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Prognostic factors for thyroid-stimulating immunoglobulin normalization in moderate-to-severe Graves’ orbitopathy: a 36-month longitudinal study

BMC Ophthalmology volume 24, Article number: 361 (2024) Cite this article

Abstract

Purpose

The primary objective of this study was to identify predictive factors linked to the normalization of thyroid-stimulating immunoglobulin (TSI) levels in patients diagnosed with active, moderate-to-severe Graves’ orbitopathy (GO). The study also tracked the longitudinal changes in TSI levels over a 36-month period following treatment.

Methods

The study population consisted of individuals who were recently diagnosed with active, moderate-to-severe GO and received a 12-week course of intravenous methylprednisolone (IVMP) treatment. A subgroup of patients who did not respond to the initial treatment received an additional 20 Gy of radiation therapy (RTx). TSI levels were monitored at the time of diagnosis, after treatment, and subsequently every 6 months for 36 months. Normalization was defined as a TSI level below 140%. Patients were divdied into two groups with success and failure group depending on whether TSI became normal or not.

Results

Out of 83 patients, 36 (43.4%) achieved normalized TSI levels within two years post-IVMP treatment. Lower initial TSI levels (< 425%), absence of additional RTx, and early treatment initiation were associated with a higher likelihood of TSI normalization (P = 0.035, P = 0.028, P < 0.001, respectively). Notably, significant differences in TSI level reduction were observed from 18 months post-treatment between the two groups (P = 0.031). A TSI cutoff value of 413% was identified as predictive for normalization at 24 months (P = 0.002).

Conclusion

This study is the first to identify key factors that influence normalization of TSI levels in moderate-to-severe Graves’ Orbitopathy. It highlights the importance of early treatment decisions, particularly for patients with initial TSI levels above 425%. Despite the treatment, less than half of the patients achieved TSI normalization within 24 months, underscoring the need for additional research to explore the relationship between TSI levels and the clinical manifestations of chronic GO.

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Introduction

Graves’ orbitopathy (GO), also known as thyroid eye disease, is the most prevalent extrathyroidal manifestation of Graves’ disease (GD). It is characterized by the influence of thyrotropin receptor (TSH-R) antibodies (TRAb) on orbital and periorbital tissues [1, 2]. Studies have found that TRAb is the underlying cause of both GO and GD, and it directly affects the metabolic activity of the thyroid gland [3,4,5]. TRAb can either have stimulating or inhibitory properties, and there are currently two established assays for measuring TRAb: thyrotropin-binding inhibitor immunoglobulin (TBII) assay and functional TSH-R stimulating immunoglobulin (TSI) bioassay [6]. TSI, also known as thyroid-stimulating autoantibodies (TSAb), along with inflammatory cytokines, causes metabolic changes in TSH-R-positive fibroblasts, which are the target cells of orbital tissues and are believed to be the main contributors to the development of GO [7, 8].

Several studies have explored the association between TSI levels and the clinical manifestations of GO. These studies have consistently demonstrated that the level of TSI is higher in cases of GO that are both severe and active. Furthermore, they have identified a positive correlation between serum TSI concentrations and the clinical activity of Graves’ orbitopathy [6, 8,9,10]. Emerging literature suggests [11] that TRAb and TSAb are efficacious markers for forecasting the recurrence of proptosis following orbital decompression surgery. Additionally, various investigations have demonstrated the utility of TSI concentrations as predictive markers for identifying the likelihood of GD relapse and for distinguishing between responsive and non-responsive patients undergoing antithyroid drug therapy [12, 13]. These findings support the theory that significantly elevated levels of TSI exert both pro-inflammatory and perpetuating effects, contributing to sustained inflammation and disease activity in GO [14,15,16,17].

Despite these well-established findings on the central role of TSI in the clinicopathological aspects of GO, there are still many unresolved issues regarding the clinical assessment of TSI, particularly with regard to long-term courses over time and factors that decrease TSI levels. Rundle and Wilson proposed that 24 months is a critical time for the disease to become inactive, and time is considered a crucial factor that affects the outcome of treatment in patients with GO [18, 19].

