Skip to main content
SpringerLink
Log in
Book cover

Core Concepts in Parenchymal Kidney Disease pp 137–151Cite as

Pathogenesis and Management of ANCA-Associated Vasculitis

  • Chapter
  • First Online:

  • 1304 Accesses

Abstract

The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) represent a group of three heterogeneous syndromes: granulomatosis with polyangiitis (GPA, formerly Wegener’s granulomatosis), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg–Strauss syndrome). They share a primary necrotizing small vessel vasculitis with propensity to involve the kidneys and the respiratory tract. The majority of patients with these syndromes have ANCA detectable in the serum at the time of diagnosis. Two types of ANCA are of clinical significance: C-ANCA reacting with the neutrophil enzyme proteinase 3 (PR3-ANCA) occur in over 80 % of patients with GPA and P-ANCA reacting with myeloperoxidase (MPO-ANCA) occur in less than 10 % of patients with GPA but in the majority of patients with MPA. MPO-ANCA is also the predominant type of ANCA encountered in patients with EGPA, where PR3-ANCA is the exception. The pathogenesis is not fully understood, but there is mounting evidence for a genetic predisposition, environmental triggers including infections, and ANCA all playing significant roles in the development of the syndromes. The outcome of untreated AAV with renal involvement is usually fatal. Treatment with the combination of glucocorticosteroids and cyclophosphamide (CYC) has turned these syndromes into manageable chronically relapsing disorders. Not all patients respond satisfactorily to CYC, and even for those who do, the subsequent relapse rate is high. Up to half of the patients who achieve remission relapse within the first 3–5 years. The need for retreatment exposes patients to significant long-term toxicities of glucocorticoids and less toxic alternatives have been sought. Rituximab has recently emerged as an alternative for CYC and currently represents the only FDA-approved treatment for remission induction in patients with severe AAV. This chapter reviews recent advances in the pathogenesis and treatment of AAV.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides: the proposal of an international consensus conference. Arthritis Rheum. 1994;37:187–92.

    PubMed  CAS  Google Scholar 

  2. Hoffman GS, Specks U. Anti-neutrophil cytoplasmic antibodies. Arthritis Rheum. 1998;41:1521–37.

    PubMed  CAS  Google Scholar 

  3. Keogh KA, Specks U. Churg-Strauss syndrome. clinical presentation, antineutrophil cytoplasmic antibodies, and leukotriene receptor antagonists. Am J Med. 2003;115(4):284–90.

    PubMed  CAS  Google Scholar 

  4. Sinico RA, Di Toma L, Maggiore U, et al. Prevalence and clinical significance of antineutrophil cytoplasmic antibodies in Churg-Strauss syndrome. Arthritis Rheum. 2005;52(9):2926–35.

    PubMed  CAS  Google Scholar 

  5. Sable-Fourtassou R, Cohen P, Mahr A, et al. Antineutrophil cytoplasmic antibodies and the Churg-Strauss syndrome. Ann Intern Med. 2005;143(9):632–8.

    PubMed  Google Scholar 

  6. Finkielman JD, Lee AS, Hummel AM, et al. ANCA are detectable in nearly all patients with active severe Wegener’s granulomatosis. Am J Med. 2007;120(7):643.e9–14.

    Google Scholar 

  7. Guillevin L, Durand-Gasselin B, Cevallos R, et al. Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients. Arthritis Rheum. 1999;42(3):421–30.

    PubMed  CAS  Google Scholar 

  8. Sinico RA, Di Toma L, Maggiore U, et al. Renal involvement in Churg-Strauss syndrome. Am J Kidney Dis. 2006;47(5):770–9.

    PubMed  Google Scholar 

  9. Watts RA, Lane SE, Bentham G, Scott DG. Epidemiology of systemic vasculitis: a ten-year study in the United Kingdom. Arthritis Rheum. 2000;43(2):414–9.

    PubMed  CAS  Google Scholar 

  10. Watts RA, Gonzalez-Gay MA, Lane SE, Garcia-Porrua C, Bentham G, Scott DG. Geoepidemiology of systemic vasculitis: comparison of the incidence in two regions of Europe. Ann Rheum Dis. 2001;60(2):170–2.

    PubMed  CAS  Google Scholar 

  11. Cotch MF, Hoffman GS, Yerg DE, Kaufman GI, Targonski P, Kaslow RA. The epidemiology of Wegener’s granulomatosis. Estimates of the five-year period prevalence, annual mortality, and geographic disease distribution from population-based data sources. Arthritis Rheum. 1996;39:87–92.

    PubMed  CAS  Google Scholar 

  12. Watts RA, Scott DG, Jayne DR, et al. Renal vasculitis in Japan and the UK—are there differences in epidemiology and clinical phenotype? Nephrol Dial Transplant. 2008;23(12):3928–31.

    PubMed  Google Scholar 

  13. O'Donnell JL, Stevanovic VR, Frampton C, Stamp LK, Chapman PT. Wegener’s granulomatosis in New Zealand: evidence for a latitude-dependent incidence gradient. Intern Med J. 2007; 37(4):242–6.

    PubMed  Google Scholar 

  14. Mahr A, Guillevin L, Poissonnet M, Ayme S. Prevalences of polyarteritis nodosa, microscopic polyangiitis, Wegener’s granulomatosis, and Churg-Strauss syndrome in a French urban multiethnic population in 2000: a capture-recapture estimate. Arthritis Rheum. 2004;51(1):92–9.

    PubMed  Google Scholar 

  15. Knight A, Sandin S, Askling J. Risks and relative risks of Wegener’s granulomatosis among close relatives of patients with the disease. Arthritis Rheum. 2008;58(1):302–7.

