The Relation of Initial Methimazole Dose to the Incidence of Methimazole-induced Agranulocytosis in Patients with Graves Disease

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1 Endocrine Journal 2007, 54 (1), The Relation of Initial Methimazole Dose to the Incidence of Methimazole-induced Agranulocytosis in Patients with Graves Disease KUMIKO TSUBOI, HAJIME UESHIBA, MASAKO SHIMOJO, MAYUMI ISHIKAWA, NATSUKO WATANABE, KAORU NAGASAWA, RENA YUASA AND GEN YOSHINO Division of Diabetes, Metabolism and Endocrinology, Department of Medicine, Toho University School of Medicine, , Omori-nishi, Ota-ku, Tokyo , Japan Abstract. The relation between the incidence of methimazole (methylmercaptoimidazole; MMI)-induced agranulocytosis and initial MMI dose was evaluated in a group of 514 patients with Graves disease who were treated between 1995 and One hundred and forty-six (28.40%) patients had received an initial dose of 30 mg MMI and 277 (53.89%) patients had been treated with 15 mg MMI. Nine patients (1.75%) developed agranulocytosis due to MMI treatment. Six (4.11%) of 146 patients who received an initial dose of 30 mg MMI, two (4.54%) of 44 patients given an initial dose of 20 mg MMI, and one (0.36%) of 277 patients given an initial dose of 15 mg MMI developed agranulocytosis. There was a statistically significant difference in agranulocytosis incidence between patients receiving an initial dose of 30 mg MMI and those who received an initial dose of 15 mg. Although 8 (4.10%) of 195 patients in the high-dose group (20 mg or higher) developed agranulocytosis, only 1 (0.31%) of 319 patients in the low-dose group (15 mg or lower) did. In conclusion, the incidence of agranulocytosis with low-dose MMI therapy was ten times lower than that of the high-dose regimen. Key words: Antithyroid-drug, ATD, Agranulocytosis, Graves disease, MMI, Methimazole, Methylmercaptoimidazole (Endocrine Journal 54: 39 43, 2007) AGRANULOCYTOSIS is a potentially fatal side effect of the antithyroid drugs (ATD) that are widely used for the treatment of Graves disease. Shirooze et al. [1] and Okamura et al. [2] reported that the effectiveness of low-dose methimazole (methylmercaptoimidazole; MMI) for the treatment of hyperthyroidism was no less than that of 30 mg MMI. In addition, a European prospective randomized study [3] reported that 10 mg and 40 mg MMI regimens were equally effective. Before 1994, when the standard initial dose of MMI was 30 mg, MMI-induced agranulocytosis was a not uncommon, extremely serious, adverse effect. Received: May 30, 2005 Accepted: September 4, 2006 Correspondence to: Dr. Kumiko TSUBOI, Division of Diabetes, Metabolism and Endocrinology, Department of Medicine, Toho University School of Medicine, , Omori-nishi, Ota-ku, Tokyo , Japan After implementing a low-dose MMI regimen, patients given an initial dose of 15 mg MMI only rarely developed agranulocytosis. We examined records of patients with Graves disease to determine the incidence of MMI-induced agranulocytosis and to identify any association with dose. Patients and Methods We analyzed the incidence of MMI-induced agranulocytosis by reviewing the records of patients with Graves disease treated at the thyroid clinics of Toho University Oomori Hospital from 1995 to A diagnosis of Graves disease was based on clinical findings, laboratory tests, and the Japan Thyroid Association s guidelines for the diagnosis of Graves disease [4]. Patients who were referred to our clinic after surgery or 131 I therapy, some of whom had agranulocytosis,

2 40 TSUBOI et al. were excluded from the study. Agranulocytosis was defined as a circulating neutrophil count lower than 500/µL. Statistical analysis Analysis of population proportions was performed using Fisher s exact test. Statistical significance was defined as P<0.05. Results A total of 772 patients were diagnosed as having Graves disease between 1995 and Of these, 514 patients with hyperthyroidism were treated with MMI. One hundred and forty-six patients (28.40%) had received an initial dose of 30 mg MMI, and 277 patients Table 1. Initial dose of MMI Initial MMI dose and incidence of MMI-induced agranulocytosis in patients with Graves disease Number of patients Number who developed agranulocytosis Incidence (%) 60 mg mg mg mg mg mg mg mg Total (53.89%) had received 15 mg MMI. Nine (1.75%) of these 514 patients developed agranulocytosis due to MMI. Six (4.11%) of the 146 patients who received an initial dose of 30 mg MMI developed agranulocytosis, as did 2 (4.54%) of 44 patients at 20 mg MMI and 1 (0.36%) of 277 at 15 mg MMI. All patients with agranulocytosis had clinical signs and symptoms of infection. Table 1 shows the total number of patients and the number of patients who developed agranulocytosis at each initial dose point. The clinical data of the 9 patients who developed agranulocytosis due to MMI, including the initial dose of MMI, the duration of MMI therapy, leukocyte count (WBC), neutrophil count, and patient outcome, are summarized in Table 2. Of particular importance is that 5 of the 9 patients who developed agranulocytosis had voluntarily interrupted medical treatment (indicated by * in Table 2). There was a statistically significant difference in agranulocytosis incidence between patients receiving 30 mg MMI and those receiving 15 mg MMI. If we define an initial dose of 20 mg or higher as the high-dose group and an initial dose of 15 mg or lower as the low-dose group, 8 (4.10%) of the 195 patients in the high-dose group developed agranulocytosis and only 1 (0.31%) of the 319 patients in the low-dose group developed agranulocytosis. The difference between the high-dose and lowdose groups was statistically significant. Discussion Although the incidence of agranulocytosis with lowdose MMI was one-tenth that of the high-dose regimen, Table 2. Clinical characteristics and outcome of patients with Graves disease complicated by MMI-induced agranulocytosis # Year of the onset Sex/Age MMIdose mg/d * Duration (weeks) WBC counts Neutrophil counts Treatment for agranulocytosis Outcome F/44 30 * 3** G-CSF PTU M/42 30 * 6** G-CSF RI M/ W/o G-CSF Surgery F/18 20 * 10** G-CSF RI F/ G-CSF RI M/62 30 * 4** G-CSF Surgery F/26 30 * W/o G-CSF PTU F/ ** 1) G-CSF RI F/ G-CSF Surgery Duration: Duration of MMI therapy at the time of agranulocytosis onset; *: Medication had been voluntarily discontinued, then resumed; **: Duration after resumption of therapy; 1): MMI dose was 30 mg 11 days, then 15 mg 20 days; G-CSF: Granulocyte colony-stimulating factor; W/o G-CSF: without G-CSF therapy; PTU: Propylthiouracil; RI: Radioiodine ( 131 I) therapy

3 AGRANULOCYTOSIS AND MMI 41 the clinical effectiveness of the regimens was similar [1 3, 5], suggesting that there is no longer a convincing rationale for continuing high-dose MMI. Despite convincing evidence for the effectiveness of low-dose MMI, many patients referred to our clinic had been placed on high-dose MMI, perhaps because Japanese reference books recommend an initial dose of 30 mg. We do not have data for the other major antithyroid drug, propylthiouracil (PTU), because it is not our first choice for treatment of Graves disease. When fever or infection develops, many patients who initially receive treatment at clinics are referred to a general hospital or medical center such as our university hospital. Our hospital therefore receives an unrepresentative percentage of more serious cases. To avoid such hospital bias, dropout cases from other clinics were not included in this report. ATD-induced agranulocytosis is comparatively rare, and is less common than other adverse effects, such as skin rash and itchiness. The Noguchi Thyroid Clinic and Hospital Foundation [6] reported that the incidence of