Wegenersche Granulomatose

Zusammenfassung

Die Wegenersche Granulomatose (WG) gehört zu den primär-systemischen Vaskulitiden mit überwiegendem Befall kleiner Gefäße, eng assoziiert mit dem Nachweis eines C-ANCA/PR3-ANCA. Die Inzidenz der WG in Europa beträgt ca. 8 Neuerkrankungen pro Jahr pro eine Million. Klinisch führend sind Beteiligungen des oberen und unteren Respirationstrakts und der Nieren. Die Diagnostik ist interdisziplinär zur Festlegung von Krankheitsausdehnung und Aktivität unter Hinzuziehung labortechnischer und bildgebender Verfahren, der Goldstandard bleibt die Histologie mit Nachweis einer granulomatösen pauci-immunen nekrotisierenden Vaskulitis. Die Therapie wird stadien- und aktivitätsadaptiert durchgeführt. Eine Remissionsinduktion bei isoliertem Befall des oberen Respirationstraktes (und/oder granulomatösen Veränderungen der Lunge), der sog. Initialphase der WG (localised), ist mit Cotrimoxazol möglich. Bei der „early systemic” WG ohne lebens- oder organbedrohende Manifestationen, insbesondere ohne relevante Nierenbeteiligung, kann eine remissionsinduzierende Therapie mit Methotrexat eingesetzt werden. Bei schwer generalisiert verlaufender WG ist CYC nach wie vor unverzichtbar, bei zusätzlich bestehender RPGN kommt eine additive Plasmapherese zum Einsatz. Nach ca. 3 - 6-monatiger remissionsinduzierender Therapie ist eine Umstellung auf eine weniger aggressive remissionserhaltende Therapie mit Azathioprin möglich, Alternativen sind Leflunomid bzw. bei normaler Nierenfunktion Methotrexat. Für die Dauer der remissionserhaltenden Therapie liegen keine studienbasierten Empfehlungen vor, sie sollte aber mindestens ein Jahr betragen. Ein Alter bei Diagnose von 50 Jahren oder älter, eine Lungen- oder Nierenbeteiligung mit eingeschränkter Nierenfunktion bei Diagnose sind mit einer 3 - 5fach erhöhten Mortalität assoziiert. Die häufigsten Todesursachen sind die WG selbst oder infektiöse Komplikationen. Das Hauptproblem im Langzeitverlauf ist die hohe Rezidivrate, die fast unabhängig von den eingesetzten remissionserhaltenden Therapien um 50 % innerhalb von 5 Jahren liegt.

Abstract

Wegener’s granulomatosis (WG) is a primary systemic vasculitis with predominant manifestations in small vessel provinces and a strong association with C-/PR3-ANCA. In Europe the incidence is about 8 newly diagnosed cases per year per million. The most prominent clinical manifestations are the involvement of the upper and lower respiratory tracts and necrotising glomerulonephritis. Diagnostic evaluations with an interdisciplinary medical team in conjunction with imaging procedures and serological tests enable the assessment of disease activity and extent. The biopsy of a site affected by active disease with histological proof of granulomatous necrotising vasculitis remains the golden standard for diagnosing WG. Treatment is adapted to disease stage and activity. In the “initial phase (localised) disease” with isolated, mainly granulomatous disease of the upper and/or lower respiratory tract, remission can be induced with cotrimoxazole. For more advanced stages immunosuppression consisting of a cytotoxic drug and prednisolone is required, in the early systemic stage methotrexate can be used, provided the glomerular filtration rate is > 50 mL/min, in the generalised stage cyclophosphamide is indispensable, in cases of rapidly progressive glomerulonephritis additional plasma exchange enables a better renal survival. Remission is usually achieved after 3 - 6 months, thereafter patients should be switched to a less aggressive maintenance medication for at least another 12 months. The golden standard is azathioprine, leflunomide and methotrexate are alternatives, mycophenolate is currently being evaluated. The optimal length of the maintenance treatment is the subject of current studies. Age > 50 years, pulmonary or renal involvement with impaired renal function are associated with a 3 - 5-fold increased mortality. The main causes of death are uncontrolled disease activity or infectious complications. After realisation of a significantly improved overall survival over the last 30 years the main problem in the long-term follow-up is a relapse rate of about 50 % in 5 years, irrespective of the choice of the maintenance of remission drug.

