Changes in Molecular Signature on the Ocular Surface in Response to Optimising Therapy in Aqueous-Deficient Dry Eye...

To explore the molecular mechanisms underlying severe aqueous-deficient dry eye disease (ADDED) secondary to primary Sjögren's syndrome (pSS) and chronic ocular graft-versus-host disease (GvHD), focusing on conjunctival epithelial cell (CEC) microRNA expression in disease and response to therapy.

Patients with severe ADDED secondary to pSS or chronic ocular GvHD and matched healthy controls were enrolled (n=8 per group). Patients received ciclosporin A (CsA) 0.1% cationic emulsion (CE) daily for six months, with supplementary treatments as needed. Baseline and follow-up assessments (one, three, and six months) included visual acuity, Schirmer's I test, tear break-up time (TBUT), ocular surface staining (OSS), and Ocular Surface Disease Index (OSDI). CECs underwent microRNA profiling via Affymetrix microarrays, and tear cytokines were analysed using 10-plex ELISA. MicroRNA analysis utilized R-based tools and pathway enrichment analysis.

Optimisation of therapy including CsA 0.1% CE significantly improved clinical and patient reported outcome measures. No statistically significant changes in tear cytokine concentrations were observed over the treatment period. Three upregulated microRNA, miR-4484, miR-6126 and miR-7107-5p were identified and linked to immune and fibrotic pathways via TGF-β/SMAD2 and CDH11. Despite clinical improvements, microRNA elevation persisted, indicating limited molecular response to treatment.

Optimisation of therapy including CsA 0.1% CE resulted in significant improvements in objective and subjective clinical parameters, however, minimally impacted epigenetic markers. Despite this, microRNA were detectable at elevated levels, suggesting limited epigenetic impact of current therapy. The persistent dysregulation of microRNA targeting the TGF-β/SMAD2 pathway and CDH11 provides a molecular rationale and direct for future research and therapeutic innovations aimed at achieving more comprehensive disease control in patients with immune-mediated ADDED.