Epidemiology of thyroid-stimulating immunoglobulin in recent-onset symptomatic thyroid eye disease

in European Thyroid Journal
Authors:
Kenneth Ka Hei Lai Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong Special Administrative Region, China
Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China

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Fatema Mohamed Ali Abdulla Aljufairi Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
Department of Ophthalmology, Salmaniya Medical Complex, Government Hospitals, Bahrain

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Jake Uy Sebastian Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
Department of Ophthalmology, Vicente Sotto Memorial Medical Center, Cebu City, Philippines

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Yingying Wei Department of Statistics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China

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Ruofan Jia Department of Statistics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China

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Karen Kar Wun Chan Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong Special Administrative Region, China

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Elaine Yuen Ling Au Division of Clinical Immunology, Department of Pathology, Queen Mary Hospital, Hong Kong Special Administrative Region, China

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Alan Chun Hong Lee Division of Endocrinology and Metabolism, Department of Medicine, Queen Mary Hospital, Hong Kong Special Administrative Region, China

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Chiu Ming Ng Department of Medicine, Queen Elizabeth Hospital, Hong Kong Special Administrative Region, China

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Hunter Kwok Lai Yuen Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
Hong Kong Eye Hospital, Hong Kong Special Administrative Region, China

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Wilson Wai Kuen Yip Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong Special Administrative Region, China

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Alvin Lerrmann Young Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong Special Administrative Region, China

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George Pak Man Cheng Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China

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Clement Chee Yung Tham Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong Special Administrative Region, China
Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
Hong Kong Eye Hospital, Hong Kong Special Administrative Region, China

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Chi Pui Pang Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China

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Kelvin Kam Lung Chong Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong Special Administrative Region, China
Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
Hong Kong Eye Hospital, Hong Kong Special Administrative Region, China

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https://orcid.org/0000-0003-2587-1323

Correspondence should be addressed to K K L Chong: chongkamlung@cuhk.edu.hk or C P Pang: cppang@cuhk.edu.hk
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Purpose

This study aims to report correlations between thyroid-stimulating immunoglobulin (TSI) and both clinical and radiological parameters in recent-onset symptomatic thyroid eye disease (TED) patients.

Methods

A prospective cohort study of TED patients managed at the Chinese University of Hong Kong from January 2014 to May 2022. Serum TSI levels were determined with the functional assay. Outcomes included the Clinical Activity Score (CAS), marginal reflex distance1 (MRD1), extraocular muscle motility restriction (EOMy), exophthalmos, and diplopia. The radiological assessment included cross-sectional areas and signal of extraocular muscles on STIR-sequence MRI.

Results

A total of 255 (197 female) treatment-naive patients, with an average onset age of 50 ± 14 years (mean ± s.d.), were included. Elevated pre-treatment TSI level was observed in 223 (88%) patients. There was a weak positive correlation between TSI and CAS (r = 0.28, P = 0.000031), MRD1 (r = 0.17, P = 0.0080), and the size of the levator palpebrae superioris/superior rectus complex (r = 0.25, P = 0.018). No significant correlation existed between TSI and STIR signals. The AUC and optimal cut-off value for clinical active TED were 0.67 (95% CI: 0.60–0.75) and 284% (specificity: 50%, sensitivity: 85%). In total, 64 patients received intravenous methylprednisolone (IVMP) during the study interval, and they had a higher baseline TSI level than those who did not have IVMP (P = 0.000044). Serial post-IVMP TSI among the 62 patients showed a significant reduction compared to the baseline level (P < 0.001). Both the baseline and post-IVMP TSI levels, and percentages of TSI changes were comparable between patients who responded and did not respond to the first course of IVMP.

Conclusion

TSI can be a serum biomarker for the diagnosis, prognosis, and treatment response of TED. Further validation should be warranted.

Abstract

Purpose

This study aims to report correlations between thyroid-stimulating immunoglobulin (TSI) and both clinical and radiological parameters in recent-onset symptomatic thyroid eye disease (TED) patients.

Methods

A prospective cohort study of TED patients managed at the Chinese University of Hong Kong from January 2014 to May 2022. Serum TSI levels were determined with the functional assay. Outcomes included the Clinical Activity Score (CAS), marginal reflex distance1 (MRD1), extraocular muscle motility restriction (EOMy), exophthalmos, and diplopia. The radiological assessment included cross-sectional areas and signal of extraocular muscles on STIR-sequence MRI.

Results

A total of 255 (197 female) treatment-naive patients, with an average onset age of 50 ± 14 years (mean ± s.d.), were included. Elevated pre-treatment TSI level was observed in 223 (88%) patients. There was a weak positive correlation between TSI and CAS (r = 0.28, P = 0.000031), MRD1 (r = 0.17, P = 0.0080), and the size of the levator palpebrae superioris/superior rectus complex (r = 0.25, P = 0.018). No significant correlation existed between TSI and STIR signals. The AUC and optimal cut-off value for clinical active TED were 0.67 (95% CI: 0.60–0.75) and 284% (specificity: 50%, sensitivity: 85%). In total, 64 patients received intravenous methylprednisolone (IVMP) during the study interval, and they had a higher baseline TSI level than those who did not have IVMP (P = 0.000044). Serial post-IVMP TSI among the 62 patients showed a significant reduction compared to the baseline level (P < 0.001). Both the baseline and post-IVMP TSI levels, and percentages of TSI changes were comparable between patients who responded and did not respond to the first course of IVMP.

Conclusion

TSI can be a serum biomarker for the diagnosis, prognosis, and treatment response of TED. Further validation should be warranted.

