Aqueous humor cytokine levels in patients with subretinal fibrosis in neovascular age-related macular degeneration.

PURPOSE: 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. CONCLUSION: 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.

Treatment of neovascular age-related macular degeneration with anti-vascular endothelial growth factor drugs: progress from mechanisms to clinical applications.

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.

Cost-effectiveness Analysis of Ranibizumab Biosimilar for Neovascular Age-Related Macular Degeneration and its Subtypes from the Societal and Patient Perspectives in Japan.

INTRODUCTION: This study evaluated the cost-effectiveness of anti-vascular endothelial growth factor (VEGF) therapies for subtypes of neovascular age-related macular degeneration (nAMD) from the societal perspective, and for any nAMD from the patient perspective in Japan. METHODS: A Markov model was developed to simulate the lifetime transitions of a cohort of patients with nAMD through various health states based on the involvement of nAMD, the treatment status, and decimal best-corrected visual acuity. Ranibizumab biosimilar was compared with aflibercept from the societal perspective regardless of treatment regimen for the analysis of three subtypes (typical nAMD, polypoidal choroidal vasculopathy (PCV), and retinal angiomatous proliferation (RAP)). Two analyses from the patient perspective focusing on the treat-and-extend regimens were performed, one with a cap on patients' copayments and one without. Ranibizumab biosimilar was compared with branded ranibizumab, aflibercept, aflibercept as the loading dose switching to ranibizumab biosimilar during maintenance (aflibercept switching to ranibizumab biosimilar), and best supportive care (BSC), for patients with any nAMD. RESULTS: In the subtype analyses, ranibizumab biosimilar when compared with aflibercept resulted in incremental quality-adjusted life years (QALYs) of - 0.015, 0.026, and 0.009, and the incremental costs of Japanese yen (JPY) - 50,447, JPY - 997,243, and JPY - 1,286,570 for typical nAMD, PCV, and RAP, respectively. From the patient perspective, ranibizumab biosimilar had incremental QALYs of 0.015, 0.009, and 0.307, compared with aflibercept, aflibercept switching to ranibizumab biosimilar, and BSC, respectively. The incremental costs for ranibizumab biosimilar over a patient lifetime excluding the cap on copayment were estimated to be JPY - 138,948, JPY - 391,935, JPY - 209,099, and JPY - 6,377,345, compared with branded ranibizumab, aflibercept, aflibercept switching to ranibizumab biosimilar, and BSC, respectively. CONCLUSIONS: Ranibizumab biosimilar was demonstrated as a cost-saving option compared to aflibercept across all subtypes of nAMD, irrespective of the perspectives considered.

Health-related quality of life in patients with neovascular age-related macular degeneration: a prospective cohort study.

BACKGROUND: Neovascular age-related macular degeneration (nAMD) is a common cause of visual impairment and blindness in the elderly with globally increasing prevalence. Vascular endothelial growth factor inhibitor (anti-VEGF) treatment has improved visual prognosis of nAMD, but continuous treatment may cause anxiety and stress, although increase in visual acuity (VA) may also have positive effects on patients' quality of life. The health care burden due to frequent treatment and monitoring is apparent, but the effect of anti-VEGF treatment on patients' quality of life is not fully understood. We evaluated the overall impact of nAMD and its treatment on newly diagnosed patients' health-related quality of life (HRQoL) in real-world setting. METHODS: The present prospective cohort study included newly diagnosed nAMD patients treated with anti-VEGF injections at Oulu University Hospital during 2019-2020. Data included parameters from comprehensive ophthalmic examination and fundus imaging, age at diagnosis, sex, comorbidities, visual acuity, and frequency of anti-VEGF injections. HRQoL was assessed by 15D questionnaire at diagnosis, 6 months, and 12 months. RESULTS: 95 nAMD patients were included. They were 78 ± 8 years old, 56 (59%) were female, and 74 (78%) had more than one comorbidity. The patients received 8 ± 3 anti-VEGF-injections. Visual acuity (VA) improved from 56 ± 18 to 61 ± 24 Early treatment diabetic retinopathy study (ETDRS) letters in 12 months. VA improved > 5 ETDRS letters in 45 (47%), remained stable in 30 (32%) and decreased > 5 letters in 17 (18%) eyes. The mean total 15D score reflecting overall HRQoL decreased from 0.850 ± 0.104 to 0.834 ± 0.103 in 12 months. Decreased HRQoL was associated with baseline best-corrected VA (BCVA) ≥ 70 ETDRS letters (p = 0.023) and more than one comorbidity (p = 0.034). HRQoL regarding visual function increased from 0.765 ± 0.194 to 0.789 ± 0.184 during the 12-month follow-up. CONCLUSIONS: In real world setting, HRQoL regarding visual function improved in anti-VEGF-treated nAMD patients during the first 12 months after the diagnosis and treatment initiation. Good baseline VA or several comorbidities were associated with decreased overall HRQoL during the follow-up. Despite the effectiveness of anti-VEGF treatment on visual function, several other aspects affecting elderly patients' everyday life should be considered when nAMD treatment is implemented.

