Genetic Factors Associated with Intraocular Inflammation After Brolucizumab Administration in Patients with Exudative Age-Related Macular Degeneration
Abstract
1. Introduction
2. Methods
3. Participants
4. Definition of IOI
5. Statistical Analysis
6. Results
7. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Wong, W.L.; Su, X.; Li, X.; Cheung, C.M.; Klein, R.; Cheng, C.Y.; Wong, T.Y. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: A systematic review and meta-analysis. Lancet Glob. Health 2014, 2, e106–e116. [Google Scholar] [CrossRef] [PubMed]
- Sakurada, Y.; Tanaka, K.; Fragiotta, S. Differentiating drusen and drusenoid deposits subtypes on multimodal imaging and risk of advanced age-related macular degeneration. Jpn. J. Ophthalmol. 2023, 67, 1–13. [Google Scholar] [CrossRef] [PubMed]
- Shijo, T.; Sakurada, Y.; Tanaka, K.; Miki, A.; Sugiyama, A.; Onoe, H.; Chubachi, A.; Kikushima, W.; Wakatsuki, Y.; Yoneyama, S.; et al. Incidence and risk of advanced age-related macular degeneration in eyes with drusenoid pigment epithelial detachment. Sci. Rep. 2022, 12, 4715. [Google Scholar] [CrossRef] [PubMed]
- Spaide, R.F.; Jaffe, G.J.; Sarraf, D.; Freund, K.B.; Sadda, S.R.; Staurenghi, G.; Waheed, N.K.; Chakravarthy, U.; Rosenfeld, P.J.; Holz, F.G.; et al. Consensus Nomenclature for Reporting Neovascular Age-Related Macular Degeneration Data: Consensus on Neovascular Age-Related Macular Degeneration Nomenclature Study Group. Ophthalmology 2020, 127, 616–636. [Google Scholar] [CrossRef] [PubMed]
- Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: One-year results of 2 randomized clinical trials--TAP report. Arch. Ophthalmol. 1999, 117, 1329–1345. [Google Scholar] [CrossRef]
- Gragoudas, E.S.; Adamis, A.P.; Cunningham, E.T., Jr.; Feinsod, M.; Guyer, D.R.; VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. N. Engl. J. Med. 2004, 351, 2805–2816. [Google Scholar] [CrossRef] [PubMed]
- Brown, D.M.; Kaiser, P.K.; Michels, M.; Soubrane, G.; Heier, J.S.; Kim, R.Y.; Sy, J.P.; Schneider, S.; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N. Engl. J. Med. 2006, 355, 1432–1444. [Google Scholar] [CrossRef]
- Rosenfeld, P.J.; Brown, D.M.; Heier, J.S.; Boyer, D.S.; Kaiser, P.K.; Chung, C.Y.; Kim, R.Y.; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N. Engl. J. Med. 2006, 355, 1419–1431. [Google Scholar] [CrossRef] [PubMed]
- Heier, J.S.; Brown, D.M.; Chong, V.; Korobelnik, J.F.; Kaiser, P.K.; Nguyen, Q.D.; Kirchhof, B.; Ho, A.; Ogura, Y.; Yancopoulos, G.D.; et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 2012, 119, 2537–2548. [Google Scholar] [CrossRef]
- Lalwani, G.A.; Rosenfeld, P.J.; Fung, A.E.; Dubovy, S.R.; Michels, S.; Feuer, W.; Davis, J.L.; Flynn, H.W., Jr.; Esquiabro, M. A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: Year 2 of the PrONTO Study. Am. J. Ophthalmol. 2009, 148, 43–58.e1. [Google Scholar] [CrossRef] [PubMed]
