Advertisement

Pediatric Nephrology

, Volume 33, Issue 1, pp 1–11 | Cite as

Pathogenesis and treatment of ANCA-associated vasculitis—a role for complement

  • Damien Noone
  • Diane Hebert
  • Christoph Licht
Review

Abstract

The antineutrophil cytoplasm autoantibody (ANCA)-associated vasculitides (AAV), although rare in childhood, can have devastating effects on affected organs, especially the kidney. In this review we present an update on the pathogenesis and treatment of ANCA vasculitis, with a particular emphasis on the role of the alternative pathway of complement. The rationale and evidence for the current treatment strategies are summarized. Targeting the activation of neutrophils by the anaphylatoxin C5a may serve as an additional therapeutic strategy, however the results of clinical studies are awaited.

Keywords

Anti-neutrophil cytoplasm antibody Granulomatosis with polyangiitis Microscopic polyangiitis Eosinophilic granulomatosis with polyangiitis Children treatment 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare there are no conflicts.

References

  1. 1.
    Twilt M, Benseler S (2014) Childhood antineutrophil cytoplasmic antibodies associated vasculitides. Curr Opin Rheumatol 26:50–55CrossRefPubMedGoogle Scholar
  2. 2.
    Westman K, Flossmann O, Gregorini G (2015) The long-term outcomes of systemic vasculitis. Nephrol Dial Transplant 30:i60–i66PubMedGoogle Scholar
  3. 3.
    Rottem M, Fauci AS, Hallahan CW, Kerr GS, Lebovics R, Leavitt RY, Hoffman GS (1993) Wegener granulomatosis in children and adolescents: clinical presentation and outcome. J Pediatr 122:26–31CrossRefPubMedGoogle Scholar
  4. 4.
    Arulkumaran N, Jawad S, Smith SW, Harper L, Brogan P, Pusey CD, Salama AD (2011) Long-term outcome of paediatric patients with ANCA vasculitis. Pediatr Rheumatol Online J 9:12CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Noone DG, Twilt M, Hayes WN, Thorner PS, Benseler S, Laxer RM, Parekh RS, Hebert D (2014) The new histopathologic classification of ANCA-associated GN and its association with renal outcomes in childhood. Clin J Am Soc Nephrol 9:1684–1691CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Akikusa JD, Schneider R, Harvey EA, Hebert D, Thorner PS, Laxer RM, Silverman ED (2007) Clinical features and outcome of pediatric Wegener’s granulomatosis. Arthritis Rheum 57:837–844CrossRefPubMedGoogle Scholar
  7. 7.
    Sacri AS, Chambaraud T, Ranchin B, Florkin B, See H, Decramer S, Flodrops H, Ulinski T, Allain-Launay E, Boyer O, Dunand O, Fischbach M, Hachulla E, Pietrement C, Le Pogamp P, Stephan JL, Belot A, Nivet H, Nobili F, Guillevin L, Quartier P, Deschenes G, Salomon R, Essig M, Harambat J (2015) Clinical characteristics and outcomes of childhood-onset ANCA-associated vasculitis: a French nationwide study. Nephrol Dial Transplant 30[Suppl 1]:i104–i112PubMedGoogle Scholar
  8. 8.
    Ozen S, Pistorio A, Iusan SM, Bakkaloglu A, Herlin T, Brik R, Buoncompagni A, Lazar C, Bilge I, Uziel Y, Rigante D, Cantarini L, Hilario MO, Silva CA, Alegria M, Norambuena X, Belot A, Berkun Y, Estrella AI, Olivieri AN, Alpigiani MG, Rumba I, Sztajnbok F, Tambic-Bukovac L, Breda L, Al-Mayouf S, Mihaylova D, Chasnyk V, Sengler C, Klein-Gitelman M, Djeddi D, Nuno L, Pruunsild C, Brunner J, Kondi A, Pagava K, Pederzoli S, Martini A, Ruperto N, Paediatric Rheumatology International Trials Organisation (PRINTO) (2010) EULAR/PRINTO/PRES criteria for Henoch-Schonlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: final classification criteria. Ann Rheum Dis 69:798–806CrossRefPubMedGoogle Scholar
  9. 9.
    Eleftheriou D, Batu ED, Ozen S, Brogan PA (2015) Vasculitis in children. Nephrol Dial Transplant 30:i94–i103PubMedGoogle Scholar
