Retinal, choroidal and optic disc analysis in patients with Graves' disease with or without orbitopathy.

PURPOSE: To compare optic disc, retinal and choroidal measurements in patients with Graves' disease with or without orbitopathy, and healthy controls. METHODS: Optical coherence tomography and Heidelberg retinal tomography were performed in 40 patients with Graves' orbitopathy (GO), 40 subjects with Graves's disease (GD) with no sign of orbitopathy and 40 healthy controls. Degree of exophthalmos, ocular alignment, clinical activity score (CAS), choroidal thickness, retinal thickness, ganglion cell layer (GCL) thickness, disc area, cup area, rim area, cup/disc area ratio, linear cup/disc ratio and mean peripapillary retinal nerve fibre layer thickness were analysed. RESULTS: GO patients and healthy controls significantly differ regarding mean central retinal thickness (275 ± 19 µm and 285 ± 20 µm, P = 0.017); mean central GCL thickness (14.87 ± 3.0 µm and 17.92 ± 5.02 µm, P = 0.001); mean disc area (2.00 ± 0.44 mm2 and 1.72 ± 0.37 mm2, P = 0.003); mean cup area (0.53 ± 0.52 mm2 and 0.31 ± 0.20 mm2, P = 0.003); cup/disc area ratio (0.22 ± 0.10 and 0.17 ± 0.08, P = 0.010); and linear cup/disc ratio (0.47 ± 0.15 and 0.40 ± 0.13, respectively, P = 0.011). No difference was found between patients without orbitopathy and healthy controls. No significant difference was found regarding the choroidal thickness between the three groups. There was no statistically significant relationship between retinal thickness, ganglion cell layer thickness, mean disc area, mean cup area, cup/disc area ratio, linear cup/disc ratio, CAS, exophthalmometric value and ocular alignment. CONCLUSION: GO patients showed significant changes in foveal and GCL thickness, and optic nerve head morphology suggesting a possible influence of the orbital inflammatory process.

VARIABLES AFFECTING THE LONG-TERM OUTCOME OF GRAVES ORBITOPATHY FOLLOWING HIGH-DOSE INTRAVENOUS GLUCOCORTICOID PULSE THERAPY IN PATIENTS NOT TREATED WITH ORBITAL RADIOTHERAPY.

OBJECTIVE: Intravenous (iv) glucocorticoids (GC) (ivGC) are used for active Graves orbitopathy (GO), but factors affecting GO outcome are poorly understood. We performed a retrospective study to investigate the variables affecting GO after ivGC. METHODS: We evaluated 83 consecutive GO patients treated with ivGC but not orbital radiotherapy (ORT) and re-examined them after a median of 47 months. The endpoints were the relationships between GO outcome or additional treatments with age, sex, smoking habits, thyroid volume, thyroid treatment, time since thyroid treatment, antithyroid-stimulating hormone receptor antibodies (TRAb), GO duration, GO features, and follow-up time. RESULTS: GO features improved after treatment, resulting in moderate and marked amelioration in ~75% and ~41% of patients respectively. By multivariate analysis, a moderate GO improvement correlated with diplopia at first observation, which was more severe in responders. A marked GO improvement correlated with time between first and last observation and time after thyroid treatment, which were longer in responders. This likely reflected the combination of an early effect of GC and a late, spontaneous improvement of GO, as shown by analyses of GO outcome at various time points. Additional treatments after ivGC correlated by multivariate analysis with eyelid aperture, diplopia and NOSPECS score (NOSPECS stands for no GO signs [N], only eyelid sign [O], soft tissue involvement [S], proptosis [P], extraocular motility restriction [E], corneal involvement [C], and sight loss [S]) at first observation, which were more severe in responders. CONCLUSION: Our study shows that response to ivGC increases with time, likely reflecting the known tendency of GO to improve spontaneously, and is more pronounced when GO is more severe to begin with, which is associated with more additional treatments. ABBREVIATIONS: ANOVA = analysis of variance CAS = clinical activity score GC = glucocorticoids GO = Graves orbitopathy 131I = radioactive iodine iv = intravenous ivGC = high-dose intravenous glucocorticoid pulse therapy MMI = methimazole OD = orbital decompression ORT = orbital radiotherapy TRAb = antithyroid-stimulating hormone receptor antibodies.

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.

Disappearance of Anti-Thyroid Autoantibodies following Thymectomy in Patients with Myasthenia Gravis.

OBJECTIVES: The thymus plays a central role in immune tolerance, which prevents autoimmunity. Myasthenia gravis (MG) is commonly associated with thymoma or thymus hyperplasia, and it can coexist with autoimmune thyroid diseases. However, the role of the thymus in thyroid autoimmunity remains to be clarified, which we investigated here. STUDY DESIGN: The study design entailed the inclusion of consecutive MG patients and the measurement of anti-thyroid autoantibodies at baseline and, limited to autoantibody-positive patients, also at 24 and 48 weeks. One hundred and seven MG patients were studied. The main outcome measure was the behaviour of anti-thyroglobulin autoantibodies (TgAbs) and anti-thyroperoxidase autoantibodies (TPOAbs) over time in relation to thymectomy. RESULTS: Serum TgAbs and/or TPOAbs were detected in ∼20% of patients in the absence of thyroid dysfunction. The prevalence of positive serum TgAbs and/or TPOAbs decreased significantly (p = 0.002) over the follow-up period in patients who underwent thymectomy, but not in patients who were not thymectomized. When the analysis was restricted to TgAbs or TPOAbs, findings were similar. On the same line, there was a general trend towards a reduction in the serum concentrations of anti-thyroid autoantibodies in patients who underwent thymectomy, which was significant for TPOAbs (p = 0.009). CONCLUSIONS: Our findings suggest a role of the thymus in the maintenance of humoral thyroid autoimmunity.

Cholesterol Serum Levels and Use of Statins in Graves' Orbitopathy: A New Starting Point for the Therapy.

Graves' Orbitopathy (GO) is the most frequent extrathyroidal manifestation of Graves' disease (GD). Its ultimate cause remains unclear, but it is commonly considered an autoimmune disorder due to self recognition of autoantigens constitutively expressed by orbital fibroblasts (OFs), and thyroid epithelial cells. High dose intravenous glucocorticoids (ivGC) are the most commonly used treatment for moderately severe and active GO. However, based on the complex pathogenesis of GO, a number of factors may have a protective and maybe a therapeutic role. The use of other medications improving the effect of GC may increase the overall effectiveness of the therapy and reduce GC doses, thereby limiting side effects. Recently, a possible protective role of 3-hydroxy-3-methylglutaryl-coenzyme reductase inhibitors, the so-called statins, and perhaps of lowering cholesterol levels, has been proposed. Thus, statins have been reported to be associated with a reduced frequency of GO in GD patients and in recent cross-sectional and retrospective studies a significant correlation was found between the occurrence of GO and both total and LDL-cholesterol in patients with a GD of relatively recent onset, suggesting a role of cholesterol in the development of GO. Moreover, a correlation was found between the GO clinical activity score and total as well as LDL-cholesterol in untreated GO patients, depending on GO duration, indicating a role of cholesterol on GO activity. Therefore, statin treatment may be beneficial for GO. Here we review this subject, which offers new therapeutic perspectives for patients with GO.

Occurrence of Graves' Orbitopathy and Graves' Hyperthyroidism after a Trauma to the Eye.

BACKGROUND: Graves' orbitopathy (GO) is believed to be the consequence of autoimmunity against antigens that are present both in the thyroid and orbital tissues. Massive release of thyroid antigens causes the appearance or deterioration of GO in patients with Graves' hyperthyroidism (GH), as it occurs following radioiodine treatment. In theory, a similar release of autoantigens may occur at the eye level, for example due to an orbital trauma or surgical manipulation. To our knowledge, this is the first report of a case of de novo appearance of GO and then GH after an eye trauma, possibly reflecting spreading of autoantigens and activation of the immune system against shared orbital and thyroid antigens. CASE REPORT: An otherwise healthy, 57-year-old man presented 6 months after the appearance of a monolateral right orbitopathy, which occurred 40 days after a trauma in the ipsilateral eye. His thyroid function was normal, with positive serum anti-TSH receptor autoantibodies. The thyroid was normal on ultrasound. A month later he developed hyperthyroidism and orbitopathy in the left eye. DISCUSSION: The development of GO after an eye trauma may reflect tissue damage with release of autoantigens and consequent autoimmunity in a predisposed individual (our patient had a familial history of autoimmune thyroid disease). The subsequent development of hyperthyroidism is in keeping with the hypothesis that GH and GO are due to autoimmunity against antigens present both in the thyroid and in orbital tissues.

High Serum Cholesterol Is a Novel Risk Factor for Graves' Orbitopathy: Results of a Cross-Sectional Study.

