FRI0003 Determination of interferon (IFN) signatures for sle patients may be critical for optimal treatment selection but depends on the genes chosen: report from the bold (biomarkers of lupus disease) study

Background Elevated expression of IFN pathway genes, known as the IFN signature (IS) is found in roughly half of SLE patients 1 . Various studies have used different IFN genes to define the IS, and different methods to assign patients to “IFN high” or “low” expression groups. Importantly a recent report from the Genentech ROSE study found higher responsiveness to an interferon antagonist in patients with lower IFN expression using a 7 gene set (G-7), suggesting that IS might inform optimal selection of treatments in the future 2 . Objectives As a step toward understanding the clinical relevance and molecular drivers of the IS, we used data from the BOLD study to test the difference between IS-derived patient groupings derived from different sets of IFN genes. Methods The BOLD study enrolled SLE patients with active disease (minimum SLEDAI of 6 or two BILAG B scores). 41 patients had background immune suppressives withdrawn, were given brief steroids until improvement, then followed with serial samples until disease flare. 62 additional active SLE patients were evaluated only once. RNA expression levels for 329 genes were assayed using TaqMan ® Low Density Arrays. 238 SLE patient-visits were partitioned into two groups by unsupervised hierarchical clustering of the expression levels of IFN-related genes. Results Clustering was done separately for 5 gene sets, denoted B-30, P-11, M-20, G-7, and O-3. Two of the gene sets (M-20 and G-7) were 95% and 100% matched to sets used in clinical trials of IFN-inhibiting treatments. Consistent with previous reports, all of the gene sets assigned about 40-50% of visits (96 to 118 patient-visits) to an “IFN high” group characterized by IFN pathway expression that was higher than healthy volunteers. In a cross-sectional analysis using the P-11 gene set, membership in the IFN high group was associated with higher SLEDAI score than IFN low assignment (9.73 vs. 7.70, p Conclusions The comparison of IFN group assignments for the same samples, derived using different IFN gene sets, highlights the need for more investigation of the molecular and cellular drivers of IFN gene expression in SLE blood. An optimal IFN gene set, once determined, might improve how patients are selected for targeted therapies in the future. References Baechler et al., PNAS 100(5) 2610-2615 (2003); Kalunian et al., ACR 2012 Washington D.C, Abstract 2622. Disclosure of Interest None Declared