Mild Graves' Ophthalmopathy Research Articles

Selenium and Graves’ Disease

Selenium, a trace element present in specific selenoproteins, is essential for thyroid hormone metabolism. Selenium is also an antioxidant with immunosuppressive properties and may help in managing thyroid autoimmune diseases, including Graves’ (GD) hyperthyroidism and Graves’ ophthalmopathy (GO). There were 320 clinical studies related to selenium and thyroid published in English and French between January 1, 2000, and June 1, 2023. Our focus was to identify studies reporting levels of serum selenium in patients with GD and studies that assessed the effect of selenium supplementation on outcomes of GD hyperthyroidism and GO. We also reviewed 20 systematic reviews and meta-analyses of randomized controlled trials that reported selenium levels in GD and the effects of supplementation on GD and GO outcomes. Our review showed that patients with GD had serum selenium levels lower than those of various control patients. In the short-term, a selenium supplement to antithyroid drugs showed benefit for GD hyperthyroidism in most studies, but long-term benefits and positive effects on remission rate were unclear. Some studies did not show benefit. The benefits may depend on baseline selenium deficiency. Two randomized controlled trials showed positive effects of supplementation for mild GO; however, studies about moderate and severe GO are still needed. There is evidence for benefit with short-term selenium supplementation for GD hyperthyroidism, but controlled studies are needed to assess long-term benefits, and benefits in selenium-sufficient areas.

6662 Effect of Selenium Supplementation on Mild Graves’ Ophthalmopathy at a Tertiary Hospital - A Six-Month Open-Labelled, Assessor-Masked, Randomized-Controlled Trial

Abstract Disclosure: J.M. Flores: None. N.G. Sioson: None. J.D. Uy-Ho: None. A.L. Suller-Pansacola: None. Graves’ orbitopathy is associated with increased oxidative stress. Selenium, with its antioxidant and immunoregulatory actions, has been proposed as an adjuvant therapy. Objective: This study was undertaken to determine whether selenium supplementation for six months can decrease signs and prevent worsening of mild Graves ophthalmopathy among Filipinos. Methods: We conducted an open-labelled, assessor-masked, Randomized-Controlled Trial on patients with mild Graves’ ophthalmopathy wherein one arm was assigned to standard of care (eye drops) only for a period of six months while another arm was assigned to 200 ug/day oral Selenium supplementation alongside standard of care. Population: Adult patients with Graves’ hyperthyroidism, with at least one sign of mild ophthalmopathy with GO disease duration of less than 18 months Results: Independent Sample T-test, Mann-Whitney U test and Fisher’s Exact/Chi-square test were used to determine the difference of mean, rank and frequency, between patients given Selenium versus patients given standard of care. Paired Sample T-test, Wilcoxon Sign rank test and McNemar test were used to determine the difference of mean, rank and frequency on patients from initial to 3rd month or 6th month observation. Null hypotheses were rejected at 0.05α-level of significance. There was a significant difference in Clinical Activity Score (CAS) between patients given selenium supplementation and those assigned to standard of care. On initial examination for the Selenium group, 14 eyes (33.33%) had a CAS score of 0, which increased to 27 eyes (64.29%) on the third month and ended to a 26 eyes (61.9%) at the sixth month of treatment. For the non-selenium group, 11 eyes had a CAS score of zero initially, increased to 16 eyes (and 38.1%) then finally arrived to a total count of 14 eyes (33.33%). Improvement in CAS may be attributed specifically to improvement in caruncle/plical swelling showing a significant difference (p-value 0.040). Comparing the two groups, a statistical significance in CAS is noted between the treatment versus the control group with a p-value of 0.017 on the 6th month. Conclusion: Selenium supplementation provided significant benefit in terms of decreasing signs and preventing worsening of mild GO through improved CAS score. Further studies exploring the baseline and end of treatment selenium concentrations in the Philippines may be warranted. Presentation: 6/3/2024

Optical coherence tomography and shear wave elastography findings in Graves ophthalmopathy.

