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Safety and efficacy of an oral histone deacetylase inhibitor in systemic-onset juvenile idiopathic arthritis.

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ARTHRITIS & RHEUMATISM
Vol. 63, No. 5, May 2011, pp 1452–1458
DOI 10.1002/art.30238
© 2011, American College of Rheumatology
BRIEF REPORT
Safety and Efficacy of an Oral Histone Deacetylase Inhibitor in Systemic-Onset
Juvenile Idiopathic Arthritis
Jelena Vojinovic,1 Nemanja Damjanov,2 Carmine D’Urzo,3 Antonio Furlan,4 Gordana Susic,2 Srdjan Pasic,5
Nicola Iagaru,6 Mariana Stefan,7 and Charles A. Dinarello8
vomiting, and fatigue) were related to the study drug,
but each resolved spontaneously and no patient was
withdrawn from the study due to drug-related AEs. In
the per-protocol population at week 4, the improvement
as measured by the ACR Pedi 30, ACR Pedi 50, and
ACR Pedi 70, respectively, was 77.8%, 55.6%, and 22.2%,
and this increased further to 77.8%, 77.8%, and 66.7% at
week 12. The most consistent finding was the reduction
in the number of joints with active disease or with
limited range of motion.
Conclusion. After 12 weeks, givinostat exhibited
significant therapeutic benefit in patients with systemiconset JIA, particularly with regard to the arthritic
component of the disease, and showed an excellent
safety profile.
Objective. The current treatment options for
systemic-onset juvenile idiopathic arthritis (JIA) are
methotrexate, steroids, and biologic agents. This study
was undertaken to evaluate the safety of the orally active
histone deacetylase inhibitor givinostat (ITF2357) and
its ability to affect the disease.
Methods. Givinostat was administered orally, for
up to 12 weeks at a dosage of 1.5 mg/kg/day, to 17
patients with systemic-onset JIA who had had active
disease for >1 month. Disease activity was clinically
assessed using the American College of Rheumatology
Pediatric 30 (ACR Pedi 30), ACR Pedi 50, or ACR Pedi
70 criteria for improvement and a systemic feature
score. The primary goal was safety and the primary
efficacy end point was the number of patients completing 12 weeks of treatment who were responders.
Results. Givinostat was safe and well tolerated,
with adverse events (AEs) being mild or moderate, of
short duration, and self-limited. The 17 patients from
the intent-to-treat population reported a total of 44 AEs,
and the 9 patients in the per-protocol population reported a total of 25. Six AEs in 3 patients (nausea,
Histone deacetylases (HDAs) are intracellular
enzymes that maintain nucleosome histones in a state of
deacetylation so that DNA remains tightly bound and
inaccessible to transcription factors. Inhibition of HDAs
results in hyperacetylation of histones, which allows for
the sufficient unraveling of DNA for binding transcription factors and the synthesis of messenger RNA (1,2).
There is increasing evidence that HDA inhibitors may
also exhibit antiinflammatory properties (3). ITF2357
(recently named givinostat) is a hydroxamic acid containing an HDA inhibitor, which reduces the production
and release of several proinflammatory cytokines (tumor
necrosis factor ␣, interleukin-1␤ [⌱L-1␤], interferon-␥,
IL-6, and IL-12) from human blood monocytes (4) as
well as in models of autoimmune diseases and inflammation, including models of arthritis and synovial cell
functions (5,6).
Systemic-onset juvenile idiopathic arthritis (JIA)
is an example of combined autoinflammatory and autoimmune disease. Reduction of the painful and destructive arthritis component of the disease remains a goal
that has still not been achieved even with anticytokine
parenteral therapies (7,8). The primary objective of the
ClinicalTrials.gov identifier: NCT00570661.
Supported by Italfarmaco SpA, Cinisello Balsamo, Italy. Dr.
Dinarello’s work was supported by the NIH (grant AF-15614).
