Peripheral and ocular microvascular alterations in systemic sclerosis: observations from capillaroscopic assessments, perfusion peripheral analysis, and optical coherence tomography angiography.

To investigate the correlations between finger microvascular morphology and function in patients with systemic sclerosis (SSc) and the status of ocular microcirculation, as detected by nailfold videocapillaroscopy (NVC), laser speckle contrast analysis (LASCA), and optical coherence tomography angiography (OCTA). The enrollment included 32 SSc patients, classified according to the 2013 ACR/EULAR criteria, and 27 sex- and age-matched healthy controls. The participants underwent comprehensive rheumatological and ophthalmological examinations, as well as NVC, LASCA, and OCTA analysis on the same day at a single center from March to October 2022. SSc patients receiving intravenous prostanoids cycles were assessed at least 1 month after infusion. Statistical analysis was conducted using Stata® 15.1. Significant direct correlations were observed between the mean capillary number (at NVC) and the mean perfusion of fingers (at LASCA) with the retinal and choroidal perfusion (at OCTA) (all p < 0.05). In addition, a significantly reduced retinal and choroidal perfusion was detected in SSc patients vs controls (all p < 0.05). Interestingly, diffuse cutaneous SSc (dcSSc) patients exhibited a lower choroidal perfusion (p = 0.03) but an increased choroidal thickness (CT) than limited cutaneous SSc patients (p < 0.001). CT was increased also in patients with positive Scl70 antibodies and with a history of digital ulcers directly correlating with disease duration (r = 0.67, p = 0.001). Finally, the combination of LASCA and OCTA parameters showed a significant discrimination capacity between SSc patients and controls, with an area under the curve of 0.80 [95% CI (0.74, 0.87)]. Peripheral microvascular damage is correlated with impaired ocular microcirculation in SSc. The increased choroidal thickness observed in dcSSc may be related to local sub-endothelial extracellular matrix deposition. The combined analysis of choroidal and fingertip perfusion offers preliminary insights that may complement traditional diagnostic methods for SSc.

PERSEUS-IT 24-month analysis: a prospective observational study to assess the effectiveness of intravitreal aflibercept in routine clinical practice in Italy in patients with neovascular age-related macular degeneration.

PURPOSE: PERSEUS-IT (NCT02289924) was a prospective, observational, 2-year study evaluating the effectiveness and treatment patterns of intravitreal aflibercept (IVT-AFL) in patients with neovascular age-related macular degeneration (nAMD) in routine clinical practice in Italy. METHODS: Treatment-naïve patients with nAMD receiving IVT-AFL per routine clinical practice were enrolled. The primary endpoint was mean change in visual acuity (VA; decimals) from baseline to month (M) 12 and M24. Outcomes were evaluated for the overall study population and independently for the 2 treatment cohorts: regular (3 initial monthly doses, ≥ 7 injections by M12, and ≥ 4 injections between M12 and M24) and irregular (any other pattern). RESULTS: Of 813 patients enrolled, 709 were included in the full analysis set (FAS); VA assessments were available for 342 patients at M12 (FAS1Y, 140 regular and 202 irregular) and 233 patients at M24 (FAS2Y, 37 regular and 196 irregular). In the overall FAS, the mean ± SD change in VA from baseline to M12 and M24 was + 0.09 ± 0.24 and + 0.02 ± 0.25 decimals, and there was a statistically significant difference between the regular and irregular cohorts in both FAS1Y (p = 0.0034) and FAS2Y (p = 0.0222). Ocular treatment-emergent adverse events were reported in 4.1% (n = 33/810 [safety set]) of patients. CONCLUSION: In PERSEUS-IT, clinically relevant functional and anatomic improvements were observed within the first 12 months of IVT-AFL treatment in routine clinical practice in Italy in patients with treatment-naïve nAMD. These gains were generally maintained across the 2-year study. The safety profile of IVT-AFL was consistent with prior studies. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT02289924. DATE OF REGISTRATION: November 13, 2014.

Concerns on ranibizumab and zoledronic acid safety for experimentally treating women with endometriosis.

Correspondence to the original research entitled "Effects of ranibizumab and zoledronic acid on endometriosis in a rat model" published by Ozdemir et al.

