Reticular Pseudodrusen: The Third Macular Risk Feature for Progression to Late Age-Related Macular Degeneration: Age-Related Eye Disease Study 2 Report 30

Abstract

Purpose: To analyze reticular pseudodrusen (RPD) as an independent risk factor for progression to late age-related macular degeneration (AMD), alongside traditional macular risk factors (soft drusen and pigmentary abnormalities) considered simultaneously.

Design: Post hoc analysis of 2 clinical trial cohorts: Age-Related Eye Disease Study (AREDS) and AREDS2.

Participants: Eyes with no late AMD at baseline in AREDS (6959 eyes, 3780 participants) and AREDS2 (3355 eyes, 2056 participants).

Methods: Color fundus photographs (CFPs) from annual visits were graded for soft drusen, pigmentary abnormalities, and late AMD. Presence of RPD was from grading of fundus autofluorescence images (AREDS2) and deep learning grading of CFPs (AREDS). Proportional hazards regression analyses were performed, considering AREDS AMD severity scales (modified simplified severity scale [person] and 9-step scale [eye]) and RPD presence simultaneously.

Main outcome measures: Progression to late AMD, geographic atrophy (GA), and neovascular AMD.

Results: In AREDS, for late AMD analyses by person, in a model considering the simplified severity scale simultaneously, RPD presence was associated with a higher risk of progression: hazard ratio (HR), 2.15 (95% confidence interval [CI], 1.75-2.64). However, the risk associated with RPD presence differed at different severity scale levels: HR, 3.23 (95% CI, 1.60-6.51), HR, 3.81 (95% CI, 2.38-6.10), HR, 2.28 (95% CI, 1.59-3.27), and HR, 1.64 (95% CI, 1.20-2.24), at levels 0-1, 2, 3, and 4, respectively. Considering the 9-step scale (by eye), RPD presence was associated with higher risk: HR, 2.54 (95% CI, 2.07-3.13). The HRs were 5.11 (95% CI, 3.93-6.66) at levels 1-6 and 1.78 (95% CI, 1.43-2.22) at levels 7 and 8. In AREDS2, by person, RPD presence was not associated with higher risk: HR, 1.18 (95% CI, 0.90-1.56); by eye, it was HR, 1.57 (95% CI, 1.31-1.89). In both cohorts, RPD presence carried a higher risk for GA than neovascular AMD.

Conclusions: Reticular pseudodrusen represent an important risk factor for progression to late AMD, particularly GA. However, the added risk varies markedly by severity level, with highly increased risk at lower/moderate levels and less increased risk at higher levels. Reticular pseudodrusen status should be included in updated AMD classification systems, risk calculators, and clinical trials.

Keywords: Age-Related Eye Disease Study; Age-Related Eye Disease Study 2; Age-related macular degeneration; Choroidal neovascularization; Disease progression; Geographic atrophy; Reticular pseudodrusen; Risk calculator; Risk factor; Severity scale; Subretinal drusenoid deposits.

Figure 1.

Forest plot of hazard ratios associated with reticular pseudodrusen presence for progression to late age-related macular degeneration (and its subtypes) in the Age-Related Eye Disease Study, at the person level, separately according to different levels on the modified Simplified Severity Scale. The 95% confidence intervals and associated p-values are also shown.

Figure 2.

Kaplan-Meier curves of progression to late age-related macular degeneration and its subtypes, stratified according to reticular pseudodrusen presence and the modified Simplified Severity Scale, considered simultaneously, in the Age-Related Eye Disease Study, at the person level: (A) late age-related macular degeneration; (B) geographic atrophy; (C) neovascular age-related macular degeneration.

Figure 2.

Kaplan-Meier curves of progression to late age-related macular degeneration and its subtypes, stratified according to reticular pseudodrusen presence and the modified Simplified Severity Scale, considered simultaneously, in the Age-Related Eye Disease Study, at the person level: (A) late age-related macular degeneration; (B) geographic atrophy; (C) neovascular age-related macular degeneration.

Figure 2.

Kaplan-Meier curves of progression to late age-related macular degeneration and its subtypes, stratified according to reticular pseudodrusen presence and the modified Simplified Severity Scale, considered simultaneously, in the Age-Related Eye Disease Study, at the person level: (A) late age-related macular degeneration; (B) geographic atrophy; (C) neovascular age-related macular degeneration.

Figure 3.

Forest plot of hazard ratios associated with reticular pseudodrusen presence for progression to late age-related macular degeneration (and its subtypes) in the Age-Related Eye Disease Study, at the eye level, separately according to different levels on the 9-step Severity Scale. The 95% confidence intervals and associated p-values are also shown.

Figure 4.

Kaplan-Meier curves of progression to late age-related macular degeneration and its subtypes, stratified according to reticular pseudodrusen presence and the 9-step Severity Scale, considered simultaneously, in the Age-Related Eye Disease Study, at the eye level: (A) late age-related macular degeneration; (B) geographic atrophy; (C) neovascular age-related macular degeneration.

Figure 4.

Kaplan-Meier curves of progression to late age-related macular degeneration and its subtypes, stratified according to reticular pseudodrusen presence and the 9-step Severity Scale, considered simultaneously, in the Age-Related Eye Disease Study, at the eye level: (A) late age-related macular degeneration; (B) geographic atrophy; (C) neovascular age-related macular degeneration.

Figure 4.

Kaplan-Meier curves of progression to late age-related macular degeneration and its subtypes, stratified according to reticular pseudodrusen presence and the 9-step Severity Scale, considered simultaneously, in the Age-Related Eye Disease Study, at the eye level: (A) late age-related macular degeneration; (B) geographic atrophy; (C) neovascular age-related macular degeneration.