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Temporal patterns of response to d-penicillamine hydroxychloroquine and placebo in juvenile rheumatoid arthritis patients.

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1252
TEMPORAL PATTERNS OF RESPONSE TO
D-PENICILLAMINE, HYDROXYCHLOROQUINE,
AND PLACEBO IN
JUVENILE RHEUMATOID ARTHRITIS PATIENTS
CATHERINE
VAN
KERCKHOVE, EDWARD H. GIANNINI, and DANIEL J. LOVELL
We calculated the time required for therapeutic
benefit to become apparent following initiation of treatment with D-penicillamine (DP), hydroxychloroquine
(HCQ), or placebo (each administered concomitantly
with a nonsteroidal antiinflammatory drug) using data
from a double-blind, randomized 12-month trial in 162
patients with juvenile rheumatoid arthritis. Using previously published criteria to classify the outcome, we
found that 60% of the HCQ group, 46% of the DP
group, and 39% of the placebo group responded favorably after 12 months of therapy. Data from examinations between the initial and final assessments were used
to determine when the response first occurred. Approximately 50% of all patients who showed improvement at
12 months had already done so by 2 months. After 6
months, 96% of the DP group, 88% of the HCQ group,
and 85% of the placebo group responders had met the
criteria for response. The average time until response
From the Children’s Hospital Medical Center, University
of Cincinnati, Cincinnati, Ohio, and the Department of Pediatrics,
Rheumatology Section, Baylor College of Medicine, Houston,
Texas.
Supported by NIH grant 1-AM-02211 and the Southern
Ohio Chapter of the Arthritis Foundation. Dr. Van Kerckhove is the
recipient of a research grant from the National Fund of Scientific
Research, Belgium.
Catherine van Kerckhove, MD: Fellow, Special Treatment
Center for Juvenile Arthritis, Children’s Hospital Medical Center,
and Junior Researcher, National Fund of Scientific Research, Belgium; Edward H. Giannini, DrPH: Assistant Professor, Department
of Pediatrics, Rheumatology Section, Baylor College of Medicine;
Daniel J. Lovell, MD, MPH: Assistant Professor, Special Treatment
Center for Juvenile Arthritis, Children’s Hospital Medical Center,
University of Cincinnati.
Address reprint requests to Daniel .I.Lovell, MD, MPH,
Children’s Hospital Medical Center, Elland and Bethesda Avenues,
Pavilion 1-29, Cincinnati, OH 45229.
Submitted for publication December 3 I , 1987; accepted in
revised form May 10, 1988.
Arthritis and Rheumatism, Vol. 31, No. 10 (October 1988)
was attained was 105 days for the DP group, 129 days
for the HCQ group, and 140 days for the placebo group.
Our results indicate that a favorable response to these
slow-acting antirheumatic drugs is unlikely if improvement has not occurred within the first 6 months of
therapy.
Juvenile rheumatoid arthritis (JRA) is the most
common cause of chronic inflammatory joint disease
in children. Its prevalence in the United States has
been estimated to be 0.5-1 .O per 1,000 children under
the age of 16 (1). Initial treatment usually consists of
nonsteroidal antiinflammatory drugs (NSAIDs) with
supportive physical therapy. In the absence of response to this regimen, approximately 25% of the
patients are treated with second-line drugs, such as
gold, D-penicillamine (DP), or hydroxychloroquine
(HCQ) (refs. 2 , 3, and Lovell DJ: unpublished observations).
Adult RA patients have shown statistically significant improvement in double-blind, placebocontrolled clinical trials using DP (4-6) and HCQ (7,8),
but only 2 double-blind, placebo-controlled studies of
DP in JRA patients have been reported, and those
produced conflicting results (9,lO). Direct comparison
of these studies is difficult, because the protocols used
were considerably different.
The only double-blind, placebo-controlled trial
of HCQ in JRA patients failed to demonstrate statistically significant clinical efficacy. This was due in part
to a surprisingly high degree of improvement in the
placebo group (10). Nevertheless, because of the limited number of remittive agents available and a general
reluctance to use cytotoxic drugs in children, physicians will continue to prescribe DP and HCQ for JRA
RESPONSE TO DP, HCQ, AND PLACEBO IN JRA
1253
Table 1. Clinical characteristics of juvenile rheumatoid arthritis patients overall and by treatment
group at entry into the study*
No.
