TMEM2 inhibits the development of Graves' orbitopathy through the JAK-STAT signaling pathway.

A mouse model was used to investigate the role of the hyaluronidase, transmembrane protein 2 (TMEM2), on the progression of Graves' orbital (GO) disease. We established a GO mouse model through immunization with a plasmid expressing the thyroid stimulating hormone receptor. Orbital fibroblasts (OFs) were subsequently isolated from both GO and non-GO mice for comprehensive in vitro analyses. The expression of TMEM2 was assessed using qRT-PCR, Western blot and immunohistochemistry in vivo. Disease pathology was evaluated by H&E staining and Masson's trichrome staining in GO mouse tissues. Our investigation revealed a notable reduction in TMEM2 expression in GO mouse orbital tissues. Through overexpression and knockdown assays, we demonstrated that TMEM2 suppresses inflammatory cytokines and reactive oxygen species production. TMEM2 also inhibits the formation of lipid droplets in OFs and the expression of adipogenic factors. Further incorporating Gene Set Enrichment Analysis of relevant GEO datasets and subsequent in vitro cell experiments, robustly confirmed that TMEM2 overexpression was associated with a pronounced upregulation of the JAK/STAT signaling pathway. In vivo, TMEM2 overexpression reduced inflammatory cell infiltration, adipogenesis, and fibrosis in orbital tissues. These findings highlight the varied regulatory role of TMEM2 in GO pathogenesis. Our study reveals that TMEM2 plays a crucial role in mitigating inflammation, suppressing adipogenesis, and reducing fibrosis in GO. TMEM2 has potential as a therapeutic target and biomarker for treating or alleviating GO. These findings advance our understanding of GO pathophysiology and provide opportunities for targeted interventions to modulate TMEM2 for therapeutic purposes.

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

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

The insular cortex is not insular in thyroid eye disease: neuroimaging revelations of central-peripheral system interaction.

BACKGROUND: Thyroid eye disease (TED) is highly correlated with dysregulated immunoendocrine status. The insular cortex was found to regulate peripheral inflammation and immunomodulation in mice. This study aimed to explore whether the insular cortex in patients with TED played a modulatory role including the aberrant brain functional alteration and its association with immunoendocrine status. METHODS: This study included 34 active patients (AP), 30 inactive patients (IP) with TED, and 45 healthy controls (HC) matched for age, sex, and educational level. Comprehensive clinical details (especially immunoendocrine markers) and resting-state functional magnetic resonance imaging data were collected from each participant. The amplitude of low-frequency fluctuation (ALFF) was used to probe the aberrant alterations of local neural activity. The seed-based functional connectivity (FC) analysis was used to explore the relationship between the insular cortex and each voxel throughout the whole brain. The correlation analysis was conducted to assess the association between insular neurobiomarkers and immunoendocrine parameters. RESULTS: When compared with the IP and HC groups, the AP group displayed significantly higher ALFF values in the right insular cortex (INS.R) and lower FC values between the INS.R and the bilateral cerebellum. None of the neurobiomarkers differed between the IP and HC groups. Besides, correlations between insular neurobiomarkers and immunoendocrine markers (free thyroxine, the proportion of T cells, and natural killer cells) were identified in both AP and IP groups. CONCLUSIONS: This study was novel in reporting that the dysregulation of the insular cortex activity in TED was associated with abnormal peripheral immunoendocrine status. The insular cortex might play a key role in central-peripheral system interaction in TED. Further research is crucial to enhance our understanding of the central-peripheral system interaction mechanisms involved in autoimmune diseases.

Whole-orbit radiomics: machine learning-based multi- and fused- region radiomics signatures for intravenous glucocorticoid response prediction in thyroid eye disease.