    PubMed  Google Scholar 

  16. Rottem M, Cotch MF, Fauci AS, Hoffman GS. Familial vasculitis: report of 2 families. J Rheumatol. 1994;21(3):561–3.

    PubMed  CAS  Google Scholar 

  17. Manganelli P, Giacosa R, Fietta P, Zanetti A, Neri TM. Familial vasculitides: Churg-Strauss syndrome and Wegener’s granulomatosis in 2 first-degree relatives. J Rheumatol. 2003;30(3):618–21.

    PubMed  Google Scholar 

  18. Willcocks LC, Lyons PA, Rees AJ, Smith KG. The contribution of genetic variation and infection to the pathogenesis of ANCA-associated systemic vasculitis. Arthritis Res Ther. 2010;12(1):202.

    PubMed  Google Scholar 

  19. Vaglio A, Martorana D, Maggiore U, et al. HLA-DRB4 as a genetic risk factor for Churg-Strauss syndrome. Arthritis Rheum. 2007;56(9):3159–66.

    PubMed  CAS  Google Scholar 

  20. Wieczorek S, Hellmich B, Gross WL, Epplen JT. Associations of Churg-Strauss syndrome with the HLA-DRB1 locus, and relationship to the genetics of antineutrophil cytoplasmic antibody-associated vasculitides: comment on the article by Vaglio et al. Arthritis Rheum. 2008;58(1):329–30.

    PubMed  CAS  Google Scholar 

  21. Arning L, Holle JU, Harper L, et al. Are there specific genetic risk factors for the different forms of ANCA-associated vasculitis? Ann Rheum Dis. 2011;70(4):707–8.

    PubMed  Google Scholar 

  22. Cao Y, Schmitz JL, Yang J, et al. DRB1*15 allele is a risk factor for PR3-ANCA disease in African Americans. J Am Soc Nephrol. 2011;22(6):1161–7.

    PubMed  CAS  Google Scholar 

  23. Jagiello P, Aries P, Arning L, et al. The PTPN22 620W allele is a risk factor for Wegener’s granulomatosis. Arthritis Rheum. 2005;52(12):4039–43.

    PubMed  CAS  Google Scholar 

  24. Carr EJ, Niederer HA, Williams J, et al. Confirmation of the genetic association of CTLA4 and PTPN22 with ANCA-associated vasculitis. BMC Med Genet. 2009;10:121.

    PubMed  Google Scholar 

  25. Gregersen PK, Lee HS, Batliwalla F, Begovich AB. PTPN22: setting thresholds for autoimmunity. Semin Immunol. 2006; 18(4):214–23.

    PubMed  CAS  Google Scholar 

  26. Bluestone JA. Is CTLA-4 a master switch for peripheral T cell tolerance? J Immunol. 1997;158(5):1989–93.

    PubMed  CAS  Google Scholar 

  27. Steiner K, Moosig F, Csernok E, et al. Increased expression of CTLA-4 (CD152) by T and B lymphocytes in Wegener’s granulomatosis. Clin Exp Immunol. 2001;126(1):143–50.

    PubMed  CAS  Google Scholar 

  28. Gough SC, Walker LS, Sansom DM. CTLA4 gene polymorphism and autoimmunity. Immunol Rev. 2005;204:102–15.

    PubMed  CAS  Google Scholar 

  29. Wang XB, Zhao X, Giscombe R, Lefvert AK. A CTLA-4 gene polymorphism at position-318 in the promoter region affects the expression of protein. Genes Immun. 2002;3(4):233–4.

    PubMed  Google Scholar 

  30. Gencik M, Meller S, Borgmann S, Fricke H. Proteinase 3 gene polymorphisms and Wegener’s granulomatosis. Kidney Int. 2000; 58(6):2473–7.

    PubMed  CAS  Google Scholar 

  31. Halbwachs-Mecarelli L, Bessou G, Lesavre P, Lopez S, Witko-Sarsat V. Bimodal distribution of proteinase 3 (PR3) surface expression reflects a constitutive heterogeneity in the polymorphonuclear neutrophil pool. FEBS Lett. 1995;374:29–33.

    PubMed  CAS  Google Scholar 

  32. Schreiber A, Busjahn A, Luft FC, Kettritz R. Membrane expression of proteinase 3 is genetically determined. J Am Soc Nephrol. 2003;14(1):68–75.

    PubMed  CAS  Google Scholar 

  33. von Vietinghoff S, Busjahn A, Schonemann C, et al. Major histocompatibility complex HLA region largely explains the genetic variance exercised on neutrophil membrane proteinase 3 expression. J Am Soc Nephrol. 2006;17(11):3185–91.

    Google Scholar 

  34. Witko-Sarsat V, Lesavre P, Lopez S, et al. A large subset of neutrophils expressing membrane proteinase 3 is a risk factor for vasculitis and rheumatoid arthritis. J Am Soc Nephrol. 1999; 10(6):1224–33.

    PubMed  CAS  Google Scholar 

  35. Rarok AA, Stegeman CA, Limburg PC, Kallenberg CG. Neutrophil membrane expression of proteinase 3 (PR3) is related to relapse in PR3-ANCA-associated vasculitis. J Am Soc Nephrol. 2002;13(9):2232–8.

    PubMed  CAS  Google Scholar 

  36. Mahr AD, Edberg JC, Stone JH, et al. Alpha 1-antitrypsin deficiency-related alleles Z and S and the risk for Wegener’s granulomatosis. Arthritis Rheum. 2010;62(12):3760–7.

