Anti-TNF-alpha in asthma: Myth or reality

TNF-alpha has been widely studied in asthma and proposed as a possible target for the treatment of severe asthma. Unfortunately, toxic effects of monoclonal antibodies against TNF-alpha have precluded their use in patients with severe disease. Moreover, the clinical benefits have always been very small.

A new trial assessed the efficacy and safety of ethanercept, a biologic against TNF-apha (fusion protein of TNF-alpha receptor), in moderate-to-severe persistent asthma. In a 12-week, randomized, double-blind, placebo-controlled, phase 2 trial, 132 subjects with asthma received subcutaneous injections of etanercept or placebo twice weekly.

Clinical efficacy of etanercept was not shown in any of the outcomes studied over 12 weeks. However, etanercept treatment was well-tolerated.

The authors propose that studies in specific subsets of patients with asthma with longer-term follow-up may be needed to fully evaluate the clinical efficacy of etanercept in asthma.

Is Bisphenol A a risk factor for allergy in children?

Exposure to environmental toxicants is associated with numerous disease outcomes, many of which involve underlying immune and inflammatory dysfunction. The U.S. government declared Bisphenol A (BPA) a hazardous substance in October 2008 and has since placed it on its list of toxic substances. Triclosan (2,4,4’ –trichloro-2’-hydroxydiphenyl ether) is a chlorinated aromatic anti-microbial agent under review by the U.S. Environmental Protection Agency (EPA) using the new National Health and Nutrition Examination Survey (NHANES) 2003-2006 data.

Using data from the 2003-2006 NHANES, a study in the journal Environmental Health Perspectives compared urinary BPA and triclosan with diagnoses of allergies or hayfever in U.S. adults and children age ≥ 6 years.

Triclosan, but not BPA, showed a positive association with allergy/hayfever diagnosis. In the under-18 age group, higher levels of triclosan were associated with greater odds of having been diagnosed with allergies or hayfever (p<0.01).

Although additional studies should be done to investigate these interesting findings, shall we further restrict the use of BPA ?

Osteopontin implicated in maintenance of chronic allergic contact dermatitis

Acute allergic contact dermatitis (ACD) has been previously linked to secreted osteopontin (sOPN), a glycoprotein with cytokine and chemokine functions. OPN is known to attract myeloid dendritic cells (mDCs) to activate naïve T cells in draining lymph nodes in the skin and induce a TH1 phenotype.

Seier et al. (Am J Path 2010, 176:246-258) follow up on their work identifying osteopontin as a principal player in acute ACD with investigations into the pathophysiology that leads to the chronic condition, which is associated with severe eczema. They discover that OPN attracts memory T cells, monocytes, macrophages, and DCs to the skin in acute exposure. Cytokine function of OPN specifically induces IL-12 secretion and suppresses IL-10 production in macrophages. Then, OPN-related IL-12 production establishes Th1 conditions by skewing mDCs toward IL-12 production, which in turn, augments further OPN secretion. The authors also find that IFN-γ from antigen-specific T cells is critical for activation of OPN production in keratinocytes. The Th1 environment in the epidermis is maintained through cybernetic mechanisms involving OPN, IL-12, and antigen-specific T cells, which support persistent, chronic inflammatory conditions in the skin.

Seier et al. also report that anti-OPN antibody treatment can suppress response in established chronic ACD, suggesting possible prevention and intervention possibilities.

Please feel free to post your own comments below. Topics and articles that you think would be of interest in our NBOP section and/or this blog can be sent to the JACI Editorial Office at jaci@njhealth.org.

Inhaled corticosteroids do not increase pneumonia risk in asthma

Previous research has reported an increased risk of pneumonia in patients with COPD who are on inhaled corticosteroids (ICS). This finding was associated with use of fluticasone, but not with budesonide-treated COPD. O’Byrne et al. (Am J Respir Crit Care Med 2010, doi:10.1164/rccm.201005-0694OC) present results from their analyses on pneumonia adverse events [AEs] and serious adverse events [SAE] from budesonide and budesonide/formoterol clinical trials involving asthma subjects. AstraZeneca collected and analyzed the data, which was reviewed by an independent statistician for the purposes of this research.

O’Byrne and co-authors evaluate two datasets, one from studies in subjects 4 years of age and older comparing placebo to Pulmicort® or Symbicort®, and a second dataset from studies of similar design that also include comparative data on fluticasone and high- and low-dosing effects. Pneumonia AEs from the first dataset were 0.5% in the budesonide group and 1.2% in the placebo group. Pneumonia SAEs were lower in the budesonide and placebo groups.

Analyses of the second dataset show pneumonia AEs in the budesonide group were slightly higher, but still lower than in the placebo group from the first dataset. Pneumonia SAEs were similar between the two datasets. The authors note that the risk of pneumonia between high-dose subjects and low-dose subjects was nearly equivalent. In contrast to the findings in COPD, pneumonia risk was similar, low, and not significant between budesonide and fluticasone.

