The evolving landscape of thyroid eye disease: present and future.

Risk Factors of Thyroid Eye Disease

Background: The thyroid eye disease (TED) treatment landscape is rapidly evolving. How new treatment options have impacted practice is unknown. Methods: We conducted a cross-sectional electronic survey of American and European Thyroid Association members between June 2 and June 30, 2021. The survey included TED questions about resources for its management, index cases for different severities and presentations of TED, barriers for the management of TED, and participants' concerns about TED. We classified respondents into three geographic categories: North America, Europe, or other regions. Results: Two hundred fifty-two eligible participants started the survey (15% response rate), and 227 completed it. Participants were mostly men (50.2%, 114/227), white (79.7%, 181/227), endocrinologists with a thyroid focus (66.1%, 150/227), practicing in a tertiary academic center (46.7%, 106/227), caring for 10 or more TED patients over the last 12 months (40.5%, 92/227), and reported not having a multidisciplinary TED clinic in their institution (52.8%, 120/227). The majority reported that new TED cases per annum have not changed in the past 10 years (47.5%, 108/227), and that TED patients are found in practice during the management of hyperthyroidism (41.8%, 95/227). For mild active TED, participants from Europe reported a higher use of selenium (73%[96/132] vs. 32%[20/62] of respondents from North America and 24%[8/33] of respondents from other regions). For moderate-to-severe active TED, there was a modest preference for teprotumumab as first-line therapy (37%, 23/62) among North American participants and intravenous (IV) steroids (73%[96/132], and 42%[14/33]) for participants from Europe and other regions, respectively. These treatment preferences did not change in patients with moderate-to-severe active TED with poorly controlled diabetes. In contrast, participants from the three geographic categories preferred IV steroids for optic neuropathy and women planning pregnancy. The three top "very important" concerns about TED management according to participants were: the cost of TED treatment (31.3%, 71/227), lack of effective TED treatments (19.8%, 45/227), and difficulty in predicting whether TED will develop (18.9%, 43/227). Conclusions: There is a marked geographic practice variation in the management of TED. Clinicians' concerns about TED management demand ongoing research on more effective treatment, TED predictive tools, and policy changes to improve the affordability of new TED therapies.

Thyroid Eye Disease (TED) is an autoimmune disease that affects the extraocular muscles and periorbital fat. It most commonly occurs with Graves' Disease (GD) as an extrathyroidal manifestation, hence, it is also sometimes used interchangeably with Graves' Ophthalmopathy (GO). Well-known autoimmune markers for GD include thyroid stimulating hormone (TSH) receptor antibodies (TSH-R-Ab) which contribute to hyperthyroidism and ocular signs. Currently, apart from radiological investigations, detection of TED is based on clinical signs and symptoms which is largely subjective, with no established biomarkers which could differentiate TED from merely GD. We evaluated a total of 28 studies on potential biomarkers for diagnosis of TED. Articles included were published in English, which investigated clinical markers in tear fluid, orbital adipose-connective tissues, orbital fibroblasts and extraocular muscles, serum, thyroid tissue, as well as imaging biomarkers. Results demonstrated that biomarkers with reported diagnostic power have high sensitivity and specificity for TED, including those using a combination of biomarkers to differentiate between TED and GD, as well as the use of magnetic resonance imaging (MRI). Other biomarkers which were upregulated include cytokines, proinflammatory markers, and acute phase reactants in subjects with TED, which are however, deemed less specific to TED. Further clinical investigations for these biomarkers, scrutinising their specificity and sensitivity on a larger sample of patients, may point towards selection of suitable biomarkers for aiding detection and prognosis of TED in the future.

ObjectiveThe management of thyroid eye disease (TED) has undergone significant changes for decades. The study sought to investigate current clinical practice on the management of TED in China.MethodsAn online questionnaire survey was conducted from April to May 2023. The questionnaire involved diagnostic criteria for TED, multidisciplinary treatment (MDT) collaboration, and treatment preference for mild, moderate, and severe TED.ResultsA total of 289 questionnaires were collected, with 165 from endocrinologists and 124 from ophthalmologists. Only 36.7% of participants claimed there was an MDT clinical pattern for TED in their institutions. The coverage of biological agents was around 10% or lower. These were distinctly lower than in Western countries. About 62.6% of participants believed the incidence of TED has increased in recent years. Imaging techniques were used widely to assist in the diagnosis of TED. However, there was still controversy regarding the definition of proptosis in the Chinese population. Most doctors managed risk factors and provided orbital supportive treatments of artificial tears and glasses. For mild active TED, endocrinologists (39.4%) were inclined to recommend therapy for hyperthyroidism alone, while ophthalmologists (43.6%) preferred orbital corticosteroid injections. Currently, the most widely used treatment for moderate to severe active TED was high-dose intravenous corticosteroid (94.8%), while orbital radiotherapy combined with immunosuppressive agents was the most recognized second-line therapy (43.6%).ConclusionThe study documented the consistency and differences between current clinical practices in the management of TED in China and the recently updated guidelines. There was a remarkable difference between ophthalmology and endocrinology departments, warranting management optimization.

