Safety of non-standard regimen of systemic steroid therapy in patients with Graves' orbitopathy: a single-centre experience.

BACKGROUND: Graves' orbitopathy (GO) is an autoimmune disorder of the orbit and retro-ocular tissues and the primary extrathyroidal manifestation of Graves' disease. In moderate-to-severe and active GO iv glucocorticoids (GCs) are recommended as first-line treatment. The aim was to assess the safety profile of methylprednisolone administered intravenously for three consecutive days at 1 g in patients with active, moderate-to-severe or sight-threatening Graves' orbitopathy. METHODS: We retrospectively evaluated 161 medical records of patients with GO treated with high-dose systemic GCs in the Department of Endocrinology, Metabolic Disorders, and Internal Medicine in Poznan between 2014 and 2021. Clinical data included age, gender, laboratory results, activity and severity of GO, smoking status, disease duration, and presented side effects. RESULTS: The presence of mild side effects was observed during 114 (71%) hospitalizations. The most common complications were hyperglycemia (n = 95) and elevated aminotransferases (n = 31). Increased levels of aminotransferases were more likely observed in smokers and GO duration above 12 months. Based on the multivariate logistic regression, higher TRAb and CAS values were significantly associated with lower odds of hyperglycemia. In turn, the increased odds of elevated aminotransferases were significantly correlated with higher initial ALT levels, female gender, and GO duration above 12 months. In addition, the multidimensional correspondence analysis (MPA) showed that GO patients who declared smoking and had not L-ornithine L-aspartate applied demonstrated a higher probability of elevated aminotransferases. CONCLUSIONS: Active GO treatment with high-dose systemic GCs is not associated with serious side effects. Hyperglycemia is the most common steroid-induced complication.

Radioactive iodine treatment for Graves' hyperthyroidism: incidence of Graves orbitopathy.

PURPOSE: There are limited recent data on the effect of radioactive iodine (RAI) for Graves' disease on Graves' orbitopathy (GO) development or reactivation. This audit investigates the GO incidence in patients with Graves' disease after RAI treatment, and explores risk factors present, and steroid prophylaxis use. METHODS: A retrospective audit of Graves' disease patients treated with RAI over a 5-year period. Data collected: smoking status, thyroid-stimulating hormone receptor antibody (TRAb) status, GO history, Graves' disease duration, eye features pre- and post-treatment, prophylactic corticosteroids, RAI dose given, post-RAI thyroid status, duration until hypothyroid. RESULTS: One hundred one patients were included, with a median Graves' disease duration 36 months. 34/101 (33.7%) were active/ex-smokers, 86/101 (85.1%) were TRAb-positive, 11/101 (10.9%) had a GO history; 32 (31.7%) had eye features present. Median RAI dose given was 596MBq. 8/101 (7.9%) patients received prophylactic corticosteroid; 89/101 (88.1%) achieved hypothyroid state in the year after RAI. GO developed in 5/101 (5.0%), of which 4/5 (80%) were de novo in high-risk individuals who did not receive steroids. One was a GO reactivation despite steroids. Two required intravenous steroids with/without orbital radiotherapy, one completed oral steroid taper; the remainder were treated conservatively. CONCLUSION: Our cohort had a lower GO incidence in patients with Graves' disease receiving RAI, with majority arising de novo . It is essential that all patients are assessed for Graves orbitopathy risk factors and counselled adequately prior to RAI. The decision to initiate steroids should be undertaken in a multi-disciplinary setting involving endocrinologists and ophthalmologists.

Thyroid Eye Disease: Epidemiology, Natural History, and Risk Factors.

