Dynamic Risk of Systemic Complement Activation With Time to Progression to Advanced Age-Related Macular Degeneration.

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.