Abstract
Systemic inflammation is present in chronic obstructive pulmonary disease (COPD), which has been linked to cardiovascular morbidity and mortality. We determined the effects of oral and inhaled corticosteroids on serum markers of inflammation in patients with stable COPD. We recruited 41 patients with mild to moderate COPD. After 4 weeks during which inhaled corticosteroids were discontinued, patients were assigned to fluticasone (500 mcg twice a day), oral prednisone (30 mg/day), or placebo over 2 weeks, followed by 8 weeks of fluticasone at 500 mcg twice a day and another 8 weeks at 1,000 mcg twice a day. Withdrawal of inhaled corticosteroids increased baseline C-reactive protein (CRP) levels by 71% (95% confidence interval [CI], 16–152%). Two weeks with inhaled fluticasone reduced CRP levels by 50% (95% CI, 9–73%); prednisone reduced it by 63% (95% CI, 29–81%). No significant changes were observed with the placebo. An additional 8 weeks of fluticasone were associated with CRP levels that were lower than those at baseline (a 29% reduction; 95% CI, 7–46%). Inhaled and oral corticosteroids are effective in reducing serum CRP levels in patients with COPD and suggest their potential use for improving cardiovascular outcomes in COPD.
Chronic obstructive pulmonary disease (COPD) is a worldwide epidemic, affecting nearly 600 million people worldwide (1) and accounting for over 2.2 million deaths every year (2). It is the only major worldwide disorder in which the morbidity and mortality are increasing. Although these figures are alarming, they most certainly underestimate the true health burdens of COPD, as airflow obstruction is an important contributor to other common causes of morbidity and mortality, including ischemic heart disease, arrhythmias, and strokes (3–5). The potential link between COPD and cardiovascular events has large clinical relevance because ischemic heart disease is the leading cause of mortality and hospitalization among patients with mild to moderate COPD (6). Large population-based studies suggest that patients with COPD are two to three times more at risk for cardiovascular mortality, which accounts for a large proportion of the total number of deaths (3, 5–8). Although not generally recognized, poor lung function has been shown to be as powerful a predictor of cardiac mortality as established risk factors such as total serum cholesterol (5). For every 10% decrease in FEV1, cardiovascular mortality increases by approximately 28%, and nonfatal coronary event increases by approximately 20% in mild to moderate COPD (9).
How COPD increases the risk of poor cardiovascular outcomes is largely unknown. However, there is growing evidence that persistent low-grade systemic inflammation is present in COPD and that this may contribute to the pathogenesis of atherosclerosis and cardiovascular disease among patients with COPD (4). Inflammation, more specifically C-reactive protein (CRP), has been linked with all stages of atherosclerosis, including plaque genesis, rupture, and subsequent thrombofibrosis of vulnerable vessels (10, 11). Circulating levels of CRP, which has been strongly linked to poor cardiovascular outcomes in the general population (11), have been demonstrated to be elevated in COPD (4). Moreover, an elevated level of CRP has been associated with myocardial injury in COPD (4). A reduction in the level of CRP, on the other hand, has been shown to be associated with improved outcomes in other populations (12, 13). Systemic inflammation and/or its markers may, therefore, provide new therapeutic targets for COPD management.
Corticosteroids can reduce CRP and other circulating inflammatory cytokine levels in acute proinflammatory states (14, 15). They can also downregulate certain (16–18) but not all (19) inflammatory cells and cytokine expression in the airways of patients with COPD and attenuate airway hyperresponsiveness related to COPD (20). Whether they can reduce circulating CRP levels or cytokines that regulate CRP expression such as interleukin (IL)-6 or monocyte chemoattractant protein-1 (MCP-1) in stable COPD is unknown. To better understand the effects of inhaled (or oral) corticosteroids on CRP and other markers of systemic inflammation, we conducted a randomized, placebo-controlled, double-blind study in patients with mild to moderate COPD.
