Epithelial senescence predicts salivary dysfunction in Sjögren disease and glandular integrity defines residual capacity

OBJECTIVE: To investigate whether structural integrity and epithelial senescence in the submandibular gland (SMG) predict longitudinal salivary gland dysfunction in Sjögren disease (SjD). METHODS: This retrospective cohort study analysed 51 anti-SSA-positive SjD patients who underwent US-guided SMG core needle biopsy and longitudinal assessments of unstimulated whole saliva flow (UWSF). Glandular preservation was quantified as the SMG gland ratio (glandular area/total area), and epithelial senescence was assessed by p16INK4a expression in striated ductal epithelial cells. Associations with baseline and longitudinal UWSF were analysed using generalized estimating equations (GEEs). RESULTS: The SMG gland ratio correlated positively with baseline UWSF, serologic immunologic markers and imaging scores, supporting its role as a structural integrity index. However, patients with intermediate gland ratios experienced the steepest UWSF decline over time. Ductal p16 expression exhibited an inverted U-shaped distribution across the gland ratio spectrum, peaking at moderate preservation (ratio ≈ 0.55). In longitudinal models, higher p16 expression independently predicted greater UWSF decline (P < 0.001), whereas gland ratio alone was not significant. Patients with intermediate gland ratio and high p16 burden had the most rapid decline in salivary function. CONCLUSION: The SMG gland ratio reflects preserved glandular structure, while p16-mediated senescence captures functional vulnerability. Senescence peaks at an intermediate preservation stage, delineating a transitional disease phase in which function deteriorates despite intact architecture. These findings support a dual-pathology framework and may inform early risk stratification and therapeutic targeting in SjD.