Partners Asthma Center Grand Rounds
Jeffrey M. Drazen, M.D.
Leukotriene Modifying Drugs: Two Years'
Leukotriene modifying drugs were the first class of asthma treatments derived from understanding the basic pathobiology of the disorder. The first leukotriene antagonist (pranlukast) was introduced into the practice of medicine in Japan in July, 1995; it is not available in the United States. Since then, three additional leukotriene modifying agents have become available worldwide, beginning in the United States with zileuton (Zyflo®) in November, 1996, zafirlukast (Accolate®) in January, 1997, and montelukast (Singulair®) in March of the following year. By last count over 2.5 million people with asthma were taking these drugs. What have we learned so far? In this presentation I will review briefly the biochemistry of leukotriene formation and pharmacology of leukotriene inhibition, discuss early clinical trials regarding the efficacy of these drugs, and consider their association with a rare complication in asthma, Churg-Strauss syndrome (granulomatous eosinophilic vasculitis).
Leukotrienes received their name because they were originally found in leukocytes and because they contain three double carbon bonds in a row, making their chemical structure a conjugated triene. They are derived from fatty acids, most of which are released from the perinuclear membrane separating the nucleus from the cytosol. Cytosolic phospholipase A2 is the enzyme that cleaves arachidonic acid from the membrane phospholipids. One might inhibit this pathway by inhibiting the action of cytosolic phospholipase A2, but this has not yet been done successfully in man. However, early animal studies in mice and guinea pigs suggest that this may prove to be an effective therapeutic approach.
At the next step of the leukotriene pathway, the arachidonic acid liberated by cytosolic phospholipase A2 interacts with 5-lipoxygenase and the 5-lipoxygenase activating protein (FLAP). Drugs that inhibit FLAP are effective asthma treatments, but none is commercially available. On the other hand, an inhibitor of 5-lipoxygenase is available, namely zileuton or Zyflo®. It inhibits production of both the cysteinyl leukotrienes, LTC4, LTD4, and LTE4, as well as leukotriene B4, an important mediator of neutrophilic inflammation. Specific inhibitors of the next enzymatic steps, LTC4 synthase and epoxide hydolase, have not been developed. Likewise, we do not yet have the means to block export of LTC4 out of cells or the conversion of LTC4 to LTD4 by gammaglutamyl transpeptidase. What is available are drugs with the ability to antagonize the action of LTD4 at its receptor; this class of drugs is referred to as "lukasts."
The leukotriene receptor antagonists, montelukast (Singulair®) and zafirlukast (Accolate®), are of approximately equivalent potency. They are very potent receptor antagonists, shifting the leukotriene dose-response curve over 100-fold. They account for the vast majority of sales of leukotriene modifying drugs and will be the focus of my subsequent comments. The rapid rise in their sales over just 1-2 years bespeaks their widespread acceptance among both patients and physicians.
Clinical trials with the leukotriene blockers
Two important clinical trials have addressed the efficacy of leukotriene receptor antagonists for treatment of mild asthma. They give support to the position, argued in a recent editorial written by Dr. Elliot Israel and me for the American Journal of Respiratory and Critical Care Medicine, that leukotriene blockers are appropriate first-line treatment for mild persistent asthma.
The first study is a randomized, placebo-controlled, double-blind clinical trial comparing zafirlukast with placebo in mild asthma. The major outcome of the study was control of asthmatic symptoms. Patients had only mild airflow obstruction at the start of the trial. In fact, one third of the patients in this trial had an initial FEV1 greater than 90% of predicted. At this level of lung function, it is difficult to demonstrate quantitative improvements in expiratory flow. The focus of the trial was asthmatic symptoms, with the inference that if symptoms improved, so did lung function. After all, it is asthmatic symptoms that bring patients to their doctors, seeking relief.
Patients scored their asthma symptoms at home on a daily basis. The scale ranged from 0 (no symptoms) to 3 (lots of symptoms). Entry into the study required a minimal average weekly score of 8. Upon entry, patients were randomly assigned to treatment with zafirlukast 20 mg or placebo taken twice daily and then followed over 13 weeks of therapy.
In the zafirlukast-treated group, there were major improvements in the patients' symptoms. Half as many patients dropped out of the study with an asthmatic exacerbation in the zafirlukast-treated group as did in the placebo group. Symptom scores were significantly lower (indicating greater well-being) with zafirlukast. The number of days that patients did not need to use their beta-agonist inhaler was twice as great in the zafirlukast group. In addition, a number of outcomes with economic implications were tracked. The number of minor episodes of asthma, the number of days per month lost from work or school, and the number of healthcare contacts about asthma were all cut in half by the active treatment. An interesting observation that comes out of this study, then, is that in mild asthma, patients may have only small increases in their lung function and yet experience substantial subjective improvement. Zafirlukast-treated patients felt better and had significantly better outcomes, both clinically and statistically, than did patients treated with placebo.
