, Volume 66, Issue 9, pp 1209–1228 | Cite as

Pharmacological Therapy for Wegener’s Granulomatosis

Review Article


Wegener’s granulomatosis (WG) is the most common pulmonary granulomatous vasculitis and was a uniformly fatal disease prior to the identification of efficacious pharmacological regimens. The pathogenesis of WG remains elusive but proteinase 3-specific anti-neutrophil cytoplasmic antibodies may be involved. Histologically, WG is defined by the triad of small vessel necrotising vasculitis, ‘geographic’ necrosis and granulomatous inflammation. Organ involvement characteristically includes the upper and lower respiratory tracts and kidney, but virtually any organ can be involved. The severity of the disease varies, ranging from asymptomatic disease to fulminant, fatal vasculitis. Similarly, the degree of organ involvement is highly variable; WG may be limited to a single organ (typically the lungs or upper respiratory tract), or may be systemic. Currently, a regimen consisting of daily cyclophosphamide and corticosteroids, which induces complete remission in the majority of patients, is considered standard therapy. Since approximately 50% of patients experience a relapse following discontinuation of therapy, alternative regimens designed to maintain remissions after using cyclophosphamide and corticosteroids are usually necessary. This ‘induction maintenance’ approach to treatment has emerged as a central premise in planning therapy for patients with WG.

A number of trials have evaluated the efficacy of less toxic immunosuppressants (e.g. methotrexate, azathioprine, mycophenolate mofetil) and antibacterials (i.e. cotrimoxazole [trimethoprim/sulfamethoxazole]) for treating patients with WG, resulting in the identification of effective alternative regimens to induce or maintain remissions in certain sub-populations of patients. Given the efficacy of methotrexate (for early systemic WG) and cotrimoxazole (in WG limited solely to the upper airways) to induce remissions, and the relatively decreased associated morbidity compared with cyclophosphamide, these alternative regimens are preferred in appropriate patients. Similarly, therapeutic options to maintain disease remission that are less toxic than cyclophosphamide should be offered following induction of remission unless a specific contraindication exists. By following this premise, the development of cyclophosphamide-induced morbidities (e.g. haemorrhagic cystitis, uroepithelial cancers and prolonged myelosuppression) may be minimised. Recent investigation has focussed on other immunomodulatory agents (tumour necrosis factor-α inhibitors [infliximab and etanercept] and anti-CD20 antibodies [rituximab]) for treating patients with WG. However, the current data are conflicting and difficult to interpret. As a result, these newer agents cannot be recommended for routine use until vigorous clinical study confirms their efficacy.


Cyclophosphamide Infliximab Etanercept Birmingham Vasculitis Activity Score Rapidly Progressive Glomerulonephritis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Dr White is supported in part by National Institutes of Health Grant K08-HL70990 and by an Association of Subspecialty Professors — CHEST Foundation T. Franklin Williams Geriatrics Research Development Award. The authors have no conflict of interest to report.


  1. 1.
    Mark EJ, Matsubara O, Tan-Liu NS, et al. The pulmonary biopsy in the early diagnosis of Wegener’s (pathergic) granulomatosis: a study based on 35 open lung biopsies. Hum Pathol 1988; 19(9): 1065–71PubMedCrossRefGoogle Scholar
  2. 2.
    Travis WD, Hoffman GS, Leavitt RY, et al. Surgical pathology of the lung in Wegener’s granulomatosis: review of 87 open lung biopsies from 67 patients. Am J Surg Pathol 1991; 15(4): 315–33PubMedCrossRefGoogle Scholar
  3. 3.
    Devaney K, Travis W, Hoffman G, et al. Interpretation of head and neck biopsies in Wegener’s granulomatosis: a pathologic study of 126 biopsies in 70 patients. Am J Surg Pathol 1990; 14: 555–64PubMedCrossRefGoogle Scholar
  4. 4.
    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(1): 76–85PubMedGoogle Scholar
  5. 5.
    Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 1992; 116(6): 488–98PubMedGoogle Scholar
  6. 6.
    Luqmani RA, Bacon PA, Beaman M, et al. Classical versus non-renal Wegener’s granulomatosis. Q J Med 1994; 87(3): 161–7PubMedGoogle Scholar
  7. 7.
    Reinhold-Keller E, Beuge N, Latza U, et al. An interdisciplinary approach to the care of patients with Wegener’s granulomatosis: long-term outcome in 155 patients. Arthritis Rheum 2000; 43(5): 1021–32PubMedCrossRefGoogle Scholar
  8. 8.
    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(8): 1101–7PubMedCrossRefGoogle Scholar
  9. 9.
    Langford CA, Talar-Williams C, Barron KS, et al. A staged approach to the treatment of Wegener’s granulomatosis: induction of remission with glucocorticoids and daily cyclophosphamide switching to methotrexate for remission maintenance. Arthritis Rheum 1999; 42(12): 2666–73PubMedCrossRefGoogle Scholar
  10. 10.
    Abdou NI, Kullman GJ, Hoffman GS, et al. Wegener’s granulomatosis: survey of 701 patients in North America: changes in outcome in the 1990s. J Rheumatol 2002; 29(2): 309–16PubMedGoogle Scholar
  11. 11.
    Lynch JP, Hoffman GS. Wegener’s granulomatosis: controversies and current concepts. Compr Ther 1998; 24: 421–40PubMedGoogle Scholar
  12. 12.
