Grading Severity and Activity in Thyroid Eye Disease.

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.

Background: Thyroid eye disease (TED) is a sight-threatening autoimmune disease with cigarette smoking as one of the key risk factors. Cigarette smoking affects both the severity of TED and the patient's response to medication. However, the underlying pathogenic mechanisms of smoking in TED remain unclear. Methods: Orbital fibroblasts (OFs) were extracted from patients with TED and non-TED controls, and treated with cigarette smoking extract (CSE). Luminex assays and Western blots were employed to examine inflammatory status and pathological phenotypes of OFs. A specific reactive oxygen species (ROS) probe was used to evaluate oxidative stress levels. RNA-sequencing of CSE-treated OFs was used to analyze differentially expressed genes. Immunofluorescence and RNA-sequencing were used to examine the expression of receptor for advanced glycation end products (RAGE) signaling molecules in patients. Small interfering RNA sequences and a RAGE-specific inhibitor were employed to investigate the effects of RAGE blockade on cigarette smoking-related pathological phenotypes. To validate our findings invivo, we generated an adenovirus-induced TED mouse model with exposure to cigarette smoke. Results: Exposure to CSE resulted in an inflammatory phenotype of OFs together with higher levels of oxidative stress. OFs exposed to CSE presented susceptibility to transforming growth factor-β-induced myofibroblast differentiation, and 15-D-PGJ2-induced adipocyte differentiation, indicating pro-fibrotic and pro-adipogenic phenotypes. RNA-sequencing of CSE-treated OFs revealed upregulation of RAGE signaling molecules. TED patients with smoking history also exhibited higher levels of RAGE signaling, both in the orbit and peripheral blood, compared with non-smoking patients. Enhancement of inflammatory status was associated with activation of the ROS-nuclear factor-kappa B pathway downstream of RAGE. RAGE gene interference or administration of RAGE inhibitor effectively mitigated cigarette smoking-related pathological changes in OFs. Disrupting RAGE signaling in TED mice efficiently ameliorated smoking-induced disease progression invivo. Conclusions: Cigarette smoking-relevant TED progression was linked with RAGE signaling activation, leading to the exacerbation of orbital inflammation and tissue-remodeling, including fibrosis and adipogenesis. Our findings demonstrate that cigarette smoke exposure affects the biological characteristics of TED-derived OFs and supports RAGE as a promising therapeutic target for the management of patients with TED and smoking habits.

To identify the relationship between thyroid eye disease (TED) and supraorbital neuralgia (SON) and establish a reliable approach to the diagnosis and management of TED-associated SON. This retrospective study included 1,126 patients. Demographics, active and inactive phase status and duration, and reactivation rate were noted. TED clinical activity was determined using the vision, inflammation, strabismus, and appearance assessment system, and TED severity was classified using the European Group of Graves' Orbitopathy system. Subtypes of periorbital pain were identified, and suspected SON was confirmed by supraorbital nerve block. Of the study's 1,126 patients, 935 (83%) were deemed "active" at some point during the follow up and 34 (3%) remained "active" at the study's conclusion. Of the 2,251 eyes studied, 1,193 (53%) underwent orbital decompression. Of the 1,126 patients, 946 (84%) reported a retrobulbar "pressure" or "aching," but a distinct, more debilitating pain suggestive of SON was reported in 91 (8%). All 91 patients were given a supraorbital nerve block, and all had complete pain resolution lasting from hours to weeks. Eighty-eight (97%) of the 91 patients with SON-type pain underwent orbital decompression compared to 496 (48%) of the 1,035 without SON-type pain (p < 0.00001). A difference was found in the rate of TED reactivation between those with SON-type symptoms (8%) as compared to those without (2%), p = 0.01. SON of uncertain etiology appears to be a previously underreported but significant pain associated with TED. Paradoxically, although the SON does not appear to be related to the type or severity of TED on standard rating scales, the presence of SON was found to be associated with increased likelihood of both orbital decompression and TED reactivation.

