close

Вход

Забыли?

вход по аккаунту

?

Development and validation of a preliminary definition of minimal disease activity in patients with juvenile idiopathic arthritis.

код для вставкиСкачать
Arthritis & Rheumatism (Arthritis Care & Research)
Vol. 59, No. 8, August 15, 2008, pp 1120 –1127
DOI 10.1002/art.23916
© 2008, American College of Rheumatology
ORIGINAL ARTICLE
Development and Validation of a Preliminary
Definition of Minimal Disease Activity in Patients
With Juvenile Idiopathic Arthritis
SILVIA MAGNI-MANZONI,1 NICOLINO RUPERTO,2 ANGELA PISTORIO,2 ELENA SALA,2
NICOLETTA SOLARI,2 ELENA PALMISANI,2 CHIARA CUGNO,1 ELENA BOZZOLA,1
ALBERTO MARTINI,3 AND ANGELO RAVELLI3
Objective. To develop and validate a definition of minimal disease activity (MDA) in patients with juvenile idiopathic
arthritis (JIA).
Methods. The clinical charts of JIA patients followed over a 16-year period were reviewed to identify visits with high
disease activity and MDA, defined on the basis of therapeutic decisions made by the attending physician. For each JIA
activity measure recorded at the time of the visit, the cutoff value that best identified states of MDA was calculated by
means of the area under the receiver operating characteristic curve analysis. A definition of MDA for oligoarthritis and
polyarthritis was set up after testing the relative power of each variable in a multivariate analysis. Validation procedures
included assessment of discriminant and construct validity.
Results. The definition that resulted from the analyses led to establish that a state of MDA could be defined as the
presence of a physician global assessment <2.5 cm and a swollen joint count of 0 in patients with oligoarthritis; and as
the presence of a physician global assessment <3.4 cm, a parent global assessment <2.1 cm, and a swollen joint count <1
in patients with polyarthritis. Validation procedures demonstrated that the MDA definition had good discriminant and
construct validity in the context of both observational studies and controlled trials.
Conclusion. We developed a preliminary definition of MDA in patients with JIA that represents a useful treatment target
state and is proposed for inclusion as an outcome measure in future observational studies and clinical trials in patients
with JIA.
INTRODUCTION
Juvenile idiopathic arthritis (JIA) is a broad term that describes a clinically heterogeneous group of arthritides of
unknown cause that begins before age 16 years. The International League of Associations for Rheumatology (ILAR)
has provided the most recent classification of JIA, which
1
Silvia Magni-Manzoni, MD, Chiara Cugno, MD, Elena
Bozzola, MD: Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo, Pavia, Italy; 2Nicolino Ruperto, MD, MPH, Angela Pistorio, MD, PhD, Elena
Sala, MD, Nicoletta Solari, MD, Elena Palmisani, MD: Istituto di Ricovero e Cura a Carattere Scientifico G. Gaslini,
Genoa, Italy; 3Alberto Martini, MD, Angelo Ravelli, MD:
Istituto di Ricovero e Cura a Carattere Scientifico G. Gaslini
and Università degli Studi di Genova, Genoa, Italy.
Drs. Magni-Manzoni and Ruperto contributed equally to
this work.
Address correspondence to Angelo Ravelli, MD, Pediatria
II, Istituto G. Gaslini, Largo G. Gaslini 5, 16147 Genoa, Italy.
E-mail: angeloravelli@ospedale-gaslini.ge.it.
Submitted for publication July 27, 2007; accepted in revised form March 3, 2008.
1120
recognizes the following 7 disease categories on the basis
of the features present in the first 6 months of illness:
systemic arthritis, oligoarthritis (persistent and extended),
rheumatoid factor–positive polyarthritis, rheumatoid factor–negative polyarthritis, enthesitis-related arthritis, psoriatic arthritis, and undifferentiated arthritis (1).
In the past decade, there have been major advances in
the treatment of JIA, which include the widespread use of
methotrexate (MTX) and intraarticular corticosteroids
(IACs), the earlier introduction of these medications, and
in recent years, the availability of biologic agents (2– 4).
These advances have increased the expectations of treatment benefit, with disease remission now being the goal
for many pediatric rheumatologists (5–7). Although this
objective has been easier to achieve in children with oligoarthritis who are treated with only IACs, it is still problematic in the subset of patients who have polyarticular
disease. No medication or combination of medications has
yet been demonstrated to be effective for inducing remission in the majority of these patients. Few randomized
controlled trials in patients with JIA report remission data,
which is indirect evidence of the infrequency of remission.
Minimal Disease Activity in Patients With JIA
For adult patients with rheumatoid arthritis (RA), remission is not a frequent occurrence in daily clinical care.
Furthermore, it has been argued that achieving (and maintaining) a satisfactory state of disease activity is probably
more important in the long term than the improvement
from a high level of disease activity documented in trials
(i.e., that provided by the application of American College
of Rheumatology [ACR] criteria for a 20%, 50%, or 70%
response) (8). These issues have raised the need for defining a state of low disease activity (i.e., minimal disease
activity [MDA]) as an intermediate state between high
disease activity (HDA) and remission (9 –11). As a result, a
preliminary definition of MDA for use in RA clinical trials
was recently developed through a consensus process (10).
