The airway diseases asthma and COPD affect millions of individuals worldwide.1 These
diseases are major determinants of chronic morbidity and mortality, and represent
a substantial public health burden.2–4 Despite differences in etiology, clinical characteristics,
and pathophysiology, both conditions share important features, such as airway obstruction
and chronic airway inflammation. As a result of modern lifestyle, the incidence of
both diseases is steadily increasing worldwide and effective preventive and treatment
strategies are unmet needs.5
Traditionally, airway eosinophilia has been regarded as a major hallmark of asthma,
whereas COPD has been associated with neutrophilic airway inflammation.6 For treatment
of chronic inflammatory airway diseases, inhaled corticosteroids (ICS) are usually
prescribed as maintenance therapy, most often as part of a combination therapy. While
the majority of asthma patients generally respond well to ICS,7 this is not often
the case in COPD.8 Hence, reliable algorithms and easily implemented tools are needed
to identify ICS responders in clinical practice, to optimize clinical benefits and
minimize adverse events.
Over the past two decades, increasing insights into the pathobiology of chronic airway
disease have enabled an understanding of its heterogeneous nature and thus helped
to shape precision medicine.9 These novel insights are gradually being adapted by
(inter)national guidelines for disease management in daily practice. In asthma, this
has – among others – resulted in adding targeted therapies with biologicals for refractory
allergic and/or eosinophilic asthma at treatment step 5 and, more recently, in adding
house dust mite (HDM) sublingual immunotherapy for HDM-sensitized asthma patients
uncontrolled on standard therapy in steps 3 and 4.3
Until recently, the Global Initiative for Obstructive Lung Disease (GOLD) strategy
did not differentiate across the COPD spectrum.10 For example, the GOLD-D category
comprised three different phenotypes, ie, patients with a severe airway obstruction
or frequent exacerbations, or both. Recent advances have led to the recognition that
these different subsets may require different treatment approaches instead of the
“one-size fits all” ICS-containing therapy as advocated in the treatment strategy
at that time.10 This has resulted in default prescription of ICS for COPD patients.8
Increasing evidence of limited clinical effectiveness in distinct phenotypes,11–14
along with safety concerns associated with long-term use of high-dose ICS,15,33 has
driven a personalized treatment strategy for chronic inflammatory airway disease recently
proposed by an international expert panel.16
Precision medicine is the cornerstone of this innovative approach advocating identification
and treatment of “treatable traits” in individual patients.17,18 In this context,
blood eosinophils as indicators of eosinophilic exacerbations have been identified
as a “treatable trait”.19,20 Data from several studies showed that benefits from ICS
in COPD were limited to patients with frequent exacerbations and blood eosinophilia
(the higher the initial blood eosinophil count the more the benefit).13,21 The recently
updated GOLD classification is based on symptoms and exacerbations and hence provides
a more differentiated treatment algorithm.22 Consequently, ICS therapy is only recommended
for patients with frequent exacerbations uncontrolled on a combination of bronchodilators
(ie, GOLD C and D).22 In this paper, we will provide a rationale toward more effective
ICS prescription for patients with chronic inflammatory airway disease based on treatable
traits.
Over-prescription of inhaled corticosteroids in chronic inflammatory airway disease
ICS have been available to treat chronic inflammatory airway disease for almost 70
years.23 Consequently, ICS-containing treatments have been amongst the most commonly
prescribed and thus most profitable medications.24 This has enabled pharmaceutical
companies to further develop this area of therapeutics. However, despite a massive
level of prescription of (optimized) ICS and long-acting beta-agonist (LABA) combinations,
many patients remain suboptimally controlled,25,26 with only small changes in morbidity
and mortality of both asthma and COPD, while numbers of hospital admissions continue
to rise increasing health care costs as a consequence.27 Although this may partly
be ascribed to an increase in the prevalence of both conditions, we cannot attribute
the clinical reality to this factor alone. Is it possible that many of the patients
treated with ICS are either non-responsive or respond suboptimally to this treatment?
Dogmatic prescription of ICS in chronic airway disease has resulted in a significant
level of over-prescription.28 In asthma, awareness of the potential for a customized
approach to ICS prescription has been incorporated into the guidelines advocating
a step-down regime after control has been reached. Moreover, guidelines now accept
a role for a more flexible maintenance and rescue from the use of ICS/LABA combinations.29
In COPD, the efficacy of ICS therapy has been investigated for over 25 years now.
Initially, it was assumed that the benefits seen in many asthma patients would be
transferrable to those with COPD. Large scale studies were performed with high doses
of ICS, all of which were either negative or demonstrated modest benefits at best.30
No protection was observed against a decline in lung function and overall, only modest
effects on exacerbations and quality of life were seen.31 Despite these findings,
in clinical practice, ICS continued to be prescribed to COPD patients at every level
of lung function deficit and for every disease category as defined by the GOLD approach.8
Moreover, ICS are prescribed for at least 40% of smokers presenting with symptoms
without any measurable lung function abnormality.28,32 In these individuals, there
is no evidence to support the use of ICS.
The results of the over-prescription of ICS affect all parties involved. First, the
individuals treated erroneously are being exposed to medication they do not actually
need along with the potential for side effects (eg, oropharyngeal candidiasis, dysphonia,
skin bruising, osteoporosis, cataract, loss of diabetic control, and pneumonia).33–35
Second, the prescribers feel that they are treating their patient and thus do not
reflect on other – more effective – therapies, and, finally, the insurance ends up
paying for ineffective medication and is thus unable to fund much more cost-effective
approaches in the long term (smoking cessation, bronchodilators, pulmonary rehabilitation).
Prescribing ICS on a “one size fits all basis” could be justified in the early years
because this was the only available medication option. Presently, prescribing by default
is no longer acceptable and a more personalized approach based on treatable traits
should be encouraged.
From “one size fits all” toward personalized treatment
In many ways, proposing a more precise approach to the prescription of ICS may seem
contradictory, as corticosteroids are a non-precise treatment by their very mechanism
of action. Nevertheless, it is crucial for physicians to appropriately prescribe ICS
to ensure effectiveness and limit side effects. Both for asthma and COPD, utilizing
biomarkers has been shown to aid the diagnosis, to predict exacerbations and to drive
treatment.36,37 In this respect, fractionated exhaled nitric oxide (FeNO) and blood
eosinophils are easily measurable biomarkers that can be used to predict and to monitor
treatment response and adherence to ICS.16,38,39
Currently, there is increasing understanding that both asthma and COPD are heterogeneous
disorders with overlapping characteristics.3,9,18 Even though at times they may appear
to be clinically indistinguishable, cluster analyses have identified distinct clinical,
biological, and pathological clusters with different responses to treatment.7,20,40–43
Importantly, cluster analyses can link inflammatory phenotypes to treatment algorithms.
For instance, the hierarchical cluster analysis by Haldar et al on data from over
400 asthma patients revealed five different phenotypic clusters based on concordance
between symptoms, sputum eosinophilia, and the response to ICS.7
Patients with concordant symptoms and sputum eosinophilia presented with milder, often
atopic disease, with an overall good response to ICS and a benign disease course,
while those with discordant symptoms or inflammation usually presented with a more
complex disease with varying response to ICS. Similar observations have been previously
made in a number of clinical studies.44,45 Overall, these findings support a symptom-guided
approach to management for mild to moderate, “concordant”-type asthma, while “discordant”-type,
refractory asthmatics might benefit from inflammatory biomarker-guided, personalized
therapeutic options including targeted therapy with biologics.
How do these findings relate to COPD? ISOLDE was one of the first studies to investigate
the effect of ICS on the rate of decline in lung function in COPD patients. The study
was negative for its primary end point.31 However, data from a post hoc analysis of
the ISOLDE study revealed that patients with moderate to severe COPD with persistent
blood eosinophilia of ≥2% show an accelerated lung function decline that can be prevented
by ICS treatment, while ICS did not affect lung function decline in patients with
blood eosinophila <2%.46 This compelling evidence in combination with novel insights
into underlying disease mechanisms urged a panel of international experts to propose
a personalized approach to chronic inflammatory airway disease management beyond clinical
labels.17,18 Hence, the concept of “treatable traits” was conceived, implementing
precision medicine into clinical practice.
