Jurnal 3

The
n e w e ng l a n d j o u r na l
of
m e dic i n e
original article
Comparison of Ustekinumab and Etanercept

for Moderate-to-Severe Psoriasis
Christopher E.M. Griffiths, M.D., Bruce E. Strober, M.D., Ph.D.,
Peter van de Kerkhof, M.D., Vincent Ho, M.D., Roseanne Fidelus-Gort, Ph.D.,
Newman Yeilding, M.D., Cynthia Guzzo, M.D., Yichuan Xia, Ph.D.,
Bei Zhou, Ph.D., Shu Li, M.S., Lisa T. Dooley, Dr.P.H., Neil H. Goldstein, M.D.,
and Alan Menter, M.D., for the ACCEPT Study Group*
A BS T R AC T
Background
From the University of Manchester, Manchester Academic Health Science Centre,
Manchester, United Kingdom (C.E.M.G.);
New York University Medical Center, New
York (B.E.S.); University Hospital Nijmegen, Nijmegen, the Netherlands (P.K.);
University of British Columbia, Vancouver, BC, Canada (V.H.); Incyte Corporation, Wilmington, DE (R.F.-G.); Centocor
Research and Development (N.Y., C.G.,
Y.X., B.Z., S.L., L.T.D.) and Precision Research (N.H.G.) both in Malvern, PA;
and the Psoriasis Research Unit, Baylor
University Medical Center, Dallas (A.M.).
Address reprint requests to Dr. Griffiths
at the Dermatology Centre, Salford Royal
Hospital, University of Manchester, Manchester M6 8HD, United Kingdom, or at
christopher.griffiths@manchester.ac.uk.
*The investigators participating in the Active Comparator (CNTO 1275/Enbrel)
Psoriasis Trial (ACCEPT) study group are
listed in the Supplementary Appendix,
available with the full text of this article
at NEJM.org.
This article (10.1056/NEJMoa0810652) was
updated on January 25, 2010, at NEJM.org.
N Engl J Med 2010;362:118-28.
Copyright 2010 Massachusetts Medical Society.
Biologic agents offer a range of new therapeutic options for patients with psoriasis;
however, the relative benefitrisk profiles of such therapies are not well known. We
compared two biologic agents, ustekinumab (an interleukin-12 and interleukin-23
blocker) and etanercept (an inhibitor of tumor necrosis factor ), for the treatment
of psoriasis.
Methods
We randomly assigned 903 patients with moderate-to-severe psoriasis to receive

subcutaneous injections of either 45 or 90 mg of ustekinumab (at weeks 0 and 4) or
high-dose etanercept (50 mg twice weekly for 12 weeks). The primary end point was
the proportion of patients with at least 75% improvement in the psoriasis area-andseverity index (PASI) at week 12; a secondary end point was the proportion with
cleared or minimal disease on the basis of the physicians global assessment. Assessors were unaware of the treatment assignments. The efficacy and safety of a
crossover from etanercept to ustekinumab were evaluated after week 12.
Results
There was at least 75% improvement in the PASI at week 12 in 67.5% of patients who
received 45 mg of ustekinumab and 73.8% of patients who received 90 mg, as compared with 56.8% of those who received etanercept (P=0.01 and P<0.001, respective
ly). Similarly, 65.1% of patients who received 45 mg of ustekinumab and 70.6% of
patients who received 90 mg of ustekinumab had cleared or minimal disease according to the physicians global assessment, as compared with 49.0% of those who
received etanercept (P<0.001 for both comparisons). Among patients who did not
have a response to etanercept, 48.9% had at least 75% improvement in the PASI
within 12 weeks after crossover to ustekinumab. One or more adverse events occurred
through week 12 in 66.0% of patients who received 45 mg of ustekinumab and 69.2%
of patients who received 90 mg of ustekinumab and in 70.0% who received etanercept; 1.9%, 1.2%, and 1.2%, respectively, had serious adverse events. Safety patterns
were similar before and after crossover from etanercept to ustekinumab.
Conclusions
The efficacy of ustekinumab at a dose of 45 or 90 mg was superior to that of highdose etanercept over a 12-week period in patients with psoriasis. (ClinicalTrials.gov
number, NCT00454584.)
118
n engl j med 362;2 nejm.org january 14, 2010
The New England Journal of Medicine

Downloaded from nejm.org on December 22, 2014. For personal use only. No other uses without permission.
Copyright 2010 Massachusetts Medical Society. All rights reserved.
Ustekinumab or Etanercept for Psoriasis
soriasis is a chronic, inflammatory

skin disease affecting approximately 2% of
the worlds population.1,2 Therapeutic agents
used for the management of psoriasis commonly
target the underlying inflammation. Immunosuppressive agents such as methotrexate and cyclo
sporine have proved effective in the treatment of
psoriasis.3 Biologic agents that selectively block
steps in the inflammatory cascade have provided
additional therapies for psoriasis and have led to
a better understanding of its immunologic and
pathophysiological basis.4-9
Proinflammatory cytokines such as tumor
necrosis factor (TNF-) play a central role in
the inflammation underlying psoriasis. Agents
that selectively block TNF- have proved highly
effective in treating psoriasis.10-12 More recently,
interleukin-12 and interleukin-23, cytokines that
induce naive CD4+ lymphocytes to differentiate
into type 1 helper T cells (Th1 cells) and type 17
helper T cells (Th17 cells), respectively, have been
identified as key mediators of psoriasis.13-18 A
new class of biologic agents that block both interleukin-12 and interleukin-23 has been shown to
be effective for the treatment of psoriasis.19,20
The phase 3 Active Comparator (CNTO 1275/
Enbrel) Psoriasis Trial (ACCEPT) was designed
to compare the efficacy of two effective biologic
agents, one that inhibits TNF- (etanercept [Enbrel, Amgen and Wyeth]) and one that blocks
interleukin-12 and interleukin-23 (ustekinumab
[Stelara, Centocor Ortho Biotech Services, a subsidiary of Johnson & Johnson]).
Me thods
Patients
We conducted this study at 67 sites worldwide,

and the study protocol was approved by the institutional review board or ethics committee at each
site. Written informed consent was obtained from
each patient. The first patient was enrolled on
March 26, 2007, and the last patient visit occurred
on January 15, 2009. Patients were eligible for the
study if they were adults (18 years of age) who
had received a diagnosis of plaque psoriasis at
least 6 months earlier, were candidates for phototherapy or systemic treatment, had a score on the
psoriasis area-and-severity index (PASI) of 12 or
higher (on a scale of 0 to 72, with higher scores
indicating more severe disease), had a score of at
least 3 on the physicians global assessment (on a
scale of 0 to 5, with 0 indicating no disease and

