For this Series paper, we used several search approaches. We searched the Cochrane Library, Medline, and Embase using the search term “COPD” in combination with “clinical trial”, “effectiveness”, or “systematic review”, for 1 year between Jan 1, 2014 and Feb 28, 2015. For the years preceding this search we used the bibliography cited in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) document (GOLD search strategy used COPD, filters “human”, “all adult”, or “items” with
SeriesCurrent concepts in targeting chronic obstructive pulmonary disease pharmacotherapy: making progress towards personalised management
Introduction
Chronic obstructive pulmonary disease (COPD) is a common, complex, and heterogeneous condition that is responsible for substantial and growing morbidity, mortality, and health-care expenses worldwide.1 In this context, complexity relates to many different components with non-linear dynamic interactions, whereas heterogeneity implies that not all of these components are present in all patients at any given timepoint or in the same patient at different timepoints.2 To address this complexity and heterogeneity, identification of groups of patients with similar clinical characteristics, prognosis or treatment needs (so-called clinical phenotypes), is imperative.3 On one hand, this strategy is logical for research because it might create an increasingly homogeneous selection of patients in whom to decipher the complexity of COPD. On the other hand, this strategy might be of restricted clinical value because, first, clinical phenotypes can overlap in the same patient and, second, the same clinical phenotype could result from different biological mechanisms (ie, aetiological heterogeneity). Although the development of therapeutic approaches has increasingly attempted to address these complexities, so far most treatment options belong to a restricted number of pharmacological classes—ie, bronchodilators (eg, short-acting beta-2 agonists [SABA] and long-acting beta-2 agonists [LABA]), antimuscarinics (eg, short-acting antimuscarinic agent [SAMA] and long-acting antimuscarinic agent [LAMA]), and inhaled corticosteroids.
The Global Initiative for Chronic Obstructive Lung Disease (GOLD) was established in 1998 to improve the diagnosis, management, and prevention of COPD. A challenge for GOLD has since been to provide recommendations for the correct use of the available treatments and at the same time to flexibly position recommendations to allow the use of future innovative treatments that have the potential to target a personalised medicine approach. Another challenge faced by GOLD and other guideline or strategy documents is the paucity of evidence on how clinicians can identify patients who are most likely to benefit from available COPD treatments. This difficulty underlines the need for new treatment approaches in conjunction with refining of the way treatment indications are established. Finally, in most patients COPD is associated with other chronic diseases, a factor that should be addressed globally. This comorbidity might decrease the likelihood that treatments targeting only the COPD component will change the natural history of a patient's disease.
This Series paper addresses the strengths and limitations, including gaps in the evidence, of the approaches taken to move treatment of COPD towards personalised medicine, and also addresses potential future approaches to position emerging treatments that will probably target specific biological pathways. As such, we review the concept of an endotype, a subtype of a clinical disorder defined by a distinct pathophysiological mechanism,4 because it could be associated with future COPD treatments, and also review the role of biomarkers in marking endotypes and directing treatment.
Section snippets
GOLD revolution
The GOLD 20015 and 20066 reports used airflow limitation alone (as assessed by the forced expiratory volume in 1 s [FEV1] value) to assess disease severity. Bronchodilators were recommended as treatments to improve lung function and reduce symptoms in all patients, with inhaled corticosteroids reserved for patients with severe and very severe airflow limitation and repeated exacerbations. In 2011, the GOLD document acknowledged that use of FEV1 alone to assess disease severity was an overly
COPD endotypes
As previously discussed, an endotype4 is a subtype of a clinical disorder defined by a distinct pathophysiological mechanism, whereas a clinical phenotype3 is a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes (ie, symptoms, exacerbations, response to treatment, rate of disease progression, or death; figure 2). In the past decade, studies aiming to identify and characterise subpopulations of
Conclusions and future directions
We will gain empiric knowledge from proof-of-concept trials in COPD with emerging drugs that target specific inflammatory pathways (eg, monoclonal antibodies against interleukins 4, 5, 6, 13, 17, and 1β).96 Yet, at least two reasons exist for caution as these clinical trials are approached. First, a given endotype might possibly be relevant for only a small subset of the population with this disease. If so, these trials will have to consider either enrolment of only people who are likely to
Search strategy and selection criteria
References (107)
- et al.
Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome
J Allergy Clin Immunol
(2011) - et al.
Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study
Lancet Respir Med
(2013) - et al.
Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial
Lancet
(2015) - et al.
Inhaled steroids in COPD: when should they be used?
Lancet Respir Med
(2014) - et al.
Extrafine beclomethasone/formoterol in severe COPD patients with history of exacerbations
Respir Med
(2014) - et al.
Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials
Lancet Respir Med
(2013) - et al.
Glucocorticoid resistance in inflammatory diseases
Lancet
(2009) - et al.
Integrating real-life studies in the global therapeutic research framework
Lancet Respir Med
(2013) - et al.
α-1-Antitrypsin deficiency: clinical variability, assessment, and treatment
Trends Mol Med
(2014) - et al.
Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial
Lancet
(2000)