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Abstract Background Age-related macular degeneration (AMD) is a leading cause of visual impairment in the elderly. The neovascular (wet) form of AMD can be treated with intravitreal injections of different anti-vascular endothelial growth factor (VEGF) agents. Placental growth factor (PGF) is another member of the VEGF family of cytokines with pro-angiogenic and pro-inflammatory effects. Here, we aimed to compare single and combined inhibition of VEGF-A and PGF in the laser-induced mouse model of choroidal neovascularization (CNV) with a focus on the effects on retinal mononuclear phagocytes. Methods CNV was induced in C57BL/6J mice using a YAG-Laser. Immediately after laser damage antibodies against VEGF-A (aVEGF), anti-PGF (aPGF), aVEGF combined with aPGF, aflibercept, or IgG control were injected intravitreally in both eyes. Three and 7 days after laser damage, the vascular leakage was determined by fluorescence angiography. Lectin staining of retinal and RPE/choroidal flat mounts was used to monitor CNV. In situ mRNA co-expression of Iba1, VEGF and PGF were quantified using in situ hybridization. Retinal and RPE/choroidal protein levels of VEGF and PGF as well as the pro-inflammatory cytokines IL-6, IL1-beta, and TNF were determined by ELISA. Results Early (day 3) and intermediate (day 7) vascular leakage and CNV were significantly inhibited by PGF and VEGF-A co-inhibition, most effectively with the trap molecule aflibercept. While VEGF-A blockage alone had no effects, trapping PGF especially with aflibercept prevented the accumulation of reactive microglia and macrophages in laser lesions. The lesion-related mRNA expression and secretion of VEGF-A and PGF by mononuclear phagocytes were potently suppressed by PGF and partially by VEGF-A inhibition. Protein levels of IL-6 and IL1-beta were strongly reduced in all treatment groups. Conclusions Retinal inhibition of PGF in combination with VEGF-A prevents vascular leakage and CNV possibly via modulating their own expression in mononuclear phagocytes. PGF-related, optimized strategies to target inflammation-mediated angiogenesis may help to increase efficacy and reduce non-responders in the treatment of wet AMD patients.

Abstract Background Lipids are implicated in the pathogenesis of age-related macular degeneration (AMD). The relationship between systemic lipids and AMD has not been well characterized. The objective was to investigate the relationship between serum lipids and AMD in older adults using a lipidomic approach. Methods In a case-control study, 240 adults, aged ≥66 years, a third each having geographic atrophy, neovascular AMD, or no signs of AMD, were selected from a population-based sample of participants in the Age Gene/Environment Susceptibility-Reykjavik Study. The exposure was serum lipids and risk factors for AMD. The outcome was late AMD, assessed through fundus images taken through dilated pupils using a 45-degree digital camera and grading for neovascular AMD and geographic atrophy using the modified Wisconsin Age-Related Maculopathy Grading System. Results Of 177 serum lipid species measured, there were no significant differences in serum lipids between controls and those with geographic atrophy or neovascular AMD, respectively. Adults with neovascular AMD had higher total serum lysophosphatidylcholine (LPC) (P = 0.004) and serum LPC 18:0 (P = 0.0002) compared to those with geographic atrophy. Conclusion Late AMD was not characterized by alterations in systemic lipids compared with normal controls. These findings suggest that there may be differences in the LPC pathway between adults with neovascular AMD and geographic atrophy.

Objective: The purpose of this study is to determine if ziv-aflibercept is a safe and effective maintenance drug for nAMD.Study Design and Methods: This is a randomized, prospective, single-blinded trial. Inclusion criteria were active nAMD, prior anti-VEGF treatment, and BCVA ≤20/200. The treatment group received ziv-aflibercept. The control group continued their existing anti-VEGF regimen. The main outcome measures were BCVA, CFT, and safety.Results: Mean baseline BCVA was 1.58 ± 0.44 logMAR and 1.71 ± 0.39 logMAR in the control (n = 27) and treatment (n = 29) groups, respectively. After 24 months, the mean change in BCVA was 0.11 in the control group (equivalent to a loss of 5 ETDRS letters) and 0.01 logMAR in the treatment group (p = .48). Baseline CFT was 257 ± 33 μm and 247 ± 30 μm in the control and treatment groups, respectively, and after 24 months mean change in CFT was 26 μm and -5 μm (p = .24). There were no ocular or systemic adverse events during the study.Conclusion: Ziv-aflibercept is a safe and effective as a maintenance drug for patients with nAMD. It may represent a cost-effective alternative to aflibercept and second-line therapy for eye resistant bevacizumab or ranibizumab. [ABSTRACT FROM AUTHOR]

Neovascular age-related macular degeneration (nAMD) is the leading cause of blindness in aging populations. Here, we applied metabolomics to human sera of patients with nAMD during an active (exudative) phase of the pathology and found higher lactate levels and a shift in the lipoprotein profile (increased VLDL-LDL/HDL ratio). Similar metabolomics changes were detected in the sera of mice subjected to laser-induced choroidal neovascularization (CNV). In this experimental model, we provide evidence for two sites of lactate production: first, a local one in the injured eye, and second a systemic site associated with the recruitment of bone marrow–derived inflammatory cells. Mechanistically, lactate promotes the angiogenic response and M2-like macrophage accumulation in the eyes. The therapeutic potential of our findings is demonstrated by the pharmacological control of lactate levels through pyruvate dehydrogenase kinase (PDK) inhibition by dichloroacetic acid (DCA). Mice treated with DCA exhibited normalized lactate levels and lipoprotein profiles, and inhibited CNV formation. Collectively, our findings implicate the key role of the PDK/lactate axis in AMD pathogenesis and reveal that the regulation of PDK activity has potential therapeutic value in this ocular disease. The results indicate that the lipoprotein profile is a traceable pattern that is worth considering for patient follow-up. Key messages: Lactate and lipoprotein profile are associated with the active phase of AMD and CNV development. Lactate is a relevant and functional metabolite correlated with AMD progression. Modulating lactate through pyruvate dehydrogenase kinase led to a decrease of CNV progression. Pyruvate dehydrogenase kinase is a new therapeutic target for neovascular AMD. [ABSTRACT FROM AUTHOR]