  10. 10.
    Cabral DA, Uribe AG, Benseler S, O’Neil KM, Hashkes PJ, Higgins G, Zeft AS, Lovell DJ, Kingsbury DJ, Stevens A, McCurdy D, Chira P, Abramson L, Arkachaisri T, Campillo S, Eberhard A, Hersh AO, Huber AM, Kim S, Klein-Gitelman M, Levy DM, Li SC, Mason T, Dewitt EM, Muscal E, Nassi L, Reiff A, Schikler K, Singer NG, Wahezi D, Woodward A, ARChiVe (A Registry for Childhood Vasculitis: e-entry) Investigators Network (2009) Classification, presentation, and initial treatment of Wegener’s granulomatosis in childhood. Arthritis Rheum 60:3413–3424CrossRefPubMedGoogle Scholar
  11. 11.
    Siomou E, Tramma D, Bowen C, Milford DV (2012) ANCA-associated glomerulonephritis/systemic vasculitis in childhood: clinical features-outcome. Pediatr Nephrol 27:1911–1920CrossRefPubMedGoogle Scholar
  12. 12.
    Cabral DA, Canter DL, Muscal E, Nanda K, Wahezi DM, Spalding SJ, Twilt M, Benseler SM, Campillo S, Charuvanij S, Dancey P, Eberhard BA, Elder ME, Hersh A, Higgins G, Huber AM, Khubchandani R, Kim S, Klein-Gitelman M, Kostik M, Lawson E, Lee T, Lubieniecka JM, McCurdy D, Moorthy LN, Morishita KA, Nielsen SM, O’Neil KM, Reiff A, Ristic G, Robinson AB, Sarmiento A, Shenoi S, Toth MB, Van Mater H, Wagner-Weiner L, Weiss JE, White AJ, Yeung RS, ARChiVe Investigators Network within the PedVas initiative (2016) Comparing presenting clinical features of 48 children with microscopic polyangiitis (MPA) against 183 having granulomatosis with polyangiitis (GPA). An ARChiVe study. Arthritis Rheumatol. doi: 10.1002/art.39729 PubMedGoogle Scholar
  13. 13.
    Zwerina J, Eger G, Englbrecht M, Manger B, Schett G (2009) Churg-Strauss syndrome in childhood: a systematic literature review and clinical comparison with adult patients. Semin Arthritis Rheum 39:108–115CrossRefPubMedGoogle Scholar
  14. 14.
    Davies DJ, Moran JE, Niall JF, Ryan GB (1982) Segmental necrotising glomerulonephritis with antineutrophil antibody: possible arbovirus aetiology? Br Med J (Clin Res Ed) 285:606CrossRefGoogle Scholar
  15. 15.
    Savige J, Gillis D, Benson E, Davies D, Esnault V, Falk RJ, Hagen EC, Jayne D, Jennette JC, Paspaliaris B, Pollock W, Pusey C, Savage CO, Silvestrini R, van der Woude F, Wieslander J, Wiik A (1999) International consensus statement on testing and reporting of antineutrophil cytoplasmic antibodies (ANCA). Am J Clin Pathol 111:507–513CrossRefPubMedGoogle Scholar
  16. 16.
    Radice A, Bianchi L, Sinico RA (2013) Anti-neutrophil cytoplasmic autoantibodies: methodological aspects and clinical significance in systemic vasculitis. Autoimmun Rev 12:487–495CrossRefPubMedGoogle Scholar
  17. 17.
    Bonaci-Nikolic B, Andrejevic S, Pavlovic M, Dimcic Z, Ivanovic B, Nikolic M (2010) Prolonged infections associated with antineutrophil cytoplasmic antibodies specific to proteinase 3 and myeloperoxidase: diagnostic and therapeutic challenge. Clin Rheumatol 29:893–904CrossRefPubMedGoogle Scholar
  18. 18.
    Sugiyama H, Sahara M, Imai Y, Ono M, Okamoto K, Kikuchi K, Nagai R (2009) Infective endocarditis by Bartonella quintana masquerading as antineutrophil cytoplasmic antibody-associated small vessel vasculitis. Cardiology 114:208–211Google Scholar
  19. 19.
