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Previous Volume 342:763-769 March 16, 2000 Number 11 Next

Abstract PDF Editorial by Pisetsky, D. S. Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background We evaluated the safety and efficacy of etanercept, a soluble tumor necrosis factor receptor (p75):Fc fusion protein, in children with polyarticular juvenile rheumatoid arthritis who did not tolerate or had an inadequate response to methotrexate.

Methods Patients 4 to 17 years old received 0.4 mg of etanercept per kilogram of body weight subcutaneously twice weekly for up to three months in the initial, open-label part of a multicenter trial. Those who responded to treatment then entered a double-blind study and were randomly assigned to receive either placebo or etanercept for four months or until a flare of the disease occurred. A response was defined as an improvement of 30 percent or more in at least three of six indicators of disease activity, with no more than one indicator worsening by more than 30 percent.

Results At the end of the open-label study, 51 of the 69 patients (74 percent) had had responses to etanercept treatment. In the double-blind study, 21 of the 26 patients who received placebo (81 percent) withdrew because of disease flare, as compared with 7 of the 25 patients who received etanercept (28 percent) (P=0.003). The median time to disease flare with placebo was 28 days, as compared with more than 116 days with etanercept (P<0.001). In the double-blind study, there were no significant differences between the two treatment groups in the frequency of adverse events.

Conclusions Treatment with etanercept leads to significant improvement in patients with active polyarticular juvenile rheumatoid arthritis. Etanercept is well tolerated by pediatric patients.

Methotrexate was shown to have a therapeutic advantage over placebo, with an acceptable safety profile, in a randomized, controlled trial in children with juvenile rheumatoid arthritis who had polyarticular involvement (regardless of the type of onset).³ Long-term studies showed that methotrexate is efficacious and well tolerated in most children with juvenile rheumatoid arthritis.^3,4,5,6 However, some patients do not have an adequate response to methotrexate, even at doses of up to 1 mg per kilogram of body weight per week.^7,8 The frequency and severity of side effects increase with higher doses of methotrexate, and the consequences of long-term use are not known. Exacerbation of disease during treatment with stable doses of methotrexate and the need to increase the methotrexate dose over time suggest that drug resistance to methotrexate may develop.⁹

Tumor necrosis factor (TNF) is a proinflammatory cytokine that has a complex role in the pathogenesis of rheumatoid arthritis.^{10,11,12,13,14,15,16,17} TNF is elevated in both the serum and the synovial fluid of children with juvenile rheumatoid arthritis. Serum levels of soluble TNF receptor are elevated in patients with juvenile rheumatoid arthritis (all subtypes), and the level is correlated with disease activity.¹⁸ In one study, tumor necrosis factor was detected in 45 percent of samples of synovial fluid from 44 children with juvenile rheumatoid arthritis (all subtypes).¹⁹ Further evidence that TNF may amplify local inflammation and lead to joint destruction came from a study in which both TNF and lymphotoxin- were detected in the majority of synovial-tissue samples from patients with juvenile rheumatoid arthritis.²⁰

Etanercept (Enbrel, Immunex, Seattle), a genetically engineered fusion protein consisting of two identical chains of the recombinant extracellular human TNF-receptor p75 monomer fused with the Fc domain of human IgG1, effectively binds TNF and lymphotoxin- and inhibits their activity.^21,22 Randomized, double-blind, placebo-controlled trials showed that etanercept treatment had significant clinical benefit with minimal toxicity in adults with active rheumatoid arthritis that did not respond to other disease-modifying drugs.^23,24,25 We conducted a randomized, multicenter, double-blind trial of etanercept for the treatment of polyarticular juvenile rheumatoid arthritis in children who did not tolerate or who had an inadequate response to methotrexate.

Methods

Patients

Eligible patients were 4 to 17 years of age and had active polyarticular juvenile rheumatoid arthritis. During the first six months of the disease, some patients had had pauciarticular arthritis (four or fewer joints involved), some had had polyarticular arthritis (five or more joints involved), and some had had systemic arthritis (associated with spiking fever and rheumatoid rash). "Active" polyarticular disease was defined by the presence of five or more swollen joints and three or more joints with limitation of motion and pain, tenderness, or both. Before enrollment, patients had active disease despite treatment with nonsteroidal antiinflammatory drugs and with methotrexate at doses of at least 10 mg per square meter of body-surface area per week. The patients had normal or nearly normal platelet, white-cell, and neutrophil counts, hepatic aminotransferase levels, and results of renal-function tests. Pregnant and lactating patients were excluded, and girls with childbearing potential were required to use contraception throughout the study. Patients with major concurrent medical conditions were also ineligible.

Study Design

An independent review committee at each study site approved the protocol and amendments, and each patient's parent or legal guardian gave written informed consent before the start of the study. A safety monitoring board reviewed adverse events that occurred during the study. Methotrexate was discontinued 14 days and other disease-modifying antirheumatic drugs 28 days before receipt of etanercept. Intraarticular and soft-tissue corticosteroid injections were not permitted during or for one month before the trial. Stable doses of nonsteroidal antiinflammatory drugs, low doses of corticosteroids (0.2 mg of prednisone per kilogram per day, with a maximum of 10 mg per day), or both were permitted. Pain medications were allowed except during the 12 hours before a joint assessment.

Vials of study medication contained either 25 mg of lyophilized etanercept (for both parts of the study) or placebo (for the double-blind study). Before injection, study-site staff who were not involved in patient assessments reconstituted the contents with 1 ml of bacteriostatic water containing 0.9 percent benzyl alcohol.

All patients received 0.4 mg of etanercept per kilogram (maximum, 25 mg) subcutaneously twice weekly for up to three months in the open-label part of the trial. At the end of the third month, patients whose condition had improved according to the definition of Giannini et al.²⁶ were randomly assigned to receive either placebo or 0.4 mg of etanercept per kilogram subcutaneously twice weekly in the double-blind study (months 4 through 7) until disease flare occurred or four months elapsed, whichever was earlier. Efficacy was assessed according to the number of patients with disease flare after receipt of placebo or etanercept.

Physical examinations, measures of disease activity, and laboratory tests (hematologic analysis, serum chemical analysis, and urinalysis) were performed at screening and repeated on day 1 (before the administration of etanercept or placebo) and day 15 and at the end of each month during the study. Final safety assessments were made 30 days after the discontinuation of the study drug for patients who withdrew from the study or did not continue to the double-blind study, or at the patient's next scheduled visit if the patient withdrew from the study because of disease flare. Serum was obtained at screening and at the end of months 3 and 7 for testing for autoantibodies (antinuclear antibodies, antibodies to double-stranded DNA, IgG and IgM anticardiolipin antibodies, and antibodies to extractable nuclear antigens), and on day 1 before the administration of the study drug and at the end of months 3 and 7 for testing for antibodies to etanercept.

Definition of Improvement

The definition of improvement used to assess disease response employs a core set of six response variables: global assessment of the severity of disease by the physician, global assessment of overall well-being by the patient or parent, number of "active" joints (joints with swelling not due to deformity or joints with limitation of motion and with pain, tenderness, or both), number of joints with limitation of motion, functional ability, and erythrocyte sedimentation rate.^26,27 In this study, the fourth measure was modified to the "number of joints with limitation of motion and with pain, tenderness, or both" so as to eliminate counting joints with contractures that might not have improved during the short course of treatment.

