Longitudinal Analysis of Tear Cytokine Ratios in Association with Dry Eye Signs and Symptoms in the Dry Eye Assessment and Management (DREAM) Study

Purpose To extend cross-sectional data on cytokine ratios (CRs) in dry eye disease (DED) signs by investigating longitudinal change in pro- to anti-inflammatory CRs and associations with change in DED signs and symptoms. Methods Secondary analysis of fifty-four subjects [mean age 57.3 (SD 13.2) years, 85.2% female; 68.5% white] with >= 4 uL pooled tear volumes at months 0, 6, and 12. Pro-inflammatory (IL-1b, IL-6, IL-8, IL-17A, IFN-g, and TNF-a) to anti-inflammatory (IL-6, IL-10) cytokine ratios (CR) were calculated. DED signs (corneal and conjunctival staining scores, tear break-up time, Schirmer test, Meibomian gland plugging, tear osmolarity, composite sign severity score) and symptoms [Ocular Surface Disease Index (OSDI)] were measured. Changes over time in DED signs, symptoms, and CRs were evaluated using longitudinal models. Correlations between changes in CR and changes in DED signs and symptoms were evaluated using Spearman correlation coefficients (rho). Results DED signs which improved over time (p < 0.001) included corneal and conjunctival staining score, tear break-up time, tear osmolarity, and composite sign severity score. Using IL-10 as anti-inflammatory, changes in corneal and conjunctival staining and composite severity score significantly correlated with changes in pro- to anti-inflammatory CRs from month 0 to 6 (|rho|: 0.29-0.45, p: 0.003-0.04) but not between month 0 to 12 (|rho|: 0.01 to 0.24, all p > 0.08). DED symptoms decreased across one year (p < = 0.001) for all OSDI measures; these changes did not correlate with changes in CRs (|rho|: 0.00 to 0.29, all p > 0.04). Conclusions Improvement in some DED signs across one year correlated weakly with decreases in pro- to anti-inflammatory CRs, in alignment with the understanding of DED as inflammatory. CRs may provide greater insight than absolute tear cytokine concentrations as possible DED biomarkers. Additional studies that provide standardized clinical information and tear collection and analysis are needed to validate CRs in DED.