Clinical Activity Score Score Research Articles

Correlation between choroidal vascularity and retrobulbar ocular blood flow changes and thyroid-associated ophthalmopathy activity: a cross-sectional study

ObjectiveTo evaluate the alterations in retrobulbar color Doppler imaging (CDI) parameters and retinal/choroidal optical coherence tomography angiography (OCTA) parameters and their association with the clinical activity and severity in thyroid-associated orbitopathy (TAO) patients.MethodsIn this study, the retrobulbar flow parameters including resistance index (RI), Pulsatile Index(PI), peak systolic velocity (PSV) and end diastolic velocity (EDV) in posterior ciliary artery (PCA), central retinal artery (CRA) and ophthalmic artery (OA) were determined by CDI. Moreover, the retina and choroidal vascularity including the superficial vessel density (SVD), deep vessel density (DVD), choroidal thickness (ChT) and choroidal vascularity, including total choroidal area (TCA), luminal area (LA), stromal area (SA) and Choroidal Vascularity Index (CVI), were determined by OCTA. All patients grouped as active TAO and inactive TAO based on Clinical activity score (CAS). We picked the severe eye among the subjects and compared all parameters between two groups. We analyzed the correlations among those parameters.ResultsThere was a significant difference in CAS score, proptosis value, ChT, LA, CVI between patients with active TAO and inactive TAO. In the active group, PSV and EDV of PCA were significantly higher than the inactive group. On logistic regression analysis, CAS was closely associated with PSV-PCA. On multiple linear regression, proptosis value was closely associated with ChT, LA, SA and CVI.ConclusionChoroidal vascularization and retrobulbar blood flow were concurrently higher in active TAO patients and several variables in choroid circulation was closely related to TAO clinical features.

Selenium supplementation in inactive moderate to severe Graves’ orbitopathy patients: a randomized controlled trial

ABSTRACT Purpose This study was designed to evaluate the effect of selenium supplementation in inactive moderate-severe Graves’ orbitopathy (GO) patients. Methods This study was a single-center, placebo-controlled, double-masked, randomized trial. Inactive moderate-severe GO participants were randomized to receive six months of 200 micrograms/day of selenium supplementation or placebo. Thorough eye exams, clinical activity score (CAS), Graves’ Ophthalmopathy quality of life questionnaire (GO-QOL), and serum selenium level were evaluated at baseline and 6 months after the interventions. The chi-squared or Fisher’s exact test was used to compare categorical variables. The t-test and the paired t-test were used to compare continuous variables between two independent samples and two dependent samples, respectively. Results A total of 25 participants were enrolled, 13 in the selenium group and 12 in the placebo group. Both groups had adequate baseline serum selenium levels at 98.96 ± 15.63 mcg/L and 102.55 ± 17.71 mcg/L, respectively. After 6 months of intervention, the selenium group showed a greater improvement in palpebral aperture (mean difference: −1.4 ± 1.7 mm, p = .04) compared to the placebo group (−0.3 ± 2.7 mm). Notably, 5(41.67%) people in the placebo group developed larger palpebral apertures. Proptosis, ocular motility, and soft tissue signs did not change significantly. GO-QOL and CAS score improvement showed no statistically significant difference between both groups. Minor adverse effects were observed. Conclusions Selenium supplementation has a positive effect on eyelid aperture even in inactive moderate-to-severe GO patients with a sufficient baseline selenium level.

