Epigenetics effect on pathogenesis of thyroid-associated ophthalmopathy

Thyroid-associated ophthalmopathy (TAO) is an autoimmune disease. Recent studies have found the aberrant epigenetics in TAO, including DNA methylation, non-coding RNAs, and histone modification. Many genes have an aberrant level of methylation in TAO. For example, higher levels are found in CD14, MBP, ANGLE1, LYAR and lower levels in DRD4 and BOLL. Non-coding RNAs are involved in the immune response (miR-146a, miR-155, miR-96, miR-183), fibrosis regulation (miR-146a, miR-21, miR-29), adipogenesis (miR-27) and are thought to play roles in TAO. MicroRNA is also related to the clinical activity score (miR-Let7d-5p) and may be a predictor of glucocorticoid therapy (miR-224-5p). The quantities of H4 in TAO are increased compared with euthyroid control subjects, and the role of histone modifications in Graves’ disease may lead to better understanding of its role in TAO. More studies are needed to explain the role of epigenetics in TAO and provide potential therapeutic strategies.

Proportion and Clinical Profile of Thyroid Ophthalmopathy in Patients with Graves’ Disease Presenting at a Tertiary Care Centre in Kerala

BACKGROUND Thyroid eye disease is a relatively rare condition, with an incidence of 2.9 to 16.0 cases per 100 000 population per year. Approximately 50 % of patients with Graves’ disease (GD) develop clinically apparent thyroid eye disease. It may cause severe damage to vision and orbital architecture. It is the most frequent cause of unilateral or bilateral proptosis in adults. METHODS A cross sectional study of 80 patients with GD was carried out in association with thyroid clinic of Government Medical college Thiruvananthapuram for a period of 1 year from April 2017 to March 2018. Subjects who have a prior diagnosis of Graves’ disease including those who are on antithyroid drugs were included in the study. Patients who are sick due to other systemic diseases like cardiac failure and end stage renal disease were excluded. RESULTS Eighty patients with mean age of 45.31 years were studied. Out of them, 66% were females and 34% were males. Ophthalmopathy was present in 38.8%.Majority had mild and bilateral disease (61.2 %). Only a small percentage had sight threatening disease (6.4 %).The mean age of patients with ophthalmopathy was 47.93. Major population with ophthalmopathy was females. Majority of patients with ophthalmopathy (64.5 %) retained a good visual acuity better than 6 / 9. Lid retraction was the most common manifestation among patients with Graves’ ophthalmopathy that is 74.2% followed by exophthalmos (64.5 %) and eye movement restriction and soft tissue involvement (58.1 %). Diplopia, optic nerve dysfunction were rare (3.2 %). Only 19.3 % patients had active disease according to clinical activity score. Major clinical sign of activity was redness of conjunctiva. Maximum no. of patients with active disease had a clinical activity score of 4. Smoking showed a significant association with the severity of ophthalmopathy. (p value 0.001) There was a significant association between age and activity of disease. (p value 0.021). No association was found between duration of disease with presence or severity of ophthalmopathy. There was no association between co- morbidities with presence or severity of ophthalmopathy. No association was found between hormone status and presence or severity of ophthalmopathy. CONCLUSIONS Our results indicated that the prevalence of ophthalmopathy in our population with GD evaluated at our tertiary care centre was similar to that reported in the Caucasians of European origin. Clinically active and sight threatening ophthalmopathy was uncommon. KEYWORDS Graves’ Disease, Ophthalmopathy

POS0259 ULTRASOUND AS AN IMAGING BIOMARKER OF EARLY RESPONSE TO TOCILIZUMAB AND METHOTREXATE IN VERY EARLY RHEUMATOID ARTHRITIS, TOVERA – A LONGITUDINAL STUDY

