Search Results (56)

Background: Thyroid eye disease (TED) is a rare autoimmune orbital disorder predominantly associated with Graves’ disease. It is characterized by orbital inflammation, tissue remodeling, and potential visual morbidity. Conventional therapies, particularly systemic glucocorticoids, offer only partial symptomatic relief, failing to reverse chronic structural changes such as proptosis and diplopia, and are associated with substantial adverse effects. This review aims to synthesize recent developments in understandings of TED pathogenesis and to critically evaluate emerging therapeutic strategies. Methods: A systematic literature review was conducted using MEDLINE, Embase, and international clinical trial registries focusing on pivotal clinical trials and investigational therapies targeting core molecular pathways involved in TED. Results: Current evidence suggests that TED pathogenesis is primarily driven by the autoimmune activation of orbital fibroblasts (OFs) through thyrotropin receptor (TSH-R) and insulin-like growth factor-1 receptor (IGF-1R) signaling. Teprotumumab, a monoclonal IGF-1R inhibitor and the first therapy approved by the U.S. Food and Drug Administration for TED, has demonstrated substantial clinical benefit, including improvements in proptosis, diplopia, and quality of life. However, concerns remain regarding relapse rates and treatment-associated adverse events, particularly hearing impairment. Investigational therapies, including next-generation IGF-1R inhibitors, small-molecule antagonists, TSH-R inhibitors, neonatal Fc receptor (FcRn) blockers, cytokine-targeting agents, and gene-based interventions, are under development. These novel approaches aim to address both inflammatory and fibrotic components of TED. Conclusions: Teprotumumab has changed TED management but sustained control and toxicity reduction remain challenges. Future therapies should focus on targeted, mechanism-based, personalized approaches to improve long-term outcomes and patient quality of life. Full article

Background/Objectives: We aimed to explore long-term trajectories of thyroid-stimulating hormone receptor antibody (TRAb) in patients with Graves’ disease (GD) and to identify key factors associated with TRAb normalization. We also investigated whether these trajectories correlate with Graves’ orbitopathy (GO) comorbidity. Methods: We retrospectively reviewed 403 patients with GD who had an initial TRAb level ≥ 1.5 IU/L between 2010 and 2021, monitoring their TRAb levels for at least 3 years. K-means clustering was performed to categorize patients into distinct TRAb change patterns (A, B, C, D). We employed a Cox regression–based time-to-event model, expressing results as “Survival ratio” rather than the conventional Hazard ratio, to reflect the proportion of patients achieving TRAb normalization over time. Key variables included age, sex, initial TRAb, and GO comorbidity. Results: Four unique TRAb patterns emerged, differing primarily in baseline TRAb levels, duration of GD, and treatment approaches. Pattern A demonstrated the highest TRAb normalization rate (96%), whereas Patterns B (80%), C (29%), and D (13%) showed lower probabilities. Regrouping into A vs. BCD further emphasized the distinct normalization profile of Pattern A. A higher “Survival ratio” was observed in female patients and those with baseline TRAb < 6.14 IU/L. In contrast, patients whose TRAb levels were ≥6.14 IU/L frequently exhibited persistently elevated values over a decade. GO comorbidity did not significantly differ among the four patterns. Conclusions: K-means clustering revealed four unique TRAb change patterns in GD, with baseline TRAb (stratified by the median of 6.14 IU/L) and sex emerging as significant predictors of normalization. These findings highlight the importance of early TRAb monitoring and tailored therapeutic strategies, particularly for those with persistently elevated TRAb levels. Full article

Graves’ ophthalmopathy is the most common extrathyroidal manifestation of Graves–Basedow disease. Radiotherapy is effective especially when used in synergy with the administration of glucocorticoids. The aim of our study was to analyze the effectiveness and safety of radiotherapy, using different protocols, to improve ocular symptoms and quality of life. Methods: We retrospectively analyzed the clinical data of two-hundred and three patients treated with retrobulbar radiotherapy between January 2002 and June 2023. Ninety-nine patients were treated with a schedule of 10 Gy in 10 fractions and one-hundred and four were treated with 10 Gy in 5 fractions. Radiotherapy (RT) was administrated during the 12 weeks of pulse steroid therapy. Patients were evaluated with a clinical exam, orbital CT, thyroid assessment, and Clinical Activity Score (CAS). Results: The median follow-up was 28.6 months (range 12–240). Complete response was found in ninety-four pts (46.31%), partial response or stabilization in one hundred pts (49.26%), and progression in nine pts (4.43%). In most subjects, an improvement in visual acuity and a reduction in CAS of at least 2 points and proptosis by more than 3 mm were observed. Three patients needed decompressive surgery after treatment. Only G1 and G2 acute eye disorders and no cases of xerophthalmia or cataract were assessed. Conclusions: RT is an effective and well-tolerated treatment in this setting, especially when associated with the administration of glucocorticoids. Although the most used fractionation schedule in the literature is 20 Gy in 10 fractions, in our clinical practice, we have achieved comparable results with 10 Gy in 5 or 10 fractions with a lower incidence of toxicity. Full article

Thyroid-associated ophthalmopathy (TAO), or Graves’ orbitopathy (GO), is a complex autoimmune disorder affecting orbital tissues, often leading to vision-threatening complications such as dysthyroid optic neuropathy (DON). In this systematic review, conducted following PRISMA guidelines, 22 studies were evaluated to investigate the role of optical coherence tomography (OCT) in assessing retinal and choroidal changes in TAO. Parameters such as the retinal nerve fiber layer (RNFL), ganglion cell complex (GCC), ganglion cell layer (GCL), and choroidal thickness were analyzed. RNFL changes varied by disease severity, with significant thinning in DON due to nerve fiber loss and thickening in early DON due to optic disk edema. Subfoveal choroidal thickness (SFCT) was consistently higher in active TAO, correlating positively with the clinical activity score (CAS) and proptosis, suggesting its role as a marker of disease activity. Subgroup analysis revealed that spectral-domain OCT (SD-OCT) was the most sensitive for detecting retinal changes. The findings highlight the effectiveness of OCT in detecting minor retinal and choroidal alterations in TAO. However, the variability of study designs, as well as the lack of longitudinal data, limits the ability to draw broad conclusions. Further standardized, long-term investigations are required to properly understand OCT’s diagnostic and prognostic value in TAO. Full article

Background/Objectives: The thyroid gland has an important influence on the heart. Long-term exposure to high levels of thyroid hormones may lead to cardiac hypertrophy and dysfunction. The aim of the study was to evaluate the morphological and functional changes in the left ventricle in patients with hyperthyroidism caused by Graves’ disease (GD) in comparison with healthy individuals, as well as to investigate potential differences in these parameters in GD patients in relation to the presence of orbitopathy. Methods: The prospective study included 39 patients with clinical manifestations and laboratory confirmation of GD and 35 healthy controls. All participants underwent a detailed echocardiographic examination. The groups were compared according to demographic characteristics (age and gender), heart rate and echocardiographic characteristics. Results: The patients with hyperthyroidism caused by GD had significantly higher values of left ventricular diameter, left ventricular volume and left ventricular mass compared to the healthy controls. In addition, hyperthyroidism significantly influenced the left ventricular contractility and led to the deterioration of the systolic and diastolic function, as shown together by longitudinal strain, color Doppler and tissue Doppler imaging. However, the patients with GD and orbitopathy showed better left ventricular function than those without orbitopathy. Conclusions: Besides the confirmation of previously known findings, our study indicates possible differences in echocardiographic parameters in GD patients in relation to the presence of orbitopathy. Further investigation with larger samples and meta-analyses of data focused on the evaluation of echocardiographic findings in the context of detailed biochemical and molecular analyses is required to confirm our preliminary results and their clinical significance. Full article

Thyroid eye disease is a complex inflammatory disorder of the orbit that has gained tremendous interest over the past years, and numerous scientific efforts have been deployed to elucidate its pathophysiology for novel drug development. Our manuscript will delve into the molecular dysregulations involved in the pathogenesis of thyroid eye disease that led to its clinical manifestations. Abnormalities within the apoptotic pathway, inflammatory cascade, and autoimmune regulatory systems will be covered. We will further discuss the challenges involved in its diagnosis and management and provide a summary of the current diagnostic tools (i.e., molecular biomarkers, diagnostic scores) from the perspective of clinicians. Finally, our comprehensive literature review will provide a thorough summary of most recent preclinical and clinical studies around the topic of thyroid eye disease, with an emphasis on the manuscripts published within the last five years. We believe our manuscript will bring novelty within the field by bridging the fundamental sciences with the clinical aspect of this disease. This review will be a great tool for clinicians in better understanding the pathogenesis of thyroid eye disease while providing an outlook on future perspectives (i.e., liquid biopsies, artificial intelligence). Full article