Purpose: To estimate the impact of delayed care during the coronavirus disease 2019 (COVID-19) pandemic on the outcomes of patients with neovascular age-related macular degeneration (AMD). Methods: Consecutive patients with diagnosis of neovascular AMD were consecutively enrolled between March 9, 2020, and June 12, 2020, (during and immediately after the Italian COVID-19 quarantine). During the inclusion (or pandemic) visit (V0), patients received a complete ophthalmologic evaluation, including optical coherence tomography (OCT). Best-corrected visual acuity (BCVA) and OCT findings from the two preceding visits (V−1 and V−2) were compared with data at V0. Results: One-hundred patients (112 eyes) were enrolled in this study. The time interval between following visits was 110.7 ± 37.5 days within V0 and V−1 and 80.8 ± 39.7 days within V−1 and V−2, respectively (P < 0.0001). BCVA was statistically worse at the V0 visit as compared with the immediately preceding (V−1) visit (0.50 ± 0.43 LogMAR and 0.45 ± 0.38 LogMAR at the V0 and V−1 visits, respectively; P = 0.046). On structural OCT, 91 out of 112 (81.2%) neovascular AMD eyes displayed the evidence of exudative disease activity at the V0 visit, while 77 (68.7%) eyes exhibited signs of exudation at the V−1 visit (P = 0.022). No differences in terms of BCVA and OCT findings were detected between the V−1 and V−2 visits. In multiple regression analysis, the difference in BCVA between V0 and V−1 visits was significantly associated with the interval time within these two visits (P = 0.026). Conclusion: The COVID-19 pandemic-related postponement in patient care proved to be significantly associated with worse short-term outcomes in these patients. [ABSTRACT FROM AUTHOR]

We summarize the most important findings presented at the 2020 angiogenesis, exudation and degeneration symposium in five topic areas: (1) epidemiology of retinal vascular disease and macular degeneration; (2) dry AMD and geographic atrophy; (3) neovascular age-related macular degeneration; (4) drug delivery and devices and (5) diabetic retinopathy. [ABSTRACT FROM AUTHOR]

Abstract Background The aim of this study is to analyze mortality in patients treated with bevacizumab for wet AMD. Methods We conducted a retrospective case-control study between patients who received intravitreal injections of bevacizumab as the sole treatment for exudative AMD between September 2008 and October 2014 (n = 5385) and age and gender matched controls (n = 10,756). All individuals included in the study were reviewed for sociodemographic data and comorbidities. Survival analysis was performed using adjusted Cox regression, using relevant adjusted variables. Results During follow-up (maximum: 73 months), 1063 (19.7%) individuals after bevacizumab died compared with 1298 (12.1%) in the control group (P

Marion Schroeder,1 Lena Rung,2 Monica Lövestam-Adrian1 1Division of Ophthalmology, Department of Clinical Sciences Lund, Lund University, Skåne University Hospital, Lund, 2Department of Ophthalmology, Helsingborg Hospital, Helsingborg, Sweden Background: Although ranibizumab has been used for the treatment of wet age-related macular degeneration (AMD) since 2007, real-world studies still report undertreatment resulting in a less favorable visual outcome. In this study, two different time cohorts of patients treated with ranibizumab for wet AMD in routine care were analyzed to observe whether there was a change over time regarding visual outcome, injection frequency, and quality of life (QoL). Methods: We compared patients with treatment-naïve wet AMD in two observational follow-up cohorts 2007–2010 (n=50 patients) and 2009–2013 (n=26). After a loading dose of three intravitreal ranibizumab injections, the patients were treated under the pro re nata regimen. Visual acuity (VA) was examined by Early Treatment Diabetic Retinopathy Study (ETDRS) charts. The National Eye Institute Visual Functioning Questionnaire 25 was answered by patients at baseline and at 37±7 months (cohort 1) and at 45±4 months (cohort 2). Results: At baseline, the cohorts were homogeneous considering mean age (76±7 vs 75±8 years), mean VA (53±14 vs 52±15 ETDRS letters), and mean self-reported symptom duration (14±11 vs 13±11 weeks). Mean VA decreased in both cohorts over time, from 53±14 to 45±24 letters (P=0.011) and from 52±15 to 46±22 letters (P=0.175), respectively. The patients received a mean of 8±5 and 9±7 injections, respectively. The mean composite score change from baseline to follow-up decreased in cohort 1 from 64±21 to 59±25 scores (P=0.04) but increased in cohort 2 from 64±28 to 67±23 scores (P=0.38). Conclusion: We could not demonstrate any improvement in the number of injections in two different time cohorts of patients treated with ranibizumab for wet AMD in a Swedish county. Visual outcomes decreased after 3 years of follow-up, but QoL scores were divergent. Keywords: neovascular AMD, anti-VEGF, NEI VFQ-25, clinical care

Introduction: Despite consistent use of anti-vascular endothelial growth factor (anti-VEGF), prognosis of large, fovea-involving submacular hemorrhage (SMH) has remained guarded, particularly in patients with neovascular age-related macular degeneration. Areas covered: This review provides an update on management of SMH, with particular focus on the role of anti-VEGF therapy and surgical management of thick, large, and/or subfoveal SMH. A literature search and meta-analysis of studies published from January 2010 to February 2019 was performed to evaluate outcomes of eyes with SMH following management with either medical treatment (i.e. anti-VEGF monotherapy) or a combined surgical approach of pars plana vitrectomy, subretinal tPA with or without subretinal air, pneumatic displacement, and anti-VEGF. The surgical techniques are summarized, with emphasis on novel surgical techniques described in the past decade. Prognostic factors associated with, and potential indications for, choice of management approach were evaluated. Expert commentary: SMH represents a continuing treatment challenge. Anti-VEGF monotherapy is a reasonable approach in patients with small, thin, and localized hemorrhage. Combination vitrectomy, tPA, pneumatic displacement, and anti-VEGF may be effective in managing thick, large SMH in some cases. While no consensus exists on optimal treatment algorithm, choice of medical or surgical therapy should be tailored to each patient. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate ganglion cell complex (GCC) thickness in patients with neovascular age-related macular degeneration (AMD) who underwent aflibercept injection by using optical coherence tomography (OCT). Methods:The study included 28 eyes of 28 patients with neovascular AMD who had at least 6 months of follow-up following 3-dose anti-VEGF injection. Central macular thickness (CMT) and GCC thickness were evaluated with SD-OCT. Visual acuity, intraocular pressure, CMT, GCC thickness were recorded at the first month, 3 months and 6 months after the injection. Results:The mean age of the patients was 71.9 ± 7.2 (55-82) years. Best corrected visual acuity (logMAR) before injection was 0.90±0.24, at third month it was 0.32±0.22 idi (p=0.005). Before injection the mean CMT was 383.75 ± 28.6 µm, it was 267 ± 67 µm in the 6th month (p = 0.001). Mean GCC thickness was 93.20 µm before injection and 92.56 µm at 6 months. (P = 0.250) Conclusion: It was found that intravitreal Aflibercept injection did not have a significant effect on GCC thickness after 6 months of follow-up. Aflibercept is an effective, reliable treatment option in the treatment of neovascular AMD. [ABSTRACT FROM AUTHOR]

