ARTHRITIS & RHEUMATISM
Vol. 60, No. 12, December 2009, pp 37763783
Associations Between the American College of
Rheumatology Pediatric Response Measures and the
Continuous Measures of Disease Activity Used in
Adult Rheumatoid Arthritis
A Secondary Analysis of Clinical Trial Data From Children With
Polyarticular-Course Juvenile Idiopathic Arthritis
Sarah Ringold,1 Yun Chon,2 and Nora G. Singer3
Objective. To measure associations between the
American College of Rheumatology (ACR) pediatric
criteria for improvement and the continuous measures
of disease activity used for rheumatoid arthritis in adult
patients with polyarticular-course juvenile idiopathic
arthritis (JIA).
Methods. In this retrospective analysis of 2 etan-
ercept trials, disease activity was calculated at baseline,
3 months, and 6 months using the Disease Activity Score
(DAS), the DAS based on 28 joints (DAS28), the Sim-
plified Disease Activity Index (SDAI), and the Clinical
Disease Activity Index (CDAI). The ACR pediatric
response and the European League Against Rheuma-
tism (EULAR) response were also determined for the
3-month and 6-month evaluations. Data were analyzed
in 94 patients with JIA independent of the treatment
arm. Correlation coefficients between measures were
calculated for each visit. The areas under the receiver
Supported by Immunex Corporation, a wholly owned subsid-
iary of Amgen, Inc., and by Wyeth Pharmaceuticals. Dr. Ringolds
work was supported by the Mentored Scholar Program of the Center
for Clinical and Translational Research, Seattle Childrens Hospital,
Seattle, Washington.
1
Sarah Ringold, MS, MD: Childrens Hospital & Regional
Medical Center, and University of Washington, Seattle; 2Yun Chon,
PhD: Amgen, Thousand Oaks, California; 3Nora G. Singer, MD:
University Hospitals/Case Medical Center, Rainbow Babies & Chil-
drens Hospital, Cleveland, Ohio.
Dr. Chon owns stock or stock options in Amgen.
Address correspondence and reprint requests to Sarah
Ringold, MS, MD, Seattle Childrens Hospital, 4800 Sandpoint Way
NE, MS R-5420, Seattle, WA 98105. E-mail: sringold@u.washington.
edu.
Submitted for publication March 24, 2009; accepted in revised
form August 18, 2009.
3776
DOI 10.1002/art.24983
2009, American College of Rheumatology
operating characteristic curve (AUC of ROC) were
calculated to assess the discriminative properties of the
scores for the ACR pediatric response measures.
Results. The mean DAS, DAS28, CDAI score, and
SDAI score were 3.7, 4.7, 30.8, and 36.4, respectively, at
baseline, corresponding to high levels of disease activity
(CDAI/SDAI) or moderate levels of disease activity
(DAS/DAS28). At 3 months, the mean scores corre-
sponded to low (DAS/DAS28) or moderate (CDAI/
SDAI) disease activity. At 6 months, the mean scores
corresponded to low disease activity (DAS/DAS28/
CDAI) or moderate disease activity (SDAI). Most chil-
dren met the criteria for a good or moderate EULAR
response at 3 months and 6 months. The correlation
between continuous outcome measures and each pedi-
atric core set component was moderate to very good. The
AUC of ROC values for each measure were high (range
0.760.98).
Conclusion. Good correlation and discriminative
abilities were seen between the DAS, DAS28, CDAI, and
SDAI for the ACR pediatric criteria for improvement.
These disease activity measures may be useful for
research and clinical care in polyarticular-course JIA.
Juvenile idiopathic arthritis (JIA) is the most
common pediatric rheumatic disease, with an estimated
annual incidence of 3.26.1 cases per 100,000 persons,
depending on the case definition used and the popula-
tion studied (13). Polyarticular JIA, which accounts for
40% of cases of JIA, is particularly refractory to
standard medical therapies. Previous observational stud-
CORRELATION BETWEEN ACR PEDIATRIC AND ADULT RESPONSE MEASURES IN RA
ies have demonstrated that children with polyarticular
JIA have only a 15% probability of achieving disease
remission within 10 years of the initial diagnosis, and
6570% of children with polyarticular-onset JIA enter
adulthood with ongoing active disease (46). In addi-
tion, a recent retrospective cohort study showed that in
the majority of children with polyarticular JIA, 60% of
their disease course involved active disease (7).
However, outcomes in both observational and
interventional studies of polyarticular JIA remain in-
completely described, primarily due to limited data and
to a lack of standardized outcome measures. Because
prior studies have focused on variably defined outcome
measures, the scope of these results has been limited,
and it is difficult both to draw comparisons between
cohorts and to apply the results to clinical practice.
Given that children with polyarticular JIA continue to
have active disease for the majority of their disease
course, the development of continuous measures of
