DOI: 10.1111/jdv.

12238 JEADV

ORIGINAL ARTICLE

Efficacy of biologics in the treatment of moderate-to-severe

plaque psoriasis: a systematic review and meta-analysis of
randomized controlled trials with different time points
 pez,1 E. Vilarrasa,1 I. Garcıa2
L. Puig,1,* A. Lo
1
noma de Barcelona, Barcelona, Spain
Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Universitat Auto
2
Janssen-Cilag S.A., Madrid, Spain
*Correspondence: L. Puig. E-mail: lpuig@santpau.cat

Abstract
Background Differences in response rates of biologics for the treatment of moderate-to-severe plaque psoriasis have
been reported in several meta-analyses published to date. However, the usefulness of these meta-analyses is limited as
they do not reflect currently approved recommendations in the Summaries of Product Characteristics (SmPCs) and
clinical practice.
Objective To estimate the efficacy of biologics in the treatment of moderate-to-severe plaque psoriasis in the
currently approved conditions of use in the European Union (EU) at relevant time points for evaluation of response
in clinical practice (failure assessment as recommended in the SmPCs and/or at the end of the induction phase).
Methods Randomized placebo-controlled studies of biologics currently authorized in the EU in adult patients with a
diagnosis of moderate-to-severe plaque psoriasis were searched in several databases. A meta-analysis using fixed or
random-effects model depending on heterogeneity across and within studies was performed. The efficacy was estimated
using risk difference (RD) of Psoriasis Area and Severity Index (PASI) 50, PASI 75 and PASI 90 response rates at the end-
point in clinical trials, at the end of the induction phase (week 24) and at the time points recommended for evaluation of
primary failure in the approved SmPCs. Several sensitivity analyses were performed to assess for robustness.
Results Sixteen publications met the defined inclusion criteria. According to this meta-analysis at the primary endpoint
times, infliximab (at week 10) has the greatest probability of response with respect to placebo for all PASI-based efficacy
measures (PASI 50, PASI 75 and PASI 90). At the end of the induction phase (week 24), ustekinumab 45 mg has the
greatest probability of achieving PASI 75 response (RD 75.5%, 95%CI 71.5–79.4%], followed by ustekinumab 90 mg,
infliximab, adalimumab and etanercept. At the time points recommended for primary failure assessment according to the
approved SmPCs, ustekinumab 45 mg (at week 28) also has the greatest probability of achieving PASI 50 response [RD
80.7%, 95%CI 77.2–84.2%], followed by ustekinumab 90 mg, infliximab, adalimumab and etanercept.
Conclusion From a clinical practice perspective, and in terms of the most relevant efficacy measures (PASI 50 and
PASI 75) and time points (end of induction phase [week 24] and time to assess primary failure as per the SmPCs), in the
currently approved conditions of use ustekinumab is the most efficacious therapeutic alternative for moderate-to-severe
plaque psoriasis, followed by infliximab, adalimumab and etanercept.
Received: 21 March 2013; Accepted: 12 July 2013

Conflicts of interest
Lluís Puig has received consultancy and speaker’s honoraria from Abbott, Janssen, MSD, and Pfizer, and participated in
clinical trials sponsored by these laboratories. Ignacio García González is an employee of Janssen-Cilag, S.A and owns
stock in Johnson & Johnson.

Funding sources
Janssen-Cilag, S.A. provided funding for independent data analysis by Pertica, Spain.

Introduction In the European Union (EU), the recommended first line

Psoriasis is a chronic, systemic, immune-mediated inflammatory therapy for moderate-to-severe psoriasis is phototherapy and
skin disease of unknown aetiology,1 affecting 2%–3% of the conventional systemic therapies.4 However, the long-term use of
European population,2 and having a substantial negative impact these conventional systemic therapies can be limited by
on patients’ quality of life.3 intolerance or accumulated organ-specific toxic effects. Patients

