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

Arndt H Brachat; Alexei A Grom; Nico Wulffraat; Hermine I Brunner; Pierre Quartier; Riva Brik; Liza McCann; Huri Ozdogan; Lidia Rutkowska-Sak; Rayfel Schneider; Valeria Gerloni; Liora Harel; Maria Terreri; Kristin Houghton; Rik Joos; Daniel Kingsbury; Jorge M Lopez-Benitez; Stephan Bek; Martin Schumacher; Marie-Anne Valentin; Hermann Gram; Ken Abrams; Alberto Martini; Daniel J Lovell; Nanguneri R Nirmala; Nicolino Ruperto; Pediatric Rheumatology International Trials Organization (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG)

doi:10.1186/s13075-016-1212-x

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

Arndt H Brachat, Alexei A Grom, Nico Wulffraat, Hermine I Brunner, Pierre Quartier, Riva Brik, Liza McCann, Huri Ozdogan, Lidia Rutkowska-Sak, Rayfel Schneider, Valeria Gerloni, Liora Harel, Maria Terreri, Kristin Houghton, Rik Joos, Daniel Kingsbury, Jorge M Lopez-Benitez, Stephan Bek, Martin Schumacher, Marie-Anne ValentinHermann Gram, Ken Abrams, Alberto Martini, Daniel J Lovell, Nanguneri R Nirmala, Nicolino Ruperto, Pediatric Rheumatology International Trials Organization (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG)

Istituto "Giannina Gaslini"

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: Canakinumab 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).

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-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).

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.

TRIAL REGISTRATION: Clinicaltrials.gov: NCT00886769 (trial 1). Registered on 22 April 2009; NCT00889863 (trial 2). Registered on 21 April 2009.

Original language	English
Pages (from-to)	13
Journal	Arthritis Research and Therapy
Volume	19
Issue number	1
DOIs	https://doi.org/10.1186/s13075-016-1212-x
Publication status	Published - Jan 23 2017

Keywords

Adolescent
Antibodies, Monoclonal
Arthritis, Juvenile
Child
Child, Preschool
Down-Regulation
Female
Gene Expression Profiling
Humans
Immunoassay
Interleukin-18
Interleukin-6
Male
Oligonucleotide Array Sequence Analysis
Transcriptome
Young Adult
Clinical Trial, Phase III
Journal Article
Randomized Controlled Trial

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10.1186/s13075-016-1212-x

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Brachat, A. H., Grom, A. A., Wulffraat, N., Brunner, H. I., Quartier, P., Brik, R., McCann, L., Ozdogan, H., Rutkowska-Sak, L., Schneider, R., Gerloni, V., Harel, L., Terreri, M., Houghton, K., Joos, R., Kingsbury, D., Lopez-Benitez, J. M., Bek, S., Schumacher, M., ... Pediatric Rheumatology International Trials Organization (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG) (2017). Early changes in gene expression and inflammatory proteins in systemic juvenile idiopathic arthritis patients on canakinumab therapy. Arthritis Research and Therapy, 19(1), 13. https://doi.org/10.1186/s13075-016-1212-x

Brachat, AH, Grom, AA, Wulffraat, N, Brunner, HI, Quartier, P, Brik, R, McCann, L, Ozdogan, H, Rutkowska-Sak, L, Schneider, R, Gerloni, V, Harel, L, Terreri, M, Houghton, K, Joos, R, Kingsbury, D, Lopez-Benitez, JM, Bek, S, Schumacher, M, Valentin, M-A, Gram, H, Abrams, K, Martini, A, Lovell, DJ, Nirmala, NR, Ruperto, N & Pediatric Rheumatology International Trials Organization (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG) 2017, 'Early changes in gene expression and inflammatory proteins in systemic juvenile idiopathic arthritis patients on canakinumab therapy', Arthritis Research and Therapy, vol. 19, no. 1, pp. 13. https://doi.org/10.1186/s13075-016-1212-x

