ANCA associated vasculitis: The journey to complement-targeted therapies

Abstract

ANCA associated vasculitis is a serious, very often recurrent disease that despite the current standard treatment with high-dose glucocorticoids and either cyclophosphamide or rituximab, patients have a nine-fold increased mortality risk in the first year compared with healthy controls, attributed to infections, vasculitis activity, and renal disease. During the last few years, novel findings have suggested that activation of the complement system, in particular the alternative complement system, has a significant role in ANCA associated vasculitis pathogenesis. Detection of several components of this system in the circulation and urine reflects disease activity, and thus may be useful for clinical prognosis and to set up personalised treatments. In fact, some components of the complement system, such as C5a, might be potential targets for therapy. In this Review an update on clinical evidence for the role of complement activation in AAV is provided and subsequently we discuss potential therapeutic strategies that target complement components and open the way for clinical use of this target therapy in the near future.

Animal Models of ANCA Associated Vasculitis

“…Several disease models are required to comprehensively model and study AAV. Thus far, passive transfer models have proven valuable in studying early effector responses and have resulted in the translation of anti-C5aR therapies into Phase 2 and Phase 3 clinical trials (21,42,162). Further work is necessary to refine and establish animal models that reflect human disease as accurately as possible.…”

Immunopathogenesis of ANCA-Associated Vasculitis

“…The alternative complement pathway is crucially involved in the pathogenesis of ANCA-associated vasculitis [ 165 ]. CCX168 (avacopan) treatment in a mouse model dose-dependently reduced the formation of crescents, the key hallmark of renal involvement in patients with ANCA-associated vasculitis.…”

Nierenbeteiligung bei ANCA-assoziierten Vaskulitiden

“…Beide Avacopan ® -Gruppen zeigten ein ähnliches Therapieanspre-chen und es kam zu einer tendenziell effektiveren Reduktion der Albuminurie als in der Kontrollgruppe [34]. Eine multizentrische internationale Studie, die Avacopan ® gegen Steroid in Kombination mit entweder Cyclophosphamid/Azathioprin oder Rituximab vergleicht, hat die Rekrutierung beendet, Ergebnisse werden Anfang 2020 erwartet (ADVOCATE, NCT02994927) [38]. .…”