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Published ahead of print on February 8, 2007, doi:10.1164/rccm.200607-995OC
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American Journal of Respiratory and Critical Care Medicine Vol 175. pp. 926-934, (2007)
© 2007 American Thoracic Society
doi: 10.1164/rccm.200607-995OC

Original Article

The Safety and Efficacy of Infliximab in Moderate to Severe Chronic Obstructive Pulmonary Disease

Stephen I. Rennard1, Charles Fogarty2, Steven Kelsen3, William Long4, Joe Ramsdell5, James Allison6, Donald Mahler7, Constantine Saadeh8, Thomas Siler9, Phillip Snell10, Phillip Korenblat11, William Smith12, Mitchell Kaye13, Michael Mandel14, Charles Andrews15, Rachakonda Prabhu16, James F. Donohue17, Rosemary Watt18, Kim Hung Lo18, Rozsa Schlenker-Herceg18, Elliot S. Barnathan18 and John Murray19 on behalf of the COPD Investigators

1 University of Nebraska Medical Center, Omaha, Nebraska; 2 Spartanburg Pharmaceutical Research, Spartanburg, South Carolina; 3 Temple University Medical Center, Philadelphia, Pennsylvania; 4 Neem Research Group, Charlotte, North Carolina; 5 University of California, San Diego, Clinical Trials Center, San Diego, California; 6 Neem Research Group, Columbia, South Carolina; 7 Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; 8 Amarillo Center for Clinical Research, Ltd., Amarillo, Texas; 9 Midwest Chest Consultants, P.C., St. Charles, Missouri; 10 Mountain View Clinical Research, Inc., Greer, South Carolina; 11 The Clinical Research Center, LLC, St. Louis, Missouri; 12 New Orleans Center for Clinical Research, New Orleans, Louisiana; 13 Minnesota Lung Center, Minneapolis, Minnesota; 14 Pulmonary Research Associates, LLC, Larchmont, New York; 15 Lung Diagnostics, Ltd., San Antonio, Texas; 16 Red Rock Research Center, Las Vegas, Nevada; 17 University of North Carolina, Chapel Hill, North Carolina; 18 Centocor Research and Development, Inc., Malvern, Pennsylvania; and 19 Vanderbilt University Medical Center, Nashville, Tennessee

Correspondence and requests for reprints should be addressed to Stephen I. Rennard, M.D., University of Nebraska Medical Center, 985125 Nebraska Medical Center, Omaha, NE 68198. E-mail: srennard{at}unmc.edu


   ABSTRACT
TOP
 ABSTRACT
AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Rationale: Chronic obstructive pulmonary disease (COPD) is a progressive, smoking-related, inflammatory lung disease in which tumor necrosis factor-{alpha} is overexpressed and has been suggested to play a pathogenic role.

Objectives: To determine if infliximab, an anti–TNF-{alpha} antibody, results in clinical benefit and has an acceptable safety profile in patients with moderate to severe COPD.

Methods: In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study, subjects with moderate to severe COPD received infliximab (3 mg/kg [n = 78] or 5 mg/kg [n = 79]) or placebo (n = 77) at Weeks 0, 2, 6, 12, 18, and 24. Efficacy, health status, and safety were assessed through Week 44.

Measurements and Main Results: Infliximab was generally well tolerated, but showed no treatment benefit as measured by the primary endpoint, Chronic Respiratory Questionnaire total score. Similarly, there was no change in secondary measures, including prebronchodilator FEV1, 6-min walk distance, SF-36 physical score, transition dyspnea index, or moderate-to-severe COPD exacerbations. Post hoc analysis revealed that subjects who were younger or cachectic showed improvement in the 6-min walk distance. Malignancies were diagnosed during the study in 9 of 157 infliximab-treated subjects versus 1 of 77 placebo-treated subjects. No opportunistic infections were observed, and there were no differences in the occurrence of antibiotic-requiring infections, although the incidence of pneumonia was higher in infliximab-treated subjects. No infection-related mortality was observed. Higher proportions of infliximab-treated subjects discontinued the study agent due to adverse events (20–27%) than did placebo-treated subjects (9%).

Conclusions: Subjects with moderate to severe COPD did not benefit from treatment with infliximab. Although not statistically significant, more cases of cancer and pneumonia were observed in the infliximab-treated subjects. The impact of infliximab on malignancy risk in patients with COPD needs to be further elucidated.

