PMID- 34721402 OWN - NLM STAT- MEDLINE DCOM- 20211222 LR - 20211222 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 12 DP - 2021 TI - Inflammatory Factors of Macular Atrophy in Eyes With Neovascular Age-Related Macular Degeneration Treated With Aflibercept. PG - 738521 LID - 10.3389/fimmu.2021.738521 [doi] LID - 738521 AB - BACKGROUND: Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness in older people. Low-grade inflammation is well-known as one of the pathogenic mechanisms in nAMD. Anti-vascular endothelial growth factor (VEGF) therapy is the first-line treatment for nAMD, although macula atrophy (MA) developed under anti-VEGF therapy causes irreversible visual function impairment and is recognized as a serious disorder. Here, we show specific expression patterns of aqueous humor (AH) cytokines in nAMD eyes developing MA under intravitreal injection of aflibercept (IVA) as an anti-VEGF antibody and present predictive cytokines as biomarkers for the incidence of MA in nAMD eyes under IVA treatment. METHODS: Twenty-eight nAMD patients received three consecutive monthly IVA, followed by a pro re nata regimen for 2 years. AH specimens were collected before first IVA (pre-IVA) and before third IVA (post-IVA). AH cytokine levels, visual acuity (VA), and central retinal thickness (CRT) were measured. RESULTS: Two-year incidence of MA was 21.4%. In nAMD eyes developing MA [MA (+) group], pre-IVA levels of monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1beta, VEGF and post-IVA level of MCP-1 were higher than those in nAMD eyes without MA [MA (-) group]. In hierarchical cluster analysis, pre-IVA MCP-1 and VEGF were grouped into the same subcluster, as were post-IVA MCP-1 and CRT. In principal component analysis, principal component loading (PCL) of pre-IVA interferon-gamma-inducible protein 10 (IP-10) was 0.61, but PCL of post-IVA IP-10 decreased to -0.09. In receiver operating characteristic analysis and Kaplan-Meier curves, pre-IVA MCP-1, MIP-1beta, and VEGF and post-IVA interleukin-6, MCP-1, and MIP-1beta were detected as predictive factors for MA incidence. In 2-year clinical course, changes of VA in groups with high levels of pre-IVA MIP-1beta (over 39.9 pg/ml) and VEGF (over 150.4 pg/ml) were comparable to those in MA (+) group. CONCLUSION: Substantial loss of IP-10 effects and persistent inflammation contribute to incidence of MA, and screening of AH cytokine levels could be a useful method to predict MA incidence in nAMD eyes under anti-VEGF therapy. CI - Copyright (c) 2021 Sato, Enoki, Karasawa, Someya, Taguchi, Harimoto, Takayama, Kanda, Ito and Takeuchi. FAU - Sato, Tomohito AU - Sato T AD - Department of Ophthalmology, National Defense Medical College, Tokorozawa, Japan. FAU - Enoki, Toshio AU - Enoki T AD - Enoki Eye Clinic, Sayama, Japan. FAU - Karasawa, Yoko AU - Karasawa Y AD - Department of Ophthalmology, National Defense Medical College, Tokorozawa, Japan. FAU - Someya, Hideaki AU - Someya H AD - Department of Ophthalmology, National Defense Medical College, Tokorozawa, Japan. FAU - Taguchi, Manzo AU - Taguchi M AD - Department of Ophthalmology, National Defense Medical College, Tokorozawa, Japan. FAU - Harimoto, Kozo AU - Harimoto K AD - Department of Ophthalmology, National Defense Medical College, Tokorozawa, Japan. FAU - Takayama, Kei AU - Takayama K AD - Department of Ophthalmology, National Defense Medical College, Tokorozawa, Japan. FAU - Kanda, Takayuki AU - Kanda T AD - Department of Ophthalmology, National Defense Medical College, Tokorozawa, Japan. FAU - Ito, Masataka AU - Ito M AD - Department of Developmental Anatomy and Regenerative Biology, National Defense Medical College, Tokorozawa, Japan. FAU - Takeuchi, Masaru AU - Takeuchi M AD - Department of Ophthalmology, National Defense Medical College, Tokorozawa, Japan. LA - eng PT - Journal Article PT - Observational Study PT - Research Support, Non-U.S. Gov't DEP - 20211013 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Angiogenesis Inhibitors) RN - 0 (Biomarkers) RN - 0 (Cytokines) RN - 0 (Inflammation Mediators) RN - 0 (Recombinant Fusion Proteins) RN - 15C2VL427D (aflibercept) RN - EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Angiogenesis Inhibitors/administration & dosage/*adverse effects MH - Aqueous Humor/immunology/*metabolism MH - Atrophy MH - Biomarkers/metabolism MH - Cytokines/*metabolism MH - Female MH - Humans MH - Inflammation Mediators/*metabolism MH - Intravitreal Injections MH - Macula Lutea/*drug effects/immunology/metabolism/pathology MH - Macular Degeneration/*drug therapy/immunology/metabolism/pathology MH - Male MH - Middle Aged MH - Prospective Studies MH - Receptors, Vascular Endothelial Growth Factor/administration & dosage MH - Recombinant Fusion Proteins/administration & dosage/*adverse effects MH - *Retinal Neovascularization MH - Time Factors MH - Treatment Outcome MH - Visual Acuity/drug effects PMC - PMC8548619 OTO - NOTNLM OT - aflibercept OT - aqueous humor cytokine OT - interferon-gamma-inducible protein 10 OT - macrophage inflammatory protein-1beta OT - macular atrophy OT - monocyte chemoattractant protein-1 OT - neovascular age-related macular degeneration OT - vascular endothelial growth factor COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/11/02 06:00 MHDA- 2021/12/24 06:00 PMCR- 2021/01/01 CRDT- 2021/11/01 09:11 PHST- 2021/07/08 00:00 [received] PHST- 2021/09/17 00:00 [accepted] PHST- 2021/11/01 09:11 [entrez] PHST- 2021/11/02 06:00 [pubmed] PHST- 2021/12/24 06:00 [medline] PHST- 2021/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2021.738521 [doi] PST - epublish SO - Front Immunol. 2021 Oct 13;12:738521. doi: 10.3389/fimmu.2021.738521. eCollection 2021.