Faricimab in Neovascular AMD Complicated by Pigment Epithelium Detachment: An AI-Assisted Evaluation of Early Morphological Changes.

INTRODUCTION: This study investigates the early temporal changes in pigment epithelial detachment (PED) morphology following treatment with faricimab in patients with neovascular age-related macular degeneration (nAMD). Utilizing an artificial intelligence (AI)-assisted approach, we provide a detailed quantification and characterization of the dynamics of these morphological changes. METHODS: A prospective observational study was conducted on 22 eyes from 22 treatment-naïve patients with nAMD-associated PED (presenting either type 1 or type 3 macular neovascularization). Participants were administered intravitreal faricimab (6 mg) at baseline and at days 30, 60, and 90. Comprehensive ophthalmic evaluations and spectral-domain optical coherence tomography (SD-OCT) imaging were conducted at baseline and at seven additional follow-up visits on days 1, 7, 14, 30, 60, 90, and 120. An AI-based automated segmentation algorithm was utilized to precisely quantify changes in PED volume, alongside intraretinal (IRF) and subretinal fluid (SRF) volumes, at each time point. RESULTS: Treatment with faricimab resulted in a significant reduction in mean PED volume, with an average decrease of 12% at day 1, 29% at day 7, 51% at day 14, 68% at day 30, 72% at day 60, 79% at day 90, and 84% at day 120 (p < 0.0001 for all time points). Similarly rapid and marked reductions were noted in both mean IRF (23.5% at day 1, 90.7% at day 14) and SRF (14.4% at day 1, 91.2% at day 14) volumes. The study also showed a statistically significant improvement in best-corrected visual acuity (BCVA) over the follow-up period, correlating with the reduction in PED volume. CONCLUSION: Faricimab demonstrates early and significant efficacy in improving PED architecture in patients with nAMD. The rapid morphological improvements observed in this study suggest faricimab may represent a valid therapeutic option for PEDs associated with nAMD.

Predict and Protect: Evaluating the Double-Layer Sign in Age-Related Macular Degeneration.

INTRODUCTION: Advanced age-related macular degeneration (AMD) is a major cause of vision loss. Therefore, there is interest in precursor lesions that may predict or prevent the onset of advanced AMD. One such lesion is a shallow separation of the retinal pigment epithelium (RPE) and Bruch's membrane (BM), which is described by various terms, including double-layer sign (DLS). METHODS: In this article, we aim to examine and clarify the different terms referring to shallow separation of the RPE and BM. We also review current evidence on the outcomes associated with DLS: firstly, whether DLS is predictive of exudative neovascular AMD; and secondly, whether DLS has potential protective properties against geographic atrophy. RESULTS: The range of terms used to describe a shallow separation of the RPE and BM reflects that DLS can present with different characteristics. While vascularised DLS appears to protect against atrophy but can progress to exudation, non-vascularised DLS is associated with an increased risk of atrophy. Optical coherence tomography (OCT) angiography (OCTA) is the principal method for identifying and differentiating various forms of DLS. If OCTA is unavailable or not practically possible, simplified classification of DLS as thick or thin, using OCT, enables the likelihood of vascularisation to be approximated. Research is ongoing to automate DLS detection by applying deep-learning algorithms to OCT scans. CONCLUSIONS: The term DLS remains applicable for describing shallow separation of the RPE and BM. Detection and classification of this feature provides valuable information regarding the risk of progression to advanced AMD. However, the appearance of DLS and its value in predicting AMD progression can vary between patients. With further research, individualised risks can be confirmed to inform appropriate treatment.