Schlüsselwörter

Wegenersche Granulomatose - antineutrophile zytoplasmatische Antikörper - C-ANCA - Proteinase 3 - Cyclophosphamid

Key words

Wegener’s granulomatosis - antineutrophile cytoplasmatic autoantibody - C-ANCA - proteinase 3 - cyclophosphamide

Literatur

• 1 Aasarod K, Iversen B M, Hammerstrom J. et al . Wegener’s granulomatosis: clinical course in 108 patients with renal involvement.  Nephrol Dial Transplant. 2000;  15 611-618
• 2 Aries P M, Hellmich B, Reinhold-Keller E. et al . High-dose intravenous azathioprine pulse treatment in refractory Wegener’s granulomatosis.  Rheumatology (Oxford). 2004;  43 1307-1308
• 3 Aries P M, Hellmich B, Voswinkel J. et al . Lack of efficacy of rituximab in Wegener’s granulomatosis with refractory granulomatous manifestations.  Ann Rheum Dis. 2006;  65 853-858
• 4 Booth A D, Almond M K, Burns A. et al . Outcome of ANCA-associated renal vasculitis: a 5-year retrospective study.  Am J Kidney Dis. 2003;  41 776-784
• 5 Choi H K, Liu S, Merkel P A. et al . Diagnostic performance of antineutrophil cytoplasmic antibody tests for idiopathic vasculitides: metaanalysis with a focus on antimyeloperoxidase antibodies.  J Rheumatol. 2001;  28 1584-1590
• 6 Chung J B, Armstrong K, Schwartz J S. et al . Cost-effectiveness of prophylaxis against Pneumocystis carinii pneumonia in patients with Wegner’s granulomatosis undergoing immunosuppressive therapy.  Arthritis Rheum. 2000;  43 1841-1848
• 7 Cordier J F. A lung biopsy is unnecessary in the management of ANCA-positive patients with chest-roentgenographic abnormalities.  Sarcoidosis Vasc Diffuse Lung Dis. 1996;  13 235-237
• 8 Cotch M F, Hoffman G S, Yerg D E. 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 87-92
• 9 Csernok E, Holle J, Hellmich B. et al . Evaluation of capture ELISA for detection of antineutrophil cytoplasmic antibodies directed against proteinase 3 in Wegener’s granulomatosis: first results from a multicentre study.  Rheumatology (Oxford). 2004;  43 174-180
• 10 Dadoniene J, Kirdaite G, Mackiewicz Z. et al . Incidence of primary systemic vasculitides in Vilnius: a university hospital population based study.  Ann Rheum Dis. 2005;  64 335-336
• 11 Groot de K, Gross W L, Herlyn K. et al . Development and validation of a disease extent index for Wegener’s granulomatosis.  Clin Nephrol. 2001;  55 31-38
• 12 Groot de 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.  Arthritis Rheum. 2005;  52 2461-2469
• 13 Groot de K, Schmidt D K, Arlt A C. et al . Standardized neurologic evaluations of 128 patients with Wegener’s granulomatosis.  Arch Neurol. 2001;  58 1215-1251
• 14 de Lind van Wijngaarden R A, Hauer H A, Wolterbeek R. et al . Clinical and histologic determinants of renal outcome in ANCA-associated vasculitis: A prospective analysis of 100 patients with severe renal involvement.  J Am Soc Nephrol. 2006;  17 2264-2274
• 15 Exley A R, Bacon P A, Luqmani R A. et al . Development and Initial Validation of the Vasvulitis Damage Index (VDI) for the Standardized Clinical Assessment of Damage in the Systemic Vasculitides.  Arthritis Rheum. 1997;  40 371-380
• 16 Falk R J, Jennette J C. ANCA small-vessel vasculitis.  J Am Soc Nephrol. 1997;  8 314-322
• 17 Fauci A S, Haynes B F, 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
• 18 Fauci A S, Wolff S M. Wegener’s granulomatosis: studies in eighteen patients and a review of the literature.  Medicine (Baltimore). 1973;  52 535-561
