Introduction

Graves’ disease (GD) is an autoimmune disease characterized by hyperthyroidism due to increased thyroid-stimulating hormone (TSH) receptor antibodies (TRAb) [1]. TRAb mimic TSH and stimulate its receptors. TSH receptor stimulation via TRAb subsequently causes an excessive production of thyroid hormones (T3 and T4). These thyroid hormones circulate in the bloodstream and affect nearly every tissue system in the body, including the cardiac muscle and the nervous system. Patients with GD hyperthyroidism exhibit many symptoms, such as tremors, palpitations, weight loss, and diarrhea [2]. Graves’ ophthalmopathy is a specific complication of GD that occurs due to TRAb-induced inflammation of the orbital structures. It manifests as swelling of the tissues around the eyes and the exophthalmos [3].

The prevalence of GD is estimated at 2–3% of the overall population worldwide. It usually affects more women than men at a ratio of 10:1. GD affects all age groups; however, it is more common in middle-aged individuals, with a peak incidence in the 40–60-year-old age group [4, 5]. In Saudi Arabia, there are limited epidemiological data on GD. The exact prevalence of GD in the Saudi population is unknown. However, Malabu et al. reported a female-to-male ratio of 2.9:1 and a mean age of 32 ± 0.9 years in a study conducted in Riyadh, Saudi Arabia [6].

GD treatment aims to restore euthyroidism to improve clinical symptoms and prevent long-term complications. Treatment varies depending on clinical characteristics and the patient’s preferences [7, 8]. RAI, surgery, and anti-thyroid drugs (ATD) are approved options for treating GD [7,8,9]. RAI is widely considered safe and has a low morbidity rate [8]. Successful RAI therapy for GD can be accomplished in most patients (> 90%) with a single dose [10]. Thyroidectomy is another treatment option for GD patients with large goiter or thyroid nodules [11]. The thyroid gland can either be totally removed with a lower incidence of recurrence or partially removed with an approximately 8% chance of recurrence [12]. Nevertheless, in Europe, Asia, and the USA, ATD, including propylthiouracil (PTU) and methimazole (MMI), are considered the first-line treatment for GD before RAI therapy or thyroidectomy [7]. MMI is often preferred over PTU due to its better safety profile [7, 8, 13]. Both PTU and MMI take around 18 months to induce a sustainable remission of GD, although a relapse rate of up to 50–60% has been reported [7, 8].

GD remission is defined as an euthyroid state for at least six months while off or on a small dose of ATD [13, 14]. Several studies have confirmed that ATD could result in long-term remission in up to 50% of patients [7, 8]. The predictors of ATD course outcomes have been examined in many studies. These predictors include TRAb level, goiter size, baseline free T4 level, and the degree of ophthalmopathy [7, 8, 12, 14, 15]. In Saudi Arabia, only a few studies have collected data on the remission rates of GD after treatment with ATD [6]. Therefore, this study aimed to assess the efficacy of ATD in treating GD in the Saudi population and the clinical predictors of long-term remission. This study aids in managing patients with GD by delineating the factors associated with sustainable remission and relapse with ATD use.

Method

This retrospective chart review study was conducted in the endocrinology clinics at King Abdulaziz Medical City in Riyadh, Saudi Arabia. All GD patients, adults, and adolescents aged 14 years and older treated with ATD as first-line therapy at the discretion of the treating endocrinologist were included. The study period was from July 2015 to December 2022. All the patient had at least 18 months of follow-up. GD diagnosis was based on clinical presentation with symptoms of thyrotoxicosis with suppressed TSH, high levels of either free T4 or free T3, or both. The confirmation of GD diagnosis was achieved through either a high TRAb level, a high thyroid uptake on 99mTc-pertechnetate scan, or both. Patients with insufficient follow-up and those who had undergone RAI therapy or thyroidectomy as a first-line therapy for GD were excluded from the study.

The collected data included demographic variables, such as age, and gender. Clinical variables included TRAb levels, TSH, free T4 and T3 levels, 99mTc-pertechnetate scan uptake results, duration of ATD therapy, and Graves’ ophthalmopathy severity. TSH, free T4, and free T3 were measured with a Chemiluminescent Microparticle Immunoassay (the Abbot Alinity i system). The reference range was 0.35 − 4.94 mIU/L for TSH, 9–19 pmol/L for free T4, and 2.9–4.9 pmol/L for free T3. TRAb levels were measured using an electrochemiluminescence immunoassay (Roche Cobas e411), and the normal reference value was < 1.8 Iu/l. The severity of ophthalmopathy was assessed and documented by the treating endocrinologist based on the grading system established by the European Group on Graves Orbitopathy (EUGOGO) [16].

