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Published ahead of print on September 13, 2007, doi:10.1164/rccm.200701-085OC
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American Journal of Respiratory and Critical Care Medicine Vol 176. pp. 1062-1071, (2007)
© 2007 American Thoracic Society
doi: 10.1164/rccm.200701-085OC

Original Article

A Study to Evaluate Safety and Efficacy of Mepolizumab in Patients with Moderate Persistent Asthma

Patrick Flood-Page1, Cheri Swenson2, Isidore Faiferman3, John Matthews3, Michael Williams3, Lesley Brannick3, Douglas Robinson4, Sally Wenzel5, William Busse2, Trevor T. Hansel4, Neil C. Barnes6 and on behalf of the International Mepolizumab Study Group*

1 Royal Gwent Hospital, Newport, Wales, United Kingdom; 2 Allergy and Asthma Clinical Research Unit, University of Wisconsin-Madison, Madison, Wisconsin; 3 Respiratory and Inflammation Discovery Medicine, GlaxoSmithKline, Greenford, United Kingdom; 4 National Heart and Lung Institute, Imperial College London, London, United Kingdom; 5 National Jewish Medical and Research Center, Denver, Colorado; and 6 London Chest Hospital, London, United Kingdom

Correspondence and requests for reprints should be addressed to N. C. Barnes, F.R.C.P., London Chest Hospital, Bonner Road, London E2 9JX, UK. E-mail: neil.barnes{at}bartsandthelondon.nhs.uk


   ABSTRACT
TOP
 ABSTRACT
AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Rationale: Accumulation of eosinophils in the bronchial mucosa of individuals with asthma is considered to be a central event in the pathogenesis of asthma. In animal models, airway eosinophil recruitment and airway hyperresponsiveness in response to allergen challenge are reduced by specific targeting of interleukin-5. A previous small dose-finding study found that mepolizumab, a humanized anti–interleukin-5 monoclonal antibody, had no effect on allergen challenge in humans.

Objectives: To investigate the effect of three intravenous infusions of mepolizumab, 250 or 750 mg at monthly intervals, on clinical outcome measures in 362 patients with asthma experiencing persistent symptoms despite inhaled corticosteroid therapy (400–1,000 µg of beclomethasone or equivalent).

Methods: Multicenter, randomized, double-blind, placebo-controlled study.

Measurements and Main Results: Morning peak expiratory flow, forced expiratory volume in 1 second, daily beta2-agonist use, symptom scores, exacerbation rates, and quality of life measures. Sputum eosinophil levels were also measured in a subgroup of 37 individuals. Mepolizumab was associated with a significant reduction in blood and sputum eosinophils in both treatment groups (blood, P < 0.001 for both doses; sputum, P = 0.006 for 250 mg and P = 0.004 for 750 mg). There were no statistically significant changes in any of the clinical end points measured. There was a nonsignificant trend for decrease in exacerbation rates in the mepolizumab 750-mg treatment group (P = 0.065).

Conclusions: Mepolizumab treatment does not appear to add significant clinical benefit in patients with asthma with persistent symptoms despite inhaled corticosteroid therapy. Further studies are needed to investigate the effect of mepolizumab on exacerbation rates, using protocols specifically tailored to patients with asthma with persistent airway eosinophilia.

Key Words: anti–interleukin-5 • asthma • eosinophils • mepolizumab • monoclonal antibodies



   AT A GLANCE COMMENTARY
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Scientific Knowledge on the Subject
IL-5 is believed to be a key cytokine in eosinophil function at sites of allergic inflammation. A previous small dose-finding study found the humanized anti–IL-5 monoclonal antibody mepolizumab had no effect on allergen challenge in humans.

What This Study Adds to the Field
Mepolizumab treatment does not appear to add significant clinical benefit in patients with asthma with persistent symptoms despite inhaled corticosteroid therapy.

 
Selective accumulation and activation of eosinophils in the bronchial mucosa is considered a central event in the pathogenesis of asthma. Eosinophils are an important source of mediators of airway narrowing such as leukotriene C4 and release of basic granule proteins has been linked to airway hyperresponsiveness (AHR) in animal models and humans (1, 2). Airway eosinophilia has been related to AHR, asthma symptoms, and airway narrowing in subjects with asthma (3). IL-5 is believed to be a key cytokine in eosinophil differentiation (4), recruitment (5), activation, and survival (6) at sites of allergic inflammation. Expression of IL-5 is elevated in bronchoalveolar lavage (BAL) fluid and bronchial biopsies in patients with asthma (7). Moreover, the level of IL-5 in BAL fluid and the bronchial mucosa correlates with disease activity (8–10). Although inhaled corticosteroid therapy reduces airway eosinophilia, approximately 50% of patients with severe asthma nevertheless experience persistent eosinophilic airway inflammation (11, 12). Thus, specific targeting of airway eosinophilia is an attractive option for improving asthma control. In animal models of asthma, IL-5 gene disruption abolished eosinophilia and AHR in mice (13), and anti–IL-5 monoclonal antibody treatment prevented allergen-induced airway eosinophilia and AHR both in primates (14) and murine models (15, 16).

Humanized monoclonal antibodies against IL-5 have been synthesized that allow the role of this cytokine to be studied in individuals with asthma. One such antibody, mepolizumab, is a high-affinity humanized, non–complement-fixing monoclonal antibody (IgG1) specific for human IL-5 (17). Mepolizumab blocks the binding of human IL-5 to the {alpha} chain of the IL-5 receptor complex expressed on the eosinophil cell surface (17). In two pilot studies of anti–IL-5 therapy, one in steroid-naive patients with mild asthma, and the other including corticosteroid-dependent patients with severe asthma, IL-5 receptor blockade resulted in a profound reduction in both circulating and sputum eosinophils (18, 19). However, in contrast to the results of animal studies, there was no discernable effect of IL-5 blockade on either AHR or the late asthmatic response after allergen challenge in patients with mild asthma (18, 20), or sustained effect on lung function in patients with symptomatic disease (19). Because these studies were too small to reliably measure clinical outcomes we performed a randomized, placebo-controlled trial administering mepolizumab monthly for 3 months to patients with moderately severe asthma and with persistent symptoms despite inhaled corticosteroid treatment.


