COMPARATIVE EFFECTIVENESS OF IMMUNOSUPPRESSIVE AGENTS IN MODERATE-TO-SEVERE GRAVES’ ORBITOPATHY: A SYSTEMATIC REVIEW

Abstract

Introduction: Graves’ orbitopathy (GO) represents the most frequent extrathyroidal manifestation of Graves’ disease, characterized by inflammation and expansion of orbital tissues leading to functional and aesthetic impairment. Immunosuppressive therapy remains the cornerstone of treatment for moderate-to-severe active GO, but the relative efficacy of various agents remains controversial.

Objective: To evaluate and compare the clinical effectiveness and safety of different immunosuppressive agents used in the treatment of moderate-to-severe active GO, including corticosteroids, mycophenolate mofetil, rituximab, tocilizumab, teprotumumab, and other immunomodulatory drugs. Secondary objectives included assessing relapse rates, long-term outcomes, and adverse effects associated with each therapeutic approach.

Methods: A systematic search was conducted in PubMed, Scopus, Web of Science, Cochrane Library, LILACS, ClinicalTrials.gov, and the WHO ICTRP, covering publications from 2015 to 2025. Randomized controlled trials, cohort studies, and observational studies involving adult patients with moderate-to-severe GO treated with immunosuppressive agents were included. Studies with insufficient clinical data, case reports, or lacking therapeutic outcomes were excluded. Data extraction followed PRISMA 2020 guidelines, and the certainty of evidence was assessed using GRADE methodology.

Results and Discussion: Of 1,243 records initially identified, 37 met inclusion criteria after screening and eligibility assessment. Intravenous methylprednisolone combined with mycophenolate mofetil showed superior response rates and lower relapse risk compared to corticosteroids alone. Rituximab and teprotumumab demonstrated promising improvements in clinical activity scores and proptosis reduction, though cost and accessibility remain limitations. Tocilizumab exhibited benefit in steroid-refractory cases. Adverse events were generally mild to moderate and varied across agents.

Conclusion: Current evidence supports intravenous corticosteroids combined with mycophenolate as first-line therapy for moderate-to-severe GO, while biologics such as rituximab, tocilizumab, and teprotumumab represent effective alternatives in refractory or recurrent disease. Personalized and multidisciplinary approaches are recommended to optimize outcomes and minimize treatment-related risks.