We recruited 43 patients (aged 45 to 80 years), who had stable symptoms of COPD in the previous 3 months before study entry. All patients had an FEV1 after bronchodilation with 400 μg salbutamol that was 25 to 90% of predicted, a change of less than 20% of predicted FEV1, 30 minutes after bronchodilation, and an FEV1/FVC of less than 75%. Patients also had a history of at least 10 pack-years of smoking or prolonged exposure (> 10 years) to noxious gases (e.g., diesel fumes) (1).
At the first visit, patients who were taking inhaled corticosteroids were asked to immediately discontinue the use of these medications. They were allowed to take other anti-COPD medications. None of the patients took theophyllines at the time of study entry, and no new medications were commenced between the first and second visits. The patients returned 4 weeks later for a second visit, at which point they were randomized into one of the three arms of the trial: placebo capsules and a placebo puffer, fluticasone (500 mcg twice daily) and placebo capsules, or prednisone (30 mg once daily) and a placebo puffer. The trial period lasted 2 weeks. Patients were then assigned to fluticasone (500 mcg twice daily) for 8 weeks in an unblinded fashion, followed by an additional 8 weeks of fluticasone at 1,000 mcg twice daily. At each visit, we measured the participants' serum CRP level using nephelometry in accordance with recommendations from Centers for Disease Control and Prevention and the American Heart Association (21). We also measured serum concentrations of IL-6 and MCP-1. IL-6 was measured because it is a powerful signaling cytokine for CRP expression by the liver and is a known independent risk factor for cardiovascular events (22, 23). MCP-1 was measured because it may play a central role in the pathogenesis of COPD (24) and by itself is a known risk factor for atherosclerosis, myocardial infarction, and cardiac deaths (25). All samples were analyzed in duplicate.
For analytic purposes, continuous variables that were not normally distributed (including CRP values) were log transformed to achieve normality. We used a paired t test to compare the log-transformed CRP values between Visit 2 (i.e., at the time of randomization) and Visit 3 (at the end of the randomized trial phase) within each treatment group. Similarly, using Visit 2 as the referent CRP value, we used paired t tests to compare log-transformed CRP values across the visits. To assess whether there was a gradient in the log-transformed CRP values between placebo, fluticasone, and prednisone groups, we also used a Mantel-Haenszel test for trend. We reasoned a priori that oral prednisone, a more potent systemic corticosteroid than inhaled fluticasone, would have the largest effect on CRP, followed by fluticasone. Linear regression was used to examine the association between changes in IL-6 and log-transformed CRP values between Visit 1 and Visit 2 and between Visit 2 and Visit 3. Continuous variables are expressed as mean ± SD unless otherwise specified.
We enrolled 43 patients. However, two patients dropped out after Visit 1 (“no shows” at Visit 2). The final analysis was based on data from 41 study patients. The average age was 64 ± 9 years, and 71% (n = 29) were men. The average FEV1 was 1.68 ± 0.67 L (55 ± 18% of predicted). FVC was 3.13 ± 1.12 L (83 ± 20% of predicted), and FEV1/FVC was 52 ± 12%. Of the total, 20% (n = 8) were current smokers, and 64% (n = 27) were on an inhaled corticosteroid at Visit 1. Patients who were taking inhaled corticosteroids at the time of enrollment had worse baseline FEV1 compared with those not taking inhaled corticosteroids at the time of enrollment (50.1 ± 18.2% of predicted vs. 63.6 ± 15.7% of predicted; p = 0.019). The baseline characteristics of the study patients divided according to treatment assignment are summarized in Table 1