   METHODS
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
Enrolled into the study were nonsmoking subjects, aged 18–55 years, with asthma managed with inhaled corticosteroids (maximum dose of beclomethasone dipropionate [BDP] or equivalent, 1,000 µg/d) (21). The FEV1 had to be at least 50% and not more than 80% of the predicted value for age, sex, and height with documented beta2-agonist reversibility of at least 12% after administration of 180 µg of albuterol (salbutamol). The daily symptom score had to be at least 4 (maximum score, 12) during the 7 days preceding the baseline assessment (see below).

The principal exclusion criteria to ensure asthma stability and safety before dosing were as follows: an absolute FEV1 value measured at randomization (visit 3) that had changed by more than 20% from the value determined at a baseline signs-and-symptoms visit 2 weeks before dosing (visit 2); an upper respiratory tract infection in the 2 weeks before the first visit; use of oral corticosteroids in the 4 weeks before the first visit; or poorly controlled asthma, defined as hospitalization or an emergency room visit for the treatment of asthma in the 6 weeks before the first visit.

Study Design
The study was a randomized, double-blind, placebo-controlled, parallel group trial. The study was conducted at 55 centers in five countries (France, Germany, the Netherlands, the United Kingdom, and the United States). Participating centers and investigators are listed at the end of this article. The protocol was approved by local ethics committees and review boards and all subjects provided written, informed consent.

After screening, eligible individuals were entered into a 4-week run-in period to ensure stable disease. Patients who continued to meet the entry criteria at visit 3 (baseline) were randomized to one of three treatment groups: mepolizumab (750 mg), mepolizumab (250 mg), or placebo (Figure 1). Study medication was first administered by intravenous infusion at baseline (visit 3) and subsequently on two further occasions at intervals of 4 weeks. The primary end point was determined 4 weeks after the last dose (i.e., at Week 12), when significant systemic drugs levels would still be measurable. This was based on the pharmacokinetics of mepolizumab, with a 21-day elimination half-life, and the observation of a prolonged effect on blood eosinophil counts after a single dose (18) suggested that monthly dosing would be sufficient to elicit clinical benefit in patients with asthma. After the assessment 4 weeks after the last dosing, subjects entered an 8-week follow-up period.


Figure 1
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  		Figure 1. Overview of study design.

 
Safety Assessments
At each scheduled clinic visit, a respiratory examination was performed and vital signs and adverse events were recorded. Electrocardiograms were obtained and blood samples were collected for routine clinical chemistry and hematologic analysis at visits 1, 3, 4, 6, 8, 10, and 12. Patients were tested at the same time for the presence of anti-idiotypic or anti-framework antibodies to mepolizumab.

Outcomes Measures
The primary efficacy variable was the change from baseline in domiciliary morning peak expiratory flow (PEF) recorded at Weeks 12 and 20. This was recorded as the mean PEF over the 7 days preceding the treatment period (baseline value) and preceding Weeks 12 and 20. The secondary efficacy variables were the changes from baseline of FEV1, asthma summary symptom scores (the total of the daytime asthma, nighttime asthma, and morning asthma scores), use of rescue medication such as albuterol (salbutamol), quality of life scores, asthma exacerbation rates, and eosinophil counts in blood and sputum.

Diary Card Data
Patients filled in a daily diary card throughout the study. This recorded (1) the best of three measurements of PEF made with a peak flow meter (Miniwright; Armstrong Industries, Northbrook, IL) in the morning and evening before medication, (2) symptoms of asthma during the night, on wakening, and throughout the day (according to a five-point scale, with 0 indicating no symptoms and 4 indicating incapacitating symptoms, giving a daily summary score out of 12), and (3) daily use of beta2-agonist rescue medication. The average of each of the diary card outcome variables was taken over the 7 days before baseline, at Week 12, and again at Week 20.

Measurement of Lung Function
FEV1 was measured at each scheduled visit, and the best of three expirations was recorded (Jaeger Masterscope GmbH, Hoechberg, Germany).

Assessment of Quality of Life
Quality of life was evaluated with the Asthma Quality of Life Questionnaire, a validated asthma-specific health status instrument (22).

Asthma Exacerbations
An asthma exacerbation was defined as an acute worsening of asthma requiring additional treatment in excess of an increase in short-acting beta2-agonist. This included a deterioration of asthma that necessitated presentation to an emergency department, admission to a hospital, or withdrawal from the study. The dose of inhaled corticosteroid could be increased for a maximum of 2 weeks to treat an exacerbation. Similarly, oral corticosteroids were allowed for a maximum of 2 weeks to treat a more severe exacerbation. However, if additional treatment beyond this 2-week period was necessary, or if an asthma exacerbation requiring increased doses of inhaled corticosteroids occurred on more than two occasions, the patient was to be withdrawn from the study. All exacerbations of asthma were to be recorded in the adverse experience module of the case report form. In addition, the type of medical care the patient received for the exacerbation was recorded in the resource utilization module of the case report form. Any asthma exacerbation resulting in hospitalization was to be reported as a serious adverse experience.

Exacerbations were divided into level 1 (requiring treatment with increased doses of inhaled corticosteroids, nebulized bronchodilator, or oral xanthines), level 2 (requiring treatment with oral corticosteroids), or level 3 (requiring hospitalization). Exacerbations were recorded for three time periods: Weeks 0–12, 12–20, and 0–20. For individuals with more than one exacerbation, only the highest exacerbation level was counted for each time period. Individuals with more than two exacerbations were withdrawn.

