ARTHRITIS & RHEUMATISM
Vol. 60, No. 9, September 2009, pp 27942804
Long-Term Safety and Effectiveness of Etanercept in
Children With Selected Categories of
Juvenile Idiopathic Arthritis
E. H. Giannini,1 N. T. Ilowite,2 D. J. Lovell,1 C. A. Wallace,3 C. E. Rabinovich,4 A. Reiff,5
G. Higgins,6 B. Gottlieb,7 N. G. Singer,8 for the Pediatric Rheumatology Collaborative Study
Group, Y. Chon,9 S.-L. Lin,9 and S. W. Baumgartner9
Objective. This study was undertaken to evaluate
the long-term safety and effectiveness of etanercept
alone or in combination with methotrexate (MTX) in
children with selected categories of juvenile idiopathic
arthritis (JIA).
Methods. Patients ages 218 years with rheuma-
toid factor (RF)positive or RF-negative polyarthritis,
systemic JIA, or extended oligoarthritis were eligible for
ClinicalTrials.gov identifier: NCT00078793.
Supported by Immunex Corporation, a wholly owned subsid-
iary of Amgen Inc., and by Wyeth Pharmaceuticals.
1
E. H. Giannini, DrPH, MSc, D. J. Lovell, MD, MPH:
Cincinnati Childrens Hospital Medical Center, Cincinnati, Ohio;
2
N. T. Ilowite, MD: Albert Einstein College of Medicine, Bronx, New
York; 3C. A. Wallace, MD: Childrens Hospital and Regional Medical
Center, Seattle, Washington; 4C. E. Rabinovich, MD: Duke University
Medical Center, Durham, North Carolina; 5A. Reiff, MD: Childrens
Hospital Los Angeles, Los Angeles, California; 6G. Higgins, MD, PhD:
Ohio State University and Nationwide Childrens Hospital, Columbus,
Ohio; 7B. Gottlieb, MD, MS: Schneider Childrens Hospital, New
Hyde Park, New York; 8N. G. Singer, MD: University Hospitals Case
Medical Center, and University Hospitals Rainbow Babies & Chil-
drens Hospital, Cleveland, Ohio; 9Y. Chon, PhD, S.-L. Lin, MD, PhD,
S. W. Baumgartner, MD: Amgen Inc., Thousand Oaks, California.
Dr. Giannini received grant support from Amgen to serve as
Principal Investigator of this study (more than $10,000). Dr. Ilowite
has received consulting fees, speaking fees, and/or honoraria from
Novartis, Bristol-Myers Squibb, and Abbott (less than $10,000 each).
Dr. Lovell has served on the Amgen speakers bureau. Dr. Wallace has
received a grant from Amgen (more than $10,000). Dr. Reiff has
received consulting fees, speaking fees, and/or honoraria from Amgen
and Wyeth (more than $10,000 each) and has provided expert testi-
mony on behalf of Amgen, Wyeth, Pfizer, and Merck. Dr. Singer has
received consulting fees, speaking fees, and/or honoraria from Acu-
mentis, CME Solutions, and the Vienna Medical Academy (less than
$10,000 each) and from Abbott Immunology (more than $10,000). Drs.
Chon, Lin, and Baumgartner own stock or stock options in Amgen.
Address correspondence and reprint requests to E. H. Gian-
nini, DrPH, MSc, Pediatrics and Rheumatology/Pav 2-129, Childrens
Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229.
E-mail: Edward.Giannini@cchmc.org.
Submitted for publication December 23, 2008; accepted in
revised form June 1, 2009.
2794
DOI 10.1002/art.24777
2009, American College of Rheumatology
the study. Patients received MTX alone (>10 mg/m2/
week [0.3 mg/kg/week], maximum dosage 1 mg/kg/
week), etanercept alone (0.8 mg/kg/week, maximum dose
50 mg), or etanercept plus MTX for 3 years in an
open-label, nonrandomized study. Safety was assessed
by measuring rates of adverse events, and effectiveness
was assessed using the physicians global assessment of
disease activity and the pediatric total joint assessment.
Results. A total of 197, 103, and 294 patients were
enrolled in the MTX, etanercept, and etanercept plus
MTX groups, respectively. Exposure-adjusted rates of
adverse events were similar among the 3 treatment
groups (18.3, 18.7, and 21.6 per 100 patient-years in the
MTX, etanercept, and etanercept plus MTX groups,
respectively). Respective rates per 100 patient-years of
serious adverse events (4.6, 7.1, and 6.0) and medically
important infections (1.3, 1.8, and 2.1) were also similar
among the 3 treatment groups. Scores for physicians
global assessment and total active joints improved from
baseline, and improvement was maintained for the
duration of the study.
Conclusion. These data confirm the findings of
other long-term studies and suggest that etanercept or
etanercept plus MTX has an acceptable safety and
effectiveness profile in children with selected categories
of JIA. Improvement was maintained for 3 years in
those continuing to receive medication.
Juvenile idiopathic arthritis (JIA) is the most
common childhood rheumatic disease (1,2), and it often
extends into or relapses during adulthood (3). The pain
and functional disability associated with JIA cause a
significant burden for patients and their families and
caregivers. Indeed, JIA has an important adverse impact
on health-related quality of life and well-being that is
LONG-TERM ETANERCEPT THERAPY IN JIA
largely explained by the degree of functional disability,
pain, and disease activity (410). To add to these
potential problems, JIA can have a negative effect on
normal physical growth and development (1). The de-
structive and persistent nature of JIA underscores the
need for more effective treatments.
Nonsteroidal antiinflammatory drugs (NSAIDs)
are considered first-line treatments for JIA. Disease-
modifying antirheumatic drugs (DMARDs), of which
methotrexate (MTX) is the most commonly used, are
second-line treatments (1115). Although MTX pro-
vides significant clinical benefit, its use may be limited by
toxicity and/or incomplete response or nonresponse in
patients with JIA (12,16). Biologic agents are now a
therapeutic option that offers the potential for improv-
ing efficacy and safety outcomes in patients with JIA
(1719).
Etanercept, a fully human soluble tumor necrosis
factor (TNF) receptor fusion protein, has been demon-
strated to be safe and efficacious for the treatment of
patients with rheumatoid arthritis (RA), psoriatic arthri-
tis, psoriasis, and ankylosing spondylitis and is currently
approved for these indications (2023). It is also ap-
proved for reducing the signs and symptoms of polyar-
ticular JIA (rheumatoid factor [RF] positive or negative)
in children ages 2 years and older. A number of studies
have demonstrated the efficacy and safety of etanercept
in JIA (2432), but relatively few long-term studies have
been performed to date. Consequently, there is a need
to undertake longer-term studies to assess the safety and
effectiveness of etanercept in patients with JIA. To this
end, we report herein the results of a 3-year, phase IV,
open-label, multicenter registry of patients with selected
categories of JIA who received etanercept, MTX, or
etanercept plus MTX.
PATIENTS AND METHODS
Patients. Patients ages 218 years with selected cate-
gories of JIA (33) (systemic, oligoarticular, or polyarticular
[RF positive or negative]) were eligible for enrollment; how-
ever, 3 patients younger than 2 years of age were also included.
Patients were enrolled and classified at study entry using the
JIA classification system. Although there were no limits on
disease duration, patients had to have had an adequate trial of
NSAIDs and/or prednisone prior to study enrollment. Gener-
ally, patients were required to have at least 3 joints with active
arthritis at the time of entry into the registry. However,
patients were eligible if their disease was under control on 1 or
more DMARDs or etanercept with 0 active joints at entry.
At the time of entry into the registry, patients were
receiving 1 of the following treatments, with or without other
DMARDs (allowable DMARDs included sulfasalazine, MTX,
2795
cyclosporine, leflunomide, injectable gold, hydroxychloro-
quine, and azathioprine): etanercept, etanercept plus MTX, or
MTX. Investigators were strongly encouraged to enroll pa-
tients who were just beginning to receive MTX or etanercept
or were just beginning to receive etanercept in addition to
MTX. Patients in the etanercept arm had to have started
etanercept treatment within 6 months prior to enrollment into
the registry. Patients in the MTX arm had to have recently
started MTX or must have started MTX within 6 months after
enrollment into the registry. Patients in the comparator
(MTX) arm may have had disease that did not respond to 1
DMARD other than MTX, and coadministration of 1 other
DMARD was allowed provided that it did not specifically
inhibit TNF. Patients were also allowed to receive concomitant
NSAIDs and/or prednisone.
Patients were excluded if they were pregnant or nurs-
ing; had previously received anti-TNF antibody, anti-CD4
antibody, or interleukin-2 diphtheria fusion protein treatment;
or had participated in an investigational study of a drug or
biologic agent other than etanercept 6 months before enroll-
ment. Patients were also excluded if, at the time of enrollment,
they were receiving an anti-TNF agent other than etanercept
(e.g., infliximab, thalidomide, or adalimumab), cyclo-
phosphamide, or other experimental or biologic agents; had
any serious medical condition; had a history of drug and/or
alcohol abuse; or had had any malignancies within the 5 years
prior to the enrollment date.
Study design. This was a phase IV, open-label, multi-
center registry to evaluate the long-term safety of etanercept,
MTX, or the combination of etanercept and MTX in children
with the following selected categories of JIA: systemic, RF-
positive polyarthritis, RF-negative polyarthritis, or oligoarthri-
tis (extended subtype). Study sites were from the Pediatric
Rheumatology Collaborative Study Group in the US and
Canada. The study protocol was reviewed and approved by the
Institutional Review Boards of the participating study sites,
and the study was conducted in accordance with the Helsinki
Declaration. Written informed consent was obtained from a
parent or legal guardian before patients entered the study.
Etanercept was administered subcutaneously twice
weekly at a dosage of 0.4 mg/kg (maximum dose 25 mg) or
once weekly at a dosage of 0.8 mg/kg (maximum dose 50 mg).
Previous findings using the adult dosing regimen for etaner-
cept showed no differences in efficacy or safety between twice
weekly and once weekly dosing in adults (34). Etanercept
could be used alone or in combination with MTX at a dose
determined by the treating physician. In the comparator
cohort, MTX was administered at a dosage of at least 10
mg/m2/week (0.3 mg/kg/week) and not exceeding 1 mg/kg/
week for up to 36 months. The protocol specified that treating
physicians could prescribe other DMARDs along with etaner-
cept and MTX, excluding TNF antagonists or other biologics,
investigational agents, and drugs not specifically approved for
JIA.
Patients enrolled in the MTX arm could switch to
etanercept or etanercept plus MTX treatment and re-enroll
into the etanercept or etanercept plus MTX arms within 30
months of enrollment. Patients who discontinued etanercept
and started MTX treatment were not re-enrolled. Patients
were considered to have completed the registry at their
36-month visit or at discontinuation of etanercept or MTX.
2796 GIANNINI ET AL