Introduction

Thyroid eye disease (TED), also known as thyroid-associated orbitopathy or Graves’ ophthalmopathy, is the most common extrathyroidal manifestation of Graves’ disease. It can also occur in euthyroid patients, known as euthyroid Graves’ ophthalmopathy (EGO) (1, 2, 4). TED is an autoimmune inflammatory orbital disorder with a biphasic clinical course that begins with active inflammation followed by a chronic fibrotic phase (4). Prompt immunosuppressive treatment is recommended to suppress the inflammation during the inflammatory phase to reduce both the disease activity and severity (5, 6). The pathogenesis involves orbital inflammatory infiltration, adipogenesis, and hyaluronan production. A presumed mechanism is the activation of orbital fibroblasts by autoantibodies that results in tissue fibrosis (7).

Increased expression of thyroid-stimulating hormone (TSH) receptors has been found in the orbital tissue of TED patients, and TSH receptor antibodies (TRAbs) are recognized to have a pivotal role in the pathogenesis (8). According to their properties, TRAbs can be subdivided into thyroid-stimulating antibodies, thyroid-blocking antibodies, and neutral antibodies (9). The thyrotropin binding inhibitor immunoglobulin (TBII) assay is the conventional method, and it does not differentiate between the TRAbs subtypes (10). TBII level is closely related to Graves’ disease; however, the relationship with TED is inconsistent (11, 12, 13). Another assay is the functional thyroid-stimulating immunoglobulin (TSI) bioassay, which mainly detects the thyroid-stimulating antibody subtype. Despite TSI being more closely related to disease activity and severity than TBII, the clinical implications and correlations are not fully understood (14, 15, 16).

This study correlates the TSI levels with both clinical and radiological parameters and determines their clinical value in the management of TED.

Methods

We conducted a prospective cohort study including 255 TED patients managed at the Thyroid Eye Clinic at The Chinese University of Hong Kong from 1 January 2014 to 31 May 2022. Written informed consent was obtained from all the patients in this study. This study followed the Declaration of Helsinki, and ethical approval was obtained from the Institutional Review Board: Kowloon Central / Kowloon East Cluster Research Ethics Committees (10-0218/ER-3 and 2010_594). We included patients who met the following inclusion criteria: i) TED patients with pre-treatment TSI levels (17); ii) No concurrent orbital disorders; iii) Patient age ranges from 18 to 75 years; iv) The venous blood sample was collected for a functional TSI bioassay; v) Patients who were recruited for this study were followed up for at least 12 months.

Outcome measures

Clinical Activity Score (CAS) was used to assess the disease activity clinically (18). Gorman diplopia score was used to score diplopia: 1, no diplopia; 2, gaze-evoked diplopia; 3, intermittent primary-gaze diplopia; and 4, constant primary-gaze (intractable) diplopia (19). Extraocular motility (EOMy) restriction was scored according to the position of the limbus in nine cardinal gaze photos. We scored 0 for the full excursion and −5 for failure to reach the midline (−4 to −1 for an excursion in 25% increments) (20). Exophthalmos was measured by the Hertel exophthalmometer (21). Eyelid positions were documented using margin reflex distance (MRD): MRD1 was defined as the distance between the upper lid margin and the central corneal light reflex. Ophthalmic examinations were performed by two ophthalmologists at every visit.

MRI was performed on a whole-body 3T magnet (Achieva TX, Philips Healthcare, Best, the Netherlands) using a standard 8-channel head coil covering both eyes for signal reception. The scanning sequence for the orbit consisted of coronal contrast-enhanced STIR (TR/TE: 4800/80 ms; TI: 200 ms; NEX: 2; matrix 281 × 300) and coronal non-contrast T1-weighted (TR/TE: 641/13 ms; NEX: 1; matrix 239 × 300). All images were acquired using a slice thickness of 3 mm, a slice gap of 0.3 mm, and a field-of-view of 180 mm. Images were analyzed using a Philips DICOM Viewer (R3.0-SP13, Philips Medical Systems Nederland B.V.).

Two trained research assistants independently segmented the cross-sectional areas of both lacrimal glands and extraocular muscles on a T1-weighted image of the worse affected eye clinically. The average area from the three consecutive measurements was used for data analysis. The Short Tau Inversion Recovery (STIR) sequence signal, which provides a useful measure of TED activity radiologically, was measured by comparing the signal intensity of individual EOMy and lacrimal gland with the ipsilateral temporalis muscle of the clinically worst affected eye to give the signal intensity ratio (SIR) (22, 23). The highest SIR value among the three consecutive slices was used for data analysis.

Intravenous methylprednisolone (IVMP) was indicated in progressive moderate to severe TED with a CAS greater than three or radiological evidence of active disease. The 12-weekly IVMP regimen treatment protocol was prescribed for patients with active disease, clinically or radiologically: 6-weekly 500 mg IVMP succinate diluted in 500 mL normal saline for slow infusion over 2 h, followed by 6-week infusions of 250 mg IVMP succinate diluted in 250 mL normal saline for slow infusion over 1 h. Oral immunosuppressants (including methotrexate and mycophenolate mofetil) were optionally prescribed during the 12-weekly IVMP treatment for patients with moderate to severe disease. Patients were assessed every 4 weeks in those who received the IVMP course, and repeated TSI assessments were arranged within the 12 weeks post first course of IVMP. In patients with mild inactive disease, we would follow up every 6 months.

The venous blood sample was collected at the Thyroid Eye Clinic. TSI levels were measured using the TSI bioassay (Quest Diagnostic Hybrids, San Juan Capistrano, CA), according to the manufacturer’s instructions. The bioassay utilizes genetically engineered Chinese hamster ovary (CHO) cells expressing TSH receptors and a luciferase reporter gene induced by cAMP. If the TSH receptor is stimulated by TSI in patient serum, the TSH receptor signaling increases intracellular cAMP and induces luciferase enzyme activity, which is measured by the luminescence. Results were considered positive if the specimen-to-reference ratio was greater or equal to 140%.

