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(Chest. 2003;124:177-185.)
© 2003 American College of Chest Physicians

Etanercept for the Treatment of Stage II and III Progressive Pulmonary Sarcoidosis*

James P. Utz, MD, FCCP; Andrew H. Limper, MD, FCCP; Sanjay Kalra, MD, FCCP; Ulrich Specks, MD; John P. Scott, MD; Zvezdana Vuk-Pavlovic, PhD and Darrell R. Schroeder, MS

* From the Divisions of Pulmonary and Critical Care Medicine (Drs. Utz, Limper, Kalra, Specks, Scott, and Vuk-Pavlovic) and Biostatistics (Mr. Schroeder), Mayo Clinic and Mayo Foundation, Rochester, MN.

Correspondence to: James P. Utz, MD, FCCP, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN 55905


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Tumor necrosis factor (TNF)-{alpha} is produced by macrophages and other cells, and is believed to participate in granulomatous inflammation. Targeted antagonism of TNF-{alpha} has been proposed as a novel treatment strategy for sarcoidosis. Etanercept is a dimeric fusion protein that binds specifically to TNF-{alpha}, rendering it biologically inactive.

Objective: To assess whether etanercept has potential efficacy in the treatment of progressive pulmonary sarcoidosis.

Design: Prospective, open-label, phase-2 treatment trial.

Setting: Mayo Clinic, Rochester, MN.

Patients: Stage II or III progressive pulmonary sarcoidosis.

Intervention: Etanercept, 25 mg subcutaneously twice weekly.

Measurements: Pulmonary function, chest radiographs, dyspnea, and TNF-{alpha} levels in serum and BAL fluid.

Results: The study was terminated after the enrollment of 17 patients due to an early-stop clause of the pretrial study design related to excessive treatment failures. Neither absolute levels of TNF-{alpha} nor TNF-{alpha} activity in the serum, BAL fluid, or alveolar macrophages were able to predict which patients would respond to etanercept.

Conclusions: In patients with progressive stage II or III pulmonary sarcoidosis, etanercept was frequently associated with early or late treatment failure. These data would not support the design of a large multicenter randomized trial comparing etanercept with conventional corticosteroid therapy.

Key Words: BAL • etanercept • sarcoidosis • tumor necrosis factor-{alpha}


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Sarcoidosis is a systemic granulomatous disorder of indeterminate origin manifested by the presence of noncaseating granulomas. The natural history of pulmonary sarcoidosis ranges from spontaneous remission to chronic disease, resulting in the insidious loss of lung function.1 2 3 4 5 Corticosteroids are the mainstay of therapy, although their use frequently results in significant side effects.

The initiation, maintenance, and resolution of granulomatous lesions are orchestrated through a complex interaction between helper T cells, accessory cells, and cytokines.6 7 8 9 10 Tumor necrosis factor (TNF)-{alpha} is a 17.5-kd protein that plays a significant role in antigen-stimulated, cell-mediated immune responses and in the development of noncaseating granulomas in a variety of diseases.11 12 13 14 15 In sarcoidosis, alveolar macrophage-derived TNF-{alpha} participates in the induction and maintenance of granulomas.8 16 17 18 High levels of TNF-{alpha} and high levels of TNF-{alpha} released from alveolar macrophages seem to correlate with disease progression.19 In light of its inhibitory activity against TNF-{alpha}, pentoxifylline has been proposed as a therapeutic agent for sarcoidosis.15 19 20 21

Etanercept is a dimeric fusion protein consisting of the extracellular ligand-binding domain of the human TNF receptor linked to the Fc portion of human IgG1. Etanercept specifically binds TNF-{alpha}, blocking its interaction with cell surface TNF-{alpha} receptors, rendering TNF-{alpha} biologically inactive. The major focus of this study was to secure preliminary data regarding the potential efficacy of etanercept in the treatment of pulmonary sarcoidosis. Study hypotheses included the following: (1) patients treated with etanercept will clinically improve or remain stable, obviating the need for corticosteroid treatment; and (2) patients responding to etanercept will exhibit higher pretreatment lung TNF-{alpha} expression as well as the suppression of lung TNF-{alpha} expression during treatment compared to nonresponders.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The institutional review board approved the study and an investigative new drug number was obtained from the US Food and Drug Administration. Sponsoring organizations had no part in the design of the study, the collection, analysis, and interpretation of the data, or the decision to publish the finished article. Seventeen patients (10 women and 7 men) with progressive stage II or III pulmonary sarcoidosis3 were enrolled into the study. The diagnosis of sarcoidosis was based on biopsy demonstrating noncaseating granulomas and a compatible clinical picture, consistent with American Thoracic Society guidelines. In order to minimize the confounding issue of spontaneous remission, only patients demonstrating progressive radiographic and/or physiologic changes were eligible. Exclusion criteria included extrapulmonary organ involvement or metabolic derangement requiring treatment, other pulmonary disease, or use of other immunosuppressive agents within the preceding 3 months.