Table 1. Baseline demographic and clinical characteristics of the patients with JIA*
MTX only Etanercept only Etanercept plus MTX
(n 197) (n 103) (n 294)
Sex, no. (%) male/female 52 (26.4)/145 (73.6) 20 (19.4)/83 (80.6) 80 (27.2)/214 (72.8)
Race, no. (%)
Asian 1 (0.5) 4 (3.9) 6 (2.0)
African American 12 (6.1) 5 (4.9) 29 (9.9)
White 151 (76.6) 78 (75.7) 214 (72.8)
Hispanic 24 (12.2) 7 (6.8) 29 (9.9)
Native American 0 (0.0) 1 (1.0) 1 (0.3)
Other 9 (4.6) 8 (7.8) 15 (5.1)
Age, mean SD years 9.0 4.4 10.8 4.1 10.1 4.7
JIA type, no. (%)
Systemic 13 (6.6) 8 (7.8) 37 (12.6)
Polyarticular (RF or RF) 184 (93.4) 95 (92.2) 256 (87.1)
Unknown 0 (0.0) 0 (0.0) 1 (0.3)
Disease duration, mean SD months 20.2 30.7 58.1 44.5 40.7 41.7
RF, no. (%)
Positive 34 (17.3) 14 (13.6) 69 (23.5)
Negative 157 (79.7) 89 (86.4) 219 (74.5)
Unknown 6 (3.0) 0 (0.0) 6 (2.0)
Medication at baseline, no. (%)
NSAIDs 180 (91.4) 75 (72.8) 249 (84.7)
Prednisone 36 (18.3) 21 (20.4) 78 (26.5)
Intraarticular corticosteroids 22 (11.2) 13 (12.6) 46 (15.6)
MTX 197 (100.0) 0 (0.0) 294 (100.0)
Folinic or folic acid 120 (60.9) 9 (8.7) 200 (68.0)
Etanercept 1 (0.5) 102 (99.0) 292 (99.3)
Hydroxychloroquine 7 (3.6) 7 (6.8) 15 (5.1)
Sulfasalazine 3 (1.5) 3 (2.9) 9 (3.1)
Cyclosporine 0 (0) 4 (3.9) 3 (1.0)
Medication use before enrollment
Prior etanercept therapy, no. (%) 1 (0.5) 86 (83.5) 240 (81.6)
Duration of etanercept use before 79.0 (76.6) 78.8 (91.9)
enrollment, mean SD days
Prior MTX therapy, no. (%) 192 (97.5) 89 (86.4) 294 (100.0)
Duration of MTX use before 92.7 78.1 770.1 812.6 723.8 832.5
enrollment, mean SD days

