Interaction of MMP-9 in the active phase of Graves' disease with and without ophthalmopathy.

Thyroid eye disease (TED) is expressed as orbital inflammation, and serum levels of several proinflammatory cytokines have been studied among patients with Graves' disease (GD) with and without TED; however, a more sensitive and specific marker for the different phases of GD and TED is still lacking. Seventeen active TED, 16 inactive TED, 16 GD without TED, and 16 healthy controls were recruited. Serum IL-17A, MMP-2, MMP-3, and MMP-9 were measured by multiplex bead assay. TED hormone and eye parameters were evaluated, and their relationship with cytokine levels was analyzed. Serum MMP-9 was higher in active TED than healthy controls, whereas IL-17A was lower among these patients than in GD without TED and healthy controls. No differences were found in MMP-3 and MMP-2 concentrations. MMP-9 levels were lower in patients with inactive TED who underwent radioactive iodine (RAI) therapy and those on levothyroxine replacement. MMP-9 levels were elevated in patients on methimazole. A negative correlation was found between age at assessment and time of follow-up with MMP-9 levels in inactive TED. Free T3 and ophthalmometry values were positively correlated with MMP-9 in the GD without TED and inactive TED groups, respectively. In conclusion, serum MMP-9 was increased in patients with active TED and was related to the RAI treatment, longer follow-up time, and higher ophthalmometry in patients with inactive TED, as well as thyroid function in GD without TED. MMP-9 may be involved in both the active phase of TED and the active phase of inflammation related to GD.NEW & NOTEWORTHY Our study addresses clinical aspects of specific ophthalmological examination and serum cytokine concentrations of patients with Graves' disease (GD) with and without ophthalmopathy. Our findings suggest that MMP-9 may be involved in the active phase of ophthalmopathy and in the active phase of GD. The central question is whether MMP-9 is a potential target for future treatments.

The insular cortex is not insular in thyroid eye disease: neuroimaging revelations of central-peripheral system interaction.

BACKGROUND: Thyroid eye disease (TED) is highly correlated with dysregulated immunoendocrine status. The insular cortex was found to regulate peripheral inflammation and immunomodulation in mice. This study aimed to explore whether the insular cortex in patients with TED played a modulatory role including the aberrant brain functional alteration and its association with immunoendocrine status. METHODS: This study included 34 active patients (AP), 30 inactive patients (IP) with TED, and 45 healthy controls (HC) matched for age, sex, and educational level. Comprehensive clinical details (especially immunoendocrine markers) and resting-state functional magnetic resonance imaging data were collected from each participant. The amplitude of low-frequency fluctuation (ALFF) was used to probe the aberrant alterations of local neural activity. The seed-based functional connectivity (FC) analysis was used to explore the relationship between the insular cortex and each voxel throughout the whole brain. The correlation analysis was conducted to assess the association between insular neurobiomarkers and immunoendocrine parameters. RESULTS: When compared with the IP and HC groups, the AP group displayed significantly higher ALFF values in the right insular cortex (INS.R) and lower FC values between the INS.R and the bilateral cerebellum. None of the neurobiomarkers differed between the IP and HC groups. Besides, correlations between insular neurobiomarkers and immunoendocrine markers (free thyroxine, the proportion of T cells, and natural killer cells) were identified in both AP and IP groups. CONCLUSIONS: This study was novel in reporting that the dysregulation of the insular cortex activity in TED was associated with abnormal peripheral immunoendocrine status. The insular cortex might play a key role in central-peripheral system interaction in TED. Further research is crucial to enhance our understanding of the central-peripheral system interaction mechanisms involved in autoimmune diseases.

Whole-orbit radiomics: machine learning-based multi- and fused- region radiomics signatures for intravenous glucocorticoid response prediction in thyroid eye disease.

