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Page 2 of 14 Almeida et al. Vessel Plus 2021;5:44 https://dx.doi.org/10.20517/2574-1209.2021.66

the major antigens targets of ANCAs [myeloperoxidase (MPO) and proteinase 3 (PR3)] led to the creation
of an inclusive group of AAVs. Classification criteria based on clinical findings and tissue biopsy, if possible
[2,3]
or reasonable, have not always been widely accepted and new scores are being proposed .

The AAV group incorporates at least four particular diseases: granulomatosis with polyangiitis (GPA),
microscopic polyangiitis (MPA), eosinophilic GPA (EGPA; formerly Churg-Strauss syndrome), and drug-
[4]
induced AAV .

GPA is a necrotizing small-vessel vasculitis characterized by the involvement of the respiratory tract with
granulomatous inflammation. These patients are mainly PR3-ANCA positive. In contrast, MPA preferably
targets renal glomeruli small vessels and presents a histological pattern of necrotizing vasculitis normally
lacking granulomatous inflammation. The serum of these patients commonly presents MPO-ANCA
positivity.

The EGPA histological pattern is similar to GPA, except its main feature of eosinophil-rich reaction that
involves small- to medium-sized vessels. Patients with this disease typically have associated adult-onset
asthma and allergic sinusitis, eosinophilia, tissue infiltrating eosinophils, and around 50% of the cases have
MPO-ANCA positivity.

Drugs such as propylthiouracil, hydralazine, or cocaine induce ANCA production and generate drug-
induced AAV. The clinical features of this particular spectrum of AAV have a wide and global variation
according to ethnic differences . More commonly, MPA- and MPO-ANCA positivity is observed in East
[5]
[6]
Asian countries, while GPA- and PR3-ANCA is more noticeable in Western countries .
Worldwide identification of these diseases prompted international guidelines and treatment management
for remission and maintenance . However, methods for the monitoring of AAVs activity are still lacking.
[7-9]
In this review, we characterize the current knowledge regarding AAV’s risk factors and pathogenesis and
subsequently review newly discovered biomarkers for its diagnosis, monitoring, and prognosis.

RISK FACTORS OF AAV
A multiplicity of risk factors for AAV has been described in the literature, as summarized in Table 1.

Genetics
Even though familiar reports of AAV are rare , as for other autoimmune disorders, genome-wide
[10]
association studies (GWAS) have been performed to further identify alleles related with patterns of
susceptivity or resistance to AAV. Among these, the strongest associations were found for major
histocompatibility complex class II (MHC II) and HLA gene locus on chromosome 6.

The differences in HLA are related to the ethnicity of the population and the appearance of certain
[11]
circulating antibodies rather than the clinical appearance . A GWAS conduced in the UK found strong
associations between HLA-DPB1*04 and PR3-ANCA (OR = 7.03), MPO-ANCA and DQ loci (OR = 0.65),
[11]
and HLA-DP allele and GPA (OR = 5.39) . In Japan, population studies linked HLA-DRB1*09:01 with
MPO-ANCA (OR = 1.57) and MPA (OR = 1.56). Curiously, HLA-DRB1*13:02 was suggested as a protective
factor against AAV .
[12]