The other study on which I would like to focus was conducted in asthmatic children using montelukast. Children with moderate persistent asthma aged 6-14 (median age = 11 years) were randomized in a 2:1 ratio to montelukast 5 mg chewable tablet at bedtime or placebo. Approximately 35%-40% of the subjects were using inhaled corticosteroids concomitantly. The observed improvement in lung function (FEV1) was 10-15% in the montelukast-treated group compared to only 5% with placebo, a clinically significant difference. At the same time, beta agonist use decreased by about 10% in the montelukast group. Interestingly, the number of eosinophils in the peripheral blood decreased approximately 10-15% with montelukast treatment over the 8-week duration of the trial. This is a characteristic response to the leukotriene modifiers, confirming their antiinflammatory activity. Perhaps the most important outcome in this study was the change in asthma-specific quality of life as measured by questionnaire survey. In each of the 3 domains of this survey — activity, symptoms, and emotions — there was greater improvement with active treatment than with placebo. In short, in this study leukotriene modifying therapy improved lung function and improved how the children felt.
Comparison with inhaled steroids
It is clear from studies that have compared the response to leukotriene receptor antagonists with inhaled corticosteroids that the latter result in a greater overall improvement in lung function. In this comparison (Figure 1) between montelukast and inhaled beclomethasone, the results are displayed as a histogram showing the percent of patients (height of the bars) against the percent change in FEV1 from baseline (horizontal axis) for the treatment with the two agents. This representation of the results allows you to see how many patients improved their FEV1 by a certain amount. The two treatment groups overlap closely in the middle range: for example, approximately 24% of the patients had a 10-20% increase in FEV1 with montelukast compared to approximately 26% with beclomethasone. It is only at the very high levels of improvement (e.g., greater than 30% increase in FEV1) that the bars are 2-3 times higher with beclomethasone than montelukast. This observation indicates that the overall improvement in FEV1, nearly twice as great in the steroid-treated group, was driven mainly by a few patients who had very large responses to the inhaled steroids.
In comparing these two forms of asthma therapy, one also needs to consider the issue of medication compliance. Patients often prefer to take tablets to using inhalers, and once- or twice-daily oral administration is very convenient. Long-term medication compliance is an important consideration with controller medications in asthma. In a study by Kelloway and colleagues comparing oral versus inhaled drug therapy (theophylline twice daily versus cromolyn four times daily), medication compliance at 3 months was 80% with oral therapy compared with 65% with inhaler use.
Consider, then, the following analysis. If you were to treat 100 patients with mild asthma with conventional doses of inhaled beclomethasone (400 µg twice daily), you might expect 50 of them to have a greater than 10% improvement in FEV1. At three months, with only 65% still compliant with inhaled medication, only 32 patients will sustain this benefit. On the other hand, if you were to treat these same 100 patients with a leukotriene modifying drug, 42 would be expected to have improvement in FEV1 of more than 10%. At three months, with 80% compliance with oral medication, 36 patients would be expected to have sustained improvement. By taking medication compliance into account, this analysis gives a slight advantage to initial treatment with leukotriene modifiers in mild asthma.
If patients don't improve with leukotriene modifying therapy, it is appropriate then to begin inhaled corticosteroids. Or if a patient has moderate persistent asthma, with an FEV1 60% of predicted and waking up twice each week with asthmatic symptoms, one might start both inhaled steroids and leukotriene modifiers simultaneously. It is important to remember that these two types of therapies are not at war with each other; they are complementary. In the leukotriene modifiers we have a new weapon in our fight against asthma, one that patients will take and that will help to make them better.
When zafirlukast was launched in early 1997, approximately 4000 patients had been treated with the drug in clinical trials for about one year. The drug had proven to be extremely safe, with an incidence of side effects or chemical abnormalities (including liver function tests) no greater than placebo. However, after approximately 6 months, with approximately 40,000 patient-years of clinical experience with the leukotriene receptor antagonist, a rare (and, in many ways, very informative) complication emerged, the Churg-Strauss syndrome. One of the first patients reported was my patient, as described below.
This 45 year-old woman had had sinusitis and asthma for 5 years. Her asthma had required multiple courses of oral corticosteroids for control. After starting zafirlukast, she did remarkably well. She had normal lung function and was pleased to report that she could now beat her husband at paddle tennis. However, after about one month of therapy, she presented with flu-like symptoms, including fever. She did not have wheezing. Suspecting a potential systemic reaction to the medication, I stopped her zafirlukast.
Within 3-4 days she deteriorated significantly and presented to the emergency department with shortness of breath, severe wheezing, and a new erythematous skin rash. She had leukocytosis with 36% peripheral blood eosinophils. Her chest X-ray (Figure 2) revealed dense, bilateral airspace infiltrates and mild cardiomegaly. She developed a unilateral foot drop that was subsequently shown to represent a mononeuritis multiplex. Her work-up included a positive peripheral antinuclear cytoplasmic antibody titer (p-ANCA), an echocardiogram that showed global ventricular hypokinesis with an ejection fraction of 40%, and a skin biopsy showing a perivascular infiltrate with lymphocytes and eosinophils and intravascular thrombi. She underwent thoracoscopic lung biopsy, which found an organizing eosinophilic pneumonia with some necrosis in vessel walls (Figure 2).