1
Jelena Vojinovic, MD, PhD: University Clinic Center, Nis,
Serbia; 2Nemanja Damjanov, MD, PhD, Gordana Susic, MD: Institute
of Rheumatology, Belgrade, Serbia; 3Carmine D’Urzo, MD: Italfarmaco SpA, Cinisello Balsamo, Italy; 4Antonio Furlan, MD, PhD:
University of Colorado, Aurora, and University of Padua, Padua, Italy;
5
Srdjan Pasic, MD, PhD: Institute of Child and Mother Health,
Belgrade, Serbia; 6Nicola Iagaru, MD, PhD: Institute for Mother and
Child Care, Bucharest, Romania; 7Mariana Stefan, MD: M.S. Curie
Emergency Hospital for Children, Bucharest, Romania; 8Charles A.
Dinarello MD, PhD: University of Colorado, Aurora.
Dr. Dinarello has received consulting fees, speaking fees,
and/or honoraria from Italfarmaco SpA, Capstone, and Source MdX
(less than $10,000 each).
Address correspondence to Jelena Vojinovic, MD, PhD,
Department of Pediatric Rheumatology, University Clinic Center Nis,
Bul dr Zoran Djindjic 48, 18000 Nis, Serbia. E-mail:
vojinovic.jelena@gmail.com.
Submitted for publication October 22, 2010; accepted in
revised form January 4, 2011.
1452
GIVINOSTAT IN SYSTEMIC-ONSET JIA
trial described herein was to determine the safety and
tolerability of givinostat in patients with active systemiconset JIA. The secondary objective was to evaluate the
effect of givinostat on disease activity.
PATIENTS AND METHODS
The study was conducted in compliance with the
Declaration of Helsinki, the International Conference on
Harmonisation, and the Guidelines for Good Clinical Practice
in the European Community. The study documents were
approved by local independent ethics committees (IECs) or
institutional review boards (IRBs). Each patient’s information
and informed consent form (approved by the IEC/IRB) were
provided in both written and oral form and signed by parents,
and, when possible, the patients.
Patient population. All 17 patients were white, and the
cohort was composed of 6 girls and 11 boys, who had a mean ⫾
SD age of 11.60 ⫾ 5.43 years, with a mean ⫾ SD disease
duration of 59.53 ⫾ 49.16 months and a duration of active
disease of 14.19 ⫾ 24.41 months. Of the 17 patients in the
intent-to-treat population, 10 completed the 12 weeks of
treatment (58.8%). Eight patients were excluded from the
per-protocol population, for the following reasons: 2 patients
for insufficient response, assessed using the Systemic Feature
Score (SFS; a measure specifically designed by the authors for
the present study) at week 4 or subsequent visits, 2 patients for
use of concomitant medication not allowed by study protocol,
and 4 other patients who were withdrawn from the study for
safety reasons (including 1 of the 10 patients who received 12
weeks of treatment but was diagnosed as having varicella)
(Table 1). The final per-protocol population consisted of 9
patients.
Study design. The study was a phase II, open-label,
international, multicenter clinical trial. To be eligible for
enrollment, patients had to have systemic-onset JIA according
to the International League Against Rheumatism criteria (9).
Disease duration had to be ⱖ6 months, with active disease for
ⱖ1 month. Additional inclusion criteria were 1) age 2–25 years
at the time of enrollment, 2) an unsatisfactory response to
previously administered treatment with steroids, at a dosage
equivalent to ⱖ0.2 mg/kg/day of prednisolone, unchanged for
ⱖ4 weeks before the patient’s enrollment, 3) an unsatisfactory
response or drug intolerance to previously administered methotrexate (MTX) (if it was administered) given for ⱖ6 months
at a stable dosage of 10–20 mg/week for ⱖ4 weeks before
patient enrollment, 4) an unsatisfactory response or drug
intolerance to previous treatment with biologic agents (if any
were administered) for ⱖ3 months, discontinued ⱖ5 drug
half-lives before enrollment, and 5) stable dosage of concomitant nonsteroidal antiinflammatory drugs (if any were administered) for ⱖ4 weeks before the patient’s enrollment.
