Effect of tumor necrosis factor antagonism on allergen-mediated asthmatic airway inflammation.
OBJECTIVE
To assess whether tumor necrosis factor (TNF) antagonism can attenuate eosinophilic airway inflammation in patients with mild-to-moderate allergic asthma.


METHODS
Randomized, double-blind, placebo-controlled trial.


METHODS
National Institutes of Health (NIH) Clinical Center.


METHODS
Twenty-six patients with mild-to-moderate allergic asthma, receiving only inhaled beta-2-agonists, who demonstrated both an early and late phase response to inhalational allergen challenge.


METHODS
Injection of a soluble TNF receptor (TNFR:Fc, etanercept, Enbrel) or placebo, 25mg subcutaneously, twice weekly for 2 weeks, followed by a bronchoscopic segmental allergen challenge.


METHODS
The primary outcome measure was whether TNFR:Fc can access the lung and inhibit TNF bioactivity. Secondary outcome measures included pulmonary eosinophilia, Th2-type cytokines, and airway hyperresponsiveness.


RESULTS
Anti-TNF therapy was associated with transient hemiplegia in one patient, which resulted in suspension of the study. Data from the 21 participants who completed the study were analyzed. Following treatment, patients receiving anti-TNF therapy had significantly increased TNFR2 levels in epithelial lining fluid (ELF) (P<0.001), consistent with delivery of TNFR:Fc to the lung. TNF antagonism did not attenuate pulmonary eosinophilia and was associated with an increase in ELF IL-4 levels (P=0.033) at 24h following segmental allergen challenge. TNF antagonism was not associated with a change in airway hyperresponsiveness to methacholine.


CONCLUSIONS
TNF antagonism may not be effective for preventing allergen-mediated eosinophilic airway inflammation in mild-to-moderate asthmatics. Transient hemiplegia, which may mimic an evolving stroke, may be a potential toxicity of anti-TNF therapy.
Rouhani
Farshid N
FN
Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Building 10, Room 6D03, MSC 1590, Bethesda, MD 20892-1590, USA.
Meitin
Catherine A
CA
Kaler
Maryann
M
Miskinis-Hilligoss
Dianne
D
Stylianou
Mario
M
Levine
Stewart J
SJ
D000328:Adult; D000402:Airway Obstruction / Q000188:drug therapy; D000485:Allergens / Q000276:immunology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016207:Cytokines / Q000096:biosynthesis; D004311:Double-Blind Method; D000068800:Etanercept; D005260:Female; D006429:Hemiplegia / Q000139:chemically induced; D006801:Humans; D007074:Immunoglobulin G / Q000009:adverse effects / Q000627:therapeutic use*; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D011657:Pulmonary Eosinophilia / Q000188:drug therapy*; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D018418:Th2 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D000485:Allergens; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept