Immunophenotypic Stratification of Primary Sjögren’s Syndrome Reveals Distinct Lymphocyte Profiles and Clinical Manifestations

Objective Primary Sjögren’s syndrome (pSS) is a heterogeneous autoimmune disorder with diverse clinical manifestations and limited effective therapies. This study aimed to stratify pSS patients into distinct immunophenotypic subgroups based on peripheral lymphocyte profiles and to explore the clinical relevance of these subgroups, thereby informing personalized management for pSS. Methods A retrospective cohort of 133 Chinese pSS patients and 241 age‐ and sex‐matched healthy controls (HCs) was analyzed. Immunophenotyping of 11 lymphocyte subsets was performed using flow cytometry in peripheral blood. K‐means clustering was employed to identify patient subgroups based on lymphocyte profile. Clinical data were collected and compared across clusters. Results Lymphocyte profiles in pSS patients differed from those in HCs, featuring elevated proportions and estimated counts of activated CD8 + T cells along with reduced naïve CD4 + T cells and NK cells. Unsupervised clustering analysis identified three distinct patient subgroups based on immunophenotypic patterns: Cluster 1 was characterized by significantly higher proportions of CD8 + T cells and showed more frequent hematologic and serological abnormalities, including higher rates of hyperglobulinemia, anti‐Ro52 positivity, and high‐titer ANA positivity. Cluster 2 was distinguished by higher NK and B cell proportions and clinically presented with greater pulmonary and hepatic involvement along with higher disease damage scores. Cluster 3 maintained lymphocyte distributions closest to HCs but exhibited more frequent constitutional symptoms and cutaneous involvement coupled with lower serological activity. Conclusion Lymphocyte profiling may help stratify pSS patients into clinically distinct subgroups, potentially corresponding to different pathobiological endotypes, and could thus inform patient stratification.