Ocular fluid biomarkers and anti-retinal autoantibodies in neovascular age-related macular degeneration: compartment-specific evidence and a provisional multidomain framework

Neovascular age-related macular degeneration (nAMD) shows substantial heterogeneity in fluid resolution, recurrence, treatment burden, and structural outcomes under anti-VEGF therapy. Anti-retinal autoantibodies (ARAs) and ocular fluid biomarkers may provide complementary information about this heterogeneity, but their interpretation depends on assay design, sampling compartment, clinical phenotype, and treatment exposure. Human autoantibody studies report heterogeneous patterns of retinal autoreactivity, with substantial background reactivity in some control cohorts, limited concordance among reported antigenic targets, and marked differences across assay platforms. The antigen-specific functional significance of ARAs in human nAMD remains unestablished. Longitudinal changes in antibody titers or antigen-specific profiles have been observed during anti-VEGF treatment, but prognostic and treatment-predictive utility has not been independently validated. Aqueous and vitreous studies identify phenotype- and treatment-associated angiogenic, complement-related, and inflammatory signals. Cross-compartment proteomic data from mixed retinal-disease cohorts show stronger aqueous–vitreous than ocular–serum correspondence, supporting compartment-specific interpretation. We therefore propose a provisional multidomain framework comprising angiogenic leakage, complement-linked injury, and cytokine-rich remodeling, with autoantibodies positioned as a cross-cutting humoral overlay. This framework may guide phenotype-based cohort selection and endpoint definition in prospective biomarker studies, whereas biomarker-based trial enrichment and treatment selection require further validation. Clinical translation will require longitudinal, treatment-aware sampling, paired ocular and systemic studies, assay-specific validation, and independent replication against prespecified clinical outcomes.