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

Osteopontin might be associated with remodeling in asthmatic patients. Morimoto et al (Immunity 2018;49:134-50, e6; https://doi.org/10.1016/j.immuni.2018.04.023) have identified an important role for amphiregulin-producing pathogenic memory TH2 (Tpath2) cells in this process. The epithelium-derived cytokine IL-33 induced amphiregulin-producing TH2 cells through its cell-surface receptor ST2. Amphiregulin led to reprogramming of eosinophils into an inflammatory state with enhanced secretion of the profibrotic protein osteopontin. Amphiregulin-producing ST2+ Tpath2 cells were identified as distinct from IL-5–producing ST2+ Tpath2 cells, and both cell populations cooperatively promoted airway fibrosis. These results likely generalize to human subjects because analysis of nasal polyps from patients with eosinophilic chronic rhinosinusitis revealed significant fibrosis, amphiregulin-producing CD161highCRTH2high memory-type TH2 cells, and osteopontin-producing eosinophils. In total, the authors have identified a profibrotic IL-33–amphiregulin–osteopontin axis as active during eosinophilic allergic inflammation. We asked corresponding author Toshinori Nakayama, MD, PhD, of Chiba University, Chiba, Japan, to comment on the study. He writes, “The molecular mechanism underlying the lung fibrosis in chronic eosinophilic airway inflammation is revealed in both mouse and human systems. The molecules involved in the process such as amphiregulin, osteopontin and their receptors will be novel therapeutic targets for lung fibrosis.” Preserved ratio impaired spirometry (PRISm), also known as restrictive or Global Initiative for Chronic Obstructive Lung Disease (GOLD)–unclassified spirometry, is a group of disorders characterized by proportional reductions in both FEV1 and forced vital capacity (FVC; FEV1/FVC ratio ≥ 0.7 and FEV1 < 80% of predicted value) and are associated with increased mortality. Because of uncertainty regarding the long-term outcomes and heterogeneity present among patients with PRISm, Wan et al (Am J Respir Crit Care Med 2018; https://doi.org/10.1164/rccm.201804-0663OC) examined longitudinal data from a cohort of patients who were current or former smokers aged 45 to 80 years enrolled in the COPDGene study who had prospectively ascertained mortality, respiratory exacerbation, and (in a subset) longitudinal lung function and chest computed tomographic data at a 5-year follow-up visit. Answers to questionnaires and results of chest computed tomography, spirometry, and 6-minute walk tests were obtained at both study visits. Subjects with PRISm at enrollment exhibited higher mortality than those with GOLD0 spirometry (FEV1/FVC ratio ≥ 0.7 and FEV1 ≥ 80% of predicted value) but less than those with GOLD1-4 spirometry (FEV1/FVC ratio < 0.7). Additionally, an increased proportion of patients with PRISm transitioned to a different lung function category at the 5-year follow-up relative to patients with either GOL0 or GOLD1-4 spirometry, with 22% and 25% of patients with PRISm at the first study visit transitioning to GOLD0 and GOLD1-4 spirometry, respectively. Finally, the authors introduce the concept that higher and lower risk PRISm subtypes can exist based on observed trends in lung function decrease and mortality. Patients with PRISm at both study visits (stable PRISm) had reduced FEV1 decrease compared with patients with stable GOLD0 spirometry, whereas patients who transitioned from GOLD0 at enrollment to PRISm (incident PRISm) had significantly accelerated decrease in both FEV1 and FVC. On the basis of these results, the authors propose that PRISm is likely composed of distinct subtypes and represents a transitional state in a significant subset of patients. Future studies examining mortality and clinical outcomes in the proposed PRISm subtypes in the general population are warranted. Image attribution: by user BruceBlaus from Wikimedia Commons. Used under Creative Commons CC BY 4.0 license CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0).PRISm is likely composed of distinct subtypes and represents a transitional state in a significant subset of patientsEmily S. WanView Large Image Figure ViewerDownload Hi-res image Download (PPT) PRISm is likely composed of distinct subtypes and represents a transitional state in a significant subset of patients We asked first author Emily S. Wan, MD, MPH, of Brigham & Women’s Hospital, Boston, Massachusetts, for her comments on this study. She writes, “PRISm, which has been more commonly referred to as restrictive, nonspecific, or ‘unclassified’ spirometry, represents a heterogeneous group of patients. Using data from the largest cohort of patients with PRISm with longitudinal data examined to date, we present evidence that PRISm is likely comprised of distinct subtypes and represents a transitional state in a significant subset of patients.” In response to safety concerns with the use of long-acting β2-agonists (LABAs) in asthma management, in 2010, the US Food and Drug Administration (FDA) mandated that randomized controlled trials be performed by companies marketing the use of LABAs in asthmatic patients to study the safety of the addition of LABAs to inhaled glucocorticoid maintenance therapy in patients aged 12 years and older with asthma. Busse et al (N Engl J Med 