2021 Asia-Pacific Graves’ Disease Consortium Survey of Clinical Practice Patterns in the Management of Graves’ Disease

Although Graves’ disease (GD) is common in endocrine practices worldwide, global differences in diagnosis and management remain. We sought to assess the current practices for GD in countries across Asia and the Pacific (APAC), and to compare these with previously published surveys from North America and Europe. A web-based survey on GD management was conducted on practicing clinicians. Responses from 542 clinicians were received and subsequently analysed and compared to outcomes from similar surveys from other regions. A total of 542 respondents participated in the survey, 515 (95%) of whom completed all sections. Of these, 86% were medical specialists, 11% surgeons, and 3% nuclear medicine physicians. In addition to serum thyroid-stimulating hormone (TSH) and free thyroxine assays, most respondents would request TSH-receptor autoantibody (TRAb) measurement (68%) during initial work-up. Thyroid ultrasound is requested by about half of respondents (53%), while the use of nuclear medicine scans is limited. The preferred first-line treatment is anti-thyroid drug (ATD) therapy (79%) with methimazole (MMI) or carbimazole (CBZ), followed by radioiodine (RAI; 19%) and surgery (2%). In case of surgery, one-third of respondents would opt for a subtotal rather than a total thyroidectomy. In case of mild Graves orbitopathy (GO), ATDs (67%) remains the preferred treatment, but a larger proportion of clinicians prefer surgery (20%). For a patient with intention to conceive, the preferred treatment pattern remained unchanged, although propylthiouracil (PTU) became the preferred ATD-agent during the first trimester. In comparison to European and American practices, marked differences were noted in the relatively infrequent usage of nuclear medicine scans and the overall higher use of a ATDs and β-blockers and adjunctive ATD-treatment during RAI in the APAC-group. Although regional differences regarding the diagnosis and management of GD are apparent in this first pan-Asia-Pacific survey, this study reveals the overall approach to the management of this disease in Asia-Pacific generally tends to fall between the trends appreciated in the American and European cohorts.


Introduction
Graves' disease (GD) is the most common cause of hyperthyroidism [1], and its treatment is highly heterogeneous worldwide. The use of anti-thyroid drugs (ATD), radioactive iodine (RAI) or surgery is guided by local practices, based on international guidelines. The presentation of GD is also non-uniform, both in terms of symptom severity and patient characteristics. Additionally, access to treatment modalities might be limited in some areas, leading to discrepancies in available options.
Two recent surveys on the management of GD demonstrated marked differences between Europe and the United States of America, depending on local interpretation and experience [2,3]. Previous publications from individual countries around Asia and the Pacific (APAC) assessing the treatment of GD [4][5][6][7][8] are not very recent, and did not consider any heterogeneity among countries. The objective of this study was to assess the current practices of GD management in countries across APAC, and to compare these with previously published international data [2,3] in order to establish regional differences.

Settings
The survey was endorsed by the Asian Graves' Disease Study Consortium and used the cloud-based platform Sur-veyMonkey ® . An email with a link (see Supplementary Appendix) was sent out to practicing clinicians throughout APAC, through their local specialty societies. The survey was opened to respondents from July 2020 to June 2021. Local ethics approval was attained for this study. Nonresponders were sent a reminder twice within 14-day intervals. The risk of duplicate responses was minimised by allowing only one response per email address. Data was accessible using an electronic password. Anonymity was maintained by grouping respondents to their practicing country. There were no respondents from China or Japan.

Questionnaire
The survey was modelled on previous surveys conducted by the American Thyroid Association (ATA) and the European Thyroid Association (ETA), with slight modifications, and reviewed and approved by the Asian Graves' Disease Study Consortium, consisting of endocrinologists, endocrine surgeons, and nuclear medicine physicians [2,3].
A scenario of a patient with moderate hyperthyroid symptoms for 2 months, a moderate goitre, and no signs of GD ophthalmopathy (GO) was presented (Supplementary Appendix). Questions were centred on diagnosis, therapy options and follow-up. Similarly, there were sections to evaluate aspects of two clinical variants. One with mild to moderate GO, and one with a patient anticipating pregnancy within the next 6-12 months. The questionnaire-language was English, except for Vietnam (where the survey was professionally translated without changing any of the content; Supplementary Appendix 2).

Statistical analysis
Data were compiled, and summary statistics were performed. In view of some partial completions, respondent percentage was calculated per question. A chi-square test was used when appropriate, to compare the results of the present survey with those of the American and European surveys. Data was analysed using Graphpad Prism V8 (GraphPad Software, California, USA).