- Rofagha, S.; Bhisitkul, R.B.; Boyer, D.S.; Sadda, S.R.; Zhang, K.; SEVEN-UP Study Group. Seven-year outcomes in ranibizumab-treated patients in ANCHOR, MARINA, and HORIZON: A multicenter cohort study (SEVEN-UP). Ophthalmology 2013, 120, 2292–2299. [Google Scholar] [CrossRef] [PubMed]
- Wykoff, C.C.; Croft, D.E.; Brown, D.M.; Wang, R.; Payne, J.F.; Clark, L.; Abdelfattah, N.S.; Sadda, S.R.; TREX-AMD Study Group. Prospective Trial of Treat-and-Extend versus Monthly Dosing for Neovascular Age-Related Macular Degeneration: TREX-AMD 1-Year Results. Ophthalmology 2015, 122, 2514–2522. [Google Scholar] [CrossRef] [PubMed]
- Nguyen, Q.D.; Das, A.; Do, D.V.; Dugel, P.U.; Gomes, A.; Holz, F.G.; Koh, A.; Pan, C.K.; Sepah, Y.J.; Patel, N.; et al. Brolucizumab: Evolution through Preclinical and Clinical Studies and the Implications for the Management of Neovascular Age-Related Macular Degeneration. Ophthalmology 2020, 127, 963–976. [Google Scholar] [CrossRef] [PubMed]
- Dugel, P.U.; Singh, R.P.; Koh, A.; Ogura, Y.; Weissgerber, G.; Gedif, K.; Jaffe, G.J.; Tadayoni, R.; Schmidt-Erfurth, U.; Holz, F.G. HAWK and HARRIER: Ninety-Six-Week Outcomes from the Phase 3 Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration. Ophthalmology 2021, 128, 89–99. [Google Scholar] [CrossRef] [PubMed]
- Mukai, R.; Matsumoto, H.; Akiyama, H. Risk factors for emerging intraocular inflammation after intravitreal brolucizumab injection for age-related macular degeneration. PLoS ONE 2021, 16, e0259879. [Google Scholar] [CrossRef] [PubMed]
- Hashimoto, Y.; Inoda, S.; Takahashi, H.; Takahashi, R.; Yoshida, H.; Fujino, Y.; Sakamoto, S.; Kawashima, H.; Yanagi, Y. Factors Associated with Intraocular Inflammation in Neovascular Age-Related Macular Degeneration Patients Treated with Brolucizumab. Investig. Ophthalmol. Vis. Sci. 2024, 65, 8. [Google Scholar] [CrossRef]
- Ruamviboonsuk, V.; Kongwattananon, W.; Chuaypen, N. Changes in Aqueous Humor Cytokine Profile Following Intravitreal Brolucizumab Injection. Clin. Ophthalmol. 2025, 19, 427–437. [Google Scholar] [CrossRef]
- Fukuda, Y.; Sakurada, Y.; Matsubara, M.; Kotoda, Y.; Kasai, Y.; Sugiyama, A.; Kashiwagi, K. Comparison of one-year outcomes between as-needed brolucizumab and aflibercept for polypoidal choroidal vasculopathy. Jpn. J. Ophthalmol. 2023, 67, 402–409. [Google Scholar] [CrossRef]
- Kikushima, W.; Sakurada, Y.; Fukuda, Y.; Matsubara, M.; Kotoda, Y.; Sugiyama, A.; Kashiwagi, K. A Treat-and-Extend Regimen of Intravitreal Brolucizumab for Exudative Age-Related Macular Degeneration Refractory to Aflibercept: A 12-Month Result. Pharmaceuticals 2023, 16, 562. [Google Scholar] [CrossRef]
- Sadda, S.R.; Holz, F.G.; Staurenghi, G.; Invernizzi, A.; Arnold, J.; Tadayoni, R. The Importance of Imaging to Identify Early Signs of Intraocular Inflammation Expert Opinion for Brolucizumab. Ophthalmologica 2022, 245, 588–591. [Google Scholar] [CrossRef]
