ARTHRITIS & RHEUMATISM
Vol. 62, No. 11, November 2010, pp 3259–3264
© 2010, American College of Rheumatology
Effects of Long-Term Etanercept Treatment on Growth in
Children With Selected Categories of Juvenile Idiopathic Arthritis
Edward H. Giannini,1Norman T. Ilowite,2Daniel J. Lovell,1Carol A. Wallace,3
C. Egla Rabinovich,4Andreas Reiff,5Gloria Higgins,6Beth Gottlieb,7
for the Pediatric Rheumatology Collaborative Study Group, Yun Chon,8
Nan Zhang,8and Scott W. Baumgartner8
Objective. To evaluate the effects of long-term
etanercept treatment, with or without methotrexate, on
growth in children with selected categories of juvenile
idiopathic arthritis (JIA).
Methods. We conducted a 3-year, open-label, non-
randomized registry of 594 patients with polyarticular
or systemic JIA treated with etanercept only, etanercept
plus methotrexate, or methotrexate only. Height, weight,
and body mass index (BMI) were assessed at baseline
and at years 1, 2, and 3, using percentiles derived from
US Centers for Disease Control and Prevention stan-
dardized growth charts.
Results. Statistically significant increases in the
mean height percentiles from baseline were observed in
etanercept-treated patients at year 3 (4.8 percentile
points) and in patients treated with etanercept plus
methotrexate at years 1, 2, and 3 (2.4, 3.3, and 5.6
percentile points, respectively). Statistically significant
increases from baseline in the mean weight percentiles
were observed at years 1, 2, and 3 in both the etanercept
group (7.4, 10.0, and 13.0 percentile points) and the
etanercept-plus-methotrexate group (2.9, 6.9, and 8.4
percentile points, respectively). Statistically significant
increases from baseline in the mean BMI percentiles
were observed in both the etanercept group (range
9.6–13.8 percentile points) and the etanercept-plus-
methotrexate group (range 2.1–5.2 percentile points).
The mean height, weight, and BMI percentiles did not
change significantly in patients in the methotrexate-only
Conclusion. Etanercept treatment, with or with-
out methotrexate, may contribute to the restoration of
normal growth in children with JIA.
Juvenile idiopathic arthritis (JIA) is a common
childhood rheumatic disease that is associated with
significant pain and functional disability, which ad-
versely impacts quality of life and well-being (1). Pa-
tients with JIA can experience impairment of normal
physical growth and development related to the severity
of chronic inflammation, longer disease duration, and a
higher degree of functional joint involvement (2,3).
Therefore, a realistic treatment goal should include
therapy aimed at reducing inflammation to minimize
disease-related disability, including growth impairment.
The advent of biologic agents has been an impor-
tant development in the management of patients with
JIA, especially for those patients in whom inflammation
ClinicalTrials.gov identifier: NCT00078793.
Supported by Immunex Corporation, a wholly owned subsid-
iary of Amgen Inc., and by Wyeth, which was acquired by Pfizer Inc. in
1Edward H. Giannini, DrPH, MSc, Daniel J. Lovell, MD,
MPH: Cincinnati Children’s Hospital Medical Center, Cincinnati,
Ohio;2Norman T. Ilowite, MD: Albert Einstein College of Medicine,
Bronx, New York;3Carol A. Wallace, MD: Children’s Hospital and
Regional Medical Center, Seattle, Washington;4C. Egla Rabinovich,
MD: Duke University Medical Center, Durham, North Carolina;
5Andreas Reiff, MD: Children’s Hospital Los Angeles, Los Angeles,
Nationwide Children’s Hospital, Columbus, Ohio;
MD, MS: Schneider Children’s Hospital, New Hyde Park, New York;
8Yun Chon, PhD, Nan Zhang, PhD, Scott W. Baumgartner, MD:
Amgen Inc., Thousand Oaks, California.
