ARTHRITIS & RHEUMATISM

Vol. 52, No. 2, February 2005, pp 563–572

DOI 10.1002/art.20860
© 2005, American College of Rheumatology

A Randomized, Double-Blind Clinical Trial of Two Doses of

Meloxicam Compared With Naproxen in Children With
Juvenile Idiopathic Arthritis
Short- and Long-Term Efficacy and Safety Results

Nicolino Ruperto,1 Irina Nikishina,2 Evgueni D. Pachanov,3 Ynessa Shachbazian,4

Anne Marie Prieur,5 Richard Mouy,5 Rik Joos,6 Francesco Zulian,7 Rudolf Schwarz,8
Valeria Artamonova,9 Wolfgang Emminger,10 Marcia Bandeira,1 Antonella Buoncompagni,1
Ivan Foeldvari,11 Fernanda Falcini,12 Eileen Baildam,13 Isabelle Kone-Paut,14 Maria Alessio,15
Valeria Gerloni,16 Alessandro Lenhardt,17 Alberto Martini,18 for the Pediatric Rheumatology
International Trials Organization (PRINTO), Gertraud Hanft,19 Ralf Sigmund,19 and Stefan Simianer19

Objective. In an international, multicenter,
double-blind, randomized clinical trial we evaluated the
short-term (3 months) and long-term (12 months) effi-
Supported by a grant to the Pediatric Rheumatology Interna-
tional Trials Organization from Boehringer Ingelheim Pharma GmbH
& Co. KG, Biberach, Germany.
1
Nicolino Ruperto, MD, MPH, Marcia Bandeira, MD, An-
tonella Buoncompagni, MD: IRCCS G. Gaslini, Pediatria II, Reumato-
logia, Genoa, Italy; 2Irina Nikishina, MD: Institute of Rheumatology of
the Russian Academy of Medical Science, Moscow, Russia; 3Evgueni D.
Pachanov, MD: Scientific Research Institute of Pediatrics, Moscow,
Russia; 4Ynessa Shachbazian, MD: Moscow Medical Academy, Moscow,
Russia; 5Anne Marie Prieur, MD, Richard Mouy, MD: Hôpital Necker
des Enfants Malades, Paris, France; 6Rik Joos, MD: Universitair Zieken-
huis Gent, Ghent, Belgium; 7Francesco Zulian, MD: Unità di Rheuma-
tologia Pediatrica, Padua, Italy; 8Rudolf Schwarz, MD: Landeskinderk-
linik Linz, Linz, Austria; 9Valeria Artamonova, MD: Morozovskaya
Children City Clinical Hospital, Moscow, Russia; 10Wolfgang Emminger,
MD: University of Wien, Vienna, Austria; 11Ivan Foeldvari, MD: Kinder-
rheumatologische Praxis am AK Eilbek, Hamburg, Germany; 12Fernanda
Falcini, MD: Clinica Pediatrica III, Florence, Italy; 13Eileen Baildam,
MD: Booth Hall Children’s Hospital, Manchester, UK; 14Isabelle Kone-
Paut, MD: Hôpital Nord, Pavillon Mère-Enfant, Marseilles, France;
15
Maria Alessio, MD: Università Federico II, Naples, Italy; 16Valeria
Gerloni, MD: Instituto Gaetano Pini, Milan, Italy; 17Alessandro Len-
hardt, MD: IRCCS Burlo Garofalo, Trieste, Italy; 18Alberto Martini, MD,
IRCCS G. Gaslini, Pediatria II, Reumatologia, and University of Genoa,
Genoa, Italy; 19Gertraud Hanft, MD, Ralf Sigmund, Dipl.-Math. Dec.,
Stefan Simianer, MD: Boehringer Ingelheim Pharma GmbH & Co. KG,
Biberach, Germany.
Dr. Foeldvari has received consulting fees of less than $10,000
per year from Bristol-Meyers Squibb.
Address correspondence and reprint requests to Nicolino Ru-
perto, MD, MPH, Pediatric Rheumatology International Trials Organi-
zation, IRCCS G. Gaslini Pediatria II–Reumatologia, University of
Genoa, Largo Gaslini, 5, 16147 Genoa, Italy. E-mail: nicolaruperto@
ospedale-gaslini.ge.it.
Submitted for publication July 5, 2004; accepted in revised
form November 4, 2004.
563
cacy and safety of 2 different doses of meloxicam oral
suspension compared with the efficacy and safety of
naproxen oral suspension in children with
oligoarticular-course (oligo-course) or polyarticular-
course (poly-course) juvenile idiopathic arthritis (JIA).
Methods. Children ages 2–16 years who had ac-
tive oligo-course or poly-course JIA and who required
therapy with a nonsteroidal antiinflammatory drug
were eligible for this trial. Patients were randomly
allocated to receive therapy with meloxicam oral sus-
pension, 0.125 mg/kg body weight in a single daily dose;
meloxicam oral suspension, 0.25 mg/kg body weight in a
single daily dose; or naproxen, 10 mg/kg body weight in
2 daily doses. The trial drugs were administered in a
double-blind, double-dummy design for up to 12
months. Response rates were determined according to
the American College of Rheumatology pediatric 30%
improvement criteria (ACR pediatric 30). Safety para-
meters were assessed by evaluating the frequency of
adverse events in the 3 groups.
Results. Of 232 patients enrolled, 225 received
treatment, 6 were not eligible for randomization, and 1
randomized patient was not treated. One hundred
eighty-two patients (81%) completed the 12-month
treatment period. Response rates according to the ACR
pediatric 30 criteria improved from month 3 to month
12, as follows: from 63% to 77% in the meloxicam 0.125
mg/kg group, from 58% to 76% in the meloxicam 0.25
mg/kg group, and from 64% to 74% in the naproxen
group. No statistically significant differences in re-
564
sponse rates were observed between the groups. There
were no differences in the frequency of adverse events or
abnormal laboratory values between the 3 groups.
Conclusion. The short- and long-term safety and
efficacy of meloxicam oral suspension appear to be
comparable with the safety and efficacy of naproxen oral
suspension in the treatment of oligo-course and poly-
course JIA. The once-daily administration of meloxicam
oral suspension might represent an improvement in the
treatment of JIA.
Juvenile idiopathic arthritis (JIA) encompasses a
heterogeneous group of disorders involving chronic ar-
thritis, disease onset before 16 years of age, and un-
known etiology. With a reported prevalence of 86.1–94
per 100,000 children (1), JIA is the most common
chronic rheumatic disease in childhood and is one of the
leading causes of pediatric acquired disability (2).
Nonsteroidal antiinflammatory drugs (NSAIDs),
either as monotherapy or in combination with other
agents, are considered to be the agents of first choice for