BACKGROUND: Radiomics analysis of orbital magnetic resonance imaging (MRI) shows preliminary potential for intravenous glucocorticoid (IVGC) response prediction of thyroid eye disease (TED). The current region of interest segmentation contains only a single organ as extraocular muscles (EOMs). It would be of great value to consider all orbital soft tissues and construct a better prediction model. METHODS: In this retrospective study, we enrolled 127 patients with TED that received 4·5 g IVGC therapy and had complete follow-up examinations. Pre-treatment orbital T2-weighted imaging (T2WI) was acquired for all subjects. Using multi-organ segmentation (MOS) strategy, we contoured the EOMs, lacrimal gland (LG), orbital fat (OF), and optic nerve (ON), respectively. By fused-organ segmentation (FOS), we contoured the aforementioned structures as a cohesive unit. Whole-orbit radiomics (WOR) models consisting of a multi-regional radiomics (MRR) model and a fused-regional radiomics (FRR) model were further constructed using six machine learning (ML) algorithms. RESULTS: The support vector machine (SVM) classifier had the best performance on the MRR model (AUC = 0·961). The MRR model outperformed the single-regional radiomics (SRR) models (highest AUC = 0·766, XGBoost on EOMs, or LR on OF) and conventional semiquantitative imaging model (highest AUC = 0·760, NaiveBayes). The application of different ML algorithms for the comparison between the MRR model and the FRR model (highest AUC = 0·916, LR) led to different conclusions. CONCLUSIONS: The WOR models achieved a satisfactory result in IVGC response prediction of TED. It would be beneficial to include more orbital structures and implement ML algorithms while constructing radiomics models. The selection of separate or overall segmentation of orbital soft tissues has not yet attained its final optimal result.

Risk of non-thyroidal autoimmune diseases in patients with Graves' disease: a nationwide retrospective cohort study.

OBJECTIVE: Graves' disease (GD) is a major autoimmune thyroid disorder and associated with non-thyroidal autoimmune disease (NTAD). We aimed to investigate the risk of NTAD in patients with GD compared with age- and sex-matched controls and to evaluate whether the risk differs between individuals with or without Graves' ophthalmopathy (GO). METHODS: This was a retrospective cohort study using data from the Korean National Health Claims database. We included 77 401 patients with GD (2,310 with GO) and 77 401 age- and sex-matched controls. Risk of NTAD were compared between the entire cohort and within the GD cohort. RESULTS: During a mean follow-up period of 9 years, NTAD developed in 12 341 (16.1%) patients in the GD cohort. Risk for systemic lupus erythematosus (SLE) [adjusted hazard ratio (aHR):1.15, 95% confidence interval (CI): 1.02-1.29], vitiligo (aHR: 1.24, 95% CI: 1.10-1.40), and alopecia areata (aHR: 1.11, 95% CI: 1.10-1.40) were higher in the GD cohort than in the control cohort. In the GD cohort, risk for SLE (aHR: 1.60, 95% CI: 1.11-2.33), Sjogren's syndrome (aHR: 1.89, 95% CI: 1.30-2.74), and ankylosing spondylitis (aHR: 1.53, 95% CI: 1.08-2.17) were higher in the GO group than in the non-GO group. CONCLUSION: This study demonstrated an increased risk of SLE, vitiligo and alopecia areata in patient with GD. In the GD cohort, patients with GO had an increased risk of SLE, Sjogren's syndrome and ankylosing spondylitis. These findings suggest that importance of implementing a strategy for early detection of NTAD based on the presence of GO.

Frequency and Patterns of Hearing Dysfunction in Patients Treated with Teprotumumab.

PURPOSE: To better characterize the frequency and patterns of hearing dysfunction in patients who have received teprotumumab to treat thyroid eye disease. DESIGN: Noncomparative case series. PARTICIPANTS: Patients who underwent audiology testing before and after completion of teprotumumab infusions. METHODS: A review of patients who underwent audiology testing before and after completion of teprotumumab infusions was carried out. Additional audiogram testing during treatment was included when available. Hearing function was analyzed using audiogram data measuring threshold hearing levels at specific frequencies. Basic demographic data as well as information regarding otologic symptoms also were obtained and analyzed. MAIN OUTCOME MEASURES: Hearing loss demonstrated by a significant change in decibel hearing thresholds or that meets criteria for ototoxicity. RESULTS: Twenty-two patients (44 ears) were included in the study, with baseline and most recent audiology testing after treatment ranging from 84 days before to 496 days after treatment. Fifteen patients (30 ears) also underwent testing during treatment starting after the second infusion up until the day of, but before, the eighth infusion. Hearing loss after treatment met criteria for ototoxicity in 17 of the 44 ears (38.6%), with 11 of the 22 patients (50.0%) meeting criteria in at least 1 ear. The pure-tone average decibel hearing levels (HLs) across all 44 ears demonstrated hearing loss after treatment (P = 0.0029), specifically at high (P = 0.0008) and middle frequencies (P = 0.0042), but not at low frequencies (P = 0.8344). Patients who were older also were more likely to experience hearing loss after treatment (P = 0.0048). CONCLUSIONS: Audiometric data demonstrate that teprotumumab influences hearing function, most significantly at higher frequencies and in older patients. Audiometric testing is critical for counseling patients regarding teprotumumab treatment. A protocol for monitoring hearing during treatment is needed to detect and manage hearing changes associated with teprotumumab use. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The Rate of Re-treatment in Patients Treated with Teprotumumab: A Multicenter Study of 119 Patients with 1 Year of Follow-up.

