Association of Systemic Inflammatory Factors with Progression to Advanced Age-related Macular Degeneration

ABSTRACT

Purpose

Age-related macular degeneration (AMD) is a leading cause of vision loss in the elderly. The role of systemic inflammation in AMD remains unclear specifically in patients with intermediate AMD (iAMD). We sought to determine whether systemic inflammation was associated with future iAMD progression.

Methods

Combinations of 27 circulating inflammatory markers including complement factors, cytokines, chemokines, and high-sensitivity C-reactive protein (hsCRP) were evaluated in iAMD patients recruited into a Colorado AMD registry. Systemic inflammatory markers were combined using principal component analysis. Risk factors for AMD progression were evaluated using Cox regression models.

Results

This study included 99 subjects with iAMD, 21 of which progressed to advanced AMD. Two principal components (PCs) were identified that contributed to the risk of progression to advanced AMD, after adjusting for age and bilateral reticular pseudodrusen. The strongest associated PC was explained largely by the pro-inflammatory cytokine TNFα and the anti-inflammatory IL1ra antagonist of IL1. The additional PC was largely explained by IL6, IL8, C3 and factor D in the positive direction and CRP, MCP1, factor B and factor I in the negative direction.

Conclusion

When evaluated through multivariate analyses, combinations of biomarkers distinguished patients who did and did not progress to future advanced AMD. Increased risk could result from different combinations of analyte levels indicating a complex relationship rather than a simple increase in a few markers. This suggests that studying systemic inflammation in iAMD can provide insights into early pathologic events and potentially identify patients at highest risk for the development of severe AMD.

KEYWORDS:

• Systems-based analysis
• classical and alternative complement pathways
• reticular pseudodrusen
• chronic inflammation

Disclosure of interest

None of the following authors have any proprietary interests or conflicts of interest related to this submission: BDW, JLP, AGP, AAF-A, RB, MTM, NM. VMH receives royalty payments from Alexion and receives sponsored research support, stock and consulting income from Q32 Bio.

Additional information

Funding

This work was supported by a Macula Society Research Grant supported by Regeneron (2018), a Challenge Grant to the Department of Ophthalmology from Research to Prevent Blindness, Inc., and the Frederic C. Hamilton Macular Degeneration Center. Supported by NIH/NCATS Colorado CTSA Grant Number UL1 TR002535. Contents are the authors’ sole responsibility and do not necessarily represent official NIH views.