Selenium supplementation in inactive moderate to severe Graves' orbitopathy patients: a randomized controlled trial.

PURPOSE: This study was designed to evaluate the effect of selenium supplementation in inactive moderate-severe Graves' orbitopathy (GO) patients. METHODS: This study was a single-center, placebo-controlled, double-masked, randomized trial. Inactive moderate-severe GO participants were randomized to receive six months of 200 micrograms/day of selenium supplementation or placebo. Thorough eye exams, clinical activity score (CAS), Graves' Ophthalmopathy quality of life questionnaire (GO-QOL), and serum selenium level were evaluated at baseline and 6 months after the interventions. The chi-squared or Fisher's exact test was used to compare categorical variables. The t-test and the paired t-test were used to compare continuous variables between two independent samples and two dependent samples, respectively. RESULTS: A total of 25 participants were enrolled, 13 in the selenium group and 12 in the placebo group. Both groups had adequate baseline serum selenium levels at 98.96 ± 15.63 mcg/L and 102.55 ± 17.71 mcg/L, respectively. After 6 months of intervention, the selenium group showed a greater improvement in palpebral aperture (mean difference: -1.4 ± 1.7 mm, p = .04) compared to the placebo group (-0.3 ± 2.7 mm). Notably, 5(41.67%) people in the placebo group developed larger palpebral apertures. Proptosis, ocular motility, and soft tissue signs did not change significantly. GO-QOL and CAS score improvement showed no statistically significant difference between both groups. Minor adverse effects were observed. CONCLUSIONS: Selenium supplementation has a positive effect on eyelid aperture even in inactive moderate-to-severe GO patients with a sufficient baseline selenium level.

Selenium in the treatment of mild-to-moderate Graves' orbitopathy: a 5-year prospective controlled cohort study.

PURPOSE: Graves' orbitopathy (GO) is the main extrathyroidal manifestation of Graves' disease. However, limited studies have investigated the actual efficacy of selenium in GO therapy. This longitudinal study explored the effect of selenium on QOL and prognosis of patients with mild-to-moderate GO. METHODS: We conducted a 5-year prospective controlled cohort clinical trial to determine the effect of selenium on 74 patients with mild-to-moderate GO. Patients received selenium yeast or placebo orally for 6 months and were followed up at 6 months and at 5 years by biochemical examination, ophthalmologist evaluation and QOL questionnaire to assess oculopathy and QOL. RESULTS: (1) During a follow-up period of 3-6 months, in the selenium group, the symptoms of tearing, grittiness and conjunctival congestion improved (P < 0.01); clinical activity scores and total GO-QOL scores increased relative to baseline (P < 0.01); TRAb was decreased at the 6-month evaluation (P = 0.003); and patients treated with selenium had a higher rate of improvement and a lower rate of worsening than patients treated with placebo (P < 0.05). (2) Exploratory evaluations at 6 months after drug withdrawal confirmed the earlier results; further changes included alleviation of blurred vision and double vision symptoms in the selenium group (P < 0.01). (3) At the 5-year follow-up, compared with baseline, proptosis, clinical activity scores, TRAb level and total GO-QOL scores in both the selenium and placebo groups were significantly improved (P < 0.01). CONCLUSION: Six months of selenium supplementation may effectively change the early course of mild-to-moderate GO, but this regimen makes no difference in long-term outcomes.

Statins in Graves Orbitopathy: A New Therapeutic Tool.

