Asthma diagnosis and treatmentThe anti-inflammatory effects of omalizumab confirm the central role of IgE in allergic inflammation
Section snippets
IgE and asthma
The airflow limitation and episodic worsening that typify asthma are the clinical manifestations of a complex pattern of chronic and continuing inflammation in the airways tissue in which IgE plays a key role. The concept that IgE was only central in allergic asthma was first challenged by data from a population-based study, which showed a close and highly significant relationship between serum IgE levels and the prevalence of all asthma.1 Since then, others have confirmed the view that most
IgE receptors
The interaction between IgE and mast cells and basophils is the best characterized, although it is not fully elucidated. Mature mast cells resident in airway tissue are primed with IgE molecules bound to FcεRI receptors. Mast cells activated by antigen complexed with IgE through the FcεRI release an array of products that can have effector, immunoregulatory, or autocrine effects. These products have not yet been fully identified. By using complementary DNA microarrays, stimulation of FcεRI in
Effect of omalizumab on IgE receptors
The recently developed humanized monoclonal anti-IgE antibody omalizumab decreases levels of circulating IgE by binding to the constant region (cε3) of the IgE molecule, which prevents free IgE from interacting with IgE receptors (FcεRI and FcεRII). Because omalizumab does not bind to the variable allergen-specific region of the IgE molecule, it will inhibit allergen-induced responses regardless of allergen specificity. Omalizumab does not bind to cell-bound IgE, thus avoiding the FcεRI
Inflammation in asthma
Early proof-of-concept studies showed that omalizumab inhibited both early asthmatic responses (EARs) and late asthmatic responses (LARs) to inhaled allergen in patients with asthma. Assessed as the mean maximal decrease in FEV1, the EAR was reduced by 85% (P = .01) and the LAR by more than 65% (P = .047) compared with results with placebo in a study of 19 subjects with mild allergic asthma.19 Sputum eosinophilia was reduced 11-fold from baseline (P = .02 vs baseline; not significant vs placebo).
Clinical efficacy of omalizumab
The efficacy of omalizumab has been demonstrated in patients with moderate-to-severe and severe allergic asthma, in patients with SAR15, 16 and perennial allergic rhinitis,29 and in subjects with concomitant allergic asthma and allergic rhinitis.30 In large placebo-controlled studies in children and adults with moderate-to-severe allergic asthma,31, 32, 33 omalizumab significantly reduced the level of asthma exacerbations, and patients significantly reduced their intake of ICSs, with median
Summary
IgE plays a central role in allergic asthma, and there is also growing evidence suggestive of a role in nonallergic (intrinsic) asthma. The central role of IgE in allergic inflammation and the proposed mechanisms of action of omalizumab in inhibiting IgE-mediated processes are depicted schematically in Fig 2. Omalizumab treatment results in a rapid reduction in free IgE levels and downregulation of FcεRI on basophils, mast cells, and other inflammatory cells.13, 14, 17, 31, 32, 33 Recent
Conclusion
Omalizumab has a central role in inhibiting the allergic inflammatory cascade. Evidence to date supports a marked effect on underlying steady-state inflammation and a preventive effect on the worsening inflammation (on allergen exposure) that underlies disease flares or exacerbations. Taken together, the activity of omalizumab against IgE, eosinophils, basophils, mast cells, and dendritic cells suggests that the effects of omalizumab therapy encompass not only inhibition of IgE-mediated
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Disclosure of potential conflict of interest: S. T. Holgate is chairman of the Novartis International Respiratory Advisory Board (2002-present) and a member of the PrestIgE faculty, has received a grant from Novartis to investigate IL-13 receptor functions, and has lectured at Novartis/Genentech-sponsored symposia. T. B. Casale has consultant arrangements with, has received grants/research support from, and is on the Speakers' Bureau for Novartis and Genentech. S. Wenzel has consultant arrangements with and is on the Speakers' Bureau of Genentech. J. Bousquet has received consulting fees and honoraria for meetings concerning the products of Novartis—Xolair in particular. Y. Deniz has no relevant conflicts of interest to declare. C. Reisner is employed by Novartis.