controlling joint inflammation in patients with all forms
of juvenile arthritis (3,4). In order to maintain control of
symptoms, therapy with NSAIDs may need to be con-
tinued for several years.
Meloxicam is an NSAID that selectively inhibits
the cyclooxygenase 2 (COX-2) enzyme and has the
advantage of once-daily dosing. An oral suspension
formulation is available for use in children. Data regard-
ing use of meloxicam for treating the signs and symp-
toms of adult rheumatoid arthritis demonstrate its com-
parability with other NSAIDs in terms of efficacy and
safety (5,6). Results of postmarketing surveillance stud-
ies also demonstrated that meloxicam is comparable
with other, more selective COX-2 inhibitors with regard
to the reduced frequency of upper gastrointestinal (GI)
complications such as perforation or bleeding (7). Al-
though meloxicam is currently registered in many coun-
tries for the treatment of adult rheumatoid arthritis, few
data exist for its use in children (8).
For these reasons, we conducted an interna-
tional, multicenter, double-blind, double-dummy, ran-
domized clinical trial to evaluate the short-term (3
months) and long-term (12 months) efficacy and safety
of 2 different doses of meloxicam oral suspension com-
pared with the safety and efficacy of naproxen oral
suspension in children ages 2–16 years with
oligoarticular-course (oligo-course) or polyarticular-
course (poly-course) JIA.
RUPERTO ET AL
PATIENTS AND METHODS
The trial was conducted in accordance with the 1996
Declaration of Helsinki. Each investigational site obtained
approval from its independent institutional review board
and/or relevant ethics committee before the start of the trial,
and all parents/legal guardians of the patients gave written
informed consent. Children who were able to understand the
given information also had to provide their active assent to
participate in the study.
Patients. Children ages 2–16 years with a diagnosis of
JIA, as defined according to the Durban criteria (9), and for
whom therapy with an NSAID was required were candidates
for the trial. In order to be eligible, patients had to have at least
2 joints with active arthritis plus abnormal results in at least 2
of any of the 5 remaining JIA core set criteria (10,11).
Exclusion criteria included the presence of current systemic
manifestations (e.g., fever, rash, hepatosplenomegaly); abnor-
mal, clinically relevant laboratory values unrelated to JIA;
pregnancy, breast-feeding, and/or inadequate contraception in
females of childbearing potential; history of bleeding disor-
ders; active peptic ulcer within the past 6 months; known or
suspected hypersensitivity reaction to NSAIDs, analgesics, or
antipyretics; a planned surgical procedure during the course of
the trial; participation in another clinical trial; known drug
abuse; and other concomitant rheumatic and clinically signifi-
cant nonrheumatic conditions. Other exclusion criteria were
successful previous treatment with an NSAID; concomitant
therapy with other NSAIDs or with prednisone (or equivalent)
at a dosage exceeding 0.2 mg/kg/day or 10 mg/day, whichever
was lower; treatment with ⬎1 disease-modifying antirheumatic
drug within the past 3 months before enrollment, including
hydroxychloroquine, cyclosporine, methotrexate, cytotoxic
agents, gold compounds, D-penicillamine, etanercept, or other
biologic agents; and intraarticular corticosteroid injections
during the last month before enrollment and intended for the
first 4 weeks of therapy. Concomitant therapy had to be
maintained at a stable dosage throughout the trial.
Study design. The trial was performed according to a
double-blind, double-dummy design in patients with oligo-
course or poly-course JIA. Eligible patients were allocated to 1
of the 3 treatment groups in a 1:1:1 randomization scheme.
Patients were seen after 2 weeks, 4 weeks, 6 weeks, 8 weeks,
and 3 months, and thereafter every 3 months until month 12,
by their treating physician.
After a washout period of 1–7 days, depending on the
serum half-life of the previous NSAID, the children were
randomly allocated to 1 of 3 therapies, as follows: meloxicam,
0.125 mg/kg body weight in a single daily dose; meloxicam, 0.25
mg/kg body weight in a single daily dose; or naproxen, 5 mg/kg
body weight twice daily. To keep the trial blinded, children in
the meloxicam group also received naproxen placebo suspen-
sion and vice versa, in a double-dummy design. Meloxicam oral
suspension or placebo was administered once daily in the
morning with food, while naproxen oral suspension or placebo
was administered twice daily (morning and evening). The
selected dosage of naproxen is the dosage registered for JIA in
most of the countries participating in the trial. The doses of
meloxicam chosen were equivalent to the registered adult
doses of 7.5 mg and 15 mg, based on pharmacokinetic and
clinical data obtained in children (8). The trial drug was
MELOXICAM VERSUS NAPROXEN FOR JIA
administered continuously until the end of the trial. Patients
who missed taking their trial medication on ⬎7 consecutive
days were considered noncompliant.
End points. As primary outcome measures, we used
the validated American College of Rheumatology pediatric 30
definition of improvement (ACR pediatric 30) (10–12). Ac-
cording to the ACR pediatric 30 criteria, patients were con-
sidered to be responders to treatment if they demonstrated at
least 30% improvement from baseline in at least 3 of any 6 JIA
core set variables, with no more than 1 of the remaining
variables worsening by ⬎30% (11). The ACR pediatric 30
definition allows researchers or clinicians to dichotomize pa-
tients into responders or nonresponders. Patients were also
evaluated by ACR response levels of at least 50% and at least
