Predicting responses to LTRA therapy
Heterogeneous effects of LTRA therapy in asthma and allergic diseases have been reported in many studies. Although some genetic65,66 and acquired factors have been suggested,67 other reasons for this heterogeneity remain unclear. While currently no clinical characteristics or laboratory assay can reliably predict responses to LTRAs, the most plausible biomarker that could potentially serve as response predictor to LTRAs seems LTE4 production. Urinary LTE4 (uLTE4) is a biomarker of total body cysteinyl-LT production,1 associated with Type 2 asthma, asthma severity, exacerbations and NERD.68,69Increased uLTE4 to fractional exhaled nitric oxide (LTE4: FeNO) ratio has been suggested to predict favourable response to LTRA therapy (montelukast) in asthmatic children,70,71 but these observations have not been confirmed in adult patients. There is a considerable amount of evidence supporting the concept that some patients or clinical phenotypes seem sensitive to LTRAs, especially in a real-life setting, due to enhanced cysteinyl-LT production, better adherence to oral therapy or oral drug delivery. LTRAs have proven to be particularly effective in exercise-induced asthma,72 asthma associated with allergic rhinitis,73 NERD,74 viral induced wheezing episodes,75 and patients having difficulties with inhaled therapy such as children and elderly.76,77 Cigarette smoking while inhibiting steroid anti-inflammatory responses,78 increases cysteinyl-LT production,79 leading to a greater response to montelukast in smokers with asthma, suggesting that LTRA could be more effective in treating such individuals.80 In fact, asthmatic patients with smoking history above 11 pack-years showed more benefit with montelukast treatment than inhaled steroids.81 Obesity is another potential risk factor for asthma development and efficacy of treatment. Interestingly, higher body mass index (BMI) is associated with increased LT production in asthmatics82 and as therapeutic response to inhaled corticosteroids decreases with increasing BMI, response to montelukast remains unaffected,83suggesting LTRA therapy to be more effective in obese patients. The response to LTRA may also be associated with sex differences. The existence of a sex bias in LT biology is already suggested by the fact that many LT-related diseases including asthma, allergic rhinitis, rheumatoid arthritis or NERD have a higher occurrence in women compared to men, pointing to more pronounced pathophysiological roles of LTs in females.84,85 Furthermore, several observations suggest that female sex is associated with higher LT biosynthesis, while androgens seem to exert a suppressing role on LT formation both in vitro and in vivo.86-90 Although the clinical significance of these data is still to be confirmed, in a small prospective cohort study, montelukast showed superior effects on symptoms and lung function in women compared to men,91 while a tendency for a better response to montelukast was evident in girls exposed to tobacco smoke.92