Fibrosis in dysthyroid eye disease

Abstract

Dysthyroid eye disease is a rare condition, mainly found in people with Graves' hyperthyroidism.Autoimmune responses to thyroid/orbit shared antigens drive extensive tissue remodelling. This includes excess adipogenesis and over-production of extra-cellular matrix, which both tend to occur in the earlier 'active' inflammatory stages of disease. With time these give way to fibrosis, which has a profound impact on eye motility and may be life-long. Progress has been made in identifying the shared autoantigen(s) and the role of specific T cells and autoantibodies in remodelling, which have facilitated development of novel therapies. However relatively little is known of the autoimmune processes under-pinning fibrosis and currently there are no adequate medical treatments. Dysthyroid eye disease-vital statisticsDysthyroid eye disease is also known as thyroid eye disease (TED) or Graves' orbitopathy (GO) and has a prevalence of approximately 10/10,000 in Europe, which is reducing. It is an autoimmune disease and consequently more common in women, although when present in men, can be more severe (1).The main signs and symptoms include periorbital oedema, lid lag, proptosis, chemosis, reduced ocular motility, reduced visual acuity, diplopia and optic neuropathy (2). The severity and activity of TED can be assessed using a variety of scoring systems whose relative merits have been recently reviewed (3). The Clinical Activity Score (CAS) and VISA scale (Vision, Inflammation, Strabismus, Appearance) reflect disease activity, whereas the EUGOGO, NOSPECS (No symptoms/signs, Only signs, Soft tissue involvement, Proptosis, Extraocular muscle involvement, Corneal involvement, Sight loss), VISA-VSA scales and Ophthalmopathy Index measure severity.

The Role of the Microbiota in Graves’ Disease and Graves’ Orbitopathy

“…GO is characterized by orbital tissue remodeling, retro-orbital inflammation, and glycosaminoglycan accumulation ( Hansen et al., 1999 ). The major clinical features include periorbital edema, eyelid lag, proptosis, limited ocular movement, orbital disfigurement, and diplopia ( Ludgate, 2020 ). Glucocorticoids are the primary treatment for GO at the active stage; smoking cessation, selenium supplements, and ocular lubricants are also helpful.…”

Pathogenesis of Thyroid Eye Disease

“…In the later stages of disease, Th2 cytokines predominate, including IL-4, IL-5, IL-10, and IL-13 1,34,58. The dampening of the immune response may reflect shifts in the cytokine profile or cytokine environment, such as a hypoxic state 8,43,63. Interestingly, there have been few cases of elderly TED patients presenting with severe progressive fibrosis without evidence of a previously active inflammatory condition 64…”

“…Compared with fibroblasts from healthy individuals, orbital fibroblasts in GD display an exaggerated inflammatory response to stimuli and synthesize higher levels of HA 3,62,73. The basal rate of orbital fibroblast proliferation is reported to be higher in patients with TED compared with healthy individuals 43. Excessive fibroblast activation has also been implicated in other inflammatory fibroproliferative diseases, such as lung, liver, and skin fibrosis 67…”

“…54 The presence of Th17 cells and their cytokine IL-17A is associated with proinflammatory and profibrotic properties. 35,43,55 Imbalance between Th17 and Treg responses has been implicated in various autoimmune and inflammatory diseases, including arthritis, multiple sclerosis, psoriasis, and inflammatory bowel disease, in addition to TED. 4 Similarly, polymorphisms in CTLA-4, an immune modulatory protein, has been implicated in the pathogenesis of GD and TED and studied as a potential treatment target.…”

Orbitopatía tiroidea. Revisión sobre puntos clave para el diagnóstico y tratamiento

“…En la OT nos encontramos con un aumento de volumen de los músculos extraoculares, de la grasa y del tejido conectivo al que se llega por un mecanismo de reconocimiento del antígeno que comparten tiroides y tejidos orbitarios por parte de los linfocitos T autorreacivos y los linfocitos T CD4+, segregando estos últimos citocinas que van a activar a los CD8+ y los fibroblastos que secretan glucasaminoglicanos, produciendo un efecto osmótico que edematiza el espacio retroorbitario, con el consiguiente edema periorbitario y muscular que conduce a la aparición de proptosis. Por otro lado, se produce un aumento del tejido graso de la órbita debido a la transformación hormonodependiente de los fibroblastos en adipocitos; además existe una infiltración muscular de linfocitos, macrófagos y mastocitos que producen desestructuración-atrofia de dicha musculatura que altera su función [6][7][8]. Sin embargo hay pacientes con OT en los que no se detecta anti TSI.…”