Abstract
Objective
This study evaluated the efficacy of antithyroid drugs (ATDs) and risk factors associated with the recurrence of Graves’ hyperthyroidism using a comprehensive retrospective cohort.
Methods
We included 1829 patients newly diagnosed with Graves’ hyperthyroidism, with sufficient follow-up data. Clinical outcomes of the patients and risk factors associated with recurrence-free survival, including the changes in thyrotropin receptor antibody, were evaluated.
Results
The median age of the patients was 44.5 years, and 69% were female. Among the patients, 1235 had a chance to withdraw ATD after a median of 23 (interquartile range (IQR) 17.0–35.5) months of treatment. The first remission rate was 55.6% during a median of 72.7 months of follow-up. After the first recurrence, 95% of patients underwent the second course of ATD treatment for a median of 21.1 (IQR 14.8–31.7) months, and the remission rate was 54.1%. During a median of 67 months of follow-up, 7.7% of patients underwent surgery, and 10.5% underwent radioactive iodine therapy. Approximately 30% were still on ATD therapy for recurrent disease or prolonged low-dose maintenance. Younger age (<45 years), male sex, and fluctuating or smoldering of TRAb levels were independent risk factors of the first recurrence after ATD treatment.
Conclusions
ATD treatment is an acceptable option for the initial treatment of Graves’ hyperthyroidism as well as for recurrent disease. The optimal treatment period for ATD treatment needs to be determined using the individual risk factors of recurrence.
Introduction
Graves’ hyperthyroidism is an autoimmune disease in which thyrotropin (thyroid-stimulating hormone (TSH)) receptor antibody (TRAb) stimulates thyroid follicular cells, resulting in thyrotoxicosis and enlargement of the thyroid gland (1, 2). Current treatment options for patients with Graves’ hyperthyroidism include antithyroid drugs (ATDs), radioactive iodine (RAI) therapy, and surgery (1, 3, 4). Although geographical difference exists, ATD is the preferred first-line therapy in most areas due to its safety and easy accessibility (5, 6). However, compared with RAI therapy or surgery, characterized by a relatively more definite treatment, the major clinical issue with ATD is always the risk of recurrence when therapy is discontinued (7, 8).
The American and European guidelines recommend maintaining ATD for approximately 12–18 months, and the remission rates achieved are 50–55% (1, 9). However, some studies, including a randomized clinical trial, report that a longer treatment period of up to 41–120 months is associated with a better prognosis, with remission rates of 57–85% (10, 11, 12). This raises the question of whether long-term ATD treatment is appropriate for all patients with Graves’ hyperthyroidism. Many predicting risk factors, including age, sex, goiter size, smoking history, and the presence of thyroid-associated ophthalmopathy (TAO), have been reported to be associated with disease prognosis (2, 12, 13, 14, 15, 16, 17). Therefore, it would be reasonable to define the individual risk of recurrence and determine the optimal treatment period rather than a predetermined long-term period.
Considering individual characteristics, TRAb level is also an essential risk factor due to its inherent role in the pathophysiology of the disease. Measurement of TRAb prior to stopping ATD therapy is recommended according to the American and European guidelines because it aids in predicting the chance for remission (1, 9). The baseline TRAb was also identified to help predict the disease recurrence before ATD treatment along with age, goiter, and initial free T4 (fT4) level (17). Bandai and colleagues (18) suggested that in addition to TRAb at initiation and discontinuation of ATD, the trend of TRAb, classified as smooth disappearance, fluctuating type, and smoldering type, can help predict the clinical course of Graves’ hyperthyroidism from a long-term cohort study (18, 19). This study illuminated the importance of the dynamic change of TRAb for the first time, which needed to be verified and highlighted. Patients with persistently elevated (smoldering) TRAb could continue long-term ATD maintenance or alternate to definite therapy with RAI or thyroidectomy (1). A high recurrence rate can be expected in this case; however, no specific prognosis has been revealed. In addition, deciding whether to stop ATD when the TRAb is widely fluctuating is always a challenge for clinicians.
Therefore, we aimed to identify the efficacy of ATD in patients with Graves’ hyperthyroidism using a comprehensive cohort with a large size and long-term follow-up. Thereby, we intended to identify risk factors, including the change of TRAb during ATD treatment associated with prognosis.
