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Published ahead of print on July 13, 2006, doi:10.1164/rccm.200601-072OC
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American Journal of Respiratory and Critical Care Medicine Vol 174. pp. 753-762, (2006)
© 2006 American Thoracic Society
doi: 10.1164/rccm.200601-072OC

Original Article

The Effects of a Monoclonal Antibody Directed against Tumor Necrosis Factor-{alpha} in Asthma

Edward M. Erin, Brian R. Leaker, Grant C. Nicholson, Andrew J. Tan, Linda M. Green, Helen Neighbour, Angela S. Zacharasiewicz, Jackie Turner, Elliot S. Barnathan, Onn Min Kon, Peter J. Barnes and Trevor T. Hansel

Clinical Studies Unit, National Heart and Lung Institute, and Department of Thoracic Medicine, Imperial College, London; Department of Nephrology, Royal Free Hospital, London; Department of Respiratory Medicine, St. Mary's Hospital, London, United Kingdom; and Centocor, Inc., Malvern, Pennsylvania

Correspondence and requests for reprints should be addressed to Trevor T. Hansel, F.R.C.Path., Ph.D., NHLI Clinical Studies Unit, Royal Brompton Hospital, Fulham Road, London SW3 6HP, UK. E-mail: t.hansel{at}imperial.ac.uk


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Rationale: Neutralization of tumor necrosis factor-{alpha} (TNF-{alpha}) is an effective antiinflammatory therapy for several chronic inflammatory diseases.

Methods and Objectives: We undertook a double-blind, placebo-controlled, parallel-group design study in 38 patients with moderate asthma treated with inhaled corticosteroids but symptomatic during a run-in phase. Infliximab (5 mg/kg) or placebo was administered by intravenous infusion at Weeks 0, 2, and 6. We assessed clinical response by monitoring lung function, symptoms, and inhaled beta2-agonist usage using hand-held electronic devices.

Results: The primary endpoint, change in morning PEF at Days 50–56 compared with the last 7 d of the run-in, was not significantly different on treatment. However, infliximab was associated with a decrease in mean diurnal variation of PEF at Week 8 (p = 0.02; 95% confidence interval [CI], –8.1 to –0.72). Furthermore, there was a decrease in the number of patients with exacerbations of asthma (p = 0.01; 95% CI, 4.4 to 52.7) and an increased probability of freedom from exacerbation with time (p = 0.03) in patients on infliximab (n = 14) compared with placebo (n = 18). In addition, infliximab decreased levels of TNF-{alpha} (p = 0.01) and other cytokines in sputum supernatants. There were no serious adverse events related to the study agent.

Conclusions: Treatment with infliximab was well tolerated and caused a decrease in the number of patients with exacerbations in symptomatic moderate asthma. The promising preliminary findings underscore the need to evaluate therapy directed against TNF-{alpha} in larger trials enrolling patients with more severe asthma.

Key Words: asthma • monoclonal antibody • pharmacology • tumor necrosis factor-{alpha} •

Severe asthma comprises airflow obstruction, airway hyperresponsiveness, and airway remodeling (1, 2). Asthma therapy mediates symptom relief through inhaled short- and long-acting beta2-agonists, and treats the underlying inflammation with corticosteroids (3). Although therapy with inhaled corticosteroids is highly effective in the majority of patients, a cohort of patients with severe asthma continues to experience symptoms despite treatment with high-dose corticosteroids (4–6), and novel therapeutic approaches are needed (1, 7–9).

Asthmatic airways are infiltrated with eosinophils, mast cells, Th2 lymphocytes, neutrophils, and macrophages (10); and numerous cytokines and chemokines are involved in regulating the immune response (11). Both structural and inflammatory cells in the airways can elaborate and release cytokines, such as tumor necrosis factor-{alpha} (TNF-{alpha}) (12). The genetics of asthma are complex (13), but TNF-{alpha} genotypes have been associated with atopic asthma (14, 15). Consistent with this, elevated levels of TNF-{alpha} have been observed in induced sputum from patients with asthma (16, 17). Interestingly, inhalation of TNF-{alpha} by normal individuals increased airway responsiveness and neutrophil counts in induced sputum (18), and TNF-{alpha} inhalation in patients with mild asthma causes airway hyperresponsiveness and sputum neutrophilia and eosinophilia (19). We hypothesize that TNF-{alpha} may have a role in maintaining the inflammatory state in patients with asthma (20, 21), and may thus represent a logical therapeutic target.

Infliximab (Remicade) is a recombinant human-murine chimeric monoclonal antibody (mAb) that specifically and potently binds and neutralizes the soluble TNF-{alpha} homotrimer and its membrane-bound precursor (22). Anti–TNF-{alpha} therapy has been shown to be effective in patients with rheumatoid arthritis (23), ankylosing spondylitis (24), Crohn's disease (25), and psoriasis (26), but ineffective in patients with chronic obstructive pulmonary disease (27). Preliminary reports of efficacy in asthma in patients with concomitant rheumatoid arthritis have been encouraging (28, 29). In addition, small prospective studies of a soluble receptor directed against TNF-{alpha} (etanercept) in severe refractory asthma have shown improvements in lung function and airway hyperresponsiveness (30–32).

We chose to study the effects of infliximab in patients with moderate asthma because they have a greater safety margin than patients with severe asthma. This was because we were concerned that infliximab might have the potential to increase susceptibility to infection, exacerbate stable asthma, and worsen the severity of exacerbations. However, in this preliminary study, we selected patients with persistent symptoms of their asthma and diurnal variation in peak flow despite the use of inhaled corticosteroids in the absence of long-acting beta2-agonists, with the aim of identifying effects of infliximab on lung function.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients
The study was approved by the Brompton Harefield and National Heart and Lung Institute Research Ethics Committee. All patients provided full written, informed consent. Adult patients eligible for the study had to have a diagnosis of moderate-to-severe persistent asthma as defined by the Global Initiative on Asthma (GINA) for at least 1 yr (3), with an FEV1 of 40 to 90% of predicted at screening. Reversible airway obstruction (with at least a 12% increase in FEV1 compared with baseline shown within 30 min of taking 200 µg salbutamol) was also required at screening. Patients continued inhaled corticosteroids at a stable dose regimen throughout the study. Salbutamol (albuterol), a short-acting beta2-agonist, was allowed as needed to relieve symptoms, but other asthma medications were not permitted. A history of serious diseases or other lung conditions precluded study entry, and patients had negative tuberculin tests and normal chest radiography.

Study Design
This was a double-blind, placebo-controlled, parallel-group, randomized study. There was a run-in of 2–4 wk, three infusions over 6 wk, detailed assessment for up to 8 wk after first infusion, and a final visit at 12 wk. After meeting the screening eligibility criteria, patients participated in a 2- to 4-wk run-in period, which started after demonstration of reversible lung disease. Patients were required to have a mean total daily symptom score of at least 4 in the last 7 d of the run-in period (baseline period: Days –7 to –1), or at least 10% but less than 40% diurnal variation in peak expiratory flow (PEF) measured on at least 2 of 7 d in the same period (33). Patients meeting these criteria were randomly assigned in a 1:1 ratio to receive infliximab (5 mg/kg) or placebo at Weeks 0 (Day 1), 2 (Day 15), and 6 (Day 43).

Breath nitric oxide (NO) levels (nonnasal), pulmonary function (FEV1 and PEF), markers of lung inflammation (induced sputum), and markers of systemic inflammation (blood sample) were assessed at Week 0 (Day 1). Vital signs were documented and pulmonary function tests were performed immediately after and at 1 and 2 h following each infusion of study agent. At all subsequent visits, pulmonary function tests (FEV1 and PEF), routine blood sampling, and breath NO level tests were performed. Sputum induction and processing was performed at Weeks 1, 8, and 12.

Study Agent
Infliximab is chimeric A2 (cA2) IgG supplied as a lyophilized solid in a 100-mg formulation, and was supplied by Centocor, Inc. (Malvern, PA). The 100-mg formulation contained 0.5 g of sucrose, 6.1 mg of dibasic sodium phosphate dihydrate, 2.2 mg of monobasic sodium phosphate monohydrate, and 0.5 mg of polysorbate in a 20-ml vial for reconstitution with 10 ml of sterile water for injection. The total dose of the reconstituted infliximab at 5 mg/kg was diluted to 250 ml with 0.9% sodium chloride and infused intravenously over 2 h. The placebo was supplied as a lyophilized solid containing 0.5 g of sucrose, 6.1 mg of dibasic sodium phosphate dihydrate, 2.2 mg of monobasic sodium phosphate monohydrate, and 0.5 mg of polysorbate in a 20-ml vial for reconstitution with 10 ml of sterile water for injection. After the patient was randomly assigned to a treatment, the pharmacist prepared the appropriate dose of infliximab or placebo. The patient and attending physicians/nurses/laboratory staff, as well as the sponsor and clinical site monitors all remained blinded to the treatment assignment until the database was locked on completion of clinical assessment after 12 wk of the study.

