NEWS Beyond our Pages
Authors: Marc E. Rothenberg, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2017)

The mAb tezepelumab (AMG 157), which neutralizes the proallergic cytokine thymic stromal lymphopoietin (TSLP), has been shown previously to decrease type 2 inflammation in response to respiratory allergen challenge in patients with mild asthma. Corren et al (N Engl J Med 2017;377:936-46; doi: https://doi.org/10.1056/NEJMoa1704064) performed a phase 2, double-blind, placebo-controlled randomized trial to compare the efficacy of tezepelumab in patients with asthma not adequately controlled by long-acting β-agonists and inhaled glucocorticoids. Over the course of 52 weeks, patients received tezepelumab subcutaneously at doses of 70 mg every 4 weeks (low dose), 210 mg every 4 weeks (medium dose), or 280 mg every 2 weeks (high dose) or placebo. The frequencies of asthma exacerbations in all 3 tezepelumab treatment groups were lower than in the placebo group. The annualized asthma exacerbation rates (in exacerbations per patient year) in the low-, medium-, and high-dose tezepelumab treatment groups were 0.26, 0.19, and 0.22 (61%, 71%, and 66% decreases compared with the rate in the placebo group [0.67]). Furthermore, all doses of tezepelumab increased FEV1 compared with the placebo group. Collectively, these results demonstrate that neutralization of TSLP significantly reduced asthma exacerbation frequency and is a promising therapeutic strategy for treatment-resistant asthma.Neutralization of TSLP significantly reduced asthma exacerbation frequency Neutralization of TSLP significantly reduced asthma exacerbation frequency A consortium from the Global Burden of Disease 2015 study (Lancet Respir Med 2017;5:691-706; doi: https://doi.org/10.1016/S2213-2600(17)30293-X) recently characterized the global disease burden and related risk factors of chronic obstructive pulmonary disease (COPD) and asthma. Increases were noted in the prevalence (+44.2% in 2015 compared with 1990) and mortality (+11.6%) of COPD in 2015, as well as in the prevalence (+12.6%) of asthma. These increases were driven by aging of the population because they were not reproduced when using age-standardized data. Importantly, COPD had an 8-fold greater mortality rate compared with asthma despite only being half as prevalent. Furthermore, COPD and asthma caused 2.6% and 1.1% of disability-adjusted life years (DALYs) worldwide, respectively. Smoking and occupational exposure to allergens were identified as risk factors for asthma, accounting for 17% of the DALYs attributed to asthma. Risk factors accounted for 73% of the COPD-related DALYs and included smoking, ambient particle exposure, household air pollution, occupational particulates, ozone, and secondhand smoke. These results demonstrate that COPD and asthma impose a significant global burden, which is likely to increase as our population continues to age, and imply a need for future interventions to decrease modifiable risk factors to decrease the prevalence of these diseases and improve access to quality treatments that can alleviate severity and prevent deaths.COPD and asthma caused 2.6% and 1.1% of DALYs worldwide, respectively COPD and asthma caused 2.6% and 1.1% of DALYs worldwide, respectively We asked first author Theo Vos, MD, MPH, PhD, of the University of Washington (Seattle, Washington) to comment on the study. He writes, “The Institute for Health Metrics and Evaluation, together with over 2,700 collaborators in over 130 countries, is committed to producing annual accounts of the health status of the world’s population from 1990 to the most recent year. Policymakers, researchers, clinicians, and the general public are encouraged to use this large ‘public good’ through attractive and interactive visualization tools that help to navigate the large amount of detail by disease, risk factor, country, year, age, and sex.” Changes in management were associated with a significant reduction in asthma mortality between 1985 and 2005. Ebmeier et al (Lancet 2017;390:935-945; doi: https://doi.org/10.1016/S0140-6736(17)31448-4) examined whether any further changes in the asthma mortality rate occurred between 2006 and 2012. Asthma mortality rates for the 5- to 34-year-old age group were obtained from the online World Health Organization Mortality Database for those 46 countries with sufficient data available. The estimated global asthma mortality rate decreased from 1993 (0.44 deaths per 100,000 persons) to 2006 (0.19 deaths per 100,000 persons). However, this rate did not change from 2006 to 2012, remaining at 0.19 deaths per 100,000 persons through 2012. The fact that estimated global asthma mortality rates have not changed appreciably since 2006 suggests a need for better implementation of current management regimens and development of novel therapeutic strategies to further reduce asthma mortality.Global asthma mortality rates have not appreciably changed since 2006 Global asthma mortality rates have not appreciably changed since 2006 We asked first author Stefan Ebmeier, BMBCh, of the Medical Research Institute of New Zealand (Wellington, New Zealand) to comment on the study. He writes, “International trends in asthma mortality rates provide useful information about the burden of asthma and the impact of changes in management. With 46 countries represented, this is the most comprehensive analysis of international asthma mortality trends to date.” For unknown reasons, targeting the TNF-α signaling pathway has proved therapeutic in only some patients with asthma. Whitehead et al (J Clin Invest 2017;127:3313-26; doi: https://doi.org/10.1172/JCI90890) characterized the molecular mechanisms, including the requirement for TNF-α, in different experimental models of allergic airway inflammation in mice. Use of Toll-like receptor (TLR) ligands or house dust extracts as adjuvants during the allergic sensitization phase led to mixed eosinophilic and neutrophilic airway inflammation after allergen challenge, whereas use of proteases as adjuvants led to a predominantly eosinophilic inflammation. TNF-α was induced by TLR ligands and house dust extracts, but not proteases, during sensitization. Importantly, TNF-α signaling was required for inflammation in the TLR ligand–mediated model but not in the protease-mediated model of asthma. These results reveal differential requirements for TNF-α in different experimental murine models of asthma and might explain, at least in part, why blocking TNF-α signaling benefits only a subset of patients with asthma. Figure attribution: accessed by Wikimedia Commons, made by Yale Rosen [CC BY-SA 2.0 (https://creativecommons.org/licenses/by-sa/2.0)].TNF-a signaling was required for inflammation in the TLR ligand–mediated model but not in the protease-mediated model of asthma TNF-a signaling was required for inflammation in the TLR ligand–mediated model but not in the protease-mediated model of asthma We asked senior author Donald N. Cook, PhD, of the National Institute of Environmental Health Sciences (Research Triangle Park, North Carolina) to comment on the study. He writes, “The work by Cook and colleagues shows that the requirement for TNF in animal models of asthma depends on the adjuvant used for allergic sensitization. This provides a plausible mechanistic explanation for why anti-TNF therapies benefit only a subset of patients with asthma.”News items were written by medical writer Jared Travers, PhD.Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com. News items were written by medical writer Jared Travers, PhD. Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com.