disease activity is needed for a better description of the
response to therapy in clinical trials, for defining and
describing disease activity states at a single point in time
and over time, for the translation of clinical trial results
into the care of individual patients, and for the followup
of individual patients in routine clinical care.
Currently, the primary outcome measure used in
therapeutic trials in polyarticular JIA is the American
College of Rheumatology (ACR) Pediatric 30 (Pedi 30)
criteria for improvement (8). Developed in 1997, the
ACR Pedi 30 was designed to distinguish between active
treatment and placebo and is the only prospectively
validated measure of disease activity in JIA. Although
not prospectively evaluated, the ACR Pedi 20, Pedi 50,
Pedi 70, and Pedi 90 measures are now also used as
outcome measures in clinical trials. Preliminary defini-
tions of disease flare and inactive disease in polyarticular
JIA have also been proposed (9,10). Furthermore, al-
though the development of the ACR pediatric response
measures was a significant advance for pediatric rheu-
matology, the utility of these measures is limited, be-
cause they assess the relative response (i.e., the change
in disease status relative to a baseline clinic visit or other
prior clinic visit), are dichotomous, and do not provide
an absolute measure of the disease state.
Continuous measures of disease activity have
been in use in adult rheumatoid arthritis (RA) since
development of the Disease Activity Score (DAS) in
1993 (11). Subsequently, additional continuous mea-
sures have been proposed and validated in adult RA,
including the DAS in 28 joints (DAS28) (12), the
Simplified Disease Activity Index (SDAI) (13), and the
3777
Clinical Disease Activity Index (CDAI) (14). Although
these measures have apparent face validity for
polyarticular-course JIA, the utility of these measures in
polyarticular-course JIA has not been extensively evalu-
ated. We therefore sought to determine whether the
DAS, DAS28, SDAI, and CDAI are potentially useful as
continuous measures of disease activity in patients with
polyarticular-course JIA, by measuring their predictive
and discriminative abilities for the ACR pediatric mea-
sures of relative response. In this secondary analysis of 2
previously conducted clinical trials, disease activity was
determined before and after treatment with etanercept
in patients with polyarticular-course JIA.
PATIENTS AND METHODS
Patients. We conducted a secondary analysis of data
from 2 trials of etanercept in children and adolescents with
polyarticular-course JIA (known as juvenile RA at the time
when the trials were conducted). As a result of these trials,
etanercept, a soluble tumor necrosis factor (TNF) receptorFc
fusion protein, was approved by the US Food and Drug
Administration for the treatment of moderately to severely
active polyarticular-course JIA in patients ages 2 years and
older (15). Approval for the analyses reported here was
obtained from the Seattle Childrens Hospital institutional
review board.
Key eligibility criteria that were common to both
studies included the following: a diagnosis of JIA according to
the ACR (formerly, the American Rheumatism Association)
criteria (16); a systemic, polyarticular, or pauciarticular disease
onset, with a polyarticular disease course; 5 swollen joints
accompanied by pain and/or tenderness and/or warmth, and
3 joints with limitation of motion at screening; a disease
duration that was long enough for the patient to have received
an adequate trial of nonsteroidal antiinflammatory drugs;
normal hepatic, renal, and immunologic function; and no prior
anti-TNF antibody therapy. Patients enrolled in the first study
(17) were ages 417 years, could not have received methotrex-
ate (MTX) for 14 days before receiving etanercept, could not
have functional class IV disease according to the ACR criteria
(18), and could not have tested positive for antidouble-
stranded DNA antibodies. Patients in the second study (19)
were ages 218 years, were receiving MTX at a stable dosage
of 0.31.0 mg/kg/week at the time of randomization, and could
not have received intraarticular glucocorticoid injections
within 28 days prior to enrollment.
The first study was a phase II/III clinical trial con-
ducted in 2 phases: an open-label phase and a double-blind,
controlled phase. During the open-label phase, all patients
(n 69) received etanercept 0.4 mg/kg (maximum 25 mg)
subcutaneously twice weekly for up to 3 months. After 3
months, patients who had achieved a clinical response were
randomly assigned to receive etanercept 0.4 mg/kg or placebo
(n 51). Patients continued on this regimen for up to 4
months or until the occurrence of a disease flare. Patients who
had some response but did not meet criteria to be considered
a responder in the first open-label phase, patients with a
3778 RINGOLD ET AL

