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Key Points Anti-neutrophil cytoplasmic antibodies (ANCAs) specific for leukocyte proteinase 3 and myeloperoxidase — PR3-ANCAs and MPO-ANCAs, respectively — define distinct conditions among patients with ANCA-associated vasculitides (AAV) Classification of patients with small-vessel vasculitis based on ANCA specificity is feasible and could provide timely and clinically relevant diagnostic information more readily than clinical syndromes based on current classification systems Patients with PR3-AAV and MPO-AAV do not share the same genetic background and have only some pathophysiologic mechanisms in common ANCA specificity predicts response to induction therapies: rituximab is more effective than cyclophosphamide in patients with PR3-AAV (by contrast, both treatments are similarly effective in patients with MPO-AAV) ANCA specificity predicts differences in long-term prognosis: patients with PR3-ANCAs are at higher risk of relapse than patients with MPO-ANCAs Future studies should evaluate whether the duration of immunosuppressive maintenance therapy should be different for patients with PR3-AAV versus those with MPO-AAV after remission induction The type of anti-neutrophil cytoplasmic antibody (ANCA) seems to be a major determinant of clinical presentation in ANCA-associated vasculitides (AAV). The authors of this Review argue that ANCA specificity for PR3 or MPO provides clinically useful information and should be used in the classification of AAV. 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.

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.

Background Granulomatosis with polyangiitis (Wegener's) (GPA) and microscopic polyangiitis (MPA) are subgroups of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) defined historically by clinical and histological features. GPA and MPA are heterogeneous entities with overlapping phenotypes. To identify novel subgroupings, cluster analysis was used to explore the phenotypic spectrum of AAV. Methods This study used a dataset of patients newly diagnosed as having GPA and MPA enrolled in five clinical trials. One cluster model included nine clinical baseline variables as input variables, and a second cluster model additionally included ANCA specificities. The clustering process involved multiple correspondence analyses followed by hierarchical ascendant cluster analysis. The clinical relevance of the generated clusters was analysed by their summary characteristics and outcomes. Results The analyses involved data for 673 subjects: 396 (59%) with GPA and 277 (41%) with MPA. Both cluster models resulted in five partially redundant clusters of subjects, and the model including ANCA resulted in more pertinent separations. These clusters were named ‘renal AAV with proteinase 3 (PR3)-ANCA’ (40% of subjects), ‘renal AAV without PR3-ANCA’ (32%) and ‘non-renal AAV’ (12%), ‘cardiovascular AAV’ (9%) and ‘gastrointestinal AAV’ (7%). The five clusters had distinct death and relapse rates. On the basis of 4 variables, 651 subjects (97%) could be accurately allocated to 1 of the 5 classes. Conclusions This analysis suggests that AAV encompasses five classes associated with different outcomes. As compared with the traditional GPA–MPA separation, this classification system may better reflect the phenotypic spectrum of AAV.

Objective This study aimed to evaluate the utility of ANCA specificity as a primary criterion for classifying AAV subtypes to simplify the diagnostic process without compromising accuracy. Methods A retrospective cohort study was conducted involving 310 patients diagnosed with AAV between January 2015 and December 2023 across three tertiary care centers affiliated with Peking University. Patients were reclassified using three methods: the European Medicines Agency (EMA) algorithm, the 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) criteria, and ANCA specificity-based classification. Concordance between classification systems was assessed using Cohen’s kappa coefficients. Results ANCA specificity-based classification demonstrated substantial to almost perfect agreement with the 2022 ACR/EULAR criteria for MPA/MPO-AAV (kappa = 0.806) and GPA/PR3-AAV (kappa = 0.663). Many patients initially classified as GPA under the EMA algorithm were reclassified as MPA when using ANCA specificity. EGPA classification remained consistent across all methods (kappa = 0.725 between EMA and ACR/EULAR), suggesting that ANCA specificity is less critical for EGPA. The use of ANCA specificity simplified the classification process, aligning closely with the underlying pathophysiology of AAV subtypes. Conclusion ANCA specificity serves as a valuable adjunct in the classification of AAV, particularly for distinguishing between MPA and GPA. Utilizing ANCA serotypes can simplify the diagnostic process, potentially facilitating earlier diagnosis and targeted treatment. For EGPA, traditional classification criteria remain effective. Incorporating ANCA specificity into clinical practice may enhance diagnostic accuracy and improve patient outcomes in AAV management. Key Points • ANCA-based classification aligns strongly with the 2022 ACR/EULAR criteria for MPA and GPA, providing a simplified diagnostic approach. • Adopting this approach can streamline the classification process, reduce invasive procedures, and enable earlier diagnosis while maintaining high concordance with established systems.