PurposeThere is no universal consensus on second-line agents for the treatment of moderate/severe to sight-threatening thyroid eye disease (TED) to maintain remission after first-line intravenous methylprednisolone (IVMP). This study investigates the efficacy and safety of mycophenolate mofetil (MMF) in TED patients in a real-world setting and over a longer period than previous randomized controlled trials.MethodsA retrospective cohort study of TED patients with active moderate/severe to sight-threatening TED seen over a 4-year period. Data collected were visual acuity (VA), Clinical Activity Score (CAS), Gorman Diplopia scores, MMF dosing and side effects at 24, 52 and 78 weeks. Clinical efficacy was defined as an absence of relapse: no decline in best corrected LogMAR VA, no need for further steroids, no increase in CAS of ≥2.ResultsOut of 23 patients, 20 patients were included in this study. 10% (2/20) stopped MMF before 24 weeks. Median duration of MMF treatment was 76 weeks (1–140 weeks). 55% (11/20) had dysthyroid optic neuropathy (DON). In those with active moderate-severe TED without DON, clinical efficacy was seen in 100% (8/8) at 24 weeks, 87.5% (7/8) at 52 weeks, and 83.3% (5/6) at 78 weeks, with CAS decreasing from a baseline of 2.78±1.99 to 0.50±0.58 at 24 weeks, 0.50±0.82 at 52 weeks and 1.00±1.30 at 78 weeks. In DON, improvements were seen in 90% (9/10) at 24 weeks, 100% (7/7) at 52 weeks and 100% (4/4) at 78 weeks, with significantly reduced CAS scores from 2.55±1.54 to 0.83±1.27, 1.00±1.17 and 0.63±0.95 at 24, 52 and 78 weeks, respectively. Gorman score, VA and soft tissue inflammation parameters also improved throughout. There were two significant side effects over the treatment period.ConclusionMMF appears to be an effective and safe second-line immunosuppressive agent. Further studies aimed at elucidating optimal dosing regimens and ideal treatment duration will prove helpful.

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.

Retinal structure and microcirculation alterations in dysthyroid optic neuropathy: A comprehensive OCTA study.

ABSTRACTPurpose: To evaluate alterations in orbital color Doppler imaging (CDI) parameters and their correlation to disease activity and severity in patients with thyroid eye disease (TED).Methods: Seventy-six orbits of 45 TED patients and 40 orbits of 40 normal controls were enrolled in this cross-sectional study. According to clinical activity score (CAS), patients were categorized to active (CAS ≥ 3) or inactive disease (CAS < 3). Patients were also classified as having mild, moderate or severe disease. Peak systolic velocity (PSV), end diastolic velocity (EDV), and resistance index (RI) in ophthalmic artery and central retinal artery, and maximum and minimum velocity in superior ophthalmic vein and central retinal vein were determined in all subjects.Results: There was a significant difference in maximum velocity of superior ophthalmic vein and EDV and RI of ophthalmic artery between patients with TED and normal subjects. Superior ophthalmic vein maximum and minimum velocity and ophthalmic artery RI were significantly higher in patients with active disease than inactive cases. Disease severity did not affect the blood flow parameters independently. A cutoff point of 3.99 cm/s in superior ophthalmic vein maximum velocity yielded a sensitivity of 91.2% and specificity of 81.2% in detecting active disease.Conclusion: Retrobulbar blood flow is altered in TED and is related to disease activity. Superior ophthalmic vein maximum velocity could be helpful in differentiation of active and inactive cases.

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.

Orbital decompression is an established surgical treatment option for a range of orbital conditions. Traditionally, Ear, Nose and Throat surgeons have adopted the endoscopic route while ophthalmologists operate via an external approach. The authors report the outcomes of endonasal decompression performed by oculoplastic surgeons experienced in endonasal techniques. This was a retrospective case series of patients who underwent endoscopic orbital decompression for proptosis secondary to thyroid eye disease across 2 hospital sites between January 2011 and July 2018. Inclusion criteria were patients who had endoscopic decompression for proptosis in inactive thyroid eye disease or active disease without dysthyroid optic neuropathy. Information collected includes patient demographics, diagnosis, surgical details, preoperative and postoperative clinical findings (including, visual acuity, color vision, exophthalmometry readings, palpebral aperture, intraocular pressure, ocular motility, diplopia, and visual field), complications, and further treatment. There were 70 cases of endoscopic decompression. The majority of patients had endoscopic medial and posterior medial wall/floor decompression (44.3%; 31/70 cases). Visual acuity remained stable in 98.6% (69/70). There was an average reduction in proptosis of 3.5 ± 1.2 mm (standard deviation [SD]) in the endoscopic medial wall only group, 3.9 ± 0.9 mm (SD) in endoscopic medial wall and posterior medial portion of the floor group, and 7.6 ± 2.1 mm (SD) in the 3-wall decompression group. Motility improved in 11.4% (8/70) and worsened in 2.9% (2/70). There were no significant intraoperative or postoperative complications associated with endoscopic surgery. Oculoplastic surgeons experienced in endonasal techniques can perform endoscopic orbital decompression with outcomes comparable to the literature.The authors report the outcomes of a series of endonasal orbital decompression carried out by oculoplastic surgeons.

Purpose:To describe the clinical features of thyroid eye disease (TED) in patients presenting at a tertiary eye care centre in North India and to identify factors predictive of severe disease.Methods:This observational cross-sectional study involved clinical evaluation of all patients with TED who presented at the oculoplastic clinic based on the ITEDS VISA proforma. Risk factors for the severe disease were assessed using univariate and multivariate logistic regression.Results:A total of 106 patients (50 males, 56 females; mean age 41.30 ± 14.76 years) were identified during the study period, 46.23% hyperthyroid, 33.96% hypothyroid and 19.81% euthyroid. The proportion of the patients with hypothyroid was higher as compared with prior studies and most patients with hypothyroid had the mild disease (63.89%). Orbitopathy symptoms were the presenting feature leading to the diagnosis of systemic thyroid abnormality in 25% of the patients with hypothyroid and 59.18% of the patients with hyperthyroid, respectively (P < 0.05). Eyelid and orbitopathy signs were more common in the patients with hyperthyroid (51.2% and 87.7%) as compared with hypothyroid where the commonest presenting symptoms were related to dry eye (50.1%). Active disease was seen in 22.6% of the patients. Mild, moderate to severe and sight-threatening disease was seen in 54.7%, 37.7% and 7.5%, respectively. On multivariate analyses, hyperthyroid status and activity was associated with severe disease. Smoking was not associated with activity or severity.Conclusion:There is no significant difference in the gender profile of the patients with TED in this cohort. The patients with hypothyroid have a milder disease compared to the patients with hyperthyroid, and dry eye symptoms are the commonest presenting symptoms in hypothyroid subjects. Hyperthyroidism and activity were associated with severe and sight-threatening disease.

Diagnostic methods for dysthyroid optic neuropathy: A systematic review and analysis

To evaluate progressive changes in retinal nerve fibre layer (RNFL), ganglion cell layer/inner plexiform layer (GCL/IPL) and visual function in thyroid eye disease (TED) patients with and without orbital decompression. Sixty TED patients (105 eyes) were included. All patients were divided into mild, moderate-to-severe and dysthyroid optic neuropathy (DON) groups. Orbital decompression was performed in the moderate-to-severe and DON groups. Optic coherence tomography (OCT), visual field (VF) and best-corrected visual acuity (BCVA) were performed pre- and postoperatively. Preoperative follow-up was performed in the mild group and in part of the moderate-to-severe and DON groups. After decompression, the thickness of GCL/IPL and RNFL significantly decreased in DON group (p < 0.05), with varying degrees of decrease in eyes with optic disc swelling, atrophy and normal appearance. The mean GCL/IPL thickness significantly decreased in moderate-to-severe group (p < 0.05), the mean RNFL thickness slightly decreased with no statistical significance (p = 0.07). During the preoperative follow-ups, the mean GCL/IPL thickness significantly decreased (p = 0.04), whereas the mean RNFL thickness tended to increase (p = 0.13) in DON group. The thickness of GCL/IPL and RNFL did not change significantly in the mild and moderate-to-severe groups (p > 0.05). BCVA and VF did not change significantly in any group (p > 0.05) preoperatively. Swelling and degeneration of retinal ganglion cells (RGCs) may coexist in DON eyes, leading to continuous changes in the RNFL and GCL/IPL thickness either before or after decompression. Slight swelling and degeneration of RGCs may exist in moderate-to-severe TED eyes, although OCT measurements and visual functions remain stable before surgery.

Dysthyroid optic neuropathy (DON) leads to vision loss. This study aimed to investigate a new method that can directly evaluate the change in muscle cone inner volume (MCIV) and distinguish DON orbits from non-DONs. This study included 54 patients (108 orbits) who were diagnosed with thyroid eye disease and treated at the Beijing Tongren Hospital between December 2019 and September 2021. The extraocular muscle volume (EOMV), orbital fat volume (OFV), and bony orbit volume (BOV) of the patients were measured using three-dimensional reconstruction. MCIV was measured using artificially defined boundaries. The associations between these volumes and clinical indicators were studied, and the diagnostic efficacy of these volumes for DON was described using receiver operating characteristic (ROC) curves. The ROC curve showed that the area under the curve of MCIV/BOV (%) combined with EOMV/BOV (%) reached 0.862 (p < 0.001), with a sensitivity of 85.7% and a specificity of 76.1%. The combination of MCIV/BOV (%) and EOMV/BOV (%) is a good indicator for the diagnosis of DON, which aids in the early detection and intervention of DON.

Rituximab for Thyroid Eye Disease

Background: Intravenous glucocorticoids (IVGCs) are the first-line treatment for active moderate-to-severe thyroid eye disease (TED) in many countries worldwide, mainly because of their anti-inflammatory efficacy. Methods: Retrospective cohort study of 64 patients with active moderate-to-severe TED, without dysthyroid optic neuropathy, treated between 2003 and 2023 at a single tertiary centre with the 12 weeks IVGC EUGOGO (European Group on Graves Orbitopathy) protocol. All patients were evaluated for response to IVGC according to the clinical judgment (CL) and 44/64 (69%) patients were also evaluated with the EUGOGO 2021 revised composite index (CI). Results: The mean patients' age at IVGC initiation was 51.7 ± 11 years, 47/64 (73.5%) were women, 56/64 (87.5%) were Caucasians, and 33/64 (51.5%) were active smokers. At 6 months after IVGC, 48 out of 64 (75%) patients evaluated with CL and 32 out of 44 (73%) patients evaluated with EUGOGO CI responded to the treatment. Nonresponders tended to be older than responders (56.6 ± 10.2 vs. 50.1 ± 10.8 years, p = 0.040 for CL and 56.5 ± 11.9 vs. 50.3 ± 11.6 years, p = 0.131 for EUGOGO CI) and had higher clinical activity score (CAS) before IVGC (5.0 ± 1.1 vs.4.2 ± 1.1, p = 0.022 for CL and 4.7 ± 0.6 vs. 3.1 ± 0.8, p < 0.001 for EUGOGO CI). In patients evaluated with CL or EUGOGO CI, respectively, multivariable logistic regression identified age at IVGC initiation (odds ratio [OR] = 0.92 [95% confidence interval (CI) 0.86-0.99], p = 0.024 and OR = 0.88 [CI 0.77-0.99], p = 0.046) and CAS before IVGC (OR = 0.53 [CI 0.31-0.90], p = 0.021 and OR= 0.08 [CI 0.01-0.38], p = 0.001) but not active smoking as independent factors associated with response to IVGC. The optimal cut-off associated with poorer response to IVGC was CAS ≥4.5/7 (66.7% specificity, 56.3% sensitivity; Area Under the Curve [AUC] = 0.689 [CI 0.54-0.83], p = 0.010) in patients evaluated with CL and CAS ≥3.5/5 (65.6% specificity, 91.7% sensitivity; AUC = 0.910 [CI 0.80-1.01], p < 0.001) in patients evaluated with EUGOGO CI. Conclusion: Older age and higher CAS before treatment were associated with poorer response to IVGC. Patients with these characteristics could be offered other immunotherapies as a first-line treatment for active moderate-to-severe TED.