The main feature of Graves ophthalmopathy (GO) is revealed by determining the activity and severity of the disease. We aimed to evaluate the use of imaging methods can also provide additional information about the severity of this disease. Optical coherence tomography (OCT) and shear wave elastography (SWE) findings were compared in 32 patients with mild GO group and in the healthy control group. Measuring for TSH receptor antibody (TRAb) serum level is used third-generation assay. In Graves group, optic nerve sheath diameter (ONSD) values were increased in both eyes (p < 0.001, p < 0.001). SWE measurements showed a significant increase both eye optic nerve (ON) and right eye soft tissue elasticity values in GO group (p < 0.001, p < 0.001, p < 0.001, respectively). There was a significant thinning in left temporal retinal nerve fiber layer (RNFL) thickness and left RNFL peripapillary thickness in GO group (p < 0.001, p < 0.025, respectively). There was a correlation between left eye OCT and SWE findings. Also, there was a significant difference between the median left eye ON and soft tissue elasticity results in the TRAb-positive GO group (p = 0.049, p = 0.048, respectively). SWE measurements showed a significant increase both eyes ONSD, ON and right eye soft tissue elasticity values in GO group. GO group was significant thinning in some left eye regions in OCT measurements. There was a correlation between left eye OCT and SWE findings. In addition to clinical activity score and TRAb, SWE and OCT can be used to monitor in patients with GO.

Is Corneal Subbasal Nerve Loss Associated With Meibomian Gland Loss in Inactive Mild and Moderate-to-Severe Graves' Ophthalmopathy?

To evaluate meibomian gland and subbasal nerve plexus parameters in Graves' Ophthalmopathy (GO) and association of meibomian gland loss with corneal subbasal nerve plexus loss. Fifty-two eyes of 52 mild and moderate-to-severe GO patients and 32 eyes of 32 healthy controls were enrolled. The meibomian gland dropout area (MGDA) and meibography scores were evaluated using noncontact meibography. In vivo confocal microscopy of corneal subbasal nerve plexus were conducted. ACCMetrics was used to obtain corneal parameters. Compared with healthy subjects, GO patients had worse upper and lower eyelid MGDA ( p < 0.001, for all) and upper, lower and total meibography scores ( p < 0.001, p = 0.001, and p < 0.001, respectively). Eyelid margin scores were worse in the GO group ( p < 0.001) and showed correlation with all noncontact meibography parameters ( p < 0.001 for all). All corneal subbasal nerve parameters were significantly lower in the GO group compared with the controls ( p < 0.05 for all). Subbasal nerve parameters of GO patients did not reveal a correlation with MGDA and meibography scores but showed correlations with ocular surface disease index score and Schirmer I test (r = -0.304; p = 0.042 and r = 0.336; p = 0.021, respectively). Meibomian gland and corneal nerve loss could be observed even in the inactive phase and mild GO. The lack of a correlation between meibomian gland loss and subbasal nerve loss suggests that meibomian gland loss is not a significant additional component in the pathogenesis of subbasal nerve damage in GO. Furthermore, our study revealed new evidence regarding the use of eyelid margin score to represent meibomian gland loss in GO.

RhoA with Associated TRAb or FT3 in the Diagnosis and Prediction of Graves' Ophthalmopathy.

During Graves' disease (GD) treatment, Graves' ophthalmopathy (GO) is often ignored because only mild ocular symptoms are present in early GD. Therefore, we performed isobaric tags for relative and absolute quantification (iTRAQ) analysis and measured relevant endocrine hormones to identify predisposing factors of GO. Serum samples from 3 patients with mild GD and GO and 3 patients with GD but without GO were analyzed by iTRAQ. Based on their clinical data, 60 patients with GD were divided into the GO-free and GO groups. All patients were followed up for 7 months. Their eye conditions and changes in related biochemical indexes were recorded. The iTRAQ results showed that RhoA expression was upregulated and correlated significantly with the tight junction pathway and immunity. The changes in FT3 and RhoA from baseline to 7 months, the FT3 and RhoA baseline levels, and the TRAb titer levels in patients with GD significantly differed between the groups. ELISA and western blotting for RhoA, TRAb, and FT3 in the serum samples from GO patients showed significant upregulation, as well as elevated serum RhoA and TRAb levels in the mild stage of GO. At 7 months, the serum RhoA and FT3 levels were elevated. RhoA is a potential biomarker for mild GO. In GD patients, if an elevated serum RhoA level is accompanied by an elevated TRAb or FT3 level, GO is highly likely to occur, even when obvious ocular symptoms are absent.

Efficacy and safety of radioiodine therapy for mild Graves ophthalmopathy depending on cigarette consumption: a 6‑month follow‑up.