Antineutrophil cytoplasm antibody (ANCA)–associated vasculitis (AAV) is a group of vasculitides characterized by small-to-medium-sized blood vessel vasculitis and the presence of ANCA. Although our understanding of the causes of AAV remains limited, new information supporting an autoimmune basis is emerging. This review highlights recent progresses in etiology, pathogenesis, classification, and treatment. A genome-wide association study has confirmed a role for genetic susceptibility in AAV, and links between environmental factors and AAV induction through abnormal neutrophil extracellular traps has been demonstrated. Ongoing international consensus initiatives have revised approaches to the classification of vasculitis that has been enhanced by the analysis of large-scale prospective clinical data sets. New autoantibodies to human lysosome–associated membrane protein-2 antibody, moesin, and plasminogen have been detected in AAV sera and a prognostic classification of renal biopsies developed. Clinical trial networks have extended the evidence base for the treatment of AAV, and rituximab has emerged as an alternative to cyclophosphamide for remission induction. Long-term outcomes following current treatment strategies have been determined and increased risks for cardiovascular and malignant disease reported.

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.

Childhood-onset antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) represents a heterogeneous group of multi-system autoimmune conditions associated with chronic inflammation, characteristically affecting small blood vessels, leading to various organ and system manifestations. Although rare in paediatric populations, AAV poses challenges in early recognition, diagnosis and management of refractory cases. This review highlights the characteristics of clinical presentation and outcomes of AAV in children, as well as its current classification and progress achieved in understanding the disease pathogenesis, with a focus on adult and paediatric genetic studies. Furthermore, we discuss the management of AAV in children, as well as new emerging therapies and future research needs, while proposing a potential algorithm for a childhood-onset-AAV therapeutic approach based on the disease phenotype.

The classification of vasculitis according to a schema with universal acceptance is challenging, given the heterogeneous and protean nature of these diseases. Formal nomenclature and classification criteria for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have suffered several changes since their first description; none provides comprehensive diagnostic and classification criteria. Different factors account for the difficulties in the classification of vasculitis, including the incomplete understanding of the pathogenesis, the multisystemic nature of the disease, the non-specific patterns of vascular involvement, the overlap between entities, and the presence of various classification systems. The present article reviews the classification of AAV considering different points of view, including clinical, serologic, pathogenetic, organ predilection, therapeutic, and prognostic factors, and provides perspectives on future challenges in the understanding of AAV. There is an unmet need for a unifying view of the disease spectrum that considers the constantly evolving paradigms.

Purpose of Review This review aims to summarize the evolution and recent developments in the classification of ANCA associated vasculitis (AAV) and to summarize evaluations of the 2022 ACR/EULAR classification criteria of AAV in several cohorts. Recent Findings The classification of AAV has been a field of controversy for some time. The parallel existence of classification criteria and disease definitions produced some overlap in classification, leading to challenges when comparing different cohorts. The 2022 ACR/EULAR classification criteria derived from the largest study ever conducted in vasculitis account for significant changes in vasculitis classification with the integration of ANCA and modern imaging. These criteria show good performance compared to previous ones but also raise questions as ANCA serotypes have substantial impact on classification. In addition, there are some discrepancies with earlier agreed histopathological features of AAV disease phenotypes. Summary During the last 35 years, several sets of classification criteria have evolved to facilitate epidemiologic studies and clinical trials in AAV. While some of these criteria have been in use for many years, they were criticized due to either not using ANCA or not integrating surrogate markers for vasculitis but also due to overlapping when used in parallel. The long-awaited new ACR/EULAR criteria for AAV were published in 2022 and are the result of a large international study, introducing for the first time ANCA and modern imaging in the classification of AAV. Though the criteria show good performance, they bring several other challenges with practical application.

ANCA-associated vasculitis (AAV) in general involves small blood vessels and includes granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), and microscopic polyangiitis (MPA). Although reported in a few studies, the prevalence of large vessel vasculitis (LVV) in patients with AAV remains to be further explored. The goal of the present study was to assess the prevalence of LVV in a cohort of patients with AAV and to characterize this population. We conducted a ten-year retrospective study of a single-center cohort of AAV, including 101 patients with GPA (n = 58), EGPA (n = 28), MPA (n = 15), and compared the groups with or without associated LVV. LVV was diagnosed in five patients, two with aortitis and three with temporal arteritis, corresponding to a total prevalence of 5.0% [95% CI 1.6–11.2%]. This value was significantly higher than the estimated prevalence of LVV in the normal Swiss population (OR 234.9 95% CI 91.18–605.2, p < 0.001). All five patients had GPA, whereas no cases with EGPA or MPA were identified. Anti-PR3 antibodies were detected in four out of five patients, anti-MPO in one patient. Since LVV can occur in a significant proportion of patients with GPA, evaluation for LVV may be considered systematically in the diagnostic workup of AAV.