* JIA juvenile idiopathic arthritis; MTX methotrexate; RF rheumatoid factor; NSAIDs nonsteroidal
antiinflammatory drugs.
Includes patients with extended oligoarthritis.
A single patient in the MTX-only group received prior etanercept treatment for 152 days (protocol violation that
needed to be reported).

Patients who switched from the MTX group to the etanercept
or etanercept plus MTX group were considered to have
completed the registry at their 36-month visit or at early
discontinuation.
Outcomes. Safety data obtained from patients under-
going therapy for up to 3 years (June 1, 2005 to January 31,
2008) are reported in this analysis. Adverse events were
assessed at baseline and at each subsequent visit (months 3, 6,
9, 12, 18, 24, 30, and 36 or at early discontinuation). The study
protocol specified that infections be listed on a separate
infection report and that only medically important infections
(defined as infections requiring intravenous antibiotics or
hospitalization) be included. A serious adverse event was
defined as one that resulted in death, was life threatening
(patient was at immediate risk of death from the reaction as it
occurred), resulted in permanent, persistent, or significant
disability or incapacity, required inpatient or prolonged hos-
pitalization, or was a congenital anomaly or birth defect. Other
events of interest, including malignancy, sepsis, behavioral
disorders, and autoimmune disorders, were also reported.
Routine laboratory assessments were not a part of the study
protocol. Physicians were to practice the standard of care for
monitoring toxicities.
Data for other outcome measures (exploratory end
points) were also collected, including the physicians global
assessment of disease activity (a measure of current disease
activity, rated from 0 [no symptoms] to 10 [severe symptoms])
and pediatric total joint assessment (measure of swelling in 66
joints, tenderness and/or pain on motion in 75 joints, and
limitation of motion in 69 joints). Pediatric total joint assess-
ment was performed at baseline and at months 6, 12, 18, 24, 30,
and 36 or at early discontinuation. Physicians global assess-
ment of disease activity was performed at baseline and at
months 3, 6, 9, 12, 18, 24, 30, and 36, or at early discontinuation.
Statistical analysis. All patients who were enrolled
into the registry and completed at least 1 evaluation while
receiving MTX or etanercept were included in the analysis of
safety and effectiveness end points. At full enrollment (197
LONG-TERM ETANERCEPT THERAPY IN JIA
Figure 1. Disposition of the patients. Note that the denominators for calculations for reasons for discontinuation (bottom row) are based on the
number of patients enrolled in each group, (i.e., 197 for the methotrexate [MTX] group, 103 for the etanercept [ETN] group, and 294 for the
etanercept plus MTX group).
patients in the MTX arm, 103 patients in the etanercept arm,
and 294 patients in the etanercept plus MTX arm), the trial
had 80% power to detect an increase from 0.10 to 0.19 in the
proportion of patients who experienced an event (relative risk
1.9). Descriptive statistics were used to assess the effectiveness
and safety outcomes in each treatment cohort and other
characteristics of the registry population.
RESULTS
Patient demographics and disposition. Baseline
patient demographics are summarized in Table 1. Ap-
proximately three-quarters of the patients were female
(range of mean values across groups 7381%), and
approximately three-quarters were white (range of mean
values 7377%). Their mean ages were 9.010.8 years.
Most patients (93%, 92%, and 87% in the MTX, etan-
ercept, and etanercept plus MTX groups, respectively)
had polyarticular disease, and 1424% were RF positive.
The proportion of patients receiving NSAIDs at base-
line ranged from 73% to 91%, and the proportion of
patients receiving prednisone at baseline ranged from 18%
to 27%.
The mean disease duration for patients in the
MTX group was shorter (20.2 months) than the mean
disease duration for patients in the etanercept group
(58.1 months) or etanercept plus MTX group (40.7
months). Most patients (97.5%, 86.4%, and 100.0% in
the MTX, etanercept, and etanercept plus MTX groups,
respectively) had received MTX before study enroll-
ment. Longer mean durations of MTX treatment before
2797
enrollment were reported in patients from the etaner-
cept group (770.1 days) and the etanercept plus MTX
group (723.8 days) compared with patients in the MTX
group (92.7 days). Most patients in the etanercept group
(83.5%) and etanercept plus MTX group (81.6%) had
received etanercept therapy before enrollment with a
mean duration of 79.0 days and 78.8 days, respectively.
One patient in the MTX group (0.5%) received 152
days treatment with etanercept before study enrollment.
The mean SD dosage of MTX during the study
was 12.6 5.3 mg/week for the MTX-only patients and
16.9 5.9 mg/week for the etanercept plus MTX
patients. The percentages of patients receiving pred-
nisone at baseline were slightly lower in the MTX and
etanercept groups than in the etanercept plus MTX
group (18% and 20% versus 27%, respectively), as were
the percentages of patients who received prednisone
during the study (16.2% of the patients receiving MTX,
18.4% of the patients receiving etanercept, and 22.8% of
patients receiving both etanercept and MTX). Mean
SD dosages of prednisone during the study were 8.6
7.1 mg/day for the MTX group, 10.6 10.4 mg/day for
the etanercept group, and 7.8 5.4 mg/day for the
etanercept plus MTX group. In addition, 1116% of the
patients in the 3 groups had received intraarticular
corticosteroid injections at baseline, and 1%, 0%, and
1% in the MTX, etanercept, and MTX plus etanercept
groups, respectively, had received corticosteroid pulses.
Patient disposition and patient retention over
2798 GIANNINI ET AL

