Graves' Ophthalmopathy Research Articles

Investigation of Conjunctival Goblet Cell and Tear MUC5AC Protein in Patients With Graves' Ophthalmopathy.

The aim of this study was to investigate conjunctival goblet cell density (GCD) and tear mucin-5AC (MUC5AC) protein levels in patients with Graves' ophthalmopathy (GO) and their association with dry eye indicators. A total of 99 patients with GO (54 active, 45 inactive) and 40 healthy controls were recruited. Comprehensive ophthalmic examinations, including the external eye, ocular surface, GCD, and tear MUC5AC ELISA, were performed. The GCD examination was performed in temporal bulbar conjunctiva, including IVCM GCD by in vivo confocal microscopy (IVCM) and filled GCD of cytokeratin-7 and MUC5AC-positive co-immunomarkers by impression cytology. Tear MUC5AC protein was detected using samples extracted from Schirmer strips. The GO group showed a significant decrease in IVCM GCD, filled GCD, and normalized tear MUC5AC protein compared to controls, with the active GO group showing the greatest decrease (all P<0.05). Tear MUC5AC protein levels in GO correlated with those of IVCM GCD (r = 0.40, P<0.001) and filled GCD (r = 0.54, P<0.001, respectively). Higher ocular surface disease index (r = -0.22, P<0.05; r = -0.20, P<0.05; r = -0.21, P<0.05) and lisamine green staining (r = -0.23, P<0.05; r = -0.38, P<0.001; r = -0.42, P<0.001) were associated with lower tear MUC5AC protein levels, IVCM GCD, and filled GCD, respectively, which decreased with increasing clinical activity score (r = -0.24, P<0.05; r = -0.28, P<0.01; r = -0.27, P<0.01) and conjunctival congestion score (r = -0.27, P<0.01; r = -0.33, P<0.001; r = -0.42, P<0.001). The goblet cell count and tear MUC5AC protein in GO eyes were decreased, possibly due to ocular surface inflammation. This study observed the change of tear film mucin in GO patients.

Serum Lipoprotein(a) Is Not Associated with Graves' Ophthalmopathy.

Aim: To investigate the relationship of serum lipoprotein(a) [Lp(a)] and other serum lipids with presence of Graves' ophthalmopathy (GO). Methods: A total of 99 consecutive patients diagnosed with Graves' disease (GD), aged 18-65 years, who had not received prior treatment for GO, thyroid surgery, or radioactive iodine therapy, were recruited between June 2020 and July 2022. In addition, 56 healthy controls (HCs) were included as the control group. All patients underwent an ophthalmological examination, and were classified based on the presence of GO into the GO group (n = 45) and no GO group (n = 54). Fasting blood samples were collected from all participants to analyze serum lipid parameters, including Lp(a), total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides. Results: The median serum levels of Lp(a) were 5.7 [4.3-9.2] in the GO group, 6.7 [3.7-9.9] in the no GO group, and 4.7 [3-7.6] in the HC group. The intergroup comparisons of serum Lp(a) levels showed no significant result. The serum levels of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides were also similar between the groups (P > 0.05 for all). However, when analyzing only euthyroid GD patients and the control group, the serum LDL cholesterol levels were found to be significantly higher in the euthyroid GO group [median: 132 interquartile range (IQR) (110-148) mg/dL] than in the HCs [median: 96 IQR (94-118) mg/dL] (P = 0.002). Conclusion: The findings of our study did not support the association between serum Lp(a) levels and GO.

TSH receptor autoantibody levels post-total thyroidectomy in Graves’ ophthalmopathy: a meta-analysis

BackgroundTSH receptor autoantibodies (TRAbs) are pathognomonic for Graves’ disease and are thought to also underly the pathogenesis of Graves’ ophthalmopathy (GO). A decline in TRAb levels has been documented post-total thyroidectomy (TTx) in GO, however with conflicting correlations with disease outcomes. The aim of the study was to compare the effectiveness of TTx to other treatment modalities of Graves’ disease and examine whether the lowering of TRAbs is associated with GO improvements.MethodWe searched electronic databases including Medline, Embase, Scopus, and Web of Science until 31 September 2022 using a broad range of keywords. Patients with GO undergoing TTx with measurements of both TRAbs and progression of the disease using a validated GO scoring system were included. Fourteen studies encompassing data from 1047 patients with GO met our eligibility criteria. The PRISMA guidelines were followed, and five studies had comparable data that were suitable for a meta-analysis.ResultsThe Cochrane Risk of Bias tool for RCTs showed low risk of bias across most domains. The pooled odds ratio showed that more patients significantly had normalized TRAb levels post-TTx as compared to other interventions (OR: 1.36, 95% CI: 1.02–1.81, p = 0.035). But, there was no significant difference in GO improvement post-TTx as compared with other intervention groups.ConclusionsThis meta-analysis shows that TRAb levels may decline largely post-TTx, but may not predict added improvements to the progression of GO. Thus, future studies with uniform designs are required to assess the minimal significant GO improvements.