PURPOSE: Graves orbitopathy (GO) is the most common extrathyroidal manifestation of Graves disease. Although its pathogenesis is not fully elucidated, GO is commonly considered an autoimmune disease due to loss of self-tolerance against autoantigens shared by thyroid epithelial cells and orbital fibroblasts. High-dose intravenous glucocorticoids (ivGCs) are the most used treatment for moderate-to-severe, active GO, but the addition of other immunomodulating treatments can improve the efficacy of ivGCs. Among the various risk factors that can affect the occurrence of GO, cholesterol may be worthy of interest. Since 2015 the role of cholesterol and cholesterol-lowering medications has been investigated. The purpose of this review is to discuss this topic, thereby offering new therapeutic opportunities for patients with GO. METHODS: We searched PubMed for studies published between January 1, 1980 and June 1, 2023, using the search terms "Graves orbitopathy," "thyroid eye disease," "Graves ophthalmopathy," "thyroid ophthalmopathy," "thyroid-associated ophthalmopathy," "endocrine ophthalmopathy," "cholesterol," "lipids," "statins," "low-density lipoprotein," "atorvastatin," and "cholesterol-lowering drugs." Only English-language articles were included. RESULTS: A correlation between low-density lipoprotein cholesterol and the risk of GO development has been reported. Furthermore, low-density lipoprotein cholesterol has been proposed as a risk factor that can affect the course of GO and the response to ivGCs. The protective role of cholesterol-lowering medications in preventing GO has been also investigated. Statin treatment was found to have potential benefits in reducing the risk of GO in patients with Graves disease. Given these findings, measurement of low-density lipoprotein cholesterol and treatment of hypercholesterolemia in patients with moderate-to-severe, active GO may be considered before starting ivGCs administration. Recently, a randomized clinical trial aimed at investigating the effects of statins in GO suggested that the addition of oral atorvastatin to ivGCs improves the overall outcome of moderate-to-severe, active GO in hypercholesterolemic patients given ivGCs. CONCLUSIONS: Overall, statins seem to have a preventive and therapeutic role in moderate-to-severe active GO. Their efficacy can be related to cholesterol-lowering activity, pleiotropic actions, and interaction with methylprednisolone.

Bone turnover decreases and bone structure improves during treatment with weekly high-dose methylprednisolone for 12 weeks in Graves' orbitopathy.

PURPOSE: Weekly treatment with the intravenous glucocorticoid methylprednisolone for 12 weeks is mainstay in the treatment of Graves' orbitopathy but may decrease bone mass and impair bone structure. We therefore investigated bone turnover, -mass and -structure during the treatment cause in these patients. METHODS: We included 32 patients with Graves' orbitopathy scheduled for treatment with methylprednisolone. Bone turnover and thyroid function was measured at baseline and after 3, 9, 12, and 24 weeks, bone mineral density (BMD) was measured using dual x-ray absorptiometry at baseline and after 12 and 24 weeks, and bone structure was measured using high-resolution peripheral quantitative computed tomography at baseline and after 12 weeks. RESULTS: Bone turnover and tri-iodothyronine decreased throughout the study. Cortical volumetric BMD at both the radius and tibia increased significantly by 0.98 ± 0.38% (p = 0.01) and 1.35 ± 0.50% (p = 0.01), respectively and cortical porosity at both the radius and tibia decreased significantly by -7.67 ± 3.13% (p = 0.04) and -3.30 ± 2.17% (p = 0.04), respectively. Bone mineral density was stable during the first 12 weeks but increased significantly by 2.26 ± 3.61% at the femoral neck (p < 0.01) and by 2.24 ± 4.24% at the total hip towards week 24 (p = 0.02). Stratified analyses suggested that remission of hyperthyroidism was the most important determinant of changes in bone turnover, bone mass and structure. CONCLUSION: During a 12-week course of high-dose intravenous methylprednisolone bone turnover and cortical porosity decreased and during 24 weeks follow up bone mineral density increased. In terms of bone, methylprednisolone therefore is a safe treatment for Graves' orbitopathy.

A Randomized Clinical Trial of Intravenous Methylprednisolone With 2 Protocols in Patients With Graves Orbitopathy.

