rspНаучно-практическая ревматологияRheumatology Science and Practice1995-44841995-4492IMA-PRESS, LLC10.14412/1995-4484-2012-1277rsp-1171Research ArticleСтатьиArticlesПервый опыт использования флударабина в лечении пациента с рефрактерным течением гранулематоза ВегенераThe first experience with fludarabine used to treat a patient with refractory Wegener's granulomatosisГородецкийВ. Р.GorodetskyVadim Romanovichgorodetskiyblood@mail.ruВасильевВ. И.VasilyevV I-СедышевС. Х.SedyshevS Kh-OgorodnikovaM DOgorodnikovaM D-БожьеваЛ. А.BozhyevaL A-НасоновЕвгений ЛьвовичNasonovE L-201215042012502№2 (2012)7680Copyright © Городецкий В.Р., Васильев В.И., Седышев С.Х., Ogorodnikova M.D., Божьева Л.А., Насонов Е.Л., 20122012Городецкий В.Р., Васильев В.И., Седышев С.Х., Ogorodnikova M.D., Божьева Л.А., Насонов Е.Л.Gorodetsky V.R., Vasilyev V.I., Sedyshev S.K., Ogorodnikova M.D., Bozhyeva L.A., Nasonov E.L.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://rsp.mediar-press.net/rsp/article/view/1171References<div><p>Wegener F. On generalised septic vessel diseases. Thorax 1987;42:918-9.</p><p>Godman G.C., Churg J. Wegener's granulomatosis: pathology and review of the literature. AMA Arch Path 1954;58:533-53.</p><p>Leavitt R.Y., Fauci A.S., Bloch D.A. et al. The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis. Arthr Rheum 1990;33:1101-7.</p><p>Jennette J.C., Falk R.J., Andrassy K. et al. Nomenclature of systemic vasculitides: the proposal of an international consensus conference. Arthr Rheum 1994;37:187-92.</p><p>Hoffman G.S., Kerr G.S., Leavitt R.Y. et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 1992;116:488-98.</p><p>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. Arthr Rheum 2000;43:1021-32.</p><p>Yi E.S., Colby T.V. Wegener Granulomatosis. Semin Diagn Pathology 2001;18:34-46.</p><p>Bosch X., Guilabert A., Font J. Antineutrophil cytoplasmic antibodies. Lancet 2006;368:404-18.</p><p>Wiik A. Rational use of ANCA in the diagnosis of vasculitis. Rheumatology (Oxford) 2002;41:481-3.</p><p>Hewins P., Tervaert J.W., Savage C.O. et al. Is Wegener's granulomatosis an autoimmune disease? Curr Opin Rheumatol 2000;12:3-10.</p><p>Hellmich B., Flossmann O., Gross W.L. 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;66:605-17.</p><p>Hunder G.G., Arend W.P., Bloch D.A. et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis: Introduction. Arthr Rheum 1990;33:1065-7.</p><p>Bloch D.A., Michel B.A., Hunder G.G. et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis: patients and methods. Arthr Rheum 1990;33:1068-73.</p><p>Jayne D. Update on the European Vasculitis Study Group trials. Curr Opin Rheumatol 2001;13:48-55.</p><p>Schmitt W.H., Hagen E.C., Neumann I. et al. Treatment of refractory Wegener's granulomatosis with antithymocyte globulin (ATG): an open study in 15 patients. Kidney Int 2004;65:1440-8.</p><p>Langford C.A., Hoffman G.S. Wegener's granulomatosis. Thorax 2000;54:629-37.</p><p>Novack S.N., Pearson C.M. Cyclophosphamide therapy in Wegener's granulomatosis. N Engl J Med 1971;284:938-42.</p><p>Fauci A.S., Wolff S.M. Wegener's granulomatosis: studies in eighteen patients and a review of the literature. Medicine (Baltimore) 1973;52:535-61.</p><p>Hoffman G.S., Kerr G.S., Leavitt R.Y. et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 1992;116:488-98.</p><p>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. Arthr Rheum 2000;43:1021-32.</p><p>Stone J.H., Merkel P.A., Spiera R. et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010;363:221-32.</p><p>Jones R.B., Tervaert J.W., Hauser T. et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 2010;363:211-20.</p><p>de Groot K., Harper L., Jayne D.R. et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med 2009;150:670-80.</p><p>Jayne D.R., 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;18:2180-8.</p><p>de Groot K., Rasmussen N., Bacon P.A. et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthr Rheum 2005;52:2461-9.</p><p>Rutgers A., Kallenberg C.G.M. Refractory vasculitis. Autoimmun Rev 2011;10:702-6.