DOI: 10.1542/peds.109.1.109
2002;109;109-115 Pediatrics
Norman T. Ilowite
Current Treatment of Juvenile Rheumatoid Arthritis
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SPECIAL ARTICLE
Current Treatment of Juvenile Rheumatoid Arthritis
Norman T. Ilowite, MD
ABSTRACT. Prognostic factors in juvenile rheumatoid
arthritis (JRA) include polyarticular onset, polyarticular
disease course, and rheumatoid factor positivity; in the
systemic onset subtype, persistence of systemic features
at 6 months after onset confers a worse prognosis. Timely
diagnosis and appropriate aggressive treatment of patients
with poor prognostic features improve quality of
life and outcome. After nonsteroidal anti-inflammatory
drugs, methotrexate is the most commonly used secondline
agent. However, approximately one third of patients
do not respond to methotrexate adequately. Randomized,
placebo-controlled, clinical trials in patients with JRA are
few, but one such trial with the tumor necrosis factor
inhibitor etanercept shows that this drug is effective and
well-tolerated. Other recently approved agents for rheumatoid
arthritis, including infliximab, leflunomide, celecoxib,
and rofecoxib, have not been adequately studied
in pediatric patients, and the role of these agents in
children with JRA remains to be determined. Pediatrics
2002;109:109 –115; antirheumatic agents, disease-modifying
antirheumatic drugs, tumor necrosis factor.
ABBREVIATIONS. JRA, juvenile rheumatoid arthritis; RA, rheumatoid
arthritis; NSAID, nonsteroidal antiinflammatory drug;
FDA, Food and Drug Administration; COX, cyclooxygenase;
DMARD, disease-modifying antirheumatic drug; JCA, juvenile
chronic arthritis; TNF, tumor necrosis factor; LT-_, lymphotoxin_.
J
uvenile rheumatoid arthritis (JRA) is the most
common rheumatic condition in children. Between
5 and 18 of every 100 000 children develop
JRA each year; the overall prevalence is approximately
30 to 150 per 100 000.1 The course of JRA can
be highly variable: some patients recover fully,
whereas others experience lifelong symptoms and
significant disability.
The variability in disease course may partly explain
the misconception that JRA is usually a benign
disease. Although an 80% remission rate by the time
the child reaches adulthood has been cited frequently,
2 this figure is not supported by available data. A
cohort study in which 506 JRA cases were followed
from 1970 to 1999 (mean follow-up of 10 years) found
that only approximately one third of JRA patients
achieved disease remission; for some disease subtypes,
this figure was as low as 20%.3 The visual
complications of iritis are also important in determining
outcome. In 1 study, 17% of patients with
JRA developed chronic iritis; 20% of these children
were left with impaired vision.4 Functional disability
is common and can be long lasting. In patients with
a median disease duration of 7.1 years, 60% reported
some difficulty in activities of daily living, and almost
half still required medication.5,6 Overall, approximately
30% of patients who have been followed
for 10 or more years have severe functional limitations.
2 Even more than 20 years after disease onset,
JRA patients report significantly greater pain and
lower physical functioning, health perception, and
vitality than case control subjects.7 These data indicate
that JRA is often associated with severe, longlasting
effects.
Several new antirheumatic treatments have become
available within the past 2 years. This review
summarizes clinical data available on currently used
agents for JRA and discusses the potential of new
adult rheumatoid arthritis (RA) agents in the treatment
of JRA.
DEFINITION OF JRA
JRA is defined as persistent arthritis in 1 or more
joints for at least 6 weeks if certain exclusionary
conditions have been eliminated; disease onset subtype
is defined by clinical symptoms in the first 6
months of disease.8 The course of JRA is defined by
what happens after the first 6 months.
SUBTYPES OF JRA
The 3 major subtypes of JRA are based on the
symptoms at disease onset and are designated systemic
onset, pauciarticular onset, and polyarticular
onset (Table 1). Pauciarticular-onset and polyarticularonset JRA are further divided into 2 subsets each
by some investigators (Table 1).9
Although the major JRA classifications are based
on onset type, the course of the disease is also critical
to patient prognosis. For instance, systemic-onset
JRA can eventually become indistinguishable from
polyarticular JRA.10 Patients with this pattern of onset
and disease course may be particularly difficult to
treat. JRA that begins as pauciarticular-onset disease,
with more extensive joint involvement over time, is
frequently referred to as “extended pauciarticular”
or “extended oligoarticular” disease.
