Risk factors for developing thyroid-associated ophthalmopathy among individuals with Graves disease.
Stein Joshua D,Childers David,Gupta Shivani,Talwar Nidhi,Nan Bin,Lee Brian J,Smith Terry J,Douglas Raymond
IMPORTANCE:Thyroid-associated ophthalmopathy (TAO) is a common and debilitating manifestation of Graves disease (GD). Presently little is known about factors that may increase the risk of developing TAO among patients with GD. OBJECTIVE:To identify risk factors associated with the development of TAO among individuals with newly diagnosed GD. DESIGN, SETTING, AND PARTICIPANTS:In this longitudinal cohort study, all beneficiaries 18 years of age or older with newly diagnosed GD who were continuously enrolled in a large nationwide US managed care network and who visited an eye care professional 1 or more times from 2001 to 2009 were identified. International Classification of Diseases, Ninth Revision, Clinical Modification billing codes were used to identify those who developed manifestations of TAO. Multivariable Cox regression was used to determine the hazard of developing TAO among persons with newly diagnosed GD, with adjustment for sociodemographic factors, systemic medical conditions, thyrotropin levels, and medical and surgical interventions for management of hyperthyroidism. MAIN OUTCOMES AND MEASURES:Manifestations of TAO measured by hazard ratios (HRs) with 95% CIs. RESULTS:Of 8404 patients with GD who met the inclusion criteria, 740 (8.8%) developed TAO (mean follow-up, 374 days since initial GD diagnosis). After adjustment for potential confounders, surgical thyroidectomy, alone or in combination with medical therapy, was associated with a 74% decreased hazard for TAO (adjusted HR, 0.26 [95% CI, 0.12-0.51]) compared with radioactive iodine therapy alone. Statin use (for ≥60 days in the past year vs <60 days or nonuse) was associated with a 40% decreased hazard (adjusted HR, 0.60 [CI, 0.37-0.93]). No significant association was found for the use of nonstatin cholesterol-lowering medications or cyclooxygenase 2 inhibitors and the development of TAO. CONCLUSIONS AND RELEVANCE:If prospective studies can confirm our finding that a thyroidectomy and statin use are associated with substantially reduced hazards for TAO among patients with GD, preventive measures for this burdensome manifestation of GD may become a reality.
Clinical Implications of Immunoglobulin G4 to Graves' Ophthalmopathy.
Yu Sung Hoon,Kang Jun Goo,Kim Chul Sik,Ihm Sung-Hee,Choi Moon Gi,Yoo Hyung Joon,Lee Seong Jin
Thyroid : official journal of the American Thyroid Association
BACKGROUND:This study aimed to explore the relation of immunoglobulin G4 (IgG4) to clinical and laboratory characteristics of patients newly diagnosed with Graves' disease (GD) without or with Graves' ophthalmopathy (GO) and to analyze association of IgG4 with development and grade of GO in GD patients. METHODS:Sixty-four GD patients and 64 sex- and age-matched euthyroid subjects were enrolled. Serum levels of thyroid hormones, thyroid autoantibodies, immunoglobulin G (IgG), and IgG4 were measured, and ophthalmological and ultrasonographical evaluation was performed. RESULTS:In GD patients compared with euthyroid subjects, levels of thyroid hormones, thyroid autoantibodies and IgG4 as well as the IgG4/IgG ratio were elevated. GD patients having GO in comparison to not having GO were characterized by a female predominance; a high incidence of smoking history; high levels of T3, free T4, TSH receptor autoantibody (TRAb) and IgG4; and a high IgG4/IgG ratio after adjusting for sex. In GD patients, the IgG4 level was the independent factor associated with GO development on multivariate analysis. When severity and activity of GO were classified using the European Group on Graves' Orbitopathy criteria in GD patients with GO, IgG4 levels and IgG4/IgG ratio were elevated in the moderate-to-severe group compared with the mild group and in the active group compared with the inactive group. IgG4 levels and IgG4/IgG ratio became elevated as clinical activity score increased. IgG4 levels were positively correlated with TRAb levels. The high IgG4 group in comparison to the normal IgG4 group had a high incidence of family history of autoimmune thyroid disease, high levels of free T4, TRAb and IgG4, a high IgG4/IgG ratio and extensive hypoechogenicity. CONCLUSIONS:These results suggest that IgG4 levels are elevated in newly diagnosed GD patients compared with euthyroid subjects and in the presence of GO compared with the absence of GO. Moreover, our findings suggest that IgG4 levels are associated with the development and grade of GO in GD patients.
