Progressive Inflammatory Coupling Drives Glaucoma Progression - a Longitudinal Analysis of Cytokine-RNFL Dynamics

Inflammatory biomarkers in glaucoma have shown promise but lack the longitudinal analysis necessary for clinical translation. We developed a comprehensive mixed-effects modeling approach to characterize temporal cytokine-RNFL dynamics and reveal patterns in the cytokine-RNFL progression.

We analyzed a 24-month longitudinal cohort of 57 patients (19 each: controls, untreated POAG, treated POAG) using: (1) mixed-effects models with individual heterogeneity modeling; (2) censoring-informed cytokine analysis; and (3) temporal correlation network analysis.fi.

Mixed-effects models revealed significant group differences in RNFL progression: controls (-0.20 ± 0.10 μm/year), untreated POAG (-1.94 ± 0.54 μm/year), and treated POAG (-1.06 ± 0.49 μm/year). Cytokine censoring patterns provided biological validation-pro-inflammatory cytokines showed 1.37-fold higher detection in untreated POAG versus controls (TNF-alpha: 85.3% vs. 62.1%), independently confirming elevated disease inflammation. Temporal correlation analysis showed progressive inflammatory coupling, with the TNF-alpha of ~ IL6 correlation increasing from r = 0.23 to r = 0.49 over 24 months.

Our findings suggest that POAG pathogenesis can be linked to a progressive inflammatory dysregulation, in which other cytokines follow increases in an initial inflammatory cytokine. The doubling of the correlation between TNF alpha and IL6 over time could suggest that the disease progression could be self-amplifying.

This study establishes that glaucoma involves progressive inflammatory coupling, in which initially independent cytokine signals evolve into self-reinforcing mechanisms. The differential censoring patterns provide compelling biological validation. These findings enable precision medicine approaches based on inflammatory phenotypes and support early intervention strategies targeting network establishment.