BACKGROUND: Thyroid eye disease (TED) is an autoimmune disorder of the orbit and the most frequent extrathyroidal manifestation of Graves' disease but it may rarely occur in euthyroid/hypothyroid patients with chronic autoimmune thyroiditis. EPIDEMIOLOGY: TED is a relatively infrequent disorder, particularly in its severe forms. Men tend to have more severe TED at an older age. The prevalence of TED is lower than in the past among patients with recent onset Graves' hyperthyroidism, and moderate-to-severe forms requiring aggressive treatments are no more than 5% to 6% of all cases. NATURAL HISTORY: After an initial inflammatory (active) phase and a plateau phase, TED stabilizes and eventually inactivates (inactive or burnt-out phase) after an estimated period of 18-24 months. Minimal-to-mild TED often remits spontaneously, but complete restitutio ad integrum almost never occurs when TED is more than mild. RISK FACTORS: Several risk factors contribute to its development on a yet undefined genetic background. Cigarette smoking is the most important of them, but thyroid dysfunction (both hyper- and hypothyroidism), radioactive iodine therapy (if not accompanied by low-dose steroid prophylaxis), elevated thyrotropin receptor antibodies, and, probably, hypercholesterolemia represent relevant modifiable risk factors. Early diagnosis, control and removal of modifiable risk factors, and early treatment of mild forms of GO (local treatment and selenium) may effectively limit the risk of progression to more severe forms.

Graves' Orbitopathy Models: Valuable Tools for Exploring Pathogenesis and Treatment.

Graves' orbitopathy (GO) is the most common extrathyroidal complication of Graves' disease (GD) and severely affects quality of life. However, its pathogenesis is still poorly understood, and therapeutic options are limited. Animal models are important tools for preclinical research. The animals in some previous models only exhibited symptoms of hyperthyroidism without ocular lesions. With the improvements achieved in modeling methods, some progressive animal models have been established. Immunization of mice with A subunit of the human thyroid stimulating hormone receptor (TSHR) by either adenovirus or plasmid (with electroporation) is widely used and convincing. These models are successful to identify that the gut microbiota influences the occurrence and severity of GD and GO, and sex-related risk factors may be key contributors to the female bias in the occurrence of GO rather than sex itself. Some data provide insight that macrophages and CD8+ T cells may play an important pathogenic role in the early stage of GO. Our team also replicated the time window from GD onset to GO onset and identified a group of CD4+ cytotoxic T cells. In therapeutic exploration, TSHR derived peptides, fingolimod, and rapamycin offer new potential options. Further clinical trials are needed to investigate these drugs. With the increasing use of these animal models and more in-depth studies of the new findings, scientists will gain a clearer understanding of the pathogenesis of GO and identify more treatments for patients.

Influence of biological sex, age and smoking on Graves' orbitopathy - a ten-year tertiary referral center analysis.

Purpose: Severity of Graves' orbitopathy (GO) shows wide individual differences. For optimal treatment, it is important to be able to predict the natural course of the disease as accurate as possible to counteract with anti-inflammatory and surgical treatment. Therefore, we aimed to further elucidate the impact of sex, age and smoking on GO. Methods: We collected the clinical and demographic data of all patients of our tertiary referral center from January 2008 till December 2018 and analyzed it with descriptive statistics. Only patients with a complete data set were included in the further analysis. Odds ratio's for moderate-to-severe and sight-threatening GO in relation to age, sex and smoking were calculated by means of multivariate logistic regression models. Results: We evaluated the data of 4260 patient with GO and complete data sets. Most of these were women (83%). There were no significant differences between male and female patients regarding smoking habits and thyroid treatment. Men were significantly older at initial manifestation of TED (51.8 vs. 49.9y, p<0.01) and showed significant more often severe stages (61% vs. 53%, p<0.0001). Therefore, they needed significantly more intense treatment with steroids, irradiation, orbital decompression and muscle surgery. In multivariate logistic regression analyses age (OR 0.97, 95% CI:0.97-0.98, p<0.0001), male sex (OR 1.64, 95% CI:1.38-1.9, p<0.0001), smoking (OR 1.19, 95% CI:1.04-1.36, p=0.01), Grave's disease (OR 1.55, 95% CI:1.26-1.90, p<0.0001) and history of radioiodine treatment (RAI) (OR 2.44, 95% CI:2.10-2.86, p<0.0001) showed an significant association with severe stages of GO. Discussion: Our retrospective analysis showed once more that women are more often afflicted by GO. In contrast, men seem to be more severely afflicted and in need of anti-inflammatory and surgical treatments. This might be due to a different approach to the health system and resilience to GO specific symptoms, as well as previously described worse thyroid control. Estrogen mediated effects might also play a role as in other autoimmune diseases and should be subject of further trials. Besides the biological sex, smoking could again be confirmed as serious risk factor for severe GO. Of note, RAI was associated with more severe stages of GO, which should be subject to further investigation.

