Nagy, Endrewahdan, mohannad2025-05-192025-05-192025-04-07https://hdl.handle.net/2437/390065Thyroid Eye Disease (TED) is a complex autoimmune disorder influenced by thyroid dysfunction, orbital autoimmunity, and intraorbital pressure. It follows a biphasic course, beginning with an active inflammatory phase characterized by immune cell infiltration and cytokine-driven tissue remodeling, followed by a chronic fibrotic phase that leads to irreversible structural changes. TED is closely associated with Graves' disease (GD), where thyroid-stimulating hormone receptor antibodies (TRAbs) drive both hyperthyroidism and orbital fibroblast activation. While thyroid dysfunction can be managed with antithyroid drugs, radioactive iodine therapy, or thyroidectomy, TED remains an independent immune-mediated condition that can persist even in euthyroid or hypothyroid states. Therefore, maintaining a stable euthyroid state is optimal for disease control. TED affects up to 40% of GD patients, with 3-5% developing moderate to severe or sight- threatening forms. Risk factors such as smoking and high TRAb levels significantly contribute to disease severity. Advanced imaging suggests that subclinical TED is more common than previously thought. Diagnosis relies on clinical assessment, with classification systems such as the EUGOGO and ATA-ETA scores for severity, and the Clinical Activity Score (CAS) for activity, guiding treatment decisions. TED pathogenesis is driven by autoimmunity against shared thyroid and orbital antigens, particularly thyroid-stimulating hormone receptor (TSHR) and insulin-like growth factor- 1 receptor (IGF-1R). Activation of antigen-presenting cells triggers T-helper cell- mediated cytokine release, which stimulates fibroblast proliferation, glycosaminoglycan accumulation, and orbital tissue expansion. Orbital fibroblasts, key effector cells in TED, further contribute to disease progression by differentiating into adipocytes and myofibroblasts, exacerbating proptosis and fibrosis. Additionally, increased intraorbital pressure activates mechanosensitive Piezo1 receptors, further worsening orbital congestion and inflammation. TED treatment directly targets its pathogenesis by addressing immune dysregulation, fibroblast activation, and mechanical complications. Glucocorticoids remain the first-line 37 therapy for moderate-to-severe TED, suppressing NF-κB signaling to reduce cytokine release and fibroblast activation. Orbital irradiation is an effective adjunct. For steroid- refractory cases, biologics such as rituximab (B-cell depletion) and tocilizumab (IL-6 receptor blockade) help modulate autoantibody production and inflammation. Teprotumumab, an IGF-1R antagonist, represents a major breakthrough by directly inhibiting fibroblast proliferation and adipogenesis, making it the first true disease- modifying therapy. Mycophenolate mofetil offers an alternative immunosuppressive option, while cyclosporine-A contributes by mitigating oxidative stress and immune hyperactivity. Selenium has gained attention for its antioxidant effects, particularly in selenium- deficient patients. Local therapies play a crucial role across all TED stages. In severe cases, orbital decompression surgery alleviates intraorbital pressure, while strabismus and eyelid surgeries restore function and aesthetics. Smoking cessation remains the most critical preventive strategy, as smoking exacerbates inflammation and reduces treatment efficacy. Additionally, radioiodine therapy for Graves’ hyperthyroidism is contraindicated in active TED; in inactive TED cases, corticosteroid prophylaxis is used to prevent disease exacerbation. In conclusion, biologic therapies such as teprotumumab and rituximab have revolutionized TED management by altering disease mechanisms at a molecular level, while traditional treatments, including glucocorticoids and surgery, remain essential for controlling inflammation and structural complications. As TED management evolves, novel agents such as VRDN-001 and CAR-based therapy offer promising therapeutic avenues by precisely modulating immune pathways. Advances in biologics, refined surgical techniques, and preventive strategies are shifting TED treatment toward a more personalized, disease-modifying approach. Future therapies will not only suppress inflammation but also reshape disease progression, ultimately improving patient outcomes and reducing long-term complications.45enPathogenesistreatmentThyroid eye diseaseteprotumumaborbital decompressionMedicine::Internal MedicineHozzáférhető a 2022 decemberi felsőoktatási törvénymódosítás értelmében.