• 19 Finkielman J D, Merkel P A, Schroeder D. et al . Antiproteinase 3 antineutrophil cytoplasmic antibodies and disease activity in Wegener granulomatosis.  Ann Intern Med. 2007;  147 611-619
• 20 Flossmann O, Groot de K. When should patients with ANCA-associated vasculitis be switched from induction to maintenance therapy?.  Nature clinical practice. 2007;  3 236-237
• 21 Flossmann O, Jones R B, Jayne D R. et al . Should rituximab be used to treat antineutrophil cytoplasmic antibody associated vasculitis?.  Ann Rheum Dis. 2006;  65 841-844
• 22 Gibson A, Stamp L K, Chapman P T. et al . The epidemiology of Wegener’s granulomatosis and microscopic polyangiitis in a Southern Hemisphere region.  Rheumatology (Oxford). 2006;  45 624-628
• 23 Gonzalez-Gay M A, Garcia-Porrua C, Guerrero J. et al . The epidemiology of the primary systemic vasculitides in northwest Spain: implications of the Chapel Hill Consensus Conference definitions.  Arthritis Rheum. 2003;  49 388-393
• 24 Gross W L, Schnabel A, Trabandt A. New perspectives in pulmonary angiitis. From pulmonary angiitis and granulomatosis to ANCA associated vasculitis.  Sarcoidosis Vasc Diffuse Lung Dis. 2000;  17 33-52
• 25 Hagen E C, Daha M R, Hermans J. et al . Diagnostic value of standardized assays for antineutrophil cytoplasmic antibodies in idiopathic systemic vasculitis.  Kidney Int. 1998;  53 743-753
• 26 Han W K, Choi H K, Roth R M. et al . Serial ANCA titers: useful tool for prevention of relapses in ANCA-associated vasculitis.  Kidney Int. 2003;  63 1079-1085
• 27 Hauer H A, Bajema I M, Van Houwelingen H C. et al . Determinants of outcome in ANCA-associated glomerulonephritis: a prospective clinico-histopathological analysis of 96 patients.  Kidney Int. 2002;  62 1732-1742
• 28 Hellmich B, Csernok E, Fredenhagen G. et al . A novel high sensitivity ELISA for detection of antineutrophil cytoplasm antibodies against proteinase-3.  Clin Exp Rheumatol. 2007;  25 S1-5
• 29 Hellmich B, Kausch I, Doehn C. et al . Urinary bladder cancer in Wegener’s granulomatosis: is it more than cyclophosphamide?.  Ann Rheum Dis. 2004;  63 1183-1185
• 30 Herlyn K, Gross W, Reinhold-Keller E. Stabile Inzidenzraten der primär-systemischen Vaskulitiden in Schleswig-Holstein von 1998 - 2006.  Zeitschrift für Rheumatologie. 2006;  66 65
• 31 Herlyn K, Hoder J, Gross W L. et al . A new training program - a status report: vasculitis.  Zeitschrift fur Rheumatologie. 2005;  64 198-201
• 32 Hoffman G S, Kerr G S, Leavitt R Y. et al . Wegener’s granulomatosis: an analysis of 158 patients.  Ann Intern Med. 1992;  116 488-498
• 33 Hoffman G S, Thomas-Golbanov C K, Chan J. et al . Treatment of subglottic stenosis, due to Wegener’s granulomatosis, with intralesional corticosteroids and dilation.  J Rheumatol. 2003;  30 1017-1021
• 34 Jayne D. Update on the European Vasculitis Study group trials.  Curr Opin Rheumatol. 2001;  13 48-55
• 35 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
• 36 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 2180-2188
• 37 Jennette J C, Falk R J, Andrassy K. et al . Nomenclature of systemic vasculitides: The proposal of an International Consensus Conference.  Arthritis Rheum. 1994;  37 187-192
• 38 Knight A, Askling J, Ekbom A. Cancer incidence in a population-based cohort of patients with Wegener’s granulomatosis.  International journal of cancer. 2002;  100 82-85
• 39 Knight A, Ekbom A, Brandt L. et al . Increasing incidence of Wegener’s granulomatosis in Sweden, 1975 - 2001.  J Rheumatol. 2006;  33 2060-2063
