New pathophysiological insights and treatment of ANCA-associated vasculitis

Kidney International

Volumn 79, Issue 6, 2011, Pages 599-612

  Wilde, Benjamin ^a,b   Van Paassen, Pieter ^a   Witzke, Oliver ^b   Tervaert, Jan Willem Cohen ^a  

^a MAASTRICHT UNIVERSITY MEDICAL CENTER   (Netherlands)

^b UNIVERSITY OF DUISBURG ESSEN   (Germany)

Author keywords

ANCA; glomerulonephritis; vasculitis

Indexed keywords

15 DEOXYSPERGUALIN; ABATACEPT; ADALIMUMAB; ALEMTUZUMAB; ALPHA INTERFERON; AZATHIOPRINE; BASILIXIMAB; BELATACEPT; COTRIMOXAZOLE; CYCLOPHOSPHAMIDE; DACLIZUMAB; ECULIZUMAB; EPRATUZUMAB; ETANERCEPT; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; IMMUNOGLOBULIN; INFLIXIMAB; LEFLUNOMIDE; MEPOLIZUMAB; METHOTREXATE; METHYLPREDNISOLONE; MYCOPHENOLIC ACID 2 MORPHOLINOETHYL ESTER; NATALIZUMAB; PEXELIZUMAB; PLACEBO; PREDNISOLONE; RITUXIMAB; STEROID; THYMOCYTE ANTIBODY; UNINDEXED DRUG;

ANCA ASSOCIATED VASCULITIS; ANTIBODY PRODUCTION; B LYMPHOCYTE; CELLULAR IMMUNITY; CHURG STRAUSS SYNDROME; COMPLEMENT SYSTEM; DEGRANULATION; DRUG DOSE REDUCTION; DRUG SAFETY; DRUG TARGETING; HUMAN; IMMUNOPATHOGENESIS; LIVER FAILURE; LIVER TOXICITY; LOW DRUG DOSE; LYMPHOID TISSUE; MALIGNANT NEOPLASTIC DISEASE; MICROSCOPIC POLYANGIITIS; MULTIPLE CYCLE TREATMENT; MULTIPLE SCLEROSIS; NEUTROPHIL; NONHUMAN; PATHOPHYSIOLOGY; PLASMAPHERESIS; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; STAPHYLOCOCCUS AUREUS; T LYMPHOCYTE; UNSPECIFIED SIDE EFFECT; WEGENER GRANULOMATOSIS;

EID: 79952184992     PISSN: 00852538     EISSN: 15231755     Source Type: Journal    
DOI: 10.1038/ki.2010.472     Document Type: Review

References (181)

1. Kallenberg CG, Brouwer E, Weening JJ et al. Anti-neutrophil cytoplasmic antibodies: current diagnostic and pathophysiological potential. Kidney Int 1994; 46: 1-15. (Pubitemid 24210431)
2. Jennette JC, Falk RJ, Andrassy K et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994; 37: 187-192.
3. Lie JT. Illustrated histopathologic classification criteria for selected vasculitis syndromes. Arthritis Rheum 1990; 33: 1074-1087. (Pubitemid 20273291)
4. Tervaert JWC, Goldschmeding R, Elema JD et al. Autoantibodies against myeloid lysosomal-enzymes in crescentic glomerulonephritis. Kidney Int 1990; 37: 799-806. (Pubitemid 20056854)
5. Masi AT, Hunder GG, Lie JT et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum 1990; 33: 1094-1100. (Pubitemid 20273293)
6. Leavitt RY, Fauci AS, Bloch DA et al. The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis. Arthritis Rheum 1990; 33: 1101-1107. (Pubitemid 20273294)
7. Cohen Tervaert JW, Limburg PC, Elema JD et al. Detection of autoantibodies against myeloid lysosomal-enzymes-a useful adjunct to classification of patients with biopsy-proven necrotizing arteritis. Am J Med 1991; 91: 59-66.
8. Falk RJ, Terrell RS, Charles LA et al. Antineutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proc Natl Acad Sci USA 1990; 87: 4115-4119. (Pubitemid 20217992)
9. van Paassen P, Tervaert JWC, Heeringa P. Mechanisms of vasculitis: how pauci-immune is ANCA-associated renal vasculitis? Nephron Exp Nephrol 2007; 105: 10-16.
10. Muller Kobold AC, van Wijk RT, Franssen CF et al. 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: 433-440.
11. Tervaert JW. Proteinase 3: a cofactor for the binding of antineutrophil cytoplasm antibodies (ANCA) to endothelial cells? Kidney Int 2000; 57: 2171-2172.
12. Gomez-Puerta JA, Bosch X. Anti-neutrophil cytoplasmic antibody pathogenesis in small-vessel vasculitis: an update. Am J Pathol 2009; 175: 1790-1798.
