ANCA-Associated Vasculitis (AAV)

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises a group of rare autoimmune and systemic diseases that are characterized by inflammation, endothelial injury, and necrosis of small and medium blood vessels.1-3 Multiple organs and systems may be affected by AAV, including the kidneys, skin, central and peripheral nervous system, and gastrointestinal system, leading to variable clinical manifestations of the disease.3,4

There are 3 primary types of AAV identified and described: granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), and microscopic polyangiitis (MPA).3,5 These AAV subtypes share general features such as constitutional symptoms (fever, arthralgia, myalgia) and purpuric skin rash.3,5 AAV is also associated with the presence of antibodies directed against 2 key protein targets located in the cytoplasmic granules of neutrophils: leukocyte proteinase 3 (PR3) and myeloperoxidase (MPO).3,4

ANCA-associated vasculitis also occurs in a rarer fourth type as renal-limited AAV with purely renal involvement. The renal manifestations of this condition can range from rapidly progressive glomerulonephritis, such as pauci-immune necrotizing crescentic glomerulonephritis, to less aggressive and indolent disease. This indolent disease can then slowly progress to end-stage renal disease.6

Granulomatosis With Polyangiitis

Granulomatosis with polyangiitis (previously known as Wegener’s granulomatosis) is a type of AAV that affects small to medium blood vessels (capillaries, venules, arterioles, arteries, and veins).3 It is the most common type of AAV, with an incidence of 5 to 10 cases per 1 million people.7 The disease can affect both men and women aged 45 to 60 years, with a peak incidence at approximately 55 years of age.3,7 It is believed that environmental or viral triggers in individuals with a genetic predisposition who exhibit tolerance to ANCA self-antigens are the basis of the immunopathogenesis of this AAV subtype.3

Typical clinical features of GPA include recurrent sinusitis, nasal crusting, stuffiness, epistaxis, uveitis, frequent upper respiratory tract involvement (pulmonary nodules), and renal involvement (necrotizing glomerulonephritis).1,3,5 Other clinical manifestations include eye problems such as scleritis and orbital tumors.5 Many cases of GPA that are localized to the upper airway are persistent and refractory to treatment, with patients experiencing many relapses.5

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Granulomatosis with polyangiitis has been linked to the presence of ANCAs directed against PR3 in about 80% of patients and against MPO in about 10% of patients. One hallmark of GPA is the presence of ANCAs against PR3 in about 90% of the systemic forms of the disease and 50% of the localized forms.3 

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Eosinophilic Granulomatosis With Polyangiitis

Eosinophilic granulomatosis with polyangiitis (previously known as Churg-Strauss syndrome) affects small- and medium-sized blood vessels.3 Several immunological dysregulations are the basis of the pathogenesis of this type of AAV. Eosinophils and their granule degradation products are likely players in these events.3,5

Eosinophilic granulomatosis with polyangiitis typically develops in patients with asthma, nasal polyposis, and peripheral blood eosinophilia.1 Cardiomyopathy can be observed in 10% to 50% of patients.5 This type of AAV has an impact on several organs and systems, including the lungs and skin. Compared to GPA and MPA, EGPA is rarer, with an annual incidence rate of 4 cases per 1 million in the United States.3

Only about 30% to 40% of patients with EGPA express ANCAs, mainly MPO-ANCA, contrasting with the higher percentages found in patients with GPA and MPA.3,5 Patients with EGPA may not present with histologic signs of vasculitis, which can lead to the diagnosis of other conditions, such as hypereosinophilic syndromes or eosinophilic lung disease.3

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Microscopic Polyangiitis

Microscopic polyangiitis primarily affects small blood vessels (capillaries, venules, and arterioles).5 Patients with this type of AAV are typically older and tend to be MPO-ANCA positive, presenting with rash, neuropathy, and severe renal involvement (necrotizing glomerulonephritis).1-3 

In MPA, neutrophils are exposed to proinflammatory cytokines such as interleukin 1 (IL-1) and tumor necrosis factor α (TNF-α), which promote the expression of MPO and PR3 on the cell surface. ANCAs can then bind to MPO and PR3 on the cellular surface, resulting in cell activation. Neutrophils can also be activated following interactions with ANCAs.3 In contrast to the other subtypes of the disease, no granulomas are typically formed in MPA.5

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1. Yates M, Watts R. ANCA-associated vasculitis. Clin Med (Lond). 2017;17(1):60-64. doi:10.7861/clinmedicine.17-1-60

2. Austin K, Janagan S, Wells M, Crawshaw H, McAdoo S, Robson JC. ANCA associated vasculitis subtypes: recent insights and future perspectives. J Inflamm Res. 2022;15:2567-2582. doi:10.2147/JIR.S284768

3. 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

4. Bantis K, Stangou MJ, Kalpakidis S, et al. Different types of ANCA determine different clinical phenotypes and outcome in ANCA-associated vasculitis (AAV). Front Med (Lausanne). 2022;8:783757. doi:10.3389/fmed.2021.783757

5. Ross C, Makhzoum JP, Pagnoux C. Updates in ANCA-associated vasculitis. Eur J Rheumatol. 2022;9(3):153-166. doi:10.5152/eujrheum.2022.20248

6. Yamaguchi M, Ito M, Sugiyama H, et al. Association between renal-limited vasculitis and relapse of antineutrophil cytoplasmic antibody-associated vasculitis: a single-center retrospective cohort study in Japan. PLoS One. 2022;17(9):e0274483. doi:10.1371/journal.pone.0274483

7. Qasim A, Patel JB. ANCA positive vasculitis. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated May 29, 2022. Accessed March 1, 2023.

Reviewed by Hasan Avcu, MD, on 3/13/2023.