Blood Eosinophils
Peripheral venous blood samples were taken at visits 1, 3, 4, 6, 8, 10, and 12. For subjects who were outside the normal range subsequent follow-up visits were arranged until the eosinophil count was within the normal range. Blood eosinophil numbers were measured at a central laboratory (Quest Diagnostics, Madison, NJ) with an automated cell counter (Coulter Counter; Beckman Coulter, Fullerton, CA). To prevent unblinding during the study, the eosinophil count and the total white blood cell count were not disclosed to the investigator or other personnel involved in the study, until the study was completed. Differential white cell counts, apart from the eosinophil count, were reported, however. SBCL Laboratories informed investigators if a patient had an eosinophil count below the normal range at visit 12 or at the final early withdrawal visit, and at any subsequent follow-up visits.

Sputum Induction and Analysis
In a subgroup of 37 patients, sputum was induced and processed at four centers in the United States and at three centers in Europe by a procedure similar to that described by Fahy and coworkers (23), using nebulized 3% saline. Cells were deposited onto slides by low-speed centrifugation (Shandon Cytospin; Thermo Fisher Scientific, Waltham, MA) and stained for eosinophils, using a commercial preparation (Diff-Quik; Dade Behring, Marburg, Germany). Sputum processing was performed at baseline and subsequently at visits 8, 12, 16, and 20. Blinded slides were read at two central sites, one in Europe and one in the United States. Counts were then checked by an exchange of slides between sites. Eosinophil numbers were expressed as the percentage of the total white blood cells. Patients who were unable to produce a processable sample continued in the study but were excluded from the sputum arm.

Pharmacokinetic Sampling
Five blood samples for pharmacokinetic analysis of mepolizumab plasma concentration data were collected from all randomized patients. Blood samples were drawn from designated subgroups of patients who were randomized on the basis of patient identification numbers (PIDs) to various time points. From patients with even-numbered PIDs, blood samples were obtained at the following times: Day 1 (Week 0 [visit 3], immediately after the end of infusion), Week 1 (visit 4), Week 2 (visit 5), Week 4 (visit 6, before administration of the second dose), and Week 8 (visit 8, before administration of the third dose). From a second group of patients with odd-numbered PIDs, blood samples were obtained at the following times: Week 8 (visit 8, two samples: one before the start of infusion and one immediately after the end of infusion), Week 12 (visit 10), Week 16 (visit 11), and Week 20 (visit 12).

Statistical Analysis
Assuming a standard deviation (SD) for change in morning domiciliary PEF to be 40 L/minute, an estimated 100 evaluable patients per treatment arm were required to detect a difference of 20 L/minute between either mepolizumab group and placebo, with 90% power and a type I error rate of 5%. The assumption of 40 L/minute is entirely consistent with historical evidence of the between-group SD for morning PEF.

The primary endpoint for this study (mean change from baseline in domiciliary PEF) was analyzed by analysis of variance. Adjustment for multiple comparisons was made via the modified Bonferroni procedure (24). Confidence intervals (95%) for the means were calculated for each treatment group as well as for the difference in means between each dose of mepolizumab and placebo. The same method was used to analyze changes in clinic visit FEV1 and other diary card data. Blood and sputum eosinophils were evaluated by Wilcoxon rank-sum test. Asthma exacerbation rates were compared by chi-square test. There was no statistical powering of the sputum sampling as this was based on the feasibility of assessing in a subgroup of centers with the aim of assessments from at least 50 subjects.


   RESULTS
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
A total of 624 patients were screened and 362 patients entered the randomized phase of the study (Figure 2). The most common reason for patient withdrawal before randomization was "did not meet inclusion/exclusion criteria" (n = 215; 82.1%), followed by "other reasons" (32; 12.2%) including consent withdrawal (14; 5.3%), and baseline signs and symptoms (15; 5.7%). Of the 362 patients randomized into the study, a total of 21 patients (5.8%) were withdrawn. The percentage of patients completing the study was high for all treatment arms. The most common reason for withdrawal during the study was adverse experience (n = 10; 2.8%). The percentage of patients who were withdrawn because of adverse experiences was higher among patients receiving placebo (4.0%) and mepolizumab at 250 mg (3.3%) compared with patients receiving mepolizumab at 750 mg (0.9%). A total of 37 patients were randomized to the induced sputum arm of the study, and 3 patients were subsequently withdrawn.


Figure 2
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  		Figure 2. Disposition of patients.

 
Subjects were well matched at baseline (Table 1). Although the baseline asthma summary symptom score for the mepolizumab (250 mg) group was significantly lower than for the placebo group (P = 0.003), the magnitude of the difference was small.


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  		TABLE 1. CHARACTERISTICS OF PATIENTS AT BASELINE

 
Safety
Mepolizumab was well tolerated. Nine serious adverse events were reported: four in patients receiving placebo (vertigo, bladder carcinoma, unintended pregnancy, and asthma exacerbation), three in patients receiving mepolizumab at 250 mg (hydrocephalus/cerebrovascular disorder, constipation, and gastrointestinal disturbance), and two in patients receiving mepolizumab at 750 mg (asthma exacerbation). None of these serious adverse events was considered by the investigators to be related to study medication. There were no significant differences between the treatment groups for these or any other adverse events reported. The most common adverse events (at least 5% of subjects in any treatment group) were as follows: upper respiratory tract infection, asthma, headache, rhinitis, bronchitis, sinusitis, viral infection, injury, back pain, nausea, and pharyngitis. No antiidiotypic or antiframework antibodies to mepolizumab were detected at any time during the study.

Efficacy Variables
Morning domiciliary PEF.
Summary results for the clinical end points are presented in Table 2. The mean morning PEF increased from baseline values throughout the study in all three treatment groups (Figure 3). There was a greater increase in morning PEF in the mepolizumab 250-mg treatment group by Week 20 compared with the placebo group (P = 0.039). However, the size of the difference compared with placebo was only 13.5 L/minute.


Figure 3
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  		Figure 3. Mean (SEM) values for morning domiciliary peak expiratory flow rate (PEFR; L/min).

 

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  		TABLE 2. CLINICAL ENDPOINTS

 
FEV1.
There were no significant differences in the changes in FEV1 between the three treatment groups (Figure 4).


Figure 4
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  		Figure 4. Mean (SEM) values for clinic FEV1 (L).

