DR GERKLOS BAST ALMONACID

MR2 NEFROLOGIA HERM JUNIO 2010

1.- Inflamacion granulomatosa de tracto respiratorio

2.- glomerulonefritis progresiva3.- vasculitis necrotizante de arterias y

venas de mediano y pequeño calibre

ORGANOS COMPROMETIDOS

95% Pulmón (vasos )

90% senos 85% riñón 75%

nasofaringe, bazo 70%

articulaciones

50% piel 50% ojos 35% oído medio 30% corazón 20% nervios

periféricos 20% SNC

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)

CAUSAS

Desconocida Probablemente inmunologica

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

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

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 RheumatologyArthritis Rheum 2009 Aug;33(8):1101

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

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)

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.

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

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

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.

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.

   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.

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 reportMayo Clin Proc 2005 May;80(5):671

Lancet 1999 Nov 6;354(9190):1598

COMPLICACIONES Glomerulonefritis

rápidamente progresiva (gnrp)

Falla renal Sepsis Anemia normocítica

normocrómica CID Trombo embolismo

venoso (1) Compromiso meníngeo

(3) Hemorragia alveolar pápulas, ulceras y

lesiones urticariales uveítis, neuritis óptica

(2) cardiomiopatía

dilatada y pericarditis enfermedad orbital

inflamatoria (4)

Ann Intern Med 2005 Apr 19;142(8):620Rheumatology (Oxford) 2008 Apr;47(4):530 Mayo Clin Proc 2000 Aug;75(8):856 Eye 2006 Oct;20(10):1196

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.