Anti-VEGF safety in evolution: A comprehensive review of ocular and systemic considerations

Intravitreal anti-vascular endothelial growth factor (VEGF) therapy has transformed the management of retinal and choroidal vascular diseases, delivering substantial and sustained visual benefits across neovascular age-related macular degeneration, diabetic macular edema, and retinal vein occlusions. As treatment paradigms have evolved toward chronic, often lifelong therapy with repeated injections, attention has increasingly shifted from short-term procedural safety to a broader evaluation of ocular and systemic adverse events. Among these, intraocular inflammation (IOI) has emerged as the most debated ocular safety signal, ranging from mild, self-limited sterile inflammation to rare but vision-threatening occlusive retinal vasculitis. At the same time, systemic adverse events remain biologically plausible yet uncommon in the general population. This review provides a contemporary, clinically oriented synthesis of anti-VEGF safety, emphasizing that IOI and systemic events are not uniform drug effects but reflect complex interactions among drug-specific properties, delivery factors, disease substrate, patient susceptibility, and immunogenicity. We outline a mechanistic framework distinguishing acute sterile inflammation driven by innate immune activation from delayed vasculitic phenotypes associated with adaptive immune responses and anti-drug antibodies. A structured five-pillar susceptibility model is proposed to contextualize risk modifiers, alongside phenotype-driven management and prevention strategies. Systemic safety considerations are reviewed with attention to agent-specific pharmacokinetics, high-risk patient phenotypes, and cumulative exposure. By integrating mechanistic insights with clinical phenotyping, risk stratification, and preventive strategies, this review aims to support informed, individualized decision-making. A balanced, prevention-focused approach enables clinicians to preserve the transformative benefits of anti-VEGF therapy while maintaining a high standard of long-term ocular and systemic safety.