Abstract

Background: Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a cluster of potentially life-threatening disorders, often involving the kidney with a necrotizing crescentic glomerulonephritis with scanty deposition of immunoglobulins and complement. Historically the role of complement has been considered ancillary. Recently, an anti-myeloperoxidase (MPO) AAV model in complement-deficient mice has shown an involvement for the complement cascade in the development of the renal injuries. Further animal studies showing that in contrast to mice deficient for factor B and C5 animals deficient for C4 were susceptible to AAV development by injection of anti-MPO antibodies emphasized the specific involvement of the alternative pathway. Consonantly, the C5a receptor (Cd88) blockade was found to protect mice from MPO-AAV. CCX168, i.e., avacopan, a powerful inhibitor of C5a receptor that can be administered orally, was shown to reduce the proinflammatory effects of C5a and abolish the activation of neutrophils, their migration and adherence to endothelium, and the vascular endothelial cell retraction that increases permeability. Summary: Avacopan was found to be safe in healthy volunteers given a wide range of doses in a phase 1 clinical trial. The phase 2 trial CLEAR assessed the possibility to decrease dose or entirely replace glucocorticosteroids in the standard-of-care therapy of AAV. Avacopan, added to CYC or RTX either in combination with GCs or not, shortened the time to remission in patients with either newly diagnosed or relapsing AAV. The phase 3 ADVOCATE study compared the ability of an avacopan-associated regimen to induce and sustain remission in AAV patients versus a conventional GC-associated scheme. Remission at week 26 was observed in 72.3% of patients given avacopan and in 70.1% of those given prednisone. Sustained remission at week 52 (second primary endpoint) was obtained in 65.7% of patients given avacopan and in 54.9% receiving prednisone. The avacopan-associated regimen was noninferior at week 26 and superior at week 52 in sustaining remission as compared to the GC-based scheme. Key Messages: The results of the ADVOCATE trial opened new prospects for the treatment of AAV and also other immune-mediated diseases with renal involvement. The possible position of avacopan in a routine clinical setting and its possible indications in specific subsets of patients with AAV are extensively discussed.