Methods
Patients
This historical cohort study screened patients newly diagnosed with Graves’ hyperthyroidism in a single tertiary center between 2005 and 2018 (Fig. 1). A total of 3633 patients were screened; patients with ATD treatment duration of less than 12 months due to poor compliance (n = 451) or who had insufficient follow-up data (follow-up duration less than 12 months, n = 1353) were excluded. Finally, 1829 patients were evaluated in this study. This study was approved by the Institutional Review Board of Asan Medical Center (no. 2021-1121), and the need for informed consent was waived due to the retrospective design of the study.
Flowchart of the total number of patients with Graves’ hyperthyroidism. Treatment durations of the patients are presented as median (IQR). ATD, antithyroid drug; RAI, radioactive iodine; IQR. interquartile range.
Citation: European Thyroid Journal 12, 2; 10.1530/ETJ-22-0226
Diagnosis, treatment, and follow-up
Graves’ hyperthyroidism was diagnosed based on the laboratory data that consisted of suppressed TSH levels with elevated serum fT4 and TRAb. An increased uptake on a 99m-technetium (99m-Tc) thyroid scan and the presence of thyrotoxicosis signs and symptoms were also considered for the diagnosis of Graves’ hyperthyroidism. Patients were initially started with methimazole (MMI) (15–30 mg/day), carbimazole (CAM, 20–40 mg/day), or propylthiouracil (PTU, 100–400 mg/day), and dose titration was performed as previously described (20). Discontinuation of ATD was considered when serum TSH and fT4 levels were normalized with adequate treatment duration. For most patients, ATD was stopped when TRAb was negative. Minimum maintenance of treatment (MMI, 2.5 mg/day; CAM, 5 mg/day; and PTU, 25 mg/day) was also conducted in the euthyroid state, as reported (21, 22). Serum TSH, fT4, total T3, and TRAb were measured every 2–3 months during ATD treatment and every 3–6 months after discontinuation of ATD.
Laboratory measurements
Serum TSH levels were measured using the TSH-CTK-3 kit (radioimmunoassay (RIA); DiaSorin SpA, Saluggia, Italy) with a functional sensitivity of 0.07 mIU/L (23). Serum fT4 levels were measured using the fT4 RIA (Immunotech, Prague, Czech Republic), and serum total T3 levels were measured by RIA using T3-CTK (DiaSorin SpA). The reference ranges of TSH, fT4, and total T3 were 0.4–4.5 mIU/L, 0.80–1.90 ng/dL, and 151–277 ng/dL, respectively. TRAb was measured using a competitive TSH-binding inhibitory immunoglobulin (TBII) assay by the B·R·A·H·M·S TRAK human RIA (B·R·A·H·M·S GmbH, Hennigsdorf, Berlin, Germany) according to the manufacturer’s instructions (2). TBII titers ≥ 1.5 IU/L were considered positive, with an analytical sensitivity of 0.3 IU/L and a functional assay sensitivity of 1.0 ± 0.2 IU/L.
Definitions and outcomes
Goiter was classified according to the World Health Organization goiter classification system: grade 0, no goiter; grade 1, thyroid palpable but not visible; and grade 2, thyroid visible with the neck in normal position via physical examination by a physician (24). TAO was classified by disease activity and severity as mild, moderate, or severe (25). The change of TRAb was assessed using all the available TRAbs during ATD treatment, categorized into three groups: smooth disappearance, fluctuating, and smoldering type (18, 19). Smooth disappearance was defined as when TRAb smoothly decreased to become negative before discontinuation of ATD. The fluctuating type was defined when the tier of TRAb fluctuated from positive to negative during the ATD treatment period. The smoldering type was defined when the titer of TRAb consistently remained positive during the treatment course. The typical pattern of each TRAb trend is schematically presented in Supplementary Figure 1 (see the section on supplementary materials given at the end of this article). The pattern of TRAb was assessed at the end of treatment. Remission was defined when the euthyroid status was maintained for more than 12 months after ATD withdrawal (1, 2). Recurrence was defined as persistently suppressed TSH with or without increased fT4 during follow-up after discontinuation of ATD (2). Transient thyrotoxicosis other than that of recurrence of Graves’ hyperthyroidism, such as painless thyroiditis, was excluded. Upon recurrence, a second course of ATD therapy, RAI, or surgery was considered by each physician. Recurrence-free survival (RFS) was defined as the time from the date of ATD discontinuation until the date of recurrence or the last follow-up.
Statistical analysis
The software R version 3.4.4 (R Foundation for Statistical Computing; https://www.r-project.org/), was used for statistical analyses. Continuous variables were presented as the median and interquartile range (IQR), and categorical variables as numbers (percentage). Wilcoxon rank-sum and chi-square tests were used to compare variables. Fisher’s least significant difference was used for the post-hoc analysis. Survival curves were plotted using the Kaplan–Meier method, and the log-rank test was used to determine significance. The Cox-proportional hazard model was used to evaluate risk factors, presented as hazard ratios (HRs) and 95% confidence intervals (CIs). All P values were two sided, with values below 0.05 considered significant.
