Meta-analysis of Anti-TNF Therapies in Clinical Sepsis Trials

尽管常规治疗，感染引起脓毒症和脓毒性休克与高死亡率相关。脓毒症的发病率也在上升，与几个因素有关。尽管在20世纪90年代期间使用介质选择性抗炎剂作为脓毒症的连续治疗的临床经验令人失望，但过度的宿主炎症仍然被认为是脓毒症的重要致病机制。这一点通过正在进行的和拟议的针对这种反应中的组分（例如皮质类固醇、阿托伐他汀、重组人活化蛋白C5）的治疗的临床脓毒症试验得到强调。这些试剂之一是AZD 9773（AstraZeneca），一种针对人肿瘤坏死因子（TNF）的多克隆抗体（ClinicalTrials.gov标识符：NCT 01145560和NCT 01144624）。 业界对选择性TNF抑制剂治疗脓毒症的持续兴趣可能是出乎意料的。在20世纪90年代，当业界对开发脓毒症的介质选择性抗炎疗法有很高的热情时，抗TNF药物是研究最多的。然而，尽管临床前研究结果很有希望，但在10多项随机对照试验（RCT）中，选择性TNF抑制剂几乎没有获益。然而，从总体上看，这种方法似乎确实有潜在的好处。然而，目前尚未对这一整个经历进行系统分析，这一经历目前包括15项审判。 鉴于抗炎药在脓毒症中的应用持续受到关注，以及正在进行的AZD 9773（专门针对TNF）研究，因此有必要全面系统地回顾抗TNF药在脓毒症中的既往经验。本项目的目的是进行这样的分析，不仅检查这类药物对生存的总体影响，而且检查对其他结果的影响，如休克的逆转、器官损伤的预防和潜在的不良反应。此外，还进行了系统分析，以确定是否存在更适合这种治疗的潜在有益作用的可识别患者亚组。 该分析表明，在所检查的试验中，总体抗TNF药物显示出高度一致和显著的获益。然而，虽然在大多数研究中，抗TNF治疗确实导致TNF水平降低，但无法检测到其他变化，如休克或器官损伤的逆转，从而为这种对生存的有益作用提供依据。 这项研究的结果在2012年安非他明类兴奋剂国际会议上作了介绍，介绍这项工作的手稿已经提交，正在考虑出版。

Despite conventional therapy, infection causing sepsis and septic shock is associated with a high mortality rate. The incidence of sepsis is also rising related to several factors. Despite a disappointing clinical experience with mediator-selective anti-inflammatory agents as adjunctive treatments for sepsis during the 1990s, excessive host inflammation is still considered an important pathogenic mechanism underlying sepsis. This point is highlighted by ongoing and proposed clinical sepsis trials of therapies targeting components in this response (e.g. corticosteroids, Eritoran tetrasodium, recombinant human activated protein C5). One of these agents is AZD9773 (AstraZeneca), a polyclonal antibody directed against human tumor necrosis factor- (TNF) (ClinicalTrials.gov identifier: NCT01145560 and NCT01144624). Continued industry interest in selective TNF inhibitors for sepsis might be unexpected. During the 1990s when there was high industry enthusiasm for the development of mediator-selective anti-inflammatory therapies for sepsis, anti-TNF agents were the most studied. Despite promising preclinical findings however, selective TNF inhibitors showed little benefit in more than 10 randomized controlled trials (RCT). However, when examined overall, there does appear to be potential benefit with this approach. At this time however, a systematic analysis of this entire experience, which now includes 15 trials, has not been undertaken. In light of continued interest in the application of anti-inflammatory agents for sepsis and with the ongoing studies of AZD9773, which is directed specifically at TNF, it is relevant to systematically review the prior experience with anti-TNF agents in sepsis in its entirety. The purpose of the present project has been to do such an analysis, examining not only the overall effect of this type of agent on survival, but on other outcomes such as reversal of shock, prevention of organ injury and potential adverse effects. In addition, systematic analysis has been performed to determine whether there are identifiable patient subgroups which are more amenable to the potential beneficial effects of this type of therapy. This analysis shows that overall anti-TNF agents showed highly consistent and significant benefit across the trials examined. However, while anti-TNF therapies did result in reductions in TNF levels in most studies in which this was examined, other changes such as reversal of shock or organ injury, could not be detected to provide a basis for this beneficial effect on survival. Findings from this study were presented at the 2012 ATS International Conference and a manuscript describing the work has been submitted and is under consideration of publication.