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Study of Infliximab Treatment in Asthma

We read with great interest the recent article by Erin and colleagues (1) on a single-center, randomized, controlled trial of the chimeric mouse/human monoclonal anti–tumor necrosis factor (TNF)- antibody infliximab (Remicade) in patients with mild-to-moderate asthma. Although this study added to the literature in this area, it failed to reach any definite conclusions about the efficacy of infliximab in mild-to-moderate asthma. Change in morning PEF (primary endpoint), symptom scores, and use of rescue medication (salbutamol) were no different between groups. Nonetheless, treatment with infliximab resulted in a substantial decrease in the number of patients with asthma exacerbations. Given that the study was not powered to detect drug effects on exacerbations, this result could be due to a chance finding. We believe that changes to the study design might have produced a greater opportunity of showing clinical efficacy.

Morning PEF in the infliximab group appeared to show a trend toward improvement in the last couple of weeks, and it is a pity that the authors did not explore effects beyond the eighth week of observation. Also, the assumption that dosage and duration of infliximab known to be effective in rheumatoid arthritis would also work well in asthma may be incorrect. Hence, it is possible that greater doses of infliximab for a prolonged period of time may be required to assess the full potential of TNF- blockade in asthma. Some of these issues could have been settled in a dose escalation study (up to 10 mg/kg) of longer duration (up to 26–30 wk) similar to those performed in rheumatoid arthritis (2, 3).

Perhaps there are some additional considerations that may explain the essentially negative findings of this study. First, the total symptoms score showed a large improvement over placebo, potentially offsetting any benefit observed within the infliximab group; why patients on placebo manifested such substantial improvements is not clear. Second, the degree of disease severity in this patient group may not be adequate to show a significant response. Last, the occurrence of neutralizing antibodies against infliximab is a common event, and this may compromise drug efficacy (4, 5).

The observations of decreased levels of TNF- and interleukin (IL)-1 in sputum supernatants after infliximab are interesting. Perhaps it would have been possible for the authors to identify a group of responders on the basis of absolute values or changes in cytokine levels. Therapy with infliximab is expensive and knowing who is going to respond is of great importance. In addition, the inclusion of individual patient data would allow an estimate of the variability in response between subjects.

We acknowledge that the authors chose to study the effects of infliximab in patients with limited severity of their asthma because of safety concerns, but given the larger role of TNF- on airway inflammation in chronic severe asthma (6, 7), the lack of efficacy of infliximab in the present study is not unexpected. We agree with the authors' conclusion that large multicenter, placebo-controlled, randomized, controlled trials in patients with severe chronic asthma are required.

Christopher J. Edwards

Southampton General Hospital, Southampton, United Kingdom

Riccardo Polosa

Presidio Ospedaliero Ascoli-Tomaselli, Catania, Italy

FOOTNOTES

Conflict of Interest Statement: C.J.E. has attended advisory boards for Schering-Plough, Abbott, Roche, and Wyeth. The total honoraria for these was $5,000. He has also been sponsored to attend the American College of Rheumatology by Schering-Plough and Roche. R.P. has participated as a speaker for CV Therapeutics, Novartis, and Roche. The total honoraria for these was $5,000. He is also a consultant for CV Therapeutics.

REFERENCES

1. Erin EM, Leaker BR, Nicholson GC, Tan AJ, Green LM, Neighbour H, Zacharasiewicz AS, Turner J, Barnathan ES, Kon OM, et al. The effects of a monoclonal antibody directed against tumor necrosis factor- in asthma. Am J Respir Crit Care Med 2006;174:753–762.[Abstract/Free Full Text]
2. Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD, Antoni C, Leeb B, Elliott MJ, Woody JN, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998;41:1552–1563.[CrossRef][Medline]
3. Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, Smolen J, Emery P, Harriman G, Feldmann M, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 1999;354:1932–1939.[CrossRef][Medline]
4. 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]
5. van der Laken CJ, Voskuyl AE, Roos JC, Stigter van Walsum M, de Groot ER, Wolbink G, Dijkmans BA, Aarden LA. Imaging and serum analysis of immune complex formation of radiolabeled infliximab and anti-infliximab in responders and non-responders to therapy for rheumatoid arthritis. Ann Rheum Dis (In press)
6. Russo C, Polosa R. TNF- as a promising therapeutic target in chronic asthma: a lesson from rheumatoid arthritis. Clin Sci (Lond) 2005;109:135–142.[Medline]
7. Holgate ST, Polosa R. The mechanisms, diagnosis, and management of severe asthma in adults. Lancet 2006;368:780–793.[CrossRef][Medline]

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