Active Thyroid-associated Ophthalmopathy Research Articles

Expression of Collagen XIII in Tissues of the Thyroid and Orbit With Relevance to Thyroid-Associated Ophthalmopathy.

Antibodies against collagen XIII have previously been identified in patients with active thyroid-associated ophthalmopathy (TAO). Although collagen XIII expression has been described in extraocular muscles and orbital fat, its detailed localization in extraocular and thyroid tissues and the connection to autoimmunity for collagen XIII remain unclear. Our objective was to map the potential targets for these antibodies in the tissues of the orbit and thyroid. We evaluated the expression of collagen XIII in human patient and mouse orbital and thyroid tissues with immunostainings and RT-qPCR using Col13a1-/- mice as negative controls. COL13A1 expression in Graves' disease and goiter thyroid samples was compared with TGF-β1 and TNF, and these were also studied in human thyroid epithelial cells and fibroblasts. Collagen XIII expression was found in the neuromuscular and myotendinous junctions of extraocular muscles, blood vessels of orbital connective tissue and fat and the thyroid, and in the thyroid epithelium. Thyroid expression was also seen in germinal centers in Graves' disease and in neoplastic epithelium. The expression of COL13A1 in goiter samples correlated with levels of TGF-B1. Upregulation of COL13A1 was reproduced in thyroid epithelial cells treated with TGF-β1. We mapped the expression of collagen XIII to various locations in the orbit, demonstrated its expression in the pathologies of the Graves' disease thyroid and confirmed the relationship between collagen XIII and TGF-β1. Altogether, these data add to our understanding of the targets of anti-collagen XIII autoantibodies in TAO.

An ensemble deep learning diagnostic system for determining Clinical Activity Scores in thyroid-associated ophthalmopathy: integrating multi-view multimodal images from anterior segment slit-lamp photographs and facial images.

Thyroid-associated ophthalmopathy (TAO) is the most prevalent autoimmune orbital condition, significantly impacting patients' appearance and quality of life. Early and accurate identification of active TAO along with timely treatment can enhance prognosis and reduce the occurrence of severe cases. Although the Clinical Activity Score (CAS) serves as an effective assessment system for TAO, it is susceptible to assessor experience bias. This study aimed to develop an ensemble deep learning system that combines anterior segment slit-lamp photographs of patients with facial images to simulate expert assessment of TAO. The study included 156 patients with TAO who underwent detailed diagnosis and treatment at Shanxi Eye Hospital Affiliated to Shanxi Medical University from May 2020 to September 2023. Anterior segment slit-lamp photographs and facial images were used as different modalities and analyzed from multiple perspectives. Two ophthalmologists with more than 10 years of clinical experience independently determined the reference CAS for each image. An ensemble deep learning model based on the residual network was constructed under supervised learning to predict five key inflammatory signs (redness of the eyelids and conjunctiva, and swelling of the eyelids, conjunctiva, and caruncle or plica) associated with TAO, and to integrate these objective signs with two subjective symptoms (spontaneous retrobulbar pain and pain on attempted upward or downward gaze) in order to assess TAO activity. The proposed model achieved 0.906 accuracy, 0.833 specificity, 0.906 precision, 0.906 recall, and 0.906 F1-score in active TAO diagnosis, demonstrating advanced performance in predicting CAS and TAO activity signs compared to conventional single-view unimodal approaches. The integration of multiple views and modalities, encompassing both anterior segment slit-lamp photographs and facial images, significantly improved the prediction accuracy of the model for TAO activity and CAS. The ensemble multi-view multimodal deep learning system developed in this study can more accurately assess the clinical activity of TAO than traditional methods that solely rely on facial images. This innovative approach is intended to enhance the efficiency of TAO activity assessment, providing a novel means for its comprehensive, early, and precise evaluation.

