Evidence of a role of tumor necrosis factor alpha in refractory asthma

N Engl J Med. 2006 Feb 16;354(7):697-708. doi: 10.1056/NEJMoa050580.


Background: The development of tumor necrosis factor alpha (TNF-alpha) antagonists has made it feasible to investigate the role of this cytokine in refractory asthma.

Methods: We measured markers of TNF-alpha activity on peripheral-blood monocytes in 10 patients with refractory asthma, 10 patients with mild-to-moderate asthma, and 10 control subjects. We also investigated the effects of treatment with the soluble TNF-alpha receptor etanercept (25 mg twice weekly) in the patients with refractory asthma in a placebo-controlled, double-blind, crossover pilot study.

Results: As compared with patients with mild-to-moderate asthma and controls, patients with refractory asthma had increased expression of membrane-bound TNF-alpha, TNF-alpha receptor 1, and TNF-alpha-converting enzyme by peripheral-blood monocytes. In the clinical trial, as compared with placebo, 10 weeks of treatment with etanercept was associated with a significant increase in the concentration of methacholine required to provoke a 20 percent decrease in the forced expiratory volume in one second (FEV1) (mean difference in doubling concentration changes between etanercept and placebo, 3.5; 95 percent confidence interval, 0.07 to 7.0; P=0.05), an improvement in the asthma-related quality-of-life score (by 0.85 point; 95 percent confidence interval, 0.16 to 1.54 on a 7-point scale; P=0.02), and a 0.32-liter increase in post-bronchodilator FEV1 (95 percent confidence interval, 0.08 to 0.55; P=0.01).

Conclusions: Patients with refractory asthma have evidence of up-regulation of the TNF-alpha axis. (ClinicalTrials.gov number, NCT00276029.).

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / biosynthesis
  • ADAM17 Protein
  • Adolescent
  • Adult
  • Aged
  • Asthma / drug therapy*
  • Asthma / metabolism*
  • Asthma / physiopathology
  • Biomarkers / metabolism
  • Bronchial Hyperreactivity / drug therapy
  • Bronchial Hyperreactivity / metabolism
  • Case-Control Studies
  • Cross-Over Studies
  • Double-Blind Method
  • Etanercept
  • Female
  • Forced Expiratory Volume / drug effects
  • Humans
  • Immunoglobulin G / therapeutic use*
  • Immunologic Factors / therapeutic use
  • Male
  • Methacholine Chloride
  • Middle Aged
  • Monocytes / metabolism
  • Pilot Projects
  • Receptors, Tumor Necrosis Factor / therapeutic use*
  • Receptors, Tumor Necrosis Factor, Type I / biosynthesis
  • Treatment Outcome
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / metabolism*
  • Up-Regulation


  • Biomarkers
  • Immunoglobulin G
  • Immunologic Factors
  • Receptors, Tumor Necrosis Factor
  • Receptors, Tumor Necrosis Factor, Type I
  • Tumor Necrosis Factor-alpha
  • Methacholine Chloride
  • ADAM Proteins
  • ADAM17 Protein
  • Etanercept

Associated data

  • ClinicalTrials.gov/NCT00276029