Rapid advances in the diagnosis and treatment of thyroid eye disease (TED) have led to the development of three patient care guidelines by regional professional societies: the European Group on Graves’ Orbitopathy, the Oculoplastics and Orbital Diseases Group of the Chinese Medical Association Ophthalmology Branch/Thyroid Group of the Chinese Medical Association Endocrinology Branch, and the American Thyroid Association/European Thyroid Association. Although broad consensus can be found across the three guidelines, important differences could affect patient management. This review examines and compares the recommendations of these guidelines across 11 dimensions, from disease diagnosis to treatment strategies. We explore the possible root sources of these variations. The review also suggests future directions and potential implications, thus providing a comprehensive perspective of current and future management of TED.

ABSTRACT Autoimmune thyroid diseases (AITD) are systemic conditions frequently associated with neurological manifestations, yet the underlying neural and immunological mechanisms remain unclear. This study focuses on thyroid eye disease (TED), a representative AITD, to provide a deeper insight into its neural mechanism. We first combined resting‐state functional magnetic resonance imaging (rs‐fMRI) data from a retrospective cohort of 116 TED patients with transcriptomic data from the Allen Human Brain Atlas. The analysis of rs‐fMRI data demonstrated significant alterations in frontal, parietal, subcortical, and brainstem regions in TED. By integrating rs‐fMRI data with regional transcriptomic profiles derived from the postmortem Allen Human Brain Atlas, enabling region‐level transcriptional inference, we revealed enriched pathways related to synaptic signaling, neurovascular regulation, and immune activation. Tissue and cellular level enrichment further showed close association with the cortex and neurons. Key neuroimaging findings identified in the retrospective cohort were subsequently validated in an independent prospective cohort of TED patients and healthy controls (TED: 39; HC: 42) using paired rs‐fMRI and peripheral blood RNA sequencing data, which identified significant associations between immune cell infiltration and neural activity patterns. Collectively, these findings delineate coordinated brain–immune associations in TED and generate hypotheses regarding neuroimmune interactions in AITD.

Metallic atrial septal defect (ASD) occluders are associated with various mid- to long-term complications. To address this, our team developed a novel biodegradable Pansy ASD occluder, and this multicenter RCT aimed to evaluate its effectiveness and safety. A prospective, multicenter, randomized controlled trial was carried out on adult and pediatric patients using the Pansy occluder with a biodegradable polydioxanone (PDO) framework. The primary efficacy endpoint of this clinical trial is the closure success rate at six months post-operation. From May 2021 to March 2023, a total of 127 patients were screened across seven research centers, with 112 patients (including 71 pediatric patients; 57 to the experimental group, 55 to the metal occluder control group) ultimately underwent occluder implantation. In these patients, the average defect size was 8.48 ± 2.86 mm in the experimental group and 10.41 ± 5.21 mm in the control group. The closure success rate at six months post-operation was 100

PURPOSE:This study aims to investigate retinal structure and vessel density (VD) alterations in the macular and optic nerve head (ONH) regions of patients with dysthyroid optic neuropathy (DON), and to assess their correlation with visual function. METHODS:A total of 133 thyroid eye disease (TED) patients (63 with DON and 70 without DON) and 24 healthy controls were enrolled. Retinal structural and vascular parameters were quantified using optical coherence tomography angiography (OCTA) in the macular (6 × 6 mm) and ONH (4 × 4 mm) regions. Visual function in TED patients was assessed by best corrected visual acuity (BCVA), visual field (VF), and visual evoked potentials. The diagnostic performance of OCTA parameters for identifying DON was evaluated using the area under the receiver operating characteristic curve (AUC). RESULTS:Compared with the non-DON patients, those with DON exhibited significantly decreased retinal VD in both macular and ONH regions, accompanied by thinner macular retina. The most pronounced changes were observed in macular whole retinal layer (WRL) and superficial retinal layer VD (P < 0.001). Both retinal VD and thickness correlated positively with BCVA and VF mean deviation. Furthermore, the macular WRL-VD demonstrated the highest diagnostic performance for DON (AUC = 0.833) and the combination parameters further improved accuracy (AUC = 0.861). CONCLUSIONS:OCTA reveals retinal microvascular and structural alterations in DON and may serve as a simple, precise, and noninvasive tool for early detection and clinical management to prevent irreversible visual loss.