70% (ACR pediatric 50 and ACR pediatric 70, respectively) in
at least 3 of any 6 JIA core set variables, with no more than 1
of the remaining variables worsening by ⬎30%.
As secondary end points, we used the individual vali-
dated JIA core set variables (10,11), which include the number
of joints with active arthritis, defined as a joint with swelling or
a joint with pain and limitation on movement (range 0–75)
(13); the number of joints with limited range of motion (range
0–67) (14); the physician’s global evaluation of disease activity
on a double-anchored 100-mm visual analog scale (VAS)
(anchoring words 0 ⫽ inactive, 100 ⫽ very severe); the parent’s
global assessment of the child’s overall well-being on a double-
anchored 100-mm VAS (anchoring words 0 ⫽ very well, 100 ⫽
very poor) as reported on the Childhood Health Assessment
Questionnaire (C-HAQ) (15,16); the disability index of the
C-HAQ; and the Westergren erythrocyte sedimentation rate
(ESR). The C-HAQ (15,16) is a validated disease-specific
instrument for JIA adapted from the adult Health Assessment
Questionnaire. It measures functional ability in 8 activities of
daily living: dressing and grooming, arising, eating, walking,
hygiene, reach, grip, and activities. These 8 domains are then
averaged into a summary score ranging from 0 to 3, with higher
scores meaning greater disability. The C-HAQ has been fully
cross-culturally adapted, validated, and translated in all of the
languages of the countries participating in this trial (16–23).
As additional assessments, we reported the parent’s
evaluation of the child’s pain on a double-anchored 100-mm
VAS (anchoring words 0 ⫽ no pain, 100 ⫽ very severe pain) as
reported on the C-HAQ, the parent’s global assessment of the
child’s arthritis on a double-anchored 100-mm VAS (anchor-
ing words 0 ⫽ very well, 100 ⫽ very poor), the child’s
assessment of discomfort on a facial affective scale (range 1–9
points) (24), and the final global assessment of efficacy and
tolerability by the investigator (at months 3 and 12) on a verbal
rating scale (with the ratings good, satisfactory, not satisfac-
tory, or bad).
Safety was evaluated at every visit by tabulating the
number of reported adverse events (graded as mild, moderate,
or severe) that occurred during the course of the trial, as well
as by reviewing the results of routine laboratory tests (e.g.,
differential blood cell count, and levels of liver enzymes
and serum creatinine) performed in local laboratories. Assess-
ments of efficacy and safety were performed at baseline
and after 2 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 6
months, 9 months, and 12 months of therapy (except for the
ESR, which was determined only at week 4 and at months 3, 6,
9, and 12).
565
Statistical analysis. Analyses were completed accord-
ing to the recommendation of the Consolidated Standards of
Reporting Trials statement (25). Each patient who received at
least 1 dose of the trial drug was included in the analysis,
according to the intent-to-treat (ITT) principle.
The primary analysis of efficacy was performed for the
ITT population after 3 months of therapy (and every 3 months
thereafter) according to the last observation carried forward
approach for missing data. Patients who withdrew were
counted with their response status as reported in the last
observation. In a second, more conservative approach, all
patients who withdrew were considered to be nonresponders.
Descriptive statistics were used for reporting demo-
graphics, clinical characteristics, efficacy variables, and adverse
events. For the other secondary efficacy parameters, treatment
comparisons were performed using analysis of covariance at
months 3, 6, 9, and 12, controlling for baseline data. Confi-
dence intervals were expressed with limits of 95% (95% CIs).
The area under the curve (AUC) approach was used to
provide an average response over the entire 1-year treatment
period. To obtain the AUC, the percent response was summed
for certain periods of time according to the trapezoidal rule,
and the average was calculated by division through the respec-
tive time intervals used. The chi-square test or the unadjusted
Fisher’s exact test was applied for the paired comparisons, as
appropriate. Logistic regression was used, if necessary, to
analyze potential confounder variables, such as the center from
which the patient was referred, disease severity, age, or sex.
Safety data were analyzed descriptively by tabulating
the reported adverse events according to the Medical Diction-
ary for Regulatory Activities (26). Laboratory values were
standardized and normalized before analysis, based on consid-
eration of age- and-sex specific differences in the trial popu-
lation.
For the primary end point, a sample size of 219
evaluable patients (73 per group) was determined to be
sufficient to show superiority of meloxicam (both doses)
compared with naproxen according to the ACR pediatric 30
criteria, based on an expected response rate of 60% for
naproxen and a clinically meaningful delta of 20%, power of
90%, using a 1-sided Fisher’s exact test (␣ ⫽ 5%).
Random numbers were generated centrally. Individual
sealed envelopes containing the randomization for each pa-
tient were sent to the referring centers together with the trial
medication.
RESULTS
A total of 232 children were enrolled from Sep-
tember 2000 to December 2001. These children were
recruited from 34 pediatric rheumatology tertiary care
units in 7 countries: Austria (n ⫽ 21; 3 units), Belgium
(n ⫽ 11; 2 units), France (n ⫽ 29; 7 units), Germany
(n ⫽ 20; 6 units), Italy (n ⫽ 45; 9 units), Russia (n ⫽ 97;
4 units), and the UK (n ⫽ 9; 3 units). In a confounder
analysis, the origin of the patient was found to have no
impact on the primary end point.
566 RUPERTO ET AL