Vascular Density and Retinal Function in Patients with Retinitis Pigmentosa Evaluated by Swept-Source OCT Angiography and Microperimetry.

PURPOSE: To determine the retinal and choroidal vessel density in the macular area with swept-source optical coherence tomography (OCT) angiography (SS-OCTA) in patients affected by retinitis pigmentosa (RP), to compare their data with those on healthy subjects, and to study a possible morphofunctional correlation by microperimetry (MP-1). METHODS: A total of 40 eyes of 40 patients affected by RP and 24 eyes of 24 healthy subjects were included in the study. Manually moving down the segmentation line of the SS-OCTA, we have evaluated the vessel density for the superficial retinal plexus, deep retinal plexus, choriocapillaris, and three levels of the choroid. RESULTS: Linear regression analyses were performed of the retinal structure and function. No significant correlation was detected in any case (R2 = 0, p > 0.05). A comparison between RP and healthy controls revealed a significant reduction in SS-OCTA mean capillary density in the RP group (p = 0.0011). This relationship was consistent across vascular layers (p = 0.2413). A significant association between the capillary density of the various vascular complexes was detected within individual eyes (p < 0.0001). CONCLUSIONS: This study represents the first comparing MP-1 and SS-OCTA data in the largest cohort of patients. RP patients showed a reduction in both the retinal and the choroidal vascular network in the macular area compared to healthy subjects.

Hydroxychloroquine and chloroquine retinal safety concerns during COVID-19 outbreak.

PURPOSE: The current coronavirus disease 2019 (COVID-19) has been declared by the World Health Organization a global pandemic. Chloroquine (CQ) and hydroxychloroquine (HCQ) have been largely adopted in the clinical setting for the management of SARS-CoV-2 infection; however, their known retinal toxicity has raised some safety concerns, especially considering the higher-dosage employed for COVID-19 patients as compared with their suggested posology for their usual indications, including systemic lupus erythematosus and other rheumatic diseases. In this review, we will discuss the optimal dosages recommended for COVID-19 patients when treated with HCQ and CQ. METHODS: A comprehensive literature search was performed in PubMed, Cochrane library, Embase and Scopus, by using the following search terms: "chloroquine retinal toxicity" and "hydroxychloroquine retinal toxicity" alone or in combination with "coronavirus", "COVID-19", " SARS-CoV-2 infection " from inception to August 2020. RESULTS: Although there is still no consistent evidence about HCQ/CQ retinal toxicity in patients with COVID-19, these possible drug-related retinal adverse events may represent a major safety concern. For this reason, appropriate screening strategies, including telemedicine, should be developed in the near future. CONCLUSION: A possible future clinical perspective for patients with COVID-19 treated with HCQ/CQ could reside in the multidisciplinary collaboration between ophthalmologists monitoring the risk of HCQ/CQ-related retinal toxicity and those physicians treating COVID-19 infection.

Evaluation of choroidal thickness and choroidal vascular blood flow in patients with thyroid-associated orbitopathy (TAO) using SD-OCT and Angio-OCT.

PURPOSE: The aim of this study was to evaluate changes in choroidal thickness and in choroidal vascular blood flow in patients with thyroid-associated orbitopathy (TAO) and their relationship with clinical features and disease activity using spectral domain optical coherence tomography (SD-OCT) and Angio-OCT technology. METHODS: Eighteen patients and control subjects underwent a complete eye examination, OCT, and Angio-OCT. We also obtained angiographic scans at 3 different consecutive levels (L1, L2, and L3) below the choriocapillary. RESULTS: The subfoveal choroid was significantly thicker in TAO patients than the control eyes (285.6275 ± 32.5 µm compared with 135.89 ± 19.8 µm, respectively, p = 0.0089). The correlation analysis in the TAO group showed a significant correlation between the choroidal thickness and EUGOGO clinical score (r = 0.84, p = 8.44032E-07). Vascular flow of choriocapillary was markedly reduced in subjects with TAO compared with healthy subjects (49.78 ± 4.5 vs. 53.36 ± 1.07; p = 2.5105E-07) and vascular flow of the deeper layer L3 resulted higher in subjects with TAO than in healthy subjects (46.9 ± 20.23 and 41.475 ± 3.06; p = 0.01168). CONCLUSIONS: Subfoveal choroidal thickness and choroidal blood flow were significantly different in patients with TAO compared with healthy subjects.

Real-Life Data in the Treatment of Neovascular Age-Related Macular Degeneration: Results from the Imaculaweb Registry Evaluated in a Single Italian Medical Retina Center.

INTRODUCTION: The aim of this study is to assess and compare the long-term clinical efficacy of anti-VEGF drugs using the Imaculaweb registry. METHODS: In this observational study based on the Imaculaweb registry, outcome measures were the number of injections, the change in mean visual acuity (VA) and central macular thickness (CMT), and the time between diagnosis and the first injection. RESULTS: In total, 126 eyes of 109 patients were included in the study. The mean VA was 49.4 ± 21.4, 54.1 ± 22.2, 51.6 ± 24.9, and 48.3 ± 25.7 letters at baseline and at the 1-, 2-, and 3-year follow-ups, respectively. Significant VA increases (p = 0.0002 for the first year and p = 0.045 for the second year) were documented at years 1 and 2 but not at year 3 (p = 0.8). The mean number of injections was 5.2, 2.6, and 2.3 at the 1-, 2-, and 3-year follow-ups, respectively. In the first year, 30% of the patients received at least 7 injections, while only 6.4% received <3 injections. CMT decreased significantly during the overall follow-up period, and intra- and subretinal fluid decreased (p < 0.0001). CONCLUSION: Imaculaweb turned out to be an effective tool to collect and share clinical data as well as to monitor patient outcome.

Chorioretinal folds: a proposed diagnostic algorithm.

PURPOSE: To create a diagnostic algorithm for the management of chorioretinal folds. METHODS: We reviewed the existing literature about chorioretinal folds focusing our attention on three specific conditions and created a diagnostic algorithm in order to otpimize the choice and the number of investigations. RESULTS: Chorioretinal folds are visible striations of the fundus usually arranged in parallel lines and disposed horizontally. They may be either unilateral or bilateral, symptomatic or asymptomatic and are often associated with different possible ocular and extra ocular pathologies, including systemic diseases like autoimmune disorders and intracranial hypertension. They are named idiopathic when no apparent cause for their development is detectable. However, with improved diagnostic testing, the patients with idiopathic choroidal folds are likely to represent only a smaller portion of the total. CONCLUSIONS: Since choroidal folds be the sole sign of an underlying disease possibly requiring a multidisciplinary approach, an appropriate work-up varying according to the specific clinical features of each case is needed to define the etiology and the treatment. A diagnosting algorithm may be useful in order to optimize the diagnostic approach and management.

Response to anti-VEGF-A treatment of endothelial cells in vitro.

This study was conducted to compare the effects of two anti-VEGF-A drugs, Ranibizumab and Aflibercept, on the expression and secretion of VEGFs family members, and on their influence in proliferation and migration of endothelial cells (HECV) in vitro. HECV cells were exposed 24 h (T1), 4 days (T2) and 6 days (T3) to Ranibizumab or Aflibercept at pharmacodynamically relevant concentrations (Ranibizumab: 12.5 µg/ml and 125 µg/ml; Aflibercept: 50 µg/ml and 500 µg/ml). Cell viability and then expression and secretion of VEGF-A, VEGF-B, VEGF-C and PlGF were evaluated respectively by Real Time-PCR and ELISA. Intracellular signaling activated by VEGF-A and VEGF-C was investigated evaluating phosphorylation of VEGFR2. Influence in would healing was evaluated through scratch assay. In general no differences were observed among the tested concentrations of anti-vegf drugs. Ranibizumab and Aflibercept did not affect HECV cell viability in all experimental times. At T1, Ranibizumab decreased mRNA levels of VEGF-A, induced VEGF-C secretion, abrogated phosphorylation of VEGFR2 stimulated by VEGF-A, and impaired ability of HECV cells to repair wound healing. Aflibercept decreased mRNA levels of VEGF-A, -B and PlGF; slightly increased basal level of phVEGFR2, and completely abrogated phosphorylation stimulated by VEGF-A and VEGF-C. No effects on secretion of VEGF-B and on would healing were observed after exposure to Aflibercept. Prolonged exposure to anti-VEGFs decreased expression and secretion of VEGF-A and VEGF-B, up-regulated VEGF-C mRNA levels and its secretion, and increased basal phosphorylation of VEGFR2. Acute treatment with Ranibizumab or Aflibercept evoked different responses on endothelial cells, however these differences were lost after prolonged exposure. Scratch test results suggest that treatment with Ranibizumab may be more effective than Aflibercept in reducing angiogenic potential of endothelial cells in vitro.

Combining macula clinical signs and patient characteristics for age-related macular degeneration diagnosis: a machine learning approach.

BACKGROUND: To investigate machine learning methods, ranging from simpler interpretable techniques to complex (non-linear) "black-box" approaches, for automated diagnosis of Age-related Macular Degeneration (AMD). METHODS: Data from healthy subjects and patients diagnosed with AMD or other retinal diseases were collected during routine visits via an Electronic Health Record (EHR) system. Patients' attributes included demographics and, for each eye, presence/absence of major AMD-related clinical signs (soft drusen, retinal pigment epitelium, defects/pigment mottling, depigmentation area, subretinal haemorrhage, subretinal fluid, macula thickness, macular scar, subretinal fibrosis). Interpretable techniques known as white box methods including logistic regression and decision trees as well as less interpreitable techniques known as black box methods, such as support vector machines (SVM), random forests and AdaBoost, were used to develop models (trained and validated on unseen data) to diagnose AMD. The gold standard was confirmed diagnosis of AMD by physicians. Sensitivity, specificity and area under the receiver operating characteristic (AUC) were used to assess performance. RESULTS: Study population included 487 patients (912 eyes). In terms of AUC, random forests, logistic regression and adaboost showed a mean performance of (0.92), followed by SVM and decision trees (0.90). All machine learning models identified soft drusen and age as the most discriminating variables in clinicians' decision pathways to diagnose AMD. CONCLUSIONS: Both black-box and white box methods performed well in identifying diagnoses of AMD and their decision pathways. Machine learning models developed through the proposed approach, relying on clinical signs identified by retinal specialists, could be embedded into EHR to provide physicians with real time (interpretable) support.

Prechoroidal Cleft Regression After Switch to Intravitreal Brolucizumab.

INTRODUCTION: Prechoroidal cleft has been described as a negative prognostic biomarker in patients affected with neovascular age related macular degeneration (nAMD). This peculiar finding consists of a lenticular hyporeflective space located between an outward bowing of Bruch's membrane and the base of a fibrovascular retinal pigment epithelium detachment (PED). Previous studies have reported the partial or complete regression of prechoroidal clefts after treatment with anti-vascular endothelial growth factor (VEGF) injections. CASE REPORT: To report a case of complete anatomical regression of an unresponsive prechoroidal cleft after switching to intravitreal Brolucizumab. The patient maintained cleft regression over time and no adverse events (i.e., RPE tears, intraocular inflammation) were observed during follow-up. CONCLUSIONS AND IMPORTANCE: To our knowledge, this case report is the first to analyze the clinical efficacy of brolucizumab targeting prechoroidal clefts. Clinical implication and pathogenesis of prechoroidal clefts are yet to be fully elucidated.

Autonomous artificial intelligence versus teleophthalmology for diabetic retinopathy.

Purpose: To assess the role of artificial intelligence (AI) based automated software for detection of Diabetic Retinopathy (DR) compared with the evaluation of digital retinography by two double masked retina specialists. Methods: Two-hundred one patients (mean age 65 ± 13 years) with type 1 diabetes mellitus or type 2 diabetes mellitus were included. All patients were undergoing a retinography and spectral domain optical coherence tomography (SD-OCT, DRI 3D OCT-2000, Topcon) of the macula. The retinal photographs were graded using two validated AI DR screening software (Eye Art TM and IDx-DR) designed to identify more than mild DR. Results: Retinal images of 201 patients were graded. DR (more than mild DR) was detected by the ophthalmologists in 38 (18.9%) patients and by the AI-algorithms in 36 patients (with 30 eyes diagnosed by both algorithms). Ungradable patients by the AI software were 13 (6.5%) and 16 (8%) for the Eye Art and IDx-DR, respectively. Both AI software strategies showed a high sensitivity and specificity for detecting any more than mild DR without showing any statistically significant difference between them. Conclusions: The comparison between the diagnosis provided by artificial intelligence based automated software and the reference clinical diagnosis showed that they can work at a level of sensitivity that is similar to that achieved by experts.

Predictors of 24-month onset of macular fibrosis in type 3 macular neovascularisation.

AIMS: To explore prognostic multimarker models for progression to macular fibrosis (MF) over 24 months specific to type 3 macular neovascularisation (T3 MNV). METHODS: This retrospective, exploratory, single-centre, cohort study comprised 65 eyes of 43 Caucasian patients with treatment naive T3 MNV, all with a 24-month follow-up post anti-VEGF therapy using a strict pro-re-nata (PRN) regimen. Data on demographic features, clinical findings, frequency of intravitreal treatments and optical coherence tomography biomarkers were collected at baseline and after 12 and 24 months of follow-up. Logistic regression models (LRM) and receiver-operating curve (C-index) analyses were performed to evaluate the prognostic ability of the studied biomarkers in discriminating between MF affected and unaffected patients. RESULTS: At final follow-up, MF was present in 46.2% of eyes. Subretinal hyper-reflective material (SHRM) and subretinal pigment epithelium multilaminar hyper-reflectivity (multilaminae) emerged as significant predictors for MF, with adjusted odds ratios (OR) of 18.0 (95% CL 13.4 to 24.1) and 11.8 (95% CL 8.66 to 16.0), respectively. Additionally, the presence of multifocal lesions (OR 0.04, 95% CL 0.01 to 0.30) appeared to decrease the likelihood of MF. C-indexes for the selected LRMs ranged between 0.92 and 0.88, indicating a comparably high discriminant ability. Despite consistent treatment schedules between the two groups (MF: median intravitreal treatment (IVT) number=10.5, IQR=7; non-MF: median IVT=10, IQR=6), a decline in best-corrected visual acuity was noted in the group with MF onset over the 24-month follow-up (-13.0 ETDRS letters; 95% CL -22.1 to -3.9; p=0.006). CONCLUSION: Our study identifies SHRM and multilaminae as relevant predictors of 24-month onset of MF in patients with T3 MNV. These findings enrich our understanding of the development of MF in T3 MNV and can guide improved risk prognostication. Future research should consider larger samples and prospective designs to validate these predictors.

Safety, Tolerability, and Short-Term Efficacy of Low-Level Light Therapy for Dry Age-Related Macular Degeneration.

INTRODUCTION: Photobiomodulation (PBM) has become a promising approach for slowing the progression of early and intermediate dry age-related macular degeneration (dAMD) to advanced AMD. This technique uses light to penetrate tissues and activate molecules that influence biochemical reactions and cellular metabolism. This preliminary analysis is aimed at assessing the safety, tolerability, and short-term effectiveness of the EYE-LIGHT®PBM treatment device in patients with dAMD. METHODS: The EYE-LIGHT® device employs two wavelengths, 590 nm (yellow) and 630 nm (red), in both continuous and pulsed modes. Patients over 50 years of age with a diagnosis of dAMD in any AREDS (Age-Related Eye Disease Study) category were randomly assigned to either the treatment group or the sham group. The treatment plan consisted of an initial cycle of two sessions per week for 4 weeks. Safety, tolerability, and compliance outcomes, along with functional and anatomical outcomes, were assessed at the end of the fourth month. RESULTS: This preliminary analysis included data from 76 patients (152 eyes). All patients were fully compliant with treatment sessions, and only one fifth of patients treated with PBM reported mild ocular adverse events, highlighting exceptional results in terms of tolerability and adherence. Changes in best-corrected visual acuity (BCVA) from baseline to month 4 differed significantly between the sham and PBM-treated groups, favoring the latter, with a higher proportion achieving a gain of five or more letters post-treatment (8.9% vs. 20.3%, respectively; p = 0.043). No significant differences in central subfield thickness (CST) were observed between the two groups over the 4-month period. The study also found a statistically significant disparity in mean drusen volume changes from baseline to month 4 between the groups in favor of patients treated with PBM (p = 0.013). CONCLUSION: These preliminary results indicate that PBM treatment using the EYE-LIGHT® system is safe and well tolerated among patients with dAMD. Furthermore, both functional and anatomical data support the treatment's short-term efficacy. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT06046118.

Faricimab for the Treatment of Diabetic Macular Edema and Neovascular Age-Related Macular Degeneration.

Nowadays; intravitreal anti-vascular endothelial growth factor (VEGF) drugs are considered the first-line therapeutic strategy for treating macular exudative diseases; including wet age-related macular degeneration (w-AMD) and diabetic macular edema (DME). Despite the important clinical achievements obtained by anti-VEGF drugs in the management of w-AMD and DME; some limits still remain; including high treatment burden; the presence of unsatisfactory results in a certain percentage of patients and long-term visual acuity decline due to complications such as macular atrophy and fibrosis. Targeting the angiopoietin/Tie (Ang/Tie) pathway beyond the VEGF pathway may be a possible therapeutic strategy; which may has the potential to solve some of the previous mentioned challenges. Faricimab is a new; bispecific antibody targeting both VEGF-A and the Ang-Tie/pathway. It was approved by FDA and; more recently; by EMA for treating w-AMD and DME. Results from phase III trials TENAYA and LUCERNE (w-AMD) and RHINE and YOSEMITE (DME) have shown the potential of faricimab to maintain clinical efficacy with more prolonged treatment regimens compared to aflibercept (12 or 16 weeks) with a a good safety profile.

Multimodal imaging for the management of Lyme-associated uveitis: A case report from an Italian tertiary center.

INTRODUCTION: Lyme borreliosis may present with different systemic manifestations and also the ocular involvement may be difficult to diagnose because of its multifaceted presentation. Considering the growing incidence of Lyme disease in European countries, ophthalmologist should be trained to distinguish ocular borreliosis. CASE REPORT: Several clinical presentations have been previously described, including uveitis, unilateral or bilateral chorioretinitis, keratitis, episcleritis, papillitis and ischemic optic neuropathy, retinal vasculitis and acute posterior multifocal placoid pigment epitheliopathy (APMPPE); however our case report showed a rare presentation with the presence of unilateral uveitis with vitreitis and multiple, patchy, yellowish lesions, in association with retinal vasculitis. This clinical picture was to be considered in differential diagnosis with ocular Toxoplasmosis. CONCLUSIONS: The appropriate management of this patient was made possible by the combination of multimodal imaging and appropriate laboratory tests, representing the optimal process in the diagnostic and therapeutic pathway in high-risk patients for ocular Lyme disease.

Clinical Outcomes of Topical 0.1% Ciclosporin Cationic Emulsion Used on Label in Children with Vernal Keratoconjunctivitis.

INTRODUCTION: The purpose of this short article is to report the clinical outcomes of topical 0.1% ciclosporin cationic emulsion (CsA-CE) used on label in children with vernal keratoconjunctivitis (VKC). METHODS: In this prospective, non-comparative, observational study children affected by active severe VKC were treated for at least 12 months with topical 0.1% CsA-CE. The drug was instilled in both eyes 4 times daily. Data collected from medical charts for the baseline visit (T0) and 1-year follow-up visit (T1) included symptomatic score (0-15), clinical score (0-15), side effects, rescue therapy (need and total number of courses with 0.1% dexamethasone 4 times daily for 5 days), ocular complications and tolerability (visual analog scale [0-100]). RESULTS: Data from 25 children (20 boys, 5 girls; mean [± standard deviation] age 8.40 ± 2.54 years) were included in the study. Of the 25 patients, 23 (92%) used 0.1% CsA-CE eye drops as per label recommendations, including four patients who had prematurely stopped using topical galenic CsA due to side effects. Symptomatic and clinical scores decreased significantly after treatment, with the mean symptomatic score decreasing from 9.76 ± 1.27 at T0 to 3.80 ± 1.08 at T1, and the mean clinical score decreasing from 9.20 ± 1.32 at T0 to 3.44 ± 1.00 at T1; both P < 0.0001). Five patients (20%) required at least one course of rescue medication (mean 3.4 ± 4.8 courses/year). No patients experienced ocular complications during the study, and treatment tolerability was very high (mean score 89.40 ± 5.46). CONCLUSION: Our findings confirm that topical CsA-CE is an effective on-label option for children with VKC in the real-life setting. In our pediatric patient population, CsA-CE provided good clinical outcomes with a limited need for rescue medication, and it was well tolerated by almost all patients, including those who were intolerant to galenic formulations.

Vascular endothelial growth factor-C secretion is increased by advanced glycation end-products: possible implication in ocular neovascularization.

PURPOSE: Neovascularization is a common complication of many degenerative and vascular diseases of the retina. Advanced glycation end-products (AGEs) have a pathologic role in the development of retinal neovascularization, mainly for their ability in upregulating vascular endothelial growth factor-A (VEGF-A) secretion. The aim of this study was to investigate whether AGEs are able to modulate the secretion of VEGF-C, another angiogenic factor that increases the effect of VEGF-A. METHODS: A human retinal pigment epithelial cell line (ARPE-19) and human endothelial vascular cell line (HECV) cells were cultured for 24 h in presence of AGEs, and then mRNA expression of VEGF-C was analyzed with reverse transcription-polymerase chain reaction (RT-PCR). To verify whether AGEs-induced VEGF secretion is mediated by RAGE (Receptor for AGEs), RAGE expression was depleted using the small interfering RNA method. To investigate whether VEGF-A is involved in upregulating VEGF-C secretion, the cells were cultured for 24 h in the presence of bevacizumab, a monoclonal antibody against VEGF-A, alone or in combination with AGEs. VEGF-A and VEGF-C levels in the supernatants of the treated cells were evaluated with enzyme-linked immunosorbent assay. RESULTS: Exposure to AGEs significantly increased VEGF-C gene expression in ARPE-19 cells. AGEs-induced VEGF-C secretion was upregulated in retinal pigment epithelium (RPE) and endothelial cells. Downregulation of RAGE expression decreased VEGF-A secretion in cell models, and increased VEGF-C secretion in ARPE-19 cells. Adding bevacizumab to the culture medium upregulated constitutive VEGF-C secretion but did not affect AGEs-induced VEGF-C secretion. CONCLUSIONS: These findings suggest that AGEs take part in the onset of retinal neovascularization, not only by modulating VEGF-A but also by increasing VEGF-C secretion. In addition, our results suggest that VEGF-C may compensate for treatments that reduce VEGF-A.

The emerging role of the Angiopoietin-Tie pathway as therapeutic target for treating retinal diseases.

INTRODUCTION: Several approaches have been investigated for treating wet age-related macular degeneration (w-AMD), diabetic macular edema (DME) and retinal vein occlusions (RVOs). The first-line treatment for these exudative retinal diseases consists of anti-vascular endothelial growth factor (VEGF) agents; however, the high treatment burden and the percentage of 'non responder' patients have highlighted the need for other approaches. Increasing evidence has shown the role of angiopoietin/Tie (Ang/Tie) pathway in the pathogenesis of these exudative retinal diseases; therefore, novel drugs targeting this pathway are under evaluation in clinical trials. AREAS COVERED: We analyzed the novel, emerging drugs (ARP- 1536, the coformulation of aflibercept and nesvacumab, AXT107 and AKB-9778) that target the Ang/Tie pathway. These drugs are still in early phase clinical trials, but encouraging outcomes have emerged. We also discuss the clinical efficacy of faricimab, a bispecific monoclonal antibody that inhibits VEGF-A and Ang-2. EXPERT OPINION: The simultaneous targeting of the VEGF and Ang/Tie pathways may be more beneficial than monotherapy in patients with exudative retinal diseases. Among the investigational drugs targeting the Ang/Tie pathway, faricimab has shown promising results in phase II/III trials and in the near future may represent a viable treatment option for the management of exudative macular diseases.