disease flare during the double-blind phase, and patients who treatment arm. Pearsons correlations were used to correlate
completed the double-blind phase were then eligible to partic- the DAS, DAS28, CDAI, and SDAI values with the pediatric
ipate in an open-label extension study for up to 120 months core set components. The ACR Pedi 30 was used as the
(n 58). standard to evaluate the agreement of disease improvement
In the second trial (phase III), patients (n 25) were between the DAS and the pediatric outcome measures. Kappa
randomly assigned to receive MTX (at the dose received prior statistics (25) were calculated between the ACR Pedi 30 and
to study entry) once weekly plus either etanercept (0.4 mg/kg the European League Against Rheumatism (EULAR) re-
up to 25 mg) or placebo subcutaneously twice weekly for 6 sponse criteria based on the DAS and the DAS28 (26).
months. After the controlled portion of the trial, all patients Participants were dichotomized into levels of response using
(n 20) received etanercept plus MTX on an open-label basis the EULAR response criteria. Children who achieved good or
for an additional 6 months. Patients were allowed to enter the moderate levels of response were categorized as responders,
open-label phase after 2 months of blinded treatment for and children who did not meet these criteria were categorized
disease flare or lack of response. The trial was stopped before as nonresponders.
meeting its enrollment goals because of challenges in patient The areas under the curve (AUCs) of the receiver
operating curve (ROC) (26) were calculated to assess the
recruitment.
diagnostic accuracy of the adult RA measures for discriminat-
In both trials, the response to treatment was assessed
ing the ACR Pedi 30 response. ROCs are obtained by plotting
using the following pediatric core set components: physicians
the sensitivity of a test versus (1 specificity) and are used to
global assessment of disease severity (PhGA) as measured in
assess the diagnostic accuracy of a test. The AUC of an ROC
centimeters on a 10-point visual analog scale (VAS), patients/ reflects the discriminative properties of a test. AUC values
parents global assessment of overall well-being (PtGA) as range from 1.0 (perfect test) to 0.5 (useless test). In general,
measured in millimeters on a 100-point VAS or in centimeters higher AUC values indicate better diagnostic properties (27).
on a 10-point VAS, number of active joints (tender joint count
[TJC] and swollen joint count [SJC]), number of joints with
limitation of motion, Childhood Health Assessment Question- RESULTS
naire (C-HAQ), and measurements of the C-reactive protein
(CRP) level (mg/liter or mg/dl) or the erythrocyte sedimenta- Patients. Ninety-four patients with JIA were in-
tion rate (ESR; mm/hour) (8). cluded in these analyses. The baseline characteristics of
Statistical analysis. Pooled data from these trials were the patients are shown in Table 1.
used to calculate values for the DAS and the DAS28, the Disease activity score values and disease activity
SDAI, and the CDAI, using the following equations:
states. At baseline, the median number of joints with
DAS CRP 0.53938 53TJC 0.06544SJC 0.17 active disease per patient was 27, and the mean C-HAQ
lnCRPmg/liter 1 0.00722PtGAmm 0.45 score was 1.4. Patients entered in the trials had a history
of 5.4 3.8 years (mean SD) of disease and thus were
DAS28 CRP 0.56 28TJC 0.28 28SJC 0.36 considered to have established disease. The mean DAS,
lnCRPmg/liter 1 0.014PtGAmm 0.96 DAS28, CDAI score, and SDAI score at baseline were
SDAI 28SJC 28TJC PhGAcm PtGAcm 3.7, 4.7, 30.8, and 36.4, respectively, and corresponded to
a high disease activity state based on the CDAI and the
CRPmg/dl
SDAI, and moderate disease activity according to the
CDAI 28SJC 28TJC PhGAcm PtGAcm. DAS and the DAS28 (Table 2).
The DAS was calculated using a 53-TJC in place of the At the 3-month followup, the mean number of
Ritchie Articular Index (20), based on the modified DAS joints with active disease per patient decreased from 27
formula described by Fransen et al (21). Because the SDAI is to 10. The mean C-HAQ score decreased from 1.4 to
based on the CRP value, the versions of the DAS and DAS28 0.9, for a mean change in the C-HAQ score of 0.5,
also based on the CRP value were chosen so that comparisons
would be performed across scores based on the same marker of
inflammation. Cutoffs for disease states were determined
based on previously published cutoff points in adult RA Table 1. Characteristics of the 94 patients at baseline*
(22,23). The cutoffs for high disease activity were as follows: Age, mean SD years 10.4 4.1
DAS 3.7, DAS28 5.1, CDAI score 22, and SDAI score Female sex, no. (%) 56 (60)
26. Cutoffs for moderate disease activity were as follows: Rheumatoid factor positive, no. (%) 17 (21)
DAS 2.4 and 3.7, DAS28 3.2 and 5.1, CDAI score 10 JIA onset type, no. (%)
and 22, and SDAI score 11 and 26. Cutoffs for low Pauciarticular 12 (13)
disease activity were as follows: DAS 2.4, DAS28 3.2, Polyarticular 56 (60)
CDAI score 10, and SDAI score 11. Disease was consid- Systemic 26 (28)
ered to be in remission if the patient had a DAS 1.6, a * The analysis included all patients with at least 1 nonmissing baseline
DAS28 2.6, a CDAI score 2.8, or an SDAI score 3.3 (24). value or efficacy end point. JIA juvenile idiopathic arthritis.
All children were analyzed together, irrespective of the Data were available for 83 patients.
CORRELATION BETWEEN ACR PEDIATRIC AND ADULT RESPONSE MEASURES IN RA 3779

