Asthma continues to place an enormous burden on the U.S. health care system. More than 31 million people have asthma, with the total cost of disease estimated to be $12 billion in 1998. Utilization of health care resources for asthma is disproportionately high among the 20% of patients with difficult-to-treat asthma. These patients consume 80% of all asthma-related health care resources in the form of increased emergency visits, hospitalizations, and medication use. Indirect costs include absence from work or school and decreased potential earnings resulting from disability and death. A large observational study highlighted the lack of control in patients with moderate-to-severe asthma and confirmed the increased use of health care resources and the reduced quality of life experienced by these patients.
Role of Immunoglobulin E in the Pathogenesis of Asthma
In recent years, airway inflammation and atopy have become recognized as key factors in the pathogenesis of asthma. Atopy, the predisposition to form antibodies and to acquire allergies, is strongly correlated with the incidence of asthma. National statistics show that more than 70% of Americans with asthma also have allergies. The World Health Organization has suggested that allergic rhinitis is not a solitary disease but a complex syndrome that affects the upper and lower airways and that its presence may be a major risk factor in the development of asthma. canada pharmacy mall
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Mark Baumel, MD David Nash, MD, MBA
Immoglobulin E (IgE)-dependent mechanisms are involved in many allergic responses at the level of the airway. Once IgE antibodies are produced, mast cells and other airway cells are sensitized and become activated when specific antigens are encountered (Figure 1).
Figure 1 Allergens and mast cells. (Courtesy of Gailen D. Marshall, MD, PhD,Director, Division of Allergy and Immunology, University of Mississippi, Jackson.)
IgE is the initiator of the inflammatory cascade in the airways that produces the classic early-phase and late-phase airway responses to an inhaled allergen. Airway inflammation is initiated when an inhaled allergen forms a cross-link with a mast cell or basophil-bound IgE. Linking of the allergen and receptor-bound IgE provokes mast-cell and basophil degranulation and a release of inflammatory mediators, including histamine, prosta-glandins, and leukotrienes. Together, these mediators are responsible for the mucosal edema and smooth muscle contraction that are the hallmarks of the early asthma re-sponse.
IgE Blockers: A Novel Approach to Treating Asthma
Most patients with asthma have atopy and possess specific IgE antibodies to the allergens responsible for causing airway inflamma-tion. Because of the central role of IgE in atopic disease, inhibiting IgE-mediated events with IgE blockers represents a novel approach to reducing the severity of asthma.
Omalizumab, a monoclonal antibody, forms complexes with circulating free IgE at the site of binding to mast cells. The formation of these complexes removes free IgE from circulation and inhibits the binding of IgE to mast cells, indirectly down-regulating IgE receptor expression on mast cells. Omalizumab also down-regulates Fce receptor I on mast cells and basophils and on other cells involved in inflammatory responses, including type 1 and 2 dendritic cells. Treatment of allergic asthmatic patients with omalizumab prevents IgE from triggering the release of inflammatory mediators in response to an allergen, thereby inhibiting inflammation at its source rather than suppressing it after it has occurred.
Omalizumab has undergone extensive study in randomized, controlled trials. In phase 3 trials, the agent was tested in adolescents and adults, 12 to 75 years of age, with difficult-to-control, moderate-to-severe allergic asthma. The primary endpoint of these trials was the number of exacerbations experienced by patients, defined as an episode severe enough to result in a doubling of the inhaled steroid dose or a course of systemic corticosteroids.
In the pooled phase 3 trials, omalizumab decreased asthma exacerbations by 50%, compared with the rate for placebo, and it improved asthma-related quality of life in all domains. Omalizumab reduced the use of health care resources, as manifested by lower rates of hospitalizations and emergency-department visits.