Anneke ten Brinke

Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsìveness, and the late asthmatic response

BACKGROUND Interleukin-5 (IL-5) is essential for the formation of eosinophils, which are thought to have a major role in the pathogenesis of asthma and other allergic diseases. We aimed to assess the effects of monoclonal antibody to IL-5 on blood and sputum eosinophils, airway hyper-responsiveness, and the late asthmatic reaction to inhaled allergen in patients with mild asthma. METHODS We did a double-blind randomised placebo-controlled trial, in which a single intravenous infusion of humanised (IgG-K) monoclonal antibody to IL-5 (SB-240563) was given at doses of 2.5 mg/kg (n=8) or 10.0 mg/kg (n=8). The effects of treatment on responses to inhaled allergen challenge, sputum eosinophils, and airway hyper-responsiveness to histamine were measured at weeks 1 and 4 with monitoring of blood eosinophil counts for up to 16 weeks. FINDINGS Monoclonal antibody against IL-5 lowered the mean blood eosinophil count at day 29 from 0.25x10(9)/L (95% CI 0.16-0.34) in the placebo group to 0.04x10(9)/L (0.00-0.07) in the 10 mg/kg group (p<0.0001), and prevented the blood eosinophilia that follows allergen challenge. After inhaled allergen challenge, 9 days after treatment, the percentage sputum eosinophils were 12.2% in the placebo group and lowered to 0.9% (-1.2 to 3.0; p=0.0076) in the 10 mg/kg group, and this effect persisted at day 30 after the dose. There was no significant effect of monoclonal antibody to IL-5 on the late asthmatic response or on airway hyper-responsiveness to histamine. INTERPRETATION A single dose of monoclonal antibody to IL-5 decreased blood eosinophils for up to 16 weeks and sputum eosinophils at 4 weeks, which has considerable therapeutic potential for asthma and allergy. However, our findings question the role of eosinophils in mediating the late asthmatic response and causing airway hyper-responsiveness.

Severe adult-onset asthma: A distinct phenotype.

BACKGROUND Some patients with adult-onset asthma have severe disease, whereas others have mild transient disease. It is currently unknown whether patients with severe adult-onset asthma represent a distinct clinical phenotype. OBJECTIVE We sought to investigate whether disease severity in patients with adult-onset asthma is associated with specific phenotypic characteristics. METHODS One hundred seventy-six patients with adult-onset asthma were recruited from 1 academic and 3 nonacademic outpatient clinics. Severe refractory asthma was defined according to international Innovative Medicines Initiative criteria, and mild-to-moderate persistent asthma was defined according to Global Initiative for Asthma criteria. Patients were characterized with respect to clinical, functional, and inflammatory parameters. Unpaired t tests and χ(2) tests were used for group comparisons; both univariate and multivariate logistic regression were used to determine factors associated with disease severity. RESULTS Apart from the expected high symptom scores, poor quality of life, need for high-intensity treatment, low lung function, and high exacerbation rate, patients with severe adult-onset asthma were more often nonatopic (52% vs 34%, P = .02) and had more nasal symptoms and nasal polyposis (54% vs 27%, P ≤ .001), higher exhaled nitric oxide levels (38 vs 27 ppb, P = .02) and blood neutrophil counts (5.3 vs 4.0 10(9)/L, P ≤ .001) and sputum eosinophilia (11.8% vs 0.8%, P ≤ .001). Multiple logistic regression analysis showed that increased blood neutrophil (odds ratio, 10.9; P = .002) and sputum eosinophil (odds ratio, 1.5; P = .005) counts were independently associated with severe adult-onset disease. CONCLUSION The majority of patients with severe adult-onset asthma are nonatopic and have persistent eosinophilic airway inflammation. This suggests that severe adult-onset asthma has a distinct underlying mechanism compared with milder disease.