Table 2. Summary of patient retention over time

MTX only Etanercept only Etanercept plus MTX
(n 197)* (n 103) (n 294)
Months 06
No. of patients available at the beginning of the period 197 103 294
Patient-years during the period 98.3 50.6 141.8
No. (%) of patients who withdrew during the period 42 (21.3) 12 (11.7) 39 (13.3)
No. (%) of patients who withdrew due to adverse events 2 (1.0) 2 (1.9) 1 (0.3)
during the period
No. (%) of patients who withdrew due to insufficient 14 (7.1) 5 (4.9) 20 (6.8)
therapeutic effect during the period
Months 612
No. of patients available at the beginning of the period 155 91 255
Patient-years during the period 77.8 45.4 127.8
No. (%) of patients who withdrew during the period 22 (14.2) 15 (16.5) 27 (10.6)
No. (%) of patients who withdrew due to adverse events 0 (0.0) 0 (0.0) 0 (0.0)
during the period
No. (%) of patients who withdrew due to insufficient 8 (5.2) 1 (1.1) 13 (5.1)
therapeutic effect during the period
Months 1224
No. of patients available at the beginning of the period 133 76 228
Patient-years during the period 125.4 70.6 206.3
No. (%) of patients who withdrew during the period 38 (28.6) 19 (25.0) 58 (25.4)
No. (%) of patients who withdrew due to adverse events 1 (0.8) 0 (0.0) 0 (0.0)
during the period
No. (%) of patients who withdrew due to insufficient 9 (6.8) 1 (1.3) 18 (7.9)
therapeutic effect during the period
Months 2436
No. of patients available at the beginning of the period 95 57 170
Patient-years during the period 86.3 57.4 159.4
No. (%) of patients who withdrew during the period 29 (30.5) 10 (17.5) 38 (22.4)
No. (%) of patients who withdrew due to adverse events 0 (0.0) 0 (0.0) 0 (0.0)
during the period
No. (%) of patients who withdrew due to insufficient 5 (5.3) 1 (1.8) 8 (4.7)
therapeutic effect during the period

* MTX methotrexate.

time are summarized in Figure 1 and Table 2, respec-
tively. A total of 245 (41%) completed the study, and 349
(59%) discontinued. Overall, 103 patients (17%) discon-
tinued due to lack of effectiveness (36 [18%], 8 [8%],
and 59 [20%] in the MTX, etanercept, and etanercept
plus MTX groups, respectively), and 6 (1%) discontin-
ued because of an adverse event (3 [2%], 2 [2%], and 1
[0.3%] in the MTX, etanercept, and etanercept plus
MTX groups, respectively). Two patients became preg-
nant during the study, and drug treatment was discon-
tinued when the pregnancy was reported. The adverse
events that led to study withdrawal were elevated liver
enzymes (n 2) and rash (n 1) in the MTX group,
juvenile dermatomyositis (n 1) and headache (n 1)
in the etanercept group, and injection site reaction (n
1) in the etanercept plus MTX group. A total of 32
patients in the MTX group who discontinued switched
to the etanercept group (n 8) or etanercept plus MTX
(n 24) group.
Safety assessments. A summary of adverse
events listed by Coding Symbols for Thesaurus of Ad-
verse Reaction Terms (COSTART) preferred terms is
presented in Table 3. The exposure-adjusted rates of
adverse events per 100 patient-years were similar in the
MTX (18.3), etanercept (18.7), and etanercept plus
MTX (21.6) groups. The exposure-adjusted rates of
arthritis flares per 100 patient-years were 1.0 in the
MTX group, 0.5 in the etanercept group, and 2.4 in the
etanercept plus MTX group. There were 3 cases of
neuropathy (COSTART preferred term) reported in the
etanercept group but none of these cases were demyeli-
nating events. The 3 reports of neuropathy included 2
reports of reflex sympathetic dystrophy in 1 patient and
1 report of anxiety secondary to reflex neurovascular
dystrophy. One case of peripheral neuropathy (classified
as peripheral neuritis by COSTART preferred term) was
reported in the etanercept plus MTX group. One case of
optic neuritis was noted in the MTX group. Two cases of
uveitis were reported, both in the etanercept plus MTX
group (1 case of uveitis of the left eye and 1 case of flare
of uveitis). One case of dermatomyositis was reported in
LONG-TERM ETANERCEPT THERAPY IN JIA 2799