    Cotch MF, Hoffman GS, Yerg DE, et al. 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(1): 87–92PubMedCrossRefGoogle Scholar
  13. 13.
    Koldingsnes W, Nossent H. Epidemiology of Wegener’s granulomatosis in northern Norway. Arthritis Rheum 2000; 43(11): 2481–7PubMedCrossRefGoogle Scholar
  14. 14.
    Watts RA, Gonzales-Gay M, Garcia-Porrua C, et al. ANCA-associated vasculitis in two European regions [abstract]. Clin Exp Immunol 2000; 120 Suppl. 1: 60Google Scholar
  15. 15.
    Rottem M, Fauci AS, Hallahan CW, et al. Wegener granulomatosis in children and adolescents: clinical presentation and outcome. J Pediatr 1993; 122(1): 26–31PubMedCrossRefGoogle Scholar
  16. 16.
    Stegmayr BG, Gothefors L, Malmer B, et al. Wegener granulomatosis in children and young adults: a case study of ten patients. Pediatr Nephrol 2000; 14(3): 208–13PubMedCrossRefGoogle Scholar
  17. 17.
    Yalcindag A, Sundel R. Vasculitis in childhood. Curr Opin Rheumatol 2001; 13(5): 422–7PubMedCrossRefGoogle Scholar
  18. 18.
    Wardyn KA, Ycinska K, Matuszkiewicz-Rowinska J, et al. Pseudotumour orbitae as the initial manifestation in Wegener’s granulomatosis in a 7-year-old girl. Clin Rheumatol 2003; 22(6): 472–4PubMedCrossRefGoogle Scholar
  19. 19.
    Belostotsky VM, Shah V, Dillon MJ. Clinical features in 17 paediatric patients with Wegener granulomatosis. Pediatr Nephrol 2002; 17(9): 754–61PubMedCrossRefGoogle Scholar
  20. 20.
    Langford CA, Hoffman GS. Rare diseases. 3: Wegener’s granulomatosis. Thorax 1999; 54(7): 629–37Google Scholar
  21. 21.
    Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides: proposal of an international consensus conference. Arthritis Rheum 1994; 37(2): 187–92PubMedCrossRefGoogle Scholar
  22. 22.
    Jayne DR, Rasmussen N. Treatment of antineutrophil cytoplasm autoantibody-associated systemic vasculitis: initiatives of the European Community Systemic Vasculitis Clinical Trials Study Group. Mayo Clin Proc 1997; 72(8): 737–47PubMedCrossRefGoogle Scholar
  23. 23.
    Rao JK, Weinberger M, Oddone EZ, et al. The role of antineutrophil cytoplasmic antibody (c-ANCA) testing in the diagnosis of Wegener granulomatosis: a literature review and meta-analysis. Ann Intern Med 1995; 123(12): 925–32PubMedGoogle Scholar
  24. 24.
    Jayne DR, Gaskin G, Pusey CD, et al. ANCA and predicting relapse in systemic vasculitis. Q J Med 1995; 88(2): 127–33Google Scholar
  25. 25.
    Nolle B, Specks U, Ludemann J, et al. Anticytoplasmic autoantibodies: their immunodiagnostic value in Wegener granulomatosis. Ann Intern Med 1989; 111(1): 28–40PubMedGoogle Scholar
  26. 26.
    Hoffman GS, Specks U. Antineutrophil cytoplasmic antibodies. Arthritis Rheum 1998; 41(9): 1521–37PubMedGoogle Scholar
  27. 27.
    Gaudin PB, Askin FB, Falk RJ, et al. The pathologic spectrum of pulmonary lesions in patients with anti-neutrophil cytoplasmic autoantibodies specific for anti-proteinase 3 and antimyeloperoxidase. Am J Clin Pathol 1995; 104(1): 7–16PubMedGoogle Scholar
  28. 28.
    Gaskin G, Savage CO, Ryan JJ, et al. Anti-neutrophil cytoplasmic antibodies and disease activity during long-term follow-up of 70 patients with systemic vasculitis. Nephrol Dial Transplant 1991; 6(10): 689–94PubMedCrossRefGoogle Scholar
  29. 29.
    Hauschild S, Schmitt WH, Csernok E, et al. ANCA in systemic vasculitides, collagen vascular diseases, rheumatic disorders and inflammatory bowel diseases. Adv Exp Med Biol 1993; 336: 245–51PubMedGoogle Scholar
  30. 30.
    Lynch JP, White E, Tazelaar H, et al. Wegener’s granulomatosis: evolving concepts in treatment. Semin Respir Crit Care Med 2004; 25(5): 491–521PubMedCrossRefGoogle Scholar
  31. 31.
    van Rossum AP, Limburg PC, Kallenberg CG. Membrane proteinase 3 expression on resting neutrophils as a pathogenic factor in PR3-ANCA-associated vasculitis. Clin Exp Rheumatol 2003; 21 (6 Suppl. 32): S64–8PubMedGoogle Scholar
  32. 32.
    Sanders JS, Huitma MG, Kallenberg CG, et al. Prediction of relapses in PR3-ANCA-associated vasculitis by assessing responses of ANCA titres to treatment. Rheumatology (Oxford) 2006; 45(6): E724–9CrossRefGoogle Scholar
  33. 33.
    Deguchi Y, Shibata N, Kishimoto S. Enhanced expression of the tumour necrosis factor/cachectin gene in peripheral blood mononuclear cells from patients with systemic vasculitis. Clin Exp Immunol 1990; 81(2): 311–4PubMedCrossRefGoogle Scholar
  34. 34.
