Early changes in gene expression and inflammatory proteins in systemic juvenile idiopathic arthritis patients on canakinumab therapy

Abstract

Background: Canakinumab is a human anti-interleukin-1 beta (IL-1 beta) monoclonal antibody neutralizing IL-1 beta-mediated pathways. We sought to characterize the molecular response to canakinumab and evaluate potential markers of response using samples from two pivotal trials in systemic juvenile idiopathic arthritis (SJIA). Methods: Gene expression was measured in patients with febrile SJIA and in matched healthy controls by Affymetrix DNA microarrays. Transcriptional response was assessed by gene expression changes from baseline to day 3 using adapted JIA American College of Rheumatology (aACR) response criteria (50 aACR JIA). Changes in pro-inflammatory cytokines IL-6 and IL-18 were assessed up to day 197. Results: Microarray analysis identified 984 probe sets differentially expressed (>= 2-fold difference

P < 0.05) in patients versus controls. Over 50% of patients with >= 50 aACR JIA were recognizable by baseline expression values. Analysis of gene expression profiles from patients achieving = 50 aACR JIA response at day 15 identified 102 probe sets differentially expressed upon treatment (>= 2-fold difference

P < 0.05) on day 3 versus baseline, including IL-1 beta, IL-1 receptors (IL1-R1 and IL1-R2), IL-1 receptor accessory protein (IL1-RAP), and IL-6. The strongest clinical response was observed in patients with higher baseline expression of dysregulated genes and a strong transcriptional response on day 3. IL-6 declined by day 3 (>= 8-fold decline

P < 0.0001) and remained suppressed. IL-18 declined on day 57 (>= 1.5-fold decline, P <= 0.002). Conclusions: Treatment with canakinumab in SJIA patients resulted in downregulation of innate immune response genes and reductions in IL-6 and clinical symptoms. Additional research is needed to investigate potential differences in the disease mechanisms in patients with heterogeneous gene transcription profiles.