5 severe disease), and had involvement of at least
10% of body-surface area at baseline. Additional
eligibility criteria were an inadequate response,
intolerance, or contraindication to at least one
conventional systemic agent for the treatment of
psoriasis (i.e., methotrexate, cyclosporine, or psoralen plus ultraviolet A) and no previous treatment with ustekinumab or etanercept.
Patients were ineligible for participation in the
study if they had nonplaque (i.e., pustular, guttate, or erythrodermic) or drug-induced forms of
psoriasis, a recent serious infection or a history
of chronic or recurrent infectious disease, or a
known malignant condition (with the exception
of treated basal-cell or squamous-cell skin cancer
or cervical cancer in situ with no evidence of
recurrence for 5 years). Patients could not have
received conventional systemic therapy or phototherapy within 4 weeks before enrollment, topical
psoriasis agents within 2 weeks, investigational
drugs within 4 weeks or five half-lives, whichever
was longer, or biologic agents within 3 months
or five half-lives, whichever was longer.
Study Design
We randomly assigned patients (in a 3:5:5 ratio)

to one of three treatment groups (ustekinumab at
a dose of 45 or 90 mg at weeks 0 and 4 or etanercept at a dose of 50 mg twice weekly [hereafter
called high-dose etanercept] for 12 weeks), using
an adaptive randomization scheme that was stratified according to investigational site and baseline weight (<90 kg or 90 kg).21 Patients in the
etanercept group who did not have a response
(i.e., patients who had moderate, marked, or severe psoriasis) at week 12 received 90 mg of
ustekinumab at weeks 16 and 20, and patients
who did not have a response to ustekinumab received one additional dose of ustekinumab at week
16 (Fig. 1). Treatment was interrupted starting at
week 12 in all patients with cleared, minimal, or
mild psoriasis; patients were retreated with
ustekinumab if psoriasis recurred and was classified as moderate, marked, or severe disease (Fig. 1).
Patients were aware of their treatment assignment, although patients who were randomly assigned to ustekinumab received double injections
(one injection of active treatment and one injection of placebo) to maintain blinding for the dose.
All study personnel, except those who dispensed
or administered a study agent, remained unaware

119
The
Treatment
interruption
Controlled period
Randomization
Week
of
m e dic i n e
Crossover and retreatment
50 mg of etanercept
twice weekly
Crossover to 90 mg of ustekinumab
45 mg of ustekinumab
at wk 0 and 4
Retreatment with 45 mg of ustekinumab
90 mg of ustekinumab
at wk 0 and 4
Retreatment with 90 mg of ustekinumab
12
16
Follow-up
44
64
Figure 1. Schematic Representation of the Study Design.

Patients who were randomly assigned to receive ustekinumab and who had a physicians global assessment score of 3 or higher at week 12
1st
AUTHOR:
Griffiths
received one additional dose of ustekinumab
at week
16 and no further therapy. RETAKE:
2nd
3rd
FIGURE: 1 of 3
ARTIST: MRL
Revised
SIZE
7 col
death, myocardial infarction, and
of the treatment assignments
TYPE: Line throughout
Combo
4-C the
H/T (cardiovascular
39p6
stroke) were adjudicated by an independent panel
study.
AUTHOR, PLEASE NOTE:
cardiologists. In addition, serum
The study was sponsored
Re-has of
Figure has by
beenCentocor
redrawn and type
beenacademic
reset.
Please check
carefully. samples were evaluated for antibodies to ustekisearch and Development. The academic
authors
and Centocor representatives
designed the study, numab.
JOB: 361xx
ISSUE: 1-14-10
and Centocor conducted the data analyses. The
authors interpreted the data and, with support Statistical Analysis
from a professional medical writer employed by Efficacy data for all patients who underwent ranCentocor Ortho Biotech Services, collaborated in domization were analyzed according to the asthe preparation of the manuscript. The academic signed treatment, and safety data were summaauthors had access to the data and vouch for the rized according to the actual treatment received.
completeness and accuracy of the data and data The prespecified data-analysis plan was finalized
analyses. The lead author served as guarantor of before the treatment assignments were revealed.
the analyses, which were verified by the BiostaThe primary end point was the proportion of
tistics Department at Centocor Research and patients who had at least 75% improvement in
Development.
the PASI score from baseline to week 12. A total
enrollment of 850 patients was planned on the
Efficacy and Safety Evaluations
basis of a step-down test procedure in which the
Efficacy evaluations included the PASI and the proportions of patients with at least 75% imphysicians global assessment. The PASI score is provement in the PASI score were assumed to be
based on the extent of psoriatic involvement of 64%, 65%, and 50% in the groups receiving 45
body-surface area on the head, trunk, arms, and mg of ustekinumab, 90 mg of ustekinumab, and
legs, as well as the severity of scale formation, etanercept, respectively. With 325 patients each
erythema, and plaque induration in each region in the group receiving 90 mg of ustekinumab and
of the body.22 The physicians global assessment the group receiving etanercept, the power to descore reflects the overall status of psoriatic lesions tect a significant treatment difference at an alpha
(induration, erythema, and scaling) at a given level of 0.05 was 97%; with 200 patients in the
time point. Safety was evaluated by assessing ad- group receiving 45 mg of ustekinumab, the power
verse events and routine hematologic and labora- to further detect a significant treatment differtory values. Possible major cardiovascular events ence between 45 mg of ustekinumab and etaner-
120