    PubMed  CAS  Google Scholar 

  37. Morris H, Morgan MD, Wood AM, et al. ANCA-associated vasculitis is linked to carriage of the Z allele of alpha antitrypsin and its polymers. Ann Rheum Dis. 2011;70(10):1851–6.

    PubMed  CAS  Google Scholar 

  38. Segelmark M, Elzouki AN, Wieslander J, Eriksson S. The PiZ gene of alpha 1-antitrypsin as a determinant of outcome in PR3-ANCA-positive vasculitis. Kidney Int. 1995; 48(3):844–50.

    PubMed  CAS  Google Scholar 

  39. Stankiewicz P, Lupski JR. Structural variation in the human genome and its role in disease. Annu Rev Med. 2010;61:437–55.

    PubMed  CAS  Google Scholar 

  40. Hogan SL, Cooper GS, Savitz DA, et al. Association of silica exposure with anti-neutrophil cytoplasmic autoantibody small-vessel vasculitis: a population-based, case-control study. Clin J Am Soc Nephrol. 2007;2(2):290–9.

    PubMed  Google Scholar 

  41. Short AK, Lockwood CM. Antigen specificity in hydralazine associated ANCA positive systemic vasculitis. Q J Med. 1995; 88:775–83.

    CAS  Google Scholar 

  42. Choi HK, Merkel PA, Walker AM, Niles JL. Drug-associated antineutrophil cytoplasmic antibody-positive vasculitis: prevalence among patients with high titers of antimyeloperoxidase antibodies. Arthritis Rheum. 2000;43(2):405–13.

    PubMed  CAS  Google Scholar 

  43. Choi HK, Lamprecht P, Niles JL, Gross WL, Merkel PA. Subacute bacterial endocarditis with positive cytoplasmic antineutrophil cytoplasmic antibodies and anti-proteinase 3 antibodies. Arthritis Rheum. 2000;43(1):226–31.

    PubMed  CAS  Google Scholar 

  44. Capizzi SA, Specks U. Does infection play a role in the pathogenesis of pulmonary vasculitis? Semin Respir Infect. 2003; 18(1):17–22.

    PubMed  Google Scholar 

  45. Albert LJ, Inman RD. Molecular mimicry and autoimmunity. N Engl J Med. 1999;341(27):2068–74.

    PubMed  CAS  Google Scholar 

  46. Craft J, Fatenejad S. Self antigens and epitope spreading in systemic autoimmunity. Arthritis Rheum. 1997;40:1374–82.

    PubMed  CAS  Google Scholar 

  47. Vanderlugt CJ, Miller SD. Epitope spreading. Curr Opin Immunol. 1996;8:831–6.

    PubMed  CAS  Google Scholar 

  48. Kain R, Exner M, Brandes R, et al. Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis. Nat Med. 2008;14(10):1088–96.

    PubMed  CAS  Google Scholar 

  49. Kain R, Tadema H, McKinney EF, et al. High prevalence of autoantibodies to hLAMP-2 in anti-neutrophil cytoplasmic antibody-associated vasculitis. J Am Soc Nephrol. 2012; 23(3):556–66.

    PubMed  CAS  Google Scholar 

  50. Roth AJ, Brown MC, Smith RN, et al. Anti-LAMP-2 antibodies are not prevalent in patients with antineutrophil cytoplasmic autoantibody glomerulonephritis. J Am Soc Nephrol. 2012; 23(3):545–55.

    PubMed  CAS  Google Scholar 

  51. Pendergraft III WF, Preston GA, Shah RR, et al. Autoimmunity is triggered by cPR-3(105–201), a protein complementary to human autoantigen proteinase-3. Nat Med. 2004;10(1):72–9.

    PubMed  CAS  Google Scholar 

  52. Shoenfeld Y. Idiotypic induction of autoimmunity: a new aspect of the idiotypic network. FASEB J. 1994;8(15):1296–301.

    PubMed  CAS  Google Scholar 

  53. Astern JM. Myeloperoxidase in vascular disease and autoimmunity. Chapel Hill: Department of Pathology and Laboratory Medicine, University of North Carolina; 2007.

    Google Scholar 

  54. Tadema H, Kallenberg CG, Stegeman CA, Heeringa P. Reactivity against complementary proteinase-3 is not increased in patients with PR3-ANCA-associated vasculitis. PLoS One. 2011; 6(3):e17972.

    PubMed  CAS  Google Scholar 

  55. Bautz DJ, Preston GA, Lionaki S, et al. Antibodies with dual reactivity to plasminogen and complementary PR3 in PR3-ANCA vasculitis. J Am Soc Nephrol. 2008;19(12):2421–9.

    PubMed  CAS  Google Scholar 

  56. Merkel PA, Lo GH, Holbrook JT, et al. High incidence of venous thrombotic events among patients with Wegener granulomatosis: the Wegener’s Clinical Occurrence of Thrombosis (WeCLOT) Study. Ann Intern Med. 2005;142(8):620–6.

    PubMed  Google Scholar 

  57. Stegeman CA, Cohen Tervaert JW, Sluiter WJ, Manson WL, de Jong PE, Kallenberg CGM. Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis. Ann Intern Med. 1994;120:12–7.

    PubMed  CAS  Google Scholar 

  58. Stegeman CA, Cohen Tervaert JW, de Jong PE, Kallenberg CG. Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener’s granulomatosis. N Engl J Med. 1996;335(1):16–20.

    PubMed  CAS  Google Scholar 

  59. Zycinska K, Wardyn KA, Zielonka TM, Krupa R, Lukas W. Co-trimoxazole and prevention of relapses of PR3-ANCA positive vasculitis with pulmonary involvement. Eur J Med Res. 2009;14 Suppl 4:265–7.

