Review of Fibrosis in Neovascular Age-Related Macular Degeneration

Cheong, Kai Xiong; Cheung, Chui Ming Gemmy; Teo, Kelvin Yi Chong

doi:10.1016/j.ajo.2022.09.008

Cited by 14 publications

(10 citation statements)

References 57 publications

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“…Another interesting point was our low rate of fibrosis that could be explained by the small number of eyes with type 2 CNV that are most likely to present fibrosis. Fibrosis and macular atrophy have previously been described as the main restricting features for long-term visual ability [44, 45], and limiting their occurrence represents a challenge for future therapies.…”

Section: Discussionmentioning

confidence: 99%

Long Intervals between Intravitreal Injections Using a Treat-and-Extend Protocol in a Real-Life Context in AMD: The LIRE Study

Leroux,

Agard,

Billant

et al. 2023

Ophthalmologica

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Introduction: To assess the outcome of long Treat-and-Extend (TE) anti-VEGF intravitreal injection (IVI) intervals (≥every 12 weeks [Q12W]) in neovascular age-related macular degeneration (nAMD). The aims of this retrospective study were to determine the proportion of nAMD eyes treated ≥Q12W, to analyze their longitudinal, functional and anatomical outcomes, and to compare functional and anatomical outcomes between eyes that rapidly versus slowly reached a Q12W regimen, and between eyes directly treated with versus initiating lately the TE regimen. Methods: All patients receiving IVIs for nAMD were screened. The longitudinal, functional and anatomical characteristics of Q12W-treated eyes were reported at different timepoints. Results: Ninety-one eyes were included (38% of our total nAMD cohort). The mean TE regimen time to reach a Q12W interval was 20.1 +/- 16.2 months. During this time, a mean number of 12.1 +/- 9.3 IVIs were needed. The mean BCVA was 68 letters at the time of diagnosis and was maintained (p >0.05). Eyes that rapidly reached a Q12W interval had a shorter follow-up before TE regimen initiation (p=0.04) and received fewer IVIs (p=0.02) than eyes that slowly reached a Q12W interval. Eyes directly treated with the TE regimen reached a Q12W interval more rapidly than eyes with late TE initiation. The neovascularization subtype was not a predictor of outcome in TE-treated eyes. Conclusion: ≥Q12W eyes represent an important part of the nAMD population in our real-life study. No baseline anatomical characteristics was associated with the outcome under a TE regimen, although early TE regimen initiation allowed extending more rapidly the IVI interval.

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Section: Discussionmentioning

confidence: 99%

Long Intervals between Intravitreal Injections Using a Treat-and-Extend Protocol in a Real-Life Context in AMD: The LIRE Study

Leroux,

Agard,

Billant

et al. 2023

Ophthalmologica

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“…The diagnosis of subretinal fibrosis using a conventional OCT device may therefore often be imprecise or even impossible [9]. However, increasing the precision of diagnosing retinal fibrosis is crucial as scarring is still a relevant limiting factor for the visual acuity of patients with nAMD [10][11][12][13]. Furthermore, evaluation of the efficacy of anti-fibrotic agents is challenging since reliable study endpoints are lacking using standard imaging modalities.…”

Section: Introductionmentioning

confidence: 99%

“…MP may therefore be used to detect impaired retinal sensitivity as an independent functional correlate of subretinal fibrosis, however, data on the structure-function correlation in eyes with retinal fibrosis due to nAMD is limited. Recently, a review paper on fibrosis in nAMD by Cheong et al concluded that more studies involving multimodal imaging are necessary to clarify our understanding of retinal fibrosis, as each imaging modality has its advantages and disadvantages for imaging fibrosis [11]. Furthermore, while there is plenty of data evaluating visual acuity in eyes with retinal fibrosis there is a lack of data considering focal retinal sensitivity to our knowledge [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Structure-Function Correlation of Retinal Fibrosis in Eyes with Neovascular Age-Related Macular Degeneration

Schranz,

Sacu,

Reiter

et al. 2024

JCM

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Purpose: To assess retinal function in areas of presumed fibrosis due to neovascular age-related macular degeneration (nAMD), using multimodal imaging and structure-function correlation. Design: Cross-sectional observational study. Methods: 30 eyes of 30 consecutive patients with nAMD with a minimum history of one year of anti-vascular endothelial growth factor therapy were included. Each patient underwent microperimetry (MP), color fundus photography (CFP), standard spectral-domain-based OCT (SD-OCT), and polarization sensitive-OCT (PS-OCT) imaging. PS-OCT technology can depict retinal fibrosis based on its birefringence. CFP, SD-OCT, and PS-OCT were evaluated independently for the presence of fibrosis at the corresponding MP stimuli locations. MP results and morphologic findings in CFP, SD-OCT, and PS-OCT were co-registered and analyzed using mixed linear models. Results: In total, 1350 MP locations were evaluated to assess the functional impact of fibrosis according to a standardized protocol. The estimated means of retinal areas with signs of fibrosis were 12.60 db (95% confidence interval: 10.44–14.76) in CFP, 11.60 db (95% COI: 8.84–14.36) in OCT, and 11.02 db (95% COI 8.10–13.94) in PS-OCT. Areas evaluated as subretinal fibrosis in three (7.2 db) or two (10.1 db) modalities were significantly correlated with a lower retinal sensitivity than a subretinal fibrosis observed in only one (15.3 db) or none (23.3 db) modality (p < 0.001). Conclusions: CFP, SD-OCT and PS-OCT are all suited to detect areas of reduced retinal sensitivity related to fibrosis, however, a multimodal imaging approach provides higher accuracy in the identification of areas with low sensitivity in MP (i.e., impaired retinal function), and thereby improves the detection rate of subretinal fibrosis in nAMD.

