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Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare heterogeneous disease in which treatment must be initiated early to prevent irreversible organ damage and death. There are several diseases that can mimic AAV, even in the presence of positive ANCA serology and/or histological evidence of vasculitis, as demonstrated in this case series. We reflect on the diagnostic approach of patients with AAV and provide an overview of AAV-mimicking diseases that can be considered in patients with atypical disease presentation or course. [ABSTRACT FROM AUTHOR]

Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) is associated with an increased cardiovascular risk, particularly the myeloperoxidase AAV serotype (MPO-AAV). Distinct alterations in monocyte phenotypes may cause accelerated atherosclerotic disease in AAV. A cohort including 43 AAV patients and 19 healthy controls was included for downstream analyses. Extensive phenotyping of monocytes and monocyte-derived macrophages was performed using bulk RNA-sequencing and flow cytometry. An in vitro transendothelial migration assay reflecting intrinsic adhesive and migratory capacities of monocytes was employed. Subsequent sub-analyses were performed to investigate differences between serological subtypes. Monocyte subset analysis showed increased classical monocytes during active disease, whereas non-classical monocytes were decreased compared to healthy controls (HC). RNA-sequencing revealed upregulation of distinct inflammatory pathways and lipid metabolism-related markers in monocytes of active AAV patients. No differences were detected in the intrinsic monocyte adhesion and migration capacity. Compared to proteinase-3(PR3)-AAV, monocytes of MPO-AAV patients in remission expressed genes related to inflammation, coagulation, platelet-binding and interferon signalling, whereas the expression of chemokine receptors indicative of acute inflammation and monocyte extravasation (i.e., CCR2 and CCR5) was increased in monocytes of PR3-AAV patients. During active disease, PR3-AAV was linked with elevated serum CRP and increased platelet counts compared to MPO-AAV. These findings highlight changes in monocyte subset composition and activation, but not in the intrinsic migration capacity of AAV monocytes. MPO-AAV monocytes are associated with sustained upregulation of inflammatory genes, whereas PR3-AAV monocytes exhibit chemokine receptor upregulation. These molecular changes may play a role in elevating cardiovascular risk as well as in the underlying pathophysiology of AAV. [Display omitted] • Monocytes are activated during active ANCA-associated vasculitis (AAV) and upregulate lipid metabolism-related markers. • AAV monocytes have a normal intrinsic adhesion and migration capacity although net migration likely rises by other mechanisms. • The two serological subsets MPO-AAV and PR3-AAV exhibit differences in monocyte activation and chemokine receptor expression. [ABSTRACT FROM AUTHOR]

Anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) are characterized by inflammation of small-to-medium-sized blood vessels and the presence of autoantibodies against cytoplasmic proteases sited in neutrophils and monocytes. Increasing evidence indicates a substantial role of monocytes and macrophages in the pathogenesis of AAV. Activated monocytes and macrophages contribute to necroinflammation in peripheral vasculitic lesions as well as to central and peripheral mechanisms of autoimmunity. The intermediate monocyte subset (CD14++CD16+) is increased and monocytes show elevated expression of CD14, Toll-like receptor 2/4, MHCII and integrins, likely reflecting activation and increased monocyte extravasation. Monocytes differentiate locally predominantly into alternatively activated (M2) macrophages, which are known for cell-clearance and phagocytosis, but may ultimately lead to fibrosis. Phagocytotic function of macrophages can be impaired by surface expression of cytoplasmic proteases on apoptotic neutrophils and causes release of inflammatory cytokines and immunogenic contents, presumably resulting in a vicious circle of increased neutrophil, T and B cell activation and consequent ANCA production. Considering their crucial role in initiating necroinflammation as well as fibrogenesis, monocytes and macrophages may represent a logic first-line target for new treatment options in AAV. [Display omitted] • Monocytes and macrophages contribute to necroinflammation and autoimmunity in AAV. • Monocytes express markers of activation and the CD14++ CD16+ subset is increased. • Monocytes differentiate into alternatively activated macrophages (M2), promoting fibrosis. • Targeting activated monocytes and macrophages may form new therapeutic options. [ABSTRACT FROM AUTHOR]