HARVARD DEPARTMENT OF OPHTHALMOLOGY
Category : Clinical Research Candidate : Jonathan Lin Poster #: C9
Systemic Complement Activation in Non-Exudative Age-Related Macular Degeneration
Jonathan B . Lin , Stylianos Serghiou , Joan W . Miller , and Demetrios G . Vavvas
Purpose : Although complement inhibition has emerged as a possible therapeutic strategy for certain forms of advanced age-related macular degeneration ( AMD ), it is unknown what portions of the complement pathway are dysregulated in AMD or when this dysregulation occurs relative to AMD stage ; in this meta-analysis , we tested the hypothesis that complement dysregulation may occur during early / intermediate but not advanced non-exudative AMD .
Methods : Using PubMed , Google Scholar , and Embase , we identified articles from database inception to October 11 , 2020 that reported systemic complement activation profiles in patients with early / intermediate nonexudative AMD or geographic atrophy ( GA ) and non-AMD controls . We meta-analyzed the data by generating multi-level random-effects models using restricted maximum likelihood estimation . Standard errors were adjusted using the Knapp-Hartung correction . Risk of bias was assessed using a modified Newcastle-Ottawa score .
Results : The seven meta-analyzed studies included 710 independent participants ( mean per study : 101 ; standard deviation : 35 ) with 23 effect sizes . Compared with non-AMD controls , patients with early / intermediate non-exudative AMD ( N = 246 ) had significantly higher systemic complement activation as quantified by the levels of complement proteins generated by common final pathway activation ( standardized mean difference [ SMD ]= 0.52 [ 95 % confidence interval ( CI ): 0.19 to 0.86 ]) and significantly lower systemic complement inhibition ( SMD = -0.57 [ 95 % CI : -1.07 to -0.07 ]). In contrast , there were no statistically significant differences in systemic levels of complement common final pathway activation products ( SMD = 0.34 [ 95 % CI : -0.05 to 0.74 ]) or complement inhibition ( SMD = -0.02 [ 95 % CI : -0.29 to 0.24 ]) in patients with GA ( N = 178 ) versus non-AMD controls .
Conclusions : We provide evidence that systemic complement over-activation is a feature of early / intermediate non-exudative AMD ; no such evidence was identified in patients with advanced nonexudative AMD , suggesting that complement inhibition may have improved efficacy for patients with early disease rather than for patients who have already developed GA as has been studied in multiple clinical trials to date .