Tezepelumab and Mucus Plugs in Patients with Moderate-to-Severe Asthma.

Tezepelumab and Mucus Plugs in Patients with AsthmaMucus plugs in airways of asthma patients are associated with airway obstruction and the activity of inflammatory cytokines. This article reports prespecified and post hoc analyses of the effect of tezepelumab treatment on mucus plugs identified by computed tomography imaging in patients with moderate-to-severe asthma. At baseline, mucus plug scores correlated positively with levels of inflammatory biomarkers and negatively with lung function measures. Patients treated with tezepelumab had resolution of more mucus plugs than patients taking placebo.

Relationship between Emphysema Progression at CT and Mortality in Ever-Smokers: Results from the COPDGene and ECLIPSE Cohorts.

Background The relationship between emphysema progression and long-term outcomes is unclear. Purpose To determine the relationship between emphysema progression at CT and mortality among participants with emphysema. Materials and Methods In a secondary analysis of two prospective observational studies, COPDGene (clinicaltrials.gov, NCT00608764) and Evaluation of Chronic Obstructive Pulmonary Disease Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE; clinicaltrials.gov, NCT00292552), emphysema was measured at CT at two points by using the volume-adjusted lung density at the 15th percentile of the lung density histogram (hereafter, lung density perc15) method. The association between emphysema progression rate and all-cause mortality was analyzed by using Cox regression adjusted for ethnicity, sex, baseline age, pack-years, and lung density, baseline and change in smoking status, forced expiratory volume in 1 second, and 6-minute walk distance. In COPDGene, respiratory mortality was analyzed by using the Fine and Gray method. Results A total of 5143 participants (2613 men [51%]; mean age, 60 years ± 9 [standard deviation]) in COPDGene and 1549 participants (973 men [63%]; mean age, 62 years ± 8) in ECLIPSE were evaluated, of which 2097 (40.8%) and 1179 (76.1%) had emphysema, respectively. Baseline imaging was performed between January 2008 and December 2010 for COPDGene and January 2006 and August 2007 for ECLIPSE. Follow-up imaging was performed after 5.5 years ± 0.6 in COPDGene and 3.0 years ± 0.2 in ECLIPSE, and mortality was assessed over the ensuing 5 years in both. For every 1 g/L per year faster rate of decline in lung density perc15, all-cause mortality increased by 8% in COPDGene (hazard ratio [HR], 1.08; 95% CI: 1.01, 1.16; P = .03) and 6% in ECLIPSE (HR, 1.06; 95% CI: 1.00, 1.13; P = .045). In COPDGene, respiratory mortality increased by 22% (HR, 1.22; 95% CI: 1.13, 1.31; P < .001) for the same increase in the rate of change in lung density perc15. Conclusion In ever-smokers with emphysema, emphysema progression at CT was associated with increased all-cause and respiratory mortality. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Lee and Park in this issue.

Unreported and Overlooked: A Post Hoc Analysis of COPD Symptom-Related Attacks from the RISE Study.

Purpose: Moderate and severe COPD exacerbations are a significant health-care burden, but patients also experience "mild" exacerbations, or COPD symptom-related attacks, which often go unreported. We aimed to define and then determine the incidence of COPD symptom-related attacks and their impact on future risk of moderate/severe exacerbations, health-related quality of life (HRQoL), and lung function. The effect of COPD maintenance therapy on the attack definition was then evaluated by comparing budesonide/formoterol with formoterol alone. Patients and Methods: This post hoc analysis of the RISE study defined COPD symptom-related attacks as ≥2 consecutive days of both worsening symptoms and increased daily rescue medication use based upon thresholds of >2 and >4 short-acting ß2-agonist (SABA) inhalations/day above baseline. The impact of these events on subsequent moderate/severe exacerbation risk was estimated using a time-varying Cox proportional hazards model. The effects of COPD symptom-related attacks on St George's Respiratory Questionnaire (SGRQ) total score and pre-bronchodilator forced expiratory volume in 1 second (FEV1) were evaluated as average changes from baseline to first post-attack measurement. Rates of attacks were compared between treatment groups using negative binomial regression models. Results: COPD symptom-related attacks elevated the risk of subsequent moderate/severe exacerbations at both >2 and >4 inhalations/day above baseline (HR 1.86 and 2.21, respectively; p<0.0001), with a cumulative increase in risk with increasing attacks. HRQoL and lung function were reduced for patients with ≥1 versus no COPD symptom-related attacks at both rescue medication thresholds. There were fewer COPD symptom-related attacks with budesonide/formoterol versus formoterol alone, with no increased risk of pneumonia and lower respiratory tract infections. Conclusion: COPD symptom-related attacks are common and typically unreported. Importantly, these attacks can account for considerable morbidity and should not be regarded as "mild". Detection of such exacerbations may be valuable in identifying patients at greater risk and guiding preventive therapeutic interventions.