No.
No.
No.
Hydroxychloroquine
(n = 57)
Clinical parameters
All patients
(n = 162)
D-penicillamine
(n = 54)
of swollen joints
of painful joints
of tender joints
of joints with limited
15.1 t 10.9
9.7 ? 11.4
8.8 2 12.1
13.9 t 12.8
15.5 t 11.8
10.1 ? 13.4
10.4 t 14.4
15.2 t 13.7
15.3
11.2
8.6
14.9
t 11.5
t 11.4
t 11.7
t 13.8
14.4 ? 9.2
7.4 2 8.4
7.2 2 9.4
11.5 t 10.3
17.6 2 12.4
64.7 ? 60.2
18.0 t 13.4
76.3 2 79.7
18.6 t 13.1
65.0 2 53.4
16.2 2 10.5
52.1 2 38.1
49.6 t 87.9
60.4 t 97.3
39.3 t 43.3
49.3
25.6 t 20.6
26.8 t 20.1
24.2 t 21.6
25.7 t 20.3
movement
Total no. of involved joints
Total sum of severity score
of joints
Duration of morning stiffness,
minutes
ESR, mm/hour
* Values are the mean
t 1 SD. ESR =
Placebo
(n = 51)
?
111.3
erythrocyte sedimentation rate.
patients. Little objective information is available about
the temporal patterns of response that these drugs may
induce. In adults, recommendations for the duration of
an adequate trial range from 3 months to 6 months for
both drugs ( 1 1-13). These recommendations are based
on efficacy trials, which rarely specifically address the
temporal response pattern. No objective information
concerning the time to achieve clinical response in
children is available, and recommendations for duration of treatment vary from 2 months to 3 years for
DP (14-16) and from 2 months to 12 months for HCQ
(16-18).
This study was designed to define the time
course and clinical response pattern in patients with
active JRA taking an NSAID and either DP, HCQ, or
placebo, and to determine the probability of an eventual response after various treatment intervals.
PATIENTS AND METHODS
Study design. Data generated during a double-blind,
randomized, placebo-controlled, multicenter, prospective,
12-month parallel clinical trial of DP and HCQ in 162 patients
were analyzed. The trial was conducted by the Pediatric
Rheumatology Collaborative Study Group in the United
States, in cooperation with pediatric rheumatology centers
in the Union of Soviet Socialist Republics (see Acknowledgments). Standardized case report forms and an identical
clinical protocol were used by all centers. Results of efficacy
and toxicity in the trial have been described previously (10).
Patient population. All patients entered into the study
had definite JRA as defined either by the revised criteria of
the American Rheumatism Association (19) or by criteria
used in the Soviet Union and Eastern Europe (20). One
hundred sixty-two patients (40 boys and 122 girls) entered
the study over a 2-year period. Eighty-one patients (50%)
had polyarticular onset, 65 (40%) had pauciarticular onset,
and 16 (10%) had systemic onset disease. The disease course
was polyarticular in 142 (88%), pauciarticular in 11 (7%), and
systemic in 9 (6%). All patients had severe, clinically active
disease at the time of enrollment, as demonstrated by an
average of 15 swollen joints, 10 painful joints, 14 joints with
limited motion, and a sum of severity score of 65 (Table 1).
At study entry, the mean age was 9.7 years, and the mean
disease duration was 3.2 years; the mean age at disease onset
was 6.5 years.
Patients who had taken antimalarial drugs within 6
months, injectable or oral gold or cytotoxic agents within 3
months, or corticosteroids within 1 month of randomization
were excluded. Patients who had taken DP prior to the study
were also excluded.
Medication. Fifty-four patients were started on a
regimen of DP at a dosage of 5 mg/kg/day, 57 patients took
HCQ 3 mg/kg/day, and 51 patients took placebo. If no side
effects occurred, the dosage was doubled after 2 months. At
study entry, there were no significant differences among
these 3 treatment groups in any of the demographic variables
or clinical disease characteristics (Table 1). In addition, all
patients took a single NSAID in a constant dosage for at
least 1 month before randomization and throughout the
duration of the trial. A change in NSAID was necessary in 9
patients who experienced adverse reactions attributable to
the initial NSAID during the trial.
