ANCA-Associated Vasculitis (AAV)

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises a group of autoimmune disorders that affect small blood vessels in various organs, including the kidneys, lungs, and skin, leading to life-threatening conditions such as renal failure and alveolar hemorrhage. During the testing and diagnosis stage, histology can identify signature pathophysiological features and confirm a diagnosis of AAV.1

Most patients with AAV test positive for the presence of ANCA, which cause inflammation and necrosis of blood vessels.2 In AAV, the 2 main target antigens of ANCA are myeloperoxidase (MPO) and proteinase 3 (PR3), localized in the granules of neutrophils and the lysosomes of monocytes.3

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In AAV, three main subtypes have been identified, including granulomatosis with polyangiitis (GPA, previously known as Wegener granulomatosis); microscopic polyangiitis (MPA); and eosinophilic GPA (EGPA, previously known as Churg-Strauss syndrome). Renal-limited necrotizing and crescentic glomerulonephritis may also be diagnosed.3

One of the key features of AAV is inflammatory cell infiltration (neutrophils and monocytes) in and around vessels. This can lead to tissue damage, seen in histology as the deposition of cellulose, degeneration of collagen fibers, and necrosis of endothelial and smooth cells.1,3 Within days, neutrophils undergo leukocytoclasis and are replaced by macrophages, monocytes, and T lymphocytes.3

Renal Histological Features

In the kidneys, AAV can cause a type of glomerulonephritis called pauci-immune glomerulonephritis,4 characterized by inflammation and damage of the glomeruli with segmental fibrinoid necrosis, although normal glomeruli are usually still present. With acute glomerular injury, segmental necrosis with extravasation of fibrin and erythrocytes can be observed. In addition, the parietal glomerular epithelial cells proliferate and form a cellular crescent. The Bowman capsule can be destroyed, and over time, glomerulosclerosis develops due to periglomerular and glomerular inflammation that can be global or segmental.4 

The 4 patterns of glomerular lesions used to stage renal disease in AAV are focal, crescentic, mixed, and sclerotic. In the focal pattern, more than 50% of glomeruli are normal. The crescentic pattern exhibits more than 50% of glomeruli cellular crescents. In the mixed pattern, fewer than 50% of glomeruli are normal, and crescentic or sclerotic lesions are present. The sclerotic pattern exhibits more than 50% of glomeruli as sclerotic (global sclerosis).4,5 The sclerotic pattern is associated with the worst outcomes.4 

Glomerular lesions can be accompanied by inflammation of the small arteries, and interstitial infiltrates around the lesions may form granulomas.4

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Pulmonary Histological Features

Pulmonary involvement in AAV is frequent and increases mortality.6 In the lungs, AAV can cause necrotizing granulomatous inflammation (lung nodules), tracheobronchial inflammation, and pulmonary capillaritis that manifests as diffuse alveolar hemorrhage.6 

In granulomatous inflammation, biopsy of the nodules reveals neutrophilic microabscesses, fibrinoid necrosis, palisading histiocytes, and giant cells that form a pattern of granulomatous inflammation. In tracheobronchial inflammation, nonspecific mucosal inflammation, ulcerations, and stenosing fibrosis can be seen.6 Histologically, pulmonary capillaritis appears as infiltration of inflammatory cells, such as neutrophils, into the walls of capillaries. This can lead to alveolar hemorrhage, in which blood leaks into the air sacs in the lungs.6

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Cutaneous Histological Features

Cutaneous manifestations are also frequent in AAV.7 Approximately 50% of patients who have GPA present with skin involvement. In EGPA and MPA, 40% to 50% and 30% to 60% of patients, respectively, present with cutaneous lesions.7 

Up to 50% of the lesions in GPA consist of leukocytoclastic vasculitis with fibrinoid necrosis in the vessel wall. Granulomatous inflammation can also be seen around the vessels. In EGPA, leukocytoclastic vasculitis with fibrinoid necrosis and granulomatous inflammation involving the venules is observed. In MPA, leukocytoclastic vasculitis with fibrinoid necrosis and neutrophilic infiltration of the dermal small vessels is reported.7

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1. Ge S, Zhu X, Xu Q, et al. Neutrophils in ANCA-associated vasculitis: mechanisms and implications for management. Front Pharmacol. 2022;13:957660. doi:10.3389/fphar.2022.957660

2. Koike H, Nishi R, Ohyama K, et al. ANCA-associated vasculitic neuropathies: a review. Neurol Ther. 2022;11(1):21-38. doi:10.1007/s40120-021-00315-7

3. Xiao H, Hu P, Falk RJ, Jennette JC. Overview of the pathogenesis of ANCA-associated vasculitis. Kidney Dis (Basel). 2016;1(4):205-215. doi:10.1159/000442323

4. Kitching AR, Anders HJ, Basu N, et al. ANCA-associated vasculitis. Nat Rev Dis Primers. 2020;6(1):71. doi:10.1038/s41572-020-0204-y

5. Binda V, Moroni G, Messa P. ANCA-associated vasculitis with renal involvement. J Nephrol. 2018;31(2):197-208. doi:10.1007/s40620-017-0412-z

6. Sacoto G, Boukhlal S, Specks U, et al. Lung involvement in ANCA-associated vasculitis. Presse Med. 2020;49(3):104039. doi:10.1016/j.lpm.2020.104039

7. Marzano AV, Raimondo MG, Berti E, et al. Cutaneous manifestations of ANCA-associated small vessels vasculitis. Clin Rev Allergy Immunol. 2017;53(3):428-438. doi:10.1007/s12016-017-8616-5

Reviewed by Debjyoti Talukdar, MD, on 3/16/2023.