Comparative Efficacy of Cyclosporine, Tacrolimus, and Neurostimulatory Nasal Sprays for Moderate-to-Severe Dry Eye Disease: A Systematic Review and Network Meta-Analysis.

AIM: To compare the efficacy and tolerability of topical cyclosporine A (CsA) 0.05%, 0.09%, and 0.1%; tacrolimus 0.03%; and neurostimulatory nasal sprays (varenicline and simpinicline) in moderate-to-severe dry eye disease (DED), focusing on tear production, ocular surface integrity, and tear film stability. CLINICAL RELEVANCE: DED management remains complex due to heterogeneous presentation and variable therapeutic responses. While immunomodulators like CsA and tacrolimus are widely used, novel neuromodulatory agents such as varenicline nasal spray are emerging. Comparative data across these treatment classes remain scarce. METHODS: A systematic search of MEDLINE, Embase, and CENTRAL was performed up to January 2025. Randomized controlled trials assessing CsA 0.05%, 0.09%, or 0.1%; tacrolimus 0.03%; or nicotinic acetylcholine receptor agonist nasal sprays in moderate-to-severe DED were included. Primary endpoints included Schirmer test score (STS), tear break-up time (TBUT), corneal fluorescein staining (CFS), and ocular surface disease index (OSDI). A Bayesian network meta-analysis estimated comparative efficacy using the surface under the cumulative ranking curve (SUCRA). RESULTS: Twenty-nine RCTs (n = 8453 patients) were included in the systematic review; fourteen qualified for network meta-analysis. CsA 0.09% and 0.1% ranked highest for CFS improvement at the evaluated time points. Tacrolimus 0.03% showed favorable early STS and TBUT trends but did not consistently improve longer-term ocular surface outcomes. Varenicline improved tear production but lacked CFS data. Placebo ranked favorably for STS and TBUT at 3 months and beyond, possibly because several vehicles had lubricating or tear-stabilizing effects. CsA 0.05% showed modest efficacy. CONCLUSION: CsA 0.09% and 0.1% showed the most favorable corneal healing outcomes, while tacrolimus 0.03% showed an early tear-stimulating effect. Varenicline offers a distinct neurostimulatory mechanism but requires further comparative validation. These findings support phenotype-guided therapy and future head-to-head trials.