A retrospective study on the effectiveness of intensity modulated radiation therapy for thyroid associated ophthalmopathy at a single institute.

Thyroid-associated ophthalmopathy (TAO) is a hallmark autoimmune condition, and the treatment of TAO requires a multidisciplinary approach. Radiation therapy (RT) is a viable treatment option for active TAO, IMRT is a more precise technology in radiation oncology. This study aims to evaluate the efficacy, feasibility, and safety of orbital intensity-modulated radiation therapy (IMRT) in the treatment of TAO. A single-center retrospective analysis was conducted, including patients diagnosed with moderate to severe active TAO at the Department of Radiation Oncology, Peking University Third Hospital, from October 2020 to October 2023, who had poor responses to corticosteroid treatment. These patients subsequently received IMRT treatment, followed by a period of follow-up and retrospective analysis. The study focused on the outcomes of treatment efficacy, safety, and acute toxic reactions induced by radiation therapy. Improvements in clinical activity score (CAS) at 4 and 12 months were considered as primary and secondary study endpoints, respectively, along with the incidence rate of adverse events. The median follow-up period was 12 months. The median follow-up time after radiation therapy was 12 months. There was no statistically significant difference in CAS between before and 4 months after radiation therapy (CAS: 5.53 ± 2.07 vs.4.68 ± 2.62; R squared: 0.21; 95% CI: - 1.01-0.02; P = 0.054). However, there was a significant reduction in CAS 12 months post-treatment compared to pre-treatment (CAS: 5.53 ± 2.07 vs. 3.06 ± 2.38; R squared: 0.66; 95% CI: 3.42 - 1.52; P < 0.001). The CAS showed a progressively decreasing trend at both 4 months and 12 months post-treatment. In the combined radiotherapy with glucocorticoid treatment group, a statistically significant difference was found between the CAS before treatment and 12 months after radiotherapy (CAS: 6.38 ± 2.00 vs. 3.88 ± 2.85; R squared: 0.66; 95% CI - 4.11 to 0.89; P = 0.008). In the radiotherapy alone group, a statistically significant difference was found between the CAS before treatment and 12 months after radiotherapy (CAS: 4.78 ± 1.92 vs. 2.33 ± 1.73; R squared: 0.66; 95% CI - 3.89 to 1.00; P = 0.005). A few patients experienced Grade I periorbital edema, conjunctival congestion, and dry eye syndrome, but no adverse events such as cataracts, radiation retinopathy, or radiation-induced optic neuropathy were observed by the end of the follow-up period. Orbital IMRT is an effective treatment modality for moderate to severe active TAO, demonstrating significant efficacy even in patients who had not achieved success with previous treatments such as corticosteroids. This retrospective study was approved by the Ethics Committee of Peking University Third Hospital. The permit number was M2024220 and data of registration was April I, 2024.

A TSHR-Targeting Aptamer in Monocytes Correlating with Clinical Activity in TAO.

Background: Manifestations of thyroid-associated ophthalmopathy (TAO) vary greatly. Few tools and indicators are available to assess TAO, restricting personalized diagnosis and treatment. Aim: To identify an aptamer targeting thyroid-stimulating hormone receptor (TSHR) and utilize this aptamer to evaluate clinical activity in patients with TAO. Methods: An aptamer targeting TSHR was developed by exponential enrichment and systematic evaluation of TSHR ligands. After truncation and optimization, the affinity, equilibrium dissociation constant, and serum stability of this aptamer were evaluated. The affinity of the TSHR-targeting aptamer to isolated fibrocytes was assessed, as was aptamer internalization by fibrocytes. The mechanism of binding was determined by molecular docking. The correlation between disease manifestations and the percentage of TSHR-positive cells was assessed by correlation analysis. Results: The aptamer TSHR-21-42 was developed to bind to TSHR, with the equilibrium dissociation constant being 71.46 Kd. Isolated fibrocytes were shown to bind TSHR-21-42 through TSHR, with its affinity maintained at various temperatures and ion concentrations. TSHR-21-42 could compete with anti-TSHR antibody, both for binding site to TSHR and uptake by cells after binding. In addition, TSHR-21-42 could bind to leukocytes in peripheral blood, with this binding differing in patients with TAO and healthy control subjects. The percentage of TSHR-positive monocytes, as determined by binding of TSHR-21-42, correlated positively with clinical activity score in patients with TAO, indicating that TSHR-21-42 binding could assess the severity of TAO. Conclusion: This aptamer targeting TSHR may be used to objectively assess disease activity in patients with TAO, by evaluating the percentages of TSHR positive cells in peripheral blood.