Biomarkers to identify sputum eosinophilia in different adult asthma phenotypes

Several biomarkers have been used to assess sputum eosinophilia in asthma. It has been suggested that the diagnostic accuracy of these biomarkers might differ between asthma phenotypes. We investigated the accuracy of biomarkers in detecting sputum eosinophilia (≥3%) in different adult asthma phenotypes. Levels of eosinophils in blood and sputum, exhaled nitric oxide fraction (FeNO) and total immunoglobulin (Ig)E from 336 adult patients, enrolled in three prospective observational clinical trials and recruited at five pulmonology outpatient departments, were analysed. Areas under the receiver operating characteristics curves (AUC) for detecting sputum eosinophilia were calculated and compared between severe and mild, obese and nonobese, atopic and nonatopic and (ex-)smoking and never-smoking asthma patients. Sputum eosinophilia was present in 116 patients (35%). In the total group the AUC was 0.83 (95% CI 0.78–0.87) for blood eosinophils, 0.82 (0.77–0.87) for FeNO and 0.69 (0.63–0.75) for total IgE. AUCs were similar for blood eosinophils and FeNO between different phenotypes. Total IgE was less accurate in detecting sputum eosinophilia in atopic and obese patients than in nonatopic and nonobese patients. Blood eosinophils and FeNO had comparable diagnostic accuracy (superior to total IgE) in identifying sputum eosinophilia in adult asthma patients, irrespective of asthma phenotype such as severe, nonatopic, obese and smoking-related asthma. FeNO and blood eosinophils can be used to detect sputum eosinophilia in adult asthma patients regardless of phenotype http://ow.ly/MnGqF

Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial

BACKGROUND Mepolizumab, an anti-interleukin-5 monoclonal antibody approved as add-on therapy to standard of care for patients with severe eosinophilic asthma, has been shown in previous studies to reduce exacerbations and dependency on oral corticosteroids compared with placebo. We aimed to further assess mepolizumab in patients with severe eosinophilic asthma by examining its effect on health-related quality of life (HRQOL). METHODS We did a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial (MUSCA) in 146 hospitals or research centres in 19 countries worldwide. Eligible participants were patients aged 12 years or older with severe eosinophilic asthma and a history of at least two exacerbations requiring treatment in the previous 12 months before screening despite regular use of high-dose inhaled corticosteroids plus other controller medicines. Exclusion criteria included current smokers or former smokers with a history of at least ten pack-years. We randomly assigned participants (1:1) by country to receive a subcutaneous injection of either mepolizumab 100 mg or placebo, plus standard of care, every 4 weeks for 24 weeks (the final dose was given at week 20). We did the randomisation using an interactive voice response system and a centralised, computer-generated, permuted-block design of block size six. The two treatments were identical in appearance and administered in a masked manner; patients, investigators, other site staff and the entire study team including those assessing outcomes data were also masked to group assignment. The primary endpoint was the mean change from baseline in the St Georges Respiratory Questionnaire (SGRQ) total score at week 24 in the modified intention-to-treat (modified ITT) population (analysed according to their randomly assigned treatment). Safety was assessed in all patients who received at least one dose of trial medication (analysed according to the actual treatment received). This trial is registered with ClinicalTrials.gov, number NCT02281318. FINDINGS We recruited patients between Dec 11, 2014, and Nov 20, 2015, and the study was undertaken between Dec 11, 2014, and June 10, 2016. The modified ITT population comprised 274 patients assigned to mepolizumab 100 mg and 277 assigned to placebo. Mepolizumab versus placebo showed significant improvements at week 24 from baseline in SGRQ total score (least squares mean [SE] change from baseline -15·6 (1·0) vs -7·9 (1·0), a treatment difference of -7·7 (95% CI -10·5 to -4·9; p<0·0001). No deaths occurred during the study. 192 (70%) of 273 patients who received mepolizumab and 207 (74%) of 278 who received placebo reported at least one on-treatment adverse event, the most common of which were headache (in 45 [16%] given mepolizumab vs 59 [21%] given placebo) and nasopharyngitis (in 31 [11%] given mepolizumab vs 46 [17%] given placebo). 15 (5%) and 22 (8%) patients had an on-treatment serious adverse event in the mepolizumab and placebo groups, respectively; the most common was asthma in both groups (in three [1%] given mepolizumab vs nine [3%] given placebo). INTERPRETATION Mepolizumab was associated with significant improvements in HRQOL in patients with severe eosinophilic asthma, and had a safety profile similar to that of placebo. These results add to and support the use of mepolizumab as a favourable add-on treatment option to standard of care in patients with severe eosinophilic asthma. FUNDING GlaxoSmithKline.

