Pathogenesis of Pulmonary Manifestations in ANCA-Associated Vasculitis and Goodpasture Syndrome.

Pulmonary manifestations of vasculitis are associated with significant morbidity and mortality in affected individuals. They result from a complex interplay between immune dysregulation, which leads to vascular inflammation and tissue damage. This review explored the underlying pathogenesis of pulmonary involvement in vasculitis, encompassing various forms such as granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and anti-GBM disease. Mechanisms involving ANCA and anti-GBM autoantibodies, neutrophil activation, and neutrophil extracellular trap (NETs) formation are discussed, along with the role of the complement system in inducing pulmonary injury. Furthermore, the impact of genetic predisposition and environmental factors on disease susceptibility and severity was considered, and the current treatment options were presented. Understanding the mechanisms involved in the pathogenesis of pulmonary vasculitis is crucial for developing targeted therapies and improving clinical outcomes in affected individuals.

[Pharmacological and clinical profiles of avacopan (TAVNEOS® capsule), a selective C5a receptor antagonist].

Avacopan (TAVNEOS® capsules) is an orally available selective C5a receptor (C5aR) antagonist. It has been approved in Japan since 2021 for the treatment of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), the two major subtypes of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The current standard therapy combining glucocorticoids (GC) and immunosuppressants has greatly improved the prognosis of AAV, however, issues such as side effects associated with GC use remain to be resolved. Avacopan suppresses priming of neutrophils induced by the complement component C5a, a process deeply involved in the pathogenesis of AAV. In pre-clinical studies, avacopan inhibited chemotaxis and priming of neutrophils induced by C5a-C5aR signaling. It also significantly suppressed nephritis and renal damage in an ANCA-induced glomerulonephritis mouse model. In the global phase 3 study "ADVOCATE", avacopan achieved both primary endpoints being 1) non-inferior to prednisone in inducing remission at week 26 and 2) superior in sustained remission at week 52 for MPA and GPA patients. Additionally, with avacopan, GC toxicity score was significantly lower and fewer adverse events possibly related to GC were observed. Furthermore, avacopan increased estimated glomerular filtration rate (eGFR) more than prednisone indicating improved renal function. Thus, the novel mechanism of avacopan targeting the complement system is a promising new therapeutic option for AAV with fewer GC-related side effects and better improvement of renal function.

Interstitial Lung Disease and Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis: A Review.

Interstitial lung disease is a common complication of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). It is seen most commonly in microscopic polyangiitis owing to the pathogenic effect of myeloperoxidase in the lung. Oxidative stress, neutrophil elastase release, and expression of inflammatory proteins by neutrophil extracellular traps result in fibroblast proliferation and differentiation and therefore fibrosis. Usually, interstitial pneumonia pattern fibrosis is common and associated with poor survival. Treatment for patients with AAV and interstitial lung disease lacks evidence, and those with vasculitis are treated with immunosuppression, whereas those with progressive fibrosis may well benefit from antifibrotic therapy.

Giant cell arteritis with myeloperoxidase anti-neutrophil cytoplasmic antibody seropositivity in a patient with systemic sclerosis.

To the best of our knowledge, systemic sclerosis with overlapping characteristics of both microscopic polyangiitis and giant cell arteritis (i.e. microscopic polyangiitis involving the superficial temporal artery or giant cell arteritis with myeloperoxidase anti-neutrophil cytoplasmic antibody seropositivity) has not been reported previously. An 82-year-old woman with diffuse cutaneous systemic sclerosis experienced dyspnoea on exertion and fever. No signs of infection were observed on computed tomography. Her fever persisted despite antibiotic treatment for occult bacterial infection and secondary Clostridioides difficile-associated diarrhoea. Microscopic polyangiitis was suspected because of myeloperoxidase anti-neutrophil cytoplasmic antibody seropositivity, and giant cell arteritis was suspected as a differential diagnosis due to swelling of the superficial temporal artery. Arterial biopsy revealed inflammatory cell infiltration with granuloma formation. Based on the presence of granulomatous inflammation in the superficial temporal artery, we concluded that giant cell arteritis with myeloperoxidase anti-neutrophil cytoplasmic antibody seropositivity occurred as a complication. After glucocorticoid therapy, her fever and dyspnoea on exertion improved with a gradual decline in the serum myeloperoxidase anti-neutrophil cytoplasmic antibody levels. It is possible that vasculitis occurs as a complication in patients with systemic sclerosis in cases where the fever persists and cannot be explained by systemic sclerosis itself, infectious disease, or malignancy. Clinicians must be careful not to prematurely diagnose microscopic polyangiitis based on myeloperoxidase anti-neutrophil cytoplasmic antibody seropositivity or giant cell arteritis based on the swelling of the superficial temporal artery. Careful evaluation of the presence of granulomatous inflammation in an arterial biopsy specimen is essential to differentiate between microscopic polyangiitis and giant cell arteritis.

