NOSPECS Score Research Articles

PREVALENCE OF THYROID EYE DISEASE IN PATIENTS WITH THYROID DYSFUNCTION IN A TERTIARY CARE HOSPITAL OF CENTRAL NEPAL

Background: Thyroid eye disease is the most common extra thyroidal manifestation of Graves’ disease. The pattern and prevalence of thyroid eye disease vary widely from a mild disorder characterized by dry eye symptoms and ocular irritation to a severe disfiguring form of orbitopathy. Thyroid eye disease is a frequently encountered Ophthalmological morbidity in Nepal and across the globe. The aim of this study was to ascertain the prevalence of thyroid eye disease in subjects with thyroid dysfunction in a tertiary care hospital in central Nepal.. Methods: This was a prospective cross-sectional study, conducted in Chitwan medical college Teaching hospital (CMCTH), department of Ophthalmology. Subjects presenting to Ophthalmology department or referred patients from different departments with thyroid dysfunction were enrolled in the study. The data thus collected was analyzed using SPSS version 26 and the data was presented as frequency and percentage. Results: Among 320 subjects screened for Thyroid eye disease prevalence, 106 (33.3%) were hyperthyroid, 207 (64.7%) were hypothyroid whereas, 7 (2.2%) were euthyroid. The prevalence of Thyroid eye disease was 40% and this was more prevalent among hypothyroid. Among the 320 patients with thyroid eye disease, 126 (39.4%), 95 (29.7%), 53 (16.6%), 24 (7.5%), 15 (4.7%), 5 (1.6%) and 2 (0.6%) had CAS score of 1,2,3,4,5,6 and 7 respectively. Similarly, NOSPECS score (American Thyroid Association) 243 (75.9%), 57 (17.8%), 1 (0.3%), 7 (2.2%), 8 (2.5%), 3(0.9%) and 1 (0.3%) were graded from 0-6 accordingly respectively. Conclusions: Thyroid eye disease was more prevalent in hypothyroid middle-aged females and the overall prevalence of Thyroid Eye disease was more in hypothyroid patients. Though sight threatening complications didn’t exist in our study, close workup by endocrinologist and ophthalmologist can decrease ocular morbidity.

Corneal Morphological and Biomechanical Changes in Thyroid-Associated Ophthalmopathy.

This study aimed to evaluate corneal morphological and biomechanical changes in patients with thyroid-associated ophthalmopathy (TAO) and their correlations with activity and severity. Patients diagnosed with TAO were recruited and divided into groups by activity and severity. All subjects underwent a complete ophthalmic examination, including magnetic resonance imaging. Corneal topography was measured using a Pentacam device, and biomechanical parameters were obtained using a CorVis ST tonometer. Correlations among the corneal parameters, clinical activity score, and NOSPECS score were analyzed. Areas under the receiver operating characteristic curves were calculated to evaluate the diagnostic accuracy of corneal changes for active and severe TAO. Fifty-three eyes with TAO and 16 healthy eyes were enrolled in our study. The back elevation, CorVis biomechanical index, tomographic and biomechanical index, stiffness parameter at the first applanation, deviation from normality in back elevation, relational thickness, and overall deviation from normality were significantly increased in patients with TAO (all P <0.05), whereas the smallest corneal thickness, maximum Ambrósio relational thickness, and deformation amplitude (DA) ratio were significantly decreased (all P <0.05). The clinical activity score was strongly positively correlated with back elevation (γ = 0.515, P <0.001). The NOSPECS score was strongly positively correlated with relational thickness and tomographic and biomechanical index (γ = 0.429 and 0.515, P <0.001) and negatively correlated with maximum Ambrósio relational thickness (γ = -0.53, P <0.001). Moreover, maximum Ambrósio relational thickness and the Ambrósio relational thickness through the horizontal meridian showed desirable diagnostic capacity in distinguishing mild TAO from moderate-severe TAO (areas under the receiver operating characteristic curve, 0.799 and 0.769). Corneal morphological and biomechanical changes were found in patients with TAO, which might be related to the presence of inflammation. Measurements of corneal morphological and biomechanical parameters could serve as references in evaluating TAO.