Key Words: chronic obstructive pulmonary disease • infliximab • tumor necrosis factor-{alpha}



   AT A GLANCE COMMENTARY
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Scientific Knowledge on the Subject
Tumor necrosis factor (TNF)-{alpha} has been suggested to play a pathophysiologic role in chronic obstructive pulmonary disease. The therapeutic benefit of TNF-{alpha} antagonism is unknown.

What This Study Adds to the Field
This study demonstrates lack of clinical effect of anti-TNF antibody (infliximab) in patients with moderate to severe chronic obstructive pulmonary disease.

 
Chronic obstructive pulmonary disease (COPD), the fourth leading cause of death in the United States, is primarily a smoking-related inflammatory lung disease (1). COPD has a prevalence of approximately 10% in individuals aged 55 to 85 years old (2). By definition, COPD is characterized by loss of expiratory airflow that is associated with an abnormal inflammatory response of the lung. Symptoms of COPD include cough, sputum production, and dyspnea; these symptoms are typically more obvious with physical exertion, which is related to the pulmonary abnormalities of COPD. Exercise limitation, however, is often more closely related to skeletal muscle weakness, which is believed to be a systemic manifestation of COPD (3).

Tumor necrosis factor (TNF)-{alpha} appears to play a role in the pathogenesis of COPD as a primary mediator driving the inflammation characteristic of COPD. A number of studies have reported increased production of TNF-{alpha} in patients with COPD, and have related this increase to the systemic manifestations of COPD (4–9). Specifically, the increased TNF-{alpha} levels have been associated with weight loss in patients with COPD (9–11). An additional study suggested that monocytes from underweight patients with COPD produce increased amounts of TNF-{alpha} in response to endotoxin challenge (12). In this context, TNF-{alpha} may contribute to the muscle weakness, muscle loss, and cachexia, which limit exercise performance.

Several mechanisms by which TNF-{alpha} could contribute to the pathogenesis of COPD have been suggested. TNF-{alpha} activates inflammatory cells and plays key roles in the defense against several infectious pathogens, including mycobacteria and fungi (13). A role for TNF-{alpha} in immune surveillance control of malignancy has been suggested (14), although TNF-{alpha} has also been suggested to be a growth factor for some tumors (15). TNF-{alpha} induces apoptosis in normal cells, and has been suggested to be a major driver of the cachexia that characterizes chronic inflammation (16). Additionally, when infused into the peritoneal cavity in rats, TNF-{alpha} induces emphysema (17). Because emphysema has been associated with apoptosis of cells present in the alveolar wall (18), this is a potential mechanism by which TNF-{alpha} could contribute to the development of emphysema (19).

COPD is characterized by the progressive loss of expiratory airflow, which is believed to result from several processes characterized by lower respiratory tract inflammation. The clinical features of COPD, however, are driven not only by ventilatory limitation, but also by systemic features. Muscle weakness, for example, is often more important in restricting exercise performance than is ventilatory limitation (3). Integrative measures of disease-related health status (sometimes called "quality of life" measures) are characteristically abnormal in COPD. These measures, however, correlate relatively poorly with measures of airflow. They correlate somewhat better with measures of exercise performance, consistent with the concept that the systemic features of COPD are important clinical features that are somewhat independent of airflow.

Current therapies for COPD are aimed at improving airflow and reducing COPD exacerbations. Although these therapies can produce considerable symptomatic benefit, therapy specifically targeting the systemic inflammatory manifestations of COPD could represent a major clinical advance (20). Inhibitors of TNF-{alpha} have proven to be effective therapies in several chronic inflammatory conditions, including rheumatoid arthritis (21) and Crohn's disease (22), although they have been ineffective in congestive heart failure (23), which is also associated with systemic inflammation. The suggested role for TNF-{alpha} in the pathogenesis of COPD, together with the lack of effective therapy that alters the inflammatory process in COPD, and the availability of effective anti–TNF-{alpha} interventions in other inflammatory diseases, provide the rationale for investigating the role of such therapy in COPD.

The current study was designed to determine whether infliximab, an anti–TNF-{alpha} antibody, results in clinical benefit in patients with COPD. Within the time frame of this study, an integrative measure of disease-related health status was used as the primary outcome variable, as this was believed to be the most appropriate measure to reflect the systemic manifestations of COPD within the timeframe of this study. Dyspnea, lung function, walking distance, and acute exacerbations of COPD were assessed as secondary outcome variables. Some of the results of this study have been previously reported in abstract form (24, 25).


