4D label-free proteomics analysis of oxygen-induced retinopathy with or without anti-VEGF treatment.

Oxygen-induced retinopathy (OIR) animal model is widely used for retinopathy of prematurity (ROP) researches. The purpose of this study was to identify proteins and related pathways of OIR with or without anti-vascular endothelial growth factor (VEGF) treatment, for use as biomarkers in diagnosing and treating ROP. Nine samples were subjected to proteomic analysis. Retina specimens were collected from 3 OIR mice, 3 OIR mice with anti-VEGF treatment and 3 normal mice (control group). Liquid chromatography-tandem mass spectrometry analysis was performed using the 4D label-free technique. Statistically significant differentially expressed proteins, gene ontology (GO) terms, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway representations, InterPro (IPR) and protein interactions were analyzed. In total, 4585 unique proteins were identified as differentially expressed proteins (DEPs). Enrichment analysis of the GO and KEGG indicated functional clusters related to peptide biosynthetic and metabolic process, cellular macromolecule biosynthetic process and nucleic acid binding in OIR group. For anti-VEGF treatment group, DEPs were clustered in DNA replication, PI3K/Akt signaling pathway and Jak/STAT signaling pathway. Proteomic profiling is useful for the exploration of molecular mechanisms of OIR and mechanisms of anti-VEGF treatment. These findings may be useful for identification of novel biomarkers for ROP pathogenesis and treatment.

The landscape of angiogenesis and inflammatory factors in eyes with myopic choroidal neovascularization before and after anti-VEGF injection.

INTRODUCTION: To investigate the levels of angiogenesis and inflammatory cytokines in individuals with myopic choroidal neovascularization (mCNV) and the changes in these factors following intravitreal anti-VEGF injection. METHODS: Aqueous humor samples were gathered from eyes with mCNV, those with single macular bleeding (SMB) without mCNV in highly myopic eyes, and those with age-related cataracts. Using a multiplex bead immunoassay, we analyzed 28 angiogenesis and inflammatory factors in the aqueous humor. Furthermore, clinical data were documented for correlation analysis. RESULTS: In this study, the levels of vascular endothelial growth factor A (VEGF-A), interleukin 8 (IL-8), and fibroblast growth factors 1 (FGF-1) were significantly elevated in mCNV compared to SMB eyes (p < 0.05). Their odds ratios for mCNV occurrence were 1.05, 3.45, and 2.64, respectively. Hepatocyte growth factor (HGF) and VEGF-C were notably higher in mCNV than in cataract patients (p < 0.05), and VEGF-C correlated to the degree of myopic atrophic maculopathy (p = 0.024). Axial length exhibited a negative correlation with VEGF-A and positive correlations with VEGF-C, HGF, and MCP-1 (p < 0.01). Following anti-VEGF treatment, a reduction in VEGF-A, endothelin-1, and FGF-2 was noted in mCNV patients (p < 0.05), but MCP-1 levels increased. CONCLUSION: Our findings highlight the predominant role of angiogenesis and inflammation factors in mCNV pathogenesis. VEGF-C's correlation with axial length and atrophy suggests its involvement in the process of myopic atrophic maculopathy.

Long-term choroidal thickness changes based on the subtype of macular neovascularization in neovascular age-related macular degeneration (5-year follow-up).

PURPOSE: To evaluate the long-term choroidal thickness changes in combination with other morphological and functional outcomes during anti-vascular endothelial growth factor (VEGF) treatment for neovascular age-related macular degeneration (nAMD) based on the subtype of macular neovascularization (MNV): MNV-1 (within the subretinal pigment epithelium space) and MNV-2 (within the subretinal space). METHODS: This retrospective study included 58 eyes from 53 patients with naïve nAMD who received anti-VEGF therapy over a 60-month period. All eyes were treated initially with intravitreal bevacizumab following Pro re nata regimen. Main outcome measures included the following: subfoveal choroidal thickness (SFCT), best corrected visual acuity (BCVA), central macular thickness (CMT), development of subfoveal geographic atrophy (GA), and the number of injections. RESULTS: Thirty-four eyes had MNV-1 (group 1) and 24 eyes had MNV-2 (group 2). SFCT in group 1 vs group 2 was (210 ± 45 µm vs 191 ± 52 µm, p = 0.01) before treatment and (170 ± 47 µm vs 179 ± 48 µm, p = 0.24) after 60 months. BCVA (log MAR) in group 1 vs group 2 was (0.57 ± 0.18 vs 0.53 ± 0.22, p = 0.47) before treatment and (0.59 ± 0.23 vs 0.69 ± 0.16, p = 0.04) after 60 months. CMT in group 1 vs group 2 was (398 ± 154 µm vs 382 ± 103 µm, p = 0.86) before treatment and (297 ± 68 µm vs 283 ± 67 µm, p = 0.14) after 60 months. The number of injections per eye over a period of 60 months was significantly higher in group 1 (34.9 ± 11 vs 29.0 ± 14, p = 0.04). The proportion of eyes with subfoveal GA after 60 months was significantly higher in group 2 (13 eyes, 54%) than in group 1 (9 eyes, 25%) (p = 0.03). CONCLUSION: Over the full 60 months of anti-VEGF treatment, eyes with MNV-1 showed a greater reduction in choroidal thickness, better visual acuity, and less development of subfoveal geographic atrophy compared with eyes with MNV-2. The significantly thicker choroid in eyes with MNV type 1 at baseline seems to have a positive impact on long-term outcomes.