    Lyons PA, Rayner TF, Trivedi S, Holle JU, Watts RA, Jayne DR, Baslund B, Brenchley P, Bruchfeld A, Chaudhry AN, Cohen Tervaert JW, Deloukas P, Feighery C, Gross WL, Guillevin L, Gunnarsson I, Harper L, Hruskova Z, Little MA, Martorana D, Neumann T, Ohlsson S, Padmanabhan S, Pusey CD, Salama AD, Sanders JS, Savage CO, Segelmark M, Stegeman CA, Tesar V, Vaglio A, Wieczorek S, Wilde B, Zwerina J, Rees AJ, Clayton DG, Smith KG (2012) Genetically distinct subsets within ANCA-associated vasculitis. N Engl J Med 367:214–223CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Savage CO (2011) Pathogenesis of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis. Clin Exp Immunol 164[Suppl 1]:23–26CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    van Timmeren MM, Heeringa P (2012) Pathogenesis of ANCA-associated vasculitis: recent insights from animal models. Curr Opin Rheumatol 24:8–14CrossRefPubMedGoogle Scholar
  22. 22.
    Kallenberg CG (2014) Advances in pathogenesis and treatment of ANCA-associated vasculitis. Discov Med 18:195–201PubMedGoogle Scholar
  23. 23.
    Jennette JC, Falk RJ (2014) B cell-mediated pathogenesis of ANCA-mediated vasculitis. Semin Immunopathol 36:327–338CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Jennette JC, Falk RJ (2014) Pathogenesis of antineutrophil cytoplasmic autoantibody-mediated disease. Nat Rev Rheumatol 10:463–473CrossRefPubMedGoogle Scholar
  25. 25.
    Kain R, Exner M, Brandes R, Ziebermayr R, Cunningham D, Alderson CA, Davidovits A, Raab I, Jahn R, Ashour O, Spitzauer S, Sunder-Plassmann G, Fukuda M, Klemm P, Rees AJ, Kerjaschki D (2008) Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis. Nat Med 14:1088–1096CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Pendergraft WF 3rd, Preston GA, Shah RR, Tropsha A, Carter CW Jr, Jennette JC, Falk RJ (2004) Autoimmunity is triggered by cPR-3(105–201), a protein complementary to human autoantigen proteinase-3. Nat Med 10:72–79CrossRefPubMedGoogle Scholar
  27. 27.
    Jennette JC, Falk RJ, Hu P, Xiao H (2013) Pathogenesis of antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis. Annu Rev Pathol 8:139–160CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Yang J, Bautz DJ, Lionaki S, Hogan SL, Chin H, Tisch RM, Schmitz JL, Pressler BM, Jennette JC, Falk RJ, Preston GA (2008) ANCA patients have T cells responsive to complementary PR-3 antigen. Kidney Int 74:1159–1169CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Jarrot PA, Kaplanski G (2016) Pathogenesis of ANCA-associated vasculitis: an update. Autoimmun Rev 15:704–713CrossRefPubMedGoogle Scholar
  30. 30.
    Culton DA, Nicholas MW, Bunch DO, Zhen QL, Kepler TB, Dooley MA, Mohan C, Nachman PH, Clarke SH (2007) Similar CD19 dysregulation in two autoantibody-associated autoimmune diseases suggests a shared mechanism of B-cell tolerance loss. J Clin Immunol 27:53–68CrossRefPubMedGoogle Scholar
  31. 31.
    Morgan MD, Day CJ, Piper KP, Khan N, Harper L, Moss PA, Savage CO (2010) Patients with Wegener’s granulomatosis demonstrate a relative deficiency and functional impairment of T-regulatory cells. Immunology 130:64–73CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Nogueira E, Hamour S, Sawant D, Henderson S, Mansfield N, Chavele KM, Pusey CD, Salama AD (2010) Serum IL-17 and IL-23 levels and autoantigen-specific Th17 cells are elevated in patients with ANCA-associated vasculitis. Nephrol Dial Transplant 25:2209–2217CrossRefPubMedGoogle Scholar
  33. 33.
    Gan PY, Steinmetz OM, Tan DS, O’Sullivan KM, Ooi JD, Iwakura Y, Kitching AR, Holdsworth SR (2010) Th17 cells promote autoimmune anti-myeloperoxidase glomerulonephritis. J Am Soc Nephrol 21:925–931CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Wilde B, Thewissen M, Damoiseaux J, Knippenberg S, Hilhorst M, van Paassen P, Witzke O, Cohen Tervaert JW (2013) Regulatory B cells in ANCA-associated vasculitis. Ann Rheum Dis 72:1416–1419CrossRefPubMedGoogle Scholar
  35. 35.
    Schonermarck U, Csernok E, Gross WL (2015) Pathogenesis of anti-neutrophil cytoplasmic antibody-associated vasculitis: challenges and solutions 2014. Nephrol Dial Transplant 30[Suppl 1]:i46–52PubMedGoogle Scholar
