Physicians must look at the bigger picture when it comes to understanding COPD, delegates heard
Respiratory experts from all over the world gathered in Birmingham, UK, recently for the COPD7 International Conference on chronic obstructive pulmonary disease (COPD).
The international, multi-disciplinary conference, which ran from 30 June to 2 July, heard from speakers from all over Europe and from the US, Canada and Australia.
In the opening plenary session, Prof Bart Celli spoke on ‘FEV1 independent – clinical phenotypes’. According to Prof Celli, Professor of Medicine at Tufts University and Chief of the Division of Pulmonary and Critical Care at St Elizabeth’s Medical Center in Boston, understanding COPD phenotypes is the future of the condition and of finding ways to treat it.
He said significant hetero-geneity of clinical presentation and disease progression exists within COPD. “Although FEV1 doesn’t properly describe this heterogeneity, we don’t actually have a clear alternative.”
The goal of phenotyping is to identify patient groups with unique prognostic or therapeutic characteristics, he continued, “but significant variation and confusion surrounds our use of the term ‘phenotype’ in COPD”.
The term, in general, refers to any observable characteristic of an organism. Until now, multiple disease characteristics have been termed phenotypes for COPD patients. “I’d like to propose a different definition: ‘a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes (symptoms, exacerbations, response to therapy, rate of disease progression or death)’,” said Prof Celli.
This more focused definition, he said, allows for classification of patients into distinct prognostic and therapeutic subgroups, for both clinical and research purposes. Patients who share a unique phenotype would also, ideally, ultimately be determined to have a similar underlying biologic or physiologic mechanism to guide the development of therapy, where possible.
“Of course, then, any proposed phenotype – whether defined by symptoms, radiography, physiology, cellular or molecular fingerprint – will require a validation process, in which ‘candidate’ phenotypes are identified before their relevance to clinical outcome is determined,” said Prof Celli.
He acknowledged, however, that this represents an ideal construct, and that “any phenotype may be etiologically heterogeneous”. Also, any one patient may have multiple phenotypes.
“We have a lot to learn, but the first step is establishing a common language for future research, which will help our understanding and management of this complex disease,” Prof Celli concluded.
Tailoring approaches
In the ‘Nycomed Symposium: Thinking Differently in COPD’, Prof Robert Stockley spoke on ‘Different types of patients, different approaches’. Prof Stockley, Professor of Respiratory Medicine at the Lung Resource Centre, University Hospital Birmingham, built on the concept of meeting individual patient needs, rather than adapting a one-size-fits-all treatment approach.
“Current anti-inflammatory medications used to treat COPD, such as inhaled corticosteroids [ICS], don’t reduce the neutrophil-mediated inflammation seen in COPD. This is the primary unmet need in our patients,” he said.
The pathogenesis of COPD is complex and airway inflammation plays an important role. “The inflammation that we see in COPD is obviously different from what we find in asthma, with a predominantly neutrophilic rather than eosinophilic bronchitis.” The lung is a primary target for neutrophil recruitment and activation and the neutrophil is a primary mediator of inflammation in COPD.
“What I want to stress is that we mustn’t put patients in a single box. This is especially true in COPD. We must learn to assess what we see, not just what we think.”
He added that COPD is actually an umbrella term for a group of respiratory-tract diseases that are characterised by airflow obstruction or limitation. It covers an ‘irreversible’ aspect of chronic bronchitis, emphysema and asthma. “If a patient has emphysema, aerosol deflation becomes patchy. If we give systemic drugs, we can get to the connective tissue substrate. This can be of help in emphysema.”
In another example of different approaches for different types of patients, he said that if a patient has a chronic bronchitis phenotype, they are more likely to have exacerbations than patients who just have obstruction. “This all needs to be borne in mind when treating patients.”
Prof Stockley said that the current thinking on COPD suggests that it is a systemic disorder. This is why appropriating drugs to treat COPD from other chronic respiratory conditions, such as asthma, is no longer adequate.
He concluded with just some of the types that doctors must consider when treating COPD patients. These include:
- Airways versus alveolar;
- Bronchitis versus absence of bronchitis;
- Colonised or not;
- Bronchiectasis;
- Exacerbating phenotypes; and
- Systemic phenotypes.
Need for new treatments
Prof Klaus F Rabe, Leiden University Hospital, the Netherlands, addressed delegates on ‘COPD treatments: building blocks for a different future’. He said that there remain some major unmet clinical needs in the treatment of COPD. These include more effective diagnosis and disease prevention, better symptom control, prevention of exacerbations, slowing and possible prevention of disease progression, reduction of disease-related mortality, and identification and reduction of systemic disease secondary to COPD and co-morbidities.
“We ultimately would like to change mortality, so we need new treatments,” said Prof Rabe.
“Our current therapeutic options are mainly limited to symptomatic treatment, and there’s increasing attention being paid to the inflammatory component of COPD in the airways and lung parenchyma,” he continued.
