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

Benoit Brilland1, Anne-Sophie Garnier2, Alain Chevailler3

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Autoimmunity Reviews
|November 18, 2019
PubMed
Summary

Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides involve complement alternative pathway (cAP) activation, crucial for disease pathogenesis. Targeting C5aR with avacopan offers a promising therapeutic strategy, reducing reliance on toxic glucocorticoids.

Keywords:
ANCA-associated vasculitisAvacopanC5aRComplement alternative pathwayNeutrophils

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Area of Science:

  • Nephrology
  • Immunology
  • Rheumatology

Background:

  • Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAVs) are severe small vessel diseases affecting kidneys, lungs, and nerves.
  • AAVs are classified as pauci-immune glomerulonephritis (GN), traditionally considered complement-independent.
  • Recent evidence suggests the complement alternative pathway (cAP) plays a significant role in AAV pathogenesis.

Purpose of the Study:

  • To review evidence supporting the role of cAP in murine models and human AAVs.
  • To discuss the therapeutic potential of targeting c5a receptor (C5aR) in AAVs.
  • To explore the development and future prospects of avacopan (CCX168).

Main Methods:

  • Review of in vitro and in vivo data from animal models and human studies.
  • Analysis of the role of complement activation, specifically cAP and C5a generation.
  • Discussion of clinical development of anti-C5aR therapies.

Main Results:

  • Complement alternative pathway (cAP) activation, via C5a generation, is critical in AAV pathogenesis.
  • C5a acts as a chemoattractant and priming agent for neutrophils, contributing to inflammation.
  • Preclinical and clinical data support the efficacy of targeting C5aR.

Conclusions:

  • The complement alternative pathway (cAP) is a key driver in ANCA-associated vasculitis (AAV) pathogenesis.
  • Targeting C5aR with molecules like avacopan presents a novel therapeutic approach for AAV.
  • Avacopan offers a potential alternative to reduce glucocorticoid toxicity in AAV treatment.