Persistent Proinflammatory Cytokine Profile in the Tear Fluid of Stable Keratoconus: Rethinking Clinical Quiescence.

Purpose: Keratoconus is traditionally classified as a noninflammatory corneal ectasia, despite growing evidence suggesting an underlying inflammatory component. This study evaluates whether patients with stable keratoconus exhibit persistent inflammatory activity in tear fluid compared to healthy controls. Methods: Cross-sectional case-control study. Keratoconus progression was evaluated using tomographic and clinical criteria. Tear fluid samples were collected under standardized conditions and concentrations of nine cytokines (IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-17A, and TNF-α) were quantified using a multiplex assay. Group comparisons, correlation analyses, and receiver operating characteristic (ROC) curves were performed to evaluate cytokine expression and network behavior. Results: A total of 23 stable keratoconus patients and 25 age-matched healthy controls were included. The stable keratoconus group exhibited significantly elevated levels of tear fluid inflammatory cytokines compared to controls (all P < 0.05, except IL-2). Spearman correlation heatmaps revealed a coordinated cytokine network in the keratoconus group, suggesting persistent immunological activation despite clinical quiescence. No significant correlations were observed between cytokine levels and keratoconus staging indices. ROC analysis indicated moderate discriminatory performance of IL-6 (area under the curve = 0.68). Conclusions: Even clinically stable keratoconus is associated with a distinct proinflammatory tear fluid cytokine profile, challenging the traditional paradigm of keratoconus as a noninflammatory disease. These findings highlight the potential utility of tear fluid-based inflammatory biomarkers in keratoconus and suggest inflammation may persist independently of clinical progression. Translational Relevance: This study highlights the potential role of tear-based inflammatory biomarkers for monitoring disease activity, understanding keratoconus pathophysiology and guiding adjunctive anti-inflammatory therapies in keratoconus beyond structural stabilization.