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

ABSTRACT Topic Systematic review and meta-analysis of the natural history of atrophy secondary to Choroideremia (CHM). Clinical Relevance 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. Methods 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 changes 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. Results 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% CI, 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 Conclusions 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.