Systemic Immune and miRNA Signatures Associated with Long-Term Ranibizumab Response in Neovascular Age-Related Macular Degeneration

Objectives: To characterize the one-year functional, anatomical, and molecular responses to intravitreal Ranibizumab in treatment-naïve patients with neovascular age-related macular degeneration (nAMD), and to identify systemic immune and miRNA signatures associated with treatment response. Methods: This prospective longitudinal observational study included 44 treatment-naïve patients with nAMD. Patients received up to four monthly intravitreal Ranibizumab injections, followed by a treat-and-extend regimen. Best-corrected visual acuity using ETDRS letters, central retinal thickness by optical coherence tomography, fluorescein angiography, and OCT angiography were assessed at baseline and 12 months. Peripheral blood samples were collected at both time points to quantify seven circulating cytokines using an IMMULITE chemiluminescent immunoassay and to profile 37 candidate miRNAs by TaqMan OpenArray RT-qPCR from leukocyte-derived RNA. Treatment response was classified using composite anatomical and functional criteria, including intraretinal/subretinal fluid resolution, ≥25% central retinal thickness reduction, and a ≥5 ETDRS letter gain. Results: At one year, patients showed significant central retinal thickness reduction and overall visual stabilization, although good and poor responders differed according to composite response criteria. Statin use was numerically more frequent among poor responders, although this difference was not statistically significant. Soluble IL-2R increased significantly over time in the overall cohort, mainly driven by good responders who showed higher median levels at both visits. IL-8 also increased globally, without significant between-group differences. Among differentially expressed miRNAs, miR-3121 was the only candidate reaching statistical significance and was downregulated in good responders. ROC analysis showed moderate discriminative performance for miR-3121, with an AUC of 0.76. Conclusions: One-year response to Ranibizumab in nAMD may involve systemic immune activation and miRNA regulation. miR-3121 emerges as a candidate biomarker of treatment response, supporting further validation in larger independent cohorts.