Background: Fc receptor-like (FCRL) genes play a role in the immune system by encoding proteins that function as receptors on the surface of immune cells. The clinical significance of FCRL gene expression in Graves’ Disease (GD) and Graves’ Orbitopathy (GO) remains unclear. We evaluated the expression of FCRL 2, 3, 4 mRNA in patients with GD and GO and its role in the development and activity of these diseases. Methods: Peripheral blood samples from patients with GD (n = 24) or GO (n = 49) hospitalized in the Department of Endocrinology and Metabolic Diseases, Medical University of Lodz, were collected. Expressions of FCRL2, FCRL3 and FCRL4 were measured by real-time PCR. Results: FCRL3 expression was higher in patients with GD compared to GO (1.375 vs. 0.673, p = 0.004) and, specifically, active GO (1.375 vs. 0.639, p = 0.005). Regarding FCRL4, mRNA expression was higher in GD compared to Control (3.078 vs. 0.916, p = 0.003), GO (3.078 vs. 1.178, p < 0.001), active GO (3.078 vs. 1.186, p = 0.002) and inactive GO (3.078 vs. 1.171, p = 0.008). In turn, FCRL4 mRNA expression was higher in patients with hyperthyroidism (subclinical + overt) than in euthyroid patients (2.509 vs. 0.995, p = 0.001 when the whole group of individuals was considered; 2.509 vs. 1.073, p = 0.004 when GO + GD was considered). Conclusions: The increased FCRL mRNA expression in patients with GD is associated with hyperthyroidism (but not with positive TSHRAbs), and our study is the first one to confirm this relationship. Full article

This study aimed to investigate the presence of structural and functional changes in extraocular muscles (EMs) among patients with inactive Graves’ orbitopathy (GO) classified according to the Clinical Activity Score (CAS). Sixty-seven patients with Graves’ disease (GD) and inactive GO were included. The data collected included clinical parameters, thyroid function, autoantibody levels, EOM morphology via orbital ultrasound (US), and ocular motility. Patients were stratified into Red Filter Test (RFT)-positive or RFT-negative groups based on the presence or absence of latent diplopia during the RFT examination. Thirty-three patients (49.25%) exhibited latent diplopia on the RFT, despite not reporting double vision during standard ocular motility tests. Significant differences were observed between the two groups in terms of age, disease duration, intraocular pressure (IOP) elevation in up-gaze, and medial rectus muscle thickness (p < 0.05). No significant differences were found in thyroid status, TRAb and ATA levels, CASs, exophthalmos, or lateral rectus thickness between the two groups. This study revealed that in inactive GO, subclinical EM dysfunction and morphological changes may be present, which might not be apparent through routine ocular examinations. The RFT is effective in detecting latent diplopia, highlighting its utility in identifying subtle ocular motility issues and subclinical muscle involvement. Comprehensive evaluations combining functional tests like the RFT and imaging are essential for early detection of GO-related abnormalities, enabling tailored and prompt management and improving patient outcomes. Full article

Introduction: Graves’ disease (GD) is an autoimmune disorder affecting the thyroid gland, leading to systemic manifestations such as hyperthyroidism, Graves’ orbitopathy, and pretibial myxedema. Contrary to previous beliefs that hyperthyroidism protects against thyroid cancer, recent studies reveal an increased incidence of thyroid malignancies in GD patients, particularly differentiated thyroid carcinomas and, in rare cases, medullary thyroid carcinoma (MTC). Case series: This case series presents three female GD patients diagnosed with MTC, highlighting the complexities of diagnosis and management. All patients exhibited thyroid nodules with suspicious ultrasonographic features, elevated plasma calcitonin levels, and required total thyroidectomy. Histological examination confirmed MTC. Discussion: These cases underscore the importance of routine calcitonin screening in GD patients with thyroid nodules to facilitate early detection and improve prognosis. Our findings suggest that while the coexistence of GD and MTC is likely incidental, vigilant monitoring and comprehensive evaluation are crucial for timely intervention. Conclusions: This study advocates for integrating calcitonin testing into the standard diagnostic protocol for GD patients presenting with thyroid abnormalities. Full article

This study explores the complication of secondary intraocular pressure (IOP) elevation and consequent glaucoma development in Graves’ orbitopathy (GO), an autoimmune disorder associated with hyperthyroidism. Utilizing Octopus 900 visual field testing and optical coherence tomography (OCT), the research established correlations between functional and structural changes in optic nerve regions in patients with GO and patients with GO with elevated IOP (GO IOP) groups. A comparison with primary open-angle glaucoma (POAG) was conducted in a cohort of 182 subjects. The study identifies optic nerve head parameters that effectively differentiate changes in GO and GO IOP groups. In the GO group, the strongest correlation between structural and functional changes was observed in sector 7, while in the GO IOP group, it was in sectors 1 and 7. For POAG, correlation was found in six sectors. Elevated IOP in GO correlates with structural and functional impairments similarly to early glaucoma. Risk factors for GO-related elevated IOP included older age, longer duration of thyroid disease, and higher anti-thyroglobulin values. The study highlights the significance of regular IOP measurements, visual field assessments, and OCT examinations in GO patients. Early antiglaucoma intervention is warranted when characteristic structural and functional changes and/or risk factors are identified. Full article

