PLoS One. 2019 Oct 23;14(10):e0223793.
Evaluation of ranibizumab and aflibercept for the treatment of diabetic macular edema in daily clinical practice.
Plaza-Ramos P, Borque E, García-Layana A.
Purpose: To evaluate the efficacy and safety of ranibizumab and aflibercept in the treatment of diabetic macular edema in a real world study, and to compare the two treatments with each other.
Methods: Retrospective observational study of 213 eyes from 141 patients with diabetic macular edema was completed between June 2014 and June 2016. 122 were treated with ranibizumab intravitreal injection and 91 with aflibercept intravitreal injection, with a loading phase of 3 injections and a Pro Re Nata protocol. The drug was selected by the physician and fluorescein angiography was performed by physician`s criteria. Re-treatment was performed when a decline in BCVA, an increase of central macular thickness or an increase or persistence of intraretinal fluid in OCT was observed. The primary outcome was the mean change in best corrected visual acuity at 1 year, while central macular thickness, central macular volume, the number of injections and visits were evaluated as secondary outcomes. The correlation between BCVA at 4th month visit and BCVA at 12th month visit was also evaluated.
Results: The mean baseline best corrected visual acuity for the eyes treated with ranibizumab was 0.55 (+/- 0.35) logMAR, and with aflibercept it was 0.48 (+/- 0.29) (P = 0.109). Best corrected visual acuity improved in both groups, and at the end of the follow-up was 0.40 (+/- 0.35) in the ranibizumab group and 0.40 (+/- 0.29) in the aflibercept group (P = 0.864). Best corrected visual acuity at 4th month visit is correlated at a high value (R = 0.789) with the one at the end of the study. No differences were found in central macular thickness, central macular volume and glycosylated hemoglobin when adjusting with baseline values. The overall number of injections was 5.77 (+/- 2.01), being 5.56 (+/- 2.0) in the ranibizumab group and 6.07 (+/- 1.99) in the aflibercept group (P = 0.069). The main outcome determining final best corrected visual acuity was the baseline best corrected visual acuity (P<0.001).
Conclusion: There are no differences in efficacy between ranibizumab and aflibercept in diabetic macular edema treatment in this real world study.
PMID: 31644594 DOI: 10.1371/journal.pone.0223793
Int J Ophthalmol. 2019 Oct 18;12(10):1589-1597.
Anatomical and functional changes after dexamethasone implant and ranibizumab in diabetic macular edema: a retrospective cohort study.
Mastropasqua L, Di Staso S, D'Aloisio R, Mastropasqua A, Di Antonio L, Senatore A, Ciancaglini M, Di Nicola M, Di Martino G, Tognetto D, Toto L.
Aim: To investigate the efficacy and safety of ranibizumab (RZB group) and dexamethasone implant (DEX group) intravitreal treatments in patients with treatment-naïve center involved diabetic macular edema (DME) by means of functional and morphological assessments.
Methods: This retrospective cohort study included 50 eyes of 50 patients with DME treated either with RBZ or DEX. Best-corrected visual acuity (BCVA) and microperimetry were evaluated at baseline and during a 6-month follow-up. In addition, central macular thickness (CMT) by means of structural optical coherence tomography (OCT) and retinal capillary plexus density and choriocapillary density by means of OCT angiography were assessed in all cases.
Results: Functional and morphological parameters significantly improved during the study period in both groups. BCVA improved significantly in both groups with a greater increase in the DEX group compared to the RBZ group (P=0.030). Microperimetry significantly differed during follow-up between the two treatments (P=0.031). In both groups CMT significantly decreased (P<0.001) without statistically significant differences between the two groups. A statistically significant increase of deep capillary plexus density was detected in both groups at 30d after therapy. The retreatment rate was 0.70±0.10 and 0.65±0.10 in the RBZ group and 0.65±0.10 and 0.50±0.11 in DEX group at 120 and 180d respectively. Two out of 25 patients in DEX group showed intraocular pressure increase requiring hypotonic eye drops.
Conclusion: Both treatments are very effective for DME treatment during 6mo of follow-up with a lower retreatment rate in DEX group.
PMID: 31637195 PMCID: PMC6796097 DOI: 10.18240/ijo.2019.10.11
Ophthalmic Res. 2019 Oct 23:1-7.
Evidence for activation of lectin and classical pathway complement components in aqueous humor of neovascular age-related macular degeneration.
Omori T, Oguchi Y, Machida T, Kato Y, Ishida Y, Ojima A, Itagaki K, Shintake H, Tomita R, Kasai A, Sugano Y, Ogasawara M, Sekine H, Sekiryu T.
Purpose: The complement system is activated via 3 different pathways; the lectin pathway (LP), classical pathway (CP), and alternative pathway. To investigate the possible roles for the LP or CP in the development of neovascular age-related macular degeneration (nAMD), we compared aqueous humor levels of complement proteins of the LP and CP between eyes with nAMD and those with cataract as controls.
