Tofacitinib for Refractory Thyroid Eye Disease

Thyroid eye disease (TED) is a complex ocular autoimmune disorder primarily associated with Graves' disease. It leads to significant morbidity due to orbital inflammation, fibrosis, and tissue expansion. While corticosteroids have been the traditional mainstay of therapy, recent advancements in understanding TED pathophysiology have driven the development of targeted treatments. Notably, inhibition of the insulin-like growth factor-1 receptor with teprotumumab has revolutionized TED management, demonstrating efficacy in reducing proptosis and disease severity. Additional emerging therapies, including neonatal Fc receptor inhibitors, thyroid-stimulating hormone receptor blockers, and interleukin-6 receptor antagonists, offer promising alternatives for patients with active and refractory disease. Despite these advancements, challenges remain in disease classification and outcome assessment. As the landscape of TED management continues to evolve, this review provides a comprehensive overview of current and emerging therapies for TED, critically examines gaps in disease evaluation, and highlights the evolving paradigm of patient-centered care. Future efforts should focus on optimizing therapeutic algorithms, refining risk stratification models, guiding personalized treatment, and promoting a multidisciplinary approach, which remain essential in improving outcomes and quality of life for affected individuals.

BackgroundThyroid eye disease is an extrathyroidal manifestation of Graves’ disease and is associated with dry eye disease. This is the first systematic review and meta-analysis to evaluate the role of magnetic resonance imaging lacrimal gland parameters in thyroid eye disease diagnosis, activity grading, and therapeutic responses prediction.MethodsUp to 23 August, 2022, 504 studies from PubMed and Cochrane Library were analyzed. After removing duplicates and imposing selection criteria, nine eligible studies were included. Risk of bias assessment was done. Meta-analyses were performed using random-effect model if heterogeneity was significant. Otherwise, fixed-effect model was used. Main outcome measures include seven structural magnetic resonance imaging parameters (lacrimal gland herniation, maximum axial area, maximum coronal area, maximum axial length, maximum coronal length, maximum axial width, maximum coronal width), and three functional magnetic resonance imaging parameters (diffusion tensor imaging-fractional anisotropy, diffusion tensor imaging-apparent diffusion coefficient or mean diffusivity, diffusion-weighted imaging-apparent diffusion coefficient).ResultsThyroid eye disease showed larger maximum axial area, maximum coronal area, maximum axial length, maximum axial width, maximum coronal width, diffusion tensor imaging-apparent diffusion coefficient/ mean diffusivity, and lower diffusion tensor imaging-fractional anisotropy than controls. Active thyroid eye disease showed larger lacrimal gland herniation, maximum coronal area, diffusion-weighted imaging-apparent diffusion coefficient than inactive. Lacrimal gland dimensional (maximum axial area, maximum coronal area, maximum axial length, maximum axial width, maximum coronal width) and functional parameters (diffusion tensor imaging-apparent diffusion coefficient, diffusion tensor imaging-apparent diffusion coefficient) could be used for diagnosing thyroid eye disease; lacrimal gland herniation, maximum coronal area, and diffusion-weighted imaging-apparent diffusion coefficient for differentiating active from inactive thyroid eye disease; diffusion tensor imaging parameters (diffusion tensor imaging-fractional anisotropy, diffusion tensor imaging-mean diffusivity) and lacrimal gland herniation for helping grading and therapeutic responses prediction respectively.ConclusionsMagnetic resonance imaging lacrimal gland parameters can detect active thyroid eye disease and differentiate thyroid eye disease from controls. Maximum coronal area is the most effective indicator for thyroid eye disease diagnosis and activity grading. There are inconclusive results showing whether structural or functional lacrimal gland parameters have diagnostic superiority. Future studies are warranted to determine the use of magnetic resonance imaging lacrimal gland parameters in 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.

Risk Factors of Thyroid Eye Disease

Thyroid eye disease (TED) is a complex autoimmune condition that can cause proptosis, ophthalmoplegia, diplopia, optic nerve compression, and vision loss. These clinical findings are caused by a complex pathological mechanism characterized by thyroid-stimulating hormone receptor autoantibodies activating thyroid-stimulating hormone receptors (TSH-Rs). Overexpressed insulin-like growth factor 1 (IGF-1) receptors found in orbital fibroblasts form complexes with these TSH-Rs, leading to the inflammation and expansion of these tissues. Teprotumumab, a human monoclonal antibody sold under the brand name Tepezza, is currently the only FDA-approved immunotherapy for the treatment of TED. Given as an intravenous infusion every three weeks, teprotumumab works by suppressing IGF-1 receptors, thereby interfering with TSH-R and IGF-1 complex-mediated actions in these fibroblasts. The efficacy of teprotumumab was established in randomized, placebo-controlled clinical trials, which demonstrated clinically meaningful improvements in proptosis, inflammation, and diplopia. While teprotumumab has been shown to be efficacious, our patient with TSHRAb-positive euthyroid thyroid-associated ophthalmopathy who presented with diplopia did not have any significant improvement following the standard treatment dose of eight infusions over a 24-week period. This case underscores not only barriers to treatment, such as the high cost of teprotumumab but also highlights the importance of identifying risks for nonresponse.

