Study of Infliximab Treatment in Smokers with COPD: What Next?/From the Authors

To the Editor:

We read with great interest the recent Phase II trial of the chimeric mouse/human monoclonal anti-TNF-a antibody infliximab in patients with mild-to-moderate COPD by van der Vaart and colleagues (1). This study failed to reach any definite conclusions about the efficacy of infliximab in COPD. Given the broad effect of TNF-a on the induction and maintenance of airway inflammation in COPD (2) and the recent encouraging findings with anti-TNF-a drugs in chronic asthma (3), the lack of efficacy of infliximab on patients with COPD in the present study is rather disappointing.

These authors ascribed the observed lack in clinical response to a number of problems with the study design: (1) all participants were current smokers, and cigarette smoking appears to impair rate and duration of response to infliximab; (2) the degree of disease severity was not adequate to show a significant response; (3) it is possible that the dose was too low and the duration too short to measure significant changes; (4) duration of follow-up was too short to detect significant changes; (5) the small sample size did not have enough power to detect changes.

Perhaps there are some additional considerations that may explain the negative findings of this study. First, the occurrence of neutralizing antibodies is a common event with infliximab, and this is likely to compromise drug efficacy (4). Future studies with infliximab will require careful evaluation of neutralizing antibodies or the addition of weekly methotrexate since patients on this drug are less likely to develop an immunogenic response to infliximab. Second, given that TNF-a antagonists with lower immunogenicity, such as the soluble fusion protein etanercept, have proven to be remarkably effective in chronic severe asthma in two separate studies (5, 6), it would be very important to test etanercept in patients with COPD before reaching any definite conclusions about the value of TNF-a inhibition in COPD.

Finally, the inability of infliximab to modify clinical and inflammatory parameters in smokers with COPD is not surprising. It is well known that each and every one of the drugs used for treating COPD (bronchodilators, inhaled corticosteroids, and combinations of inhaled steroids and long-acting ß2 agonists) has limited effects. Although this disappointing trend may reflect the natural history of the disease, it is also likely to result from the deleterious effects of active smoking on the clinical and inflammatory parameters under scrutiny. Tobacco smoke contains a high concentration of oxidants, and oxidative stress is a significant contributor to the pathogenesis of COPD. The consequences of increased oxidative stress in the lung include increased transcription of inflammatory genes, protease activity, and mucus secretion. Therefore, ongoing oxidative stress is likely to contribute to inability of drugs to modify clinical and inflammatory parameters in patients with COPD who smoke, as was the case for those participating in the study of van der Vaart and coworkers (1). This interaction has been recently reported in asthma, where it has been shown that cigarette smoking markedly reduces the efficacy of inhaled corticosteroids (7). In future clinical trials, drugs for COPD should be tested only in patients who commit themselves to smoking cessation programs.

Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

CRISTINA RUSSO

FRANCESCA D'ANGELO

RICCARDO POLOSA

University of Catania

Catania, Italy

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