Systemic-onset JIA is a clinically dichotomous disease
with predominant systemic features (not necessarily including
arthritis), or the presence of polyarthritis (without systemic
features). Criteria for active disease were thus defined in 2
ways: in patients without arthritis, and in patients with the
presence of arthritis. Patients without arthritis must have had
ⱖ1 systemic feature present (fever [defined as a body temperature ⱖ37.5°C at least once a day during at least 5 consecutive
1453
days], rash [defined by the presence of typical systemic-onset
JIA salmon-pink rash on the trunk and elsewhere during the
febrile episodes], serositis, lymphadenopathy [defined by
lymph node enlargement to ⱖ1.5 cm localized anywhere within
the body], or hepatomegaly and/or splenomegaly that had been
confirmed by ultrasound evaluation), as well as an erythrocyte
sedimentation rate (ESR) of ⱖ20 mm/hour and/or C-reactive
protein (CRP) level of ⱖ10 mg/liter. In order for patients with
arthritis to satisfy criteria for active disease they must have had
ⱖ1 active joint (defined as presence of limited range of motion
and/or pain and swelling) and the presence of ⱖ1 systemic
feature and/or abnormal ESR and CRP levels, as described
above.
Clinical outcomes were assessed by 6 core variables
defined in the American College of Rheumatology Pediatric 30
(ACR Pedi 30), ACR Pedi 50, and ACR Pedi 70 criteria for
improvement (10,11), and the SFS at screening at 2-week
intervals during the treatment phase, and at followup visits 1
and 3 months after the last administration of givinostat.
The SFS was designed to evaluate systemic disease
features and consisted of 5 clinical and 5 laboratory assessments. Clinical features assessed included temperature (with
parents recording temperature in a diary to document fever),
presence of rash, enlargement of lymph nodes, liver and spleen
size, and clinical evidence of serositis. The 5 laboratory features measured were ESR, CRP, leukocyte count, hemoglobin
level, and platelet count. Each clinical and laboratory feature
was assigned a score of 1 (present) or 0 (absent). At baseline,
laboratory features were considered present based on the
following: ESR ⱖ20 mm/hour, CRP ⱖ10 mg/liter, white blood
cell (WBC) count ⱖ12 ⫻ 109/liter, hemoglobin ⱕ11 gm/dl, and
platelet count ⱖ400 ⫻ 109/liter. During treatment phases and
at followup visits, the laboratory parameters were scored as
follows: for ESR, score of 0 if ⬍20 mm/hour or if decreased by
ⱖ30% compared to baseline, score of 1 if increased or if
decreased by ⬍30% compared to baseline; for CRP, score of 0
if ⬍10 mg/liter or if decreased by ⱖ30% compared to baseline,
score of 1 if increased or if decreased by ⬍30%; for WBC
count, score of 0 if ⬍12 ⫻ 109/liter or if decreased by 20%
compared to baseline, score of 1 if increased or if decreased by
⬍20%; for hemoglobin level, score of 0 if ⬍11 gm/dl or if
increased by 20% compared to baseline, but score of 1 if
decreased or if increased by ⬍20%; for platelet count, score of
0 if ⬍400 ⫻ 109/liter or if decreased by 20% compared to
baseline, score of 1 if increased or if decreased by ⬍20%.
At week 4, a 2-point decrease in the SFS (including a
decrease in at least 1 of the 5 clinical variables) compared to
baseline was required, as this was defined as sufficient therapeutic response for the patient to continue in the study.
Decreases recorded at week 4 had to be maintained or
improved throughout the duration of the study in order for the
patient to continue.