In this study, we aimed to evaluate the course of TSI over a period of 24 months. Additionally, we also aimed to provide insights in terms of prognostic factors that contribute to decrease the TSI levels. Lastly, we tried to establish a cutoff value for TBII and TSI that can predict TSI normalization within a two-year timeframe.

Methods

This retrospective, longitudinal observational study followed patients over a 36-month period. The participants were patients with newly diagnosed moderate-to-severe active GO at Pusan National University Hospital between Jan 2016 and Jan 2020. All patients were treated with IVMP for 12 weeks by an endocrinologist, given once weekly on the same day for the first 6 weeks at a dose of 0.5 g, then at a dose of 0.25 g for the remaining 6 weeks. During the follow-up period, 20 Gy of RTx was administered to patients who developed significant restriction in ocular motility, were intolerant to corticosteroids, or had inadequate control of disease activity, such as whose clinical activity score (CAS) had worsened (CAS ≥ 4) at 6 weeks [20, 21]. Patients with a history of steroid or immunosuppressive treatment, RTx, or who were aged < 19 years and received additional immunosuppressive treatment during the follow-up period were excluded. The study was conducted in accordance with the principles of the Declaration of Helsinki and approved by the Institutional Review Board (IRB) of Pusan National University Hospital (IRB No. 2112-006-109), South Korea.

CAS, TSI, and TBII were obtained at the time of initial diagnosis and within a week of the last IVMP treatment dosage. The subsequent level of TSI after therapy was monitored every 6 months for the next 36 months. Past medical history, body mass index, smoking history, family history, GD duration, GO duration, the time interval between diagnosis and treatment of GO, doses of daily methimazole treatment, history of statin medication, serum thyroid function test, cholesterol level, and lipid profile values were assessed on study inclusion.

Using computed tomography, the GO types were determined to be either fat- or muscle-predominant. Symmetric GO, asymmetric GO, and unilateral GO were identified according to the criteria stated by Soroudi et al. [22]. Diplopia was defined as double vision in the primary position or diplopia within 30° based on the results of the Goldman diplopia test. Extraocular movement (EOM) limitations were assessed in the more severely affected eye using a 0 to -4 scale. The 24 − 2 visual field examinations were conducted using a Humphrey field analyzer (Carl Zeiss Meditec, Inc., Dublin, California, USA). The modified CAS (range 0–7) was used to assess GO activity, and the modified NOSPECS (no signs or symptoms, only signs, soft tissue involvement, proptosis, extraocular muscle involvement, corneal involvement, vision loss) classification was used to determine the severity of GO as described by Eckstein et al. [23].

Treatment response and TSI normalization

If the CAS decreased to < 4 and there was no recurrence of symptoms of GO such as pain, injection, swelling or decreased vision within 3 months of the final dose of IVMP, it was determined as a “response.” If the CAS increased to ≥ 4, or the symptoms recurred within 3 months of the last dose of IVMP, it was determined as “no response.”

We divided patients into two groups with “success” group and “failure” group. Success group was defined as the TSI level was normalized within 24 months while whose TSI level was not normalized within 24months defined as failure group.

TRAb assays

TBII was measured using the third generation TBII assay, which blocks the binding of labeled TSAb (clone #M22) to TSH-R. TSI was measured using a thyroid-stimulating immunoglobulin (TSI) bioassay to evaluate cyclic adenosine monophosphate synthesis after TSAb binds to TSH-R [24]. The TBII cutoff value was 1.75 IU/L, while the TSI specimen-to-reference (SRR) ratio cutoff value was 140%. In the longitudinal analysis, TSI levels before treatment and subsequent levels following treatment were measured every 6 months for over 36 months. In the survival analysis, the event was defined as 1: success of TSI normalization and 0: failure of normalization (including intermediate cessation). The survival time was defined as the date of initial TSI normalization or the last follow up period.

