This study assessed complement activation in Still disease (SD) using transcriptomics, proteomics, and in vitro methods across patients with active SD, inactive SD, juvenile idiopathic arthritis (JIA), and healthy donors, examining links between complement and type II interferon (IFN-γ) signaling.
Monocytes from SD-onset patients showed marked enrichment of the complement cascade vs. remission patients (adjusted P = 3.7 × 10⁻³⁶); active SD had elevated C1q, C3a, C5a, and terminal complement complex levels, with C1QB/C1QC expression correlating with IFN-γ markers (IL-18, CXCL9, CXCL10), and a feed-forward loop was identified where IFN-γ induces monocytic C1q and C1q in turn enhances IFN-γ production by CD8+ T cells.
Macrophage activation syndrome subgroup was very small (n = 2), limiting conclusions for that phenotype; the study is largely observational and cross-sectional, so causality of the C1q–IFN-γ loop in human disease cannot be fully established; in vitro findings may not fully recapitulate the in vivo inflammatory milieu.
Complement activation, particularly via C1q and the classical pathway, is a feature of active Still disease linked to IFN-γ signaling—clinicians should be aware that complement and IFN-γ pathways may act together, potentially informing future therapeutic targets in SD.
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