© 2022 The Author(s). Published by S. Karger AG, Basel

References Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, et al. 2012 revised International Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum. 2013 Jan;65(1):1–11. Davies DJ, Moran JE, Niall JF, Ryan GB. Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology? Br Med J. 1982 Sep;285(6342):606. Jennette JC, Falk RJ. B cell-mediated pathogenesis of ANCA-mediated vasculitis. Semin Immunopathol. 2014 May;36:327–38. Kain R, Exner M, Brandes R, Ziebermayr R, Cunningham D, Alderson CA, et al. Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis. Nat Med. 2008 Oct;14(10):1088–96. Pendergraft WF, Preston GA, Shah RR, Tropsha A, Carter CW Jr, Jennette JC, et al. Autoimmunity is triggered by cPR-3(105-201), a protein complementary to human autoantigen proteinase-3. Nat Med. 2004 Jan;10(1):72–9. Jennette JC, Falk RJ, Hu P, Xiao H. Pathogenesis of antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis. Annu Rev Pathol. 2013 Jan;8:139–60. Yang J, Bautz DJ, Lionaki S, Hogan SL, Chin H, Tisch RM, et al. ANCA patients have T cells responsive to complementary PR-3 antigen. Kidney Int. 2008 Nov;74(9):1159–69. Noone D, Hebert D, Licht C. Pathogenesis and treatment of ANCA-associated vasculitis-a role for complement. Pediatr Nephrol. 2018 Jan;33(1):1–11. Daigo N, Sakiko M, Utano T, Akihiro I. Pathogenesis and therapeutic interventions for ANCA-associated vasculitis. Nat Rev Rheum. 2019 Feb;15(2):91–101. Kessenbrock K, Krumbholz M, Schönermarck U, Back W, Gross WL, Werb Z, et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med. 2009 Jun;15(6):623–5. Wang H, Wang C, Zhao MH, Chen M. Neutrophil extracellular traps can activate alternative complement pathways. Clin Exp Immunol. 2015 Sept;181(3):518–27. Dudreuilh C, Fakhouri F, Vigneau C, Augusto JF, Machet MC, Rabot N, et al. The presence of renal IgG deposits in necrotizing crescentic glomerulonephritis associated with ANCA Is not related to worse renal clinical outcomes. Kidney Dis. 2020 Mar;6(2):98–108. Fauci A, Wolff S. Wegener’s granulomatosis: studies in eighteen patients and a review of the literature. 1973. Medicine. 1994 Nov;73(6):315–24. van Paassen P, Tervaert JW, Heeringa P. Mechanisms of vasculitis: how Pauci-Immune is ANCA-associated renal vasculitis? Nephron Exp Nephrol. 2007;105(1):e10–6. Daha NA, Banda NK, Roos A, Beurskens FJ, Bakker JM, Daha MR, et al. Complement activation by (auto-) antibodies. Mol Immunol. 2011 Aug;48(14):1656–65. Sörman A, Zhang L, Ding Z, Heyman B. How antibodies use complement to regulate antibody responses. Mol Immunol. 2014 Oct;61(2):79–88. Xiao H, Schreiber A, Heeringa P, Falk RJ, Jennette JC. Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies. Am J Pathol. 2007 Jan;170(1):52–64. Xiao H, Dairaghi DJ, Powers JP, Ertl LS, Baumgart T, Wang Y, et al. C5a receptor (CD88) blockade protects against MPO-ANCA GN. J Am Soc Nephrol. 2014 Feb;25(2):225–31. Schreiber A, Xiao H, Jennette JC, Schneider W, Luft FC, Kettritz R. C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis. J Am Soc Nephrol. 2009 Feb;20(2):289–98. Hao J, Meng LQ, Xu PC, Chen M, Zhao MH. p38MAPK, ERK and PI3K signaling pathways are involved in C5a-primed neutrophils for ANCA-mediated activation. PLoS One. 2012;7(5):e38317. Gou SJ, Yuan J, Wang C, Zhao MH, Chen M. Alternative complement pathway activation products in urine and kidneys of patients with ANCA-associated GN. Clin J Am Soc Nephrol. 2013 Nov;8(11):1884–91. Gou SJ, Yuan J, Chen M, Yu F, Zhao MH. Circulating complement activation in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Kidney Int. 2013 Jan;83(1):129–37. Wu EY, McInnis EA, Boyer-Suavet S, Mendoza CE, Aybar LT, Kennedy KB, et al. Measuring circulating complement activation products in myeloperoxidase- and proteinase 3-antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheumatol. 