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Abstract

Effective asthma treatment requires long-- term inflammation control. Patient adherence to corticosteroid treatment regimens remains problematic. Leukotriene modif iers, a newer drug class, add to the pharmacologic approaches to asthma management Here, we review the role of leukotrienes in asthma pathogenesis and appropriate uses for leukotriene modifiers in asthma management

For unknown reasons, asthma incidence in the United States and other industrialized nations has more than doubled in the past 20 years. Asthma now afflicts an estimated 17.3 million individuals, resulting in more than 5,000 deaths in America alone. Because asthma often remains undiagnosed and therefore under-reported, the actual prevalence maybe even higher. With total disease-related costs exceeding $4 billion annually,1 asthma places a considerable financial burden on society.

Asthma ranks as the third leading cause of preventable hospitalization in the United States. It is a leading cause of school absenteeism, and its costs continue to grow.2?3 Effectively managing this disorder remains a national public health priority. A new class of drugs, leukotriene modifiers, has joined the ranks of effective treatment options, which include inhaled corticosteroids and short-acting and long-acting beta^sub 2^-agonists.

The National Heart, Lung, and Blood Institute's (NHLBI) asthma guidelines include a potential role for leukotriene modifiers in the asthma management stepwise approach.2 When the 1997 asthma guidelines were published, experts did not have enough information to determine the precise placement of this new drug class in the guidelines. Leukotriene modifiers fall into two general classes: leukotriene receptor antagonists and leukotriene synthesis inhibitors. This article reviews the evidence that leukotriene modifiers improve asthma treatment and recommends appropriate placement of these agents in an asthma treatment plan.

* Pathogenesis

Understanding how leukotriene modifiers work in treating asthma requires reviewing the role of leukotrienes, inter- . leukins, and other mediators in the pathogenesis of airway inflammation. Patients with untreated asthma have an excessive number of inflammatory cells in the airway mucosa and submucosa. Even without symptoms, these patients always have airway inflammation, demonstrated by increased numbers of eosinophils, neutrophils, and type-2 T lymphocytes in the airway mucosa. The type-2 T lymphocytes are characterized by the profile of cytokines they produce, the interleukins IL-3, IL-4, and IL-5.

Interleukins play an important role in the growth and differentiation of eosinophils and mast cells and stimulate the production of immunoglobulin E (IgE) by B lymphocytes. Increased concentrations of IL-3, IL-4, and IL-5 can lead to atopy. Atopy signifies the tendency to develop an immune response, characterized by increased production of IgE in response to certain antigens. When atopic patients are exposed to an allergen they are sensitive to, they experience cross-linking of IgE at the surface of mast cells. This initiates an inflammatory cascade that causes immediate bronchoconstriction and chronic inflammatory airway response. Although this response involves many cytokines and mediators released from a variety of inflammatory cells, experts believe cysteinyl leukotrienes produced by mast cells and eosinophils are especially important in promoting the inflammatory processes in the airway.

The action of the enzyme 5-lipoxygenase on the free arachidonic acid (derived from cellular membranes) forms the leukotrienes LTC,, LTD,,, and LTE,. These leukotrienes can produce potent bronchoconstriction and the cardinal symptoms of asthma. Therefore, experts believe that antileukotriene agents have an appropriate role in managing asthma.

Leukotrienes in Asthma Pathogenesis

The increased production of leukotrienes in asthma, as detected by elevated levels of urinary LTE 4, contributes to the inflammatory process.4 Leukotrienes are potent constrictors of bronchial smooth muscle, up to 1,000 times more potent than histamine. They increase vascular permeability, cause edema of the airway mucosa, stimulate mucus secretion, and inhibit mucus clearance by reducing ciliary efficiency. Leukotrienes also attract eosinophils to the airway mucosa, which subsequently promote inflammation. Research supports the role of leukotrienes in inflammation promotion. In two studies, inhalation of LTE^sub 4^ by persons with mild asthma produced increased numbers of eosinophils in the bronchial mucosa; eosinophilia persisted for up to 6 weeks.5,6