FRI572 Teprotumumab In Unexplored Presentation Of Thyroid Eye Disease

Abstract Disclosure: M.T. Torres Torres: None. A.N. Gonzalez Bossolo: None. M.M. Mangual Garcia: None. Thyroid eye disease (TED) is an autoimmune disease of the orbital soft tissue associated with facial disfigurement, diminished quality of life, and potentially vision-threatening consequences that can occur in 40% of patients with Graves’ disease (GD). All the therapies for this condition were off-label with questionable long-term effects until 2020 when the Federal Drug Administration approved teprotumumab, a human monoclonal antibody against insulin-like growth factor-1 receptor, for the treatment of TED. Randomized placebo-controlled trials have demonstrated that teprotumumab reduces proptosis, diplopia, and Clinical Activity Score (CAS) in patients with active TED of less than 1.3 years of duration who were treatment-naïve or previously treated with < 1g of methylprednisolone equivalent therapy. Data on the efficacy of teprotumumab on cases of longer TED duration or previously treated with eye surgery or > 1g of methylprednisolone equivalent therapy for TED is limited as these patients were excluded from the trials. A 76-year-old nonsmoker male with long-standing hyperthyroidism due to GD, glaucoma, and type 1 diabetes mellitus was referred by ophthalmologist due to TED. He received radioactive iodine (RAI) for treatment of GD after failure to Methimazole therapy. After RAI, he reported progressively worsening bilateral eye edema, redness, pain, vision loss, and diplopia requiring hospitalization for an emergent orbital decompressive surgery and intravenous steroid therapy due to sight-threatening Grave’s orbitopathy. He was discharged home with oral prednisone taper down until it was discontinued 6 months later with mild improvement of symptoms. Physical exam was remarkable for bilateral strabismus, orbital chemosis, conjunctival injection and redness, eyelid swelling, limited eye motion, severely impaired visual acuity and color vision, no proptosis, and a CAS of 5 suggesting active TED. Laboratories showed biochemical euthyroidism and controlled glycemia. Teprotumumab was started 2 years and 8 months after symptom onset with marked improvement of inflammatory signs and symptoms, eye motion, visual acuity, diplopia, intraocular pressure, and CAS score decrease to 1 point suggesting inactive disease within 4 weeks of therapy without adverse side effects. This case describes the positive effects of teprotumumab in a patient with characteristics not previously studied such as active TED of longer duration than in clinical trials, previous treatment with orbital surgery or > 1g of methylprednisolone equivalent therapy, and increased IOP. Rather than drawing conclusions, our goal is to create awareness and promote further research of teprotumumab and novel agents in patients with TED with previously uncharacterized presentations as it may have important implications for their management including significant improvement in their quality of life. Presentation: Friday, June 16, 2023

Inter-observer Variability of Clinical Activity Score: Assessments in Patients With Thyroid Eye Disease

Thyroid eye disease (TED) can be difficult to manage. The range of available treatments is expanding rapidly, however cost is a concern and some patients do not respond. The Clinical Activity Score (CAS) was devised as a measure of disease activity and a potential predictor of response to anti-inflammatory treatment. Despite its widespread use, inter-observer variability of CAS has not been investigated. The aim of the study was to determine the inter-observer variability of CAS in patients with TED. Prospective reliability analysis METHODS: Nine patients with a spectrum of clinical features of TED were assessed by 6 experienced observers on the same day. The agreement between the observers were analysed using Krippendorff alpha. The Krippendorff alpha for the total CAS score was 0.532 (95% confidence interval (CI) 0.199-0.665), while alpha values for the individual components of CAS varied between 0.171 (CI 0.000-0.334) for lid redness and 0.671 (CI 0.294-1.000) for spontaneous pain. Assuming that a CAS ≥3 implies suitability of the patient for anti-inflammatory treatment, the calculated Krippendorff's alpha for agreement between assessors on whether treatment should be given or not, was 0.332 (95% CI 0.0011-0.5862). This study has shown unreliable inter-observer variability in total CAS and most individual CAS components, thus highlighting the need for improving the performance of CAS, or seeking other methods to assess activity.

Therapeutic outcomes of mycophenolate mofetil and glucocorticoid in thyroid-associated ophthalmopathy patients.

To analyze the efficacy of mycophenolate mofetil (MMF) and glucocorticoid administration in patients with thyroid-associated ophthalmopathy (TAO). Sixty patients with moderate to severe TAO treated in Jingzhou Central Hospital from January 2022 to June 2022 were selected and enrtolled in this study. The subjects were divided into experimental group (n=30) and control group (n=30) based on the random number table method. Glucocorticoid pulse therapy was provided in the control group, while MMF was given in the experimental group on the basis of Control group. Clinical activity score (CAS), quality of life (QOL), visual acuity, eyelid fissure width, intraocular pressure, and degree of exophthalmos were observed at the time of admission and at the 12th week and 24th post-treatment weeks. We compared the immune function (TRAb, IL-6, and CD4+/CD8+) of the two groups pre-treatment and 24 weeks post-treatment, and evaluated the clinical therapeutic effect. The clinical effective rates at 12 and 24 weeks in the experimental group were higher (73.3% and 83.3%) than those in the control group (46.7% and 60.0%) (P <0.05). After 12 weeks of treatment, patients' CAS scores, and bilateral lid fissure width decreased and right eye visual acuity increased in the control group compared with those before treatment (P < 0.05); further, after 24 weeks of treatment, patients' QOL scores and bilateral visual acuity increased and CAS scores, bilateral lid fissure width and proptosis decreased compared with those before treatment, and patients' QOL scores, CAS scores and bilateral proptosis improved more than those at 12 weeks of treatment (P <0.05). Additionally, greater improvements were observed in the patients' QOL and CAS scores, and proptosis after 24-week treatment than after 12-week treatment (P<0.05). In the experimental group, the QOL score and binocular visual acuity increased, whereas the CAS score, intraocular pressure, lid width, and proptosis decreased after 12 weeks of treatment as compared to the values of these parameters in the pre-treatment period (P < 0.05); after 24 weeks of treatment, greater improvements were established in the ocular-related indexes improved compared to the pre-treatment period and after 12 weeks of treatment (P < 0.05). After 12 weeks of treatment, the patients in the experimental group had more considerable improvements in the right visual acuity, right intraocular pressure, and left lid fissure width than the control group (P < 0.05); at 24 weeks of treatment, patients in the experimental group had greater improvements in the QOL score, bilateral visual acuity, intraocular pressure, bilateral lid fissure width, and bilateral proptosis than the control group (P < 0.05). No significant differences were found in the values of TRAb, IL-6, and CD4+/CD8+ between the two groups before treatment (P>0.05); the values of TRAb, IL-6, and CD4+/CD8+ in the experimental group was significantly lower than those before treatment and in the control group after 24weeks of treatment. (P>0.05). No statistically significant difference was observed in the incidence of liver damage and menstrual disorders between the two groups during the 24 weeks of treatment (P>0.05). The combination of oral MMF and glucocorticoid shock therapy is an effective drug for the treatment of patients with moderately active TAO.