Artificial Intelligence-based quantitative evaluation of retinal vascular parameters in thyroid-associated ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO) may result in increased metabolism and abnormalities in microcirculation. The fractal dimension (Df) of retinal vessels has been shown to be related to the pathology of a number of ophthalmic disorders, but it hasn't been investigated in TAO. We analyzed 1078 participants aged 18 to 72 (548 healthy volunteers and 530 TAO). Images were captured using a non-mydriatic 45-degree fundus camera. Baseline retinal characteristics, such as vessel width, tortuosity, and Df were measured using semiautomated software from fundus images. The average retinal parameters were compared between the two groups. The receiver operation curve (ROC) was used to assess the diagnostic efficacy of various retinal vascular parameters for TAO. Despite controlling for potential confounding variables, Df, vessel width, and tortuosity significantly increased in TAO compared to healthy volunteers. Compared to active TAO, patients in the inactive phase had a larger retinal venous caliber (p < 0.05), but there was no difference in Df or arterial caliber. Moderate and severe cases had a higher Df compared with mild cases (EUGOGO guidelines). The area under the ROC for Df, tortuosity, and vascular caliber in the diagnosis of TAO was 0.904 (95% CI: 0.884-0.924), 0.638 (95% CI: 0.598-0.679), and 0.617 (95% CI: 0.576-0.658), respectively. Due to its accessibility, affordability, and non-invasive nature, retinal vascular Df may serve as a surrogate marker for TAO and might be used to identify severe cases. With relatively high diagnostic performance, the Df is of some utility for the detection of TAO.

Choroidal thickness in patients with thyroid-associated ophthalmopathy, as determined by swept-source optical coherence tomography

AimThis study used swept-source optical coherence tomography (SS-OCT) to investigate subfoveal choroidal thickness (SFCT) in patients with thyroid-associated ophthalmopathy (TAO) who displayed different levels of disease activity and severity.MethodsThirty patients...

Clinical significance of the detection of serum IgG4 and IgG4/IgG ratio in patients with thyroid-associated ophthalmopathy.

To evaluate the clinical significance of detecting serum IgG4 and the IgG4/IgG ratio in patients with thyroid-associated ophthalmopathy (TAO) and to explore whether high serum IgG4 levels and the IgG4/IgG ratio are associated with the severity and activity of TAO, we retrospectively assessed the records of 78 TAO patients and 32 controls collected in our hospital from July 2020 to July 2022. The TAO patients were divided into TAO inactive and TAO active phase groups according to the clinical activity score (CAS), and we evaluated the association between the serum IgG4 levels, the IgG4/IgG ratio, and the clinical data of the participants. The levels of IgG4 significantly increased in the TAO active group compared to those in the inactive and control groups (P < 0.05). Additionally, the number of patients with increased IgG4 levels (≥135 mg/dL) in the TAO active group was markedly higher than that in the inactive and control groups (P < 0.05). The IgG4/IgG ratio was also significantly enhanced in the TAO active group compared to the inactive and control groups (P < 0.05). CAS was identified as an independent factor influencing IgG4 levels in patients with TAO. The levels of serum IgG4, as well as the IgG4/IgG ratio, were significantly increased in some patients with active TAO, and they were related to the CAS, suggesting that the pathogenesis of TAO may be heterogeneous.

Measurement of Sub-Foveal Choroidal Thickness in Hyperthyroid Patients with Thyroid Associated Ophthalmopathy, Using Spectral Domain OCT

Background Thyroid associated ophthalmopathy (TAO) is an auto-immune orbitopathy, associated with thyroid dysfunction. It results in compression of the orbital contents, impairment of the blood flow and thus affects the choroidal and retinal microstructure and function. Aim of the Work The purpose of this study is to measure the central choroidal thickness in active and inactive TAO using Optical Coherence Tomography (OCT) and compare it to the control group. Patients and Methods The cross section study was conducted on participants recruited from the ophthalmology clinic of the National Institute of Diabetes and Endocrinology (NIDE). The study included 160 eyes from 80 participants (40 hyperthyroidism patients and 40 control subjects). Data was collected during the period of December 2019 to June 2020. Results There was no significant difference regarding age, gender, vision and IOP between TAO patients (either active or inactive) and normal subjects. Our study showed that there was a significant increase in sub-foveal choroidal thickness in patients with TAO compared to the control group. It also showed a significant increase in sub-foveal choroidal thickness in the active subgroup more than the inactive subgroup. In addition, a decrease in central foveal thickness was found in patients with TAO compared to the control group, but there was no significant difference found between active and inactive subgroups. Conclusion The findings of this study suggest that there is a significant affection of sub-foveal choroidal thickness and central foveal thickness in thyroid-associated-ophthalmopathy (TAO) patients.