According to this definition, patients with no tender joints,
no swollen joints, and an erythrocyte sedimentation rate
(ESR) ⱕ10 mm/hour are considered to have MDA. If patients do not meet this criterion, they are still considered
to have MDA if either their Disease Activity Score in 28
joints is ⱕ2.85 or they meet 5 of the following 7 criteria:
pain ⱕ2, swollen joint count ⱕ1, tender joint count ⱕ1,
Health Assessment Questionnaire score ⱕ0.5, physician
global assessment ⱕ1.5, parent global assessment ⱕ2, and
ESR ⱕ20 mm/hour. It has been suggested that describing
the proportion of patients achieving and maintaining such
a state for a specific period of time would add useful
information for the practicing physician and aid in the
interpretation of trials and longitudinal results (12).
The aim of the present study is to devise a preliminary
definition of MDA in patients with JIA and to provide
evidence of the clinical validity of the definition.
PATIENTS AND METHODS
Study design and patient selection. The clinical charts
of all consecutive patients who were seen in the study
units between January 1988 and December 2003, had JIA
according to ILAR criteria (1), and had received ⱖ1 clinic
visit were retrospectively reviewed. Patients seen before
the publication of ILAR criteria were reclassified according to such criteria. The study protocol was approved by
the Ethics Committee of the Istituto G. Gaslini, Genoa,
Italy.
Criteria for states of HDA and MDA. All patients’ visits
were examined to identify those who met the criteria for
HDA or MDA (Table 1). These criteria were based on the
therapeutic decision made by the attending pediatric rheumatologist at the time of the visit. The criteria were based
on consensus of study investigators and literature review.
For a patient to be placed in an activity state, the patient
had to meet any 1 of the criteria for that state. If a patient
met the criteria in more than 1 visit, only the first visit (or,
in case the first visit had insufficient clinical data, the
subsequent visit with more clinical information available)
meeting the criteria for HDA or MDA was selected. Therefore, each patient contributed to the analysis with a maximum of 1 HDA visit and 1 MDA visit. Owing to their
peculiar clinical features, patients with enthesitis-related
arthritis deserved distinctive definitions of MDA. For this
1121
Table 1. Criteria for the definition of states of high and
minimal disease activity and their frequency in
529 visits
Frequency, %
High disease activity (n ⫽ 321)
New start or restart of nonsteroidal
antiinflammatory drug therapy*
Administration of intraarticular
corticosteroid therapy
New start or restart of prednisone
therapy or increase in
prednisone dose by ⬎0.2 mg/kg
New start or restart of a secondline or biologic medication
Increase in methotrexate dose by
⬎50%
Addition of another second-line
medication or biologic agent to
methotrexate
Minimal disease activity (n ⫽ 208)
Termination of nonsteroidal
antiinflammatory drug therapy
because of disease remission*
Not administering intraarticular
corticosteroid therapy in a
patient receiving no systemic
medication*
Discontinuation of prednisone
therapy because of satisfactory
disease control
Termination of methotrexate
therapy because of disease
remission
Not changing a second-line or
biologic medication for ⱖ1 year
Not receiving treatment with a
second-line or biologic
medication for ⱖ1 year†
16.4
51.6
9.2
25.6
15.1
6.3
10.0
31.3
2.4
10.0
38.5
7.8
* Assessed only in patients with oligoarthritis.
† Assessed only in patients with polyarthritis.
reason and owing to the relatively small number of available observations, this patient subgroup was excluded
from the analysis.
Clinical assessment. General patient information included age at onset, sex, and ILAR category. The following
clinical measures of JIA activity were recorded, whenever
available, for each instance of HDA and MDA: physician’s
global assessment of disease activity, measured on a 10-cm
visual analog scale (VAS; where 0 ⫽ no activity and 10 ⫽
maximum activity); parent’s global assessment of the
child’s well-being, measured on a 10-cm VAS (where 0 ⫽
very good and 10 ⫽ very poor); parent’s rating of the
intensity of the child’s pain, measured on a 10-cm VAS
(where 0 ⫽ no pain and 10 ⫽ maximum pain); swollen
joint count, pain on motion/tenderness, restricted motion,
and active disease (13); functional ability assessment
through the Italian version of the Childhood Health Assessment Questionnaire (C-HAQ; where 0 ⫽ best and 3 ⫽
1122
worst) (14), or before 1994, through the Modified Lee Index
(15) or the Juvenile Arthritis Functional Assessment Report (to ensure uniformity, scores of the 2 latter instruments were converted to the 0 –3 score of the C-HAQ, as
reported) (13,16); duration of morning stiffness; ESR
(Westergren method); C-reactive protein level (nephelometry); white blood cell count; hemoglobin level; and platelet count.
Development of the definition of MDA. In the first phase
of the study, we considered all measures of JIA activity to
be of potentially equal importance to define the states of
HDA and MDA, and calculated for each of them the cutoff
value that best identified the states of MDA by means of
the area under the receiver operating characteristic curve
(AUC-ROC) analysis. Because JIA patients with oligoarthritis or polyarthritis have a different severity potential,
deserve diverse treatment strategies, and are usually included in distinct clinical trials, we believed each subgroup required a distinct definition of MDA. For this reason, the calculation was performed separately for patients
with oligoarthritis (i.e., patients with the ILAR category of
persistent oligoarthritis) or polyarthritis (i.e., patients with
the ILAR categories of extended oligoarthritis, polyarthritis, and systemic arthritis whose disease followed a polyarticular course). For purposes of the analysis, patients
with psoriatic arthritis and undifferentiated arthritis were
classified within polyarthritis or oligoarthritis categories
based on the number of joints affected throughout the
disease course. In the subsequent step, the relative discriminating power of each variable was further scrutinized
by means of multiple logistic regression analysis. This
analyis was carried out by entering JIA activity measures
as explanatory variables and the presence of MDA as an
outcome variable. Cases with missing variables were excluded from the analysis.