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

Purpose To evaluate the evidence for changes in choroidal thickness and choroidal vascularity index (CVI) in people with thyroid eye disease (TED), stratified by severity, as measured by optical coherence tomography (OCT). Methods Systematic review, including quality assessment, of published studies investigating choroidal thickness in TED. Outcomes of interest included CVI, subfoveal choroidal thickness, mean choroidal thickness, and peripheral choroidal thickness in four quadrants (superior, inferior, medial, lateral). Results Nineteen studies were included which contained measurements from 1067 eyes in 798 patients with TED. Most studies found an increased CVI and increased choroidal thickness in patients with TED compared to normal controls, especially in the subfoveal region. In addition, several studies reported an increased thickness in patients with active vs. inactive TED, although the results are equivocal. Finally, many studies reported associations between increased choroidal thickness and worsened clinical measurements of disease activity, such as Clinical Activity Score (CAS). Conclusions This systematic review provided evidence for an association between increased CVI/choroidal thickness and TED, suggesting a potential for OCT-measured CVI/choroidal thickness as an objective clinical marker. Given heterogeneity, future studies are needed to assess the role of measuring the choroidal changes in diagnosis and management of TED.

The Thyrotropin receptor antibody (TRAb) is the main driver of Graves' disease (GD) and its most common extra-thyroidal manifestation: thyroid eye disease (TED). Though key to diagnosis, it has not been used routinely as a marker of disease activity or to guide treatment. Here we demonstrate, through a retrospective review of 105 patients with TED, that serial TRAb levels vary with time, correlate with disease activity and are affected by smoking and endocrine control. Such serial measurements can guide the modern management of thyroid eye disease, helping to prevent the more serious manifestations. We show that surgical thyroidectomy is associated with a reduction in antibody levels and a reduced rate of TED reactivation when compared to radio-iodine ablation where the stimulating antigen is not removed. This provides a molecular explanation for epidemiological studies showing radio-ablation being associated with an increased risk of orbitopathy. To demonstrate the effect of our clinical approach on a patient population, we then compared the incidence and severity of TED in a clinic in a period before and after the introduction of serial TRAb measurements. Despite an increase in disease incidence and severity at presentation over the two-decade study period, our approach saw a significant reduction in the need for surgical intervention for this orbital disorder.

The European Group on Graves' Orbitopathy (EUGOGO) recommends the use of specialised multidisciplinary clinics for the management of thyroid eye disease (TED). In the UK, many patients with TED are managed outside of specialised clinics. We describe the organisation of a combined TED clinic in a secondary care setting and present the result of a prospective audit of the patient characteristics and outcomes during the first four years of a combined TED clinic. Of a total of 132 patients referred to the TED clinic, 114 (86%) had TED (90 females, median age 56years; range 17-90years). At presentation, 77 (67%) were current or ex-smokers and 99 (87%) were biochemically euthyroid. Median duration of eye symptoms was 12months. Fifty-two percent, 45 and 3 had mild, moderate-to-severe and sight-threatening TED, respectively. Only 18% of patients had a clinical activity score (CAS) of ≥3. Sixty-nine patients (61%) required follow-up appointments in the TED clinic. In those who required follow-up, 43% (n=30) received either immunosuppressive or surgical treatment. CAS improved from first to final visit, with 29% (n=20) having a CAS of ≥3 at the first visit and 1% (n=1) at the final visit (p=0.0001). There was also a decrease in prevalence of smoking and thyroid dysfunction at the final visit. A multidisciplinary specialised TED clinic offers an optimal setting for managing patients with TED; however, patients are often referred late to a specialist TED clinic.

To report the most recent therapeutic advances of thyroid eye disease (TED) and offer general recommendations for management of TED. Treatment of Graves ophthalmopathy is traditionally based on the use of high doses of corticosteroids and/or radiotherapy (RT) to decrease the activity of the disease, with the subsequent proptosis, strabismus and eyelid deformites treated with different surgical procedures. In recent years, the evidence that oxidative stress plays a relevant role in exacerbating TED severity has encouraged the use of antioxydative agents such as selenium, which has shown a capacity in limiting the disease progression. In addition, reports have shown the effectiveness of biological immunosuppressive agents in the management of TED. The main advantage of these medications seems to be the long lasting effects, which may reduce recurrence, and effectiveness in steroid-resistant cases. The reported increased accuracy of imaging techniques in evaluating fat and muscle volumes may provide useful information for surgical management. The use of selenium, in mild TED, seems to limit disease progression without carrying the risk of relevant side-effects. Biological agents may provide an effective and long lasting block of the inflammatory activity of TED, with a possible lower risk of recurrence and reduction in the need for surgical intervention in moderate-to-severe disease. The accurate evaluation of fat and muscle volume, using a recently published algorithm for imaging, gives relevant information for preoperative assessment, allowing the customization of orbital decompression.