Evidence of increased leukotriene production is apparent in elevated urinary LTE^sub 4^ levels after an acute asthma attack,7 during exercise-- induced asthma (bronchoconstriction),8 and during aspirin-induced asthma.9 LTE^sub 4^ plasma levels correlate with reduced forced expiratory volume in I second (FEVI) during asthma attacks, demonstrating their pulmonary function effect.10 Researchers have found elevated levels of LTC^sub 4^ in the bronchoalveolar lavage fluid and sputurn of asthma patients.11,12

In antigen-induced asthma, leukotrienes result in an early response (10 to 15 minutes after allergen challenge) or a late response (4 to 8 hours later). Urinary LTE^sub 4^ excretion peaks 6 to 7 hours after allergen challenge. This late response, associated with increased airway inflammation and bronchial hyperresponsiveness, suggests that leukotriene production and subsequent eosinophil chemotaxis are stimulated by antigen challenge, resulting in the late-phase inflammatory response.13

Cysteine-leukotriene receptors, present in airway and lung tissue, mediate the principal actions of leukotrienes.14 Drugs that specifically block cysteine-leukotriene receptors are called leukotriene receptor antagonists (LTRAs) and indude the U.S. drugs montelukast (Singulair) and zafirlukast (Accolate) and the Japanese drug pranlukast (Ultair). Leukotriene synthesis inhibitors (zileuton [Zyflo]) inhibit 5-lipoxygenase, the enzyme responsible for converting arachidonic acid to leukotrienes.

*Management Strategies Controlling asthma and preventing deleterious clinical out

comes remain the fundamental goals of asthma pharmacotherapy. Base initial therapy on the NHLBI's severity assessment (see Table 1).

The NHLBI recommends two pharmacotherapeutic approaches, both enlisting the stepwise approach (see Table 2). One approach entails initiating therapy appropriate to asthma symptom severity at the time of the initial evaluation. If the patient does not achieve control, step-up the drug doses or add other drugs to the regimen. The second approach entails initiating therapy at a higher dose and, perhaps, adding a second drug class to achieve rapid control. Then, step-down the drugs to a lower dose that still maintains long-term control.

After several weeks or months of consistent asthma control, use a step-down approach to reduce drugs to the minimal, efficient amount.2,15 Evaluate treatment plan efficacy using the patients pulmonary function and symptom profile.

Long-term inflammation control is a vital component of asthma treatment.2 Clinicians have considered inhaled corticosteroids the gold standard, but because of adverse effects, they may reluctantly use them in maximum doses. Clinicians often use alternative anti-inflammatory drugs, such as cromolyn and nedocromil, for treating pediatric asthma. These drugs do not have any adverse effects, but they offer less efficacy than inhaled corticosteroids.

Long-acting beta^sub 2^-agonists, such as salmeterol (Serevent) and formoterol (Foradil), offer long-term control of bronchoconstriction. Short-acting beta,-agonists, albuterol (Ventolin, Proventil) and pirbuterol (Maxair) offer quick relief of bronchoconstriction.

LTRAs offer another drug class for long-term asthma control. A growing body of evidence indicates that LTRAs are effective, well tolerated, and have a low risk of adverse effects, and their place in asthma therapy continues to evolve.

The NHLBI asthma guidelines recommend a daily antiinflammatory drug for patients with mild persistent asthma, either an inhaled steroid or cromolyn or nedocromil. The NHLBI recommends LTRA consideration in adults and children with mild persistent asthma. Available LTRAs include montelukast (Singulair) and zafirlukast (Accolate). The Food and Drug Administration (FDA) approved montelukast for patients age 2 and older and zafirlukast for patients age 7 and older. Since 1995, the manufacturers of pranlukast have marketed this drug in Japan, but researchers continue to conduct clinical trials in Europe and the United States in patients age 18 and older. 16,17

The NHLBI guidelines also recommend leukotriene synthesis inhibitors for adults and children older than age 12. Medication adherence, however, can be problematic because patients must take the drug four times a day. Because of this adherence issue, clinicians do not use this drug as commonly as the leukotriene antagonists; therefore, further management discussion will focus on leukotriene antagonists.

