The complement system in antineutrophil cytoplasmic antibody-associated vasculitis: pathogenic player and therapeutic...

The purpose of this review is to discuss the role of the complement system in the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) as well as the employment of complement inhibitors in AAV treatment.

AAV has traditionally been considered a pauci-immune disease until recent findings demonstrated the pathogenic role of the complement system. The complement alternative pathway is crucial in AAV, and C5a seems to be a key molecule for AAV to develop. Avacopan, a C5a-receptor (C5aR) antagonist, proved effective in achieving AAV remission and ameliorating kidney function.

The increased circulating levels of some complement components - as well as the consumption of others - in patients with AAV suggested a systemic activation of the complement system. Low C3 levels correlate with a more aggressive disease and a worse renal prognosis. In ANCA-associated glomerulonephritis, renal deposits of C3d and properdin, suggestive of local alternative pathway activation, correlate with glomerular crescents and proteinuria. The interaction between C5a and neutrophil triggers alternative pathway activation, suggesting the central role of C5a in AAV pathogenesis. Avacopan, a C5aR inhibitor, showed beneficial effects in AAV and represents a promising therapy to achieve sustained remission and to spare glucocorticoids.