Vincent Le Gros

A Proof-of-Concept, Randomized, Controlled Trial of Omalizumab in Patients With Severe, Difficult-to-Control, Nonatopic Asthma

BACKGROUND While up to 50% of patients with severe asthma have no evidence of allergy, IgE has been linked to asthma, irrespective of atopic status. Omalizumab, an anti-IgE monoclonal antibody, is reported to significantly benefit a subset of patients with severe, persistent, allergic asthma. Therefore, we investigated whether omalizumab has biologic and clinical effects in patients with refractory nonatopic asthma. METHODS Forty-one adult patients who, despite daily treatment with or without maintenance oral corticosteroids, had severe, nonatopic, refractory asthma according to GINA (Global Initiative for Asthma) step 4, were randomized to receive omalizumab or placebo in a 1:1 ratio. The primary end point was the change in expression of high-affinity IgE receptor (FcεRI) on blood basophils and plasmacytoid dendritic cells (pDC2) after 16 weeks. The impact of omalizumab on lung function and clinical variables was also examined. RESULTS Compared with placebo, omalizumab resulted in a statistically significant reduction in FcεRI expression on basophils and pDC2 (P < .001). The omalizumab group also showed an overall increase in FEV1 compared with baseline (+250 mL, P = .032; +9.9%, P = .029). A trend toward improvement in global evaluation of treatment effectiveness and asthma exacerbation rate was also observed. CONCLUSIONS Omalizumab negatively regulates FcεRI expression in patients with severe nonatopic asthma, as it does in severe atopic asthma. Omalizumab may have a therapeutic role in severe nonatopic asthma. Nonetheless, our preliminary findings support further investigation to better assess the clinical efficacy of omalizumab. TRIAL REGISTRY ClinicalTrials.gov; No.: NCT01007149; URL: www.clinicaltrials.gov and European Clinical Trials Database, EudraCT; No.: 2009-010937-38; URL: https://www.clinicaltrialsregister.eu.

Impact of patient-related factors on asthma control.

Background. Patient-related factors are a significant component in the serious public health problem of poor asthma control, yet they have not been extensively studied. Aims. To gauge the impact of baseline patient characteristics, compliance and inhaler device manipulation on Asthma Control Score (ACS). Methods. ACS (between 0 and 9) was calculated from data recorded in a routine consultation in 4,362 patients with persistent asthma using a maintenance treatment with only inhaled corticosteroid and correlated with patient characteristics, compliance (using 2 methods) and critical errors in inhaler handling. Results. Mean ASC was 2.95 (95%CI: 2.88–3.02) and asthma control was unsatisfactory (i.e., ACS ≥ 4) in 41.1% of subjects, with higher proportions in smokers, non-compliant patients, and those misusing their device. Mean ACS tended to rise with age, and was higher in smokers than in non-smokers (+0.83 point) and ex-smokers (+0.49 point). More than 20% of all subjects were using their inhaler device incorrectly (Turbuhaler 37.1%; Metered-dose inhaler 28.1%; Diskus 21.3%; Aerolizer 7.4%) and this was associated with a 0.84-point increase in ACS. Mean ACS was lower in the most compliant patients (−0.74 points in the 13.4% with a perfect score on a compliance questionnaire) and much lower than in the least compliant (−1.84 points in the 6.6% who reported missing 4 or more doses per week). Conclusion. Patient-related factors including smoking, poor compliance and critical errors in device manipulation, have significant negative impact on asthma control. This could be addressed by patient education.