Corneal Morphological and Biomechanical Changes in Thyroid-Associated Ophthalmopathy.

This study aimed to evaluate corneal morphological and biomechanical changes in patients with thyroid-associated ophthalmopathy (TAO) and their correlations with activity and severity. Patients diagnosed with TAO were recruited and divided into groups by activity and severity. All subjects underwent a complete ophthalmic examination, including magnetic resonance imaging. Corneal topography was measured using a Pentacam device, and biomechanical parameters were obtained using a CorVis ST tonometer. Correlations among the corneal parameters, clinical activity score, and NOSPECS score were analyzed. Areas under the receiver operating characteristic curves were calculated to evaluate the diagnostic accuracy of corneal changes for active and severe TAO. Fifty-three eyes with TAO and 16 healthy eyes were enrolled in our study. The back elevation, CorVis biomechanical index, tomographic and biomechanical index, stiffness parameter at the first applanation, deviation from normality in back elevation, relational thickness, and overall deviation from normality were significantly increased in patients with TAO (all P <0.05), whereas the smallest corneal thickness, maximum Ambrósio relational thickness, and deformation amplitude (DA) ratio were significantly decreased (all P <0.05). The clinical activity score was strongly positively correlated with back elevation (γ = 0.515, P <0.001). The NOSPECS score was strongly positively correlated with relational thickness and tomographic and biomechanical index (γ = 0.429 and 0.515, P <0.001) and negatively correlated with maximum Ambrósio relational thickness (γ = -0.53, P <0.001). Moreover, maximum Ambrósio relational thickness and the Ambrósio relational thickness through the horizontal meridian showed desirable diagnostic capacity in distinguishing mild TAO from moderate-severe TAO (areas under the receiver operating characteristic curve, 0.799 and 0.769). Corneal morphological and biomechanical changes were found in patients with TAO, which might be related to the presence of inflammation. Measurements of corneal morphological and biomechanical parameters could serve as references in evaluating TAO.

Image quality and evaluation ability of magnetic resonance imaging techniques for thyroid-associated ophthalmopathy: Dixon fat-suppression technique vs. spectral attenuated inversion recovery.

We aimed to compare two magnetic resonance imaging (MRI) techniques, Dixon and spectral attenuated inversion recovery (SPAIR) fat-suppression, in terms of image quality and suitability for evaluating thyroid-associated ophthalmopathy (TAO) lesion characteristics. This cross-sectional, retrospective study involved 70 patients with TAO (140 eyes) who underwent orbital coronal MRI examinations, including Dixon-transverse relaxation (T2)-weighted imaging (T2WI) and SPAIR-T2WI, between 2020 and 2022. We compared the fat-suppression quality and artifacts, noise (N), signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), signal intensity ratio (SIR) of extraocular muscles (SIR-EOM) and lacrimal glands (SIR-LG), and TAO activity evaluation efficiency. Dixon-T2WI showed a higher frequency of better subjective image quality and suitability for evaluating the characteristics of TAO lesions (65.7% vs. 14.3%) than SPAIR-T2WI. Fat-suppression quality and artifact scores were lower for Dixon-T2WI than for SPAIR-T2WI (p < 0.001). The N, SNR, and CNR values, EOM-SIR, and LG-SIR were higher for orbital coronal Dixon-T2WI than for SPAIR-T2WI (all p < 0.001). Clinical activity scores (CASs) showed positive correlations with SIR. The correlation between EOM-SIR and LG-SIR of orbital coronal Dixon-T2WI with CAS was higher than that of SPAIR-T2WI (0.590 vs. 0.493, all p < 0.001; 0.340 vs. 0.295, all p < 0.01). EOM-SIR and LG-SIR of Dixon-T2WI yielded a higher area under the curve than SPAIR-T2WI for evaluating TAO activity (0.865 vs. 0.760, p < 0.001; 0.695 vs. 0.617, p = 0.017). Dixon-T2WI yields higher image quality than SPAIR-T2WI. Furthermore, it has a stronger ability to evaluate TAO inflammation than SPAIR, with higher sensitivity and specificity in active TAO staging.

Abnormal regional spontaneous neural activity and functional connectivity in thyroid-associated ophthalmopathy patients with different activity: a resting-state fMRI study.

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). 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. 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). 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.

T Cell Subsets are Associated with Clinical Activity and Efficacy of 4.5g Intravenous Glucocorticoid for Moderate-To-Severe Thyroid-Associated Ophthalmopathy

ABSTRACT Background Intravenous glucocorticoid (IVGC) remains the main treatment for moderate-to-severe and active thyroid-associated ophthalmopathy (TAO). However, a substantial number (20–30%) of active moderate-to-severe TAO patients may not respond to IVGC. Some patients may have disease progression despite IVGC treatment or relapse after steroid withdrawal. Objectives To analyze risk factors for clinical activity and predictive factors for clinical outcomes of 4.5 g IVGC therapy in patients with moderate-to-severe TAO. Design and methods Our study was performed in two steps: step 1 involved 110 moderate-to-severe TAO patients and analyzed risk factors for TAO activity; step 2 involved 53 active moderate-to-severe TAO patients from step 1 who were treated with 4.5 g IVGC therapy and analyzed predictive factors for clinical outcomes of IVGC therapy. Multivariate logistic regression analysis was used to identify the independent predictors and establish the predictive model. Results Abnormal TRAb (OR = 4.717; P = 0.019) and the percentage of CD3+CD4+ T cell (OR = 1.092; P = 0.028) were independently associated with the activity of moderate-to-severe TAO patients. The pretreatment CAS-max in both eyes (OR = 7.221; P = 0.013) and the percentage of pretreatment CD3+T cell (OR = 0.718; P = 0.037) were independently associated with therapeutic efficacy. The pretreatment CAS-max in both eyes (OR = 156.53; P = 0.028) and the percentage of post-treatment CD3+T cell (OR = 0.554; P = 0.043) were independently associated with therapeutic efficacy. Besides, multivariable prediction models were established, which were better in the forecasting aspect than single-variable prediction models. Conclusions Based on the findings of this study, we should monitor the peripheral blood T cell subsets for TAO, which could be helpful to timely judge the condition of clinical manifestation and effect of treatment for TAO patients. Multivariable prediction models have been established, which have great significance for clinical work.

Disrupted dynamic amplitude of low-frequency fluctuations in patients with active thyroid-associated ophthalmopathy.

Purpose: Thyroid-associated ophthalmopathy (TAO) is an autoimmune disease that affects the orbit and is the most prevalent extra-thyroidal complication of Graves' disease. Previous neuroimaging studies have focused on abnormal static regional activity and functional connectivity in patients with TAO. However, the characteristics of local brain activity over time are poorly understood. This study aimed to investigate alterations in the dynamic amplitude of low-frequency fluctuation (dALFF) in patients with active TAO and to distinguish patients with TAO from healthy controls (HCs) using a support vector machine (SVM) classifier. Methods: A total of 21 patients with TAO and 21 HCs underwent resting-state functional magnetic resonance imaging scans. dALFFs were calculated in conjunction with sliding window approaches to assess dynamic regional brain activity and to compare the groups. Then, we used SVM, a machine learning algorithm, to determine whether dALFF maps may be used as diagnostic indicators for TAO. Results: Compared with HCs, patients with active TAO showed decreased dALFF in the right calcarine, lingual gyrus, superior parietal lobule, and precuneus. The SVM model showed an accuracy of 45.24%-47.62% and area under the curve of 0.35-0.44 in distinguishing TAO from HCs. No correlation was found between clinical variables and regional dALFF. Conclusion: Patients with active TAO showed altered dALFF in the visual cortex and the ventral and dorsal visual pathways, providing further details on the pathogenesis of TAO.

Efficacy and Safety of 6-Weekly versus 12-Weekly Intravenous Methylprednisolone in Moderate-to-Severe Active Thyroid-Associated Ophthalmopathy.

