RPD and Higher Risk of Progression to Late AMD

Two common methods exist to make a prediction of progression to late age-related macular degeneration (AMD): the Age-Related Eye Disease Study (AREDS) 9-step severity scale and the AREDS simplified severity scale. Both use two phenotypic features: soft drusen and pigmentary abnormalities. Reticular pseudodrusen (RPD) has started gaining attention because clinical studies such as AREDS2 have shown that RPD is associated with an increased risk of progression to AMD. The study aims to evaluate the risk of progression to late AMD incorporating this new risk factor, RPD, and the two traditional risk factors, soft drusen and pigmentary abnormalities.

The AREDS and the AREDS2 studies were both multicenter phase 3 randomized controlled clinical trials. The AREDS study assessed the effects of nutritional supplements on AMD and cataract progression, whereas the AREDS2 study assessed the effects of carotenoid and omega-3 fatty acid supplements in patients at moderate to high risk of progression to late AMD. Both clinical trials had a 5-year follow-up with comprehensive eye examinations and color fundus photos taken at baseline visit and annually. The primary endpoint was progression to advanced AMD (defined as neovascular AMD or central geographic atrophy [GA]). The authors used the simplified severity scale and the 9-step severity scale as well as RPD presence/absence at baseline to determine the risk of progression to late AMD, neovascular AMD, and GA, as three separate outcomes.

MODIFIED SIMPLIFIED SEVERITY SCALE AND RPD STATUS IN AREDS

Both modified simplified severity scale and RPD status considered in isolation were significantly associated with high risks of progression to late AMD, including GA and neovascular AMD. The hazard ratios (HRs) for RPD presence at each severity level were 3.23, 3.81, 2.28, 1.64, for severity 0-1, 2, 3, 4, respectively. The HRs of RPD at each severity levels for GA were 3.47, 4.97, 3.08, 1.91, for severity 0-1, 2, 3, 4, respectively; for neovascular AMD were 2.96, 3.03, 1.13, 0.96, for severity 0-1, 2, 3, 4, respectively. Kaplan-Meier curves demonstrated that patients with severity level 4 and RPD had the highest progression rate to late AMD, including GA and neovascular AMD.

9-STEP SEVERITY SCALE AND RPD STATUS IN AREDS

Both the 9-step severity scale and RPD status considered in isolation were significantly associated with higher risks of progression to late AMD, including GA and neovascular AMD. The HRs of RPD presence was 5.11 for severity level 1-6 and 1.78 for severity level 7-8. In stratified analyses, the HRs of RPD at level 1-6 was 5.9 and at level 7-8 was 1.86 for GA; the HRs of RPD at level 1-6 was 3.73 and at level 7-8 was 1.05 for neovascular AMD. Kaplan-Meier curves demonstrated that patients with severity level 7-8 and RPD had the highest progression rate to late AMD, including GA and neovascular AMD.

MODIFIED SIMPLIFIED SEVERITY SCALE AND RPD STATUS IN AREDS2

In isolation, both the modified simplified severity scale and RPD presence were associated with a higher risk of progression to late AMD, however when considered simultaneously, while the risk with the severity scale persisted (HR=2.16 for level 3 and HR=4 for level 4), the risk associated with RPD was only significant for GA (HR=2.05) and not for neovascular AMD (HR=1.14).

9-STEP SEVERITY SCALE AND RPD STATUS IN AREDS2

Both the 9-step severity scale and RPD presence in isolation were significantly associated with progression to late AMD, in general, however RPD presence was associated with significantly increased risks for GA (HR=1.62) but not for neovascular AMD (HR=0.80). When considered simultaneously, each remained significantly associated with increased risks.

This study demonstrated that RPD presence when considered in isolation was associated with higher risk of progression to late AMD. Furthermore, RPD presence conferred an additional and independent risk of progression to late AMD when the other two traditional risk factors were taken into account. The study also showed that RPD presence conferred higher risk at lower severity level and higher risk for GA. The authors conclude that incorporating RPD status into the risk profile is important for assessing risk of progression as well as differential risk of GA versus neovascular AMD.