13. van Rossum AP, Rarok AA, Huitema MG et al. Constitutive membrane expression of proteinase 3 (PR3) and neutrophil activation by anti-PR3 antibodies. J Leukoc Biol 2004; 76: 1162-1170. (Pubitemid 39602952)
14. Radford DJ, Lord JM, Savage COS. 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: 171-179. (Pubitemid 29479799)
15. Csernok E, Ernst M, Schmitt W et al. Activated neutrophils express proteinase-3 on their plasma-membrane in-vitro and in-vivo. Clin Exp Immunol 1994; 95: 244-250. (Pubitemid 24207134)
16. Muller Kobold AC, van der Geld YM, Limburg PC et al. Pathophysiology of ANCA-associated glomerulonephritis. Nephrol Dial Transplant 1999; 14: 1366-1375. (Pubitemid 29241725)
17. Muller Kobold AC, Kallenberg CG, Tervaert JW. Leucocyte membrane expression of proteinase 3 correlates with disease activity in patients with Wegener's granulomatosis. Br J Rheumatol 1998; 37: 901-907.
18. Radford DJ, Savage COS, Nash GB. Treatment of rolling neutrophils with antineutrophil cytoplasmic antibodies causes conversion to firm integrin-mediated adhesion. Arthritis Rheum 2000; 43: 1337-1345. (Pubitemid 30416318)
19. Schreiber A, Luft FC, Kettritz R. Membrane proteinase 3 expression and ANCA-induced neutrophil activation. Kidney Int 2004; 65: 2172-2183. (Pubitemid 38670003)
20. Lu X, Garfield A, Rainger GE et al. Mediation of endothelial cell damage by serine proteases, but not superoxide, released from antineutrophil cytoplasmic antibody-stimulated neutrophils. Arthritis Rheum 2006; 54: 1619-1628.
21. Westlin WF, Gimbrone Jr MA. Neutrophil-mediated damage to human vascular endothelium. Role of cytokine activation. Am J Pathol 1993; 142: 117-128. (Pubitemid 23026916)
22. Weiss S. Tissue destruction by neutrophils. N Engl J Med 1989; 320: 365-376. (Pubitemid 19106873)
23. Dean RT, Nick HP, Schnebli HP. Free radicals inactivate human neutrophil elastase and its inhibitors with comparable efficiency. Biochem Biophys Res Commun 1989; 159: 821-827. (Pubitemid 19089825)
24. Dolman KM, Stegeman CA, van de Wiel BA et al. Relevance of classic anti-neutrophil cytoplasmic autoantibody (C-ANCA)-mediated inhibition of proteinase 3-alpha 1-antitrypsin complexation to disease activity in Wegener's granulomatosis. Clin Exp Immunol 1993; 93: 405-410. (Pubitemid 23276267)
25. Sibelius U, Hattar K, Schenkel A et al. Wegener's granulomatosis: antiproteinase 3 antibodies are potent inductors of human endothelial cell signaling and leakage response. J Exp Med 1998; 187: 497-503. (Pubitemid 28093352)
26. De Bandt M, Meyer O, Dacosta L et al. Anti-proteinase-3 (PR3) antibodies (C-ANCA) recognize various targets on the human umbilical vein endothelial cell (HUVEC) membrane. Clin Exp Immunol 1999; 115: 362-368. (Pubitemid 29052464)
27. Pan LF, Kreisle RA, Shi YD. Detection of Fcgamma receptors on human endothelial cells stimulated with cytokines tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). Clin Exp Immunol 1998; 112: 533-538. (Pubitemid 28267438)
28. Nagao T, Matsumura M, Mabuchi A et al. Up-regulation of adhesion molecule expression in glomerular endothelial cells by antimyeloperoxidase antibody. Nephrol Dial Transplant 2007; 22: 77-87. (Pubitemid 46050331)
29. Radford DJ, Luu NT, Hewins P et al. Antineutrophil cytoplasmic antibodies stabilize adhesion and promote migration of flowing neutrophils on endothelial cells. Arthritis Rheum 2001; 44: 2851-2861. (Pubitemid 34016205)
30. Calderwood JW, Williams JM, Morgan MD et al. ANCA induces beta(2) integrin and CXC chemokine-dependent neutrophil-endothelial cell interactions that mimic those of highly cytokine-activated endothelium. J Leukoc Biol 2005; 77: 33-43. (Pubitemid 40310690)
31. Heeringa P, Huugen D, Tervaert JW. Anti-neutrophil cytoplasmic autoantibodies and leukocyte-endothelial interactions: a sticky connection? Trends Immunol 2005; 26: 561-564. (Pubitemid 41726442)
32. Xiao H, Heeringa P, Hu PQ et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest 2002; 110: 955-963.
33. Huugen D, Xiao H, van Esch A et al. Aggravation of antimyeloperoxidase antibody-induced glomerulonephritis by bacterial lipopolysaccharide: role of tumor necrosis factor-alpha. Am J Pathol 2005; 167: 47-58. (Pubitemid 40884769)
34. Xiao H, Heeringa P, Liu Z et al. The role of neutrophils in the induction of glomerulonephritis by anti-myeloperoxidase antibodies. Am J Pathol 2005; 167: 39-45. (Pubitemid 40884768)
35. Little MA, Smyth L, Salama AD et al. Experimental autoimmune vasculitis: an animal model of anti-neutrophil cytoplasmic autoantibodyassociated systemic vasculitis. Am J Pathol 2009; 174: 1212-1220.