cept was 87%, with an overall type I error rate

of 0.05.
Major secondary end points included the proportion of patients with a physicians global assessment score of 0 (clearance of disease) or 1
(minimal disease) at week 12, the proportion
with at least 90% improvement in the PASI score
from baseline to week 12, and the difference
between the PASI score at week 12 and the score
12 weeks after retreatment on recurrence of psoriasis. To maintain an overall type I error rate of
0.05, a step-down test procedure was applied,
first comparing 90 mg of ustekinumab with
etanercept, and then comparing 45 mg of ustekinumab with etanercept only if the 90-mg dose
was significantly superior to etanercept. A twosided CochranMantelHaenszel chi-square test
stratified according to the patients weight (<90 kg
or 90 kg) was conducted to evaluate each superiority hypothesis. All tests were two-sided.
R e sult s
Patient Characteristics
of patients who received 45 mg or 90 mg of

ustekinumab (36.4% and 44.7%, respectively) than
by patients who received etanercept (23.1%) (P<0.001
for both comparisons) (Table 2, and Figure 1 of the
Supplementary Appendix). The proportion of patients who had cleared disease (a score of 0) or minimal disease (a score of 1) based on the physicians
global assessment score at week 12 was also significantly higher in each ustekinumab group; 65.1% of
patients who received 45 mg and 70.6% of patients
who received 90 mg of ustekinumab, as compared
with 49.0% of patients who received high-dose
etanercept, had cleared or minimal disease (P<0.001
for both comparisons with etanercept) (Table 2).
The onset of a clinical response was more rapid in
patients treated with ustekinumab than in patients
treated with etanercept (Fig. 3A, 3B, and 3C).
Among patients who did not have a response
to etanercept, 48.9% had at least 75% improvement in the PASI score and 23.4% had at least
90% improvement after crossing over to 90 mg of
ustekinumab for 12 weeks; 40.4% achieved cleared
or minimal disease according to the physicians
global assessment during this period (Fig. 3D,
3E, and 3F). For patients who received a physicians global assessment score indicating cleared,
minimal, or mild disease at week 12, the treatment was interrupted until psoriasis recurred and
was classified as moderate, marked, or severe
disease. The median time to recurrence was 14.4
weeks among patients who received 45 mg of
ustekinumab, 18.1 weeks among those who received 90 mg of ustekinumab, and 7.3 weeks
among those who received etanercept. Of the
633 patients who were treated with ustekinumab
again after the recurrence of psoriasis, 534
(84.4%) had a physicians global assessment score
of 0 to 2 within 12 weeks after retreatment.
Of the 1175 patients screened for enrollment,

903 were randomly assigned in a 3:5:5 ratio to
one of three treatment groups: 209 patients to
45 mg of ustekinumab, 347 patients to 90 mg of
ustekinumab, and 347 patients to high-dose
etanercept (Fig. 2). Baseline demographic and disease characteristics of the patients were similar
among the three treatment groups (Table 1).
More than two thirds of the patients were male,
the mean age was approximately 45 years, and the
average duration of psoriasis was approximately
19 years. The mean body-surface area affected by
psoriasis was approximately 25%, and the mean
PASI score was approximately 20. Approximately
one quarter of patients reported a history of psoriatic arthritis. The vast majority of patients had Safety
used topical agents previously, and more than During the first 12 weeks of the trial, the proportions of patients who had at least one adverse
10% had used biologic agents (Table 1).
event were similar in the etanercept group (70.0%)
Efficacy
and both ustekinumab groups (66.0% in the
At week 12, a total of 67.5% of patients who re- group that received 45 mg of ustekinumab and
ceived 45 mg of ustekinumab and 73.8% of pa- 69.2% in the group that received 90 mg) (Table 3,
tients who received 90 mg of ustekinumab had at and Table 1 of the Supplementary Appendix,
least 75% improvement in the PASI score, as com- available with the full text of this article at NEJM
pared with 56.8% of those who received high- .org), and similar proportions of patients discondose etanercept (P=0.01 and P<0.001, respectively) tinued treatment because of adverse events (2.3%
(Table 2). A 90% improvement in the PASI score of patients in the etanercept group, as compared
was achieved at week 12 by a higher proportion with 1.9% of those who received 45 mg of ustekin engl j med 362;2 nejm.org january 14, 2010

121
The
of
m e dic i n e
1175 Patients were screened
903 Underwent randomization
209 Were assigned to 45 mg of

ustekinumab at 0 and 4 wk

etanercept twice weekly
11 Discontinued treatment
5 Had adverse event
1 Was lost to follow-up
5 Had other reason

ustekinumab at 0 and 4 wk
2 Had adverse event
2 Were lost to follow-up
4 Had other reason
1 Had adverse event
2 Had other reason
336 Completed 12-wk treatment

41 Did not cross over to 90 mg
of ustekinumab after wk 12
5 Had adverse event
11 Had other reason
1 Did not report reason
23 Completed treatment
without requiring
additional treatment

27 Did not receive retreatment
with 45 mg of ustekinumab
after wk 12
3 Had adverse event
5 Had other reason
without requiring

72 Did not receive retreatment
with 90 mg of ustekinumab
after wk 12
6 Had adverse event
14 Had other reason
without requiring
295 Crossed over to 90 mg of

ustekinumab
50 Did not have PGA
response at wk 12 and
received 90 mg of ustekinumab at wk 16 and 20
245 Had a PGA response at
wk 12 and received 90 mg
of ustekinumab at wk 0
and 4 when psoriasis
recurred
174 Received additional ustekinumab treatment

20 Did not have PGA
received an additional
dose at wk 16
wk 12 and received two
retreatment doses when
psoriasis recurred
270 Received additional ustekinumab treatment

25 Did not have PGA
received an additional
dose at wk 16
wk 12 and received two
retreatment doses when
psoriasis recurred
4 Had adverse event
3 Had other reason
0 Had adverse event
0 Had other reason
3 Had adverse event
3 Had other reason
Figure 2. Enrollment, Randomization, and Treatment through Week 64.

