Critical Appraisal of Antileukotriene Use In Asthma Management
Critical Appraisal of Antileukotriene Use In Asthma Management
Purpose of review: Recognition of the importance of leukotrienes in the pathogenesis of asthma has led to the development of leukotriene modifiers, the first new class of drugs for asthma treatment to become available since the introduction of inhaled corticosteroids. Nevertheless, despite their widespread use in clinical practice, the role of leukotriene modifiers in the management of asthma remains controversial. In the present article the clinical applications of this class of drugs have been critically reviewed based on recent evidence.
Recent findings: In an effort to try and establish the proper place of antileukotrienes in the management of asthma, important systematic reviews have been carried out over these recent years in three critical areas: antileukotrienes as second choice first line agents after inhaled corticosteroids; antileukotrienes as add-on therapy to inhaled corticosteroids; add-on antileukotrienes versus long acting β-agonists to patients not controlled by inhaled corticosteroids. In addition, novel and useful clinical targets for this class of drugs have been recently explored and include: patients with severe asthma; aspirin-intolerant asthma; asthmatic patients with allergic rhinitis.
Summary: Use of antileukotrienes is not recommended as first-line monotherapy in patients with asthma, except those who have aspirin intolerant asthma. Patients with concomitant allergic rhinitis may be a good target population for therapy with antileukotrienes. Addition of leukotriene modifiers to inhaled corticosteroids produces only a modest improvement in the clinical response, and is not greater to that of add-on long acting β-agonists. The exact role of antileukotrienes in asthma management guidelines still continues to evolve.
The recognition of the inflammatory basis of asthma by the early 1990s has provided the basis for a passionate hunt for those mediators of inflammation dictating the asthma phenotype. Moreover, the understanding of asthma as an inflammatory disease of the airways has endorsed the common use of inhaled corticosteroids (ICSs) as a baseline asthma therapy. ICSs have been the mainstay of asthma treatment for more than 20 years. When used regularly, ICSs are known to decrease airway inflammation, improve lung function and reduce both morbidity and mortality. Thus, it is universally recommended that patients with recurrent symptoms are best managed with ICS on a daily basis, although it is acknowledged that adherence to therapy may be unsatisfactory. Yet, despite undoubted efficacy for most patients, it appears that some degree of airway inflammation still persists in patients with asthma who have poor airway function.
Most likely, this is due to the fact that corticosteroids do not suppress all the inflammatory mediators involved in asthma. As a matter of fact, corticosteroids do not suppress leukotriene synthesis or pathways and may even increase ex-vivo leukotriene biosynthesis by blood neutrophils. Moreover, the recent work by Gyllfors et al. appears to indicate that neither the biosynthesis, assessed as urinary LTE(4) concentrations, nor the actions of leukotrienes, measured as bronchial responsiveness to LTD(4), appear to be sensitive to ICSs. Taken together these studies provide mechanistic support for the additive therapeutic efficacy of antileukotrienes in asthma.
Leukotrienes are not only known for their potent bronchospastic effects but they also initiate several other pathophysiological changes dictating the asthma phenotype. Moreover, increased cysteinyl leukotriene (CysLT; collectively comprising LTC4, LTD4 and LTE4) levels have been detected in the urine, bronchoalveolar lavage fluid, sputum, and exhaled breath condensates of patients with asthma. Taken together, these observations suggest that leukotrienes are one of the key mediators and modulators of the asthmatic inflammatory response. Recognition of the importance of leukotrienes in the pathogenesis of asthma has led to the development of leukotriene modifiers, the first new class of drugs for asthma treatment to become available since the introduction of ICSs.
Purpose of review: Recognition of the importance of leukotrienes in the pathogenesis of asthma has led to the development of leukotriene modifiers, the first new class of drugs for asthma treatment to become available since the introduction of inhaled corticosteroids. Nevertheless, despite their widespread use in clinical practice, the role of leukotriene modifiers in the management of asthma remains controversial. In the present article the clinical applications of this class of drugs have been critically reviewed based on recent evidence.
Recent findings: In an effort to try and establish the proper place of antileukotrienes in the management of asthma, important systematic reviews have been carried out over these recent years in three critical areas: antileukotrienes as second choice first line agents after inhaled corticosteroids; antileukotrienes as add-on therapy to inhaled corticosteroids; add-on antileukotrienes versus long acting β-agonists to patients not controlled by inhaled corticosteroids. In addition, novel and useful clinical targets for this class of drugs have been recently explored and include: patients with severe asthma; aspirin-intolerant asthma; asthmatic patients with allergic rhinitis.
Summary: Use of antileukotrienes is not recommended as first-line monotherapy in patients with asthma, except those who have aspirin intolerant asthma. Patients with concomitant allergic rhinitis may be a good target population for therapy with antileukotrienes. Addition of leukotriene modifiers to inhaled corticosteroids produces only a modest improvement in the clinical response, and is not greater to that of add-on long acting β-agonists. The exact role of antileukotrienes in asthma management guidelines still continues to evolve.
The recognition of the inflammatory basis of asthma by the early 1990s has provided the basis for a passionate hunt for those mediators of inflammation dictating the asthma phenotype. Moreover, the understanding of asthma as an inflammatory disease of the airways has endorsed the common use of inhaled corticosteroids (ICSs) as a baseline asthma therapy. ICSs have been the mainstay of asthma treatment for more than 20 years. When used regularly, ICSs are known to decrease airway inflammation, improve lung function and reduce both morbidity and mortality. Thus, it is universally recommended that patients with recurrent symptoms are best managed with ICS on a daily basis, although it is acknowledged that adherence to therapy may be unsatisfactory. Yet, despite undoubted efficacy for most patients, it appears that some degree of airway inflammation still persists in patients with asthma who have poor airway function.
Most likely, this is due to the fact that corticosteroids do not suppress all the inflammatory mediators involved in asthma. As a matter of fact, corticosteroids do not suppress leukotriene synthesis or pathways and may even increase ex-vivo leukotriene biosynthesis by blood neutrophils. Moreover, the recent work by Gyllfors et al. appears to indicate that neither the biosynthesis, assessed as urinary LTE(4) concentrations, nor the actions of leukotrienes, measured as bronchial responsiveness to LTD(4), appear to be sensitive to ICSs. Taken together these studies provide mechanistic support for the additive therapeutic efficacy of antileukotrienes in asthma.
Leukotrienes are not only known for their potent bronchospastic effects but they also initiate several other pathophysiological changes dictating the asthma phenotype. Moreover, increased cysteinyl leukotriene (CysLT; collectively comprising LTC4, LTD4 and LTE4) levels have been detected in the urine, bronchoalveolar lavage fluid, sputum, and exhaled breath condensates of patients with asthma. Taken together, these observations suggest that leukotrienes are one of the key mediators and modulators of the asthmatic inflammatory response. Recognition of the importance of leukotrienes in the pathogenesis of asthma has led to the development of leukotriene modifiers, the first new class of drugs for asthma treatment to become available since the introduction of ICSs.