FEATURED ARTICLE
The phenotypic course of age-related macular degeneration for ARMS2/HTRA1: The EYE-RISK Consortium.
Thee EF, Colijn JM, Cougnard-Grégoire A, Meester-Smoor MA, Verzijden T, Hoyng CB, Fauser S, Hense HW, Silva R, Creuzot-Garcher C, Ueffing M, Delcourt C, den Hollander AI, Klaver CCW; European Eye Epidemiology Consortium and EYE-RISK Project.
Purpose: ARMS2 is considered the most enigmatic of the genes for age-related macular degeneration (AMD). We investigated the phenotypic course and spectrum of AMD for the risk haplotype at ARMS2/HTRA1 in a large European consortium.
Design: Pooled analysis of 4 case-control and 6 cohort studies
Participants: Ten studies from the European Eye Epidemiology consortium provided data on 17,204 individuals aged 55+ years
Methods: AMD features and macular thickness were determined on multimodal images; data on genetics and phenotype were harmonized. Risks of AMD features for rs3750486 genotypes at the ARMS2/HTRA1 locus were determined by logistic regression, and compared with a genetic risk score (GRS) of 19 variants at the complement pathway. Lifetime risks were estimated with Kaplan Meier product-limit analyses in prospective population-based cohorts.
Main Outcome Measures: AMD features and stage.
Results: Of 2068 individuals with late AMD, 64.7% carried the ARMS2/HTRA1 risk allele. For homozygous carriers, the odds ratio (OR) of geographic atrophy was 8.6 (95%CI 6.5-11.4), of choroidal neovascularization (CNV) was 11.2 (95%CI 9.4-13.3), and of mixed late AMD was 12.2 (95%CI 7.3-20.6). Cumulative life-time risk of late AMD ranged from 4.4% for carriers of the non-risk genotype to 9.4% and 26.8% for heterozygous and homozygous carriers, respectively. The latter received the diagnosis of late AMD 9.6 (95%CI 8.0-11.2) years earlier than carriers of the non-risk genotype. The risk haplotype was not associated with hard or soft distinct drusen <125um (OR 1.2, 95% 0.9-1.7), but risks increased significantly for soft indistinct drusen ≥125um (OR 2.1, 95%CI 1.5-3.0), up to OR 7.2 (95% CI 3.8-13.8) for reticular pseudodrusen. Compared to persons with a high GRS for complement, homozygous carriers of ARMS2/HTRA1 had a significantly higher risk of CNV (OR 4.1, 95%CI 3.2-5.4); risks of other characteristics including macular thickness were not significantly different.
Conclusions: Carriers of the risk haplotype at ARMS2/HTRA1 have a particularly high risk of late AMD at a relatively early age. Our data suggest that risk variants at ARMS2/HTRA1 act as a strong catalyst of progression once early signs are present. The phenotypic spectrum resembles that of complement genes, only with higher risks of CNV.
DOI: 10.1016
DRUG TREATMENT
Title: three-year treatment outcomes of aflibercept versus ranibizumab for diabetic macular edema: data from the fight retinal blindness! Registry.
Retina. 2022 Feb 7.
Gabrielle PH, Nguyen V, Creuzot-Garcher C, Arnold JJ, Mehta H, Duran MA, Bougamha W, Carreño E, Viola F, Squirrell D, Barthelmes D, Gillies M.
Purpose: Compare the three-year outcomes of ranibizumab versus aflibercept in eyes with DME in daily practice.
Methods: This was a retrospective analysis of naive DME eyes starting intravitreal injections of ranibizumab (0.5mg) or aflibercept (2mg) from 1 January 2013 to 31 December 2017 that were collected in the Fight Retinal Blindness! registry.
Results: We identified 534 eyes (ranibizumab – 267, aflibercept – 267) of 402 patients. The adjusted mean (95% CI) VA change of +1.3 (-0.1, 4.2) letters in the ranibizumab group and +2.4 (-0.2, 5.1) letters (P = 0.001) in the aflibercept group at 3 years was not clinically different. However, the adjusted mean CST change appeared to remain significantly different throughout the three-year period with higher reductions in favor of aflibercept (-87.8 [-108.3, -67.4] µm for ranibizumab vs. -114.4 [-134.4, -94.3] for aflibercept; P < 0.01). When baseline visual impairment was moderate (VA ≤68 ETDRS letters), we found a faster improvement in VA in eyes treated with aflibercept up until 18 months of treatment than eyes treated with ranibizumab, which then stayed similar until 36 months of treatment, while there was no apparent difference when baseline visual impairment was mild (VA ≥69 ETDRS letters). The rate of serious adverse events was low.
Conclusions: Aflibercept and ranibizumab were both effective and safe for DME over 3 years.
DOI: 10.1097/IAE.0000000000003428
Dexamethasone Implant for Diabetic Macular Oedema: 1-Year Treatment Outcomes from the Fight Retinal Blindness! Registry.
Ophthalmology and Therapy. 2022 Feb 18
Bhandari S, Gabrielle PH, Nguyen V, Daien V, Viola F, Bougamha W, Young S, Romero-Nuñez B, Figueras-Roca M, Zarranz-Ventura J, Barthelmes D, Sararols L, Gillies M, Creuzot-Garcher C.
Introduction: Phase III clinical trials of dexamethasone intravitreal implant for diabetic macular oedema (DMO) have reported significant improvements in visual acuity (VA). Studies evaluating the treatment of DMO in routine clinical practice provide data to identify areas that need improvement. This study evaluated 12-month treatment outcomes of dexamethasone implant for DMO in routine clinical practice.
Methods: Retrospective data analysis of eyes that started dexamethasone implant for DMO from 1 June 2013 to 30 April 2019 in routine clinical practice tracked in the Fight Retinal Blindness! Registry.
Results: Of the 4282 eyes (2518 patients) that started DMO treatment in the specified period, 267 (6%) eyes (204 patients) received 454 dexamethasone implant injections. Two-fifths (106 eyes) had received prior treatment for DMO. The mean (95% confidence interval [CI]) VA change at 12 months was 1.8 (- 0.5, 4.2) letters from the mean (standard deviation [SD]) VA of 56.5 (19.8) letters at baseline, with 41% eyes achieving at least 20/40. The mean (95% CI) change in central subfield thickness over 1 year was - 79 (- 104, - 54) µm from a mean (SD) of 459 (120) µm at baseline. Eyes that completed 1 year of follow-up received a median (Q1, Q3) of 2 (1, 2) dexamethasone implants. One-tenth of phakic eyes received cataract surgery while 2% had a pressure response requiring anti-glaucoma medications.
Conclusions: One-year treatment outcomes of dexamethasone intravitreal implant for DMO in routine clinical practice were inferior to those in the clinical trials perhaps because of fewer treatments in clinical practice.
DOI: 10.1007/s40123-022-00473-3
BMC Ophthalmology. 2022 Feb 28
Gurung RL, FitzGerald LM, Liu E, McComish BJ, Kaidonis G, Ridge B, Hewitt AW, Vote BJ, Verma N, Craig JE, Burdon KP.
Objectives: To assess whether insulin therapy impacts the effectiveness of anti-vascular endothelial growth factor (anti-VEGF) injection for the treatment of diabetic macular edema (DME) in type 2 diabetes mellitus.
Methods: This was a retrospective multi-center analysis. The best-corrected visual acuity (BCVA) at 12 months, BCVA change, central macular thickness (CMT), CMT change, and cumulative injection number were compared between the insulin and the oral hypoglycemic agent (OHA) groups. Results: The mean final BCVA and CMT improved in both the insulin (N = 137; p < 0.001; p < 0.001, respectively) and the OHA group (N = 61; p = 0.199; p < 0.001, respectively). The two treatment groups were comparable for final BCVA (p = 0.263), BCVA change (p = 0.184), final CMT (p = 0.741), CMT change (p = 0.458), and the cumulative injections received (p = 0.594). The results were comparable between the two groups when stratified by baseline vision (p > 0.05) and baseline HbA1c (p > 0.05).
Conclusion: Insulin therapy does not alter treatment outcomes for anti-VEGF therapy in DME.
DIAGNOSIS AND ASSESSMENT
Multimodal assessments of drusenoid pigment epithelial detachments in the Age-Related Eye Disease Study 2 Ancillary (A2A) spectral-domain optical coherence tomography (SD-OCT) study cohort.
Retina. 2022 Feb 4
Thavikulwat AT, De Silva T, Agrón E, Keenan TDL, Toth CA, Chew EY, Cukras CA; Age-Related Eye Disease Study 2 Ancillary Spectral Domain Optical Coherence Tomography Study Group.
Purpose: To identify features correlating with drusenoid pigment epithelial detachment (DPED) progression in the AREDS2 Ancillary (A2A) spectral-domain optical coherence tomography (SD-OCT) study cohort.
Methods: In this retrospective analysis of a prospective longitudinal study, eyes with intermediate age-related macular degeneration (AMD) and DPEDs were followed longitudinally with annual multimodal imaging.
Results: Thirty-one eyes of 25 participants (mean age 72.6 years) in the A2A AREDS2 substudy had DPED identified in color fundus images. SD-OCT inspection confirmed a sub-retinal pigment epithelium drusenoid elevation of ≥433 µm diameter in 25 (80.6%) eyes. Twenty-four of these eyes were followed longitudinally (median 4.0 years) during which 7 eyes (29.2%) underwent DPED collapse (with 3/7 further progressing to geographic atrophy), 6 (25.0%) developing neovascular AMD, and 11 (45.8%) maintaining DPED persistence without late AMD. On Kaplan-Meier analysis, mean time to DPED collapse was 3.9 years. Both DPED collapse and progression to neovascular AMD were preceded by the presence of hyperreflective foci over the DPED.
Conclusion: The natural history of DPED comprises: collapse – sometimes followed by the development of atrophy, vascularization followed by exudation, or DPED persistence. SD-OCT can confirm RPE elevation caused by drusenoid accumulation and facilitate the identification of high-risk features that correlate with progression.
DOI: 10.1097/IAE.0000000000003423
Optical coherence tomography predictors of 3-year visual outcome for type 3 macular neovascularization.
Ophthalmology Retina. 2022 Feb 25
Sacconi R(1), Forte P(1), Tombolini B(1), Grosso D(1), Fantaguzzi F(1), Pina A(2), Querques L(2), Bandello F(1), Querques G(3).
Purpose: To identify baseline optical coherence tomography (OCT) predictors of the 3-year visual outcome for type 3 (T3) macular neovascularization (MNV) secondary to age-related macular degeneration (AMD) treated by anti-vascular endothelial growth factor (VEGF) therapy. DESIGN: Retrospective longitudinal study. PARTICIPANTS: Forty eyes of 30 patients affected by exudative treatment-naïve T3 MNV were enrolled.
Methods: Baseline best-corrected visual acuity (BCVA) and several baseline OCT features were assessed and included in the analysis. Univariate and multivariate analyses served to identify risk factors associated with the 3-year BCVA.
Main Outcome Measures: Baseline OCT features that are associated with bad or good visual outcome of type 3 MNV treated by anti-VEGF injections.
Results: Mean baseline BCVA was 0.34±0.28LogMAR and significantly decreased to 0.52±0.37LogMAR at the end of 3-year follow-up (p=0.002). In the univariate analysis, the following baseline features were associated with the 3-year BCVA outcome: baseline BCVA (p=0.004), foveal involvement of exudation (p=0.004), and presence of subretinal fluid (SRF)(p=0.004). In the multivariate model, baseline BCVA (p=0.032), central macular thickness (p=0.036), number of active T3 lesions (p=0.034), and presence of SRF (p=0.008) were associated with the 3-year BCVA outcome. Interestingly, 3-year BCVA was significantly lower in 19 eyes with SRF at the baseline (0.69±0.42 LogMAR) in comparison to 21 eyes without SRF (0.37±0.24 LogMAR, p=0.004).
Conclusion: We identified structural OCT features associated with BCVA outcome after 3-year treatment with anti-VEGF injections. Different from previous studies on neovascular AMD, in our series, the presence of SRF at baseline was the most significant independent negative predictor of functional outcomes. Current findings may be employed to identify less favorable T3 patterns potentially deserving a more intensive treatment.
DOI: 10.1016/j.oret.2022.02.010
REVIEWS
The blue-light-hazard vs. blue-light-hype.
American Journal of Ophthalmology 2022 Feb 25
Mainster MA, Findl O, Dick HB, Desmettre T, Ledesma-Gil G, Curcio CA, Turner PL.
Purpose: The blue-light-hazard is the experimental finding that blue light is highly toxic to the retina (photic retinopathy), in brief abnormally intense exposures, including sungazing or vitreoretinal endoillumination. This term has been misused commercially to suggest, falsely, that ambient environmental light exposure causes phototoxicity to the retina, leading to age-related macular degeneration (AMD). We analyze clinical, epidemiological and biophysical data regarding blue-filtering optical chromophores.
Design: Perspective.
Methods: Analysis and integration of data regarding the blue-light-hazard and blue-blocking filters in ophthalmology and related disciplines.
Results: Large epidemiological studies show that blue-blocking intraocular lenses (IOLs) do not decrease AMD risk or progression. Blue-filtering lenses cannot reduce disability glare because image and glare illumination are decreased in the same proportion. Blue light essential for optimal rod and retinal ganglion photoreception is decreased by progressive age-related crystalline lens yellowing, pupillary miosis and rod and retinal ganglion photoreceptor degeneration. Healthful daily environmental blue light exposure decreases in older adults, especially women. Blue light is important in dim environments where inadequate illumination increases risk of falls and associated morbidities.
Conclusions: The blue-light-hazard is misused as a marketing stratagem to alarm people into using spectacles and IOLs that restrict blue light. Blue light loss is permanent for pseudophakes with blue-blocking IOLs. Blue-light-hazard misrepresentation flourishes despite absence of proof that environmental light exposure or cataract surgery causes AMD or that IOL chromophores provide clinical protection. Blue-filtering chromophores suppress blue light critical for good mental and physical health and for optimal scotopic and mesopic vision.
DOI: 10.1016/j.ajo.2022.02.016
BIOMARKERS
Photoreceptor layer thinning is an early biomarker for age-related macular degeneration: Epidemiological and genetic evidence from UK Biobank optical coherence tomography data.
Ophthalmology. 2022 Feb 8
Zekavat SM, Sekimitsu S, Ye Y, Raghu V, Zhao H, Elze T, Segrè AV, Wiggs JL, Natarajan P, Del Priore L, Zebardast N, Wang JC.
Objective: Despite widespread use of optical coherence tomography (OCT), an early-stage imaging biomarker for age-related macular degeneration (AMD) has not been identified. Pathophysiologically, the timing of drusen accumulation in relation to photoreceptor degeneration in AMD remains unclear, as are the inherited genetic variants contributing to these processes. Here, we jointly analyzed OCT, electronic health record, and genomic data to characterize the time sequence of changes in retinal layer thicknesses in AMD, as well as epidemiological and genetic associations between retinal layer thicknesses and AMD.
Design: Cohort study
Participants: 44,823 UK Biobank individuals (enrollment ages 40-70y, 54% female, median 10y follow-up).
Methods: The Topcon Advanced Boundary Segmentation algorithm was used for retinal layer segmentation. We associated 9 retinal layer thicknesses with prevalent AMD (present at enrollment) in a logistic regression model, and with incident AMD (diagnosed after enrollment) in a Cox proportional hazards model. Next, we associated AMD-associated genetic alleles, individually and as a polygenic risk score (PRS), with retinal layer thicknesses. All analyses were adjusted for age, age2, sex, smoking status, and principal components of ancestry.
Main outcome measures: Prevalent and incident AMD
Results: Photoreceptor segment (PS) thinning was observed throughout the lifespan of individuals analyzed, while retinal pigment epithelium and Bruch’s membrane complex (RPE+BM) thickening started after age 57y. Each standard deviation (SD) of PS thinning and RPE+BM thickening were associated with incident AMD (PS: HR 1.35, 95% CI 1.23-1.47, P=3.7×10-11; RPE+BM: HR 1.14, 95% CI 1.06-1.22, P=0.00024). The AMD PRS was associated with PS thinning (Beta -0.21 SD per 2-fold genetically increased risk of AMD, 95% CI -0.23 to -0.19, P=2.8×10-74), and its association with RPE+BM was U-shaped (thinning with AMD PRS<92nd percentile and thickening with AMD PRS>92nd percentile). The loci with strongest support for genetic correlation were AMD risk-raising variants CFH:rs570618-T, CFH:10922109-C, and ARMS2/HTRA1:rs3750846-C on PS thinning, and SYN3/TIMP3:rs5754227-T on RPE+BM thickening.
Conclusions: Epidemiologically, PS thinning precedes RPE+BM thickening by decades, and is the retinal layer most strongly predictive of future AMD risk. Genetically, AMD risk variants are associated with decreased PS thickness. Overall, these findings support PS thinning as an early-stage biomarker for future AMD development.
DOI: 10.1016/j.ophtha.2022.02.001
Subretinal Drusenoid Deposits and Soft Drusen: Are They Markers for Distinct Retinal Diseases?
Retina. 2022 Feb 23.
Thomson RJ, Chazaro J, Otero-Marquez O, Ledesma-Gil G, Tong Y, Coughlin AC, Teibel ZR, Alauddin S, Tai K, Lloyd H, Scolaro M, Govindaiah A, Bhuiyan A, Dhamoon MS, Deobhakta A, Narula J, Rosen RB, Yannuzzi LA, Freund KB, Smith RT.
Purpose: Soft drusen and subretinal drusenoid deposits (SDDs) characterize two pathways to advanced age-related macular degeneration (AMD), with distinct genetic risks, serum risks and associated systemic diseases.
Methods: 126 Subjects with AMD were classified as SDD (with or without soft drusen), or non-SDD (drusen only) by retinal imaging, with serum risks, genetic testing, and histories of cardiovascular disease (CVD) and stroke.
Results: There were 62 SDD subjects and 64 non-SDD subjects, 51 total had CVD or stroke.SDD correlated significantly with: lower mean serum HDL (61±18 vs. 69±22 mg/dl, p= 0.038, t test); CVD and stroke (34/51 SDD, p= 0.001, chi square); ARMS2 risk allele (p= 0.019, chi square), but not with CFH risk allele (p = 0.66). Non-SDD (drusen only) correlated/trended with: APOE2 (p= 0.032) and CETP (p= 0.072) risk alleles (chi square). Multivariate independent risks for SDD were: CVD and stroke (p= 0.008), and ARMS2 homozygous risk (p= 0.038).
Conclusion: SDD and non-SDD subjects have distinct systemic associations, serum and genetic risks. SDD are associated with CVD and stroke, ARMS2 risk, and lower HDL; non-SDD with higher HDL, CFH risk and two lipid risk genes. These and other distinct associations suggest these lesions are markers for distinct diseases.
