New advances in understanding thyroid-associated ophthalmopathy and the potential role for insulin-like growth factor-I receptor

Abstract

Thyroid-associated ophthalmopathy (TAO), a localized periocular manifestation of the autoimmune syndrome known as Graves’ disease, remains incompletely understood. Discussions of its pathogenesis are generally focused on the thyrotropin receptor, the proposed role for which is supported by substantial evidence. Considerations of any involvement of the insulin-like growth factor-I receptor (IGF-IR) in the disease are frequently contentious. In this brief, topically focused review, I have attempted to provide a balanced perspective based entirely on experimental results that either favor or refute involvement of IGF-IR in TAO. Discussion in this matter seems particularly timely since the currently available treatments of this disfiguring and potentially sight-threatening disease remain inadequate. Importantly, no medical therapy has thus far received approval from the US Food and Drug Administration. Results from a very recently published clinical trial assessing the safety and efficacy of teprotumumab, an inhibitory human anti–IGF-IR monoclonal antibody, in active, moderate to severe TAO are extremely encouraging. That double-masked, placebo-controlled study involved 88 patients and revealed unprecedented clinical responses in the improvement of proptosis and clinical activity as well as a favorable safety profile. Should those results prove reproducible in an ongoing phase III trial, therapeutic inhibition of IGF-IR could become the basis for paradigm-shifting treatment of this vexing disease.

Teprotumumab, an insulin-like growth factor-1 receptor antagonist antibody, in the treatment of active thyroid eye disease: a focus on proptosis

“…The pathogenesis of TED remains poorly understood; the current theory is that autoantibodies to the thyroid-stimulating hormone receptor (TSHR) play a pivotal role in the pathogenesis of TED. Autoantibodies to TSHR alone, however, do not explain the disease presence in TED patients who are euthyroid or hypothyroid, suggesting that there might be another receptor at play in the pathogenesis of TED, such as the insulin-like growth factor 1 receptor (IGF-1R) [6]. Mounting evidence for this includes the overexpression of IGF-1R in TED, the presence of anti-IGF-1R antibodies in TED patients that are able to block signaling in the orbital fibroblasts, and the production of hyaluronan by the orbital fibroblasts in TED patients induced by both thyroid stimulating immunoglobulins (TSIs) and IGF-1 [7–10].…”

Disrupting Insulin and IGF Receptor Function in Cancer

“…The IGF system contributes to not only malignant diseases, but also to autoimmune diseases such as thyroid eye disease (TED) or thyroid-associated ophthalmopathy (TAO) [ 28 ]. It is proposed that activation of the thyroid-stimulating hormone receptor (TSHR) by activating autoantibodies leads to excessive production of thyroid hormones and eventually causes TED [ 29 , 30 ].…”

Current Understanding of the Progression and Management of Thyroid Associated Orbitopathy: A Systematic Review

“…Though IGF-1R is a widely expressed receptor, IGF-1R expression is increased on fibroblasts from the orbit, skin, and thyroid of patients with Graves' disease. The upregulation of IGF-1R and the TSHR in orbital fibroblasts has been proposed to lead to the accumulation of hyaluronan within orbital fat and muscle [10,53,54].…”