Aim To evaluate the monocyte/high-density lipoprotein (HDL) ratio (MHR) and neutrophil-to-lymphocyte ratio (NLR) as biomarkers of systemic inflammation in age-related macular degeneration (AMD). Materials and Methods: HDL, hematological profiles, erythrocyte sedimentation rates, C-reactive protein, MHRs, and NLRs were evaluated in 30 patients with neovascular AMD (Group 1), 30 with non-neovascular AMD (Group 2), and 30 controls (Group 3). Results: MHRs and NLRs were significantly higher in Group 1 than in Group 3 (p = 0.002 and p < 0.001, respectively) and were independent predictors of neovascular AMD in multivariate analysis (odds ratio = 1.231 and 3.332; 95% confidence interval = 1.035-1.466 and 1.385-8.019; p = 0.019 and 0.007, respectively). The areas under the receiver operating characteristics curve for MHR and NLR were 0.669 and 0.769. The sensitivity and specificity of MHRs and NLRs in predicting neovascular AMD were 47% and 97% versus 63% and 80%, respectively. Conclusions: By reflecting the balance of pro- and anti-inflammatory responses, the MHR can reliably indicate systemic inflammation in AMD. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate treatment outcome at 12 months in eyes with neovascular age‐related macular degeneration (nAMD) treated with antivascular endothelial growth factor (anti‐VEGF) injections according to either pro re nata (PRN)‐ or treat‐and‐extend (TE)‐regimen in one clinical setting in Sweden. Methods: Data were obtained retrospectively from the Swedish Macula Register, optical coherence tomography‐database and electronic patient charts. The study included 443 eyes; 223 PRN‐ and 220 TE‐treated eyes. Baseline (BL) characteristics and follow‐up data at 6 and 12 months were collected. Statistical regression analysis was performed to evaluate association between treatment strategy and visual outcome at 12 months. Results: Baseline (BL) characteristics were well balanced between cohorts. Visual acuity at 12 months was higher in TE‐cohort 66.5 (13.1) compared to PRN‐cohort 60.1 (17.6) (p = 0.000). Visual improvement at 12 months was +5.2 (11.8) and +1.2 (12.7) letters Early Treatment Diabetic Retinopathy Study (ETDRS) in TE‐ and PRN‐cohorts, respectively (p = 0.002). Number of administered injections at 12 months was 10.2 (2.1) and 6.3 (2.1) in the two cohorts (p = 0.000). Statistical analysis demonstrated a strong association between TE treatment strategy and improvement in visual acuity at 12 months. Conclusion: Eyes treated according to TE had better visual outcome at 12 months. The results indicate that treatment according to proactive TE‐regimen is superior to treatment according to PRN‐regimen in clinical routine care of nAMD. [ABSTRACT FROM AUTHOR]

Purpose: To determine the proportion of treatment-experienced eyes with exudative age-related macular degeneration successfully treated with every-4-week aflibercept that can be kept dry on fixed every-8-week aflibercept injections (maintenance). Methods: In this retrospective chart review, we evaluated our cohort of patients treated with a treatment paradigm for CNV in AMD. Initially, patients were treated with bevacizumab or ranibizumab and switched to every-4-week aflibercept when therapeutic responses were not durable or were suboptimal. Maintenance every-8-week therapy was initiated when the retina was completely dry on every-4-week aflibercept therapy. The primary outcome measure was recurrence of exudation on optical coherence tomography (OCT) during maintenance. Results: Thirty-six eyes of 31 consecutive patients with median age of 79 years (range, 65–89) were included. Maintenance was started after a median of 34 (range, 8–88) injections. Recurrence was observed in 20 eyes (55%). Of these, 11 eyes (31%) reactivated at 8 weeks. Median time to failure of maintenance schedule was 40 weeks by Kaplan-Meier analysis. Baseline demographic and anatomic characteristics were not associated with failure of maintenance schedule. Conclusion: In treatment-experienced eyes that respond completely to every-4-week aflibercept, maintenance therapy with every-8-week injections can only temporarily maintain anatomic success with the majority of eyes developing recurring activity. This regimen fails early in one third of eyes and has a median effective duration of 40 weeks. Aflibercept appears to be inadequate to maintain control of exudation in most eyes in at least half of eyes undergoing long-term therapy. [ABSTRACT FROM AUTHOR]

Purpose: The main objective of this study was to assess choroidal thickness (CT) changes during an exudative recurrence of age-related macular degeneration (AMD). Methods: A real-life prospective non-interventional 9-month study was conducted in two centers in consecutive patients with exudative AMD between November 2016 and July 2017. CT was measured manually in both eyes based on enhanced-depth imaging spectral-domain optical coherence tomography at different follow-up visits scheduled in the morning. Results: A total of 134 patients were included. Ninety-five patients presented at least one episode, defined by a follow-up visit under controlled condition (dry retina) followed by a visit for exudative recurrence. A total of 119 episodes were analyzed. The mean CT change in the treated eye was + 8.45 ± 13.52 μm (p < 0.001) and + 5.62 ± 14.77 μm (p = 0.009) respectively in the subfoveal area and nasal area. No significant change in CT was observed in the fellow eye. No significant association between CT changes and treatment, number of intravitreal injections, and blood pressure was observed. Conclusion: CT increased in case of exudative recurrence of neovascular AMD. The increase was mild but significant. Thus, CT could be used as a monitoring criterion, like the central retinal thickness, in AMD management. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is a chronic and progressive retinal degenerative disease of the macula that affects the elderly and causes impairment of central vision. AMD is a multifactorial disease that encompasses a complex interplay between aging, environmental risk factors, and genetic susceptibility. Chronic inflammation, lipid deposition, oxidative stress, and impaired extracellular matrix maintenance are strongly implicated in the pathogenesis of AMD. Advanced AMD can be classified into two types: dry and wet. Although dry AMD accounts for the majority of diagnosed cases, wet AMD is responsible for the majority of severe vision loss and usually occurs within weeks or months. Although neovascularization was the most common cause of severe vision loss, geographic atrophy, the most advanced form of dry AMD, can also cause significant vision loss. The medical treatment of neovascular AMD has seen significant progress due to the introduction of vascular endothelial growth factor (anti-VEGF) inhibitors, which have dramatically changed the prognosis of the disease. Research does not prove the need to change treatment methods in every patient, there may be occasions when patients with AMD show a more robust response to one anti-VEGF agent than another. Clinicians may consider alternatives to switching, such as increasing injection frequency, when managing a patient who appears to be unresponsive to therapy. In this regard, it may be helpful to have a patient return for evaluation 1 to 2 weeks after injection with repeat testing to assess whether there has been a reduction in subretinal fluid or retinal edema shortly after anti-VEGF injection. [ABSTRACT FROM AUTHOR]

