Distinct Gene Expression Signatures Characterize Strong Clinical Responders Versus Nonresponders to Canakinumab in Children With Systemic Juvenile Idiopathic Arthritis.
Distinct Gene Expression Signatures Characterize Strong Clinical Responders Versus Nonresponders to Canakinumab in Children With Systemic Juvenile Idiopathic Arthritis.
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DOI：
10.1002/art.41640
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发表时间：
2021-07
期刊：
影响因子：
--
通讯作者：
Schulert GS
中科院分区：
文献类型：
--
作者：
Verweyen EL;Pickering A;Grom AA;Schulert GS
Canakinumab是一种人源抗IL-1β阻断剂，可有效中和IL-1β介导的信号传导，用于治疗全身性幼年特发性关节炎（sJIA）。虽然许多患者对IL-1阻断剂有显著的临床反应，但约三分之一的患者没有反应，但目前还没有有效的临床或免疫学反应预测因子。在这里，我们描述了sJIA患者对canakinumab治疗反应和无反应的不同基因特征。我们对健康对照和sJIA患者在基线和治疗后第3天的全血基因表达微阵列进行了二次分析[GEO：GSE 80060]。强临床应答者基于JIA美国流变学会应答标准，定义为≥ ACR 90（无应答者≤ ACR 30）。差异表达分析采用随机效应模型，以患者身份作为随机变量。与无应答者相比，我们在对canakinumab治疗具有强烈临床应答的患者中鉴定了不同的基因表达特征，其由中性粒细胞和IL-1相关基因的上调介导，并且其特征在于随着临床应答的增加而与对照转录组的差异增加。我们还鉴定了一个特征，包括与卡那奴单抗无应答相关的上调的CD 163表达。有趣的是，canakinumab治疗诱导I型IFN基因上调或下调，与临床反应无关。在这里，我们确定了一个基因特征，它在治疗开始前将canakinumab的强应答者与无应答者区分开来。需要进一步的前瞻性研究来评估这些见解对sJIA治疗决策的效用，并跟踪上调的I型IFN信号与sJIA并发症的关联。
Canakinumab is a human anti-IL-1β blocking agent that effectively neutralizes IL-1β mediated signaling for treatment of systemic juvenile idiopathic arthritis (sJIA). While many patients have dramatic clinical response to IL-1 blockade, approximately one-third fail to respond, but there currently exist no validated clinical or immunologic predictors of response. Here, we characterize distinct gene signatures for treatment response and non-response to canakinumab in sJIA patients. We performed a secondary analysis of whole blood gene expression microarrays of healthy controls and sJIA patients during baseline and day 3 after treatment [GEO:GSE80060]. Strong clinical responders were based on the JIA American College of Rheumatology response criteria and defined as ≥ACR90 (≤ACR30 for non-responders). A random effects model with patient identity as the random variable was used for differential expression analysis. We identified a distinct gene expression signature in patients with a strong clinical response to canakinumab treatment as compared to non-responders, mediated by upregulation of neutrophil and IL-1 associated genes, and characterized by increasing divergence from control transcriptomes with increasing clinical response. We also identify a signature including upregulated CD163 expression associated with canakinumab non-response. Intriguingly, canakinumab treatment either induces up- or downregulation of type I IFN genes, independent of clinical response. Here, we identify a gene signature which distinguishes strong responders to canakinumab from non-responders before treatment onset. Further prospective study is needed to assess the utility of these insights for treatment decisions in sJIA and tracking the association of upregulated type I IFN signatures with sJIA complications.
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影响因子：
14.9
作者：
Ritchie ME;Phipson B;Wu D;Hu Y;Law CW;Shi W;Smyth GK
通讯作者：
Smyth GK
影响因子：
158.5
作者：
Lachmann, Helen J.;Kone-Paut, Isabelle;Hawkins, Philip N.
通讯作者：
Hawkins, Philip N.
影响因子：
--
作者：
Ogilvie, Emma Mary;Khan, Arshad;Woo, Patricia
通讯作者：
Woo, Patricia
影响因子：
158.5
作者：
De Benedetti, Fabrizio;Brunner, Hermine I.;Martini, Alberto
通讯作者：
Martini, Alberto
DOI：
10.1084/jem.20050473
发表时间：
2005-05-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Pascual V;Allantaz F;Arce E;Punaro M;Banchereau J
通讯作者：
Banchereau J