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Abstract This study aimed to investigate the effect of orbital wall decompression surgery and reduction of proptosis on the choroidal vascularity index (CVI) and subfoveal choroidal thickness (SFCT) in patients with thyroid eye disease (TED). Fifty-one eyes from 38 patients with controlled TED and proptosis were enrolled in this study. The majority of the patients (50.9%) had a clinical activity score (CAS) of zero, and none had a CAS greater than 2. The patients underwent a complete baseline ophthalmologic examination, and their choroidal profile alterations were monitored using enhanced depth imaging optical coherence tomography (EDI-OCT) before and during the three months after surgery. Changes in SFCT, luminance area (LA), total choroidal area (TCA), and the choroidal vascularity index (CVI) were measured as the ratio of LA to TCA in EDI-OCT images. The participants had an average age of 46.47 years, and 22 were female (57.9%). The SFCT of the patients exhibited a significant reduction over the follow-up period, decreasing from 388 ± 103 to 355 ± 95 µm in the first month (p

IntroductionApproximately 85% of patients with thyroid eye disease experience ocular surface symptoms. Although corneal exposure plays a role in inducing inflammatory changes to the ocular surface, multiple studies reveal more complexity to the abnormal tear film composition and parameters in thyroid eye disease patients including those who do not have proptosis or increased corneal exposure. Currently, a majority of cases of thyroid associated dry eye symptoms are given treatments intended for ocular surface disease arising from different etiologies. MethodsMedline via Ovid, Cochrane CENTRAL, PubMed, and Google Scholar were systematically searched for articles evaluating the efficacy of treatments for dry eye symptoms in patients with thyroid eye disease. Articles were from all geographic regions and dates ranged from inception until October 2023. ResultsSeven papers ultimately met inclusion criteria and were included in this review. These papers revealed that multiple topical and non-topical treatment modalities address dry eye symptoms in thyroid eye disease and improve subjective and objective ocular surface parameters. However, due to the few studies that exist and due to disparities in sample size and study design, no overwhelming best practices were identified that could influence clinical practice.ConclusionThis systematic review identifies the current treatments that exist and highlights the clear unmet need for a large population suffering with dry eye symptoms. Ideally, further well-designed investigations into this area would target topical, non-invasive modalities to develop first line options for thyroid eye disease patients.

PurposeTo evaluate percutaneous triamcinolone (TA) injection efficacy in treating upper eyelid retraction (UER) for Australian thyroid eye disease (TED) patients.MethodsWe conducted a retrospective analysis across 8 years and multiple diverse Australian centres identified UER patients who received TA injections. A single operator administered 40mg/1ml TA through upper eyelid skin. Assessments at 4-6 weeks and subsequent eyelid measurements gauged treatment response and complications.Results24 patients and 25 eyelids were included in the study. 91.6% were female, mean age 40.8 ± 10.3 years with mean follow-up of 17.5 months (± 18.5). Pre-treatment MRD1 was 6.2mm ± 1.4, and we observed a mean improvement of 2.2mm from pre-treatment to post-treatment (p

