Immune checkpoints: new insights into the pathogenesis of thyroid eye disease.

Thyroid eye disease (TED) is a disfiguring autoimmune disease characterized by changes in the orbital tissues and is caused by abnormal thyroid function or thyroid-related antibodies. It is the ocular manifestation of Graves' disease. The expression of thyroid-stimulating hormone receptor (TSHR) and the insulin-like growth factor-1 receptor (IGF-1 R) on the cell membrane of orbital fibroblasts (OFs) is responsible for TED pathology. Excessive inflammation is caused when these receptors in the orbit are stimulated by autoantibodies. CD34+ fibrocytes, found in the peripheral blood and orbital tissues of patients with TED, express immune checkpoints (ICs) like MHC II, B7, and PD-L1, indicating their potential role in presenting antigens and regulating the immune response in TED pathogenesis. Immune checkpoint inhibitors (ICIs) have significantly transformed cancer treatment. However, it can also lead to the occurrence of TED in some instances, suggesting the abnormality of ICs in TED. This review will examine the overall pathogenic mechanism linked to the immune cells of TED and then discuss the latest research findings on the immunomodulatory role of ICs in the development and pathogenesis of TED. This will offer fresh perspectives on the study of pathogenesis and the identification of potential therapeutic targets.

Safety of non-standard regimen of systemic steroid therapy in patients with Graves' orbitopathy: a single-centre experience.

BACKGROUND: Graves' orbitopathy (GO) is an autoimmune disorder of the orbit and retro-ocular tissues and the primary extrathyroidal manifestation of Graves' disease. In moderate-to-severe and active GO iv glucocorticoids (GCs) are recommended as first-line treatment. The aim was to assess the safety profile of methylprednisolone administered intravenously for three consecutive days at 1 g in patients with active, moderate-to-severe or sight-threatening Graves' orbitopathy. METHODS: We retrospectively evaluated 161 medical records of patients with GO treated with high-dose systemic GCs in the Department of Endocrinology, Metabolic Disorders, and Internal Medicine in Poznan between 2014 and 2021. Clinical data included age, gender, laboratory results, activity and severity of GO, smoking status, disease duration, and presented side effects. RESULTS: The presence of mild side effects was observed during 114 (71%) hospitalizations. The most common complications were hyperglycemia (n = 95) and elevated aminotransferases (n = 31). Increased levels of aminotransferases were more likely observed in smokers and GO duration above 12 months. Based on the multivariate logistic regression, higher TRAb and CAS values were significantly associated with lower odds of hyperglycemia. In turn, the increased odds of elevated aminotransferases were significantly correlated with higher initial ALT levels, female gender, and GO duration above 12 months. In addition, the multidimensional correspondence analysis (MPA) showed that GO patients who declared smoking and had not L-ornithine L-aspartate applied demonstrated a higher probability of elevated aminotransferases. CONCLUSIONS: Active GO treatment with high-dose systemic GCs is not associated with serious side effects. Hyperglycemia is the most common steroid-induced complication.

Radioactive iodine treatment for Graves' hyperthyroidism: incidence of Graves orbitopathy.

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.

Thyroid Eye Disease: Epidemiology, Natural History, and Risk Factors.

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.

Graves' Orbitopathy Models: Valuable Tools for Exploring Pathogenesis and Treatment.

Graves' orbitopathy (GO) is the most common extrathyroidal complication of Graves' disease (GD) and severely affects quality of life. However, its pathogenesis is still poorly understood, and therapeutic options are limited. Animal models are important tools for preclinical research. The animals in some previous models only exhibited symptoms of hyperthyroidism without ocular lesions. With the improvements achieved in modeling methods, some progressive animal models have been established. Immunization of mice with A subunit of the human thyroid stimulating hormone receptor (TSHR) by either adenovirus or plasmid (with electroporation) is widely used and convincing. These models are successful to identify that the gut microbiota influences the occurrence and severity of GD and GO, and sex-related risk factors may be key contributors to the female bias in the occurrence of GO rather than sex itself. Some data provide insight that macrophages and CD8+ T cells may play an important pathogenic role in the early stage of GO. Our team also replicated the time window from GD onset to GO onset and identified a group of CD4+ cytotoxic T cells. In therapeutic exploration, TSHR derived peptides, fingolimod, and rapamycin offer new potential options. Further clinical trials are needed to investigate these drugs. With the increasing use of these animal models and more in-depth studies of the new findings, scientists will gain a clearer understanding of the pathogenesis of GO and identify more treatments for patients.