  36. 36.
    Kessenbrock K, Krumbholz M, Schonermarck U, Back W, Gross WL, Werb Z, Grone HJ, Brinkmann V, Jenne DE (2009) Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med 15:623–625CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Sangaletti S, Tripodo C, Chiodoni C, Guarnotta C, Cappetti B, Casalini P, Piconese S, Parenza M, Guiducci C, Vitali C, Colombo MP (2012) Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity. Blood 120:3007–3018CrossRefPubMedGoogle Scholar
  38. 38.
    Nakazawa D, Tomaru U, Ishizu A (2013) Possible implication of disordered neutrophil extracellular traps in the pathogenesis of MPO-ANCA-associated vasculitis. Clin Exp Nephrol 17:631–633CrossRefPubMedGoogle Scholar
  39. 39.
    Nakazawa D, Shida H, Tomaru U, Yoshida M, Nishio S, Atsumi T, Ishizu A (2014) Enhanced formation and disordered regulation of NETs in myeloperoxidase-ANCA-associated microscopic polyangiitis. J Am Soc Nephrol 25:990–997CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Leffler J, Martin M, Gullstrand B, Tyden H, Lood C, Truedsson L, Bengtsson AA, Blom AM (2012) Neutrophil extracellular traps that are not degraded in systemic lupus erythematosus activate complement exacerbating the disease. J Immunol 188:3522–3531CrossRefPubMedGoogle Scholar
  41. 41.
    Wang H, Wang C, Zhao MH, Chen M (2015) Neutrophil extracellular traps can activate alternative complement pathways. Clin Exp Immunol 181:518–527CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Fauci AS, Wolff SM (1973) Wegener’s granulomatosis: studies in eighteen patients and a review of the literature. Medicine 52:535–561CrossRefPubMedGoogle Scholar
  43. 43.
    Hollander D, Manning RT (1967) The use of alkylating agents in the treatment of Wegener’s granulomatosis. Ann Intern Med 67:393–398CrossRefPubMedGoogle Scholar
  44. 44.
    Hoffman GS, Kerr GS, Leavitt RY, Hallahan CW, Lebovics RS, Travis WD, Rottem M, Fauci AS (1992) Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 116:488–498CrossRefPubMedGoogle Scholar
  45. 45.
    Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Dadoniene J, Ekstrand A, Gaskin G, Gregorini G, de Groot K, Gross W, Hagen EC, Mirapeix E, Pettersson E, Siegert C, Sinico A, Tesar V, Westman K, Pusey C, European Vasculitis Study Group (2003) A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 349:36–44CrossRefPubMedGoogle Scholar
  46. 46.
    Lockwood CM, Pinching AJ, Sweny P, Rees AJ, Pussell B, Uff J, Peters DK (1977) Plasma-exchange and immunosuppression in the treatment of fulminating immune-complex crescentic nephritis. Lancet 1:63–67CrossRefPubMedGoogle Scholar
  47. 47.
    Pusey CD, Rees AJ, Evans DJ, Peters DK, Lockwood CM (1991) Plasma exchange in focal necrotizing glomerulonephritis without anti-GBM antibodies. Kidney Int 40:757–763CrossRefPubMedGoogle Scholar
  48. 48.
    Szpirt WM (2015) Plasma exchange in antineutrophil cytoplasmic antibody-associated vasculitis—a 25-year perspective. Nephrol Dial Transplant 30:i146–i149PubMedGoogle Scholar
  49. 49.
    Jayne DR, Gaskin G, Rasmussen N, Abramowicz D, Ferrario F, Guillevin L, Mirapeix E, Savage CO, Sinico RA, Stegeman CA, Westman KW, van der Woude FJ, de Lind van Wijngaarden RA, Pusey CD, European Vasculitis Study Group (2007) Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol 18:2180–2188CrossRefPubMedGoogle Scholar
  50. 50.
    Walsh M, Catapano F, Szpirt W, Thorlund K, Bruchfeld A, Guillevin L, Haubitz M, Merkel PA, Peh CA, Pusey C, Jayne D (2011) Plasma exchange for renal vasculitis and idiopathic rapidly progressive glomerulonephritis: a meta-analysis. Am J Kidney Dis 57:566–574CrossRefPubMedGoogle Scholar
