Pharmacologic Therapies for Active Moderate-to-Severe TED: A Comprehensive Systematic Review.

Background: Moderate-to-severe thyroid eye disease (TED) is a potentially vision-threatening inflammatory condition that requires timely, evidence-based medical management. Although intravenous glucocorticoids remain the mainstay of therapy, several biologic and immunosuppressive agents have emerged as potential alternatives, particularly in steroid-refractory disease. Objectives: To evaluate and compare the efficacy, safety, and therapeutic positioning of medical treatments for active moderate-to-severe thyroid eye disease. Data Sources and Methods: A comprehensive search of PubMed, Embase, and the Cochrane Library was conducted through February 2025. Eligible studies included randomized controlled trials, meta-analyses, systematic reviews, observational cohorts, and selected case series evaluating pharmacological interventions for moderate-to-severe TED. Outcomes of interest were proptosis reduction, Clinical Activity Score (CAS) improvement, diplopia response, and safety/tolerability. A semi-quantitative synthesis approach was used to integrate evidence across heterogeneous study designs. Results: Fifty-eight studies met the inclusion criteria. Intravenous glucocorticoids (IVGCs) demonstrated the most consistent efficacy in controlling inflammatory activity, with modest effects on proptosis and favorable tolerability at cumulative doses below 8 g. Among biologic therapies, teprotumumab showed the greatest magnitude of benefit across all efficacy domains but was limited by safety considerations and access constraints. Rituximab and tocilizumab demonstrated moderate efficacy, particularly in glucocorticoid-resistant cases. Mycophenolate mofetil emerged as the most reliable non-biologic immunosuppressive option. Oral glucocorticoids and several adjunctive therapies showed limited or inconsistent benefit. Conclusion: This systematic review provides an integrated framework to support therapeutic decision-making in moderate-to-severe TED. Intravenous glucocorticoids remain the most consistently supported first-line therapy, while IGF-1R-targeted biologic therapy offers the most comprehensive efficacy across key clinical domains in selected patients. Registration: Not registered.