Safety and efficacy of a <scp>CXCR</scp>2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo‐controlled clinical trial

Nair, Parameswaran; Gaga, Mina; Ζervas, Εleftherios; Alagha, Khuder; Fe, Hargreave; O'Byrne, Paul M.; Stryszak, Paul; Gann, L.; Sadeh, Jonathan; Chanez, Pascal

doi:10.1111/j.1365-2222.2012.04014.x

Cited by 298 publications

(200 citation statements)

References 27 publications

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“…Daclizumab, a humanised IgG1 monoclonal antibody against the IL-2 receptor-a chain of activated lymphocytes improved FEV1 and asthma control in moderate-to-severe asthmatic adults inadequately controlled on ICS [162]. A CXCR2 antagonist, SCH527123, reduced sputum neutrophilia in severe adult asthma, and was associated with a modest reduction in mild exacerbations, but without an improvement in asthma control [163]. It is unclear whether better efficacy would have been seen with additional phenotyping as the definition of sputum neutrophilia remains unsatisfactory.…”

Section: Remarksmentioning

confidence: 99%

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

et al. 2013

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Severe or therapy-resistant asthma is increasingly recognised as a major unmet need. A Task Force, supported by the European Respiratory Society and American Thoracic Society, reviewed the definition and provided recommendations and guidelines on the evaluation and treatment of severe asthma in children and adults.A literature review was performed, followed by discussion by an expert committee according to the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for development of specific clinical recommendations.When the diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as asthma that requires treatment with high dose inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from becoming “uncontrolled” or that remains “uncontrolled” despite this therapy. Severe asthma is a heterogeneous condition consisting of phenotypes such as eosinophilic asthma. Specific recommendations on the use of sputum eosinophil count and exhaled nitric oxide to guide therapy, as well as treatment with anti-IgE antibody, methotrexate, macrolide antibiotics, antifungal agents and bronchial thermoplasty are provided.Coordinated research efforts for improved phenotyping will provide safe and effective biomarker-driven approaches to severe asthma therapy.

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Section: Remarksmentioning

confidence: 99%

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

et al. 2013

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“…However, if we select the patients with neutrophil-dominant asthma, these antagonists may have effects in a similar way to anti-IL-5 Ab in eosinophil-dominant asthma. Recent studies suggested that some drugs, including macrolide antibiotics and CXCR2 Ab, are expected to have effects [48][49][50][51]. The effect of these drugs on eosinophil TBM induced by neutrophils should be examined in the future.…”

Section: Discussionmentioning

confidence: 99%

Trans-Basement Membrane Migration of Eosinophils Induced By LPS-Stimulated Neutrophils from Human Peripheral Blood in Vitro

Nakagome

Nishihara

Kobayashi

et al. 2016

Journal of Allergy and Clinical Immunology

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In the airways of severe asthmatics, an increase of neutrophils and eosinophils is often observed despite high-dose corticosteroid therapy. We previously reported that interleukin-8-stimulated neutrophils induced trans-basement membrane migration (TBM) of eosinophils, suggesting the link between neutrophils and eosinophils. Concentrations of lipopolysaccharide (LPS) in the airway increase in severe asthma. As neutrophils express Toll-like receptor (TLR)4 and can release chemoattractants for eosinophils, we investigated whether LPS-stimulated neutrophils modify eosinophil TBM.Neutrophils and eosinophils were isolated from peripheral blood of healthy volunteers and severe asthmatics. Eosinophil TBM was examined using a modified Boyden's chamber technique. Eosinophils were added to the upper compartment, and neutrophils and LPS were added to the lower compartment. Migrated eosinophils were measured by eosinophil peroxidase assays.LPS-stimulated neutrophils induced eosinophil TBM (about 10-fold increase), although LPS or neutrophils alone did not. A leukotriene B 4 receptor antagonist, a platelet-activating factor receptor antagonist or an anti-TLR4 antibody decreased eosinophil TBM enhanced by LPS-stimulated neutrophils by almost half. Neutrophils from severe asthmatics induced eosinophil TBM and lower concentrations of LPS augmented neutrophil-induced eosinophil TBM.These results suggest that the combination of neutrophils and LPS leads eosinophils to accumulate in the airways, possibly involved the pathogenesis of severe asthma. @ERSpublications LPS-stimulated neutrophils induced eosinophil TBM, which may be involved in the pathogenesis of severe asthma

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“…This agent showed improvement in asthma scores and pulmonary function [92]. Furthermore, a CXCR2 antagonist showed modest improvement in exacerbation rate without improvement in asthma control in a subgroup of asthma patients with increased sputum neutrophils [93]. Antibodies against IL-13, lebrikizumab, showed improved pulmonary function testing but no effect on exacerbation rate or symptoms [94].…”

Section: Other Targeted Treatmentsmentioning

confidence: 99%

Severe refractory asthma: an update

Wener

Bel

2013

European Respiratory Review

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Asthma is a heterogeneous disease in which adequate asthma control cannot be achieved in a substantial proportion despite currently available treatment possibilities. This subgroup has been defined as ''severe refractory'' asthma. Over the past years considerable progress has been made regarding a more exact definition of severe refractory asthma. A systematic approach to evaluate the asthma patient has been postulated. Further detailed classification into distinct phenotypes is ongoing to target the right treatment to the right patient. And, new therapeutic targeted treatment options are currently in development to provide possible new targets to improve disease state, symptoms and quality of life. This review will provide an update on the latest advancements with regard to all these domains. @ERSpublications Phenotyping the severe asthma patient is essential to ensure the right treatment is given to the right patient

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Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo‐controlled clinical trial

Abstract: This new treatment provides an opportunity to investigate the role of neutrophils in severe asthma with potential clinical benefits. Larger studies of longer duration are needed to evaluate the impact on other outcomes of asthma including exacerbations.

Cited by 298 publications

References 27 publications

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma

Trans-Basement Membrane Migration of Eosinophils Induced By LPS-Stimulated Neutrophils from Human Peripheral Blood in Vitro

Severe refractory asthma: an update

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