The Role of Thermal Camera in the Assessment of Thyroid Eye Disease Activity.

Thyroid eye disease (TED; also known as thyroid - associated orbitopathy, Graves ophthalmopathy) is an autoimmune inflammatory disease which presents in typical signs and symptoms such as deep orbital pain, chemosis with or without caruncular edema, unilateral or bilateral proptosis, eyelid retraction, eyelid edema or erythema, restrictive strabismus and compressive optic neuropathy. The aim of this study was to investigate the role of thermal camera in the assessment of thyroid eye disease (TED) activity compared to the Clinical Activity Score (CAS) scale, exophthalmometry values, and thyroid hormone and antibody levels. A total of 50 patients participated in this cross-sectional study of whom 29 were in the active phase of TED according to the sum on CAS scale and 21 patients in the inactive phase. The Flir E8® thermal camera was used to measure the temperature of the orbital area and the values were compared with the CAS scale, exophthalmometry values and thyroid hormone and antibody levels. Higher values of temperature (p>0.0001), CAS score (p>0.0001), exophthalmometry (p=0.022), FT4 (p=0.0176) and TRAb (p=0.0091) were found in patients in the active phase of TED. Temperature of orbital area showed statistically significant positive correlation with CAS scale (p=0.0001), exophthalmometry values (p=0.0022) and anti-TPO levels (p=0.019). Thermal camera showed higher values of the temperature of the orbital area in patients in the active phase of the disease and positively correlated with the CAS scale, exophthalmometry findings and anti-TPO levels.

Association of clinical course with thyroid-stimulating immunoglobulin in Graves' ophthalmopathy in Mongolians.

Graves' ophthalmopathy (GO) is a complex inflammatory condition affecting the orbit and is often associated with Graves' disease (GD). This study aims to determine the levels of thyroid-stimulating immunoglobulin (TSI) and thyroid-stimulating hormone receptor autoantibody (TSHR-ab) in the serum of patients with GO, compare it with the GD, and determine whether there is a correlation with the clinical course of GO. The cross-sectional study included 82 patients with GO, 81 patients with GD, and 75 healthy subjects. The ocular manifestations of GO were identified and evaluated by the clinical activity score (CAS) and severity of GO using the European Group of Graves' Orbitopathy (EUGOGO). TSI and TSHR-ab levels in the serum of participants were determined with ELISA kits and correlated with clinical findings. A total of 238 participant's data were analyzed. There were 14 patients (17%) with unilateral GO. The most common ocular signs were eyelid retraction 68 (82.3%) and proptosis 61 (74.4%). The mean CAS score was 2.65±1.64 in GO patients and was higher in men than women (P = 0.008). The mean of TSI was 37.95±35.41 in GO, 14.16±15.67 in GD, and 4.33±2.94 in healthy controls (P<0.0001). The TSI was significantly higher in patients with GO than in those with GD (P<0.0001). There were no correlations between TSI and TSHR-ab levels and CAS scores. However, we observed a correlation between the TSI level and the severity of GO (P = 0.023). The area under the ROC curve (AUC) of TSI was 0.933 and selected 14.1 IU/ml was the optimal cutoff value (98.78% of sensitivity, 83.97% of specificity). Our study showed that TSI is significantly related to GO and the severity of GO. Therefore, TSI can be used as a predictor of severe GO to help in prognostication, follow-up and treatment planning.

