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

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

Author Brachat, Arndt H. Google Scholar
Grom, Alexei A. Google Scholar
Wulffraat, Nico Google Scholar
Brunner, Hermine I. Google Scholar
Quartier, Pierre Google Scholar
Brik, Riva Google Scholar
McCann, Liza Google Scholar
Ozdogan, Huri Google Scholar
Rutkowska-Sak, Lidia Google Scholar
Schneider, Rayfel Google Scholar
Gerloni, Valeria Google Scholar
Harel, Liora Google Scholar
Terreri, Maria Autor UNIFESP Google Scholar
Houghton, Kristin Google Scholar
Joos, Rik Google Scholar
Kingsbury, Daniel Google Scholar
Lopez-Benitez, Jorge M. Google Scholar
Bek, Stephan Google Scholar
Schumacher, Martin Google Scholar
Valentin, Marie-Anne Google Scholar
Gram, Hermann Google Scholar
Abrams, Ken Google Scholar
Martini, Alberto Google Scholar
Lovell, Daniel J. Google Scholar
Nirmala, Nanguneri R. Google Scholar
Ruperto, Nicolino Google Scholar
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.
Keywords Biomarkers
Canakinumab
Gene expression
Interleukin-1 beta
Juvenile idiopathic arthritis
SJIA
xmlui.dri2xhtml.METS-1.0.item-coverage London
Language English
Sponsor Novartis Pharma
Date 2017
Published in Arthritis Research & Therapy. London, v. 19, p. -, 2017.
ISSN 1478-6354 (Sherpa/Romeo, impact factor)
Publisher Biomed Central Ltd
Extent -
Origin http://dx.doi.org/10.1186/s13075-016-1212-x
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000396272700003
URI https://repositorio.unifesp.br/handle/11600/55236

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