Role of tear film biomarkers in the diagnosis and management of dry eye disease

Pak Yui Fong, Kendrick Co Shih, Pun Yuet Lam, Tommy Chung Yan Chan, Vishal Jhanji, Louis Tong, Pak Yui Fong, Kendrick Co Shih, Pun Yuet Lam, Tommy Chung Yan Chan, Vishal Jhanji, Louis Tong

Abstract

In recent years, there has been increasing scientific interest in the use of tear film biomarkers in the diagnosis and management of dry eye disease (DED), owing to their potential important roles in the pathogenesis of ocular surface damage, as well as the technical feasibility of tear sample collection techniques. An Entrez PubMed search was conducted on March 2, 2019, to include papers investigating the use of tear film biomarkers in DED, and the results were classified according to whether the DED is associated with systemic inflammatory disease or not and further classified within each section according to the molecular nature of the biomarker for further discussion. A total of 58 relevant articles were reviewed. Certain cytokines, including interleukin-6 (IL-6), tumor necrosis factor-alpha, IL-17, and IL-8, were found by a number of studies to consistently reflect disease severity well and had strong correlations with tear film metrics and tests for ocular surface damage in dry eye without systemic inflammatory disease. For dry eye with systemic inflammatory disease, IL-17, IL-8, and IL-1 receptor antagonists were shown to be consistently higher in affected eyes and correlated well with ocular surface disease severity in more than one type of inflammatory disease. With the advancement in technology and lowered costs in the future, tear film biomarker counts would allow better diagnosis and monitoring of DED, as well as facilitate personalized treatment strategies.

Keywords: Diagnosis; dry eye disease; inflammation; systematic review; tear film biomarkers; treatment.

Conflict of interest statement

The authors declare that there are no conflicts of interests of this paper.

Copyright: © 2019 Taiwan J Ophthalmol.