 
Symptom Scores, beta2-Agonist Use, and Quality of Life Assessment
The mean asthma summary symptom score decreased from baseline to Week 20 in all three treatment groups (indicating an improvement in asthma symptoms). There was a greater decrease in the placebo group than in the mepolizumab 750-mg treatment group (Figure 5). There were no differences between the treatment groups in beta2-agonist use or mean Asthma Quality of Life Questionnaire overall score.


Figure 5
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  		Figure 5. Mean (SEM) values for asthma summary symptom score.

 
Exacerbation Rates
Exacerbation rate data are summarized in Figure 6. A higher proportion of patients in the placebo group (20 of 126; 16%) and mepolizumab 250-mg treatment groups (21 of 120; 18%) had an exacerbation of any level during the study, compared with the mepolizumab 750-mg treatment group (11 of 116; 10%). These differences did not reach significance (P = 0.265) but there was a (nonsignificant) trend toward a reduction in exacerbation rates for level 2 and 3 exacerbations recorded from Weeks 12 to 20 (P = 0.065, chi-square test). There were no significant differences between the treatment groups for each exacerbation level.


Figure 6
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  		Figure 6. Percentage of exacerbations by level of severity, within each treatment group, by period in the study (each subject was counted only once, at the highest level of severity). Mepo = mepolizumab.

 
Blood and Sputum Eosinophils
Infusion of mepolizumab at both 250 and 750 mg produced a rapid and marked reduction in blood eosinophils that was significant at Week 1 and sustained throughout the study (P < 0.001) (Figure 7). Mepolizumab caused a significant decrease in sputum eosinophils at both doses (P = 0.006, 250 mg; P = 0.004, 750 mg). These changes were significantly different from those in the placebo group (P = 0.005, 250 mg; P = 0.001, 750 mg) (Figure 8). Of the 32 patients who provided baseline and Week 12 samples, 17 had sputum eosinophilia (more than 3%) at baseline: 7 patients in the placebo group, 7 patients in the mepolizumab 250-mg group, and 3 patients in the mepolizumab 750-mg group.


Figure 7
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  		Figure 7. Mean (SEM) values for blood eosinophils (x109/L).

 

Figure 8
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  		Figure 8. Sputum eosinophils (%) at baseline and at Week 12 in evaluable patients (n = 32). Sputum induction was performed at seven centers: 18 of 32 subjects had baseline sputum eosinophilia exceeding 3% (only 3 subjects receiving mepolizumab at 750 mg).

 
The fall in blood eosinophils in the mepolizumab-treated groups was sustained for 12 weeks after the last treatment, until the end of the study. A total of 71 subjects had blood eosinophil counts below the normal range at visit 12 and these returned to normal during follow-up. For 34% of individuals, the recovery took 3 months or more and for one subject it occurred after 9 months of follow-up. Sixteen subjects were lost to follow-up and no samples were available to assess recovery.

Pharmacokinetic Results
The planned population pharmacokinetic and pharmacokinetic–pharmacodynamic analyses were not conducted because of the observation of a lack of effect of mepolizumab on the primary endpoint. Mepolizumab plasma concentration–time data are summarized descriptively in Figure 9. At Week 12 (visit 10) the plasma mepolizumab concentration of drug was 22.2 (9.1) [mean (SD)] ng/ml in the 250-mg dose group (n = 36) and for the 750-mg dose group it was 51.2 (19.5) ng/ml (n = 47). Mepolizumab exhibited approximately dose-proportional pharmacokinetics and a long terminal half-life of approximately 21 days.


Figure 9
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  		Figure 9. Mepolizumab mean and individual concentration data, summarized by visit. (a) 250-mg dose level; (b) 750-mg dose level.

 

   DISCUSSION
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the present study, we report on the use of mepolizumab, a monoclonal antibody to IL-5, in patients with moderately severe asthma with persistent symptoms despite treatment with inhaled corticosteroids. Mepolizumab was well tolerated with minimal adverse events associated with drug administration. Despite significant reductions in blood eosinophil numbers and sputum eosinophilia (where this was measured) with 250 and 750 mg of mepolizumab versus placebo, effects on lung function were minimal (a 13.5-L/min increase relative to placebo with mepolizumab at 250 mg only) and no significant effect was seen on FEV1 or symptom scores.

At higher doses of mepolizumab there was a 50% reduction in exacerbation rates compared with placebo. This difference did not reach significance and the study was underpowered to detect such changes. Nonetheless, these findings are in accord with data linking airway eosinophilia with asthma exacerbations. In particular, Green and coworkers devised a treatment algorithm adjusting inhaled steroid dose according to sputum eosinophilia and showed that this resulted in a dramatic reduction in exacerbation frequency when compared with current best care and patients without sputum eosinophilia did not benefit from this strategy (25). In one study these findings have been confirmed in a similar study in which monitoring sputum cell counts was found to benefit patients with moderate-to-severe asthma by reducing the number of eosinophilic exacerbations and by reducing the severity of both eosinophilic and noneosinophilic exacerbations without increasing the total corticosteroid dose. It had no influence on the frequency of noneosinophilic exacerbations, which were the most common exacerbations (26).

The findings of the current study suggest that anti–IL-5 treatment is not effective in improving lung function or symptoms in patients with persistent symptoms despite treatment with inhaled steroids. These findings are in keeping with data from a small exploratory study of mepolizumab treatment, which showed no effect on AHR or allergen-induced late responses in patients with mild asthma (18), and from a study using another humanized anti–IL-5 treatment, which showed no significant effect on lung function in subjects with symptomatic asthma despite inhaled steroids (19).

