Antineutrophil Cytoplasmic Autoantibodies Research Articles

Insights into the paradoxical effect of smoking on vasculitis: a comprehensive review.

Vasculitis is a group of uncommon diseases characterized by inflammation of blood vessels, which contributes to the organ ischemia and damage. Cigarette smoke contains a high concentration of various toxins, which have the potential to affect the immune response and development of autoimmune/autoinflammatory rheumatic diseases including vasculitis. Smoking influences both innate and adaptive immune systems and plays binary functions in modulating immunity by either aggravating pathogenic immune responses or attenuating defensive immunity. Smoking contributes to the pathogenesis of autoimmune diseases by various mechanisms including induction of tissue damage and apoptosis, changes in innate immune function and production of proinflammatory cytokines, changes in humoral immunity and T cell responses and anti-estrogen effects. In this review, we considered the available evidence on the association between smoking with the risk, clinical manifestations, response to treatment and outcomes of vasculitis, and the effect of smoking cessation on these parameters. In conclusion, despite inconclusive evidence of an increased risk of giant cell arthritis and anti-neutrophil cytoplasmic autoantibody associated vasculitis (AAV) in smokers, there is strong evidence that smokers have a lower risk of Behcet's disease (BD). Furthermore, smoking changes the clinical picture and outcomes of BD and AAV.

Glucocorticoid doses according to tissue/organ involvement in ANCA-associated vasculitis

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV) are a group of disorders that include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), renal-limited vasculitis, and eosinophilic granulomatosis with polyangiitis (EGPA). Infections and cardiovascular diseases are the main causes of death in patients with AAV. New treatment regimens with low-dose glucocorticoidsare proposed to reduce the frequency of side effects. Studies related to the use of glucocorticoids in AAV patients were searched in the literature and results were summarized. Low-dose steroid protocols are not inferior to standard dose treatment and have fewer side effects. Although their effectiveness appears to be similar and their side effects appear to be less, the long-term results of low-dose regimens should also be evaluated.New studies are needed for alternative treatment regimens.

Explainability of a Deep Learning-Based Classification Model for Antineutrophil Cytoplasmic Autoantibody–Associated Glomerulonephritis

Explainability of a Deep Learning-Based Classification Model for Antineutrophil Cytoplasmic Autoantibody–Associated Glomerulonephritis

“Normal” Glomerular Score Correlates With Outcomes in Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis With Glomerulonephritis

“Normal” Glomerular Score Correlates With Outcomes in Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis With Glomerulonephritis

Antineutrophil Cytoplasmic Autoantibody Levels in Patients in the Avacopan Phase 3 Trial

Antineutrophil Cytoplasmic Autoantibody Levels in Patients in the Avacopan Phase 3 Trial

Cocaine- and Levamisole-Induced Vasculitis: Defining the Spectrum of Autoimmune Manifestations.

Drug-induced or associated vasculitis is a prevalent form of vasculitis that resembles primary idiopathic antineutrophil cytoplasmic autoantibody (ANCA) vasculitis (AAV). Cocaine is a diffuse psychostimulant drug and levamisole is a synthetic compound used to cut cocaine. Their abuse may result in a spectrum of autoimmune manifestations which could be categorized into three overlapping clinical pictures: cocaine-induced midline destructive lesion (CIMDL), levamisole-adulterated cocaine (LAC) vasculopathy/vasculitis, and cocaine-induced vasculitis (CIV). The mechanisms by which cocaine use leads to disorders resembling AAV are not well understood. Cocaine can cause autoimmune manifestations ranging from localized nasal lesions to systemic diseases, with neutrophils playing a key role through NETosis and ANCA development, which exacerbates immune responses and tissue damage. Diagnosing and treating these conditions becomes challenging when cocaine and levamisole abuse is not suspected, due to the differences and overlaps in clinical, diagnostic, therapeutic, and prognostic aspects compared to primary idiopathic vasculitides.