References

    1. Lee H, Chung B, Kim KS, Seo KY, Choi BJ, Kim TI, et al. Effects of topical loteprednol etabonate on tear cytokines and clinical outcomes in moderate and severe meibomian gland dysfunction: Randomized clinical trial. Am J Ophthalmol. 2014;158:1172–830.e1.
    1. Jackson DC, Zeng W, Wong CY, Mifsud EJ, Williamson NA, Ang CS, et al. Tear interferon-gamma as a biomarker for evaporative dry eye disease. Invest Ophthalmol Vis Sci. 2016;57:4824–30.
    1. Dohlman TH, Ciralsky JB, Lai EC. Tear film assessments for the diagnosis of dry eye. Curr Opin Allergy Clin Immunol. 2016;16:487–91.
    1. Lam H, Bleiden L, de Paiva CS, Farley W, Stern ME, Pflugfelder SC, et al. Tear cytokine profiles in dysfunctional tear syndrome. Am J Ophthalmol. 2009;147:198–205. e1.
    1. Jee D, Park SH, Kim MS, Kim EC. Antioxidant and inflammatory cytokine in tears of patients with dry eye syndrome treated with preservative-free versus preserved eye drops. Invest Ophthalmol Vis Sci. 2014;55:5081–9.
    1. Ren Y, Lu H, Reinach PS, Zheng Q, Li J, Tan Q, et al. Hyperosmolarity-induced AQP5 upregulation promotes inflammation and cell death via JNK1/2 activation in human corneal epithelial cells. Sci Rep. 2017;7:4727.
    1. Stevenson W, Chauhan SK, Dana R. Dry eye disease: An immune-mediated ocular surface disorder. Arch Ophthalmol. 2012;130:90–100.
    1. Tong L, Beuerman R, Simonyi S, Hollander DA, Stern ME. Effects of punctal occlusion on clinical signs and symptoms and on tear cytokine levels in patients with dry eye. Ocul Surf. 2016;14:233–41.
    1. Leonardi A, Flamion B, Baudouin C. Keratitis in dry eye disease and topical ciclosporin A. Ocul Immunol Inflamm. 2017;25:577–86.
    1. Pflugfelder SC, de Paiva CS. The pathophysiology of dry eye disease: What we know and future directions for research. Ophthalmology. 2017;124:S4–13.
    1. Zheng Q, Ren Y, Reinach PS, Xiao B, Lu H, Zhu Y, et al. Reactive oxygen species activated NLRP3 inflammasomes initiate inflammation in hyperosmolarity stressed human corneal epithelial cells and environment-induced dry eye patients. Exp Eye Res. 2015;134:133–40.
    1. Pflugfelder SC, De Paiva CS, Moore QL, Volpe EA, Li DQ, Gumus K, et al. Aqueous tear deficiency increases conjunctival interferon-γ (IFN-γ) expression and goblet cell loss. Invest Ophthalmol Vis Sci. 2015;56:7545–50.
    1. Gerber-Hollbach N, Plattner K, O’Leary OE, Jenoe P, Moes S, Drexler B, et al. Tear film proteomics reveal important differences between patients with and without ocular GvHD after allogeneic hematopoietic cell transplantation. Invest Ophthalmol Vis Sci. 2018;59:3521–30.
    1. Roy NS, Wei Y, Kuklinski E, Asbell PA. The growing need for validated biomarkers and endpoints for dry eye clinical research. Invest Ophthalmol Vis Sci. 2017;58:BIO1–19.
    1. Balne PK, Au VB, Tong L, Ghosh A, Agrawal M, Connolly J, et al. Bead based multiplex assay for analysis of tear cytokine profiles. J Vis Exp. 2017;128 doi: 10.3791/55993.
    1. Cocho L, Fernández I, Calonge M, Martínez V, González-García MJ, Caballero D, et al. Biomarkers in ocular chronic graft versus host disease: Tear cytokine- and chemokine-based predictive model. Invest Ophthalmol Vis Sci. 2016;57:746–58.
    1. Benitez-Del-Castillo Sánchez J, Morillo-Rojas MD, Galbis-Estrada C, Pinazo-Duran MD. Determination of inmune response and inflammation mediators in tears: Changes in dry eye and glaucoma as compared to healthy controls. Arch Soc Esp Oftalmol. 2017;92:210–7.
    1. Jung JW, Han SJ, Nam SM, Kim TI, Kim EK, Seo KY, et al. Meibomian gland dysfunction and tear cytokines after cataract surgery according to preoperative meibomian gland status. Clin Exp Ophthalmol. 2016;44:555–62.
    1. Enríquez-de-Salamanca A, Castellanos E, Stern ME, Fernández I, Carreño E, García-Vázquez C, et al. Tear cytokine and chemokine analysis and clinical correlations in evaporative-type dry eye disease. Mol Vis. 2010;16:862–73.
