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Mechanisms of Disease: pathogenesis and treatment of ANCA-associated vasculitides

Nature Clinical Practice Rheumatology volume 2, pages 661–670 (2006)Cite this article

Abstract

Wegener's granulomatosis and microscopic polyangiitis are idiopathic systemic vasculitides strongly associated with antineutrophil cytoplasmic autoantibodies (ANCA). In Wegener's granulomatosis, ANCA are mostly directed against proteinase 3 (PR3), whereas in microscopic polyangiitis ANCA are directed against myeloperoxidase; increases in levels of these autoantibodies precede or coincide with clinical relapses in many cases. In vitro, ANCA can further activate primed neutrophils to release reactive oxygen species and lytic enzymes, and, in conjunction with neutrophils, can damage and lyse endothelial cells. Patients with Wegener's granulomatosis or microscopic polyangiitis have an increased percentage of neutrophils that constitutively express PR3 on their membrane. These neutrophils can be stimulated by ANCA, without priming. In vivo, transfer of splenocytes from myeloperoxidase-deficient mice immunized with mouse myeloperoxidase into wild-type mice resulted in pauci-immune systemic vasculitis. A similar experiment in PR3-deficient mice did not cause significant vasculitic lesions. Together, clinical, in vitro and in vivo experimental data support a pathogenic role for ANCA in Wegener's granulomatosis and microscopic polyangiitis, although this role is more evident for myeloperoxidase-specific ANCA than for PR3-specific ANCA. Several controlled trials have led to an evidence-based approach for the treatment of ANCA-associated vasculitis, and further studies, based on new insights into pathogenesis, are in progress.

Key Points

  • In patients with suspected vasculitis, the presence of antineutrophil cytoplasmic autoantibodies (ANCA) to proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA) strongly suggests one of the ANCA-associated vasculitides: Wegener's granulomatosis, microscopic polyangiitis, or Churg–Strauss syndrome

  • Rising ANCA titers should alert physicians to the possibility of clinical relapse of ANCA-associated vasculitides, although the correlation between rising ANCA titers and disease relapse is not perfect

  • A pathogenic role for MPO-ANCA is strongly supported by experimental studies, particularly in animal models, but the role of PR3-ANCA is less clear

  • Wegener's granulomatosis is associated with PR3-ANCA, and microscopic polyangiitis is associated with MPO-ANCA; these observations, together with experimental findings and the observed clinical differences between these two conditions, suggest a distinct pathogenesis for these diseases

  • Data from recent, randomized, controlled trials allow an evidence-based approach to the treatment of patients with ANCA-associated vasculitides

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Figure 1: Cytoplasmic components of ethanol-fixed neutrophils, stained by indirect immunofluorescence, in a serum sample from a patient with active Wegener's granulomatosis and antineutrophil cytoplasmic autoantibodies to proteinase 3
Figure 2: Schematic representation of the neutrophil responses that are putatively involved in the pathogenesis of ANCA-associated small vessel vasculitis

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References

  1. Hunder GG et al. (1990) The American College of Rheumatology 1990 criteria for the classification of vasculitis. Arthritis Rheum 33: 1065–1067

    Article  CAS  Google Scholar 

  2. Jennette JC et al. (1994) A nomenclature of systemic vasculitides: the proposal of an international consensus conference. Arthritis Rheum 37: 187–192

    Article  CAS  Google Scholar 

  3. Weyand CM and Goronzy JJ (2003) Medium- and large-vessel vasculitis. N Engl J Med 349: 160–169

    Article  CAS  Google Scholar 

  4. Jennette JC and Falk RJ (1997) Small-vessel vasculitis. N Engl J Med 337: 1512–1523

    Article  CAS  Google Scholar 

  5. Haas M and Eustace JA (2004) Immune complex deposits in ANCA-associated crescentic glomerulonephritis: a study of 126 cases. Kidney Int 65: 2145–2152

    Article  CAS  Google Scholar 

  6. Kallenberg CGM et al. (1994) Anti-neutrophil cytoplasmic antibodies: current diagnostic and pathophysiological potential. Kidney Int 46: 1–15

    Article  CAS  Google Scholar 

  7. Savige J et al. (1999) International Consensus Statement on testing and reporting of antineutrophil cytoplasmic antibodies (ANCA). Am J Clin Pathol 111: 507–513

