Gene expression and autoantibody analysis reveals distinct ancestry-specific profiles associated with response to rituximab in refractory systemic lupus erythematosus

Objective

Gene expression profiles are associated with the clinical heterogeneity of SLE but are not well studied as biomarkers for therapy. Many clinical and demographic features influence treatment responses. We studied gene expression and response to rituximab in a multi-ethnic UK cohort refractory to standard therapy.

Methods

Baseline expression of transcripts known to associate with clinical features of SLE was evaluated in whole blood by 96-probe Taqman® array in patients (n=213) with active SLE, prospectively enrolled in British Isles Lupus Assessment Group (BILAG) Biologics Registry. Autoantibodies were measured using immunoprecipitation and ELISA. Response to first cycle rituximab (n=110) was determined by BILAG-2004 criteria at 6 months.

Results

Interferon scores were lower in European ancestry patients than all other groups. The relationship between blood interferon scores and plasmablast, neutrophil, myeloid, inflammation and erythropoiesis-annotated scores differed between patients of European and non-European ancestries. Hierarchical clustering revealed 3 distinct non-European ancestry patient subsets with stratified response to rituximab which was not explained by sociodemographic and clinical variables. Response was lowest in an interferon-low, neutrophil-high cluster and highest in a cluster with high expression across all signatures (p<0.001). Clusters within European ancestry patients did not predict response to rituximab but segregated patients by global disease activity and renal involvement. In both ancestral groups, interferon-high clusters associated with U1RNP-Sm antibodies.

Conclusion

Ancestry appears central to the immunological and clinical heterogeneity in SLE. These results suggest that ancestry, disease activity and transcriptional signatures could each assist predict the effectiveness of B-cell depletion.