Why might specific targeting of IL-5 fail to improve asthma control in patients with persistent symptoms despite use of inhaled steroids? Clearly, there are possible explanations for the lack of observed benefit from mepolizumab treatment seen in the current study. Because inhaled corticosteroids themselves suppress sputum eosinophils by between 60 and 90% (27, 28) it is possible that the inhaled corticosteroids in this study may have masked a small clinical effect associated with mepolizumab therapy. In the present study 27 of 37 (73%) patients from whom induced sputum was obtained exhibited eosinophilia above the normal range (more than 1.9%). The mechanisms by which noneosinophilic and neutrophilic airway inflammation might contribute to persistent asthma symptoms in patients treated with inhaled corticosteroids remain unclear, but such patients would be unlikely to respond to anti–IL-5 treatment. Our subgroup analysis has shown no correlation between either baseline eosinophil numbers or the magnitude of the decrease in blood eosinophils in response to mepolizumab therapy and changes in clinical measures. Nonetheless, this study does not exclude that specific targeting of those with persistent eosinophilic disease might identify those likely to respond to anti–IL-5, although further studies would be required to clarify this point.

It seems unlikely that mepolizumab did not reach the airway at sufficient concentration to antagonize IL-5. Mepolizumab levels in the BAL fluid of cynomolgus monkeys administered mepolizumab (10 mg/kg, intravenous) were found to be 0.1 µg/ml (29). In patients with asthma, levels of IL-5 in BAL fluid have been reported at 0.5 pg/ml (30). If the tissue penetration of mepolizumab in monkeys is similar to that in humans and is reflected in its concentration in BAL fluid, mepolizumab at doses of 10 mg/kg (approximately 750 mg) would be present in considerable excess over IL-5.

A bronchoscopy study using a regimen of three doses given monthly, similar to this study, demonstrated that treatment with mepolizumab reduced airway mucosal eosinophil numbers by 55% in contrast to the 85% or more reduction in blood and sputum eosinophils seen in this and other studies (20). Moreover, anti–IL-5 treatment had no effect on bronchial mucosal staining of eosinophil major basic protein, suggesting that reduction in eosinophil numbers does not reflect tissue deposition of granule proteins (20). Therefore, tissue eosinophils may be unresponsive to IL-5, making the elimination of IL-5 redundant. Preincubation of eosinophils with IL-5 in vitro leads to long-term downregulation of IL-5 receptor {alpha} chain expression with concomitant reduction in IL-5 responsiveness (31–33), and IL-5 receptor {alpha} chain expression was reduced on BAL eosinophils obtained after local airway allergen challenge. Thus, airway eosinophils that have developed and migrated to the airway in response to IL-5 may not rely on this cytokine for survival and function in the tissues, but may instead respond to the related cytokines IL-3 and granulocyte-macrophage colony–stimulating factor, receptors for which are not downregulated by cytokine exposure (33). This is supported by animal models of allergy, in which more effective eosinophil depletion can be achieved by combining IL-5 inhibition with blockade of granulocyte-macrophage colony-stimulating factor and IL-3 (34), or of the eotaxin receptor CCR3 (35). However, the significant changes in parameters of airway remodeling seen in patients with asthma treated with mepolizumab (36, 37), together with effective clinical response to mepolizumab in hypereosinophilic syndromes driven by IL-5 (38–40), would argue that tissue eosinophils are at least partially responsive to mepolizumab therapy (38–41).

The lack of response to anti–IL-5 therapy has been widely interpreted as suggesting that the eosinophil does not contribute significantly to the late asthmatic reaction and has no influence on asthma symptoms and other clinical outcome measures. However, the two other studies (18, 20) reporting the effect of mepolizumab in individuals with asthma not receiving inhaled corticosteroid therapy did not show significant clinical effect but were not suitably powered for efficacy in allergen challenge in a parallel group study design or for efficacy in clinical end points. In contrast to the results in asthma, studies investigating the effect of mepolizumab in hypereosinophilic syndromes with eosinophil-mediated tissue damage have reported promising therapeutic effect in individuals already receiving high-dose oral steroids (38–41). The reasons for these varying responses in tissue eosinophils in different diseases are not known and require further study.

In conclusion, the current study suggests that mepolizumab will not be useful for all patients with persistent asthma despite inhaled steroid therapy. As new biological treatments for asthma become available it will be important to carefully characterize patients with asthma and to define which subgroups might respond to each specific therapy. Further studies will be required to determine whether this treatment will be useful for the control of exacerbations in those individuals with persistent airway eosinophilia.


   Acknowledgments
 
The authors thank the patients and staff at the participating centers.


   FOOTNOTES
 
Supported by GlaxoSmithKline Research and Development.

* A list of participating centers and investigators may be found at the end of this article. Back

Originally Published in Press as DOI: 10.1164/rccm.200701-085OC on September 13, 2007

Conflict of Interest Statement: P.F.-P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. I.F. was a consultant for GlaxoSmithKline for 15 years, retired in 2001, and has served as a part-time consultant for GlaxoSmithKline for the last 5 years. J.M. has been an employee of GlaxoSmithKline since October 2003 and has 7,075 in share options from October 2006 to February 16 and 1,280 ordinary shares restricted to February 2009. M.W. has been an employee of GlaxoSmithKline's R&D since 1998. L.B. is an employee of GlaxoSmithKline with a salary of $130,000 per year and has $100,000 in stock and options from GlaxoSmithKline. D.R. received $500 from GlaxoSmithKline and $1,000 from AstraZeneca in lecture fees, $50,000 from GlaxoSmithKline from 1997 to 2006 in grants, and has been reimbursed by GlaxoSmithKline, AstraZeneca, Schering Plough, and Novartis for attending various conferences, and has served on an advisory board for Lorantis from 2000 to 2005. S.W. received £2,000 per year in consultancy fees from GlaxoSmithKline from 2005 to 2007. W.B. received $1,200 in 2006 from GlaxoSmithKline, $3,750 and $750 in 2006 from Wyeth, $500 in 2006 from Altana, $750 in 2006 from Johnson & Johnson, and $1,750 in 2006 from Alza Corporation for consultancy fees; serves on advisory boards for Genetech/Novartis, Isis, GlaxoSmithKline, Altana, Wyeth, Pfizer, Dynavax, and Centocor; serves on a speakers' bureau for GlaxoSmithKline, Novartis, Merck, and AstraZeneca; and received $42,226 in May 2004, $40,000 in July 2004, $2,000 in October 2004, and $21,742 in February 2005 in grants from GlaxoSmithKline. T.T.H. received £450,000 from 2006 to 2007 from GlaxoSmithKline, £550,000 from 2006 to 2007 from Novartis, £42,000 in 2007 from Pfizer, £250,000 from 2006 to 2007 from Oxagen, £22,000 in 2006 from CMP Therapeutics, £250,000 in 2006 from IMMD, and £250,000 pending from Pfizer in grants. N.C.B. received $20,000 in consultancy fees from Merck Generics in 2007, received $4,500 in 2005, $3,000 in 2006, and $3,000 in 2007 in advisory board fees from GlaxoSmithKline, and received $3,000 in 2005 in advisory board fees from Altana; received $25,000 in 2005, $25,000 in 2006, and $15,000 in 2007 in lecture fees from GlaxoSmithKline, and received $80,000 in 2005 from GlaxoSmithKline and $60,000 in 2005 from AstraZeneca in grants.

