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Background: Significant individual differences exist in the clinical manifestations of thyroid-associated ophthalmopathy (TAO). Age and gender have an impact on the presentation and severity of TAO., Objective: To evaluate the clinical characteristics of TAO patients, with particular consideration of their age and gender., Methods: Demographic and clinical data of 2479 TAO patients were collected. Patients were divided into 7 groups based on age: Group 1: ≤18 years old; Group 2: 19-29 years old; Group 3: 30-39 years old; Group 4: 40-49 years old; Group 5: 50-59 years old; Group 6: 60-69 years old; Group 7: ≥70 years old. Compared clinical manifestations among different groups and between males and females., Result: In age group 1, the ratio of female to male TAO patients was 3.79, and in age group 7, it was 0.86. As age increased, there was a decline in the percentage of females (γ=-0.168, p <0.001). During the aging process, the proportion of TAO patients with unilateral involvement also gradually decreased (γ=-0.23, p <0.001). In addition, the proportion of TAO patients with upper eyelid retraction ≥2mm and exophthalmometry ≥17mm also decreased (γ=-0.158, p <0.001, γ=-0.23, p <0.001). In comparison to males, females with TAO showed a higher proportion of unilateral eye involvement and upper eyelid retraction ≥2mm ( p =0.038, p <0.001). However, males had a higher proportion of exophthalmometry ≥17mm ( p <0.001). The proportions of patients with eye movement disorder (γ=0.535, p <0.001), diplopia (γ=0.446, p <0.001), intraocular pressure (IOP) ≥30mmHg (γ=0.149, p <0.001), sight-threatening TAO (γ=0.479, p <0.001), and active TAO (γ=0.469, p <0.001) were positively correlated with age in TAO patients. Additionally, the proportion of male patients is higher than that of female patients., Conclusion: TAO Patients exhibit different clinical features depending on age and gender. In elderly and male patients, TAO tends to be more severe, with a higher prevalence of eye muscle involvement, IOP ≥30mmHg, active phases, and a lower proportion of patients with upper eyelid retraction ≥2mm. Elderly female patients also have a lower proportion of exophthalmometry ≥17mm., Competing Interests: The 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., (Copyright © 2024 Yang and He.)

Background/objectives: We aimed to investigate the prevalence, risk factors, and prognosis of Graves' orbitopathy (GO) in patients with thyroid cancer without a history of hyperthyroidism., Subjects/methods: This retrospective cohort study analysed a sample from the Korean National Health Insurance Service database, which included 1,137,861 subjects from 2002 through 2019. Patients diagnosed with thyroid cancer, without a history of hyperthyroidism, were identified according to the Korean Standard Classification of Disease codes. The study compared the type of surgery, dose of radioactive iodine (RAI), and daily average thyroid hormone dose between patients who developed GO after being diagnosed with thyroid cancer and those who did not develop GO. We analysed the course of GO and the type of treatment., Results: A total of 8499 cancer patients without a history of hyperthyroidism were identified, among whom 7836 underwent thyroidectomy. Of those who underwent thyroidectomy, 12 developed GO postoperatively. Among the 663 patients who did not undergo thyroidectomy, none developed GO. The prevalence of GO among thyroid cancer patients was 0.14%. The GO group received a significantly higher total RAI dose than the non-GO group (p = 0.036). There were no significant differences in sex, age, type of surgery, rate of RAI treatment, or average thyroid hormone dose between the two groups. One of the 12 patients who developed GO required intravenous steroids., Conclusions: Although GO rarely develops in thyroid cancer patients without coexisting hyperthyroidism, the total RAI dose may increase its risk. Further research would help clarify GO's association with thyroid cancer., (© 2024. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Objectives: A subtype of patients with thyroid eye disease (TED) were found to be euthyroid without prior thyroid dysfunction or treatment, known as Euthyroid Graves' Ophthalmopathy (EGO). We report the prevalence, clinical and serological phenotypes of EGO in a Chinese population., Methods: A cross-sectional follow-up study. Ethnic Chinese TED patients were managed at the Thyroid Eye Clinic(TEC), Prince of Wales Hospital and TEC, the Chinese University of Hong Kong between September 2007 and July 2021., Results: A total of 66 (5%) patients among the 1266 ethnic Han Chinese TED cohort were diagnosed as EGO, and 6 (9%)of them become dysthyroid over an average of 74-month follow-up. EGO patients were associated with a longer duration between onset of the symptoms to our first consultation ( P  < 0.0001), a higher male-to-female ratio ( P  = 0.0045) and a higher age of disease onset ( P  = 0.0092). Family history of thyroid disease was more common in TED patients ( P  = 0.0216) than in EGO patients. EGO patients were more likely to present unilaterally ( P  < 0.0001), and they have a larger difference in MRD1 ( P  < 0.0001), and extraocular motility ( P  < 0.0001) between the 2 eyes when compared to the TED patients. Notably, the extraocular motility restriction of the worst eye was more affected in EGO patients ( P  = 0.0113). The percentages of patients who received IVMP, ORT and emergency or elective surgeries(decompression or squint operation) between EGO and TED were similar., Conclusions: Understanding the important clinical phenotypes of EGO may help the clinician to make the correct diagnosis. Further study to compare EGO and TED is warranted., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: Graves' ophthalmopathy (GO) is an autoimmune disease that affects orbital soft tissues and represents the most common extrathyroidal manifestation of Graves' disease (GD). The European Group of Graves' Ophthalmopathy (EUGOGO) has attempted to shed light on the European epidemiological picture of GO, suggesting that GO in newly diagnosed patients in recent years has a trend towards a less severe clinical presentation. There are no studies that focus this issue on the population of our area; we aimed to evaluate the trend of GO clinical presentation in our outpatient clinic through an observation period of 10 years., Methods: We compared 55 consecutive patients, 11 males (F) and 44 females (M), who came to our observation from January 2005 to December 2006 [Group 1 (G1)], with 56 patients, 15 males, and 41 females, who were referred to us from 2015 to 2016 [Group 2 (G2)]. We studied the following putative predictors of GO presentation and severity: thyroid function, smoking, diabetes, hypercholesterolemia, time from GO diagnosis to referral to our thyroid centre (TGOD), sex and age., Results: GO severity was significantly reduced in G2 vs. G1 (p = 0.04). TGOD ≥ 3 months was related to clinical characteristics of GO (severity and Clinical Activity Score ≥ 4) and was an independent predictor of GO severity (p = 0.01). The other variables evaluated had no independent effects., Conclusions: We found that GO severity at presentation was significantly reduced over a ten-year observation period (2005-2006 vs. 2015-2016) in GO patients referred to our tertiary thyroid centre. TGOD ≥ 3 months was an independent predictor of GO severity., (© 2024. The Author(s).)

