Thyroid Eye Disease
Thyroid eye disease (TED), also known as Graves’ orbitopathy, Graves’ ophthalmopathy, or thyroid-associated ophthalmopathy (TAO), is an autoimmune disease associated with Graves' Disease (GD). In the United States, the annual incidence of TED is approximately 16 per 100,000 women and 3 per 100,000 men (Bartley, 1994). Individuals between 30 to 50 years of age are most commonly affected, while severe cases occur more frequently among patients older than 50 years (Ing, 2011). TED is characterized by activation and proliferation of orbital fibroblasts, which leads to enlargement of the extraocular muscles, cellular infiltration of interstitial tissues, and an increase in orbital fat and connective tissue. Clinically, TED manifests as swelling and redness of the lids and ocular surface, excessive tearing, eyelid thickening or retraction, bulging of the eyes (proptosis or exophthalmos), and misalignment of the eyes with diplopia (Mallika et al. 2009; Bahn, 2010). Corneal defects such as exposure keratopathy or ulceration occur in severe cases. TED is typically mild and self-limiting but may become sight-threatening due to optic nerve compression in 3 to 5% of cases.
Symptomatic treatments include lubricating ointments and artificial tears for mild cases. In moderate to severe cases, systemic or topical corticosteroids are used but can have significant side effects. Immunosuppressive agents such as cyclosporin sometimes provide efficacy in combination with corticosteroids. Severe disease can be treated with orbital decompression surgery. Infusion of teprotumumab (Tepezza®), an antibody targeting the insulin-like growth factor-1 (IGF-1) receptor, is also an approved therapy for TED. Side effects of Tepezza can include hearing loss, infusion reactions and hyperglycemia. As currently available therapies carry attendant serious side effects and complications, there is a clear medical need for new therapies.
Inflammasome activation in TED
IGF-1 and IGF-1 receptor (IGF-1R) play an important role in TED. IGF-1R is upregulated in orbital fibroblasts from patients with TED. IGF-1 increases hyaluronan synthesis in orbital fibroblasts isolated from patients with TED and induces inflammasome activation. Expression of NLRP3, a principal inflammasome component, is increased in the thyroid of autoimmune thyroiditis patients and multiple studies have found that the expression of the inflammasome effector cytokines IL-1β & IL-18 as well as their downstream targets IL-6, IL-17, and IFN-γ are elevated in TED patients. Inhibition of NLRP3 was found to suppress autoimmune thyroiditis, reduce the numbers of thyroid-infiltrating CD4+ & CD8+ T cells, Th1 & Th17 cells, and the cytokines IL-17 & IFN-γ in an animal model. Collectively, these data support the concept that inflammasome inhibition can be beneficial in TED. A clinical trial of our oral inflammasome inhibitor, K9, is underway.