The International Mepolizumab Study Group participating centers and investigators are as follows: United States: CRS-Clinical Research Services, Feasterville, PA (Robert Coifman); University of Pittsburgh, Pittsburgh, PA (William J. Calhoun); Vivra Research, Tucson, AZ (Jay Grossman); Clinical Trials of Orange County, Orange, CA (Stanley P. Galant); HealthQuest Therapy and Research Institute, Inc., Austin, TX (William C. Howland III); IMTCI, Lenexa, KS (Robert Dockhorn); New Horizons Health Research, Atlanta, GA (Theodore M. Lee); Asthma and Allergy Research Center, Institute for Research and Education, Minneapolis, MN (William F. Schoenwetter); University of Wisconsin-Madison, Allergy/Asthma Clinical Research Unit, Madison, WI (William Walter Busse); The Clinical Research Center, LLC, St. Louis, MO (Phillip Korenblat); Allergy & Asthma Medical Group of Diablo Valley, Inc., Danville, CA (David Cook); Neem Research Group, Columbia, SC (J. Richard Allison III); Allergy, Asthma Associates, Bend, OR (David B. Coutin); Hill Top–AACC Research, Inc., Charleston, SC (Charles H. Banov); Allergy and Asthma Associates, Kirkland, WA (D. Robert Webb); Commonwealth Clinical Research Specialists, Richmond, VA (Robert S. Call); Health Advance Institute, Melbourne, FL (Jeannette G. Warner); Allergy and Asthma Medical Group and Research Center, APC, San Diego, CA (Nancy K. Ostrom); Physicians Research Center, Inc., Hartford, CT (Eric T. Shore); New England Clinical Studies, North Dartmouth, MA (Paul Chervinsky); Spartanburg Pharmaceutical Research, Spartanburg, SC (Charles M. Fogarty); 2137 Welsh Road, Philadelphia, PA (Eliot H. Dunsky); 1145 19th Street NW, Suite #202, Washington, DC (Howard Boltansky); Allergy & Asthma Associates of Santa Clara Valley Research Center, San Jose, CA (James D. Wolfe); 822 Pine Street, Philadelphia, PA (Sheryl Talbot, Mary Fontana-Penn); Rockwood Clinic, PS, Spokane, WA (Richard Gower); Allergy Research Foundation, Inc., Los Angeles, CA (Gary Rachelefsky); HANA Research Medical Center, Inc., Buena Park, CA (William A. Jannetti); National Jewish Medical and Research Center, Denver, CO (Sally E. Wenzel); Johns Hopkins Asthma and Allergy Center, Baltimore, MD (Mark C. Liu). France: Clinique des Maladies Respiratoires du Pr. Michel, Hôpital Arnaud de Villeneuve, Montpellier (Philippe Godard); Service de Pneumo-Physiologie, CHU–Hôpital Albert Michallon, Grenoble (Christian Brambilla); Service de Pneumologie, Centre Cardio-Pneumologie-Niveau 7, Rennes (Philippe Delaval); Service de Pneumologie, Hôpital Pasteur–H2, Nice (Fernand Macone); Service de Medecine (Orientation Pneumologie), Polyclinique de Rillieux Lyon Nord (Yann Martinat); Unite de Consultation Externe–Service de Reanimation Polyvalente, CHD Félix Guyon, Bellepierre, Ile de la Reunion (Fabrice Paganin); Service de Pneumo-Physiologie, Hôpital Civil–Pavillon Laënnec, Strasbourg (Gabrielle Pauli); Service de Pneumo-Physiologie, Hôpital Calmette, Lille (Andre Tonnel); Thérapharm Recherches, Boulogne-Billancourt, Paris (Serge Fitoussi); Aster–Cephac, Paris (Violette Leclerc); Service de Maladies Respiratoires, Hôpital de Haute Leveque, Pessac (Andre Teytard). Germany: Theodor-Heuss-Str. 3, Witten (Rolf Dichmann); Fachkrankenhaus Kloster Grafschaft, Schmallenberg-Grafschaft (Dieter Koehler); Universitaetsklinikum Jena, Klinik fuer Innere Medizin, Jena (Claus Kroegel); Krankenhaus Großhansdorf (Helgo Magnussen); Universitaetsklinikum Freiburg Abt. Pneumologie, Freiburg (Heinrich Matthys); Spöttinger Str. 14, Landsberg, Bayerrn (Heiner Steffen); Nymphenburger Str. 152, Munich (Ulf Harnest); Virchow-Klinikum, Kl. Immunologie/Asthma Poliklinik, Berlin (Gert Kunkel); Universitätsklinikum, Abt. Innere Medizin 5, Bad Homburg (Dieter Ukena). The Netherlands: Catharina Ziekenhuis, Longfunctieafdeling, Eindhoven (Jacques PHM Creemers); Sophia Ziekenhuis, Poli Longziekten, Zwolle, The Netherlands (Albertus F. Kuipers). UK: Department of Respiratory Medicine, The London Chest Hospital, London (Neil Barnes); Royal Brompton Hospital, London (Trevor Hansel); University Medicine, Southampton General Hospital, Southampton (Stephen Holgate); Department of Respiratory Medicine Nottingham City Hospital, Nottingham (Anne Tattersfield).