Study drug. Each patient received givinostat (supplied
by Italfarmaco SpA) for up to 12 weeks. The drug was
administered orally under fed conditions in hard gelatin capsules supplied at different strengths to accommodate body
weight. The treatment regimen for each patient remained
unchanged for the entire study, in the absence of treatmentlimiting toxicity. The medication dosage was 1.5 mg/kg/day (0.75
mg/kg at 12-hour intervals). This dosing regimen was thought to
be the safest and most efficacious based on the previous dosing
1454
VOJINOVIC ET AL
Table 1. Detailed description of the patients with systemic-onset juvenile idiopathic arthritis at baseline and at the end of treatment with
givinostat*
Baseline
Patient/
treatment
regimen at
baseline
End of treatment
Systemic
Feature
Score
No. of
painful
joints
No. of
swollen
joints
No. of joints
with limited
range of
motion
Systemic
Feature
Score
No. of
painful
joints
No. of
swollen
joints
No. of joints
with limited
range of
motion
1/MTX, steroids,
NSAIDs
2/MTX, steroids,
NSAIDs
3/MTX, steroids,
NSAIDs
6
19
18
20
3
0
13
15
5
8
4
8
3
2
4
4
4
2
1
2
3
1
1
2
4/steroids,
NSAIDs
6
10
6
9
4
3
4
6
5/MTX, steroids,
NSAIDs
5
9
3
53
3
16
2
44
6/steroids,
NSAIDs
7/MTX, steroids,
NSAIDs
8/steroids,
NSAIDs
1
9
8
7
2
3
0
2
5
4
2
5
0
0
0
1
5
17
10
28
3
5
8
22
9/steroids,
NSAIDs
10/MTX,
steroids,
NSAIDs
11/steroids,
NSAIDs
12/MTX,
steroids
13/MTX,
steroids,
NSAIDs
14/MTX,
steroids,
NSAIDs
15/MTX,
steroids
16/MTX,
steroids
17/MTX,
steroids,
NSAIDs
4
5
5
12
1
0
0
2
6
27
16
29
2
2
7
13
5
8
4
8
3
0
2
7
7
1
2
5
4
0
1
1
4
11
10
12
0
1
0
3
5
33
33
0
4
35
35
0
4/insufficient SFS
response
7
0
0
0
4
0
0
0
7
1
0
2
1
0
0
0
7
2
3
2
4
2
4
2
10/thigh cellulitis,
QTc prolongation
12/per-protocol
population
12/per-protocol
population
Week/reason for end
of treatment
12/per-protocol
population
12/varicella
6/flu, worsening
disease, and
intraarticular
steroid injection
4/flu, concomitant
medication, PI
decision
8/otitis media,
concomitant
medication for
pain, PI decision
4/insufficient SFS
response
12/per-protocol
population
4/worsening arthritis,
intraarticular
steroid injection,
PI decision
12/per-protocol
population
12/per-protocol
population
12/per-protocol
population
12/per-protocol
population
12/per-protocol
population
* MTX ⫽ methotrexate; NSAIDs ⫽ nonsteroidal antiinflammatory drugs; PI ⫽ principal investigator; SFS ⫽ Systemic Feature Score.
experiences in adults in phase I trials (12) and trials of its use in
other diseases, after applying calculations for adult drug dosing
in children.
Safety and tolerability. The safety and tolerability of
givinostat were evaluated throughout the study at clinical
examinations every 2 weeks during the treatment period, and
at 1 and 3 months thereafter during the followup phase. Each
of these evaluations included physical examination, electrocar-
diography, hematologic and blood chemistry assessment, urinalysis, and recording of any adverse events.
Statistical analysis. Results from the intent-to-treat
population, defined as all patients who received ⱖ1 dose of the
study drug, and the per-protocol population, defined as all
patients who completed the study protocol, were analyzed. For
the primary efficacy end point, missing data were entered using
the worst observation carried forward method. Differences
GIVINOSTAT IN SYSTEMIC-ONSET JIA
before and after treatment were compared by Wilcoxon’s
matched pairs test.
RESULTS
Safety. The 17 patients in the intent-to-treat
population reported a total of 44 adverse events (AEs),
and the 9 patients in the per-protocol population reported a total of 25. The majority of events were mild or
moderate. The most frequently reported events were
shortlived and self-limited respiratory or gastrointestinal
disturbances, or were signs of worsening disease.
