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MEDICAL FRONTIERS - American Thoracic Society International Conference

San Diego, California / May 15-20, 2009

There is a growing conviction that the reduction of pro-inflammatory mediators in the systemic circulation and in tissues outside of the lung is relevant to better control of chronic obstructive pulmonary disease (COPD) and its comorbidities. A number of novel therapies with direct or indirect anti-inflammatory effects are in varying stages of development with the goal of preventing both progressive deterioration of lung function and protecting other tissues adversely affected by inflammatory upregulation. This represents a major reorientation in understanding the pathophysiology of COPD.

Update on the Pathophysiology of COPD

“As respirologists, we used to think that smoking starts a process that damages the lung, but it’s much more than that. We know particles from smoke can be found in the circulation and in many tissues, and this may explain a more generalized inflammatory state and the fact that almost all COPD patients have one or more comorbidities. I think it is very important that we now recognize COPD as a systemic disease,” stated Dr. Leonardo M. Fabbri, Department of Respiratory Disease, University of Modena & Reggio Emilia, Italy.

Although this orientation is rapidly being embraced, it is not new. Dr. Peter Calverley, School of Clinical Sciences, University Hospital Aintree, Liverpool, UK, indicated that the evidence supporting an important systemic component of COPD has been available for years. He has been actively involved in developing and testing a variety of systemic therapies for COPD. Some have been targeted at very specific mediators of inflammation, such as tumour necrosis factor alpha (TNF-a) and C-reactive protein (CRP), while others are designed to offer a more global effect on inflammatory cell regulation. He suggested several approaches appear viable.

“Of all the agents that have been developed recently, the ones that are closest to actually moving from a future therapy to an actual therapy are the phosphodiesterase-4 (PDE-4) inhibitors,” Dr. Calverley told delegates. He explained that inhibition of PDE-4 enzyme is an attractive target “because it mediates inflammatory effects not just in the respiratory tract but throughout the body.” He added, “A systemically administered drug with systemic effects for a systemic disease makes sense on logic alone.”

PDE-4 inhibitor in COPD Treatment

A large clinical trial in COPD with a PDE-4 inhibitor was published two years ago (Calverley et al. Am J Respir Crit Care Med 2007;176:154-61). The study was conducted with roflumilast, a once-daily PDE-4 inhibitor characterized by Dr. Calverley as the “most potent one of these agents to be tested clinically.” In the published study, 1513 patients with severe COPD (median FEV₁ 41% predicted) were randomized to roflumilast 500 µg or placebo. On treatments, the post-bronchodilator FEV₁ increased by 39 mL relative to placebo at the end of 52 weeks of study (P=0.001). The exacerbation rate was not significantly reduced on roflumilast overall, but there was a reduction in those with the most severe disease (Figure 1).

Figure 1.

“The development of roflumilast is going forward, and much more data are coming,” noted Dr. Calverley, who also reported that the tolerability was acceptable. He indicated that the agent’s activity provides a proof of concept that systemic therapies can produce improvements on classical measures of COPD control such as lung function. This is important because the ultimate potential for systemic therapies is improvements on outcomes influenced by lung function and by control of comorbid conditions.

Systemic Manifestations

Employing a single therapeutic agent to protect multiple organs influenced by a common inflammatory pathology is a reasonable goal based on the concept of COPD as a systemic condition. Dr. Fabbri went so far as to describe change in FEV₁ as a “biomarker of a comprehensive systemic disease process,” and cautioned clinicians that it is imperative to consider COPD beyond lung function. While he acknowledged that respirologists are increasingly vigilant in looking for concomitant heart disease, diabetes, anemia, osteoporosis and depression in COPD patients, he suggested that opposite should also be true.

“We recently asked our colleagues in a cardiovascular (CV) clinic if we could evaluate their patients for COPD. Of the patients with congestive heart failure, 29% had COPD. Only two of the patients were aware of it,” Dr. Fabbri reported.

The importance of promoting a reorientation that places COPD in the context of a systemic inflammatory process is the potential opportunity it may provide to reduce adverse outcomes, including early death. Dr. Bartolome Celli, Tufts University, Boston, Massachusetts. noted that when cause of death was audited among patients who participated in the three-year TORCH study, 35% of mortality was considered to be respiratory-related, but 27% was due to CV causes and 21% was due to cancer, another disease related to altered immune system activity. He, like others, described the common comorbidities of COPD as “extra-pulmonary manifestations,” indicating commonality among these disease processes.

New strategies for controlling systemic inflammation relative to pulmonary inflammation are being sought because the targets appear to be different. In the lung, inflammation appears to be largely driven by an influx of neutrophils, eosinophils, macrophages, and monocytes, which are most closely associated with release of leukotriene B4, interleukin (IL)-1ß, IL-1-a and IL-12. Activation of lymphocytes is common to both lung and systemic inflammation, but such inflammatory mediators as CRP, fibrinogen, TNF-a, IL-6 and IL-8 appear to be more characteristic of a systemic inflammatory state. Dr. Steven I. Rennard, University of Nebraska School of Medicine, Omaha, offered that specific and measurable markers of inflammation in the blood are likely to emerge as tools not only for evaluating systemic inflammation but for guiding CV disease and diabetes therapy as well. He suggested that the appropriate analogy for such markers might be blood cholesterol or hemoglobin A1c.

