Successful anti-inflammatory therapy leads to long-term prevention of symptoms through suppressing, controlling, and reversing inflammation

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Phyllis C. Braun, PhD
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John D. Zoidis, MD

Allergic diseases are characterized by biphasic reactions mediated by immunoglobulin E (IgE). The immediate reaction appears within minutes after exposure to an antigen, and the late-phase reaction may occur 2 to 8 hours afterward.1 Lung biopsy and bronchoalveolar lavage in patients with stable asthma show the presence of inflammation consistent with a late-phase reaction, whereas pulmonary-function tests show hyperresponsiveness of the airway that is proportional to the magnitude of the late-phase reaction.2 IgE binds to high-affinity receptors on tissue mast cells and circulating basophils. In subjects with asthma, there is a correlation between serum IgE concentrations and both airway responsiveness and the number of high-affinity receptors.3

Effective allergen immunotherapy attenuates the late-phase reaction, but immunotherapy has not been uniformly effective in the treatment of asthma and other allergic diseases.4 Consequently, the basis of therapy remains the consistent use of anti-inflammatory medication (see sidebar), most often in the form of inhaled corticosteroids, to block the late-phase reaction and reduce airway hyperresponsiveness. Successful anti-inflammatory therapy leads to long-term prevention of the symptoms of asthma by suppressing, controlling, and reversing inflammation.

Prevalence and Impact
Asthma affects 4% to 5% of the US population, a figure that translates into approximately 13 million patients.5 It is the most common chronic disease of childhood, affecting an estimated 4.8 million children. According to the latest surveillance information6 from the US National Institutes of Health, the prevalence rates for asthma are increasing for individuals of all ages. Children and young adults not only have the greatest relative prevalence of asthma, but it is in this group that prevalence is increasing at the most rapid rate.

In the United States, people with asthma have more than 100 million days of restricted activity and 470,000 hospitalizations annually.6 More than 5,000 people die of asthma each year.6 Asthma hospitalization rates have been greatest among African Americans and children, while death rates for asthma are consistently highest among African Americans aged 15 to 24 years.7 These rates have generally increased over the past decade.

The total annual estimated cost of asthma is approximately $6 billion.8 Direct costs (which include payments for ambulatory care visits, hospital outpatient services, hospital inpatient stays, emergency-department visits, physician and facility payments, and prescribed medicines) account for approximately $5 billion.9 Indirect costs, which include costs resulting from missed work or school and days with restricted activity at work, account for nearly $1 billion.8,9

Hospitalization accounts for more than half of all expenditures. More than 80% of resources are used by 20% of the population (defined as high-cost patients). The estimated annual per-patient cost for high-cost patients is approximately $2,600, as compared with $140 for the total asthma-patient population.9

The key inflammatory cells involved in the genesis of asthma are mast cells, eosinophils, lymphocytes, and epithelial cells. Upon exposure to an initiating stimulus (an asthma inducer), these inflammatory cells release inflammatory mediators such as histamine, leukotrienes, prostaglandins, cytokines, chemokines, and platelet-activating factor. These compounds have direct and indirect effects on airway smooth muscle and capillary permeability.

Inflammatory mediators contribute to epithelial injury, mucosal edema, abnormalities in smooth-muscle responsiveness, and airflow obstruction. The airflow obstruction produces the signs and symptoms of asthma: coughing, wheezing, dyspnea, and a sensation of chest tightness.

The airway response to antigen has provided a laboratory model for the study of the events that take place during allergic inflammation. At the cellular level, the inflammatory response in asthma is similar to that in other allergic diseases. Upon exposure to the initiating stimulus, an intense local reaction (the early-phase response) takes place, causing epithelial damage, damage to nerve endings within muscles lining the airways, and subsequent activation of an axonal reflex. These cellular responses correlate with the clinical manifestations of the early-phase response. For example, if sufficient antigen is inhaled by an asthma patient, there is, invariably, an immediate fall in forced expiratory volume in 1 second. This bronchospastic response to antigen is related to the release of inflammatory mediators from the pulmonary mast cell.

The late-phase response is characterized by more persistent airflow obstruction, an increase in airway responsiveness, and infiltration by inflammatory cells.