Placebo | Fluticasone | Prednisone | |
|---|---|---|---|
| Number of patients | 12 | 15 | 14 |
| Age, yr | 63.5 ± 5.8 | 62.3 ± 10.5 | 65.6 ± 8.6 |
| Male, % | 6 (50) | 13 (87) | 10 (71) |
| FEV1, L | 1.79 ± 0.76 | 1.83 ± 0.75 | 1.40 ± 0.53 |
| FEV1 predicted, % | 61 ± 17 | 56 ± 20 | 47 ± 16 |
| FVC, L | 3.06 ± 1.36 | 3.33 ± 1.05 | 3.01 ± 1.01 |
| FVC predicted, L | 90 ± 20 | 81 ± 19 | 78 ± 21 |
| FEV1/FVC | 53 ± 11 | 56 ± 11 | 48 ± 12 |
| BMI, kg/m2 | 27.6 ± 6.4 | 32.7 ± 6.8 | 31.9 ± 7.8 |
| Current smokers, % | 3 (25) | 2 (13) | 3 (21) |
| Taking inhaled steroids at enrollment, % | 8 (67) | 8 (54) | 11 (79) |
| Short-acting β2 agonists | 12 (100) | 15 (100) | 14 (100) |
| Ipratropium bromide | 3 (25) | 5 (33) | 5 (36) |
| Long-acting β2 agonists | 6 (50) | 6 (40) | 9 (64) |
| Hemoglobin, g/L | 148.7 ± 10.9 | 148.0 ± 12.4 | 146.1 ± 16.3 |
| WBC, × 103/μl | 6.86 ± 2.02 | 7.75 ± 2.23 | 6.92 ± 1.18 |
| Platelets, × 103/μl | 269.9 ± 56.4 | 227.1 ± 49.7 | 246.2 ± 31.7 |
CRP values increased by 24.8% (95% confidence interval [CI], 1.7–44.4%) from Visit 1 to Visit 2 (Figure 1)
Figure 1. Changes in C-reactive protein (CRP) levels across the study period. The circles represent changes in CRP values from Visit 2 (i.e., time of randomization) in those assigned to placebo. The squares represent changes in CRP values from Visit 2 in those assigned to fluticasone. The diamonds represent changes in CRP values from Visit 2 in those assigned to prednisone. The triangles represent changes in CRP values from Visit 1 to Visit 2. The hexagon represents changes in CRP from Visit 2. *p < 0.05 compared with Visit 2 values. FP = fluticasone propionate; ICS = inhaled corticosteroid; RCT = randomized controlled trial.
[More] [Minimize]At the time of randomization (Visit 2), the serum CRP and cytokine levels that we measured were similar across the three groups (Table 2)
Cytokines | Placebo | Fluticasone | Prednisone |
|---|---|---|---|
| CRP, mg/L, log transformed | 1.19 ± 1.31 | 1.48 ± 1.47 | 2.02 ± 0.76 |
| MCP-1, pg/ml, log transformed | 5.78 ± 0.34 | 6.13 ± 0.82 | 6.02 ± 0.32 |
| IL-6, pg/ml, log transformed | 0.68 ± 0.82 | 1.00 ± 0.88 | 1.15 ± 0.68 |
% Change from Visit 2 to Visit 3 (Unless Otherwise Indicated) | |||||||
|---|---|---|---|---|---|---|---|
| Placebo | Fluticasone | Prednisone | p for Trend* | ||||
| CRP, % | −7.6 (−36.6 to 34.8) | −50.3 (−72.9 to −9.0)† | −62.9 (−80.7 to −28.7)† | 0.039 | |||
| MCP-1, % | 0.3 (−6.6 to 7.7) | −6.1 (−12.2 to 0.4) | −10.5 (−26.6 to 9.2) | 0.534 | |||
| IL-6, % | 5.0 (−31.6 to 61.0) | −26.1 (−43.6 to −3.2)† | 14.2 (−17.3 to 57.5) | 0.599 | |||
| FEV1, % | 2.1 (−3.3, 7.8) | 0.3 (−7.9, 9.1) | 5.2 (−2.4, 13.3) | 0.583 | |||
During the open-labeled phase of the study (fluticasone 500 μg twice daily), Visit 4, the CRP values were significantly lower than those obtained during Visit 2 when all participants were off inhaled corticosteroids for at least 4 weeks (n = 38; −29.1%; 95% CI, −46.2 to −6.7%). Visit 5 values (on fluticasone of 1,000 μg twice daily) were also significantly lower than those for Visit 2 (−32.3%; 95% CI, −50.0 to −8.3%). However, only 17 patients were able to complete this phase; some dropped out because of development of oral thrush and dysphonia while on very high doses of fluticasone.