* Leukotriene Receptor Antagonists in Asthma Therapy

Mild-to-Moderate Asthma

In clinical studies, all LTRAs effectively improved the objective measures of pulmonary function in adults with mild-tomoderate asthma. Montelukast (10 mg per day) compared with placebo produced a rapid (within the first day) and significant (P

Improvement in pulmonary function with LTRAs remained stable throughout the clinical trials. Additionally, the LTRAs were equally effective in improving pulmonary function in patients using inhaled corticosteroids and in those who did not. 17,18,20

LTRAs also improved subjective measures of asthma control by reducing asthma daytime symptom scores (7% to 13%), nocturnal awakenings (15% to 22%), and beta^sub 2^-- agonist use (15% to 26%).16,18,19 Montelukast decreased oral corticosteroid rescue in 28% of patients compared with placebo (P = 0.20), days with asthma (-31%, P

During clinical trials, all LTRAs were well tolerated. Adverse effects did not differ from those reported with placebo treatment;16- 119 however, 4% of patients who received zafirlukast showed a mild elevation of serum glutamic-pyruvic transaminase (SGPT) levels (liver enzyme).21 The clinical significance of this finding is unknown.

These research studies indicate that LTRAs improved pulmonary function and patient-reported end points in patients with mild-to-moderate asthma. For these patients, LTRAs may provide an effective and safe therapy or addition to therapy for persistent asthma.

Moderate-to-Severe Persistent Asthma

Researchers have demonstrated the efficacy of LTRAs in managing moderate-to-severe asthma. In these patients, use LTRA add-on therapy with inhaled corticosteroids to improve asthma control or to reduce high doses of inhaled steroids while maintaining the same level of asthma control.

In three studies, LTRAs improved pulmonary function with or without concomitant inhaled corticosteroids. 17,18,20 A prospective study explored whether patients with persistent mild-to-severe asthma (FEVI 50% to 85% of predicted), who were incompletely controlled with inhaled beclomethasone (200 mcg b.i.d.), could benefit from montelukast.22 In patients on concomitant inhaled corticosteroid and montelukast, FEV, increased significantly (0.14 L, P

For patients who are incompletely controlled by low doses of inhaled corticosteroid, a zafirlukast addition may be an effective alternative to doubling the daily dose of inhaled steroid.23 These studies show that LTRAs can provide additional asthma control in patients who receive incomplete control with inhaled corticosteroids alone.

LTRAs may add to the efficacy of inhaled corticosteroids but may also prove useful in reducing the need for higher inhaled steroid doses. Researchers demonstrated this premise in 226 patients with chronic asthma treated with high doses of inhaled corticosteroids. Montelukast (10 mg per day for 12 weeks) permitted a significant 47% reduction (P = 0.046) in the need for inhaled corticosteroids compared with placebo." Indeed, 40% of montelukast-treated patients were able to taper their use of inhaled corticosteroids completely, compared with 29% of placebo-treated patients. These results indicate that LTRAs can be an effective means of reducing inhaled corticosteroids in patients with chronic asthma, while still maintaining control. However, two studies with zafirlukast have failed to show an effect on an inhaled corticosteroid dose that was greater than placebo.21,26

LTRAs vs. Inhaled Corticosteroids

Researchers have compared zafirlukast and montelukast with low-dose, inhaled corticosteroids. A study with montelukast showed beclomethasone had greater effects on pulmonary function, symptoms, and beta 2-agonist use, but both drugs were significantly better than placebo." Researchers found similar results when comparing zafirlukast with beclomethasone: The inhaled corticosteroid was more effective." A range of responses, however, existed. Researchers are unsure why some patients are poor responders and some are good responders to LTRAs, and a method does not exist to predict response.

Pediatric Asthma

The FDA approved montelukast for children age 2 and older and zafirlukast for children age 7 and older. In children ages 6 to 14 with mild-to-- moderate persistent asthma, montelukast (5 mg per day chewable tablets) produced a rapid (within the first day) and significant improvement of pulmonary function (8.2% increase in FEV, and 8.4% increase in morning peak expiratory flow) compared to placebo.29 Study subjects also had decreases in symptoms and beta 2-agonist use. In this study, 30% of the children used inhaled corticosteroids; however, researchers noted benefits both in children using an inhaled steroid and those not using an inhaled steroid. The magnitude of response in children, however, was not as great as the response in adults.

