Analysis of the serum and aqueous humor levels of interleukin 6 (IL-6) in patients with neovascular (wet) age-related macular degeneration (nAMD) receiving anti-vascular endothelial growth factor A (VEGF) monotherapy

Session Details

Session Title: Free Paper Session 9: AMD III

Session Date/Time: Friday 08/09/2017 | 08:00-09:30

Paper Time: 09:18

Venue: Room 117

First Author: : I.Stoilov USA

Co Author(s): :    K. Hong   B. Day   M. Bao   H. Lin   E. Wakshull                 

Abstract Details


Interleukin 6 (IL-6) is a potent proinflammatory cytokine, which has been implicated in the pathogenesis of different intraocular vascular diseases. The first objective of this study was to measure and compare the IL-6 level of patients enrolled in the HARBOR trial of ranibizumab in wAMD who had matching aqueous humor and serum samples (n=44). The second objective of the study was to describe the vision outcomes with ranibizumab in the patients with IL-6 data.


HARBOR ( NCT00891735) was a 24-month, multicentre, randomized, double-masked, active treatment-controlled phase 3 trial conducted in the Unites States. Patients (n=1097) with treatment-naïve subfoveal wAMD were randomized to receive intravitreal injections of ranibizumab 0.5 mg or 2.0 mg monthly or as needed (PRN) after 3 monthly loading doses.


Aqueous humor and serum samples were collected at the study month 2 visit after the patients received their third monthly ranibizumab dose. IL-6 levels were measured using a proprietary multiplex chip technology, which was qualified by our team for use with small volumes of aqueous humor. The distributions of IL-6 levels in aqueous versus serum at month 2 were compared using the Wilcoxon rank-sum test. Change from month 2 in best-corrected visual acuity (BCVA) in Early Treatment Diabetic Retinopathy Study (ETDRS) letters was calculated for each patient over the course of the study. Mean BCVA change from month 2 was compared for groups of patients stratified by their aqueous IL-6 levels.


Matching aqueous and serum samples were available from a total of 44 patients, who were all white, (including 57% female) and had fewer predominantly classic lesions compared with the overall HARBOR population (9% vs 15%). IL-6 concentrations were on average higher in the aqueous humor compared to serum: mean 6 pg/mL (range <1 to 55.7) versus a mean of 3.7 pg/mL (range <1 to 19.1), p=0.008, Wilcoxon rank-sum test comparing the distribution of IL-6 levels in aqueous versus serum. Given that the aqueous and serum samples were collected after the third dose of ranibizumab, the ETDRS score at month 2 was used as a baseline to calculate the change in BCVA through the end of the study at month 24. Patients with the highest aqueous IL-6 levels (>/=15 pg/mL; n=9) on average lost 9 letters at month 24 while patients with IL-6 <15 pg/mL (n=27) on average gained 2.9 letters. The reduction in central foveal thickness at month 24 was similar for both groups. These finding were consistent using a range of cutpoints for IL-6, ranging from 8 to 20. Given the small number of patients, the differences in vision outcomes are descriptive and did not reach statistical significance.


The results from this HARBOR substudy suggest that in patients with wAMD, aqueous levels of IL-6 are higher and exhibit a significantly broader distribution compared to serum levels, which may allow patient stratification. With respect to vision outcomes in this small sample, wAMD patients with levels of IL-6 >8 pg/mL in the aqueous humor on average had a suboptimal response to anti-VEGF monotherapy compared with the complement of patients with lower levels of IL-6. These results should be interpreted with caution due to the small number of patients and the post hoc nature of the analysis.

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