Effect of tralokinumab, an interleukin-13 neutralising monoclonal antibody, on eosinophilic airway inflammation in uncontrolled moderate-to-severe asthma (MESOS): a multicentre, double-blind, randomised, placebo-controlled phase 2 trial.

BACKGROUND: The role of interleukin 13 in airway inflammation and remodelling in asthma is unclear. Tralokinumab is a human monoclonal antibody that neutralises interleukin 13. We aimed to evaluate whether tralokinumab would have an effect on airway eosinophilic infiltration, blood and sputum eosinophil concentrations, eosinophil activation, and airway remodelling. METHODS: We did a multicentre, double-blind, randomised, placebo-controlled phase 2 trial at 15 centres across the UK, Denmark, and Canada. We enrolled participants of either sex aged 18-75 years with inadequately controlled moderate-to-severe asthma for 12 months or more, requiring treatment with inhaled corticosteroids at a stable dose. We randomly assigned participants (1:1) to receive tralokinumab (300 mg) or placebo by an interactive web-based system or voice response system. Participants and study personnel were masked to treatment allocation. Both tralokinumab and placebo were administered subcutaneously every 2 weeks. The primary outcome measure was change from baseline to week 12 in bronchial biopsy eosinophil count. Secondary outcome measures included change in blood and sputum eosinophil counts. Exploratory outcomes included fractional exhaled nitric oxide (FENO) and blood IgE concentrations. Safety analyses were carried out in all participants who received study drug. This trial is registered with ClinicalTrials.gov, number NCT02449473, and with the European Clinical Trials Database, EudraCT 2015-000857-19. FINDINGS: Between Sept 25, 2015, and June 21, 2017, 224 participants were enrolled and screened. Of these participants, 79 were randomly assigned to receive tralokinumab (n=39) or placebo (n=40). Tralokinumab did not significantly affect bronchial eosinophil count compared with placebo at week 12 (treatment effect ratio 1·43, 95% CI 0·63-3·27; p=0·39). Compared with placebo, tralokinumab did not significantly affect blood eosinophil count (treatment effect ratio 1·21, 95% CI 1·00-1·48; p=0·055) or sputum eosinophil count (0·57, 0·06-6·00; p=0·63), but FENO concentration (0·78, 0·63-0·96; p=0·023) and total blood IgE concentration (0·86, 0·77-0·97; p=0·014) were significantly reduced. 33 (85%) of 39 patients receiving tralokinumab and 32 (80%) of 40 receiving placebo reported at least one adverse event during the treatment period. No deaths in either treatment group were observed. Treatment-related adverse events occurred more frequently in the tralokinumab group than in the placebo group (11 [28%] of 39 vs seven [18%] of 40). INTERPRETATION: Tralokinumab did not significantly affect eosinophilic inflammation in bronchial submucosa, blood, or sputum compared with placebo, but did reduce FENO and IgE concentrations. These results suggest interleukin 13 is not crucial for eosinophilic airway inflammation control in moderate-to-severe asthma. FUNDING: AstraZeneca.

Repeatability and response to therapy of dynamic contrast-enhanced magnetic resonance imaging biomarkers in rheumatoid arthritis in a large multicentre trial setting.