    Jennette JC, Falk RJ. Pathogenesis of the vascular and glomerular damage in ANCA-positive vasculitis. Nephrol Dial Transplant 1998; 13 Suppl. 1: 16–20PubMedCrossRefGoogle Scholar
  35. 35.
    Ludviksson BR, Sneller MC, Chua KS, et al. Active Wegener’s granulomatosis is associated with HLA-DR+ CD4+ T cells exhibiting an unbalanced Th1-type T cell cytokine pattern: reversal with IL-10. J Immunol 1998; 160(7): 3602–9PubMedGoogle Scholar
  36. 36.
    Phillips B, Ball C, Sackett D, et al. Oxford centre for evidence-based medicine levels of evidence, 2001 [online]. Available from URL: [Accessed 2006 Feb 10]
  37. 37.
    White ES, Langford CA, Tazelaar HD, et al. Management of Wegener Granulomatosis. Clin Pulm Med 2005; 12(4): 220–31CrossRefGoogle Scholar
  38. 38.
    Walton EW. Giant cell granuloma of the respiratory tract (Wegener’s granulomatosis). BMJ 1958; 2: 265–70PubMedCrossRefGoogle Scholar
  39. 39.
    Hoffman GS. “Wegener’s granulomatosis”: the path traveled since 1931. Medicine (Baltimore) 1994; 73(6): 325–9Google Scholar
  40. 40.
    Hollander D, Manning RT. The use of alkylating agents in the treatment of Wegener’s granulomatosis. Ann Intern Med 1967; 67(2): 393–8PubMedGoogle Scholar
  41. 41.
    Fauci AS, Wolff SM. Wegener’s granulomatosis: studies in eighteen patients and a review of the literature. Medicine (Baltimore) 1973; 52(6): 535–61CrossRefGoogle Scholar
  42. 42.
    Brandwein S, Esdaile J, Danoff D, et al. Wegener’s granulomatosis: clinical features and outcome in 13 patients. Arch Intern Med 1983; 143(3): 476–9PubMedCrossRefGoogle Scholar
  43. 43.
    Boomsma MM, Stegeman CA, van der Leij MJ, et al. Prediction of relapses in Wegener’s granulomatosis by measurement of antineutrophil cytoplasmic antibody levels: a prospective study. Arthritis Rheum 2000; 43(9): 2025–33PubMedCrossRefGoogle Scholar
  44. 44.
    Guillevin L, Cordier JF, Lhote F, et al. A prospective, multicenter, randomized trial comparing steroids and pulse cyclophosphamide versus steroids and oral cyclophosphamide in the treatment of generalized Wegener’s granulomatosis. Arthritis Rheum 1997; 40(12): 2187–98PubMedCrossRefGoogle Scholar
  45. 45.
    Mahr A, Girard T, Agher R, et al. Analysis of factors predictive of survival based on 49 patients with systemic Wegener’s granulomatosis and prospective follow-up. Rheumatology (Oxford) 2001; 40(5): 492–8CrossRefGoogle Scholar
  46. 46.
    Talar-Williams C, Hijazi YM, Walther MM, et al. Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med 1996; 124(5): 477–84PubMedGoogle Scholar
  47. 47.
    Lynch JP, McCune WJ. Immunosuppressive and cytotoxic pharmacotherapy for pulmonary disorders. Am J Respir Crit Care Med 1997; 155(2): 395–420PubMedGoogle Scholar
  48. 48.
    Steinberg AD, Steinberg SC. Long-term preservation of renal function in patients with lupus nephritis receiving treatment that includes cyclophosphamide versus those treated with prednisone only. Arthritis Rheum 1991; 34(8): 945–50PubMedCrossRefGoogle Scholar
  49. 49.
    Ortmann RA, Klippel JH. Update on cyclophosphamide for systemic lupus erythematosus. Rheum Dis Clin North Am 2000; 26(2): 363–75, viiPubMedCrossRefGoogle Scholar
  50. 50.
    Appel GB, Valeri A. The course and treatment of lupus nephritis. Annu Rev Med 1994; 45: 525–37PubMedCrossRefGoogle Scholar
  51. 51.
    Boumpas DT, Barez S, Klippel JH, et al. Intermittent cyclophosphamide for the treatment of autoimmune thrombocytopenia in systemic lupus erythematosus. Ann Intern Med 1990; 112(9): 674–7PubMedGoogle Scholar
  52. 52.
    Wallace CA, Sherry DD. Trial of intravenous pulse cyclophosphamide and methylprednisolone in the treatment of severe systemic-onset juvenile rheumatoid arthritis. Arthritis Rheum 1997; 40(10): 1852–5PubMedCrossRefGoogle Scholar
  53. 53.
    Hoffman GS, Leavitt RY, Fleisher TA, et al. Treatment of Wegener’s granulomatosis with intermittent high-dose intravenous cyclophosphamide. Am J Med 1990; 89(4): 403–10PubMedCrossRefGoogle Scholar
  54. 54.
    Le Thi Huong D, Papo T, Piette JC, et al. Monthly intravenous pulse cyclophosphamide therapy in Wegener’s granulomatosis. Clin Exp Rheumatol 1996; 14(1): 9–16PubMedGoogle Scholar
  55. 55.
