Comparison of clinical features of eyes with subretinal fibrosis and non-subretinal fibrosis in neovascular age-related macular degeneration_Chinese Journal of Ocular Fundus Diseases

Authors：

Sun Wu ¹ , Gao Jiangsheng ² , Ru Shuting ¹ , Li Xin ¹ , Shi Hang ¹ , Chen Shuiling ¹ , Zhou Wanyu ¹ , Tao Fangfang ¹ ,  Chu Liqun ¹

1. Department of Ophthalmology, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, China;
2. Guangdong Medical University, Guangzhou 524000, China;

Corresponding author：

Chu Liqun, Email: chuliqunok@163.com

Keywords：

Subretinal fibrosis; Neovascular age-related macular degeneration; Risk factors; Case-control study

DOI：

10.3760/cma.j.cn511434-20241203-00461

Video：

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Objective To compare the clinical characteristics of neovascular age-related macular degeneration (nAMD) patients with or without secondary subretinal fibrosis (SF). Methods A retrospective case-control study. A total of 88 patients (92 eyes) diagnosed with nAMD at Department of Ophthalmology, Xiyuan Hospital of China Academy of Chinese Medical Sciences from January 2020 to January 2024 were enrolled in this study. All eyes underwent best-corrected visual acuity (BCVA), color fundus photography, and optical coherence tomography (OCT) examinations. BCVA was measured using the international standard visual acuity chart and converted to logarithm of the minimum angle of resolution for statistical analysis. SF area was measured on color fundus images. OCT was used to assess the presence of shallow irregular retinal pigment epithelial (RPE) elevation, RPE detachment, ellipsoid zone/external limiting membrane disruption, subretinal fluid and/or intraretinal fluid, thinning of the inner nuclear layer or inner plexiform layer, complete RPE and outer retinal atrophy (cRORA), epiretinal membrane, and suprachoroidal fluid. Device-integrated software measured central retinal thickness (CRT), subfoveal choroidal thickness (SFCT), and the height and width of subfoveal fibrosis in SF eyes. Based on the presence of SF, patients were divided into the SF group (47 eyes) and the non-SF (NSF) group (45 eyes). Baseline characteristics, OCT, and color fundus photography imaging features were compared between groups. Independent samples t tests were used for intergroup comparisons, and multiple linear regression was performed to analyze potential factors influencing SF height. Results Compared with the NSF group, the SF group had a longer disease duration, longer symptom onset to initial treatment interval to receiving anti-vascular endothelial growth factor (VEGF) drug treatment, a lower proportion of patients receiving 3 anti-VEGF drug injections within 6 months, worse BCVA, thicker SFCT, higher rates of pigment epithelial detachment and inner nuclear layer or inner plexiform layer thinning, and a lower rate of subretinal fluid (P＜0.05). No significant differences were observed in CRT or the proportions of irregular retinal pigment epithelia, ellipsoid zone/external limiting membrane disruption, cRORA, suprachoroidal fluid, or epiretinal membrane between the two groups (P＞0.05). Conclusion nAMD eyes with secondary SF exhibit distinct OCT imaging features compared to NSF eyes.

Citation： Sun Wu, Gao Jiangsheng, Ru Shuting, Li Xin, Shi Hang, Chen Shuiling, Zhou Wanyu, Tao Fangfang, Chu Liqun. Comparison of clinical features of eyes with subretinal fibrosis and non-subretinal fibrosis in neovascular age-related macular degeneration. Chinese Journal of Ocular Fundus Diseases, 2025, 41(9): 684-689. doi: 10.3760/cma.j.cn511434-20241203-00461 Copy