Age-related macular degeneration (AMD) is an eye disease that may develop in older people, usually those aged over 60 years. Early in the disease, people often do not show any symptoms, but as the disease progresses, vision loss may occur. The advanced forms of AMD are called neovascular AMD (also called "wet" AMD) and advanced dry AMD (called geographic atrophy; GA). It is important to identify features and signs on eye scans that can help to predict if someone with AMD will develop an advanced form of the disease because this will help doctors plan the most appropriate treatment. One such feature on eye scans is the double-layer sign (DLS). In this article, we summarise the different names used for DLS, and assess if having a DLS increases the likelihood of someone with early AMD developing wet AMD or GA. We conclude that how DLS looks varies between people, which leads to DLS being called by various names. Someone with early AMD and a DLS containing blood vessels may be more likely to develop wet AMD; whereas someone with early AMD and a DLS without blood vessels may be more likely to develop GA. Taking photos of the eye using optical coherence tomography angiography imaging is the main method of identifying DLS and confirming whether it contains blood vessels.

Publication trends of vascular endothelial growth factor (VEGF) and anti-VEGF treatment in neovascular age-related macular degeneration during 2001-2020: a 20-year bibliometric study.

PURPOSE: 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.

Cataract Surgery in nAMD Patients Receiving Intravitreal Aflibercept Injections.

Background: To evaluate functional and anatomical outcomesof cataract surgery in neovascular age-related macular neovascularization (nAMD) eyes receiving anti-vascular endothelial growth factor (anti-VEGF) intravitreal injections in modified pro re nata (PRN) regimen. Materials and Methods: Sixty eyes of 60 nAMD patients, including 41 women (68.3%) and 19 men (31.7%) in an average age of 77.35 ± 6.41 years, under treatment with intravitreal aflibercept injections in modified PRN regimen with no signs of macular neovascularization (MNV) activity during two consecutive visits were included in this prospective, observational study. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), as well as the number of anti-VEGF injections were monitored six months before and after phacoemulsification with intraocular lens (IOL) implantation. Further, the change of the abovementioned parameters was assessed during the six-month follow-up period for CRT and the number of injections, while the BCVA was monitored for 54 months. Results: BCVA measured on the first day after surgery (0.17 ± 0.19 logMAR) as well as in the six-month post-surgery (0.13 ± 0.16 logMAR) significantly improved compared to preop values (0.42 ± 0.20 logMAR). BCVA remains stable during the observational period. We found that both differences were statistically significant (p < 0.01). The mean CRT and the mean number of injections did not differ between the six-month pre- and post-surgical periods. Conclusions: We showed the beneficial effect of phacoemulsification in nAMD patients treated with anti-VEGF agents on visual outcomes in the short and long term. Cataract surgery in nAMD eyes treated with anti-VEGF injections does not increase the frequency of anti-VEGF injections and does not cause deterioration of the macular status.

Effect of brolucizumab and aflibercept on the maximum thickness of pigment epithelial detachments and sub-RPE fluid in HAWK and HARRIER.

OBJECTIVE: To compare the efficacy of brolucizumab and aflibercept treatment in reducing maximum thickness of pigment epithelial detachments (PED) and sub-retinal pigment epithelium (sub-RPE) fluid in patients with neovascular age-related macular degeneration (nAMD) in the HAWK and HARRIER studies. DESIGN: HAWK and HARRIER were 96-week, prospective, randomized, double-masked, controlled, multicenter studies SUBJECTS, PARTICIPANTS, AND/OR CONTROLS: 1,775 patients across 11 countries were included in the HAWK study and 1,048 patients across 29 countries were included in the HARRIER study. METHOD AND INTERVENTIONS: After three monthly loading doses, brolucizumab-treated eyes received injections every 12 weeks (q12w) or q8w if disease activity (DA) was detected. Aflibercept-treated eyes received fixed q8w dosing. MAIN OUTCOMES MEASURES: Maximum thickness of PED and sub-RPE fluid across the macula were assessed at baseline through Week 96 in the brolucizumab- and aflibercept-treated patients, and in the patient subgroups with DA at Week 16 (matched in terms of injection number and treatment interval). RESULTS: At Week 96, there were greater mean percentage reductions from baseline in maximum thickness of both PED and sub-RPE fluid in brolucizumab-treated patients versus aflibercept-treated patients (PED: 19.7% [n=336] vs 11.9% [n=335] in HAWK; 29.5% [n=364] vs 18.3% [n=361] in HARRIER. Sub-RPE fluid: 75.4% vs 57.3% in HAWK; 86.0% vs 76.3% in HARRIER). A similar trend in mean percentage reductions was observed in patients with DA at Week 16. CONCLUSIONS: This analysis shows that brolucizumab achieved greater reductions in PED and sub-RPE fluid thickness than aflibercept in HAWK and HARRIER.

