Chest Email Content Delivery
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Guest Access | Sign In via User Name/Password
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via ISI Web of Science (24)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Baughman, R. P.
Right arrow Articles by Kaufman, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Baughman, R. P.
Right arrow Articles by Kaufman, A.
(Chest. 2005;128:1062-1047.)
© 2005 American College of Chest Physicians

Etanercept for Refractory Ocular Sarcoidosis*

Results of a Double-Blind Randomized Trial

Robert P. Baughman, MD, FCCP; Elyse E. Lower, MD; Deborah A. Bradley, MD; Lawrence A. Raymond, MD and Adam Kaufman, MD

*From the Departments of Internal Medicine (Drs. Baughman, Lower, and Bradley) and Ophthalmology (Drs. Raymond and Kaufman), University of Cincinnati Medical Center, Cincinnati, OH.

Correspondence to: Robert P. Baughman MD, 1001 Holmes, Eden Ave, University of Cincinnati Medical Center, Cincinnati, OH 45267-0565; e-mail address bob.baughman{at}uc.edu


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Purpose: Study a tumor necrosis factor receptor antagonist (etanercept) in the treatment of chronic ocular sarcoidosis.

Subjects and methods: Eighteen patients with ocular sarcoidosis and ongoing inflammation in the eyes. All patients had received at least 6 months of therapy with methotrexate and were currently receiving corticosteroids. Patients were randomized to receive either etanercept, 25 mg subcutaneously twice a week, or placebo in a double-blind randomized trial. Treatment for ocular inflammation with systemic and local corticosteroids at the beginning and end of 6 months of treatment was noted. All patients underwent an ocular examination at the beginning and the end of the study by one ophthalmologist who was unaware of what treatment the patient was receiving.

Results: Three of the patients treated with etanercept and one treated with placebo were being treated with lower doses of corticosteroids by the end of the study. However, three of the etanercept patients and one of the placebo patients required larger doses of corticosteroids by the end of the study. The ophthalmology global assessment improved for two of the etanercept-treated patients and three of the placebo-treated patients.

Conclusion: For most patients, therapy with etanercept was not associated with a significant improvement in their chronic ocular disease.

Key Words: etanercept • methotrexate • ocular sarcoidosis • tumor necrosis factor


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Ocular disease is a common feature of sarcoidosis.123 The manifestations include anterior, intermediate, and posterior uveitis. The intermediate and/or posterior uveitis is often chronic and can be associated with a loss of vision.3 In addition to the inflammation, lumpy or flat glial membrane, known as snowbanking, over the pars plana of the ciliary body transforms intermediate uveitis into pars planitis. The pars plana has been used as a specific landmark for inflammation. Inflammation in that area is associated with chronic disease and represents a difficult management issue for the ophthalmologist.4 Sarcoidosis is one of the more important causes of pars planitis.

The treatment for uveitis includes therapy with corticosteroids, used topically, periocularly, and/or systemically.5 However, the long-term local and systemic use of corticosteroids is often associated with side effects, including cataracts and glaucoma.56 Because of these complications, alternatives to steroid therapy are often sought for the treatment of chronic uveitis. Among the immunosuppressive drugs, methotrexate has been commonly used.78 Although methotrexate is useful in many patients, incomplete control of the uveitis can sometimes occur.789

The monoclonal antibody infliximab binds tumor necrosis factor (TNF) and has been used successfully to treat chronic uveitis in patients with Behcet disease.10 We have also reported11 the utility of infliximab for the treatment of chronic sarcoidosis. However, none of those patients had ocular disease due to their sarcoidosis.

Etanercept is a TNF receptor antagonist that has been found to be as effective as infliximab for the treatment of rheumatoid arthritis.121314 We studied the effectiveness of etanercept in the treatment of patients with ocular sarcoidosis who have persistent disease despite treatment with methotrexate. In this study, we were unable to demonstrate a significant additional effect of etanercept.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Sarcoidosis was diagnosed based on the American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disease criteria.15 One or more manifestations of ocular disease due to sarcoidosis were diagnosed in all patients. Although patients could have other manifestations of sarcoidosis, it was their ocular disease that drove their therapy. Patients had received methotrexate for at least 6 months for the treatment of their sarcoidosis using a previously described protocol.16 Patients with active ocular disease despite this regimen were eligible for randomization. All patients provided written informed consent to participate in a protocol approved by the University of Cincinnati Institutional Review Board.

