Granulomatosis with Polyangiitis (Wegener Granulomatosis)

Justin P. Stocks and Michael Tripp

Granulomatosis with polyangiitis (GPA), formerly known as Wegener granulomatosis (WG), is an idiopathic systemic vasculitis that may involve any organ system, but most frequently involves the upper respiratory tract, lungs, and kidneys. In a 2010 consensus statement, the American College of Rheumatology, the American Society of Nephrology, and the European League Against Rheumatism recommended changing the name of Wegener granulomatosis to shift the emphasis from an eponym-based label to a more disease-descriptive nomenclature.

GPA is a rare entity with an estimated annual incidence of 11.3 per million population. The estimated prevalence of GPA in the United States is 3.0 per 100,000 persons, with an equal male/female ratio. Caucasians are affected predominantly, comprising up to 95% in epidemiological studies. A class of autoantibodies known as antineutrophil cytoplasmic antibodies (ANCA) is closely associated with GPA and likely contributes to the pathogenesis of these disorders. Up to 90% of patients with GPA have involvement of the upper or lower respiratory tracts. Upper respiratory symptoms in GPA include chronic sinusitis, rhinorrhea, epistaxis, sinus pain, otitis media, and nasal or oral ulcerations. Tracheal involvement can lead to stenosis, obstruction, and stridor. Pulmonary symptoms may include cough, pleuritic chest pain, dyspnea, or hemoptysis. GPA can present as fulminating pulmonary hemorrhage leading to hypoxic respiratory failure or as acute lung injury with a systemic inflammatory response syndrome in 50% to 75% of acutely ill patients. Conversely, up to one-third of patients with pulmonary involvement may be asymptomatic. Other manifestations of GPA include arthralgias or myalgias, mono- or polyarthritis, constitutional symptoms, neurologic symptoms including mononeuritis multiplex, skin lesions, and pericarditis.

The diagnosis of GPA is made by a combination of clinical, radiographic, serological, and histopathological findings on biopsy. The presence of two or more American College of Rheumatology classification criteria (abnormal urinary sediment, characteristic chest radiograph abnormalities, oral ulcers or nasal discharge, and granulomatous inflammation on biopsy) has a sensitivity of 88% and a specificity of 92%. ANCA serologies are indicated in all patients. Pulmonary function abnormalities are nonspecific but may reveal an obstructive pattern, reflecting airway stenosis, or a reduction in carbon monoxide diffusion capacity (DLCO) and lung volumes related to significant parenchymal disease. The definitive diagnosis of GPA is confirmed by tissue biopsy. Samples from the upper respiratory tract may demonstrate necrotizing granulomatous inflammation but have a sensitivity as low as 44% to 53%. In the presence of impaired renal function or active urinary sediment, renal biopsy can demonstrate a characteristic pattern of segmental necrotizing glomerulonephritis and is less invasive than surgical lung biopsy. Bronchoscopic abnormalities are nonspecific and may be found in up to 80% of patients with GPA; alveolar hemorrhage, sublglottic stenosis, and tracheobronchial and laryngeal inflammation are the most frequent findings. In one large bronchoscopic study of 197 patients with GPA, segmental stenosis and airway inflammation were most common and predominated in the right lung. Transbronchial lung biopsy is of limited usefulness in the diagnosis of pulmonary GPA, but it is valuable for excluding infection and evaluating hemoptysis. Nonspecific elevations in either neutrophils or lymphocytes have been described in alveolar lavage samples with no pathognomonic CD4/CD8 ratio. Progressively, hemorrhagic lavage aliquots may be seen in alveolar hemorrhage with associated hemosiderin-laden macrophages. Surgical lung biopsy is the gold standard for diagnosis of pulmonary GPA and may demonstrate a plethora findings, including, most commonly, neutrophilic microabscesses with necrosis, polymorphic granulomas with giant cells, angiitis with eccentric focal parietal crescent-shaped microabscesses, geographic necrosis surrounded by palisading histiocytes, and alveolar hemorrhage.

Radiographic findings in pulmonary GPA span a spectrum, including consolidation, solitary or multiple nodules that may cavitate, pleural effusions, parenchymal bands, and focal or diffuse ground-glass opacities. Computed tomography (CT) is superior to conventional chest radiography for detecting and characterizing pulmonary opacities. Lung nodules occur in 40% to 70% of patients, usually bilateral without segmental predilection, multiple in number, and with cavitation in up to 25% to 50% of cases. High-Resolution CT (HRCT) findings of nodules and areas of parenchymal opacification have been correlated directly with disease activity in multiple studies. Unilateral or bilateral pleural effusions may occur in up to 12% of patients. Enlarged mediastinal lymph nodes have been seen in 0% to 15% of patients, but bronchiectasis, honeycombing, pleural thickening, and pneumothorax are rare. Tracheobronchial stenosis may be appreciated on HRCT. Sinus radiographs may demonstrate air–fluid levels.

Renal involvement occurs in up to 80% of patients with GPA. Microscopic hematuria and red cell casts may be seen on urinalysis. Renal biopsies can demonstrate varying degrees of inflammation, from focal or segmental glomerulitis to rapidly progressing necrotizing glomerulonephritis. Immunofluorescence shows this to be a “pauci-immune” glomerulonephritis, with absent or minimal immunoglobulin deposits. Glomerulonephritis may precede pulmonary GPA by a period of months to years.

GPA is associated with a class of autoantibodies to specific antigens in neutrophils (ANCA) that are present in several forms of systemic vasculitis, including Churg–Strauss syndrome, polyarteritis nodosa, and microscopic polyangiitis. Two patterns of indirect immunofluorescence have been described: a diffuse cytoplasmic (cANCA) and a perinuclear pattern (pANCA). The specific antigens involved have been identified. Proteinase 3 (PR3) is the usual target of cANCA, and myeloperoxidase (MPO) is the most common target of pANCA. Approximately 90% of patients with active GPA are ANCA positive. The cANCA associated with GPA is almost always an anti-PR3 antibody. Therefore, it is prudent to confirm a finding of cANCA by a specific ELISA assay for anti-PR3 or anti-MPO. Up to 10% of patients with GPA do not have evidence of ANCA. Titers of ANCA correlate weakly with disease activity in two-thirds of patients.

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