OA09 Gene expression analysis reveals distinct ancestry-specific profiles associated with response to rituximab in SLE

Abstract Background/Aims SLE patients of European ancestry frequently have milder and more treatment-responsive disease which is poorly explained. Transcriptional signatures are one approach to stratifying SLE which can distinguish by disease activity, autoantibodies and organ involvement but also vary significantly between patients of different ancestry. We developed two interferon-stimulated gene expression scores (IFN-Score-A and IFN-Score-B) that predict clinical outcomes in SLE. Additional modules of differentially expressed genes associated with disease activity have been described but have not been evaluated for association with ancestry or treatment response. Here, we evaluated the association between pre-defined transcriptional scores for these previously described modules, ancestry and response to B cell depletion with rituximab in a multi-ethnic UK cohort with active SLE. Methods Baseline gene expression was evaluated in pre-treatment whole blood using a customised 96-probe Taqman array in 213 patients with active SLE prospectively enrolled in British Isles Lupus Assessment Group (BILAG) Biologics Register on commencing biologic therapy. Interferon status was evaluated using IFN-Score-A and IFN-Score-B as previously described. Gene expression scores representing Plasmablast, Neutrophil, Myeloid and Inflammation-annotated modules were represented by the median expression of 4-16 genes per annotation. Response to first cycle rituximab was evaluable in 110 patients and was defined by BILAG-2004 criteria at 6 months. Results 128 patients were of European ancestry and 85 were of African ancestry, Subcontinental Asian, East Asian or mixed race. Transcriptional signatures differed between ancestral groups. Patients of European ancestry had lower baseline IFN-scores than non-European ancestries. IFN-scores among European patients were highly correlated with Plasmablast (R2=0.32), Neutrophil (R2=0.54), Myeloid (R2=0.72) and Inflammation (R2=0.62) -annotated scores (p < 0.001). Among patients of non-European ancestry the picture was more heterogeneous; IFN-scores showed no correlation with Neutrophil (R2=0.19, p = 0.08) or Plasmablast (R2=0.02, p = 0.83) scores and their correlation with the other annotations was weaker. Overall BILAG response to rituximab was observed in 70/110 (63%) patients. However, transcript-level hierarchical clustering in non-European ancestry patients revealed distinct profiles for response to rituximab. Cluster 1 were IFN-low and were older with lower serological activity and higher glucocorticoid use. Response to rituximab was observed in only 14%. Cluster 2 were IFN-high with low Neutrophil, Myeloid and Inflammation signatures. 42% achieved a BILAG response to rituximab. Cluster 3 showed globally high expression across all transcript annotations and best response rate to rituximab at 84%. Clusters 2 and 3 were clinically and serologically similar. Clusters derived from European ancestry patients were not significantly associated with response to rituximab but were distinguished by renal involvement. Conclusion We describe distinct transcriptional profiles in a multi-ethnic UK SLE cohort. Baseline gene expression, in particular IFN status, stratified response to rituximab among non-European subjects but was not prognostic among European patients. Development of transcriptional biomarkers should account for ancestral variation. Disclosure L. Carter: None. A. Alase: None. Z. Wigston: None. A. Psarras: None. A. Burska: None. M. Md Yusof: Consultancies; YY has provided consultancy to UCB. J.A. Reynolds: None. M. Wittmann: Consultancies; MW has received consultancy fees from Abbvie, Celgene, Janssen, L’Oreal, Novartis and Pfizer. I. Bruce: Consultancies; IB has provided consultancy to AstraZeneca, Eli Lilly, GlaxoSmithKline, ILTOO Pharma, MedImmune, Merck Serono. Grants/research support; IB has received research funding from Genzyme Sanofi & GlaxoSmithKline. E.M. Vital: Consultancies; MEV has provided Consultancies to Genentech, AstraZeneca, Aurinia, Lilly and Modus Therapeutics. Grants/research support; EMV has received research funding from Astra Zeneca and Sandoz.