B-Cell Targeted Therapy With Rituximab for Thyroid Eye Disease: Closer to the Clinic

Background Thyroid eye disease (TED) causes lid retraction, extraocular muscle enlargement, and tear film changes, which can affect corneal topography. Aim To assess the corneal topographic changes associated with TED and relate these changes to disease activity and severity. Patients and methods This prospective cross-sectional case-control study was carried out on 50 eyes of 25 patients aged less than or equal to 50 years old, both sexes, diagnosed with TED and present or past serological evidence for thyroid disease (TED group). Patients were divided into two groups: the TED group: 30 eyes of 15 patients with TED and the control group: 20 eyes of 10 patients with age-matched and sex-matched without TED. Results In the TED group, axial proptosis was negatively correlated with minimal corneal thickness. Both upper and lower lid infrared meibography showed a positive correlation with axial proptosis. Active patients had considerably greater Baiocchi-Calossi-Versaci front and upper lid meibomian glands loss than inactive cases. In moderate to severe instances, upper and lower lid meibomian gland loss was much greater than in mild cases. Baiocchi-Calossi-Versaci front, Baiocchi-Calossi-Versaci back, Baiocchi-Calossi-Versaci total, and meibomian glands loss were considerably greater in TED than the control group. The TED group had significantly lower flat, steep, and average keratometry than the control group. Conclusion Corneal anterior surface flattening is the most characteristic topographic change in TED not related to disease activity or severity. TED increases meibomian gland loss, which is a major factor of ocular surface alteration in TED.

Purpose Thyroid eye disease (TED) is a complex autoimmune disease. Early detection with routine disease monitoring using biomarker assessment would help in mitigating TED-associated vision loss. Hence, we performed a non-invasive tear fluid (TF) based screening in patients with TED as part of the South Indian Thyroid Eye Disease Study (SITED). Materials and Methods We used TF from healthy controls (HC;13 eyes;13 subjects), patients with thyroid dysfunction but without TED (No TED;11 eyes;11 subjects) and patients with TED (18 eyes;18 subjects). TED subjects were further sub-divided into those with and without an active form of the disease. Patients with dysthyroid optic neuropathy (DON) were analyzed separately. The diagnosis of TED was based on Gorman and Bartley’s criteria. Activity was defined as scoring more than 4 in the Vision, Inflammation, Strabismus and Appearance (VISA). Schirmer’s strip was used to collect TF and the levels of IL-2, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-13, IL-17A, IL-17F, IL-22, IFNγ, TNFα, PDGF-AA and PDGF-BB were determined by multiplex ELISA using flow cytometry. Results Significantly (p < 0.05) higher levels of IL-6 and IL-10 were observed in TED patients compared to HC and No TED subjects. TF levels of IL-6 and IL-10 were significantly higher in active TED patients compared to No TED subjects. Interestingly, TF levels of PDGF-AA were observed to be negatively associated with IL-4 and IL-13. Conclusion Elevated TF levels of IL-6 and IL-10 can be explored for their role as a non-invasive risk stratification biomarker or as targets to modulate management of TED.

PurposeThe purpose of this study was to assess the relationship between thyroid eye disease (TED) in patients undergoing orbital decompression and immunoglobulin G4 (IgG4) levels.MethodsA prospective observational cohort study was conducted among 185 consecutive patients who were diagnosed with TED and underwent orbital decompression. Serum levels of IgG4 were measured, and immunohistochemical staining for IgG and IgG4 was performed in orbital adipose tissue. Data related to clinicopathologic features were analyzed.ResultsAmong the 185 enrolled patients with TED, 64 (34.6%) were IgG4-positive. The IgG4-positive patients were older, had higher clinical activity scores (CAS), and had worse best-corrected visual acuity (BCVA) than the IgG4-negative patients. Higher thyrotropin receptor antibody (TRAb) levels, histopathological IgG4 counts, IgG4/IgG ratios, and dense lymphocyte infiltration were more frequently observed in IgG4-positive than in IgG4-negative patients. Definitive and probable IgG4 subtypes were independently associated with the active stage in patients with TED.ConclusionsOur data suggest that the IgG4 subtype in TED is common. IgG4-positive patients with TED may be older, have more severe disease, and have higher clinical activity scores. IgG4 may play an important role in the pathogenesis of TED.

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

Thyroid eye disease is the most frequent extrathyroidal manifestation of Graves' disease and it can have a major negative impact on the quality of life of affected patients. Therefore, it is crucial to have a correct and early diagnosis. Thyroid eye disease management should be multidisciplinary.