Wrapping up, O’Byrne et al. point out that subjects in the second dataset with the lowest FEV1 values had higher risk of pneumonia. They comment that, in general, COPD subjects have lower baseline FEV1 than asthma subjects, which could account for greater risk of pneumonia in COPD.

Tell us what you think. Please feel free to post your own comments and/or predictions below. Topics and articles that you think would be of interest in our NBOP section and/or this blog can be sent to the JACI Editorial Office at jaci@njhealth.org.

Simvastatin provides little help for reducing steroid use in asthma

Statins have shown anti-inflammatory properties in animal models and human tissues, reducing airway hyperreactivity, mast cell degranulation, and inhibition of airway smooth muscle proliferation. Great hopes have been placed in the treatment of asthma by statins, but only two clinical trials have been published, though, using statins in subjects with asthma.

A double-blind, placebo-controlled, crossover study by Cowan et al. (Thorax 2010, 65:891-896) examines whether simvastatin demonstrates steroid-sparing effects across a 6 month period in 43 subjects with stable persistent asthma. All subjects started on 500μg of fluticasone and simvastatin or placebo. Fluticasone was stepped down each month for 6 months or until loss of control (LOC). Subjects were stepped up at the point of LOC until “minimum necessary” ICS dose to achieve control.

Cowan et al report that subjects at the LOC point were not significantly different between simvastatin and placebo. Nevertheless, the authors note that sputum eosinophils were lower on simvastatin than placebo. They conclude that simvastatin did not produce clinically important steroid-sparing effects, though it was associated with improvements in Asthma Control Questionnaire score and FEV1 as well as mitigating eosinophilia.

Tell us what you think. Please feel free to post your own comments below. Topics and articles that you think would be of interest in our NBOP section and/or this blog can be sent to the JACI Editorial Office at jaci@njhealth.org.

Occupation increases risk of severe exacerbation in workers with asthma

Much research has been published on the association of new-onset asthma diagnosis and occupation. Not surprisingly, the association is significant and has implicated both sensitizing and non-sensitizing agents.

Recently, Henneberger et al. (Eur Respir J 2010, 36:743-750) asked another related question: Is severe asthma exacerbation in current asthma patients associated with occupation? Using the European Community Respiratory Health Survey results, they compiled a cohort of workers with current asthma that reported severe exacerbation in a 12 month period. The authors focused on asthma worsening as related to jobs with high risk of exposure to irritants. They found that the relative risk was significant for occupations with high exposure to dust, gas, and fumes and used that to calculate the population-attributable risk percentage. Approximately 15% of severe asthma exacerbations were associated with occupation. Further, the authors found that both sensitizing and non-sensitizing occupational exposures were implicated, which, they pointed out, was consistent with published reports for occupational, new-onset asthma.

Wrapping up, the authors commented that the size of their cohort provided more robust statistical indices and their focus on current asthma exacerbation delineated more clearly the distinction between occupational asthma and work-exacerbated asthma.

Tell us what you think. Please feel free to post your own comments and/or predictions below. Topics and articles that you think would be of interest in our NBOP section and/or this blog can be sent to the JACI Editorial Office at jaci@njhealth.org.

Smoking ban in Scotland has greater impact than expected

In a recent issue of the New England Journal of Medicine, Mackay et al. (N Engl J Med 2010, 363:1139-1145) follow up on the outcome of a 2006 smoking ban in enclosed public places in Scotland. The law was enacted to protect workers exposed to occupational smoke, such as bar workers. To examine evidence for a wider impact, data from the Scottish Morbidity Record (SMR) was pulled for asthma-attributed hospital admissions for infants and children up to 14 years.

Banning smoking in public places has been shown to reduce acute myocardial infarction deaths and hospitalizations as well as decrease hospital admissions because of respiratory conditions, but there have been no studies on how the bans affect asthma in children.

In Scotland, prior to the 2006 ban, there was an increasing trend in admissions for childhood asthma symptoms. After the ban, Mackay et al. report a significant reduction in asthma-related admissions by 13%. They discuss previous studies that have reported significant reduction in respiratory symptoms of workers exposed to occupational smoke as well – even if they are smokers.

Of particular interest, Mackay et al. discuss concerns among Scottish public health officials that the ban would cause increased smoking in the home. In fact, studies had found that voluntary smoking bans in the home increased after the legislation based on objective findings of salivary cotinine in children from those homes.

Tell us what you think. Please feel free to post your own comments and/or predictions below. Topics and articles that you think would be of interest in our NBOP section and/or this blog can be sent to the JACI Editorial Office at jaci@njhealth.org.