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The efficacy and safety of auranofin in the treatment of juvenile rheumatoid arthritis.

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979
THE EFFICACY AND SAFETY OF AURANOFIN
IN THE TREATMENT OF
JUVENILE RHEUMATOID ARTHRITIS
A Long-Term Open Study
ROBERTO MARCOLONGO, ALESSANDRO MATHIEU, RICCARDA PALA, NICOLA GIORDANO,
ANTONELLA FIORAVANTI, and RITA PANZARASA
The safety and efficacy of auranofin in the longterm treatment of children with juvenile rheumatoid
arthritis was investigated in an open study of 14 patients. Twelve patients completed at least 12 months of
treatment, and 7 patients completed 36 months of
treatment. Classic parameters of disease activity showed
improvement over baseline values after 6 months of
treatment, and laboratory indices remained stable or
improved throughout the study. Auranofin was well
tolerated; the frequency of adverse effects was lower in
these patients than has been previously reported in
either adults or children whose arthritis has been
treated with injectable gold.
Monarthritis or polyarthritis with onset before
the age of 16 has many of the characteristics of rheumatoid arthritis (RA) that occurs in adults; the condition is usually differentiated from adult RA and has
been designated juvenile rheumatoid arthritis (JRA).
Standard therapy for JRA initially consists of aspirin or
From the Institute of Rheumatology, University of Siena,
Siena, the Chair of Medical Therapy and the First Chair of Clinical
Medicine, University of Cagliari, Cagliari, and the Medical Department, Smith Kline & French, Milano, Italy.
Roberto Marcolongo, MD: Full Professor of Rheumatology, Institute of Rheumatology, University of Siena; Alessandro
Mathieu, MD: Associate Professor of Medical Therapy, Chair of
Medical Therapy, University of Cagliari; Riccarda Pala, MD: Assistant Professor of Clinical Medicine, First Chair of Clinical Medicine, University of Cagliari; Nicola Giordano, MD: Assistant
Professor of Rheumatology, Institute of Rheumatology, University
of Siena; Antonella Fioravanti, MD: Assistant Professor of Rheumatology, Institute of Rheumatology, University of Siena; Rita
Panzarasa, BSc: Medical Department, Smith Kline & French.
Address reprint requests to Roberto Marcolongo, MD,
Institute of Rheumatology, Via Tufi 1, Siena 53100, Italy.
Submitted for publication August 29, 1986; accepted in
revised form March 1, 1988.
Arthritis and Rheumatism, Vol. 31, No. 8 (August 1988)
other nonsteroidal antiinflammatory drugs (NSAIDs)
and is often accompanied by corticosteroid therapy.
Intramuscular administration of gold is often used to
replace treatment with steroids and NSAIDs, and its
use as a first-choice remission-inducing drug is increasing. The adverse reactions to intramuscular gold administration in children with JRA are similar to those
reported in adults, i.e., rash, headache, anemia, nitritoid reaction, as well as the nephrotic syndrome (1,2).
Auranofin (Ridaura; Smith Kline & French,
Milan, Italy) is a new gold preparation that can be
taken orally for the treatment of RA. The efficacy of
this preparation is similar to that of gold that is
administered intramuscularly, but the frequency of
serious side effects is lower (3).
Preliminary studies reported previously ( 4 3
have shown encouraging results of short-term therapy
with auranofin in JRA patients. The purpose of the
current study was to investigate the efficacy and safety
of auranofin in a long-term trial in children with JRA.
PATIENTS AND METHODS
Patient population. Fourteen patients (7 males and 7
females) whose age range was 4.9-18.7 years (median age
13.3 years) and whose disease duration ranged from 6
months to 8 years (median duration 1 year) entered the trial.
Five patients exhibited monarticular disease, 3 had pauciarticular manifestations, and 6 had the polyarticular form. JRA
was diagnosed according to the American Rheumatism Association criteria (6).