2018;378:2497-505; https://doi.org/10.1056/NEJMoa1716868) performed a final combined safety analysis on completion of the trials, which involved a total of 36,010 patients with at least 1 asthma exacerbation in the previous year. Importantly and with respect to safety concerns, patients with life-threatening asthma, including intubation, were excluded from enrollment. No statistically significant difference in asthma-related intubation (n = 3) and death (n = 2), which were rare events, was observed between the 2 treatment groups, and a subsequent secondary analysis detected no difference in the rate of serious asthma-related events, which were defined as hospitalization, intubation, or death. Furthermore, the addition of LABA therapy decreased the proportion of patients with at least 1 asthma exacerbation (9.8% vs 11.7%, P < .001). Overall, these results show that addition of LABAs to inhaled glucocorticoid therapy does not increase the risk for serious asthma-related events but, importantly, decreases the rate of asthma exacerbations. Finally, the combined analysis provided strong evidence for the FDA’s decision to remove the boxed safety warning on combination products containing an inhaled corticosteroid and a LABA.Addition of LABAs to inhaled glucocorticoid therapy does not increase the risk for serious asthma-related eventsWilliam BusseView Large Image Figure ViewerDownload Hi-res image Download (PPT) Addition of LABAs to inhaled glucocorticoid therapy does not increase the risk for serious asthma-related events We asked first author William Busse, MD, of the University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin to comment on this study. He writes, “The placement of a box warning by the FDA on LABA use in combination with inhaled corticosteroids (ICSs) was of considerable concern to patients and caregivers given the frequency of their use in the treatment of asthma. Our combined analysis of the 36,010 patients enrolled in the FDA-mandated studies provided strong evidence on the safety of LABA/ICS use in asthmatic patients; the “not common” removal of the box warning occurred because “the evidence in this instance was decisive” [Seymour SM, Lim R, Xia C, Andraca-Carrera, EA, Chowdhury BA. Inhaled corticosteroids and LABAs—removal of the FDA’s boxed warning. N Engl J Med 2018;378: 2461-3]. Our analysis of the LABA safety trials has provided a strong safety reassurance for a major asthma treatment medication.” A mainstay of asthma management has been as-needed use of a short-acting β2-agonist combined with regular use of inhaled glucocorticoids with or without a long-acting β2-agonists (LABAs). However, adherence to maintenance inhaled glucocorticoid therapy is poor, often leaving patients prone to exacerbations. Two recent randomized controlled trials (Symbicort Given as Needed in Mild Asthma [SYGMA] 1 and 2) have been conducted to assess the efficacy of an alternative treatment model involving as-needed use of a LABA with rapid onset of action (formoterol) in combination with an inhaled glucocorticoid (budesonide) in patients aged 12 years or older with mild asthma who met the criteria for daily inhaled glucocorticoid therapy. In the SYGMA 1 trial O’Byrne et al (N Engl J Med 2018;378:1865-76; https://doi.org/10.1056/NEJMoa1715274) randomized 3849 patients to receive twice-daily placebo plus as-needed 0.5 mg of terbutaline (terbutaline group), placebo plus as-needed 200 μg of budesonide and 6 μg of formoterol (budesonide-formoterol group), or 200 μg of budesonide plus as-needed terbutaline (budesonide maintenance group) for 52 weeks. Compared with terbutaline, budesonide-formoterol increased the mean percentage of weeks in which asthma was well controlled and decreased exacerbations. However, the budesonide-formoterol treatment group had a similar reduction of exacerbations and a lower percentage of weeks with well-controlled asthma compared with the budesonide maintenance group, although it did reduce the cumulative dose of budesonide by 83%. In the SYGMA 2 trial Bateman et al (N Engl J Med 2018;378:1877-87; https://doi.org/10.1056/NEJMoa1715275) randomized 4215 patients into either the budesonide-formoterol or budesonide maintenance groups as above. Budesonide-formoterol was determined to be noninferior to budesonide maintenance therapy because a statistically significant difference in the rate of severe exacerbations was not observed. Additionally, the 2 treatment groups exhibited a similar time to first exacerbation. However, the budesonide maintenance group had a greater improvement in patient symptomatology, as assessed by using the Asthma Control Questionnaire 5. Collectively, these trials demonstrate that treatment with as-needed budesonide-formoterol is effective in decreasing asthma exacerbations and suggest that switching from regular maintenance therapy with inhaled glucocorticoids to on-demand therapy could potentially increase adherence while maintaining efficacy.As-needed budesonide-formoterol is effective in decreasing asthma exacerbationsNews items were written by medical writer Jared Travers, PhD.Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com. As-needed budesonide-formoterol is effective in decreasing asthma exacerbations News items were written by medical writer Jared Travers, PhD. Find more News Beyond Our Pages online at www.jaci-nbop.blogspot.com.