agranulocytosis was 0.31% in 13,208 Graves disease cases with a mean dosage of 27.8 ± 8.9 mg/d. Because a minimum of 1000 to 5000 patients is necessary to determine the incidence of relatively rare adverse effects, our sample size was insufficient to calculate accurately the incidence of agranulocytosis. Tajiri et al. [7] studied the largest collection of Graves disease cases, 30,798 patients, and found that the incidence of ATD-induced agranulocytosis was 0.35%; our overall incidence of 1.75% (9 of 514) was much higher. Although we are unable to explain this relatively high incidence, we were able to analyze differences between a high-dose group and low-dose group. It has been suggested that high doses of MMI are associated with development of agranulocytosis. ATD-induced agranulocytosis, however, is not a result of dose-related toxicity. It might be caused by an immune mechanism that tends to occur relatively early in the course of medical treatment with drugs to which patients have been previously exposed. In our experience, voluntary discontinuation of medical treatment is not exceptional. Indeed, in the present study, 5 of the 9 patients who suffered agranulocytosis had undergone re-treatment with MMI. We believe that this repeated exposure may be a risk factor for MMI-induced agranulocytosis. The mechanisms responsible for the agranulocytosis are unclear, but cellular autoimmunity may be involved in its development. Positive associations between HLA class II allele and agranulocytosis were observed [8], many antibodies such as anti-leukocyte antibodies and anti-granulocyte antibodies have been proposed. PTU-induced autoimmune disease was known as PTU-induced lupus-like syndrome, PTU is also known as a trigger for antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis. Recently, complement-mediated cytotoxicity was postulated as a mechanism of PTU-induced ANCA-positive neutropenia [9]. ANCA specific for proteinase 3 (PR3) and myeloperoxidase (MPO) are associated with necrotizing vasculitis, and ANCA-activated neutrophils contribute to oxidative and proteolytic damage of blood vessels [10]. Priming (TNF-alpha)-induced translocation of PR3 and MPO to the cell surface may induce cytotoxicity [9]. ANCA-associated vasculitis and ATD-associated ANCA-positive patients in Belgrade were reported [11]. In this 11-year retrospective study, they obtained 72 patients with PR3-ANCA or MPO-ANCA positive, 16/72 (22.3%) patients developed symptoms of systemic disease during ATD therapy. PTU is a very common trigger for ANCA, and 12 of these 16 were induced by PTU. There were only 2 patients showed leukopenia (< /l) among the clinically and serologically ANCA-positive ATDtreated patients [11]. Among the 16 patients, ANCA developed or was detected after more than a year of ATD therapy. The duration of ATD therapy in their study is much longer than that in our cases of MMIinduced agranulocytosis. In a series of 18 cases, Dai et al. [12] reported that ATD-induced agranulocytosis developed 2 to 12 weeks after treatment, which is an interval similar to the 4 to 10 weeks observed in our cases. Slight leukopenia and neutropenia are frequent events in thyrotoxicosis before treatment with ATD. Granulocyte colony-stimulating factor (G-CSF) is one of the hematopoietic cytokines, which stimulates granulocyte proliferation and activation. Serum G-CSF levels in untreated patients with Graves hyperthyroidism were higher than those of healthy control [13], or were not different from normal subjects [14]. At least deficiency of G-CSF does not appear to be a cause of agranulocytosis by ATD. Although recombinant human G-CSF (rhg-csf) is clinically applicable for patients with agranulocytosis and GM-CSF use resulted in faster restoration [12], the recovery time in the G-CSF-treated group did not differ from that of the untreated group [15].