Efficacy, durability, and safety of faricimab up to every 16 weeks in patients with neovascular age-related macular degeneration: 2-year results from the Japan subgroup of the phase III TENAYA trial.

PURPOSE: To evaluate 2-year efficacy, durability, and safety of faricimab in the TENAYA Japan subgroup and pooled global TENAYA/LUCERNE cohort of patients with neovascular age-related macular degeneration (nAMD). METHODS: Subgroup analysis of TENAYA/LUCERNE (NCT03823287/NCT03823300): phase III, multicentre, randomised, active comparator-controlled, double-masked, non-inferiority trials. Treatment-naïve patients aged ≥ 50 years with nAMD were randomised (1:1) to intravitreal faricimab (6.0 mg up to every 16 weeks [Q16W] after 4 initial Q4W doses) or aflibercept (2.0 mg Q8W after 3 initial Q4W doses). Outcomes were assessed through year 2 for the TENAYA Japan subgroup (N = 133) and global pooled TENAYA/LUCERNE cohort (N = 1329). RESULTS: Vision and anatomic improvements achieved with faricimab at year 1 were maintained over 2 years and were generally comparable between the TENAYA Japan subgroup and pooled TENAYA/LUCERNE cohort. Adjusted mean best-corrected visual acuity (BCVA) change from baseline at year 2 for the TENAYA Japan subgroup and global pooled TENAYA/LUCERNE cohort was +7.1 (3.7-10.5) and +4.4 (3.2-5.5) letters in the faricimab arm, respectively, and +5.2 (1.9-8.6) and +4.3 (3.1-5.4) letters in the aflibercept arm, respectively. At week 112, the proportion of faricimab-treated patients on Q16W dosing was 61.0% and 63.1% in the TENAYA Japan subgroup and pooled TENAYA/LUCERNE cohort. Faricimab was well tolerated through year 2. CONCLUSION: Year 2 TENAYA Japan subgroup findings for faricimab were generally consistent with the pooled global TENAYA/LUCERNE results in patients with nAMD. Vision and anatomical benefits with faricimab were similar to those with aflibercept but with fewer injections.

Anti-VEGF therapy for the long-term management of diabetic macular edema: a treat-to-target strategy based on macular morphology.

In an aging population, the prevalence and burden of diabetes mellitus, diabetic retinopathy, and vision-threatening diabetic macular edema (DME) are only expected to rise around the world. Similarly to other complications of diabetes mellitus, DME requires long-term management. This article aims to review the current challenges associated with the long-term management of DME, opportunities to improve outcomes for patients, and to develop a treat-to-target strategy based on macular morphology. At present, intravitreal anti-vascular endothelial growth factor (VEGF) therapy is the standard of care for the management of DME; however, best-achievable vision outcomes with treatment are reliant on frequent injections and close monitoring, which are difficult to maintain in current clinical practice because of the burden this imposes on patients. Achieving and maintaining good vision with treatment are the most important factors for patients with DME. Landmark trials have shown that vision gains with anti-VEGF therapy are typically accompanied by anatomical improvements (e.g., reductions in retinal thickness); therefore, multimodal imaging measures of macular morphology are often used in patients with DME to guide real-world treatment decisions. We would like to propose a hypothetical treat-to-target algorithm to guide physicians on treatment strategies for the long-term management of DME. Alternative measures of retinal fluid (e.g., persistence, stability, location) may be stronger predictors of visual acuity in DME, although further research is required to confirm whether alternate quantifiable biomarkers such as subretinal fluid and intraretinal fluid volumes can be used as a biomarker of clinical improvement. Identifying novel biomarkers and treatments that target neuroinflammation and neurodegeneration, improving patient-physician communication around treatment adherence, and using treat-to-target measures may help to ensure that the long-term benefits of treatment are realized.

Real-world experience of using stereotactic radiotherapy combined with anti-vascular endothelial growth factor to treat neovascular AMD.

INTRODUCTION: Adjunctive treatment or longer-acting drugs are required to treat nAMD to help ease burdens for patients and hospital clinics alike. Stereotactic therapy is one such option, providing a reduction in the number of injections over time. OBJECTIVE: To determine the clinical outcomes in a cohort of patients with nAMD receiving a combination therapy of stereotactic radiotherapy (SRT) with intravitreal anti-VEGF injections (IVI). METHOD: A retrospective analysis of 74 patients with nAMD, who had received IVI and SRT (16 Gray maximum dose to the macula) at a large tertiary university eye hospital, between March 2018 and September 2019 was performed. The number of IVIs, visual acuity (VA), and central retinal thickness (CRT) were evaluated at 12, 24, and 36 months after patients received SRT and compared to the same time interval prior to SRT. RESULTS: Follow-up data at 12, 24, and 36 months following and prior to SRT was available for 74, 48, and 22 patients respectively. Overall there was a significant reduction in the number of injections post-SRT. Twelve months following SRT, the median number of IVI was reduced by 1 (p < 0.05). The reduction in the median number of IVI was significantly reduced by 3 and 6 injections at 24- and 36-month follow-up respectively (p < 0.05). The CRT was significantly reduced post-SRT compared to the baseline values at all time periods. There was no statistically significant difference in VA at 12-month follow-up compared to baseline. The VA, however, significantly decreased at 24- and 36-month follow-up (p < 0.05). CONCLUSION: A therapy combining SRT with IVI has shown an overall reduction in the number of injections required in nAMD patients at 12, 24, and 36 months following SRT compared to IVI treatment alone. These real-world outcomes are comparable to other studies while also confirming the maintenance of the reduced frequency of required IVI for patients with nAMD.

Evaluation of the First-Dose Anti-VEGF Anatomical Response in Polypoidal Choroidal Vasculopathy Patients: Correlation with the Third-Dose Response and Risk Factor Analysis.

INTRODUCTION: The aims of the study were to investigate whether first-dose efficacy can predict third-dose anatomical response and analyze the risk factors for first-dose response of polypoidal choroidal vasculopathy (PCV) patients. METHODS: We retrospectively reviewed patients' medical records from 27 centers of China PCV Research Alliance. PCV patients treated with intravitreal injections of conbercept (IVC) based on the 3+ pro re nata regimen (three initial monthly injections, followed by injections as needed) with complete 3-month injection data were included. Response correlations, risk factor associations, changes in central macular thickness (CMT) or best-corrected visual acuity (BCVA), and number of injections in the first year of follow-up were evaluated separately in the pachy-PCV and non-pachy-PCV phenotypes. RESULTS: Overall, 165 eligible patients were included. There was a significant correlation between first-dose and third-dose anatomical response in pachy-PCV or non-pachy-PCV patients (rs = 0.611, p < 0.001; rs = 0.638, p < 0.001). Multivariate analysis revealed associations of good first-dose anatomical response in pachy-PCV patients with baseline CMT with a predicted area under the curve (AUC) of 0.847, while a good response in non-pachy-PCV patients was associated with baseline BCVA, baseline CMT, pigment epithelial detachment (PED) height, higher proportion of intraretinal fluid, and lower PED minimum diameter with a predicted AUC of 0.940. CMT in the good first-dose response group was significantly decreased from baseline at all first-year follow-up visits in both groups (p < 0.001), and mean BCVA was improved in the good versus poor first-dose anatomical response group (5.4 vs. 1.6 ETDRS letters in pachy-PCV, 10.6 vs. 7.4 letters in non-pachy-PCV) after the third injection. No significant difference was observed in the number of injections in the first year of follow-up between different response groups. CONCLUSION: In PCV patients receiving IVC, the first- and third-dose responses are significantly correlated, and different factors influence the first-dose response in different subtypes of PCV.

A New Generation of Gene Therapies as the Future of Wet AMD Treatment.