From the Division of Rheumatology, Schneider Children’s Hospital, New
Hyde Park, New York, and Department of Pediatrics, Albert Einstein College
of Medicine, Bronx, New York.
Received for publication Apr 20, 2001; accepted Jun 26, 2001.
Reprint requests to (N.T.I.) Schneider Children’s Hospital, 269-01 76th Ave,
Rm 197, New Hyde Park, NY 11040. E-mail: ilowite@lij.edu
PEDIATRICS (ISSN 0031 4005). Copyright © 2002 by the American Academy
of Pediatrics.
PEDIATRICS Vol. 109 No. 1 January 2002 109
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PROGNOSTIC INDICATORS
The course of the disease is highly variable. Figure
1 shows the percentage of patients who had remission
or articular erosions at 5 years by disease onset
subtype and who were followed at tertiary centers in
North America.10 In systemic-onset JRA, active systemic
disease at 6 months (ie, with fever, the need for
corticosteroids, and thrombocytosis) is a strong predictor
of poor functional outcome.11 Only approximately
one quarter of patients with polyarticular
onset are in remission at 5 years after disease onset,
and more than two thirds develop erosions within
the first 5 years of the disease. 10 The extended oligoarthritis
phenotype has a similar prognosis.
As might be expected from the high frequency of
erosions in patients with polyarticular disease, polyarticular
onset and polyarticular disease course both
have been identified as significant risk factors for
disability (Table 2).5 Other factors that determine
disability include female gender and the presence of
rheumatoid factor.5 Lower remission rates have been
observed in patients with polyarticular onset, rheumatoid
factor, persistent morning stiffness, tenosynovitis,
subcutaneous nodules, or antinuclear antibody.
12 Poor outcomes are also associated with early
involvement of the small joints of the hands and feet
and rapid appearance of erosions.13
The most challenging patients to treat are those
with poor prognostic indicators (Table 2). These patients
are likely to require more aggressive therapy,
as well as early initiation of treatment. A recent study
of predictive factors that influence the outcome of
patients with JRA or juvenile spondyloarthropathy
found that patients who developed erosions and disability
tended to have received treatment later than
those who did not.14
THERAPY FOR JRA
General Considerations
For all patients, the goals of therapy are to decrease
chronic joint pain and suppress the inflammatory
process. Accomplishing these goals will lead not
only to improved short-term and long-term function
but also to normal growth and development.
First-line therapy includes nonsteroidal antiinflammatory
drugs (NSAIDs). In addition, intra-articular
corticosteroid injections have been shown to be
safe and effective, may have beneficial effects on
growth parameters, and can be administered with
little psychologic trauma, even in young patients.
15–20 Cognitive-behavioral pain management
techniques have also been successful in reducing
pain intensity in pediatric patients.21 Physical ther-
TABLE 1. Key Clinical Characteristics of JRA Onset Types
Onset Type Clinical Symptoms Subtypes Associated Characteristics
Systemic Fever, light salmon-colored rash,
extra-articular manifestations
Not applicable Organomegaly and lymphadenopathy
sometimes present
Pauciarticular Fewer than 5 joints involved
during the first 6 mo of illness
Early childhood onset Usually young females; high incidence of
chronic uveitis; antinuclear antibodypositive
Late childhood onset Usually males older than 8 years; high
incidence of sacroiliitis; HLA B27-positive
Polyarticular Five or more joints involved
during the first 6 mo of illness
RF-negative Onset later in childhood
RF-positive Onset later in childhood; similar to adult RA
Fig 1. Percentage of JRA patients with remission
or articular erosions at 5 years after
disease onset according to disease onset
subtype. Data are from Cassidy et al.10
TABLE 2. Poor Prognostic Indicators for Patients With JRA
Active systemic disease at 6 months
Polyarticular onset or disease course
Female gender
Rheumatoid factor
Persistent morning stiffness
Tenosynovitis
Subcutaneous nodules
Antinuclear antibodies
Early involvement of small joints of hands and feet
Rapid appearance of erosions
Extended pauciarticular disease course
From Ga¨re and Fasthr,5 Takei et al,12 and Cassidy and Petty.13
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apy is important not only for reducing pain but also
for maintaining joint and muscle function.13
Preventing eye damage is another important goal
of JRA therapy. Because of the risk of chronic uveitis
in patients with JRA, careful ophthalmologic surveillance
is essential. Pharmacotherapy of uveitis with
methotrexate and cyclosporin A may be beneficial in
decreasing the severity of this condition.22,23
The toxicities associated with therapeutic agents
pose a significant problem in effective treatment. For
instance, agents that work by general immunosuppression
may be associated with increased susceptibility
to infection, complication of vaccine administration,
or increased oncogenic risk. The distinction
between symptom control and prevention of erosive
disease must also be recognized. Many of the agents
that are most effective at pain and symptom control,
including corticosteroids and NSAIDs, have no effect
on erosive disease. Even methotrexate, which is
known to have disease-modifying activity,24,25 may
relieve symptoms and signs without halting disease
progression in some patients.
