Efficacy of immunosuppressive treatment of Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is complicated by its toxicity. With the replacement of cyclophosphamide with rituximab, serious adverse events seem to be associated especially with high-dose corticosteroids. Activation of alternative complement pathway plays an important role in the pathogenesis of AAV. Avacopan (C5a receptor inhibitor) was demonstrated to have at least similar efficacy and better safety (in terms of corticosteroid-related adverse events) compared with high-dose corticosteroids in the induction treatment of AAV. Other modes of the inhibition of alternative complement pathway are currently tested in AAV or could be considered on the basis of the experience in other glomerular diseases.

Department of Nephrology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czechia

See more in PubMed

Flossmann O, Berden A, de Groot K, Hagen C, Harper L, Heijl C, et al. . Long-Term Patient Survival in ANCA-Associated Vasculitis. Ann Rheum Dis (2011) 70:488–94. doi: 10.1136/ard.2010.137778 PubMed DOI

Faurschou M, Sorensen IJ, Mellemkjaer L, Loft AG, Thomsen BS, Tvede N, et al. . Malignancies in Wegener´s Granulomatosis: Incidence and Relation to Cyclophosphamide Therapy in a Cohort of 293 Patients. J Rheumatol (2008) 35:100–5. PubMed

Van Daalen E, Rizzo R, Kronbichler A, Wolterbeek R, Bruijn JA, Jayne DR, et al. . Effect of Rituximab on Malignancy Risk in Patients With ANCA-Associated Vasculitis. Ann Rheum Dis (2016) 76:1064–9. doi: 10.1136/annrheumdis-2016-209925 PubMed DOI

Jones RB, Cohen 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) 363:211–20. doi: 10.1056/NEJMoa0909169 PubMed DOI

Walsh M, Merkel PA, Peh CA, Szpirt W, Guillevin L, Pusey CD, et al. . Plasma Exchange and Glucocorticoid Dosing in the Treatment of Anti-Neutrophil Cytoplasm Antibody Associated Vasculitis (PEXIVAS): Protocol for a Randomized Controlled Trial. Trials (2013) 14:73. doi: 10.1186/1745-6215-14-73 PubMed DOI PMC

Walsh M, Merkel PA, Peh CA, Szpirt WM, Puéchal X, Fujimoto S, et al. . Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis. N Engl J Med (2020) 382:622–31. doi: 10.1186/1745-6215-14-73 PubMed DOI PMC

Huscher D, Thiele K, Gromnica-Ihle E, Hein G, Demary W, Dreher R, et al. . Dose-Related Patterns of Glucocorticoid-Induced Side Effects. Ann Rheum Dis (2009) 68:1119–24. doi: 10.1136/ard.2008.092163 PubMed DOI

Jennette JC, Xiao H, Falk RJ. Pathogenesis of Vascular Inflammation by Anti-Neutrophil Cytoplasmic Antibodies. J Am Soc Nephrol (2006) 17:1235–42. doi: 10.1681/ASN.2005101048 PubMed DOI

Ronco P, Verroust P, Mignon F, Kourilsky O, Vanhille P, Meyrier A, et al. . Immunopathological Studies of Polyarteritis Nodosa and Wegener´s Granulomatosis: A Report of 43 Patients With 51 Renal Biopsies. Q J Med (1983) 206:212–23. PubMed

Haas M, Eustace JA. Immune Complex Deposits in ANCA-Associated Crescentic Glomerulonephritis: A Study of 126 Cases. Kidney Int (2004) 65:2145–52. doi: 10.1111/j.1523-1755.2004.00632.x PubMed DOI

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) 32:1302–13. doi: 10.1093/ndt/gfv288 PubMed DOI

Augusto J-F, 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) 11:e0158871. doi: 10.1371/journal.pone.0158871 PubMed DOI PMC

Crnogorac M, Horvatic I, Kacinari P, Galesic Ljubanovic D, Galesic K. Serum C3 Complement Levels in ANCA Associated Vasculitis at Diagnosis Is a Predictor of Patient and Renal Outcome. J Nephrol (2018) 31:257–62. doi: 10.1007/s40620-017-0445-3 PubMed DOI

Deshayes S, Aouba A, Khoy K, Mariotte D, Lobbedez T, Matin Silva N. Hypocomplementemia is Associated With Worse Renal Survival in ANCA-Positive Granulomatosis With Polyangiitis and Microscopic Polyangiitis. PLos One (2018) 13:e0195680. doi: 10.1371/journal.pone.0195680 PubMed DOI PMC

Gou S-J, Yuan J, Chen M, Yu F, Zhao MH. Circulating Complement Activation in Patients With Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis. Kidney Int (2012) 83:129–37. doi: 10.1038/ki.2012.313 PubMed DOI

Gou S-J, 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) 8:1884–91. doi: 10.2215/CJN.02790313 PubMed DOI PMC

