Ophthalmol Retina. 2019 May;3(5):393-399.
Long-term outcome of intravitreal aflibercept treatment for neovascular age-related macular degeneration using a "treat-and-extend" regimen.
Traine PG, Pfister IB, Zandi S, Spindler J, Garweg JG.
Purpose: To report outcomes in patients with neovascular age-related macular degeneration (nAMD) after treatment with aflibercept for up to 4 years using a treat-and-extend (T&E) regimen.
Design: Observational study.
Participants: Patients with newly diagnosed nAMD treated with aflibercept in a T&E protocol.
Methods: Subjects received 3 injections of aflibercept at monthly intervals followed by a T&E protocol for at least 12 months. At each clinical visit after the loading phase, OCT and best-corrected visual acuity (BCVA) testing were performed to monitor disease activity.
Main Outcome Measures: Change in BCVA over time, number of injections and visits per year, and percentage of patients reaching a treatment interval of ≥12 weeks.
Results: Of 231 consecutive eyes (231 patients) with a mean follow-up time of 2.9 (1-5.5) years, 173 were followed up for ≥2 years, 112 were followed up for ≥3 years, and 62 were followed up for ≥4 years. Mean BCVA increased from 59.8 letters (20/60) at diagnosis to 65.8 letters (20/50) after the loading phase (+6.0 letters; standard deviation [SD], 11.1) and to 65.5 letters at 12 months (+5.7 letters; [SD], 17). After 4 years of treatment, mean BCVA was maintained insignificantly better than baseline (63.4 letters, +3.6 letters gain, SD, 20.6; P > 0.05). To achieve this, a mean of 7.7 (±1.2) injections and 4.4 (±1.6) clinic visits in the first year and 4.4 (±1.9) injections and 4.3 (±1.3) clinical visits per year thereafter were required. By 2 years of follow-up, 46.9% of patients reached a treatment interval of ≥12 weeks.
Conclusions: By using a T&E regimen, patients with nAMD maintained stable visual function over 4 years in a real-world setting with a reasonable treatment burden.
PMID: 31044729 DOI: 10.1016/j.oret.2019.01.018
Br J Ophthalmol. 2019 Apr 30. pii: bjophthalmol-2018-313462.
Posterior segment drug delivery for the treatment of exudative age-related macular degeneration and diabetic macular oedema.
Wong CW, Wong TT.
Abstract: Inhibitors of vascular endothelial growth factors are used to treat a myriad of retinal conditions, including exudative age-related macular degeneration (AMD), diabetic macular oedema (DME) and diabetic retinopathy. Although effective, long-term efficacy is limited by the need for frequent and invasive intravitreal injections. The quest for sustained action therapeutics that can be delivered to target tissue in the least invasive manner is an arduous endeavour that has ended in premature failure for several technologies in Phase II or III trials. Nevertheless, there have been promising preclinical studies, and more are on the horizon: port delivery systems for the treatment of exudative AMD have entered Phase III trials and a wide array of preclinical studies have demonstrated the potential for nanoparticles, such as liposomes, dendrimers and cell penetrating peptides to deliver therapeutics into the posterior segment via minimally invasive routes. In this review, we discuss the challenges posed by ocular barriers for drug penetration and present the recent advancements of the most pertinent drug delivery platforms with a focus on the treatment of exudative AMD and DME.
PMID: 31040133 DOI: 10.1136/bjophthalmol-2018-313462
JAMA. 2019 Apr 29.
Effect of initial management with aflibercept vs laser photocoagulation vs observation on vision loss among patients with diabetic macular edema involving the center of the macula
and good visual acuity: A Randomized Clinical Trial.
Baker CW, Glassman AR, Beaulieu WT, Antoszyk AN, Browning DJ, Chalam KV, Grover S, Jampol LM, Jhaveri CD, Melia M, Stockdale CR, Martin DF, Sun JK; DRCR Retina Network.
Importance: Intravitreous injections of antivascular endothelial growth factor agents are effective for treating diabetic macular edema (DME) involving the center of the macula (center-involved DME [CI-DME]) with visual acuity impairment (20/32 or worse). The best approach to treating patients with CI-DME and good visual acuity (20/25 or better) is unknown.
Objective: To compare vision loss at 2 years among eyes initially managed with aflibercept, laser photocoagulation, or observation.
Design, Setting and Participants: Randomized clinical trial conducted at 91 US and Canadian sites among 702 adults with type 1 or type 2 diabetes. Participants had 1 study eye with CI-DME and visual acuity of 20/25 or better. The first participant was randomized on November 8, 2013, and the final date of follow-up was September 11, 2018.
