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.
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%).
Correlation between thyroid-stimulating immunoglobulin and the presenting clinical activity score.
Citation: European Thyroid Journal 13, 4; 10.1530/ETJ-23-0129
Correlation between thyroid-stimulating immunoglobulin and the presenting marginal reflex distance 1.
Citation: European Thyroid Journal 13, 4; 10.1530/ETJ-23-0129
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).
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).
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
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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