   METHODS
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
A total of 234 subjects from 41 centers in the United States were randomized to treatment between January 2003 and January 2004. Eligible subjects included males and females, aged 40 years or older, with moderate to severe COPD, as defined using the GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria (26). Subjects were required to have less than a 20% increase in FEV1 after a fixed dose of bronchodilator (180 µg inhaled albuterol), a history of at least 10 pack-years of smoking, have at least one episode of COPD-related symptoms (e.g., cough, sputum production, shortness of breath) within the 2 months before screening, and a score of less than 120 points on the Chronic Respiratory Questionnaire (CRQ) (27).

Major exclusion criteria included a prebronchodilator FEV1 of less than 500 ml, more than a 20% variation between the screening and baseline FEV1 assessments, and resting arterial oxygen saturation of less than 90% on room air. Also excluded were subjects meeting the following criteria: asthma as the main component of the obstructive airway disease, a moderate or severe exacerbation of COPD within 1 month of the start of the study, long-term oxygen therapy, New York Heart Association class III or IV congestive heart failure, a history of severe right-sided heart failure or cor pulmonale, serious infection or major surgery within the previous 3 months, use of oral corticosteroids within 2 weeks of screening, or previous anti-TNF therapy.

Subjects with a malignancy within the past 5 years (except for squamous or basal cell carcinoma of the skin that was treated with no evidence of recurrence), or evidence of prior or currently active tuberculosis, were considered ineligible.

Study Design
After written, informed consent was obtained, eligible subjects were randomized to one of three groups (placebo, 3 mg/kg infliximab, or 5 mg/kg infliximab) in a 1:1:1 manner using an adaptive, stratified design based on investigational site and baseline smoking status. Institutional review boards for each center approved the study protocol.

Patients were administered study drug at Weeks 0, 2, 6, 12, 18, and 24; all study procedures were performed before study drug infusion at these visits, as well as at Weeks 30, 36, and 44. Spirometry measurements were made according to BTPS (body temperature and pressure, saturated) convention using standardized spirometers (28), and fat-free mass was determined by bioimpedence at Weeks 0, 12, 24, and 44 using standardized equipment (29). Patients were required to have refrained from using bronchodilators during the 6-hour period preceding each visit, and to have refrained from smoking for the 2-hour period preceding each visit, and during the clinic visit. Study agent infusions were administered over a period of not less than 2 hours. Subjects were assessed for infusion reactions at each visit through Week 24. Follow-up efficacy and safety assessments were performed at the final three study visits. All efficacy and safety measurements were performed before each infusion.

The primary endpoint was change from baseline in CRQ total score at Week 24. This questionnaire is designed to assess health-related quality of life in patients with functionally limiting chronic lung disease. The validated CRQ, administered at screening and Weeks 12, 24, and 44, examines 4 aspects of patients' lives, including dyspnea, fatigue, emotional function, and control over the disease and its effects.

Additional secondary efficacy endpoints included change from baseline to Week 24 and/or various time points in the following: prebronchodilator percent predicted FEV1, 6-minute-walk distance (6MWD) (30, 31), Short form (SF)-36 physical component summary score (32), transition dyspnea index (33), and the incidence of moderate or severe COPD exacerbations, defined as worsening of symptoms requiring a physician visit or hospitalization, respectively, from Weeks 0–24.

Safety assessments were performed through Week 44. All adverse events (AEs) that occurred during the study were assessed. Samples were collected for routine laboratory analyses, antibodies to infliximab, serum infliximab concentrations (using an ELISA), and serum TNF levels (R&D Systems, Inc., Minneapolis, MN), and antinuclear antibodies.

Serum samples from patients positive for antinuclear antibodies were also tested for anti–double-stranded (ds) DNA antibodies using the Crithidia method (Sanofi Diagnostics, Paris, France) and the Farr assay (Diagnostic Products Corp., Los Angeles, CA). C-reactive protein (CRP) levels were determined (non–high sensitivity; Roche Tinaquant, Roche Diagnostics, Indianapolis, IN) during the study to assess the pharmacodynamic effect of infliximab on systemic inflammation.

