Treatment of Graves’ Disease: Faster Remission or Longer but Safe, That Is the Question
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Graves’ disease (GD) exhibits fluctuations due to an active autoimmune process. The natural history of GD is highly variable. A considerable portion of patients experience an uneven course, with transitions between hyperthyroid and euthyroid states, while a smaller portion achieve remission. Some patients never experience remission, and their GD persists [1].
There are three treatment modalities for GD that have remained unchanged for nearly 80 years: antithyroid drugs (ATD), radioactive iodine (RAI) therapy, and surgery. In terms of prognosis, it is important to choose a treatment modality that rapidly normalizes hyperthyroidism and has a high remission rate. Nevertheless, debate continues regarding the optimal treatment method for GD in clinical practice, even though definite indications and contraindications for each modality have been proposed.
Many studies have reported on the patterns, efficacy, safety, remission, and failure rates of GD treatment in various countries around the world. ATD is the most commonly used first-line treatment for GD in many countries [2]. Moreover, there is increasing evidence that long-term ATD treatment may safely and effectively decrease relapses [3]. The duration of ATD therapy is inversely associated with the relapse rate; treatment durations as long as 35 years have even been reported [4-6]. Although the risk of recurrence during ATD treatment ranges from 30% to 70%, long-term therapy reduces this risk to 15% [7]. Based on these results, there is a recent trend toward considering long-term ATD treatment. Furthermore, although definitive treatments such as RAI or surgery are usually recommended for patients with recurrent GD, the current trend in clinical practice is to restart ATD as a secondary treatment option [8]. In Korea, ATD is the most preferred retreatment modality, and the duration of ATD therapy is longer compared to other countries [9]. According to a survey conducted by the Korean Thyroid Association, 48.4% of Korean endocrinologists selected RAI as second-line therapy, compared to only 4.7% who opted for thyroidectomy. There is a significant gap between the recommendations of standard guidelines and actual clinical practice.
Clinical experience over the past 70 years has proven that RAI is highly effective and safe [10]. Nevertheless, ATD remains much more preferred than RAI [8]. According to a recent survey conducted in 85 countries, the use of RAI as a first-line therapy has decreased in all geographic regions [11]. Even the United States experienced the sharpest decline in the selection of RAI as initial treatment, decreasing from 69% in 1990 to 11.1% in 2023.
In a recent article in Endocrinology and Metabolism, Kim et al. [12] reported trends in the initial treatment modalities and treatment failure rates using data from the largest nationwide cohort in South Korea between 2004 and 2020. ATD was the most common treatment (98%) for GD, followed by thyroidectomy (1.3%) and RAI (0.7%). During a median follow-up of 8.5 years, the treatment failure rate for ATD was 58.5%, which is higher than that for RAI (21.3%) and surgery (2.1%). This treatment pattern is similar to those reported in other recent studies, although the proportion of RAI treatment is particularly low. It is difficult to determine exactly why the use of RAI is even lower than that of surgery. However, there may be several reasons for the refusal of RAI. Reluctance to use RAI in clinical practice stems from concerns about short- and long-term complications—including permanent hypothyroidism—and its failure rate is similar to that of long-term low-dose ATD therapy. In addition, cultural fears and anxieties regarding its use, misinformation, and the negative connotations associated with terms such as ‘destruction,’ ‘radiation,’ and ‘nuclear’ may influence treatment decisions, along with physicians’ preferences [13].
Thyroidectomy is the least preferred choice for GD treatment [14]. However, surgery for GD is currently being reconsidered. Recent studies comparing the long-term outcomes of RAI and surgery are shedding new light on the potential benefits of surgery [15,16]. The need for retreatment after initial therapy for GD is significantly lower after thyroidectomy than after RAI [16]. Sixteen well-conducted trials have demonstrated that, although surgery is used less frequently for the treatment of GD, it controls symptoms more successfully and does not worsen Graves’ ophthalmopathy [15].
Another important consideration when choosing treatment is the risk of comorbidities. Untreated or inadequately treated GD is often accompanied by several comorbidities. GD may be complicated by various cardiovascular abnormalities, including atrial fibrillation (Af), congestive heart failure, and angina [17]. Af is the most frequent complication of hyperthyroidism, and insufficient treatment of GD is associated with a higher risk of Af regardless of the treatment modality. Because hyperthyroidism-related Af can be reversed by restoring euthyroidism, rapid correction of hyperthyroidism is essential [18,19]. Evidence supporting the importance of definitive GD treatment in reducing Af risk has increased. A study by Cho et al. [20] revealed that, among the three treatment modalities, only the surgical group did not have a significantly increased risk of Af compared to controls. Based on the results of several studies, including a network meta-analysis, prolonged ATD treatment for hyperthyroidism may be associated with a higher risk of Af, whereas rapid remission appears to result in a lower risk of cardiovascular outcomes [20-22]. In a nationwide cohort study in Taiwan conducted between 2011 and 2020, surgery was associated with lower long-term risks of major adverse cardiovascular events (MACE) and all-cause mortality, while RAI was associated with a lower MACE risk compared with ATD [23]. In addition, it is well known that the severity of hyperthyroidism influences bone mass and increases the risk of osteoporosis [24]. Therefore, effective treatment of GD has a beneficial effect on bone metabolism. In a study by Kim et al. [12], 97.2% of patients with Af were treated with ATD, compared with only 1.2% with RAI and 1.6% with surgery. Of course, several clinical variables and individual circumstances must be taken into account, raising the question of whether this treatment approach is overly one-sided.
If we define ‘cure’ or ‘resolution’ as achieving a normal range of thyroid hormone levels and a negative thyrotropin receptor antibodies state without any thyroid medication, the proportion of cured patients would be very low. Even when using the less strict definition of ‘remission,’ achieving this outcome remains difficult in clinical practice. Therefore, it is important to choose a treatment modality that offers a greater chance of remission. Moreover, complications induced by longstanding hyperthyroidism must be minimized. Given that most patients rely on their doctors for treatment decisions, physicians must thoroughly explain the pathogenesis of GD, as well as the mechanisms, benefits, risks, and side effects of each treatment modality.
Until now, ATD has always been the treatment of choice for uncomplicated GD. However, in the era of individualized medicine, physicians must select the treatment that is most appropriate for each patient’s condition and actively recommend a switch to definitive therapy when necessary.
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CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.