Monoclonal antibodies for the treatment of Graves' ophthalmopathy: A systematic review and meta-analysis.

The traditional standard of care for Graves' ophthalmopathy (GO) is glucocorticoid therapy, which is associated with many long-term side effects. The aim of this systematic review and meta-analysis was to compare the traditional therapy to novel monoclonal antibodies (e.g. rituximab [RTX], teprotumumab, and tocilizumab [TCZ]). We searched the Medline, Embase, and Cochrane Central Register of Controlled Trials databases. We included randomized controlled trials (RCTs) that compared different monoclonal antibodies (e.g. RTX, teprotumumab, and TCZ) with glucocorticoids or placebo in patients with GO. We evaluated the clinical activity score (CAS), proptosis, subjective diplopia using the Gorman score, quality of life (QoT), adverse events, change in lid fissure, NOSPECS score, and TSH receptor antibody (TRAb) levels. The odds ratio (OR) was used to represent dichotomous outcomes. The continuous outcomes were represented as standardized mean difference (SMD). Data were pooled using the inverse variance weighting method. Risk of bias was assessed using the revised Cochrane risk-of-bias tool for randomized trials. Six (n = 571) RCTs were deemed eligible. The different monoclonal antibodies were significantly more efficacious than glucocorticoid/placebo in terms of reduction in CAS (SMD = -1.44, 95% confidence interval (CI): -1.91--0.97, P < 0.00001, I2 = 74%), change in proptosis (SMD = -4.96, 95% CI: -8.02--1.89, P = 0.002, I2 = 99%), QoL (SMD = 2.64, 95% CI: 0.50-4.79, P = 0.02, I2 = 97%), and Gorman score for diplopia (OR = 3.42, 95% CI: 1.62-7.22, P = 0.001, I2 = 8%). However, monoclonal antibodies have shown higher rates of adverse events (OR = 2.91, 95% CI: 1.12-7.56, P = 0.03, I2 = 62%). No significant difference was found with respect to lid fissure, NOSPECS, and TRAb levels. This meta-analysis demonstrated that monoclonal antibodies were associated with more favorable clinical outcomes than standard steroid therapy or placebo, especially with regard to CAS, change in proptosis, diplopia, and QoL, with teprotumumab being superior. In addition, only minor safety concerns were identified with monoclonal antibodies though less worrisome than using traditional steroids.

Longitudinal association of thyroid-stimulating immunoglobulin levels with clinical characteristics in thyroid eye disease

ObjectivesThe clinical course of thyroid eye disease (TED) is heterogeneous and predicting patients who may develop the severe sequelae of the disease is difficult. In this study, we evaluated the...

The Effect of Thyroid Eye Disease on Corneal Biomechanical Properties.

