Charlene M. Prazma

Oral Glucocorticoid-Sparing Effect of Mepolizumab in Eosinophilic Asthma

BACKGROUND Many patients with severe asthma require regular treatment with oral glucocorticoids despite the use of high-dose inhaled therapy. However, the regular use of systemic glucocorticoids can result in serious and often irreversible adverse effects. Mepolizumab, a humanized monoclonal antibody that binds to and inactivates interleukin-5, has been shown to reduce asthma exacerbations in patients with severe eosinophilic asthma. METHODS In a randomized, double-blind trial involving 135 patients with severe eosinophilic asthma, we compared the glucocorticoid-sparing effect of mepolizumab (at a dose of 100 mg) with that of placebo administered subcutaneously every 4 weeks for 20 weeks. The primary outcome was the degree of reduction in the glucocorticoid dose (90 to 100% reduction, 75 to less than 90% reduction, 50 to less than 75% reduction, more than 0 to less than 50% reduction, or no decrease in oral glucocorticoid dose, a lack of asthma control during weeks 20 to 24, or withdrawal from treatment). Other outcomes included the rate of asthma exacerbations, asthma control, and safety. RESULTS The likelihood of a reduction in the glucocorticoid-dose stratum was 2.39 times greater in the mepolizumab group than in the placebo group (95% confidence interval, 1.25 to 4.56; P=0.008). The median percentage reduction from baseline in the glucocorticoid dose was 50% in the mepolizumab group, as compared with no reduction in the placebo group (P=0.007). Despite receiving a reduced glucocorticoid dose, patients in the mepolizumab group, as compared with those in the placebo group, had a relative reduction of 32% in the annualized rate of exacerbations (1.44 vs. 2.12, P=0.04) and a reduction of 0.52 points with respect to asthma symptoms (P=0.004), as measured on the Asthma Control Questionnaire 5 (in which the minimal clinically important difference is 0.5 points). The safety profile of mepolizumab was similar to that of placebo. CONCLUSIONS In patients requiring daily oral glucocorticoid therapy to maintain asthma control, mepolizumab had a significant glucocorticoid-sparing effect, reduced exacerbations, and improved control of asthma symptoms. (Funded by GlaxoSmithKline; SIRIUS ClinicalTrials.gov number, NCT01691508.).

Role of local eosinophilopoietic processes in the development of airway eosinophilia in prednisone-dependent severe asthma.

In severe asthmatics with persistent airway eosinophilia, blockade of interleukin‐5 has significant steroid‐sparing effects and attenuates blood and sputum eosinophilia. The contribution of local maturational processes of progenitors within the airways relative to the recruitment of mature cells from the peripheral circulation to the development of airway eosinophilia is not known. We hypothesize that local eosinophilopoiesis may be the predominant process that drives persistent airway eosinophilia and corticosteroid requirement in severe asthmatics.

Characterisation of an OCS-dependent severe asthma population treated with mepolizumab

A subpopulation of patients with asthma treated with maximal inhaled treatments is unable to maintain asthma control and requires additional therapy with oral corticosteroids (OCS); a subset of this population continues to have frequent exacerbations. Alternate treatment options are needed as daily use of OCS is associated with significant systemic adverse effects that affect many body systems and have a direct association with the dose and duration of OCS use. We compared the population demographics, medical conditions and efficacy responses of the OCS-dependent group from the DREAM study of mepolizumab with the group not managed with daily OCS. Trial Registration Number NCT01000506.

Controller medications and their effects on asthma exacerbations temporally associated with upper respiratory infections

BACKGROUND Exacerbations are a major risk and a cause of asthma morbidity and healthcare utilization. Viral-induced upper respiratory tract infections are the most frequent trigger of asthma-related exacerbations. Studies have traditionally assessed exacerbations without documentation regarding exacerbation etiology. Therefore, it remains unknown whether asthma medications can alter exacerbation susceptibility based on a specific etiology. OBJECTIVE To examine whether treatment with inhaled corticosteroids plus long-acting beta(2)-agonists reduced the number of exacerbations associated with upper respiratory tract infections versus inhaled corticosteroids alone. METHODS Two large datasets comparing treatment with fluticasone propionate and fluticasone propionate plus salmeterol were analyzed, including the number of clinically reported upper respiratory tract infections, asthma-related exacerbations, and the presence of an exacerbation and concurrent report of an upper respiratory tract infection. RESULTS Both treatment groups had similar incidences of upper respiratory tract infections. Of those reporting an upper respiratory tract infection, statistically significantly fewer reported an asthma-related exacerbation comparing fluticasone propionate plus salmeterol with fluticasone propionate (p=0.0057). DISCUSSION This retrospective analysis suggests that therapy with fluticasone propionate plus salmeterol provides protection against asthma exacerbations temporally associated with upper respiratory tract infections. This retrospective analysis supports the hypothesis that specific therapeutic approaches to mitigate virus-associated exacerbations may benefit asthma care. Well-controlled prospective studies are warranted.

