iRORA phenotypes characterized using fundus autofluorescence

The research team explained that “while the criteria for iRORA are well-defined, the iRORA phenotype on optical coherence tomography (OCT) B-scans can vary based on the extension of the lesions, hypertransmission into the choroid, disruption of the retinal pigment epithelium (RPE), and the number of signs of photoreceptor degeneration present.”

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An investigation into incomplete retinal pigment epithelial and outer retinal atrophy (iRORA) identified a wide spectrum of fundus autofluorescence (FAF) patterns that corresponded with iRORA lesions and that those patterns were associated with conversion to complete RORA (cRORA) over time. First author Giulia Corradetti, MD, reported the study findings at the Association for Research in Vision and Ophthalmology 2025 annual meeting in Salt Lake City. She is from the Doheny Eye Institute, Pasadena, CA, and the Department of Ophthalmology, David Geffen School of Medicine at the University of California Los Angeles.

The research team explained that “while the criteria for iRORA are well-defined, the iRORA phenotype on optical coherence tomography (OCT) B-scans can vary based on the extension of the lesions, hypertransmission into the choroid, disruption of the retinal pigment epithelium (RPE), and the number of signs of photoreceptor degeneration present.”

In light of that, the group set out to define the FAF phenotypes of iRORA lesions and the baseline FAF patterns associated with conversion of iRORA to cRORA within 18 months. iRORA has been characterized on OCT by hypertransmission into the choroid and RPE attenuation or disruption by less than 250 microns and by signs of photoreceptor degradation, ie, at least one of the following: ellipsoidal zone (EZ) attenuation/disruption, external limiting membrane (ELM) attenuation/disruption, outer nuclear layer (ONL) thinning, outer plexiform layer (OPL)/inner nuclear layer (INL) subsidence, and hyporeflective wedges in the Henle fiber layer.

In contrast, cRORA is characterized by hypertransmission into the choroid and RPE attenuation or disruption by more than 250 microns and by signs of photoreceptor degradation, ie, EZ and interdigitization zone discontinuity, ELM attenuation/disruption, ONL thinning, and OPL/INL subsidence.

In this study, Corradetti and colleagues pooled data for a post hoc analysis from 448 patients who participated in the phase 3 GATHER2 trial (NCT04435366) that evaluated the efficacy and safety of avacincaptad pegol 2 mg (Izervay, Astellas Pharma) in patients with geographic atrophy (GA) that did not involve the foveal center.¹ The patients were evaluated for the presence of baseline iRORA and completed three follow-up visits at 6, 12, and 18 months.

Studying the patterns

The investigators evaluated each iRORA lesion at baseline and during follow-up to identify any changes in FAF phenotypes. The patterns were defined as “none,” indicating no autofluorescence abnormalities; not classifiable; increased autofluorescence (IAF); questionably decreased autofluorescence (QDAF); or definite decreased autofluorescence (DDAF).

The results identified 153 iRORA lesions in 95 eyes. Most were classified as none (53 lesions; 34.6%) or as QDAF (53 lesions, 34.6%). The remainder were not classifiable (27 lesions, 17.6%), DDAF (11 lesions, 7.2%) and IAF (9 lesions, 5.9%), Corradetti and colleagues reported.

After 18 months, OCT showed that the number of iRORA lesions decreased to 51.0%, and the number of new cRORA lesions increased and peaked at 15.0% by 12 months.

At the same time point, the FAF phenotypes were seen to have changed over time. The proportion of total iRORA lesions manifesting QDAF and DDAF patterns increased to 38.1% and 23.0%, respectively, whereas the “none” pattern decreased to 16.8%.

At 18 months, the majority of lesions that remained as persistent iRORA were classified as having the the none (28/78) or QDAF FAF pattern. The none classification decreased from 90.6% of lesions at 6 months to 52.8% at 18 months and the QDAF pattern from 79.2% to 49.1% at the respective time points.

At 18 months, the iRORA lesions that converted to cRORA were more likely to have more advanced FAF abnormalities, with cumulative 44.4% IAF, 30.2% QDAF, and 27.3% DDAF patterns, the investigators reported.

“This first large study characterizing the phenotype of iRORA on FAF highlights the heterogeneity of these lesions. Multimodal imaging including both OCT and FAF may allow a more granular classification of iRORA. A wide spectrum of FAF patterns corresponded with iRORA lesions identified on OCT at baseline and was associated with conversion of iRORA to cRORA over time. These findings underline a novel opportunity to potentially categorize those patterns from early to late lesion phenotypes using FAF. Early identification of atrophic changes may help doctors make informed treatment decisions to slow disease progression, help preserve photoreceptors, and help preserve vision,” Corradetti and colleagues concluded.

Reference

Khanani AM, Patel SS, Staurenghi G, et al. Efficacy and safety of avacincaptad pegol in patients with geographic atrophy (GATHER2): 12-month results from a randomised, double-masked, phase 3 trial. Lancet. 2023;402(10411):1449-1458.