Vitamin D reduces eosinophilic airway inflammation in nonatopic asthma

BACKGROUND Low levels of vitamin D are associated with asthma severity, airway remodeling, and exacerbation rate increase, especially in nonatopic asthma. Reduced steroid responsiveness or impaired antimicrobial defense might be underlying mechanisms. OBJECTIVE We sought to evaluate the effect of vitamin D supplementation on eosinophilic and neutrophilic airway inflammation in patients with nonatopic asthma. METHODS In a double-blind, randomized, placebo-controlled trial, we investigated the effect of long-acting vitamin D3 (400,000 IU) on sputum neutrophils and eosinophils in 44 patients with nonatopic asthma with neutrophilic (≥53%) and/or eosinophilic (≥3%) airway inflammation. Sputum induction was performed at baseline and after 9 weeks. Other measurements included questionnaires, blood samples, and pulmonary function. RESULTS Treatment with vitamin D did not significantly affect sputum neutrophils or eosinophils compared with treatment with placebo in the total group. Regarding sputum eosinophils, the effect of vitamin D appeared to be dependent on baseline sputum eosinophil levels (interaction P = .015). In patients with eosinophil levels of 26.2% or more (median in patients with sputum eosinophilia, >3%), eosinophils decreased from a median of 41.0% to 11.8% after vitamin D treatment as compared with an increase from 51.8% to 63.3% in patients receiving placebo (P = .034). Vitamin D treatment also resulted in slightly better Asthma Control Questionnaire scores (P = .08). CONCLUSIONS Vitamin D supplementation reduced eosinophilic airway inflammation in patients with nonatopic asthma with severe eosinophilic airway inflammation, but did not affect sputum neutrophils. Also, a small effect on asthma control was observed. These findings suggest that vitamin D might have potential as an add-on treatment option in eosinophilic asthma.

Internet-based tapering of oral corticosteroids in severe asthma: a pragmatic randomised controlled trial

Background In patients with prednisone-dependent asthma the dose of oral corticosteroids should be adjusted to the lowest possible level to reduce long-term adverse effects. However, the optimal strategy for tapering oral corticosteroids is unknown. Objective To investigate whether an internet-based management tool including home monitoring of symptoms, lung function and fraction of exhaled nitric oxide (FENO) facilitates tapering of oral corticosteroids and leads to reduction of corticosteroid consumption without worsening asthma control or asthma-related quality of life. Methods In a 6-month pragmatic randomised prospective multicentre study, 95 adults with prednisone-dependent asthma from six pulmonary outpatient clinics were allocated to two tapering strategies: according to conventional treatment (n=43) or guided by a novel internet-based monitoring system (internet strategy) (n=52). Primary outcomes were cumulative sparing of prednisone, asthma control and asthma-related quality of life. Secondary outcomes were forced expiratory volume in 1 s (FEV1), exacerbations, hospitalisations and patients satisfaction with the tapering strategy. Results Median cumulative sparing of prednisone was 205 (25–75th percentile −221 to 777) mg in the internet strategy group compared with 0 (−497 to 282) mg in the conventional treatment group (p=0.02). Changes in prednisone dose (mixed effect regression model) from baseline were −4.79 mg/day and +1.59 mg/day, respectively (p<0.001). Asthma control, asthma-related quality of life, FEV1, exacerbations, hospitalisations and satisfaction with the strategy were not different between groups. Conclusions An internet-based management tool including home monitoring of symptoms, lung function and FENO in severe asthma is superior to conventional treatment in reducing total corticosteroid consumption without compromising asthma control or asthma-related quality of life. Clinical trial registration number Clinical trial registered with http://www.trialregister.nl (Netherlands Trial Register number 1146).

Clinical profile of patients with adult-onset eosinophilic asthma.

Adult-onset eosinophilic asthma is increasingly recognised as a severe and difficult-to-treat subtype of asthma. In clinical practice, early recognition of patients with this asthma subtype is important because it may have treatment implications. Therefore, physicians need to know the distinct characteristics of this asthma phenotype. The objective of the present study was to determine the characteristic profile of patients with adult-onset eosinophilic asthma. 130 patients with adult-onset (>18 years of age) asthma and high blood eosinophil counts (≥0.3×109 L−1) were compared with 361 adult-onset asthma patients with low (<0.3×109 L−1) blood eosinophils. Measurements included a series of clinical, functional and imaging parameters. Patients with high blood eosinophils were more often male, had less well controlled asthma and higher exacerbation rates, despite the use of higher doses of inhaled corticosteroids. They had higher levels of total IgE without more sensitisation to common inhaled allergens. In addition, these patients had worse lung function, and more often showed fixed airflow limitation, air trapping, nasal polyposis and abnormalities on sinus computed tomography scanning. Chronic rhinosinusitis, air trapping and male sex were three independent factors associated with blood eosinophilia (adjusted OR 3.8 (95% CI 1.7–8.1), 3.0 (95% CI 1.1–8.1) and 2.4 (95% CI 1.3–4.4), respectively). Patients with adult-onset asthma with elevated blood eosinophils exhibit a distinct profile, which can readily be recognised in clinical practice. Adult-onset eosinophilic asthma has a distinct clinical profile http://ow.ly/4mQSQk