</p><p>Ramos-Casals M., Garcia-Hernandez F.J., de Ramon E. et al. Off-label use of rituximab in 196 patients with severe, refractory systemic autoimmune diseases. Clin Exp Rheumatol 2010;28:468-76.</p><p>Jones R.B., Ferraro A.J., Chaudhry A.N. et al. A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthr Rheum 2009;60:2156-68.</p><p>Roccatello D., Baldovino S., Alpa M. et al. Effects of anti-CD20 monoclonal antibody as a rescue treatment for ANCA-associated idiopathic systemic vasculitis with or without overt renal involvement. Clin Exp Rheumatol 2008;26:S67-S71.</p><p>Seo P., Specks U., Keogh K.A. Efficacy of rituximab in limited Wegeners granulomatosis with refractory granulomatous manifestations. J Rheumatol 2008;35:2017-23.</p><p>Smith K.G., Jones R.B., Burns S.M., Jayne D.R. Long-term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis: Remission, relapse, and re-treatment. Arthr Rheum 2006;54:2970-82.</p><p>Stasi R., Stipa E., Del Poeta G. et al. Long-term observation of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis treated with rituximab. Rheumatology (Oxford) 2006;45:1432-6.</p><p>Keogh K.A., Ytterberg S.R., Fervenza F.C. et al. Rituximab for refractory Wegeners granulomatosis: report of a prospective, open-label pilot trial. Am J Respir Crit Care Med 2006;173:180-7.</p><p>Walsh M., Chaudhry A., Jayne D. Long-term follow-up of relapsing/refractory antineutrophil cytoplasm antibody associated vasculitis treated with the lymphocyte depleting antibody alemtuzumab (CAMPATH-1 H). Ann Rheum Dis 2008;67:1322-7.</p><p>Benenson E., Fries J.W., Heilig B. et al. High-dose azathioprine pulse therapy as a new treatment option in patients with active Wegeners granulomatosis and lupus nephritis refractory or intolerant to cyclophosphamide. Clin Rheumatol 2005;24:251-7.</p><p>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;41:1126-32.</p><p>Booth A., Harper L., Hammad T. et al. Prospective study of TNFalpha blockade with infliximab in anti-neutrophil cytoplasmic antibodyassociated systemic vasculitis. J Am Soc Nephrol 2004;15:717-21.</p><p>Birck R., Warnatz K., Lorenz H.M. 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;14:440-7.</p><p>Flossmann O., Baslund B., Bruchfeld A. et al. Deoxyspergualin in relapsing and refractory Wegeners granulomatosis. Ann Rheum Dis 2009;68:1125-30.</p><p>Stassen P.M., Tervaert J.W., Stegeman C.A. Induction of remission in active antineutrophil cytoplasmic antibody-associated vasculitis with mycophenolate mofetil in patients who cannot be treated with cyclophosphamide. Ann Rheum Dis 2007;66:798-802.</p><p>Statkute L., Oyama Y., Barr W.G. et al. Autologous nonmyeloablative haematopoietic stem cell transplantation for refractory systemic vasculitis. Ann Rheum Dis 2008;67:991-7.</p><p>Kotter I., Daikeler T., Amberger C. et al. Autologous stem cell transplantation of treatment-resistant systemic vasculitis-a single center experience and review of the literature. Clin Nephrol 2005;64:485-9.</p><p>Schlieben D.J., Korbet S.M., Kimura R.E. et al. Pulmonary-renal syndrome in a newborn with placental transmission of ANCAs. Am J Kidney Dis 2005;45:758-61.</p><p>Xiao H., Heeringa P., Hu P. et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest 2002;110:955-63.</p><p>Bolton W.K., Innes D., Sturgill B.C., Kaiser D.L. T cells and macrophages in rapidly progressive glomerulonephritis: Clinicopathological correlates. Kidney Int 1987;32:869-76.</p><p>Csernok E., Trabandt A., Muller A. et al. Cytokine profiles in Wegener's granulomatosis: predominace of type 1 (Th1) in the granulomatous inflammation. Arthr Rheum 1999;42:742-50.</p><p>Balding C.E.J., Howie A.J., Drake-Lee A.B., Savage C.O.S. Th2 dominance in nasal mucosa in patients with Wegener's granulomatosis. Clin Exp Immunol 2001;125:332-9.</p><p>Komocsi A., Lamprecht P., Csernok E. et al. Peripheral blood and granuloma CD4+ CD28- T cells are a major source of interferon-а and tumor necrosis factor-а in Wegener's granulomatosis. Am J Pathol 2002;160:1717-24.</p><p>Cunningham M.A., Huang X.R., Dowling J.P. et al. Effectors of cellmediated immunity are prominent in “pauci-immune” glomerulonephritis. J Am Soc Nephrol 1999;10:499-506.</p><p>Lamprecht P., Moosig F., Csernok E. et al. CD28 negative T cells are enriched in the granulomatous lesions of the respiratory tract in Wegener's granulomatosis. Thorax 2001;56:751-7.</p><p>Van der Woude F.J., van Es L.A., Daha M.R. The role of c-ANCA antigen in the pathogenesis of Wegener's granulomatosis. A hypothesis based on both humeral and cellular mechanisms. Neth J Med 1990;36:169-71.</p><p>Brouwer E., Stegeman C., Muitema M. et al. T-cell reactivity to proteinase 3 and myeloperoxidase in patients withWegener's granulomatosis. Clin Exp Immunol 1994;98:448-53.</p><p>King W.J., Brooks C.J., Holder R. et al. T lymphocyte responses to anti-neutrophil cytoplasmic antibody (ANCA) antigens are present in patients with ANCA associated systemic vasculitis and persist during disease remission. Clin Exp Immunol 1998;112:539-46.</p><p>Popa E.R., Franssen C.F., Limburg P.C. et al. In vitro cytokine production and proliferation of T cells from patients with antiproteinase 3-and antimyeloperoxidase-associated vasculitis, in response to proteinase 3 and myeloperoxidase. Arthr Rheum 2002;46:1894-904.</p><p>Brouwer E., Tervaert J.W., 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;83:379-86.</p><p>Schmitt W.H., Heesen C., Csernok E. et al. Elevated serum levels of soluble interleukin-2 receptor in patients with Wegener's granulomatosis. Arthr Rheum 1992;35:1088-96.</p><p>Wang G., Csernok E., Gross W.L. High plasma levels of the soluble form of CD30 activation molecule reflect disease activity in patients with Wegener's granulomatosis. Am J Med 1997;102:517-23.</p><p>Ludviksson B.J., Sneller M.C., Chua K.S. 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;160:3602-9.</p><p>Plunkett W., Gandhi V., Cheson B. et al. Cellular pharmacology, mechanisms of action and strategies for combination therapy. In: Cheson B., Keating M., Plunkett W. (eds). Nucleoside analogs in cancer therapy. New York: Marcel Dekker, 1997;1 —35.</p><p>Frank D.A., Mahajan S., Ritz J. Fludarabine-induced immunosuppression is associated with inhibition of STAT1 signaling. Nat Med 1999;5:444-7.</p><p>Meng H., Yang C., Ni W. et al. Antitumor activity of fludarabine against human multiple myeloma in vitro and in vivo. Eur J Haematol 2007;79:486-93.</p></div><br /><div><p>Wegener F. On generalised septic vessel diseases. Thorax 1987;42:918-9.</p><p>Godman G.C., Churg J. Wegener's granulomatosis: pathology and review of the literature. AMA Arch Path 1954;58:533-53.</p><p>Leavitt R.Y., Fauci A.S., Bloch D.A. et al. The American College of Rheumatology 1990 criteria for the classification of Wegener's granulomatosis. Arthr Rheum 1990;33:1101-7.</p><p>Jennette J.C., Falk R.J., Andrassy K. et al. Nomenclature of systemic vasculitides: the proposal of an international consensus conference. Arthr Rheum 1994;37:187-92.</p><p>Hoffman G.S., Kerr G.S., Leavitt R.Y. et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 1992;116:488-98.</p><p>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. Arthr Rheum 2000;43:1021-32.</p><p>Yi E.S., Colby T.V. Wegener Granulomatosis. Semin Diagn Pathology 2001;18:34-46.</p><p>Bosch X., Guilabert A., Font J. Antineutrophil cytoplasmic antibodies. Lancet 2006;368:404-18.</p><p>Wiik A. Rational use of ANCA in the diagnosis of vasculitis. Rheumatology (Oxford) 2002;41:481-3.</p><p>Hewins P., Tervaert J.W., Savage C.O. et al. Is Wegener's granulomatosis an autoimmune disease? Curr Opin Rheumatol 2000;12:3-10.</p><p>Hellmich B., Flossmann O., Gross W.L. 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;66:605-17.</p><p>Hunder G.G., Arend W.P., Bloch D.A. et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis: Introduction. Arthr Rheum 1990;33:1065-7.</p><p>Bloch D.A., Michel B.A., Hunder G.G. et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis: patients and methods. Arthr Rheum 1990;33:1068-73.