Age-related macular degeneration (AMD) is an eye disease and the most common cause of vision loss in the Western World. In its advanced stage, AMD occurs in two clinically distinguished forms, dry and wet, but only wet AMD is treatable. However, the treatment based on repeated injections with vascular endothelial growth factor A (VEGFA) antagonists may at best stop the disease progression and prevent or delay vision loss but without an improvement of visual dysfunction. Moreover, it is a serious mental and financial burden for patients and may be linked with some complications. The recent first success of intravitreal gene therapy with ADVM-022, which transformed retinal cells to continuous production of aflibercept, a VEGF antagonist, after a single injection, has opened a revolutionary perspective in wet AMD treatment. Promising results obtained so far in other ongoing clinical trials support this perspective. In this narrative/hypothesis review, we present basic information on wet AMD pathogenesis and treatment, the concept of gene therapy in retinal diseases, update evidence on completed and ongoing clinical trials with gene therapy for wet AMD, and perspectives on the progress to the clinic of "one and done" therapy for wet AMD to replace a lifetime of injections. Gene editing targeting the VEGFA gene is also presented as another gene therapy strategy to improve wet AMD management.

Benefits of a combined surgical technique for patients with secondary neovascular glaucoma.

OBJECTIVE: Aim: To assess the effectiveness and safety of the proposed surgical technique for treating secondary neovascular glaucoma. PATIENTS AND METHODS: Materials and Methods: We examined 28 eyes of 28 patients (16 women and 12 men), aged 46}7,2 years, with secondary neovascular glaucoma. All patients underwent a comprehensive ophthalmological examination before and during treatment. Two-stage treatment was applied to all patients. At the first stage - performed an advanced technique of non-penetrating deep sclerectomy while administering anti-VEGF (anti-vascular endothelial growth factor) intravitreal or intracameral injections. At the second - we performed externalization of Schlemm's canal followed by YAG laser trabeculectomy. Statistical analysis of the results was used the SPSS v. 11.0, MedStat v.15.1 software package for medical and biological research. RESULTS: Results: The proposed surgical technique, leads to a gradual decrease in intraocular pressure (IOP) and regression of the iris and anterior chamber angle neovascularization. The postoperative course was uneventful for all the patients. In the early postoperative period, the IOP was observed to be normalized in all the eyes. The IOP ranged from 12 to 16 mm Hg. The neovascularization regression occurred (in 100 % of cases) within 5-7 days. CONCLUSION: Conclusions: Gradual reduction of IOP reduces intraoperative complications. Intravitreal or intracameral injections of anti-proliferative agents contribute to the regression of neovascularization and further gradual reduction of IOP. Performing a laser trabeculectomy in the area where a non-penetrating deep sclerectomy was previously performed creates new pathways for the outflow of intraocular fluid from the anterior chamber and reduces the risks of reintervention.

Emerging therapeutic strategies for unmet need in neovascular age-related macular degeneration.

Neovascular age-related macular degeneration (nAMD) is a major cause of visual impairment and blindness. Anti-vascular endothelial growth factor (VEGF) agents, such as ranibizumab, bevacizumab, aflibercept, brolucizumab and faricimab have revolutionized the clinical management of nAMD. However, there remains an unmet clinical need for new and improved therapies for nAMD, since many patients do not respond optimally, may lose response over time or exhibit sub-optimal durability, impacting on real world effectiveness. Evidence is emerging that targeting VEGF-A alone, as most agents have done until recently, may be insufficient and agents that target multiple pathways (e.g., aflibercept, faricimab and others in development) may be more efficacious. This article reviews issues and limitations that have arisen from the use of existing anti-VEGF agents, and argues that the future may lie in multi-targeted therapies including alternative agents and modalities that target both the VEGF ligand/receptor system as well as other pathways.

Loss to Follow-up in Patients with Neovascular Age-Related Macular Degeneration Treated with Anti-VEGF Therapy in the United States in the IRIS® Registry.