Orbital rim repositioning is a pivotal step in lateral orbitotomy. This study aims to introduce a novel mortise-tenon joint fixation (MTF) technique inspired by traditional Chinese woodcraft for lateral orbital rim reconstruction. This retrospective case series analyzed outcomes in patients with thyroid eye disease (TED) undergoing balanced orbital decompression surgery using MTF. The clinical outcomes, the number of surgical implants used, and hospitalization costs were analyzed. Additionally, an orbital model of the same laterality, derived from another patient treated with titanium plate-and-screw fixation (PSF), was selected as the comparator for the three-dimensional finite element analysis. Analysis was conducted with masseter muscle fixation and the application of occlusal force on the masseter muscle. Nine TED patients (12 orbits) undergoing MTF reconstruction were enrolled. A mean proptosis reduction of 5.3 ± 0.9 mm was achieved. No complications such as severe hemorrhage, vision loss, or orbital rim displacement were observed. Finite element analysis showed that maximum stress was lower with MTF than with PSF: 8.59 MPa vs. 91.33 MPa (masseter muscle fixation) and 16.33 MPa vs. 91.20 MPa (force applied). Maximum displacement was also lower for MTF: 0.010 mm vs. 0.014 mm (masseter muscle fixation) and 0.026 mm vs. 0.033 mm (force applied). Implant material expenses in hospitalization costs decreased by $288.43-$412.00, representing an approximate 84.3% reduction compared to PSF. In summary, the MTF technique demonstrates safety, effectiveness, and biomechanical advantages for orbital rim repositioning during lateral orbitotomy. It also reduces patient costs, offering a promising alternative to traditional fixation methods.

Purpose:Restrictive myopathy is an important subtype of thyroid eye disease (TED) characterized by ocular motility restriction. Emerging evidence has indicated brain remodeling in TED restrictive myopathy, yet the underlying mechanism remains elusive. Therefore, this study aims to investigate brain activity and extraocular muscles (EOMs) abnormalities in TED restrictive myopathy, providing a deeper insight into the relationship between ocular motility restriction and brain functional changes. Patients and Methods:This prospective observational study recruited 45 TED patients recruited (28 with restrictive myopathy and 17 without). Brain function parameters and EOMs metrics were obtained. The two-sample t test was performed to compare intergroup differences, and correlation analysis was applied to uncover the association between brain functional activity and EOMs involvement. Results:TED restrictive myopathy exhibited increased intraocular pressure (IOP), long diameters (LD) and short diameters (SD) of inferior rectus, and decreased visual functioning score in Graves' orbitopathy-specific quality of life questionnaire (GO-QoL). Increased amplitude of low-frequency fluctuations (ALFF) in the left middle temporal gyrus (MTG.L) were found in TED restrictive myopathy. The functional connectivity (FC) analysis further discovered higher FC between MTG.L and the right cerebellum_8 and bilateral middle frontal gyrus (MFG). The brain imaging parameters were significantly correlated with vertical deviation, exophthalmos and EOMs metrics in TED restrictive myopathy. Conclusion:This study explored the brain alterations in TED restrictive myopathy, underscoring oculomotor restriction-associated brain functional changes. The study also serves as a preliminary exploration of the alterations in visual pathway in restrictive strabismus, represented by TED with restrictive myopathy.

