News Beyond Our Pages
Authors: Marc E. Rothenberg, Jean Bousquet
Journal: Journal of Allergy and Clinical Immunology (2019)

Hereditary angioedema (HAE) is characterized by recurrent and unpredictable angioedema attacks and occurs as a result of impairment of C1 esterase inhibitor activity, which leads to dysregulation of plasma kallikrein activity and excessive production of bradykinin. Banerji et al (JAMA 2018;320:2108-2; https://doi.org/10.1001/jama.2018.16773) assessed the efficacy of lanadelumab, an mAb that targets active plasma kallikrein, in the prevention of HAE attacks in a multicenter phase 3 trial. One hundred thirteen patients were randomized to receive one of 3 doses of subcutaneous lanadelumab or placebo over 26 weeks. All 3 doses of lanadelumab significantly decreased the mean number of HAE attacks per month (range, 0.3-0.5 attacks per month) compared with placebo (2.0 attacks per month, P < .001). The most common adverse effects were injection-site reactions and dizziness. In summary, these results demonstrate that prophylactic use of lanadelumab decreases the frequency of HAE attacks. A longer-term open-label study is ongoing.Prophylactic use of lanadelumab decreases the frequency of HAE attacksAleena BanerjiView Large Image Figure ViewerDownload Hi-res image Download (PPT) Prophylactic use of lanadelumab decreases the frequency of HAE attacks We asked first author Aleena Banerji, MD, at Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, to comment on the study. She writes, “The results from this clinical trial are very exciting and offer patients with HAE a new option with significant benefit for prevention of attacks of swelling.” Exacerbation patterns among patients with asthma are variable and not well understood because their characterization has historically been based on studies limited by duration and/or focus on severe disease. Bloom et al (Am J Respir Crit Care Med 2018; https://doi.org/10.1164/rccm.201808-1516OC) recently performed the largest longitudinal study to date of patterns of exacerbations over at least 7 years in a cohort of adult patients with asthma in England. Exacerbation only occurred in 36% of the more than 50,000 subjects in the study, of whom approximately half only experienced a single sporadic event. Additionally, frequent exacerbations were identified in only a very small proportion of patients across the spectrum of disease severity but more commonly in patients with more severe disease. Notably, past exacerbation was identified as the factor indicating the greatest risk of a future exacerbation. However, no clear risk factors were identified to distinguish between patients with sporadic versus recurrent exacerbation phenotypes. Collectively, these findings show that although the most likely course is an absence of exacerbations, recurrent exacerbations occur across the spectrum of disease severity but are more common in those with severe disease and that further study is needed to identify risk factors that underlie the different exacerbation phenotypes.Recurrent exacerbations occur across the spectrum of disease severity but are more common in those with severe diseaseChloe BloomView Large Image Figure ViewerDownload Hi-res image Download (PPT) Recurrent exacerbations occur across the spectrum of disease severity but are more common in those with severe disease We asked first author Chloe Bloom, MBChB, BSc, PhD, MSc, of Imperial College London, London, United Kingdom, to comment on the study. She writes, “Our large observational study showed that most asthmatic patients do not exacerbate; however, exacerbations occurred across all levels of disease severity, even in those managed as having mild asthma. Although we found that a past history of exacerbations (even up to 5 years previously) and asthma severity were highly prognostic factors for a future exacerbation, overall, the ability to predict a patient’s risk remains incomplete.” Although numerous investigations into the genetic bases of asthma have been performed, there are few studies focused on moderate-to-severe asthma. Shrine et al (Lancet Respir Med 2018; https://doi.org/10.1016/S2213-2600(18)30389-8) have conducted the largest genome-wide association study of the genetic contributions to susceptibility to development of moderate-to-severe asthma. Variants in 24 loci were found to be statistically significantly associated with moderate-to-severe asthma, including 21 signals that were replicated from previous studies on asthma. The 3 novel signals were present in the MUC5AC, GATA3, and KIAA1109 loci. Although the GATA3 and KIAA1109 signals were significantly associated with all asthma, signal in the MUC5AC gene, which regulates mucin production, lost statistical significance when patients with mild asthma were included in the analysis. Overall, these findings suggest there is a high degree of similarity in the underlying genetic architecture between patients with mild and those with moderate-to-severe asthma; however, dysregulation of mucin production might be particularly important for patients with moderate-to-severe disease. Although they require further validation and mechanistic study, these findings can lead to development of improved therapeutics for patients with moderate-to-severe asthma. Image attribution: Figure by user M. Kamran Ikram et al [CC BY 2.5 (https://creativecommons.org/licenses/by/2.5) ], via Wikimedia Commons.These findings suggest, however, dysregulation of mucin production might be particularly important for moderate-to-severe asthmaIan SayersView Large Image Figure ViewerDownload Hi-res image Download (PPT) These findings suggest, however, dysregulation of mucin production might be particularly important for moderate-to-severe asthma We asked senior author Ian Sayers, BSc, PhD, of the University of Nottingham, Nottingham, United Kingdom, to comment on the study. He writes, “Our study showed that most of the genetic variants and genes we identified are important in both patients with mild and those with moderate-to-severe asthma, which is important because it suggests additional nongenetic factors might be relevant for the development of severe asthma, such as the environment.” Asthma is heterogeneous with regard to the presence type 2 (T2) inflammation in the airways (T2-high vs T2-low). To clarify the poorly understood immune abnormalities underlying these distinct phenotypes, Peters et al (Am J Respir Crit Care Med 2018; https://doi.org/10.1164/rccm.201807-1291OC) performed gene network analysis of genome-wide transcriptional data derived from sputum samples from 84 patients with asthma and 27 control subjects. A core T2 gene signature was generated, with significant contributions from eosinophils, basophils, mast cells, and inflammatory dendritic cells. Notably, a subset of T2-high patients (T2-ultrahigh asthma) was identified with increased expression of T2 genes and clinically by eosinophilia and more severe airflow obstruction. Genes specific for CD11b+, CD103−, and interferon regulatory factor 4–positive classical dendritic cells were enriched in patients with T2-high asthma and to a greater degree in patients with T2-ultrahigh asthma. Patients with T2-low asthma exhibited lower expression of a network of genes associated with cytotoxic CD8+ T cells, and this deficiency correlated with obesity-related systemic inflammation, as indicated by body mass index and levels of IL-6 in plasma. Through their analysis, the authors have characterized sputum immune gene expression networks that distinguish T2-high and T2-low asthma and identified a subpopulation of patients with asthma with enhanced T2 inflammation. Image attribution: Figure by user Thomas Shafee [CC BY 4.0 (https://creativecommons.org/licenses/by/4.0) ], from Wikimedia Commons.Sputum immune gene expression networks that distinguish T2-high and T2-low asthmaNews items were written by medical writer Jared Travers, PhD.Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com. Sputum immune gene expression networks that distinguish T2-high and T2-low asthma News items were written by medical writer Jared Travers, PhD. Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com.