The results were expressed as mean ± s.d. The baseline and post-treatment TSI levels were compared using a paired T-test. The diagnostic performance of TSI for clinically active TED was evaluated using the area under the curve (AUC) of the receiver-operating characteristic (ROC) curve, and the optimal clinical cut-off value was determined using the maximization of the Youden index. The correlation between TSI and both clinical and radiological parameters (worst affected eyes) was measured using Spearman's correlation. Multiple testing corrections using the Bonferroni algorithm were implemented to address the risk of type 1 errors. We set the significance threshold at 0.05. For example, if five comparisons are made, we would adjust the threshold level to 0.05/5 = 0.01. All statistical analyses were performed using SPSS statistical software package (Windows version 24.0; IBM Corp.).

Results

A total of 255 (197 female) treatment-naive TED patients were included in this study. All patients were ethnically Han Chinese, with an average TED onset of 50 ± 14 years old (range: 29–90 years old). The average follow-up was 32 ± 2 months. The average presenting CAS was 1.5 ± 1.4. Elevated pre-treatment TSI levels were observed in 223 (88%) patients, and the average baseline TSI level was 301 ± 131% among all patients. The background and initial clinical presentation information are summarized in Table 1.

Table 1

Demographic and background information of the thyroid eye disease patients. Data are presented as n, n (%) or mean ± s.d. Age refers to the age of TED onset; diplopia refers to the Gorman Diplopia Scale; duration refers to the duration from ocular symptom to consultation; proptosis refers to exophthalmometer reading of the most protruding eye.

Characteristics Values
n 255
Age (years) 50 ± 14
Female 195 (76%)
Ex/chronic smoker 43 (17%)
Duration (months) 6 ± 3
EGO 7 (3%)
Antithyroid treatment 248
Thyroidectomy 30
Radioactive iodine 21
Clinically active vs clinically inactive 53:202
TSI (%)*,# 301 ± 131
Free T4 (pmol/L)**,# 22 ± 29
Free T3 (pmol/L)***,# 7.6 ± 9.5
TSH(mIU/L)# 0.6 ± 0.8
CAS 1.5 ± 1.4
MRD1 (mm) 5.3 ± 1.7
EOMy 1.8 ± 1.0
Diplopia 0.7 ± 0.8
Exophthalmos (mm) 19 ± 3
Mild^ 88
Moderate to severe^ 157
DON 10 (4%)

*Reference range of TSH = 0.27 to 4.20 mIU/L; **Reference range of free T4 = 7.9–14.4 pmol/L; ***Reference range of free T3 = 3.8–6.0 pmol/L; Carbimazole/PTU/methimazole; #Tested in the first ophthalmic consultation (only 31% of the patients in euthyroid state on presentation); ^According to the EUGOGO criteria.

CAS, Clinical Activity Score; DON, dysthyroid optic neuropathy; EGO, euthyroid Graves’ ophthalmopathy; EOMy, extraocular motility restriction; GD, Graves’ disease; MRD1, Marginal reflex distance 1; TED, thyroid eye disease; TSI, thyroid-stimulating immunoglobulin; TSH, thyroid-stimulating hormone.

There were weak positive correlations between the baseline TSI level with the clinical parameters and there were weak positive correlations with CAS (r = 0.28, P = 0.000031), and MRD1 (r = 0.17, P = 0.0080) (Figs 1 and 2). For exophthalmos (r = 0.14, P = 0.023), there were no significant correlations with TSI after Bonferroni correction (Table 2). The area under the curve (AUC) and optimal cut-off value for clinically active TED were 0.67 (95% confidence interval: 0.60–0.75) and 284% (specificity: 50% and sensitivity: 85%).

Figure 1
Figure 1

Correlation between thyroid-stimulating immunoglobulin and the presenting clinical activity score.

Citation: European Thyroid Journal 13, 4; 10.1530/ETJ-23-0129

Figure 2
Figure 2

Correlation between thyroid-stimulating immunoglobulin and the presenting marginal reflex distance 1.

Citation: European Thyroid Journal 13, 4; 10.1530/ETJ-23-0129

Table 2

The correlations between clinical parameters and TSI in n = 255 patients/eye. Diplopia refers to the Gorman Diplopia Scale; proptosis refers to exophthalmometer reading of the most protruding eye.

Parameters Correlation with TSI (r) P
CAS 0.26 0.000031**
MRD1 0.17 0.0080**
EOMy 0.11 0.082
Diplopia 0.034 0.63
Proptosis 0.14 0.023

**Statistically significant with P < 0.01 after Bonferroni correction.

CAS, Clinical Activity Score; EOMy, extraocular motility restriction; MRD1, marginal reflex distance 1; TED, thyroid eye disease; TSI, thyroid-stimulating immunoglobulin; TSH, thyroid-stimulating hormone.

Correlation between baseline TSI level and size of the levator palpebral superioris /superior rectus complex was 0.25 (P = 0.018). No significant correlation between TSI and SIRs of other extraocular muscles was found (Table 3).

Table 3

The correlations between radiological parameters and TSI in n = 90 patients/eyes.

Radiological parameters Correlation with TSI (r) P
SR SIR 0.18 0.088
MR SIR 0.17 0.10
IR SIR 0.15 0.16
LR SIR 0.12 0.25
LG SIR −0.028 0.79
SR Size 0.25 0.018**
MR Size 0.036 0.74
IR Size 0.20 0.061
LR Size −0.084 0.43
LG Size 0.025 0.82

**Statistically significant with P < 0.01 after Bonferroni correction.

IR, inferior rectus;, LG, lacrimal gland; LPS, levator palpebrae superioris; LR, lateral rectus; MR, medial rectus; SIR, signal intensity ratio; SR, superior rectus.

