Poor Response to Bevacizumab Correlates With Higher IL-6 and IL-8 Aqueous Cytokines in AMD

Abstract

Purpose: To evaluate the effect of intravitreal bevacizumab on aqueous levels of a panel of 12 inflammatory cytokines in patients with neovascular age-related macular degeneration (nAMD) and correlate response to treatment, as measured by change in the central subfovea thickness (CST), with cytokine levels.

Methods: Thirty-three treatment-naïve patients with nAMD received a loading dose of intravitreal bevacizumab consisting of three injections at six weekly intervals. The aqueous samples prior to the first (baseline), second (week 6), and third (week 12) injections were analyzed for cytokine levels. Participants were subgrouped based on changes in CST on spectral-domain optical coherence tomography (SD-OCT) at 12 weeks. Group 1 included patients with a decrease in CST (responders; n = 27). Group 2 included patients who had no decrease in CST (poor responders; n = 6).

Results: Aqueous IL-8 was the only cytokine to demonstrate a significant difference in levels between responders and poor responders, with higher interleukin-8 (IL-8) at week 12 in the poor responder group. Aqueous IL-6 and IL-8 levels showed a positive correlation with CST on SD-OCT (Spearman r = 0.45 and 0.55, respectively). There was a temporal increase overall in cytokine concentration accompanying bevacizumab treatment.

Conclusions: Aqueous IL-6 and IL-8 may be important markers of treatment response or poor response in nAMD. Future therapeutic strategies may include targeted treatment against both vascular endothelial cell growth factor (VEGF) and IL-6 and/or IL-8 in patients who do not respond to anti-VEGF treatment alone.

Figure 1.

Changes in CST in the clinical neovascular cohort. (A) Change in CST from BL to W12 for all participants, including those who responded to treatment and those who had poor response as based on SD-OCT. (B) Representative SD-OCT images demonstrating changes in CST from BL to W12 in responders and poor responders. Bar graphs show mean ± SEM analyzed using two-way ANOVA with Sidak's multiple comparison test.

Figure 2.

Levels of inflammatory cytokines in patients deemed responders or poor responders as measured by OCT. Patients were grouped by changes in central subfield macular thickness over the 12-week course of treatment measured by OCT. Cytokines were measured in aqueous humor at BL, W6, and W12, and presented grouped by associated function i.e Innate Immune activators, T-Cell Polarisation, Immunomodulation and Chemotaxis. Data are presented as mean ± SEM and were analyzed using two-way ANOVA with Tukey's multiple comparison test for changes between matched samples within each group (solid line) and Sidak's multiple comparison test between groups at each time point (dashed line).

Figure 3.

Correlation of ∆CST with cytokine concentration at BL, W6, and W12. (A) Summary table of the correlation of ∆CST with cytokine concentrations at BL, W6, and W12. (B, C) Spearman's rank correlations of log-transformed IL-6 and IL-8 cytokine levels at BL, W6, and W12 with changes in CST between BL and W12. Graphs display regression lines and 95% confidence intervals with Spearman's rho coefficient and associated P values. Ct, chemotaxis; IM, immunomodulation; Innate, innate immune activators; T-cell, T-cell polarization.