She was diagnosed with Churg-Strauss syndrome and treated with systemic corticosteroids and cyclophosphamide. Within two weeks her respiratory symptoms resolved and her pulmonary function returned to normal. Her chest X-ray cleared entirely, her blood eosinophilia resolved, and her echocardiogram showed recovered cardiac function. She was left with a mild residual foot drop.
With the help of Dr. Michael Wechsler in our Division, we collected and reported 8 cases of Churg-Strauss vasculitis among persons who had recently been begun on treatment with zafirlukast. There were 7 women and one man with an age range of 20-60 years. They all had steroid-dependent asthma. All of these patients presented with pulmonary infiltrates and blood eosinophilia. They all had evidence for myocarditis on biopsy or cardiomyopathy on echocardiogram. Additional findings included peripheral mononeuritis in two, sinusitis in six, skin rash (palpable purpura) in three, muscle pain in seven, and fever in six. Six had elevated erythrocyte sedimentation rates. A common theme was that they had all started zafirlukast within the prior four months and then discontinued their high-dose steroids within three months of presentation.
These patients responded rapidly to re-initiation of high-dose systemic corticosteroids (and in two cases, to cyclophosphamide in combination with steroids). Dr. Wechsler has provided long-term follow-up for five of these patients. (Two were lost to follow up; one died of pre-existing heart disease.) Despite remaining off zafirlukast, one patient developed recurrence of rash and eosinophilia on a lower dose of prednisone, and two other patients experienced asthma flairs at lower steroid doses. Four of the five still require regular systemic steroids for control of their disease.
The incidence of Churg-Strauss syndrome among patients treated with leukotriene receptor antagonists is extremely low. The Food and Drug Administration (FDA) reports one case per 64 million patient-years of treatment. This incidence is comparable to the frequency of anaphylaxis to penicillin (a medicine that we do not hesitate to administer). It is a rare event, found almost exclusively among patients previously with severe, hard-to-manage asthma.
As we thought about potential mechanisms for precipitating Churg-Strauss syndrome in these patients, we considered several possibilities. First, it was possible that these events occurred independent of initiation of the leukotriene blocker, but the case rate (compared to the usual prevalence of the disease) made this unlikely. Second, it might have been a direct effect of the specific drug, zafirlukast, but we now know that this is not the case. Fourteen definite cases have been described with montelukast, an incidence estimated at 56 cases per million patient-years of treatment. Interestingly, several cases of Churg-Strauss syndrome have recently been described among persons with asthma who were newly begun on the inhaled steroid, fluticasone, arguing against a specific drug class effect with the leukotriene modifiers.
We believe that the best explanation for the association between the leukotriene modifying drugs and Churg-Strauss syndrome is that these patients had a pre-existing forme fruste of Churg-Strauss syndrome that was masked by chronic steroid therapy and then revealed when antileukotriene therapy was begun and the steroids withdrawn. Remember that eosinophils make not only leukotrienes but also proteases and cationic proteins that mediate tissue injury, giving them a kind of "one-two punch." With effective anti-leukotriene therapy, the bronchoconstrictive effect of the leukotrienes is inhibited and asthmatic symptoms well controlled. Prior to the leukotriene modifiers, when these patients with an occult eosinophilic vasculitis tapered their corticosteroids, they experienced a flare of their asthma, and the steroid dose would again be increased. Now, on a leukotriene modifier, they did not experience wheezing with steroid taper, and the underlying Churg-Strauss syndrome could become manifest with tissue injury expressed at sites other than the airways. What we have learned is that some of our patients with severe, steroid-dependent asthma in fact may have an undiagnosed underlying eosinophilic vasculitis.
If you have a case of Churg-Strauss syndrome associated with use of leukotriene modifiers, I urge you to contact the drug manufacturer and the FDA. The paperwork is not onerous, and we will all benefit as we learn more about this syndrome, its epidemiology, and its expression.
My focusing on this very rare complication of asthma therapy today is somewhat analogous to the time devoted on each airplane flight to use of the oxygen masks. Although the event is exceedingly uncommon, you will be prepared to deal with it should it occur.
1. Suissa S, Rodolfo D, Pierre E, et al. Effectiveness of the leukotriene receptor antagonist zafirlukast for mild-to-moderate asthma: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1997; 126:177-83.
2. Knorr B, Matz J, Bernstein J, et al. Montelukast for chronic asthma in 6- to 14-year-old children: a randomized, double-blind trial. JAMA 1998; 279:1181-6.
3. Wechsler ME, Garpestad E, Flier SR, et al. Pulmonary infiltrates, eosinophilia, and cardiomyopathy following corticosteroid withdrawal in patients with asthma receiving zafirlukast. JAMA 1998; 279:455-7.
About the author: Dr. Jeffrey Drazen has conducted research into the role of leukotrienes in asthma since medical school. He is currently Chief of the Pulmonary and Critical Care Division at the Brigham and Women's Hospital, Director of the Partners Asthma Center, and the Parker B. Francis Professor of Medicine at Harvard Medical School. (Editor's Note: Dr. Drazen is now Editor-in-Chief at the New England Journal of Medicine.)