2022 Update on Clinical Management of Graves Disease and Thyroid Eye Disease.

The management of hyperthyroidism and extrathyroidal manifestations of Graves disease remains complex. Considerations that include patient preference, age, comorbidity, pregnancy, tobacco smoking, and social determinants of health must all be weaved into a cohesive management plan. A multidisciplinary team is required to manage all aspects of Graves disease, particularly thyroid eye disease, for which new therapeutic options are now available.

Current concepts regarding Graves' orbitopathy.

Graves' orbitopathy (GO) is an orbital autoimmune disorder and the main extrathyroidal manifestation of Graves' disease, the most common cause of hyperthyroidism. GO affects about 30% of Graves' patients, although fewer than 10% have severe forms requiring immunosuppressive treatments. Management of GO requires a multidisciplinary approach. Medical therapies for active moderate-to-severe forms of GO (traditionally, high-dose glucocorticoids) often provide unsatisfactory results, and subsequently surgeries are often needed to cure residual manifestations. The aim of this review is to provide an updated overview of current concepts regarding the epidemiology, pathogenesis, assessment, and treatment of GO, and to present emerging targeted therapies and therapeutic perspectives. Original articles, clinical trials, systematic reviews, and meta-analyses from 1980 to 2021 were searched using the following terms: Graves' disease, Graves' orbitopathy, thyroid eye disease, glucocorticoids, orbital radiotherapy, rituximab, cyclosporine, azathioprine, teprotumumab, TSH-receptor antibody, smoking, hyperthyroidism, hypothyroidism, thyroidectomy, radioactive iodine, and antithyroid drugs. Recent studies suggest a secular trend toward a milder phenotype of GO. Standardized assessment at a thyroid eye clinic allows for a better general management plan. Treatment of active moderate-to-severe forms of GO still relies in most cases on high-dose systemic-mainly intravenous-glucocorticoids as monotherapy or in combination with other therapies-such as mycophenolate, cyclosporine, azathioprine, or orbital radiotherapy-but novel biological agents-including teprotumumab, rituximab, and tocilizumab-have achieved encouraging results.

[A man with bulging eyes]. / Een man met uitpuilende ogen.

Graves' orbitopathy may cause multiple symptoms, such as proptosis, redness or inflammation of the conjunctiva, excessive tearing, swelling of the eyelids and pain. Smoking, male gender and old age are significant risk factors for a more severe and active disease.

[LIFESTYLE ADJUSTMENT AS THERAPEUTIC TOOL IN THYROID EYE DISEASE].

OBJECTIVES: Thyroid Eye Disease (TED), also known as Graves' ophthalmopathy, is the most frequent extrathyroidal manifestation of autoimmune dysthyroidism. The most common ocular signs are eyelid retraction, proptosis, and strabismus, alongside specific dermatopathies. This article aims to review the options to improve TED manifestation by lifestyle adjustment. RESULTS: Tobacco smoking is the strongest risk factor for the development of TED and is associated with increased incidence and severity of TED and reduction in response to treatment. Smoking cessation decreases the incidence of TED and compares the risk level of ex-smokers to the risk level of the general population. Selenium is a chemical element with anti-oxidative properties. Selenium levels were significantly lower in Graves' disease patients with TED compared with those without TED. A double-blinded, randomized-control trial demonstrated that supplementation of selenium was associated with improved quality of life, decreased ocular involvement, and slowed TED progression while taken for a limited period. Statins administration to thyroid patients is associated with a reduced risk of TED. Recently, a few studies have shown an increased risk of developing TED and increased severity depending on the level of lipids in the blood, which suggests that balancing blood lipid levels by statins or by low-fat diet can help prevent TED. CONCLUSIONS: Lifestyle adjustment might be critical for a significant portion of patients. By supporting smoking cessation, the recommendation of selenium supplementation for a limited period and reducing serum cholesterol levels can prevent the development of TED, reduce its severity, and improve the patient's quality of life.

