Interaction of MMP-9 in the active phase of Graves' disease with and without ophthalmopathy.

Thyroid eye disease (TED) is expressed as orbital inflammation, and serum levels of several proinflammatory cytokines have been studied among patients with Graves' disease (GD) with and without TED; however, a more sensitive and specific marker for the different phases of GD and TED is still lacking. Seventeen active TED, 16 inactive TED, 16 GD without TED, and 16 healthy controls were recruited. Serum IL-17A, MMP-2, MMP-3, and MMP-9 were measured by multiplex bead assay. TED hormone and eye parameters were evaluated, and their relationship with cytokine levels was analyzed. Serum MMP-9 was higher in active TED than healthy controls, whereas IL-17A was lower among these patients than in GD without TED and healthy controls. No differences were found in MMP-3 and MMP-2 concentrations. MMP-9 levels were lower in patients with inactive TED who underwent radioactive iodine (RAI) therapy and those on levothyroxine replacement. MMP-9 levels were elevated in patients on methimazole. A negative correlation was found between age at assessment and time of follow-up with MMP-9 levels in inactive TED. Free T3 and ophthalmometry values were positively correlated with MMP-9 in the GD without TED and inactive TED groups, respectively. In conclusion, serum MMP-9 was increased in patients with active TED and was related to the RAI treatment, longer follow-up time, and higher ophthalmometry in patients with inactive TED, as well as thyroid function in GD without TED. MMP-9 may be involved in both the active phase of TED and the active phase of inflammation related to GD.NEW & NOTEWORTHY Our study addresses clinical aspects of specific ophthalmological examination and serum cytokine concentrations of patients with Graves' disease (GD) with and without ophthalmopathy. Our findings suggest that MMP-9 may be involved in the active phase of ophthalmopathy and in the active phase of GD. The central question is whether MMP-9 is a potential target for future treatments.

Potential role of IGF-1R in the interaction between orbital fibroblasts and B lymphocytes: an implication for B lymphocyte depletion in the active inflammatory phase of thyroid-associated ophthalmopathy.

BACKGROUND: Thyroid eye disease (TED) is an inflammatory process involving lymphocyte-mediated immune response and orbital tissue damage. The anti-insulin-like growth factor-1 receptor (IGF-1R) antibodies produced by B lymphocytes are involved in the activation of orbital fibroblasts and the inflammatory process of orbital tissue damage in TED. The purpose of this study was to explore the role of IGF-1R in the mechanistic connection between orbital fibroblasts and B lymphocytes in TED. METHODS: Orbital fibroblasts sampled from orbital connective tissues and peripheral B lymphocytes isolated from peripheral blood, which were obtained from 15 patients with TED and 15 control patients, were co-cultured at a ratio of 1:20. The level of IGF-1R expression in orbital fibroblasts was evaluated by flow cytometry and confocal microscopy. Transient B lymphocyte depletion was induced with anti-CD20 monoclonal antibody rituximab, while the IGF-1R pathway was blocked by the IGF-1R binding protein. The expression levels of interleukin-6 (IL-6) and regulated upon activation, normal T cell expressed and secreted (RANTES) in the co-culture model were quantified via ELISA. RESULTS: IGF-1R expression was significantly elevated in TED orbital fibroblasts compared to that of controls. A 24-h co-culture of orbital fibroblasts with peripheral B lymphocytes induced elevated expression levels of IL-6 and RANTES in each group (TED patients and controls), with the highest levels occurring in TED patients (T + T group). Rituximab and IGF-1R binding protein significantly inhibited increased levels of IL-6 and RANTES in the co-culture model of TED patients. CONCLUSIONS: IGF-1R may mediate interaction between orbital fibroblasts and peripheral B lymphocytes; thus, blocking IGF-1R may reduce the local inflammatory response in TED. Rituximab-mediated B lymphocyte depletion played a role in inhibiting inflammatory responses in this in vitro co-culture model, providing a theoretical basis for the clinical application of anti-CD20 monoclonal antibodies in TED.

Risk of non-thyroidal autoimmune diseases in patients with Graves' disease: a nationwide retrospective cohort study.