36. 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: 1411-1418. (Pubitemid 39166519)
37. Primo VC, Marusic S, Franklin CC et al. Anti-PR3 immune responses induce segmental and necrotizing glomerulonephritis. Clin Exp Immunol 2010; 159: 327-337.
38. Hattar K, Oppermann S, Ankele C et al. c-ANCA induce neutrophilmediated lung injury: a model of acute Wegener's granulomatosis. Eur Respir J 2010; 36: 187-195.
39. Cohen Tervaert JW, Damoiseaux J. Fifty years of antineutrophil cytoplasmic antibodies (ANCA) testing: do we need to revise the international consensus statement on testing and reporting on ANCA? APMIS 2009; 117: 55-59.
40. Tervaert JW, Goldschmeding R, Elema JD et al. Association of autoantibodies to myeloperoxidase with different forms of vasculitis. Arthritis Rheum 1990; 33: 1264-1272. (Pubitemid 20273316)
41. Falk RJ, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engl J Med 1988; 318: 1651-1657.
42. Goldschmeding R, van der Schoot CE, ten Bokkel Huinink D et al. Wegener's granulomatosis autoantibodies identify a novel diisopropylfluorophosphate- binding protein in the lysosomes of normal human neutrophils. J Clin Invest 1989; 84: 1577-1587. (Pubitemid 19272247)
43. Niles JL, McCluskey RT, Ahmad MF et al. Wegener's granulomatosis autoantigen is a novel neutrophil serine proteinase. Blood 1989; 74: 1888-1893. (Pubitemid 19269085)
44. Jenne DE, Tschopp J, Ludemann J et al. Wegener's autoantigen decoded. Nature 1990; 346: 520. (Pubitemid 20238800)
45. Kain R, Exner M, Brandes R et al. Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis. Nat Med 2008; 14: 1088-1096.
46. Pendergraft 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: 72-79. (Pubitemid 38524701)
47. McGuire KL, Holmes DS. Role of complementary proteins in autoimmunity: an old idea re-emerges with new twists. Trends Immunol 2005; 26: 367-372. (Pubitemid 40835842)
48. Stegeman CA, Tervaert JWC, Sluiter WJ et al. Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis. Ann Intern Med 1994; 120: 12-17. (Pubitemid 24011495)
49. Stegeman CA, Cohen Tervaert JW, de Jong PE et al. Trimethoprimsulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's granulomatosis. New Engl J Med 1996; 335: 16-20. (Pubitemid 26230808)
50. Popa ER, Tervaert JW. The relation between Staphylococcus aureus and Wegener's granulomatosis: current knowledge and future directions. Intern Med 2003; 42: 771-780. (Pubitemid 37258688)
51. Stegeman C, Cohen Tervaert J, Kallenberg C. Co-trimoxazole and Wegener's granulomatosis: more than a coincidence? Nephrol Dial Transplant 1997; 12: 652-655.
52. Tervaert JW, Mulder L, Stegeman C et al. Occurrence of autoantibodies to human leucocyte elastase in Wegener's granulomatosis and other inflammatory disorders. Ann Rheum Dis 1993; 52: 115-120. (Pubitemid 23065670)
53. Wiesner O, Russell KA, Lee AS et al. Antineutrophil cytoplasmic antibodies reacting with human neutrophil elastase as a diagnostic marker for cocaine-induced midline destructive lesions but not autoimmune vasculitis. Arthritis Rheum 2004; 50: 2954-2965. (Pubitemid 39209534)
54. Dolman KM, Gans RO, Vervaat TJ et al. Vasculitis and antineutrophil cytoplasmic autoantibodies associated with propylthiouracil therapy. Lancet 1993; 342: 651-652. (Pubitemid 23271506)
55. Slot MC, Links TP, Stegeman CA et al. Occurrence of antineutrophil cytoplasmic antibodies and associated vasculitis in patients with hyperthyroidism treated with antithyroid drugs: a long-term followup study. Arthritis Rheum 2005; 53: 108-113. (Pubitemid 40216359)
56. Hu CH, O'Loughlin S, Winkelmann RK. Cutaneous manifestations of Wegener granulomatosis. Arch Dermatol 1977; 113: 175-182. (Pubitemid 8033156)
57. Van Timmeren MM, Chen M, Heeringa P. Review article: pathogenic role of complement activation in anti-neutrophil cytoplasmic auto-antibodyassociated vasculitis. Nephrology 2009; 14: 16-25.
58. Haas M, Eustace JA. Immune complex deposits in ANCA-associated crescentic glomerulonephritis: a study of 126 cases. Kidney Int 2004; 65: 2145-2152. (Pubitemid 38670000)
59. Haas M, Jafri J, Bartosh SM et al. ANCA-associated crescentic glomerulonephritis with mesangial IgA deposits. Am J Kidney Dis 2000; 36: 709-718.