Purpose: To assess mean change in visual acuity (VA) overall and stratified by baseline VA after 1 and 2 years' treatment with aflibercept in a real‐life setting. Methods: This was an observational cohort study using nationwide data from the Swedish Macula Register. Treatment‐naïve patient eyes with wet age‐related macular degeneration and prescribed aflibercept from January 2013 to December 2014 were followed for 1 year (2478 eyes) or 2 years (831 eyes) to assess VA. Eyes were grouped by baseline VA. Results: Mean number of injections in patients treated according to label (72%) versus patients treated not according to label was 8.0 ± 1.5 versus 4.4 ± 0.8 (p < 0.0001) at 1 year, and 12.5 ± 3.2 versus 7.3 ± 1.9 (p < 0.0001) at 2 years. Among all eyes, mean VA increased from 61.3 ± 13.4 Early Treatment Diabetic Retinopathy Study letters at baseline to 64.5 ± 15.6 at 1 year and 65.1 ± 15.1 letters at 2 years. At 2 years, eyes with good baseline vision (≥70 letters) lost a mean of 2.4 ± 11.3 to 72.3 letters, eyes with intermediate baseline VA (36–69 letters) gained 5.7 ± 14.1 to 62.7 letters, and eyes with poor baseline VA (≤35 letters) gained 13.2 ± 18.3 to 41.0 letters. Also at 2 years, 75% of treated eyes were stable or had improved VA. Among eyes with intermediate baseline VA, near vision was significantly better among those treated according to label versus not according to label at 3 (p = 0.019), 6 (p = 0.0002) and 12 months (p ≤ 0.0001). Conclusion: While gain in vision was especially pronounced in eyes with poor baseline VA, good baseline VA was important for best prognosis. [ABSTRACT FROM AUTHOR]

Purpose:: To evaluate intravitreal bevacizumab every 2 weeks (biweekly) in refractory neovascular age-related macular degeneration (nAMD).Study design:: Retrospective study.Methods:: A retrospective study of consecutive nAMD patients unresponsive to monthly intravitreal anti-vascular endothelial growth factor (VEGF) switched to 3-4 biweekly injections.Results:: Twenty-seven eyes of patients aged 82.08  ± 6.85 years were included. Prior to the 2-week interval bevacizumab injections, 74.1% (n=20) were treated with both bevacizumab and ranibizumab, 11.1% (3 eyes) also received aflibercept and 14.8% (4 eyes) had received prior treatment of monthly bevacizumab (average number of injections 21.5 ± 6.7). Best corrected visual acuity (BCVA) remained stable between baseline (logMAR 0.72± 0.60) and follow-up (0.76± 0.66) (p=0.41). Mean central macular thickness and macular volume did not change significantly between baseline and follow-up (p=0.35 and p=0.60, respectively). Six eyes (22.2%) showed morphologic anatomic improvements, while 19 eyes (70.4%) were stable and two eyes (7.4%) deteriorated from baseline. Subretinal fluid completely resolved in 3 of the eyes and improved in the other 3 eyes and in this group (22.2%) both central macular thickness (326.2 ± 101.4 versus 297.5 ± 97.2, p=0.002) and macular volume (8.69 ± 1.69 versus 8.22 ± 1.43, p=0.03) were significantly reduced. No adverse events were observed in any of the treated eyes.Conclusion:: This study demonstrates that biweekly bevacizumab injections are effective in nearly one-quarter of nAMD non-responders with no adverse events reported. Switching earlier, rather than later, to this low cost modality may be of benefit for a portion of non-responders to conventional treatment. [ABSTRACT FROM AUTHOR]

Purpose: To analyse the mortality associated with intravitreal injections of bevacizumab for age‐related macular degeneration (AMD) in patients previously diagnosed with stroke or transient ischaemic attack (TIA). Methods: We reviewed bevacizumab‐treated AMD patients with a diagnosis of stroke or TIA prior to their first bevacizumab injection (n = 948). Those patients, naïve to any anti‐vascular endothelial growth factor (anti‐VEGF) at the time of stroke/TIA, were then compared to age‐ and gender‐matched patients who had a stroke/TIA at the same time and had never been exposed to anti‐VEGF. Survival analysis was performed using adjusted Cox regression. The main outcome measure was survival. Adjusted variables were age, smoking, alcohol abuse, hypertension, diabetes mellitus, obesity, ischaemic heart disease, congestive heart failure and liver cancer. Results: Age and gender distribution of bevacizumab‐treated patients and controls were similar (mean age: 83.4 versus 83.7 years, p = 0.3; 51.7% males versus 52.5% males, p = 0.7). The adjusted mortality in patients who received bevacizumab within 3 months after stroke/TIA was significantly different than in patients non‐exposed to bevacizumab (OR = 6.92, 95%, CI 1.88–25.43, p < 0.01). Within 6 months after stroke/TIA, the difference in adjusted mortality showed a strong trend (OR = 2.00, 95%, CI 0.96–4.16, p = 0.064). Within 12 months, it was insignificant (OR = 1.30, 95%, CI 0.75–2.26, p = 0.348). Conclusion: We found increased mortality within three months after a cerebrovascular event in patients treated with bevacizumab for AMD compared to patients for whom there was no record of a prescription to any anti‐VEGF agent. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the effect of microRNA-16 on hypoxia-induced VEGF expression of ARPE-19 cells. Methods: ARPE-19 cells were cultivated under normoxia and hypoxia state. At 0 h, 12 h, 24 h, and 48 h after cultivation, the supernate of the culture medium was separated to test the VEGF secretion by ELISA, and the cells were purified to measure the expression of VEGF mRNA and microRNA-16 by qRT-PCR; microRNA-16 mimic was then transfected into ARPE-19 cells by the Hiperfect transfection reagent, a liposome transfection system. Scramble group and the non-transfected group were set as the controls. VEGF secretion and the level of VEGF mRNA were measured in these three groups. Results: The VEGF secretion of the hypoxia ARPE cells was significantly higher than the initial state (p < 0.01). Compared with the normoxia cells, the VEGF secretion of the hypoxia cell was significantly increased (p < 0.01), and the division of VEGF secretion between these two groups increased by time. VEGF mRNA of the hypoxia ARPE cell was significantly higher than the initial state (p < 0.01). Compared with the normoxia cells, VEGF mRNA of the hypoxia cells was significantly increased (p < 0.01), and the division of VEGF mRNA between these two groups increased by time. After cultivating under hypoxia, the expression of microRNA-16 in ARPE-19 cells decreased significantly compared with the normal group, and the division of these two groups augmented by time. MicroRNA-16 was successfully transfected into ARPE-19 cells by the Hiperfect transfection system. Twenty four hours and 48 h after the transfection, the VEGF secretion of the miR-16 transfected cell was decreased significantly (p < 0.01) compared with the scramble and the non-transfected group under hypoxia, while VEGF mRNA level had no significant difference among these three groups. Conclusions: Hypoxia can increase the expression of VEGF mRNA and the secretion of VEGF protein of ARPE-19 cells. At the same time, microRNA-16 expression can be down-regulated by hypoxia. Transfection of microRNA-16 exogenously can down-regulate the VEGF protein secretion but cannot affect the expression of VEGF mRNA. [ABSTRACT FROM AUTHOR]

Background: Intraocular injections of antivascular endothelial growth factor (VEGF) agents are currently the main therapy in age-related macular degeneration (AMD). The safety of bevacizumab, an anti-VEGF compound frequently delivered off label, is debated, particularly for high-group risks. We aim to analyze the mortality associated with intravitreal injections of bevacizumab for AMD in patients previously diagnosed with acute myocardial infarct (MI).Methods: In a national database, we identified bevacizumab-treated AMD patients with a diagnosis of MI prior to their first bevacizumab injection, delivered between September 2008 and October 2014 (n = 2100). We then generated sub-groups of patients treated within 3 months (n = 11), 6 months (n = 24), 12 months (n = 52), and 24 months (n = 124) after MI. Those patients were compared to age- and gender-matched members that had a MI at the same time and had never been exposed to anti-VEGF. Survival analysis was performed using propensity score-adjusted Cox regression.Results: Bevacizumab-treated patients were slightly and insignificantly older than controls (mean age 83.25 vs 83.19 year, P = .75). Gender distribution was similar. In a Cox regression adjusted with propensity score, the following differences in mortality were found: within 3 months between MI and initiation of bevacizumab treatment, OR = 6.22 (95% C.I 1.08-35.97, P < .05); within 6 months, OR = 2.37 (95% C.I 0.93-6.02, P = .071); within 12 months, OR = 3.00 (95% C.I 1.44-6.28, P < .01); within 24 months after MI, OR = 2.24 (95% C.I 1.35-3.70, P < .01); and MI any time prior to first bevacizumab injection, OR = 1.71 (95% C.I 1.53-1.92, P < .001).Conclusions: We report increased mortality associated with the use of intravitreal bevacizumab in AMD patients after MI, compared to age- and gender-matched post-MI patients with no exposure to any anti-VEGF agent. Caution should be taken while offering bevacizumab to AMD patients after MI. [ABSTRACT FROM AUTHOR]

Neovascular age-related macular degeneration (AMD) is a leading cause of vision loss worldwide. Although intravitreal injection of anti-VEGF antibodies and VEGF Trap have significant clinical benefits, the complications of intravitreal injection, drug resistance and patient compliance still need to be concerned. In this study, the effects of an orally administered multi-targeted tyrosine kinase inhibitor (Lenvatinib, E7080) were evaluated in vitro and in vivo on neovascular AMD mouse model. The results showed that E7080 effectively inhibited the proliferation, migration and tubule formation of human choroidal microvascular endothelial cells (HCMECs), and suppressed the angiogenesis of zebrafish subintestinal vessels without causing malformation. The anti-angiogenic effect of E7080 on the laser-induced choroidal neovascularization (CNV) mouse model by oral administration of 10 mg/kg/day was observed. The fluorescein angiography showed CNV leakage area in treatment group vs control group was 3.407 ± 0.2939 vs 5.202 ± 0.9001 ( P  = .0133) at day 7th post laser-induced CNV, 1.138 ± 0.4334 vs 3.122 ± 0.3466 ( P  = .0064) at day 14th, 1.401 ± 0.6577 vs 2.781 ± 0.9815 ( P  = .00262) at day 21th respectively. Moreover, pharmacokinetics analysis in rat retina showed that E7080 rapidly penetrated the blood-retina barrier to retina through oral administration. The T 1/2 in retina was 3.81 ± 0.77 h, the T max was 4.60 ± 0.73 h, the AUC 0-∞ was 110448.51 ± 18532.51 h*ng/g after a single dose administration analyzed by liquid chromatography-tandem mass spectrometry (LC/MS/MS). In conclusion, our study suggested that orally administered E7080 can be a novel therapeutic strategy for neovascular AMD. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) was first described in 1885 by Otto Haab as a disease in patients above 50 years of age with progressive retinal pigment epithelial and atrophic degenerations of the macula reducing the central visual acuity. AMD is a neurodegenerative disease and is now the most common cause of registrable blindness in the western world. The prevalence of the disease is given as 10% in 65-75-year-old population and as 25% after 75 of age. AMD is a multi-faceted and complex condition. Although different forms of AMD share some common underlying pathological features and causes, there are unique mechanisms for each form. Effective therapies should be derived from in-depth knowledge about each subtype of AMD and should be tailored to address the specific needs in each disease subtype. (Turk J Ophthalmol 2014; 44: 476-80)

Purpose To present Swedish Macula Register (SMR) data regarding treatment of neovascular age-related macular degeneration (AMD) in clinical practice since 2008. Methods A retrospective register-based study was conducted. Evaluation of baseline demographics, visual outcome and number of injections during this period is presented. Results Mean age at diagnosis was 79 ± (SD) 8 years; 65% were female. The proportion of patients with <2 months' duration of symptoms increased from 26% in 2008 to 41% in 2014 (p = 0.001). Mean visual acuity (VA) at baseline increased from 54.3 ± 15.0 early treatment diabetic retinopathy study (ETDRS) letters in 2008 to 57.8 ± 15.6 letters in 2014 (CI95 2.6; 4.3; p < 0.001). Mean VA after 1 year of treatment increased from 57.8 ± 17.7 ETDRS letters for patients who started the treatment in 2008 to 62.8 ± 16.4 ETDRS letters in patients starting treatment in 2014 (CI95 2.67; 4.64; p < 0.001). During all study years, the proportion of patients with an improvement in VA of between 5 and 15 letters was around 30%, while 14% had VA improvement of more than 15 letters. The mean number of injections during the first treatment year increased from 4.3 ± 1.9 in 2008 to 5.9 ± 2.9 in 2014 (CI95 1.40; 1.67; p < 0.001). Seven-year follow-up of 322 eyes showed a mean change of −1 letters from baseline, with a mean of 21 injections for the entire period. Conclusion The duration of symptoms before treatment decreased, while VA at baseline and after 1 year of treatment increased over the years and so did the number of injections. Long-term follow-up demonstrated stable VA. [ABSTRACT FROM AUTHOR]