To meet the definition of improvement at a scheduled visit or at the end of month 3, patients had to have a 30 percent improvement from base line in at least three of the six response variables. They could also have worsening of 30 percent or more in no more than one of the six response variables. Additional assessments of disease activity included the articular severity score,²⁸ duration of morning stiffness, degree of pain (on a visual-analogue scale), and C-reactive protein levels. Patients were also evaluated for 50 percent and 70 percent improvement (50 percent and 70 percent improvement in at least three of the six response variables and a worsening of 30 percent or more in no more than one of the six response variables).

The primary efficacy end point, which was evaluated in the double-blind study, was the number of patients with disease flare. The definition of disease flare created specifically for this pediatric trial was based on the change in the core set of response variables from the beginning of the double-blind study. Patients who met the criteria for disease flare had worsening of 30 percent or more in three of the six response variables and a minimum of two active joints. They also could have improvement of 30 percent or more in no more than one of the six response variables. Global assessments, if used to define flare, had to change by at least 2 units on a scale from 0 to 10.

Statistical Analysis

A blocked randomization scheme with stratification according to study center and number of active joints (2 vs. >2) at the end of month 3 (in the open-label study) was used to assign patients to placebo or etanercept in the double-blind study.

In the double-blind study, base-line and demographic characteristics were compared between treatment groups by the Wilcoxon rank-sum test and the likelihood-ratio chi-square test. Laboratory results were summarized separately from adverse events according to a modification of the National Cancer Institute Common Toxicity Criteria and the testing laboratory's normal ranges. Comparisons of shifts in laboratory values (to below normal, normal, or above normal) were made with use of the Stuart–Maxwell chi-square test.²⁹

The percentages of patients with a response to therapy who had disease flare while receiving placebo or etanercept in the double-blind study were compared by Mantel–Haenszel methods.³⁰ Patients who withdrew early without disease flare were counted in the analysis with those who continued to have a response.

To evaluate any bias introduced by the withdrawal assumption in the primary analysis, an analysis of time to flare (by the log-rank test) was undertaken in which data on patients who withdrew without flare were censored at the time of withdrawal. The effect of base-line characteristics on flare rates was assessed by main-effects logistic regression. The percentages of patients with a response who continued to have a response after receiving etanercept or placebo in the double-blind study were compared by Mantel–Haenszel methods. All tests were two-sided, with a significance level of 0.05.

In all summaries of measures of disease activity, a last-observation-carried-forward approach was used for missing data or visits and for patients who withdrew early.

Results

Base-Line Characteristics

The base-line demographic and disease characteristics of the study patients are summarized in Table 1. Forty-three female and 26 male patients were enrolled in the open-label study; of these, 34 female and 17 male patients continued to the double-blind study. At enrollment, the mean age was 10.5 years (range, 4 to 17) and the mean duration of juvenile rheumatoid arthritis was 5.9 years. The groups were well balanced in the double-blind study, except for age group and race (P<0.02) and corticosteroid use at base line (P=0.05). The unequal randomization did not affect the study results.

View this table: [in this window] [in a new window]   Table 1. Demographic Characteristics and Disease History.

 
Sixty-four of the 69 patients enrolled in part 1 (93 percent) completed treatment. Early discontinuations were due to an adverse event in one patient who had urticaria with the first dose of etanercept, refusal of treatment by two patients, and lack of response in two patients. Of the 25 patients in the etanercept group in the double-blind trial, 19 (76 percent) completed treatment and 6 withdrew because of disease flare. Seven of the 26 patients in the placebo group (27 percent) completed the study; 1 withdrew because of parental refusal to allow continuation, and 18 withdrew because of disease flare.

Disease Response (Open-Label Study)

Fifty-one of the 69 patients enrolled in the open-label study (74 percent) met the definition of improvement at the end of that study. Considerable improvements in all measures of disease activity were seen with etanercept, and improvement was noted in patients as early as the first evaluation, two weeks after the beginning of treatment (Table 2). Forty-four of the 69 patients (64 percent) met the definition of 50 percent improvement, and 25 (36 percent) met the definition of 70 percent improvement at the end of the open-label study (Figure 1).

View this table: [in this window] [in a new window]   Table 2. Measures of Disease Activity and Improvement from Base Line.

 

View larger version (5K): [in this window] [in a new window]   Figure 1. Incidence of 30, 50, and 70 Percent Improvement in the 69 Patients Who Received Etanercept in the Open-Label Study. At the end of the open-label study, 51 (74 percent) of the patients had a 30 percent improvement, 44 (64 percent) had a 50 percent improvement, and 25 (36 percent) had a 70 percent improvement, as compared with base line.

 
Efficacy (Double-Blind Study)

            Disease Flare

In the double-blind study, significantly more patients who received placebo (21 of 26 [81 percent]) than patients who received etanercept (7 of 25 [28 percent], P=0.003) had disease flare. The rates of flare remained consistently and significantly lower in the etanercept group (P<0.001) after adjustment for the effects of base-line characteristics (Table 3). With the exception of corticosteroid use at base line (P= 0.05), none of the base-line characteristics were significant predictors of flare rates (P>0.15) (Table 3).

View this table: [in this window] [in a new window]   Table 3. Incidence of Disease Flare in the Double-Blind Study According to the Base-Line Characteristics of the Patients.

 
The median time to flare was more than 116 days for patients who received etanercept and 28 days for patients who received placebo (P<0.001) (Figure 2). Because 13 of 25 patients were still receiving etanercept at the end of the study (day 116) without disease flare, the median time to flare was greater than 116 days.

View larger version (4K): [in this window] [in a new window]   Figure 2. Kaplan–Meier Analysis of the Time to Disease Flare. The median time to disease flare was significantly shorter among the patients who received placebo (28 days) than among those who received etanercept (>116 days, P<0.001) in the double-blind study.

 
            Disease Response at End of Study

The definition of improvement was based on changes from base-line values, whereas disease flare was based on changes from values at the time of randomization to either etanercept or placebo in the double-blind study. Depending on the magnitude of a patient's response in the open-label study, response to treatment and presence of disease flare were not mutually exclusive outcomes. For example, if a patient had 28 active joints at base line but only 2 active joints at the time of randomization, a change to 3 active joints would be considered a flare (at least 30 percent worse than the condition at the time of randomization) but would also still be considered improvement (at least 30 percent improved from base line). At the end of the seven-month study, 20 of the 25 patients who received etanercept in the double-blind study (80 percent) still met the definition of improvement, as compared with 9 of the 26 patients who received placebo (35 percent, P<0.01).

At the end of the study, 72 percent of the patients who received etanercept (18 patients) and 23 percent of those who received placebo (6 patients) met the definition of 50 percent improvement. Forty-four percent of the patients who received etanercept (11 patients) and 19 percent of those who received placebo (5 patients) met the definition of 70 percent improvement. Measures of disease activity continued to improve in patients who received etanercept in the double-blind study, whereas disease activity increased in those who received placebo (Table 2).