Developing quantitative analysis program of blood flow velocity according to vessel diameter for neovascular age-related macular degeneration using OCTA-VISTA.

This study aimed to develop a quantitative analysis program of blood flow velocity by vessel diameter in neovascular age-related macular degeneration (nAMD) subjects using high-speed swept-source optical coherence tomography angiography. This retrospective, observational, cross-sectional study included 10 eyes of healthy volunteers and 4 eyes of patients with representative nAMD. Novel scan patterns and variable interscan time analysis were utilized to measure the flow parameter, a surrogate marker of blood flow velocity, by vessel diameter within different depths. Detected vessels at superficial and deep as well as outer retinal regions were categorized into three vessel diameters (major vessels (> 40 µm), medium vessels (20-40 µm), and capillaries (< 20 µm)). The flow parameter increased with enlarged vessel diameter in all participants at superficial and deep layer. All nAMD subjects, except for type 3 macular neovascularization (MNV), contained a structure dominated by medium vessels at outer retinal region. The mean flow parameter at outer retinal region was type 1 MNV (1.46 ms-1), type 1 + 2 MNV (0.98 ms-1), and polypoidal choroidal vasculopathy, including branching vascular networks (1.46 ms-1). This program provides the possibility to extract the blood flow information at different depths by vessel diameter types, which is considered to be useful tool for evaluating nAMD pathology and activity.

Combination of optical coherence tomography-derived shape and texture features are associated with development of sub-foveal geographic atrophy in dry AMD.

Geographic atrophy (GA) is an advanced form of dry age-related macular degeneration (AMD) that leads to progressive and irreversible vision loss. Identifying patients with greatest risk of GA progression is important for targeted utilization of emerging therapies. This study aimed to comprehensively evaluate the role of shape-based fractal dimension features ( F fd ) of sub-retinal pigment epithelium (sub-RPE) compartment and texture-based radiomics features ( F t ) of Ellipsoid Zone (EZ)-RPE and sub-RPE compartments for risk stratification for subfoveal GA (sfGA) progression. This was a retrospective study of 137 dry AMD subjects with a 5-year follow-up. Based on sfGA status at year 5, eyes were categorized as Progressors and Non-progressors. A total of 15 shape-based F fd of sub-RPE surface and 494 F t from each of sub-RPE and EZ-RPE compartments were extracted from baseline spectral domain-optical coherence tomography scans. The top nine features were identified from F fd and F t feature pool separately using minimum Redundancy maximum Relevance feature selection and used to train a Random Forest (RF) classifier independently using three-fold cross validation on the training set ( S t , N = 90) to distinguish between sfGA Progressors and Non-progressors. Combined F fd and F t was also evaluated in predicting risk of sfGA progression. The RF classifier yielded AUC of 0.85, 0.79 and 0.89 on independent test set ( S v , N = 47) using F fd , F t , and their combination, respectively. Using combined F fd and F t , the improvement in AUC was statistically significant on S v with p-values of 0.032 and 0.04 compared to using only F fd and only F t , respectively. Combined F fd and F t appears to identify high-risk patients. Our results show that FD and texture features could be potentially used for predicting risk of sfGA progression and future therapeutic response.

Role of inflammation in diabetic macular edema and neovascular age-related macular degeneration.

Diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD) are multifactorial disorders that affect the macula and cause significant vision loss. Although inflammation and neoangiogenesis are hallmarks of DME and nAMD, respectively, they share some biochemical mediators. While inflammation is a trigger for the processes that lead to the development of DME, in nAMD inflammation seems to be the consequence of retinal pigment epithelium and Bruch membrane alterations. These pathophysiologic differences may be the key issue that justifies the difference in treatment strategies. Vascular endothelial growth factor inhibitors have changed the treatment of both diseases, however, many patients with DME fail to achieve the established therapeutic goals. From a clinical perspective, targeting inflammatory pathways with intravitreal corticosteroids has been proven to be effective in patients with DME. On the contrary, the clinical relevance of addressing inflammation in patients with nAMD has not been proven yet. We explore the role and implication of inflammation in the development of nAMD and DME and its therapeutical relevance.