Results
Baseline characteristics of patients with Graves’ hyperthyroidism
The baseline characteristics of 1829 patients with Graves’ hyperthyroidism are summarized in Table 1. The median age of patients at the time of the first diagnosis was 44.5 years, and 571 (31.2%) were male. Among the total number of patients, 138 (7.6%) were ex- or current smokers. Grades 1 and 2 goiter were identified in 773 (42.3%) and 329 (18.0%) patients, respectively. Regarding TAO, 135 (7.4%) patients had moderate-to-severe disease and underwent systemic steroid therapy. More than half of the patients (56.5%) received MMI as first-line ATD, and only 7.2% received PTU as the first treatment. At diagnosis, the median level of fT4 was 2.5 ng/dL, and the initial titer of TRAb was 9.8 IU/L.
Baseline characteristics of the total number of patients with Graves’ hyperthyroidism.
| Characteristics | Values |
|---|---|
| Total, n | 1829 |
| Age (years) | 44.5 (33.5–54.3) |
| Sex, male | 571 (31.2%) |
| Smoking | |
| Non-smoker | 1691 (92.5%) |
| Ex-smoker | 60 (3.3%) |
| Current smoker | 78 (4.3%) |
| Goitera | |
| Grade 0 | 727 (39.7%) |
| Grade 1 | 773 (42.3%) |
| Grade 2 | 329 (18.0%) |
| TAO | |
| Absence | 1564 (85.5%) |
| Mild | 130 (7.1%) |
| Moderate to severe | 135 (7.4%) |
| Initial ATD typeb | |
| Methimazole | 1034 (56.5%) |
| Carbimazole | 662 (36.2%) |
| Propylthiouracil | 132 (7.2%) |
| Initial TSH (μM/mL) | 0.04 (0.04–0.04) |
| Initial free T4 (ng/dL) | 2.5 (1.9–3.4) |
| Initial total T3c (ng/dL) | 238.0 (185.0–323.0) |
| Initial TRAb (IU/L) | 9.8 (5.2–22.2) |
Continuous variables are presented as median (interquartile range) and categorical variables as numbers (percentages).
aWHO goiter classification system: grade 0, no goiter; grade 1, thyroid palpable but not visible; grade 2, thyroid visible with the neck in normal position; bOne patient undergoes radioactive iodine ablation without ATD treatment; cInitial T3 values are available for 1346 patients.
ATD, antithyroid drug; TAO, thyroid-associated ophthalmopathy; TSH, thyroid-stimulating hormone; TRAb, thyrotropin receptor antibody.
Clinical course and outcome of the total cohort
Figure 1 shows the initial treatment flow of the patients. Sixty-nine (3.7%) patients underwent surgical treatment, and 42 (2.3%) underwent RAI therapy. The majority of the 1718 (93.9%) patients underwent ATD treatment as the initial therapy. During ATD therapy, 65 and 127 patients underwent surgery and RAI therapy after a median of 27.3 and 29.2 months of ATD therapy, respectively. Younger age, larger goiter size, higher number of smokers, and higher titer of TRAb were seen in these patients compared to 1235 treated with ATD (Supplementary Table 1). The number of patients treated with continuous ATD therapy without withdrawal was 291 (15.9%), and the median duration was 55.4 months. They were treated with long-term minimal maintenance treatment depending on the physician’s opinion or patient’s preference. Finally, 1235 patients (67.5%) had the chance to withdraw ATD. The duration of ATD treatment in these patients was 23.0 (IQR 17.0–35.5) months, and the median follow-up duration was 72.7 months.
Remission of Graves’ hyperthyroidism after withdrawal of the initial ATD was identified in 687 patients (55.6%) (Fig. 2A). Furthermore, 548 (44.4%) patients had recurrent disease, including 324 (59.1%) within 12 months and 224 (40.9%) after 12 months since discontinuation of ATD. Most patients with recurrent Graves’ hyperthyroidism (95.4%) underwent the second ATD therapy, and 281 (51.2%) had another chance to withdraw ATD. Excluding 52 patients whose follow-up period was less than 1 year after withdrawal of ATD, 229 were identified and treated at a median of 21.1 (IQR 14.8–31.7) months of ATD therapy. After the second course of treatment, 124 patients (54.1%) had second remission, and 105 (45.9%) presented with recurrent disease. We evaluated the prognosis in 229 patients (Fig. 2) who completed the second treatment course according to the thyroid function at initial recurrence. Patients with subclinical hyperthyroidism at initial recurrence showed a 33.3% of second recurrence rate, significantly lower than that of those with overt hyperthyroidism at initial recurrence (52.3%, P = 0.01). There was no significant difference between the first (55.6%) and second (54.1%, P = 0.73) remission rates. Although not significant, the remission rate (38.9%) of patients who withdraw ATD for the third time was lower than that of those who withdraw after the first and second times (P = 0.07 and 0.13, respectively). The duration of the third ATD treatment was 20.6 months.