INTRODUCTION Graves ophthalmopathy (GO) is an autoimmune disease associated with Graves disease. Its treatment is largely dependent on the severity and activity of ocular lesions. Particular attention should be given to radioiodine (RAI) therapy. Although its use is a valuable therapeutic option for hyperthyroidism, it may be followed by worsening of GO. OBJECTIVES The aim of the present study was to analyze how the severity of nicotine addiction affects the response to RAI treatment in patients with GO. PATIENTS AND METHODS A total of 106 patients (58 smokers and 48 nonsmokers) with mild GO treated with 800 MBq of RAI were included to the study. We assessed the serum levels of thyroid‑stimulating hormone (TSH), thyroid hormones, autoantibodies against thyroperoxidase, thyroglobulin, and TSH receptor (TSHR‑Abs), as well as urinary cotinine levels and severity of ophthalmopathy. Analyses were conducted at baseline (before RAI treatment) and 2 and 6 months after the therapy. RESULTS Significant differences in serum levels of TSHR‑Abs were found between nonsmokers and smokers at 2 and 6 months after RAI therapy, whereas there were no differences at baseline. In smokers, there were significant differences in the severity of ophthalmopathy and the concentration of serum TSHR‑Abs assessed at baseline and at 6 months of follow‑up. Six months after RAI therapy, 46.2% of smokers and 4.3% of nonsmokers (P <0.001) progressed from mild to moderate GO. CONCLUSIONS High urinary cotinine levels in smokers were associated with the deterioration of ocular lesions after RAI treatment. A high dose of RAI did not induce an exacerbation of GO in nonsmokers who were administered oral steroid prophylaxis.

Glucocorticoid regimens for prevention of Graves' ophthalmopathy progression following radioiodine treatment: systematic review and meta-analysis.

Glucocorticoid (GC) therapy has been shown to prevent Graves' ophthalmopathy (GO) progression following radioactive iodine (RAI) treatment. However, the optimal regimen is controversial, with studies from recent years suggesting the use of lower doses and shorter GC treatment courses. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) and retrospective controlled trials comparing GC regimens versus placebo, no treatment, or other GC regimens. Eight trials evaluating 850 patients fulfilled inclusion criteria. In patients with preexisting GO, standard dose prednisone (0.4-0.5 mg/kg tapered over 3 months) was very effective for prevention of GO progression (OR 0.14 [CI 0.06-0.35], p<0.01) in patients with mild to moderate GO. Two studies evaluated low-dose prednisone (0.2-0.3 mg/kg for 4-6 weeks) in patients with mild GO or risk factors, but were limited by not including patients with preexisting GO in the control groups. Therefore, the two low-dose groups were evaluated using indirect comparisons with control groups matched for age and clinical activity score, showing excellent efficacy versus no treatment or placebo (OR 0.20 [CI 0.07-0.60], p=0.004) and no significant difference compared with standard dose (OR 1.7 [CI 0.52-5.52], p=0.47). In patients without preexisting GO, steroid prophylaxis had no beneficial effect (OR 1.87 [CI 0.81-4.3]), though there were insufficient data regarding patients with risk factors for GO development. GC prophylaxis had no impact on hyperthyroidism resolution (OR 1.05 [CI 0.69-1.58]), and GC side effects were common but mild. Current evidence supports a three-tier approach for prevention of GO progression following RAI. Standard dose prednisone is the best validated regimen and should be used in patients with mild to moderate GO who have high risk of progression, while low dose prednisone can be used in patients with mild GO, and in patients without preexisting GO who have risk factors and are selected for GC prophylaxis. Patients without preexisting GO and without risk factors should not be treated with GC prophylaxis.

Graves′ orbitopathy: Management of difficult cases

Management of Graves′ ophthalmopathy (GO) is based on three pillars: to stop smoking, to restore and maintain euthyroidism, and to treat the eye changes according to severity and activity of GO. Difficulties are frequently encountered in each of these three management issues. The advice to discontinue smoking is straightforward, but just a small minority of smokers is able to quit smoking. Detailed information on how smoking adversely affects the outcome of Graves′ disease may convince patients they have to stop smoking right away. Controversy exists on the most appropriate treatment of Graves′ hyperthyroidism in the presence of GO. 131I therapy is associated with a risk of about 15% for worsening of GO; a preventive course of steroids is indicated in the presence of risk factors (smoking, biochemically severe hyperthyroidism, high level of TSH receptor antibodies, active GO). Alternatives are thyroidectomy or long-term treatment with antithyroid drugs, which apparently are rather neutral with respect to the course of GO. Mild GO is not always perceived as being mild by the patients themselves. Selenium improves mild GO. Moderate-to-severe GO is preferably treated with intravenous methylprednisolone pulses, but serious side effects and relapsing GO do occur. After steroid failure combination therapy with low-dose oral prednisone with either cyclosporine or retrobulbar irradiation can be effective. Dysthyroid optic neuropathy is best treated with IV pulses, followed by orbital decompression if visual functions do not improve. In resistant cases, rituximab might be considered, although failures of this drug are also described.