Remission and relapse status was collected for all patients. Remission was defined in this study as a state of being clinically euthyroid, with normal levels of TSH and free T4 and T3 for any period off ATD. Patients who continued to require any dose of ATD after a minimum of 18 months of ATD use to maintain euthyroidism were considered to have persistent GD and did not achieve remission. Relapse was defined as a clinical recurrence of hyperthyroidism, with low TSH and high free T4 and T3 at any time after being off ATD.

Statistical analysis was conducted using SAS 9.4 software (SAS Institute Inc., Cary, NC, USA). Continuous variables were reported as mean and standard deviation (SD) if normally distributed, while abnormally distributed variables were reported as median and inter-quartile ranges (IQR) with appropriate statistical tests use. Categorical variables were reported as frequencies and percentages.

To determine the factors associated with remission and relapse, the study participants were divided into two groups based on remission and relapse status. The groups were compared using the Chi-square test or Fisher’s exact test for categorical variables, and the T-test or the Kruskal–Wallis test for continuous variables, as appropriate. Then, a multivariate logistic regression analysis used to identify independent risk factors. All variables found to be associated with remission and relapse in the univariate analysis, as well as available variables previously associated with remission and relapsse in the literature, such as age, gender, free T4 levels, and TRAb levels, were used in the multivariate analysis. Area under the curve (AUC) calculation was employed to study the receiver operating characteristic curve (ROC) to determine the free T4 and TRAb cut-off values to predict remission. Inferential statistical tests were considered significant if their P values were < 0.05.

The study was approved by the Institution Review Board (IRB) at King Abdullah International Medical Research Center-Riyadh with Protocol Number: NRC22R/314/06 and approval number IRB/1431/22 with a waiver of the study subjects’ consent per the institutional policy for retrospective studies.

Results

Study sample characteristics

Out of 227 patients diagnosed with GD during the study period, 189 patients met the study inclusion and exclusion criteria. The majority of the study sample (72%) was female, and the patients’ ages ranged from 18 to 80 years old. Around 71.3% of the study sample had mild Graves’ ophthalmopathy. The TRAb titer ranged from 0.9 to 36 Iu/l. The median thyroid uptake on the 99mTc-pertechnetate scan was 10.0 (4.20, 16.69), consistent with GD diagnosis. The median follow-up period for the patients was 22.0 months (9, 36). All the patients except one were treated with methimazole with a median initial dose of 15 mg (10, 20) with gradual titration as per the treating endocrinologist. Table 1 shows the study sample’s clinical characteristics.

Table 1 Clinical characteristics of the study sample
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Assessment of patients who achieved remission

A total of 103 out of 189 patients (54.5%) achieved GD remission. The free T4 level at the time of diagnosis was significantly lower in patients who achieved remission versus patients who did not, with a mean difference of 3.0pmol/l (P = 0.038). Similarly, the TRAb level at diagnosis was significantly lower in patients who achieved remission than in patients who did not, with a median difference of 5.4 Iu/l (P = 0.001). A significant proportion of the female patients (61.7%) achieved remission, while only 35% of the male patients achieved remission. The only two patients with severe ophthalmopathy and 67% of the patients with moderate ophthalmopathy did not achieve remission. A detailed comparison of the patients who achieved remission versus those who did not is shown in Table 2. Of the patients who did not achieve remission, 22 patients underwent thyroidectomy, 17 patients received RAI, and 47 patients continued on ATD.

Table 2 Comparison of ATD-treated Graves’ disease patients who achieved remission versus patients who did not achieve remission
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Assessment of patients who developed relapses

In terms of relapses, of the 103 patients who achieved remission, 35 (34%), 30 of whom were female, relapsed after ATD discontinuation. The median time to relapse was 14 months (7, 20). Figure 1 shows the remission survival curve of the 103 patients with remission during follow-up. Patients who relapsed showed significantly higher thyroid uptake on 99mTc-pertechnetate scan at baseline than patients who did not relapse, with a median difference of 4.3% (P = 0.03). Similarly, patients who relapsed were treated with ATD for a longer period than patients without relapse, with a median difference of 15 months (P < 0.0001). No significant differences in free T4 or TRAb levels were identified (Table 3). Of the patients who relapsed after the discontinuation of ATD, 10 received RAI, 2 underwent thyroidectomy, and the remaining 23 were restarted on a second course of ATD.

