The changing landscape of thyroid eye disease: current clinical advances and future outlook

Abstract

Aims: This review aims to provide an overview of the current understanding of TED and its pathophysiology. To describe the evidence base for current consensus treatment recommendations and newer biological therapies available as well as to present future therapeutic research.

Methods: We reviewed and assessed the peer-reviewed literature placing particular emphasis on recent studies evaluating the pathophysiology of TED, landmark trials forming the basis of current management and recent clinical trials informing future therapeutics. Searched were made in MEDLINE Ovid, Embase Ovid, US National Institutes of Health Ongoing Trials Register and EU Clinical Trials Register. Keywords included: "Thyroid Eye Disease", "Graves Orbitopathy", "Thyroid Orbitopathy" and "Graves' Ophthalmopathy".

Results and conclusions: The pathophysiology of TED involves a complex array of cellular and humoral based autoimmune dysfunction. Previous therapies have been broad-based acting as a blunt instrument on this mechanism with varying efficacy but often accompanied with a significant side effect profile. The recent development of targeted therapy, spearheaded by Teprotumumab has led to an array of treatments focusing on specific components of the molecular pathway optimising their impact whilst possibly minimising their side effect profile. Future challenges involve identifying the most effective target for each patient rather than any single agent being a panacea. Long-term safety profiles will require clarification as unintended immunological consequence downstream may become manifest as seen in other diseases. Finally, future novel therapeutics will entail significant expenditure and may lead to a divergence of available treatment modalities between healthcare systems due to funding disparities.

Fig. 1. A pictorial representation of the pathogenesis of Thyroid Eye Disease.

Depicts overexpression of TSH-Receptors (TSHR), on the orbital fibroblasts in TED patients. The activation of these, by IgG Thyroid Stimulating Antibody (TSAB) produced by plasma cells, results in the differentiation into adipocytes. Insulin-like growth factor-1 (IGF-1) and its receptors are also found on Orbital Fibroblasts Graves IgG Immunoglobulin, directed towards the IGF-1 receptor, results in activation of orbital fibroblast proliferation, cytokine secretion and hyaluronan synthesis. The two receptors IGFR-1 and TSHR, are co-localised on orbital fibroblasts, and are thought to have a synergistic relationship with a degree of cross-communication. Activation of the TSHR via the TSAB may also activate the IGF1-R intracellular cascade. The diagram shows the drugs Viridian, Teprotumumab and K-170 exerting their therapeutic effect by targeting these receptors. The diagram also shows Activated T-Cells and Orbital Fibroblasts secreting cytokines which encourages B-Cell maturation and subsequent secretion of TSAB by plasma cells resulting in further cellular recruitment, cytokine secretion and tissue expansion. Cellular structures are depicted which show the mechanism of antibody degradation and recycling. Batoclimab is shown to target the FcRn receptor, which is key in prolonging the half-life and preventing the degradation of IgG antibodies in circulation. Targeting this receptor blocks its function by competitively adhering to the IgG receptor site on FcRn and subsequently there is enhanced catabolism of IgG resulting in a drop in plasma levels.