Purpose: Thyroid eye disease (TED) phenotype varies by ethnicity/race and genetic/environmental factors. This study compared demographic and clinical characteristics of TED patients from the US and India., Design: Observational pilot study ., Methods: Sixty-four patients with TED ages ≥18 years old with active disease (onset of symptoms ≤18 months or presenting clinical activity score (CAS) ≥4) were recruited between March and October 2021 from clinical practices in the United States (Philadelphia, PA) (n = 30) and India (Hyderabad, India) (n = 34). Data collection at baseline and 3 months included clinical measurements, thyroid disease history, and photographs. Ocular symptoms and quality of life data were obtained by phone interview. CAS was calculated using the standard 7-point scale., Results: There was no statistically significant difference in age, TED duration, or smoking status between patient groups. Both groups had good vision, a low rate of optic neuropathy, and comparable exophthalmometry. US patients were predominantly female (86.7% [26/30]), with a history of hyperthyroidism (96% 29/30). In comparison, Indian patients were 52.9% (18/34, P = .004) female; underlying thyroid disease was distributed between hyperthyroidism (52%), hypothyroidism (17.6%) and euthyroid (9.7%). Mean (SD) CAS in the US cohort was double the score in the India cohort (4.2 (1.7) vs 1.65 (1.7), respectively) (P < .0001). However, patients at both sites experienced subjective symptoms of TED at a similar frequency., Conclusions: Observed differences in TED between US and Indian patients warrant further investigation to elucidate differences in pathogenesis, disease expression, or other factors that may influence TED in diverse populations., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: This study aims to report correlations between thyroid-stimulating immunoglobulin (TSI) and both clinical and radiological parameters in recent-onset symptomatic thyroid eye disease (TED) patients., Methods: A prospective cohort study of TED patients managed at the Chinese University of Hong Kong from January 2014 to May 2022. Serum TSI levels were determined with the functional assay. Outcomes included the Clinical Activity Score (CAS), marginal reflex distance1 (MRD1), extraocular muscle motility restriction (EOMy), exophthalmos, and diplopia. The radiological assessment included cross-sectional areas and signal of extraocular muscles on STIR-sequence MRI., Results: A total of 255 (197 female) treatment-naive patients, with an average onset age of 50 ± 14 years (mean ± s.d.), were included. Elevated pre-treatment TSI level was observed in 223 (88%) patients. There was a weak positive correlation between TSI and CAS (r = 0.28, P = 0.000031), MRD1 (r = 0.17, P = 0.0080), and the size of the levator palpebrae superioris/superior rectus complex (r = 0.25, P = 0.018). No significant correlation existed between TSI and STIR signals. The AUC and optimal cut-off value for clinical active TED were 0.67 (95% CI: 0.60-0.75) and 284% (specificity: 50%, sensitivity: 85%). In total, 64 patients received intravenous methylprednisolone (IVMP) during the study interval, and they had a higher baseline TSI level than those who did not have IVMP (P = 0.000044). Serial post-IVMP TSI among the 62 patients showed a significant reduction compared to the baseline level (P < 0.001). Both the baseline and post-IVMP TSI levels, and percentages of TSI changes were comparable between patients who responded and did not respond to the first course of IVMP., Conclusion: TSI can be a serum biomarker for the diagnosis, prognosis, and treatment response of TED. Further validation should be warranted.

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., (© 2023. The Author(s), under exclusive licence to Italian Society of Endocrinology (SIE).)

Background: Endocrine orbitopathy (EO) is an autoimmune disease mostly associated with a disease of the thyroid gland, which leads to inflammation, adipogenesis and fibrosis. The severity of EO can vary greatly between individuals, which makes it difficult to exactly predict the natural course of the disease; however, this is important to be able to individually adapt the treatment. The aim of this study was to compare the clinical features, course, treatment and prognosis for patients with EO under 50 years old with older patients. The results of the study with a focus on motility are presented in this special issue., Patients and Methods: The hospital records of a randomly selected sample of 1000 patients from the EO databank in Essen (GODE), which includes 4260 patients, were analyzed. The patients were divided into two groups: group 1 ≤50 years and group 2 >50 years. Only patients with complete data sets were included in the statistical analyses., Results: Younger patients (n = 484) presented significantly more frequently with milder EO (53% vs. 33%, p < 0.0001), whereas older patients (n = 448) more frequently suffered from moderate or severe forms (44% vs. 64%, p < 0.0001). Older patients showed more severe strabismus, motility and clinical activity scores (5.9 vs. 2.3 prism diopters, PD/310° vs. 330°, both p < 0.0001, CAS 2.1 vs. 1.7, p = 0.001). Proptosis and the occurrence of optic nerve compression showed no significant differences between the groups (3% each). Multiple logistic regression showed that the necessity for a second eye muscle surgery was most strongly associated with a previous decompression (OR = 0.12, 95 % CI 0.1-0.2, p < 0.0001), followed by orbital irradiation and age., Conclusion: In summary, younger patients with EO presented with milder clinical features, such as a lower rate of restrictive motility disorders and weaker expression of signs of inflammation. Therefore, older patients needed steroids, irradiation, eyelid and eye muscle surgery more frequently; however, the risk of dysthyroid optic neuropathy and the necessity of a second eye surgery were not or only slightly associated with age., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Purpose: To determine the prevalence, clinical features, and radiographic findings of superior ophthalmic vein periphlebitis (SOVP) in thyroid eye disease (TED)., Methods: Patients with a clinical diagnosis of thyroid eye disease and contrast-enhanced imaging were included. Imaging was reviewed for the presence of SOVP, and patients with SOVP were compared to those without. A random eye was determined to be the affected eye in patients without SOVP., Results: A total of 212 patients met the inclusion criteria. Unilateral SOVP was identified in 4.7% of cases. There was no significant difference in age ( p = 0.22), gender ( p = 0.09), or disease duration ( p = 0.14) between patients with and without SOVP. There was a significant ( p < 0.05) difference in stage classification and clinical activity core between the groups. The affected eye in patients with SOVP had significantly ( p < 0.05) greater margin reflex distance 1, degree of relative proptosis, horizontal motility restriction, and vertical motility restriction than in patients without SOVP. There was no significant difference in horizontal strabismus ( p = 1.0), vertical strabismus ( p = 0.87), or relative intraocular pressure ( p = 0.77). On imaging, the maximal diameter of the SR and IR were found to be significantly ( p < 0.05) larger in the affected eye of patients with periphlebitis; however, there was no difference in measured diameter of the medial rectus and ( p = 0.30) or lateral rectus ( p = 0.78)., Conclusions: SOVP is an under-reported imaging finding of thyroid eye disease. It is associated with significantly greater margin reflex distance 1, relative proptosis, and motility restriction on exam as well as larger superior rectus and inferior rectus diameter on imaging. These patients tend to present in the active stage of disease with greater clinical activity score., Competing Interests: D.B.R. has acted as a marketing consultant for Horizon pharmaceuticals and is a member of the speaker’s bureau. Other authors have no conflicts of interest to disclose., (Copyright © 2024 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Purpose: This study aimed to develop a model for predicting the progression of inactive thyroid eye disease (TED)., Methods: We retrospectively analyzed 107 patients with inactive TED, who did not receive any TED treatment during the follow-up period of 3-6 months. A multivariable regression analysis was employed to examine the clinical risk factors influencing the progress of TED and a predictive model based on risk factors was established., Results: Seventeen (15.9%) patients had progressed at the last observation. Male (p = 0.024), having smoking history (p = 0.009), compound indicator combined the duration of TED and immunosuppressive treatment history before 3 months (p = 0.026) and more severe diplopia (p = 0.015) were found to be the potential risk factors for progression. Among the subset of patients who exhibited progression, there was a notable escalation in the severity of proptosis (p = 0.021), margin reflex distance-1 (p = 0.031), and clinical activity score (p = 0.011). The multivariable stepwise regression analysis identified positive smoking history as well as untreated and having a duration of TED > 12 months as independent risk factors of TED progression. A predictive model including these risk factors was built, with the AUC (Area Under Curve) score of 0.783., Conclusions: The predictors of TED progression include smoking history and composite indicators of duration time and treatment history. Our model may provide recommendations for immunosuppressive therapy and prognostic predictions for inactive TED patients preparing for surgery., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: Forkhead box P3 ( FOXP3 ) gene polymorphisms have been evaluated in many autoimmune diseases, including Graves' disease (GD), in different populations. However, those polymorphisms have not been analyzed in GD or Graves' ophthalmopathy (GO) in the Turkish population. In this study, we aimed to evaluate the frequency of FOXP3 polymorphisms in GD with or without ophthalmopathy in a Turkish population., Materials and Methods: The study included 100 patients with GO, 74 patients with GD without ophthalmopathy, and 100 age- and sex-matched healthy controls. In all study participants, rs3761547 (-3499 A/G), rs3761548 (-3279 C/A), and rs3761549 (-2383 C/T) single nucleotide polymorphisms (SNPs) were detected using the polymerase chain reaction-restriction fragment length polymorphism method. The chi-square test was used to evaluate genotype and allele frequencies. Odds ratios and 95% confidence intervals were calculated for genotype and allele risks., Results: In the patient group (including GD with or without ophthalmopathy), the rs3761548 AC and AA genotype and rs3761549 CT genotype were significantly more frequent than in the control group (all p<0.05). No genotypic and allelic differences were observed for rs3761547 between the patient and control groups (all p>0.05). There was no statistically significant difference between the GO and GD without ophthalmopathy groups concerning the allele and genotype frequencies of all three FOXP3 SNPs (all p>0.05)., Conclusion: The AC and AA genotypes of rs3761548 (-3279) and CT genotype of rs3761549 (-2383 C/T) were shown to be possible risk factors for GD development in the Turkish population. However, none of the three SNPs was shown to be associated with the development of GO in patients with GD., Competing Interests: Conflict of Interest: No conflict of interest was declared by the authors., (©Copyright 2024 by the Turkish Ophthalmological Association / Turkish Journal of Ophthalmology published by Galenos Publishing House.)

