Xiangrong Kong1,2,3, Kaoru Fujinami4,5,6,7, Rupert W Strauss6,7,8,9, Beatriz Munoz3, Sheila K West3, Artur V Cideciyan10, Michel Michaelides6,7, Mohamed Ahmed3, Ann-Margret Ervin2,3, Etienne Schönbach3, Janet K Cheetham11, Hendrik P N Scholl3,12,13. 1. School of Public Health and Health Sciences, University of Massachusetts-Amherst, Amherst. 2. Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland. 3. Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland. 4. Laboratory of Visual Physiology, Division for Vision Research, National Institute of Sensory Organs, National Hospital Organization, Tokyo Medical Center, Tokyo, Japan. 5. Department of Ophthalmology, Keio University, School of Medicine, Tokyo, Japan. 6. Moorfields Eye Hospital, London, United Kingdom. 7. UCL Institute of Ophthalmology, University College London, London, United Kingdom. 8. Department of Ophthalmology, Johannes Kepler University (Clinic) Linz, Linz, Austria. 9. Department of Ophthalmology, Medical University Graz, Graz, Austria. 10. Scheie Eye Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia. 11. Foundation Fighting Blindness, Clinical Research Institute, Columbia, Maryland. 12. Department of Ophthalmology, University of Basel, Basel, Switzerland. 13. Institute of Molecular and Clinical Ophthalmology Basel, Basel, Switzerland.
Abstract
Importance: Limited data from prospective studies are available to understand the natural history of ABCA4-related Stargardt disease (STGD1). Such data are important for determining appropriate outcome measures for future STGD1 trials. Objective: To estimate the rate of loss of best-corrected visual acuity (BCVA) during 2 years and to estimate the associations of BCVA loss with foveal phenotype and genotype in patients with STGD1. Design, Setting, and Participants: This multicenter prospective cohort study included 259 participants (489 study eyes) with molecularly confirmed STGD1 who were 6 years or older. The participants were enrolled at 9 centers in the United States and Europe and were followed up every 6 months for 2 years. Exposures: Baseline BCVA and presence and type of foveal lesion (determined via fundus autofluorescence images) and genotype (classified into 4 groups based on the number and pathogenicity of ABCA4 mutations). Main Outcomes and Measures: Rate of BCVA change per year. Results: The mean (SD) age was 33 (15) years. Of 259 the participants, 141 (54%) were female, and 222 (85%) were white. The overall rate of BCVA loss was 0.55 (95% CI, 0.20-0.90) letters per year during the 2 years. Eyes with baseline BCVA worse than 20/200 showed an improvement of 0.65 (95% CI, 0.1-1.2) letters per year. At baseline, the mean BCVA for eyes without foveal lesion was 20/32, and their BCVA change rate over time was 0.1 (95% CI, -1.2 to 1.35) letters per year (P = .89). Eyes with a foveal lesion but having BCVA of 20/70 or better at baseline lost BCVA at a rate of 3 (95% CI, 1.5-4.4) letters per year (P < .001). Genotype was neither associated with baseline BCVA nor with the rate of BCVA change during the follow-up. Conclusions and Relevance: A clinically small BCVA loss was observed during 2 years, and the change rate varied depending on baseline BCVA. Eyes without lesion in the fovea had better BCVA at baseline and showed minimal change of BCVA throughout 2 years. Eyes with no or modest acuity impairment but with a foveal lesion at baseline had the fastest loss rate. For trials of STGD1 with 2 years of duration, it may be difficult to show efficacy using BCVA as an end point owing to its slow rate of change over this time.
Importance: Limited data from prospective studies are available to understand the natural history of ABCA4-related Stargardt disease (STGD1). Such data are important for determining appropriate outcome measures for future STGD1 trials. Objective: To estimate the rate of loss of best-corrected visual acuity (BCVA) during 2 years and to estimate the associations of BCVA loss with foveal phenotype and genotype in patients with STGD1. Design, Setting, and Participants: This multicenter prospective cohort study included 259 participants (489 study eyes) with molecularly confirmed STGD1 who were 6 years or older. The participants were enrolled at 9 centers in the United States and Europe and were followed up every 6 months for 2 years. Exposures: Baseline BCVA and presence and type of foveal lesion (determined via fundus autofluorescence images) and genotype (classified into 4 groups based on the number and pathogenicity of ABCA4 mutations). Main Outcomes and Measures: Rate of BCVA change per year. Results: The mean (SD) age was 33 (15) years. Of 259 the participants, 141 (54%) were female, and 222 (85%) were white. The overall rate of BCVA loss was 0.55 (95% CI, 0.20-0.90) letters per year during the 2 years. Eyes with baseline BCVA worse than 20/200 showed an improvement of 0.65 (95% CI, 0.1-1.2) letters per year. At baseline, the mean BCVA for eyes without foveal lesion was 20/32, and their BCVA change rate over time was 0.1 (95% CI, -1.2 to 1.35) letters per year (P = .89). Eyes with a foveal lesion but having BCVA of 20/70 or better at baseline lost BCVA at a rate of 3 (95% CI, 1.5-4.4) letters per year (P < .001). Genotype was neither associated with baseline BCVA nor with the rate of BCVA change during the follow-up. Conclusions and Relevance: A clinically small BCVA loss was observed during 2 years, and the change rate varied depending on baseline BCVA. Eyes without lesion in the fovea had better BCVA at baseline and showed minimal change of BCVA throughout 2 years. Eyes with no or modest acuity impairment but with a foveal lesion at baseline had the fastest loss rate. For trials of STGD1 with 2 years of duration, it may be difficult to show efficacy using BCVA as an end point owing to its slow rate of change over this time.
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