Objectives:The aim of this study was to identify corneal biomechanical parameters measured by ORA in patients with TED compared to the healthy group. The NOSPECS classification of patients is used to assess the relation between biomechanical changes and disease severity.Methods:We included 22 TED patients, diagnosed with TED for more than five years, and 43 healthy participants. The NOSPECS classification was assessed as mild (grade 1-3) and severe (grade 4-6) disease. For each group, corneal hysteresis (CH), corneal resistance factor (CRF), central corneal thickness (CCT), Goldmann-correlated intraocular pressure (IOPg) and corneal compensated intraocular pressure (IOPcc) parameters were measured by ORA.Results:The mean age was 38.8±11.6 years for the TED patients and 42.9±15.58 years for the control group. For TED patients and healthy volunteers, the mean levels of CRF, CH, and CCT were measured as follows: 10.43±2.04 vs 10.28±1.91mmHg, p=0.67; 10.18±1.81 vs 10.21±1.68 mmHg, p=0.90; 550.31±35.73 vs 545.23±37.91 µm, p=0.47, respectively. These values were not significant between groups, but they were significantly higher in females compared to males in TED patients [CRF;10.68 (IQR: 9.49-12.14) vs 8.96 (IQR: 8.04-9.92) mmHg, p=0.002, CH; 10.43 (IQR: 9.48-11.25) vs 8.58 (IQR: 7.90-9.95) mmHg, p=0.003 and CCT; 554.25 (IQR: 536.05-579.52) vs 527.40 (IQR: 492.25-545.90) μm, p=0.014]. CRF values were negatively correlated with NOSPECS score (r=-0.317, p=0.036) and significantly higher CRF was observed in mild patients compared to severe disease (11.43 (IQR: 10.14-12.87) vs 9.46 (IQR: 8.75-10.28) mmHg, p=0.008).Conclusion:We found a significant gender effect on corneal biomechanical parameters of TED patients. CRF, CH and CCT values were significantly higher in females compared to males with TED. The clinical severity score of TED showed negative correlation with CRF. CRF value might be a useful parameter in follow-up of TED patients in clinical practice.

Clinical features and clinical course of thyroid-associated ophthalmopathy: a case series of 3620 Chinese cases.

To determine the clinical features and course of thyroid-associated ophthalmopathy (TAO) in a large sample of Chinese patients. We retrospectively identified a cohort of consecutive patients diagnosed with TAO at the West China Hospital from October 1, 2009 to October 1, 2019. We analysed clinical data from 3620 patients, including demographic data, clinical manifestations, ophthalmology examinations, and prognosis. TAO most frequently occurred with hyperthyroidism, with most patients developing TAO after thyroid disease (TD). The TAO phenotype was asymmetric in 375 (50.7%) euthyroid patients, 25 (27.8%) hypothyroid patients, and 314 (12.1%) hyperthyroid patients (p < 0.0001). The most frequent symptom was lid lag and the most commonly involved extraocular muscle was the inferior rectus. Severity assessment (NOSPECS score) and clinical activity assessment (Clinical Activity Scores, CAS) differed significantly between male and female patients (P < 0.000). The majority (88.8%) of patients had clinically inactive TAO, and only 3.2% of cases were sight-threatening. Regarding the clinical process, 75.5% of patients had an active phase time less than 12 months and 2.1% showed complete remission. TAO most commonly develops in females and is closely related to hyperthyroidism. Euthyroid TAO often has an asymmetric clinical phenotype. CAS combined with magnetic resonance imaging can improve the detection of TAO. NOSPECS scores should be slightly refined regarding the criteria for corneal involvement. Clinical management of TAO should be individualized according to CAS or NOSPECS assessments and a multidisciplinary approach is paramount. A minority of patients showed complete remission.

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.

Correlation between serum anti-TSH receptor autoantibodies (TRAbs) and the clinical feature of Graves' orbitopathy.

Graves' orbitopathy (GO) is the most common extrathyroidal manifestation of Graves' disease (GD). Several studies support the involvement of TSH receptor autoantibodies (TRAbs) in the pathogenesis of GO, and a correlation between GO features and TRAbs has been reported, but not confirmed by all studies. Thus, we conducted a cross-sectional investigation to determine whether there is a correlation between TRAbs and the clinical features of GO in an initial phase of the eye disease. Ninety consecutive patients with untreated GO (67 women and 23 men, age 48.9 ± 12.6years) were included. Patients who had received treatments other than anti-thyroid drugs for hyperthyroidism or lubricants for GO were excluded. All patients underwent an endocrinological and ophthalmological evaluation, the latter including exophthalmometry, measurement of eyelid width, clinical activity score (CAS), visual acuity, assessment of diplopia, and NOSPECS score. TRAb levels were measured by a third-generation competitive immunoassay. There was a statistically significant, direct correlation between serum TRAb levels and CAS by linear regression analysis (R = 0.278, P = 0.007). The correlation was confirmed by a multiple regression analysis (R = 0.285; P = 0.006) including age and FT3 levels, which also correlated with CAS. There were no relationships between TRAbs and exophthalmometry, eyelid aperture, degree of diplopia, visual acuity, and NOSPECS score. The levels of TRAb in subjects with a recent-onset, untreated GO are directly correlated with the clinical activity of the disease, confirming a possible role of these antibodies in the pathogenesis ofGO.