    PubMed  Google Scholar 

  60. Proft T, Fraser JD. Bacterial superantigens. Clin Exp Immunol. 2003;133(3):299–306.

    PubMed  CAS  Google Scholar 

  61. Zouali M. Exploitation of host signaling pathways by B cell superantigens—potential strategies for developing targeted therapies in systemic autoimmunity. Ann N Y Acad Sci. 2007; 1095:342–54.

    PubMed  CAS  Google Scholar 

  62. Popa ER, Stegeman CA, Abdulahad WH, et al. Staphylococcal toxic-shock-syndrome-toxin-1 as a risk factor for disease relapse in Wegener’s granulomatosis. Rheumatology. 2007;46(6):1029–33.

    PubMed  CAS  Google Scholar 

  63. Popa ER, Stegeman CA, Bos NA, Kallenberg CG, Tervaert JW. Staphylococcal superantigens and T cell expansions in Wegener’s granulomatosis. Clin Exp Immunol. 2003;132(3):496–504.

    PubMed  CAS  Google Scholar 

  64. Li H, Nooh MM, Kotb M, Re F. Commercial peptidoglycan preparations are contaminated with superantigen-like activity that stimulates IL-17 production. J Leukoc Biol. 2008;83(2):409–18.

    PubMed  CAS  Google Scholar 

  65. Acosta-Rodriguez EV, Rivino L, Geginat J, et al. Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol. 2007;8(6):639–46.

    PubMed  CAS  Google Scholar 

  66. Gerosa F, Baldani-Guerra B, Lyakh LA, et al. Differential regulation of interleukin 12 and interleukin 23 production in human dendritic cells. J Exp Med. 2008;205(6):1447–61.

    PubMed  CAS  Google Scholar 

  67. Fouser LA, Wright JF, Dunussi-Joannopoulos K, Collins M. Th17 cytokines and their emerging roles in inflammation and autoimmunity. Immunol Rev. 2008;226:87–102.

    PubMed  CAS  Google Scholar 

  68. Oukka M. Th17 cells in immunity and autoimmunity. Ann Rheum Dis. 2008;67 Suppl 3:iii26–9.

    PubMed  CAS  Google Scholar 

  69. Nogueira E, Hamour S, Sawant D, et al. Serum IL-17 and IL-23 levels and autoantigen-specific Th17 cells are elevated in patients with ANCA-associated vasculitis. Nephrol Dial Transplant. 2010;25(7):2209–17.

    PubMed  CAS  Google Scholar 

  70. Abdulahad WH, Stegeman CA, Limburg PC, Kallenberg CG. Skewed distribution of Th17 lymphocytes in patients with Wegener’s granulomatosis in remission. Arthritis Rheum. 2008; 58(7):2196–205.

    PubMed  Google Scholar 

  71. Jovanovic DV, Di Battista JA, Martel-Pelletier J, et al. IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages. J Immunol. 1998;160(7):3513–21.

    PubMed  CAS  Google Scholar 

  72. Voswinkel J, Mueller A, Kraemer JA, et al. B lymphocyte maturation in Wegener’s granulomatosis: a comparative analysis of VH genes from endonasal lesions. Ann Rheum Dis. 2006; 65(7):859–64.

    PubMed  CAS  Google Scholar 

  73. Hurtado PR, Jeffs L, Nitschke J, et al. CpG oligodeoxynucleotide stimulates production of anti-neutrophil cytoplasmic antibodies in ANCA associated vasculitis. BMC Immunol. 2008;9:34.

    PubMed  Google Scholar 

  74. Tadema H, Abdulahad WH, Lepse N, Stegeman CA, Kallenberg CG, Heeringa P. Bacterial DNA motifs trigger ANCA production in ANCA-associated vasculitis in remission. Rheumatology. 2011;50(4):689–96.

    PubMed  CAS  Google Scholar 

  75. Brinkmann V, Zychlinsky A. Beneficial suicide: why neutrophils die to make NETs. Nat Rev Microbiol. 2007;5(8):577–82.

    PubMed  CAS  Google Scholar 

  76. Fuchs TA, Abed U, Goosmann C, et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol. 2007; 176(2):231–41.

    PubMed  CAS  Google Scholar 

  77. Kessenbrock K, Krumbholz M, Schonermarck U, et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med. 2009;15(6):623–5.

    PubMed  CAS  Google Scholar 

  78. Pilsczek FH, Salina D, Poon KK, et al. A novel mechanism of rapid nuclear neutrophil extracellular trap formation in response to Staphylococcus aureus. J Immunol. 2010;185(12):7413–25.

    PubMed  CAS  Google Scholar 

  79. Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak-Rothstein A. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature. 2002;416(6881):603–7.

    PubMed  CAS  Google Scholar 

  80. Tadema H, Abdulahad WH, Stegeman CA, Kallenberg CG, Heeringa P. Increased expression of Toll-like receptors by monocytes and natural killer cells in ANCA-associated vasculitis. PLoS One. 2011;6(9):e24315.

    PubMed  CAS  Google Scholar 

  81. Mellbye OJ, Mollnes TE, Steen LS. IgG subclass distribution and complement activation ability of autoantibodies to neutrophil cytoplasmic antigens (ANCA). Clin Immunol Immunopathol. 1994;70(1):32–9.

    PubMed  CAS  Google Scholar 

  82. Popa ER, Stegeman CA, Bos NA, Kallenberg CG, Tervaert JW. Differential B- and T-cell activation in Wegener’s granulomatosis. J Allergy Clin Immunol. 1999;103(5 Pt 1):885–94.