Three patients had study drug–related AEs (total
of 6 events, consisting of nausea, vomiting, and fatigue),
1455
but each resolved spontaneously and no patient was
withdrawn from the study due to drug-related AEs.
Serious AEs were reported in 2 patients: 1 patient was
diagnosed as having varicella during an outbreak at his
nursery (diagnosed at week 12 of the study). The clinical
course was typical, did not require hospitalization, and
resolved spontaneously. The second patient developed
thigh cellulitis. Both AEs were judged to be unrelated to
the drug. In 2 other cases, AEs led to treatment discontinuation (an episode of moderate otitis media judged to
be unrelated to the experimental drug, and a single
documentation of mild QTc prolongation [455 msec], for
which the relationship to the drug was judged as un-
Figure 1. Results measured with standardized scales in patients with systemic-onset juvenile idiopathic arthritis (JIA), following treatment with
givinostat. A, Systemic Feature Score (SFS) at different time points of the study after treatment with givinostat, measured in both the intent-to-treat
(ITT) population and the per-protocol (PP) population. Values are the mean. W4 ⫽ week 4; EoT ⫽ end of treatment (12 weeks); FU1 ⫽ 1-month
followup. B, American College of Rheumatology Pediatric 30 (ACR Pedi 30), ACR Pedi 50, and ACR Pedi 70 scores in the per-protocol population
after treatment with givinostat. Data are shown as the percentage of patients with improvement over baseline. C, Clinical outcomes of treatment
with givinostat in the per-protocol population. ppVAS ⫽ patient/parent global assessment (on a 0–10–cm visual analog scale [VAS]); phVAS ⫽
physician global assessment (on a 0–10–cm VAS); AA ⫽ number of joints with active arthritis (of a total of 75); LOM ⫽ number of joints with limited
range of motion (of a total of 75); C-HAQ ⫽ Childhood Health Assessment Questionnaire (0–3). Values are the mean. ⴱ ⫽ P ⬍ 0.01 versus baseline,
by Wilcoxon’s matched pairs signed rank test.
1456
VOJINOVIC ET AL
Table 2. Disease characteristics of the patients with systemic-onset juvenile idiopathic arthritis at baseline and at the end of treatment*
Intent-to-treat population (n ⫽ 17)
Physician global assessment
(0–100-mm VAS)
Mean ⫾ SEM
Median (range)
Patient/parent global assessment
(0–100-mm VAS)
Mean ⫾ SEM
Median (range)
No. of joints with active arthritis
Mean ⫾ SEM
Median (range)
No. of painful joints
Mean ⫾ SEM
Median (range)
No. of swollen joints
Mean ⫾ SEM
Median (range)
No. of joints with limited ROM
Mean ⫾ SEM
Median (range)
ESR, mm/hour
Mean ⫾ SEM
Median (range)
CRP, mg/liter
Mean ⫾ SEM
Median (range)
C-HAQ, 0–3
Mean ⫾ SEM
Median (range)
SFS
Mean ⫾ SEM
Median (range)
Per-protocol population (n ⫽ 9)
Baseline
End of treatment
Baseline
End of treatment (week 12)
56.18 ⫾ 3.14
50 (36–80)
36.29 ⫾ 6.31†
27.5 (0–67)
49.1 ⫾ 2.9
50 (40–71)
20.4 ⫾ 5.55†
22.5 (0–55)
47.71 ⫾ 5.2
50 (5–80)
25.71 ⫾ 4.71†
20 (2–79)
45.5 ⫾ 7.48
48 (17–80)
15.8 ⫾ 4.53†
15 (2–44)
9.76 ⫾ 2.23
8 (0–33)
5.52 ⫾ 2.08†
3.5 (0–13)
8.0 ⫾ 2.34
5 (1–27)
2.2 ⫾ 0.95†
1.5 (0–13)
9.77 ⫾ 2.27
8.5 (0–33)
4.12 ⫾ 2.14†
