Disentangling the Association Between Excess Thyroid Hormone and Cognition in Older Adults.

PURPOSE: To identify biomarkers related to disease activity, severity and response to intravenous methylprednisolone (IVMP) in Graves' orbitopathy (GO), and to evaluate differences in serum proteome between GO, IgG4-related orbital disease (IgG4-ROD) and idiopathic orbital inflammation (IOI).

METHODS

Serum proteomics targeting 368 inflammatory proteins (Olink Explore Inflammation panel) was performed on biobank samples from patients with GO (n = 111), IOI (n = 16), IgG4-ROD (n = 10), and healthy controls (n = 25). GO activity, severity and response to IVMP were assessed retrospectively. Differentially expressed proteins (DEPs) were defined as Log2-fold change <-0.5 or >0.5 and false discovery rate (FDR)-adjusted P < 0.05.

RESULTS

No DEPs were associated with GO activity or severity. No DEPs linked to IVMP response were seen after FDR correction, likely because of limited sample size (22 responders vs. 16 non-responders). However, five top-ranked proteins related to IVMP response prior to FDR correction were further evaluated by Luminex or ELISA, showing significantly higher VEGF-A in IVMP non-responders. Receiver operator characteristic analysis showed that VEGF-A predicted treatment response with an area under the curve (AUC) of 77.3% (sensitivity = 77.3%, specificity = 75%). Combining VEGF-A and thyroid stimulating immunoglobulins improved predictive accuracy, especially in patients receiving standard IVMP treatment for moderate-to-severe disease (AUC 84%, sensitivity 91.7%, specificity 75%). Compared to healthy controls, 105 DEPs were found in GO, 83 in IOI and 57 in IgG4-ROD. Forty-eight DEPs were differentially expressed across all three conditions.

CONCLUSIONS

Serum VEGF-A is increased in IVMP non-responders and thus may be a biomarker for predicting treatment response in GO. Furthermore, GO shares immunopathobiological features with IOI and IgG4-ROD.