All JIA activity measures were dichotomized into binary
variables, using the thresholds yielded by the AUC-ROC
analysis as cut points. Using a backward selection procedure, the most significant independent variables were
identified, using a P value ⬎0.05 as the removal criterion.
The effect was expressed in odd ratios and 95% confidence intervals were calculated; statistical significance
was tested by means of the likelihood ratio test. The predictive ability of multivariate models was evaluated by
calculating their AUC-ROC.
Validation procedures. Validation of the definition of
MDA was based on the assessment of discriminant and
construct validity. For evaluation of discriminant validity,
3 different data sources were used. The first data sets were
composed of 2 controlled trials, including 1 aimed to
compare intermediate and higher doses of MTX in 633
patients with polyarthritis (17), and 1 aimed to compare
meloxicam and naproxen in 225 patients with polyarthritis or oligoarthritis (18). Data from the trials were provided
by the Paediatric Rheumatology International Trials Organisation and by Boehringer Ingelheim, respectively.
Patients in the 2 trials were divided into 4 mutually ex-
Magni-Manzoni et al
clusive groups (nonresponders, responders at 30%, responders at 50%, and responders at 70%) by their degree
of improvement at 6 and 3 months after treatment start,
respectively, and according to ACR Pediatric 30 (Pedi 30)
criteria for improvement (19). Patients were classified as
responders at 30%, 50%, and 70% if they had an improvement of ⱖ30%, 50%, or 70%, respectively, with respect to
baseline in ⱖ3 of the 6 core set items, with no more than 1
of the remaining items worsened by ⬎30%. Patients were
classified as nonresponders if they did not have an improvement of ⱖ30%. The proportions of patients with
polyarthritis or oligoarthritis in each response group who
met the respective MDA definition were then compared. It
was considered that the definition would have demonstrated good discriminant ability if the percentage of patients meeting MDA criteria was significantly greater in the
group that exhibited the greater degree of therapeutic response (i.e., the ACR Pedi 70 responders).
The third dataset consisted of 42 patients with oligoarthritis who received an IAC injection and were included in
a previous study of responsiveness of JIA outcome measures (20). At 6 months after the injection, patients were
classified by the physician and the parent as improved,
stable, or worsened, compared with the preinjection status. The proportion of patients meeting the MDA definition in the groups judged as improved or not improved
(stable to worsened) by the physician or the parent was
compared. We anticipated that the definition would demonstrate good discriminant ability if the proportion of patients meeting MDA criteria was significantly greater in the
improved group than in the not improved group.
Percentages of patients meeting MDA criteria in each
response group were compared by means of the chi-square
test or by Fisher’s exact test in case of expected frequencies
⬍5. Bonferroni adjustment was applied as a correction for
multiple comparisons to explore post hoc differences between pairs of patient groups.
Construct validity was examined using a clinical database that included 270 consecutive patients with oligoarthritis or polyarthritis who had long-standing disease and
had received a cross-sectional assessment of JIA outcome
measures at last followup visit, 5–21 years after disease
onset. The following measures of disease damage and
health-related quality of life (HRQOL) were compared in
patients who met or did not meet the MDA definition:
restricted joint count, C-HAQ score (14), Steinbrocker
functional class (21), Juvenile Arthritis Damage Index
(JADI) score (22), Poznanski score of radiographic damage
(23,24), and the Child Health Questionnaire of HRQOL
(14). We anticipated that the definition would demonstrate
good construct validity if the amount of damage was significantly lower in patients who had reached an MDA state
at last followup visit than in those who did not. Comparison of quantitative variables was made by means of the
Mann-Whitney U test, whereas comparison of qualitative
variables was performed by means of the chi-square test
or by Fisher’s exact test in case of expected frequencies
⬍5.
All statistical tests were 2-sided; P values less than 0.05
were considered statistically significant. The statistical
Minimal Disease Activity in Patients With JIA
1123
Table 2. Comparison of demographic and clinical features between patients/visits with minimal disease activity or high
disease activity*
Minimal disease activity
Oligoarthritis
(n ⴝ 89)
Men, no. (%)
Women, no. (%)
ILAR category, no. (%)
Oligoarthritis persistent
Oligoarthritis extended
Polyarthritis
Systemic arthritis
Psoriatic arthritis
Undifferentiated arthritis
Physician’s global assessment of disease
activity†
Parent’s global assessment of well-being†
Parent’s pain assessment†
Childhood Health Assessment
Questionnaire score‡
Swollen joint count
Tender joint count
Restricted joint count
Active joint count
Morning stiffness, minutes
Erythrocyte sedimentation rate, mm/hour§
C-reactive protein level, mg/dl¶
White blood cells, ⫻109/liter
Hemoglobin, gm/liter
Platelets, ⫻109/liter
Polyarthritis
(n ⴝ 119)
High disease activity
Oligoarthritis
(n ⴝ 159)
Polyarthritis
(n ⴝ 162)
18 (20.2)
71 (79.8)
35 (29.4)
84 (70.6)
33 (20.7)
126 (79.3)
45 (27.8)
117 (72.2)
75 (84.2)
0 (0)
0 (0)
0 (0)
7 (7.9)
7 (7.9)
0 (0, 0.5)
0 (0)
38 (31.9)
37 (31.1)
35 (29.4)
4 (3.4)
5 (4.2)
1 (0, 2.5)
141 (88.7)
0 (0)
0 (0)
0 (0)
8 (5.0)
10 (6.3)
7.4 (4.5, 8.7)
0 (0)
51 (31.5)
54 (33.3)
40 (24.7)
7 (4.3)
10 (6.2)
7.1 (5.3, 10)
0 (0, 1.1)
0 (0, 0.9)
0 (0, 0)
0.5 (0, 1.7)
0.4 (0, 1.6)
0.1 (0, 0.6)
3 (1, 5)
2.8 (1.2, 5.0)
0.3 (0, 0.8)
4.2 (2.5, 5.9)
4 (2, 6.5)
0.8 (0.3, 1.4)
2 (1, 3)
1 (1, 2)
1 (1, 2)
2 (1, 3)
15 (0, 60)
30 (15, 54)
0.6 (0.1, 1.8)
8.6 (6.7, 10.3)
121 (112, 129)
374 (307, 447)
5 (3, 9)
5 (2, 9)
5 (2, 8)
7 (4, 12)
20 (0, 60)
40 (20, 63)
2.3 (0.4, 5.9)
9.1 (7.3, 12.2)
114 (103, 124)
400 (326, 517)
0 (0, 0)
0 (0, 0)
0 (0, 0)
0 (0, 1)
0 (0, 0)
12 (8, 19)
0.1 (0.1, 0.3)
6.8 (5.7, 8)
129 (122, 137)
333 (270, 371)
1 (0, 3)
0 (0, 2)
1 (0, 4)
1 (0, 4)
0 (0, 6)
12.5 (8, 25)
0.1 (0.1, 0.9)
7.5 (6.0, 9.7)
125 (116, 133)
337 (241, 389)
* Values are the median (interquartile range) unless otherwise indicated. ILAR ⫽ International League of Associations for Rheumatology.