1 (0–35)
8.67 ⫾ 2.99
5 (1–27)
0.56 ⫾ 0.29†
0 (0–2)
7.35 ⫾ 2.04
4.5 (0–33)
4.76 ⫾ 2.08†
2 (0–35)
6.67 ⫾ 2.17
4 (0–18)
3.0 ⫾ 1.48†
1 (0–13)
11.76 ⫾ 3.34
8 (0–53)
7.29 ⫾ 2.74†
3.5 (0–45)
8.8 ⫾ 2.55
8 (0–29)
3.5 ⫾ 1.22†
3.5 (0–15)
62.71 ⫾ 7.70
72 (18–116)
57.29 ⫾ 9.21
59 (2–116)
60.07 ⫾ 8.42
75 (21–91)
49.8 ⫾ 11.68
59 (2–116)
87.28 ⫾ 13.56
74 (22–230)
72.05 ⫾ 22.31
46 (0–306)
71.58 ⫾ 12.13
73.9 (22–151)
61.44 ⫾ 28.92
29.3 (0–306)
1.75 ⫾ 0.18
2 (0.625–3)
1.09 ⫾ 0.23†
0.75 (0–3)
1.69 ⫾ 0.18
1.75 (0.75–2.2)
0.62 ⫾ 0.15†
0.625 (0–1.62)
5.24 ⫾ 0.37
5 (1–7)
2.59 ⫾ 0.33†
2 (0–4)
5.1 ⫾ 0.59
5.5 (4–7)
2.0 ⫾ 0.47†
2.5 (0–4)
* There were no statistically significant differences between the intent-to-treat and per-protocol populations at baseline. VAS ⫽ visual analog scale;
ROM ⫽ range of motion; ESR ⫽ erythrocyte sedimentation rate; CRP ⫽ C-reactive protein; C-HAQ ⫽ Childhood Health Assessment
Questionnaire; SFS ⫽ Systemic Feature Score.
† P ⬍ 0.01 versus baseline, by Wilcoxon’s matched pairs signed rank test.
known). Nonetheless, QTc prolongation is a known
class-associated toxicity of HDA inhibitors, and it is
therefore reasonable to consider this event related to the
administration of givinostat; the QTc prolongation resolved promptly after drug discontinuation (Table 1).
There were no changes in hepatic or renal function. No
serious bacterial or viral infections were documented
during the treatment period or followup.
Efficacy. Systemic disease features observed at
baseline among patients in the intent-to-treat population
included fever (7 patients), rash (3 patients), lymph node
enlargement (4 patients), hepatosplenomegaly (1 patient), and serositis (1 patient). Systemic disease features
present at baseline among the patients in the perprotocol population included fever (5 patients), rash (3
patients), lymph node enlargement (2 patients), and
hepatosplenomegaly (1 patient). At week 4, the only
systemic features observed consisted of fever in 3 patients and serositis in 1 patient in the intent-to-treat
population, and fever (1 patient) in the per-protocol
population. There was a statistically significant decrease
in the SFS in both populations starting at week 4, which
was sustained until the end of treatment (Figure 1A).
Results of clinical assessments at baseline and at the end
of treatment are shown in Table 2.
An ACR Pedi 30, ACR Pedi 50, or ACR Pedi 70
improvement (Figure 1B) was achieved in 77.8%, 55.6%,
and 22.2% of patients, respectively, at week 4 in the
per-protocol population and 56.6%, 31.3%, and 12.5%,
respectively, in the intent-to-treat population. At week
12, the rate of improvement was 77.8%, 77.8%, and
66.7% in the per-protocol population and 52.9%, 41.2%,
and 35.3% in the intent-to-treat population, respectively
(even including the worst observation carried forward at
GIVINOSTAT IN SYSTEMIC-ONSET JIA
end of treatment). There was a consistent trend toward
a reduction in the number of joints with active arthritis
and limited range of motion with givinostat treatment
(Figure 1C). Moreover, parents and patients reported
dramatic improvements in mobility and well-being.