  51. 51.
    Walsh M, Merkel PA, Peh CA, Szpirt W, Guillevin L, Pusey CD, De Zoysa J, Ives N, Clark WF, Quillen K, Winters JL, Wheatley K, Jayne D, Investigators PEXIVAS (2013) Plasma exchange and glucocorticoid dosing in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis (PEXIVAS): protocol for a randomized controlled trial. Trials 14:73CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Wong L, Harper L, Little MA (2015) Getting the balance right: adverse events of therapy in anti-neutrophil cytoplasm antibody vasculitis. Nephrol Dial Transplant 30:i164–i170CrossRefPubMedGoogle Scholar
  53. 53.
    Twilt M, Benseler S, Cabral D (2012) Granulomatosis with polyangiitis in childhood. Curr Rheumatol Rep 14:107–115CrossRefPubMedGoogle Scholar
  54. 54.
    McGeoch L, Twilt M, Famorca L, Bakowsky V, Barra L, Benseler S, Cabral DA, Carette S, Cox GP, Dhindsa N, Dipchand C, Fifi-Mah A, Goulet M, Khalidi N, Khraishi MM, Liang P, Milman N, Pineau CA, Reich H, Samadi N, Shojania K, Taylor-Gjevre R, Towheed TE, Trudeau J, Walsh M, Yacyshyn E, Pagnoux C, Canadian Vasculitis research network (CanVasc) (2015) CanVasc recommendations for the management of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides—Executive summary. Can J Kidney Health Dis 2:43CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    McGeoch L, Twilt M, Famorca L, Bakowsky V, Barra L, Benseler SM, Cabral DA, Carette S, Cox GP, Dhindsa N, Dipchand CS, Fifi-Mah A, Goulet M, Khalidi N, Khraishi MM, Liang P, Milman N, Pineau CA, Reich HN, Samadi N, Shojania K, Taylor-Gjevre R, Towheed TE, Trudeau J, Walsh M, Yacyshyn E, Pagnoux C, Canadian Vasculitis Research Network (2016) CanVasc recommendations for the management of antineutrophil cytoplasm antibody-associated vasculitides. J Rheumatol 43:97–120CrossRefPubMedGoogle Scholar
  56. 56.
    Mukhtyar C, Guillevin L, Cid MC, Dasgupta B, de Groot K, Gross W, Hauser T, Hellmich B, Jayne D, Kallenberg CG, Merkel PA, Raspe H, Salvarani C, Scott DG, Stegeman C, Watts R, Westman K, Witter J, Yazici H, Luqmani R, European Vasculitis Study Group (2009) EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis 68:310–317CrossRefPubMedGoogle Scholar
  57. 57.
    Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Working Group (2012) KDIGO clinical practice guideline for glomerulonephritis. Kidney Int 2[Suppl 2]:139–274Google Scholar
  58. 58.
    Ntatsaki E, Carruthers D, Chakravarty K, D’Cruz D, Harper L, Jayne D, Luqmani R, Mills J, Mooney J, Venning M, Watts RA, BSR and BHPR Standards, Guidelines and Audit Working Group (2014) BSR and BHPR guideline for the management of adults with ANCA-associated vasculitis. Rheumatology 53:2306–2309CrossRefPubMedGoogle Scholar
  59. 59.
    Jones RB, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, Savage CO, Segelmark M, Tesar V, van Paassen P, Walsh D, Walsh M, Westman K, Jayne DR, European Vasculitis Study Group (2010) Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 363:211–220CrossRefPubMedGoogle Scholar
  60. 60.
    Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CG, St Clair EW, Turkiewicz A, Tchao NK, Webber L, Ding L, Sejismundo LP, Mieras K, Weitzenkamp D, Ikle D, Seyfert-Margolis V, Mueller M, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh KA, Kissin EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Specks U, RAVE-ITN Research Group (2010) Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 363:221–232CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Jones RB, Furuta S, Tervaert JW, Hauser T, Luqmani R, Morgan MD, Peh CA, Savage CO, Segelmark M, Tesar V, van Paassen P, Walsh M, Westman K, Jayne DR, European Vasculitis Society (EUVAS) (2015) Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis: 2-year results of a randomised trial. Ann Rheum Dis 74:1178–1182CrossRefPubMedGoogle Scholar
