Immunopathogenesis of Thyroid Eye Disease: Emerging Paradigms

Abstract

Graves disease represents a systemic autoimmune process targeting the thyroid, orbit, and pretibial skin. The thyroid dysfunction is treatable, but no consistently effective medical therapy has yet been described for the orbital manifestations of Graves disease, also known as thyroid-associated ophthalmopathy or thyroid eye disease. Several autoantigens are potentially relevant to the pathogenesis of thyroid eye disease. Activating antibodies generated against the thyrotropin receptor can be detected in a majority of patients, and these drive hyperthyroidism. However, stimulating antibodies against the insulin-like growth factor-1 receptor (IGF-1R) may also play a role in the extra-thyroid manifestations of GD. IGF-1R is over-expressed by orbital fibroblasts derived from patients with TED, while IGF-1R + T and IGF-1R + B cells are considerably more frequent in GD. Actions of several cytokines and the molecular interplay peculiar to the orbit appear to provoke the inflammation, fat expansion, and deposition of excessive extracellular matrix molecules in thyroid eye disease. Based upon these new insights, several therapeutic strategies can now be proposed that, for the first time, might specifically interrupt its pathogenesis.

Sight Threatening Thyroid Eye Disease Complicating Hashimoto’s Thyroiditis

“…Thyroid eye disease is an inflammatory disorder of the extraocular muscles and surrounding orbital connective tissue and fat, thought to be autoimmune in origin [1][2][3][4]. TED most commonly occurs in the presence of Graves disease [2].…”

Correlation between magnetic resonance imaging and ultrasound measurements of eye muscle thickness in thyroid-associated orbitopathy

“…It is closely associated with Graves' disease, a form of hyperthyroidism in which autoantibodies stimulate the thyrotropin receptor. As much as 50% of patients with Graves' disease will develop orbital changes [1][2][3][4][5] , even though activity is clinically detected in only a few cases 2,3,6 . The diagnosis of hyperthyroidism and TAO usually occurs within 18 months of each other 7 .…”

“…Women are affected about 10 times more often than men 7 . Relatively rarely, in up to 10% of the time, TAO can also occur in euthyroid and hypothyroid patients 4,5 . The symptoms and signs of TAO vary.…”

“…The natural course of the disease shows an initial active inflammatory phase followed by a static fibrotic phase. The exact rate and duration of disease phases can vary and sometimes be unpredictable 4 . The distinction between the two phases is important.…”

Acute thyroid eye disease (TED): Principles of medical and surgical management

“…4 Hypertrophy of extraocular muscles and enhanced adipogenesis, together with deposition of nonsulfated glycosaminoglycans and hyaluronate, compress the soft tissues within the confined bony orbit, with orbital functions impeded due to compressive congestion and the complications of acute and chronic inflammation. 5 Unique among human 'autoimmune' diseases, active TED is self-limiting, manifesting with an active (dynamic) phase lasting up to 24 months, followed by an inactive (static) disease phase. Furthermore, most of the orbit lacks lymphoid tissue, unlike the target organs for other human autoimmune diseases, such as synovium in rheumatoid arthritis.…”