ODP509 Proof-of-concept, Multicenter, Open-Label Phase 2a Study of Batoclimab in Active and Moderate-to-Severe Thyroid Eye Disease

Abstract In thyroid eye disease (TED), immunoglobulin G (IgG) autoantibodies target thyrotropin receptors (TSHR) on the thyroid gland causing Graves’ disease. These TSHR-Ab also bind to the TSHR on orbital fibrocytes, inducing inflammation and hyaluronan production, resulting in extraocular muscle swelling and orbital fat expansion, causing the clinical manifestations of TED. Batoclimab (IMVT-1401) is a selective, fully human monoclonal antibody with high affinity for the IgG binding site on the neonatal Fc receptor (FcRn). Normally, the half-life of IgG is extended by FcRn-mediated recycling from lysosomal degradation. By competitively binding to the IgG binding site on FcRn, batoclimab blocks FcRn-mediated recycling of IgG, resulting in increased elimination and decreased levels of IgG. Batoclimab thus has the potential to provide clinical benefit for TED patients by reducing the level of pathogenic IgG anti-TSHR-Ab. In this open-label, multicenter, phase 2a study (NCT03922321), subjects with anti-TSHR-Ab positive, moderate-to-severe TED with a clinical activity score (CAS) ≥4 received weekly subcutaneous (SC) injections of batoclimab for six weeks (680 mg for two weeks followed by 340 mg for four weeks). Subjects were monitored for up to an additional 11 weeks. Safety and tolerability were assessed throughout the study. Pharmacodynamic changes in serum IgG and anti-TSHR-Ab were monitored weekly. Clinical efficacy was assessed weekly by response rate for proptosis (≥2 mm reduction in study eye without a deterioration in the other eye). The study eye was defined as the eye with greater proptosis at baseline. CAS response was defined as having a CAS score of 0 or 1. Seven subjects enrolled and completed this study (baseline mean [SD] age 56.7 [14.9] years, CAS 5.4 [1.1], proptosis 23.1 [3.3] mm). Serum IgG and anti-TSHR-Ab were reduced by a mean (SD) of 64.8% (17.7) and 56.7% (33.6), respectively at Week 6 compared to baseline. Similar reductions were also observed with each IgG subclass. Three of seven subjects were proptosis responders and four subjects were CAS responders. Three of seven subjects were joint responders for both proptosis and CAS. All adverse events (AEs) were mild to moderate in severity and no participant reported serious AEs or discontinuation due to AE. The most common AEs were increased lacrimation, fatigue, and dizziness (n=2 for each).There was a reversible reduction in serum albumin while on treatment which returned to normal levels in all subjects by the end of the study. In conclusion, batoclimab reduced serum IgG and especially the pathogenic anti-TSHR-Ab with an acceptable tolerability profile. Approximately half of study subjects demonstrated improvement in ophthalmologic assessments with six weeks of treatment. Together, these results support further evaluation of SC batoclimab as a therapeutic option for patients with TED. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Clinical Manifestations of Thyroid-associated Ophthalmopathy Accompanied by Thyroid Cancer

Purpose: To analyze the clinical manifestations of thyroid-associated ophthalmopathy accompanied by thyroid cancer.Methods: We performed a retrospective chart review of 33 patients diagnosed at our ophthalmology department with both thyroid- associated ophthalmopathy and thyroid cancer. We performed thyroid function tests at the first visit and at diagnosis of the thyroid cancer, and recorded the type of thyroid cancer, thyroidectomy history, clinical activity score (CAS), exophthalmometry, margin reflex distance (MRD) 1, diplopia, follow-up duration of ophthalmopathy, and ocular treatments. We divided patients into two groups according to the time of diagnosis of thyroid ophthalmopathy and thyroid cancer.Results: The average age of the 33 patients was 45.55 years, and eight and 25 were males and females, respectively. The average CAS score, exophthalmometry measurement, and MRD1 were 2.00 ± 1.67, 19.28 ± 3.24 mm, and 4.52 ± 1.58 mm, respectively. Patients whose ocular symptoms preceded the diagnosis of thyroid cancer tended to have a higher thyroid hormone level, CAS score, and exophthalmometry measurement, and required more ocular treatments, compared to the other patients. The average thyroid auto-antibody levels were increased in both groups. In patients whose ophthalmopathy preceded the thyroid cancer, exophthalmometry measurements were significantly decreased after thyroidectomy.Conclusions: It is crucial to identify ophthalmopathy in association with thyroid cancer. Patients whose ocular symptoms started before the diagnosis of thyroid cancer may present with hyperthyroidism and severe ocular symptoms, and may need ocular treatments. Patients should be informed that thyroid-associated ophthalmopathy may develop after thyroidectomy or radioiodine therapy, and their ocular symptoms should be closely monitored.