To compare the efficacy and safety of 6-weekly and 12-weekly intravenous methylprednisolone (IVMP) regimens in moderate-to-severe, active thyroid-associated orbitopathy (TAO) patients. Retrospective comparative study of patients who received IVMP between January 2011 and July 2021 at the Thyroid Eye Clinic, the Chinese University of Hong Kong. Outcome measures included the 7-item clinical activity score (CAS), exophthalmos, extraocular muscle motility (EOMy), marginal reflex distance (MRD), best corrected visual acuity (BCVA), intraocular pressure (IOP), the requirement of additional treatment, and complications. A total of 65 (63% (41/65) females) moderate-to-severe, active TAO patients aged 50 ± 13 (25-74) years received 6-weekly (n = 22) or 12-weekly (n = 43) IVMP. Sex, age, smoking status, and Graves' disease status were comparable in the two groups (all p > 0.05). CAS at week 6 (p = 0.0279), 12 (p = 0.00228), and 52 (p = 0.0228) were lower at each time for the 12-weekly group. Exophthalmos improved more at week 6 (p = 0.0453) and 12 (p = 0.0347) in the 12-weekly group. The improvement of diplopia, MRD1, MRD2, and EOMy were comparable between the two groups. More patients in the 6-weekly group (p = 0.00169) required additional treatments including IVMP+/-ORT. Patients in the 6-weekly group who did not require additional treatment had a lower presenting CAS (p = 0.0193) than those who required additional treatment. The total numbers of adverse events were comparable between the two groups.

An evaluation of corneal endothelial cell morphology in patients with thyroid-associated ophthalmopathy.

To evaluate corneal endothelial cell morphology in patients with thyroid-associated ophthalmopathy (TAO). Seventy-two eyes of 36 patients with TAO presenting to the ophthalmology department between January 2018 and January 2022 were included in the study. The findings were compared with 98 eyes of 49 healthy individuals. Mean endothelial cell density (ECD), coefficient of variation (CV), maximum cell area, minimum cell area, average cell area, and hexagonality ratio were obtained using non-contact specular microscopy. The thicknesses of peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell complex (GCC) were measured using optical coherence tomography (OCT). The TAO group consisted of 36 patients, 11 (30.6%) men and 25 (69.4%) women, and the control group of 49 healthy individuals, 14 (28.6%) men and 35 (71.4%). No significant differences were determined between the TAO and control groups in terms of the specular microscopy findings of mean ECD, CV, or hexagonality ratio values (p > 0,05). However, the mean Hertel values differed significantly between the two groups (p = 0.001). When the TAO group was divided into two subgroups based on patients who had previously received prednisolone therapy and those who had not, significant differences were observed in terms of mean ECD, CV, and hexagonality ratio values (p > 0.05). Comparison of patients diagnosed with active TAO and receiving prednisolone therapy and the TAO patients with inactive disease revealed lower ECD, higher CV values, and lower hexagonality ratios in the prednisolone therapy group. These findings all suggest that inflammation in patients undergoing active disease affects the corneal endothelium.

Therapeutic outcomes of mycophenolate mofetil and glucocorticoid in thyroid-associated ophthalmopathy patients.

