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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.
Insights
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.
Importance:
Understanding the relationship between longitudinally measured systemic complement factors and intermediate AMD (iAMD) progression may enable the introduction of systemic therapeutics earlier in the disease course, before vision loss occurs.
Objective:
To determine the contribution of longitudinal measures of systemic complement factors and ratios to time to progression to advanced AMD (geographic atrophy [GA] or neovascular AMD [NVAMD]).
Design, Setting, And Participants:
This cohort study was conducted at Sue Anschutz Rodgers Eye Center, Aurora, Colorado, from 2014 to 2022. Participants were patients with iAMD and at least 1 month of follow-up. Data analysis was performed from September to December 2024.
Exposures:
Complement factors.
Main Outcomes And Measures:
Time to progression to advanced AMD, either GA or NVAMD. Joint models were used to estimate the relationship between the exposures and the outcomes. The hazard ratio (HR) was a measure of association.
Results:
Among 325 participants, the mean (SD) age was 76 (7.0) years; 212 participants (65%) were female and 113 (35%) male. During the 8-year follow-up period (mean, 3.9 years), 110 participants (34%) progressed to any advanced AMD. Sixty-four participants (20%) progressed to GA and 46 (14%) to NVAMD. Higher systemic levels of C4 (HR, 6.8; 95% credible interval [CrI], 1.7-26.2; P = .03), C4b (HR, 60.4; 95% CrI, 6.5-544; P < .001), C3a/C3 (HR, 49.4; 95% CrI, 5.2-675; P < .001), C5a/C5 (HR, 29.3; 95% CrI, 4.8-258; P < .001), sC5b-9/C5 (HR, 297; 95% CrI, 10-14 877; P = .003), and factor I (HR, 525.9; 95% CrI, 5.5-107 589; P = .02) were associated with shorter time to progression to any AMD. Levels of C3a/C3 (HR, 9.5; 95% CrI, 1.9-55.9; P = .01) and C5a/C5 (HR, 28.6; 95% CrI, 5.7-157.9; P < .001) were associated with the hazard of GA.
Conclusions And Relevance:
Continued dysregulation of complement pathways appears to increase the hazard of iAMD progression. This supports the possibility of identifying a high-risk group of patients with iAMD for personalized ophthalmic care and targeted treatments to attenuate the risk of iAMD progression.
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