Occurrence of Antineutrophil Cytoplasmic Antibodies and Associated Vasculitis in Patients With Hyperthyroidism Treated With Antithyroid Drugs: A Long-Term Followup Study MARJAN C. SLOT, 1 THERA P. LINKS, 1 COEN A. STEGEMAN, 1 AND JAN WILLEM COHEN TERVAERT 2 Objective. To test whether antineutrophil cytoplasmic antibodies (ANCA) and ANCA-associated vasculitis (AAV) are not only induced during treatment with antithyroid drugs, but can also become evident when medication has been ceased, possibly after years. Methods. Patients who visited our hospital for the treatment of hyperthyroidism were included (n  207). Treatment consisted of antithyroid medications, radioactive iodide, thyroidectomy, or a combination of these treatment options. Patients were retested 3– 6 years later to evaluate long-term effects of antithyroid drugs. Patients were tested for the presence of ANCA and, if positive, evaluated for the presence of AAV. Results. Of 209 patients with hyperthyroidism, 12 patients (6%) were positive for myeloperoxidase- (MPO-), proteinase 3-, or human leukocyte elastase-ANCA. Seventy-seven of 209 patients were retested; 1 patient who had not been treated with antithyroid drugs had developed MPO-ANCA. In 3 of 6 patients previously positive, ANCA could still be detected. The presence of ANCA was highly associated with treatment with antithyroid drugs (odds ratio 11.8 [95% confidence interval 1.5–93.3]). Of 13 patients with a positive ANCA result on enzyme-linked immunosorbent assay, AAV with glomerulonephritis was diagnosed in 4 (31%). Conclusion. The presence of ANCA with or without vasculitis is associated with previous treatment with antithyroid drugs, possibly after years. KEY WORDS. ANCA-associated vasculitis; Drug induced; Propylthiouracil; Hyperthyroidism. INTRODUCTION Antineutrophil cytoplasmic antibodies (ANCA) with spec- ificity for proteinase 3 (PR3) or myeloperoxidase (MPO) are strongly associated with small-vessel vasculitides, such as Wegener’s granulomatosis and microscopic poly- angiitis (1–3). There is evidence that ANCA play a patho- physiologic role in the induction of these vasculitides. First, elevations in ANCA titers appear to correlate with risk of future disease flares, although they do not reliably predict the timing of such flares (4,5). Second, it has been demonstrated in vitro that ANCA induce neutrophil acti- vation, i.e., degranulation and production of a respiratory burst (6). In addition, ANCA activate other cells in vitro, such as monocytes and endothelial cells (7). Finally, in vivo experimental data also suggest an important role for ANCA in the pathophysiology of vasculitis (8,9). Certain drugs have been linked to the induction of ANCA and the onset of ANCA-associated vasculitis (AAV) (10). There are several case reports implicating hydralazine (11–14) and propylthiouracil (PTU) (15–19) in the induction of AAV. Occasionally, other drugs are mentioned, including other antithyroid drugs, such as carbimazole (17) and methima- zole (20,21). ANCA in drug-induced AAV are most frequently di- rected against MPO (11–16,18 –22); however, cases in which patients were PR3-ANCA positive are also observed (12,15,18,20,22). ANCA in these patients may also be di- rected against human leukocyte elastase (HLE) or lactofer- rin, and the presence of ANCA directed to 2 or more antigens may even be an indication of drug-induced dis- 1 Marjan C. Slot, MD (current address: University Hospital Maastricht, Maastricht, The Netherlands), Thera P. Links, MD, PhD, Coen A. Stegeman, MD, PhD: University Hospital Groningen, Groningen, The Netherlands; 2 Jan Willem Co- hen Tervaert, MD, PhD: University Hospital Maastricht, Maastricht, The Netherlands. Address correspondence to Marjan C. Slot, MD, Depart- ment of Clinical and Experimental Immunology, University Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, the Netherlands. E-mail: m.slot@immuno.unimaas.nl. Submitted for publication January 8, 2004; accepted in revised form August 6, 2004. Arthritis & Rheumatism (Arthritis Care & Research) Vol. 53, No. 1, February 15, 2005, pp 108 –113 DOI 10.1002/art.20927 © 2005, American College of Rheumatology ORIGINAL ARTICLE 108