An understanding of the inflammatory cells involved in the asthma response forms the pharmacologic basis for anti-inflammatory drugs used in the treatment of asthma. The key inflammatory cells of the asthma response—mast cells, eosinophils, lymphocytes, and epithelial cells—are found in increased numbers in the airways of patients with asthma.2,3

Eosinophils contribute to inflammation by causing the release of leukotrienes, prostaglandins, granular proteins, and proinflammatory cytokines. Granular proteins may damage airway tissue and promote airway hyperresponsiveness. Lymphocytes, particularly subpopulations of T-helper lymphocytes, are believed to contribute to inflammation in asthma through the release of various cytokines.10 Epithelial cells are another source of proinflammatory mediators in asthma, including leukotrienes and other eicosanoids, cytokines, chemokines, and nitric oxide.

The airways of patients with asthma are infiltrated by eosinophils and mononuclear cells, and there is vasodilation and evidence of microvascular leakage and epithelial disruption. The airway smooth muscle is often hypertrophied, which is characterized by new vessel formation, increased numbers of epithelial goblet cells, and deposition of interstitial collagens beneath the epithelium. These features of airway-wall remodeling in asthma patients further underscore the importance of chronic, recurrent inflammation in asthma and its effects on the airway.

The clinical consequences of mild, untreated asthma are largely a result of underlying airway inflammation. They include recurrent chest tightness, shortness of breath, wheezing, and sputum production that interfere with activity and sleep; impairment of the ability to work or go to school; and impairment of the quality of life. One of the more recently appreciated clinical consequences of untreated asthma is the development of incapacitating, irreversible airflow obstruction. In some patients, untreated asthma may lead to severe attacks that require emergency treatment and/or hospitalization. In others, untreated asthma may result in death.

In patients with asthma, the risk of short-term consequences appears to be related to the severity of the disease. For example, patients who have been hospitalized previously for severe exacerbations, those whose baseline spirometry shows evidence of airflow obstruction, and those who have required systemic corticosteroids in the past for the control of symptoms are more likely to require hospitalization for asthma.

Management of Asthma:
Pharmacotherapeutic Options

b-Adrenergic Agonists
These agents relax airway smooth muscle. Inhaled b-agonists are the medication of choice for the treatment of acute exacerbations of asthma and for the prevention of exercise-induced asthma. b-Agonists are also used chronically to aid in the control of persistent airway narrowing. Therefore, exceeding three to four doses of inhaled b-agonists on a daily, regularly scheduled basis is not recommended.

Using oral corticosteroids in the early treatment of severe exacerbations of asthma prevents progression of the exacerbation, decreases the need for emergency-department visits or hospitalizations, and reduces the morbidity of the disease. Oral or parenteral corticosteroids are, however, associated with many adverse effects in both short-term and long-term therapeutic use. Inhaled corticosteroids appear to be safe and effective for the treatment of asthma and have, in recent years, become a cornerstone of management. Inhaled corticosteroids are indicated for the long-term prevention of asthma symptoms and for the suppression, control, and reversal of inflammation. They are also used to reduce the need for oral corticosteroid treatment. At the usual therapeutic doses, side effects are transitory and include cough, dysphonia, and oral candidiasis.

Administered prophylactically, cromolyn sodium inhibits early-phase and late-phase allergen-induced airway narrowing, as well as acute airway narrowing after exercise and after exposure to cold dry air and sulfur dioxide. The mechanism of action is not fully understood, but it may be that cromolyn sodium stabilizes, and prevents mediator release from, mast cells. Whether a patient will respond to cromolyn sodium cannot be reliably predicted.

This agent is a pyranoquinoline dicarboxylic acid derivative. Its mechanism of action is believed to involve the release of mediators of inflammation from mast cells, as well as inhibition of the bronchoconstrictor response to exercise and hyperventilation of cold, dry air. Nedocromil appears to be less potent than inhaled corticosteroids.

Leukotriene Modifiers
Leukotrienes, a family of lipid mediators derived from arachidonic acid, are produced by leukocytes and many other cells, including those found in the lung. Several leukotrienes have been implicated in the inflammatory cascade leading to asthma. Arachidonic acid is converted to leukotriene A4 (LTA4) and various other leukotrienes by the enzyme 5-lipoxygenase, which must bind to a membrane-bound protein known as 5-lipoxygenase-activating protein (FLAP) in order to work. LTA4 can be converted by different enzymes to either leukotriene B4 (LTB4) or leukotriene C4 (LTC4). LTC4 can form leukotriene D4 (LTD4) and leukotriene E4 (LTE4) in sequential cascade reactions. Collectively, LTC4, LTD4, and LTE4 are referred to as cysteinyl leukotrienes because they have cysteinyl residues. The cysteinyl leukotrienes can elicit many of the hallmark features of asthma. In addition, LTB4 may have a minor role in the pathogenesis of asthma.