OBJECTIVE: Graves' disease (GD) is a major autoimmune thyroid disorder and associated with non-thyroidal autoimmune disease (NTAD). We aimed to investigate the risk of NTAD in patients with GD compared with age- and sex-matched controls and to evaluate whether the risk differs between individuals with or without Graves' ophthalmopathy (GO). METHODS: This was a retrospective cohort study using data from the Korean National Health Claims database. We included 77 401 patients with GD (2,310 with GO) and 77 401 age- and sex-matched controls. Risk of NTAD were compared between the entire cohort and within the GD cohort. RESULTS: During a mean follow-up period of 9 years, NTAD developed in 12 341 (16.1%) patients in the GD cohort. Risk for systemic lupus erythematosus (SLE) [adjusted hazard ratio (aHR):1.15, 95% confidence interval (CI): 1.02-1.29], vitiligo (aHR: 1.24, 95% CI: 1.10-1.40), and alopecia areata (aHR: 1.11, 95% CI: 1.10-1.40) were higher in the GD cohort than in the control cohort. In the GD cohort, risk for SLE (aHR: 1.60, 95% CI: 1.11-2.33), Sjogren's syndrome (aHR: 1.89, 95% CI: 1.30-2.74), and ankylosing spondylitis (aHR: 1.53, 95% CI: 1.08-2.17) were higher in the GO group than in the non-GO group. CONCLUSION: This study demonstrated an increased risk of SLE, vitiligo and alopecia areata in patient with GD. In the GD cohort, patients with GO had an increased risk of SLE, Sjogren's syndrome and ankylosing spondylitis. These findings suggest that importance of implementing a strategy for early detection of NTAD based on the presence of GO.

The Rate of Re-treatment in Patients Treated with Teprotumumab: A Multicenter Study of 119 Patients with 1 Year of Follow-up.

PURPOSE: To determine the rate of re-treatment in patients who receive a full course of teprotumumab therapy for thyroid eye disease (TED) and drivers of re-treatment. DESIGN: Multicenter retrospective study. PARTICIPANTS: All patients who received a full course of treatment and had available data at 1 year after initial treatment were included. METHODS: Charts were reviewed for the following information: age, sex, months since diagnosis of TED, smoking status, and prior treatments. Further, the clinical activity score (CAS), proptosis, and the Gorman diplopia score were reviewed at baseline, at the end of the first course, and at baseline for the second course in those who received it. A logistic regression model was created to review the drivers of re-treatment. MAIN OUTCOME MEASURES: Rate of re-treatment and the drivers of re-treatment. RESULTS: One hundred nineteen patients were included from 3 centers across the United States. The overall re-treatment rate was 24% (29/119). No difference was found among the 3 sites (P = 0.6). In univariable analyses, at baseline, no difference was found in proptosis (P = 0.07), diplopia score (P = 0.4), or duration of TED (P = 0.4) between patients who were re-treated and those not re-treated. From the re-treated group, 82% showed a significant proptosis response (≥ 2-mm reduction from baseline) after the initial course, whereas 68% of patients who were not re-treated showed a clinically significant proptosis response (P = 0.16). The mean ± standard deviation difference between the end of the first treatment and at baseline before the second treatment (in those who received it) was 2 ± 2 for CAS, 2 ± 4 mm for proptosis, and 1 ± 1 for diplopia score. Age was the only significant driver of re-treatment (P < 0.05). Re-treated patients were 7 years older than patients who were not re-treated (60 years vs. 53 years; P < 0.05). CONCLUSIONS: In patients receiving a full course of teprotumumab therapy, the rate of re-treatment was 24%. Age was the only driver of re-treatment. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The efficacy and safety of selenium supplementation versus placebo in the treatment of Graves' orbitopathy: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Selenium is a trace element crucial for thyroid function, and has potential therapeutic benefits in Graves' orbitopathy (GO). Therefore, we aim to evaluate its efficacy and safety in GO patients to provide valuable insights into its role as a therapeutic option for this condition. DESIGN: Systematic review and meta-analysis. PATIENTS: GO Patients treated with selenium compared to placebo. MEASUREMENTS: Clinical activity score (CAS), Graves' orbitopathy quality of life (GO-QOL), eye symptoms and signs, and adverse events. RESULTS: Out of 1684 records screened, four randomised controlled trials were included. Selenium was superior at 6 months in lowering the CAS (MD = -1.27, 95% confidence interval [CI] [-1.68, -0.85], p < .0001]), improving total GO-QOL (RR = 2.54, 95% CI [1.69-3.81], p < .00001), and improving the visual and the psychological functioning scores (MD = 10.84, 95% CI [4.94-16.73], p = .003), (MD = 12.76, 95% CI [8.51-17.00], p < .00001) respectively. Similarly, it significantly improved these outcomes at 12 months. It also showed a significant decrease in the palpebral aperture at 6 months (MD = -1.49, 95% CI [-2.90, -0.08], p = .04). However, no significant differences were observed in proptosis, soft tissue involvement, ocular motility, and adverse effects. CONCLUSIONS: Selenium is effective in reducing CAS and improving the palpebral aperture and GO-QOL in patients with GO. Additionally, it is safe and has promising therapeutic implications. However, further research is needed to validate its long-term efficacy and safety.

Immune-related visual dysfunction in thyroid eye disease: a combined orbital and brain neuroimaging study.

OBJECTIVES: To investigate the pathological interplay between immunity and the visual processing system (VPS) in thyroid eye disease (TED). METHODS: A total of 24 active patients (AP), 26 inactive patients (IP) of TED, and 27 healthy controls (HCs) were enrolled. Orbital magnetic resonance imaging (MRI) and resting-state functional MRI (rs-fMRI) were conducted for each participant. Multiple MRI parameters of the intraorbital optic nerve (ON) were assessed. The amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) were calculated. Correlation analyses were carried out on the above parameters and clinical characteristics. RESULTS: Visual functioning scores differentiated between the AP and IP groups. The ON subarachnoid space and ON sheath diameter were significantly higher in AP than in IP. Six vision-related brain regions were identified in TED patients compared with HCs, including right calcarine (CAL.R), right cuneus (CUN.R), left postcentral gyrus (PoCG.L), right middle temporal gyrus (MTG.R), left superior frontal gyrus (SFG.L), and left caudate (CAU.L). The brain activity of MTG.R, SFG.L, and CAU.L differentiated between the AP and IP groups. The correlation analysis revealed a close association among the vision-related brain regions, MRI parameters of ON, and clinical characteristics in AP and IP, respectively. CONCLUSIONS: Combined orbital and brain neuroimaging revealed abnormalities of the VPS in TED, which had a close correlation with immune statuses. Vision-related brain regions in TED might be possibly altered by peripheral immunity via a direct or indirect approach. CLINICAL RELEVANCE STATEMENT: The discovery of this study explained the disparity of visual dysfunction in TED patients with different immune statuses. With the uncovered neuroimaging markers, early detection and intervention of visual dysfunction could be achieved and potentially benefit TED patients. KEY POINTS: • Patients with different immune statuses of thyroid eye disease varied in the presentation of visual dysfunction. • The combined orbital and brain neuroimaging study identified six altered vision-related brain regions, which had a significant correlation with the MRI parameters of the intraorbital optic nerve and immunological characteristics. • Peripheral immunity might possibly give rise to alterations in the central nervous system part of the visual processing system via a direct or indirect approach.

Fat-suppression T2 relaxation time and water fraction predict response to intravenous glucocorticoid therapy for thyroid-associated ophthalmopathy.

OBJECTIVE: To investigate the value of fat-suppression (FS) T2 relaxation time (T2RT) derived from FS T2 mapping and water fraction (WF) derived from T2 IDEAL to predict the treatment response to intravenous glucocorticoids (IVGC) in patients with thyroid-associated ophthalmopathy (TAO) based on texture analysis. MATERIALS AND METHODS: In this study, 89 patients clinically diagnosed with active and moderate-to-severe TAO were enroled (responsive group, 48 patients; unresponsive group, 41 patients). The baseline clinical characteristics and texture features were compared between the two groups. Multivariate analysis was performed to identify the independent predictors of treatment response to IVGC. ROC analysis and the DeLong test were used to assess and compare the predictive performance of different models. RESULTS: The responsive group exhibited significantly shorter disease duration and higher 90th percentile of FS T2RT and kurtosis of WF in the extraocular muscle (EOM) and 95th percentile of WF in the orbital fat (OF) than the unresponsive group. Model 2 (disease duration + WF; AUC, 0.816) and model 3 (disease duration + FS T2RT + WF; AUC, 0.823) demonstrated superior predictive efficacy compared to model 1 (disease duration + FS T2RT; AUC, 0.756), while there was no significant difference between models 2 and 3. CONCLUSIONS: The orbital tissues of responders exhibited more oedema and heterogeneity. Furthermore, OF is as valuable as EOM for assessing the therapeutic efficacy of IVGC. Finally, WF derived from T2 IDEAL processed by texture analysis can provide valuable information for predicting the treatment response to IVGC in patients with active and moderate-to-severe TAO. CLINICAL RELEVANCE STATEMENT: The texture features of FS T2RT and WF are different between responders and non-responders, which can be the predictive tool for treatment response to IVGC. KEY POINTS: Texture analysis can be used for predicting response to IVGC in TAO patients. TAO patients responsive to IVGC show more oedema and heterogeneity in the orbital tissues. WF from T2 IDEAL is a tool to predict the therapeutic response of TAO.

Combined glucocorticoids and cyclophosphamide in the treatment of Graves' ophthalmopathy: a systematic review and meta-analysis.

PURPOSE: To evaluate the efficacy and safety of combined glucocorticoids (GCs) and cyclophosphamide (CYC) treatment in Graves' ophthalmopathy (GO). METHODS: We searched PubMed, Embase, Cochrane Library, and four Chinese databases (Chinese National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), WanFang, and SinoMed) for any published randomized controlled trials (RCTs) produced from inception to December 1, 2023. Articles obtained using appropriate keywords were selected independently by two reviewers according to the established inclusion and exclusion criteria. FINDINGS: We retrieved 1120 records which were eventually reduced to 13 RCTs which were then included in this evaluation. Pooled results indicated that the experimental group (CYC/GCs) showed a higher response rate than control group (GCs or negative control) (RR 1.27; 95% confidence interval 1.19 to 1.37). The subgroup analysis showed that the difference in response rates among treatment protocols (CYC/P, CYC/MPS, CYC/DEX) was not statistically significant (p = 0.23). IMPLICATIONS: The combination of GCs and CYC could be recommended as a therapeutic option for GO, especially in patients who experience recurrence after a withdrawal GCs, have a poor response to GCs, or cannot obtain monoclonal antibody agents for various reasons.

A comparison of cardiovascular disease, cancer, mortality, and Graves' ophthalmopathy following treatment for hyperthyroidism: A Bayesian network meta-analysis.

OBJECTIVES: This network meta-analysis aimed to evaluate the association of anti-thyroid drugs (ATD), radioactive iodine (RAI), and thyroidectomy with subsequent outcomes in patients with newly-diagnosed hyperthyroidism. METHODS: The Ovid Medline, Ovid Embase, and Cochrane Library databases were searched for observational studies and randomized controlled trials. Included studies were published on or before 1st May 2022 involving at least two of the treatments among ATD, RAI, and thyroidectomy for hyperthyroidism. Pairwise comparisons and Bayesian network meta-analysis were used to estimate hazard ratios (HRs) and their credible interval (CrI) of outcomes, including cardiovascular disease (CVD), cancer, overall mortality, and Graves' ophthalmopathy (GO). RESULTS: A total of 22 cohort studies with 131,297 hyperthyroidism patients were included. Thyroidectomy was associated with lower risks of mortality and GO than ATD (HR = 0.54, 95% CrI: 0.31, 0.96; HR = 0.31, 95% CrI: 0.12, 0.64) and RAI (HR = 0.62, 95% CrI: 0.41, 0.95; HR = 0.18, 95% CrI: 0.07, 0.35). RAI had a higher risk of GO (HR = 1.70, 95% CrI: 1.02, 2.99) than ATD treatment. CONCLUSIONS: This Bayesian network meta-analysis indicated that thyroidectomy was associated with lower risks of mortality and GO in newly-diagnosed hyperthyroid patients compared to ATD and RAI. Relative to ATD, RAI therapy increased the risk of GO.

Temporal trends in the clinical presentation of Graves' orbitopathy: a single-center retrospective study.

PURPOSE: Graves' ophthalmopathy (GO) is an autoimmune disease that affects orbital soft tissues and represents the most common extrathyroidal manifestation of Graves' disease (GD). The European Group of Graves' Ophthalmopathy (EUGOGO) has attempted to shed light on the European epidemiological picture of GO, suggesting that GO in newly diagnosed patients in recent years has a trend towards a less severe clinical presentation. There are no studies that focus this issue on the population of our area; we aimed to evaluate the trend of GO clinical presentation in our outpatient clinic through an observation period of 10 years. METHODS: We compared 55 consecutive patients, 11 males (F) and 44 females (M), who came to our observation from January 2005 to December 2006 [Group 1 (G1)], with 56 patients, 15 males, and 41 females, who were referred to us from 2015 to 2016 [Group 2 (G2)]. We studied the following putative predictors of GO presentation and severity: thyroid function, smoking, diabetes, hypercholesterolemia, time from GO diagnosis to referral to our thyroid centre (TGOD), sex and age. RESULTS: GO severity was significantly reduced in G2 vs. G1 (p = 0.04). TGOD ≥ 3 months was related to clinical characteristics of GO (severity and Clinical Activity Score ≥ 4) and was an independent predictor of GO severity (p = 0.01). The other variables evaluated had no independent effects. CONCLUSIONS: We found that GO severity at presentation was significantly reduced over a ten-year observation period (2005-2006 vs. 2015-2016) in GO patients referred to our tertiary thyroid centre. TGOD ≥ 3 months was an independent predictor of GO severity.

Assessment of Schlemm's canal with swept-source optical coherence tomography in Graves' ophthalmopathy.

PURPOSE: To evaluate the Schlemm's canal (SC) parameters obtained by swept-source optical coherence tomography (OCT) different in Graves' ophthalmopathy (GO) eyes compared to healthy eyes. METHODS: This cross-sectional observational study evaluated 64 eyes of 32 GO cases and 56 eyes of 28 healthy controls. The study was conducted between October 2020 and June 2021. SC images were obtained from the temporal limbus of individuals using swept-source OCT. SC length (SCL) and SC area (SCA) were measured. The relationship between SC parameters in the patient group and intraocular pressure (IOP), retinal nerve fiber layer (RNFL) thickness, Graves' disease (GD) duration, and clinical activity score (CAS) was evaluated. RESULTS: In the GO group, 64 eyes of 32 patients were evaluated, and in the age and gender-matched healthy control group, 56 eyes of 28 individuals were assessed. SC images from 4 eyes of 4 patients in the patient group and 1 eye of 1 patient in the control group were not clear, preventing SCL and SCA measurements for these eyes. SCL and SCA measurements were found to be lower, and IOP and Hertel values were higher in the GO group compared to the healthy controls. However, no significant correlation was observed between SCL and SCA with IOP, RNFL thickness, GD duration, GO duration, or CAS in the GO group. In the GO group, the mean value of SCA was found to be higher in eyes with glaucoma or OHT compared to those without. CONCLUSION: These findings indicate that SC in GO-affected eyes is shorter and has a smaller area than in healthy individuals. Additionally, higher IOP and Hertel values were observed in the GO group compared to healthy controls. This study suggests that assessing SC using anterior segment OCT could provide valuable insights into the regulation of IOP and the development of glaucoma in GO-affected eyes.

Use of extreme gradient boosting, light gradient boosting machine, and deep neural networks to evaluate the activity stage of extraocular muscles in thyroid-associated ophthalmopathy.

PURPOSE: To develop a machine learning model to evaluate the activity stage of extraocular muscles in thyroid-associated ophthalmopathy (TAO). METHODS: This study retrospectively analysed data from patients with TAO who underwent contrast-enhanced magnetic resonance imaging (MRI) from 2015 to 2022. Three independent machine learning models, namely, extreme gradient boosting (XGBoost), light gradient boosting machine (LightGBM), and deep neural networks (DNNs), were constructed using common clinical features. The performance of these models was compared using evaluation metrics such as the area under the receiver operating curve (AUC), accuracy, precision, recall, and F1 score. The importance of features was explained using Shapley additive explanations (SHAP). RESULTS: A total of 2561 eyes of 1479 TAO patients were included in this study. The original dataset was randomly divided into a training set (80%, n = 2048) and a test set (20%, n = 513). In the performance evaluation of the test set, the LightGBM model had the best diagnostic performance (AUC 0.9260). According to the SHAP results, features such as conjunctival congestion, swollen caruncles, oedema of the upper eyelid, course of TAO, and intraocular pressure had the most significant impact on the LightGBM model. CONCLUSION: This study used contrast-enhanced MRI as an objective evaluation criterion and constructed a LightGBM model based on readily accessible clinical data. The model had good classification performance, making it a promising artificial intelligence (AI)-assisted tool to help community hospitals evaluate the inflammatory activity of extraocular muscles in TAO patients in a timely manner.

