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Boston, MA
Dr. Celli is Chief, Pulmonary and Critical Care Medicine, St. Elizabeth’s Medical Center.
Correspondence to: Bartolome Celli, MD, FCCP, Caritas St. Elizabeth’s Medical Center, Chief Pulmonary and Critical Care Medicine, St. Elizabeth’s Medical Center, 736 Cambridge St, Boston, MA 02135-2997; e-mail: bcelli{at}copdnet.org
The American Thoracic Society and the European Respiratory Society have redefined COPD as a preventable and treatable disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is associated with an abnormal inflammatory response to inhaled particles or gases, primarily cigarette smoke. COPD also has important systemic consequences.1 This definition provides a shift from a narrow paradigm, centered solely on the degree and progression of airflow obstruction, to a broader one, providing a more optimistic view in which interventions can be envisioned at different levels of the pathogenetic mechanisms.
Until now, most studies evaluating the efficacy of novel therapies has continued to center on the effect of the agent tested on FEV1. This approach is justified when only evaluating the bronchodilator property of a medication, as has been true for asthma, but fails to consider much more promising mechanistic therapies that can have effects beyond bronchodilation. Indeed, as we unravel the injury and repair mechanisms involved in the pathogenesis of COPD, we must expand the ways in which to evaluate therapies that may modify those mechanisms. Inflammation plays an important role in the perpetuation of COPD. Recent evidence2 has indicated that in patients who have stopped smoking long before portions of the lung were removed for therapeutic pneumoplasty, there is an active inflammatory process with evidence of abnormal repair. This issue of CHEST (page 56) includes a report by Rennard and coworkers9 of a relatively short-term (6 months) trial testing the efficacy of a novel antiinflammatory agent, cilomilast. This agent is one of the members of the family of phosphodiesterase (PDE) 4 inhibitors, which in vitro have been shown to suppress the production of cytokines, cell proliferation, and chemotaxis, the release of inflammatory mediators, and nicotinamide adenine dinucleotide phosphate oxidase activity.3 PDE4 inhibitors also have activity in animal models of airway inflammation.4 Through its action on cyclic adenosine monophosphate and guanosine monophosphate, PDE4 inhibitors have effects on various inflammatory cells including epithelial cells, dendritic cells, eosinophils, macrophages, mast cells, monocytes, basophils, and T and B lymphocytes. Administered orally, the agents reach the lungs via the systemic circulation, a fact that provides direct access to the most distal portions of the lungs, the site of the small airways. This is important since most inhaled bronchodilators or inhaled corticosteroids may not fully reach the distal portion of the airways where a large share of the inflammatory process seems to continue unabated. Based on the current knowledge of inflammation and the natural course of COPD, a 6-month window to evaluate the effect of a therapy is very short and can only provide "proof of concept" rather than "definitive" data regarding the value of the intervention. It is very encouraging that the data provided by Rennard and coworkers showed an FEV1 difference in favor of cilomilast compared to placebo. Even more interesting is the larger difference in the quality-of-life score measured with the St. George questionnaire, which reached the minimal important difference of 4 U after only 6 months of therapy. These findings are in line with those recently reported5 for roflumilast in a similar large 6-month trial. In addition, even though it was only a secondary outcome of the two studies, patients in both studies receiving the PDE4 inhibitors had a delay in the time to the next exacerbation. The 40-mL difference in FEV1 between cilomilast and placebo is unlikely to explain the difference in health status and the recurrence of exacerbation between groups.
If not the change in airflow limitation, what then is responsible for the larger change in health status? Although the explanations for this discrepancy remain to be defined, it is possible to speculate on the likely mechanisms. Because of its systemic distribution, it is possible that the PED4 inhibitors may reach the distal airways, whereby decreasing inflammation around the small airways they could have more important changes in resting lung volumes than in absolute FEV1. Unfortunately, lung volumes were not tested in this trial. On the other hand the PED4 inhibitors could also have effects on other inflammatory events that result in fewer symptoms and less propensity for COPD exacerbations.
In caring for patients with COPD and asthma, we have learned that nonspecific PDE inhibitors such as theophylline have limitations because of the narrow therapeutic window and the frequency of side effects, which are primarily GI in nature.1 It is comforting to see that for cilomilast only 9% of the patients withdrew from the study because of GI disturbances. On the other hand, the frequency of side effects is such that it would be prudent to closely monitor patients during the initiation of therapy. From the data reported here, most symptoms developed early (within 3 weeks of therapy), thereby providing guidance to the clinician.
The magnitude of the problem of COPD around the world6 needs all of the therapeutic resources we currently have plus the development of new therapies that are capable of altering the pathophysiologic processes known to be involved in disease maintenance and progression. Because inflammation and repair are central elements of COPD, it is refreshing to begin to see the results of novel pharmacologic trials. On the other hand, it is time to expand the horizon and look beyond FEV1 since it is likely that we will find changes in patient-centered outcomes and even perhaps in survival that have little relationship to the degree of airflow obstruction. After all, oxygen therapy improves survival in hypoxemic patients with COPD without altering the FEV1.78 The message is clear, let us look into the future with optimism.
Received for publication October 10, 2005. Accepted for publication October 12, 2005.
References
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