    Article  CAS  Google Scholar 

  8. Rao JK et al. (1995) The role of antineutrophil cytoplasmic antibody testing in the diagnosis of Wegener granulomatosis. Ann Intern Med 123: 925–932

    Article  CAS  Google Scholar 

  9. Hagen EC et al. (1998) Diagnostic value of standardized assays for anti-neutrophil cytoplasmic antibodies in idiopathic systemic vasculitis. EC/BCR project for ANCA assay standardization. Kidney Int 53: 743–753

    Article  CAS  Google Scholar 

  10. Sinico RA et al. (2005) Prevalence and clinical significance of antineutrophil cytoplasmic antibodies in Churg–Strauss syndrome. Arthritis Rheum 52: 2926–2935

    Article  CAS  Google Scholar 

  11. Sable-Fourtassou R et al. (2005) Antineutrophil cytoplasmic antibodies and the Churg–Strauss syndrome. Ann Intern Med 143: 632–638

    Article  Google Scholar 

  12. Kallenberg CGM (2005) Churg–Strauss syndrome: just one disease entity? Arthritis Rheum 52: 2589–2593

    Article  Google Scholar 

  13. Franssen CF et al. (2000) Antiproteinase 3- and antimyeloperoxidase-associated vasculitis. Kidney Int 57: 2195–2206

    Article  CAS  Google Scholar 

  14. Boomsma MM et al. (2000) Prediction of relapses in Wegener's granulomatosis by measurement of anti-neutrophil cytoplasmic antibody levels: a prospective study. Arthritis Rheum 43: 2025–2033

    Article  CAS  Google Scholar 

  15. Stegeman CA (2002) Anti-neutrophil cytoplasmic antibody (ANCA) levels directed against proteinase-3 and myeloperoxidase are helpful in predicting disease relapse in ANCA-associated small-vessel vasculitis. Nephrol Dial Transplant 17: 2077–2080

    Article  CAS  Google Scholar 

  16. Falk RJ et al. (1990) Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci USA 87: 4115–4119

    Article  CAS  Google Scholar 

  17. Reumaux D et al. (1995) Effect of tumor necrosis factor-induced integrin activation on Fc gamma receptor II-mediated signal transduction: relevance for activation of neutrophils by anti-proteinase 3 or anti-myeloperoxidase antibodies. Blood 86: 3189–3195

    CAS  PubMed  Google Scholar 

  18. Grimminger F et al. (1996) Neutrophil activation by anti-proteinase 3 antibodies in Wegener's granulomatosis: role of exogenous arachidonic acid and leukotriene B4 generation. J Exp Med 184: 1567–1572

    Article  CAS  Google Scholar 

  19. Rarok AA et al. (2003) Neutrophil-activating potential of antineutrophil cytoplasm autoantibodies. J Leukoc Biol 74: 3–15

    Article  CAS  Google Scholar 

  20. Kettritz R et al. (1997) Crosslinking of ANCA-antigens stimulates superoxide release by human neutrophils. J Am Soc Nephrol 8: 386–394

    CAS  PubMed  Google Scholar 

  21. Porges AJ et al. (1994) Anti-neutrophil cytoplasmic antibodies engage and activate human neutrophils via Fc gamma RIIa. J Immunol 153: 1271–1280

    CAS  PubMed  Google Scholar 

  22. Mulder AH et al. (1994) Activation of granulocytes by anti-neutrophil cytoplasmic antibodies (ANCA): a Fc RII-dependent process. Clin Exp Immunol 98: 270–278

    Article  CAS  Google Scholar 

  23. Kocher M et al. (1998) Antineutrophil cytoplasmic antibodies preferentially engage Fc gamma RIIIb on human neutrophils. J Immunol 161: 6909–6914

    CAS  PubMed  Google Scholar 

  24. Williams JM et al. (2003) Activation of the Gi heterotrimeric G protein by ANCA IgG F(ab')2 fragments is necessary but not sufficient to stimulate the recruitment of those downstream mediators used by intact ANCA IgG. J Am Soc Nephrol 4: 661–669

    Article  Google Scholar 

  25. Witko-Sarsat V et al. (1999) A large subset of neutrophils expressing membrane proteinase 3 is a risk factor for vasculitis and rheumatoid arthritis. J Am Soc Nephrol 10: 1224–1233

    CAS  PubMed  Google Scholar 

  26. Schreiber A et al. (2003) Membrane expression of proteinase 3 is genetically determined. J Am Soc Nephrol 14: 68–75

    Article  CAS  Google Scholar 

  27. Rarok AA et al. (2002) Neutrophil membrane expression of proteinase 3 (PR3) is related to relapse in PR3-ANCA-associated vasculitis. J Am Soc Nephrol 13: 2232–2238

    Article  CAS  Google Scholar 

  28. Van Rossum AP et al. (2004) Constitutive membrane expression of proteinase 3 and neutrophil activation by anti-PR3 antibodies. J Leukoc Biol 76: 1162–1170

    Article  CAS  Google Scholar 

  29. Reumaux D et al. (2003) Expression of myeloperoxidase (MPO) by neutrophils is necessary for their activation by anti-neutrophil cytoplasmic autoantibodies (ANCA) against MPO. J Leukoc Biol 73: 841–849

    Article  CAS  Google Scholar 

  30. Hess C et al. (2000) Induction of neutrophil responsiveness to myeloperoxidase antibodies by their exposure to supernatant of degranulated autologous neutrophils. Blood 96: 2822–2827

    CAS  PubMed  Google Scholar 

  31. Kettritz R et al. (2001) Role of mitogen-activated protein kinases in activation of human neutrophils by antineutrophil cytoplasmic antibodies. J Am Soc Nephrol 12: 37–46

    CAS  PubMed  Google Scholar 

  32. Weidner S et al. (2001) Antineutrophil cytoplasmic antibodies induce human monocytes to produce oxygen radicals in vitro. Arthritis Rheum 44: 1698–1706

    Article  CAS  Google Scholar 

  33. Wikman A et al. (2003) Antineutrophil cytoplasmic antibodies induce decreased CD62L expression and enhanced metabolic activity in monocytes. Scand J Immunol 57: 179–184

    Article  CAS  Google Scholar 

  34. Stegeman CA et al. (1994) Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis. Ann Intern Med 120: 12–17

    Article  CAS  Google Scholar 

  35. Stegeman CA et al. (1996) Trimethoprim–sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis. N Engl J Med 335: 16–20

    Article  CAS  Google Scholar 

  36. Savage CO et al. (1992) Autoantibodies developing to myeloperoxidase and proteinase 3 in systemic vasculitis stimulate neutrophil cytotoxicity toward cultured endothelial cells. Am J Pathol 141: 335–342

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Radford DJ et al. (2001) Antineutrophil cytoplasmic antibodies stabilize adhesion and promote migration of flowing neutrophils on endothelial cells. Arthritis Rheum 44: 2851–2861

    Article  CAS  Google Scholar 

  38. Mayet WJ et al. (1993) Human endothelial cells express proteinase 3, the target antigen of anticytoplasmic antibodies in Wegener's granulomatosis. Blood 82: 1221–1229

    CAS  PubMed  Google Scholar 

  39. De Bandt M et al. (1999) Anti-proteinase-3 (PR3) antibodies (C-ANCA) recognize various targets on the human umbilical vein endothelial cell (HUVEC) membrane. Clin Exp Immunol 115: 362–368

    Article  CAS  Google Scholar 

  40. King WJ et al. (1995) Endothelial cells and renal epithelial cells do not express the Wegener's autoantigen, proteinase 3. Clin Exp Immunol 102: 98–105

    Article  CAS  Google Scholar 

  41. Lamprecht P (2005) Off balance: T-cells in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Clin Exp Immunol 141: 201–210

    Article  CAS  Google Scholar 

  42. Brouwer E et al. (1993) Antimyeloperoxidase-associated proliferative glomerulonephritis: an animal model. J Exp Med 177: 905–914

    Article  CAS  Google Scholar 

  43. Foucher P et al (1999) Antimyeloperoxidase-associated lung disease. An experimental model. Am J Respir Crit Care Med 160: 987–994

    Article  CAS  Google Scholar 

  44. Heeringa P et al. (1996) Autoantibodies to myeloperoxidase aggravate mild anti-glomerular-basement-membrane-mediated glomerular injury in the rat. Am J Pathol 149: 1695–1706

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Xiao H et al. (2002) Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest 110: 955–963

    Article  CAS  Google Scholar 

  46. Huugen D et al. (2005) Aggravation of anti-myeloperoxidase antibody-induced glomerulonephritis by bacterial lipopolysaccharide: role of tumor necrosis factor-α. Am J Pathol 167: 47–58

    Article  CAS  Google Scholar 

  47. Little MA et al. (2005) Antineutrophil cytoplasm antibodies directed against myeloperoxidase augment leukocyte–microvascular interactions in vivo. Blood 106: 2050–2058

    Article  CAS  Google Scholar 

  48. Xiao H et al. (2005) The role of neutrophils in the induction of glomerulonephritis by anti-myeloperoxidase antibodies. Am J Pathol 167: 39–45

    Article  CAS  Google Scholar 

  49. Bansal PJ and Tobin MC (2004) Neonatal microscopic polyangiitis secondary to transfer of maternal myeloperoxidase-antineutrophil cytoplasmic antibody resulting in neonatal pulmonary hemorrhage and renal involvement. Ann Allergy Asthma Immunol 93: 398–401

    Article  Google Scholar 

  50. Pfister H et al. (2004) Antineutrophil cytoplasmic autoantibodies against the murine homolog of proteinase 3 (Wegener autoantigen) are pathogenic in vivo. Blood 104: 1411–1418

    Article  CAS  Google Scholar 

  51. Van der Geld YM et al. (2001) Proteinase 3, Wegener's autoantigen: from gene to antigen. J Leukoc Biol 69: 177–190

    CAS  PubMed  Google Scholar 

  52. Hoffman GS et al. (1992) Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 116: 488–498

    Article  CAS  Google Scholar 

  53. Westman KW et al. (1998) Relapse rate, renal survival, and cancer morbidity in patients with Wegener's granulomatosis or microscopic polyangiitis with renal involvement. J Am Soc Nephrol 9: 842–852

    CAS  PubMed  Google Scholar 

  54. Jayne D et al. (2003) European Vasculitis Study Group. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 349: 36–44

    Article  CAS  Google Scholar 

  55. Sanders JS et al (2003) Maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 349: 2072–2073

    Article  CAS  Google Scholar 

  56. Slot MC et al. (2004) A positive PR3-ANCA titer at switch to azathioprine therapy is associated with a disquieting relapse rate in ANCA-related vasculitis. Arthritis Rheum 51: 269–273

    Article  CAS  Google Scholar 

  57. Little MA and Pusey CD (2004) Rapidly progressive glomerulonephritis: current and evolving treatment strategies. J Nephrol 17: 10–19

    Google Scholar 

  58. Wegener's Granulomatosis Etanercept Trial (WGET) Research Group (2005) Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med 352: 351–361

  59. Booth AD (2002) Safety and efficacy of TNFα blockade in relapsing vasculitis. Ann Rheum Dis 61: 559

    Article  CAS  Google Scholar 

  60. Jayne DR et al. (2000) Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity. QJM 93: 433–439

    Article  CAS  Google Scholar 

  61. De Groot K et al. (2005) European, multicenter randomised controlled trial of daily oral versus pulse cyclophosphamide for induction of remission in ANCA-associated systemic vasculitis [abstract]. J Am Soc Nephrol 16: 7A

    Article  Google Scholar 

  62. De Groot K et al. (2005) Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 52: 2461–2469

    Article  CAS  Google Scholar 

  63. Keogh KA et al. (2005) Induction of remission by B lymphocyte depletion in eleven patients with refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 52: 262–268

    Article  Google Scholar 

  64. Heeringa P et al. (2005) Anti-neutrophil cytoplasmic autoantibodies and leukocyte–endothelial interactions: a sticky connection? Trends Immunol 26: 561–564

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Rheumatology and Clinical Immunology,

    Cees GM Kallenberg, Peter Heeringa & Coen A Stegeman

  2. Department of Pathology and Laboratory Medicine,

    Cees GM Kallenberg, Peter Heeringa & Coen A Stegeman

  3. Department of Nephrology, all at the University of Groningen, Groningen, The Netherlands

    Cees GM Kallenberg, Peter Heeringa & Coen A Stegeman

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  1. Cees GM Kallenberg
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Correspondence to Cees GM Kallenberg.

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Kallenberg, C., Heeringa, P. & Stegeman, C. Mechanisms of Disease: pathogenesis and treatment of ANCA-associated vasculitides. Nat Rev Rheumatol 2, 661–670 (2006). https://doi.org/10.1038/ncprheum0355

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