Scores in the disability domain of the Childhood Health Assessment Questionnaire^31,32 (a measure of the patient's physical functional ability) began to improve at the first evaluation two weeks after the beginning of etanercept treatment. At the end of the open-label study, a 37 percent median improvement in scores was seen for all patients. In the double-blind study, a 54 percent median improvement in scores from base line was seen in patients who continued to receive etanercept, as compared with no change from base line in patients who received placebo (P=0.01).

In a significant proportion of patients, there were shifts from elevated values at base line to normal values of C-reactive protein, erythrocyte sedimentation rate, and white-cell and platelet counts after treatment with etanercept in the open-label study (P<0.03 for each variable). In the double-blind study as compared with the end of the open-label study, a significant proportion of patients who received placebo had shifts from normal levels of C-reactive protein and erythrocyte sedimentation rates to above-normal values (P 0.03 for each variable).

Safety

Etanercept was safe and well tolerated. There were no deaths. One patient withdrew because of urticaria after the first dose of etanercept; the urticaria responded to oral antihistamines. This patient later received commercially available etanercept without recurrence of urticaria. Two patients who received etanercept were hospitalized for serious adverse events (one for depression and a personality disorder and one for gastroenteritis–flu syndrome). All other adverse events were of mild-to-moderate intensity.

In the open-label study, the most common adverse events were injection-site reactions (39 percent of patients), upper respiratory tract infections (35 percent), headache (20 percent), rhinitis (16 percent), abdominal pain (16 percent), vomiting (14 percent), pharyngitis (14 percent), nausea (12 percent), gastrointestinal infection (12 percent), and rash (10 percent).

In the double-blind study, there were no significant differences in the frequencies of adverse events between patients who received etanercept and those who received placebo. Injection-site reactions occurred in one patient in each of the treatment groups in the double-blind study. There were no laboratory abnormalities requiring urgent treatment in the etanercept group. No patient had persistent elevations in autoantibodies or had signs or symptoms of another autoimmune disease. Two patients tested positive for non-neutralizing antibody to etanercept. Fifty-nine of the 68 eligible patients in the study chose to continue treatment in an open-label, extended-treatment study.

Discussion

The choice of a second-line agent for the treatment of juvenile rheumatoid arthritis has become more difficult because placebo-controlled trials and long-term prospective studies in children with juvenile rheumatoid arthritis have shown a lack of efficacy of agents commonly used in adults.^{33,34,35,36,37} Methotrexate is not efficacious or well tolerated in some patients with juvenile rheumatoid arthritis, and higher doses of methotrexate may be associated with greater toxicity.⁷

The design of this double-blind, placebo-controlled trial was sensitive to the problems of the population of patients with severe juvenile rheumatoid arthritis, for whom few treatment options are available. The study design allowed all patients to try the new treatment; only those who had a response to treatment were enrolled in the randomized portion of the trial. In addition, the definition of disease flare did not require the disease to become as severe as at base line. The protocol allowed patients to discontinue the study immediately after disease flare and be treated with etanercept in an open-label, long-term program. With the definition of disease flare used in this study, we effectively demonstrated differences in flare rates between the treatment groups.

The dose of etanercept used in this study (0.4 mg per kilogram) provided a favorable risk–benefit profile in children with polyarticular juvenile rheumatoid arthritis. Adverse events were of the types and intensity seen in a general pediatric population. There were no life-threatening adverse events, and the events were self-limited. A continued response was documented in patients who received etanercept in the double-blind study. At the end of the study, 80 percent of the patients who received etanercept for seven months met the definition of 30 percent improvement, as compared with 35 percent of the patients who received etanercept for three months and placebo for up to four months.

The results of this study confirm that TNF, lymphotoxin-, or both have a role in juvenile rheumatoid arthritis, and that inhibition of these substances is a valid therapeutic intervention. Etanercept was effective in pediatric patients with severe polyarticular juvenile rheumatoid arthritis (regardless of the type of onset) who did not tolerate or have an adequate response to methotrexate. The significant clinical response supports the use of etanercept in children with juvenile rheumatoid arthritis.

Supported by Immunex Corporation, Seattle, which provided the study drug and grants to investigational sites, by the Children's Hospital Foundation of Cincinnati, and by grants from the National Institutes of Health (AR42632 and AR44059-P60 MAMDC).

Drs. Lovell and Giannini have served as ad hoc consultants to Immunex.

We are indebted to the following members of the Pediatric Rheumatology Collaborative Study Group, who served as investigators at the clinical sites and made critically important contributions to this study: Bram Bernstein, M.D., Ronald Laxer, M.D., Judyann Olson, M.D., Ann Marie Reed, M.D., Rayfel Schneider, M.B., B.Ch., Bracha Shaham, M.D., David Sherry, M.D., and Brian Feldman, M.D.; to Jeffrey Siegel, M.D., and Lisa Rider, M.D., at the Food and Drug Administration for assistance in designing the protocol; to clinical research associates Lawrence Soffes and Kate Flanders at Immunex Corporation; to study-site coordinators Nikki Bradford, Sophie Costilla, Karen Felty, Trudy Leicht, Mark Massanari, Josee Quenneville, Kathy Salmonson, Janalee Taylor, Edna Williams, and Diann Wingert; and to Orysia V. Lutz for editorial assistance.

Source Information

From Children's Hospital Medical Center, Cincinnati (D.J.L., E.H.G.); Children's Hospital of Los Angeles, Los Angeles (A.R.); All Children's Hospital, St. Petersburg, Fla. (G.D.C.); the Hospital for Sick Children, Toronto (E.D.S.); the Medical College of Wisconsin, Milwaukee (J.J.N.); the University of North Carolina, Chapel Hill (L.D.S.); Children's Hospital, New Orleans (A.G.); Schneider Children's Hospital, New Hyde Park, N.Y. (N.T.I.); Children's Hospital and Medical Center, Seattle (C.A.W.); and Immunex Corporation, Seattle (J.W., B.K.F.).

Address reprint requests to Dr. Lovell at Children's Hospital Medical Center, Pavilion Bldg. 2-129, 3333 Burnet Ave., Cincinnati, OH 45229-3039.

