Abstract
Objectives: Sjögren's syndrome (SjS) is a chronic autoimmune disease primarily affecting the salivary and lacrimal glands. Conventional diagnosis depends on invasive procedures, underscoring the need for non-invasive biomarkers. This systematic review summarizes evidence from 2014 to 2024 on the diagnostic and monitoring potential of salivary biomarkers in SjS. Methods: A systematic search of PubMed, Scopus, and Web of Science was performed according to PRISMA guidelines. Eligible human studies investigating salivary biomarkers in SjS were included. Data extraction and quality assessment were conducted independently by two reviewers. The protocol was registered in the OSF Registries. Results: Thirty-one studies were analyzed, identifying diverse metabolomic, proteomic, and molecular biomarkers. Consistent findings included increased levels of lactate, alanine, taurine, NGAL, β(2)-microglobulin, annexin A2, and regulatory RNAs (let-7i-5p, miR-17-5p), along with H19 ICR hypomethylation. Several extracellular vesicle (EV)-derived biomarkers demonstrated improved diagnostic stability and specificity. Conclusions: Saliva represents a promising, non-invasive diagnostic medium for Sjögren's syndrome. Integrating multi-omics approaches-particularly EV-based analyses may enhance early diagnosis and personalized monitoring. Large, multicenter studies using standardized protocols are needed to validate these findings.