BACKGROUND: Radiomics analysis of orbital magnetic resonance imaging (MRI) shows preliminary potential for intravenous glucocorticoid (IVGC) response prediction of thyroid eye disease (TED). The current region of interest segmentation contains only a single organ as extraocular muscles (EOMs). It would be of great value to consider all orbital soft tissues and construct a better prediction model. METHODS: In this retrospective study, we enrolled 127 patients with TED that received 4·5 g IVGC therapy and had complete follow-up examinations. Pre-treatment orbital T2-weighted imaging (T2WI) was acquired for all subjects. Using multi-organ segmentation (MOS) strategy, we contoured the EOMs, lacrimal gland (LG), orbital fat (OF), and optic nerve (ON), respectively. By fused-organ segmentation (FOS), we contoured the aforementioned structures as a cohesive unit. Whole-orbit radiomics (WOR) models consisting of a multi-regional radiomics (MRR) model and a fused-regional radiomics (FRR) model were further constructed using six machine learning (ML) algorithms. RESULTS: The support vector machine (SVM) classifier had the best performance on the MRR model (AUC = 0·961). The MRR model outperformed the single-regional radiomics (SRR) models (highest AUC = 0·766, XGBoost on EOMs, or LR on OF) and conventional semiquantitative imaging model (highest AUC = 0·760, NaiveBayes). The application of different ML algorithms for the comparison between the MRR model and the FRR model (highest AUC = 0·916, LR) led to different conclusions. CONCLUSIONS: The WOR models achieved a satisfactory result in IVGC response prediction of TED. It would be beneficial to include more orbital structures and implement ML algorithms while constructing radiomics models. The selection of separate or overall segmentation of orbital soft tissues has not yet attained its final optimal result.

Plasma exosomes from patients with active thyroid-associated orbitopathy induce inflammation and fibrosis in orbital fibroblasts.

BACKGROUND: The pathogenesis of thyroid-associated orbitopathy (TAO) remains incompletely understand. The interaction between immunocytes and orbital fibroblasts (OFs) play a critical role in orbital inflammatory and fibrosis. Accumulating reports indicate that a significant portion of plasma exosomes (Pla-Exos) are derived from immune cells; however, their impact upon OFs function is unclear. METHODS: OFs were primary cultured from inactive TAO patients. Exosomes isolated from plasma samples of patients with active TAO and healthy controls (HCs) were utilized for functional and RNA cargo analysis. Functional analysis in thymocyte differentiation antigen-1+ (Thy-1+) OFs measured expression of inflammatory and fibrotic markers (mRNAs and proteins) and cell activity in response to Pla-Exos. RNA cargo analysis was performed by RNA sequencing and RT-qPCR. Thy-1+ OFs were transfected with miR-144-3p mimics/inhibitors to evaluate its regulation of inflammation, fibrosis, and proliferation. RESULTS: Pla-Exos derived from active TAO patients (Pla-ExosTAO-A) induced stronger production of inflammatory cytokines and hyaluronic acid (HA) in Thy-1+ OFs while inhibiting their proliferation. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and single sample gene set enrichment analysis (ssGSEA) suggested that the difference in mRNA expression levels between Pla-ExosTAO-A and Pla-ExosHC was closely related to immune cells. Differential expression analysis revealed that 62 upregulated and 45 downregulated miRNAs in Pla-ExosTAO-A, with the elevation of miR-144-3p in both Pla-Exos and PBMCs in active TAO group. KEGG analysis revealed that the target genes of differentially expressed miRNA and miR-144-3p enriched in immune-related signaling pathways. Overexpression of the miR-144-3p mimic significantly upregulated the secretion of inflammatory cytokines and HA in Thy-1+ OFs while inhibiting their proliferation. CONCLUSION: Pla-Exos derived from patients with active TAO were immune-active, which may be a long-term stimulus casual for inflammatory and fibrotic progression of TAO. Our finding suggests that Pla-Exos could be used as biomarkers or treatment targets in TAO patients.

Teprotumumab-Related Adverse Events in Thyroid Eye Disease: A Multicenter Study.

