JAMA Ophthalmology Journal Club Slides: Validity of the Age-Related Eye Disease Study Grading Scale Vitale S, Clemons TE, Agrón E, et al; Age-Related Eye Disease Study 2 (AREDS2) Research Group. Evaluating the validity of the Age-Related Eye Disease Study grading scale for age-related macular degeneration: AREDS2 report 10. JAMA Ophthalmol. Published online July 21, 2016. doi:10.1001/jamaophthalmol.2016.2383.

Introduction Age-related macular degeneration (AMD) is a leading cause of visual impairment and blindness in older populations. Current treatments for AMD are targeted at specific risk groups based on type and severity of AMD lesions. A standardized grading scale was developed in the Age-Related Eye Disease Study (AREDS) to characterize AMD phenotypes. In AREDS, higher scores on the AMD scale at baseline were significantly associated with higher risk of developing late AMD (neovascular AMD or central geographic atrophy). Objective To assess whether the AREDS AMD grading scale had similar ability to predict late AMD in AREDS2 as it did in the original AREDS.

Methods Study Design AREDS (1992-2001) and AREDS2 (2006-2012) were randomized clinical trials to evaluate whether nutritional supplements could slow the progression of AMD. Participants From clinical sites across the United States. AREDS: no AMD, early AMD, intermediate AMD, or late AMD in the fellow eye. AREDS2: bilateral large drusen or large drusen in the study eye plus late AMD in the fellow eye. Color stereo fundus photographs were obtained at baseline and annually thereafter and were graded at the University of Wisconsin reading center by masked, certified graders.

Methods Data Analysis Late AMD: ≥2 of 5 neovascularization signs noted on photographic grading (subretinal fluid; intraretinal, subretinal, or subretinal pigment epithelium blood associated with neovascular AMD; intraretinal lipid exudates; subretinal fibrin or fibrosis; and fibrovascular or serous pigment epithelial detachment), or Central geographic atrophy noted on photographic grading, or History of treatment for neovascular AMD. Calculated 5-year incidence rates of late AMD (number of incident late AMD cases divided by number at risk at baseline). Stratified by baseline AMD detailed severity scale score (eye level). Compared AREDS2 and AREDS rates within each stratum (z test). Performed same analysis but stratifying by baseline simple scale score (person level).

Results Percentage of Participants Developing Late AMD in 5 Years With Both Eyes Free of Late AMD at Baseline, Stratified by AREDS Detailed Severity Scale Score for All Eyes Rates of late AMD were similar between AREDS2 and AREDS when stratified by baseline AREDS detailed severity scale scores for AMD. AREDS Detailed Severity Scale Score for All Eyes No. (%)/Total No. of Participants  P Value AREDSa (n = 4302) AREDS2 (n = 5440) Total 285/4302 (6.6) 1232/5440 (22.6)  Not applicable 1, 2, or 3 13/2630 (0.5) 5/206 (2.4) <.001 4 25/506 (4.9) 21/323 (6.5) .34 5 15/268 (5.6) 47/591 (8.0) .22 6 50/364 (13.7) 174/1354 (12.8) .66 7 97/349 (27.8) 563/2145 (26.2) .54 8 63/141 (44.7) 257/554 (46.4) .72 9 (Noncentral geographic atrophy) 22/44 (50.0) 134/219 (61.2) .17 a Includes treated eyes only (excludes placebo).

Results Comparing Rates of Progression to Late AMD (Neovascular AMD, Central Geographic Atrophy, or Both) in AREDS and AREDS2 Rates of late AMD were similar between AREDS2 and AREDS when stratified by baseline AREDS detailed severity scale scores for AMD.

Results Percentage of Participants Developing Late AMD in 5 Years With Both Eyes Free of Late AMD at Baseline, Stratified by AREDS Simple Scale Score for All Participants Rates of late AMD were similar between AREDS2 and AREDS when stratified by baseline AREDS simple scale severity scores for AMD. AREDS Simple Scale Score for All Participants No. (%)/Total No. of Participants  P Value AREDS (n = 3211) AREDS2 (n = 2719) Total 316/3211 (9.8) 910/2719 (33.5)  Not applicable 6/1466 (0.4) 0/9 (0) .85 1 20/635 (3.1) 5/53 (9.4) .02 2 55/465 (11.8) 68/532 (12.8) .65 3 85/328 (25.9) 179/681 (26.3) .90 4 150/317 (47.3) 658/1444 (45.6) .57

Results Five-Year Rates of Progression of Late Neovascular AMD in AREDS2, Stratified by Status of Fellow Eye at Baseline In AREDS2, rates of late AMD were higher when the fellow eye had late AMD at baseline than when it was free of late AMD at baseline.

Comment Limitations Clinical trial participants in AREDS2 may differ from participants in other types of AMD treatment trials and from the general population with AMD, so these results may not be generalizable to all populations. Evaluation of the AREDS grading scales in different populations will help to establish their validity in varied settings.

Comment The AREDS detailed severity scale was designed to provide baseline risk categories that would allow quantification of the risk of developing late AMD. AREDS2 recruited participants with more severe levels of AMD than in AREDS; therefore, this analysis was stratified by baseline severity. Rates of late AMD were similar in AREDS and AREDS2 after stratifying for baseline severity. This study provides further evidence that the AREDS severity scales are useful for assessing risk of developing late AMD and should be useful tools in future clinical trials of treatments for AMD.

Conflict of Interest Disclosures Contact Information If you have questions, please contact the corresponding author: Susan Vitale, PhD, MHS, Division of Epidemiology and Clinical Applications, National Eye Institute, National Institutes of Health, 10 Center Dr, Room 10D45, Bethesda, MD 20892 (sev@nei.nih.gov). Funding/Support This study was supported by the intramural program funds and contract HHS-N-260-2005-00007-C and ABD contract N01-EY-5-00007 from the National Eye Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, and in part by an unrestricted grant from Research to Prevent Blindness to the Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison (Drs Domalpally and Danis). Conflict of Interest Disclosures All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Ferris reported holding a patent for the AREDS formulation with Bausch & Lomb. No other disclosures were reported.