• 40 Koldingsnes W, Nossent H. Epidemiology of Wegener’s granulomatosis in northern Norway.  Arthritis Rheum. 2000;  43 2481-2487
• 41 Komocsi A, Reuter M, Heller M. et al . Active disease and residual damage in treated Wegener’s granulomatosis: an observational study using pulmonary high-resolution computed tomography.  European radiology. 2003;  13 36-42
• 42 Lamprecht P, Voswinkel J, Lilienthal T. et al . Effectiveness of TNF-alpha blockade with infliximab in refractory Wegener’s granulomatosis.  Rheumatology (Oxford). 2002;  41 1303-1307
• 43 Lane S E, Watts R A, Shepstone L. et al . Primary systemic vasculitis: clinical features and mortality.  Qjm. 2005;  98 97-111
• 44 Langford C A, Sneller M C, Hallahan C W. et al . Clinical features and therapeutic management of subglottic stenosis in patients with Wegener’s granulomatosis.  Arthritis Rheum. 1996;  39 1754-1760
• 45 Langford C A, Talar-Williams C, Sneller M C. Mycophenolate mofetil for remission maintenance in the treatment of Wegener’s granulomatosis.  Arthritis Rheum. 2004;  51 278-283
• 46 Lapraik C, Watts R, Bacon P. et al . BSR and BHPR guidelines for the management of adults with ANCA associated vasculitis.  Rheumatology (Oxford). 2007;  46 1615-1616
• 47 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.  Arthritis Rheum. 1990;  33 1101-1107
• 48 Luqmani R A, Bacon P A, Moots R J. et al . Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis.  Q J Med. 1994;  87 671-678
• 49 Mahr A, Guillevin L, Poissonnet M. et al . Prevalences of polyarteritis nodosa, microscopic polyangiitis, Wegener’s granulomatosis, and Churg-Strauss syndrome in a French urban multiethnic population in 2000: a capture-recapture estimate.  Arthritis Rheum. 2004;  51 92-99
• 50 Martinez V, Cohen P, Pagnoux C. et al . Intravenous immunoglobulins for relapses of systemic vasculitides associated with antineutrophil cytoplasmic autoantibodies: results of a multicenter, prospective, open-label study of twenty-two patients.  Arthritis Rheum. 2008;  58 308-317
• 51 Matteson E L, Gold K N, Bloch D A. et al . Long-term survival of patients with Wegener’s granulomatosis from the American College of Rheumatology Wegener’s Granulomatosis Classification Criteria Cohort.  The American journal of medicine. 1996;  101 129-134
• 52 Merkel P A, Lo G H, Holbrook J T. et al . Brief communication: high incidence of venous thrombotic events among patients with Wegener granulomatosis: the Wegener’s Clinical Occurrence of Thrombosis (WeCLOT) Study.  Ann Intern Med. 2005;  142 620-626
• 53 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 (Oxford). 2007;  46 1087-1091
• 54 Mohammad A J, Jacobsson L T, Mahr A D. et al . Prevalence of Wegener’s granulomatosis, microscopic polyangiitis, polyarteritis nodosa and Churg-Strauss syndrome within a defined population in southern Sweden.  Rheumatology (Oxford). 2007;  46 1329-1337
• 55 Muhle C, Reinhold-Keller E, Richter C. et al . MRI of the nasal cavity, paranasal sinuses and orbit in Wegener’s granulomatosis.  Eur Radiology. 1997;  7 566-570
• 56 Pusey C D, Rees A J, Evans D J. et al . Plasma exchange in focal necrotizing glomerulonephritis without anti-GBM antibodies.  Kidney Int. 1991;  40 757-763
• 57 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 1021-1032
• 58 Reinhold-Keller E, Groot de K, Gross W L. Cystitis, bladder cancer and myelodysplasia in patients with Wegener’s granulomatosis, letter to the editor.  Arthritis Rheum. 2000;  43 2854-2855
• 59 Reinhold-Keller E, Groot de K, Rudert H. et al . Response to trimethroprim-sulfamethoxazole (T/S) in Wegener’s granulomatosis (WG) depends on the phase of disease.  Q J Med. 1996;  89 15-23