Data analysis and statistics

The Kolmogorov–Smirnov test was used to determine the normality of the data distribution. The Kaplan–Meier method with log-rank test was used to determine the normalization of TSI (success). Multivariable analysis with the Cox proportional hazards model was used to compare the risk factors associated with “success”. We defined success rates as SR instead of hazard rates, which correspond to the conditions of normalization described by explanatory variables. To compare prediction performance, we used the area under the receiver operating characteristic (AUROC) curve. We used the point on the ROC curve with the shortest distance from the upper left corner of the unit square and largest Youden’s index to establish the cutoff value. The Statistical Package for the Social Sciences (SPSS) software (version 22.0; SPSS, Chicago, IL, USA), R (http://cran.r-project.org) version 4.0.5, and additional packages (survival) were used for statistical analysis. Statistical significance was set at P < 0.05.

Results

Characteristics of patients

In this study, a total of 96 clinical charts of patients who received IVMP treatment were reviewed. Of these, 89 patients had their TSI levels monitored over a 36-month period following IVMP treatment. Among these, six patients whose TSI level was within the normal range at the time of initial diagnosis were excluded. Thus, 83 patients satisfied the inclusion criteria. The Kaplan–Meier survival analysis of TSI in these participants is illustrated in Fig. 1. TSI levels were normalized in 36 (43.4%) patients at 24 months, and by the 36-month time, fewer than 60% of patients were considered “success” in terms of TSI normalization.

Fig. 1
figure 1

Long-term changes of thyroid-stimulating immunoglobulin (TSI) in moderate-to-severe, active GO after treatment. At the 24 months, only 36 patients (representing 43.4% of the total) could be considered successful, evidenced by a reduction in their TSAb levels to a level below 140%. TSI, thyroid-stimulating immunoglobulin; GO, Graves’ orbitopathy; CI, confidence interval

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Demographic, clinical, and biochemical characteristics of the 83 patients are presented in Table 1. Of these patients, 36 (43.4%) were classified in the “success” group and 47 (56.6%) were categorized in the “failure (censored)” group. Overall, 64 (77.1%) patients whose orbits responded to the treatment, whereas 19 (22.9%) who showed no response. Among those who showed response, 31 (48.4%) patients were part of the “failure (censored)” group. Interestingly, 14 (73.7%) were still classified in the “failure (censored)” group who showed no response. Pre-treatment levels of TBII and TSI in the ‘failure (censored)’ group were 15.24 ± 14.34 IU/L and 461.72 ± 134.43 SRR%, respectively. In contrast, in the “success” group, these levels were 6.34 ± 8.99 IU/L and 360.31 ± 138.57 SRR%, respectively. The CAS before treatment was 4.06 ± 1.11 in the “failure (censored)” group and 3.97 ± 0.88 in the “success” group. After treatment, the CAS values changed to 1.68 ± 1.84 in the “failure (censored)” group and 1.11 ± 1.35 in the “success” group. Of the 17 patients who underwent RTx, 14 (82.4%) were in the “failure (censored)” group and three (17.6%) were in the “success” group. Among the 19 patients who did not respond to IVMP treatment, 14 (73.7%) belonged to the “failure (censored)” group and five (26.3%) were in the “success” group. This study revealed that the time interval between diagnosis and treatment of GO was longer in the “failure (censored)” group (6.87 months) compared to the “success” group (4.23 months). A similar trend was observed in disease duration; the “failure (censored)” group had a longer duration of GO (6 months) compared to the “success” group (4 months). Additionally, the levels of low-density lipoprotein (LDL) and triglyceride (Tg) were higher in the “success” group (LDL: 116.35 ± 28.47 mg/dL; Tg: 161.5 mg/dL) compared to the “failure (censored)” group. The use of statins during the study period showed no association with TSI normalization. Of the 83 patients, 15 took statin during the study; seven were in the “failure (censored)”. No significant differences were observed in terms of TSI normalization between the two groups. Four patients had been taking statins prior to treatment, with one patient included in the “success” group.

Table 1 Clinical and biochemical characteristics of patients
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A decrease in TSI level over time after treatment

Figure 2 illustrates the decline in TSI levels over time, starting from baseline levels. The reduction in TSI levels was greater in the “success” group compared to the “failure (censored)” group starting from 6 months, becoming statistically significant at 18 months post-treatment (-244.2% vs. -121.1%, P = 0.031). Subsequent differences in TSI reduction between the two groups were also statistically significant, with P-values of 0.004 at 24 months and P < 0.001 at 30 months.

