A Deep Learning Framework for Predicting Teprotumumab Treatment Response in Thyroid Eye Disease.

Thyroid eye disease (TED) is an autoimmune disorder causing inflammation, expansion, and fibrosis of orbital fat, muscle, and lacrimal gland. This article reviews the different methods of grading severity and activity of TED and focuses on the VISA Classification for disease evaluation and planning management. Accurate evaluation of the clinical features of TED is essential for early diagnosis, identification of high-risk disease, planning medical and surgical intervention, and assessing response to therapy. Evaluation of the activity and severity of TED is based on a number of clinical features: appearance and exposure, periorbital tissue inflammation and congestion, restricted ocular motility and strabismus, and dysthyroid optic neuropathy. The authors review these clinical features in relation to disease activity and severity. Several classification systems have been devised to grade severity of these clinical manifestations. These include the NO SPECS Classification, the European Group on Graves Orbitopathy severity scale, the Clinical Activity Score of Mourits, and the VISA Classification as outlined here. The authors compare and contrast these evaluation schemes. An accurate clinical assessment of TED, including grading of disease severity and activity, is necessary for early diagnosis, recognition of those cases likely to develop more serious complications, and appropriate management planning. The VISA Classification grades both disease severity and activity using subjective and objective inputs. It organizes the clinical features of TED into 4 discrete groupings: V (vision, dysthyroid optic neuropathy); I (inflammation, congestion); S (strabismus, motility restriction); A (appearance, exposure). The layout follows the usual sequence of the eye examination and facilitates comparison of measurements between visits and data collation for research.

Background: Thyroid eye disease (TED) is a debilitating autoimmune disorder linked to thyroid dysfunction. There is limited knowledge of TED in Asian populations. This multicenter study characterizes the clinical features and treatment response of TED in a large Chinese cohort. Methods: A retrospective multicenterstudy included 4157 patients with TED from nine Chinese hospitals from February 2016 to July 2023. Disease severity and activity were evaluated according to the European Group on Graves' Orbitopathy standards. We examined associations of variables including sex, age, smoking status, I131 treatment, consultation department, and geographical region with clinical outcomes. Logistic regression and nomogram models were developed to examine associations with sight-threatening TED and, in a subgroup analysis (n = 126), patients' responsiveness to intravenous glucocorticoid (IVGC) therapy. Results: We included 4157 patients with mean age and standard deviation (SD) 45.96 ± 16.44 years. Of these, 63.6% (n = 2644) were females. Over half (55.6%, n = 2310) of participants were in the inactive phase, with a mean clinical activity score of 2.19 ± 1.61 (SD) for all patients. TED severity was categorized as mild (9.3%, n = 385), moderate-to-severe (82.5%, n = 3428), and sight-threatening (8.2%, n = 344). The average degree of exophthalmos was 20.04 ± 5.27 mm, and 48.8% (n = 2029) of patients had diplopia. Patients treated with I131 had higher disease activity (47.5%, n = 468, vs. 43.5%, n = 1379, p < 0.05). Coastal region patients exhibited more severe TED (sight-threatening cases: 10.1%, n = 195, vs. 7.2%, n = 147) and higher diplopia scores (1.00 ± 1.10 vs. 0.86 ± 1.09, p < 0.001) than inland counterparts. TED severity was also greater in patients treated in Ophthalmology departments (mild cases: 6.0%, n = 213; moderate-to-severe cases: 85.6%, n = 3055) compared with Endocrinology departments (mild cases: 29.3%, n = 172; moderate-to-severe cases: 63.5%, n = 373). Nomograms had an area under the receiver operating curve of 0.742 (confidence interval [CI] 0.716-0.768) for sight-threatening TED and 0.759 (CI 0.674-0.843) for IVGC therapy responsiveness. Conclusions: We characterized the clinical features and treatment response of TED in a large Chinese cohort. These findings offer valuable insights informing TED risk stratification in Asian patients and forming a foundation for future prospective studies.

Background:Thyroid eye disease (TED) is an autoimmune inflammatory condition affecting the orbit and ocular surface, often leading to proptosis, diplopia, and evaporative dry eye. Tear film instability, eyelid retraction, and lagophthalmos contribute significantly to ocular surface dysfunction in TED. Smoking is a major risk factor that worsens disease severity and reduces treatment response.Objectives:To evaluate ocular surface changes, treatment responses, and risk factors—including smoking—in patients with TED, and to assess the effects of different therapeutic modalities.Design:Retrospective observational cohort study.Methods:This retrospective study analyzed the records of 365 patients with TED followed between 2014 and 2021. Complete clinical data were available for 362 patients. Ocular parameters, including TBUT, OSDI, Oxford staining score, MRD-1, MRD-2, and Hertel exophthalmometry, were evaluated at baseline and follow-up. Treatment modalities included antithyroid drugs, corticosteroids, selenium supplementation, RAI, and surgery. Data were compared between smokers and nonsmokers.Results:Among 362 patients (76% female), 105 (29%) were smokers. TED severity and persistent dry eye symptoms were significantly higher among smokers (p < 0.05). Posttreatment, significant improvements were observed in TBUT, OSDI, and Oxford scores (p < 0.05). Selenium supplementation showed potential benefit. CAS decreased significantly over follow-up (from 7.7% to 4.7% active cases, p < 0.05). TED progression was observed in 18.7% of patients receiving RAI therapy. Surgical intervention rates were low.Conclusion:TED causes notable ocular surface dysfunction and dry eye symptoms, particularly in smokers. Medical and surgical treatments provide effective disease control, while selenium appears promising for disease stabilization. Smoking cessation and early multidisciplinary management are critical to improving outcomes.

To evaluate the changes of retinal nerve fibre layer (RNFL) and ganglion cell layer/inner plexiform layer (GCL/IPL) with the severity of thyroid eye disease (TED). One hundred and forty-five eyes of 75 patients with TED and 70 eyes of 35 healthy controls were included. The eyes with TED were divided into mild group (35 eyes), moderate-to-severe group (42 eyes) and DON group (68 eyes). The thickness of RNFL and GCL/IPL were measured by optic coherence tomography (OCT). Clinical activity score (CAS), best corrected visual acuity (BCVA), intraocular pressure (IOP), proptosis and mean deviation (MD) by Humphrey perimetry were assessed. The CAS had significant difference between the three groups (p < 0.001). The proptosis and IOP were significantly higher in DON group and moderate-to-severe group than mild group (p < 0.05). The MD and BCVA were significantly worse in DON group compared with mild group and moderate-to-severe group (p < 0.001). The mean GCL/IPL thickness was thinnest in DON group (p < 0.001). The mean RNFL thickness had significant difference between moderate-to-severe group and DON group (p = 0.036). The mean GCL/IPL thickness had a significant correlation with MD (r = 0.449, p < 0.001) and VA (r = -0.388, p < 0.001), whereas the mean RNFL thickness had no significant correlation with MD (p = 0.082) or VA (p = 0.226). Subclinical optic neuropathy might progress in the patients with moderate-to-severe TED. OCT measurements of GCL/IPL and RNFL are useful to detect the early changes of optic nerve. The thinning of GCL/IPL might be a strong suggestion for closer vision follow-up and earlier decompression surgery.

Background Thyroid eye disease (TED) is an autoimmune disorder caused by autoantibodies targeting thyroid-stimulating hormone (TSH) receptors. Aim To correlate the clinical profile of TED with the level of circulating biomarkers [TSH receptor antibody and antithyroglobulin antibody (anti-TgAb)]. Patients and methods A prospective observational cross-sectional study carried out on 40 TED patients. The patients were subjected to full history taking, endocrinological evaluation, and full ophthalmological examination. All the participants underwent thyroid function tests (TSH, free T3, and free T4), autoantibody tests such as TSH receptor-stimulating antibody (TSAb) and anti-TgAb. Results A significant positive correlation was observed between TSH receptor antibodies and proptosis. TSAb were significantly higher among moderate to severe TED patients compared with those with mild disease. There was a statistically significant positive correlation between TSAb and severity of TED. Conclusion TSAb is indicative of TED with TSAb titers in serum positively correlating with activity and severity of TED. Anti-TgAb has a negative relationship with TED activity and severity.