Effects of various extraocular muscle enlargement patterns on muscle diameter index in graves ophthalmopathy patients: a retrospective cohort study

Graves ophthalmopathy (GO) patients often undergo retrobulbar injection of glucocorticoids (GCs) as a common therapeutic approach. This study aimed to explore the impact of various patterns of extraocular muscle (EOM) enlargement on EOM changes following retrobulbar GCs injection in patients with GO. A retrospective analysis was conducted on GO patients who underwent retrobulbar GCs injections. Data pertaining to EOM diameter (EMD) and muscle diameter index (MDI) were collected from orbital computed tomography (CT) scans. The MDI change (ΔMDI) was calculated by comparing pre- and post-injection MDI values. The relationship between each pre EMD/MDI and ΔMDI was assessed using univariate and multivariate logistic regression analysis. A total of 68 patients with GO were included in this study, accounting for 118 eyes. After retrobulbar injections of GCs, 84 eyes showed a decrease in the MDI, while 34 eyes exhibited an increase in MDI. A threshold effect was observed in the relationship between medial pre EMD/MDI and ΔMDI. When the medial pre EMD/MDI was less than 0.28, a higher medial pre EMD/MDI was associated with a smaller ΔMDI (β = − 25.21, p = 0.0175). However, when the medial pre EMD/MDI was greater than 0.28, no significant association was found between pre EMD/MDI and ΔMDI. There was a negative correlation between medial + lateral pre EMD/MDI and ΔMDI (β = − 11.76, p < 0.0189). A higher medial + lateral pre EMD/MDI was associated with a greater decrease in MDI. Additionally, there was a positive correlation between superior rectus muscle-levator complex (SRLC) pre EMD/MDI and ΔMDI (β = 11.92, p = 0.040). The higher the value of SRLC pre EMD/MDI, the greater the ΔMDI. There was an association between pre EMD/MDI and changes in EOMs after retrobulbar injection of GCs in GO patients. In patients with predominantly enlarged medial rectus muscles and severe degrees of enlargement, retrobulbar injection of GCs should be assessed for its benefit; a combination of medial and lateral rectus muscle enlargement is beneficial for the shrinkage of EOMs following retrobulbar injections; the involvement of the SRLC rectus muscle may be a disadvantageous pattern of shrinkage of EOMs following retrobulbar injections.Trial registration This study is retrospectively registered. We have registered this study with the Chinese Clinical Trials Registry (www.chictr.org.cn, registration number: ChiCTR2200063429).

FRI530 Immune-Modulation By Rapamycin, Or Mycophenolic Acid, Of Th1 And Th2 Chemokines Secretion In Retro-orbital Cells Of Patients With Graves’ Ophthalmopathy

Abstract Disclosure: G. Elia: None. F. Ragusa: None. S. Paparo: None. V. Mazzi: None. A. Patrizio: None. P. Fallahi: None. A. Antonelli: None. S. Ferrari: None. Objectives: Cytokines and chemokines contribute to the inflammation of Graves’ ophthalmopathy (GO). Indeed cytokines stimulate the T helper (Th)1 and Th2 chemokines release from orbital cells (fibroblasts, preadipocytes and myocytes).We aim to investigate the effects of rapamycin or mycophenolic acid on the secretion of these chemokines in GO orbital cells. Methods: We obtained primary cultures of fibroblasts, preadipocytes and myoblasts from the orbits of GO patients, and we tested increasing concentrations of rapamycin and/or mycophenolic acid evaluating the secretion of the prototype Th1 [chemokine (C-X-C motif) ligand 10 (CXCL10)] and Th2 [chemokine (C-C motif) ligand 2 (CCL2)] chemokines. Results: We observed that CXCL10 secretion in the retro-orbital cells of GO was undetectable in the supernatants, whereas interferon (IFN)-gamma induce its release in a dose-dependently manner. No effect was observed under the tumor necrosis factor (TNF)-alpha stimuli, while the combination of both cytokines had a significant synergistic effect on CXCL10 secretion. As regards the effect on the CCL2 secretion, it was released in low amounts in basal condition; TNF-alpha dose-dependently induced its release, whereas IFN-gamma alone had no effect. The combination of TNF-alpha plus IFN-gamma had a significant synergistic effect on CCL2 secretion. By adding mycophenolic acid, or rapamycin, (in a pharmacological range) at the time of IFN-gamma and TNF-alpha stimulation, we observed a dose-dependently inhibitory effect on the chemokines release in the retro-orbital cells of GO. Furthermore, the combination of mycophenolic acid with rapamycin, have a synergistic inhibitory effect on the release of chemokines. Conclusion: Our data showed an immune-modulating effect of mycophenolic acid or rapamycin on the Th1 and Th2 chemokines secretion, in GO orbital cells. These findings suggest the therapeutic role of these drugs that could obtained, at least in part, through this mechanism. Presentation: Friday, June 16, 2023