† Range 0 (best) to 10 (worst).
‡ Range 0 (best) to 3 (worst).
§ Normal value ⬍15 mm/hour.
¶ Normal value ⬍0.4 mg/dl.
packages used were Statistica (StatSoft, Tulsa, OK) and
Stata, release 7 (StataCorp, College Station, TX).
RESULTS
A total of 1,080 visits (made in 414 patients) that met the
criteria for HDA or MDA were identified. According to the
above criteria, 1 HDA visit and/or 1 MDA visit for each
patient was chosen. This led us to select 529 visits, 321 of
which met the criteria for HDA and 208 of which met the
criteria for MDA. The values of the clinical measures of JIA
activity in visits included and excluded were comparable
(data not shown). Table 2 shows the main demographic
and clinical features of the visits/patients with HDA or
MDA included in the analyses.
Calculation of the best thresholds through AUC-ROC
analysis. The cutoff values of clinical measures of JIA
activity, obtained through the AUC-ROC analysis, that best
identified states of MDA in patients with oligoarthritis and
polyarthritis are shown in Table 3. As expected, most
cutoffs were higher in patients with polyarthritis than in
those with oligoarthritis. That the cutoff for the physician
global assessment was greater than that of the parent global
assessment is consistent with our previous observations
that parents of children with JIA tend to provide lower
global ratings than physicians (25,26). All joint counts
should equal 0 for patients with oligoarthritis to be considered as having MDA, whereas in patients with polyarthritis the presence of 1 swollen or tender joint or 3 active
joints would still enable classification of a patient in MDA
status. Patients with either oligoarthritis or polyarthritis
should have no morning stiffness for being considered as
having MDA. Cutoffs for laboratory measures were in their
normal range or very close to it.
Data for the development of the definition of MDA. For
the multivariate analysis, complete data were available for
388 patients. The best-fitting model obtained through logistic regression procedures, which had the presence of
MDA as its dependent variable and JIA activity measures
as explanatory variables, is shown in Table 4. The physician global assessment and the swollen joint count were
the independent predictive variables for MDA in oligoarthritis, whereas the physician global assessment, the swollen joint count, and the parent global assessment were the
independent predictive variables for MDA in polyarthritis.
The AUC-ROC of the model was 0.95 for oligoarthritis and
1124
Magni-Manzoni et al
Table 3. Threshold values for juvenile idiopathic arthritis activity measures that best
discriminated between states of high and minimal disease activity obtained through the
area under the receiver operating characteristic curve analysis
Oligoarthritis
(n ⴝ 248)
Polyarthritis
(n ⴝ 281)
ⱕ2.5
ⱕ0.3
ⱕ0.9
ⱕ0.25
0
0
0
0
0
ⱕ16
ⱕ0.41
ⱕ8.2
⬎121
ⱕ392
ⱕ3.4
ⱕ2.1
ⱕ2
ⱕ0.25
ⱕ1
ⱕ1
0
ⱕ3
0
ⱕ20
ⱕ0.9
ⱕ7.1
⬎119
ⱕ379
Physician’s global assessment of disease activity*
Parent’s global assessment of well-being*
Parent’s pain assessment*
Childhood Health Assessment Questionnaire score†
Number of swollen joints
Number of tender joints
Number of joints with restricted motion
Number of active joints
Morning stiffness, minutes
Erythrocyte sedimentation rate, mm/hour‡
C-reactive protein level, mg/dl§
White blood cells, ⫻109/liter
Hemoglobin, gm/liter
Platelets, ⫻109/liter
* Range 0 (best) to 10 (worst).
† Range 0 (best) to 3 (worst).
‡ Normal value ⬍15 mm/hour.