(A) Clinical course and outcome of the patients treated with antirhyoid drug. (B) Final clinical outcome of the 1829 patients. ATD, antithyroid drug; RAI, radioactive iodine; F/U, follow-up.
Citation: European Thyroid Journal 12, 2; 10.1530/ETJ-22-0226
Figure 2B shows the final clinical outcome of all the 1829 patients, including those who underwent RAI or surgery as initial treatment. During a median follow-up period of 67.5 (IQR 46–101) months, 7.7% of patients underwent surgery, and 10.5% underwent RAI therapy. Of patients treated with ATD, 48.5% were off ATD (45.1% with remission state and 3.4% were within 1 year after withdrawal of ATD), and 29.3% were still on ATD therapy for recurrent disease and prolonged low-dose ATD maintenance.
Clinical features associated with recurrence and changes of TRAb levels
We focused on the 1235 patients who discontinued ATD after the first ATD therapy (Table 2). The median age of patients in the recurrence group was 44.0 years, which tends to be significantly younger than that of the remission group (P < 0.001). More male patients and smokers were observed in the recurrence group than those in the remission group (P = 0.02 and P = 0.01, respectively). Clinical evident TAO was also frequent in the recurrence group (P = 0.04). Among 1235 patients, 318 (25.7%) showed positivity in TRAb when ATD was discontinued, and the median level of TRAb in these patients was 2.8 IU/L. Many patients discontinued ATD when the TRAb level was negative in the remission group (P < 0.001). The treatment duration was significantly shorter in patients in the remission group (median 21.8 months) than in those in the recurrence group (median 23.9 months, P < 0.001). The time required for the normalization of serum TSH level was significantly different between the remission (5.0 months) and recurrent groups (5.8 months, P = 0.01). However, the time required for the normalization of serum TRAb was not different based on remission or recurrence in patients with smooth disappearance and fluctuating type of TRAb (P = 0.64). At initial diagnosis, 728 out of 1235 patients underwent a 99m-Tc thyroid scan, and there was no significant difference between the uptake rate in the remission (8.8%) and recurrent group (9.3%, P = 0.48).
Clinical features of patients with Graves’ hyperthyroidism in remission or recurrence after antithyroid drug treatment.
| Total | Remission | Recurrence | P | |
|---|---|---|---|---|
| n | 1235 | 687 | 548 | |
| Age (years) | 45.9 (35.2–55.0) | 47.8 (37.0–55.4) | 44.0 (32.7–53.5) | <0.001 |
| Sex, male | 385 (31.2%) | 195 (28.4%) | 190 (34.7%) | 0.02 |
| Smoking | 0.01 | |||
| None | 1172 (94.9%) | 663 (96.5%) | 509 (92.9%) | |
| Ex or current | 63 (5.1%) | 24 (3.5%) | 39 (7.1%) | |
| Goitera | 0.51 | |||
| Grade 0 | 556 (45.0%) | 317 (46.1%) | 239 (43.6%) | |
| Grade 1 | 534 (43.2%) | 295 (42.9%) | 239 (43.6%) | |
| Grade 2 | 145 (11.7%) | 75 (10.9%) | 70 (12.8%) | |
| TAO | 0.04 | |||
| None | 1073 (86.9%) | 609 (88.6%) | 464 (84.7%) | |