Purpose: There are limited recent data on the effect of radioactive iodine (RAI) for Graves' disease on Graves' orbitopathy (GO) development or reactivation. This audit investigates the GO incidence in patients with Graves' disease after RAI treatment, and explores risk factors present, and steroid prophylaxis use., Methods: A retrospective audit of Graves' disease patients treated with RAI over a 5-year period. Data collected: smoking status, thyroid-stimulating hormone receptor antibody (TRAb) status, GO history, Graves' disease duration, eye features pre- and post-treatment, prophylactic corticosteroids, RAI dose given, post-RAI thyroid status, duration until hypothyroid., Results: One hundred one patients were included, with a median Graves' disease duration 36 months. 34/101 (33.7%) were active/ex-smokers, 86/101 (85.1%) were TRAb-positive, 11/101 (10.9%) had a GO history; 32 (31.7%) had eye features present. Median RAI dose given was 596MBq. 8/101 (7.9%) patients received prophylactic corticosteroid; 89/101 (88.1%) achieved hypothyroid state in the year after RAI. GO developed in 5/101 (5.0%), of which 4/5 (80%) were de novo in high-risk individuals who did not receive steroids. One was a GO reactivation despite steroids. Two required intravenous steroids with/without orbital radiotherapy, one completed oral steroid taper; the remainder were treated conservatively., Conclusion: Our cohort had a lower GO incidence in patients with Graves' disease receiving RAI, with majority arising de novo . It is essential that all patients are assessed for Graves orbitopathy risk factors and counselled adequately prior to RAI. The decision to initiate steroids should be undertaken in a multi-disciplinary setting involving endocrinologists and ophthalmologists., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: To obtain clinical data about disease activity and severity of thyroid eye disease (TED) in a tertiary eye hospital in the Eastern Province of Saudi Arabia and to correlate this data with vitamin D levels., Methods: A clinical observational study was conducted in a specialized eye hospital in Saudi Arabia. It included prospective enrollment of Saudi patients with confirmed TED to evaluate activity and severity according to Clinical Activity Score (CAS) and European Group on Graves' Orbitopathy (EUGOGO), respectively, and also for blood investigation, including thyroid profile and vitamin D levels. In addition, some retrospective data collection included previous medical and surgical treatment and complications., Results: A total of 74 TED patients were included, with a median age of 42 years and a female predominance of 64.9%. Smokers were 18.9%. A family history of thyroid disease was noted in 12.16% of patients. There were 10.8% of patients with active TED. A moderate to severe severity level was observed in 71% of the cases, mild in 15%, and sight-threatening in 6%. Smoking and older age were associated with the active form of TED. There was a 48.4% prevalence of vitamin D deficiency among TED patients and it was not associated with TED severity or activity., Conclusions: This is the first study demonstrating the clinical profile of TED among Saudi patients. Smoking and older age were associated with TED. Vitamin D deficiency among TED patients was not worse than that of the general Saudi population.

Background: Graves' orbitopathy (GO) is subject to epidemiological and care-related changes. Aim of the survey was to identify trends in presentation of GO to the European Group On Graves' Orbitopathy (EUGOGO) tertiary referral centres and initial management over time., Methods: Prospective observational multicentre study. All new referrals with diagnosis of GO within September-December 2019 were included. Clinical and demographic characteristics, referral timelines and initial therapeutic decisions were recorded. Data were compared with a similar EUGOGO survey performed in 2012., Results: Besides age (mean age: 50.5±13 years vs 47.7±14 years; p 0.007), demographic characteristics of 432 patients studied in 2019 were similar to those in 2012. In 2019, there was a decrease of severe cases (9.8% vs 14.9; p<0.001), but no significant change in proportion of active cases (41.3% vs 36.6%; p 0.217). After first diagnosis of GO, median referral time to an EUGOGO tertiary centre was shorter (2 (0-350) vs 6 (0-552) months; p<0.001) in 2019. At the time of first visit, more patients were already on antithyroid medications (80.2% vs 45.0%; p<0.001) or selenium (22.3% vs 3.0%; p<0.001). In 2019, the initial management plans for GO were similar to 2012, except for lid surgery (2.4% vs 13.9%; p<0.001) and prescription of selenium (28.5% vs 21.0%; p 0.027)., Conclusion: GO patients are referred to tertiary EUGOGO centres in a less severe stage of the disease than before. We speculate that this might be linked to a broader awareness of the disease and faster and adequate delivered treatment., Competing Interests: Competing interests: Non-financial: LB is president of the European Group on Graves Orbitopathy, Scientific Chair of the Italian Society of Ophthalmic Plastic Surgery and member of the ethic committee of the Italian Society of Ophthalmic Plastic Surgery. BV is secretary of the British Thyroid Association, member of the Executive Committee of the European Thyroid Association, member of the UK Society for Endocrinology Program Committee, trustee of the Thyroid Eye Disease Charitable Trust (TEDct) and Joint Editor-in-chief of Thyroid Research journal. Financial: SD receives financial support to his institution form Bayer, Novartis, Abbvie, SIFI and ORSANA. AE receives financial support for lectures by NocoNordisk and Sanofi. MH receives financial support for travels and consultant fees of anonymous sponsors. MS receives consultant fees by Valenza Bio, speaker fees and financial support for attending meetings by IBSA international. BV receives traveling support from NovoNordisk, Speaker Honorarium form Berlin-Chemie and Sondoz. All other authors have nothing to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Atypical Graves disease (GD) is a common complication in multiple sclerosis (MS) patients treated with alemtuzumab. We present epidemiological, clinical, and biochemical characteristics of alemtuzumab-induced GD., Methods: Retrospective follow-up study of MS patients treated with alemtuzumab from 2014 to 2020, including clinical course of GD, pregnancy outcome, and thyroid eye disease (TED)., Results: We enrolled 183 of 203 patients (90%, 68% women) treated with alemtuzumab at 4 hospitals in Norway. Seventy-five (41%) developed thyroid dysfunction, of whom 58 (77%) had GD. Median time from the first dose of alemtuzumab to GD diagnosis was 25 months (range, 0-64). Twenty-four of 58 GD patients (41%) had alternating phases of hyper- and hypothyroidism. Thyrotropin receptor antibodies became undetectable in 23 of 58 (40%) and they could discontinue antithyroid drug treatment after a median of 22 (range, 2-58) months. Conversely, 26 (44%) had active disease during a median follow-up of 39 months (range, 11-72). Two patients (3%) received definitive treatment with radioiodine, 6 (10%) with thyroidectomy. Nine developed TED (16%), 7 had mild and 2 moderate to severe disease. Four patients completed pregnancy, all without maternal or fetal complications. Patients who developed GD had a lower frequency of new MS relapses and MRI lesions than those without., Conclusion: GD is a very common complication of alemtuzumab treatment and is characterized by alternating hyper- and hypothyroidism. Both remission rates and the prevalence of TED were lower than those reported for conventional GD. Pregnancies were uncomplicated and GD was associated with a lower risk of subsequent MS activity., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Treatment with Alemtuzumab (ALZ) in patients with Relapsing-Remitting Multiple Sclerosis (RRMS) is associated with the development of ALZ-induced Graves' disease (GD-ALZ). Some cases may develop associated Graves´ Orbitopathy (GO-ALZ), with possible visual compromise., Aim: The aim of this study was to describe the main clinical and biochemical characteristics of GD-ALZ, as well as the clinical course of a case series of GO-ALZ METHODS: This study is a retrospective observational study, carried out in a reference hospital for the care of patients with RRMS in Spain. Cases treated with ALZ in the period 2014-2022 were included. GO-ALZ cases were identified among those with clinical symptoms compatible with thyroid eye disease after initiating ALZ treatment., Results: A total of 135 cases, with a mean follow-up of 69.6 months after the first ALZ cycle, were included. The incidence of GD-ALZ was 32.6% (44/135), with a predominance of women (77.3%) and mean age of 41.9 years. The presence of first-degree relatives with hypothyroidism was identified as risk factor for the development of GD-ALZ (adjusted P-value: 0.02). GO-ALZ was diagnosed in 6 cases (incidence: 13.6%), of which 3 had severe clinical forms of GO, requiring anti-IL-6 treatment. A favorable response was reported in all of them, with a significant decrease in disease activity and improvement in proptosis., Conclusions: We report one of the largest cohorts of GD-ALZ and GO-ALZ cases. The diagnosis of these entities should be taken into account in patients treated with Alemtuzumab, given the risk of developing severe clinical forms. In moderate-severe forms of GO-ALZ, drugs with anti-IL-6 activity are a safe and effective option., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Purpose: To evaluate the association between obstructive sleep apnea (OSA) and thyroid eye disease (TED) and its effect on disease activity., Methods: A prospective case-control study was conducted from January 2020 to March 2022. All TED patients (group A) were clinically evaluated. The activity of thyroid eye disease was calculated based on the clinical activity score (CAS), and grading of severity was done according to the EUGOGO classification. All TED patients (group A) were screened for OSA using the Snoring Tired Observed Pressure (STOP)-Bang survey. Age- and gender-matched control group patients (group B) without TED were screened for OSA., Results: One hundred TED patients and 138 control patients without TED were included in the respective groups. Sixty-two (62%) patients in group A and 48 (34.78%) patients in group B were having high risk of OSA, and this difference was statistically significant (P = 0.001). Further, in group A patients, on univariate analysis, TED activity was significantly associated with a high risk of OSA (P = 0.009). On multivariate logistic regression analysis, OSA also showed significant association with TED activity (odds ratio [OR]: 4.14, 95% confidence interval [CI]: 1.11-18.85 at 10% level; P = 0.05)., Conclusion: Our study showed that OSA is significantly associated with TED disease and its activity. However, no significant association was found between OSA and severity of the disease., (Copyright © 2023 Copyright: © 2023 Indian Journal of Ophthalmology.)