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“…Neovascular AMD (nAMD), accounting for up to 90% of AMD-associated vision loss and blindness [ 2 ], is primarily characterized by the presence of choroidal or retinal neovascularization (CNV or RNV) in the macular region, ultimately resulting in the formation of fibrotic scar [ 2 ]. The prevalence of fibrosis at baseline, 12, 24, and 60 months in patients with nAMD was reported as follow: 13%, 32%, 36%, and 56%, respectively, according to a recent epidemiological report [ 3 ]. Despite the efficacy of anti-vascular endothelial growth factor (anti-VEGF) therapy as the cornerstone in nAMD management, capable of stabilizing or even enhancing the visual function [ 4 ], approximately 1/3 of the patients with subretinal fibrosis still experience poor prognosis, and even deterioration of the visual acuity [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Wnt5a/β-catenin-mediated epithelial-mesenchymal transition: a key driver of subretinal fibrosis in neovascular age-related macular degeneration

Liu,

Du,

Xie

et al. 2024

J Neuroinflammation

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Background Neovascular age-related macular degeneration (nAMD), accounts for up to 90% of AMD-associated vision loss, ultimately resulting in the formation of fibrotic scar in the macular region. The pathogenesis of subretinal fibrosis in nAMD involves the process of epithelial–mesenchymal transition (EMT) occurring in retinal pigment epithelium (RPE). Here, we aim to investigate the underlying mechanisms involved in the Wnt signaling during the EMT of RPE cells and in the pathological process of subretinal fibrosis secondary to nAMD. Methods In vivo, the induction of subretinal fibrosis was performed in male C57BL/6J mice through laser photocoagulation. Either FH535 (a β-catenin inhibitor) or Box5 (a Wnt5a inhibitor) was intravitreally administered on the same day or 14 days following laser induction. The RPE-Bruch's membrane-choriocapillaris complex (RBCC) tissues were collected and subjected to Western blot analysis and immunofluorescence to examine fibrovascular and Wnt-related markers. In vitro, transforming growth factor beta 1 (TGFβ1)-treated ARPE-19 cells were co-incubated with or without FH535, Foxy-5 (a Wnt5a-mimicking peptide), Box5, or Wnt5a shRNA, respectively. The changes in EMT- and Wnt-related signaling molecules, as well as cell functions were assessed using qRT-PCR, nuclear-cytoplasmic fractionation assay, Western blot, immunofluorescence, scratch assay or transwell migration assay. The cell viability of ARPE-19 cells was determined using Cell Counting Kit (CCK)-8. Results The in vivo analysis demonstrated Wnt5a/ROR1, but not Wnt3a, was upregulated in the RBCCs of the laser-induced CNV mice compared to the normal control group. Intravitreal injection of FH535 effectively reduced Wnt5a protein expression. Both FH535 and Box5 effectively attenuated subretinal fibrosis and EMT, as well as the activation of β-catenin in laser-induced CNV mice, as evidenced by the significant reduction in areas positive for fibronectin, alpha-smooth muscle actin (α-SMA), collagen I, and active β-catenin labeling. In vitro, Wnt5a/ROR1, active β-catenin, and some other Wnt signaling molecules were upregulated in the TGFβ1-induced EMT cell model using ARPE-19 cells. Co-treatment with FH535, Box5, or Wnt5a shRNA markedly suppressed the activation of Wnt5a, nuclear translocation of active β-catenin, as well as the EMT in TGFβ1-treated ARPE-19 cells. Conversely, treatment with Foxy-5 independently resulted in the activation of abovementioned molecules and subsequent induction of EMT in ARPE-19 cells. Conclusions Our study reveals a reciprocal activation between Wnt5a and β-catenin to mediate EMT as a pivotal driver of subretinal fibrosis in nAMD. This positive feedback loop provides valuable insights into potential therapeutic strategies to treat subretinal fibrosis in nAMD patients.

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Review of Fibrosis in Neovascular Age-Related Macular Degeneration

Cited by 14 publications

References 57 publications

Long Intervals between Intravitreal Injections Using a Treat-and-Extend Protocol in a Real-Life Context in AMD: The LIRE Study

Long Intervals between Intravitreal Injections Using a Treat-and-Extend Protocol in a Real-Life Context in AMD: The LIRE Study

Structure-Function Correlation of Retinal Fibrosis in Eyes with Neovascular Age-Related Macular Degeneration

Wnt5a/β-catenin-mediated epithelial-mesenchymal transition: a key driver of subretinal fibrosis in neovascular age-related macular degeneration

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