Incidence of Atrophic Lesions in Stargardt Disease in the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) Study: Report No. 5

Abstract

Importance: Outcome measures that are sensitive to disease progression are needed as clinical end points for future treatment trials in Stargardt disease.

Objective: To examine the incidence of atrophic lesions of the retinal pigment epithelium in patients with Stargardt disease as determined by fundus autofluorescence imaging.

Design, setting, and participants: In this retrospective multicenter cohort study, 217 patients 6 years and older at baseline at tertiary referral centers in Europe, the United States, and the United Kingdom who were harboring disease-causing variants in the adenosine triphosphate (ATP)-binding cassette subfamily A member 4 (ABCA4) gene and who met the following criteria were enrolled: (1) at least 1 well-demarcated area of atrophy with a minimum diameter of 300 µm, with the total area of all atrophic lesions being less than or equal to 12 mm2 in at least 1 eye at the most recent visit, and (2) fundus autofluorescence images for at least 2 visits with a minimum of 6 months between at least 2 visits. Data were collected between August 22, 2013, and December 12, 2014. Data analysis was performed from March 15, 2015, through January 31, 2017.

Exposures: Images were evaluated by staff at a central reading center. Areas of definitely decreased autofluorescence (DDAF) and questionably decreased autofluorescence (QDAF) were outlined and quantified. Lesion-free survival rates were estimated using Kaplan-Meier survival curves.

Main outcomes and measures: Incidence of atrophic lesions as determined by fundus autofluorescence.

Results: The 217 patients (mean [SD] age, 21.8 [13.3] years; 127 female [57.5%]; 148 white [68.2%]) contributed 390 eyes for which the mean (SD) follow-up time was 3.9 (1.6) years (range, 0.7-12.1 years). Among eyes without DDAF at first visit, the median time to develop a DDAF lesion was 4.9 years (95% CI, 4.3-5.6 years). Among eyes without QDAF, the median time to develop a QDAF lesion was 6.3 years (95% CI, 5.6-9.7 years). Eyes with a lesion of DDAF at the first visit were less likely to develop a QDAF lesion compared with eyes without a lesion of DDAF (hazard ratio, 0.19; 95% CI, 0.05-0.70; P = .01).

Conclusions and relevance: An estimated 50% of the eyes without DDAF at first visit will develop the lesion in less than 5 years, suggesting that incidence of DDAF could serve as an outcome measure for treatment trials.

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 Birch reported working as a consultant for AGTC, Alachua, Florida; Acucela Inc, Seattle, Washington; Shire Pharmaceuticals, Lexington, Massachusetts; Ionis/GSK, Carlsbad, California; QLT, Vancouver, British Columbia, Canada; and Thrombogenics, Iselin, New Jersey. Dr Sadda reported receiving financial support from Optos, Marlborough, Massachusetts; Carl Zeiss Meditec, Jena, Germany; Nidek, Padova, Italy; Topcon Medical Systems, Oakland, New Jersey; Scientific Technical Advisory Committee at Alcon Research Institute, Fort Worth, Texas; and Research to Prevent Blindness Inc, New York, New York. Dr Scholl reported receiving support from the Foundation Fighting Blindness Clinical Research Institute and a grant to the Foundation Fighting Blindness Clinical Research Institute by the US Department of Defense, US Army Medical Research and Materiel Command, Telemedicine and Advanced Technology Research Center, Fort Meade, Maryland; and the Shulsky Foundation, New York, NY; working 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 boards of Gensight Biologics, Vision Medicines Inc, and Intellia Therapeutics Inc; serving as a member of the data monitoring and safety boards or committees of Genentech Inc/F. Hoffmann-La Roche Ltd, Genzyme Corp/Sanofi, and ReNeuron Group Plc/Ora Inc; and previously serving as a member of the Ophthalmic Devices Panel of the Medical Devices Advisory Committee, US Food and Drug Administration, Silver Spring, Maryland. 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 in accordance with its conflict of interest policies. Dr Scholl reported serving as a principal investigator of grants at the University of Basel sponsored by the following entity: Acucela Inc, NightstaRx Ltd, and QLT Inc. Grants at the University of Basel are negotiated and administered by the institution, which 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). Dr Strauss reported receiving support from the Austrian Science Fund, Vienna, Austria, and Foundation Fighting Blindness Clinical Research Institute. Dr Cideciyan reported receiving partial support from the National Institutes of Health, Bethesda, Maryland. Dr Michaelides reported receiving support from a Foundation Fighting Blindess Career Development Award and the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital National Health Service Foundation Trust and University College London Institute of Ophthalmology, London, England. No other disclosures were reported.

Figures

Figure 1.. Different Decreased Autofluorescence Categories Used for Grading of Fundus Autofluorescence Images

A, For areas with levels between 50% and 90% of darkness in reference to the optic nerve head, the term questionably decreased autofluorescence (QDAF) is used. B, For lesions with at least 90% darkness, the term definitely decreased autofluorescence is used (DDAF) (blue arrowhead).

Figure 2.. Probability of Developing Lesions of Definitely Decreased Autofluorescence (DDAF) and Questionably Decreased Autofluorescence (QDAF)

A, A total of 206 eyes at risk for developing DDAF lesions (black lines indicate median time to develop a DDAF lesion). B, A total of 196 eyes with QDAF lesions at risk for developing DDAF lesions. C, A total of 171 eyes with homogeneous background and 35 eyes with heterogeneous background at risk for developing DDAF lesions. D, A total of 69 eyes at risk for developing QDAF lesions (black lines indicate median time to develop at QDAF lesion). E, A total of 59 with DDAF lesions and 10 eyes without DDAF lesions at risk for developing QDAF lesions.