ANCA-Associated Vasculitis (AAV)

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare group of autoimmune hematological conditions defined by inflammation and the destruction of blood vessels throughout the body. These conditions included in AAV are: granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA), and microscopic polyangiitis (MPA).

Risk Factors for Granulomatosis With Polyangiitis

The underlying cause of granulomatosis with polyangiitis remains poorly understood. Although ANCA have been implicated in the etiopathogenesis of this disease, the complex interactions of genetics and microbes have not been elucidated. ANCA are regarded as a main driver of the inflammation observed in GPA.1 

Risk Factors of Genetics

Several genetic associations have been identified in GPA: a defective allele for alpha 1 antitrypsin; cytotoxic T-lymphocyte-associated protein 4 (CTLA-4); the proteinase 3 (PRTN3) gene; the major histocompatibility complex, class II, DP alpha 1 (HLA-DPA1) gene; and certain types of FC gamma receptor IIIb on the surface of neutrophils and macrocytes/monocytes.1 

Risk Factors of Environment

Defective immune-regulatory responses to environmental insults, such as infection and autoantigens, have been shown to result in the excessive production of Th1 and Th17 cytokines, including interleukin 17, tumor necrosis factor, and interferon gamma, which can contribute to the development of an inflammatory granulomatous vascular lesion.1

Additionally, infectious agents can modulate the clinical phenotype of the disease, with infections by bacteria such as Staphylococcus aureus hypothesized to be an initiating factor for inflammation in some cases of GPA.1 Associations with a variety of viruses, including parvovirus, hepatitis C virus (HCV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV), have also been reported.2-5 

Risk Factors of Treatment

Various medications, such as sulfasalazine, hydralazine, antithyroid medications, phenytoin, and allopurinol, have been implicated. Identifying these genetic and environmental factors will be important for the development of new treatments and personalized approaches to managing GPA.1

Risk factors for relapse are conflicting between studies. A recent multicenter study demonstrated that the main predictors of relapse are PR3-ANCA positivity, nasal manifestations, mucosal membrane involvement, and gastrointestinal tract complications.6

Read more about AAV life expectancy

Risk Factors for Eosinophilic Granulomatosis With Polyangiitis 

The risk factors associated with eosinophilic granulomatosis with polyangiitis have been the subject of much study. Although many risk factors have been suggested, including environmental and pharmaceutical considerations, some have been more strongly linked to the onset of the disease than others.7 

Risk Factors of Genetics

HLA alleles such as HLA-DRB1 04 and HLA-DRB1 07 have been identified as potential risk factors, given the presence of specific clonally expanded subpopulations of T cells harboring these alleles.7

Risk Factors of Environment

Various environmental risk factors have been studied, including allergies and infections. Some authors even suggest that airway colonization with Aspergillus or Actinomyces may be a risk factor.7 

Risk Factors of Treatment

Among medications, sulfonamides, macrolides, and diphenylhydantoin have been implicated, but none have been as strongly associated with the onset of EGPA as the leukotriene inhibitors Singulair® (montelukast) and Accolate® (zafirlukast). In a review of the US Food and Drug Administration database, Bibby et al reported that in 90% of 181 cases of EGPA in which a pharmacological trigger was suspected, a leukotriene receptor antagonist was involved.7 

However, this finding is controversial. Some experts have pointed out that leukotriene receptor antagonists are used to help patients with asthma taper their steroid treatments. The underlying vasculitis is simply unmasked in the process, and the medications are not themselves a trigger for EGPA.7  

EGPA relapse occurs in approximately 20% to 30% of patients. Certain risk factors have been identified that are associated with an increased risk of relapse. These include persistent ANCA positivity, gastrointestinal tract involvement, and an increase in ANCA titers. Eosinophilia is a hallmark feature of EGPA, and its severity correlates with the extent of vasculitic disease. Additionally, a sudden rise in the eosinophil count has been shown to precede a relapse of vasculitis. Clinicians should be aware of these risk factors and monitor patients accordingly to prevent and manage relapses.7

