Mechanisms of Allergy
Anti–interleukin-5 (mepolizumab) therapy for hypereosinophilic syndromes

https://doi.org/10.1016/j.jaci.2003.10.049Get rights and content

Abstract

Background

IL-5 is a cytokine critically involved in regulating several aspects of eosinophils including their production, activation, and tissue recruitment. As such, IL-5 may be involved in the pathogenesis of hypereosinophilic syndromes, a group of poorly treated diverse disorders characterized by sustained peripheral blood and/or tissue eosinophilia.

Objective

We aimed to assess the safety and efficacy of a humanized blocking monoclonal antibody against IL-5 (mepolizumab) in patients with several forms of hyper-eosinophilic syndromes.

Methods

We performed an open-label trial of anti–IL-5 in which 3 intravenous doses (10 mg/kg, maximum 750 mg) were administered at 4-week intervals to 4 patients with hypereosinophilic syndromes (defined by peripheral blood and/or tissue eosinophilia). The effects of treatment on safety, eosinophil levels (in peripheral blood and/or diseased tissue), pulmonary function, and quality of life were measured over a 28-week period.

Results

Anti–IL-5 was well tolerated in all patients and lowered peripheral blood eosinophil counts despite ongoing systemic glucocorticoid therapy. The decline in circulating eosinophil counts was sustained for at least 12 weeks after the last dose of anti–IL-5. In addition, anti–IL-5 improved clinical and quality of life measurements. In one patient with striking tissue eosinophilia (eosinophilic esophagitis), anti–IL-5 resulted in a 10-fold reduction in tissue eosinophil levels.

Conclusions

These results suggest that anti–IL-5 is safe, effective in lowering eosinophil levels, and has potential glucocorticoid-sparing effects in patients with a variety of hyper-eosinophilic syndromes. As such, anti–IL-5 may have significant therapeutic potential for hypereosinophilic syndromes.

Section snippets

Methods

After local institutional review board and FDA approval and informed consent was obtained, patients with HES involving peripheral blood and/or tissue eosinophilia (18 to 65 years old) were monitored (by complete blood counts and physical examination) at 2- to 4-week intervals for a period of 28 weeks. Patients were also evaluated by pulmonary function testing, electrocardiograms, and echocardiograms at weeks 0, 8, and 20. It is important to note that the entry criteria for this study permitted

Results

Patient 1 was a 48-year-old woman with a 10-year history of IHES with biopsy-proven involvement of the lungs, gastrointestinal tract, and skin (eosinophilic cellulitis). Her treatment had been primarily oral methylprednisolone and methotrexate with previous trials of hydroxyurea, interferon-α, and phototherapy. At the time of the study, her gastrointestinal symptoms were inactive and her main target organs were the skin and lungs. During the initial 8 weeks of the protocol, she had an

Discussion

In summary, we have shown that anti–IL-5 appears to be safe in 4 patients with diverse manifestations of HES. In addition, several disease parameters appear to be improved by anti–IL-5 therapy, including peripheral blood eosinophil counts in all patients, FEV1 measurements, a variety of clinical symptoms, QOL measurements, and tissue eosinophilia in 1 patient. However, since this study is an open-label, noncontrolled trial, definitive proof that anti–IL-5 is responsible for these improvements

Acknowledgments

We thank Dr A. Rosen for providing clinical care, members of the Data Safety Monitoring Board (Drs Leonard Bernstein, Charles Pierce, and Philip Walson and Alice Ostendorf, RN), and Carol Johnson and Andrea Lippelman for administrative assistance.

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Supported in part by the Burroughs Wellcome Fund and the NIH-supported Clinical Research Center and the Translational Research Office at Cincinnati Children's Hospital Medical Center.

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