Association between serological profiles and clinical manifestations in Sjögren’s disease

Sjögren’s Disease (SjD) is a clinically heterogeneous autoimmune disorder with both glandular and extraglandular manifestations. Although serological markers are routinely assessed, their relationships with individual organ-specific phenotypes remain incompletely defined. We therefore systematically mapped associations between clinical manifestations and a broad panel of serological parameters in a treatment-naïve SjD cohort. We conducted a retrospective study of 206 treatment-naïve patients who fulfilled the 2016 ACR/EULAR classification criteria for SjD. Associations between serological variables, including autoantibodies, immunoglobulins, complement, inflammatory markers, and electrolytes, and glandular, systemic, hematologic, and organ-specific manifestations were evaluated. Candidate predictors identified by univariate screening ( P < 0.10) were entered into multivariable models with age and sex as a priori confounders. Before modeling, multicollinearity was addressed by iterative variance inflation factor (VIF) screening (VIF < 5). Modeling was stratified by events per variable (EPV): standard logistic regression for EPV ≥ 10 and Firth’s penalized-likelihood regression for EPV < 10; outcomes with EPV < 2 were not modeled multivariately. False discovery rate correction was applied using the Benjamini–Hochberg procedure, with q < 0.10 considered potentially significant. Glandular manifestations showed distinct serological associations: xerostomia and xerophthalmia were both independently and inversely associated with CRP elevation; keratoconjunctivitis sicca was independently and inversely associated with ESR elevation and positively associated with anti-SSB/La positivity. Hematologic abnormalities showed the strongest associations with immune-related laboratory markers, particularly hypocomplementemia, anti-SSA/Ro52 positivity, and elevated ESR. At the cytopenia level, hypocomplementemia was independently associated with lymphopenia, thrombocytopenia, and anemia, while anemia was also associated with anti-SSA/Ro60 positivity and elevated IgM. Peripheral neuropathy was associated with anti-U1 RNP positivity, lymphadenopathy with lymphopenia, pulmonary arterial hypertension with IgG elevation, and arthralgia with ANA positivity. Systemic symptoms were independently associated with hypoalbuminemia and elevated liver enzymes, and inversely associated with anti-SSB/La positivity. Low-frequency phenotypes suggested additional exploratory associations, including Raynaud’s phenomenon with anti-centromere antibody, nephropathy with hyperchloremia and hypokalemia, and hepatic involvement with elevated liver enzymes, anti-mitochondrial antibody, and elevated IgM. In this treatment-naïve SjD cohort, distinct clinical phenotypes were associated with characteristic serological profiles, supporting a more nuanced, phenotype-dependent interpretation of laboratory markers. Our findings suggest that established serological abnormalities may help refine organ-specific risk stratification and surveillance, rather than serving as uniform indicators of disease across all manifestations. Prospective validation in larger, independent cohorts is required before these associations can be incorporated into routine clinical decision-making.