Laboratory studies performed at baseline, 3, 6, 12, and 15 months included a chest radiograph (CXR), pulmonary function testing (PFT), arterial blood gas analysis, chemistry panel, CBC count, and ophthalmology evaluation. PFT was performed according to American Thoracic Society guidelines22 23 using spirometer, body plethysmograph, and single-breath diffusion capacity systems (models 1070 and 1085; Medical Graphics Corporation; St. Paul, MN). CXRs were compared to the original baseline CXR and were classified as improved, stable, or deteriorated based on the consensus review of two radiologists, who had no knowledge of any of the other clinical data. Dyspnea was evaluated at each visit and was classified on a scale of 0 to 4, as outlined by the American Thoracic Society and the American Medical Association.24 Answers to the 36-item short form health survey (SF-36) were obtained at each visit, but the information was not used for treatment decisions.25 All patients underwent measurements of baseline levels of TNF-{alpha} in serum and BAL fluid, and patients who were still receiving the study drug at 6 months underwent a repeat measurements. All patients received etanercept, 25 mg subcutaneously twice weekly, as the sole therapy.

BAL
BAL was performed in the region of greatest radiographic abnormality using five 20-mL aliquots of normal saline solution, as previously described.26 The fluid returned from all five aliquots was pooled and placed on ice. The cellular components were separated by centrifugation at 500g for 5 min. The cell-free supernatant was flash frozen at -70°C, and soluble TNF-{alpha} assays were performed on the entire study group simultaneously as described below. Cell pellets were washed twice with Hanks’ balanced salt solution, and differential cell counts were determined using cytopreparation smears.26

Assessment of Macrophage Release of TNF-{alpha}: The spontaneous and lipopolysaccharide (LPS)-stimulatable release of TNF-{alpha} from alveolar macrophages recovered by BAL was evaluated as follows. Cells were resuspended in mixed media (50% medium 199, 50% RPMI, 2 mmol/L glutamine, penicillin [10,000 U/L], streptomycin [1 mg/L], and amphotericin [25 µg/L]), and the macrophages were purified by adhesion to plastic.27 Macrophages (2 x 105 cells per well) were placed in 96-well plates, were allowed to adhere for 60 min, and were gently washed to remove any unattached cells. Macrophages were incubated for 18 h at 37°C in the presence of 0 or 5 µg/mL LPS (from Pseudomonas aeruginosa; Sigma; St. Louis, MO). The media were removed and frozen (-70°C) until the TNF-{alpha} assays were performed.

Quantification of TNF-{alpha} Bioactivity and Immunoreactivity: TNF-{alpha} immunoreactivity and bioactivity were assayed separately on the sera, the BAL supernatants, and the media derived from macrophages cultured with or without LPS. Total TNF-{alpha} was determined using commercial enzyme-linked immunoassay (ELISA) reagents (eBioscience; San Diego, CA). In parallel, TNF-{alpha} bioactivity was assayed using an L929 bioassay, as previously described.28 29 Recombinant human TNF-{alpha} (Genzyme; Cambridge, MA) was used as the standard for this bioassay. Following incubation with standards and samples, L929 viability was assessed by staining (XTT Proliferation Assay; Roche Pharmaceuticals; Basel, Switzerland).

