Longitudinal Changes in Aqueous Humor Cytokines in Diabetic Macular Edema Treated with Anti-Vascular Endothelial Growth Factor Therapy

Abstract

Purpose : The clinical response to anti-vascular endothelial growth factor (VEGF) therapy in diabetic macular edema (DME) is heterogeneous with a wide spectrum of efficacy. The objective of this work was to evaluate the longitudinal cytokine dynamics in treatment-naïve DME following anti-VEGF therapy in a prospective clinical trial setting.

Methods : The IMAGINE study is a post-hoc assessment that includes cytokine expression within the aqueous samples and in-depth assessment of the imaging studies obtained throughout the DAVE study. The DAVE study was a prospective randomized trial evaluating ranibizumab alone compared to combination therapy with targeted retinal photocoagulation (TRP) at areas of nonperfusion in treatment-naïve eyes with DME. Aqueous samples were obtained at baseline, month 3, and month 12. Concentrations of 54 cytokines associated with inflammation and angiogenesis including VEGF, ANG2, MCP-1, IL-6, and IL-8 were measured at each timepoint in quadruplicate. In addition to the overall group effect, the effect of monotherapy versus combination therapy with TRP and baseline diabetic profiling (HA1c) were evaluated for their impact on aqueous cytokine dynamics.

Results : Of the 40 eyes studied in the DAVE trial, 24 had sufficient baseline aqueous samples for analysis (60%). Among the included eyes, the mean age was 54, and 19 patients were male (79%). Of the 54 cytokines evaluated, 27 had levels above detection threshold. VEGF concentrations were significantly lower at month 3 (p=0.002) and month 12 (p<0.0001) following initiation of treatment. IP-10 trended toward a significant elevation at month 12 (p=0.07). At month 12, subjects receiving combination therapy (n=13) with TRP had increased uPAR (p=0.02) and PECAM1 (p=0.05) compared to ranibizumab alone (n=11). There was no significant difference in reduction in VEGF between the groups at month 12 (p=0.06), though VEGF trended towards greater reduction with monotherapy. HA1c at baseline correlated with CXCL16 (p=0.045), MCP-4 (p=0.016), and TIMP-1 (p=0.0018).

Conclusions : In this expansive longitudinal cytokine assessment in DME, ranibizumab was associated with decreased intraocular concentration of VEGF in concordance with prior studies. The addition of laser therapy and systemic control of diabetes appears to also alter cytokine expression.

This is a 2020 ARVO Annual Meeting abstract.