OBJECTIVES: To determine the repeatability and response to therapy of dynamic contrast-enhanced (DCE) MRI biomarkers of synovitis in the hand and wrist of rheumatoid arthritis (RA) patients, and in particular the performance of the transfer constant K trans , in a multicentre trial setting. METHODS: DCE-MRI and RA MRI scoring (RAMRIS) were performed with meticulous standardisation at baseline and 6 and 24 weeks in a substudy of fostamatinib monotherapy in reducing synovitis compared with placebo or adalimumab. Analysis employed statistical shape modelling to avoid biased regions-of-interest, kinetic modelling and heuristic analyses. Repeatability was also evaluated. RESULTS: At early study termination, DCE-MRI data had been acquired from 58 patients in 19 imaging centres. K trans intra-subject coefficient of variation (N = 14) was 30%. K trans change demonstrated inferiority of fostamatinib (N = 11) relative to adalimumab (N = 10) after 6 weeks (treatment ratio = 1.92, p = 0.003), and failed to distinguish fostamatinib from placebo (N = 10, p = 0.79). RAMRIS showed superiority of fostamatinib relative to placebo at 6 weeks (p = 0.023), and did not distinguish fostamatinib from adalimumab at either 6 (p = 0.175) or 24 (p = 0.230) weeks. CONCLUSION: This demonstrated repeatability of K trans and its ability to distinguish treatment groups show that DCE-MRI biomarkers are suitable for use in multicentre RA trials. KEY POINTS: • DCE-MRI biomarkers are feasible in large multicentre studies of joint inflammation. • DCE-MRI K trans showed fostamatinib inferior to adalimumab after 6 weeks. • K trans repeatability coefficient of variation was 30% multicentre.

COPD Patients Have Short Lung Magnetic Resonance T1 Relaxation Time.

Magnetic resonance imaging (MRI) may provide attractive biomarkers for assessment of pulmonary disease in clinical trials as it is free from ionizing radiation, minimally invasive and allows regional information. The aim of this study was to characterize lung MRI T1 relaxation time as a biomarker of chronic obstructive pulmonary disease (COPD); and specifically its relationship to smoking history, computed tomography (CT), and pulmonary function test (PFT) measurements in comparison to healthy age-matched controls. Lung T1 and inter-quartile range (IQR) of T1 maps from 24 COPD subjects and 12 healthy age-matched non-smokers were retrospectively analyzed from an institutional review board approved study. The subjects underwent PFTs and two separate MR imaging sessions at 1.5 tesla to test T1 repeatability. CT scans were performed on the COPD subjects. T1 repeatability (intraclass correlation coefficient) was 0.72 for repeated scans acquired on two visits. The lung T1 was significantly shorter (p < 0.0001) and T1 IQR was significantly larger (p = 0.0002) for the COPD subjects compared to healthy controls. Lung T1 significantly (p = 0.001) correlated with lung density assessed with CT. Strong significant correlations (p < 0.0001) between lung T1 and all PFT measurements were observed. Cigarette exposure did not correlate with lung T1 in COPD subjects. In conclusion, lung MRI T1 mapping shows potential as a repeatable, radiation free, non-invasive imaging technique in the evaluation of COPD.

Feasibility of Computed Tomography in a Multicenter COPD Trial: A Study of the Effect of AZD9668 on Structural Airway Changes.

INTRODUCTION: The aim of this study was to establish the feasibility of using computed tomography (CT) in a multicenter setting to assess structural airway changes. METHODS: This was a 12-week, randomized, double-blind, placebo-controlled, Phase IIb trial using CT to investigate the effect of a novel, oral, reversible neutrophil elastase inhibitor, AZD9668 60 mg twice daily (BID), on structural airway changes in patients aged 50-80 years with chronic obstructive pulmonary disease (COPD) (ex-smokers). PRIMARY OUTCOME VARIABLE: airway wall thickness at an extrapolated interior perimeter of 10 mm (AWT-Pi10). Secondary outcome variables: fifth-generation wall area %; air trapping index; pre- and post-bronchodilator forced expiratory volume in 1 s (FEV1); morning and evening peak expiratory flow and FEV1; body plethysmography; EXAcerbations of Chronic pulmonary disease Tool (EXACT); Breathlessness, Cough, and Sputum Scale (BCSS); St George's Respiratory Questionnaire for COPD; and proportion of reliever-medication-free trial days. Safety variables were also assessed. RESULTS: There was no difference between placebo (n = 19) and AZD9668 (n = 17) for AWT-Pi10 at treatment end. This was consistent with results for most secondary variables. However, patients randomized to AZD9668 experienced an improvement versus placebo for morning and evening FEV1, and EXACT and BCSS cough and sputum scores. AZD9668 60 mg BID was well tolerated and no new safety concerns were identified. CONCLUSIONS: This study confirmed the feasibility of using CT to assess structural airway changes in COPD. However, there was no evidence of improvements in CT structural measures following 12 weeks' treatment with AZD9668 60 mg BID. FUNDING: AstraZeneca.