Omalizumab-induced decrease of FcɛRI expression in patients with severe allergic asthma

BACKGROUND It is documented that omalizumab treatment reduces the cell surface expression of immunoglobulin E high-affinity receptor (FcɛRI) on several cell types. This has not been investigated in patients with uncontrolled severe persistent allergic asthma. METHODS In a double-blind, randomized, placebo-controlled study, patients with severe allergic asthma uncontrolled by high dose inhaled corticosteroids and long-acting β(2)-agonist received either omalizumab (n = 20) or placebo (n = 11) over 16 weeks at appropriate doses and frequencies. Baseline and end of study (week 16) FcɛRI expression on basophils and plasmacytoid dendritic cells was determined by flow cytometry for the primary endpoint. Secondary efficacy endpoints included asthma control and lung function as part of an initial investigation into the use of FcɛRI expression as a marker of response. RESULTS In the omalizumab group, and with respect to placebo, FcɛRI expression was significantly reduced at end of study on basophils (-82.6%, p < 0.01) and plasmacytoid dendritic cells (-44.2%, p = 0.029). FcɛRI expression reduction was not found to be correlated with clinical response. CONCLUSIONS Long-term omalizumab treatment induced reduction of FcɛRI expression on circulating basophils and plasmacytoid dendritic cells. These changes were not associated with those of clinical features related to severe asthma, which does not support further investigation into its use as a predictive marker of response. TRIAL REGISTRATION The study was registered with ClinicalTrials.gov (identifier: NCT00454051) and the European Clinical Trials Database, EudraCT (identifier: 2006-003591-35).

Prevalence and Associated Factors of Oropharyngeal Side Effects in Users of Inhaled Corticosteroids in a Real-Life Setting

BACKGROUND Inhaled corticosteroids (ICS) are extensively used to treat asthma, and more recently, chronic obstructive pulmonary disease (COPD). Oropharyngeal disorders represent the most frequent side effect of these drugs, which may have a negative impact on adherence. OBJECTIVES To evaluate the prevalence of oropharyngeal disorders in users of ICS in a real-life setting and investigate the factors associated with their occurrence. METHODS For this observational cross-sectional study, general practitioners and pulmonologists were contacted and asked to include patients suffering from asthma or COPD treated by ICS. Physicians collected data during a medical examination. A multivariate regression model for the occurrence of oropharyngeal disorders was constructed. RESULTS A total of 1778 physicians included 6740 patients. The mean (SD) age was 51.3 (18.5) years, 44.0% had no smoking history, and the ICS indication was asthma in 63.9% of subjects. Of the study subjects, 52.3% used beclometasone (43.4% without a long-acting ss(2)-agonist, LABA); 22.1% used budesonide (18.8% with a LABA), and 25.6% used fluticasone (19.3% with a LABA in a single inhaler). One-third (34.7%) of subjects suffered from at least one oropharyngeal disorder; the most frequently reported were hoarseness, tingling, mouth irritation, and reddening. Multivariate regression analysis found that the factors positively associated with oropharyngeal disorders were COPD indication [odds ratio (OR) 1.600; 95% confidence intervals (95% CI) 1.391, 1.839], nominal daily dose (OR = 1.388; 95% CI 1.227, 1.569), decreased adherence (OR = 1.318; 95% CI 1.104, 1.574) and the use of fluticasone (OR = 1.176; 95% CI 1.008, 1.372), whereas those negatively associated were the absence of smoking history (OR = 0.837; 95% CI 0.742, 0.945), increased adherence (OR = 0.663; 95% CI 0.581, 0.755), and beclometasone use (OR = 0.630; 95% CI 0.543, 0.732). CONCLUSIONS The high prevalence of oropharyngeal disorders and the association of adherence with these must be taken into account by prescribers, especially in patients suffering from COPD, a relatively new group of ICS users.

Formoterol 12 μg BID administered via single-dose dry powder inhaler in adults with asthma suboptimally controlled with salmeterol or on-demand salbutamol: A multicenter, randomized, open-label, parallel-group study

