New and Controversial Therapies for Chronic Obstructive Pulmonary Disease Jean Bourbeau1 and Malcolm Johnson2 1 2
Respiratory Epidemiology and Clinical Research Unit, Montreal Chest Institute, McGill University Health Center, Montre´al, Quebec, Canada; and Respiratory Medicines Development Centre, GlaxoSmithKline, Uxbridge, United Kingdom
There is a medical need in chronic obstructive pulmonary disease (COPD) for novel therapies with improved anti-inflammatory activity and the potential to affect disease progression. The concept of ‘‘super bronchodilators’’ is currently in development. Nonsteroidal antiinflammatory approaches are now being developed and are going under investigation. Restoration of steroid sensitivity is also a potential target in COPD. This could be done by increasing HDAC-2 expression and/or activation, by decreasing p38-kinase or delta-isoform of PI3K. Disease modification that may impact on long-term health status and survival of the patient is the primary and most challenging target for novel therapy in COPD. There is need, however, for new methods and biomarkers to follow disease progression. There has been significant innovation in the nonpharmacological management of COPD including team-based approaches with collaborative selfmanagement. Information and guidelines about self-management, coupled with interventions that provide patients with needed skills to increase their confidence, have potential impact on patient health. Recently, it has been shown that self-management programs reduce the probability of COPD hospital admissions. We should certainly be enthusiastic about these results, but there is need to increase our understanding of the relative effectiveness of specific components and how to best support COPD patients in self-management. Conceptualization of a research plan for COPD selfmanagement is needed for future research to be successful. Keywords: COPD; drug therapy; antiinflammatory effect; selfmanagement
This article outlines recent management initiatives and models of care that should be considered as components of chronic obstructive pulmonary disease (COPD) management. In the last decade, we have made important progress, providing evidence of the benefits of many pharmacologic and nonpharmacologic treatments.
IMPROVED ANTIINFLAMMATORY EFFECT AND DISEASE MODIFICATION IN COPD The pharmacologic management of COPD will likely change over the years to come. Pharmacologic treatments have largely targeted patients’ symptoms and functional capacity. Longacting b2-agonists (LABA) and muscarinic antagonists (LAMA) are both effective bronchodilators in patients with COPD. When administered together, the increase in lung function is significantly greater than either alone (1). This raises the concept of a LABA/LAMA combination as a ‘‘super bronchodilator’’ for COPD. These drugs are currently in development. Another approach is a dual pharmacophore that has both M-3-antagonist and b2-agonist activity in a single molecule (MABA). (Received in original form June 12, 2009; accepted in final form June 23, 2009) Correspondence and requests for reprints should be addressed to J. Bourbeau, M.D., Montreal Chest Institute, 3650 rue St. Urbain, Montre´al, QC, H2X 2P4 Canada. E-mail: jean.bourbeau@mcgill.ca Proc Am Thorac Soc Vol 6. pp 553–554, 2009 DOI: 10.1513/pats.200906-039DS Internet address: www.atsjournals.org
There is a need for novel therapies that have improved antiinflammatory activity and affect disease progression. Nonsteroidal antiinflammatory approaches are being developed and are undergoing investigation in COPD. A number of studies have shown inhaled corticosteroids to be less efficacious in COPD. However, inhaled corticosteroid combined with long-acting b2agonist has airway antiinflammatory effects not seen with inhaled corticosteroids alone (2, 3). Restoration of steroid sensitivity is therefore a potential target in COPD. Histone deacetylase-2 (HDAC-2), which has been implicated in sensitivity to corticosteroids, is significantly reduced in airway tissue from patients with COPD compared with healthy nonsmokers (4). This raises the possibility that increasing HDAC-2 expression and/or activation may be an approach to reversing corticosteroid sub-sensitivity in COPD. There is increased p38-kinase activity in alveolar macrophages from patients with COPD. The selective p38-a-kinase inhibitor GW 856553 suppressed LPS-induced p38-kinase activity in blood monocytes and inhibited IL-8 production in peripheral blood mononuclear cells from patients with COPD (5). GW 856553 also synergistically increased the suppressive effects of dexamethasone, the same inhibition of IL-8 being achieved with a significant reduction in steroid concentration (4). Other p38 kinase inhibitors, such as PH 797804, are also in development for COPD. There is evidence of significantly increased PI3K activity in peripheral blood monocytes (PBMCs) from patients with COPD compared with smokers and normal control subjects. This is associated with decreased sensitivity to corticosteroids. The addition of a PI3K inhibitor restores steroid sensitivity toward normal and other studies suggest that the delta-isoform of PI3K is a potential target in restoring corticosteroid sensitivity in COPD (6). There are a number of PI3K-delta inhibitors under development, including GSK373561A. Disease modification that may impact on long-term health status and survival of the patient is the primary and most challenging target for novel therapy in COPD. The cathepsin C pathway is involved in the recruitment of inflammatory cells to the lung in response to cigarette smoke and in the release of serine proteases and subsequent tissue damage. This raises the possibility that cathepsin C may be a target for a disease-modifying drug in COPD. There is a need, however, for new methods, surrogate endpoints, and/or biomarkers to follow disease progression.