Table 3. Summary of adverse events with exposure-adjusted rates of 0.5 per 100 patient-years*
MTX Etanercept Etanercept plus MTX
(n 197) (n 103) (n 294)
Total patient-years of exposure 387.80 224.11 635.17
Total adverse events, no. (rate per 100 patient- 71 (18.31) 42 (18.74) 137 (21.57)
years)
Preferred term, no. (rate per 100 patient-years)
Arthritis flare 4 (1.03) 1 (0.45) 15 (2.36)
Depression 4 (1.03) 3 (1.34) 11 (1.73)
Personality disorder 2 (0.52) 2 (0.89) 8 (1.26)
Emotional lability 2 (0.52) 2 (0.89) 6 (0.94)
Headache 0 (0.0) 1 (0.45) 6 (0.94)
Abnormal thinking 0 (0.0) 1 (0.45) 5 (0.79)
Leukopenia 1 (0.26) 0 (0.0) 4 (0.63)
Asthenia 1 (0.26) 1 (0.45) 5 (0.79)
Anxiety 1 (0.26) 4 (1.78) 3 (0.47)
Anemia 1 (0.26) 2 (0.89) 1 (0.16)
Increased SGOT 3 (0.77) 0 (0.0) 1 (0.16)
Increased SGPT 8 (2.06) 0 (0.0) 1 (0.16)
Asthma 2 (0.52) 0 (0.0) 1 (0.16)
Abnormal liver function (hepatic enzymes 8 (2.06) 0 (0.0) 0 (0.0)
increased)
Hydroureter 3 (0.77) 0 (0.0) 0 (0.0)
Hostility 3 (0.77) 0 (0.0) 0 (0.0)
Agitation 3 (0.77) 1 (0.45) 0 (0.0)
Thyroiditis 2 (0.52) 0 (0.0) 0 (0.0)
Viral infection 0 (0.0) 2 (0.89) 0 (0.0)
Neuropathy 0 (0.0) 3 (1.34) 0 (0.0)

* MTX methotrexate; SGOT serum glutamic oxaloacetic transaminase; SGPT serum glutamic
pyruvic transaminase.
Although the protocol specified that only medically important infections be reported and that they be
reported separately from noninfectious adverse events, viral infection was inadvertently recorded on the
adverse event form. One of the 2 viral infections reported in this table was classified as medically
important and is therefore also reported in Table 4.

the etanercept only group, but the event was thought to
be unrelated to treatment.
A total of 21 adverse events of elevated findings
on liver function tests were reported: 19 events in the
MTX-only group and 2 events in the etanercept plus
MTX group. Events of elevated findings on liver func-
tion tests (2.55 times the upper limit of normal) were
classified by preferred term as elevated serum glutamic
pyruvic transaminase (SGPT) level, elevated serum glu-
tamic oxaloacetic transaminase (SGOT) level, and liver
function abnormality (unspecified). Exposure-adjusted
rates (per 100 patient-years) of elevated liver function
test results were higher in MTX-treated patients than in
etanercept-treated patients or patients treated with et-
anercept plus MTX, including elevated SGPT level (2.1,
0.0, and 0.2 in the MTX, etanercept, and etanercept plus
MTX groups, respectively), liver function abnormality
(2.1, 0.0, and 0.0 in the MTX, etanercept, and etanercept
plus MTX groups, respectively), and elevated SGOT
level (0.8, 0.0, and 0.2 in the MTX, etanercept, and
etanercept plus MTX groups, respectively).
The exposure-adjusted rates of serious adverse
events per 100 patient-years were 4.6, 7.1, and 6.0 in the
MTX, etanercept, and etanercept plus MTX groups,
respectively. Serious adverse events reported in 0.5 per
100 patient-years in any group were headache (0.0, 0.0,
and 0.6 in the MTX, etanercept, and etanercept plus
MTX groups, respectively), viral infection (0.0, 0.9, and
0.0, respectively), arthritis flare (0.5, 0.5, and 0.9, respec-
tively), and asthma (0.5, 0.0, and 0.0, respectively). Two
serious adverse events were reported more than once in
the MTX group (arthritis flare and asthma, 2 events
each; exposure-adjusted rates of 0.52 per 100 patient-
years). The only serious adverse event reported more
than once in the etanercept group was viral infection (2
events; exposure-adjusted rate of 0.9 per 100 patient-
years). In the etanercept plus MTX group, headache was
reported 4 times (exposure-adjusted rate of 0.6 per 100
patient-years) and arthritis flare was reported 6 times
(0.9 per 100 patient-years). Other serious adverse events
reported more than once in the etanercept plus MTX
group included abscess, gastrointestinal disturbance, di-
abetes mellitus, and herpes zoster infection (2 events each;
exposure-adjusted rates of 0.3 per 100 patient-years).
The exposure-adjusted rates of medically impor-
tant infections were 1.3, 1.8, and 2.1 per 100 patient-
2800 GIANNINI ET AL

Table 4. Summary of medically important infections with exposure-adjusted rates per 100 patient-years
MTX Etanercept Etanercept plus MTX
(n 197)* (n 103) (n 294)
Total patient-years of exposure 387.80 224.11 635.17
Total medically important infections, no. 5 (1.29) 4 (1.78) 13 (2.05)
(rate per 100 patient-years)
Preferred term, no. (rate per 100 patient-years)
Body as a whole
Abscess 1 (0.26) 0 (0.0) 2 (0.31)
Sepsis 0 (0.0) 0 (0.0) 1 (0.16)
Blood culture positive 0 (0.0) 1 (0.45) 0 (0.0)
Infection 0 (0.0) 2 (0.89) 1 (0.16)
Bacterial infection 1 (0.26) 0 (0.0) 0 (0.0)
Viral infection 0 (0.0) 1 (0.45) 0 (0.0)
Digestive system
Colitis 0 (0.0) 0 (0.0) 1 (0.16)
Gastroenteritis 0 (0.0) 0 (0.0) 1 (0.16)
Respiratory system
Bronchitis 0 (0.0) 0 (0.0) 1 (0.16)
Pharyngitis 0 (0.0) 0 (0.0) 1 (0.16)
Sinusitis 1 (0.26) 0 (0.0) 0 (0.0)
Skin and appendages
Herpes zoster 1 (0.26) 0 (0.0) 2 (0.31)
Urogenital system
Pyelonephritis 1 (0.26) 0 (0.0) 2 (0.31)
Urinary tract infection 0 (0.0) 0 (0.0) 1 (0.16)