    Reinhold-Keller E, Kekow J, Schnabel A, et al. Influence of disease manifestation and antineutrophil cytoplasmic antibody titer on the response to pulse cyclophosphamide therapy in patients with Wegener’s granulomatosis. Arthritis Rheum 1994; 37(6): 919–24PubMedCrossRefGoogle Scholar
  56. 56.
    Haubitz M, Frei U, Rother U, et al. Cyclophosphamide pulse therapy in Wegener’s granulomatosis. Nephrol Dial Transplant 1991; 6(8): 531–5PubMedCrossRefGoogle Scholar
  57. 57.
    Drosos AA, Sakkas LI, Goussia A, et al. Pulse cyclophosphamide therapy in Wegener’s granulomatosis: a pilot study. J Intern Med 1992; 232(3): 279–82PubMedCrossRefGoogle Scholar
  58. 58.
    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): 2018–27PubMedCrossRefGoogle Scholar
  59. 59.
    de Groot K, Muhler M, Reinhold-Keller E, et al. Induction of remission in Wegener’s granulomatosis with low dose methotrexate. J Rheumatol 1998; 25(3): 492–5PubMedGoogle Scholar
  60. 60.
    Langford CA, Talar-Williams C, Sneller MC. Use of methotrexate and glucocorticoids in the treatment of Wegener’s granulomatosis: long-term renal outcome in patients with glomerulonephritis. Arthritis Rheum 2000; 43(8): 1836–40PubMedCrossRefGoogle Scholar
  61. 61.
    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): 36–44PubMedCrossRefGoogle Scholar
  62. 62.
    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(9): 1965–71PubMedGoogle Scholar
  63. 63.
    Langford CA, Talar-Williams C, Sneller MC. Mycophenolate mofetil for remission maintenance in the treatment of Wegener’s granulomatosis. Arthritis Rheum 2004; 51(2): 278–83PubMedCrossRefGoogle Scholar
  64. 64.
    Sneller MC, Hoffman GS, Talar-Williams C, et al. An analysis of forty-two Wegener’s granulomatosis patients treated with methotrexate and prednisone. Arthritis Rheum 1995; 38(5): 608–13PubMedCrossRefGoogle Scholar
  65. 65.
    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): 2461–9PubMedCrossRefGoogle Scholar
  66. 66.
    de Groot K, Gross WL, Herlyn K, et al. Development and validation of a disease extent index for Wegener’s granulomatosis. Clin Nephrol 2001; 55(1): 31–8PubMedGoogle Scholar
  67. 67.
    Stone JH, Tun W, Hellman DB. Treatment of non-life threatening Wegener’s granulomatosis with methotrexate and daily prednisone as the initial therapy of choice. J Rheumatol 1999; 26(5): 1134–9PubMedGoogle Scholar
  68. 68.
    de Groot K, Reinhold-Keller E, Tatsis E, et al. Therapy for the maintenance of remission in sixty-five patients with generalized Wegener’s granulomatosis: methotrexate versus trimethoprim/sulfamethoxazole. Arthritis Rheum 1996; 39(12): 2052–61PubMedCrossRefGoogle Scholar
  69. 69.
    Reinhold-Keller E, Fink CO, Herlyn K, et al. High rate of renal relapse in 71 patients with Wegener’s granulomatosis under maintenance of remission with low-dose methotrexate. Arthritis Rheum 2002; 47(3): 326–32PubMedCrossRefGoogle Scholar
  70. 70.
    Langford CA, Talar-Williams C, Barron KS, et al. Use of a cyclophosphamide-induction methotrexate-maintenance regimen for the treatment of Wegener’s granulomatosis: extended follow-up and rate of relapse. Am J Med 2003; 114(6): 463–9PubMedCrossRefGoogle Scholar
  71. 71.
    Weiner SR, Paulus HE. Treatment of Wegener’s granulomatosis. Semin Respir Med 1989; 10: 156–61CrossRefGoogle Scholar
  72. 72.
    Sanders JS, Slot MC, Stegeman CA. Maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 2003; 349(21): 2072–3PubMedCrossRefGoogle Scholar
  73. 73.
    Slot MC, Tervaert JW, 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(2): 269–73PubMedCrossRefGoogle Scholar
  74. 74.
    Benenson E, Fries JW, Heilig B, et al. High-dose azathioprine pulse therapy as a new treatment option in patients with active Wegener’s granulomatosis and lupus nephritis refractory or intolerant to cyclophosphamide. Clin Rheumatol 2005; 24(3): 251–7PubMedCrossRefGoogle Scholar
  75. 75.
    Stegeman CA, Tervaert JW, Sluiter WJ, et al. Association of chronic nasal carriage of Staphylococcus aureus and higher relapse rates in Wegener granulomatosis. Ann Intern Med 1994; 120(1): 12–7PubMedGoogle Scholar
  76. 76.
    Stegeman CA, Cohen Tervaert JW, de Jong PE, et al. Trimethoprim-surfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener’s granulomatosis. Dutch Co-Trimoxazole Wegener Study Group. N Engl J Med 1996; 335(1): 16–20Google Scholar
  77. 77.
    Hoffman GS. Immunosuppressive therapy is always required for the treatment of limited Wegener’s granulomatosis. Sarcoidosis Vasc Diffuse Lung Dis 1996; 13(3): 249–52PubMedGoogle Scholar
  78. 78.
    DeRemee RA, McDonald TJ, Weiland LH. Wegener’s granulomatosis: observations on treatment with antimicrobial agents. Mayo Clin Proc 1985; 60(1): 27–32PubMedCrossRefGoogle Scholar
  79. 79.