2019 Nov;71(11):1894–903. Ohlsson S, Holm L, Hansson C, Ohlsson SM, Gunnarsson L, Pettersson Å, et al. Neutrophils from ANCA-associated vasculitis patients show an increased capacity to activate the complement system via the alternative pathway after ANCA stimulation. PLoS One. 2019 Jun;14(6):e0218272. Brilland B, Garnier AS, Chevailler A, Jeannin P, Subra JF, Augusto JF. Complement alternative pathway in ANCA-associated vasculitis: two decades from bench to bedside. Autoimmun Rev. 2020 Jan;19(1):102424. Jennette JC, Xiao H, Hu P. Complement in ANCA-associated vasculitis. Semin Nephrol. 2013 Nov;33(6):557–64. Jayne D. Complement inhibition in ANCA vasculitis. Néphrol Thér. 2019 Nov;15(6):409–12. Manthey HD, Woodruff TM, Taylor SM, Monk PN. Complement component 5a (C5a). Int J Biochem Cell Biol. 2009 Nov;41(11):2114–7. Raby AC, Holst B, Davies J, Colmont C, Laumonnier Y, Coles B, et al. TLR activation enhances C5a-induced pro-inflammatory responses by negatively modulating the second C5a receptor, C5L2. Eur J Immunol. 2011 Sept;41(9):2741–52. Hao J, Huang YM, Zhao MH, Chen M. The interaction between C5a and sphingosine-1-phosphate in neutrophils for antineutrophil cytoplasmic antibody mediated activation. Arthritis Res Ther. 2014 Jul;16(4):R142. Kallenberg CG, Heeringa P. Complement is crucial in the pathogenesis of ANCA-associated vasculitis. Kidney Int. 2013 Jan;83(1):16–8. Camous L, Roumenina L, Bigot S, Brachemi S, Frémeaux-Bacchi V, Lesavre P, et al. Complement alternative pathway acts as a positive feedback amplification of neutrophil activation. Blood. 2011 Jan;117(4):1340–9. Chen SF, Wang FM, Li ZY, Yu F, Chen M, Zhao MH. The functional activities of complement factor H are impaired in patients with ANCA-positive vasculitis. Clin Immunol. 2017 Feb;175:41–50. Chen SF, Wang FM, Li ZY, Yu F, Chen M, Zhao MH. Complement factor H inhibits anti-neutrophil cytoplasmic autoantibody-induced neutrophil activation by interacting with neutrophils. Front Immunol. 2018 Mar;9:559. Cheng L, Gou SJ, Qiu HY, Ma L, Fu P. Complement regulatory proteins in kidneys of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Clin Exp Immunol. 2018 Jan;191(1):116–24. Deshayes S, Aouba A, Khoy K, Mariotte D, Lobbedez NM, Martin Silva N. Hypocomplementemia is associated with worse renal survival in ANCA-positive granulomatosis with polyangiitis and microscopic polyangiitis. PLoS One. 2018 Apr;13(4):e0195680. Crnogorac M, Horvatic I, Kacinari P, Galesic D, Galesic K. Serum C3 complement levels in ANCA associated vasculitis at diagnosis is a predictor of patient and renal outcome. J Nephrol. 2018 Apr;31(2):257–62. Augusto JF, Langs V, Demiselle J, Lavigne C, Brilland B, Duveau A, et al. Low serum complement C3 levels at diagnosis of renal ANCA-associated vasculitis is associated with poor prognosis. PLoS One. 2016 Jul;11(7):e0158871. Choi H, Kim Y, Jung SM, Song JJ, Park YB, Lee SW. Low serum complement 3 level is associated with severe ANCA-associated vasculitis at diagnosis. Clin Exp Nephrol. 2019 Feb;23(2):223–30. García L, Pena CE, Maldonado RÁ, Costi C, Mamberti M, Martins E, et al. Increased renal damage in hypocomplementemic patients with ANCA-associated vasculitis: retrospective cohort study. Clin Rheumatol. 2019 Oct;38(10):2819–24. Hirayama K, Kobayashi M, Usui J, Arimura Y, Sugiyama H, Nitta K, et al. Pulmonary involvements of anti-neutrophil cytoplasmic autoantibody-associated renal vasculitis in Japan. Nephrol Dial Transplant. 2015 Apr;30 Suppl 1:i83–93. Molad Y, Tovar A, Ofer-Shiber S. Association of low serum complement C3 with reduced patient and renal survival in antimyeloperoxidase-associated small-vessel vasculitis. Nephron Clin Pract. 2014;126(1):67–74. Fukui S, Iwamoto N, Umeda M, Nishino A, Nakashima Y, Koga T, et al. Antineutrophilic cytoplasmic antibody-associated vasculitis with hypocomplementemia has a higher incidence of serious organ damage and a poor prognosis. Medicine. 2016;95(37):e4871. Hilhorst M, van Paassen P, van Rie H, Bijnens N, Heerings-Rewinkel P, van Breda Vriesman P, et al. Complement in ANCA-associated glomerulonephritis. Nephrol Dial Transplant. 