Included in the study were patients who 1) had a
clinical history of JRA or Still’s disease and presented with
active disease that was not adequately controlled with
NSAID treatment alone; 2) were currently taking steroids at
dosages of not more than 6 mgiday and had not been given
MARCOLONGO ET AL
980
parenteral gold, D-penicillamine, or immunosuppressive
agents during the previous 3 months; and 3 ) had no severe
cardiac, hepatic, pulmonary, or renal disease.
At the start of the study, all patients were being
treated with aspirin or other NSAIDs. One patient was also
receiving corticosteroids, and corticosteroids were added to
the regimen of 2 of the patients after the start of the trial. The
dosages of these drugs during auranofin treatment are given
in Table 1.
Clinical and laboratory assessments. A clinical assessment was performed prior to entry into the trial. Included
was a complete medical history, a medication history, a
clinical and rheumatologic examination, and laboratory tests
of blood and urine samples. These studies were repeated
every 15 days for the first 2 months of auranofin therapy,
monthly for the next 10 months, and every 3 months
thereafter.
The rheumatologic assessments included a standardized evaluation of morning stiffness, pain, time to onset of
fatigue, number of swollen and tender joints, the Ritchie
articular index, functional class according to the Steinbrocker criteria (7), and the physician’s assessment of disease activity (expressed as a score of 0-3, where 0 =
absence of clinical manifestation, I = mild, 2 = moderate,
and 3 = severe).
Laboratory analyses included a complete blood cell
count, Westergren erythrocyte sedimentation rate (ESR),
immunoglobulin levels, and the following liver and renal
function tests: aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin, creatinine, and
blood urea nitrogen (BUN). A complete urinalysis to detect
glucose, protein loss, and microscopic sediment was also
performed at each visit. Moreover, we evaluated plasma
levels of gold, using an atomic absorption spectrophotometric method (8), once a month for the first 2 months of
therapy and then every 3 months for 2 years.
Standard radiographs of affected joints were taken at
the beginning of the trial and every 12 months thereafter.
Study design. The study was designed as an open trial
of a minimum of 12 months of therapy. No control subjects
Table 1. Concomitant antiinflammatory therapy in patients with juvenile rheumatoid arthritis
taking auranofin*
Months of auranofin therapy
Patient, medication
Patient I
Aspirin
Patient 2
Aspirin
Patient 3
Aspirin
Patient 4
Aspirin
Patient 5
Aspirin
Patient 6
Aspirin
Patient 7
Aspirin
Patient 8
Methylprednisolone
Flurbiprofen
Patient 9
Prednisone
Flurbiprofen
Aspirin
Patient 10
Flurbiprofen
Patient 1 1
Aspirin
Patient 12
Pyrazinobutazone
Patient 13
Aspirin
Diclofenac
Patient 14
Ketaprofen
Pyrazinobutazone
Prednisone
Total no. of patients
receiving auranofin
0
6
12
18
24
30
36
42
48
1.5
1.5
1.o
0.5
0
0
0
0
0
2.0
2.0
2.0
2.0
2.0
0
0
0
0
2.0
2.0
2.0
2.0
1.5
1.o
0
1.5
1.5
I .5
1.5
1.5
0
0
3.0
2.0
2.0
1.5
1.5
1.5
I .o
3 .O
I .5
I .5
0.5
0
0
0
0
300
0
300
2
300
2
300
0.5
300
0
300
0
300
0
300
0
4
400
0
2
400
0
2
400
0
2
0
2.0
300
300
300
1.5
2
2
1.o
100
7
7
2
2
2.0
1,200
600
1 .o
0
1.o
0
I .o
50
1 .O
100
80
0
5
80
150
0
80
300
0
80
300
0
14
13
12
10
9
* Values are dosages, in mgiday, except for aspirin, which is in gmiday.
AURANOFIN IN JRA
were used. The study was conducted under the provisions of
the declarations of Helsinki and Tokyo, with the amendments of Venice 1983. Informed consent was obtained from
the patients or their parents.
Patients began auranofin therapy at a dosage of 0.1
mg/kg/day.If no evidence of clinical improvement was noted
after 4 months of therapy, the daily dosage was increased by
1 mg. The total daily dose did not exceed 6 mg.