In our cohort, 62 patients received 12-weekly intravenous methylprednisolone (IVMP), and 18 of them also received oral immunosuppressants (Table 4). The post-IVMP TSI levels assessed within 3 months after the first course of IVMP showed a significant reduction from 357 ± 97% to 239 ± 125% (P < 0.001). The baseline TSI level among the 62 TED patients who received IVMP was higher than those who did not receive IVMP (352 ±98 % versus 273 ± 137%, P = 0.000044). Both the baseline and post-treatment TSI levels (baseline: 325 ± 120% versus 359 ± 87%, P = 0.14, post-IVMP: 232 ± 141% versus 224 ± 120%, P = 0.42), and the percentage of TSI changes (−28 ± 34% vs −29 ± 58%, P = 0.48) were similar between the 14 patients who required additional IVMP and the 48 patients who did not require additional IVMP after the first course. Of the 193 patients who did not receive IVMP, only 12 had repeated TSI at 12 ± 10 months, and the percentage of TSI change was −28 ± 25%, which was similar to the 62 patients who received IVMP (−29 ± 30%, P = 0.49) (Fig. 3).

Figure 3
Figure 3

The change of thyroid stimulating immunoglobulin in patients who received/did not receive intravenous methylprednisolone.

Citation: European Thyroid Journal 13, 4; 10.1530/ETJ-23-0129

Table 4

Background information of the thyroid eye disease patients who did and did not receive intravenous methylprednisolone. Age refers to the age of TED onset; diplopia refers to the Gorman Diplopia Scale; duration refers to the duration from ocular symptom to consultation; proptosis refers to exophthalmometer reading of the most protruding eye.

IVMP Without IVMP
Patients, n 62 193
Age (years) 53 ± 12 44 ± 14
Female 41 154
Ex/chronic smoker 10 23
Duration (months) 5 ± 3 6 ± 3
EGO 2 5
CAS 1.9 ± 1.2 1.0 ± 1.2
MRD1 (mm) 5.6 ± 1.7 5.2 ± 1.6
EOMy 1.6 ± 1.3 1.3 ± 0.9
Gorman Diplopia Scale 1.3 ± 1.1 0.5 ± 0.7
Exophthalmos (mm) 19.6 ± 1.8 19.0 ± 1.6

CAS, clinical Activity Score; EGO, euthyroid Graves’ ophthalmopathy; EOMy, extraocular motility restriction; GD, Graves’ disease; MRD1, Marginal reflex distance 1; TED, thyroid eye disease.

Discussion

This cross-sectional follow-up study reports TSI levels in 255 treatment-naive TED patients. Up to 88% of patients presented with an elevated baseline TSI level. Our results show a significant positive correlation between baseline TSI and both disease activity (CAS) and severity (MRD1, exophthalmos, and size of the levator palpebrae superioris/superior rectus). However, the relationship is weak. In addition, patients who received IVMP had a higher TSI level than those who did not require IVMP. The optimal cut-off value for clinically active TED was 284%. There was a reduction in TSI following the course of IVMP. Importantly, there was no difference in both baseline and post-treatment TSI levels, and the percentage of TSI changes between those who responded and those who did not responded to the first course of IVMP.

The pathogenesis of TED involves orbital inflammatory infiltration, de novo adipogenesis, and glycosaminoglycan synthesis. Both TSH receptors and insulin growth factor-1 (IGF-1) receptors are overexpressed in the orbital tissue (24, 25). The activation of TSH receptors can enhance hyaluronic acid synthesis in orbital fibroblasts and promote adipogenesis (26, 27, 28). TSH receptor expression was found to be higher during the active phase of the disease (29). TRAb lebvels have been suggested as one of the key autoantigens in TED, as it was elevated in most TED patients, particularly those with EGO (30). An elevated TRAb level was found to be associated with TED after the diagnosis of Graves’ disease, and persistently high TRAb levels were associated with the severity of TED (31, 32).

Conventionally, serum TRAbs are detected using the TBII immunoassay which does not differentiate the TRAbs subtypes. The functional TSI bioassay can detect only the functional thyroid-stimulating antibody. Noh et al. reported in a study of Japanese patients that there was a correlation of TED severity with TSI, and not with TBII (33). In an earlier study on Korean patients, there were more active and severe TED patients with predominant TSI than patients with predominant TBII (16). Ponto had previously reported in European patients that the correlation was stronger between TED parameters and TSI than with TBII (34). On the contrary, Khamisi et al. did not show additional benefit of using TSI compared to the conventional TRAb assay in a Japanese study (35). A systematic review revealed that the discrepancies in the relationship between TBII and TSI could be due to ethnic differences. The relationship between TED and TBII seems to be stronger in Asian patients. Meanwhile, TSI was associated with both Asian and Caucasian TED patients (12).

STIR sequence suppresses the fat signal and becomes hyperintense with fluid-filled tissues. Hyperintensity on the STIR sequence gives an objective assessment of disease activity in TED patients (21). Mukasa et al. studied the TRAb level using the third-generation assay and found no correlation with the STIR signals on MRI, which is comparable to our study that the TSI level does not correlate with radiological activity. Also, in Japanese patients, an elevated TSI level was associated with proptosis but not extraocular muscle involvement (36). Ko et al. recently reported that TSI was significantly correlated with the NOSPECS score in a cohort of Korean patients (37). Jeon et al. reported a cross-sectional study that included 101 patients with TED and found the TSI level was higher among male patients and smokers, and the TSI level was inversely correlated with the duration of ocular symptoms (38). Ponto et al. reported that TSI level can help to identify patients with DON of recent onset requiring urgent treatment (39). East Asian TED patients are associated with a lower presenting CAS and less common eyelid involvement when compared to Caucasian patients (40). The predictive value of disease activity using CAS is unclear in the Asian population. This may explain why the positive correlations between CAS and TSI were relatively weak in our study.

Serial measurements of TSI may help to evaluate the disease prognosis. There are some notable studies on Korean patients. Ko et al. reported that the TSI level decreased at 1-year follow-up regardless of the treatment received (37). Lee et al. reported that both TRAb and TSI levels dropped after receiving IVMP among 57 TED patients, and both antibodies correlated with the restoration of chorioretinal capillary perfusion (41). Another recent Korean study reported a diminished decline of both TRAb and TSI levels in TED patients who are non-responsive to IVMP (42). On the contrary, our study did not show any difference in either the baseline or post-IVMP TSI levels between IVMP responders and non-responders, which is comparable to the study reported by Bluszcz et al. that found no difference in either TRAbs and TSI baseline levels between IVMP responders and non-responders in Polish patients (43). The predictive value of TSI in the treatment response of TED patients is unclear, and the discrepancies in results among different groups may be due to the undersized studies. The clinical implications of TED should be further explored with a larger sample size and in different ethnic groups.