Background:The combination of methotrexate (MTX) and tocilizumab (TCZ) has been proven to be superior to MTX alone in early rheumatoid arthritis (RA)1 and was able to prevent radiographic progression. Ultrasound (US) has become a valid imaging modality in managing RA. Together with clinical examination, US may allow a comprehensive monitoring of response to therapy. So far, few data are available concerning the early response to TCZ plus MTX in very early RA (VERA).Objectives:In this study we aimed to assess the early US response to TCZ plus MTX in VERA, DMARD-naïve patients.Methods:In this open-label, single-arm study, VERA patients received TCZ (162 mg/week, subcutaneously) and MTX (15-20 mg/week, per os) for 24 weeks as induction therapy, followed by MTX as maintenance therapy. RA was diagnosed according to the 2010 ACR/European league against rheumatism (EULAR) criteria. All patients who fulfilled the inclusion criteria (ClinicalTrials.gov: NCT02837146) underwent blood tests, clinical and ultrasound examinations at the predefined time-points: 0,2,4,8,12,24,32,48,54 weeks (w). Ultrasound examination of 34 joints (elbows, wrists, MCP [1-5, bilateral], PIP ([2-5, bilateral], knees, ankles and MTP [2-5, bilateral]) was performed blindly to clinical data. Gray-scale (GS), power-Doppler (PD) scores, and the global OMERACT-EULAR synovitis score (GLOESS) were assessed in each joint. The sum of individual scores was calculated for 17-joint score (JS) (whole joint set), 10-JS (wrists, MCP, ankles and MTP joints), 12-JS2, and 7-JS3.Results:Forty-four patients (77% women), aged 46.7 ± 12.4 years, completed the 24-week period. Two-thirds (72.7%) were positive for anti-citrullinated protein antibody (ACPA) and 18.2% had bone erosions. At baseline, the mean 28 swollen joints count (28-SJC) was 7.55± 4.5, mean disease activity score (DAS28)-CRP score was 5.2 ± 0.15, mean simplified clinical activity score (SDAI) was 31.4 ± 1.9, mean clinical activity score (CDAI) was 29.1 ± 1.8 and mean health assessments questionnaire (HAQ) score was 1.3 ± 0.1. The C-reactive protein (CRP) decreased significantly at 2w (p<0.05) and, accordingly DAS28-CRP score decreased significantly at 4w (p<0.05). The 28-SJC and CDAI scores decreased significantly at 8w (p<0.05). The HAQ and visual analogue scale (VAS) disease activity reported by patients decreased significantly at 8w (p<0.05) and VAS fatigue at 12w (p<0.05).The GLOESS and GS scores allowed us detecting the earliest significant treatment response at 2w and PD scores at 4w (p<0.05). Among US joint subsets, 17-JS (p<0.01), 12-JS (p<0.05) and 10-JS (p<0.05) were able to detect the earliest treatment response at 2w. The 7-joint score detected the earliest response at 4w, both in GS and PD (p<0.05).Conclusion:US scores were able to detect therapeutic response to TCZ plus MTX earlier than clinical scores and may therefore be a promising imaging biomarker.References:[1]Burmester GR et al. Ann Rheum Dis 2017; 76; 1279-1284.[2]Naredo E et al. Arthritis Rheum 2008; 59(4): 515-522.[3]Backhaus M et al. Arthritis Rheum 2009; 61: 1194-1201.Disclosure of Interests:Maria Stoenoiu Grant/research support from: UCB, Roche, Abbvie, MSD, Sanofi, Celgene, Mihaela Maruseac: None declared, Mouna Messaoudi: None declared, Adrien Nzeusseu Toukap Grant/research support from: AbbVie, Eli Lilly, Janssen, UCB, Novartis, Celgene Corporation, Pfizer, Esperanza Naredo Grant/research support from: AbbVie, Roche, BMS, Pfizer, UCB, Eli Lilly, Novartis, Janssen, Celgene

Choroidal vascularity index in thyroid-associated ophthalmopathy: a cross-sectional study

Background Hemodynamic changes have been observed in patients with Graves’ disease. The aim of our study was to evaluate choroidal vascular change using the choroidal vascularity index (CVI) in patients with thyroid-associated ophthalmopathy (TAO). Methods In this cross-sectional observational study, 40 patients affected by TAO were recruited. Forty healthy individuals, matched for age and sex, served as controls. Foveal enhanced-depth imaging optical coherence tomography scans were obtained from all participants. Images were binarized using the ImageJ software and luminal area (LA) and total choroidal area (TCA) were measured. CVI was calculated as the proportion of LA to TCA. The relation between CVI or subfoveal choroidal thickness (SFCT) and clinical activity score, exophthalmometric value, diplopia status, gender, and age was evaluated. Results CVI was significantly higher in patients with TAO (P = 0.004). No significant difference was observed in SFCT (P = 0.200) and TCA (P = 0.153) comparing TAO patients and healthy controls. LA was significantly higher in TAO group (P = 0.045). On multiple regression analysis, CVI was associated with TCA (P = 0.043). No association was found between SFCT or CVI and TCA, clinical activity score, exophthalmometric value, Inami value, diplopia status, gender or age (P > 0.05). Conclusions This is the first study that has demonstrated an increase in CVI in eyes with TAO compared with healthy controls and has assessed its association with clinical features.

