Antitumor Necrosis Factor Therapy Is Associated With Improved Survival in Clinical Sepsis Trials

Abstract

Background Sepsis is a lethal syndrome annually affecting ~900,000 patients in the United States alone. Despite their benefit in rheumatoid disease, selective anti-tumor necrosis factor (anti-TNF) agents failed to improve outcome in early sepsis trials in the 1990’s. However, data from additional sepsis trials testing these agents is now available. Purpose To determine the effect on survival of selective anti-TNF agents in randomized clinical sepsis trials. Data Sources PubMed, Scopus, EMBASE, and Web of Science. Study Selection Randomized human sepsis trials of selective anti-TNF agents reporting survival rates. Data Synthesis Two investigators independently collected relevant data on study characteristics, treatment interventions, and patient from each study. Results Anti-TNF agents in 15 sepsis trials (n=8,896 patients) meeting inclusion criteria had similar effects (I2=0, p=0.84) and compared to controls (placebo in 14 trials or a lower dose in 1 trial) overall decreased the relative risk (RR) of death (95% CI) [0.93 (0.88, 0.98), p=0.01]. In subgroup analysis, TNF monoclonal antibodies (10 trials, n=6,818) alone produced a significant survival benefit [0.93 (0.87, 0.99), p=0.02] (I2=0, p=0.83). TNF polyclonal antibodies (2 trials, n=151) and low molecular weight soluble receptor (2 trials, n=1,786) had similar beneficial effects to anti-TNF agents overall [0.82(0.49, 1.37), p=0.45; 0.93(0.81, 1.08), p=0.33, respectively]. The effect of TNF high molecular weight soluble receptor (1 trial, n=141) was not significantly different from other agents but was on the side of harm [1.50 (0.86, 2.61), p=0.16]. Limitations Limited secondary end-point data. Conclusion Anti-TNF agents produced a modest but significant decrease in the risk of dying with sepsis. Prior individual trials failed to demonstrate benefit, likely because they were underpowered. A definitive trial demonstrating the potential benefit of such agents might require 10,000 or more septic patients.

Serious infection across biologic-treated patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis

“…Many of the initial trials of anti-TNF in sepsis found no significant change in the mortality rates but they may have been underpowered. A recent meta-analysis has shown a small but significant reduction in mortality with anti-TNF among patients with sepsis 19. These clinical trials were looking at the benefit of giving a single dose of anti-TNF to patients who already had developed sepsis.…”

Clinical Utility of Extracorporeal Cytokine Hemoadsorption Therapy: A Literature Review

“…Although the clinical efficacy of anti-TNF-α therapy remains disputed, there is some evidence that it may reduce the number of days of mechanical ventilation and days in the intensive care unit in patients with severe sepsis [38]. Two meta-analyses also demonstrated that anti-TNF-α therapy is associated with a significant decrease in sepsis-related mortality [39,40]. A large, multicenter randomized follow-up trial may be warranted to confirm these benefits and to evaluate the incidence of drug-related side effects.…”

Abandon the Mouse Research Ship? Not Just Yet!

“…After “successfully” executing various treatments (i.e., against circulating cytokines or endotoxins) in the mouse (98), rat (102), rabbit (103), dog (104) and non-human primates (105), the striking failure of similar anti-inflammatory therapeutic protocols in septic patients has brought a painful realization that injecting mice and other species with a lethal dose of bacterial LPS is not a good predictive model for a typical human sepsis. It must be stressed, however, that a complete renouncement of anti-inflammatory treatments based on the failed trials would be equally short sighted and the most recent meta-analysis argues that application of anti-TNF agents in septic patients should be revisited (106). It has become clear that responses elicited in sepsis are highly mixed and the immunosuppressive component frequently exceeds hyperinflammation (107).…”