A Preliminary Evaluation of the Diagnostic Performance of a Smartphone-Based Machine Learning-Assisted System for Evaluation of Clinical Activity Score in Digital Images of Thyroid-Associated Orbitopathy.

Background: We previously developed a machine learning (ML)-assisted system for predicting the clinical activity score (CAS) in thyroid-associated orbitopathy (TAO) using digital facial images taken by a digital single-lens reflex camera in a studio setting. In this study, we aimed to apply this system to smartphones and detect active TAO (CAS ≥3) using facial images captured by smartphone cameras. We evaluated the performance of our system on various smartphone models and compared it with the performance of ophthalmologists with varying clinical experience. Methods: We applied the preexisting ML architecture to classify photos taken with smartphones (Galaxy S21 Ultra, iPhone 12 pro, iPhone 11, iPhone SE 2020, Galaxy M20, and Galaxy A21S). The performance was evaluated with smartphone-captured images from 100 patients with TAO. Three ophthalmology residents, three general ophthalmologists with <5 years of clinical experience, and three oculoplastic specialists independently interpreted the same set of images taken under a studio environment and compared their results with those generated by the smartphone-based ML-assisted system. Reference CAS was determined by a consensus of three oculoplastic specialists. Results: Active TAO (CAS ≥3) was identified in 28 patients. Smartphone model used in capturing facial images influenced active TAO detection performance (F1 score 0.59-0.72). The smartphone-based system showed 74.5% sensitivity, 84.8% specificity, and F1 score 0.70 on top three smartphones. On images from all six smartphones, average sensitivity, specificity, and F1 score were 71.4%, 81.6%, and 0.66, respectively. Ophthalmology residents' values were 69.1%, 55.1%, and 0.46. General ophthalmologists' values were 61.9%, 79.6%, and 0.55. Oculoplastic specialists' values were 73.8%, 90.7%, and 0.75. This smartphone-based ML-assisted system predicted CAS within 1 point of reference CAS in 90.7% using facial images from smartphones. Conclusions: Our smartphone-based ML-assisted system shows reasonable accuracy in detecting active TAO, comparable with oculoplastic specialists and outperforming residents and general ophthalmologists. It may enable reliable self-monitoring for disease activity, but confirmatory research is needed for clinical application.

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

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

Evaluation of Aqueous Flare in Graves' Ophthalmopathy and its Relationship with Thyroid Hormones, Antibodies, and Clinical Activity Score.

Objectives: The aim of this study was to assess intraocular inflammation in patients with active and inactive Graves' ophthalmopathy (GO) using an aqueous laser flash meter and to assess its relationship with thyroid hormones, antibodies, and clinical activity score (CAS). Methods: Forty patients (29 females and 11 males) were included in the study. The patients were divided into two groups according to CAS; patients with CAS <3 (inactive) were included in Group 1 and patients with CAS ≥3 (active) were included in Group 2. The laser flare meter was used to measure the flare of aqueous humor. Each patient's ocular findings, thyroid hormone, and antibody levels were also recorded. Results: The mean age of patients was 46.88±11.79 years in Group 1 and 44.50±12.59 years in Group 2 (p=0.555). The mean CAS was 0.88±0.65 in Group 1 and 3.57±0.85 in Group 2 (p<0.001). The mean aqueous flare was 6.5±2.2 ph/ms in Group 1 and 7.0±6.4 ph/ms in Group 2 (p=0.73). Hertel exophthalmometry, intraocular pressure (IOP), antithyroglobulin antibody, and thyroid stimulating hormone receptor antibody (TRAb) levels were similar in both groups (each p>0.05). There was no correlation between aqueous flare value and CAS, Hertel exophthalmometry, IOP, thyroid hormone, and antibody levels (each p>0.05). There was a significant correlation between CAS and antibody levels (each p<0.05). Conclusion: Flare values that are not much above the normal range may be an indication that intraocular inflammation is not elevated in GO patients. This suggests that the damage to the blood-aqueous barrier in these patients is not severe enough to increase intraocular inflammation.

Tocilizumab improves clinical outcome in patients with active corticosteroid-resistant moderate-to-severe Graves' orbitopathy: an observational study.

