Until now, the optimal duration of ATD therapy as an initial treatment modality for patients with Graves’ disease was recommended to be 12 to 18 months, but the risk of relapse is as high as 50% to 70% [6,11]. Intriguingly, this study reveals that long-term ATD treatment over 18 months could reduce the risk of relapse by as low as 20%. The results show that, the longer the ATD treatment duration, the lower the relapse rate, and this finding was statistically significant. This large cohort study also demonstrates the duration of ATD treatment as an independent risk factor for relapse in Graves’ disease patients.
The preferred duration of ATD treatment as well as the preferred initial treatment modality vary geographically [12, 13]. As a result, remission rates are considerably different between geographical regions. In the United States, it has been recommended to continue ATD treatment for approximately 12 to 18 months and then cease drug use if the serum TSH level is normal at that time, although a recent guideline also recommended considering TRAb levels at the end of ATD treatment . A European guideline also recommended the same duration of ATD treatment , but some data in Europe have indicated a high remission rate of 50–60% may exist after five to six years of ATD treatment . On the other hand, a Japanese guideline recommended to maintain ATD treatment for a certain period with minimum maintenance dose after restoring the euthyroid state, noting a remission rate as high as 81% after five to six years of ATD treatment [2, 15]. According to a 2013 Korean survey of clinical practice patterns, the normalization of TRAb was considered more important than the fixed duration of ATD treatment as a criterion for ATD discontinuation; thus, the average duration of ATD treatment was longer in Korea than in other countries [16, 17].
Two systematic review articles published in 2005 and 2010 concluded that there was no clear benefit that accrued to longer duration ATD treatment over 18 months [5, 6], but this finding was based on the data of only two studies performed in the late 1990s [9, 10]. Since few studies were conducted in the early 2000s, currently, most guidelines still recommended a 12- to 18-month course of ATD treatment [3, 4]. There have been several reports that long-term ATD treatment might be effective for adolescents or patients with Graves’ orbitopathy, but this consideration has not been generally adopted [18, 19]. Recently, considerable new reports have been published, suggesting long-term ATD treatment induced a higher remission rate than a fixed treatment duration [14, 2, 7, 20, 21]. A recent randomized clinical trial reported a significantly lower relapse rate with a 60- to 120-month course of low-dose ATD treatment compared to a conventional 12- to 18-month course of ATD treatment (15% vs. 53%) . The results of these recent studies are consistent with our findings. In particular, the relapse rate of this study, which was less than 20% in patients treated for six years or more, was similar to that from the randomized clinical trial study .
This study is distinctive in that it shows a significant relationship between relapse rate and duration of ATD treatment—that is, the longer the treatment duration, the lower the relapse rate. A recent meta-analysis revealed that long-term ATD treatment was effective and safe, with a remission rate of 16% per year of treatment . This meta-analysis suggested the positive relationship between treatment duration and remission rate but it was just calculated based on only a small number of studies. Our study is meaningful because it reports clinical experience that supports the results derived from recent meta-analyses.
Several factors associated with relapse, including male sex, young age, past or current smoker, large goiter size, high level of free T4, and high titer of TRAb, have been reported [22–25]. In this study, the duration of ATD treatment is suggested as an independent risk factor for relapse after adjusting for other risk factors for relapse. The possible mechanism is associated with establishing and maintaining the euthyroid state for a long period . Although still controversial, remission during ATD treatment seems to be primarily related to the restoration and maintenance of the euthyroid state rather than the direct immunosuppressive effects of ATD therapy itself [26–29]. A number of reports have suggested that remission is not related to ATD type, ATD dose, or the additional use of levothyroxine [30, 31]. The fall in serum TRAb is similar in patients treated by ATD or by thyroid surgery [32, 33]. The hyperthyroid state worsens autoimmunity and leads to increases in TRAb titer [34, 35]. Once this vicious cycle is broken by either ATD or surgery, most patients gradually enter the remission state. Conversely, if ATD is stopped without sufficient time to improve autoimmunity, it can be easy for the patient to return to the hyperthyroid state. In most previous studies of patients treated with ATD for 12 to 18 months, approximately 75% of relapses occurred within the first three months after ATD withdrawal . However, considerable instances of relapse occurred after one year in this study. This result suggested that a relatively prolonged course of ATD treatment could reduce the number of early relapses that happen within one year after ATD withdrawal.
A recent systemic review demonstrated that long-term ATD treatment has few adverse events and that any major adverse reactions will occur in the first few months of treatment . This study also showed that long-term ATD treatment is safe. Among a total of 4,578 patients who were initially screened in this study, only 19 patients (0.4%) were unable to complete the ATD treatment due to serious side effects including agranulocytosis and hepatic damage. Among a total of 908 patients who completed the initial ATD treatment, only 26 patients (2.9%) experienced minor side effects, most of which were pruritus or rash, and all were tolerable without stopping ATD treatment. Serious adverse reactions were not observed with low-dose ATD treatment that continued after restoring hyperthyroidism at an initial dose. Graves’ disease is associated with a significant adverse impact on the quality of life (QoL) . Some reports have found that patients who take a thyroid hormone for their remaining lifetime after thyroid surgery continue to experience worse QoL than the general population [38–40]. Remaining in a state of euthyroidism for a longer ATD course may be a better choice for patients who do not experience adverse events of ATD treatment, or who may have a poorer QoL after thyroid surgery or RAI therapy.
Although this is a multicenter and large cohort study reflecting real-world experience, there are several limitations because of the retrospective nature of the study. Because there was no consensus protocol for ATD discontinuation, TRAb titers were not routinely taken prior to ATD discontinuation. In addition, this study was conducted in an iodine-replete area, which is a well-known risk factor for relapse. Since the hospitals participating in this study were tertiary referral hospitals, some patients were referred to the primary care centers, which caused an increase in follow up loss. Further studies will be necessary to evaluate the effectiveness of long-term ATD treatment and to clarify how it can be applied in patients with Graves’ disease, especially in countries where medical costs are high.
Over the last century, there have been several changes in Graves’ disease treatment strategies, including a shift away from RAI therapy to ATD and a near-elimination of the use of propylthiouracil . Because of the fears of worsening Graves’ orbitopathy and increasing the radiation-induced malignancy rate, ATDs are increasingly used worldwide. However, current recommendations of ATD treatment lead to high relapse and need improvement. Since long-term ATD treatment has not proven to be effective until recently, a 12- to 18-month course of ATD treatment is consistently recommended based on expert opinion and cost-effectiveness. Especially in countries where medical costs are not high, it may be more cost-effective to improve the remission rate with long-term ATD treatment rather than risk relapse after short-term treatment. These findings included in our study should be considered seriously to revise future practice guidelines.
In conclusion, this large multicenter retrospective study demonstrated that, the longer ATD was used, the lower the relapse rate in patients with newly diagnosed Graves’ disease. ATD treatment lasting longer than 18 months should be considered as an initial treatment modality. Long-term ATD treatment may be considered in Graves’ patients who are at a high risk of relapse, who are concerned about the side effects of hyperthyroidism such as cardiac arrhythmia, or who do not have complications or an economic burden of ATD treatment.