OBJECTIVE: To investigate aqueous humor cytokine levels in neovascular age-related macular degeneration (nAMD) patients with subretinal fibrosis and to explore the relationship between cytokine levels and disease severity.
METHODS: The aqueous humor samples were collected from 16 eyes with subretinal fibrosis due to nAMD (SRFi group), 33 eyes with nAMD without subretinal fibrosis (nAMD group) and 28 eyes with cataract patients (control group). Clinical samples were analyzed for 5 cytokines,including vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), basic fibroblast growth factor (bFGF), transforming growth factor-α (TGF-α), platelet-derived growth factor-BB (PDGF-BB).
RESULTS: Aqueous humor cytokines VEGF and bFGF were significantly higher in nAMD patients than controls (all P < 0.05), and VEGF, bFGF and TGF-α levels were significantly higher in SRFi patients than controls (all P < 0.05). No significant differences in 4 cytokine levels were observed between nAMD and SRFi patients in aqueous humor. We also identified a positive correlation between the aqueous humor levels of IL-6 and VEGF in the SRFi group, while bFGF and TGF-α in the nAMD group. Moreover, VEGF levels were strongly related to BCVA, and bFGF levels were positively related to the maximum thickness of subretinal hyperreflective material (SHRM) in fibrosis due to nAMD.
CONCLUSIONS: VEGF and bFGF levels in aqueous humor were elevated in macular neovascularization with and without subretinal fibrosis. TGF-α levels exclusively differed in neovascular AMD with fibrosis. Cytokines are distributed differently and play a synergistic role in different stages (angiogenesis and fibrogenesis) of nAMD. The bFGF levels could predict the negative prognosis in fibrosis due to nAMD.

Neovascular age-related macular degeneration (nARMD) is an important cause of visual impairment and blindness in the elderly, with choroidal neovascularization in the macula as the main pathological feature. The onset of nARMD is closely related to factors including age, oxidative stress, and lipid metabolism. Vascular endothelial growth factor (VEGF) is an important factor contributing to nARMD as well as choroidal neovascularization and retinal leakage formation. At present, anti-VEGF therapy is the only treatment that improves vision and halts disease progression in most patients, making anti-VEGF drugs a landmark development for nARMD treatment. Although intravitreal injection of anti-VEGF drugs has become the first-line treatment for nARMD, this treatment has many shortcomings including repeated injections, poor or no response in some patients, and complications such as retinal fibrosis. As a result, several new anti-VEGF drugs are being developed. This review provides a discussion of these new anti-VEGF drugs for the treatment of nARMD.

UNASSIGNED: The study aims to investigate the protective effect of Mingjing granule (MG) in a fibrovascular membrane rat model of neovascular age-related macular degeneration (nAMD) and explore the underlying mechanism.
UNASSIGNED: The nAMD fibrovascular membrane model was established by two-stage laser photocoagulation. BN rats were randomly divided into four groups: the model group was gavaged with distilled water, the anti-VEGF group was given an intravitreous injection of ranibizumab, the MG + anti-VEGF group was gavaged with MG combined with an intravitreous injection of ranibizumab, and the normal group not modeled only fed conventionally. Lesions were evaluated by color fundus photograph, optical coherence tomography, fundus fluorescein angiography, and retinal pigment epithelial-choroid-sclera flat mount. The changes in the retinal structure were observed by histopathology. The expression of inflammatory cell markers F4/80, Iba-1, and glial fibrillary acidic protein (GFAP); the fibrosis-related factors collagen-1, fibronectin, α-smooth muscle actin (α-SMA), and transforming growth factor-beta (TGF-β); and the complement system-related factors C3a and C3aR in the retina were detected by immunofluorescence or qRT-PCR.
UNASSIGNED: The current study revealed that MG + anti-VEGF administration more significantly reduced the thickness of fibrovascular lesions, suppressed vascular leakage (exudation area and mean density value), inhibited the area of fibrovascular lesions, and restrained the formation of the fibrovascular membrane than the anti-VEGF agent alone in the two-stage laser-induced rat model. The fluorescence intensities of F4/80, Iba-1, collagen-1, fibronectin, TGF-β, and C3aR showed more significant inhibition in MG + anti-VEGF-treated rats than the anti-VEGF agent alone. The mRNA expression levels of F4/80, Iba-1, GFAP, collagen-1, fibronectin, α-SMA, TGF-β, and C3a showed lower levels in rats treated with MG + anti-VEGF than the anti-VEGF agent alone.
UNASSIGNED: Combining MG with anti-VEGF treatment inhibits the growth of the fibrovascular membrane more effectively than using anti-VEGF treatment alone. The mechanism underlying this effect may involve limiting inflammatory cell aggregation, controlling complement system activation, and decreasing the expression of the fibrotic protein.

