Management Of Thyroid Eye Disease Research Articles

Emerging therapies in the medical management of thyroid eye disease

IntroductionThyroid eye disease (TED) is an immune-mediated disorder associated with a heterogenous array of manifestations that may unfavorably impact vision and quality of life. As understanding of this entity’s complex pathogenesis has evolved, so have therapies with novel molecular targets offering promise for improved patient outcomes.ResultsEmerging immunologic therapies for the management of thyroid eye disease have diverse mechanisms of actions and routes of administration. Different conventional and biological immunosuppressive agents have been studied as mediators of the autoimmune and autoinflammatory pathways in thyroid eye disease. Teprotumumab – an anti-IGF-1R monoclonal antibody that has recently emerged as a first-line therapy for active, moderate-to-severe TED – has demonstrated statistically significant improvements in proptosis, diplopia, clinical activity score, and quality of life compared to placebo. Currently under investigation are several other agents, with varying administration modalities, that aim to inhibit IGF-1R: VRDN-001 (intravenous), VRDN-002 or VRDN-003 (subcutaneous), lonigutamab (subcutaneous), and linsitinib (oral). Tocilizumab, a monoclonal antibody of interleukin 6, has played a role in the management of multiple autoimmune and inflammatory conditions and may offer promise in TED. Another incipient biologic target for TED management is the neonatal Fc receptor, inhibition of which has potential to decrease recycling of immunoglobulin and antibody levels; agents addressing this target including monoclonal antibodies as well as antibody fragments. Finally, hypolipidemic agents may play a role as mediators of TED-associated inflammation.ConclusionAmong the agents under investigation that aim to decrease ocular morbidity associated with TED are agents that IGF-1R, interleukin 6, and the neonatal Fc receptor. The management of TED continues to expand with novel immunologic approaches for disease therapy.

Clinical features, pathophysiology, and management of thyroid eye disease

Clinical features, pathophysiology, and management of thyroid eye disease

Thyroid Eye Disease and Its Association With Diabetes Mellitus: A Major Review.

Thyroid eye disease (TED) associated with diabetes mellitus (DM) presents unique challenges. DM is a risk factor for TED. Standard management of TED with glucocorticoids (GC), orbital radiation, or teprotumumab can cause adverse events in poor glycemic control. The authors reviewed the literature on the relationship between TED and DM and the management of co-existing diseases. The authors searched PubMed with keywords "thyroid eye disease," "diabetes mellitus," and similar terms from 2013 to 2022. The authors included relevant studies after screening the abstracts. Additional references to the selected studies were included where applicable. Data were extracted from the final articles according to the preplanned outline of the review. The initial search yielded 279 abstracts. The final review included 93 articles. TED and DM interact at multiple levels-genetic, immunologic, cellular, nutritional, and metabolic. Both DM and thyroid dysfunction exacerbate the morbidity caused by the other. Metabolic factors also affect the inflammatory pathway for TED. Patients with DM develop TED with greater frequency and severity, necessitating interventions for vision salvage. Agents (GC, teprotumumab, or radiation) used for TED are often unsuitable for treatment with DM, especially if there is poor glycemic control or diabetic retinopathy. There were no studies on using steroid-sparing agents in TED with DM. TED and DM co-exist because of multiple intersections in the pathophysiology. Challenges in the treatment include increased TED severity and risk of hyperglycemia and retinopathy. Multidisciplinary teams best undertake treatment of TED with DM.

Application of Quantitative MRI in Thyroid Eye Disease: Imaging Techniques and Clinical Practices.