Treatment was interrupted in patients who had a response based on a physicians global assessment (PGA) score of 2 or less (cleared,
RETAKE:
1st
AUTHOR: Griffiths
minimal, or mild psoriasis) at week 12. Patients in the etanercept group crossed over to receive2nd
two 90-mg doses of ustekinumab 4 weeks
apart, beginning at week 16, if they did notFIGURE:
have a 2response
to etanercept (PGA score, 3 [moderate,
marked, or severe psoriasis]) or if
of 3
3rd
Revised
psoriasis recurred as moderate or more severe disease after they had had a response.
Patients in the ustekinumab group were treated
ARTIST: MRL
SIZE disease.
again with their original ustekinumab dose if psoriasis recurred as moderate or more severe
TYPE:
Line
Combo
4-C
H/T
7 col
39p6
AUTHOR, PLEASE NOTE:

Figure has been redrawn and type has been reset.
Please check carefully.
JOB: 361xx
122
ISSUE: 1-14-10

Table 1. Baseline Characteristics of the Patients.*

Variable
Etanercept Group (N=347)
Ustekinumab Group
45 mg
(N=209)
90 mg
(N=347)
Age yr
45.713.4
45.112.6
44.812.3
Male sex no. (%)
246 (70.9)
133 (63.6)
234 (67.4)
White race no. (%)
316 (91.1)
193 (92.3)
309 (89.0)
Weight kg
90.820.9
90.421.1
91.022.8
Duration of psoriasis yr
18.812.1
18.911.8
18.711.8
Involved body-surface area %
23.813.9
26.717.8
26.117.6
18.66.2
20.59.2
19.98.4
Marked or severe psoriasis based on physicians global

assessment no. (%)
Psoriasis area-and-severity index score
148 (42.7)
98 (46.9)
144 (41.5)
Psoriatic arthritis no. (%)
95 (27.4)
62 (29.7)
95 (27.4)
Previous treatment no. (%)

Topical agents
336 (96.8)
202 (96.7)
336 (96.8)
Phototherapy
224 (64.6)
138 (66.0)
230 (66.3)
Conventional systemic agents
199 (57.3)
129 (61.7)
182 (52.4)
Biologic agents
41 (11.8)
26 (12.4)
36 (10.4)
1 Agent
347 (100.0)
209 (100.0)
346 (99.7)
2 Agents
186 (53.6)
118 (56.5)
185 (53.3)
3 Agents
52 (15.0)
31 (14.8)
47 (13.5)
Unsuitable conventional systemic agents no. (%)
* Plusminus values are means SD.

Race was self-reported.
Phototherapy included ultraviolet B light and psoralen plus ultraviolet A (PUVA).
Conventional systemic agents included PUVA, methotrexate, and cyclosporine.
Biologic agents included alefacept, efalizumab, infliximab, and adalimumab.
Unsuitable conventional systemic agents were those for which patients had an inadequate response, a lack of tolerance,
or a contraindication. Categories were not mutually exclusive. For example, patients with intolerance to three agents
were also included as having intolerance to one or more agents and two or more agents.
numab and 1.2% of those who received 90 mg of

ustekinumab). The greatest disparity in adverse
events was observed in the proportions of patients who reported injection-site reactions (24.8%
of patients who received etanercept as compared
with 4.3% of patients who received 45 mg of
ustekinumab and 3.7% of patients who received
90 mg of ustekinumab); the majority of these reactions were mild, and no anaphylaxis or serum
sicknesslike reactions were reported.
Through week 12, serious adverse events occurred in four patients in each treatment group
(Table 3). In the etanercept group, one patient
each had upper abdominal pain, bacterial meningitis, nephrolithiasis, and the rotator-cuff syn-
drome. In the group of patients who received

45 mg of ustekinumab, one patient each had
pancreatitis, psychotic disorder, and hypertension
with chest pain, and one patient with a family
history of breast cancer received a diagnosis of
breast cancer at week 7 of the study. In the
group of patients who received 90 mg of ustekinumab, one patient each had appendicitis, gastrointestinal infection due to food poisoning, and
uvulitis, and one patient was hospitalized twice:
initially for urosepsis complicated by acute renal
failure, gastritis, peptic-ulcer hemorrhage, nosocomial pneumonia, and chest pain (reported as
a myocardial infarction by the investigator but
determined not to be a myocardial infarction by

123
The
of
m e dic i n e
Table 2. Clinical Responses at Week 12.*

Variable
Etanercept (N=347)
Ustekinumab
45 mg
(N=209)
90 mg
(N=347)
Improvement in PASI score

At least 75% no. (%)
197 (56.8)
141 (67.5)
P value
Treatment difference (95% CI)
At least 90% no. (%)
80 (23.1)
P value
256 (73.8)
0.01
<0.001
10.7 (2.419.0)
17.0 (10.024.0)
76 (36.4)
155 (44.7)
<0.001
<0.001
13.3 (5.820.7)
21.6 (14.628.5)
136 (65.1)
245 (70.6)
Physicians global assessment