Statistical Analysis
All efficacy analyses were conducted using the intent-to-treat principle. The primary efficacy endpoint was change from baseline to Week 24 in the CRQ total score. Analysis of covariance was employed to assess the effect of treatment on the primary endpoint at Week 24 and for major secondary endpoints, except for incidence of COPD exacerbations. Assuming a within-group SD of 17 points, the sample size had approximately 90% power to detect a 10-point absolute difference (considered the minimal clinically important difference) in CRQ total score in the primary analysis. This analysis is the comparison between the combined active treatment group and placebo followed by pairwise comparisons (each at {alpha} = 0.05 [two sided]). Similar simulations were also performed to assess the power in the major secondary analysis of change from baseline to Week 24 in percent-predicted FEV1 (approximately 90% power to detect a 9% difference, assuming a within-group SD of 15%).

Baseline measurements, baseline smoking status, treatment group, and institution were included as independent variables. The incidence of COPD exacerbations through Week 24 was summarized for frequency and percentage. Kaplan-Meier curves were used to investigate the time to first exacerbation, and the log-rank test was used to compare the data. Nonparametric analyses, using the same model with van der Waerden normal scores as a dependent variable, were also performed to assess the robustness of the analysis for the primary and the first four major secondary endpoints.


   RESULTS
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Of the 234 subjects randomized, 77 received placebo, 78 received infliximab 3 mg/kg, and 79 received infliximab 5 mg/kg (Figure 1).


Figure 1
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  		Figure 1. Schematic: enrollment and outcome of subjects in the study. *Based on an intent-to-treat analysis. {dagger}Other category includes withdrawal of consent, IV access issues, scheduling conflicts, and so forth.

 
Overall, baseline demographics and disease characteristics were well balanced across the treatment arms (Table 1). The majority of subjects, as defined by the protocol, had moderate to severe COPD. A higher percentage of infliximab-treated subjects had very severe COPD (stage IV), characterized by baseline FEV1 less than 30% predicted. The majority of the randomized subjects completed study treatment. Of those randomized, 21% in the placebo group, 37% in the infliximab 3 mg/kg group, and 30% in the infliximab 5 mg/kg group discontinued study agent. Higher proportions of infliximab-treated subjects discontinued study agent due to AEs (20–27%) compared with those treated with placebo (9%; p = 0.004; Table 2).


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  		TABLE 1. SUMMARY OF DEMOGRAPHICS AND DISEASE CHARACTERISTICS AT BASELINE

 

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  		TABLE 2. SUMMARY OF SAFETY ANALYSES FOR TREATED SUBJECTS THROUGH WEEK 44

 
Efficacy: Primary Endpoint
Changes from baseline to Week 24 in the CRQ total score were similar across treatment groups (Figure 2), with further subgroup analyses (including smoking status, corticosteroid use, and individual components of the CRQ) showing no significant differences. Similar findings were observed for changes from baseline to Week 44.


Figure 2
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  		Figure 2. Change from baseline to Week 24 in Chronic Respiratory Questionnaire (CRQ) total score (patients with available data; patients with GOLD stage I disease not included). Each horizontal bar represents the difference and 95% confidence interval in the least square (LS) means of change from baseline to Week 24 between the combined infliximab and placebo groups.

 
Efficacy: Major Secondary Endpoints
No significant treatment group differences were observed in the change from baseline to Week 24 in prebronchodilator % predicted FEV1. An improvement in 6MWD at Week 24 was observed in the infliximab-treated groups; however, the magnitude of the improvement was neither statistically significant nor clinically meaningful (Figure 3). Post hoc subgroup analyses were performed to identify characteristics associated with increased 6MWD. Subjects with cachexia (defined as fat-free mass < 67% or < 63% of ideal weight in males and females, respectively) or younger subjects (< 65 yr old) had greater increases in 6MWD, although the numbers of subjects in the subgroups were small. Further subgroup analysis, based on TNF-{alpha} or CRP levels, did not demonstrate any treatment benefit.


Figure 3
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  		Figure 3. Subgroup analysis for 6-min-walk distance at Week 24 (patients with available data). Each horizontal bar represents the difference (in meters) and 95% confidence interval (CI) in the least square (LS) means of change from baseline to Week 24 between the combined infliximab and placebo groups. Median values: age (66 yr), % predicted FEV1 (43.0), disease duration (5.1 yr). Cachexia defined as fat-free mass less than 67% or less than 63% of ideal weight in males and females, respectively.

