Lancet Diabetes Endocrinol. 2025 May 2:S2213-8587(25)00066-X. doi: 10.1016/S2213-8587(25)00066-X. Online ahead of print.
ABSTRACT
Thyroid eye disease (TED; also known as Graves' orbitopathy), causes swollen extraocular muscles and orbital fat. Mechanistically, TED involves lid retraction, oedema and redness of the eyelids and conjunctiva, proptosis, diplopia, and optic neuropathy. Investigation of TED involves assessment of disease activity (inflammation) and disease severity. TED is predominantly mild in 77% of cases, moderate-to-severe in 22%, and rarely sight-threatening in 1% of patients. While most patients with TED have Graves' hyperthyroidism, up to 5% are euthyroid or even hypothyroid. Risk factors include male sex, older age, smoking, diabetes, hypercholesterolaemia, duration of hyperthyroidism, radioactive iodine therapy, and the presence of thyrotropin receptor (TSHR) antibodies (detectable in more than 95% of patients and directly related to TED activity and severity). Genetic immunisation of mice with TSHR, but not with insulin-like growth factor-1 receptor (IGF-1R), provides a reliable animal model of TED, demonstrating that TSHR is the primary autoantigen in the disease. Crosstalk between TSHR and IGF-1R occurs via a β-arrestin scaffold. Teprotumumab, a human monoclonal antibody that blocks IGF-1R without binding to TSHR, has been shown to significantly improve outcomes in moderate-to-severe TED, including greater proptosis reduction compared with intravenous methylprednisolone. However, its disadvantages include side effects (eg, hearing loss in 30% of patients), a high cost, and a high relapse rate. Therefore, intravenous steroids remain the treatment of choice in many parts of the world. Tocilizumab, which blocks the interleukin-6 receptor, is an effective treatment option for patients with TED who are steroid-resistant. This Review further discusses alternative medications, surgical treatments, local measures, and the importance of quality-of-life assessments and multidisciplinary care.
PMID:40324443 | DOI:10.1016/S2213-8587(25)00066-X