Thyroid eye disease (TED) is a disfiguring and potentially sight-threatening autoimmune orbital disorder. Intravenous glucocorticoid (IVGC) is the current first-line treatment for active, moderate-to-severe TED but its efficacy in reducing proptosis and diplopia is limited and inconsistent, with high relapse rates. In recent years, inhibitors of the insulin-like growth factor-1 receptor (IGF-1R) have emerged as a novel therapeutic class for TED. Clinical studies have demonstrated that IGF-1R inhibitors can significantly reduce proptosis and improve overall disease activity in patients with active, moderate-to-severe TED. Although both therapies are available, no head-to-head clinical trial has directly compared IGF-1R inhibitors with IVGC. Therefore, this study aims to evaluate the efficacy and safety of an IGF-1R inhibitor compared with IVGC pulse therapy on proptosis in patients with active TED. This is a multicenter, randomized, open-label, active-controlled phase 4 trial. Adults with active moderate-to-severe TED and baseline proptosis ≥ 16 mm in the study eye will be enrolled. Participants will be randomized 1:1 to receive either intravenous teprotumumab N01 (10 mg/kg initial dose on day 1, followed by 20 mg/kg at weeks 3, 6, 9, and 12) or IVGC pulse therapy (methylprednisolone 500 mg on day 1 and from week 1 to week 5, followed by 250 mg from week 6 to week 11). After completing the 12-week treatment period, participants will enter an extended treatment and observation phase. The primary outcome measure is the proportion of participants who achieve a ≥ 2-mm reduction in proptosis in the study eye at week 15. Key secondary outcome measures include the change from baseline in proptosis and the overall responder rate in the study eye at week 15. This study plans to enroll approximately 92 participants with active TED. This trial is the first head-to-head clinical study comparing an IGF-1R (Insulin-like growth factor-1 receptor) inhibitor with IVGC. It aims to address the limitations of IVGC, including its uncertain efficacy on proptosis and diplopia, by utilizing a targeted approach to provide more comprehensive clinical evidence for TED treatment. ClinicalTrials.gov identifier, NCT07265258 (RESTORE-4).

Organ-specific autoimmune diseases, particularly Graves’ disease (GD) and its extrathyroidal manifestation, Graves’ orbitopathy (GO), are characterized by systemic autoimmunity that may extend its impact to the central nervous system (CNS). While thyroid-stimulating hormone receptor (TSHR) is the primary driver of pathological remodeling in the thyroid and orbital tissues, emerging evidence suggests it is also expressed in the brain and may participate in neuroimmune signaling. However, the molecular mechanisms linking peripheral TSHR-driven autoimmunity to these extended systemic features remain unclear. Thus, GD and GO provide a unique window to investigate how peripheral autoantibodies influence CNS involvement as part of its broader pathological spectrum. Genome-wide association studies (GWAS) and post-GWAS analyses were integrated with bulk RNA sequencing, single-cell and spatial transcriptomics, and brain imaging phenotypes to comprehensively characterize peripheral and central alterations in GD and GO. Mendelian randomization was applied to test causal relationships between genetic variants and brain signatures. Structural biology analyses were further conducted including protein–protein docking, small-molecule docking, and normal mode dynamics to identify prospective modulators of TSHR. Immunofluorescence staining was performed in a GO mouse model to validate the colocalization of potential interacted proteins in the specific brain region. Brain imaging-derived phenotypes (IDPs) alterations in GO and GO were systematically analyzed to identify neuroanatomical and functional alterations. TSHR was further identified as a shared genetic driver across peripheral and central compartments. TSHR was expressed in spiny projection neurons, microglia, and peripheral T cells, with cell–cell communication analyses highlighting TSHR-mediated interactions among neurons, endothelial cells, and microglia. Immunofluorescence staining in a GO mouse model confirmed the colocalization of TSHR with FN1 and GNAS in the basal ganglia, providing tissue-level validation of the computationally predicted ligand–receptor interactions. Immune profiling further showed immune alterations in GD and GO. Structural modeling supported plausible physical interfaces between TSHR and interacting proteins, and small-molecule screening identified three repurposable compounds — venetoclax, irinotecan, and dutasteride — with predicted favorable docking scores and stable binding poses in our simulations. These findings demonstrate that TSHR acts as a molecular hub mediating peripheral–central neuroimmune crosstalk in GD and GO. The results support a broader “disease–molecule axis” framework that links genetic susceptibility with multi-level immune and neural mechanisms. This work provides mechanistic insights relevant to the development of TSHR-targeted therapies, with implications for both peripheral immune modulation and central regulation. However, the limited sample size, lack of longitudinal follow-up, and absence of in vivo validation warrant cautious interpretation and further investigation.

