Elsevier

Clinics in Chest Medicine

Volume 33, Issue 3, September 2012, Pages 531-541
Clinics in Chest Medicine

Corticosteroids: Still at the Frontline in Asthma Treatment?

https://doi.org/10.1016/j.ccm.2012.05.004Get rights and content

Introduction

There was a time when asthmatics had their symptoms treated with a regular short-acting bronchodilator and theophylline, while reserving the use of systemic corticosteroids for severe exacerbations and for chronic maintenance treatment of the most severe patients. The emergence of corticosteroids suitable for the inhaled route in the 1970s followed by convincing clinical trials during the late 1980s has dramatically changed the picture of asthma treatment. The class of inhaled corticosteroids (ICS) has rapidly demonstrated its superiority over other classes of drugs used in asthma.1 The first Global Initiative for Asthma consensus in the early 1990s further highlighted the importance of the role of ICS in asthma treatment.2 There is no doubt that the reduced mortality and morbidity of asthma observed since the 1990s is, in a large part, related to the regular use of ICS as the mainstay of asthma treatment. Yet some studies have pointed out the variability of the response to ICS in patients with asthma, suggesting that ICS administered alone might not be the best drug for all patients.3

Section snippets

From early promise to the time of certitude

The first studies using inhaled hydrocortisone and prednisone in asthma were disappointing. It became apparent that this was because of the inappropriate chemical structure of prednisone, which has first to be metabolized to become pharmacologically effective, and the lack of topical activity of these corticosteroids. The chemical transformation of prednisone to increase both lipophilicity and interaction with glucocorticosteroid receptor made it possible to find compounds that were suitable

Corticosteroids and loss of lung function

Accelerated lung decline is a well-known feature of chronic obstructive pulmonary disease (COPD) and it is generally accepted that ICS fails to prevent it when patients continue to smoke.25 The recognition that patients with asthma also have an accelerated lung function decline regardless of smoking26, 27 and despite regular treatment with ICS24, 28 has questioned the role of this class of drugs as a disease-modifying agent in asthma. In contrast to what has been shown for airway inflammation,

The recognition of refractory asthma

The Gaining Optimal Asthma Control study showed that most patients with asthma can become largely asymptomatic when regularly treated by a combination ICS/LABA.35 This therapeutic strategy also proved to be efficient in preventing asthma exacerbation in most patients. Yet a small fraction of patients with asthma, called patients with refractory or severe asthma, escape to that treatment. Severe or refractory asthma is generally thought to affect 1% to 5% of all patients with asthma and accounts

The molecular concept of corticosteroid resistance

It has been well demonstrated that corticosteroids have a positive interaction with β2-agonists at the molecular level. Indeed, corticosteroids increase the transcription of the β2-agonist receptor, resulting in increased expression of the receptor at the cell surface.52, 53 On the other hand, there is growing evidence to show that β2-agonists enhance the action of corticosteroids, particularly through enhancing the translocation of glucocorticoid receptor (GR), therefore, increasing the

Complementary treatment to corticosteroids in refractory asthma

Although abundantly used in COPD, tiotropium has been poorly validated in asthma treatment. A recent study conducted in patients with uncontrolled asthma, despite a moderate dose of inhaled beclomethasone, showed that tiotropium was at least equivalent to salmeterol in improving asthma lung function and symptoms.65 Further studies focusing on patients with more severe asthma and looking at exacerbations as the major outcome are now warranted to validate the use of a long-acting anticholinergic

Emergence of the concept of asthma phenotype in mild to moderate asthma

The development of the technique of induced sputum has been a key step in the appearance of the concept of inflammatory phenotype in asthma. Although it confirmed the eosinophilic inflammation as a prominent feature of asthma,96 which relates to disease severity,43, 50, 72 it also showed that up to 50% of patients with asthma failed to exhibit this eosinophilic phenotype.97, 98 Almost half of them are characterized by intense neutrophilic inflammation99 but the other half fails to show any

