Standardized Classifications Are Needed for Geographic Atrophy

Monika Fleckenstein, MD

In order to better understand geographic atrophy (GA) progression, clinicians and researchers must work towards a standardized classification and description of GA, according to a review published by the American Academy of Ophthalmology.

“Understanding GA progression and its individual variability is critical in the design of clinical studies, in the interpretation and application of clinical trial results, and for counseling patients on how disease progression may affect their individual prognosis,” said lead author Monika Fleckenstein, MD, head of the Clinical Trial Center at the Department of Ophthalmology at the University of Bonn, in Germany.

Fleckenstein and colleagues stated that GA, secondary to age-related macular degeneration (AMD), is currently defined by "the presence of sharply demarcated atrophic lesions of the outer retina" which results in the loss of visual function in patients via a "progressive and irreversible loss of photoreceptors, retinal pigment epithelium (RPE), and choriocapillaris."

GA is associated with advanced or late AMD, and GA progression is assessed via several imaging modalities, including color fundus photography, fundus autofluorescence, near-infrared reflectance (NIR), near-infrared autofluorescence, fluorescein angiography, optical coherence tomography (OCT), optical coherence tomography angiography, and multicolor confocal scanning laser ophthalmoscopy.

Each of these modalities for assessing GA lesion size and progression has its strengths and limitations.

Fundus autofluorescence (FAF) is the predominant and accepted modality by regulators such as the European Medicines Agency and US Food and Drug Administration for assessment in clinical trials, but according to Fleckenstein, the use of FAF alone for evaluating the presence of GA can be challenging and requires "the adjunctive use of other modalities such as NIR and OCT" to confirm lesion boundaries.

Confirmation of lesion boundaries is crucial, said Fleckenstein and associates, because baseline lesion size and precise progression rates can help determine an individual's future progression rate. Many clinical studies "report progression rates normalized for baseline lesion size" but it is not clear if that association is predictive of disease progression, Fleckenstein said

Fleckenstein and colleagues point to recent studies focusing on the role of genetics in the development and progression of AMD as an additional complication and confounder for vision loss.

They called for a better understanding of the multiple factors which can inform prognosis for individuals, and focused their review on the variability in GA progression rates, emphasizing that the identified prognostic factors are interconnected — not necessarily independent – and may reflect “differences in the pathophysiologic mechanisms of GA.”

Fleckenstein and colleagues remarked that although clinical phase 2 and 3 trials for therapeutic agents to treat GA are currently underway, these trials may be hampered by the fact that there is currently “no systematic method for rating an individual's GA severity that incorporates various lesion characteristics, particular those affecting visual function.”

Many of the trials focus on halting or reversing GA lesion size alone and do not consider other factors such as foveal involvement and the impact of parafoveal legions.

Fleckenstein argued that a "validated scale" which standardizes disease classification could better assist researchers and clinicians in predicting GA progression, monitoring progression over time, and providing a "holistic view of GA disease status."

That system, according to the article, should include GA severity measures that move beyond size alone. A standardized GA classification system will help create a common language for clinical and research discussion of GA and AMD, and may “facilitate discussion with patients about disease progression and future treatments,” Fleckenstein said.

The study was published in Ophthalmology.

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