60. Neumann I, Regele H, Kain R et al. Glomerular immune deposits are associated with increased proteinuria in patients with ANCA-associated crescentic nephritis. Nephrol Dial Transplant 2003; 18: 524-531. (Pubitemid 36305657)
61. Andrassy K, Waldherr R, Erb A et al. De novo glomerulonephritis in patients during remission from Wegener's granulomatosis. Clin Nephrol 1992; 38: 295-298. (Pubitemid 23030778)
62. Brouwer E, Huitema MG, Mulder AHL et al. Neutrophil activation in-vitro and in-vivo in Wegener's granulomatosis. Kidney Int 1994; 45: 1120-1131. (Pubitemid 24234730)
63. Allmaras E, Nowack R, Andrassy K et al. Rapidly progressive IgA nephropathy with anti-myeloperoxidase antibodies benefits from immunosuppression. Clin Nephrol 1997; 48: 269-273. (Pubitemid 27496649)
64. Grotz W, Wanner C, Keller E et al. Crescentic glomerulonephritis in Wegener's granulomatosis: morphology, therapy, outcome. Clin Nephrol 1991; 35: 243-251.
65. Pinching AJ, Lockwood CM, Pussell BA et al. Wegener's granulomatosis: observations on 18 patients with severe renal disease. Q JMed 1983; 52: 435-460. (Pubitemid 14245583)
66. Ronco P, Verroust P, Mignon F et al. Immunopathological studies of polyarteritis nodosa and Wegener's granulomatosis: a report of 43 patients with 51 renal biopsies. Q J Med 1983; 52: 212-223. (Pubitemid 14248295)
67. Vizjak A, Rott T, Koselj-Kajtna M et al. Histologic and immunohistologic study and clinical presentation of ANCA-associated glomerulonephritis with correlation to ANCA antigen specificity. Am J Kidney Dis 2003; 41: 539-549. (Pubitemid 36278370)
68. Brons RH, de Jong MCJM, de Boer NK et al. Detection of immune deposits in skin lesions of patients with Wegener's granulomatosis. Ann Rheum Dis 2001; 60: 1097-1102. (Pubitemid 33096073)
69. Shingu M, Nonaka S, Nishimukai H et al. Activation of complement in normal serum by hydrogen-peroxide and hydrogen peroxide-related oxygen radicals produced by activated neutrophils. Clin Exp Immunol 1992; 90: 72-78.
70. Vogt W. Complement activation by myeloperoxidase products released from stimulated human polymorphonuclear leukocytes. Immunobiology 1996; 195: 334-346. (Pubitemid 26275778)
71. Johnson U, Ohlsson K, Olsson I. Effects of granulocyte neutral proteases on complement components. Scand J Immunol 1976; 5: 421-426.
72. Xiao H, Schreiber A, Heeringa P et al. Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies. Am J Pathol 2007; 170: 52-64. (Pubitemid 47339189)
73. Schreiber A, Xiao H, Jennette JC et al. C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis. J Am Soc Nephrol 2009; 20: 289-298.
74. 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: 646-654. (Pubitemid 46494558)
75. Stassen PM, Derks RPH, Kallenberg CGM et al. Venous thromboembolism in ANCA-associated vasculitis-incidence and risk factors. Rheumatology 2008; 47: 530-534.
76. Markiewski MM, Nilsson B, Nilsson Ekdahl K et al. Complement and coagulation: strangers or partners in crime? Trends Immunol 2007; 28: 184-192.
77. Tipping PG, Holdsworth SR. T cells in crescentic glomerulonephritis. J Am Soc Nephrol 2006; 17: 1253-1263. (Pubitemid 43673405)
78. Mueller A, Holl-Ulrich K, Lamprecht P et al. Germinal centre-like structures in Wegener's granuloma: the morphological basis for autoimmunity? Rheumatology 2008; 47: 1111-1113.
79. Bolton WK, Innes Jr DJ, Sturgill BC et al. T-cells and macrophages in rapidly progressive glomerulonephritis: clinicopathologic correlations. Kidney Int 1987; 32: 869-876. (Pubitemid 18015518)
80. Gephardt GN, Ahmad M, Tubbs RR. Pulmonary vasculitis (Wegener's granulomatosis). Immunohistochemical study of T and B cell markers. Am J Med 1983; 74: 700-704. (Pubitemid 13125990)
81. Popa ER, Stegeman CA, Bos NA et al. Differential B-and T-cell activation in Wegener's granulomatosis. J Allergy Clin Immunol 1999; 103: 885-894. (Pubitemid 29297593)
82. Stegeman CA, Tervaert JWC, Huitema MG et al. Serum markers of T-cell activation in relapses of Wegener's granulomatosis. Clin Exp Immunol 1993; 91: 415-420. (Pubitemid 23074146)
83. Schmitt WH, Heesen C, Csernok E et al. Elevated serum levels of soluble interleukin-2 receptor in patients with Wegener's granulomatosis. Association with disease activity. Arthritis Rheum 1992; 35: 1088-1096.