MR Quantitative Equilibrium Signal Mapping: A Reliable Alternative to CT in the Assessment of Emphysema in Patients with Chronic Obstructive Pulmonary Disease.

PURPOSE: To compare magnetic resonance (MR) quantitative equilibrium signal (qS0) mapping with quantitative computed tomography (CT) in the estimation of emphysema in patients with chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: Written informed consent of the original study permitted future reanalysis of data. This study was a retrospective analysis of data from an institutional review board-approved study. Twenty-four patients with COPD and 12 healthy patients who did not smoke underwent spirometry and two separate 1.5-T MR imaging examinations. All patients with COPD underwent additional chest CT. Lung MR qS0 maps were generated from MR images obtained with multiple inversion times by fitting the inversion recovery signal equation. Mean, 15th percentile, and standard deviation of whole-lung qS0 and relative lung area with a qS0 value below 0.20 (RA0.20) were measured and compared between groups with an unpaired t test. Reproducibility between two examinations was tested with intraclass correlation coefficients (ICCs), and their associations with spirometry and CT measurements of 15th percentile attenuation (PA15) and relative lung area with attenuation below -950 HU (RA-950) were assessed with the Pearson correlation coefficient. RESULTS: Whole-lung mean qS0 and 15th percentile of qS0 were significantly lower, whereas RA0.20 and standard deviation of qS0 were significantly higher in patients with COPD than in healthy control subjects (P = .014, P = .002, P = .005, and P < .001, respectively). Whole-lung mean qS0, the 15th percentile of qS0, and RA0.20 strongly correlated with RA-950 (r = -0.78, r = -0.81, and r = 0.86, respectively; P < .001) and PA15 (r = 0.78, r = 0.79, and r = -0.71, respectively; P < .001) and moderately correlated with the ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (r = 0.63, r = 0.67, and r = -0.60, respectively; P < .001) and percentage predicted FEV1 (r = 0.54, r = 0.62, and r = -0.56, respectively; P ≤ .001). Good reproducibility of qS0 readouts was found in both groups (ICC range, 0.89-0.98). CONCLUSION: Lung MR qS0 mapping may be a reliable noncontrast nonradiation alternative to CT in the assessment of emphysema in patients with COPD.

Feasibility assessment of using oxygen-enhanced magnetic resonance imaging for evaluating the effect of pharmacological treatment in COPD.

OBJECTIVES: Oxygen-enhanced MRI (OE-MRI) biomarkers have potential value in assessment of COPD, but need further evaluation before treatment-induced changes can be interpreted. The objective was to evaluate how OE-MRI parameters of regional ventilation and oxygen uptake respond to standard pharmacological interventions in COPD, and how the response compares to that of gold standard pulmonary function tests. MATERIALS AND METHODS: COPD patients (n=40), mean FEV1 58% predicted normal, received single-dose inhaled formoterol 9µg, or placebo, followed by 8 weeks treatment bid with a combination of budesonide and formoterol Turbuhaler(®) 320/9µg or formoterol Turbuhaler(®). OE-MRI biomarkers were obtained, as well as X-ray computed tomography (CT) biomarkers and pulmonary function tests, in a two-center study. An ANCOVA statistical model was used to assess effect size of intervention measurable in OE-MRI parameters of lung function. RESULTS: OE-MRI data were successfully acquired at both study sites. 8-week treatment with budesonide/formoterol significantly decreased lung wash-out time by 31% (p<0.01), decreased the change in lung oxygen level upon breathing pure oxygen by 13% (p<0.05) and increased oxygen extraction from the lung by 58% (p<0.01). Single-dose formoterol increased both lung wash-out time (+47%, p<0.05) and lung oxygenation time (+47%, p<0.05). FEV1 was improved by single-dose formoterol (+12%, p<0.001) and 8 weeks of budesonide/formoterol (+ 18%, p<0.001), consistent with published studies. CONCLUSIONS: In COPD, OE-MRI parameters showed response to both single-dose bronchodilatory effects of a ß2-agonist, formoterol, and 8-week treatment with an inhaled corticosteroid, budesonide, and the measurements are feasible in a small-scale multi-center trial setting.