Cleared or minimal disease no. (%)
170 (49.0)
P value
Cleared disease no. (%)
30 (8.6)
P value
<0.001
<0.001
16.1 (7.624.4)
21.6 (14.428.6)
34 (16.3)
0.006
7.7 (2.213.2)
91 (26.2)
<0.001
17.6 (11.623.7)
* P values are for the comparison of rates between each ustekinumab group and the etanercept group. Treatment differences are percentage-point differences between each ustekinumab group and the etanercept group. CI denotes confidence interval, and PASI psoriasis area-and-severity index.
adjudication) and subsequently for angina. Infections occurred at similar rates in the three treatment groups (29.1%, 30.6%, and 29.7% in the
groups that received etanercept, 45 mg of ustekinumab, and 90 mg of ustekinumab, respectively).
Nonmelanoma skin cancers occurred in two patients in the group that received 45 mg of ustekinumab and in one patient in the group that received 90 mg of ustekinumab; all cases occurred
in areas of cleared psoriatic plaques.
Through week 64, the rates and types of common adverse events were similar in the lowerdose and higher-dose ustekinumab groups and
also before and after crossover from etanercept
to ustekinumab, with the exception of injectionsite reactions through week 12, noted above
(Table 3, and Table 1 of the Supplementary Appendix). Three deaths occurred, one each in the
etanercept group (from a motor vehicle accident),
the lower-dose ustekinumab group (from a gunshot wound), and the higher-dose ustekinumab
group (from multisystem organ failure and sepsis in a patient who was retrospectively shown to
be positive for the human immunodeficiency
virus at study entry and who had methicillinresistant Staphylococcus epidermidis bacteremia). Se124
rious infections of a common bacterial or viral

origin occurred in 4 patients in the etanercept
group (1.2%) (3 before crossover to ustekinumab
and 1 after crossover), 2 patients in the group that
received 45 mg of ustekinumab (1.0%), and 10
patients in the group that received 90 mg of
ustekinumab (2.9%) (P=0.23 for the comparison
between the group that received 45 mg of ustekinumab and the group that received 90 mg) (see
Table 1 in the Supplementary Appendix). Nonmelanoma skin cancers were reported in nine
patients, and other malignant conditions were
reported in five patients treated with ustekinumab,
including one case of mycosis fungoides, which
the investigator retrospectively concluded was
present before randomization but had been incorrectly diagnosed as psoriasis (Table 3). Major adverse cardiovascular events were reported in three
patients overall: one patient each had a myocardial infarction in the etanercept group after crossover to ustekinumab, in the lower-dose ustekinu
mab group, and in the higher-dose ustekinumab
group.
The proportions of patients with abnormalities in hematologic and laboratory measures, including tests of liver and renal function, were

A At Least 75% Improvement in PASI Score
D At Least 75% Improvement in PASI Score
90 mg ustekinumab (N=347)
100
45 mg ustekinumab (N=209)
Etanercept (N=347)
80
Percent of Patients
Percent of Patients
100
P<0.001
60
40
P=0.01
20
0
10
Crossover to 90 mg of ustekinumab
after no response to etanercept
80
60
40
20
0
12
16
20
Week
24
28
32
Week
B Physicians Global Assessment of Cleared or Minimal
E Physicians Global Assessment of Cleared or Minimal

Disease
Disease
100
100
80
Percent of Patients
Percent of Patients
P<0.001
P<0.001
60
P=0.008
P=0.02
40
20
0
80
60
40
20
0
10
12
16
20
100
80
80
60
P<0.001
40
P=0.03
28
32
F At Least 90% Improvement in PASI Score
100
Percent of Patients
Percent of Patients
C At Least 90% Improvement in PASI Score
20
24
Week
Week
Week
10
12
60
40
20
0
No. of
Patients
16
20
49
50
24
28
32
47
49
Week
50
Figure 3. Clinical Response to Treatment, as Measured by the Psoriasis Area-and-Severity Index (PASI) and the Physicians
Global Assessment, over Time.AUTHOR: Griffiths
RETAKE:
1st
The proportions of patients randomly assigned to receive ustekinumab, at a dose of 2nd
either 45 or 90 mg, or etanercept,
of 3 12, who had at least 75% improvement
3rd in the score on the psoriasis
at a dose of 50 mg twice weeklyFIGURE:
through3week
Revised
area-and-severity index (PASI) (Panel
A),MRL
a physicians global assessment of cleared or minimal disease (Panel B),
ARTIST:
SIZE
and at least 90% improvement in the PASI score (Panel C) are shown. Patients
6 colwho were randomly assigned to reTYPE:
LinehaveCombo
4-Cat week
H/T 12 crossed
33p9 over to receive 90 mg of ustekiceive etanercept at baseline and who
did not
a response
numab at weeks 16 through week 32. The proportions
these NOTE:
patients who had at least 75% improvement in the
AUTHOR,ofPLEASE
has been
has been
reset.(Panel E), and at least 90% improvePASI (Panel D), the physicians global Figure
assessment
ofredrawn
clearedand
or type
minimal
disease
Please check carefully.
ment in the PASI (Panel F) are shown.
JOB: 361xx
ISSUE: 1-14-10
similar among the groups (see Table 1 in the Sup numab (3.8%); 26 of these 32 patients had low
plementary Appendix). Antibodies to ustekinumab titers (<1:320), and the presence of antibodies was
developed in 32 of 835 patients treated with usteki- not associated with injection-site reactions.