CONTEXT: Intravenous glucocorticoid (IVGC) is an accessible and affordable treatment for Graves orbitopathy (GO); the 4.5-g protocol is well studied, but many details of treatment protocols need to be clarified. OBJECTIVE: To compare the efficacy and safety of weekly and monthly protocol of IVGC in GO. METHODS: A prospective, randomized, observer-masked, single-center clinical trial, followed up to week 24, at the third affiliated hospital of Southern Medical University; 58 patients with active and moderate to severe GO, aged 18-60 years old, who had not received relevant treatment were included. The intervention was weekly protocol or monthly protocol of IVGC; both received a cumulative dose of methylprednisolone 4.5 g and had a duration of 12 weeks. The overall effective rate, improvement of quality of life (QOL) and signal intensity ratio (SIR) were measured. RESULTS: There was no significant difference in the effective rate between the 2 groups at week 12 and week 24 (86.21% vs 72.41%, P = .195; 86.21% vs 82.61%, P = .441), there was no significant difference in the improvement of clinical activity score, exophthalmos, soft tissue involvement, diplopia, and QOL. At week 24, the mean SIR and maximum SIR of the 2 groups were lower than those before treatment, and there were no statistically significant difference between the 2 groups. There was no significant difference in the incidence of adverse events between the 2 groups (31.03% vs 27.59%, P = .773). CONCLUSION: The efficacy and safety of the 2 protocols are comparable; the monthly protocol could be used as an alternative to the weekly protocol.

Efficacy of selenium supplementation for mild-to-moderate Graves' ophthalmopathy in a selenium-sufficient area (SeGOSS trial): study protocol for a phase III, multicenter, open-label, randomized, controlled intervention trial.

BACKGROUND: The therapeutic effect of selenium has been demonstrated in mild Graves' ophthalmopathy (GO) in a European region where selenium status is suboptimal. However, there is a lack of evidence to support selenium use in selenium-sufficient areas. The aim of this study is to evaluate the therapeutic effect of selenium in mild-to-moderate GO in selenium-sufficient South Korea. METHODS: The SeGOSS trial is a multicenter, prospective, randomized, open-label trial in South Korea. Eighty-four patients aged 19 years or older with mild-to-moderate GO will be randomized to receive either vitamin B complex alone or vitamin B complex with selenium for 6 months with three monthly follow-up visits. The primary outcome is comparison of the improvement in quality of life at 6 months from baseline between the control and selenium groups. The secondary outcomes are intergroup differences in changes in quality of life at 3 months, clinical activity of GO at 3 and 6 months, thyroid autoantibody titers at 3 and 6 months, and the response rate at 3 and 6 months from baseline. Quality of life will be measured by questionnaire for patients with GO, and the clinical activity of GO will be evaluated by the clinical activity score (CAS). A positive response is defined as either changes in the CAS < 0 or the changes in the GO-QOL score ≥ 6. DISCUSSION: The SeGOSS study will evaluate the therapeutic potential of selenium for mild-to-moderate GO in a selenium-sufficient area and provide support in tailoring better treatment for GO. TRIAL REGISTRATION: KCT0004040. Retrospectively registered on 5 June 2019. https://cris.nih.go.kr/cris/search/detailSearch.do/14160 .

Therapeutic Effect of Gypenosides on Antioxidant Stress Injury in Orbital Fibroblasts of Graves' Orbitopathy.

