Higher plasma levels of complement C3a, C4a and C5a increase the risk of subretinal fibrosis in neovascular age-related macular degeneration: Complement activation in AMD.

Judith Lechner,Heping Xu,Mei Chen,Ruth E Hogg,Usha Chakravarthy,Giuliana Silvestri,Levente Toth

doi:10.1186/s12979-016-0060-5

Abstract

BackgroundThe aim of this study was to investigate the plasma levels of complement C3a, C4a, and C5a in different types of neovascular age-related macular degeneration (nAMD) and whether the levels were related to patients’ responsiveness to anti-VEGF therapy.ResultsNinety-six nAMD patients (including 61 with choroidal neovascularisation (CNV), 17 with retinal angiomatous proliferation (RAP), 14 with polypoidal choroidal vasculopathy (PCV) and 4 unclassified patients) and 43 controls were recruited to this case–control study. Subretinal fibrosis was observed in 45 nAMD patients and was absent in 51 nAMD patients. In addition, the responsiveness to anti-VEGF (Lucentis) therapy was also evaluated in nAMD patients. Forty-four patients were complete responders, 48 were partially responders, and only 4 patients did not respond to the therapy. The plasma levels of C3a, C4a and C5a were significantly higher in nAMD patients compared to controls. Further analysis of nAMD subgroups showed that the levels of C3a, C4a and C5a were significantly increased in patients with CNV but not RAP and PCV. Significantly increased levels of C3a, C4a and C5a were also observed in nAMD patients with subretinal fibrosis but not in those without subretinal fibrosis. Higher levels of C3a were observed in nAMD patients who responded partially to anti-VEGF therapy.ConclusionsOur results suggest increased systemic complement activation in nAMD patients with CNV but not RAP and PCV. Our results also suggest that higher levels of systemic complement activation may increase the risk of subretinal fibrosis in nAMD patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12979-016-0060-5) contains supplementary material, which is available to authorized users.

Highlights

The aim of this study was to investigate the plasma levels of complement C3a, C4a, and C5a in different types of neovascular age-related macular degeneration and whether the levels were related to patients’ responsiveness to anti-VEGF therapy
In this study we found that higher plasma levels of C3a, C4a and C5a are associated with subretinal fibrosis and with choroidal neovascularisation (CNV) rather than retinal angiomatous proliferation (RAP) and polypoidal choroidal vasculopathy (PCV) and that C3a was significantly increased in patients partially responding to anti-VEGF therapy
We found significantly increased plasma levels of C3a, C4a and C5a in patients with CNV, but not RAP or PCV when compared to controls, suggesting that systemic complement activation may play a bigger role in CNV than in RAP or PCV

Summary

Introduction

The aim of this study was to investigate the plasma levels of complement C3a, C4a, and C5a in different types of neovascular age-related macular degeneration (nAMD) and whether the levels were related to patients’ responsiveness to anti-VEGF therapy. Neovascular complexes may arise de novo from retinal vasculature known as retinal angiomatous proliferation (RAP) and these are known to fuse with CNV [2] Another subtype of neovascularisation, polypoidal choroidal vasculopathy (PCV), is characterised by a branching vascular network arising from the choroid with polypoidal lesions underneath the RPE [3]. In view of the diversity of AMD phenotype, it is likely that different immune mechanisms may be involved in different types of AMD, and this is exemplified by the diverse response to anti-VEGF therapy observed in various clinical studies [25]. It is important to understand which type(s) of AMD is associated with uncontrolled complement activation

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