The Complement System and ANCA Associated Vasculitis in the Era of Anti-Complement Drugs

Abstract

ANCA (anti-neutrophil cytoplasmic antibody)-associated vasculitis (AAV) is the condition in which ANCA, as an autoantibody, is associated with the pathogenesis of vasculitis in small blood vessels, mainly in the ear, nose, throat, kidney, lung, and nerves. These diseases are important because they can be fatal due to renal failure and pulmonary hemorrhage if not promptly and appropriately treated. Recently accumulated evidence has shown that C5a produced by the complement alternative pathway primes neutrophils, which in turn activate the complement alternative pathway, leading to the pathogenesis of AAV. Avacopan (CCX168), a C5aR antagonist was shown to be effective against AAV, and it has been a novel therapeutic option, becoming a novel anti-complement drug to modulate inflammatory diseases.

Avacopan as an additional therapeutic intervention to promote renal recovery in severe ANCA‐associated vasculitis: A case report

“…Standard remission-induction treatment for ANCA-associated vasculitis (AAV) consists of glucocorticoids and immunosuppression (typically rituximab and/or cyclophosphamide), with subsequent maintenance therapy with tapering glucocorticoids. 2,3 Recently the role of the alternate pathway of complement in AAV has been uncovered, 4,5 mediated by C5a, which primes neutrophils for activation by ANCA. 6 Avacopan, a C5aR antagonist acts on this pathway.…”

Complement‐targeted therapeutics: An emerging field enabled by academic drug discovery

“…The PMX line of C5aR1 antagonists in particular have proven fruitful for the ongoing drug development in this class, with some of the members of this family having entered clinical development and evaluation 21 . At this point, the recently approved C5aR1 antagonist avacopan is the only orally bioavailable complement inhibitor in the clinic, 22 while other oral complement modulators are in late‐stage development (Table 1). 23,24 …”

“…20 The PMX line of C5aR1 antagonists in particular have proven fruitful for the ongoing drug development in this class, with some of the members of this family having entered clinical development and evaluation. 21 At this point, the recently approved C5aR1 antagonist avacopan is the only orally bioavailable complement inhibitor in the clinic, 22 while other oral complement modulators are in late-stage development (Table 1). 23,24 Perhaps the most prominent example for a drug discovery and development process in the complement field that continues to involve partners from the academic, clinical, and industrial branch is the compstatin family of C3 inhibitors, which was identified in the academic lab of John Lambris at the University of Pennsylvania.…”

C-Reactive Protein Levels Are Associated with Complement C4 Deposits and Interstitial Arteritis in ANCA-Associated Renal Vasculitis

“…Two principal antigens on neutrophils—namely, proteinase 3 (PR3) and myeloperoxidase (MPO)—provide epitopes for ANCA binding, promoting endothelial damage and vascular inflammation, culminating in necrotizing vasculitis [ 5 , 6 , 7 ]. Innate immunity with complement system activation is increasingly recognized in the pathogenesis of AAV and as an attractive therapeutic target [ 8 , 9 ]. Although C-reactive protein (CRP) was thought to be a passive, nonspecific marker of inflammation, recent studies indicate that CRP plays a key role in the innate immune system by recognizing pathogens and altered self-determinants [ 10 , 11 ].…”