ized to receive meloxicam, 0.25 mg/kg/day; and 78

Figure 1. Flow diagram of the patients with juvenile idiopathic ar-
thritis.
As shown in Figure 1, 6 of the 232 patients did
not meet the eligibility criteria for randomization, and 1
randomized patient withdrew consent on the same day
and therefore did not receive the trial drug. Of the 225
treated patients, 73 were randomized to receive treat-
ment with meloxicam, 0.125 mg/kg/day; 74 were random-
patients were randomized to receive naproxen, 5 mg/kg
twice daily. Some differences in the patients’ baseline
characteristics or medical histories were observed be-
tween the treatment groups (Table 1), especially for age
and age group. A confounder analysis revealed that
none of the observed differences had a meaningful
impact on the primary end point, and that the effects
were not working unidirectionally for any treatment
arm. Because there is no evidence that differences in age
would impact the efficacy or safety of treatments in JIA,
the observed difference in age was considered irrelevant
with respect to the analysis of the trial.
One hundred eighty-two patients (81%) com-
pleted the 12-month treatment period. Nine patients in
the 0.125 mg/kg meloxicam group, 4 patients in the 0.25
mg/kg meloxicam group, and 13 patients in the naproxen
group discontinued treatment due to adverse events or
lack of efficacy (Figure 1). Among the patients who
discontinued treatment for other reasons, 2 patients in
each of the meloxicam groups discontinued because of
disease remission.
On average, patients in the 0.125 mg/kg meloxi-
cam group were treated for 327 days with a mean daily
dose of 0.122 mg/kg, patients in the 0.25 mg/kg meloxi-
cam group were treated for 326 days with a mean daily

Table 1. Characteristics and disease history of the study patients at baseline*

Meloxicam, Meloxicam, Naproxen,
0.125 mg/kg 0.25 mg/kg 10 mg/kg
Characteristic (n ⫽ 73) (n ⫽ 74) (n ⫽ 78) P
Disease duration, mean ⫾ SD months 41.6 ⫾ 40.6 30.0 ⫾ 33.4 27.7 ⫾ 24.9 0.154
Age, mean ⫾ SD years 8.9 ⫾ 3.8 9.0 ⫾ 3.9 7.5 ⫾ 3.7 0.021
Age group
ⱕ6 years 23 (31.5) 20 (27.0) 37 (47.4) 0.022
7–16 years 50 (68.5) 54 (73.0) 41 (52.6)
Sex
Male 24 (32.9) 25 (33.8) 18 (23.1) 0.276
Female 49 (67.1) 49 (66.2) 60 (76.9)
JIA onset type
Oligoarticular 60 (82.2) 59 (79.7) 56 (71.8) 0.156
Polyarticular 13 (17.8) 12 (16.2) 21 (26.9)
Systemic 0 3 (4.1) 1 (1.3)
JIA subtype at enrollment†
Oligoarticular 49 (67.1) 42 (56.8) 46 (59.0) 0.398
Polyarticular 24 (32.9) 32 (43.2) 32 (41.0)
Uveitis at baseline 9 (12.3) 7 (9.5) 6 (7.7) 0.628
Use of any DMARD at baseline 18 (24.7) 21 (28.4) 29 (37.2) 0.225
Use of methotrexate at baseline 15 (20.5) 19 (25.7) 23 (29.5) 0.449
Previous intake of other NSAID 71 (97.3) 67 (90.5) 74 (94.9) 0.214
within past 5 years