Background: Thyroid eye disease (TED) is an autoimmune disorder of the orbit and the most frequent extrathyroidal manifestation of Graves' disease but it may rarely occur in euthyroid/hypothyroid patients with chronic autoimmune thyroiditis., Epidemiology: TED is a relatively infrequent disorder, particularly in its severe forms. Men tend to have more severe TED at an older age. The prevalence of TED is lower than in the past among patients with recent onset Graves' hyperthyroidism, and moderate-to-severe forms requiring aggressive treatments are no more than 5% to 6% of all cases., Natural History: After an initial inflammatory (active) phase and a plateau phase, TED stabilizes and eventually inactivates (inactive or burnt-out phase) after an estimated period of 18-24 months. Minimal-to-mild TED often remits spontaneously, but complete restitutio ad integrum almost never occurs when TED is more than mild., Risk Factors: Several risk factors contribute to its development on a yet undefined genetic background. Cigarette smoking is the most important of them, but thyroid dysfunction (both hyper- and hypothyroidism), radioactive iodine therapy (if not accompanied by low-dose steroid prophylaxis), elevated thyrotropin receptor antibodies, and, probably, hypercholesterolemia represent relevant modifiable risk factors. Early diagnosis, control and removal of modifiable risk factors, and early treatment of mild forms of GO (local treatment and selenium) may effectively limit the risk of progression to more severe forms., Competing Interests: The authors have no financial or conflicts of interest to disclose., (Copyright © 2023 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Appropriate administration of anti-inflammatory and immunosuppressive treatment (AIIST) is important for patients with Graves' orbitopathy (GO). This study aimed to clarify the incidence and risk factors for GO treated with AIIST and propose a predictive score, among newly diagnosed Graves' disease (GD) patients in Japan. A total of 1,553 GD patients who were newly diagnosed during the year 2011 were investigated. AIIST included local and/or systemic glucocorticoid administration and retrobulbar irradiation. A multivariable Cox proportional hazards model was used to investigate the risk factors for GO underwent AIIST during medical treatment, including at diagnosis, of GD. Then, a GO score was created by summing each point assigned to risk factors based on their coefficient obtained in the Cox model. AIIST was administered to 107 patients (6.9%). The risk factors and hazard ratios for GO underwent AIIST were: age (per 10 years), 1.32 (95% confidence interval: 1.16-1.50), p < 0.0001; TSH binding inhibitory immunoglobulin (TBII) (per 10 IU/L), 1.33 (1.15-1.54), p = 0.0001; and thyroglobulin antibody (TgAb) negativity, 2.98 (1.96-4.59), p < 0.0001. The GO score, ranging from 0 to 8 points, showed moderate performance (area under the curve: 0.71, cut-off value: 5 points, sensitivity: 0.76, specificity: 0.59, positive predictive value: 0.12, negative predictive value: 0.97). AIIST was performed for patients with active manifestations of GO in 6.9% of newly diagnosed GD patients. The risk factors for GO underwent AIIST were higher age, higher TBII, and TgAb negativity. The GO score based on these factors may be useful in managing GO.

Purpose: Knowledge of thyroid eye disease (TED) is based on predominantly Caucasian populations. To date, no studies in the United States examine the presentation in Black and Hispanic patients. The purpose of this study is to introduce the presentation of TED in two previously undescribed populations., Methods: This is a retrospective, cross-sectional, chart review study of patients with TED at a tertiary center using the Strengthening the Reporting of Observational Studies in Epidemiology checklist. The main outcome measure for severity was the European Group on Graves' Orbitopathy 2016 Severity Scale., Results: Of the 2905 charts reviewed, 99 met the inclusion criteria. The mean age was 51 (standard deviation 16) years with 78% women. Race was 49.4% Black, 39.1% Hispanic, 9.2% Caucasian, and 2.3% Asian. Smoking rates were 25% current smokers and 14% former smokers. Manifestations were proptosis (94% Hispanic and 91% Black), eyelid retraction (85% Hispanic and 79% Black), extraocular muscle (EOM) restriction (79% Hispanic and 63% Black), eyelid edema (41% Hispanic and 30% Black), chemosis (24% Hispanic and 14% Black), and optic neuropathy (18% Hispanic and 9% Black). Overall, disease severity was 22% mild, 65% moderate to severe, and 13% sight-threatening. Older patients had increased rates of optic neuropathy ( P = 0.04). Younger patients had increased rates of proptosis ( P = 0.02). Socioeconomic status was not associated with disease severity ( P = 0.67)., Conclusion: Hispanic and Black patients with TED presented with higher than previously established rates of proptosis, EOM restriction, and optic neuropathy. Including research of different races broadens understanding of presentation and management, improving patient outcomes., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Middle East African Journal of Ophthalmology.)

Objective: To determine the impact of thyroid eye disease (TED) on patients in various stages of the disease., Background: TED is a debilitating and potentially sight-threatening inflammatory autoimmune disease that is frequently misdiagnosed. Challenging quality-of-life (QoL) issues can persist long after the active phase of disease has subsided., Methods: A 62-question survey was designed as a hypothesis-generating instrument to identify key issues confronting patients ≥18 years old with physician-diagnosed TED. Questions focused primarily on physical and emotional status, and QoL experiences in the 2 months prior to the survey. Data for individual questions are presented as summary statistics. Correlations between questions were determined using χ 2 analyses., Results: The 443 respondents were 18 to >80 years old; >90% female, and >80% from the United States. Time since TED diagnosis ranged from <1 year to >10 years. Participants provided >500 free-form responses describing experiences of living with TED. Physical signs/symptoms were experienced by 307/443 (69%) patients. Of those responding to the QoL questions (N = 394), 53 (13%) reported symptoms improving, 73 (19%) reported symptoms worsening, and 255 (65%) reported no change in the 2 months prior to the survey. The most bothersome signs/symptoms were dry/gritty eyes, light sensitivity, bulging eyes, and pressure or pain behind the eyes. Respondents <60 years were significantly (p < 0.0001) more likely to report symptomatic TED than older patients. Of 394 respondents, 179 (45%) reported feeling depressed and/or anxious, 174 (44%) reported concern about their appearance, and 73 (19%) avoided public situations; 192 (49%) reported declines in confidence or feelings of general well-being, and 78 (20%) reported an inability to achieve goals. Activities limited by TED included reading, driving, and socializing. The proportion of respondents experiencing these negative QoL measures was higher when patients reported experiencing >5 symptoms, had been diagnosed within the last 5 years, or were <60 years of age., Conclusions: Physical manifestations of TED impact QoL for patients through all phases of the disease. It is essential that physicians and healthcare professionals become more familiar with patient experiences such as those described here to better help patients manage their disease., Competing Interests: TS has been issued US patents covering the use of IGF-I receptor antagonists as therapy for autoimmune disease. These are held by UCLA/Lundquist Institute. He is a consultant for Horizon Therapeutics, Veridian Therapeutics, Inc., Minghui Pharmaceutical, and Lundbeck. LH has received honoraria from Horizon Therapeutics and Lundbeck A/S. IL has no conflicts to declare. PP has received honoraria from IBSA. KD is an employee of GDATF which has received grants from Horizon Therapeutics. MK, PT-O, LW, and MN are employees of rareLife solutions, Inc., Westport, CT, United States., (Copyright © 2023 Smith, Hegedüs, Lesser, Perros, Dorris, Kinrade, Troy-Ott, Wuerth and Nori.)

