Thyroid eye disease (TED) is a complex disease associated with myriad clinical presentations, including facial disfigurement, vision loss, and decreased quality of life. Traditionally, steroid therapy and/or radiation therapy were commonly used in the treatment of active TED. While these therapies can help reduce inflammation, they often do not have a sustainable, significant long-term effect on disease outcomes, including proptosis and diplopia. Recent advances in our understanding of the pathophysiology of TED have shifted the focus of treatment toward targeted biologic therapies. Biologics have the advantage of precise immune modulation, which can have better safety profiles and greater efficacy compared to traditional approaches. For instance, the insulin-like growth factor-1 receptor (IGF-1R) has been found to be upregulated in TED patients and to colocalize with the thyroid-stimulating hormone receptor (TSHR), forming a signaling complex. Teprotumumab is an antibody targeted against IGF-1R. By inhibiting the IGF-1R/TSHR signaling pathway, teprotumumab may reduce the production of proinflammatory cytokines, hyaluronan secretion, and orbital fibroblast activation in patients with TED. Due to promising phase II and III clinical trial results, teprotumumab has become the first biologic US Food and Drug Administration (FDA)-approved for the treatment of TED. In addition, there are currently ongoing studies looking at the use of antibodies targeting the neonatal Fc receptor (FcRn) in various autoimmune diseases, including TED. FcRn functions to transport immunoglobulin G (IgG) and prevent their lysosomal degradation. By blocking the recycling of IgG, this approach may dampen the body’s immune response, in particular the pathogenic IgG implicated in some autoimmune diseases. Advances in our understanding of the pathophysiology of TED, therefore, are leading to more targeted therapeutic options, and we are entering an exciting new phase in the management of TED. This review will cover recent insights into the understanding of TED pathophysiology and novel treatment options as well as ongoing studies of new potential treatment options for TED.

Context Graves orbitopathy (GO) or thyroid eye disease is a potentially sight-threatening and disfiguring autoimmune disease. Teprotumumab is a monoclonal antibody against the insulin-like growth factor-I receptor that was recently approved for GO treatment. Hyperglycemia is a recognized adverse event of teprotumumab, occurring in 10% of patients in 2 recent randomized controlled trials. Objective Our study aimed to report the incidence, severity, management, and longitudinal glycemic changes in patients treated with teprotumumab in an academic practice cohort. Methods This longitudinal, observational study included all consecutive patients treated with teprotumumab between March 2020 and May 2022 at 1 institution. Hemoglobin A1c (HbA1c) was measured every 3 months. Results Forty-two patients with baseline normoglycemia (n = 22), prediabetes (n = 10), and diabetes (n = 10) were followed for a mean of 47.5 weeks. Overall, HbA1c increased by 0.5% at 3 months. Least-squares mean changes in HbA1c at 3 months were 1.3 (P < .001), 0.7 (P = .01), and 0.1 (P = .41) in patients with diabetes, prediabetes, and normoglycemia, respectively. Twenty-two patients (52%) had hyperglycemia, which was graded as mild, moderate, and life-threatening in 55% (12/22), 41% (9/22), and 5% (1/22) of cases, respectively. Age, pre-existing diabetes, and Hispanic and Asian race/ethnicity were significant risk factors for hyperglycemia. Among patients with hyperglycemia, 36.4% (8/22) returned to baseline glycemic status at last follow-up. Conclusion While effective, teprotumumab carries a significant risk of hyperglycemia, especially in patients with diabetes. Hyperglycemia may persist after stopping teprotumumab. These findings underscore the importance of guidelines for screening and management of teprotumumab-related hyperglycemia.

A 45-year-old male presented with active progressive thyroid eye disease refractory to intravenous steroids and right orbital radiation. Visual acuity, left relative afferent pupillary defect, and Humphrey visual field defects were consistent with worsening left dysthyroid optic neuropathy. Orbital MRI demonstrated extraocular muscle enlargement and effacement of the left optic nerve sheath. After 2 infusions of teprotumumab, the patient’s visual acuity, relative afferent pupillary defect, Humphrey visual fields, proptosis, and extraocular muscle size improved. This is the first report of dysthyroid optic neuropathy responsive to teprotumumab, and it supports the need for further studies to better understand the role of teprotumumab in treating sight-threatening thyroid eye disease.

Thyroid eye disease (TED) is a complex inflammatory disease that can have a long clinical course with sight-threatening and debilitating ocular sequelae. Until recently, there were limited therapeutic options available. In the last decade we have gained a deeper understanding of the underlying pathophysiology, which has led to the development of novel effective targeted therapies. This article discusses the challenges encountered in the clinical evaluation and treatment of TED patients, with the goal to empower endocrinologists and ophthalmologists to work together to provide effective multidisciplinary care. We will review recommendations of past clinical guidelines around evaluation and management of TED patients, discuss the randomized controlled trials of new biologic therapies, and explore how to navigate the emerging therapeutic landscape.