Abstract Background : Although salmeterol and formoterol are both long-acting beta 2 adrenergic receptor agonist bronchodilators, there are distinct differences between them that could translate into differences in clinical response in some patients. Objective : The goal of this study was to examine the efficacy of formoterol in patients with moderate to severe persistent asthma that was suboptimally controlled with an inhaled corticosteroid (ICS) combined with on-demand salbutamol (albuterol in the United States) with or without salmeterol. Methods : This multicenter, 4-week, randomized, open-label, parallel-group study included adult patients (age ≥18 years) with suboptimally controlled asthma (mean salbutamol use, ≥2 puffs/d via pressurized metered-dose inhaler [100 μg/puff]). Patients were randomized in a 2:1 ratio to receive formoterol 12 μg BID via single-dose dry powder inhaler plus on-demand salbutamol or to continue their existing treatment with either on-demand salbutamol alone or salmeterol 50 μg BID via multidose dry powder inhaler plus on-demand salbutamol. ICS regimens were unchanged during the trial. The primary efficacy variable was evening predose peak expiratory flow (PEF). Secondary variables included further measures of asthma symptom control. Results : A total of 6239 adult patients entered the study; data from 6155 patients were available for analysis. Patients who were switched from salmeterol to formoterol reported a significant increase in mean (SD) evening predose PEF compared with patients who continued their existing treatment (402.9 [112.1] vs 385.5 [107.5] Umin, respectively; P P Conclusion : In this study, formoterol significantly improved lung function and control of asthma symptoms and decreased use of rescue medication in patients whose asthma had been suboptimally controlled with an ICS in combination with on-demand salbutamol with or without salmeterol.

Omalizumab effectiveness in patients with severe allergic asthma according to blood eosinophil count: the STELLAIR study

Omalizumab is a monoclonal anti-IgE antibody used to treat severe allergic asthma (SAA). The aim of the STELLAIR study was to determine the importance of pre-treatment blood eosinophil count as a predictive measure for response to omalizumab. This retrospective real-life study was conducted in France between December 2015 and September 2016 using medical records of SAA omalizumab-treated patients. Response to omalizumab was assessed by three criteria: physician evaluation, reduction of ≥40% in annual exacerbation rate and a combination of both. Response rate was calculated according to blood eosinophil count measured in the year prior to omalizumab initiation. 872 SAA omalizumab-treated patients were included by 78 physicians (723 adults (age ≥18 years) and 149 minors (age 6–17 years)). Blood eosinophil count was ≥300 cells·µL−1 in 52.1% of adults and 73.8% of minors. By physician evaluation, 67.2% of adults and 77.2% of minors were responders and 71.1% adults and 78.5% minors had a ≥40% reduction in the exacerbation rate. In adults, the response rate for combined criteria was 58.4% (95% CI 53.2–63.4%) for blood eosinophils ≥300 cells·µL−1 (n=377) and 58.1% (95% CI 52.7–63.4%) for blood eosinophils <300 cells·µL−1 (n=346). This study shows that a large proportion of patients with SAA have a blood eosinophil count ≥300 cells·µL−1, and suggests that omalizumab effectiveness is similar in “high” and “low” eosinophil subgroups. Omalizumab is a treatment option for severe allergic asthma irrespective of blood eosinophil count http://ow.ly/7tQh30iXNTW

Insights into severe asthma control as assessed by guidelines, pulmonologist, patient, and partner

Introduction. The most recent guidelines on asthma management advocate a treatment strategy based on control of the disease rather than severity, a switch based on reported evidence. Aims. This observational, questionnaire-based study set out to investigate how control of the disease is assessed by the physician as well as the patient and his/her live-in partner and to compare these assessments with an assessment made according to the guidelines. Methods. In 169 patients with severe, persistent asthma on at least a high-dose inhaled corticosteroid plus an inhaled long-acting β2-agonist, control of the disease was assessed by the pulmonologist, the patient, and the patients live-in partner. These assessments were compared with an assessment based on the guidelines. Results. Both patients and partners tended to judge disease control as better than their pulmonologists who, in turn, estimated control as acceptable in 58% of their patients in whom the guidelines would advocate more aggressive treatment. The most common guidelines criteria defining inadequate control in the “uncontrolled” 87.4% of this population were “limitation of physical activity” (72.3%) and “FEV1 ≤ 85% of personal best” (63.3%). Conclusions. To assess control in severe asthma, the patients opinion is of limited value, as is that of their partners. Although a guidelines-based strategy has been shown to be effective in clinical trials conducted on large-scale populations in which mild or moderate disease is predominant, more aggressive treatment to achieve definitive control may not be appropriate in the 10% of asthma sufferers with severe disease; in everyday practice, lung specialists appear to implement such a strategy.