Influence of biological sex, age and smoking on Graves' orbitopathy - a ten-year tertiary referral center analysis.

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.

A review of TSHR- and IGF-1R-related pathogenesis and treatment of Graves' orbitopathy.

Graves' orbitopathy (GO) is an organ-specific autoimmune disease, but its pathogenesis remains unclear. There are few review articles on GO research from the perspective of target cells and target antigens. A systematic search of PubMed was performed, focusing mainly on studies published after 2015 that involve the role of target cells, orbital fibroblasts (OFs) and orbital adipocytes (OAs), target antigens, thyrotropin receptor (TSHR) and insulin-like growth factor-1 receptor (IGF-1R), and their corresponding antibodies, TSHR antibodies (TRAbs) and IGF-1R antibodies (IGF-1R Abs), in GO pathogenesis and the potentially effective therapies that target TSHR and IGF-1R. Based on the results, OFs may be derived from bone marrow-derived CD34+ fibrocytes. In addition to CD34+ OFs, CD34- OFs are important in the pathogenesis of GO and may be involved in hyaluronan formation. CD34- OFs expressing Slit2 suppress the phenotype of CD34+ OFs. ß-arrestin 1 can be involved in TSHR/IGF-1R crosstalk as a scaffold. Research on TRAbs has gradually shifted to TSAbs, TBAbs and the titre of TRAbs. However, the existence and role of IGF-1R Abs are still unknown and deserve further study. Basic and clinical trials of TSHR-inhibiting therapies are increasing, and TSHR is an expected therapeutic target. Teprotumumab has become the latest second-line treatment for GO. This review aims to effectively describe the pathogenesis of GO from the perspective of target cells and target antigens and provide ideas for its fundamental treatment.

Reactivation of Graves' Disease and Thyroid Eye Disease following COVID-19 Vaccination - A Case Report.

A 51-year-old male had a history of well-controlled Graves' disease (GD) under regular follow-up, and thyroid eye disease (TED) with post bilateral orbital decompression. However, after COVID-19 vaccination, recrudescence of GD and moderate-to-severe TED were diagnosed by increased thyroxine levels and decreased thyrotropin levels in serum, and positive results of thyrotropin receptor antibody and thyroid peroxidase antibody. Weekly intravenous methylprednisolone was prescribed. Symptoms gradually improved accompanied with reduction in proptosis: 1.5 mm of the OD and 2.5 mm of the OS. Possible pathophysiological mechanisms discussed included molecular mimicry theory, autoimmune/inflammatory syndrome induced by adjuvants, and certain genetic predisposition of human leukocyte antigen. Physicians should remind patients to seek treatment if the symptoms and signs of TED recur following COVID-19 vaccination.

New Onset or Deterioration of Thyroid Eye Disease After mRNA SARS-CoV-2 Vaccines: Report of 2 Cases and Literature Review.

CONTEXT: Occurrence of Graves' disease (GD) has been reported following SARS-CoV-2 vaccine administration, but little is known about thyroid eye disease (TED) after SARS-CoV-2 vaccination. OBJECTIVE: We describe 2 cases of TED activation following mRNA SARS-CoV-2 vaccination and review additional cases reported in the literature. METHODS: We report 2 cases of TED activation following SARS-CoV-2 vaccination: 1 case of TED worsening in a patient with GD, and 1 of de novo active TED progressing to dysthyroid optic neuropathy in a patient with a history of Hashimoto hypothyroidism. Our literature search revealed 8 additional reported TED cases associated with SARS-CoV-2 vaccination until June 2022. We review the characteristics, duration, and management of TED following SARS-CoV-2 vaccination in these cases. RESULTS: Of all 10 reported TED cases following SARS-CoV-2 vaccination, 4 developed new-onset TED and 6 previously stable TED cases experienced significant deterioration. Six patients had known GD and 2 patients had Hashimoto thyroiditis. Two cases progressed to dysthyroid optic neuropathy, 6 had moderate/severe active disease, and 2 had mild disease that did not require treatment. Seven TED cases received teprotumumab and had a favorable response, 2 of whom had prior limited response to initial prednisone or methylprednisolone and tocilizumab therapy. CONCLUSION: New diagnosis or deterioration of TED after mRNA SARS-CoV-2 vaccination can occur, with most cases described in patients with underlying autoimmune thyroid disease. Our report raises awareness to this potential complication to promote early recognition and prompt management of TED associated with mRNA SARS-CoV-2 vaccines. Further studies are needed to explore the mechanism, risk factors, prevention, and treatment of TED following mRNA SARS-CoV-2 vaccination.

