Molecular discrimination of responders and nonresponders to anti-TNF alpha therapy in rheumatoid arthritis by etanercept.
Molecular discrimination of responders and nonresponders to anti-TNF alpha therapy in rheumatoid arthritis by etanercept.
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DOI：
10.1186/ar2419
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发表时间：
2008
影响因子：
4.9
通讯作者：
Thiesen HJ
中科院分区：
文献类型：
--
作者：
Koczan D;Drynda S;Hecker M;Drynda A;Guthke R;Kekow J;Thiesen HJ
大约 30% 的类风湿性关节炎患者对 TNFα 阻断疗法没有充分反应。医学和社会经济需要识别分子标记以早期预测应答者和无应答者。在首次使用 TNFα 阻滞剂依那西普之前以及 72 小时后，从 19 名类风湿关节炎患者的外周血单核细胞中提取 RNA。使用 28 关节计数疾病活动评分和 X 射线扫描评估 3 个月内的临床反应。将监督学习方法应用于 Affymetrix 人类基因组 U133 微阵列数据分析，以确定与临床结果具有预后相关性的高度选择性辨别基因对或三联体，通过 28 关节计数疾病活动评分下降 1.2 来证明。继发于 TNFα 中和的早期表达水平下调与良好的临床反应相关，如治疗开始 3 个月后总体疾病活动度下降所示。信息丰富的基因集包括参与不同途径和细胞过程的基因（例如 NFKBIA、CCL4、IL8、IL1B、TNFAIP3、PDE4B、PPP1R15A 和 ADM），例如通过 NFκB 进行的 TNFα 信号传导、通过 cAMP 进行的不依赖于 NFκB 的信号传导，以及细胞和氧化应激反应的调节。这些基因对和三联体被发现具有很高的预后价值，7 个选定基因对的预测准确度超过 89%，10 个特定基因三联体的预测准确度超过 95%。我们的数据强调，早期基因表达谱有助于识别候选生物标志物，以预测抗 TNFα 治疗方案的治疗结果。
About 30% of rheumatoid arthritis patients fail to respond adequately to TNFα-blocking therapy. There is a medical and socioeconomic need to identify molecular markers for an early prediction of responders and nonresponders. RNA was extracted from peripheral blood mononuclear cells of 19 rheumatoid arthritis patients before the first application of the TNFα blocker etanercept as well as after 72 hours. Clinical response was assessed over 3 months using the 28-joint-count Disease Activity Score and X-ray scans. Supervised learning methods were applied to Affymetrix Human Genome U133 microarray data analysis to determine highly selective discriminatory gene pairs or triplets with prognostic relevance for the clinical outcome evinced by a decline of the 28-joint-count Disease Activity Score by 1.2. Early downregulation of expression levels secondary to TNFα neutralization was associated with good clinical responses, as shown by a decline in overall disease activity 3 months after the start of treatment. Informative gene sets include genes (for example, NFKBIA, CCL4, IL8, IL1B, TNFAIP3, PDE4B, PPP1R15A and ADM) involved in different pathways and cellular processes such as TNFα signalling via NFκB, NFκB-independent signalling via cAMP, and the regulation of cellular and oxidative stress response. Pairs and triplets within these genes were found to have a high prognostic value, reflected by prediction accuracies of over 89% for seven selected gene pairs and of 95% for 10 specific gene triplets. Our data underline that early gene expression profiling is instrumental in identifying candidate biomarkers to predict therapeutic outcomes of anti-TNFα treatment regimes.
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DOI：
10.1186/ar395
发表时间：
2002
期刊：
Arthritis research
影响因子：
--
作者：
van Boekel MA;Vossenaar ER;van den Hoogen FH;van Venrooij WJ
通讯作者：
van Venrooij WJ
影响因子：
5.5
作者：
Catrina, AI;Lampa, J;Ulfgren, AK
通讯作者：
Ulfgren, AK
影响因子：
30.8
作者：
Spielman, Richard S.;Bastone, Laurel A.;Cheung, Vivian G.
通讯作者：
Cheung, Vivian G.
影响因子：
27.4
作者：
Drynda, S;Kühne, C;Kekow, J
通讯作者：
Kekow, J
英夫利昔单抗对类风湿关节炎患者滑膜组织 mRNA 表达谱的影响。
影响因子：
4.9
作者：
Lindberg, Johan;af Klint, Erik;Catrina, Anca Irinel;Nilsson, Peter;Klareskog, Lars;Ulfgren, Ann-Kristin;Lundeberg, Joakim
通讯作者：
Lundeberg, Joakim