Methods: Seventeen eyes from 17 patients with treatment-naïve nAMD and 9 eyes from 9 patients with cataract were studied. Aqueous humor samples were collected before intravitreal aflibercept or ranibizumab injection for the nAMD patients and before cataract surgery for the cataract patients. Aqueous humor levels of complement C4 of the LP and CP, complement C3 of all 3 complement pathways, and mannose-binding lectin-associated serine protease (MASP)-2 of the LP were measured by enzyme-linked immunosorbent assay. Aqueous humor levels of C4a and C3a, the activation products of C4 and C3, respectively, were measured by a bead-based immunoassay. The ratios of C4a to C4 and C3a to C3, representing the degree of C4 and C3 activation, respectively, were calculated in individual patients.
Results: The aqueous humor levels of C4, C3, and MASP-2 were significantly lower in the nAMD eyes compared to the controls (p = 0.008, p = 0.011, and p = 0.018, respectively). In contrast, the aqueous humor levels of C4a and C3a, as well as the C4a/C4 and C3a/C3 ratios, were significantly higher in the nAMD eyes compared to the controls (p = 0.039, p = 0.003, p < 0.001, and p < 0.001, respectively).
Conclusions: This study provides evidence for significant intraocular activation of either or both of the LP and CP in nAMD eyes that might be involved in the development of nAMD. The significantly lower levels of MASP-2 in the aqueous humor of the nAMD eyes were likely due to MASP-2 consumption by activation of the LP.
PMID: 31645047 DOI: 10.1159/000503258
PLoS One. 2019 Oct 23;14(10):e0223839.
Blue-violet light decreases VEGFa production in an in vitro model of AMD.
Marie M, Gondouin P, Pagan D, Barrau C, Villette T, Sahel J, Picaud S.
Abstract: Blue light is an identified risk factor for age-related macular degeneration (AMD). The production of vascular endothelial growth factor (VEGF), leading to neovascularization, is a major complication of the wet form of this disease. We investigated how blue light affects VEGF expression and secretion using A2E-loaded retinal pigment epithelium (RPE) cells, a cell model of AMD. Incubation of RPE cells with A2E resulted in a significant increase in VEGF mRNA and, intracellular and secreted VEGF protein levels, but not mRNA levels of VEGFR1 or VEGFR2. Blue light exposure of A2E-loaded RPE cells resulted in a decrease in VEGF mRNA and protein levels, but an increase in VEGFR1 levels. The toxicity of 440 nm light on A2E-loaded RPE cells was enhanced by VEGF supplementation. Our results suggest that age-related A2E accumulation may result in VEGF synthesis and release. This synthesis of VEGF, which enhances blue light toxicity for the RPE cells, is itself suppressed by blue light. Anti-VEGF therapy may therefore improve RPE survival in AMD.
PMID: 31644596 DOI: 10.1371/journal.pone.0223839
PLoS One. 2019 Oct 23;14(10):e0222919.
Increased incidence of age-related macular degeneration in sensorineural hearing loss: A population-based cohort study.
Lee CY, Chen HC, Wu PH, Chi JC, Sun CC, Huang JY, Lin HY, Yang SF.
Background: To evaluate the incidence of age-related macular degeneration (AMD) in patients diagnosed with sensorineural hearing loss (SNHL) via the application of the National Health Insurance Research Database in Taiwan.
Methodology/Principal Findings: A retrospective cohort study was conducted. Patients with a diagnosis of SNHL was enrolled in the study group after exclusion and a propensity score matched group without SNHL was served as the control group with a 1:2 ratio. The main outcome was regarded as the emergence of AMD diagnostic codes. Cox proportional hazard regression was applied to analyze the incidence and adjusted hazard ratio (aHR) of AMD in the multivariate model. A total of 15,686 patients with SNHL were included in the study group while another 31,372 non-SNHL patients served as the control group. After a follow-up interval up to 16 years, there were 484 AMD events occurred in the study group and 660 AMD cases in those non-SNHL patients with a significantly higher aHR compared to the control group after adjusting for multiple potential risk factors (aHR: 1.399, 95% CI: 1.244-1.574). Other prominent risk factors for AMD included older age, ischemic heart disease, hyperlipidemia, Alzheimer's disease, liver disease and kidney disease. Besides, a higher cumulative probability of AMD was observed in the study group (log-rank P <0.0001).
Conclusion: The patients with SNHL demonstrated a higher incidence of developing AMD.
PMID: 31644539 DOI: 10.1371/journal.pone.0222919
Genes (Basel). 2019 Oct 18;10(10). pii: E825.
Rare genetic variants in Jewish patients suffering from age-related macular degeneration.
Shoshany N, Weiner C, Safir M, Einan-Lifshitz A, Pokroy R, Kol A, Modai S, Shomron N, Pras E.
Purpose: To identify rare genetic variants in early age-related macular degeneration (AMD) utilizing whole-exome sequencing (WES).
Methods: Eight non-related early-AMD families of different Jewish ethnicities were ascertained. Initial mutation screening (phase-1) included common complement factor-H (CFH) p.Y402H; and age related maculopathy susceptibility 2 (ARMS2) p.A69S; and rare variants complement factor-I (CFI) p.V412M; and hemicentin1 (HMCN1) c.4163delC identified previously in our population. Four families, whose initial screening for the aforementioned variants was negative, underwent WES (phase-2). Bioinformatics filtering was based on functionality (from a panel of 234 genes with proven or presumed association to AMD); predicted severity; and frequency (rare variants with minor allele frequency <1%). When applicable, further screening for specific rare variants was carried out on additional cases of similar ethnicities and phenotypes (phase-3).
Results: Phase-1 identified three families carrying CFI p.V412M mutation. WES analysis detected probable disease-related variants in three out of the remaining families. These included: a family with a variant in PLEKHA1 gene p.S177N; a family with previously reported variant p.R1210C in CFH gene; and two families with the C3 p.R735W variant.
Conclusions: Rare, high-penetrance variants have a profound contribution to early-AMD pathogenesis. Utilization of WES in genetic research of multifactorial diseases as AMD, allows a thorough comprehensive analysis with the identification of previously unreported rare variants.
PMID: 31635417 DOI: 10.3390/genes10100825
Int J Retina Vitreous. 2019 Oct 21;5:45.
In vitro differentiation of cGMP-grade retinal pigmented epithelium from human embryonic stem cells.
Lojudice FH, Fernandes RAB, Innocenti F, Franciozi CE, Cristovam P, Maia M, Sogayar MC, Junior RB.
Background: The World Health Organization (WHO) estimates that the number of individuals who lose their vision due to retinal degeneration is expected to reach 6 million annually in 2020. The retinal degenerative diseases affect the macula, which is responsible for central and detailed vision. Most macular degeneration, i.e., age-related macular degeneration (AMD) develops in the elderly; however, certain hereditary diseases, such as the Stargardt disease, also affect young people. This degeneration begins with loss of retinal pigmented epithelium (RPE) due to formation of drusen (atrophic) or abnormal vessels (exudative). In wet AMD, numerous drugs are available to successful treat the disease; however, no proven therapy currently is available to treat dry AMD or Stargardt. Since its discovery, human embryonic stem cells (hESCs) have been considered a valuable therapeutic tool. Some evidence has shown that transplantation of RPEs differentiated from hESCs cells can result in recovery of both RPE and photoreceptors and prevent visual loss.
Methods: The human embryonic WA-09 stem cell lineage was cultured under current Good Manufacturing Practices (cGMP) conditions using serum-free media and supplements. The colonies were isolated manually and allowed to spontaneously differentiate into RPE cells.
Results: This simple and effective protocol required minimal manipulation and yielded more than 10e8 RPE cells by the end of the differentiation and enrichment processes, with cells exhibiting a cobblestone morphology and displaying cellular markers and a gene expression profile typical of mature RPE cells. Moreover, the differentiated cells displayed phagocytic activity and only a small percentage of the total cells remained positive for the Octamer-binding transcriptions factor 4 (OCT-4) pluripotency cell marker.
Conclusions: These results showed that functional RPE cells can be produced efficiently and suggested the possibility of scaling-up to aim at therapeutic protocols for retinal diseases associated with RPE degeneration.
PMID: 31646003 PMCID: PMC6802162 DOI: 10.1186/s40942-019-0194-7
PLoS One. 2019 Oct 21;14(10):e0222045.
Impact of visual impairment on physical activity in early and late age-related macular degeneration.
Heinemann M, Welker SG, Li JQ, Wintergerst MWM, Turski GN, Turski CA, Terheyden JH, Mauschitz MM, Holz FG, Finger RP.
Background: Modifiable risk factors for age-related macular degeneration (AMD) include smoking, nutrition and likely physical activity (PA). Levels of PA, however, are impacted by any visual impairment which makes the assessment of any association with AMD difficult.
Purpose: To assess the impact of visual impairment under both high and low luminance conditions on levels of PA in early and late AMD.
Methods: Ninety participants with early to late AMD underwent a clinical assessment including conventional best-corrected visual acuity, low luminance visual acuity, contrast sensitivity and the Moorfields acuity test. PA was recorded using a wrist-worn accelerometer (GENEActiv, Activeinsights) on seven consecutive days. Patient characteristics were compared with the Wilcoxon rank-sum test and determinants of moderate-to-vigorous-PA (MVPA) were assessed using linear regression models.
Results: Mean age was 73.9 ± 8.5 years (range 50-89) and 47 subjects (52.2%) were women. Average MVPA time was longer in the early (355.1 ± 252.0 minutes/week) compared to the late AMD group (162.2 ± 134.6 minutes/week; p<0.001). Using linear regression, age [β = -0.25; 95% confidence interval (CI): -12.9; -0.8, p = 0.028] and AMD stage (β = -0.28; 95% CI: -230.9, -25.0; p = 0.015) but not visual impairment on any of the employed tests were associated with MVPA (minutes/week).
Conclusions: We found late AMD to be associated with reduced PA. As performance on any of the visual tests was not associated with PA, this association cannot entirely be explained by functional impairment. More research is needed to further explore the association of PA and AMD as PA may be a potentially modifiable risk factor.
PMID: 31634374 DOI: 10.1371/journal.pone.0222045