Systemic Complement Activation Profiles in Nonexudative Age-Related Macular Degeneration: A Meta-Analysis.

Although complement inhibition has emerged as a possible therapeutic strategy for age-related macular degeneration (AMD), there is not a clear consensus regarding what aspects of the complement pathway are dysregulated in AMD and when this occurs relative to disease stage. We recently published a systematic review describing systemic complement activation profiles in patients with early/intermediate AMD or geographic atrophy (GA) compared to non-AMD controls. Here, we sought to meta-analyze these results to estimate the magnitude of complement dysregulation in AMD using restricted maximum likelihood estimation. The seven meta-analyzed studies included 710 independent participants with 23 effect sizes. Compared with non-AMD controls, patients with early/intermediate nonexudative AMD (N = 246) had significantly higher systemic complement activation, as quantified by the levels of complement proteins generated by common final pathway activation, and significantly lower systemic complement inhibition. In contrast, there were no statistically significant differences in the systemic levels of complement common final pathway activation products or complement inhibition in patients with GA (N = 178) versus non-AMD controls. We provide evidence that systemic complement over-activation is a feature of early/intermediate nonexudative AMD; no such evidence was identified for patients with GA. These findings provide mechanistic insights and inform future clinical trials.