IntroductionClassification of thyroid eye disease (TED) is largely based on guidelines developed in Europe and North America. Few studies have investigated the presentation and treatment of TED in Black populations. The objective is to examine the manifestations of TED in secondary and tertiary care center-based populations with a significant proportion of Black patients.Materials and methodsRetrospective chart review identifying patients with a reported race/ethnicity and a presenting clinical diagnosis of TED at Kings County Hospital and SUNY Downstate Medical Center and affiliated clinics from January 1, 2010 through July 31, 2021. Main outcome measures include age of disease onset, sex, smoking status, insurance status, postal code of residence, clinical exam features, number of follow-up visits, length of follow-up, and treatments received.ResultsOf the 80 patients analyzed, 49 were Black (61.2%) and 31 were White (38.8%). Between Black and White patients, there were differences in the mean age of presentation (48.1 [range 21-76] vs 56.8 [range 28-87] years, P=0.03), insurance status (51.0% vs 77.4% private insurance, P=0.02), and mean follow up length among those with multiple visits (21.6 [range 2-88] vs 9.7 [range 1-48] months, P=0.02). The distribution of EUGOGO scores were not significantly different between Black and White patients. On initial presentation, fewer Black patients had chemosis (OR 0.21, 95% CI, 0.08 to 0.57, P=0.002), and caruncular swelling (OR 0.19, 95% CI, 0.06 to 0.59, P=0.002) compared to White patients. During the overall disease course, fewer Black patients had subjective diplopia (OR 0.20, 95% CI, 0.07 to 0.56, P=0.002), chemosis (OR 0.24, 95% CI, 0.09 to 0.63, P=0.004), and caruncular swelling (OR 0.18, 95% CI, 0.07 to 0.51, P=0.001) compared to White patients. Black patients received oral steroids (42.9% vs 67.7%, P=0.03), intravenous steroids (18.4% vs 16.1%, P=0.8), orbital decompression surgery (16.7% vs 6.5%, P=0.19), and teprotumumab (22.9% vs 22.6%, P=0.99) at similar rates.DiscussionBlack patients presented with fewer external exam findings suggestive of active TED compared to White patients, but the rate of compressive optic neuropathy and decompression surgery were similar in the two groups. These differences may be due to disease phenotypes, which warrant further study.

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.

IntroductionGraves’ disease is an autoimmune disorder caused by auto-antibodies against the thyroid stimulating hormone receptor (TSHR). Overstimulation of the TSHR induces hyperthyroidism and thyroid eye disease (TED) as the most common extra thyroidal manifestation of Graves’ disease. In TED, the TSHR cross talks with the insulin-like growth factor 1 receptor (IGF-1R) in orbital fibroblasts leading to inflammation, deposition of hyaluronan and adipogenesis. The bone marrow may play an important role in autoimmune diseases, but its role in Graves’ disease and TED is unknown. Here, we investigated whether induction of experimental Graves’ disease and accompanying TED involves bone marrow activation and whether interference with IGF-1R signaling prevents this activation.ResultsImmunization of mice with TSHR resulted in an increase the numbers of CD4-positive T-lymphocytes (p ≤0.0001), which was normalized by linsitinib (p = 0.0029), an increase of CD19-positive B-lymphocytes (p= 0.0018), which was unaffected by linsitinib and a decrease of GR1-positive cells (p= 0.0038), which was prevented by linsitinib (p= 0.0027). In addition, we observed an increase of Sca-1 positive hematopietic stem cells (p= 0.0007) and of stromal cell-derived factor 1 (SDF-1) (p ≤0.0001) after immunization with TSHR which was prevented by linsitinib (Sca-1: p= 0.0008, SDF-1: p ≤0.0001). TSHR-immunization also resulted in upregulation of CCL-5, IL-6 and osteopontin (all p ≤0.0001) and a concomitant decrease of the immune-inhibitory cytokines IL-10 (p= 0.0064) and PGE2 (p ≤0.0001) in the bone marrow (all p≤ 0.0001). Treatment with the IGF-1R antagonist linsitinib blocked these events (all p ≤0.0001). We further demonstrate a down-regulation of arginase-1 expression (p= 0.0005) in the bone marrow in TSHR immunized mice, with a concomitant increase of local arginine (p ≤0.0001). Linsitinib induces an upregulation of arginase-1 resulting in low arginase levels in the bone marrow. Reconstitution of arginine in bone marrow cells in vitro prevented immune-inhibition by linsitinib.ConclusionCollectively, these data indicate that the bone marrow is activated in experimental Graves’ disease and TED, which is prevented by linsitinib. Linsitinib-mediated immune-inhibition is mediated, at least in part, by arginase-1 up-regulation, consumption of arginine and thereby immune inhibition.