Evaluation of Effectiveness of Therapy
Patients were classified as improved, stable, or deteriorated, relative to their baseline status, based on five measures of pulmonary function (FEV1, FVC, total lung capacity, diffusing capacity of the lung for carbon monoxide, and PaO2), CXR, and dyspnea level. Deterioration was defined as a significant worsening from baseline in two or more of these parameters. A significant worsening was defined as deterioration of >= 10% from baseline in a PFT parameter, a progression of one level in the dyspnea scale, or a worsening in the CXR. Stability was defined as no significant change in these parameters. A significant deterioration or improvement in a single parameter only or a combination of one better and one worse parameter were also considered to represent stability. Improvement was defined as a significant improvement in at least two of the previously noted parameters. In the absence of deterioration, patients continued receiving therapy with etanercept. At 12 months, if stability or improvement was maintained, the patient was considered to be a treatment success and was withdrawn from therapy with the medication. Treatment failure was defined as deterioration of the patient while receiving etanercept, the inability to tolerate etanercept, or the concurrent use of other immunosuppressive agents.

Statistical Analysis
Treatment success was defined as clinical improvement or stability through the end of the treatment phase (ie, 12 months). Prior to initiating the trial, it was anticipated that the success rate would be > 75% and that any success rate of > 50% would be clinically relevant. A pretrial statistical analysis predicted that a sample size of 30 patients would provide statistical power of approximately 90% to test (one-tailed test; {alpha} = 0.05) the hypothesized success rate of 50%. Given the open-label, one-sample study design, an early-stopping rule was included, whereby if 11 patients were observed to experience treatment failure, the enrollment of additional subjects would be discontinued with the conclusion that the null hypothesis (H0, success rate <= 50%) could not be rejected at the 0.05 significance level.

The data are presented as the mean ± SD or the median (25th to 75th percentile) for continuous variables and percentages for categoric variables. Health status was measured using the SF-36. The physical and mental composite scores for the SF-36 were scored according to published guidelines.25 Standardized t scores, scaled to have a mean of 50 and an SD of 10 for the reference population, were calculated for each composite scale using age-specific and sex-specific means and SDs for the general US population.25 Potential changes in the SF-36 composite scores over time were assessed using a repeated measures analysis, with time modeled as a regression variable.30 Changes in TNF-{alpha} immunoreactivity and bioactivity from baseline to 6 months were evaluated using the signed rank test. The baseline characteristics of patients determined to be treatment successes vs failures were compared using the two-sample t test for continuous variables and the Fisher exact test for categoric variables. In all cases, p values of <= 0.05 were considered to be statistically significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Seventeen patients were treated based on progressive infiltrates or worsening pulmonary function (white, 16 patients; African-American, 1 patient). Fourteen patients demonstrated stage II disease, and 3 demonstrated stage III disease. Baseline results of PFTs are outlined in Table 1 . The study intended to enroll 30 participants but was stopped after enrolling 17 patients due to reaching the conditions of the early-stop rule. Sixteen patients completed the treatment phase, while 1 patient withdrew at 3 months after learning that the early-stop rule had been engaged. At withdrawal from the study, her condition was improved. One patient declined to return for her 15-month visit but was considered to be a success at her 12-month visit and was withdrawn from etanercept therapy per the protocol. All patients returned for all other visits.


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  		Table 1.. Baseline Characteristics (n = 17)*

 
Treatment outcomes are summarized in Table 2 . Five of 17 patients were treatment successes, while another patient withdrew from the study after 3 months, as described previously. Eleven patients did not respond to therapy (ie, were "treatment failures") [3 months, 5 patients; 6 months, 1 patient; 9 months, 1 patient; 12 months, 4 patients]. The fact that patients did not respond to therapy was secondary to the deterioration seen both in radiographs and in the results of PFTs. No patient demonstrated hypoxemia, and therefore follow-up arterial blood gas measurements were not performed. One patient failed therapy because of hypercalcemia and renal insufficiency. At the time of treatment failure, the patient was otherwise stable. Among the five patients who underwent treatment successfully, none had uniform improvement in all parameters. Although statistical analyses are limited by the sample size, there did not appear to be any significant correlation or trend predicting success or failure with respect to gender, age, race, height, weight, radiographic stage, baseline dyspnea level, or pulmonary function parameters.


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  		Table 2.. Treatment Outcome*

 
All five patients still successful at 12 months were withdrawn from the study drug. Four of the five patients returned for a 15-month follow-up, and none demonstrated disease progression. The fifth patient was subjectively stable but declined to return for her 15-month visit. Of the 11 patients who failed treatment, 8 patients began receiving therapy with corticosteroids. Seven of eight patients showed improvement, while the remaining patient obtained follow-up elsewhere. Of the remaining three patients, one improved after receiving therapy with hydroxychloroquine and two declined therapy. One of those patients declining therapy was stable at 6 months, and the other began receiving therapy with pentoxifylline for disease progression at 6 months (the patient was intolerant of corticosteroids). The patient’s condition had improved after 4 months of therapy.

The administration of etanercept was welltolerated, but two serious adverse events occurred. One patient did not respond to etanercept therapy at 9 months and subsequently (8 months later) was found to have a localized intestinal lymphoma. He underwent surgery and chemotherapy, and had no evidence of lymphoma 16 months later. Another patient failed to respond to etanercept therapy at 12 months. Concurrently, he complained of worsening of chronic nasal congestion, and a nasopharyngeal extramedullary plasmacytoma was discovered and resected. The findings of an extensive workup for multiple myeloma were negative. The patient was disease-free at 12 months.

Serum TNF-{alpha} was present at low but measurable levels at baseline, with a median level of 5 pg/mL (25th to 75th percentile, 3 to 6 pg/mL) detected by ELISA (Fig 1 ). Interestingly, ELISA measurements at 6 months demonstrated significant increases in total serum level of TNF-{alpha} (median, 156 pg/mL; 25th to 75th percentile, 102 to 368 pg/mL; p = 0.001) compared to baseline. No consistent differences were observed in either TNF-{alpha} level (determined by ELISA) or bioactivity comparing those patients whose conditions had improved or those in whom the disease had progressed while receiving etanercept. In contrast to measurements performed on BAL fluid and cell culture media, the L929 assay could not be used to determine TNF-{alpha} bioactivity in the serum samples. The basal absorbance spectrum of serum rendered the assay unreliable.



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  		Figure 1.. Total serum TNF-{alpha} levels detected by ELISA at baseline and 6 months according to treatment outcome. Total serum TNF-{alpha} level at 6 months was significantly increased relative to baseline (p = 0.001 [signed rank test]).

 
ELISA measurements of cell-free BAL fluid similarly revealed low levels of TNF-{alpha} at baseline (median, 6 pg/mL; 25th to 75th percentile, 5 to 7 pg/mL), with some suggestion of a minimal increase at 6 months (median, 7 pg/mL; 25th to 75th percentile, 5 to 10 pg/mL; p = 0.064) compared to baseline. TNF-{alpha} bioactivity in cell-free BAL fluid was again low and unchanged following treatment with etanercept. Furthermore, no significant differences were observed between responders and nonresponders.

Alveolar macrophages derived from these sarcoidosis patients exhibited variable basal release of TNF-{alpha} in the absence of LPS stimulation (Fig 2 , top). No consistent differences in macrophage secretion of TNF-{alpha} at baseline were observed comparing those patients who ultimately had a favorable course to those in whom the disease progressed during treatment with etanercept. Similar findings were observed in the extent of TNF-{alpha} bioactivity released from macrophages under LPS-free culture conditions (Fig 2 , bottom) Furthermore, treatment with etanercept was associated with no consistent changes in basal macrophage TNF-{alpha} release, as measured by either ELISA or L929 bioassay.



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  		Figure 2.. Release of TNF-{alpha} (top) and TNF-{alpha} bioactivity (bottom) from alveolar macrophages in the absence of LPS stimulation at baseline and 6 months according to treatment outcome.

 
Macrophages cultured with LPS (5 µg/mL) responded with strong but variable release of TNF-{alpha} into the culture media (Fig 3 , top). Again, no consistent differences in macrophage secretion of TNF-{alpha}, as measured by ELISA after LPS stimulation, were observed in those patients with a favorable outcome compared to those whose disease progressed. The extent of TNF-{alpha} bioactivity released from macrophages cultured with LPS also was not consistently associated with a favorable clinical response (Fig 3 , bottom).



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  		Figure 3.. Release of TNF-{alpha} (top) and TNF-{alpha} bioactivity (bottom) from alveolar macrophages in the presence of LPS stimulation at baseline and 6 months according to treatment outcome.

 
Baseline SF-36 composite scores are summarized in Table 1 . At baseline, the mean physical composite t score (41.8 ± 10.0) was significantly (p = 0.003) < 50, indicating physical status that is worse than expected for people of similar age and gender in the US population. The mean mental composite t score (49.0 ± 8.8) was not significantly different than that expected for the general population. From repeated measures analysis of data collected over the 12-month treatment phase, there was no evidence to suggest that the physical (p = 0.17) or mental (p = 0.15) composite score changed as a function of time.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
TNF-{alpha} is produced by macrophages and other cells, and is believed to participate in the induction and maintenance of granulomatous inflammation.8 13 14 15 16 17 Based on a preliminary report suggesting that pentoxifylline may be an effective agent in treating patients with pulmonary sarcoidosis because of its anti-TNF-{alpha} effect,20 etanercept was selected for this study because it specifically binds TNF-{alpha}, rendering it biologically inactive. Because most patients who were treated in the pentoxifylline study exhibited a favorable response, we postulated that a pure and potent TNF-{alpha} antagonist, such as etenercept, might be expected to produce similar or greater response rates.21 The dose of etanercept that was tested was that which induced remission in patients with rheumatoid arthritis.31 32 This trial was ended early because an excessive number of patients experienced disease progression while taking etanercept.

Since this study was completed, two reports have been published using infliximab (a chimeric, monoclonal, human-murine antibody against human TNF-{alpha}) in the treatment of several patients with sarcoidosis. The first study33 involved the apparently successful treatment of a patient with an unusual presentation of sarcoidosis, including a severe protein-losing enteropathy, hypoalbuminemia, and proximal myopathy, which had not responded to therapy with corticosteroids. The second study34 reported on three patients (two with skin involvement, and one with pulmonary involvement) who were treated successfully with infliximab. In two patients, cutaneous disease (lupus pernio) improved while they were receiving infliximab therapy, while the single patient with interstitial disease had an improvement in vital capacity that was coincident with treatment.

In our study, only 5 of 17 patients clinically improved with etanercept as the exclusive therapy. No baseline characteristics predicted whether patients would clinically respond. In particular, the basal level of total TNF-{alpha} or TNF-{alpha} bioactivity in serum or BAL fluid, or released from cultured alveolar macrophages failed to predict the subset of patients who had favorable responses.

One of the difficulties in evaluating therapeutic efficacy in sarcoidosis is that spontaneous remission may occur, confounding the interpretation of any potential drug benefit. Since spontaneous remission is common in stage I disease, those patients were excluded from the study. In order to mitigate the issue of spontaneous remission, only patients with stage II and III disease demonstrating progressive pulmonary disease were enrolled. Since etanercept had not been used to treat sarcoidosis previously, a preliminary open-label phase 2 strategy was employed in order to assess the potential efficacy and safety of using this agent prior to considering a larger multicenter trial comparing etanercept to conventional corticosteroid therapy.

The reason for the significant difference in treatment response between the patients treated with etanercept in our trial and those treated with pentoxifylline in the study by Zabel et al21 is unclear. In that study,21 23 previously untreated patients with documented pulmonary disease progression received pentoxifylline (25 mg/kg daily) for 6 months. Three patients discontinued pentoxifylline therapy because of side effects, while two others were lost to follow-up. Of the 18 remaining patients, all responded (ie, their condition remained stable or improved), compared with 5 of 17 in our study who used a more specific TNF-{alpha} antagonist. There were some differences in the baseline characteristics of the patients. In the pentoxifylline study, only 15 of 23 patients had stage II or III disease, compared with 17 of 17 patients in our study. Zabel et al21 included three patients with stage I disease and five with stage IV disease. This may overestimate the positive treatment effect (which was defined as stability or improvement) because stage I patients frequently spontaneously remit and stage IV patients have fixed fibrosis. To our knowledge, the report by Zabel et al21 is the only published prospective experience using pentoxifylline to treat patients with sarcoidosis. Pentoxifylline may be superior to etanercept by virtue of some other anti-inflammatory or immunomodulatory effect. Alternatively, it is possible that etanercept at the concentrations provided did not adequately suppress TNF-{alpha} activity or that incomparable study populations may obscure the true relative efficacy of the two drugs. For instance, recent work has suggested that TNF-{alpha} polymorphisms may be responsible for disparate clinical manifestations of the disease.35 36 37 38 This raises the possibility that genetic differences may confer heterogeneous treatment responses to anti-TNF-{alpha} agents, even though TNF-{alpha} gene polymorphisms do not seem to affect the TNF-{alpha} release of mononuclear cells from sarcoidosis patients.39

BAL was performed in the study by Zabel et al21 at entry, and BAL findings and radiographic stage did not "facilitate" distinguishing patients whose conditions improved with pentoxifylline therapy from those with the disease whose conditions became stable. In our study, neither absolute TNF-{alpha} levels nor TNF-{alpha} activity in serum or BAL, or the amount released from alveolar macrophages predicted treatment response. Interestingly, we observed a significant increase in total TNF-{alpha} measured by ELISA in the serum following treatment with etanercept. This may reflect increased circulating levels of total TNF-{alpha} bound to etanercept and potentially neutralized by this agent. Attempts to measure residual TNF-{alpha} bioactivity in the serum were not possible due to the assay conditions. Nonetheless, the increased circulating levels of TNF-{alpha} detected by ELISA provide biological evidence that the patients enrolled in this study likely were compliant with the treatment regimen.

Anti-TNF-{alpha} therapy may be associated with adverse events, including injection site reactions and increased mortality among patients in septic states. Infliximab use has been associated with the development of active tuberculosis,40 and postmarketing reports of rare cases of tuberculosis have been observed in patients receiving etanercept (US Food and Drug Administration; unpublished data). All patients in this study tolerated the administration of etanercept without difficulty. There were no serious infections in any patient. There were two patients with serious adverse events. One patient was found to have a nasopharyngeal plasmacytoma after 12 months of receiving etanercept therapy, while another patient had an intestinal lymphoma resected 9 months after stopping etanercept therapy. Although lymphoproliferative disorders have been seen with increased frequency in patients with immune deficiency states, prelicensure and postlicensure reports have not yet established an increase in lymphoproliferative disorders with the use of etanercept (unpublished data). This potential association must be monitored carefully if anti-TNF-{alpha} agents are to be considered for use in patients with sarcoidosis and other inflammatory conditions.

To our knowledge, this prospective study is the only report on the use of etanercept therapy in the treatment of sarcoidosis. In patients with progressive stage II or III pulmonary sarcoidosis, there was a preponderance of treatment failures using etanercept as a single agent. The potential weaknesses of this study include the fact that our study population was predominantly white and that the mean age was higher than that of the average pulmonary sarcoidosis patient. It is possible that the dose of etanercept used in this study (that which is used in rheumatoid arthritis) is insufficient for patients with sarcoidosis. It is not clear from these data whether there exists a small subset of patients with pulmonary sarcoidosis who respond to therapy with etanercept alone. Given the relative efficacy of therapy with corticosteroids in patients with pulmonary sarcoidosis, newer therapies must demonstrate increased efficacy, reduced toxicity, or reduced cost. These issues are important when one considers the potential toxicity and expense of anti-TNF-{alpha} agents, particularly with longer term use. Because of the frequency of treatment failure, there would appear to be less than compelling evidence of efficacy with which to propose a larger multicenter randomized trial comparing etanercept to conventional corticosteroid therapy in patients with progressive pulmonary sarcoidosis.


   Acknowledgements
 
The authors wish to thank Susan D. Fisher, RN, Ms. Gail Caron, and Ms. Kimberly Franks, whose administrative support was essential for completion of this trial. The authors also appreciate the technical assistance of Mr. Joseph Standing who assisted in the measurement of TNF-{alpha}.


   Footnotes
 
Abbreviations: CXR = chest radiograph; ELISA = enzyme-linked immunoassay; LPS = lipopolysaccharide; PFT = pulmonary function test; SF-36 = 36-item short form health survey; TNF = tumor necrosis factor

This research was supported by funds from the Mayo Foundation, Immunex Corporation, and the Robert N. Brewer Foundation.

Received for publication September 10, 2002. Accepted for publication December 20, 2002.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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