    DeRemee RA. The treatment of Wegener’s granulomatosis with trimethoprim/sulfamethoxazole: illusion or vision? Arthritis Rheum 1988; 31(8): 1068–74PubMedCrossRefGoogle Scholar
  80. 80.
    Georgi J, Ulmer M, Gross WL. Cotrimoxazole in Wegener’s granulomatosis: a prospective study. Immun Infekt 1991; 19(3): 97–8PubMedGoogle Scholar
  81. 81.
    Reinhold-Keller E, De Groot K, Rudert H, et al. Response to trimethoprim/sulfamethoxazole in Wegener’s granulomatosis depends on the phase of disease. Q J Med 1996; 89(1): 15–23CrossRefGoogle Scholar
  82. 82.
    Godeau B, Mainardi JL, Roudot-Thoraval F, et al. Factors associated with Pneumocystis carinii pneumonia in Wegener’s granulomatosis. Ann Rheum Dis 1995; 54(12): 991–4PubMedCrossRefGoogle Scholar
  83. 83.
    Huynh-Do U, Gantenbein H, Binswanger U. Pneumocystis carinii pneumonia during immunosuppressive therapy for antineutrophil cytoplasmic autoantibody-positive vasculitis. Arch Intern Med 1995; 155(8): 872–4PubMedCrossRefGoogle Scholar
  84. 84.
    Ognibene FP, Shelhamer JH, Hoffman GS, et al. Pneumocystis carinii pneumonia: a major complication of immunosuppressive therapy in patients with Wegener’s granulomatosis [see comments]. Am J Respir Crit Care Med 1995; 151 (3 Pt 1): 795–9PubMedGoogle Scholar
  85. 85.
    Jarrousse B, Guillevin L, Bindi P, et al. Increased risk of Pneumocystis carinii pneumonia in patients with Wegener’s granulomatosis. Clin Exp Rheumatol 1993; 11(6): 615–21PubMedGoogle Scholar
  86. 86.
    Gross WL. New concepts in treatment protocols for severe systemic vasculitis. Curr Opin Rheumatol 1999; 11(1): 41–6PubMedCrossRefGoogle Scholar
  87. 87.
    Chung JB, Armstrong K, Schwartz JS, et al. Cost-effectiveness of prophylaxis against Pneumocystis carinii pneumonia in patients with Wegner’s granulomatosis undergoing immunosuppressive therapy. Arthritis Rheum 2000; 43(8): 1841–8PubMedCrossRefGoogle Scholar
  88. 88.
    Munoz P, Munoz RM, Palomo J, et al. Pneumocystis carinii infection in heart transplant recipients: efficacy of a weekend prophylaxis schedule. Medicine (Baltimore) 1997; 76(6): 415–22CrossRefGoogle Scholar
  89. 89.
    El-Sadr WM, Luskin-Hawk R, Yurik TM, et al. A randomized trial of daily and thrice-weekly tremthoprim-sulfamethoxazole for the prevention of Pneumocystis carinii pneumonia in human immunodeficiency virus-infected persons. Clin Infect Dis 1999; 29(4): 775–83PubMedCrossRefGoogle Scholar
  90. 90.
    El-Sadr WM, Murphy RL, Yurik TM, et al. Atovaquone compared with dapsone for the prevention of Pneumocystis carinii pneumonia in patients with HIV infection who cannot tolerate trimethoprim, sulfonamides, or both. Community Program for Clinical Research on AIDS and the AIDS Clinical Trials Group. N Engl J Med 1998; 339(26): 1889–95Google Scholar
  91. 91.
    Leoung GS, Feigal DW, Montgomery AB, et al. Aerosolized pentamidine for prophylaxis against Pneumocystis carinii pneumonia. The San Francisco community prophylaxis trial. N Engl J Med 1990; 323(12): 769–75Google Scholar
  92. 92.
    Govert JA, Patton S, Fine RL. Pancytopenia from using trimethoprim and methotrexate. Ann Intern Med 1992; 117(10): 877–8PubMedGoogle Scholar
  93. 93.
    Groenendal H, Rampen FH. Methotrexate and trimethoprimsulphamethoxazole: a potentially hazardous combination. Clin Exp Dermatol 1990; 15(5): 358–60PubMedCrossRefGoogle Scholar
  94. 94.
    Jeurissen ME, Boerbooms AM, van de Putte LB. Pancytopenia and methotrexate with trimethoprim-sulfamethoxazole. Ann Intern Med 1989; 111(3): 261PubMedGoogle Scholar
  95. 95.
    Maricic M, Davis M, Gall EP. Megaloblastic pancytopenia in a patient receiving concurrent methotrexate and trimethoprim-sulfamethoxazole treatment. Arthritis Rheum 1986; 29(1): 133–5PubMedCrossRefGoogle Scholar
  96. 96.
    Steuer A, Gumpel JM. Methotrexate and trimethoprim: a fatal interaction. Br J Rheumatol 1998; 37(1): 105–6PubMedCrossRefGoogle Scholar
  97. 97.
    Thomas DR, Dover JS, Camp RD. Pancytopenia induced by the interaction between methotrexate and trimethoprim-sulfamethoxazole. J Am Acad Dermatol 1987; 17(6): 1055–6PubMedCrossRefGoogle Scholar
  98. 98.