1.	Liu D, Zhang C, Zhang J, et al. Molecular pathogenesis of subretinal fibrosis in neovascular AMD focusing on epithelial-mesenchymal transformation of retinal pigment epithelium[J/OL]. Neurobiol Dis, 2023, 185: 106250[2023-08-02]. https://pubmed.ncbi.nlm.nih.gov/37536385/. DOI: 10.1016/j.nbd.2023.106250.
2.	Cheong KX, Cheung CMG, Teo KYC. Review of fibrosis in neovascular age-related macular degeneration[J]. Am J Ophthalmol, 2023, 246: 192-222. DOI: 10.1016/j.ajo.2022.09.008.
3.	Cheung CMG, Grewal DS, Teo KYC, et al. The evolution of fibrosis and atrophy and their relationship with visual outcomes in Asian persons with neovascular age-related macular degeneration[J]. Ophthalmol Retina, 2019, 3(12): 1045-1055. DOI: 10.1016/j.oret.2019.06.002.
4.	Llorián-Salvador M, Byrne EM, Szczepan M, et al. Complement activation contributes to subretinal fibrosis through the induction of epithelial-to-mesenchymal transition (EMT) in retinal pigment epithelial cells[J/OL]. J Neuroinflammation, 2022, 19(1): 182[2022-07-14]. https://pubmed.ncbi.nlm.nih.gov/35831910/. DOI: 10.1186/s12974-022-02546-3.
5.	Cao J, Zhao L, Li Y, et al. A subretinal matrigel rat choroidal neovascularization (CNV) model and inhibition of CNV and associated inflammation and fibrosis by VEGF trap[J]. Invest Ophthalmol Vis Sci, 2010, 51(11): 6009-6017. DOI: 10.1167/iovs.09-4956.
6.	Sreekumar PG, Reddy ST, Hinton DR, et al. Mechanisms of RPE senescence and potential role of αB crystallin peptide as a senolytic agent in experimental AMD[J/OL]. Exp Eye Res, 2022, 215: 108918[2022-02-01]. https://pubmed.ncbi.nlm.nih.gov/34986369/. DOI: 10.1016/j.exer.2021.108918.
7.	Hua Z, Yang W, Li D, et al. Metformin regulates the LIN28B-mediated JNK/STAT3 signaling pathway through miR-140-3p in subretinal fibrosis[J/OL]. Exp Ther Med, 2023, 26(5): 528[2023-09-27]. https://pubmed.ncbi.nlm.nih.gov/37869644/. DOI: 10.3892/etm.2023.12227.
8.	Daniel E, Toth CA, Grunwald JE, et al. Risk of scar in the comparison of age-related macular degeneration treatments trials[J]. Ophthalmology, 2014, 121(3): 656-666. DOI: 10.1016/j.ophtha.2013.10.019.
9.	Gräfe MGO, van de Kreeke JA, Willemse J, et al. Subretinal fibrosis detection using polarization sensitive optical coherence tomography[J/OL]. Transl Vis Sci Technol, 2020, 9(4): 13[2020-04-16]. https://pubmed.ncbi.nlm.nih.gov/32818100/. DOI: 10.1167/tvst.9.4.13.
10.	Armendariz BG, Chakravarthy U. Fibrosis in age-related neovascular macular degeneration in the anti-VEGF era[J]. Eye (Lond), 2024, 38(17): 3243-3251. DOI: 10.1038/s41433-024-03308-6.
11.	Bachmeier I, Armendariz BG, Yu S, et al. Fibrosis in neovascular age-related macular degeneration: a review of definitions based on clinical imaging[J]. Surv Ophthalmol, 2023, 68(5): 835-848. DOI: 10.1016/j.survophthal.2023.03.004.
12.	Wong WM, Sun W, Vyas C, et al. Analysis of the pachychoroid phenotype in an Asian population: methodology and baseline study population characteristics[J]. Br J Ophthalmol, 2023, 107(5): 698-704. DOI: 10.1136/bjo-2022-322457.
13.	Teo KYC, Joe AW, Nguyen V, et al. Prevalence and risk factors for thedevelopment of physician-graded subretinal fibrosis in eyes treatedfor neovascular age-related macular degeneration[J]. Retina, 2020, 40(12): 2285-2295. DOI: 10.1097/IAE.0000000000002779.
14.	Willoughby AS, Ying GS, Toth CA, et al. Subretinal hyperreflective material in the comparison of age-related macular degeneration treatments trials[J]. Ophthalmology, 2015, 122(9): 1846-1853. DOI: 10.1016/j.ophtha.2015.05.042.
15.	Daniel E, Pan W, Ying GS, et al. Development and course of scars in the comparison of age-related macular degeneration treatments trials[J]. Ophthalmology, 2018, 125(7): 1037-1046. DOI: 10.1016/j.ophtha.2018.01.004.
16.	Finn AP, Pistilli M, Tai V, et al. Localized optical coherence tomography precursors of macular atrophy and fibrotic scar in the comparison of age-related macular degenerationtreatments trials[J]. Am J Ophthalmol, 2021, 223: 338-347. DOI: 10.1016/j.ajo.2020.11.002.
17.	Roberts PK, Schranz M, Motschi A, et al. Morphologic and microvascular differences between macular neovascularization with and without subretinal fibrosis[J/OL]. Transl Vis SciTechnol, 2021, 10(14): 1[2021-12-01]. https://pubmed.ncbi.nlm.nih.gov/34851359/. DOI: 10.1167/tvst.10.14.1.
18.	Llorente-González S, Hernandez M, González-Zamora J, et al. The role of retinal fluidlocation in atrophy and fibrosis evolution of patients with neovascular age-related maculardegeneration long-term treated in real world[J/OL]. Acta Ophthalmol, 2022, 100(2): e521-e531[2021-06-04]. https://pubmed.ncbi.nlm.nih.gov/34085771/. DOI: 10.1111/aos.14905.
19.	Roberts PK, Schranz M, Motschi A, et al. Baseline predictors for subretinal fibrosis inneovascular age-related macular degeneration[J/OL]. Sci Rep, 2022, 12(1): 88[2022-01-07]. https://pubmed.ncbi.nlm.nih.gov/34996934/. DOI: 10.1038/s41598-021-03716-8.
20.	Angermann R, Franchi A, Stöckl V, et al. Intravitreal Aflibercept therapy and treatment outcomes of eyes with neovascular age-related macular degeneration in a real-lifesetting: a five-year follow-up investigation[J]. Ophthalmol Ther, 2022, 11(2): 559-571. DOI: 10.1007/s40123-022-00452-8.
21.	Zhao X, Meng L, Luo M, et al. The influence of delayed treatment due to COVID-19 onpatients with neovascular age-related macular degeneration and polypoidal choroidalvasculopathy[J/OL]. Ther Adv Chronic Dis, 2021, 12: 20406223211026389[2021-06-22]. https://pubmed.ncbi.nlm.nih.gov/34221305/. DOI: 10.1177/20406223211026389.
22.	Tenbrock L, Wolf J, Boneva S, et al. Subretinal fibrosis in neovascular age-related maculardegeneration: current concepts, therapeutic avenues, and future perspectives[J]. Cell TissueRes, 2022, 387(3): 361-375. DOI: 10.1007/s00441-021-03514-8.
23.	Wichrowska M, Wichrowski P, Kocięcki J. Morphological and functional assessment of the optic nerve head and retinal ganglion cells in dry vs chronically treated wet age-related macular degeneration[J]. Clin Ophthalmol, 2022, 16: 2373-2384. DOI: 10.2147/OPTH.S372626.

