2021年欧洲Graves眼病专家组Graves眼病管理指南解读

2021年7月, 欧洲Graves眼病专家组(EUGOGO)发布了新一版Graves眼病(GO)管理指南, 在2016版指南的基础上, 新版指南重点更新了中重度、活动期GO患者的一线治疗方案, 提供了多种二线治疗策略, 对病情评估、一般管理、病情针对性管理等方面做了详细的推荐, 并增加了疗效评估、新型冠状病毒肺炎疫情下管理、甲状腺功能控制等内容, 共包含32条推荐条目, 新版指南也指出部分治疗方案用于治疗GO仍需进一步疗效和安全性验证。     

情理之中, 亦有意料之外——2021版欧洲格雷夫斯眼眶病协作组临床实践指南中的主要更新点

2021年7月, 欧洲格雷夫斯眼眶病协作组(EUGOGO)推出《2021版格雷夫斯眼眶病医学管理的EUGOGO临床实践指南》, 侧重于格雷夫斯眼眶病(GO)的药物治疗, 充分回顾了有关GO治疗的循证研究结果。与前版(2016版)相比, 新指南增加了GO的新风险因素, 明确了GO治疗结局评估方法, 对中重度活动性GO的一线和二线治疗建议进行了大幅修改, 是指导和规范GO临床实践行为的重要参考。     

血清可溶性细胞间黏附分子1、透明质酸水平与Graves眼病疾病活动性之间的关系

探讨可溶性细胞间黏附分子1( sICAM-1)和透明质酸(HA)能否反映Graves眼病(GO)的疾病活动性.用ELISA方法检测48例GO患者(眼病组)的sICAM-1、HA水平,同时检测30例单纯Graves甲状腺功能亢进患者作为对照组.与对照组相比,眼病组的血清sICAM-1、HA水平明显增高(P＜0.05);且眼病组活动期的血清sICAM-1、HA水平明显高于稳定期(P＜0.05).Pearson相关性分析显示眼病组的血清sICAM-1、HA水平均与眼病活动分数(CAS)呈显著正相关(r=0.53,P＜0.01;r=0.46,P＜0.01),且sICAM-1与HA亦呈正相关(r=0.31,P＜0.05).GO患者外周血sICAM-1、HA水平可作为评价GO活动性的指标.     

如何测量静息心率?

2021年4月高血压心率管理多学科共识组发表了《中国高血压患者心率管理多学科专家共识(2021年版)》(新共识)[1].新共识在2017年《高血压患者心率管理中国专家共识》的基础上增加了一些新的、有价值的内容[2],建议将我国高血压患者的心率干预切点定义为静息心率＞80次/min.如在静息状态下不同时间点的多次家庭自测...     

氧化应激与Graves眼病

Graves眼病(GO)患者血清活性氧簇(ROS)水平明显增高;后者刺激患者眼眶成纤维细胞(OF)分化,促进氨基葡聚糖(GAG)的生成,诱导人白细胞抗原-DR(HLA-DR)和热休克蛋白-72、细胞间黏附分子-1(ICAM-1)的表达,促进GO的发生、发展.吸烟作为最重要的环境因素,主要通过促进ROS的增加和抗氧化物质的减少,加剧GO的发展.因此,抗氧化剂可通过清除氧自由基抑制ROS所诱导的一系列反应.可见,氧化应激在GO发病机制中发挥重要作用.     

Graves眼病的诊断和治疗

甲状腺相关性眼病(TAO),顾名思义是指与甲状腺疾病有关的眼病,由于其最常见于Graves病,因此有人对TAO与Graves眼病(Graves ophthalmopathy,GO)不作区分,互相通用。关于命名问题迄今仍然比较混乱,但严格地讲,TAO是大概念,GO是小概念,即GO只是TAO的一种类型。TAO     

血清白介素6及其可溶性受体水平与Graves眼病活动性

测定Graves眼病 (GO)组 ,Graves病无眼病组 (NGO) ,正常对照组 3组血清白介素 6(IL 6)、可溶性IL 6受体 (sIL 6R)的水平和对GO组中激素治疗有效亚组与无效亚组间临床活动性评分 (CAS) ,结果显示血清IL 6、sIL 6R和CAS可以反映GO的活动性并预测糖皮质激素治疗效果     

Graves眼病的诊治新进展

Graves眼病(GO)又称内分泌突眼,其病因及发病机制尚未彻底阐明,治疗效果欠 佳,严重影响患者生存质量。近年,在对GO发病机制进行深入研究的同时,也对临床治疗 进行了积极探讨。本文主要对目前GO诊断和治疗方面资料作一综述。     

氧化应激DNA损伤与Graves眼病关系的临床研究

Graves眼病(GO)通常被认为是一种与甲状腺相关的自身免疫病[1].有关GO发病机制的研究很多,但尚不明确.近年来,越来越多的证据显示氧化应激参与GO的发病[2].8-羟基脱氧鸟嘌呤(8-OHdG)是DNA的氧化核苷,是机体DNA氧化应激损伤的敏感生物指标.本研究通过检测GO患者的血8-OHdG水平,初步探讨其在GO发病机制中的作用及与GO活动性的关系.     

甲状腺刺激抗体与Graves眼病临床特点的关系

比较分析32例初诊的Graves眼病（GO）患者和27例无眼病Graves病（GD）患者甲状腺刺激抗体（TSAb）与临床特点的关系；并且分析影响糖皮质激素冲击治疗GO预后的因素，发现GO组TSAb水平明显高于GD组，且对预后有显著影响，提示TSAb可能是TSH受体抗体中与眼病损伤更为密切的抗体成分，可作为GO的预测指标。     

Psychological implications of Graves' orbitopathy

Patients with thyroid eye disease, Graves' orbitopathy (GO), often appear distressed and it is likely that features of the condition such as disturbances in visual function, orbital discomfort and alterations in facial appearance can impart significant psychological morbidity upon the patient, which in turn can be detrimental to their quality of life. When considering the psychological impact of GO, two elements of the disease are important. The disfiguring changes to the eyes and face can have a direct effect upon psychological health, while physical aspects of the disease such as altered visual acuity, diplopia, orbital pain and lacrimation may influence psychological function as a secondary phenomenon, due to interference with daily living. Evidence appears to confirm the anecdotal impression of many clinicians dealing with GO patients that the prevalence of psychological morbidity in this patient group is high. A 'biopsychosocial' approach to care that addresses biological and psychosocial functioning as major determinants of health is an appropriate strategy when treating patients with GO.     

A questionnaire survey on the management of Graves' orbitopathy in Europe

OBJECTIVE: To determine management patterns among clinicians who treat patients with Graves' orbitopathy (GO) in Europe. DESIGN AND METHODS: Questionnaire survey including a case scenario of members of professional organisations representing endocrinologists, ophthalmologists and nuclear medicine physicians. RESULTS: A multidisciplinary approach to manage GO was valued by 96.3% of responders, although 31.5% did not participate or refer to a multidisciplinary team and 21.5% of patients with GO treated by responders were not managed in a multidisciplinary setting. Access to surgery for sight-threatening GO was available only within weeks or months according to 59.5% of responders. Reluctance to refer urgently to an ophthalmologist was noted by 32.7% of responders despite the presence of suspected optic neuropathy. The use of steroids was not influenced by the age of the patient, but fewer responders chose to use steroids in a diabetic patient (72.1 vs 90.5%, P<0.001). Development of cushingoid features resulted in a reduction in steroid use (90.5 vs 36.5%, P<0.001) and increase in the use of orbital irradiation (from 23.8% to 40.4%, P<0.05) and surgical decompression (from 20.9 to 52.9%, P<0.001). More ophthalmologists chose surgical decompression for patients with threatened vision due to optic neuropathy, who were intolerant to steroids than other specialists (70.3 vs 41.8%, P<0.01). CONCLUSION: Deficiencies in the management of patients with GO in Europe were identified by this survey. Further training of clinicians, easier access of patients to specialist multidisciplinary centres and the publication of practice guidelines may help improve the management of this condition in Europe.     

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.     

Psychosocial morbidity of Graves' orbitopathy

OBJECTIVE: Ocular diseases markedly impair daily function. In Graves' orbitopathy (GO), an associated psychosocial burden is present due to disfiguring proptosis and/or diplopia, signs with significant impact on functional status and well-being. We have therefore surveyed and assessed the psychosocial morbidity of GO. DESIGN: A prospective controlled study on subjects with GO using internationally validated, self-reporting questionnaires. PATIENTS: One hundred and two consecutive patients with varying degrees of severity and activity of GO. Measurements Emotional distress, coping styles and quality of life (QoL) were assessed by the Hospital Anxiety and Depression Scale, by a German adaptation of the Ways-of-Coping Checklist, and with the 36-item Short Form, respectively. Stressful events in the 6 months preceding diagnosis were registered with the Life Experience Survey. QoL findings were compared to German reference values, as well as to 102 age- and gender-matched patients, each with type 1 diabetes (insulin-dependent diabetes mellitus, IDDM) and inflammatory bowel disease (IBD), respectively. RESULTS: Compared to the German reference population, all QoL scales were at a lower rate and were especially decreased in subjects with active and/or severe GO, orbital pain, diplopia and stressful life events. Compared to diabetics, psychosocial scales were considerably reduced in GO (z = -1 vs. 0.1, P < 0.001) and higher scores for depressive coping (2.32 vs. 1.71, P < 0.001) and trivializing (2.37 vs. 1.97, P < 0.006) were noted. In GO, depressive coping and trivializing were negatively correlated with the mental (r = -0.603 and r =-0.411, both P < 0.001) and physical (r = -0.487 and r = -0.354, both P < 0.001) components of QoL. Depressive coping also positively correlated with anxiety (r = 0.636) and depression (r = 0.590), respectively, both P < 0.001. Emotional distress noted in 46 subjects, mostly with active and severe GO, was associated with poor QoL. Anxiety and depression were present in 41 and 24 GO patients, respectively. The number of stressful events positively correlated with the scores of anxiety (r = 0.3335) and depression (r = 0.3178), both P = 0.001. Foremost emotional distress, but also diplopia, stressful events and depressive coping had a major impact on QoL (proportion of variance explained = 13.1%, P < 0.001, multiple regression analysis). More than 75% of the psychosocial impairment in GO (R2= 0.76, P < 0.001) was associated with seven variables only (e.g. depression and anxiety). Six months prior to GO onset, 74 patients experienced a mean of 4 (range 0-13) stressful life events. Subjects with optic neuropathy had more stressful events than those without nerve involvement (5.1 vs. 2.7, P = 0.0425). CONCLUSIONS: Psychosocial morbidity is present in severe and/or active GO, which negatively affects QoL. The patients are not only physically ill, they also exhibit emotional distress. Accompanying psychosomatic treatment is indicated among about half of all GO patients.     

The pathogenesis of Graves' ophthalmopathy

The pathology of the orbital changes in Graves' ophthalmopathy (GO) has been discussed in detail. The target tissue is the eye muscle and the damage probably results from autoimmune processes. Cell-mediated immune responses have been demonstrated and an antibody to eye muscle is detectable in 70% of patients. There is no direct evidence for an effect of thyroid hormones or TSH on orbital tissues in GO. The relation between GO and autoimmune thyroid disease is discussed. Present evidence suggests that in GO autoimmune responses are directed to orbital tissue antigens and do not cross-react with thyroid antigens. Clinical studies suggest that all patients with hyperthyroidism have some abnormality of eye muscle, whereas not all patients with ophthalmopathy have evidence of thyroid disease. It is not possible at the present time to be certain whether GO is an integral part of Graves' disease or a separate entity.     

Effects of total thyroid ablation versus near-total thyroidectomy alone on mild to moderate Graves' orbitopathy treated with intravenous glucocorticoids

CONTEXT: Graves' orbitopathy (GO) is probably caused by autoimmune reactions against autoantigen(s) shared by thyroid and orbital tissues sustained by intrathyroidal autoreactive T-lymphocytes infiltrating the orbit. Total thyroid ablation (TTA) may be beneficial for GO through removal of shared antigen(s) and autoreactive T-lymphocytes, but randomized studies are lacking. OBJECTIVE: Our objective was to evaluate the effects of TTA in patients with GO treated with iv glucocorticoids (GC). DESIGN/SETTING: A prospective, single-blind, randomized study was conducted at a referral center. PATIENTS/INTERVENTIONS: Sixty patients with mild to moderate GO were randomized into: 1) near-total thyroidectomy (TX); or 2) TX plus (131)I (TTA) groups, and then treated with iv GC. Patients were evaluated 3 and 9 months after iv GC. MAIN OUTCOME MEASURE: Overall improvement of GO at 9 months was the main outcome measure. RESULTS: The distribution of GO outcome at 9 months was significantly more favorable in TTA than in TX patients (P = 0.0014 by chi(2) test). A cumulative significant (P = 0.0054) difference between the two groups at 3 and 9 months was found using a generalized linear model. Radioiodine uptake test and thyroglobulin assay in a patient sample showed complete ablation in the majority of TTA, but not of TX patients. CONCLUSIONS: Compared with thyroidectomy alone, TTA is followed by a better outcome of GO in patients given iv GC. Whether TTA maintains this advantage in the long-term remains to be established.     

Novel aspects of immunosuppressive and radiotherapy management of Graves' ophthalmopathy

Treatment of severe Graves' ophthalmopathy (GO) is a complex therapeutic challenge and, in spite of any efforts, about one third of patients are disappointed with the outcome of treatment. Glucocorticoids (GC), orbital radiotherapy (RT), or a combination of both, are most frequently used for their immunosuppressive effects. Novel immunosuppressive treatment procedures (or novel modalities of established treatments) are reviewed in the present article. GC has recently been used by the i.v. route and this treatment modality has been shown to be more effective and better tolerated than the oral route. Promising preliminary results have been reported by some authors with somatostatin analogs, octreotide and lanreotide. The number of patients treated so far is limited, most of the results have been obtained in nonrandomized or uncontrolled studies, and comparison with other validated methods of treatment is also needed. Because of the pathogenic role of cytokines, cytokine antagonists, currently evaluated in other autoimmune diseases, have been tested with positive results also in a small series of GO patients. The use of antioxidants might also be envisioned in the future, since in vitro studies have shown that oxygen free radicals might be involved in GO. Based on the shared antigen(s) theory, total thyroid ablation, by removing the bulk of shared antigens(s), might be beneficial for the course of GO. New data on recently performed placebo-controlled studies on orbital radiotherapy are discussed, together with studies on long-term safety of orbital radiotherapy.     

Graves' ophthalmopathy: state of the art and perspectives

Graves' ophthalmopathy (GO) is an autoimmune orbital disorder most commonly associated with Graves' disease. Recent studies have underscored the role that orbital cells, particularly fibroblasts and adipocytes, play in causing the increase in orbital content responsible for clinical manifestations of the disease. GO seems to be related to autoimmune reactions triggered by autoreactive T lymphocytes of thyroid origin, which recognize antigen(s) shared by thyroid and orbit. The nature of the antigen (or antigens) involved is not fully understood, but TSH receptor is likely to be involved. Cytokines secreted by T lymphocytes, macrophages and fibroblasts play an essential role in perpetuating the disease. Animal models of GO have been developed, but results have not clarified GO pathogenesis yet. Progress in the management of the ophthalmopathy has been very limited, and glucocorticoids, orbital radiotherapy and orbital decompression remain the mainstays in GO treatment. Novel treatments, such as somatostatin analogues, antioxidants, cytokine antagonists are currently under investigation, as well as the effects of total thyroid ablation. Cessation of smoking currently represents the only form of GO (secondary and tertiary) prevention.     

Pathogenesis of Graves' ophthalmopathy: the role of autoantibodies.

The clinical manifestations of Graves' ophthalmopathy (GO) stem from a combination of increased orbital fat and extraocular muscle volume within the orbital space. Fibroblasts residing within orbital tissues are thought to be targets of autoimmune attack in the disease. Thyrotropin receptor (TSHr) mRNA and functional protein have been demonstrated in orbital fibroblasts from both normal individuals and GO patients, with higher levels present in the latter. Autoantibodies directed against TSHr or the insulin-like growth factor-1 (IGF-1) receptor have been implicated in GO pathogenesis. Evidence from our laboratory suggests that monoclonal TSHr autoantibodies (TRAbs) are potent stimulators of adipogenesis in GO orbital cells. Therefore, it is possible that circulating TRAbs in Graves' patients both stimulate overproduction of thyroid hormones and increase orbital adipose tissue volume. Antibodies to the IGF-1 receptor appear to impact GO pathogenesis through recruitment and activation of T-cells and stimulation of hyaluronan production, processes that play key roles in the development of inflammation and increased orbital tissue swelling. Although originally thought to represent another causative agent, antibodies to extraocular muscles are now generally thought to be secondary to extraocular muscle inflammation and damage.