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Rebecca S Bahn - One of the best experts on this subject based on the ideXlab platform.
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current insights into the pathogenesis of Graves Ophthalmopathy
Hormone and Metabolic Research, 2015Co-Authors: Rebecca S BahnAbstract:Environmental, genetic, and immune factors are at play in the development of the variable clinical manifestations of Graves’ Ophthalmopathy (GO). Among the environmental contributions, smoking is the risk factor most consistently linked to the development or worsening of the disease. The close temporal relationship between the diagnoses of Graves’ hyperthyroidism and GO have long suggested that these 2 autoimmune conditions may share pathophysiologic features. The finding that the thyrotropin receptor (TSHR) is expressed in orbital fibroblasts, the target cells in GO, supported the notion of a common autoantigen. Both cellular and humeral immunity directed against TSHR expressed on orbital fibroblasts likely initiate the disease process. Activation of helper T cells recognizing TSHR peptides and ligation of TSHR by TRAb lead to the secretion of inflammatory cytokines and chemokines, and enhanced hyaluronic acid (HA) production and adipogenesis. The resulting connective tissue remodeling results in varying degrees extraocular muscle enlargement and orbital fat expansion. A subset of orbital fibroblasts express CD34, are bone-marrow derived, and circulate as fibrocytes that infiltrate connective tissues at sites of injury or inflammation. As these express high levels of TSHR and are capable of producing copious cytokines and chemokines, they may represent an orbital fibroblast population that plays a central role in GO development. In addition to TSHR, orbital fibroblasts from patients with GO express high levels of IGF-1R. Recent studies suggest that these receptors engage in cross-talk induced by TSHR ligation to synergistically enhance TSHR signaling, HA production, and the secretion of inflammatory mediators.
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cohort study on radioactive iodine induced hypothyroidism implications for Graves Ophthalmopathy and optimal timing for thyroid hormone assessment
Thyroid, 2013Co-Authors: Marius N Stan, Jolanta M Durski, Juan P Brito, Sumit Bhagra, Prabin Thapa, Rebecca S BahnAbstract: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...
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a small molecule antagonist inhibits thyrotropin receptor antibody induced orbital fibroblast functions involved in the pathogenesis of Graves Ophthalmopathy
The Journal of Clinical Endocrinology and Metabolism, 2013Co-Authors: Adina F Turcu, Susanne Neumann, Marvin C Gershengorn, Seethalakshmi Iyer, Seema Kumar, Michael J Coenen, Pamela Chiriboga, Rebecca S BahnAbstract:Context: Graves Ophthalmopathy (GO) is an autoimmune disorder characterized by increased adipogenesis and hyaluronan (HA) production by orbital fibroblasts. Circulating autoantibodies (thyroid-stimulating antibodies [TSAbs]) directed at the thyrotropin receptor (TSHR) on these cells stimulate or augment these cellular processes. A recently developed drug-like small molecule inverse agonist of TSHR, NCGC00229600, termed 1, binds to TSHR and blocks basal and stimulated signal transduction. Objective: The purpose of this article was to determine whether 1 might inhibit HA production and relevant signaling pathways in orbital fibroblasts cultured in the presence of monoclonal TSAbs or bovine TSH (bTSH). Design: Primary cultures of undifferentiated GO orbital fibroblasts (n = 13) were untreated or treated with a TSAb (M22 or MS-1) or bTSH in serum-free medium, with or without 1 or a TSHR neutral antagonist, NCGC00242595, termed 2, which does not inhibit basal signaling but does inhibit stimulated signaling. Ma...
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immunopathogenesis of Graves Ophthalmopathy the role of the tsh receptor
Best Practice & Research Clinical Endocrinology & Metabolism, 2012Co-Authors: Seethalakshmi Iyer, Rebecca S BahnAbstract:Graves' Ophthalmopathy is an inflammatory autoimmune disorder of the orbit. The close clinical and temporal relationships between Graves' hyperthyroidism and Ophthalmopathy have long suggested that both conditions derive from a single systemic process and share the thyrotropin receptor as a common autoantigen. This receptor is expressed not only in thyroid follicular cells, but also in orbital fibroblasts with higher levels measured in orbital cells from Ophthalmopathy patients than in cells from normal individuals. Recent studies from several laboratories have shown that thyrotropin receptor activation in orbital fibroblasts enhances hyaluronic acid synthesis and adipogenesis, both cellular functions that appear to be upregulated in the diseased orbit. The phosphoinositide 3-kinase/Akt signaling cascade, along with other effector pathways including adenylyl cyclase/cAMP, appears to mediate these processes. Future therapies for this condition may involve inhibition of thyrotropin receptor signaling in orbital fibroblasts.