Table 2. Estimated responses based on the pediatric core set components and adult rheumatoid arthritis
measures*
Patients with JIA

Baseline Month 3 Month 6

(n 94) (n 81) (n 39)
DAS, mean SD 3.7 1.4 2.2 1.3 1.7 1.4
DAS28, mean SD 4.7 1.3 3.1 1.3 2.6 1.3
CDAI, mean SD 30.8 12.5 14.9 11.1 9.9 12.5
SDAI, mean SD 36.4 16.9 17.7 14.2 11.1 14.0
Total number of joints with active disease, 27 (1635) 10 (422) 3 (111)
median (IQR) (range 071)
Joints with loss of movement, median 22 (1232) 15 (824) 6 (425)
(IQR) (range 071)
Physicians global assessment, median 6.0 (5.08.0) 2.0 (1.04.0) 1.0 (1.02.0)
(IQR) (range 110)
Patients global assessment, median (IQR) 5.0 (3.07.0) 2.0 (1.04.0) 1.0 (1.03.0)
(range 110)
C-HAQ score, mean SD 1.4 0.9 0.9 0.8 0.6 0.8
CRP, mean SD mg/dl 6.0 7.9 3.0 5.8 1.4 2.5
ESR, mean SD mm/hour 41.0 29.6 24.9 26.4 14.2 15.3
ACR Pediatric 20 70/81 (86.4) 33/39 (84.6)
ACR Pediatric 30 64/81 (79.0) 33/39 (84.6)
ACR Pediatric 50 49/81 (60.5) 32/39 (82.1)
ACR Pediatric 70 35/81 (43.2) 23/39 (59.0)
ACR Pediatric 90 9/81 (11.1) 9/39 (23.1)
EULAR responder based on DAS 59/79 (74.7) 34/35 (97.1)
EULAR responder based on DAS28 66/79 (83.5) 32/35 (91.4)