125
The
of
m e dic i n e
Table 3. Adverse Events and Other Key Safety Data through Week 64.
Variable
Wk 012
Etanercept
Wk 064
Etanercept with Crossover
to 90 mg
Ustekinumab
Ustekinumab
45 mg
90 mg
347
209
347
Mean duration of follow-up wk
12.1
12.1
Mean no. of doses
23.2
2.0
Total no. of patients
1 Adverse event no. of patients (%)
243 (70.0)
Before
After
Crossover Crossover
Episodic Treatment
with Ustekinumab
45 mg
90 mg
347
295
209
347
12.2
24.3
24.4
47.5
51.2
2.0
23.2
2.0
3.5
3.5
138 (66.0) 240 (69.2)
275 (79.3) 191 (64.7)
182 (87.1) 309 (89.0)
Common adverse events no. of patients (%)*

Nasopharyngitis
30 (8.6)
21 (10.0)
34 (9.8)
52 (15.0)
38 (12.9)
50 (23.9)
84 (24.2)
Upper respiratory tract infection
20 (5.8)
13 (6.2)
22 (6.3)
39 (11.2)
35 (11.9)
37 (17.7)
71 (20.5)
Headache
38 (11.0)
31 (14.8)
42 (12.1)
41 (11.8)
9 (3.1)
35 (16.7)
55 (15.9)
Back pain
7 (2.0)
14 (6.7)
15 (4.3)
9 (2.6)
3 (1.0)
17 (8.1)
36 (10.4)
86 (24.8)
9 (4.3)
13 (3.7)
86 (24.8)
5 (1.7)
12 (5.7)
18 (5.2)
Adverse event leading to withdrawal of study

agent no. of patients (%)
Injection-site reaction
8 (2.3)
4 (1.9)
4 (1.2)
11 (3.2)
2 (0.7)
5 (2.4)
10 (2.9)
1 Serious adverse event no. of patients (%)
4 (1.2)
4 (1.9)
4 (1.2)
12 (3.5)
10 (3.4)
17 (8.1)
25 (7.2)
Adverse events of interest no. of patients (%)

Infection
101 (29.1)
Infection requiring treatment
34 (9.8)
64 (30.6) 103 (29.7)

18 (8.6)
33 (9.5)
150 (43.2) 116 (39.3)

56 (16.1)
133 (63.6) 229 (66.0)
33 (11.2)
59 (28.2)
99 (28.5)
Malignant condition other than nonmelanoma skin cancer
1 (0.5)
1 (0.3)
2 (1.0)
2 (0.6)
Nonmelanoma skin cancer
2 (1.0)
1 (0.3)
1 (0.3)
2 (1.0)
6 (1.7)
* Common adverse events were those that occurred in at least 10% of patients in any treatment group.
Malignant conditions other than nonmelanoma skin cancer included breast cancer in one patient and an oral neoplasm in one patient in
the group of patients who received 45 mg of ustekinumab, chronic lymphocytic leukemia in one patient and mycosis fungoides in one patient in the group of patients who received 90 mg of ustekinumab, and prostate cancer in one patient who received etanercept followed by
crossover to 90 mg of ustekinumab.
A total of nine patients had nonmelanoma skin cancers: six with basal-cell carcinoma, one with squamous-cell carcinoma, and two with basal-cell and squamous-cell carcinoma.
Discussion
Biologic agents offer a range of new therapeutic
options for patients with psoriasis; however, the
relative benefitrisk profiles of such therapies are
not well known. A direct comparison between a
systemic medication (methotrexate) and a biologic
agent (adalimumab)23 showed the superiority of
adalimumab 16 weeks after the start of treatment. Our comparison of two biologic agents,
ustekinumab and high-dose etanercept, showed
that ustekinumab has superior efficacy in patients with moderate-to-severe psoriasis, according to both the PASI score and the physicians
global assessment, over a 12-week period.
The safety of ustekinumab and etanercept,
126
including the rates and types of adverse events

and laboratory abnormalities, appeared to be generally similar with short-term treatment, with the
exception of injection-site reactions, which were
more common (albeit mild in the majority of
cases) with etanercept than with ustekinumab.
Patients in the etanercept group received more
injections than did those in the ustekinumab
groups, which may account for the disparity in
the number of patients with injection-site reactions. Through 64 weeks, the rate of serious infections was higher among patients who received
90 mg of ustekinumab than among patients who
received 45 mg of ustekinumab, but the difference was not significant. Rates of noncutaneous
malignant conditions were low in all groups, pre-

cluding meaningful comparisons, and the majority of skin cancers were basal-cell carcinomas.
The safety of ustekinumab did not appear to be
compromised by crossover after treatment with
etanercept or retreatment with ustekinumab after
a treatment interruption. The size and duration
of the study do not eliminate the potential for
differences between these agents with regard to
safety events that occur infrequently or after a
longer period of treatment. In addition, although
TNF- inhibitory agents have been used in clinical practice for the past decade and their safety
is generally well understood,4,7-9 data on the use
of ustekinumab are more limited.
The results of this study provide additional
evidence of the central role of proinflammatory
cytokines in psoriasis and suggest that agents
targeting interleukin-12 and interleukin-23 provide effective treatment of psoriasis. TNF- is
produced by a wide range of immune and nonimmune cells and has broad inflammatory effects, up-regulating both innate and adaptive
immunity and activating a range of nonimmune
tissues, including keratinocytes. Accordingly,
TNF- blockers have broad antiinflammatory effects that may be important in their therapeutic
effect.10-12 In contrast, interleukin-12 and interleukin-23 are produced primarily by activated
antigen-presenting cells, including dermal dendritic cells, and they serve to activate natural
killer cells, CD8+ T cells, and CD4+ T cells, inducing the differentiation of CD4+ T cells into Th1
and Th17 cells. Th1 cells produce proinflammatory cytokines, most prominently interferon-
and TNF-.4,7,8 Th17 cells produce a different
profile and a wider range of proinflammatory
cytokines, which include TNF-, interleukin-17,
and interleukin-22.24 The activities of these cyto
kines affect many cell types, including epithelial
tissues and keratinocytes, possibly providing
communication between the immune system and
the epidermis that results in the keratinocyte
hyperplasia observed in psoriasis.12,24,25 An intriguing aspect that gives credence to the clinical use of interleukin-12 and interleukin-23 anti-
bodies in psoriasis is the recent discovery in a

genomewide association study that polymorphisms in interleukin-12 and interleukin-23 genes
are associated with psoriasis.26
The results of our direct comparison of two
biologic agents, ustekinumab and high-dose etanercept, in the treatment of psoriasis suggest that
ustekinumab provides superior efficacy with similar safety over a 12-week period. Our findings
are generally consistent with those of previous
studies.4,19,27,28 The high level of efficacy of usteki
numab treatment that we observed was achieved
with only two injections during the 12-week period, as compared with twice-weekly injections of
etanercept, which may be important for improved
treatment compliance. Furthermore, the results
of this study could have implications for determining the optimal approach to the treatment of
psoriasis and, in particular, the need for therapeutic strategies targeting Th1 cells, Th17 cells,
or both to provide optimal benefit and safety.
Supported by Centocor Research and Development.

Dr. Griffiths reports receiving consulting and lecture fees from
Abbott, Janssen-Cilag, Merck Serono, Novartis, Schering-Plough,
and Wyeth and grant support from Merck Serono; Dr. Strober, receiving consulting and lecture fees from Centocor, Johnson &
Johnson, Amgen, and Abbott Laboratories and grant support from
Amgen and Abbott Laboratories; Dr. van de Kerkhof, receiving
consulting fees from Schering-Plough, Celgene, Centocor, Al
mirall, UCB, Wyeth, Pfizer, Soffinova, Abbott, Actelion, Galderma, Novartis, Janssen-Cilag, and Leo Pharma; Dr. Ho, receiving
advisory-board and lecture fees from Schering, Abbott, JanssenOrtho, Pfizer, Amgen, and Wyeth and grant support from Centocor, Abbott, Amgen, and Wyeth; Dr. Menter, receiving advisoryboard, consulting, and lecture fees from Abbott, Amgen, Astellas,
Biogen Idec, Celgene, Centocor, Genentech, Warner Chilcott, and
Wyeth; Drs. Yeilding, Guzzo, Xia, and Dooley and Ms. Li, being
employees of Johnson & Johnson and having equity and holding
stock options in Johnson & Johnson; Dr. Zhou, being an employee
of Johnson & Johnson, having equity and holding stock options in
Johnson & Johnson, and having equity in Wyeth; Dr. Fidelus-Gort,
being a former employee of Johnson & Johnson and having equity
and holding stock options in Johnson & Johnson; and Dr. Goldstein, receiving consulting fees from Centocor. No other potential
conflict of interest relevant to this article was reported.
We thank C. Arnold of Centocor Ortho Biotech Services Research and Development for her writing support and editorial
assistance, J. Krueger of Rockefeller University and J. Benson of
Centocor Research and Development for their critical review of
an earlier version of the manuscript, Y. You of Centocor Research
and Development for her programming support, and the National Institute for Health Research, Manchester Biomedical
Research Centre, for support to Dr. Griffiths.
References
1. Schn MP, Boehncke W-H. Psoriasis.
N Engl J Med 2005;352:1899-912.

2. Griffiths CEM, Barker JNWN. Pathogenesis and clinical features of psoriasis.
Lancet 2007;370:263-71.
3. Heydendael VMR, Spuls PI, Opmeer
BC, et al. Methotrexate versus cyclosporine
in moderate-to-severe chronic plaque psoriasis. N Engl J Med 2003;349:658-65.

4. Leonardi CL, Powers JL, Matheson RT,
et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med 2003;
349:2014-22.
5. Lebwohl M, Tyring SK, Hamilton TK,
et al. A novel targeted T-cell modulator,

efalizumab, for plaque psoriasis. N Engl J
Med 2003;349:2004-13.
6. Lebwohl M, Christophers E, Langley
R, Ortonne JP, Roberts J, Griffiths CEM.
An international, randomized, doubleblind, placebo-controlled phase 3 trial of

127

intramuscular alefacept in patients with
chronic plaque psoriasis. Arch Dermatol
2003;139:719-27.
7. Gordon KB, Langley RG, Leonardi C,
et al. Clinical response to adalimumab
treatment in patients with moderate to
severe psoriasis: double-blind, randomized
controlled trial and open-label extension
study. J Am Acad Dermatol 2006;55:598606.
8. Reich K, Nestle FO, Papp K, et al. In
fliximab induction and maintenance
therapy for moderate-to-severe psoriasis:
a phase III, multicentre, double-blind trial.
Lancet 2005;366:1367-74.
9. Menter AM, Feldman SR, Weinstein
GD, et al. A randomized comparison of
continuous vs. intermittent infliximab
maintenance regimens over 1 year in the
treatment of moderate-to-severe plaque
psoriasis. J Am Acad Dermatol 2007;56:31.
e1-31.e15.
10. Hehlgans T, Pfeffer K. The intriguing
biology of the tumour necrosis factor/
tumor necrosis factor receptor superfamily: players, rules and the games. Immunology 2005;115:1-20.
11. Gottlieb AB, Chamian F, Masud S, et
al. TNF inhibition rapidly down-regulates
multiple proinflammatory pathways in
psoriasis plaques. J Immunol 2005;175:
2721-9.
12. Zaba LC, Cardinale I, Gilleaudeau P,
et al. Amelioration of epidermal hyperplasia by TNF inhibition is associated with
reduced Th17 responses. J Exp Med 2007;
204:3183-94.
13. Steinman L. A rush to judgment on
Th17. J Exp Med 2008;205:1517-22.
14. McKenzie BS, Kastelein RA, Cua DJ.
Understanding the IL-23IL-17 immune

