The document summarizes Wegener's granulomatosis (WG), a rare necrotizing vasculitis that commonly involves the respiratory tract and kidneys. It describes the pathogenesis as a type III hypersensitivity reaction mediated by immune complexes. Treatment typically involves cyclophosphamide and glucocorticoids to induce remission, followed by azathioprine or methotrexate as maintenance therapy to sustain remission for 12-18 months. Complications can include rapidly progressive glomerulonephritis, renal failure, and other organ involvement.

1. DR GERKLOS BAST ALMONACID
MR2 NEFROLOGIA
HERM JUNIO 2010

2. 1.- Inflamacion granulomatosa de tracto
respiratorio
2.- glomerulonefritis progresiva
3.- vasculitis necrotizante de arterias y venas de
mediano y pequeño calibre

3. ORGANOS COMPROMETIDOS
 95% Pulmón (vasos )  35% oído medio
 90% senos  30% corazón
 85% riñón  20% nervios
 75% nasofaringe, periféricos
 bazo  20% SNC
 70% articulaciones
 50% piel
 50% ojos

4. INCIDENCIA – PREVALENCIA
 Bastante rara
 > Hombres
 Edad 50-60 años
 > 95% Caucasicos
Arthritis Rheum 2000 Feb;43(2):414
J Watch 2000 Mar 15;20(6):49)

5. CAUSAS
 Desconocida
 Probablemente inmunologica

6. PATOGENESIS
 Inmunidad tipo III hipersensibilidad
mediada por inmunmocomplejos
 Vasculitis necrotizante de arterias y venas de
mediano y pequeño calibre
 Matriz de metaloproteinasas (MMPs) y sus
inhibidores endogenos han sido sugeridos en
rol patologico
 Infeccion con Staphylococcus pueden
provocar recaidas

7. CUADRO CLINICO
 Presentaciones comunes
 Sinusitis , descarga nasal crónica
 Pérdida de audición
 Dolor articular
 hemoptisis
 Hematuria microscópica
 Fiebre ( 90 %)
 Ocasionalmente
 Glomerulonefritis, tos, rinitis, otitis, disnea , dolor
muscular , neuritis, pérdida de peso
Tervaert, JW. Anti-neutrophil cytoplasmic antibodies: Current diagnostic
and pathophysiological potential. Kidney Int 2004 ; 46:1

10. DIAGNOSTICO
 1.-Nasal or oral inflammation (painful or
painless oral ulcers or purulent or bloody
nasal discharge)
 2.-Abnormal chest radiograph showing
nodules, fixed infiltrates, or cavities
 3.-Abnormal urinary sediment (microscopic
hematuria with or without red cell casts)
 4.- Granulomatous inflammation on biopsy of
an artery or perivascular area
American College of Rheumatology
Arthritis Rheum 2009 Aug;33(8):1101

11. PRUEBAS A CONSIDERAR
 Hematometría ,creatinina sérica
 Examen completo de orina
 Factor reumatoideo
 ANA
 hepatitis serología
 (ANCA) anti-neutrophil cytoplasmic antibody
 biopsia
 Piel (> rendim), anormalidades en uro análisis
 Biopsia de nervio sural
 Biopsia nasal (vasculitis and inflamación granulomatosa)
 Radiografía de tórax
 Angiografía
 Ecocardiografía
Mayo Clin Proc 2005 Nov;80(11):1435

13. PRUEBAS SEROLOGICAS
 ANCA – C 90 % G W alta
sensibilidad y especificidad (1,3)
 ANCA – p negativo (1, 5)
 ANCA –c
 81% sensitivity, 98%
specificity, 54% VPP and 99% VPN ;
(2,3,4)
 ELISA para ANCA –PR3 (5)
Ann Intern Med 1997 Jun 1;126(11):866
Journal Club on the Web 1997 Jun 10)
Arthritis Rheum 1998 Sep;41(9):1521
Arch Intern Med 2002 Jul 8;162(13):1509
(Ann Rheum Dis 2009 Feb;68(2):228 (5)

15. ANATOMIA PATOLOGICA
 PULMON : vasculitis granulomatosa
, necrotizante (fibrinoide) , granulomas no
caseificantes
 RIÑÓN : GMN focal y segmentaria con
progresión a medias lunas GMN necrotizante
 VASOS : infiltrado inflamatorio y fibrosis
 ARTERITIS GRANULOMATOSA :
predominantemente infiltrado monocítico
con cell gigantes y formación de granuloma
Koderisch, J, et al. Wegener's granulomatosis with renal involvement: Patient
survival and correlations between initial renal function, renal histology, therapy
and renal outcome. Clin Nephrol 2007; 35:139.

16. EULAR CLASSIFICATION
classification of ANCA-associated vasculitis
1.-Localized — Upper and/or lower respiratory tract
disease without any other systemic involvement or
constitutional symptoms.
2.-Early systemic — Any, without organ-threatening or
life-threatening disease.
3.-Generalized — Renal or other organ-threatening
disease, serum creatinine ≤ 5.6 mg/dL (500
micromol/L).
4.-Severe — Renal or other vital organ failure, serum
creatinine ≥ 5.7 mg/dL (500 micromol/L)
5.-Refractory — Progressive disease unresponsive to
glucocorticoids and cyclophosphamide.
European League Against Rheumatism (EULAR) 2008
EULAR recommendation for the management of
primary small vessel vasculitis. Ann Rheum Dis 2008

18. TRATAMIENTO
 INDUCCION - REMISION
 Típicamente altas dosis de esteroides y ciclophosphamide (
oral pulsos IV )
 methotrexate (o azatioprina si cr > 2 mg/dL ciclofosfamida i
 IV IG 2 g/kg
 Mantenimiento de remisión
 methotrexate 20-25 mg/sem o azathioprine 2 mg/kg/d x 12-
18 m (menos toxica q ciclofl )
 trimethoprim-sulfamethoxazole 160/800 mg 2v/d x 24 m
reduce el promedio de recaída

19. SUMMARY AND RECOMMENDATIONS
— The treatment of Wegener's granulomatosis
usually begins with cyclophosphamide and
glucocorticoid therapy to induce remission.
 Cyclophosphamide is discontinued one to
two months after complete remission is
achieved, which usually occurs 3 a 6 m.
 After cyclophosphamide has been
discontinued: Maintenance therapy should
not be started until the white BCC is >4000 c
and the absolute neutrophil count is >1500 c .
Tatsis, E, et al. Therapy for the maintenance of remission in sixty-five patients
with generalized Wegener's granulomatosis. Arthritis Rheum 2003 ; 39:2052.

20.  If these criteria are met, maintenance can be
begun within days after cessation of oral
cyclophosphamide and within two to four
weeks after the last monthly dose of
intravenous cyclophosphamide
 Initiation of maintenance therapy with
methotrexate or azathioprine to sustain the
remission (Grade 1A)
Bacon, P. A randomized trial of maintenance therapy for vasculitis associated
with antineutrophil cytoplasmic autoantibodies. N Engl J Med 2003; 349:36.

21.  azathioprine rather than methotrexate for initial
maintenance therapy GFR < 50 mL/´ (Grade 2B).
 - Azathioprine : initial dose of 2 mg/kg x d The dose
can be lowered to 1.5 mg/kg x d at one year from the time
of initiation of induction therapy
 - methotrexate : initial dose 0.3 mg/kg 1 v/sem (max 15
mg) increased by 2.5 mg x sem - max dose of 25 mg 1 v
/sem + folic acid (1 to 2 mg/day) or folinic acid (2.5 to 5
mg/week, 24 hours after methotrexate)
 Maintenance immunosuppressive therapy should be
continued for 12 to 18 ms.
 Longer term or indefinite maintenance therapy may be
warranted in patients with multiple relapses.
 glucocorticoid therapy (prednisone or equivalent), using
the lowest dose required for control of extrarenal
symptoms (Grade 1C).
Bacon, P. A randomized trial of maintenance therapy for vasculitis associated
with antineutrophil cytoplasmic autoantibodies. N Engl J Med 2008; 349:36.

22. DIAGNOSTICO DIFERENCIAL
 hypersensitivity vasculitis, septic arthritis
(fungal, tuberculosis), lymphomatoid granulomatosis
 other causes of granulomatous arteritis - Churg-Strauss
vasculitis, temporal arteritis, Takayasu's arteritis, seronegative
spondylarthropathy (aortitis)
 other vasculitis of small-to-medium arteries - polyarteritis
nodosa, inflammatory rheumatic diseases, HBV, HCV, HIV infection
 embolic disease - endocarditis (septic, marantic), atrial
myxoma, cholesterol embolization
 vessel stenosis or spasm - atherosclerosis, fibromuscular dysplasia, drug-
induced vasospasm
(ergotamines, cocaine, phenylpropanolamine), intravascular lymphoma
 vessel thrombosis - disseminated intravascular coagulation
(DIC), thrombotic thrombocytopenic purpura (TTP), coumadin-associated
necrosis, antiphospholipid antibody syndrome
 similar syndrome described in 5 adults with autosomal recessive defective
surface expression of HLA class-I molecules.
 cocaine-induced pseudovasculitis described in case report
Mayo Clin Proc 2005 May;80(5):671
Lancet 1999 Nov 6;354(9190):1598

24. COMPLICACIONES
 Glomerulonefritis (3)
rápidamente progresiva  Hemorragia alveolar
(gnrp)
 pápulas, ulceras y
 Falla renal lesiones urticariales
 Sepsis  uveítis, neuritis óptica
 Anemia normocítica (2)
normocrómica  cardiomiopatía dilatada
 CID y pericarditis
 Trombo embolismo  enfermedad orbital
venoso (1) inflamatoria (4)
 Compromiso meníngeo
Ann Intern Med 2005 Apr 19;142(8):620
Rheumatology (Oxford) 2008 Apr;47(4):530
Mayo Clin Proc 2000 Aug;75(8):856
Eye 2006 Oct;20(10):1196

25. RESISTENCIA A LA CICLOFOSFAMIDA
 the first step is to ensure that the
cyclophosphamide regimen has been
optimized and, if indicated, plasma exchange
has been administered.
 Mycophenolate mofetil or rituximab (Grade
2C).
 mycophenolate mofetil 500 mg 2v/d which is
increased, if there is no response, by 250 mg
2v/d c/2 sem to a max dose 500 mg 2v/d
 rituximab : 375 mg/m2 weekly for 4 weeks.