 
At Week 24, the SF-36 score, the transition dyspnea index score, cough symptoms, and sputum production improved in all treatment groups, with no significant treatment group differences (data not shown). With regard to moderate to severe COPD exacerbations, no significant treatment group differences were observed for the incidence during the first 24-week treatment period or for time to the first exacerbation during the 24-week treatment period. The majority of subjects in all treatment groups (82% in the placebo group, 82% in the infliximab 3 mg/kg group, and 73% in the infliximab 5 mg/kg group) did not have a moderate to severe COPD exacerbation through Week 24.

Pharmacokinetics and Pharmacodynamics
Peak serum levels of infliximab achieved after the first infusion were similar to those observed after subsequent infusions. However, predose levels of infliximab declined over the first three infusions and then stabilized for the remainder of the 24-week period. At baseline, serum TNF-{alpha} levels were low across all the treatment groups, with approximately half of the subjects having TNF-{alpha} levels below the limit of detection of the assay (3.2 pg/ml). The mean TNF-{alpha} levels for all subjects with detectable levels was 5.7 pg/ml. There were no significant changes in measured TNF-{alpha} levels during the treatment period in any of the treatment groups, nor in the subgroups with shorter disease duration or cachexia, in which post hoc analyses suggested trends toward improvement in 6MWD. However, the validity of these postbaseline TNF-{alpha} measurements is questionable, due to the potential for interference of infliximab in the TNF-{alpha} assay.

For the entire subject population, and specifically for those subjects with a baseline CRP level greater than 1 mg/dl, no significant differences were observed between treatment groups for the change from baseline in CRP levels during the 24-week treatment period.

Safety
Through Week 44, AEs occurred in 88.3% of subjects in the placebo group and 88.3% and 92.5% of subjects in the infliximab 3- and 5-mg/kg treatment groups, respectively (Table 2). The most common reason for the discontinuation of study agent in all randomized subjects was the occurrence of AEs, with 9.1% of placebo subjects, 27.3% of infliximab 3-mg/kg subjects, and 20.0% of infliximab 5-mg/kg subjects discontinuing study agent before Week 24. With the exception of COPD exacerbation, the most frequently reported AEs leading to discontinuation of study agent (peripheral edema, infusion or allergic reactions, malignancy and infection) were reported primarily among infliximab-treated subjects. The most frequently reported AEs in the combined infliximab treatment groups were COPD exacerbation, upper respiratory tract infection, sinusitis, pain, back pain, headache, and diarrhea (Table 2).

The most frequently reported serious AEs were related to respiratory system disorders. COPD exacerbation was the most common individual serious AE (Table 2). Three subjects died during the study. Two subjects received infliximab 5 mg/kg: a 74-year-old man died as a result of an intraventricular hemorrhage and coma secondary to a fall, and a 68-year-old man died due to acute cardiopulmonary arrest after hospitalization for a COPD exacerbation. One placebo-treated subject died during hospitalization for a COPD exacerbation. As of February 2006, seven additional deaths were reported in subjects after completion of the study or after withdrawal from the study. Three of these subjects received infliximab 3 mg/kg: one subject died as a result of renal cell carcinoma; one subject died due to metastatic alveolar cell carcinoma of the lung; and one subject died due to a heart attack. Four of these subjects received infliximab 5 mg/kg: one subject died of septic shock after aspiration pneumonia 2 months after the last study agent infusion; one subject died due to pancreatic or liver cancer (investigator unable to assess relationship to study drug); one subject died due to lung cancer (investigator considered possibly related to study drug); and one subject died due to suicide. The investigators considered the deaths unlikely or not related to study treatment, except as described above.

Ten subjects had malignancies reported during the study (one in the placebo group, five in the infliximab 3-mg/kg group, and four in the infliximab 5-mg/kg group) (Table 3). Of the nine malignancies in infliximab-treated subjects, four were pulmonary in origin, two were head and neck malignancies, and the remaining were single cases of breast cancer, renal cell carcinoma, and Hodgkin's lymphoma. All 10 subjects had a history of at least 40 pack-years of smoking, and 6 of 10 were current smokers at the time of study entry. The mean (± SD) number of pack-years of smoking for the COPD study population was 58.0 ± 27.5. Three subjects had evidence of cancer present at randomization or within 3 weeks of study entry (1 subject in the infliximab 3-mg/kg group had a mass present on chest X-ray at baseline that was not originally recognized; 1 subject in the infliximab 5-mg/kg group had throat discomfort at baseline and was diagnosed with laryngeal cancer 3 wk after entering the study; and 1 subject in the infliximab 3-mg/kg group had a renal mass discovered 2 wk after randomization).


