OP0099 Modular Repertoire Analysis Identifies Complex Coordinated Type I- Type II Transcriptional Signatures in Adult SLE Patients
Authors: L. Chiche, N. Jourde-Chiche, E. Whalen, K. Dang, S. Presnell, V. Gersuk, Q.-A. Nguyen, E. Anguiano, C. Quinn, B. Dussol, S. Burtey, Y. Berland, N. Bardin, N. Schleinitz, G. Kaplanski, J.-M. Durand, J.-R. Harle, V. Pascual, D. Chaussabel
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> A pivotal role for Type I interferon (IFN) in SLE is supported by gene expression studies that identified the so-called type I IFN signature (IS). <h3>Objectives</h3> The aim of this study was to improve characterization of the blood-IFN signature in adult SLE patients. <h3>Methods</h3> Consecutive SLE patients fulfilling the ACR criteria were enrolled and followed-up prospectively. Microarray data were generated using Illumina beadchips. A modular transcriptional repertoire was employed as a framework for the analysis. <h3>Results</h3> Our repertoire of 260 modules, which consist of co-clustered gene sets, included 3 IFN-annotated modules (M1.2, M3.4 and M5.12) that were strongly up-regulated in SLE patients. At the individual level, a modular IS (ie, over-expression of at least 1 of the 3 IFN modules) was observed in 54/62 (87%) of patients or 131/157 (83%) of samples. The IFN signature was more complex than expected with each module displaying a distinct activation threshold (M1.2&lt;M3.4&lt;M5.12), thus providing a modular score to stratify SLE patients based on the presence of 0, 1, 2 or 3 active IFN modules. This "gradient" mIS was similarly observed in 2 independent SLE datasets. Samples were then classified in 4 groups according to their individual "modular IFN score" corresponding to the number of up-regulated IFN modules: Absent (0) in 26 (17%), Mild (1) in 17 (11%), Moderate (2) in 68 (43%) and Strong (3) in 46 (29%) samples. No differences in age, gender, ethnicity or disease duration was observed between the 4 groups. Compared to patients with absent/mild mIS, those with moderate/strong mIS had significantly higher anti-dsDNA titers (p=0.03) and lower lymphocyte count (p&lt;0.0001). SLEDAI score was not significantly different between groups, but patients with moderate/strong mIS were less likely to be treated with antimalarials (p=0.002) or with a combination of immunosuppressant and antimalarials (p=0.0006). A similar gradient in mIS was observed within clinically quiescent patients, for whom moderate/strong modular scores (2 or 3 active IFN modules) were associated with higher anti-dsDNA titers and lower lymphocyte count than patients with absent/mild modular scores (0 or 1 active IFN modules). Longitudinal analyses (at least 3 consecutive visits, n=29) showed that whereas module M1.2 was very stable (mean coefficient of variation CV=0.05), M3.4 and M5.12 could vary over time in a single patient (mean CV=0.39 and 0.91 respectively). Interestingly, mining of other datasets suggested that M3.4 and M5.12 could be also driven by INF-b and g. <h3>Conclusions</h3> Modular repertoire analysis reveals complex IFN signatures in SLE, not restricted to the previous IFN-a signature, but involving also b and g IFNs. These modular IFN signatures may help in the design of disease activity biomarkers. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2405