Selenium, Mild Graves Ophthalmopathy and Current Smoking Status

Selenium, Mild Graves Ophthalmopathy and Current Smoking Status

Does selenium supplementation improve Graves ophthalmopathy?

A recent study of selenium supplementation in patients with mild Graves ophthalmopathy (GO) has demonstrated improvements in associated soft-tissue manifestations of the disease. The findings of this multicenter trial reveal a potential treatment option for the mild form of this vexing disease, which affects the majority of patients with GO.

Clinical Relevance of Thyroid-Stimulating Immunoglobulins in Graves' Ophthalmopathy

Thyroid-stimulating immunoglobulins (TSIs) likely mediate Graves' ophthalmopathy (GO). The clinical relevance of these functional autoantibodies was assessed in GO. Cross-sectional trial. A total of 108 untreated patients with GO. Thyroid-stimulating immunoglobulins, assessed with a novel bioassay, bind to the thyrotropin receptor (TSHR) and transmit signals for cyclic adenosine monophosphate (cAMP)-dependent activation of luciferase gene expression. The cAMP/cAMP response element-binding protein/cAMP-regulatory element complex induces luciferase that is quantified after cell lysis. The TSI levels were correlated with activity and severity of GO and compared with a TSHR binding inhibitory immunoglobulin (TBII) assay. Thyroid-stimulating immunoglobulins, activity and severity of GO, diplopia, and TBII. Thyroid-stimulating immunoglobulins were detected in 106 of 108 patients (98%) with GO. All 53 hyperthyroid patients were TSI positive versus 47 patients (89%) who were TBII positive. All 69 patients with active GO were TSI positive, whereas only 58 of 69 patients (84%) were TBII positive. Thyroid-stimulating immunoglobulins correlated with the activity (r=0.83, P < 0.001) and severity (r=0.81, P < 0.001) of GO. All 59 patients with GO with diplopia were TSI positive, and 50 of 59 patients (85%) were TBII positive. Among patients with moderate-to-severe and mild GO, 75 of 75 (100%) and 31 of 33 (94%) were TSI positive compared with TBII positivity in 63 of 75 (84%) and 24 of 33 (73%), respectively. The TSI levels were higher in moderate-to-severe versus mild GO (489%±137% vs. 251%±100%, P < 0.001). Chemosis and GO activity predicted TSI levels alone (P < 0.001, multivariable analysis). The TSI levels were higher in patients with chemosis (527%±131%) than in patients without chemosis (313%±127%, P < 0.001). Thyroid-stimulating immunoglobulins show more significant association with clinical features of GO than TBII and may be regarded as functional biomarkers for GO. Proprietary or commercial disclosure may be found after the references.

Graves opthalmopathy and psychoendocrinopathies

Purpose:To assess the psychiatric and endocrinological changes in patients with Graves ophthalmopathy (GO).Design:A prospective, controlled, University Hospital based studySubjects and Methods:The current study comprised 60 patients diagnosed with GO at Mansoura Ophthalmic Center. Thirty five patients of them with moderate to severe GO formed the study group and twenty five patients with negligible to very mild GO formed the control group in the euthyroid state. The study group was further subdivided based on their predominant clinical signs into a proptosis subgroup and a muscle restriction subgroup. Psychiatric changes were assessed with the Middlesex Hospital Questionnaire (MHQ). Biochemical analyses included serum-free thyroxine and thyroid-stimulating hormone (TSH) concentrations, TSH receptor antibody (TRAb) activity and anti-thyroglobulin particle agglutination (TGPA) and antithyroid microsomal particle agglutination (MCPA).Results:The proptosis group reported significantly higher scores on anxiety, depression, and phobia than the muscle restriction group (P<0.0001). The proptosis and muscle restriction subgroups reported significantly higher scores on all subscales compared to the control group (P<0.05). The scale scores of depression and phobia showed a positive correlation with scores of anxiety (P<0.0001). The serum TRAb activity showed a significant correlation with anxiety, phobia and hysteria (P<0.0001).Conclusion:The psychiatric aspect of GO should be evaluated during routine follow-up and should be considered when making management decisions. Thyroid specific antibodies may be useful in confirming the diagnosis of GO.