Changes in ocular biomechanics after treatment for active Graves' orbitopathy.

To evaluate the changes in ocular biomechanical properties in active moderate-to-severe Graves' orbitopathy (GO) after intravenous glucocorticoids (IVGCs), and to clarify correlations between clinical findings and ocular biomechanical properties. A prospective study. A total of 20 consecutive GO patients and 20 age- and sex-matched healthy control subjects were included. GO was diagnosed on the basis of the recommendation by the European Group on Graves' Orbitopathy (EUGOGO), and disease activity was assessed by the clinical activity score (CAS). Patients were assigned to receive once weekly IVGCs (0.5g, then 0.25g, 6weeks each). All participants received a full ophthalmic examination and biomechanical evaluation was performed with dynamic Scheimpflug analyzer (Corvis ST) at baseline and 12th weeks after therapy. The biomechanically corrected intraocular pressure (bIOP) in GO patients was significantly higher than that in healthy subjects. In contrast, the whole eye movement (WEM) in GO patients was significantly lower than in healthy subjects after adjusting for bIOP. The CAS, NOSPECS score, and exophthalmos were significantly positively correlated with the bIOP and negatively correlated with the WEM after adjusting for bIOP, CCT and age. The WEM significantly increased, whereas bIOP significantly decreased after IVGCs (P < 0.001, P = 0.001 respectively). The overall response rate at the 12th week was 85% (17 of 20). The changes of ocular biomechanical properties measured by Corvis ST were an objective indicator of inflammatory activity and severity of GO. Combining CAS and ocular biomechanical properties could better evaluate the therapeutic outcome of active moderate-to-severe GO.

Total thyroidectomy (Tx) versus thionamides (antithyroid drugs) in patients with moderate-to-severe Graves\u2019 ophthalmopathy \u2013 a 1-year follow-up: study protocol for a randomized controlled trial

BackgroundGraves’ disease (GD) is characterized by thyrotoxicosis and goiter and arises through circulating autoantibodies that bind to, and stimulate, the thyroid hormone receptor (TSHR). A temporal relation between the onset of hyperthyroidism and the onset of ophthalmopathy, a common extrathyroidal manifestation, has been demonstrated. Graves’ ophthalmopathy (GO) is typically characterized by an inflammation and expansion of the extraocular muscles and an increase in retroorbital fat. There are currently three forms of therapies offered for hyperthyroidism caused by Graves’ disease: antithyroid drugs (ATD) (thionamides), radioiodine ablation (RAI) and thyroidectomy (Tx). To date, there is no clear recommendation on the treatment of Graves’ disease and GO, mainly due to the individuality of the disease in each patient. The aim of the study is to examine the difference in the outcome of GO in patients with moderate-to-severe GO who receive Tx versus further ATD after suffering their first relapse of GO, or in which GO stays the same following the initial decrease in ATD therapy after 6 months.Methods/DesignThis prospective randomized clinical trial with observer-blinded analysis will analyze 60 patients with moderate-to-severe GO who receive Tx versus ATD without surgery. Main outcome variables include: muscle index measurements via ultrasound and thyroid antibody levels. Additional outcome variables include: Clinical Activity Score (CAScore), NOSPECS score, superonasal index measurements via ultrasound, and quality of life score.DiscussionThis study should allow for better therapeutic choices in patients with moderate-to-severe GO. In addition, it should demonstrate whether the outcome of GO in patients with moderate-to-severe GO is better in those who receive early Tx versus further ATD. Furthermore, this study will aim to establish a standard glucocorticoid scheme before and after Tx in patients with moderate-to-severe EO.Trial registrationEudra-CT: 2015–003515-38; Medical University of Vienna Protocol Record 1839/2015.Date of Ethics Committee approval: 19 January 2017.Registered on 27 January 2017.

Prevalence and severity of ocular involvement in Graves' disease according to sex and age: A clinical study from Babol, Iran.

Background:Thyroid-associated eye disease (TED), previously known as Graves’ ophthalmopathy is a cosmetically and functionally debilitating disease that is seen worldwide. The aim of this study was to evaluate the prevalence and clinical severity of ocular manifestations of Graves’ disease according to sex, age and duration in northern Iran.Methods: Between April 2011 and March 2012, 105 patients with Graves’ disease, underwent ophthalmic examination, including ocular motility, exophthalmometry, intraocular pressure (IOP), slit lamp and fundoscopy. Patients received scores according to modified Werner’s NO SPECS classification.Results:Ocular involvement was found in 70 patients with established Graves’s disease. The mean age was 35.0 years, (SD 13.0, range 15 to 69). The most common ocular findings were exophthalmometric proptosis of more than 20 mm (63.8%), lid lag (55.7%), lid retraction (52.8%) and tearing (38.6%). Almost 70% of patients had bilateral involvement. Elevated IOP was seen in 15 (25.4%) patients, and was significantly related to proptosis (P=0.007). More than half of the patients (n=36, 52.2%) had a modified Werner’s NO SPECS score of 3.00. Clinical severity as shown by the increasing number of signs and symptoms per patient was correlated to increasing age (r=0.31, P=0.01) but not to gender (P=0.17).Conclusions:Both functional (ocular motility disorders, increased IOP) and cosmetic (proptosis, periorbital edema) sequels are common ocular presentations in patients with Graves' disease. Proptosis was the most common finding in this study and was associated with elevated IOP. Clinical severity was found to correlate to increasing age.

Variables Affecting the Long-Term Outcome of Graves Orbitopathy Following High-Dose Intravenous Glucocorticoid Pulse Therapy in Patients not Treated with Orbital Radiotherapy

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. 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. 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. 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. 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.

Implications of FoxP3-positive and -negative CD4(+) CD25(+) T cells in Graves' ophthalmopathy.

Graves' ophthalmopathy (GO) is a common manifestation of Graves' disease (GD); however, its pathogenesis is not well understood. Recently, the dysregulation of regulatory T cells (Tregs) has been thought to be closely associated with the pathogenesis and clinical symptoms of autoimmune disease. We therefore evaluated whether T cell subsets, including Tregs, are associated with GO pathogenesis and clinical symptoms. In this observational study we evaluated 35 GD patients with overt ophthalmopathy (GOs) and 28 patients without ophthalmopathy (non-GOs). Fifteen healthy euthyroid patients served as healthy controls (HCs). Peripheral blood mononuclear cells from GOs, non-GOs and HCs were analyzed for CD4, CD25, and FoxP3 expression using flow cytometry. We also evaluated their correlation with disease activity according to the clinical activity score (CAS) and magnetic resonance imaging (MRI) findings. Disease severity was evaluated using the NOSPECS score, and clinical progression of GO was followed for 24 weeks. The main outcome measures were the frequencies of FoxP3-positive and -negative CD4(+) CD25(+) T cells at study outset, namely Tregs and effector T cells (Teffs), respectively. GOs had higher frequencies of Teffs (30.8±8.4%) than non-GOs (19.4±7.1%) and HCs (22.7±7.9%). Notably, patients with improved GOs had lower frequencies of Tregs (5.8±1.1%) than patients with stable or deteriorated GOs (7.3±1.2%), although ophthalmic and radiological parameters were not significantly different at the start of the study. In conclusion, an expanded Teff population may be associated with GO pathogenesis. Additionally, decreased Tregs in peripheral blood may predict a good clinical outcome.

