Background: This study investigates the clinical characteristics and differences between primary Sjögren’s Syndrome (pSS) and secondary Sjögren’s Syndrome (sSS) in a cohort of 50 patients. Methods: Conducted across two academic facilities in North-East Romania, the study emphasizes the importance of glandular and extraglandular manifestations, focusing on salivary flow rates, pH levels, and buffer capacity. Patients were diagnosed using the 2016 ACR-EULAR classification criteria, with a detailed examination including salivary tests, biopsies, and antibody presence. Results: The findings highlight significant differences between pSS and sSS, particularly in salivary function, with pSS patients exhibiting more severe glandular dysfunction. The study also notes a higher prevalence of inflammatory joint involvement in sSS patients, often associated with rheumatoid arthritis. Statistical analysis revealed correlations between salivary parameters and disease progression, underscoring the necessity of tailored treatment strategies. The research suggests that lower salivary flow rates and altered pH levels in pSS patients contribute to compromised oral health, including increased dental cavities and periodontal disease. Conclusions: The study’s results contribute to a deeper understanding of Sjögren’s Syndrome and reinforce the need for multidisciplinary management to address both systemic and oral health complications in these patients.

Primary Sjögren’s syndrome (pSS) exhibits considerable clinical and immunological heterogeneity, complicating personalized management. We aimed to delineate the demographic, functional, serological, histopathological, and therapeutic features of a Romanian pSS cohort and to identify biomarker–treatment correlations that could inform patient-oriented strategies. Thirty-two patients meeting the 2016 ACR/EULAR classification criteria for pSS were retrospectively analyzed. Data collected included demographics, autoantibody profiles (Anti-Ro/SSA, Anti-La/SSB, ANA, RF, Anti-CCP), immunoglobulin levels, complement consumption (C3/C4), minor salivary gland biopsy (focus score), salivary flow tests, and systemic inflammation markers (CRP). Pearson correlation matrices were constructed to explore the associations between serological markers and prescribed therapies. The cohort was predominantly female (87.5%) with a mean age of 52.8 ± 9.9 years. Seropositivity rates were 50% for Anti-Ro/SSA, 77% for Anti-La/SSB, and 40% for ANA. Clinically significant glandular dysfunction was evident in 65% of patients (unstimulated flow ≤ 0.1 mL/min), and all biopsies demonstrated focus scores > 1. Methotrexate use correlated strongly with Anti-Ro/SSA and Anti-La/SSB positivity (p ≤ 0.05), indicating its targeted application in seropositive sub-phenotypes. Conclusion: These findings underscore the immunologic and clinical diversity of pSS and support a biomarker-driven, multidisciplinary framework for personalized treatment. Larger prospective and multicenter studies are warranted to validate these correlations and to refine precision medicine approaches in pSS.