Objective: To assess sex-specific risk factors for Graves' orbitopathy (GO) in newly diagnosed Graves' disease (GD) patients., Methods: A retrospective cohort study was conducted using the National Health Insurance Service's sample database, which consisted of 1,137,861 subjects from 2002 to 2019. The international classification of disease-10 codes was used to identify those who developed GD (E05) and GO (H062). A multivariable Cox proportional hazards model was used to estimate the effect of risk factors on GO development., Results: Among 2145 male and 5047 female GD patients, GO occurred in 134 men (6.2%) and 293 women (5.8%). A multivariable Cox regression model revealed that GO development was significantly associated with younger age (HR = 0.84, 95% CI = 0.73-0.98), low income (HR = 0.55, 95% CI = 0.35-0.86), and heavy drinking (HR = 1.79, 95% CI = 1.10-2.90) in men, and with younger age (HR = 0.89, 95% CI = 0.81-0.98), lower body mass index (HR = 0.55, 95% CI = 0.33-0.90), high total cholesterol (HR = 1.04, 95% CI = 1.01-1.06), hyperlipidaemia (HR = 1.37, 95% CI = 1.02-1.85), and lower statin dose (HR = 0.37, 95% CI = 0.22-0.62) in women. There was no association between smoking and GO development in both men and women., Conclusions: The risk factors for GO development were sex-dependent. These results show the need for more sophisticated attention and support considering sex characteristics in GO surveillance., (© 2023. The Author(s).)

Purpose: To evaluate prevalence of thyroid eye disease (TED) and associated factors in the American Academy of Ophthalmology IRIS Ⓡ Registry (Intelligent Research in Sight)., Design: Cross-sectional analysis of the IRIS Registry., Methods: IRIS Registry patients (18-90 years old) were classified as TED (ICD-9: 242.00, ICD-10: E05.00 on ≥2 visits) or non-TED cases, and prevalence was estimated. Odds ratios (OR) and 95% Confidence Intervals (CIs) were estimated using logistic regression., Results: 41,211 TED patients were identified. TED prevalence was 0.09%, showed a unimodal age distribution (highest prevalence in ages 50-59 years (y) (0.12%)), higher rates in females than males (0.12% vs. 0.04%) and in non-Hispanics than Hispanics (0.10% vs. 0.05%). Prevalence differed by race (from 0.08% in Asians to 0.12% in Black/African-Americans), with varying peak ages of prevalence. Factors associated with TED in multivariate analysis included age: ((18-<30y (reference), 30-39y: OR (95%CI) 2.2 (2.0, 2.4), 40-49y: 2.9 (2.7,3.1), 50-59y: 3.3 (3.1, 3. 5), 60-69y: 2.7 (2.54, 2.85), 70+: 1.5 (1.46, 1.64)); female sex vs male (reference), 3.5 (3.4,3.6), race: White (reference), Blacks: 1.1 (1.1,1.2), Asian: 0.9 (0.8,0.9), Hispanic ethnicity vs not Hispanic (reference), 0.68 (0.6,0.7), smoking status: (never (ref), former: 1.64 (1.6,1.7), current 2.16: (2.1,2.2)) and Type 1 diabetes (yes vs no (reference): 1.87 (1.8, 1.9)., Conclusions: This epidemiologic profile of TED includes new observations such as a unimodal age distribution and racial variation in prevalence. Associations with female sex, smoking, and Type 1 diabetes are consistent with prior reports. These findings raise novel questions about TED in different populations., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: To assess the association between thyroid eye disease (TED) and glaucoma., Methods: Patients 18 years of age and over enrolled in the NIH All of Us Research Program, a nationwide cohort, were extracted. Those with conditions relating to TED were identified and compared with 2020 US Census-matched controls without a diagnosis of TED in a 1:4 ratio. The authors used Pearson's χ 2 tests to study demographics by TED status, and logistic regression to generate odds ratios and 95% confidence intervals to evaluate the association between TED and glaucoma (any type, including glaucoma suspect), using those without TED as the reference group. Multivariable models were adjusted for age, gender, race/ethnicity, eye doctor visits, and smoking status., Results: A total of 393 cases of TED and 1,572 US Census-matched controls were identified. The median age of the cohort was 63 years (interquartile range: 48-73 years). Age, gender, and race/ethnicity varied by TED status ( p < 0.001). Overall, 114 (29.0%) of TED cases had a diagnosis of glaucoma, compared with 94 (6.0%) of non-TED controls. On bivariate logistic regression models, those diagnosed with TED were significantly more likely to be diagnosed with glaucoma compared with controls (odds ratio: 6.42; 95% confidence interval: 4.76-8.70; p < 0.001). This trend persisted on multivariable logistic regression controlling for confounding factors (odds ratio: 3.37; 95% confidence interval: 1.85-6.20 p < 0.001)., Conclusions: Individuals with TED were significantly more likely to be diagnosed with glaucoma. Clinicians caring for patients with TED should be aware of this elevated risk and arrange glaucoma evaluation, accordingly., Competing Interests: The authors have no financial or conflicts of interest to disclose., (Copyright © 2023 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Purpose: Severity of Graves' orbitopathy (GO) shows wide individual differences. For optimal treatment, it is important to be able to predict the natural course of the disease as accurate as possible to counteract with anti-inflammatory and surgical treatment. Therefore, we aimed to further elucidate the impact of sex, age and smoking on GO., Methods: We collected the clinical and demographic data of all patients of our tertiary referral center from January 2008 till December 2018 and analyzed it with descriptive statistics. Only patients with a complete data set were included in the further analysis. Odds ratio's for moderate-to-severe and sight-threatening GO in relation to age, sex and smoking were calculated by means of multivariate logistic regression models., Results: We evaluated the data of 4260 patient with GO and complete data sets. Most of these were women (83%). There were no significant differences between male and female patients regarding smoking habits and thyroid treatment. Men were significantly older at initial manifestation of TED (51.8 vs. 49.9y, p<0.01) and showed significant more often severe stages (61% vs. 53%, p<0.0001). Therefore, they needed significantly more intense treatment with steroids, irradiation, orbital decompression and muscle surgery. In multivariate logistic regression analyses age (OR 0.97, 95% CI:0.97-0.98, p<0.0001), male sex (OR 1.64, 95% CI:1.38-1.9, p<0.0001), smoking (OR 1.19, 95% CI:1.04-1.36, p=0.01), Grave's disease (OR 1.55, 95% CI:1.26-1.90, p<0.0001) and history of radioiodine treatment (RAI) (OR 2.44, 95% CI:2.10-2.86, p<0.0001) showed an significant association with severe stages of GO., Discussion: Our retrospective analysis showed once more that women are more often afflicted by GO. In contrast, men seem to be more severely afflicted and in need of anti-inflammatory and surgical treatments. This might be due to a different approach to the health system and resilience to GO specific symptoms, as well as previously described worse thyroid control. Estrogen mediated effects might also play a role as in other autoimmune diseases and should be subject of further trials. Besides the biological sex, smoking could again be confirmed as serious risk factor for severe GO. Of note, RAI was associated with more severe stages of GO, which should be subject to further investigation., Competing Interests: The 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., (Copyright © 2023 Oeverhaus, Winkler, Stähr, Daser, Bechrakis, Stöhr, Chen and Eckstein.)