Role of the underlying thyroid disease on the phenotype of Graves' orbitopathy in a tertiary referral center.

Clinically overt Graves' orbitopathy (GO) is associated with Graves' disease (GD) in approximately 95% of cases, whereas the remaining 5% is observed in patients with hypothyroid autoimmune thyroiditis (AT) or without overt thyroid dysfunction (euthyroid GO). However, it is not known whether there is a difference in terms of GO phenotype between patients with GD and those with hypothyroid AT or without thyroid dysfunction, and hence this is investigated here. The study design was to evaluate retrospectively all consecutive patients with a recent manifestation of GO, seen at their first visit to a tertiary referral center over a period of 10 years. In total, 358 GO patients were studied, and all of them underwent GO assessment. Of the 358 patients studied, 341 had hyperthyroid GD, 10 had AT with hypothyroidism, and seven had euthyroid GO. Age, sex, and smoking habits were similar in the three groups, as was the time since GO was first noticed (GO duration). The vast majority of patients had moderate to severe, active GO, as expected in a tertiary referral center. Exophthalmometry, eyelid width, clinical activity score (CAS), diplopia, and visual acuity did not differ between patients with GD and those with AT or euthyroid GO, suggesting that the GO phenotype was similar. Accordingly, the NOSPECS score did not differ between the three groups. The phenotype of GO is similar regardless of the underlying thyroid disease. Because this study was performed in a tertiary referral center, this conclusion can be restricted only to patients who develop moderate to severe GO.

Clinical Association of Thyroid Stimulating Hormone Receptor Antibody Levels with Disease Severity in the Chronic Inactive Stage of Graves' Orbitopathy.

PurposeTo investigate associations between serum thyroid stimulating hormone (TSH) receptor antibody (TRAb) levels and Graves' orbitopathy (GO) activity/severity in chronic-stage GO and compare the performance of two newly-developed TRAb assays (third-generation TSH-binding inhibition immunoglobulin [TBII] assay versus Mc4 thyroid-stimulating immunoglobulin [TSI] bioassay).MethodsThis study is a retrospective review of medical charts and blood tests from Korean GO patients who first visited the departments of ophthalmology and endocrinology, Yonsei University College of Medicine from January 2008 to December 2011, were diagnosed with GO and Graves' hyperthyroidism, and were followed up for ≥18 months. Third-generation M22-TBII and Mc4-TSI assays were performed in the chronic-inactive GO patients in whom euthyroidism status was restored. Patients' GO activity/severity clinical activity scores (CAS), and modified NOSPECS scores were examined for a correlation with TRAb assays.ResultsFifty patients (mean age, 41.3 years; 41 females) were analyzed. The mean duration of Graves' hyperthyroidism symptom was 63 months (range, 18 to 401 months) and that of GO was 46 months (range, 18 to 240 months). All patients had been treated previously with anti-thyroid drugs for a median period of 52.3 months, and two patients underwent either radioiodine therapy or total thyroidectomy. Mean CAS and NOSPECS scores were 0.5 ± 0.9 (standard deviation) and 4.8 ± 3.1, respectively. Mean M22-TBII and Mc4-TSI values were 7.5 ± 10.2 IL/L and 325.9 ± 210.1 specimen-to-reference control ratio. TSI was significantly correlated with NOSPECS score (R = 0.479, p < 0.001); however, TBII was not associated with NOSPECS score (p = 0.097). Neither TSI nor TBII correlated with CAS (p > 0.05), because GO inflammatory activity subsided in the chronic stages of GO.ConclusionsIn chronic-inactive GO after euthyroid restoration, GO activity score did not associate with serum levels of TRAb or TBII. However, levels of the functional antibody Mc4-TSI did correlate with GO severity. Therefore, the TSI bioassay is a clinically relevant measure of disease severity even in chronic inactive GO.