Introduction: Thyroid Eye Disease (TED) is an autoimmune inflammatory disease of the orbit that affects orbital fat, extraocular muscles, periocular tissue and lacrimal glands. TED activity can be assessed with a Clinical Activity Score (CAS) to identify active or inactive TED conditions. Dry Eye Diseases (DED) is one of the manifestations in patients with TED with a prevalence that varies from 27%-96%. The Asia Dry Eye Society (ADES) 2017 proposed a new concept for DED diagnosis and therapy, namely Tear Film Oriented Diagnosis (TFOD) and Tear Film Oriented Diagnosis Therapy (TFOT) with Tear Film Breakup Pattern (TBUP) examination. TBUP examination help in determine specific management of DED. The aim of this study is to determine the differences in TBUP in TED patients based on active and inactive. Methods: This is an analytical observational study with a cross-sectional design. The subjects were TED patients who came to the Cicendo Eye Hospital and met the inclusion criteria. The study was conducted at the National Eye Center of Cicendo Eye Hospital in April - June 2022. The data were analysed with the Chi-Square Test. Result: This study was conducted on 23 patients or 46 eyes. This study found a statistically significant differences in TBUP features in active and inactive TED patients (p=0.0001). The most common features of TBUP was found in active TEDs was dimples (55%). Conclusion: There are differences of TBUP features in active and inactive TED patient.

IntroductionThyroid eye disease (TED) is most often associated with Graves’ hyperthyroidism and bilateral involvement, whereas presentation with hypothyroidism or as a unilateral process is uncommon. Even more rarely, autoimmune hypothyroidism may evolve into Graves’ hyperthyroidism due to a shift in TSH receptor antibody (TRAb) activity.Clinical CaseA 48-year-old man with hypertension, dyslipidemia, and a current smoker was referred by an ophthalmologist for progressive right eye bulging, ocular pain, and redness. Examination revealed right-sided unilateral proptosis and lid retraction, with a Clinical Activity Score (CAS) of 5, consistent with active thyroid eye disease (TED) and severe disease according to the European Group on Graves’ Orbitopathy (EUGOGO) classification. Laboratory evaluation demonstrated overt hypothyroidism with strongly positive TPO and total TRAb antibodies. Thyroid ultrasound showed mild diffuse enlargement with heterogeneous echotexture, and orbital MRI confirmed hypertrophy of the right extraocular muscles (Figure 1). The patient received high-dose intravenous methylprednisolone (total 4.5 g over 12 weeks) and levothyroxine 50 μg/day. Smoking cessation was achieved. At follow-up, thyroid function initially improved, but TED remained active. Subsequently, while TED stabilized, the patient developed biochemical hyperthyroidism; levothyroxine was discontinued. On further follow up, overt hyperthyroidism was confirmed, and methimazole was initiated and titrated to 10 mg/day, resulting in biochemical stabilization and maintenance of stable TED without optic nerve involvement. At the last follow-up, the patient was maintained on carbimazole 10 mg/day with good clinical outcomes. Table 1 summarizes the follow-up stages of the patient. In fact, as we are in a resources-limited area, TRAb blocking and stimulating antibodies are not availableConclusionThis case highlights a rare presentation of severe unilateral TED initially associated with autoimmune hypothyroidism, later evolving into Graves’ hyperthyroidism. It emphasizes the importance of close biochemical monitoring, awareness of possible immune conversion, and multidisciplinary management to prevent sight-threatening complications, especially in high-risk patients such as smokers with elevated TRAb titers.Figure 1:CT scan of orbits showing extraoccular muscles enlargement Table 1:Patient follow up visits

