Search

Background: For the selective detection of thyroid-stimulating hormone receptor antibodies with stimulating properties (thyroid-stimulating immunoglobulins; TSI), a novel and rapid bioassay (Turbo TSI) has been introduced. We evaluate the clinical performance of Turbo TSI in Graves’ orbitopathy (GO) patients and compare it to a bridge-based TSI binding immunoassay and third generation TSH-R-binding inhibitory immunoglobulins (TBII) assay. Also, we investigate the association of Turbo TSI and TBII measurements with GO activity and severity, as well as response to intravenous methylprednisolone (IVMP), and compare results to previous findings on the bridge-based TSI binding immunoassay. Methods: Turbo TSI, TBII and bridge-based TSI binding immunoassay measurements were performed in biobank serum from 111 GO patients and control cases (healthy controls [HC; n=47], primary Sjögren’s disease [SD; n=10], systemic sclerosis [SSc; n= 10], systemic lupus erythematosus [SLE; n=10]). Clinical characteristics and response to treatment were retrospectively retrieved from GO patient files. Results: Turbo TSI had the highest sensitivity (97.3%) and negative predictive value (96.1%), while bridge-based TSI binding immunoassay showed the highest specificity (100%) and positive predictive value (100%). Differentiating GO patients from control cases, receiver operating characteristic (ROC) analysis showed an area under the curve (AUC) of 98.5%, 95.7% and 99.8% for Turbo TSI, TBII and bridge-based TSI binding immunoassay, respectively. Turbo TSI (p<0.001) and TBII (p<0.01) levels were higher in patients with active compared to inactive GO. Correlation with CAS was stronger for Turbo TSI (r=0.42) than TBII (r=0.25). No statistically significant differences were observed in IVMP responders vs. non-responders for Turbo TSI (p=0.092) and TBII (p=0.21). For identifying active GO, an AUC of 75% with Turbo TSI and 67% with TBII was found. For IVMP response, AUC was 66.3% with Turbo TSI and 62.1% with TBII. In multivariate logistic regression analyses, both assays were independently associated with disease activity (p<0.01 for both assays) and IVMP response (p<0.01 for Turbo TSI; p<0.05 for TBII). Conclusions: The new Turbo TSI functional bioassay has good clinical performance. Although turbo TSI is a stronger marker of activity and IVMP response than TBII, results are comparable to our previously published findings on the bridge-based TSI binding immunoassay. [ABSTRACT FROM AUTHOR]

This study aims to establish a random forest model for detecting the severity of Graves Orbitopathy (GO) and identify significant classification factors. This is a hospital-based study of 199 patients with GO that were collected between December 2019 and February 2022. Clinical information was collected from medical records. The severity of GO can be categorized as mild, moderate-to-severe, and sight-threatening GO based on guidelines of the European Group on Graves' orbitopathy. A random forest model was constructed according to the risk factors of GO and the main ocular symptoms of patients to differentiate mild GO from severe GO and finally was compared with logistic regression analysis, Support Vector Machine (SVM), and Naive Bayes. A random forest model with 15 variables was constructed. Blurred vision, disease course, thyroid-stimulating hormone receptor antibodies, and age ranked high both in mini-decreased gini and mini decrease accuracy. The accuracy, positive predictive value, negative predictive value, and the F1 Score of the random forest model are 0.83, 0.82, 0.86, and 0.82, respectively. Compared to the three other models, our random forest model showed a more reliable performance based on AUC (0.85 vs. 0.83 vs. 0.80 vs. 0.76) and accuracy (0.83 vs. 0.78 vs. 0.77 vs. 0.70). In conclusion, this study shows the potential for applying a random forest model as a complementary tool to differentiate GO severity. [ABSTRACT FROM AUTHOR]

Abstract Introduction Graves’ ophthalmopathy (GO) is an autoimmune inflammatory disorder observed in a substantial proportion of patients with Graves’ disease (GD), with debilitating symptoms of disfiguring, periorbital pain, dry eyes, diplopia, and even visual disturbances. Previous studies involving Western populations have noted discrepancies in risk factors for GO. Therefore, this study aimed to determine the risk factors for GO development and the protective effect of statins in newly diagnosed patients with GD in Taiwan. Methods This retrospective case–control study was based on a tertiary center cohort involving patients with GD diagnosed between 2010 and 2019 at the National Taiwan University Hospital (n = 11,035). Patients who were diagnosed or treated elsewhere, had been followed up for less than 6 months or were with a diagnosis of orbital tumor were excluded. Overall, 3578 patients with GD met the inclusion criteria. Univariate and multivariate logistic regression analyses were used to ascertain the odds ratio (OR) of developing GO, with adjustment for sociodemographic factors, interventions for managing GD and thyroid hormone levels, to determine protective and risk factors for GO. Results In our multivariate model, the use of statins reduced the risk of GO development (OR 0.2; 95% confidence interval [CI] 0.08–0.50; p

Introduction: Graves' ophthalmopathy (GO) is an autoimmune inflammatory disorder observed in a substantial proportion of patients with Graves' disease (GD), with debilitating symptoms of disfiguring, periorbital pain, dry eyes, diplopia, and even visual disturbances. Previous studies involving Western populations have noted discrepancies in risk factors for GO. Therefore, this study aimed to determine the risk factors for GO development and the protective effect of statins in newly diagnosed patients with GD in Taiwan. Methods: This retrospective case–control study was based on a tertiary center cohort involving patients with GD diagnosed between 2010 and 2019 at the National Taiwan University Hospital (n = 11,035). Patients who were diagnosed or treated elsewhere, had been followed up for less than 6 months or were with a diagnosis of orbital tumor were excluded. Overall, 3578 patients with GD met the inclusion criteria. Univariate and multivariate logistic regression analyses were used to ascertain the odds ratio (OR) of developing GO, with adjustment for sociodemographic factors, interventions for managing GD and thyroid hormone levels, to determine protective and risk factors for GO. Results: In our multivariate model, the use of statins reduced the risk of GO development (OR 0.2; 95% confidence interval [CI] 0.08–0.50; p < 0.001). Thyroid dysfunction including hyperthyroidism (OR 4.2; 95% CI 2.97–5.88; p < 0.001) and hypothyroidism (OR 4.7; 95% CI 3.02–7.19; p < 0.001) was associated with an increased risk of developing GO. Smoking status and lipid profile were not risk factors in our cohort. Conclusion: In newly diagnosed patients with GD, the use of statins decreased the risk of developing GO by 80%, whereas serum lipid levels were not considered risk factors. Further nationwide population-based studies may help clarify the differences in risk factors between various ethnic groups. Trail Registration: This trial was approved by the Research Ethics Committee of National Taiwan University Hospital (202202066RINC), retrospectively registered from January 1, 2010 to December 31, 2019. [ABSTRACT FROM AUTHOR]

BackgroundFor the selective detection of thyroid-stimulating hormone receptor antibodies with stimulating properties (thyroid-stimulating immunoglobulins; TSI), a novel and rapid bioassay (Turbo TSI) has been introduced. We evaluate the clinical performance of Turbo TSI in Graves’ orbitopathy (GO) patients and compare it to a bridge-based TSI binding immunoassay and third generation TSH-R-binding inhibitory immunoglobulins (TBII) assay. Also, we investigate the association of Turbo TSI and TBII measurements with GO activity and severity, as well as response to intravenous methylprednisolone (IVMP), and compare results to previous findings on the bridge-based TSI binding immunoassay.MethodsTurbo TSI, TBII and bridge-based TSI binding immunoassay measurements were performed in biobank serum from 111 GO patients and control cases (healthy controls [HC; n=47], primary Sjögren’s disease [SD; n=10], systemic sclerosis [SSc; n= 10], systemic lupus erythematosus [SLE; n=10]). Clinical characteristics and response to treatment were retrospectively retrieved from GO patient files.ResultsTurbo TSI had the highest sensitivity (97.3%) and negative predictive value (96.1%), while bridge-based TSI binding immunoassay showed the highest specificity (100%) and positive predictive value (100%). Differentiating GO patients from control cases, receiver operating characteristic (ROC) analysis showed an area under the curve (AUC) of 98.5%, 95.7% and 99.8% for Turbo TSI, TBII and bridge-based TSI binding immunoassay, respectively. Turbo TSI (p