§ Normal value ⬍0.4 mg/dl.
of 70% responders versus nonresponders, P ⫽ 0.002 for
comparison of 70% responders versus 30% responders,
P ⫽ 0.009 for comparison of 70% responders versus 50%
responders). No patient enrolled in the 2 trials was in an
MDA state at baseline, providing face validity to the definitions. Among patients with oligoarthritis who received
an IAC injection, the percentage of patients who met the
MDA definition at 6 months after the procedure was 50%
and 0%, respectively (P ⬍ 0.0001), among patients who
were judged as improved or not improved by the physician, and 40% and 6%, respectively (P ⫽ 0.02), among
patients who were judged as improved or not improved by
the parent. Altogether, these results demonstrate that the
MDA criteria had a strong capability to discriminate between different levels of clinical response to therapy.
0.93 for polyarthritis. Based on the results of the multivariate analysis, a preliminary definition of MDA in oligoarthritis and polyarthritis was set up (Table 5).
Assessment of discriminant validity. In the MTX trial
(17), the percentage of patients meeting the MDA definition among the nonresponders, 30% responders, 50% responders, and 70% responders was 2.3%, 8.6%, 17.8%,
and 62.2%, respectively (P ⫽ 0.0002 for comparison of
50% responders versus nonresponders, P ⬍ 0.0001 for
comparison of 70% responders versus nonresponders,
30% responders, and 50% responders). In the meloxicam
trial (18), the percentage of patients meeting the MDA
definition among the nonresponders, 30% responders,
50% responders, and 70% responders was 5.1%, 0%,
15%, and 61.7%, respectively, among 137 patients with
oligoarthritis (P ⬍ 0.0001 for comparison of 70% responders versus nonresponders, P ⫽ 0.001 for comparison of
70% responders versus 30% responders, P ⫽ 0.003 for
comparison of 70% responders versus 50% responders),
and 7.7%, 5.5%, 14.3%, and 60.9%, respectively, among
88 patients with polyarthritis (P ⫽ 0.0004 for comparison
Assessment of construct validity. Table 6 shows the
comparison of the measures of damage and HRQOL between patients with oligoarthritis or polyarthritis who met
or did not meet the MDA criteria at last followup visit,
5–21 years after disease onset. Compared with patients
who had not achieved an MDA state, patients who had
Table 4. Best-fitting model obtained through logistic regression procedures with the presence of minimal disease activity as
the outcome*
Explanatory variable
Oligoarthritis (n ⫽ 195)
Physician’s global assessment of disease activity ⱕ2.5
Number of swollen joints 0
Polyarthritis (n ⫽ 193)
Physician’s global assessment of disease activity ⱕ3.4
Parent’s global assessment of well-being ⱕ2.1
Number of swollen joints ⱕ1
␤
SE
OR
95% CI
P
3.8
3.2
0.7
1.1
45.3
25.3
12.6–163.3
2.9–224.6
⬍ 0.0001
⬍ 0.0001
3.2
1.6
1.6
0.5
0.5
0.7
24.9
4.8
4.9
9.4–66.0
1.9–12.4
1.3–18.1
⬍ 0.0001
0.0013
0.015
* The area under the receiver operating characteristic curve of the model was 0.95 for oligoarthritis and 0.93 for polyarthritis. OR ⫽ odds ratio; 95%
CI ⫽ 95% confidence interval.
Minimal Disease Activity in Patients With JIA
1125
Table 5. Definition of minimal disease activity in patients with oligoarticular and
polyarticular juvenile idiopathic arthritis (JIA)*
Physician’s global assessment of disease activity, cm†
Parent’s global assessment of well-being, cm†
No. swollen joints
Oligoarticular
JIA
Polyarticular
JIA
ⱕ2.5
ⱕ3.4
ⱕ2.1
ⱕ1
0
* To be classified as being in a minimal disease activity state, patients should meet all criteria for their
disease subtype simultaneously. In addition to the above criteria, patients with systemic-onset disease
should have no fever, rash, serositis, splenomegaly, or generalized lymphadenopathy attributable to JIA.
† Measured on a 10-cm visual analog scale, where 0 ⫽ best and 10 ⫽ worst.
reached this state had significantly less functional impairment, as measured through the restricted joint count, the
C-HAQ, or the Steinbrocker classification, and better
HRQOL. Likewise, in the polyarthritis group, patients with
MDA had a smaller amount of articular and extraarticular
damage as measured through the JADI, and tended to have
a smaller amount of radiographic damage, as assessed
through the Poznanski score. All of these findings were
consistent with a priori predictions, thereby demonstrating that the MDA definition has good construct validity.
DISCUSSION
In recent years, it has been increasingly recognized that in
chronic arthritis clinical trials, it is not only important to
know the magnitude of clinical improvement from baseline, but also to understand whether the observed change
leads to an acceptable state according to the physician
and/or the patient (12,27). Although the best condition is
obviously the absence of symptoms, that is, a state of
disease remission, this objective may prove difficult to
achieve for many patients. Therefore, alongside the concept of remission, the concept of an MDA state, perceived
as a more realistic goal of treatment, has recently emerged
(28). In adult patients with RA, MDA has been defined as
that state of disease activity deemed a useful target of
treatment by both the patient and the physician, given
current treatment possibilities and limitations (12). Recent
studies have shown that patient outcomes are improved if
RA activity is regularly assessed and if low levels of disease activity are aimed for by adjustments of therapy (29 –
31).
Because the state of MDA has not yet been characterized
in patients with JIA, we aimed to create such a definition
through the retrospective analysis of a large set of clinical
data. We reasoned that any index of disease activity
should reflect clinical practice, and therefore, we focused
on real decision points in patient management. We defined
as high the level of disease activity demonstrated at a
clinic visit where the physician decided to initiate or
change disease-specific treatment, and as minimal the
level at a visit where the physician did not change treatment policy or discontinued therapy because of disease
remission. The MDA definition then resulted from a discriminant function that optimally distinguished between
these 2 states.
