RPD and Higher Risk of Progression to Late AMD
February 2023
Youning Zhang, MD
Location/Affiliation: Los Angeles, Olive View – UCLA Medical Center
Agron E, Domalpally A, Cukras C, Clemons TE, Chen Q, Lu Z, Chew EY, Keenan TDL, for the AREDS and AREDS2 Research Group. Ophthalmology 2022;129:1107-1119. Reticular Pseudodrusen: The Third Macular Risk Feature for Progression to Late Age-Related Macular Degeneration. doi: 10.1016/j.ophtha.2022.05.021. Epub 2022 May 31. PMID: 35660417
Two common methods exist to predict progression to late age-related macular degeneration (AMD): 1) the Age-Related Eye Disease Study (AREDS) 9- step severity scale, and 2) the AREDS simplified severity scale. Both use only 2 phenotypic features: soft drusen and pigmentary abnormalities. Reticular pseudodrusen (RPD) started gaining attention as clinical studies such as AREDS2 have shown that RPD are associated with increased risk of progression to late AMD. This study aims to evaluate the risk of progression to late AMD incorporating this additional 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 trial assessed the effects of nutritional supplements on AMD and cataract progression, whereas the AREDS2 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 thereafter. The primary endpoint was progression to advanced AMD [defined as neovascular AMD or central geographic atrophy (GA)]. The authors used both the aforementioned simplified severity scale as well as the 9-step severity scale, in addition to RPD presence/absence at baseline to determine the risk of progression to late AMD, neovascular AMD, and GA, as 3 separate outcomes.
Risk of progression to late AMD by 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.
Risk of progression to late AMD by the 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 were 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.
Risk of progression to late AMD by the 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)
Risk of progression to late AMD by the 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 of progression as well as differential risk of GA versus neovascular AMD.