Active eye disease was defined on the basis of new or recurrent eye disease, including cystoid macular edema or the presence of more than trace cells on slit lamp examination. Patients to whom a regimen of topical steroids applied four or more times a day was prescribed were considered to have active disease, as well as patients who had received a periocular injection of corticosteroids within a month of randomization. In patients who had received an intraocular injection, the examination findings at the time of the injection were used as the baseline data. Patients with posterior uveitis were examined specifically for evidence of pars planitis. We defined pars planitis as a chronic inflammatory process in the pars plane, associated with snowballs and snowbanking.4

All patients gave a focused medical history, and a physical examination assessed extraocular organ involvement. In addition, a chest roentgenogram, FVC measurement, serum liver function studies, serum calcium level, and a CBC count were obtained at the time of the screening visit. The presence of definite or probable organ involvement due to sarcoidosis was determined using a previously described organ system score.17

Patients were then randomized to receive either etanercept, 25 mg, or an equal volume of physiologic saline solution subcutaneously twice a week for 6 months. Patients were seen monthly to assess for local toxicity from the injections. They were seen every 2 months for a CBC count, and liver and renal function studies to monitor methotrexate toxicity while participating in the study. Patients were followed up for a total of 7 months, including 1 month after withdrawal of the study drug to monitor for the worsening of symptoms.

The ophthalmologist saw the patient initially and at the end of 6 months of therapy. The patients continued receiving treatment with etanercept or placebo until the ophthalmologist could see them at the follow-up examination. In some cases, the patients may have received as much as 2 extra weeks of treatment before they could be evaluated. There was no significant difference in the number of days the etanercept group received compared to the placebo group. The ophthalmologist conducted a detailed examination, including visual acuity, external examination, slitlamp biomicroscopy, pressure measurement, and dilated vitreous and fundus examinations. An examination conducted with the pupil dilated with indirect ophthalmoscopy and scleral indentation was performed every 3 to 6 months. A slitlamp examination was also performed every 1 to 3 months. Fluorescein angiography to detect retinal vasculitis and macular edema was performed as indicated.

One ophthalmologist (A.K.) evaluated all 18 of the patients initially and at the end of the study. A retinal specialist (L.R.) saw 10 of these patients during the course of the study. All patients were seen in the interstitial lung disease and sarcoidosis clinic (by R.B. and E.L.) at least once every month. Changes in systemic therapy, including the use of prednisone and methotrexate, were made in this clinic on the advice of the ophthalmologists. None of the physicians was aware of whether the patient was receiving etanercept or placebo.

We assessed the ocular outcome in two ways. The dose of corticosteroids either systemically or topical initially and at 6 months was compared. In addition, if a patient had received a periocular injection of corticosteroids after month 4, the patient was assumed to have worsening disease. In addition, one ophthalmologist (A.K.) provided his global assessment of whether the patient was better or worse after 6 months of therapy. This assessment was provided before the blind was broken.

The primary end point of the study was the change of the ophthalmologist examination after 6 months of therapy. This was based on a specific evaluation by one ophthalmologist (A.K.) who was unaware of which treatment the patient was receiving. The routine examinations by the treating ophthalmologists could take place every 1 to 6 months, usually every 2 months. These evaluations led to changes in the patient’s therapy, including the changes in topical corticosteroids, the use of periocular corticosteroid injections, and changes in systemic corticosteroids, as indicated. This was the other end point of the study that we reported. The patient was also seen every 2 months to monitor for toxicity from methotrexate and the study medications. These visits were to nonophthalmologists (R.B. and E.L.), and the patients were evaluated in a sarcoidosis clinic.

Statistical Analysis
Comparisons between groups were made using nonparametric techniques. These included the Mann Whitney U test and the {chi}2 test. A p value of < 0.05 was considered to be significant. Based on our prior clinical experience with the use of methotrexate for the treatment of ocular sarcoidosis,9 we projected that the condition of < 10% of patients would improve with placebo therapy after receiving methotrexate for at least 6 months. Our study was powered to show a significant improvement if half of the patients responded to etanercept.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Twenty patients were randomized into the study. Ten received etanercept. All patients completed the study and were evaluated at 6 months. There were two patients (one in each group) who did not have anterior or pars planitis (intermediate uveitis) and were treated by other ophthalmologists for retinal vasculitis (one case) or optic neuritis (one case). These patients were not included in the final analysis. The patient with optic neuritis received etanercept and was receiving a lower dose of prednisone by the end of 6 months (from 20 mg at beginning to 5 mg at the end). The patient with a case of retinal vasculitis received placebo and had no change in the dose of prednisone from the beginning to the end of the study (10 mg).