84. Brouwer E, Tervaert JW, Horst G et al. Predominance of IgG1 and IgG4 subclasses of anti-neutrophil cytoplasmic autoantibodies (ANCA) in patients with Wegener's granulomatosis and clinically related disorders. Clin Exp Immunol 1991; 83: 379-386.
85. Schmitt WH, Hagen EC, Neumann I et al. Treatment of refractory Wegener's granulomatosis with antithymocyte globulin (ATG): an open study in 15 patients. Kidney Int 2004; 65: 1440-1448. (Pubitemid 38406986)
86. Marinaki S, Neumann I, Kalsch AI et al. Abnormalities of CD4 T cell subpopulations in ANCA-associated vasculitis. Clin Exp Immunol 2005; 140: 181-191. (Pubitemid 40461088)
87. Marinaki S, Kalsch AI, Grimminger P et al. Persistent T-cell activation and clinical correlations in patients with ANCA-associated systemic vasculitis. Nephrol Dial Transplant 2006; 21: 1825-1832. (Pubitemid 43985709)
88. Wilde B, Dolff S, Cai X et al. CD4+CD25+ T-cell populations expressing CD134 and GITR are associated with disease activity in patients with Wegener's granulomatosis. Nephrol Dial Transplant 2009; 24: 161-171.
89. Abdulahad WH, Kallenberg CG, Limburg PC et al. Urinary CD4+ effector memory T cells reflect renal disease activity in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2009; 60: 2830-2838.
90. Lamprecht P, Csernok E, Gross WL. Effector memory T cells as driving force of granuloma formation and autoimmunity in Wegener's granulomatosis. J Intern Med 2006; 260: 187-191. (Pubitemid 44253632)
91. Bettelli E, Oukka M, Kuchroo VK. TH-17 cells in the circle of immunity and autoimmunity. Nat Immunol 2007; 8: 345-350. (Pubitemid 46745409)
92. Abdulahad WH, Stegeman CA, Limburg PC et al. Skewed distribution of Th17 lymphocytes in patients with Wegener's granulomatosis in remission. Arthritis Rheum 2008; 58: 2196-2205. (Pubitemid 351988114)
93. 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 ANCAassociated vasculitis. Nephrol Dial Transplant 2010; 25: 2209-2217.
94. Ordonez L, Bernard I, L'Faqihi-Olive F et al. CD45RC isoform expression identifies functionally distinct T cell subsets differentially distributed between healthy individuals and AAV patients. PLoS ONE 2009; 4: e5287.
95. 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: 3513-3521. (Pubitemid 28164746)
96. Brusko TM, Putnam AL, Bluestone JA. Human regulatory T cells: role in autoimmune disease and therapeutic opportunities. Immunol Rev 2008; 223: 371-390. (Pubitemid 351986182)
97. Abdulahad WH, van der Geld YM, Stegeman CA et al. Persistent expansion of CD4+ effector memory T cells in Wegener's granulomatosis. Kidney Int 2006; 70: 938-947. (Pubitemid 44285972)
98. Abdulahad WH, Stegeman CA, van der Geld YM et al. Functional defect of circulating regulatory CD4+ T cells in patients with Wegener's granulomatosis in remission. Arthritis Rheum 2007; 56: 2080-2091. (Pubitemid 47110408)
99. 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: 64-73.
100. Aloisi F, Pujol-Borrell R. Lymphoid neogenesis in chronic inflammatory diseases. Nat Rev Immunol 2006; 6: 205-217. (Pubitemid 43290990)
101. Voswinkel J, Muller A, Lamprecht P. Is PR3-ANCA formation initiated in Wegener's granulomatosis lesions? Granulomas as potential lymphoid tissue maintaining autoantibody production. Ann NY Acad Sci 2005; 1051: 12-19. (Pubitemid 41362728)
102. Csernok E, Ai M, Gross WL et al. Wegener autoantigen induces maturation of dendritic cells and licenses them for Th1 priming via the protease-activated receptor-2 pathway. Blood 2006; 107: 4440-4448. (Pubitemid 43801371)
103. Capraru D, Mü ller A, Csernok E et al. Expansion of circulating NKG2D+ effector memory T-cells and expression of NKG2D-ligand MIC in granulomaous lesions in Wegener's granulomatosis. Clin Immunol 2008; 127: 144-150.
104. 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: 859-864.
105. Segerer S, Heller F, Lindenmeyer MT et al. Compartment specific expression of dendritic cell markers in human glomerulonephritis. Kidney Int 2008; 74: 37-46. (Pubitemid 351841902)
106. Wilde B, van Paassen P, Damoiseaux J et al. Dendritic cells in renal biopsies of patients with ANCA-associated vasculitis. Nephrol Dial Transplant 2009; 24: 2151-2156.
107. Steinmetz O, Velden J, Kneissler U et al. Analysis and classification of Bcell infiltrates in lupus and ANCA-associated nephritis. Kidney Int 2008; 74: 448-457.
