The Effects of a Monoclonal Antibody Directed against Tumor Necrosis Factor-α in Asthma

Erin, Edward M.; Leaker, Brian; Nicholson, GC; Tan, Andrew J.; Green, Linda M.; Neighbour, Helen; Zacharasiewicz, Angela; Turner, Jackie; Barnathan, Elliot S.; Kon, Onn Min; Barnes, Peter J.; Hansel, Trevor T.

doi:10.1164/rccm.200601-072oc

Cited by 239 publications

(142 citation statements)

References 47 publications

Supporting

Mentioning

132

Contrasting

Unclassified

Order By: Relevance

“…This mAb reduced diurnal PEF variability and, interestingly, the number of mild exacerbations encountered, but not morning PEF, in a trial of symptomatic patients with moderate asthma despite receiving inhaled corticosteroid (ICS) therapy [96].…”

Section: Tnf-α Inhibitors and Asthmamentioning

confidence: 95%

TNF-α inhibitors in asthma and COPD: We must not throw the baby out with the bath water

Matera

Calzetta

Cazzola

2010

Pulmonary Pharmacology & Therapeutics

113

View full text Add to dashboard Cite

Tumor necrosis factor (TNF)-α, a pleiotropic cytokine that exerts a variety of effects, such as growth promotion, growth inhibition, angiogenesis, cytotoxicity, inflammation, and immunomodulation, has been implicated in several inflammatory conditions. It plays a significant role in many inflammatory diseases of lung. Given that there is significant literature supporting the pathobiologic role of TNF-α in asthma, mainly in severe refractory asthma, and COPD, TNF-α inhibitors (infliximab, golimumab and etanercept) are now regarded as potential new medications in asthma and COPD management. The studies reported in literature indicate that TNF-α inhibitors are effective in a relatively small subgroup of patients with severe asthma, possibly defined by an increased TNF axis, but they seem to be ineffective in COPD, although an observational study demonstrated that TNF-α inhibitors were associated with a reduction in the rate of COPD hospitalisation among patients with COPD receiving these agents to treat their rheumatoid arthritis. These findings require a smart approach because there is still good reason to target TNF-α, perhaps in a more carefully selected patient group. TNF-α treatment should therefore not be thrown out, or abandoned. Indeed, since severe asthma and COPD are heterogeneous diseases that have characteristics that occur with different phenotypes remained poorly characterized and little known about the underlying pathobiology contributing to them, it is likely that definition of these phenotypes and choice of the right outcome measure will allow us to understand which kind of patients can benefit from TNF-α inhibitors.

show abstract

Section: Tnf-α Inhibitors and Asthmamentioning

confidence: 95%

TNF-α inhibitors in asthma and COPD: We must not throw the baby out with the bath water

Matera

Calzetta

Cazzola

2010

Pulmonary Pharmacology & Therapeutics

113

View full text Add to dashboard Cite

show abstract

“…The pathophysiologic role of TNF-a is shown by the fact that it is found in high levels in bronchoalveolar lavage fluid and sputum of patients with asthma and chronic obstructive pulmonary disease (86,87). Results of recent human clinical trials with anti-TNF-a-immunomodulators (etanercept) (88,89) and anti-TNF-a monoclonal antibodies (infliximab) (90) have shown that TNF-a has a pathobiologic role in asthma, particularly in severe asthma that is refractory to corticosteroids. TNF-a appears to have a central role in the initiation of airway inflammation and AHR, hallmarks of asthma.…”

