Biomarkers from Tears may Provide Clarity on Thyroid Eye Disease Diagnosis, Disease State Progression, and Targeted Treatment Options
Rasha Bara
Background: Thyroid Eye Disease (TED) is an autoimmune condition occurring in ~50% of Graves’ Disease patients.1 Disease status is defined by the clinical activity score (CAS), resulting in scores from 0 to 7. The active phase (CAS ≳ 3) is defined by conjunctiva swelling, redness, inflammation, and eyelid retraction. Over 1-3 years, the inactive phase predominates. TED treatments include selenium and IV-glucocorticoids. However, due to side effects, interest in targeted immunomodulation therapies has been growing. Therefore, researchers have been evaluating non-invasive biomarker collection methods to elucidate new therapeutic targets.
Methods: A PubMed search was performed with keywords “thyroid eye disease”, “biomarkers”, “tears”, and “interleukins,” using Boolean operators “AND” and “OR”. Studies published more than five years prior were excluded.
Results: A 2019 study compared collection of orbital tissue (via surgery) and tears for biomarker isolation.1 They found increased IL15 and IL17 in orbital tissues of inactive TED patients compared to controls. From tears, researchers showed inactive TED patients had the highest levels of IL15 and IL17, followed by active TED patients, with controls having the lowest levels.1 Another study evaluated caspase-3, C4A and GAPDH from orbital tissue, showing all were elevated in TED compared to controls.2 In fact, caspase-3 showed 1.9x higher levels in TED.2 Tear exosomes showed increased caspase-3 and C4a, in addition to elevated APO-A-IV. While caspase-3 levels were higher in TED compared to controls irrespective of collection methods, caspase-3 from orbital tissue showed a significant difference while those from tears did not reach significance.2 Furthermore, lacrimal and tissue IL1 and IL18 were increased in TED but only lacrimal ILs reached significance.2 Lacrimal IL10, IL12p70, IL13, IL6, TNF-alpha, vitamin D-binding protein, CRP, CHI3L1, MMP-9, and VCAM-1 were significantly increased in active TED compared to healthy patients.3,4 Specifically, IL12, IL6 and TNF-alpha were elevated in patients with CAS ≥ 3.4 Additionally, lacrimal IL14, IL6, and IL8 had a positive correlation with CAS, providing evidence that their levels may be directly related to disease activity.4 IL7, which has late disease manifestation, was significantly decreased in active TED compared to controls 18-months post-collection – indicating that IL7 replacement may reduce disease activity.5
Conclusions: Studies evaluating biomarkers indicative of TED phases proved tears as a viable source, with the most promising biomarkers being IL1, IL5, IL6, IL7, IL8, IL12, IL14, IL15, IL17, and IL18. These may be effective therapeutic targets for personalized TED treatment.
Works Cited:
- Chen Q. The expression of interleukin-15 and interleukin-17 in tears and orbital tissues of Graves ophthalmopathy patients. J Cell Biochem. 2019;120(4):6299-6303. doi:10.1002/jcb.27916
- Shi TT, Zhao RX, Xin Z, et al. Tear-derived exosomal biomarkers of Graves’ ophthalmopathy (GO). Front Immunol. 2022;13:1088606. Published 2022 Dec 6. doi:10.3389/fimmu.2022.1088606
- Han JS, Kim SE, Jin JQ, et al. Tear-Derived Exosome Proteins Are Increased in Patients with Thyroid Eye Disease. Int J Mol Sci. 2021;22(3):1115. Published 2021 Jan 23. doi:10.3390/ijms22031115
- Kishazi E, Dor M, Eperon S, Oberic A, Turck N, Hamedani M. Differential profiling of lacrimal cytokines in patients suffering from thyroid-associated orbitopathy. Sci Rep. 2018;8(1):10792. Published 2018 Jul 17. doi:10.1038/s41598-018-29113-2
- Yang M, Chung Y, Lang S, Yawata N, Seah LL, Looi A. The tear cytokine profile in patients with active Graves’ orbitopathy. Endocrine. 2018;59(2):402-409. doi:10.1007/s12020-017-1467-2