The FDA approved montelukast 4-mg chewable tablets for children ages 2 to 5. Researchers measured efficacy end points of this dose after 12 weeks of treatment. Preliminary results showed that, compared with placebo, montelukast improved days with symptoms (P = 0.012), days with beta 2agonist use (P = 0.001), daytime asthma symptom scores (P = 0.003), corticosteroid rescues (P = 0.008), physician's global evaluation (P = 0.007), and peripheral blood eosinophils (P = 0.034).10 The safety profile of 5-mg and 4-mg pediatric doses was similar to placebo.29-11 These preliminary results suggest that montelukast significantly improved the control of asthma in these children. Exercise-Induced Asthma

LTRAs show promise in treating exercise-induced asthma and allergic rhinitis. In adults, montelukast (10 mg per day) inhibited exercise-induced bronchoconstriction by 47%.32 Also in adults, zafirlukast (20 mg b.i.d.) significantly reduced the decrease in FEV^sup 1^ during exercise-induced bronchoconstriction from -30.2% to -14.5% (P = 0.043).33

In children ages 6 to 14, montelukast (5 mg per day) significantly inhibited exercise-induced bronchoconstriction by 59%, 20 to 24 hours ofter the last dose.14 Similarly, 4 hours after a single dose, zafirlukast significantly inhibited exercise-induced bronchoconstriction (P

LTRAs also protect against allergeninduced asthma. In adults, montelukast significantly inhibited both early- and late-phase allergen responses by 75.4% and 56.9%, respectively (P = 0.003). Zafirlukast presented a similar pattern and significantly attenuated early- (P

Asthma and allergic rhinitis have a common pathophysiology (tissue inflammation); therefore, these conditions can respond to a single treatment.,39 Because LTRAs ameliorate the inflammatory response, they should effectively treat allergic rhinitis, with or without comorbid asthma. In patients with ragweed-induced allergic rhinitis, zafirlukast 40 mg daily reduced nasal congestion and attenuated rhinorrhea.40 Adherence and Tolerability When considering treatment, carefully evaluate a drug's effectiveness, which is a combination of its efficacy and the patient's regimen adherence. LTRAs' simple oral administration and once- or twice-daily dosing help promote patient adherence. Patient perception of drug efficacy and tolerability is another adherence factor. LTRAs have a tolerability profile similar to placebo.18,19,29 In a meta-analysis of safety data from 10 phase IIb/III clinical trials, common adverse effects in 1,955 adults age 15 and older were headache (18.1% placebo, 18.4% montelukast), asthma (19.7% placebo, 14.1% montelukast), and upper respiratory infection (24.6% placebo, 21.5% montelukast).41 In 201 children ages 6 to 14, common adverse effects were headache (21.5% placebo, 18.9% montelukast), asthma (22.2% placebo, 16.4% montelukast), and upper respiratory infection (29.6% placebo, 23.9% montelukast).

Researchers have not noted drug interactions with montelukast; however, zafirlukast interacts with warfarin to lengthen prothrombin time. When prescribing zafirlukast to patients taking warfarin, closely monitor anticoagulation.42

Churg-Strauss syndrome, an eosinophilic vasculitis, has occurred in some asthma patients taking LTRAs who were being weaned from systemic corticosteroids. Researchers believe that ChurgStrauss syndrome, which occurs exclusively in people with asthma, is unmasked by the withdrawal of corticosteroids, not by an allergic reaction to LTRAs.43 Researchers, however, have noted two recent cases of Churg-Strauss syndrome in asthma patients on zafirlukast who had not received oral steroids.44 Use caution when decreasing an oral steroid dose in asthma patients who are oral steroid-dependent and who have started LTRA therapy.

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Susan Janson, RN, ANP, DNSc, FAAN Stephen C. Lazarus, MD

ABOUT THE AUTHORS

Susan Janson is professor of nursing and medicine, University of California, San Francisco.

Stephen C. Lazarus is professor of medicine and director of the chest faculty practice, University of California, San Francisco.

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