THU670 Serum TSI Concentration In Patients With Graves’ Disease Undergoing Maintenance-dose Of Antithyroid Drug (ATD) And Its Relationship With Disease Relapse After ATD Withdrawal

Abstract Disclosure: P.V. Nguyen: None. K.T. Nguyen: None. Background: Graves' disease (GD) is an autoimmune disorder in which thyroid-stimulating immunoglobulin (TSI) plays a key role in its pathogenesis. TSI assays have been recently optimized in their accuracy, and the procedure has also been simplified, which can potentially replace TRAb measured by conventional TSH-binding inhibitory immunoglobulins (TBII) assays in routine clinical practice. Objectives: Our objective was to study the serum TSI concentration in patients with Graves’ disease undergoing maintenance-dose ATD. We also aimed to assess the predictive value of TSI immunoassay, as well as the clinical signs and thyroid function tests in predicting Graves’ disease relapse following ATD discontinuation. Finally, follow-up would be continued to check for relapse or long term euthyroid status. Methods: Retrospective follow-up study of 352 patients with hyperthyroidism due to GD, treated at the endocrine outpatient clinic of Medic Medical Center, Ho Chi Minh City from January 2000 to April 2021. TSI was measured several times during the course of treatment when planning to stop the medication (at the discretion of the attending physician). ATD withdrawal would be considered when the patients achieved clinical euthyroidism with normal FT4 tests for at least 3 months with minimal dose of ATD. The decision to withdraw ATD was also based on TSI concentration, as well as the goiter’s characteristics and parenchymal vascularity observed via thyroid Doppler ultrasound. Results: The median TSI concentration of patients with GD undergoing maintenance-dose ATD was 1.45 IU/L (normal range &amp;lt;0.10 IU/L), and their thyroid function measured at the same time tended to be euthyroid in our study. TSI cut-off level at ATD withdrawal to predict the recurrence of GD was 1.31 IU/L which corresponded with the sensitivity, specificity, positive and negative predictive values of 63.64%, 78,79%, 50% and 86.67%, respectively. Multiple logistic regression analysis showed that the following factors were associated with an increased risk of relapse after the end of medical treatment: Graves' ophthalmopathy (GO), OR 3.69 (95% CI: 1.06-12.87; p=0.04), treatment duration less than 18 months, OR 7.77 (95% CI: 1.92-31.42; p&amp;lt;0.01), TSI level before ATD withdrawal ≥1.31 IU/L, OR 9.92 (95% CI: 2.77-35.42; p&amp;lt;0.01). Conclusion: At the time of ATD withdrawal, while normal FT4 levels were observed, high TSI levels were indicative of an ongoing immune process. These findings suggest that TSI measurements, in addition to clinical and ultrasound evaluations, may aid in the prediction of GD relapse after ATD discontinuation. In addition, GO, treatment duration of less than 18 months and TSI level before ATD withdrawal ≥1.31 IU/L were associated with an increased risk of relapse of GD after ATD discontinuation. Our study contributes to the expanding literature supporting the clinical utility of TSI assay in the management of GD. Presentation: Thursday, June 15, 2023

FRI563 Subacute Thyroiditis Is An Uncommon Cause Of Pyrexia Of Unknown Origin

Abstract Disclosure: N. Luke: None. D. Tay: None. Introduction: Subacute thyroiditis is a rare self-limiting inflammatory thyroid disorder often follows a viral infection. It is a diagnosis that is made clinically when patients present with typical features of anterior neck pain and thyrotoxic symptoms. We share our experience in unraveling a diagnostic challenge of a patient with an atypical presentation of subacute thyroiditis presenting with pyrexia of unknown origin during the Covid 19 pandemic. Clinical case: A 29 years old previously healthy Burmese domestic helper was admitted to a hospital in Singapore for persistent fever of 2 weeks duration associated with persistent sore throat. She had a brief 3 days duration of cough at the onset of fever with no other localizing infective symptoms. She had a booster dose of COVID 19 Moderna vaccination 6 months prior to her presentation with 2 preceding doses of Pfizer-BioNtech vaccine 12 months prior. She was empirically treated for acute pharyngitis with a course of intravenous antibiotics without improvement of her fever. Extensive workup for the fever was performed. A complete blood count showed monocytosis. Blood and urine cultures, urinalysis, COVID polymerase chain reaction (PCR), CMV, EBV, and HIV testing were negative. Respiratory multiplex PCR was negative for adenovirus, coronavirus, influenza, parainfluenza, respiratory syncytial virus, metapneumovirus, rhinovirus, chlamydia, mycoplasma, and Bordetella. CT of the thorax, abdomen, and pelvis was normal. She denied heat intolerance, weight loss, diarrhea, palpitations, or hand tremors. Clinical examination revealed mild anterior neck tenderness but no thyrotoxic features. There were no signs of Graves ophthalmopathy or pre-tibial myxoedema. Thyroid function tests were performed in view of persistent tachycardia which showed elevated free T4 at 51.6 pmol/L (12.7-20.3) with suppressed TSH &amp;lt;0.005 mIU/L (0.3-4.2). TSH receptor stimulating antibody levels (TRab) was elevated at 5.23IU/L (&amp;lt;1.76) and ESR was markedly elevated (115 mm/hr). Thyroid ultrasound showed homogeneous thyroid echotexture with no discrete suspicious nodules or abnormal vascularity. She was started on non-steroidal anti-inflammatory drug (Etoricoxib) with resolution of her fever and neck pain Clinical lesson: Clinicians should be aware that subacute thyroiditis can be a rare cause of pyrexia of unknown origin even in the absence of typical features. Presentation: Friday, June 16, 2023

