Choroidal neovascularization activity and structure by optical coherence tomography angiography in age related macular degeneration

Background. In economically developed countries, age-related macular degeneration (AMD) is the leading cause of visual disability among the population of the older age group. The main criterion for the anti-VEGF treatment of neovascular AMD is the activity of choroidal neovascularization (CNV), which is determined by its confi guration. The search for optimal criteria for quantifying the state of the macular region in order to decide on the appointment of anti-VEGF therapy continues.Aim: improving the effi ciency of diagnosis and treatment of AMD based on the assessment of the configuration of vascular system on the “Key to Diagnosis II” platform.Material and methods. The study included 341 patients: 64 % (218 patients, 267 eyes) with non-neovascular AMD, 36 % (123 patients, 174 eyes) – with neovascular AMD. 56 patients (58 eyes) had active type I CNV. Group 1A – active CNV before treatment (9 patients, 9 eyes), group 1B – non-active CNV after treatment with antiVEGF (9 patients, 9 eyes); control group – 10 patients (10 eyes) without AMD. Analysis of OCT-angio images of choriocapillaries included the isolation of CNV, its area, fractal dimension (Df) and the complexity of the vascular system (CVS) counting.Results. Group 1A: Df – 1.5871 ± 0.05, CVS – 2.29 ± 0.29, area – 11734 ± 4866; group 1B: Df – 1.6462 ± 0.08, CVS – 1.65 ± 0.18, area – 6797 ± 3818; control: Df – 1.9167 ± 0.06, CVS – 1, area – 0. Significant differences were found for CVS (p = 0.0003). Df correlates with the CNV area (p = 0.7) and is probably an unreliable parameter due to incomplete visualization of active CNV.Conclusions. CVS is a quantitative biomarker for determining the activity of type 1 CNV in patients with AMD and can serve as a parameter for convolutional neural networks training for automated analysis of OCT angiography images based on the “Key to Diagnosis II” platform

Manifestations of intraocular inflammation over time in patients on brolucizumab for neovascular AMD

Purpose To describe the adverse events associated with brolucizumab, in particular the sequence of intraocular inflammation (IOI), retinal vasculitis (RV), and/or retinal vascular occlusion (RO). Methods This was an unmasked post hoc analysis of the randomized HAWK/HARRIER clinical trials. Patients with neovascular AMD in the brolucizumab arms of the trials were included. IOI-related adverse events reported by study investigators were analyzed to determine early signs and the time course of IOI-related adverse events, using a subgroup of patients with definite/probable IOI cases identified in an independent unmasked post hoc review by an external safety review committee. A limited literature review on IOI following anti-VEGF therapy was also conducted. Results Among 50 patients with definite/probable IOI cases identified by the safety review committee, 12 had RV or RO adverse events reported by the investigators. For 6 of 12, IOI (other than RV) was reported before RV or RO. The duration from the first IOI adverse event to the first RV or RO adverse event ranged from 16 to 171 days for 5 patients and was 553 days for 1 patient. Four of the 6 patients received ≥ 1 brolucizumab injection on or after the date of the first IOI adverse event and before the first RV or RO adverse event. Conclusions IOI may precede RV or RO in some patients treated with brolucizumab.

Progression of macular atrophy in patients receiving long-term anti-VEGF therapy for age-related macular degeneration; Real Life Data

Purpose To evaluate the progression of macular atrophy (MA) based on near-infrared reflectance (NIR) and optical coherence tomography (OCT) images, in patients with age-related macular degeneration (AMD), receiving anti-vascular endothelial growth factor (anti-VEGF) treatment for at least a 6-year period. Materials and Methods This retrospective study included 53 naïve patients (53 eyes) with neovascular AMD from two centers, who were treated with anti-VEGF intravitreal injections and had no MA at baseline. MA was evaluated in an annual basis using NIR images, while all available OCT images were used to confirm that the atrophic area fulfilled the criteria proposed by the Classification of Atrophy Meetings (CAM) group for complete retinal pigment epithelium RPE and outer retinal atrophy (cRORA). Incidence and progression of MA were evaluated. Associations with best-corrected visual acuity (BCVA) and total number of injections were also studied. Results Treatment duration of our patients was 7.34 ± 1.54 years. The mean number of anti-VEGF injections was 24.4 ± 13.6. BCVA at baseline was 0.38 ± 0.27 logMAR while at final visit it was 0.60 ± 0.35 logMAR (p=0.731). The cumulative incidence of new MA at years 1, 2, 3, 4, 5, and 6 was 1.89%, 18.87% 32.08%, 39.62%, 49.06% and 50.94% respectively. In patients who developed MA, mean MA area increased from zero at baseline to 5.66 ± 7.18 mm2 at final visit. The estimated annual enlargement of MA was 0.45 mm/year based on square root transformation (1.12 mm2/year, untransformed data). MA progression does not appear to be significantly associated with age (R=0.055; p=0.784), gender (R=0.113; p=0.576), BCVA (R=0.168; p=0.404) and total number of injections (R=0.133; p=0.255). Conclusion In this real-life setting, half of neovascular AMD patients under anti-VEGF treatment, without MA at therapy initiation, developed MA over a period of at least 6 years. In this work, the number of injections did not seem to have a significant association with MA progression.

