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- PATIENTS AND METHODS
Antineutrophil cytoplasmic antibodies (ANCA) with specificity for proteinase 3 (PR3) or myeloperoxidase (MPO) are strongly associated with small-vessel vasculitides, such as Wegener's granulomatosis and microscopic polyangiitis (1–3). There is evidence that ANCA play a pathophysiologic 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 activation, 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 methimazole (20, 21).
ANCA in drug-induced AAV are most frequently directed 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 directed against human leukocyte elastase (HLE) or lactoferrin, and the presence of ANCA directed to 2 or more antigens may even be an indication of drug-induced disease (15, 23). Clinically, drug-induced AAV can be substantially milder than idiopathic vasculitis, and drug-induced AAV may resolve in many cases with discontinuation of the offending agent. However, severe disease courses may be observed and treatment with immunosuppressive therapy can be necessary.
To our knowledge, the time span between medication use and induction of ANCA and AAV has not been studied. Furthermore, whether ANCA are induced by hyperthyroidism or by antithyroid medication is still uncertain. We hypothesized that ANCA and AAV may not only be induced during treatment with antithyroid drugs, but can also become evident when medication has been ceased, possibly after years. To test this hypothesis, we evaluated patients with hyperthyroidism receiving various antithyroid treatment modalities for the presence of ANCA. Additionally, we evaluated induction of ANCA after long-term followup by retesting patients >3 years after previous testing for ANCA.
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- PATIENTS AND METHODS
In the current study, we investigated the presence of ANCA in patients diagnosed with hyperthyroidism receiving various treatment modalities. In our cross-sectional evaluation, we found 12 patients (5.7%) positive for MPO, PR3, or HLE ANCA on first testing. Furthermore during followup, 1 patient became ANCA positive. ANCA positivity was significantly related to the use of antithyroid drugs. Clinical signs were present in 2 of 6 ANCA-positive patients who had used PTU, in 2 patients using other antithyroid drugs, and in none of the patients who were not treated with antithyroid drugs.
The presence of ANCA, and of ANCA-associated vasculitis, in patients using antithyroid drugs for treatment of hyperthyroidism have been recurrently reported (15–23, 27). Reported prevalence of ANCA in patients treated with antithyroid drugs varies from 4% to 46%; prevalence of AAV is lower (0–1.4%) (22, 27–29). In our population, ANCA and AAV were present in 11% and 4%, respectively, of patients treated with antithyroid drugs. Prevalence of primary systemic vasculitis (Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, polyarteritis nodosa) has been estimated at 144.5/million (0.01%) in a population comparable with the general population in Groningen (30). Therefore, a prevalence of AAV of 4% in our patients treated with antithyroid drugs clearly suggests a relationship between these drugs and the presence of AAV.
Although ANCA are present relatively often in patients treated with antithyroid drugs, the prevalence of AAV is much lower (22, 27–29). In our study, 7 of 11 patients treated with antithyroid drugs who were positive for MPO, PR3, or HLE ANCA did not have, or develop, vasculitis (64%). This false-positive rate is much higher than could be expected from our earlier studies in which we found false-positive results in <1% of patients with related disorders or healthy controls (25, 31). Therefore, the use of PTU, carbimazole, and methimazole seems an important cause for positive ANCA results not related to small-vessel vasculitis.
The presence of ANCA without vasculitis indicates that ANCA alone are not enough for the induction of vasculitis. Indeed, in patients with clinically quiescent AAV, high ANCA titers can persist without reactivation of vasculitis (5, 32–34). It has been suggested that the characteristics of ANCA present in active disease may differ from those present in disease remission and in sera from patients without vasculitis, possibly in the mechanism of neutrophil activation (7, 35).
The mechanism by which PTU, and other antithyroid drugs, may induce ANCA and AAV remains to be elucidated, although some clues do exist. A study by Jiang et al showed that propylthiouracil, among other drugs, was highly cytotoxic in the presence of activated neutrophils, at concentrations that are therapeutically relevant (36). Oxidation of PTU by activated neutrophils provides a way to generate reactive drug metabolites, and the finding of MPO ANCA in patients with drug-induced lupus and vasculitis is consistent with an autoimmune reaction initiated by drug bioactivation mediated by neutrophil-derived MPO (37).
It is possible that AAV in the patients in our study was not induced by antithyroid drugs, but merely is associated with hyperthyroidism. Unfortunately, we did not have ANCA titers prior to the initiation of treatment in these patients. In a previous study on the induction of ANCA by minocycline, sulfasalazine, and penicillamine, we showed that when ANCA were present in patients after treatment with these drugs, they had already been present prior to treatment start (38). The presence of MPO ANCA may also be explained by the presence of anti-TPO antibodies that given the partial homology between both proteins, may crossreact with MPO (39), although this has been disputed by others (40). In our patients, the presence of MPO ANCA was not related to anti-TPO antibodies. Moreover, crossreactivity to TPO cannot explain the presence of HLE or PR3 ANCA in our patients.
In conclusion, we showed that the presence of ANCA, and associated vasculitis, is not uncommon in patients treated with antithyroid drugs. The presence of ANCA and AAV extends beyond antithyroid treatment duration. This risk of using antithyroid drugs should be included in the decision to use these drugs for the treatment of hyperthyroidism.