    1. López-Miguel A, Tesón M, Martín-Montañez V, Enríquez-de-Salamanca A, Stern ME, González-García MJ, et al. Clinical and molecular inflammatory response in Sjögren syndrome-associated dry eye patients under desiccating stress. Am J Ophthalmol. 2016;161:133–41.e1-2.
    1. Massingale ML, Li X, Vallabhajosyula M, Chen D, Wei Y, Asbell PA, et al. Analysis of inflammatory cytokines in the tears of dry eye patients. Cornea. 2009;28:1023–7.
    1. Igarashi T, Fujimoto C, Suzuki H, Ono M, Iijima O, Takahashi H, et al. Short-time exposure of hyperosmolarity triggers interleukin-6 expression in corneal epithelial cells. Cornea. 2014;33:1342–7.
    1. Liu R, Gao C, Chen H, Li Y, Jin Y, Qi H, et al. Analysis of Th17-associated cytokines and clinical correlations in patients with dry eye disease. PLoS One. 2017;12:e0173301.
    1. Lee SY, Han SJ, Nam SM, Yoon SC, Ahn JM, Kim TI, et al. Analysis of tear cytokines and clinical correlations in Sjögren syndrome dry eye patients and non-Sjögren syndrome dry eye patients. Am J Ophthalmol. 2013;156:247–530.
    1. Liu R, Rong B, Tu P, Tang Y, Song W, Toyos R, et al. Analysis of cytokine levels in tears and clinical correlations after intense pulsed light treating meibomian gland dysfunction. Am J Ophthalmol. 2017;183:81–90.
    1. Ribelles A, Galbis-Estrada C, Parras MA, Vivar-Llopis B, Marco-Ramírez C, Diaz-Llopis M, et al. Ocular surface and tear film changes in older women working with computers. Biomed Res Int. 2015;2015:467039.
    1. McDonnell PJ, Pflugfelder SC, Stern ME, Hardten DR, Conway T, Villanueva L, et al. Study design and baseline findings from the progression of ocular findings (PROOF) natural history study of dry eye. BMC Ophthalmol. 2017;17:265.
    1. Gurumurthy S, Iyer G, Srinivasan B, Agarwal S, Angayarkanni N. Ocular surface cytokine profile in chronic Stevens-Johnson syndrome and its response to mucous membrane grafting for lid margin keratinisation. Br J Ophthalmol. 2018;102:169–76.
    1. Lim SA, Nam DH, Lee JH, Kwok SK, Park SH, Chung SH, et al. Association of IL-21 cytokine with severity of primary Sjögren syndrome dry eye. Cornea. 2015;34:248–52.
    1. Baudouin C, Irkeç M, Messmer EM, Benítez-Del-Castillo JM, Bonini S, Figueiredo FC, et al. Clinical impact of inflammation in dry eye disease: Proceedings of the ODISSEY group meeting. Acta Ophthalmol. 2018;96:111–9.
    1. Zhang LW, Zhou PR, Wei P, Cong X, Wu LL, Hua H, et al. Expression of interleukin-17 in primary Sjögren's syndrome and the correlation with disease severity: A systematic review and meta-analysis. Scand J Immunol. 2018;87:e12649.
    1. Kang MH, Kim MK, Lee HJ, Lee HI, Wee WR, Lee JH, et al. Interleukin-17 in various ocular surface inflammatory diseases. J Korean Med Sci. 2011;26:938–44.
    1. Meadows JF, Dionne K, Nichols KK. Differential profiling of T-cell cytokines as measured by protein microarray across dry eye subgroups. Cornea. 2016;35:329–35.
    1. Tan X, Sun S, Liu Y, Zhu T, Wang K, Ren T, et al. Analysis of Th17-associated cytokines in tears of patients with dry eye syndrome. Eye (Lond) 2014;28:608–13.
    1. Grosskreutz CL, Hockey HU, Serra D, Dryja TP. Dry eye signs and symptoms persist during systemic neutralization of IL-1β by canakinumab or IL-17A by secukinumab. Cornea. 2015;34:1551–6.
    1. Luo G, Xin Y, Qin D, Yan A, Zhou Z, Liu Z, et al. Correlation of interleukin-33 with Th cytokines and clinical severity of dry eye disease. Indian J Ophthalmol. 2018;66:39–43.
    1. Landsend EC, Utheim ØA, Pedersen HR, Aass HC, Lagali N, Dartt DA, et al. The level of inflammatory tear cytokines is elevated in congenital aniridia and associated with meibomian gland dysfunction. Invest Ophthalmol Vis Sci. 2018;59:2197–204.
    1. Carreño E, Portero A, Herreras JM, García-Vázquez C, Whitcup SM, Stern ME, et al. Cytokine and chemokine tear levels in patients with uveitis. Acta Ophthalmol. 2017;95:e405–14.