108. Scholz J, Lukacs-Kornek V, Engel DR et al. Renal dendritic cells stimulate IL-10 production and attenuate nephrotoxic nephritis. J Am Soc Nephrol 2008; 19: 527-537. (Pubitemid 351355396)
109. Lutz MB, Schuler G. Immature, semi-mature and fully mature dendritic cells: which signals induce tolerance or immunity? Trends Immunol 2002; 23: 445-449.
110. Kessenbrock K, Krumbholz M, Schonermarck U et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med 2009; 15: 623-625.
111. Brinkmann V, Reichard U, Goosmann C et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303: 1532-1535. (Pubitemid 38314426)
112. Leadbetter EA, Rifkin IR, Hohlbaum AM et al. Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 2002; 416: 603-607. (Pubitemid 34406754)
113. Yan B, Ye S, Chen G et al. Dysfunctional CD4+, CD25+ regulatory T cells in untreated active systemic lupus erythematosus secondary to interferon-alpha-producing antigen-presenting cells. Arthritis Rheum 2008; 58: 801-812.
114. Papayannopoulos V, Zychlinsky A. NETs: a new strategy for using old weapons. Trends Immunol 2009; 30: 513-521.
115. Fauci AS, Haynes BF, Katz P et al. Wegener's granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years. Ann Intern Med 1983; 98: 76-85. (Pubitemid 13217969)
116. Walton EW. Giant-cell granuloma of the respiratory tract (Wegener's granulomatosis). Br Med J 1958; 2: 265-270.
117. Emadi A, Jones RJ, Brodsky RA. Cyclophosphamide and cancer: golden anniversary. Nat Rev Clin Oncol 2009; 6: 638-647.
118. Cupps TR, Edgar LC, Fauci AS. Suppression of human B lymphocyte function by cyclophosphamide. J Immunol 1982; 128: 2453-2457. (Pubitemid 12124460)
119. Jones RB, Cohen Tervaert JW, Hauser T et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 2010; 363: 211-220.
120. Jayne DRW, 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: 2180-2188. (Pubitemid 47041083)
121. Stone JH, Merkel PA, Spiera R et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010; 363: 221-232.
122. Golbin JM, Specks U. Part 2: Synopsis of B-lymphocyte targeted therapy of ANCA-associated vasculitis. Clin Exp Rheumatol 2007; 25: S74-S76. (Pubitemid 46656608)
123. Walsh M, Chaudhry A, Jayne D. Long-term follow-up of relapsing/ refractory anti-neutrophil cytoplasm antibody associated vasculitis treated with the lymphocyte depleting antibody alemtuzumab (CAMPATH-1H). Ann Rheum Dis 2008; 67: 1322-1327.
124. Mukhtyar C, Guillevin L, Cid MC et al. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis 2009; 68: 310-317.
125. Faurschou M, Sorensen IJ, Mellemkjaer L et al. Malignancies in Wegener's granulomatosis: incidence and relation to cyclophosphamide therapy in a cohort of 293 patients. J Rheumatol 2008; 35: 100-105.
126. de Groot K, Harper L, Jayne DRW et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody associated vasculitis. Ann Intern Med 2009; 150: 670-680.
127. 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: 36-44. (Pubitemid 36765101)
128. Walters GD, Willis NS, Craig JC. Interventions for renal vasculitis in adults. A systematic review. BMC Nephrol 2010; 11: 12
129. EUVAS study group. Plasma exchange and glucocorticoid dosing in the treatment of anti-neutrophil cytoplasm antibody associated vasculitis: an international randomized controlled trial. 2009. http://vasculitis.org/ images/documents/pexivas%20protocol.pdf, accessed on 18 June 2010.
130. Groot KD, 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: 2461-2469. (Pubitemid 41117433)
131. Koukoulaki M, Jayne DRW. Mycophenolate mofetil in anti-neutrophil cytoplasm antibodies-associated systemic vasculitis. Nephron Clinical Practice 2006; 102: c100-c107. (Pubitemid 43289524)
132. Stassen PM, Cohen Tervaert JW, Stegeman CA. Induction of remission in active anti-neutrophil cytoplasmic antibody-associated vasculitis with mycophenolate mofetil in patients who cannot be treated with cyclophosphamide. Ann Rheum Dis 2007; 66: 798-802. (Pubitemid 46846700)
133. Hu W, Liu C, Xie H et al. Mycophenolate mofetil versus cyclophosphamide for inducing remission of ANCA vasculitis with moderate renal involvement. Nephrol Dial Transplant 2008; 23: 1307-1312. (Pubitemid 351767500)
134. Stone JH, Hoffman GS, Holbrook JT et al. Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med 2005; 352: 351-361.
135. Stone JH, Holbrook JT, Marriott MA et al. Solid malignancies among patients in the Wegener's granulomatosis etanercept trial. Arthritis Rheum 2006; 54: 1608-1618.
