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    Research update: 514

    The latest research highlights for 11 October 2021.

    research update

    DRUG TREATMENT

    Archway Randomized Phase 3 Trial of the Port Delivery System With Ranibizumab for Neovascular Age-Related Macular Degeneration 

    Ophthalmology. 2021 Sep 28;S0161-6420(21)00734-X. 

    Nancy M Holekamp, Peter A Campochiaro, Margaret Chang, Daniel Miller, Dante Pieramici, Anthony P Adamis , Christopher Brittain, Erica Evans, Derrick Kaufman, Katie F Maass, Shienal Patel, Shrirang Ranade, Natasha Singh, Giulio Barteselli, Carl Regillo, Archway Investigators

    Purpose: To evaluate the safety and efficacy of the Port Delivery System with ranibizumab (PDS) for the treatment of neovascular age-related macular degeneration (nAMD). 

    Design: Phase 3, open-label, randomized, visual acuity assessor-masked noninferiority (NI) and equivalence trial. 

    Participants: Patients with nAMD diagnosed within 9 months of screening previously treated with and responsive to anti-vascular endothelial growth factor therapy. 

    Methods: Patients were randomized 3:2 to treatment with the PDS with ranibizumab 100 mg/mL with fixed 24-week refill-exchanges (PDS Q24W) or intravitreal ranibizumab 0.5 mg injections every 4 weeks (monthly ranibizumab). 

    Main outcome measures: Primary end point was change in best-corrected visual acuity (BCVA) score from baseline averaged over weeks 36 and 40 (NI margin, -4.5 Early Treatment Diabetic Retinopathy Study [ETDRS] letters; equivalence margin, ±4.5 ETDRS letters). 

    Results: Archway enrolled 418 patients; 251 were randomized to and 248 received treatment with PDS Q24W, and 167 were randomized to and received treatment with monthly ranibizumab. Baseline BCVA was 74.4 (PDS Q24W) and 75.5 (monthly ranibizumab) ETDRS letters (Snellen equivalent 20/32). Adjusted mean (standard error) change in BCVA score from baseline averaged over weeks 36 and 40 was +0.2 (0.5) ETDRS letters in the PDS Q24W arm and +0.5 (0.6) in the monthly ranibizumab arm (difference, -0.3; 95% confidence interval, -1.7 to 1.1). The PDS Q24W was both noninferior and equivalent to monthly ranibizumab. Out of 246 PDS-treated patients assessed for supplemental ranibizumab treatment, 242 (98.4%) did not receive supplemental ranibizumab treatment before the first refill-exchange procedure, including 4 patients who discontinued treatment before the first refill-exchange procedure. Prespecified ocular adverse events of special interest (AESIs) were reported in 47 (19.0%) PDS Q24W and 10 (6.0%) monthly ranibizumab patients. Ocular AESIs in PDS-treated patients included 4 (1.6%) endophthalmitis cases, 2 (0.8%) retinal detachments, 13 (5.2%) vitreous hemorrhages, 6 (2.4%) conjunctival erosions, and 5 (2.0%) conjunctival retractions. Most ocular adverse events in PDS patients occurred within 1 month of implantation. 

    Conclusions: Archway met its primary objective and PDS Q24W demonstrated noninferior and equivalent efficacy to monthly ranibizumab with 98.4% of PDS-treated patients not receiving supplemental treatment in the first 24-week interval. 

    DOI: 10.1016/j.ophtha.2021.09.016  

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

    Br J Ophthalmol.2021 Sep 24;bjophthalmol-2021-319602.

    Mengyuan Fang, Karntida Chanwimol, Jyotsna Maram, Ghazala A Datoo O’Keefe, Charles C Wykoff, David Sarraf, A’sha Brown, Shaun Ian Retief Lampen , Brenda Zhou, Alexander M Rusakevich, SriniVas Sadda 

    Purpose: To analyse the morphological characteristics of eyes with neovascular age-related macular degeneration (AMD) with good long-term visual acuity after anti-VEGF (vascular endothelial growth factor) therapy. 

    Methods: Retrospective, observational study of 175 patients with neovascular AMD with >5 years of follow-up after initiating anti-VEGF therapy. Spectral-domain optical coherence tomography images were assessed for thickness of pigment epithelial detachment (PED), subretinal hyper-reflective material (SHRM), subretinal fluid and subfoveal choroidal, as well as the integrity of the outer retinal bands. 

    Results: The final analysis cohort included 203 eyes (175 patients) followed for a mean of 7.84±1.70 years (range: 5-11). The maximum PED thickness in the foveal central subfield (FCS) was significantly lower (p<0.001) in the poor vision group (13.11 μm) compared with the intermediate (86.25 μm) or good (97.92 μm) vision groups, respectively. In contrast, the maximum thickness of SHRM in the FCS was significantly thicker (p<0.001) in eyes with poor vision (149.46 μm) compared with eyes with intermediate vision (64.37 μm) which in turn were significantly thicker (p<0.001) than eyes with good vision (9.35 μm). The good vision group also had better continuity of all outer retinal bands (external limiting membrane, ellipsoid zone, and retinal pigment epithelium) compared with the other two groups (all p<0.001). 

    Conclusion: A thicker PED and thinner SHRM were correlated with better vision in eyes with neovascular AMD following long-term anti-VEGF therapy. If replicated in future prospective studies, these findings may have implications for design of optimal anatomic endpoints for neovascular AMD treatment. 

    DOI: 10.1136/bjophthalmol-2021-319602 

    DIAGNOSIS & IMAGING

    Long-Term Outcomes of Bacillary Layer Detachment in Neovascular Age-Related Macular Degeneration

    Ophthalmol Retina.2021 Sep 26;S2468-6530(21)00297-9. 

    Prithvi Ramtohul, Ariane Malclès, Edward Gigon, K Bailey Freund, Ugo Introini, Francesco Bandello, Maria Vittoria Cicinelli

    Purpose: To evaluate the clinical characteristics, multimodal imaging features, and long-term treatment outcomes of eyes with neovascular age-related macular degeneration (nAMD) and bacillary layer detachment (BALAD) treated with intravitreal anti-vascular endothelial growth factor (VEGF) therapy. 

    Design: Retrospective, longitudinal, case series. 

    Participants: Treatment-naive nAMD patients (n=30) showing BALAD on optical coherence tomography (OCT) and undergoing anti-VEGF therapy. 

    Methods: Clinical records and multimodal imaging were reviewed up to 4 years after diagnosis. 

    Main outcomes measures: Best-corrected visual acuity (BCVA) values were compared over time. The cumulative risk and the risk factors of subretinal fibrosis were assessed with Cox regression analyses, and the adjusted hazard ratio (aHR) was computed. 

    Results: Thirty eyes of 30 patients were included. Macular neovascularization (MNV) subtypes were distributed as follows: type 1, 63%; type 2, 27%; mixed type 1 and type 2, 3%; type 3, 3%; aneurysmal type 1, 3%. The BCVA significantly improved after anti-VEGF loading phase (Snellen equivalent, from 20/118 to 20/71, P = 0.03), but it returned to baseline levels at 4 years (Snellen equivalent, 20/103, P = 0.6). The cumulative risk of subretinal fibrosis was 77% at 4 years. Risk factors associated with subretinal fibrosis included hemorrhagic BALAD (aHR, 2.02; 95% CI 1.54 to 3.22; P < 0.01) and the presence of subretinal hyperreflective material (aHR, 1.83; 95% CI 1.35 to 3.14; P < 0.01). 

    Conclusions: BALAD was found in association with all types of MNV in nAMD patients. Long-term observation revealed poor functional outcomes related to the high risk of subretinal fibrosis. 

    DOI: 10.1016/j.oret.2021.09.010 

    Prevalence of polypoidal choroidal vasculopathy using non-ICGA based criteria 

    Ophthalmol Retina.2021 Sep 24;S2468-6530(21)00296-7.

    Beau J Fenner, Kelvin Y C Teo, Yih Chung Tham, Usha Chakravarthy, Chui Ming Gemmy Cheung

    Abstract 

    Polypoidal choroidal vasculopathy (PCV) is a form of neovascular AMD characterized by polypoidal lesions and branching vascular networks. Diagnosis has traditionally required the use of invasive indocyanine green angiography, though recently a validated non-invasive diagnostic system has been developed that identified PCV-specific features using optical coherence tomography (OCT) and color fundus photography. In this work we applied this new system to a large population-based cohort of ethnic Chinese and successfully identified PCV and related anatomical features. We estimated a population prevalence of 0.31% (95% CI, 0.06-0.91%) and additionally demonstrate that PCV-related retinal findings were relatively rare in the population. 

    DOI: 10.1016/j.oret.2021.09.009 

    Choroidal vascularity index is associated with geographic atrophy progression

    Retina.2021 Sep 17.

    Riccardo Sacconi, Marco Battista, Enrico Borrelli, Carlotta Senni, Beatrice Tombolini, Domenico Grosso, Lea Querques, Francesco Bandello, Giuseppe Querques

    Purpose: To investigate the correlation between choroidal vascularity index (CVI) and the enlargement of geographic atrophy(GA) lesion secondary to age-related macular degeneration(AMD) during 2-year follow-up. 

    Methods: In this longitudinal observational study, 26 eyes (26 patients, mean age 75.7±8.8 years) affected by GA were included. CVI was calculated in the subfoveal 3000μm area. The main outcome measure included correlation analysis between baseline CVI and the rate of GA enlargement. 

    Results: During the 2-year follow-up, mean GA area increased from 6.99±5.28mm2 to 10.69±6.61 mm2(p<0.001), accounting for a growth rate of 0.35±0.20 and 0.31±0.17 mm/year after the square root transformation in the first and second year of follow-up, respectively . Stromal choroidal area (SCA) significantly decreased during the 2-year follow-up(p=0.002). Interestingly, there was a significant correlation between the baseline CVI and the rate of GA enlargement(r=-0.432, p=0.027), and between SCA and the rate of GA enlargement(r=0.422, p=0.032). No other significant relationship was disclosed among choroidal parameters with the rate of GA enlargement. 

    Conclusions: CVI impairment is strictly related to the rate of enlargement during the 1-year and 2-year follow-up in patients affected by GA. For this reason, CVI could be considered a predictor of GA progression in the clinical setting, and it could be considered as a new potential biomarker in the efficacy evaluation of new GA interventions. 

    DOI: 10.1097/IAE.0000000000003305 

    REVIEWS

    Clinical Manifestations of Cuticular Drusen: Current Perspectives 

    Clin Ophthalmol.2021 Sep 21;15:3877-3887.

    Serena Fragiotta, Pedro Fernández-Avellaneda, Mark P Breazzano, Gianluca Scuderi

    Abstract 

    Cuticular drusen are part of the spectrum of age-related macular degeneration (AMD) with particular clinical and multimodal imaging characteristics. This drusen subpopulation shares several high-risk single nucleotide polymorphisms with AMD. Despite this feature, they can manifest at a relatively young age, presenting with a female preponderance. Multimodal imaging is essential for characterizing such lesions, using a combination of color fundus photographs, optical coherence tomography (OCT), fluorescein angiography (FA), and fundus autofluorescence (FAF). The classic starry-sky pattern visible on FA and the typical central hypoautofluorescent lesion with hyperautofluorescent rim on FAF is considered the result of a central retinal pigment epithelium (RPE) erosion from these triangular elevations of the RPE-basal lamina. This finding may also be responsible for the typical choroidal hypertransmission appreciated through OCT. The clinical course of cuticular drusen may be relatively benign at early stages, with small drusen presenting at a young age. However, the presence of clinical phenotypes characterized by diffuse involvement and/or accompanying large drusen in patients older than 60 years may confer a significant risk for either macular neovascularization or geographic atrophy. 

    DOI: 10.2147/OPTH.S272345 

    VISUAL FUNCTION

    Association of Reading Performance in Geographic Atrophy Secondary to Age-Related Macular Degeneration With Visual Function and Structural Biomarkers 

    JAMA Ophthalmol.2021 Sep 30.

    Sandrine H Künzel, Moritz Lindner, Josua Sassen, Philipp T Möller, Lukas Goerdt, Matthias Schmid, Steffen Schmitz-Valckenberg, Frank G Holz, Monika Fleckenstein, Maximilian Pfau 

    Importance: As a disabling and frequent disease, geographic atrophy secondary to age-related macular degeneration (AMD) constitutes an important study subject. Emerging clinical trials require suitable end points. The characterization and validation of reading performance as a functional outcome parameter is warranted. 

    Objective: To prospectively evaluate reading performance in geographic atrophy and to assess its association with established visual function assessments and structural biomarkers. 

    Design, setting, and participants: The noninterventional, prospective natural history Directional Spread in Geographic Atrophy study included patients with geographic atrophy secondary to AMD who were recruited at the University Hospital in Bonn, Germany. Participants were enrolled from June 2013 to June 2016. Analysis began December 2019 and ended January 2021. 

    Main outcomes and measures: Reading acuity and reading speed were assessed using Radner charts. Longitudinal fundus autofluorescence and infrared reflectance images were semiautomatically annotated for geographic atrophy, followed by extraction of shape-descriptive variables. Linear mixed-effects models were applied to investigate the association of those variables with reading performance. 

    Results: A total of 150 eyes of 85 participants were included in this study (median [IQR] age, 77.9 [72.4-82.1] years; 51 women [60%]; 34 men [40%]). Reading performance was impaired with a median (IQR) monocular reading acuity of 0.9 (0.4-1.3) logarithm of the reading acuity determination and a reading speed of 52.8 (0-123) words per minute. In the multivariable cross-sectional analysis, best-corrected visual acuity, area of geographic atrophy in the central Early Treatment Diabetic Retinopathy Study (ETDRS) subfield, classification of noncenter vs center-involving geographic atrophy, and area of geographic atrophy in the inner-right ETDRS subfield showed strongest associations with reading acuity (cross-validated R2for reading acuity = 0.69). Regarding reading speed, the most relevant variables were best-corrected visual acuity, low-luminance visual acuity, area of geographic atrophy in the central ETDRS subfield, in the inner-right ETDRS subfield, and in the inner-upper ETDRS subfield (R2 for reading speed = 0.67). In the longitudinal analysis, a similar prediction accuracy for reading performance was determined (R2 for reading acuity = 0.73; R2 for reading speed = 0.70). Prediction accuracy did not improve when follow-up time was added as an independent variable. Binocular reading performance did not differ from reading performance in the better-seeing eye. 

    Conclusions and relevance: The association of reading acuity and speed with visual functional and structural biomarkers supports the validity of reading performance as a meaningful end point in clinical trials. These findings suggest that measures in clinical and low-vision care for patients with geographic atrophy should focus primarily on the better-seeing eye. 

    DOI: 10.1001/jamaophthalmol.2021.3826 

    GENETICS

    Protective chromosome 1q32 haplotypes mitigate risk for age-related macular degeneration associated with the CFH-CFHR5 and ARMS2/HTRA1 loci 

    Hum Genomics.2021 Sep 25;15(1):60.

    Chris M Pappas, Moussa A Zouache, Stacie Matthews,  Caitlin D Faust, Jill L Hageman, Brandi L Williams, Burt T Richards, Gregory S Hageman

    Background: Single-variant associations with age-related macular degeneration (AMD), one of the most prevalent causes of irreversible vision loss worldwide, have been studied extensively. However, because of a lack of refinement of these associations, there remains considerable ambiguity regarding what constitutes genetic risk and/or protection for this disease, and how genetic combinations affect this risk. In this study, we consider the two most common and strongly AMD-associated loci, the CFH-CFHR5 region on chromosome 1q32 (Chr1 locus) and ARMS2/HTRA1 gene on chromosome 10q26 (Chr10 locus). 

    Results: By refining associations within the CFH-CFHR5 locus, we show that all genetic protection against the development of AMD in this region is described by the combination of the amino acid-altering variant CFH I62V (rs800292) and genetic deletion of CFHR3/1. Haplotypes based on CFH I62V, a CFHR3/1 deletion tagging SNP and the risk variant CFH Y402H are associated with either risk, protection or neutrality for AMD and capture more than 99% of control- and case-associated chromosomes. We find that genetic combinations of CFH-CFHR5 haplotypes (diplotypes) strongly influence AMD susceptibility and that individuals with risk/protective diplotypes are substantially protected against the development of disease. Finally, we demonstrate that AMD risk in the ARMS2/HTRA1 locus is also mitigated by combinations of CFH-CFHR5 haplotypes, with Chr10 risk variants essentially neutralized by protective CFH-CFHR5 haplotypes. 

    Conclusions: Our study highlights the importance of considering protective CFH-CFHR5 haplotypes when assessing genetic susceptibility for AMD. It establishes a framework that describes the full spectrum of AMD susceptibility using an optimal set of single-nucleotide polymorphisms with known functional consequences. It also indicates that protective or preventive complement-directed therapies targeting AMD driven by CFH-CFHR5 risk haplotypes may also be effective when AMD is driven by ARMS2/HTRA1 risk variants. 

    DOI: 10.1186/s40246-021-00359-8 

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