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

Abstract

To investigate whether structural integrity and epithelial senescence in the submandibular gland (SMG) predict longitudinal salivary gland dysfunction in Sjögren disease (SjD). 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). 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. 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.