* Except where indicated otherwise, values are the number (%). P values refer to the differences between
the 3 treatment groups. JIA ⫽ juvenile idiopathic arthritis; DMARD ⫽ disease-modifying antirheumatic
drug; NSAID ⫽ nonsteroidal antiinflammatory drug.
† According to investigator classification.
MELOXICAM VERSUS NAPROXEN FOR JIA
Figure 2. Frequency of treatment response as determined by the
American College of Rheumatology pediatric 30 definition of im-
provement in the 3 treatment groups. No statistically significant
differences in the response rate among the 3 groups were observed.
Bars show the mean and 95% confidence intervals. MEL L ⫽
meloxicam 0.125 mg/kg/day; MEL H ⫽ meloxicam 0.25 mg/kg/day;
NAP ⫽ naproxen 5 mg/kg twice daily.
dose of 0.261 mg/kg, and those in the naproxen group
were treated for 315 days with a mean daily dose of 11.52
mg/kg.
Efficacy results. The response rate, according to
the ACR pediatric 30 criteria, increased over time (from
month 3 to month 12) in all 3 treatment groups (Figure
2). In the group receiving meloxicam 0.125 mg/kg, ACR
pediatric 30 response rates increased from 63% (46 of 73
patients) at month 3 (95% CI 52–74%) to 77% (56 of 73
patients) at month 12 (95% CI 67–86%); in the group
receiving meloxicam 0.25 mg/kg, response rates in-
creased from 58% (43 of 74 patients) at month 3 (95%
CI 47–69%) to 76% (56 of 74 patients) at month 12
(95% CI 66–85%); and in the group receiving naproxen,
response rates increased from 64% (50 of 78 patients) at
month 3 (95% CI 53–75%) to 74% (58 of 78 patients) at
month 12 (95% CI 65–84%). The primary end point
analysis between the pooled meloxicam groups and the
naproxen group showed no statistical difference (P ⫽
0.6).
According to the ACR pediatric 50 criteria, re-
sponse rates in the group receiving meloxicam 0.125
mg/kg increased from 52% (38 of 73 patients) at month
3 (95% CI 41–64%) to 68% (50 of 73 patients) at month
12 (95% CI 58–79%); response rates in the group
receiving meloxicam 0.25 mg/kg increased from 43% (32
of 74 patients) at month 3 (95% CI 32–55%) to 65% (48
of 74 patients) at month 12 (95% CI 54–76%); and in
the group receiving naproxen, response rates increased
from 50% (39 of 78 patients) at month 3 (95% CI
39–61%) to 68% (53 of 78 patients) at month 12 (95%
CI 58–78%). The analysis between the pooled meloxi-
cam groups and the naproxen group showed no statisti-
cal difference (P ⫽ 0.7).
Finally, according to the ACR pediatric 70 crite-
ria, response rates in the group randomized to receive
567
meloxicam 0.125 mg/kg increased from 38% (28 of 73
patients) at month 3 (95% CI 27–50%) to 53% (39 of 73
patients) at month 12 (95% CI 42–65%); in the group
assigned to receive meloxicam 0.25 mg/kg, response
rates increased from 26% (19 of 74 patients) at month 3
(95% CI 16–36%) to 43% (32 of 74 patients) at month
12 (95% CI 32–55%); and in the group receiving
naproxen, response rates increased from 29% (23 of 78
patients) at month 3 (95% CI 19–40%) to 50% (39 of 78
patients) at month 12 (95% CI 39–61%). Again, the
difference between the pooled meloxicam groups and
the naproxen group was not significant (P ⫽ 0.7).
When applying the AUC approach, according to
the ACR pediatric 30 definition, the average response
rates per month over the whole treatment period were
57%, 55%, and 54%, respectively, in the groups receiv-
ing meloxicam 0.125 mg/kg, meloxicam 0.25 mg/kg, and
naproxen. In a more conservative approach, all patients
who withdrew from the study were counted as nonre-
sponders. In this analysis, the response rates according
to ACR pediatric 30 criteria at month 12 decreased to
68% (50 of 73 patients) in the group receiving meloxi-
cam 0.125 mg/kg (95% CI 58–79%), to 69% (51 of 74
patients) in the group receiving meloxicam 0.25 mg/kg
(95% CI 58–79%), and to 63% (49 of 78 patients) in the
group receiving naproxen (95% CI 52–74%). Similar
trends were observed for the ACR pediatric 50 and
ACR pediatric 70 criteria (data not shown).
As shown in Table 2 and Figure 3, patients in all
3 treatment groups demonstrated improvement from
baseline in all 6 JIA core set variables and in all
additional measures; a statistically significant improve-
ment for all JIA core set variables except the ESR, and
secondary efficacy end point parameters was observed
during the first 3 months of the trial. This improvement
was maintained for the rest of the trial (P values not
shown). The investigators rated global efficacy as good
or satisfactory in 88% of patients treated with meloxi-
cam 0.125 mg/kg, in 85% of those treated with meloxi-
cam 0.25 mg/kg, and in 87% of patients treated with
naproxen.
As exploratory analyses, we evaluated the re-
sponse rate, according to the ACR pediatric 30 criteria,
in the subgroups of patients with oligo-course JIA and
those with poly-course JIA. At month 3, all treatments
had shown a trend toward better efficacy response rates
in patients with poly-course JIA compared with those
with oligo-course disease, with only the meloxicam 0.25
mg/kg group showing a statistically significant difference
(73% for poly-course versus 48% for oligo-course; P ⫽
0.03). Beyond month 3, the difference in efficacy be-
 568