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  		TABLE 3. MALIGNANCIES REPORTED THROUGH WEEK 44

 
There were five additional malignancies reported after the completion of the study: two subjects in the placebo group (1 subject with cervical cancer and 1 subject with prostate cancer) and three subjects in the infliximab 5-mg/kg group. In the infliximab-treated subjects, two malignancies were pulmonary in origin and one was a reported case of pancreatic or liver cancer. One subject who was reported to have lung cancer expired from cancer with metastasis to the brain approximately 1 year after completing the follow-up phase of the study. The subject who was reported to have pancreatic or liver cancer expired approximately 5 months after completing the follow-up phase of the study.

Infections requiring antimicrobial treatment occurred in approximately half of subjects in each of the treatment groups (Table 2). Although there appeared to be an increased incidence of pneumonia in infliximab-treated subjects, there was no difference in the total number of antibiotic-requiring infections. Through Week 44, pneumonia occurred in 10 infliximab-treated patients compared with 1 report in the placebo group. There was no difference in the total number of fungal, mycobacterial, or antibiotic-requiring infections, and no infection-related mortality was observed.

The number of subjects with infusion reactions was greater in the infliximab treatment groups (4% placebo, 10% combined infliximab), as was the number of subjects with possible delayed hypersensitivity (serum sickness-like) reactions (0% placebo, 4% combined infliximab) (Table 2).

No subject in any treatment group experienced an anaphylactic reaction. Newly positive results for anti-dsDNA antibodies occurred in more infliximab-treated than placebo-treated subjects (Table 2). These results were within the range for positive anti-dsDNA antibody response that has been observed in previous clinical trials, and were not associated with any symptoms. There was one report of a lupus-like syndrome, and no reports of other autoimmune disease. No other notable changes in laboratory parameters or vital signs were observed during the study.


   DISCUSSION
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The current study was designed to evaluate the efficacy and safety of infliximab in subjects with moderate to severe COPD. No therapeutic benefit was observed in the primary outcome variable: health status as assessed by the CRQ. Similarly, no therapeutic benefit was noted in lung function, dyspnea, or in the incidence of moderate to severe COPD exacerbations. A modest trend toward improved 6MWD was demonstrated in the infliximab treatment groups, although this did not reach statistical or clinical significance. No opportunistic infections were observed, and there were no differences in the occurrence of antibiotic-requiring infections between the infliximab and placebo groups, although the incidence of pneumonia was higher in the infliximab-treated subjects. More malignancies appeared in the infliximab-treated subjects, although the total number of malignancies was too small to draw definitive conclusions.

A recently reported small pilot study, evaluating the effect of three infusions of infliximab (5 mg/kg) in patients with COPD, also demonstrated no beneficial therapeutic response or effect on sputum neutrophils (34). Taken together, these observations do not support the use of infliximab for subjects with moderate or severe COPD.

Several lines of evidence suggest TNF-{alpha} may play a role in the pathogenesis of COPD, including increased levels of TNF-{alpha} in the sputum (8) and peripheral blood (9) of patients with COPD, as well as the fact that genetic polymorphisms in the promoter regions of the TNF-{alpha} gene have been associated with chronic bronchitis (5, 6). In addition, increased levels of TNF-{alpha} have been associated with weight loss in patients with COPD (9–11). Taken together, these findings suggest increased production of TNF-{alpha} may be present in patients with COPD and could, therefore, contribute to the pathogenesis and systemic manifestations of the disease.

The current study was designed to evaluate the hypothesis that TNF-{alpha} may be a major driver of clinical features in COPD and that anti–TNF-{alpha} antibodies, by blocking TNF-{alpha}, could result in a beneficial clinical response. This concept is supported by findings from a preclinical study in which mice lacking TNF-{alpha} receptors, as well as wild-type mice, were exposed to smoke for 6 months. Study results demonstrated a key role for TNF-{alpha} in smoking-induced emphysema, accounting for 70% of the airspace enlargement and the majority of inflammatory cell influx/matrix breakdown observed in the mouse model (35). This concept is also supported by the therapeutic benefit of anti–TNF-{alpha} antibodies in several other chronic inflammatory diseases, including Crohn's disease, ankylosing spondylitis, and, in particular, rheumatoid arthritis. In this latter condition, both local and systemic manifestations respond rapidly to anti–TNF-{alpha} antibody therapy (36), which is routinely used without selection of patients based on circulating TNF-{alpha} levels.

