Volume. 35, No. 2 july. 2011 - The Chest and Heart Association of ...

Incorporating Omalizumab into Asthma Management: A ReviewMd. Khairul Hassan Jessy et al.department, and a reduced quality of life. As aresult, patients and their family members haveboth personal and economic hardship. From theperspective of public and societal health,approximately 17 million people in the UnitedStates have been estimated to have asthma, onethird of them children. Asthma in the United Statescosts an estimated $12.7 billion annually, withmost of this cost attributable to direct medicalexpenditures and medication. 3IgE plays a central role in the pathophysiology ofasthma. The two essential phases in thispathophysiology are sensitization to allergen andclinical expression of symptoms on re-exposure tothe sensitizing allergen. During sensitization,inhaled antigen (i.e., aeroallergen) is taken up byantigen-presenting dendritic cells lining theairways. The allergen is then processed andpresented to antigen-specific T cells. In somepersons, these T cells respond by producingcytokines that stimulate the development of IgEproducingB cells. The Fc portion of circulatingIgE then binds to high-affinity receptors (FcåRIs)present on the surfaces of mast cells andbasophils. 4,5,6 On re-exposure, the sensitizingallergen cross-links IgE molecules present on mastcelland basophil surfaces. This initiatesdegranulation and the release of inflammatorymediators, including histamine, prostaglandins,leukotrienes, chemokines, and cytokines. Thesemediators precipitate an immediate acute-phasereaction, resulting in acute bronchospasm,expressed clinically as an episode of acute asthma.Continued expression of mediators enlists aninflammatory response designated the late-phasereaction, which causes persistent symptoms,airway hyper-responsiveness, and bronchospasm.IgE may also facilitate sensitization to allergens.Dendritic cells express FcåRIs and have been foundto bind IgE, which is thought to focus antigen atthe cell surface. In addition IgE binds to low affinityFCe receptors on B cells, which it altersdifferentiation and regulation of further IgEsynthesis. 3,4Unmet Needs: Barriers to ImprovedOutcomesPatients with the greatest unmet needs are thosewith moderate-to-severe asthma that is suboptimallycontrolled. These patients remainsymptomatic despite the use of multiplemedications. The hallmark feature of thesepatients is frequent, severe exacerbations thatoften require costly emergency treatment,hospitalization, or both. 7,8 This observationsupports the theory that current therapies areunderused, are used inappropriately, or are notconsistently effective. 9 The Epidemiology andNatural History of Asthma Outcomes andTreatment Regimen (TENOR) Study was initiatedto describe the natural history of asthma patients,to elucidate the relationship between IgE anddisease, and to examine the relationship betweenseverity of asthma, its treatment, and clinicaloutcomes. 8,9Emerging Asthma TherapiesOmalizumab is a recombinant humanized IgG1monoclonal anti-IgE antibody that binds to the IgEmolecule at the same epitome on the Fact regionthat binds to FcåRI. 4,5 This design means thatOmalizumab is not anaphylactogenic, since itcannot interact with IgE that is already bound tocell surfaces and thus cannot induce degranulationof mast cells or basophils. 4,5 Instead, Omalizumabbinds to circulating IgE, regardless of allergenspecificity, forming small, biologically inert IgE–anti-IgE complexes without activating thecomplement cascade. 3,4,5 An 89 to 99% reductionin free serum IgE (i.e., IgE not bound toOmalizumab) occurs soon after the administrationof Omalizumab, and low levels persist throughouttreatment with appropriate doses. Proof-of-conceptstudies have shown that Omalizumab reduces bothearly- and late-phase asthmatic responses afterallergen inhalation challenge, has a marked effecton late-phase as compared with early-phase skinresponses, decreases eosinophil numbers insputum and submucosal bronchial specimens, andalso down-regulates FcåRI on basophils, mast cells,and dendritic cells. A reduction in the expressionof FcåRI on basophils and mast cells decreases thebinding of circulating IgE, thus preventing therelease of inflammatory mediators. A reduction inthe expression of FcåRI on dendritic cells maydecrease allergen processing and presentation.Evidence of Clinical BenefitThere are four core randomized, double-blindclinical trials that have compared Omalizumab,administered subcutaneously, with placebo. In121