Association of Other Autoimmune Diseases With Thyroid Eye Disease

BackgroundThyroid eye disease (TED) is a potentially disfiguring and sight-threatening autoimmune (AI) orbitopathy, affecting up to 400,000 people in the UK. There are no accurate early predictors of TED severity. Although polyautoimmunity has been shown to affect AI disease severity, its influence on TED severity has never been investigated. The prevalence of polyautoimmunity among TED patients is also unclear, with discordant results reported in the literature. This study evaluates the prevalence of non-thyroid/“other” AI (OAI) conditions in an ethnically diverse TED cohort and assesses how polyautoimmunity affects TED severity and activity.MethodsA retrospective study of patients presenting to multidisciplinary TED clinics across three North-West London hospitals between 2011 and 2019. Data collected included: 1) demographics; 2) OAI conditions and management; 3) endocrine management of thyroid dysfunction; 4) details of TED and clinical activity score at presentation.ResultsTwo hundred and sixty-seven patients with a median age of 46 (35–54) years were included, 79.4% were female and 55% were Black, Asian and minority ethnic (BAME). Thirty-seven patients (13.9%) had OAI conditions, with rheumatoid arthritis (3.7%), vitiligo (3.0%) and psoriasis (3.0%) among the most prevalent. Of patients with OAI conditions, 43.2% (16/37) required immunosuppression prior to TED onset. Non-immunosuppressed patients with OAI conditions had a significantly higher clinical activity score at presentation than TED-only and previously immunosuppressed patients (p=0.02). No significant differences were observed in thyroid receptor antibody titers between these groups.ConclusionsThis study finds a 13.9% prevalence of OAI conditions among TED patients. Patients with OAI conditions overall have a tendency for more severe and significantly more clinically active TED than those without OAI conditions. Larger, prospective studies are warranted to further evaluate polyautoimmunity as an early predictor of TED severity.

A Clinical Activity Score That Discriminates Between Inflammatory and Noninflammatory Graves’ Ophthalmopathy

In this chapter the results of a retrospective analysis of pooled data from a randomized, double blind, clinical trial comparing oral prednisone to radiotherapy in patients with both inflammatory and noninflammatory Graves’ disease are described. The aim of the analysis was to determine whether a previously developed index (the Clinical Activity Score, CAS) could discriminate between inflammatory and noninflammatory Graves’ ophthalmopathy. The analysis showed that the CAS had a high predictive value for the outcome of immunosuppressive treatment in Graves’ ophthalmopathy. A high CAS helped to select patients who benefited from immunosuppressive treatment; a low CAS, however, did not exclude favorable therapeutic results. Disease activity (measured by the CAS), and not disease duration, is the prime determinant of therapeutic outcome in Graves’ ophthalmopathy.

ALTERED RETINAL PERFUSION IN PATIENTS WITH INACTIVE GRAVES OPHTHALMOPATHY USING OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY

Objective: The aim of this study was to evaluate retinal and optic nerve head (ONH) perfusion in patients with inactive Graves ophthalmopathy (GO) and compare it to healthy controls using optical coherence tomography angiography (OCTA). Methods: Twenty-nine eyes of 29 patients with inactive GO (study group) and 29 eyes of 29 healthy subjects (control group) were included in this study. The vessel density (VD) data in the superficial and deep retinal OCT angiogram of the macula and the radial peripapillary capillary network (RPC) were extracted and analyzed. OCTA was performed using RTVue XR Avanti with AngioVue (Optovue Inc, Fremont, CA). Clinical activity was evaluated using the clinical activity score, the severity assessment using the NOSPECS classification. Results: The VD in the superficial OCT angiogram and in the OCT angiogram of the ONH was significantly lower in the GO group when compared to the control group (whole en face, P = .016; parafovea, P = .026; RPC peripapillary, P = .027). There was no significant correlation between VD and functional parameters or the NOSPECS classification. Conclusion: Macular VD and ONH capillary density measured using OCTA were significantly lower in the study group compared to healthy controls. Noninvasive quantitative analysis of retinal perfusion using OCTA could be useful in monitoring patients with GO. Abbreviations: CAS = clinical activity score; GO = Graves ophthalmopathy; OCTA = optical coherence tomography angiography; ONH = optic nerve head; RPC = radial peripapillary capillary; rSp = Spearman's correlation coefficient; VD = vessel density