Table 2. Measures of disease activity and improvement from baseline*

Meloxicam, 0.125 mg/kg (n ⫽ 73) Meloxicam, 0.25 mg/kg (n ⫽ 74) Naproxen, 10 mg/kg (n ⫽ 78)

Measure Month 0 Month 3 Month 12 Month 0 Month 3 Month 12 Month 0 Month 3 Month 12
JIA core set measures
No. of active joints (0–75 joints) 6.2 ⫾ 8.4 3⫾5 2.5 ⫾ 5.2 7.3 ⫾ 8.3 3.9 ⫾ 6 3.5 ⫾ 6.3 6.7 ⫾ 7.9 3.8 ⫾ 5.2 2.9 ⫾ 4.6
No. of limited joints (0–67 joints) 6.1 ⫾ 8.5 3.4 ⫾ 5.3 2.8 ⫾ 5.8 6.6 ⫾ 7.9 4.7 ⫾ 7.1 4.7 ⫾ 8.9 6.5 ⫾ 8 4.1 ⫾ 5.7 3.3 ⫾ 5.6
Physician’s global assessment of 37.1 ⫾ 19.6 19.4 ⫾ 20.7 15.4 ⫾ 20.5 38.5 ⫾ 21.6 20.6 ⫾ 20.3 16.8 ⫾ 19 37.6 ⫾ 17.9 21.1 ⫾ 19.2 14.4 ⫾ 16.7
disease activity by VAS (0–100
mm)
Erythrocyte sedimentation rate, 16.2 ⫾ 14.7 16.5 ⫾ 15.3 14 ⫾ 14.7 21.4 ⫾ 22.8 17.2 ⫾ 17.5 14.8 ⫾ 13.5 20.5 ⫾ 18.6 19.4 ⫾ 17.1 16.7 ⫾ 16.8
mm/hour
Parent’s global assessment of 36.9 ⫾ 20.1 21.1 ⫾ 19.3 18.2 ⫾ 19.2 38.7 ⫾ 23.3 23.5 ⫾ 21.9 17.7 ⫾ 20.3 38 ⫾ 19.5 22.5 ⫾ 20.4 16.9 ⫾ 18.2
overall well-being by VAS
(0–100 mm)
Disability index of the C-HAQ 0.6 ⫾ 0.6 0.4 ⫾ 0.5 0.3 ⫾ 0.4 0.8 ⫾ 0.6 0.5 ⫾ 0.6 0.4 ⫾ 0.6 0.8 ⫾ 0.6 0.5 ⫾ 0.6 0.3 ⫾ 0.5
(0–3 points)
Additional measures
Parent’s global assessment of 35 ⫾ 22.4 17.6 ⫾ 20.2 13.4 ⫾ 17.6 39 ⫾ 24.6 21.9 ⫾ 23.6 17.2 ⫾ 22.5 38.1 ⫾ 23.4 20.8 ⫾ 22.4 15.9 ⫾ 21.3
pain by VAS (0–100 mm)
Parent’s global assessment of 40.8 ⫾ 21.9 21.7 ⫾ 19.6 16.9 ⫾ 19 42.7 ⫾ 22.8 26 ⫾ 22 19.3 ⫾ 20.4 44 ⫾ 22 24 ⫾ 21.9 17.9 ⫾ 20.5
arthritis by VAS (0–100 mm)
Child’s assessment of discomfort 0.5 ⫾ 0.2 0.3 ⫾ 0.2 0.3 ⫾ 0.2 0.5 ⫾ 0.2 0.4 ⫾ 0.2 0.3 ⫾ 0.2 0.4 ⫾ 0.2 0.3 ⫾ 0.2 0.2 ⫾ 0.2
by facial affective scale (1–9
points)

