OBJECTIVE: 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.
METHODS: Multicenter retrospective study.
METHODS: 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.
METHODS: 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.
BACKGROUND: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

OBJECTIVE: Aimed to create a nomogram using clinical and eye-specific metrics to predict the efficacy of intravenous glucocorticoid (IVGC) therapy in patients with active and moderate-to-severe Thyroid-Associated Ophthalmopathy (TAO).
METHODS: This study was conducted on 84 eyes from 42 moderate-to-severe TAO patients who received systemic IVGC therapy, and 42 eyes from 21 controls. Data were collected retrospectively from June 2020 to December 2021. The least absolute shrinkage and selection operator (LASSO) method was used to identify predictive factors for \"unresponsiveness\" to IVGC therapy. These factors were then analyzed using logistic regression to create a nomogram. The model\'s discriminative ability was robustly assessed using a Bootstrap resampling method with 1000 iterations for receiver operating characteristic (ROC) curve analysis.
RESULTS: The LASSO analysis identified six factors with non-zero coefficients as significant, including Schirmer I test values, Meibomian gland (MG) diameter, MG length, disease duration, whole capillary vessel density (VD) in the radial peripapillary capillary (RPC), and whole macular VD for the superficial retinal capillary plexus (SRCP). The subsequent logistic regression model highlighted MG length, whole macular VD for SRCP, and disease duration as independent predictors of IVGC therapy response. The constructed nomogram demonstrated an area under the curve (AUC) of 0.82 (95% CI: 0.73-0.91), affirming the model\'s consistent and reliable ability to distinguish between responsive and non-responsive TAO patients.
CONCLUSIONS: Our nomogram, combining MG length (<4.875 mm), SRCP VD (<50.25%), and disease duration (>5.5 months), reliably predicts lower IVGC therapy effectiveness in active, moderate-to-severe TAO patients.

BACKGROUND: Graves\' ophthalmopathy (GO) is an autoimmune inflammatory disorder observed in a substantial proportion of patients with Graves\' disease (GD), with debilitating symptoms of disfiguring, periorbital pain, dry eyes, diplopia, and even visual disturbances. Previous studies involving Western populations have noted discrepancies in risk factors for GO. Therefore, this study aimed to determine the risk factors for GO development and the protective effect of statins in newly diagnosed patients with GD in Taiwan.
METHODS: This retrospective case-control study was based on a tertiary center cohort involving patients with GD diagnosed between 2010 and 2019 at the National Taiwan University Hospital (n = 11,035). Patients who were diagnosed or treated elsewhere, had been followed up for less than 6 months or were with a diagnosis of orbital tumor were excluded. Overall, 3578 patients with GD met the inclusion criteria. Univariate and multivariate logistic regression analyses were used to ascertain the odds ratio (OR) of developing GO, with adjustment for sociodemographic factors, interventions for managing GD and thyroid hormone levels, to determine protective and risk factors for GO.
RESULTS: In our multivariate model, the use of statins reduced the risk of GO development (OR 0.2; 95% confidence interval [CI] 0.08-0.50; p < 0.001). Thyroid dysfunction including hyperthyroidism (OR 4.2; 95% CI 2.97-5.88; p < 0.001) and hypothyroidism (OR 4.7; 95% CI 3.02-7.19; p < 0.001) was associated with an increased risk of developing GO. Smoking status and lipid profile were not risk factors in our cohort.
CONCLUSIONS: In newly diagnosed patients with GD, the use of statins decreased the risk of developing GO by 80%, whereas serum lipid levels were not considered risk factors. Further nationwide population-based studies may help clarify the differences in risk factors between various ethnic groups.
BACKGROUND: This trial was approved by the Research Ethics Committee of National Taiwan University Hospital (202202066RINC), retrospectively registered from January 1, 2010 to December 31, 2019.

UNASSIGNED: We aimed to evaluate the spontaneous neuronal activity and functional connectivity pattern variations using resting-state functional magnetic resonance imaging (rs-fMRI) measures, such as amplitude of low-frequency fluctuation (ALFF), fractional amplitude of low-frequency fluctuation (fALFF), and functional connectivity (FC), in patients with thyroid-associated ophthalmopathy (TAO).
UNASSIGNED: A total of 24 active TAO patients, 26 inactive TAO patients, and 27 matched healthy controls (HCs) were included. First, ALFF and fALFF were used to detect local neural activity changes, the MRI data were analyzed, and regions with group differences were taken as seeds. Second, FC analysis was performed to explore the altered connection between seeds and other brain regions. A correlation analysis was performed to assess the relationship between functional brain activity and clinical indices and neuropsychiatric behaviors.
UNASSIGNED: Compared to HCs, both active and inactive TAO patients exhibited significantly lower ALFF values in the right calcarine (Calcarine_R) and left postcentral gyrus (Postcentral_L). Active TAO patients also showed significantly higher ALFF values in the left caudate nucleus (Caudate_L) and increased fALFF values in the superior lobe of the right cerebellum (Cerebelum_Crus1_R). Moreover, both active and inactive TAO patients demonstrated decreased FC within the left postcentral gyrus (Postcentral_L) compared to HCs. Additionally, active TAO patients exhibited lower FC compared to inactive TAO patients. The ALFF values in the Calcarine_R of active TAO patients positively correlated with disease duration (r = 0.5892, p = 0.0049) and the Hamilton Anxiety Rating Scale (HARS; r = 0.5377, p = 0.0119). Furthermore, the ALFF value in the Calcarine_R of inactive TAO patients negatively correlated with visual functioning (r = -0.5449, p = 0.0072), while the ALFF values in the Caudate_L of active TAO patients positively correlated with visual functioning (r = 0.6496, p = 0.0014).
UNASSIGNED: We found that the Caudate_L and Cerebelum_Crus1_R related to motor control and coordination in active TAO patients exhibit significant compensatory mechanisms; whereas, the Calcarine_R and Postcentral_L related to visual and somatosensory cortices show varying degrees of impairment. Our findings complement the functional neural mechanism of TAO.

OBJECTIVE: To investigate the brain functional alterations in dysthyroid optic neuropathy (DON) by evaluating spontaneous neural activity, using functional magnetic resonance imaging (fMRI) with regional homogeneity (ReHo), and its relationship with ophthalmologic performance.
METHODS: Forty-seven patients with thyroid-associated ophthalmopathy (TAO; 20 with DON, 27 with non-DON) and 33 age-, sex-, and education-matched healthy controls (HCs) underwent fMRI. ReHo values were compared using one-way analysis of variance (ANOVA) with post hoc pairwise comparisons (voxel-level p < 0.01, Gaussian random field correction, cluster-level p < 0.05). Correlations between ReHo values and ophthalmological metrics were assessed for DONs, with Bonferroni correction for multiple comparisons (p < 0.004). ROC curves were applied to evaluate the diagnostic performance of ReHo metrics.
RESULTS: ReHo values were significantly lower in the left insula and right superior temporal gyrus, and higher in the left posterior cingulate cortex (LPCC), of DON than of non-DON patients. ReHo values were also significantly lower in the right middle temporal, left insula, and left precentral gyrus in DON than in HCs. Meanwhile, ReHo values were higher in LPCC in non-DON than in HCs. ReHo values correlated with ophthalmic examinations to varying degrees in DON. For distinguishing DON, the ReHo values in LPCC showed optimal individually (AUC = 0.843), the combination of the ReHo in both the left insula and LPCC performed better (AUC = 0.915).
CONCLUSIONS: Spontaneous brain activity differed between TAO with and without DON, which may reflect the underlying pathological mechanism of DON. The ReHo index can be considered a diagnostic biomarker.
CONCLUSIONS: Spontaneous brain activity in DON differed from that in TAO without DON, which may reflect the underlying pathological mechanism of DON. The ReHo index can be considered a diagnostic biomarker for early detection of DON.
CONCLUSIONS: • Dysthyroid optic neuropathy (DON) affects brain activity, which contributes in the understanding of its visual dysfunction. • Regional homogeneity values differ between thyroid-associated ophthalmopathy with and without DON in various brain regions. • Regional homogeneity values can be used as a biomarker in the differential diagnosis of DON.

Thyroid-associated ophthalmopathy (TAO), also known as Graves\' ophthalmopathy, is an autoimmune disease that is usually accompanied by hyperthyroidism. Its pathogenesis involves the activation of autoimmune T lymphocytes by a cross-antigen reaction of thyroid and orbital tissues. The thyroid-stimulating hormone receptor (TSHR) is known to play an important role in the development of TAO. Because of the difficulty of orbital tissue biopsy, the establishment of an ideal animal model is important for developing novel clinical therapies of TAO. To date, TAO animal modeling methods are mainly based on inducing experimental animals to produce anti-thyroid-stimulating hormone receptor antibodies (TRAbs) and then recruit autoimmune T lymphocytes. Currently, the most common methods are hTSHR-A subunit plasmid electroporation and hTSHR-A subunit adenovirus transfection. These animal models provide a powerful tool for exploring the internal relationship between local and systemic immune microenvironment disorders of the TAO orbit, facilitating the development of new drugs. However, existing TAO modeling methods still have some defects, such as low modeling rate, long modeling cycles, low repetition rate, and considerable differences from human histology. Hence, the modeling methods require further innovation, improvement, and in-depth exploration.

BACKGROUND: Clinically, thyroid-associated ophthalmopathy (TAO) patients were suffered from dry eye syndrome. Only a few relevant studies were about this topic. Our study was determined to provide high-level evidence for the treatment of TAO with dry eye syndrome.
OBJECTIVE: To compare the clinical effects of vitamin A palmitate eye gel and sodium hyaluronate eye drop forTAO patients with dry eye syndrome.
METHODS: The study was conducted in the Ophthalmology Department of the Ninth People\'s Hospital Affiliated with the Medical College of Shanghai Jiao Tong University from May to October 2020. A total of 80 mild or moderate-to-severe TAO patients with dry eye syndrome were randomly divided into two groups. The disease stages of all subjects were inactive. Patients in group A were treated with vitamin A palmitate eye gel three times/day for one month and sodium hyaluronate eye drop in group B. The index including break-up time (BUT) and Schirmer I test (ST), corneal fluorescence staining (FL), ocular surface disease index (OSDI), and adverse reactions were recorded by the same clinician at baseline and 1 month after treatment. The data were analyzed by SPSS 24.0.
RESULTS: Finally, 65 subjects completed the treatment. The average age of the patients in Group A was 38.1 ± 11.4 years, and that in Group B was 37.26 ± 10.67 years. 82% of the subjects in group A were female and 74% in group B. There was no significant difference between the two groups at baseline, including the value of ST, BUT, OSDI, and FL grade. After the treatment, the effective rate was 91.2% in group A, of which the value of BUT and FL grade was significantly improved (P < 0.001). The effective rate in group B was 67.7%, of which the value of OSDI score and FL grade was significantly improved (P = 0.002). In addition, the BUT value of group A was significantly longer than that of group B (P = 0.009).
CONCLUSIONS: InTAO patients with dry eye syndrome, vitamin A palmitate gel and sodium hyaluronate eye drop improved the dry eye and promoted corneal epithelial repair. Vitamin A palmitate gel improves the stability of tear film, while sodium hyaluronate eye drop improves patients\' subjective discomfort.