NEW INSIGHTS IN NONPHARMACOLOGIC MANAGEMENT OF COPD An inordinate amount of healthcare resources are required to manage patients with COPD. Similar to many other chronic illnesses, COPD management is often focused on acute disease treatment. A shift of the paradigm for healthcare from acute to chronic care is required for the optimal management of patients with COPD. In the trajectory of a chronic illness such as COPD, the patient and family are in a constant process of learning new skilled behaviors that are needed for appropriate management of their
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disease. The patient and family must learn to engage in selfmanagement activities that promote health and prevent complications, ensuring the patient’s engagement in daily management decisions (7). Self-management support is aiming to achieve a shift from management by the health care provider, to management by the patients themselves, which implies structural behavior change. As the disease progresses to different stages and complications, self-management in the continuum of care will help the patient and family in adapting to COPD-related changes and in maintaining healthy behaviors (8). We may be enthusiastic about recent results (9), but there remains uncertainty about what aspects of self-management programs are most effective, mainly due to the wide variety in the way self-management programs are designed, delivered, and evaluated. In the past, failure to recognize this wide variety has led not only to inappropriate conclusions about the effectiveness of these programs but also to a high likelihood of inappropriate application of research results in clinical practice. Better research is needed to increase our understanding of the relative effectiveness of specific components and how to best support patients with COPD in self-management. Conceptualization of a research plan for COPD selfmanagement is needed for future research to be successful. First, we have to define a theoretical concept (series of concepts) that can be verified through testing. For example: ‘‘Early treatment of COPD exacerbation through self-management will benefit patient’s health and reduce health service utilization (emergency department visits, hospital admissions).’’ Second, we have to review the existing literature that supports these series of concepts. Individualized action plans have been shown from systematic reviews to be feasible (i.e., patients recognize and react appropriately to an exacerbation by promptly self-initiating antibiotics and oral steroids) (10). Patients with a written action plan and reserve supplies of antibiotic and prednisone are more likely to be the initiators of such treatment (increased likelihood of prompter treatment of exacerbation) than control patients, where treatment was initiated by the family physician (11). Third, we have to show that patient self-efficacy and behaviors change before we can assess a reduction in hospitalizations and cost. In a qualitative study, it has been shown that one of the most important helping strategies ‘‘disease-related skills’’ perceived by the patient was the use of the action plan in the event of an exacerbation (7). Furthermore, the intervention has to be properly defined (i.e., case manager training, support to patients, program content and protocols regarding program delivery). Finally, the measurement timeframe needs to be defined (i.e., it has to match the timeframe in which the selfmanagement support objectives [self-efficacy] and behavior change can be attained). Fourth, we can then develop and proceed with a large multicenter randomized clinical trial that includes (1) a welldefined population; (2) a well-defined intervention that has shown change in the intended behavior (‘‘early recognition and treatment of AECOPD’’); (3) a measurement timeframe that matches
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the timeframe in which the self-management support objectives (e.g., behavior change) can be attained; and (4) a properly powered study. A self-management approach including the use of a written action plan for early treatment of exacerbations holds promise for positive benefits on COPD care delivery (11, 12). However, many studies that have shown negative results have had methodologic limitations and lack of statistical power (10). Fifth, we have to know about factors that both help and limit dissemination of these interventions in real-world settings. Conflict of Interest Statement: J.B. served on the Board or Advisory Board for AstraZeneca (AZ), Boehringer-Ingelheim (BI), GlaxoSmithKline (GSK), Pfizer $10,001–$50,000, and Topigen $5,001–$10,000. He received lecture fees from AZ, BI, GSK, and Pfizer $10,001–$50,000 and received grant support from AZ, BI, GSK, and Pfizer $100,001–more. M.J. owns stocks or options of GSK $1,001– $5,000.
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