Long-term Natural History of Atrophy in Eyes with Choroideremia—A Systematic Review and Meta-analysis of Individual-Level Data

Abstract

To conduct a systematic review and meta-analysis of the natural history of atrophy secondary to choroideremia (CHM). A sensitive and reliable anatomic measure to monitor disease progression is needed in treatment trials for CHM. However, the long-term natural history of the residual retinal pigment epithelium (RPE) is unclear, with reported RPE area decline rates varying widely among patients. We searched in 7 literature databases up through July 17, 2019, to identify studies that assessed the residual RPE area in untreated eyes with CHM using fundus autofluorescence (FAF). We sought individual-eye data and investigated the RPE decline pattern using 3 models: the area linear model (ALM), radius linear model (RLM), and area exponential model (AEM), in which the area, radius, and log-transformed area of RPE change linearly with time, respectively. To account for different eyes' entry times into the studies, we added a horizontal translation factor to each dataset. The RPE decline rate was estimated using a 2-stage random-effects meta-analysis. We assessed the risk of bias using the Quality In Prognosis Studies tool. Of 807 articles screened, we included 9 articles containing cross-sectional data (257 eyes) from 6 studies and longitudinal data (229 visits from 68 eyes) from 5 studies. The residual RPE area followed a trend of exponential decay as a function of patient age. After the introduction of horizontal translation factors to longitudinal datasets of individual eyes, the datasets fit along a straight line in the AEM over nearly 60 years (r2= 0.997). The decline rate of log-transformed RPE area was 0.050 (95% confidence interval, 0.046-0.055) log(mm2)/year and was independent of the baseline RPE area (r= -0.18; P= 0.15) and age (r= 0.06; P= 0.63). In contrast, the decline rates of the area and effective radius of residual RPE strongly correlated with the baseline RPE area (r= 0.90 and 0.61, respectively; P < 0.001). The loss of residual RPE area in untreated eyes with CHM follows the AEM over approximately 60 years. Log-transformed residual RPE area measured by FAF can serve as an anatomic endpoint to monitor CHM.