Biologic Therapies in Thyroid Eye Disease: A PRISMA-Based Systematic Review and Meta-Analysis of Clinical Outcomes, Safety Profiles and Impact on Surgical Management

Abstract

Background: Biologic therapies have transformed Thyroid Eye Disease (TED) management, but their comparative efficacy, safety, durability and effects on subsequent rehabilitative surgery remain uncertain. Objective: To evaluate the efficacy and safety of teprotumumab, rituximab and tocilizumab across TED phenotypes and assess durability, retreatment and surgical requirements. Methods: PubMed/MEDLINE, Scopus, Cochrane Library and Web of Science were searched from 1 January 1975 to 31 July 2024, with an updated PubMed search through 18 August 2026. Grey literature, conference proceedings, references and forward citations were also reviewed. Randomized and non-randomized studies of biologic therapy in TED were eligible. Two reviewers independently performed selection, extraction and risk-of-bias assessment using RoB 2, ROBINS-I or Joanna Briggs Institute tools. Random-effects meta-analysis was performed when appropriate; otherwise, findings were synthesized narratively. Certainty was assessed using GRADE. Results: Seventy-seven cohorts met inclusion criteria; 58 contributed quantitative data and linked reports produced an 87-publication evidence map. The disease-specific synthesis included 54 publications: five randomized trials, two non-randomized controlled studies, 10 prospective cohorts, 21 retrospective cohorts, three case-control studies and 13 case series. Teprotumumab showed the broadest and most consistent efficacy. In active, moderate-to-severe TED, proptosis response occurred in 77.4% versus 14.9% with placebo and diplopia response in 69.7% versus 30.5%. In chronic, low-activity TED, proptosis response was 61.9% versus 25.0%. Tocilizumab showed marked anti-inflammatory efficacy in glucocorticoid-resistant disease: a ≥2-point Clinical Activity Score reduction occurred in 93.3% versus 58.8% with placebo and disease inactivation in 86.7% versus 35.3%. Rituximab reduced inflammatory activity but showed less consistent effects on proptosis, diplopia, fibrosis and restrictive myopathy. Teprotumumab’s principal safety concerns were hearing dysfunction and dysglycaemia. Evidence for durability, retreatment and surgical avoidance was heterogeneous and mainly observational. Conclusion: Biologic effects vary by agent and phenotype. Teprotumumab has the strongest evidence across inflammatory and structural outcomes, tocilizumab appears especially useful in glucocorticoid-resistant inflammatory TED and rituximab may benefit selected active cases. Biologics may modify, but do not reliably eliminate, rehabilitative surgery. Head-to-head trials with standardized outcomes and longer off-treatment follow-up are needed.