Eye Muscle MRI in Myasthenia Gravis and Other Neuromuscular Disorders.

MRI of extra-ocular muscles (EOM) in patients with myasthenia gravis (MG) could aid in diagnosis and provide insights in therapy-resistant ophthalmoplegia. We used quantitative MRI to study the EOM in MG, healthy and disease controls, including Graves' ophthalmopathy (GO), oculopharyngeal muscular dystrophy (OPMD) and chronic progressive external ophthalmoplegia (CPEO). Twenty recently diagnosed MG (59±19yrs), nineteen chronic MG (51±16yrs), fourteen seronegative MG (57±9yrs) and sixteen healthy controls (54±13yrs) were included. Six CPEO (49±14yrs), OPMD (62±10yrs) and GO patients (44±12yrs) served as disease controls. We quantified muscle fat fraction (FF), T2water and volume. Eye ductions and gaze deviations were assessed by synoptophore and Hess-charting. Chronic, but not recent onset, MG patients showed volume increases (e.g. superior rectus and levator palpebrae [SR+LPS] 985±155 mm3 compared to 884±269 mm3 for healthy controls, p < 0.05). As expected, in CPEO volume was decreased (e.g. SR+LPS 602±193 mm3, p < 0.0001), and in GO volume was increased (e.g. SR+LPS 1419±457 mm3, p < 0.0001). FF was increased in chronic MG (e.g. medial rectus increased 0.017, p < 0.05). In CPEO and OPMD the FF was more severely increased. The severity of ophthalmoplegia did not correlate with EOM volume in MG, but did in CPEO and OPMD. No differences in T2water were found. We observed small increases in EOM volume and FF in chronic MG compared to healthy controls. Surprisingly, we found no atrophy in MG, even in patients with long-term ophthalmoplegia. This implies that even long-term ophthalmoplegia in MG does not lead to secondary structural myopathic changes precluding functional recovery.

Finding the Common Single-Nucleotide Polymorphisms in Three Autoimmune Diseases and Exploring Their Bio-Function by Using a Reporter Assay.

In clinical practice, it is found that autoimmune thyroid disease often additionally occurs with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). In addition, several studies showed that eye-specific autoimmune diseases may have a strong relationship with systemic autoimmune diseases. We focused on Graves' disease (GD) with ocular conditions, also known as Graves' ophthalmopathy (GO), trying to find out the potential genetic background related to GO, RA, and SLE. There were 40 GO cases and 40 healthy controls enrolled in this study. The association between single-nucleotide polymorphisms (SNPs) of the co-stimulatory molecule genes and GO was analyzed using a chi-square test. It showed that rs11571315, rs733618, rs4553808, rs11571316, rs16840252, and rs11571319 of CTLA4, rs3181098 of CD28, rs36084323 and rs10204525 of PDCD1, and rs11889352 and rs4675379 of ICOS were significantly associated with GO based on genotype analysis and/or allele analysis (p < 0.05). After summarizing the GO data and the previously published SLE and RA data, it was found that rs11571315, rs733618, rs4553808, rs16840252, rs11571319, and rs36084323 were shared in these three diseases. Furthermore, the bio-function was confirmed by dual-luciferase reporter assay. It was shown that rs733618 T > C and rs4553808 A > G significantly decreased the transcriptional activity (both p < 0.001). This study is the first to confirm that these three diseases share genetically predisposing factors, and our results support the proposal that rs733618 T > C and rs4553808 A > G have bio-functional effects on the transcriptional activity of the CTLA4 gene.

Thyroid hormones and minerals in immunocorrection of disorders in autoimmune thyroid diseases.