Mingjing granule inhibits the subretinal fibrovascular membrane of two-stage laser-induced neovascular age-related macular degeneration in rats.

Objective: 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. Methods: 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-ß); and the complement system-related factors C3a and C3aR in the retina were detected by immunofluorescence or qRT-PCR. Results: 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-ß, 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-ß, and C3a showed lower levels in rats treated with MG + anti-VEGF than the anti-VEGF agent alone. Conclusion: 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.

Optical coherence tomography-derived texture-based radiomics features identify eyes with intraocular inflammation in the HAWK clinical trial.

Background and objective: Intravitreal injection of anti-VEGF agents is the first-line treatment for patients with neovascular-age related macular degeneration (nAMD). One unique serious adverse event that may be associated with these agents is intraocular inflammation (IOI). The main purpose of this analysis was to evaluate the potential presence of texture-based radiomics features characterizing heterogeneity within the vitreous compartment of spectral domain optical coherence tomography (SD-OCT) images that may precede or develop in association with IOI and might serve as OCT biomarkers for IOI. Methods: This is a post-hoc analysis of a subset of cases (N = 67) involving IOI, endophthalmitis, and/or retinal vascular occlusion in the phase 3 HAWK trial. These were investigator determined diagnoses that were also confirmed by the safety review committee. Intraocular inflammation was any signs of inflammation within the eye, endophthalmitis was inflammation associated with presumed infection, and retinal vascular occlusions consisted of intraocular inflammation with concurrent vascular occlusions/vasculitis. Out of 67 eyes, 34 belonged to the Safety group with an IOI event and 33 were propensity-matched Controls. A total of 481 texture-based radiomics features were extracted from the vitreous compartment of the SD-OCT scans at pre-IOI time point (i.e., much earlier than the actual event). Most discriminating five features, selected by the Wilcoxon Rank Sum feature selection were evaluated using Random Forest (RF) classifier on the training set ( S t r , N = 47) to differentiate between the two patient groups. Classifier performance was subsequently validated on the independent test set ( S t , N = 20). Additionally, the classifier performance in discriminating the Control and Safety group was also validated on S t at the IOI event timepoint. Results: The RF classifier yielded area under the Receiver Operating Characteristics curve (AUC) of 0.76 and 0.81 on S t using texture-based radiomics features at pre-IOI and event time-point, respectively. Conclusions: In this analysis, the presence of a pre-IOI safety signal was detected in the form of textural heterogeneity within the vitreous compartment even prior to the actual event being identified by the investigator. This finding may help the clinicians to assess for underlying posterior inflammation.

Three-month outcomes of treatment with faricimab or aflibercept for neovascular age-related macular degeneration: a propensity score matching study in a Japanese population.

PURPOSE: This study aimed to compare the treatment outcomes of patients with neovascular age-related macular degeneration (nAMD) who initially received faricimab or aflibercept treatment using propensity score matching (PSM) to align patient backgrounds. METHODS: Patients with treatment-naïve nAMD who received either faricimab or aflibercept for three consecutive monthly injections as the loading phase were enrolled in this study. In the 1:1 PSM, sex, age, best-corrected visual acuity (BCVA), central macular thickness (CMT), central choroidal thickness (CCT), and AMD subtypes in the pre-treatment state were selected as covariates. We examined the BCVA, CMT, CCT, and remaining fluid at 1-, 2-, and 3-month after the first injection. RESULTS: After PSM, 43 eyes were included in the faricimab and aflibercept group each. Both groups showed significant improvements in BCVA, CMT, and CCT at 1-, 2-, and 3-month after the initial injection compared with baseline. Meanwhile, no significant differences were observed between the two groups at any time point regarding BCVA, CMT, and CCT. At 1-month, 18.6% of patients in the faricimab group and 41.9% in the aflibercept group demonstrated residual subretinal fluid or intraretinal fluid, with a significant difference between the groups (P = 0.03). CONCLUSION: The BCVA improved after three loading injections of both faricimab and aflibercept. Faricimab may provide a favorable early treatment response in reducing subretinal fluid in a Japanese cohort.