Background: Mood disorders are common in Graves’ disease despite treatment. The pathogenic mechanisms involved are unknown and so is whether previous psychiatric disease influences these symptoms. Methods: This is a longitudinal study conducted in Sweden on 65 women with newly diagnosed Graves’ disease and 65 matched controls. Participants were examined during hyperthyroidism and after 15 months of treatment. Examinations included blood sampling, and psychiatric testing with the Comprehensive Psychopathological Rating Scale for Affective Syndromes and the Structured Clinical Interview for DSM-IV – Axis I Disorders. We also performed two analyses of a national population-based registry to determine previous psychiatric diagnoses and previous prescriptions of psychoactive drugs in (i) all patients we asked to participate and (ii) all Swedish women given a diagnosis of hyperthyroidism during 2013–2018, comparing them to matched controls. Results: There was no increased previous psychiatric comorbidity in Graves’ patients compared to controls. There was no higher prevalence of psychiatric diagnoses and prescriptions of psychoactive drugs between (i) included GD patients compared to those who declined participation and (ii) women with a hyperthyroidism diagnosis in 5 years prior to their diagnosis, compared to matched controls. Depression scores and anxiety scores were higher in patients compared to controls both during hyperthyroidism (depression (median (IQR): 7.5 (5.0–9.5) vs 1.0 (0.5–2.5) P < 0.001), anxiety: 7.7 (5.0–11) vs 2.5 (1.0–4.0) P < 0.001) and after treatment (depression: 2.5 (1.5–5.0) vs 1.5 (0.5-3.5) P < 0.05), anxiety: 4.0 (2.5–7.5) vs 3.0 (1.5-5.0) P < 0.05). Patients with a previous psychiatric condition, mild eye symptoms, and a younger age had more anxiety at 15 months compared to patients without these symptoms and a higher age (all p

Context SARS-CoV-2 infection and Covid-19 vaccines have been associated with thyroid disorders. Objective We analyzed the risk of thyroid eye disease (TED) following Covid-19 vaccination. This was a self-controlled case series study at a tertiary referral center for TED. A total of 98 consecutive patients with newly developed (n = 92) or reactivated (n = 6) TED occurring between January 1, 2021, and August 31, 2022, were included. TED was assessed in patients undergoing Covid-19 vaccination. Person-days were defined as exposed if TED occurred 1 to 28 days after vaccination, and unexposed if occurring outside this time window. Conditional Poisson regression models were fitted to calculate incidence rate ratio (IRR) and 95% CI of exposed vs unexposed. Sensitivity analyses were conducted considering different exposed periods, and effect modification by potential TED risk factors. Results Covid-19 vaccines were administered in 81 people, 25 (31%) of whom developed TED in exposed and 56 (69%) in unexposed periods. The IRR for TED was 3.24 (95% CI 2.01-5.20) and 4.70 (95% CI 2.39-9.23) in patients below 50 years of age. Sex, smoking, and radioiodine treatment did not modify the association between TED and vaccination. TED risk was unrelated to the number of vaccine doses, and progressively decreased over time following vaccination (P trend =.03). Conclusion The risk of TED was significantly increased after Covid-19 vaccination, especially in people below 50 years of age. Possible mechanisms include spike protein interaction with the angiotensin-converting enzyme II receptor, cross-reactivity with thyroid self-proteins, and immune reactions induced by adjuvants. We suggest monitoring of individuals undergoing Covid-19 vaccination, especially if young and at risk for autoimmunity. [ABSTRACT FROM AUTHOR]

Background: There is emerging evidence which suggests the utility of artificial intelligence (AI) in the diagnostic assessment and pre-treatment evaluation of thyroid eye disease (TED). This scoping review aims to (1) identify the extent of the available evidence (2) provide an in-depth analysis of AI research methodology of the studies included in the review (3) Identify knowledge gaps pertaining to research in this area. Methods: This review was performed according to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA). We quantify the diagnostic accuracy of AI models in the field of TED assessment and appraise the quality of these studies using the modified QUADAS-2 tool. Results: A total of 13 studies were included in this review. The most common AI models used in these studies are convolutional neural networks (CNN). The majority of the studies compared algorithm performance against healthcare professionals. The overall risk of bias and applicability using the modified Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool led to most of the studies being classified as low risk, although higher deficiency was noted in the risk of bias in flow and timing. Conclusions: While the results of the review showed high diagnostic accuracy of the AI models in identifying features of TED relevant to disease assessment, deficiencies in study design causing study bias and compromising study applicability were noted. Moving forward, limitations and challenges inherent to machine learning should be addressed with improved standardized guidance around study design, reporting, and legislative framework. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Periostin is a matricellular protein that is ubiquitously expressed in normal human tissues and is involved in pathologic mechanism of chronic inflammatory and fibrotic disease. In this study we investigate periostin in the pathogenesis of Graves orbitopathy (GO) using human orbital adipose tissue obtained from surgery and primary cultured orbital fibroblasts in vitro. POSTN (gene encoding periostin) expression in Graves orbital tissues and healthy control tissues was studied, and the role of periostin in GO pathologic mechanism was examined through small-interfering RNA (siRNA)-mediated silencing. POSTN gene expression was significantly higher in Graves orbital tissues than healthy control tissues in real-time PCR results, and immunohistochemical staining revealed higher expression of periostin in Graves orbital tissues than normal tissues. Silencing periostin using siRNA transfection significantly attenuated TGF-β-induced profibrotic protein production and phosphorylated p38 and SMAD protein production. Knockdown of periostin inhibited interleukin-1 β -induced proinflammatory cytokines production as well as phosphorylation of NF-κB and Ak signaling protein. Adipocyte differentiation was also suppressed in periostin-targeting siRNA transfected GO cells. We hypothesize that periostin contributes to the pathogenic process of inflammation, fibrosis and adipogenesis of GO. Our study provides in vitro evidence that periostin may be a novel potential therapeutic target for the treatment of GO.

PurposeTo study the efficacy of orbital injections of triamcinolone acetonide mixed 1:1 with dexamethasone in the treatment of active thyroid eye disease.MethodsPatients that received orbital injection(s) of triamcinolone acetonide mixed 1:1 with dexamethasone for thyroid eye disease were included in this retrospective study. Demographic and clinical data were collected from the pre-treatment and 1 month follow up evaluations. Clinical data included subjective pain and diplopia scores, best-corrected visual acuity, Intraocular pressure, extraocular motility, clinical activity score, Hertel exophthalmometry, and upper eyelid margin to reflex distance.ResultsFifteen patients, 33 orbital injections, were included in the study. The average patient age was 59.2 years (SD ± 13.0) and 89% female. Subjectively, 67% of patients reported improvement of orbital pain and pressure versus 28% stable and 5% worse (p

Purpose: The purpose of the study was to measure the effect of rim-off deep lateral decompression for Graves orbitopathy on the lateral rectus muscle path and oculomotor balance. Methods: Retrospective analysis of the medical records and pre- and postoperative computed tomography scans of 34 orbits of 23 patients who underwent deep lateral decompression alone. The oculomotor balance of these 23 patients was measured with the alternate cover test and prisms before and after surgery. Bezier functions were used to measure the postoperative path of the lateral rectus in all decompressed orbits. Results: Deep lateral decompression induced a curvilinear deformation of the lateral rectus. There was no significant correlation between the position of the point of maximum muscle displacement and the size of the residual lateral wall. The changes in the lateral rectus path had no adverse effects on the oculomotor balance of the patients. Conclusions: The location of the curvilinear deformation of the lateral rectus does not depend on the residual segment of the lateral wall. The changes of the lateral rectus path have no deleterious effect on the oculomotor balance. [ABSTRACT FROM AUTHOR]

Graves orbitopathy is both disabling and disfiguring. Medical therapies to reduce inflammation are widely used, but there is limited trial data beyond 18 months of follow-up. Methods: Three-year follow-up of a subset of the CIRTED trial (N = 68), which randomized patients to receive high-dose oral steroid with azathioprine/placebo and radiotherapy/sham radiotherapy. Results: Data were available at 3 years from 68 of 126 randomized subjects (54%). No additional benefit was seen at 3 years for patients randomized to azathioprine or radiotherapy with regard to a binary clinical composite outcome measure (BCCOM), modified European Group on Graves’ Orbitopathy score, or Ophthalmopathy Index. Clinical Activity Score (CAS), Ophthalmopathy Index, and Total Eye Score improved over 3 years (P < .001). However, quality of life at 3 years remained poor. Of 64 individuals with available surgical outcome data, 24 of 64 (37.5%) required surgical intervention. Disease duration of greater than 6 months before treatment was associated with increased need for surgery [odds ratio (OR) 16.8; 95% CI 2.95, 95.0; P = .001]. Higher baseline levels of CAS, Ophthalmopathy Index, and Total Eye Score but not early improvement in CAS were associated with increased requirement for surgery. Conclusion: In this long-term follow-up from a clinical trial, 3-year outcomes remained suboptimal with ongoing poor quality of life and high numbers requiring surgery. Importantly, reduction in CAS in the first year, a commonly used surrogate outcome measure, was not associated with improved long-term outcomes. [ABSTRACT FROM AUTHOR]

