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

Abstract

BackgroundCanakinumab is a human anti-interleukin-1β (IL-1β) monoclonal antibody neutralizing IL-1β-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).MethodsGene 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.ResultsMicroarray 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-1β, 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).ConclusionsTreatment 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.Trial registrationClinicaltrials.gov: NCT00886769 (trial 1). Registered on 22 April 2009; NCT00889863 (trial 2). Registered on 21 April 2009.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1212-x) contains supplementary material, which is available to authorized users.

Transcriptional response modules characterise IL-1β and IL-6 activity in COVID-19

“…These are conditions in which elevated IL-1 and IL-6 activity are considered to play a key role in disease pathogenesis, evidenced by clinical improvement following therapeutic antagonism of these cytokines (22)(23)(24)(25). The blood transcriptome of untreated JIA patients displayed elevated IL-1 and IL-6 bioactivity (fig 2A) (26), but this was not consistently evident in several RA blood transcriptome datasets (fig S1) (27)(28)(29).…”

“…We used the elevated cytokine activity in the blood of JIA patients to test the hypothesis that therapeutic cytokine modulation would result in changes in cytokine bioactivity as determined by module expression. We made use of the blood transcriptome of JIA patients 3 days following administration of canakinumab, a human monoclonal antibody to IL-1β (26). Patients who had a therapeutic response to canakinumab showed elevated IL-1 module expression which reduced 3 days after canakinumab administration ( fig 3A).…”

NFIL3 mutations alter immune homeostasis and sensitise for arthritis pathology

“…JIA shows similarities to adult autoimmune diseases, and, indeed, genome-wide association studies identify a strong overlap in the common variants linked to autoimmune susceptibility and JIA susceptibility 1. JIA also has similarities to autoinflammatory diseases, such as genetic associations to innate inflammatory pathways2 and response to IL-1β blockade 3. The recent success in identifying monogenic causes of autoinflammatory diseases4 suggests that monogenic causes may also underlie a subset of patients with JIA.…”

Transcription factor motif enrichment in whole transcriptome analysis identifies STAT4 and BCL6 as the most prominent binding motif in systemic juvenile idiopathic arthritis

“…Peripheral blood mononuclear cells (PBMC) and monocytic cells from patients with active sJIA have been analyzed in gene expression studies and have been shown to have a variable RNA expression pattern in patients with sJIA compared to healthy controls, patients with other autoimmune diseases, and patients with other subtypes of JIA, with uneven results [ 4 , 5 ]. With the exception of a recent study looking at RNA expression in patient samples from two clinical trials of canakinumab, these studies have so far only used a cross-sectional approach, and patients with sJIA were not stratified according to their disease activity [ 6 ].…”