RARE DISEASE
Euthyroid Graves orbitopathy
Euthyroid Graves orbitopathy
Euthyroid Graves orbitopathy
Synonyms: Euthyroid Graves ophthalmopathy
Synonyms: Euthyroid Graves ophthalmopathy
Synonyms: Euthyroid Graves ophthalmopathy
Drug discovery
2
drugs
With orphan designations
Overview
Euthyroid Graves orbitopathy (EGO) is a rare variant of thyroid eye disease characterized by orbital inflammation (proptosis, diplopia, eyelid retraction) without current or past thyroid dysfunction. Diagnosis relies on clinical features, orbital imaging, and exclusion of mimics like IgG4-related disease. While euthyroid, 9-15% develop thyroid dysfunction over time. TRAb levels may be low or absent initially but often emerge later [1][4][12]. Misdiagnosis is common due to frequent asymmetrical presentation [7][12].
Categories: rare developmental anomalies during embryogenesis, rare ophthalmic disorders
Research Papers
791 drug discovery papers about Euthyroid Graves orbitopathy, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
791 drug discovery papers about Euthyroid Graves orbitopathy, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-08 | Ultrasound-guided thermal ablation in patients affected by Graves' disease: a systematic review and meta-analysis.
Ultrasound-guided thermal ablation (U-GTA) techniques, including radiofrequency ablation (RFA) and microwave ablation (MWA), have recently been proposed as minimally invasive alternatives to surgery or radioiodine (RAI) therapy for patients with Graves' disease (GD) who are unresponsive to antithyroid drugs. However, evidence supporting its effectiveness and safety remains limited. A PubMed/MEDLINE, Web of Science, and Scopus research updated until January 31, 2026, was performed. The review question was: What is the euthyroidism rate (outcome) one year after U-GTA (intervention) in Graves' disease (population)? Two reviewers independently conducted the study screening, data extraction, and risk of bias assessment. A random-effects model was adopted to pool the prevalence with corresponding 95% confidence intervals. Four studies comprising 82 patients (88% female) were included in the analysis. Approximately 2.4% of patients required levothyroxine replacement after U-GTA. Thyroid volume significantly decreased following treatment, and baseline thyroid volume was identified as a predictor of relapse in one study. A transient increase in anti-TSH receptor antibodies was observed one month after U-GTA, followed by a subsequent decline. No worsening or new onset of Graves' orbitopathy was reported. Post-procedural adverse events occurred in 6.1% of patients and were transient. At 12 months, pooled euthyroidism rate was 67.0% (95% CI 54-78), with low heterogeneity (I² = 0%). U-GTA appears to induce biochemical remission in approximately two-thirds of selected patients with persistent or relapsed GD, with a favourable short-term safety profile and preservation of thyroid function in most cases. However, remission rates remain lower than those typically reported for definitive surgical treatment, and current evidence is limited to small, non-randomized studies with relatively short follow-up. Larger prospective comparative trials with standardized protocols are required to define the role of U-GTA within current management strategies for GD.
2026-01-28 | Euthyroid Graves' Ophthalmopathy With Negative Antibodies (EGONA): A Comprehensive Case-Based Review.
Euthyroid Graves' ophthalmopathy with negative antibodies (EGONA) is a rare form of thyroid eye disease. This literature review aims to establish the different presentations seen in the cases of euthyroid Graves' ophthalmopathy with negative antibodies. Despite the thyroid levels being normal, the mechanism by which EGONA causes eye disease is the same as the classical Graves' ophthalmopathy. Proper diagnosis relies mainly on clinical signs and imaging of the eye. A systematic search of PubMed, PubMed Central, and ScienceDirect was conducted with no date restrictions. Articles were included if they were English-language case reports describing patients with euthyroid ophthalmopathy and negative thyroid antibodies during initial presentation, with full-text availability and a documented clinical course. Data from nine articles (12 cases) were extracted, focusing on presentation, management, and outcomes. Treatments include corticosteroids, anti-thyroid medication, and surgery. Prognosis varied between those who developed thyroid imbalances and the presence of antibodies later down the course.
2026-01-06 | Periphlebitis of the Superior Ophthalmic Vein in Noninflammatory Thyroid Eye Disease
A 32-year-old female with euthyroid Graves’ disease presented with right-sided proptosis, first noticed 3 months prior to consultation. Although she was euthyroid, her thyroid-stimulating receptor antibodies were positive. An orbital CT scan, requested by her general ophthalmologist, demonstrated an inflammatory lesion involving the right superior muscle complex. On examination, visual acuity was 20/20 in OU. Margin reflex distances were 7 mm in the OD and 5 mm in the OS (panel A). Hertel exophthalmometry measured 22 mm in OD and 14 mm in OS (panel B). No clinical inflammatory signs were detected, with both VISA (vision, inflammation, strabisumus and appearance) and CAS (clinical activity score) inflammation scores graded as zero in OU. Intraocular pressure was asymmetric, measuring 19 mm Hg in the proptotic eye and 12 mm Hg in OS. Fundus examination was normal in OU. Axial T1-weighted postcontrast magnetic resonance imaging of the orbits with fat saturation revealed periphlebitis of the right superior orbital vein, characterized by a poorly defined, enhancing inflammatory process surrounding the vein (panel C). Color Doppler ultrasonography showed reduced flow velocity in OD (3.8 cm/s vs. 5.97 cm/s in OS) (panel D). Periphlebitis of the superior orbital vein is a rare manifestation of thyroid eye disease, usually associated with the active form of the orbitopathy. The present case highlights that superior orbital vein periphlebitis in thyroid eye disease may reduce orbital venous flow without the classic conjunctival signs of venous impedance or clinical signs of disease activity.FIG.
2025-11-03 | The role of mycophenolate mofetil in the therapy of thyroid eye disease.
Thyroid eye disease (TED) is an autoimmune disorder that can threaten vision loss. In 90% cases, it is related to Graves' disease, and in 10% cases, it occurs with euthyroidism or with chronic autoimmune thyroiditis. It is the leading cause of orbital pathology in adults. The TED treatment remains challenging for clinicians, particularly in moderate-to-severe or sight-threatening forms of the disease. One-third of TED patients experience a relapse despite the corticosteroids as a first-line treatment. Some patients show poor response or even no response to the treatment. There are many adverse effects associated with chronic use of intravenous methylprednisolone (IVMP). There is a need for new, efficient therapeutic methods, such as immunomodulating drugs like mycophenolate mofetil (MMF). This paper describes the role and potential efficiency of MMF application in TED by its direct action on TED pathogenic mechanisms. The introduction of MMF in the second-line treatment helps decrease the level of clinical symptoms and the risk of chronic complications, while causing only a small number of adverse events. Nevertheless, it should be noted that there are no unified guidelines available for consolidating treatment focused on maintaining remission after the first dose of IVMP. Moreover, clinical knowledge on the use of MMF application in TED is still limited, and further research is needed. Nonetheless, the available evidence is promising and MMF may play a vital role in future therapeutic strategies.
2025-10-29 | Unlocking the Therapeutic Potential: Selenium and Myo-Inositol Supplementation in Thyroid Disorders-Efficacy and Future Directions.
Background/Objectives: Thyroid disorders such as Hashimoto's thyroiditis and Graves' disease represent major endocrine challenges worldwide, often requiring long-term management. Recently, nutritional supplementation with selenium and myo-inositol has been proposed as a supportive strategy. This review aims to summarize the current evidence regarding their efficacy in improving thyroid function, reducing thyroid autoantibodies in Hashimoto's disease, and restoring biochemical euthyroidism in Graves' disease. Methods: A narrative review of the available literature was undertaken, concentrating on randomized controlled trials and observational studies evaluating selenium and myo-inositol, alone or in combination (MYO+Se), in patients with autoimmune thyroid disorders and benign thyroid nodules. Search Strategy and Study Selection: We searched MEDLINE/PubMed, Embase, Cochrane CENTRAL, and Scopus from inception to 31 July 2025. The search used Boolean operators to combine the following keywords: ("selenium" OR "selenomethionine") AND ("myo-inositol" OR "inositol") AND (thyroid OR Hashimoto* OR Graves' OR hyperthyroid* OR hypothyroid* OR nodule* OR goiter OR orbitopathy). We included human studies in English. Inclusion criteria: Research designs include RCTs, quasi-experimental studies, cohort/case-control studies, and big case series (n ≥ 30). Exclusion criteria: Animal-only or in vitro studies (unless mechanistic), pediatric case reports, and editorials/commentaries. Study selection and data extraction: Two reviewers screened independently; discrepancies were settled through consensus. The data retrieved included the population, baseline iodine/selenium status (if reported), dose/formulation, treatment duration, outcomes (TSH, FT4, FT3, TPOAb, TgAb, TRAb, nodule metrics), and adverse events. Quality assessment: The risk of bias was assessed using the RoB-2 for RCTs and the Newcastle-Ottawa Scale or JBI checklists for observational studies. A qualitative synthesis emphasized study quality, consistency, directness, and accuracy. Results: Clinical research indicate that selenium supplementation may reduce thyroid peroxidase antibody (TPOAb) levels in Hashimoto's disease, thereby attenuating autoimmune activity. Myo-inositol, particularly when combined with selenium, has been proven to improve thyroid hormone profiles while also lowering nodule size or growth. In Graves' disease, supplementation has been linked to the restoration of biochemical euthyroidism in certain patients, albeit data are limited. Despite these encouraging results, diversity in trial design, treatment length, and dosages restrict the robustness of existing recommendations. Conclusions: Selenium and myo-inositol supplementation have shown promise as adjuvant treatments for autoimmune thyroid diseases and benign thyroid nodules. However, further large-scale, well-designed clinical trials are needed to determine the appropriate dosages, treatment duration, and patient selection criteria. Personalized supplementation solutions may improve medication efficacy and help with more comprehensive thyroid disease care.
cell therapies
2023-11-17 | Regulatory T Cells in the Pathogenesis of Graves’ Disease
Maintaining a delicate balance between the prompt immune response to pathogens and tolerance towards self-antigens and commensals is crucial for health. T regulatory (Treg) cells are pivotal in preserving self-tolerance, serving as negative regulators of inflammation through the secretion of anti-inflammatory cytokines, interleukin-2 neutralization, and direct suppression of effector T cells. Graves’ disease (GD) is a thyroid-specific autoimmune disorder primarily attributed to the breakdown of tolerance to the thyroid-stimulating hormone receptor. Given the limitations of currently available GD treatments, identifying potential pathogenetic factors for pharmacological targeting is of paramount importance. Both functional impairment and frequency reduction of Tregs seem likely in GD pathogenesis. Genome-wide association studies in GD have identified polymorphisms of genes involved in Tregs’ functions, such as CD25 (interleukin 2 receptor), and Forkhead box protein P3 (FOXP3). Clinical studies have reported both functional impairment and a reduction in Treg frequency or suppressive actions in GD, although their precise involvement remains a subject of debate. This review begins with an overview of Treg phenotype and functions, subsequently delves into the pathophysiology of GD and into the existing literature concerning the role of Tregs and the balance between Tregs and T helper 17 cells in GD, and finally explores the ongoing studies on target therapies for GD.