Statistical analysis. Statistical analysis was performed
at 6-month intervals for up to 36 months of therapy. A
nonparametric test (Wilcoxon’s signed rank test) was used
because of the small sample size and the likelihood that the
data were not normally distributed. In all instances, 2-tailed
comparisons were made. Data obtained for each 6-month
period were compared with those obtained for the previous
6-month period (6 months versus 0 months, or baseline, and
12 months versus 6 months, etc.). No further statistical
evaluation was performed for the 2 patients who continued
auranofin therapy beyond 36 months.
RESULTS
Of the 14 patients who initially enrolled in the
study, 2 failed to complete 12 months of therapy: One
was lost to followup after 3 months of therapy, and
another withdrew after 8 months (JRA was in remission). One patient withdrew at 18 months because of
inadequate response. Seven patients completed 36
months of therapy, and 2 patients continued therapy
for 48 months.
The dosage of auranofin was increased in 2
patients because of increased body weight, and it was
increased in a third patient after I23 weeks of therapy
(2Vz years) in order to maintain good results. The
dosage was decreased from 6 mg/day to 4.5 mg/day in
1 patient because the disease went into remission.
Efficacy parameters. The clinical parameters of
pain, time to onset of fatigue, Ritchie articular index,
and physician’s assessment of disease activity showed
statistically significant improvement between baseline
(0 months) and 6 months and between 6 months and 12
months. There was no statistically significant difference in morning stiffness between the sixth month and
the twelfth month of therapy, although there had been
a statistically significant difference (improvement) between 0 months and 6 months (Table 2 and Figure 1).
Time to onset of fatigue and pain scores showed
further improvement between 12 months and 18
months of therapy, and this difference was statistically
significant. All clinical parameters reached a plateau in
improvement around the twelfth month, and were
statistically significant compared with baseline values
throughout therapy (Figure 1).
The ESR decreased over time, but the differences were statistically significant only between 6
98 1
Table 2. Statistical significance of the changes in clinical and
laboratory parameters studied in patients with juvenile rheumatoid
arthritis taking auranofin*
Months of auranofin therapy
Parameter
Ritchie articular
index
Morning stiffness
Pain score
Time to onset of
fatigue
Disease assessment
Erythrocyte
sedimentation rate
6
12
30
36
-
18
24
NS
NS
NS
NS
NS
NS
NS
NS
NS
<0.01
<0.05
CO.01
<0.05
NS
NS
NS
<0.005
<0.05
<0.005
<0.01
<0.05
<0.02
NS
NS
NS
NS
NS
NS
NS
NS
CO.01
NS
NS
NS
NS
<0.05
* Comparisons are between 2 consecutive 6-month periods (beginning at baseline versus 6 months), by Wilcoxon’s rank sum test. NS
= not significant.
months and 12 months. However, all ESR values from
12 months to 36 months were statistically significantly
different from those at baseline, and the significance of
the difference continued to increase throughout therapy (P < 0.0001, 36 months versus baseline).
Serum gold levels achieved during auranofin
therapy are shown in Figure 2. These levels reached a
plateau of approximately 500 ng/ml after 6 months of
therapy.
In 6 patients, radiographs of affected joints
were taken every year. Four of these patients showed
radiographic evidence of improvement after 1 year of
therapy (specifically, the hips and knees in 2 patients,
the knees in 1 patient, and the wrists and elbows in 1
patient). In one patient, hip joint improvement was
radiographically evident only after 2 years of therapy.
In the sixth patient, the radiographic patterns (wrists
and hands) did not change from those seen at baseline.
Safety parameters. White blood cell counts did
not change significantly at any time during treatment.
Red blood cell counts, however, appeared to be significantly increased after 36 months of therapy, and
hemoglobin values showed a statistically significant
increase after 12 months of treatment.
Liver function test results did not show significant change from the baseline values. Renal function
test results (serum creatinine and BUN) and results of
urinalysis were essentially unchanged over the study
period. Immunoglobulin levels remained unchanged,
except for IgA, which showed a statistically significant
decrease after 6 months of therapy.