Dropouts. One hundred twenty-three patients (76%)
completed the 12-month trial period; 39 patients (1 1 DP, 11
HCQ, and 17 placebo) discontinued therapy before the end
of the year (Table 2). Chi-square analysis did not show a
significant difference in the dropout rate between DP and
placebo ( P = 0.13) or between HCQ and placebo (P = 0.09).
The higher dropout rate in the placebo group was caused by
various reasons, but not by drug inefficacy.
Patient evaluation. All patients were examined by a
pediatric rheurnatologist at the time of randomization, and
then after 2, 4 , 6 , 9, and 12 months of followup. Clinical and
laboratory assessments of disease activity and drug safety
were made at each visit. Clinical indexes of articular inflammation assessed included swelling, pain on motion, tenderness (each score based on severity, from 0 to 3+), and
1254
VAN KERCKHOVE ET AL
Table 2. Number (%) of patients with juvenile rheumatoid
arthritis who showed 25% or 50% improvement after 12 months of
treatment with D-penicillamine (DP), hydroxychloroquine (HCQ),
or placebo
Outcome
25% improvement
Responders
Nonresponders*
Pt
50% improvement
Responders
Nonresponders*
Pt
Dropouts
All
patients
(n = 162)
(n
HCQ
(n = 57)
DP
= 54)
Placebo
= 51)
(n
79 (49)
44 (27)
-
25 (46)
18 (33)
0.46
34 (60)
12 (21)
0.03$.
20 (39)
14 (27)
-
36 (22)
87 (54)
39 (24)
12 (22)
31 (57)
0.39
11 (20)
16 (28)
30 (53)
0.12
11 (19)
8 (16)
26 (51)
17 (33)
* Nonresponders failed to reach the improvement level specified.
t Drug-treatment group versus placebo-treatment group.
$ Adjusted P = 0.06 (Bonferroni’s correction).
limitation of motion (from 0 = full motion to 4 + = no
motion). A sum of the severity scores and the total number
of involved joints was calculated for each patient.
Previously published criteria were used to classify
each patient as a “responder” or “nonresponder” (21,22).
The criteria considered 5 parameters of patient response,
including: (a) the total number of joints with active arthritis
(defined by the American Rheumatism Association JRA
criteria as either swelling or, if no swelling is present,
limitation of motion with tenderness or pain [19]); (b) the
total sum of severity score; (c) the duration of morning
stiffness; (d) the physician’s global assessment of the patient’s response; and (e) the parent’s global assessment of
the patient’s response.
For the numerically discrete outcome variables (a, b,
and c listed above), the percentage of change was calculated
by expressing the arithmetic difference between the scores at
the initial visit and the score at the followup visit as a
100
percentage of the initial value. The categorical variables (d
and e listed above) have as their possible outcomes: much
better, better, the same, worse, much worse. Thus, a change
in one category (e.g., same to better) represents a change of
25%; in 2 categories, 50%; and so on. Using this method,
based on his or her status at the final visit, each patient was
classified as either a responder (improvement 225% in at
least 3 of the 5 criteria), or a nonresponder (25% improvement in fewer than 3 of the criteria). Among those who
responded, each subject was further classified as either a
25% responder (as defined above) or a 50% responder (250%
improvement in at least 3 of the 5 criteria).
Patient responses were classified at each followup
visit to determine when a response first occurred and
whether it persisted. A patient who was found to have
responded at each of the final 3 visits, or who, over the year,
responded at a minimum of 4 of the 5 followup visits,
including the last visit, was defined as a “consistent responder. ”
Statistical methods. Data accuracy was ensured by
range checks, checks of the original forms against computer
data printouts, and when necessary, checks of outlying
information against original data on the patient report forms.
Data were presented and analyzed according to standards
that have been published previously (23).
When appropriate, Bonferroni’s correction was used
to adjust P values for multiple comparisons performed by
chi-square tests. The Shapiro and Wilk test (24) was used to
determine the normality of the data, before statistical tests
that required a Gaussian distribution were performed.
RESULTS
Drug efficacy. The cumulative response curves
for the 3 treatment groups at the 25% and 50% improvement levels are shown in Figure 1. As shown in
Table 2 , 79 patients (49%) were classified as 25%
responders at completion of the trial. These 79 patients
D-flHydroxychloroquine (25x1
*D-Penicillamine
(25-1
V - - V P l a c e b o (251)
75
Percentage of
Total Patients
Receiving Drug
W Hydroxychloroquine ( 5 0 x : )
H D-Pentcillamlne ( 5 0 ~ )
-Placebo
(50-1
50
25
0
0
2
4
6
9
Duration of Therapy (months)
12
Figure 1. Cumulative response curves of 162 juvenile rheumatoid arthritis patients at the 25% and
50% improvement levels, by drug treatment.