</p><p>Jayne D. Update on the European Vasculitis Study Group trials. Curr Opin Rheumatol 2001;13:48-55.</p><p>Schmitt W.H., Hagen E.C., Neumann I. et al. Treatment of refractory Wegener's granulomatosis with antithymocyte globulin (ATG): an open study in 15 patients. Kidney Int 2004;65:1440-8.</p><p>Langford C.A., Hoffman G.S. Wegener's granulomatosis. Thorax 2000;54:629-37.</p><p>Novack S.N., Pearson C.M. Cyclophosphamide therapy in Wegener's granulomatosis. N Engl J Med 1971;284:938-42.</p><p>Fauci A.S., Wolff S.M. Wegener's granulomatosis: studies in eighteen patients and a review of the literature. Medicine (Baltimore) 1973;52:535-61.</p><p>Hoffman G.S., Kerr G.S., Leavitt R.Y. et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med 1992;116:488-98.</p><p>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. Arthr Rheum 2000;43:1021-32.</p><p>Stone J.H., Merkel P.A., Spiera R. et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med 2010;363:221-32.</p><p>Jones R.B., Tervaert J.W., Hauser T. et al. Rituximab versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med 2010;363:211-20.</p><p>de Groot K., Harper L., Jayne D.R. et al. Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med 2009;150:670-80.</p><p>Jayne D.R., 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;18:2180-8.</p><p>de Groot K., Rasmussen N., Bacon P.A. et al. Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthr Rheum 2005;52:2461-9.</p><p>Rutgers A., Kallenberg C.G.M. Refractory vasculitis. Autoimmun Rev 2011;10:702-6.</p><p>Ramos-Casals M., Garcia-Hernandez F.J., de Ramon E. et al. Off-label use of rituximab in 196 patients with severe, refractory systemic autoimmune diseases. Clin Exp Rheumatol 2010;28:468-76.</p><p>Jones R.B., Ferraro A.J., Chaudhry A.N. et al. A multicenter survey of rituximab therapy for refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthr Rheum 2009;60:2156-68.</p><p>Roccatello D., Baldovino S., Alpa M. et al. Effects of anti-CD20 monoclonal antibody as a rescue treatment for ANCA-associated idiopathic systemic vasculitis with or without overt renal involvement. Clin Exp Rheumatol 2008;26:S67-S71.</p><p>Seo P., Specks U., Keogh K.A. Efficacy of rituximab in limited Wegeners granulomatosis with refractory granulomatous manifestations. J Rheumatol 2008;35:2017-23.</p><p>Smith K.G., Jones R.B., Burns S.M., Jayne D.R. Long-term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis: Remission, relapse, and re-treatment. Arthr Rheum 2006;54:2970-82.</p><p>Stasi R., Stipa E., Del Poeta G. et al. Long-term observation of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis treated with rituximab. Rheumatology (Oxford) 2006;45:1432-6.</p><p>Keogh K.A., Ytterberg S.R., Fervenza F.C. et al. Rituximab for refractory Wegeners granulomatosis: report of a prospective, open-label pilot trial. Am J Respir Crit Care Med 2006;173:180-7.</p><p>Walsh M., Chaudhry A., Jayne D. Long-term follow-up of relapsing/refractory antineutrophil cytoplasm antibody associated vasculitis treated with the lymphocyte depleting antibody alemtuzumab (CAMPATH-1 H). Ann Rheum Dis 2008;67:1322-7.</p><p>Benenson E., Fries J.W., Heilig B. et al. High-dose azathioprine pulse therapy as a new treatment option in patients with active Wegeners granulomatosis and lupus nephritis refractory or intolerant to cyclophosphamide. Clin Rheumatol 2005;24:251-7.</p><p>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;41:1126-32.</p><p>Booth A., Harper L., Hammad T. et al. Prospective study of TNFalpha blockade with infliximab in anti-neutrophil cytoplasmic antibodyassociated systemic vasculitis. J Am Soc Nephrol 2004;15:717-21.</p><p>Birck R., Warnatz K., Lorenz H.M. 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;14:440-7.</p><p>Flossmann O., Baslund B., Bruchfeld A. et al. Deoxyspergualin in relapsing and refractory Wegeners granulomatosis. Ann Rheum Dis 2009;68:1125-30.</p><p>Stassen P.M., Tervaert J.W., Stegeman C.A. Induction of remission in active antineutrophil cytoplasmic antibody-associated vasculitis with mycophenolate mofetil in patients who cannot be treated with cyclophosphamide. Ann Rheum Dis 2007;66:798-802.