Deficient spontaneous in vitro apoptosis and increased tmTNF reverse signaling-induced apoptosis of monocytes predict suboptimal therapeutic response of rheumatoid arthritis to TNF inhibition
Deficient spontaneous in vitro apoptosis and increased tmTNF reverse signaling-induced apoptosis of monocytes predict suboptimal therapeutic response of rheumatoid arthritis to TNF inhibition
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DOI：
10.1186/ar4416
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发表时间：
2013-01-01
影响因子：
4.9
通讯作者：
Wagner, Ulf
中科院分区：
文献类型：
--
作者：
Meusch, Undine;Klingner, Maria;Wagner, Ulf
简介：类风湿关节炎（RA）患者外周血单核细胞凋亡受到细胞因子产生和跨膜TNF（tmTNF）反向信号的干扰和影响。本研究的目的是分析体外细胞凋亡率对抗TNF治疗的治疗反应的预测价值。方法：在开始用依那西普进行治疗性TNF抑制之前，在20名RA患者的单核细胞中体外测定自发和tmTNF反向信号诱导的细胞凋亡，并监测随后的临床反应。与对照组相比，RA患者的体外自发细胞凋亡显著减少。根据欧洲抗风湿联盟（EULAR）反应标准，自发性细胞凋亡的缺乏与治疗反应不足相关，疾病活动评分（DAS）28确定的疾病活动减少较少。对反向信号诱导的细胞凋亡的高度敏感性也与DAS 28的降低效率较低相关。值得注意的是，两个凋亡参数之间的强负相关性是可辨别的，可能指示两个致病相关过程相互反调节。tmTNF反向信号诱导的可溶性IL 1-RI和IL-1 RII只在单核细胞的体外生产不缺乏自发性凋亡，和可溶性IL 1-RII的水平被发现是一个良好的临床反应Etanercept.Conclusion预测：虽然tmTNF反向信号是能够诱导RA单核细胞在体外的凋亡，这个过程似乎发生在体外优先在患者次优的治疗反应。相反，对体外自发凋亡的抵抗是对治疗反应不足的预测因子。
Introduction: In vitro apoptosis of peripheral monocytes in rheumatoid arthritis (RA) is disturbed and influenced by cytokine production and transmembrane TNF (tmTNF) reverse signaling. The goal of the study was the analysis of the predictive value of the rate of in vitro apoptosis for the therapeutic response to anti-TNF treatment.Methods: Spontaneous and tmTNF reverse signaling-induced apoptosis were determined in vitro in monocytes from 20 RA patients prior to initiation of therapeutic TNF inhibition with etanercept, and the subsequent clinical response was monitored.Results: Spontaneous in vitro apoptosis was significantly reduced in RA patients compared to controls. Deficiency in spontaneous apoptosis was associated with an insufficient therapeutic response according to the European League Against Rheumatism (EULAR) response criteria and less reduction of the disease activity determined by disease activity score (DAS) 28. High susceptibility to reverse signaling-induced apoptosis was also associated with less efficient reduction in the DAS28. Of note, a strong negative correlation between the two apoptotic parameters was discernible, possibly indicative of two pathogenetically relevant processes counter-regulating each other. tmTNF reverse signaling induced in vitro production of soluble IL1-RI and IL-1RII only in monocytes not deficient in spontaneous apoptosis, and the levels of soluble IL1-RII were found to be predictive of a good clinical response to Etanercept.Conclusion: Although tmTNF reverse signaling is able to induce apoptosis of RA monocytes in vitro, this process appears to occur in vitro preferentially in patients with suboptimal therapeutic response. Resistance to spontaneous in vitro apoptosis, in contrast, is a predictor of insufficient response to treatment.