“I believe that systemic inflammation is key to understanding COPD and that measuring inflammation will be absolutely essential to both developing and implementing the novel therapies we need to control the disease process,” Dr. Rennard reported.

As an example, surfactant protein D in the peripheral blood has been found to be reproducibly elevated in COPD patients relative to smokers without COPD and in smokers relative to non-smokers, according to Dr. Rennard. The levels have not correlated with GOLD-stage COPD, but he suggested that impairment in lung function, once initiated, might proceed on a trajectory independent of systemic inflammation even if control of systemic inflammation is important for treatment. However, other markers, such as CRP, fibrinogen, TNF-a, IL-6 and IL-8, have correlated with FEV₁ and forced vital capacity (FVC) in published studies. The challenge is finding a marker that is specific to COPD and predictive of outcomes.

Markers of Inflammation

One of the potential advantages of identifying a marker of COPD-related inflammation is early detection of the disease process. While a marker of progression may be useful, COPD is typically detected at a relatively advanced stage when the opportunity to reverse the disease process may already be lost.

“COPD does not start when we see a change in lung function on spirometry. It almost certainly started years earlier,” observed Dr. Ravi Kalhan, Feinberg School of Medicine, Northwestern University, Chicago, Illinois. “Right now, we not only have no marker of early disease, we have no definition of early disease. An upregulation of systemic inflammation may be the tool to find these patients before there is significant lung damage.”

One potential source of this information is an ongoing prospective study called the CARDIA (Coronary Artery Risk Development in young Adults) cohort. Started in 1985, the study is following a broad array of markers of inflammation in order to study signs of CV disease development, but Dr. Kalhan has been evaluating lung function in relation to these same markers. In analyses of CRP and fibrinogen, an age-related decline in lung function has correlated strongly with CRP and fibrinogen after controlling for body mass index (BMI) but only when measured with FVC. FEV₁ has not correlated with these inflammatory markers. The cohort is not yet old enough to have produced a sufficient incidence of COPD to test inflammatory markers as predictors, but such studies are planned.

“We are at a very early stage of measuring systemic inflammation in relation to COPD, but I think we are going to identify a phenotype for inflammation in which susceptible COPD patients are at risk for a broad range of inflammatory-related diseases,” Dr. Kalhan speculated.

Current Therapies: Their Role in COPD

For systemic inflammatory markers, current therapies for COPD do not appear to offer any significant effects, according to Dr. Klaus F. Rabe, Department of Respiratory Medicine, Leiden University Medical Centre, The Netherlands. For example, tiotropium, a long-acting bronchodilator, was recently associated with improvements in lung function and quality of life in COPD patients evaluated over four years, but it was not associated with any substantial reduction of CRP or TNF-a. Dr. Rabe reported the same is true of inhaled corticosteroids such as fluticasone even though such agents downregulate lung-tissue-specific inflammatory cytokines.

According to Dr. Rabe, “The classic drugs do not affect systemic inflammation, so if this is important we need to develop new treatment strategies.” Conversely, there are data that statins may offer benefit in COPD through their anti-inflammatory systemic effect. Citing a retrospective study published last year (van Gestel et al. Am J Cardiol 2008;102:192-6), Dr. Rabe reported that statins were associated with a significant 33% improvement (HR 0.67; 95%:CI, 0.52–0.85) in long-term survival in COPD patients. Although it is unclear whether the benefit stemmed directly from anti-inflammatory activity, the authors reported that the analysis was undertaken on the premise that COPD is an inflammatory disease with the potential to be controlled through this mechanism.

The possibility that COPD is at least partially driven by an autoimmune process is one potential complication in our attempts to understand upregulation of systemic inflammation. Upregulation of Th1 cytokines and chemokines has been identified in several studies, and a variety of proteins have been proposed as self-antigen triggers. For example, one animal study tested elastin peptides as self-antigens and was able to demonstrate increased numbers of activated macrophages and neutrophils as well as increased MMP9 and MMP12 in the airway fluid, mimicking the presentation of COPD. In his overview of the autoimmune hypothesis, Dr. Fabbri noted that several researchers have speculated that an autoimmune response may be the key determinant for smokers who do or do not develop COPD.

Persistent pulmonary inflammation is a characteristic manifestation of COPD, but inhaled anti-inflammatory therapies provide only modest improvement in lung function; they do not modify disease progression and they have no measurable effect on COPD comorbidities, such as CV disease. Systemic anti-inflammatory therapies are unlikely to be able to reverse lung damage incurred by advanced COPD, but they may slow progression and offer benefits by controlling the inflammatory process affecting other organs. Moreover, the effort to reframe COPD as a systemic inflammatory process promises new opportunities to develop methods of early detection with the potential for earlier treatment and a greater opportunity to preserve lung function.

Summary

COPD does not appear to be appropriately characterized as a disease solely of the lungs. The evidence that inflammatory mediators are upregulated in multiple organs may explain the frequency with which COPD is associated with other major disorders, including CV disease. Strategies to address systemic inflammation may not only yield better control of disease in the lung relative to that currently achieved with inhaled anti-inflammatory drugs and bronchodilators, but also slow or halt concomitant disease processes. Evidence of clinical benefit from systemically active anti-inflammatory drugs in development provides a proof of concept that oral therapies may have a therapeutic role. The growing focus on this area of research may also generate better methods of diagnosing COPD and evaluating its progression.