Procedures
Electronic diaries.
Patients recorded daily PEF and FEV1 (best of three attempts, morning and evening), short-acting beta2-agonist use, and clinical symptoms using hand-held electronic devices (AM2; Jaeger, Wurzburg, Germany). A symptom scale ranging from 0 to 3 was used to assess six symptoms on a daily basis, five during the day and evening (cough, wheeze, shortness of breath, level of activity, and chest tightness) and one (sleep disturbance) in the morning.

Definition of exacerbations.
Exacerbations were defined as in the Formoterol and Corticosteroids Enabling Therapy (FACET) study (34), but because our study design required patients to be unstable rather than stable at baseline, we have adopted a new definition for "moderate exacerbations" in contrast to the FACET definition of "mild exacerbations." Patients with moderate exacerbations had 2 or more consecutive days with one or more of the following (when compared with baseline): at least a 20% decrease in morning PEF, use of at least three additional actuations of short-acting beta2-agonist rescue medication within a 24-h period, or increased nighttime symptoms. Severe exacerbations were those requiring treatment with oral corticosteroids or a decrease in the morning PEF of at least 30% below baseline on 2 consecutive days.

Induced sputum collection and processing.
All sputum samples were collected and processed in a standardized manner (35). After pretreatment with inhaled salbutamol, sputum was induced, using nebulized hypertonic saline at 3.5%, for three periods of 5 min each. Induced sputum was selected away from saliva and liquified with four volumes of 6.5 mM dithiothreitol (Sigma, St. Louis, MO) in phosphate-buffered saline (PBS). Liquefaction of sputum was performed on a roller at room temperature for 15 min, then four volumes of PBS were added and the sample was filtered through a 48-µm nylon gauze. The sputum supernatant was collected after centrifugation at 400 g for 10 min and stored at –80°C.

Optimized dialysis of sputum supernatants and TNF-{alpha} assay.
Thawed sputum supernatants were treated with a cocktail of protease inhibitors (Sigma P8340) and added ethylenediaminetetraacetic acid (1 mM). Dithiothreitol was removed from the supernatant by dialysis across a 3.5-kD molecular weight cutoff dialysis membrane at 4°C for 12 h into a 0.055-M Tris buffer at pH 8.2. This Tris buffer had optimized redox and denaturant conditions, containing oxidized glutathione (0.4 mM), reduced glutathione (2 mM), ethylenediaminetetraacetic acid (1 mM), and L-arginine (440 mM). Dialysis media was changed after 12 h to PBS at pH 7.4. Levels of human TNF-{alpha}, interleukin (IL)-1{alpha}, IL-6, human interferon-inducible protein (IP)-10, eotaxin, and IL-8 were analyzed using a bead array system (Upstate Biotechnology, Austin, TX) used with a Luminex 100 IS analyzer (Luminex B.V., Oosterhout, The Netherlands).

Measurement of exhaled NO.
Exhaled NO was measured by a chemoluminescence analyzer (Logan 2000; Logan Research Ltd., Rochester, UK) and methods in accordance with international guidelines (36, 37).

Statistical Analysis
The primary efficacy endpoint was the change from baseline (Days –7 to –1) to Week 8 (Days 50 to 56) in mean morning PEF, obtained from the patient diary data, in the per protocol (PP) population. Daily and weekly means and change from baseline were calculated for all data from the electronic diaries (lung function, symptoms, and salbutamol usage). Data were tested for normal distribution using the Shapiro-Wilks test, and the appropriate statistical tests were performed for parametric or nonparametric data, with confidence intervals (CIs) at 95%. The change from baseline for the primary efficacy endpoint and other lung function parameters was tested using a paired t test. An appropriate analysis of covariance model (with baseline value as a covariate) was used to analyze for differences in responses between treatment groups at Week 8 (Days 50 to 56). The least squares means from this model were calculated, along with the 95% CI.