Glomerulonephritis, mononeuritis, and biopsy-proven vasculitis are more likely to develop in patients with ANCA positivity. In addition, ANCA positivity carries a higher risk for alveolar hemorrhage vs ANCA negativity, and fewer cardiac manifestations are observed in ANCA-negative patients and in those without eosinophilia.7 

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Risk Factors for Microscopic Polyangiitis

Age, sex, and race each impart risk for microscopic polyangiitis. The median age at onset is 50 years. MPA is more common in Whites than in Blacks and more prevalent in men than in women.8 

The etiopathogenesis of MPA and related vasculitides has traditionally been ascribed to ANCA. However, ANCA are not present at the time of diagnosis in 30% of patients with MPA, and a limited number of MPA cases lack ANCA. As such, it is now appreciated that other factors may contribute to the etiology of MPA, including infections, drugs, and genetic factors.8

Risk Factors of Genetics

Recently, a genome-wide study in Europe has identified genetic factors, such as HLA-DP, HLA-DR3, and alpha-1 antitrypsin, as contributing to the pathogenesis of ANCA-associated vasculitides.8

Risk Factors of Environment

The overlap in the clinical presentation of various infectious processes and those of MPA suggests a possible infectious contributor to the etiology in some cases. Similarly, the role of chronic nasal carriage of S aureus has been implicated in relapsing granulomatosis with polyangiitis. Furthermore, exposure to silica has been linked to MPA induction of autoimmunity in patients with genetic susceptibility.8

Risk Factors of Treatment

Certain drugs, including hydralazine, thionamides, sulfasalazine, and minocycline, have been associated with ANCA-associated vasculitis.8 

MPA relapse occurs in approximately 25% of patients. Risk factors for relapse may include a positive PR3-ANCA status, cardiovascular involvement, renal failure, pulmonary involvement, and adverse complications related to medication. One study by Hassan et al. indicated that patients with lung involvement at baseline were subject to increased damage and disease activity scores. Patients showing pulmonary involvement were linked to a higher risk of renal and cardiovascular complications, as well as pulmonary fibrosis.8
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1. Garlapati P, Qurie A. Granulomatosis with polyangiitis. StatPearls [Internet]. Updated December 5, 2022. Accessed February 22, 2023.

2. Morgan MD, Pachnio A, Begum J, et al. CD4+CD28- T cell expansion in granulomatosis with polyangiitis (Wegener’s) is driven by latent cytomegalovirus infection and is associated with an increased risk of infection and mortality. Arthritis Rheum. 2011;63(7):2127-2137. doi:10.1002/art.30366

3. Yasuda M, Araki H, Fujitomo Y, et al. [Case of MPO-ANCA-positive Wegener’s granulomatosis with hepatitis C virus infection]. Nihon Jinzo Gakkai Shi. 2011;53(7):1053-1058.

4. Yamaguchi M, Yoshioka T, Yamakawa T, et al. Anti-neutrophil cytoplasmic antibody-associated vasculitis associated with infectious mononucleosis due to primary Epstein–Barr virus infection: report of three cases. Clin Kidney J. 2014;7(1):45-48. doi:10.1093/ckj/sft140

5. Nikkari S, Mertsola J, Korvenranta H, Vainionpää R, Toivanen P. Wegener’s granulomatosis and parvovirus B19 infection. Arthritis Rheum. 1994;37(11):1707-1708. doi:10.1002/art.1780371122

6. Safari S, Alesaeidi S, Pakzad B, Abbaspour S. Predictors of relapse in granulomatosis with polyangiitis: a multi-center study. Egypt Rheumatol Rehabil. 2022;49(1):59. doi:10.1186/s43166-022-00160-y

7. Chakraborty RK, Aeddula NR. Churg Strauss syndrome. StatPearls [Internet]. Updated August 10, 2022. Accessed February 22, 2023.

8. Hashmi MF, Jain V, Tiwari V. Microscopic polyangiitis. StatPearls [Internet]. Updated November 27, 2022. Accessed February 22, 2023.

Reviewed by Harshi Dhingra, MD, on 2/24/2023.