1. Liu D, Zhang C, Zhang J, et al. Molecular pathogenesis of subretinal fibrosis in neovascular AMD focusing on epithelial-mesenchymal transformation of retinal pigment epithelium[J/OL]. Neurobiol Dis, 2023, 185: 106250[2023-08-02]. https://pubmed.ncbi.nlm.nih.gov/37536385/. DOI: 10.1016/j.nbd.2023.106250.
2. Cheong KX, Cheung CMG, Teo KYC. Review of fibrosis in neovascular age-related macular degeneration[J]. Am J Ophthalmol, 2023, 246: 192-222. DOI: 10.1016/j.ajo.2022.09.008.
3. Cheung CMG, Grewal DS, Teo KYC, et al. The evolution of fibrosis and atrophy and their relationship with visual outcomes in Asian persons with neovascular age-related macular degeneration[J]. Ophthalmol Retina, 2019, 3(12): 1045-1055. DOI: 10.1016/j.oret.2019.06.002.
4. Llorián-Salvador M, Byrne EM, Szczepan M, et al. Complement activation contributes to subretinal fibrosis through the induction of epithelial-to-mesenchymal transition (EMT) in retinal pigment epithelial cells[J/OL]. J Neuroinflammation, 2022, 19(1): 182[2022-07-14]. https://pubmed.ncbi.nlm.nih.gov/35831910/. DOI: 10.1186/s12974-022-02546-3.
5. Cao J, Zhao L, Li Y, et al. A subretinal matrigel rat choroidal neovascularization (CNV) model and inhibition of CNV and associated inflammation and fibrosis by VEGF trap[J]. Invest Ophthalmol Vis Sci, 2010, 51(11): 6009-6017. DOI: 10.1167/iovs.09-4956.
6. Sreekumar PG, Reddy ST, Hinton DR, et al. Mechanisms of RPE senescence and potential role of αB crystallin peptide as a senolytic agent in experimental AMD[J/OL]. Exp Eye Res, 2022, 215: 108918[2022-02-01]. https://pubmed.ncbi.nlm.nih.gov/34986369/. DOI: 10.1016/j.exer.2021.108918.
7. Hua Z, Yang W, Li D, et al. Metformin regulates the LIN28B-mediated JNK/STAT3 signaling pathway through miR-140-3p in subretinal fibrosis[J/OL]. Exp Ther Med, 2023, 26(5): 528[2023-09-27]. https://pubmed.ncbi.nlm.nih.gov/37869644/. DOI: 10.3892/etm.2023.12227.
8. Daniel E, Toth CA, Grunwald JE, et al. Risk of scar in the comparison of age-related macular degeneration treatments trials[J]. Ophthalmology, 2014, 121(3): 656-666. DOI: 10.1016/j.ophtha.2013.10.019.
9. Gräfe MGO, van de Kreeke JA, Willemse J, et al. Subretinal fibrosis detection using polarization sensitive optical coherence tomography[J/OL]. Transl Vis Sci Technol, 2020, 9(4): 13[2020-04-16]. https://pubmed.ncbi.nlm.nih.gov/32818100/. DOI: 10.1167/tvst.9.4.13.
10. Armendariz BG, Chakravarthy U. Fibrosis in age-related neovascular macular degeneration in the anti-VEGF era[J]. Eye (Lond), 2024, 38(17): 3243-3251. DOI: 10.1038/s41433-024-03308-6.
11. Bachmeier I, Armendariz BG, Yu S, et al. Fibrosis in neovascular age-related macular degeneration: a review of definitions based on clinical imaging[J]. Surv Ophthalmol, 2023, 68(5): 835-848. DOI: 10.1016/j.survophthal.2023.03.004.
12. Wong WM, Sun W, Vyas C, et al. Analysis of the pachychoroid phenotype in an Asian population: methodology and baseline study population characteristics[J]. Br J Ophthalmol, 2023, 107(5): 698-704. DOI: 10.1136/bjo-2022-322457.