Received in original form January 16, 2007; accepted in final form August 15, 2007


   REFERENCES
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Coyle AJ, Ackerman SJ, Irvin CG. Cationic proteins induce airway hyperresponsiveness dependent on charge interactions. Am Rev Respir Dis 1993;147:896–900.[Medline]
  2. Wardlaw AJ, Brightling CE, Green R, Woltmann G, Bradding P, Pavord ID. New insights into the relationship between airway inflammation and asthma. Clin Sci (Lond) 2002;103:201–211.[Medline]
  3. Bousquet J, Chanez P, Lacoste JY, Barneon G, Ghavanian N, Enander I, Venge P, Ahlstedt S, Simony-Lafontaine J, Godard P, et al. Eosinophilic inflammation in asthma. N Engl J Med 1990;323:1033–1039.[Abstract]
  4. Yamaguchi Y, Suda T, Suda J, Eguchi M, Miura Y, Harada N, Tominaga A, Takatsu K. Purified interleukin 5 supports the terminal differentiation and proliferation of murine eosinophilic precursors. J Exp Med 1988;167:43–56.[Abstract/Free Full Text]
  5. Sehmi R, Wardlaw AJ, Cromwell O, Kurihara K, Waltmann P, Kay AB. Interleukin-5 selectively enhances the chemotactic response of eosinophils obtained from normal but not eosinophilic subjects. Blood 1992;79:2952–2959.[Abstract/Free Full Text]
  6. Yamaguchi Y, Hayashi Y, Sugama Y, Miura Y, Kasahara T, Kitamura S, Torisu M, Mita S, Tominaga A, Takatsu K. Highly purified murine interleukin 5 (IL-5) stimulates eosinophil function and prolongs in vitro survival. IL-5 as an eosinophil chemotactic factor. J Exp Med 1988;167:1737–1742.[Abstract/Free Full Text]
  7. Hamid Q, Azzawi M, Ying S, Moqbel R, Wardlaw AJ, Corrigan CJ, Bradley B, Durham SR, Collins JV, Jeffery PK, et al. Expression of mRNA for interleukin-5 in mucosal bronchial biopsies from asthma. J Clin Invest 1991;87:1541–1546.[Medline]
  8. Robinson DS, Hamid Q, Ying S, Tsicopoulos A, Barkans J, Bentley AM, Corrigan C, Durham SR, Kay AB. Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med 1992;326:298–304.[Abstract]
  9. Robinson D, Hamid Q, Bentley A, Ying S, Kay AB, Durham SR. Activation of CD4+ T cells, increased TH2-type cytokine mRNA expression, and eosinophil recruitment in bronchoalveolar lavage after allergen inhalation challenge in patients with atopic asthma. J Allergy Clin Immunol 1993;92:313–324.[CrossRef][Medline]
  10. Humbert M, Corrigan CJ, Kimmitt P, Till SJ, Kay AB, Durham SR. Relationship between IL-4 and IL-5 mRNA expression and disease severity in atopic asthma. Am J Respir Crit Care Med 1997;156:704–708.[Abstract/Free Full Text]
  11. Wenzel SE, Schwartz LB, Langmack EL, Halliday JL, Trudeau JB, Gibbs RL, Chu HW. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 1999;160:1001–1008.[Abstract/Free Full Text]
  12. Green RH, Brightling CE, Woltmann G, Parker D, Wardlaw AJ, Pavord ID. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax 2002;57:875–879.[Abstract/Free Full Text]
  13. Foster PS, Hogan SP, Ramsay AJ, Matthaei KI, Young IG. Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J Exp Med 1996;183:195–201.[Abstract/Free Full Text]
  14. Mauser PJ, Pitman AM, Fernandez X, Foran SK, Adams GK III, Kreutner W, Egan RW, Chapman RW. Effects of an antibody to interleukin-5 in a monkey model of asthma. Am J Respir Crit Care Med 1995;152:467–472.[Abstract]
  15. Shardonofsky FR, Venzor J III, Barrios R, Leong KP, Huston DP. Therapeutic efficacy of an anti–IL-5 monoclonal antibody delivered into the respiratory tract in a murine model of asthma. J Allergy Clin Immunol 1999;104:215–221.[CrossRef][Medline]
  16. Tanaka H, Komai M, Nagao K, Ishizaki M, Kajiwara D, Takatsu K, Delespesse G, Nagai H. Role of interleukin-5 and eosinophils in allergen-induced airway remodeling in mice. Am J Respir Cell Mol Biol 2004;31:62–68.[Abstract/Free Full Text]
  17. Gnanakumaran G, Babu KS. Technology evaluation: mepolizumab, GlaxoSmithKline. Curr Opin Mol Ther 2003;5:321–325.[Medline]
  18. Leckie MJ, ten Brinke A, Khan J, Diamant Z, O'Connor BJ, Walls CM, Mathur AK, Cowley HC, Chung KF, Djukanovic R, et al. Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response. Lancet 2000;356:2144–2148.[CrossRef][Medline]
  19. Kips JC, O'Connor BJ, Langley SJ, Woodcock A, Kerstjens HA, Postma DS, Danzig M, Cuss F, Pauwels RA. Effect of SCH55700, a humanized anti–human interleukin-5 antibody, in severe persistent asthma: a pilot study. Am J Respir Crit Care Med 2003;167:1655–1659.[Abstract/Free Full Text]
  20. Flood-Page PT, Menzies-Gow AN, Kay AB, Robinson DS. Eosinophil's role remains uncertain as anti–interleukin-5 only partially depletes numbers in asthmatic airway. Am J Respir Crit Care Med 2003;167:199–204.[Abstract/Free Full Text]
  21. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention: updated 2005 [Internet] [accessed September 2007]. Available from www.ginasthma.org
  22. Juniper EF, Buist AS, Cox FM, Ferrie PJ, King DR. Validation of a standardized version of the Asthma Quality of Life Questionnaire. Chest 1999;115:1265–1270.[CrossRef][Medline]