Kidney biopsy in patients with antineutrophil cytoplasmic antibody-associated vasculitis with mild renal abnormality.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a systemic inflammation of small or medium blood vessels that includes microscopic polyangiitis. A diagnosis of ANCA-associated vasculitis can be aided by histological identification of vasculitis, and identification of renal impairment can help predict outcomes. However, kidney biopsy is not generally indicated in the absence of renal findings. We report two cases of ANCA-associated vasculitis diagnosed by kidney biopsy despite the absence of remarkable urinary abnormality and renal impairment. These patients had fever of unknown origin and were positive for myeloperoxidase (MPO)-ANCA but showed few findings that would suggest small-vessel vasculitis in the kidney. Nevertheless, kidney biopsies revealed small-vessel arteritis, necrotizing glomerulonephritis, and interstitial nephritis. Immunofluorescent antibody tests performed using samples of glomeruli were all negative, suggesting microscopic polyangiitis. Therefore, kidney biopsy may be useful in confirming the diagnosis, even if patients have completely normal urinary findings in the absence of other organ lesions.

SARS-COV-2 INFECTION AS A POSSIBLE TRIGGER FOR MICROSCOPIC POLYANGIITIS: CASE REPORT AND MINI-REVIEW.

The paper presents a clinical case of MPA in a 67-year-old woman following COVID-19, characterized by significant difficulties when working with the early etiological verification of diagnosis. The patient presented with polyarthritis affecting the upper and lower limbs, fever, and comorbid urological pathology in the form of urolithiasis and recurrent cystitis. This clinical presentation, hyperuricemia, azotaemia and anemia were mistakenly interpreted as chronic kidney disease: gouty nephropathy, gouty arthritis, which masked the underlying disease for a long time delaying the timely MPA diagnosis and treatment. Given that MPA is a multisystemic disease, it is essential to enhance awareness and knowledge of healthcare professionals of various specialties regarding AAVs and MPA in particular, as evidenced by the online survey data during COVID-19 pandemic among doctors in 21 countries.

Early ultrastructural lesions of anti-neutrophil cytoplasmic antibody- versus complement-associated vasculitis.

This study aims to describe electron microscopic findings of vasculitis associated with anti-neutrophil cytoplasmic antibody (ANCA) and complement. Sural nerve biopsy specimens were obtained from 10 patients with microscopic polyangiitis (MPA), a representative ANCA-associated vasculitis, and six patients with nonsystemic vasculitic neuropathy (NSVN), who were negative for ANCA but positive for complement deposition. In patients with MPA, attachment of neutrophils to epineurial vascular endothelial cells, migration of neutrophils to the extravascular space via the penetration of the endothelial layer, and release of neutrophil components to the extracellular space were observed. Such neutrophil-associated lesions were not observed in patients with NSVN. Nonetheless, morphological changes in epineurial vascular endothelial cells, such as increases in cytoplasmic organelles and cytoplasmic protrusions into the vascular lumen, were observed in patients with NSVN. Since these findings were observed where light microscopy-based findings suggestive of vasculitis (e.g., the disruption of vascular structures and fibrinoid necrosis) were absent, they were considered early lesions that preceded the formation of the so-called necrotizing vasculitis. In conclusion, this study enabled the visualization of distinctive early ultrastructural lesions associated with ANCA and complement. Further studies are needed to elucidate the molecular basis of the induction of these fine structural changes, which will contribute to the development of targeted therapies based on specific mechanisms of vasculitis.

Fibrosis-5 predicts end-stage renal disease in patients with microscopic polyangiitis and granulomatosis with polyangiitis without substantial liver diseases.

We previously reported that fibrosis-4 (FIB-4) was associated with poor outcomes of microscopic polyangiitis (MPA) and granuloma with polyangiitis (GPA). We also investigated the potential of FIB-5, a novel index, in predicting all-cause mortality and end-stage renal disease (ESRD) during follow-up in patients with MPA and GPA without substantial liver diseases. Clinical and laboratory data at diagnosis were collected by reviewing the medical records of 180 patients with MPA and GPA. FIB-5 was obtained by a following equation: FIB-5 = (serum albumin (g/L) × 0.3 + platelet count (109/L) × 0.05) - (alkaline phosphatase (IU/L) × 0.014 + aspartate aminotransferase/alanine aminotransferase ratio × 6 + 14). The median age of the patients at diagnosis was 61.0 years. FIB-5 at diagnosis could not reflect the cross-sectional vasculitis activity. The cutoffs of FIB-5 for poor outcomes was set as 0.82 (the lowest tertile) and -0.42 (the lowest quartile) at diagnosis. In Kaplan-Meier survival analysis, patients with FIB-5 < 0.82 and those with FIB-5 < -0.42 exhibited lower ESRD-free survival rates than those without. However, it could not predict all-cause mortality. In multivariable Cox hazards analysis, both FFS (Hazard ratio (HR) 1.554) and FIB-5 < 0.82 (HR 2.096) as well as both FFS (HR 1.534) and FIB-5 < -0.42 (HR 2.073) at diagnosis independently predicted ESRD during follow-up. In conclusion, FIB-5 < 0.82 and FIB-5 < -0.42 at diagnosis could predict the occurrence of ESRD, but not all-cause mortality, during follow-up in patients with MPA and GPA without substantial liver diseases.