</p><p>Statkute L., Oyama Y., Barr W.G. et al. Autologous nonmyeloablative haematopoietic stem cell transplantation for refractory systemic vasculitis. Ann Rheum Dis 2008;67:991-7.</p><p>Kotter I., Daikeler T., Amberger C. et al. Autologous stem cell transplantation of treatment-resistant systemic vasculitis-a single center experience and review of the literature. Clin Nephrol 2005;64:485-9.</p><p>Schlieben D.J., Korbet S.M., Kimura R.E. et al. Pulmonary-renal syndrome in a newborn with placental transmission of ANCAs. Am J Kidney Dis 2005;45:758-61.</p><p>Xiao H., Heeringa P., Hu P. et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest 2002;110:955-63.</p><p>Bolton W.K., Innes D., Sturgill B.C., Kaiser D.L. T cells and macrophages in rapidly progressive glomerulonephritis: Clinicopathological correlates. Kidney Int 1987;32:869-76.</p><p>Csernok E., Trabandt A., Muller A. et al. Cytokine profiles in Wegener's granulomatosis: predominace of type 1 (Th1) in the granulomatous inflammation. Arthr Rheum 1999;42:742-50.</p><p>Balding C.E.J., Howie A.J., Drake-Lee A.B., Savage C.O.S. Th2 dominance in nasal mucosa in patients with Wegener's granulomatosis. Clin Exp Immunol 2001;125:332-9.</p><p>Komocsi A., Lamprecht P., Csernok E. et al. Peripheral blood and granuloma CD4+ CD28- T cells are a major source of interferon-а and tumor necrosis factor-а in Wegener's granulomatosis. Am J Pathol 2002;160:1717-24.</p><p>Cunningham M.A., Huang X.R., Dowling J.P. et al. Effectors of cellmediated immunity are prominent in “pauci-immune” glomerulonephritis. J Am Soc Nephrol 1999;10:499-506.</p><p>Lamprecht P., Moosig F., Csernok E. et al. CD28 negative T cells are enriched in the granulomatous lesions of the respiratory tract in Wegener's granulomatosis. Thorax 2001;56:751-7.</p><p>Van der Woude F.J., van Es L.A., Daha M.R. The role of c-ANCA antigen in the pathogenesis of Wegener's granulomatosis. A hypothesis based on both humeral and cellular mechanisms. Neth J Med 1990;36:169-71.</p><p>Brouwer E., Stegeman C., Muitema M. et al. T-cell reactivity to proteinase 3 and myeloperoxidase in patients withWegener's granulomatosis. Clin Exp Immunol 1994;98:448-53.</p><p>King W.J., Brooks C.J., Holder R. et al. T lymphocyte responses to anti-neutrophil cytoplasmic antibody (ANCA) antigens are present in patients with ANCA associated systemic vasculitis and persist during disease remission. Clin Exp Immunol 1998;112:539-46.</p><p>Popa E.R., Franssen C.F., Limburg P.C. et al. In vitro cytokine production and proliferation of T cells from patients with antiproteinase 3-and antimyeloperoxidase-associated vasculitis, in response to proteinase 3 and myeloperoxidase. Arthr Rheum 2002;46:1894-904.</p><p>Brouwer E., Tervaert J.W., 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;83:379-86.</p><p>Schmitt W.H., Heesen C., Csernok E. et al. Elevated serum levels of soluble interleukin-2 receptor in patients with Wegener's granulomatosis. Arthr Rheum 1992;35:1088-96.</p><p>Wang G., Csernok E., Gross W.L. High plasma levels of the soluble form of CD30 activation molecule reflect disease activity in patients with Wegener's granulomatosis. Am J Med 1997;102:517-23.</p><p>Ludviksson B.J., Sneller M.C., Chua K.S. 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;160:3602-9.</p><p>Plunkett W., Gandhi V., Cheson B. et al. Cellular pharmacology, mechanisms of action and strategies for combination therapy. In: Cheson B., Keating M., Plunkett W. (eds). Nucleoside analogs in cancer therapy. New York: Marcel Dekker, 1997;1 —35.</p><p>Frank D.A., Mahajan S., Ritz J. Fludarabine-induced immunosuppression is associated with inhibition of STAT1 signaling. Nat Med 1999;5:444-7.</p><p>Meng H., Yang C., Ni W. et al. Antitumor activity of fludarabine against human multiple myeloma in vitro and in vivo. Eur J Haematol 2007;79:486-93.</p></div><br />
The authors declare that there are no conflicts of interest present.