Addressing corticosteroid insensitivity in adults with asthma

Abstract

Corticosteroids are the most effective treatment for asthma, but the therapeutic response varies markedly between individuals, with up to one third of patients showing evidence of insensitivity to corticosteroids. This article summarizes information on genetic, environmental and asthma-related factors as well as demographic and pharmacokinetic variables associated with corticosteroid insensitivity in asthma. Molecular mechanisms proposed to explain corticosteroid insensitivity are reviewed including alterations in glucocorticoid receptor subtype, binding and nuclear translocation, increased proinflammatory transcription factors and defective histone acetylation. Current therapies and future interventions that may restore corticosteroid sensitivity in asthma are discussed, including small molecule drugs and biological agents. In the future, biomarkers may be used in the clinic to predict corticosteroid sensitivity in patients with poorly controlled asthma.

Keywords:

• Adherence
• asthma
• biological agents
• biomarkers
• cigarette smoking
• corticosteroids
• corticosteroid insensitivity
• corticosteroid resistance
• small molecule drugs

Key issues

• Corticosteroids are the most effective treatment for asthma, but the therapeutic response varies markedly between individuals, with up to one-third of patients showing evidence of insensitivity to corticosteroids.

• Multiple factors including genetic, environmental such as cigarette smoking and asthma-related factors such as non-adherence and non-eosinophilic inflammation as well as demographic and pharmacokinetic variables are likely to contribute to the heterogeneous response to corticosteroids between people.

• Molecular mechanisms proposed to explain corticosteroid insensitivity include alterations in GRα and β subtypes, impaired GR binding and nuclear translocation, increased proinflammatory transcription factors, and defective histone acetylation.

• Non-adherence with inhaled and oral corticosteroid treatment is one of the most important reasons for poor symptom control and apparent corticosteroid insensitivity.

• There is limited information on the effectiveness of non-pharmacological interventions for the management of asthma on specific factors associated with corticosteroid insensitivity in asthma. Advice on smoking cessation is essential in smokers with asthma and may improve corticosteroid responsiveness.

• A step-up in the dose of corticosteroid as well as the addition of other therapies for asthma may benefit some individuals with asthma that is associated with corticosteroid insensitivity. High-dose inhaled corticosteroids treatment improves clinical outcomes in some patients with severe asthma and in smokers with asthma, but many patients remain symptomatic. Long acting β₂-agonists have been shown in vitro to increase the translocation of GR to the nucleus. In an exploratory clinical trial in smokers with asthma low-dose theophylline added too inhaled corticosteroid resulted in improvement in lung function and suggested the restoration of corticosteroid sensitivity in those treated with the combination.

• Future interventions that may restore corticosteroid sensitivity in asthma include small molecule drugs such as macrolides, several protein kinase inhibitors, PI3K inhibitors, NF-κB inhibitors, PDE₄ and PDE₃/PDE₄ inhibitors, PPARγ agonists as well as statins, and biological agents.

• In the future, biomarkers may be used in the clinic to predict corticosteroid insensitivity in patients with poorly controlled asthma.

Financial and competing interests disclosure

In the last three years NC Thomson has participated in advisory boards and/or received consultancy/lecture fees from Boston Scientific, Chiesi, Genentech, GlaxoSmithKline, Novartis, Respivert, Roche and Takeda and industry-sponsored grant funding to the University of Glasgow from Boston Scientific, Genentech, Glaxo SmithKline, Novartis, and Respivert for participating in clinical trials. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.