Thyroid eye disease (TED) is a complex autoimmune disorder that impairs various orbital structures, leading to cosmetic damage and vision loss. Magnetic resonance imaging (MRI) is a fundamental diagnostic tool utilized in clinical settings of TED, for its accurate demonstration of orbital lesions and indication of disease conditions. The application of quantitative MRI has brought a new prospect to the management and research of TED, offering more detailed information on morphological and functional changes in the orbit. Therefore, many researchers concentrated on the implementation of different quantitative MRI techniques on TED for the exploration of clinical practices. Despite the abundance of studies utilizing quantitative MRI in TED, there remain considerable barriers and disputes on the best exploitation of this tool. This could possibly be attributed to the complexity of TED and the fast development of MRI techniques. It is necessary that clinical and radiological aspects of quantitative MRI in TED be better integrated into comprehensive insights. Hence, this review traces back 30 years of publications regarding quantitative MRI utilized in TED and elucidates this promising application in the facets of imaging techniques and clinical practices. We believe that a deeper understanding of the application of quantitative MRI in TED will enhance the efficacy of the multidisciplinary management of TED. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 3.

Approach to the Management of Thyroid Eye Disease

Thyroid Eye Disease (TED), also known as Grave’s orbitopathy, is an autoimmune condition characterized by inflammation of the extraocular muscles, orbital fat and periocular tissues. As the most common orbital disease worldwide, its prevalence is estimated to be between 0.5–2% and it disproportionately affects females 4:1. Although the majority of TED cases occur in patients with Graves’ disease (80–90%), it can also be seen with patients with Hashimoto’s thyroiditis (10%), euthyroid individuals (5–10%) and thyroid cancer. At the time of initial Graves’ disease diagnosis, 25% of patients have clinically detectable orbital involvement that is often mild. The natural history of TED typically consists of an initial active inflammatory period lasting 6–36 months, which then plateaus and is followed by a quiescent fibrotic phase with stabilization of disease.

Objective Diplopia Outcomes for Patients Treated With Teprotumumab for Thyroid Eye Disease.

Thyroid eye disease (TED) is a condition caused by inflammatory damage to the periocular tissue that often leads to double vision. Teprotumumab is an insulin-like growth factor 1 receptor antibody that was FDA approved for the management of TED in 2020, although much is yet to be elucidated regarding its effects on diplopia outcomes among patients with TED. Diplopia is a significant and life-altering effect of TED. Previous studies have reported the effect of teprotumumab on double vision subjectively using the Gorman diplopia score. However, there is a gap in the literature addressing the effect of teprotumumab treatment on objective ocular alignment measures. The purpose of our study was to address this gap. We performed a retrospective review of patients who were diagnosed with TED, presented with diplopia, and treated with teprotumumab in a single-center academic ophthalmology practice. The primary outcome was change in ocular alignment in primary gaze position at 6 months (completion of teprotumumab treatment). Secondary outcomes included change in ocular alignment in other gaze positions, proptosis, eyelid position, and clinical activity score (CAS) at 6 months compared with baseline. To determine what factors may predict ocular alignment response to teprotumumab, we analyzed baseline characteristics among 3 groups, divided based on whether ocular alignment was worsened, stable, or improved at 6 months. Seventeen patients met inclusion criteria, 3 (18%) worsened, 10 (59%) were stable, and 4 (24%) improved. CAS ( P = 0.02) was significantly different among the groups and was higher in those who worsened and those who improved compared with those who remained stable. Right gaze horizontal prism deviation ( P = 0.01) and left gaze horizontal prism deviation ( P = 0.03) were significantly different among the groups, with a greater degree of left gaze horizontal prism deviation in the worse group than the stable group ( P = 0.04). Our study demonstrated that most patients remained stable after teprotumumab treatment regarding ocular alignment in primary gaze and the number of patients who improved was slightly higher than the number of patients who worsened after teprotumumab treatment. There are some baseline measures, such as CAS and right and left gaze horizontal prism deviation that can help better predict how a patient will respond to teprotumumab treatment. Our results can better inform physicians of how to counsel patients with TED when considering teprotumumab therapy.