RESPONSE TO DP, HCQ, AND PLACEBO IN JRA
Table 3. Days needed to reach 25% or 50% improvement levels
in juvenile rheumatoid arthritis patients treated with Dpenicillamine (DP), hydroxychloroquine (HCQ), or placebo
Treatment group
(no. of patients)
25% improvement
DP (25)
H C Q (34)
Placebo (20)
50% improvement
DP (12)
H C Q (16)
Placebo (8)
No. of days
* SD
Median
Range
P*
105 2 57
129 2 86
140 106
*
70
112
113
56274
52-365
56-317
0.23
0.83
249 2 118
211 2 131
164 2 64
274
142
156
63-377
56443
59-246
0.10
0.83
Mean
-
-
* Drug-treatment group versus placebo-treatment group by 2-tailed
Wilcoxon rank sum test.
consisted of 25 (46%) of the DP patients, 34 (60%) of
the HCQ patients, and 20 (39%) of the placebo patients. There was no statistically significant difference
in the 25% response rate of HCQ versus placebo
(adjusted P = 0.06) or D P versus placebo ( P = 0.46).
Overall, 36 patients (22%) responded at the 50%
improvement level after a year. Twelve (22%) taking
DP, 16 (28%) taking HCQ, and 8 (16%) taking placebo
were in this responder group. The 50% response rates
were not statistically different for either drug versus
placebo (Table 2).
Using the aforementioned criteria, 17 (32%) of
the DP-, 22 (39%) of the HCQ-, and 11 (22%) of the
placebo-treated patients were consistent responders at
the 25% improvement level. Chi-square analysis revealed greater consistency in response to HCQ versus
placebo (adjusted P = 0.11) than to DP versus placebo
(adjusted P = 0.50). No difference was seen in the
consistency of response to HCQ versus DP ( P = 0.43).
Time to demonstrated response. The mean + SD
length of time needed for patients to reach the 25%
improvement level was 105 + 57 days (median 70) for
DP, 129 ? 86 days (median 112) for HCQ, and 140 t
106 days (median 113) for placebo (Table 3).
At the 50% improvement level, the mean 5 SD
duration to response was 249 118 days (median 274)
for DP, 21 1 t 131 days (median 142) for HCQ, and 164
? 64 days (median 156) for placebo (Table 3). No
statistically significant differences in mean response
times were observed between the treatment and the
control groups at either the 25% or the 50% improvement level. All 3 groups took longer to show 50%
clinical improvement than it took to show 25%. However, the difference in mean time to response between
the 25% and 50% improvement level for placebo was
*
1255
only 24 days, compared with 144 and 82 days for DP
and HCQ, respectively.
Temporal response pattern. The cumulative percentage of patients in the responder subset who responded at each followup visit was assessed to define
the temporal pattern of response to each drug.
Of the 25 patients taking DP who showed at
least 25% improvement at the 12-month visit, 56% had
done so by 2 months, 80% by 4 months, 96% by 6
months, and 100% by 9 months. Of the 34 HCQtreated patients, 47% responded by 2 months, 76% by
4 months, 88% by 6 months, and 94% by 9 months. For
the 20 placebo-treated patients, 45% responded at 2
months, 80% at 4 months, and 85% at 6 and 9 months.
Since the temporal response pattern was analyzed
using the responder subset only, 100% showed response at 12 months in each group (Figure 2).
The temporal response pattern at the 50% improvement level is shown in Figure 3. Of the 12
patients taking DP who improved at least 50% after 1
year, 8% had done so by 2 months, 25% by 4 months,
42% by 6 months, and 58% by 9 months. Twelve
percent of the 16 patients on a regimen of HCQ had
attained the 50% improvement level by 2 months, 56%
by 4 months, 62% by 6 months, and 75% by 9 months.
Of the 8 patients taking placebo, 12% showed 50%
response by 2 months, 63% by 4 months, 88% by 6
months, and 100% by 9 months.