Our data may serve as a reference for correlations between TSI and clinical and radiological parameters in ethnic Han Chinese TED patients. There are several limitations in the present study. First, long-term changes in TSI levels in the TED patients are still to be assessed. Secondly, TSI was ordered in 255 patients among our TED cohort of 1500 patients, and further study with a bigger sample size would be warranted to increase the power of the result. Thirdly, our study used the average STIR of both the extraocular muscles and lacrimal gland; hotpot was not applied. Fourthly, the correlation between disease parameters and other serological markers such as TBII was not reported.

In summary, up to 88% of patients exhibited elevated pre-treatment levels of TSI. There was a weak positive correlation between TSI and both disease activity and severity. Our data suggest that TSI may serve as a useful biomarker for diagnosis, monitoring treatment response, and guiding the management of TED. Further research is needed to validate these findings.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.

Funding

The work in this paper was supported in part by a research grant from the General Research Fund, Research Grants Council, Hong Kong (14103221 to C.PP)

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  • 14

    Lantz M, Planck T, Asman P, & Hallengren B. Increased TRAb and/or low anti-TPO titers at diagnosis of Graves’ disease are associated with an increased risk of developing ophthalmopathy after onset. Experimental and Clinical Endocrinology and Diabetes 2014 122 113117. (https://doi.org/10.1055/s-0033-1363193)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Jang SY, Shin DY, Lee EJ, Lee SY, & Yoon JS. Relevance of TSH-receptor antibody levels in predicting disease course in Graves’ orbitopathy: comparison of the third-generation TBII assay and Mc4-TSI bioassay. Eye 2013 27 964971. (https://doi.org/10.1038/eye.2013.120)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Jang SY, Shin DY, Lee EJ, & Yoon JS. Clinical characteristics of Graves’ orbitopathy in patients showing discrepancy between levels from TBII assays and TSI bioassay. Clinical Endocrinology 2014 80 591597. (https://doi.org/10.1111/cen.12318)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Bartalena L, Kahaly GJ, Baldeschi L, Dayan CM, Eckstein A, Marcocci C, Marinò M, Vaidya B, Wiersinga WM & EUGOGO . The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathy. European Journal of Endocrinology 2021 185 G43G67. (https://doi.org/10.1530/EJE-21-0479)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Mourits MP, Prummel MF, Wiersinga WM, & Koornneef L. Clinical activity score as a guide in the management of patients with Graves’ ophthalmopathy. Clinical Endocrinology 1997 47 914. (https://doi.org/10.1046/j.1365-2265.1997.2331047.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Gorman CA. The measurement of change in Graves’ ophthalmopathy. Thyroid 1998 8 539543. (https://doi.org/10.1089/thy.1998.8.539)