Abstract #1413021: Teprotumumab Induced Type 1 Diabetes Mellitus

Thyroid Eye disease is a potentially vison impairing condition for which Teprotumumab has emerged as a premier option in managing disease activity. The primary mechanism of action is monoclonal antibody against the insulin-like growth factor-I receptor but a large portion remains unknown. In the original trial for Teprotumumab about 10% of patients developed hyperglycemia which was described as self limited and mild. Since commercial release there has been great heterogeneity of hyperglycemia shown with case reports of HHS and DKA despite a third of trial patients returning to baseline after completion of therapy. We present a case of type 1 diabetes after starting Teprotumumab which may help advise decisions for therapy, monitoring, and surveillance. A 52-year-old female with prediabetes (A1C 6.1%), mild hypothyroidism and tobacco use who presents with diplopia, proptosis, palpitations in January of 2022 to PCP. She had lab work performed in March 2022 with TSH 0.007, FT4 2.45, TPO antibodies 219 positive. Last normal TFTs in Feb of 2020. Her levothyroxine was stopped by PCP and she was started on methimazole 10 mg tid and propranolol ER 60 mg daily. April 2022 referred to Endocrinology, Labs: TSI index of 2.9, TSH now of 13, Free T4 of 0.56 (0.93 - 1.7) while on methimazole 10 mg tid. She was reduced to 10 mg bid and referred to Ophthalmology for co-management of thyroid eye disease with plan for Teprotumumab for moderate to severe disease. Subsequent follow up in June 2022, she had been tapered down to 5 mg bid between visits and labs showed: TSH 0.074, FT4 1.08, FT3 3.8. Methimazole was further reduced to 5 mg daily. She was started on metformin XR 500 mg bid given her diagnosis of prediabetes and plan for Teprotumumab therapy. She achieved smoking cessation with varenicline. CBC and LFT monitoring were remarkable for chronic mild ALP elevation. Teprotumumab was started and her eye symptoms improved significantly by the second infusion. Hyperglycemia worsened and A1C increased to 7.5%.TSH was 6.32 and Free T4 1.1 on 5 mg of methimazole. Subsequently methimazole was decreased to 2.5 mg daily and Metformin increased to 1g bid and addition of glimepiride 2mg daily. She had continued hyperglycemia. Subsequent labs we obtained GAD antibodies with continued hyperglycemia and monitoring labs for remission. GAD antibodies >125 exceeding beyond the upper limit of normal for the assay and subsequent thyroid tests with c-peptide are pending at this time. Teprotumumab has revolutionized thyroid eye disease treatment. This case demonstrates there are multiple modalities of hyperglycemia that may be non-reversible after completion of Teprotumumab. The importance of monitoring and perhaps a role in evaluating antibodies and insulin reserve in Teprotumumab induced hyperglycemia surveillance. This case supports that this group is heterogenous and needs further studies. Further evaluation for this patient is still pending with initiation of insulin therapy. We hope that this case can help guide research, safety protocols, and awareness in the management of thyroid eye disease.

Teprotumumab in thyroid eye disease: wonder drug or great divider?

Progress in the management of thyroid eye disease (TED) has been slow for many decades. The recent introduction of teprotumumab (TEP) in the therapeutic arena for TED has had a major impact in view of its efficacy, particularly with respect to its ability to reduce proptosis. However, the high cost of TEP, limited availability to patients outside the USA, and the lack of data on cost-effectiveness are significant barriers to improving the care of patients with TED globally. Recent guidance from authoritative professional organisations deliver different perspectives on the role of TEP in the routine management of patients with TED, underscoring the complexities of interpreting the evidence. The advance that TEP undoubtedly represents in managing TED effectively has highlighted inequities faced by patients and uncertainties about appropriate metrics of efficacy. Professional organisations have an important role addressing these problems. Future studies need to focus on optimising the measurement of outcomes and on assessing cost-effectiveness.

Medical Management of Thyroid Eye Disease.

Kamboj, Alisha MD, MBA; Lee, Michael S. MD; McClelland, Collin M. MD Author Information

Management of thyroid eye disease: a Consensus Statement by the American Thyroid Association and the European Thyroid Association.

Thyroid eye disease (TED) remains challenging for clinicians to evaluate and manage. Novel therapies have recently emerged, and their specific roles are still being determined. Most patients with TED develop eye manifestations while being treated for hyperthyroidism and under the care of endocrinologists. Endocrinologists, therefore, have a key role in diagnosis, initial management, and selection of patients who require referral to specialist care. Given that the need for guidance to endocrinologists charged with meeting the needs of patients with TED transcends national borders, and to maximize an international exchange of knowledge and practices, the American Thyroid Association and European Thyroid Association joined forces to produce this Consensus Statement.