Purpose: To analyse risk factors for the development of superior limbic keratoconjunctivitis (SLK) in thyroid eye disease (TED)., Methods: This prospective, observational study included 638 eyes/sides from 319 patients with TED. The eyes were classified into two groups, based on the presence and absence of SLK. Multivariate logistic regression analysis was performed to evaluate potential risk factors, including sex, patient age, past treatment history (steroid, orbital radiotherapy and radioiodine therapy), smoking, clinical activity score, margin reflex distance (MRD)-1 and -2, Graefe sign/lid lag, Hertel exophthalmometric results, Schirmer's test results, tear break-up time (TBUT) and tear meniscus height (TMH)., Results: SLK was found in 198 eyes (31.0%) from 121 patients. Young age (OR, 0.977; P = 0.006), smoker (OR, 1.785; P = 0.009), presence of Graefe sign (OR, 2.912; P < 0.001), absence of lid lag (OR, 0.485; P = 0.031), high Hertel exophthalmometric values (OR, 1.125; P = 0.002), shorter Schirmer's test results (OR, 0.962; P < 0.001), shorter TBUT (OR, 0.815; P = 0.002) and high upper TMH (OR, 1.003; P = 0.013) were associated with the development of SLK. A high MRD-1 measurement value also tended to be associated with a risk of SLK, with an OR of 1.187 (P = 0.056)., Conclusion: The present study proposed several risk factors in relation to the development of SLK in TED., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To evaluate the changes in demographics, clinical findings, and treatment modalities in Graves' orbitopathy (GO) patients at a tertiary referral center in Turkey over the last two decades., Methods: The clinical data of 752 GO patients were evaluated retrospectively. Patients were divided into 2 groups according to the first ophthalmic examination date; Group 1(n:344) between January 1998 and December 2007 and Group 2(n:408) between January 2008 and December 2017., Results: The number of nonsmokers was significantly higher in Group 2 (44.0 vs. 26.5%, p < 0.001). The time from the diagnosis of thyroid dysfunction and referral to our center was 32.4 months in Group 1 and 34.8 months in Group 2, (p = 0.166). The most common treatment of hyperthyroidism was antithyroid medications. Radioiodine ablation treatment rate was significantly lower in Group 2 (14.8 vs. 9.1%, p < 0.001). The time between the diagnosis of thyroid disease and orbital involvement was 22.0 vs. 26.6 months in Groups 1 and 2, respectively (p = 0.009). The time elapsed between the diagnosis of orbital disease and referral to our clinic was 21.0 months vs. 22.4 months in Group 1 and 2, respectively (p = 0.068). Orbital disease was most commonly mild, and inactive. Mild and moderate to severe GO and the mean Clinical Activity Score significantly increased, and the rate of sight-threatening disease and orbital decompression surgery significantly decreased in Group 2 (p = 0.042; p < 0.001, respectively)., Conclusions: Mild and inactive orbital disease was the most common form of GO. The severity of GO is declining over the last two decades in Turkey., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Introduction and Purpose: Patients with Graves' orbitopathy (GO) may develop restricted elevation; this can lead to hypotropia, sometimes in combination with an abnormal head posture. Recession of one or both inferior rectus muscles is the first line surgery to restore eye motility in these patients. However, this may result in A pattern strabismus. This study was performed to determine the rate of occurrence of this type of incomitant strabismus and potential predictive factors., Methods: All patients undergoing surgery on one or two inferior rectus muscles over a 10-year period were screened retrospectively for the A pattern, defined as a ≥5° difference in squint angle between the primary gaze and downgaze. The extraocular muscle thickness in patients with acquired A pattern was determined by computed tomography (CT) and compared with a control group consisting of patients randomly selected from the total cohort., Results: In a total of 590 patients, surgery was performed on the inferior rectus muscle(s) during the study period; the A pattern was identified in 59 patients. Simultaneous surgery was performed on one or both medial rectus muscles in 32% of the patients. This group had significant incyclotorsion (p = 0.000) and less depression (p = 0.000) postoperatively. The mean amount of recession was 4.38 ± 1.53 mm in the A pattern group and 3.91 ± 1.37 mm in the control group (p = 0.032). The amount of depression was 50.2° ± 7.4° in the A pattern group and 57.3° ± 4.4° in the control group (p = 0.045). The inferior rectus muscle was significantly thicker in the A pattern than in the control group (p = 0.027), while there was no significant difference in the thickness of the superior oblique muscle between the two groups (p = 0.870). Of all patients with the A pattern, 47% required further surgery to achieve adequate binocular single vision., Conclusion: Increased preoperative inferior rectus muscle thickness and relatively limited depression could be predictors of postoperative A pattern inferior rectus recession in patients with GO. Step-by-step procedures are preferable in this surgically challenging group of patients., (© 2022 The Authors. Acta Ophthalmologica published by John Wiley & Sons Ltd on behalf of Acta Ophthalmologica Scandinavica Foundation.)

An assessment of the risk of Graves' orbitopathy (GO) is an important challenge in Graves' disease (GD) management. The purpose of this study was to compare non-genetic parameters in GD patients with and without GO in order to find novel risk factors and to verify the factors already reported. A total number of 161 people, 70 with GO and 91 non-GO patients were included in this study. GO was confirmed to be associated with smoking, older age, higher TSH receptor antibodies (TRAb) and lower thyroglobulin antibody (TgAb) levels and hypercholesterolemia. We demonstrated the latter correlation even for only a mild increase in LDL cholesterol. Importantly, our study provides novel potential GO risk factors, including higher serum creatinine levels, higher MCV and lower PLT. If further confirmed, these new, simple and easily accessible potential GO markers may constitute valuable auxiliary markers in GO risk assessments. We additionally proved that in moderate to severe GO, gender-related differences attenuate. No impact of vitamin D deficiency in GO development in patients with 25-hydroxyvitamin D [25(OH)D] > 20 ng/mL was found. The present report provides a set of GO risk factors, which can be used as a precise tool for an individual GO risk assessment.

Background: The most prevalent extrathyroidal manifestation of Graves' disease (GD) is Graves' ophthalmopathy (GO). However, only few methods allow for predictions of GO occurrence or progression in patients with GD. Methods: We retrospectively analyzed 1,074 patients with new-onset GD, and divided them into a derivation and a validation cohort based on the date of their GD diagnosis. We then separately analyzed clinical risk factors affecting the occurrence and progression of GO using multivariable regression analysis and created a predictive model based on the factors we identified as significant. Results: Of the 853 GD patients included in the derivation cohort, 101 (11.8%) developed GO. Those who developed GO were more likely to be smokers (25.7% vs. 8.5%, p  < 0.001), were younger at the time of their GD diagnosis (35.0 years vs. 42.0 years, p  < 0.001), more commonly had a family history of GD (27.7% vs. 17.2%, p  = 0.015), and had higher thyrotropin-binding inhibitor immunoglobulin (TBII) levels at the time of their diagnosis (13.5 IU/L vs. 10.0 IU/L, p  = 0.020) than those who did not develop GO. Of the 101 GO patients in the derivation cohort, after excluding 8 who initially had active and moderate-to-severe GO, 11 of the remaining 93 had progressed to more active or severe GO. GO patients with confirmed progression had a higher proportion of those older than 45 years (54.5% vs. 19.8%, p  = 0.031), and they had a different initial clinical activity score distribution. The multivariable regression analysis identified age at GD diagnosis, sex, smoking history, family history of GD, total cholesterol level, and TBII level at the time of the diagnosis as significant risk factors of GO occurrence, and a predictive model including these risk factors was built to create a nomogram. Conclusions: The predictors of GO occurrence in patients with new-onset GD were female sex, positive smoking history, young age, family history of GD, high cholesterol level, and high TBII level. The predictive nomogram developed in this study may be useful in patient counseling and facilitating informed treatment decision-making.