PURPOSE: To determine the rate of re-treatment in patients who receive a full course of teprotumumab therapy for thyroid eye disease (TED) and drivers of re-treatment. DESIGN: Multicenter retrospective study. PARTICIPANTS: All patients who received a full course of treatment and had available data at 1 year after initial treatment were included. METHODS: Charts were reviewed for the following information: age, sex, months since diagnosis of TED, smoking status, and prior treatments. Further, the clinical activity score (CAS), proptosis, and the Gorman diplopia score were reviewed at baseline, at the end of the first course, and at baseline for the second course in those who received it. A logistic regression model was created to review the drivers of re-treatment. MAIN OUTCOME MEASURES: Rate of re-treatment and the drivers of re-treatment. RESULTS: One hundred nineteen patients were included from 3 centers across the United States. The overall re-treatment rate was 24% (29/119). No difference was found among the 3 sites (P = 0.6). In univariable analyses, at baseline, no difference was found in proptosis (P = 0.07), diplopia score (P = 0.4), or duration of TED (P = 0.4) between patients who were re-treated and those not re-treated. From the re-treated group, 82% showed a significant proptosis response (≥ 2-mm reduction from baseline) after the initial course, whereas 68% of patients who were not re-treated showed a clinically significant proptosis response (P = 0.16). The mean ± standard deviation difference between the end of the first treatment and at baseline before the second treatment (in those who received it) was 2 ± 2 for CAS, 2 ± 4 mm for proptosis, and 1 ± 1 for diplopia score. Age was the only significant driver of re-treatment (P < 0.05). Re-treated patients were 7 years older than patients who were not re-treated (60 years vs. 53 years; P < 0.05). CONCLUSIONS: In patients receiving a full course of teprotumumab therapy, the rate of re-treatment was 24%. Age was the only driver of re-treatment. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Glycemic Trends in Patients with Thyroid Eye Disease Treated with Teprotumumab in 3 Clinical Trials.

PURPOSE: Assess incidence, severity, and glucose excursion outcomes in thyroid eye disease (TED) patients receiving the insulin-like growth factor-1 receptor inhibitor teprotumumab from 3 clinical trials. DESIGN: Analysis of pooled glycemic data over time. PARTICIPANTS: Eighty-four teprotumumab- and 86 placebo-treated active TED patients from the phase 2 and phase 3 (OPTIC) controlled clinical trials and 51 teprotumumab-treated patients from the OPTIC extension (OPTIC-X) trial. METHODS: Eight intravenous infusions were given over 21 weeks. Phase 2 serum glucose was measured at weeks 1, 4, 15, and 21, with fasting measurements at weeks 1 and 4. Serum glucose was measured at each study visit in OPTIC and OPTIC-X, with fasting measurements at weeks 1 and 4 (in patients without diabetes) or all visits (in patients with diabetes). In all studies, hemoglobin A1c (HbA1c) was measured at baseline, 12, and 24 weeks plus weeks 36 and 48 in OPTIC-X. MAIN OUTCOME MEASURES: Serum glucose and HbA1c. RESULTS: In the phase 2 and 3 studies, 9 hyperglycemic episodes occurred in 8 teprotumumab patients; mean HbA1c level increased 0.22% from baseline to week 24 (to 5.8%; range, 5.0%-7.9%) versus 0.04% in patients receiving the placebo (to 5.6%; range, 4.6%-8.1%). At study end, 78% (59/76) of teprotumumab patients and 87% (67/77) of patients receiving placebo had normoglycemic findings. Normoglycemia was maintained in 84% (57/68) of patients receiving teprotumumab and 93% (64/69) of patients receiving placebo. Among baseline prediabetic patients, 43% (3/7) remained prediabetic in both groups, and 29% (2/7) of teprotumumab patients and 14% (1/7) of patients receiving placebo had diabetic findings at week 24. OPTIC-X patients trended toward increased fasting glucose and HbA1c whether initially treated or retreated with teprotumumab. Fasting glucose commonly rose after 2 or 3 infusions and stabilized thereafter. Most hyperglycemic incidents occurred in patients with baseline prediabetes/diabetes but were controlled with medication. No evidence was found for progression or increased incidence of hyperglycemia with subsequent doses. CONCLUSIONS: Serious glycemic excursions are uncommon in patients with normoglycemia before teprotumumab therapy. Patients with controlled diabetes or impaired glucose tolerance can be treated safely if baseline screening, regular monitoring of glycemic control, and timely treatment of hyperglycemia are practiced. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Teprotumumab-Related Adverse Events in Thyroid Eye Disease: A Multicenter Study.

