Clinical and Immunological Effects of Systemic Vitamin D Supplementation in Vitamin D–Deficient Dry Eye Disease: A Prospective Comparative Study

Purpose: To evaluate the clinical and immunological effects of systemic vitamin D supplementation in patients with dry eye disease (DED) and vitamin D deficiency, and to compare outcomes between topical therapy alone and combined topical plus oral vitamin D treatment over 6 months. Methods: This prospective, non-randomized comparative study enrolled 34 patients with DED and serum 25-hydroxyvitamin D [25(OH)D] levels <20 ng/mL. Participants received preservative-free artificial tears for three months (topical-only group, n=17) or combined topical therapy and oral cholecalciferol supplementation (50,000 IU weekly for 8 weeks; topical + vitamin D group, n=17). Clinical parameters (Schirmer I test, TBUT, Oxford-graded corneal staining, lid margin hyperemia) and tear cytokines (TNF-α, IL-1β, IL-4) were assessed at baseline and at 1, 3, and 6 months. The prespecified primary endpoint was TBUT at 3 months. Longitudinal analyses were performed using generalized estimating equations adjusted for age, baseline 25(OH)D level, and DED severity, with false discovery rate correction. Results: At 3 months, the topical + vitamin D group demonstrated greater improvement in TBUT compared with the topical-only group (adjusted mean difference 1.25 seconds, 95% CI 0.62-1.88; p<0.001). Schirmer values also increased more in the topical + vitamin D group (adjusted mean difference 1.45 mm, 95% CI 0.73-2.17; p<0.001). Greater reductions in TNF-α, IL-1β, and IL-4 were observed at 3 months in the topical + vitamin D group, remaining significant after false discovery rate adjustment. At 6 months, partial attenuation of improvement was observed in both groups after discontinuation of topical therapy. Conclusion: In vitamin D-deficient DED, systemic vitamin D supplementation added to topical therapy was associated with greater improvement in tear film parameters and modulation of selected inflammatory cytokines compared with topical therapy alone. These findings warrant confirmation in adequately powered randomized controlled trials.