Anti-Tumor Necrosis Factor-[alpha] in Asthma/From the Authors

To the Editor:

In their recent article on the effects of anti-tumor necrosis factor (TNF)-a in asthma, Erin and colleagues report that infliximab reduces the number of asthma exacerbations in symptomatic patients with moderate asthma who are taking inhaled corticosteroids (1). Although I recognize the need for new asthma treatment modalities, I have serious problems with the use of anti-TNF-a in this patient group as the drug can induce severe side effects.

The dose of inhaled corticosteroids used was not high (in placebo and infliximab groups, respectively, 605 and 753

Anti-TNF-a is now used for patients with severe and invalidating complaints of Crohn's disease or rheumatoid arthritis. Pulmonologists became familiar with this treatment when severe cases of tuberculosis were found in these patients. The incidence of anti-TNF-a induced tuberculosis can be as high as 224/100,000 treated patients. Manifestations are often extrapulmonary, and in 24% of the cases there is disseminated disease (3, 4) with a significant risk of death. Physicians are now more aware of this problem, and when mycobacterial infections are suspected anti-tuberculosis treatment is now advised. But there is still an increased risk as the protective effect of such treatment is estimated not to be higher than 60%.

Therefore, in my opinion, anti-TNF-a should be used with much care, and studies on the therapeutic value in asthma should be focused on patients with severe debilitating disease. In such cases, the effects of anti-TNF-a should be studied in addition to the best current modalities, which are high doses of inhaled corticosteroids in combination with a long-acting ß-agonist.

Conflict of Interest Statement: F.H.K. received $4,950 from various pharmaceutical companies (GlaxoSmithKline; AstraZeneca; Merck, Sharpe & Dohme) for giving lectures at meetings and courses.

FRANS H. KROUWELS

OLVG Hospital Amsterdam

Amsterdam, The Netherlands

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-a in asthma. Am J Respir Crit Care Med 2006;174:753-762.

2. National Institutes of Health; National Mean, Lung, and Blood Institute. Global Initiative for Asthma (GINA): global strategy for asthma management and prevention. Available from: www.ginasthma.com (updated 2005).

3. Keane J, Gershon SK, Braun MM. Tuberculosis and treatment with infliximab. N Engl J Med 2002;346:625-626.

4. British Thoracic Society Standards of Care Committee. BTS recommendation for assessing risk and for managing mycobacterium tuberculosis infection and disease in patients due to start anti-TNFa treatment. Thorax 2005;60:800-805.

From the Authors:

We are grateful to Dr. Krouwels for highlighting the significant risk of severe side effects that must be considered before employing therapy directed against TNF-a, and that the risk-benefit of this therapy becomes more favorable in patients with severe refractory asthma.

Our study was performed in a selected group of patients with asthma who remained symptomatic on moderate doses of inhaled corticosteroids and who were not treated with long-acting ß-agonists (LABAs) (1). These patients were judged to be sufficiently symptomatic and with enough impairment of lung function to have "room to move" for the assessment of a monoclonal antibody directed against TNF-a. We employed electronic monitoring of morning and evening lung function and symptoms, judging that these parameters may be sensitive to effects of a novel therapeutic in patients with asthma not taking twice-daily LABAs. However, we should stress that the patients we studied were not on optimal therapy as recommended by the GINA guidelines (2), and these patients should have been receiving combination therapy with inhaled corticosteroids and LABAs. Indeed, we stress in our discussion that, in the future, rather than study patients with asthma of the severity included in our study, there is the need to study therapy directed against TNF-a in patients with more severe asthma who are refractory to available current therapy.

The classification of exacerbations of asthma remains controversial, and the definition of exacerbations we employed in our study was based on that used in the FACET study, which defines "mild" and "severe" exacerbations of asthma (3). The FACET definitions of asthma severity relate to differences from baseline in that study, and in the FACET study, patients were stable at baseline. Since our patients were unstable at baseline, worsening of their condition was judged to cause "moderate" exacerbations, which were not of sufficient severity to justify hospitalization or oral corticosteroid therapy.

Dr. Krouwels is entirely correct to highlight the significant risk of reactivation of tuberculosis, which may be extrapulmonary, disseminated, and refractory to antituberculosis therapy (4, 5). Hence, it is mandatory to carefully assess the potential risks of tuberculosis in patients being considered for anti-TNF-a therapy, and we were careful to take extensive precautions in our published study. Nevertheless, such is the degree of impairment of quality of life and requirement for hospitalization in some patients with severe asthma, we still consider that meticulously designed studies of therapy against TNF-a remain warranted in severe refractory asthma.

Conflict of Interest Statement: E.M.E. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. O.M.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.J.B. has received research funding and has served on scientific advisory boards for GlaxoSmithKline, AstraZeneca, BoehringerIngelheim, Novartis, Altana, Pfizer, and Millennium. T.T.H. has received research grants in 2004 to May 2006 from GlaxoSmithKline ($250,000), Novartis ($500,000), and Oxagen ($360,000).

EDWARD M. ERIN

ONN MIN KON

PETER J. BARNES

TREVOR T. HANSEL

National Heart and Lung Institute

Royal Brompton Hospital

London, United Kingdom

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-a in asthma. Am J Respir Crit Care Med 2006;174:753-762.

2. National Institutes of Health; National Heart Lung and Blood Institute. Global Initiative for Asthma (GINA): global strategy for asthma management and prevention. Available from: www.ginasthma.com (updated 2005).

3. Pauwels RA, Lofdahl CG, Postma DS, Tattersfield AE, O'Byrne P, Barnes PJ, Ullman A, for the Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 1997;337:1405-1411.

4. Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, Siegel JN, Braun M. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001; 345:1098-1104.

5. British Thoracic Society. BTS recommendations for assessing risk and for managing Mycobacterium tuberculosis infection and disease in patients due to start anti-TNF-alpha treatment. Thorax 2005;60:800-805.