OBJECTIVES: Type I interferon (IFN) is implicated in systemic lupus 
erythematosus (SLE) pathogenesis. We aimed to identify type I IFN 
signaling-dependent and -independent molecular pathways in a large population of 
patients with SLE.
METHODS: Baseline blood samples from adult patients with moderate to severe SLE 
from two Phase IIb studies (NCT01438489, n = 265; NCT01283139, n = 416) were 
profiled using whole transcriptome array analyses. Type I IFN gene signature 
(IFNGS) test status (high or low) was determined using a validated qualitative 
polymerase chain reaction-based test. IFN-type-specific signatures were 
developed by stimulating healthy blood with IFN-β, IFN-γ, IFN-λ, IFN-ω, or 
pooled IFN-α. These, and multiple literature-derived cell type and cytokine 
pathway signatures, were evaluated in individual and pooled study populations. A 
Fisher's exact test was used for associations, adjusted for false discovery 
rate.
RESULTS: Whole blood samples from IFNGS test-high patients were enriched versus 
IFNGS test-low patients for CD40L signaling (Q < 0.001), CXC cytokine 
(Q < 0.001), TLR8-mediated monocyte activation (Q < 0.001), IgG (Q < 0.001), 
major histocompatibility complex class I (Q < 0.001), and plasma cell 
(Q < 0.001) gene expression signatures. IFNGS test-low patients had significant 
enrichment of eosinophil (Q < 0.001), IFN-γ-specific (Q = 0.005), and T-cell or 
B-cell (Q < 0.001) signatures. Similar enrichment profiles were demonstrated in 
patients with primary Sjögren's syndrome, systemic sclerosis, and 
dermatomyositis.
CONCLUSIONS: IFNGS test-high patients overexpressed many gene signatures 
associated with SLE pathogenesis compared with IFNGS test-low patients, 
reflecting broad immune activation. These results provide new insights into the 
molecular heterogeneity underlying SLE pathogenesis, highlighting shared 
mechanisms beyond type I IFN, across several autoimmune diseases.
TRIAL REGISTRATION: Clinicaltrials.gov: NCT01438489 and NCT01283139.