  • 20

    Chong K, Lee D, & Khadavi. Comparing the clinical characteristics of muscle predominant versus fat predominant manifestation in thyroid eye Disease (TED). (Conference presentation abstract). 2nd International Orbital Society Symposium, New York, United State.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Lai KKH, Aljufairi FMAA, Yuen HKL, & Chong KKL. Paediatric-onset versus adult-onset thyroid eye disease: difference in clinical presentations. Clinical and Experiment Ophthalmology 2024 52 115117. (https://doi.org/10.1111/ceo.14303)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Hoh HB, Laitt RD, Wakeley C, Kabala J, Goddard P, Potts MJ, & Harrad RA. The STIR sequence MRI in the assessment of extraocular muscles in thyroid eye disease. Eye 1994 8 506510. (https://doi.org/10.1038/eye.1994.126)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Lai KKH, Wang Y, Pang CP, & Chong KKL. Sirolimus versus mycophenolate mofetil for triple immunosuppression in thyroid eye disease patients with recent-onset intractable diplopia: a prospective comparative case series. Clinical and Experimental Ophthalmology 2023 51 878881. (https://doi.org/10.1111/ceo.14290)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Hai YP, Lee ACH, Frommer L, Diana T, & Kahaly GJ. Immunohistochemical analysis of human orbital tissue in Graves’ orbitopathy. Journal of Endocrinological Investigation 2020 43 123137. (https://doi.org/10.1007/s40618-019-01116-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Girnita L, Smith TJ, & Janssen JAMJL. It takes two to tango: IGF-I and TSH receptors in thyroid eye disease. Journal of Clinical Endocrinology and Metabolism 2022 107(Supplement 1):S1S12. (https://doi.org/10.1210/clinem/dgac045)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Kumar S, Iyer S, Bauer H, Coenen M, & Bahn RS. A stimulatory thyrotropin receptor antibody enhances hyaluronic acid synthesis in Graves’ orbital fibroblasts: inhibition by an IGF-I receptor blocking antibody. Journal of Clinical Endocrinology and Metabolism 2012 97 16811687. (https://doi.org/10.1210/jc.2011-2890)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Zhang L, Bowen T, Grennan-Jones F, Paddon C, Giles P, Webber J, Steadman R, & Ludgate M. Thyrotropin receptor activation increases hyaluronan production in preadipocyte fibroblasts: contributory role in hyaluronan accumulation in thyroid dysfunction. Journal of Biological Chemistry 2009 284 2644726455. (https://doi.org/10.1074/jbc.M109.003616)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Tsui S, Naik V, Hoa N, Hwang CJ, Afifiyan NF, Sinha Hikim A, Gianoukakis AG, Douglas RS, & Smith TJ. Evidence for an association between thyroid-stimulating hormone and insulin-like growth factor 1 receptors: a tale of two antigens implicated in Graves’ disease. Journal of Immunology 2008 181 43974405. (https://doi.org/10.4049/jimmunol.181.6.4397)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Wakelkamp IM, Bakker O, Baldeschi L, Wiersinga WM, & Prummel MF. TSH-R expression and cytokine profile in orbital tissue of active vs. inactive Graves’ ophthalmopathy patients. Clinical Endocrinology 2003 58 280287. (https://doi.org/10.1046/j.1365-2265.2003.01708.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Tabasum A, Khan I, Taylor P, Das G, & Okosieme OE. Thyroid antibody-negative euthyroid Graves’ ophthalmopathy. Endocrinology, Diabetes and Metabolism Case Reports 2016 2016 160008. (https://doi.org/10.1530/EDM-16-0008)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Lantz M, Planck T, Asman P, & Hallengren B. Increased TRAb and/or low anti-TPO titers at diagnosis of Graves’ disease are associated with an increased risk of developing ophthalmopathy after onset. Experimental and Clinical Endocrinology and Diabetes 2014 122 113117. (https://doi.org/10.1055/s-0033-1363193)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Eckstein A, Esser J, Mann K, & Schott M. Clinical value of TSH receptor antibodies measurement in patients with Graves’ orbitopathy. Pediatric Endocrinology Reviews 2010 7(Supplement 2) 198203.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Noh JY, Hamada N, Inoue Y, Abe Y, Ito K, & Ito K. Thyroid-stimulating antibody is related to Graves’ ophthalmopathy, but thyrotropin-binding inhibitor immunoglobulin is related to hyperthyroidism in patients with Graves’ disease. Thyroid 2000 10 809813. (https://doi.org/10.1089/thy.2000.10.809)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Ponto KA, Kanitz M, Olivo PD, Pitz S, Pfeiffer N, & Kahaly GJ. Clinical relevance of thyroid-stimulating immunoglobulins in graves’ ophthalmopathy. Ophthalmology 2011 118 22792285. (https://doi.org/10.1016/j.ophtha.2011.03.030)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Khamisi S, Lundqvist M, Engström BE, Larsson A, Karlsson FA, & Ljunggren Ö. Comparison between thyroid stimulating immunoglobulin and TSH-receptor antibodies in the management of Graves’ orbitopathy. Experimental and Clinical Endocrinology and Diabetes 2023 131 236241. (https://doi.org/10.1055/a-2021-0596)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Ohtsuka K, & Hashimoto M. Serum levels of soluble Fas in patients with Graves’ ophthalmopathy. British Journal of Ophthalmology 2000 84 103106. (https://doi.org/10.1136/bjo.84.1.103)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Ko J, Kook KH, Yoon JS, Woo KI, Yang JW & Korean Society of Ophthalmic Plastic & Reconstructive Surgery. Longitudinal association of thyroid-stimulating immunoglobulin levels with clinical characteristics in thyroid eye disease. BMJ Open 2022 12 e050337. (https://doi.org/10.1136/bmjopen-2021-050337)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Jeon H, Lee JY, Kim YJ, & Lee MJ. Clinical relevance of thyroid-stimulating immunoglobulin as a biomarker of the activity of thyroid eye disease. Eye 2023 37 543547. (https://doi.org/10.1038/s41433-022-01981-z)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Ponto KA, Diana T, Binder H, Matheis N, Pitz S, Pfeiffer N, & Kahaly GJ. Thyroid-stimulating immunoglobulins indicate the onset of dysthyroid optic neuropathy. Journal of Endocrinological Investigation 2015 38 769777. (https://doi.org/10.1007/s40618-015-0254-2)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Lim NCS, Sundar G, Amrith S, & Lee KO. Thyroid eye disease: a Southeast Asian experience. British Journal of Ophthalmology 2015 99 512518. (https://doi.org/10.1136/bjophthalmol-2014-305649)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Lee J, & Lee DC. Changes in clinical activity, serum autoantibody levels, and chorioretinal vessels after systemic glucocorticoid therapy in thyroid eye disease. Ophthalmology and Therapy 2023 12 18511863. (https://doi.org/10.1007/s40123-023-00696-y)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Park J, Kim J, Kim SS, & Choi HY. Prognostic significance of thyroid-stimulating hormone receptor antibodies in moderate-to-severe graves’ orbitopathy. Frontiers in Endocrinology 2023 14 1153312. (https://doi.org/10.3389/fendo.2023.1153312)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Bluszcz GA, Bednarczuk T, Bartoszewicz Z, Kondracka A, Walczak K, Żurecka Z, Demkow U, & Miśkiewicz P. Clinical utility of TSH receptor antibody levels in Graves' orbitopathy: a comparison of two TSH receptor antibody immunoassays. Central-European Journal of Immunology 2018 43 405412. (https://doi.org/10.5114/ceji.2018.80224)

    • PubMed
    • Search Google Scholar
    • Export Citation

 

  • Collapse
  • Expand
  • Figure 1

    Correlation between thyroid-stimulating immunoglobulin and the presenting clinical activity score.

  • Figure 2

    Correlation between thyroid-stimulating immunoglobulin and the presenting marginal reflex distance 1.

  • Figure 3

    The change of thyroid stimulating immunoglobulin in patients who received/did not receive intravenous methylprednisolone.

  • 1

    Bartalena L, & Fatourechi V. Extrathyroidal manifestations of Graves’ disease: a 2014 update. Journal of Endocrinological Investigation 2014 37 691700. (https://doi.org/10.1007/s40618-014-0097-2)

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  • 2

    Bahn RS. Graves’ ophthalmopathy. New England Journal of Medicine 2010 362 726738. (https://doi.org/10.1056/NEJMra0905750)

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    Lai KKH, Liao X, Aljufairi FMAA, Sebastian JU, Ma A, Man Wong Y, Lam Lee C, Chen W, Hu Z, Cheng GPMet al. Ocular surface and meibomian gland evaluation in euthyroid Graves’ ophthalmopathy. International Ophthalmology 2024 44 124. (https://doi.org/10.1007/s10792-024-02919-y)

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    Rundle FF, & Wilson CW. Development and course of exophthalmos and ophthalmoplegia in Graves’ disease with special reference to the effect of thyroidectomy. Clinical Science 1945 5 177194.