Management of Graves' hyperthyroidism: present and future.

INTRODUCTION: Graves' disease (GD) is an autoimmune disorder due to loss of tolerance to the thyrotropin receptor (TSHR) and ultimately caused by stimulatory TSHR antibodies (TSHR-Ab). GD may be associated with extrathyroidal manifestations, mainly Graves' orbitopathy. Treatment of GD relies on antithyroid drugs (ATDs), radioactive iodine (RAI), thyroidectomy. The major ATD limitation is the high recurrence rate after treatment. The major drawback of RAI and thyroidectomy is the inevitable development of permanent hypothyroidism. AREAS COVERED: Original articles, clinical trials, systematic reviews, meta-analyses from 1980 to 2021 were searched using the following terms: Graves' disease, management of Graves' disease, antithyroid drugs, radioactive iodine, thyroidectomy, Graves' orbitopathy, thyroid-eye disease. EXPERT OPINION: ATDs are the first-line treatment worldwide, are overall safe and usually given for 18-24 months, long-term treatment may decrease relapses. RAI is safe, although associated with a low risk of GO progression, particularly in smokers. Thyroidectomy requires skilled and high-volume surgeons. Patients play a central role in the choice of treatment within a shared decision-making process. Results from targeted therapies acting on different steps of the autoimmune process, including iscalimab, ATX-GD-59, rituximab, blocking TSHR-Ab, small molecules acting as antagonists of the TSHR, are preliminary or preclinical, but promising in medium-to-long perspective.

Serum CYR61 Levels are Associated with Graves' Ophthalmopathy and Smoking in Patients with Graves' Disease.

Smoking is a well-known risk factor for Graves' ophthalmopathy (GO) in patients suffering from Graves' disease (GD). Cysteine-rich angiogenic inducer 61 (CYR61), which has multiple physiological functions, has been shown to be associated with GD and GO. In this study, we aimed to investigate the association between smoking and CYR61 concentrations in GD patients with and without GO. Serum CYR61 was measured by ELISA. The association between CYR61 concentration and GO was assessed with binary logistic regression in all patients and in subgroups of smokers and nonsmokers. The Spearman correlation coefficient was used to determine the correlations between CYR61 concentration and clinical parameters. CYR61 levels were significantly higher in GD patients with GO than in patients without GO, in smokers than in nonsmokers and in individuals older than 50 years than in those younger than 50 years. The subgroup of "GO smokers" had the highest CYR61 levels [median (IQR), 119 pg/ml (129.8)], compared with "GO nonsmokers" [84.2 pg/ml (90.8), p=0.04], "no GO smokers" [88.9 pg/ml (109.8), p=0.01] and "no GO nonsmokers" [79.4 pg/ml (129.89), p=0.003]. For each unit increase in CYR61 concentration, the odds of having GO in smokers significantly and independently increased by 1% (OR=1.010; 95% CI: 1.002-1.018, p=0.012). In conclusion, our results indicate that smoking and age increase serum CYR61 levels in patients with GD and GO. The role of CYR61 as a predictor of GO in patients with GD should be evaluated in prospective studies.

The risk factors for Graves' ophthalmopathy.

PURPOSE: This review aimed to provide an overview of current research into the risk factors for Graves' ophthalmopathy (GO). METHODS: To find information about the risk factors for GO, the research database PubMed was searched and relevant articles were obtained to extract information about risk factors. RESULTS: Smoking has been widely accepted as an important risk factor and cigarette smoking cessation has been shown to improve the outcome and decrease the onset of GO. Radioactive iodine on the thyroid may induce hyperthyroidism and increase the occurrence of GO. Selenium deficiency is a risk factor for GO and the supplementation of selenium has been an adjuvant therapy. Decreasing stressful life events (SLE) may help improve GO. Imbalance in intestinal flora is essential to GO, with Yersinia enterocolitica and Escherichia coli both increased in the digestive tract of the individual with GO. In addition, controlling serum cholesterol may help improve GO since adipogenesis is an important pathological change in its pathogenesis. Considering the correlation between Graves' disease and GO, maintaining normal thyroid function hormone level is the first-line therapeutic strategy to prevent progression of GO. An increase in antibodies such as TSHR and IGF-1R is the main predictor of GO. Besides, gender and gene polymorphism are also risk factors towards GO. CONCLUSIONS: Risk factors for GO arise from five sources: physical and chemical environment, social-psychological environment, biological environment, the human organism, and genetic codes. Risk factors within these categories may interact with each other and their mechanisms in promoting the development of GO are complex. Research into risk factors for GO may promote emerging fields related to GO such as control of autoantibodies and intestinal microbiota.

The Potential Role of Osteopontin in the Pathogenesis of Graves' Ophthalmopathy.

Purpose: The aim of this study is to evaluate the expression of osteopontin (OPN) and its relationship with relative cytokines in patients with Graves' ophthalmopathy (GO), and to observe the effect of OPN on orbital fibroblasts (OFs) proliferation, migration, and the expression of relative cytokines, as well as the signaling pathways involved in its effect. Methods: The orbital adipose connective tissue was obtained from 24 patients with GO (12 cases of active GO, and 12 cases of inactive GO) and 12 healthy controls. OFs were isolated from orbital tissues obtained from patients with active GO who were undergoing orbital decompression surgery. Quantitative PCR and Western blot were performed to detect RNA and protein expression. The proliferation and cell migration rates of OFs were measured by methylthiazol tetrazolium (MTT) and the cell scratch test. Signaling pathway inhibitors, such as OPN monoclonal antibody 1A12, ERK1/2 inhibitor PD98059, and PI3K inhibitor LY294002, were applied to determine the involved pathways. Results: The mRNA and protein levels of OPN were increased in orbital adipose connective tissue from patients with active GO than those from patients with inactive GO (2.83-fold increase, P < 0.001; 1.91-fold increase, P < 0.05). The OPN mRNA level was positively correlated with CD40 ligand (CD40L) and hyaluronan synthases 2 (HAS2) mRNA in patients with GO. OPN promoted proliferation and migration rate of OFs and induced vascular endothelial growth factor (VEGF) and collagen I mRNA expression, and the effects were inhibited by 1A12 or LY294002. Conclusions: OPN in orbital adipose connective tissues were significantly increase in active GO, and there were significant correlations of OPN with CD40L and HAS2 mRNA levels in patients with GO. OPN promoted proliferation and migration of OFs and induced VEGF and collagen I mRNA expression in OFs through PI3K/Akt signaling pathway. This suggested a role for OPN in the pathogenesis of GO through the activation of OFs.

Thyroid Eye Disease Following COVID-19 Vaccine in a Patient With a History Graves' Disease: A Case Report.

A 50-year-old woman with a history of controlled Graves' disease without clinical ophthalmopathy presents with 2 months of left more than right periorbital swelling and proptosis. Her eye symptoms and signs began 3 days following her second vaccination against the COVID-19 virus. Orbital imaging, elevated thyroid stimulating immunoglobulin, and negative systemic work up for other diseases were consistent with a diagnosis of active thyroid eye disease. The temporal relationship to her vaccination was likely consistent with autoimmune/inflammatory syndrome associated with adjuvants. Clinicians should remind patients of the symptoms and signs of thyroid eye disease and to seek appropriate medical and ophthalmic advice if they occur after the COVID-19 vaccine.

Curcumin Suppresses TGF-ß1-Induced Myofibroblast Differentiation and Attenuates Angiogenic Activity of Orbital Fibroblasts.

