Abstract
BackgroundChronic obstructive pulmonary disease (COPD) is characterized by progressive worsening of airflow limitation associated with abnormally inflamed airways in older smokers. Despite correlative evidence for a role for tumor necrosis factor-alpha in the pathogenesis of COPD, the anti-tumor necrosis factor-alpha, infliximab did not show clinical efficacy in a double-blind, placebo-controlled, phase II clinical trial. This study sought to evaluate the systemic inflammatory profile associated with COPD and to assess the impact of tumor necrosis factor neutralization on systemic inflammation.MethodsSerum samples (n = 234) from the phase II trial were collected at baseline and after 24 weeks of placebo or infliximab. Additionally, baseline serum samples were obtained from an independent COPD cohort (n = 160) and 2 healthy control cohorts (n = 50; n = 109). Serum concentrations of a broad panel of inflammation-associated analytes were measured using a 92-analyte multiplex assay.ResultsTwenty-five proteins were significantly elevated and 2 were decreased in COPD, including highly elevated CD40 ligand, brain-derived neurotrophic factor, epidermal growth factor, acute-phase proteins, and neutrophil-associated proteins. This profile was largely independent of smoking status, age, and clinical phenotype. The majority of these associations of serum analytes with COPD are novel findings. Increased serum creatine kinase-muscle/brain and myoglobin correlated modestly with decreased forced expiratory volume at 1 second, suggesting cardiac involvement. Infliximab did not affect this systemic inflammatory profile.ConclusionsA robust systemic inflammatory profile was associated with COPD. This profile was generally independent of disease severity. Because anti-tumor necrosis factor-alpha did not influence systemic inflammation, how to control the underlying pathology beyond symptom suppression remains unclear.Trial RegistrationClinicalTrials.gov, No.: NCT00056264.
Highlights
Chronic obstructive pulmonary disease (COPD) is characterized by progressive worsening of airflow limitation associated with abnormally inflamed airways in older smokers
Additional serum samples from patients with mild-tosevere COPD with available demographics and disease characteristics data were purchased from a commercial vendor (BioServe Biotechnologies, Ltd., Beltsville, MD, USA) and evaluated according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria
COPD and healthy control cohorts Before examining whether infliximab treatment was able to modify the systemic inflammatory and biochemical profile in COPD patients, this systemic profile first needed to be rigorously established in both the study population and an independent COPD population compared to healthy control populations
Summary
Chronic obstructive pulmonary disease (COPD) is characterized by progressive worsening of airflow limitation associated with abnormally inflamed airways in older smokers. Chronic obstructive pulmonary disease (COPD) is a complex syndrome characterized by progressive expiratory airflow loss associated with abnormal inflammation in the lungs. Because TNF-alpha inhibitors have demonstrated clinical efficacy in various chronic inflammatory disorders,[11,12,13] a phase II, double-blind, multicenter, placebo-controlled clinical study was performed to evaluate the safety and efficacy of infliximab (Janssen Biotech, Inc., Horsham, PA, USA), an anti-TNF-alpha monoclonal antibody, in the treatment of COPD [14]. The goal of this study was to test the hypothesis that the lack of clinical efficacy of infliximab in COPD patients was associated with a failure of infliximab to significantly impact the underlying systemic inflammation associated with COPD. The general systemic inflammatory and biochemical profile associated with COPD was defined and evaluated for whether infliximab treatment could impact this broader disease-associated profile
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