    Verbov JL. Methotrexate and trimethoprim-sulphamethoxazole. Clin Exp Dermatol 1991; 16(3): 231PubMedCrossRefGoogle Scholar
  99. 99.
    Yang CH, Yang LJ, Jaing TH, et al. Toxic epidermal necrolysis following combination of methotrexate and trimethoprim-sulfamethoxazole. Int J Dermatol 2000; 39(8): 621–3PubMedCrossRefGoogle Scholar
  100. 100.
    Bologna C, Viu P, Picot MC, et al. Long-term follow-up of 453 rheumatoid arthritis patients treated with methotrexate: an open, retrospective, observational study. Br J Rheumatol 1997; 36(5): 535–40PubMedCrossRefGoogle Scholar
  101. 101.
    Guidelines for monitoring drug therapy in rheumatoid arthritis. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Arthritis Rheum 1996; 39(5): 723–31CrossRefGoogle Scholar
  102. 102.
    Lebovics RS, Hoffman GS, Leavitt RY, et al. The management of subglottic stenosis in patients with Wegener’s granulomatosis. Laryngoscope 1992; 102 (12 Pt 1): 1341–5PubMedCrossRefGoogle Scholar
  103. 103.
    Daum TE, Specks U, Colby TV, et al. Tracheobronchial involvement in Wegener’s granulomatosis. Am J Respir Crit Care Med 1995; 151 (2 Pt 1): 522–6PubMedGoogle Scholar
  104. 104.
    Cordier JF, Valeyre D, Guillevin L, et al. Pulmonary Wegener’s granulomatosis: a clinical and imaging study of 77 cases. Chest 1990; 97(4): 906–12PubMedCrossRefGoogle Scholar
  105. 105.
    Haynes BF, Fishman ML, Fauci AS, et al. The ocular manifestations of Wegener’s granulomatosis: fifteen years experience and review of the literature. Am J Med 1977; 63(1): 131–41PubMedCrossRefGoogle Scholar
  106. 106.
    Woo TL, Francis IC, Wilcsek GA, et al. Australasian orbital and adnexal Wegener’s granulomatosis. Ophthalmology 2001; 108(9): 1535–43PubMedCrossRefGoogle Scholar
  107. 107.
    Langford C, Sneller M, Hallahan C, et al. Clinical features and therapeutic management of subglottic stenosis in patients with Wegener’s granulomatosis. Arthritis Rheum 1996; 39: 1754–60PubMedCrossRefGoogle Scholar
  108. 108.
    Gotway MB, Golden JA, LaBerge JM, et al. Benign tracheobronchial stenoses: changes in short-term and long-term pulmonary function testing after expandable metallic stent placement. J Comput Assist Tomogr 2002; 26(4): 564–72PubMedCrossRefGoogle Scholar
  109. 109.
    McDonald TJ, Neel HB, DeRemee RA. Wegener’s granulomatosis of the subglottis and the upper portion of the trachea. Ann Otol Rhinol Laryngol 1982; 91 (6 Pt 1): 588–92PubMedGoogle Scholar
  110. 110.
    Gluth MB, Shinners PA, Kasperbauer JL. Subglottic stenosis associated with Wegener’s granulomatosis. Laryngoscope 2003; 113(8): 1304–7PubMedCrossRefGoogle Scholar
  111. 111.
    Utzig MJ, Warzelhan J, Wertzel H, et al. Role of thoracic surgery and interventional bronchoscopy in Wegener’s granulomatosis. Ann Thorac Surg 2002; 74(6): 1948–52PubMedCrossRefGoogle Scholar
  112. 112.
    Hoffman GS, Thomas-Golbanov CK, Chan J, et al. Treatment of subglottic stenosis, due to Wegener’s granulomatosis, with intralesional corticosteroids and dilation. J Rheumatol 2003; 30(5): 1017–21PubMedGoogle Scholar
  113. 113.
    Newman NJ, Slamovits TL, Friedland S, et al. Neuro-ophthalmic manifestations of meningocerebral inflammation from the limited form of Wegener’s granulomatosis. Am J Ophthalmol 1995; 120(5): 613–21PubMedGoogle Scholar
  114. 114.
    Bullen CL, Liesegang TJ, McDonald TJ, et al. Ocular complications of Wegener’s granulomatosis. Ophthalmology 1983; 90(3): 279–90PubMedGoogle Scholar
  115. 115.
    Fechner FP, Faquin WC, Pilch BZ. Wegener’s granulomatosis of the orbit: a clinicopathological study of 15 patients. Laryngoscope 2002; 112(11): 1945–50PubMedCrossRefGoogle Scholar
  116. 116.
    Klemmer PJ, Chalermskulrat W, Reif MS, et al. Plasmapheresis therapy for diffuse alveolar hemorrhage in patients with smallvessel vasculitis. Am J Kidney Dis 2003; 42(6): 1149–53PubMedCrossRefGoogle Scholar
  117. 117.
    Nenov D, Stanchev I, Gurdevski M, et al. Treatment of Wegener’s granulomatosis using plasmapheresis. Vutr Boles 1983; 22(6): 58–61PubMedGoogle Scholar
  118. 118.
    Lang SM, Astner S, Fischer R, et al. Dissociation between high anti-PR3 titers (c-ANCA) and the clinical course of disease in a case of Wegener granulomatosis. Wien Klin Wochenschr 1998; 110(19): 691–4PubMedGoogle Scholar
  119. 119.