References

1. Peterson LS, Mason T, Nelson AM, O'Fallon WM, Gabriel SE. Juvenile rheumatoid arthritis in Rochester, Minnesota 1960-1993: is the epidemiology changing? Arthritis Rheum 1996;39:1385-1390. [Medline]
2. Petty RE, Malleson P. Epidemiology of juvenile rheumatoid arthritis. World Pediatr Child Care 1987;3:205-10.
3. Giannini EH, Brewer EJ, Kuzmina N, et al. Methotrexate in resistant juvenile rheumatoid arthritis: results of the U.S.A.-U.S.S.R. double-blind, placebo-controlled trial. N Engl J Med 1992;326:1043-1049. [Abstract]
4. Giannini EH, Newman AJ, Fink CW. Low-dose methotrexate in children with JRA: results of a post-trial, long-term follow-up program. Arthritis Rheum 1993;36:Suppl:S54-S54.abstract 
5. Graham LD, Myones BL, Rivas-Chacon RF, Pachman LM. Morbidity associated with long-term methotrexate therapy in juvenile rheumatoid arthritis. J Pediatr 1992;120:468-473. [CrossRef][Medline]
6. Halle F, Prieur AM. Evaluation of methotrexate in the treatment of juvenile chronic arthritis according to the subtype. Clin Exp Rheumatol 1991;9:297-302. [Medline]
7. Wallace CA, Sherry DD. Preliminary report of higher dose methotrexate treatment in juvenile rheumatoid arthritis. J Rheumatol 1992;19:1604-1607. [Medline]
8. Reiff A, Shaham B, Wood BP, Bernstein BH, Stanley P, Szer IS. High dose methotrexate in the treatment of refractory juvenile rheumatoid arthritis. Clin Exp Rheumatol 1995;13:113-118. [Medline]
9. Wallace CA. The use of methotrexate in childhood rheumatic diseases. Arthritis Rheum 1998;41:381-391. [CrossRef][Medline]
10. Thornton SC, Por SB, Penny R, Richter M, Shelley L, Breit SN. Identification of the major fibroblast growth factors released spontaneously in inflammatory arthritis as platelet derived growth factor and tumour necrosis factor-alpha. Clin Exp Immunol 1991;86:79-86. [Medline]
11. Dayer JM, Beutler B, Cerami A. Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E₂ production by human synovial cells and dermal fibroblasts. J Exp Med 1985;162:2163-2168. [Free Full Text]
12. Bertolini DR, Nedwin GE, Bringman TS, Smith DD, Mundy GR. Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors. Nature 1986;319:516-518. [CrossRef][Medline]
13. Saklatvala J. Tumour necrosis factor stimulates resorption and inhibits synthesis of proteoglycan in cartilage. Nature 1986;322:547-549. [CrossRef][Medline]
14. von Asmuth EJU, van der Linden CJ, Leeuwenberg JFM, Buurman WA. Involvement of the CD11b/CD18 integrin, but not of the endothelial cell adhesion molecules ELAM-1 and ICAM-1 in tumor necrosis factor--induced neutrophil toxicity. J Immunol 1991;147:3869-3875. [Abstract]
15. Beckham JC, Caldwell DS, Peterson BL, et al. Disease severity in rheumatoid arthritis: relationships of plasma tumor necrosis factor-, soluble interleukin 2-receptor, soluble CD4/CD8 ratio, neopterin, and fibrin D-dimer to traditional severity and functional measures. J Clin Immunol 1992;12:353-361. [CrossRef][Medline]
16. Brennan FM, Chantry D, Jackson A, Maini R, Feldmann M. Inhibitory effect of TNF antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet 1989;2:244-247. [CrossRef][Medline]
17. Saez-Llorens X, Jafari HS, Olsen KD, Nariuchi H, Hansen EJ, McCracken GH Jr. Induction of suppurative arthritis in rabbits by Haemophilus endotoxin, tumor necrosis factor-, and interleukin-1 ß. J Infect Dis 1991;163:1267-1272. [Medline]
18. Mangge H, Kenzian H, Gallistl S, et al. Serum cytokines in juvenile rheumatoid arthritis: correlation with conventional inflammation parameters and clinical subtypes. Arthritis Rheum 1995;38:211-220. [Medline]
19. Eberhard BA, Laxer RM, Andersson U, Silverman ED. Local synthesis of both macrophage and T cell cytokines by synovial fluid cells from children with juvenile rheumatoid arthritis. Clin Exp Immunol 1994;96:260-266. [Medline]
20. Grom AA, Murray KJ, Luyrink L, et al. Patterns of expression of tumor necrosis factor , tumor necrosis factor ß, and their receptors in synovia of patients with juvenile rheumatoid arthritis and juvenile spondyloarthropathy. Arthritis Rheum 1996;39:1703-1710. [Medline]
21. Mohler KM, Sleath PR, Fitzner JN, et al. Protection against a lethal dose of endotoxin by an inhibitor of tumour necrosis factor processing. Nature 1994;370:218-220. [CrossRef][Medline]
22. Mohler KM, Torrance DS, Smith CA, et al. Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists. J Immunol 1993;151:1548-1561. [Abstract]
23. Moreland LW, Baumgartner SW, Schiff MH, et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med 1997;337:141-147. [Free Full Text]
24. Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis: a randomized, controlled trial. Ann Intern Med 1999;130:478-486. [Free Full Text]
25. 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. [Free Full Text]
26. Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum 1997;40:1202-1209. [Medline]
27. Giannini EH, Lovell DJ, Felson DT, Goldsmith CH. Preliminary core set of outcome variables for use in JRA clinical trials. Arthritis Rheum 1994;37:Suppl:S428-S428.abstract [CrossRef]
28. Giannini EH, Cassidy JT. Methotrexate in juvenile rheumatoid arthritis: do the benefits outweigh the risks? Drug Saf 1993;9:325-339. [Medline]
29. Stuart A. A test for homogeneity of the marginal distributions in a two-way classification. Biometrika 1955;42:412-416. [Free Full Text]
30. Mehta CR, Walsh SJ. Comparison of exact, mid-p, and Mantel-Haenszel confidence intervals for the common odds ratio across several 2 x 2 contingency tables. Am Stat 1992;46:146-50.
31. Singh G, Athreya BH, Fries JF, Goldsmith DP. Measurement of health status in children with juvenile rheumatoid arthritis. Arthritis Rheum 1994;37:1761-1769. [Medline]
32. Ramey DR, Raynauld JP, Fries JF. The Health Assessment Questionnaire 1992: status and review. Arthritis Care Res 1992;5:119-129. [Medline]
33. Brewer EJ, Giannini EH, Kuzmina N, Alekseev L. Penicillamine and hydroxychloroquine in the treatment of severe juvenile rheumatoid arthritis: results of the U.S.A.-U.S.S.R. double-blind placebo-controlled trial. N Engl J Med 1986;314:1269-1276. [Abstract]
34. Giannini EH, Brewer EJ, Kuzmina N, Alekseev L, Shokh BP. Characteristics of responders and nonresponders to slow-acting antirheumatic drugs in juvenile rheumatoid arthritis. Arthritis Rheum 1988;31:15-20. [Medline]
35. Giannini EH, Brewer EJ Jr, Kuzmina N, Shaikov A, Wallin B. Auranofin in the treatment of juvenile rheumatoid arthritis: results of the USA-USSR double-blind, placebo-controlled trial. Arthritis Rheum 1990;33:466-476. [Medline]
36. Giannini EH, Barron KS, Spencer CH, et al. Auranofin therapy for juvenile rheumatoid arthritis: results of the five-year open label extension trial. J Rheumatol 1991;18:1240-1242. [Medline]
37. Silverman ED, Giannini EH, Cawkwell G. Intravenous immune globulin in systemic JRA: results of a randomized controlled trial. Arthritis Rheum 1993;36:Suppl:S59-S59.abstract 

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• Horneff, G., Ebert, A., Fitter, S., Minden, K., Foeldvari, I., Kummerle-Deschner, J., Thon, A., Girschick, H. J., Weller, F., Huppertz, H. I. (2009). Safety and efficacy of once weekly etanercept 0.8 mg/kg in a multicentre 12 week trial in active polyarticular course juvenile idiopathic arthritis. Rheumatology (Oxford) 48: 916-919 [Abstract] [Full Text]  
• Prince, F H M, Twilt, M, Cate, R t., van Rossum, M A J, Armbrust, W, Hoppenreijs, E P A H, van Santen-Hoeufft, M, Koopman-Keemink, Y, Wulffraat, N M, van Suijlekom-Smit, L W A (2009). Long-term follow-up on effectiveness and safety of etanercept in juvenile idiopathic arthritis: the Dutch national register. Ann Rheum Dis 68: 635-641 [Abstract] [Full Text]  
• Horneff, G, De Bock, F, Foeldvari, I, Girschick, H J, Michels, H, Moebius, D, Schmeling, H, and the German and Austrian Paediatric Rheumatolog, (2009). Safety and efficacy of combination of etanercept and methotrexate compared to treatment with etanercept only in patients with juvenile idiopathic arthritis (JIA): preliminary data from the German JIA Registry. Ann Rheum Dis 68: 519-525 [Abstract] [Full Text]  
• Tynjala, P, Vahasalo, P, Honkanen, V, Lahdenne, P (2009). Drug survival of the first and second course of anti-tumour necrosis factor agents in juvenile idiopathic arthritis. Ann Rheum Dis 68: 552-557 [Abstract] [Full Text]  
• Bell, E. A. (2009). Pharmacotherapy of Juvenile Idiopathic Arthritis. Journal of Pharmacy Practice 22: 17-28 [Abstract]  
• Sfriso, P., Ravaioli, F., Taddio, A., Marchetti, F., de Vries, M. K., van der Horst-Bruinsma, I. E., Wolbink, G. J., Lovell, D. J., Ruperto, N. (2008). Adalimumab in Juvenile Rheumatoid Arthritis. NEJM 359: 2495-2497 [Full Text]  
• Furst, D E, Keystone, E C, Kirkham, B, Fleischmann, R, Mease, P, Breedveld, F C, Smolen, J S, Kalden, J R, Burmester, G R, Braun, J, Emery, P, Winthrop, K, Bresnihan, B, De Benedetti, F, Dorner, T, Gibofsky, A, Schiff, M H, Sieper, J, Singer, N, Van Riel, P L C M, Weinblatt, M E, Weisman, M H (2008). Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2008. Ann Rheum Dis 67: iii2-iii25 [Full Text]  
• Yanik, G. A., Ho, V. T., Levine, J. E., White, E. S., Braun, T., Antin, J. H., Whitfield, J., Custer, J., Jones, D., Ferrara, J. L. M., Cooke, K. R. (2008). The impact of soluble tumor necrosis factor receptor etanercept on the treatment of idiopathic pneumonia syndrome after allogeneic hematopoietic stem cell transplantation. Blood 112: 3073-3081 [Abstract] [Full Text]  
• Prince, F. H. M., Ferket, I. S., Kamphuis, S., Armbrust, W., ten Cate, R., Hoppenreijs, E. P. A. H., Koopman-Keemink, Y., van Rossum, M. A. J., van Santen-Hoeufft, M., Twilt, M., van Suijlekom-Smit, L. W. A. (2008). Development of a web-based register for the Dutch national study on biologicals in JIA: www.ABC-register.nl. Rheumatology (Oxford) 47: 1413-1416 [Abstract] [Full Text]  
• Lovell, D. J., Ruperto, N., Goodman, S., Reiff, A., Jung, L., Jarosova, K., Nemcova, D., Mouy, R., Sandborg, C., Bohnsack, J., Elewaut, D., Foeldvari, I., Gerloni, V., Rovensky, J., Minden, K., Vehe, R. K., Weiner, L. W., Horneff, G., Huppertz, H.-I., Olson, N. Y., Medich, J. R., Carcereri-De-Prati, R., McIlraith, M. J., Giannini, E. H., Martini, A., the Pediatric Rheumatology Collaborative Study Gro, (2008). Adalimumab with or without Methotrexate in Juvenile Rheumatoid Arthritis. NEJM 359: 810-820 [Abstract] [Full Text]  
• Gerloni, V, Pontikaki, I, Gattinara, M, Fantini, F (2008). Focus on adverse events of tumour necrosis factor {alpha} blockade in juvenile idiopathic arthritis in an open monocentric long-term prospective study of 163 patients. Ann Rheum Dis 67: 1145-1152 [Abstract] [Full Text]  
• Riley, P., McCann, L. J., Maillard, S. M., Woo, P., Murray, K. J., Pilkington, C. A. (2008). Effectiveness of infliximab in the treatment of refractory juvenile dermatomyositis with calcinosis. Rheumatology (Oxford) 47: 877-880 [Abstract] [Full Text]  
• Roord, S. T. A., de Jager, W., Boon, L., Wulffraat, N., Martens, A., Prakken, B., van Wijk, F. (2008). Autologous bone marrow transplantation in autoimmune arthritis restores immune homeostasis through CD4+CD25+Foxp3+ regulatory T cells. Blood 111: 5233-5241 [Abstract] [Full Text]  
• Bartoli, M, Taro, M, Magni-Manzoni, S, Pistorio, A, Traverso, F, Viola, S, Magnani, A, Gasparini, C, Martini, A, Ravelli, A (2008). The magnitude of early response to methotrexate therapy predicts long-term outcome of patients with juvenile idiopathic arthritis. Ann Rheum Dis 67: 370-374 [Abstract] [Full Text]  
• Cespedes-Cruz, A, Gutierrez-Suarez, R, Pistorio, A, Ravelli, A, Loy, A, Murray, K J, Gerloni, V, Wulffraat, N, Oliveira, S, Walsh, J, Calvo Penades, I, Alpigiani, M G, Lahdenne, P, Saad-Magalhaes, C, Cortis, E, Lepore, L, Kimura, Y, Wouters, C, Martini, A, Ruperto, N, for the Pediatric Rheumatology International Trial, (2008). Methotrexate improves the health-related quality of life of children with juvenile idiopathic arthritis. Ann Rheum Dis 67: 309-314 [Abstract] [Full Text]  
• Furst, D E, Breedveld, F C, Kalden, J R, Smolen, J S, Burmester, G R, Sieper, J, Emery, P, Keystone, E C, Schiff, M H, Mease, P, van Riel, P L C M, Fleischmann, R, Weisman, M H, Weinblatt, M E (2007). Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2007. Ann Rheum Dis 66: iii2-iii22 [Full Text]  
• de Jager, W., Hoppenreijs, E. P A H, Wulffraat, N. M, Wedderburn, L. R, Kuis, W., Prakken, B. J (2007). Blood and synovial fluid cytokine signatures in patients with juvenile idiopathic arthritis: a cross-sectional study. Ann Rheum Dis 66: 589-598 [Abstract] [Full Text]  