Other inflammatory cytokines also changed with fluticasone and prednisone therapy, but less dramatically so (Table 3). Combined, corticosteroids reduced circulating MCP-1 by 8.2% (95% CI, −1.5 to 17.0%) from Visit 2 to Visit 3. In contrast, placebo had no effect on MCP-1 (95% CI, 0.3%; −6.6 to 7.7%). Inhaled corticosteroids significantly reduced IL-6 by 26% (95% CI, 3.2–43.6%; p = 0.045). Placebo had no effect on IL-6 levels (5.0% increase; 95% CI, −31.6 to 61.0%).
IL-6 values were significantly correlated with CRP values at each visit. For Visit 1, the correlation coefficient was 0.498 (r2 = 24.8%, p = 0.001). For Visit 2, the correlation coefficient was 0.682 (r2 = 46.5%, p < 0.001). For Visit 3, it was 0.440 (r2 = 19.3%, p = 0.005). For Visit 4, it was 0.514 (r2 = 26.4%, p = 0.001). Finally, for Visit 5, it was 0.673 (r2 = 45.2%, p = 0.001). More importantly, between Visit 1 and Visit 2, a 1-pg/ml increase in IL-6 was associated with a 28.3% (95% CI, 18.9–38.5%) increase in CRP (Figure 2)
Figure 2. The relationship between changes in interleukin (IL)-6 and CRP levels from Visit 1 to Visit 2. CRP values are plotted on a logarithmic scale to achieve best fit. The r2 value for the fitted line is 53.4% (p < 0.001).
[More] [Minimize]Prebronchodilator FEV1 values did not change significantly across the visits (Table 3). However, this study was underpowered to detect subtle but potentially important changes in FEV1 across the treatment categories and over time.
Patients with COPD are at an increased risk of cardiovascular complications, including ischemic heart disease, strokes, and sudden deaths (3–5, 7, 8). Indeed, cardiovascular diseases are the leading causes of mortality among patients with COPD (7, 8). Interestingly, serum levels of CRP, a known risk factor for atherosclerosis and plaque rupture, are also elevated in COPD (4). This raises the possibility that persistent, low-grade inflammation related to COPD may be responsible, at least in part, for the previously mentioned relationship. Moreover, systemic inflammation has been implicated in the pathogenesis of cachexia, muscle wasting, and generalized debility of patients with COPD (26).
The primary aim of this study was to prove the concept that systemic inflammation in COPD could be reduced by either oral or inhaled corticosteroids. We found that the withdrawal of inhaled corticosteroids for 4 weeks was associated with a 70% increase in serum CRP levels, whereas in the subjects who were corticosteroid naive, the CRP levels did not materially change during this same time period. Importantly, the institution of fluticasone (1 mg/day) reduced CRP levels by 50%, whereas prednisone therapy (30 mg/day) reduced CRP levels by 62%. The reductions in CRP levels achieved by either oral or inhaled corticosteroids were sustained during the 4 months of fluticasone therapy. On the other hand, FEV1 did not materially change with fluticasone therapy.
Our finding that therapy with inhaled or oral corticosteroids can repress CRP levels by approximately 50% to 60% below the baseline levels among a well characterized group of patients with COPD is likely to have clinical relevance. In addition to being an excellent prognostic marker of vascular morbidity and mortality, CRP may have direct effects on the pathogenesis of atherosclerosis and endothelial dysfunction (27). For example, CRP downregulates endothelial nitric oxide synthase activity, leading to decreased production of nitric oxide (28). CRP also stimulates IL-6 and endothelin-1 production and upregulates adhesion molecules, promoting a cascade of events that can lead to clot formation (29, 30). Interventions to attenuate systemic inflammation and, more specifically, CRP levels may improve health and/or cardiovascular outcomes of patients with COPD. The powerful effects on CRP may explain how prednisone may reduce rates of restenosis in coronary vasculature by approximately 70% among those with established coronary syndromes (15).
