Mepolizumab versus placebo for asthma

Background Mepolizumab is a human monoclonal antibody against interleukin-5 (IL-5), the main cytokine involved in the activation of eosinophils, which in turn causes airway inflammation. Recent studies have suggested these agents may have a role in reducing exacerbations and improving health-related quality of life (HRQoL). There are no recommendations for the use of mepolizumab in adults or children in the recent update of the BTS/SIGN guidelines (BTS/SIGN 2014). Objectives To compare the effects of mepolizumab with placebo on exacerbations and HRQoL in adults and children with chronic asthma. Search methods We searched the Cochrane Airways Group Register (CAGR) of trials, clinical trial registries, manufacturers' websites and the reference lists of included studies. Searches were conducted in November 2013 and updated in November 2014. Selection criteria We included randomised controlled trials comparing mepolizumab versus placebo in adults and children with asthma. Data collection and analysis Two authors independently extracted data and analysed outcomes using a random-effects model. We used standard methods expected by The Cochrane Collaboration. Main results Eight studies on 1707 participants met the inclusion criteria. Only two studies included children (over 12 years of age), but they did not report separate findings for the adolescents. Seven studies involved intravenous mepolizumab alone; one included a subcutaneous arm. There was heterogeneity in the severity and clinical pattern of asthma among the participants in the eight studies, varying from mild to moderate atopic asthma, to persistent asthma and eosinophilic asthma with recurrent exacerbations. Selection bias was a concern in several of the studies included in this review. Four trials compared intravenous mepolizumab to placebo in relation to HRQoL. Two studies measured scores from the Asthma Quality of Life Questionnaire (AQLQ), which showed a non-significant difference between mepolizumab and placebo (mean difference (MD) 0.21, 95% confidence interval (CI) − 0.01 to 0.44; participants = 682), in the direction favouring mepolizumab. The third study used the St. George's Respiratory Questionnaire (SGRQ) and found a significant difference between mepolizumab and placebo (MD 6.40, 95% CI 3.15 to 9.65; participants = 576), which indicated a clinically important benefit favouring mepolizumab. A fourth study noted that there was no significant difference but did not provide any data. The two studies in people with eosinophilic asthma showed a reduction in clinically significant exacerbation rates (Risk Ratio 0.52, 95% CI 0.43 to 0.64; participants = 690). However, an analysis of four studies that were not confined to people with eosinophilic asthma indicated considerable heterogeneity and no significant difference in people with one or more exacerbations between mepolizumab and placebo using a random-effects model (Risk Ratio 0.67, 95% CI 0.34 to 1.31; participants = 468; I2 = 59%).The analysis of serious adverse events indicated a significant difference favouring mepolizumab (Risk ratio 0.49, 95% CI 0.30 to 0.80; participants = 1441; studies = 5; I2 = 0%). It was not possible to combine the results for adverse events, and we deemed the quality of this evidence to be low. A single study compared subcutaneous mepolizumab to placebo in 385 adults with severe eosinophilic asthma and found an improvement in HRQoL scores and a reduction in asthma exacerbations, including exacerbations requiring admission to hospital. Authors' conclusions It is not possible to draw firm conclusions from this review with respect to the role of mepolizumab in patients with asthma. Our confidence in the results of this review are limited by the fact that the intravenous route is not currently licensed for mepolizumab, and the evidence for the currently licenced subcutaneous route is limited to a single study in participants with severe eosinophilic asthma. The currently available studies provide evidence that mepolizumab can lead to an improvement in health-related quality of life scores and reduce asthma exacerbations in people with severe eosinophilic asthma. Further research is needed to clarify which subgroups of patients with asthma could potentially benefit from this treatment. Dosage, ideal dosing regimens and duration of treatment need to be clarified, as the studies included in this review differed in their protocols. There are no studies reporting results from children, so we cannot comment on treatment for this age group. At the present time, larger studies using licenced treatment regimens are required to establish the role of mepolizumab in the treatment of severe asthma

Observation of the Baryonic Flavor-Changing Neutral Current Decay Lambda_b -> Lambda mu+ mu-

We report the first observation of the baryonic flavor-changing neutral current decay Lambda_b -> Lambda mu+ mu- with 24 signal events and a statistical significance of 5.8 Gaussian standard deviations. This measurement uses ppbar collisions data sample corresponding to 6.8fb-1 at sqrt{s}=1.96TeV collected by the CDF II detector at the Tevatron collider. The total and differential branching ratios for Lambda_b -> Lambda mu+ mu- are measured. We find B(Lambda_b -> Lambda mu+ mu-) = [1.73+-0.42(stat)+-0.55(syst)] x 10^{-6}. We also report the first measurement of the differential branching ratio of B_s -> phi mu+ mu- using 49 signal events. In addition, we report branching ratios for B+ -> K+ mu+ mu-, B0 -> K0 mu+ mu-, and B -> K*(892) mu+ mu- decays.Comment: 8 pages, 2 figures, 4 tables. Submitted to Phys. Rev. Let