Serum 25-hydroxy vitamin D levels in age-related macular degeneration

Purpose The aim of this study was to determine the 25-hydroxy vitamin D (25(OH)D) levels in age-related macular degeneration (AMD) patients. Methods Age-related macular degeneration (AMD) patients were classified into four groups: early AMD (N =10), intermediate AMD (N=12), advanced atrophic AMD (N=19) and advanced neovascular AMD (N=52) after undergoing fundus photography. Serum 25(OH)D levels of all subjects were evaluated. From a random control group of 326 patients whose 25(OH)D levels had been measured, a group of 93 were selected to match the age range of the AMD group. We measured 25(OH)D levels during the same period to rule out seasonal variation. Results A total of 93 AMD patients (36 males and 57 females) and 93 healthy individuals (39 males and 54 females) were enrolled in this study with the mean age of 78.96±8.46 vs. 78.80±8.35, respectively. The patients affected by AMD had statistically significant lower 25(OH)D levels (15±10 ng/mL) than the healthy subjects control group (21±14 ng/mL) (p = 0.004). However, the median 25(OH)D levels in early AMD, intermediate AMD, advanced atrophic AMD and advanced neovascular AMD (12.5±7.3; 15±11; 15±8 and 17±11.5, respectively) were not statistically significant (p = 0.442). Conclusion This study shows that patients affected by AMD had lower vitamin D levels compared to healthy subjects. Further research is necessary to investigate the possible association between 25(OH)D levels and AMD.

Pipeline therapies for neovascular age related macular degeneration

Age related macular degeneration (AMD) is the most common cause of vision loss in the elderly population. Neovascular AMD comprises 10% of all cases and can lead to devastating visual loss due to choroidal neovascularization (CNV). There are various cytokine pathways involved in the formation and leakage from CNV. Prior treatments have included focal laser therapy, verteporfin (Visudyne, Bausch and Lomb, Rochester, New York) ocular photodynamic therapy, transpupillary thermotherapy, intravitreal steroids and surgical excision of choroidal neovascular membranes. Currently, the major therapies in AMD focus on the VEGF-A pathway, of which the most common are bevacizumab (Avastin; Genentech, San Francisco, California), ranibizumab (Lucentis; Genentech, South San Francisco, California), and aflibercept (Eylea; Regeneron, Tarrytown, New York). Anti-VEGF agents have revolutionized our treatment of wet AMD; however, real world studies have shown limited visual improvement in patients over time, largely due to the large treatment burden. Cheaper alternatives, including ranibizumab biosimilars, include razumab (Intas Pharmaceuticals Ltd., Ahmedabad, India), FYB 201 (Formycon AG, Munich, Germany and Bioeq Gmbh Holzkirchen, Germany), SB-11 (Samsung Bioepsis, Incheon, South Korea), xlucane (Xbrane Biopharma, Solna, Sweden), PF582 (Pfnex, San Diego, California), CHS3551 (Coherus BioSciences, Redwood City, California). Additionally, aflibercept biosimilars under development include FYB203 (Formycon AG, Munich, Germany and Bioeq Gmbh Holzkirchen, Germany), ALT-L9 (Alteogen, Deajeon, South Korea), MYL1710 (Momenta Pharamaceuticals, Cambridge, MA, and Mylan Pharmacueticals, Canonsburg, PA), CHS-2020 (Coherus BioSciences, Redwood City, California). Those in the pipeline of VEGF targets include abicipar pegol (Abicipar; Allergan, Coolock, Dublin), OPT-302 (Opthea; OPTHEA limited; Victoria, Melbourne), conbercept (Lumitin; Chengdu Kanghong Pharmaceutical Group, Chengdu, Sichuan), and KSI-301 (Kodiak Sciences, Palo Alto, CA). There are also combination medications, which target VEGF and PDGF, VEGF and tissue factor, VEGF and Tie-2, which this paper will also discuss in depth. Furthermore, long lasting depots, such as the ranibizumab port delivery system (PDS) (Genentech, San Francisco, CA), as well as others are under evaluation. Gene therapy present possible longer treatments options as well and are reviewed here. This paper will highlight the past approved medications as well as pipeline therapies for neovascular AMD.

Correlation between Subfoveal Choroidal Thickness and Disease Activity in Wet Age-Related Macular Degeneration Using Spectral Domain Optical Coherence Tomography

Background Age-related macular degeneration (AMD) is the leading cause of severe irreversible visual impairment worldwide. The disease has a deep impact on the quality of life of affected person and represents a major socioeconomic challenge. Neovascular age-related macular degeneration (nAMD) is a rapidly progressing disease which impacts central vision. It is responsible for 90% of cases of AMD associated severe vision loss. Choroidal thicknening is hypothesized to occur in the active phase of neovascular AMD. On the other hand, multiple studies reported progressive choroidal thinning in nAMD. Aim to study the correlation between choroidal thickness, and the activity of choroidal neovascularization in cases of neovascular (wet) Age related macular degeneration using Spectral domain Ocular coherence tomography. Methodology Our study included 33 eyes of 30 participants subdivided into neovascular AMD group (23 eyes of 20 patients), and age matched control group (10 eyes of 10 participants). Spectral domain optical coherence tomography (Avanti RTVue XR AngioVue OCT (Optovue Inc, Fremont, USA) was used to measure central foveal thickness (CFT), and subfoveal choroidal thickness (SFCT) after conduction of complete ocular examination and history taking. Results Our study shows a significant decrease in subfoveal choroidal thickness in neovascular AMD group (157.82 + 68.67 µm) when compared to the age matched control group (266.9+ 48.37 µm) with (P value <0.001). But, we found no clinically significant difference in SFCT between active CNV (179.23 + 64.36 µm) and inactive CNV groups (136.4 + 72.97 µm) (P value = 0.19). Conclusion there is a significant thinning of choroid in nAMD in comparison to control. But no statistically significant difference in SFCT between active and inactive choroidal neovascular groups.

Morphological characteristics of eyes with neovascular age-related macular degeneration and good long-term visual outcomes after anti-VEGF therapy

PurposeTo analyse the morphological characteristics of eyes with neovascular age-related macular degeneration (AMD) with good long-term visual acuity after anti-VEGF (vascular endothelial growth factor) therapy.MethodsRetrospective, observational study of 175 patients with neovascular AMD with >5 years of follow-up after initiating anti-VEGF therapy. Spectral-domain optical coherence tomography images were assessed for thickness of pigment epithelial detachment (PED), subretinal hyper-reflective material (SHRM), subretinal fluid and subfoveal choroidal, as well as the integrity of the outer retinal bands.ResultsThe final analysis cohort included 203 eyes (175 patients) followed for a mean of 7.84±1.70 years (range: 5–11). The maximum PED thickness in the foveal central subfield (FCS) was significantly lower (p<0.001) in the poor vision group (13.11 μm) compared with the intermediate (86.25 μm) or good (97.92 μm) vision groups, respectively. In contrast, the maximum thickness of SHRM in the FCS was significantly thicker (p<0.001) in eyes with poor vision (149.46 μm) compared with eyes with intermediate vision (64.37 μm) which in turn were significantly thicker (p<0.001) than eyes with good vision (9.35 μm). The good vision group also had better continuity of all outer retinal bands (external limiting membrane, ellipsoid zone, and retinal pigment epithelium) compared with the other two groups (all p<0.001).ConclusionA thicker PED and thinner SHRM were correlated with better vision in eyes with neovascular AMD following long-term anti-VEGF therapy. If replicated in future prospective studies, these findings may have implications for design of optimal anatomic endpoints for neovascular AMD treatment.

Limited Treatment Response during Follow-up after Switching to Aflibercept in Neovascular Age-related Macular Degeneration

Purpose: To investigate the limited response to aflibercept after switching to aflibercept in neovascular age-related macular degeneration (AMD). Methods: This retrospective study included 70 eyes with neovascular AMD that were initially treated with ranibizumab and then switched to aflibercept. The incidence and timing of the limited response to aflibercept were identified and visual outcome was compared between eyes with and without limited response. In addition, factors predictive of limited response were analyzed. Results: A limited response to aflibercept was noted in approximately 1/5 of the patients who underwent switching to aflibercept in neovascular AMD. Switching to aflibercept was performed at a mean of 16.2 ± 12.7 months after diagnosis. During the mean 34.7 months of follow-up after switching, limited response was noted in 15 eyes (21.4%) at a mean of 22.0 ± 13.9 months after switching. The degree of reduction in visual acuity was mean logMAR 0.34 ± 0.41 in eyes with limited response and mean 0.06 ± 0.20 in eyes without (p = 0.002). In addition, the duration between the diagnosis and the switching was shorter (p = 0.012), and the number of ranibizumab injections before switching was lower (p = 0.016) in eyes with limited response than in eyes without. Conclusions: Patients who showed limited response to aflibercept after switching to aflibercept showed a worse visual outcome. The probability of having a limited response is higher when the switching is performed earlier.