Systemic Pharmacologic Therapy
NSAIDs
Conventional NSAIDs inhibit both the cyclooxygenase
(COX)-1 constitutive form of the enzyme,
which releases prostaglandins that protect the stomach
and kidneys, and the COX-2 inducible form,
which produces prostaglandins involved in the inflammatory
process. Only a handful of NSAIDs have
been approved by the US Food and Drug Administration
(FDA) for use in JRA (ibuprofen, naproxen,
tolmetin, and choline magnesium trisalicylate).
However, most of the other NSAIDs are also commonly
used for JRA, including indomethacin and
diclofenac.13
Pseudoporphyria may occur with all of the propionic
acid NSAIDs and may be more common with
naproxen sodium, especially in fair-skinned young
patients.26 Because of the lack of a clear-cut consensus
on the optimal NSAID for patients with JRA,
many clinicians choose an NSAID on the basis of
considerations such as dosing schedule, patient preference,
or medication taste.
Disease-Modifying Antirheumatic Drugs
The term “disease-modifying antirheumatic drugs”
(DMARD) is limited to agents that retard radiologic
progression of disease. Only 3 DMARDs have been
proved to be effective in controlling disease activity
in double-blind, placebo-controlled studies of children
with JRA: methotrexate, sulfasalazine, and,
more recently, etanercept.
Methotrexate
Methotrexate is currently the most frequently used
DMARD for JRA.27 This agent, demonstrated to be
effective in polyarticular JRA, has been used to treat
juvenile arthritis for more than 10 years.28,29 Data
from uncontrolled studies suggest that methotrexate
slows radiographic progression in JRA.24,25 Overall,
between 60% and 80% of JRA patients who are
treated with methotrexate experience some clinical
improvement.30–32
Some controversy exists concerning whether
methotrexate is more effective in certain JRA subtypes
than in others. Highest response rates to methotrexate
are obtained in children with oligoarticular
onset, particularly those with extended polyarticular
disease33; patients with systemic onset may respond
less frequently.34
The most common adverse events associated with
methotrexate use in children with JRA are gastrointestinal
symptoms, which occur in approximately
13% of patients.29 Liver toxicity does not seem to be
a major concern in pediatric patients. In adults, recommendations
are to follow serum transaminase
and albumin levels every 4 to 8 weeks35; most pediatric
rheumatologists check blood counts and
transaminases similarly. Significant liver damage
seems to be rare, probably in part because comorbid
hepatotoxic risk factors are absent in most pediatric
patients. In a study of 14 JRA patients who were
treated with methotrexate for a mean of 6.3 years,
needle biopsies failed to detect signs of significant
liver fibrosis in any of the patients, although some
histologic abnormalities were noted.36 Despite the
widespread use of methotrexate, data on immunosuppressive,
teratogenic, or oncogenic risks associated
with long-term methotrexate therapy in JRA
patients are lacking.29 Current recommendations are
not to administer live virus vaccines to patients who
are taking methotrexate. For help in minimizing potential
long-term effects, discontinuation of methotrexate
in patients whose disease is completely controlled
for extended periods may be advisable.30,37
Sulfasalazine
In a double-blind, placebo-controlled, multicenter
study of patients with juvenile chronic arthritis
(JCA), sulfasalazine was significantly more effective
than placebo in suppressing disease activity, as indicated
by decreases in overall articular severity scores,
all global assessments, and laboratory parameters.38
However, drug toxicity is a problem: elevated liver
transaminases, leukopenia, hypoimmunoglobulinemia,
and gastrointestinal problems contributed to a
30% withdrawal rate in this trial.38 The manufacturer
recommendations are to check blood counts and
transaminase levels before treatment, every other
week for the first 3 months, monthly for the next 3
months, then every 3 months. In a small trial of
sulfasalazine in systemic JCA, 3 of 4 children had to
withdraw as a result of severe toxic side effects possibly
related to a hypersensitivity reaction, including
high fevers and rash.39 Some data suggest that sulfasalazine
may be most useful for pauciarticularonset
JRA.40,41
Other DMARDs
Double-blind, placebo-controlled studies have
failed to demonstrate efficacy of penicillamine, hydroxychloroquine,