Myeloperoxidase-ANCA IgG induces different forms of small vessel vasculitis based on type of synergistic immune stimuli

Anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis has diverse patterns of injury including microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Necrotizing and crescentic glomerulonephritis (NCGN) occurs in all syndromes and as renal limited vasculitis (RLV). Single dose intravenous ANCA IgG-specific for mouse myeloperoxidase (MPO) causes RLV in mice. Although multiple mouse models have elucidated ANCA-IgG induced necrotizing and crescentic glomerulonephritis (NCGN), pathogenesis of ANCA-induced granulomatosis and vasculitis outside the kidney has not been clarified. To investigate this, we used intravenous MPO-ANCA IgG in the same strain of mice to induce different patterns of lung disease mirroring patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Repeated intravenous MPO-ANCA IgG induced GPA with NCGN, lung capillaritis, arteritis and granulomatosis. Lung leukocyte phenotypes were evaluated by immunohistochemical image analysis and by flow cytometry. ANCA lung capillaritis and microabscesses began within one day and evolved into granulomas in under seven days. Influenza plus single dose MPO-ANCA IgG induced MPA with NCGN, lung capillaritis and arteritis, but no granulomatosis. Allergic airway disease caused by house dust mites or ovalbumin plus single dose intravenous MPO-ANCA IgG induced EGPA with eosinophilic bronchiolitis, NCGN, capillaritis, arteritis, and granulomatosis. Thus, our study shows that the occurrence and pattern of lung lesions are determined by the same ANCA IgG accompanied by different synergistic immune factors.

Genetic and Non-Genetic Contributions to Eosinophilic Granulomatosis with Polyangiitis: Current Knowledge and Future Perspectives.

In this work, we present a comprehensive overview of the genetic and non-genetic complexity of eosinophilic granulomatosis with polyangiitis (EGPA). EGPA is a rare complex systemic disease that occurs in people presenting with severe asthma and high eosinophilia. After briefly introducing EGPA and its relationship with the anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis (AAVs), we delve into the complexity of this disease. At first, the two main biological actors, ANCA and eosinophils, are presented. Biological and clinical phenotypes related to ANCA positivity or negativity are explained, as well as the role of eosinophils and their pathological subtypes, pointing out their intricate relations with EGPA. Then, the genetics of EGPA are described, providing an overview of the research effort to unravel them. Candidate gene studies have investigated biologically relevant candidate genes; the more recent genome-wide association studies and meta-analyses, able to analyze the whole genome, have confirmed previous associations and discovered novel risk loci; in the end, family-based studies have dissected the contribution of rare variants and the heritability of EGPA. Then, we briefly present the environmental contribution to EGPA, reporting seasonal events and pollutants as triggering factors. In the end, the latest omic research is discussed and the most recent epigenomic, transcriptomic and microbiome studies are presented, highlighting the current challenges, open questions and suggesting approaches to unraveling this complex disease.

Update on antineutrophil cytoplasmic autoantibody vasculitis in children.

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) is often organ- or life-threatening in children and impacts them during important periods of psychosocial and physical development. This review covers recent advances in the pathophysiology, diagnosis, management, and outcomes of AAV in children and highlights the ongoing need for funding and increased research collaboration. Recent work has improved our understanding of AAV disease pathogenesis, potentially identifying new biomarkers and therapeutic targets. Collaborative clinical studies have also highlighted the variable manifestations in children and identified potential factors associated with poorer outcomes. Consensus-based treatment guidelines are also appearing, but clinical trials are still essential to better understanding treatment efficacy and safety in children affected by AAV. New, validated outcome measures, including those that are patient-reported, will facilitate these much-needed clinical trials in pediatric AAV. There is a continued need for more rigorous study in pediatric AAV, however, there is certainly excitement with the increase in recent research relevant to the pediatric population.

Avacopan in Anti-Neutrophil Cytoplasmic Autoantibodies–Associated Vasculitis in a Real-World Setting

Avacopan in Anti-Neutrophil Cytoplasmic Autoantibodies–Associated Vasculitis in a Real-World Setting

ANCA-Positive Small-Vessel Vasculitis Following SARS-CoV-2 Vaccination-A Systematic Review.