Predicting factors of clinical response to corticosteroids

The results of large, randomized controlled clinical trials have perhaps masked for too long the fact that the response of ICS is variable in patients with asthma.105 As pointed out earlier, the response to ICS is characterized by a high intraindividual repeatability and a high interindividual variability, with up to 40% of patients showing no short-term response to the treatment.3 The presence of a persistent airway eosinophilic inflammation seems to be a good predicting factor for a

Corticosteroids in clinical practice

Like in many chronic diseases, poor compliance to maintenance treatment has been shown to be a major issue in asthma.117 Poor inhalation technique is a further impediment in achieving a successful treatment with inhaled therapies in patients with asthma.117 Because corticosteroids do not bring acute relief for asthma symptoms, it is likely to play a role in poor compliance. Although ICS have clearly demonstrated superior efficacy to leukotriene receptor antagonists with respect to most clinical

New class drug in development

There are several new drugs for asthma currently in development that may be suited more for patients who do not respond well to corticosteroids.91 Several cytokines are involved in the pathophysiology of asthma, including Th2 cytokines. Anti–IL-5 antibodies (mepolizumab, reslizumab) are currently in clinical trials for severe eosinophilic asthma that is resistant to corticosteroids, as discussed earlier. IL-13 is increased in severe asthma and causes corticosteroid resistance, so it is a

Summary

There is no doubt that ICS have led to considerably improved asthma control and reduced asthma mortality in the Western world over the last 2 decades. ICS are particularly effective in combating Th2-driven inflammation featuring mast-cell and eosinophilic airway infiltration. Their effect on innate immunity-driven neutrophilic inflammation is poor and their ability to prevent airway remodeling and accelerated lung decline is highly controversial. Although ICS remain pivotal drugs in asthma

Acknowledgments

The work was supported by federal grant PAI P7/30 Aireway II. We also thank Anne Chevremont for excellent technical assistance.

First page preview

First page preview
Click to open first page preview

References (124)

  • M. Roth et al.

    Interaction between glucocorticoids and beta2 agonists on bronchial airway smooth muscle cells through synchronised cellular signalling

    Lancet

    (2002)
  • P.J. Barnes

    Reduced histone deacetylase in COPD: clinical implications

    Chest

    (2006)
  • E. Irusen et al.

    p38 mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthma

    J Allergy Clin Immunol

    (2002)
  • J.G. Matthews et al.

    Defective glucocorticoid receptor nuclear translocation and altered histone acetylation patterns in glucocorticoid-resistant patients

    J Allergy Clin Immunol

    (2004)
  • A.C. Wu et al.

    Cost-effectiveness of omalizumab in adults with severe asthma: results from the Asthma Policy Model

    J Allergy Clin Immunol

    (2007)
  • M.J. Leckie et al.

    Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response

    Lancet

    (2000)
  • C. Moermans et al.

    Local and systemic cellular inflammation and cytokine release in chronic obstructive pulmonary disease

    Cytokine

    (2011)
  • P.J. Barnes

    New therapies for asthma: is there any progress?

    Trends Pharmacol Sci

    (2010)
  • P.G. Gibson et al.

    Heterogeneity of airway inflammation in persistent asthma: evidence of neutrophilic inflammation and increased sputum interleukin-8

    Chest

    (2001)
  • G.P. Anderson

    Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease

    Lancet

    (2008)
  • P.J. Barnes

    Will it be steroids for ever?

    Clin Exp Allergy

    (2005)
  • Global strategy for asthma management and prevention: NHLBI/WHO workshop report March 1993

    (2002)
  • J.M. Drazen et al.

    Heterogeneity of therapeutic responses in asthma

    Br Med Bull

    (2000)
  • H.M. Brown et al.

    Beclomethasone dipropionate: a new steroid aerosol for the treatment of allergic asthma

    Br Med J

    (1972)
  • U.G. Gerdtham et al.

    Impact of inhaled corticosteroids on acute asthma hospitalization in Sweden 1978 to 1991

    Med Care

    (1996)
  • L. Blais et al.