* Values are the mean ⫾ SD. Month 0 is baseline, month 3 is the end of the short-term efficacy phase, and month 12 is the end of the long-term extension phase. JIA ⫽ juvenile
idiopathic arthritis; VAS ⫽ visual analog scale; C-HAQ ⫽ Childhood Health Assessment Questionnaire.
RUPERTO ET AL
MELOXICAM VERSUS NAPROXEN FOR JIA
Figure 3. Analysis of covariance for the 6 individual variables in-
cluded in the juvenile idiopathic arthritis core set of outcome mea-
sures, in the 3 treatment groups. P values refer to the differences
between the 3 treatment groups. Bars show the mean and 95%
confidence intervals. Mel H ⫽ meloxicam 0.25 mg/kg/day; Mel L ⫽
meloxicam 0.125 mg/kg/day; Nap ⫽ naproxen 5 mg/kg twice daily;
ESR ⫽ erythrocyte sedimentation rate; C-HAQ ⫽ Childhood Health
Assessment Questionnaire.
tween patients with oligo-course JIA and those with
poly-course JIA was vanishing or not visible.
Safety results. Fifty-four patients (74%) in the
meloxicam 0.125 mg/kg group, 59 patients (80%) in the
meloxicam 0.25 mg/kg group, and 66 patients (85%) in
the naproxen group experienced at least 1 adverse event
during the course of the 12-month trial period. The
investigators considered adverse events to be drug-
related in 7 patients (10%) in the meloxicam 0.125
mg/kg group, in 11 patients (15%) in the meloxicam 0.25
mg/kg group, and in 10 patients (13%) in the naproxen
group.
Seven patients in the meloxicam 0.125 mg/kg
group, 3 patients in the meloxicam 0.25 mg/kg group,
and 10 patients in the naproxen group discontinued
therapy prematurely due to an adverse event (Figure 1).
Among these patients, treatment was most often discon-
tinued because of an arthritis flare (2% of all patients
treated), followed by GI system disorders (2% of all
patients treated) and skin disorders (1% of all patients
treated). One patient in the meloxicam 0.125 mg/kg
569
group experienced reversible hyperbilirubinemia that
resulted in withdrawal from the trial.
Table 3 shows all adverse events occurring in at
least 10% of the patients, irrespective of severity or
relatedness to the study drugs, according to the Medical
Dictionary for Regulatory Activities. The majority of ad-
verse events were considered to be mild. The incidence
of musculoskeletal disorders was highest in the group
receiving meloxicam 0.25 mg/kg, and these disorders
were attributable mainly to an arthritis flare.
Bleeding-associated disorders and skin disorders
were more often observed in the naproxen group.
Among the skin disorders, 1 case of moderate pseu-
doporphyria was observed in the naproxen group. From
baseline until the end of the trial, the number of patients
with active uveitis decreased, from 9 to 4 in the meloxi-
cam 0.125 mg/kg group, from 7 to 4 in the meloxicam
0.25 mg/kg group, and from 6 to 5 in the naproxen
group. Global tolerability was assessed by the investiga-
tor as “good” or “satisfactory” in 93% of patients in the
0.125 mg/kg meloxicam group and in 95% of the patients
treated with meloxicam 0.25 mg/kg or naproxen.
No remarkable changes in the laboratory para-
meters were observed (data not shown), except for
changes in bilirubin values. During the trial, 14 patients
in the meloxicam 0.125 mg/kg group (20% of all patients
with available data), 5 patients in the meloxicam 0.25
mg/kg group (7% of all patients with available data), and
10 patients in the naproxen group (13% of all patients
with available data) showed an increase in the bilirubin
concentration above the upper limit of normal.
Four patients receiving the 0.125 mg/kg dose of
meloxicam, 7 receiving the 0.25 mg/kg dose of meloxi-
cam, and 10 patients receiving naproxen experienced a
serious adverse event (data not shown). All serious
adverse events were categorized as “severe” due to the
fact that hospitalization was required to treat either the
underlying disease or intercurrent diseases such as ap-
pendicitis, and none of these adverse events were con-
sidered to be drug-related.
DISCUSSION
The present trial was performed to assess the
efficacy and safety of meloxicam oral suspension in the
treatment of JIA. This study represents the first example
of a large-scale randomized trial to evaluate the efficacy
and safety of an NSAID selective for COX-2 inhibition
in children with JIA.
Apart from aspirin, only a few NSAIDs have
been studied at all, and even fewer have been approved
570 RUPERTO ET AL

Table 3. Adverse events occurring in at least 10% of the study patients*

Meloxicam, Meloxicam, Naproxen,
0.125 mg/kg 0.25 mg/kg 10 mg/kg
Adverse event (n ⫽ 73) (n ⫽ 74) (n ⫽ 78) P
Eye disorders 5 (7) 6 (8) 8 (10) 0.7
Gastrointestinal disorders 28 (38) 27 (37) 25 (32) 0.7
Pain, diarrhea, nausea, vomiting† 21 (29) 19 (26) 19 (24) 0.8
Pharyngolaryngeal pain 9 (12) 5 (7) 4 (5) 0.2
General disorders 13 (18) 14 (19) 19 (24) 0.6
Pyrexia 11 (15) 13 (18) 14 (18) 0.9
Infections and infestations 30 (41) 38 (51) 39 (50) 0.4
Nasopharyngitis 4 (6) 9 (12) 7 (9) 0.3
Physical examination‡ 9 (12) 6 (8) 4 (5) 0.3
Musculoskeletal and connective tissue disorders 11 (15) 22 (30) 10 (13) 0.02
Nervous system disorders 10 (14) 11 (15) 7 (9) 0.5
Headache NOS 9 (12) 10 (14) 5 (6) 0.3
Respiratory, thoracic, and mediastinal disorders 22 (30) 19 (26) 26 (33) 0.6
Cough 7 (10) 9 (12) 14 (18) 0.3
Rhinitis NOS 13 (18) 11 (15) 16 (21) 0.66
Skin and subcutaneous tissue disorders 4 (6) 5 (7) 13 (17) 0.049§
Eczema, erythema, pruritus, rash† 0 (0) 3 (4) 8 (10) 0.008§
Bleeding disorders (rectal hemorrhage, 3 (4) 2 (3) 9 (12) 0.07§
epistaxis, hematuria, hematoma, Henoch-
Schönlein purpura)†

* Values are the number (%). Adverse events were defined according to the Medical Dictionary for Regulatory Activities (26). Except
where indicated otherwise, P values were determined by chi-square test. NOS ⫽ not otherwise specified.
† Selected preferred terms were grouped together, and each patient was counted only once.
‡ Abnormal laboratory results or findings from physical examination (e.g., increased body temperature).
§ By Fisher’s exact test.

