Clinical characteristics and prognosis of primary Sjögren's disease patients with hypocomplementemia: reduced C3 is independently associated with new-onset peripheral cytopenias.

OBJECTIVES

To investigate the clinical characteristics and prognostic significance of hypocomplementemia in patients with primary Sjögren's disease (pSjD), with a particular focus on its association with new-onset peripheral cytopenias.

METHODS

This ambispective cohort study included patients with pSjD treated at the China-Japan Friendship Hospital from 2016 to 2023. Baseline features and associated factors were compared between patients with and without hypocomplementemia. Prospective analyses were performed to evaluate the association between complement levels and new-onset peripheral cytopenias using Fine-Gray competing risk models. Survival outcomes during follow-up were also assessed in patients with and without baseline hypocomplementemia.

RESULTS

Among 1013 patients with pSjD, 52.6% exhibited hypocomplementemia. At baseline, patients with hypocomplementemia had higher disease activity and a greater prevalence of immunological abnormalities, including hyper-IgG and positivity for anti-SSA, anti-SSB, and anti-Ro52 antibodies, as well as more frequent peripheral cytopenias (including leukopenia, neutropenia, lymphocytopenia, erythrocytopenia, anemia, and thrombocytopenia). In multivariable analyses, thrombocytopenia and hyper-IgM were independently associated with hypocomplementemia, whereas C1q levels and C-reactive protein were inversely associated. During follow-up, lower C3 levels were independently associated with an increased risk of new-onset peripheral cytopenias; each 0.1 g/L decrease in C3 corresponded to a 30% higher risk. No significant association was observed between hypocomplementemia and all-cause mortality.

CONCLUSION

Hypocomplementemia in pSjD is associated with higher disease activity, immune dysregulation, and a greater prevalence of peripheral cytopenias. Decreased C3, but not C4, is independently associated with new-onset peripheral cytopenias, supporting further investigation of C3 as a candidate biomarker for risk stratification. Key Points • Hypocomplementemia is common in primary Sjögren's disease and is associated with younger age at onset, female predominance, and higher disease activity. • Hypocomplementemia may reflect a systemic disease phenotype characterized by hematologic involvement and immune dysregulation. • Reduced C3, but not C4, is independently associated with new-onset peripheral cytopenias, suggesting differential involvement of complement components in disease stratification. • C3 is associated with cytopenia risk in a dose-dependent manner, with each 0.1 g/L decrease corresponding to an approximately 30% increased risk.