    PubMed  CAS  Google Scholar 

  83. Abdulahad WH, van der Geld YM, Stegeman CA, Kallenberg CG. Persistent expansion of CD4+ effector memory T cells in Wegener’s granulomatosis. Kidney Int. 2006;70(5):938–47.

    PubMed  CAS  Google Scholar 

  84. Abdulahad WH, Stegeman CA, van der Geld YM, Doornbos-van der Meer B, Limburg PC, Kallenberg CG. Functional defect of circulating regulatory CD4+ T cells in patients with Wegener’s granulomatosis in remission. Arthritis Rheum. 2007; 56(6):2080–91.

    PubMed  CAS  Google Scholar 

  85. Morgan MD, Day CJ, Piper KP, et al. Patients with Wegener’s granulomatosis demonstrate a relative deficiency and functional impairment of T-regulatory cells. Immunology. 2010; 130(1):64–73.

    PubMed  CAS  Google Scholar 

  86. Odendahl M, Mei H, Hoyer BF, et al. Generation of migratory antigen-specific plasma blasts and mobilization of resident plasma cells in a secondary immune response. Blood. 2005; 105(4):1614–21.

    PubMed  CAS  Google Scholar 

  87. Huang H, Benoist C, Mathis D. Rituximab specifically depletes short-lived autoreactive plasma cells in a mouse model of inflammatory arthritis. Proc Natl Acad Sci U S A. 2010; 107(10):4658–63.

    PubMed  CAS  Google Scholar 

  88. Cupps TR, Edgar LC, Fauci AS. Suppression of human B lymphocyte function by cyclophosphamide. J Immunol. 1982; 128(6):2453–7.

    PubMed  CAS  Google Scholar 

  89. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221–32.

    PubMed  CAS  Google Scholar 

  90. Falk RJ, Terrell RS, Charles LA, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci U S A. 1990;87:4115–9.

    PubMed  CAS  Google Scholar 

  91. Csernok E, Ernst M, Schmitt W, Bainton DF, Gross WL. Activated neutrophils express proteinase 3 on their plasma membrane in vitro and in vivo. Clin Exp Immunol. 1994;95(2):244–50.

    PubMed  CAS  Google Scholar 

  92. Franssen CF, Huitema MG, Muller Kobold AC, et al. In vitro neutrophil activation by antibodies to proteinase 3 and myeloperoxidase from patients with crescentic glomerulonephritis. J Am Soc Nephrol. 1999;10(7):1506–15.

    PubMed  CAS  Google Scholar 

  93. Kettritz R, Jennette JC, Falk RJ. Crosslinking of ANCA-antigens stimulates superoxide release by human neutrophils. J Am Soc Nephrol. 1997;8:386–94.

    PubMed  CAS  Google Scholar 

  94. Weidner S, Neupert W, Goppelt-Struebe M, Rupprecht HD. Antineutrophil cytoplasmic antibodies induce human monocytes to produce oxygen radicals in vitro. Arthritis Rheum. 2001;44(7):1698–706.

    PubMed  CAS  Google Scholar 

  95. Hewins P, Williams JM, Wakelam MJ, Savage CO. Activation of Syk in neutrophils by antineutrophil cytoplasm antibodies occurs via Fcgamma receptors and CD18. J Am Soc Nephrol. 2004;15(3):796–808.

    PubMed  CAS  Google Scholar 

  96. van der Veen BS, Chen M, Muller R, et al. Effects of p38 mitogen-activated protein kinase inhibition on anti-neutrophil cytoplasmic autoantibody pathogenicity in vitro and in vivo. Ann Rheum Dis. 2011;70(2):356–65.

    PubMed  Google Scholar 

  97. Radford DJ, Lord JM, Savage CO. The activation of the neutrophil respiratory burst by anti-neutrophil cytoplasm autoantibody (ANCA) from patients with systemic vasculitis requires tyrosine kinases and protein kinase C activation. Clin Exp Immunol. 1999;118(1):171–9.

    PubMed  CAS  Google Scholar 

  98. Mayet WJ, Schwarting A, Orth T, Duchmann R, Meyer zum Buschenfelde KH. Antibodies to proteinase 3 mediate expression of vascular cell adhesion molecule-1 (VCAM-1). Clin Exp Immunol. 1996;103(2):259–67.

    PubMed  CAS  Google Scholar 

  99. De Bandt M, Meyer O, Hakim J, Pasquier C. Antibodies to proteinase-3 mediate expression of intercellular adhesion molecule-1 (ICAM-1, CD 54). Br J Rheumatol. 1997;36(8):839–46.

    PubMed  Google Scholar 

  100. Muller Kobold AC, van Wijk RT, Franssen CF, Molema G, Kallenberg CG, Tervaert JW. In vitro up-regulation of E-selectin and induction of interleukin-6 in endothelial cells by autoantibodies in Wegener’s granulomatosis and microscopic polyangiitis. Clin Exp Rheumatol. 1999;17(4):433–40.

    PubMed  CAS  Google Scholar 

  101. Radford DJ, Savage CO, Nash GB. Treatment of rolling neutrophils with antineutrophil cytoplasmic antibodies causes conversion to firm integrin-mediated adhesion. Arthritis Rheum. 2000;43(6):1337–45.

    PubMed  CAS  Google Scholar 

  102. Taekema-Roelvink ME, Kooten C, Kooij SV, Heemskerk E, Daha MR. Proteinase 3 enhances endothelial monocyte chemoattractant protein-1 production and induces increased adhesion of neutrophils to endothelial cells by upregulating intercellular cell adhesion molecule-1. J Am Soc Nephrol. 2001;12(5):932–40.

