Association of clinical-immunologic clusters and anti-RNP/Ro52 antibody profiles with prognostic trajectories in primary Sjögren's disease.

OBJECTIVE: To delineate the prognostic architecture of primary Sjögren's disease (pSjD) through an integrated analysis of clinical-immunologic clusters and anti-RNP/anti-Ro52 antibody profiles. METHODS: This ambispective cohort study enrolled 1293 patients with pSjD from China-Japan Friendship Hospital (2013-2023). Unsupervised hierarchical clustering was performed using 13 immunologic and demographic features. Patients were followed for a median of 4.5 years for six pre-specified endpoints including all-cause mortality, incident interstitial lung disease (ILD), and incident malignancy. Cluster-level and antibody-level prognostic associations were evaluated using Fine-Gray competing-risk and Cox regression models with multiply imputed estimates. RESULTS: Four phenotypic clusters were identified among the 1293 patients, each with distinct prognostic trajectories for mortality, ILD, and malignancy. Cluster membership and antibody status captured non-redundant prognostic information. Anti-RNP positivity was independently associated with incident ILD (adjusted subdistribution hazard ratio [SHR] 2.64, 95% CI 1.07-6.48) and, in a propensity score-matched analysis (85 pairs), with lower all-cause mortality (HR 0.25, 95% CI 0.07-0.89). Anti-Ro52 positivity was the most consistent predictor of incident hematologic involvement (adjusted SHR 1.54, 95% CI 1.12-2.11). Both antibodies were independently associated with incident malignancy, and double-positive patients exhibited an approximately sixfold increased risk compared with double-negative patients (adjusted SHR 6.05, 95% CI 1.93-18.94). CONCLUSION: Immunophenotypic clustering and autoantibody profiling jointly stratify long-term outcomes in this single-center pSjD cohort. Dual anti-RNP and anti-Ro52 positivity identifies a small subgroup with an elevated risk of malignancy; these findings require independent validation before informing clinical surveillance strategies.