Purpose:To evaluate the combined use of optical coherence tomography and angiography (OCT-A) for imaging choroidal neovascularization (CNV) secondary to neovascular age-related macular degeneration (nAMD). Materials and Methods:This prospective observational study was conducted from May 2015 to April 2017. Included in the study were 54 patients (n = 63 eyes), all of whom had CNV secondary to nAMD and all of whom had been examined by OCT-A. Angioscans (3x3 and 6 × 6) and conventional B-scan OCT scans were obtained for all patients at baseline and at various times during the 24-month follow-up period. For diagnostic confirmation, conventional imaging methods fluorescein angiography (FA) and indocyanine green angiography (ICGA) were performed at baseline. A total of 13 patients (n = 15 eyes) underwent serial imaging during 34 follow-up visits. The main outcomes included (i) determination of OCT-A sensitivity for the detection of CNV (classic and occult) and (ii) the correlation between B-scan OCT and OCT-A vis-à-vis consecutive follow-up changes. Results:At baseline, the detection rate (i.e., overall sensitivity) of OCT-A for detecting CNV was 64.4% (75.7 and 48.0% for classic and occult CNV, respectively), independent of prior treatment status. In terms of quality, 6 × 6 angioscans were superior to 3 × 3. Moreover, specific CNV morphologic patterns by B-scan OCT did not correlate with lesion composition. Correspondence between OCT-A and B-scan OCT was observed in only 53% of the cases. Conclusions:OCT-A may prove to be a valuable adjunctive diagnostic tool for the interpretation of CNV, as it not only reduces the need for invasive angiographic procedures but also facilitates the follow-up process. [ABSTRACT FROM AUTHOR]

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Background: The aim of this study is to analyze mortality in patients treated with bevacizumab for wet AMD.Methods: We conducted a retrospective case-control study between patients who received intravitreal injections of bevacizumab as the sole treatment for exudative AMD between September 2008 and October 2014 (n = 5385) and age and gender matched controls (n = 10,756). All individuals included in the study were reviewed for sociodemographic data and comorbidities. Survival analysis was performed using adjusted Cox regression, using relevant adjusted variables.Results: During follow-up (maximum: 73 months), 1063 (19.7%) individuals after bevacizumab died compared with 1298 (12.1%) in the control group (P < .001). After adjusted Cox survival regression, mortality differed significantly between the groups, Odds ratio = 1.69, (95% C.I. 1.54-1.84), P < .001.Conclusions: We found an increased long-term mortality in individuals with wet AMD treated with bevacizumab compared to a same age and gender group without wet AMD. [ABSTRACT FROM AUTHOR]

Introduction: The purpose of this project was to evaluate the role of MR antagonists as an adjunct in patients with neovascular age-related macular degeneration (AMD) who have chronic subretinal fluid. Methods: Inclusion criteria were patients with a diagnosis of neovascular AMD, who had completed at least six anti-VEGF injections, and had persistent subretinal fluid (SRF) on optical coherence tomography (OCT). Treatment with oral eplerenone was initiated and dose titrated according to protocol. Results: 23 patients were included in the study (mean age = 54.6, 52.2% female, 47.8% male). 13 of the 23 patients had predominantly chronic subretinal fluid without large PEDs. In this subgroup, mean initial central macular thickness (CMT) prior to starting oral eplerenone was 305.3 μm, and mean injection interval was 40.25 days. Mean final CMT after at least 3 months of adjunctive eplerenone treatment was 240.6 μm and mean injection interval with adjunctive treatment was 54.61 days. Mean extension of the injection interval after commencing oral eplerenone was 14.36 days. Conclusions: These findings suggest oral MR antagonists may have a role as an adjunctive treatment in neovascular AMD, and may be particularly useful in dehydration of the subretinal space in the setting of chronic subretinal fluid. Further research is needed in randomized controlled trials to elucidate the precise role of oral MR antagonists in neovascular AMD. [ABSTRACT FROM AUTHOR]

Neovascular age-related macular degeneration (nAMD) is one of the leading causes of blindness among the aging population. The current treatment options for nAMD include intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF). However, standardized frequent administration of anti-VEGF injections only improves vision in approximately 30–40% of nAMD patients. Current therapies targeting nAMD pose a significant risk of retinal fibrosis and geographic atrophy (GA) development in nAMD patients. A need exists to develop new therapies to treat nAMD with effective and long-term anti-angiogenic effects. Recent research on nAMD has identified novel therapeutic targets and angiogenic signaling mechanisms involved in its pathogenesis. For example, tissue factor, human intravenous immune globulin, interferon-β signaling, cyclooxygenase-2 (COX-2) and cytochrome P450 monooxygenase lipid metabolites have been identified as key players in the development of angiogenesis in AMD disease models. Furthermore, novel therapies such as NACHT, LRR and PYD domains containing protein 3 (NLRP3) inflammasome inhibition, inhibitors of integrins and tissue factor are currently being tested at the level of clinical trials to treat nAMD. The aim of this review is to discuss the scope for alternative therapies proposed as anti-VEGFs for the treatment of nAMD.

Background: Traditionally, visual acuity gain and central retinal thickness have been used to measure outcomes when investigating the efficacy of vascular endothelial growth factor (VEGF) inhibitors for patients with neovascular age-related macular degeneration (nARMD). However, localization of retinal fluid may offer additional prognostic value for treatment. The primary aim of this retrospective clinical audit was to investigate whether the presence and location of subretinal fluid has an effect on the visual outcomes of treatment naïve patients with nARMD treated in the real-world setting with VEGF inhibitors. Secondary aims included investigation of change to visual and anatomical outcomes and investigation of the dosing schedule., Methods: Retrospective observational study of patients attending one suburban and one regional ophthalmology clinic requiring treatment with VEGF inhibitors for nARMD using single-user non-identifiable data from the Fight Retinal Blindness! Registry from 2014 to 2020. Visual acuity (VA) and central subfield thickness (CST) were recorded at baseline, 3, 6, 12 and 24 months., Results: Forty-nine eyes of 42 treatment naïve patients were included for analysis (aged 62-89 years). Almost half (49%) presented with a combination of intra- and subretinal fluid at baseline. Intraretinal fluid was present in 75% of eyes but decreased to 22.7% of eyes by 24 months. VA at baseline was 55 letters, and this improved by 6 letters. The change in VA from baseline to 3, 6 and 12 months was statistically significant (p < .05). The mean change in CST from baseline to 3 months was significant (-76 µm). This change was also observed at the other milestones (p < .001)., Conclusions: The findings of this study suggest that allowing some subretinal fluid to remain will not affect treatment outcomes.