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the evaluation and treatment of Graves Ophthalmopathy
Medical Clinics of North America, 2012Co-Authors: Marius N Stan, James A Garrity, Rebecca S BahnAbstract:Optimum care of the patient with Graves Ophthalmopathy (GO) is achieved through teamwork between the endocrinologist and ophthalmologist, with input from ancillary specialists as needed. Clinical evaluation should include determination of both the severity and the activity of the disease. It is important to assess early in the evaluation the impact of the disease on the patient's quality of life and their priorities and expectations regarding management. Once this information has been gathered, careful discussion between patient and physicians can define the management plan. This article reviews the pathophysiology, epidemiology, evaluation, and management of GO.
Wilmar M Wiersinga - One of the best experts on this subject based on the ideXlab platform.
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advances in treatment of active moderate to severe Graves Ophthalmopathy
The Lancet Diabetes & Endocrinology, 2017Co-Authors: Wilmar M WiersingaAbstract:Summary Graves' Ophthalmopathy is defined as autoimmune inflammation of extraocular muscles and orbital fat or connective tissue, usually in patients with Graves' disease. About one in 20 patients with Graves' hyperthyroidism has moderate-to-severe Graves' Ophthalmopathy. Corticosteroids have been the mainstay of treatment, but new evidence about immune mechanisms has provided a basis to explore other drug classes. Intravenous methylprednisolone pulses are more effective and better tolerated than oral prednisone in the treatment of active, moderate-to-severe Graves' Ophthalmopathy. Rituximab has also been suggested as a possible replacement for intravenous corticosteroids. Two randomised controlled trials of rituximab reached seemingly contradictory conclusions—rituximab was not better with respect to the primary outcome (clinical activity score) than placebo in one trial (which, however, was confounded by rather long Graves' Ophthalmopathy duration), but was slightly better than intravenous methylprednisolone pulses in the other (disease flare-ups occurred only in the latter group). On the basis of evidence published so far, rituximab cannot replace intravenous methylprednisolone pulses, but could have a role in corticosteroid-resistant cases. Open-label studies of tumour-necrosis-factor-α blockade had limited efficacy, but other studies showed that interleukin-6 receptor antibodies were effective. Results of randomised controlled trials investigating the efficacy of the IGF-1 receptor antibody teprotumumab and the interleukin-6 receptor antibody tocilizumab are expected shortly. Approaches that target the causal mechanism of Graves' Ophthalmopathy (antibodies or antagonists that block thyroid-stimulating-hormone receptors) also look promising.
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differential involvement of orbital fat and extraocular muscles in Graves Ophthalmopathy
European thyroid journal, 2013Co-Authors: Wilmar M Wiersinga, Noortje I Regensburg, Maarten P MouritsAbstract:Graves' Ophthalmopathy (GO) is characterized by swelling of orbital fat and extraocular muscles, but little attention has been given to differential involvement of fat and muscles. Advancements in imaging allow rather accurate measurements of orbital bony cavity volume (OV), fat volume (FV) and muscle volume (MV), and are the topics of this review. Ratios of FV/OV and MV/OV neutralize gender differences. In adult Caucasian controls, mean values ± SD of FV/OV are 0.56 ± 0.11 and of MV/OV are 0.15 ± 0.02. FV increases substantially and MV decreases slightly with advancing age, requiring age-specific reference ranges. In 95 consecutive untreated Caucasian GO patients, both FV and MV were within normal limits in 25%, increased FV but normal MV was present in 5%, normal FV but increased MV was detected in 61%, and both increased FV and MV was evident in 9%. Increased FV was associated with more proptosis and longer GO duration. Increased MV was associated with older age, more severe GO (more proptosis and diplopia, worse eye muscle ductions), higher TBII and current smoking. At the cellular and molecular level differential involvement of fat and muscles might be related to differences between fibroblast phenotypes and cytokine profiles in each compartment, to different orbital T cell subsets during the course of the disease and to peroxisome proliferator activator receptor-γ polymorphisms and modulation of 11β-hydroxysteroid dehydrogenase-1. Enlarged muscles are apparently a rather early phenomenon in GO, whereas increases in fat mass occur relatively late. Why a minor subset of GO patients presents with an increase of only fat remains poorly understood.
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circulating iggs may modulate igf i receptor stimulating activity in a subset of patients with Graves Ophthalmopathy
The Journal of Clinical Endocrinology and Metabolism, 2013Co-Authors: Aimee J Varewijck, Wilmar M Wiersinga, Anita Boelen, Steven W J Lamberts, Eric Fliers, Leo J Hofland, Joseph A M J L JanssenAbstract:Context: There is a close association between levels of TSH binding inhibitory immunoglobulins (TBIIs) and Graves' Ophthalmopathy (GO). In addition to the TSH receptor, the IGF-I receptor (IGF-IR) has been proposed to be a second autoantigen that plays a role in the pathogenesis of GO. Objective: The aim was to study relationships between TBII and serum IGF-IR stimulating activity in relationship to age in patients with GO. Methods: We performed a prospective study of 70 patients with GO (26 euthyroid, 39 subclinical hyperthyroid, 5 hyperthyroid; 8 males, 62 females; age, 47.9 ± 1.0 y). Patients were graded according to clinical activity score. IGF-IR stimulating activity was determined by IGF-IR kinase receptor activation assay; TBIIs were measured by immunoassay (Trak). Protein G magnetic beads were used to deplete serum of IgGs. Results: TBII and clinical activity score were positively related (r = 0.30; P = .01). In subjects with TBII above mean +1 SD, IGF-IR stimulating activity was positively relate...
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quality of life in Graves Ophthalmopathy
Best Practice & Research Clinical Endocrinology & Metabolism, 2012Co-Authors: Wilmar M WiersingaAbstract:General health-related quality-of-life (QoL) questionnaires (MOS SF-24 and SF-36) and the more sensitive disease-specific QoL questionnaire (GO-QoL) both indicate substantial impairment of quality of life in patients with Graves' Ophthalmopathy (GO). The GO-QoL contains 8 questions on visual functioning and 8 questions on appearance; answers on each subscale are transformed to scores ranging from 0 (worst) to 100 (best). The minimal clinically important difference in scores is ≥10 points for invasive therapies, but a change of 6 points on one of both subscales is already perceived by patients as beneficial and associated with an important change in daily functioning. The GO-QoL is well validated, widely used, and available in eight languages. The GO-QoL is recommended as an independent primary outcome measure in randomized clinical trials. Incorporating the GO-QoL in the routine assessment of GO in daily clinical practice is also recommended: although unproven, it is likely to improve the quality of care by identifying patients who are in need for psychological support in order to address poor psychosocial functioning and low self-esteem.
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autoimmunity in Graves Ophthalmopathy the result of an unfortunate marriage between tsh receptors and igf 1 receptors
The Journal of Clinical Endocrinology and Metabolism, 2011Co-Authors: Wilmar M WiersingaAbstract:Context: The immunopathogenesis of Graves' Ophthalmopathy (GO) is still incompletely understood. Attention has shifted from the TSH receptor (TSHR) to the IGF-I receptor (IGF-1R) as a major autoantigen. This review on the pathophysiology of GO focused on orbital fibroblasts and the question whether autoimmunity against TSHR or IGF-1R is primarily involved. Evidence Acquisition: Relevant papers on GO were identified by a search on PubMed and scrutiny of their reference lists. In addition, abstracts presented on GO at the 14th International Thyroid Congress in 2010 in Paris, France, were read. Evidence Synthesis: Orbital fibroblasts (OF) are recognized as the prime target cells of the autoimmune attack in GO. In early stages OF are undifferentiated with low TSHR expression and are stimulated to produce hyaluronan by cytokines (released by activated infiltrating T cells) and not by Graves' IgG. OF lacking the surface glycoprotein Thy-1 (not present in the muscle compartment) may differentiate into adipocytes...
Marvin C Gershengorn - One of the best experts on this subject based on the ideXlab platform.
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evidence that Graves Ophthalmopathy immunoglobulins do not directly activate igf 1 receptors
Thyroid, 2018Co-Authors: Bernice Marcussamuels, George J Kahaly, Christine C Krieger, Alisa Boutin, Susanne Neumann, Marvin C GershengornAbstract:Background: Graves' Ophthalmopathy (GO) pathogenesis involves thyrotropin (TSH) receptor (TSHR)-stimulating autoantibodies. Whether there are autoantibodies that directly stimulate insulin-like gro...
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tsh igf 1 receptor cross talk in Graves Ophthalmopathy pathogenesis
The Journal of Clinical Endocrinology and Metabolism, 2016Co-Authors: Christine C Krieger, George J Kahaly, Bernice Marcussamuels, Susanne Neumann, Robert F Place, Carmine Bevilacqua, Brent S Abel, Monica C Skarulis, Marvin C GershengornAbstract:Context: The TSH receptor (TSHR) is considered the main target of stimulatory autoantibodies in the pathogenesis of Graves' Ophthalmopathy (GO); however, it has been suggested that stimulatory IGF-1 receptor (IGF-1R) autoantibodies also play a role. Objective: We previously demonstrated that a monoclonal stimulatory TSHR antibody, M22, activates TSHR/IGF-1R cross talk in orbital fibroblasts/preadipocytes obtained from patients with GO (GO fibroblasts [GOFs]). We show that cross talk between TSHR and IGF-1R, not direct IGF-1R activation, is involved in the mediation of GO pathogenesis stimulated by Graves' autoantibodies. Design/Setting/Participants: Immunoglobulins were purified from the sera of 57 GO patients (GO-Igs) and tested for their ability to activate TSHR and/or IGF-1R directly and TSHR/IGF-1R cross talk in primary cultures of GOFs. Cells were treated with M22 or GO-Igs with or without IGF-1R inhibitory antibodies or linsitinib, an IGF-1R kinase inhibitor. Main Outcome Measures: Hyaluronan (hyalu...
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a small molecule antagonist inhibits thyrotropin receptor antibody induced orbital fibroblast functions involved in the pathogenesis of Graves Ophthalmopathy
The Journal of Clinical Endocrinology and Metabolism, 2013Co-Authors: Adina F Turcu, Susanne Neumann, Marvin C Gershengorn, Seethalakshmi Iyer, Seema Kumar, Michael J Coenen, Pamela Chiriboga, Rebecca S BahnAbstract:Context: Graves Ophthalmopathy (GO) is an autoimmune disorder characterized by increased adipogenesis and hyaluronan (HA) production by orbital fibroblasts. Circulating autoantibodies (thyroid-stimulating antibodies [TSAbs]) directed at the thyrotropin receptor (TSHR) on these cells stimulate or augment these cellular processes. A recently developed drug-like small molecule inverse agonist of TSHR, NCGC00229600, termed 1, binds to TSHR and blocks basal and stimulated signal transduction. Objective: The purpose of this article was to determine whether 1 might inhibit HA production and relevant signaling pathways in orbital fibroblasts cultured in the presence of monoclonal TSAbs or bovine TSH (bTSH). Design: Primary cultures of undifferentiated GO orbital fibroblasts (n = 13) were untreated or treated with a TSAb (M22 or MS-1) or bTSH in serum-free medium, with or without 1 or a TSHR neutral antagonist, NCGC00242595, termed 2, which does not inhibit basal signaling but does inhibit stimulated signaling. Ma...
George J Kahaly - One of the best experts on this subject based on the ideXlab platform.
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evidence that Graves Ophthalmopathy immunoglobulins do not directly activate igf 1 receptors
Thyroid, 2018Co-Authors: Bernice Marcussamuels, George J Kahaly, Christine C Krieger, Alisa Boutin, Susanne Neumann, Marvin C GershengornAbstract:Background: Graves' Ophthalmopathy (GO) pathogenesis involves thyrotropin (TSH) receptor (TSHR)-stimulating autoantibodies. Whether there are autoantibodies that directly stimulate insulin-like gro...