PURPOSE: To assess the duration, incidence, reversibility, and severity of adverse events (AEs) in patients with thyroid eye disease (TED) treated with teprotumumab. DESIGN: Multicenter, retrospective, observational cohort study. PARTICIPANTS: Patients with TED of all stages and activity levels treated with at least 4 infusions of teprotumumab. METHODS: Patients were treated with teprotumumab between February 2020 and October 2022 at 6 tertiary centers. Adverse event metrics were recorded at each visit. MAIN OUTCOME MEASURES: The primary outcomes measure was AE incidence and onset. Secondary outcome measures included AE severity, AE reversibility, AE duration, proptosis response, clinical activity score (CAS) reduction, and Gorman diplopia score improvement. RESULTS: The study evaluated 131 patients. Proptosis improved by 2 mm or more in 77% of patients (101/131), with average proptosis improvement of 3.0 ± 2.1 mm and average CAS reduction of 3.2 points. Gorman diplopia score improved by at least 1 point for 50% of patients (36/72) with baseline diplopia. Adverse events occurred in 81.7% of patients (107/131). Patients experienced a median of 4 AEs. Most AEs were mild (74.0% [97/131]), 28.2% (37/131) were moderate, and 8.4% (11/131) were severe. Mean interval AE onset was 7.9 weeks after the first infusion. Mean resolved AE duration was 17.6 weeks. Forty-six percent of patients (60/131) demonstrated at least 1 persistent AE at last follow-up. Mean follow-up was 70.2 ± 38.5 weeks after the first infusion. The most common type of AEs was musculoskeletal (58.0% [76/131]), followed by gastrointestinal (38.2% [50/131]), skin (38.2% [50/131]), ear and labyrinth (30.5% [40/131]), nervous system (20.6% [27/131]), metabolic (15.3% [20/131]), and reproductive system (12.2% [16/131]). Sixteen patients (12.2%) discontinued therapy because of AEs, including hearing loss (n = 4), inflammatory bowel disease flare (n = 2), hyperglycemia (n = 1), muscle spasms (n = 1), and multiple AEs (n = 8). CONCLUSIONS: Adverse events are commonly reported while receiving teprotumumab treatment. Most are mild and reversible; however, serious AEs can occur and may warrant treatment cessation. Treating physicians should inform patients about AE risk, properly screen patients before treatment, monitor patients closely throughout therapy, and understand how to manage AEs should they develop. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Glycemic Trends in Patients with Thyroid Eye Disease Treated with Teprotumumab in 3 Clinical Trials.

PURPOSE: Assess incidence, severity, and glucose excursion outcomes in thyroid eye disease (TED) patients receiving the insulin-like growth factor-1 receptor inhibitor teprotumumab from 3 clinical trials. DESIGN: Analysis of pooled glycemic data over time. PARTICIPANTS: Eighty-four teprotumumab- and 86 placebo-treated active TED patients from the phase 2 and phase 3 (OPTIC) controlled clinical trials and 51 teprotumumab-treated patients from the OPTIC extension (OPTIC-X) trial. METHODS: Eight intravenous infusions were given over 21 weeks. Phase 2 serum glucose was measured at weeks 1, 4, 15, and 21, with fasting measurements at weeks 1 and 4. Serum glucose was measured at each study visit in OPTIC and OPTIC-X, with fasting measurements at weeks 1 and 4 (in patients without diabetes) or all visits (in patients with diabetes). In all studies, hemoglobin A1c (HbA1c) was measured at baseline, 12, and 24 weeks plus weeks 36 and 48 in OPTIC-X. MAIN OUTCOME MEASURES: Serum glucose and HbA1c. RESULTS: In the phase 2 and 3 studies, 9 hyperglycemic episodes occurred in 8 teprotumumab patients; mean HbA1c level increased 0.22% from baseline to week 24 (to 5.8%; range, 5.0%-7.9%) versus 0.04% in patients receiving the placebo (to 5.6%; range, 4.6%-8.1%). At study end, 78% (59/76) of teprotumumab patients and 87% (67/77) of patients receiving placebo had normoglycemic findings. Normoglycemia was maintained in 84% (57/68) of patients receiving teprotumumab and 93% (64/69) of patients receiving placebo. Among baseline prediabetic patients, 43% (3/7) remained prediabetic in both groups, and 29% (2/7) of teprotumumab patients and 14% (1/7) of patients receiving placebo had diabetic findings at week 24. OPTIC-X patients trended toward increased fasting glucose and HbA1c whether initially treated or retreated with teprotumumab. Fasting glucose commonly rose after 2 or 3 infusions and stabilized thereafter. Most hyperglycemic incidents occurred in patients with baseline prediabetes/diabetes but were controlled with medication. No evidence was found for progression or increased incidence of hyperglycemia with subsequent doses. CONCLUSIONS: Serious glycemic excursions are uncommon in patients with normoglycemia before teprotumumab therapy. Patients with controlled diabetes or impaired glucose tolerance can be treated safely if baseline screening, regular monitoring of glycemic control, and timely treatment of hyperglycemia are practiced. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The genetics of Graves' disease.