• 60 Reinhold-Keller E, Fink C O, 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;  47 326-332
• 61 Reinhold-Keller E, Zeidler A, Gutfleisch J. et al . Giant cell arteritis is more prevalent in urban than in rural populations: results of an epidemiological study of primary systemic vasculitides in Germany.  Rheumatology (Oxford). 2000;  39 1396-1402
• 62 Schmidt W A, Both M, Reinhold-Keller E. [Imaging procedures in rheumatology: imaging in vasculitis].  Zeitschrift fur Rheumatologie. 2006;  65 652-656, 658 - 661
• 63 Schmitt W H, Birck R, Heinzel P A. et al . Prolonged treatment of refractory Wegener’s granulomatosis with 15-deoxyspergualin: an open study in seven patients.  Nephrol Dial Transplant. 2005;  20 1083-1092
• 64 Slot M C, Tervaert J W, Boomsma M M. 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
• 65 Sneller M C, Hoffman G S, Talar-Williams C. et al . An analysis of forty-two Wegener’s granulomatosis patients treated with methotrexate and prednisone.  Arthritis Rheum. 1995;  38 608-613
• 66 Stassen P M, Sanders J S, Kallenberg C G. et al . Influenza vaccination does not result in an increase in relapses in patients with ANCA-associated vasculitis.  Nephrol Dial Transplant. 2008;  23 654-658
• 67 Stegeman C A, Cohen Tervaert J W, De Jong P E. et al . Trimethoprim-sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener’s granulomatosis.  N Engl J Med. 1996;  335 16-20
• 68 Stone J H, Hoffman G S, Merkel P A. et al . A disease-specific activity index for Wegener’s granulomatosis: modification of the Birmingham Vasculitis Activity Score. International Network for the Study of the Systemic Vasculitides (INSSYS).  Arthritis Rheum. 2001;  44 912-920
• 69 Stone J H, Holbrook J T, Marriott M A. et al . Solid malignancies among patients in the Wegener’s Granulomatosis Etanercept Trial.  Arthritis Rheum. 2006;  54 1608-1618
• 70 Talar-Williams C, Hijazi Y M, Walther M M. et al . Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener’s granulomatosis.  Ann Inter Med. 1996;  124 477-484
• 71 Villa-Forte A, Clark T M, Gomes M. et al . Substitution of methotrexate for cyclophosphamide in Wegener granulomatosis: a 12-year single-practice experience.  Medicine (Baltimore). 2007;  86 269-277
• 72 Walsh M, Merkel P, Mahr A. et al . Systematic Review and Meta-Analysis of Relapses in ANCA-Associated Vasculitis (AAV): What Is the Effect of Low-Dose Corticosteroids?.  Journal of the American Society of Nephrology. 2007;  18 P09
• 73 Watts R A, Gonzalez-Gay M A, Lane S E. et al . Geoepidemiology of systemic vasculitis: comparison of the incidence in two regions of Europe.  Ann Rheum Dis. 2001;  60 170-172
• 74 Watts R A, Lane S E, Bentham G. et al . Epidemiology of systemic vasculitis: a ten-year study in the United Kingdom.  Arthritis Rheum. 2000;  43 414-419
• 75 Weidner S, Geuss S, Hafezi-Rachti S. et al . ANCA-associated vasculitis with renal involvement: an outcome analysis.  Nephrol Dial Transplant. 2004;  19 1403-1411
• 76 Westman K WA, Bygren P G, Olsson H. et al . Relapse rate, renal survival and cancer morbidity in patients with Wegener’ s granulomatosis or microscopic polyangiitis with renal involvement.  JASN. 1998;  9 842-852
• 77 WGET Research Group . Etanercept plus standard therapy for Wegener’s granulomatosis.  N Engl J Med. 2005;  352 351-361

5 Mit freundlicher Genehmigung von Frau Dr. Elena Csernok (Immunologisches Forschungslabor Bad Bramstedt).