Dysregulation of Complement Pathway May Increase Risk of AMD Progression

Research from the University of Colorado suggests dysregulation of complement pathways may increase the hazard of progression to advanced age-related macular degeneration (AMD) in patients with intermediate AMD (iAMD).

Existing studies comparing patients with AMD to those without have indicated systemic overactivation of the complement system in AMD. However, many of these studies were limited by smaller sample sizes, and few complement factors were included in the examination.2

“Moreover, the relationship of longitudinally measured complement factors to dynamically update the risk estimates for individuals with iAMD developing advanced AMD, to our knowledge, has not been evaluated,” wrote Anne M. Lynch, MD, department of ophthalmology, University of Colorado School of Medicine, and colleagues. “The objective of this study was to assess in an iAMD cohort the relationship of 25 longitudinally measured systemic complement factors/ratios with time to progression to any advanced AMD, either (geographic atrophy [GA]) or (neovascular age-related macular degeneration [NVAMD]).”1

The team gathered data from the University of Colorado AMD registry and repository, which consists of patients with AMD aged 55 to 99 years. Investigators collected plasma samples and multimodal imaging at enrollment and annually during routine visits to the clinic. The images were utilized to categorize patients into the AMD phenotypes: GA or NVAMD. The study’s analytic dataset was limited to patients with iAMD who had ≥1 month of follow-up.1

A total of 325 patients with iAMD were included, with a mean (standard deviation [SD]) of 76 (7.0) years. During the 8-year follow-up period (mean, 3.9 years; median, 3.6 years), 110 patients (34%) progressed to a form of advanced AMD. Of these, 64 patients (20%) progressed to GA and 46 (14%) progressed to NVAMD. No risk factors or comorbidities were associated with time to progression to either form.1

Lynch and colleagues noted a relationship between higher systemic levels of C4 and C4b and the hazard of progression to any form of AMD. A 1-log10 reduction was also illustrated in systemic levels of C3 (ng/mL) and was associated with a 66.7-fold increase in progression hazard. A higher ratio of C3a/C3 was also related to shorter progression time to any advanced AMD (HR, 49.4; 95% CI, 5.2 to 675.3). Higher levels of factor I inhibitor were also associated with progression hazard (HR, 525.9; 95% CI, 5.5 to 1.1x105).1

The terminal pathway (TP) was also monitored; investigators found a higher risk of progression with lower levels of systemic C5. This suggested activation and consumption of this protein. Along with this finding, a higher systemic C5a/C5 and a higher sC5b-9/C5 ratio had higher hazard ratios as well.1

Investigators noted four core findings from this study. First, a contribution of select systemic complement factors from the classical pathway, C4 and C4b, with time to progression to any advanced form of AMD; second, a higher hazard of progression to advanced AMD with elevated C3a/C3, C5a/C5, or sC5b-9/C5 ratios; third, a relationship between complement ratios C3a/C3 and C5a/C5 with GA progression hazard; fourth, a higher hazard of progression with higher factor I levels.1

However, investigators still noted inherent limitations of the study’s structure. Statistical power was reduced, particularly when event outcomes were separated into GA and NVAMD as competing risks. Additionally, a small sample size may have limited the predictive performance of the model. Loss to follow-up also presented a limitation, through either death or declining health.1

“The findings of this study support the possibility of identifying a high-risk group of patients with iAMD for personal ophthalmic care and targeted systemic treatments to attenuate the risk of progression to advanced AMD,” Lynch and colleagues wrote.1

References

1. Lynch AM, Grove NC, Wagner BD, et al. Dynamic risk of systemic complement activation with time to progression to advanced age-related macular degeneration. JAMA Ophthalmology. Published online June 12, 2025. doi:10.1001/jamaophthalmol.2025.1608

2. Lin JB, Serghiou S, Miller JW, Vavvas DG. Systemic Complement Activation Profiles in Nonexudative Age-Related Macular Degeneration: A Meta-Analysis. J Clin Med. 2022;11(9):2371. Published 2022 Apr 23. doi:10.3390/jcm11092371