Graves' disease (GD) is the commonest cause of hyperthyroidism and has a strong female preponderance. Everyday clinical practice suggests strong aggregation within families and twin studies demonstrate that genetic factors account for 60-80% of risk of developing GD. In this review, we collate numerous genetic studies and outline the discoveries over the years, starting with historic candidate gene studies and then exploring more recent genome-wide linkage and association studies, which have involved substantial cohorts of East Asian patients as well as those of European descent. Variants in genes including HLA, CTLA4, and PTPN22 have been shown to have substantial individual effects on disease susceptibility. In addition, we examine emerging evidence concerning the possibility that genetic variants may correlate with relevant clinical phenotypes including age of onset of GD, severity of thyrotoxicosis, goitre size and relapse of hyperthyroidism following antithyroid drug therapy, as well as thyroid eye disease. This review supports the inheritance of GD as a complex genetic trait, with a growing number of more than 80 susceptibility loci identified so far. Future implementation of more targeted clinical therapies requires larger studies investigating the influence of these genetic variants on the various phenotypes and different outcomes of conventional treatments.

GSDMD mediated pyroptosis induced inflammation of Graves' orbitopathy via the NF-κB/ AIM2/ Caspase-1 pathway.

Gasdermin D (GSDMD) is a key executor which triggers pyroptosis as well as an attractive checkpoint in various inflammatory and autoimmune diseases but it has yet to prove its function in Graves'orbitopathy (GO). Our aim was to investigate GSDMD levels in orbital connective tissue and serum of GO patients and then assess the association between serum levels and patients' clinical activity score (CAS). Further, GSDMD-mediated pyroptosis and the underlying mechanism in inflammatory pathogenesis in the cultured orbital fibroblasts (OFs) of GO patients were examined. OFs were collected after tumor necrosis factor (TNF)-α or interferon (IFN)-γ treatment or combination treatment at different times, and the expression of GSDMD and related molecular mechanisms were analyzed. Then, we constructed the GSDMD knockout system with siRNA and the system was further exposed to the medium with or without IFN-γ and TNF-α for a specified time. Finally, we evaluated the production of interleukin (IL)-1ß and IL-18. We found that serum GSDMD levels were elevated and positively correlated with the CAS in GO patients. Meanwhile, the expression of GSDMD and N-terminal domain (NT-GSDMD) in orbital connective tissue of GO patients was augmented. Also, increased expression of GSDMD and related pyroptosis factors was observed in vitro model of GO. We further demonstrated that GSDMD-mediated pyroptosis induced inflammation via the nuclear factor kB (NF-κB)/absent in melanoma-2 (AIM-2)/caspase-1 pathway. In addition, blocking GSDMD suppressed proinflammatory cytokine production in GO. We concluded that GSDMD may be a biomarker as well as a potential target for the evaluation and treatment of inflammation related with GO.

Thyroid Inflammation and Immunity During the COVID-19 Pandemic: A Comprehensive Review and Case Study.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the development of various vaccines. Reports have emerged suggesting a possible association between SARS-CoV-2 vaccination and the onset of thyroid diseases. This review explores the clinical aspects of thyroid disorders following SARS-CoV-2 vaccination, including a case report of a patient with concomitant subacute thyroiditis (SAT) and Graves' disease (GD) with blocking thyrotropin receptor autoantibodies (TSH-R-Ab) following SARS-CoV-2 vaccination. SAT, characterized by transient inflammation of the thyroid gland, has been reported after SARS-CoV-2 vaccination. GD, an autoimmune hyperthyroidism, has also been observed post-vaccination, often with stimulating TSH-R-Ab. Graves' orbitopathy (GO) has been associated with SARS-CoV-2 vaccination in patients with a history of immune thyroid disease. The unique case underscores a very rare thyroid condition of functional hypothyroidism in possible relation to SARS-CoV-2 vaccination and the usefulness of functional analysis of TSH-R-Ab that can provide valuable insights into disease pathogenesis and help to guide treatment. This review highlights the need for continued monitoring and awareness of potential thyroid-related complications following SARS-CoV-2 vaccination.