pathway. Trends Immunol 2006;27:17-23.
15. Vanden Eijnden S, Goriely S, De Wit
D, Willems F, Goldman M. IL-23 up-regulates IL-10 and induces IL-17 synthesis by
polyclonally activated naive T cells in human. Eur J Immunol 2005;35:469-75.
16. Caproni M, Antiga E, Melani L, Volpi
W, Del Bianco E, Fabbri P. Serum levels of
IL-17 and IL-22 are reduced by etanercept,
but not by acitretin, in patients with psoriasis: a randomized-controlled trial. J Clin
Immunol 2009;29:210-4.
17. Liu H, Rohowsky-Kochan C. Regulation of IL-17 in human CCR6+ effector
memory T cells. J Immunol 2008;180:
7948-57.
18. Acosta-Rodriguez EV, Napolitani G,
Lanzavecchia A, Sallusto F. Interleukins
1 and 6 but not transforming growth
factor- are essential for the differentiation of interleukin 17-producing human
T helper cells. Nat Immunol 2007;8:942-9.
19. Leonardi CL, Kimball AB, Papp KA, et
al. Efficacy and safety of ustekinumab, a
human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week
results from a randomised, double-blind,
placebo-controlled trial (PHOENIX 1).
Lancet 2008;371:1665-74.
20. Kimball AB, Gordon KB, Langley RG,
Menter A, Chartash EK, Valdes J. Safety
and efficacy of ABT-874, a fully human
interleukin-12/23 monoclonal antibody,
in the treatment of moderate to severe
chronic plaque psoriasis: results of a randomized, placebo-controlled, phase 2 trial.
Arch Dermatol 2008;144:200-7.
21. Pocock SJ, Simon R. Sequential treat-
ment assignment with balancing for prognostic factors in the controlled clinical
trial. Biometrics 1975;31:103-15.
22. Fredriksson T, Pettersson U. Severe
psoriasis oral therapy with a new reti
noid. Dermatologica 1978;157:238-44.
23. Saurat J-H, Stingl G, Dubertret L, et al.
Efficacy and safety results from the randomized controlled comparative study of
adalimumab vs. methotrexate vs. placebo
in patients with psoriasis (CHAMPION).
Br J Dermatol 2008;158:558-66.
24. Ouyang W, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity
2008;28:454-67.
25. Kryczek I, Bruce AT, Gudjonsson JE,
et al. Induction of IL-17+ T cell trafficking
and development by IFN-: mechanism
and pathological relevance in psoriasis.
J Immunol 2008;181:4733-41.
26. Liu Y, Helms C, Liao W, et al. A genome-wide association study of psoriasis
and psoriatic arthritis identifies new disease loci. PLoS Genet 2008;4(3):e1000041.
27. Krueger GG, Langley RG, Leonardi C,
et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J Med 2007;356:580-92.
28. Papp KA, Langley RG, Lebwohl M, et
al. Efficacy and safety of ustekinumab,
a human interleukin-12/23 monoclonal
antibody, in patients with psoriasis: 52week results from a randomised, doubleblind, placebo-controlled trial (PHOENIX
2). Lancet 2008;371:1675-84.
Copyright 2010 Massachusetts Medical Society.
electronic access to the journals cumulative index
At the Journals site on the World Wide Web (NEJM.org),

you can search an index of all articles published since January 1975
(abstracts 19751992, full text 1993present). You can search by author,
key word, title, type of article, and date. The results will include the citations
for the articles plus links to the full text of articles published since 1993.
For nonsubscribers, time-limited access to single articles and 24-hour site
access can also be ordered for a fee through the Internet (NEJM.org).
128


Jurnal 3

Enviado por

Dados do documento

Título original

Direitos autorais

Formatos disponíveis

Compartilhar este documento

Compartilhar ou incorporar documento

Opções de compartilhamento

Você considera este documento útil?

Este conteúdo é inapropriado?

Direitos autorais:

Formatos disponíveis

Jurnal 3

Enviado por

Direitos autorais:

Formatos disponíveis

The

Comparison of Ustekinumab and Etanercept

We randomly assigned 903 patients with moderate-to-severe psoriasis to receive

n engl j med 362;2 nejm.org january 14, 2010

The New England Journal of Medicine

Ustekinumab or Etanercept for Psoriasis

soriasis is a chronic, inflammatory

We conducted this study at 67 sites worldwide,

scale of 0 to 5, with 0 indicating no disease and

We randomly assigned patients (in a 3:5:5 ratio)

n engl j med 362;2 nejm.org january 14, 2010

The New England Journal of Medicine

Crossover and retreatment

Retreatment with 45 mg of ustekinumab

Retreatment with 90 mg of ustekinumab

Figure 1. Schematic Representation of the Study Design.

n engl j med 362;2 nejm.org january 14, 2010

The New England Journal of Medicine

Ustekinumab or Etanercept for Psoriasis

cept was 87%, with an overall type I error rate

of patients who received 45 mg or 90 mg of

Of the 1175 patients screened for enrollment,

The New England Journal of Medicine

1175 Patients were screened

903 Underwent randomization

209 Were assigned to 45 mg of

347 Were assigned to 50 mg of

347 Were assigned to 90 mg of

336 Completed 12-wk treatment

201 Completed 12-wk treatment

342 Completed 12-wk treatment

295 Crossed over to 90 mg of

174 Received additional ustekinumab treatment

270 Received additional ustekinumab treatment

287 Completed treatment

172 Completed treatment

263 Completed treatment

Figure 2. Enrollment, Randomization, and Treatment through Week 64.

AUTHOR, PLEASE NOTE:

n engl j med 362;2 nejm.org january 14, 2010

The New England Journal of Medicine

Ustekinumab or Etanercept for Psoriasis

Table 1. Baseline Characteristics of the Patients.*

Etanercept Group (N=347)

Male sex no. (%)

White race no. (%)

Involved body-surface area %

Marked or severe psoriasis based on physicians global

Psoriasis area-and-severity index score

Psoriatic arthritis no. (%)

Previous treatment no. (%)

Conventional systemic agents

Unsuitable conventional systemic agents no. (%)

* Plusminus values are means SD.

numab and 1.2% of those who received 90 mg of

drome. In the group of patients who received

n engl j med 362;2 nejm.org january 14, 2010

The New England Journal of Medicine

Table 2. Clinical Responses at Week 12.*

Improvement in PASI score

Physicians global assessment

Treatment difference (95% CI)

rious infections of a common bacterial or viral