| Mild to severe | 162 (13.1%) | 78 (11.4%) | 84 (15.3%) | |
| ATD | 0.23 | |||
| MMI | 688 (55.7%) | 368 (53.6%) | 320 (58.4%) | |
| CAM | 461 (37.3%) | 270 (39.3%) | 191 (34.9%) | |
| PTU | 86 (7.0%) | 49 (7.1%) | 37 (6.8%) | |
| Initial dose of ATD (MMI, mg)b | 13.3 (10.0–20.0) | 13.3 (10.0–15.0) | 13.3 (10.0–20.0) | 0.12 |
| Initial free T4 (ng/dL) | 2.5 (2.0–3.4) | 2.5 (1.9–3.3) | 2.6 (2.0–3.4) | 0.24 |
| Initial TRAb (IU/L) | 8.9 (4.7–17.5) | 8.9 (4.7–17.4) | 8.8 (4.8–17.5) | 0.99 |
| TRAb at withdrawal (negative) | 917 (74.3%) | 559 (81.4%) | 358 (65.3%) | <0.001 |
| TRAb level at withdraw (IU/L) | 1.1 (0.6–1.6) | 0.9 (0.6–1.4) | 1.1 (0.7–1.5) | <0.001 |
| MMDT (yes) | 1024 (28.9%) | 582 (84.7%) | 442 (80.7%) | 0.07 |
| Duration of MMDT (months) | 10.1 (6.2–15.2) | 10.3 (6.3–15.6) | 9.9 (6.0–14.6) | 0.14 |
| Duration of ATD (months) | 23.0 (17.0–35.5) | 21.8 (16.8–33.0) | 23.9 (17.4–39.1) | <0.001 |
| TSH normalization (months) | 5.3 (3.2–10.9) | 5.0 (3.0–10.4) | 5.8 (3.4–11.7) | 0.01 |
| TRAb normalization (months)c | 13.5 (7.2–22.2) | 13.1 (7.1–21.7) | 14.1 (7.3–22.4) | 0.64 |
| Thyroid scan uptake rated (%) | 9.0 (5.9–41.7) | 8.8 (5.9–13.9) | 9.3 (5.9–13.9) | 0.48 |
Continuous variables are presented as median (interquartile range) and categorical variables as numbers (percentages). Statistically significant values are shown in bold.
aWHO goiter classification system: grade 0, no goiter; grade 1, thyroid palpable but not visible; grade 2, thyroid visible with the neck in normal position; bA 7.5 mg CAM and 100 mg PTU dose are equivalent to 5 mg MMI; cDuration of TRAb normalization is measured in patients with smooth remission and fluctuating groups; d99m-Tc thyroid scan and uptake are performed in 728 patients.
ATD, antithyroid drug; CAM, carbimazole; MMDT, minimum maintenance dose therapy; MMI, methimazole; PTU, propylthiouracil; TAO, thyroid-associated ophthalmopathy; TRAb, thyrotropin receptor antibody; TSH, thyroid-stimulating hormone.
Patients were classified into three groups based on TRAb trajectories: smooth disappearance (n = 756, 61.2%), fluctuating (n = 241, 19.5%), and smoldering (n = 238, 19.3%) (Table 3). The median age of patients in the smoldering group was 48.8 years, which was significantly older than that in the other groups (P = 0.03 and P = 0.001, respectively). TAO was more frequent in the smoldering (18.5%) and fluctuating (17.0%) groups than in the smooth disappearance group (10.1%, P = 0.01 and P = 0.01, respectively). Patients in the fluctuating group were treated with ATD for a longer duration (37.4 months) than those in the smoldering (25.8 months) and smooth disappearance (19.5 months) groups (P < 0.001 and P < 0.001, respectively). The time required for the normalization of serum TRAb level was significantly longer in the fluctuating group (20.2 months) than that in the remission group (12.3 months, P < 0.001).
Clinical characteristics of patients with Graves’ hyperthyroidism according to trend of TRAb.
