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Context Thyroid eye disease (TED), a vision-threatening and disfiguring autoimmune process, has thwarted our efforts to understand its pathogenesis and develop effective and safe treatments. Recent scientific advances have facilitated improved treatment options. Objective Review historically remote and recent advances in understanding TED. Design/Setting/Participants PubMed was scanned using search terms including thyroid-associated ophthalmopathy, thyroid eye disease, Graves’ orbitopathy, autoimmune thyroid disease, and orbital inflammation. Main outcome measures Strength of scientific evidence, size, scope, and controls of clinical trials/observations. Results Glucocorticoid steroids are widely prescribed systemic medical therapy. They can lessen inflammation-related manifestations of TED but fail to reliably reduce proptosis and diplopia, 2 major causes of morbidity. Other current therapies include mycophenolate, rituximab (anti-CD20 B cell-depleting monoclonal antibody), tocilizumab (interleukin-6 receptor antagonist), and teprotumumab (IGF-I receptor inhibitor). Several new therapeutic approaches have been proposed including targeting prostaglandin receptors, vascular endothelial growth factor, mTOR, and cholesterol pathways. Of potentially greater long-term importance are attempts to restore immune tolerance. Conclusion Despite their current wide use, steroids may no longer enjoy first-tier status for TED as more effective and better tolerated medical options become available. Multiple current and emerging therapies, the rationales for which are rooted in theoretical and experimental science, promise better options. These include teprotumumab, rituximab, and tocilizumab. Restoration of immune tolerance could ultimately become the most effective and safe medical management for TED.
Context Thyroid eye disease (TED), a vision-threatening and disfiguring autoimmune process, has thwarted our efforts to understand its pathogenesis and develop effective and safe treatments. Recent scientific advances have facilitated improved treatment options. Objective Review historically remote and recent advances in understanding TED. Design/Setting/Participants PubMed was scanned using search terms including thyroid-associated ophthalmopathy, thyroid eye disease, Graves’ orbitopathy, autoimmune thyroid disease, and orbital inflammation. Main outcome measures Strength of scientific evidence, size, scope, and controls of clinical trials/observations. Results Glucocorticoid steroids are widely prescribed systemic medical therapy. They can lessen inflammation-related manifestations of TED but fail to reliably reduce proptosis and diplopia, 2 major causes of morbidity. Other current therapies include mycophenolate, rituximab (anti-CD20 B cell-depleting monoclonal antibody), tocilizumab (interleukin-6 receptor antagonist), and teprotumumab (IGF-I receptor inhibitor). Several new therapeutic approaches have been proposed including targeting prostaglandin receptors, vascular endothelial growth factor, mTOR, and cholesterol pathways. Of potentially greater long-term importance are attempts to restore immune tolerance. Conclusion Despite their current wide use, steroids may no longer enjoy first-tier status for TED as more effective and better tolerated medical options become available. Multiple current and emerging therapies, the rationales for which are rooted in theoretical and experimental science, promise better options. These include teprotumumab, rituximab, and tocilizumab. Restoration of immune tolerance could ultimately become the most effective and safe medical management for TED.
Thyroid eye disease (TED) is the most common extra thyroidal manifestation of Graves’ disease (GD). It may also present in those who are hypothyroid or euthyroid. The characteristic clinical manifestations of TED: chemosis, lid swelling, proptosis and diplopia are driven by a combination of inflammation and extracellular matrix modification. It has recently emerged that one of the major drivers of this molecular signature is the over-expression of the insulin like growth factor-1 receptor (IGF-1R) on key effector cells in TED pathogenesis. The overexpression of the IGF-1R is coupled with a dysregulation of the IGF-1R axis, which links other pathways that modulate inflammation, such as fibrosis and extracellular matrix organization, in patients with TED. This overexpression is also found to persist from the acute stage into the chronic phase. Teprotumumab, a fully human immunoglobulin (Ig) G1 monoclonal antibody that inhibits the IGF-1R, recently gained approval in the US for the treatment of TED. In phase 2 and phase 3 clinical studies, teprotumumab showed efficacy in reducing inflammation, proptosis, diplopia and burden on quality of life, in patients who were treated. Post introduction studies have confirmed the results of the phase 2 and phase 3 studies. Since 2020, over 5, 800 patients have been treated with teprotumumab and it appears to be well tolerated. The American Thyroid Association and the European Thyroid Association have recommended it as first line therapy for patients with moderate to severe TED, who display features of proptosis and diplopia.
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