ATLANTA—In a rematch of one of the most popular pro/con debates from last year’s meeting of the American Thoracic Society (ATS), Romain A. Pauwels, MD, and Peter J. Barnes, MD, squared off again at this year’s ATS meeting to argue the merits of using inhaled corticosteroids to treat chronic obstructive pulmonary disease (COPD).[1]

“There is a large body of evidence demonstrating that inhaled corticosteroids provide substantial clinical and lung functional benefit when added to bronchodilator therapy in moderate to severe COPD,” stated Dr. Pauwels, a Professor of Medicine at the University of Ghent in Belgium. “There are even some data to suggest that inhaled corticosteroids decrease all-cause mortality in COPD,” he added.

Dr. Barnes, a Professor of Thoracic Medicine at the Imperial College in London, answered with a resounding no. He posited that inhaled corticosteroids are not effective in treating COPD because the disease results from a neutrophilic inflammation, which does not respond to corticosteroids. In contrast, asthma results from an eosinophilic response that can be alleviated with corticosteroids.

FEWER EXACERBATIONS, BETTER LUNG FUNCTION

Two major new clinical studies, still unpublished, showed that both inhaled fluticasone and budesonide reduce COPD exacerbations, Dr. Pauwels reported. In one study, inhaled fluticasone was compared to salmeterol, an inhaled fluticasone/salmeterol combination, and placebo. All agents were administered twice daily for one year.

Each study arm included more than 300 patients with poorly reversible COPD. These patients had a mean forced expiratory volume in one second (FEV1) of 44% of predicted, a history of chronic bronchitis, and a long smoking history. They had had at least one COPD exacerbation—a symptom increase requiring antibiotic or oral corticosteroid therapy—per year for the past three years.

“All three active treatments caused a reduction in the exacerbation rate,” reported Dr. Pauwels; the reductions were all statistically significant in comparison to results in the placebo group. Although the decline in COPD exacerbations was greatest with combination therapy, no significant difference between the active treatments was observed.

In the other study, budesonide was similarly evaluated; about 200 patients each received twice-daily inhaled budesonide, formoterol, inhaled budesonide/formoterol, or placebo. Treatment was given for nine months. These patients, like the subjects in the fluticasone trial, had poorly reversible COPD and an average FEV1 of 36% of predicted.

Only the two corticosteroid regimens were significantly more effective than placebo in reducing the rate of COPD exacerbations. Both were also significantly better than formoterol alone.

Inhaled corticosteroid therapy may also improve lung function in COPD patients, said Dr. Pauwels. For example, one year of the combination of inhaled fluticasone and salmeterol increased FEV1 to a much greater extent than did salmeterol alone. Similar findings have been obtained with inhaled budesonide in combination with formoterol.

Furthermore, inhaled corticosteroids have been associated with decreased use of reliever medication in patients with moderate to severe COPD, a finding typically regarded as a reflection of symptom improvement. Also, epidemiologic studies have suggested that corticosteroid use may lower the rates of all-cause mortality in COPD by about 30%. In addition, a Canadian study has reported that corticosteroid use diminished the risk of rehospitalization among patients with one COPD-related hospital stay, Dr. Pauwels said.

COPD IS STEROID RESISTANT

“Inhaled steroids are still not beneficial in COPD,” countered Dr. Barnes. The reason for the lack of benefit, he explained, is that the neutrophilic inflammation associated with COPD is resistant to corticosteroids in humans. “And, in fact, we know that steroids prolong neutrophil survival,” he added.

Dr. Barnes cited one study that showed that in COPD patients, inhaled corticosteroids fail to affect even inflammatory agents that they clearly should suppress, and indeed do inhibit in asthma patients. Among these agents are matrix metalloproteinase-9, neutrophil elastase, and interleukin 8 (IL-8).

In patients with COPD, particularly those who smoke, corticosteroid resistance appears to be related to a decline in the histone deacetylase activity necessary to “switch off” multiple inflammatory genes, Dr. Barnes said. The decline correlates with an increased inflammatory response by the alveolar macrophages, which step up production of tumor necrosis factor alpha.

NO DOSE RESPONSE

Clinical data do not support the efficacy of inhaled corticosteroids as treatment for COPD, either, said Dr. Barnes. Although many studies have shown a dose response to this treatment in asthma, no such response is apparent in COPD. “One reason why you do not see a dose response is because there is no response,” he asserted.

Statistically significant improvements in exacerbation rates and other markers of lung function have been observed in large studies of high-dose inhaled corticosteroid therapy for COPD, Dr. Barnes acknowledged. However, he described most of these results as clinically insignificant, especially when weighed against the high risk of bone mineral density loss and subsequent bone fractures among postmenopausal women given long-term inhaled corticosteroid therapy. (Postmenopausal women make up an increasing proportion of COPD patients.)

Dr. Barnes concluded that in COPD, inhaled corticosteroids have no significant effect on inflammation or disease progression and a clinically irrelevant effect on exacerbations, but they are associated with a high risk of adverse systemic effects. “Also, high doses of inhaled steroids over many years are expensive and therefore should not be routinely recommended,” he stressed.

He did concede, however, that Dr. Pauwels’ observation regarding the effectiveness of an inhaled corticosteroid/ß-agonist combination on COPD exacerbations is important. “This is very likely to be a class effect,” Dr. Barnes suggested, noting that the combinations of fluticasone and salmeterol and of budesonide and formoterol produced similar results.

Inhaled corticosteroids could somehow make ß-agonists more effective in COPD, he speculated (for example, by preserving the latter drug’s effect on neutrophilic inflammation). Or, ß-agonists may somehow unlock the corticosteroid resistance of COPD.

However, rather than debate the minutia of inhaled corticosteroid use in COPD, it makes more sense to develop better anti-inflammatory drugs for the disease, Dr. Barnes suggested. One such drug—theophylline—is already available, he pointed out. “If you use it in a low dose … it does have a significant effect on neutrophilic inflammation, IL-8, and neutrophil chemotaxis,” he said.

—Timothy Begany