Oral corticosteroids have a potent antiinflammatory action, although it is not certain how they can specifically reduce serum CRP levels. How inhaled corticosteroids can modify serum CRP levels, in the absence of discernible effects on FEV1, is even more of a mystery. The exclusive source of circulating CRP is the liver (31). Therefore, superficially, it would appear to make little sense that aerosol therapy, which deposits mostly in the respiratory tract, could repress serum levels of CRP. We hypothesize, however, that inhaled corticosteroids may affect CRP production indirectly by downregulating the expression of certain cytokines, which have an important regulatory role in CRP production. IL-6 may be such a molecule (32). Previous studies indicate that IL-6, once known as hepatocyte-stimulating factor, is a major signaling cytokine for CRP expression by hepatocytes and is known for its ability to stimulate the production of other acute-phase proteins (32). IL-6 is produced by a variety of cells, including T lymphocytes, macrophages, B cells, fibroblasts, endothelial cells, and airway epithelial cells. In COPD, IL-6 expression in the airways is increased (32). Importantly, persistent therapy with inhaled corticosteroids attenuates IL-6 expression in patients with COPD (33). It is plausible that, in our group of patients, fluticasone downregulated IL-6 production in the airways, which then reduced CRP expression by the liver. Alternatively, fluticasone could have been absorbed systemically and may have directly affected the hepatocytes. In those with asthma, the systemic bioavailability of fluticasone among those with moderate lung function impairment is less than 10% (34). If this is also true in COPD, direct absorptive effect of fluticasone on CRP would be less likely. Among those who were treated with oral corticosteroids, a significant reduction in CRP levels occurred in the absence of significant changes in IL-6 levels. It is possible that systemic corticosteroids may have had a suppressant effect on CRP through pathways that were independent of IL-6. It is also possible that the powerful actions of systemic corticosteroids could have altered the production and/or metabolism of IL-6 or other cytokines, influencing the expression or regulation of IL-6.
Although the causal relationship is not firmly established, patients with elevated IL-6 levels in the airways have been shown to be more susceptible to frequent clinical exacerbations compared with those with reduced levels (35). During exacerbations, both IL-6 and serum CRP levels increase sharply, and these changes are associated with reduced health status and increased symptoms (36). Frequent exacerbations, in turn, decrease the health status of patients with COPD (37). Our findings may provide a plausible mechanism for the reductions in clinically relevant exacerbations and health improvements associated with inhaled corticosteroids, which have been observed in the absence of material changes in the rate of descent of FEV1 (38). They also suggest a potential usefulness of these medications in altering long-term mortality in COPD, although such a hypothesis requires testing through a large multicenter clinical trial.
There are several limitations to this study. First, we did not measure many other inflammatory cytokines that may have important mechanistic and prognostic roles in COPD. We had limited serum samples, and as such, we decided a priori to evaluate CRP, IL-6, and MCP-1 because of their potential role in the pathogenesis of cardiovascular diseases, which are a major source of morbidity and mortality in COPD. Second, because of a high dropout rate among those on 2 mg/day of fluticasone, we could not adequately determine whether very high doses of fluticasone could achieve further reductions in CRP above and beyond that achieved with 1 mg/day. Finally, we did not determine whether similar reductions in circulating CRP could be achieved using a lower dose of fluticasone (e.g., 500 mcg/day) than the dose we used for this study. Therefore, the dose–response relationship of fluticasone and CRP remains unknown.
In summary, we found that withdrawal of inhaled corticosteroids led to an increase in serum CRP, whereas reintroduction of inhaled corticosteroids resulted in a significant reduction in CRP levels. Prednisone also reduced CRP levels. The reductions in CRP were largely sustained over a 4-month period with inhaled fluticasone. These data suggest that inhaled corticosteroids can reduce systemic inflammation and raise the possibility that they could have salutary effects on cardiovascular morbidity and mortality in COPD. Long-term, large-scale, multicenter studies are needed in the future to determine whether inhaled corticosteroids can indeed modify cardiovascular and all-cause mortality of COPD.
The authors thank Mrs. Jennifer Lee and Marian Langevin for their assistance in obtaining and processing blood samples from the study participants.
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