Food and Drug Administration. moderate to severe, active TAO in two completed multicenter, double masked, and placebo controlled clinical trials. The drug exhibits a favorable safety profile. Should teprotumumab become approved by the U.S. F.D.A, it may rapidly become the first line therapy for this disfiguring and potentially blinding condition. Keywords: autoimmune, insulin-like growth factor-I receptor, Graves disease, biological agents, monoclonal antibodies, teprotumumab 1.0.?Introduction Thyroid-associated ophthalmopathy (TAO, aka Graves ophthalmopathy/orbitopathy or thyroid eye disease) is a disfiguring, potentially blinding autoimmune component most frequently associated with Graves disease (GD) but also occurring in patients with Hashimotos thyroiditis (Figure 1) (1C3). In both instances, it is presumed to represent a consequence of similar if not identical autoimmune processes occurring within the thyroid gland. Lack of a more complete understanding of TAO has been delayed by the wide variations in clinical presentation seen in afflicted patients. In addition, many aspects of the disease (i.e. eyelid swelling, redness, dry eye symptoms) are shared with other ocular disease processes, some of which occur with far greater INHBB frequency. The long-standing absence of high-fidelity preclinical models of TAO in which to study disease pathophysiology and test candidate therapeutics has also proven to represent an important barrier; however, recent developments in generating small animal models represent significant improvements (4). Uncertainty surrounding many aspects of disease development has in turn severely constricted development of specific, targeted medical therapies which have proven safe and effective in adequately-powered, prospective, and placebo-controlled clinical trials. To date, no medical therapy has achieved registration by the U.S. Food and Drug Administration. But the insights gathered in recent years concerning disease development has led to recent identification of plausible therapeutic targets for TAO. In this brief, focused review, I have attempted to provide an overview of the current understanding of the Nicardipine hydrochloride mechanistic underpinnings of TAO, how it is diagnosed, and to identify both current therapeutic options and those emerging treatments in various stages of development for this vexing disease. Open in a separate window Figure 1. Moderate to severe thyroid-associated ophthalmopathy characterized by bilateral proptosis, periorbital edema, scleral injection, and lid retraction.From N. Engl. J. Med, Smith T.J. and Hegedus L., Graves Disease, 375; 1552C1565. Copyright ? (2016) Massachusetts Medical Society. Reprinted with permission. 1.1. Pathogenic mechanisms The basis for thyroid-centric GD and TAO is thought to be shared by the two anatomically dispersed components of the disease and revolves around the thyrotropin receptor (TSHR) (Figure 2) (5). TSHR becomes targeted by pathogenic antibodies that uniquely in GD activate the receptor and result in dysthyroidemia (6). Like other autoantigens, immunoreactivity to TSHR is initiated as the consequence of defects of either central or peripheral tolerance (or both). More complete understanding the loss of immune tolerance to TSHR in GD has been the focused topic of inquiry for many years and substantial advances have been reported recently (7). It appears, based on studies conducted in hTSHR/NOD.transgenic mice, that the availability of TSHR A-subunit protein is important to the generation of pathogenic anti-TSHR antibodies in GD (8). But the generation of anti-TSHR antibodies represents only one aspect Nicardipine hydrochloride Nicardipine hydrochloride of the autoimmunity against TSHR. Further, while these receptor-targeting IgGs can be identified in a majority of patients with active TAO (9), they cannot be detected in a small fraction of those individuals affected by GD, some of whom exhibit severe ocular disease (10,11). This raises the important question of whether another autoantigen might also Nicardipine hydrochloride play a role in the development of TAO. Antigen-specific autoreactive T cells are also generated and their roles in disease development include their endorsement of B cells and the production of IgG1 antibodies. While these TSIs engage TSHR, activate signaling, and increase hormone production and thyroid gland volume expansion (2), their consequences within orbital connective tissues and extraocular muscles remain uncertain. Further, the roles of T Nicardipine hydrochloride cells infiltrating the TAO orbit remain to be fully understood but they likely participate in the tissue activation and remodeling characteristic of the disease. Access to orbital fibroblasts from patients with TAO has allowed investigation into the effects of TSH.