Purpose To obtain clinical data about disease activity and severity of thyroid eye disease (TED) in a tertiary eye hospital in the Eastern Province of Saudi Arabia and to correlate this data with vitamin D levels. Methods A clinical observational study was conducted in a specialized eye hospital in Saudi Arabia. It included prospective enrollment of Saudi patients with confirmed TED to evaluate activity and severity according to Clinical Activity Score (CAS) and European Group on Graves’ Orbitopathy (EUGOGO), respectively, and also for blood investigation, including thyroid profile and vitamin D levels. In addition, some retrospective data collection included previous medical and surgical treatment and complications. Results A total of 74 TED patients were included, with a median age of 42 years and a female predominance of 64.9%. Smokers were 18.9%. A family history of thyroid disease was noted in 12.16% of patients. There were 10.8% of patients with active TED. A moderate to severe severity level was observed in 71% of the cases, mild in 15%, and sight-threatening in 6%. Smoking and older age were associated with the active form of TED. There was a 48.4% prevalence of vitamin D deficiency among TED patients and it was not associated with TED severity or activity. Conclusions This is the first study demonstrating the clinical profile of TED among Saudi patients. Smoking and older age were associated with TED. Vitamin D deficiency among TED patients was not worse than that of the general Saudi population.

There are no reliable biomarkers to predict thyroid eye disease (TED) in patients with autoimmune thyroid disease (AITD) currently. Several evidences support the involvement of the lacrimal gland in TED. The aim of our study was to quantitatively correlate the changes in tear protein profile with increasing severity of TED. Tear samples were collected from four groups of patients; AITD without TED (AITD), AITD with mild TED (mild TED), AITD with severe TED (severe TED) and normal controls. A total of 72 patients were recruited for the study. In discovery phase, isobaric tags for relative and absolute quantification (iTRAQ) 4-plex was used for quantitative proteomics analysis. For verification of results from discovery phase, sequential window acquisition of all theoretical fragment ion spectra (SWATH) was used to analyze an independent cohort from normal controls, AITD, mild TED and severe TED. Two proteins, S100A4 and PIP showed consistent dysregulation trends in the discovery and validation phase experiments. Our study demonstrated the differences in tear proteome across the spectrum of different severity and activity of TED in patients with AITD. Two tear proteins, S100A4 and PIP may serve as potential biomarkers to predict progression to severe TED in patients with AITD.

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 invivo, 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 invivo. 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.

Although it has been reported that thyroid-stimulating immunoglobulin (TSI) is associated with the clinical characteristics of thyroid eye disease (TED), there is a paucity of literature regarding the role of TSI in diagnosing active TED. This study investigated the relationship between the level of TSI and the activity of TED and assessed the cut-off value of TSI discriminating active TED from inactive TED. This cross-sectional study included 101 patients with TED. TSI was quantitatively measured with a cell-based bioassay using a chimeric TSH receptor and a cyclic adenosine monophosphate response element-dependent luciferase. The association between TSI and a variety of demographic and clinical features of TED was analysed. Multivariate regression analysis was performed to determine possible independent factors affecting the level of TSI. TSI level was higher in males than in females (p = 0.023) and smokers than in nonsmokers (p = 0.004). TSI level was inversely correlated with the duration of ocular symptoms (r = -0.295, p = 0.003). The level of TSI was also significantly different when compared to the thyroid function (p = 0.003), TED activity (p < 0.001), and TED severity (p = 0.001). Multivariate regression analysis revealed a significant relationship between TED activity and thyroid function jointly and the TSI level. The cut-off level of TSI for predicting active TED was a specimen-to-reference ratio of 406.7 (p < 0.001, area under the curve = 0.847, sensitivity 77.4%, specificity 81.3%). TSI was a functional biomarker strongly associated with TED activity even after being adjusted by other clinical characteristics. Serum TSI level may help identify patients with active TED in clinics.

