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Almeida et al. Vessel Plus 2021;5:44 https://dx.doi.org/10.20517/2574-1209.2021.66 Page 7 of 14

The value of ANCA goes beyond its simple diagnostic value. The ANCA-positive patient subtypes, namely
PR3-ANCA and MPO-ANCA, differ from one another regarding genetic basis, epidemiology, clinical
manifestations, histological findings, response to therapy, and pathogenesis. These facts sustain the reason
to distinguish between PR3-ANCA and MPO-ANCA patients, meaning GPA (commonly associated with
PR3-ANCA) and MPA (commonly associated with MPO-ANCA) [36,39] .

Whereas the ANCA diagnostic value is no longer under doubt, its role as a disease activity marker has been
the subject of frequent studies with varying outcomes . Discrepant results regarding disease activity have
[40]
been a matter of discussion in the literature [41-43] . This misalignment in the results can be interpreted by
differences in the epitopes and affinities of ANCAs. Patients with a recognizable N-terminus of MPO heavy
[44]
chain are more prone to develop a severe disease , while patients with low-affinity despite high titers of
[45]
MPO-ANCA have a lower vasculitic disease activity . Some clinical studies show a direct link between an
increment in PR3-ANCA levels during complete remission and an increased risk of relapse [46,47] , while others
find a direct link between PR3-ANCA-positive patients and relapse probability compared to MPO-ANCA
patients [48,49] .

The role of ANCA subtypes in predicting response to treatment is also a subject under scrutiny. Some
studies suggest that adult PR3-ANCA-positive patients respond better to rituximab than to conventional
induction/remission maintenance treatment with cyclophosphamide and azathioprine, leading to the belief
that ANCA serotype may guide the type of treatment in AAV .
[50]

Biomarkers derived from neutrophil activation - NMPs and NETs
Neutrophil microparticles (NMPs) are membrane vesicles that induce endothelial damage in AAV, whereas
NETs, composed of DNA, histones, and neutrophil proteins and released by ANCA-stimulated neutrophils,
[51]
contain antigenic components including PR3 and MPO .
Removal of NMPs by filtration abolished a pathological trigger connected to endothelial activation,
suggesting a target for therapeutic plasma exchange in AAV. Despite the suggestion, clinical utility remains
unvalidated. A recent study concluded that MPO patients’ NMPs express higher levels of pentraxin-3
(PTX3), high mobility group box 1 protein (HMGB1), and tumor necrosis factor-like weak inducer of
apoptosis (TWEAK) when compared to healthy controls . Concentrations of PTX3 and HMGB1 were
+
+
[52]
significantly higher in active AAV patients compared to those in remission . PTX3 serum levels were
[52]
strongly correlated with the Birmingham vasculitis activity score .
[52]
[53]
Moreover, Lange et al. detected a significant increase in serum circulating free DNA (cfDNA) levels in
PR3-ANCA GPA patients compared to EGPA and concluded that there is an association between
concentration of cfDNA and disease activity. These findings suggest that abnormal formation and/or
insufficient clearance of NETs may contribute to increase the levels of cfDNA in GPA. The detection of
cfDNA levels or NETs may serve as a marker of disease activity in AAV, namely PR3-ANCA-positive
GPA [53,54] .

Urinary biomarkers
Urinary biomarkers could be ideal for the non-invasive monitoring of disease activity and renal
involvement.

Lieberthal et al. found that urinary levels of monocyte chemotactic protein 1 (MCP-1), α-1-acid
[55]
glycoprotein (AGP), kidney injury molecule 1 (KIM-1), and neutrophil gelatinase-associated lipocalin