OBJECTIVE: This study sought to provide an overview of the current research and further analyze publication trends in the field of vascular endothelial growth factor (VEGF) and anti-VEGF treatment for neovascular age-related macular degeneration (NVAMD).
METHODS: We downloaded all related publications from 2001 to 2020 from the Web of Science Core Collection and conducted a bibliometric analysis using the bibiometrix package in R programming software.
RESULTS: A total of 3717 publications were included in the analysis. The USA contributed the largest number of publications (1443), and achieved the highest number of citations (74,946) and H-index value (28). Johns Hopkins University, USA, was the top institution with the most publications, and Peter A. Campochiaro was the most productive professor at The Wilmer Eye Institute, USA. 9.60% of the total publications were from the Journal of Retinal and Vitreous Diseases. Trend analysis demonstrated that anti-VEGF therapy was introduced in early 2000 after steroids, and the last 2 decades have witnessed the blossom of several anti-VEGF agents. \"Treat-and-extend\" and \"resistance\" were two popular trend topics in recent years.
CONCLUSIONS: The USA occupies a dominant position in the research field of VEGF and anti-VEGF treatments in NVAMD. Steroid administration, photodynamic therapy, and anti-VEGF therapy have been pivotal advances in the treatment of NVAMD patients over the past 2 decades. Limited acting period and resistance are potential investigation directions in future studies.

This study compares the effectiveness of Conbercept and Aflibercept in treating neovascular age-related macular degeneration (nAMD). Conducted at the First Affiliated Hospital of Chongqing Medical University\'s Ophthalmology Department (May 2020-May 2023), this prospective study enrolled 159 nAMD patients. Participants were randomly divided into two groups: one receiving 0.5 mg Conbercept and the other 2 mg Aflibercept intravitreal injections. Over 12 months, the study, employing a Treat-and-Extend (T&E) regimen, assessed Best-Corrected Visual Acuity (BCVA), Central Retinal Thickness (CRT) changes and injection frequency. Of the 159 patients, 137 (149 eyes) completed the study. No significant age difference was found between the groups (P = 0.331). After 12 months, BCVA improved similarly in both groups (Conbercept: 52.8 ± 18.9, Aflibercept: 52.0 ± 19.7 letters; P = 0.820). CRT reduction was also comparable (Conbercept: 246.3 ± 82.8 µm, Aflibercept: 275.9 ± 114.3 µm; P = 0.079). Injection frequencies averaged 6.9 ± 0.7 (Conbercept) and 6.7 ± 0.7 (Aflibercept; P = 0.255). Subtype analysis revealed Type 1 MNV had higher baseline BCVA and lower CRT, with more frequent injections compared to other types. Both Conbercept and Aflibercept are clinically similar in efficacy for nAMD, with the T&E regimen proving therapeutically effective and potentially reducing patient costs. Anti-VEGF treatment efficacy varies across nAMD subtypes, indicating a potential benefit in tailored treatments for specific subtypes.Clinical trial registration number NCT05539235 (Protocol Registration and Results System).