• Prince, F. H M, Twilt, M., Jansen-Wijngaarden, N. C J A, van Suijlekom-Smit, L. W A (2007). Effectiveness of a once weekly double dose of etanercept in patients with juvenile idiopathic arthritis: a clinical study. Ann Rheum Dis 66: 704-705 [Full Text]  
• Gattorno, M., Chicha, L., Gregorio, A., Ferlito, F., Rossi, F., Jarrossay, D., Lanzavecchia, A., Martini, A., Manz, M. G. (2007). Distinct expression pattern of IFN-{alpha} and TNF-{alpha} in juvenile idiopathic arthritis synovial tissue. Rheumatology (Oxford) 46: 657-665 [Abstract] [Full Text]  
• Biester, S., Deuter, C., Michels, H., Haefner, R., Kuemmerle-Deschner, J., Doycheva, D., Zierhut, M. (2007). Adalimumab in the therapy of uveitis in childhood. Br J Ophthalmol 91: 319-324 [Abstract] [Full Text]  
• Kuek, A., Hazleman, B. L., Gaston, J. H., Ostor, A. J. K. (2006). Successful treatment of refractory polyarticular juvenile idiopathic arthritis with rituximab. Rheumatology (Oxford) 45: 1448-1449 [Full Text]  
• Furst, D E, Breedveld, F C, Kalden, J R, Smolen, J S, Burmester, G R, Emery, P, Keystone, E C, Schiff, M H, van Riel, P L C M, Weinblatt, M E, Weisman, M H (2006). Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2006. Ann Rheum Dis 65: iii2-iii15 [Full Text]  
• Li, S. C. (2006). Sustained Benefit from Treatment of Polyarticular Juvenile Arthritis with a Biologic Agent. AAP Grand Rounds 16: 38-39 [Full Text]  
• McCann, L. J, Wedderburn, L. R, Hasson, N. (2006). JUVENILE IDIOPATHIC ARTHRITIS. EDUCATION AND PRACTICE 91: ep29-ep36 [Full Text]  
• Tynjala, P, Lahdenne, P, Vahasalo, P, Kautiainen, H, Honkanen, V (2006). Impact of anti-TNF treatment on growth in severe juvenile idiopathic arthritis. Ann Rheum Dis 65: 1044-1049 [Abstract] [Full Text]  
• Nevessignsky, M. T., Ferster, A. (2006). Haematopoietic stem cell transplantation for severe autoimmune diseases: new perspectives. Nephrol Dial Transplant 21: 1154-1157 [Full Text]  
• Monk, J. P., Phillips, G., Waite, R., Kuhn, J., Schaaf, L. J., Otterson, G. A., Guttridge, D., Rhoades, C., Shah, M., Criswell, T., Caligiuri, M. A., Villalona-Calero, M. A. (2006). Assessment of Tumor Necrosis Factor Alpha Blockade As an Intervention to Improve Tolerability of Dose-Intensive Chemotherapy in Cancer Patients. JCO 24: 1852-1859 [Abstract] [Full Text]  
• Fleischmann, R, Baumgartner, S W, Weisman, M H, Liu, T, White, B, Peloso, P (2006). Long term safety of etanercept in elderly subjects with rheumatic diseases. Ann Rheum Dis 65: 379-384 [Abstract] [Full Text]  
• Bandeira, M., Falcone, A., Pistorio, A., Ruperto, N., Magni-Manzoni, S., Buoncompagni, A., Sala, E., Loy, A., Martini, A., Ravelli, A. (2006). Weighting improves the information provided by joint counts on the severity of arthritis and its impact on patients' well-being in juvenile idiopathic arthritis. Rheumatology (Oxford) 45: 343-347 [Abstract] [Full Text]  
• Weinblatt, M E (2005). Will our current success in treating rheumatoid arthritis hinder new drug development? That is the question!!. Ann Rheum Dis 64: 1529-1531 [Full Text]  
• Furst, D E, Breedveld, F C, Kalden, J R, Smolen, J S, Burmester, G R, Bijlsma, J W J, Dougados, M, Emery, P, Keystone, E C, Klareskog, L, Mease, P J (2005). Updated consensus statement on biological agents, specifically tumour necrosis factor {alpha} (TNF{alpha}) blocking agents and interleukin-1 receptor antagonist (IL-1ra), for the treatment of rheumatic diseases, 2005. Ann Rheum Dis 64: iv2-iv14 [Full Text]  
• Hashkes, P. J., Laxer, R. M. (2005). Medical Treatment of Juvenile Idiopathic Arthritis. JAMA 294: 1671-1684 [Abstract] [Full Text]  
• Baughman, R. P., Lower, E. E., Bradley, D. A., Raymond, L. A., Kaufman, A. (2005). Etanercept for Refractory Ocular Sarcoidosis: Results of a Double-Blind Randomized Trial. Chest 128: 1062-1047 [Abstract] [Full Text]  
• Adib, N., Silman, A., Thomson, W. (2005). Outcome following onset of juvenile idiopathic inflammatory arthritis: I. Frequency of different outcomes. Rheumatology (Oxford) 44: 995-1001 [Abstract] [Full Text]  
• Schmeling, H., Horneff, G. (2005). Etanercept and uveitis in patients with juvenile idiopathic arthritis. Rheumatology (Oxford) 44: 1008-1011 [Abstract] [Full Text]  
• Foster, H, Fitzgerald, J (2005). Dental disease in children with chronic illness. Arch. Dis. Child. 90: 703-708 [Abstract] [Full Text]  
• Simonini, G., Giani, T., Stagi, S., de Martino, M., Falcini, F. (2005). Bone status over 1 yr of etanercept treatment in juvenile idiopathic arthritis. Rheumatology (Oxford) 44: 777-780 [Abstract] [Full Text]  
• Pascual, V., Allantaz, F., Arce, E., Punaro, M., Banchereau, J. (2005). Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. JEM 201: 1479-1486 [Abstract] [Full Text]  
• Silverman, E., Mouy, R., Spiegel, L., Jung, L. K., Saurenmann, R. K., Lahdenne, P., Horneff, G., Calvo, I., Szer, I. S., Simpson, K., Stewart, J. A., Strand, V., the Leflunomide in Juvenile Rheumatoid Arthritis (, (2005). Leflunomide or Methotrexate for Juvenile Rheumatoid Arthritis. NEJM 352: 1655-1666 [Abstract] [Full Text]  
• Yim, D.-S., Zhou, H., Buckwalter, M., Nestorov, I., Peck, C. C., Lee, H. (2005). Population Pharmacokinetic Analysis and Simulation of the Time-Concentration Profile of Etanercept in Pediatric Patients With Juvenile Rheumatoid Arthritis. J Clin Pharmacol 45: 246-256 [Abstract] [Full Text]  
• Gedalia, A., Shetty, A. K. (2004). Chronic Steroid and Immunosuppressant Therapy in Children. Pediatr. Rev. 25: 425-434 [Full Text]  
• Horneff, G, Schmeling, H, Biedermann, T, Foeldvari, I, Ganser, G, Girschick, H J, Hospach, T, Huppertz, H I, Keitzer, R, Kuster, R M, Michels, H, Moebius, D, Rogalski, B, Thon, A, for the Paediatric Rheumatology Collaborative Grou, (2004). The German etanercept registry for treatment of juvenile idiopathic arthritis. Ann Rheum Dis 63: 1638-1644 [Abstract] [Full Text]  
• Calin, A, Dijkmans, B A C, Emery, P, Hakala, M, Kalden, J, Leirisalo-Repo, M, Mola, E M, Salvarani, C, Sanmarti, R, Sany, J, Sibilia, J, Sieper, J, van der Linden, S, Veys, E, Appel, A M, Fatenejad, S (2004). Outcomes of a multicentre randomised clinical trial of etanercept to treat ankylosing spondylitis. Ann Rheum Dis 63: 1594-1600 [Abstract] [Full Text]  
• Cleary, A. G., Lancaster, G. A., Annan, F., Sills, J. A., Davidson, J. E. (2004). Nutritional impairment in juvenile idiopathic arthritis. Rheumatology (Oxford) 43: 1569-1573 [Abstract] [Full Text]  
• Furst, D E, Breedveld, F C, Kalden, J R, Smolen, J S, Burmester, G R, Bijlsma, J W J, Dougados, M, Emery, P, Keystone, E C, Klareskog, L, Mease, P J (2004). Updated consensus statement on biological agents, specifically tumour necrosis factor {alpha} (TNF{alpha}) blocking agents and interleukin-1 receptor antagonist (IL-1ra), for the treatment of rheumatic diseases, 2004. Ann Rheum Dis 63: ii2-ii12 [Full Text]  
• de Kleer, I M, Brinkman, D M C, Ferster, A, Abinun, M, Quartier, P, van der Net, J, ten Cate, R, Wedderburn, L R, Horneff, G, Oppermann, J, Zintl, F, Foster, H E, Prieur, A M, Fasth, A, van Rossum, M A J, Kuis, W, Wulffraat, N M (2004). Autologous stem cell transplantation for refractory juvenile idiopathic arthritis: analysis of clinical effects, mortality, and transplant related morbidity. Ann Rheum Dis 63: 1318-1326 [Abstract] [Full Text]  
• Kovach, B. T., Calamia, K. T., Walsh, J. S., Ginsburg, W. W. (2004). Treatment of Multicentric Reticulohistiocytosis With Etanercept. Arch Dermatol 140: 919-921 [Full Text]  
• Armbrust, W., Kamphuis, S. S. M., Wolfs, T. W. F., Fiselier, T. J. W., Nikkels, P. G., Kuis, W., Wulffraat, N. M. (2004). Tuberculosis in a nine-year-old girl treated with infliximab for systemic juvenile idiopathic arthritis. Rheumatology (Oxford) 43: 527-529 [Full Text]  
• Welbury, R. R., Thomason, J. M., Fitzgerald, J. L., Steen, I. N., Marshall, N. J., Foster, H. E. (2003). Increased prevalence of dental caries and poor oral hygiene in juvenile idiopathic arthritis. Rheumatology (Oxford) 42: 1445-1451 [Abstract] [Full Text]  
• Amital, H., Aamar, S., Rubinow, A. (2003). Bilateral Septic Arthritis of the Hip: Does Etanercept Play a Role? A Case Report. JBJS 85: 2205-2206 [Full Text]  
• Furst, D E, Breedveld, F C, Kalden, J R, Smolen, J S, Burmester, G R, Dougados, M, Emery, P, Gibofsky, A, Kavenaugh, A F, Keystone, E C, Klareskog, L, Russell, A S, van de Putte, L B A, Weisman, M H (2003). Updated consensus statement on biological agents for the treatment of rheumatoid arthritis and other immune mediated inflammatory diseases (May 2003). Ann Rheum Dis 62: ii2-9 [Full Text]  
• Foxwell, B, Andreakos, E, Brennan, F, Feldmann, M, Smith, C, Conron, M (2003). Prospects for the development of small molecular weight compounds to replace anti-tumour necrosis factor biological agents. Ann Rheum Dis 62: ii90-93 [Full Text]  
• Robinson, N. D., Guitart, J. (2003). Recalcitrant, Recurrent Aphthous Stomatitis Treated With Etanercept. Arch Dermatol 139: 1259-1262 [Full Text]  
• Barber, J, Sheeran, T, Mulherin, D (2003). Anti-tumour necrosis factor treatment in a patient with anorexia nervosa and juvenile idiopathic arthritis. Ann Rheum Dis 62: 490-491 [Full Text]  
• Schwartz, R. S. (2003). Diversity of the Immune Repertoire and Immunoregulation. NEJM 348: 1017-1026 [Full Text]  
• Lahdenne, P, Vahasalo, P, Honkanen, V (2003). Infliximab or etanercept in the treatment of children with refractory juvenile idiopathic arthritis: an open label study. Ann Rheum Dis 62: 245-247 [Abstract] [Full Text]  
• Wilkinson, N, Jackson, G, Gardner-Medwin, J (2003). Biologic therapies for juvenile arthritis. Arch. Dis. Child. 88: 186-191 [Abstract] [Full Text]  
• Ramanan, A V, Whitworth, P, Baildam, E M (2003). Use of methotrexate in juvenile idiopathic arthritis. Arch. Dis. Child. 88: 197-200 [Abstract] [Full Text]  
• Wedderburn, L R, Abinun, M, Palmer, P, Foster, H E (2003). Autologous haematopoietic stem cell transplantation in juvenile idiopathic arthritis. Arch. Dis. Child. 88: 201-205 [Full Text]  
• Agusti, A.G.N., Noguera, A., Sauleda, J., Sala, E., Pons, J., Busquets, X. (2003). Systemic effects of chronic obstructive pulmonary disease. Eur Respir J 21: 347-360 [Abstract] [Full Text]  
• Drewe, E., McDermott, E. M., Powell, P. T., Isaacs, J. D., Powell, R. J. (2003). Prospective study of anti-tumour necrosis factor receptor superfamily 1B fusion protein, and case study of anti-tumour necrosis factor receptor superfamily 1A fusion protein, in tumour necrosis factor receptor associated periodic syndrome (TRAPS): clinical and laboratory findings in a series of seven patients. Rheumatology (Oxford) 42: 235-239 [Abstract] [Full Text]  
• Furst, D E, Breedveld, F C, Kalden, J R, Smolen, J S, Antoni, C E, Bijlsma, J W J, Burmester, G R, Cronstein, B, Keystone, E C, Kavanaugh, A, Klareskog, L (2002). Updated consensus statement on biological agents for the treatment of rheumatoid arthritis and other rheumatic diseases (May 2002). Ann Rheum Dis 61: ii2-7 [Full Text]  
• Khan, M A (2002). Ankylosing spondylitis: introductory comments on its diagnosis and treatment. Ann Rheum Dis 61: iii3-7 [Full Text]  
• Khan, M. A. (2002). Update on Spondyloarthropathies. ANN INTERN MED 136: 896-907 [Abstract] [Full Text]  
• Gorman, J. D., Sack, K. E., Davis, J. C. Jr. (2002). Treatment of Ankylosing Spondylitis by Inhibition of Tumor Necrosis Factor {alpha}. NEJM 346: 1349-1356 [Abstract] [Full Text]  
• Zeggini, E., Thomson, W., Alansari, A., Ollier, W., Donn, R. (2002). Tumour necrosis factor receptor II polymorphism and juvenile idiopathic arthritis. Rheumatology (Oxford) 41: 462-465 [Abstract] [Full Text]  
• Song, X.-y. R., Torphy, T. J., Griswold, D. E., Shealy, D. (2002). Coming of Age:Anti-Cytokine Therapies. Mol. Interv. 2: 36-46 [Abstract] [Full Text]  
• Kietz, D A, Pepmueller, P H, Moore, T L (2002). Therapeutic use of etanercept in polyarticular course juvenile idiopathic arthritis over a two year period. Ann Rheum Dis 61: 171-173 [Abstract] [Full Text]  
• ten Cate, R., van Suijlekom-Smit, L. W. A., Brinkman, D. M. C., Bekkering, W. P., Jansen-van Wijngaarden, C. J. A., Vossen, J. M. (2002). Etanercept in four children with therapy-resistant systemic juvenile idiopathic arthritis. Rheumatology (Oxford) 41: 228-229 [Full Text]  
• Henter, J.-I., Karlen, J., Calming, U., Bernstrand, C., Andersson, U., Fadeel, B. (2001). Successful Treatment of Langerhans'-Cell Histiocytosis with Etanercept. NEJM 345: 1577-1578 [Full Text]  
• FURST, D E, KEYSTONE, E C, BREEDVELD, F C, KALDEN, J R, SMOLEN, J S, ANTONI, C E, BURMESTER, G R, CROFFORD, L J, KAVANAUGH, A (2001). Updated consensus statement on tumour necrosis factor blocking agents for the treatment of rheumatoid arthritis and other rheumatic diseases (April 2001). Ann Rheum Dis 60: iii2-5 [Full Text]  
• Gylys-Morin, V. M., Graham, T. B., Blebea, J. S., Dardzinski, B. J., Laor, T., Johnson, N. D., Oestreich, A. E., Passo, M. H. (2001). Knee in Early Juvenile Rheumatoid Arthritis: MR Imaging Findings. Radiology 220: 696-706 [Abstract] [Full Text]  
• (2001). {blacktriangledown}Etanercept and {blacktriangledown}infliximab for rheumatoid arthritis. DTB 39: 49-52 [Abstract] [Full Text]  
• Werth, V. P., Levinson, A. I. (2001). Etanercept-Induced Injection Site Reactions: Mechanistic Insights From Clinical Findings and Immunohistochemistry. Arch Dermatol 137: 953-955 [Full Text]  
• Girolomoni, G., Abeni, D. (2001). Anti-Tumor Necrosis Factor {alpha} Therapy in Psoriatic Arthritis and Psoriasis. Arch Dermatol 137: 784-785 [Full Text]  
• Schmeling, H, Mathony, K, John, V, KeyBer, G, Burdach, S., Horneff, G (2001). A combination of etanercept and methotrexate for the treatment of refractory juvenile idiopathic arthritis: a pilot study. Ann Rheum Dis 60: 410-412 [Abstract] [Full Text]  
• Choy, E. H.S., Panayi, G. S. (2001). Cytokine Pathways and Joint Inflammation in Rheumatoid Arthritis. NEJM 344: 907-916 [Full Text]  
• DENG, H., NICHOLAS MASON, S., AUTEN, R. L. Jr. (2000). Lung Inflammation in Hyperoxia Can Be Prevented By Antichemokine Treatment in Newborn Rats. Am. J. Respir. Crit. Care Med. 162: 2316-2323 [Abstract] [Full Text]  
• Bathon, J. M., Martin, R. W., Fleischmann, R. M., Tesser, J. R., Schiff, M. H., Keystone, E. C., Genovese, M. C., Wasko, M. C., Moreland, L. W., Weaver, A. L., Markenson, J., Finck, B. K. (2000). A Comparison of Etanercept and Methotrexate in Patients with Early Rheumatoid Arthritis. NEJM 343: 1586-1593 [Abstract] [Full Text]  
• Klippel, J. H. (2000). Biologic Therapy for Rheumatoid Arthritis. NEJM 343: 1640-1641 [Full Text]  
• FURST, D E, BREEDVELD, F C, BURMESTER, G R, CROFFORD, J J, EMERY, P, FELDMANN, M, KALDEN, J R, KAVANAUGH, A F, KEYSTONE, E C, KLARESKOG, L G, LIPSKY, P E, MAINI, R N, RUSSELL, A S, SCOTT, D L, SMOLEN, J S, VAN DE PUTTE, L B A, VISHER, T L, WEISMAN, M H (2000). Updated consensus statement on tumour necrosis factor blocking agents for the treatment of rheumatoid arthritis (May 2000). Ann Rheum Dis 59: i1-2 [Full Text]  
• Spencer-Green, G. (2000). Etanercept (Enbrel): update on therapeutic use. Ann Rheum Dis 59: i46-49 [Abstract] [Full Text]  
• VOUGIOUKA, O, DEMETRIOU, L, VLAHOU, C, LIOTSOU, A, KYRZOPOULOS;, D, ROSE, C., MCILVAIN-SIMPSON;, G, CLEARY, A., SILLS, J., DEVINE, K, KELLY, J, BAILDAM, E, DAVIDSON;, J., GERLONI, V, PONTIKAKI, I, DESIATI, F, LUPI, E, GATTINARA, M, FANTINI;, F, MODESTO, C, BORONAT, M, MARSAL, S, ARNAL-GUIMERA;, C, DE MARCO, R, ALPIGIANI, M., MUSTICA, T, CERBONI, M, VITTONE, P, IESTER;, A, FALCINI, F, BINDI, G, GALLUZZI, F, STAGI, S, SIMONINI, G, CALABRI, G., MASI, L, CIMAZ;, R, KIMURA, Y, LI, S, IMUNDO;, L, RUTKOWSKA-SAK, L, ROMICKA;, A, KÜMMERLE-DESCHNER, J, BRANDT, G, HOLZER, U, IHLE, J, HAUTZINGER, M, DANNECKER;, G E, KIREN, V, LEPORE, L, TOMMASINI;, A, LEPORE, L, TOMMASINI, A, KIREN, V, DEL SANTO, M, MALORGIO;, C, LEPORE, L, ANDOLINA, M, RABUSIN, M, MAXIMOVA, N, PARCO, S, KIREN;, V, BARDARE, M, GRASSI, A, DELL'ERA, L, CORONA, F, BIANCHI;, M., PUNARO, M, SARDANI;, Y, HAAPASAARI, J, KAUTIAINEN, H, LEIRISALO-REPO;, M, COMMARE, M., BATICLE, M, RUA, M., JOURNEAU, P, PRIEUR;, A., KANAKOUDI-TSAKALIDOU, F, TRACHANA, M, PRATSIDOU-GERTSI, P, TSITSAMI, E, KYRIAZOPOULOU-DALAINA;, B, GATTINARA, M, PONTIKAKI, I, GERLONI, V, FANTINI;, F, BILLIAU, A., WOUTERS;, C, JOB-DESLANDRE, C, CHKIRATE;, B, NORDAL, E, JAKOBSEN, A., RYGG;, M, WULFFRAAT, N., VLIEGER, A., KAMPHUIS, S., SANDERS, E., KUIS;, W, SUSIC, G, STOJANOVIC, R, GACIC, D, DJORDJEVIC;, S, VINJE, O, OBIORA, E, FORRE;, O, FOELDVARI, I, BURGOS-VARGAS, R, THON, A, TUERCK;, D, SCHUCHMANN, L, FRANCK;, P, PRIEUR, A., MOUY, R, DEBRÉ, M, QUARTIER, P (2000). 11 Treatment of paediatric rheumatic diseases. Ann Rheum Dis 59: 740-746 [Full Text]  
• Pisetsky, D. S. (2000). Tumor Necrosis Factor Blockers in Rheumatoid Arthritis. NEJM 342: 810-811 [Full Text]  
• Sullivan, K. M., Parkman, R., Walters, M. C. (2000). Bone Marrow Transplantation for Non-Malignant Disease. ASH Education Book 2000: 319-338 [Abstract] [Full Text]