Purpose: To examine the impact of gypenosides (Gyps) on oxidative stress damage of orbital fibroblasts (OFs) from Graves' ophthalmopathy (GO) patients. Methods: The relationship between Gyps and GO oxidative stress was understood by bioinformatics analysis. Orbital connective tissues of GO and non-GO patients were obtained for primary OF culture. The proliferation level of OFs was measured by Cell Counting Kit-8 method, and the appropriate intervention concentration of Gyps and H2O2 was obtained. The expression of apoptosis-related protein mRNA was analyzed by RT-qPCR technique. ROS and SOD test suites were employed to detect the oxidative stress level in OFs. Flow cytometry apoptosis detection, TUNEL detection, and lactate dehydrogenase detection were used to analyze the level of apoptosis. Western blotting detection was utilized to examine the regulatory pathway of oxidative stress, apoptosis, and autophagy-related proteins. The changes of cell morphology, autophagosome, and autophagy lysosome were observed by transmission electron microscope. Results: The suitable intervention concentration of Gyps is 100 µg/mL, and the suitable intervention concentration of high concentration H2O2 is 350 µM. In comparison with the blank control group, the H2O2 intervention group enhanced the expression of apoptosis-related mRNA, the expression of ROS and SOD, the apoptosis rate, the expression of autophagy activation-related protein and Nrf2/ERK/HO-1 protein, and the number of autophagosomes and autophagy lysosomes. Compared with H2O2 intervention group, the expression of apoptosis-related mRNA decreased, ROS expression decreased, SOD expression increased, apoptosis rate decreased, autophagy activation-related protein expression decreased, Nrf2/ERK/HO-1 protein expression increased, and the quantity of autophagosomes and autophagy lysosomes decreased in H2O2 + Gyps intervention group. Conclusion: Gyps can decrease the oxidative stress level of OFs generated by H2O2, reduce cell autophagy, and reduce apoptosis. Gyps may regulate the oxidative stress response of OFs in GO patients via the Nrf2/ERK/HO-1 signaling pathway.

Therapy With Intravenous Methylprednisolone Pulses Is Associated With Loss of Bone Microarchitecture in Trabecular Bone Score -Assessment Among Patients With Moderate-to-Severe Graves' Orbitopathy: A Pilot Study.

Background: Therapy with intravenous glucocorticoids (GCs) is associated with various side effects, however, the impact on bone remains elusive. Trabecular bone score (TBS) is a diagnostic tool providing information on bone microarchitecture based on images obtained from dual-energy X-ray absorptiometry. We investigated the influence of the intravenous methylprednisolone (IVMP) pulse administration on TBS in patients with moderate-to-severe Graves' orbitopathy (GO). Methods: Fifteen patients with GO were treated with 12 IVMP pulses (6x0.5g, 6x0.25 g on a weekly schedule). They received supplementation with 2000 IU of vitamin D and 1.0 g of calcium throughout the study period. TBS was assessed at baseline and after last IVMP pulse. To determine the difference between values at baseline and after treatment the least significant change (LSC) methodology was used. We compared pre- and posttreatment mean TBS values. Results: We found a significant decrease of TBS in 5 out of 15 (33%) patients. Mean TBS value decreased becoming 2.4% lower than at baseline (p<0.05). Conclusions: IVMP pulse therapy exerts negative effect on bone microarchitecture in TBS assessment. The analysis of the clinical risk factors for osteoporosis and the evaluation of bone mineral density and TBS should be considered before initiating IVMP therapy.

Insight Into Mouse Models of Hyperthyroidism.

Hyperthyroidism is characterized by an increase in the synthesis and secretion of thyroid hormones in the thyroid gland, and the most common cause of overproduction of thyroid hormones is Graves' disease (GD). Long-term disease models of hyperthyroidism have been established. In general, methods to induce GD include transfection of fibroblasts, injecting plasmids or adenovirus containing thyroid stimulating hormone receptor (TSHR) or TSHR subunit, and exogenous artificial thyroid hormone supplementation. Fortunately, in mouse studies, novel treatments for GD and Graves' orbitopathy (GO) were discovered. It has been reported that prophylactic administration of TSHR A subunit protein in genetically susceptible individuals could induce immune tolerance and provide protection for the future development of GD. Biologically active monoclonal antibody against intracellular adhesion molecule-1 (ICAM-1 mAb) and siRNA targeting TSHR can also be used to treat GD. Moreover, new potential therapeutic targets have been identified in GO mouse models, and these targets could present novel therapeutic approaches. Besides, human placental mesenchymal stem cells (hPMSCs) into the orbit, fucoxanthin and icariin may be new alternative therapies that could be used in addition to the existing drugs, although further research is needed.

A Paradigm Shift in the Management of Thyroid Eye Disease How Teprotumumab Has Changed the Therapeutic Interface.

BACKGROUND: Teprotumumab, a monoclonal antibody that blocks the insulin-like growth factor-1 receptor, has recently been approved by the US Food and Drug Administration (FDA) for the treatment of thyroid eye disease (TED). Since its approval, aside from data on the safety and clinical efficacy of teprotumumab from Phase-2 and Phase-3 trials, only a handful of reports have been published regarding its use in the wider population. In this review, we briefly describe the mechanism of action of teprotumumab and review the literature to provide an overview of published clinical experience. This information was used to provide recommendations for patient selection, management of patient expectations, infusion details and site options, tips to optimize the authorization process, and how to monitor and mitigate side effects. EVIDENCE ACQUISITION: A systemic review of the literature was performed regarding teprotumumab, focusing on its mechanisms of action and published reports on its use on patients with TED. A review of Embase, Medline (PubMed), Web of Science, and Google Scholar was conducted. RESULTS: Clinical experience following the approval of teprotumumab has confirmed its efficacy in reducing inflammation and proptosis in patients with acute TED (<2 years). The reduction in proptosis occurs due to a reduction in orbital fat and muscle volume. Furthermore, there is evidence for its use in patients with compressive optic neuropathy. There are also reports that show its efficacy in reducing proptosis, inflammation, and diplopia in patients with chronic TED (>2 years). Teprotumumab was associated with side effects, such as muscle spasm, hearing loss, and hyperglycemia. To date, 2 case reports have shown a possible association with flares of inflammatory bowel disease. CONCLUSIONS: Teprotumumab is a powerful therapeutic option for the treatment of TED. Clinical experience following FDA approval has demonstrated efficacy in treating patients with acute and chronic TED. It is the only therapeutic option that has been shown to reduce orbital soft tissue expansion in TED. However, it is expensive, and sometimes, obtaining insurance authorization can be time consuming and difficult. Further work will reveal its full side effect profile and help to establish its role in the armamentarium used to treat TED.

Medical and surgical treatment of thyroid eye disease.

Thyroid eye disease is an autoimmune inflammatory disease strongly associated with thyroid disease, principally Graves disease. It can range from mild disease requiring observation or symptomatic treatments only, through to sight-threatening disease requiring major drug therapy and orbital surgery. Severity is graded by the NOSPECS system and activity by the clinical activity score (CAS) to assist in treatment selection. Non-surgical management can extend from observation alone to minor therapy such as oral selenium, then glucocorticoid therapy, cyclosporin, mycophenolate, rituximab, immunoglobulin, teprotumumab, and orbital radiotherapy. High-dose intravenous methylprednisolone therapy is used in active vision-threatening disease with early use of tarsorrhaphy and orbital decompression. Inactive but moderate to severe disease may be treated by orbital decompression, strabismus and eyelid surgery. Systematic assessment and management by both an endocrinologist and ophthalmologist to achieve and maintain euthyroidism and select and sequence treatments according to activity and severity of thyroid eye disease gives the best results for quality of life and vision.

Oral selenium improved the disease activity in patients with mild Graves' orbitopathy.