Orbital fibrosis, a hallmark of tissue remodeling in Graves' ophthalmopathy (GO), is a chronic, progressive orbitopathy with few effective treatments. Orbital fibroblasts are effector cells, and transforming growth factor ß1 (TGF-ß1) acts as a critical inducer to promote myofibroblast differentiation and subsequent tissue fibrosis. Curcumin is a natural compound with anti-fibrotic activity. This study aims to investigate the effects of curcumin on TGF-ß1-induced myofibroblast differentiation and on the pro-angiogenic activities of orbital fibroblasts. Orbital fibroblasts from one healthy donor and three patients with GO were collected for primary cell culture and subjected to myofibroblast differentiation under the administration of 1 or 5 ng/mL TGF-ß1 for 24 h. The effects of curcumin on TGF-ß1-induced orbital fibroblasts were assessed by measuring the cellular viability and detecting the expression of myofibroblast differentiation markers, including connective tissue growth factor (CTGF) and α-smooth muscle actin (α-SMA). The pro-angiogenic potential of curcumin-treated orbital fibroblasts was evaluated by examining the transwell migration and tube-forming capacities of fibroblast-conditioned EA.hy926 and HMEC-1 endothelial cells. Treatment of orbital fibroblasts with curcumin inhibited the TGF-ß1 signaling pathway and attenuated the expression of CTGF and α-SMA induced by TGF-ß1. Curcumin, at the concentration of 5 µg/mL, suppressed 5 ng/mL TGF-ß1-induced pro-angiogenic activities of orbital fibroblast-conditioned EA hy926 and HMEC-1 endothelial cells. Our findings suggest that curcumin reduces the TGF-ß1-induced myofibroblast differentiation and pro-angiogenic activity in orbital fibroblasts. The results support the potential application of curcumin for the treatment of GO.

Risk Factors of Thyroid Eye Disease.

OBJECTIVE: To examine risk factors that might be associated with thyroid eye disease (TED) in patients with Graves' disease (GD), which may guide physicians in the prevention and management of TED. METHODS: Medline and Embase were searched for articles discussing risk factors of TED. Comparisons were made between GD patients with and without TED, and between active and inactive TED GD patients. Weighted mean differences (WMDs) and odds ratios (ORs) were determined for continuous and dichotomous outcomes, respectively. Results were pooled with random effects using the DerSimonian and Laird model. RESULTS: Fifty-six articles were included in the analysis. Smoking, inclusive of current and previous smoking status, was a significant risk factor for TED (OR: 2.401; CI: 1.958-2.945; P < .001). Statistical significance was found upon meta-regression between male sex and the odds of smoking and TED (ß = 1.195; SE = 0.436; P = .013). Other risk factors were also examined, and patients with TED were significantly older than those without TED (WMD: 1.350; CI: 0.328-2.372; P = .010). While both age (WMD: 5.546; CI: 3.075-8.017; P < .001) and male sex (OR: 1.819; CI: 1.178-2.808; P = .007) were found to be significant risk factors for active TED patients compared to inactive TED patients, no statistical significance was found for family history, thyroid status, cholesterol levels, or body mass index. CONCLUSION: Factors such as smoking, sex, and age predispose GD patients to TED, and TED patients to active TED. A targeted approach in the management of GD and TED is required to reduce the modifiable risk factor of smoking.

Risk factors for Graves' Orbitopathy in surgical patients-Results of a 10-year retrospective study with review of the literature.

Introduction: We investigated known (eg age, smoking, thyrotropin receptor autoantibody (TRAb)) and new risk factors (eg thyroid peroxidase autoantibodies (TPO-Ab), thyroid size, or BMI) for Graves' disease (GD) and Graves' orbitopathy (GO), especially in combination with each other, to determine which factors play the most important role in the development of GO. Methods: From 2008 to 2018, n = 500 patients with GD were included in this retrospective single-centre case-control study. N = 231 (46%) had a GO and n = 269 (54%) showed no GO. Differences in risk factors were determined by Mann-Whitney U and chi-square test. Combined influences of factors were examined by multivariable logistic regression. Results: Age at first diagnosis of GD (OR = 1.043, p < .006), smoking status (OR = 2.64, p < .026) and TRAb (OR = 1.046, p < .01) had a significant impact on GO. The factors gender, TPO-Ab titre, BMI, TSH titre, T3 and T4 were not significant. Conclusion: As it has been shown in univariate analyses, smoking, age and TRAb levels have a negative impact on the onset and course of GD and GO. Via multivariable regression, we could additionally show that smoking is the most important factor out of those analysed. TRAb might be a helpful surrogate parameter in the assessment of the progress of GO and therefore might be one factor in the decision-making process for potential early operative surgery. With regard to the hitherto unclear role of BMI, thyroid size and TPO-Ab in the course of GO, this study could not find any clinically relevant influence.

