The rise of complement in ANCA-associated vasculitis: from marginal player to target of modern therapy

Abstract

The complement system plays a central role in autoimmune diseases, including anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Although complement deposition is scarce in AAV pathological samples, complement activation is required for the development of necrotizing crescentic glomerulonephritis (NCGN) in mouse models of AAV and occurs via the alternative pathway. The anaphylatoxin C5a, produced by the final complement pathway, is determinant to drive the disease in animal models. C5a primes human neutrophils and enhances their activation induced by ANCA; activated neutrophils, in turn, release factors that lead to C5a generation, establishing a self-amplifying loop. C5a is also significantly increased in the serum of AAV patients with active disease compared to those in remission or healthy controls. Inhibition of the C5a receptor with avacopan is an emerging therapy that will probably allow AAV treatment with glucocorticoid-free regimens.

Keywords: ANCA; C5a; avacopan; complement; vasculitis.

Fig. 1

Neutrophil activation and the C5a pathway in anti‐neutrophil cytoplasmic antibody (ANCA)‐associated vasculitis (AAV) pathogenesis. Neutrophils primed by inflammatory stimuli express myeloperoxidase (MPO) and proteinase 3 (PR3), the main ANCA antigens, on their membrane surface. The binding of ANCA leads to neutrophil activation, with release of reactive oxygen species (ROS) and toxic enzymes, and consequent vascular inflammation. Neutrophil degranulation also results in complement activation via the alternative pathway. C5a, a complement product with anaphylatoxic and chemotactic properties, recruits further neutrophils into the affected tissues and primes them, perpetrating the ANCA‐induced pathogenic process. Avacopan, an orally administered molecule, and the monoclonal antibody IFX‐1 inhibit the amplification loop mediated by the C5a pathway, targeting, respectively, the C5a receptor (C5aR) and C5a itself.