Asthma pharmacotherapy: an update on leukotriene treatments

ABSTRACT

Introduction: Asthma is a chronic inflammatory disease of the airways with a large heterogeneity of clinical phenotypes. There has been increasing interest regarding the role of cysteinyl leukotriene (LT) and leukotriene receptor antagonists (LTRA) in asthma treatment.

Areas covered: This review summarized the data (published in PubMed during 1984–2019) regarding LTRA treatment in asthma and LTs-related airway inflammation mechanisms. Involvement of LTs C₄/D₄/E₄ has been demonstrated in the several aspects of airway inflammation and remodeling. Novel pathways related to LTE₄, the most potent mediator, and its respective receptors have recently been studied. Antagonists against cysteinyl leukotriene receptor (CysLTR) type 1, including montelukast, pranlukast and zafirlukast, have been widely prescribed in clinical practices; however, some clinical trials have shown insignificant responses to LTRAs in adult asthmatics, while some phenotypes of adult asthma showed more favorable responses to LTRAs including aspirin-exacerbated respiratory disease, elderly asthma, asthma associated with smoking, obesity and allergic rhinitis.

Expert opinion: Further investigations are needed to understand the role of LTs in airway inflammation and remodeling of the asthmatic airways. There is a lack of biomarkers to predict responsiveness to LTRA, especially in adult asthmatics. Besides CysLTR1 antagonists, targets aiming other LT pathways should be considered.

KEYWORDS:

• Asthma
• cysteinyl leukotrienes
• leukotriene receptor antagonist

Article highlights

• Asthma is a chronic heterogeneous airway disease with various phenotypes and variable responsiveness to anti-asthmatic medications.

• The cysteinyl leukotrienes (LT) C₄, D₄, and E₄ are involved in modulating airway inflammation and remodeling by either direct or indirect effects via enhancing inflammatory cytokine cascades.

• LTE₄ mediates activation of various inflammatory cells, including mast cells, eosinophils, T helper 2 cells and group 2 innate lymphoid cells, through cysteinyl leukotriene receptor (CysLTR) type 1 or an indirect receptor (purinergic receptor P₂Y₁₂). Meanwhile, the axes LTC₄/platelet/IL-33 and LTB₄/eosinophils are being investigated.

• Leukotriene receptor antagonists (LTRAs) are approved in the treatment guidelines of asthma and widely prescribed in real practice. However, it is not certain whether they are effective in attenuating airway remodeling found in chronic asthmatic airways.

• LTRAs are found to be beneficial for patients with aspirin-exacerbated respiratory disease, elderly asthma, smoking asthma, asthma associated with obesity and asthma comorbid with allergic rhinitis; moreover they are known to prevent exercise-induced bronchoconstriction and viral-induced wheezing episodes.

• There are still unmet needs left to identify useful biomarkers for predicting favorable responders who may benefit from LTRA use.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This study is supported by a grant of the Korea Health Technology R&D project through the KHIDI, funded by the Ministry and Health &Welfare, ROK (HI16C0992).