Graves orbitopathy, also known as thyroid eye disease, affects around 20% of patients with Graves disease. It is disfiguring and has a significant impact on quality of life. In the past, the standard approach was to wait for the disease to "burn-out" and then perform corrective surgeries. However, high-dose steroids have been shown to reduce symptoms and became the standard of care. In 2017, a failed cancer therapeutic called teprotumumab showed remarkable results in reducing proptosis, leading to an explosion of drug repurposing for this condition. One approach involves using monoclonal antibodies to target the neonatal fragment crystallizable receptor (FcRn). A study using batoclimab, an FcRn inhibitor, showed promising results in reducing proptosis, but the trial was stopped due to adverse effects on LDL and serum albumin levels. These findings provide important insights into the disease process and expand therapeutic options. However, the long-term safety and cost-effectiveness of FcRn inhibitors need to be further investigated. Overall, the paradigm for treating Graves orbitopathy is expected to change in the coming years, with surgery and high-dose steroids playing a smaller role. [Extracted from the article]

BackgroundThere is emerging evidence which suggests the utility of artificial intelligence (AI) in the diagnostic assessment and pre-treatment evaluation of thyroid eye disease (TED). This scoping review aims to (1) identify the extent of the available evidence (2) provide an in-depth analysis of AI research methodology of the studies included in the review (3) Identify knowledge gaps pertaining to research in this area.MethodsThis review was performed according to the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (PRISMA). We quantify the diagnostic accuracy of AI models in the field of TED assessment and appraise the quality of these studies using the modified QUADAS-2 tool.ResultsA total of 13 studies were included in this review. The most common AI models used in these studies are convolutional neural networks (CNN). The majority of the studies compared algorithm performance against healthcare professionals. The overall risk of bias and applicability using the modified Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool led to most of the studies being classified as low risk, although higher deficiency was noted in the risk of bias in flow and timing.ConclusionsWhile the results of the review showed high diagnostic accuracy of the AI models in identifying features of TED relevant to disease assessment, deficiencies in study design causing study bias and compromising study applicability were noted. Moving forward, limitations and challenges inherent to machine learning should be addressed with improved standardized guidance around study design, reporting, and legislative framework.

Background: Graves’ disease (GD) is caused by the production of TSH-receptor (TSHR) stimulating auto-antibodies. Over the years various TSHR-antibody (TRAb) detection assays have been developed. Most clinical laboratories use competitive TSH-binding inhibitory immunoglobulin (TBII) assays, which measure the total amount of stimulating and blocking auto-antibodies. Selective detection of TSHR stimulating auto-antibodies (TSI) was previously only possible with functional cell-based bioassays. However, more recently an automated bridge-based binding assay to more specifically measure TSI has become available. The aim of our study was to compare the third-generation automated competitive immunoassay (TBII) with the automated bridge immunoassay (TSI) in clinical practice in an academic thyroid expert center. Methods: A retrospective study in 356 patients with Graves’ disease, Graves orbitopathy (GO), and other (thyroid) disease treated in an academic thyroid center was performed. All samples were analyzed for TBII and TSI. For both assays, sensitivity, specificity, positive predictive value (PVV), negative predictive value (NPV) and diagnostic odds ratios were calculated using different cut-offs for negativity. Results: Using the provided cut-off, the overall sensitivity appeared similar between TBII and TSI, but TSI showed higher overall specificity, PPV, NPV and diagnostic odds ratio. Using two or three times the cut-off for negativity resulted in a decrease in sensitivity, but an increase in specificity and PPV, which was most pronounced for the TBII-assay. Analysis in a subgroup of newly diagnosed treatment naïve GD/GO patients also revealed overall favorable results for the TSI-assay. Increasing the cut-off for negativity resulted in increased specificity for both assays, with similar results using two or three times the cut-off. Most patients with concordant positive results for TBII and TSI suffered from GD or GD + GO (n = 110, 95.6 %), while patients negative for both TBII and TSI mostly suffered from other (thyroid) disease (n = 143, 77.3 %). From patients with positive TBII but negative TSI only 42.1 % had GD/GO (n = 16), whereas 57.9 % (n = 22) had other (thyroid) disease. In contrast, 88.9 % of patients with positive TSI but negative TBII had GD/GO (n = 16), whereas 11.1 % (n = 2) had other (thyroid) disease. Conclusion: In our academic thyroid center, the diagnostic performance of the TSI-assay outperformed the TBII-assay. Using a higher cut-off value for negativity can be helpful in assessing clinical relevance.

Context: Gut bacteria can influence host immune responses but little is known about their role in tolerance-loss mechanisms in Graves disease (GD; hyperthyroidism caused by autoantibodies, TRAb, to the thyrotropin receptor, TSHR) and its progression to Graves orbitopathy (GO). Objective: This work aimed to compare the fecal microbiota in GD patients, with GO of varying severity, and healthy controls (HCs). Methods: Patients were recruited from 4 European countries (105 GD patients, 41 HCs) for an observational study with cross-sectional and longitudinal components. Results: At recruitment, when patients were hyperthyroid and TRAb positive, Actinobacteria were significantly increased and Bacteroidetes significantly decreased in GD/GO compared with HCs. The Firmicutes to Bacteroidetes (F:B) ratio was significantly higher in GD/GO than in HCs. Differential abundance of 15 genera was observed in patients, being most skewed in mild GO. Bacteroides displayed positive and negative correlations with TSH and free thyroxine, respectively, and was also significantly associated with smoking in GO; smoking is a risk factor for GO but not GD. Longitudinal analyses revealed that the presence of certain bacteria (Clostridiales) at diagnosis correlated with the persistence of TRAb more than 200 days after commencing antithyroid drug treatment. Conclusion: The increased F:B ratio observed in GD/GO mirrors our finding in a murine model comparing TSHR-immunized with control mice. We defined a microbiome signature and identified changes associated with autoimmunity as distinct from those due to hyperthyroidism. Persistence of TRAb is predictive of relapse; identification of these patients at diagnosis, via their microbiome, could improve management with potential to eradicate Clostridiales. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

INTRODUCTION: HIV fourth-generation assay, designed for the detection of HIV p24 antigen along with anti-HIV antibodies of both immunoglobulin M and immunoglobulin G type against HIV 1 and HIV 2 viral antigens, have helped in the early detection of HIV infection and supports in minimizing the transmission risk in the acute phase of infection. The objective of this study was to evaluate the analytical and clinical performance of HIV fourth-generation assay based on enhanced chemiluminescence technology. MATERIALS AND METHODS: The analytical performance of the assay was evaluated in terms of accuracy, precision, limit of detection, type of sample (serum vs. plasma), cross-reactivity (with other transfusion transmissible infections markers), and interference (with endogenous substances). Proficiency control material included kit-controls, archived known positive donor samples, third-party controls, and World Health Organization (WHO)/National Institute for Biological Standards and Controls (NIBSC, MHRA, UK) controls. The clinical performance was evaluated using routine donor and patient samples received during the study period. RESULTS: HIV fourth-generation assay showed reliable and reproducible results measured in terms of coefficient of variation % with kit-controls, archived known positive donor samples, third-party controls, and WHO international standards for anti-HIV 1 and 2 antibodies, HIV1 p24 antigens and HIV2 p26 antigen controls. The analytical sensitivity of the HIV fourth-generation assay was found to be 0.1 IU/mL of HIV1 p24 antigen control and there was no cross-reactivity or interference observed. In the clinical performance of the assay, HIV fourth-generation assay showed reliable performance in both donor and patient samples. CONCLUSION: HIV fourth-generation assay meets the requirements for its use as a screening assay for HIV infection based on the analytical and clinical performance of the assay. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the corneal biomechanical properties and central corneal thickness in patients with Graves' orbitopathy (GO). Method: A total of 132 eyes of 66 patients with GO and 108 eyes of 54 healthy subjects were enrolled. Eyes with GO were classified as high score clinical activity score (CAS, ≥ 3) (Group 1, n = 64) and low CAS score (< 3) (Group 2, n = 68). Corneal biomechanical parameters [corneal hysteresis (CH), corneal resistance factor (CRF)], Goldmann-correlated intraocular pressure (IOPg), and corneal-compensated IOP (IOPcc) levels were measured with Ocular Response Analyzer (ORA, Reichert Ophthalmic Instruments, Buffalo, NY) and compared between the groups. Results: The mean CH values were found as 9.6 ± 1 mmHg in Group 1, 10.2 ± 0.9 mmHg in Group 2, and 11.4 ± 1.7 mmHg in the Control Group (p < 0.001). In post hoc analysis the mean CH was significantly lower in Group 1 than Group 2 and Control Group (Group 1-Group 2, p < 0.001; Group 1-Control Group, p < 0.001). The mean CRF was found as 10.5 ± 2.1 in Group 1, 10.4 ± 2.2 in Group 2, and 10.43 ± 2.0 in the Control group. There was no statistically significant difference between the groups in CRF measurements (p = 0.959). The mean IOPcc values were found as 17.1 ± 3.6 mmHg in Group 1, 15.8 ± 4.0 mmHg in Group 2 and 15.2 ± 4.1 mmHg in the Control Group. The IOPcc and IOPg measurements between all groups were statistically significant (p = 0.009, p = 0.027, respectively). Conclusions: Corneal biomechanical measurements were different in the GO patients with varying CAS scores compared to healthy individuals. [ABSTRACT FROM AUTHOR]