* MTX methotrexate.

years in the MTX, etanercept, and MTX plus etanercept
groups (Table 4). The medically important infections in
the MTX group (1 each) included herpes zoster infec-
tion, blood culturepositive pyelonephritis, sinusitis, or-
bital cellulitis/abscess, and a possible mycoplasma infec-
tion. Medically important infections in the etanercept
group (1 each) included pilonidal cyst infection, postap-
pendectomy wound infection, blood culturepositive bac-
teremia, and acute viral syndrome. In the etanercept plus
MTX group, medically important infections included 2
reports each of herpes zoster infection, pyelonephritis,
and abscess, and 1 report each of bronchitis, viral
gastroenteritis, joint effusion, urosepsis, Clostridium dif-
ficile colitis, urinary tract infection, and pharyngitis.
No cases of lymphoma, tuberculosis, malignancy,
or death were reported. During each visit, patients were
assessed for signs or symptoms of new autoimmune
disease. The exposure-adjusted rates of autoimmune
events were 4.4 (n 17 events), 5.4 (n 12 events), and
2.4 (n 15 events) per 100 patient-years in the MTX,
etanercept, and etanercept plus MTX groups, respec-
tively. The most commonly reported autoimmune event
was the presence of autoantibodies (exposure-adjusted
rates of 1.8 [n 7], 1.8 [n 4], and 0.6 [n 4] per 100
patient-years in the MTX, etanercept, and etanercept
plus MTX groups, respectively). Information about the
type of autoantibodies was not collected. The only other
autoimmune events reported more than once in any
group were type 1 diabetes mellitus and Raynauds
phenomenon (twice each in the etanercept plus MTX
group). One case of moderate systemic lupus erythem-
atosus, which was considered unrelated to study drug,
was reported in the MTX group.
Effectiveness. Physicians global assessment and
total active joint scores for the 3 treatment groups were
similar at baseline, and improvement was achieved in all
groups at 3 months and 6 months and was sustained
through 36 months. Median physicians global assess-
ment scores were 4 for MTX, 3 for etanercept, and 4 for
etanercept plus MTX at baseline, 2 for all groups at
month 3, 1 for MTX and 2 for both etanercept groups at
month 6, and 1 for all groups at months 12, 24, and 36.
The median numbers of active joints were 6 for MTX, 4
for etanercept, and 6 for etanercept plus MTX at
baseline, 1 for MTX and 2 for both etanercept groups at
month 6, 0 for MTX, 1 for etanercept, and 2 for
etanercept plus MTX at month 12, 0 for MTX and
etanercept and 1 for etanercept plus MTX at month 24,
and 0 for all groups at month 36. An ad hoc analysis was
performed in which patients were separated into groups
to account for those who had switched from the MTX
group into the etanercept or etanercept plus MTX
groups. These data showed improvements in median
physicians global assessment and total active joint
scores over time in all treatment groups (data not
shown). In addition, physicians global assessment scores
LONG-TERM ETANERCEPT THERAPY IN JIA 2801

Table 5. Patients with physicians global assessment or total active joint scores of 0*
MTX to
Etanercept etanercept MTX to
MTX only Etanercept only plus MTX plus MTX etanercept
(n 197) (n 95) (n 270) (n 24) (n 8)
Physicians global assessment score of 0, no. (%)
Baseline 14/197 (7.1) 7/95 (7.4) 18/270 (6.7) 1/24 (4.2) 0/8 (0)
Month 3 21/175 (12.0) 16/86 (18.6) 25/246 (10.2) 2/24 (8.3) 0/6 (0)
Month 6 39/145 (26.9) 18/79 (22.8) 37/215 (17.2) 4/23 (17.4) 1/6 (16.7)
Month 9 43/131 (32.8) 20/71 (28.2) 44/202 (21.8) 6/22 (27.3) 1/5 (20.0)
Month 12 44/124 (35.5) 18/68 (26.5) 54/200 (27.0) 9/23 (39.1) 3/4 (75.0)
Month 18 46/114 (40.4) 25/58 (43.1) 54/167 (32.3) 9/18 (50.0) 3/5 (60.0)
Month 24 40/93 (43.0) 16/46 (34.8) 44/143 (30.8) 8/16 (50.0) 4/5 (80.0)
Month 30 31/74 (41.9) 16/45 (35.6) 33/131 (25.2) 8/16 (50.0) 4/5 (80.0)
Month 36 31/67 (46.3) 17/42 (40.5) 35/115 (30.4) 8/17 (47.1) 4/5 (80.0)
Total active joint score of 0, no. (%)
Baseline 23/197 (11.7) 17/95 (17.9) 33/270 (12.2) 1/24 (4.2) 0/8 (0.0)
Month 6 35/79 (44.3) 12/35 (34.3) 32/106 (30.2) 8/16 (50.0) 0/3 (0.0)
Month 12 47/68 (69.1) 14/35 (40.0) 34/89 (38.2) 8/14 (57.1) 2/3 (66.7)
Month 18 40/59 (67.8) 14/23 (60.9) 36/73 (49.3) 10/13 (76.9) 2/3 (66.7)
Month 24 28/50 (56.0) 11/19 (57.9) 26/65 (40.0) 8/13 (61.5) 3/3 (100.0)
Month 30 22/39 (56.4) 13/20 (65.0) 18/55 (32.7) 7/12 (58.3) 2/3 (66.7)
Month 36 43/66 (65.2) 24/42 (57.1) 58/115 (50.4) 10/18 (55.6) 5/5 (100.0)