Application of MRI in severity grading and activity staging in thyroid associated ophthalmopathy

The influence of MRI on severity grading and activity staging in thyroid associated ophthalmopathy (TAO) was evaluated.The results showed that MRI had a higher detection rate in abnormalextraocular muscle than NOSPECS scores(χ~2 = 19.37,P = 0.000).MRI had higher sensitivity,specificity,and accuracy in detection of active TAO than clinical activity score (100% vs 95.7%,88.2% vs 35.3%,96.9% vs 79.7%,respectively).Therefore,MRI improves early detection of atypical grade 4 cases.Signal intensity elevation in adipose suppressed T2WI is helpful to define active stage. Key words: Thyroid associated ophthalmopathy; NOSPECS scores; Clinical activity; Magnetic resonance imaging

New immunomodulators in the treatment of Graves’ ophthalmopathy

Steroids have been used in the therapy of the moderate to severe forms of Graves’ ophthalmopathy (GO) and other autoimmune diseases as they act only as general immunosuppressants. Previous work has shown that blocking the CD-20 receptor on B lymphocytes has significantly affected the clinical course of GO, by rapidly reducing inflammation and the degree of proptosis. We have studied nine patients with Graves’ disease, of whom seven had active GO and two, with newly diagnosed hyperthyroidism, only mild lid signs. We also studied a group of 20 consecutive patients, treated with intravenous glucocorticoids (IVGC) according to a standard protocol. Patients treated with RTX (1000 mg i.v. twice at two-week interval) and those treated with IVGC (500 mg i.v. for 16 weeks) were studied monthly up to 12 months after the first drug infusion. By ophthalmological examination, GO was assessed by the clinical activity score (CAS) and by the NOSPECS score. Thyroid function and lymphocyte count were measured by standardized methods. RTX was well-tolerated and only minor side-effects were reported in 30% of patients during the first infusion. All patients attained peripheral B-cell depletion with the first RTX infusion. All but one patients showed both CD20+ cells and CD19+ cells depletion, while one had persistent 3–5% CD19+ cells in the periphery, mostly CD19 + 5+. Thyroid function was not affected by RTX therapy. Titers of antithyroglobulin (TgAb), antithyroperoxidase and anti-TSH receptor antibodies (TRAb) did not change significantly ( P = NS) and did not correlate to CD20+ depletion ( P = NS). CAS values decreased significantly ( P < 0.0001). Proptosis decreased significantly after RTX in both patients with active GO (ANOVA; P < 0.0001) and in those with Graves’ hyperthyroidism and lid signs (ANOVA; P < 0.003). The degree of inflammation (NOSPECS class 2) decreased significantly in response to RTX (ANOVA; P < 0.001). In patients treated with IVGC, mean CAS value decreased significantly less than in those treated with RTX ( P < 0.05). Adverse effects were more frequent after IVGC (45% of patients). Seventy-five percent of patients responded to IVGC and 10% showed relapse of active GO six to eight weeks after withdrawal. The results of this study on RTX in GO suggest that the drug is effective in modifying the disease course and that the improvement of the clinical activity of GO after RTX was more significant than after IVGC. We did not observe relapse of active GO, even after B-cell return in peripheral blood. This might be related to the persistence of a significant degree of B-cell depletion after RTX observed in the peripheral blood as late as two years of follow-up. RTX therapy was also effective in improving proptosis and soft tissue inflammation. The mechanism by which RTX affects GO is unknown. It may act as a true immunosuppressor by switching off reactions inducing the active phase of TAO, perhaps by influencing the cytokine production in the orbit or by inducing depletion of antigen presenting B-cells.

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.

Somatostatin receptor scintigraphy before and after treatment with somatostatin analogues in patients with thyroid eye disease.