The lack of clinical benefit demonstrated in the current study does not exclude a role for TNF-{alpha} in COPD pathogenesis. It seems unlikely that the dose of anti–TNF-{alpha} antibody studied was insufficient, as the doses used are effective in rheumatoid arthritis and Crohn's disease. However, the treatment period of 6 months may have been too short to demonstrate changes in health status with infliximab. It is also possible that other mediators, in addition to TNF-{alpha}, are sufficient to cause COPD symptoms. Similarly, in the case of the preclinical study involving mice lacking TNF-{alpha} receptors, a second TNF-{alpha}–independent process, possibly related to direct metalloprotease attack on matrix, produced approximately 30% of the airspace enlargement observed (35). The clear lack of clinical response in the current study is evidence that anti–TNF-{alpha} antibody therapy in otherwise unselected, clinically defined patients with moderate to severe COPD is unwarranted.

It is possible that subsets of subjects with COPD may respond to anti–TNF-{alpha} therapy. In support of this, the 6MWD post hoc analyses suggest that cachectic individuals, as well as younger individuals, derived relatively greater benefit from treatment with infliximab. A recent study by Troosters and colleagues (37) has demonstrated that rehabilitation programs may interact synergistically with medical therapy in patients with COPD. No rehabilitation program was included in the current study. Whether greater effects in 6MWD would have been observed with treatment combined with rehabilitation remains undetermined. Because of the limited number of study subjects, the post hoc nature of the analyses, and the multiple comparisons involved, such observations must be interpreted with caution. However, it is plausible that TNF-{alpha} may play a greater role for two groups of subjects: those individuals experiencing weight loss sufficient to manifest as cachexia, and those individuals in the early course of the disease.

In the current study, subjects were selected based on COPD severity using the GOLD criteria (26). Serum TNF-{alpha} was measured at baseline and at selected time points during the study, but was not used as a parameter to select individuals for treatment. Serum TNF-{alpha} concentrations were low: approximately half of the subjects had TNF-{alpha} concentrations below the limit of detection of 3.2 pg/ml, and the mean for the remaining subjects was 5.7 pg/ml. This is similar to the range reported for normal subjects and substantially less than that measured in patients with rheumatoid arthritis. The measured serum concentration of TNF-{alpha} did not change markedly over the treatment period. However, measurement of serum TNF-{alpha} can be confounded by the presence of binding proteins, such as soluble receptors, and infliximab binding can result in pools of TNF-{alpha} that are poorly detected by ELISA. Infliximab therapy may also alter TNF-{alpha} clearance. Thus, it is unlikely that the postbaseline TNF-{alpha} measurements reflect actual serum TNF-{alpha} levels. Whether a subject group selected for elevated serum TNF-{alpha} concentrations would have responded differently remains undetermined.

When used clinically, the ability of anti–TNF-{alpha} antibodies to suppress inflammatory defenses against fungal and mycobacterial pathogens requires careful clinical oversight. Appropriate precautions were used in the current trial, and no such infections were observed. This suggests that infectious complications are not likely to be a major problem with anti–TNF-{alpha} therapy in patients with COPD if appropriate precautions are used.

The increased number of malignancies observed in the infliximab-treated subjects seen in this study raises concerns related to the role of TNF in immune surveillance of malignancies in this subject group. However, given the small sample size of the study, the limited number of reported malignancies, and the inclusion of subjects with symptoms that, in retrospect, were likely related to the presence of malignancy at study entry, the strength of any potential safety signal in the COPD population is unclear. Nevertheless, the possibility that infliximab contributed to the progression, and thus the diagnosis, of malignancies remains a serious concern. This impact of infliximab on malignancy risk in patients with COPD needs to be further elucidated. To obtain a better estimate of this risk, all subjects from the current study have been encouraged to participate in a follow-up 5-year safety study.

In summary, considerable evidence suggests that TNF-{alpha} may play a role in the pathogenesis of COPD. However, administration of infliximab was without benefit over a 6-month treatment period in subjects with moderate to severe COPD selected by GOLD staging. Whether subgroups of patients selected using other clinical criteria, such as cachexia or TNF-{alpha} levels, may benefit is unknown. The current study, however, clearly does not support the use of infliximab routinely in moderate to severe COPD.