Purpose:To study the correlation between thyroid eye disease (TED) with type-2 diabetes mellitus.Methods:A cross-sectional cohort study was conducted from Jan 2018 to Dec 2018, in patients presenting with thyroid eye disease to orbit and oculoplasty clinic of a tertiary eye care hospital. A total of 105 patients were included in the study. All patients underwent detailed ophthalmic evaluation and thyroid eye disease workup. Patients were categorized into mild, moderate, and severe/sight-threatening TED based on EUGOGO classification. Systemic history of diabetes was noted. RBS was done in all patients.Results:Mild disease was noted 61 patients of which 11 were diabetics, moderate in 26 patients (8 diabetics), and severe disease in 18 patients (14 diabetics). All patients were treated accordingly. Among the TED patients, the percentage of diabetic patients was noted to be in increasing order toward the severity spectrum of TED. The prevalence of severe TED was found to be much higher in diabetic patients accounting upto 77.77% of 18 patients. A statistically significant correlation was noted (P = 0.014) between severe TED and type-2 diabetes mellitus. In addition, early onset of thyroid eye disease was noted in type-2 diabetes patients. Even though female preponderance was noted, severe TED was more in men (66.6%).Conclusion:An autoimmune etiology for the association of thyroid and type-1diabetes has been well established. This study shows that type-2 diabetic patients can have more severity in the clinical presentation of TED. Therefore, the presence of type-2 DM in patients with TED can be a predictive factor for onset, progression, and severity of disease. Hence, a high concern of interest among treating ophthalmologists and endocrinologists regarding this entity would help in early prediction and decreased morbidity among such patients.

Thyroid eye disease (TED) consists of a spectrum of autoimmune orbital pathology that threatens patients’ quality of life and vision. Research suggests that oxidative stress plays a role in both the thyroid gland and orbit. Selenium has been proposed as a potential therapeutic adjunct given its role in thyroid physiology and antioxidant metabolism. Furthermore, selenium status has been linked to multiple pathological thyroid states. Despite the preponderance of evidence demonstrating a role for selenium in thyroid disease, limited research exists highlighting its role in TED specifically. This review summarizes the pathophysiology and role of selenium in thyroid eye disease (TED) and the current body of evidence including in vitro and in vivo studies highlighting the role for supplementation in clinical ophthalmic practice. Notably, relatively lower selenium levels have been shown to have a modest correlation with severity of thyroid eye disease. Selenium supplementation has shown some benefit in patients with mild Graves’ Orbitopathy in European populations presumed deficient. Despite the preponderance of evidence demonstrating a role for selenium in thyroid disease, limited data is available to conclusively expand its role in TED outside of a 6-month course of supplementation in selenium deficient or relatively deficient populations. Data subject to geographic and population differences in selenium levels limits the generalizability of supplementation in TED. Despite mechanistic evidence of its antioxidant effects in TED beyond the advantages of thyroid disease in general, the benefits of selenium supplementation should be interrogated further and contextually tailored in both clinical and research formats for ophthalmic practice.

Thyroid eye disease (TED) is the major extrathyroidal manifestation of Graves’ disease (GD). Treatment choice is based on clinical activity and severity of TED, as evaluated with clinical activity score (CAS) and magnetic resonance (MR) imaging. We aimed to determine the relationship between neutrophil-to-lymphocyte ratio (NLR), a readily available indicator of systemic inflammation, and clinical and MR imaging parameters in TED patients. Eighty-seven consecutive TED patients were included. The average signal intensity ratio (SIR), average extraocular muscle (EOM) diameter, and proptosis of the study eye were extracted from MR images. A baseline NLR ≥ 2.0 was recorded in 37 (42.5%) patients and NLR < 2.0 in 50 (57.5%) patients. TED patients with NLR ≥ 2.0 were older, had a higher CAS, average SIR, average EOM diameter and proptosis, and a lower serum thyrotrophin receptor antibody level than patients with NLR < 2.0 (all P < 0.05). All MR parameters showed significant correlation with CAS (P < 0.05). NLR correlated significantly with CAS (P = 0.001), average SIR (P = 0.004), average EOM diameter (P = 0.007), and proptosis (P = 0.007). Multiple regression revealed a significant correlation between NLR and CAS (P = 0.001), average SIR (P = 0.029), and proptosis (P = 0.037). Cox regression analysis showed that a high NLR at baseline was associated with a worse clinical outcome of TED (hazard ratio 3.7, 95% CI 1.22–11.2, P = 0.02), at a median follow-up of 25 months. In conclusion, NLR was correlated with CAS and MR imaging parameters and was associated with a worse clinical outcome of TED at follow-up in patients with TED. Additional prospective studies are needed to validate our findings.