2023-07-18 | Therapeutic Plasma Exchange as a Bridging Therapy for the Definitive Treatment of a Patient with Graves’ Disease and Methimazole-Induced Liver Injury
Graves' disease (GD) is an autoimmune condition affecting the thyroid gland. The aim of treating GD is to control the symptoms of hyperthyroidism and achieve long-term remission. Antithyroid drugs (ATDs) are the medications of choice among newly-diagnosed GD patients as they are easy to be delivered and cause remission in more than 50% of patients. However, ATDs increase the risk of hepatotoxicity, especially among patients with liver abnormalities. Patients who cannot tolerate ATDs should receive definitive therapy such as radioactive iodine (RAI) or surgery. In order to minimize the risk of thyroid storm during these procedures, patients should be in euthyroid condition and receive bridging therapy. Therapeutic plasma exchange (TPE), which aims to remove thyroid hormones from plasma, is one of the modalities that can be considered as a bridging therapy during the perioperative period among GD patients who cannot tolerate ATD.A 35-year-old man with general weakness and thyrotoxicosis symptoms was admitted to the emergency room. Lid retraction, diffuse Goiter, and tremors were evident. Laboratory findings revealed TSH = 0.005 µIU/mL, FT4 = 7.77 ng/dL, TRAb = 9.90 IU/L, ALT = 123 U/L, total bilirubin = 23.94 µmol/L, and direct bilirubin = 10.26 µmol/L. Ultrasonographic examination showed the enlargement of the thyroid gland, and abdomen ultrasonographic evaluation showed mild hepatomegaly with mild fatty infiltration. The patient was diagnosed with GD, suspected thyroid storm, elevated liver transaminases, and fatty liver disease. The patient then received methimazole, propranolol, and glycyrrhizin. During observation, the patient developed drug-induced liver injury (DILI) evidenced by an increase in liver enzymes (ALT up to 1023 U/L) and the elevation of total bilirubin to 258.21 µmol/L, so methimazole was stopped. After discontinuing methimazole, liver injury improved. However, thyrotoxicosis symptoms returned, so the patient underwent a total thyroidectomy. In order to achieve a euthyroid status before surgery, five sessions of therapeutic plasma exchange were performed, which improved the signs and symptoms of hyperthyroidism and retained the thyroxine hormone within the normal range. Thyroidectomy was then performed successfully without serious complications (e.g., thyroid storm, etc.).Therapeutic plasma exchange is a safe and effective bridging therapy for GD patients who require thyroidectomy but cannot tolerate ATDs.
2019-11-28 | Novel therapies for thyroid autoimmune diseases: An update
A Th1 immune-preponderance has been shown in the immunopathogenesis of autoimmune thyroiditis (AT), Graves' disease (GD) and Graves’ Ophthalmopathy (GO), in which the Th1-chemokines (CXCL9, CXCL10, CXCL11), and their (C-X-C)R3 receptor, have a crucial role. Methimazole, and corticosteroids have been shown to modulate these chemokines; several efforts have been done to modulate the autoimmune reaction with other drugs, i.e. PPAR-γ, or -α ligands, or antibodies, or small molecules directed against CXCL10, or CXCR3. Antigen-specific therapy for GD, by inducing T cell tolerance through an immunization with TSH-R peptides, has been published. Drugs targeting cytokines [anti-TNFα (Etanercept), and anti-IL-6 (Tocilizumab)], and RTX (a chimeric monoclonal antibody vs. CD20) have been used in GO, with promising results. Teprotumumab (a human monoclonal anti-IGF-1R blocking antibody) has been investigated in a trial, showing it was very effective in GO patients. Still, more studies are needed for new therapies targeting autoimmune thyroid disorders.
2012-02-14 | Adoptive Transfer of Antithyrotropin Receptor (TSHR) Autoimmunity from TSHR Knockout Mice to Athymic Nude Mice
We have recently shown that wild type mice are highly tolerant, whereas thyrotropin receptor (TSHR) knockout (KO) mice are susceptible to immunization with the mouse TSHR, the autoantigen in Graves' disease. However, because TSHR KO mice lack the endogenous TSHR, Graves-like hyperthyroidism cannot be expected to occur in these mice. We therefore performed adoptive transfer of splenocytes from TSHR KO mice into nude mice expressing the endogenous TSHR. Anti-TSHR autoantibodies were detected in approximately 50 % recipient mice 4 wk after adoptive transfer of splenocytes (5 × 107/mouse) from TSHR KO mice immunized with adenovirus expressing mTSHR A subunit and persisted for 24 wk. Depletion of regulatory T cells by anti-CD25 antibody in the donor mice increased successful transfer rates without increasing antibody levels. Some recipient mice showed transient increases in thyroid-stimulating antibodies and T4 levels 4–8 wk after transfer, but many became thyroid-blocking antibody positive and hypothyroid 24 wk later. Adoptive transfer of splenocytes from naïve TSHR KO mice transiently induced very low antibody titers when the recipient mice were treated with anticytotoxic lymphocyte antigen 4 and antiprogrammed cell death 1 ligand 1 antibodies for 8 wk after transfer. Histologically, macrophages infiltrated the retrobulbar adipose tissues and extraocular muscles in a small fraction of the recipients. Our findings demonstrate successful adoptive transfer of anti-TSHR immune response from TSHR KO mice to nude mice. Although the recipient mice developed only transient and infrequent hyperthyroidism, followed by eventual hypothyroidism, induction of orbital inflammation suggests the possible role of anti-TSHR immune response for Graves' orbitopathy.
2011-08-19 | Graves’ Ophthalmopathy as an Indication Increased the Risk of Hypoparathyroidism After Bilateral Thyroidectomy
Studies have evaluated the effect of thyroidectomy on the course of Graves' ophthalmopathy (GO) but it is unclear how GO as an indication might affect surgical outcomes. We aimed to evaluate the impact of this indication on surgical outcomes in Graves' disease (GD).From 1995 to 2008, 329 patients with GD underwent thyroidectomy. Patients were stratified into two groups, namely, those with GO as indication (GO) and those with non-GO indication (non-GO). Outcomes were compared between the groups and outcomes with significance were further analyzed by multivariate analyses to determine independent factors.The GO group was significantly older (P < 0.001), had more males (P < 0.001), and fewer relapses (P < 0.001) than the non-GO group. It also had a higher proportion of total/near-total thyroidectomy (P < 0.001), despite a shorter operating time (P = 0.024) and less blood loss (P = 0.010). When only total/near-total thyroidectomy was considered, the GO group had significantly more permanent hypoparathyroidism than the non-GO group (9.2 vs. 1.6%, P = 0.038), but the rate of permanent hypoparathyroidism was similar in the two groups when only those with parathyroid autotransplantation were considered. Other complications were similar between the two groups. By multivariate analysis, GO as indication was an independent risk factor for temporary (OR 1.97, P = 0.033) and permanent hypoparathyroidism (OR 4.76, P = 0.007).GO as a surgical indication (i.e., unstable or active GO requiring ophthalmic treatment or follow-up) was associated with increased risk of temporary and permanent hypoparathyroidism after bilateral thyroidectomy. Routine parathyroid autotransplantation may reduce the risk of permanent hypoparathyroidism in this select patient group.
antibodies
2026-04-01 | Thyroid Eye Disease: Current Perspectives in Pathogenesis, Risk Factors, and Management
Thyroid eye disease (TED), also referred to as Graves’ orbitopathy or thyroid-associated ophthalmopathy, is an autoimmune inflammatory disorder of the orbit that most often accompanies hyperthyroidism due to Graves’ disease. This review summarises current understanding of its immunopathogenesis, including the role of autoantibodies against the thyroid-stimulating hormone receptor (TSH-R) and insulin-like growth factor-1 receptor (IGF-1R), the subsequent activation of orbital fibroblasts, cytokine-mediated inflammation, glycosaminoglycan deposition and fibrosis. The clinical spectrum ranges from mild ocular surface irritation to sight-threatening dysthyroid optic neuropathy — and the classification systems (e.g., CAS, VISA, EUGOGO) used to assess disease activity and severity. Key modifiable risk factors such as smoking, uncontrolled thyroid status, micronutrient deficiencies (selenium, iron, iodine), dyslipidaemia, and vitamin D deficiency are reviewed. We present management strategies from achieving euthyroidism and risk-factor control, to supportive care (lubrication, eyelid taping) and medical therapies — from high-dose intravenous methylprednisolone to immunosuppressants (mycophenolate, azathioprine) and novel biologics such as teprotumumab (anti-IGF-1R), rituximab (anti-CD20) and tocilizumab (anti-IL-6R). Surgical options (orbital decompression, strabismus correction, eyelid surgery) for disfiguring or sight-threatening disease are discussed. Finally, we highlight future directions including biomarker development and personalised, mechanism-based therapy. Early recognition and intervention, along with risk factor modification and targeted treatments, may improve functional and psychosocial outcomes in TED.
2025-11-04 | Assessing the Role of Tocilizumab in the Treatment of Thyroid Eye Disease: A Retrospective Single Centre Analysis.
Due to the variable course of thyroid eye disease (TED), treatment should be tailored to disease severity, individual risk factors, and clinical course. This study is based on a retrospective analysis at the orbital centre of the University Eye Clinic Essen and evaluates the efficacy of the IL-6 receptor blocker tocilizumab as a second-line therapy in patients with therapy-refractory TED. After approval of cost coverage, 20 patients were treated with tocilizumab over a mean period of 4.8 ± 2.7 months. The following parameters were assessed: sex, age, underlying thyroid disease, disease activity and severity, prior therapies, visual acuity, intraocular pressure, eyelid position, exophthalmos, monocular excursions, strabismus/diplopia, levels of TSH receptor antibodies (TRAb), and adverse events. The female-to-male ratio was 3 : 1. Mean patient age was 58.2 ± 8.5 years. The majority (90%, n = 18) had Graves' disease; one patient had primary hypothyroidism and one was euthyroid. All patients had previously failed various treatment regimens (median cumulative steroid dose 4.6 g [1.5 - 7.5 g], 55% mycophenolate, 65% orbital apex radiation, 20% balanced orbital decompression). Among 17 patients with detectable TRAb at baseline, mean antibody levels decreased by 48.4%. A reduction of at least 30% was achieved in 70.6% of these patients (n = 17). A decrease in the Clinical Activity Score (CAS) by ≥ 2 points was observed in 70% of cases. The mean inflammation score (maximum 20 points per patient) decreased from 8.8 ± 3.9 to 3.4 ± 2.4. The effect on exophthalmos was moderate: mean reduction was 0.9 ± 1.8 mm (range - 6 mm to + 3 mm). A decrease of ≥ 2 mm was documented in 25% of patients, whereas an increase was noted in 12.5% (0.5 to 3 mm). Improvement in ocular motility was documented in 22.5% of patients, while 10% showed deterioration. This cohort exclusively included therapy-refractory patients, some with protracted disease. The significant reduction in inflammation and particularly in TRAb levels, as a biomarker of disease activity, demonstrate the efficacy of tocilizumab in this highly selected population. Tocilizumab may therefore be an important treatment option for patients with high antibody levels and predominantly inflammatory disease manifestations. Further studies are warranted to evaluate whether it reduces the risk of relapse after successful treatment with an IGF-1 receptor blocker.
