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Graves’ disease (GD) is a condition caused by an autoimmune process involving the thyroid gland, whose main outcome is hyperthyroidism. TSAb start the autoimmune process stimulating the overproduction of thyroid hormones. In addition, TSAb can stimulate TSH-R expressed in fibroblasts and orbital pre-adipocytes leading to the manifestation of Graves’ ophtalmopathy (GO). Also, autoantibodies directed against IGF-1R have an important role in immune-pathogenesis of GO. Fundamental is the role played by cytokines (IFN-γ, TNF-α, Il-6), and Th1 chemokines in the immune-pathogenesis of both disorders, particularly in the active phase. Novel discoveries in the field led to the investigation of promising therapies, such as immune-therapies towards specific antigens (for example against TSH-R), aiming in restoring the immune tolerance versus the immune dominant epitopes associated with autoimmunity in GD. Moreover, Etanercept (that blocks the TNF-mediated inflammatory responses), TCZ (that acts against the IL-6 receptor), and RTX (that acts against CD20) have proven to be useful and safe therapeutic options in refractory GO treatment. Furthermore, teprotumumab (a human monoclonal anti-IGF-1R blocking antibody), have been revealed effective in the treatment of patients with moderate-severe GO and it is now approved for GO therapy in United States. Molecules able to act as antagonists of CXCR3, or to block CXCL10, are also under study. More extensive researches are needed to deepen out these drugs as well as to identify new targeted and effective therapies, that will permit a more precise identification of GD, or GO, patients able to respond to specific targeted therapies.

Key Words: thyroid eye disease, teprotumumab

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).

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

Background Teprotumumab, a novel IGF-1R antibody was recently shown to significantly reduce the signs of acute and chronic thyroid eye disease (TED) related to hyperthyroidism. Given the lower incidence of TED associated with hypothyroidism / euthyroidism, there is a paucity of data regarding the efficacy of teprotumumab in this group. Methods In this multicenter study, consecutive patients who had been diagnosed with TED, presenting with either hypothyroidism or euthyroidism as their baseline thyroid dysfunction and treated with teprotumumab were included. All patients had measurements of proptosis, clinical activity scores (CAS), diplopia scores and four-point strabismus scores before and after therapy. Results Twenty-six patients met the inclusion criteria. Mean age was 48 ± 14 years old and mean duration of TED prior to treatment was 31 ± 43 months. All patients received 8 infusions. Mean (SD) reduction in proptosis for study orbits was 2.7 mm (1.8) ( p  < 0.05) and 1.8 mm (2.0) for the fellow orbit ( p  < 0.05). In the study orbit, mean (SD) CAS was 2.3 (1.3) before therapy and 1.0 (1.0) following therapy ( p  < 0.05). At baseline, mean (SD) diplopia score was 1.2 (1.1) and 0.9 (1.1) following therapy ( p  < 0.05). Conclusion Teprotumumab reduces proptosis and inflammation in patients presenting with TED associated with hypothyroidism and euthyroidism. The results of this study highlight the potential for teprotumumab therapy in this subgroup and also provide a unique insight into the potential role of the IGF-1R in these patients. Key messages What is known Teprotumumab’s established efficacy in treating Thyroid Eye Disease (TED) associated with Grave’s disease is grounded in its ability to target and modulate the insulin-like growth factor 1 receptor (IGF-1R) pathway. What is new This series highlights teprotumumab’s efficacy in treating TED in patients suffering from autoimmune thyroid disease with hypothyroid or euthyroid state. The results suggest that teprotumumab effectiveness in this group is not inferior to what is currently known, suggesting dysfunction of the IGF-1R pathway is common to all patients with TED irrespective of the accompanying thyroid dysfunction.

Background To describe the implementation of a registry system for patients with thyroid eye disease (TED) in Iran to obtain more information about its nature, prevalence, and annual incidence, as well as extend insight into the etiology, pathogenesis, and eventually make an accurate prognosis of different medical or surgical treatment methods. Methods After receiving approval from the Disease Registry Committee of Iran University of Medical Sciences (IUMS) in 2019 and the Ministry of Health and Medical Education (MOHME) in 2020, the protocol was introduced in three consecutive phases at regional, provincial and national levels. The establishment of a registry committee in Rassoul Akram Hospital, one of the medical centers affiliated to IUMS, was the first step to organizing the registry project's main core. The steering committee included six subgroups of required subject fields. The members are experts in developing a guideline, providing a new dataset, drawing an outline for the next steps, and structuring user-friendly software through several panel discussion meetings. The data is collected from clinical and para-clinical/imaging findings, laboratory evaluations, and their selected treatment strategy, retrospectively and prospectively. Results The purpose is to broaden our knowledge about the profile of TED; accordingly, data related to patients’ demographics, thyroid gland disease (status, duration, treatments, and function tests), general medical and ocular history, along with visual/ocular exams resulting TED status are collected and recorded in a 2- language software. The web-based software system is accessible at https://orc.iums.ac.ir . To maintain data security, prioritized user access was defined for different members. Furthermore, diverse methods, such as employing trained staff and utilizing software validation rules, were implemented to control data quality in every step of data collection, entry, and registration. Medical records of retrospective subjects were also evaluated and entered after accuracy verification. Conclusion Iran's TED registry provides practitioners with comprehensive data on natural history and phenotype variations in clinical features and outcomes. It facilitates patient recruitment and, consequently, earlier diagnosis on a large scale which helps improve treatment and quality of life for patients.