  62. 62.
    Guillevin L, Pagnoux C, Karras A, Khouatra C, Aumaitre O, Cohen P, Maurier F, Decaux O, Ninet J, Gobert P, Quemeneur T, Blanchard-Delaunay C, Godmer P, Puechal X, Carron PL, Hatron PY, Limal N, Hamidou M, Ducret M, Daugas E, Papo T, Bonnotte B, Mahr A, Ravaud P, Mouthon L, French Vasculitis Study Group (2014) Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med 371:1771–1780CrossRefPubMedGoogle Scholar
  63. 63.
    Huugen D, Tervaert JW, Heeringa P (2006) TNF-alpha bioactivity-inhibiting therapy in ANCA-associated vasculitis: clinical and experimental considerations. Clin J Am Soc Nephrol 1:1100–1107CrossRefPubMedGoogle Scholar
  64. 64.
    Little MA, Bhangal G, Smyth CL, Nakada MT, Cook HT, Nourshargh S, Pusey CD (2006) Therapeutic effect of anti-TNF-alpha antibodies in an experimental model of anti-neutrophil cytoplasm antibody-associated systemic vasculitis. J Am Soc Nephrol 17:160–169CrossRefPubMedGoogle Scholar
  65. 65.
    Bartolucci P, Ramanoelina J, Cohen P, Mahr A, Godmer P, Le Hello C, Guillevin L (2002) Efficacy of the anti-TNF-alpha antibody infliximab against refractory systemic vasculitides: an open pilot study on 10 patients. Rheumatology 41:1126–1132CrossRefPubMedGoogle Scholar
  66. 66.
    Lamprecht P, Voswinkel J, Lilienthal T, Nolle B, Heller M, Gross WL, Gause A (2002) Effectiveness of TNF-alpha blockade with infliximab in refractory Wegener’s granulomatosis. Rheumatology 41:1303–1307CrossRefPubMedGoogle Scholar
  67. 67.
    Booth AD, Jayne DR, Kharbanda RK, McEniery CM, Mackenzie IS, Brown J, Wilkinson IB (2004) Infliximab improves endothelial dysfunction in systemic vasculitis: a model of vascular inflammation. Circulation 109:1718–1723CrossRefPubMedGoogle Scholar
  68. 68.
    Wegener’s Granulomatosis Etanercept Trial (WGET) Research Group (2005) Etanercept plus standard therapy for Wegener’s granulomatosis. N Engl J Med 352:351–361CrossRefGoogle Scholar
  69. 69.
    Mukhtyar C, Luqmani R (2005) Current state of tumour necrosis factor {alpha} blockade in Wegener’s granulomatosis. Ann Rheum Dis 64[Suppl 4]:iv31–36PubMedPubMedCentralGoogle Scholar
  70. 70.
    Silva F, Cisternas M, Specks U (2012) TNF-alpha blocker therapy and solid malignancy risk in ANCA-associated vasculitis. Curr Rheumatol Rep 14:501–508CrossRefPubMedGoogle Scholar
  71. 71.
    Berti A, Cavalli G, Campochiaro C, Guglielmi B, Baldissera E, Cappio S, Sabbadini MG, Doglioni C, Dagna L (2015) Interleukin-6 in ANCA-associated vasculitis: rationale for successful treatment with tocilizumab. Semin Arthritis Rheum 45:48–54CrossRefPubMedGoogle Scholar
  72. 72.
    Jennette JC, Wilkman AS, Falk RJ (1989) Anti-neutrophil cytoplasmic autoantibody-associated glomerulonephritis and vasculitis. Am J Pathol 135:921–930PubMedPubMedCentralGoogle Scholar
  73. 73.
    Xing GQ, Chen M, Liu G, Heeringa P, Zhang JJ, Zheng XEJ, Kallenberg CG, Zhao MH (2009) Complement activation is involved in renal damage in human antineutrophil cytoplasmic autoantibody associated pauci-immune vasculitis. J Clin Immunol 29:282–291CrossRefPubMedGoogle Scholar
  74. 74.
    Xiao H, Schreiber A, Heeringa P, Falk RJ, Jennette JC (2007) Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies. Am J Pathol 170:52–64CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Wirthmueller U, Dewald B, Thelen M, Schafer MK, Stover C, Whaley K, North J, Eggleton P, Reid KB, Schwaeble WJ (1997) Properdin, a positive regulator of complement activation, is released from secondary granules of stimulated peripheral blood neutrophils. J Immunol 158:4444–4451PubMedGoogle Scholar
  76. 76.
    Vogt W (1996) Complement activation by myeloperoxidase products released from stimulated human polymorphonuclear leukocytes. Immunobiology 195:334–346CrossRefPubMedGoogle Scholar
  77. 77.
    Huugen D, van Esch A, Xiao H, Peutz-Kootstra CJ, Buurman WA, Tervaert JW, Jennette JC, Heeringa P (2007) Inhibition of complement factor C5 protects against anti-myeloperoxidase antibody-mediated glomerulonephritis in mice. Kidney Int 71:646–654CrossRefPubMedGoogle Scholar
  78. 78.
    Schreiber A, Xiao H, Jennette JC, Schneider W, Luft FC, Kettritz R (2009) C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis. J Am Soc Nephrol 20:289–298CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Hao J, Meng LQ, Xu PC, Chen M, Zhao MH (2012) p38MAPK, ERK and PI3K signaling pathways are involved in C5a-primed neutrophils for ANCA-mediated activation. PLoS One 7, e38317CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Hao J, Chen M, Zhao MH (2013) Involvement of protein kinase C in C5a-primed neutrophils for ANCA-mediated activation. Mol Immunol 54:68–73CrossRefPubMedGoogle Scholar
  81. 81.
    Neumann I, Regele H, Kain R, Birck R, Meisl FT (2003) Glomerular immune deposits are associated with increased proteinuria in patients with ANCA-associated crescentic nephritis. Nephrol Dial Transplant 18:524–531CrossRefPubMedGoogle Scholar
  82. 82.
    Ronco P, Mougenot B, Bindi P, Vanhille P, Mignon F (1991) Clinicohistological features and long-term outcome of Wegener’s granulomatosis. Contrib Nephrol 94:47–57CrossRefPubMedGoogle Scholar
  83. 83.
    Haas M, Eustace JA (2004) Immune complex deposits in ANCA-associated crescentic glomerulonephritis: a study of 126 cases. Kidney Int 65:2145–2152CrossRefPubMedGoogle Scholar
  84. 84.
    Yuan J, Gou SJ, Huang J, Hao J, Chen M, Zhao MH (2012) C5a and its receptors in human anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Arthritis Res Ther 14:R140CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Le Roux S, Pepper RJ, Dufay A, Neel M, Meffray E, Lamande N, Rimbert M, Josien R, Hamidou M, Hourmant M, Cook HT, Charreau B, Larger E, Salama AD, Fakhouri F (2012) Elevated soluble Flt1 inhibits endothelial repair in PR3-ANCA-associated vasculitis. J Am Soc Nephrol 23:155–164CrossRefPubMedGoogle Scholar
  86. 86.
    Gou SJ, Yuan J, Chen M, Yu F, Zhao MH (2013) Circulating complement activation in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Kidney Int 83:129–137CrossRefPubMedGoogle Scholar
  87. 87.
    Chen SF, Wang FM, Li ZY, Yu F, Zhao MH, Chen M (2015) Plasma complement factor H is associated with disease activity of patients with ANCA-associated vasculitis. Arthritis Res Ther 17:129CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Hilhorst M, van Paassen P, van Rie H, Bijnens N, Heerings-Rewinkel P, van Breda VP, Cohen Tervaert JW, Limburg Renal R (2015) Complement in ANCA-associated glomerulonephritis. Nephrol Dial Transplant. doi: 10.1093/ndt/gfv288 PubMedGoogle Scholar
  89. 89.
    Manenti L, Vaglio A, Gnappi E, Maggiore U, Allegri L, Allinovi M, Urban ML, Delsante M, Galetti M, Nicastro M, Pilato FP, Buzio C (2015) Association of serum C3 concentration and histologic signs of thrombotic microangiopathy with outcomes among patients with ANCA-associated renal vasculitis. Clin J Am Soc Nephrol 10:2143–2151CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Xiao H, Dairaghi DJ, Powers JP, Ertl LS, Baumgart T, Wang Y, Seitz LC, Penfold ME, Gan L, Hu P, Lu B, Gerard NP, Gerard C, Schall TJ, Jaen JC, Falk RJ, Jennette JC (2014) C5a receptor (CD88) blockade protects against MPO-ANCA GN. J Am Soc Nephrol 25:225–231CrossRefPubMedGoogle Scholar