To analyze the efficacy of mycophenolate mofetil (MMF) and glucocorticoid administration in patients with thyroid-associated ophthalmopathy (TAO). Sixty patients with moderate to severe TAO treated in Jingzhou Central Hospital from January 2022 to June 2022 were selected and enrtolled in this study. The subjects were divided into experimental group (n=30) and control group (n=30) based on the random number table method. Glucocorticoid pulse therapy was provided in the control group, while MMF was given in the experimental group on the basis of Control group. Clinical activity score (CAS), quality of life (QOL), visual acuity, eyelid fissure width, intraocular pressure, and degree of exophthalmos were observed at the time of admission and at the 12th week and 24th post-treatment weeks. We compared the immune function (TRAb, IL-6, and CD4+/CD8+) of the two groups pre-treatment and 24 weeks post-treatment, and evaluated the clinical therapeutic effect. The clinical effective rates at 12 and 24 weeks in the experimental group were higher (73.3% and 83.3%) than those in the control group (46.7% and 60.0%) (P <0.05). After 12 weeks of treatment, patients' CAS scores, and bilateral lid fissure width decreased and right eye visual acuity increased in the control group compared with those before treatment (P < 0.05); further, after 24 weeks of treatment, patients' QOL scores and bilateral visual acuity increased and CAS scores, bilateral lid fissure width and proptosis decreased compared with those before treatment, and patients' QOL scores, CAS scores and bilateral proptosis improved more than those at 12 weeks of treatment (P <0.05). Additionally, greater improvements were observed in the patients' QOL and CAS scores, and proptosis after 24-week treatment than after 12-week treatment (P<0.05). In the experimental group, the QOL score and binocular visual acuity increased, whereas the CAS score, intraocular pressure, lid width, and proptosis decreased after 12 weeks of treatment as compared to the values of these parameters in the pre-treatment period (P < 0.05); after 24 weeks of treatment, greater improvements were established in the ocular-related indexes improved compared to the pre-treatment period and after 12 weeks of treatment (P < 0.05). After 12 weeks of treatment, the patients in the experimental group had more considerable improvements in the right visual acuity, right intraocular pressure, and left lid fissure width than the control group (P < 0.05); at 24 weeks of treatment, patients in the experimental group had greater improvements in the QOL score, bilateral visual acuity, intraocular pressure, bilateral lid fissure width, and bilateral proptosis than the control group (P < 0.05). No significant differences were found in the values of TRAb, IL-6, and CD4+/CD8+ between the two groups before treatment (P>0.05); the values of TRAb, IL-6, and CD4+/CD8+ in the experimental group was significantly lower than those before treatment and in the control group after 24weeks of treatment. (P>0.05). No statistically significant difference was observed in the incidence of liver damage and menstrual disorders between the two groups during the 24 weeks of treatment (P>0.05). The combination of oral MMF and glucocorticoid shock therapy is an effective drug for the treatment of patients with moderately active TAO.

Clinical phenotypes of euthyroid, hyperthyroid, and hypothyroid thyroid-associated ophthalmopathy.

To compare the demographic and clinical phenotypes of thyroid-associated ophthalmopathy (TAO) with euthyroidism (Eu-TAO), hyperthyroidism (Hr-TAO), and hypothyroidism (Ho-TAO). We enrolled 2158 TAO patients in this retrospective study and assessed their demographics, clinical manifestations, activity, and severity. Among the enrolled patients, 526 (24.37%) had Eu-TAO, 1544 (71.55%) had Hr-TAO, and 88 (4.08%) had Ho-TAO. Compared to Hr-TAO (2.02) and Ho-TAO (2.52) patients, Eu-TAO (1.57) patients had the lowest female-to-male ratio (p = 0.026). The mean ages of Eu-TAO, Hr-TAO, and Ho-TAO patients were 43.11 ± 12.05, 42.23 ± 13.63, and 47.39 ± 13.28years, respectively (p = 0.001). Patients with Eu-TAO had more unilateral involvement (50% vs. 14.38% vs. 21.59%, p < 0.001) than Hr-TAO or Ho-TAO patients. Clinically active TAO patients presented 8.56% in euthyroid vs. 13.86% in hyperthyroid vs. 11.36% in hypothyroid (p = 0.006). Regarding the severity of the European Group on Graves' Orbitopathy (EUGOGO) classification among euthyroid, hyperthyroid, and hypothyroid patients, mild TAO was present in 67.68, 54.27, and 72.72% of participants, moderate-to-severe TAO in 31.18, 42.49, and 26.14%, and sight-threatening TAO in 1.14, 3.24, and 1.14%, respectively. Eu-TAO was positively correlated with unilateral involvement (OR = 5.671, p < 0.001) and age (OR = 1.013, p = 0.003) and negatively correlated with the female-to-male ratio (OR = 0.656, p < 0.001) and TAO severity (OR = 0.742, p < 0.01). Eu-TAO patients are older and less likely to be female, and show more unilateral and milder clinical phenotypes than hyper/hypothyroid TAO patients.

The effect of acromegaly on thyroid disease.

