TED is a complex, debilitating and potentially sight-threatening autoimmune condition that can significantly affect quality of life. Its incidence in recent studies ranges from 3.3-8.9 cases per 100 000 population/year in women and 0.9-1.9 cases per 100 000 population/year in men, 1,2,3,4 while the population prevalence in Europe is estimated to be between 90 and 155/100,000, meeting criteria for an infrequent, but not rare disease.5,1 TED affects 25-50% of patients with Graves’ disease (GD); among TED patients, 90% have hyperthyroidism, while 5-10% have hypothyroidism or euthyroidism.6 One retrospective study at a single tertiary referral center in Italy demonstrated that regardless of the underlying type of thyroid dysfunction, the phenotype of TED was similar.7 The diagnosis of TED can sometimes be challenging, especially in atypical presentations such as euthyroid patients or unilateral disease. All cases with suspected TED should undergo a comprehensive ophthalmic examination to accurately diagnose and stage the condition, as well as to exclude potential alternative ophthalmic or orbital disorders. The differential diagnosis of TED encompasses a range of conditions, including idiopathic orbital inflammation, orbital tumors, vasculitis, systemic diseases such as Sjogren syndrome or sarcoidosis, infection, IgG4-related disease, or arteriovenous malformations.8 TED is more prevalent in women; other risk factors include age, smoking, higher TSH-receptor antibody levels and radioactive iodine therapy exposure.1 Certain genetic polymorphisms have been linked to propensity for TED in Asian populations.9 The risk is slightly lower in former smokers compared with current smokers, highlighting that smoking cessation is useful.10 Cannabis use, vitamin D deficiency, elevated LDL levels, obstructive sleep apnea, and obesity, particularly in relation to orbital fat expansion, have been identified as emerging risk factors.11, 12, 13, 14, 15

The pathophysiology of TED involves the activation of the thyroid-stimulating hormone receptor (TSHR) and the insulin-like growth factor-1 receptor (IGF-1R) on orbital fibroblasts (OFs) by TSHR-stimulating autoantibodes.16 This leads to a cascade of events, including release of pro-inflammatory cytokines, which activate OFs to proliferate and differentiate into both myofibroblasts and adipocytes. In addition, signaling through the TSHR/IGF-1R complex stimulates production of hyaluronic acid and glycosaminoglycans. These changes, along with recruitment and activation of T and B lymphocytes and cytokine release, lead to muscle swelling, inflammation, increased orbital fat, and tissue remodeling.16

TED can be classified into distinct categories based on the degree of inflammation and the severity of clinical signs; this helps guide treatment decisions and monitor the disease over time. The Clinical Activity Score (CAS), developed initially to identify steroid-responsive disease,17 can be used as a 7-point scale to assess inflammatory signs and symptoms. The 10-point CAS, which can assess disease progression, includes three additional items: an increase in proptosis ≥ 2 mm, a decrease of eye movements in any direction of gaze ≥ 8°, and a decrease of visual acuity ≥ 1 line on the Snellen chart during a period of 1–3 months. TED is defined as active if CAS is ≥ 3/7 or ≥ 4/10. TED can also be classified according to its severity into mild, moderate-severe, and sight-threatening disease, based on the effects of the soft tissue changes, diplopia, and proptosis on the patient’s quality of life.18

This review aims to provide an overview of the advances in the understanding of TED in the last 2 years, with a focus on current management and emerging therapies for this complicated disease.

Smoking cessation and the control of other modifiable risk factors such as obstructive sleep apnea, diabetes, dyslipidemia, and vitamin D deficiency are important for all patients. Other essential elements of management include achieving and maintaining euthyroidism and the judicious use of radioactive iodine therapy with steroid prophylaxis when indicated.1