2025-10-01 | Potential of Tocilizumab in Inducing Remission of Graves’ Disease
Background: The efficacy of tocilizumab in reducing TSH receptor antibodies (TRAb) and inducing remission in patients with Graves’ disease (GD) is an area of ongoing research and clinical studies. Case Description: A 42-year-old gentleman presented with spontaneous progressive eye pain that intensified with eye movement. Biochemical tests showed euthyroidism and elevated TRAb. Orbits CT scan showed bilateral extraocular muscle enlargement with proptosis. He was diagnosed with euthyroid Graves’ ophthalmopathy and started on methylprednisolone 500 mg intravenous infusion weekly for 10 weeks. His symptoms progressed to diplopia. Daily oral prednisolone was initiated with minimal improvement. Whereafter, he was referred to radiation and underwent ten sessions of radiotherapy to the bilateral orbits, complemented by triamcinolone periorbital injections. Meanwhile, he progressed to subclinical hyperthyroidism. A repeated thyroid function test confirmed subclinical hyperthyroidism, and TRAb increased. A diagnostic thyroid scan (Tc-99m) showed a normal uptake. He returned to our clinic with worsening eye symptoms. Repeated thyroid function tests showed hypothyroidism, and he was started on carbimazole 5 mg daily in a different center, which we discontinued when he came for follow-up. Tocilizumab initiation for his eye disease was decided to be every 4 weeks, completing a total of three doses. A repeat of TRAb 2 months after completing tocilizumab yielded negative TRAb levels and a reversal of his thyroid functions to euthyroidism. On follow-up, he presented again with active eye disease and positive TRAb level 7 months after tocilizumab treatment, suggesting that while tocilizumab may initially induce remission, it did not provide a long-lasting effect or sustained remission, underscoring the challenge in achieving durable management of Graves’ disease. Conclusion: Tocilizumab holds promise as a novel therapeutic option for inducing remission in patients with GD, as evidenced by negative TRAb and euthyroidism. Further research is warranted to establish the long-term efficacy and safety of tocilizumab in GD. Publication History Article published online: 29 December 2025 © 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
2025-05-06 | Thyroid eye disease (Graves' orbitopathy): clinical presentation, epidemiology, pathogenesis, and management.
Thyroid eye disease (TED; also known as Graves' orbitopathy), causes swollen extraocular muscles and orbital fat. Mechanistically, TED involves lid retraction, oedema and redness of the eyelids and conjunctiva, proptosis, diplopia, and optic neuropathy. Investigation of TED involves assessment of disease activity (inflammation) and disease severity. TED is predominantly mild in 77% of cases, moderate-to-severe in 22%, and rarely sight-threatening in 1% of patients. While most patients with TED have Graves' hyperthyroidism, up to 5% are euthyroid or even hypothyroid. Risk factors include male sex, older age, smoking, diabetes, hypercholesterolaemia, duration of hyperthyroidism, radioactive iodine therapy, and the presence of thyrotropin receptor (TSHR) antibodies (detectable in more than 95% of patients and directly related to TED activity and severity). Genetic immunisation of mice with TSHR, but not with insulin-like growth factor-1 receptor (IGF-1R), provides a reliable animal model of TED, demonstrating that TSHR is the primary autoantigen in the disease. Crosstalk between TSHR and IGF-1R occurs via a β-arrestin scaffold. Teprotumumab, a human monoclonal antibody that blocks IGF-1R without binding to TSHR, has been shown to significantly improve outcomes in moderate-to-severe TED, including greater proptosis reduction compared with intravenous methylprednisolone. However, its disadvantages include side effects (eg, hearing loss in 30% of patients), a high cost, and a high relapse rate. Therefore, intravenous steroids remain the treatment of choice in many parts of the world. Tocilizumab, which blocks the interleukin-6 receptor, is an effective treatment option for patients with TED who are steroid-resistant. This Review further discusses alternative medications, surgical treatments, local measures, and the importance of quality-of-life assessments and multidisciplinary care.
2025-01-12 | Low clinical activity score, 'progressive' thyroid eye disease: presentations of 1439 patients from a tertiary centre in Hong Kong.
To report the presenting clinical, serological and treatment profiles of 1439 patients with thyroid eye disease (TED) from a tertiary centre in Hong Kong. Consecutive patients with TED presented to the Thyroid Eye Clinic (TEC), the Chinese University of Hong Kong between 2014 and 2023. Prospective cohort and masked review of medical records and orbital images. A total of 1439 (70% female, 98% Han Chinese) patients with TED (26% ex/current smoker), presented at 43±5.9 years old, were reviewed. The first TED symptoms to TEC evaluation was 6±3 months. 85% had Graves' disease and 12% were given radioactive iodine before presentation. 35% of patients had a family history of autoimmune thyroid diseases. Baseline thyroid-stimulating hormone receptor antibody, thyroid-stimulating immunoglobulin and thyroid peroxidase antibody were elevated in 75%, 69% and 57% tested. Euthyroid TED (E-TED) was diagnosed in 6%, associated with asymmetric presentation (p<0.001). The most common signs were exophthalmos (69%), upper eyelid retraction (53%), swelling (36%), conjunctival injection (34%) and lower eyelid retraction (32%). Notably, 547 (38%) presented with moderate-to-severe and 150 (10%) vision-threatening TED, whose clinical activity score (CAS) was just 2.4±1.4 and 2.6±1.5, respectively. Male and TED onset after 40 were associated with higher CAS and NOSPEC (No physical signs or symptoms, Only signs, Soft tissue involvement, Proptosis, Extraocular muscle signs, Corneal involvement, and Sight loss) score (both p<0.05). 471 (33%), 361 (25%), 263 (18%) and 138 (9%) patients received intravenous methylprednisolone, orbital radiotherapy, steroid-sparing immunosuppressants and surgical decompression, respectively. Around one-third (34%) of our cohort presented with 'low-CAS, progressive', moderate-to-severe or vision-threatening TED, while only one-fifth (18%) were clinically active (CAS≥3). Our results showed the limitations and unmet need of the existing 'high-CAS only' approach, especially in managing 'non-inflammatory' TED, prevalent in non-Caucasian populations.
proteins
2023-10-30 | 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.
2023-01-01 | Nonsurgical treatment for upper eyelid retraction in patients with inactive Graves’ orbitopathy
To evaluate the effectiveness of incobotulinumtoxinA (Xeomin®) in treating upper eyelid retraction in patients with Graves orbitopathy (GO) initially scheduled for surgery via two different application sites.This is a comparative, prospective study, conducted at the Department of Ophthalmology, Medical School, University Hospital Centre Zagreb, EUGOGO site (EUropean Group On Graves' Orbitopathy) in Croatia from January 2020 till January of 2021 in accordance with national health headquarter recommendations. All patients were classified as inactive with marked eyelid retraction and randomly divided into groups according to application sites. Group A underwent transconjunctival application (18 eyes) and group B transcutaneous application (20 eyes) of incobotulinumtoxinA. The primary end point of this study was lowering the eyelid, to alleviate anterior eye segment symptoms and achieve acceptable aesthetic appearance until surgery becomes available.There were no nonresponders and we found no statistically significant difference in the degree of lowering the eyelid between the two application sites. Following rules for avoiding spread of SARS-CoV-19, none of the patients included in this study were infected. Moreover, participants reported diminishing of anterior eye segment irritation and improved aesthetics.Treatment of inactive GO patients with incobotulinumtoxinA for upper eyelid retraction is efficient and safe and can be used as an adjuvant treatment while patients wait for surgery, by alleviating symptoms and improving the level of aesthetic satisfaction without causing a threat to anterior eye segment and visual function. The study showed that effect of treatment was the same, whether we applied the toxin transconjunctivaly or transcutaneously.
2022-07-26 | Murine Thyroid IL-4 Expression Worsens Hypothyroidism on Iodine Restriction and Mitigates Graves Disease Development
Abstract Cytokines are known to perturb thyroid function and the role of interleukin-4 (IL-4) in the pathogenesis of Graves disease (GD) remains controversial. In our mouse model overexpressing IL-4 in thyrocytes (Thyr-IL4), we have reported that adult mice preserved normal serum thyroxine despite an iodide uptake defect. In the present work, we evaluated if iodine restriction could uncover the thyroid deficiency in Thyr-IL4 animals as well as the role of pendrin overexpression as a compensatory mechanism. Moreover, using an experimental model of GD we investigated the effect of a local expression of IL-4 on the incidence of hyperthyroidism. Thyr-IL4 mice developed more rapidly elevated serum thyrotropin under low-iodine supply with thyroid enlargement and classical histological modifications. These hallmarks of hypothyroidism were all enhanced in Thyr-IL4 mice with complete pendrin invalidation. Following immunization, a lower proportion of Thyr-IL4 animals developed hyperthyroidism. Surprisingly, immunized Thyr-IL4 animals presented numerous leukocyte infiltrates, associated with increased intrathyroidal expression of IFN-γ. We have demonstrated that thyroid deficiency in Thyr-IL4 mice is partially compensated for by the excessive iodide content of the standard chow and the overexpression of pendrin in these animals. Furthermore, we have shown that the local expression of IL-4 in the thyroid attenuates GD progression, which was associated with enhanced thyroid infiltration by immune cells that could negatively affect thyroid function.