    Veys N, Offner F, Lameire N. Wegener’s granulomatosis: a review of 5 cases. Acta Clin Belg 1990; 45(3): 176–87PubMedGoogle Scholar
  120. 120.
    Moosig F, Csernok E, Kumanovics G, et al. Opsonization of apoptotic neutrophils by anti-neutrophil cytoplasmic antibodies (ANCA) leads to enhanced uptake by macrophages and increased release of tumour necrosis factor-alpha (TNF-alpha). Clin Exp Immunol 2000; 122(3): 499–503PubMedCrossRefGoogle Scholar
  121. 121.
    Savage CO, Pottinger BE, Gaskin G, et al. Autoantibodies developing to myeloperoxidase and proteinase 3 in systemic vasculitis stimulate neutrophil cytotoxicity toward cultured endothelial cells. Am J Pathol 1992; 141(2): 335–42PubMedGoogle Scholar
  122. 122.
    Mayet WJ, Schwarting A, Orth T, et al. Signal transduction pathways of membrane expression of proteinase 3 (PR-3) in human endothelial cells. Eur J Clin Invest 1997; 27(11): 893–9PubMedCrossRefGoogle Scholar
  123. 123.
    Charles LA, Caldas ML, Falk RJ, et al. Antibodies against granule proteins activate neutrophils in vitro. J Leukoc Biol 1991; 50(6): 539–46PubMedGoogle Scholar
  124. 124.
    Bratt J, Palmblad J. Cytokine-induced neutrophil-mediated injury of human endothelial cells. J Immunol 1997; 159(2): 912–8PubMedGoogle Scholar
  125. 125.
    Henn V, Slupsky JR, Grafe M, et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998; 391(6667): 591–4PubMedCrossRefGoogle Scholar
  126. 126.
    Mease PJ, Goffe BS, Metz J, et al. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet 2000; 356(9227): 385–90PubMedCrossRefGoogle Scholar
  127. 127.
    Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999; 340(4): 253–9PubMedCrossRefGoogle Scholar
  128. 128.
    Goldenberg M. Etanercept, a novel drug for the treatment of patients with severe, active rheumatoid arthritis. Clin Ther 1999; 21(1): 75–87PubMedCrossRefGoogle Scholar
  129. 129.
    van Dullemen HM, Van Deventer SJ, Hommes DW, et al. Treatment of Crohn’s disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 1995; 109(1): 129–35PubMedCrossRefGoogle Scholar
  130. 130.
    Targan SR, Hanauer SB, van Deventer SJH, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor {alpha} for Crohn’s disease. N Engl J Med 1997; 337(15): 1029–36PubMedCrossRefGoogle Scholar
  131. 131.
    Wegener’s Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus Standard Therapy for Wegener’s Granulomatosis. N Engl J Med 2005; 352(4): 351–61CrossRefGoogle Scholar
  132. 132.
    WGET Research Group. Design of the Wegener’s Granulomatosis Etanercept Trial (WGET). Control Clin Trials 2002; 23(4): 450–68CrossRefGoogle Scholar
  133. 133.
    Lamprecht P, Voswinkel J, Lilienthal T, et al. Effectiveness of TNF-alpha blockade with infliximab in refractory Wegener’s granulomatosis. Rheumatology (Oxford) 2002; 41(11): 1303–7CrossRefGoogle Scholar
  134. 134.
    Bartolucci P, Ramanoelina J, Cohen P, et al. Efficacy of the anti-TNF-alpha antibody infliximab against refractory systemic vasculitides: an open pilot study on 10 patients. Rheumatology (Oxford) 2002; 41(10): 1126–32CrossRefGoogle Scholar
  135. 135.
    Booth A, Harper L, Hammad T, et al. Prospective study of TNFalpha blockade with infliximab in anti-neutrophil cytoplasmic antibody-associated systemic vasculitis. J Am Soc Nephrol 2004; 15(3): 717–21PubMedCrossRefGoogle Scholar
  136. 136.
    Booth AD, Jefferson HJ, Ayliffe W, et al. Safety and efficacy of TNFalpha blockade in relapsing vasculitis. Ann Rheum Dis 2002; 61(6): 559PubMedCrossRefGoogle Scholar
  137. 137.
    Joy MS, Hogan SL, Jennette JC, et al. A pilot study using mycophenolate mofetil in relapsing or resistant ANCA small vessel vasculitis. Nephrol Dial Transplant 2005; 20(12): 2725–32PubMedCrossRefGoogle Scholar
  138. 138.
    Exley AR, Bacon PA, Luqmani RA, et al. Examination of disease severity in systemic vasculitis from the novel perspective of damage using the vasculitis damage index (VDI). Br J Rheumatol 1998; 37(1): 57–63PubMedCrossRefGoogle Scholar
  139. 139.
    Clayton AR, Savage CO. Production of antineutrophil cytoplasm antibodies derived from circulating B cells in patients with systemic vasculitis. Clin Exp Immunol 2003; 132(1): 174–9PubMedCrossRefGoogle Scholar
  140. 140.
    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. Epub 2005 Nov 16Google Scholar
  141. 141.
    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): 1411–8PubMedCrossRefGoogle Scholar
  142. 142.
    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): 955–63PubMedGoogle Scholar
  143. 143.
    Uchida J, Hamaguchi Y, Oliver JA, et al. The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy. J Exp Med 2004; 199(12): 1659–69PubMedCrossRefGoogle Scholar
  144. 144.