There are four pharmacotherapeutic classes of leukotriene modifiers. Each is defined by its mechanism of action: inhibitors of 5-lipoxygenase, inhibitors of FLAP, cysteinyl leukotriene-receptor antagonists, and LTB4-receptor antagonists. Currently available leukotriene modifiers are zafirlukast and montelukast, both LTD4-receptor antagonists, and zileuton, a 5-lipoxygenase inhibitor.

Methylxanthines (Theophylline)
Theophylline is the principal methylxanthine used in asthma therapy. When given in a sustained-release preparation, it has a long duration of action and is particularly useful in the control of nocturnal asthma. Because theophylline is rapidly cleared from the body by some asthma patients (particularly children), sustained-release preparations have been developed that allow once-daily dosing.

Inhaled anticholinergic agents produce bronchodilation by reducing intrinsic vagal tone in the airways. Such agents also block reflex bronchoconstriction caused by inhaled irritants, but anticholinergic agents such as atropine have lost favor because of the length of time needed for their onset of action and because of such local and systemic adverse effects as the drying of respiratory secretions, blurred vision, and cardiac and central–nervous-system stimulation.

Effective allergen immunotherapy attenuates the late-phase reaction. Immunotherapy, as currently practiced, has not been uniformly effective in the treatment of asthma and other allergic diseases. Consequently, the basis of therapy remains the consistent use of anti-inflammatory medication (most often, in the form of inhaled cortico-steroids) to block the late-phase reaction and reduce airway hyper-responsiveness.

Recombinant humanized monoclonal antibody to immunoglobulin E (IgE), also known as anti-IgE, was developed to interfere early in the allergic process by targeting the source of allergy symptoms. By binding to circulating IgE in the blood, this antibody blocks the release of inflammatory mediators by keeping the IgE from binding to mast cells. These inflammatory mediators, which include histamine, prostaglandins, and leukotrienes, play a role in the pathogenesis of allergic diseases such as allergic asthma, allergic rhinitis, and atopic dermatitis. Anti-IgE is currently undergoing phase III clinical trials to evaluate the safety and efficacy of the agent’s use by patients with allergic asthma and seasonal allergic rhinitis. Anti-IgE is administered via subcutaneous injection. This approach is an important step forward because severe asthma is poorly controlled by existing therapies other than oral corticosteroids, the long-term use of which is associated with numerous adverse effects.

Humanized Monoclonal Antibody Treatment
Antibodies produced during a natural immune response or after immunization are a heterogeneous mixture of immunoglobulins of different specificities and affinities generated by a population of B-lymphocytes. Monoclonal proteins are homogenous antibodies with a known specificity produced by a single cell (clone). A humanized monoclonal antibody was developed by immunizing mice with human IgE. Spleen cells removed from the immunized mice were fused with murine myeloma cells to produce hybrid (hybridoma) cells that both proliferate indefinitely and secrete antibodies. Specific monoclonal antibodies were selected that attached to free IgE by binding to the region where IgE associates with its cellular receptor, FceR1. The murine monoclonal antibody (anti-IgE) formed a complex with free (unbound) IgE, thereby preventing its attachment to mast cells and basophils.

As a clinical agent, the murine monoclonal antibody is not the molecule of choice for a variety of reasons. The use of nonhuman IgE antibodies may cause an allergic response during immunotherapy, and therapeutic efficacy may be reduced by the rapid clearance of the nonhuman antibodies. To avoid the clinical problems associated with murine antibodies, humanization of the murine anti-IgE was performed. The problems of antigenicity in humans were avoided by obtaining the amino acid residues of the variable immunoglobulin region that were involved in the binding of IgE. This variable region from the mouse immunoglobulin was grafted onto the constant region of human IgG1, resulting in an immunoglobulin protein that is more than 95% human (Figure 1).

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Figure 1. Humanization of the murine antibody.

Developed to interfere early in the allergic process, recombinant humanized monoclonal antibody to IgE (omalizumab) targets the source of allergy symptoms. By binding to circulating IgE in the blood, this antibody blocks the release of inflammatory mediators by keeping the IgE from binding to mast cells.11

Clinical Data
Twice-weekly injections of omalizumab lead to a rapid, dose-related, and sustained fall in plasma IgE levels in patients with atopic asthma.12,13

Initial studies12 in patients with mild asthma showed that omalizumab reduced the early bronchoconstrictor response to inhaled allergen, which is prompted by the activation of mast cells.12 Somewhat surprisingly, however, it also reduced the late response orchestrated by T cells and associated with the infiltration of eosinophils that occurs approximately 6 hours after inhalation of the allergen.13 Treatment with omalizumab also reduced the number of eosinophils in the sputum and decreased airway hyperresponsiveness, indicating that it has a long-term anti-inflammatory effect.12,13 Such findings suggest that omalizumab affects cells other than mast cells and basophils, and may inhibit low-affinity IgE receptors on other cells, such as macrophages and T cells (as observed in mice).14 Furthermore, inhibition of the production of IgE by B cells helps keep circulating levels of IgE low.13

One additional surprising finding is that omalizumab reduces the number of high-affinity IgE receptors on circulating basophils (and, presumably, tissue mast cells), with the numbers returning to normal after treatment is stopped.15 Thus, circulating IgE appears to regulate the expression of high-affinity IgE receptors. The administration of nebulized omalizumab, however, does not reduce circulating levels of IgE or affect the response to allergen challenge, demonstrating that systemic administration is necessary.16

Milgrom et al17 conducted a placebo-controlled study of omalizumab in 317 subjects with moderate-to-severe perennial allergic asthma who were taking inhaled or oral corticosteroids. During the first 12 weeks of treatment, while corticosteroid therapy was continued, intravenous injections of either a high dose or a low dose of omalizumab every 2 weeks significantly reduced the symptoms of asthma and improved the subjects’ quality of life, with a moderate increase in airway function and a reduced need for the use of bronchodilators as rescue medication. During the next 8 weeks of the study, the doses of inhaled or oral corticosteroids were tapered. There were greater reductions in the doses of inhaled and oral corticosteroids and higher rates of discontinuation of these drugs in the high-dose and low-dose groups than in the placebo group. In the group of 35 subjects who required oral corticosteroids at baseline, there was a significant reduction in the requirement for oral corticosteroids, and nearly twice as many subjects in the high-dose group as in the placebo group were able to stop taking oral corticosteroids.

Treatment with omalizumab has been well tolerated in all studies to date, with no specific adverse effects, apart from an urticarial rash after the first dose in a small number of subjects. There is no evidence that antibodies develop against omalizumab, presumably because of the humanization of the antibody. Moreover, the immune complexes formed by the interaction of omalizumab and IgE appear to be removed by the reticuloendothelial system, with no evidence of damage to the kidneys (or other organs or tissues). Concern that reducing the plasma levels of IgE might impair immunity to parasitic infections has been addressed by experiments in mice. Mice infected with Nippostrongylus and Schistosoma had increased rates of elimination of parasites, rather than decreased rates.14

Although asthma has been the main focus of studies of omalizumab, this approach may have a role in the treatment of other atopic diseases, including allergic rhinitis and atopic dermatitis. Twelve weeks of treatment with omalizumab reduced symptoms and the use of other medications in patients with seasonal allergic rhinitis.18 Many patients with asthma also have allergic diseases, and rhinitis may worsen in these patients as asthma is brought under control. By reducing the levels of IgE, omalizumab therapy could ameliorate all these atopic diseases, thereby avoiding the need for a multidrug approach.

Practical Considerations
Most patients with asthma have atopy, with specific IgE antibodies to antigens in inhaled allergens (such as house–dust-mite allergen, cockroach antigen, pollens, and molds) driving the inflammatory process in the airways. Immunotherapy directed against common allergens has been disappointing as a treatment for asthma, and has a small risk of serious adverse effects.4,19 Immunotherapy is directed at specific allergens, whereas anti-IgE antibodies nonspecifically inhibit all IgE.

A small proportion of patients with asthma have no evidence of atopy, as assessed by skin-prick tests for common allergens or total and specific IgE levels in plasma. These patients, who have nonatopic (or intrinsic) asthma, tend to have more serious disease. A recent study suggests that IgE may be produced locally in the airways,20 and that omalizumab may therefore also be effective in these patients.

The findings of Milgrom et al17 suggest that treatment with omalizumab may be useful in patients with severe asthma who require oral corticosteroids. Such treatment may allow the dose of oral corticosteroids to be reduced or permit the drug to be discontinued, thereby eliminating the side effects associated with long-term use of these drugs.

The need to give omalizumab by intravenous injection is an inconvenience, but further studies to determine the optimal dose may lead to less frequent or subcutaneous administration. In the future, it may be possible to identify small-molecule inhibitors of IgE. The use of injections may also be a way to increase compliance with long-term therapy.