- Hoffmann, L.; Michels, S.; Eandi, C.; Karam, M.A.; Figueiredo, E.C.O.; Hatz, K. Aflibercept high-dose (8mg) related intraocular inflammation (IOI)—A case series. BMC Ophthalmol. 2024, 24, 520. [Google Scholar] [CrossRef]
- Ben Ghezala, I.; Gabrielle, P.H.; Sibert, M.; Steinberg, L.A.; Dautriche, A.; Arnould, L.; Creuzot-Garcher, C. Severe Intraocular Inflammation After Intravitreal Injection of Faricimab: A Single-Site Case Series of Six Patients. Am. J. Ophthalmol. 2025, 269, 11–19. [Google Scholar] [CrossRef]
- Montesel, A.; Sen, S.; Preston, E.; Patel, P.J.; Huemer, J.; Hamilton, R.D.; Nicholson, L.; Papasavvas, I.; Tucker, W.R.; Yeung, I. Intraocular Inflammation Associated with Faricimab Therapy: One-Year Real-World Outcomes. Retina 2025, 45, 827–832. [Google Scholar] [CrossRef]
- Inoda, S.; Takahashi, H.; Maruyama-Inoue, M.; Ikeda, S.; Sekiryu, T.; Itagaki, K.; Matsumoto, H.; Mukai, R.; Nagai, Y.; Ohnaka, M.; et al. Incidence and Risk Factors of Intraocular Inflammation After Brolucizumab Treatment in Japan: A Multicenter Age-Related Macular Degeneration Study. Retina 2024, 44, 714–722. [Google Scholar] [CrossRef]
- Park, H.S.; Lee, S.W.; Park, H.; Lee, N.K.; Kim, Y.J.; Lee, C.S.; Byeon, S.H.; Kim, S.S. Incidence of intraocular inflammation and its risk factors in patients treated with brolucizumab: A nationwide cohort study. Sci. Rep. 2024, 14, 22913. [Google Scholar] [CrossRef]
- Zhou, H.; Li, Z.; Silver, D.L.; Jiang, X.C. Cholesteryl ester transfer protein (CETP) expression enhances HDL cholesteryl ester liver delivery, which is independent of scavenger receptor BI, LDL receptor related protein and possibly LDL receptor. Biochim. Biophys. Acta 2006, 1761, 1482–1488. [Google Scholar] [CrossRef]
- Chen, W.; Stambolian, D.; Edwards, A.O.; Branham, K.E.; Othman, M.; Jakobsdottir, J.; Tosakulwong, N.; Pericak-Vance, M.A.; Campochiaro, P.A.; Klein, M.L.; et al. Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc. Natl. Acad. Sci. USA 2010, 107, 7401–7406. [Google Scholar] [CrossRef]
- Torczynski, E. Normal and abnormal ocular development in man. Prog. Clin. Biol. Res. 1982, 82, 35–51. [Google Scholar]
IOI (+) (n = 21) | IOI (−) (n = 185) | p-Value | |
---|---|---|---|
Age (years) | 72.8 ± 6.5 | 74.1 ± 8.6 | 0.37 |
Gender (male) | 15 (71.4%) | 141 (76.2%) | 0.63 |
AMD subtype (tAMD vs. PCV) | 5:16 | 81:104 | 0.078 |
HT | 9 (42.9%) | 104 (56.2%) | 0.24 |
DM | 3 (14.3%) | 29 (15.7%) | 0.87 |
Smoking (never/past/current) | 6:10:5 | 60:97:28 | 0.96 |
Switch | 12 (57.1%) | 66 (35.7%) | 0.055 |
ARMS2 A69S (rs10490924) T allele frequency | 57.1% | 59.5% | 0.77 |
CFH I62V (rs800292) G allele frequency | 76.2% | 74.3% | 0.79 |
CFH (rs1329428) C allele frequency | 73.8% | 65.1% | 0.26 |
SKIV2L (rs429608) A allele frequency | 9.5% | 9.5% | 0.99 |
C3 (rs2241394) G allele frequency | 2.4% | 6.2% | 0.31 |
CETP (rs3764261) T allele frequency | 9.5% | 23.5% | 0.038 |
