Subretinal fibrosis in neovascular age-related macular degeneration: risk factors, mechanisms of development, and current options for prevention and treatment

The results of numerous randomized clinical trials and clinical practice have demonstrated the effect of angiogenesis inhibitors (anti-VEGF agents) on the activity and growth of the neovascular complex in neovascular age-related macular degeneration (nAMD). At the same time, a reduction in the risk of macular fibrosis has been demonstrated, with its incidence decreasing from 39—100% in the “pre-antiangiogenic era” to 20.4—61.4% during anti-VEGF therapy. The main factors determining the risk of subretinal fibrosis are disease activity, timing of treatment initiation, treatment regimen and regularity, and type of drug. Fluctuations in retinal thickness and volatility of specific fluid compartments lead to an increase in the volume of subretinal hyperreflective material (SHRM) and hinder complete restoration of ellipsoid zone integrity. Extensive investigation of the role of angiopoietin-2 (Ang-2) in the development of fibrosis has shown that it acts not only as a cofactor of angiogenesis but also as an independent regulator of fibrogenesis through vascular destabilization with increased VEGF-mediated permeability and exudation, activation of macrophages and microglia with production of TGF-β and CTGF, as well as cross-talk with classical fibrotic pathways. The synergistic action of Ang-2 and VEGF-A promotes subretinal scarring and underscores the high potential of bispecific therapy for improving clinical outcomes in patients with nAMD. Compensatory activation of Ang-2 during anti-VEGF monotherapy may sustain tissue remodeling, contributing to the development of treatment resistance. Preclinical studies in models of choroidal neovascularization and clinical data on the effectiveness of faricimab 6 mg through dual Ang-2/VEGF-A inhibition have demonstrated not only superiority in controlling exudation and resolving retinal edema, but also a targeted effect on preventing proliferation and the development of subretinal fibrosis, as evidenced by a significant reduction in SHRM volume — a key precursor of fibrotic changes.