Vasculitis
Abstract 2130: Antineutrophil Cytoplasmic Antibodies against Proteinase 3 Do Not Predict Disease Relapses in Wegener’s Granulomatosis
Authors: Javier D. Finkielman, Peter A. Merkel, Darrell Schroeder, Gary S. Hoffman, Robert Spiera, E. William St. Clair, John C. Davis, W. Joseph McCune, Andrea K. Tibbs, Steven R. Ytterberg, Amber M. Hummel, Margaret A. Viss, Tobias Peikert, John H. Stone, and Ulrich Specks for the WGET Research Group
Background: Antineutrophil cytoplasmic autoantibodies (ANCA) are detected in upwards of 80% of patients with Wegener’s granulomatosis. Although many types of ANCA can be identified with immunofluorescence, ANCA with specificity for proteinase-3 (PR3) are strongly correlated with Wegener’s granulomatosis. It is not known, however, if ANCA are pathogenic. In particular, it is not clear if rising ANCA titers herald impending flare. Previous work by this group suggested that antibodies against pro-PR3 might correlate more reliably with disease activity than antibodies against PR3 itself. This study examined whether PR3-ANCA or pro-PR3 ANCA might be used to predict disease flare.
Study Design: The Wegener’s Granulomatosis Etanercept Trial (WGET) was a multicenter, double-blinded, randomized clinical controlled trial that examined the utility of adding etanercept to standard-of-care therapies for the treatment of Wegener’s granulomatosis. As part of this trial, serum samples were collected approximately every 3 months. The WGET cohort was used as the basis of this study. PR3-ANCA levels were measured by capture ELISA, and disease activity was measured using the Birmingham Vasculitis Activity Score for Wegener’s Granulomatosis.
Results: 180 patients are in the WGET cohort; 24 patients were excluded because they were MPO-positive. Both PR3-ANCA and pro-PR3-ANCA correlated positively—but weakly—with disease activity at baseline. The coefficient of determination (r2) for PR3-ANCA was 0.030 (P=0.031); for pro-PR3-ANCA, it was 0.038 (P=0.016). The difference in strength of correlation was not statistically significant. The median time to sustained remission (defined as a BVAS/WG score of 0 for 6 months in the absence of glucocorticoids) was 12 months among those with a declining PR3-ANCA titer, as opposed to 19 months among patients in whom the ANCA titer was stable or increased (adjusted P=0.043). This analysis did not achieve statistical significance for pro-PR3-ANCA (adjusted P=0.284). Forty percent of patients with increase in ANCA titers flared within 1 year, but Cox proportional hazards regression analysis showed that neither increases in mature nor pro-PR3 ANCA levels predicted disease flares (hazard ratio=1.0 for both analyses).
Editorial Comments: When Wegener’s granulomatosis was first described, the absence of effective therapies almost always ensured a poor outcome. In the modern era, much of the morbidity associated with Wegener’s granulomatosis is the result of the untoward complications of therapy, particularly among patients who have been treated with multiple courses of cyclophosphamide and high-dose glucocorticoids. Because relapse is difficult to predict, many patients are subjected to long courses of immunosuppression. Some have advocated the use of ANCA-titers to guide therapy, but this study demonstrates that this strategy is not effective in the majority of cases.