Predicting the response to glucocorticoid therapy in thyroid-associated ophthalmopathy: mobilizing structural MRI-based quantitative measurements of orbital tissues.
Hu Hao,Xu Xiao-Quan,Chen Lu,Chen Wen,Wu Qian,Chen Huan-Huan,Zhu Hui,Shi Hai-Bin,Wu Fei-Yun
PURPOSE:We aimed to evaluate the performance of structural magnetic resonance imaging (MRI)-based quantitative measurements at extraocular muscle (EOM), orbital fat (OF), and especially lacrimal gland (LG) in predicting response to glucocorticoid (GC) in patients with active and moderate-severe thyroid-associated ophthalmopathy (TAO). METHODS:Forty-seven active and moderate-severe TAOs (responsive group, 29 patients and 58 eyes; unresponsive group, 18 patients and 36 eyes) were enrolled. Pretreatment MRI-based parameters of EOM, OF, and LG, and clinical factors were retrospectively collected and compared between two groups. Logistic regression and receiver operating characteristic curve analyses were used to assess the predictive value of identified independent variables. RESULTS:Responsive group showed significantly higher minimum signal intensity ratio of EOM (EOM-SIR) (p < 0.001), higher EOM-SIR (p = 0.034), higher LG herniation (LGH) (p = 0.019), lower OF thickness (OFT) (p = 0.017), higher LGH/OFT ratio (p = 0.001), and shorter disease duration (p = 0.004) than unresponsive group. Multivariate analysis showed that EOM-SIR, LGH/OFT ratio, and disease duration were independent predictors for responsive TAOs (all p < 0.05). Integration of three independent predictors demonstrated optimal predictive efficiency (area under curve, 0.829). Combining EOM-SIR ≥1.43 and LGH/OFT ratio ≥1.65, optimal predictive specificity (94.4%) could be obtained, while optimal predictive sensitivity (82.8%) was achieved when integrating disease duration ≤3.5 and LGH/OFT ratio ≥1.65. CONCLUSIONS:Structural MRI-based quantitative measurements at EOM, OF, and LG, specially EOM-SIR and LGH/OFT ratio, together with disease duration, may serve as promising markers to predict response to GC in patients with active and moderate-severe TAO.
Defective Regulatory B Cells Are Associated with Thyroid Associated Ophthalmopathy.
Chen Guo,Ding Yungang,Li Qian,Li Yanbing,Wen Xiaofeng,Ji Xian,Bi Shaowei,Chen Jingqiao,Xu Jianan,Chen Rongxin,Ye Huijing,Wei Lai,Yang Huasheng
The Journal of clinical endocrinology and metabolism
PURPOSE:To investigate the change of IL-10 producing regulatory B cells (Bregs), which function to suppress peripheral immune responses, in patients with thyroid associated ophthalmopathy (TAO). METHODS:Peripheral blood mononuclear cells (PBMCs) were isolated from healthy controls (N=54), patients with Grave's disease (N=26), and TAO patients (N=125), and stimulated with CpG/CD40L. The frequency of IL-10 producing Bregs and the expression of IL-10 in response to thyroid-stimulating hormone (TSH) stimulation were measured by flow cytometry. CD4+ T cells were cultured with Breg-depleted PBMCs to elucidate the function of Bregs in TAO patients. The potential immunoregulatory mechanism was also investigated by western blot and chromatin immunoprecipitation assays. RESULTS:Active TAO patients had higher baseline levels of Bregs in their peripheral blood than both healthy controls and inactive patients. TSH promoted Bregs. Bregs from TAO patients were defective in suppressing the activation of IFN-γ+ and IL-17+ T cells in vitro. CONCLUSIONS:We found that regulatory B cells in TAO patients are functionally defective, suggesting the defective Bregs might be responsible for the pathogenesis of TAO.
Clinical results of anti-inflammatory therapy in Graves' ophthalmopathy and association with thyroidal autoantibodies.
Eckstein Anja K,Plicht Marco,Lax Hildegard,Hirche Herbert,Quadbeck Beate,Mann Klaus,Steuhl Klaus P,Esser Joachim,Morgenthaler Nils G
OBJECTIVE: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. RESULTS: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. CONCLUSIONS: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.
Thyrotropin receptor autoantibodies are independent risk factors for Graves' ophthalmopathy and help to predict severity and outcome of the disease.