* Values were calculated as the number of patients with physicians global assessment of 0 (on a scale of 0 [no symptoms] to 10 [severe symptoms])
or total active joint score of 0 enrolling into the registry who completed at least 1 evaluation while receiving methotrexate (MTX) or etanercept divided
by the number of patients enrolling into the registry who completed at least 1 evaluation while receiving MTX or etanercept and had data available
at each visit.

or total active joint counts of 0 were achieved in patients
in all treatment groups (Table 5).
DISCUSSION
The results of this registry study, the largest
cohort of JIA patients treated with a biologic agent
studied prospectively over 3 years, indicate that etaner-
cept is generally well tolerated in children with polyar-
ticular (RF positive or negative) or systemic JIA. It is
worth noting some key differences in the patient popu-
lations that were evaluated. The patients in the etaner-
cept groups had a longer disease duration at baseline
than the patients in the MTX group (by at least 2-fold).
The duration of prior drug exposure also differed be-
tween treatment groups; indeed, there was a much
shorter duration of MTX treatment in the MTX group
(mean 3 months) than in the etanercept groups (mean
2 years). This suggests that a large proportion of
patients in the etanercept and etanercept plus MTX
groups had refractory JIA that had failed to respond to
MTX, which is consistent with the Food and Drug
Administrationapproved use of etanercept at the time
of the initiation of the study. Most etanercept-treated
patients (81%) had received etanercept before entering
the study, and the mean duration of etanercept treat-
ment was 80 days. Because of eligibility criteria, these
differences in duration of previous drug exposure were
expected and did not occur by chance; nonetheless, the
potential cumulative effects of these previous therapies
and disease duration on adverse events are not known.
The exposure-adjusted rates of adverse events
were similar for all 3 treatment groups (1822 events per
100 patient-years). The most common adverse events
reported in the etanercept group were anxiety (n 4),
neuropathy (n 3), and depression (n 3) (exposure-
adjusted rates of 1.8, 1.3, and 1.3 per 100 patient-years,
respectively). The most common adverse event reported
in the etanercept plus MTX group was arthritis flare
(n 15; rate of 2.4 per 100 patient-years). In the MTX
group, an increase in SGPT and abnormal liver enzymes
(n 8 each; rate of 2.1 per 100 patient-years) were the
most common events. However, the longer exposure
time to MTX before study enrollment in the etanercept
and etanercept plus MTX groups could have resulted in
a bias in those populations to include only patients who
tolerated long-term MTX treatment.
The rates of serious adverse events and medically
important infections were similar across groups. The
overall rates of serious adverse events were 7.1 and 6.0
per 100 patient-years in the etanercept and etanercept
plus MTX groups, respectively, and the rates of medi-
cally important infections were 1.8 and 2.1 per 100
patient-years, respectively. Rates of autoimmune events
per 100 patient-years were 4.4, 5.4, and 2.4 for the MTX,
etanercept, and etanercept plus MTX groups, respec-
tively, the most common of which was autoantibodies.
2802
These safety findings are consistent with those reported
in other analyses of etanercept in JIA (25,26,32). Rates
of discontinuation in the etanercept group also appeared
to be consistent with those previously reported (26).
No cases of lymphoma, tuberculosis, malignancy,
or death were reported in any treatment group; how-
ever, this study was not powered to detect an increase in
rates of rare events. The precise risk of lymphoma in
adult patients with RA treated with either traditional
DMARDs or with biologic agents remains a subject of
controversy because RA itself appears to confer an in-
creased risk of lymphoma not reported in JIA (3539).
Nonetheless, physicians treating patients who have JIA
should be familiar with, and comfortable talking about, the
data regarding RA and lymphoma risk and make parents
aware of these data, with the caveat that while the same
theoretical concerns may exist in JIA, there are no reports
that suggest an increased underlying risk of lymphoma.
Additional important safety issues include being
able to provide guidance to patients with JIA who
become pregnant during etanercept therapy. Data from
the Organization of Teratology Information Specialists
registry indicated no specific pattern of defects in infants
exposed to etanercept prenatally, and pregnancy out-
comes were similar to a disease-matched cohort group
(40). During the course of this study, 2 patients became
pregnant, and etanercept treatment and followup were
discontinued. Therefore, information is not available on
the outcomes of these pregnancies. Etanercept is classi-
fied as Category B with regard to use in pregnancy (i.e.,
no harm to fetus reported in animal studies, but no
well-controlled studies have been conducted in pregnant
women; therefore, etanercept should be used during
pregnancy only if clearly needed) (20).
Patients showed improvement in physicians
global assessment scores and total active joint scores that
was sustained for 3 years in this study. Despite a longer
mean disease duration in the etanercept-only group than
in the MTX-only or etanercept plus MTX groups (58
months versus 20 months and 41 months, respectively),
baseline values and improvement in these parameters
were similar in all 3 treatment groups. However, patients
in the MTX group had recently started MTX therapy
before enrollment. In contrast, those in the etanercept
groups had been receiving MTX therapy for 2 years
before enrollment. Therefore, the similarity in baseline
physicians global assessment scores and total active
joint scores among the 3 groups may reflect the similar-
ities between patients initiating MTX therapy and those
whose disease was managed with long-term MTX treat-
ment. To further evaluate the effectiveness of etanercept
GIANNINI ET AL
in these populations, those who had switched from the
MTX group into one of the etanercept groups were
analyzed separately. Based on higher mean joint counts
and higher mean physicians global assessment scores
upon study entry, these patients had the most severe
disease (as might be expected in patients switching
therapies); nevertheless, they also experienced good
responses to etanercept therapy.
Data from this long-term registry study are con-
sistent with the findings of clinical trials and data from