Management of Thyroid Eye Disease: A Consensus Statement by the American Thyroid Association and the European Thyroid Association

Thyroid eye disease (TED) remains challenging for clinicians to evaluate and manage. Novel therapies have recently emerged, and their specific roles are still being determined. Most patients with TED develop eye manifestations while being treated for hyperthyroidism and under the care of endocrinologists. Endocrinologists, therefore, have a key role in diagnosis, initial management, and selection of patients who require referral to specialist care. Given that the need for guidance to endocrinologists charged with meeting the needs of patients with TED transcends national borders, and to maximize an international exchange of knowledge and practices, the American Thyroid Association and European Thyroid Association joined forces to produce this consensus statement.

New Onset or Deterioration of Thyroid Eye Disease After mRNA SARS-CoV-2 Vaccines: Report of 2 Cases and Literature Review.

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.

A Survey on the Management of Thyroid Eye Disease Among American and European Thyroid Association Members.

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.

A Paradigm Shift in the Management of Thyroid Eye Disease How Teprotumumab Has Changed the Therapeutic Interface.

Teprotumumab, a monoclonal antibody that blocks the insulin-like growth factor-1 receptor, has recently been approved by the US Food and Drug Administration (FDA) for the treatment of thyroid eye disease (TED). Since its approval, aside from data on the safety and clinical efficacy of teprotumumab from Phase-2 and Phase-3 trials, only a handful of reports have been published regarding its use in the wider population. In this review, we briefly describe the mechanism of action of teprotumumab and review the literature to provide an overview of published clinical experience. This information was used to provide recommendations for patient selection, management of patient expectations, infusion details and site options, tips to optimize the authorization process, and how to monitor and mitigate side effects. A systemic review of the literature was performed regarding teprotumumab, focusing on its mechanisms of action and published reports on its use on patients with TED. A review of Embase, Medline (PubMed), Web of Science, and Google Scholar was conducted. Clinical experience following the approval of teprotumumab has confirmed its efficacy in reducing inflammation and proptosis in patients with acute TED (<2 years). The reduction in proptosis occurs due to a reduction in orbital fat and muscle volume. Furthermore, there is evidence for its use in patients with compressive optic neuropathy. There are also reports that show its efficacy in reducing proptosis, inflammation, and diplopia in patients with chronic TED (>2 years). Teprotumumab was associated with side effects, such as muscle spasm, hearing loss, and hyperglycemia. To date, 2 case reports have shown a possible association with flares of inflammatory bowel disease. Teprotumumab is a powerful therapeutic option for the treatment of TED. Clinical experience following FDA approval has demonstrated efficacy in treating patients with acute and chronic TED. It is the only therapeutic option that has been shown to reduce orbital soft tissue expansion in TED. However, it is expensive, and sometimes, obtaining insurance authorization can be time consuming and difficult. Further work will reveal its full side effect profile and help to establish its role in the armamentarium used to treat TED.

A systematic review of multimodal clinical biomarkers in the management of thyroid eye disease.

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.

Update on thyroid eye disease: Regional variations in prevalence, diagnosis, and management.

Thyroid eye disease (TED) is a rare disease that can lead to decreased quality of life, permanent disfigurement, and vision loss. Clinically, TED presents with exophthalmos, periorbital edema, extraocular muscle dysfunction, and eyelid retraction, and can lead to vision-threatening complications such as exposure to keratopathy and dysthyroid optic neuropathy (DON). Over the last several years, significant advancements have been made in the understanding of its pathophysiology as well as optimal management. Ethnic variations in the prevalence, clinical presentation, and risk of vision-threatening complications of TED are summarized, and risk factors associated with TED are discussed. Additionally, significant advances have been made in the management of TED. The management of TED traditionally included anti-inflammatory medications, orbital radiation therapy, orbital surgical decompression, and biologic therapies. Most recently, targeted therapies such as teprotumumab, an insulin-like growth factor-1 receptor antagonist, have been studied in the context of TED, with promising initial data. In this review, updates in the understanding and management of TED are presented with a focus on the international variations in presentation and management.

A Systematic Review on the Role of Antioxidants in Thyroid Eye Disease.

Purpose:To systematically review the role of antioxidants in management of patients with thyroid eye disease (TED).Methods:A literature search of the electronic databases was performed without restrictions on the date of publication till the end of March 2021, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Clinical trials, case–control studies, cohorts, case series, case reports, and experimental (including in vitro) studies in the English language were included. The primary outcome in human studies was improvement in severity, activity scores, and/or quality of life scores. There was a decrease in the level of H2O2-dependent oxidative stress, Hyaluronic acid release, reactive oxygen species, cell proliferation, or antifibrotic/antiproliferative actions in the in vitro studies.Results:Out of 374 initially screened articles, 157 studies were selected, the full texts of 82 were reviewed, and 14 papers were finally included. There were 4 clinical and 10 in vitro studies from 1993 to 2018. While β-carotene, retinol, Vitamin E, Vitamin C, melatonin, resveratrol, N-acetyl-l-cysteine, and quercetin showed some efficacy in in vitro studies; allopurinol, nicotinamide, pentoxifylline, and selenium (Se) were effective in both clinical and experimental reports. Se was the only recommended antioxidant based on one high-level randomized controlled trial.Conclusion:While different antioxidants could potentially be effective in the management of TED, no strong recommendation for any or combination of antioxidants could be made to be implemented in the daily practice.

Orbital Radiation for Thyroid Eye Disease: A Report by the American Academy of Ophthalmology

To review the current literature on the safety and efficacy of orbital radiation for the management of thyroid eye disease (TED). A literature search was conducted last in February 2021 of the PubMed database to identify all articles published in the English language on original research that assessed the effect of orbital radiation on TED. The search identified 55 articles, and 18 met the inclusion criteria for this assessment. A panel methodologist then assigned a level of evidence rating for each study, and all of them were rated level III. Two large retrospective studies demonstrated the efficacy of radiation treatment, with or without corticosteroid use, in preventing or treating compressive optic neuropathy (CON). Three studies highlighted the role of orbital radiation therapy (RT) to facilitate the tapering of corticosteroids. Several other studies showed a possible role for RT to improve diplopia and soft tissue signs. Although no level I or level II evidence exists, the best available evidence suggests that orbital radiation, used with or without corticosteroids, is efficacious in preventing CON, improving motility restriction, and decreasing clinical activity in TED. Orbital radiation also may facilitate a corticosteroid taper. Together, these studies show that RT seems to modify the active phase of TED. Short-term risks of orbital radiation are minor, but long-term outcome data are lacking.

Current Management of Thyroid Eye Disease

Current Management of Thyroid Eye Disease

Surgical management of the orbit in thyroid eye disease: lateral orbital decompression.

Lateral orbital wall decompression is one of many well established techniques available to surgeons in management of patients with clinically significant thyroid eye disease (TED). Several different surgical approaches have been described in the literature and are reviewed herein. Lateral orbital wall decompression remains a popular technique for surgical management of TED, with a recent American Society of Ophthalmic Plastic and Reconstructive Surgery survey showing that 22.6% of respondents preferred a single-wall procedure, with 36.8% of that subset preferring lateral wall decompression alone. Surgical techniques for lateral orbital wall decompression differ based on several steps, such as the incisional approach, whether to take an ab-interno versus ab-externo approach, and whether to remove orbital fat to achieve further decompression. In addition, technological advances have produced an array of tools available to the orbital surgeon to achieve efficient and accurate bone removal. Lateral orbital wall decompression for TED, despite being an older technique, remains a popular and well established procedure for orbital decompression. Though no randomized controlled clinical trial supports one decompression technique over another for TED, lateral orbital wall decompression offers many benefits such as its ease of access and visualization of the orbital space.