| Smooth disappearance | Fluctuating | Smoldering | P | |
|---|---|---|---|---|
| n (%) | 756 (61.2%) | 241 (19.5%) | 238 (19.3%) | |
| Age (years) | 46.0 (35.8–54.7) | 43.1 (31.9–53.5) | 48.8 (36.3–56.6) | 0.01bc |
| Sex, male | 238 (31.5%) | 80 (33.2%) | 67 (28.2%) | 0.47 |
| Smoking | 0.08 | |||
| Non-smoker | 721 (95.4%) | 222 (92.1%) | 229 (96.2%) | |
| Ex or current | 35 (4.6%) | 19 (7.9%) | 9 (3.8%) | |
| Goiterd | 0.93 | |||
| Grade 0 | 336 (44.4%) | 108 (44.8%) | 111 (47.1%) | |
| Grade 1 | 329 (43.5%) | 107 (44.4%) | 98 (41.2%) | |
| Grade 2 | 91 (12.0%) | 26 (10.8%) | 28 (11.8%) | |
| TAO | 0.01 ab | |||
| No | 679 (89.8%) | 200 (83.0%) | 194 (81.5%) | |
| Mild | 36 (4.8%) | 19 (7.9%) | 23 (9.7%) | |
| Moderate to severe | 41 (5.4%) | 22 (9.1%) | 21 (8.8%) | |
| Initial ATD | 0.06 | |||
| MMI | 438 (57.9%) | 117 (48.5%) | 133 (55.9%) | |
| CAM | 274 (36.2%) | 103 (42.7%) | 84 (35.3%) | |
| PTU | 44 (5.8%) | 21 (8.7%) | 21 (8.8%) | |
| Initial free T4 (ng/dL) | 2.6 (2.0–3.4) | 2.6 (1.8–3.7) | 2.5 (1.9–2.9) | 0.10 |
| Initial TRAb (IU/L) | 7.8 (4.1–15.1) | 8.9 (4.7–20.2) | 12.6 (6.9–25.5) | <0.001abc |
| TRAb at withdrawal (IU/L) | 0.8 (0.5–1.2) | 1.2 (0.8–1.6) | 3.1 (2.4–4.8) | <0.001abc |
| TSH normalization (months) | 5.1 (3.2–9.2) | 6.1 (3.2–16.1) | 5.8 (3.3–13.5) | 0.001abc |
| TRAb normalization (months)c | 12.3 (6.7–18.5) | 20.2 (10.4–38.7) | - | <0.001a |
| Duration of ATD (months) | 19.5 (16.1–27.3) | 37.4 (24.3–57.2) | 25.8 (17.9–44.8) | <0.001abc |
| MMDT (yes) | 638 (84.4%) | 196 (81.3%) | 190 (79.8%) | 0.20 |
| First recurrence | 274 (36.2%) | 127 (52.7%) | 147 (61.8%) | <0.001abc |
Continuous variables are presented as median (interquartile range) and categorical variables as numbers (percentages). Statistically significant values are shown in bold.
aP < 0.05 between the smooth disappearance and fluctuating groups; bP < 0.05 between the smooth disappearance and smoldering groups; cP < 0.05 between the fluctuating and smoldering groups; dWHO goiter classification system: grade 0, no goiter; grade 1, thyroid palpable but not visible; grade 2, thyroid visible with the neck in normal position.
ATD, antithyroid drug; CAM, carbimazole; MMDT, minimum maintenance dose therapy; MMI, methimazole; PTU, propylthiouracil; TAO, thyroid-associated ophthalmopathy; TRAb, thyrotropin receptor antibody; TSH, thyroid-stimulating hormone.
RFS after initial ATD treatment
We evaluated clinical factors associated with time to recurrence (RFS) in patients with Graves’ hyperthyroidism (Table 4). The cutoff value of age and fT4 were determined based on the median values of the total number of patients, and patients were then divided into subgroups according to cutoff values. In univariate analysis, younger age (<45 years), male sex, TAO, and smoking were significantly and inversely associated with RFS. The positive TRAb level at ATD discontinuation (HR = 1.91, 95% CI 1.60–2.27, P < 0.001) was also associated with short RFS after initial ATD therapy (Fig. 3A). Regarding the patterns of TRAb changes, fluctuating (HR = 1.75, 95% CI 1.42–2.17, P < 0.001) and smoldering types (HR = 2.26, 95% CI 1.85–2.76, P < 0.001) were also associated with low RFS compared with that of the smooth disappearance group (Fig. 3B). In multivariate analysis, younger age (<45 years) (HR = 1.31, 95% CI 1.11–1.56, P = 0.002), male sex (HR = 1.25, 95% CI 1.04–1.51, P = 0.02), and changing patterns of TRAb (fluctuating group: HR = 1.61, 95% CI 1.28–2.03, P < 0.001; smoldering group: HR = 1.93, 95% CI 1.33–2.80, P < 0.001) were independent risk factors associated with short RFS of Graves’ hyperthyroidism.
Kaplan‒Meier plot of the RFS of patients with Graves’ hyperthyroidism. (A) RFS according to TRAb at ATD withdrawal. (B) RFS according to the change of TRAb during ATD treatment. ATD, TAO, thyroid-associated ophthalmopathy; RFS, recurrence-free survival; TRAb, thyrotropin receptor antibody.