Abstract Background Dysthyroid optic neuropathy (DON) is a serious threatening vision loss in Graves’ ophthalmopathy (GO). Although the European Group on Graves’ Ophthalmopathy (EUGOGO) recommend intravenous methylprednisolone therapy for first line treatment, some characteristics predicting the response are still inconclusive. Aim To study the efficacy of intravenous pulse methylprednisolone (IVMP) in treating dysthyroid optic neuropathy (DON) and to identify factors predicting poor response to the treatment. Methods All patients diagnosed with DON between January 2010 and December 2021 at Rajavithi Hospital, Thailand, receiving IVMP 1 g/ day for 3 consecutive days were analyzed. The efficacy at 1 week and 3, 6, 12-months in terms of improvement of best corrected visual acuity (BCVA) and proptosis were compiled. Results Of the entire 57 DON cases that received IVMP, 50.9% gained at least 0.2 Logarithm of the Minimum Angle of Resolution (logMAR) at 1 week, and the improvement from initial to 1-week BCVA was 0.63 ± 0.63 logMAR (p

Context: A role of DNA methylation in Graves orbitopathy (GO) has been proposed. Objective: This work aimed to investigate DNA methylation and gene expression in orbital fibroblasts from control and GO patients, under basal conditions or following challenge with an anti- thyrotropin (TSH) receptor antibody (M22) or cytokines involved in GO; to investigate the relationship between DNA methylation and cell function (proliferation); and to perform a methylome analysis. Methods: Orbital fibroblasts from 6 GO and 6 control patients from a referral center underwent methylome analysis of the whole genome. Results: Global DNA methylation increased significantly both in control and GO fibroblasts on incubation with M22. Expression of 2 selected genes (CYP19A1 and AIFM2) was variably affected by M22 and interleukin-6. M22 increased cell proliferation in control and GO fibroblasts, which correlated with global DNA methylation. Methylome analysis revealed 19 869 DNA regions differently methylated in GO fibroblasts, encompassing 3957 genes and involving CpG islands, shores, and shelves. A total of 119 gene families and subfamilies, 89 protein groups, 402 biological processes, and 7 pathways were involved. Three genes found to be differentially expressed were concordantly hypermethylated or hypomethylated. Among the differently methylated genes, insulin-like growth factor-1 receptor and several fibroblast growth factors and receptors were included. Conclusion: We propose that, when exposed to an autoimmune environment, orbital fibroblasts undergo hypermethylation or hypomethylation of certain genes, involving CpG promoters, which results in differential gene expression, which may be responsible for functional alterations, in particular higher proliferation, and ultimately for the GO phenotype in vivo. [ABSTRACT FROM AUTHOR]

BackgroundGraves’ 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.MethodsWe 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 2mm and diplopia response.ResultsThe 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.ConclusionTocilizumab appears to be a safe and cost effective therapeutic option for patients with active, corticosteroid-resistant, moderate to severe Graves’ orbitopathy.

A 30-year-old man presented with 3-year history of Graves disease. He was initially diagnosed after he developed unilateral proptosis and was initiated on methimazole 5 mg, on which he was currently euthyroid. Visible right-sided thyromegaly and trouble swallowing developed 2 months after presentation to our practice. Biochemical evaluation revealed suppressed TSH, normal free T4 and total T3, and elevated thyroid stimulating immunoglobulin with normal thyroid receptor antibody. An ultrasound of the thyroid demonstrated left-sided small nodules with right-sided thyromegaly. A nuclear medicine uptake scan revealed significantly greater uptake in the right thyroid lobe, with overall minimal uptake in the left lobe. The need for definitive therapy that would not exacerbate orbitopathy was discussed, and the patient elected for a right-sided hemithyroidectomy. Postoperative biochemical evaluation demonstrated biochemical euthyroidism despite continued elevation in thyroid stimulating immunoglobulin and newly elevated thyroid receptor antibody while remaining off methimazole. Graves disease can rarely involve a single thyroid lobe. Given the rarity, further investigation is needed to determine the natural course of this form of Graves disease. [ABSTRACT FROM AUTHOR]

Background: The aim of the study was to evaluate the differences in clinical profile, laboratory parameters, and ophthalmological signs, and symptoms between patients with high IgG4 Graves orbitopathy and patients with normal IgG4 Graves orbitopathy. Methods: This was a prospective observational study. We recruited adult patients with Graves Orbitopathy(GO) referred to our clinic for further diagnostics and treatment. Eventually, 60 patients with GO were enrolled in the study. All patients underwent ophthalmological assessment, magnetic resonance imaging (MRI) of the orbits, and laboratory tests, including IgG4 serum concentration measurement. High IgG4 GO was diagnosed if the IgG4 concentration exceeded 135 mg/dl. We used both the clinical activity score (CAS) and magnetic resonance imaging (MRI) to assess the activity of GO. Eventually, active GO was defined according to MRI results. Results: Among 60 GO patients, 15 (25%) patients had elevated IgG4 levels. Patients in the high IgG4 group had a higher prevalence of active GO by MRI than patients with normal IgG4 (100% vs. 64.44%, P=0.006). They also had a higher eosinophile count in peripheral blood, a lower bilirubin level, a more frequent lower eyelid retraction, and a lower prevalence of glaucoma. There were no statistically significant differences between the groups in CAS. Patients with active GO, had higher median IgG4 level [89.95 (55.48; 171.1) vs 43.45 (32.48; 49.68) mg/dl, P<0.001]. The receiver operating characteristic (ROC) analysis for IgG4 as a marker of active GO revealed the following results: AUC 0.848 for the cut-off value of 54.2 mg/dl, sensitivity 79.5%, specificity 87.5%, positive predictive value 94.6%, negative predictive value 59.1%. Conclusions: We demonstrated that IgG4 is a marker of GO activity. Certain differences in the clinical profile of patients with high IgG4 GO, and normal IgG4 GO were observed. More data is needed to establish whether patients with high IgG4 GO are GO patients with particularly active disease or actually represent a distinct clinical entity related to IgG4-Related Disease. [ABSTRACT FROM AUTHOR]

Introduction: The primary treatment for active thyroid eye disease (TED) is immunosuppressive therapy with intravenous steroids. In this study, we attempted to predict responsiveness to steroid treatment in TED patients using eXtreme Gradient Boosting (XGBoost). Factors associated with steroid responsiveness were also statistically evaluated. Methods: Clinical characteristics and laboratory results of 89 patients with TED who received steroid treatment were retrospectively reviewed. XGBoost was used to explore responsiveness to steroid treatment, and the diagnostic performance was evaluated. Factors contributing to the model output were investigated using the SHapley Additive exPlanation (SHAP), and the treatment response was investigated statistically using SPSS software. Results: The eXtra Gradient Boost model showed high performance, with an excellent accuracy of 0.861. Thyroid-stimulating hormone, thyroid-stimulating immunoglobulin (TSI), and low-density lipoprotein (LDL) cholesterol had the highest impact on the model. Multivariate logistic regression analysis showed that less extraocular muscle limitation and high TSI levels were associated with a high risk of poor intravenous methylprednisolone treatment response. As a result of analysis through SHAP, TSH, TSI, and LDL had the highest impact on the XGBoost model. Conclusion: TSI, extraocular muscle limitation, and LDL cholesterol levels may be useful in predicting steroid treatment response in patients with TED. In terms of machine learning, XGBoost showed relatively robust and reliable results for small datasets. The machine-learning model can assist in decision-making for further treatment of patients with TED. [ABSTRACT FROM AUTHOR]

