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Unexpected Failure of Anti–Tumor Necrosis Factor Therapy in Chronic Obstructive Pulmonary Disease

National Heart and Lung Institute, Imperial College, London, United Kingdom

New treatments for chronic obstructive pulmonary disease (COPD) are urgently needed, as none of the current therapies have been shown to reduce the relentless progression of the disease and are poor at preventing exacerbations (1). Tumor necrosis factor- (TNF-) is a proinflammatory cytokine that would appear to be a good target for inhibition in COPD, especially as anti-TNF therapies have proved to be so effective in rheumatoid arthritis and inflammatory bowel disease, which have many similar inflammatory features to COPD (2). TNF- concentrations are increased in the sputum of patients with COPD (3), particularly during acute exacerbations (4). Several studies have also demonstrated that TNF- concentrations are raised in the plasma of patients with COPD, presumably due to an overspill from the inflamed lung. An increase in systemic TNF- has been implicated in the cachexia and skeletal muscle wasting found in some patients, particularly those with more severe disease, as TNF- induces apoptosis of skeletal muscle cells through activation of the transcription factor nuclear factor-B (NF-B) (5). However, a recent large study showed no elevation of plasma concentrations of TNF- even in patients with cachexia, although there was an increase in the p75 or Type II soluble TNF receptor (6). The clinical findings in patients with COPD have been supported by experimental studies in mice exposed to chronic cigarette smoke, in which lung emphysema and inflammation are markedly reduced in animals with TNF-receptor knock-out (7) and in mice with pulmonary overexpression of TNF- (which results in emphysema), high plasma TNF- concentrations, and skeletal muscle wasting (8). Taken together, a strong case can be made for inhibiting TNF- production or its effects in patients with COPD.

The first report of a specific anti–TNF- strategy in patients with COPD, using the chimeric monoclonal antibody infliximab (Remicade), was entirely negative in terms of any improvement in symptoms, lung function, or in reducing inflammation in induced sputum (9). However, this negative study included only 14 patients in the active treatment group. In the present issue of the Journal, Rennard and colleagues (pp. 926–934) report a much larger placebo-controlled trial of infliximab in over 200 patients with COPD (157 of whom received active therapy) followed for 6 mo, with essentially similar results (10). There were no improvements in symptom score (the primary outcome variable) or any of the secondary endpoints, including lung function, exercise capacity, dyspnea score, health status, and acute exacerbations. The doses of infliximab are similar to those that have been effective in other inflammatory diseases and presumably were sufficient to neutralize endogenous TNF- in the lungs of patients with COPD. It is possible that a systemically administered antibody may not neutralize TNF within the alveolar space and airway lumen, but treatment with infliximab and the TNF receptor antagonist etanercept appear to have clinical effects in patients with asthma, with whom similar access issues would arise (11, 12). The failure of anti-TNF therapy is more likely a result of the fact that COPD is a highly complex inflammatory disease in which many other cytokines and mediators are involved, and that blocking a single cytokine does not have any effect, as other cytokines such as interleukin(IL)-1 and IL-6 may play a similar role (13). The success of anti–TNF- therapy in rheumatoid arthritis and inflammatory bowel disease may reflect a more central role for TNF in these diseases.

The failure of anti-TNF therapy raises questions about the potential for other antiinflammatory approaches, such as inhibition of phosphodiesterase-4, NF-B, and p38 MAP kinase, since inhibition of TNF- synthesis is one of the most prominent effects of such interventions (1). These approaches are more likely to be successful in that they inhibit the expression of many other inflammatory genes in addition to TNF-, including proinflammatory cytokines and chemokines. The failure of anti-TNF in patients with COPD also questions the value of animal models in predicting useful therapies, since inhibiting TNF- has a marked inhibitory effect on experimental emphysema and inflammation induced by cigarette smoke.

The patients selected for these studies have severe or very severe disease, but it is possible that TNF- and innate immunity play a critical role in the early stages of the disease, with other mechanisms involving acquired immunity taking over as the disease progresses. Thus anti-TNF strategies may be more effective in patients with less severe COPD, but even if effective in such patients it would be difficult to justify expensive biological treatments in early disease. A post hoc analysis revealed a small improvement in exercise capacity in patients who were defined as cachectic, but these analyses were not predefined and are therefore of doubtful significance. However, this may indicate that anti-TNF therapy could be more useful in patients with cachexia and muscle wasting and with other systemic manifestation and comorbidities (14). A new large clinical trial in patients with COPD selected for these systemic features would be required to test this hypothesis.

There are safety issues in using anti-TNF therapy chronically. An important concern is reactivation of tuberculosis (15), and this study excluded any patients with evidence of previous tuberculosis. TNF- is also involved in immune defense against other infections, and it has always been a potential problem that infections may be increased in patients with COPD in whom the lower respiratory tract may be colonized with bacteria. It is worrying that there was a numerical increase in clinically diagnosed pneumonia in the patients on anti-TNF therapy, although this did not achieve statistical significance. Of greater concern is the increase in diagnosed malignancies in view of the anti-tumor action of TNF-, with 10 in the anti-TNF–treated groups compared with only 1 in the placebo group, although these changes were not significant. Most of the cancers involved the respiratory tract, and it is possible that anti-TNF accelerated the growth of preexisting cancers in a smoking population already at high risk. Anti-TNF has previously been linked to increased malignancies in patients with rheumatoid arthritis (16), and therefore careful screening is required in smokers with COPD who already have an increased lung cancer and other malignancies.