“The underlying chronic inflammation plays a central role in the progression of the disease. We need a better understanding of this COPD-specific inflammation.”
Prof Rabe said that there has been a “certain lack of creativity” when it comes to drug therapies for COPD. “Targeting the function of macrophages isn’t done. We’ve just been taking anti-inflammatory drugs from asthma and applying them to COPD.”
He went on to speak about roflumilast. This new proprietary selective phosphodiesterase 4 (PDE4) enzyme inhibitor has been indicated for maintenance treatment of severe COPD (FEV1 post-bronchodilator less than 50 per cent predicted) associated with chronic bronchitis in patients with a history of frequent exacerbations.
It is intended to be used as an add-on to bronchodilator treatment. Roflumilast is the first new class of treatment for COPD in more than a decade and is the first to utilise phenotype targeting, he said.
“It has been shown to improve lung function and reduce exacerbations. We’ve a large number of patients who remain symptomatic and have frequent exacerbations, despite existing treatments,” said Prof Rabe. “For that more severe end of the spectrum, we need new therapeutic options. Roflumilast’s main additional benefit, on top of what’s already achieved with bronchodilators, is to reduce the number of exacerbations.”
He examined the results from Phase III trials of roflumilast in the treatment of symptomatic COPD. In two placebo-controlled, 12-month studies involving a total of over 3,000 patients with COPD, roflumilast demonstrated statistically significant improvements on both co-primary endpoints: moderate-to-severe exacerbations and pre-bronchodilator FEV1. The effect was independent of concomitant use of long-acting beta2-agonist (LABA).
Roflumilast also demonstrated a statistically significant improvement compared to placebo on lung function, in two supportive studies over a six-month period when added to the long-acting bronchodilators, tiotropium or salmeterol.
Prof Kabe added that in the four trials, the most common adverse effects associated with the drug were diarrhoea, nausea and weight decrease (2kg mean loss). He said that more studies were needed to assess its use in combination with corticosteroids. “However, it may also have a cardioprotective side-effect, but more studies are needed in this regard, too,” he concluded.
Treatment aims and methods
Prof Neil Barnes, Professor of Respiratory Medicine at Barts and the London Hospital, concluded the Nycomed Symposium with a presentation called, ‘The Holy Grail: how far forward are we?’ He said that what clinicians have tried to achieve in COPD patients over the years has changed.
“In the 1980s, the aim was to reduce the rate of FEV1 decline, but we’ve failed to show any convincing evidence for this. One ‘Holy Grail’ that’s within our grasp, however, is prevention. The biggest factor in this regard is smoking cessation.” Prof Barnes cited a study on the effects of England’s smoke-free legislation on hospital admissions: “There were 1,200 fewer emergency admissions for myocardial infarction – 1,600, including readmissions – in the first year after the legislation was introduced on 1 July, 2007. It’s hoped that this positive effect will follow through to reducing COPD instance.”
Today’s main treatment aims, he said, are:
- Relieve symptoms;
- Prevent disease progress;
- Improve exercise tolerance; and
- Reduce mortality.
“When it comes to relieving symptoms, we have bronchodilators, pulmonary rehabilitation and smoking cessation. To prevent exacerbations, we advocate the flu vaccine and use long-acting inhaled anticholinergics. In terms of reducing mortality, there’s the option of lung-volume reduction surgery in very selected patients, smoking cessation of course, and long-term oxygen therapy in hypoxic patients,” said Prof Barnes.
Investigating
Echoing earlier speakers, he said physicians must look at the bigger picture when it comes to understanding COPD. This involves tailoring treatment when the condition develops, but also investigating why it occurs in the first instance and focusing on prevention.
“We know there are different factors determining lung function. A person’s maximum FEV1 may be affected by early life events and severe childhood respiratory infections. The rate of decline of FEV1 is affected by the number of smoking pack-years, the age of smoking onset, frequent inflammatory exacerbations, tuberculosis, systemic inflammation and bronchial hyperreactivity.”
To slow this rate of decline, smoking cessation must be undertaken early in COPD development and, possibly, inhaled steroids could be started, Prof Barnes said. A LABA/ICS combination should also be used, but tiotropium will not be of benefit.
“Reduction in inflammation is the probable mechanism behind a reduced rate of decline of lung function. Looking to the future, PDE4 inhibitors such as cilomast and roflumilast affect inflammation in COPD,” he continued, “and the pattern of inflammation reduction is different to combination therapy.
“We must learn from cardiologists – they start patients on different drugs at the same time. In COPD, we also need to get away from thinking about individual drugs and start combining therapies.”
Prof Barnes concluded by saying that COPD is at a turning point: “Reducing mortality and limiting disease progression is now the ‘Holy Grail’ in COPD. This is a very exciting time, as we’re beginning to get drugs for these in combination.”
- References on request.
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