Purpose Fatty infiltration of the extraocular muscles has been described radiographically in patients with thyroid eye disease (TED), yet it has not been studied on a large scale nor quantified. Our purpose was to define and characterize this entity in patients with TED. Methods An IRB-approved cross-sectional retrospective review of medical records identified patients with a clinical diagnosis of TED and at least one CT of the orbits. A 2:1 age and sex-matched control population consisted of patients without a history nor radiographic evidence of orbital disease or systemic thyroid abnormality. The presence of fatty infiltration in each extraocular rectus muscle was defined using Hounsfield units (HU). Laterality, muscles involved, and pattern of fatty infiltration were also evaluated. Student’s t-tests, Chi-square, and Fisher’s exact tests were used to compare TED and control groups. Results The study population consisted of 252 patients with TED and 504 age and sex-matched controls. Fatty infiltration was significantly more prevalent in TED patients (36/252, 14.3%) compared to controls (11/504, 2.2%) (p < .001). The mean density of fat infiltration was significantly lower in TED patients (−40.4 HU) than controls (−34.8 HU) (p = .048). In TED patients, the frequency of muscle involvement was inferior rectus (61.8%), lateral rectus (19.7%), superior rectus (11.8%) and medial rectus (6.6%), which was not significantly different than controls (p > .05). Most muscles (88.2%) in the TED group exhibited a heterogeneous pattern of infiltration, which did not differ from controls (p = .34). Conclusions This study characterizes fatty infiltration of the extraocular muscles in patients with TED.

Thyroid eye disease (TED) is the most consequential extrathyroidal manifestation or complication of Graves' disease (GD). Treatment of hyperthyroidism in GD complicated by TED is challenging. Antithyroid drugs (ATDs) and thyroidectomy do not change the natural course of TED, while radioactive iodine (RAI) is associated with a small but well-documented risk of TED de novo occurrence or its progression/worsening. In the presence of mild TED, any treatment for hyperthyroidism can be used, but should RAI treatment be selected, steroid prophylaxis (short course of low-dose prednisone) is strongly recommended if TED is of recent onset and/or risk factors for progression exist. In moderate to severe and active TED, ATDs are the preferred treatment, but thyroidectomy is a valid option. RAI ablation is generally avoided; it might be used when the clinical situation calls for it, but with extreme caution, if an aggressive treatment for TED with high-dose glucocorticoids (with or without orbital radiotherapy) is administered concomitantly. In moderate to severe and inactive TED, all 3 treatments for hyperthyroidism are acceptable, and steroid prophylaxis in RAI-treated patients should be given when risk factors for TED progression are identified. Management of sight-threatening TED represents the absolute priority, and hyperthyroidism should be controlled with ATDs until TED has been controlled. Search Strategies Current guidelines, original articles, clinical trials, systematic reviews, and meta-analyses up to June 2024 were searched using the following terms: "Graves' disease," "management of Graves' disease," "antithyroid drugs," "radioactive iodine," "thyroidectomy," "thyroid eye disease," "Graves' orbitopathy or ophthalmopathy."

Disclosure: L. Miller-Wilson: Employee of Immunovant, Inc. N. Princic: Employee of Merative. K. Evans: Employee of Merative. N. Atreja: Employee of Immunovant, Inc. K. Tollefsen: Employee of Immunovant, Inc.. D. Toro-Tobón: None. Objectives: Graves’ disease (GD) is an autoimmune condition responsible for most cases of hyperthyroidism in the United States. An estimated 20%-50% of patients with GD will also develop thyroid eye disease (TED). Current treatments for GD focus on managing hyperthyroidism, but frequent monitoring, dose adjustments, and the high rate of relapse after discontinuation of antithyroid drugs can increase treatment costs and complicate long-term management. This study describes healthcare resource utilization (HCRU) and costs among patients with GD, with and without TED. Methods: This retrospective analysis utilized claims data from the Merative™ MarketScan® Research Databases. Individuals aged ≥18 years with ≥2 claims for a GD diagnosis from January 1, 2017-December 31, 2023 were included (first claim = index). To ensure a newly diagnosed cohort, patients with a history of GD-specific treatment or a GD diagnosis in the 12 months preceding the index were excluded. The final GD cohort was stratified into patients who had evidence of TED at any time during the 12-month pre-index period through 90 days post-index, and those who did not. Propensity score matching was used to balance patients with GD (with and without TED) with non-GD controls (1:3) on demographic and baseline clinical characteristics. Both GD cases (with and without TED) and controls were required to have ≥12 months of post-index follow-up. HCRU and costs were compared between cases and controls during a fixed 12-month post-index period. Categorical outcomes were compared using chi-squared tests, while continuous endpoints were compared using paired t-tests. Results: The analysis included 1,767 GD cases with TED matched with 5,301 controls (mean age, 53.1 years [standardized mean difference (SMD), 0.00]; 77% female [SMD, 0.00]; mean Charlson comorbidity score, 0.9 [SMD, 0.02]) and 43,120 GD cases without TED matched with 129,360 controls (mean age, 49.8 years [SMD, 0.00]; 78% female [SMD, 0.00]; mean Charlson comorbidity score, 0.7 [SMD, 0.01]). Compared with matched controls, patients with GD and TED had 78% more inpatient visits (0.16 vs 0.09), 104% more outpatient visits (65.06 vs 31.86), and 43% more prescriptions (30.21 vs 21.13) during the 12-month post-index period, while patients with GD without TED had 75% more inpatient visits (0.14 vs 0.08), 83% more outpatient visits (52.15 vs 28.48), and 38% more prescriptions (24.27 vs 17.56) (p&amp;lt;0.001 for all). Annual mean healthcare costs were 305% higher ($56,584 vs. $13,981) among GD patients with TED and 65% higher ($19,913 vs $12,076) in those without TED compared with matched controls. Conclusion: Patients with GD had significantly higher HCRU and healthcare costs than matched controls in the 12 months following diagnosis, and this difference was notably greater among GD patients who also had TED. More effective treatments are needed to address the health and financial burden of GD. Presentation: Monday, July 14, 2025