for use in children (e.g., naproxen, tolmetin, and ibupro-
fen in the US), and most of them are used off-label,
meaning that no indication for pediatric use is reported
on the drug label. Nonvalidated drug treatment may not
provide optimal benefit to the individual child and
usually does not generate new information for identify-
ing the best use of the medication.
A placebo group, although desirable, was not
included due to ethical considerations. Ethics commit-
tees and expert guidelines prefer the exclusive use of
active comparators instead of placebo in children, and
alternative trial designs are suggested (27). Some regu-
latory authorities, such as the US Food and Drug
Administration and the European Medicines Agency,
refer to the systematic advantages of comparing investi-
gational drugs with placebo during the evaluation of new
drugs (28,29). It is interesting to note that a placebo
response rate of 29% (95% CI 24–34%) was obtained
from a meta-analysis of previous placebo-controlled
trials in children with JIA (30), applying the ACR
pediatric 30 criteria. The CIs of the response rates in this
trial are clearly separate from those assessed in the
meta-analysis, showing indirectly the superiority of the
active treatments compared with placebo. All 3 treat-
ment groups showed substantial improvement of the
symptoms of JIA over time. The treatment effect in this
trial was expressed almost completely after 3 months of
therapy. Still, further improvement appeared to occur
until 1 year, which confirms the data obtained from an
open trial with meloxicam (8). In the absence of a
placebo group, it remains speculative whether this fur-
ther improvement is the result of additional effects of
the trial drug beyond the underlying trend of the disease
to be self-limiting, a bias from natural fluctuations of the
disease, or the variability in the assessment of the
disease by investigator and parent.
The therapeutic effect was clear in all 3 treatment
groups, but the responses observed in this trial were
higher than expected. Response to treatment was de-
fined according to the ACR pediatric 30 criteria. The
ACR pediatric 30 criteria were proposed with the intent
that they would be robust enough to cover all different
subtypes of JIA (10), but the performance of this criteria
set in children with oligo-course JIA, who constituted
the majority of the patients enrolled in this trial, has
never been formally tested. It is conceivable that the use
of the ACR pediatric 30 definition in patients with
oligo-course disease, in whom the total number of joints
involved is low, may have led to an overestimation of the
MELOXICAM VERSUS NAPROXEN FOR JIA
percentage of change, leading to an unreasonably high
response rate.
Anecdotal information and common clinical
practice suggest that higher doses of naproxen might
be needed in certain cases of JIA (31). However, from
published literature it is impossible to demonstrate that
a higher dosage of naproxen would be more effective
than the registered dosage of 10 mg/kg/day divided into
2 daily doses. Indeed, 3 published trials of naproxen used
the registered dosage of 10 mg/kg/day (32–34), with the
remaining 2 studies (35,36) using dosages up to 15–20
mg/kg/day. A dosage of 5 mg/kg twice daily in children
corresponds to an adult dose of 1,000 mg (37), the
highest recommended daily dose. In the absence of any
other comparative data on the use of different doses of
naproxen in JIA, we performed an exploratory subgroup
analysis within the naproxen-treated patient group in
this trial, based on the actual naproxen doses adminis-
tered to every child (data not shown). The administra-
tion of higher doses of naproxen did not translate into
better response rates.
The safety profile of meloxicam was largely com-
parable with that of naproxen, including the frequency
and nature of GI adverse events. Although GI adverse
events would be expected side effects of NSAID use in
adults, the majority of such events in this trial were not
considered by the investigators to be drug-related. This
could be attributable to the fact that many concomitant
diseases, especially infections in younger children, are
accompanied by GI symptoms. No ulcerations, perfora-
tions, or major bleeds from the upper GI tract were
reported, which supports data from literature indicating
that children are less likely than adults to experience
significant GI problems (4,38).
Although a higher frequency of increases in the
serum bilirubin level was observed in the group receiving
meloxicam 0.125 mg/kg compared with the other 2
treatment groups, this observation, in the absence of
dose dependency, is not considered to affect the safety
assessment of meloxicam. Also, data from studies of
meloxicam in adults did not reveal an increase in the
bilirubin level above the upper limit of normal, as was
observed in the current study. The observed higher
incidence of musculoskeletal adverse events in the group
receiving meloxicam 0.25 mg/kg was mainly attributable
to an arthritis flare; however, because such an increased
incidence of these adverse events was not detected in the
group receiving meloxicam 0.125 mg/kg, this observation
was not considered relevant.
In conclusion, the short- and long-term safety
and efficacy of meloxicam oral suspension appear to be
571
comparable with the safety and efficacy of naproxen in
the treatment of oligo-course and poly-course JIA. The
benefit of the once-daily administration of meloxicam
oral suspension might represent an improvement in the
treatment of children with JIA.
ACKNOWLEDGMENTS
We thank the following members of the Pediatric
Rheumatology International Trials Organization (PRINTO)
who enrolled children for the trial: C. Huemer, MD, H.
Schacherl, MD (Austria); C. Wouters, MD (Belgium); C.
Barbier, MD, L. Gourmy, MD, C. Job-Deslandre, MD, J.
Terzic, MD, I. Lemelle, MD (France); H. Girschick, MD, G.
Horneff, MD, H. I. Huppertz, MD, R. Küster, MD, M.
Metzler, MD (Germany); R. Di Toro II, MD, M. G. Alpigiani,
MD (Italy); J. Anderson, MD, and P. Woo, MD (UK).
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