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abstract = "BACKGROUND: Canakinumab 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).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-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).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.TRIAL REGISTRATION: Clinicaltrials.gov: NCT00886769 (trial 1). Registered on 22 April 2009; NCT00889863 (trial 2). Registered on 21 April 2009.",

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author = "Brachat, {Arndt H} and Grom, {Alexei A} and Nico Wulffraat and Brunner, {Hermine I} and Pierre Quartier and Riva Brik and Liza McCann and Huri Ozdogan and Lidia Rutkowska-Sak and Rayfel Schneider and Valeria Gerloni and Liora Harel and Maria Terreri and Kristin Houghton and Rik Joos and Daniel Kingsbury and Lopez-Benitez, {Jorge M} and Stephan Bek and Martin Schumacher and Marie-Anne Valentin and Hermann Gram and Ken Abrams and Alberto Martini and Lovell, {Daniel J} and Nirmala, {Nanguneri R} and Nicolino Ruperto and {Pediatric Rheumatology International Trials Organization (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG)}",

year = "2017",

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doi = "10.1186/s13075-016-1212-x",

language = "English",

volume = "19",

pages = "13",

journal = "Arthritis Research and Therapy",

issn = "1478-6354",

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TY - JOUR

T1 - Early changes in gene expression and inflammatory proteins in systemic juvenile idiopathic arthritis patients on canakinumab therapy

AU - Brachat, Arndt H

AU - Grom, Alexei A

AU - Wulffraat, Nico

AU - Brunner, Hermine I

AU - Quartier, Pierre

AU - Brik, Riva

AU - McCann, Liza

AU - Ozdogan, Huri

AU - Rutkowska-Sak, Lidia

AU - Schneider, Rayfel

AU - Gerloni, Valeria

AU - Harel, Liora

AU - Terreri, Maria

AU - Houghton, Kristin

AU - Joos, Rik

AU - Kingsbury, Daniel

AU - Lopez-Benitez, Jorge M

AU - Bek, Stephan

AU - Schumacher, Martin

AU - Valentin, Marie-Anne

AU - Gram, Hermann

AU - Abrams, Ken

AU - Martini, Alberto

AU - Lovell, Daniel J

AU - Nirmala, Nanguneri R

AU - Ruperto, Nicolino

AU - Pediatric Rheumatology International Trials Organization (PRINTO) and the Pediatric Rheumatology Collaborative Study Group (PRCSG)

PY - 2017/1/23

Y1 - 2017/1/23

N2 - BACKGROUND: Canakinumab 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).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-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).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.TRIAL REGISTRATION: Clinicaltrials.gov: NCT00886769 (trial 1). Registered on 22 April 2009; NCT00889863 (trial 2). Registered on 21 April 2009.

AB - BACKGROUND: Canakinumab 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).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-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).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.TRIAL REGISTRATION: Clinicaltrials.gov: NCT00886769 (trial 1). Registered on 22 April 2009; NCT00889863 (trial 2). Registered on 21 April 2009.

KW - Adolescent

KW - Antibodies, Monoclonal

KW - Arthritis, Juvenile

KW - Child

KW - Child, Preschool

KW - Down-Regulation

KW - Female

KW - Gene Expression Profiling

KW - Humans

KW - Immunoassay

KW - Interleukin-18

KW - Interleukin-6

KW - Male

KW - Oligonucleotide Array Sequence Analysis

KW - Transcriptome

KW - Young Adult

KW - Clinical Trial, Phase III

KW - Journal Article

KW - Randomized Controlled Trial

U2 - 10.1186/s13075-016-1212-x

DO - 10.1186/s13075-016-1212-x

M3 - Article

C2 - 28115015

VL - 19

SP - 13

JO - Arthritis Research and Therapy

JF - Arthritis Research and Therapy

SN - 1478-6354

IS - 1

ER -

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

Abstract

Keywords

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