Evaluations of Tear Protein Markers in Dry Eye Disease: Repeatability of Measurement and Correlation with Disease

Abstract

PURPOSE. We characterized tear protein markers in dry eye disease (DED).METHODS. In this prospective study, based on the ocular surface disease index (OSDI) and corneal staining (CS), 95 DED patients (OSDI ‡13) with increasing CS were enrolled into 3 severity groups: DE1 (CS <4), DE2 (CS 4-7), and DE3 (CS >7), while 25 asymptomatic subjects with no CS were enrolled into the control group (OSDI <13 and CS ¼ 0). Tear fluid was collected at day 0 and day 7 visits, and concentrations of 43 protein markers were measured by multiplexed immunoassay. RESULTS.We analyzed 22 control and 80 DED subjects. Among 33 markers detectable, good inter-visit repeatability was observed with 25 markers, with intraclass correlation coefficients (ICC) ranging from 0.85-0.60; ICCs were <0.60 in the other 8. Correlation with clinical measures was found with two markers, with absolute partial correlation coefficients >0.40: Interleukin-1 receptor antagonist (IL-1Ra) and IL-8. IL-1Ra and IL-8 correlated with conjunctival staining (0.43, P < 0.001 and 0.35, P < 0.01, respectively), and with Schirmer test (À0.58 and À0.42, P < 0.001). IL-1Ra and IL-8 in DE3 were 4.4-and 2.1-fold higher than in DE1 (P ¼ 0.0001 and 0.0007), and 1.9-and 1.6-fold higher than in DE2 (P ¼ 0.022 and 0.017). IL-1Ra in DE2 was 2.3-fold higher than in DE1 (P ¼ 0.038).CONCLUSIONS. Tear levels of many immune mediators were highly repeatable between visits in DED. Among them, IL-1Ra and IL-8 were associated with clinical signs and disease severity defined by corneal staining. (Invest Ophthalmol Vis Sci. 2012; 53:4556-4564) DOI:10.1167/iovs.11-9054 D ry eye disease (DED) is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.1 DED is a highly prevalent condition that affects 5% or more people of various ages in the United States, and the ocular discomfort, irritation, and blurred vision often experienced by dry eye patients can affect daily activity and workrelated tasks, thus leading to reduced quality of life. 1-5Symptoms of ocular discomfort or irritation felt by patients generally is the first step of diagnosis of DED and, currently, disease severity is classified by certain clinical objective measurements, such as corneal staining (CS) or tear break up time (TBUT).Significant progress has been made towards identifying and characterizing the underlying inflammation on the ocular surface in DED through clinical and preclinical research, which has led to better understanding of the key role of inflammation in DED pathogenesis. 6-12 Different methodologies have been used to collect ocular specimens from patients, and to quantify the molecular and cellular components involved in ocular surface inflammation and in other biologic or pathologic aspects of DED.7,13-18 Up-regulated cell surface expression of human leukocyte antigen (HLA)-DR, inter...

Clinical and Molecular Inflammatory Response in Sjögren Syndrome–Associated Dry Eye Patients Under Desiccating Stress

“…41 Additionally, increased IL-6 tear levels might be one of the earliest observable changes in patients with dry eye, 16 as we also showed after exposing our SS dry eye patients to adverse conditions. However, its moderate percentage of detection as shown in this study and previous ones, 13,25,37 as well as its moderate inter-day 36 and intra-day 42 variability, might still prevent this tear molecule from being the gold-standard biomarker for dry eye disease.…”

“…Inter-day differences can be assigned to the inter-day variability reported in these tear molecules. 36 Despite this fact, tear molecule levels could be more consistent than in some clinical dry eye tests. 34 We did not observe any significant changes in tear molecule concentrations after the normal condition exposure.…”

“…IL-1RA is an endogenous inhibitor of IL-1 that impedes the activities of the pro-inflammatory forms of IL-1 by competitively binding to the type 1 IL-1 receptor. Huang et al 36 have reported that the concentration of this tear molecule is proportional to the severity of the dry eye, correlating with corneal staining. Moreover, our group 37 found that there was an inverse relationship between the levels of IL-1RA and Schirmer and tear break-up time values.…”

Dry Eye in Patients With Fibromyalgia and Its Relevance to Functional and Emotional Status

“…1 Inflammatory cytokines, IL-1 receptor antagonist, IL-6, and IL-8 have been shown to be elevated in the tear film of DE patients and have been related to DE. 19,20 The same cytokines associated with DE were elevated in the sera of patients with FM. 21 FM may be an early sign of autoimmune disease, 22 and the lacrimal gland may be a target organ in FM, similar to the other autoimmune rheumatic diseases.…”

Comparison of Low-Abundance Biomarker Levels in Capillary-Collected Nonstimulated Tears and Washout Tears of Aqueous-Deficient and Normal Patients

“…All five cytokines have been linked to AD dry eye in numerous other studies, 7,22-30 IL-8 [22][23][24][25][26] and IL-1b 7,27-30 in particular. This group of cytokines demonstrates the potential of the WO method to detect AD dry eye without the need to corroborate findings by collecting NS tears.…”