Importance:Thyroid eye disease (TED), a disfiguring and potentially sight-threatening condition with racial phenotypic variations, currently has limited effective treatments. Insulin-like growth factor 1 receptor (IGF-1R) inhibitors therapy has emerged as a promising treatment option, although it remains less accessible and lacks substantial evidence in Asian patients. Objective:To assess efficacy and safety of IBI311, an IGF-1R inhibitor with an identical amino acid sequence to teprotumumab but a different dosage form, in Chinese patients with active TED. Design, Setting, and Participants:This was a randomized, double-masked, placebo-controlled, multicenter, 24-week phase 3 trial with recruitment conducted across 20 tertiary hospitals in China from May to December 2023. Chinese participants with active (clinical activity score [CAS] ≥3) moderate to severe TED were included after excluding individuals with active TED onset over 270 days; sight-threatening TED; or history of steroid pulse therapy, radiotherapy, or surgery for TED. Interventions:Eighty-two participants were randomized 2:1 to receive intravenous infusions of either IBI311 or placebo once every 3 weeks for 21 weeks with follow-up through week 24. Main Outcomes and Measures:The primary outcome was the proptosis response rate (proptosis reduction ≥2 mm) in the study eye at week 24. Results:Participants (mean [SD] age, 39.6 [10.9] years; 56 [68.3%] women) were randomized to receive IBI311 (n = 54) or placebo (n = 28). At week 24, 45 of 52 participants receiving IBI311 (85.8%) and 1 of 26 receiving placebo (3.8%) had proptosis response (difference, 81.9 percentage points; 95% CI, 69.8 to 93.9; P < .001). The secondary outcomes included overall response (proptosis reduction ≥2 mm and CAS reduction ≥2, 80.2% vs 3.6%; difference, 76.3 percentage points; 95% CI, 63.3 to 89.4), CAS of 0 or 1 (83.5% vs 16.6%; difference, 67.1 percentage points; 95% CI, 49.4 to 84.8), least-squares mean (SE) change from baseline in proptosis (-2.85 [0.18] mm vs -0.02 [0.24] mm; difference, -2.83 mm; 95% CI, -3.39 mm to -2.27 mm) in the study eye (all P < .001), and diplopia response (diplopia reduction ≥1 grade, 66.0% vs 53.3%; P = .46). All adverse events of interest (infusion reaction, hearing impairment, hyperglycemia, muscle spasm, and nausea or diarrhea) were mild or moderate in severity. No serious adverse event or death occurred in the IBI311 group. Conclusions and Relevance:In this phase 3 randomized clinical trial, IBI311 demonstrated better and clinically relevant outcomes in proptosis and CAS than placebo with no new safety issues not identified in previous clinical trials. The results suggest that IBI311 represents a viable treatment option for Chinese patients with active TED. Trial Registration:ClinicalTrials.gov Identifier: NCT05795621.

Thyroid eye disease (TED), a disfiguring and potentially sight-threatening condition with racial phenotypic variations, currently has limited effective treatments. Insulin-like growth factor 1 receptor (IGF-1R) inhibitors therapy has emerged as a promising treatment option, although it remains less accessible and lacks substantial evidence in Asian patients. To assess efficacy and safety of IBI311, an IGF-1R inhibitor with an identical amino acid sequence to teprotumumab but a different dosage form, in Chinese patients with active TED. This was a randomized, double-masked, placebo-controlled, multicenter, 24-week phase 3 trial with recruitment conducted across 20 tertiary hospitals in China from May to December 2023. Chinese participants with active (clinical activity score [CAS] ≥3) moderate to severe TED were included after excluding individuals with active TED onset over 270 days; sight-threatening TED; or history of steroid pulse therapy, radiotherapy, or surgery for TED. Eighty-two participants were randomized 2:1 to receive intravenous infusions of either IBI311 or placebo once every 3 weeks for 21 weeks with follow-up through week 24. The primary outcome was the proptosis response rate (proptosis reduction ≥2 mm) in the study eye at week 24. Participants (mean [SD] age, 39.6 [10.9] years; 56 [68.3%] women) were randomized to receive IBI311 (n = 54) or placebo (n = 28). At week 24, 45 of 52 participants receiving IBI311 (85.8%) and 1 of 26 receiving placebo (3.8%) had proptosis response (difference, 81.9 percentage points; 95% CI, 69.8 to 93.9; P < .001). The secondary outcomes included overall response (proptosis reduction ≥2 mm and CAS reduction ≥2, 80.2% vs 3.6%; difference, 76.3 percentage points; 95% CI, 63.3 to 89.4), CAS of 0 or 1 (83.5% vs 16.6%; difference, 67.1 percentage points; 95% CI, 49.4 to 84.8), least-squares mean (SE) change from baseline in proptosis (−2.85 [0.18] mm vs −0.02 [0.24] mm; difference, −2.83 mm; 95% CI, −3.39 mm to −2.27 mm) in the study eye (all P < .001), and diplopia response (diplopia reduction ≥1 grade, 66.0% vs 53.3%; P = .46). All adverse events of interest (infusion reaction, hearing impairment, hyperglycemia, muscle spasm, and nausea or diarrhea) were mild or moderate in severity. No serious adverse event or death occurred in the IBI311 group. In this phase 3 randomized clinical trial, IBI311 demonstrated better and clinically relevant outcomes in proptosis and CAS than placebo with no new safety issues not identified in previous clinical trials. The results suggest that IBI311 represents a viable treatment option for Chinese patients with active TED. ClinicalTrials.gov Identifier: NCT05795621