2017 Aug;32(8):1302–13. Lin W, Shen C, Zhong Y, Ooi JD, Eggenhuizen P, Zhou YO, et al. Glomerular immune deposition in MPO-ANCA associated glomerulonephritis is associated with poor renal survival. Front Immunol. 2021 Mar;12:625672. Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010 Jul;363(3):221–322. Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010 Jul;363(3):211–20. Kettritz R. Vasculitis: a CLEAR argument for targeting complement in ANCA vasculitis. Nat Rev Nephrol. 2017 Aug;13(8):448–50. Bekker P, Dairaghi D, Seitz L, Leleti M, Wang Y, Ertl L, et al. Characterization of pharmacologic and pharmacokinetic properties of CCX168, a potent and selective orally administered complement 5a receptor inhibitor, based on preclinical evaluation and randomized phase 1 clinical study. PLoS One. 2016 Oct;11(10):e0164646. Jayne DRW, Bruchfeld AN, Harper L, Schaier M, Venning MC, Hamilton P, et al. Randomized trial of C5a receptor inhibitor Avacopan in ANCA-associated vasculitis. J Am Soc Nephrol. 2017 Sep;28(9):2756–67. Merkel PA, Niles J, Jimenez R, Spiera RF, Rovin BH, Bomback A, et al. Adjunctive treatment with Avacopan, an Oral C5a receptor inhibitor, in patients with antineutrophil cytoplasmic antibody-associated vasculitis. ACR Open Rheumatol. 2020 Nov;2(11):662–71. Jayne DRW, Merkel PA, Schall TJ, Bekker P, Study Group ADVOCATE. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med. 2021 Feb;384(7):599–609. Anders HJ, Nakazawa D. Being an ADVOCATE for People with ANCA Vasculitis. Clin J Am Soc Nephrol. 2021 Oct;16(10):1581–3. Guillevin L, Pagnoux C, Karras A, Khouatra C, Aumaître O, Cohen P, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med. 2014 Nov;371(19):1771–80. Charles P, Terrier B, Perrodeau E, Cohen P, Faguer S, Huart A, et al. Comparison of individually tailored versus fixed-schedule rituximab regimen to maintain ANCA-associated vasculitis remission: results of a multicentre, randomised controlled, phase III trial (MAINRITSAN2). Ann Rheum Dis. 2018 Aug;77(8):1143–9. Charles P, Perrodeau E, Samson M, Bonnotte B, Néel A, Agard C, et al. Long-term rituximab use to maintain remission of antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2020 Aug;173(3):179–87. Cortazar FB, Pendergraft WF, Wenger J, Owens CT, Laliberte K, Niles JL. Effect of continuous B cell depletion with rituximab on pathogenic autoantibodies and total IgG levels in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheumatol. 2017 May;69(5):1045–53. Gulati K, Edwards H, Prendecki M, Cairns TD, Condon M, Galliford J, et al. Combination treatment with rituximab, low-dose cyclophosphamide and plasma exchange for severe antineutrophil cytoplasmic antibody-associated vasculitis. Kidney Int. 2021 Dec;100(6):1316–24. Roccatello D, Sciascia S, Rossi D, Alpa M, Naretto C, Radin M, et al. The “4 plus 2” rituximab protocol makes maintenance treatment unneeded in patients with refractory ANCA-associated vasculitis: a 10 years observation study. Oncotarget. 2017 May;8(32):52072–7. Rovin BH, Caster DJ, Cattran DC, Gibson KL, Hogan JJ, Moeller MJ, et al. Management and treatment of glomerular diseases (part 2): conclusions from a kidney disease – improving global outcomes (KDIGO) Controversies Conference. Kidney Int. 2019 Feb;95(2):281–95. Manenti L, Urban ML, Maritati F, Galetti M, Vaglio A. Complement blockade in ANCA-associated vasculitis: an index case, current concepts and future perspectives. Intern Emerg Med. 2017 Sept;12(6):727–31. Sethi S, Zand L, De Vriese AS, Specks U, Vrana JA, Kanwar S, et al. Complement activation in pauci-immune necrotizing and crescentic glomerulonephritis: results of a proteomic analysis. Nephrol Dial Transpl. 2017 Jan;32(Suppl_1):i139–45. Article / Publication Details

First-Page Preview

Received: February 01, 2022
Accepted: May 04, 2022
Published online: June 03, 2022

Number of Print Pages: 8
Number of Figures: 1
Number of Tables: 2

ISSN: 1420-4096 (Print)
eISSN: 1423-0143 (Online)

For additional information: https://www.karger.com/KBR

Figures Tables