Geographic atrophy: Mechanism of disease, pathophysiology, and role of the complement system

Geographic atrophy (GA) is an advanced form of age-related macular degeneration (AMD), characterized by atrophic lesions that first start in the outer retina and progressively expand to cover the macula and the fovea, the center of the macula, leading to irreversible loss of vision over time. GA is distinct from wet or neovascular AMD (nAMD), the other form of advanced AMD. Neovascular AMD is characterized by new invading leaky blood vessels in the macula that can lead to acute vision loss. GA and nAMD may coexist in the same eye. The underlying pathophysiology of GA is complex and thought to involve chronic inflammation due to overactivation of the complement system that leads to the loss of photoreceptors, retinal pigment epithelium (RPE), and the underlying choriocapillaris. The disappearance of these structures appears as sharply demarcated atrophic lesions that are typical of GA. Researchers have reported about 1 million reported cases of GA in the United States, and about 160,000 cases occur per year. The most important risk factors for GA are increasing age and family history. Diagnosis of GA is usually made by using multimodal imaging techniques. Lesions associated with GA are highly heterogeneous, and the growth rate may differ from patient to patient. Despite the progressive nature of GA, the fovea may be spared until much later in the disease, thereby retaining central vision in patients. With time, atrophic lesions may progressively grow to involve the fovea, thereby severely impairing central vision. Vision loss can happen rapidly once the lesions reach the fovea. However, even without the involvement of the fovea, ongoing vision impairment impacting daily life may be present. Median time from GA not involving the center of the fovea (without subfoveal involvement) to GA with lesion boundary affecting the foveal center (subfoveal involvement) ranges from 1.4 to 2.5 years. GA can greatly impact patients’ functioning and quality of life and limit their independence by interfering with activities of daily living, including difficulties with reading, driving, watching television, recognizing faces, and being unable to do household chores. No treatments have been available until intravitreal pegcetacoplan was recently approved by the US Food and Drug Administration for GA secondary to AMD.