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Stanley Lambertus, Moritz Lindner, Nathalie M. Bax, Matthias M. Mauschitz, Jennifer Nadal, Matthias Schmid, Steffen Schmitz-Valckenberg, Anneke I. den Hollander, Bernhard H. F. Weber, Frank G. Holz, Gert Jan van der Wilt, Monika Fleckenstein, Carel B. Hoyng, ; Progression of Late-Onset Stargardt Disease. Invest. Ophthalmol. Vis. Sci. 2016;57(13):5186-5191. doi: 10.1167/iovs.16-19833.
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Identification of sensitive biomarkers is essential to determine potential effects of emerging therapeutic trials for Stargardt disease. This study aimed to describe the natural history of late-onset Stargardt, and demonstrates the accuracy of retinal pigment epithelium (RPE) atrophy progression as an outcome measure.
We performed a retrospective cohort study collecting multicenter data from 47 patients (91 eyes) with late-onset Stargardt, defined by clinical phenotype, at least one ABCA4 mutation, and age at disease onset ≥ 45 years. We analyzed RPE atrophy progression on fundus autofluorescence and near-infrared reflectance imaging using semiautomated software and a linear mixed model. We performed sample size calculations to assess the power in a simulated 2-year interventional study and assessed visual endpoints using time-to-event analysis.
Over time, progression of RPE atrophy was observed (mean: 0.22 mm/year, 95% confidence interval [CI]: 0.19–0.27). By including only patients with bilateral RPE atrophy in a future trial, 32 patients are needed to reach a power of 83.9% (95% CI: 83.1–84.6), assuming a fixed therapeutic effect size of 30%. We found a median interval between disease onset and visual acuity decline to 20/32, 20/80, and 20/200 of 2.74 (95% CI: 0.54–4.41), 10.15 (95% CI: 6.13–11.38), and 11.38 (95% CI: 6.13–13.34) years, respectively.
We show that RPE atrophy represents a robust biomarker to monitor disease progression in future therapeutic trials. In contrast, the variability in terms of the course of visual acuity was high.
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