BACKGROUND: Graves' orbitopathy (GO) is the most common extrathyroidal manifestation of Graves' disease (GD), an autoimmune disorder arising from the activity of T lymphocytes against antigens that infiltrate thyroid tissue, orbital tissue and extraocular muscles. An increase in oxidative stress has been discovered in autoimmune thyroid disease, encouraging investigation into new forms of treatment. Selenium has been described as a treatment option given its antioxidant properties. The present study evaluates the decrease of progression and inflammatory signs in patients with mild GO with oral selenium supplementation. METHODS: Controlled, randomized, single center trial at an ophthalmology referral center in Mexico City. Patients at least 18years of age with mild GO according to the CAS classification were included; exclusion criteria in addition to corticosteroid treatment included smokers or selenium allergy. Each patient was randomized into one of two groups. Group A took placebo tablets which consisted of 100µg of starch twice a day for 6months, and group B took a 100µg selenium tablet twice a day for 6months. The patients from both groups were examined and evaluated using a CAS score before and after the first, third and sixth month of treatment. RESULTS: Thirty eyes of 30 patients were studied. The pretreatment values showed no statistically significant differences between groups (P>0.05). Intergroup analysis showed statistically significant differences in palpebral fissure and CAS score between the pretreatment values and six months after treatment in the selenium group (P<0.05). No differences were found in any variables in the placebo group during the study period (P>0.05). No adverse events were reported. CONCLUSIONS: This is the first study in a Mexican population demonstrating that oral selenium decreases clinical activity and stops progression in patients with mild GO.

Anti-inflammatory and Antioxidant Effects of Selenium on Orbital Fibroblasts of Patients With Graves Ophthalmopathy.

PURPOSE: In the present study, the authors investigated the effects of selenium on inflammation, hyaluronan production, and oxidative stress in primary cultured orbital fibroblasts of patients with Graves ophthalmopathy (GO). METHODS: Orbital adipose/connective tissue specimens were obtained during the course of orbital surgery for patients with GO (n = 7) and other noninflammatory problems (n = 5). After incubation with various concentrations of sodium selenite for 48 hours, supernatants from primary cultures were collected. Hyaluronan and cytokine levels were measured using commercially available enzyme-linked immunosorbent assay kits. To determine the effect of selenium on reactive oxygen species (ROS) production stimulated by H2O2 (100 µM) for 30 minutes, the cells were pretreated with various concentrations of sodium selenite for 60 minutes. RESULTS: Interleukin (IL)-6 and tumor necrosis factor-alpha levels were significantly higher in orbital fibroblasts of patients with GO than in orbital fibroblasts of control patients. Hyaluronan production was suppressed by selenium in cultured orbital fibroblasts of patients with GO. Inflammatory cytokines such as IL-1α, IL-8, and tumor necrosis factor-alpha were suppressed by selenium in cultured orbital fibroblasts of patients with GO. IL-1ß and IL-6 were not suppressed by selenium in cultured orbital fibroblasts of patients with GO. Selenium pretreatment reduced intracellular ROS generation stimulated by H2O2 in cultured orbital fibroblasts of patients with GO. CONCLUSIONS: In conclusion, hyaluronan production, inflammatory cytokines, and intracellular ROS generation were suppressed by selenium in cultured orbital fibroblasts of patients with GO. Several inflammatory cytokines may be suppressed by selenium in cultured orbital fibroblasts of patients with GO. This study provide the basis for use of selenium in the treatment of GO.

Baseline Volumetric T2 Relaxation Time Histogram Analysis: Can It Be Used to Predict the Response to Intravenous Methylprednisolone Therapy in Patients With Thyroid-Associated Ophthalmopathy?

Objective: Prediction of therapy response to intravenous methylprednisolone pulses (ivMP) is crucial for thyroid-associated ophthalmopathy (TAO). Image histograms may offer sensitive imaging biomarkers for therapy effect prediction. This study aimed to investigate whether pretherapeutic, multiparametric T2 relaxation time(T2RT) histogram features of extraocular muscles (EOMs) can be used to predict therapy response. Materials and Methods: Forty-five active and moderate-severe TAO patients, who were treated with standard ivMP and underwent orbital MRI before therapy, were retrospectively included in this study. The patients were divided into responsive (n = 24, 48 eyes) and unresponsive group(n = 21, 42 eyes) according to clinical evaluation. Baseline clinical features of patients and histogram-derived T2RT parameters of the EOMs were analyzed and compared. Logistic regression model was conducted to determine independent predictors, and a histogram features nomogram was formulated for personalized prediction. Results: Responsive group displayed lower values for 5th, 10th percentiles (P < 0.050, respectively), and higher values for 75th, 90th, and 95th percentiles, skewness, entropy, and inhomogeneity (P < 0.050, respectively) than unresponsive group. Multivariate logistic regression analysis showed that 95th percentile of >88.1 [odds ratio (OR) = 12.078; 95% confidence interval (CI) = 3.98-36.655, p < 0.001], skewness of >0.31 (OR = 3.935; 95% CI = 2.28-6.788, p < 0.001) and entropy of >3.41 (OR = 4.375; 95% CI = 2.604-7.351, p < 0.001) were independent predictors for favorable response. The nomogram integration of three independent predictors demonstrated optimal predictive efficiency, with a C-index of 0.792. Conclusions: Pre-treatment volumetric T2RT histogram features of EOMs could function to predict the response to ivMP in patients with TAO. The nomogram based on histogram features facilitates the selection of patients who will derive maximal benefit from ivMP.

Efficacy and safety of tripterygium glycosides for active moderate to severe Graves' ophthalmopathy: a randomised, observer-masked, single-centre trial.

BACKGROUND: Tripterygium glycosides (TG) has been used to treat a spectrum of inflammatory and autoimmune diseases. Our preliminary studies have shown that TG is effective in the treatment of active Graves' ophthalmopathy (GO). OBJECTIVE: We aimed to compare the efficacy and tolerability of TG with intravenous methylprednisolone (iv.MP) in patients with active moderate-to-severe GO. METHODS: This study was an observer-masked, single-centre, block-randomised trial. Patients with active moderate-to-severe GO were randomly assigned to receive iv.MP (500 mg once per week for 6 weeks followed by 250 mg per week for 6 weeks) or with TG (20 mg tablet three times per day for 24 weeks). The primary endpoints were the overall response rate and the patients' quality of life at 12 and 24 weeks. RESULTS: In this study, 161 patients were enrolled and randomised from 2015 to 2019. A total of 79 were randomly assigned to receive iv.MP and 82 to receive TG. A greater overall response rate was found in the TG group compared with the iv.MP group at week 24 (90.2% vs 68.4%, P = 0.000). Similarly, the patients' quality of life of the TG group showed a significantly higher response than the iv.MP group at week 24 (89.02% vs 72.15%, P = 0.001). The TG therapy showed a better CAS response than the iv.MP (91.5% vs 70.9% improved, P < 0.05), and up to 91.2% of patients were inactive. Also, the TG group showed a significantly higher improved rate of diplopia, proptosis, visual acuity, soft tissue involved and the decrease of eye muscle motility than the iv.MP group at week 24. Significantly more patients in the iv.MP group than the TG group experienced adverse events. CONCLUSION: Compared with iv.MP treatment, TG therapy is more effective and safer for patients with active moderate to severe GO.

Graves' Orbitopathy: Current Concepts for Medical Treatment. / Endokrine Orbitopathie: aktueller Stand der medikamentösen Therapie.

BACKGROUND: The therapy of severe manifestations of Graves' orbitopathy (GO) is still a challenge and requires good interdisciplinary cooperation. It is especially important to use stage-adapted anti-inflammatory therapy to avoid irreversible damage. MATERIAL AND METHODS: Discussion of the latest results of multicentre randomised therapy studies on anti-inflammatory treatments for Graves' orbitopathy, as well as new therapeutic concepts. RESULTS: Mild cases of GO can be treated with only selenium supplementation and a watchful waiting strategy. In the moderate-to-severe active form of GO, primary therapy consists of i. v. steroids (cumulative 4 - 5 g) in combination with orbital irradiation in patients with impaired motility. In patients with insufficient therapeutic response after 6 weeks, treatment should be switched to other immunosuppressive agents. In severe sight-threatening disease, bony orbital decompression is usually necessary. As basic research has improved our understanding of the underlying pathophysiology of GO, it has been possible to develop targeted therapies for GO. Teprotumumab, an IGF-1 receptor antibody, was effective in treating GO patients in a phase III trial and should soon be awarded approval for Europe. CONCLUSION: The current therapy concept for Graves' orbitopathy is as follows: first anti-inflammatory therapy then surgical correction of the permanent defects. This may soon be modified, due to the use of targeted therapies.