Diagnostic evaluation of the index case
Serum TSH and free thyroxine (FT4) assays were the most requested tests for the index case, both in the current survey and in the American survey (73% versus 89% and 75% versus 89%, respectively), although this proportion was relatively lower in the APAC-cohort (both p < 0.05). Data on requesting these laboratory tests were not available from the European survey. Interestingly, TRAb would be ordered by almost two thirds of APAC-respondents (64%), slightly higher than the American survey (i.e. 58%), but significantly lower than the European survey (i.e. 85%; overall p < 0.05).
Ultrasound scan (US) would be requested by over half of APAC-respondents (53%), compared to only one-in-four (25%) of American respondents. Conversely, a much higher proportion of responders from the European survey (70%) would order an US (overall p < 0.05) (Fig. 2). Furthermore, only a minority of the APAC-cohort would order thyroid nuclear scans; specifically, 15% would request a Tc 99 -scan, 10% an I 131 -scan and only 0.4% an I 123 -scan. These numbers contrast with those from the other surveys, where almost one-third of respondents would request a thyroid nuclear scan, most commonly an I 131 -scan in America (31%), and a Tc 99 -scan in Europe (32%) (overall p < 0.05).

Treatment of uncomplicated GD (index case)
Preferred first treatment option Figure 3 depicts the differences in initial choice of therapy for uncomplicated GD across the three studies. Most APAC-respondents chose ATD (79%), like the European survey (84%), though much higher than the American survey (54%) (p < 0.05). RAI was the preferred treatment option for about one-in-five (19%) respondents in the APAC-survey, quite like the European survey (14%), while almost half of American respondents (45%) preferred RAI in this scenario (p < 0.05). For all three surveys, thyroid surgery would be the first option treatment for only a small proportion (APAC: 2% versus Europe: 2% versus America: 0.7%).

ATD-therapy and monitoring
Among respondents of the APAC-survey, methimazole (MMI) was the preferred ATD in 51% of respondents, carbimazole (CBZ) in 47%, and propylthiouracil (PTU) in 2%. In contrast, a larger proportion of the American (84%) and European (79%) respondents preferred MMI. After commencement of ATD-therapy, the initial evaluation of serum thyroid hormone levels would be performed after 4 or 6 weeks by 50% and 28% of respondents, respectively. Furthermore, after achieving a euthyroid state, these tests would be performed every 3 months by 53%, and every 2 months by 23% of respondents. Moreover, about half of respondents routinely monitored biochemical markers, such as complete blood count (45%) or liver function tests (54%), while the other half of respondents (47%) did not monitor these blood results in addition to thyroid hormone levels, when using ATD. If a patient developed a rash that failed to improve with antihistamine during the first 2 weeks on ATD, almost two thirds of respondents from the APACsurvey switched to another ATD (63%), similar to the rates from the American (55%) and European (75%) survey.
When asked about the duration of the course of ATDtherapy, if used to achieve a remission, about half of respondents (49%) indicated this trial period to be 18 months. While this 18-month duration of initial trial of treatment was also the most selected option in the European survey (with 50% of respondents preferring this option), only one-third (35%) of American respondents would continue ATD-therapy for 18 months. Use of beta-adrenergic blocking agents Beta-adrenergic blocking drugs (most frequently propranolol, 83%) were used by most of respondents (82%) of our survey, like the American (62%) and European (71%) surveys. The target heart rate was less than 100 beats per minute for almost all respondents (99%), like respondents from the American survey (90%), while this data was not reported for the European cohort.
Details on adjunctive ATD-treatment in patients receiving RAI-therapy For patients receiving RAI-treatment, pre-treatment with ATDs was used routinely by about three-quarters (73%) of respondents, compared to 38% of American and 61% of European respondents. Interestingly, selective use of ATD was reported by 12% of the respondents, a much lower proportion than for the American (50%) and the European (34%) (overall p < 0.05). More than one-third of respondents withdrew ATDs 7 days before RAI-administration (for CBZ/MMI: 39%; PTU: 38%) In the period directly post RAI-treatment, ATDs were routinely continued by 41% of respondents, showing a marked difference compared with the American (24%) and European groups (19%) (overall p < 0.05).

