Complement alternative pathway in ANCA-associated vasculitis: Two decades from bench to bedside

Anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitides (AAVs) are small vessel vasculitides involving predominantly ear-nose-throat, kidneys, lungs and nerves. AAVs are life-threatening diseases, especially in their most severe forms such as necrotizing crescentic glomerulonephritis (GN) and/or intra-alveolar hemorrhage. Unlike immune complex GN or anti-glomerular basement membrane GN, AAVs are classified as pauci-immune GN. However, based on recent insights from animal models, the view of AAVs as a complement-unrelated disease has been challenged. Indeed, complement activation, and especially complement alternative pathway (cAP) activation, has been shown to be determinant in AAV pathogenesis through C5a generation, a potent chemoattractant for neutrophils with priming capacities. Here, we review in vitro and in vivo data supporting the role of cAP in murine models and in human AAVs. These findings, together with the need to eradicate glucocorticoid toxicity, led to the development of an anti-C5aR molecule, CCX168, also known as avacopan. Its development and future opportunities are also discussed. •Murine and human data support a critical role of complement alternative pathway (cAP) in AAV pathogenesis•cAP activation leads to C5a generation resulting in neutrophils priming and chemotaxis in an auto-amplification loop manner•C5aR blockade suppresses glomerular lesions in murine AAV models•Avacopan, a C5aR antagonist, has proven its safety and efficiency in phase I and II trials conducted in AAV patients•CCX168 is currently being compared to steroids in a phase III trial for remission induction in AAV patients