We aimed to determine the effect of sampling time during the day on serum periostin levels in adult participants with and without asthma.Serum periostin was measured at 2-h intervals from 0800 to 1800 h in 16 adult participants with stable asthma prescribed inhaled corticosteroid and long-acting beta-agonist therapy, and in 16 otherwise healthy participants without asthma. Mixed linear models were used to compare time zero (08:00 h) with subsequent measurement time for serum periostin for both groups.In both asthma and non-asthma, the mean (SD) serum periostin levels continuously reduced during the day from 53.5 (13.6) ng/mL at 0800 h to 50.9 (13.4) ng/mL at 1800 h (difference log periostin -0.05, P ≤ 0.001) and 50.5 (13.0) ng/mL at 0800 h to 46.2 (11.5) ng/mL at 1800 h (difference log periostin -0.08, P ≤ 0.001) respectively.Periostin values are higher in the morning compared with the afternoon in asthmatic and non-asthmatic adults. The small magnitude of the variation in serum periostin levels suggests that the time of day in which the serum periostin measurements are made is unlikely to influence treatment decisions if a specific serum periostin level is used to predict treatment responsiveness. Trial registration Australia New Zealand Trials Registry (ACTRN12614000072617).
The UK Refractory Asthma Stratification Programme (RASP-UK) will explore novel biomarker stratification strategies in severe asthma to improve clinical management and accelerate development of new therapies. Prior asthma mechanistic studies have not stratified on inflammatory phenotype and the understanding of pathophysiological mechanisms in asthma without Type 2 cytokine inflammation is limited. RASP-UK will objectively assess adherence to corticosteroids (CS) and examine a novel composite biomarker strategy to optimise CS dose; this will also address what proportion of patients with severe asthma have persistent symptoms without eosinophilic airways inflammation after progressive CS withdrawal. There will be interactive partnership with the pharmaceutical industry to facilitate access to stratified populations for novel therapeutic studies.
Serum periostin is a potential biomarker of response to therapies that target type 2 inflammation in asthma. The objectives of this study were to describe: 1) the distribution of serum periostin levels in adults with symptomatic airflow obstruction; 2) its relationship with other variables, including type 2 biomarkers; and 3) the effect of inhaled corticosteroids on periostin levels. Serum periostin levels were measured in a cross-sectional study exploring phenotypes and biomarkers in 386 patients aged 18–75 years who reported wheeze and breathlessness in the past 12 months. In 49 ICS-naïve patients, periostin levels were measured again after 12 weeks of budesonide (800 μg·day −1 ). The distribution of serum periostin levels was right skewed (mean± sd 57.3±18.6 ng·mL −1 , median (interquartile range) 54.0 (45.1–65.6) ng·mL −1 , range 15.0–164.7 ng·mL −1 ). Periostin was positively associated with exhaled nitric oxide (Spearman's rho=0.22, p<0.001), blood eosinophil count (Spearman's rho=0.21, p<0.001), and total IgE (Spearman's rho=0.14, p=0.007). The Hodges–Lehmann estimator (95% CI) of change in periostin level after ICS therapy was −4.8 (−6.7– −3.2) ng·mL −1 (p<0.001). These findings provide data on the distribution of serum periostin in adults with symptomatic airflow obstruction, the weak associations between periostin and other type 2 markers, and the reduction in periostin with inhaled corticosteroid therapy.
Background Understanding why patients with severe asthma do not follow healthcare provider (HCP) advice to adjust treatment is critical to achieving personalised disease management. Methods We reviewed patient choice to follow HCP advice to adjust asthma treatment in a UK-based randomised, controlled, single-blind (study participant), multicentre, parallel group 48-week clinical study comparing biomarker-directed treatment adjustment with standard care in severe asthma. Results Of 1572 treatment advisories (291 participants), instructions were followed in 1377 cases (87.6%). Patients were more likely to follow advice to remain on treatment (96.7%) than to either reduce (70.3%) or increase (67.1%) their treatment, with 64% of patients following all treatment advice. Multivariate analysis associated belonging to an ethnic minority group (OR 3.10, 95% CI 1.68–5.73) and prior study medication changes (two or more changes: OR 2.77, 95% CI 1.51–5.10) with failure to follow treatment advice. In contrast, emergency room attendance in the prior year (OR 0.54, 95% CI 0.32–0.92) was associated with following treatment advice. The largest effect was seen with transition onto or off oral corticosteroids (OR 29.28, 95% CI 16.07–53.36) when compared with those requested to maintain treatment. Centre was also an important determinant regarding the likelihood of patients to follow treatment advice. Conclusions Belonging to an ethnic minority group and multiple prior treatment adjustments were associated with not following HCP treatment advice. Patients also responded differently to HCP advice across UK specialist centres. These findings have implications for the generalisability of models of care in severe asthma and require further focused studies.