Optic nerve head optical coherence tomography angiography findings in patients with thyroid eye disease: a case–control study

BackgroundTo evaluate changes in the vessel density (VD) of the optic nerve head (ONH) microvasculature in thyroid eye disease (TED) using optical coherence tomography angiography (OCTA). This study aimed to applicate the OCTA as a noninvasive modality in screening TED patients to assess sub-clinical changes.MethodsIn a cross-sectional study, the control group patients were healthy individuals with no ocular abnormalities and were euthyroid. All patients with TED had clinical features of the disease. We divided them into two groups using the clinical activity score (CAS). Patients with CAS scores 0–2 were categorized as group A, and scores three or more as group B. All vessels (AV) and small vessels (SV) VD inside disc and radial peripapillary capillary network were measured using the ONH-OCTA.ResultsWe evaluated 29 patients with TED and 28 healthy controls. The mean whole image AV VD (mean ± SD: 56.33 ± 2.56, p-value = 0.17) and the mean whole image SV VD (mean ± SD: 49.94 ± 2.56, p-value = 0.16) in the TED group had no statically significant difference compared with the control group (AV mean ± SD: 57.20 ± 20.22, SV mean ± SD: 50.84 ± 2.23). We found a non-significant decrease in AV and SV radial peripapillary capillary VD in the TED group. There was a significant decrease in the mean whole image AV VD (mean ± SD: 54.83 ± 3.07, p-value = 0.005) and the mean whole image SV VD (mean ± SD: 48.60 ± 3.18, p-value = 0.013) in CAS group B compared to group A (AV mean ± SD: 57.45 ± 1.33, SV mean ± SD: 50.95 ± 1.37).ConclusionOur study showed non-significant ONH vascular alterations in patients with TED, including reduced VD of ONH in the radial peripapillary capillary. Patients with higher CAS scores had a more noticeable decrease in ONH microvasculature.

Role of orbital magnetic resonance imaging in early detection of graves’ orbitopathy and disease activity

We aim to evaluate feasibility of using orbital diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) of extraocular muscles (EOMs) in patients with Graves’ orbitopathy (GO) versus clinical activity score (CAS) in early detection of GO activity. This case control study was conducted on 20 consecutive patients (10 males, 10 females with a mean age of 35.50±13.65 years) with Graves’ orbitopathy and 10 age- and sex-matched volunteers without any thyroid abnormality as a health control (HC). The patients and HCs underwent DTI MRI of the orbit in the coronal plane. The mean diffusivity (MD) was calculated. Thyroid stimulating hormone receptor antibody (TRAb) was measured using third generation thyroid binding inhibiting immunoglobulin (TBII) with ELISA method. CAS score, according to the standardized criteria of the European Group on Graves Orbitopathy (EUGOGO), was calculated for the patients. GO patients’ EOMs showed significantly higher MD values and higher compared to HCs’ (P &lt; 0.001). Median CAS score was 4. A statistically significant positive correlation was only detected between CAS score and inferior rectus (IR) MD (r=.360, p=.023).

Evaluation of macular blood flow after intermittent intravenous infusion of high-dose corticosteroids (pulse therapy) in patients with thyroid-associated orbitopathy (TAO) using angio-OCT

PurposeThe aim of this study is to evaluate the changes in macular blood flow index (BFI) in patients with moderate to severe thyroid-associated orbitopathy (TAO) before and after pulse therapy and their relationship with clinical features and disease activity using angio-OCT technology.MethodsWe analyzed twenty-four eyes. Every patient underwent a complete eye examination and angio-OCT analysis (OCT Topcon ImageNet 6; DRI OCT Triton, Topcon Corporation) before (T0) and two months (T2) after pulse therapy. We analyzed macular vascular blood flow in four angiographic levels: superficial plexus (SP), deep plexus (DP), external retina (ER), and choriocapillaris (CC). We used the clinical activity score (CAS) score to define TAO as moderate or severe.ResultsMacular BFI significantly increased at T2 in the DP, ER, and CC (p < 0.01). CAS score (5.8 ± 0.8 vs. 3.9 ± 0.9, p < 0.01) and Hertel exophthalmometry values (22.6 ± 2.3 mm vs. 21.2 ± 2,5 mm, p < 0.01) improved for all patients at T2 compared T0. Mean IOP increased from 13.3 ± 2.8 mmHg to 14.3 ± 2.1 mmHg (p < 0.01). No correlation was found between CAS score and macular BFI in all the analyzed levels.ConclusionsPulse therapy treatment can change macular BFI. In particular, two months alter pulse therapy, all the patients show an increase in macular vascular blood flow in each angiographic level. According to our results, angio-OCT analysis of the macular BFI may be a useful tool in the follow-up of TAO patients after pulse therapy.