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

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

Diagnosis of dysthyroid optic neuropathy: combined value of orbital MRI and intracranial visual pathway diffusion kurtosis imaging.

OBJECTIVES: To evaluate the combined performance of orbital MRI and intracranial visual pathway diffusion kurtosis imaging (DKI) in diagnosing dysthyroid optic neuropathy (DON). METHODS: We retrospectively enrolled 61 thyroid-associated ophthalmopathy (TAO) patients, including 25 with DON (40 eyes) and 36 without DON (72 eyes). Orbital MRI-based apical muscle index (MI), diameter index (DI) of the optic nerve (ON), area index (AI) of the ON, apparent diffusion coefficient (ADC) and signal intensity ratio (SIR) of the ON, DKI-based kurtosis fractional anisotropy (KFA) and mean kurtosis (MK) of the optic tract (OT), optic radiation (OR), and Brodmann areas (BAs) 17, 18, and 19 were measured and compared between groups. The diagnostic performances of models were evaluated using receiver operating characteristic curve analyses and compared using the DeLong test. RESULTS: TAO patients with DON had significantly higher apical MI, apical AI, and SIR of the ON, but significantly lower ADC of the ON than those without DON (p < 0.05). Meanwhile, the DON group exhibited significantly lower KFA across the OT, OR, BA17, BA18, and BA19 and lower MK at the OT and OR than the non-DON group (p < 0.05). The model integrating orbital MRI and intracranial visual pathway DKI parameters performed the best in diagnosing DON (AUC = 0.926), with optimal diagnostic sensitivity (80%) and specificity (94.4%), followed by orbital MRI combination (AUC = 0.890), and then intracranial visual pathway DKI combination (AUC = 0.832). CONCLUSION: Orbital MRI and intracranial visual pathway DKI can both assist in diagnosing DON. Combining orbital and intracranial imaging parameters could further optimize diagnostic efficiency. CLINICAL RELEVANCE STATEMENT: The novel finding could bring novel insights into the precise diagnosis and treatment of dysthyroid optic neuropathy, accordingly, contributing to the improvement of the patients' prognosis and quality of life in the future. KEY POINTS: • Orbital MRI and intracranial visual pathway diffusion kurtosis imaging can both assist in diagnosing dysthyroid optic neuropathy. • Combining orbital MRI and intracranial visual pathway diffusion kurtosis imaging optimized the diagnostic efficiency of dysthyroid optic neuropathy.

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

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

Restoration of vision by combined experimental antithymocyte therapy, and orbital radiation with high-dose steroids for severe, acute, steroid-refractory, congestive thyroid orbitopathy.