* Except where indicated otherwise, values are the number of patients/number of patients tested (%). All
patients with 1 nonmissing baseline value or efficacy end point value were included. JIA juvenile
idiopathic arthritis; DAS Disease Activity Score; DAS28 DAS in 28 joints; CDAI Clinical Disease
Activity Index; SDAI Simplified Disease Activity Index; IQR interquartile range; C-HAQ
Childhood Health Assessment Questionnaire; CRP C-reactive protein; ESR erythrocyte sedimen-
tation rate; ACR American College of Rheumatology; EULAR European League Against
Rheumatism.

indicating a greater than minimum clinically important
difference for improvement from baseline, which has
been shown to be a change in the C-HAQ score of
0.188 (28). The mean values for the DAS/DAS28 also
decreased and corresponded to a low disease activity
state (with improvement of 1.2 in the DAS28 indicat-
ing a clinically meaningful response to therapy) (22).
The mean values of the CDAI/SDAI corresponded to a
state of moderate disease activity. At the 6-month
followup, the mean number of joints with active disease
per patient was 3, and the mean C-HAQ score was 0.6.
The mean DAS/DAS28/CDAI score for this visit corre-
sponded to low or minimally detectable disease activity,
and the mean SDAI score corresponded to moderate
disease.
At 3 months, a total of 69 patients had been
treated with etanercept alone, 13 patients had been
treated with etanercept plus MTX, and 12 patients
received MTX alone. At 6 months, 25 patients were
receiving etanercept alone, 26 patients were receiving no
biologic or traditional disease-modifying antirheumatic
drug, 13 patients were receiving etanercept plus MTX,
and 12 patients were receiving MTX alone. The majority
of patients achieved a response level of good (decrease
in the DAS or DAS28 of 1.2, and DAS 2.4 or DAS28
3.2) or moderate (decrease in the DAS or DAS28 of
0.6 but 1.2 and DAS 3.7 or DAS28 5.1, or
decrease in the DAS or DAS28 of 1.2 and DAS 2.4
and 3.7 or DAS28 3.2 and 5.1) by 3 and 6 months,
as defined by the EULAR criteria based on the DAS or
DAS28 (22,23).
The sensitivity of the EULAR response (good or
moderate) for the ACR Pedi 30 was high at both 3
months and 6 months, indicating that if a EULAR
response was achieved, then an ACR Pedi 30 response
was also likely, although the specificity was substantially
lower at both time points, indicating that not achieving a
EULAR response was not always associated with non-
response for the ACR Pedi 30 (Table 3). The positive
predictive value for a EULAR response based on the
DAS was 0.93 at 3 months and 0.91 at 6 months, whereas
3780 RINGOLD ET AL

Table 3. Agreement between the EULAR response based on the DAS, DAS28, and ACR Pedi 30 criteria*
Positive Negative
No. of predictive predictive
EULAR response patients (95% CI) Sensitivity Specificity value value Accuracy
Based on DAS and ACR Pedi 30
Month 3 79 0.5 (0.3, 0.7) 0.86 0.73 0.93 0.55 0.84
Month 6 35 0.4 (0.2, 0.9) 1.00 0.25 0.91 1.00 0.91
Based on DAS28 and ACR Pedi 30
Month 3 79 0.5 (0.2, 0.7) 0.92 0.53 0.89 0.62 0.85
Month 6 35 0.5 (0.1, 1.0) 0.97 0.50 0.94 0.67 0.91

