Background/Purpose: Canakinumab is a human anti-IL1β blocking agent that effectively neutralizes IL1β mediated signaling and is used to treat diseases such as systemic juvenile idiopathic arthritis (sJIA). To date there is no predictive analysis that can identify patients that respond to canakinumab or those that do not respond, requiring alternative treatments.  Here, we investigate and characterize a potentially predictive gene signature for treatment response to canakinumab in sJIA patients.

Methods: Whole blood gene expression of healthy controls and patients with sJIA during baseline (day 0, before treatment) and day 3 after treatment onset was previously measured by Affymetrix DNA microarrays [GEO:GSE80060]. Strong responders were based on the JIA American College of Rheumatology (aACR) response criteria and defined as >90, while non-responders were defined as < 30. A random effects model with patient identity as the random variable was used for differential expression analysis.

Results: We identified a distinct gene expression signature in patients with strong clinical response to canakinumab treatment vs non-responders. This signature was characterized by a severely dysregulated gene profile at baseline, and the degree of clinical response (ACR 90/100 vs 50/70 vs 30/0) correlated with upregulation of this signature. The gene profile of responders was mediated by significant (adj. P-val ≤0.05) upregulation of neutrophil and IL1β related genes, as well as Toll-like-receptor and inflammasome associated genes. In line with this, GO pathway analysis top upregulated pathway was ficolin-1-rich granule membrane (P-val 5.74E-13), representing neutrophil activation. Interestingly, while there was no direct upregulation of IL-6 or of IFNγ, SOCS3 was upregulated. Upon treatment initiation, early changes by day 3 in the gene expression profile of the responders were highlighted by significantly decreased expression of these above noted genes and pathways. Interestingly, CD163, a marker for polarization of haemophagocytic macrophages that is upregulated in sJIA-MAS (Macrophage activation syndrome) and sJIA-LD (lung disease), was among the genes upregulated in non-responders, and was not affected by treatment, suggesting IL-1-independent gene pathways in these patients.

Conclusion: Here, we identify several genes and gene pathways whose expression levels distinguish high clinical responders to IL-1 blockade from non-responders before treatment onset. Further study is needed to assess this potentially valuable tool aiding treatment decisions in sJIA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/distinct-gene-signature-predicts-strong-clinical-responses-to-canakinumab-in-children-with-systemic-juvenile-idiopathic-arthritis/