136. Laurino S, Chaudhry A, Booth A et al. Prospective study of TNF{alpha} blockade with adalimumab in ANCA-associated systemic vasculitis with renal involvement. Nephrol Dial Transplant 2010; 25: 3307.
137. Ribi C, Cohen P, Pagnoux C et al. Treatment of Churg-Strauss syndrome without poor-prognosis factors: a multicenter, prospective, randomized, open-label study of seventy-two patients. Arthritis Rheum 2008; 58: 586-594. (Pubitemid 351294896)
138. Metzler C, Hellmich B, Gause A et al. Churg Strauss syndrome-successful induction of remission with methotrexate and unexpected high cardiac and pulmonary relapse ratio during maintenance treatment. Clin Exp Rheumatol 2004; 22: S52-S61.
139. Jayne DR, Chapel H, Adu D et al. Intravenous immunoglobulin for ANCAassociated systemic vasculitis with persistent disease activity. QJM 2000; 93: 433-439. (Pubitemid 30459921)
140. Birck R, Warnatz K, Lorenz HM et al. 15-Deoxyspergualin in patients with refractory ANCA-associated systemic vasculitis: a six-month open-label trial to evaluate safety and efficacy. J Am Soc Nephrol 2003; 14: 440-447. (Pubitemid 36150868)
141. Flossmann O, Baslund B, Bruchfeld A et al. Deoxyspergualin in relapsing and refractory Wegener's granulomatosis. Ann Rheum Dis 2009; 68: 1125-1130.
142. Bornhauser M, Aringer M, Thiede C. Mixed lymphohematopoietic chimerism and response in Wegener's granulomatosis. N Engl J Med 2010; 362: 2431-2432.
143. Jones RB, Ferraro AJ, Chaudhry AN et al. A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibodyassociated vasculitis. Arthritis Rheum 2009; 60: 2156-2168.
144. Martinez Del Pero M, Chaudhry A, Jones RB et al. B-cell depletion with rituximab for refractory head and neck Wegener's granulomatosis: a cohort study. Clin Otolaryngol 2009; 34: 328-335.
145. Metzler C, Schnabel A, Gross WL et al. A phase II study of interferonalpha for the treatment of refractory Churg-Strauss syndrome. Clin Exp Rheumatol 2008; 26: S35-S40.
146. Giavina-Bianchi P, Kalil J. Omalizumab administration in Churg-Strauss syndrome. Eur J Intern Med 2009; 20: e139.
147. Kahn JE, Grandpeix-Guyodo C, Marroun I et al. Sustained response to mepolizumab in refractory Churg-Strauss syndrome. J Allergy Clin Immunol 2010; 125: 267-270.
148. Mukhtyar C, Flossmann O, Hellmich B et al. Outcomes from studies of antineutrophil cytoplasm antibody associated vasculitis: a systematic review by the European League Against Rheumatism systemic vasculitis task force. Ann Rheum Dis 2008; 67: 1004-1010. (Pubitemid 351956664)
149. Falk RJ, Hoffman GS. Controversies in small vessel vasculitis-comparing the rheumatology and nephrology views. Curr Opin Rheumatol 2007; 19: 1-9. (Pubitemid 44885720)
150. Pagnoux C, Hogan SL, Chin H et al. Predictors of treatment resistance and relapse in antineutrophil cytoplasmic antibody-associated smallvessel vasculitis: comparison of two independent cohorts. Arthritis Rheum 2008; 58: 2908-2918.
151. Langford CA, Talar-Williams C, Sneller MC. Mycophenolate mofetil for remission maintenance in the treatment of Wegener's granulomatosis. Arthritis Rheum 2004; 51: 278-283. (Pubitemid 38468715)
152. Nowack R, Gobel U, Klooker P et al. Mycophenolate mofetil for maintenance therapy of Wegener's granulomatosis and microscopic polyangiitis: a pilot study in 11 patients with renal involvement. J Am Soc Nephrol 1999; 10: 1965-1971. (Pubitemid 29402518)
153. 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; e-pub ahead of print; doi:10.1001/jama.2010.1658.
154. Pagnoux C, Mahr A, Hamidou MA et al. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med 2008; 359: 2790-2803.
155. Metzler C, Miehle N, Manger K et al. Elevated relapse rate under oral methotrexate versus leflunomide for maintenance of remission in Wegener's granulomatosis. Rheumatology 2007; 46: 1087-1091. (Pubitemid 47050609)
156. European Medicines Agency. Public statement on Arava (Leflunomide)- severe and serious hepatic reactions. 2001. http://www.ema.europa.eu/ humandocs/PDFs/EPAR/Arava/561101en.pdf, accessed 18 June 2010.
157. Walsh M, Merkel PA, Mahr A et al. The effects of duration of glucocorticoid therapy on relapse rate in anti-neutrophil cytoplasm antibody associated vasculitis: a meta-analysis. Arthritis Care Res (Hoboken) 2010; 62: 1166-1173.
158. Metzler C, Csernok E, Gross WL et al. Interferon-alpha for maintenance of remission in Churg-Strauss syndrome: a long-term observational study. Clin Exp Rheumatol 2010; 28: 24-30.
