International Ophthalmology · 8 authors, 3 centres
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This comprehensive review summarizes the pathogenesis, risk factors, and medical management of Graves ophthalmopathy (GO). Key advances include the approval of teprotumumab as a targeted therapy and evidence supporting selenium, mycophenolate, and combination therapies. The review highlights the importance of early intervention and individualized treatment based on disease activity and severity.
**Background:** Graves ophthalmopathy (GO), also known as thyroid-associated ophthalmopathy (TAO) or thyroid eye disease (TED), is an autoimmune orbital disease primarily associated with hyperthyroidism. It has a prevalence of 90–155/100,000 in Europe, with a higher incidence in women and peak onset between 30–50 years. Pathogenesis involves immune cell infiltration, hyaluronan deposition, and lipogenesis, leading to eyelid retraction, proptosis, and potential vision loss. The review covers recent advances in medical therapy, focusing on pathogenesis, risk factors, and both nonspecific and targeted treatments.
**Methods:** The authors conducted structured searches in PubMed and Web of Science using keywords including Graves ophthalmopathy, thyroid-associated ophthalmopathy, thyroid eye disease, Graves orbitopathy, diagnosis, and treatment. References up to July 2022 were traced, with most cited literature published in the last five years. Only English-language studies were included.
**Key Results:** The review details several therapeutic approaches: - **Antioxidants:** Selenium supplementation (100 mcg twice daily for six months) improved GO course in a multicenter double-blind trial, with effects maintained at six months. Other antioxidants (quercetin, vitamin C, N-acetyl-l-cysteine, melatonin, β-carotene) show potential but require further clinical study. - **Corticosteroids:** Intravenous methylprednisolone (IVMP) is more effective and has fewer adverse events than oral glucocorticoids. The 2021 EUGOGO guideline recommends a moderate cumulative dose of IVMP (0.5 g/week for 6 weeks) combined with mycophenolate sodium (0.72 g/day for 6 weeks) as first-line treatment. - **Mycophenolate mofetil (MMF):** In a study of 174 patients, MMF showed a significantly higher overall response rate (91.3% vs. 67.9%, p<0.001), better CAS response (92.5% vs. 70.5% improvement, p<0.05), and improvement in diplopia (90.4%) and proptosis (68.8%). - **Cyclosporine:** Combined with oral glucocorticoids, it achieves better cure rates than cyclosporine alone, but dose-dependent liver and renal toxicities limit its use. - **Azathioprine:** May improve 48-week outcomes when combined with glucocorticoids and potentially prevent long-term recurrence. - **Statins:** A large register-based study of 34,894 GD patients found statins may protect against GO development. A phase 2 RCT suggested atorvastatin plus IVGC improves outcomes in moderate-to-severe active GO. - **TNF-α inhibitors:** Etanercept (25 mg twice weekly for 3 months) reduced mean CAS from 4 to 1.6 (60%) in 10 patients, but recurrence occurred in three. Adalimumab and imatinib mesylate show limited efficacy. - **Rituximab (RTX):** Efficacy is inconsistent; some studies show no benefit, while others report improved ocular mobility and reduced surgery demand. Response appears influenced by disease duration. - **Tocilizumab:** In an RCT, 93.3% of treated patients improved by at least 2 points on CAS, with greater EUGOGO score improvement and exophthalmos reduction compared to placebo. - **Teprotumumab:** A phase III trial showed ≥2 mm reduction in proptosis in 82.9% of patients at week 24. It received FDA breakthrough therapy designation in 2020. Adverse events include muscle spasms, nausea, hyperglycemia, and hearing impairment.
**Clinical Implications:** Early intervention can alter disease course and improve long-term outcomes. The review emphasizes the need for individualized treatment based on disease activity and severity, with first-line therapy including IVMP plus mycophenolate. Teprotumumab represents a significant milestone, but its high cost, durability of response, and safety profile require further study. Selenium supplementation is beneficial in selenium-deficient regions. Smoking cessation and control of thyroid dysfunction, hypercholesterolemia, and other modifiable risk factors are essential. The review underscores the importance of ongoing research into targeted molecular therapies and the complex cytokine network underlying GO pathogenesis.