2022-06-07 | Potential Therapeutic Role of Bone Morphogenic Protein 7 (BMP7) in the Pathogenesis of Graves’ Orbitopathy
We investigated a role of bone morphogenic protein 7 (BMP7), a member of the TGF-β superfamily on pathogenic mechanism of Graves' orbitopathy (GO). The therapeutic effects of BMP7 on inflammation and fibrosis were evaluated in cultured Graves' orbital fibroblasts.Expression of BMP7 was compared in cultured orbital tissue explants from GO (n = 12) and normal control (n = 12) subjects using real-time PCR. Orbital fibroblasts were cultured from orbital connective tissues obtained from GO (n = 3) and normal control patients (n = 3). Cells were pretreated with recombinant human BMP7 (rhBMP7) before stimulation with TGF-β, IL-1β, and TNF-α. Fibrosis-related proteins and inflammatory cytokines were analyzed by Western blotting. The activation of signaling molecules in inflammation and fibrosis was also analyzed.The expressions of BMP7 mRNA were lower in GO orbital tissues than control. Fibrosis-related proteins, fibronectin, collagen 1α, and α-SMA induced by TGF-β were suppressed by treating rhBMP7, and rhBMP7 upregulated TGF-β induced SMAD1/5/8 protein expression, whereas downregulated SMAD2/3. Increased pro-inflammatory molecules, IL-6, IL-8, and intercellular adhesion molecule-1 (ICAM-1) by IL-1β or TNF-α were blocked by rhBMP7 treatment, and the expression of phosphorylated NFκB and Akt was suppressed by rhBMP7 treatment.BMP7 transcript levels were downregulated in Graves' orbital tissues. Exogenous BMP7 treatment showed inhibitory effects on the production of profibrotic proteins and proinflammatory cytokines in orbital fibroblasts. Our results provide a molecular basis of BMP7 as a new potential therapeutic agent through the opposing mechanism of profibrotic TGF-β/SMAD signaling and proinflammatory cytokine production.
2022-05-09 | Antithymocyte Globulin as Second-Line Therapy in Graves Orbitopathy—Preliminary Results From a Prospective Single-Center Study
Objective Management of Graves’ orbitopathy remains a challenge. Our previous case report has shown promising results for rabbit antithymocyte globulin (rATG) in the treatment of Graves’ orbitopathy. Design We present the response of 7 individuals with active moderate-to-severe steroid-resistant Graves’ orbitopathy to rATG, representing preliminary results from a prospective single-center study. Methods rATG was administered intravenously at a dose of 0.8–1.0 mg/kg daily (cumulative dose of 150–200 mg). The primary outcome measures at weeks 24 and 48 were ≥2-point reduction in Clinical Activity Score from baseline, a proptosis response, a diplopia response, and improvement of distant best-corrected visual acuity and mean retinal sensitivity. Key secondary outcomes included stabilization of ganglion cell complex thickness, a decrease of retinal nerve fiber layer in OCT, and a reduction in CD4/CD8 ratio and TRAb at 48 weeks. Results An improvement in clinical activity score was observed in all patients, with disease inactivation in 3 cases. Proptosis reduction equal to or greater than 2 mm was noted for 8 of 10 eyes. Diplopia improved in three of 6 patients. There was an improvement in best-corrected visual acuity (from 0.69 to 0.78) and mean retinal sensitivity (from 20.8 to 23.5 dB). In addition, there was a long-lasting improvement in CD4/CD8 ratio in 6 patients. Two patients experienced adverse events (influenza and serum sickness). Conclusion rATG therapy offers a long-lasting improvement in moderate-to-severe steroid-resistant Graves’ orbitopathy with improvement in functional vision (reduction of diplopia, improvement of visual acuity, retinal sensitivity, and VEP pattern). The therapy is well-tolerated. Clinical Trial Registration ClinicalTrials.gov, identifier NCT05199103.
other
2022-05-30 | Therapeutic Potential of Targeting Periostin in the Treatment of Graves’ Orbitopathy
Periostin is a matricellular protein that is ubiquitously expressed in normal human tissues and is involved in pathologic mechanism of chronic inflammatory and fibrotic disease. In this study we investigate periostin in the pathogenesis of Graves’ orbitopathy (GO) using human orbital adipose tissue obtained from surgery and primary cultured orbital fibroblasts in vitro . POSTN (gene encoding periostin) expression in Graves’ orbital tissues and healthy control tissues was studied, and the role of periostin in GO pathologic mechanism was examined through small-interfering RNA (siRNA)-mediated silencing. POSTN gene expression was significantly higher in Graves’ orbital tissues than healthy control tissues in real-time PCR results, and immunohistochemical staining revealed higher expression of periostin in Graves’ orbital tissues than normal tissues. Silencing periostin using siRNA transfection significantly attenuated TGF-β-induced profibrotic protein production and phosphorylated p38 and SMAD protein production. Knockdown of periostin inhibited interleukin-1 β -induced proinflammatory cytokines production as well as phosphorylation of NF-κB and Ak signaling protein. Adipocyte differentiation was also suppressed in periostin-targeting siRNA transfected GO cells. We hypothesize that periostin contributes to the pathogenic process of inflammation, fibrosis and adipogenesis of GO. Our study provides in vitro evidence that periostin may be a novel potential therapeutic target for the treatment of GO.
2022-04-04 | Identification of tRNA-Related Fragments and Their Potential Regulatory Effects in Thyroid-Associated Ophthalmopathy
Recently, the potential role of tRNA-related fragments (tRFs) in ophthalmic diseases has been extensively researched. However, systematic studies on the potential regulatory effects of tRFs in thyroid-associated ophthalmopathy (TAO) are lacking. We used high-throughput sequencing techniques to measure expression levels of mRNAs and tRFs in patients with TAO, and the results were verified by real-time quantitative reverse transcription polymerase chain reaction (q-PCR). Next, the potential biological regulatory effect of differentially expressed tRFs was analyzed, and potential downstream target RNAs of differentially expressed tRFs were predicted to explore the potential role of tRFs as therapeutic targets and biomarkers of TAO. A total of 50 tRFs and 361 mRNAs were dysregulated in the TAO group, and tRF5-GluCTC, PMAIP1, HSD17B2 and ATF3 were verified to be significantly differentially expressed in TAO. Our research reveals that several associated pathways likely play a role in the pathogenesis of TAO. By targeting ATF3, HSD17B2 and PMAIP1, tRF5-GluCTC may play a potential role in regulating the orbital fibroblast adipogenic response and fibrotic hyperplasia in patients with TAO.
2021-12-15 | A Novel Competing Endogenous RNA Network Associated With the Pathogenesis of Graves’ Ophthalmopathy
Background: Growing evidence has recently revealed the characteristics of long noncoding (lncRNA)/circular RNA (circRNA)-microRNA (miRNA)-mRNA networks in numerous human diseases. However, a scientific lncRNA/circRNA-miRNA-mRNA network related to Graves' ophthalmopathy (GO) remains lacking. Materials and methods: The expression levels of RNAs in GO patients were measured through high-throughput sequencing technology, and the results were proven by quantitative real-time PCR (qPCR). We constructed a protein-protein interaction (PPI) network using the Search Tool for the Retrieval of Interacting Genes (STRING) database and identified hub genes by the Cytoscape plug-in CytoHubba. Then, the miRNAs related to differentially expressed lncRNAs/circRNAs and mRNAs were predicted through seed sequence matching analysis. Correlation coefficient analysis was performed on the interesting RNAs to construct a novel competing endogenous RNA (ceRNA) network. Results: In total, 361 mRNAs, 355 circRNAs, and 242 lncRNAs were differentially expressed in GO patients compared with control patients, 166 pairs were identified, and ceRNA networks were constructed. The qPCR results showed that 4 mRNAs (THBS2, CHRM3, CXCL1, FPR2) and 2 lncRNAs (LINC01820:13, ENST00000499452) were differentially expressed between the GO patients and control patients. Conclusion: An innovative lncRNA/circRNA-miRNA-mRNA ceRNA network between GO patients and control patients was constructed, and two important ceRNA pathways were identified, the LINC01820:13-hsa-miR-27b-3p-FPR2 ceRNA pathway and the ENST00000499452-hsa-miR-27a-3p-CXCL1 pathway, which probably affect the autoimmune response and inflammation in GO patients.
2020-12-01 | The critical role of m6A methylation in the pathogenesis of Graves' ophthalmopathy
To investigate the role of N6-methyladenosine (m6A) RNA modification in the pathogenesis of Graves' ophthalmopathy (GO).Surgically excised extraocular muscles from 7 patients with GO and 5 subjects without GO were used. The global m6A levels in the specimens were determined using an m6A RNA methylation quantification kit. RNA sequencing (RNA-seq) was used to analyze the molecules involved in the regulation of m6A RNA methylation and the differential expression of mRNAs between the two groups (4 eyes, respectively). The expression of m6A RNA modification genes was evaluated by real-time PCR. The functional implications of the gene alterations between the GO and control specimens were determined by Gene Ontology analysis.The m6A level was significantly increased in the specimens of GO patients compared to the control specimens (P < 0.05). The expression of m6A methylation regulators, such as WT1 associated protein (WTAP), alkylation repair homolog protein 5 (ALKBH5), E74 like ETS transcription factor 3 (ELF3), YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), YTHDF3 and YTH domain containing 2 (YTHDC2), was significantly upregulated (P < 0.05). Gene Ontology enrichment analysis showed that the most highly upregulated genes and biological pathways were related to the immune response and inflammatory processes such as lymphocyte activation, leukocyte differentiation, cytokine production and cytokine-mediated signaling pathways.Our results suggest that m6A methylation may play a critical role in the pathogenesis of GO and that targeting genes that regulate m6A methylation may provide a new therapeutic approach for GO.
2020-10-20 | Role of binding immunoglobulin protein (BiP) in Graves’ orbitopathy pathogenesis
Inflammation and adipogenesis represent the main pathogenic mechanisms of Graves' orbitopathy (GO), and oxidative stress is a well-known inducer of GO pathology. Endoplasmic reticulum (ER) stress has been suggested as a major contributor to inflammation and reactive oxygen species (ROS) generation. In this study, we investigated the role of the ER-stress chaperone protein, binding immunoglobulin protein (BiP), in GO pathogenesis. Using primary cultures of orbital fibroblasts from patients with GO, we examined the role of BiP in GO pathogenesis by silencing its expression with small-interfering RNA (siRNA). Inflammatory cytokine expression was analysed by Western blotting and ELISA. Intracellular ROS levels induced by hydrogen peroxide or cigarette smoke extract were measured by 5-(and 6)-carboxy-20,70-dichlorodihydrofluorescein diacetate staining and flow cytometry. After adipogenic differentiation in BiP siRNA-transfected cells, the cells were stained with Oil Red O, and the levels of adipogenic transcription factors were determined by Western blot analysis. BiP mRNA expression levels were significantly higher in GO orbital tissues than in non-GO orbital tissues. Silencing BiP attenuated the expression of pro-inflammatory cytokines (interleukin-6, intercellular adhesion molecule-1, and monocyte chemotactic protein-1) in primary cultured GO orbital fibroblasts. Silencing BiP also reduced ROS generation, hyaluronan production, and adipocyte differentiation. These findings suggest that ER stress is involved in the aetiology of GO and that modulation of ER stress has therapeutic potential for GO.
small molecules
2026-08-08 | Ultrasound-guided thermal ablation in patients affected by Graves' disease: a systematic review and meta-analysis.