Thyroid Eye Disease (TED) is a debilitating autoimmune condition characterized by significant inflammation of orbital tissues, including the extraocular muscles and adipose tissues. The pathological mechanisms underlying this inflammation involve a complex interplay of stress responses at the cellular and molecular level. This review aims to critically evaluate and synthesize existing literature on the mechanisms of orbital inflammation in TED. We discuss the role of autoantibodies, cytokines, and reactive oxygen species (ROS) in the initiation and propagation of the inflammatory process. Additionally, we explore how stress responses triggered by these elements affect the integrity of orbital tissues and contribute to its remodeling. Our review underscores the need for continued research in this field, which may pave the way for novel therapeutic strategies for TED. Full article

Purpose: Graves’ orbitopathy (GO) is an autoimmune disorder leading to inflammation, adipogenesis, and fibrosis. The severity of GO can vary widely among individuals, making it challenging to predict the natural course of the disease accurately, which is important for tailoring the treatment approach to the individual patient. The aim of this study was to compare the clinical characteristics, course, treatment, and prognosis of GO patients under 50 years with older patients. Methods: We reviewed the medical records of a random sample of 1000 patients in our GO database Essen (GODE) comprising 4260 patients at our tertiary referral center. Patients were divided into two groups: Group 1 (≤50 years) and Group 2 (>50 years). Only patients with a complete data set were included in the further statistical analysis. Results: The results showed that younger patients (n = 484) presented significantly more often with mild GO (53% vs. 33%, p < 0.0001), while older patients (n = 448) were more likely to experience moderate-to-severe disease (44% vs. 64%, p < 0.0001). Older patients showed more severe strabismus, motility, and clinical activity scores (5.9 vs. 2.3 PD/310° vs. 330° both p < 0.0001, CAS: 2.1 vs. 1.7, p = 0.001). Proptosis and occurrence of dysthyroid optic neuropathy (DON) showed no significant difference between groups (both 3%). Multiple logistic regression revealed that the need for a second step of eye muscle surgery was most strongly associated with prior decompression (OR = 0.12, 95% CI: 0.1–0.2, p < 0.0001) followed by orbital irradiation and age. The model showed good fitness regarding the area under the curve (AUC = 0.83). Discussion: In conclusion, younger GO patients present with milder clinical features such as a lower rate of restrictive motility disorders and less pronounced inflammatory signs. Therefore, older patients tend to need more steroids, irradiation, and lid and eye muscle surgery. Still, the risk of DON and the necessity of secondary eye muscle surgery are not or only slightly associated with age, respectively. Full article

This study aims to systematise subfoveal choroidal thickness (SFCT) measured using optical coherence tomography (OCT) in patients with different severities of thyroid eye disease (TED) compared with healthy subjects. The PubMed, Web of Science and Scopus databases were searched for the following terms: ((Graves’ ophthalmopathy) OR (thyroid eye disease) OR (Graves’ orbitopathy) OR (thyroid-associated orbitopathy)) AND (choroidal thickness) AND ((optical coherence tomography) OR (OCT)). The pool of papers was narrowed down to articles published until 31 January 2023 (26, 26 and 96 papers, respectively). Twenty-five (25) articles were taken into consideration, which were original papers and included the choroidal thickness measurements among TED patients in their results. Finally, eight papers were included in the comparative analysis of the SFCT parameter in TED patients and a group of healthy controls, and seven papers in the comparative analysis of the same parameter between active and inactive TED patients. The mean value of the difference between the TED group and the healthy group was 38.79 μm, with a confidence interval (CI) from 0.09 to 77.49 μm (p = 0.0495). The mean difference between the active TED group and inactive TED group was 38.02 μm, with a CI from 8.62 to 67.42 μm (p = 0.0113). All the results were statistically significant. Full article

The risk of Graves’ orbitopathy (GO) is related to the human leukocyte antigen (HLA) profile and was demonstrated to be increased in patients with elevated total cholesterol (TC) and/or low-density lipoprotein (LDL) cholesterol. We hypothesized that there were some HLA alleles that were related to both GO and TC and/or LDL levels. Therefore, the aim of the study was to compare the TC/LDL results in patients in whom GO-related HLA alleles were present to those in whom they did not occur. HLA classes were genotyped using a next-generation sequencing method in 118 patients with Graves’ disease (GD), including 63 and 55 patients with and without GO, respectively. Lipid profiles were assessed at the time of the GD diagnosis. A significant correlation between the presence of GO high-risk alleles (HLA-B*37:01 and C*03:02) and higher TC/LDL levels was found. Additionally, the presence of alleles associated with non-GO GD (HLA-C*17:01 and B*08:01), as well as alleles in linkage disequilibrium with B*08:01 (i.e., HLA-DRB1*03:01 and DQB1*02:01), was correlated with lower TC levels. These results further confirm the significance of TC/LDL in the risk of GO development and provide evidence that associations between TC/LDL and GO can be HLA-dependent. Full article