Fig. 1
figure 1

Survival curve of patients who achieved remission

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Table 3 Comparison of Graves’ disease patients who experienced relapse after ATDs discontinuation versus patients who did not experience relapse
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Predictors of remission

Available and previously reported variables associated with remission and the variables showed significance in the univariate analysis were incorporated in a multivariate analysis to assess the factors associated with remission. TSH receptor levels and ophthalmopathy severity were found to be significantly associated with remission (Table 4). The ROC curve, which determined the free T4 level cutoff to predict remission using Youden’s J statistics, showed the best AUC of 0.5887, at the best cutoff value of 28.5 pmol/l, with a sensitivity of 52% and a specificity of 66% (Fig. 2). Similarly, the ROC curve, which determined the TRAb level cutoff to predict remission using Youden’s J statistics, showed the best AUC of 0.6697 at the best cutoff value of 13.4 Iu/l, with a sensitivity of 47% and a specificity of 84% (Fig. 3).

Table 4 Multivariate analysis for variables as predictors for remission
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Fig. 2
figure 2

Receiver operating characteristic curve of free T4 predicting remission

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Fig. 3
figure 3

Receiver operating characteristic curve of TRAb predicting remission

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Predictors of relapse

Available and previously reported variables associated with relapse and the variables that showed significance in the univariate analysis were incorporated into a multivariate analysis to assess the factors associated with relapse. Only the duration of ATD treatment was associated with relapse (Table 5).

Table 5 Multivariate analysis for variables as predictors for relapse
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Discussion

This retrospective cohort study evaluated the demographics of patients from Saudi Arabia with GD. The remission and relapse rates and the factors affecting both outcomes were also investigated. Like other autoimmune diseases, GD is more commonly diagnosed in middle-aged women [7, 17]. Accordingly, in this study, around two-thirds of the patients were female, and the median age at diagnosis was 38 years.

GD diagnosis is based on the documentation of thyrotoxicosis with suppressed TSH, with the elevation of free T4 and T3. GD is usually confirmed by the documentation of elevated TRAb or with high thyroid uptake on nuclear imaging [7, 8]. Thyroid I123 is commonly used to confirm GD; however, the 99mTc pertechnetate scan is also widely used due to its availability and the short time the scanning takes [7, 8]. In this study, TRAb and 99mTc-pertechnetate scans confirmed a GD diagnosis.

The management strategies for overt hyperthyroidism caused by GD are either the reduction of thyroid hormone production with ATD or reduction of thyroid tissue, leading to hypothyroidism through radioactive iodine ablation or thyroidectomy. The American Thyroid Association and the European Thyroid Association recommend the three treatment options as a first-line therapy for GD [7, 8]. ATDs are widely accepted as a first-line treatment given their safety and efficacy [18].

When considering ATDs as a treatment option for GD, the treating physician and the patient should be aware of the possibility of not achieving remission and of experiencing relapse after achieving remission. Studies have found an ATD-induced remission of GD in 30–70% of patients [7, 8, 19]. The current study’s failure rate for achieving remission with ATDs was 45.4%, which is consistent with that of previous studies [13, 18].

TSH receptor antibodies level known to predict clinical and biochemical outcomes among GD patients treated with ATD. The American Thyroid Association and European Thyroid Association recommend measuring TRAb at the end of the treatment period and before stopping the ATD to guide the decision of whether to discontinue ATD, prolong low-dose ATD, or proceed with definitive therapy (RAI or surgery) [7, 8]. We found that the remission rate was inversely related to the initial TRAb level; thus, a lower TRAb level was observed in patients who achieved remission than in those who did not. In addition, we established that remission was achieved more often among females, patients with low baseline free T4, and patients with mild Graves’s ophthalmopathy. These findings are, to an extent, consistent with previous studies. Karmisholt et al. determined that patients with higher free T4 and TRAb levels upon diagnosis were less likely to experience remission. However, there was no difference in the likelihood of remission based on gender or eye disease status [13]. In contrast, Song et al. found that only the free T4 level at diagnosis predicts remission [20]. Zuhur et al. observed that females achieved sustained remission more often than males did [21]. Similar to this study, previous studies have associated Graves’s ophthalmopathy severity and remission rates with ATD [14, 22].