OBJECTIVE:To investigate the performance of contrast-enhanced orbital MRI (T1-weighted contrast-enhanced [T1CE] and dynamic contrast-enhanced MRI [DCE-MRI]) for activity assessment and prediction of treatment response to intravenous glucocorticoid (IVGC) treatment in thyroid eye disease (TED). METHODS:A retrospective study of 59 active moderate-to-severe TED patients (36 responsive and 23 unresponsive) treated with IVGC, matched with 31 inactive TED patients were included. T1CE and DCE-MRI were collected from each subject. Univariate and multivariate logistic regression analyses, as well as receiver operating characteristic (ROC) curves (evaluated by area under the curve, AUC) were used to evaluate the diagnostic and predictive models. RESULTS:Active patients showed a higher signal intensity ratio of lateral rectus (LR-SIR) on T1CE and a higher wash-in rate of inferior rectus (IR-WIR) on DCE-MRI compared to inactive patients (p < 0.05). The AUC for T1CE and DCE-MRI based models were 0.866, and 0.844, respectively. The combined model (LR-SIR and IR-WIR) significantly enhanced model performance (AUC = 0.914, 95 % CI: 0.858-0.970). Responsive patients demonstrated a longer time to peak of lateral rectus (LR-TTP) than unresponsive patients (p < 0.05). The cutoff value of prediction probability was 0.678, and the AUC based on this model was 0.739 (95 % CI: 0.608-0.807). CONCLUSIONS:T1CE and DCE-MRI could effectively assist in TED activity assessment, and DCE-MRI could help predict IVGC treatment response. Specifically, LR-SIR and IR-WIR were indicators of TED activity, and IR-TTP was predictive of IVGC treatment response. Combining both contrast-enhanced sequences could further enhance the efficiency of TED activity assessment.

PURPOSE. Thyroid eye disease (TED) is the most common extrathyroidal manifestation of Graves' disease (GD). Despite its clinical significance, the pathogenic mechanisms and reliable diagnostic biomarkers for TED remain incompletely defined. Tear fluid offers a noninvasive window into disease-related molecular changes. METHODS. Tear samples were collected using Schirmer strips from 20 patients with TED, 20 patients with GD without ocular involvement, and 14 healthy controls (HCs). Proteomic profiling was performed using a novel pressure cycling technology-pulse data-independent acquisition mass spectrometry (PCT-PulseDIA-MS) workflow. RESULTS. A total of 5966 tear proteins were quantified. Differentially expressed proteins (DEPs) were identified through pairwise group comparisons. Patients with TED showed the most extensive tear proteomic alterations among the studied groups. One hundred seventy-four DEPs were associated with ophthalmopathy, 14 with autoimmunity, and 13 with hyperthyroidism. The ophthalmopathy-related DEPs were enriched in immune regulation, lipid metabolism, vascular function, and extracellular matrix remodeling. Several key DEPs showed significant correlations with clinical, laboratory, and imaging variables. A three-protein panel comprising calcium-activated nucleotidase 1 (CANT1), insulin-like growth factor-binding protein 7 (IGFBP7), and caspase 14 (CASP14) achieved excellent diagnostic performance in distinguishing TED from GD, with an area under the curve (AUC) of 0.971. CONCLUSIONS. Tear proteomics reveals distinct molecular signatures shaped by the combined influences of ophthalmopathy, autoimmunity, and hyperthyroidism throughout the pathogenesis of TED, underscoring the potential of tear proteins as early, noninvasive biomarkers for disease diagnosis.

