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Graves’ disease (GD) is a common autoimmune thyroid disorder and is often accompanied by Graves’ orbitopathy (GO), an inflammatory eye disease that can significantly reduce the quality of patients’ life. Despite understanding of GD and GO has progressed, the mechanisms driving disease progression remain incompletely defined. Emerging evidence highlights extracellular vesicles (EVs), particularly exosomes, as important mediators of immune regulation and tissue remodeling in autoimmune disorders, including GD and GO. This review summarizes current knowledge of EVs biogenesis and molecular compositions, highlighting their contributions to GD and GO pathogenesis. We also discuss the diagnostic and prognostic potential of EV-associated miRNAs and proteins, and consider findings from other immune-mediated ocular diseases to place these observations in a broader immunopathological context. Overall, EVs appear to be actively involved in GD and GO and may serve as useful tools for disease monitoring and therapy development. Nonetheless, challenges such as methodological variability and limited functional validation remains. Standardized protocols and larger, multicenter studies are needed to support the clinical translation of EV-based approaches.

Abstract Context Invited update on the management of systemic autoimmune Graves disease (GD) and associated Graves orbitopathy (GO). Evidence acquisition Guidelines, pertinent original articles, systemic reviews, and meta-analyses. Evidence synthesis Thyrotropin receptor antibodies (TSH-R-Abs), foremost the stimulatory TSH-R-Abs, are a specific biomarker for GD. Their measurement assists in the differential diagnosis of hyperthyroidism and offers accurate and rapid diagnosis of GD. Thyroid ultrasound is a sensitive imaging tool for GD. Worldwide, thionamides are the favored treatment (12-18 months) of newly diagnosed GD, with methimazole (MMI) as the preferred drug. Patients with persistently high TSH-R-Abs and/or persistent hyperthyroidism at 18 months, or with a relapse after completing a course of MMI, can opt for a definitive therapy with radioactive iodine (RAI) or total thyroidectomy (TX). Continued long-term, low-dose MMI administration is a valuable and safe alternative. Patient choice, both at initial presentation of GD and at recurrence, should be emphasized. Propylthiouracil is preferred to MMI during the first trimester of pregnancy. TX is best performed by a high-volume thyroid surgeon. RAI should be avoided in GD patients with active GO, especially in smokers. Recently, a promising therapy with an anti-insulin-like growth factor-1 monoclonal antibody for patients with active/severe GO was approved by the Food and Drug Administration. COVID-19 infection is a risk factor for poorly controlled hyperthyroidism, which contributes to the infection–related mortality risk. If GO is not severe, systemic steroid treatment should be postponed during COVID-19 while local treatment and preventive measures are offered. Conclusions A clear trend towards serological diagnosis and medical treatment of GD has emerged.

Abstract Thyroid-associated ophthalmopathy (TAO) is a complex disease process presumed to emerge from autoimmunity occurring in the thyroid gland, most frequently in Graves disease (GD). It is disfiguring and potentially blinding, culminating in orbital tissue remodeling and disruption of function of structures adjacent to the eye. There are currently no medical therapies proven capable of altering the clinical outcome of TAO in randomized, placebo-controlled multicenter trials. The orbital fibroblast represents the central target for immune reactivity. Recent identification of fibroblasts that putatively originate in the bone marrow as monocyte progenitors provides a plausible explanation for why antigens, the expressions of which were once considered restricted to the thyroid, are detected in the TAO orbit. These cells, known as fibrocytes, express relatively high levels of functional TSH receptor (TSHR) through which they can be activated by TSH and the GD-specific pathogenic antibodies that underpin thyroid overactivity. Fibrocytes also express insulin-like growth factor I receptor (IGF-IR) with which TSHR forms a physical and functional signaling complex. Notably, inhibition of IGF-IR activity results in the attenuation of signaling initiated at either receptor. Some studies suggest that IGF-IR-activating antibodies are generated in GD, whereas others refute this concept. These observations served as the rationale for implementing a recently completed therapeutic trial of teprotumumab, a monoclonal inhibitory antibody targeting IGF-IR in TAO. Results of that trial in active, moderate to severe disease revealed dramatic and rapid reductions in disease activity and severity. The targeting of IGF-IR with specific biologic agents may represent a paradigm shift in the therapy of TAO.