Objective: To predict 2-year visual acuity (VA) responses to anti-VEGF therapy, using early morphologic and functional responses in patients with neovascular age-related macular degeneration (nAMD)., Design: Cohort within a randomized clinical trial., Participants: A total of 1185 participants with untreated active nAMD and best-corrected visual acuity (BCVA) 20/25 to 20/320 at baseline., Methods: Secondary analysis of data from participants randomized to either ranibizumab or bevacizumab and to 1 of 3 dosing regimens. Associations of 2-year BCVA responses with baseline morphologic and functional characteristics and their change from baseline at 3 months were assessed, using univariable and multivariable linear regression models for BCVA change and logistic regression models for ≥ 3-line BCVA gain from baseline. The performance of predictions for 2-year BCVA outcomes using these characteristics was assessed using R 2 for BCVA change and area under the receiver operating characteristic curve (AUC) for ≥ 3-line BCVA gain., Main Outcome Measures: Best-corrected visual acuity change and ≥ 3-line gain from baseline at year 2., Results: In multivariable analyses that included previously reported significant baseline predictors (baseline BCVA, baseline macular atrophy, baseline retinal pigment epithelium elevation [RPEE], and maximum width and early BCVA change from baseline at 3 months), new RPEE occurrence at 3 months was significantly associated with more BCVA gain at 2 years (10.2 letters vs. 3.5 letters for RPEE resolved, P < 0.001), and none of the other morphologic responses at 3 months were significantly associated with BCVA responses at 2 years. These significant predictors moderately predicted 2-year BCVA gain with an R 2  = 0.36. Baseline BCVA and ≥ 3-line BCVA gain at 3 months predicted 2-year ≥ 3-line gain with AUC 0.83 (95% confidence interval, 0.81-0.86)., Conclusions: Most structural responses on OCT at 3 months were not independently predictive of the 2-year BCVA responses, which were associated with baseline factors and the 3-month BCVA response to anti-VEGF therapy. A combination of baseline predictors, early BCVA, and morphologic responses at 3 months only moderately predicted the long-term BCVA responses. Future research is needed to better understand the factors contributing to the variation in long-term vision outcomes with anti-VEGF therapy., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

The purpose of this study was to investigate the changes in subfoveal choroidal thickness (SFCT) after intravitreal injection of bevacizumab (IVB) for neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME). This retrospective, consecutive, interventional case series study included 43 eyes [21 affected eyes with neovascular AMD (AMD group) and 22 affected eyes with DME (DME group)] which were treated with 1.25 mg/0.5 ml IVB and 43 untreated fellow eyes of 43 patients. SFCT was measured in all 86 eyes at baseline before IVB injection and at day 1, week 1, and month 1 after injection by use of enhanced depth imaging optical coherence tomography (EDI OCT). Central foveal thickness (CFT) and best-corrected visual acuity were analyzed at baseline and during follow-up visits. Main outcome measure was change in SFCT in 1 month after treatment. All 43 eyes treated with IVB showed a significant reduction in SFCT. Mean SFCT in treated eyes decreased from 237.1 ± 75.3 µm at baseline to 214.0 ± 65.7 µm at day 1, 205.4 ± 59.7 at week 1, and 222.7 ± 73.3 at month 1, whereas SFCT in fellow eyes changed from 228.4 ± 63.6 at baseline to 224.5 ± 68.5 at day 1, 220.4 ± 72.1 at week 1, and 226.9 ± 74.0 at month 1. SFCT demonstrated a similar trend toward decrease in both groups. CFT decreased significantly and visual acuity improved significantly. SFCT decreased significantly in AMD and DME eyes following injection. The decreasing effect of bevacizumab on choroidal thickness was highest at first week and continued to the end of first month after injection. [ABSTRACT FROM AUTHOR]

Purpose To examine the outcome after cataract surgery in patients with neovascular age-related macular degeneration (AMD) treated with intravitreal anti-vascular endothelial growth factor (VEGF) injections in routine clinical practice. Methods We extracted information about patients recorded in electronic databases managing anti-VEGF injections and cataract surgery. We compared Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity and frequency of anti-VEGF injections before and after cataract surgery. Results We identified 89 eyes from 89 patients who had cataract surgery after being treated with a median of 10 (range 3-36) anti-VEGF injections for neovascular AMD. Visual acuity improved by a mean of 7.1 [95% confidence interval (CI) 4.6-9.6] ETDRS letters in the first 6 months after cataract surgery. The need of anti-VEGF injections did not change after cataract surgery with an average of 1.5 in the 6 months before surgery versus 1.7 in the 6 months after surgery (p = 0.25). Visual improvement was greater in patients when the time from latest injection to cataract surgery was lower. Conclusions Cataract surgery improves vision in patients undergoing treatment for neovascular AMD. Cataract surgery was not associated with an increased need for anti-VEGF treatment and patients who were in active anti-VEGF treatment had better visual outcomes than patients who had cataract surgery after long injection-free periods. [ABSTRACT FROM AUTHOR]

Background: With increasing experience using anti-VEGF therapy for the treatment of neovascular age-related macular degeneration (nAMD), ophthalmologists have shifted away from a "one size fits all" to an "individualised" approach based on disease activity with the aim of achieving a fluid-free retina. The FLUID study investigates the non-inferiority of a Treat and Extend (T&E) protocol of 0.5 mg ranibizumab, which allows treatment extension in the presence of incomplete resolution of sub-retinal fluid (SRF) ≤200 μm at the foveal centre relative to a T&E protocol that requires complete resolution of all retinal fluid (i.e., both SRF and intra-retinal fluid [IRF]) in patients with nAMD.Methods/design: This 24 month, randomised, phase IV trial has completed recruitment of treatment-naïve patients randomised 1:1 to ranibizumab "intensive" treatment (complete resolution of IRF and SRF) or ranibizumab "relaxed" treatment (resolution of IRF or >200 μm SRF only at foveal centre). Patients in both arms follow a T&E regimen where extension decisions are based upon assessment of lesion activity: loss of ≥5 letters of visual acuity, new haemorrhage, presence of IRF and SRF on an optical coherence tomography (OCT) scan. The determination of SRF is conducted at a reading centre while the assessment of IRF is physician-determined. The primary endpoint is the mean change in best-corrected visual acuity (BCVA) from baseline to 24 months. Secondary endpoints include the mean change in central retinal thickness (CRT) from baseline to 12 and 24 months, the number of ranibizumab injections administered at 12 and 24 months, and the pharmacogenomic assessment of AMD Gene Consortium-identified single-nucleotide polymorphisms (SNPs) and their association with treatment response. Three hundred and forty seven (347) patients have been recruited by 16 Australian sites within approximately 16 months. A protocol to adjudicate on SRF has been established by the central reading centre and is demonstrating good concordance with investigator assessment.Discussion: This study will provide important insights into retreatment criteria for managing nAMD using a T&E regimen. The current paper describes the clinical rationale for using a less intensive treatment approach using ranibizumab and details of the treatment protocol.Trial Registration: Trial Registration Number: NCT01972789. Date of registration: 24th October 2013. [ABSTRACT FROM AUTHOR]