Eckstein Anja K,Plicht Marco,Lax Hildegard,Neuhäuser Markus,Mann Klaus,Lederbogen Sebastian,Heckmann Christian,Esser Joachim,Morgenthaler Nils G
The Journal of clinical endocrinology and metabolism
OBJECTIVE: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. METHODS AND PATIENTS: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%). RESULTS: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. CONCLUSION: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.
Smoking was associated with poor response to intravenous steroids therapy in Graves' ophthalmopathy.
Xing Lijing,Ye Lei,Zhu Wei,Shen Liyun,Huang Fengjiao,Jiao Qin,Zhou Xiaoyi,Wang Shu,Wang Weiqing,Ning Guang
The British journal of ophthalmology
BACKGROUND:Previous studies have shown that smoking is closely related to the occurrence, severity and response to orbital radiation in Graves' ophthalmopathy (GO). The aim of this study was to investigate whether smoking impacts the response to intravenous 4.5 g methylprednisolone therapy in patients with active moderate-to-severe GO. METHODS:Ninety-two individuals with active moderate-to-severe GO who were treated with cumulative doses of 4.5 g intravenous methylprednisolone within 3 months were recruited. The patients were grouped as never smokers, active smokers (including smokers and quit smokers) and passive smokers. RESULTS:We observed significantly greater response rate in never smokers compared with active smokers (73.9% vs 29.0%, p=0.001). After adjusting the confounding factors such as age, sex, body mass index, clinical activity score, thyroid-stimulating hormone receptor antibody and the duration of GO, smoking was independently associated with poor intravenous glucocorticoid (GC) response (OR 12.40, 95% CI 1.20 to 128.14, p=0.035). We also found the response rate was significantly higher in never smokers than in quit smokers (73.9% vs 16.7%, p=0.001), while no statistical significance between current smokers and quit smokers (36.8% vs 16.7%, p=0.228). There was a trend of poor response for passive smokers compared with never smokers (64.7% vs 72.2%, p=0.583). CONCLUSIONS:Smoking, even past smoking, was an independent risk factor associated with impaired response to intravenous corticosteroids in patients with GO. Smokers with GO should be given optimised treatment strategy such as higher dose of GC or combined radiation therapy.
Cohort study on radioactive iodine-induced hypothyroidism: implications for Graves' ophthalmopathy and optimal timing for thyroid hormone assessment.
Stan Marius N,Durski Jolanta M,Brito Juan P,Bhagra Sumit,Thapa Prabin,Bahn Rebecca S
Thyroid : official journal of the American Thyroid Association
BACKGROUND:Graves' ophthalmopathy (GO) develops or worsens in up to one-third of patients treated with radioactive iodine (RAI) for Graves' hyperthyroidism. We sought to identify the prevalence of development or worsening of GO in patients treated with RAI for Graves' hyperthyroidism and to identify the risk factors associated with that outcome. METHODS:We identified a retrospective cohort of consecutive patients treated with RAI at Mayo Clinic (Rochester, MN) between 2005 and 2006. We assessed their medical records for evidence of hypothyroidism and development or worsening of GO in the year after therapy. Hypothyroidism was defined as thyrotropin >3.0 mIU/L or free thyroxine <0.8 ng/dL. RESULTS:We identified 291 consecutive patients who received RAI therapy during the study period, with 195 out of 291 having complete follow-up data for a one-year period. GO was present in 46 out of 195 patients (23.6%) at baseline. After RAI treatment, GO developed or worsened in 25 out of 195 patients (12.8%) and it was associated with hypothyroidism at first follow-up (p=0.011) with an odds ratio (OR) of 3.3 [95% confidence interval (CI) 1.3-8.7]. More smokers than nonsmokers developed new or worse GO (17.7% vs. 11.8%), but that difference did not reach statistical significance (p=0.35). Preexisting GO (24% of patients) was associated with a higher risk for negative GO outcome compared with patients who had no GO at baseline (11%; p=0.021). Both development of hypothyroidism by the first visit after RAI therapy (OR 3.6) and preexistent GO (OR 2.8) remained significant in a multivariate analysis. Development of hypothyroidism was more likely in patients with longer duration to first follow-up (p<0.001). By 6-8 weeks after RAI treatment, the prevalence of hypothyroidism was ∼40%, while that of hyperthyroidism was only 20%. CONCLUSIONS:The presence of hypothyroidism at the first assessment of thyroid function after RAI administration is a strong predictor for adverse GO outcome. This risk is highest in patients with preexisting GO. We suggest that in order to prevent clinical hypothyroidism and the associated risk for GO, the optimal time for first measurement of fT4 is before 6 weeks after RAI therapy.