Background: Thyroid eye disease (TED) is a complex autoimmune disorder that is frequently disfiguring and sight-threatening. Recent advances have shifted treatment from surgery toward targeted biologic therapies like teprotumumab (TMB), an IGF-1R inhibitor that improves proptosis, diplopia, and inflammation. However, ocular surface symptoms often persist.
Methods: We conducted a longitudinal pre-post comparative study of patients with active, moderate-to-severe TED treated with TMB at a tertiary academic medical center, with tear sampling at two prespecified time points: baseline (collected within the 3 weeks strictly antecedent to the first infusion) and post-treatment (within 6 months of the final infusion). Adults with active, moderate-to-severe TED who received ≥4 TMB infusions were eligible. All patients contributed paired pre- and post-treatment tear samples (22 eyes). Controls were adults without TED or ocular surface disease (32 eyes). Tear fluid was collected by Schirmer strips and analyzed by liquid chromatography-tandem mass spectrometry. Differential expression was assessed using a linear mixed-effects model to explicitly account for the intrinsic correlation between paired eyes; correlations between LFQ intensities and clinical metrics used Spearman rank correlation.
Results: A total of 2974 proteins were identified across 76 tear samples. Unsupervised analyses demonstrated separation between control, pre-treatment, and post-treatment TED tear proteomes. Although TMB induced substantial proteomic changes, post-treatment profiles did not revert to a control-like state. Proteins involved in inflammation, oxidative stress, and cytoskeletal organization remained persistently dysregulated, while a subset of tear film stability-associated proteins normalized. Several persistently dysregulated protein targets overlapped with FDA-approved drugs.
Conclusions: These observational findings support tear proteomics as a platform for biomarker discovery and therapeutic prioritization and warrant validation in larger, independent cohorts.
Plain language summary
Thyroid eye disease is an autoimmune condition that can cause eye bulging (proptosis), double vision, and chronic eye discomfort. Although the drug teprotumumab improves many clinical signs, patients often continue to experience dry eye symptoms, and the reasons for this are not well understood. In this study, we analyzed proteins in tear fluid collected from patients with thyroid eye disease before and after teprotumumab treatment and compared them with tears from people without the disease. Tears are easy to collect and reflect the health of the ocular surface. We found that while treatment caused major changes in tear composition, many proteins linked to inflammation and cellular stress remained abnormal, even after therapy. Some protective tear proteins improved, but overall the tear profile did not fully return to normal. These findings suggest that eye surface disease may persist despite treatment and that tear protein measurements could help guide future therapies.
Velez G, Ngo GH, Young D, Amarikwa L, Dufour A, Kossler AL, Mahajan VB. Paired longitudinal tear proteomics reveals persistent ocular surface dysregulation after teprotumumab therapy in thyroid eye disease. Commun Med (Lond). 2026 Jun 30. doi: 10.1038/s43856-026-01757-6. Epub ahead of print. PMID: 42380591.
