Distinct Cytokine Profiles in Lupus Low Disease Activity State Subgroups Identify Patients at Risk for Disease Flare

We compared the cytokine profiles between two lupus low disease activity state (LLDAS) subgroups—clinically active (CA) and serologically active clinically quiescent (SACQ)—and identified predictors of disease flare. Fifty patients with systemic lupus erythematosus (25 CA, 25 SACQ) who maintained LLDAS for ≥6 months were enrolled and followed for 6 months. Cytokine modules were identified using weighted gene co-expression network analysis, and correlations with clinical traits were assessed. Predictors of flare were assessed using Cox regression. Three cytokine modules were identified. The brown (MCP-1 and IL-8) and turquoise (IFN-α, IFN-γ, IL-17A, IL-10, IL-12p70, IL-18, IL-23A, and IL-33) modules correlated with mucocutaneous and physician global assessment, respectively. These modules showed a positive, but not significant, correlation with CA. The comparison analysis revealed that IL-6 and IL-8 were higher in CA than in SACQ. Nine patients (18%) flared, six of whom belonged to the CA group. Flares were associated with a lower sustained LLDAS rate (77.8% vs. 34.1%) and higher levels of IL-1β, IL-6, and IL-33. In multivariable analysis, non-sustained LLDAS (HR 8.73) and IL-6 ≥ 45.1 pg/mL (HR 10.4) independently predicted a flare. Our study demonstrated that cytokine elevation persists despite LLDAS. Non-sustained LLDAS and elevated IL-6 predict a flare, suggesting that IL-6 may enhance the flare prediction biomarker.