A humanized monoclonal antibody is likely to be expensive, but more than half the health care spending on asthma is accounted for by patients with severe asthma, who make up less than 5% of all patients with the disease.8 Furthermore, alternative therapies for corticosteroid-dependent asthma, such as methotrexate, cyclosporine, and oral gold, can cause problems and have a high incidence of adverse effects.21 Therefore, despite the probable high cost of treatment with omalizumab, it is likely that the need for therapy with toxic alternative agents can be reduced, thereby lowering the overall cost of care.

Phyllis C. Braun, PhD, is a professor, Department of Biology, Fairfield University, Fairfield, Conn. John D. Zoidis, MD, is a contributing writer for RT Magazine.

1. Menz G, Ying S, Durham SR, et al. Molecular concepts of IgE-initiated inflammation in atopic and nonatopic asthma. Allergy. 1998;53:15-21.
2. Fahy JV, Fleming HE, Wong HH, et al. The effect of an anti-IgE monoclonal antibody on the early- and late-phase responses to allergen inhalation in asthmatic subjects. Am J Respir Crit Care Med. 1997;155:1828-1834.
3. Heaney LG, Cross LJ, Ennis M. Histamine release from bronchoalveolar lavage cells from asthmatic subjects after allergen challenge and relationship to the late asthmatic response. Clin Exp Allergy. 1998;28:196-204.
4. Barnes PJ. Is immunotherapy for asthma worthwhile? N Engl J Med. 1996;334:521-532.
5. Barnes PJ, Woolcock AJ. Difficult asthma. Eur Respir J. 1998;12:1209-1218.
6. National Asthma Education and Prevention Program. Expert Panel Report 2. Guidelines for the Diagnosis and Management of Asthma. Bethesda, Md: National Institutes of Health; 1997.
7. Kaliner M, Lemanske R. Rhinitis and asthma. JAMA. 1992;268:2807-2829.
8. Barnes PJ, Jonsson B, Klim JB. The costs of asthma. Eur Respir J. 1996;9:636-642.
9. McFadden ER, Gilbert IA. Asthma. N Engl J Med. 1992;327:1928-1937.
10. Chang TW. The pharmacological basis of anti-IgE therapy. Nature Biotechnology. 2000;18:157-162.
11. Corne J, Djukanovic R, Thomas L, et al. The effect of intravenous administration of a chimeric anti-IgE antibody on serum IgE levels in atopic subjects: efficacy, safety, and pharmacokinetics. J Clin Invest. 1997;99:879-887.
12. Boulet LP, Chapman KR, Cote J, et al. Inhibitory effects of an anti-IgE antibody E25 on allergen-induced early asthmatic response. Am J Respir Crit Care Med. 1997;155:1835-1840.
13. Jardieu PM, Fick RB Jr. IgE inhibition as a therapy for allergic disease. Int Arch Allergy Immunol. 1999;118:112-115.
14. Coyle AJ, Wagner K, Bertrand C, Tsuyuki S, Bews J, Heusser C. Central role of immunoglobulin (Ig) E in the induction of lung eosinophil infiltration and T-helper 2 cell cytokine production: inhibition by a non-anaphylactogenic anti-IgE antibody. J Exp Med. 1996;183:1303-1310.
15. Saini SS, MacGlashan DW Jr, Sterbinsky SA, et al. Down-regulation of human basophil IgE and FC epsilon RI alpha surface densities and mediator release by anti-IgE infusions is reversible in vitro and in vivo. J Immunol. 1999;162:5624-5630.
16. Fahy JV, Cockcroft DW, Boulet LP, et al. Effect of aerosolized anti-IgE (E25) on airway responses to inhaled allergen in asthmatic subjects. Am J Respir Crit Care Med. 1999;160:1023-1027.
17. Milgrom H, Fick RB Jr, Su JQ, et al. Treatment of allergic asthma with monoclonal anti-IgE antibody. N Engl J Med. 1999;341:1966-1973.
18. Casale TB, Bernstein IL, Busse WW, et al. Use of an anti-IgE humanized monoclonal antibody in ragweed-induced allergic rhinitis. J Allergy Clin Immunol. 1997;100:110-121.
19. Creticos PS, Reed CE, Norman PS, et al. Ragweed immunotherapy in adult asthma. N Engl J Med. 1996;334:501-506.
20. Menz G, Ying S, Durham SR, et al. Molecular concepts of IgE-initiated inflammation in atopic and nonatopic asthma. Allergy. 1998;53:15-21.
21. Hill JM, Tattersfield AE. Corticosteroid sparing agents in asthma. Thorax. 1995;50:577-582.