42 or auranofin,43 although the
power of these studies with relatively small numbers
of patients has been questioned. Cyclosporin A has
not been studied in a double-blind, placebo-controlled
manner. Combination chemotherapy early in
RA,44,45 with withdrawal of drug after response, akin
to the oncology paradigm of induction, consolidaSPECIAL ARTICLE 111
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tion, and maintenance regimes, is less applicable in
JRA for which the prognosis is highly variable.
New Drugs for Adult RA and Their Potential Use in
JRA
Leflunomide
The FDA approval of leflunomide in August 1998
marked the arrival of the first new drug for adult RA
in many years. Leflunomide, an immunosuppressive
agent that acts as a reversible inhibitor of de novo
pyrimidine synthesis, has been shown to be significantly
superior to placebo and comparable to sulfasalazine
and methotrexate in controlling measures
of disease activity in patients with adult RA.46,47 The
ability of these 3 agents to retard radiographic progression
is also similar.48 The most common adverse
effects associated with leflunomide are diarrhea, elevated
liver enzymes, alopecia, and rash.46,47 Although
leflunomide has good efficacy and safety
profiles in adults, it has not been studied in pediatric
patients, possibly because of the cytotoxic nature of
this agent. In particular, the teratogenic potential of
this agent may be a concern when treating pediatric
patients, especially adolescent females. The long
half-life of this agent (2 weeks) may also be a drawback,
although a regimen of thrice-daily cholestyramine
for 8 days can eliminate the drug by 11 days, if
necessary (eg, pregnancy).
Etanercept
Etanercept is a new agent recently approved by the
FDA for use in reducing signs and symptoms and
delaying structural damage in patients with moderately
to severely active adult RA, and for reducing
signs and symptoms of moderately to severely active
polyarticular-course JRA that is refractory to 1 or
more DMARDs.49 This agent consists of 2 soluble p75
tumor necrosis factor (TNF) receptors fused to the Fc
portion of immunoglobulin G. Etanercept is a potent
inhibitor of TNF and lymphotoxin-_ (formerly
known as TNF_). TNF is a key proinflammatory
cytokine that is found in the synovial tissue of patients
with JRA and is believed to play an important
role in proinflammatory signaling (Table 3), whereas
lymphotoxin-_ is a related cytokine that binds to
TNF receptors and is also found specifically in JRA
patients.50
In a 2-part study, etanercept was tested in 69 patients
who had active polyarticular-course JRA and
were refractory or intolerant to methotrexate.51 All of
the 3 major onset types were represented (Fig 2). The
study was designed so that the efficacy of etanercept
could initially be assessed without subjecting a control
group to placebo injections. Accordingly, in the
first part of the study, all patients received open-label
etanercept at 0.4 mg/kg subcutaneously twice
weekly for 90 days. Fifty-one patients (74%) achieved
the JRA definition of improvement.52 To meet these
criteria, a patient must show a 30% or greater improvement
from baseline in at least 3 of the 6 core set
response variables (physician global assessment, parent/
patient global assessment, number of active
joints, number of joints with limited range of motion,
functional ability, and erythrocyte sedimentation
rate), with a 30% or greater worsening in not more
than 1 of these variables. As shown in Fig 2, patients
of all 3 JRA onset subtypes showed improvement
from baseline in response variables after open-label
etanercept treatment.53
The second part of the study was a double-blind,
placebo-controlled trial in which the efficacy of etanercept
was more rigorously assessed. Patients who
responded in part 1 were randomized to receive
blinded treatment with placebo or etanercept 0.4
mg/kg subcutaneously (maximum 25 mg subcutaneously
twice weekly) twice weekly for 4 months or
until disease flare. Significantly fewer etanercepttreated
patients experienced a disease flare compared
with patients who received placebo (28% vs
81%; P _ .003), and the median time to disease flare
was much longer (_116 days vs 28 days; P _ .001)
for those in the etanercept group.51 A subsequent
open-label extension trial demonstrated that, with
continued treatment, the clinical effect of etanercept
is maintained for at least 16 months.54 Etanercept
was generally well-tolerated in pediatric patients.