Association of CHI3L1 in African-Americans with Prior History of Asthma Exacerbations and Stress

Rationale. Asthma exacerbations are influenced by multiple factors including environmental exposures, psychosocial interactions, and genetic variations. Aim. To better understand the correlation between clinical, physiologic, genetic, and psychological dimensions in asthma phenotypes and exacerbations. Methods. Supervised cluster analysis of a previously conducted clinical trial of asthma was used to identify subpopulations with differing exacerbation rates in an African-American study population (n = 475). The clusters were characterized by their clinical characteristics and genetic variations. The genetic analysis (n = 322) compared subgroups across 40 different polymorphisms of 10 genes associated with asthma exacerbations. Results. Four clusters were identified with varying annualized rates of exacerbations. Cluster 1 (n = 272) was represented by subjects with a mean age of 25 years and 52% females. In contrast, cluster 4, most divergent from cluster 1, was represented by subjects with the highest rate of asthma exacerbations (1.18 events per year), was mostly female (>80%), with a mean body mass index of 34, and was distinguished by the report of stress and emotions as the cause for prior exacerbations. Lower lung function and increased rescue medication use was also reported in cluster 4. Additionally, genetic analysis revealed a significant difference in distribution of genotypes among the four clusters for rs4950928, a single nucleotide polymorphism (SNP) located in the promoter region of the CHI3L1, the chitinase 3-like 1 gene encoding YKL-40. Conclusions. African-Americans who reported stress and emotions as a primary historical cause of exacerbations had the highest annualized rate of exacerbation. Further, a significant correlation with the genotypes in CHI3L1/YKL-40 was observed in the context of stress and asthma severity.

Long-term treatment with fluticasone propionate/salmeterol via Diskus improves asthma control versus fluticasone propionate alone.

This 52-week study was designed to assess the safety and efficacy of fluticasone propionate/salmeterol combination (FSC) 250/50 micrograms versus fluticasone propionate (FP) 250 micrograms in subjects with persistent asthma symptomatic on open-label FP 100 micrograms. The primary objective of this study was to show that FSC 250/50 micrograms was superior to FP 250 micrograms at increasing pulmonary function as measured by forced expiratory volume in 1 second over a 52-week treatment period. A secondary objective was to compare the rate of asthma attacks defined as (1) a sustained 2-day decrease in morning peak expiratory flow or increase in albuterol use for 2 consecutive days, (2) an asthma exacerbation requiring systemic corticosteroids, or (3) an unscheduled clinic or hospital visit for acute asthma symptoms. Three hundred six subjects received FSC 250/50 micrograms and 315 subjects received FP 250 micrograms. Both treatments were administered twice daily. Treatment with FSC 250/50 micrograms resulted in a significant improvement in lung function compared with FP 250 micrograms (p < 0.001). Additionally, treatment with FSC 250/50 micrograms resulted in a reduction in the rate of exacerbations of asthma (i.e., requiring systemic corticosteroids or unscheduled urgent care intervention) compared with FP 250 micrograms (0.170 versus 0.273, respectively; p = 0.017). There was no differentiation between treatments for less severe attacks of asthma. FSC 250/50 micrograms showed consistently greater improvement in lung function, symptom control, and decreased albuterol use. In addition, FSC 250/50 micrograms-treated subjects experienced fewer severe asthma exacerbations than subjects treated with FP 250 micrograms.

Safety and efficacy of long-term treatment with fluticasone propionate and salmeterol via DISKUS versus fluticasone propionate alone

This 52 week study (ADA109057; ClinicalTrials.gov identifier: NCT00452348) was designed to assess the safety and efficacy of fluticasone propionate (FP)/salmeterol 250/50 mcg via DISKUS (FSC) vs FP 250 mcg in subjects with persistent asthma symptomatic on FP 100 mcg. The objective was to demonstrate superiority in lung function (FEV1) of FSC 250/50 mcg vs FP 250 mcg. Secondary objectives included AM PEF, percentage of symptom-free days, and rate of asthma attacks. Three hundred and ten subjects received FSC 250/50 mcg and 318 subjects received FP 250 mcg, both administered twice daily following a 14–21 days of open-label FP 100 mcg. Treatment with FSC 250/50 mcg resulted in an improvement in lung function vs FP 250 mcg (p = 0.09). Additionally, treatment with FSC 250/50 mcg improved AM PEF and increased the percentage of symptom-free days. The asthma attack rate was similar between treatments, as was the safety profile. FSC 250/50 mcg demonstrated improvements in lung function and asthma control vs FP 250 mcg, although statistically significant differences were not consistent. The differences may be representative of this population with less severe disease at entry. In patients with mild-to-moderate persistent asthma FSC offers improved parameters of asthma control compared with ICS alone.