استكشف المجموعة الواسعة من العناوين المتاحة.

In a good example of translational research, investigators who had initially demonstrated a role for insulin-like growth factor I in the pathogenesis of thyroid eye disease showed that an antibody to the receptor (teprotumumab) produced a meaningful improvement in 83% of patients.

This article reviews the mechanisms that lead to the development of Graves' ophthalmopathy. A central feature in its development is autoimmunity that involves not only T cells, B cells, and macrophages but also fibroblasts and adipose tissue within the orbit. Intraorbital cytokine-mediated inflammation also has a prominent role. These recent findings suggest new ways of treating this debilitating disease. This article reviews the mechanisms that lead to the development of Graves' ophthalmopathy. Recent findings suggest new ways of treating this debilitating disease. Graves' ophthalmopathy, also called Graves' orbitopathy, is a potentially sight-threatening ocular disease that has puzzled physicians and scientists for nearly two centuries. 1 – 3 Generally occurring in patients with hyperthyroidism or a history of hyperthyroidism due to Graves' disease, Graves' ophthalmopathy is also known as thyroid-associated ophthalmopathy or thyroid eye disease, because it sometimes occurs in patients with euthyroid or hypothyroid chronic autoimmune thyroiditis. The condition has an annual adjusted incidence rate of 16 women and 3 men per 100,000 population. 4 This review explores the perplexing relationship between Graves' ophthalmopathy, hyperthyroidism, and thyroid dermopathy, the associated skin condition. I examine clinical . . .

Graves orbitopathy, also known as thyroid eye disease or thyroid-associated orbitopathy, is visually disabling, cosmetically disfiguring and has a substantial negative impact on a patient's quality of life. There is increasing awareness of the need for early diagnosis and rapid specialist input from endocrinologists and ophthalmologists. Glucocorticoids are the mainstay of treatment; however, recurrence occurs frequently once these are withdrawn. Furthermore, in >60% of cases, normal orbital anatomy is not restored, and skilled rehabilitative surgery is required. Clinical trials have shown that considerable benefit can be derived from the addition of antiproliferative agents (such as mycophenolate or azathioprine) in preventing deterioration after steroid cessation. In addition, targeted biologic therapies have shown promise, including teprotumumab, which reduces proptosis, rituximab (anti-CD20), which reduces inflammation, and tocilizumab, which potentially benefits both of these parameters. Other strategies such as orbital radiotherapy have had their widespread role in combination therapy called into question. The pathophysiology of Graves orbitopathy has also been revised with identification of new potential therapeutic targets. In this Review we provide an up-to-date overview of the field, outline the optimal management of Graves orbitopathy and summarize the research developments in this area to highlight future research questions and direct future clinical trials.

In patients with thyroid-associated ophthalmopathy, responses to treatment are rare and usually minor. Teprotumumab, an antibody to the insulin-like growth factor I receptor, led to significant responses in 69% of patients and to decreased proptosis. Medical therapies for moderate-to-severe thyroid-associated ophthalmopathy (Graves’ orbitopathy) that have proved to be effective and safe in adequately powered, prospective, placebo-controlled trials are lacking. This unmet need is due to the incompletely understood pathogenesis of the disease. 1 Current treatments are inconsistently beneficial and often associated with side effects, and their modification of the ultimate disease outcome is uncertain. 1 – 3 Previous clinical trials, which were rarely placebo-controlled, suggest that high-dose glucocorticoids, alone 3 – 5 or with radiotherapy, 6 , 7 can reduce inflammation-related signs and symptoms in patients with active ophthalmopathy. However, glucocorticoids and orbital radiotherapy minimally affect proptosis and can cause dose-limiting adverse . . .

Objective To demonstrate the efficacy of the anti-interleukin-6 receptor monoclonal antibody tocilizumab in patients with moderate-to-severe corticosteroid-resistant Graves orbitopathy (GO).Design Double-masked randomized clinical trial.Methods Setting and Participants: Thirty-two adults with moderate-to-severe corticosteroid-resistant GO from 10 medical centers in Spain were randomized (1:1). Intervention: Randomization to either 8 mg/kg body weight tocilizumab or placebo administered intravenously at weeks 0, 4, 8, and 12, and follow-up for an additional 28 weeks. Main Outcomes and Measures: The primary outcome was the proportion of patients with a change from baseline to week 16 of at least 2 in the clinical activity score (CAS).Results The primary outcome was met by 93.3% (95% confidence interval [CI] 70.1%-98.8%) of the patients receiving tocilizumab and 58.8% (36%-78.3%) receiving placebo (P = .04; odds ratio, 9.8 [CI 1.3-73.2]). A significant difference was also observed in the proportion of patients achieving a CAS < 3 (86.7% [CI 62.1%-96.2%] vs 35.2% [CI 17.3%-58.7%], P = .005; OR 11.9 [CI 2.1-63.1]) at week 16. Additionally, a larger proportion of patients with improvement in the European Group on GO–proposed composite ophthalmic score at week 16 (73.3% [CI 48%-89.1%] vs 29.4% [CI 13.2%-53.1%]; P = .03), and exophthalmos size change from baseline to week 16 (-1.5 [-2.0 to 0.5] mm vs 0.0 [-1.0 to 0.5] mm; P = .01) were seen with tocilizumab. One patient experienced a moderate increase in transaminases at week 8; another had an acute pyelonephritis at week 32 in the tocilizumab-treated group.Conclusion Tocilizumab offers a meaningful improvement in activity and severity in corticosteroid-resistant GO. This trial justifies further studies to characterize the role of tocilizumab in GO.

Purpose Improved understanding of thyroid eye disease (TED) pathogenesis has facilitated identification of a targeted molecular approach for TED treatment offering the potential to halt or slow disease progression in a nonsurgical manner. Herein, we provide a summary of the current knowledge of TED management, followed by discussion of a novel insulin-like growth factor-1 receptor (IGF-1R) antagonist antibody and its potential to change the course of the disease.Design Perspective.Methods Review of the literature and authors' experience.Results Many publications demonstrate IGF-1R overexpression in TED, and its activation as an autoantigen as a critical factor in TED pathogenesis. Several in vitro studies demonstrate that IGF-1R inhibition attenuates downstream molecular events including cytokine and hyaluronan production, and cellular differentiation. These observations led to the hypothesis that blocking IGF-1R may abrogate the clinical progression of TED. The recent completion of phase 2 and 3 randomized, placebo-controlled trials demonstrate the efficacy and safety of teprotumumab, a fully human monoclonal IGF-1R antagonist antibody, in patients with moderate-to-severe, active TED. Both the phase 2 and the recent phase 3 study results demonstrate that more patients with active TED receiving teprotumumab experienced a meaningful improvement in proptosis.Conclusions Current TED treatment strategies target inflammation and symptoms, but do not modify the disease course. Therefore, proptosis as well as strabismus and its resulting diplopia often remain, impacting patient well-being and quality of life over the long term. Targeted molecular therapy using teprotumumab demonstrates disease-modifying benefits with the potential to shift the paradigm for TED treatment.

Fibrosis is the late stage of thyroid-associated ophthalmopathy (TAO), resulting in serious complications. Effective therapeutic drugs are still lacking. We aimed to explore the mechanism of TAO fibrosis and to find a targeted drug. High-throughput RNA sequencing was performed on orbital connective tissues from twelve patients with TAO and six healthy controls. Protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes (STRING) database and we identified the hub gene by Cytoscape software. Additionally, the RNA sequencing results were validated by quantitative real-time polymerase chain reaction (qRT-PCR). Bioinformatic prediction identified the functions of differentially expressed genes (DEGs). Further orbital connective tissue and serum samples of the TAO and control groups were collected for subsequent experiments. Histologic staining, Western blotting (WB), qRT-PCR, enzyme-linked immunosorbent assays (ELISAs), gene overexpression through lentiviral infection or silencing gene by short interfering RNA (siRNA) were performed. We found that the relaxin signaling pathway is an important regulatory pathway in TAO fibrosis pathogenesis. Serelaxin exerts antifibrotic and anti-inflammatory effects in TAO. Furthermore, the downstream Notch pathway was activated by serelaxin and was essential to the antifibrotic effect of serelaxin in TAO. The antifibrotic effect of serelaxin is dependent on RXFP1.

This trial compared oral selenium, an antioxidant agent, or oral pentoxifylline, an antiinflammatory agent, with placebo in mild Graves' orbitopathy. Selenium significantly improved quality of life and eye involvement and slowed disease progression. Approximately half the patients with Graves' disease have ocular involvement (Graves' orbitopathy). 1 Moderately severe and active forms of Graves' orbitopathy can be effectively treated with glucocorticoids, orbital irradiation, or both, 1 , 2 whereas milder forms may improve spontaneously and generally require only local measures to control symptoms (i.e., artificial tears, ointments, and prisms). A wait-and-see strategy in which patients are monitored until symptoms worsen can be challenged. First, many patients with even mild Graves' orbitopathy have a substantial decrease in their quality of life, as assessed either by general health–related quality-of-life questionnaires 3 or by a Graves' orbitopathy–specific quality-of-life questionnaire (GO-QOL). 4 Second, . . .

Graves ophthalmopathy (GO), which occurs in autoimmune thyroid disease, can reduce patients’ quality of life due to its impact on visual function, physical appearance, and emotional health. Corticosteroids have been the first-line treatment for GO. More recently, the pathogenesis of GO has made significant progress. Various targeting biological agents and immunosuppressive agents make GO management more promising. Fully understanding GO pathogenesis and precise clinical management are beneficial for the prognosis of patients. Therefore, we conducted a comprehensive review of the medical management of GO and summarized research developments to highlight future research issues.

PurposeThyroid eye disease (TED) is a progressive, debilitating and potentially vision-threatening autoimmune disease. Teprotumumab, a novel human monoclonal antibody, has been shown to reverse the clinical manifestations of TED. Patients receiving teprotumumab have been shown in two multicenter, randomized placebo-controlled trials to have decreased proptosis, diplopia and inflammation after 24 weeks of treatment. This study aims to analyse volumetric and inflammatory changes on orbital imaging prior to and after teprotumumab treatment from one of these trials.DesignRetrospective review.SubjectsSix patients enrolled in the phase III teprotumumab clinical trial (OPTIC, NCT03298867) with active TED who received 24 weeks of teprotumumab and had pre- and post-treatment orbital imaging (CT or MRI). Additionally, 12 non-TED patients (24 orbits) were analysed as a comparative control group.Methods3D volumetric calculations of the extraocular muscles (EOMs), orbital fat, and bony orbit were measured using previously validated image processing software. 3D volumetric results and changes in EOM inflammation were compared with clinical measurements of TED.ResultsTotal EOM volume within each orbit was markedly reduced post-teprotumumab in all patients (n=six patients, 12/12 orbits, p<0.02). There was no statistical difference in post-treatment EOM volume when compared to non-TED controls. Total orbital fat volume was also reduced in 11 of 12 studied orbits (n=six patients, p=0.04). Overall EOM inflammation based on MRI signal intensity ratio was reduced in 8/8 orbits (n=four patients, p<0.01).ConclusionOrbital imaging demonstrated decreased EOM volumes and orbital fat tissue volumes after teprotumumab treatment.