Ultrasound-guided thermal ablation (U-GTA) techniques, including radiofrequency ablation (RFA) and microwave ablation (MWA), have recently been proposed as minimally invasive alternatives to surgery or radioiodine (RAI) therapy for patients with Graves' disease (GD) who are unresponsive to antithyroid drugs. However, evidence supporting its effectiveness and safety remains limited. A PubMed/MEDLINE, Web of Science, and Scopus research updated until January 31, 2026, was performed. The review question was: What is the euthyroidism rate (outcome) one year after U-GTA (intervention) in Graves' disease (population)? Two reviewers independently conducted the study screening, data extraction, and risk of bias assessment. A random-effects model was adopted to pool the prevalence with corresponding 95% confidence intervals. Four studies comprising 82 patients (88% female) were included in the analysis. Approximately 2.4% of patients required levothyroxine replacement after U-GTA. Thyroid volume significantly decreased following treatment, and baseline thyroid volume was identified as a predictor of relapse in one study. A transient increase in anti-TSH receptor antibodies was observed one month after U-GTA, followed by a subsequent decline. No worsening or new onset of Graves' orbitopathy was reported. Post-procedural adverse events occurred in 6.1% of patients and were transient. At 12 months, pooled euthyroidism rate was 67.0% (95% CI 54-78), with low heterogeneity (I² = 0%). U-GTA appears to induce biochemical remission in approximately two-thirds of selected patients with persistent or relapsed GD, with a favourable short-term safety profile and preservation of thyroid function in most cases. However, remission rates remain lower than those typically reported for definitive surgical treatment, and current evidence is limited to small, non-randomized studies with relatively short follow-up. Larger prospective comparative trials with standardized protocols are required to define the role of U-GTA within current management strategies for GD.
2026-01-28 | Euthyroid Graves' Ophthalmopathy With Negative Antibodies (EGONA): A Comprehensive Case-Based Review.
Euthyroid Graves' ophthalmopathy with negative antibodies (EGONA) is a rare form of thyroid eye disease. This literature review aims to establish the different presentations seen in the cases of euthyroid Graves' ophthalmopathy with negative antibodies. Despite the thyroid levels being normal, the mechanism by which EGONA causes eye disease is the same as the classical Graves' ophthalmopathy. Proper diagnosis relies mainly on clinical signs and imaging of the eye. A systematic search of PubMed, PubMed Central, and ScienceDirect was conducted with no date restrictions. Articles were included if they were English-language case reports describing patients with euthyroid ophthalmopathy and negative thyroid antibodies during initial presentation, with full-text availability and a documented clinical course. Data from nine articles (12 cases) were extracted, focusing on presentation, management, and outcomes. Treatments include corticosteroids, anti-thyroid medication, and surgery. Prognosis varied between those who developed thyroid imbalances and the presence of antibodies later down the course.
2026-01-06 | Periphlebitis of the Superior Ophthalmic Vein in Noninflammatory Thyroid Eye Disease
A 32-year-old female with euthyroid Graves’ disease presented with right-sided proptosis, first noticed 3 months prior to consultation. Although she was euthyroid, her thyroid-stimulating receptor antibodies were positive. An orbital CT scan, requested by her general ophthalmologist, demonstrated an inflammatory lesion involving the right superior muscle complex. On examination, visual acuity was 20/20 in OU. Margin reflex distances were 7 mm in the OD and 5 mm in the OS (panel A). Hertel exophthalmometry measured 22 mm in OD and 14 mm in OS (panel B). No clinical inflammatory signs were detected, with both VISA (vision, inflammation, strabisumus and appearance) and CAS (clinical activity score) inflammation scores graded as zero in OU. Intraocular pressure was asymmetric, measuring 19 mm Hg in the proptotic eye and 12 mm Hg in OS. Fundus examination was normal in OU. Axial T1-weighted postcontrast magnetic resonance imaging of the orbits with fat saturation revealed periphlebitis of the right superior orbital vein, characterized by a poorly defined, enhancing inflammatory process surrounding the vein (panel C). Color Doppler ultrasonography showed reduced flow velocity in OD (3.8 cm/s vs. 5.97 cm/s in OS) (panel D). Periphlebitis of the superior orbital vein is a rare manifestation of thyroid eye disease, usually associated with the active form of the orbitopathy. The present case highlights that superior orbital vein periphlebitis in thyroid eye disease may reduce orbital venous flow without the classic conjunctival signs of venous impedance or clinical signs of disease activity.FIG.
2025-11-03 | The role of mycophenolate mofetil in the therapy of thyroid eye disease.
Thyroid eye disease (TED) is an autoimmune disorder that can threaten vision loss. In 90% cases, it is related to Graves' disease, and in 10% cases, it occurs with euthyroidism or with chronic autoimmune thyroiditis. It is the leading cause of orbital pathology in adults. The TED treatment remains challenging for clinicians, particularly in moderate-to-severe or sight-threatening forms of the disease. One-third of TED patients experience a relapse despite the corticosteroids as a first-line treatment. Some patients show poor response or even no response to the treatment. There are many adverse effects associated with chronic use of intravenous methylprednisolone (IVMP). There is a need for new, efficient therapeutic methods, such as immunomodulating drugs like mycophenolate mofetil (MMF). This paper describes the role and potential efficiency of MMF application in TED by its direct action on TED pathogenic mechanisms. The introduction of MMF in the second-line treatment helps decrease the level of clinical symptoms and the risk of chronic complications, while causing only a small number of adverse events. Nevertheless, it should be noted that there are no unified guidelines available for consolidating treatment focused on maintaining remission after the first dose of IVMP. Moreover, clinical knowledge on the use of MMF application in TED is still limited, and further research is needed. Nonetheless, the available evidence is promising and MMF may play a vital role in future therapeutic strategies.
2025-10-29 | Unlocking the Therapeutic Potential: Selenium and Myo-Inositol Supplementation in Thyroid Disorders-Efficacy and Future Directions.
Background/Objectives: Thyroid disorders such as Hashimoto's thyroiditis and Graves' disease represent major endocrine challenges worldwide, often requiring long-term management. Recently, nutritional supplementation with selenium and myo-inositol has been proposed as a supportive strategy. This review aims to summarize the current evidence regarding their efficacy in improving thyroid function, reducing thyroid autoantibodies in Hashimoto's disease, and restoring biochemical euthyroidism in Graves' disease. Methods: A narrative review of the available literature was undertaken, concentrating on randomized controlled trials and observational studies evaluating selenium and myo-inositol, alone or in combination (MYO+Se), in patients with autoimmune thyroid disorders and benign thyroid nodules. Search Strategy and Study Selection: We searched MEDLINE/PubMed, Embase, Cochrane CENTRAL, and Scopus from inception to 31 July 2025. The search used Boolean operators to combine the following keywords: ("selenium" OR "selenomethionine") AND ("myo-inositol" OR "inositol") AND (thyroid OR Hashimoto* OR Graves' OR hyperthyroid* OR hypothyroid* OR nodule* OR goiter OR orbitopathy). We included human studies in English. Inclusion criteria: Research designs include RCTs, quasi-experimental studies, cohort/case-control studies, and big case series (n ≥ 30). Exclusion criteria: Animal-only or in vitro studies (unless mechanistic), pediatric case reports, and editorials/commentaries. Study selection and data extraction: Two reviewers screened independently; discrepancies were settled through consensus. The data retrieved included the population, baseline iodine/selenium status (if reported), dose/formulation, treatment duration, outcomes (TSH, FT4, FT3, TPOAb, TgAb, TRAb, nodule metrics), and adverse events. Quality assessment: The risk of bias was assessed using the RoB-2 for RCTs and the Newcastle-Ottawa Scale or JBI checklists for observational studies. A qualitative synthesis emphasized study quality, consistency, directness, and accuracy. Results: Clinical research indicate that selenium supplementation may reduce thyroid peroxidase antibody (TPOAb) levels in Hashimoto's disease, thereby attenuating autoimmune activity. Myo-inositol, particularly when combined with selenium, has been proven to improve thyroid hormone profiles while also lowering nodule size or growth. In Graves' disease, supplementation has been linked to the restoration of biochemical euthyroidism in certain patients, albeit data are limited. Despite these encouraging results, diversity in trial design, treatment length, and dosages restrict the robustness of existing recommendations. Conclusions: Selenium and myo-inositol supplementation have shown promise as adjuvant treatments for autoimmune thyroid diseases and benign thyroid nodules. However, further large-scale, well-designed clinical trials are needed to determine the appropriate dosages, treatment duration, and patient selection criteria. Personalized supplementation solutions may improve medication efficacy and help with more comprehensive thyroid disease care.
cell therapies
2023-11-17 | Regulatory T Cells in the Pathogenesis of Graves’ Disease
Maintaining a delicate balance between the prompt immune response to pathogens and tolerance towards self-antigens and commensals is crucial for health. T regulatory (Treg) cells are pivotal in preserving self-tolerance, serving as negative regulators of inflammation through the secretion of anti-inflammatory cytokines, interleukin-2 neutralization, and direct suppression of effector T cells. Graves’ disease (GD) is a thyroid-specific autoimmune disorder primarily attributed to the breakdown of tolerance to the thyroid-stimulating hormone receptor. Given the limitations of currently available GD treatments, identifying potential pathogenetic factors for pharmacological targeting is of paramount importance. Both functional impairment and frequency reduction of Tregs seem likely in GD pathogenesis. Genome-wide association studies in GD have identified polymorphisms of genes involved in Tregs’ functions, such as CD25 (interleukin 2 receptor), and Forkhead box protein P3 (FOXP3). Clinical studies have reported both functional impairment and a reduction in Treg frequency or suppressive actions in GD, although their precise involvement remains a subject of debate. This review begins with an overview of Treg phenotype and functions, subsequently delves into the pathophysiology of GD and into the existing literature concerning the role of Tregs and the balance between Tregs and T helper 17 cells in GD, and finally explores the ongoing studies on target therapies for GD.
