Distinct gene expression signatures characterize strong clinical responders vs non-responders to Canakinumab in children with sJIA

Canakinumab is a human anti-IL-1β blocking agent that effectively neutralizes IL-1β mediated signaling for treatment of systemic juvenile idiopathic arthritis (sJIA). While many patients have dramatic clinical response to IL-1 blockade, approximately one-third fail to respond, but there currently exist no validated clinical or immunologic predictors of response. Here, we characterize distinct gene signatures for treatment response and non-response to canakinumab in sJIA patients. We performed a secondary analysis of whole blood gene expression microarrays of healthy controls and sJIA patients during baseline and day 3 after treatment [GEO:GSE80060]. Strong clinical responders were based on the JIA American College of Rheumatology response criteria and defined as ≥ACR90 (≤ACR30 for non-responders). A random effects model with patient identity as the random variable was used for differential expression analysis. We identified a distinct gene expression signature in patients with a strong clinical response to canakinumab treatment as compared to non-responders, mediated by upregulation of neutrophil and IL-1 associated genes, and characterized by increasing divergence from control transcriptomes with increasing clinical response. We also identify a signature including upregulated CD163 expression associated with canakinumab non-response. Intriguingly, canakinumab treatment either induces up- or downregulation of type I IFN genes, independent of clinical response. Here, we identify a gene signature which distinguishes strong responders to canakinumab from non-responders before treatment onset. Further prospective study is needed to assess the utility of these insights for treatment decisions in sJIA and tracking the association of upregulated type I IFN signatures with sJIA complications.