Noninvasive Biomarkers for Graves’ Orbitopathy: Clinical Relevance of Circulating PAI-1, TGF-β and IGF-1R

PURPOSE: Graves' orbitopathy (GO) involves fibrotic and inflammatory processes. Plasminogen activator inhibitor-1 (PAI-1), transforming growth factor-β (TGF-β), and soluble insulin-like growth factor-1 receptor (IGF-1R) have been identified as key mediators. This study primarily focused on the diagnostic value of circulating PAI-1, TGF-β, and IGF-1R, with their prognostic and treatment-monitoring significance assessed as exploratory endpoints. METHODS: Circulating levels of PAI-1, TGF-β, and IGF-1R were analyzed in patients with moderate-to-severe active GO (Group 1, n = 28), sight-threatening active GO (Group 2, n = 9), mild inactive GO (Group 3, n = 34), Graves' disease (GD) without orbitopathy (Group 4, n = 22), and control group (CG, n = 27). In Group 1, biomarker concentrations were assessed before and after intravenous glucocorticosteroids (GC). Treatment response in Group 1 was evaluated based on predefined criteria for Clinical Activity Score (CAS), diplopia, and proptosis. FINDINGS: PAI-1 was significantly elevated in GO versus GD and CG (p < 0.05). TGF-β was elevated in GO versus CG, but did not significantly differ between GO and GD. IGF-1R was elevated across all patient groups versus CG. Lower baseline PAI-1 was significantly associated with GC response for CAS and diplopia (p = 0.0006 and p = 0.04). Following GC, TGF-β declined only in CAS (p = 0.02) and diplopia (p = 0.02) responders. IMPLICATIONS: Circulating PAI-1 may help differentiate GO from GD, representing a potential diagnostic marker, while its association with treatment response should be considered exploratory. TGF-β dynamics may reflect therapeutic efficacy, and IGF-1R appears to indicate the general autoimmune background of GD, both in an exploratory context. Overall, PAI-1 emerges as a promising biomarker candidate; however, further validation in larger prospective studies is required to confirm its utility for patient stratification and monitoring of individualized therapy in clinical practice.