Citation: European Thyroid Journal 12, 2; 10.1530/ETJ-22-0226
Clinical factors associated with recurrence of Graves’ hyperthyroidism after antithyroid drug treatment.
| Reference | Univariate analysis | Multivariate analysis | |||
|---|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | ||
| Age < 45 years | ≥ 45 | 1.32 (1.11–1.56) | 0.001 | 1.31 (1.11–1.56) | 0.002 |
| Male sex | Female | 1.29 (1.08–1.54) | 0.004 | 1.25 (1.04–1.51) | 0.02 |
| TAO | No TAO | 1.27 (1.01–1.61) | 0.04 | 1.10 (0.87–1.39) | 0.43 |
| Goitera | Grade 0 | 1.18 (1.00–1.40) | 0.05 | – | – |
| Smoking | Never smoke | 1.61 (1.16–2.23) | 0.004 | 1.34 (0.95–1.90) | 0.09 |
| Initial free T4 | ≤2.5 ng/dL | 1.02 (0.86–1.21) | 0.80 | – | – |
| Initial TRAb (IU/L) | |||||
| <6 | – | – | – | – | |
| 6‒19.9 | 1.09 (0.90–1.32) | 0.37 | |||
| >19.9 | 1.11 (0.88–1.40) | 0.36 | |||
| Positive TRAb at ATD withdrawal | Negative | 1.91 (1.60–2.27) | <0.001 | 1.20 (0.86–1.67) | 0.28 |
| TRAb | |||||
| Smooth disappearance | - | - | - | - | |
| Fluctuating | 1.75 (1.42–2.17) | <0.001 | 1.61 (1.28–2.03) | <0.001 | |
| Smoldering | 2.26 (1.85–2.76) | <0.001 | 1.93 (1.33–2.80) | <0.001 | |
Statistically significant values are shown in bold.
aWHO goiter classification system: grade 0, no goiter; grade 1, thyroid palpable but not visible; grade 2, thyroid visible with the neck in normal position.
ATD, antithyroid drug; CI, confidence interval; HR, hazards ratio; TAO, thyroid-associated ophthalmopathy; TRAb, thyrotropin receptor antibody.
Discussion
In this large retrospective cohort study, we showed the clinical outcomes of 1829 patients newly diagnosed with Graves’ hyperthyroidism with sufficient follow-up data. After a median of 67 months of total follow-up, 18% of patients underwent RAI or surgery, 45% were in remission, and 30% were still on ATD therapy for recurrent disease and prolonged low-dose maintenance. In 1235 patients who discontinued ATD after a median of 23 months of treatment, 55.6% of patients experienced remission after the first ATD therapy. The remission rate for the second course of ATD treatment was similar (54.1%) to that of the first course of ATD. Along with age and sex, the change of TRAb helps predict the individual risk of recurrence, which can optimize the treatment duration.
Because the main mechanism of ATD is to inhibit thyroid hormone synthesis rather than modulate autoimmune pathogenesis, the remission rate is lower than that of the other ablative treatment modalities, such as thyroidectomy or RAI therapy (26). The remission rate following ATD treatment varies across several previous studies (4, 8, 27, 28, 29). The lowest remission rate was reported to be 20–30% (27), while inconsistency exists according to ethnic background and treatment protocols and was generally reported to be 50–60% (4, 8, 28). According to recent European studies that looked at the long-term treatment effects of ATD in large cohorts, remission was observed in 45.3–47.3% of patients with autoimmune thyrotoxicosis (29, 30). This study also presented comparable results. We found that the remission rate was 55.6% in patients who had a chance to withdraw ATD for the first time. The total cumulated remission rate was also identified as 45% during the median 67-month period of follow-up. Nevertheless, regarding the total efficacy of ATD, 48.5% of patients that discontinued ATD and 29.3% of those on ATD had prolonged low-dose maintenance benefits from ATD without suffering from adverse effects related to thyroidectomy or RAI therapy. Among 1718 patients who underwent ATD treatment as the initial therapy, 221 (12.9%) changed to RAI or surgery during a median of 67-month follow-up in this study. This is certainly lower than that reported in the study by Sjölin and colleagues after 6–10 years of follow-up (49.7%, 385 of 774 patients) (30).
The optimal duration of ATD therapy for patients with Graves’ hyperthyroidism was diverse. Although the current guidelines recommend a duration of 12–18 months, some suggest a longer period is better (10, 11, 12). A recent meta-analysis reported that the remission rate was 57% (95% CI 45–68%) in 587 patients treated with ATD for a mean duration of 41–98 months (11). In a prospective randomized clinical trial including 258 patients with Graves’ hyperthyroidism, the recurrence rates were 15% and 53% in those treated with ATD for 95 ± 22 months and 19 ± 23 months, respectively (10). However, the shorter treatment group had patients with younger age and larger goiter size than that of the longer treatment group in the study (10). A recent multicenter retrospective cohort study also suggested that the recurrence rate decreased gradually according to ATD treatment duration as 42.4% for 1 year and 19.1% for more than 6 years (12). The results of these studies suggested that long-term ATD treatment is effective and safe in patients with Graves’ hyperthyroidism (10, 11, 12). However, considering the diverse disease characteristics of each patient, it would not be appropriate to establish and recommend a uniform and longer treatment period. In our study, patients with smooth disappearance of TRAb had shorter treatment duration, and the recurrence rate was the lowest (36%). In contrast, patients with a fluctuating or smoldering type of TRAb had longer treatment periods and higher recurrence rates of 53% and 62%, respectively. Treating these patients for a longer period is reasonable because they are expected to have worse outcomes. If patients were adequately treated, the treatment duration might be tailored to individual clinical situations.