* The number of patients includes those with nonmissing values for both the Disease Activity Score (DAS) or DAS in 28 joints
(DAS28) and the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30). Accuracy was calculated as the proportion
of patients with a correct diagnosis (yes for both the ACR Pedi 30 and European League Against Rheumatism [EULAR]
response or no for both the ACR Pedi 30 and EULAR response). 95% CI 95% confidence interval.

the negative predictive value was only 0.55 at 3 months
but was 1.0 at 6 months.
Correlations between the DAS and the pediatric
core set components. The correlation between the con-
tinuous outcome measures and each of the pediatric
core set components was moderate to very good (Table
4). As anticipated, because the swollen and tender
joint counts make the greatest contribution to each
DAS equation, the closest correlation was measured
for the total count of joints with active disease (r 0.927
at 6 months) (Figure 1).
AUCs of ROCs for the disease activity scores and
the pediatric ACR measures of response. The AUCs of
the ROC for each disease activity score and each ACR
Pedi 30 response were 0.75, indicating good conver-
gent validity between the disease activity scores and the
ACR Pedi 30 criteria (Table 5). There was a trend
toward the AUCs of the ROC being higher for the ACR
Pedi 30, Pedi 50, and Pedi 70 than for the ACR Pedi 20
and ACR Pedi 90.
DISCUSSION
In this sample of children with polyarticular-
course JIA enrolled in clinical trials of etanercept, the
DAS, DAS28, SDAI score, and CDAI score correlated
well with the individual components of the pediatric core
set of criteria. There was an overall decrease in the mean

Table 4. Correlations between disease activity scores/indices and other indicators of disease activity*
No. of Physicians global Patients global No. of joints with
patients C-HAQ assessment assessment active disease CRP
DAS
Baseline 93 0.53 (0.36, 0.66) 0.51 (0.35, 0.65) 0.58 (0.42, 0.70) 0.74 (0.63, 0.82) 0.52 (0.35, 0.65)
Month 3 80 0.58 (0.42, 0.71) 0.64 (0.48, 0.75) 0.65 (0.50, 0.76) 0.79 (0.69, 0.86) 0.47 (0.28, 0.63)
Month 6 36 0.62 (0.37, 0.79) 0.68 (0.45, 0.83) 0.65 (0.41, 0.81) 0.93 (0.86, 0.96) 0.57 (0.30, 0.76)
DAS28
Baseline 93 0.60 (0.45, 0.71) 0.61 (0.46, 0.72) 0.68 (0.55, 0.77) 0.62 (0.47, 0.73) 0.68 (0.55, 0.78)
Month 3 80 0.62 (0.46, 0.74) 0.68 (0.53, 0.78) 0.67 (0.53, 0.78) 0.72 (0.59, 0.81) 0.62 (0.46, 0.74)
Month 6 36 0.66 (0.42, 0.81) 0.67 (0.44, 0.82) 0.59 (0.33, 0.77) 0.91 (0.82, 0.95) 0.66 (0.43, 0.81)
CDAI
Baseline 94 0.49 (0.32, 0.63) 0.55 (0.39, 0.68) 0.55 (0.39, 0.68) 0.85 (0.79, 0.90) 0.43 (0.25, 0.58)
Month 3 81 0.56 (0.39, 0.69) 0.73 (0.60, 0.81) 0.71 (0.58, 0.80) 0.83 (0.75, 0.89) 0.37 (0.17, 0.55)
Month 6 39 0.60 (0.34, 0.77) 0.77 (0.60, 0.87) 0.58 (0.32, 0.76) 0.97 (0.93, 0.98) 0.54 (0.26, 0.74)
SDAI
Baseline 93 0.58 (0.43, 0.70) 0.62 (0.47, 0.73) 0.60 (0.45, 0.71) 0.74 (0.64, 0.82) 0.77 (0.67, 0.84)
Month 3 80 0.63 (0.48, 0.75) 0.72 (0.60, 0.81) 0.63 (0.48, 0.75) 0.76 (0.65, 0.84) 0.70 (0.56, 0.80)
Month 6 36 0.70 (0.48, 0.84) 0.71 (0.50, 0.84) 0.58 (0.31, 0.76) 0.94 (0.89, 0.97) 0.66 (0.43, 0.81)

