Change in Dendritiform Cell Density by In Vivo Confocal Microscopy may be used as a Surrogate Biomarker for Therapeutic Response in Dry Eye Disease Patients Enriched for Presence of Inflammation: Results from the Therapeutic Response to Anti-inflammatory agents in the Corneal Epithelium (TRACE) Study

Abstract

Purpose : Corneal immune dendritiform cell (DC) density and morphology, as visualized by in vivo confocal microscopy (IVCM), is altered in dry eye disease (DED). DC density may thus be used as a surrogate biomarker of response to anti-inflammatory therapy. The purpose of this study was to test if after enrichment of DED patients by IVCM for increased inflammation, DC density and morphology can be used as optical biomarkers for therapeutic efficacy to topical steroids.

Methods : A prospective, multicenter, double-masked randomized placebo-control trial was conducted in 38 DED patients [n=67 eyes with central DC density >75cells/mm², calculated as >2 SD from healthy cornea (32.0 ± 24.4cells/mm²)]. Patients were randomized into treatment arm (18 patients, n=31 eyes) receiving loteprednol etabonate (LE) 0.5% suspension, and control arm (20 patients, n=36 eyes) receiving Soothe Tired Eyes Lubricant Eye Drops artificial tears (AT) 4x/day for 2 weeks, 2x/day for 2 weeks, and once daily for 2 weeks. Clinical and DC parameters were assessed at baseline, 2 and 6 weeks (significance=p<0.05).

Results : Mean(±SD) age of LE and AT arm was 57.2±12.1 and 55.4±15.6 years, respectively (p>0.05). Clinical and imaging parameters were comparable at baseline (p>0.05 for all). DC density decreased from baseline (mean difference ±SEM) in the LE arm at 2 weeks (-104.3±17.2cells/mm², p<0.0001) and 6 weeks (-107.6±18.1cells/mm², p<0.0001) but not in the AT arm (2 weeks=-34.4±26.2cells/mm², p=0.20 6 weeks=-17.3±27.8cells/mm², p=0.20). Similarly, DC field decreased from baseline in the LE arm at 2 weeks (-1,378.0±199.3mm², p<0.0001) and 6 weeks (-1,462.0±230.3mm², p<0.0001), but not in the AT arm (2 weeks=-474.1±354.1mm², p=0.19; 6 weeks=44.3±404.1mm², p=0.91). DC size did not differ from baseline to 6 weeks (p>0.05 for both arms). Corneal fluorescein staining correlated with DC density (R=0.37, p<0.0001) and field (R=0.38, p<0.0001).

Conclusions : Enrichment of DED patients for inflammation using IVCM prior to treatment with topical steroids yields a pronounced decrease in DC density and field. Hence, these DC parameters may be used as surrogate biomarkers of inflammation to assess therapeutic efficacy to anti-inflammatory therapies.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.