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    Wiersinga WM. Advances in medical therapy of thyroid-associated ophthalmopathy. Orbit 1996 15 177186. (https://doi.org/10.3109/01676839609150235)

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    Khong JJ, McNab AA, Ebeling PR, Craig JE, & Selva D. Pathogenesis of thyroid eye disease: review and update on molecular mechanisms. British Journal of Ophthalmology 2016 100 142150. (https://doi.org/10.1136/bjophthalmol-2015-307399)

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  • 8

    Lee ACH, & Kahaly GJ. Pathophysiology of thyroid-associated orbitopathy. Best Practice and Research 2023 37 101620. (https://doi.org/10.1016/j.beem.2022.101620)

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    Barbesino G, & Tomer Y. Clinical review: clinical utility of TSH receptor antibodies. Journal of Clinical Endocrinology and Metabolism 2013 98 22472255. (https://doi.org/10.1210/jc.2012-4309)

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  • 10

    Kahaly GJ, & Diana T. TSH receptor antibody functionality and nomenclature. Frontiers in Endocrinology 2017 8 28. (https://doi.org/10.3389/fendo.2017.00028)

  • 11

    Ajjan RA, & Weetman AP. Techniques to quantify TSH receptor antibodies. Nature Reviews Endocrinology 2008 4 46.

  • 12

    Seo S, & Sánchez Robledo M. Usefulness of TSH receptor antibodies as biomarkers for Graves’ ophthalmopathy: a systematic review. Journal of Endocrinological Investigation 2018 41 14571468. (https://doi.org/10.1007/s40618-018-0945-6)

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  • 13

    Eckstein AK, Plicht M, Lax H, Neuhäuser M, Mann K, Lederbogen S, Heckmann C, Esser J, & Morgenthaler NG. Thyrotropin receptor autoantibodies are independent risk factors for Graves’ ophthalmopathy and help to predict severity and outcome of the disease. Journal of Clinical Endocrinology and Metabolism 2006 91 34643470. (https://doi.org/10.1210/jc.2005-2813)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14

    Lantz M, Planck T, Asman P, & Hallengren B. Increased TRAb and/or low anti-TPO titers at diagnosis of Graves’ disease are associated with an increased risk of developing ophthalmopathy after onset. Experimental and Clinical Endocrinology and Diabetes 2014 122 113117. (https://doi.org/10.1055/s-0033-1363193)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Jang SY, Shin DY, Lee EJ, Lee SY, & Yoon JS. Relevance of TSH-receptor antibody levels in predicting disease course in Graves’ orbitopathy: comparison of the third-generation TBII assay and Mc4-TSI bioassay. Eye 2013 27 964971. (https://doi.org/10.1038/eye.2013.120)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16

    Jang SY, Shin DY, Lee EJ, & Yoon JS. Clinical characteristics of Graves’ orbitopathy in patients showing discrepancy between levels from TBII assays and TSI bioassay. Clinical Endocrinology 2014 80 591597. (https://doi.org/10.1111/cen.12318)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Bartalena L, Kahaly GJ, Baldeschi L, Dayan CM, Eckstein A, Marcocci C, Marinò M, Vaidya B, Wiersinga WM & EUGOGO . The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathy. European Journal of Endocrinology 2021 185 G43G67. (https://doi.org/10.1530/EJE-21-0479)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Mourits MP, Prummel MF, Wiersinga WM, & Koornneef L. Clinical activity score as a guide in the management of patients with Graves’ ophthalmopathy. Clinical Endocrinology 1997 47 914. (https://doi.org/10.1046/j.1365-2265.1997.2331047.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19

    Gorman CA. The measurement of change in Graves’ ophthalmopathy. Thyroid 1998 8 539543. (https://doi.org/10.1089/thy.1998.8.539)

  • 20

    Chong K, Lee D, & Khadavi. Comparing the clinical characteristics of muscle predominant versus fat predominant manifestation in thyroid eye Disease (TED). (Conference presentation abstract). 2nd International Orbital Society Symposium, New York, United State.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21

    Lai KKH, Aljufairi FMAA, Yuen HKL, & Chong KKL. Paediatric-onset versus adult-onset thyroid eye disease: difference in clinical presentations. Clinical and Experiment Ophthalmology 2024 52 115117. (https://doi.org/10.1111/ceo.14303)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Hoh HB, Laitt RD, Wakeley C, Kabala J, Goddard P, Potts MJ, & Harrad RA. The STIR sequence MRI in the assessment of extraocular muscles in thyroid eye disease. Eye 1994 8 506510. (https://doi.org/10.1038/eye.1994.126)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Lai KKH, Wang Y, Pang CP, & Chong KKL. Sirolimus versus mycophenolate mofetil for triple immunosuppression in thyroid eye disease patients with recent-onset intractable diplopia: a prospective comparative case series. Clinical and Experimental Ophthalmology 2023 51 878881. (https://doi.org/10.1111/ceo.14290)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24

    Hai YP, Lee ACH, Frommer L, Diana T, & Kahaly GJ. Immunohistochemical analysis of human orbital tissue in Graves’ orbitopathy. Journal of Endocrinological Investigation 2020 43 123137. (https://doi.org/10.1007/s40618-019-01116-4)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25

    Girnita L, Smith TJ, & Janssen JAMJL. It takes two to tango: IGF-I and TSH receptors in thyroid eye disease. Journal of Clinical Endocrinology and Metabolism 2022 107(Supplement 1):S1S12. (https://doi.org/10.1210/clinem/dgac045)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26