    Golay J, Zaffaroni L, Vaccari T, et al. Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis. Blood 2000; 95(12): 3900–8PubMedGoogle Scholar
  145. 145.
    Shan D, Ledbetter JA, Press OW. Signaling events involved in anti-CD20-induced apoptosis of malignant human B cells. Cancer Immunol Immunother 2000; 48(12): 673–83PubMedCrossRefGoogle Scholar
  146. 146.
    Keogh KA, Ytterberg SR, Fervenza FC, et al. Rituximab for refractory Wegener’s granulomatosis: report of a prospective, open-label pilot trial. Am J Respir Crit Care Med 2006 Jan 15; 173(2): 180–7PubMedCrossRefGoogle Scholar
  147. 147.
    Clarke AE, Bitton A, Eappen R, et al. Treatment of Wegener’s granulomatosis after renal transplantation: is cyclosporine the preferred treatment? Transplantation 1990; 50(6): 1047–51PubMedCrossRefGoogle Scholar
  148. 148.
    Allen NB, Caldwell DS, Rice JR, et al. Cyclosporin A therapy for Wegener’s granulomatosis. Adv Exp Med Biol 1993; 336: 473–6PubMedGoogle Scholar
  149. 149.
    Ghez D, Westeel PF, Henry I, et al. Control of a relapse and induction of long-term remission of Wegener’s granulomatosis by cyclosporine. Am J Kidney Dis 2002; 40(2): E6PubMedCrossRefGoogle Scholar
  150. 150.
    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(2): 440–7PubMedCrossRefGoogle Scholar
  151. 151.
    Jayne DR, Chapel H, Adu D, et al. Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity. QJM 2000; 93(7): 433–9PubMedCrossRefGoogle Scholar
  152. 152.
    Jayne DR, Esnault VL, Lockwood CM. ANCA anti-idiotype antibodies and the treatment of systemic vasculitis with intravenous immunoglobulin. J Autoimmun 1993; 6(2): 207–19PubMedCrossRefGoogle Scholar
  153. 153.
    Jayne DR, Davies MJ, Fox CJ, et al. Treatment of systemic vasculitis with pooled intravenous immunoglobulin. Lancet 1991; 337(8750): 1137–9PubMedCrossRefGoogle Scholar
  154. 154.
    Richter C, Schnabel A, Csernok E, et al. Treatment of antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis with high-dose intravenous immunoglobulin. Clin Exp Immunol 1995; 101(1): 2–7PubMedCrossRefGoogle Scholar
  155. 155.
    Taylor CT, Buring SM, Taylor KH. Treatment of Wegener’s granulomatosis with immune globulin: CNS involvement in an adolescent female. Ann Pharmacother 1999; 33(10): 1055–9PubMedCrossRefGoogle Scholar
  156. 156.
    Blum M, Andrassy K, Adler D, et al. Early experience with intravenous immunoglobulin treatment in Wegener’s granulomatosis with ocular involvement. Graefes Arch Clin Exp Ophthalmol 1997; 235(9): 599–602PubMedCrossRefGoogle Scholar
  157. 157.
    Lockwood CM, Thiru S, Isaacs JD, et al. Long-term remission of intractable systemic vasculitis with monoclonal antibody therapy. Lancet 1993; 341(8861): 1620–2PubMedCrossRefGoogle Scholar
  158. 158.
    Lockwood CM. New treatment strategies for systemic vasculitis: the role of intravenous immune globulin therapy. Clin Exp Immunol 1996; 104 Suppl. 1: 77–82PubMedGoogle Scholar
  159. 159.
    Lockwood CM, Thiru S, Stewart S, et al. Treatment of refractory Wegener’s granulomatosis with humanized monoclonal antibodies. Q J Med 1996; 89(12): 903–12CrossRefGoogle Scholar
  160. 160.
    Dick AD, Meyer P, James T, et al. Campath-1H therapy in refractory ocular inflammatory disease. Br J Ophthalmol 2000; 84(1): 107–9PubMedCrossRefGoogle Scholar
  161. 161.
    Murphy JM, Gomez-Anson B, Gillard JH, et al. Wegener granulomatosis: MR imaging findings in brain and meninges. Radiology 1999; 213(3): 794–9PubMedGoogle Scholar
  162. 162.
    Kool J, de Keizer RJ, Siegert CE. Antithymocyte globulin treatment of orbital Wegener granulomatosis: a follow-up study. Am J Ophthalmol 1999; 127(6): 738–9PubMedCrossRefGoogle Scholar
  163. 163.
    Papo T, Le Thi Huong D, Wiederkehr JL, et al. Etoposide in Wegener’s granulomatosis. Rheumatology (Oxford) 1999; 38(5): 473–5CrossRefGoogle Scholar
  164. 164.
    Stone JH, Uhlfelder ML, Hellmann DB, et al. Etanercept combined with conventional treatment in Wegener’s granulomatosis: a six-month open-label trial to evaluate safety. Arthritis Rheum 2001; 44(5): 1149–54PubMedCrossRefGoogle Scholar

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© Adis Data Information BV 2006

Authors and Affiliations

  1. 1.Division of Pulmonary and Critical Medicine, Department of Internal MedicineUniversity of Michigan Medical CenterAnn ArborUSA
  2. 2.Department of Medicine, Division of PulmonaryThe David Geffen School of Medicine at UCLA, Critical Care Medicine and HospitalistsLos AngelesUSA

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