Ocular Surface Changes in Patients with Thyroid Eye Disease: An Observational Clinical Study.

BackgroundThis study aimed to compare ocular surface parameter changes in active and inactive thyroid eye disease (TED) patients and controls.MethodsThis is an observational clinical study that included 60 eyes divided into three groups following clinical activity score (CAS) assessment. The first group (Group A) comprised 20 eyes with active TED (CAS score ≥3/7), while the second group (Group B) comprised 20 eyes with inactive TED (CAS score <3/7) and the third group (Group C) comprised 20 eyes of controls without dry eye manifestations. The palpebral fissure height, degree of proptosis, degree of lagophthalmos, ocular surface disease index (OSDI), Schirmer test without anesthesia, corneal fluorescein staining (CFS), non-invasive tear break-up time (NITBUT), tear meniscus height (TMH), lipid layer thickness (LLT), meiboscore, meibomian gland dysfunction (MGD), and thyroid antibodies were assessed and data were compared between study participants.ResultsThe mean OSDI was 40.0 ±5.80 in Group A, which significantly differed from Group B with a mean of 26.5 ±5.10 (p=0.02). There were significant differences between the two groups regarding palpebral fissure height (p=0.02), amount of proptosis (p=0.008), and degree of lagophthalmos (p=0.001). Similarly, active TED patients had more decreased tear secretion than inactive TED patients (p=0.012). Moreover, active TED patients showed a significant increase in Meibomian gland loss areas in both upper and lower eyelids compared with inactive TED patients (p=0.001). Corneal fluorescein staining also revealed a statistically significant difference between the studied groups (p=0.0001).ConclusionThis study showed differences regarding ocular surface parameter changes between both active and inactive TED and compared to controls. Further studies are needed to confirm these results.

Real-World Efficacy and Safety of Mycophenolate Mofetil in Active Moderate-to-Sight-Threatening Thyroid Eye Disease.

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.

Effect of systemic steroid therapy in Graves' orbitopathy on regulatory T cells and Th17/Treg ratio.

Glucocorticoids are a mainstay treatment for Graves' orbitopathy, yet their exact mechanisms of action remain unclear. We aimed to determine whether the therapeutic effects of systemic steroid therapy in Graves' orbitopathy are mediated by changes in regulatory T lymphocytes (Tregs) and T helper 17 lymphocytes (Th17). We assessed Treg and Th17 levels in the peripheral blood of 32 patients with active, moderate-to-severe Graves' orbitopathy who received 12 weekly pulses of methylprednisolone, and determined their association with disease severity, disease activity, and treatment outcomes. The acute orbitopathy phase was confirmed based on clinical evaluation and magnetic resonance imaging, and assessed using the clinical activity score (CAS). The severity of the disease was classified according to ETA/EUGOGO guidelines, and quantified based on the total eye score. Treatment response was determined based on specific criteria (e.g., changes in CAS score, diplopia grade, visual acuity, etc.). Treg and Th17 cells were identified using flow cytometry. Methylprednisolone treatment improved the activity of the disease and altered the Th17/Treg balance (i.e., the percentage of Tregs decreased while the number of Th17 cells remained unchanged). There was no association between the Treg/Th17 ratio and the activity and severity of the disease or the treatment response. Therapeutic effects of steroid therapy in Graves' orbitopathy are not mediated by Treg and Th17 alterations in the peripheral blood. The decrease in peripheral Treg percentage is likely a consequence of the non-specific effects of steroids and does not impact clinical outcome.

Teprotumumab in Clinical Practice: Recommendations and Considerations From the OPTIC Trial Investigators.