Graves' orbitopathy (GO) is an orbital autoimmune disorder and the main extrathyroidal manifestation of Graves' disease, the most common cause of hyperthyroidism. GO affects about 30% of Graves' patients, although fewer than 10% have severe forms requiring immunosuppressive treatments. Management of GO requires a multidisciplinary approach. Medical therapies for active moderate-to-severe forms of GO (traditionally, high-dose glucocorticoids) often provide unsatisfactory results, and subsequently surgeries are often needed to cure residual manifestations. The aim of this review is to provide an updated overview of current concepts regarding the epidemiology, pathogenesis, assessment, and treatment of GO, and to present emerging targeted therapies and therapeutic perspectives. Original articles, clinical trials, systematic reviews, and meta-analyses from 1980 to 2021 were searched using the following terms: Graves' disease, Graves' orbitopathy, thyroid eye disease, glucocorticoids, orbital radiotherapy, rituximab, cyclosporine, azathioprine, teprotumumab, TSH-receptor antibody, smoking, hyperthyroidism, hypothyroidism, thyroidectomy, radioactive iodine, and antithyroid drugs. Recent studies suggest a secular trend toward a milder phenotype of GO. Standardized assessment at a thyroid eye clinic allows for a better general management plan. Treatment of active moderate-to-severe forms of GO still relies in most cases on high-dose systemic-mainly intravenous-glucocorticoids as monotherapy or in combination with other therapies-such as mycophenolate, cyclosporine, azathioprine, or orbital radiotherapy-but novel biological agents-including teprotumumab, rituximab, and tocilizumab-have achieved encouraging results., (© 2022 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Purpose: Ocular hypertension (OHT) is an important clinical feature of thyroid-associated orbitopathy (TAO).While the prevalence and outcome of OHT in TAO remains unclear. This study investigates this in moderate-severe active TAO., Methods: Sixty-eight patients with active moderate-severe TAO were recruited, 49 of whom were treated with 12-week GC therapy.The clinical and biochemical parameters were collected.Treatment outcomes were evaluated after GC therapy., Results: The prevalence of OHT was 44.85% in moderate-severe active TAO patients,including 81.97% of mild hypertension, 13.11% of moderate hypertension and 4.92% of severe hypertension. Clinical and biochemical parameters had no significant difference between OHT patients and non-OHT patients,such as age, sex distributions, smoking status, the kind and the duration of thyroid disease,the duration of eye symptoms and the level of FT3,FT4,TSH, TR-Ab, and Tpo-Ab, Tg-Ab(all P > 0.05). After GC therapy,the intraocular pressure(IOP) in OHT eyes decreased significantly (P < 0.05), while IOP in non-OHT eyes remained unchanged (P > 0.05).There was no significant difference in CAS and the effective rate of GC therapy between OHT eyes and non-OHT eyes (P > 0.05)., Conclusion: In moderate-severe active TAO, the prevalence of OHT was 44.85%, most of which were mild hypertension.OHT was relieved by GC therapy,which had no effect on the efficacy of GC therapy.Our results will enhance physicians' confidence in GC therapy., (© 2022. The Author(s).)

Objective: Thyroid eye disease (TED) is an autoimmune, inflammatory disease resulting in retro-orbital fat and extraocular muscle expansion. TED quiets ("inactivates") as inflammation wanes; however, signs/symptoms often persist. Signs/symptoms of the disease and the impact on quality of life (QoL) were examined in noninflammatory and inflammatory TED., Methods: Data of patients with moderate-to-severe TED were collected from treating physicians. Clinical activity score (CAS, 6/7 measures available) was used to classify TED as inflammatory (CAS ≥ 3) or noninflammatory (CAS = 0 or 1). QoL impact was scored as 1 = "not at all impaired" to 7 = "extremely impaired." Patients with noninflammatory TED were further grouped into longer (>3 years) and shorter (≤3 years) disease courses., Results: Patients with inflammatory (N = 307) and noninflammatory (N = 281) TED had comparable age (50.0 ± 13.3 years vs 48.3 ± 13.8 years), gender (66% men vs 64% women), TED duration (4.0 ± 4.9 years vs 4.6 ± 5.5 years), and proportion of smokers (15% vs 11%). The most common signs/symptoms of noninflammatory TED included ocular dryness/grittiness (77%), proptosis (56%), excessive tearing (43%), soft tissue edema (42%), conjunctival redness (24%) decreased vision (24%), and eye muscle involvement (22%; 14% had diplopia). All signs/symptoms were less frequently reported in these patients than in those with inflammatory TED. QoL was impacted by noninflammatory TED, although to a lesser degree than the inflammatory disease (3.6 ± 1.5 vs 4.7 ± 1.4). However, mental health issues were similarly reported. Patients with noninflammatory TED with a longer disease course (9.0 ± 6.0 years) had similar QoL impact, mental health diagnoses, and TED signs/symptoms as those with a shorter disease course (1.4 ± 1.0 years)., Conclusion: The signs/symptoms of TED often chronically persist long after TED has "quieted," continuing to impact a patient's QoL and mental health. These data suggest that moderate-to-severe TED should be thought of as a robust symptomatic chronic disease, regardless of its inflammatory status., (Copyright © 2022 AACE. Published by Elsevier Inc. All rights reserved.)

Purpose: Thyroid eye disease (TED), an autoimmune orbital disorder, follows a time-of-onset bimodal peak: 40-44 and 60-64 years for women, 45-49 and 65-69 years for men. TED, however, can also commence in old age. The study's purpose was to evaluate TED in octo- and nonagenarians., Methods: Medical records of 19 ≥ 80 years geriatric patients at time of diagnosis were compared to 122 TED patients, aged 20-79. A second analysis was performed after subdividing the control group into two age groups, ≤ 40 ("young group," 16 patients) and 41-79 years ("middle-aged group," 106 patients)., Results: The geriatric group's mean age was 84 years (80-94), 11 males and 8 females. Mean follow-up time was 16 months. Compared to the controls, the geriatric patients smoked less (p = 0.012), were more often hypothyroid (p = 0.019), and had concurrent myasthenia gravis (p = 0.02) at time of diagnosis. Diplopia was the most common presenting symptom among the elderly (p = 0.005) and proptosis among the controls, specifically the young group (p = 0.027). Bilateral signs were more common among seniors (p = 0.049). Optic neuropathy was diagnosed in 10% of the geriatric group (2/19) and 11% of middle-aged group (12/106), all being resolved after steroids or orbital decompression. Active disease (clinical activity score (CAS) score =  > 3) was more common among the middle-aged group (p = 0.024) while the geriatric patients tended towards higher TED severity grades. Orbital decompression and eyelid repositioning surgeries were more common among the middle-aged group. Strabismus surgeries were more common among seniors., Conclusions: TED among octo- and nonagenarians has unique patterns, with different demographic features, more exposed to diplopia, hypothyroidism, association with myasthenia gravis, and bilateral involvement. Special attention should be given when medically managing this subgroup., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Thyroid eye disease (TED) is a rare disease that can lead to decreased quality of life, permanent disfigurement, and vision loss. Clinically, TED presents with exophthalmos, periorbital edema, extraocular muscle dysfunction, and eyelid retraction, and can lead to vision-threatening complications such as exposure to keratopathy and dysthyroid optic neuropathy (DON). Over the last several years, significant advancements have been made in the understanding of its pathophysiology as well as optimal management. Ethnic variations in the prevalence, clinical presentation, and risk of vision-threatening complications of TED are summarized, and risk factors associated with TED are discussed. Additionally, significant advances have been made in the management of TED. The management of TED traditionally included anti-inflammatory medications, orbital radiation therapy, orbital surgical decompression, and biologic therapies. Most recently, targeted therapies such as teprotumumab, an insulin-like growth factor-1 receptor antagonist, have been studied in the context of TED, with promising initial data. In this review, updates in the understanding and management of TED are presented with a focus on the international variations in presentation and management., Competing Interests: None