Medial orbital wall decompression: Demographics influencing surgical follow-up and complications: Impacts on follow-up and complications.

OBJECTIVE: Identify the impact of demographics and social determinants of health on surgical follow-up and complications after medial orbital wall decompression (MOWD) secondary to thyroid associated orbitopathy (TAO). METHODS: Demographics and social determinants of health (age, sex, race, insurance status) for 46 patients undergoing MOWD secondary to TAO were correlated with post-operative compliance and surgical complications by chi-square analyses. RESULTS: Among 46 patients, 23 were compliant with follow-up. There was no statistically significant difference between compliance and non-compliance based on age (60.25 vs 56.4, p = .41), sex (71.9 % female vs 85.7 % female, p = .31), race (65.6 % white vs 71.4 % white, p = .70) or insurance status (59.4 % private vs 42.9 % private, p = .30). Complications were noted in 50 % of patients of which sinus infection was most common (47.8 % of complications) and epistaxis rare (4.3 % of complications). No correlation was noted between development of complications and compliance (p = .20). Likewise, age, race and insurance status did not correlate with complications. CONCLUSION: For patients undergoing MOWD, no correlations with compliance or complication rate were noted with age, sex, race, or insurance status. A larger cohort may be indicated to identify such patterns. The overall complication rate was 50 % and the increased number of visits may have economic impact. KEY POINTS: This study provides a unique chance to assess demographic correlates of compliance and complication while controlling for surgeon preference. There was no association between sociodemographics and compliance or complications.

2022 Update on Clinical Management of Graves Disease and Thyroid Eye Disease.

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.

[A man with bulging eyes]. / Een man met uitpuilende ogen.

Graves' orbitopathy may cause multiple symptoms, such as proptosis, redness or inflammation of the conjunctiva, excessive tearing, swelling of the eyelids and pain. Smoking, male gender and old age are significant risk factors for a more severe and active disease.

Understanding the pathogenesis of Graves' orbitopathy: A new age paradigm.

Graves' orbitopathy or thyroid associated orbitopathy (TAO) is a disquieting condition both for the patient and the clinician. While the mainstay of treatment of the orbitopathy is corticosteroids, its action is non-specific. The arguments against its use also include multiple side effects and recurrence on stopping it. While some clinicians are complacent with the drug due to our long term experience with it, many are in search for specific so called 'targeted' treatment. The autoimmune process in TAO is rather complex where multiple cytokines act at more than one level making it challenging to control the inflammation. Hence, in order to discover better treatment strategies, having a sound understanding of the pathogenesis of the disease is essential.

Current concepts regarding Graves' orbitopathy.

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.

[LIFESTYLE ADJUSTMENT AS THERAPEUTIC TOOL IN THYROID EYE DISEASE].

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.

Worsening of Graves' ophthalmopathy after SARS-CoV-2 mRNA vaccination.

More reports are documenting how vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could represent new external triggers for autoimmune endocrine diseases (AIED) in patients with individual predisposition. We report two cases of Graves' Ophthalmopathy (GO) recrudescence few days after the administration of BNT162B2 (Pfizer-BioNTech) SARS-CoV-2 vaccine. Even if causality relationship cannot be excluded, the development of these events could be explained through immune mediated mechanism such as the autoimmune/inflammatory syndrome induced by adjuvants (ASIA). While further investigations are necessary to improve our knowledge of the underlying pathogenesis of these phenomena, caution may be warranted when vaccinating individuals with known autoimmune diseases.