Fig. 2
figure 2

Patterns of the thyroid-stimulating immunoglobulin (TSI) changes from baseline over time. The results of the study demonstrate that there were no substantial variations in TSI alterations until 12 months; however, a statistically significant difference in TSI alterations was observed at 18 months. The disparity between the two groups (success vs. failure) was found to be increasingly pronounced over the course of time. Success: the group that succeeded in normalizing TSI at 24 months; Failure (Censored): the group that failed to normalize TSI at 24 months. ns, no significance; *, p < 0.05; **, p < 0.005; ***, p < 0.0005

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Univariate and Multivariable Cox regression for TSI normalization

Univariate and multivariable analyses using the Cox proportional hazards model were conducted to identify factors associated with the normalization of TSI (“success”) (Table 2). All continuous variables were categorized into two groups based on their mean or median values, depending on their distribution. Treatment response was not significantly associated with TSI normalization (P = 0.117, data not shown). Factors such as TBII, TSI, history of RTx, time interval between diagnosis and treatment of GO, and unilateral type were identified as associated with “success”. Upon adjusting for confounders, the multivariable analysis revealed that a TSI level exceeding 425% negatively impacted “success” (SR = 0.411, P < 0.035). Patients who had undergone RTx were more likely to belong to the “failure (censored)” group (SR = 4.841, P = 0.028). Early initiation of GO treatment was positively associated with TSI normalization (SR = 0.251, P < 0.001). Although, a shorter duration of GO initially identified as an important factor, it was excluded from the analysis due to collinearity with the timing of GO treatment (Fig. 3A-D). In the multivariable model, elevated Tg levels were positively associated with TSI normalization (SR = 2.678, P = 0.011). The results remained consistent when continuous variables were analyzed as such (TSI: SR = 0.995, P = 0.001; RTx: SR = 6.296, P = 0.009; time interval to GO treatment: SR = 0.95, P = 0.032; Tg: SR = 1.004, P = 0.009).

Table 2 Factors associated with TSI normalization in moderate-to-severe, active GO after treatment analysis with univariate and multivariable Cox regression
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Fig. 3
figure 3

Factors associated with thyroid-stimulating immunoglobulin (TSI) normalization. Graves’ orbitopathy (GO) patients with a disease duration longer than 6 months experienced a negative impact on treatment success (A). Early initiation of treatment for GO resulted in a higher success rate of TSI normalization (B). TSI levels exceeding 425% adversely affected treatment success (C), and patients who underwent radiation therapy (RTx) demonstrated a higher likelihood of being in the “failure (censored)” group. gr, group; GO, graves’ orbitopathy; Mo., months; TSI, thyroid-stimulating immunoglobulin; RTx, radiation therapy. In each figure, ‘gr’ stands for group. Square brackets [ ] indicate that the endpoint is not included, while parentheses ( ) indicate that the endpoint is included

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In a multivariable analysis focused on individuals with low Tg levels, early initiation of treatment for GO emerged as a significant factor for TSI normalization (P = 0.004). For those with high Tg levels, lower levels of TBII and TSI were identified as significant factors for achieving TSI normalization within 24 months (P = 0.031 and P = 0.012, respectively).

The area under the receiver operating characteristic curve (AUROC) was employed to determine the cutoff values of TBII and TSI for predicting TSI normalization. These AUROC values are detailed in Table 3. The AUC for TBII was 0.740, with a cutoff value of 5.49 IU/L (P < 0.001), while the AUC for TSI was 0.700, with a cutoff value of 413% (P = 0.002).”

Table 3 Cutoff values of TBII and TSI levels to predict normalization
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Discussion

This is the first study to analyze long-term changes in TSI levels following treatment in patients with active, moderate-to-severe GO, as well as the prognostic factors associated with TSI normalization. Understanding the long-term changes in TSI levels and the factors associated with TSI normalization is essential for determining optimal treatment strategies and the best timing for rehabilitative decompression surgery. While recent studies by the Korean Society of Ophthalmic Plastic and Reconstructive Surgery (KSOPRS) have reported on longitudinal changes in TSI, there have been limited reports on long-term changes in antibody levels in both GD and GO patients in recent decades [10, 25]. Furthermore, there is a lack of research on prognostic factors associated with TSI normalization in patients with active GO. This information can aid physicians in managing GO patients by providing insights into how TSI levels are likely to change, informing the optimal timing for initiating treatment, and guiding decisions regarding the ideal timing for decompression surgery.