Background: Graves' orbitopathy (GO) is an autoimmune disorder affecting the orbital fat and muscles. A significant role of IL-6 in the pathogenesis of GO has been described and tocilizumab (TCZ), an IL-6 inhibitor targeting IL-6R has been given in some patients. The aim of our case study was to evaluate the therapeutic outcome of TCZ in non-responders to first line treatments with corticosteroids. Methods: We conducted an observational study of patients with moderate to severe GO. Twelve patients received TCZ in intravenous infusions at a dose of 8mg/kg every 28 days for 4 months and followed up for additionally 6 weeks. The primary outcome was improvement in CAS by at least 2 points, 6 weeks after the last dose of TCZ. Secondary outcomes included CAS <3 (inactive disease) 6 weeks after TCZ last dose, reduced TSI levels, proptosis reduction by > 2mm and diplopia response. Results: The primary outcome, was achieved in all patients 6 weeks after treatment course. Furthermore all patients had inactive disease 6 weeks after treatment cessation. Treatment with TCZ reduced significantly median CAS by 3 units (p=0.002), TSI levels by 11.02 IU/L (p=0.006), Hertel score on the right eye by 2.3 mm (p=0.003), Hertel score on the left eye by 1.6 mm (p=0.002), while diplopia persisted in fewer patients (25%) after treatment with TCZ (not statistically significant, p=0.250). After treatment with TCZ, there was a radiological improvement in 75% of patients, while 16.7% showed no response, and in 8.3% of patients deterioration was established. Conclusion: Tocilizumab appears to be a safe and cost effective therapeutic option for patients with active, corticosteroid-resistant, moderate to severe Graves' orbitopathy.

Changes in Clinical Activity, Serum Autoantibody Levels, and Chorioretinal Vessels After Systemic Glucocorticoid Therapy in Thyroid Eye Disease.

INTRODUCTION: The aim of this study was to investigate changes in the Clinical Activity Score, serum thyroid-stimulating hormone receptor antibody and thyroid-stimulating immunoglobulin levels, chorioretinal blood vessels, and extraocular muscle thickness in patients with thyroid eye disease following systemic steroid treatment. METHODS: This prospective observational study enrolled 57 patients with active thyroid eye disease who received systemic intravenous glucocorticoids for 12 weeks. Demographics, clinical activity scores, optical coherence tomography images, and serum thyroid-stimulating immunoglobulin and thyroid-stimulating hormone receptor antibody levels were assessed at baseline, at 6 and 12 weeks after intravenous (IV) GC therapy initiation, and 2 months after IV GC therapy termination. The extraocular muscle thickness, choroidal thickness, and choroidal vascularity index were measured. RESULTS: The clinical activity scores showed a significant decrease. Serum thyroid-stimulating immunoglobulin levels dropped continuously for 2 months. The thyroid-stimulating hormone receptor antibody level decreased until 12 weeks after treatment but returned to within the normal range in 75% of patients after 77 and 126 days, respectively. The choroidal thickness decreased at all time points. The thickness of the medial and inferior rectus muscles decreased at 2 months after treatment. The clinical activity score decreased to < 3 points in 50% of patients after 78 days. CONCLUSION: Intravenous glucocorticoid therapy improved the clinical activity score, chorioretinal blood flow, and extraocular muscle thickness. The serum autoantibody levels were normalized in patients with active thyroid eye disease 2 months after IV GC termination. The serum thyroid-stimulating immunoglobulin and thyroid-stimulating hormone receptor antibody levels correlated with restoration of chorioretinal capillary perfusion and improved clinical symptoms and muscle thickness. Non-invasive optical coherence tomography findings and serologic factors predict the response to intravenous glucocorticoid therapy.

Clinical evaluation of lacrimal gland parameters in patients with thyroid-associated ophthalmopathy using orbital magnetic resonance imagining / 国际眼科杂志(Guoji Yanke Zazhi)

AIM: To evaluate the lacrimal gland parameters and their correlation with clinical examination in patients with thyroid-associated ophthalmopathy(TAO)using orbital magnetic resonance imaging(MRI).METHODS: A total of 38 patients(76 eyes)with TAO were selected as case group, and 26 patients(52 eyes)who matched the gender and age with case group and volunteered to accept examination were selected as normal control group. Patients in case group were categorized into active TAO group and inactive TAO group according to the modified clinical activity score(CAS). The exophthalmos was evaluated on T1WI after obtaining the MRI images, the longest lacrimal gland length, width, and the biggest area in axial and coronal images were evaluated on T2WI, and the maximum T2 value and mean T2 value of the lacrimal gland were recorded.RESULTS: There were no significant differences in age, gender and exophthalmos between active TAO and inactive TAO(P&#x0026;#x003E;0.05). The area of lacrimal gland was higher in active TAO than that in inactive TAO, and was higher in inactive TAO than that in control group in coronal and axial section(all P&#x0026;#x003C;0.01). The length of lacrimal gland in coronal and axial section was higher in the active TAO than that in the inactive TAO and the control group(all P&#x0026;#x003C;0.05). The width of lacrimal gland in coronal and axial section was higher in active TAO and inactive TAO than that in the control group(all P&#x0026;#x003C;0.05). The maximum T2 value in the active TAO was higher than that in the inactive TAO and control group, and the inactive TAO was higher than that in the control group(all P&#x0026;#x003C;0.05). The average T2 value in the active TAO was higher than that in the inactive TAO and control group(all P&#x0026;#x003C;0.05). CAS was positively correlated with lacrimal gland area in axial, coronal section and maximum T2 value(all P&#x0026;#x003C;0.01).CONCLUSION: The lacrimal gland is significantly enlarged in patients with TAO, especially in active TAO. The lacrimal gland area in axial, coronal section and maximum T2 value could be potentially utilized as valuable radiographic biomarkers for the activity of TAO.

The Role of Thermal Camera in the Assessment of Thyroid Eye Disease Activity.

Background: Thyroid eye disease (TED; also known as thyroid - associated orbitopathy, Graves ophthalmopathy) is an autoimmune inflammatory disease which presents in typical signs and symptoms such as deep orbital pain, chemosis with or without caruncular edema, unilateral or bilateral proptosis, eyelid retraction, eyelid edema or erythema, restrictive strabismus and compressive optic neuropathy. Objective: The aim of this study was to investigate the role of thermal camera in the assessment of thyroid eye disease (TED) activity compared to the Clinical Activity Score (CAS) scale, exophthalmometry values, and thyroid hormone and antibody levels. Methods: A total of 50 patients participated in this cross-sectional study of whom 29 were in the active phase of TED according to the sum on CAS scale and 21 patients in the inactive phase. The Flir E8® thermal camera was used to measure the temperature of the orbital area and the values were compared with the CAS scale, exophthalmometry values and thyroid hormone and antibody levels. Results: Higher values of temperature (p>0.0001), CAS score (p>0.0001), exophthalmometry (p=0.022), FT4 (p=0.0176) and TRAb (p=0.0091) were found in patients in the active phase of TED. Temperature of orbital area showed statistically significant positive correlation with CAS scale (p=0.0001), exophthalmometry values (p=0.0022) and anti-TPO levels (p=0.019). Conclusion: Thermal camera showed higher values of the temperature of the orbital area in patients in the active phase of the disease and positively correlated with the CAS scale, exophthalmometry findings and anti-TPO levels.

Management of Graves ophthalmopathy - 2022 update.

Graves ophthalmopathy (GO) occurs in 25-50% cases of Graves disease. Most cases are just mild, only 5% represents eye threatening diseases. About 5-10% of cases could be euthyroid and 10% hypothyroid, respectively. All patients with GO should be assessed for activity (clinical activity score - CAS) and severity of the disease. Essential conditions of the successful treatment are well controlled thyroid dysfunction, smoking cessation and to refer patients with moderate to severe and sight threatening GO to specialized thyroid eye centers as soon as possible. Local therapy to maintain wet eye (lubricants) and supplementation of selenium deficiency is adequate in mild cases of GO. In cases of moderate to severe and sight threatening GO, administration of intravenous glucocorticoids in thyroid eye centers is first line treatment and a combination with mycophenolate or radiotherapy could be considered. When the first-line treatment fails or a contraindication/intolerance to them is present, non-steroid immunosuppressive drugs (mycophenolate, ciclosporin), rituximab, or radiotherapy could be considered. In rare cases of sight threatening GO urge surgical orbital decompression or tarsorrhaphy is warranted.

Influence of Clinically Active Graves' Ophthalmopathy on Spherical Equivalent and Visual Acuity.

Purpose: Clinical experience regarding the fluctuations of the refractive error of the eye during the different stages of Graves' ophthalmopathy observed through outpatient clinic frequent check-ups points towards an underestimated and often overlooked problem. Published data about it are sparse. The clinical manifestations of Graves' ophthalmopathy can be understood from the perspective of "compartment syndrome" and literature implies how such changes can affect the refractive error and consequently, the visual acuity. The purpose of the study was to explore how the clinical activity score of Graves' ophthalmopathy affects refractive error and visual acuity. Patients and Methods: The study was prospective and observational, including 60 eyes of 30 patients with clinically active Graves' ophthalmopathy. All the patients were monitored and evaluated over a period of 36 months by the clinical activity score, spherical equivalent and visual acuity. All the observed parameters were statistically analyzed. Results: The mean values of spherical equivalent and visual acuity throughout the observed period showed continuous fluctuation. Repeated measure analysis of variance showed statistically significant differences in visual acuity and spherical equivalent over the observed period. There was a statistically significant positive correlation between visual acuity and clinical activity score. The correlation between spherical equivalent and clinical activity score was also positive but not statistically significant. Conclusion: A decrease in the clinical activity score is either the result of a spontaneously resolving course of Graves' ophthalmopathy or a consequence of treatment, so lowering in fluctuation of refractive error and improved visual acuity may be associated with a reduction in orbital inflammation.

Evaluation of Intraocular Pressure in Thyroid-associated Orbitopathy.

BACKGROUND: Elevated intraocular pressure in thyroid associated orbitopathy may lead to development of secondary glaucoma in them. This study evaluated IOP in primary gaze correlation with clinical activity score in them. METHODS: A cross-sectional study was conducted from November 2020 to October 2021.Information on age, gender, thyroid function test, intraocular pressure, cup-disc ratio and clinical activity score were recorded. Purposive sampling was done. Statistical analysis was done using Statistical Package for Social Sciences version 21. RESULTS: Total of 74 thyroid dysfunction patients was included in the study. There were14.86% patients with raised intraocular pressure. The mean intraocular pressure in hyperthyroidism was 15.4 ± 1.92 mm Hg and 15.48 ± 2.11mm Hg on right and left eyes respectively and in hypothyroidism, it was 15.08 ± 2.7mmHg and 15.12 ± 3.02 mmHg on right and left eyes respectively. The mean clinical activity score was 1.06 ± 1.23 mmHg. The mean intraocular pressure in eyes in active stage (n=9) was 16.3 ± 3.4 mm Hg, which was not significantly different from the mean intraocular pressure of 15 ± 2.4 mm Hg in inactive eyes (64), p= 0.1. Clinical activity score showed a significant correlation (p=0.03) with intraocular pressure in right eyes whereas it showed no significant correlation with intraocular pressure in left eyes (p=0.37). CONCLUSIONS: In this study elevated intraocular pressure occurred in about 1 in 7 thyroid associated orbitopathy. It also had positive correlation with clinically activity score in right eyes. Regular intraocular pressure measurement should be done in thyroid associated orbitopathy to prevent intraocular morbidity.

Multiparametric magnetic resonance imaging for differentiating active from inactive thyroid-associated ophthalmopathy: Added value from magnetization transfer imaging.

PURPOSE: To investigate the feasibility of using magnetization transfer (MT) magnetic resonance imaging for evaluating patients with thyroid-associated ophthalmopathy (TAO), and determine its added value for differentiating active from inactive TAO and predicting clinical activity score (CAS), compared with conventional fat-saturated T2-weighted and diffusion-weighted imaging. METHODS: Orbital MT, fat-saturated T2-weighted, and diffusion-weighted imaging of 60 prospectively enrolled consecutive patients with TAO was analyzed. Simplified histogram parameters (mean, max, min) of magnetization transfer ratio (MTR), signal intensity ratio (SIR), and apparent diffusion coefficient (ADC) at extraocular muscles were calculated for each orbit and compared between the active and inactive groups. RESULTS: Intraclass correlation coefficients of MTRs and SIRs were similar (0.802-0.963 vs 0.812-0.974, respectively), followed by those of ADCs (0.714-0.855). Patients with active TAO showed significantly lower MTRs and higher SIRs and ADCs than those with inactive TAO (P < 0.05). MTRmean achieved the highest area under the curve (AUC) of 0.868 for differentiating active from inactive group, followed by SIRmax (AUC, 0.836). MTRmean also demonstrated a higher and negative correlation with CAS (r = -0.614, P < 0.001) than MTRmax and MTRmin (r = -0.495, P < 0.001; r = -0.243, P = 0.007; respectively). Support vector machine-based analysis revealed that uniting MTRs could prosper concurrently added performance for disease activity differentiation and CAS prediction, compared with merely combining SIRs and ADCs (AUC, 0.933 vs 0.901; r = 0.703 vs. 0.673). CONCLUSIONS: MT imaging could potentially be used as a noninvasive method for differentiating the activity of TAO and predicting CAS, thereby offering added value to conventional SIR and ADC.

IL-11 Is Elevated and Drives the Profibrotic Phenotype Transition of Orbital Fibroblasts in Thyroid-Associated Ophthalmopathy.

Orbital fibrosis is a hallmark of tissue remodeling in thyroid-associated ophthalmopathy (TAO). Previous studies have shown that interleukin (IL)-11 plays a pivotal profibrotic role in various inflammatory and autoimmune diseases. However, the expression pattern of IL-11 in patients with TAO and whether IL-11 is mechanistically linked with pathological fibrosis remains unknown. In this study, we investigated IL-11 levels in the serum and orbital connective tissue of patients with TAO, and evaluated the correlation of these levels with the patient's clinical activity score. We also evaluated the expression pattern of IL-11Rα in orbital connective tissue. Furthermore, we elucidated the regulatory factors, profibrotic function, and downstream signaling pathways for IL-11 in TAO using in vitro studies. IL-11 levels in serum and orbital connective tissues were increased in patients with TAO, as compared with healthy controls. In addition, both levels were positively correlated with disease activity. Single-cell RNA sequencing of orbital connective tissue indicated that IL-11Rα was dominantly expressed in orbital fibroblasts (OFs). RNA sequencing of paired unstimulated and transforming growth factor (TGF)-ß1-stimulated samples demonstrated that upregulation of IL-11 expression defined the dominant transcriptional response. IL-11 signaling was also confirmed to be downstream of TGF-ß1 and IL-1ß. Therefore, we deduced that IL-11 protein is secreted in an autocrine loop in TAO. We also indicated that IL-11 mediated the profibrotic phenotype switch by inducing the expression of myofibroblast differentiation markers, including α-smooth muscle actin and collagen type I α1, which could be abrogated by an anti-IL-11 neutralizing antibody. Furthermore, we revealed that extracellular regulated protein kinase may be a crucial factor in the pro-fibrotic, translationally specific signaling activity of IL-11. These data demonstrate that IL-11 plays a crucial role in orbital fibroblast phenotype switching and may be a potential therapeutic target candidate for the treatment of TAO.

Teprotumumab in advanced reactivated thyroid eye disease.

Purpose: To report the case of a patient with reactivated, refractory thyroid eye disease (TED) treated with teprotumumab. Observations: A 51-year-old female with a 16-year history of thyroid eye disease previously treated with orbital decompression and multiple eyelid surgeries presented in a recurrent flare of the disease. The disease recurrence was refractory to intravenous steroid therapy and only partially responsive to oral steroid therapy, and the patient developed dysthyroid optic neuropathy in the right eye with decreased visual acuity and color vision. Clinical activity score was 8/10 and proptosis measurements were 27 mm OD and 26 mm OS. The patient underwent treatment with eight infusions of teprotumumab coinciding with a low taper of oral prednisone and experienced resolution of dysthyroid optic neuropathy, decrease of clinical activity score to 1, and dramatic improvement in proptosis (17 mm OD, 17 mm OS) and extraocular muscle size on imaging. Thirty weeks after completion of teprotumumab and 2 weeks after the second dose of the COVID vaccine, she experienced another flare and subsequently underwent bilateral orbital decompressions. Conclusion: This case report suggests teprotumumab may be used in patients with reactivation of longstanding thyroid eye disease. Reduction of extraocular muscle size and improvement in proptosis suggest teprotumumab may be disease-modifying even in advanced cases.

Choroidal vascularity index in thyroid eye disease: comparison with controls and application in diagnosing non-inflammatory active disease.

PURPOSE: To report the differences in choroidal vascularity index (CVI) in thyroid eye disease (TED) and normals and its discriminatory value for differentiating various stages of TED. METHODS: Prospective, cross-sectional, non-interventional imaging study. Ninety-four eyes of 54 patients were included and divided into 5 groups - normal controls (C), inactive TED (I), active TED (A), non-inflammatory active TED (NIA) and systemic hyperthyroid disorder but no TED (SYS). Choroidal images were acquired using the swept-source optical coherence tomography and the choroid was binarized to calculate the CVI. RESULTS: Ninety-four eyes were included. Mean age was 44.52 ± 10.02 years (median 46 years, range 19-65 years). Mean IOP was 16.1 ± 3.37 mm Hg (median 16 mm Hg, range 16-24 mm Hg). Mean Spherical equivalent (SE) was -0.08 ± 1.86 diopters (median 0, range -2.5 to +2.25). Intra-rater agreement was 0.84 (p < 0.001). Inter-rater agreement was noted to be 0.85 (p < 0.001) for consistency and 0.77 (p < 0.001) for absolute agreement. CVI in the A group was 70.11 ± 3.38% and in the NIA group was 69.32 ± 3.5%. Both were comparable to each other and significantly higher than the C, I and SYS groups (p < 0.001). Multiple regression showed that the Clinical Activity Score (CAS) had a positive effect and spheroequivalent had a negative effect on the CVI. At CVI of 66.83%, active TED can be diagnosed with sensitivity of 91.67% and specificity of 82.14%                 . CONCLUSIONS: CVI is significantly higher in active TED and NIA TED compared to other groups. It has a good value in differentiating the non-inflammatory active TED eyes from the inactive eyes.

Long-term outcomes in corticosteroid-refractory Graves' orbitopathy treated with tocilizumab.

BACKGROUND: Up to 20% of patients with moderate to severe Graves' orbitopathy (GO) do not respond to high-dose glucocorticoids (GC). A few studies, including a randomized trial, have demonstrated the efficacy of interleukin-6 (IL-6) blockade with tocilizumab (TCZ) in GC-refractory GO. However, data on predictors of response to TCZ and long-term outcomes are lacking. METHODS: Observational single-center study on ten consecutive patients treated with TCZ for GC-refractory GO, between 2016 and 2020. Median (interquartile range) follow-up was 24 (12-36) months. RESULTS: Inflammation and exophthalmos improved dramatically in all patients within months after starting TCZ. Mean Clinical Activity Score decreased from 4.80 ± 1.13 to 0.70 ± 0.82 points at 6 months (mean change: -4.10 ± 1.52; p < .0001). Proptosis improved from 23.2 ± 2.1 to 20.6 ± 2.0 mm at 6 months (mean change: -2.9 ± 1.4 mm; p < .0001). Diplopia resolved in 7 patients. Thyroid receptor antibodies decreased markedly during TCZ treatment. Baseline serum IL-6 levels did not predict clinical response. TCZ was well-tolerated. During follow-up, 3 patients were diagnosed with cancer (breast cancer in 2 and urothelial cancer in 1). CONCLUSIONS: TCZ was rapidly effective and well-tolerated in our patients with GC-refractory GO. Four patients experienced mild/moderate adverse events as neutropenia, hyperlipidemia, and infections; nearly a third developed cancer during the follow-up. The increased incidence observed could be explained by the high prevalence of smokers, that are at higher risk for Graves' orbitopathy and solid malignancies as breast cancer. Thus, regular cancer screening could be proposed to this vulnerable population receiving high doses of immunosuppressants.

Teprotumumab: Interpreting the Clinical Trials in the Context of Thyroid Eye Disease Pathogenesis and Current Therapies.

Teprotumumab, a monoclonal antibody targeted against the insulin-like growth factor 1 (IGF-1) receptor, was recently approved by the United States Food and Drug Administration for the treatment of thyroid eye disease (TED). Phase 1 studies of teprotumumab for the treatment of malignancies demonstrated an acceptable safety profile but limited effectiveness. Basic research implicating the IGF-1 receptor on the CD-34+ orbital fibrocyte in the pathogenesis of TED renewed interest in the drug. Two multicenter, randomized, double-masked, clinical trials (phase 2 and 3) evaluated the efficacy of 8 infusions of teprotumumab every 3 weeks versus placebo in 170 patients with recent-onset active TED, as defined by a clinical activity score (CAS) of at least 4. Teprotumumab was superior to placebo for the primary efficacy end points in both studies: overall responder rate as defined by a reduction of 2 or more CAS points and a reduction of 2 mm or more in proptosis (69% vs. 20%; P < 0.001; phase 2 study) and proptosis responder rate as defined by a reduction of 2 mm or more in proptosis (83% vs. 10%; P < 0.001; phase 3 study). In both studies, treatment with teprotumumab compared with placebo achieved a significant mean reduction of proptosis (-3.0 mm vs. -0.3 mm, phase 2 study; -3.32 mm vs. -0.53 mm, phase 3 study) and CAS (-4.0 vs. -2.5, phase 2 study; -3.7 vs. -2.0, phase 3 study). Teprotumumab also resulted in a greater proportion of patients with a final CAS of 0 or 1, higher diplopia responder rate, and a larger improvement in the Graves' Ophthalmopathy Quality of Life overall score. More than half of patients (62%, phase 2 trial; 56%, phase 3 trial) who were primary end point responders maintained this response at 51 weeks after the last dose of therapy. The most common adverse events reported with teprotumumab included muscle spasms (25%), nausea (17%), alopecia (13%), diarrhea (13%), fatigue (10%), hearing impairment (10%), and hyperglycemia (8%). Teprotumumab is contraindicated for those with inflammatory bowel disease and who are pregnant. Although the current dosing regimen has proven effective for TED, dose-ranging studies including variable concentrations, infusion frequencies, and durations of teprotumumab therapy in the setting of TED have not been performed.

Association between Clinical Activity Score and Serum Interleukin-6, Interleukin-8 and Interleukin-10 during Systemic Glucocorticoid Treatment for Active Moderate-to-Severe Graves' Orbitopathy.

Purpose: Some interleukins (ILs) play an important role in Graves' orbitopathy (GO) pathogenesis. We aimed to compare serum IL-6, IL-8 and IL-10 in GO patients, patients with Graves' disease (GD) without GO and healthy controls (HC); to follow IL changes during glucocorticoid (GC) treatment for GO; to examine associations between ILs and Clinical Activity Score (CAS).Materials and Methods: Thirty-one patients with active moderate-to-severe GO (GO(+) group), 30 patients with GD without GO (GO(-) group) and 30 HC were enrolled. At baseline, ILs were measured in all groups, CAS was evaluated in GO(+) patients, who were then treated with systemic GCs for 12 weeks. ILs and CAS were reassessed after the first week of treatment (W2) and at the end of the therapy (W12).Results: At baseline, IL-6 was significantly higher in GO(+) and GO(-) patients, IL-8 - higher in GO(-) patients and IL-10 - lower in GO(+) patients compared to HC. Baseline ILs did not correlate with CAS. At W2, all ILs and CAS decreased significantly. At W12, CAS decreased further, IL-6 remained low, IL-8 and IL-10 returned to baseline. CAS reduction correlated positively with IL-6 reduction at W12 (ρ = 0.38, p = .04).GO(+) patients with overall CAS reduction≥2 had higher baseline IL-6 (3.4 vs 2.6 pg/ml, p = .15), smaller IL-10 reduction at W2 (10.5 vs 18.2%, p = .09), lower IL-6 (1.4 vs 2.4 pg/ml, p < .01) and higher IL-6 reduction at W12 (48.6 vs 21.4%, p = .01) compared to patients with CAS reduction<2. Logistic regression analysis confirmed that overall CAS reduction≥2 was associated with higher baseline IL-6, lower IL-6 at W12 and smaller IL-10 reduction at W2 (R2 = 0.66).Conclusions: Higher baseline IL-6, lower IL-6 at W12 and smaller IL-10 reduction at W2 were associated with higher probability of significant overall CAS reduction. IL-6 might be a potential additional marker for assessing disease activity.

Association of Other Autoimmune Diseases With Thyroid Eye Disease.

Background: Thyroid eye disease (TED) is a potentially disfiguring and sight-threatening autoimmune (AI) orbitopathy, affecting up to 400,000 people in the UK. There are no accurate early predictors of TED severity. Although polyautoimmunity has been shown to affect AI disease severity, its influence on TED severity has never been investigated. The prevalence of polyautoimmunity among TED patients is also unclear, with discordant results reported in the literature. This study evaluates the prevalence of non-thyroid/"other" AI (OAI) conditions in an ethnically diverse TED cohort and assesses how polyautoimmunity affects TED severity and activity. Methods: A retrospective study of patients presenting to multidisciplinary TED clinics across three North-West London hospitals between 2011 and 2019. Data collected included: 1) demographics; 2) OAI conditions and management; 3) endocrine management of thyroid dysfunction; 4) details of TED and clinical activity score at presentation. Results: Two hundred and sixty-seven patients with a median age of 46 (35-54) years were included, 79.4% were female and 55% were Black, Asian and minority ethnic (BAME). Thirty-seven patients (13.9%) had OAI conditions, with rheumatoid arthritis (3.7%), vitiligo (3.0%) and psoriasis (3.0%) among the most prevalent. Of patients with OAI conditions, 43.2% (16/37) required immunosuppression prior to TED onset. Non-immunosuppressed patients with OAI conditions had a significantly higher clinical activity score at presentation than TED-only and previously immunosuppressed patients (p=0.02). No significant differences were observed in thyroid receptor antibody titers between these groups. Conclusions: This study finds a 13.9% prevalence of OAI conditions among TED patients. Patients with OAI conditions overall have a tendency for more severe and significantly more clinically active TED than those without OAI conditions. Larger, prospective studies are warranted to further evaluate polyautoimmunity as an early predictor of TED severity.