BACKGROUND: To investigate the clinical effects of double-dose (4 mg) aflibercept treatment in neovascular age-related macular degeneration (nAMD), compared with the standard-dose (2 mg) treatment.
METHODS: A total of 108 eyes from 97 patients with nAMD and received intravitreal aflibercept 2 mg and/or 4 mg treatment were retrospectively reviewed. The changes of central macular thickness (CMT)/ pigmental epithelium detachment height and the recurrence rate of exudation during the 12-month follow-up were compared between the 2 mg group and the 4 mg group. Self-control comparisons (2 mg switch to 4 mg) were also made between two regimens.
RESULTS: Compared with the 2 mg group, tendencies of lower intraretinal fluid incidence and more CMT reduction were observed in the 4 mg group. The later one was also observed when eyes switching from 2 mg to 4 mg regimen. The median remission interval was 5 months in the 4 mg group, 2 months longer than the 3 months in the 2 mg group (P = 0.452). Injections needed in the 4 mg group were 3.644 ± 1.670, less than the 4.286 ± 2.334 injections in the 2 mg group within 12 months as well (P = 0.151). However, no associated vision benefits were gained from the double-douse regimen. No markedly increased-intraocular pressure events, or other adverse events were found in two groups.
CONCLUSIONS: Compared to the aflibercept 2 mg treatment in nAMD, tendencies of anatomic gains and relieving treatment burden were brought by the aflibercept 4 mg treatment. This study may have additional importance, given the further application of high-dose aflibercept in real-world settings.

The present study aimed to examine the optical coherence tomography angiography (OCTA) parameters associated with macular neovascularization (MNV) in patients diagnosed with neovascular age-related macular degeneration (nAMD) and treated with either intravitreal conbercept (IVC) or ranibizumab (IVR). It enrolled 39 nAMD patients presenting with MNV, including 23 in the IVC group and 16 in the IVR group. All participants were treatment-naïve with intravitreal therapy and they underwent treatment following a \'3+PRN\' regimen. The MNV patterns identified through OCTA were categorized as Medusa, tangled, seafan and other variations. Key outcome measures encompassed best-corrected visual acuity (BCVA), MNV vascular area (MNV-VA), MNV vascular density (MNV-VD) ratio and central macular thickness (CMT). In the present study, 44 eyes were included, with 28 eyes undergoing treatment with IVC and 18 eyes with IVR. On day 90, there was a statistically significant improvement in mean BCVA from baseline among all patients treated with IVC (P=0.002). Notably, improved outcomes were observed in those with the \'tangled\' pattern compared with the other three patterns (P=0.007). CMT exhibited a significant decrease from baseline (P=0.007), with consistent improvement observed across all four patterns (P=0.052) on day 90. The mean MNV-VA decreased in all patients, reaching statistical significance for the Medusa pattern (P=0.008), although the improvement in visual acuity was deemed unsatisfactory. Patients with the seafan pattern treated with IVR improved significantly in BCVA (P=0.042). The mean CMT significantly improved from baseline (P=0.001), consistent across the four patterns (P=0.114). Significant improvements were noted in the mean MNV-VA for the seafan pattern and in the mean MNV-VD ratio for the other patterns. The two regimens had no significant differences regarding BCVA, CMT, and MNV parameters. Conbercept emerged as a viable treatment option for patients presenting with tangled MNV patterns. On the other hand, ranibizumab might be considered an effective intervention for individuals with seafan MNV patterns. Notably, the Medusa MNV pattern was associated with a morphologic configuration indicative of a poor prognosis.

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.