Thyroid hormones and essential elements iodine (I), selenium (Se), iron (Fe), copper (Cu), zinc (Zn), calcium (Ca), magnesium (Mg), etc. play an important role in the work of many organs and systems of the body, including the immune system and the thyroid gland, and a violation of their supply can be the cause of pathological changes in them. In pathology, the interaction between thyroid hormones (TG), minerals and the immune system is disturbed. The review of the literature examines the immunomodulatory role of TG, minerals, their properties, and their participation in the pathogenesis of autoimmune thyroid diseases (AITD). The study of the relationship between the excess or deficiency of minerals and AITD is described. The basis of the development of AITD - Hashimoto's thyroiditis (HT), Graves' disease (GD), Graves' ophthalmopathy (GO) is the loss of immune tolerance to thyroid antigens - thyroid peroxidase (TPO), thyroglobulin (Tg) and thyroid-stimulating hormone receptor (TSH-R). Immune-mediated mechanisms - production of autoantibodies to thyroid antigens and lymphocytic thyroid infiltration - are involved in the pathogenesis of AITD. Insufficiency of regulatory T cells (Treg) and regulatory B cells (Breg), imbalance between Th17-lymphocytes and Treg-lymphocytes, abnormal production of pro-inflammatory cytokines has a significant influence on the progression of AITD. With AITD, the balance between oxidants and antioxidants is disturbed and oxidative stress (OS) occurs. The lack of modern effective pharmacological therapy of AITD prompted us to consider the mechanisms of influence, possibilities of immunocorrection of pathogenetic factors using TG, micro/macronutrients. In order to develop a more effective treatment strategy, as well as approaches to prevention, a critical analysis of the ways of immunotherapeutic use of dietary supplements of I, Se, Zn, Mg and other minerals in AITD was carried out.

Construction of predictive ceRNA network and identification of the patterns of immune cells infiltrated in Graves' ophthalmopathy.

Graves' ophthalmopathy (GO) is a multifactorial disease, and the mechanism of non coding RNA interactions and inflammatory cell infiltration patterns are not fully understood. This study aims to construct a competing endogenous RNA (ceRNA) network for this disease and clarify the infiltration patterns of inflammatory cells in orbital tissue to further explore the pathogenesis of GO. The differentially expressed genes were identified using the GEO2R analysis tool. The Kyoto encyclopedia of genes and genomes (KEGG) and gene ontology analysis were used to analyze differential genes. RNA interaction relationships were extracted from the RNA interactome database. Protein-protein interactions were identified using the STRING database and were visualized using Cytoscape. StarBase, miRcode, and DIANA-LncBase Experimental v.2 were used to construct ceRNA networks together with their interacted non-coding RNA. The CIBERSORT algorithm was used to detect the patterns of infiltrating immune cells in GO using R software. A total of 114 differentially expressed genes for GO and 121 pathways were detected using both the KEGG and gene ontology enrichment analysis. Four hub genes (SRSF6, DDX5, HNRNPC,and HNRNPM) were extracted from protein-protein interaction using cytoHubba in Cytoscape, 104 nodes and 142 edges were extracted, and a ceRNA network was identified (MALAT1-MIR21-DDX5). The results of immune cell analysis showed that in GO, the proportions of CD8+ T cells and CD4+ memory resting T cells were upregulated and downregulated, respectively. The proportion of CD4 memory resting T cells was positively correlated with the expression of MALAT1, MIR21, and DDX5. This study has constructed a ceRNA regulatory network (MALAT1-MIR21-DDX5) in GO orbital tissue, clarifying the downregulation of the proportion of CD4+ stationary memory T cells and their positive regulatory relationship with ceRNA components, further revealing the pathogenesis of GO.

Commentary on the role of berberine in addition to methimazole compare to methimazole alone in the treatment of Graves’ Diseas

Graves’ Disease (GD) is the most common form of hyperthyroidism. It affects 3% of female patients and 0.5% of male patients usually between the age of 30-60. It is the cause of 80% of hyperthyroid cases in the USA. The pathogenesis of the disease is complex and autoimmunity plays a key role. The antibodies stimulating the thyrotropin receptor (TRAb) lead to uncontrolled Thyroid-stimulating Hormone (TSH) overproduction of thyroid hormones from the overactive thyroid gland. The disease is frequently associated with Graves's ophthalmopathy, dermatopathy, and clubbing. It affects the whole body with deleterious effects on the Cardiovascular system, vision, bones, etc. The treatment of the disease is with anti-thyroid medications, Radioactive iodine, or thyroid surgery each one of which has its pluses and minuses. Other factors like Genetic, inflammatory, immune, environmental factors, etc. play critical roles in disease pathogenesis as well. In this article, we are discussing the newfound role of the gut-thyroid axis in the pathogenesis of GD. We are describing the role of the probiotic Berberine added to the anti-thyroid medication Methimazole in changing the gut microbiota by increasing the benefits and decreasing the deleterious bacteria in the gut. This can lead to the induction of anti-inflammatory cytokines and reduction of inflammatory ones which can regulate the immune system faster and better than with treatment with Methimazole alone. This treatment combination can eventually lead through the effect on the gut-thyroid axis to faster disappearance of the TRAb and remission and cure of GD.

A novel method of measuring proptosis with computed tomography.

Computed tomography (CT) can avoid interference factors and has been imported into some software to measure proptosis clinically as the golden standard. To establish a new method for semi-automatically measuring the proptosis on CT and evaluate its accuracy and reproducibility. A total of 50 orbital CT images were collected of healthy individuals, 25 patients with Graves ophthalmopathy (GO), and 25 patients with orbital fracture (OF). A new image processing software, MedrawHDC, was developed to semi-automatically measure the proptosis (MedrawHDC method). The classic radiological (CR) method (measuring proptosis with the software called Mimics) and MedrawHDC method were applied in all three groups (measured by observer S). Hertel's exophthalmometer (HE) method was also applied in the GO group. Moreover, two other observers were asked to measure the proptosis using MedrawHDC, to evaluate its reproducibility. The MedrawHDC method was highly consistent with the CR method in measuring proptosis (normal group: intraclass correlation coefficient [ICC] = 0.989; GO group: ICC = 0.979; OF group: ICC = 0.979). In the GO group, the value of proptosis measured by two radiological methods were consistent with that measured by the HE method (CR method: ICC = 0.703; MedrawHDC method: ICC = 0.697). Bland-Altman plots showed similar results. The measurements obtained by three observers were highly reproducible (ICC = 0.995). The newly established MedrawHDC method, with high accessibility, convenience, and repeatability, is reliable in assessing proptosis. It shows high potential for wide application, having clinical value for scientific evaluation of proptosis.

Quantitative assessment of extraocular muscles in Graves' ophthalmopathy using T1 mapping.

To evaluate the performance of T1 mapping in the characterization of extraocular muscles (EOMs) of Graves' ophthalmopathy (GO) patients and investigate its feasibility in assessing the response to glucocorticoid therapy in active GO patients. A total of 133 participants (78 active GO, 23 inactive GO, 18 Graves' disease (GD) patients, and 14 healthy volunteers) were consecutively enrolled from July 2018 to December 2020. Native T1 (nT1) and postcontrast T1 (cT1) values of EOMs were measured and compared. The variations in T1 mapping metrics of EOMs were compared pre/post glucocorticoid treatment in 23 follow-up active GO patients. Logistic regression analysis and receiver operating characteristic (ROC) curve analysis were performed. The nT1 of EOMs in GO patients was higher than that in GD patients and healthy volunteers. The nT1 of superior rectus (SR) in active GO was higher than that in inactive GO patients, and it could be used as a potential marker of GO activity (OR: 1.003; 95% CI: 1.001, 1.004), with a diagnostic sensitivity of 86.3% and specificity of 43.7%. Meanwhile, the cT1 of SR, inferior rectus (IR), and medial rectus (MR) in inactive GO patients were higher than those in active GO patients. The nT1 of EOMs achieved sufficient diagnostic performance in evaluating the response to glucocorticoid therapy for follow-up active GO patients (AUC, 0.797; sensitivity, 71.9%; specificity, 85.7%). T1 mapping could quantitatively assess the activity of GO and the response to glucocorticoid therapy in active GO patients and may even potentially reflect the fibrosis of EOMs. T1 values can reflect the pathological status of the extraocular muscle. T1 mapping could help to quantitatively assess the clinical activity of GO and the response to glucocorticoid therapy in active GO patients. • Graves' ophthalmopathy patients had greater nT1 of extraocular muscles than Graves' disease patients and healthy volunteers, and nT1 of the superior rectus could be a potential marker of Graves' ophthalmopathy activity. • The cT1 of extraocular muscles in inactive Graves' ophthalmopathy patients was higher than that in active Graves' ophthalmopathy patients, and it might be associated with muscle fibrosis. • nT1 of extraocular muscles could offer sufficient diagnostic performance in evaluating the response to glucocorticoid therapy for follow-up active Graves' ophthalmopathy patients.

Osteopathic manipulative treatment in improving symptoms and quality of life in patients with Graves’ ophthalmopathy: A case report

BackgroundGraves' Disease (GD) is an autoimmune disorder, with ∼50% of GD patients developing Graves’ Ophthalmopathy (GO). Common presentations include lid retraction, exophthalmos, disfigurement, ocular pain, and pressure. Treatment of GD depends on disease severity, ranging from artificial tears to ocular surgeries. Patients with GO symptoms experience a decreased quality of life (QoL) and could benefit from additional treatment options. ObjectiveThis case report describes the use of osteopathic manipulative treatment (OMT) as an adjunct to standard care for a patient with symptomatic GO, and measurement of treatment response with a standardized QoL assessment tool. Clinical featuresClinical evaluation of a patient with GO showed clinical activity score to be 4 with oppressive feeling behind globes, hyperemia, and eyelid edema. Corneal displacement measured by Hertel exophthalmometer indicated increased proptosis. CT scan showed enlarged extraocular muscles bilaterally, with signs of edema in retrobulbar fat. Visual acuity and optic nerves were within normal limits. Intervention and outcomesThis case report demonstrates the use of OMT in long-term reduction of ocular pain and pressure by relieving orbital myofascial tension along with improving ocular circulation, in a patient with GO. Using the European Group On Graves’ Orbitopathy QoL questionnaire, the patient noted better quality of life (93, 81.3 for pretreatment visual and appearance scores, respectively, and 100, 87.5 for post-treatment visual and appearance scores, respectively) and perceived reduced exophthalmos. ConclusionsProviding OMT as a cost effective, non-invasive treatment option for GO symptoms could meet a significant need for GO patients and warrants further study.

Optical coherence tomography angiography findings in pediatric patients with graves ophthalmopathy.

The aim of this study was to evaluate peripapillary, macular microvascular structure, and retinal nerve fiber layer (RNFL) thickness profile in children with Graves Ophthalmopathy (GO). Thirty-six eyes of 18 children with GO were prospectively compared with 40 eyes of 20-age and sex-matched controls. The severity and activity of the disease were evaluated according to the criteria of the European Group on Graves' Ophthalmopathy (EUGOGO) and Clinical Activity Score (CAS). After complete ophthalmologic and endocrinologic examination, all patients underwent optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) measurements. Retinal nerve fiber layer (RNFL) thickness, macular superficial capillary plexus (SCP), deep capillary plexus (DCP), foveal avascular zone (FAZ) area, acircularity index (AI) of the FAZ and peripapillary microvascular structure were analyzed. The mean age was 12.1 ± 2.4years in the GO group and 11.2 ± 2.6years in healthy control group (p = 0.11). Duration of disease was 8.9 ± 4.2months in the GO group. All patients in GO group had mild and inactive ophthalmopathy. In temporal inferior quadrant, RNFL thickness was significantly thinner in the GO group compared to the control group (p = 0.03). No significant difference was seen between groups both peripapillary and macular microvascular structure (all p > 0.05). GO has no effect on optic nerve thickness, peripapillary and macular vascular parameters except inferior temporal RNFL in children.

Association between high mobility group box-1 circulation level and Graves' ophthalmopathy

Background: Graves' disease is a prevalent autoimmune disorder that causes hyperthyroidism. Despite being widely recognized, the risk factors for its associated condition, ophthalmopathy, are not well understood. High Mobility Group Box 1 (HMGB1), a damage-associated molecular pattern biomarker, has been linked to autoimmune diseases and may play a role in Graves' ophthalmopathy. The aim of this study is to assess the correlation between the levels of circulating HMGB1 and the occurrence of Graves' ophthalmopathy (GO). Methods: This cross-sectional study evaluated 44 recently diagnosed Graves' disease patients at Sardjito Hospital. The presence of Graves' ophthalmopathy (GO) was determined using criteria set by Bartley and Gormans. The levels of HMGB1 were measured in the blood of both groups (22 GO patients and 22 controls without GO) using ELISA. Statistical analysis, including binomial logistic regression and Mann-Whitney test, was conducted to analyze the data and adjust for confounding factors with multinomial logistic regression. Results: The baseline characteristics of 22 GO patients and 22 non-GO patients were similar, including age (30.91±6.06 vs. 30.68±6.63 years, p&gt;0.05), gender distribution (77.3% vs. 81.8% female, 22.7% vs. 18.2% male, p&gt;0.05), and duration of diagnosis (5.13±2.21 vs. 4.82±1.89 months, p&gt;0.05). However, a significant difference (p&lt;0.001) was found in the levels of circulating HMGB1, with GO patients having a median value of 15.49 pg/mL (5.12-47.59 pg/mL) compared to 2.33 pg/mL (0.82-15.66 pg/mL) in the control group. The risk of developing ophthalmopathy increased 12 times when Graves disease patients had HMGB1 levels above 8.86 pg/mL. Conclusion: The study found a significant association between elevated levels of HMGB1 (&gt; 8.86 pg/mL) and an increased risk (12 times) of Graves’ ophthalmopathy in newly diagnosed Graves' disease patients. The results suggest that HMGB1 may be a potential biomarker for predicting the development of ophthalmopathy in Graves' disease patients.

Establishment and Comparison of Two Different Animal Models of Graves' Orbitopathy.

