Optimizing Dry Eye Disease Management with Topical Anti-Inflammatory or Immunomodulatory Drugs Combined with Artificial Tears: A Systematic Review and Meta-Analysis of Clinical Trials

Background/Objectives: Dry eye disease (DED) is an ocular condition that significantly impairs quality of life. In mild cases, it is commonly treated with artificial tears (ATs), while more advanced cases are managed with immunomodulatory and anti-inflammatory drugs. The aim of this systematic review and meta-analysis was to evaluate the efficacy and safety of topical anti-inflammatory drugs, immunomodulatory drugs, AT, and their combination in adults with DED. Methods: The protocol was registered in the PROSPERO database (CRD420251245079). Intervention studies were searched in MEDLINE and Scopus databases. Random-effects meta-analyses were performed with the R software (version 4.5.2). Results: A total of 42 studies were included in the meta-analysis of efficacy and 46 in the analysis of safety. Overall, ATs and anti-inflammatory drugs did not produce significant improvements in clinical outcomes compared with controls. Immunomodulatory drugs showed variable results, with inconsistent efficacy and an increased risk of ocular adverse events (AEs). In contrast, combination therapy with ATs significantly improved clinical outcomes, including tear production (mean difference, MD, mm: 1.96, 95% CI [0.58–3.34] for anti-inflammatory drugs and 2.73, 95% CI [0.93; 4.52] for immunomodulatory drugs) and tear break-up time (MD, s: 1.43, 95% CI [0.81; 2.05] for anti-inflammatory drugs and 1.41, 95% CI [0.68; 2.13] for immunomodulatory drugs), without increasing the risk of AEs. Conclusions: Topical combination therapy with anti-inflammatory or immunomodulatory drugs and ATs appears to provide clinical improvements in tear function and patient- reported outcomes in DED, without additional safety concerns compared with ATs alone. These findings support combination treatment as a promising therapeutic strategy.