Exploratory analysis of IFN-α-high and CXCL9-high cytokine distributions in systemic lupus erythematosus-associated macrophage activation syndrome.

Abstract

Macrophage activation syndrome (MAS) is a life-threatening hyperinflammatory complication of systemic lupus erythematosus (SLE), but its immunopathology remains poorly understood. We investigated cytokine-associated inflammatory heterogeneity in SLE-associated MAS (SLE-MAS). Serum levels of interferon (IFN)-α, C-X-C motif chemokine ligand 9 (CXCL9), interleukin (IL)-6, IL-18 and soluble TNF receptor type II (sTNF-RII) were measured in nine patients with SLE-MAS and compared with patients with systemic juvenile idiopathic arthritis-associated MAS (sJIA-MAS), Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) and healthy controls. Exploratory principal component analysis (PCA) was performed to visualize cytokine patterns. Patients with SLE-MAS exhibited elevated IFN-α levels, whereas IL-6 and IL-18 levels were lower than those in sJIA-MAS and EBV-HLH. Exploratory PCA suggested descriptive IFN-α-high and CXCL9-high cytokine distributions. Patients with the IFN-α-high pattern tended to have leukopenia and lupus nephritis, whereas those with the CXCL9-high pattern showed higher LDH levels and HScore values. IFN-α levels were associated with leukopenia but were not significantly correlated with SLEDAI-2K scores. These exploratory findings suggest that SLE-MAS may exhibit heterogeneous IFN-α-high and CXCL9-high cytokine distributions. These observations should be interpreted as descriptive, and hypothesis-generating rather than as validated biological subtypes or a treatment-stratification tool.