These insights based on emerging data from large clinical trials helped to further
shape the updated GOLD strategy.22 This update has reclassified COPD and emphasizes
the dual goals of symptom control and reduction in risk of exacerbation. Presently,
optimal bronchodilator therapy, often comprising a LABA with a long-acting muscarinic
antagonist (LAMA) in a fixed dose combination (FDC), is the cornerstone of COPD treatment.22
This combination treatment decreases both the static and dynamic hyperinflation, which
helps to optimize lung function, daily activities, to improve exercise capacity and
endurance, and the overall quality of life.47–49 LABA–LAMA bronchodilator combination
therapy has been recommended based on the outcomes of large randomized controlled
trials including the recently published FLAME study.50 This large prospective study
showed superiority of the LABA–LAMA combination in preventing exacerbations in patients
with COPD as compared to those on a fixed ICS–LABA combination, irrespective of baseline
blood eosinophils.51 The study had tightly controlled inclusion criteria which excluded
participants with baseline eosinophils >600 cells/µL, and the run-in period excluded
ICS with the potential that eosinophilic participants will become unstable and be
excluded. During this 52-week study, the incidence of pneumonia was significantly
higher in patients on ICS–LABA compared to those on LABA–LAMA combination (4.8% vs
3.2%, p=0.02). These findings are in line with previous large studies investigating
the effect of ICS (containing) therapy on exacerbations, lung function decline, and
mortality in COPD which could not demonstrate substantial or additional clinical benefits
of ICS in many patients over time.31,51–54 Several other studies have examined the
risk benefit of the use of ICS and also ICS withdrawal.16,53–59 Specifically, during
the 12-month study (WISDOM) that included patients with (very) severe COPD taking
tiotropium plus salmeterol, the risk of moderate or severe exacerbations was similar
among those who discontinued ICS and those on ICS co-treatment.52 A recent post hoc
analysis showed that only patients with at least one exacerbation in the previous
year and a high blood eosinophil count (ie, ≥300 cells/µL or ≥4%) at baseline were
at increased risk of an exacerbation after complete ICS withdrawal, representing a
minority of the entire study population (n=2296).58 Indeed, other studies confirmed
that blood eosinophils may further help to identify COPD patients with frequent exacerbations
as a distinct phenotype that may benefit from ICS, while eosinophilic airway inflammation
has been proposed as a “treatable trait”.8,17,20,59
Consequently, it is crucial to critically assess the benefits versus risks in the
individual COPD patient and positively prescribe ICS based on phenotype-related treatable
traits.17,18 The updated GOLD strategy now better reflects this personalized approach.22
Changing of guidelines?
The future management of inflammatory airways disease is potentially very exciting.
We believe that given the ample supportive evidence, which is shaping the current
guidelines, the journey toward a “treatable trait” approach can really start. Our
goal must be to give more effective therapy to patients who will respond – this applies
not only to targeted treatments with biologic agents or small molecules but also existing
therapy with ICS – and thus improve disease outcome while reducing the side effects
of unnecessary pharmacotherapy. An aspirational goal should be to never have to prescribe
oral corticosteroids again to any patient with a proven inflammatory airways disease.16
To be able to move forward, we need to have a clear and accurate diagnosis. Focusing
on obtaining information as to the individual patient’s symptoms, comorbidities and
pathophysiology (clinical phenotype) complemented with the inflammatory phenotype.
Based on these individual characteristics, the correct treatment can be initiated.
Presently, ICS with or without the addition of LABA are considered the basis of asthma
pharmaceutical treatment. Comorbidities should be treated, and treatment should be
adjusted/reconsidered with the goal of achieving optimal control of symptoms, reducing
the risk of acute exacerbations and improving the patient’s daily activities/quality
of life.
COPD treatment goals are similar: improving symptoms (dyspnea), reducing the risk
of acute exacerbations, and improving quality of life. Apart from pharmacotherapy,
non-drug treatment modalities are helpful to achieve optimal outcomes in COPD patients.
Smoking cessation is essential in combination with bronchodilator therapy, to improve
dyspnea, while the opportunity for pulmonary rehabilitation should not be missed.
Although challenging to many patients, pulmonary rehabilitation and necessary lifestyle
adjustments are often critical to improve and reverse loss of lung function and exercise
endurance. Bronchodilator therapy in COPD should always be optimized, ie, a combination
of a LAMA and a LABA, now available as a FDC. Finally, based on the clinical phenotype
stratification according to GOLD, we should make further treatment decisions based
upon a detailed assessment of the underlying inflammatory mechanisms (inflammatory
phenotype). Clinical (GOLD) phenotype should, at present, be given primacy when making
decisions to intensify therapy – especially moving triple therapy with ICS – as we
lack definitive prospective data as to the utility of a true focused “treatable trait”
prescription approach. However, it is clear that simply measurable and available biomarkers
such as FeNO and blood eosinophil counts may help to predict a favorable response
to ICS not only in asthma but also in COPD. More biomarkers will emerge and the use
of a composite approach may have even more clinical utility, leading to mechanistic
insights as well as directing disease modifying therapy such as new biological agents
and small molecule inhibitors of specific inflammatory pathway targets.
In summary, our goals for patients with asthma should be: to have minimal (none) symptoms,
be free of restrictions in daily activities, and patients should never die of their
disease. All patients should have their treatment titrated to the lowest level required
to achieve and maintain these goals. COPD patients should be treated with the goal
of reversing the disability that years of accelerated lung function decline have caused
with a reduction in risk of exacerbations. This will be best achieved by a personalized
approach, leading to an individual understanding of risks and benefits. The correct
treatments should be given to the patients who will achieve the maximum benefit with
the minimum risk. With current therapies, such management goals are within our grasp,
although taking an individualized approach to management will maximize benefit and
minimize risk.