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We appreciate the comments by Russo and colleagues regarding our recent article (1). Our trial was designed as a pilot and safety study of infliximab in COPD, which explains the inclusion of patients with rather mild COPD, moderate dosing of infliximab, short duration of study, and small sample size. Russo and colleagues suggest some additional explanations for the negative findings.

First, they suggest that neutralizing antibodies (human antichimeric antibodies [HACAs]) may affect the efficacy of infliximab. Although we agree, it is clear that infliximab has impressive clinical efficacy in Crohn's disease and rheumatoid arthritis (RA). The true incidence of HACA formation in adult patients receiving infliximab is unknown. The large ACCENT1 trial in Crohn's disease and the ATTRACT trial in RA reported an overall incidence in 8–14% of patients during 1 yr of treatment. In contrast, Baert and coworkers (2) reported HACA formation in 68% of Crohn's patients who received infliximab "on-demand," i.e., 3.9 infusions (range 1–17) per patient administered over 10 mo on average. We do not know if the prevalence of HACA formation is similar in COPD. Furthermore, we used a short induction scheme including three infusions within 6 wk, which is not comparable with the aforementioned examples.

Second, etanercept might be more effective than infliximab. Indeed, etanercept has lower immunogenicity and has been suggested to be effective in chronic asthma (3). Because chronic asthma and COPD are different diseases (specific Th-2– mediated eosinophilic response to allergens versus nonspecific neutrophilic response to smoke), we are not convinced that etanercerpt's efficacy in asthma will predict efficacy in COPD. Nevertheless, it is of interest to test etanercept in COPD before reaching any definite conclusions about the clinical value of TNF- inhibition. The main reason for testing etanercerpt in our opinion is not its lower immunogenicity or efficacy in asthma, but its differences in pharmacokinetic and pharmacodynamic profile as compared with infliximab (4).

Third, current smoking might have negatively affected the clinical and antiinflammatory efficacy of infliximab. Reports on smoking in relation to response rates in Crohn's disease vary from adverse effects to no effect. In our study we intentionally included current smokers instead of exsmokers for several reasons:

• Most patients with COPD smoke and are unable to quit.
  
• Smoking patients with COPD have more respiratory symptoms than nonsmoking patients, worse bronchial hyperresponsiveness, and faster lung function decline. The need for effective treatment is higher in smokers.
  
• We wished to ensure increased TNF- levels (as far as possible). Indeed, cigarette smoke exposure has been shown to increase TNF- production in animal models (5).
  
• We reasoned that inclusion of current smokers would provide a more homogeneous group of patients, thereby enhancing the putative effects of TNF- blockade. Patients with COPD who quit smoking show an increase 1 yr later in some aspects of inflammation (6), which may fade away within a few years. Little is known about the time course and interindividual differences of this response.
  

Patients with COPD should always try to quit smoking. However, we also feel it is not ethical to exclude smoking patients with COPD from effective treatments, nor to exclude them from explorative research trials.

Nick ten Hacken, Hester van der Vaart, Gerard Koëter, Henk Kauffman and Dirkje Postma

University Medical Centre Groningen University of Groningen Groningen, The Netherlands

FOOTNOTES

Conflict of Interest Statement: N.T.H. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. H.v.d.V. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. G.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. H.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.P. received grants for research purposes from AstraZeneca, GlaxoSmithKline (GSK) (two multicenter studies), Altana, and Centocor in local single center research on asthma and COPD. She serves as a consultant for Altana. She has been reimbursed to attend international meetings by AstraZeneca, Altana, and GSK. Her institute has received an unrestricted educational grant from GSK.

REFERENCES

1. van der Vaart H, Koeter GH, Postma DS, Kauffman HF, ten Hacken NH. First study of infliximab treatment in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005;172:465–469.[Abstract/Free Full Text]
2. Baert F, Noman M, Vermeire S, Van Assche G, D'Haens G, Carbonez A, Rutgeerts P. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N Engl J Med 2003;348:601–608.[Abstract/Free Full Text]
3. Babu K, Arshad SH, Howarth PH, Chaunan AJ, Puddicombe S, Davies DE, Holgate ST. Soluble TNF-a receptor (Enbrel) as an effective therapeutic strategy in chronic severe asthma. J Allergy Clin Immunol 2003;111(Vol.2, Suppl):S277.
4. Jit M, Henderson B, Stevens M, Seymour RM. TNF-alpha neutralization in cytokine-driven diseases: a mathematical model to account for therapeutic success in rheumatoid arthritis but therapeutic failure in systemic inflammatory response syndrome. Rheumatology (Oxford) 2005;44: 323–331.
5. van der Vaart H, Postma DS, Timens W, ten Hacken NH. Acute effects of cigarette smoke on inflammation and oxidative stress: a review. Thorax 2004;59:713–721.[Abstract/Free Full Text]
6. Willemse BW, ten Hacken NH, Rutgers B, Lesman-Leegte IG, Timens W, Postma DS. Smoking cessation improves both direct and indirect airway hyperresponsiveness in COPD. Eur Respir J 2004;24:391–396.[Abstract/Free Full Text]

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