Section: Inflammatory Cytokines and Cd38/cadpr-mediated Cellular Calcmentioning

confidence: 99%

Calcium Signaling in Airway Smooth Muscle

Jude¹,

Wylam²,

Walseth³

et al. 2008

Proceedings of the American Thoracic Society

View full text Add to dashboard Cite

Contractility of airway smooth muscle requires elevation of intracellular calcium concentration. Under resting conditions, airway smooth muscle cells maintain a relatively low intracellular calcium concentration, and activation of the surface receptors by contractile agonists results in an elevation of intracellular calcium, culminating in contraction of the cell. The pattern of elevation of intracellular calcium brought about by agonists is a dynamic process and involves the coordinated activities of ion channels located in the plasma membrane and the sarcoplasmic reticulum. Among the signaling molecules involved in this dynamic calcium regulation in airway smooth muscle cells are inositol 1,4,5-trisphosphate and cyclic ADPribose, which mobilize calcium from the sarcoplasmic reticulum by acting via the inositol 1,4,5-trisphosphate and ryanodine receptors, respectively. In addition, calcium influx from the extracellular space is critical for the repletion of the intracellular calcium stores during activation of the cells by agonists. Calcium influx can occur via voltage-and receptor-gated channels in the plasma membrane, as well as by influx that is triggered by depletion of the intracellular stores (i.e., store-operated calcium entry mechanism). Transient receptor potential proteins appear to mediate the calcium influx via receptor-and store-operated channels. Recent studies have shown that proinflammatory cytokines regulate the expression and activity of the pathways involved in intracellular calcium regulation, thereby contributing to airway smooth muscle cell hyperresponsiveness. In this review, we will discuss the specific roles of cyclic ADP-ribose/ryanodine receptor channels and transient receptor potential channels in the regulation of intracellular calcium in airway smooth muscle cells. DYNAMIC INTRACELLULAR CALCIUM REGULATION IN AIRWAY SMOOTH MUSCLE CELLSExposure of airway smooth muscle (ASM) cells to contractile agonists results in a biphasic elevation of intracellular calcium concentration ([Ca 21 ] i ) that is characterized by an initial rapid and transient rise in calcium, followed by a decline to a lower, sustained steady-state concentration above the basal level (1-3). This biphasic [Ca 21 ] i response results from calcium influx from the extracellular space and release of calcium from the intracellular stores (i.e., the sarcoplasmic reticulum [SR]). Earlier studies have attributed the initial rapid and transient phase of the [Ca 21 ] i response to release from the SR, while the sustained phase of the response was thought to be due to influx from the extracellular space (2-6). Recent investigations using the improved temporal and spatial resolution features of real-time confocal microscopy have shed light on the dynamics of the [Ca 21 ] i response in ASM cells. These studies have shown that the biphasic [Ca 21 ] i response of ASM cells elicited by contractile agonists in reality consists of propagating regenerative calcium oscillations that originate at a location within a cell and propagate...

show abstract

“…A recent study evaluating infliximab failed to demonstrate clinical efficacy for the primary end-point in subjects with moderate asthma [3]. Similarly, no significant differences between placebo and anti-TNF-a biologic golimumab were observed in subjects with uncontrolled, severe, persistent asthma after 24 weeks of treatment, although a subgroup with more reversible airflow obstruction and upper airway disease did appear to respond in a dose-dependent manner [25].…”

mentioning

confidence: 96%

“…This inflammatory disorder involves the recruitment of eosinophils, mast cells, T-helper type 2 lymphocytes, neutrophils and macrophages, which is regulated by local release of autacoid mediators, cytokines and chemokines [3,4].…”

mentioning

confidence: 99%

Efficacy and safety of etanercept in moderate-to-severe asthma: a randomised, controlled trial

Holgate

Noonan

Chanez

et al. 2010

European Respiratory Journal

147

View full text Add to dashboard Cite

Increased tumour necrosis factor-a levels have been observed in bronchial biopsies and induced sputum from subjects with severe asthma. We investigated etanercept (ETN) as a therapeutic option for treating moderate-to-severe persistent asthma.In this 12-week, randomised, double-blind, placebo-controlled, phase 2 trial, subjects (n5132) with moderate-to-severe persistent asthma received subcutaneous injections of 25 mg ETN or placebo twice weekly, and were evaluated at baseline, and at weeks 2, 4, 8 and 12. The primary end-point was the change from baseline to week 12 in pre-bronchodilator forced expiratory volume in 1 s (FEV1) % predicted. Secondary end-points included morning peak expiratory flow, FEV1 % pred, Asthma Control Questionnaire (5-item version), asthma exacerbations, provocative concentration of methacholine causing a 20% decrease in FEV1, and the Asthma Quality of Life Questionnaire.No significant differences were observed between ETN and placebo for any of the efficacy endpoints. ETN treatment was well tolerated, with no unexpected safety findings observed during the study.Clinical efficacy of ETN was not shown in subjects with moderate-to-severe persistent asthma over 12 weeks. However, ETN treatment was a well-tolerated therapy. Studies in specific subsets of patients with asthma with longer-term follow-up may be needed to fully evaluate the clinical efficacy of ETN in this population.

show abstract

The Effects of a Monoclonal Antibody Directed against Tumor Necrosis Factor-α in Asthma

Cited by 239 publications

References 47 publications

TNF-α inhibitors in asthma and COPD: We must not throw the baby out with the bath water

TNF-α inhibitors in asthma and COPD: We must not throw the baby out with the bath water

Calcium Signaling in Airway Smooth Muscle

Efficacy and safety of etanercept in moderate-to-severe asthma: a randomised, controlled trial

Contact Info

Product

Resources

About