Background:Thyroid eye disease (TED) is a vision-threatening and debilitating condition that until very recently had no Food and Drug Administration (FDA)-approved medical therapies. Teprotumumab has recently been approved to treat TED. We aim to provide guidance for its use, based on the input of the US investigators who participated in Phase 2 and Phase 3 clinical trials.Methods:An expert panel was convened on October 11th and November 16th of 2019. All panel members had extensive experience as investigators in the Phase 2 and/or Phase 3 clinical trials of teprotumumab. Consensus among those investigators was reached to determine patient characteristics most appropriate for teprotumumab treatment. Safety guidelines were also reviewed and agreed on.Results:The authors recommend that teprotumumab be considered first-line therapy for patients with clinically significant ophthalmopathy, including those with disease duration exceeding 9 months. The clinical activity score (CAS) may be useful for longitudinal monitoring but should not be used to determine treatment eligibility. Criteria will likely be expanded after more experience with the drug. Using teprotumumab for patients with TED with substantial signs, symptoms, or morbidity without a CAS score of >4 (e.g., progressive proptosis, diplopia, and early compressive optic neuropathy) or more, could be considered. Diabetes mellitus and inflammatory bowel disease comorbidities should not be exclusionary, but stringent monitoring in these patients is recommended. Drug dosing, administration interval, and duration should adhere to the study protocol: 8 infusions, separated by 3 weeks. Patients with more severe disease may benefit from additional doses. Corticosteroids can be used before or during teprotumumab therapy. Clinical and laboratory monitoring should be consistent with good clinical practice for patients receiving teprotumumab.Conclusions:Confirming the efficacy of teprotumumab usage outside the narrow parameters of the completed clinical trials will require rigorous scientific validation. As a step in that direction, we believe its on-label usage is appropriately applied to all patients with TED with substantial symptoms or morbidity, as judged by their physician.

Clinical outcomes of hypofractionated radiotherapy for thyroid-associated ophthalmopathy.

Objective:To evaluate the safety and effectiveness of hypofractionated orbital radiotherapy applied in the treatment of thyroid-associated ophthalmopathy (TAO) patients.Methods:Between 2014 and 2018, we retrospectively reviewed the cases of 28 patients with TAO. All patients underwent radiotherapy on both retroocular tissues and received an oral steroid. Patients were divided into two treatment groups: 14 patients received conventional fractionated radiotherapy (20 Gy in 10 fractions), and the second group of 14 patients received hypofractionated radiotherapy (20 Gy in five fractions). The clinical activity score (CAS), NOSPECS (No physical signs or symptoms, Only signs, Soft tissue involvement, Proptosis, Extraocular muscle signs, Corneal involvement, and Sight loss) classification, Hess screen test and binocular single vision (BSV) were evaluated to determine the response to treatment before and at 1 month after radiotherapy.Results:There were no significant differences in any of the variables between the two treatment groups. In both groups, the CAS and NOSPECS score decreased significantly, and the range of extraocular muscle motility in Hess screen test and BSV improved significantly after radiotherapy (p < 0.05). There were no significant differences in CAS, NOSPECS score, Hess screen test or BSV between the two groups. No radiation-related, acute severe toxicity was observed.Conclusion:Hypofractionated radiotherapy for TAO produced a comparable clinical outcome to that of conventional fractionated radiotherapy. Further case accumulation and long-term follow-up are required to determine if late toxicity occurs and to confirm efficacy.Advances in knowledge:This is the first study to show that the efficacy and risk of adverse events are comparable between hypofractionated radiotherapy and conventional radiotherapy in the treatment of TAO.

Natural history of inflammatory and non-inflammatory dry eye in thyroid eye disease

ABSTRACT Purpose The purpose is to understand the natural history and physical findings in thyroid eye disease (TED) patients with severe dry eye symptoms (DES). Methods Prospective cohort study, studying DES in TED patients over two years. Baseline data included clinical activity score (CAS), time since disease onset, punctate epithelial erosions (PEE), lagophthalmos, superior limbic keratoconjunctivitis (SLK), and marginal reflex distance 1 (MRD1). Ocular Surface Disease Index (OSDI) was utilized to measure symptomatology and scores > 33 (severe) were the primary outcome measure. Multivariate logistic regression was performed on two groups (<9 months, >9 months) to assess if variables change in early versus late disease. Results 88 met the inclusion criteria. 80.7% (n = 71) were female. There were 42 patients in the group with onset of symptoms under nine months and 46 patients over nine months. Mean CAS score was greater under nine months (2.45) than over nine months (1.29) (p < .05). In the multivariate logistic regression for the group presenting with symptoms under nine months, CAS was the only significant predictor of severe OSDI. Every increase in CAS of one yielded a 2.0x increased risk of severe OSDI. For the patients over nine months from onset, PEE was the significant predictor of severe OSDI. PEE was associated with a 5.9x increased risk of severe OSDI. Conclusions Severe DES correlate with inflammatory features within the first nine months. Afterward, presence of PEE became more important. DES in TED tends to be a manifestation of orbital inflammation early in disease and exposure later.

SUN-LB87 De-Novo Graves Ophthalmopathy After Total Thyroidectomy With Exacerbation Following Rifampicin Therapy for Latent Tuberculosis: A Call for Attention to Disease Modifying Interventions

Introduction Factors influencing development and course of ophthalmopathy, the most common extrathyroidal manifestation of Graves’ disease, remain poorly defined. Clinical Case A 46 year old healthy, non-smoking, medical secretary, presented with Graves’ disease. Laboratory investigation showed thyrotoxicosis with high thyroid stimulation immunoglobulin (TSI) levels (1608 %, normal <140%). At presentation there was no evidence of thyroid eye disease on clinical exam and orbital MRI. Treatment with Methimazol and PTU induced severe pruritus and she underwent total thyroidectomy. One month after surgery she presented with retroorbital pain, eyelid edema and chemosis, as well as bilateral limitation in abduction; a clinical activity score (CAS) of 3/7. She received IV pulse methylprednisolone 4.5 gr with minor improvement. MRI showed bilateral thickening of all rectus muscles with orbital fat infiltration. TSI increased concomitantly to 3600%. Three months later, she underwent standard retrobulbar radiotherapy (20 Gy), again with only minor improvement. She continued treatment with oral prednisone 20mg with small fluctuations in disease activity in the following months during which TSI remained high (3145%) and latent tuberculosis was detected (elevated interferon-gamma release assay). Therefore, rifampicin 600mg/d was started. A month later the ophthalmopathy worsened (a CAS score of 5/7 without optic neuropathy). Laboratory tests showed new perturbation in thyroid function tests (TSH increased from 5 to 15 mIU/l, normal: 0.5-5; FT4 decreased from 16 to 11 pmol/l, normal: 10-20) and TSI increased to 3879%. Euthyrox dose was increased by 50% from 800 to 1200 microgram/week. It was postulated that prednisone was also being rapidly metabolized by rifampicin mediated induction of the CYP450, and therefore the dose was increased from 20 to 40 mg/d. Six weeks later, normalization of thyroid function tests was followed by improvement in the ophthalmopathy (CAS-3). Conclusion (Clinical lesson) A) De-novo severe Graves’ ophthalmopathy after thyroidectomy requiring multiple forms of treatment is rare but close surveillance is advisable, perhaps particularly in the presence of high TSI. A plausible mechanism may be transient increase in antigenic exposure/dissemination during surgery. B) Rifampicin, through induction of cytochrome P450-mediated metabolism of levothyroxine, steroids and mycophenolate (the latter not used in our patient) can lead to disease flare-up. Tight clinical and laboratory monitoring of thyroid function tests with individualized dose escalation might be needed. In the future, pharmacogenomics may serve to personalize treatment protocols.

Optical Coherence TomographyStudy of peripapillary Nerve Fiber layer ThicknessinThyroid Associated Ophthalmopathy

Abstract Background Thyroid Associated Ophthalmopathy (TAO) or Graves Opthalmopathy (GO) is a very common autoimmune disorder of the thyroid gland which activates the gland function and result in hyperthyroidism. Some patients with graves disease(GD) develop localized manifestations including GO and dermopathy. Dysthyroid optic neuropathy (DON) is impairment of optic nerve function due to GO, the most serious complication of GO which occurs in about 4–8% of patients, it occurs due to ischemia and inflammation of the optic nerve, also compression of the optic nerve due to enlargement of extraocular muscles at the apex of orbit. Objective To assess peripapillary retinal nerve fiber layer (pRNFL) thickness in GD and to correlate it with the severity of the disease. Patients and Methods This study was conducted on 40 eyes of 21 recently diagnosed GO patients (two patients were single eyed) recruited from Endocrinology clinic and examined at Ophthalmology clinic, Ain Shams University Hospital in the period from March 2018 to September 2018. Complete ophthalmologic examination, proptosis assessment of direction and degree, Visual Field (VF) examination, clinical activity score (CAS), severity score assessment and Optical Coherence Tomography (OCT) were performed to all patients . Results In the whole group of patients; the mean average pRNFL was 109.53 um ± 12.33 SD (range: 86 – 140), median MD was -4.53 (range:-0.66 to-18.95) and -8.04 ± -2.15 SD, mean PSD was 5.55 ± 3.8 SD (range: 1.11 to 12.73). Normal average pRNFL thickness (according to normative data base included in the OCT program) was found in 15 eyes (37.5%) and those had abnormal increase in thickness was 12 eyes (30%). Abnormal decrease in thickness was detected in 13 eyes (32.5%). Conclusion PRNFL thickness abnormalities were detected in 25 eyes (62%) of recently diagnosed GO patients. This might be associated with localized visual field defects. Regular follow up of intra ocular pressure (IOP), serial VF examinations, are required to decide further management of those patients, as OCT results were correlated with degree of eye protrusion and the severity of the disease (CAS and severity score).