Cluster Analysis of Obesity and Asthma Phenotypes

Asthma is a heterogeneous disease with variability among patients in characteristics such as lung function, symptoms and control, body weight, markers of inflammation, and responsiveness to glucocorticoids (GC). Cluster analysis of well-characterized cohorts can advance understanding of disease subgroups in asthma and point to unsuspected disease mechanisms. We utilized an hypothesis-free cluster analytical approach to define the contribution of obesity and related variables to asthma phenotype.In a cohort of clinical trial participants (n = 250), minimum-variance hierarchical clustering was used to identify clinical and inflammatory biomarkers important in determining disease cluster membership in mild and moderate persistent asthmatics. In a subset of participants, GC sensitivity was assessed via expression of GC receptor alpha (GCRα) and induction of MAP kinase phosphatase-1 (MKP-1) expression by dexamethasone. Four asthma clusters were identified, with body mass index (BMI, kg/m(2)) and severity of asthma symptoms (AEQ score) the most significant determinants of cluster membership (F = 57.1, p<0.0001 and F = 44.8, p<0.0001, respectively). Two clusters were composed of predominantly obese individuals; these two obese asthma clusters differed from one another with regard to age of asthma onset, measures of asthma symptoms (AEQ) and control (ACQ), exhaled nitric oxide concentration (F(E)NO) and airway hyperresponsiveness (methacholine PC(20)) but were similar with regard to measures of lung function (FEV(1) (%) and FEV(1)/FVC), airway eosinophilia, IgE, leptin, adiponectin and C-reactive protein (hsCRP). Members of obese clusters demonstrated evidence of reduced expression of GCRα, a finding which was correlated with a reduced induction of MKP-1 expression by dexamethasoneObesity is an important determinant of asthma phenotype in adults. There is heterogeneity in expression of clinical and inflammatory biomarkers of asthma across obese individuals. Reduced expression of the dominant functional isoform of the GCR may mediate GC insensitivity in obese asthmatics

Experiences with treprostinil in the treatment of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a chronic condition of elevated pulmonary arterial pressures with associated increases in pulmonary vascular resistance leading to right ventricular failure, which was almost uniformly fatal prior to the introduction of pulmonary hypertension specific therapy. Systemic prostacyclin analogs are the first PAH-specific therapies to be made available and are typically recommended as first-line therapy for subjects with severe disease. Treprostinil is a newer prostacyclin analog similar to epoprostenol in its mechanism of action and relative efficacy with the advantage of a longer half life in human serum and room temperature stability. It is unique in that it is available in multiple formulations for alternative routes of delivery, including subcutaneous, intravenous and inhalational routes. Additionally, oral treprostinil is currently under investigation. Both subcutaneous and intravenous forms of treprostinil have demonstrated efficacy in short-term clinical trials and are currently approved for use in subjects with PAH and New York Heart Association functional class (NYHA FC) II–IV symptoms in the USA and for subjects with NYHA FC III and IV in Europe. Inhaled treprostinil has also demonstrated efficacy in short-term clinical trials primarily as add-on therapy and is currently approved for use in subjects with PAH and NYHA FC III–IV symptoms in the USA and Europe. The different formulations of treprostinil have significantly increased the treatment options and opportunities for treatment of patients with PAH

Correlation between expression of GCRα and baseline expression of MKP-1 in PBMC (both log-transformed).

<p>Correlation between expression of GCRα and baseline expression of MKP-1 in PBMC (both log-transformed).</p

Characteristics of asthma disease clusters.

<p>Table p values from Pearson chi-square test (Exact or CMH test) or analysis of variance comparing all 4 clusters.</p>*<p>indicates p<0.05 for comparison of clusters 3 and 4.</p><p>Numeric data presented as Mean (Standard Deviation), except.</p>†<p>Geometric Mean (Coefficient of Variation), log-transformed for analysis.</p><p>ACQ: asthma control questionnaire score after 4 weeks of HFA-BDP, AEQ: asthma evaluation questionnaire score after 4 weeks of HFA-BDP.</p

Correlation between expression of GCRα in PBMC and serum hsCRP concentrations of (both log-transformed).

<p>Correlation between expression of GCRα in PBMC and serum hsCRP concentrations of (both log-transformed).</p

Results of discriminant analysis demonstrating relative contribution of variables in determining cluster membership.

<p>Results of discriminant analysis demonstrating relative contribution of variables in determining cluster membership.</p

Characteristics of study population.

<p>Numeric data presented as mean (standard deviation), except ^†geometric mean (coefficient of variation), log-transformed for analysis.</p