Dr. Ilowite has received consulting fees, speaking fees, and/or
honoraria from Abbott (less than $10,000). Dr. Lovell has received
consulting fees, speaking fees, and/or honoraria from Amgen, Bristol-
Myers Squibb, Abbott, Pfizer, Novartis, Regeneron, UCB, Xoma, and
Centocor (less than $10,000 each). Dr. Wallace has received a research
grant from Amgen. Dr. Reiff has received consulting fees, speaking
fees, and/or honoraria from Amgen, Wyeth, and Pfizer (more than
$10,000 each). Drs. Chon, Zhang, and Baumgartner own stock or stock
options in Amgen.
Address correspondence and reprint requests to Edward H.
Giannini, DrPH, MSc, Pediatric Rheumatology/Pavilion 2-129, Cincin-
nati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cin-
cinnati, OH 45229. E-mail: Edward.Giannini@cchmc.org.
Submitted for publication March 30, 2010; accepted in revised
form July 22, 2010.
6Gloria Higgins, MD, PhD: Ohio State University and
cannot be controlled with traditional treatments. Etan-
ercept is a fully human soluble tumor necrosis factor
(TNF) receptor fusion protein that is approved for
reducing the signs and symptoms of polyarticular JIA.
Etanercept has demonstrated safety and clinical efficacy
in patients with JIA (4–6) and has also been shown to
have a positive effect on growth in patients with JIA
(7–9). In those studies, with durations of up to 2 years,
etanercept restored growth velocity in children with
treatment-refractory JIA, and this improvement ap-
peared to be related to a reduction in inflammation.
The results from a 3-year, open-label, nonran-
domized registry study that evaluated the long-term
safety and effectiveness of etanercept in 594 children
with polyarticular or systemic JIA were recently re-
ported (10). The data from that study showed that
etanercept, alone or in combination with methotrexate
(MTX), was generally well tolerated and produced
improvement in the physician’s global assessment of
disease activity and total active joint scores that was
sustained through 3 years in patients who continued to
receive medication. Another goal of this registry was to
evaluate the effects of long-term etanercept treatment
on growth in patients with polyarticular or systemic JIA.
Herein, we report the results of analysis of the growth
PATIENTS AND METHODS
The study methodology was described in detail in a
previous report (10). Briefly, patients aged 2–18 years with
selected categories of JIA (11) (systemic, oligoarticular, or
polyarticular [rheumatoid factor positive or rheumatoid factor
negative]) were eligible for enrollment in a phase IV, open-
label, multicenter registry to evaluate the long-term safety of
etanercept, etanercept plus MTX, or MTX. Patients in the
MTX group could have received MTX for a maximum of 6
months prior to enrollment. Patients in the etanercept or
etanercept plus MTX group could have received etanercept for
a maximum of 6 months prior to enrollment. The institutional
review boards of the participating study sites reviewed and
approved the study protocol, and written informed consent was
obtained from a parent or legal guardian before entry into the
Etanercept was administered subcutaneously twice
weekly at a dose of 0.4 mg/kg (maximum dose 25 mg) or once
weekly at a dose of 0.8 mg/kg (maximum dose 50 mg).
Etanercept could be used alone or in combination with MTX
(at a dosage of at least 10 mg/m2/week [?0.3 mg/kg/week] and
not exceeding 1 mg/kg/week). Coadministration of nonbiologic
disease-modifying antirheumatic drugs (DMARDs) was per-
mitted. Patients who were enrolled in the registry while being
treated with MTX but who subsequently switched to etaner-
cept treatment (alone or in combination with MTX or other
DMARDs) were eligible to re-enroll in the etanercept arm if
they had not been in the study for more than 30 months.
Patients who discontinued etanercept and started MTX treat-
ment were not re-enrolled.
