Immune-based, targeted therapy for allergic diseases.

Abstract

ALLERGIC RHINITIS IS AN INFLAMMATORY DISORDER characterized by upper airway symptoms, including nasal congestion, rhinorrhea, sneezing, and itching of the palate, and, in some patients, by conjunctivitis, otitis media with effusion, sinusitis, or asthma. The prevalence of allergic rhinitis, a common disease that affects approximately 9% to 22% of the US population, has increased substantially in the past 20 years. Symptoms of seasonal allergic rhinitis recur at times of the year corresponding to the appearance of airborne allergens such as pollens and mold spores. Some patients are symptomatic only during the pollen season while many others are allergic to multiple allergens or have a nonallergic component to their rhinitis so that they are symptomatic through much of the year. One of the common causes of allergic rhinitis in the United States is ragweed. Ragweed is found east of the Rocky Mountains and typically produces pollen in August and September. Allergens—antigens that induce allergic responses— are released from ragweed pollen grains that reach the mucosa of the upper airways. Ragweed allergic rhinitis occurs only in individuals who are predisposed to produce IgE antibody in response to these allergens. Immunoglobulin E antibody production is the proximate cause of allergic rhinitis. The tendency to make IgE typically correlates with a family history of allergic diseases. The IgE antibody circulates and binds to high-affinity IgE receptors on mast cells and basophils. Once IgE antibody is bound to receptors on these cells, allergen cross-links bound antibody, initiating secretion of allergic inflammatory mediators, including histamine, leukotrienes, and cytokines. These mediators then induce both the acute and chronic inflammatory changes that result in symptoms of allergy. Allergic rhinitis is considered a minor illness by some patients and physicians, and individuals with mild disease often obtain adequate symptom relief with over-the-counter antihistamines. However, allergic rhinitis is associated with serious morbidity for many other patients. Even those with mild disease may lose days from work or school and have reduced productivity and quality of life. Patients with moderate or severe disease usually require anti-inflammatory medications to control symptoms. Moreover, allergic rhinitis is a risk factor for the exacerbation of, and perhaps the development of, both chronic sinusitis and asthma. Many therapies are approved for the treatment of allergic rhinitis. One expert panel recommends using either oral antihistamines (with or without decongestants) or intranasal corticosteroids as the first line of therapy for moderate allergic rhinitis, and intranasal corticosteroids as the preferred therapy for severe rhinitis. Patients with severe symptoms may require a short course of oral corticosteroids followed by intranasal corticosteroids. Intranasal sodium cromoglycate is valuable in some patients, particularly when initiated before seasonal pollen exposure. Allergen-specific immunotherapy is also effective in many patients with seasonal allergic rhinitis. In this issue of THE JOURNAL, Casale et al report the results of a randomized trial evaluating a novel therapy for ragweed-induced seasonal allergic rhinitis, omalizumab (formerly called rhuMAb-E25), a humanized monoclonal anti– human IgE antibody. Omalizumab is molecularly engineered to possess a number of therapeutically useful features. It binds specifically to that region of the IgE molecule that binds to the IgE receptor on mast cells or basophils. Because omalizumab cannot bind to IgE molecules that are already bound to surface receptors on mast cells and basophils, it does not stimulate secretion of mediators from these cells. Omalizumab was originally derived from mouse B lymphocytes but has been humanized so that nearly the entire molecule, except for the IgE-binding regions, expresses human amino acid sequences. It does not appear to stimulate an immune response against itself. The actions of omalizumab are mediated by 2 effects on IgE pathways. First, it can bind more than 95% of free serum IgE when administered at an appropriate dose. Second, the decrease in free serum IgE induces a rapid and marked ( 90%) reduction in IgE receptors on basophils and mast cells. The combined effects of reduction of both free IgE and IgE recep-