* Values are the correlation coefficients (95% confidence intervals). The Childhood Health Assessment Questionnaire
(C-HAQ) scores 8 domains on a 4-point scale (03), with higher numbers representing greater disability. The physicians and
patients global assessments were based on a scale of 0 (asymptomatic) to 10 (severe). The C-reactive protein (CRP) level is
measured in mg/dl. DAS Disease Activity Score; DAS28 DAS in 28 joints; CDAI Clinical Disease Activity Index;
SDAI Simplified Disease Activity Index.
Number of patients with nonmissing disease activity score/index.
CORRELATION BETWEEN ACR PEDIATRIC AND ADULT RESPONSE MEASURES IN RA 3781

These data support the prior study by Lurati and

colleagues that retrospectively examined the concor-
dance between the ACR Pedi 30 and ACR Pedi 20, and
the DAS, DAS28, and EULAR categories of response in
a cohort of 75 children with multiple JIA types treated
with MTX or a TNF inhibitor (29). In this cohort, the
highest level of concordance (71%) was measured be-
tween the DAS and the ACR Pedi 30 (AUC 0.735).
This relationship did not appear to be significantly
different for children who were younger than age 16
years compared with those who were older than age 16
years.
Together, these data indicate that these continu-
ous measures of disease activity are potentially applica-
ble to polyarticular-course JIA. In contrast to the ACR
pediatric measures of relative response, the continuous
measures have the advantage of describing not only
change in disease activity, but also the disease state at a
single point in time. These measures are therefore useful
in both the research and clinical settings, and the
availability of a continuous measure of disease activity in
JIA would be a valuable tool, facilitating comparison of
patient disease status and treatment response across
clinical trials and their translation to routine clinical
care.
The process of validation of a new outcome
measure requires formal testing of the different compo-
nents of validity: face validity, feasibility, content valid-
ity, criterion validity, discriminant validity, and construct
validity (30). Our analyses and those of Lurati and
colleagues (29) suggest good discriminant validity for
these scores in polyarticular-course JIA, as measured by

