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Page 8 of 14 Almeida et al. Vessel Plus 2021;5:44 https://dx.doi.org/10.20517/2574-1209.2021.66

(NGAL) presented statistically significant increases during renal flares among patients with AAV. Of those,
[55]
MCP-1 chemokine granted the best discrimination between active renal disease and remission . MCP-1 is
in fact the most promising urinary biomarker for AAV still under research, with multiple studies suggesting
usefulness in the assessment of vasculitis and monitoring treatment [55-57] .

Urinary soluble CD163 was presented as an even more promising biomarker of renal vasculitis than urinary
[58]
MCP-1 . CD163 is a soluble form of a high affinity scavenger receptor for the hemoglobin-haptoglobin
receptor complex and functions as an innate sensor for bacteria. Patients with small vessel vasculitis (which
includes GPA, MPA, and EGPA) had markedly higher urinary sCD163 levels than patients in remission,
disease controls, or healthy controls . However, serum sCD163 levels failed to distinguish infections from
[58]
[59]
active disease, which may limit its use .

Inflammatory markers
Traditional inflammatory markers such as ESR (erythrocyte sedimentation rate) or CRP (C-reactive
protein) are non-specific markers for AAV.

[60]
Monach et al. evaluated whether these markers were able to distinguish severe AAV [BVAS for Wegener’s
granulomatosis (BVAS/WG) ≥ 3 at screening] from remission. All subjects with severe active vasculitis at
screening were followed during remission at Month 6, of whom 24 out of 28 showed significant decline .
[60]
Although they are not specific, traditional inflammatory markers correlate with the activity of the disease.

Eosinophilia is the hallmark of EGPA; however, the number of circulating eosinophils may not be an
adequate biomarker for active EGPA since the eosinophil count usually drops dramatically and rapidly after
treatment with glucocorticoids. Indeed, the treatment effect, mainly glucocorticoids, may directly cause the
mispresenting comparison between active and inactive EGPA. Eotaxin-3, immunoglobulin G4 (IgG4), and
CC chemokine ligand 17 (CCL17/TARC) levels were higher in active EGPA compared to healthy controls,
inactive EGPA, and/or other diseases featuring vasculitis or hypereosinophilia [35,61,62] . Interestingly, eotaxin-3
levels were lower in hypereosinophilic syndromes than EGPA, underpinning a potential diagnosis use [35,61] .

Pepper et al. suggested calprotectin as a potential disease biomarker in patients with AAV by showing
[63]
that patients with AAV had higher monocyte and neutrophil cell surface calprotectin expression than
healthy controls and that its levels increased following treatment withdrawal and were significantly elevated
in patients who relapsed.

12-Hydroxyeicosatetraenoic acid (12-HETE) measurement in exhaled breath concentrates (EBC) is a very
[64]
different approach to distinguishing EGPA from asthma or hypereosinophilic syndromes. Szczeklik et al.
identified markedly higher concentrations of 12-HETE in EBC of EGPA than of other compared diseases,
even though 19 out of 23 patients were receiving glucocorticoids and one third were clinically in remission.

Clinical trials also provide promising markers, such as MMP-3, TIMP-1, and CXCL13 (BCA-1) , which
[60]
need further investigation with proper endpoints. sRAGE (serum advanced glycation end products) is
[65]
another particular biomarker that may reflect the burden of granulomatous inflammation in GPA and
therefore be useful for assessing mild/limited disease activity.

Endothelial damage biomarkers
Two important biomarkers of endothelial injury were studied in AAV: endothelial microparticles (EMPs)
and circulating detached mature endothelial cells (CECs).