PURPOSE: To determine the incidence of being lost to follow-up (LTFU) and nonpersistence in patients with neovascular age-related macular degeneration (AMD) treated with anti-VEGF injections in the United States. DESIGN: Retrospective cohort study using the IRIS® (Intelligent Research in Sight) Registry data. PARTICIPANTS: One hundred fifty-six thousand three hundred twenty-seven treatment-naive patients with neovascular AMD who subsequently were treated with anti-VEGF therapy from 2013 through 2015 and followed up through 2019. METHODS: Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). MAIN OUTCOME MEASURES: Being LTFU was defined as no follow-up within 12 months from last intravitreal injection. Nonpersistence was defined as no follow-up within 6 months from last intravitreal injection. RESULTS: For neovascular AMD, 11.6% of patients (95% CI, 11.4%-11.7%) were LTFU, and 88.4% of patients were followed up within 12 months. The rate of being LTFU generally was higher with increasing age, with odds of being LTFU greatest for patients between 81 and 84 years of age (OR, 2.51; 95% CI, 2.31-2.74; P < 0.001) compared with patients 70 years of age and younger. Odds of being LTFU for Black or African American patients (OR, 1.32; 95% CI, 1.08-1.61; P = 0.007) were greater than for White patients. Odds of being LTFU were higher for patients with Medicaid insurance (OR, 1.27; 95% CI, 1.01-1.60; P = 0.04) and lower for patients with Medicare Fee-For-Service insurance (OR, 0.69; 95% CI, 0.64-0.74; P < 0.001) than for patients with private insurance. Furthermore, 14.3% (95% CI, 14.1-14.4) of patients were nonpersistent, and 85.7% of patients underwent follow-up within 6 months. Odds of nonpersistence also were greatest among patients between 81 and 84 years of age (OR, 2.13; 95% CI, 1.98-2.29; P < 0.001) compared with patients 70 years of age or younger. Odds of nonpersistence for Black or African-American patients (OR, 1.38; 95% CI, 1.15-1.65; P < 0.001) and Hispanic patients (OR, 1.13; 95% CI, 1.03-1.24; P = 0.009) were greater than odds for White patients. CONCLUSIONS: Nearly 1 of 9 patients with neovascular AMD treated with anti-VEGF injections became LTFU, whereas 1 of 7 patients were nonpersistent. Risk factors identified included increasing age, male sex, unilateral involvement, diabetes, Medicaid insurance, and race or ethnicity. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Differential diagnosis of myopic choroidal neovascularization (mCNV): insights from multimodal imaging and treatment implications.

PURPOSE: The aim of this article is to conduct a comprehensive systematic review about the current understandings and differential diagnosis of myopic choroidal neovascularization (mCNV) and other several similar diseases, describing their multimodal imaging analysis, prognostic implications, and current types of management. METHODS: This systematic review was performed based on a search on the PubMed database of relevant papers regarding mCNV and other entities discussed in the paper, according to our current knowledge. RESULTS: Through the integration of a multimodal imaging approach, especially optical coherence tomography (OCT), along with accurate demographic and clinical assessment, it becomes possible to effectively differentiate mCNV from similar yet heterogeneous entities. These conditions include macular hemorrhage due to new lacquer crack (LC) formation, inflammatory diseases such as punctate inner choroidopathy (PIC)/multifocal choroidits (MFC) and epiphenomenon multiple evanescent white dot syndrome (Epi-MEWDS), neovascular age-related macular degeneration (nAMD), idiopathic CNV (ICNV), dome-shaped macula (DSM) with subretinal fluid, retinal pigment epithelium (RPE) humps, angioid streaks (AS), choroidal rupture (CR), and choroidal osteoma (CO). Each one of these entities will be described and discussed in this article. CONCLUSION: Myopic choroidal neovascularization is a common retinal condition, especially among young individuals. Accurate diagnosis and differentiation from similar conditions are crucial for effective treatment. Multimodal imaging, particularly OCT, plays a crucial role in precise assessment. Future research should focus on defining biomarkers and distinguishing features to facilitate prompt treatment.

Role of Novel Inflammatory Factors in Central Retinal Vein Occlusion with Macular Edema.

Background and Objectives: To investigate associations among the aqueous humor levels of novel inflammatory factors, including FMS-related tyrosine kinase 3 ligand (Flt-3L), fractalkine, CXC chemokine ligand 16 (CXCL-16), and endocan-1; the severity of macular edema in central retinal vein occlusion (CRVO); and the prognosis of CRVO with macular edema after antivascular endothelial growth factor (VEGF) therapy. Materials and Methods: Aqueous humor was obtained during anti-VEGF treatment with intravitreal ranibizumab injection (IRI) in patients with CRVO and macular edema (n = 19) and during cataract surgery in patients with cataracts (controls, n = 20), and the levels of VEGF and novel inflammatory factors were measured. Macular edema was evaluated by central macular thickness (CMT) and neurosensory retinal thickness (TNeuro), and improvement was evaluated by calculating the percentage change in CMT and TNeuro from before to 1 month after IRI. Results: The levels of VEGF and the novel inflammatory factors were significantly higher in the CRVO group, and the levels of Flt-3L, CXCL-16, and endocan-1 were significantly correlated with each other and with the aqueous flare value. Baseline levels of Flt-3L, CXCL-16, and endocan-1 had a significantly negative correlation with the change in CMT, and the baseline level of CXCL-16 was significantly negatively correlated with the change in TNeuro. Conclusions: Relations among novel inflammatory factors should be further investigated. These findings may help improve understanding of macular edema in CRVO patients and aid the development of new treatments targeting novel inflammatory factors.

