Evidence of a role of tumor necrosis factor alpha in refractory asthma.
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.).
Institute for Lung Health, University Hospital of Leicester National Health Service Trust, Glenfield Hospital, Leicester, United Kingdom.
Mike A
MA
Berry
Beverley
B
Hargadon
Maria
M
Shelley
Debbie
D
Parker
Dominick E
DE
Shaw
Ruth H
RH
Green
Peter
P
Bradding
Christopher E
CE
Brightling
Andrew J
AJ
Wardlaw
Ian D
ID
Pavord
D051722:ADAM Proteins / Q000096:biosynthesis; D000072198:ADAM17 Protein; D000293:Adolescent; D000328:Adult; D000368:Aged; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D015415:Biomarkers / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000378:metabolism; D016022:Case-Control Studies; D018592:Cross-Over Studies; D004311:Double-Blind Method; D000068800:Etanercept; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use*; D007155:Immunologic Factors / Q000627:therapeutic use; D008297:Male; D016210:Methacholine Chloride; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D010865:Pilot Projects; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000096:biosynthesis; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D015854:Up-Regulation
D015415:Biomarkers; D007074:Immunoglobulin G; D007155:Immunologic Factors; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D016210:Methacholine Chloride; D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000068800:Etanercept