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tsh igf 1 receptor cross talk in Graves Ophthalmopathy pathogenesis
The Journal of Clinical Endocrinology and Metabolism, 2016Co-Authors: Christine C Krieger, George J Kahaly, Bernice Marcussamuels, Susanne Neumann, Robert F Place, Carmine Bevilacqua, Brent S Abel, Monica C Skarulis, Marvin C GershengornAbstract:Context: The TSH receptor (TSHR) is considered the main target of stimulatory autoantibodies in the pathogenesis of Graves' Ophthalmopathy (GO); however, it has been suggested that stimulatory IGF-1 receptor (IGF-1R) autoantibodies also play a role. Objective: We previously demonstrated that a monoclonal stimulatory TSHR antibody, M22, activates TSHR/IGF-1R cross talk in orbital fibroblasts/preadipocytes obtained from patients with GO (GO fibroblasts [GOFs]). We show that cross talk between TSHR and IGF-1R, not direct IGF-1R activation, is involved in the mediation of GO pathogenesis stimulated by Graves' autoantibodies. Design/Setting/Participants: Immunoglobulins were purified from the sera of 57 GO patients (GO-Igs) and tested for their ability to activate TSHR and/or IGF-1R directly and TSHR/IGF-1R cross talk in primary cultures of GOFs. Cells were treated with M22 or GO-Igs with or without IGF-1R inhibitory antibodies or linsitinib, an IGF-1R kinase inhibitor. Main Outcome Measures: Hyaluronan (hyalu...
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clinical relevance of thyroid stimulating immunoglobulins in Graves Ophthalmopathy
Ophthalmology, 2011Co-Authors: Katharina A Ponto, Michael Kanitz, Paul D Olivo, Susanne Pitz, Norbert Pfeiffer, George J KahalyAbstract:Purpose Thyroid-stimulating immunoglobulins (TSIs) likely mediate Graves' Ophthalmopathy (GO). The clinical relevance of these functional autoantibodies was assessed in GO. Design Cross-sectional trial. Participants A total of 108 untreated patients with GO. Methods 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. Main Outcome Measures Thyroid-stimulating immunoglobulins, activity and severity of GO, diplopia, and TBII. Results 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 r =0.81, P P P P Conclusions Thyroid-stimulating immunoglobulins show more significant association with clinical features of GO than TBII and may be regarded as functional biomarkers for GO. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.
Seethalakshmi Iyer - One of the best experts on this subject based on the ideXlab platform.
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a small molecule antagonist inhibits thyrotropin receptor antibody induced orbital fibroblast functions involved in the pathogenesis of Graves Ophthalmopathy
The Journal of Clinical Endocrinology and Metabolism, 2013Co-Authors: Adina F Turcu, Susanne Neumann, Marvin C Gershengorn, Seethalakshmi Iyer, Seema Kumar, Michael J Coenen, Pamela Chiriboga, Rebecca S BahnAbstract:Context: Graves Ophthalmopathy (GO) is an autoimmune disorder characterized by increased adipogenesis and hyaluronan (HA) production by orbital fibroblasts. Circulating autoantibodies (thyroid-stimulating antibodies [TSAbs]) directed at the thyrotropin receptor (TSHR) on these cells stimulate or augment these cellular processes. A recently developed drug-like small molecule inverse agonist of TSHR, NCGC00229600, termed 1, binds to TSHR and blocks basal and stimulated signal transduction. Objective: The purpose of this article was to determine whether 1 might inhibit HA production and relevant signaling pathways in orbital fibroblasts cultured in the presence of monoclonal TSAbs or bovine TSH (bTSH). Design: Primary cultures of undifferentiated GO orbital fibroblasts (n = 13) were untreated or treated with a TSAb (M22 or MS-1) or bTSH in serum-free medium, with or without 1 or a TSHR neutral antagonist, NCGC00242595, termed 2, which does not inhibit basal signaling but does inhibit stimulated signaling. Ma...
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immunopathogenesis of Graves Ophthalmopathy the role of the tsh receptor
Best Practice & Research Clinical Endocrinology & Metabolism, 2012Co-Authors: Seethalakshmi Iyer, Rebecca S BahnAbstract:Graves' Ophthalmopathy is an inflammatory autoimmune disorder of the orbit. The close clinical and temporal relationships between Graves' hyperthyroidism and Ophthalmopathy have long suggested that both conditions derive from a single systemic process and share the thyrotropin receptor as a common autoantigen. This receptor is expressed not only in thyroid follicular cells, but also in orbital fibroblasts with higher levels measured in orbital cells from Ophthalmopathy patients than in cells from normal individuals. Recent studies from several laboratories have shown that thyrotropin receptor activation in orbital fibroblasts enhances hyaluronic acid synthesis and adipogenesis, both cellular functions that appear to be upregulated in the diseased orbit. The phosphoinositide 3-kinase/Akt signaling cascade, along with other effector pathways including adenylyl cyclase/cAMP, appears to mediate these processes. Future therapies for this condition may involve inhibition of thyrotropin receptor signaling in orbital fibroblasts.