IntroductionGraves’ disease (GD) is an autoimmune disorder caused by autoantibodies against the thyroid stimulating hormone receptor (TSHR) leading to overstimulation of the thyroid gland. Thyroid eye disease (TED) is the most common extra thyroidal manifestation of GD. Therapeutic options to treat TED are very limited and novel treatments need to be developed. In the present study we investigated the effect of linsitinib, a dual small-molecule kinase inhibitor of the insulin-like growth factor 1 receptor (IGF-1R) and the Insulin receptor (IR) on the disease outcome of GD and TED.MethodsLinsitinib was administered orally for four weeks with therapy initiating in either the early (“active”) or the late (“chronic”) phases of the disease. In the thyroid and the orbit, autoimmune hyperthyroidism and orbitopathy were analyzed serologically (total anti-TSHR binding antibodies, stimulating anti TSHR antibodies, total T4 levels), immunohistochemically (H&E-, CD3-, TNFa- and Sirius red staining) and with immunofluorescence (F4/80 staining). An MRI was performed to quantify in vivo tissue remodeling inside the orbit.ResultsLinsitinib prevented autoimmune hyperthyroidism in the early state of the disease, by reducing morphological changes indicative for hyperthyroidism and blocking T-cell infiltration, visualized by CD3 staining. In the late state of the disease linsitinib had its main effect in the orbit. Linsitinib reduced immune infiltration of T-cells (CD3 staining) and macrophages (F4/80 and TNFa staining) in the orbita in experimental GD suggesting an additional, direct effect of linsitinib on the autoimmune response. In addition, treatment with linsitinib normalized the amount of brown adipose tissue in both the early and late group. An in vivo MRI of the late group was performed and revealed a marked decrease of inflammation, visualized by 19F MR imaging, significant reduction of existing muscle edema and formation of brown adipose tissue.ConclusionHere, we demonstrate that linsitinib effectively prevents development and progression of thyroid eye disease in an experimental murine model for Graves’ disease. Linsitinib improved the total disease outcome, indicating the clinical significance of the findings and providing a path to therapeutic intervention of Graves’ Disease. Our data support the use of linsitinib as a novel treatment for thyroid eye disease.

PurposeSeverity of Graves’ orbitopathy (GO) shows wide individual differences. For optimal treatment, it is important to be able to predict the natural course of the disease as accurate as possible to counteract with anti-inflammatory and surgical treatment. Therefore, we aimed to further elucidate the impact of sex, age and smoking on GO.MethodsWe collected the clinical and demographic data of all patients of our tertiary referral center from January 2008 till December 2018 and analyzed it with descriptive statistics. Only patients with a complete data set were included in the further analysis. Odds ratio’s for moderate-to-severe and sight-threatening GO in relation to age, sex and smoking were calculated by means of multivariate logistic regression models.ResultsWe evaluated the data of 4260 patient with GO and complete data sets. Most of these were women (83%). There were no significant differences between male and female patients regarding smoking habits and thyroid treatment. Men were significantly older at initial manifestation of TED (51.8 vs. 49.9y, p

Graves’ disease (GD) is caused by an autoimmune formation of autoantibodies and autoreactive T-cells against the thyroid stimulating hormone receptor (TSHR). The autoimmune reaction does not only lead to overstimulation of the thyroid gland, but very often also to an immune reaction against antigens within the orbital tissue leading to thyroid eye disease, which is characterized by activation of orbital fibroblasts, orbital generation of adipocytes and myofibroblasts and increased hyaluronan production in the orbit. Thyroid eye disease is the most common extra-thyroidal manifestation of the autoimmune Graves’ disease. Several studies indicate an important role of sphingolipids, in particular the acid sphingomyelinase/ceramide system and sphingosine 1-phosphate in thyroid eye disease. Here, we discuss how the biophysical properties of sphingolipids contribute to cell signaling, in particular in the context of thyroid eye disease. We further review the role of the acid sphingomyelinase/ceramide system in autoimmune diseases and its function in T lymphocytes to provide some novel hypotheses for the pathogenesis of thyroid eye disease and potentially allowing the development of novel treatments.

