The diagnosis of WG is typically confirmed by biopsy of the affected organs. As the histologic changes are patchy, the diagnostic yield is associated with the biopsy location and amount of tissue obtained. Surgical biopsies of radiographically abnormal pulmonary parenchyma have a yield of 90%, but diagnostic features are found in fewer than 10% of transbronchial biopsies.
Breakthrough: Antineutrophil Cytoplasmic Antibodies
The discovery of antineutrophil cytoplasmic antibodies (ANCA) opened many clinical and investigational avenues in WG. Antibodies directed against proteinase-3 (PR-3) produce a cytoplasmic staining pattern (cANCA) by immunoflurorescence. These types of antibodies occur in 75% to 90% of patients with WG, and 5% to 20% of patients have anti-myeloperoxidase (MPO) antibodies that have a perinuclear staining pattern (pANCA).3
Because WG is a rare disease, the utility of ANCA testing for diagnosis depends upon the site of organ involvement. In patients with sinus, lung, and renal disease, a (+) PR3-ANCA has a predictive value of over 90% for WG. However, the predictive value is only 30% to 60% in patients with sinus and lung disease, making biopsy confirmation important in this setting to rule out infection or neoplasm.
WG is not the only vasculitic disease in which ANCA occur. MPO-ANCA are seen in 50% to 80% of patients with microscopic polyangiitis, with 10% to 20% having PR3-ANCA. ANCA are also found in up to 40% of patients with Churg-Strauss syndrome, where anti-MPO ANCA are seen predominantly. Although these observations have led some investigators to view these diseases as “ANCA-associated vasculitis,” the unique phenotypic features and absence of ANCA in some patients support that they should viewed as individual entities.
ANCA can also be seen in a broad range of nonvasculitic diseases where they are associated with antigens other than PR3 or MPO. Inflammatory bowel disease, autoimmune hepatitis, and cystic fibrosis can be associated with pANCA. In these diseases, ANCA react to a range of antigens that include bactericidal/permeability-increasing protein (BPI), lactoferrin, cathepsin G, lysozyme, and a myeloid cell–specific 50-kilodalton nuclear envelope protein. For this reason, a positive cANCA or pANCA should always be confirmed by target antigen specific testing for anti-PR3 and anti-MPO ANCA.
The initial observation that ANCA levels were higher in those with active disease raised hope that ANCA could be a biomarker for disease activity. In a prospective study of 156 patients, Finkielman et al demonstrated that PR3-ANCA levels were only weakly associated with disease activity, that decreases in PR3-ANCA levels during remission induction treatment were not associated with a shorter time to sustained remission, and that increases in PR3-ANCA levels were not associated with relapse in the following year.4 These results provide compelling evidence that serial ANCA levels should not be used to monitor disease activity or guide decisions about immunosuppressive treatment in WG.