OBJECTIVES: The interferon (IFN) signature (IS) in patients with systemic lupus 
erythematosus (SLE) includes over 100 genes induced by type I IFN pathway 
activation. We developed a method to quantify the IS using three genes-the IS 
metric (ISM)-and characterised the clinical characteristics of patients with SLE 
with different ISM status from multiple clinical trials.
METHODS: Blood microarray expression data from a training cohort of patients 
with SLE confirmed the presence of the IS and identified surrogate genes. We 
assayed these genes in a quantitative PCR (qPCR) assay, yielding an ISM from the 
IS. The association of ISM status with clinical disease characteristics was 
assessed in patients with extrarenal lupus and lupus nephritis from four 
clinical trials.
RESULTS: Three genes, HERC5, EPSTI and CMPK2, correlated well with the IS 
(p>0.96), and composed the ISM qPCR assay. Using the 95th centile for healthy 
control data, patients with SLE from different studies were classified into two 
ISM subsets-ISM-Low and ISM-High-that are longitudinally stable over 36 weeks. 
Significant associations were identified between ISM-High status and higher 
titres of anti-dsDNA antibodies, presence of anti extractable nuclear antigen 
autoantibodies, elevated serum B cell activating factor of the tumour necrosis 
factor family (BAFF) levels, and hypocomplementaemia. However, measures of 
overall clinical disease activity were similar for ISM-High and ISM-Low groups.
CONCLUSIONS: The ISM is an IS biomarker that divides patients with SLE into two 
subpopulations-ISM-High and ISM-Low-with differing serological manifestations. 
The ISM does not distinguish between high and low disease activity, but may have 
utility in identifying patients more likely to respond to treatment(s) targeting 
IFN-α.
CLINICALTRIALSGOV REGISTRATION NUMBER: NCT00962832.