159. Kim S, Marigowda G, Oren E et al. Mepolizumab as a steroid-sparing treatment option in patients with Churg-Strauss syndrome. J Allergy Clin Immunol 2010; 125: 1336-1343.
160. Mukhtyar C, Hellmich B, Jayne D et al. Remission in antineutrophil cytoplasmic antibody-associated systemic vasculitis. Clin Exp Rheumatol 2006; 24: S93-S98.
161. Hellmich B, Flossmann O, Gross WL et al. EULAR recommendations for conducting clinical studies and/or clinical trials in systemic vasculitis: focus on anti-neutrophil cytoplasm antibody-associated vasculitis. Ann Rheum Dis 2007; 66: 605-617. (Pubitemid 46707128)
162. Slot MC, Tervaert JWC, Boomsma MM et al. Positive classic antineutrophil cytoplasmic antibody (C-ANCA) titer at switch to azathioprine therapy associated with relapse in proteinase 3-related vasculitis. Arthritis Rheum 2004; 51: 269-273. (Pubitemid 38468713)
163. Tervaert JWC, Vanderwoude FJ, Fauci AS et al. Association between active Wegener's granulomatosis and anticytoplasmic antibodies. Arch Intern Med 1989; 149: 2461-2465. (Pubitemid 19283202)
164. Cohen Tervaert JW, Huitema MG, Sluiter WJ et al. Prevention of relapses in Wegener's granulomatosis by treatment based on antineutrophil cytoplasmic antibody titre. Lancet 1990; 336: 709-711. (Pubitemid 20309129)
165. Tervaert JW. ANCA testing in monitoring the activity of the disease. Kidney Blood Press Res 2003; 26: 226-230. (Pubitemid 37176864)
166. Golbin JM, Specks U. Targeting B lymphocytes as therapy for ANCAassociated vasculitis. Rheum Dis Clin North Am 2007; 33: 741-754. (Pubitemid 350122977)
167. Kang SM, Tang Q, Bluestone JA. CD4+CD25+ regulatory T cells in transplantation: progress, challenges and prospects. Am J Transplant 2007; 7: 1457-1463. (Pubitemid 46776267)
168. Kreijveld E, Koenen HJPM, van Cranenbroek B et al. Immunological monitoring of renal transplant recipients to predict acute allograft rejection following the discontinuation of tacrolimus. PLoS ONE 2008; 3: e2711.
169. Stuve O, Cravens PD, Frohman EM et al. Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy. Neurology 2009; 72: 396-401.
170. Stuve O, Wiendl H. Iatrogenic immunosuppression with biologics in MS: expecting the unexpected? Neurology 2009; 73: 1346-1347.
171. Koenen HJPM, Smeets RL, Vink PM et al. Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. Blood 2008; 112: 2340-2352.
172. Vincenti F. Costimulation blockade in autoimmunity and transplantation. J Allergy Clin Immunol 2008; 121: 299-306. (Pubitemid 351215188)
173. Leone AM, Valgimigli M, Giannico MB et al. From bone marrow to the arterial wall: the ongoing tale of endothelial progenitor cells. Eur Heart J 2009; 30: 890-899.
174. Morgan MD, Turnbull J, Selamet U et al. Increased incidence of cardiovascular events in patients with antineutrophil cytoplasmic antibody-associated vasculitides: a matched-pair cohort study. Arthritis Rheum 2009; 60: 3493-3500.
175. Zavada J, Kideryova L, Pytlik R et al. Reduced number of endothelial progenitor cells is predictive of early relapse in anti-neutrophil cytoplasmic antibody-associated vasculitis. Rheumatology 2009; 48: 1197-1201.
176. Tervaert JWC. Translational mini-review series on immunology of vascular disease: accelerated atherosclerosis in vasculitis. Clin Exp Immunol 2009; 156: 377-385.
177. Krumbholz M, Specks U, Wick M et al. BAFF is elevated in serum of patients with Wegener's granulomatosis. J Autoimmun 2005; 25: 298-302. (Pubitemid 41642976)
178. Forbess JM, Hiramatsu T, Nomura F et al. Anti-CD11b monoclonal antibody improves myocardial function after six hours of hypothermic storage. Ann Thorac Surg 1995; 60: 1238-1244.
179. Webster Angela C, Ruster Lorenn P, McGee R, Matheson Sandra L et al. Interleukin 2 receptor antagonists for kidney transplant recipients. http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/ CD003897/frame.html, accessed on 24 August 2010.
180. Liu J, Wang L, Zhan S, Tan J et al. Daclizumab for relapsing remitting multiple sclerosis. http://www.mrw.interscience.wiley.com/cochrane/ clsysrev/articles/CD008127/frame.html, accessed on 24 August 2010.
181. Popa ER, Stegeman CA, Abdulahad WH et al. Staphylococcal toxicshock-syndrome-toxin-1 as a risk factor for disease relapse in Wegener's granulomatosis. Rheumatology 2007; 46: 1029-1033. (Pubitemid 47062516)