Purpose:To investigate the alterations in the glymphatic system in patients with thyroid eye disease (TED) using diffusion tensor imaging (DTI) analysis along the perivascular space (ALPS) and to explore the correlation between the glymphatic system and clinical features of TED. Methods:The study included 47 patients with TED, including 20 active TED patients (AP) and 27 inactive TED patients (IP), along with 24 healthy controls (HC). Imaging data including DTI sequence were acquired using a 3.0 Tesla scanner. ALPS values were calculated based on the diffusivity of the bilateral superior corona radiata and superior longitudinal fasciculus. Correlation analysis were thus performed between ALPS values and clinical characteristics. Results:The DTI-ALPS analysis in the TED patient group collectively showed lower mean and left ALPS values compared to the HC, with statistically significant differences observed (mean ALPS: P=0.0308, left ALPS: P=0.0032). Among the TED subgroups, the IP had significantly lower left ALPS values than HC (P=0.006). Correlation analysis within the IP subgroup indicated that lower ALPS values were significantly associated with longer disease duration (P=0.015) and greater palpebral fissure height (P=0.028). Conclusions:Glymphatic system dysfunction is evident in TED patients, with its extent influenced by disease activity and duration.

Context CD34+ orbital fibroblasts (OFs) play a pathogenic role in thyroid eye disease (TED). Several micro (mi)RNAs have been shown to promote TED progression.Objective This study aims to explore the regulatory effects of miRNAs on CD34+ OFs and to find potential therapeutic targets.Methods In this case-control study, orbital connective tissues (OCTs) and OFs were obtained from 25 TED patients and 24 healthy donors. MiRNA-seq was performed to examine differential expression of miRNAs in OCTs, and miR-182-5p was selected for subsequent experiments. MiR-182-5p was detected both in CD34+ and CD34- OFs. The upstream regulators of miR-182-5p were studied. Downstream targets of miR-182-5p were analyzed. The functionality of miR-182-5p in CD34+ OFs was evaluated.Results MiR-182-5p was highly expressed in TED OCTs and their derived CD34+ OFs. TED OCTs displayed increased expression of interleukin (IL)-6, IL-17A, CD34, and phosphorylated STAT3 at Ser727 and Tyr705. Activation of IL-6/STAT3 signaling promoted the expression of miR-182-5p in CD34+ OFs. MiR-182-5p enhanced wound repair ability, proliferation, and RANTES expression while inhibiting apoptosis in CD34+ OFs. CD34+ OFs transfected with miR-182-5p were susceptible to TGF-beta-initiated myofibroblast differentiation. Luciferase reporter and pull-down assays revealed Smad7 as the downstream target of miR-182-5p, which modulated the proliferation, migration, fibrosis, and apoptosis of CD34+ OFs.Conclusion The IL-6/STAT3/miR-182-5p pathway led to activation of CD34+ OFs. MiR-182-5p promoted the proliferation, migration, fibrosis, and anti-apoptosis of CD34+ OFs via targeting Smad7. Our findings suggest that miR-182-5p may potentially serve as a therapeutic target for TED.