BACKGROUND: The objective of this study was to compare the outcome of submacular hemorrhage (SMH) displacement using pneumatic displacement with intravitreal expansile gas versus pars plana vitrectomy (PPV) with subretinal injection of tissue plasminogen activator (tPA), anti-vascular endothelial growth factor (VEGF) agent, and air as primary surgery.
METHODS: Retrospective interventional case series of 63 patients who underwent surgical displacement of SMH secondary to neovascular age-related macular degeneration (nAMD) or polypoidal choroidal vasculopathy (PCV) from May 1, 2015, to October 31, 2022. Medical records were reviewed for diagnosis, logMAR visual acuity (VA), central subfield thickness (CST), and postoperative displacement rates and complications up to 12 months after operation.
RESULTS: The diagnosis was nAMD in 24 (38.1%) and PCV in 39 (61.9%) eyes. There were 40 (63.5%) eyes in the pneumatic displacement group (38 received C3F8, 2 received SF6) and 23 (36.5%) eyes in the subretinal cocktail injection. Mean baseline VA was 1.46 and 1.62, respectively (p = 0.404). The subretinal injection group had more extensive SMH (p = 0.005), thicker CST (1,006.6 μm vs. 780.2 μm, p = 0.012), and longer interval between symptom and operation (10.65 vs. 5.53 days, p < 0.001). The mean postoperative VA at 6 months was 0.67 and 0.91 (p = 0.180) for pneumatic displacement and subretinal injection groups, respectively, though VA was significantly better in the pneumatic group at 12-month visit (0.64 vs. 1.03, p = 0.040). At least 10 mean change in VA were >10 letters gain in both groups up to 12 months. Postoperative CST reduction was greater (625.1 μm vs. 326.5 μm, p = 0.008) and complete foveal displacement (87.0% vs. 37.5%), p < 0.001, odds ratio [OR] = 11.1) and displacement to arcade or beyond (52.5% vs. 17.5%, p = 0.009, OR = 5.15) were more frequent in the subretinal injection group. Two patients with failed pneumatic displacement were successfully treated with subretinal cocktail injection as a second operation.
CONCLUSIONS: Surgical displacement of SMH leads to clinically meaningful improvement in VA. PPV with subretinal cocktail injection is more effective than pneumatic displacement in displacing SMH with similar safety profile despite longer interval before operation, higher CST, and more extensive SMH at baseline. Retinal surgeons could consider this novel technique in cases with thick and extensive SMH or as a rescue secondary operation in selected cases.

OBJECTIVE: To evaluate 2-year efficacy, durability, and safety of the bispecific antibody faricimab, which inhibits both angiopoietin-2 and VEGF-A.
METHODS: TENAYA (ClinicalTrials.gov identifier, NCT03823287) and LUCERNE (ClinicalTrials.gov identifier, NCT03823300) were identically designed, randomized, double-masked, active comparator-controlled phase 3 noninferiority trials.
METHODS: Treatment-naive patients with neovascular age-related macular degeneration (nAMD) 50 years of age or older.
METHODS: Patients were randomized (1:1) to intravitreal faricimab 6.0 mg up to every 16 weeks (Q16W) or aflibercept 2.0 mg every 8 weeks (Q8W). Faricimab fixed dosing based on protocol-defined disease activity at weeks 20 and 24 up to week 60, followed up to week 108 by a treat-and-extend personalized treatment interval regimen.
METHODS: Efficacy analyses included change in best-corrected visual acuity (BCVA) from baseline at 2 years (averaged over weeks 104, 108, and 112) and proportion of patients receiving Q16W, every 12 weeks (Q12W), and Q8W dosing at week 112 in the intention-to-treat population. Safety analyses included ocular adverse events (AEs) in the study eye through study end at week 112.
RESULTS: Of 1326 patients treated across TENAYA/LUCERNE, 1113 (83.9%) completed treatment (n = 555 faricimab; n = 558 aflibercept). The BCVA change from baseline at 2 years was comparable between faricimab and aflibercept groups in TENAYA (adjusted mean change, +3.7 letters [95% confidence interval (CI), +2.1 to +5.4] and +3.3 letters [95% CI, +1.7 to +4.9], respectively; mean difference, +0.4 letters [95% CI, -1.9 to +2.8]) and LUCERNE (adjusted mean change, +5.0 letters [95% CI, +3.4 to +6.6] and +5.2 letters [95% CI, +3.6 to +6.8], respectively; mean difference, -0.2 letters [95% CI, -2.4 to +2.1]). At week 112 in TENAYA and LUCERNE, 59.0% and 66.9%, respectively, achieved Q16W faricimab dosing, increasing from year 1, and 74.1% and 81.2%, achieved Q12W or longer dosing. Ocular AEs in the study eye were comparable between faricimab and aflibercept groups in TENAYA (55.0% and 56.5% of patients, respectively) and LUCERNE (52.9% and 47.5% of patients, respectively) through week 112.
CONCLUSIONS: Treat-and-extend faricimab treatment based on nAMD disease activity maintained vision gains through year 2, with most patients achieving extended dosing intervals.
BACKGROUND: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.