As vaccinations against the SARS-CoV-2 virus have become a crucial tool in controlling the spread of the disease, reports of rare health complications have emerged, including new-onset antineutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis (AAV). We systematically reviewed new-onset AAV following COVID-19 vaccination case reports and case series published in three databases before January 2024 following PRISMA guidelines to understand the characteristics of possible causal relationships or coincidences. In total, 404 articles were screened respectively by title, abstracts, and full-texts. Thirty-four papers fulfilled the inclusion criteria and have been analyzed, covering 44 patients with new-onset AAV after COVID-19 vaccination with no prior history of COVID-19 infection. Data regarding patients' metrics, comorbidities, vaccination characteristics, symptoms, diagnostics, treatment, and outcomes were investigated and summarized. The cohort consisted predominantly of females. AAV diagnosis was confirmed via biopsy, with renal dysfunction as a prevailing manifestation. In most cases, the first symptoms of AAV developed after the second dose; moreover, Pfizer-BioNTech was the most frequently administered vaccine among the analyzed cohort. Primary treatment involved glucocorticoid therapy, with a mostly favourable response. This systematic review aims to raise awareness among clinicians in the field regarding this rare but possible complication, to promote the prompt recognition and diagnosis of de novo ANCA-positive small-vessel vasculitis in timely association with SARS-CoV-2 vaccination.

Antineutrophil cytoplasmic antibody-associated vasculitis.

This review focuses on latest developments in managing antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV), a systemic autoimmune condition characterized by inflammation and necrosis of small blood vessels due to circulating autoantibodies that target neutrophilic granules. Our understanding of AAV pathogenesis has evolved in the past decades highlighting the central pathogenic roles of autoantibodies and complement activation. In parallel, the appreciation for glucocorticoid toxicity has led the research on crucial steroid-sparing therapeutic alternatives. Complement inhibitors (like avacopan) that have emerged are associated with better preservation of kidney function in AAV patients with severe kidney impairment. The role of plasma-exchange (PLEX) was revisited in updated guidelines that recommended its potential use in the context of diffuse alveolar hemorrhage associated hypoxia and severe kidney involvement, particularly with a serum creatinine level above 3.4 mg/dl. The ANCA Kidney Risk Score risk prediction and Glucocorticoid Toxicity Index score aid in identifying high-risk patients and individualizing management plans. Kidney involvement in AAV requires prompt diagnosis and initiation of immunosuppression to prevent irreversible nephron loss. Newer therapeutic targets are on the horizon and offer hope for personalized treatment strategies.

#1517 Glomerular immune complex deposits on electron microscopy in ANCA associated vasculitis: clinical and outcomes features

Abstract Background and Aims Glomerulonephritis related to antineutrophil cytoplasmic autoantibodies (ANCA) is typically referred to as “pauci-immune”, however, it is not unusual for kidney biopsies to exhibit some immune complex deposition within glomeruli on electron microscopic study. Such deposits in ANCA-glomerulonephritis have not been widely studied, and their potential pathologic and clinical significance is not clear, although a possible synergistic effect between immune complexes and ANCA in producing more severe glomerulonephritis is suggested in the literature. Method An observational retrospective study was conducted using a dataset comprising all patients with ANCA associated vasculitis diagnosis from a Portuguese Center between march 2011 and march 2023. Demographic and clinical data were collected from medical records. Electron microscopy reports from kidney biopsies were examined for the presence of electron-dense deposits. Descriptive statistics were used to describe all reports. The objective of this study was to explore associations between the presence or absence of such deposits and clinical data, including serum creatinine, urine protein-creatinine ratio levels (PCR) at the time of biopsy as well as overall survival and renal outcomes at follow-up. Non-parametric Mann-Whitney U test and the Chi-squared test were used for continuous and categorical variables respectively. Kaplan-Meier curves were used for assessing time to event data. All analyses were two-tailed and a p value ≤ 0.05 was considered significant. Results From a total of 39 patients with ANCA associated vasculitis diagnosis, 33 underwent at least one kidney biopsy, and among them, 17 were analysed by electron microscopy. 8 (47%) of biopsies showed glomerular immune complex deposits by electron microscopy; Table 1 describes demographic data of both groups (immune complex deposits—D; no-immune complex deposits—ND). The median numbers of glomeruli examined by electron microscopy were identical between the two groups. In group D there was less patients with positive titers for ANCA (p = 0.034) and serum creatinine levels were higher at admission (mean 7.1 mg/dL IQR: 5.6-8.1 versus 4.2 IQR 3.2-7.1), despite the lack of definitive statistical significance (p = 0.123). Urine protein-to-creatinine ratio did not differ between groups. The need for renal replacement therapy at admission was greater for patients with dense deposits on kidney biopsy (p = 0.008). At the end of follow-up (median 48, IQR 24-48 months), death and progression to end stage kidney disease occurred in 25.0% and 37.5% of group D patients versus 11.1% and 22.2% of ND patients, respectively (Fig. 1). Conclusion Immune complex deposits were found on electron microscopy in nearly half of kidney biopsies. Our data suggest that these immune complex deposits are common and might play a role in clinical presentation, overall survival and renal prognosis. The small sample size of our cohort is a limitation, as well as the retrospective nature of the study. Larger cohorts and more comprehensive electron microscopic studies are warranted to better characterize this population.

Laboratory diagnostics for vasculitis beyond antineutrophil cytoplasmatic autoantibodies

The diagnosis of systemic vasculitis (SV) is amajor clinical challenge due to the very different forms of presentation and requires an interdisciplinary approach. Targeted laboratory diagnostics support making the diagnosis, differential diagnosis and classification and are also akey component in the detection of active organ manifestations and treatment complications. The basic laboratory tests include the erythrocyte sedimentation rate (ESR), C‑reactive protein (CRP), blood count, serum creatinine, urinalysis, specific autoantibodies, complement, immunoglobulins, cryoglobulins and hepatitisB and C serology. Antineutrophil cytoplasmic autoantibodies (ANCA), antiglomerular basement membrane antibodies (anti-GBM antibodies) and anti-C1q antibodies are valuable laboratory markers for the diagnosis of the various forms of small vessel vasculitis. There are no specific laboratory tests for the diagnosis of medium and large vessel vasculitis. Despite advances in our understanding of the pathogenesis of vasculitis, no biomarkers have yet been identified that can be reliably used to guide treatment or that are useful in distinguishing vasculitis from other inflammatory diseases such as infections or treatment complications.

The Diagnosis of Granulomatosis With Polyangiitis When Serology and Biopsies are Negative.

Granulomatosis with polyangiitis (GPA) is a potentially fatal condition which often manifests in the head and neck. Currently, diagnosis relies on antineutrophil cytoplasmic autoantibody (c-ANCA) serology and mucosal or renal biopsy. However, a significant proportion of patients with GPA limited to the head and neck are seronegative and biopsy negative. This study evaluates the role of clinical diagnosis of GPA in the absence of positive laboratory findings. Case series with chart review. Academic Tertiary Medical Center. This was a retrospective review of 143 patients treated in an outpatient otolaryngology clinic at a tertiary care hospital for known or suspected GPA from 1998 to 2021. Presenting symptoms, C-ANCA status at initial presentation, biopsy results, long-term serology results, and time to initiation of treatment were analyzed. Twenty-six of 143 (18.2%) patients were seronegative; only 3 of these patients (12%) had positive biopsies. Seventeen (73.9%) of these patients presented with nasal and sinus disease and 12 (52.2%) presented with airway involvement. Only 4 (17.4%) patients had renal involvement. Delay in treatment of patients with negative laboratory workup ranged from 0 months to 11 years. All patients who were seronegative and/or biopsy negative at presentation responded clinically to immunosuppressive therapy. GPA cases are often limited to the upper respiratory tract, making diagnosis difficult, particularly in seronegative patients. These results suggest that, when GPA is suspected, despite negative serology, the diagnosis of GPA should be made on clinical grounds, and empiric therapy encouraged to prevent delay in treatment.

Real-World Experience With Avacopan in Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis

Postmarketing data on outcomes of avacopan use in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) are lacking. We performed a multicenter retrospective analysis of 92 patients with newly diagnosed or relapsing AAV who received therapy with avacopan. The coprimary outcome measures were clinical remission at 26 and 52 weeks. We use descriptive statistics and univariate logistic regression to assess outcomes and predictors of remission, respectively. Of the 92 patients, 23% (n = 21) had a baseline estimated glomerular filtration rate (eGFR)< 15 ml/min per 1.73 m2 and 10% on kidney replacement therapy at baseline. Among those with kidney involvement, mean (SD) enrollment eGFR was 33 (27) ml/min per 1.73 m2 with a mean (SD) change of+12 (25) and+20 (23) ml/min per 1.73 m2 at weeks 26 and 52, respectively. In addition to avacopan, 47% of patients received combination therapy of rituximab and low-dose cyclophosphamide, and 14% of patients received plasma exchange (PLEX). After induction, the median (interquartile range [IQR]) time to start avacopan was 3.6 (2.1-7.7) weeks, and the median time to discontinue prednisone after starting avacopan was 5.6 (3.3-9.5) weeks. Clinical remission was achieved in 90% of patients at week 26 and 84% of patients at week 52. Of the patients, 20% stopped avacopan due to adverse events, with the most common being elevated serum aminotransferases (4.3%). A high rate of remission and an acceptable safety profile were observed with the use of avacopan in the treatment of AAV in this postmarketing analysis, including the populations excluded from the ADVOCATE trial.