Because JIA patients with oligoarticular or polyarticular
course have different severity potential, deserve diverse
Table 6. Measures of disease damage and health-related quality of life at last followup visits in 270 patients with juvenile
idiopathic arthritis who met or did not meet the definition of MDA*
Oligoarthritis (n ⴝ 106)
MDA
(n ⴝ 39)
No MDA
(n ⴝ 67)
Polyarthritis (n ⴝ 164)
P
MDA
(n ⴝ 60)
No MDA
(n ⴝ 104)
P
Age at onset, years
2.7 (1.8, 3.8)
3.0 (1.9, 5.3)
0.35
2.9 (1.8, 5.9)
3.0 (1.7, 5.9)
0.83
Disease duration, years
6.4 (5.2, 9.7)
7.2 (5.7, 10.4)
0.14
6.7 (5.5, 8.6)
6.4 (5.5, 8.9)
0.96
No. joints with restricted motion
0 (0, 0)
1.0 (0.0, 1.0) ⬍ 0.0001
0.0 (0.0, 1.5)
4.0 (1.0, 9.0)
⬍ 0.0001
C-HAQ score†
0 (0, 0)
0 (0, 0.25)
0.0008
0 (0, 0.25)
0.38 (0, 0.75)
⬍ 0.0001
Steinbrocker class II–III, no. (%)‡
1 (2.6)
9 (13.4)
0.09
4 (6.7)
50 (48.1)
⬍ 0.0001
JADI articular score
0 (0, 0)
0 (0, 0)
0.29
0 (0, 0)
1.0 (0, 3.0)
⬍ 0.0001
JADI extraarticular score
0 (0, 0)
0 (0, 0.5)
0.13
0 (0, 0)
0 (0, 1.0)
0.0004
Poznanski score, units (n ⫽ 116)§
⫺0.58 (⫺1.29, 0.38) ⫺1.18 (⫺3.12, 0.03) 0.05
CHQ physical summary score¶
54.1 (51.9, 57.5) 51.4 (44.8, 54.2) 0.007
53.4 (51.2, 55.6)
47.2 (38.2, 52.8) ⬍ 0.0001
CHQ psychosocial summary score¶ 46.9 (43.6, 53.8) 52.2 (43.9, 57.4) 0.06
54.2 (46.0, 59.0)
48.3 (42.7, 53.2)
0.007
* Values are the median (interquartile range) unless otherwise indicated. All patients had ⱖ5 years of disease duration. MDA ⫽ minimal disease
activity; C-HAQ ⫽ Childhood Health Assessment Questionnaire; JADI ⫽ Juvenile Arthritis Damage Index; CHQ ⫽ Child Health Questionnaire.
† Range 0 (best) to 3 (worst).
‡ No patient was in Steinbrocker class IV.
§ Abnormal score less than ⫺2.0.
¶ Mean ⫾ SD norm-based score (for both physical and psychosocial scores) 50 ⫾ 10, where a higher score means better quality of life.
1126
treatment strategies, and are usually included in distinct
clinical trials, we believed the 2 subgroups required a
separate definition of MDA. As expected, the cutoff levels
of disease activity variables that best identified MDA states
in AUC-ROC analysis were, in general, lower for oligoarthritis than for polyarthritis. The definition of MDA that
emerged from the multivariate analysis was based on 2
variables (physician global assessment and swollen joint
count) for oligoarthritis and on 3 variables (physician
global assessment, parent global assessment, and swollen
joint count) for polyarthritis. Notably, the physician global
assessment appears to be quite dominant, particularly for
polyarticular disease. This adds to the previous demonstration of the good psychometric properties of this measure in patients with JIA (21,32,33). The inclusion of the
parent’s global rating in the definition of MDA for polyarthritis, which is the most severe subset of JIA, ensures that
it incorporates the parent’s perception of the impact of
disease activity on the child. The fact that the swollen joint
count was the only articular index that entered the bestfitting model of multivariate analyses is consistent with
the notion that it represents the purest indicator of joint
synovitis (34). As expected, neither the functional ability
assessment nor the restricted joint count, which largely
incorporate the level of disease damage (34), proved useful
in discriminating between disease activity states. None of
the laboratory parameters of systemic inflammation entered the best fit model of multivariate analyses. This
offers the advantage of avoiding misclassification due to
extraneously elevated acute phase proteins.
The definition of MDA revealed good discriminant and
construct validity. As expected, none of the patients included in 2 controlled clinical trials in oligoarticular and
polyarticular JIA met the criteria for MDA at the time of
enrollment, when all patients should have, by definition, a
high level of disease activity. Also as expected, the frequency of patients meeting the MDA definition at 6 or 3
months after baseline was significantly greater in the
groups who experienced the greatest level of improvement
(i.e., an ACR Pedi 70 response) in both trials. In a group of
JIA patients with oligoarthritis who underwent an IAC
injection, the frequency of MDA was significantly greater
among patients who were judged as improved by the physician or parent at 6 months after the procedure. In a crosssectional data set, we determined that patients with longstanding oligoarthritis or polyarthritis who were in a state of
MDA at the last followup visit had better outcomes in terms
of functional disability, damage, and HRQOL than patients
who had not achieved such a state. This finding suggests that
entering a state of MDA during the disease course is associated with a more favorable long-term outcome.