2023-07-18 | Therapeutic Plasma Exchange as a Bridging Therapy for the Definitive Treatment of a Patient with Graves’ Disease and Methimazole-Induced Liver Injury
Graves' disease (GD) is an autoimmune condition affecting the thyroid gland. The aim of treating GD is to control the symptoms of hyperthyroidism and achieve long-term remission. Antithyroid drugs (ATDs) are the medications of choice among newly-diagnosed GD patients as they are easy to be delivered and cause remission in more than 50% of patients. However, ATDs increase the risk of hepatotoxicity, especially among patients with liver abnormalities. Patients who cannot tolerate ATDs should receive definitive therapy such as radioactive iodine (RAI) or surgery. In order to minimize the risk of thyroid storm during these procedures, patients should be in euthyroid condition and receive bridging therapy. Therapeutic plasma exchange (TPE), which aims to remove thyroid hormones from plasma, is one of the modalities that can be considered as a bridging therapy during the perioperative period among GD patients who cannot tolerate ATD.A 35-year-old man with general weakness and thyrotoxicosis symptoms was admitted to the emergency room. Lid retraction, diffuse Goiter, and tremors were evident. Laboratory findings revealed TSH = 0.005 µIU/mL, FT4 = 7.77 ng/dL, TRAb = 9.90 IU/L, ALT = 123 U/L, total bilirubin = 23.94 µmol/L, and direct bilirubin = 10.26 µmol/L. Ultrasonographic examination showed the enlargement of the thyroid gland, and abdomen ultrasonographic evaluation showed mild hepatomegaly with mild fatty infiltration. The patient was diagnosed with GD, suspected thyroid storm, elevated liver transaminases, and fatty liver disease. The patient then received methimazole, propranolol, and glycyrrhizin. During observation, the patient developed drug-induced liver injury (DILI) evidenced by an increase in liver enzymes (ALT up to 1023 U/L) and the elevation of total bilirubin to 258.21 µmol/L, so methimazole was stopped. After discontinuing methimazole, liver injury improved. However, thyrotoxicosis symptoms returned, so the patient underwent a total thyroidectomy. In order to achieve a euthyroid status before surgery, five sessions of therapeutic plasma exchange were performed, which improved the signs and symptoms of hyperthyroidism and retained the thyroxine hormone within the normal range. Thyroidectomy was then performed successfully without serious complications (e.g., thyroid storm, etc.).Therapeutic plasma exchange is a safe and effective bridging therapy for GD patients who require thyroidectomy but cannot tolerate ATDs.
2019-11-28 | Novel therapies for thyroid autoimmune diseases: An update
A Th1 immune-preponderance has been shown in the immunopathogenesis of autoimmune thyroiditis (AT), Graves' disease (GD) and Graves’ Ophthalmopathy (GO), in which the Th1-chemokines (CXCL9, CXCL10, CXCL11), and their (C-X-C)R3 receptor, have a crucial role. Methimazole, and corticosteroids have been shown to modulate these chemokines; several efforts have been done to modulate the autoimmune reaction with other drugs, i.e. PPAR-γ, or -α ligands, or antibodies, or small molecules directed against CXCL10, or CXCR3. Antigen-specific therapy for GD, by inducing T cell tolerance through an immunization with TSH-R peptides, has been published. Drugs targeting cytokines [anti-TNFα (Etanercept), and anti-IL-6 (Tocilizumab)], and RTX (a chimeric monoclonal antibody vs. CD20) have been used in GO, with promising results. Teprotumumab (a human monoclonal anti-IGF-1R blocking antibody) has been investigated in a trial, showing it was very effective in GO patients. Still, more studies are needed for new therapies targeting autoimmune thyroid disorders.
2012-02-14 | Adoptive Transfer of Antithyrotropin Receptor (TSHR) Autoimmunity from TSHR Knockout Mice to Athymic Nude Mice
We have recently shown that wild type mice are highly tolerant, whereas thyrotropin receptor (TSHR) knockout (KO) mice are susceptible to immunization with the mouse TSHR, the autoantigen in Graves' disease. However, because TSHR KO mice lack the endogenous TSHR, Graves-like hyperthyroidism cannot be expected to occur in these mice. We therefore performed adoptive transfer of splenocytes from TSHR KO mice into nude mice expressing the endogenous TSHR. Anti-TSHR autoantibodies were detected in approximately 50 % recipient mice 4 wk after adoptive transfer of splenocytes (5 × 107/mouse) from TSHR KO mice immunized with adenovirus expressing mTSHR A subunit and persisted for 24 wk. Depletion of regulatory T cells by anti-CD25 antibody in the donor mice increased successful transfer rates without increasing antibody levels. Some recipient mice showed transient increases in thyroid-stimulating antibodies and T4 levels 4–8 wk after transfer, but many became thyroid-blocking antibody positive and hypothyroid 24 wk later. Adoptive transfer of splenocytes from naïve TSHR KO mice transiently induced very low antibody titers when the recipient mice were treated with anticytotoxic lymphocyte antigen 4 and antiprogrammed cell death 1 ligand 1 antibodies for 8 wk after transfer. Histologically, macrophages infiltrated the retrobulbar adipose tissues and extraocular muscles in a small fraction of the recipients. Our findings demonstrate successful adoptive transfer of anti-TSHR immune response from TSHR KO mice to nude mice. Although the recipient mice developed only transient and infrequent hyperthyroidism, followed by eventual hypothyroidism, induction of orbital inflammation suggests the possible role of anti-TSHR immune response for Graves' orbitopathy.
2011-08-19 | Graves’ Ophthalmopathy as an Indication Increased the Risk of Hypoparathyroidism After Bilateral Thyroidectomy
Studies have evaluated the effect of thyroidectomy on the course of Graves' ophthalmopathy (GO) but it is unclear how GO as an indication might affect surgical outcomes. We aimed to evaluate the impact of this indication on surgical outcomes in Graves' disease (GD).From 1995 to 2008, 329 patients with GD underwent thyroidectomy. Patients were stratified into two groups, namely, those with GO as indication (GO) and those with non-GO indication (non-GO). Outcomes were compared between the groups and outcomes with significance were further analyzed by multivariate analyses to determine independent factors.The GO group was significantly older (P < 0.001), had more males (P < 0.001), and fewer relapses (P < 0.001) than the non-GO group. It also had a higher proportion of total/near-total thyroidectomy (P < 0.001), despite a shorter operating time (P = 0.024) and less blood loss (P = 0.010). When only total/near-total thyroidectomy was considered, the GO group had significantly more permanent hypoparathyroidism than the non-GO group (9.2 vs. 1.6%, P = 0.038), but the rate of permanent hypoparathyroidism was similar in the two groups when only those with parathyroid autotransplantation were considered. Other complications were similar between the two groups. By multivariate analysis, GO as indication was an independent risk factor for temporary (OR 1.97, P = 0.033) and permanent hypoparathyroidism (OR 4.76, P = 0.007).GO as a surgical indication (i.e., unstable or active GO requiring ophthalmic treatment or follow-up) was associated with increased risk of temporary and permanent hypoparathyroidism after bilateral thyroidectomy. Routine parathyroid autotransplantation may reduce the risk of permanent hypoparathyroidism in this select patient group.
antibodies
2026-04-01 | Thyroid Eye Disease: Current Perspectives in Pathogenesis, Risk Factors, and Management
Thyroid eye disease (TED), also referred to as Graves’ orbitopathy or thyroid-associated ophthalmopathy, is an autoimmune inflammatory disorder of the orbit that most often accompanies hyperthyroidism due to Graves’ disease. This review summarises current understanding of its immunopathogenesis, including the role of autoantibodies against the thyroid-stimulating hormone receptor (TSH-R) and insulin-like growth factor-1 receptor (IGF-1R), the subsequent activation of orbital fibroblasts, cytokine-mediated inflammation, glycosaminoglycan deposition and fibrosis. The clinical spectrum ranges from mild ocular surface irritation to sight-threatening dysthyroid optic neuropathy — and the classification systems (e.g., CAS, VISA, EUGOGO) used to assess disease activity and severity. Key modifiable risk factors such as smoking, uncontrolled thyroid status, micronutrient deficiencies (selenium, iron, iodine), dyslipidaemia, and vitamin D deficiency are reviewed. We present management strategies from achieving euthyroidism and risk-factor control, to supportive care (lubrication, eyelid taping) and medical therapies — from high-dose intravenous methylprednisolone to immunosuppressants (mycophenolate, azathioprine) and novel biologics such as teprotumumab (anti-IGF-1R), rituximab (anti-CD20) and tocilizumab (anti-IL-6R). Surgical options (orbital decompression, strabismus correction, eyelid surgery) for disfiguring or sight-threatening disease are discussed. Finally, we highlight future directions including biomarker development and personalised, mechanism-based therapy. Early recognition and intervention, along with risk factor modification and targeted treatments, may improve functional and psychosocial outcomes in TED.
2025-11-04 | Assessing the Role of Tocilizumab in the Treatment of Thyroid Eye Disease: A Retrospective Single Centre Analysis.
Due to the variable course of thyroid eye disease (TED), treatment should be tailored to disease severity, individual risk factors, and clinical course. This study is based on a retrospective analysis at the orbital centre of the University Eye Clinic Essen and evaluates the efficacy of the IL-6 receptor blocker tocilizumab as a second-line therapy in patients with therapy-refractory TED. After approval of cost coverage, 20 patients were treated with tocilizumab over a mean period of 4.8 ± 2.7 months. The following parameters were assessed: sex, age, underlying thyroid disease, disease activity and severity, prior therapies, visual acuity, intraocular pressure, eyelid position, exophthalmos, monocular excursions, strabismus/diplopia, levels of TSH receptor antibodies (TRAb), and adverse events. The female-to-male ratio was 3 : 1. Mean patient age was 58.2 ± 8.5 years. The majority (90%, n = 18) had Graves' disease; one patient had primary hypothyroidism and one was euthyroid. All patients had previously failed various treatment regimens (median cumulative steroid dose 4.6 g [1.5 - 7.5 g], 55% mycophenolate, 65% orbital apex radiation, 20% balanced orbital decompression). Among 17 patients with detectable TRAb at baseline, mean antibody levels decreased by 48.4%. A reduction of at least 30% was achieved in 70.6% of these patients (n = 17). A decrease in the Clinical Activity Score (CAS) by ≥ 2 points was observed in 70% of cases. The mean inflammation score (maximum 20 points per patient) decreased from 8.8 ± 3.9 to 3.4 ± 2.4. The effect on exophthalmos was moderate: mean reduction was 0.9 ± 1.8 mm (range - 6 mm to + 3 mm). A decrease of ≥ 2 mm was documented in 25% of patients, whereas an increase was noted in 12.5% (0.5 to 3 mm). Improvement in ocular motility was documented in 22.5% of patients, while 10% showed deterioration. This cohort exclusively included therapy-refractory patients, some with protracted disease. The significant reduction in inflammation and particularly in TRAb levels, as a biomarker of disease activity, demonstrate the efficacy of tocilizumab in this highly selected population. Tocilizumab may therefore be an important treatment option for patients with high antibody levels and predominantly inflammatory disease manifestations. Further studies are warranted to evaluate whether it reduces the risk of relapse after successful treatment with an IGF-1 receptor blocker.