To identify the relationship between thyroid eye disease (TED) and supraorbital neuralgia (SON) and establish a reliable approach to the diagnosis and management of TED-associated SON. This retrospective study included 1,126 patients. Demographics, active and inactive phase status and duration, and reactivation rate were noted. TED clinical activity was determined using the vision, inflammation, strabismus, and appearance assessment system, and TED severity was classified using the European Group of Graves' Orbitopathy system. Subtypes of periorbital pain were identified, and suspected SON was confirmed by supraorbital nerve block. Of the study's 1,126 patients, 935 (83%) were deemed "active" at some point during the follow up and 34 (3%) remained "active" at the study's conclusion. Of the 2,251 eyes studied, 1,193 (53%) underwent orbital decompression. Of the 1,126 patients, 946 (84%) reported a retrobulbar "pressure" or "aching," but a distinct, more debilitating pain suggestive of SON was reported in 91 (8%). All 91 patients were given a supraorbital nerve block, and all had complete pain resolution lasting from hours to weeks. Eighty-eight (97%) of the 91 patients with SON-type pain underwent orbital decompression compared to 496 (48%) of the 1,035 without SON-type pain (p < 0.00001). A difference was found in the rate of TED reactivation between those with SON-type symptoms (8%) as compared to those without (2%), p = 0.01. SON of uncertain etiology appears to be a previously underreported but significant pain associated with TED. Paradoxically, although the SON does not appear to be related to the type or severity of TED on standard rating scales, the presence of SON was found to be associated with increased likelihood of both orbital decompression and TED reactivation.

The CXC chemokine receptor CXCR3 and its chemokines CXCL10, CXCL9, and CXCL11 are implicated in the pathogenesis of autoimmune diseases. Here, we review these chemokines in autoimmune thyroiditis (AT), Graves disease (GD), thyroid eye disease (TED), type 1 diabetes (T1D), and Addison's disease (AAD). A PubMed review of the literature was conducted, searching for the above-mentioned chemokines in combination with AT, GD, TED, T1D, and AAD. Thyroid follicular cells in AT and GD, retroorbital cells in TED (fibroblasts, preadipocytes, myoblasts), β cells and islets in T1D, and adrenal cells in AAD respond to interferon-γ (IFN-γ) stimulation producing large amounts of these chemokines. Furthermore, lymphocytes and peripheral blood mononuclear cells (PBMC) are in part responsible for the secreted Th1 chemokines. In AT, GD, TED, T1D, and AAD, the circulating levels of these chemokines have been shown to be high. Furthermore, these chemokines have been associated with the early phases of the autoimmune response in all the above-mentioned disorders. High levels of these chemokines have been associated also with the "active phase" of the disease in GD, and also in TED. Other studies have shown an association with the severity of hypothyroidism in AD, of hyperthyroidism in GD, with severity of TED, or with fulminant T1D. The reviewed data have shown the importance of the Th1 immune response in different endocrine autoimmune diseases, and many studies have suggested that CXCR3 and its chemokines might be considered as potential targets of new drugs for the treatment of these disorders.

Background: Thyroid eye disease (TED), or Graves’ orbitopathy, is the most common extra-thyroidal manifestation of Graves’ disease, but it has only rarely been reported after SARS-CoV-2 vaccination. Autoimmune thyroid disease, including subacute thyroiditis and Graves’ disease, has been described following COVID-19 vaccination; we present a case series of TED occurring shortly after different COVID-19 vaccines to provide clinical data on this potential safety signal. Case presentation: We describe five women (mean age 47 years; range 27–69) who developed TED 3–20 days after COVID-19 vaccination with mRNA or adenoviral vector vaccines, three of whom had pre-existing thyroid disease. Presentations included ocular and retro-orbital pain, exophthalmos, headache, goiter, tremor, depressive symptoms, and, in one case, anterior neck pain and fever. TED severity (ETA/EUGOGO) ranged from mild to severe, with frequent findings of suppressed TSH, elevated thyroid autoantibodies, and inflammatory markers, as well as imaging evidence of exophthalmos, extraocular muscle enlargement, and diffuse or multinodular goiter. Management with intravenous corticosteroids, selenium, levothyroxine adjustment, and/or intramuscular corticosteroids led to improvement in thyroid function and inflammation by 3 months, although mild TED often persisted. Conclusions: This case series supports a temporal association between COVID-19 vaccination and new-onset or exacerbated TED in individuals with autoimmune thyroid disease. Although vaccination benefits outweigh potential risks, clinicians should remain alert to ocular and thyroid symptoms after immunization to ensure timely diagnosis and management.