Understanding Pathogenesis Intersects With Effective Treatment for Thyroid Eye Disease

Abstract

Context: Thyroid eye disease (TED), a vision-threatening and disfiguring autoimmune process, has thwarted our efforts to understand its pathogenesis and develop effective and safe treatments. Recent scientific advances have facilitated improved treatment options.

Objective: Review historically remote and recent advances in understanding TED.

Design/setting/participants: PubMed was scanned using search terms including thyroid-associated ophthalmopathy, thyroid eye disease, Graves' orbitopathy, autoimmune thyroid disease, and orbital inflammation.

Main outcome measures: Strength of scientific evidence, size, scope, and controls of clinical trials/observations.

Results: Glucocorticoid steroids are widely prescribed systemic medical therapy. They can lessen inflammation-related manifestations of TED but fail to reliably reduce proptosis and diplopia, 2 major causes of morbidity. Other current therapies include mycophenolate, rituximab (anti-CD20 B cell-depleting monoclonal antibody), tocilizumab (interleukin-6 receptor antagonist), and teprotumumab (IGF-I receptor inhibitor). Several new therapeutic approaches have been proposed including targeting prostaglandin receptors, vascular endothelial growth factor, mTOR, and cholesterol pathways. Of potentially greater long-term importance are attempts to restore immune tolerance.

Conclusion: Despite their current wide use, steroids may no longer enjoy first-tier status for TED as more effective and better tolerated medical options become available. Multiple current and emerging therapies, the rationales for which are rooted in theoretical and experimental science, promise better options. These include teprotumumab, rituximab, and tocilizumab. Restoration of immune tolerance could ultimately become the most effective and safe medical management for TED.

Keywords: Graves’ disease; IGF-I receptor; IL-6 receptor; TSH receptor; autoimmunity; glucocorticoids; ophthalmopathy; orbit; teprotumumab.

Figure 1.

Clinical manifestations of Graves’ disease. (A) Diffuse moderately enlarged goiter in a woman with hyperthyroidism from Graves’ disease. (B) Moderate to severe thyroid eye disease including bilateral proptosis, periorbital edema, scleral injection, and lid retraction in this patient. (C) Pretibial dermopathy of the plaque form affecting both legs in this patient. (D) Acropachy with fingernail clubbing. From N Engl J Med, Smith T.J. and Hegedus L. Graves’ disease. 375; 1552-1565. Copyright © (2016) Massachusetts Medical Society. Reprinted with permission.

Figure 2.

Proposed theoretical model of thyroid eye disease (TED) pathogenesis. Orbital fibroblasts exhibiting robust responses to inflammatory mediators appear to represent the central effector cells. CD34⁺fibroblasts derived from CD34⁺CXCR4⁺collagen 1⁺fibrocytes, monocyte-derived progenitors traffic from bone marrow to the TED orbit. Fibrocytes express several thyroid-specific proteins, including thyrotropin receptor (TSHR), thyroglobulin, thyroperoxidase, and sodium-iodide symporter and express class II major histocompatibility complex (MHC). Fibrocytes and orbital fibroblasts undergo differentiation into myofibroblasts and adipocytes. Slit2 expressed and released by CD34^- fibroblasts down regulates expression of many genes expressed by fibrocytes and CD34⁺fibroblasts. Interleukins 1β, 6, 8, 10, 12, 16, and 23, tumor necrosis factor α, and Regulated on Activation, Normal T Expressed and Secreted (RANTES), CXCL-12, and CD40-CD154 are expressed in the TED orbit by various cell types and contribute to the inflammatory milieu. CD34⁺and CD34^- orbital fibroblasts cell-surface display insulin-like growth factor-I receptor (IGF-IR) and express 3 mammalian hyaluronan synthase isoenzymes and UDP glucose dehydrogenase and synthesize hyaluronan. This glycosaminoglycan underlies in part orbital tissue expansion in TED. Hyaluronan synthesis localizes primarily to CD34^- orbital fibroblasts.

Figure 3.

Use of current therapies and those under development in active and stable, moderate to severe TED. Medical treatment for mild active TED is typically limited to local, nonsurgical measures. In contrast, management of moderate to severe, active TED often involves systemic medications. Some of these drugs can reduce disease activity (signs and symptoms related to inflammation) but most appear relatively ineffective in stable TED. Preliminary reports suggest that teprotumumab may also be effective during stable disease, but clinical trials will be necessary to establish its effectiveness in nonprogressive TED. Relative size of question marks reflects the relative uncertainty of specific treatment effectiveness in stable TED. Surgery is typically reserved for TED reaching the stable phase. The exception is the development of vision loss from compressive optic neuropathy or severe anterior eye surface deterioration. Rituximab (anti-CD20 displayed on B cells), tocilizumab (IL-6 receptor inhibitor), teprotumumab, VRDN-001, linsitinib (IGF-IR inhibitors), K1-70 (TSHR inhibitor), RVT-1401 and HBM9161 (FcRn antagonists), CFZ533 (anti-CD40 antagonist), and TSHR and IGF-IR vaccines (for potentially restoring immune tolerance).

Figure 4.

Putative molecular targets for current medical therapies and those under development. Glucocorticoid steroids target many cell types, where they induce several target genes while inhibiting the expression of others. Many of their anti-inflammatory actions are mediated through nuclear factor-κB. Other agents are more target-specific, such as mycophenolate (targets inosine monophosphate dehydrogenase [IMPDH] and GTP synthesis in lymphocytes), rituximab (anti-CD20 displayed on B cells), tocilizumab (IL-6 receptor inhibitor), teprotumumab, VRDN-001, linsitinib (IGF-IR inhibitors), K1-70 (TSHR inhibitor), RVT-1401, HBM9161 (FcRn antagonists), CFZ533 (anti-CD40 antagonist), and TSHR and IGF-IR vaccines. It is possible that additional, as-yet unidentified targets may play important roles in mediating clinical responses.