Distinct Immunological Features Characterize Early-Onset Primary Sjögren’s Disease

Abstract Objectives Early-onset primary Sjögren’s Disease (pSjD) represents a specific clinical phenotype with poorer prognosis. We aim to compare early- and late-onset pSjD immunophenotypes to identify key distinct immunological features. Methods We retrospectively studied 204 newly diagnosed, untreated pSjD patients categorized by age at diagnosis (≤35 years). Clinical features, peripheral lymphocyte profiles, CD4+ T cell subsets, and cytokine levels were compared. Key immune variables were screened via random forest and LASSO regression. LASSO-selected variables were analyzed using forward stepwise logistic regression to determine independent immune factors associated with early-onset pSjD. Results Among 204 enrolled patients, 43 (21.08%) were classified as early-onset pSjD and 161 (78.92%) as late-onset pSjD. Compared with the late-onset group, early-onset patients showed significantly lower CD4+ T cell counts 442.62 (236.92–558.89) vs 563.11 (386.98–762.60), p = 0.005 and NK cell counts 71.36 (51.69–134.58) vs 138.05 (91.65–241.90), p 0.001. In terms of CD4+ T cell subsets, the early-onset group exhibited higher Th17/Treg cell ratios 0.42 (0.33–0.59) vs 0.30 (0.21–0.46), p = 0.006 and lower Treg cell counts 22.07 (12.89–34.96) vs 28.00 (20.35–38.93), p = 0.032. Three independent factors for early-onset disease were identified: NK cell counts (OR = 0.993, p = 0.010), CD4+ T cell percentage (OR = 0.947, p = 0.019), and Th17/Treg cell ratios (OR = 5.215, p = 0.029). Conclusion This study characterizes the distinct peripheral immunological landscapes of early- and late-onset pSjD and identifies an immunological triad that may represent a unique 'immune endotype’ for early-onset disease, offering insights into targeted monitoring and therapies.