[Faricimab: from research to clinical practice]. / Faritsimab: ot klinicheskikh issledovanii k real'noi klinicheskoi praktike.

Development of new molecules for anti-angiogenic therapy pursues the following objectives: to increase the interval between injections, which can reduce the treatment burden; to improve the effectiveness of treatment by affecting various links of pathogenesis; to ensure a good safety profile. Faricimab is a humanized immunoglobulin G antibody that targets two key angiogenesis sites: vascular endothelial growth factor A (VEGF-A) and angiopoietin-2 (Ang-2). In the STAIRWAY clinical trial, faricimab was shown to produce similar results to monthly ranibizumab at longer intervals and fewer intravitreal injections in patients with neovascular age-related macular degeneration, specifically in terms of visual preservation and reduction in central retinal thickness (CRT). In the BOULEVARD trial, which lasted 36 weeks, the severity of diabetic retinopathy according to DRSS improved in previously untreated patients with diabetic macular edema by two stages and more in 12.2% of the 0.3 mg ranibizumab group, in 27.7% of patients in the 1.5 mg faricimab group, and in 38.6% of patients in the group treated with 6.0 mg faricimab. In the TENAYA, as well as LUCERNE, YOSEMITE and RHINE trials, the increase in best-corrected visual acuity (BCVA) from baseline in the faricimab group was comparable to that in the aflibercept group. Real clinical practice showed an increase in BCVA from 59.5 to 60.6 letters (p=0.035) due to a decrease in CRT from 334.3 to 303.3 µm (p=0.001). The first published studies are now appearing, and their results correspond to the clinical trials, which indicates a stable effect of the drug and the prospects for use in a large cohort of patients.

[Prognostic factors and a customized approach to anti-VEGF therapy for exudative age-related macular degeneration. Analysis of the risk of macular atrophy development]. / Prognosticheskie faktory i kastomizirovannyi podkhod k anti-VEGF-terapii pri ekssudativnoi forme vozrastnoi makulyarnoi degeneratsii. Analiz riska vozniknoveniya makulyarnoi atrofii.

Age-related macular degeneration (AMD) is a chronic progressive multifactorial disease characterized by a degenerative process in the retinal pigment epithelium (RPE), Bruch's membrane and choriocapillaris of the fovea with secondary neuroepithelial (NE) damage. Intravitreal administration of drugs that inhibit VEGF is recognized as the only treatment for exudative form of AMD. Literature data is limited, and do not allow drawing conclusions about the influence of various factors (identified using OCT in the EDI mode) on the development of various subtypes of atrophy and their progression, so we decided to conduct our own study and research the possible timing and risks of developing various subtypes of macular atrophy in patients with exudative AMD receiving anti-VEGF therapy. As a result of the study, it was revealed that general macular atrophy (p=0.005) has a predominant effect on BCVA in the first year of the follow-up, while subtypes of atrophy anatomically less pronounced at one year of the follow-up manifest themselves only in the second year of the follow-up (p<0.05). Although color photography and autofluorescence are currently the only approved methods for assessing the degree of atrophy, the use of OCT may reveal reliable precursor endpoints that will facilitate and allow earlier and more accurate assessment of neurosensory tissue loss resulting from the atrophy. Thus, the development of macular atrophy is influenced by such parameters of disease activity as intraretinal fluid (p=0.006952), RPE detachment (p=0.001530) and the type of neovascularization (p=0.028860), as well as neurodenegerative changes in the form of drusen (p=0.011259) and cysts (p=0.042023). The new classification of atrophy according to the degree and localization of the lesion allows more differentiated conclusions about the effect of anti-VEGF drugs on the development of certain types of atrophy, which can be a decisive factor in determining the treatment tactics.

[Prognosis criteria of optical coherence tomography angiography for the long-term efficacy of anti-VEGF therapy of neovascular age-related macular degeneration]. / Prognosticheskie kriterii opticheskoi kogerentnoi tomografii-angiografii v otsenke dolgosrochnoi effektivnosti anti-VEGF-terapii neovaskulyarnoi vozrastnoi makulyarnoi degeneratsii setchatki.

PURPOSE: The study aimed to determine the most significant optical coherence tomography angiography (OCTA) parameters in terms of predicting anti-VEGF therapy effectiveness during long-term (3-year) follow-up of patients with neovascular age-related macular degeneration (nAMD). MATERIAL AND METHODS: The study included 122 patients (122 eyes) with mean age of 73.4±6.6 years who were diagnosed with nAMD. Subgroup analysis included 50 patients (50 eyes) with detailed OCT angiography examination of macular neovascularization (MNV) characteristics and their changes in the course of the follow-up, which lasted 144 weeks. All patients were treated by angiogenesis inhibitor (aflibercept 2 mg), most of them - according to Treat-and-Extend protocol. RESULTS: Treatment response (either 'good' or 'partial') was achieved in all patients, and the proportion of the response types was similar in both types 1 and 2 MNV. Key OCTA parameters associated with the number of injections, as well as morphological and functional response (best-corrected visual acuity, retinal neuroepithelium and pigment epithelium detachment), were vascular network area and MNV area assessed at baseline and three months after treatment initiation. Both of these parameters were closely related in both MNV types during the follow-up. Key parameter with maximum number of clinically significant correlations ('very high' strength, p<0.05) in eyes with 'good' response was MNV area, in eyes with 'partial' response - vascular density and greatest vascular caliber. CONCLUSIONS: Vascular network area and MNV area assessed at baseline and after three loading doses were determined as the most significant OCTA characteristics for predicting the number of injections and treatment response based on functional and morphological parameters. MNV area was found to be the most clinically significant marker in 'good' response, vascular density and greatest vascular caliber - in 'partial' response.

[Choroidal neovascularization in central serous chorioretinopathy]. / Khorioidal'naya neovaskulyarizatsiya pri tsentral'noi seroznoi khorioretinopatii.

The literature review discusses the features of the pathogenesis, differential diagnosis and antiangiogenic therapy of choroidal neovascularization (CNV) associated with central serous chorioretinopathy (CSC), with particular attention given to the choice of antiangiogenic drug and therapy regimen to achieve optimal anatomical and functional outcomes in patients with CSC complicated by CNV.

The 12- and 24-Month Effects of Intravitreal Ranibizumab, Aflibercept, and Bevacizumab on Intraocular Pressure: A Network Meta-Analysis.

TOPIC: To investigate the effect of anti-vascular endothelial growth factor (VEGF) therapy on intraocular pressure (IOP) 12 and 24 months after initiation. CLINICAL RELEVANCE: It is unclear whether serial anti-VEGF injections result in sustained IOP increases. METHODS: Randomized controlled trials (RCTs) comparing anti-VEGF agents with each other or with controls for the treatment of neovascular age-related macular degeneration, retinal vein occlusions, or diabetic macular edema were included. Pairwise meta-analysis and Bayesian network meta-analysis examined the proportion of patients whose IOP (1) increased 5 mmHg or more from baseline on consecutive visits, (2) increased 10 mmHg or more from baseline at any visit, (3) was 21 mmHg or more on consecutive visits, (4) was 25 mmHg or more at any visit, (5) was 30 mmHg or more at any visit, (6) prompted initiation of IOP-lowering medications, or (7) increased as per the clinicians' discretion. Grading of Recommendations Assessments, Development, and Evaluations methodology informed the certainty of evidence. RESULTS: Twenty-six RCTs of 12 522 eyes were included. Aflibercept, bevacizumab, ranibizumab (0.3 mg and 0.5 mg), and noninjection controls were analyzed. Eighty-three of 84 network estimates for comparisons between anti-VEGF agents demonstrated no statistically significant difference (low to moderate certainty of evidence). Ranibizumab 0.5 mg showed higher rates than bevacizumab of IOP measurements of 30 mmHg or more at 12 months (low certainty of evidence). Fifty-three of 56 network estimates for comparisons between anti-VEGF agents and controls demonstrated no statistically significant difference (low to moderate certainty of evidence). Ranibizumab 0.5 mg showed higher rates of consecutive IOP increases of 5 mmHg or more at 24 months (low certainty of evidence) and higher rates of IOP increases as per the clinicians' discretion at 12 and 24 months (low and very low certainty of evidence, respectively). The 95% credible intervals in comparisons without statistically significant effects did not rule out important clinical effects. The certainty of evidence in these comparisons is limited by imprecision. CONCLUSION: This network meta-analysis does not show any clear difference in IOP increases 12 and 24 months after treatment initiation between anti-VEGF agents and controls. Imprecision precludes definitive conclusions.

Analysis of the sustained release ability of bevacizumab-loaded tetra-PEG gel.

Multiple intravitreal injections, which are painful and costly, are often required in the treatment of retinal disorders. Therefore, a novel drug delivery system using hydrogels is currently being evaluated as an alternative. This study aimed to evaluate the ability of tetra-armed polyethylene glycol (tetra-PEG) gel for sustained release in vitro. Bevacizumab-loaded tetra-PEG gel and 5-Carboxyfluorescein N-succinimidyl ester (FAM-NHS)-labeled IgG-loaded tetra-PEG gel were prepared by mixing tetra-PEG with thiol termini (tetra-PEG-SH) solution, maleimide termini (tetra-PEG-MA) solution, and bevacizumab or FAM-NHS labeled IgG. The gels were prepared with three different polymer concentrations of 1.5%, 5%, and 10%, then an in vitro release study performed to assess the sustained release ability of the drug-loaded tetra-PEG gels. High performance liquid chromatography (HPLC) was used to test the structural stability of the bevacizumab released from the tetra-PEG gel. The binding of bevacizumab to tetra-PEG-SH or MA was assessed using SDS-polyacrylamide gel electrophoresis (PAGE). The bioactivity of released bevacizumab was tested using KDR/NFAT-RE HEK293 cells. In addition, in vitro degradation and swelling studies were also performed. The in vitro release analysis showed that the release of bevacizumab was slower in the 5% and 10% tetra-PEG gels than that of 1.5% tetra-PEG gels. Similarly, the release of FAM-NHS-labeled IgG was slowest in the 1.5%, 5%, and 10% tetra-PEG gels, in that order. The 5% and 10% tetra-PEG gels released bevacizumab and FAM-NHS-labeled IgG over a period of 1-2 weeks. Both bevacizumab and FAM-NHS-labeled IgG were not fully released in 2 weeks. HPLC analysis showed that the retention time of the samples released from the bevacizumab-loaded tetra-PEG gel was similar to that of the bevacizumab standard. The SDS-PAGE analysis showed that bevacizumab binds to tetra-PEG-MA. The bioactivity assay test revealed no decrease in the bioactivity of the released bevacizumab. In vitro degradation and swelling studies revealed that 1.5%, 5%, and 10% tetra-PEG gels expanded by approximately 1.4-, 2-, and 3-fold, respectively. Based on the results of the release and swelling tests, 5% tetra-PEG gels are considered good candidates for controlled release systems for therapeutic antibodies such as bevacizumab. The binding of PEG to the therapeutic antibodies may reduce the availability of therapeutic antibodies that can be released.

Brolucizumab for pre-treated patients with choroidal neovascularization and signs of tachyphylaxis to aflibercept and bevacizumab.

PURPOSE: Treatment of choroidal neovascularization due to age-related macular degeneration is a challenging topic since an increasing number of patients show reduced morphological response to conventional treatment with intravitreal injections. The present study tested the hypothesis that the newly introduced anti-VEGF antibody brolucizumab does not only show promising results in pre-treated patients but is also a viable option in cases of tachyphylaxis to aflibercept or bevacizumab. METHODS: Thirty-six eyes of 34 patients with a history of at least 10 anti-VEGF injections as well as persistent retinal fluid following the past 5 monthly injections with aflibercept and bevacizumab prior to first treatment with brolucizumab were included in the study. Morphological and functional treatment response was compared before and after switching to brolucizumab. RESULTS: Mean best-corrected visual acuity did not significantly change after treatment with brolucizumab. In contrast, central retinal thickness significantly decreased 4 weeks after treatment with brolucizumab from 340.36 to 282.22 µm (p < 0.001) as well as pigment epithelial detachment from 346.73 to 280.47 µm (p < 0.001). In 24 eyes (66.67%), complete resolution of intra-and subretinal fluid was observed after a single dose of brolucizumab. No serious adverse events, such as intraocular inflammation and retinal vasculitis, were reported after a single injection of brolucizumab. CONCLUSION: Brolucizumab is not only effective in treatment-naïve patients as shown in the pivotal HAWK and Harrier trials, but also in pre-treated patients as seen in the present study. Our data also suggest that brolucizumab is potent in patients with signs of tachyphylaxis to other anti-VEGF agents and thus a viable treatment option.