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Dynamic Risk of Systemic Complement Activation With Time to Progression to Advanced Age-Related Macular Degeneration
Anne M Lynch1, Nathan C Grove1, Brandie D Wagner2
1Department of Ophthalmology, University of Colorado School of Medicine, Aurora.
JAMA Ophthalmology
|June 12, 2025
Summary
Elevated systemic complement factors, including C4, C4b, C3a/C3, C5a/C5, sC5b-9/C5, and factor I, significantly increase the risk of intermediate age-related macular degeneration (iAMD) progression to advanced stages. Early identification of these markers may allow for timely therapeutic intervention.
Area of Science:
- Ophthalmology and Vision Science
- Immunology and Complement System Biology
- Medical Diagnostics and Therapeutics
Background:
- Intermediate age-related macular degeneration (iAMD) is a significant cause of vision impairment.
- Understanding progression factors is crucial for early intervention before irreversible vision loss.
- The role of systemic complement factors in iAMD progression requires further elucidation.
Purpose of the Study:
- To investigate the association between longitudinal systemic complement factor levels and the progression of iAMD to advanced stages (geographic atrophy [GA] or neovascular AMD [NVAMD]).
- To determine if specific complement factor ratios contribute to the risk of AMD progression.
Main Methods:
- A cohort study was conducted with patients diagnosed with iAMD, followed for disease progression.
- Longitudinal measurements of systemic complement factors and their ratios were analyzed.
- Joint models were employed to assess the relationship between complement factors and time to advanced AMD, with hazard ratios (HR) as the measure of association.
Main Results:
- Higher systemic levels of C4, C4b, C3a/C3, C5a/C5, sC5b-9/C5, and factor I were significantly associated with a shorter time to progression to any advanced AMD.
- Specifically, elevated C3a/C3 and C5a/C5 levels were linked to an increased hazard of developing geographic atrophy (GA).
- Out of 325 participants, 34% progressed to advanced AMD over a mean follow-up of 3.9 years.
Conclusions:
- Dysregulation of complement pathways is strongly implicated in accelerating iAMD progression.
- Systemic complement factor levels serve as potential biomarkers for identifying individuals at high risk of AMD progression.
- These findings support the development of personalized ophthalmic care and targeted systemic therapies to mitigate AMD progression.
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