The role of interferon‐α (IFNα) in the pathogenesis of systemic lupus erythematosus (SLE) is strongly supported by gene expression studies. The aim of this study was to improve characterization of the blood IFN signature in adult SLE patients.

Consecutive patients were enrolled and followed up prospectively. Microarray data were generated using Illumina BeadChips. A modular transcriptional repertoire was used as a framework for the analysis.

Our repertoire of 260 modules, which consisted of coclustered gene sets, included 3 IFN‐annotated modules (M1.2, M3.4, and M5.12) that were strongly up‐regulated in SLE patients. A modular IFN signature was observed in 54 of 62 patients (87%) or 131 of all 157 samples (83%). The IFN signature was more complex than expected, with each module displaying a distinct activation threshold (M1.2 < M3.4 < M5.12), thus providing a modular score by which to stratify SLE patients based on the presence of 0, 1, 2, or 3 active IFN modules. A similar gradient in modular IFN signature was observed within patients with clinically quiescent disease, for whom moderate/strong modular scores (2 or 3 active IFN modules) were associated with higher anti–double‐stranded DNA titers and lower lymphocyte counts than those in patients with absent/mild modular scores (0 or 1 active IFN modules). Longitudinal analyses revealed both stable (M1.2) and variable (M3.4 and M5.12) components of modular IFN signature over time in single patients. Interestingly, mining of other data sets suggested that M3.4 and M5.12 could also be driven by IFNβ and IFNγ.

Modular repertoire analysis reveals complex IFN signatures in SLE, which are not restricted to the previous IFNα signature, but which also involve IFNβ and IFNγ.