Thyroid Eye Disease in the Teprotumumab Era: Pathophysiology, Clinical Activity Assessment, and an Updated Therapeutic Landscape
- 1Mitchel and Shannon Wong Eye Institute, Department of Ophthalmology, Dell Medical School, University of Texas at Austin, Austin, TX 78712, USA
Abstract
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.
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BibTeX
@article{shooshani2026thyroid,
title = {{Thyroid Eye Disease in the Teprotumumab Era: Pathophysiology, Clinical Activity Assessment, and an Updated Therapeutic Landscape}},
author = {Tara Shooshani and Balaji Cherupalla and Amy Durand and Moe Hein Aung},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27209071},
url = {https://www.mdpi.com/1422-0067/27/20/9071},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Thyroid Eye Disease in the Teprotumumab Era: Pathophysiology, Clinical Activity Assessment, and an Updated Therapeutic Landscape
AU - Tara Shooshani
AU - Balaji Cherupalla
AU - Amy Durand
AU - Moe Hein Aung
PY - 2026
DA - 2026/10/13
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27209071
UR - https://www.mdpi.com/1422-0067/27/20/9071
AB - 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.
SN - 1422-0067
ER -