Correlations Between the Neutrophil-Lymphocyte Ratio, Platelet-Lymphocyte Ratio, and Serum Lipid Fractions With Neovascular Age-Related Macular Degeneration.

Introduction Age-related macular degeneration, a chronic and progressive disease, is one of the leading causes of vision loss globally among the elderly population. Multiple hypotheses have been proposed regarding its pathogenesis, including the presence of lipid metabolism alteration. Dysfunctional lipid handling within retinal pigment epithelial cells has been implicated in the accumulation of lipofuscin and subsequent induction of oxidative stress and inflammation, all contributing to retinal degeneration. The present study aims to comparatively analyze the serum lipid fraction distributions in patients with neovascular age-related macular degeneration (AMD) and controls. Materials and methods A retrospective study was carried out between January 2021 and December 2023 on 91 naïve patients with neovascular AMD and 90 controls admitted for routine cataract surgery. All subjects underwent a comprehensive ophthalmological exam, including ophthalmoscopy and optical coherence tomography (OCT) with central macular thickness (CMT) measurement. A complete blood count with differential and lipid fractions values was analyzed. The neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) were comparatively analyzed between the control group and the test group. Results The groups were comparable in terms of age (73.84 ±7.52 years for the neovascular AMD group vs 72.1±10.92 years in controls; p=0.8) and gender distribution (p=0.243). The mean NLR and PLR values were slightly higher in the AMD group but not statistically significant (p=0.51, p>0.99, respectively). Comparative analysis of lipid profile fractions showed significantly higher HDL-C values in the exudative AMD group compared to normal subjects (61.27±19.4 mg/dL vs 50.99±7.86 mg/dL, p=0.006). Also, the proportion of subjects with HDL-C>60 mg/dL was higher in the exudative AMD group (p=0.014). There were no significant differences in total cholesterol (189.77±53.39 mg/dL vs 190.43±37.84 mg/dL, p=0.681), LDL-C, and TG. Logistic regression analysis showed that serum HDL-C and HDL-C values >60 mg/dL are significantly associated factors with neovascular AMD. However, there is no statistical correlation between the values of these biochemical parameters and visual acuity or CMT in the neovascular AMD patient group. Conclusions There were no correlations between NLR and PLR with neovascular AMD in the study group. Higher HDL-C values exceeding 60 mg/dL were associated with neovascular age-related macular degeneration and could represent a possible therapeutic target in neovascular AMD.

AI-driven discovery of blood xenobiotic biomarkers in neovascular age-related macular degeneration using iterative random forests.

PURPOSE: To investigate the xenobiotic profiles of patients with neovascular age-related macular degeneration (nAMD) undergoing anti-vascular endothelial growth factor (anti-VEGF) intravitreal therapy (IVT) to identify biomarkers indicative of clinical phenotypes through advanced AI methodologies. METHODS: In this cross-sectional observational study, we analyzed 156 peripheral blood xenobiotic features in a cohort of 46 nAMD patients stratified by choroidal neovascularization (CNV) control under anti-VEGF IVT. We employed Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) for measurement and leveraged an AI-driven iterative Random Forests (iRF) approach for robust pattern recognition and feature selection, aligning molecular profiles with clinical phenotypes. RESULTS: AI-augmented iRF models effectively refined the metabolite spectrum by discarding non-predictive elements. Perfluorooctanesulfonate (PFOS) and Ethyl ß-glucopyranoside were identified as significant biomarkers through this process, associated with various clinically relevant phenotypes. Unlike single metabolite classes, drug metabolites were distinctly correlated with subretinal fluid presence. CONCLUSIONS: This study underscores the enhanced capability of AI, particularly iRF, in dissecting complex metabolomic data to elucidate the xenobiotic landscape of nAMD and environmental impact on the disease. The preliminary biomarkers discovered offer promising directions for personalized treatment strategies, although further validation in broader cohorts is essential for clinical application.

Risk of post-injection endophthalmitis peaks within the first three injections of anti-vascular endothelial growth factor therapy: A nationwide registry-based study.