Each patient’s height, weight, and body mass index
(BMI) at baseline, year 1, year 2, and year 3 were recorded and
compared with the US Centers for Disease Control and
Prevention standardized growth charts (12) for the specific age
and sex, in order to obtain the percentiles; the changes in
percentiles from baseline to year 1, year 2, and year 3 were
then calculated. Wilcoxon’s signed rank test was used to
evaluate whether the mean change in percentiles from baseline
within a treatment was different from 0. To evaluate the effect
of disease control on growth, changes in height from baseline
were correlated with the physician’s global assessment of
disease activity scores, using Pearson’s correlation coefficients.
Tanner scores (13) were recorded for a subset of the patients,
with the patient’s physician performing the maturation assess-
ments. The change in Tanner scores from baseline to year 3
was analyzed according to sex and age group.
The patient demographics and clinical character-
istics have been reported previously (10). Baseline an-
thropomorphic measures and medications are summa-
rized in Table 1. Most patients were female (range of
mean values across groups 73–81%) and white (range of
mean values 73–77%). The mean age of patients in the
MTX group (9.0 years) was younger than that of patients
in the etanercept group (10.8 years) and the etanercept-
plus-MTX group (10.1 years) (Table 1). The mean
height and weight values were lower in the MTX group
than in the etanercept groups, which likely reflects the
younger mean age of patients in the MTX group.
Approximately 90% of patients overall had polyarticular
disease. Patients in the MTX group had the shortest
mean disease duration (20 months) relative to those in
the etanercept group (58 months) and the etanercept-
plus-MTX group (41 months). Rheumatoid factor posi-
tivity was observed in 14–24% of the patients.
The majority of patients had received MTX
before enrollment in the registry (86.4% in the etaner-
cept group, 100% in etanercept-plus-MTX group, and
97.5% in the MTX group). Patients in both etanercept
groups had a longer duration of MTX treatment before
enrollment (110.0 weeks for the etanercept group and
103.4 weeks for the etanercept-plus-MTX group com-
pared with 13.2 weeks for the MTX group). More than
80% of patients in the etanercept groups had received
etanercept therapy before enrollment in the registry.
The mean duration of etanercept therapy was 11.3 weeks
for both the etanercept group and the etanercept-plus-
MTX group. A single patient in the MTX group received
3260 GIANNINI ET AL
etanercept therapy for 21.7 weeks before enrollment in
At baseline, nonsteroidal antiinflammatory drugs
were commonly used by patients in all 3 groups (range of
means 73–91%). Prednisone was used by 18–27% of the
patients, and intraarticular corticosteroids were used by
11–16% of the patients.
The mean height percentile (Figure 1A) was
significantly increased from baseline for etanercept at
year 3 (4.8 percentile points) and for etanercept plus
MTX at years 1, 2, and 3 (2.4, 3.3, and 5.6 percentile
points, respectively). In the MTX-only group, however,
the mean height percentiles showed nonsignificant de-
creases from baseline at years 1, 2, and 3 (?0.2, ?1.0,
and ?2.4 percentile points, respectively). At the end of
year 3, the mean height percentile values were 45.1 for
MTX, 42.0 for etanercept, and 43.4 for etanercept plus
MTX. In a post hoc analysis, when patients with Tanner
staging scores of 4 or 5 (i.e., patients who were more
sexually mature with less potential for growth) were
excluded, a statistically significant improvement in the
height percentile from baseline was still observed at
years 2 and 3 for etanercept (3.8 and 6.2 percentile
points, respectively; both P ? 0.05) and at years 1, 2, and
3 for etanercept plus MTX (2.3, 4.1, and 6.1 percentile
points, respectively; all P ? 0.001).
