INflammatory MediatorS in the PathophysIology of Diabetic REtinopathy Study: Baseline Analysis of 24 Aqueous Cytokines.

Objective: We analyzed the cross-sectional associations of 24 inflammatory cytokines with diabetic retinopathy (DR) severity. Design: Prospective, clinical trial at a tertiary academic medical center. Subjects: Three hundred twenty-eight eyes of 164 patients with diabetes with varying severity of DR, including none. Methods: All diabetic eyes had aqueous sampling of both eyes, ETDRS visual acuity, and color fundus photographs. Three groups were enrolled according to grading of baseline color fundus photographs: 23 (46 eyes) patients with diabetes with no DR, 118 (236 eyes) patients with diabetes with moderate nonproliferative DR (NPDR), and 23 (46 eyes) patients with diabetes with proliferative DR. The moderate NPDR group was further subdivided into mild-moderate and moderate-severe groups based on the ETDRS severity scale. Blood was drawn to measure hemoglobin A1c. A microparticle bead-based multiplex assay was used to measure: fibroblast growth factor-2, eotaxin, granulocyte colony-stimulating factor, FMS-like tyrosine kinase 3, GRO, interleukin (IL)-10, monocyte chemotactic protein (MCP)-3, macrophage-derived chemokine, soluble CD40L, IL-17A, IL-1 receptor antagonist, IL-1β, IL-2, IL-4, IL-6, IL-8, induced protein 10, MCP-1, macrophage inflammatory protein-1β, tumor necrosis factor-α, VEGF-A, regulated on activation normal T expressed and secreted, and platelet-derived growth factor-AA and -AB/BB. Triplicate testing of all cytokines was performed. Main Outcome Measures: Aqueous cytokines, DR severity, hemoglobin A1c. Results: Median and interquartile ranges of VEGF-A by grade of eye were 100.57 (80.93-145.67), 153.40 (112.86-206.24), 223.45 (135.27-319.21), and 295.60 (177.46-388.89) pg/mL among no DR, mild-moderate NPDR, moderate-severe NPDR, and proliferative DR groups, respectively. Median and interquartile ranges of IL-6 were 5.45 (3.16-7.86), 8.28 (4.78-20.68), 12.80 (8.24-27.49), and 17.14 (10.31-52.61) pg/mL and of IL-8 were 7.06 (4.10-13.08), 10.53 (6.45-15.85), 16.25 (11.61-24.10), and 20.61 (14.00-27.65) pg/mL among no DR, mild-moderate NPDR, moderate-severe NPDR, and proliferative DR groups, respectively. Similar positive linear relationships were seen with IL-4 and MCP-1. Compared with the no DR group, significant progressive odds ratios were observed among all DR severity groups for VEGF-A, IL-6, IL-8, and IL-4. Significant progressive odds ratios from mild-moderate NPDR to moderate-severe NPDR were observed for FMS-like tyrosine kinase 3, IL-10, induced protein 10, MCP-1, macrophage-derived chemokine, and platelet-derived growth factor-AA. The majority of cytokines demonstrated no relationship with hemoglobin A1c. Conclusions: We report that several key inflammatory cytokines demonstrate cross-sectional associations with DR severity. Our results lend support to the presumption that inflammatory cytokines are important biomarkers that associate with DR severity and may represent novel targets for inhibition. Financial Disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article.