2025-10-01 | Potential of Tocilizumab in Inducing Remission of Graves’ Disease
Background: The efficacy of tocilizumab in reducing TSH receptor antibodies (TRAb) and inducing remission in patients with Graves’ disease (GD) is an area of ongoing research and clinical studies. Case Description: A 42-year-old gentleman presented with spontaneous progressive eye pain that intensified with eye movement. Biochemical tests showed euthyroidism and elevated TRAb. Orbits CT scan showed bilateral extraocular muscle enlargement with proptosis. He was diagnosed with euthyroid Graves’ ophthalmopathy and started on methylprednisolone 500 mg intravenous infusion weekly for 10 weeks. His symptoms progressed to diplopia. Daily oral prednisolone was initiated with minimal improvement. Whereafter, he was referred to radiation and underwent ten sessions of radiotherapy to the bilateral orbits, complemented by triamcinolone periorbital injections. Meanwhile, he progressed to subclinical hyperthyroidism. A repeated thyroid function test confirmed subclinical hyperthyroidism, and TRAb increased. A diagnostic thyroid scan (Tc-99m) showed a normal uptake. He returned to our clinic with worsening eye symptoms. Repeated thyroid function tests showed hypothyroidism, and he was started on carbimazole 5 mg daily in a different center, which we discontinued when he came for follow-up. Tocilizumab initiation for his eye disease was decided to be every 4 weeks, completing a total of three doses. A repeat of TRAb 2 months after completing tocilizumab yielded negative TRAb levels and a reversal of his thyroid functions to euthyroidism. On follow-up, he presented again with active eye disease and positive TRAb level 7 months after tocilizumab treatment, suggesting that while tocilizumab may initially induce remission, it did not provide a long-lasting effect or sustained remission, underscoring the challenge in achieving durable management of Graves’ disease. Conclusion: Tocilizumab holds promise as a novel therapeutic option for inducing remission in patients with GD, as evidenced by negative TRAb and euthyroidism. Further research is warranted to establish the long-term efficacy and safety of tocilizumab in GD. Publication History Article published online: 29 December 2025 © 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/) Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
2025-05-06 | Thyroid eye disease (Graves' orbitopathy): clinical presentation, epidemiology, pathogenesis, and management.
Thyroid eye disease (TED; also known as Graves' orbitopathy), causes swollen extraocular muscles and orbital fat. Mechanistically, TED involves lid retraction, oedema and redness of the eyelids and conjunctiva, proptosis, diplopia, and optic neuropathy. Investigation of TED involves assessment of disease activity (inflammation) and disease severity. TED is predominantly mild in 77% of cases, moderate-to-severe in 22%, and rarely sight-threatening in 1% of patients. While most patients with TED have Graves' hyperthyroidism, up to 5% are euthyroid or even hypothyroid. Risk factors include male sex, older age, smoking, diabetes, hypercholesterolaemia, duration of hyperthyroidism, radioactive iodine therapy, and the presence of thyrotropin receptor (TSHR) antibodies (detectable in more than 95% of patients and directly related to TED activity and severity). Genetic immunisation of mice with TSHR, but not with insulin-like growth factor-1 receptor (IGF-1R), provides a reliable animal model of TED, demonstrating that TSHR is the primary autoantigen in the disease. Crosstalk between TSHR and IGF-1R occurs via a β-arrestin scaffold. Teprotumumab, a human monoclonal antibody that blocks IGF-1R without binding to TSHR, has been shown to significantly improve outcomes in moderate-to-severe TED, including greater proptosis reduction compared with intravenous methylprednisolone. However, its disadvantages include side effects (eg, hearing loss in 30% of patients), a high cost, and a high relapse rate. Therefore, intravenous steroids remain the treatment of choice in many parts of the world. Tocilizumab, which blocks the interleukin-6 receptor, is an effective treatment option for patients with TED who are steroid-resistant. This Review further discusses alternative medications, surgical treatments, local measures, and the importance of quality-of-life assessments and multidisciplinary care.
2025-01-12 | Low clinical activity score, 'progressive' thyroid eye disease: presentations of 1439 patients from a tertiary centre in Hong Kong.
To report the presenting clinical, serological and treatment profiles of 1439 patients with thyroid eye disease (TED) from a tertiary centre in Hong Kong. Consecutive patients with TED presented to the Thyroid Eye Clinic (TEC), the Chinese University of Hong Kong between 2014 and 2023. Prospective cohort and masked review of medical records and orbital images. A total of 1439 (70% female, 98% Han Chinese) patients with TED (26% ex/current smoker), presented at 43±5.9 years old, were reviewed. The first TED symptoms to TEC evaluation was 6±3 months. 85% had Graves' disease and 12% were given radioactive iodine before presentation. 35% of patients had a family history of autoimmune thyroid diseases. Baseline thyroid-stimulating hormone receptor antibody, thyroid-stimulating immunoglobulin and thyroid peroxidase antibody were elevated in 75%, 69% and 57% tested. Euthyroid TED (E-TED) was diagnosed in 6%, associated with asymmetric presentation (p<0.001). The most common signs were exophthalmos (69%), upper eyelid retraction (53%), swelling (36%), conjunctival injection (34%) and lower eyelid retraction (32%). Notably, 547 (38%) presented with moderate-to-severe and 150 (10%) vision-threatening TED, whose clinical activity score (CAS) was just 2.4±1.4 and 2.6±1.5, respectively. Male and TED onset after 40 were associated with higher CAS and NOSPEC (No physical signs or symptoms, Only signs, Soft tissue involvement, Proptosis, Extraocular muscle signs, Corneal involvement, and Sight loss) score (both p<0.05). 471 (33%), 361 (25%), 263 (18%) and 138 (9%) patients received intravenous methylprednisolone, orbital radiotherapy, steroid-sparing immunosuppressants and surgical decompression, respectively. Around one-third (34%) of our cohort presented with 'low-CAS, progressive', moderate-to-severe or vision-threatening TED, while only one-fifth (18%) were clinically active (CAS≥3). Our results showed the limitations and unmet need of the existing 'high-CAS only' approach, especially in managing 'non-inflammatory' TED, prevalent in non-Caucasian populations.
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2023-10-30 | 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.
2023-01-01 | Nonsurgical treatment for upper eyelid retraction in patients with inactive Graves’ orbitopathy
To evaluate the effectiveness of incobotulinumtoxinA (Xeomin®) in treating upper eyelid retraction in patients with Graves orbitopathy (GO) initially scheduled for surgery via two different application sites.This is a comparative, prospective study, conducted at the Department of Ophthalmology, Medical School, University Hospital Centre Zagreb, EUGOGO site (EUropean Group On Graves' Orbitopathy) in Croatia from January 2020 till January of 2021 in accordance with national health headquarter recommendations. All patients were classified as inactive with marked eyelid retraction and randomly divided into groups according to application sites. Group A underwent transconjunctival application (18 eyes) and group B transcutaneous application (20 eyes) of incobotulinumtoxinA. The primary end point of this study was lowering the eyelid, to alleviate anterior eye segment symptoms and achieve acceptable aesthetic appearance until surgery becomes available.There were no nonresponders and we found no statistically significant difference in the degree of lowering the eyelid between the two application sites. Following rules for avoiding spread of SARS-CoV-19, none of the patients included in this study were infected. Moreover, participants reported diminishing of anterior eye segment irritation and improved aesthetics.Treatment of inactive GO patients with incobotulinumtoxinA for upper eyelid retraction is efficient and safe and can be used as an adjuvant treatment while patients wait for surgery, by alleviating symptoms and improving the level of aesthetic satisfaction without causing a threat to anterior eye segment and visual function. The study showed that effect of treatment was the same, whether we applied the toxin transconjunctivaly or transcutaneously.
2022-07-26 | Murine Thyroid IL-4 Expression Worsens Hypothyroidism on Iodine Restriction and Mitigates Graves Disease Development
Abstract Cytokines are known to perturb thyroid function and the role of interleukin-4 (IL-4) in the pathogenesis of Graves disease (GD) remains controversial. In our mouse model overexpressing IL-4 in thyrocytes (Thyr-IL4), we have reported that adult mice preserved normal serum thyroxine despite an iodide uptake defect. In the present work, we evaluated if iodine restriction could uncover the thyroid deficiency in Thyr-IL4 animals as well as the role of pendrin overexpression as a compensatory mechanism. Moreover, using an experimental model of GD we investigated the effect of a local expression of IL-4 on the incidence of hyperthyroidism. Thyr-IL4 mice developed more rapidly elevated serum thyrotropin under low-iodine supply with thyroid enlargement and classical histological modifications. These hallmarks of hypothyroidism were all enhanced in Thyr-IL4 mice with complete pendrin invalidation. Following immunization, a lower proportion of Thyr-IL4 animals developed hyperthyroidism. Surprisingly, immunized Thyr-IL4 animals presented numerous leukocyte infiltrates, associated with increased intrathyroidal expression of IFN-γ. We have demonstrated that thyroid deficiency in Thyr-IL4 mice is partially compensated for by the excessive iodide content of the standard chow and the overexpression of pendrin in these animals. Furthermore, we have shown that the local expression of IL-4 in the thyroid attenuates GD progression, which was associated with enhanced thyroid infiltration by immune cells that could negatively affect thyroid function.
2022-06-07 | Potential Therapeutic Role of Bone Morphogenic Protein 7 (BMP7) in the Pathogenesis of Graves’ Orbitopathy
We investigated a role of bone morphogenic protein 7 (BMP7), a member of the TGF-β superfamily on pathogenic mechanism of Graves' orbitopathy (GO). The therapeutic effects of BMP7 on inflammation and fibrosis were evaluated in cultured Graves' orbital fibroblasts.Expression of BMP7 was compared in cultured orbital tissue explants from GO (n = 12) and normal control (n = 12) subjects using real-time PCR. Orbital fibroblasts were cultured from orbital connective tissues obtained from GO (n = 3) and normal control patients (n = 3). Cells were pretreated with recombinant human BMP7 (rhBMP7) before stimulation with TGF-β, IL-1β, and TNF-α. Fibrosis-related proteins and inflammatory cytokines were analyzed by Western blotting. The activation of signaling molecules in inflammation and fibrosis was also analyzed.The expressions of BMP7 mRNA were lower in GO orbital tissues than control. Fibrosis-related proteins, fibronectin, collagen 1α, and α-SMA induced by TGF-β were suppressed by treating rhBMP7, and rhBMP7 upregulated TGF-β induced SMAD1/5/8 protein expression, whereas downregulated SMAD2/3. Increased pro-inflammatory molecules, IL-6, IL-8, and intercellular adhesion molecule-1 (ICAM-1) by IL-1β or TNF-α were blocked by rhBMP7 treatment, and the expression of phosphorylated NFκB and Akt was suppressed by rhBMP7 treatment.BMP7 transcript levels were downregulated in Graves' orbital tissues. Exogenous BMP7 treatment showed inhibitory effects on the production of profibrotic proteins and proinflammatory cytokines in orbital fibroblasts. Our results provide a molecular basis of BMP7 as a new potential therapeutic agent through the opposing mechanism of profibrotic TGF-β/SMAD signaling and proinflammatory cytokine production.
2022-05-09 | Antithymocyte Globulin as Second-Line Therapy in Graves Orbitopathy—Preliminary Results From a Prospective Single-Center Study
Objective Management of Graves’ orbitopathy remains a challenge. Our previous case report has shown promising results for rabbit antithymocyte globulin (rATG) in the treatment of Graves’ orbitopathy. Design We present the response of 7 individuals with active moderate-to-severe steroid-resistant Graves’ orbitopathy to rATG, representing preliminary results from a prospective single-center study. Methods rATG was administered intravenously at a dose of 0.8–1.0 mg/kg daily (cumulative dose of 150–200 mg). The primary outcome measures at weeks 24 and 48 were ≥2-point reduction in Clinical Activity Score from baseline, a proptosis response, a diplopia response, and improvement of distant best-corrected visual acuity and mean retinal sensitivity. Key secondary outcomes included stabilization of ganglion cell complex thickness, a decrease of retinal nerve fiber layer in OCT, and a reduction in CD4/CD8 ratio and TRAb at 48 weeks. Results An improvement in clinical activity score was observed in all patients, with disease inactivation in 3 cases. Proptosis reduction equal to or greater than 2 mm was noted for 8 of 10 eyes. Diplopia improved in three of 6 patients. There was an improvement in best-corrected visual acuity (from 0.69 to 0.78) and mean retinal sensitivity (from 20.8 to 23.5 dB). In addition, there was a long-lasting improvement in CD4/CD8 ratio in 6 patients. Two patients experienced adverse events (influenza and serum sickness). Conclusion rATG therapy offers a long-lasting improvement in moderate-to-severe steroid-resistant Graves’ orbitopathy with improvement in functional vision (reduction of diplopia, improvement of visual acuity, retinal sensitivity, and VEP pattern). The therapy is well-tolerated. Clinical Trial Registration ClinicalTrials.gov, identifier NCT05199103.
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2022-05-30 | Therapeutic Potential of Targeting Periostin in the Treatment of Graves’ Orbitopathy
Periostin is a matricellular protein that is ubiquitously expressed in normal human tissues and is involved in pathologic mechanism of chronic inflammatory and fibrotic disease. In this study we investigate periostin in the pathogenesis of Graves’ orbitopathy (GO) using human orbital adipose tissue obtained from surgery and primary cultured orbital fibroblasts in vitro . POSTN (gene encoding periostin) expression in Graves’ orbital tissues and healthy control tissues was studied, and the role of periostin in GO pathologic mechanism was examined through small-interfering RNA (siRNA)-mediated silencing. POSTN gene expression was significantly higher in Graves’ orbital tissues than healthy control tissues in real-time PCR results, and immunohistochemical staining revealed higher expression of periostin in Graves’ orbital tissues than normal tissues. Silencing periostin using siRNA transfection significantly attenuated TGF-β-induced profibrotic protein production and phosphorylated p38 and SMAD protein production. Knockdown of periostin inhibited interleukin-1 β -induced proinflammatory cytokines production as well as phosphorylation of NF-κB and Ak signaling protein. Adipocyte differentiation was also suppressed in periostin-targeting siRNA transfected GO cells. We hypothesize that periostin contributes to the pathogenic process of inflammation, fibrosis and adipogenesis of GO. Our study provides in vitro evidence that periostin may be a novel potential therapeutic target for the treatment of GO.
2022-04-04 | Identification of tRNA-Related Fragments and Their Potential Regulatory Effects in Thyroid-Associated Ophthalmopathy
Recently, the potential role of tRNA-related fragments (tRFs) in ophthalmic diseases has been extensively researched. However, systematic studies on the potential regulatory effects of tRFs in thyroid-associated ophthalmopathy (TAO) are lacking. We used high-throughput sequencing techniques to measure expression levels of mRNAs and tRFs in patients with TAO, and the results were verified by real-time quantitative reverse transcription polymerase chain reaction (q-PCR). Next, the potential biological regulatory effect of differentially expressed tRFs was analyzed, and potential downstream target RNAs of differentially expressed tRFs were predicted to explore the potential role of tRFs as therapeutic targets and biomarkers of TAO. A total of 50 tRFs and 361 mRNAs were dysregulated in the TAO group, and tRF5-GluCTC, PMAIP1, HSD17B2 and ATF3 were verified to be significantly differentially expressed in TAO. Our research reveals that several associated pathways likely play a role in the pathogenesis of TAO. By targeting ATF3, HSD17B2 and PMAIP1, tRF5-GluCTC may play a potential role in regulating the orbital fibroblast adipogenic response and fibrotic hyperplasia in patients with TAO.
2021-12-15 | A Novel Competing Endogenous RNA Network Associated With the Pathogenesis of Graves’ Ophthalmopathy
Background: Growing evidence has recently revealed the characteristics of long noncoding (lncRNA)/circular RNA (circRNA)-microRNA (miRNA)-mRNA networks in numerous human diseases. However, a scientific lncRNA/circRNA-miRNA-mRNA network related to Graves' ophthalmopathy (GO) remains lacking. Materials and methods: The expression levels of RNAs in GO patients were measured through high-throughput sequencing technology, and the results were proven by quantitative real-time PCR (qPCR). We constructed a protein-protein interaction (PPI) network using the Search Tool for the Retrieval of Interacting Genes (STRING) database and identified hub genes by the Cytoscape plug-in CytoHubba. Then, the miRNAs related to differentially expressed lncRNAs/circRNAs and mRNAs were predicted through seed sequence matching analysis. Correlation coefficient analysis was performed on the interesting RNAs to construct a novel competing endogenous RNA (ceRNA) network. Results: In total, 361 mRNAs, 355 circRNAs, and 242 lncRNAs were differentially expressed in GO patients compared with control patients, 166 pairs were identified, and ceRNA networks were constructed. The qPCR results showed that 4 mRNAs (THBS2, CHRM3, CXCL1, FPR2) and 2 lncRNAs (LINC01820:13, ENST00000499452) were differentially expressed between the GO patients and control patients. Conclusion: An innovative lncRNA/circRNA-miRNA-mRNA ceRNA network between GO patients and control patients was constructed, and two important ceRNA pathways were identified, the LINC01820:13-hsa-miR-27b-3p-FPR2 ceRNA pathway and the ENST00000499452-hsa-miR-27a-3p-CXCL1 pathway, which probably affect the autoimmune response and inflammation in GO patients.
2020-12-01 | The critical role of m6A methylation in the pathogenesis of Graves' ophthalmopathy
To investigate the role of N6-methyladenosine (m6A) RNA modification in the pathogenesis of Graves' ophthalmopathy (GO).Surgically excised extraocular muscles from 7 patients with GO and 5 subjects without GO were used. The global m6A levels in the specimens were determined using an m6A RNA methylation quantification kit. RNA sequencing (RNA-seq) was used to analyze the molecules involved in the regulation of m6A RNA methylation and the differential expression of mRNAs between the two groups (4 eyes, respectively). The expression of m6A RNA modification genes was evaluated by real-time PCR. The functional implications of the gene alterations between the GO and control specimens were determined by Gene Ontology analysis.The m6A level was significantly increased in the specimens of GO patients compared to the control specimens (P < 0.05). The expression of m6A methylation regulators, such as WT1 associated protein (WTAP), alkylation repair homolog protein 5 (ALKBH5), E74 like ETS transcription factor 3 (ELF3), YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), YTHDF3 and YTH domain containing 2 (YTHDC2), was significantly upregulated (P < 0.05). Gene Ontology enrichment analysis showed that the most highly upregulated genes and biological pathways were related to the immune response and inflammatory processes such as lymphocyte activation, leukocyte differentiation, cytokine production and cytokine-mediated signaling pathways.Our results suggest that m6A methylation may play a critical role in the pathogenesis of GO and that targeting genes that regulate m6A methylation may provide a new therapeutic approach for GO.
2020-10-20 | Role of binding immunoglobulin protein (BiP) in Graves’ orbitopathy pathogenesis
Inflammation and adipogenesis represent the main pathogenic mechanisms of Graves' orbitopathy (GO), and oxidative stress is a well-known inducer of GO pathology. Endoplasmic reticulum (ER) stress has been suggested as a major contributor to inflammation and reactive oxygen species (ROS) generation. In this study, we investigated the role of the ER-stress chaperone protein, binding immunoglobulin protein (BiP), in GO pathogenesis. Using primary cultures of orbital fibroblasts from patients with GO, we examined the role of BiP in GO pathogenesis by silencing its expression with small-interfering RNA (siRNA). Inflammatory cytokine expression was analysed by Western blotting and ELISA. Intracellular ROS levels induced by hydrogen peroxide or cigarette smoke extract were measured by 5-(and 6)-carboxy-20,70-dichlorodihydrofluorescein diacetate staining and flow cytometry. After adipogenic differentiation in BiP siRNA-transfected cells, the cells were stained with Oil Red O, and the levels of adipogenic transcription factors were determined by Western blot analysis. BiP mRNA expression levels were significantly higher in GO orbital tissues than in non-GO orbital tissues. Silencing BiP attenuated the expression of pro-inflammatory cytokines (interleukin-6, intercellular adhesion molecule-1, and monocyte chemotactic protein-1) in primary cultured GO orbital fibroblasts. Silencing BiP also reduced ROS generation, hyaluronan production, and adipocyte differentiation. These findings suggest that ER stress is involved in the aetiology of GO and that modulation of ER stress has therapeutic potential for GO.
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Drug Discovery Landscape
2 orphan drug designations for Euthyroid Graves orbitopathy, including 1 approved therapy.
2 orphan drug designations for Euthyroid Graves orbitopathy, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
teprotumumab | antibodies | FDA | 2013-05-06 | 2020-01-21 | Horizon Therapeutics Ireland DAC |
salmeterol xinafoate/fluticasone propionate | small molecules | FDA | 2009-10-29 | — | Lithera, Inc. |
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