Prediction of response to therapy. Next, the
probability of response to a drug after 12 months of
therapy was determined at each treatment interval,
taking into account the patient withdrawals. Fifteen
percent of the patients taking DP who had not improved 25% by 4 months, did so by the end of the year.
100
fi
70
2
4
6
9
12
Monlhr 01 liealnieilt
Figure 2. Temporal response patterns among a responder subset at
the 25% improvement level after taking D-penicillamine (B), hyor placebo (0)
for 2, 4, 6, 9, and 12 months.
droxychloroquine (a),
VAN KERCKHOVE ET AL
1256
'""1
88
a0
$
1
2o
0
63
1Li
2
4
6
9
12
Months of Treatment
Figure 3. Temporal response patterns among a responder subset at
the 50% improvement level after taking D-penicillarnine (M), hyfor 2, 4, 6, 9, and 12 months.
droxychloroquine (U), or placebo (0)
Only 4% of the patients who did not show response at
the 25% level by 6 months, did so by 12 months. Of
those patients taking HCQ who had not improved by 4
or 6 months, 29% and 17%, respectively, improved by
25% by the end of the year. Twelve percent of the
patients taking placebo who showed no improvement
at 4 months, showed improvement at the 25% level at
the end of the year; as did 1 1 % who had shown no
improvement at 6 months.
Similarly, the proportion of the patients who
responded at the 50% level at 12 months, who had not
done so at 6 months, was 15% for DP, 14% for HCQ,
and 3% for placebo (Table 4).
DISCUSSION
This study addresses the physician's dilemma
of whether to discontinue DP or HCQ treatment
because of lack of effect in a JRA patient who initially
fails to show improvement, or to continue therapy,
and risk adverse effects, in the hope of an ultimate
response. Our results indicate that 4 months of treatment with DP and 6 months of treatment with HCQ are
sufficient to allow a therapeutic response to take place.
If a 25% improvement level has not been attained by
that time, the chance of a dramatic change in the
patient's status is small, and the drug should be
discontinued. If there is a 25% improvement after
taking DP for 4 months, however, continuation of the
drug will lead to a 50% clinical improvement by the
end of the year in 40% of the patients. Of the patients
with a 25% response to HCQ after 6 months, 17% will
show a 50% improvement by the end of the year.
JRA is characterized by frequent remissions
and exacerbations. To differentiate the natural course
of the disease from the effects of drug treatment,
placebo-controlled trials are mandatory. In this study,
the response to placebo (approximately 40%) was
remarkably high. It generally occurred within the first
4 months and was very similar to the responses to DP
and HCQ; indeed, no significant difference in response
time was observed between the treatment and control
groups at the 25% or the 50% improvement levels.
There are several possible explanations for the
high response rate among the controls. The control
group was not untreated (all patients were kept on a
stable dose of NSAID). The long-term clinical effect of
NSAIDs in JRA has not been established, because
previously reported trials have usually lasted no longer
than 3 months (21). Unfortunately, we were unable to
determine the mean response time in patients taking
NSAIDs because our patients received NSAIDs for
widely varying periods of time before the initiation of
this study. Nonetheless, the high response rate in our
control population indicates that the long-term effects
of NSAIDs may be considerable. It may, therefore, be
prudent to continue JRA patients on a conservative
treatment program of NSAIDs and physical therapy
for longer than the currently accepted period of 4-6
months ( I l,l2,16,17). despite initial lack of improvement. Another factor that might have contributed to
the high response rate in the control group was the
possibly closer medical followup and more intensive
physical therapy as a result of being in the trial, and
volunteer bias, which often selects for more compliant
patients (22). In addition, JRA disease activity fluctuates, and patients tend to be admitted to a study when
their disease worsens. Therefore, there is a tendency
toward improvement. The high response rate in the
Table 4. Percentage of patients with juvenile rheumatoid arthritis
who demonstrated 25% or 50% improvement after 1 year if that
level of improvement was not reached after 2, 4, 6, or 9 months
of treatment with D-penicillamine (DP), hydroxychloroquine
(HCQ), or placebo
Drug
group
25% improvement
DP
HCQ
Placebo
50% improvement
DP
HCQ
Placebo
2
months
4
months
6
months
9
months
28
46
27
15
29
12
4
17
I1
0
12
15
21
26
14
18
16
7
15
14
3
13
11
0
RESPONSE TO DP, HCQ, AND PLACEBO IN JRA
control group might also b e entirely d u e t o the natural
true placebo
history of the disease, which-since
studies have never been done in JRA-is virtually
unknown.