Radiotherapie der endokrinen Orbitopathie – State of the Art und Literaturübersicht

Graves’ ophthalmopathy (GO), the most frequent extrathyroidal manifestation of Graves’ disease, is a disorder of autoimmune origin, the pathogenic mechanisms of which are still incompletely understood. Although GO is severe in only 3–5% of affected individuals, quality of life is severely impaired even in patients with mild GO. The role of radiotherapy in the management of GO is discussed controversially. However, recent randomized clinical trials have, with one exception, confirmed that orbital radiotherapy is an effective and safe therapeutic procedure for GO. This article describes the sequences, dosages and fractionation schemes as well as the risks and side effects of the radiotherapy.

Thyrotropin Receptor Autoantibodies Are Independent Risk Factors for Graves’ Ophthalmopathy and Help to Predict Severity and Outcome of the Disease

The objective of this study was to examine whether TSH-receptor antibody [TSH binding inhibitory antibodies (TBII)] levels are associated with the severity of Graves' ophthalmopathy (GO) over the entire course of the disease. A total of 159 patients with GO were followed for 12-24 months. One year after the first symptoms of GO, all patients were classified into mild or severe GO according to their clinical manifestations. TBII were measured every 3 months after onset of GO. Receiver operating characteristic plot analysis was performed to assess the power to discriminate both patient groups by TBII (specificity >90%). TBII levels and prevalence at each time point during follow-up were significantly higher in patients with a severe course of GO compared with patients with a mild course of GO. Prognostic statements on the course of the disease were possible for about half of the GO patients at all time points (except the first). If at first presentation and at consecutive time points TBII levels were less than 5.7, 2.6, 1.5, 1.5, 1.5, and 1.5 IU/liter, the patients had a 2.3- to 15.6-fold higher chance of a mild course. If 5-8 months after GO onset and at consecutive time points TBII levels were above 8.8, 5.1, 4.8, 2.8, and 2.8 IU/liter, the patients had a 8.7- to 31.1-fold higher risk of a severe course. This relationship of TBII to the severity was independent from age and smoking. Follow-up measurements of TBII allow, in half of the patients, assessment of the prognosis of GO and, therefore, could be of additional help for the disease management.

An update on medical management of Graves’ ophthalmopathy

Graves' ophthalmopathy (GO), the most frequent extrathyroidal manifestation of Graves' disease, is a disorder of autoimmune origin, the pathogenic mechanisms of which are still incompletely understood. Although GO is severe in only 3-5% of affected individuals, quality of life is severely impaired even in patients with mild GO. Management of severe GO can be either medical or surgical (orbital decompression, eye muscle or lid surgery). Medical management relies on the use of high-dose systemic glucocorticoids or orbital radiotherapy, either alone or in combination. Studies carried out in the last 5 yr have shown that glucocorticoids are more effective through the i.v. route than through the oral route. However, particular attention should be paid to possible liver toxicity of i.v. glucocorticoids. Recent randomized clinical trials have, with one exception, confirmed that orbital radiotherapy is an effective and safe therapeutic procedure for GO. At variance with previous encouraging data, recent randomized clinical trials have shown that currently available SS analogs are not very effective in the management of GO. Antioxidants might have a role, at least in mild forms of GO. Particular attention should be paid to correction of risk factors (cigarette smoking, thyroid dysfunction, radioiodine therapy) involved in GO progression.

Octreotide (Long-Acting Release Formulation) Treatment in Patients with Graves’ Orbitopathy: Clinical Results of a Four-Month, Randomized, Placebo-Controlled, Double-Blind Study