Background: Dysthyroid optic neuropathy (DON) is a serious threatening vision loss in Graves' ophthalmopathy (GO). Although the European Group on Graves' Ophthalmopathy (EUGOGO) recommend intravenous methylprednisolone therapy for first line treatment, some characteristics predicting the response are still inconclusive. Aim: To study the efficacy of intravenous pulse methylprednisolone (IVMP) in treating dysthyroid optic neuropathy (DON) and to identify factors predicting poor response to the treatment. Methods: All patients diagnosed with DON between January 2010 and December 2021 at Rajavithi Hospital, Thailand, receiving IVMP 1 g/ day for 3 consecutive days were analyzed. The efficacy at 1 week and 3, 6, 12-months in terms of improvement of best corrected visual acuity (BCVA) and proptosis were compiled. Results: Of the entire 57 DON cases that received IVMP, 50.9% gained at least 0.2 Logarithm of the Minimum Angle of Resolution (logMAR) at 1 week, and the improvement from initial to 1-week BCVA was 0.63 ± 0.63 logMAR (p < 0.001) and the decrease in proptosis was 1.8 ± 1.36 mm (p < 0.001). The remaining 23 orbits underwent orbital decompression and were excluded from the long-term efficacy analysis. In the last 12-months' follow-up time, there was an improvement of BCVA (0.53 ± 0.47 logMAR) and proptosis (0.59 ± 0.66 mm) (both p < 0.001). At last visit, there was an improvement of BCVA (0.2 logMAR) and proptosis (2 mm) in 76.5, and 5.9% respectively. Significant predictive factors of poor treatment response were age ≥ 55 years (odds ratio [OR]: 8.28, 95% confidence interval [CI]: 1.368–50.121, p = 0.021); longer onset duration before treatment (OR: 5.10, 95%CI: 1.061–24.501, p = 0.042); and proptosis at baseline (OR: 9.31, 95%CI: 1.872–46.280, p = 0.006). The strongest risk factor for predicting poor response to IVMP was poor initial visual acuity (OR: 10.26, 95%CI: 1.363–77.234, p = 0.024). Conclusions: IVMP is effective for both short- and long-term treatment to improve visual acuity greater than proptosis. Older age, longer disease duration, poor initial visual acuity, and proptotic orbits were identified as risk factors for predicting poor response to IVMP treatment in Thai population. DON patients having those risk factors should be suspected, and treated early with IVMP to preserve their future vision. [ABSTRACT FROM AUTHOR]

BackgroundThe aim of the study was to evaluate the differences in clinical profile, laboratory parameters, and ophthalmological signs, and symptoms between patients with high IgG4 Graves orbitopathy and patients with normal IgG4 Graves orbitopathy.MethodsThis was a prospective observational study. We recruited adult patients with Graves Orbitopathy(GO) referred to our clinic for further diagnostics and treatment. Eventually, 60 patients with GO were enrolled in the study. All patients underwent ophthalmological assessment, magnetic resonance imaging (MRI) of the orbits, and laboratory tests, including IgG4 serum concentration measurement. High IgG4 GO was diagnosed if the IgG4 concentration exceeded 135 mg/dl. We used both the clinical activity score (CAS) and magnetic resonance imaging (MRI) to assess the activity of GO. Eventually, active GO was defined according to MRI results.ResultsAmong 60 GO patients, 15 (25%) patients had elevated IgG4 levels. Patients in the high IgG4 group had a higher prevalence of active GO by MRI than patients with normal IgG4 (100% vs. 64.44%, P=0.006). They also had a higher eosinophile count in peripheral blood, a lower bilirubin level, a more frequent lower eyelid retraction, and a lower prevalence of glaucoma. There were no statistically significant differences between the groups in CAS. Patients with active GO, had higher median IgG4 level [89.95 (55.48; 171.1) vs 43.45 (32.48; 49.68) mg/dl, P

Introduction/objective: Active moderate-to-severe thyroid eye disease (TED) is a major therapeutic challenge. Pulse therapy with intravenous glucocorticoids is the standard treatment, with variable response. Radioactive iodine therapy (RAI) was reported as a risk factor for onset or worsening of TED. We evaluated putative predictive factors for response to intravenous methylprednisolone in patients with active TED., Methods: Data were collected for 64 consecutive patients (45 women) with active moderate-to-severe TED treated with a minimum cumulative dose of 4.5g methylprednisolone. Patients were classified as responders (R) or non-responders (NR) on Clinical Activity Score (CAS), and clinical features were compared between groups., Results: Sixty-two patients had Graves' disease (GD), and 2 had Hashimoto's thyroiditis (HT). Median age at thyroid dysfunction diagnosis, TED manifestation and pulse therapy was 46, 48 and 51 years, respectively; 56.2% were euthyroid when TED manifested. Among them, 73.4% were responders. R and NR were comparable for gender, age, thyroid function, serum antibodies, disease duration, pre-treatment CAS, smoking, lipid profile, and adverse events. Forty-nine patients were treated with RAI for GD: 15 before the active phase of TED (before pulse therapy), 16 during, 17 after, and 1 both before and after pulse therapy. Response rate was higher in patients who received RAI during than after pulse therapy (P=0.032) and similar to those not treated with RAI at all (P=0,599)., Conclusion: Pulse therapy was effective in the majority of patients. The only factor associated with response to pulse therapy was the timing of RAI, suggesting that it seems to be safe when used concomitantly with pulse therapy., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Nicole Quah Qin Xian,1 Ahmed Alnahrawy,2 Rashmi Akshikar,2 Vickie Lee2,3 1Department of Stroke Medicine, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UK; 2Department of Ophthalmology, Western Eye Hospital, Imperial College Healthcare NHS Trust, London, UK; 3Department of Surgery & Cancer, General Surgery, Faculty of Medicine,Imperial College London, London, UKCorrespondence: Vickie LeeDepartment of Ophthalmology, Western Eye Hospital, Imperial College Healthcare NHS Trust, 153– 173 Marylebone Road, Marylebone, London, NW1 5QH, UKTel +44 20 3312 6666Email vickie.lee@nhs.netPurpose: There is no universal consensus on second-line agents for the treatment of moderate/severe to sight-threatening thyroid eye disease (TED) to maintain remission after first-line intravenous methylprednisolone (IVMP). This study investigates the efficacy and safety of mycophenolate mofetil (MMF) in TED patients in a real-world setting and over a longer period than previous randomized controlled trials.Methods: A retrospective cohort study of TED patients with active moderate/severe to sight-threatening TED seen over a 4-year period. Data collected were visual acuity (VA), Clinical Activity Score (CAS), Gorman Diplopia scores, MMF dosing and side effects at 24, 52 and 78 weeks. Clinical efficacy was defined as an absence of relapse: no decline in best corrected LogMAR VA, no need for further steroids, no increase in CAS of ≥ 2.Results: Out of 23 patients, 20 patients were included in this study. 10% (2/20) stopped MMF before 24 weeks. Median duration of MMF treatment was 76 weeks (1– 140 weeks). 55% (11/20) had dysthyroid optic neuropathy (DON). In those with active moderate-severe TED without DON, clinical efficacy was seen in 100% (8/8) at 24 weeks, 87.5% (7/8) at 52 weeks, and 83.3% (5/6) at 78 weeks, with CAS decreasing from a baseline of 2.78± 1.99 to 0.50± 0.58 at 24 weeks, 0.50± 0.82 at 52 weeks and 1.00± 1.30 at 78 weeks. In DON, improvements were seen in 90% (9/10) at 24 weeks, 100% (7/7) at 52 weeks and 100% (4/4) at 78 weeks, with significantly reduced CAS scores from 2.55± 1.54 to 0.83± 1.27, 1.00± 1.17 and 0.63± 0.95 at 24, 52 and 78 weeks, respectively. Gorman score, VA and soft tissue inflammation parameters also improved throughout. There were two significant side effects over the treatment period.Conclusion: MMF appears to be an effective and safe second-line immunosuppressive agent. Further studies aimed at elucidating optimal dosing regimens and ideal treatment duration will prove helpful.Keywords: Graves orbitopathy, dysthyroid optic neuropathy, CellCept

