A Comprehensive Review of Thyroid Eye Disease Pathogenesis: From Immune Dysregulations to Novel Diagnostic and Therapeutic Approaches

Abstract

Thyroid eye disease is a complex inflammatory disorder of the orbit that has gained tremendous interest over the past years, and numerous scientific efforts have been deployed to elucidate its pathophysiology for novel drug development. Our manuscript will delve into the molecular dysregulations involved in the pathogenesis of thyroid eye disease that led to its clinical manifestations. Abnormalities within the apoptotic pathway, inflammatory cascade, and autoimmune regulatory systems will be covered. We will further discuss the challenges involved in its diagnosis and management and provide a summary of the current diagnostic tools (i.e., molecular biomarkers, diagnostic scores) from the perspective of clinicians. Finally, our comprehensive literature review will provide a thorough summary of most recent preclinical and clinical studies around the topic of thyroid eye disease, with an emphasis on the manuscripts published within the last five years. We believe our manuscript will bring novelty within the field by bridging the fundamental sciences with the clinical aspect of this disease. This review will be a great tool for clinicians in better understanding the pathogenesis of thyroid eye disease while providing an outlook on future perspectives (i.e., liquid biopsies, artificial intelligence).

Keywords: deep learning for thyroid eye disease; grave’s disease; grave’s orbitopathy; grave’s pathophysiology; immunotherapy for grave’s disease; thyroid eye disease.

Figure 1

Schematic representation of thyroid eye disease pathophysiology. The backbone of TED pathogenesis involves the uncontrolled activation of orbital fibroblasts by thyroid-stimulating autoantibodies, IGF-1R autoantibodies, and through the proinflammatory microenvironment created by T- and B-cells. Activated orbital fibroblasts lead to adipogenesis, which is involved in proptosis and orbital fat expansion, as well as glycosaminoglycan, hyaluronan, and proteoglycan production, markers involved in scar formation. The figure was created with BioRender.com.

Figure 2

Schematic representation of the clinical manifestations of thyroid eye disease. The most common clinical symptoms involved in thyroid eye disease are depicted in this illustration. The figure was created with BioRender.com.

Figure 3

Schematic representation of the Rundle’s curve. The thyroid eye disease course is composed of an active phase, which lasts from 1 to 3 years and may or may not involve resolution of clinical manifestations during the disease course, and an inactive phase of 3 years duration and more. The figure was created with BioRender.com.

Figure 4

Computed tomography images demonstrated extraocular muscle enlargement in thyroid eye disease. Computed tomography (CT)-based images in axial (a,b) and coronal (c) planes showcase superior (yellow arrow), medial (red arrow), and inferior (green arrow) rectus muscle enlargement bilaterally.

Figure 5

Targeting IGF-R1 for the treatment of thyroid eye disease. (A) Tetrotumumab as well as other antibodies against IGF-1R can trigger the internalization and degradation of IGF-1R. (B) Antibodies against IGF-1R can disrupt the interaction between TSHR and IGF-1R. (C) Antibodies targeting IGF-1R can disrupt ligand binding (red ✕) and downstream signal activation (red ✕). (D) Small molecules disrupt the downstream signaling cascade by targeting tyrosine kinase domains (red ✕). The figure was created with BioRender.com.

Figure 6

Mechanism of action of antibodies targeting IL-6R. (A) Uninhibited IL-6R is activated by its ligand, IL-6, leading to the dimerization of gp-130 and activation of a signaling cascade that activates the pro-inflammatory response. (B) Tocilizumab disrupts the interaction between IL-6R and its ligand (red ✕), preventing gp-130 dimerization and inhibiting the signaling cascade that triggers pro-inflammatory responses (red ✕). The figure was created with BioRender.com.

Figure 7

Mechanism of action of Rituximab, an antibody specific to CD20 on the surface of B cells. (A) Rituximab binds its ligand CD20, which can trigger an intracellular signaling cascade, leading to apoptosis of B cells. (B) Complement activation by rituximab leads to deposition of MACs that cause an influx of fluid and cell lysis of B cells. (C) Fc fragments of rituximab trigger Fc receptors on NK cells, activating them and leading to the release of granzymes and perforins and cell lysis of B cells. (D) Phagocytes are activated through their Fc receptor, recognizing the Fc fragment of rituximab, leading to the degradation of the B cell through phagocytosis. The figure was created with BioRender.com.