Table 5. Concordance between disease activity scores and the ACR

Pediatric 30 criteria*
Month 3 Month 6
DAS 0.82 (0.69, 0.94) 0.85 (0.64, 1.05)
Improvement from 0.85 (0.74, 0.96) 0.79 (0.54, 1.04)
Figure 1. Scatter plots showing the correlations between the number baseline
of joints with active disease per patient and the Disease Activity Score DAS28 0.82 (0.69, 0.94) 0.89 (0.76, 1.02)
(DAS) at baseline (A) and after 3 months (B) and 6 months (C) of Improvement from 0.87 (0.77, 0.96) 0.95 (0.87, 1.03)
etanercept therapy. baseline
CDAI 0.77 (0.64, 0.91) 0.89 (0.74, 1.04)
Improvement from 0.88 (0.79, 0.97) 0.98 (0.96, 1.01)
baseline
level of disease activity, as defined by the DAS, DAS28, SDAI 0.76 (0.63, 0.90) 0.86 (0.67, 1.04)
SDAI score, and CDAI score, between baseline and 6 Improvement from 0.90 (0.82, 0.99) 0.93 (0.78, 1.08)
months, and the majority of children achieved a good or baseline
moderate EULAR response by 3 months of followup. * Values are the areas under the curve (95% confidence intervals) of
Furthermore, the AUCs of the ROC for each of the the receiver operating curve. ACR American College of Rheuma-
tology; DAS Disease Activity Score; DAS28 DAS in 28 joints;
continuous measures of disease activity and each ACR CDAI Clinical Disease Activity Index; SDAI Simplified Disease
pediatric measure of relative response were high. Activity Index.
3782
the AUCs of the ROCs for each score relative to each
ACR pediatric measure of relative response. In addition,
these current analyses indicate good construct validity
for the DAS, DAS28, SDAI, and CDAI in polyarticular-
course JIA, with good correlation between the DAS,
DAS28, SDAI, and CDAI and the components of the
pediatric core set. The DAS, DAS28, SDAI, and CDAI
also have apparent face validity for polyarticular-course
JIA, because they capture the majority of content mea-
sured by the pediatric core set components. Never-
theless, additional work will be required to determine
whether the exclusion of joints with loss of range of
motion, exclusive of measures of disability, and the use
of reduced joint counts (i.e., the 28- and 44-joint counts),
significantly affect a providers perception of the face
validity of a measure. Most pediatric rheumatologists
would not equate DAS or DAS28 remission with clinical
remission, because of the number of joints with active
disease that persist in patients who meet the criteria for
DAS or DAS28 remission. In our analyses, SDAI and
CDAI remission appeared to be more stringent (median
01 active joints).
We were not able to assess all aspects of the
validity of these scores in this cohort, and the face
validity, feasibility, and criterion validity of these scores
will require additional study. These analyses were also
limited by the sample size, particularly at the 6-month
time point, which likely affected the precision of our
estimates and may have also resulted in higher correla-
tion and AUC measurements than would be seen in
cohorts with larger numbers of children and more
variable responses to treatment. In addition, the chil-
dren enrolled in these protocols had severe disease at
baseline, as evidenced by their total counts of joints with
active disease, and these scores may not provide similar
results in cohorts of children with less severe disease for
whom changes in disease activity may not be as large.
The lower correlation between these scores and
the 2 patient- and parent/proxy- reported outcomes (the
C-HAQ and patients global assessment of disease ac-
tivity) requires further exploration as well, particularly
given the known confounding effects of nondisease
activityrelated factors on the C-HAQ (31). Correla-
tions were lowest between the disease activity measures
and the C-HAQ, likely because there is no discrete
measure of disability in the adult RA measures, and
because the C-HAQ also reflects disability due to dam-
age from prior disease activity as well as ongoing, active
disease.
In contrast with the consistently high positive
predictive value (proportion of patients with positive test
RINGOLD ET AL
results and a correct diagnosis), the negative predictive
value (proportion of patients with negative test results
and a correct diagnosis) for a EULAR response based
on the DAS was low at the 3-month time point and
perfect at the 6-month time point. The most likely
explanation for this observation is the small sample size,
especially at 6 months.
Despite these limitations, these data indicate that
the DAS, DAS28, SDAI, and CDAI may be valid
measures of disease activity in children with
polyarticular-course JIA and support the additional val-
idation of these scores in larger cohorts of children with
polyarticular-course JIA that include children with early
JIA (disease for 1 year) and with varying degrees of
disease severity.
ACKNOWLEDGMENTS
We thank the Pediatric Rheumatology Collaborative
Study Group investigators who participated in the original
trials and Norman Ilowite, MD, for his contributions to the
execution of one of the original studies included in our data
analysis. We also thank Nan Zhang, PhD, of Amgen Inc. for
support with the statistical analysis, Michele Hooper, MD, of
Amgen Inc. for helpful discussions, and Julia R. Gage, PhD,
whose work was funded by Amgen Inc., for editorial assistance.
AUTHOR CONTRIBUTIONS
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. Ringold 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. Ringold, Chon, Singer.
Acquisition of data. Ringold, Singer.
Analysis and interpretation of data. Ringold, Chon, Singer.
ROLE OF THE STUDY SPONSOR
The study sponsors were not involved in the design or
interpretation of the data. Publication of this article was not contingent
on approval by the study sponsors.
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