PURPOSE: To assess the duration, incidence, reversibility, and severity of adverse events (AEs) in patients with thyroid eye disease (TED) treated with teprotumumab. DESIGN: Multicenter, retrospective, observational cohort study. PARTICIPANTS: Patients with TED of all stages and activity levels treated with at least 4 infusions of teprotumumab. METHODS: Patients were treated with teprotumumab between February 2020 and October 2022 at 6 tertiary centers. Adverse event metrics were recorded at each visit. MAIN OUTCOME MEASURES: The primary outcomes measure was AE incidence and onset. Secondary outcome measures included AE severity, AE reversibility, AE duration, proptosis response, clinical activity score (CAS) reduction, and Gorman diplopia score improvement. RESULTS: The study evaluated 131 patients. Proptosis improved by 2 mm or more in 77% of patients (101/131), with average proptosis improvement of 3.0 ± 2.1 mm and average CAS reduction of 3.2 points. Gorman diplopia score improved by at least 1 point for 50% of patients (36/72) with baseline diplopia. Adverse events occurred in 81.7% of patients (107/131). Patients experienced a median of 4 AEs. Most AEs were mild (74.0% [97/131]), 28.2% (37/131) were moderate, and 8.4% (11/131) were severe. Mean interval AE onset was 7.9 weeks after the first infusion. Mean resolved AE duration was 17.6 weeks. Forty-six percent of patients (60/131) demonstrated at least 1 persistent AE at last follow-up. Mean follow-up was 70.2 ± 38.5 weeks after the first infusion. The most common type of AEs was musculoskeletal (58.0% [76/131]), followed by gastrointestinal (38.2% [50/131]), skin (38.2% [50/131]), ear and labyrinth (30.5% [40/131]), nervous system (20.6% [27/131]), metabolic (15.3% [20/131]), and reproductive system (12.2% [16/131]). Sixteen patients (12.2%) discontinued therapy because of AEs, including hearing loss (n = 4), inflammatory bowel disease flare (n = 2), hyperglycemia (n = 1), muscle spasms (n = 1), and multiple AEs (n = 8). CONCLUSIONS: Adverse events are commonly reported while receiving teprotumumab treatment. Most are mild and reversible; however, serious AEs can occur and may warrant treatment cessation. Treating physicians should inform patients about AE risk, properly screen patients before treatment, monitor patients closely throughout therapy, and understand how to manage AEs should they develop. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The efficacy and safety of selenium supplementation versus placebo in the treatment of Graves' orbitopathy: A systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Selenium is a trace element crucial for thyroid function, and has potential therapeutic benefits in Graves' orbitopathy (GO). Therefore, we aim to evaluate its efficacy and safety in GO patients to provide valuable insights into its role as a therapeutic option for this condition. DESIGN: Systematic review and meta-analysis. PATIENTS: GO Patients treated with selenium compared to placebo. MEASUREMENTS: Clinical activity score (CAS), Graves' orbitopathy quality of life (GO-QOL), eye symptoms and signs, and adverse events. RESULTS: Out of 1684 records screened, four randomised controlled trials were included. Selenium was superior at 6 months in lowering the CAS (MD = -1.27, 95% confidence interval [CI] [-1.68, -0.85], p < .0001]), improving total GO-QOL (RR = 2.54, 95% CI [1.69-3.81], p < .00001), and improving the visual and the psychological functioning scores (MD = 10.84, 95% CI [4.94-16.73], p = .003), (MD = 12.76, 95% CI [8.51-17.00], p < .00001) respectively. Similarly, it significantly improved these outcomes at 12 months. It also showed a significant decrease in the palpebral aperture at 6 months (MD = -1.49, 95% CI [-2.90, -0.08], p = .04). However, no significant differences were observed in proptosis, soft tissue involvement, ocular motility, and adverse effects. CONCLUSIONS: Selenium is effective in reducing CAS and improving the palpebral aperture and GO-QOL in patients with GO. Additionally, it is safe and has promising therapeutic implications. However, further research is needed to validate its long-term efficacy and safety.

The genetics of Graves' disease.