ADAMTS9 (rs6795735) C allele frequency | 16.7% | 13.5% | 0.57 |
β-coefficient | p-value | Hazard ratio (95% confidence interval) | |
CETP (T allele) | 0.29 | 0.028 | 0.29 (0.098–0.88) |
ARMS2 A69S (rs10490924) T allele frequency | 57.1% | 59.5% | 0.77 |
CFH I62V (rs800292) G allele frequency | 76.2% | 74.3% | 0.79 |
CFH (rs1329428) C allele frequency | 73.8% | 65.1% | 0.26 |
SKIV2L (rs429608) A allele frequency | 9.5% | 9.5% | 0.99 |
C3 (rs2241394) G allele frequency | 2.4% | 6.2% | 0.31 |
CETP (rs3764261) T allele frequency | 9.5% | 23.5% | 0.038 |
ADAMTS9 (rs6795735) C allele frequency | 16.7% | 13.5% | 0.57 |
β-Coefficient | p-Value | Hazard Ratio (95% Confidence Interval) | |
---|---|---|---|
CETP (T allele) | 0.29 | 0.028 | 0.29 (0.098–0.88) |
Severe (n = 4) | Mild (n = 17) | p-Value | |
---|---|---|---|
Age | 76.3 ± 8.1 | 71.9 ± 6.1 | 0.47 |
Gender (male) | 1 (25.0%) | 14 (82.4%) | 0.02 |
AMD subtype (tAMD vs. PCV) | 1:3 | 4:13 | 0.29 |
HT | 2 (50.0%) | 7 (41.2%) | 0.41 |
DM | 0 (0%) | 3 (15.7%) | 0.36 |
Switch | 2 (50.0%) | 10 (58.8%) | 0.75 |
ARMS2 A69S (rs10490924) T allele frequency | 7:1 87.5% | 17:17 50.0% | 0.054 |
CFH I62V (rs800292) G allele frequency | 8:0 100% | 24:10 70.6% | 0.079 |
CFH (rs1329428) C allele frequency | 8:0 100% | 22:12 67.6% | 0.047 |
SKIV2L (rs429608) A allele frequency | 0:8 0% | 4:30 11.8% | 0.31 |
C3 (rs2241394) G allele frequency | 1:7 12.5% | 0:34 0% | 0.037 |
CETP (rs3764261) T allele frequency | 0:8 0% | 4:30 11.8% | 0.31 |
ADAMTS9 (rs6795735) C allele frequency | 1:7 12.5% | 6:28 17.6% | 0.73 |
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Yoneyama, S.; Sakurada, Y.; Shijo, T.; Fukuda, Y.; Kotoda, Y.; Kikushima, W.; Mabuchi, F.; Kashiwagi, K. Genetic Factors Associated with Intraocular Inflammation After Brolucizumab Administration in Patients with Exudative Age-Related Macular Degeneration. Genes 2025, 16, 797. https://doi.org/10.3390/genes16070797
Yoneyama S, Sakurada Y, Shijo T, Fukuda Y, Kotoda Y, Kikushima W, Mabuchi F, Kashiwagi K. Genetic Factors Associated with Intraocular Inflammation After Brolucizumab Administration in Patients with Exudative Age-Related Macular Degeneration. Genes. 2025; 16(7):797. https://doi.org/10.3390/genes16070797
Chicago/Turabian StyleYoneyama, Seigo, Yoichi Sakurada, Taiyo Shijo, Yoshiko Fukuda, Yumi Kotoda, Wataru Kikushima, Fumihiko Mabuchi, and Kenji Kashiwagi. 2025. "Genetic Factors Associated with Intraocular Inflammation After Brolucizumab Administration in Patients with Exudative Age-Related Macular Degeneration" Genes 16, no. 7: 797. https://doi.org/10.3390/genes16070797
APA StyleYoneyama, S., Sakurada, Y., Shijo, T., Fukuda, Y., Kotoda, Y., Kikushima, W., Mabuchi, F., & Kashiwagi, K. (2025). Genetic Factors Associated with Intraocular Inflammation After Brolucizumab Administration in Patients with Exudative Age-Related Macular Degeneration. Genes, 16(7), 797. https://doi.org/10.3390/genes16070797