Primary Sjögren’s disease (pSjD) is a chronic systemic autoimmune disease characterized by lymphocytic infiltration of the salivary and lacrimal glands, resulting in xerostomia, xerophthalmia, and a variety of extraglandular manifestations. Despite advances in disease recognition, early diagnosis remains challenging because initial symptoms are often nonspecific and may overlap with other autoimmune or sicca-related conditions. The 2016 ACR/EULAR classification criteria emphasize anti-SSA(Ro) antibody positivity and focal lymphocytic sialadenitis on minor salivary gland biopsy as major items, reflecting the importance of serologic and histopathologic evidence in current diagnosis. However, minor salivary gland biopsy is invasive and not always acceptable to patients, creating a clinical need for more convenient and reproducible non-invasive tools. In recent years, salivary biomarkers have emerged as promising candidates because saliva is easy to obtain, repeatable, and directly related to glandular involvement. This structured review aimed to summarize current evidence on salivary biomarkers in pSjD and to evaluate the diagnostic value of combining salivary markers with serum autoantibodies for early and minimally invasive disease identification.

A structured literature review was performed using English-language publications indexed in PubMed from January 2016 to February 2026. The search strategy combined the terms “primary Sjögren’s disease”, “primary Sjögren’s syndrome”, “salivary biomarkers”, “saliva”, “autoantibodies”, “anti-SSA”, “anti-Ro52”, “diagnosis”, and “tear biomarkers”. Priority was given to classification criteria articles, systematic reviews, review articles, and recent clinical studies evaluating diagnostic models that integrated salivary molecular markers with conventional serology or ocular tests. Studies focusing on proteomic, metabolomic, microRNA, extracellular vesicle, and immune-related salivary markers were included. Articles without clear diagnostic relevance, duplicate reports, and studies lacking interpretable clinical outcomes were excluded. The main outcomes extracted were the categories of candidate biomarkers, their diagnostic relevance, their relationship with established serum autoantibodies, and the major limitations affecting clinical translation, including sample heterogeneity, small cohort size, assay variability, and insufficient external validation.

The reviewed evidence showed that salivary biomarker research in pSjD has shifted from isolated candidate molecules toward integrated multi-marker diagnostic strategies. Systematic and narrative reviews consistently identified several recurring salivary biomarker categories, including inflammatory proteins, complement-related proteins, metabolites, regulatory RNAs, and extracellular vesicle-derived molecules. Among these, increased levels of NGAL, β2-microglobulin, annexin A2, lactate, alanine, taurine, and selected microRNAs were repeatedly reported as being associated with pSjD. These findings support the biological relevance of saliva as a diagnostic substrate and suggest that salivary molecular changes may reflect both glandular damage and autoimmune activation. Recent reviews further emphasized that extracellular vesicle-associated biomarkers may offer improved stability and specificity compared with free salivary analytes, making them attractive candidates for future assay development.

Importantly, recent clinical studies indicate that salivary biomarkers may provide the greatest value when interpreted together with serum autoantibodies rather than as stand-alone tests. A 2024 study developed a non-invasive diagnostic model based on salivary complement factor B, clusterin, and neutrophil elastase, combined with serum anti-SSA/Ro60, anti-SSA/Ro52, and Schirmer’s test. This combined model showed strong discriminative performance, with an area under the curve of 0.930 in the derivation cohort, suggesting that multi-component algorithms can approach clinically useful diagnostic accuracy. In parallel, tear biomarker research has also expanded, with recent reviews showing that ocular surface inflammatory mediators and immune-associated molecules may complement salivary and serologic assessment, especially in patients who present primarily with dryness symptoms. Nevertheless, the current literature also demonstrates important limitations: no single salivary biomarker has yet achieved sufficient reproducibility to replace anti-SSA testing or minor salivary gland biopsy, and substantial heterogeneity remains across sample processing methods, analytical platforms, patient selection criteria, and validation cohorts.

Current evidence suggests that salivary biomarkers have meaningful potential as non-invasive diagnostic tools in pSjD, particularly when combined with serum autoantibodies and routine ocular evaluation. This combined strategy is more realistic and clinically applicable than reliance on any single novel marker. At present, the most promising role of salivary biomarkers is to improve early screening efficiency, support risk stratification, and reduce unnecessary dependence on invasive biopsy in selected patients. However, before broad clinical implementation can be recommended, future studies should focus on multicenter validation, standardized specimen collection and assay protocols, and the establishment of reproducible diagnostic thresholds. Overall, the integration of salivary biomarkers with serum autoantibody testing represents a practical and promising direction for the early diagnosis of primary Sjögren’s disease.