Kaposi sarcoma in anti-neutrophil cytoplasmic antibody-associated vasculitis: a case-based review.

Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) are systemic necrotizing vasculitides associated with significant morbidity and mortality. Given the immunosuppression used to manage these conditions, it is important for clinicians to recognize complications, especially infectious ones, which may arise during treatment. Kaposi sarcoma (KS) is a lymphoangioproliferative neoplasm caused by human herpes virus 8 (HHV-8). Its cutaneous manifestations can mimic vasculitis. We describe a 77-year-old man with microscopic polyangiitis with pulmonary-renal syndrome treated with prednisone and intravenous cyclophosphamide who developed KS (HHV-8 positive) after 2 months of treatment. Cyclophosphamide was discontinued and prednisone gradually lowered with improvement and clinical stabilization of KS lesions. This comprehensive review includes all published cases of KS in patients with AAV, with a goal to summarize potential risk factors including the clinical characteristics of vasculitis, treatment and outcomes of patients with this rare complication of immunosuppressive therapy. We also expanded our literature review to KS in other forms of systemic vasculitis. Our case-based review emphasizes the importance of considering infectious complications of immunosuppressive therapy, especially glucocorticoids, and highlights the rare association of KS in systemic vasculitis.

CCL2 produced by CD68+/CD163+ macrophages as a promising clinical biomarker of microscopic polyangiitis-interstitial lung disease.

OBJECTIVES: Microscopic polyangiitis (MPA) is often complicated by interstitial lung disease (ILD); however, biomarkers that can be used to diagnose and predict the progression of MPA-ILD have not been identified. In this study, we evaluated various serum biomarkers in MPA-ILD to assess their diagnostic and predictive performance. METHODS: We enrolled 49 patients with anti-neutrophil cytoplasmic antibody (ANCA)+ MPA and 10 healthy controls, with 32 of the MPA patients also presenting ILD. The presence of ILD was assessed by high-resolution CT and evaluated by ground-glass opacity and fibrosis score. We compared 16 biomarker profiles among MPA-ILD patients, those without ILD, and healthy controls and extracted biomarkers with higher levels in MPA-ILD groups to determine correlations with disease activity and other biomarkers. Three lung biopsies were examined by haematoxylin-eosin staining and immunostaining. RESULTS: Initial serum C-C motif chemokine ligand 2 (CCL2) levels were significantly higher in the MPA-ILD group than those of the MPA group, and were significantly higher in MPA-ILD patients 1 year after immunosuppressive therapy than those before treatment. Initial serum CCL2 levels positively correlated with an increased fibrosis score during the year after treatment and with initial serum platelet-derived growth factor levels. Immunohistochemical staining showed intense CCL2 signals in CD68+/CD163+ macrophages and metaplastic epithelial cells in MPA-ILD lungs. CONCLUSION: CCL2 is associated with MPA-ILD pathogenesis and suggested its potential efficacy as a useful marker for diagnosing and predicting MPA-ILD progression. Therefore, targeting CCL2 in alveolar CD68+/CD163+ macrophages might represent a therapeutic intervention in ANCA+ MPA-ILD.

Relapse rate and renal prognosis in ANCA-associated vasculitis according to long-term ANCA patterns.

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.

Immunopathogenesis of ANCA-Associated Vasculitis.

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.

Fc receptor-like 5 and anti-CD20 treatment response in granulomatosis with polyangiitis and microscopic polyangiitis.

BACKGROUNDBaseline expression of FCRL5, a marker of naive and memory B cells, was shown to predict response to rituximab (RTX) in rheumatoid arthritis. This study investigated baseline expression of FCRL5 as a potential biomarker of clinical response to RTX in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).METHODSA previously validated quantitative PCR-based (qPCR-based) platform was used to assess FCRL5 expression in patients with GPA/MPA (RAVE trial, NCT00104299).RESULTSBaseline FCRL5 expression was significantly higher in patients achieving complete remission (CR) at 6, 12, and 18 months, independent of other clinical and serological variables, among those randomized to RTX but not cyclophosphamide-azathioprine (CYC/AZA). Patients with baseline FCRL5 expression ≥ 0.01 expression units (termed FCRL5hi) exhibited significantly higher CR rates at 6, 12, and 18 months as compared with FCRL5lo subjects (84% versus 57% [P = 0.016], 68% versus 40% [P = 0.02], and 68% versus 29% [P = 0.0009], respectively).CONCLUSIONOur data taken together suggest that FCRL5 is a biomarker of B cell lineage associated with increased achievement and maintenance of complete remission among patients treated with RTX and warrant further investigation in a prospective manner.FUNDINGThe analysis for this study was funded by Genentech Inc.