There was a significant reduction in the number of both
painful and swollen joints (Tables 1 and 2). CRP levels
and ESR, in both the intent-to-treat and the perprotocol populations, showed a decreasing trend until
week 4, but values then remained unchanged until the
end of the study, and the decreases did not reach
statistical significance.
DISCUSSION
This trial was the first attempt to use givinostat to
treat arthritis in humans, and as the study focused on
children, the primary outcome measure was safety.
There was no evidence of organ dysfunction or systemic
toxicity among the study patients. Patient compliance
with treatment was excellent. Most side effects were
mild or moderate, were likely unrelated to the drug, and
were self-limited, with spontaneous recovery within a
day or two.
Because the study was open labeled and conducted with an extremely small patient population, valid
conclusions about efficacy cannot be drawn. Nevertheless, parents and patients reported dramatic improvements in mobility and well-being, as verified by a decrease in the median score on the Childhood Health
Assessment Questionnaire, as well as a decrease in the
number of joints with active arthritis, as assessed by the
number of painful and swollen joints. This could indicate
that HDA inhibition can influence both pain and inflammation in arthritis. Anakinra, canakinumab, and tocilizumab have been highly effective in reducing the systemic features of systemic-onset JIA (13,14), but orally
administered givinostat led to suppression of most systemic features, except levels of ESR and CRP. Parenteral administration, cost, and side effects are of concern
in treatment with biologic agents, especially in young
patients. The use of MTX is considered to be a gold
standard in the treatment of JIA, but there are many
patients in whom disease cannot be controlled with this
drug, or who report a severe intolerance to it (15).
However, most of the biologic agents currently in use are
effective only in combination with MTX, and thus there
is a clear need to explore possibilities of finding new,
better-tolerated, and safer treatment options. In the
present study, we demonstrated an excellent safety
profile, satisfying the intended primary end point; addi-
1457
tionally, givinostat provided significant benefit to patients in the study, particularly in reducing the arthritic
features of JIA.
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. Vojinovic 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. Vojinovic, Damjanov, Dinarello.
Acquisition of data. Vojinovic, Damjanov, D’Urzo, Furlan, Susic, Pasic,
Iagaru, Stefan.
Analysis and interpretation of data. Vojinovic, D’Urzo, Dinarello.
ROLE OF THE STUDY SPONSOR
Italfarmaco SpA financially supported the study procedures
and provided the study drug (givinostat). The authors were responsible
for study design, data analysis, and writing of the manuscript. Italfarmaco approved the final content to be submitted for publication.
REFERENCES
1. Jungel A, Ospelt C, Gay S. What can we learn from epigenetics in
the year 2009? Curr Opin Rheumatol 2010;22:284–92.
2. Halili MA, Andrews MR, Sweet MJ, Fairlie DP. Histone deacetylase inhibitors in inflammatory disease. Curr Top Med Chem
2009;9:309–19.
3. Faraco G, Pittelli M, Cavone L, Fossati S, Porcu M, Mascagni P,
et al. Histone deacetylase (HDAC) inhibitors reduce the glial
inflammatory response in vitro and in vivo. Neurobiol Dis 2009;
36:269–79.
4. Leoni F, Fossati G, Lewis EC, Lee JK, Porro G, Pagani P, et al.
The histone deacetylase inhibitor ITF2357 reduces production of
pro-inflammatory cytokines in vitro and systemic inflammation in
vivo. Mol Med 2005;11:1–15.
5. Brogdon JL, Xu Y, Szabo SJ, An S, Buxton F, Cohen D, et al.
Histone deacetylase activities are required for innate immune cell
control of Th1 but not Th2 effector cell function. Blood 2007;109:
1123–30.