The most common adverse events were injection site
reactions, headaches, and upper respiratory infections
of mild to moderate severity.51,54 Although not
observed in the placebo-controlled phase of the
study, concern exists regarding increased susceptibility
to infection. However, in long-term, controlled
trials of etanercept versus placebo, no increased rate
of infection was observed.49 It is recommended that
pediatric patients be brought up to date with all
immunizations before receiving etanercept. Because
of cases of aseptic meningitis with varicella zoster
infection, immunization with varicella in susceptible
children and administration of varicella zoster immune
globulin in exposed individuals have been
recommended. However, live vaccines should not be
given concurrently with etanercept.49,51,54 Ideally,
approximately 3 months should be allowed to elapse
between live virus vaccination and initiation of etanercept
therapy. Pediatric patients with significant exposure
to varicella should temporarily discontinue
etanercept.
In patients with adult RA, etanercept effectively
controls disease symptoms.55–57 More significantly,
etanercept retards radiographic progression in
adults with early RA; patients who receive etanercept
have been found to have less radiographic disease
progression than those who receive methotrexTABLE 3. Proinflammatory Effects of TNF Leading to Inflammation,
Pannus Development, and Joint Destruction*
Inflammatory cells
Proinflammatory cytokine release (through autocrine and
paracrine stimulation)
Neutrophil degranulation
Endothelial cells
Adhesion molecule expression
Angiogenesis mediated by vascular endothelial growth factor
Synovial fibroblasts
Increased production of neutral metalloproteases,
prostaglandin E2, nitric oxide, and superoxide
Decreased production of tissue inhibitor of metalloproteases
Proliferation
* Adapted from Jarvis and Faulds.70
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ate, as assessed by total Sharp score (scores based on
radiographic evidence of joint erosion) and magnetic
resonance imaging.58,59 Although no radiographic
studies have been performed in patients with JRA,
the available data indicate that etanercept is likely to
be a valuable agent in the control of this disease.
Infliximab
Another TNF-neutralizing agent, infliximab (also
known as cA2), is a chimeric human-mouse monoclonal
antibody to TNF.60 Available data regarding
efficacy are limited; indeed, dosing and pharmacokinetic
data in pediatric patients are lacking. A case
study discusses the use of this agent to treat a patient
who had severe systemic-onset JCA resistant to conventional
therapies.61 The patient received 2 intravenous
infusions of infliximab 10 mg/kg separated by
1 week. Treatment was well-tolerated and resulted in
rapid control of fever, anorexia, and serositis.61 However,
there was no significant improvement in joint
pain or tenderness.61 The role of infliximab in the
treatment of juvenile arthritis awaits large-scale
studies.
