Risk of Systemic Adverse Events Following Intravitreal Bevacizumab, Ranibizumab, and Aflibercept in Routine Clinical Practice
Ophthalmology. 2020 Aug 8;S0161-6420(20)30782-X.
Maya H Maloney, Stephanie R Payne, Jeph Herrin, Lindsey R Sangaralingham, Nilay D Shah, Andrew J Barkmeier
PMID: 32781110 DOI: 10.1016/j.ophtha.2020.07.062
Purpose: Intravitreal anti-VEGF pharmacotherapy plays a central role in the management of neovascular age-related macular degeneration (nAMD), diabetic retinal disease (DRD), and retinal venous occlusive disease (RVO). Within clinical trials, rates of systemic serious adverse events (SAEs) following anti-VEGF treatment have been low. However, the comparative systemic safety profile of common anti-VEGF agents remains incompletely understood. The goal of this study was to compare the systemic safety of intravitreal bevacizumab, ranibizumab, and aflibercept in real-world practice.
Design: Retrospective cohort study SUBJECTS: Using a large U.S. administrative claims database of commercially-insured and Medicare Advantage enrollees, we identified adult cohorts receiving initial anti-VEGF injections for nAMD, DRD, and RVO between 1/1/2007 and 6/30/2018. We included patients with one year of insurance coverage prior to initial treatment.
Methods: We compared predefined systemic outcomes between anti-VEGF agents occurring within 180 days of treatment initiation using propensity score-weighted Cox proportional hazards models. Patients were censored upon treatment with a different anti-VEGF medication or termination of health plan coverage.
Main outcome measures: Primary outcomes were acute myocardial infarction (MI), acute cerebrovascular disease (CVD), major bleeding, and all-cause hospitalization.
Results: 87,844 patients received initial anti-VEGF injections for nAMD, DRD, and RVO between 1/1/2007 and 6/30/2018 (69,007 bevacizumab; 10,895 ranibizumab; 7,942 aflibercept). Post-injection 180-day event rates per 100 patients for MI, CVD, major bleeding, and all-cause hospitalization were similar for bevacizumab (0.64, 0.59, 0.34, and 10.41), ranibizumab (0.62, 0.53, 0.40, and 9.44), and aflibercept (0.63, 0.60, 0.20, and 9.88). No differences were identified in the risk of MI, CVD, major bleeding, or all-cause hospitalization when comparing the risk-adjusted effect of treatment initiation with bevacizumab vs ranibizumab (HR [95% CI] 0.96 [0.74,1.25], 1.04 [0.78,1.38], 0.85 [0.61,1.19], 1.03 [0.96,1.10], all p>0.05), bevacizumab vs aflibercept (HR [95% CI] 0.95 [0.68,1.33], 0.99 [0.71, 1.38], 1.02 [0.60,1.74], 1.01 [0.93,1.10], all p>0.05), or aflibercept vs ranibizumab (HR [95% CI] 0.91 [0.62,1.35], 1.12 [0.74,1.69], 0.96 [0.53,1.73], 1.02 [0.92,1.13], all p>0.05).
Conclusions: We observed no differences in the risk of acute myocardial infarction, cerebrovascular disease, major bleeding, or all-cause hospitalization, following treatment initiation with intravitreal bevacizumab, ranibizumab, or aflibercept during routine clinical practice.
Occlusive Retinal Vasculitis Following Intravitreal Brolucizumab
J Vitreoretin Dis. 2020 Jul;4(4):269-279.
Andre J Witkin, Paul Hahn, Timothy G Murray, J Fernando Arevalo, Kevin J Blinder, Netan Choudhry, Geoff G Emerson, Roger A Goldberg, Stephen J Kim, Joel Pearlman, Eric W Schneider, Homayoun Tabandeh, Robert W Wong
PMID: 32789284 PMCID: PMC7418897 DOI: 10.1177/2474126420930863
Purpose: To analyze a case series of retinal vasculitis reported to the American Society of Retina Specialists (ASRS) following Food and Drug Administration approval of brolucizumab for treatment of neovascular age-related macular degeneration.
Methods: The ASRS Research and Safety in Therapeutics Committee analyzed clinical and imaging characteristics from submitted reports of retinal vasculitis after brolucizumab.
Results: Retinal vasculitis was reported in 26 eyes of 25 patients (22 [88%] female) after treatment with brolucizumab. Imaging studies were available for 24 of 26 eyes. Most cases (92%) were associated with intraocular inflammation, which presented at a mean of 25 days (range, 3-63 days) after the most recent brolucizumab injection. Mean visual acuity (VA) was 20/52 (range, 20/25-4/200) before the adverse event, 20/151 (range, 20/25-hand motion) at presentation of the adverse event, and 20/243 (range, 20/30-light perception) at last follow-up. Twelve eyes (46%) had a greater than 3-line decrease in VA at final follow-up, and 12 eyes (46%) had a final VA of 20/200 or worse. Analysis of retinal imaging identified vasculopathy that involved retinal arteries (91%), retinal veins (79%), and choroidal vessels (48%). Occlusive disease was apparent on imaging in 83% of eyes. Treatment approaches were varied.
Conclusions: Retinal vasculitis has been identified in a series of eyes following brolucizumab. Although a few eyes in this series were asymptomatic or minimally symptomatic, some eyes had significant vision loss. A careful examination for signs of active inflammation prior to brolucizumab injection is recommended. Once vasculopathy is suspected, angiographic imaging may help define the spectrum of involvement. Optimal treatment strategies remain unknown.
Importance of continuous treatment with intravitreal aflibercept injections in patients with neovascular age-related macular degeneration-12-month post hoc analysis of the PERSEUS real-world evidence study
Graefes Arch Clin Exp Ophthalmol. 2020 Aug 13.
Joachim Wachtlin, Nicole Eter, Zoran Hasanbasic, Georgios Keramas, Christine Rech, Helmut Sachs, Harald Schilling, Peter Wiedemann, Carsten Framme
PMID: 32789651 DOI: 10.1007/s00417-020-04803-8
Purpose: To investigate the influence of treatment regularity with intravitreal aflibercept injections (IVT-AFL injections) on visual acuity (VA) outcomes in patients with neovascular age-related macular degeneration (nAMD) enrolled in the PERSEUS trial who received at least 7 IVT-AFL injections during the first year.
Methods: This was a post hoc analysis of the PERSEUS trial, a prospective, non-interventional, multicenter cohort study, and included 370 patients with nAMD who had received ≥ 7 IVT-AFL injections during year 1. In addition to the prespecified subgroups of treatment-naïve and previously treated patients, results were compared between patients with regular (n = 209) and irregular (n = 161) treatment. Regular treatment was defined as initial dosing with monthly IVT-AFL injections for 3 months, then bimonthly IVT-AFL injections until month 12. Irregular treatment was defined as any deviation from regular treatment (provided ≥ 7 injections were received). The outcome of primary interest was the mean change in VA from baseline after 12 months. Further outcomes of interest included VA gain or loss, proportion of patients achieving reading vision, and percentage of patients with fluid.
Results: At month 12, the mean (± standard deviation, SD) VA improvement from baseline was 6.1 ± 15.6 Early Treatment Diabetic Retinopathy Study letters in the regular cohort and 2.5 ± 16.7 letters in the irregular cohort with ≥ 7 IVT-AFL injections (P = 0.0514). Best results were obtained in the treatment-naïve regular sub-cohort with a mean ± SD VA improvement of 8.0 ± 17.7 letters, whereas treatment-naïve patients with irregular treatment experienced a considerably lower VA gain (2.8 ± 20.0 letters). Irregular treatment consistently correlated with inferior results in treatment-naïve patients. At month 12, the proportion of treatment-naïve patients who had experienced a worsening of ≥ 5 letters was 29.6% in the irregular sub-cohort versus 13.6% in the regular sub-cohort (P = 0.0049). However, among the treatment-naïve patients, the mean number of injections was significantly higher in the irregular than in the regular sub-cohort (8.0 ± 1.2 vs. 7.4 ± 0.6; P = 0.0001). Furthermore, compared with the treatment-naïve, regular sub-cohort, patients in the irregular sub-cohort had more visits (19.1 ± 8.6 vs. 16.1 ± 5.7), VA tests (14.2 ± 6.9 vs. 12.0 ± 4.6), and optical coherence tomography examinations (5.1 ± 3.7 vs. 3.4.0 ± 3.0).
Conclusions: Although irregularly treated patients received more injections and more monitoring visits during the first year of IVT-AFL treatment, they experienced worse VA outcomes than regularly treated patients.
The prognostic value of total macular external limiting membrane and ellipsoid zone damage for clinical outcome in treatment-resistant neovascular age-related macular degeneration
Graefes Arch Clin Exp Ophthalmol. 2020 Aug 10.
Malgorzata Woronkowicz, Sue Lightman, Oren Tomkins-Netzer
PMID: 32778909 DOI: 10.1007/s00417-020-04869-4
Purpose: To examine the prognostic value of the extent of damage to the ellipsoid zone (EZ) and external limiting membrane (ELM) in response to the treatment of age-related macular degeneration (AMD) eyes switched from ranibizumab to aflibercept.
Methods: This is a retrospective study of patients with neovascular AMD resistant to ranibizumab defined as having persistent intra- or subretinal fluid on OCT scans despite at least 6-month treatment and switched to aflibercept. Clinical data was collected and quantitative measurements of the area of EZ and ELM damage were obtained, on en-face optical coherence tomography images, at the time of switch to aflibercept (baseline) and up to 6 months of follow-up.
Results: The study included 71 eyes (52.1% right eye) of 71 patients. At baseline, there was a correlation between the size of the EZ and ELM damaged area and BCVA (R = -0.39, p = 0.001 and R = -0.47, p < 0.001, respectively). The EZ and ELM damaged areas maintained correlation with BCVA at 6 months (R = -0.28, p = 0.01 and R = -0.39, p = 0.001, respectively). Central retinal thickness did not correlate with BCVA at the time of switch (p = 0.38) or at 6 months (p = 0.36).
Conclusions: The extent of damage to the EZ and ELM correlates with BCVA following a switch in treatment.
Screening medications for association with progression to wet age-related macular degeneration (AMD)
Ophthalmology. 2020 Aug 7;S0161-6420(20)30752-1.
Shirley V Wang, Martin Kulldorff, Stephen Poor, Dennis S Rice, Angela Banks, Ning Li, Joyce Lii, Joshua J Gagne
PMID: 32777229 DOI: 10.1016/j.ophtha.2020.08.004
Objective: There is an urgent need for treatments that prevent or delay development to advanced age-related macular degeneration (AMD). Drugs already on the market for other conditions could affect progression to nAMD. If identified, these drugs could provide insights for drug development targets. The objective of this study was to use a novel data mining method that can simultaneously evaluate thousands of correlated hypotheses, while adjusting for multiple testing, to screen for associations between drugs and delayed progression to nAMD.
Design: We applied a nested case-control study to administrative insurance claims data to identify cases with nAMD and risk-set sampled controls that were 1:4 variable ratio matched on age, gender and recent healthcare utilization.
Methods: We used a tree-based scanning method to evaluate associations between hierarchical classifications of drugs that patients were exposed to within 6 months, 7-24 months, or ever prior to their index date. The index date was the date of first nAMD diagnosis in cases. Risk-set sampled controls were assigned the same index date as the case to whom they were matched. The study was implemented using Medicare data from New Jersey and Pennsylvania, and national data from IBM MarketScan Research Database. We set an a priori threshold for statistical alerting at p ≤ 0.01 and focused on associations with large magnitude (relative risks ≥ 2.0).
Results: Out of nearly 4,000 generic drugs and drug classes evaluated, the method detected 19 distinct drug exposures with statistically significant, large relative risks indicating that cases were less frequently exposed than controls. These included 1) drugs with prior evidence for a causal relationship (e.g. megestrol), 2) drugs without prior evidence for a causal relationship, but potentially worth further exploration (e.g. donepezil, epoetin alfa), 3) drugs with alternative biologic explanations for the association (e.g. sevelamer), and 4) drugs that may have resulted in statistical alerts due to their correlation with drugs that alerted for other reasons.
Conclusions: This exploratory drug screening study identified several potential targets for follow up studies to further evaluate and determine if they may prevent or delay progression to advanced AMD.
Effect of the Duration of Intraretinal or Subretinal Fluid on the Response to Treatment in Undertreated Age-Related Macular Degeneration
J Ophthalmol. 2020 Jul 26;2020:5308597.
Izumi Yoshida, Masashi Sakamoto, Asao Sakai, Takatoshi Maeno
PMID: 32774905 PMCID: PMC7399753 DOI: 10.1155/2020/5308597
We investigated the association between the duration of intraretinal fluid (IRF) or subretinal fluid (SRF) and the response to antivascular endothelial growth factor injection in patients with undertreated age-related macular degeneration (ARMD). The Ethics Committee of Toho University Sakura Medical Center approved this study (no. S18030). Eighty eyes of ARMD patients with VA ≤20/100 were retrospectively assessed. Each injection's efficacy was classified, and the fluid accumulation prior to each injection was evaluated. The effect changes following to accumulated IRF, SRF, the longest persistent IRF period (≥10 months), and their determining factors were evaluated. Throughout observation, acquired refractoriness was rarely associated with increased accumulation of IRF or SRF. The injection span had a tendency to be short, and the polypoidal choroidal vasculopathy and occult choroidal neovasculopathy (CNV) proportions had a tendency to be higher among patients with diminished effects than among those with maintained effects. VA differed significantly with continuous IRF duration, but not with accumulated fluid. The diminishing effect of injections during long-standing IRF was rarely associated with undertreatment. The mechanism underlying acquired refractoriness remains unknown; the effect change demonstrated various patterns, including diminished and improved responses. The longest continuous IRF duration was associated with VA decline. Shortening the duration of continuous IRF may be necessary.
The Timing of Large Submacular Hemorrhage Secondary to Age-related Macular Degeneration Relative to Anti-VEGF Therapy
Ophthalmol Retina. 2020 Aug 4;S2468-6530(20)30313-4.
Douglas R Matsunaga, Daniel Su, Kareem Sioufi, Anthony Obeid, Turner Wibbelsman, Allen C Ho, Carl D Regillo
PMID: 32763426 DOI: 10.1016/j.oret.2020.07.028
Purpose: To characterize the timing of large submacular hemorrhage (SMH) secondary to neovascular age-related macular degeneration (AMD) relative to anti-vascular endothelial growth factor (VEGF) therapy.
Design: Retrospective consecutive case series.
Subjects: The study included 46 eyes of 46 patients with large SMH due to neovascular AMD selected to undergo pars plana vitrectomy with subretinal tissue plasminogen activator at the Mid Atlantic Retina group of the Wills Eye Hospital.
Methods: Patient charts were reviewed to identify baseline characteristics and anti-VEGF treatment details. Optical coherence tomography was used to evaluate pigmented epithelial detachments, SMH and subretinal fluid pre- and post-SMH.
Main outcome measures: The timing of SMH in relation to last anti-VEGF injection, the anti-VEGF treatment status (i.e. naïve, stable, or recently extended/shortened) at the time of SMH, and the length of the anti-VEGF treatment interval at the time of bleeding.
Results: SMH occurred in 15 (36%) patients who were treatment naïve. In patients treated with anti-VEGF, 19 (45%) were on a stable treatment interval, 5 (12%) had recently extended their interval, and 3 (7%) had shortened their interval. The average treatment interval at the time of SMH was 6.8 weeks with a median 7 total injections prior to SMH. Seven (26%) of treated patients had a SMH on a 4-week dosing interval. The average time between last injection and SMH was 29 days. Forty-eight percent of anti-VEGF treated patients had a SMH within 30 days of anti-VEGF injection. Chi-square analysis found SMH more likely to occur within 30 days of anti-VEGF injection than after 30 days.
Conclusions: Large SMH in neovascular AMD in a treat-and-extend regimen does not appear to be associated with prolonged dosing intervals or recent interval extension, and a large proportion of such hemorrhages are likely to be a result of mechanisms other than loss of effective VEGF inhibition.
Predictors of persistent disease activity following anti-VEGF loading dose for nAMD patients in Singapore: the DIALS study
BMC Ophthalmol. 2020 Aug 6;20(1):324.
Colin S Tan, Louis W Lim, Wei Kiong Ngo, Pandiyan Pannirselvam, Clarence See, Wai Kitt Chee, Nakul Saxena
PMID: 32762659 PMCID: PMC7409440 DOI: 10.1186/s12886-020-01582-y
Background: To determine the frequency of persistent disease activity following 3 loading doses of anti- vascular endothelial growth factor (VEGF) agents, and the anatomic and demographic predictors of early persistent disease activity among patients with neovascular age-related macular degeneration (nAMD).
Methods: In a retrospective real-world cohort study, 281 consecutive patients with nAMD were reviewed at baseline and after 3 anti-VEGF injections for pre-defined indicators of disease activity. Optical coherence tomography (OCT) features such as subretinal fluid, intraretinal cysts and intraretinal fluid were assessed by reading-center certified graders. Multiple logistic regression was performed on demographic and anatomic factors.
Results: At month 3, 66.1% of patients had persistent disease activity. The best-corrected visual acuity (BCVA) improvement was 0.16 LogMAR for those with no disease activity compared to 0 for patients with persistent activity (p < 0.001). The significant risk factors for persistent activity at 3 months were male gender (odds ratio [OR] 0.54, 95% confidence interval [CI] 0.32-0.93, p = 0.025), intraretinal cysts at baseline (OR 2.95, 95% CI 1.67-5.20, p < 0.001) and subretinal fluid at baseline (OR 3.17, 95% CI 1.62-6.18, p = 0.002). At 3 months, 58% of patients had features of activity on OCT. Patients with intraretinal cysts and intraretinal fluid at baseline had worse BCVA at month 3 compared to patients without these OCT features (0.69 vs. 0.43, p < 0.001, and 0.62 vs. 0.43, p < 0.001, respectively).
Conclusions: In a real-world study, 66.1% of nAMD patients have persistent disease activity after the initial loading dose, with poorer BCVA compared to those without. Baseline OCT features (intraretinal cysts and subretinal fluid) are useful predictors of persistent disease activity at month 3.
Response to photodynamic therapy combined with intravitreal aflibercept for polypoidal choroidal vasculopathy depending on fellow-eye condition:2-year results
PLoS One. 2020 Aug 11;15(8):e0237330.
Mio Matsubara, Yoichi Sakurada, Atsushi Sugiyama, Yoshiko Fukuda, Ravi Parikh, Kenji Kashiwagi
PMID: 32780752 DOI: 10.1371/journal.pone.0237330
We investigated whether response to photodynamic therapy (PDT) with intravitreal aflibercept injection (IAI) for polypoidal choroidal vasculopathy (PCV) differs depending on fellow eye condition. A retrospective review was conducted for consecutive 60 eyes with PCV treated with PDT combined with IAI as well as 2-years of follow-up data. Fellow eyes were divided into 4 groups; Group 0: no drusen, Group 1; pachydrusen, Group 2; soft drusen, Group 3: PCV/fibrovascular scarring. Best-corrected visual acuity improved at 24-months irrespective of groups and there were no significant differences in visual improvement among treated eyes among the 4 groups. Within 2-years, 35 (58.3%) required the retreatment. The need for retreatment including additional injection and the combination therapy was significantly less in Group 1(12.5%) compared to the others (P = 0.0038) and mean number of additional IAI was also less in Group 1 compared to the others (P = 0.017). The retreatment-free period from the initial combination therapy was longest in Group 1 (23.6±1.1 months) (P = 0.0055, Group 0: 19.1±6.9, Group 2: 12.8±7.9, Group 3: 11.5±9.9). The need for retreatment was significantly different according to fellow-eye condition. Among PCV patients, pachydrusen in fellow eyes appear to be a predictive characteristic for a decreased treatment burden at 2 years.
DIAGNOSIS & IMAGING
Sensitivity and Specificity of Multimodal Imaging in Characterizing Drusen
Ophthalmol Retina. 2020 Apr 23;S2468-6530(20)30155-X.
Mariano Cozzi, Davide Monteduro, Salvatore Parrulli, Federico Corvi, Federico Zicarelli, Giulia Corradetti, SriniVas R Sadda, Giovanni Staurenghi
PMID: 32771389 DOI: 10.1016/j.oret.2020.04.013
Purpose: To calculate the measures of accuracy of different imaging modalities in patients with early/intermediate age-related macular degeneration (AMD).
Design: Prospective, observational, cross-sectional study.
Participants: Patients with early or intermediate AMD.
Methods: All participants underwent a complete multimodal imaging assessment with a confocal scanning laser ophthalmoscope, including near-infrared reflectance (NIR), green fundus autofluorescence (G-FAF), confocal pseudocolor, and retromode deviated to right (DR) and left (DL). Drusen were topographically divided as small and medium (≤125 μ diameter) and large (>125 μ diameter), whereas subretinal drusenoid deposits (SDDs) were divided into dot and ribbon phenotypes. Multimodal imaging was considered the reference standard for detecting different subtypes of drusen and SDDs. Cohen's kappa (k) was used to test interobserver agreement for each imaging modality.
Main outcome measures: Capability to differentiate subtypes of drusen and SDDs with different imaging modalities.
Results: A total of 100 eyes (62% were female participants) were evaluated. The inter-rate reliability between 2 readers for each imaging modality ranged between 0.76 and 0.95. Overall, large drusen were better identified with confocal pseudocolor imaging (96.6% sensitivity; 77.8% specificity). Smaller drusen were better detected with retromode modalities DR or DL (92% sensitivity; 58.3% specificity and 85.2% sensitivity; 83.3% specificity, respectively). Ribbon SDDs were better detected by color imaging (80.5% sensitivity; 98.3% specificity). Dot SDDs were well identified with NIR (83.1% sensitivity; 91.4% specificity) and G-FAF (84.6% sensitivity; 77.1% specificity).
Conclusions: Near-infrared reflectance and G-FAF should be considered for classification of dot SDDs, and confocal pseudocolor is optimal for characterizing ribbon SDDs. Among all imaging modalities, retromode technology DR and DL may be a potential supplementary modality to detect even smaller drusen.
Simple Vision Function Tests that Distinguish Eyes with Early to Intermediate Age-related Macular Degeneration
Ophthalmic Epidemiol. 2020 Aug 12;1-12.
Lori A Lott, Marilyn E Schneck, Gunilla Haegerstrom-Portnoy, Susan Hewlett, Natalie Stepien-Bernabe, Bonnie M Gauer, Ali Zaidi, Arthur D Fu, John A Brabyn
PMID: 32781860 DOI: 10.1080/09286586.2020.1793371
Purpose: To present and compare baseline vision findings in eyes with early age-related macular degeneration (E-AMD), intermediate AMD (I-AMD), and age-similar participants with normal aging changes to the retina (No-AMD).
Methods: Two hundred and thirty-seven eyes of 125 individuals (66.4% female, mean age 75.3 years) were tested monocularly using several simple, rapid psychophysical tests: high contrast visual acuity, low contrast visual acuity at reduced luminance, contrast sensitivity, shape discrimination hyperacuity, colour vision, reading rate, and glare recovery. Retinal status was determined using colour fundus photographs that were graded according to the Beckman Initiative for Macular Research Classification Committee scale. Logistic regression analyses with generalized estimating equations were used to assess the association between each vision variable and AMD category, while taking into account the correlation between the two eyes.
Results: Three vision measures (contrast sensitivity [CS], shape discrimination hyperacuity [SDH], and colour discrimination [DesatCCS]) were significantly and independently associated with intermediate AMD. Relative Risk Ratios (RRR), 95% Confidence Intervals (in parentheses), beta coefficients, and significance (p) for the I-AMD vs. No-AMD model are: CS: RRR = 6.5 (1.91-22.0), beta = 1.87, p < .01; SDH: RRR = 2.34 (1.24-4.44), beta = 0.85, p < .001; DesatCCS: RRR = 1.43 (1.22-1.68), beta = 0.36, p < .001. Performance on these measures was significantly poorer for participants with I-AMD vs. No-AMD.
Conclusions: Simple screening tests distinguish eyes with intermediate AMD from eyes with less severe AMD or normal aging changes. This suggests that these vision measures may be significant predictors of which participants will go on to develop advanced AMD.
Longitudinal Analysis of Structural and Functional Changes in Presence of Reticular Pseudodrusen Associated With Age-Related Macular Degeneration
Invest Ophthalmol Vis Sci. 2020 Aug 3;61(10):19.
Marlene Sassmannshausen, Maximilian Pfau, Sarah Thiele, Rolf Fimmers, Julia S Steinberg, Monika Fleckenstein, Frank G Holz, Steffen Schmitz-Valckenberg
PMID: 32780863 DOI: 10.1167/iovs.61.10.19
Purpose: To examine longitudinal changes of retinal thickness and retinal sensitivity in patients with intermediate age-related macular degeneration (iAMD) and predominantly reticular pseudodrusen (RPD).
Methods: At baseline 30 eyes of 25 iAMD patients underwent optical coherence tomography imaging, mesopic and scotopic fundus-controlled perimetry (FCP) with follow-up examinations at month 12 (20 eyes), 24 (12 eyes), and 36 (11 eyes). Thicknesses of different retinal layers and results of FCP testing (n = 56 stimuli) were spatially and longitudinally analyzed using linear mixed-effects models.
Results: At baseline, the thickness of the partial outer retinal layer (pORL, 70.21 vs. 77.47 µm) and both mesopic (16.60 vs. 18.72 dB) and scotopic (12.14 vs. 18.67 dB) retinal sensitivity were decreased in areas with RPD compared with unremarkable areas (P < 0.001). Over three years, mean change of pORL was -0.66 normative standard deviation (SD; i.e., z-score, P < 0.001) for regions with existing RPD, -0.40 SD (P < 0.001) for regions with new occurring RPD, and -0.17 SD (P = 0.041) in unremarkable regions. Decrease of scotopic and mesopic sensitivity over three years was more pronounced in areas with existing (-3.51 and -7.76 dB) and new occurring RPD (-2.06 and -5.97 dB). Structure-function analysis revealed that 1 SD decrease of pORL thickness was associated with a sensitivity reduction of 3.47 dB in scotopic and 0.79 dB in mesopic testing.
Conclusions: This study demonstrates progressive outer retinal degeneration and impairment of photoreceptor function in eyes with iAMD and RPD over three years. Preservation of outer retinal thickness and reduction of RPD formation may constitute meaningful surrogate endpoints in interventional trials on eyes with AMD and RPD aiming to slow outer retinal degeneration.
Progression of Photoreceptor Degeneration in Geographic Atrophy Secondary to Age-related Macular Degeneration
JAMA Ophthalmol. 2020 Aug 13.
Maximilian Pfau, Leon von der Emde, Luis de Sisternes, Joelle A Hallak, Theodore Leng, Steffen Schmitz-Valckenberg, Frank G Holz, Monika Fleckenstein, Daniel L Rubin
PMID: 32789526 DOI: 10.1001/jamaophthalmol.2020.2914
Importance: Sensitive outcome measures for disease progression are needed for treatment trials in geographic atrophy (GA) secondary to age-related macular degeneration (AMD).
Objective: To quantify photoreceptor degeneration outside regions of GA in eyes with nonexudative AMD, to evaluate its association with future GA progression, and to characterize its spatio-temporal progression.
Design, setting, and participants: Monocenter cohort study (Directional Spread in Geographic Atrophy [NCT02051998]) and analysis of data from a normative data study at a tertiary referral center. One hundred fifty-eight eyes of 89 patients with a mean (SD) age of 77.7 (7.1) years, median area of GA of 8.87 mm2 (IQR, 4.09-15.60), and median follow-up of 1.1 years (IQR, 0.52-1.7 years), as well as 93 normal eyes from 93 participants.
Exposures: Longitudinal spectral-domain optical coherence tomography (SD-OCT) volume scans (121 B-scans across 30° × 25°) were segmented with a deep-learning pipeline and standardized in a pointwise manner with age-adjusted normal data (z scores). Outer nuclear layer (ONL), photoreceptor inner segment (IS), and outer segment (OS) thickness were quantified along evenly spaced contour lines surrounding GA lesions. Linear mixed models were applied to assess the association between photoreceptor-related imaging features and GA progression rates and characterize the pattern of photoreceptor degeneration over time.
Main outcomes and measures: Association of ONL thinning with follow-up time (after adjusting for age, retinal topography [z score], and distance to the GA boundary).
Results: The study included 158 eyes of 89 patients (51 women and 38 men) with a mean (SD) age of 77.7 (7.1) years. The fully automated B-scan segmentation was accurate (dice coefficient, 0.82; 95% CI, 0.80-0.85; compared with manual markings) and revealed a marked interpatient variability in photoreceptor degeneration. The ellipsoid zone (EZ) loss-to-GA boundary distance and OS thickness were prognostic for future progression rates. Outer nuclear layer and IS thinning over time was significant even when adjusting for age and proximity to the GA boundary (estimates of -0.16 μm/y; 95% CI, -0.30 to -0.02; and -0.17 μm/y; 95% CI, -0.26 to -0.09).
Conclusions and relevance: Distinct and progressive alterations of photoreceptor laminae (exceeding GA spatially) were detectable and quantifiable. The degree of photoreceptor degeneration outside of regions of retinal pigment epithelium atrophy varied markedly between eyes and was associated with future GA progression. Macula-wide photoreceptor laminae thinning represents a potential candidate end point to monitor treatment effects beyond mere GA lesion size progression.
Plasma biomarkers of the amyloid pathway are associated with geographic atrophy secondary to age-related macular degeneration
PLoS One. 2020 Aug 7;15(8):e0236283.
Kameran Lashkari, Gianna C Teague, Ursula Beattie, Joanna Betts, Sanjay Kumar, Megan M McLaughlin, Francisco J López
PMID: 32764794 PMCID: PMC7413518 DOI: 10.1371/journal.pone.0236283
Geographic atrophy (GA) is an advanced form of dry age-related macular degeneration (AMD), in which local inflammation and hyperactivity of the complement pathway have been implicated in its pathophysiology. This study explores whether any surrogate biomarkers are specifically associated with GA. Plasma from subjects with GA, intermediate dry AMD and non-AMD control were evaluated in 2 cohorts. Cohort 1 was assayed in a 320-analyte Luminex library. Statistical analysis was performed using non-parametric and parametric methods (Kruskal-Wallis, principal component analysis, partial least squares and multivariate analysis of variance (MANOVA) and univariate ANCOVAs). Bioinformatic analysis was conducted and identified connections to the amyloid pathway. Statistically significant biomarkers identified in Cohort 1 were then re-evaluated in Cohort 2 using individual ELISA and multiplexing. Of 320 analytes in Cohort 1, 273 were rendered measurable, of which 56 were identified as changing. Among these markers, 40 were identified in univariate ANCOVAs. Serum amyloid precursor protein (sAPP) was analyzed by a separate ELISA and included in further analyses. The 40 biomarkers, sAPP and amyloid-β (Aβ) (1-42) (included for comparison) were evaluated in Cohort 2. This resulted in 11 statistically significant biomarkers, including sAPP and Aβ(1-40), but not Aβ(1-42). Other biomarkers identified included serum proteases- tissue plasminogen activator, tumor-associated trypsinogen inhibitor, matrix metalloproteinases 7 and 9, and non-proteases- insulin-like growth factor binding protein 6, AXL receptor tyrosine kinase, omentin, pentraxin-3 and osteopontin. Findings suggest that there is a preferential processing of APP to Aβ(1-40) over Aβ(1-42), and a potential role for the carboxylase activity of the γ-secretase protein, which preferentially splices sAPPβ to Aβ(1-40). Other markers are associated with the breakdown and remodeling of the extracellular matrix, and loss of homeostasis, possibly within the photoreceptor-retinal pigment epithelium-choriocapillaris complex. These data suggest novel disease pathways associated with GA pathogenesis and could provide potential novel targets for treatment of GA.
IQGAP1 causes choroidal neovascularization by sustaining VEGFR2-mediated Rac1 activation
Angiogenesis. 2020 Aug 11.
Haibo Wang, Aniket Ramshekar, Eric Kunz, David B Sacks, M Elizabeth Hartnett
PMID: 32783108 DOI: 10.1007/s10456-020-09740-y
Loss of visual acuity in neovascular age-related macular degeneration (nAMD) occurs when factors activate choroidal endothelial cells (CECs) to transmigrate the retinal pigment epithelium into the sensory retina and develop into choroidal neovascularization (CNV). Active Rac1 (Rac1GTP) is required for CEC migration and is induced by different AMD-related stresses, including vascular endothelial growth factor (VEGF). Besides its role in pathologic events, Rac1 also plays a role in physiologic functions. Therefore, we were interested in a method to inhibit pathologic activation of Rac1. We addressed the hypothesis that IQGAP1, a scaffold protein with a Rac1 binding domain, regulates pathologic Rac1GTP in CEC migration and CNV. Compared to littermate Iqgap1+/+, Iqgap1-/- mice had reduced volumes of laser-induced CNV and decreased Rac1GTP and phosphorylated VEGFR2 (p-VEGFR2) within lectin-stained CNV. Knockdown of IQGAP1 in CECs significantly reduced VEGF-induced Rac1GTP, mediated through p-VEGFR2, which was necessary for CEC migration. Moreover, sustained activation of Rac1GTP induced by VEGF was eliminated when CECs were transfected with an IQGAP1 construct that is unable to bind Rac1. IQGAP1-mediated Src activation was involved in initiating Rac1 activation, CEC migration, and tube formation. Our findings indicate that CEC IQGAP1 interacts with VEGFR2 to mediate Src activation and subsequent Rac1 activation and CEC migration. In addition, IQGAP1 binding to Rac1GTP results in sustained activation of Rac1, leading to CEC migration toward VEGF. Our study supports a role of IQGAP1 and the interaction between IQGAP1 and Rac1GTP to restore CECs quiescence and, therefore, prevent vision-threatening CNV in nAMD.
DICER1 in the Pathogenesis of Age-related Macular Degeneration (AMD) - Alu RNA Accumulation versus miRNA Dysregulation
Aging Dis. 2020 Jul 23;11(4):851-862.
Kai Kaarniranta, Elzbieta Pawlowska, Joanna Szczepanska, Janusz Blasiak
PMID: 32765950 PMCID: PMC7390522 DOI: 10.14336/AD.2019.0809
DICER1 deficiency in the retinal pigment epithelium (RPE) was associated with the accumulation of Alu transcripts and implicated in geographic atrophy (GA), a form of age-related macular degeneration (AMD), an eye disease leading to blindness in millions of people. Although the exact mechanism of this association is not fully known, the activation of the NLRP3 inflammasome, maturation of caspase-1 and disruption in mitochondrial homeostasis in RPE cells were shown as critical for it. DICER1 deficiency results in dysregulation of miRNAs and changes in the expression of many genes important for RPE homeostasis, which may also contribute to AMD. DICER1 deficiency can change the functions of the miR-183/96/182 cluster that regulates photoreceptors and their synaptic transmission. Aging, the main AMD risk factor, is associated with decreased expression of DICER1 and changes in its diurnal pattern that are not synchronized with circadian regulation in the retina. The initial insult inducing DICER1 deficiency in AMD may be oxidative stress, another major risk factor of AMD, but further studies on the role of deficient DICER1 in AMD pathogenesis and its therapeutic potential are needed.
Interaction of two functional genetic variants LOXL1 rs1048661 and VEGFA rs3025039 on the risk of age-related macular degeneration in Chinese women
Ann Transl Med. 2020 Jul;8(13):818.
Han Chen, Miao Mo, Guang-Yu Liu, Yang-Ming Gong, Ke-Da Yu, Ge-Zhi Xu
PMID: 32793663 PMCID: PMC7396242 DOI: 10.21037/atm-20-2447
Background: Cumulative evidence indicates that LOXL1 and VEGF-a play important roles in extracellular matrix formation and angiogenesis, respectively. The disorder of extracellular matrix and angiogenesis are the key factors of pathogenesis of age-related macular degeneration (AMD). We hypothesized that rs1048661 (T>G) in the LOXL1 gene and rs3025039 (C>T) in the VEGFA gene might be associated with risk of AMD.
Methods: A total of 533 unrelated Chinese subjects, 286 cases (247 with early AMD and 39 with late neovascular AMD) and 247 controls, were included in the study. The gene sequences of LOXL1 rs1048661 and VEGFA rs3025039 were amplified by polymerase chain reaction and genotyped. Interaction between rs1048661 and rs3025039 on AMD risk was also assessed.
Results: LOXL1 rs1048661 but not VEGFA rs3025039 was associated with a significantly increased risk of AMD. The adjusted odds ratio was 1.6 (95% CI, 1.1-2.5) for rs1048661 TT + GT genotype compared with GG homozygotes in the dominant model analysis. Moreover, there was a significant gene-gene interaction between these two polymorphic loci. In VEGFA rs3025039 CC + CT genotype which indicated sufficient expression of VEGF-a, LOXL1 rs1048661 had odds ratios of 1.7 (95% CI, 1.1-2.7) for early AMD and 3.6 (95% CI, 1.1-12.3) for late neovascular AMD in the dominant model analysis. However, LOXL1 rs1048661 did not confer the risk of AMD in subjects harboring VEGFA rs3025039 TT genotype which indicated decreased expression of VEGF-a.
Conclusions: Our findings suggest that LOXL1 rs1048661 (T>G) may be involved in the risk of AMD. In addition, LOXL1 rs1048661 and VEGFA rs3025039 interacted to confer the development of AMD, especially for late-stage neovascular AMD. Our data need to be further validated.
Combining Gene-Disease Associations with Single-Cell Gene Expression Data Provides Anatomy-Specific Subnetworks in Age-Related Macular Degeneration
Netw Syst Med. 2020 Aug 3;3(1):105-121.
Philip J Luthert, Christina Kiel
PMID: 32789304 PMCID: PMC7416628 DOI: 10.1089/nsm.2020.0005
Background: Age-related macular degeneration (AMD) is the most common cause of visual impairment in the developed world. Despite some treatment options for late AMD, there is no intervention that blocks early AMD proceeding to the late and blinding forms. This is partly due to the lack of precise drug targets, despite great advances in genetics, epidemiology, and protein-protein interaction (PPI) networks proposed to be driving the disease pathology. A systems approach to narrow down PPI networks to specific protein drug targets would provide new therapeutic options.
Materials and Methods: In this study we analyzed single cell RNAseq (RNA sequencing) datasets of 17 cell types present in choroidal, retinal pigment epithelium (RPE), and neural retina (NR) tissues to explore if a more granular analysis incorporating different cell types exposes more specific pathways and relationships. Furthermore, we developed a novel and systematic gene ontology database (SysGO) to explore if a subcellular classification of processes will further enhance the understanding of the pathogenesis of this complex disorder and its comorbidities with other age-related diseases.
Results: We found that 57% of the AMD (risk) genes are among the top 25% expressed genes in ∼1 of the 17 choroidal/RPE/NR cell types, and 9% were among the top 1% of expressed genes. Using SysGO, we identified an enrichment of AMD genes in cell membrane and extracellular anatomical locations, and we found both functional enrichments (e.g., cell adhesion) and cell types (e.g., fibroblasts, microglia) not previously associated with AMD pathogenesis. We reconstructed PPI networks among the top expressed AMD genes for all 17 choroidal/RPE/NR cell types, which provides molecular and anatomical definitions of AMD phenotypes that can guide therapeutic approaches to target this complex disease.
Conclusion: We provide mechanism-based AMD endophenotypes that can be exploited in vitro, using computational models and for drug discovery/repurposing.
The Elovl4 Spinocerebellar Ataxia-34 Mutation 736T>G (p.W246G) Impairs Retinal Function in the Absence of Photoreceptor Degeneration
Mol Neurobiol. 2020 Aug 11.
Martin-Paul Agbaga, Megan A Stiles, Richard S Brush, Michael T Sullivan, Adeline Machalinski, Kenneth L Jones, Robert E Anderson, David M Sherry
PMID: 32780351 DOI: 10.1007/s12035-020-02052-8
Elongation of very long chain fatty acids-4 (ELOVL4) is essential for synthesis of very long chain polyunsaturated and saturated fatty acids (VLC-PUFA and VLC-SFA, respectively) of chain length greater than 26 carbons. Mutations in the ELOVL4 gene cause several distinct neurodegenerative diseases including Stargardt-like macular dystrophy (STGD3), spinocerebellar ataxia 34 (SCA34), and a neuro-ichthyotic syndrome with severe seizures and spasticity, as well as erythrokeratitis variabilis (EKV), a skin disorder. However, the relationship between ELOVL4 mutations, its VLC-PUFA and VLC-SFA products, and specific neurological symptoms remains unclear. We generated a knock-in rat line (SCA34-KI) that expresses the 736T>G (p.W246G) form of ELOVL4 that causes human SCA34. Lipids were analyzed by gas chromatography and mass spectrometry. Retinal function was assessed using electroretinography. Retinal integrity was assessed by histology, optical coherence tomography, and immunolabeling. Analysis of retina and skin lipids showed that the W246G mutation selectively impaired synthesis of VLC-SFA, but not VLC-PUFA. Homozygous SCA34-KI rats showed reduced ERG a- and b-wave amplitudes by 90 days of age, particularly for scotopic responses. Anatomical analyses revealed no indication of neurodegeneration in heterozygote or homozygote SCA34-KI rats out to 6-7 months of age. These studies reveal a previously unrecognized role for VLC-SFA in regulating retinal function, particularly transmission from photoreceptors to the inner retina, in the absence of neurodegeneration. Furthermore, these findings suggest that the tissue specificity and symptoms associated with disease-causing ELOVL4 mutations likely arise from selective differences in the ability of the mutant ELOVL4 enzymes to support synthesis of VLC-PUFA and/or VLC-SFA.
Role of complement factor B rs4151667 (L9H) polymorphisms and its interactional role with CFH Y402H and C3 rs2230199 (R102G) risk variants in age-related macular degeneration: a case control study
BMC Ophthalmol. 2020 Aug 6;20(1):323.
Nasrin Roshanipour, Maryam Ghaffari Laleh, Mortaza Bonyadi, Mohammad Hossein Jabbarpoor Bonyadi, Masoud Soheilian, Alireza Javadzadeh, Mehdi Yaseri
PMID: 32762675 PMCID: PMC7409625 DOI: 10.1186/s12886-020-01552-4
Background: Age-related Macular Degeneration (AMD) is a complex eye disease, which is genetically associated with different susceptibility loci. We planned to investigate the possible association of Complement Factor B (CFB) rs4151667 (L9H) variants and their possible interaction with Complement Factor H (CFH) Y402H and Complement factor 3 (C3) rs2230199 (R102G) in AMD.
Methods: This case-control association study included 216 advanced type AMD patients and 191 healthy individuals for evaluation. Extracted-DNA samples were genotyped for the polymorphic regions of CFB rs4151667 (L9H), CFH Y402H and C3 rs2230199 (R102G).
Results: The distribution of CFB rs4151667 (L9H) genotypes was not significantly different in the AMD patients compared to that of controls (P = 0.18). The AT genotype frequencies for CFB was non significantly lower in AMD group (6.5% vs. 13.1%, AOR = 0.49, CI = 0.23-1.04, P = 0.064(. The A allele of CFB rs4151667 (L9H) was found to be non-significantly lower in AMD patients. CFB rs4151667 (L9H) had no protective interactional effect against CFH (Y402H) and C3 (R102G) risk variants.
Conclusions: This study showed that the protective role of CFB rs4151667 (L9H) in AMD is not significant and it has no significant protective interactional effect against CFH (Y402H) and C3 (R102G) risk variants.
Non-adherence or non-persistence to intravitreal injection therapy for neovascular age-related macular degeneration: a mixed-methods systematic review
Ophthalmology. 2020 Aug 4;S0161-6420(20)30748-X.
Mali Okada, Paul Mitchell, Robert P Finger, Bora Eldem, S James Talks, Ceri Hirst, Luciano Paladini, Jane Barratt, Tien Yin Wong, Anat Loewenstein
PMID: 32763265 PMCID: PMC7403101 DOI: 10.1016/j.ophtha.2020.07.060
Topic: Systematic review of risk factors for non-adherence and non-persistence to intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection therapy for neovascular age-related macular degeneration (nAMD).
Clinical relevance: Lack of adherence (non-adherence) or under-treatment (non-persistence) with respect to evidence from clinical trials remains a significant barrier to optimizing real-world outcomes for patients with nAMD. Contributing factors and strategies to address this are poorly understood.
Methods: Studies that reported factors for non-adherence and/or non-persistence to anti-VEGF therapy as well as studies examining strategies to improve this were included. Trial eligibility and data extraction were conducted according to Cochrane review methods. Risk of bias was assessed using the Mixed Method Assessment Tool and certainty of evidence evaluated according to the GRADE-CERQual (Confidence in the Evidence from Reviews of Qualitative Research) tool. Data were collated descriptively.
Results: Of the 1284 abstract results screened, 124 articles were assessed in full and 37 studies met the inclusion criteria. Definitions of non-adherence and non-persistence varied or were not reported. Non-persistence occurred early with up to 50% of patients stopping treatment by 24 months. High rates of non-adherence were similarly reported, occurring in 32 - 95% of patients. Certainty of this finding was downgraded to moderate level due to heterogeneity in definitions used across studies. Multiple factors determine non-adherence and non-persistence, including at condition, therapy, patient, social/economic and health systems/health-care team level. Moderate quality evidence points to lower baseline vision and poorer response to treatment as condition-related variables. The effects of other factors were of lower certainty, predominantly due to small numbers and potential biases in retrospective assessment. Although many factors are non-modifiable (e.g., patient co-morbidity), other factors are potentially correctable (e.g., lack of transport or mismatched patient expectations). Evidence on strategies to improve adherence and persistence is limited, but where available, these have proven effective.
Conclusions: Awareness of factors related to poor patient adherence and persistence in nAMD could help identify at-risk populations and improve real world outcomes. Further work is required to develop uniform definitions as well as establishing high quality evidence on interventions that can be easily implemented.
Targeting Angiopoietin in Retinal Vascular Diseases: A Literature Review and Summary of Clinical Trials Involving Faricimab
Cells. 2020 Aug 10;9(8):E1869.
Majid Khan, Aamir A Aziz, Noah A Shafi, Tayeb Abbas, Arshad M Khanani
PMID: 32785136 DOI: 10.3390/cells9081869
This review summarizes the latest findings in the literature of Angiopoietin-2 (Ang-2), Tyrosine-protein kinase receptor (Tie-2) complex, and faricimab along with their involvement for the treatment of retinal vascular diseases in various clinical trials. In ischemic diseases, such as diabetic retinopathy, Ang-2 is upregulated, deactivating Tie-2, resulting in vascular leakage, pericyte loss, and inflammation. Recombinant Angiopeotin-1 (Ang-1), Ang-2-blocking molecules, and inhibitors of vascular endothelial protein tyrosine phosphatase (VE-PTP) decrease inflammation-associated vascular leakage, showing therapeutic effects in diabetes, atherosclerosis, and ocular neovascular diseases. In addition, novel studies show that angiopoietin-like proteins may play an important role in cellular metabolism leading to retinal vascular diseases. Current therapeutic focus combines Ang-Tie targeted drugs with other anti-angiogenic or immune therapies. Clinical studies have identified faricimab, a novel bispecific antibody designed for intravitreal use, to simultaneously bind and neutralize Ang-2 and VEGF-A for treatment of diabetic eye disease. By targeting both Ang-2 and vascular endothelial growth factor-A (VEGF-A), faricimab displays an improved and sustained efficacy over longer treatment intervals, delivering superior vision outcomes for patients with diabetic macular edema and reducing the treatment burden for patients with neovascular age-related macular degeneration and diabetic macular edema. Phase 2 results have produced promising outcomes with regard to efficacy and durability. Faricimab is currently being evaluated in global Phase 3 studies.
OCT-Angiography in Geographic Atrophy
Ophthalmologica. 2020 Aug 7.
Philipp L Müller, Maximilian Pfau, Steffen Schmitz-Valckenberg, Monika Fleckenstein, Frank G Holz
PMID: 32772015 DOI: 10.1159/000510727
Geographic atrophy (GA) represents the nonexudative late stage of age-related macular degeneration (AMD) and constitutes a leading cause of legal blindness in the developed world. It is characterized by areas of loss of outer retinal layers including photoreceptors, degeneration of the retinal pigment epithelium, and rarefication of the choriocapillaris. As all three layers are functionally connected, the precise temporal sequence and relative contribution of these layers towards the development and progression of GA is unclear. The advent of optical coherence tomography angiography (OCT-A) has allowed for three-dimensional visualization of retinal blood flow. Using OCT-A, recent studies have demonstrated that choriocapillaris flow alterations are particularly associated with the development of GA, exceed atrophy boundaries spatially, and are a prognostic factor for future GA progression. Further, OCT-A may be helpful to differentiate GA from mimicking diseases. Evidence for a potential protective effect of specific forms of choroidal neovascularization in the context of GA has been reported. This article aims to give a comprehensive review of the current literature concerning the application of OCT-A in GA, and summarizes the opportunities and limitations with regard to pathophysiologic considerations, differential diagnosis, study design, and patient assessment.
Demographic and Clinical Factors that Influence the Visual Response to Anti-Vascular Endothelial Growth Factor Therapy in Patients with Neovascular Age-Related Macular Degeneration: A Systematic Review
Ophthalmol Ther. 2020 Aug 8.
Claire R Gill, Catherine E Hewitt, Tracy Lightfoot, Richard P Gale
PMID: 32770474 DOI: 10.1007/s40123-020-00288-0
Background: Neovascular age-related macular degeneration (nAMD) is a leading cause of blind registrations in the developed world. Standard therapy includes the use of anti-vascular endothelial growth factor (anti-VEGF) drugs, and whilst the clinical efficacy is well established, there is variability in the clinical effect of visual outcome. The purpose of this systematic review is to identify whether there is evidence for the influence of demographic and clinical factors on the effectiveness of anti-VEGF therapy in patients with nAMD, in settings comparable to the National Health Service (NHS).
Methods: This systematic review followed the PRISMA guidelines for systematic reviews. Electronic databases Medline, EMBASE, Web of Science, CINAHL and the Cochrane Library were searched for studies dated from 2005 onwards. Studies were appraised using the Newcastle-Ottawa Score, and a narrative synthesis was used.
Eligibility criteria: Population: Patients with nAMD being treated with anti-VEGF therapy. Comparator: Presence or absence of potential predictive demographic and clinical factors.
Settings: Comparable settings to NHS hospitals.
Outcomes: Predicting demographic and clinical factors.
Study designs: Randomised controlled trials, prospective cohort studies, retrospective cohort studies and case series dated from 2005.
Results: Thirty papers were identified in this review. The evidence suggests that the number of anti-VEGF injections that patients receive, age and lesion size at baseline are factors that influence how effective anti-VEGF therapy is in the short and long term. There was also evidence that suggested that baseline visual acuity influenced the effectiveness of anti-VEGF therapy at longer time points of more than 2 years. Due to a lack of standardised statistical reporting among the included studies, it was not possible to undertake a meaningful statistical synthesis or meta-analysis.
Conclusions: This review has demonstrated that there is some evidence of clinical and demographic factors that affect the effectiveness of anti-VEGF therapy and hence variation in visual acuity (VA) outcome. However, this review was unable to identify as wide a range of factors as was hoped. The findings of this review are important because some of the factors, such as VA and lesion size at diagnosis and the number of injections, are potentially modifiable through improvements in early diagnosis and service provision. Future work also needs to focus on the importance of this variation, such as the effect on patients' quality of life, and how variation can be minimised.
Systematic review registration: This review has been registered with PROSPERO (Registration number CRD42018094191).
Serum vitamin D and age-related macular degeneration: systematic review and meta-analysis
Surv Ophthalmol. 2020 Aug 5;S0039-6257(20)30123-5.
André Ferreira, Nisa Silva, Maria João Furtado, Ângela Carneiro, Miguel Lume, José P Andrade
PMID: 32768420 DOI: 10.1016/j.survophthal.2020.07.003
Vitamin D may be implicated in the pathophysiology of several ocular diseases, but its role in age-related macular degeneration (AMD) remains uncertain. We sought to review systematically the existing evidence to evaluate the association between serum 25-hydroxyvitamin D 25(OH)D levels and AMD. A four-database search (Pubmed, ISI Web of Science, Cochrane, and Scopus) was performed from inception to May 2020 using the MeSH terms: ("Macular Degeneration" OR "Age-related macular degeneration" OR "Retinal degeneration" OR "Macula lutea") AND ("Vitamin D" OR "Ergocalciferols" OR "Cholecalciferol" OR "25-Hydroxyvitamin D"). Random-effects meta-analysis were performed to compute 1) the standard mean difference in 25(OH)D concentration between AMD and non-AMD patients and 2) the AMD risk according to serum 25(OH)D levels. Eighteen observational studies enrolling 75,294 patients after a selection process among 375 original abstracts were selected. No significant differences were found, but there appears to exist a trend for late AMD among subjects with serum 25(OH)D below 50 nmol/L (OR 1.8, 95%CI: 1.00-3.24, P = 0.05). There is no clear evidence of a definitive association between serum 25(OH)D and AMD risk, mainly due to heterogeneity in studies procedures and lack of longitudinal designs.
Mechanisms of protection of retinal pigment epithelial cells from oxidant injury by humanin and other mitochondrial-derived peptides: Implications for age-related macular degeneration
Redox Biol. 2020 Jul 29;101663.
Parameswaran G Sreekumar, Ram Kannan
PMID: 32768357 DOI: 10.1016/j.redox.2020.101663
The mitochondrial-derived peptides (MDPs) are a new class of small open reading frame encoded polypeptides with pleiotropic properties. The prominent members are Humanin (HN) and small HN-like peptide (SHLP) 2, which encode 16S rRNA, while mitochondrial open reading frame of the twelve S c (MOTS-c) encodes 12S rRNA of the mitochondrial genome. While the multifunctional properties of HN and its analog 14-HNG have been well documented, their protective role in the retinal pigment epithelium (RPE)/retina has been investigated only recently. In this review, we have summarized the multiple effects of HN and its analogs, SHLP2 and MOTS-c in oxidatively stressed human RPE and the regulatory pathways of signaling, mitochondrial function, senescence, and inter-organelle crosstalk. Emphasis is given to the mitochondrial functions such as biogenesis, bioenergetics, and autophagy in RPE undergoing oxidative stress. Further, the potential use of HN and its analogs in the prevention of age-related macular degeneration (AMD) are also presented. In addition, the role of novel, long-acting HN elastin-like polypeptides in nanotherapy of AMD and other ocular diseases stemming from oxidative damage is discussed. It is expected MDPs will become a promising group of mitochondrial peptides with valuable therapeutic applications in the treatment of retinal diseases.
Coculture techniques for modeling retinal development and disease, and enabling regenerative medicine
Stem Cells Transl Med. 2020 Aug 7.
Ali E Ghareeb, Majlinda Lako, David H Steel
PMID: 32767661 DOI: 10.1002/sctm.20-0201
Stem cell-derived retinal organoids offer the opportunity to cure retinal degeneration of wide-ranging etiology either through the study of in vitro models or the generation of tissue for transplantation. However, despite much work in animals and several human pilot studies, satisfactory therapies have not been developed. Two major challenges for retinal regenerative medicine are: (a) physical cell-cell interactions, which are critical to graft function, are not formed, and (b) the host environment does not provide suitable queues for development. Several strategies offer to improve the delivery, integration, maturation, and functionality of cell transplantation. These include minimally invasive delivery, biocompatible material vehicles, retinal cell sheets, and optogenetics. Optimizing several variables in animal models is practically difficult, limited by anatomical and disease pathology which is often different to humans, and faces regulatory and ethical challenges. High-throughput methods are needed to experimentally optimize these variables. Retinal organoids will be important to the success of these models. In their current state, they do not incorporate a representative retinal pigment epithelium (RPE)-photoreceptor interface nor vascular elements, which influence the neural retina phenotype directly and are known to be dysfunctional in common retinal diseases such as age-related macular degeneration. Advanced coculture techniques, which emulate the RPE-photoreceptor and RPE-Bruch's-choriocapillaris interactions, can incorporate disease-specific, human retinal organoids and overcome these drawbacks. Herein, we review retinal coculture models of the neural retina, RPE, and choriocapillaris. We delineate the scientific need for such systems in the study of retinal organogenesis, disease modeling, and the optimization of regenerative cell therapies for retinal degeneration.