13. Teo KYC, Joe AW, Nguyen V, et al. Prevalence and risk factors for thedevelopment of physician-graded subretinal fibrosis in eyes treatedfor neovascular age-related macular degeneration[J]. Retina, 2020, 40(12): 2285-2295. DOI: 10.1097/IAE.0000000000002779.
14. Willoughby AS, Ying GS, Toth CA, et al. Subretinal hyperreflective material in the comparison of age-related macular degeneration treatments trials[J]. Ophthalmology, 2015, 122(9): 1846-1853. DOI: 10.1016/j.ophtha.2015.05.042.
15. Daniel E, Pan W, Ying GS, et al. Development and course of scars in the comparison of age-related macular degeneration treatments trials[J]. Ophthalmology, 2018, 125(7): 1037-1046. DOI: 10.1016/j.ophtha.2018.01.004.
16. Finn AP, Pistilli M, Tai V, et al. Localized optical coherence tomography precursors of macular atrophy and fibrotic scar in the comparison of age-related macular degenerationtreatments trials[J]. Am J Ophthalmol, 2021, 223: 338-347. DOI: 10.1016/j.ajo.2020.11.002.
17. Roberts PK, Schranz M, Motschi A, et al. Morphologic and microvascular differences between macular neovascularization with and without subretinal fibrosis[J/OL]. Transl Vis SciTechnol, 2021, 10(14): 1[2021-12-01]. https://pubmed.ncbi.nlm.nih.gov/34851359/. DOI: 10.1167/tvst.10.14.1.
18. Llorente-González S, Hernandez M, González-Zamora J, et al. The role of retinal fluidlocation in atrophy and fibrosis evolution of patients with neovascular age-related maculardegeneration long-term treated in real world[J/OL]. Acta Ophthalmol, 2022, 100(2): e521-e531[2021-06-04]. https://pubmed.ncbi.nlm.nih.gov/34085771/. DOI: 10.1111/aos.14905.
19. Roberts PK, Schranz M, Motschi A, et al. Baseline predictors for subretinal fibrosis inneovascular age-related macular degeneration[J/OL]. Sci Rep, 2022, 12(1): 88[2022-01-07]. https://pubmed.ncbi.nlm.nih.gov/34996934/. DOI: 10.1038/s41598-021-03716-8.
20. Angermann R, Franchi A, Stöckl V, et al. Intravitreal Aflibercept therapy and treatment outcomes of eyes with neovascular age-related macular degeneration in a real-lifesetting: a five-year follow-up investigation[J]. Ophthalmol Ther, 2022, 11(2): 559-571. DOI: 10.1007/s40123-022-00452-8.
21. Zhao X, Meng L, Luo M, et al. The influence of delayed treatment due to COVID-19 onpatients with neovascular age-related macular degeneration and polypoidal choroidalvasculopathy[J/OL]. Ther Adv Chronic Dis, 2021, 12: 20406223211026389[2021-06-22]. https://pubmed.ncbi.nlm.nih.gov/34221305/. DOI: 10.1177/20406223211026389.
22. Tenbrock L, Wolf J, Boneva S, et al. Subretinal fibrosis in neovascular age-related maculardegeneration: current concepts, therapeutic avenues, and future perspectives[J]. Cell TissueRes, 2022, 387(3): 361-375. DOI: 10.1007/s00441-021-03514-8.
23. Wichrowska M, Wichrowski P, Kocięcki J. Morphological and functional assessment of the optic nerve head and retinal ganglion cells in dry vs chronically treated wet age-related macular degeneration[J]. Clin Ophthalmol, 2022, 16: 2373-2384. DOI: 10.2147/OPTH.S372626.

Chinese Journal of Ocular Fundus Diseases

Comparison of clinical features of eyes with subretinal fibrosis and non-subretinal fibrosis in neovascular age-related macular degeneration

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