Abstract Context Observational studies suggest that variations in normal range thyroid function are associated with cardiovascular diseases. However, it remains to be determined whether these associations are causal or not. Objective To test whether genetically determined variation in normal range thyroid function is causally associated with the risk of stroke and coronary artery disease (CAD) and investigate via which pathways these relations may be mediated. Design, Setting, and Participants Mendelian randomization analyses for stroke and CAD using genetic instruments associated with normal range thyrotropin (TSH) and free thyroxine levels or Hashimoto’s thyroiditis and Graves’ disease. The potential mediating role of known stroke and CAD risk factors was examined. Publicly available summary statistics data were used. Main Outcome Measures Stroke or CAD risk per genetically predicted increase in TSH or FT4 levels. Results A 1 standard deviation increase in TSH was associated with a 5% decrease in the risk of stroke (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.91-0.99; P = 0.008). Multivariable MR analyses indicated that this effect is mainly mediated via atrial fibrillation. MR analyses did not show a causal association between normal range thyroid function and CAD. Secondary analyses showed a causal relationship between Hashimoto’s thyroiditis and a 7% increased risk of CAD (OR, 1.07; 95% CI, 1.01-1.13; P = 0.026), which was mainly mediated via body mass index. Conclusion These results provide important new insights into the causal relationships and mediating pathways between thyroid function, stroke, and CAD. We identify variation in normal range thyroid function and Hashimoto’s thyroiditis as risk factors for stroke and CAD, respectively.

Graves' disease is an autoimmune disorder in which the thyroid is activated by antibodies to the thyrotropin receptor. The hyperthyroidism that develops is one of many somatic and psychiatric manifestations of the disease that can affect the quality and length of life. Graves’ disease was first recognized in the 19th century as a syndrome comprising an enlarged and overactive thyroid gland, an accelerated heart rate, and ocular abnormalities (Figure 1). Critical for our current understanding of this disease was the discovery of its autoimmune basis, which results from complex interactions between genetic and environmental factors. 1 , 2 Graves’ disease has adverse effects on quality of life, 3 as a consequence of somatic 4 and psychiatric 5 symptoms and an inability to work, 6 and is associated with an increased risk of death. 7 Activating thyrotropin-receptor antibodies induce thyroid hormone overproduction. Many characteristic signs and symptoms of Graves’ disease . . .

Graves disease is the most common cause of hyperthyroidism in iodine-sufficient areas. The main responsible mechanism is related to autoantibodies that bind and activate the thyrotropin receptor (TSHR). Although Graves hyperthyroidism is relatively common, no causal treatment options are available. Established treatment modalities are antithyroid drugs, which reduce thyroid hormone synthesis, radioactive iodine and surgery. However, emerging drugs that target the main autoantigen (monoclonal antibodies, small molecules, peptides) or block the immune pathway have been recently tested in clinical trials. Graves disease can involve the thyroid exclusively or it can be associated with extrathyroidal manifestations, among which Graves orbitopathy is the most common. The presence of Graves orbitopathy can change the management of the disease. An established treatment for moderate-to-severe Graves orbitopathy is intravenous glucocorticoids. However, recent advances in understanding the pathogenesis of Graves orbitopathy have allowed the development of new target-based therapies by blocking pro-inflammatory cytokine receptors, lymphocytic infiltration or the insulin-like growth factor 1 receptor (IGF1R), with several clinical trials providing promising results. This article reviews the new discoveries in the pathogenesis of Graves hyperthyroidism and Graves orbitopathy that offer several important tools in disease management. Graves disease, an autoimmune disease characterized by an enlarged and overactive thyroid gland, is the most common cause of hyperthyroidism in iodine-sufficient areas. In this Review, the authors describe the epidemiology, pathogenesis, and conventional treatment of Graves hyperthyroidism and Graves orbitopathy and discuss advances that have enabled development of novel treatment modalities. Key points Graves disease is an autoimmune condition that can involve the thyroid exclusively or can be associated with extrathyroidal manifestations, of which Graves orbitopathy is the most common. The main mechanism responsible for Graves hyperthyroidism is the activation of the thyroid-stimulating hormone receptor (TSHR) by autoantibodies that act as agonists, causing thyrocyte proliferation and hyperfunction. None of the conventional treatments for Graves hyperthyroidism act on its pathogenesis; new molecules that target early recognition of TSHR peptides, T cell activation, B cell stimulation and survival, production of TSHR autoantibodies, and TSHR activation have been tested with encouraging results. Graves orbitopathy is characterized by immune-mediated inflammatory reactions against autoantigens shared by thyroid epithelial cells and orbital fibroblasts; intravenous glucocorticoids are, to date, the first-line treatments for Graves orbitopathy. New target-based therapies that block pro-inflammatory cytokine receptors, lymphocytic infiltration or the insulin-like growth factor 1 receptor (IGF1R) have been tested in several clinical trials and show promising results in Graves orbitopathy.

