News Beyond Our Pages
Authors: Marc E. Rothenberg, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2018)

Mepolizumab, an mAb that neutralizes IL-5, decreases exacerbation rates in patients with eosinophilic asthma. Pavord et al (N Engl J Med 2017; https://doi.org/10.1056/NEJMoa1708208) performed 2 separate phase 3 double-blind, placebo-controlled, randomized controlled trials named METREX and METREO to assess the efficacy of mepolizumab as an adjunct therapy in patients with chronic obstructive pulmonary disease (COPD) with an eosinophilic phenotype. Subjects with recent history of exacerbations despite treatment with glucocorticoid-based triple inhaled therapy received subcutaneous mepolizumab (100 mg in METREX and 100 or 300 mg in METREO) or placebo every 4 weeks for 1 year. The annual exacerbation rate was significantly lower among patients with an eosinophilic phenotype in the mepolizumab group in the METREX trial compared with that in the placebo group (1.40 vs 1.71 exacerbations per year, P = .04). In the METREO trial containing all patients with an eosinophilic phenotype, the annual exacerbation rate was not significantly lower in the 100-mg mepolizumab group (1.19 vs 1.49 exacerbations per year in the placebo group, P = .07) or the 300-mg mepolizumab group (1.27 exacerbations per year, P = .14). These conflicting studies suggest that mepolizumab can decrease exacerbation frequency in patients with COPD with an eosinophilic phenotype, but more data are needed.Mepolizumab can decrease exacerbation frequency in patients with COPD with an eosinophilic phenotype Mepolizumab can decrease exacerbation frequency in patients with COPD with an eosinophilic phenotype Type 2 innate lymphoid cells (ILC2s) robustly produce type 2 cytokines in response to the alarmins IL-25 and IL-33. Wallrapp et al (Nature 2017;549:351-6; https://doi.org/10.1038/nature24029) further characterized molecular signals regulating the homeostatic and proinflammatory functions of these cells. Single-cell RNA sequencing analysis of mouse pulmonary innate lymphoid cells both at baseline and after in vivo stimulation with IL-25 and IL-33 revealed transcriptionally diverse populations with differential expression of genes involved in proliferation, homeostasis, and effector functions. Nmur1, which encodes the receptor for the neuropeptide neuromedin U (NMU), was expressed uniquely by ILC2s. NMU potently activated ILC2s in vitro, and in vivo cotreatment with NMU and IL-25 dramatically increased pulmonary allergic inflammation. Finally, genetic loss of Nmur1 decreased ILC2 frequency and activation and changed in vivo allergen-induced transcriptional programs. Collectively, these results demonstrate that the neuropeptide NMU potentiates proinflammatory and ILC2-mediated responses and underscore the importance of cross-talk between the nervous and immune systems in the pathogenesis of allergic inflammation. Image credit by Thomas Shafee (Own work) [CC BY 4.0] (http://creativecommons.org/licenses/by/4.0)], via Wikimedia Commons.The neuropeptide NMU potentiates proinflammatory, ILC2-mediated responses The neuropeptide NMU potentiates proinflammatory, ILC2-mediated responses Asthma treatment guidelines are derived almost entirely from the results of intervention studies performed with intensive monitoring in patient populations with extensive exclusion criteria, leading to concerns regarding the generalizability of findings to general practice. Woodcock et al (Lancet 2017; https://doi.org/10.1016/S0140-6736(17)32397-8) performed a 52-week, open-label, randomized effectiveness trial to compare the efficacy of once-daily combined treatment with a novel dry-powder inhaler formulation of fluticasone furoate (100 or 200 μg) and vilanterol (25 μg) versus usual care in a broad population of patients with asthma diagnosed by a general practitioner. At 24 weeks, 71% of subjects receiving fluticasone furoate and vilanterol achieved significantly improved asthma control, as assessed by using the Asthma Control Test, compared with 56% of subjects continuing on usual care (P < .0001). These differences were sustained throughout the whole year of the study. In this first major randomized effectiveness study in a primary care setting, the authors found that combined treatment with fluticasone furoate and vilanterol provides superior asthma control compared with continuing usual care.Fluticasone furoate and vilanterol provides superior asthma control compared with continuing usual care Fluticasone furoate and vilanterol provides superior asthma control compared with continuing usual care We asked first author Ashley Woodcock, MD, of the University of Manchester, Manchester, United Kingdom, to comment on the study. He writes, “This novel randomized clinical effectiveness study in a broad asthma population assesses the benefit of a once-daily combination treatment on outcomes that are relevant to patients. Studies such as this, which are being requested by health care providers, will be important for future clinical guidelines.” Neutralization of IL-5 with the mAbs mepolizumab and reslizumab have demonstrated efficacy in improving blood eosinophilia and severe eosinophilic asthma. Mukherjee et al (Am J Respir Crit Care Med 2017; https://doi.org/10.1164/rccm.201707-1323OC) performed a randomized, placebo-controlled sequential trial to assess the efficacy of intravenous reslizumab in 10 patients with eosinophilic asthma in whom a 1-year trial of subcutaneous mepolizumab (100 mg every 4 weeks) failed. All subjects received 2 intravenous infusions of placebo followed by 4 infusions of reslizumab (3 mg/kg) or placebo. Compared with placebo, reslizumab decreased sputum eosinophil counts by 91.2% (P = .003), blood eosinophil counts by 87.4% (P = .004), and sputum eosinophil peroxidase protein levels by 65.6% (P = .03). Furthermore, reslizumab treatment caused sputum eosinophil counts to decrease to a greater degree than when patients were receiving subcutaneous mepolizumab (−42.7% vs −5.0%, P = .01), and this was associated with greater improvement in Asthma Control Questionnaire scores. In summary, intravenous reslizumab improved subcutaneous mepolizumab-resistant asthma and might be of clinical benefit in patients with severe treatment-resistant asthma.Intravenous reslizumab improved subcutaneous mepolizumab-resistant asthmaNews items were written by medical writer Jared Travers, PhD.Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com. Intravenous reslizumab improved subcutaneous mepolizumab-resistant asthma News items were written by medical writer Jared Travers, PhD. Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com.