Role of binding immunoglobulin protein (BiP) in Graves' orbitopathy pathogenesis.

Inflammation and adipogenesis represent the main pathogenic mechanisms of Graves' orbitopathy (GO), and oxidative stress is a well-known inducer of GO pathology. Endoplasmic reticulum (ER) stress has been suggested as a major contributor to inflammation and reactive oxygen species (ROS) generation. In this study, we investigated the role of the ER-stress chaperone protein, binding immunoglobulin protein (BiP), in GO pathogenesis. Using primary cultures of orbital fibroblasts from patients with GO, we examined the role of BiP in GO pathogenesis by silencing its expression with small-interfering RNA (siRNA). Inflammatory cytokine expression was analysed by Western blotting and ELISA. Intracellular ROS levels induced by hydrogen peroxide or cigarette smoke extract were measured by 5-(and 6)-carboxy-20,70-dichlorodihydrofluorescein diacetate staining and flow cytometry. After adipogenic differentiation in BiP siRNA-transfected cells, the cells were stained with Oil Red O, and the levels of adipogenic transcription factors were determined by Western blot analysis. BiP mRNA expression levels were significantly higher in GO orbital tissues than in non-GO orbital tissues. Silencing BiP attenuated the expression of pro-inflammatory cytokines (interleukin-6, intercellular adhesion molecule-1, and monocyte chemotactic protein-1) in primary cultured GO orbital fibroblasts. Silencing BiP also reduced ROS generation, hyaluronan production, and adipocyte differentiation. These findings suggest that ER stress is involved in the aetiology of GO and that modulation of ER stress has therapeutic potential for GO.

Unusual onset of thyroid associated orbitopathy during pregnancy: case report and review of literature.

BACKGROUND: Thyroid associated orbitopathy (TAO) is the most common extrathyroidal complication of Graves' disease. The disease course ranges from mild, where symptomatic therapy is sufficient, to severe, where high dose steroid administration or orbital decompression surgery is required. Women of their reproductive age are more likely to be affected. Although pregnancy is a state of enhanced immune tolerance, TAO may develop or worsen in 0.2-0.4% of pregnant women. CASE PRESENTATION: We present the case of a 19-year-old woman who has developed hyperthyroidism and progressive TAO during the second trimester of her third pregnancy, which has improved postpartum. The possible mechanisms and the importance of follow up in pregnancy is discussed. CONCLUSIONS: Expectant mothers with Graves' disease require follow up of eye signs throughout pregnancy, preferably in the setting of a thyroid-eye clinic.

Clinical Management and Therapeutic Strategies for the Thyroid-Associated Ophthalmopathy: Current and Future Perspectives.