Adverse effects. Adverse effects serious enough
to warrant either a decrease in dosage or discontinuation of therapy occurred in 1 patient, whose gold
therapy was discontinued after 32 months because of
MARCOLONGO ET AL
982
*
o
HOURS
SCORES MINUTES
b
13
58
40
30
20
12
-
11
-
10
-
9
-
8
-
7
-
6
-
5 -
/I
:v
4
10
0 ~ ~ " " ~ " ' " ~ " ' " " ~ " ~ " " " ' ' ' " " ' ' ' ~ ' ~ '
0
6
12
18
24
30
36
41
0
6
0
I8
12
36
30
74
48
42
t
mm 1st HOUR
SCORES
0
48
MONTHS
MONTHS
6
I?
I8
24
30
36
42
d
d8
MONTHS
MONTHS
Figure 1. Mean values of selected parameters, from baseline to 48 months of therapy, in juvenile rheumatoid arthritis patients taking
auranofin. a, Morning stiffness (0)and physician's assessment of disease activity (U). b, Time to onset of fatigue. c, Ritchie articular
index (0)and pain score (m). d, Erythrocyte sedimentation rate.
diarrhea and itching. Two other patients withdrew
from the study, I because of disease remission (after 8
months of therapy) and the other because of lack of
efficacy (after 18 months of therapy).
DISCUSSION
The efficacy of a 6-12-month treatment with
auranofin for JRA has been demonstrated previously
(43).However, the safety and efficacy of short-term
therapy, as well as that of prolonged therapy, must be
considered in the management of JRA. The results
presented here are from baseline to 36 months of
treatment with auranofin.
One of the factors that can modulate the response to conventional therapy in adults with RA is
the duration of disease when treatment is begun. The
initiation of gold therapy early in the disease has often
been associated with a good clinical outcome. The
disease duration in our patients was generally short,
although some patients entered the trial having had
active JRA for more than 5 years.
900
608
700
600
500
400
300
I
-
/-*-*
~
~
/*-•
-
:lil
100
I
I
1
1
I
1
1
I
1
1
1
1
1
1
months
Figure 2. Mean serum gold levels in 3 patients with juvenile
rheumatoid arthritis (patients 12, 13, and 14 in Table 1) who were
taking the maximum dosage of 6 mgiday.
AURANOFIN IN JRA
All patients in this study had taken antiinflammatory drugs prior to starting auranofin treatment; in the
course of auranofin treatment, the dose of the NSAIDs
and corticosteroids was reduced in 7 of the 14 patients.
In 2 patients, however, it was necessary to increase the
dose of NSAlDs during the first 6 months of therapy.
The efficacy of auranofin became evident generally by the sixth month of treatment. By this time, or
soon after, changes in clinical and laboratory indices of
disease activity showed a statistically significant improvement over the values found at baseline. In addition to the classic parameters of disease activity, relevant laboratory indices, such as the hemoglobin level
and the platelet count, remained stable or improved
throughout the long-term therapy with auranofin.
The type of adverse reaction to auranofin treatment in this study was similar to those reported for
adult patients treated with this preparation (9,lO).
One patient withdrew from the study because of
an unusual, persistent adverse reaction at 32 months
(diarrhea and itching). The timing of this side effect is
unusual. Auranofin-induced diarrhea most commonly
develops within the first 3 months of treatment; however, it may appear at any time during therapy (1 l ) .
The frequency of treatment withdrawals because of
adverse effects is similar to the 8% rate reported by
Brewer et al (2), who used injectable gold in their
study; however, their patient withdrew before completing 6 months of therapy because of severe drug
reactions, including fever, nephrotic syndrome, anemia, hematuria, and psychological disturbances. Our
patient’s side effects were minor compared with those
described by Brewer et al, and were more consistent
with those reported by Kvien et al (3,based on their
short-term trials.