Purpose: To determine the effect of ranibizumab on visual acuity (VA) following a 3-year treatment period for patients diagnosed with wet age-related macular degeneration. To establish whether baseline VA and injection frequency influence visual outcomes. Patients and methods: Retrospective review of 70 patients (76 eyes) treated with 0.5 mg intravitreal ranibizumab for 3 consecutive months, and pro re nata thereafter (three + pro re nata protocol), over a 3-year period. VA was measured using Early Treatment Diabetic Retinopathy Study (ETDRS) charts at baseline, 12, 24, and 36 months. The number of injections administered at the end of years 1, 2, and 3 were also recorded. Eyes were stratified according to baseline VA, as well as the number of injections administered at the end of year 1. Linear regression analysis determined the relationship between VA and both baseline VA and injection frequency. P<0.05 was considered statistically significant. Results: At 36 months, VA improved by a mean of 5.3 ETDRS letters (P=0.002), with 29% of eyes (n=22) demonstrating a clinically significant improvement in VA (gain of ≥15 ETDRS letters). Improvements in VA from baseline to 36 months were inversely proportional to the baseline VA (R=0.414, P=<0.001). A positive correlation was observed between injection frequency and change in VA from baseline to 36 months (R=0.244, P=0.036). Conclusion: Mean improvement in VA is inversely proportional to baseline VA, and directly proportional to injection frequency. [ABSTRACT FROM AUTHOR]

Roughly ten years ago the FDA approved most of the presently used anti-VEGF drugs for the treatment of neovascular AMD and other eye pathologies characterized by ocular neoangiogenesis. However, the recent findings on the physiologic activities of VEGF isoforms impose to reconsider the inhibitory effects of pan-VEGF antagonists and the concept that to face pathological alterations at ocular level is possible only through the full block of all VEGF isoforms. In fact, although pan-VEGF agents rapidly and effectively contrast ocular neovascularization, vascular leakage, and other pathological changes, in the long-term the inhibition of all VEGF isoforms likely may result in the loss of the physiologic effects exerted by VEGF 121 and the anti-angiogenic VEGF 165 b. Notably, selective inhibitors of VEGF 165 a, such as pegaptanib, spare these targets. Moreover, preclinical and clinical evidence suggests that also systemic side effects, secondary to intraocular treatment with non-selective anti-VEGF drugs, may be reinterpreted in light of these recent findings, which may be useful to clinicians for the choice of the most appropriate anti-VEGF agent. Another aspect that should be considered is the involvement of VEGF-independent pathways in ocular neovascularization, therefore a combined therapy can represent a more effective pharmacological approach that might help also to counteract tachyphylaxis, an important issue in anti-VEGF treatment. This complex picture and the recent findings on current anti-VEGF drugs should be therefore taken into account to guide the development of novel agents targeting VEGF and/or other key factors involved in the pathogenesis of neovascular ocular diseases along the signaling pathways stimulated by the various isoforms. Accordingly, this review also reports on novel pharmacological molecules targeting VEGF at ocular level and currently under development, with a special attention to oligonucleotide-based interventions. [ABSTRACT FROM AUTHOR]

Purpose/Aim: To compare the plasma levels of homocysteine and asymmetrical dimethyl-l-arginine (ADMA) and the degree of whole blood DNA methylation in patients with early and neovascular age-related macular degeneration (AMD) and in controls without maculopathy of any sort. Materials and methods: This observational case–control pilot study included 39 early AMD patients, 27 neovascular AMD patients and 132 sex- and age-matched controls without maculopathy. Plasma homocysteine and ADMA concentrations and the degree of whole blood DNA methylation were measured. Quantitative variables were compared by Student’st-test or Mann–Whitney test. Logistic regression models were used to investigate the significance of the association between early or wet AMD and some variables. Results: There were no significant differences in mean plasma homocysteine and ADMA concentrations and in the degree of whole blood DNA methylation between patients with early or neovascular AMD and their controls. Similarly, logistic regression analysis disclosed that plasma homocysteine and ADMA levels were not associated with an increased risk for early or neovascular AMD. Conclusions: We failed to demonstrate an association between early or neovascular AMD and increased plasma homocysteine and/or ADMA. Results also suggest that the degree of whole blood DNA methylation is not a marker of AMD. [ABSTRACT FROM PUBLISHER]

Age-related macular degeneration (AMD) is a progressive disease of the central retina and the main cause of legal blindness in industrialized countries. Risk to develop the disease is conferred by both individual as well as genetic factors with the latter being increasingly deciphered over the last decade. Therapeutically, striking advances have been made for the treatment of the neovascular form of late stage AMD while for the late stage atrophic form of the disease, which accounts for almost half of the visually impaired, there is currently no effective therapy on the market. This review highlights our current knowledge on the genetic architecture of early and late stage AMD and explores its potential for the discovery of novel, target-guided treatment options. We reflect on current clinical and experimental therapies for all forms of AMD and specifically note a persisting lack of efficacy for treatment in atrophic AMD. We further explore the current insight in AMD-associated genes and pathways and critically question whether this knowledge is suited to design novel treatment options. Specifically, we point out that known genetic factors associated with AMD govern the risk to develop disease and thus may not play a role in its severity or progression. Treatments based on such knowledge appear appropriate rather for prevention than treatment of manifest disease. As a consequence, future research in AMD needs to be greatly focused on approaches relevant to the patients and their medical needs. [ABSTRACT FROM AUTHOR]

Contemporary management of neovascular age-related macular degeneration (AMD) has evolved significantly over the last few years. The goal of treatment is shifting from merely salvaging vision to maintaining a high quality of life. There have been significant breakthroughs in the identification of viable drug targets and gene therapies. Imaging tools with near-histological precision have enhanced our knowledge about pathophysiological mechanisms that play a role in vision loss due to AMD. Visual, social, and vocational rehabilitation are all important treatment goals. In this review, evidence from landmark clinical trials is summarized to elucidate the optimum modern-day management of neovascular AMD. Therapeutic strategies currently under development, such as gene therapy and personalized medicine, are also described. [ABSTRACT FROM AUTHOR]

Purpose The HELIOS (Health Economics with Lucentis in Observational Settings) study was designed on request of the Dutch Health Authority for an observational study to assess the effectiveness and safety of ranibizumab for neovascular age-related macular degeneration (wet AMD) in daily practice. Methods The HELIOS study was a 2-year prospective, observational, open-label, multicentre study involving 14 sites. Patients with wet AMD were enrolled and observed for a period of 24 months. The data were collected at baseline and at the visits closest around the time-points 3, 6, 12, 18 and 24 months after inclusion. Results Treatment with ranibizumab resulted in prevention of vision loss. The mean ETDRS score increased from 45.1 letters at baseline to 48.5 letters at 24 months. This was achieved with a mean of 7.8 injections over 24 months. Stabilization of visual acuity was also reflected by the scores on the quality of life EQ-5D questionnaire, which did not significantly change over the study period. The more subjective EQ- VAS questionnaire showed an overall improvement. The VFQ-25 questionnaire was also mostly stable over time. After 24 months, 32.2% of the patients gained ≥1 letter and 17.1% gained >15 letters. Patients completing the loading phase were better responders, as demonstrated by increased long-term visual acuity. In addition, ranibizumab was well tolerated and had a safety profile commonly seen in routine clinical practice. Conclusion This study demonstrates that also in daily practice ranibizumab was effective in preventing vision loss over a period of 24 months. No new safety findings were identified. [ABSTRACT FROM AUTHOR]