    PubMed  CAS  Google Scholar 

  103. Casselman BL, Kilgore KS, Miller BF, Warren JS. Antibodies to neutrophil cytoplasmic antigens induce monocyte chemoattractant protein-1 secretion from human monocytes. J Lab Clin Med. 1995;126(5):495–502.

    PubMed  CAS  Google Scholar 

  104. Berger SP, Seelen MAJ, Hiemstra PS, et al. Proteinase 3, the major autoantigen of Wegener’s granulomatosis, enhances IL-8 production by endothelial cells in vitro. J Am Soc Nephrol. 1996;7:694–701.

    PubMed  CAS  Google Scholar 

  105. Brooks CJ, King WJ, Radford DJ, Adu D, McGrath M, Savage COS. IL-1b production by human polymorphonuclear leucocytes stimulated by anti-neutrophil cytoplasmic autoantibodies: relevance to systemic vasculitis. Clin Exp Immunol. 1996; 106:273–9.

    PubMed  CAS  Google Scholar 

  106. Ralston DR, Marsh CB, Lowe MP, Wewers MD. Antineutrophil cytoplasmic antibodies induce monocyte IL-8 release. Role of surface proteinase-3, alpha1-antitrypsin, and Fcgamma receptors. J Clin Invest. 1997;100(6):1416–24.

    PubMed  CAS  Google Scholar 

  107. Zhou Z, Dionne A, Richard C, Menard HA. On the origin of surface proteinase 3 of nonmyeloid cells: evidence favoring an exogenous source. Clin Immunol. 2000;97(2):171–81.

    PubMed  CAS  Google Scholar 

  108. Yang JJ, Preston GA, Pendergraft WF, et al. Internalization of proteinase 3 is concomitant with endothelial cell apoptosis and internalization of myeloperoxidase with generation of intracellular oxidants. Am J Pathol. 2001;158(2):581–92.

    PubMed  CAS  Google Scholar 

  109. Brons RH, de Jong MC, de Boer NK, Stegeman CA, Kallenberg CG, Cohen Tervaert JW. Detection of immune deposits in skin lesions of patients with Wegener’s granulomatosis. Ann Rheum Dis. 2001;60(12):1097–102.

    PubMed  CAS  Google Scholar 

  110. Haas M, Eustace JA. Immune complex deposits in ANCA-associated crescentic glomerulonephritis: a study of 126 cases. Kidney Int. 2004;65(6):2145–52.

    PubMed  CAS  Google Scholar 

  111. Harper L, Cockwell P, Adu D, Savage CO. Neutrophil priming and apoptosis in anti-neutrophil cytoplasmic autoantibody-associated vasculitis. Kidney Int. 2001;59(5):1729–38.

    PubMed  CAS  Google Scholar 

  112. Harper L, Ren Y, Savill J, Adu D, Savage CO. Antineutrophil cytoplasmic antibodies induce reactive oxygen-dependent dysregulation of primed neutrophil apoptosis and clearance by macrophages. Am J Pathol. 2000;157(1):211–20.

    PubMed  CAS  Google Scholar 

  113. Xiao H, Heeringa P, Hu P, et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest. 2002;110(7):955–63.

    PubMed  CAS  Google Scholar 

  114. Little MA, Smyth CL, Yadav R, et al. Antineutrophil cytoplasm antibodies directed against myeloperoxidase augment leukocyte-microvascular interactions in vivo. Blood. 2005;106(6):2050–8.

    PubMed  CAS  Google Scholar 

  115. Pfister H, Ollert M, Frohlich LF, et al. Antineutrophil cytoplasmic autoantibodies against the murine homolog of proteinase 3 (Wegener autoantigen) are pathogenic in vivo. Blood. 2004; 104(5):1411–8.

    PubMed  CAS  Google Scholar 

  116. 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; 170(1):52–64.

    PubMed  CAS  Google Scholar 

  117. Huugen D, van Esch A, Xiao H, et al. Inhibition of complement factor C5 protects against anti-myeloperoxidase antibody-mediated glomerulonephritis in mice. Kidney Int. 2007; 71(7):646–54.

    PubMed  CAS  Google Scholar 

  118. 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(2):289–98.

    PubMed  CAS  Google Scholar 

  119. Xing GQ, Chen M, Liu G, et al. Complement activation is involved in renal damage in human antineutrophil cytoplasmic autoantibody associated pauci-immune vasculitis. J Clin Immunol. 2009;29(3):282–91.

    PubMed  CAS  Google Scholar 

  120. Schlieben DJ, Korbet SM, Kimura RE, Schwartz MM, Lewis EJ. Pulmonary-renal syndrome in a newborn with placental transmission of ANCAs. Am J Kidney Dis. 2005;45(4):758–61.

    PubMed  Google Scholar 

  121. Silva F, Specks U, Sethi S, Irazabal MV, Fervenza FC. Successful pregnancy and delivery of a healthy newborn despite transplacental transfer of antimyeloperoxidase antibodies from a mother with microscopic polyangiitis. Am J Kidney Dis. 2009;54(3):542–5.

    PubMed  Google Scholar 

  122. Finkielman JD, Merkel PA, Schroeder D, et al. Antiproteinase 3 antineutrophil cytoplasmic antibodies and disease activity in Wegener granulomatosis. Ann Intern Med. 2007;147(9):611–9.

    PubMed  Google Scholar 

  123. Hagen EC, Daha MR, Hermans J, et al. Diagnostic value of standardized assays for anti-neutrophil cytoplasmic antibodies in idiopathic systemic vasculitis. EC/BCR Project for ANCA Assay Standardization [see comments]. Kidney Int. 1998;53(3):743–53.