  23. Fahy JV, Wong H, Liu J, Boushey HA. Comparison of samples collected by sputum induction and bronchoscopy from asthmatic and healthy subjects. Am J Respir Crit Care Med 1995;152:53–58.[Abstract]
  24. Hochberg Y. A sharper Bonferroni procedure for multiple tests of significance. Biometrika 1988;75:800–802.[Abstract/Free Full Text]
  25. Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P, Wardlaw AJ, Pavord ID. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet 2002;360:1715–1721.[CrossRef][Medline]
  26. Jayaram L, Pizzichini MM, Cook RJ, Boulet LP, Lemiere C, Pizzichini E, Cartier A, Hussack P, Goldsmith CH, Laviolette M, et al. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J 2006;27:483–494.[Abstract/Free Full Text]
  27. Jatakanon A, Kharitonov S, Lim S, Barnes PJ. Effect of differing doses of inhaled budesonide on markers of airway inflammation in patients with mild asthma. Thorax 1999;54:108–114.[Abstract/Free Full Text]
  28. Aldridge RE, Hancox RJ, Robin TD, Cowan JO, Winn MC, Frampton CM, Ian Town G. Effects of terbutaline and budesonide on sputum cells and bronchial hyperresponsiveness in asthma. Am J Respir Crit Care Med 2000;161:1459–1464.[Abstract/Free Full Text]
  29. Hart TK, Cook RM, Zia-Amirhosseini P, Minthorn E, Sellers TS, Maleeff BE, Eustis S, Schwartz LW, Tsui P, Appelbaum ER, et al. Preclinical efficacy and safety of mepolizumab (SB-240563), a humanized monoclonal antibody to IL-5, in cynomolgus monkeys. J Allergy Clin Immunol 2001;108:250–257.[CrossRef][Medline]
  30. Julius P, Hochheim D, Boser K, Schmidt S, Myrtek D, Bachert C, Luttmann W, Virchow JC. Interleukin-5 receptors on human lung eosinophils after segmental allergen challenge. Clin Exp Allergy 2004;34:1064–1070.[CrossRef][Medline]
  31. Liu LY, Sedgwick JB, Bates ME, Vrtis RF, Gern JE, Kita H, Jarjour NN, Busse WW, Kelly EA. Decreased expression of membrane IL-5 receptor {alpha} on human eosinophils. I. Loss of membrane IL-5 receptor {alpha} on airway eosinophils and increased soluble IL-5 receptor {alpha} in the airway after allergen challenge. J Immunol 2002;169:6452–6458.[Abstract/Free Full Text]
  32. Liu LY, Sedgwick JB, Bates ME, Vrtis RF, Gern JE, Kita H, Jarjour NN, Busse WW, Kelly EA. Decreased expression of membrane IL-5 receptor {alpha} on human eosinophils: II. IL-5 down-modulates its receptor via a proteinase-mediated process. J Immunol 2002;169:6459–6466.[Abstract/Free Full Text]
  33. Gregory B, Kirchem A, Phipps S, Gevaert P, Pridgeon C, Rankin SM, Robinson DS. Differential regulation of human eosinophil IL-3, IL-5, and GM-CSF receptor {alpha}-chain expression by cytokines: IL-3, IL-5, and GM-CSF down-regulate IL-5 receptor {alpha} expression with loss of IL-5 responsiveness, but up-regulate IL-3 receptor {alpha} expression. J Immunol 2003;170:5359–5366.[Abstract/Free Full Text]
  34. Nishinakamura R, Miyajima A, Mee PJ, Tybulewicz VL, Murray R. Hematopoiesis in mice lacking the entire granulocyte-macrophage colony-stimulating factor/interleukin-3/interleukin-5 functions. Blood 1996;88:2458–2464.[Abstract/Free Full Text]
  35. Foster PS, Mould AW, Yang M, Mackenzie J, Mattes J, Hogan SP, Mahalingam S, Mckenzie AN, Rothenberg ME, Young IG, et al. Elemental signals regulating eosinophil accumulation in the lung. Immunol Rev 2001;179:173–181.[CrossRef][Medline]
  36. Phipps S, Flood-Page P, Menzies-Gow A, Ong YE, Kay AB. Intravenous anti–IL-5 monoclonal antibody reduces eosinophils and tenascin deposition in allergen-challenged human atopic skin. J Invest Dermatol 2004;122:1406–1412.[CrossRef][Medline]
  37. Flood-Page P, Menzies-Gow A, Phipps S, Ying S, Wangoo A, Ludwig MS, Barnes N, Robinson D, Kay AB. Anti–IL-5 treatment reduces deposition of ECM proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics. J Clin Invest 2003;112:1029–1036.[CrossRef][Medline]
  38. Koury MJ, Newman JH, Murray JJ. Reversal of hypereosinophilic syndrome and lymphomatoid papulosis with mepolizumab and imatinib. Am J Med 2003;115:587–589.[Medline]
  39. Braun-Falco M, Fischer S, Plotz SG, Ring J. Angiolymphoid hyperplasia with eosinophilia treated with anti–interleukin-5 antibody (mepolizumab). Br J Dermatol 2004;151:1103–1104.[CrossRef][Medline]
  40. Garrett JK, Jameson SC, Thomson B, Collins MH, Wagoner LE, Freese DK, Beck LA, Boyce JA, Filipovich AH, Villanueva JM, et al. Anti–interleukin-5 (mepolizumab) therapy for hypereosinophilic syndromes. J Allergy Clin Immunol 2004;113:115–119.[CrossRef][Medline]
  41. Plotz SG, Simon HU, Darsow U, Simon D, Vassina E, Yousefi S, Hein R, Smith T, Behrendt H, Ring J. Use of an anti–interleukin-5 antibody in the hypereosinophilic syndrome with eosinophilic dermatitis. N Engl J Med 2003;349:2334–2339.[Free Full Text]

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