Correlation of the Electrophysiological and Optical Coherence Tomography Changes in patients with Thyroid-Associated Ophthalmopathy

Purpose: to study the structural and functional changes of the optic nerve & macula in patients with thyroid-associated ophthalmopathy (TAO) patients. Methods: Cross-sectional clinical study including 40 cases with TAO and 40 age and sex-matched healthy participants as a control. Complete ophthalmological assessment, evaluation of the proptosis, spectral domain OCT, and electrophysiological investigations (pattern electroretinogram [PERG], multifocal ERG (mfERG) & visual evoked potentials (PVEP) were performed to all participants. Results: Retinal nerve fibre (RNFL), central foveal (CFT) thickness and mean inner macular ring thickness are thinner in cases with proptosis. MfERG showed lower Retinal Response Density1 (RRD1), Ring 1 P1 amplitude and lower five-rings N1 amplitude. Central foveal thickness showed significant positive correlation with VA, BCVA, P50 amplitude and R1 N1 amplitude (r = 0.64, 0.65, 0.40 and 0.51 with p < 0 .001, < 0 .001, < 0 .001 and < 0 .001 respectively), and negative correlation with duration of the disease, degree of proptosis, clinical activity score and R1 N1 latency (r = -0.59, -0.78, -0.41 & -0.90 with p <0.001, <0.001, <0.001 & <0.001 respectively). RNFL thickness showed negative correlation with duration of the disease, degree of proptosis and clinical activity score (-0.77, -0.71 & -0.85 with p < 0 .001, < 0 .001 & < 0 .001 respectively). Multiple regression analyses showed that the degree of proptosis and P50 amplitude were the most important determinants for CFT (p = 0.03 & 0.02); whereas the duration of the disease, and activity score were the most important determinants for average RNFL thickness (p =‎ 0.004, and < 0.001‎ respectively). Conclusion: In the absence of fundus changes, macular thinning together with functional changes detected by PERG and mfERG could be used as good predictors of subclinical retinopathy in the cases of TAO.

ROLE OF MAGNETIC RESONANCE IMAGING IN THE ASSESSMENT OF ACTIVE THYROID-ASSOCIATED OPHTHALMOPATHY PATIENTS WITH LONG DISEASE DURATION

Objective: In thyroid-associated ophthalmopathy (TAO), long disease duration is negatively correlated with the response to immunosuppression treatment. The current treatment decision-making process does not involve magnetic resonance imaging (MRI); thus, we investigated the predictive value of MRI parameters for the immunosuppressive response in active moderate to severe TAO patients with different disease durations. Methods: We retrospectively analyzed the baseline MRI parameters of active TAO patients treated with guideline-recommended weekly glucocorticoid therapy in our center. Data were stratified by the quartile of disease duration. The signal intensity ratio (SIR) of T2-weighted images was used to describe the activity of extraocular muscles (EOMs). Results: Compared to the lowest quartile of disease duration, SIR values of EOMs were significantly lower in quartile 3 (Q3) and quartile 4 (Q4). Meanwhile, the clinical activity score (CAS) curve did not change in parallel and was not correlated with the SIR curve. In the highest quartile of disease duration, nonresponders had significantly lower SIR values of the most inflamed muscle ( P = .03) and the medial rectus ( P = .004) than did the responders, while no such significance was observed in patients within the lower 3 quartiles. A multivariable predictive model (including CAS, TAO duration, and SIR value) was established in each quartile. The fit of the model was better than CAS with regard to prognostic prediction and showed a high positive predictive value (Model 1: 86.67%; Model 2: 92.86%) and negative predictive value (Model 1: 88.89%; Model 2: 90%) in the top quartile. Conclusion: The anterior manifestation assessed by CAS is not always consistent with retro-orbital activity in long-term TAO patients. CAS is sufficient to reflect disease activity in short-term TAO patients. The supplementation of CAS with orbital MRI would be valuable in selecting appropriate active patients with a long disease duration. Abbreviations: AUC = area under the curve; CAS = clinical activity score; EOM = extraocular muscle; FT3 = free triiodothyronine; FT4 = free thyroxine; GC = glucocorticoid; ivGC = intravenous glucocorticoids; MRI = magnetic resonance imaging; NPV = negative predictive value; PPV = positive predictive value; SIR = signal intensity ratio; TAO = thyroid-associated ophthalmopathy; TRAb = thyroid-stimulating hormone receptor antibody; TSH = thyroid-stimulating hormone