There are few effective, safe modalities for the management of Graves' ophthalmopathy (GO), a cell-mediated immune comorbidity of thyroid disease. Somatostatin analogs inhibit lymphocyte proliferation and activation, and accumulate in the orbital tissue of patients with GO. A double-blind, placebo-controlled study of a long-acting somatostatin analog [16 wk of long-acting release formulation of octreotide (octreotide-LAR)] was conducted in 51 patients with mild active GO with the aim of preventing deterioration and precluding the need for more aggressive therapeutic modalities, such as glucocorticoids or radiotherapy. No treatment effect was observed for the primary end point (a composite parameter defining the outcome as either success or failure on the basis of changes in class/grade of the severity index and Clinical Activity Scale of GO). The Clinical Activity Scale score was reduced for patients treated with octreotide-LAR, but without any significant difference with respect to patients receiving placebo. However, octreotide-LAR significantly reduced proptosis (as measured by exophthalmometry). This was associated with nonsignificant differences in favor of octreotide-LAR in a series of proptosis-related parameters: class III grade, opening of the upper eyelid, the difference in ocular pressure between primary position and upgaze, and extraocular muscle involvement. By magnetic resonance imaging evaluation the extraocular muscle volumes appeared reduced, but nonsignificantly. No significant correlation between the initial uptake of the somatostatin analog indium-labeled and the response to treatment was observed. One patient in the octreotide-LAR group developed gallstones. In this study, octreotide-LAR did not seem suitable to mitigate activity in mild GO. Surprisingly, it significantly reduced proptosis, one of the most debilitating symptoms of GO. Additional studies are warranted to define the benefit to risk ratio of the somatostatin analogs in this indication.

Clinical results of anti‐inflammatory therapy in Graves’ ophthalmopathy and association with thyroidal autoantibodies*

Graves' ophthalmopathy (GO) is clinically associated with autoimmune thyroid disease, and autoantibodies to thyroidal antigens, especially to the TSH-receptor (TRAb), might be involved in the disease process. While there is mounting evidence that TRAb are associated with GO at the onset of the disease, so far no studies have looked at the association between thyroidal autoantibodies and the clinical outcome of GO therapy. The aim of this retrospective study was to evaluate whether TSH binding inhibitory immunoglobulins (TBII) and thyroid stimulating antibodies (TSAb) are still associated with the clinical activity and severity of GO after the completion of anti-inflammatory therapy. In addition, we wanted to elucidate whether thyroid peroxidase (TPO) or thyroglobulin (TG) autoantibodies (TPOAb and TGAb) are in any way related to GO. DESIGN PATIENTS AND MEASUREMENTS: Clinical activity score (CAS) and the severity of GO (modified NOSPECS score) were assessed in 108 patients with GO after steroid therapy and, if indicated, orbital irradiation. Patients were grouped according to their clinical presentation and autoantibody levels (TBII, TSAb, TPOAb and TGAb) were measured. After therapy for hyperthyroidism, all patients were clinically euthyroid but showed clear heterogeneity for GO 4-12 months after the end of anti-inflammatory therapy. Fifty-two patients had inactive GO, 41 had moderately active and 15 still had very active (non-responsive) GO. Concerning severity, 27 patients had mild GO, 64 moderately severe and 17 severe GO. TBII titres were still positive in 14 (93%) of 15 patients in the non-responsive group (CAS > 6) compared to 22 (42%) of 52 patients (P < 0.001) with post-therapeutic inactive GO (CAS </= 2). A similar result was seen between TBII levels and the NOSPECS score. The simultaneous presence of TBII and TSAb was associated with significantly higher activity and severity [odds ratios: 4.9 (activity); 9.0 (severity)] than the presence of TBII without measurable TSAb [odds ratios: 2.1 (activity), 2.0 (severity)] in comparison to absence of both antibodies. Only TBII and TSAb, but not TPOAb or TGAb medians, increased statistically significantly with CAS or NOSPECS scores. Both scores were positively associated with TBII (CAS: r = 0.31 P < 0.001; NOSPECS: r = 0.38, P < 0.0001) and, to a lesser degree, with TSAb (CAS: r = 0.27, P < 0.007, and NOSPECS: r = 0.29, P < 0.003). This association was independent of the treatment of hyperthyroidism, although highest levels of TBII were seen after radioiodine treatment. The NOSPECS score was negatively associated with TGAb (r =-0.27, P < 0.01) but not with TPOAb, while both showed no association with the CAS score. We conclude that the persistence of TBII and TSAb levels in patients with therapy-resistant disease in comparison to patients with inactive disease supports the role of TRAb in the pathogenesis of GO. Furthermore, the fact that, even after anti-inflammatory therapy, TBII and TSAb levels and prevalence still correlate with the severity and activity of GO suggests not only a trigger but also a possible role in the maintenance of the autoimmune process in the orbits.