Mechanisms of Spica Prunellae against thyroid-associated Ophthalmopathy based on network pharmacology and molecular docking.

BACKGROUND: Thyroid-associated ophthalmopathy (TAO) is an autoimmune inflammatory disorder, which lacks effective treatment currently. Spica Prunellae (SP) is popularly used for its anti-inflammatory and immune-regulating properties, indicating SP may have potential therapeutic value in TAO. Therefore, the purpose of this study is to identify the efficiency and potential mechanism of SP in treating TAO. METHODS: A network pharmacology integrated molecular docking strategy was used to predict the underlying molecular mechanism of treating TAO. Firstly, the active compounds of SP were obtained from TCMSP database and literature research. Then we collected the putative targets of SP and TAO based on multi-sources databases to generate networks. Network topology analysis, GO and KEGG pathway enrichment analysis were performed to screen the key targets and mechanism. Furthermore, molecular docking simulation provided an assessment tool for verifying drug and target binding. RESULTS: Our results showed that 8 targets (PTGS2, MAPK3, AKT1, TNF, MAPK1, CASP3, IL6, MMP9) were recognized as key therapeutic targets with excellent binding affinity after network analysis and molecular docking-based virtual screening. The results of enrichment analysis suggested that the underlying mechanism was mainly focused on the biological processes and pathways associated with immune inflammation, proliferation, and apoptosis. Notably, the key pathway was considered as the PI3K-AKT signaling pathway. CONCLUSION: In summary, the present study elucidates that SP may suppress inflammation and proliferation and promote apoptosis through the PI3K-AKT pathway, which makes SP a potential treatment against TAO. And this study offers new reference points for future experimental research and provides a scientific basis for more widespread clinical application.

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.

Therapeutic Effect of Guggulsterone in Primary Cultured Orbital Fibroblasts Obtained From Patients with Graves' Orbitopathy.

Purpose: Inflammation, hyaluronan production, and adipogenesis are the main pathological events leading to Graves' orbitopathy (GO). Guggulsterone (GS), a phytosterol found in the resin of the guggul plant, is a well-known treatment for several inflammatory disorders, such as arthritis, obesity, and hyperlipidemia. Here we investigated the effects of GS treatment on GO pathology. Methods: Using primary cultures of orbital fibroblasts from GO patients and non-GO controls, we examined the effects of GS on hyaluronan production and the production of proinflammatory cytokines induced by interleukin (IL)-1ß, using real-time reverse transcription-polymerase chain reaction analysis, western blots, and enzyme-linked immunosorbent assays. Further, adipogenic differentiation was evaluated by quantification of Oil Red O staining and assessment of protein levels of peroxisome proliferator activator gamma (PPARγ), CCAAT-enhancer-binding proteins (C/EBP) α and ß, and sterol regulatory element-binding protein-1 (SREBP-1). Results: Treatment with noncytotoxic concentrations of GS resulted in the dose-dependent inhibition of IL-1ß-induced inflammatory cytokines, including IL-6, IL-8, MCP-1, and COX-2, at both mRNA and protein levels. The hyaluronan level was also significantly suppressed by GS. Moreover, GS significantly decreased the formation of lipid droplets and expression of PPARγ, C/EBP α/ß, and SREBP-1 in a dose-dependent manner. GS pretreatment attenuated the phosphorylation of nuclear factor-kappa B induced by IL-1ß. Conclusions: Our data show significant inhibitory effects of GS on inflammation, production of hyaluronan, and adipogenesis in orbital fibroblasts. To our knowledge, this is the first in vitro preclinical evidence of the therapeutic effect of GS in GO.