First, this study emphasizes the crucial role of early detection and treatment initiation for normalizing TSI levels in patients with active, moderate-to-severe GO. Additionally, a lower initial TSI level was correlated with a higher likelihood of achieving normalization. Notably, patients who received RTx due to an inadequate response to IVMP treatment were less likely to achieve TSI normalization. However, the study found no significant association between the overall response to IVMP treatment and TSI normalization.

Overt GO is commonly understood to progress through three distinct stages: an active phase, a plateau phase where symptoms stabilize, and an inactive phase characterized by subsiding inflammation and gradual improvement [26]. Although the exact onset of the inactive phase remains unclear, it is generally believed to occur between 18 and 24 months. TSI is widely acknowledged as a major factor contributing to the development of GO, and its measurement serves as a valuable indicator for assessing disease activity, severity, and prognosis, as supported by existing research [2, 6, 27].

In this study, we explored the correlation between TSI levels and both clinical and immunological outcomes. Our findings reveal that only 43.4% of patients with moderate-to-severe active GO achieved TSI normalization after undergoing treatment with IVMP or RTx. Notably, this study’s outcomes showed TSI normalization was not associated with the response to IVMP treatment but was somewhat related to RTx administration. These results suggest that TSI normalization is less likely when RTx is employed, particularly in patients who are unresponsive to IVMP. This aligns with previous research, which has demonstrated a strong correlation between elevated TSI levels and disease exacerbation or the development of dysthyroid optic neuropathy [28].

The use of immunosuppressive treatments such as corticosteroids may lower TSI synthesis by decreasing inflammation and inhibiting immune system activity [8, 29,30,31,32]. Our study identifies early treatment with IVMP as a significant, and controllable, novel prognostic factor for TSI normalization. When we divided the treatment interval into two groups based on the median value of 5.73 months, initiating treatment earlier than 5.73 months from the time of diagnosis emerged as a crucial factor. This underscores the necessity of starting treatment as early as possible, consistent with prior studies demonstrating that early immunosuppressive therapy can improve and inactivate GO, significantly altering the disease’s natural progression and reducing the need for rehabilitative surgery [33].

Our multivariable analysis revealed the significant role that high TSI levels play in determining TSI normalization. Specifically, we found that a TSI level exceeding 425% substantially reduced the likelihood of TSI normalization, as evidenced by a success ratio (SR) of 0.411 (P < 0.035). This finding underscores the critical importance of initial TSI level as well as closely monitoring TSI levels as a prognostic indicator in the management of GO. Elevated TSI levels may serve as a red flag for clinicians, signaling the need for more aggressive or alternative therapeutic interventions to achieve favorable outcomes [32]. Moreover, this specific threshold of 413% for TSI could potentially be integrated into future treatment guidelines or algorithms, providing a quantitative measure for clinicians to gauge the likely success of therapeutic strategies and adjust them accordingly.

Another salient finding of our study is the differential rate of TSI reduction between the “success group” and the “failure (censored) group”. Notably, this difference became statistically significant after 18 months, demonstrating an increasing divergence over time. Although the long-term consequences of high TSI levels in patients remain inadequately understood, they are believed to exert a sustained impact, potentially catalyzing inflammatory responses or disease reactivation [14]. Various studies suggest that TSI has a notable influence on the trajectory and course of the disease. The commonly cited 2-year duration deemed necessary for achieving clinical stability may not be sufficient for normalizing TSI levels. Nevertheless, early diagnosis and timely decisions regarding steroid treatment are crucial for achieving immunological stability within this 2-year window.

While low serum cholesterol levels and the use of statins are believed to positively impact the progression of GO, our study did not find a corresponding influence on changes in TSI levels [34, 35]. Interestingly, we observed that high Tg levels were significantly correlated with TSI normalization. Given the complexities in interpreting these findings, we undertook a subgroup analysis, categorizing participants into low- and high-Tg groups for re-analysis. In the low-Tg group, the initiation of early treatment was a key factor for TSI normalization. Conversely, in the high-Tg group, an initially low TSI level was identified as significant for normalization. In summary, both an initial low level of TSI and the prompt initiation of treatment are vital for reducing TSI levels.