Thyroid eye disease (TED), the most common adult orbital disease, can significantly impair patients’ quality of life. Currently, effective diagnostic and predictive models for TED remain limited, making early intervention and personalized treatment for patients challenging. Oxidative stress (OS) plays an important role in pathogenesis of TED, and OS related biomarkers may serve as good candidates for TED prediction. Here, we integrated the peripheral blood bulk-RNA sequencing data and clinical features of 152 TED, 61 health control (HC), and 20 patients with simple Graves’ disease (GD) to identify potential biomarkers. The intersection of TED-HC and TED-GD differentially expressed genes (DEGs) identified 1220 genes strongly correlated with TED. Enrichment analysis showed upregulation of OS-related biological processes in patients with TED. Integration of DEGs, WGCNA results, and OS-related genes identified six genes as candidate biomarkers. Machine learning algorithms suggested three critical candidate genes (KLF2, SELENON, TXNRD1) with high predictive value and were used to construct an oxidative stress-related predictive gene score (OSRPGS). Receiver operating characteristic curve confirmed the predictive value of OSRPGS with an AUC value of 0.733 (TED vs HC) and 0.705 (TED vs GD). Further patient stratification analysis confirmed that the OSRPGS was associated with tear secretion dysfunction. Furthermore, immune infiltration analysis suggested an upregulation of innate immune responses, especially the monocytes/macrophages subtypes, indicating the initiation of OS-related inflammation. Collectively, our study provides a reliable tool for TED prediction and risk assessment based on OS-related biomarkers. OSRPGS may help with the early recognition and intervention in patients with TED.

Background: Thyroid eye disease (TED) is a sight-threatening autoimmune disease with cigarette smoking as one of the key risk factors. Cigarette smoking affects both the severity of TED and the patient's response to medication. However, the underlying pathogenic mechanisms of smoking in TED remain unclear. Methods: Orbital fibroblasts (OFs) were extracted from patients with TED and non-TED controls, and treated with cigarette smoking extract (CSE). Luminex assays and Western blots were employed to examine inflammatory status and pathological phenotypes of OFs. A specific reactive oxygen species (ROS) probe was used to evaluate oxidative stress levels. RNA-sequencing of CSE-treated OFs was used to analyze differentially expressed genes. Immunofluorescence and RNA-sequencing were used to examine the expression of receptor for advanced glycation end products (RAGE) signaling molecules in patients. Small interfering RNA sequences and a RAGE-specific inhibitor were employed to investigate the effects of RAGE blockade on cigarette smoking-related pathological phenotypes. To validate our findings in vivo, we generated an adenovirus-induced TED mouse model with exposure to cigarette smoke. Results: Exposure to CSE resulted in an inflammatory phenotype of OFs together with higher levels of oxidative stress. OFs exposed to CSE presented susceptibility to transforming growth factor-β-induced myofibroblast differentiation, and 15-D-PGJ2-induced adipocyte differentiation, indicating pro-fibrotic and pro-adipogenic phenotypes. RNA-sequencing of CSE-treated OFs revealed upregulation of RAGE signaling molecules. TED patients with smoking history also exhibited higher levels of RAGE signaling, both in the orbit and peripheral blood, compared with non-smoking patients. Enhancement of inflammatory status was associated with activation of the ROS-nuclear factor-kappa B pathway downstream of RAGE. RAGE gene interference or administration of RAGE inhibitor effectively mitigated cigarette smoking-related pathological changes in OFs. Disrupting RAGE signaling in TED mice efficiently ameliorated smoking-induced disease progression in vivo. Conclusions: Cigarette smoking-relevant TED progression was linked with RAGE signaling activation, leading to the exacerbation of orbital inflammation and tissue-remodeling, including fibrosis and adipogenesis. Our findings demonstrate that cigarette smoke exposure affects the biological characteristics of TED-derived OFs and supports RAGE as a promising therapeutic target for the management of patients with TED and smoking habits.

To assess and predict the therapeutic efficacy of intravenous glucocorticoids (IVGC) in thyroid eye disease (TED) patients with clinical activity score (CAS) < 3, but presenting magnetic resonance imaging (MRI)-confirmed intraorbital inflammation. We retrospectively analyzed the clinical data of 91 active TED patients with low CAS that received IVGC treatment (4.5 g, 12 weeks). In terms of treatment response evaluation, the EUGOGO standard (Two-Item Standard) and a One-Item Standard modified on this basis were implemented. Univariate and multivariable logistic regression analyses were used to establish prediction models. Receiver operating characteristic (ROC) curve analysis was performed and the area under the curve (AUC) was calculated. Under Two-Item Standard, 31 of the 91 patients (34.1

Thyroid eye disease (TED) is an autoimmune disorder characterized by persistent inflammation around the periphery and within the orbit, potentially driven by hypoxic conditions. Effective biomarkers and precise predictive models are still lacking for the early diagnosis of TED. Bulk RNA sequencing was conducted on peripheral blood samples from TED patients, Graves’ hyperthyroidism (GH) patients without ocular involvement, and healthy controls (HC). Differentially expressed genes between TED and HC, hypoxia-related genes and genes identified through weighted gene co-expression network analysis (WGCNA) were intersected to identify candidate biomarkers. Subsequently, nine machine learning algorithms were applied to screen for critical hypoxia-related TED diagnostic genes (HRTDGs). A diagnostic model based on HRTDG score (HRTDGS) was constructed using logistic regression analyses and then evaluated. TED patients were categorized into high and low HRTDGS groups based on the median score. Distinct immunological profiles and underlying pathological functions were investigated between two groups. Single cell RNA sequencing (scRNA-seq) data further explored HRTDGs’ roles at cellular level. Hypoxia was identified as a prominent feature of TED. Among all machine learning algorithms, random forest achieved the highest area under curve (AUC) and was used to identify three key HRTDGs: EGFR, PIK3CB, and CREBBP. The HRTDGS model was then established and found to be an independent predictive factor for TED diagnosis (odds ratio (OR): 2.656, 95

AimsThyroid eye disease (TED) is an autoimmune orbital disorder that diminishes the quality of life (QOL) in affected individuals. Graves’ ophthalmopathy (GO)-QOL questionnaire effectively assesses TED’s effect on patients. This study aims to investigate the factors influencing visual functioning (QOL-VF) and physical appearance (QOL-AP) scores in Chinese TED patients using innovative data analysis methods.MethodsThis cross-sectional study included 211 TED patients whose initial visit to our clinic was from July 2022 to March 2023. Patients with previous ophthalmic surgery or concurrent severe diseases were excluded. GO-QOL questionnaires, detailed medical histories and clinical examinations were collected. The distribution of GO-QOL scores was analyzed, and linear regression and machine learning algorithms were utilized.ResultsThe median QOL-VF and QOL-AP scores were 64.29 and 62.5, respectively. Multivariate linear regression analysis revealed age (P = 0.013), ocular motility pain (P = 0.012), vertical strabismus (P < 0.001) and diplopia scores as significant predictors for QOL-VF. For QOL-AP, gender (P = 0.013) and clinical activity (P = 0.086) were significant. The XGBoost model demonstrated superior performance, with an R2 of 0.872 and a root mean square error of 11.083. Shapley additive explanations (SHAP) analysis highlighted the importance of vertical strabismus, diplopia score and age in influencing QOL-VF and age, clinical activity and sex in QOL-AP.ConclusionTED significantly affects patient QOL. The study highlights the efficacy of XGBoost and SHAP analyses in identifying key factors influencing the QOL in TED patients. Identifying effective interventions and considering specific demographic characteristics are essential to improving the QOL of patients with TED.

Repair of large bone defects is a sophisticated physiological process involving the meticulous orchestration of cell activation, proliferation, and differentiation. Cellular interactions between different cell types are paramount for successful bone regeneration, making it a challenging yet fascinating area of research and clinical practice. With increasing evidence underscoring the essential role of exosomes in facilitating intercellular and cell-microenvironment communication, they have emerged as an encouraging therapeutic strategy to promote bone repair due to their non-immunogenicity, diverse sources, and potent bioactivity. In this study, we characterized a distinctive population of Krt14+Ctsk+ cells from the orbital mucoperiosteum. In vitro experiments confirmed that exosomes from Krt14+Ctsk+ cells dramatically boosted the capacities of human umbilical vein endothelial cells (HUVECs) to proliferate, migrate, and induce angiogenesis. Additionally, the exosomes notably elevated the expression of osteogenic markers, thereby indicating their potential to augment osteogenic capabilities. Furthermore, in vivo experiments utilizing a rat calvarial defect model verified that exosome-loaded sodium alginate (SA) hydrogels accelerated local vascularized bone regeneration within the defective regions. Collectively, these findings suggest that exosomes secreted by Krt14+Ctsk+ cells offer an innovative method to accelerate bone repair via coupling enhanced osteogenesis and angiogenesis, highlighting the therapeutic potential in bone repair.