Biological clustering supports both "Dutch'' and "British'' hypotheses of asthma and chronic obstructive pulmonary disease

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases. OBJECTIVE: We sought to determine, in terms of their sputum cellular and mediator profiles, the extent to which they represent distinct or overlapping conditions supporting either the "British" or "Dutch" hypotheses of airway disease pathogenesis. METHODS: We compared the clinical and physiological characteristics and sputum mediators between 86 subjects with severe asthma and 75 with moderate-to-severe COPD. Biological subgroups were determined using factor and cluster analyses on 18 sputum cytokines. The subgroups were validated on independent severe asthma (n = 166) and COPD (n = 58) cohorts. Two techniques were used to assign the validation subjects to subgroups: linear discriminant analysis, or the best identified discriminator (single cytokine) in combination with subject disease status (asthma or COPD). RESULTS: Discriminant analysis distinguished severe asthma from COPD completely using a combination of clinical and biological variables. Factor and cluster analyses of the sputum cytokine profiles revealed 3 biological clusters: cluster 1: asthma predominant, eosinophilic, high TH2 cytokines; cluster 2: asthma and COPD overlap, neutrophilic; cluster 3: COPD predominant, mixed eosinophilic and neutrophilic. Validation subjects were classified into 3 subgroups using discriminant analysis, or disease status with a binary assessment of sputum IL-1β expression. Sputum cellular and cytokine profiles of the validation subgroups were similar to the subgroups from the test study. CONCLUSIONS: Sputum cytokine profiling can determine distinct and overlapping groups of subjects with asthma and COPD, supporting both the British and Dutch hypotheses. These findings may contribute to improved patient classification to enable stratified medicine

Clinical and radiographic follow-up after the Wilkie procedure at 28 years: A case report

Rerouting of the parotid ducts posteriorly to drain into the tonsillar fossae (Wilkie procedure) was initially designed to address drooling in patients with cerebral palsy. This procedure was subsequently modified to include bilateral submandibular gland excision and extended to apply to other etiologies of sialorrhea. Our literature review failed to identify report of long-term follow-up beyond 2 decades following this procedure. We describe a 33-year-old female with spastic cerebral palsy who underwent the Wilkie procedure to treat sialorrhea and, 25 years later, developed right-sided facial swelling and dental infections in association with xerostomia. CT imaging showed symmetric atrophy of the parotid glands with fat replacement interspersed with fibrosis. Ultrasound analysis with shear wave elastography offered the additional interpretation of a greater degree of gland stiffness involving the tail of the recently inflamed right parotid gland compared to the left. This case report identifies long-term complications associated with xerostomia following initial success employing the Wilkie procedure to address sialorrhea. The radiographic evaluation supports the contention that rerouting of Stensen's duct may be associated with chronic obstructive changes to the parotid gland. Ultrasound shear wave elastography supplemented CT imaging by identifying asymmetric stiffness of the parotid glands as was consistent with the more recent right parotid inflammation

Targeting the interleukin-4 and interleukin-13 pathways in severe asthma : Current knowledge and future needs

Purpose of review Severe asthma is a heterogeneous disease that can be classified into phenotypes and endotypes based upon clinical or biological characteristics. Interleukin (IL)-4 and IL-13 play a key role in type 2 (T2) asthma. This article reviews the signaling pathway of IL-4 and IL-13 and highlights its targeted therapy in severe asthma. Recent findings Several clinical trials of biologics targeting the IL-4/IL-13 pathway have recently been completed. In patients with severe, uncontrolled asthma, targeting IL-13 alone with biologics including lebrikizumab and tralokinumab has not shown consistent reduction in asthma exacerbations. Simultaneous targeting of both IL-4 and IL-13 by blocking IL-4 receptor α using dupilumab has yielded more consistent results in reducing asthma exacerbations and improving lung function, especially in patients with increased blood eosinophils. Other biomarkers of T2 inflammation such as exhaled nitric oxide and serum periostin may also predict response to biologics targeting the IL-4/IL-13 pathway. Summary No biologic targeting the IL-4/IL-13 pathway is currently available for treatment of asthma, but emerging data suggest that biologics targeting IL-4 and IL-13 together may benefit patients with T2 high asthma. Additional data are needed about long-term efficacy and safety prior to incorporating these drugs into routine clinical practice