The evaluation of factors associated with remission has led to developing the Graves Recurrent Events After Therapy (GREAT) score. GREAT score variables include age, free T4 level, TRAb titer level, and thyroid goiter size. The lower the GREAT score, the more likely a patient with GD is to achieve remission [23]. However, validation studies of the GREAT score have shown that only TRAb levels are consistent predictors of GD remission [24]. In line with that finding, the multivariate analysis in this study, incorporating most of the components of the GREAT score and the variables found to be significant in univariate analysis, showed that only higher TRAb levels upon the diagnosis of GD were significantly associated with the failure to achieve remission with ATD. The best cutoff value of 13.4 Iu/l for TRAb levels on the ROC curve to predict remission was correlated with an AUC of 0.6697, with a high specificity of 83% but a low sensitivity of 47%. Similar to this study’s findings, Karmisholt et al. found that the best TRAb level cutoff value for predicting remission was 10 Iu/l with 74% specificity and 57% sensitivity [13]. These cutoff values of TRAb to predict remission require further investigation to assess their utility in clinical practice. For free T4, the best cutoff value of 28.5pmol/l on the ROC curve had a low AUC (0.5887), with a low sensitivity of 52% and a specificity of 66%, indicating that free T4 levels upon diagnosis exhibit a poor ability to predict remission. Further studies are necessary to determine the utility and cutoff values of TRAb and other biochemical variables to predict remission.

The relapse rate after remission in this study was 34%, which is comparable to previous studies that showed a 30–40% relapse rate in the first year and an overall relapse rate of GD after ATD discontinuation of up to 50–60% [7, 8, 15, 25, 26]. In this study, the median time to relapse was 14 months after ATD discontinuation, which is consistent with other studies reporting that relapse usually occurs in the first two years after ATD discontinuation [7, 23].

This study found that individuals with higher thyroid uptake on 99mTc-pertechnetate scans and who required a longer duration of treatment with ATD had an increased risk of relapse. However, after conducting a multivariate analysis, only the prolonged use of ATD was predictive of relapse. Other factors, such as gender, age, baseline free T4, TRAb level, and the presence of thyroid eye disease, did not significantly impact the risk of relapse. Similar to our findings, previous studies have established that a higher uptake on a 99mTc-pertechnetate scan is associated with more frequent relapses [27]. However, Azizi et al.’s systematic review contradicted our findings. They reported that a longer duration of ATD (> 60 months) resulted in up to an 85% chance of sustained remission without relapse [28]. This systematic review supported the findings of a randomized clinical trial that found a 15% relapse rate after a long duration (95 +/- 22 months) of ATD use versus a 53% relapse rate in patients who received ATD for 19 +/- 3 months [29]. Park et al. also established that the relapse rate in relation to ATD treatment duration was 42.4% at one year, 38.5% at two years, 33.8% at three years, 31.7% at four years, 30.2% at five years, 27.8% at six years, and 19.1% at over six years [25]. However, other studies have indicated the opposite and were thus consistent with this study. For example, Park et al. determined that ATD use for more than six months is an independent predictor of relapse [24]. Similarly, Kim et al. reported that longer ATD and multiple courses of ATD were associated with persistent GD [30]. Therefore, it is unclear whether a longer duration of ATD results in sustainable remission or indicates the need for long-term ATD use to maintain remission. This significant aspect of GD management requires further studies.

In terms of the relationships between TRAb titer, free T4 levels, and relapse rates, we found that baseline TRAb status and free T4 level did not affect the relapse rate, a finding similar to that of previous studies [15, 23]. This finding, however, contradicts those of other studies in which patients who relapsed had higher serum TRAb, free T4 levels, and larger goiter at baseline [31].

Our study was the first to report on ATD efficacy and predictors of remission and relapse of GD in the Middle-Eastern population. However, the study has limitations because it is a retrospective, single-center study missing important variables such as accurate thyroid volume and end-of-treatment TRAb levels. Future studies to evaluate the predictors of GD remission and relapse with ATD are necessary to improve first-line treatment selection for patients with GD. Moreover, studies to validate the GREAT score in different populations are needed to enhance its utility in clinical practice.

Conclusion

This study’s findings demonstrated that a significant proportion of patients achieved remission with ATD. Patients with lower levels of free T4 and TRAb at diagnosis had higher remission rates. The female gender, mild ophthalmopathy, and shorter durations of thionamide treatment are factors associated with remission. Conversely, higher thyroid uptake on 99mTc-pertechnetate scan at baseline and longer ATD treatment duration were associated with an increased risk of relapse. These findings have implications for personalized treatment approaches and highlight the necessity of monitoring specific biomarkers and clinical characteristics to optimize treatment outcomes and long-term prognosis in GD patients.