Management of the patient with eosinophilic asthma: a new era begins

Now that it is generally accepted that asthma is a heterogeneous condition, phenotyping of asthma patients has become a mandatory part of the diagnostic workup of all patients who do not respond satisfactorily to standard therapy with inhaled corticosteroids. Late-onset eosinophilic asthma is currently one of the most well-defined asthma phenotypes and seems to have a different underlying pathobiology to classical childhood-onset, allergic asthma. Patients with this phenotype can be identified in the clinic by typical symptoms (few allergies and dyspnoea on exertion), typical lung function abnormalities (“fixed” airflow obstruction, reduced forced vital capacity and increased residual volume), typical comorbidities (nasal polyposis) and a good response to systemic corticosteroids. The definitive diagnosis is based on evidence of eosinophilia in bronchial biopsies or induced sputum, which can be estimated with reasonable accuracy by eosinophilia in peripheral blood. Until recently, patients with eosinophilic asthma had a very poor quality of life and many suffered from frequent severe exacerbations or were dependent on oral corticosteroids. Now, for the first time, novel biologicals targeting the eosinophil have become available that have been shown to be able to provide full control of this type of refractory asthma, and to become a safe and efficacious substitute for oral corticosteroids. Late-onset eosinophilic asthma has a distinct clinical and functional profile with treatment implications http://ow.ly/MH7AH

Anxiety, depression and personality traits in severe, prednisone-dependent asthma

BACKGROUND Anxiety and depression are prevalent in patients with asthma, and associated with more exacerbations and increased health care utilization. Since psychiatric intervention might improve asthma control, we examined whether patients with severe, prednisone-dependent asthma are at higher risk of these disorders than patients with severe non-prednisone dependent asthma or mild-moderate asthma, and whether they exhibit different personality traits. METHODS Sixty-seven adults with severe prednisone-dependent asthma, 47 with severe non-prednisone dependent and 73 patients with mild-moderate asthma completed the HADS depression and anxiety subscale and the NEO-FFI for personality traits. In addition, asthma duration, body mass index and FEV1 were measured. RESULTS The prevalence of clinically significant depressive symptoms (9% vs. 0 vs. 0%; p = 0.009) and anxiety symptoms (19% vs. 6.4 vs. 5.5%; p = 0.01), was higher in patients with severe, prednisone-dependent asthma than in patients with severe non-prednisone dependent or mild-moderate asthma. Patients with prednisone-dependent asthma were respectively 3.4 (95%CI: 1.0-10.8 p = 0.04) and 3.5 (95%CI: 1.3-9.6 p = 0.01) times more likely to have significant depression symptoms and 1.6 (95%CI: 0.7-3.7, p = 0.2) and 2.5 (95%CI: 01.1-5.5, p = 0.02) times more likely to have symptoms of anxiety than patients with severe non-prednisone dependent or mild-moderate asthma. There were no differences found in personality traits between the 3 groups. CONCLUSION Patients with severe, prednisone-dependent asthma have more often psychological distress as compared to patients with severe non-prednisone dependent or mild-moderate asthma.

New Anti-Eosinophil Drugs for Asthma and COPD: Targeting the Trait!

&NA; Asthma and COPD are prevalent chronic inflammatory airway diseases that are responsible for a large global disease burden. Both diseases are complex and heterogeneous, and they are increasingly recognized as overlapping syndromes that may share similar pathophysiologic mechanisms and treatable traits. Eosinophilic airway inflammation is considered the most influential treatable trait of chronic airway disease, and over the last decade, several monoclonal antibodies and small molecule therapies have been developed to target this trait. These include monoclonal antibodies against IL‐5 or IL‐5 receptor alpha (mepolizumab, reslizumab, and benralizumab), IL‐13 (lebrikizumab and tralokinumab), IL‐4 receptor alpha (dupilumab), IgE (omalizumab), and anti‐thymic stromal lymphopoietin (tezepelumab) and small molecule therapies such as prostaglandin D2 blockers (fevipiprant and timapiprant). Although these novel biologic agents have shown promising results in many patients with asthma and COPD who have eosinophilic airway inflammation, it is evident that not all patients respond equally well, despite similar clinical, functional, and inflammatory characteristics. This heterogeneity in treatment response is probably related to different molecular pathways or endotypes leading to eosinophilic airway inflammation, including adaptive immune pathways mediated by T helper 2 cells and innate immune pathways mediated by innate lymphoid cells. The relative contribution of these pathways in asthma and COPD is not yet clarified, and there are currently no reliable biomarkers that represent the various pathways. Therefore, there is an urgent need for easily measurable and reproducible biomarkers that are linked to underlying pathophysiologic disease mechanisms and can predict and monitor responses to novel biologic agents.