PURPOSE: We report diagnostic and therapeutic dilemmas in the difficult case of compressive optic neuropathy with severe visual acuity and visual field loss with subsequent visual recovery in both eyes, in a patient with Graves' orbitopathy (GO) by a combination of experimental antithymocyte therapy, orbital radiotherapy with high-dose steroids. METHODS: A 72-year-old man presented with severe vision loss in both eyes. The visual symptoms had appeared over a year before the GO diagnosis. He was initially misdiagnosed with neuroborreliosis and optic neuritis based on brain and orbital magnetic resonance imaging. There was no exophthalmos. The ophthalmological examination included visual acuity, visual field, tonometry in primary and upgaze eye position, optical coherence tomography (OCT), pattern electroretinogram (PERG), pattern, and flash visual evoked potentials (PVEP and FVEP). The patient received experimental therapy with ATG, followed by high-dose of intravenous steroids and orbital radiotherapy. RESULTS: Delayed VEP peaks became shorter after treatment. After systemic and local therapy lowering of intraocular pressure was achieved. Abnormal PERG has been found three months before ganglion cells atrophy was detected in OCT. Visual acuity and visual field improvement occurred in both eyes after therapy, despite partial left optic nerve atrophy. The patient regained full decimal visual acuity (1.0 right from as poor as 0.3  to 1.0 in the right eye and from hand movements to 0.9 in the left. Severe visual field loss with advanced absolute scotomata has improved to slight relative scotomata. The duration of follow-up time after the treatment was 4 months. CONCLUSIONS: Intensive treatment of steroid-resistant Graves' orbitopathy (GO) may prevent total optic nerve atrophy. Despite severely advanced optic neuropathy, this report emphasizes the necessity of therapy even with nearly complete visual function loss hence there is always a possibility to regain full visual acuity and visual field. Patients with tense orbital septum may not present with significant exophthalmos, thus delaying the correct diagnosis of orbitopathy. A supporting sign of GO was the difference in intraocular pressure in the primary and upgaze eye positions. Electrophysiological examinations are helpful in the diagnosis and monitoring of GO therapy. To our knowledge, this is the first report of this kind presenting visual function restoration and structural recovery in a patient with advanced optic neuropathy in GO.

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

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

Bridging and Validation of the Specific Graves Ophthalmopathy Quality of Life Questionnaire With Health State Utility Values.

OBJECTIVE: In thyroid eye disease (TED), inflammation and expansion of orbital muscle and periorbital fat result in diplopia and proptosis, severely impacting patient quality of life (QOL). The reported health state utility (HSU) scores, which are QOL measures, allow quantification of TED impact and improvement with therapies; however, no current QOL instrument has been validated with HSU scores for TED. Here, we used the disease-specific Graves Ophthalmopathy Quality of Life (GO-QOL) questionnaire and HSU scores to validate QOL impact. METHODS: The GO-QOL scores from patients in 2 randomized, masked, placebo-controlled teprotumumab trials (N=171) were compared with 6 HSU values based on severity of proptosis/diplopia in those studies. Patient GO-QOL and HSU scores were compared at baseline and after 6-month treatment via regression analyses. GO-QOL and HSU scores were correlated for validation and quantification of QOL impact by severity state and to estimate quality-adjusted life year improvement. RESULTS: GO-QOL scores were correlated with TED severity, indicating that worse severity was associated with lower (worse) GO-QOL scores. Less severe health states were represented by higher (better) GO-QOL scores. Importantly, GO-QOL scores were positively correlated with utility scores of the 6 health states, allowing for conversion of the GO-QOL scores to utility scores. A positive (improved) 0.013 utility change was found for each 1-point (positive) improvement in GO-QOL score produced by teprotumumab versus placebo. CONCLUSION: Patients with moderate-to-severe active TED health states demonstrate increasing TED severity associated with declining utility values and worsening GO-QOL scores. These results indicate that the GO-QOL scores can be used to bridge to the HSU scores for benefit quantification.

IgG4 serum levels in Graves' orbitopathy.

OBJECTIVE: IgG4-related disease (IgG4-RD) can involve many organs, including thyroid and orbital tissues. A link between IgG4, Graves' disease (GD) and Graves' orbitopathy (GO) has been proposed, but results are conflicting. Here we investigated the possible association between IgG4 and GO. METHODS: Retrospective investigation in 297 patients with Graves' disease (GD), 152 with GO. PRIMARY OUTCOME: prevalence of IgG4 ≥ 135 mg/dL (cut-off for IgG4-RD). SECONDARY OBJECTIVES: (1) serum IgG4 concentrations; (2) IgG4/IgG ratio; (3) prevalence of IgG4/IgG ratio ≥ 8.0%; (4) relationship between IgG4 and eye features; (5) relationship between IgG4 and anti-TSH receptor antibodies (TRAbs). RESULTS: Because GO patients had lower FT3 concentrations, we evaluated the main objectives in the second and third FT3 quartiles subpopulation, in which there were no relevant differences between patients with (n = 81) or without GO (n = 67) for baseline parameters. Within this population, the prevalence of IgG4 levels ≥ 135 mg/dL did not differ between patients without and with GO (17.9% vs 17.3%). No difference was observed concerning IgG4 concentrations, prevalence of IgG4/IgG ≥ 8.0%, and IgG4/IgG ratio. There was no relationship between IgG4 and eye features and no correlation between IgG4 levels and TRAb was found. CONCLUSIONS: Our results suggest that, within GD, there is no relationship between serum IgG4 and GO.

