Graves’ orbitopathy following Alemtuzumab treatment for multiple sclerosis: a systematic review and real-world insights

Alemtuzumab (ALEM), an immune reconstitution therapy for multiple sclerosis (MS), has been associated with an increased risk of secondary autoimmune diseases, including Graves’ disease (GD). Graves’ orbitopathy following ALEM (GO-f-ALEM) is a rare, but relevant manifestation. GO-f-ALEM epidemiology and clinical course are still poorly characterized. The first aim of this paper was to perform a systematic review of published evidence of GO-f-ALEM in patients with MS, focusing on clinical features and management. Second aim was to integrate and compare literature data with real-world pharmacovigilance reports and institutional cases. A systematic review of published literature databases (PubMed, Embase, Scopus) from inception to December 2024 was performed according to PRISMA guidelines. A total of 42 published GO-f-ALEM cases in MS patients were identified. In parallel, as additional sources of data, which were not included in the systematic review analysis, 272 cases were retrieved from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database, and three institutional cases were described and analysed. GO-f-ALEM occurred more frequently in middle-aged adults (mean age 41 years old), with female predominance (60%) and a high rate of smoking (60%). GO generally occurred after 2–5 years from ALEM initiation. Fluctuating thyroid function and thyrotropin receptor antibody (TRAb) levels were commonly observed, with frequent need for definitive thyroid treatment (surgery or radioactive iodine - RAI). GO presentation was heterogeneous - from mild to sight-threatening forms - and mainly manifesting with lid retraction, proptosis, and diplopia. Concurrently, pharmacovigilance data from FAERS identified almost 300 reports of eye disorders potentially consistent with GO, thus suggesting under-diagnosis or under-reporting prevalence in literature. Institutional cases confirmed the potential for sight-threatening GO with dysthyroid optic neuropathy. Our data suggest that GO-f-ALEM is an underrecognized disorder within the spectrum of ALEM-induced autoimmunity, with peculiar features, as suggested by clinical and immunological observations and simultaneously by pharmacovigilance reports. Routine ophthalmic monitoring and standardized GO classification are essential for diagnosis and follow-up. Prospective studies are warranted to better define its epidemiology and guide optimised management strategies.