Optical coherence tomography angiography in thyroid associated ophthalmopathy: a systematic review.

PURPOSE: To evaluate the evidence for alterations of blood flow, vascular and perfusion densities in the choroid, macula, peripapillary region, and the area surrounding the optic nerve head (ONH) in patients with thyroid-associated ophthalmopathy (TAO) based on changes of OCTA parameters. METHODS: A systematic review of Pubmed, Google Scholar, Scopus, WOS, Cochrane, and Embase databases, including quality assessment of published studies, investigating the alterations of OCTA parameters in TAO patients was conducted. The outcomes of interest comprised changes of perfusion and vascular densities in radial peripapillary capillary (RPC), ONH, superficial and deep retinal layers (SRL and DRL), choriocapillaris (CC) flow, and the extent of the foveal avascular zone (FAZ). RESULTS: From the total of 1253 articles obtained from the databases, the pool of papers was narrowed down to studies published until March 20th, 2024. Lastly, 42 studies were taken into consideration which contained the data regarding the alterations of OCTA parameters including choriocapillary vascular flow, vascular and perfusion densities of retinal microvasculature, SRL, and DRL, changes in macular all grid sessions, changes of foveal, perifoveal and parafoveal densities, macular whole image vessel density (m-wiVD) and FAZ, in addition to alterations of ONH and RPC whole image vessel densities (onh-wiVD and rpc-wiVD) among TAO patients. The correlation of these parameters with visual field-associated parameters, such as Best-corrected visual acuity (BCVA), Visual field mean defect (VF-MD), axial length (AL), P100 amplitude, and latency, was also evaluated among TAO patients. CONCLUSION: The application of OCTA has proven helpful in distinguishing active and inactive TAO patients, as well as differentiation of patients with or without DON, indicating the potential promising role of some OCTA measures for early detection of TAO with high sensitivity and specificity in addition to preventing the irreversible outcomes of TAO. OCTA assessments have also been applied to evaluate the effectiveness of TAO treatment approaches, including systemic corticosteroid therapy and surgical decompression.

Performance of T2 mapping in the staging of Graves' ophthalmopathy based on different region of interest selection methods.

BACKGROUND: Discriminating the stage of Graves' ophthalmopathy (GO) is crucial for clinical decision. Application of conventional T2-weighted imaging in the staging is still limited. PURPOSE: To evaluate the performance of T2 mapping based on two different regions of interest (ROIs) for staging GO. MATERIAL AND METHODS: In total, 56 GO patients were retrospectively enrolled and divided into two groups according to the clinical activity score (CAS). T2 relaxation time (T2RT) of extraocular muscle (EOM) on T2 mapping based on two different ROIs (T2RTROI-1: ROIs were drawn separately in the four EOMs; T2RTROI-2: ROI was drawn in the most inflamed EOM) was measured and compared between active and inactive groups. RESULTS: Both T2RTROI-1 and T2RTROI-2 values in the active GO were significantly higher than those of inactive GO (P <0.001). T2RTROI-1 and T2RTROI-2 values were positively correlated with CAS (rs=0.73, 0.69; P <0.001). When the T2RTROI-1 value of 83.3 ms and T2RTROI-2 value of 106.3 ms were used as cutoff values for staging GO, respectively, the best results were obtained with areas under the curve (AUCs) of 0.822 and 0.827. There was no significant difference for AUCs between T2RTROI-1 and T2RTROI-2 (P = 0.751). Excellent and good inter-observer agreements were achieved in quantitative measurements for T2RTROI-1 and T2RTROI-2 values, respectively, with intraclass correlation coefficients of 0.954 and 0.882. CONCLUSION: The T2RT values derived from two different ROIs were useful for assessment of disease activity. Taking reproducibility and diagnostic performance into consideration, T2RTROI-1 would be an ideal image biomarker for staging GO compared to T2RTROI-2.

