Corticosteroids: Still at the Frontline in Asthma Treatment?
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.
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