BACKGROUND: Limited data suggest that treatment with statins is associated with a reduced risk of Graves' orbitopathy (GO) in patients with Graves' disease (GD), attributed to the anti-inflammatory rather than to the hypolipemic effects of these medications. The aim of the present study was to investigate whether there is an association between high cholesterol and GO. The primary outcome was the relation between GO and low-density lipoprotein (LDL)-cholesterol. The secondary outcomes were the relation between severity or activity (the clinical activity score [CAS]) of GO and LDL-cholesterol. METHODS: A cross-sectional investigation was conducted in consecutive patients with GD who came under the authors' observation to undergo radioiodine treatment, a stratification aimed at forming two distinct groups of patients under the same conditions. A total of 250 patients were enrolled, 133 with and 117 without GO. Ophthalmological assessments and serum lipids measurements were performed. RESULTS: In multivariate analyses with correction for the duration of hyperthyroidism, a variable that differed between patients with respect to the presence or absence of GO, a correlation between the presence of GO and both total (p = 0.01) and LDL-cholesterol (p = 0.02) was observed. In patients with hyperthyroidism lasting <44 months, total and LDL-cholesterol were higher (p = 0.01 and p = 0.008, respectively) among GO patients. In this subgroup, based on the presence/absence of GO, cutoff values were established for total (191 mg/dL) and LDL-cholesterol (118.4 mg/dL), above which an increased risk of GO was observed (total cholesterol relative risk: 1.47; p = 0.03; LDL-cholesterol relative risk: 1.28; p = 0.03). GO severity and CAS did not correlate with serum lipids. However, CAS was found to be higher (p = 0.02) in patients with high total cholesterol. When the analysis was restricted to untreated GO patients, a correlation was found between CAS and both total (p = 0.04) and LDL-cholesterol (p = 0.03), after adjustment for GO duration. CONCLUSIONS: In patients with a short duration of hyperthyroidism, total and LDL-cholesterol correlate with the presence of GO, suggesting a role of cholesterol in the development of GO. Depending on GO duration, total and LDL-cholesterol correlate with GO activity, suggesting a role of cholesterol in the clinical expression of GO.

Association of T and B Cells Infiltrating Orbital Tissues With Clinical Features of Graves Orbitopathy.

Importance: Graves orbitopathy (GO) responds to immunosuppressive treatments when clinically active but poorly when inactive. In other autoimmune diseases, response has been ascribed to a reduction in lymphocytes infiltrating the target organ. It is not known whether active vs inactive GO differs in this regard, which would help in understanding the link between GO immunologic features and clinical behavior. Objective: To investigate the association between orbital lymphocytic infiltrate and GO clinical features. Design, Setting, and Participants: A cohort study aimed at assessing the extent and immunohistochemical phenotype of orbital lymphocytes and associating it with the ophthalmologic features of GO, especially its clinical activity score (CAS), was conducted at a tertiary referral center. Twenty consecutive patients with GO who underwent orbital decompression were included. The study was conducted from January 1 to May 31, 2017. Exposures: Orbital tissue histology and immunohistochemistry testing as well as ophthalmologic evaluation. Main Outcomes and Measures: Association between CAS and orbital lymphocytes, analyzed as total number of lymphocytes and main lymphoid subsets. Results: The patient population included 8 men and 12 women, all of white race, with a mean (SD) age of 46 (13) years. With an established cutoff value of 300 lymphoid cells per tissue sample, lymphocytes above this value were found in orbital tissues of 9 of 20 patients (45%), often organized into distinct foci. The lymphocytes comprised a mixture of T (CD3-positive) and B (CD20-positive) cells, suggesting a mature, polyclonal autoimmune response. In a simple linear regression model, the total number of lymphocytes, as well as the number of CD3- and CD20-positive subsets, correlated with CAS (R = 0.63; 95% CI, 0.27-0.84; P = .003; R = 0.59; 95% CI, 0.20-0.82; P = .006; and R = 0.65; 95% CI, 0.30-0.85; P = .002, respectively). In a multiple linear regression model, lymphocytes maintained their effect on CAS when adjusted for 2 additional variables that were correlated with CAS-smoking and GO duration-highlighting even more the important role of orbital lymphocytes in affecting CAS (total number: R = 0.58; 95% CI, 0.18-0.82; P = .01; CD3-positive: R = 0.58; 95% CI, 0.17-0.82; P = .01; and CD20-positive: R = 0.59; 95% CI, 0.19-0.83; P = .01). Conclusions and Relevance: This study shows a correlation between T and B lymphocytes infiltrating orbital tissues and the activity of GO, possibly enhancing our understanding of the association between GO immunologic features and clinical expression.