    PubMed  CAS  Google Scholar 

  124. Russell KA, Wiegert E, Schroeder DR, Homburger HA, Specks U. Detection of anti-neutrophil cytoplasmic antibodies under actual clinical testing conditions. Clin Immunol. 2002; 103(2):196–203.

    PubMed  CAS  Google Scholar 

  125. Holle JU, Csernok E, Fredenhagen G, Backes M, Bremer JP, Gross WL. Clinical evaluation of hsPR3-ANCA ELISA for detection of antineutrophil cytoplasmatic antibodies directed against proteinase 3. Ann Rheum Dis. 2010;69(2):468–9.

    PubMed  CAS  Google Scholar 

  126. Holle JU, Hellmich B, Backes M, Gross WL, Csernok E. Variations in performance characteristics of commercial enzyme immunoassay kits for the detection of antineutrophil cytoplasmic antibodies: what is the optimal cut-off? Ann Rheum Dis. 2005;64(12):1773–9.

    PubMed  CAS  Google Scholar 

  127. Savige J, Gillis D, Benson E, et al. International consensus statement on testing and reporting of antineutrophil cytoplasmic antibodies (ANCA). Am J Clin Pathol. 1999;111:507–13.

    PubMed  CAS  Google Scholar 

  128. Merkel PA, Polisson RP, Chang Y, Skates SJ, Niles JL. Prevalence of antineutrophil cytoplasmic antibodies in a large inception cohort of patients with connective tissue disease. Ann Intern Med. 1997;126:866–73.

    PubMed  CAS  Google Scholar 

  129. Mandl LA, Solomon DH, Smith EL, Lew RA, Katz JN, Shmerling RH. Using antineutrophil cytoplasmic antibody testing to diagnose vasculitis: can test-ordering guidelines improve diagnostic accuracy? Arch Intern Med. 2002;162(13):1509–14.

    PubMed  Google Scholar 

  130. Vassilopoulos D, Niles JL, Villa-Forte A, et al. Prevalence of antineutrophil cytoplasmic antibodies in patients with various pulmonary diseases or multiorgan dysfunction. Arthritis Rheum. 2003; 49(2):151–5.

    PubMed  Google Scholar 

  131. Specks U. The growing complexity of the pathology associated with cocaine use. J Clin Rheumatol. 2011;17(4):167–8.

    PubMed  Google Scholar 

  132. McGrath MM, Isakova T, Rennke HG, Mottola AM, Laliberte KA, Niles JL. Contaminated cocaine and antineutrophil cytoplasmic antibody-associated disease. Clin J Am Soc Nephrol. 2011;6(12):2799–805.

    PubMed  Google Scholar 

  133. Polychronopoulos VS, Prakash UB, Golbin JM, Edell ES, Specks U. Airway involvement in Wegener’s granulomatosis. Rheum Dis Clin North Am. 2007;33(4):755–75.

    PubMed  Google Scholar 

  134. Vergunst CE, van Gurp E, Hagen EC, et al. An index for renal outcome in ANCA-associated glomerulonephritis. Am J Kidney Dis. 2003;41(3):532–8.

    PubMed  Google Scholar 

  135. Berden AE, Ferrario F, Hagen EC, et al. Histopathologic classification of ANCA-associated glomerulonephritis. J Am Soc Nephrol. 2010;21(10):1628–36.

    PubMed  Google Scholar 

  136. Berden AE, Jones RB, Erasmus DD, et al. Tubular lesions predict renal outcome in antineutrophil cytoplasmic antibody-associated glomerulonephritis after rituximab therapy. J Am Soc Nephrol. 2012;23(2):313–21.

    PubMed  CAS  Google Scholar 

  137. Hogan SL, Nachman PH, Wilkman AS, Jennette JC, Falk RJ. Prognostic markers in patients with antineutrophil cytoplasmic autoantibody-associated microscopic polyangiitis and glomerulonephritis. J Am Soc Nephrol. 1996;7(1):23–32.

    PubMed  CAS  Google Scholar 

  138. Booth AD, Almond MK, Burns A, et al. Outcome of ANCA-associated renal vasculitis: a 5-year retrospective study. Am J Kidney Dis. 2003;41(4):776–84.

    PubMed  Google Scholar 

  139. Weidner S, Geuss S, Hafezi-Rachti S, Wonka A, Rupprecht HD. ANCA-associated vasculitis with renal involvement: an outcome analysis. Nephrol Dial Transplant. 2004;19(6):1403–11.

    PubMed  Google Scholar 

  140. Flossmann O, Berden A, de Groot K, et al. Long-term patient survival in ANCA-associated vasculitis. Ann Rheum Dis. 2011; 70(3):488–94.

    PubMed  Google Scholar 

  141. Specks U. Methotrexate for Wegener’s granulomatosis: what is the evidence? Arthritis Rheum. 2005;52(8):2237–42.

    PubMed  CAS  Google Scholar 

  142. De Groot K, Rasmussen N, Bacon PA, et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2005;52(8):2461–9.

    PubMed  Google Scholar 

  143. Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003;349(1):36–44.

    PubMed  CAS  Google Scholar 

  144. The WGET Research Group. Etanercept plus standard therapy for Wegener’s granulomatosis. N Engl J Med. 2005;352(4):351–61.

    Google Scholar 

  145. Clowse ME, Copland SC, Hsieh TC, et al. Ovarian reserve diminished by oral cyclophosphamide therapy for granulomatosis with polyangiitis (Wegener’s). Arthritis Care Res. 2011; 63(12):1777–81.

    CAS  Google Scholar 

  146. de Groot K, Harper L, Jayne DR, et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody—associated vasculitis: a randomized trial. Ann Intern Med. 2009;150(10):670–80.

