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year, is the prototype of diseases associated with antineutrophil cytoplasmic antibodies (ANCA) (Other ANCA-associated vasculitides include microscopic polyangiitis and the Churg-Strauss syndrome) Wegener s granulomatosis is characterized in its full expression by vasculitis of small arteries, arterioles, and capillaries, necrotizing granulomatous lesions of both upper and lower respiratory tract, glomerulonephritis, and other organ manifestations Without treatment, generalized disease is invariably fatal, with most patients surviving less than 1 year after diagnosis It occurs most commonly in the fourth and fifth decades of life and affects men and women with equal frequency
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Clinical Findings
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A Symptoms and Signs
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The disorder usually develops over 4 12 months, with 90% of patients presenting with upper or lower respiratory tract symptoms or both Upper respiratory tract symptoms can include nasal congestion, sinusitis, otitis media, mastoiditis, inflammation of the gums, or stridor due to subglottic stenosis Since many of these symptoms are common, the underlying disease is not often suspected until the patient develops systemic symptoms or the original problem is refractory to treatment The lungs are affected initially in 40% and eventually in 80%, with symptoms including cough, dyspnea, and hemoptysis Other early symptoms can include a migratory oligoarthritis with a predilection for large joints; a variety of symptoms related to ocular disease (unilateral proptosis from orbital pseudotumor; red eye from scleritis, episcleritis, anterior uveitis, or peripheral ulcerative keratitis); purpura or other skin lesions; and dysesthesia due to neuropathy Renal involvement, which develops in three-fourths of the cases, may be subclinical until renal insufficiency is advanced Fever, malaise, and weight loss are common Physical examination can be remarkable for congestion, crusting, ulceration, bleeding, and even perforation of the nasal septum Destruction of the nasal cartilage with saddle nose deformity occurs late Otitis media, proptosis, scleritis, episcleritis, and conjunctivitis are other common findings Newly acquired hypertension, a frequent feature of polyarteritis nodosa, is rare in Wegener s granulomatosis Venous thrombotic events (eg, deep venous thrombosis and pulmonary embolism) are now recognized to be a common occurrence in Wegener s granulomatosis, at least in part because of the tendency of the disease to involve veins as well as arteries Vigilance must be maintained for venous thrombotic events Although limited forms of Wegener s granulomatosis have been described in which the kidney is spared initially, renal disease will develop in the majority of untreated patients In such cases, the urinary sediment invariably contains red cells, with or without white cells, and red cell casts Renal biopsy discloses a segmental necrotizing glomerulonephritis with multiple crescents; this is characteristic but not diagnostic Pathologists characterize the renal lesion of Wegener s granulomatosis (and other forms of ANCA-associated vasculitis ) as a pauci-immune glomerulonephritis because of the relative absence (compared with immune complex medi-
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Classic triad of upper and lower respiratory tract disease and glomerulonephritis Suspect if mild respiratory symptoms (eg, nasal congestion, sinusitis) are refractory to usual treatment Pathology defined by the triad of small vessel vasculitis, granulomatous inflammation, and necrosis ANCAs, usually directed against proteinase-3 (less commonly against myeloperoxidase present in severe, active disease) (90% of patients) Renal disease often rapidly progressive without treatment
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Wegener s granulomatosis, which has an estimated incidence of approximately 12 cases per million individuals per
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CMDT 2008
All positive immunofluorescence assays for ANCA should be confirmed by enzyme immunoassays for the specific autoantibodies directed against PR3 or MPO
ated disorders) of immunoreactants IgG, IgM, IgA, and complement proteins within glomeruli
B Laboratory Findings
Most patients have slight anemia, mild leukocytosis, and elevated acute phase reactants Chest CT is more sensitive than chest radiography; lesions include infiltrates, nodules, masses, and cavities Often the radiographs prompt concern about lung cancer Hilar adenopathy is unusual in Wegener s granulomatosis; if present, sarcoidosis, tumor, or infection is more likely Other common laboratory or radiographic abnormalities include hematuria, red blood cell casts, extensive sinusitis, and even bony sinus erosions Histologic features of Wegener s granulomatosis include vasculitis, granulomatous inflammation, geographic necrosis, and acute and chronic inflammation The full range of pathologic changes is usually evident only on thoracoscopic lung biopsy Granulomas, observed only rarely in renal biopsy specimens, are found much more commonly on lung biopsy specimens Nasal biopsies often do not show vasculitis but may show chronic inflammation and other changes which, interpreted by an experienced pathologist, can serve as convincing evidence of the diagnosis Serum tests for ANCA help in the diagnosis of Wegener s granulomatosis and related forms of vasculitis (Tables 20 10 and 19 2) Several different types of ANCA are recognized, but the two subtypes relevant to systemic vasculitis are those directed against proteinase-3 (PR3) and myeloperoxidase (MPO) Antibodies to these two antigens are termed, respectively, PR3-ANCA and MPO-ANCA The cytoplasmic pattern of immunofluorescence (C-ANCA) caused by PR3ANCA has a high specificity (> 90%) for either Wegener s granulomatosis or a closely related disease, microscopic polyangiitis (or, less commonly, the Churg-Strauss syndrome) In the setting of active disease, particularly cases in which the disease is severe and generalized to multiple organ systems, the sensitivity of PR3-ANCA is > 95% A substantial percentage of patients with limited Wegener s granulomatosis disease that does not pose an immediate threat to life and is often confined to the respiratory tract are ANCA-negative Although ANCA testing may be very helpful when used properly, it does not eliminate the need in most cases for confirmation of the diagnosis by tissue biopsy Furthermore, ANCA levels correlate erratically with disease activity, and changes in titer should not dictate changes in therapy in the absence of supporting clinical data The perinuclear (PANCA) pattern, caused by MPO-ANCA, is more likely to occur in microscopic polyangiitis or Churg-Strauss but may also be found in Wegener s granulomatosis Approximately 10 25% of patients with classic Wegener s granulomatosis have MPO-ANCA Owing to involvement of the same types of blood vessels, similar patterns of organ involvement, and the possibility of failing to identify granulomatous pathology on tissue biopsies because of sampling error, Wegener s granulomatosis is often difficult to differentiate from microscopic polyangiitis The crucial distinctions between the two disorders are the tendencies for Wegener s granulomatosis to involve the upper respiratory tract (including the ears) and to cause granulomatous inflammation
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