Similar patterns were observed for other mea-
sures of growth (weight and BMI). Significant increases
in the mean weight percentile from baseline were ob-
served for each year (Figure 1B) in the etanercept group
and the etanercept-plus-MTX group. In the group re-
ceiving etanercept only, mean changes in the weight
percentile at years 1, 2, and 3 were 7.4, 10.0, and 13.0
percentile points, respectively; in the group receiving
etanercept plus MTX, these changes were 2.9, 6.9, and
8.4 percentile points, respectively. Significant increases
in the mean BMI percentile from baseline were also
observed for each year in both the group receiving
etanercept only (range 9.6–13.8 percentile points) and
the group receiving etanercept plus MTX (range 2.1–5.2
percentile points) (Figure 1C). At the end of year 3, the
mean weight percentile values were 60.1 for MTX, 56.5
for etanercept, and 55.0 for etanercept plus MTX, and
the mean BMI percentile values were 65.9 for MTX,
63.5 for etanercept, and 60.1 for etanercept plus MTX.
The effect of disease control on height was also
assessed in an exploratory analysis. No clear trend was
noted when mean height percentile changes from base-
Baseline patient demographics and clinical characteristics*
CharacteristicMTX only (n ? 197) ETN only (n ? 103)ETN ? MTX (n ? 294)P
Age, mean ? SD years
Height, mean ? SD cm
Weight, mean ? SD kg
Body mass index, mean ? SD kg/m2
Percentile, mean ? SD
Body mass index
Polyarticular (RF? or RF?)†
JIA disease duration, mean ? SD months
Medication at baseline
Folinic or folic acid
9.0 ? 4.4
133.0 ? 25.3
37.2 ? 20.8
19.3 ? 5.1
10.8 ? 4.1
141.2 ? 22.8
42.7 ? 22.8
19.9 ? 5.8
10.1 ? 4.7
137.2 ? 26.2
40.1 ? 21.8
19.7 ? 5.2
46.2 ? 28.2
56.1 ? 32.0
60.3 ? 32.1
42.0 ? 30.8
50.8 ? 33.9
55.1 ? 33.9
41.9 ? 31.0
52.4 ? 33.6
58.9 ? 31.8
20.2 ? 30.7
58.1 ? 44.5
40.7 ? 41.7
* Except where indicated otherwise, values are the number (%). P values were calculated using analysis of variance (continuous variables) or the
Cochran-Mantel-Haenszel test (categorical variables). MTX ? methotrexate; ETN ? etanercept; JIA ? juvenile idiopathic arthritis; RF ?
rheumatoid factor; NSAIDs ? nonsteroidal antiinflammatory drugs; DMARDs ? disease-modifying antirheumatic drugs.
† Includes patients with extended oligoarthritis.
‡ Includes hydroxychloroquine, sulfasalazine, and cyclosporine.
LONG-TERM EFFECTS OF ETANERCEPT ON GROWTH IN CHILDREN WITH JIA3261
Figure 1. Mean ? SEM changes from baseline in the height percen-
tile (A), weight percentile (B), and body mass index (BMI) percentile
(C). ? ? P ? 0.05; † ? P ? 0.01; ‡ ? P ? 0.001 versus baseline. ETN ?
etanercept; MTX ? methotrexate.
Figure 2. Mean ? SEM changes from baseline in height percentile
versus change from baseline in physician’s global assessment of disease
activity scores for year 1 (A), year 2 (B), and year 3 (C). The SEM
values were not available for some data points on either end of the
x-axis, because the value was based on 1 patient, and therefore the
SEM was not calculable. ETN ? etanercept; MTX ? methotrexate.
3262 GIANNINI ET AL
line versus the physician’s global assessment of disease
activity scores were plotted (Figures 2A–C). Results
using Pearson’s correlation coefficients also failed to
show any statistically significant relationship (data not
Tanner scores were recorded for only ?40% of
patients (n ? 228) at baseline, and by year 3, the sample
size was too small for a meaningful analysis by either sex
or age group. When median Tanner score data accord-
ing to patient ages were analyzed (not shown), none of
the treatments appeared to affect normal development.
As expected, in patients younger than age 10 years, the
Tanner score remained at stage 1. By the age of 14 years,
the Tanner score in most patients had reached a later
stage of development and eventually approached stage 5
by age 18 years.