In her editorial the Chair of the Royal College of General Practitioners describes the role of GPs as gatekeepers in a negative light.1 She asserts that this role has arisen in the past 20 years as a result of GPs being encouraged to take financial, as well as clinical, responsibility for their patients. In fact the role of the GP as a gatekeeper has been recognised for at least the past 100 years.2 There should be nothing demeaning about GPs having a gatekeeper role — it has been associated with the cost-effective delivery of healthcare services the world over.3
The role of advocate, that she proposes, has legal rather than medical roots. The advocate’s only duty is to their client. It presupposes the separate and distinct role of a judge who is responsible for final arbitration. Such separation of advocacy from decision-making is a luxury that does not exist in medicine. In seeking to disengage GPs from the financial concerns of providing health care Dr Gerada is not helping us face reality. It may help us to see financial resources as we do any other finite resource, for example, a blood bank or a doctor’s time. Clinical triage principles would direct a doctor to use the blood supplies on those patients in whom it would gain the greatest benefit and not those for whom its use would be marginal or futile. Similarly, a doctor does not decide how to allocate their time simply on the basis of one patient’s need but has to spend it with regard to all their patients’ needs. In both these cases the doctor does not behave as an advocate for an individual patient but as a steward (a gatekeeper even) of a finite resource who seeks to maximise its effectiveness. It is also important to be clear that the GP would be at fault for closing the gate unnecessarily as well as for opening it irresponsibly. Therein lies the complexity and value of general practice.
The anti-interleukin 13 (IL-13) monoclonal antibody lebrikizumab improves lung function in patients with moderate-to-severe uncontrolled asthma, but its effects on airway inflammation and remodelling are unknown. CLAVIER was designed to assess lebrikizumab's effect on eosinophilic inflammation and remodelling.
Background The anti–interleukin 13 (IL‐13) monoclonal antibody lebrikizumab improves lung function in patients with moderate‐severe uncontrolled asthma, but its effects on airway inflammation and remodeling are unknown. CLAVIER was designed to assess lebrikizumab’s effect on eosinophilic inflammation and remodeling. Methods We performed bronchoscopy on patients with uncontrolled asthma before and after 12 weeks of randomised double‐masked treatment with lebrikizumab (n=31) or placebo (n=33). The primary endpoint was relative change in airway subepithelial eosinophils per mm 2 of basement membrane (cells/mm 2 ). Pre‐specified secondary and exploratory outcomes included change in IL‐13–associated biomarkers and measures of airway remodeling. Findings There was a baseline imbalance in tissue eosinophils and high variability between treatment groups. There was no discernible change in adjusted mean subepithelial eosinophils/mm 2 in response to lebrikizumab (95% CI, −82·5%, 97·5%). As previously observed, FEV 1 increased after lebrikizumab treatment. Moreover, subepithelial collagen thickness decreased 21·5% after lebrikizumab treatment (95% CI, −32·9%, −10·2%), while fractional exhaled nitric oxide, CCL26 , and SERPINB2 mRNA expression in bronchial tissues also diminished. Lebrikizumab was well tolerated, with a safety profile consistent with other lebrikizumab asthma studies. Interpretation We did not observe reduced tissue eosinophil numbers in association with lebrikizumab treatment. However, in pre‐specified secondary analyses, lebrikizumab treatment was associated with diminished degree of subepithelial fibrosis, a feature of airway remodeling, as well as improved lung function and reduced key pharmacodynamic biomarkers in bronchial tissues. These results reinforce the importance of IL‐13 in airway pathobiology and suggest that neutralization of IL‐13 may reduce asthmatic airway remodeling. Clinical trial registration NCT02099656 Support or Funding Information The study was sponsored by F. Hoffmann‐La Roche Ltd.
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