UNASSIGNED: To report the efficacy, long-term safety, and tolerability of using a small dose (125 mg/m2 weekly for 4 weeks) of rituximab to treat Chinese patients with thyroid-associated ophthalmopathy (TAO).
UNASSIGNED: Seven patients with active moderate-to-severe TAO were prospectively recruited in this study. A small dose of rituximab (125mg/m2 body surface area) was given weekly with a duration of four weeks. Thyroid function, thyrotropin receptor antibody (TRAb), B cell and T cell subsets, ophthalmological examination, magnetic resonance imaging derived parameters, and adverse reactions were recorded at each visit.
UNASSIGNED: Seven patients were followed for an average of 224 weeks. B-cell depletion was observed in all patients following rituximab infusion. The clinical activity score (CAS) decreased from 4.86 ± 0.69 to 3.00 ± 0.82 at 5 weeks after treatment (P = 0.033) and remained significantly lower than baseline values at the end of follow-up (P = 0.001). Compared to baseline values, significant decreases in exophthalmos of the right eye, the thickness of extraocular muscles with maximum signal intensity, and the highest signal intensity ratio (SIR) of extraocular muscle to ipsilateral temporal muscle values were observed at the last follow-up (all P < 0.05). Disease progressions or recurrences were not observed during follow-up. Only mild fatigue was observed after the first infusion as a side effect (n = 1).
UNASSIGNED: Small dose of rituximab may be a promising option with adequate safety, tolerability, and long-term efficacy for patients with active moderate-to-severe TAO.

OBJECTIVE: Thyroid-associated ophthalmopathy (TAO) is an autoimmune disorder involving the orbital tissue. This study aimed to understand the role of regulatory T cells (Tregs) in TAO during 12-week systemic glucocorticoid (GC) treatment.
METHODS: Thirty-two moderate-severe TAO patients with a clinical activity score (CAS) ≥3/7 or with prolonged T2 relaxation time (T2RT) on at least one side of extraocular muscle (EOM) were enrolled. The percentage of the peripheral CD4+CD25(high)CD127(-/low) Tregs was analyzed using flow cytometry before and after the GC treatment. The activity and severity of TAO, T2RT, and the clinical outcomes after the GC treatment were assessed. Their correlation with the peripheral Tregs was investigated.
RESULTS: There was no significant association between the baseline Treg fraction and the activity and severity of TAO or the treatment response. A significant reduction of Tregs was observed after the GC therapy merely in patients without any clinical improvement.
CONCLUSIONS: Treg reduction after systemic GC therapy is indicative of a poor therapeutic response. Accordingly, dynamic alterations of Tregs could help to evaluate the effectiveness of the GC treatment.

Besides the well-documented ophthalmic manifestations, thyroid-associated ophthalmopathy (TAO) is believed to be related to emotional and psychological abnormalities. Given the previous neuroimaging evidence, we hypothesized that TAO patients would have altered neurovascular coupling associated with clinical-psychiatric disturbances. This study was to investigate neurovascular coupling changes in TAO by combining resting-state functional magnetic resonance imaging (rs-fMRI) and arterial spin labeling (ASL) techniques. Amplitude of low-frequency fluctuation (ALFF) was calculated from rs-fMRI, and cerebral blood flow (CBF) was computed from ASL in 37 TAO patients and 21 healthy controls (HCs). Global neurovascular coupling was assessed by across-voxel CBF-ALFF correlation, and regional neurovascular coupling was evaluated by CBF/ALFF ratio. Auxiliary analyses were performed using fractional ALFF (fALFF) and regional homogeneity (ReHo) as rs-fMRI measures. Compared with HCs, TAO patients showed significantly reduced global CBF-ALFF coupling. Moreover, TAO patients exhibited decreased CBF/ALFF ratio in the left lingual gyrus (LG)/fusiform gyrus (FFG), and increased CBF/ALFF ratio in the bilateral precuneus (PCu). In TAOs, CBF/ALFF ratio in the left LG/FFG was positively correlated with visual acuity, while CBF/ALFF ratio in the bilateral PCu was negatively correlated with Montreal Cognitive Assessment score. The auxiliary analyses showed trends of reduced global neurovascular coupling (i.e., CBF-fALFF correlation and CBF-ReHo correlation), as well as significant altered regional neurovascular coupling (i.e., CBF/fALFF ratio and CBF/ReHo ratio) in several brain regions. These findings indicated that TAO patients had altered neurovascular coupling in the visual and higher-order cognitive cortices. The neurovascular decoupling might be a possible neuropathological mechanism of TAO.