This study has some limitations, including being a single-center, retrospective study with a small number of patients. Despite these limitations, this study offers valuable insights into the long-term changes in TSI levels, a key factor in managing GO.

In conclusion, a two-year period was not sufficient to bring TSI levels back to normal for many patients. Even in the inactive stage following IVMP treatment, more than half of the patients still had elevated TSI levels. Those who receive RTx are likely to maintain high TSI levels over time. While it is possible that patients who maintain high TSI levels are less responsive to steroids and therefore require subsequent RTx, this interpretation warrants further investigation to confirm. Low initial TSI levels and early treatment emerge as significant factors for TSI normalization. Cutoff values (TSI: 413%, TBII: 5.49IU/L) could serve as useful clinical markers for assessing the long-term courses of TSI. While some aspects of our findings remain unexplained, they pave the way for future critical research to further explore the long-term relationships between clinical variables and TSI levels. Developing more effective and personalized treatment strategies for GO will benefit from these insights.

Data availability

The datasets used and/or analysed during the current study available from the corresponding author (HYC) on reasonable request.

References

  1. Naik VM, Naik MN, Goldberg RA, Smith TJ, Douglas RS. Immunopathogenesis of thyroid eye disease: emerging paradigms. Surv Ophthalmol. 2010;55(3):215–26.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Jang S, Shin D, Lee E, Lee S, Yoon J. 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(8):964–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Smith B, Hall R. THYROID-STIMULATING IMMUNOGLOBULINS IN GRAVES’DISEASE. Lancet. 1974;304(7878):427–30.

    Article  Google Scholar 

  4. McKenzie J, Zakarija M. A reconsideration of a thyroid-stimulating immunoglobulin as the cause of hyperthyroidism in Graves’ disease. J Clin Endocrinol Metabolism. 1976;42(37):778–81.

    Article  CAS  Google Scholar 

  5. Weetman A, McGregor A. Autoimmune thyroid disease: further developments in our understanding. Endocr Rev. 1994;15(6):788–830.

    CAS  PubMed  Google Scholar 

  6. Lytton S, Ponto K, Kanitz M, Matheis N, Kohn L, Kahaly G. A novel thyroid stimulating immunoglobulin bioassay is a functional indicator of activity and severity of Graves’ orbitopathy. J Clin Endocrinol Metabolism. 2010;95(5):2123–31.

    Article  CAS  Google Scholar 

  7. Kahaly G, Yuan J, Krause U, Hülbusch K, Beyer J. Ciclosporin and thyroid-stimulating immunoglobulins in endocrine orbitopathy. Res Exp Med. 1989;189(5):355–62.

    Article  CAS  Google Scholar 

  8. Bahn RS. Graves’ ophthalmopathy. N Engl J Med. 2010;362(8):726–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kampmann E, Diana T, Kanitz M, Hoppe D, Kahaly G. Thyroid stimulating but not blocking autoantibodies are highly prevalent in severe and active thyroid-associated orbitopathy: a prospective study. International Journal of Endocrinology. 2015;2015.

  10. Ko J, Kook KH, Yoon JS, Woo KI, Yang JW. Longitudinal association of thyroid-stimulating immunoglobulin levels with clinical characteristics in thyroid eye disease. BMJ open. 2022;12(6):e050337.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Byeon HJ, Ko J, Kikkawa D, Yoon JS. Preoperative risk factors for proptosis recurrence after rehabilitative orbital decompression in Graves’ orbitopathy patients. Am J Ophthalmol. 2024;258:110–8.

    Article  CAS  PubMed  Google Scholar 

  12. Kamijo K, Murayama H, Uzu T, Togashi K, Olivo PD, Kahaly GJ. Similar clinical performance of a novel chimeric thyroid-stimulating hormone receptor bioassay and an automated thyroid stimulating hormone receptor binding assay in Graves’ disease. Thyroid. 2011;21(12):1295–9.

