Natural killer cells as biomarkers for disease activity, lupus nephritis, and time to remission in treatment-naïve childhood-onset systemic lupus erythematosus: a cohort study.

OBJECTIVES

Adaptive immunity is well-established in lupus pathogenesis, yet the clinical significance of innate immune components, particularly natural killer (NK) cells, remains underexplored. This study aims to evaluate the clinical relevance of NK cell levels in treatment-naïve, infection-free patients with childhood-onset systemic lupus erythematosus (cSLE).

METHODS

We conducted a retrospective cohort study among 96 treatment-naïve, infection-free cSLE patients diagnosed during 2015–2025. Logistic regression was applied to compare patients of moderate-to-severe disease activity (SLEDAI > 9) versus low disease activity (SLEDAI ≤ 9), and to assess the associations between NK cell levels and organ involvement. Cox regression analysis was performed to evaluate the effect of baseline NK cell counts on the time to first remission. To evaluate whether longitudinal changes in absolute NK cell counts are associated with the timing of initial remission, we performed a linear mixed-effects model analysis in the subset of patients with serial NK cell data.

RESULTS

Both absolute NK cell counts and percentages were lower than healthy references. Anti-dsDNA positivity (OR = 5.107, 95% CI: 1.257–20.757, P = 0.023), neuropsychiatric involvement (OR = 33.306, 95% CI: 6.79–163.32, P < 0.001), and absolute NK cell count (OR = 0.982, 95% CI: 0.969–0.995, P = 0.007) were independent factors associated with higher disease activity. Similarly, independent factors for lupus nephritis included anti-dsDNA positivity (OR = 8.555, 95% CI: 2.302–31.791, P = 0.001) and absolute NK cell count (OR = 0.991, 95% CI: 0.982–1.000, P = 0.041). During follow-up, in multivariate Cox regression with forward likelihood ratio, higher absolute NK cell count was independently associated with a shorter time to first remission (HR 1.005, 95% CI 1.001–1.009, P = 0.015), whereas hypocomplementemia was independently associated with a longer time to first remission (HR 0.472, 95% CI 0.244–0.912, P = 0.026). The optimal cut-off was 126 cells/µL.

CONCLUSIONS

Absolute NK cell count is a clinically relevant biomarker in cSLE. Compared with healthy controls, cSLE exhibit consistently reduced NK cell count and percentage across all age groups. Absolute NK cell count independently stratifies patients with cSLE by disease activity, clinical diagnosis of lupus nephritis, and time to first remission.