Although placebo-controlled clinical trials are
essential, f e w individual clinics have sufficient numbers of J R A patients and staff to conduct them. T h e
Pediatric Rheumatology Collaborative Study G r o u p is
facilitating this task, however, and since its founding
in 1973, has conducted several double-blind drug trials
using standardized protocols of second-line drugs.
When adequate, sufficiently similar, controlled trial
d a t a become available, the efficacy of new drugs can
be established by comparing results with those of
historic controls. If future controlled trials of slowacting antirheumatic drugs in JRA patients confirm
this placebo response rate of approximately 40%, then
a n y n e w slow-acting remittive agent being considered
for use in a blinded, placebo-controlled study should
have produced significant clinical improvement in at
least 60% of the patients in open-label, noncontrolled
trials.
In conclusion, results from this study indicate
that a favorable response t o DP or HCQ in JRA
patients is unlikely if it d o e s not occur within the first
6 months of therapy. Furthermore, t h e similarity of
response c u r v e s for DP, HCQ, and placebo supports
t h e conclusion that in the presence of N S A I D , neither
DP nor HCQ offers significant therapeutic advantage
over placebo plus NSAID in the treatment of JRA.
MD: Department of Pediatrics, University of Rochester
School of Medicine and Dentistry, Rochester, NY; Bram
Bernstein, MD and Virgil Hanson, MD: Department of
Pediatrics, Children’s Hospital of Los Angeles, University
of Southern California, School of Medicine, Los Angeles;
Jerry C. Jacobs, MD: Department of Pediatrics, Columbia
University College of Physicians and Surgeons, New York,
NY; Lauren M. Pachman, MD and Kenneth C. Rich, MD:
Department of Pediatrics, Children’s Memorial Hospital,
Northwestern University School of Medicine, Chicago, IL;
Igor Vorontsov, MD: Department of Child Diseases, Leningrad Pediatric Institute, Leningrad, USSR; Jack C. Bass,
MD: Department of Pediatrics, Ohio State University
School of Medicine, Columbus; Helen Emery, MD: Rheumatology Department, LaRabida Children’s Hospital, Chicago, IL; Deborah Kredich, MD: Department of Pediatrics,
Duke University Medical Center, Durham, NC; Donald P.
Goldsmith, MD: Department of Pediatrics, Temple University School of Medicine, Philadelphia, PA; Ludmila Isayeva,
MD: Department of Child Diseases, First Moscow State
Medical Institute, Moscow, USSR; John J. Miller, 111, MD,
PhD and Niels Brandstrup, MD: Rheumatic Disease Division, Children’s Hospital at Stanford, Palo Alto, CA; and A.
Yakovleva, MD: Arthrological Clinic, Institute of Pediatrics,
Academy of Medical Sciences, Moscow, USSR.
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ACKNOWLEDGMENTS
The authors thank the members of the Pediatric
Rheumatology Collaborative Study Group for permission to
use the data of the multicenter trial, and Sharon Burns and
Carolyn Keith Haun for typing and preparation of the
manuscript. Computation assistance was provided by the
CLINFO Project, funded by the Division of Research Resources of the NIH under grant RR-00350.
The participating clinical investigators were Earl J.
Brewer, MD: Principal Investigator, Kelsey-Seybold Foundation, Houston, TX; Donald A. Person, MD: Department
of Pediatrics. Baylor College of Medicine, Texas Children’s
Hospital, Houston; Nina Kuzmina, MD and Lev Alekseev,
MD: Institute of Rheumatology, Academy of Medical Sciences, Moscow, USSR; D. Astrauskene, MD: Department
of Pediatrics, Scientific and Research Institute of Experimental and Clinical Medicine, Vilnius, Lithuania; Balu Arthreya, MD, Carolyn Yancey, MD, and Robert Doughty,
MD, PhD: Department of Pediatrics, Children’s Hospital of
Philadelphia, Philadelphia, PA; Chester W. Fink, MD: Department of Pediatrics, University of Texas Health Science
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patients, patterns, response, hydroxychloroquine, arthritis, juvenile, penicillamine, placebo, temporal, rheumatoid
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