4 42 TSUBOI et al. Cooper et al. [16] reported that patients given an MMI dose of 40 mg or higher had an 8.6-fold higher risk of agranulocytosis than did patients receiving lower doses. Furthermore, they reported that no patients given an MMI dose lower than 30 mg/day developed agranulocytosis. In the present study, no patients given an MMI dose lower than 15 mg/d developed agranulocytosis in the period from January 1995 to September In October 2004, however, one patient developed agranulocytosis after a 6-week regimen of 15 mg MMI (Case #9 in Table 2). Tajiri et al. [5] reported that MMI dosage at the time patients developed agranulocytosis ranged from 5 to 45 mg. Because we elected to focus on the initial dose of MMI, our results are not directly comparable with those of this earlier study. A European prospective randomized study [3] of 309 patients reported that 10 mg and 40 mg MMI regimens were equally effective; however, the rate of adverse drug reactions was 15.5% in the 10 mg group and 26.0% in the 40 mg group. They reported that one patient in the 10 mg group had granulocytopenia (<2000/ µl), and one patient in the 40 mg group had agranulocytosis; however, their sample size was not large enough to determine an association with dose. Our sample size is similar and lacked the statistical power to determine conclusively the incidence of MMIinduced agranulocytosis; one patient who received an initial dose of 15 mg MMI did develop agranulocytosis, and this increased the incidence from zero to 0.36%. Although there are no prospective controlled studies confirming the safety of low-dose MMI therapy with respect to agranulocytosis, our findings strongly suggest that the incidence of agranulocytosis is much lower in a low-dose (15 mg/d or less) MMI regimen than in a high-dose regimen. Acknowledgements The authors thank David Kipler, English Language Section, Toho University Faculty of Medicine, for his assistance in preparing the manuscript for publication and Chiaki Nishimura, Ph D., Toho University Faculty of Medicine, for his assistance with the statistical analysis. References 1. Shirooze A, Okamura K, Ikenoue H, Sato K, Nakashima T, Yoshinari M, Fujishima M, Yoshizumi T (1986) Treatment of hyperthyroidism with a small single daily dose of methimazole. J Clin Endocrinol Metab 63: Okamura K, Ikenoue H, Shirooze A, Sato K, Yoshinari M, Fujishima M (1987) Reevaluation of the effects of methylmercaptoimidazole and propylthiouracil in patients with Graves hyperthyroidism. J Clin Endocrinol Metab 65: Reinwein D, Benker G, Lazarus JH, Alexander WD, The European multicenter study group on antithyroid drug treatment (1993) A prospective randomized trial of antithyroid drug dose in Graves disease therapy. J Clin Endocrinol Metab 76: Guidelines for the diagnosis of Graves disease. The Japan Thyroid Association home page, umin.ac.jp. 5. Mashio Y, Beniko M, Matsuda A, Koizumi S, Matsuya K, Mizumoto H, Ikota A, Kunita H (1997) Treatment of hyperthyroidism with a small single daily dose of methimazole: a prospective long-term follow-up study. Endocr J 44: Tajiri J, Noguchi S, Murakami T, Murakami N (1990) Antithyroid drug-induced agranulocytosis. Usefulness of routine white blood cell count monitoring. Arch Intern Med 150: Tajiri J, Noguchi S (2004) Some patients with antithyroid drug-induced agranulocytosis have normal white blood cell counts. Thyroid 14: Tamai H, Sudo T, Kimura A, Mukuta T, Matsubayashi S, Kuma K, Nagataki S, Sasazuki T (1996) Association between the DRB1*08032 histocompatibility antigen and methimazole-induced agranulocytosis in Japanese patients with Graves Disease. Ann Intern Med 124: Akamizu T, Ozaki S, Hiratani H, Uesugi H, Sobajima J, Hataya Y, Kanamoto N, Saijo M, Hattori Y, Moriyama K, Ohomori K, Nakao K (2002) Drug-induced neutropenia associated with anti-neutrophil cytoplasmic antibodies (ANCA): possible involvement of complement in granulocyte cytotoxicity. Clin Exp Immunol 127: Reumaux D, Duthilleul P, Roos D (2004) Pathogenesis of disease associated with antineutrophil cytoplasmic autoantibodies. Hum Immunol 65: Bonaci-Nikolic B, Nikolic MM, Andrejevic S, Zoric S, Bukilica M (2005) Antineutrophil cytoplasmic antibody (ANCA)-associated autoimmune disease induced by antithyroid drugs: comparison with idiopathic ANCA

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