R2 정명화 Granulomatosis with polyangiitis (Wegener`s)

ANCA(+) VASCULITIS

1. Nasal or oral inflammation 2. Abnormal chest radiograph - nodules, fixed infiltrates, or cavities 3. Urinary sediment Microhematuria (>5 red blood cells /HPF) or red cell casts in urine sediment 4. Granulomatous inflammation on biopsy Histologic changes showing granulomatous inflammation within the wall of an artery or in the perivascular or extravascular area (artery,arteriole) - Granulomatous inflammation involving the respiratory tract - Vasculitis of small to medium-size vessels. 1. Asthma 2. Eosinophilia of > 10% 3. Mononeuropathy (including multiplex) or polyneuropathy 4. Migratory or transient pulmonary infiltrates 5. Sinusitis 6. Biopsy containing a blood vessel showing the extravascular accumulation of eosinophil * Four or more criteria classify WG with a sensitivity of 85.0% -Eosinophil-rich, granulmatous inflammation involving the respiratory tract, - Necrotizing vasculitis affecting small to medium-sized vessels, associated with asthma and eosinophilia -Necrotizing vasculitis, with few or no immune deposits, affecting small vessels and medium sized arteries may be present. Necrotizing GN is common. Pulmonary capillaritis often occurs. ACR Criteria (1990)CHCC Nomenclature(1994) WG CSS MPA Granulomatosis with polyangiitis (GPA) alternative name for WG, recommended by the Boards of directors of the ACR, the ASN, and the EULAR in Jan 2011

D EFINITION Granulomatous vasculitis of the upper and lower respiratory tracts together with glomerulonephritis Disseminated vasculitis involving both small aa & vv (First described in 1936)

E PIDEMIOLOGY 서양 : GPA> MPA> CSS 중국, 일본 보고 : MPA>> GPA> CSS Male : female = 1:1 Seen at any age Mean age of onset : 40yrs But only rarely does the disease occur before adolescence

P ATHOPHYSIOLOGY - ANCA C-ANCA : - Antibody to Proteinase-3(PR3) in neutrophil,monocyte cytoplasm - >80-95% positive in GPA - More specific than P-ANCA P-ANCA: - Antibody to myeloperoxidase(MPO) in neutrophil, monocyte in perinuclear area - Other ANCA : in IBD, certain drugs, endocarditis, bacterial infections in patients

P ATHOPHYSIOLOGY - ANCA - IFN-γ ↑, TNF-α ↑,CD4+ T cells ↑, IL-12 ↑ - unbalanced T H 1-type T cell cytokine pattern

P ATHOPHYSIOLOGY Histopathologic hallmarks Necrotizing vasculitis of small arteries and veins together with granuloma formation, which may be either intravascular or extravascular

D IAGNOSIS > 2 of 4 (Sensitivity 88%, Specificity 92%) 1. Nasal or oral inflammation 2. Abnormal chest radiograph: nodules, fixed infiltrates, or cavities 3. Urinary sediment: Microhematuria (>5 red blood cells /HPF) or RBC casts 4. Granulomatous inflammation on biopsy Histologic changes showing granulomatous inflammation within the wall of an artery or in the perivascular or extravascular area(artery,arteriole) 1. Granulomatous inflammation involving the respiratory tract 2. Vasculitis of small to medium-size vessels.

D IAGNOSIS 1.Lower airways: x-ray evidence of fixed pulmonary infiltrates, nodules or cavitations for more than one month, or bronchial stenosis. 2.Upper airways: bloody nasal discharge and crusting for more than one month or nasal ulceration; chronic sinusitis, otitis media or mastoiditis for more than three months; retro-orbital mass on inflammation; subglottic stenosis; saddle nose deformity/destructive sinonasal disease 3. Glomerulonephritis: hematuria associated with RBC casts or >10 dysmorphic red cells; or 2+ hematuria or 2+ proteinuria on dipstick. 4. ANCA was included as a diagnostic criteria A positive ANCA in a patient with surrogate markers for GPA allowed a diagnosis of GPA without a biopsy.