Seven of I3 patients (54%) experienced at least
50% improvement over baseline after 12 months of
therapy, according to clinical and biochemical parameters. Nine of the 13 patients (69%) showed clinical
improvement of at least 30% over baseline values after
12 months of treatment. One patient experienced clinical
remission (12), which occurred after 7 months of therapy; to date, there has been no relapse of the disease.
The time to clinical response correlated with
attainment of the blood gold level plateau (500 nglml),
which was reached at the sixth month of therapy.
However, as observed in adult patients with RA, the
extent of the response was independent of the serum
gold levels (13).
In conclusion, auranofin is effective in the longterm treatment of children with JRA, and the results
are comparable with those obtained with this same
983
treatment in adults with RA. The adverse effects in
this 3-year long-term study were less frequent and less
severe than those reported in adults and children
treated for 6 months with injectable gold.
REFERENCES
1. Brewer EJ Jr, Giannini EH, Barkeley E: Gold therapy in
2.
3.
4.
5.
the management of juvenile rheumatoid arthritis. Arthritis Rheum 23:404-411, 1980
Brewer EJ, Giannini EH, Person DA: Juvenile rheumatoid arthritis. Second edition. Philadelphia, WB Saunders, 1982
Ward JR, Williams HJ, Egger MJ, Reading JC, Boyce E,
Altz-Smith M, Samuelson CO Jr, Willkens RF, Solsky
MA, Hayes SP, Blocka KL, Weinstein A, Meenan RF,
Guttadauria M, Kaplan SB, Klippel J: Comparison of
auranofin, gold sodium thiomalate, and placebo in the
treatment of rheumatoid arthritis: a controlled clinical
trial. Arthritis Rheum 26:1303-1315, 1983
Brewer EJ, Giannini EH, Person DA: Early experiences
with auranofin in juvenile rheumatoid arthritis. Am J
Med 30: 152-156, 1983
Kvien TK, Hoyeraal HM, Sandstadt B, Kass E: Oral
gold (auranofin) in juvenile rheumatoid arthritis: a 48
week phase 2 study (letter). CIin Rheumatol 3 5 5 1-552,
1984
6. Brewer EJ Jr, Bass J, Baum J, Cassidy JT, Fink C,
Jacobs J, Hanson V , Levinson JE, Schaller J, Stillman
JS: Current proposed revision of JRA criteria. Arthritis
Rheum 20:195-199, 1977
7. Steinbrocker0, Traeger CH, Batterman RC: Therapeutic
criteria in rheumatoid arthritis. JAMA 140:659-662, 1949
8. Lorber A, Atkins CJ, Chang CC, Lee YB, Starrs J,
Bovy RA: Monitoring serum gold values to improve
chrysotherapy in rheumatoid arthritis. Ann Rheum Dis
32~133-137, 1973
9. Raeman F, Hanssens F, Delattre M: An European
multicentre trial with auranofin in rheumatoid arthritis.
Clin Rheumatol 3 (suppl):33-38, 1984
10. Heuer MA, Morris RW: Smith Kline & French worldwide clinical experience with auranofin: a review, Auranofin: Proceedings of a Smith Kline & French International Symposium. Edited by HA Capell, DS Cole, K K
Manghani, RW Morris, Amsterdam, Excerpta Medica,
1983
11. Heuer MA, Pietrusko RG, Morris RW, Scheffler BT: An
analysis of worldwide safety experience with auranofin.
J Rheumatol 12:695-699, 1985
12. Pinals RS, Masi AT, Larsen RA, Subcommittee for
Criteria of Remission in Rheumatoid Arthritis of the
American Rheumatism Diagnostic and Therapeutic Criteria Committee: Preliminary criteria for clinical remission in rheumatoid arthritis. Arthritis Rheum 24:13081315, 1981
13. Dahl SL, Coleman ML, Williams HJ, Altz-Smith M,
Kay DR, Paulus HE, Weinstein A, Kaplan S: Lack of
correlation between blood gold concentrations and clinical response in patients with definite or classic rheumatoid arthritis receiving auranofin or gold sodium thiomalate. Arthritis Rheum 28:1211-1218, 1985
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