Abstract Context Serum TSH receptor autoantibody (TSH-R-Ab) is a biomarker of Graves disease (GD). Studies have shown that the levels of this TSH-R-Ab have clinical significance. Objective To differentiate between thyroidal GD only and Graves orbitopathy (GD + GO). Design Controlled, follow-up study. Setting Academic tertiary referral center for GD + GO. Subjects Sixty patients with GD, GD + GO, and controls. Intervention Serial serum dilution analyses with six automated, ELISA, and cell-based assays for TSH-R-Ab. Main Outcome Measure Differentiation among GD phenotypes. Results All undiluted samples of hyperthyroid-untreated GD patients were positive with the six assays but became negative at dilution 1:9 in four of six assays. In contrast, all undiluted samples of hyperthyroid-untreated GD + GO patients remained positive up to dilution 1:81, P < 0.001. At high dilutions 1:243, 1:729, 1:2187, and 1:6561, the rate of stimulating TSH-R-Ab positivity in the bioassay for GD + GO patients was 75%, 35%, 5%, and 0%, respectively (all P < 0.001). The five ELISA and/or automated assays confirmed this marked difference of anti-TSH-R-Ab detection between GD-only and GD + GO. In comparison, the baseline-undiluted samples of GD vs GD + GO showed an overlap in the ranges of TSH-R-Ab levels. Subsequent to 12-month methimazole treatment, samples from euthyroid GD + GO patients were still TSH-R-Ab positive at the high dilution of 1:243. In contrast, all GD samples were negative already at dilution 1:3. A GD patient with TSH-R-Ab positivity at dilution 1:729 developed de novo GO. Conclusions TSH-R-Ab titers, as determined by dilution analysis, significantly differentiate between GD and GD + GO. We demonstrate, for the first time, that dilution analysis of TSH receptor antibody levels markedly differentiates Graves thyroidal disease only vs Graves thyroidal and orbital disease.

Background Graves’ orbitopathy (GO) is a prevalent manifestation of Graves’ disease (GD), characterized by proptosis, eyelid retraction, soft tissue swelling, diplopia, and potential visual acuity impairment. Furthermore, even mild GO can significantly impact mental health and overall quality of life for patients with GD. Despite its severity, available medical treatments for mild GO are limited. Recent basic studies on orbital fibroblasts suggest hydroxychloroquine (HCQ) as a promising therapeutic agent for GO patients. This randomized controlled trial (RCT) was designed to assess the efficacy of HCQ in treating mild GO.  Methods This multi-center open-label RCT will be conducted in Taiwan with a total of 108 participants randomized into HCQ and control groups at 2:1 allocation ratio. The primary endpoint of this study is a composite outcome of ophthalmic parameters including eyelid aperture, soft tissue involvement, and exophthalmos. Secondary endpoints comprise changes in quality of life (GO-QoL), orbital volumetry via computed tomography (CT), diplopia scores, clinical activity scores (CAS), visual acuity, and thyroid autoantibodies. Discussion This RCT will elucidate the clinical benefits of oral HCQ in patients with mild GO, assessing ophthalmic outcomes, quality of life, disease activity, and thyroid autoantibodies. In addition, data obtained from orbital CT measurements will provide valuable insights into subtle changes in orbital fat and extra-ocular muscle volumes, potentially offering an objective tool for monitoring GO progression. Trial registration {2a, 2b} ClinicalTrials.gov NCT05126147. Registered on November 2021.  https://clinicaltrials.gov/study/NCT05126147 . All items from the World Health Organization (WHO) Trial Registration Data Set are addressed within the relevant sections of this protocol.

Abstract Purpose The purpose of this article is to investigate the characteristics of Th1-cell and Th17-cell lineages for very severe Graves orbitopathy (GO) development. Methods Flow cytometry was performed with blood samples from GO and Graves disease (GD) patients and healthy controls, to explore effector T-cell phenotypes. Lipidomics was conducted with serum from very severe GO patients before and after glucocorticoid (GC) therapy. Immunohistochemistry and Western blotting were used to examine orbital-infiltrating Th17 cells or in vitro models of Th17 polarization. Results In GD, Th1 cells predominated in peripheral effector T-cell subsets, whereas in GO, Th17-cell lineage predominated. In moderate-to-severe GO, Th17.1 cells expressed retinoic acid receptor-related orphan receptor-γt (RORγt) independently and produced interleukin-17A (IL-17A), whereas in very severe GO, Th17.1 cells co-expressed RORγt and Tbet and produced interferon-γ (IFN-γ). Increased IFN-γ–producing Th17.1 cells positively correlated with GO activity and were associated with the development of very severe GO. Additionally, GC therapy inhibited both Th1-cell and Th17-cell lineages and modulated a lipid panel consisting of 79 serum metabolites. However, in GC-resistant, very severe GO, IFN-γ–producing Th17.1 cells remained at a high level, correlating with increased serum triglycerides. Further, retro-orbital tissues from GC-resistant, very severe GO were shown to be infiltrated by CXCR3+ Th17 cells expressing Tbet and STAT4 and rich in triglycerides that promoted Th1 phenotype in Th17 cells in vitro. Conclusions Our findings address the importance of Th17.1 cells in GO pathogenesis, possibly promoting our understanding of the association between Th17-cell plasticity and disease severity of GO.