Interventions: Eyes were randomly assigned to 2.0 mg of intravitreous aflibercept (n = 226) as frequently as every 4 weeks, focal/grid laser photocoagulation (n = 240), or observation (n = 236). Aflibercept was required for eyes in the laser photocoagulation or observation groups that had decreased visual acuity from baseline by at least 10 letters (≥ 2 lines on an eye chart) at any visit or by 5 to 9 letters (1-2 lines) at 2 consecutive visits.
Main Outcomes and Measures: The primary outcome was at least a 5-letter visual acuity decrease from baseline at 2 years. Antiplatelet Trialists' Collaboration adverse events (defined as myocardial infarction, stroke, or vascular or unknown death) were reported.
Results: Among 702 randomized participants (mean age, 59 years; 38% female [n=264]), 625 of 681 (92% excluding deaths) completed the 2-year visit. For eyes with visual acuity that decreased from baseline, aflibercept was initiated in 25% (60/240) and 34% (80/326) in the laser photocoagulation and observation groups, respectively. At 2 years, the percentage of eyes with at least a 5-letter visual acuity decrease was 16% (33/205), 17% (36/212), and 19% (39/208) in the aflibercept, laser photocoagulation, and observation groups, respectively (aflibercept vs laser photocoagulation risk difference, -2% [95% CI, -9% to 5%]; relative risk, 0.88 [95% CI, 0.57-1.35; P = .79]; aflibercept vs observation risk difference, -3% [95% CI, -11% to 4%]; relative risk, 0.83 [95% CI, 0.55-1.27; P = .79]; laser photocoagulation vs observation risk difference, -1% [95% CI, -9% to 6%]; relative risk, 0.95 [95% CI, 0.64-1.41; P = .79]). Antiplatelet Trialists' Collaboration vascular events occurred in 15 (7%), 13 (5%), and 8 (3%) participants in the aflibercept, laser photocoagulation, and observation groups.
Conclusions and Relevance: Among eyes with CI-DME and good visual acuity, there was no significant difference in vision loss at 2 years whether eyes were initially managed with aflibercept or with laser photocoagulation or observation and given aflibercept only if visual acuity worsened. Observation without treatment unless visual acuity worsens may be a reasonable strategy for CI-DME.
Trial Registration: ClinicalTrials.gov Identifier: NCT01909791.
PMID: 31037289 DOI: 10.1001/jama.2019.5790
Ophthalmol Retina. 2019 May;3(5):400-409.
Multicolor fundus imaging of polypoidal choroidal vasculopathy.
Tan CS, Ting DS, Lim LW.
Purpose: Polypoidal choroidal vasculopathy (PCV) is a variant of neovascular age-related macular degeneration with distinct phenotypes, treatment, and visual prognosis. Multicolor imaging is a novel noninvasive imaging method that enables visualization of structures located at different layers of the retina and may be useful in detecting features of diseases. The features of PCV seen on multicolor imaging have not been studied. We aimed to describe the features of PCV detected using multicolor imaging and to compare these with standard color fundus photography (CFP).
Design: Hospital-based, cross-sectional study.
Participants: Fifty consecutive treatment-naive patients diagnosed with PCV seen in a tertiary referral center.
Methods: Multimodal imaging was performed using standardized protocols, and included CFP, multicolor imaging, fluorescein angiography, and indocyanine green angiography (ICGA). The CFP and ICGA images were independently graded by reading center-certified retinal specialists to confirm the diagnosis of PCV and identify lesion components. The features of the lesion components seen on multicolor images were compared with those detected using CFP and ICGA.
Main Outcome Measures: Frequency and features of lesions associated with PCV, specifically, polyps, branching vascular network (BVN), pigment epithelial detachments (PEDs), hemorrhages, and drusen.
Results: The mean age of the 50 participants was 67.9 years, and 60% were male. Polyps were most clearly seen on the infrared reflectance image and detected in 49 of 50 eyes (98%), appearing as dark gray oval lesions with distinct margins. On the multicolor composite images, polyps appeared as dark green oval lesions. The BVN appeared as mottled gray regions on infrared reflectance imaging and were seen less frequently compared with polyps (30/50 eyes, 60%). The margins of the BVN were less distinct compared with polyps. Other clinical features detected using multicolor imaging included PEDs (26%), subretinal hemorrhages (40%), and drusen (66%).
Conclusions: Multicolor imaging is able to detect polypoidal lesions in most patients with PCV. The appearance of PCV lesions on multicolor imaging differs from standard CFP, although the location and shape of lesions correlate well with features seen on CFP and ICGA. Multicolor imaging is a useful, noninvasive adjunct to detect features suggestive of PCV, which may prompt definitive investigations such as ICGA.
PMID: 31044730 DOI: 10.1016/j.oret.2019.01.009
PLoS One. 2019 Apr 29;14(4):e0216304.
Vascular maturity of type 1 and type 2 choroidal neovascularization evaluated by optical coherence tomography angiography.
Nakano Y, Kataoka K, Takeuchi J, Fujita A, Kaneko H, Shimizu H, Ito Y, Terasaki H.
Purpose: Vessel maturation is considered to proceed by pruning branches resulting in less branching vessels. This study investigated the vessel junction densities of type 1 and type 2 choroidal neovascularizations (CNVs) using optical coherence tomography angiography (OCTA).
Methods: We collected consecutive data from treatment-naïve eyes diagnosed with typical age-related macular degeneration (AMD). The OCTA images with CNV were analyzed to calculate vessel areas, vessel lengths, and vessel junction densities.
Results: Of 60 eyes in 60 patients, type 1 CNV diagnoses had been made in 40 eyes, and type 2 CNV in 20 eyes. We found no significant difference in vessel areas between type 1 CNV and type 2 CNV (type 1 CNV, 0.44 ± 0.37 mm2; type 2 CNV, 0.37 ± 0.48 mm2), and no significant difference in vessel lengths (type 1 CNV, 18.24 ± 15.96 mm; type 2 CNV, 16.13 ± 21.45 mm). However, the vessel junction density of type 1 CNV was significantly lower than that of type 2 CNV by 16.0% (P = 0.008).
Conclusion: OCTA revealed that the vessel junction densities of type 1 CNVs were lower than those of type 2 CNVs, suggesting type 1 CNV vessels are more mature than type 2 CNV vessels.
PMID: 31034505 DOI: 10.1371/journal.pone.0216304
Eye (Lond). 2019 May 1.
Reliability and diagnostic performance of a novel mobile app for hyperacuity self-monitoring in patients with age-related macular degeneration.
Schmid MK, Thiel MA, Lienhard K, Schlingemann RO, Faes L, Bachmann LM.
Purpose: To assess the reliability and the diagnostic performance of a novel CE (European Conformity)-marked and FDA (Food and Drug Administration)-cleared dot patient self-monitoring test (Alleye, Oculocare medical Inc.) for the detection and characterization of metamorphopsia in age-related macular degeneration (AMD).
Methods: Three consecutive tests were performed in 63 wet AMD, 26 dry AMD, and 19 age-matched healthy eyes. In addition, the test was performed in 34 young healthy eyes. The mean Alleye score and standard deviations (SDs) were calculated for each eye and group. We compared and tested healthy with dry and wet AMD eyes and assessed the extent to which the test discriminated between healthy subjects and patients with dry and wet AMD using the area under the receiver operating characteristic curve (AUC).
Results: The mean (SD) Alleye score was 49.5 (16.1) in wet AMD eyes, 62.1 (22.5) in dry AMD eyes, 69.8 (10.2) in age-matched healthy eyes, and 85.3 (10.0) in young healthy subjects. Compared to age-matched healthy subjects, the AUC (95% confidence interval) to detect wet AMD was 0.845 (0.759-0.932), and 0.660 (0.520-0.799) to discriminate between dry and wet AMD. Compared to young healthy subjects, the AUC to detect dry AMD was 0.799 (0.675-0.923), and 0.969 (0.940-0.997) to detect wet AMD.
Conclusions: This is the first assessment of Alleye in clinical practice. The test is highly accurate to detect wet AMD and reasonably accurate to classify dry vs. wet AMD. Data from longitudinal monitoring and its role in the therapeutic management of AMD is warranted.
PMID: 31043690 DOI: 10.1038/s41433-019-0455-6
Curr Mol Med. 2019 Apr 24.
Celastrol protects RPE cells from oxidative stress-induced cell death via activation of Nrf2 signaling pathway.
Zhou Y, Zhou L, Zhou K, Zhang J, Shang F, Zhang X.
Purpose: Oxidative stress to retinal pigment epithelial (RPE) cells and inflammation are closely related to the pathogenesis of age-related macular degeneration (AMD). Celastrol is a natural compound isolated from the root of Tripterygium wilfordii. Celastrol has been shown to have potent anti-inflammatory and anti-tumor effects in multiple disease models. The objective of this study was to test the anti-oxidative effects of celastrol in RPE cells and to investigate the underlying mechanisms.
Methods: ARPE-19 cells were treated with hydrogen peroxide (H2O2) and menadione alone or in combination with celastrol. Cell viability and apoptosis were examined by CCK-8 and TUNEL assay, respectively. The expression of Nrf2 and its target genes, such as GCLM and HO-1 were determined by Western blotting. The knockdown of Nrf2 was done by transfecting ARPE-19 cells with lentivirus encoding shRNA against Nrf2. The knockdown efficiency was determined by real-time quantitative PCR and Western blotting.
Results: Treatment of ARPE-19 cells with celastrol significantly attenuated the toxic effects of both H2O2 and menadione. Treatment with celastrol enhanced the expression of transcription factor Nrf2 and its targets, GCLM and HO-1. Knockdown of Nrf2 expression by shRNA partially abolished the protective effects of celastrol. Chemical inhibition of glutathione synthesis by L-buthionine-S,R-sulfoximine (BSO) completely abolished the protective effects of celastrol against H2O2 and menadione-induced damage. However, chemical inhibition of HO-1 activity by ZnPPIX did not reduce the protective effects of celastrol.
Conclusion: This study provides evidence that treatment of RPE cells with celastrol shows potent protective effects against oxidative insults via activation of Nrf2 signaling pathway and upregulation of GCLM expression. This finding suggests that celastrol might be used as a potential therapeutic agent for oxidative stress-related eyes diseases, such as AMD.
PMID: 31032752 DOI: 10.2174/1566524019666190424131704
Sci Rep. 2019 Apr 29;9(1):6611.
Genetic risk score has added value over initial clinical grading stage in predicting disease progression in age-related macular degeneration.
Heesterbeek TJ, de Jong EK, Acar IE, Groenewoud JMM3, Liefers B, Sánchez CI, Peto T, Hoyng CB, Pauleikhoff D, Hense HW, den Hollander AI.
Abstract: Several prediction models for progression of age-related macular degeneration (AMD) have been developed, but the added value of using genetic information in those models in addition to clinical characteristics is ambiguous. In this prospective cohort study, we explored the added value of genetics using a genetic risk score (GRS) based on 52 AMD-associated variants, in addition to the clinical severity grading at baseline as quantified by validated drusen detection software, to predict disease progression in 177 AMD patients after 6.5 years follow-up. The GRS was strongly associated with the drusen coverage at baseline (P < 0.001) and both the GRS and drusen coverage were associated with disease progression. When the GRS was added as predictor in addition to the drusen coverage, R2 increased from 0.46 to 0.56. This improvement by the GRS was predominantly seen in patients with a drusen coverage <15%. In patients with a larger drusen coverage, the GRS had less added value to predict progression. Thus, genetic information has added value over clinical characteristics in predicting disease progression in AMD, but only in patients with a less severe disease stage. Patients with a high GRS should be made aware of their risk and could be selected for clinical trials for arresting progression.
PMID: 31036867 DOI: 10.1038/s41598-019-43144-3
Case Rep Ophthalmol. 2019 Jan 24;10(1):24-31.
Two-year outcome of aflibercept for the treatment of choroidal neovascularization in punctate inner choroidopathy.
Arrevola L, Acero MA, Peral MJ.
Abstract: Punctate inner choroidopathy (PIC) is a rare inflammatory chorioretinopathy that predominantly affects young myopic women. Visual prognosis is generally good, but occurrence of choroidal neovascularization (CNV) is common and may be vision threatening. Case reports and short case series support the effectiveness of intravitreal anti-vascular endothelial growth factor (VEGF) agents (ranibizumab and bevacizumab) for CNV associated with PIC given their anti-angiogenic and anti-inflammatory effects. Evidence concerning aflibercept, a more recent intravitreal anti-VEGF, is limited to a single case report. In this case report, we illustrate the case of a 43-year-old myopic woman presenting with visual acuity loss and distortion in the right eye over the last 5 days in whom CNV associated with PIC was diagnosed. Treatment with 1 injection per month of intravitreal aflibercept for 2 months and full-dose oral prednisone for 1 week, being tapered afterwards, improved visual acuity and resolved CNV, with benefits lasting up to 24 months.
PMID: 31043958 PMCID: PMC6477474 DOI: 10.1159/000496143