Thi My Hanh Pham,1,2 Chien Thang Nguyen,1 Quoc Tung Mai,2 Thi Huong Giang Bui,2 Dung Hoa Do,2 Peter McCluskey,3 Trong Van Pham2 1Department of Ophthalmology, 103 Military Hospital, Hanoi, Vietnam; 2Department of Ophthalmology, Hanoi Medical University, Hanoi, Vietnam; 3Department of Ophthalmology, University of Sydney, Sydney, NSW, AustraliaCorrespondence: Quoc Tung MaiTung Department of Ophthalmology, Hanoi Medical University, 1 Ton That Tung Street, Hanoi, 100000, VietnamTel +84 915644181Email maiquoctung@hmu.edu.vnPurpose: To evaluate the efficacy and safety of endoscopic orbital decompression in patients with Graves’ orbitopathy.Patients and Methods: This is a prospective study in Hanoi Medical University and a Military Hospital from December 2017 to December 2018. Twenty-eight orbits of fifteen patients were undergoing endoscopic orbital decompression for Graves’ orbitopathy. Indications for surgery were proptosis in twenty-two orbits and compressive optic neuropathy in six orbits. The outcome measures were proptosis reduction, visual acuity, visual field test and diplopia. Post-operative complications including cerebrospinal fluid leakage, haemorrhage, lacrimal duct impairment, worsening diplopia, sinusitis and cellulitis were collected.Results: The mean proptosis reduction was 2.23 mm. Visual acuity and medium deviation in the Humphrey visual field were significantly improved in four of six eyes with compressive optic neuropathy. There was one patient with intra-operative excessive bleeding which resolved without affecting visual outcome. Post-operatively, two patients developed a new onset of diplopia and two others worsened diplopia; three have already undergone successful strabismus surgery and moderate proptosis reduction.Conclusion: Endoscopic orbital decompression surgery was effectively and safely to manage compressive optic neuropathy of Graves’ orbitopathy and moderately reduce proptosis in a group of Vietnamese patients.Keywords: endoscopy, Graves‘ orbitopathy, decompression, optic neuropathy

Periostin is a matricellular protein that is ubiquitously expressed in normal human tissues and is involved in pathologic mechanism of chronic inflammatory and fibrotic disease. In this study we investigate periostin in the pathogenesis of Graves' orbitopathy (GO) using human orbital adipose tissue obtained from surgery and primary cultured orbital fibroblasts in vitro. POSTN (gene encoding periostin) expression in Graves' orbital tissues and healthy control tissues was studied, and the role of periostin in GO pathologic mechanism was examined through small-interfering RNA (siRNA)-mediated silencing. POSTN gene expression was significantly higher in Graves' orbital tissues than healthy control tissues in real-time PCR results, and immunohistochemical staining revealed higher expression of periostin in Graves' orbital tissues than normal tissues. Silencing periostin using siRNA transfection significantly attenuated TGF-β-induced profibrotic protein production and phosphorylated p38 and SMAD protein production. Knockdown of periostin inhibited interleukin-1 β -induced proinflammatory cytokines production as well as phosphorylation of NF-κB and Ak signaling protein. Adipocyte differentiation was also suppressed in periostin-targeting siRNA transfected GO cells. We hypothesize that periostin contributes to the pathogenic process of inflammation, fibrosis and adipogenesis of GO. Our study provides in vitro evidence that periostin may be a novel potential therapeutic target for the treatment of GO. [ABSTRACT FROM AUTHOR]

Background/Aims: There is no universal consensus on the practical implementation and evaluation of the Amsterdam Declaration on Graves Orbitopathy in a Multidisciplinary Thyroid Eye Disease (MDTED) pathway. Recent recommendations from the UK TEAMeD-5 and BOPSS initiative highlight the importance of prevention, screening, and prompt referral of patients with moderate to severe and sight-threatening thyroid eye disease to multidisciplinary (MDTED) clinics and recommends annual auditing. We propose a practical service evaluation model with Key Performance Indicators (KPI) that are achievable and could be implemented across most TED pathways. Material and Methods: We conducted a service evaluation from an integrated TED pathway in London with three MDTED clinics. Data was collected retrospectively from consecutive TED patients included: 1) Patient demographics, 2) Referral to first appointment time, 3) Documented smoking cessation and selenium supplementation advice, 4) Presenting disease activity and severity, 5) Investigations and treatments, including radio-iodine, 6) Time from decision to treatment initiation, 7) Initial and subsequent thyroid status. Results: The median age was 49.0 yrs, 77.5% (183/236) were female and 49.5% (101/204) Afro-Caribbean or Asian. At their first clinic attendance, 47.6% (110/231) were biochemically euthyroid and 76.7% (79/103) at discharge. All 23.1% (52/225) current smokers received smoking cessation advice and 64.8% (153/236) received selenium supplementation advice. Intravenous methylprednisolone was given to 33.9% (80/236) patients and 12.7% (30/236) received second-line immunosuppression. All 7.2% (17/236) patients with sight-threatening disease received treatment within two weeks of diagnosis. Conclusions: This study forms a waymark for other units using TEAMeD-5 and BOPSS audit criteria. Dedicated electronic patient records with ongoing data capture, including quality of life assessments, and diagnostic coding would significantly aid future auditing, improve patient care, and facilitate a national audit of TED management. A future survey when the TED standards have become embedded would be instructive to see whether this has improved TED care. [ABSTRACT FROM AUTHOR]

This Research Topic provides a timely update on different aspects of GO, in 20 excellent contributions, ranging from epidemiology, pathogenesis, disease evaluation, to comments on existing therapies and novel treatment strategies. It illustrates an unlimited potential of non-surgical treatments, many of which target fundamental disease processes such as ligand-receptor binding and T cell subset imbalance underpinning GO development, and will ultimately benefit patient care in the near future. Uncontrolled hyperthyroidism, which is caused by autoantibodies (TRAB) to the TSHR in GD, is a major GO risk factor with high TRAB levels long known to correlate with GO incidence and severity ([3]). Keywords: graves orbitopathy; epidemiology; pathogenesis; evaluation; novel therapeutic approach EN graves orbitopathy epidemiology pathogenesis evaluation novel therapeutic approach 1 4 4 05/04/22 20220429 NES 220429 Graves' orbitopathy (GO) is the main extra-thyroidal manifestation in patients with Graves' disease (GD), with a prevalence of up to 50%, although in most cases GO is mild ([1]). [Extracted from the article]

Periostin is a matricellular protein that is ubiquitously expressed in normal human tissues and is involved in pathologic mechanism of chronic inflammatory and fibrotic disease. In this study we investigate periostin in the pathogenesis of Graves’ orbitopathy (GO) using human orbital adipose tissue obtained from surgery and primary cultured orbital fibroblasts in vitro. POSTN (gene encoding periostin) expression in Graves’ orbital tissues and healthy control tissues was studied, and the role of periostin in GO pathologic mechanism was examined through small-interfering RNA (siRNA)-mediated silencing. POSTN gene expression was significantly higher in Graves’ orbital tissues than healthy control tissues in real-time PCR results, and immunohistochemical staining revealed higher expression of periostin in Graves’ orbital tissues than normal tissues. Silencing periostin using siRNA transfection significantly attenuated TGF-β-induced profibrotic protein production and phosphorylated p38 and SMAD protein production. Knockdown of periostin inhibited interleukin-1 β -induced proinflammatory cytokines production as well as phosphorylation of NF-κB and Ak signaling protein. Adipocyte differentiation was also suppressed in periostin-targeting siRNA transfected GO cells. We hypothesize that periostin contributes to the pathogenic process of inflammation, fibrosis and adipogenesis of GO. Our study provides in vitro evidence that periostin may be a novel potential therapeutic target for the treatment of GO.