High-resolution epitope mapping of commercial antibodies to ANCA antigens by yeast surface display

Epitope mapping provides critical insight into antibody-antigen interactions. Epitope mapping of autoantibodies from patients with autoimmune diseases can help elucidate disease immunogenesis and guide the development of antigen-specific therapies. Similarly, epitope mapping of commercial antibodies targeting known autoantigens enables the use of those antibodies to test specific hypotheses. Anti-Neutrophil Cytoplasmic Autoantibody (ANCA) vasculitis results from the formation of autoantibodies to multiple autoantigens, including myeloperoxidase (MPO), proteinase-3 (PR3), plasminogen (PLG), and peroxidasin (PXDN). To perform high-resolution epitope mapping of commercial antibodies to these autoantigens, we developed a novel yeast surface display library based on a series of >5000 overlapping peptides derived from their protein sequences. Using both FACS and magnetic bead isolation of reactive yeast, we screened 19 commercially available antibodies to the ANCA autoantigens. This approach to epitope mapping resulted in highly specific, fine epitope mapping, down to single amino acid resolution in many cases. Our study also identified cross-reactivity between some commercial antibodies to MPO and PXDN, which suggests that patients with apparent autoantibodies to both proteins may be the result of cross-reactivity. Together, our data validate yeast surface display using maximally overlapping peptides as an excellent approach to linear epitope mapping.

Pharmacokinetic Evaluation of the CYP3A4 and CYP2C9 Drug-Drug Interaction of Avacopan in 2 Open-Label Studies in Healthy Participants.

Avacopan, a complement 5a receptor (C5aR) antagonist approved for treating severe active antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, was evaluated in 2 clinical drug-drug interaction studies. The studies assessed the impact of avacopan on the pharmacokinetics (PK) of CYP3A4 substrates midazolam and simvastatin and CYP2C9 substrate celecoxib, and the influence of CYP3A4 inhibitor itraconazole and inducer rifampin on the PKs of avacopan. The results indicated that twice-daily oral administration of 30mg of avacopan increased the area under the curve (AUC) of midazolam by 1.81-fold and celecoxib by 1.15-fold when administered without food, and twice-daily oral administration of 30 or 60mg of avacopan increased the AUC of simvastatin by approximately 2.6-3.5-fold and the AUC of the active metabolite β-hydroxy-simvastatin acid by approximately 1.4-1.7-fold when co-administered with food. Furthermore, the AUC of avacopan increased by approximately 2.19-fold when co-administered with itraconazole and decreased by approximately 13.5-fold when co-administered with rifampin. These findings provide critical insights into the potential drug-drug interactions involving avacopan, which could have significant implications for patient care and treatment planning. (NCT06207682).

Efficacy and safety of avacopan in patients with ANCA-associated vasculitis receiving rituximab in a randomised trial

ObjectivesTo evaluate the efficacy and safety of avacopan in the subgroup of patients with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis receiving background induction therapy with rituximab in the phase 3 ADVOCATE...

Granulomatosis with polyangiitis and microscopic polyangiitis

Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are two entities of ANCA-associated vasculitis (AAV). Both diseases are characterised by systemic necrotising small-vessel vasculitis, which can affect any organ. In GPA, extravascular necrotising granulomatous inflammation, usually affecting the respiratory tract, is found in addition. In the majority of cases, the clinical presentation is dominated by a pulmonary-renal syndrome with alveolar haemorrhage and rapidly progressive glomerulonephritis. Other organ involvement is found as well. In GPA, the upper respiratory tract is commonly affected. GPA is associated with anti-neutrophil cytoplasmic autoantibodies (ANCA) with specificity for proteinase 3 (PR3-ANCA) and MPA with specificity for myeloperoxidase (MPO-ANCA). Immunosuppressive therapy depends on disease activity and the severity of organ involvement.