Details on patients offered thyroidectomy
When recommending thyroid surgery, two thirds (67%) would recommend total thyroidectomy, compared to 33% recommending subtotal thyroidectomy. Upon further assessing this choice of surgery-type based on country of origin, the majority of respondents from Australia (98%), Singapore (88%), Philippines (73%), and Vietnam (62%) preferred total thyroidectomy, while respondents from the other countries included seemed to prefer subtotal thyroidectomy. Overall, most reported indications for surgery were large goitre (84%) and failure of medical therapy (79%). Conversely, less than one-quarter of respondents (23%) considered high levels of TRAb at presentation as an indication for surgery. Almost all respondents (97%) would generally render patients euthyroid with ATDs prior to surgery, similar to the responses from the previous American (91%) and European (94%) surveys. Pre-operative iodine drops (either saturated solution of potassium iodide or Lugol's solution) were used by over half of respondents (60%), a pattern similar to the American (52%) and European (63%) surveys.
Upon comparing the answers on the questions concerning the surgical approach, there were no differences in answers between endocrinologists and non-endocrinologists regarding the extent of surgery, or the peri-operative actions taken (all p > 0.05). However, upon comparing the surgical and non-surgical respondents' answers for this section, the non-surgical respondents opted for performance of a total thyroidectomy in 55% of cases, conversely, among the surgical respondents, the vast majority (i.e. 93%) answered that their preferred surgical intervention was a total thyroidectomy (p < 0.05). However, there were no differences in the approaches among surgical and non-surgical respondents about rendering the patients euthyroid with antithyroid drugs prior to thyroidectomy (97% versus 98%), nor the routine prescription of prophylactic doses of calcium and/or vitamin D therapy (47% versus 41%) (both p > 0.05).

Management of hyperthyroidism with GO (variant 1)
Similar to the American and European surveys, the index case was modified to the patient presenting with GO. The majority (81%) of respondents would request an ophthalmologic opinion in this scenario, alike the response by the American (81%) and European (66%) groups. Orbital imaging studies were requested by a minority of respondents (magnetic resonance imaging [MRI]: 6%, computed tomography [CT]: 5%; and US: 1%). While also only a minority of respondents from the American and European surveys responded to request orbital imaging studies, the proportion requesting an MRI (American: 16% versus European 11%) or CT (American: 16% versus European 14%) seemed larger (overall p < 0.05).
The preferred treatment option for this patient showed a similar pattern among the APAC-respondents, ATDs (67%) followed by thyroidectomy (20%), as for the American (62% and 19%) and European (62% and 15%) groups, respectively. Should RAI be the first choice of treatment in this scenario, administration of prophylactic corticosteroids was instituted by the ophthalmologist (46%) and endocrinologists (48%) in APAC, while endocrinologists prescribed the corticosteroids in the America (61%) and Europe (83%) surveys.

Management of hyperthyroidism in a patient planning pregnancy (variant 2)
The index case was modified to a young patient planning pregnancy in the next 6-12 months. The commonest mode of therapy recommended was the prescription of ATDs for two thirds of respondents (67%), followed by surgery by a quarter of respondents (23%) and finally RAI by one-in-ten (10%). This contrasted with responses from the American (50% versus 30% versus 20%, respectively) and European (60% versus 10% versus 30%, respectively) groups (overall p < 0.05).
Upon assessing the preferred type of ATD in this scenario, PTU was the most common choice (55%), while either MMI and CBZ were the first choice for approximately one-in-five of respondents (22% and 23%, respectively). The majority (93%) would choose to switch to PTU if the patient would be euthyroid with a positive pregnancy test after already started MMI. Only 70% would switch back to MMI after the first trimester.