Some limitations to this study need mentioning. Our
analysis was retrospective, which means that it was subject to missing and possibly erroneous data, and was based
on visits made by only 2 pediatric rheumatologists. We
used an observation-based statistical approach, in which
MDA was inferred from a proxy variable (e.g., clinician’s
decisions to reduce/not to increase drug treatment) depending on analysis of clinical visit data on patients with
JIA. A consensus definition or a judgmental approach (that
is, explicitly asking physicians and/or parents their opin-
Magni-Manzoni et al
ion on what they would consider a useful target in daily
practice) could have led to a definition with high face
validity and relevance in practice. However, the retrospective design of the study allowed us to describe the real
process of decision making in practice because the physicians were unaware that their decisions were part of an
investigation. We did not ask for parent opinion, which
would be important to establish whether the MDA definition is meaningful to patients and their families.
Additional measures potentially useful to define MDA,
such as HRQOL assessment, could not be evaluated. However, HRQOL was thought to be a different dimension of
the burden of disease that was relevant to treatment, but
only loosely bound to the concept of disease activity. We
could not consider the time dimension that makes the
definition of MDA most useful, for example, the duration
of time spent in the state; however, this aspect is complex
and requires longitudinal studies that record disease activity repeatedly and in sufficient detail. The definition of
the time component will be addressed at a later stage. We
considered MDA as a state, which is deemed a useful
target of treatment by the physician, given current treatment possibilities and limitations. However, few visits
involved biologics, which means that the definition may
change in the biologic era. Like any definition, it should be
regularly updated as treatment options and knowledge
about them evolves. These limitations do not decrease the
usefulness of the definition itself, which represents an
absolute measure of treatment efficacy that can be used to
set stricter treatment targets. Another potential limitation
of our analysis is that clinical perceptions and treatment
choices vary between physicians from different regions
and according to their particular expertise. Nevertheless,
physicians who made therapeutic decisions in our study
came from tertiary care pediatric rheumatology centers
and likely incorporated new treatment strategies and treatment aspects.
In conclusion, we developed a preliminary definition of
MDA in children with oligoarticular and polyarticular JIA,
which was found to possess good discriminant and construct validity. This definition identifies an intermediate
state between active disease and remission that represents
a useful treatment target state for both physicians and
patients/parents, and is proposed for inclusion as an outcome measure in future observational studies and clinical
trials in patients with JIA. The proportion of patients
achieving a satisfactory state of MDA is likely to become
an important measure with which to compare different
treatment strategies and provides a benchmark for comparison with future cohorts.
ACKNOWLEDGMENT
The authors thank Boehringer Ingelheim Pharma KG, Biberach, Germany, for providing access to the data of the
meloxicam trial.
AUTHOR CONTRIBUTIONS
Dr. Ravelli 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.
Minimal Disease Activity in Patients With JIA
Study design. Magni-Manzoni, Ruperto, Martini, Ravelli.
Acquisition of data. Magni-Manzoni, Sala, Solari, Palmisani,
Cugno, Bozzola.
Analysis and interpretation of data. Magni-Manzoni, Ruperto,
Ravelli.
Manuscript preparation. Ruperto, Martini, Ravelli.
Statistical analysis. Pistorio.
1127
18.
REFERENCES
1. Petty RE, Southwood TR, Manners P, Baum J, Glass DN,
Goldenberg J, et al, and the International League of Associations for Rheumatology. International League of Associations
for Rheumatology classification of juvenile idiopathic
arthritis: second revision, Edmonton 2001. J Rheumatol 2004;
31:390 –2.
2. Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet
2007;369:767–78.
3. Hashkes PJ, Laxer RM. Medical treatment of juvenile idiopathic arthritis. JAMA 2005;294:1671– 84.
4. Wallace CA. Current management of juvenile idiopathic arthritis. Best Pract Res Clin Rheumatol 2006;20:279 –300.
5. Wallace CA, Ruperto N, Giannini E, the Childhood Arthritis
and Rheumatology Research Alliance, the Pediatric Rheumatology International Trials Organization, and the Pediatric
Rheumatology Collaborative Study Group. Preliminary criteria for clinical remission for select categories of juvenile idiopathic arthritis. J Rheumatol 2004;31:2290 – 4.
6. Wallace CA, Huang B, Bandeira M, Ravelli A, Giannini EH.
Patterns of clinical remission in select categories of juvenile
idiopathic arthritis. Arthritis Rheum 2005;52:3554 – 62.
7. Ravelli A, Martini A. Remission in juvenile idiopathic arthritis. Clin Exp Rheumatol 2006;24(6 Suppl 43):S105–10.
8. Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D,
Goldsmith C, et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis.
Arthritis Rheum 1995;38:727–35.
9. Pincus T, Sokka T, Kavanaugh A. Relative versus absolute
goals of therapies for RA: ACR 20 or ACR 50 responses versus
target values for “near remission” of DAS or single measures.
Clin Exp Rheumatol 2004;22(5 Suppl 35):S50 – 6.
10. Wells GA, Boers M, Shea B, Brooks PM, Simon LS, Strand CV,
et al. Minimal disease activity for rheumatoid arthritis: a
preliminary definition. J Rheumatol 2005;32:2016 –24.
11. O’Dell JR. The horseless carriage: moving forward with the
hybrid ACR [editorial]. Arthritis Rheum 2007;57:189 –90.
12. Wells G, Boers M, Shea B, Anderson J, Felson D, Johnson K, et
al. MCID/Low Disease Activity State Workshop: low disease
activity state in rheumatoid arthritis. J Rheumatol 2003;30:
1110 –1.
13. Ravelli A, Viola S, Ruperto N, Corsi B, Ballardini G, Martini
A. Correlation between conventional disease activity measures in juvenile chronic arthritis. Ann Rheum Dis 1997;56:
197–200.
