The impact of anti-vascular endothelial growth factor therapy on the activation status of retinal macrophages/microglia in patients with diabetic retinopathy and familial exudative vitreoretinopathy and its association with treatment response

OBJECTIVE: To investigate the impact of anti-vascular endothelial growth factor (anti-VEGF) therapy on retinal macrophage/microglial activation in patients with diabetic retinopathy (DR) and familial exudative vitreoretinopathy (FEVR), and to assess its association with treatment response. METHODS: This single-center retrospective cohort study included 122 eyes in DR patients and 135 eyes in FEVR patients who received at least three intravitreal anti-VEGF injections between January 2018 and June 2025. Intraretinal hyperreflective foci (IRH) on optical coherence tomography (OCT) were used as an imaging surrogate for microglial activation, and aqueous humor levels of inflammatory cytokines (interleukin-1β [IL-1β], tumor necrosis factor-α [TNF-α], and interleukin-10 [IL-10]) were measured. At 6 months post-treatment, responders were defined as those achieving both a ≥20% reduction in central retinal thickness (CRT) and an improvement of ≥5 ETDRS letters in best-corrected visual acuity (BCVA). Spearman correlation and multivariate logistic regression analyses were performed. RESULTS: Baseline IRH counts were significantly higher in the DR group than in the FEVR group (17.37±4.99 vs. 9.56±3.33, P < 0.001). After 6 months of treatment, IRH numbers decreased significantly in both groups (both P < 0.001), with responders showing a greater reduction in IRH (ΔIRH) than non-responders (both P < 0.001). Baseline IRH was positively correlated with the magnitude of CRT reduction (ΔCRT; r = 0.294, P = 0.003). In multivariate analysis, after adjusting for potential confounders, baseline IRH emerged as an independent predictor of treatment response (OR = 1.923, 95% CI: 1.314-2.825, P = 0.002). In the DR subgroup, higher glycated hemoglobin (HbA1c) level was also a significant negative predictor of response (OR = 0.752, 95% CI: 0.613-0.924, P = 0.028). CONCLUSIONS: Anti-VEGF therapy effectively suppresses retinal macrophage/microglial activation in both DR and FEVR. The degree of activation suppression is closely linked to treatment response, suggesting that baseline IRH may serve as a non-invasive biomarker for predicting anti-VEGF efficacy.