C LINIAL MANIFESTATION

Upper respiratory tract ( 92%) Sx: Sinusitis, nasal pain, rhinorrhea,nasal obstrusion, perforation,orbital pseudotumor

Otitis media, hearing loss ( 44%) Eye: conjuctivitis,scleritis ( 18%)

Lung involve (85%) – 전형적인 병변은 nodule, cavity Sx: Cough,sputum, hemoptysis - 34% abnormal - bilateral nodular infiltrates (M/C)

Glomerulonephritis (77%)- 특히 necrotizing crescentic GN Sx: hematuria, proteinuria, red cell cast - Focal and segmental glomerulitis - Pauci- immune complex - Rapidly progressive GN

Fever (50%), weight loss (15%),appetite loss Skin involvement (46%) Papules, vesicles, palpable purpura, ulcers, or subcutaneous nodules Leukocytoclastic skin lesion Janeway lesion Osler node

Musculoskeletal involvement (50%) Arthralgia, arthritis

Pericarditis(M/C), coronary vasculitis, Rare manifestation- cardiomyopathy, AV involvement Cardiac involvement (8%)

Non-infectious endocarditis in Connective tissue disease

Most common endocarditis cause in connective tissue disease is SLE (Libman–Sacks endocarditis ) Several reports of cardiac involvement in patients with GPA (8%), pericarditis (50%), coronary arteritis (50%), and myocarditis (25%),Endocarditis(21%), MI (11%) but only a few have described mitral valve disease Cardiac complications of Wegener’s granulomatosis Semin Arthritis Rheum 1980;10:148–54. Treatment: - treat GPA - treatment failure, severe MS(MV <1 ㎠ ) or MR(LVEF<60%)  vavuloplasty or valve replacement

C.C) Fever, malaise, apeptite loss o/s: 2mo. Ago PMHx) hypertension, hyperuricemia, frequent nasal bleeding. P/E) II/VI systolic murmur at the apex. Lab) WBC 36000/ul CRP: 2mg/dl ESR 90mm/h C3: 32.3mg/dl C4 : 6.4 mg/dl, C- ANCA (+) urinalysis : RBC >100/HPF, Proteinuria Blood culture: no growth Chest PA) both CPA blunting (67/M)

C.C) Fever, malaise, apeptite loss o/s: 2mo. Ago PMHx) hypertension, hyperuricemia, frequent nasal bleeding. P/E) II/VI systolic murmur at the apex. Lab) WBC 36000/ul CRP: 2mg/dl ESR 90mm/h C3: 32.3mg/dl C4 : 6.4 mg/dl, C- ANCA (+) urinalysis : RBC >100/HPF, Proteinuria Chest X-ray) both CPA blunting Treatment) Cyclophophamide + Prednisolone No progression of mitral valve lesion Renal Bx: GN GPA

C.C) Angina, DOE o/s: 2mo. Ago PMHx) GPA (30ya) (52/M)

Immunosuppressant and steroid treatment No effect, incresed MV massValvular replacement

TREATMENT

EUVAS CATEGORY EULAR recommendations for the management of primary small and medium vessel vasculitis 2009

Remission induction General/Severe PO Cyclophosphamide + high dose glucocorticoid (2mg/kg/day, daily, 3mo) (1mg/kg/day for 1mo) IV Cyclophosphamide + high dose glucocorticoid (15mg/kg,q2wks X3  q3wks x3-6) (1mg/kg/day) Remission rate Side effectRelapse rate Standardized neurologic evaluations of 128 patientswithWegener granulomatosis. Arch Neurol 2001 PO/IV Cyclophosphamide + MPD (0.5-1g/day x 3days) (2mg/kg/day) IV cyclophosphamide 는 PO 에 비해

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL

Remission induction General/Severe PO Cyclophosphamide + high dose glucocorticoid (2mg/kg/day, daily, 3mo) (1mg/kg/day for 1mo) IV Cyclophosphamide + high dose glucocorticoid (15mg/kg,q2wks X3  q3wks x3-6) (1mg/kg/day) PO/IV Cyclophosphamide + MPD (0.5-1g/day x 3days) (2mg/kg/day) Rituximab + high dose glucocorticoid (375 mg/m2/week x4) ( 1mg/kg/day) + Plasmapheresis ( if, severe alveolar hemorrhage Cr> 5.6mg/dl RPGN )

J Am Soc Nephrol 18: 2180–2188, 2007 (MEPEX trial)

Cr >2.85 mg/dl

Am J Kidney Dis 42:

Remission induction Localized IV/PO MTX (25 mg/wk,1-2mo) +glucocorticoid Randomized trial of cyclophosphamide versus methotrexate for induction of remission in early systemic antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2005

- Azathioprine (2mg/kg/day), MTX(20-25mg/kg/week), Leflunomide wks - TMP/SMX prophylaxis for Pneumocystis jiroveci pneumonia Alternative therapy - Mycophenolate mofetil, IV globulin, abatacept Maintenance therapy