other registry studies of etanercept monotherapy or
etanercept combination therapy. Preliminary findings in
40 patients from an Italian registry suggest that etaner-
cept may reduce progression of radiographic joint dam-
age in JIA (28). A small (n 12) pilot study of German
pediatric etanercept registry patients with JIA showed
similar efficacy and tolerability with 50 mg of etanercept
once weekly and 25 mg of etanercept twice weekly (29).
A larger study of JIA patients enrolled in the
German etanercept registry included an intent-to-treat
population of 376 patients who received etanercept plus
MTX and 55 who received etanercept monotherapy
(32). After 12 months of therapy, the American College
of Rheumatology (ACR) Pediatric 30, 50, and 70 criteria
responses were 81%, 74%, and 62%, respectively, for the
combination therapy group and 70%, 63%, and 45%,
respectively, for the monotherapy group (32). There
were 52 reports of severe adverse events (26 noninfec-
tious and 26 infectious) in a total of 604 patients (504 in
the combination therapy group and 100 in the mono-
therapy group) in the safety analysis, all of whom
received at least 1 dose of etanercept. The overall rates
of serious adverse events per patient were 0.1 (n 48
events) in the etanercept plus MTX group and 0.04 (n
4 events) in the etanercept monotherapy group, and the
corresponding rates of serious infectious events were
0.05 (n 25 infections) and 0.01 (n 1 infection),
respectively. Three malignant tumors (0.26 per 100
patient-years), 2 cases of optic nerve papillitis, and 1
case of suspected demyelination were reported in that
study (in a total of 604 patients representing 1,149
patient-years of exposure).
In a 3-month, open-label study followed by a
4-month, randomized, blinded, placebo-controlled trial
of etanercept treatment in patients with polyarticular
JIA refractory to MTX, a 30% improvement in the
ACR core response variables (ACR Pediatric 30) was
achieved in 80% of 25 patients who received etanercept
(24) compared with 35% of 26 patients who received
etanercept followed by placebo (25). In a 4-year open-
label extension of this study, an ACR Pediatric 30
LONG-TERM ETANERCEPT THERAPY IN JIA
response was achieved in 94% of 32 patients for whom
complete efficacy data were available and who were still
enrolled in the study, and an ACR Pediatric 70 response
was achieved in 78% of 32 patients at the last study visit
(26). Eight-year data from this open-label extension
indicated that an ACR Pediatric 70 response was
achieved in 100% of the 11 patients still enrolled in the
study (61% of the patients according to last observation
carried forward analysis) (27). Improvements in patient-,
parent-, and physician-reported outcomes were also
sustained through year 8 of treatment. The rates of
serious adverse events and of serious infectious events
did not increase over time.
Interpretation of the long-term effectiveness and
safety results of the present study is potentially con-
founded by the typical limitations associated with open-
label nonrandomized studies. These include lack of a
comparable control group and lack of blinding. Study
groups were not comparable due to the fact that many
patients in the etanercept groups had disease that had
previously failed to respond to MTX, while many in the
MTX group were just initiating MTX treatment. In
addition, because no retrospective evaluation was per-
formed, there was no information available regarding
adverse events that occurred prior to enrollment in the
registry. Another limitation is that only medically impor-
tant infections (defined as infections requiring intrave-
nous antibiotics or hospitalization) were recorded;
therefore, no data are available on the rate of minor
infections. Nonetheless, registry studies are important
because they reflect usual care in the clinical setting and
can provide safety and effectiveness information on
real-world use of the drugs being evaluated.
These findings are clinically relevant because
there are limited therapies available for JIA, a chronic
condition that requires long-term therapy. It is impor-
tant to gather data about the long-term safety and
effectiveness of these treatments in children, and partic-
ularly in patients with more severe disease. There are
also safety concerns regarding long-term DMARD
treatment in this population; however, the safety results
of etanercept treatment in JIA are reassuring. The
results of this study indicate that patients with polyartic-
ular (RF positive or negative) or systemic JIA benefit
from etanercept or etanercept plus MTX treatment,
improvements in joint counts and physicians global
assessment scores were similar across treatment arms,
and improvement was maintained for 3 years in those
continuing to receive medication. In addition, these data
confirm findings from other long-term studies of etan-
ercept, suggesting that etanercept offers an acceptable
2803
safety profile for children with polyarticular or systemic
JIA for up to 3 years.
ACKNOWLEDGMENTS
We would like to thank the patients and their parents
who made this study possible. The authors would also like to
thank the following participating members of the Pediatric
Rheumatology Collaborative Study Group for their significant
contributions: Tash Arkachaisri, MD, Suzanne Bowyer, MD,
Peter Dent, MD, FRCPC, Ciaran M. Duffy, MB, BCh, MSc,
Michael Henrickson, MD, Lawrence K. Jung, MD, Bianca
Lang, MD, Yukiko Kimura, MD, Daniel Kingsbury, MD,
Patrick Knibbe, MD, David Kurahara, MD, Judyann Olson,
MD, Ross E. Petty, MD, PhD, Linda Wagner-Weiner, MD,
Carlos Rose, MD, Alan Rosenberg, MD, Christy Sandborg,
MD, and Laura Schanberg, MD. The authors wish to thank
Rick Davis, MS, RPh (Complete Healthcare Communications,
Chadds Ford, PA), whose work was funded by Amgen Inc., for
assistance in drafting the manuscript and Samantha Garvine
and Laura LeGower (Complete Healthcare Communications)
for administrative support.
AUTHOR CONTRIBUTIONS
Dr. Giannini had full access to all of the data in the study and
takes responsibility for the integrity of the data and the accuracy of the
data analysis.
Study design. Giannini, Lovell.
Acquisition of data. Giannini, Ilowite, Lovell, Wallace, Rabinovich,
Reiff, Higgins, Gottlieb, Singer, Lin.
Analysis and interpretation of data. Giannini, Ilowite, Lovell, Wallace,
Rabinovich, Chon, Lin, Baumgartner.
Manuscript preparation. Giannini, Ilowite, Lovell, Wallace, Rabinov-
ich, Reiff, Higgins, Gottlieb, Singer, Chon, Lin, Baumgartner.
Statistical analysis. Chon, Lin.
Review of relevant literature. Singer.
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