weekly infusions of 375 mg/m2). RTX was quantified at weeks 2, 4, 8, 16 and 24, and summarized by computing the trapezoidal area under the curve. We explored potential determinants of the PK-RTX, and analysed its association with clinical outcomes: achievement of remission at 6 months, duration of B-cell depletion and time to relapse in patients who achieved complete remission. Results:RTX serum levels were significantly lower in males and in newly diagnosed patients, and negatively correlated with body surface area, baseline B-cell count and degree of disease activity. In multivariate analyses, the main determinants of PK-RTX were sex and new diagnosis. Patients reaching complete remission at month 6 had similar RTX levels compared with patients who did not reach complete remission. Patients with higher RTX levels generally experienced longer B-cell depletion than patients with lower levels, but RTX levels at the different time points and area under the curve were not associated with time to relapse. Conclusion:Despite the body-surface-area-based dosing protocol, PK-RTX is highly variable among patients with AAV, its main determinants being sex and newly diagnosed disease. We did not observe any relevant association between PK-RTX and clinical outcomes. The monitoring of serum RTX levels does not seem clinically useful in AAV.
| S-EPMC5888934 | biostudies-literature
Project description:ObjectivesRelapses affect 30-50% of patients with ANCA-associated vasculitis (AAV) over 5 years, necessitating long-term treatment. Although there have been studies looking at predictors of relapse in AAV, this research has yet to translate clinically into guidance on tailored therapy. The aim of this systematic review was to identify and meta-analyse existing risk factors from the literature and produce a model to calculate individualised patient risk of relapse.MethodA search strategy was developed to include all studies identifying predictors of AAV relapse using multivariate analysis. Individual risk factors were extracted and pooled hazard ratios (HRs) calculated. A model to predict the time to first relapse based on identified risk factors was tested retrospectively using a cohort of patients with AAV.ResultsThe review of 2674 abstracts identified 117 papers for full text review, with 16 eligible for inclusion. Pooled HRs were calculated from significant risk factors, including anti-PR3 ANCA positivity [HR 1.69 (95% CI 1.46, 1.94)], cardiovascular involvement [HR 1.78 (95% CI 1.26, 2.53)], creatinine >200 µmol/l (relative to creatinine ≤100) [HR 0.39 (95% CI 0.22, 0.69)] and creatinine 101-200 µmol/l [HR 0.81 (95% CI 0.77, 0.85)]. Using data from 182 AAV patients to validate the model gave a C-statistic of 0.61.ConclusionAnti-PR3 ANCA positivity, lower serum creatinine and cardiovascular system involvement are all associated with an increased risk of relapse, and a combination of these risk factors can be used to predict the individualised risk of relapse. In order to produce a clinically useful model to stratify risk, we need to identify more risk factors, with a focus on robust biomarkers.
| S-EPMC8407598 | biostudies-literature