6. Grabiec AM, Krausz S, de Jager W, Burakowski T, Groot D,
Sanders ME, et al. Histone deacetylase inhibitors suppress inflammatory activation of rheumatoid arthritis patient synovial macrophages and tissue. J Immunol 2010;184:2718–28.
7. Vastert SJ, Kuis W, Grom AA. Systemic JIA: new developments in
the understanding of the pathophysiology and therapy. Best Pract
Res Clin Rheumatol 2009;23:655–64.
8. Gattorno M, Piccini A, Lasiglie D, Tassi S, Brisca G, Carta S, et al.
The pattern of response to anti–interleukin-1 treatment distinguishes two subsets of patients with systemic-onset juvenile idiopathic arthritis. Arthritis Rheum 2008;58:1505–15.
9. Petty RE, Southwood TR, Manners P, Baum J, Glass DN,
Goldenberg J, et al. International League of Associations for
Rheumatology classification of juvenile idiopathic arthritis: second
revision, Edmonton, 2001. J Rheumatol 2004;31:390–2.
10. 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.
11. Ruperto N, Ravelli A, Pistorio A, Malattia C, Cavuto S, GadoWest L et al. Cross-cultural adaptation and psychometric evaluation of the Childhood Health Assessment Questionnaire (CHAQ)
and the Child Health Questionnaire (CHQ) in 32 countries.
1458
VOJINOVIC ET AL
Review of the general methodology. Clin Exp Rheumatol 2001;19
Suppl 23:S1–9.
12. Oldoni T, Furlan A, Monznani V, Dinarello CA. Decreased whole
blood cytokine production during a phase I trial of the histone
deacetylase inhibitor ITF2357 [abstract]. Cytokine 2009;48:120.
13. Verbsky JW, White AJ. Effective use of the recombinant interleukin 1 receptor antagonist anakinra in therapy resistant systemic onset juvenile rheumatoid arthritis. J Rheumatol 2004;31:
2071–5.
14. Yokota S, Imagawa T, Mori M, Miyamae T, Aihara Y, Takei S, et
al. Efficacy and safety of tocilizumab in patients with systemiconset juvenile idiopathic arthritis: a randomised, double-blind,
placebo-controlled, withdrawal phase III trial. Lancet 2008;371:
998–1006.
15. Foell D, Wulffraat N, Wedderburn LR, Wittkowski H, Frosch M,
Gerss J, et al. Methotrexate withdrawal at 6 vs 12 months in
juvenile idiopathic arthritis in remission: a randomized clinical
trial. JAMA 2010;303:1266–73.
DOI 10.1002/art.30267
Clinical Images: Subcutaneous elbow and forearm sarcoidosis presenting as olecranon bursitis
The patient, a 29-year-old man, was referred to our unit for evaluation of swelling and mild pain in the right elbow and forearm;
these symptoms had been present for 3 months. He was initially evaluated by an orthopedic surgeon and was diagnosed as having
olecranon bursitis, and he was treated with nonsteroidal antiinflammatory drugs. After 6 weeks of treatment, the swelling increased,
progressing halfway up the posterior forearm. He was evaluated by an internist who recommended a skin biopsy, which showed
multiple noncaseating granulomas. Staining was negative for acid-fast bacilli and fungi, suggesting sarcoidosis. Magnetic resonance
imaging showed an infiltrative process that was replacing the fat signal intensity of the subcutaneous extensor surface with diffuse
fluid-like signal (right). A positron emission tomography–computed tomography scan showed increased uptake of 18F-fluorodeoxy
glucose (center, left) in the subcutaneous extensor surface and in the mediastinal lymph nodes. There were no associated respiratory
symptoms. The patient was treated with standard doses of corticosteroids and low-dose weekly methotrexate, resulting in complete
resolution of the clinical features.
Morton A. Scheinberg, MD
Akemi Osawa, MD
Carlos Henrique Longo, MD
Hospital Albert Einstein
Sao Paulo, Brazil
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efficacy, idiopathic, inhibitors, systemic, arthritis, histone, safety, oral, juvenile, deacetylase, onset
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