© 2004 American Thoracic Society doi: 10.1164/rccm.2407006
Are Inhaled Corticosteroids Systemic Therapy for Chronic Obstructive Pulmonary Disease?Clinical Research Centre University Hospital Aintree Liverpool, United Kingdom
Chronic obstructive pulmonary disease (COPD) has become, belatedly, a rather fashionable disorder to study. A major stimulus to new scientific research was the redefinition of COPD as an inflammatory disorder of the lungs (1), a step now supported by substantial data demonstrating persistent inflammation at all stages of the disease which is related to structural changes in the small airways (2). There is increasing interest in the concept of COPD as a systemic disorder (3), accompanied by reductions in body mass index and impaired quadriceps strength, which predict both mortality and healthcare use. This idea has now been extended to include increases in the white blood count, C-reactive protein (CRP) detected by high sensitivity assay, soluble tumor necrosis factor- If extrapulmonary inflammation is associated with increased cardiovascular risk, what can we do to modulate it? Unfortunately, the NHANES data found little relationship between inflammatory markers and current smoking status among patients with COPD who had ever smoked. Prospective studies of smoking cessation on these inflammatory markers have yet to be reported. Pharmacologic therapy has fared little better. Inhaled corticosteroids do not appear to modify the rate of decline of lung function, a surrogate of subsequent mortality, whereas endobronchial biopsy studies have found little effect of inhaled corticosteroids on inflammatory changes in the larger airways (10). In this issue of the Journal (pp. 760–765), new light (and doubtless, controversy) has been thrown on this field by Sin and colleagues (11). They studied 41 patients with moderate to severe COPD (mean FEV1 55% predicted), of whom two-thirds already received inhaled corticosteroids and 20% still smoked. Four weeks after discontinuation of inhaled corticosteroids in those using such treatment, all patients were randomized to receive placebo, fluticasone 500 µg twice daily, or 30 mg prednisone once daily for 2 weeks together with appropriate placebo tablets and inhalers. This was followed by open-label use of the inhaled corticosteroid for a further 8 weeks and then an increase of the fluticasone dose to 1,000 µg twice daily for a further 8 weeks. CRP, interleukin-6 (IL-6) and MCP-1, a proinflammatory chemokine, were measured at each visit. CRP increased significantly during the run-in period, although the absolute changes are not reported. This was due entirely to a 71% increase in CRP in the inhaled corticosteroid users. No data about IL-6 or MCP-1 are presented at this time-point. There were no significant differences in CRP at randomization between the different treatments, but in the next 2 weeks there was a 57% fall in the CRP value in those receiving inhaled corticosteroids and a 60% reduction in those taking oral corticosteroids compared with placebo. These changes were maintained during the follow-up period, although the use of a higher dose of inhaled corticosteroids merely increased the dropout rate substantially with only 17 patients completing the planned follow-up. Smaller but significant changes were seen in IL-6 and MCP-1. The changes in IL-6 and CRP were related in the patients taking inhaled corticosteroids but not in oral corticosteroid users. The authors postulate that changes in IL-6 are responsible for the reduction in systemic inflammation in patients receiving inhaled corticosteroids, where a lower total dose of corticosteroid was as effective as oral prednisone. There was no change in the group mean FEV1 with therapy, although this was not the primary endpoint of the study and postbronchodilator values are not reported. This study has a number of strengths, not least its blinded nature, the study of withdrawal and replacement of inhaled corticosteroids, the comparison with oral corticosteroids, and the extended follow-up period. It would have been better if the placebo limb had continued for longer than 4 weeks, although concerns about the risk of exacerbation without corticosteroids precluded this (12). The relative stability of the data in the inhaled corticosteroid-naive patients during the run-in phase of the study is encouraging and suggests that previous exacerbations which raise markers like fibrinogen acutely (13) were not influencing these results. It would be interesting to know whether there was any relationship between baseline spirometry or a simple index of systemic exposure to inhaled corticosteroid like the morning cortisol and these circulating markers of inflammation. Both these questions will need a larger study to give a proper answer. Hopefully this will determine whether lower doses of inhaled corticosteroids can be as effective as those reported here. Ultimately, we would all like to know whether any of this matters. That question will require the demonstration of a clinically important effect of inhaled corticosteroid treatment on hard endpoints like patient mortality. A large prospective randomized study of mortality in patients with severe COPD, the TORCH trial, is currently underway and includes a comparison of inhaled corticosteroid-treated and placebo-treated patients (14). Even before these findings are available in 2006, a meta-analysis of mortality experience in the previous placebo-controlled studies should be available. If these studies find that inhaled corticosteroids reduce all-cause and/or cardiovascular mortality, then data like those of Sin and colleagues may be the first indicators as to why this might occur. Whatever the outcome, the systemic effects of COPD have now been brought sharply into focus. Acknowledgments P.C. has received funding from GlaxoSmithKline (GSK) for consultancy services and an honorarium for speaking at conferences organized by GSK, AstraZeneca (AZ), and Boehringer Ingelheim, and has served on Advisory Boards for GSK and AZ. REFERENCES
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