  91. 91.
    Bekker P, Potarca A, Dairaghi D, Miao S, Powers JP, Jaen JC, Schall TJ (2012) Oral C5A receptor antagonist CCX168 in a phase 2 clinical trial in anca-associated renal vasculitis. Nephrol Dial Transplant 27:ii419–ii420Google Scholar
  92. 92.
    Dairaghi DJ, Jaen JC, Deshayes K, Johnson DA, Leleti MR, Miao S, Powers JP (2010) Phase 1 clinical safety, pharmacokinetic and pharmacodynamic evaluation of the novel C5aR antagonist CCX168, a potential therapeutic for ANCA-vasculitis. Arthritis Rheum 62:2032Google Scholar
  93. 93.
    Dairaghi D, Johnson D, Leleti M, Miao S, Xiao H, Jennette JC, Powers JP, Seitz L, Wang Y, Jaen JC, Schall TJ, Bekker P (2012) Clinical dose selection of the C5A receptor antagonist ccx168 for the phase 2 ANCA-associated renal vasculitis clinical trial (the clear trial). Nephrol Dial Transplant 27:ii401–ii402Google Scholar
  94. 94.
    Jayne DRW, Bruchfeld A, Schaier M, Ciechanowski K, Harper L, Jadoul M, Segelmark M, Selga D, Szombati I, Venning M, Hamilton P, Hugo C, Van Daele PLA, Viklicky O, Potarca A, Schall TJ, Bekker P (2014) Phase 2 randomised trial of oral C5A receptor antagonist CCX168 in ANCA-associated renal vasculitis. Nephrol Dial Transplant 29:iii27CrossRefGoogle Scholar
  95. 95.
    Jayne DR, Bruchfeld A, Schaier M, Ciechanowski K, Harper L, Jadoul M, Segelmark M, Selga D, Szombati I, Venning M, Hugo C, Van Daele PL, Viklicky O, Potarca A, Schall TJ, Bekker P (2014) OP0227 Oral C5A receptor antagonist CCX168 phase 2 clinical trial in ANCA-associated renal vasculitis. Ann Rheum Dis 73:148CrossRefGoogle Scholar
  96. 96.
    Bekker P, Jayne D, Bruchfeld A, Schaier M, Ciechanowski K, Harper L, Jadoul M, Segelmark M, Selga D, Szombati I, Venning M, Hugo C, Van Daele PL, Viklicky O, Potarca A, Schall TJ (2014) CCX168, an orally administered C5aR inhibitor for treatment of patients with antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheumatol 66:S820Google Scholar
  97. 97.
    Woodruff TM, Nandakumar KS, Tedesco F (2011) Inhibiting the C5–C5a receptor axis. Mol Immunol 48:1631–1642CrossRefPubMedGoogle Scholar
  98. 98.
    Hillmen P, Hall C, Marsh JC, Elebute M, Bombara MP, Petro BE, Cullen MJ, Richards SJ, Rollins SA, Mojcik CF, Rother RP (2004) Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med 350:552–559CrossRefPubMedGoogle Scholar
  99. 99.
    Hillmen P, Young NS, Schubert J, Brodsky RA, Socie G, Muus P, Roth A, Szer J, Elebute MO, Nakamura R, Browne P, Risitano AM, Hill A, Schrezenmeier H, Fu CL, Maciejewski J, Rollins SA, Mojcik CF, Rother RP, Luzzatto L (2006) The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 355:1233–1243CrossRefPubMedGoogle Scholar
  100. 100.
    Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, Bingham C, Cohen DJ, Delmas Y, Douglas K, Eitner F, Feldkamp T, Fouque D, Furman RR, Gaber O, Herthelius M, Hourmant M, Karpman D, Lebranchu Y, Mariat C, Menne J, Moulin B, Nurnberger J, Ogawa M, Remuzzi G, Richard T, Sberro-Soussan R, Severino B, Sheerin NS, Trivelli A, Zimmerhackl LB, Goodship T, Loirat C (2013) Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 368:2169–2181CrossRefPubMedGoogle Scholar

Copyright information

© IPNA 2016

Authors and Affiliations

  1. 1.Division of NephrologyThe Hospital for Sick ChildrenTorontoCanada
  2. 2.Department of PaediatricsUniversity of TorontoTorontoCanada
  3. 3.Program in Cell Biology, Research InstituteThe Hospital for Sick ChildrenTorontoCanada
  4. 4.Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  5. 5.Institute of Medical ScienceUniversity of TorontoTorontoCanada

Personalised recommendations