Exacerbation data were assessed in terms of number of patients with exacerbations ({chi}2), number of exacerbations (Wilcoxon), probability of freedom from exacerbation (Kaplan-Meier), and total number of flagged days. p values less than 0.05 were considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Disposition and Baseline Characteristics
Of the 77 patients screened, 38 were randomized to treatment (20 in the placebo group and 18 in the infliximab group) and included in the safety/intention-to-treat population. Most of the 39 excluded patients with asthma failed to meet the lung function and reversibility criteria. Thirty-three patients (18 in the placebo group and 15 in the infliximab group) had sufficient electronic data for analysis of the primary endpoint and were included in the PP population (Figure 1). At baseline, the mean ± SD morning PEF was 355.9 ± 95.03 (95% CI, 308.6 to 403.1) for the placebo group and 347.6 ± 85.71 (95% CI, 300.1 to 395.1) for the infliximab group; the between-group difference was not significant (p = 0.80). However, the baseline mean PEF as a percentage of predicted was 73.7 ± 14.45 (95% CI, 66.5 to 80.9) for the placebo group and 63.7 ± 13.28 (95% CI, 56.4 to 71.1) for the infliximab group; the between-group difference was significant (p = 0.049). The treatment groups were similar in other baseline and demographic characteristics (Table1).


Figure 1
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  		Figure 1. Patient disposition. ITT = intention to treat; PEP = primary endpoint group with sufficient PEF rate in the last 7 d before the penultimate clinic visit (approximately 8 wk); PP = per protocol (patients meet inclusion criteria and complete clinic visits).

 

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  		TABLE 1. PATIENT CHARACTERISTICS AT BASELINE AND DURING RUN-IN

 
Primary Efficacy Parameter: Morning PEF from Electronic Devices
The primary efficacy endpoint was the change from baseline (Days –7 to –1) to Week 8 (Days 50 to 56) in mean morning PEF, obtained from the patient diary data in the PP population. A mean ± SD increase from baseline to Week 8 of 15.0 ± 50.8 L/min was observed in the infliximab group (p = 0.27; 95% CI, –13.1 to 43.2), compared with a decrease of 15.6 ± 46.6 L/min in the placebo group (p = 0.17; 95% CI, –38.8 to 7.6; Figure 2). Although these morning PEF data suggested a trend toward improvement with infliximab, the mean between-group difference was 29.49 and not significant (p = 0.09, 95% CI, –4.6 to 63.5).


Figure 2
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  		Figure 2. Electronic diary lung function, symptoms, and beta2-agonist usage. Values are means for electronic data collected in the morning and evening in the per protocol group of patients with sufficient electronic data up to the penultimate clinic visit. Infliximab (n = 15) and placebo (n = 18).

 
Evening PEF from Electronic Devices
No statistically significant differences were observed between the treatment groups in change from baseline to Week 8 in the evening PEF (L/min or % predicted). Mean ± SD decreases of 14.5 ± 42.7 L/min (p = 0.21; 95% CI, –38.1 to 9.2) and 17.4 ± 47.6 L/min (p = 0.14; 95% CI, –41.0 to 6.3) were observed in the infliximab and placebo groups, respectively (Figure 2).

Diurnal Variation in PEF from Electronic Devices
Patients in the infliximab group had a larger mean ± SD decrease from baseline to Week 8 in diurnal variation in PEF (–4.9 ± 6.7 L/min) when compared with the placebo group (–0.3 ± 5.5 L/min). Both the change from baseline within the infliximab group (p = 0.02; 95% CI, –8.8 to –1.0) and the between-group difference (p = 0.02; CI, 8.1 to 0.72) were statistically significant (Figure 2).

Morning and Evening FEV1 from Electronic Devices
No statistically significant differences between treatment groups were observed for changes from baseline to Week 8 in either mean morning FEV1 (L or % predicted) or evening FEV1 (L or % predicted). A mean ± SD increase in morning FEV1 of 0.12 ± 0.28 L was observed in the infliximab group (p = 0.11; 95% CI, –0.03 to 0.28), whereas a mean ± SD decrease of 0.04 ± 0.25 L was seen in the placebo group (p = 0.52; 95% CI, –0.16 to 0.09). A similar trend was observed for evening FEV1, with a mean ± SD increase of 0.03 ± 0.28 L in the infliximab group (p = 0.65; 95% CI, –0.12 to 0.19) and a mean ± SD decrease of 0.01 ± 0.27 L in the placebo group (p = 0.82; 95% CI, –0.15 to 0.12).

Clinic Visit Lung Function
Patients in the infliximab group had greater improvement from baseline to Week 8 in clinic PEF (mean ± SD, 29.7 ± 87.6 L/min; p = 0.21; 95% CI, –18.9 to 78.2) when compared with the placebo group (11.6 ± 114.3 L/min; p = 0.67; 95% CI, –45.3 to 68.4). In the infliximab group, the change from baseline to Week 8 in clinic FEV1 was 0.01 ± 0.36 L (mean ± SD), p = 0.88, 95% CI, –0.18 to 0.21, compared with a change in the placebo group from baseline to Week 8 in clinic FEV1 of 0.07 ± 0.30 L (mean ± SD; p = 0.33; CI, –0.08 to 0.22). There was no significant difference for changes from baseline to Week 8 between groups for PEF (p = 0.60) or FEV1 (p = 0.67).

Asthma Symptom Scores
At baseline, patients were required to have a total daily symptom score of at least 4, with the maximum possible total daily score of 18. The actual mean baseline scores were 9.6 in the placebo group and 8.4 in the infliximab group. Total symptom scores decreased significantly by Week 8 in both the infliximab (p = 0.02; CI, –2.1 to –0.1) and placebo (p = 0.005; CI, –2.8 to –0.6) groups. There was no significant difference between treatment groups (p = 0.73; CI, –1.1 to 1.3).

Use of Rescue Short-acting beta2-Agonist (Salbutamol)
Both treatment groups had a slight, and similar, decrease in the use of short-acting beta2-agonists from baseline to Week 8 (Figure 2). Mean ± SD decreases of 0.2 ± 0.98 actuations/d (p = 0.24; 95% CI, –0.8 to 0.4) and 0.3 ± 0.70 actuations/d (p = 0.12; 95% CI, 0.6 to 0.1) were observed in the infliximab and placebo groups, respectively.

Asthma Exacerbations
One patient in the infliximab group had insufficient electronic diary data for asthma exacerbations in the first 7 wk after randomization and was thus excluded from the analysis of exacerbation data (Figure 1). Significantly more patients in the placebo group experienced asthma exacerbations (13/18, 72%) when compared with the infliximab group (4/14, 29%; p = 0.01, {chi}2 test; Figure 3). The FACET study defines mild exacerbations in terms of peak flow > 20% below baseline value, or the use of more than three additional inhalations of terbutaline per 24 h as compared with the baseline, or awakening at night due to asthma. However, in the FACET study, patients were required to meet criteria for stable disease at baseline. In our study, all patients were required to be unstable in the last 7 d of the run-in, as defined in STUDY DESIGN. Because exacerbations were defined relative to this unstable run-in, we consider them to be moderate exacerbations.


Figure 3
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  		Figure 3. Exacerbations of asthma. Data are presented for patients who are per protocol and have sufficient electronic data up to the penultimate clinic visit after randomization. (A) Incidence of exacerbations over Weeks 0–8; (B) freedom from exacerbation over time. Infliximab (n = 14) and placebo (n = 18).

 
The probability of freedom from an asthma exacerbation due to infliximab compared with placebo over time was derived using a Kaplan-Meier analysis (p = 0.03; Figure 3). Although the total number of exacerbations may be a less reliable endpoint because a number of flagged days for exacerbation may be clustered together with stable intervening days, there was a significant decrease in the total number of exacerbations after infliximab treatment (p = 0.04, Wilcoxon rank sum test). There were no severe exacerbations requiring oral corticosteroids or hospitalization in the study.

Exhaled Breath NO
No statistically significant differences were observed between the treatment groups in the changes from baseline to Week 8 in exhaled NO. A mean ± SD decrease of 0.21 ± 6.1 ppb (p = 0.95; 95% CI, –3.8 to 3.3) was observed in the infliximab group, compared with an increase of 2.38 ± 9.07 ppb (p = 0.90; 95% CI, –2.1 to 6.9) in the placebo group.

Blood Eosinophil Counts, Sputum Differential Counts, and Total Blood IgE Levels
Although variations in blood eosinophil (Figure 4A) and sputum differential (Figure 4B) counts were observed throughout the study, none of the changes were statistically significant. For sputum neutrophil, responses to infliximab versus placebo at Week 8 (p = 0.83) and changes from baseline to Week 8 within the infliximab group (p = 0.18) were not significant. A larger decrease in total blood IgE levels was seen in the infliximab group compared with the placebo group (–40.3 IU/ml compared with –16.4 IU/ml, respectively); however, none of the changes,either within a group or between groups, were statistically significant.


Figure 4
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  		Figure 4. Blood eosinophils (A), sputum eosinophils (B), and sputum neutrophils (C). Data are means ± SEM for the per protocol population. Infliximab (n = 15) and placebo (n = 18). There were no significant differences between infliximab and placebo at any time points.

 
Chemokines and Cytokines in Sputum Supernatants
Infliximab treatment resulted in a significant decrease in levels of TNF-{alpha}, IL-1{alpha}, IL-6, IP-10, and IL-8 in sputum supernatants when compared with placebo (Figure 5). Infliximab had no significant effect on eotaxin levels in sputum supernatants compared with placebo.


Figure 5
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  		Figure 5. Sputum cytokines and chemokines. Data are presented as medians for the per protocol population. Infliximab (n = 15) and placebo (n = 18). *p < 0.05 or **p < 0.01 for comparison of infliximab versus placebo at given time points, with probabilities derived from Wilcoxon rank sum tests. IL = interleukin; IP-10 = human interferon-inducible protein; TNF-{alpha} = tumor necrosis factor-{alpha}.

 
Serious Adverse Events
One patient died in a parachute accident 1 wk after the third infusion of infliximab. This unrelated tragedy was the only serious adverse event reported.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In this study, treatment with infliximab reduced the number of moderate exacerbations in patients with asthma, as monitored by morning and evening use of an electronic spirometer incorporating a clinical diary. Although infliximab therapy did not show significant efficacy for the primary endpoint of morning PEF, infliximab did produce a significant decrease in the diurnal variation of the PEF rate. The decrease in symptom scores with both infliximab and placebo may be due to a tendency to overreport symptoms during the run-in period. There were no significant effects of infliximab on levels of blood or sputum eosinophils, although levels of sputum TNF-{alpha} were decreased by infliximab therapy. No safety issues were raised in this study, with infliximab exhibiting a safety profile similar to placebo.

In patients with severe asthma, there are recognized to be multiple mechanisms underlying corticosteroid insensitivity (6), and there is clearly the need to identify novel additional antiinflammatory therapies. Despite initially promising clinical trial data in severe asthma with low-dose methotrexate (38), low-dose cyclosporin A (39, 40), and mAb against CD4 (41), these agents have generally been disappointing in clinical practice (5). mAb directed against IL-5 has been disappointing in asthma: after inhaled allergen challenge, mAbs have failed to inhibit the late asthmatic response (42) and have had limited effects on clinical parameters in a pilot study in severe asthma (43) despite reducing deposition of proteins in the bronchial subepithelial basement membrane in mild atopic asthma (44). However, although evidence that intravenous immunoglobulin therapy in severe asthma has been considered equivocal (45), in patients with refractory asthma and functional antibody deficiency immunoglobulin therapy can have remarkable benefit (46).

Our study population does not conform to the GINA guidelines, because according to these guidelines patients with symptomatic moderate persistent asthma should be treated with inhaled corticosteroids combined with inhaled long-acting beta2-agonists (3). Our preliminary study was intended to assess the safety and efficacy of infliximab on a population that has sufficient safety reserves and is free from long-acting bronchodilators to ease assessment of effects on lung function measures. Thus, the population that we studied does not conform to the real-life situation of patients treated within GINA guidelines. Hence, in the future it will be important to study effects of TNF-{alpha}–directed therapy in larger studies of patients with more severe asthma who are receiving long-acting beta2-agonists in addition to both inhaled and oral corticosteroid therapy. In this group of patients with severe asthma, there is a greater medical need, and this may justify the expense and adverse events associated with therapy targeting TNF-{alpha}. In addition, infliximab may have lead to a more clear benefit in a group of patients with more severe asthma because there is increasing evidence for a role for TNF-{alpha} in refractory asthma (31), and because patients with more severe asthma may have had more room for improvement.