    1. Aragona P, Aguennouz M, Rania L, Postorino E, Sommario MS, Roszkowska AM, et al. Matrix metalloproteinase 9 and transglutaminase 2 expression at the ocular surface in patients with different forms of dry eye disease. Ophthalmology. 2015;122:62–71.
    1. Lanza NL, McClellan AL, Batawi H, Felix ER, Sarantopoulos KD, Levitt RC, et al. Dry eye profiles in patients with a positive elevated surface matrix metalloproteinase 9 point-of-care test versus negative patients. Ocul Surf. 2016;14:216–23.
    1. Sambursky R, Davitt WF, 3rd, Friedberg M, Tauber S. Prospective, multicenter, clinical evaluation of point-of-care matrix metalloproteinase-9 test for confirming dry eye disease. Cornea. 2014;33:812–8.
    1. Schargus M, Ivanova S, Kakkassery V, Dick HB, Joachim S. Correlation of tear film osmolarity and 2 different MMP-9 tests with common dry eye tests in a cohort of non-dry eye patients. Cornea. 2015;34:739–44.
    1. Agrawal R, Balne PK, Veerappan A, Au VB, Lee B, Loo E, et al. A distinct cytokines profile in tear film of dry eye disease (DED) patients with HIV infection. Cytokine. 2016;88:77–84.
    1. Patel R, Zhu M, Robertson DM. Shifting the IGF-axis: An age-related decline in human tear IGF-1 correlates with clinical signs of dry eye. Growth Horm IGF Res. 2018;40:69–73.
    1. Chhadva P, Lee T, Sarantopoulos CD, Hackam AS, McClellan AL, Felix ER, et al. Human tear serotonin levels correlate with symptoms and signs of dry eye. Ophthalmology. 2015;122:1675–80.
    1. Schicht M, Rausch F, Beron M, Jacobi C, Garreis F, Hartjen N, et al. Palate lung nasal clone (PLUNC), a novel protein of the tear film: Three-dimensional structure, immune activation, and involvement in dry eye disease (DED) Invest Ophthalmol Vis Sci. 2015;56:7312–23.
    1. Guo Q, Huang H, Pi Y, Zhang H. Evaluation of tear malate dehydrogenase 2 in mild dry eye disease. Eye Sci. 2014;29:204–8.
    1. Pieragostino D, Agnifili L, Cicalini I, Calienno R, Zucchelli M, Mastropasqua L, et al. Tear film steroid profiling in dry eye disease by liquid chromatography tandem mass spectrometry. Int J Mol Sci. 2017;18 pii: E1349.
    1. Choi W, Lian C, Ying L, Kim GE, You IC, Park SH, et al. Expression of lipid peroxidation markers in the tear film and ocular surface of patients with non-sjogren syndrome: Potential biomarkers for dry eye disease. Curr Eye Res. 2016;41:1143–9.
    1. Hamm-Alvarez SF, Janga SR, Edman MC, Madrigal S, Shah M, Frousiakis SE, et al. Tear cathepsin S as a candidate biomarker for Sjögren's syndrome. Arthritis Rheumatol. 2014;66:1872–81.
    1. Chen W, Cao H, Lin J, Olsen N, Zheng SG. Biomarkers for primary Sjögren's syndrome. Genomics Proteomics Bioinformatics. 2015;13:219–23.
    1. Aqrawi LA, Galtung HK, Vestad B, Øvstebø R, Thiede B, Rusthen S, et al. Identification of potential saliva and tear biomarkers in primary Sjögren's syndrome, utilising the extraction of extracellular vesicles and proteomics analysis. Arthritis Res Ther. 2017;19:14.
    1. Shinzawa M, Dogru M, Den S, Ichijima T, Higa K, Kojima T, et al. Epidermal fatty acid-binding protein: A novel marker in the diagnosis of dry eye disease in Sjögren syndrome. Int J Mol Sci. 2018;19 pii: E3463.
    1. Everett S, Vishwanath S, Cavero V, Shen L, Suresh L, Malyavantham K, et al. Analysis of novel sjogren's syndrome autoantibodies in patients with dry eyes. BMC Ophthalmol. 2017;17:20.
    1. Karakus S, Baer AN, Agrawal D, Gurakar M, Massof RW, Akpek EK, et al. Utility of novel autoantibodies in the diagnosis of Sjögren's syndrome among patients with dry eye. Cornea. 2018;37:405–11.
    1. Willcox MD, Zhao Z, Naduvilath T, Lazon de la Jara P. Cytokine changes in tears and relationship to contact lens discomfort. Mol Vis. 2015;21:293–305.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren