Natural History of Geographic Atrophy Secondary to Age-Related Macular Degeneration

Holekamp, Nancy M.; Wykoff, Charles C.; Schmitz-Valckenberg, Steffen; Monés, Jordi; Souied, Eric H.; Lin, Hugh; Rabena, Melvin D.; Cantrell, Ronald A.; Henry, Erin C.; Tang, Fan; Swaminathan, Balakumar; Martin, Jillian; Ferrara, Daniela; Staurenghi, Giovanni

doi:10.1016/j.ophtha.2019.12.009

Cited by 56 publications

(53 citation statements)

References 29 publications

(28 reference statements)

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“…Of these, 81% (21/26) reported that LLVA or LLD provided useful additional information beyond standard VA. In five studies, LLD has been shown to be a strong predictor of geographic atrophy progression and subsequent VA loss 10,38,39,41,43 . LLD is significantly reduced in patients with macular telangiectasia type 1, choroideremia and pseudoxanthoma elasticum when compared with healthy controls 44,45,50 .…”

Section: Discussion and Critical Reviewmentioning

confidence: 99%

Low luminance visual acuity as a clinical measure and clinical trial outcome measure: a scoping review

Wood

Jolly

Buckley

et al. 2021

Ophthalmic Physiologic Optic

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Purpose The measurement of standard visual acuity (VA) is the most well‐known part of any ophthalmic examination to indicate visual function. Despite this, it is insensitive in detecting early disease changes. Therefore, other visual function tests have been developed including low luminance VA (LLVA) and low luminance deficit (LLD). This scoping literature review aims to summarise the current published applications of LLVA and LLD assessments to evaluate their utility as clinical markers and research outcome measures in a variety of ophthalmic conditions. Recent findings Sixty‐five peer‐reviewed publications were included. LLVA was pioneered for use in geographic atrophy, a subtype of age‐related macular degeneration, which remains the mainstay of its clinical application. However, other studies have reported additional useful applications in inherited retinal diseases including rare maculopathies and rod‐cone dystrophies. Although there are some variations in testing methodology, use of the standard Early Treatment Diabetic Retinopathy Study (ETDRS) chart with a 2.0 log unit neutral density filter is the most popular approach. The optimal testing luminance is still to be defined. Summary Overall, LLVA is an earlier clinical marker of change in central retinal function than standard VA. It has been shown to be a risk factor for disease progression and a better indicator of a patient’s level of everyday visual function. It is inexpensive and simple to implement using readily available standard ophthalmic equipment.

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Section: Discussion and Critical Reviewmentioning

confidence: 99%

Low luminance visual acuity as a clinical measure and clinical trial outcome measure: a scoping review

Wood

Jolly

Buckley

et al. 2021

Ophthalmic Physiologic Optic

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“…Different from the previous systematic review and meta-analysis of GA growth [7, 28, 29], this study is unique in that our meta-analysis is restricted to natural history eyes (from observational studies or control arm of GA trials) and is the most comprehensive meta-analysis to date that evaluated the overall GA growth rate and its variation calculated in both mm 2 /year and mm/year. Our meta-analysis included several recently published large GA studies including the Proxima natural history study of 496 eyes [30], 2 phase 3 trials (Chroma and Spectri) involving a total of 626 eyes in the control arm [31], the AREDS2 study involving 419 eyes in the placebo group [24], and the APL-2 trial with 80 eyes in the control arm [32]. Our comprehensive meta-analysis was based on 26 eligible studies (involving 3,666 eyes of 3,222 patients) with the mean baseline GA area ranging from 2.2 to 11.1 mm 2 , representing wide range of eyes with GA.…”

Section: Discussionmentioning

confidence: 99%

Growth Rate of Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Meta-Analysis of Natural History Studies and Implications for Designing Future Trials

Wang

Ying

2020

Ophthalmic Res

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Introduction: There is no effective treatment for geographic atrophy (GA). To help design future GA treatment trials, we conducted a meta-analysis for GA growth rate and its variability in natural history studies. Methods: Literatures were searched up to April 30, 2020. Data were extracted independently by 2 authors and analyzed using random-effects models. Results: The pooled mean GA growth rate was 1.66 mm²/year (SD = 1.27 mm²/year, I² = 97.0%, p < 0.001) from 23 studies (3,078 patients) reported with growth rate in mm²/year and 0.33 mm/year (SD = 0.17 mm/year, I² = 83.0%, p < 0.001) from 12 studies (1,808 patients) reported with growth rate in mm/year. Larger mean baseline GA area in mm² was associated with larger mean growth rate in both mm²/year and mm/year (p < 0.001). The sample size at 85% power for detecting 15% reduction in growth rate in a 2-arm GA trial is 464 and 209 patients per arm, respectively, for using mm²/year and mm/year as the primary outcome. Discussion/Conclusion: GA natural history studies had a pooled mean (SD) GA growth rate of 1.66 (1.27) mm²/year or 0.33 (0.17) mm/year. Because GA growth rate using mm/year requires smaller sample size than using mm²/year, GA growth rate in mm/year is recommended as the primary outcome measure for future GA trials.

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“…Two major advanced stages of AMD can occur simultaneously in one patient or even in a single eye: Choroidal neovascularization (CNV) and geographic atrophy (GA) [ 15 , 16 ]. These completely different disease patterns cause either disruption or loss of the retinal pigment epithelium (RPE).…”

Section: Introductionmentioning

confidence: 99%

Properdin Modulates Complement Component Production in Stressed Human Primary Retinal Pigment Epithelium Cells

et al. 2020

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The retinal pigment epithelium (RPE) maintains visual function and preserves structural integrity of the retina. Chronic dysfunction of the RPE is associated with retinal degeneration, including age-related macular degeneration (AMD). The AMD pathogenesis includes both increased oxidative stress and complement dysregulation. Physiological sources of oxidative stress in the retina are well known, while complement sources and regulation are still under debate. Using human primary RPE (hpRPE) cells, we have established a model to investigate complement component expression on transcript and protein level in AMD-risk and non-risk hpRPE cells. We evaluated the effect of properdin, a complement stabilizer, on the hpRPE cell-dependent complement profile exposed to oxidative stress. hpRPE cells expressed complement components, receptors and regulators. Complement proteins were also stored and secreted by hpRPE cells. We associated AMD-risk single nucleotide polymorphisms with an increased secretion of complement factors D (CFD) and I (CFI). Furthermore, we detected hpRPE cell-associated complement activation products (C3a, C5a) independent of any extracellularly added complement system. Exogenous properdin increased the mRNA expression of CFI and CFD, but decreased levels of complement components (C1Q, C3), receptors (C3AR, C5AR1, CD11B) and inflammation-associated transcripts (NLRP3, IL1B) in hpRPE cells exposed to oxidative stress. This properdin effect was time-dependently counter regulated. In conclusion, our data unveiled a local, genotype-associated complement component production in hpRPE cells, regulated by exogenous properdin. The local complement production and activation via blood-independent mechanisms can be a new therapeutic target for AMD.

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Natural History of Geographic Atrophy Secondary to Age-Related Macular Degeneration

Cited by 56 publications

References 29 publications

Low luminance visual acuity as a clinical measure and clinical trial outcome measure: a scoping review

Low luminance visual acuity as a clinical measure and clinical trial outcome measure: a scoping review

Growth Rate of Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Meta-Analysis of Natural History Studies and Implications for Designing Future Trials

Properdin Modulates Complement Component Production in Stressed Human Primary Retinal Pigment Epithelium Cells

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