Table 1 summarizes the demographics of the remaining 18 patients. There was no significant difference between the two groups. Extraocular involvement at any time was seen in all patients in the study. Table 2 summarizes the organ involvement seen for the two groups, with no differences between the groups. At no time during the study did extrapulmonary manifestations require additional systemic therapy. The percent predicted FVC for the etanercept group was lower than that for the placebo group, but this difference was not significant. We did not routinely measure the diffusing capacity of the lung for carbon monoxide.


View this table:
[in this window]
[in a new window]

  		Table 1.. Characteristics of Patients Studied

 

View this table:
[in this window]
[in a new window]

  		Table 2.. Extraorgan Involvement*

 
All patients had active ocular disease at the time of entry into the study. Table 3 summarizes the ocular manifestations recorded at the initial evaluation. Pars planitis, which was seen in seven patients in the study, is a specific form of intermediate uveitis and was scored as a separate ocular manifestation. All 18 of the patients had anterior or pars planitis along with other manifestations. Only one patient in this group underwent fluorescein angiography. The test was performed at the beginning and the end of the study period.


View this table:
[in this window]
[in a new window]

  		Table 3.. Ocular Manifestations at Time of Entry Into Study

 
The conditions of all patients were maintained with methotrexate therapy throughout the study. No other cytotoxic agent was added to the regimen during the study. Table 4 summarizes the initial and final corticosteroid therapy used for the patients in both groups. The dosage of systemic corticosteroids was allowed to change during the study. Eight patients in each group received therapy with a topical steroid applied to the eye. Five patients had received periocular steroid injections in the month prior to starting the study. Three of these patients required an injection in the last month of the study.


View this table:
[in this window]
[in a new window]

  		Table 4.. Summary of the Systemic and Topical Therapy for Ocular Sarcoidosis

 
Table 5 lists the individual scores for all nine patients in each group. The two assessment scores did not always agree, but there was never more than one level of difference between the scores. Overall, there was no significant difference between the patients treated with etanercept and those treated with placebo using the two criteria. Two of the etanercept-treated patients and one of the placebo-treated patients were treated with lower doses of corticosteroids by the end of the study. However, three of the etanercept-treated patients and one of the placebo-treated patients required larger doses of corticosteroids by the end of the study. The ophthalmology global assessment improved for two of the etanercept-treated patients and three of the placebo-treated patients. Again, there were more patients whose conditions were thought to be worse with etanercept therapy (three patients) than with placebo therapy (one patient).


View this table:
[in this window]
[in a new window]

  		Table 5.. Response to Therapy for Individual Patients

 
Visual acuity varied little during the course of the study. For the methotrexate-treated patients, there were 16 evaluable eyes, with two patients having one eye each that was opacified and unevaluable. The median prestudy visual acuity was 20/25 (range, 20/20 to 20/250), and the median poststudy acuity was 20/25 (range, 20/20 to 20/250; p > 0.20). For the placebo-treated patients, 17 eyes were in a condition to be evaluated, with one patient having one opacified eye. The median prestudy visual acuity was 20/30 (range, 20/20 to 20/100), while the median poststudy visual acuity was 20/25 (range, 20/20 to 20/80 p > 0.20). Neither group had a statistically significant change in visual acuity during the course of the study (p > 0.20).

Four patients had infections of the upper and lower respiratory tract that were treated successfully with antibiotics. Two patients received etanercept, while two patients received placebo. Two patients developed rashes; both were receiving the placebo. One patient complained of mild diarrhea, which not associated with antibiotics. This patient was receiving the placebo. No severe adverse reactions were encountered with medication.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The patient with chronic ocular sarcoidosis frequently causes a treatment dilemma. Corticosteroids are associated with significant toxicity. The use of cytotoxic drugs such as methotrexate is usually recommended but may not always work.78 We examined the role of a specific anti-TNF agent, etanercept, for the treatment of patients with chronic, refractory uveitis. We found that the drug usually provided no additional advantage in the treatment of these patients. We chose to study ocular sarcoidosis because it represents a common management problem in patients with chronic sarcoidosis. Ocular disease is relatively easy to evaluate compared to pulmonary disease, so that we could measure the response of the inflammation, which is the hallmark of active sarcoidosis. Since there was inflammation, it would seem that these patients would have benefited from more aggressive antiinflammatory measures. We did not find that to be the case in this study. We cannot comment on whether patients with less chronic disease may have benefited from etanercept.

Alveolar macrophages retrieved by BAL from sarcoidosis patients have been shown to release increased amounts of TNF.181920 Successful therapy for sarcoidosis with either a corticosteroid or methotrexate has been associated with a decrease in the amount of TNF released by alveolar macrophages.21 In a study of patients with refractory sarcoidosis who were not responding to corticosteroid therapy, TNF release by alveolar macrophages was not suppressed by systemic therapy.22

The decision to study an anti-TNF drug for use in the treatment of sarcoidosis uveitis was based on the observation that several agents used for the treatment of sarcoidosis are effective in blocking TNF release.23 These drugs include methotrexate,21 azathioprine,24 pentoxifylline,25 and thalidomide.26 Infliximab, a chimeric antibody to TNF, has been reported112728 as being useful for the treatment of refractory sarcoidosis.

The primary end point of the study was to determine whether etanercept could be steroid-sparing. There was no significant reduction in the dosage of the topical, injected, or systemic corticosteroids used in the etanercept group vs those used in the placebo group. Although this was a small study, our previous studies29 using methotrexate demonstrated systemic steroid reduction with a similar small sample size. In trials of anti-TNF agents for the treatment of advanced rheumatoid arthritis, more than half of the patients treated with etanercept have shown a remarkable improvement with therapy.1314 In a double-blind study of etanercept for the treatment of chronic uveitis that was controlled with low-dose methotrexate, Foster et al30 withdrew the methotrexate from therapy over a 6-month period. There was no significant difference between the etanercept-treated patients and the placebo-treated patients.30 None of the patients in that study had sarcoidosis. In an open-label trial31 of etanercept for the treatment of pulmonary sarcoidosis, the drug was also not thought to be effective.

In addition to assessing the steroid treatment doses, we used a global opinion offered by the treating physician, who was unaware of the patient’s therapy. This scoring system found no significant difference between therapy with etanercept and that with placebo. There were two patients receiving etanercept and one patient receiving placebo whose conditions improved, but there were as many patients whose conditions became worse.

It is possible with our small sample size that we did not detect a few patients who would benefit from etanercept therapy. This was also noted in a prior study31 of patients with pulmonary disease. However, the use of the drug itself carried some risk, including local reaction at the injection site and some concerns about the response to serious infections while receiving the drug.323334 There is also significant cost for the drug. Our original sample size was based on the idea that the drug would need to work in more than half of the patients to justify its use in patients with ocular sarcoidosis.

Infliximab is another anti-TNF agent with a different mechanism of action. It not only binds free TNF, but it has been shown to bind to cell-surface TNF, activate complement TNF, and lead to cell lysis.3536 This lysis is of cells releasing TNF and potentially other cytokines. This difference is, in effect, one possible reason for the effectiveness of infliximab treatment for Crohn disease,37 for which etanercept therapy has not proven to be beneficial.38

The blood levels of anti-TNF are lower after the subcutaneous injection of etanercept compared to the doses of infliximab that were used. Since these drugs may have to pass into the vitreous to be effective in treating ocular sarcoidosis, this may be an issue with etanercept. A report39 of patients with joint and ocular disease demonstrated that while etanercept was effective at treating the joint disease, it was ineffective in treating the eye disease in most patients. Interestingly, a few patients in this retrospective study were treated with infliximab and their eye disease seemed to respond. Infliximab has also been shown40 to be effective for the treatment of Behcet eye disease.

Etanercept was well-tolerated in the current study. However, it was not associated with a marked improvement in patients with chronic ocular sarcoidosis. The use of other anti-TNF agents to treat ocular disease requires further study.


   Footnotes
 
Abbreviations: TNF = tumor necrosis factor

This research was supported in part by Immunex.

Received for publication August 11, 2004. Accepted for publication January 13, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Usui, Y, Kaiser, D, Kaiser, E, et al (2002) Update of ocular manifestations of sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 19,167-175[ISI][Medline]
  2. Jabs, DA, Johns, CA Ocular involvement in chronic sarcoidosis. Am J Ophthalmol 1986;102,297-301[ISI][Medline]
  3. Dana, MR, Merayo-Lloves, J, Schaumberg, DA, et al Prognosticators for visual outcome in sarcoid uveitis. Ophthalmology 1996;103,1846-1853[ISI][Medline]
  4. Kaufman, AH, Foster, CS Cataract extraction in patients with pars planitis. Ophthalmology 1993;100,1210-1217[ISI][Medline]
  5. Krzystolik, M, Power, WJ, Foster, CS Diagnostic and therapeutic challenges of sarcoidosis. Int Ophthalmol Clin 1998;38,61-76[CrossRef][ISI][Medline]
  6. Francois, J, Victoria-Troncoso, V Corticosteroid glaucoma. Ophthalmologica 1977;174,195-209[ISI][Medline]
  7. Dev, S, McCallum, RM, Jaffe, GJ Methotrexate for sarcoid-associated panuveitis. Ophthalmology 1999;106,111-118[CrossRef][ISI][Medline]
  8. Samson, CM, Waheed, N, Baltatzis, S, et al Methotrexate therapy for chronic nonifectious uveitis: analysis of a case series of 160 patients. Ophthalmology 2001;108,1134-1139[CrossRef][ISI][Medline]
  9. Baughman, RP, Lower, EE, Bradley, DA, et al Use of cytotoxic therapy for chronic ophthalmic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999;16,S17
  10. Sfikakis, PP, Theodossiadis, PG, Katsiari, CG, et al Effect of infliximab on sight-threatening panuveitis in Behcet‘s disease. Lancet 2001;358,295-296[CrossRef][ISI][Medline]
  11. Baughman, RP, Lower, EE Infliximab for refractory sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2001;18,70-74[ISI][Medline]
  12. Bankhurst, AD Etanercept and methotrexate combination therapy. Clin Exp Rheum 1999;17,S69-S72[ISI][Medline]
  13. Lovell, DJ, Giannini, EH, Reiff, A, et al Etanercept in children with polyarticular juvenile rheumatoid arthritis: Pediatric Rheumatology Collaborative Study Group. N Engl J Med 2000;342,763-769[Abstract/Free Full Text]
  14. Moreland, LW, Schiff, MH, Baumgartner, SW, et al Etanercept therapy in rheumatoid arthritis: a randomized, controlled trial. Ann Intern Med 1999;130,478-486[Abstract/Free Full Text]
  15. Hunninghake, GW, Costabel, U, Ando, M, et al ATS/ERS/WASOG statement on sarcoidosis: American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders. Sarcoidosis Vasc Diffuse Lung Dis 1999;16,149-173[ISI][Medline]
  16. Lower, EE, Baughman, RP Prolonged use of methotrexate for sarcoidosis. Arch Intern Med 1995;155,846-851[Abstract]
  17. Judson, MA, Baughman, RP, Teirstein, AS, et al Defining organ involvement in sarcoidosis: the ACCESS proposed instrument. Sarcoidosis Vasc Diffuse Lung Dis 1999;16,75-86[ISI][Medline]
  18. Baughman, RP, Strohofer, SA, Buchsbaum, J, et al Release of tumor necrosis factor by alveolar macrophages of patients with sarcoidosis. J Lab Clin Med 1990;115,36-42[ISI][Medline]
  19. Pueringer, RJ, Schwartz, DA, Dayton, CS, et al The relationship between alveolar macrophage TNF, IL-1, and PGE2 release, alveolitis, and disease severity in sarcoidosis. Chest 1993;103,832-838[Medline]
  20. Bost, TW, Riches, DW, Schumacher, B, et al Alveolar macrophages from patients with beryllium disease and sarcoidosis express increased levels of mRNA for tumor necrosis factor-{alpha} and interleukin-6 but not interleukin-1ß. Am J Respir Cell Mol Biol 1994;10,506-513[Abstract]
  21. Baughman, RP, Lower, EE The effect of corticosteroid or methotrexate therapy on lung lymphocytes and macrophages in sarcoidosis. Am Rev Respir Dis 1990;142,1268-1271[ISI][Medline]
  22. Ziegenhagen, MW, Rothe, E, Zissel, G, et al Exagerated TNF{alpha} release of alveolar macrophages in corticosteroid resistant sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2002;19,185-190[ISI][Medline]
  23. Baughman, RP, Lower, EE Can persistent tumor necrosis factor release lead to refractory sarcoidosis? Sarcoidosis Vasc Diffuse Lung Dis 2002;19,164-166[ISI][Medline]
  24. Muller-Quernheim, J, Kienast, K, Held, M, et al Treatment of chronic sarcoidosis with an azathioprine/prednisolone regimen. Eur Respir J 1999;14,1117-1122[Abstract]
  25. Zabel, P, Entzian, P, Dalhoff, K, et al Pentoxifylline in treatment of sarcoidosis. Am J Respir Crit Care Med 1997;155,1665-1669[Abstract]
  26. Baughman, RP, Judson, MA, Teirstein, AS, et al Thalidomide for chronic sarcoidosis. Chest 2002;122,227-232[Medline]
  27. Yee, AMF, Pochapin, MB Treatment of complicated sarcoidosis with infliximab anti-tumor necrosis-{alpha} therapy. Ann Intern Med 2001;135,27-31[Abstract/Free Full Text]
  28. Roberts, SD, Wilkes, DS, Burgett, RA, et al Refractory sarcoidosis responding to infliximab. Chest 2003;124,2028-2031[Medline]
  29. Baughman, RP, Winget, DB, Lower, EE Methotrexate is steroid sparing in acute sarcoidosis: results of a double blind, randomized trial. Sarcoidosis 2000;17,60-66
  30. Foster, CS, Tufail, F, Waheed, NK, et al Efficacy of etanercept in preventing relapse of uveitis controlled by methotrexate. Arch Ophthalmol 2003;121,437-440[Abstract/Free Full Text]
  31. Utz, JP, Limper, AH, Kalra, S, et al Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis. Chest 2003;124,177-185[Medline]
  32. Fisher, CJ, Jr, Agosti, JM, Opal, SM, et al Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein: the Soluble TNF Receptor Sepsis Study Group. N Engl J Med 1996;334,1697-1702[Abstract/Free Full Text]
  33. Murphy, FT, Enzenauer, RJ, Battafarano, DF, et al Etanercept-associated injection-site reactions [letter]. Arch Dermatol 2000;136,556-557[Free Full Text]
  34. Weinblatt, ME, Kremer, JM, Bankhurst, AD, et al A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999;340,253-259[Abstract/Free Full Text]
  35. Scallon, BJ, Moore, MA, Trinh, H, et al Chimeric anti-TNF-{alpha} monoclonal antibody cA2 binds recombinant transmembrane TNF-{alpha} and activates immune effector functions. Cytokine 1995;7,251-259[CrossRef][ISI][Medline]
  36. Van den Brande, JM, Braat, H, van den Brink, GR, et al Infliximab but not etanercept induces apoptosis in lamina propria T-lymphocytes from patients with Crohn’s disease. Gastroenterology 2003;124,1774-1785[CrossRef][ISI][Medline]
  37. Rutgeerts, P, D‘Haens, G, Targan, S, et al Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn’s disease. Gastroenterology 1999;117,761-769[CrossRef][ISI][Medline]
  38. Sandborn, WJ, Hanauer, SB, Katz, S, et al Etanercept for active Crohn‘s disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology 2001;121,1088-1094[CrossRef][ISI][Medline]
  39. Smith, JR, Levinson, RD, Holland, GN, et al Differential efficacy of tumor necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease. Arthritis Rheum 2001;45,252-257[CrossRef][ISI][Medline]
  40. Sfikakis, PP, Theodossiadis, PG, Katsiari, CG, et al Effect of infliximab on sight-threatening panuveitis in Behcet’s disease. Lancet 2001;358,295-296[CrossRef][ISI][Medline]
  41. Scadding, JG Prognosis of intrathoracic sarcoidosis in England. BMJ 1961;4,1165-1172




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF) Free
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Article Archive
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via ISI Web of Science (24)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Baughman, R. P.
Right arrow Articles by Kaufman, A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Baughman, R. P.
Right arrow Articles by Kaufman, A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS