Download Wegener`s granulomatosis

Wegener’s granulomatosis
Department of Pulmonology and Critical Care of Medicine
R4 Kim Yeon Ju
Intruduction
• Distinct clinicopathologic entity characterized by
granulomatous vasculitis of the upper and lower
respiratory tracts together with glomerulonephritis
(First described in 1936)
• limited form : only one or two organ systems are involved,
and without renal involvement
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3/100,000 in america
Male : female 1:1
80 - 97% : caucasian, 2-8% : african-americans
seen at any age : mean age ~40yrs
cause : unknown
– develop as a result of an initial inflammation-causing event that
triggers an abnormal reaction from immune system
Am Thorac Soc 2006;3:48-57
Pathology and Pathogenesis
• histopathologic hallmarks
– necrotizing vasculitis of small arteries and veins together with
granuloma formation, which may be either intravascular or
extravascular
• sinuses and nasopharynx : inflammation, necrosis, and
granuloma formation, with or without vasculitis
• renal involvement
– focal and segmental glomerulitis that may evolve into a
rapidly progressive crescentic glomerulonephritis
– Granuloma formation is only rarely seen on renal biopsy
– evidence of immune complex deposition is not found
• immunopathogenesis
– Unclear, suggests an aberrant cell-mediated immune response
– Chronic nasal carriage of Staphylococcus aureus has been
reported to be associated with a higher relapse rate
→ there is no evidence for a role in pathogenesis
• IFN-γ ↑, TNF-α ↑,CD4+ T cells ↑, IL-12 ↑
: unbalanced TH1-type T cell cytokine pattern
• ANCA : play a role in the pathogenesis
Clinical features
• upper airways involvement : 95%
– congestion, epistaxis
• due to mucosal friability, ulceration and thickening.
– Perforation of the nasal septum and/or saddlenose deformity
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destruction of the nasal cartilage
– Serous otitis media
– Subglottic tracheal stenosis
• ~16% of patients and may result in severe airway obstruction
• Pulmonary involvement : 85-90%
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affect the pulmonary parenchyma, bronchi, and rarely the pleura
asymptomatic ~ cough, hemoptysis, dyspnea, chest discomfort
result of fibrous scarring : lead to obstruction with atelectasis
PFT : restrictive or obstructive pattern
• Eye involvement : 56% of patients
– mild conjunctivitis, dacryocystitis, episcleritis, scleritis,
granulomatous sclerouveitis, ciliary vessel vasculitis, retroorbital
mass lesions leading to proptosis
• Skin lesions : 46% of patients
– papules, vesicles, palpable purpura, ulcers, or subcutaneous
nodules
– biopsy reveals vasculitis, granuloma
• Cardiac involvement : 8% of patients
– manifests as pericarditis, coronary vasculitis
– Rarely cardiomyopathy
• Nervous system manifestations : 23% of patients
– cranial neuritis, mononeuritis multiplex
– Rarely cerebral vasculitis and/or granuloma
– intracerebral hemorrhage (3%), SAH(2%)
cerebral arterial thrombosis (3%), venous thrombosis (1%)
Ann Intern Med 1992:116;488-498
• Renal disease : 77% of patients
– mild glomerulitis with proteinuria, hematuria, RBC casts
– once clinically detectable renal functional impairment occurs,
rapidly progressive renal failure usually
Diagnosis
• Demonstration of necrotizing granulomatous vasculitis
on tissue biopsy
– Pulmonary tissue Bx: highest diagnostic yield
– Upper airway tissue Bx
• granulomatous inflammation with necrosis not vasculitis
– Renal Bx
• presence of pauci-immune glomerulonephritis
• positive cytoplasmic anti-neutrophil cytoplasmic antibody
(C-ANCA) : 80~95%
– Specificity very high, especially if active glomerulonephritis is
present
– False-positive ANCA : certain infectious and neoplastic diseases
– DDx
CLEVELAND CLINIC JOURNAL OF MEDICINE 2005;72:689-697
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ESR ↑, mild anemia, leukocytosis
mild hypergammaglobulinemia (esp. IgA)
mildly elevated RF
Thrombocytosis : as an acute-phase reactant
• Chest radiographs :
– 34% radiographic abnormalities
– bilateral nodular infiltrates (M/C)
– single nodules/infiltrates, cavitary disease, and diffuse alveolar
hemorrhage
– Inflammation and stenosis of the endobronchial airways (15%)
• Lung involvement : multiple, bilateral, nodular cavitary
infiltrates
Treatment
 In 1973, Fauci and Wolff introduced a regimen that
significantly improved outcome:
– prednisone 1 mg/kg daily
(tapered and discontinued after 6 to 9 months)
– cyclophosphamide 2 mg/kg daily (continued for 1 year)
→ CR 75%, marked improvement in 91%, survival in 80%
• Disease relapse : 50%(5yrs)
• Morbidity from drug related toxicity : 42%
• side effects
– Corticosteroid
• diabetes mellitus, cataracts, life-threatening infectious disease,
serious osteoporosis, severe cushing features
– Cyclophosphamide
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Cystitis (at least 30%)
Transitional cell carcinoma of bladder (6%)
myelodysplasia(2%)
permanent infertility in both men and women
 Strategies to reduce toxicity
• Staged treatment regimens
– Methotrexate
– Azathioprine
– Mycophenolate mofetil
• Intermittent intravenous cyclophosphamide
• associated with higher relapse → Should be administered daily
• Using another agent to induce remission
– methotrexate (20–25 mg once a week) and prednisone (1 mg/kg
daily with taper)
 trimethoprim-sulfamethoxazole
• Stegeman et al
– randomized 81 patients who were in remission
– trimethoprim-sulfamethoxazole or placebo
• 82% maintain remission (study) vs 60% maintain remission
(placebo)
• recurrence rate of nasal and upper airway lesions was lower
NEJM 1996;335:16-20
• PCP prophylaxis for all patients who are not allergic to
sulfa drugs and who are receiving glucocorticoids plus a
cytotoxic agent
 Biologic agents : Etanercept, Infliximab, Rituximab
Cardiac involvement in Wegener’s granulomatosis
• 8 ~ 44%, higher rate is related to more advanced disease
• Pericarditis, coronary arteritis : m/c
Cardiology 2004;102:7–10
• vascular involvement arterioles ~ large coronary ateries
• Conduction system abnormality : sinus and AV node
• Pathogenesis of endothelial damage
– Unknown
– but related to ANCAs
:Indirectly damage vascular endothelium through the activation of
neutrophil
• conduction disturbances : arteritis of AV nodal artery or
direct granulomatosis involvement of conduction system