The Role of Fibrogenesis and Extracellular Matrix Proteins in the Pathogenesis of Graves' Ophthalmopathy.

Graves' ophthalmopathy (GO), or thyroid eye disease (TED), is the most frequent extrathyroidal manifestation of Graves' disease (GD). Inflammation and subsequent aberrant tissue remodeling with fibrosis are important pathogenesis. There are many proposed mechanisms and molecular pathways contributing to tissue remodeling and fibrosis in GO, including adipogenesis, fibroblast proliferation and myofibroblasts differentiation, oxidative stress, endoplasmic reticulum (ER) stress, hyaluronan (HA) and glycosaminoglycans (GAGs) accumulation in the extracellular matrix (ECM) and new concepts of epigenetics modification, such as histone modification, DNA methylation, non-coding RNAs, and gut microbiome. This review summarizes the current understanding of ECM proteins and associated tissue remodeling in the pathogenesis and potential mediators for the treatment of GO.

Choroidal structural changes in inactive thyroid eye disease: a cross-sectional analysis of the choroidal vascularity index.

OBJECTIVE: In this study, we aimed to compare choroidal vascular changes using the Choroidal Vascularity Index (CVI) between patients with inactive Thyroid Eye Disease (iTED) and healthy individuals, and to assess the relationship between CVI and choroidal thickness (CT), smoking history, and clinical parameters. METHODS: In this cross-sectional observational study, the eyes of 30 patients aged 18 to 45 with iTED were compared with the randomly selected eyes of 35 age and gender-matched healthy control individuals. Optical coherence tomography (OCT) scans were taken from all participants. The images were binarized using the ImageJ software, and the total choroidal area (TCA) and luminal area (LA) were measured. The ratio of the LA to the TCA was used to calculate the CVI. The relationships between these measurement parameters and clinical activity score (CAS), exophthalmometry, smoking status, and other clinical parameters were examined. RESULTS: In the iTED group, CT and CVI values were significantly higher compared to the control group (p < 0.001, p = 0.029). No significant effect of smoking on choroidal parameters was detected in the iTED group. Additionally, there was no statistical correlation between choroidal parameters and either exophthalmometry or CAS (p > 0.05). In the multivariate regression analysis, it was determined that CT showed a significant relationship with thyroid stimulating immunoglobulin (TSI) (p = 0.003). CONCLUSIONS: This study found that CT and CVI were increased in the eyes of patients with iTED compared to healthy controls. The history of smoking did not appear to have any effect on CT and CVI in iTED patients.

Selenium supplementation in inactive moderate to severe Graves' orbitopathy patients: a randomized controlled trial.

PURPOSE: This study was designed to evaluate the effect of selenium supplementation in inactive moderate-severe Graves' orbitopathy (GO) patients. METHODS: This study was a single-center, placebo-controlled, double-masked, randomized trial. Inactive moderate-severe GO participants were randomized to receive six months of 200 micrograms/day of selenium supplementation or placebo. Thorough eye exams, clinical activity score (CAS), Graves' Ophthalmopathy quality of life questionnaire (GO-QOL), and serum selenium level were evaluated at baseline and 6 months after the interventions. The chi-squared or Fisher's exact test was used to compare categorical variables. The t-test and the paired t-test were used to compare continuous variables between two independent samples and two dependent samples, respectively. RESULTS: A total of 25 participants were enrolled, 13 in the selenium group and 12 in the placebo group. Both groups had adequate baseline serum selenium levels at 98.96 ± 15.63 mcg/L and 102.55 ± 17.71 mcg/L, respectively. After 6 months of intervention, the selenium group showed a greater improvement in palpebral aperture (mean difference: -1.4 ± 1.7 mm, p = .04) compared to the placebo group (-0.3 ± 2.7 mm). Notably, 5(41.67%) people in the placebo group developed larger palpebral apertures. Proptosis, ocular motility, and soft tissue signs did not change significantly. GO-QOL and CAS score improvement showed no statistically significant difference between both groups. Minor adverse effects were observed. CONCLUSIONS: Selenium supplementation has a positive effect on eyelid aperture even in inactive moderate-to-severe GO patients with a sufficient baseline selenium level.