Hakroush S, Tampe D, Korsten P, Ströbel P, Tampe B. Complement Components C3 and C4 Indicate Vasculitis Manifestations to Distinct Renal Compartments in ANCA-Associated Glomerulonephritis. Int J Mol Sci (2021) 22:6588. doi: 10.3390/ijms22126588 PubMed DOI PMC

Moiseev S, Lee JM, Zykova A, Bulanov N, Novikov P, Gitel E, et al. . The Alternative Complement Pathway in ANCA-Associated Vasculitis: Further Evidence and a Meta-Analysis. Clin Exp Immunol (2020) 202(3):394–402. doi: 10.1111/cei.13498 PubMed DOI PMC

Johansson L, Berglin E, Eriksson O, Mohammad AJ, Dahlqvist J, Rantapää-Dahlqvist S. Complement Activation Prior to Symptom Onset in Myeloperoxidase ANCA-Associated Vasculitis But Not Proteinase 3 ANCA Associated Vasculitis - A Swedish Biobank Study. Scand J Rheumatol (2022) 51:214–9. doi: 10.1080/03009742.2021.1989814 PubMed DOI

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) 71:1894–903. doi: 10.1002/art.41011 PubMed DOI PMC

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) 20:289–98. doi: 10.1681/ASN.2008050497 PubMed DOI PMC

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) 14:e0218272. doi: 10.1371/journal.pone.0218272 PubMed DOI PMC

Xiao H, Schreiber A, Heeringa P, Falk RJ, Jennette C. Alternative Complement Pathway in the Pathogenesis of Disease Mediated by Anti-Neutrophil Cytoplasmic Autoantibodies. Am J Pathol (2007) 170:52–64. doi: 10.2353/ajpath.2007.060573 PubMed DOI PMC

Huugen D, van Esch A, Xiao H, Peutz-Kootstra CJ, Buurman WA, Tervaert JW, et al. . Inhibition of Complement Factor C5 Protects Against Anti-Myeloperoxidase Antibody-Mediated Glomerulonephritis in Mice. Kidney Int (2007) 71:646–54. doi: 10.1038/sj.ki.5002103 PubMed DOI

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) 25:225–31. doi: 10.1681/ASN.2013020143 PubMed DOI PMC

Hao J, Wang C, Yuan J, Chen M, Zhao MH. A Pro-Inflammatory Role of C5L2 in C5a-Primed Neutrophils for ANCA-Induced Activation. PLos One (2013) 8:e66305. doi: 10.1371/journal.pone.0066305 PubMed DOI PMC

Bekker P, Dairaghi D, Seitz L, Leleti M, Wang Y, Ertl L, et al. . Characterization of Pharmacologic and Pharmacokinetic Properoperties of CCX168, a Potent and Selective Orally Adminisered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase1 Clinical Study. PLos One (2016) 11(10):e0164646. doi: 10.1371/journal.pone.0164646 PubMed DOI PMC

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) 12(6):727–31. doi: 10.1007/s11739-017-1636-6 PubMed DOI

Ribes D, Belliere J, Piedrafita A, Faguer S. Glucocorticoid-Free Induction Regimen in Severe ANCA-Associated Vasculitis Using a Combination of Rituximab and Eculizumab. Rheumatol (Oxford) (2019) 58(12):2335–7. doi: 10.1093/rheumatology/kez190 PubMed DOI

Chen M, Jayne DRW, Zhao M-H. Complement in ANCA-Associated Vasculitis: Mechanisms and Implications for Management. Nat Nephrol Rev (2017) 13:359–67. doi: 10.1038/nrneph.2017.37 PubMed DOI

Jayne DRW, Bruchfeld AN, Haper 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) 28:2756–67. doi: 10.1681/ASN.2016111179 PubMed DOI PMC

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) 2(11):662–71. doi: 10.1002/acr2.11185 PubMed DOI PMC

Jayne DRW, Merkel PA, Schall TJ, Bekker P. ADVOCATE Study Group: Avacopan for the Treatment of ANCA-Associated Vasculitis. N Engl J Med (2021) 384:599–609. doi: 10.1056/NEJMoa2023386 PubMed DOI

Lee A. Avacopan: First Approval. Drugs (2022) 82:79–85. doi: 10.1007/s40265-021-01643-6 PubMed DOI

Barratt J, Weitz I. Complement Factor D as a Strategic Target for Regulating the Alternative Complement Pathway. Front Immunol (2021) 12:712572. doi: 10.3389/fimmu.2021.712572 PubMed DOI PMC

Tesar V, Hruskova Z. Avacopan in the Treatment of ANCA-Associated Vasculitis. Expert Opin Investig Drugs (2018) 27:491–6. doi: 10.1080/13543784.2018.1472234 PubMed DOI