The results from our registry study showed that
etanercept with or without MTX improved growth rates
in children with JIA. After 3 years of treatment, patients
in the etanercept arms (either as monotherapy or in
combination with MTX) showed a significant increase in
height, weight, and BMI percentiles. No significant
changes in height, weight, or BMI from baseline were
observed in the MTX-only group at any time point. No
consistent effect of disease control on height was ob-
served for any of the treatment groups over the course of
the study. In addition, normal development (as assessed
by Tanner staging scores) did not appear to be adversely
affected in any of the treatment groups; however, the
number of patients evaluated was small. The study was
not designed to perform appropriate intergroup com-
The results from our study support and extend
data from other studies. A small study in 7 prepubertal
or pubertal patients with treatment-refractory JIA and
growth retardation showed that etanercept had a bene-
ficial effect on growth velocity (9). Another study in a
larger population of 71 prepubertal or pubertal patients
with severe JIA (43 treated with etanercept and 28
treated with infliximab) showed that anti-TNF treatment
had a positive effect on growth velocity in patients with
delayed growth (7). A more recent study in 52 prepu-
bertal or pubertal patients with JIA showed improved
longitudinal growth in most of those who were treated
with etanercept, and the improvement was independent
of the pubertal growth spurt (8).
Interpretation of the growth data in our analysis
is subject to the limitations typically associated with
registry studies, including the lack of a comparable
control group and blinding. The treatment groups dif-
fered in some baseline variables, because many patients
in the etanercept groups had failed to respond to MTX,
whereas many in the MTX group were just initiating
DMARD therapy. Accordingly, etanercept-treated pa-
tients had a longer disease duration at baseline and had
a longer duration of MTX use compared with MTX-
treated patients. This was expected because of the
eligibility criteria for the registry study; however, the
potential impact of these factors on our results is not
known. Nonetheless, the registry was conducted accord-
ing to good clinical practice standards, and data were
collected via a systematic protocol, providing useful
information on patients with JIA who were treated in a
real-world clinical setting.
Because growth retardation is associated with
systemic inflammation (14) and is an important and
potentially permanent complication of JIA (15), restor-
ing normal growth development is a relevant goal of
antiinflammatory treatment in these patients. In the
current analysis, patients treated with etanercept mono-
therapy or with etanercept in combination with MTX
had significant increases in height, weight, and BMI
percentiles, whereas patients treated with MTX showed
no change in these growth measures. None of the study
treatments appeared to affect normal development as
assessed by Tanner stages; however, the number of
children evaluated was small. According to the results of
the present study, etanercept treatment (with or without
MTX) did not adversely affect growth rates and may
contribute to the restoration of normal growth in chil-
dren with JIA.
We would like to thank the participating members of
the Pediatric Rheumatology Collaborative Study Group for
their significant contributions. We also wish to thank Tina
Sherrard, BHS, CCRC, and Rick Davis, MS, RPh, whose work
was funded by Amgen Inc., for assistance in drafting this
All authors were involved in drafting the article or revising it
critically for important intellectual content, and all authors approved
the final version to be published. 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 conception and design. Giannini, Ilowite, Lovell, Chon.
Acquisition of data. Giannini, Ilowite, Lovell, Wallace, Rabinovich,
Reiff, Higgins, Gottlieb, Zhang.
Analysis and interpretation of data. Giannini, Lovell, Chon, Zhang,
LONG-TERM EFFECTS OF ETANERCEPT ON GROWTH IN CHILDREN WITH JIA 3263
ROLE OF THE STUDY SPONSORS Download full-text
Immunex Corporation, a wholly owned subsidiary of Amgen
Inc., was responsible for the creation of the study design, in close
collaboration with Drs. Giannini, Ilowite, Lovell, and Chon. Amgen
Inc. approved the content of the manuscript prior to its submission for
publication. Publication of this article was not contingent on approval
by the study sponsors.
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