Objective: To evaluate the ability of quantitative MRI parameters for predicting dysthyroid optic neuropathy (DON). Methods: We retrospectively collected and analyzed the clinical features and 3.0 T MRI data of 59 patients with Graves orbitopathy (GO), with (n = 26) and without DON (n = 33). We compared MRI quantitative parameters, including the modified muscle index (mMI), proptosis, volume of intra-orbital fat, mean apparent diffusion coefficient value, and T2 value of the optic nerve among patients with and without DON. A logistic regression analysis was performed to identify the risk factors associated with DON. Moreover, we performed a receiver operating characteristic curve analysis and decision curve analysis to evaluate the diagnostic performance of the identified parameters for DON. Results: We studied 118 orbits (43 and 75 with and without DON, respectively). The mMI and mean T2 value of the optic nerve were significantly greater in orbits with DON (p < 0.001). A greater mMI at 21 mm (odds ratio (OR), 1.039; 95% confidence interval (CI): 1.019, 1.058) and higher mean T2 value of the optic nerve (OR, 1.035; 95% CI: 1.017, 1.054) were associated with a higher risk of DON. A model combining the mMI at 21 mm and mean T2 values for the optic nerve effectively predicted DON in patients with GO, with a sensitivity and specificity of 95.3% and 76%, respectively. Conclusion: A quantitative MRI parameter combining the mMI at 21 mm and mean T2 value of the optic nerve can be an effective imaging marker for identifying DON. Key Points: • Patients with GO and DON had greater mMI than those without DON. • Optic nerves in patients with DON demonstrated an increased T2 value. • The quantitative MRI parameter combining the mMI at 21 mm and mean T2 value of the optic nerve is the most effective method for diagnosing DON. [ABSTRACT FROM AUTHOR]

Purpose: Graves' disease (GD) is an autoimmune disorder affecting primarily the thyroid gland. The most common extrathyroidal manifestation of GD is known as Graves' orbitopathy (GO). Bone marrow-derived fibrocytes represent a subset of monocytes in peripheral blood mononuclear cells (PBMCs), infiltrate the orbital tissues, and contribute to the pathogenesis of GO. Hence objectives of the study included whether the concentration of fibrocytes in peripheral blood was higher in GO, whether TSHR m RNA expression and TSHR surface expression in peripheral blood were higher in GO in comparison to Graves' Disease (GD) and Control subjects. Methods: The percentage of circulating fibrocytes (FC) along with TSHR on its cell surface (CD 34+, CD 45+, CXCR4+, Collagen 1+, TSHR+) were assessed by flow cytometry of 50 patients with GD and GO and 15 healthy donors (Control). TSHR mRNA expression was measured by q RT PCR. Result: The concentration of circulating fibrocytes was significantly higher in GO compared to GD and control [GO 17% vs GD 3% vs control 0.7% (p < 0.05)]. Moreover, these fibrocytes express a significantly higher level of TSHR in GO. This was corroborated by the measure of TSH mRNA; in GD it was 2.3-fold higher and in GO it was 3.9 fold higher than in control, in GO this transcript level was 1.7fold higher than GD (p < 0.05). TSHR+ fibrocytes were significantly positively correlated with CAS (p = 0.004) and negatively correlated with age (p = 0.01) and duration of disease (p = 0.01) in GO. Conclusion: This study sheds further light on the pathogenesis of GO. [ABSTRACT FROM AUTHOR]

Purpose: To validate the GO-specific quality of life (QOL) questionnaire in Hindi language and to determine the correlation of scores (visual functioning and appearance) with disease severity and activity. Methods: We recruited 114 consecutive patients with GO attending Endocrinology Clinic at tertiary care center. Eye examination was performed, and QOL was assessed by questionnaire. Results: The questionnaire was validated by 50 GO patients and test-retest reliability was performed in 15 patients. Hindi version GO-QOL was administered in 49 GO patients. GO was mild in 51.0% and sight-threatening in only 2.0% of cases. Orbitopathy was clinically active in only 10 (20.4%) cases. The GO-QOL scores (median) for visual function and appearance were 81.3 and 62.5, respectively. Patients with moderate-to-severe and sight-threatening GO had significantly lower median appearance scores (56.3 vs. 68.5, P= 0.01) compared to mild disease but no difference in visual scores. Patients with active disease had significant lower median visual function (53.1 vs. 85.7, P= 0.009) and psychosocial (appearance) scores (40.6 vs. 68.8, P= 0.03) compared to inactive disease. On multivariate regression analysis of GO-QOL scores, extraocular eye movement involvement (EOM), proptosis, and severity of eye disease were significantly associated with visual functioning while appearance was significantly associated only with the severity of eye disease. Conclusion: GO-QOL scores were significantly reduced in patients with GO.

Competing Interests: AK is a consultant to BioTissue Inc. AK conducts research on thyroid eye disease with support from industry, not relevant to this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Context Depot-specific expansion of orbital adipose tissue (OAT) in Graves orbitopathy (GO; an autoimmune condition producing proptosis, visual impairment and reduced quality of life) is associated with fatty acid (FA)-uptake–driven adipogenesis in preadipocytes/fibroblasts (PFs). Objective This work sought a role for mitochondria in OAT adipogenesis in GO. Methods Confluent PFs from healthy OAT (OAT-H), OAT from GO (OAT-GO) and white adipose tissue in culture medium compared with culture medium containing a mixed hormonal cocktail as adipogenic medium (ADM), or culture-medium containing FA-supplementation, oleate:palmitate:linoleate (45:30:25%) with/without different concentration of mitochondrial biosubstrate adenosine 5′-diphosphate/guanosine 5′-diphosphate (ADP/GDP), AICAR (adenosine analogue), or inhibitor oligomycin-A for 17 days. Main outcome measures included oil-red-O staining and foci count of differentiated adipocytes for in vitro adipogenesis, flow cytometry, relative quantitative polymerase chain reaction, MTS-assay/106 cells, total cellular-ATP detection kit, and Seahorse-XFe96-Analyzer for mitochondria and oxidative-phosphorylation (OXPHOS)/glycolysis-ATP production analysis. Results During early adipogenesis before adipocyte formation (days 0, 4, and7), we observed OAT-specific cellular ATP production via mitochondrial OXPHOS in PFs both from OAT-H and OAT-GO, and substantially disrupted OXPHOS-ATP/glycolysis-ATP production in PFs from OAT-GO, for example, a 40% reduction in OXPHOS-ATP and trend-increased glycolysis-ATP production on days 4 and 7 compared with day 0, which contrasted with the stable levels in OAT-H. FA supplementation in culture-medium triggered adipogenesis in PFs both from OAT-H and OAT-GO, which was substantially enhanced by 1-mM GDP reaching 7% to 18% of ADM adipogenesis. The FA-uptake–driven adipogenesis was diminished by oligomycin-A but unaffected by treatment with ADP or AICAR. Furthermore, we observed a significant positive correlation between FA-uptake–driven adipogenesis by GDP and the ratios of OXPHOS-ATP/glycolysis-ATP through adipogenesis of PFs from OAT-GO. Conclusion Our study confirmed that FA uptake can drive OAT adipogenesis and revealed a fundamental role for mitochondria-OXPHOS in GO development, which provides potential for therapeutic interventions. [ABSTRACT FROM AUTHOR]

To assess the sensitivity and specificity of lateral midpupil lid distances for the detection of upper lid lateral flare. Lateral lid flare was determined by unanimous agreement among six experienced oculoplastic surgeons in the grading of photographs obtained for patients with Graves orbitopathy (GO). Bézier lines were employed to extract the upper eyelid contours of the patients and a control group of age and sex matched subjects. Custom software was employed to determine 5 lateral midpupil eyelid distances. The sensitivity and specificity of each measurement in detecting lateral flare were estimated from receiver operating characteristic curves. The non-parametric Kruskal–Wallis one-way analysis of variance (ANOVA) with Dunn's posthoc test was used to compare the median values of the contour parameters between groups. The degree of agreement between judges evaluated with the Fleiss' Kappa test was relatively high (K = 0.69, z = 16.6, p <.0001). The raters classified 12 lids with lateral lid flare (LLF) and 7 without LLF in patients with GO. There was no agreement on the presence or absence of LLF in 11 lids. In all eyes, lateral midpupil lid distances diminished from the center of the eyelid towards the lateral canthus. Receiver operating characteristic analysis for the midpupil distances revealed that the fourth distance from the center demonstrated high sensitivity and specificity in detecting flare. At this location (2.5 mm medial to the lateral canthus) a midpupil distance equal to or greater than 60% of the margin reflex distance (MRD1) indicated the presence of flare. – A single measurement of a lateral midpupil eyelid distance 2.5 mm medial to the lateral canthus is a sensitive and specific measurement for the diagnosis of the LLF. [ABSTRACT FROM AUTHOR]