Definite treatment such as RAI therapy or surgery is usually recommended for patients with recurrent Graves’ hyperthyroidism who have previously been treated with ATD (31, 32). Sjölin and colleagues reported that the second remission rate was only 29.4% compared with 45.3% in the first treatment (30). However, some studies demonstrate that secondary ATD treatment is also useful for recurrent Graves’ hyperthyroidism (33, 34). The recent trend is to start ATD again as a secondary treatment option, which is also seen in the USA, where RAI is preferred. According to a nationwide population-based study in the USA, 65% of patients who had treatment failure after the first ATD treatment underwent the second ATD treatment (8). In our study, most patients (95%) with recurrent Graves’ hyperthyroidism after the first ATD therapy underwent the second ATD treatment, and there was no significant difference in the remission rate between the first and second ATD treatments. Therefore, ATD is a reasonable treatment option for the first and recurrent Graves’ hyperthyroidism, according to our real-world data.
The titer of TRAb before discontinuation of ATD is an easier method than that related to the trend of TRAb. However, even if the TRAb is negative, the prognosis will be different according to the trend of TRAb (fluctuating or smooth disappearance). The importance of smooth decreases of TRAb during ATD treatment was suggested in previous studies (18, 35), and this was validated in our study. Consequently, the trend of TRAb will have a greater predictive value than that of the last TRAb at the withdrawal of ATD. In addition, the baseline TRAb level was found to help predict recurrence by constructing Graves’ Recurrent Events After Therapy (GREAT) score along with age, goiter, and initial fT4 level (17). In the current study, male sex and change of TRAb were found to be important factors instead of goiter and initial fT4. The study of the GREAT score had the benefit of being a prospective multicenter trial and establishing a model that could easily predict prognosis prior to ATD treatment. On the other hand, our study has the strength of representing real-world results, including the dynamic change of TRAb.
This study has several limitations. First, there might be bias due to its retrospective design. The incidence of RAI therapy and surgery might have been overestimated due to the nature of the study conducted in the tertiary referral center. Furthermore, the TRAb pattern could be changed depending on the duration of treatment, and therapy duration was also modified dynamically according to the trend of TRAb in this study. Second, there could have been discrepancies in patients’ compliance, which could influence the change of TRAb. However, we tried to minimize this problem by double-checking that the number of prescribed ATDs matched the timing of the next visit. Third, we did not evaluate the adverse effect of ATDs because it was not well established in patients diagnosed with Graves' hyperthyroidism in the early stages of the study period. Despite these shortcomings, this study presented the real-world data of a relatively large sample size of patients with Graves’ hyperthyroidism who were adequately treated with ATD with sufficient follow-up data.
Therefore, most patients with Graves’ hyperthyroidism are adequately treated and benefit from ATD therapy. Along with the change in TRAb, young age and male sex were independent risk factors of RFS of Graves’ hyperthyroidism. Thus, it would be reasonable to define the individual risk of recurrence and determine the optimal treatment period in patients with Graves’ hyperthyroidism. Furthermore, ATD is a considerable option for the initial treatment of Graves’ hyperthyroidism as well as for recurrent disease.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/ETJ-22-0226.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding
This study was supported by a grant (2022IL0012) from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.
Data availability
Some datasets generated and/or analyzed during the present study are not publicly available but are available from the corresponding author upon reasonable request.
Author contribution statement
MJ, MJJ, and WGK performed data collection. MJ conducted the statistical analysis and drafted the manuscript. AJ, CAK, TYK, and WBK contributed to the acquisition and interpretation of data. MJJ, WGK, and YKS contributed to the conceptualization and editing of the manuscript. All authors have seen and approved the final version of the manuscript.
Acknowledgements
A part of this study was presented as a plenary lecture and poster at the 9th Seoul International Congress of Endocrinology and Metabolism in 2021.
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