ANCA-Associated Vasculitis: An Update

Abstract

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) represents a group of small vessel vasculitides characterized by granulomatous and neutrophilic tissue inflammation, often associated with the production of antibodies that target neutrophil antigens. The two major antigens targeted by ANCAs are leukocyte proteinase 3 (PR3) and myeloperoxidase (MPO). AAV can be classified into 3 categories based on patterns of clinical involvement: namely, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic GPA (EGPA). Clinically, AAV involves many organ systems including the lungs, kidneys, skin, and nervous system. The prognosis of AAV has improved dramatically due to advances in the understanding of its pathogenesis and treatment modalities. This review will highlight some of the recent updates in our understanding of the pathogenesis, clinical manifestations, and treatment options in patients with AAV focusing on kidney involvement.

Keywords: ANCA vasculitis; crescentic glomerulonephritis; review; vasculitis.

Figure 1

Pathogenesis of ANCA-associated vasculitis and potential targeted therapies. Pathogenesis of ANCA-associated vasculitis is multifactorial, involving numerous immune cells. B lymphocytes feature prominently as producers of ANCAs, with BAFF contributing to maintenance of autoreactive B cells, plasmablasts, and plasma cells. Neutrophils also feature prominently in the pathophysiology, driving much of the tissue damage via injury to the vascular endothelium. Complement factors, particularly C5a, and NETs are also important drivers of vascular inflammation and injury. From a therapeutic perspective, multiple targets have been identified for currently approved therapies and/or future directions, as treatment of ANCA-associated vasculitis becomes more precise and personalized, aiming to minimize the risks of therapy. Among those depicted, rituximab is the only currently approved therapy for ANCA-associated vasculitis, while the remainder represent therapies currently under investigation or potential therapeutic targets. Rituximab and obinutuzumab target CD20 which is expressed in B lymphocytes and plasmablasts. Bortezomib targets the proteasome and primarily target antibody-secreting plasma cells. By targeting BAFF, belimumab impacts the maintenance of autoreactive lymphocytes, plasmablasts, and plasma cells. Abatacept inhibits T-cell stimulation by antigen-presenting cells including B-cells. At the level of the vascular endothelium, vilobelimab and avacopan, target complement factor C5a and C5a receptor, respectively. Abbreviations: ANCA: anti-neutrophil cytoplasmic antibodies. BAFF: B lymphocyte activating factor. C5a: complement factor 5 fragment a. NETs: neutrophil extracellular traps. MPO: myeloperoxidase. PR3: leukocyte proteinase 3.

Figure 2

The kidney biopsy in AAV. (A) A glomerulus with an active global cellular crescent with segmental necrosis, Hematoxylin and Eosin (H&E), Magnification 200×. (B) A glomerulus with segmental fibrocellular crescent, H&E, Magnification 200×. (C) A glomerulus with fibrous crescent, Periodic-Acid Schiff (PAS), Magnification 200×. (D) Glomeruli in different stages of involvement, including active cellular crescent (single arrow), segmental necrotizing lesion (arrowhead) and uninvolved glomerulus (double arrows), H&E, Magnification 100×. (E) Necrotizing vasculitis with severe fibrinoid changes of the arterial wall, H&E, Magnification 200×. (F) Immunofluorescence is negative for immunoglobulins.