Graves' disease (GD) is the commonest cause of hyperthyroidism and has a strong female preponderance. Everyday clinical practice suggests strong aggregation within families and twin studies demonstrate that genetic factors account for 60-80% of risk of developing GD. In this review, we collate numerous genetic studies and outline the discoveries over the years, starting with historic candidate gene studies and then exploring more recent genome-wide linkage and association studies, which have involved substantial cohorts of East Asian patients as well as those of European descent. Variants in genes including HLA, CTLA4, and PTPN22 have been shown to have substantial individual effects on disease susceptibility. In addition, we examine emerging evidence concerning the possibility that genetic variants may correlate with relevant clinical phenotypes including age of onset of GD, severity of thyrotoxicosis, goitre size and relapse of hyperthyroidism following antithyroid drug therapy, as well as thyroid eye disease. This review supports the inheritance of GD as a complex genetic trait, with a growing number of more than 80 susceptibility loci identified so far. Future implementation of more targeted clinical therapies requires larger studies investigating the influence of these genetic variants on the various phenotypes and different outcomes of conventional treatments.

Effects of Teprotumumab and Role of Human Leukocyte Antigens Markers in Patients With Thyroid Eye Disease.

OBJECTIVE: To evaluate the effects of teprotumumab on ophthalmologic and biochemical findings and assess potential genetic markers for response to treatment. METHODS: This is a retrospective study. Participants were 18-76 year old. All subjects were treated with teprotumumab. The primary outcome was the change in proptosis before and after teprotumumab treatment. Secondary outcomes include change in other ophthalmic measures and thyroid laboratory tests. Human leukocyte antigens (HLA) markers were analyzed for response to teprotumumab. RESULTS: Twenty-six patients were included in the final analysis. There was a significant decrease in thyroid stimulating immunoglobulin and thyrotropin receptor antibody levels and significant increases in glycated hemoglobin A1c, fasting glucose, and total T3 levels. There was also significant reduction in proptosis, clinical activity score, retinal nerve fiber layer thickness, ganglion cell analysis, and intraocular pressure. HLA haplotypes were distinct between responders and nonresponders, with HLA-DRB3 02:02:01G, HLA-DRB4 neg, and HLA-DQB1 02:01:01G demonstrating better response to teprotumumab and HLA-A 23:01:01G strongly correlating to nonresponse. CONCLUSIONS: Patients with both acute and chronic thyroid eye disease treated with teprotumumab had a significant reduction in thyroid stimulating immunoglobulin and thyrotropin receptor antibody levels and improvement in proptosis, clinical activity score, retinal nerve fiber layer and ganglion cell analysis thickness, and intraocular pressure. HLA may predict responders vs nonresponders. Further studies with longer duration and larger population comparing teprotumumab with steroids or other immunomodulatory agents (tocilizumab, rituximab, etc) may be helpful.

Impact of Teprotumumab on Clinical Practice in Thyroid Eye Disease.

BACKGROUND: Following its Food and Drug Administration approval in January 2020, we examined the impact of teprotumumab on thyroid eye disease (TED) clinical practices. METHODS: Across 3 referral centers from January 1, 2018, to December 30, 2022, we retrospectively analyzed demographics, clinical features, treatment choices, and insurance status of patients with active, moderate to severe TED. RESULTS: Of 74 patients recommended for medical therapy, 53% received collaborative recommendations from endocrinologists and ophthalmologists in a TED clinic. Prior to teprotumumab availability, 19 patients were recommended medical therapy, and all received medical therapy (100%), which consists of corticosteroids (14, 73.7%) or tocilizumab (5, 26.3%). After teprotumumab became available, out of 55 patients that were recommended medical therapy, only 41 (74.6%) received medical therapy, mostly teprotumumab (33, 60%), followed by corticosteroids (5, 9.1%) or tocilizumab (3, 5.4%), while 14 (25.4%) did not receive medical therapy. Discordance between physicians' recommendations and therapy received or lack thereof was explained by patients' refusal (9, 64.3%), mostly due to side effect concerns (8, 88.9%), and insurance denial (5, 35.7%). Teprotumumab use was mostly associated with otic changes (10, 30.3%), weight loss (9, 27.3%), and hyperglycemia (6, 18.2%), but 2 (6.1%) patients developed serious infections. Corticosteroids were associated with insomnia (4, 21.1%), and 1 patient in the tocilizumab group had an infusion reaction requiring hospitalization. CONCLUSION: Teprotumumab introduction increased TED therapy evaluations, yet not all received recommended treatment due to safety concerns or accessibility issues. Enhancing collaborative care, medication accessibility, and adverse effect management is crucial.

Bridging and Validation of the Specific Graves Ophthalmopathy Quality of Life Questionnaire With Health State Utility Values.

OBJECTIVE: In thyroid eye disease (TED), inflammation and expansion of orbital muscle and periorbital fat result in diplopia and proptosis, severely impacting patient quality of life (QOL). The reported health state utility (HSU) scores, which are QOL measures, allow quantification of TED impact and improvement with therapies; however, no current QOL instrument has been validated with HSU scores for TED. Here, we used the disease-specific Graves Ophthalmopathy Quality of Life (GO-QOL) questionnaire and HSU scores to validate QOL impact. METHODS: The GO-QOL scores from patients in 2 randomized, masked, placebo-controlled teprotumumab trials (N=171) were compared with 6 HSU values based on severity of proptosis/diplopia in those studies. Patient GO-QOL and HSU scores were compared at baseline and after 6-month treatment via regression analyses. GO-QOL and HSU scores were correlated for validation and quantification of QOL impact by severity state and to estimate quality-adjusted life year improvement. RESULTS: GO-QOL scores were correlated with TED severity, indicating that worse severity was associated with lower (worse) GO-QOL scores. Less severe health states were represented by higher (better) GO-QOL scores. Importantly, GO-QOL scores were positively correlated with utility scores of the 6 health states, allowing for conversion of the GO-QOL scores to utility scores. A positive (improved) 0.013 utility change was found for each 1-point (positive) improvement in GO-QOL score produced by teprotumumab versus placebo. CONCLUSION: Patients with moderate-to-severe active TED health states demonstrate increasing TED severity associated with declining utility values and worsening GO-QOL scores. These results indicate that the GO-QOL scores can be used to bridge to the HSU scores for benefit quantification.

IgG4 serum levels in Graves' orbitopathy.

OBJECTIVE: IgG4-related disease (IgG4-RD) can involve many organs, including thyroid and orbital tissues. A link between IgG4, Graves' disease (GD) and Graves' orbitopathy (GO) has been proposed, but results are conflicting. Here we investigated the possible association between IgG4 and GO. METHODS: Retrospective investigation in 297 patients with Graves' disease (GD), 152 with GO. PRIMARY OUTCOME: prevalence of IgG4 ≥ 135 mg/dL (cut-off for IgG4-RD). SECONDARY OBJECTIVES: (1) serum IgG4 concentrations; (2) IgG4/IgG ratio; (3) prevalence of IgG4/IgG ratio ≥ 8.0%; (4) relationship between IgG4 and eye features; (5) relationship between IgG4 and anti-TSH receptor antibodies (TRAbs). RESULTS: Because GO patients had lower FT3 concentrations, we evaluated the main objectives in the second and third FT3 quartiles subpopulation, in which there were no relevant differences between patients with (n = 81) or without GO (n = 67) for baseline parameters. Within this population, the prevalence of IgG4 levels ≥ 135 mg/dL did not differ between patients without and with GO (17.9% vs 17.3%). No difference was observed concerning IgG4 concentrations, prevalence of IgG4/IgG ≥ 8.0%, and IgG4/IgG ratio. There was no relationship between IgG4 and eye features and no correlation between IgG4 levels and TRAb was found. CONCLUSIONS: Our results suggest that, within GD, there is no relationship between serum IgG4 and GO.

Clinical characteristics and therapeutic effect of myasthenia gravis coexisting with thyroid eye disease.

INTRODUCTION: Here, we describe the clinical characteristics and therapeutic effects of myasthenia gravis (MG) coexisting with thyroid eye disease (TED). METHODS: We collated clinical data from MG patients in our hospital between 2012 and 2022 and analyzed the clinical characteristics of MG patients with hyperthyroidism, MG patients with TED and ocular myasthenia gravis (OMG) patients with TED. RESULTS: We recruited 62 MG patients with hyperthyroidism, including 13 MG patients with TED and 10 OMG patients with TED. There were 70 MG patients without hyperthyroidism; 29 of these were OMG. Compared with patients without hyperthyroidism, patients with hyperthyroidism had an earlier age at onset and milder clinical symptoms (P < 0.05). The incidence of thymus hyperplasia in patients with hyperthyroidism and TED was significantly lower than that in patients without TED (38.5% vs. 69.4%, P < 0.05); these patients also had a significantly lower antibody titer for the acetylcholine receptor [0.72 (0.27, 14.93) nmol/L vs. 2.38 (0.28, 49.51) nmol/L, P < 0.05]. Diplopia was significantly more frequent in OMG patients with TED than in patients with OMG (84.6% vs. 44.8%, P < 0.05), and the rate of diplopia in OMG patients with TED was significantly higher after treatment with bromostigmine and glucocorticoid (69.2% vs. 3.4%, P < 0.05). CONCLUSIONS: MG patients with TED had a significantly lower incidence of thymus hyperplasia and a lower antibody titer for the acetylcholine receptor. Patients with OMG and TED are more likely to develop diplopia; it is very difficult to treat diplopia in these patients.