Background/AimsThere is no universal consensus on the practical implementation and evaluation of the Amsterdam Declaration on Graves Orbitopathy in a Multidisciplinary Thyroid Eye Disease (MDTED) pathway. Recent recommendations from the UK TEAMeD-5 and BOPSS initiative highlight the importance of prevention, screening, and prompt referral of patients with moderate to severe and sight-threatening thyroid eye disease to multidisciplinary (MDTED) clinics and recommends annual auditing. We propose a practical service evaluation model with Key Performance Indicators (KPI) that are achievable and could be implemented across most TED pathways.Material and MethodsWe conducted a service evaluation from an integrated TED pathway in London with three MDTED clinics. Data was collected retrospectively from consecutive TED patients included: 1) Patient demographics, 2) Referral to first appointment time, 3) Documented smoking cessation and selenium supplementation advice, 4) Presenting disease activity and severity, 5) Investigations and treatments, including radio-iodine, 6) Time from decision to treatment initiation, 7) Initial and subsequent thyroid status.ResultsThe median age was 49.0 yrs, 77.5% (183/236) were female and 49.5% (101/204) Afro-Caribbean or Asian. At their first clinic attendance, 47.6% (110/231) were biochemically euthyroid and 76.7% (79/103) at discharge. All 23.1% (52/225) current smokers received smoking cessation advice and 64.8% (153/236) received selenium supplementation advice. Intravenous methylprednisolone was given to 33.9% (80/236) patients and 12.7% (30/236) received second-line immunosuppression. All 7.2% (17/236) patients with sight-threatening disease received treatment within two weeks of diagnosis.ConclusionsThis study forms a waymark for other units using TEAMeD-5 and BOPSS audit criteria. Dedicated electronic patient records with ongoing data capture, including quality of life assessments, and diagnostic coding would significantly aid future auditing, improve patient care, and facilitate a national audit of TED management. A future survey when the TED standards have become embedded would be instructive to see whether this has improved TED care.

Background/Aims: There is no universal consensus on the practical implementation and evaluation of the Amsterdam Declaration on Graves Orbitopathy in a Multidisciplinary Thyroid Eye Disease (MDTED) pathway. Recent recommendations from the UK TEAMeD-5 and BOPSS initiative highlight the importance of prevention, screening, and prompt referral of patients with moderate to severe and sight-threatening thyroid eye disease to multidisciplinary (MDTED) clinics and recommends annual auditing. We propose a practical service evaluation model with Key Performance Indicators (KPI) that are achievable and could be implemented across most TED pathways. Material and Methods: We conducted a service evaluation from an integrated TED pathway in London with three MDTED clinics. Data was collected retrospectively from consecutive TED patients included: 1) Patient demographics, 2) Referral to first appointment time, 3) Documented smoking cessation and selenium supplementation advice, 4) Presenting disease activity and severity, 5) Investigations and treatments, including radio-iodine, 6) Time from decision to treatment initiation, 7) Initial and subsequent thyroid status. Results: The median age was 49.0 yrs, 77.5% (183/236) were female and 49.5% (101/204) Afro-Caribbean or Asian. At their first clinic attendance, 47.6% (110/231) were biochemically euthyroid and 76.7% (79/103) at discharge. All 23.1% (52/225) current smokers received smoking cessation advice and 64.8% (153/236) received selenium supplementation advice. Intravenous methylprednisolone was given to 33.9% (80/236) patients and 12.7% (30/236) received second-line immunosuppression. All 7.2% (17/236) patients with sight-threatening disease received treatment within two weeks of diagnosis. Conclusions: This study forms a waymark for other units using TEAMeD-5 and BOPSS audit criteria. Dedicated electronic patient records with ongoing data capture, including quality of life assessments, and diagnostic coding would significantly aid future auditing, improve patient care, and facilitate a national audit of TED management. A future survey when the TED standards have become embedded would be instructive to see whether this has improved TED care. [ABSTRACT FROM AUTHOR]

Purpose: There is no universal consensus on second-line agents for the treatment of moderate/severe to sight-threatening thyroid eye disease (TED) to maintain remission after first-line intravenous methylprednisolone (IVMP). This study investigates the efficacy and safety of mycophenolate mofetil (MMF) in TED patients in a real-world setting and over a longer period than previous randomized controlled trials. Methods: A retrospective cohort study of TED patients with active moderate/severe to sight-threatening TED seen over a 4-year period. Data collected were visual acuity (VA), Clinical Activity Score (CAS), Gorman Diplopia scores, MMF dosing and side effects at 24, 52 and 78 weeks. Clinical efficacy was defined as an absence of relapse: no decline in best corrected LogMAR VA, no need for further steroids, no increase in CAS of ≥ 2. Results: Out of 23 patients, 20 patients were included in this study. 10% (2/20) stopped MMF before 24 weeks. Median duration of MMF treatment was 76 weeks (1– 140 weeks). 55% (11/20) had dysthyroid optic neuropathy (DON). In those with active moderate-severe TED without DON, clinical efficacy was seen in 100% (8/8) at 24 weeks, 87.5% (7/8) at 52 weeks, and 83.3% (5/6) at 78 weeks, with CAS decreasing from a baseline of 2.78± 1.99 to 0.50± 0.58 at 24 weeks, 0.50± 0.82 at 52 weeks and 1.00± 1.30 at 78 weeks. In DON, improvements were seen in 90% (9/10) at 24 weeks, 100% (7/7) at 52 weeks and 100% (4/4) at 78 weeks, with significantly reduced CAS scores from 2.55± 1.54 to 0.83± 1.27, 1.00± 1.17 and 0.63± 0.95 at 24, 52 and 78 weeks, respectively. Gorman score, VA and soft tissue inflammation parameters also improved throughout. There were two significant side effects over the treatment period. Conclusion: MMF appears to be an effective and safe second-line immunosuppressive agent. Further studies aimed at elucidating optimal dosing regimens and ideal treatment duration will prove helpful. [ABSTRACT FROM AUTHOR]

Purpose: To systematically review the literature on the deep lateral orbital decompression (DLD). Methods: The authors searched the MEDLINE, Lilac, Scopus, and EMBASE databases for all articles in English, Spanish, and French that used as keywords the terms orbital decompression and lateral wall. Two articles in German were also included. Data retrieved included the number of patients and orbits operated, types of the approach employed, exophthalmometric and horizontal eye position changes, and complications. The 95% confidence intervals (CI) of the mean Hertel changes induced by the surgery were calculated from series with 15 or more data. Results: Of the 204 publications initially retrieved, 131 were included. Detailed surgical techniques were analyzed from 59 articles representing 4559 procedures of 2705 patients. In 45.8% of the reports, the orbits were decompressed ab-interno. Ab-externo and rim-off techniques were used in 25.4% and 28.8% of the orbits, respectively. Mean and 95% CI intervals of Hertel changes, pooled from 15 articles, indicate that the effect of the surgery is not related to the technique and ranges from 2.5 to 4.5 mm. The rate of new onset of diplopia varied from zero to 8.6%. Several complications have been reported including dry eye, oscillopsia, temporal howling, lateral rectus damage, and bleeding. Unilateral amaurosis and subdural hematoma have been described in only one patients each. Conclusions: The low rate of new-onset diplopia is the main benefit of DLD. Prospective studies are needed to compare the rate of complications induced by the 3 main surgical techniques used. [ABSTRACT FROM AUTHOR]

Context/objective: The aim of this study was to examine the effect of statins and other lipid-lowering agents on the development of Graves orbitopathy (GO) in patients with newly diagnosed Graves disease (GD).Methods: Our sample included the full adult population of individuals living in Sweden with newly diagnosed GD between 2005 and 2018 (n = 34 894). We compared the GO incidence in statin users (n = 5574) and nonusers (n = 34 409) by applying Cox regression with a time-varying exposure variable. We adjusted for age, sex, and treatment for hyperthyroidism in the multivariate analyses.Results: Periods of nonusage lasted for a median of 4.3 years (interquartile range [IQR] 1.2-8.4), whereas periods of usage lasted for a median of 4.7 years (IQR 2.0-8.1). Among statin users, 77.1% had used simvastatin, 28.9% atorvastatin, and 8.2% had used other statins. Statin users were found to be significantly less likely to develop GO. In the main analysis based on the full cohort, the unadjusted hazard ratio (HR) was 0.74 (CI 0.65-0.84, P < .001), whereas full adjustment altered the effect to 0.87 (CI 0.76-1.00, P = .04). The main results were largely driven by men; the fully adjusted HR was 0.78 (CI 0.58-1.04, P = .09) for men and 0.91 (CI 0.79-1.06, P = .24) for women. Lipid-lowering agents other than statins did not exhibit a similar protective effect.Conclusion: In newly diagnosed patients with GD, treatment with statins may protect against the development of GO. Statins should be investigated in a clinical trial as a preventive treatment for GO in newly diagnosed patients with GD. [ABSTRACT FROM AUTHOR]