What should be done now? It is possible that the treatment period of 6 months is too short to see clinically measurable improvement and it is difficult to detect any effect on exacerbations or disease progression over this short period. However, the resoundingly negative results of this trial make it unlikely that a longer trial would ever be undertaken, particularly in view of the safety concerns that have been raised. It is unlikely that any different results would be obtained with a different anti-TNF approach using etanercept, as the effects of blocking antibodies and soluble receptors are usually similar in terms of clinical efficacy in other inflammatory diseases. Perhaps a study could be justified in more selected patients who have increased systemic TNF- concentrations, and who have cachexia and muscle weakness, as these patients may have a poor prognosis and are largely refractory to current therapies.

FOOTNOTES

Conflict of Interest Statement: P.B. has received research funding ($1,500,000 from GlaxoSmithKline [GSK] per annum 2003–2006, $500,000 from AstraZeneca over 2003–2006, $50,000 from Boehringer Ingelheim over 2003–2006, $100,000 from Novartis over 2004–2006, $50,000 from Scios over 2003–2005), lecture fees ($10,000 from GSK per annum 2003–2006, $10,000 from AstraZeneca per annum 2003–2006, $10,000 from Boehringer Ingelheim per annum 2003–2006), and has served on Scientific Advisory Boards ($5,000 from GSK per annum 2003–2006, $4,000 from Boehringer Ingelheim per annum 2003–2006, $5,000 from Altana per annum 2003–2006, $2,000 Pfizer per annum 2003–2006). All of these commercial entities have an interest in new therapies for COPD.

REFERENCES

1. Barnes PJ, Hansel TT. Prospects for new drugs for chronic obstructive pulmonary disease. Lancet 2004;364:985–996.[CrossRef][Medline]
2. Feldmann M, Brennan FM, Foxwell BM, Taylor PC, Williams RO, Maini RN. Anti-TNF therapy: where have we got to in 2005? J Autoimmun 2005;25:26–28. [Epub 2005 Nov 2.][CrossRef][Medline]
3. Keatings VM, Collins PD, Scott DM, Barnes PJ. Differences in interleukin-8 and tumor necrosis factor- in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med 1996;153:530–534.[Abstract]
4. Aaron SD, Angel JB, Lunau M, Wright K, Fex C, Le Saux N, Dales RE. Granulocyte inflammatory markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001;163:349–355.[Abstract/Free Full Text]
5. Stewart CE, Newcomb PV, Holly JM. Multifaceted roles of TNF- in myoblast destruction: a multitude of signal transduction pathways. J Cell Physiol 2004;198:237–247.[CrossRef][Medline]
6. Broekhuizen R, Grimble RF, Howell WM, Shale DJ, Creutzberg EC, Wouters EF, Schols AM. Pulmonary cachexia, systemic inflammatory profile, and the interleukin 1 -511 single nucleotide polymorphism. Am J Clin Nutr 2005;82:1059–1064.[Abstract/Free Full Text]
7. Churg A, Wang RD, Tai H, Wang X, Xie C, Wright JL. Tumor necrosis factor- drives 70% of cigarette smoke-induced emphysema in the mouse. Am J Respir Crit Care Med 2004;170:492–498.[Abstract/Free Full Text]
8. Langen RC, Schols AM, Kelders MC, van der Velden JL, Wouters EF, Janssen-Heininger YM. Muscle wasting and impaired muscle regeneration in a murine model of chronic pulmonary inflammation. Am J Respir Cell Mol Biol 2006;35:689–696.[Abstract/Free Full Text]
9. van der Vart 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]
10. Rennard SI, Fogarty C, Kelsen S, Long W, Ramsdell J, Allison J, Mahler D, Saadeh C, Siler T, Snell P, et al. The safety and efficacy of infliximab in moderate to severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007;175:926–934.
11. Berry MA, Hargadon B, Shelley M, Parker D, Shaw DE, Green RH, Bradding P, Brightling CE, Wardlaw AJ, Pavord ID. Evidence of a role of tumor necrosis factor in refractory asthma. N Engl J Med 2006;354:697–708.[Abstract/Free Full Text]
12. 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 tumour necrosis factor- in asthma. Am J Respir Crit Care Med. 2006;174:753–762.[Abstract/Free Full Text]
13. Barnes PJ. Mediators of chronic obstructive pulmonary disease. Pharmacol Rev 2004;56:515–548.[Abstract/Free Full Text]
14. Sevenoaks MJ, Stockley RA. Chronic obstructive pulmonary disease, inflammation and co-morbidity: a common inflammatory phenotype? Respir Res 2006;7:70.[CrossRef][Medline]
15. Winthrop KL. Risk and prevention of tuberculosis and other serious opportunistic infections associated with the inhibition of tumor necrosis factor. Nat Clin Pract Rheumatol 2006;2:602–610.[CrossRef][Medline]
16. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006;295:2275–2285.[Abstract/Free Full Text]

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