Long-term outcome of Graves' orbitopathy following treatment with sirolimus.

OBJECTIVES: Sirolimus was found to be associated with a better outcome of Graves' orbitopathy (GO) at 24 weeks compared to methylprednisolone. We conducted a retrospective study to investigate its efficacy and safety over a longer period. METHODS: Data from 40 consecutive patients with moderate-to-severe, active GO, 20 treated with sirolimus and 20 with methylprednisolone, were collected. PRIMARY OUTCOME: overall outcome (composite evaluation) of GO at 48 weeks. SECONDARY OUTCOMES: (1) GO outcome at 24 weeks, and, at 24 and 48 weeks: (2) outcome of single eye features; (3) quality of life (GO-QoL); (4) TSH-receptor antibodies; (5) GO relapse at 48 weeks; (6) adverse events. RESULTS: The overall GO outcome at 48 weeks did not differ between the two groups (responders: 55% vs 55%). At 24 weeks, prevalence of responders was greater in sirolimus group (65% vs 25%; P = 0.01). A reduction ≥ 1 point in clinical activity score (CAS) was more frequent in sirolimus patients at 24 (85% vs 40%; P = 0.005) and 48 weeks (75% vs 60%; P = 0.03). The proportion of GO-QoL responders (appearance subscale) at 24 weeks was greater in sirolimus group (62.5% vs 26.3%; P = 0.03). No difference was observed for the remaining outcome measures. CONCLUSIONS: Treatment with sirolimus is followed by a greater overall response of GO compared with methylprednisolone at 24 weeks, but not at 48 weeks, when only CAS is affected. A more prolonged period of treatment may be required for a better outcome to be observed over a longer period.

Teprotumumab improves light sensitivity in patients with thyroid eye disease.

BACKGROUND: Teprotumumab, a novel IGF-1R antibody, has been shown to significantly reduce the signs of acute and chronic Thyroid Eye Disease (TED). Light sensitivity is a reported symptom in patients with TED. There is a lack of a prospective study that has explored the effects on light sensitivity in a large cohort of patients with acute and chronic TED following treatment with teprotumumab. METHODS: Consecutive patients who were diagnosed with TED and reported light sensitivity at baseline were considered for study eligibility. All patients had measurements of Visual Light Sensitivity Questionnaire-8 (VLSQ-8), proptosis, clinical activity score (CAS), and MRD1 (distance between the upper eyelid margin and corneal reflex, mm) and MRD2 (distance between the lower eyelid margin and corneal reflex, mm) before and after treatment. RESULTS: Ninety patients (41 acute, 49 chronic) met the inclusion criteria. The mean (SD) age was 47.3 (14.3). Eighty-six (95.6%) patients completed all 8 infusions. There was a significant reduction in the total score and across all categories of the VLSQ-8 (p <  0.01 for all). Seventy-two (80%) patients had a clinically significant improvement (≥2 reduction) in at least one category. There was no significant difference in the total VLSQ-8 score between the acute and chronic group (p = 0.8). CONCLUSION: Teprotumumab improves light sensitivity in patients with acute and chronic TED. The results of this study highlight that the improvements in light sensitivity following treatment are not directly related to the mechanical changes in TED, suggesting another underlying mechanism is potentially involved.

Teprotumumab for thyroid eye disease in patients with hypothyroid/euthyroid state: a multicenter case series.

