Brachat Arndt H, Grom Alexei A, Wulffraat Nico, Brunner Hermine I, Quartier Pierre, Brik Riva, McCann Liza, Ozdogan Huri, Rutkowska-Sak Lidia, Schneider Rayfel, Gerloni Valeria, Harel Liora, Terreri Maria, Houghton Kristin, Joos Rik, Kingsbury Daniel, Lopez-Benitez Jorge M, Bek Stephan, Schumacher Martin, Valentin Marie-Anne, Gram Hermann, Abrams Ken, Martini Alberto, Lovell Daniel J, Nirmala Nanguneri R, Ruperto Nicolino
Novartis Institutes for Biomedical Research, Basel, Switzerland.
Cincinnati Children's Hospital Medical Center, PRCSG, Cincinnati, OH, USA.
Arthritis Res Ther. 2017 Jan 23;19(1):13. doi: 10.1186/s13075-016-1212-x.
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).
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.
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).
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.
Clinicaltrials.gov: NCT00886769 (trial 1). Registered on 22 April 2009; NCT00889863 (trial 2). Registered on 21 April 2009.
卡那单抗是一种人抗白细胞介素-1β（IL-1β）单克隆抗体，可中和IL-1β介导的信号通路。我们试图通过两项系统性幼年特发性关节炎（SJIA）关键试验的样本，来描述对卡那单抗的分子反应，并评估反应的潜在标志物。
采用Affymetrix DNA微阵列检测发热性SJIA患者及匹配的健康对照者的基因表达。根据改良的幼年特发性关节炎美国风湿病学会（aACR）反应标准（50 aACR JIA），通过从基线到第3天的基因表达变化评估转录反应。在第197天之前评估促炎细胞因子IL-6和IL-18的变化。
微阵列分析确定，患者与对照相比有984个探针集差异表达（差异≥2倍；P < 0.05）。超过50%的达到≥50 aACR JIA的患者可通过基线表达值识别。对在第15天达到≥50 aACR JIA反应的患者的基因表达谱分析确定，在第3天与基线相比，有102个探针集在治疗后差异表达（差异≥2倍；P < 0.05），包括IL-1β、IL-1受体（IL1-R1和IL1-R2）、IL-1受体辅助蛋白（IL1-RAP）和IL-6。在基线时失调基因表达较高且在第3天有强烈转录反应的患者中观察到最强的临床反应。IL-6在第3天时下降（下降≥8倍；P < 0.0001）并持续受到抑制。IL-18在第57天时下降（下降≥1.5倍，P≤0.002）。
SJIA患者使用卡那单抗治疗导致固有免疫反应基因下调以及IL-6和临床症状减轻。需要进一步研究以调查基因转录谱异质性患者疾病机制的潜在差异。
Clinicaltrials.gov：NCT00886769（试验1）。于2009年4月22日注册；NCT00889863（试验2）。于2009年4月21日注册。
