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