Thyroid-associated ophthalmopathy (TAO) is a complex disease process presumed to 
emerge from autoimmunity occurring in the thyroid gland, most frequently in 
Graves disease (GD). It is disfiguring and potentially blinding, culminating in 
orbital tissue remodeling and disruption of function of structures adjacent to 
the eye. There are currently no medical therapies proven capable of altering the 
clinical outcome of TAO in randomized, placebo-controlled multicenter trials. 
The orbital fibroblast represents the central target for immune reactivity. 
Recent identification of fibroblasts that putatively originate in the bone 
marrow as monocyte progenitors provides a plausible explanation for why 
antigens, the expressions of which were once considered restricted to the 
thyroid, are detected in the TAO orbit. These cells, known as fibrocytes, 
express relatively high levels of functional TSH receptor (TSHR) through which 
they can be activated by TSH and the GD-specific pathogenic antibodies that 
underpin thyroid overactivity. Fibrocytes also express insulin-like growth 
factor I receptor (IGF-IR) with which TSHR forms a physical and functional 
signaling complex. Notably, inhibition of IGF-IR activity results in the 
attenuation of signaling initiated at either receptor. Some studies suggest that 
IGF-IR-activating antibodies are generated in GD, whereas others refute this 
concept. These observations served as the rationale for implementing a recently 
completed therapeutic trial of teprotumumab, a monoclonal inhibitory antibody 
targeting IGF-IR in TAO. Results of that trial in active, moderate to severe 
disease revealed dramatic and rapid reductions in disease activity and severity. 
The targeting of IGF-IR with specific biologic agents may represent a paradigm 
shift in the therapy of TAO.