BACKGROUND: Teprotumumab, a novel IGF-1R antibody was recently shown to significantly reduce the signs of acute and chronic thyroid eye disease (TED) related to hyperthyroidism. Given the lower incidence of TED associated with hypothyroidism / euthyroidism, there is a paucity of data regarding the efficacy of teprotumumab in this group. METHODS: In this multicenter study, consecutive patients who had been diagnosed with TED, presenting with either hypothyroidism or euthyroidism as their baseline thyroid dysfunction and treated with teprotumumab were included. All patients had measurements of proptosis, clinical activity scores (CAS), diplopia scores and four-point strabismus scores before and after therapy. RESULTS: Twenty-six patients met the inclusion criteria. Mean age was 48 ± 14 years old and mean duration of TED prior to treatment was 31 ± 43 months. All patients received 8 infusions. Mean (SD) reduction in proptosis for study orbits was 2.7 mm (1.8) (p < 0.05) and 1.8 mm (2.0) for the fellow orbit (p < 0.05). In the study orbit, mean (SD) CAS was 2.3 (1.3) before therapy and 1.0 (1.0) following therapy (p < 0.05). At baseline, mean (SD) diplopia score was 1.2 (1.1) and 0.9 (1.1) following therapy (p < 0.05). CONCLUSION: Teprotumumab reduces proptosis and inflammation in patients presenting with TED associated with hypothyroidism and euthyroidism. The results of this study highlight the potential for teprotumumab therapy in this subgroup and also provide a unique insight into the potential role of the IGF-1R in these patients.

Investigation of lacrimal gland and extraocular muscle in thyroid eye disease patients with severe subjective dry eye disease: a multiparametric magnetic resonance imaging study.

PURPOSE: To analyze the radiological features of the lacrimal gland (LG) and extraocular muscle (EOM) in thyroid eye disease (TED) patients with severe subjective dry eye disease (DED) using magnetic resonance imaging (MRI) measurements. METHODS: In this cross-sectional study, mechanical ocular exposure, dry eye assessment and MRI data were collected. Patients were classified into non-severe subjective DED group with ocular surface disease index (OSDI) < 33 and severe subjective DED group with OSDI ≥ 33. Linear regression model was applied for comparing the OSDI < 33 and OSDI ≥ 33 group in TED patients. The predictive performance of MRI parameters and models was assessed by receiver operating characteristic curve (ROC) analysis. RESULTS: Consecutive 88 TED patients (176 eyes) were included in this study. In the OSDI < 33 group, 52 TED patients (104 eyes) with a mean clinical activity score (CAS) of 0.63 ± 0.75. In the OSDI ≥ 33 group, there are 36 TED patients (72 eyes), with a mean CAS of 1.50 ± 1.54. The age and sex of the patients were matched between the two groups. The OSDI ≥ 33 group had shorter tear break-up time, larger levator palpebrae superioris / superior rectus (LPS/SR), inferior rectus and lateral rectus, smaller LG, more inflammatory LPS/SR and inferior rectus than OSDI < 33 DED group (P < 0.05). In the linear regression analysis, compare to the OSDI < 33 DED group, the OSDI ≥ 33 group had larger medial rectus cross-sectional area (ß = 0.06, 95%CI: (0.02, 0.10), P = 0.008), larger inferior rectus cross-sectional area (ß = 0.06, 95%CI: (0.00, 0.12), P = 0.048), smaller LG cross-sectional area (ß = -0.14, 95%CI: (-0.25, -0.04), P = 0.008). In the ROC analysis, the area under curve of medial rectus, inferior rectus, LG, and combined model are 0.625, 0.640, 0.661 and 0.716, respectively. CONCLUSION: Multiparametric MRI parameters of the LG and EOM in TED patients with severe subjective DED were significantly altered. Novel models combining the cross-sectional area of LG, medial rectus and inferior rectus showed good predictive performance in TED patients with severe subjective DED.

Three-dimensional soft tissue reconstruction and volume measurement used for the diagnosis of dysthyroid optic neuropathy.

PURPOSE: Dysthyroid optic neuropathy (DON) leads to vision loss. This study aimed to investigate a new method that can directly evaluate the change in muscle cone inner volume (MCIV) and distinguish DON orbits from non-DONs. MATERIALS AND METHODS: This study included 54 patients (108 orbits) who were diagnosed with thyroid eye disease and treated at the Beijing Tongren Hospital between December 2019 and September 2021. The extraocular muscle volume (EOMV), orbital fat volume (OFV), and bony orbit volume (BOV) of the patients were measured using three-dimensional reconstruction. MCIV was measured using artificially defined boundaries. The associations between these volumes and clinical indicators were studied, and the diagnostic efficacy of these volumes for DON was described using receiver operating characteristic (ROC) curves. RESULTS: The ROC curve showed that the area under the curve of MCIV/BOV (%) combined with EOMV/BOV (%) reached 0.862 (p < 0.001), with a sensitivity of 85.7% and a specificity of 76.1%. CONCLUSION: The combination of MCIV/BOV (%) and EOMV/BOV (%) is a good indicator for the diagnosis of DON, which aids in the early detection and intervention of DON.