Superior orbital fissure syndrome after deep lateral orbital wall decompression in Graves' ophthalmopathy.

PURPOSE: The superior orbital fissure contains cranial nerves III, IV, VI, and V1 with their three branches: frontal, lacrimal, and nasociliary. Superior orbital fissure syndrome (SOFS) is rare and can occur as a result of compression of these nerves due to trauma, bleeding, or inflammation in the retrobulbar space, but no cases of SOFS after deep lateral orbital wall decompression (DLOWD) have been reported. The aim of this paper is to describe this pathology, its possible causes, management, and outcome. METHODS: Retrospective study of 575 DLOWD in patients with disfiguring exophthalmos due to Graves' ophthalmopathy performed in our hospital between 2010 and 2023. Three cases of postoperative SOFS were identified based on clinical presentation, history, physical examination, and radiological study. All patients were observed for a minimum of 12 months. RESULTS: SOFS was diagnosed with the presence of ophthalmoplegia, ptosis, fixed and dilated pupils, hypo/anesthesia of the upper eyelid and forehead, loss of corneal reflex, and no loss of vision after DLOWD. Fractures, edema, and hemorrhages were excluded. They were treated with high-dose intravenous steroids and the patients recovered completely. CONCLUSIONS: DLOWD challenges orbital surgeons because it requires removing bones near the globe or neurovascular structures. SOFS may occur due to the proximity and increased pressure on these structures.

Thyroid Eye Disease and Glaucoma: A Cross-Sectional Study Comparing Clinical Characteristics and Disease Severity.

Background and Objectives: This study investigates the relationship between thyroid eye disease (TED) and open-angle glaucoma (OAG), focusing on disease severity and clinical features. Materials and Methods: Conducted at the Timis County Emergency Clinical Hospital, the research included 106 patients, with 53 having both conditions and 53 having only OAG. Key metrics analyzed included intraocular pressure (IOP) using a Goldmann applanation tonometer, the retinal nerve fiber layer (RNFL) thickness, and optic nerve head (ONH) characteristics evaluated using optical coherence tomography (OCT). Results: Results indicated that patients with both TED and OAG experienced a 6.09% reduction in RNFL thickness and showed more rapid disease progression, with 48.35% having active TED. The mean IOP in TED patients was 27.5 ± 4.9 mmHg, which was similar to those with only OAG. Demographic factors, including age and gender, influenced the clinical course and disease severity. Conclusions: These findings underscore the importance of specialized monitoring and treatment strategies for patients with coexisting TED and OAG to prevent vision loss.

IL-17 and IL-38 gene polymorphisms in thyroid-associated ophthalmopathy.

BACKGROUND: Thyroid-associated ophthalmopathy (TAO) is an autoimmune condition commonly linked with Graves' disease (GD), characterized by orbital tissue inflammation and fibrosis. It is hypothesized that gene polymorphisms may influence production of the IL-17 and IL-38 cytokines, thereby impacting TAO development and progression. This study focused on investigating the gene polymorphisms of IL-17 (rs9463772 C/T in IL17F) and IL-38 (rs3811058 C/T, rs7570267 A/G in IL1F10) in patients with GD. METHODS: A case-control study was conducted on 132 patients with TAO and 153 patients without TAO according to eligibility criteria. After clinical examination blood samples were collected for further investigations. Genotyping was performed with the TaqMan™ Master Mix kit. Allele and genotype frequencies were compared between studied groups and subgroups. RESULTS: No significant differences were found in age, duration of GD, or thyroid hormone between patients with and without TAO. However, a higher predisposition to develop TAO was observed among smokers (OR = 1.682, p = 0.03). Overall, no significant associations between gene polymorphisms and TAO development were identified in GD patients. Further analysis revealed that the CC genotype in IL1F10 rs3811058 polymorphism among Caucasians was associated with an increased risk of TAO (OR = 2.7, p = 0.02), as well as allele differences were also significant (OR = 2.8, p = 0.001). CONCLUSIONS: These findings shed light on TAO genetic predispositions in Kazakhstani GD patients, notably among Caucasians, underscoring the need for further research. These results may offer valuable targets for the development of novel treatments for TAO.