Re: “Thyroid Eye Disease: A New Name,a New Guide,and a New Era” by Davies

Dear Editor:

I am writing to comment on Dr. Terry F. Davies' editorial in the December 2022 issue of Thyroid, entitled “Thyroid Eye Disease: a new name, a new guide, and a new era.” ¹ I very much appreciated his correction of the historical record by bringing attention to the not widely circulated first descriptions of thyroid eye disease (TED) by the Italians in the early 1800s; however, I take issue with his historical narrative of the basic science discoveries that led to the dawn of the “new era” of treatment for TED.

While the seminal observation in Dr. Ingbar's laboratory in the 1980s, that the actions of thyrotropin (TSH) were synergistically enhanced by insulin-like growth factor 1 (IGF-1) was important, this finding lay fallow until the early 2000s when studies in Dr. Terry J. Smith's laboratory directly implicated the IGF-1 receptor (IGF-IR) in the pathophysiology of TED. Those studies published beginning in 2002 demonstrated (1) overexpression of IGF-1R by orbital fibroblasts, T cells and B cells from patients with Graves' disease, (2) IGF-1R and TSH receptor (TSHR) form physical and functional complexes in orbital fibroblasts and thyroid epithelial cells, (3) cell signaling initiated by either IGF-1R or TSHR requires IGF-1R activity, and (4) Graves' disease-IgG induction of cytokines and hyaluronan can be blocked with an inhibitory monoclonal antibody to IGF-IR. ^{2 –5}

While Gershengorn and others contributed to other aspects of disease mechanism or subsequently added to what Smith had discovered earlier about the putative role of IGF-1R in TED, it was Dr. Smith and colleagues who were the first to recognize that IGF-1R inhibition might be therapeutically effective for TED. As they concluded in an article published in 2003, a “GD-IgG/IGF-IR bridge potentially explains T cell infiltration in GD. Interrupting this pathway may constitute a specific therapeutic strategy. ² ” It was this insight of Dr. Smith that led directly to the development of teprotumumab, the first targeted and effective therapy for TED since this disease was first described more than 200 years ago.