**Background:** Sjögren’s syndrome (SS) is a prevalent autoimmune disorder affecting approximately 0.06% of the global population, with women constituting over 90% of cases. Among patients with dry eye disease (DED), about 10% are associated with SS, yet approximately two-thirds of SS cases remain undiagnosed, with a median diagnostic delay of up to 10 years. Sjögren’s syndrome dry eye (SSDE) is distinct from non-Sjögren’s syndrome dry eye (NSSDE) but shares overlapping clinical manifestations, making differentiation challenging. Early detection is critical to prevent vision-threatening complications such as neurotrophic keratitis, corneal thinning, and perforation, as well as systemic complications including non-Hodgkin lymphoma (relative risk 13.8 times), pulmonary afflictions (10–20% of patients), and hematological abnormalities. Current diagnostic protocols, such as the 2016 ACR-EULAR Classification Criteria, rely on labial salivary gland biopsy, autoantibodies (anti-Ro/SSA, anti-La/SSB), ocular staining scores, Schirmer’s test, and saliva flow rate, but these methods have limitations including suboptimal sensitivity (e.g., anti-Ro/SSA sensitivity 69–77%, anti-La/SSB 39–44%), invasiveness, and impracticality in clinical settings. This review aims to provide an overview of SSDE classification, pathophysiology, clinical features, and management, while exploring novel diagnostic biomarkers in serum, saliva, and tears, with a focus on proteomics and exosomal biomarkers from literature spanning 2016 to 2023.
**Methods:** The authors conducted a comprehensive literature review covering studies from 2016 to 2023, examining diagnostic biomarkers for SSDE. The review includes analyses of serum, salivary, and tear biomarkers, as well as advanced imaging modalities such as in vivo confocal microscopy (IVCM), meibography, and lacrimal gland imaging (MRI/CT/US). Specific studies cited include: a 2022 retrospective analysis of 71 participants using IVCM; a 2018 study by Kang et al. on meibomian gland dysfunction; a 2021 study with 108 female eyes on meibomian gland atrophy; a 2022 radiomics study on lacrimal gland MRI; serum proteomics studies using immunoaffinity mass spectrometry and MALDI-TOF-MS; salivary proteomics using LC–MS/MS; tear proteomics using ELISA and lateral flow devices; and exosomal miRNA analyses using quantitative PCR and microarrays. The review also discusses signaling pathways, tear osmolarity (using TearLab Osmolarity System), and tear ferning patterns.
**Key Results:** The review identifies numerous potential biomarkers across different biofluids. In serum, four biomarkers (BDNF, I-TAC/CXCL11, sCD163, Fractalkine/CX3CL1) were found to distinguish SS from rheumatoid arthritis and systemic lupus erythematosus, with combinations yielding specificity up to 98.1% but low sensitivity (7.1–19%). CXCL10 levels were significantly higher in SS patients, while DPP4 levels were lower. Proteomic fingerprinting identified four protein peaks (m/z 8133.3, 4837.3, 2220.1, 11,972.4) correlated with SS. Salivary protein-1 (SP-1) autoantibody prevalence was 33% in SS vs. 19% in non-SS. In saliva, 34 proteins were significantly upregulated in SS, including neutrophil elastase, calreticulin, and clusterin; another study found 38 elevated proteins, with LCN2, GRN, CALM, NPC2, and CALML5 being most upregulated. PRG4 showed a 2.3-fold increase in SS. Salivary exosomes revealed upregulated CD44, MVP, and NGAL in SS vs. non-SS sicca, and Ficolin-1, CD44, and ANXA4 vs. healthy controls. EBV-specific miRNA (ebv-miR-BART13-3p) was increased in SS salivary glands. In tears, MUC5AC was reduced in SSDE compared to NSSDE, with IL-8 significantly elevated. MMP-9 positivity was found in 80% of SS patients with Schirmer’s test <5 mm. Low tear TSP-1/MMP-9 ratio was significantly associated with SS. LACTO and LIPOC-1 were lower in SS tears, showing higher diagnostic accuracy than traditional tests. ADAM10 was significantly increased in SS tears. Tear osmolarity was higher in SS (311.1 ± 16.4 mOsm/L) vs. non-SS DE (297.7 ± 12.7 mOsm/L), with cut-off values for dry eye at 305 mOsm/L (AUC 0.737). Tear ferning test showed abnormal patterns in 90% of primary SS and 81% of secondary SS, vs. 11% of controls. Exosomal miRNAs in tears and serum showed differential expression, with combinations like miR-1290 and let-7b-5p yielding AUC 0.856, sensitivity 91.7%, specificity 83.3%.
**Clinical Implications:** The review underscores the urgent need for non-invasive, sensitive, and specific diagnostic tools for SSDE to reduce diagnostic delays and prevent complications. Novel biomarkers such as CXCL10, MUC5AC, MMP-9, and exosomal miRNAs offer promise for early and accurate diagnosis. However, significant barriers to clinical translation remain, including lack of large-scale validation studies, cost-effectiveness analyses, and standardized cut-off values (e.g., for tear osmolarity). The authors emphasize that while proteomic and exosomal biomarkers hold substantial potential, parallel efforts are needed to bridge the translational gap to ensure these tools are pragmatically applicable in real-world settings. Achieving more rapid and precise SS diagnosis will refine disease management and improve patient outcomes.