    Inhaled corticosteroids and the prevention of readmission to hospital for asthma

    Am J Respir Crit Care Med

    (1998)
  • S. Suissa et al.

    Low-dose inhaled corticosteroids and the prevention of death from asthma

    N Engl J Med

    (2000)
  • T. Haahtela et al.

    Comparison of a beta 2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma

    N Engl J Med

    (1991)
  • R. Djukanovic et al.

    Mucosal inflammation in asthma

    Am Rev Respir Dis

    (1990)
  • A.B. Kay

    Allergy and allergic diseases. First of two parts

    N Engl J Med

    (2001)
  • C. Corrigan

    The eotaxins in asthma and allergic inflammation: implications for therapy

    Curr Opin Investig Drugs

    (2000)
  • R. Djukanovic et al.

    Effect of an inhaled corticosteroid on airway inflammation and symptoms in asthma

    Am Rev Respir Dis

    (1992)
  • R.E. Aldridge et al.

    Effects of terbutaline and budesonide on sputum cells and bronchial hyperresponsiveness in asthma

    Am J Respir Crit Care Med

    (2000)
  • J.V. Fahy et al.

    Effect of low-dose beclomethasone dipropionate on asthma control and airway inflammation

    Eur Respir J

    (1998)
  • A. Jatakanon et al.

    An inhaled steroid improves markers of airway inflammation in patients with mild asthma

    Eur Respir J

    (1998)
  • E.L. van Rensen et al.

    Effect of inhaled steroids on airway hyperresponsiveness, sputum eosinophils, and exhaled nitric oxide levels in patients with asthma

    Thorax

    (1999)
  • R.J. Meijer et al.

    Effects of inhaled fluticasone and oral prednisolone on clinical and inflammatory parameters in patients with asthma

    Thorax

    (1999)
  • C.J. Corrigan et al.

    CD4 T-lymphocyte activation in asthma is accompanied by increased serum concentrations of interleukin-5. Effect of glucocorticoid therapy

    Am Rev Respir Dis

    (1993)
  • C.M. Lilly et al.

    Expression of eotaxin by human lung epithelial cells: induction by cytokines and inhibition by glucocorticoids

    J Clin Invest

    (1997)
  • K. Maneechotesuwan et al.

    Suppression of GATA-3 nuclear import and phosphorylation: a novel mechanism of corticosteroid action in allergic disease

    PLoS Med

    (2009)
  • R.A. Pauwels et al.

    Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. European Respiratory Society Study on Chronic Obstructive Pulmonary Disease

    N Engl J Med

    (1999)
  • A.L. James et al.

    Decline in lung function in the Busselton Health Study: the effects of asthma and cigarette smoking

    Am J Respir Crit Care Med

    (2005)
  • P. Lange et al.

    15-year follow-up study of ventilatory function in adults with asthma

    N Engl J Med

    (1998)
  • J.K. Sont et al.

    Clinical control and histopathologic outcome of asthma when using airway hyperresponsiveness as an additional guide to long-term treatment. The AMPUL Study Group

    Am J Respir Crit Care Med

    (1999)
  • C. Ward et al.

    Airway inflammation, basement membrane thickening and bronchial hyperresponsiveness in asthma

    Thorax

    (2002)
  • H. Cokugras et al.

    Ultrastructural examination of bronchial biopsy specimens from children with moderate asthma

    Thorax

    (2001)
  • D.E. Davies et al.

    Airway remodeling in asthma: new insights

    J Allergy Clin Immunol

    (2003)
  • C.L. Grainge et al.

    Effect of bronchoconstriction on airway remodeling in asthma

    N Engl J Med

    (2011)
  • E.D. Bateman et al.

    Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma Control study

    Am J Respir Crit Care Med

    (2004)
  • L. Antonicelli et al.

    Asthma severity and medical resource utilisation

    Eur Respir J

    (2004)
  • Cited by (0)

    View full text