Octreotide, a potent synthetic long-acting somatostatin analogue, has been shown to have a beneficial effect in thyroid eye disease (TED). Orbital scintigraphy using ocetreoscan-111 is a useful study, which can be used to visualize somatostatin-receptor-bearing cells and also to select patients who might benefit from octreotide therapy. One major limitation of this therapy is that the drug must be administered parenterally and used several times daily. Lanreotide, a new somatostatin analogue, has a much longer duration of action in comparison with octreotide, and has recently been found to have a beneficial effect in the treatment of thyroid eye disease. The aim of this study was to investigate the orbital Indium-111-pentetreotide activity after treatment with octreotide and lanreotide in patients with thyroid ophthalmopathy. Fourteen patients were studied. 12 with bilateral and 2 with unilateral thyroid eye disease, (10 females and 4 males) and all with moderately severe symptoms of ophthalmopathy. All were treated with antithyroid drugs and were euthyroid at the time of the study. All patients were investigated with orbital scintigraphy using octreoscan-111 and selected for study on the basis of a positive octreoscan. Five patients received 30 mg lanreotide intramuscularly once every 2 weeks over a period of 3 months, and 5 patients received octreotide 100 microg subcutaneously thrice daily for 3 months. Four patients served as controls and received no treatment. The octreoscan-111 scintigraphy was repeated in all patients 3 months after the first examination. The NOSPECS classification and the clinical activity score (CAS) of thyroid ophthalmopathy were also evaluated before and 3 months after the initiation of treatment. All patients who received treatment had a negative follow-up octreoscan while controls had a positive octreoscan. NOSPECS score and CAS were improved with treatment, but unchanged in control patients. The reduced uptake of octreoscan may be the result of blocking of somatostatin receptors, or reduction in receptor-expressing tissues, downregulation of somatostatin receptors in target tissues, or a combination of these factors.

Somatostatin receptor scintigraphy and octreotide treatment in patients with thyroid eye disease

Octreotide, a potent long-acting synthetic somatostatin analogue, has been reported to have a beneficial effect in thyroid eye disease (TED), but the precise mechanism of action remains unexplained. 111In-DTPA-D-Phe1-octreotide (Octreoscan-111) has been used to localize a number of endocrine tumours and visualize somatostatin receptors in the retrobulbar tissue of patients with TED. Furthermore, this technique can predict the inhibitory effect of octreotide on hormone secretion by endocrine tumours, as there is a close relation between the clinically observed inhibition and visualization of the tumour using Octreoscan-111. The aims of the present study were to confirm the beneficial effect of octreotide in patients with TED, to investigate the presence of somatostatin receptors in the orbital area and also, if possible, to ascertain whether this technique could select those patients with TED who might benefit from treatment with octreotide. A prospective study. An endocrine clinic of a national hospital. Twenty treated thyrotoxic patients with TED, 5 treated thyrotoxic patients without TED and 5 normal individuals were studied. In 12 patients with TED, 5 without TED and 5 normal individuals, Octreoscan-111 scintigraphy of the orbits was performed. The remaining 8 patients with ophthalmopathy served as controls. In patients with TED who were investigated with Octreoscan-111, 300 micrograms octreotide daily was given for 12 weeks. Six patients in both eyes and one patient in one eye showed an improvement in ocular manifestations as assessed by clinical criteria and changes in the NOSPECS score, while the rest showed no improvement. The patients who showed an improvement had a high number of somatostatin receptors and positive orbital scans, while with one exception the patients who did not respond had a low number of receptors and negative orbital scans (P < 0.02). None of the 5 patients without TED nor the normal individuals had a positive orbital scan. Seven out of 8 control patients with TED showed no change in the disease during the trial, while 1 deteriorated. We conclude that octreotide has a beneficial effect in thyroid eye disease and that Octreoscan-111 could predict those patients with thyroid eye disease who might benefit from this treatment.