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.

#1401671: Hashimoto’s Disease with Thyroid Eye Disease, Negative TRAB and Positive TPO Antibodies Treated with Teprotumumab

Purpose The aim of this study is to identify biochemical inflammatory markers predicting the presence or risk of developing thyroid eye disease (TED) in patients with Graves’ disease (GD).Methods Patients with GD (n = 100, 77 females) were included from the National Norwegian Registry of Organ-Specific Diseases. Serum samples were analysed for 92 different inflammatory biomarkers using the proximity extension assay. Biomarker levels were compared between groups of patients with and without TED and healthy subjects (HS) (n = 120).Results TED was found in 36 of 100 GD patients. Significant (P < 0.05) differences in the levels of 52 inflammatory biomarkers were found when GD patients and HS were compared (42 elevated and 10 decreased). Out of the 42 elevated biomarkers, a significantly higher serum level of interleukin-6 (IL6) (P = 0.022) and macrophage colony-stimulating factor (CSF1) (P = 0.015) were found in patients with TED compared to patients without TED. Patients with severe TED also had significantly elevated levels of Fms-related tyrosine kinase 3 ligand (FLT3LG) (P = 0.009). Furthermore, fibroblast growth factor 21 (FGF21) was significantly increased (P = 0.008) in patients with GD who had no signs of TED at baseline but developed TED later.Conclusion We demonstrate an immunologic fingerprint of GD, as serum levels of several inflammation-related proteins were elevated, while others were decreased. Distinctly increased levels of IL6, CSF1, FLT3LG, and FGF21 were observed in TED, suggesting that these inflammatory proteins could be important in the pathogenesis, and therefore potential new biomarkers for clinical use.

Background and AimsThis review aims to summarize current and emerging therapies for treatment of thyroid eye disease (TED), in the light of novel understanding of pathogenetic mechanisms, leading to new treatment options and clinical trials.MethodsWe reviewed and analyzed peer-reviewed literature reporting recent translational studies and clinical trials in the treatment of TED. Searches were made at www.pubmed.gov with keywords “thyroid eye disease,” “Graves’ ophthalmopathy,” “thyroid orbitopathy,” and “Graves’ orbitopathy.”ResultsSurgery is reserved for rehabilitation in chronic TED or for emergent compressive optic neuropathy. Oral and intravenous glucocorticoid therapy has been used for decades with variable efficacy in acute TED, but results may be temporary and side effects significant. Nonsteroidal oral immunosuppressive agents offer modest benefit in TED. Several immunomodulatory monoclonal antibodies, including rituximab and tocilizumab, have shown efficacy for inactivating TED. Recently, teprotumumab, an insulin-like growth factor 1 receptor (IGF-1R) inhibitor, has demonstrated significant improvement in proptosis, clinical activity score, diplopia, and quality of life in patients with active TED, with good tolerability. Newly proposed TED therapies, currently in preclinical and clinical trial phases, include thyroid-stimulating hormone (TSH) receptor inhibitory drugs, RVT-1401, local anti-vascular endothelial growth factor therapy, IGF-1R drugs delivered subcutaneously and orally, and desensitization to the TSH receptor with modified TSH receptor peptides.ConclusionNew, albeit incomplete, understanding of the molecular mechanisms of TED has led to new promising therapies and offered improved outcomes in TED patients. Their full role and their relationship to classical immune suppression should be clarified over the next few years.