BackgroundThe aim of the study was to evaluate the differences in clinical profile, laboratory parameters, and ophthalmological signs, and symptoms between patients with high IgG4 Graves orbitopathy and patients with normal IgG4 Graves orbitopathy.MethodsThis was a prospective observational study. We recruited adult patients with Graves Orbitopathy(GO) referred to our clinic for further diagnostics and treatment. Eventually, 60 patients with GO were enrolled in the study. All patients underwent ophthalmological assessment, magnetic resonance imaging (MRI) of the orbits, and laboratory tests, including IgG4 serum concentration measurement. High IgG4 GO was diagnosed if the IgG4 concentration exceeded 135 mg/dl. We used both the clinical activity score (CAS) and magnetic resonance imaging (MRI) to assess the activity of GO. Eventually, active GO was defined according to MRI results.ResultsAmong 60 GO patients, 15 (25%) patients had elevated IgG4 levels. Patients in the high IgG4 group had a higher prevalence of active GO by MRI than patients with normal IgG4 (100% vs. 64.44%, P=0.006). They also had a higher eosinophile count in peripheral blood, a lower bilirubin level, a more frequent lower eyelid retraction, and a lower prevalence of glaucoma. There were no statistically significant differences between the groups in CAS. Patients with active GO, had higher median IgG4 level [89.95 (55.48; 171.1) vs 43.45 (32.48; 49.68) mg/dl, P

Purpose: To report the case of a patient with reactivated, refractory thyroid eye disease (TED) treated with teprotumumab. Observations: A 51-year-old female with a 16-year history of thyroid eye disease previously treated with orbital decompression and multiple eyelid surgeries presented in a recurrent flare of the disease. The disease recurrence was refractory to intravenous steroid therapy and only partially responsive to oral steroid therapy, and the patient developed dysthyroid optic neuropathy in the right eye with decreased visual acuity and color vision. Clinical activity score was 8/10 and proptosis measurements were 27 mm OD and 26 mm OS. The patient underwent treatment with eight infusions of teprotumumab coinciding with a low taper of oral prednisone and experienced resolution of dysthyroid optic neuropathy, decrease of clinical activity score to 1, and dramatic improvement in proptosis (17 mm OD, 17 mm OS) and extraocular muscle size on imaging. Thirty weeks after completion of teprotumumab and 2 weeks after the second dose of the COVID vaccine, she experienced another flare and subsequently underwent bilateral orbital decompressions. Conclusion: This case report suggests teprotumumab may be used in patients with reactivation of longstanding thyroid eye disease. Reduction of extraocular muscle size and improvement in proptosis suggest teprotumumab may be disease-modifying even in advanced cases.

The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor originally identified as an environmental sensor of xenobiotic chemicals. However, studies have revealed that the AHR regulates crucial aspects of cell growth and metabolism, development and the immune system. The importance of the AHR and AHR signaling in eye development, toxicology and disease is now being uncovered. The AHR is expressed in many ocular tissues including the retina, choroid, cornea and the orbit. A significant role for the AHR in age-related macular degeneration (AMD), autoimmune uveitis, and other ocular diseases has been identified. Ligands for the AHR are structurally diverse organic molecules from exogenous and endogenous sources. Natural AHR ligands include metabolites of tryptophan and byproducts of the microbiome. Xenobiotic AHR ligands include persistent environmental pollutants such as dioxins, benzo (a) pyrene [B (a) P] and polychlorinated biphenyls (PCBs). Pharmaceutical agents including the proton pump inhibitors, esomeprazole and lansoprazole, and the immunosuppressive drug, leflunomide, activate the AHR. In this review, we highlight the role of the AHR in the eye and discuss how AHR signaling is involved in responding to endogenous and environmental stimuli. We also present the emerging concept that the AHR is a promising therapeutic target for eye disease.

Although corticosteroids are currently the first-choice drug for thyroid eye disease (TED), in 20–30% of cases, patients show poor or non-existent responses, and when the drug is withdrawn, 10–20% of patients relapse. Thus, in this study, we aimed to investigate the efficacy of the combined use of mycophenolate mofetil (CellCept®) and low dose oral prednisolone in patients with moderate to severe Graves' orbitopathy (GO). For the first time, we investigated the relationship between TED-related parameters and proptosis reduction. In a prospective, non-randomized, interventional case series, 242 patients with moderate-to-severe GO were, assigned to receive oral prednisolone (5 mg/ d) and mycophenolate mofetil (CellCept®) (one 500 mg tablet twice per day according to the therapeutic response). The patients were monitored regularly during the 3rd, 6th, 12th, and 18th month of treatment. The main outcome measures were the clinical activity score (CAS), intraocular pressure (IOP), diplopia, proptosis and visual acuity. We also assessed the relationship between the main outcomes with proptosis changes and time to improvement (months). Adverse effects were recorded during each visit. The clinical response rate increased from 67.7% on the third month to 89.2% on the sixth month, and 94.2% on the 12th month. This therapeutic response continued until the 18th month of follow-up. The CAS responses [disease inactivation (CAS

Purpose: To report a case series of subjective and objective hearing function changes associated with teprotumumab treatment for thyroid eye disease. Observations: A 74-year-old female with a history of Graves' disease with thyroid eye disease was treated with teprotumumab. She had a history of bilateral tinnitus and noticed a subjective improvement in her tinnitus after the second infusion. Audiology testing obtained before, during, and after completion of infusions showed symmetric and rapidly progressive worsening of the patient's sensorineural hearing loss. In contrast, a 42-year-old male with a history of Grave's disease endorsed worsening intermittent tinnitus and low-pitched hearing loss after initiation of teprotumumab. Audiology testing before, during, and after completion of infusions showed stable and normal hearing function bilaterally. Conclusion and importance: This case series highlights the importance of objective testing in patients prior to and after teprotumumab initiation as subjective hearing changes may not accurately reflect objective hearing function. In addition, this report suggests that teprotumumab may play a role in potentiating sensorineural hearing loss.

Purpose: To study post-interventional findings in patients with dysthyroid optic neuropathy (DON) treated with teprotumumab. Observations: In this multicenter observational Case series, patients with DON were treated with teprotumumab, an insulin-like growth factor I receptor inhibitor (10 mg/kg for the first infusion then 20 mg/kg for subsequent infusions, every three weeks for a total 8 infusions). This study included patients with acute and chronic thyroid eye disease (TED) with DON who had failed conventional therapies and were not candidates for surgical decompression. Data collected included best corrected visual acuity (BCVA), color vision, RAPD when present, and orbital CT or MRI. Proptosis, clinical activity score (CAS), Gorman diplopia score (GDS), and Humphrey visual fields (HVF) were also evaluated.Ten patients (6 women, 4 men) with an average age 64 years old were included in this study. Mean follow up after completion of infusions was 15 weeks. Baseline visual acuity (VA) impairment ranged from hand motion (HM) to 20/25 in affected eyes. All patients had pre-treatment orbital CT or MRI that confirmed orbital apex compression. Seventy percent of patients had objective improvement in DON after 2 infusions of teprotumumab measured as significant improvement in visual acuity, resolution of RAPD, or both. After completion of treatment, affected eyes had a mean BCVA improvement of 0.87 logMAR (p=0.0207), proptosis reduction of 4.7 mm (p

Purpose: To report the first case of a patient with chronic thyroid eye disease (TED) treated with teprotumumab. Observations: A 50-year-old female with a 3-year history of Graves’ disease presented with bilateral exophthalmos greatest on the left side. She was followed for 2 years with stable proptosis measurements (23mm OD, 28mm OS). Her clinical activity score (CAS) was 1 and there were no examination findings reflective of active inflammation. The patient underwent systemic treatment with teprotumumab and despite chronic TED and low CAS, she had notable improvement in proptosis (18mm OD, 22mm OS) and decrease in extraocular muscle volume as noted on orbital imaging. Conclusion and importance: This case report suggests that teprotumumab may be used in patients with chronic TED and low CAS. Improvement in the proptosis and reduction in extraocular muscle volume suggest that teprotumumab may alter disease course even in patients with inactive or quiescent TED.