Thyroid Eye Disease in the Teprotumumab Era: Pathophysiology, Clinical Activity Assessment, and an Updated Therapeutic Landscape

Thyroid eye disease (TED), the principal extrathyroidal manifestation of Graves’ disease, is an autoimmune orbitopathy. The pathophysiology involves aberrant thyroid-stimulating hormone receptor (TSHR) and insulin-like growth factor 1 receptor (IGF-1R) signaling on orbital fibroblasts, leading to glycosaminoglycan accumulation, adipogenesis, inflammatory edema, and extraocular-muscle enlargement. The active phase is typically self-limited yet medically modifiable, characterized primarily by inflammation, edema, and tissue expansion, whereas chronic inactive disease is dominated by fibrosis and fixed structural change. This US-oriented review aims to provide updates in the field through 2026: (1) summarizing the molecular pathophysiology linking thyroid autoimmunity to orbital remodeling and current drug targets; (2) discussing activity-versus-severity assessment, with appraisal of the Clinical Activity Score (CAS); and (3) explaining the complementary roles of different structural and functional imaging modalities in the evaluation and management of TED. We then follow the therapeutic ladder, from conservative measures through the employment of glucocorticoids and steroid-sparing immunosuppression to the use of targeted biologics. We give particular attention to IGF-1R inhibition, including the use of teprotumumab and veligrotug, and to post-approval results, including otologic and metabolic adverse-event burden, recurrence, treatment sequencing, and the emerging efficacy of the treatment of chronic and low-activity disease. The CAS’s limited inter-observer reliability identifies additional reproducible activity measures as an open need.