Importance: Thyroid eye disease (TED) is a serious condition that can cause proptosis and strabismus and, in rare cases, lead to blindness. Incidence data for TED and strabismus and surgical interventions after TED are sparce., Objective: To investigate the nationwide incidence of TED, strabismus, and surgical interventions associated with TED., Design, Setting, and Participants: A Danish nationwide registry-based cohort study between 2000, which marks the beginning of uniform coding for the decompression surgery nationwide, and 2018. The cohort consisted of a mean 4.3 million people aged 18 to 100 years with no prior TED diagnosis each year. Total observation time was 8.22 × 107 person-years (women, 4.18 × 107 person-years; men, 4.04 × 107 person-years)., Main Outcome Measures: The annual numeric and age-standardized incidence of hospital-treated TED and cumulative incidence of strabismus, strabismus surgery, and orbital decompression surgery in patients with TED. The incidence was stratified by sex, thyroid diagnosis, and age., Results: A total of 4106 incident diagnoses of TED were identified during 19 years among 3344 women (81.4%) and 762 men (18.6%). The mean numeric annual nationwide incidence rate of TED was 5.0 per 100 000 person-years overall, 8.0 per 100 000 person-years in women, and 1.9 per 100 000 person-years in men, resulting in a 4:1 ratio of women to men with TED. The age-standardized incidence was similar. The mean (SD) age at onset was 51.3 (14.5) years. At the time of TED diagnosis, 611 patients (14.9%) were euthyroid, 477 (11.6%) were hypothyroid, and 3018 (73.5%) were hyperthyroid. In patients with TED who were euthyroid, the 4-year cumulative incidence was 41% for antithyroid medication and 13% for L-thyroxine. In patients with TED, the 4-year cumulative incidence for strabismus was 10%. The 4-year cumulative incidence of surgical interventions after TED was 8% for strabismus surgery and 5% for orbital decompression. At 4 years, strabismus surgery was more common in men (13.3%; 95% CI, 10.75-15.86) than in women (7.2%; 95% CI, 6.24-8.08), and the absolute difference was 6.1% (95% CI, 3.42-8.14; P < .001)., Conclusions and Relevance: This study in Denmark provides nationwide empirical incidence of TED and strabismus and surgical interventions after TED that required inpatient or outpatient hospital treatment, and might be used for patient information and health care planning.

The management of hyperthyroidism and extrathyroidal manifestations of Graves disease remains complex. Considerations that include patient preference, age, comorbidity, pregnancy, tobacco smoking, and social determinants of health must all be weaved into a cohesive management plan. A multidisciplinary team is required to manage all aspects of Graves disease, particularly thyroid eye disease, for which new therapeutic options are now available., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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

Graves' orbitopathy is the most common extra-thyroid complication of Graves' disease and can be a potentially severe affection, therefore requiring multidisciplinary treatment support according to clinical activity and severity assessments. This review proposes to determine physiopathological mechanisms, epidemiology and therapeutic management of Graves' orbitopathy., (Copyright © 2022 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Purpose: This review aimed to provide an overview of current research into the risk factors for Graves' ophthalmopathy (GO)., Methods: To find information about the risk factors for GO, the research database PubMed was searched and relevant articles were obtained to extract information about risk factors., Results: Smoking has been widely accepted as an important risk factor and cigarette smoking cessation has been shown to improve the outcome and decrease the onset of GO. Radioactive iodine on the thyroid may induce hyperthyroidism and increase the occurrence of GO. Selenium deficiency is a risk factor for GO and the supplementation of selenium has been an adjuvant therapy. Decreasing stressful life events (SLE) may help improve GO. Imbalance in intestinal flora is essential to GO, with Yersinia enterocolitica and Escherichia coli both increased in the digestive tract of the individual with GO. In addition, controlling serum cholesterol may help improve GO since adipogenesis is an important pathological change in its pathogenesis. Considering the correlation between Graves' disease and GO, maintaining normal thyroid function hormone level is the first-line therapeutic strategy to prevent progression of GO. An increase in antibodies such as TSHR and IGF-1R is the main predictor of GO. Besides, gender and gene polymorphism are also risk factors towards GO., Conclusions: Risk factors for GO arise from five sources: physical and chemical environment, social-psychological environment, biological environment, the human organism, and genetic codes. Risk factors within these categories may interact with each other and their mechanisms in promoting the development of GO are complex. Research into risk factors for GO may promote emerging fields related to GO such as control of autoantibodies and intestinal microbiota., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: The extent to which mononuclear cells and TSH-receptor autoantibodies (TRAb) contribute to Graves' orbitopathy (GO) is not completely defined. Here we investigated the relationship between the immunohistochemical phenotype of orbital infiltrating cells and GO features in a large number of patients., Methods: We conducted an observational cohort study in 76 consecutive patients with GO (16 men and 60 women) who underwent orbital decompression over a period of 18 consecutive months. An ophthalmological evaluation was performed in all patients, as well as immunohistochemistry for CD3, CD4, CD8, CD56 (T-cell markers), CD25 (T and B-cell marker), CD20, CD19 (B-cell markers), and CD138 (plasmacell marker) in specimens collected at decompressive surgery., Results: Having established cutoff values for each marker, cell infiltrates were found in 60 patients (78.9%; CD3: 39.4%, CD4 55.2%, CD8 50%, CD56: 0%, CD25: 28.9%, CD20: 51.3%, CD19: 25%, CD138: 26.3%). Eleven (14.4%) stained exclusively for CD138 (plasmacells). Patients with CD4-positive mononuclear cells had a significantly greater GO clinical activity score (CAS) (mean difference 1.07, 95% CI - 0.33 to - 1.82, P = 0.004 by univariate, P = 0.05 by multivariate analysis). CAS as well as the remaining GO features were not affected significantly by the mononuclear cell subpopulations in multivariate analyses., Conclusions: Mononuclear cell infiltrates are present in the majority of GO patients, with a small percentage represented exclusively by plasmacells. CD4 cells exert a major role on GO activity. These findings may represent a further advancement in the comprehension of GO pathogenesis., (© 2021. Italian Society of Endocrinology (SIE).)

Introduction: Treatment of Graves´ disease (GD) with radioiodine increases the risk of developing Graves´ ophthalmopathy (GO), and the link between thyroid and orbital tissue may be the presence of TSH-receptors. Radioiodine increases the titers of TRAb and the aim was to investigate the relationship between GO and TRAb titers after treatment with radioiodine and to define the impact of risk genes., Methods: GD patients without ophthalmopathy or previous treatment with radioiodine were prospectively included at treatment with radioiodine for hyperthyroidism. A follow-up was performed 1 year later for the registration of GO development. The study was performed at a University Hospital Clinic; a referral center of all patients treated with radioiodine in the south of Sweden. The main outcome measures were the development of TRAb, anti-TPO, and anti-TG after 3 months and GO after 12 months and relationship to the genetic background (HLA, CTLA-4, and CYR61)., Results: Three months of radioiodine TRAb titers increased in two thirds of patients (p < 0.0005) but not in the other third. Anti-TPO titers were associated with TRAb (R = 0.362, p < 0.0001) but not anti-TG. At follow-up 1 year later (n = 204) 32 patients developed GO with a proportion of 70% in the group increasing in TRAb titers and 30% in the group with unchanged or lower TRAb titers (p-value < 0.0005). Patients with GO had higher titers of TRAb than patients without GO. CTLA-4 (rs231775 SNP) was significantly (p < 0.005) associated with TRAb titers above the median three months after radioiodine., Conclusions: The increase in TRAb titers after treatment with radioiodine is associated with GO and a genetic variation in CTLA-4 is associated with higher titers of TRAb., (© 2021. The Author(s).)

Purpose: This study was conducted to identify trends in Graves' orbitopathy research in the past two decades and to elaborate on hot topics in the field., Methods: The Web of Science database was used to extract articles on Graves' orbitopathy or its synonyms. Full data and references were exported to VOSviewer software to be analyzed. Visualization maps and charts were constructed accordingly., Results: We retrieved 1067 articles on Graves' orbitopathy from the Web of Science database. The United States ranked first in terms of the article count (25), followed by Italy (141) and the People's Republic of China (120). Wiersinga's and the University of Amsterdam's articles received the highest citation count (1509 and 3052, respectively). The University of Pisa and Thyroid published the highest number of articles (65 and 93, respectively). Co-authorship analysis showed four clusters of country collaborations: red cluster, European countries; green cluster, the United States, Brazil, Canada, South Korea, and Taiwan; a yellow cluster, People's Republic of China; and blue cluster, Japan, Australia, and Poland. Keyword analysis revealed five clusters of topics: pathogenesis, management, association, quality of life, and surgery. Analysis of co-cited references also revealed five clusters: pathogenesis, management, risk factors, clinical assessment, and surgical management., Conclusion: Research on Graves' orbitopathy has grown during the past two decades. Hot research topics are pathogenesis, management, risk factors, quality of life, and complications. Research trends have changed in the past two decades. Increasing interest in exploring Graves' orbitopathy mechanisms and associations is evident. European countries are cooperating in this field of research. The United States has established more extensive international cooperation than other countries. We believe that more international collaboration involving developing countries is required.