    Article  CAS  PubMed  Google Scholar 

  13. Santos TDS, Oliveira JC, Freitas C, de Carvalho AC. Thyroid-stimulatory antibody as a predictive factor for Graves’ Disease Relapse. Cureus. 2022;14(2).

  14. Stöhr M, Oeverhaus M, Lytton SD, Horstmann M, Zwanziger D, Möller L, et al. Predicting the relapse of hyperthyroidism in treated Graves’ disease with orbitopathy by serial measurements of TSH-receptor autoantibodies. Horm Metab Res. 2021;53(04):235–44.

    Article  PubMed  Google Scholar 

  15. Goh S, Ho S, Seah L, Fong K, Khoo D. Thyroid autoantibody profiles in ophthalmic dominant and thyroid dominant Graves’ disease differ and suggest ophthalmopathy is a multiantigenic disease. Clin Endocrinol. 2004;60(5):600–7.

    Article  CAS  Google Scholar 

  16. Kahaly GJ, Diana T, Kanitz M, Frommer L, Olivo PD. Prospective trial of functional thyrotropin receptor antibodies in Graves disease. J Clin Endocrinol Metabolism. 2020;105(37):e1006–14.

    Article  Google Scholar 

  17. 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(9):809–13.

    Article  CAS  PubMed  Google Scholar 

  18. Rundle F. Development and course of exophthalmos and ophthalmoplegia in Graves’ disease with special reference to the effect of thyroidectomy. Clin Sci. 1945;5:177–94.

    CAS  PubMed  Google Scholar 

  19. Menconi F, Leo M, Sabini E, Mautone T, Nardi M, Sainato A, et al. Natural history of Graves’ orbitopathy after treatment. Endocrine. 2017;57(2):226–33.

    Article  CAS  PubMed  Google Scholar 

  20. Kim JW, Han SH, Son BJ, Rim TH, Keum KC, Yoon JS. Efficacy of combined orbital radiation and systemic steroids in the management of Graves’ orbitopathy. Graefes Arch Clin Exp Ophthalmol. 2016;254:991–8.

    Article  PubMed  Google Scholar 

  21. Shams PN, Ma R, Pickles T, Rootman J, Dolman PJ. Reduced risk of compressive optic neuropathy using orbital radiotherapy in patients with active thyroid eye disease. Am J Ophthalmol. 2014;157(6):1299–305.

    Article  PubMed  Google Scholar 

  22. Soroudi AE, Goldberg RA, McCann JD. Prevalence of asymmetric exophthalmos in Graves orbitopathy. Ophthalmic Plast Reconstr Surg. 2004;20(3):224–5.

    Article  PubMed  Google Scholar 

  23. Eckstein AK, Plicht M, Lax H, Neuhäuser M, Mann K, Lederbogen S, et al. Thyrotropin receptor autoantibodies are independent risk factors for Graves’ ophthalmopathy and help to predict severity and outcome of the disease. J Clin Endocrinol Metabolism. 2006;91(9):3464–70.

    Article  CAS  Google Scholar 

  24. Barbesino G, Tomer Y. Clinical utility of TSH receptor antibodies. J Clin Endocrinol Metabolism. 2013;98(6):2247–55.

    Article  CAS  Google Scholar 

  25. Dragan LR, Seiff SR, Lee DC. Longitudinal correlation of thyroid-stimulating immunoglobulin with clinical activity of disease in thyroid-associated orbitopathy. Ophthalmic Plast Reconstr Surg. 2006;22(38):13–9.

    Article  PubMed  Google Scholar 

  26. Bartalena L, Tanda ML. Current concepts regarding Graves’ orbitopathy. J Intern Med. 2022;292(5):692–716.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. George A, Diana T, Längericht J, Kahaly GJ. Stimulatory thyrotropin receptor antibodies are a biomarker for Graves’ orbitopathy. Front Endocrinol. 2021;11:629925.

    Article  Google Scholar 

  28. Ponto K, Diana T, Binder H, Matheis N, Pitz S, Pfeiffer N, et al. Thyroid-stimulating immunoglobulins indicate the onset of dysthyroid optic neuropathy. J Endocrinol Investig. 2015;38(7):769–77.