Discussion
The current survey presents the first dataset on the management of GD in the Asia-Pacific region. It included responses from a widely distributed representation of clinicians in the region. Building on the two landmark papers from North America and Europe [2,3], we sought to not only present the current patterns of clinical practice in GD management in APAC, but also to provide a comparison between the practices across three regions. Evaluating similarities and differences is important to educate clinicians on the standards of best care for patients with GD and associated complications.
When assessing the initial work-up of GD patients, the proportion of respondents requesting measurement of TRAb showed a similar pattern among the three surveys. The use of this assay in GD is of particular importance as it could be used as a tool to predict recurrence of disease and would thus allow counselling of patients for treatment [9,10]. This finding suggest that the American Thyroid Association Guidelines [11] were generally adopted widely among the different APAC countries. Conversely, the use of US for the initial work-up was much higher in APAC compared to America, following the European counterparts more closely. Another dissimilarity was seen in the usage of a nuclear medicine thyroid scan. While almost one-third of respondents from the American and European surveys would use this imaging modality, this was much lower among APAC (15%). This discrepancy could be due to the local costs and limited availability of certain isotopes, especially in the more rural parts of APAC.
Overall, the treatment option of choice for newly diagnosed, uncomplicated GD in APAC was ATD for over three-quarters of respondents. Although this was similar to European specialists (84%), this finding contrasts to the American cohort, where only slightly more than half would choose ATD, while the other half would prefer RAI. However, a more recent nationwide population-based study on treatment choice patterns for patients with GD in the USA, reported ATD to be the most commonly used treatment (58%), followed by RAI (35%) and then surgery (6%) [12]. These proportions are more in line with those from the European and the current APAC-survey, indicating that ATDs are now also the preferred first-line treatment for GD in the USA. Moreover, data had previously shown that RAI has not taken off as a preferred option of treatment for GD in APAC, potentially to its culturally perceived relationship to radiation [6].
Another finding perhaps underlining the difference of practicing healthcare in APAC compared with America and Europa, is the relatively low percentage of respondents who would perform monitoring tests on patients who had been started on ATD. This finding could be a surrogate for the greater difficulty some patients might have in terms of access to healthcare and certain investigations. Furthermore, APACrespondents were less likely to switch therapy at the first sign of possible ATD-related complications (e.g. rash) compared with American respondents. A recent systematic review concluded that the long-term use of ATDs in GD is safe, especially among those who are controlled on a low dose [13].
Performance of thyroid surgery would be the first treatment option for only a small proportion of the APAC-respondents for uncomplicated GD, like the American and European surveys. Moreover, it was noted that one-third of respondents from our survey would perform a subtotal rather than a total thyroidectomy. It has been stated by others [4] that the overall low inclination for surgery could be related to inevitable lifelong need for thyroxine replacement and monitoring, necessitating more follow-up visits and laboratory tests [14][15][16]. Perhaps the choice to perform less than a total thyroidectomy should be viewed in this light as well, as patients might not have ready access to a pharmacy and to thyroxine. Also, surgeons in low volume centres could prefer to do a subtotal thyroidectomy to avoid the complications of nerve injury and hypoparathyroidism. Furthermore, the overall preference of a subtotal over a total thyroidectomy, could also reflect certain non-surgical professionals being unaware of the exact surgical management, and the increased risks of recurrence and the need for repeat surgery after a subtotal thyroidectomy. Conversely, the similarities among rendering patients euthyroid prior to performance of surgery and the use of pre-operative iodine drops, were noted across the surveys from the three continents.
Despite an improved understanding of GD pathogenesis in general, the optimal treatment strategy for the subgroup of patients with GO is still not well established. The similarities for the pre-treatment evaluations between APAC and American respondents were noticeable. Overall, treatment with ATDs was the preferred choice across all three regions. However, the option of treating with RAI or surgery were more similar for the APAC and American groups, with the European group having a lowered preference for RAI and for surgery as treatment options. For this scenario, the discrepancies among the different cohorts of respondent could be based on the relative paucity of knowledge surrounding the management for patients presenting with GO.
Responses from the current survey showed that the APACapproach for a patient intending to conceive is more in line with the European respondents (i.e. ATD-therapy) than with the American Group (i.e. higher preference of the use of RAI), although this latter response could have changed similarly to the overall reduction in preference of RAI. The practices of switching the type of ATD for patients who are already on MMI to PTU during the first trimester of pregnancy, were noted across all three continents. However, respondents from the APAC-cohort were far more likely to switch back to MMI during the second trimester, as compared to both the American and European groups.
This study has several limitations. The distribution of responses was not equal among the participating countries, with several countries having a low number of respondents. Moreover, as the authors did not contact potential respondents directly, as all correspondence was conducted via local specialty societies, it in unknown how many surveys were sent out overall. The use of the English language could have limited contributions from countries in which this is not a preferred language. Differences in availability of resources within the region may exist and could restrict generalisability of the results. Additionally, several years have passed since publication of the American and European surveys (i.e. 2012 and 2016, respectively), and the publication of ATA-guidelines [11] and the ETA-guidelines [17] since then, could be causing some of the differences. Specifically, more recent developments surrounding TRAbassays, as possible adjuncts, were not included in the current or American and European surveys, and therefore no reliable declarations surrounding this could be made.
In conclusion, the present survey provides an overview of clinical practice patterns in the evaluation and management of GD in the APAC. Although regional differences regarding the diagnosis and management of this disease are appreciated, this study reveals the overall approach to the management of GD in APAC to fall between the trends appreciated in the American and European cohorts. Future studies should focus on the impact of available resources and the significance of socio-economic factors on the way GD, and associated complications, is managed in individual countries.