Updates in the treatment of granulomatosis with polyangiitis and microscopic polyangiitis: At a crossroad.

There have been great advances in the management of ANCA associated vasculitis over the past decades. We have gone from an era where the disease was almost universally fatal to trying to prevent long-term side effects of treatment regimens. With the ability to use pulse cyclophosphamide or rituximab as alternates to oral cyclophosphamide for induction of remission, side effects of therapy have been greatly reduced. New approaches have drastically changed our approach to maintenance and we now favor much longer durations of maintenance therapy, as they are more successful in preventing relapse. Steroids have long been the bane of treatment as they are associated with a significant risk of infection and metabolic consequences. We are now in a steroid-sparing and looking ahead to a steroid-free era with new data being published showing lower doses of steroids being equally effective and several ongoing seminal trials looking at agents that could completely replace steroids very early on.

Lung involvement in ANCA-associated vasculitis.

Lung involvement is one of the most common clinical features in ANCA-associated vasculitides (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). In this review, we detail the five main presentations of pulmonary involvement in AAV: necrotizing granulomatous inflammation, tracheobronchial inflammation, pulmonary capillaritis, interstitial lung disease (ILD) and asthma with their clinical, radiological and therapeutic characteristics. The prevalence of these manifestations is variable according to the subtype of AAV, necrotizing granulomatous inflammation and tracheobronchial inflammation being defining features of GPA whereas ILD is primarily seen in patients with MPA, especially in association with ANCA directed against myeloperoxydase (MPO-ANCA), and asthma is characteristic of EGPA. Despite recent progresses in the diagnosis and management of these conditions, several questions remain and are discussed here, including local treatments for subglottic stenosis, the uncertain efficacy of plasma exchanges for alveolar hemorrhage, the potential role of antifibrotic agents in ILD associated with MPA, and the use of novel anti-IL-5 strategies in EGPA.

How to improve the histopathological diagnosis of systemic vasculitides in daily practice?

The most common group of systemic vasculitides in adulthood are anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). AAV represent autoimmune systemic vasculitides and include 3 clinical phenotypes: Granulomatosis with polyangiitis (GPA, formerly Wegener granulomatosis), Microscopic polyangiitis (MPA) and Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome). Histological features are similar to each other in all affected locations, and there are represented by necrotizing vascular inflammation of small and medium calibers, often venules, capillaries or arteriols, typically with fibrinoid vessel wall necrosis. The consequences of this condition are bleeding, as well as compromise of the lumen which may result in downstream tissue ischemia and necrosis. Typically affected locations in biopsy practice are: ENT, lung, skin, GIT, and kidney. The aim of this review is to provide a comprehensive overview of the important histopathological findings. ANCA positive vasculitis is a serious life-threatening disease and therefore requires a rapid diagnosis and appropriate therapy.

Serum Mannose-Binding Lectin Levels Are Correlated with the Disease Activity of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Single-Center Study.

Mannose-binding lectin (MBL) is a soluble pattern-recognition molecule, which plays a crucial role in the innate immune system and the activation of lectin complement pathway. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease affecting the small vasculatures and is characterized by the alteration of innate and adaptive immunity and complement activation. In this study, we investigated whether serum MBL is associated with disease activity of AAV, which was measured by ELISA. Associations between serum MBL and AAV-specific indices, as well as clinical and laboratory data were assessed using Kendall's tau. Among the 80 patients, 42 (52.5%), 21 (26.3), and 17 (21.3%) patients were classified as microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA), respectively. The median values of erythrocyte sedimentation rate, C-reactive protein, and serum MBL were 36.5 (normal range < 20) mm/h, 2.4 (normal range < 8) mg/dL, and 8.6 ng/mL, respectively. The median serum levels of MBL in MPA, GPA, and EGPA patients were 8.4, 9.3, and 8.2 ng/mL. Correlation analysis showed that serum MBL was associated with Birmingham Vasculitis Activity Score (BVAS) (R = 0.169, p = 0.027), but not with other AAV-specific indices and clinical and laboratory data. In addition, serum MBL was significantly associated with the pulmonary manifestation score based on BVAS (R = 0.247, p = 0.001). In summary, among the AAV-specific indices and clinical and laboratory variables analyzed, serum MBL is correlated with BVAS and pulmonary manifestation score based on the BVAS.

ANCA-Associated Vasculitis: Core Curriculum 2020.

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.