The definition of exacerbations is a controversial issue in both asthma and chronic obstructive pulmonary disease. In our study, we used a definition similar to that used in the FACET study (34), which compares exacerbations with lung function, beta2-agonist usage, and symptoms in the baseline period. Because our patients were required to be "symptomatic" at baseline, an increased severity of clinical parameters was considered by us to represent a "moderate" exacerbation. However, we note that an increased moderate exacerbation rate in the placebo group was not mirrored by other differences in asthma control measures, such as rescue beta2-agonist usage. None of the exacerbations in our study warranted treatment with oral corticosteroids or hospitalization, so they cannot be considered to be severe. Hence, our data on exacerbations are preliminary and require confirmation in a study of appropriate power and length. In addition, some aspects of the definitions of exacerbations and loss of asthma control overlap (47), and it is possible to infer from our study that infliximab may provide superior asthma control in terms of decreased diurnal variability.

It has been hypothesized that there may be increased involvement of TNF-{alpha} in severe, oral, corticosteroid-dependent asthma. The decrease in the infliximab-treated patients who had mild exacerbations may translate into an important effect of infliximab on prevention of serious exacerbations in more severe disease, and it will also be important to also determine whether infliximab has steroid-sparing properties in stable disease. It is relevant to note that when an mAb directed against IgE (anti-IgE, omalizumab; Novartis, East Hanover, NJ) is used in severe asthma, important clinical effects including a decrease in the incidence of severe exacerbations and a decreased requirement for inhaled and oral corticosteroids are observed, despite relatively small effects on lung function (48–50).

Patients with asthma have elevated levels of sputum TNF-{alpha} (17, 51), and in this study we demonstrated that sputum TNF-{alpha} levels are lowered (by approximately one-half) when patients are given infliximab. However, it is of interest that lowering sputum TNF-{alpha} did not affect eosinophil levels in blood or sputum. Nevertheless there was a trend toward fewer sputum neutrophils, and at Week 8, there were significant differences in IL-1{alpha}, IL-6, IP-10, and IL-8. It is possible that higher and longer term doses of infliximab therapy are required to cause further reductions in sputum TNF-{alpha} and possible beneficial effects on lung function. Nevertheless, infliximab did cause a decrease in the number of patients with moderate exacerbations without causing a decrease in numbers of sputum eosinophils.

Interestingly, preliminary studies of the soluble TNF-{alpha} receptor etanercept in 10 patients with severe asthma found improvements in FEV1, airway responsiveness to methacholine, and asthma-related quality of life (30, 31). However, there are differences in the pharmacology of mAbs and soluble receptors directed against TNF-{alpha}; and although they have similar efficacy in inflammatory arthritides, infliximab may be more efficacious in the treatment of granulomatous diseases, such as Crohn's disease, sarcoidosis, and Wegener's granulomatosis (52). Although our study was not powered to detect effects on the number of exacerbations, by using detailed electronic monitoring we saw a significant decrease in moderate exacerbations, and it will be important to see whether this translates in severe asthma into decreased incidence of severe exacerbations and hospitalization. In a study of etanercept over 10 wk, there was a trend toward improvement in post-bronchodilator FEV1 with time (31), and it possible that longer term treatment with infliximab would have added benefit.

In conclusion, although infliximab did not demonstrate significant clinical efficacy in terms of the primary endpoint of lung function in patients with symptomatic moderate asthma, there was a significant decrease in the number of patients with moderate exacerbations in the infliximab group compared with placebo. Given that infliximab therapy was well tolerated and appeared to reduce the incidence of asthma exacerbations, anti–TNF-{alpha} therapy merits further study in larger clinical trials in patients with severe asthma.


   FOOTNOTES
 
Supported by Centocor Research and Development, Inc., Malvern, Pennsylvania, and R.W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey.

Originally Published in Press as DOI: 10.1164/rccm.200601-0720OC on July 13, 2006

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. B.R.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. G.C.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.J.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. L.M.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. H. N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. A.S.Z. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. J.T. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. E.S.B. is an employee of Centocor who is responsible for drugs for cardiovascular or pulmonary indication. He has collaborated on the design and analysis of this study. O.M.K. has been reimbursed by various pharmaceutical companies for attending conferences (GlaxoSmithKline, AstraZeneca, IVAX, Bayer). P.J.B. has received research funding, lecture fees, and has served on scientific advisory boards for GlaxoSmithKline, AstraZeneca, Boehringer-Ingelheim, Novartis, Altana, Pfizer, and Scios. T.T.H. has received research grants (2004 to 2005) of $250,000 from GlaxoSmithKline, $200,000 from Novartis, and $100,000 from Millenium.

Received in original form January 17, 2006; accepted in final form June 23, 2006


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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