    PubMed  Google Scholar 

  147. de Groot K, Adu D, Savage CO. The value of pulse cyclophosphamide in ANCA-associated vasculitis: meta-analysis and critical review. Nephrol Dial Transplant. 2001;16(10):2018–27.

    PubMed  Google Scholar 

  148. Jones RB, Tervaert JW, Hauser T, et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010;363(3):211–20.

    PubMed  CAS  Google Scholar 

  149. Specks U, Stone JH, RAVE Research Group. Long-term efficacy and safety results of the RAVE trial [abstract]. Clin Exp Immunol. 2011;164 Suppl 1:65.

    Google Scholar 

  150. Hu W, Liu C, Xie H, Chen H, Liu Z, Li L. Mycophenolate mofetil versus cyclophosphamide for inducing remission of ANCA vasculitis with moderate renal involvement. Nephrol Dial Transplant. 2008;23(4):1307–12.

    PubMed  CAS  Google Scholar 

  151. Silva F, Specks U, Kalra S, et al. Mycophenolate mofetil for induction and maintenance of remission in microscopic polyangiitis with mild to moderate renal involvement—a prospective, open-label pilot trial. Clin J Am Soc Nephrol. 2010; 5(3):445–53.

    PubMed  CAS  Google Scholar 

  152. Bomback AS, Appel GB, Radhakrishnan J, et al. ANCA-associated glomerulonephritis in the very elderly. Kidney Int. 2011;79(7):757–64.

    PubMed  Google Scholar 

  153. Jayne DR, Gaskin G, Rasmussen N, et al. Randomized trial of plasma exchange or high-dosage methylprednisolone as adjunctive therapy for severe renal vasculitis. J Am Soc Nephrol. 2007;18(7):2180–8.

    PubMed  CAS  Google Scholar 

  154. Klemmer PJ, Chalermskulrat W, Reif MS, Hogan SL, Henke DC, Falk RJ. Plasmapheresis therapy for diffuse alveolar hemorrhage in patients with small-vessel vasculitis. Am J Kidney Dis. 2003;42(6):1149–53.

    PubMed  Google Scholar 

  155. Cartin-Ceba R, Fervenza FC, Specks U. Treatment of antineutrophil cytoplasmic antibody-associated vasculitis with rituximab. Curr Opin Rheumatol. 2012;24(1):15–23.

    PubMed  CAS  Google Scholar 

  156. Cartin-Ceba R, Golbin JM, Keogh KA, et al. Rituximab for remission induction and maintenance in refractory granulomatosis with polyangiitis (Wegener’s): a single-center ten-year experience. Arthritis Rheum. 2012;64(11):3770–8.

    PubMed  CAS  Google Scholar 

  157. Franssen CF, Gans RO, Arends B, et al. Differences between anti-myeloperoxidase- and anti-proteinase 3-associated renal disease. Kidney Int. 1995;47(1):193–9.

    PubMed  CAS  Google Scholar 

  158. Slot MC, Tervaert JW, Franssen CF, Stegeman CA. Renal survival and prognostic factors in patients with PR3-ANCA associated vasculitis with renal involvement. Kidney Int. 2003;63(2):670–7.

    PubMed  Google Scholar 

  159. Pagnoux C, Mahr A, Hamidou MA, et al. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med. 2008;359(26):2790–803.

    PubMed  CAS  Google Scholar 

  160. Hiemstra TF, Walsh M, Mahr A, et al. Mycophenolate mofetil vs azathioprine for remission maintenance in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized controlled trial. JAMA. 2010;304(21):2381–8.

    PubMed  CAS  Google Scholar 

  161. Lionaki S, Hogan SL, Jennette CE, et al. The clinical course of ANCA small-vessel vasculitis on chronic dialysis. Kidney Int. 2009;76(6):644–51.

    PubMed  Google Scholar 

  162. Wolfe RA, Ashby VB, Milford EL, et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med. 1999;341(23):1725–30.

    PubMed  CAS  Google Scholar 

  163. Gera M, Griffin MD, Specks U, Leung N, Stegall MD, Fervenza FC. Recurrence of ANCA-associated vasculitis following renal transplantation in the modern era of immunosupression. Kidney Int. 2007;71(12):1296–301.

    PubMed  CAS  Google Scholar 

  164. Little MA, Hassan B, Jacques S, et al. Renal transplantation in systemic vasculitis: when is it safe? Nephrol Dial Transplant. 2009;24(10):3219–25.

    PubMed  Google Scholar 

  165. Geetha D, Eirin A, True K, et al. Renal transplantation in antineutrophil cytoplasmic antibody-associated vasculitis: a multicenter experience. Transplantation. 2011;91(12):1370–5.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA

    Ulrich Specks M.D.

Authors
  1. Ulrich Specks M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ulrich Specks M.D. .

Editor information

Editors and Affiliations

  1. Div. Nephrology & Hypertension, Mayo Clinic Dept. Internal Medicine, Rochester, Minnesota, USA

    Fernando C. Fervenza

  2. Renal Division, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Julie Lin

  3. Mayo Clinic, Rochester, Minnesota, USA

    Sanjeev Sethi

  4. Renal Division, Brigham and Women's Hospital Harvard Medical School, Boston, Massachusetts, USA

    Ajay K. Singh

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Specks, U. (2014). Pathogenesis and Management of ANCA-Associated Vasculitis. In: Fervenza, F., Lin, J., Sethi, S., Singh, A. (eds) Core Concepts in Parenchymal Kidney Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-8166-9_10

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-8166-9_10

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4614-8165-2

  • Online ISBN: 978-1-4614-8166-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation