Abstract Background Numerous studies have explored age‐related heterogeneity in primary Sjögren's disease (SjD); however, the links between clinical phenotypes and underlying immunophenotypes across age groups remain insufficiently defined. Because primary SjD onset is typically gradual and retrospectively uncertain, diagnostic age—corresponding to the time of confirmed disease identification and clinical management—serves as a more practical and reproducible measure for age‐related analysis. Methods We retrospectively analyzed 5778 primary SjD patients from Peking University People's Hospital diagnosed between January 2018 and December 2022, stratifying them by diagnostic age (<45 years vs. ≥45 years). Multivariable logistic regression, adjusted for confounders and with false discovery rate correction, was used to identify age‐dependent associations. Results In unadjusted analyses, early‐diagnosed patients exhibited a distinct clinical phenotype and more active humoral immunity. Subsequent multivariable adjustment, controlling for sex, smoking, comorbidities, and inflammatory/hematologic markers, confirmed early diagnosis (<45 years) as an independent risk factor for interstitial lung disease (adjusted odds ratio OR = 1.98, 95% confidence interval CI: 1.09–3.60) and hypergammaglobulinemia (adjusted OR = 3.80, 95% CI: 2.91–4.99). Immunophenotyping further revealed a reconstituted T cell landscape characterized by CD4⁺ lymphopenia (median difference: −70 cells/μL; 95% CI: −109 to −30), CD8⁺ expansion (+33 cells/μL; 95% CI: +8 cells/μL to +75 cells/μL), and a skewed CD4⁺ subset balance featuring elevated Treg (9.76% vs. 8.57%) and naïve Th cells (34.90% vs. 26.30%) but reduced Teff cells (88.93% vs. 90.30%; all p < 0.01). Conclusions This study defines the core phenotype of early‐diagnosed primary SjD by hypergammaglobulinemia and interstitial lung disease risk, unveiling its distinct T cell basis. These results highlight age‐specific immune mechanisms and suggest the need for personalized monitoring and individualized immune regulation strategies in clinical management.
Ning et al. (2026) studied this question.