Long-term stimulation of thyroid follicular epithelium by high growth hormone (GH) and insulin-like growth factor-1 (IGF-1) in patients with acromegaly can lead to thyroid dysfunction, goiter, thyroid nodules, and even thyroid cancer and thyroid-associated ophthalmopathy (TAO). Excessive GH/IGF-1 promotes goiter and thyroid nodule formation, which can be reversed by normalizing the IGF-1 levels with surgery or medical treatment. Whether patients with acromegaly have an increased risk of thyroid cancer remains controversial, and routine thyroid ultrasonography and regular cancer screening are recommended in such cases, especially when the nodules possess malignant propensity. TAO is an autoimmune disease and newer treatments are being discovered against it. Recent studies have reported that the IGF-1 receptor (IGF-1R) plays an important role in the pathogenesis of TAO, and the IGF-1R inhibitor teprotumumab involves significantly improved disease endpoints in patients with active TAO. Thyroid-stimulating hormone (TSH) receptor (TSHR) and IGF-1R co-immunoprecipitate in orbital and thyroid tissues to form a functional complex; thus, combined therapy targeting TSHR and IGF-1R may be more effective than single therapy.

The early diagnostic value of optical coherence tomography (OCT) and OCT angiography in thyroid-associated ophthalmopathy.

The retinal microvascular density changes have been identified in thyroid-associated ophthalmopathy (TAO) patients. Whereas a lack of research has been done on the diagnostic ability of optical coherence tomography (OCT) combined with optical coherence tomography angiography (OCTA) parameters. This study aims to evaluate the retina perfusion variations in eyes with active and stable TAO and its diagnostic abilities using OCT and OCTA. This is cohort longitudinal retrospective study. A total of 51 patients with TAO and 39 healthy controls (HCs) were recruited. The TAO eyes were divided into active and stable stage groups. The foveal avascular zone (FAZ), macular perfusion density (mPD), and peripapillary PD were measured by OCTA. The peripapillary retinal nerve fiber layer (RNFL), central retinal thickness (CRT), and whole macular volume (wMV) were measured by OCT. Visual evoked potential (VEP) and visual field (VF) were also assessed. The mPD of the superficial retinal capillary plexus (SRCP) was significantly different in all subfields among active, stable, and HC groups (p < 0.05) except for the temporal inner (p = 0.137), and the active group achieved the lowest PD. The FAZ size increased significantly in the active and stable groups compared with the HC group (p < 0.001). Significant difference was observed in mPD of deep retinal capillary plexus (DRCP) in all quadrants among three groups (p < 0.05). Moreover, PD parameters of optic nerve head (ONH) and radial peripapillary capillary plexus (RPCP) showed a different trend among three groups (p < 0.05). The r-value of visual field-mean deviation (VF-MD) of TAO with DRCP-whole PD (wPD) and RPCP-wPD was 0.421 and 0.299, respectively (p < 0.05). The DRCP-wPD in OCTA and RNFL in OCT were significantly higher in area under the receiver operating characteristic curve (AUC) than that of HC eyes. OCT and OCTA can noninvasively detect the peripapillary and macular changes in various stages of TAO patients, and it might be a high diagnostic value tool to monitor the TAO progression.

Turbo Gradient and Spin-Echo BLADE-DWI for Extraocular Muscles in Thyroid-Associated Ophthalmopathy

Purpose: To investigate feasibility and diagnostic performance of turbo gradient and spin-echo BLADE (proprietary name for Periodically Rotated Overlapping ParallEL Lines with Enhanced Reconstruction [PROPELLER] in Siemens MR systems)-diffusion weighted imaging (TGSE-BLADE-DWI) for depicting extraocular muscle (EOM) involvement and activity in thyroid-associated ophthalmopathy (TAO), and to compare TGSE-BLADE-DWI with readout-segmented echo-planar imaging (RESOLVE). Materials and methods: Thirty-five patients with identified TAO underwent the two DWI scans. Two radiologists visually scored the image quality of the two DWIs with respect to the susceptibility artifacts and geometric distortions on a three-point scale. The maximum size (Sizemax) of EOMs and corresponding ADCs (cADCs) of each patient were compared between the active and inactive phases. The clinical activity score (CAS) was used as a reference to assess the diagnostic performance of EOM ADCs for grading TAO activity. ROC analysis, Pearson correlation, and Wilcoxon signed-rank test were used for statistical analyses. Results: For scores of EOMs, the image quality of TGSE-BLADE-DWI was significantly higher than that of RESOLVE. There were no statistically significant differences between the AUCs of the two DWIs, Sizemax, or cADCs between the active and inactive phases. TGSE-BLADE-DWI ADCs were significantly higher than the RESOLVE ADCs in the right superior rectus, right lateral rectus, left superior rectus, and left inferior rectus. There were no statistically significant correlations between the cADC or Sizemax, and CAS. The highest AUC was 0.697 for RESOLVE and 0.657 for TGSE-BLADE-DWI. The best performing ADC threshold was 1.85 × 10-3 mm2/s with 85.7% sensitivity, 58.8% specificity and 66.67% accuracy for RESOLVE and 1.99 × 10-3 mm2/s with 79.0% sensitivity, and 55.6% specificity and 65.27% accuracy for TGSE-BLADE-DWI. Conclusion: Compared to RESOLVE, TGSE-BLADE-DWI provided improved image quality with fewer susceptibility artifacts and geometric distortions for EOM visualization and showed an equivalent performance in detecting active TAO.

