• Asthma Pharmacology

Globally, asthma remains one of the most common chronic conditions. The UK has one of the highest prevalence rates in Europe,1 with asthma accounting for 2–3% of general practitioner consultations.2 Asthma control is achieved, in most, by taking inhaled corticosteroid (ICS) containing medication regularly using an effective inhaler technique. Anything that can be done to improve the efficacy of asthma medication would be helpful, and enabling clear instructions to be given to patients may increase overall adherence and thus reduce the risk of asthma attack and lower the significant symptom burden.

It is well established that asthma demonstrates a rhythmic pattern of diurnal variation with worsening nocturnal and early morning symptoms.3 Symptoms, such as cough, tight chest and wheeze, are often worse overnight or in the early hours of the morning, with approximately 90% of asthma attacks happening within this time frame.4 In addition, significant fluctuations in lung function throughout the day, along with a noticeable decline at night, are known to be indicators of disease severity, inadequate control and increased mortality risk.5 Potential mechanisms have been discovered, which explain this phenomenon. In those patients with asthma demonstrating nocturnal symptoms, the activity of the glucocorticoid receptor has been shown to demonstrate reduced steroid responsiveness overnight.6 The PER3 gene, which is linked to chronotype, had been demonstrated previously by Krakowiak et al to exhibit significantly greater rhythmicity in individuals with asthma compared to healthy controls.7 It therefore follows that aligning drug administration with the body’s circadian rhythm—known as chronotherapy—would likely enhance the efficacy of inhaled corticosteroid treatment in patients with asthma.

This is the focus of the study by Wang et al published in this month’s Thorax, investigating the 24-hour effect on immunological and physiological measures of chronotherapy in asthma.8 The authors conducted a randomised, open label, three-way cross-over trial of beclomethasone dipropionate (BDP). Participants recruited had mild to moderate allergic asthma, diagnosed by a physician and stopped their usual asthma treatment in the run-in period for 2 to 3 weeks. Baseline measurements were then taken prior to participants being randomised to receive once daily dosing of 400 µg BDP AM (OD_AM, between 8 AM and 9 AM) or once daily PM dosing of 400 μg BDP (OD_PM, between 3 PM and 4 PM) or twice daily dosing of 200 µg BDP (BD, between 8 AM and 9 AM and 8 PM and 9 PM). Participants received three 28-day treatment periods with a 14 to 21 day washout period in between each treatment period. Following the run-in period and at the end of each treatment period, spirometry and biomarkers were measured over 6 hourly intervals for 24 hours.

Previous work by Gagnon et al had demonstrated in moderate asthma, managed with a twice-daily dose of inhaled beclomethasone, a single daily dose of beclomethasone administered in the late afternoon or evening offered equivalent asthma control over a 2 month period.9 In addition, Frezza et al had demonstrated a reduction in the nocturnal dip in FEV1 at 4 AM in steroid naïve patients with single-dose BDP/fluticasone propionate compared with placebo.10 However, no previous study had looked in detail at a combination of physiology and inflammation.

The authors demonstrated that BDP dosing mid-afternoon improved nocturnal lung function compared with once morning dosing: FEV1 increased by median 170 ml (IQR+30, +220, p<0.01). The improvement in FEV1 with OD_PM dosing compared with BD dosing was more modest at only 60 ml (IQR: −10, +240, p=0.02), not meeting what is considered the minimal clinically important difference for asthma endpoint for FEV1 of 100-200mls.11 Reviewing the effects on biomarkers of airway inflammation, there was no significant difference in suppression of FeNO levels between regimens. Blood eosinophils were significantly reduced by OD_PM dosing compared with BD dosing, reduced by −0.07×10⁹ cells /L (IQR −012 to –0.05; p<0.01) at 10 PM. This was in keeping with previous findings from the Beam et al study that demonstrated, in patients with uncontrolled asthma, a 3 PM single dose of oral prednisolone led to significant improvements in blood eosinophil counts at 4 AM compared with 8 AM or 8 PM dosing.12 Finally, Wang et al demonstrated there was no evidence of additional cortisol suppression with OD_PM dosing, measured in MESOR.

Although mid-afternoon dosing of BDP demonstrated clinically important differences in lung function of 170 ml and significant reduction in eosinophil levels, these did not lead to better symptomatic control. As noted in the paper, this lack of translation to patient outcomes may be attributed to the short duration of the follow-up period, the small numbers and the relatively low symptom burden of participants at baseline, so there was no headroom for improvement. This is likely to be the case as it is noteworthy that no patients dropped out in either the run-in or wash-out periods when they were not taking ICS-containing medication, and it would usually be expected that an improvement of 170 ml in FEV1 would lead to a measurable symptomatic improvement.

This study demonstrates the value of a cross-over design as the study power is increased by multiple measurements in the same individual; however, this leads to an increased risk of Type two errors. It is important to consider how representative the trial participants were of the broader patient population. The authors note that participants had mild to moderate allergic asthma phenotype, which means the results cannot be extrapolated necessarily to other asthmatic phenotypes. Additionally, when one considers the translation of these findings into clinical practice, with adherence to asthma therapies being the greatest challenge – around 30–40% of the general population struggles with inhaler compliance13 – introducing a specific time for inhaler use could potentially complicate matters further. A mid-afternoon dosing strategy could be challenging for patients to remember, especially as their daily lives become increasingly busy and complex in the 21st century. New strategies to manage this could be implemented leveraging smartphone applications, timed alarms and adherence reminders that could be effective solutions ensuring patients consistently follow their prescribed regimens.

The study did not permit the concomitant use of long-acting beta Agonist (LABA) inhalers. This runs contrary to the latest asthma guidelines, which now recommend combined inhaled corticosteroid and LABA inhalers as the standard of care.14 With a great many of our patients receiving dual ICS/LABA inhalers, this could impact the generalisability of the results as they are not reflective of our patient population. It will therefore be crucial to include this combination in future studies to ensure the participant population accurately reflects real-world clinical practice.

So how might we apply this data to practice and in whom may this be applicable? Is this a further opportunity to practise precision medicine in a different way to the assessment of phenotype and biomarker? This study offers promising insights into the potential benefits of using chronotherapy with inhaled corticosteroids for asthma patients. We believe that this is most likely to benefit those with more severe asthma, where marginal gains in lung function and a reduced eosinophil count are more likely to translate into better control and risk reduction. The results of this current study need to be validated in a larger trial with longer follow-up, using LABA/ICS in real-world settings to best evaluate the feasibility and practical implementation. If a more severe population was studied, then a different study design would have to be followed to prevent events during run-in or wash-out.

The underpinnings of the rhythms of our immune system and subsequent patterns of disease do merit further investigation. This may lead to mechanistic insights and thus to new therapeutic opportunities. What this study should do is make us think more about the patients in front of us with asthma, establish the pattern of their disease and their phenotypes and measure effective biomarkers such as FeNO and blood eosinophils. Of course, checking adherence at every opportunity and perhaps thinking about how, in those who are not controlled, the timing of their ICS dosing could be altered and how we could best support them to achieve this.