    Kumar S, Iyer S, Bauer H, Coenen M, & Bahn RS. A stimulatory thyrotropin receptor antibody enhances hyaluronic acid synthesis in Graves’ orbital fibroblasts: inhibition by an IGF-I receptor blocking antibody. Journal of Clinical Endocrinology and Metabolism 2012 97 16811687. (https://doi.org/10.1210/jc.2011-2890)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27

    Zhang L, Bowen T, Grennan-Jones F, Paddon C, Giles P, Webber J, Steadman R, & Ludgate M. Thyrotropin receptor activation increases hyaluronan production in preadipocyte fibroblasts: contributory role in hyaluronan accumulation in thyroid dysfunction. Journal of Biological Chemistry 2009 284 2644726455. (https://doi.org/10.1074/jbc.M109.003616)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28

    Tsui S, Naik V, Hoa N, Hwang CJ, Afifiyan NF, Sinha Hikim A, Gianoukakis AG, Douglas RS, & Smith TJ. Evidence for an association between thyroid-stimulating hormone and insulin-like growth factor 1 receptors: a tale of two antigens implicated in Graves’ disease. Journal of Immunology 2008 181 43974405. (https://doi.org/10.4049/jimmunol.181.6.4397)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29

    Wakelkamp IM, Bakker O, Baldeschi L, Wiersinga WM, & Prummel MF. TSH-R expression and cytokine profile in orbital tissue of active vs. inactive Graves’ ophthalmopathy patients. Clinical Endocrinology 2003 58 280287. (https://doi.org/10.1046/j.1365-2265.2003.01708.x)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30

    Tabasum A, Khan I, Taylor P, Das G, & Okosieme OE. Thyroid antibody-negative euthyroid Graves’ ophthalmopathy. Endocrinology, Diabetes and Metabolism Case Reports 2016 2016 160008. (https://doi.org/10.1530/EDM-16-0008)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31

    Lantz M, Planck T, Asman P, & Hallengren B. Increased TRAb and/or low anti-TPO titers at diagnosis of Graves’ disease are associated with an increased risk of developing ophthalmopathy after onset. Experimental and Clinical Endocrinology and Diabetes 2014 122 113117. (https://doi.org/10.1055/s-0033-1363193)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32

    Eckstein A, Esser J, Mann K, & Schott M. Clinical value of TSH receptor antibodies measurement in patients with Graves’ orbitopathy. Pediatric Endocrinology Reviews 2010 7(Supplement 2) 198203.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33

    Noh JY, Hamada N, Inoue Y, Abe Y, Ito K, & Ito K. Thyroid-stimulating antibody is related to Graves’ ophthalmopathy, but thyrotropin-binding inhibitor immunoglobulin is related to hyperthyroidism in patients with Graves’ disease. Thyroid 2000 10 809813. (https://doi.org/10.1089/thy.2000.10.809)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34

    Ponto KA, Kanitz M, Olivo PD, Pitz S, Pfeiffer N, & Kahaly GJ. Clinical relevance of thyroid-stimulating immunoglobulins in graves’ ophthalmopathy. Ophthalmology 2011 118 22792285. (https://doi.org/10.1016/j.ophtha.2011.03.030)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35

    Khamisi S, Lundqvist M, Engström BE, Larsson A, Karlsson FA, & Ljunggren Ö. Comparison between thyroid stimulating immunoglobulin and TSH-receptor antibodies in the management of Graves’ orbitopathy. Experimental and Clinical Endocrinology and Diabetes 2023 131 236241. (https://doi.org/10.1055/a-2021-0596)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36

    Ohtsuka K, & Hashimoto M. Serum levels of soluble Fas in patients with Graves’ ophthalmopathy. British Journal of Ophthalmology 2000 84 103106. (https://doi.org/10.1136/bjo.84.1.103)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37

    Ko J, Kook KH, Yoon JS, Woo KI, Yang JW & Korean Society of Ophthalmic Plastic & Reconstructive Surgery. Longitudinal association of thyroid-stimulating immunoglobulin levels with clinical characteristics in thyroid eye disease. BMJ Open 2022 12 e050337. (https://doi.org/10.1136/bmjopen-2021-050337)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38

    Jeon H, Lee JY, Kim YJ, & Lee MJ. Clinical relevance of thyroid-stimulating immunoglobulin as a biomarker of the activity of thyroid eye disease. Eye 2023 37 543547. (https://doi.org/10.1038/s41433-022-01981-z)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39

    Ponto KA, Diana T, Binder H, Matheis N, Pitz S, Pfeiffer N, & Kahaly GJ. Thyroid-stimulating immunoglobulins indicate the onset of dysthyroid optic neuropathy. Journal of Endocrinological Investigation 2015 38 769777. (https://doi.org/10.1007/s40618-015-0254-2)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40

    Lim NCS, Sundar G, Amrith S, & Lee KO. Thyroid eye disease: a Southeast Asian experience. British Journal of Ophthalmology 2015 99 512518. (https://doi.org/10.1136/bjophthalmol-2014-305649)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41

    Lee J, & Lee DC. Changes in clinical activity, serum autoantibody levels, and chorioretinal vessels after systemic glucocorticoid therapy in thyroid eye disease. Ophthalmology and Therapy 2023 12 18511863. (https://doi.org/10.1007/s40123-023-00696-y)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42

    Park J, Kim J, Kim SS, & Choi HY. Prognostic significance of thyroid-stimulating hormone receptor antibodies in moderate-to-severe graves’ orbitopathy. Frontiers in Endocrinology 2023 14 1153312. (https://doi.org/10.3389/fendo.2023.1153312)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43

    Bluszcz GA, Bednarczuk T, Bartoszewicz Z, Kondracka A, Walczak K, Żurecka Z, Demkow U, & Miśkiewicz P. Clinical utility of TSH receptor antibody levels in Graves' orbitopathy: a comparison of two TSH receptor antibody immunoassays. Central-European Journal of Immunology 2018 43 405412. (https://doi.org/10.5114/ceji.2018.80224)

    • PubMed
    • Search Google Scholar
    • Export Citation