COX-2 Inhibitors
A new class of therapeutic NSAID agents has been
designed to inhibit selectively the COX-2 enzyme,
thus allowing the continued production of COX-1,
an essential enzyme involved in cytoprotective and
regulatory functions in gastrointestinal mucosa,
platelets, and renal cells. Studies in adults with RA
suggest that celecoxib is associated with a lower
incidence of ulcers than conventional pain relief
agents, such as naproxen and diclofenac.62,63 Another
COX-2 inhibitor, rofecoxib, has been shown to
improve ACR 20 response, patient assessment of
pain, patient and physician assessment of disease
activity, and disability index score in RA patients
compared with placebo.64
Although COX-2 inhibitors may be a valuable addition
to the treatment of adult RA, their contribution
to JRA is likely to be less significant. Pediatric
patients do not typically experience significant gastrointestinal
problems with NSAIDs as often as
adults. For instance, in a database study of 702 patients
with JRA, only 5 patients were found to have
had a gastropathic event attributable to NSAID therapy.
65 However, in selected populations (eg, patients
with abdominal pain and anemia), the incidence of
gastroduodenal lesions is much higher.66,67 In any
case, COX-2 inhibitors may be helpful in pediatric
patients who do experience gastrointestinal adverse
events and may also be helpful in cases of other
NSAID-associated adverse effects, such as naproxeninduced
pseudoporphyria.26
REMAINING CHALLENGES IN THE
MANAGEMENT OF JRA
Our knowledge of JRA remains incomplete. An
improved understanding of disease cause and pathogenesis
could provide insights into the possible relationships
among different disease subtypes and may
also reveal new therapeutic options. Among the current
crop of new adult RA agents, only 1, etanercept,
has been adequately tested in patients with JRA. For
the foreseeable future, the optimal treatment of JRA
will continue to pose a challenge to clinicians. Our
inability to predict patient outcome accurately remains
a barrier to optimal management. Additional
studies on factors associated with favorable and unfavorable
prognoses would be invaluable in guiding
therapy. We must learn to optimize JRA therapy in
the context of new options. Studies of combination
regimens, such as etanercept plus methotrexate, may
Fig 2. Percentage improvement from baseline at day 90 in the open-label, part I study of etanercept in patients with polyarticularcourse
JRA according to disease onset type. LOM, loss of motion. Data are from Lovell et al.53
SPECIAL ARTICLE 113
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provide more effective options for first- and secondline
treatment of patients with JRA. In addition, the
optimal agent or combination of agents for resistant
and severe chronic uveitis has yet to be identified.
For most patients with a poor prognosis, methotrexate
will continue to be the first-line DMARD.
Until more clinical experience is gained, etanercept
should be reserved until after methotrexate failure in
JRA because long-term study data of etanercept therapy
in JRA are not yet available. Nevertheless, the
significant proportion of incomplete responders or
nonresponders to methotrexate suggests that etanercept
will be a valuable addition to JRA treatment
options. This agent is well-tolerated by both adults
and children, and data from long-term studies have
not revealed any cumulative toxicities. However, infections,
neoplastic complications, hematologic complications,
and multiple sclerosis-like neurologic disease
have been identified in small numbers of
patients during postmarketing surveillance, and concerns
regarding these events exist because long-term
experience is still limited.54,68 Options for etanercept
nonresponders include cyclosporin A, azathioprine,
and sulfasalazine, or parenteral gold.
Other biologics including inhibitors of interleukin1 (r-metHuIl1ra), and antibodies that bind to Bcell
surface antigens (rituximab) are being evaluated
in the treatment of arthritis. For patients who have
severe systemic JRA and have failed proven therapies,
monthly intravenous cyclophosphamide has
been studied.45 For patients with severe, recalcitrant
disease, autologous stem cell transplantation has
been considered. There is some encouraging preliminary
efficacy data regarding this procedure; however,
there is significant associated morbidity and
mortality, including the life-threatening complication
of macrophage activation syndrome.69 At
present, these treatments should be considered experimental
and should be reserved for only those
patients who have the most severe disease, and be
performed in experienced centers.
The “Pediatric Rule” of the FDA is encouraging
study of dosing, pharmacokinetics, safety, and efficacy
of new agents for JRA, and new data thus
obtained are likely to improve our future understanding
regarding optimal treatment of this disease.
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SPECIAL ARTICLE 115
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DOI: 10.1542/peds.109.1.109
2002;109;109-115 Pediatrics
Norman T. Ilowite
Current Treatment of Juvenile Rheumatoid Arthritis
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