Progression of Stargardt Disease as Determined by Fundus Autofluorescence in the Retrospective Progression of Stargardt Disease Study (ProgStar Report No. 9)

Abstract

Importance: Sensitive outcome measures for disease progression are needed for treatment trials of Stargardt disease.

Objective: To describe the yearly progression rate of atrophic lesions in the retrospective Progression of Stargardt Disease study.

Design, setting, and participants: A multicenter retrospective cohort study was conducted at tertiary referral centers in the United States and Europe. A total of 251 patients aged 6 years or older at baseline, harboring disease-causing variants in ABCA4 (OMIM 601691), enrolled in the study from 9 centers between August 2, 2013, and December 12, 2014; of these patients, 215 had at least 2 gradable fundus autofluorescence images with atrophic lesion(s) present in at least 1 eye.

Exposures: Areas of definitely decreased autofluorescence (DDAF) and questionably decreased autofluorescence were quantified by a reading center. Progression rates were estimated from linear mixed models with time as the independent variable.

Main outcomes and measures: Yearly rate of progression using the growth of atrophic lesions measured by fundus autofluorescence.

Results: A total of 251 participants (458 study eyes) were enrolled. Images from 386 eyes of 215 participants (126 females and 89 males; mean [SD] age, 29.9 [14.7] years; mean [SD] age of onset of symptoms, 21.9 [13.3] years) showed atrophic lesions present on at least 2 visits and were graded for 2 (156 eyes), 3 (174 eyes), or 4 (57 eyes) visits. A subset of 224 eyes (123 female participants and 101 male participants; mean [SD] age, 33.0 [15.1] years) had areas of DDAF present on at least 2 visits; these eyes were included in the estimation of the progression of the area of DDAF. At the first visit, DDAF was present in 224 eyes (58.0%), with a mean (SD) lesion size of 2.2 (2.7) mm2. The total mean (SD) area of decreased autofluorescence (DDAF and questionably decreased autofluorescence) at first visit was 2.6 (2.8) mm2. Mean progression of DDAF was 0.51 mm2/y (95% CI, 0.42-0.61 mm2/y), and of total decreased fundus autofluorescence was 0.35 mm2/y (95% CI, 0.28-0.43 mm2/y). Rates of progression depended on the initial size of the lesion.

Conclusions and relevance: In Stargardt disease with DDAF lesions, fundus autofluorescence may serve as a monitoring tool for interventional clinical trials that aim to slow disease progression. Rates of progression depended mainly on initial lesion size.

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Strauss reported receiving support from project number: J 3383-B23 from the Austrian Science Fund and Foundation Fighting Blindness Clinical Research Institute. Dr Birch reported serving as a consultant for AGTC, Acucela Inc, Shire Pharmaceuticals, Ionis/GSK, QLT, and Thrombogenics. Dr Sadda reported receiving financial support from Optos, Carl Zeiss Meditec, Nidek, and Topcon Medical Systems. Dr West reported serving on the Scientific Technical Advisory Committee for Alcon Research Institute and Research to Prevent Blindness Inc. Dr. Scholl reported serving as a paid consultant for Astellas Institute for Regenerative Medicine, Boehringer Ingelheim Pharma GmbH & Co KG, Daiichi Sankyo Inc, Gerson Lehrman Group, Guidepoint, and Shire; serving as a member of the Scientific Advisory Board of Gensight Biologics, Vision Medicines Inc, and Intellia Therapeutics Inc; serving as a member of the Data Monitoring and Safety Board/Committee of Genentech Inc/F. Hoffmann-La Roche Ltd, Genzyme Corp./Sanofi, and ReNeuron Group Plc/Ora Inc; and serving as a past member of the Ophthalmic Devices Panel of the Medical Devices Advisory Committee, US Food and Drug Administration. These arrangements have been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. Johns Hopkins University and Bayer Pharma AG have an active research collaboration and option agreement. These arrangements have also been reviewed and approved by the University of Basel (Universitätsspital Basel [USB]) in accordance with its conflict of interest policies. Dr Scholl reported serving as the principal investigator of grants at the USB sponsored by Acucela Inc, NightstaRx Ltd, and QLT Inc. Grants at USB are negotiated and administered by the institution (USB) that receives them on its proper accounts. Individual investigators who participate in the sponsored project(s) are not directly compensated by the sponsor but may receive salary or other support from the institution to support their effort on the project(s). No other disclosures were reported.

Figures

Figure 1.. Examples of Progression of Lesion of Definitely Decreased Autofluorescence (DDAF) and Questionably Decreased Autofluorescence (QDAF)

A, Central lesion of DDAF (0.82 mm2) with a temporal adjacent lesion of QDAF (1.53 mm2). B, Same eye after 22 months: the lesion of DDAF is enlarged (2.09 mm2), whereas the lesion of QDAF (0.45 mm2) is decreased, indicating the transformation from QDAF into DDAF; the total area enlarged from 2.35 to 2.54 mm2.

Figure 2.. Estimated Yearly Progression of Areas Based on Lesion Size at the First Included Visit

A, Estimated growth rate in eyes with definitely decreased autofluorescence (DDAF) lesion sizes ≤1.92 mm2 (66th percentile) was 0.32 mm2/y (95% CI, 0.24-0.39 mm2/y) (brown line). B, Estimated growth rate in eyes with DDAF lesion sizes >1.92 mm2 was estimated as 0.86 mm2/y (95% CI, 0.67-1.06 mm2/y) (orange line). C, For total area of decreased areas of autofluorescence, eyes with lesion sizes ≤2.50 mm2 (66th percentile) showed an estimated growth rate of 0.26 mm2/y (95% CI, 0.21-0.32 mm2/y) (brown line). D, For total area of decreased areas of autofluorescence, eyes with lesions sizes >2.50 mm2 showed an estimated growth rate of 0.74 mm2/y (95% CI, 0.57-0.91 mm2/y) (orange line). Diagonal lines in parts A-D indicate estimated growth rates.