Editorial: Can an Increase in Antineutrophil Cytoplasmic Autoantibody Titer Predict Relapses in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis?

Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) is a rare disease, but one which occurs worldwide and affects all ethnic groups with varying incidence and clinical characteristics. The pathology of AAV is characterized by inflammation and necrosis of small blood vessels with or without granuloma in such diverse organs as the skin, respiratory tract, and kidneys. Over the last decade, there have been significant advances in our understanding of the pathogenesis, diagnosis, and treatments of AAV. One historical advance is the discovery of ANCAs. ANCAs are autoantibodies directed against myeloperoxidase (MPO), proteinase 3 (PR3), or other granular constituents of neutrophils and monocytes. PR3-ANCA is associated with a cytoplasmic granular fluorescence pattern and is seen in 85–95% of individuals with granulomatosis with polyangiitis (Wegener’s). MPOANCA has a perinuclear neutrophil fluorescence pattern and is predominantly seen in patients with microscopic polyangiitis (70% of cases) and eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (40–50% of cases) (1). The diagnostic utility of serial ANCA testing for predicting AAV relapse was demonstrated shortly after the discovery of ANCAs (2). However, this could not be confirmed in several other studies, possibly due to considerable methodologic heterogeneity. Despite numerous studies, there has been an ongoing debate as to whether an increase in ANCA titer predicts disease reactivation in patients with AAV. Therefore, there is uncertainty as to whether rheumatologists should serially check serum ANCA titers in clinical settings. If an increase in ANCA levels is indeed frequently followed by a relapse, it may be beneficial to preemptively treat the patient at the time of the increase in ANCA levels in order to prevent a subsequent relapse. However, the benefits of preemptive treatment should be balanced against unnecessary exposure to immunosuppressive therapy and treatment-related side effects. Beyond its utility for the diagnosis of AAV, ANCA targeting PR3 or MPO is thought to play a direct role in the pathogenesis of AAV. It has been demonstrated in vitro that PR3-ANCA and MPO-ANCA activate neutrophils by binding cell surface–expressed PR3 and MPO via both F(ab)2 and Fcg receptors (3). PR3 and MPO are then internalized by endothelial cells and exert distinct effects, culminating in neutrophil activation and endothelial injury. Whereas PR3 induces apoptosis of the endothelial cells, MPO promotes the production of intracellular oxidants (4). The direct pathogenic role of MPO-ANCA is also supported by in vivo studies demonstrating that MPO-deficient mice immunized with purified murine MPO develop glomerulonephritis and pulmonary capillaritis as in human AAV (5). Interestingly, injection of human PR3-ANCA into humanized mice fails to induce granulomatous inflammation while promoting glomerulonephritis and pulmonary capillaritis (6), suggesting that mechanisms (perhaps cellular response) other than ANCA response are required for granuloma formation in AAV. These observations have previously led to the hypothesis that increases in ANCA levels may be highly associated with a relapse of capillaritis but not with a relapse of granulomatous disease. Indeed, a previous study showed that increases in ANCA levels are highly associated with a relapse in Supported by grants from the National Research Foundation of Korea funded by the Ministry of Education, Science, and Technology (grants 2014R1A2A1A11049812 and 2015R1A3A2032927). Jung Hee Koh, MD, Wan-Uk Kim, MD, PhD: The Catholic University of Korea, Seoul, Republic of Korea; Michael Joseph Kemna, MD, Jan Willem Cohen Tervaert, MD, PhD: Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. Drs. Koh and Kemna contributed equally to this work. Address correspondence to Wan-Uk Kim, MD, Department of Internal Medicine, Division of Rheumatology, The Catholic University of Korea, School of Medicine, Seoul 137-701, Republic of Korea. E-mail: wan725@catholic.ac. kr. Submitted for publication February 1, 2016; accepted in revised form February 9, 2016.