   Acknowledgments
 
The authors gratefully acknowledge the contributions of the following investigators: D. Riff (Anaheim, CA); B. Bowling (Endwell, NY); H. Kaiser (Minneapolis, MN); C.L. Anderson (Bay Pines, FL); W. Busse (Madison, WI); S. Sahn (Charleston, SC); L. Dunn (Clearwater, FL); D. Boerner (Raleigh, NC); G. San Pedro (Shreveport, LA); E. Blecker (Winston-Salem, NC); R. Baughman (Cincinnati, OH); J. Flescher (Raleigh, NC); M. Liu (Baltimore, MD); W. Miser (Columbus, OH); E. Schenkel (Easton, PA); A. Dahdul (Springfield, MA); N. Hanania (Houston, TX); T. Craig (Hershey, PA); J. Johnson (Metairie, LA); S. Szumstein (Salem, VA); L. Moses (Richmond, VA); R. Tidman (Blue Ridge, GA); J. Fitzgerald (Dallas, TX); J. Rehm (Fredericksburg, VA).


   FOOTNOTES
 
Supported by a research grant from Centocor, Inc. (Malvern, PA).

Originally Published in Press as DOI: 10.1164/rccm.200607-995OC on February 8, 2007

Conflict of Interest Statement: S.I.R. received sponsorship fees of $4,000 from AstraZeneca and $15,000 from GlaxoSmithKline as a speaker in scientific meetings and courses; $50,000 from Altana, $2,500 from AstraZeneca, $6,000 from Dey, $2,000 from GlaxoSmithKline, and $5,000 from Inspire for serving on advisory boards; $89,500 from AstraZeneca, $64,000 from Centocor, $3,000,000 from GlaxoSmithKline, $436,000 from Pfizer, $30,000 from Roche, and $239,000 from Sanofi in grants for conducting clinical trials; $6,000 from AstraZeneca, $19,500 from GlaxoSmithKline, $8,500 from Novartis, $6,500 from Pfizer, and $4,300 from Roche in consultancy fees; has a pending patent on the use of PDE4 inhibitors in repair; and is a coinventor of the patent owned by the University of Nebraska Medical Center. C.F. received grant support from Centocor for a current total of $218,550 for the past 3 yr and the current year. S.K. received $4,000 from GlaxoSmithKline for serving on an advisory board in 2006, $12,000/yr in 2004–2006 in lecture fees from Genentech, $3,000 in lecture fees in 2005 from GlaxoSmithKline, and $220,000 in grants from GlaxoSmithKline in 2006. W.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.S. received $1,500 in lecture fees from Pfizer. T.S. received $12,750 in lecture fees from Boehringer Ingelheim, and $16,500 in lecture fees from Pfizer; in 2004 T.S. received $91,883 from GlaxoSmithKline, $54,760 from Sepracor, $60,146 from Centocor, and $49,093 from Altana. In 2005 T.S. received $233,448 from GlaxoSmithKline, $19,200 from Centocor, $32,844 from Altana, $16,710 from AstraZeneca, and $130,501 from Dey. In 2006 T.S. received $405,881 from GlaxoSmithKline, $51,486 from Sepracor, $12,200 from Centocor, $100,642 from AstraZeneca, and $46,300 from Dey in grants (all of the payments were made to T.S.'s professional corporation, Midwest Chest Consultants, P.C., for the conduct of FDA-approved Phase II and Phase III multicenter clinical trials). T.S. is a speaker for Boehringer Ingelheim, GlaxoSmithKline, AstraZeneca, Pfizer, and Schering Plough. He has an active clinical research practice, performing multicenter clinical research trials for sponsors, including GlaxoSmithKline, Sepracor, Centocor, Altana, AstraZeneca, and Dey. P.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. P.K. received one grant from Centocor from September 2003 to February 2005 as the principal investigator, received an ongoing grant in August 2006 from Centocor as the principal investigator, and has greater than $10,000 in stock from Johnson & Johnson. W.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.K. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. M.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.A. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.F.D.'s institution has $79,000 in research contracts with Centocor for which he is a principal investigator. R.W. is an employee of Centocor. K.H.L. is an employee of Centocor. R.S.-H. is an employee of Centocor. E.S.B. is an employee of Centocor. J.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form July 21, 2006; accepted in final form February 8, 2007


   REFERENCES
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
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