PURPOSE: To report the incidence of post-injection endophthalmitis (PIE) and the cumulative risk associated with repeated injections of intravitreal anti-vascular endothelial growth factor (anti-VEGF). METHODS: We employed nationwide registries in Denmark to include all individuals aged ≥40 years who received at least one intravitreal anti-VEGF injection in 2007-2022. Our primary endpoint PIE was identified using specific diagnostic codes for endophthalmitis and procedure codes for vitreous biopsy within 10 days prior to and 120 days post-injection. Patients were stratified according to the underlying diagnoses for which they received the treatment. The relative risk (RR) for PIE was calculated between groups based on the number of injections received by the patients. RESULTS: We identified 60 825 patients who received intravitreal anti-VEGF treatment during study time, with a median age of 77.2 years and females constituting 58.1%. We identified 232 cases of PIE after 1 051 549 injections during follow-up, resulting in an incidence of 0.022% [95% CI 0.019%-0.025%]. Despite a linear growth in annual anti-VEGF use, the incidence remained stable at 0.020% [95% CI 0.017%-0.023%] from 2013 to 2022. Compared to patients receiving 1-3 injections, RR for patients receiving 4-20, 21-40, and >40 injections were 0.46 [95% CI 0.34-0.63], 0.32 [95% CI 0.21-0.50], and 0.54 [95% CI 0.36-0.81], respectively. Findings were similar across the different diagnoses. CONCLUSIONS: Based on 16 years of nationwide registry data, this study identified a low and stable incidence of PIE. Notably, the highest risk of endophthalmitis was within the first three anti-VEGF injections.

Gene Therapy for Non-Hereditary Retinal Disease: Age-Related Macular Degeneration, Diabetic Retinopathy, and Beyond.

Gene therapy holds promise as a transformative approach in the treatment landscape of age-related macular degeneration (AMD), diabetic retinopathy (DR), and diabetic macular edema (DME), aiming to address the challenges of frequent intravitreal anti-vascular endothelial growth factor (VEGF) injections. This manuscript reviews ongoing gene therapy clinical trials for these disorders, including ABBV-RGX-314, ixoberogene soroparvovec (ixo-vec), and 4D-150. ABBV-RGX-314 utilizes an adeno-associated virus (AAV) vector to deliver a transgene encoding a ranibizumab-like anti-VEGF antibody fragment, demonstrating promising results in Phase 1/2a and ongoing Phase 2b/3 trials. Ixo-vec employs an AAV2.7m8 capsid for intravitreal delivery of a transgene expressing aflibercept, showing encouraging outcomes in Phase 1 and ongoing Phase 2 trials. 4D-150 utilizes an evolved vector to express both aflibercept and a VEGF-C inhibitory RNAi, exhibiting positive interim results in Phase 1/2 studies. Other therapies reviewed include EXG102-031, FT-003, KH631, OLX10212, JNJ-1887, 4D-175, and OCU410. These therapies offer potential advantages of reduced treatment frequency and enhanced safety profiles, representing a paradigm shift in management towards durable and efficacious cellular-based biofactories. These advancements in gene therapy hold promise for improving outcomes in AMD and addressing the complex challenges of DME and DR, providing new avenues for the treatment of diabetic eye diseases.

Vascular Endothelial Growth Factor C and D Signaling Pathways as Potential Targets for the Treatment of Neovascular Age-Related Macular Degeneration: A Narrative Review.

The development of treatments targeting the vascular endothelial growth factor (VEGF) signaling pathways have traditionally been firstly investigated in oncology and then advanced into retinal disease indications. Members of the VEGF family of endogenous ligands and their respective receptors play a central role in vasculogenesis and angiogenesis during both development and physiological homeostasis. They can also play a pathogenic role in cancer and retinal diseases. Therapeutic approaches have mostly focused on targeting VEGF-A signaling; however, research has shown that VEGF-C and VEGF-D signaling pathways are also important to the disease pathogenesis of tumors and retinal diseases. This review highlights the important therapeutic advances and the remaining unmet need for improved therapies targeting additional mechanisms beyond VEGF-A. Additionally, it provides an overview of alternative VEGF-C and VEGF-D signaling involvement in both health and disease, highlighting their key contributions in the multifactorial pathophysiology of retinal disease including neovascular age-related macular degeneration (nAMD). Strategies for targeting VEGF-C/-D signaling pathways will also be reviewed, with an emphasis on agents currently being developed for the treatment of nAMD.