14. Ruperto N, Ravelli A, Pistorio A, Malattia C, Viola S, Cavuto
S, et al, and the Paediatric Rheumatology International Trials
Organisation. The Italian version of the Childhood Health
Assessment Questionnaire (CHAQ) and the Child Health
Questionnaire (CHQ). Clin Exp Rheumatol 2001;19(4 Suppl
23):S91–5.
15. Ravelli A, Viola S, Ramenghi B, Di Fuccia G, Ruperto N, Zonta
L, et al. Evaluation of response to methotrexate by a functional index in juvenile chronic arthritis. Clin Rheumatol
1995;14:322– 6.
16. Howe S, Levinson J, Shear E, Hartner S, McGirr G, Schulte M,
et al. Development of a disability measurement tool for juvenile rheumatoid arthritis: the Juvenile Arthritis Functional
Assessment Report for children and their parents. Arthritis
Rheum 1991;34:873– 80.
17. Ruperto N, Murray KJ, Gerloni V, Wulffraat N, de Oliveira SK,
Falcini F, et al, for the Pediatric Rheumatology International
Trials Organization. A randomized trial of parenteral metho-
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
trexate comparing an intermediate dose with a higher dose in
children with juvenile idiopathic arthritis who failed to respond to standard doses of methotrexate. Arthritis Rheum
2004;50:2191–201.
Ruperto N, Nikishina I, Pachanov ED, Shachbazian Y, Prieur
AM, Mouy R, et al, for the Pediatric Rheumatology International Trials Organization (PRINTO). A randomized, doubleblind clinical trial of two doses of meloxicam compared with
naproxen in children with juvenile idiopathic arthritis: shortand long-term efficacy and safety results. Arthritis Rheum
2005;52:563–72.
Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT,
Martini A. Preliminary definition of improvement in juvenile
arthritis. Arthritis Rheum 1997;40:1202–9.
Moretti C, Viola S, Pistorio A, Magni-Manzoni S, Ruperto N,
Martini A, et al. Relative responsiveness of condition specific
and generic health status measures in juvenile idiopathic
arthritis. Ann Rheum Dis 2005;64:257– 61.
Steinbrocker O, Traeger CH, Batterman RC. Therapeutic criteria in rheumatoid arthritis. J Am Med Assoc 1949;140:659 –
62.
Viola S, Felici E, Magni-Manzoni S, Pistorio A, Buoncompagni A, Ruperto N, et al. Development and validation of a
clinical index for assessment of long-term damage in juvenile
idiopathic arthritis. Arthritis Rheum 2005;52:2092–102.
Poznanski AK, Hernandez RJ, Guire KE, Bereza UL, Garn SM.
Carpal length in children: a useful measurement in the diagnosis of rheumatoid arthritis and some congenital malformation syndromes. Radiology 1978;129:661– 8.
Magni-Manzoni S, Rossi F, Pistorio A, Temporini F, Viola S,
Beluffi G, et al. Prognostic factors for radiographic progression, radiographic damage, and disability in juvenile idiopathic arthritis. Arthritis Rheum 2003;48:3509 –17.
Sztajnbok F, Coronel-Martinez DL, Diaz-Maldonado A, Novarini C, Pistorio A, Viola S, et al. Discordance between physician’s and parent’s global assessments in juvenile idiopathic
arthritis. Rheumatology (Oxford) 2007;46:141–5.
Consolaro A, Vitale R, Pistorio A, Lattanzi B, Ruperto N,
Malattia C, et al. Physician’s and parent’s ratings of inactive
disease are frequently discordant in juvenile idiopathic arthritis. J Rheumatol 2007;34:1773– 6.
Tubach F, Wells GA, Ravaud P, Dougados M. Minimal clinically important difference, low disease activity state, and
patient acceptable symptom state: methodological issues.
J Rheumatol 2005;32:2025–9.
Dougados M. It’s good to feel better but it’s better to feel good
[editorial]. J Rheumatol 2005;32:1–2.
Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF,
van Zeben D, Kerstens PJ, Hazes JM, et al. Comparison of
treatment strategies in early rheumatoid arthritis: a randomized trial. Ann Intern Med 2007;146:406 –15.
Grigor C, Capell H, Stirling A, McMahon AD, Lock P, Vallance
R, et al. Effect of a treatment strategy of tight control for
rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet 2004;364:263–9.
Smolen JS, Sokka T, Pincus T, Breedveld FC. A proposed
treatment algorithm for rheumatoid arthritis: aggressive therapy, methotrexate, and quantitative measures. Clin Exp Rheumatol 2003;21(5 Suppl 31):S209 –10.
Ruperto N, Ravelli A, Falcini F, Lepore L, Buoncompagni A,
Gerloni V, et al, for the Italian Pediatric Rheumatology Study
Group. Responsiveness of outcome measures in juvenile
chronic arthritis. Rheumatology (Oxford) 1999;38:176 – 80.
Ruperto N, Ravelli A, Migliavacca D, Viola S, Pistorio A,
Duarte C, et al. Responsiveness of clinical measures in children with oligoarticular juvenile chronic arthritis. J Rheumatol 1999;26:1827–30.
Palmisani E, Solari N, Magni-Manzoni S, Pistorio A, Labo E,
Panigada S, et al. Correlation between juvenile idiopathic
arthritis activity and damage measures in early, advanced,
and longstanding disease. Arthritis Rheum 2006;55:843–9.
Документ
Категория
Без категории
Просмотров
1
Размер файла
91 Кб
Теги
development, idiopathic, patients, arthritis, activity, definitive, disease, juvenile, minimax, preliminary, validation
1/--страниц
Пожаловаться на содержимое документа