Evidence of a Role of Tumor Necrosis Factor α in Refractory Asthma

Patients with severe asthma are distinct from patients with milder forms of the disease. Peripheral-blood monocytes from patients with severe asthma were shown to have enhanced expression of markers associated with tumor necrosis factor α (TNF-α). In a pilot, placebo-controlled, crossover study, the...

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Published inThe New England journal of medicine Vol. 354; no. 7; pp. 697 - 708
Main Authors Berry, Mike A, Hargadon, Beverley, Shelley, Maria, Parker, Debbie, Shaw, Dominick E, Green, Ruth H, Bradding, Peter, Brightling, Christopher E, Wardlaw, Andrew J, Pavord, Ian D
Format Journal Article
LanguageEnglish
Published United States Massachusetts Medical Society 16.02.2006
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Online AccessGet full text
ISSN0028-4793
1533-4406
1533-4406
DOI10.1056/NEJMoa050580

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Abstract Patients with severe asthma are distinct from patients with milder forms of the disease. Peripheral-blood monocytes from patients with severe asthma were shown to have enhanced expression of markers associated with tumor necrosis factor α (TNF-α). In a pilot, placebo-controlled, crossover study, the TNF-α receptor–binding agent etanercept improved airway responsiveness and asthma-related quality of life. TNF-α may have a role in refractory asthma. In a pilot study, the TNF-α receptor–binding agent etanercept improved airway responsiveness and asthma-related quality of life. TNF-α may have a role in refractory asthma. The rates of death and complications are high among patients with refractory asthma and account for a disproportionate amount of the health resource burden attributed to asthma. 1 Treatment options are limited for these patients. The airway abnormality in refractory asthma differs from that in mild-to-moderate asthma in having a more heterogeneous pattern of inflammatory response, 2 with greater involvement of neutrophils 3 and the distal lung 4 and increased airway remodeling. 5 Tumor necrosis factor α (TNF-α) is a pleiotropic inflammatory cytokine expressed in increased amounts by mast cells 6 and present in increased concentrations in bronchoalveolar fluid from the airways of patients with asthma. . . .
AbstractList 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 (FEV sub(1)) (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 FEV sub(1) (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.
Patients with severe asthma are distinct from patients with milder forms of the disease. Peripheral-blood monocytes from patients with severe asthma were shown to have enhanced expression of markers associated with tumor necrosis factor α (TNF-α). In a pilot, placebo-controlled, crossover study, the TNF-α receptor–binding agent etanercept improved airway responsiveness and asthma-related quality of life. TNF-α may have a role in refractory asthma. In a pilot study, the TNF-α receptor–binding agent etanercept improved airway responsiveness and asthma-related quality of life. TNF-α may have a role in refractory asthma. The rates of death and complications are high among patients with refractory asthma and account for a disproportionate amount of the health resource burden attributed to asthma. 1 Treatment options are limited for these patients. The airway abnormality in refractory asthma differs from that in mild-to-moderate asthma in having a more heterogeneous pattern of inflammatory response, 2 with greater involvement of neutrophils 3 and the distal lung 4 and increased airway remodeling. 5 Tumor necrosis factor α (TNF-α) is a pleiotropic inflammatory cytokine expressed in increased amounts by mast cells 6 and present in increased concentrations in bronchoalveolar fluid from the airways of patients with asthma. . . .
The development of tumor necrosis factor alpha (TNF-alpha) antagonists has made it feasible to investigate the role of this cytokine in refractory asthma. 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. 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). Patients with refractory asthma have evidence of up-regulation of the TNF-alpha axis. (ClinicalTrials.gov number, NCT00276029.).
The development of tumor necrosis factor alpha (TNF-alpha) antagonists has made it feasible to investigate the role of this cytokine in refractory asthma.BACKGROUNDThe development of tumor necrosis factor alpha (TNF-alpha) antagonists has made it feasible to investigate the role of this cytokine in refractory asthma.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.METHODSWe 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.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).RESULTSAs 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).Patients with refractory asthma have evidence of up-regulation of the TNF-alpha axis. (ClinicalTrials.gov number, NCT00276029.).CONCLUSIONSPatients with refractory asthma have evidence of up-regulation of the TNF-alpha axis. (ClinicalTrials.gov number, NCT00276029.).
Author Hargadon, Beverley
Parker, Debbie
Shelley, Maria
Shaw, Dominick E
Pavord, Ian D
Green, Ruth H
Berry, Mike A
Bradding, Peter
Wardlaw, Andrew J
Brightling, Christopher E
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/16481637$$D View this record in MEDLINE/PubMed
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Snippet Patients with severe asthma are distinct from patients with milder forms of the disease. Peripheral-blood monocytes from patients with severe asthma were shown...
The development of tumor necrosis factor alpha (TNF-alpha) antagonists has made it feasible to investigate the role of this cytokine in refractory asthma. We...
Background The development of tumor necrosis factor alpha (TNF- alpha ) antagonists has made it feasible to investigate the role of this cytokine in refractory...
The development of tumor necrosis factor alpha (TNF-alpha) antagonists has made it feasible to investigate the role of this cytokine in refractory...
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SubjectTerms 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
Title Evidence of a Role of Tumor Necrosis Factor α in Refractory Asthma
URI http://dx.doi.org/10.1056/NEJMoa050580
https://www.ncbi.nlm.nih.gov/pubmed/16481637
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