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. Word count: 120 wordsKey words: Adherence; asthma; biological agents; biomarkers; cigarette smoking; corticosteroids; corticosteroid insensitivity; corticosteroid resistance; small molecule drugs. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 IntroductionAsthma is a chronic inflammatory disease of the airways that affects 300 million people worldwide. Both national and international guidelines recommend daily inhaled corticosteroid as the preferred controller treatment for adults and adolescents with asthma who have poor symptom control or who at risk of exacerbations [201, 202]. Inhaled corticosteroid use in asthma reduces symptoms, improves quality of life and increases lung function as well as decreases the rate of exacerbations [201, 202]. The majority of the therapeutic benefits of inhaled corticosteroids are achieved at low to medium doses [1], although higher doses are often required in patients with more severe asthma [2] [202]. Short courses of oral corticosteroids are administered to treat severe exacerbations and daily oral corticosteroids are used in the lowest dose providing adequate control to treat patients with severe asthma when symptoms are uncontrolled despite maximal therapy [201, 202].Guideline recommendations for inhaled and oral corticosteroid use in asthma are based on average therapeutic responses from clinical trial populations that may not be representative of 'real-life' patients [3]. Numerous studies in adults and children with asthma have noted a considerable patient-to-patient variability in improvements in lung function and airway hyperreactivity with inhaled and oral corticosteroid treatment in patients with apparently similar levels of disease severity [4][5][6] (Figure 1). The findings from these studies suggest that corticosteroid insensitivity may be present in approximately one third of patients with asthma.Inhaled corticosteroids exhib...

Asthma and smoking-induced airway disease without spirometric COPD

“…Corticosteroid insensitivity occurs in chronic inflammatory diseases including severe asthma and COPD [53,54]. The effects of budesonide on epithelial barrier function in primary bronchial epithelial cells is impaired in asthma and COPD, and this effect is less evident in healthy smokers, suggesting that corticosteroid responsiveness in smokers without spirometric evidence of COPD might be better preserved than in those with COPD [55], although this hypothesis remains to be tested in clinical studies.…”

Single cell transcriptomics delineates the immune-cell landscape in equine lower airways and reveals upregulation of the FKBP5 gene in horses with asthma

“…In humans, about 10-20 % of patients with inflammatory diseases and immune disorders do not respond to treatment with glucocorticoids (59). In addition, corticosteroid insensitivity (i.e., an impaired response to corticosteroids) in asthma in humans is a well-recognized phenomenon, and it has been estimated that corticosteroid insensitivity is present in about one third of asthma patients (60). We are not aware of any published reports regarding the prevalence of corticosteroid resistance or insensitivity in horses.…”

Research advances in airway remodeling in asthma: a narrative review

“…Glucocorticoids stop the process of airway remodeling by inhibiting the metaplasia of goblet cells, the hypertrophy and phenotypic transition of ASM cells, the proliferation of lung fibroblasts, the release of inflammatory mediators, and the thickening of the subepithelial RBM and by repairing the epithelial layer (43)(44)(45). However, up to 1/3 of asthma patients are clinically insensitive to glucocorticoid therapy (46) for which airway remodeling may play an important role. Bourdin et al (47) found that a limited steroid response to short-acting glucocorticoids in severe asthma was associated with the thickening of bronchial basement membrane, and that RBM thickness could predict steroid responsiveness below 15%.…”