PURPOSE: TAO is an organ specific autoimmune disease associated with thyroid, and inflammation of the orbit and periorbital tissues, which is different from systemic autoimmune diseases such as SLE. However, Grave's disease is a kind of systemic autoimmune syndrome which might involve the thyroid, the eye ball and the anterior tibial tissue. Considering the inexplicable understanding of TAO pathogenesis, the disease worsens for the patients. Therefore, this manuscript provides insights into the recent advancements of clinical features, epidemiology, pathogenesis with gene-interactions, diagnosis, including available and novel treatment options for TAO, based on available data including RCTs, meta-analyses, and systematic reviews. METHODS: Articles with clinical features, epidemiology, pathogenesis, diagnosis, and treatment of the disease were thoroughly studied. To perform the gene expression and pathway analysis, articles were searched on PubMed, MEDLINE Cochrane Library and ClinicalTrial.gov from 1982 to 2020. To predict novel TAO-specific therapeutic molecule, structure-based drug design (SBDD) was performed. RESULTS: We observed gene expression and pathway analysis and SBDD approaches might bring new insights in the field of TAO pathogenesis, diagnosis, and treatment. A genome-wide map of human genetic interactions revealed involvement of crucial cell-signalling pathways, such as TNF-mediated signalling pathway, type-I interferon signalling pathway, toll-like receptor signalling pathway, transforming growth factor-beta receptor signalling pathway etc. Recently, FDA-approved teprotumumab a breakthrough, first drug for the treatment of active thyroid eye disease, which reduces proptosis and the need for orbital decompression surgery. Furthermore, our SBDD results revealed that cost-effective Curcumin, Withaferin A, Resveratrol, Scopolamine, Quercetin, and Berberine may have significant binding affinity for hyaluronan protein and may be exploited for therapeutic purposes in TAO. CONCLUSIONS: Considering the increasing risk and nature of disease, novel drug therapies and markers for prognosis need to be investigated. Moreover, evidence-based non-invasive/minimal surgical therapies should be developed for the better management of the disease. ABBREVIATIONS: ADIPOQ: Adiponectin; CAS: Clinical Activity Score; CCL5: C-C Motif Chemokine Ligand 5; CT: Computed Tomography; DON: Dysthyroid Optic Neuropathy; EUGOGO: European Group of Graves' Orbitopathy; FDA: U.S. Food and Drug Administration; FOS: Fos Proto-Oncogene, AP-1 Transcription Factor Subunit; HLA: Human Leukocyte Antigen; HLA-DRA: Major Histocompatibility Complex, Class II, DR Alpha; ICAM1: Intercellular Adhesion Molecule 1; IFNG: Interferon Gamma; IGF-1: Insulin-like Growth Factor 1; IGF-1R: Insulin-like Growth Factor-1 Receptor; IL12B: Interleukin 12B; IL23R: Interleukin 23 Receptor; IL6: Interleukin 6; IOP: Intraocular Pressure; IRF1: Interferon Regulatory Factor 1; IRF5: Interferon Regulatory Factor 5; IRF7: Interferon Regulatory Factor 7; IRF9: Interferon Regulatory Factor 9; JUN: Jun Proto-Oncogene, AP-1 Transcription Factor Subunit; JUNB: JunB Proto-Oncogene, AP-1 Transcription Factor Subunit; MHC: Major Histocompatibility Complex; MRI: Magnetic Resonance Imaging; NFKB1: Nuclear Factor Kappa B Subunit 1; NFKBIA: Nuclear Factor Kappa B Inhibitor Alpha; OADSCs: Orbital Adipose Derived Stromal Cells; PDGFB: Platelet Derived Growth Factor Subunit B; PPARG: Peroxisome Proliferator Activated Receptor Gamma; RANTES: Regulated on Activation Normal T cell Expressed and Secreted; RARA: Retinoic Acid Receptor Alpha; RCTs (Randomized Controlled Trials; SLE: Systemic lupus erythematosus; SOCS3: Suppressor of Cytokine Signaling 3; STAT1: Signal Transducer and Activator of Transcription 1; TAO: Thyroid-Associated Ophthalmopathy; TED: Thyroid eye disease; TGFB1: Transforming Growth Factor Beta 1; TGFB2: Transforming Growth Factor Beta 2; TGF-ß: Transforming Growth Factor-beta; TLR7: Toll like Receptor 7; TLR9: Toll like Receptor 9; TNFRSF18: Tumor Necrosis Factor Receptor Superfamily Member 18; TNFSF11: Tumor Necrosis Factor Receptor Superfamily Member 11; TNF-α: Tumor Necrosis Factor-alpha; TSHR: Thyroid Stimulating Hormone Receptor; TSIs: Thyroid Stimulating Immunoglobulin; WNT5A: Wingless-Type MMTV Integration Site Family, Member 5A.