Fibulin-1: a novel biomarker for predicting disease activity of the thyroid-associated ophthalmopathy.

This study was designed to investigate the association between fibulin-1(FBLN1) and thyroid-associated ophthalmopathy (TAO). The plasma FBLN1 levels were measured in 80 participants, including 30 active TAO patients, 25 inactive TAO patients, and 25 Graves disease (GD) patients without TAO using enzyme-linked immunosorbent assay (ELISA). TAO patients had significantly higher TRAb level than GD patients (p < 0.05). The active TAO patients consumed more tobacco and had higher CAS than inactive TAO patients (all p < 0.05). No significant differences were found in age, sex, and the level of FT3, FT4, and TSH between TAO and GD patients, and between the active and inactive TAO patients (all p > 0.05). The plasma FBLN1 level in TAO patients was higher than that in GD patients, and that in active patients was higher than that in inactive patients (all p < 0.05). Furthermore, the plasma FBLN1 level showed strong association with clinical activity score (CAS) of TAO (r = 0.67, p < 0.01). By receiver operator characteristic (ROC) curve analysis, FBLN1 demonstrated good efficiency for predicting disease activity at the cut-off value > 625.33 pg/ml with a sensitivity of 93.3% and a specificity of 88.0% (AUC:0.92, p < 0.01). The plasma FBLN1 levels correlated with TAO activity and a value >625.33 pg/ml was associated with active disease. Our results suggest that the plasma FBLN1 level could be a novel biomarker for predicting disease activity of TAO.

Alterations in Spontaneous Neuronal Activity and Microvascular Density of the Optic Nerve Head in Active Thyroid-Associated Ophthalmopathy.

PurposeTo investigate changes in local spontaneous brain activity in patients with active thyroid-associated ophthalmopathy (TAO) and explore the relationship between such alterations and microvascular indices.MethodsThirty-six active TAO patients with active phase and 39 healthy controls (HCs) were enrolled in this study. All participants underwent resting-state functional magnetic resonance imaging (rs-fMRI), neuropsychological tests, and ophthalmological examinations. The rs-fMRI-based fractional low-frequency fluctuation amplitude (fALFF) analysis methods were used to assess spontaneous brain activity in both groups. The structure (peripapillary retinal nerve fiber layer, pRNFL) and microvascular indices (the optic nerve head (ONH) whole image vessel density, ONH-wiVD, and peripapillary vessel density) were analyzed through optical coherence tomographic angiography imaging. The relationship between abnormal spontaneous brain activity and ophthalmological indices was analyzed using the Spearman’s rank correlation analysis.ResultsCompared with HCs, active TAO patients had increased fALFF in the right inferior temporal gyrus (R.ITG) and left posterior cingulate gyrus (L.PCC), but decreased fALFF in the right calcarine (R.CAL). The fALFF values in L.PCC were positively correlated with peripapillary vessel density, whereas fALFF values in R.CAL were negatively related to peripapillary vessel density.ConclusionsThis study demonstrates that changes in spontaneous brain activity of active TAO are accompanied by peripapillary microvascular variations. These results provide insights into the pathophysiological mechanisms of active TAO. In addition, the combination of fALFF values and peripapillary vessel density may be served as important references for better clinical decision making.