    Article  CAS  Google Scholar 

  29. Bartalena L, Baldeschi L, Boboridis K, Eckstein A, Kahaly G, Marcocci C et al. European Group on Graves’ Orbitopathy (EUGOGO) The 2016 European thyroid association/European group on Graves’ orbitopathy guidelines for the management of Graves’ orbitopathy. Eur Thyroid J. 2016;(38):9–26.

  30. Bartalena L, Kahaly GJ, Baldeschi L, Dayan CM, Eckstein A, Marcocci C, et al. The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathy. Eur J Endocrinol. 2021;185(37):G43–67.

    Article  CAS  PubMed  Google Scholar 

  31. Cupps TR, Gerrard TL, Falkoff R, Whalen G, Fauci AS. Effects of in vitro corticosteroids on B cell activation, proliferation, and differentiation. J Clin Investig. 1985;75(2):754–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Park J, Kim J, Kim S, Choi H. Prognostic significance of thyroid-stimulating hormone receptor antibodies in moderate-to-severe graves’ orbitopathy. Front Endocrinol. 2023;14:1153312.

    Article  Google Scholar 

  33. Bartalena L, Piantanida E, Gallo D, Lai A, Tanda ML. Epidemiology, natural history, risk factors, and prevention of Graves’ orbitopathy. Front Endocrinol. 2020;11:615993.

    Article  Google Scholar 

  34. Lanzolla G, Sabini E, Leo M, Menconi F, Rocchi R, Sframeli A, et al. Statins for Graves’ orbitopathy (STAGO): a phase 2, open-label, adaptive, single centre, randomised clinical trial. Lancet Diabetes Endocrinol. 2021;9(11):733–42.

    Article  CAS  PubMed  Google Scholar 

  35. Sabini E, Mazzi B, Profilo MA, Mautone T, Casini G, Rocchi R, et al. High serum cholesterol is a novel risk factor for graves’ orbitopathy: results of a cross-sectional study. Thyroid. 2018;28(3):386–94.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Department of Biostatistics, Biomedical Research Institute, Pusan National University Hospital.

Funding

This study was supported by Biomedical Research Institute Grant (202301420001), Pusan National University Hospital.

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Authors and Affiliations

  1. Department of Ophthalmology, Seoul St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, 06591, South Korea

    Jungyul Park

  2. Department of Ophthalmology, School of Medicine, Pusan National University Hospital, Busan, 49241, Republic of Korea

    Yubin Son & Hee-young Choi

  3. Department of Biostatistics, Biomedical Research Institute, Pusan National University Hospital, Busan, 49241, Republic of Korea

    Jinmi Kim

  4. Department of Endocrinology, School of Medicine, Pusan National University Hospital, Busan, 49241, Republic of Korea

    Sangsoo Kim

  5. Biomedical Research Institute, Pusan National University Hospital, Busan, 49241, Republic of Korea

    Sangsoo Kim & Hee-young Choi

Authors
  1. Jungyul Park
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  2. Yubin Son
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  3. Jinmi Kim
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  4. Sangsoo Kim
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  5. Hee-young Choi
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Contributions

Conception and design of the study (JYP, SSK); conduction of the study (JYP, SSK); collection and management of data (JYP, YBS); data analysis (JYP, JMK); data interpretation (JYP, JMK, HYC); and preparation, review, and approval of the manuscript (JYP, YBS, JMK, SSK, HYC).

Corresponding author

Correspondence to Hee-young Choi.

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Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The study was conducted in accordance with the principles of the Declaration of Helsinki and approved by the Institutional Review Board (IRB) of Pusan National University Hospital (IRB No. 2112-006-109), South Korea. The IRB of Pusan National University waved the requirement for informed consent, given that the study design was based on a retrospective review of medical records.

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Park, J., Son, Y., Kim, J. et al. Prognostic factors for thyroid-stimulating immunoglobulin normalization in moderate-to-severe Graves’ orbitopathy: a 36-month longitudinal study. BMC Ophthalmol 24, 361 (2024). https://doi.org/10.1186/s12886-024-03594-4

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  • DOI: https://doi.org/10.1186/s12886-024-03594-4

Keywords

BMC Ophthalmology

ISSN: 1471-2415

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