Purpose Patients with active, moderate-to-severe Graves’ orbitopathy require immunosuppressive treatments to reduce inflammation and morbidity. Since 2021 EUGOGO lists Mycophenolate-sodium (MPS) as first-line-treatment, which lead to a change in treatment regimens. In our center MPS was administered mainly for patients at risk for deterioration (e.g. unstable thyroid function, smoker etc.) or as second-line treatment. To augment the limited data we analyzed our real-world cohort retrospectively. Methods We analyzed all consecutive patients of our tertiary referral center (2019–2023) with a complete data set, who either received MPS simultaneously with intravenous methylprednisolone (IVMP), or after a first course of IVMP. Results We evaluated the data of 172 patients. Ninety-five were eligible for analysis. Clinical Activity Score showed a significant decrease between baseline (BL) and primary endpoint 6 months (3.9 ± 0.9 vs. 2.4 ± 1.4, p  < 0.0001). Inactivation was achieved in 60% of all patients at 6 months and in 77% at 12 months. Deviation, motility, upper eye lid retraction and proptosis showed no significant changes after 6 months. TSH-receptor-antibody-levels (TRAb) showed a significant decrease at 3 and 6 months ( p  < 0.0001). 10.5% developed DON. Multiple logistic regression showed a significant influence of irradiation after BL for inactivation (OR 6.18, 95% CI: 1.08 to 48.99). Discussion While inactivation is most often achieved, the severity of the disease in form of fibrosis (lid retraction, motility) and proptosis is not reversed. Further rehabilitative surgery is needed and patients should still be closely monitored for DON. Other immunosuppressants could be more effective even in IVMP resistant GO and should be subject to randomized head-to-head trials.

Background Radioiodine (RAI) is recommended by the National Institute of Clinical Excellence (NICE) as a first-line definitive treatment of Grave’s hyperthyroidism (GH). RAI is cited as a major risk factor in the development and exacerbation of thyroid eye disease (TED). We aim to identify the current risk of TED in a population treated post 2015. Methods This is a retrospective cohort study including all adult patients diagnosed with GH undergoing RAI over a seven-year period. Data collected included age; gender; thyroid diagnosis and pre- and post-treatment thyroid status; length of GH; TSHR-Ab titres; smoking status; RAI dose and number of treatments; ophthalmology assessment and use of steroid prophylaxis. Investigation results, clinical scoring and management details were collected from patients who developed TED following RAI. Results Four of 231 patients (1.7%) treated with RAI over 8 years had new onset (two patients) or progression (two patients) of TED following their RAI. One required immunosuppression and one rehabilitative TED surgery. No patient developed sight-threatening TED. Conclusions In our study, judicious screening for high-risk patients and the use of prophylactic steroids results in lower rates of RAI associated TED relative to those reported previously in the literature.

Background Alemtuzumab (ALEM), an immune reconstitution therapy for multiple sclerosis (MS), has been associated with an increased risk of secondary autoimmune diseases, including Graves’ disease (GD). Graves’ orbitopathy following ALEM (GO-f-ALEM) is a rare, but relevant manifestation. GO-f-ALEM epidemiology and clinical course are still poorly characterized. Main body The first aim of this paper was to perform a systematic review of published evidence of GO-f-ALEM in patients with MS, focusing on clinical features and management. Second aim was to integrate and compare literature data with real-world pharmacovigilance reports and institutional cases. A systematic review of published literature databases (PubMed, Embase, Scopus) from inception to December 2024 was performed according to PRISMA guidelines. A total of 42 published GO-f-ALEM cases in MS patients were identified. In parallel, as additional sources of data, which were not included in the systematic review analysis, 272 cases were retrieved from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database, and three institutional cases were described and analysed. GO-f-ALEM occurred more frequently in middle-aged adults (mean age 41 years old), with female predominance (60%) and a high rate of smoking (60%). GO generally occurred after 2–5 years from ALEM initiation. Fluctuating thyroid function and thyrotropin receptor antibody (TRAb) levels were commonly observed, with frequent need for definitive thyroid treatment (surgery or radioactive iodine - RAI). GO presentation was heterogeneous - from mild to sight-threatening forms - and mainly manifesting with lid retraction, proptosis, and diplopia. Concurrently, pharmacovigilance data from FAERS identified almost 300 reports of eye disorders potentially consistent with GO, thus suggesting under-diagnosis or under-reporting prevalence in literature. Institutional cases confirmed the potential for sight-threatening GO with dysthyroid optic neuropathy. Conclusions Our data suggest that GO-f-ALEM is an underrecognized disorder within the spectrum of ALEM-induced autoimmunity, with peculiar features, as suggested by clinical and immunological observations and simultaneously by pharmacovigilance reports. Routine ophthalmic monitoring and standardized GO classification are essential for diagnosis and follow-up. Prospective studies are warranted to better define its epidemiology and guide optimised management strategies.