Glucocorticoid-induced adrenal insufficiency after therapy with intravenous methylprednisolone in patients with moderate-to-severe and active Graves' orbitopathy: assessment with a low-dose corticotropin test.

PURPOSE: We aimed to assess adrenal function following treatment of moderate-to-severe and active Graves' orbitopathy (GO) with intravenous methylprednisolone (IVMP) in weekly pulses in a cumulative dose of 4.5 or 7.5 g. We evaluated the impact of IVMP pulses on adrenal reserve using a low-dose (1 µg) ACTH stimulation test (LDT) for the first time. METHODS: In this prospective study we evaluated adrenal function in 21 patients with moderate-to-severe and active GO treated with 12 weekly IVMP pulses according to the European Group on Graves' Orbitopathy (EUGOGO) recommendations. We assessed serum cortisol, plasma adrenocorticotropic hormone (ACTH), and dehydroepiandrosterone sulfate (DHEA-S) levels before the 1st and 12th IVMP pulse. We performed dynamic testing using LDT before the 12th IVMP pulse in all patients. In those who failed LDT, adrenal function was reassessed with LDT and the overnight metyrapone test after 4-7 weeks. RESULTS: Two patients failed to achieve serum cortisol levels ≥ 18.1 µg/dL at 30 and 60 min in LDT and were diagnosed with glucocorticoid-induced adrenal insufficiency (GC-induced AI). They were recommended to take hydrocortisone in situations of acute stress. Both patients were reassessed within 4-7 weeks after treatment cessation and showed an adequate response in LDT and overnight metyrapone test. We observed a statistically significant decrease in DHEA-S levels (p = 0.004) before the 12th IVMP pulse compared to baseline in all patients. CONCLUSION: For the first time, our research shows that administering IVMP in 12 weekly pulses can result in GC-induced AI. We suggest that patients should undergo careful evaluation for GC-induced AI, including LDT, after therapy with IVMP according to EUGOGO guidelines. Screening for altered adrenal reserve could prevent life-threatening complications, particularly during acute stress situations.

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

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

Comparison of surgical effect in active and inactive Dysthyroid Optic Neuropathy after Endoscopic Transnasal Medial Orbital Decompression.

PURPOSE: To evaluate and compare the changes in orbital soft tissue volume and visual function after endoscopic transnasal medial orbital decompression in patients with active and inactive dysthyroid optic neuropathy (DON). METHODS: This prospective, cohort study recruited 112 patients (112 eyes) with DON who were divided into an active and inactive DON group (56 eyes each) by clinical activity scores. All patients underwent endoscopic transnasal medial orbital decompression. The pre- and post-operative orbital soft tissue volumes were measured with high-resolution computed tomography (CT) using Mimics software. Visual function, including best-corrected visual acuity (BCVA), visual field (VF), and visual evoked potential (VEP), was recorded before and after surgery. RESULTS: Preoperatively, compared with the inactive DON group, the active DON group had greater extraocular muscle volume (EMV) and EMV/orbital volume (OV) ratio, but worse BCVA, VF, and exophthalmos. Postoperatively, although the EMV slightly increased, with the enlarged medial rectus muscle contributing dramatically, the EMV/OV ratio decreased in patients with DON. Besides, visual function including BCVA, VF, VEP and exophthalmos was also improved in both groups after surgery. There were no significant differences in postoperative OV; EMV; EMV/OV ratio; and the BCVA, VF, and VEP parameters between both groups (all P > 0.05). CONCLUSION: Patients with DON who did not respond well to steroids, regardless of disease activity, may benefit from orbital decompression via the decrease in the proportion of EMV in OV, especially patients with active DON, who showed more improved visual function than patients with inactive DON.