The purpose of this study was to construct an animal model of Graves' ophthalmopathy (GO) by comparing recombinant adenovirus expressing human thyrotropin receptor A subunit (Ad-TSHR A) gene immunization and dendritic cell (DC) immunization. We evaluated the animal models that are closer to the pathology of human GO, and laid the foundation for the study of GO. Ad-TSHR A was injected intramuscularly into female BALB/c mice to induce the GO animal model. A GO animal model was constructed using TSHR combined with IFN-γ-modified primary DC immunized female BALB/c. The animal models constructed by the above two methods were evaluated in terms of ocular appearance, serology, pathology, and imaging to assess the modeling rate of the animal models, respectively. Both modeled mice exhibited increased serological indexes of free thyroxine (FT4) and TSH receptor antibodies (TRAbs) levels and decreased TSH (P < 0.01). Thyroid pathology analysis revealed the number of thyroid follicles increases, the size varies, and the follicular epithelial cells proliferate to varying degrees in a cuboidal or tall columnar pattern, with a small amount of lymphocytic infiltration visible. Adipose tissue behind the eyeball was accumulated, the muscle outside the eyeball was broken and fibrotic, and hyaluronic acid (HA) behind the eyeball was increased. The animal model of GO constructed by immunization of TSHR with IFN-γ-modified DC had a modeling rate of 60%, whereas that of Ad-TSHR A gene immunization was 72%. Both gene immunization and cellular immunization can be used to construct GO models, and the modeling rate of gene immunization is higher than that of cellular immunization. In this study, two innovative methods, cellular immunity and gene immunity, were used to establish GO animal models, which improved the success rate to a certain extent. To our knowledge, this study presents the first cellular immunity modeling idea of TSHR combined with IFN-γ for the GO animal model, which provides an animal model basis for understanding the pathogenesis of GO and developing new treatment methods.

Increased plasma levels of soluble programmed death ligand 1 (sPD-L1) and fibroblast growth factor 23 (FGF-23) in patients with Graves’ ophthalmopathy in comparison to hyperthyroid patients without Graves’ ophthalmopathy

BackgroundManagement of Graves’ ophthalmopathy (GO) is still a challenge in Graves’ disease (GD). Moreover, 40% of GD patients show radiological muscle enlargement without clinically apparent GO. Delayed treatment of GO may lead to deterioration in prognosis. MethodsThirty GD patients with overt hyperthyroidism were included in this study, 17 of whom either had GO at diagnosis or developed GO during the study period. Samples were collected at the beginning of the study, at 6 months, and at 24 months. Plasma samples were analyzed for 92 cytokines using the Olink Target 96 inflammation panel. ResultsAfter adjustment for multiplicity testing using the false discovery rate approach, soluble programmed death ligand 1 (sPD-L1) and fibroblast growth factor 23 (FGF-23) were significantly elevated in GO patients. ConclusionUsing a broad cytokine panel we show that patients with Graves’ ophthalmopathy have elevated PD-L1 and FGF-23 levels. The findings support previous suggestions that PD-L1 may serve as a treatment target.

Efficacy and Safety of intravenous monoclonal antibodies in patients with moderate-to-severe active Graves'ophthalmopathy: a systematic review and meta-analysis.

The effects of various treatments on Graves' ophthalmopathy (GO) have been studied. As monoclonal antibodies (mAbs) have been proposed for the treatment of moderate to severe GO, direct comparisons between different mAbs are lacking.We therefore conducted this meta-analysis to objectively compare the efficacy and safety of intravenous mAbs. To identify eligible trials, references published before September 2022 were electronically searched in PubMed, Web of Science, Pubmed, Embase,Cochrane Library, CBM, CNKI,Wan-Fang and ICTRP databases.The Newcastle-Ottawa scale (NOS) and the Cochrane Risk of Bias Assessment Tool were used to assess the risk of bias of the original studies.The primary and secondary outcomes were the response and inactivation rates, with the secondary outcomes being the clinical activity score (CAS),the improvement of proptosis and diplopia improvement,and the adverse event rate. Publication bias was evaluated, along with subgroup and sensitivity analyses. A total of 12 trials with 448 patients were included. The meta-analysis showed that TCZ (tocilizumab) was most likely to be the best treatment in terms of response according to indirect contrast, followed by TMB (teprotumumab) and RTX (rituximab).TCZ, followed by TMB and RTX, was also most likely to be the best treatment in terms of reducing proptosis. In terms of improving diplopia, TMB was most likely to be the best treatment, followed by TCZ and RTX.TCZ was the highest probability of safety, followed by RTX and TMB. Based on the best available evidence,TCZ should be the preferred treatment for moderate to severe GO.In the absence of head-to-head trials,indirect comparisons of treatments are routinely used to estimate the effectiveness of the treatments of interest. In addition,the optimal dose and potential mechanism of action of monoclonal antibodies remain to be established,and it is encouraging that the treatment paradigm for GO may change in the future.This study was designed in accordance with the Preferred Reporting Items for conducting Systematic Reviews and Meta-Analyses (PRISMA)(27). http://www.crd.york.ac.uk/prospero, identifier CRD42023398170.