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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. ( number, NCT00276029.).

Original publication




Journal article


N Engl J Med

Publication Date





697 - 708


ADAM Proteins, ADAM17 Protein, Adolescent, Adult, Aged, Asthma, Biomarkers, Bronchial Hyperreactivity, Case-Control Studies, Cross-Over Studies, Double-Blind Method, Etanercept, Female, Forced Expiratory Volume, Humans, Immunoglobulin G, Immunologic Factors, Male, Methacholine Chloride, Middle Aged, Monocytes, Pilot Projects, Receptors, Tumor Necrosis Factor, Receptors, Tumor Necrosis Factor, Type I, Treatment Outcome, Tumor Necrosis Factor-alpha, Up-Regulation