JEADV 2014, 28, 1633–1653 © 2013 European Academy of Dermatology and Venereology
1634
failing to respond to, or having a contraindication to, or being
intolerant to other systemic therapies including cyclosporine,
methotrexate and PUVA are eligible for treatment with
biologics.
The differences in response rates of biologics are well
established as demonstrated in the only head-to-head study
comparing two approved biologics published to date,5 and
several articles presenting meta-analyses comparing biologics
indirectly.6–11 These meta-analyses are used in cost-efficacy
analyses12 that may contribute to establishing treatment
recommendations for the use of biologics in clinical practice.
When performing economic evaluations by combining costs
with efficacy estimates it is necessary to apply clinically relevant
data based on available scientific evidence, to optimize treatment
decision-making.13 Clinically relevant time points to compare
biologics currently approved in the EU for the treatment of
moderate-to-severe psoriasis are the primary endpoint (used for
regulatory evaluation of efficacy), time of failure assessment
[when a decision has to be made according to the approved
Summaries of Product Characteristics (SmPCs)], and at the end
of the induction phase (when a decision on continuing
Figure 1 Flowchart of studies included in the systematic review.
JEADV 2014, 28, 1633–1653
Lluıs Puig et al.
maintenance treatment, combination therapy, dose
intensification or switching is to be done).13 Psoriasis Area and
Severity Index (PASI) 75 and PASI 90 (namely, the percentage
of patients achieving at least a 75% or 90% improvement with
respect to baseline PASI) are the relevant outcome measures for
efficacy, whereas PASI 50 is the lower threshold of efficacy, and
100% minus the percentage of patients achieving PASI 50
response can be considered the percentage of failure.
The aim of this study was to estimate the efficacy of currently
available biologics for the treatment of moderate-to-severe
plaque psoriasis under the currently approved conditions of use
in the EU at clinically relevant time points of evaluation by
means of risk difference (RD) with respect to placebo.
Methods
Identification of randomized controlled trials
Studies published in the Medline, EMBASE, the Cochrane
Central Register of Controlled Trials databases were identified
using combinations of the following keywords: psoriasis; any of
these treatments: adalimumab, etanercept, infliximab or
© 2013 European Academy of Dermatology and Venereology
 Table 1 (a) Data abstracted from selected studies in the systematic review. (b) Data abstracted from non-placebo controlled studies included in the sensitivity analyses
Author, year Comparator and Patients (n) Week Number of Number of Number of
Dosage of evaluation patients patients patients
of response achieving PASI achieving PASI achieving
50 response 75 response PASI
90 response
(a) Data abstracted from selected studies in the systematic review
Chaudhari, 2001 Placebo 11 10 ND 2 ND

JEADV 2014, 28, 1633–1653

Infliximab 5 mg/kg 11 10 ND 9 ND
Gordon, 2006 Placebo 52 12 7 2 0
Adalimumab 40 mg eow 45 12 34 24 11
Placebo (LOCF) 52 24 7 2 0
Adalimumab 40 mg eow 45 24 35 29 14
Gottlieb, 2003 Placebo 55 12 6 1 0
Etanercept 25 mg biw 57 12 40 17 6
Placebo 55 24 7 3 0
Etanercept 25 mg biw 57 24 44 32 12
Gottlieb, 2004 Placebo 51 10 11 3 1
Infliximab 5 mg/kg 99 10 96 87 57
Gottlieb, 2011 Placebo 68 12 ND 5 1
Etanercept 50 mg biw 141 12 ND 79 33
Biologics in psoriasis: a meta-analysis at relevant time points

Leonardi, 2003 Placebo 166 12 24 6 1

Etanercept 25 mg biw 162 12 94 55 19
Etanercept 50 mg biw 164 12 121 81 36
Placebo [LOCF] 166 24 24 6 1
Etanercept 25 mg biw 162 24 113 71 32
Etanercept 50 mg biw 164 24 127 97 49
1635

© 2013 European Academy of Dermatology and Venereology

 Table 1 (Continued)
1636

Author, year Comparator and Patients (n) Week Number of Number of Number of
Dosage of evaluation patients patients patients
of response achieving PASI achieving PASI achieving
50 response 75 response PASI
90 response
Leonardi, 2008 Placebo 255 12 26 8 5
Ustekinumab 45 mg (≤100 kg) 168 12 143 124 79

JEADV 2014, 28, 1633–1653

Ustekinumab 90 mg (>100 kg) 92 12 79 63 28
Placebo [LOCF] 255 24 26 8 5
Ustekinumab 45 mg (≤100 kg) 168 24 152 137 106
Ustekinumab 90 mg (>100 kg) 92 24 84 72 48
Placebo (LOCF) 255 28 26 8 5
Ustekinumab 45 mg (≤100 kg) 168 28 152 130 95
Ustekinumab 90 mg (>100 kg) 92 28 86 67 37
Placebo 255 12 26 8 5
Ustekinumab 45 mg 255 12 213 171 106
Ustekinumab 90 mg 256 12 220 170 94
Placebo (LOCF) 255 24 26 8 5
Ustekinumab 45 mg 255 24 226 191 140
Ustekinumab 90 mg 256 24 235 209 156
Placebo (LOCF) 255 28 26 8 5
Ustekinumab 45 mg 255 28 228 178 123
Ustekinumab 90 mg 256 28 234 191 135
Menter, 2007 Placebo 208 10 ND 4 1
Infliximab 5 mg/kg 314 10 ND 237 142
Placebo (LOCF) 208 14 ND 4 ND
Infliximab 5 mg/kg 158 14 ND 115 ND
Placebo (LOCF) 208 22 ND 4 ND
Infliximab 5 mg/kg 185 22 ND 109 ND
Placebo (LOCF) 208 26 ND 4 1
Infliximab 5 mg/kg 158 26 126 110 79
Menter, 2008 Placebo 398 12 60 20 8
Adalimumab 40 mg eow 814 12 671 554 301
Placebo (LOCF) 398 16 60 26 8
Adalimumab 40 mg eow 814 16 676 578 366
Placebo (LOCF) 398 24 ND 26 8
Adalimumab 40 mg eow 814 24 ND 570 399
Lluıs Puig et al.

© 2013 European Academy of Dermatology and Venereology

 Table 1 (Continued)

Author, year Comparator and Patients (n) Week Number of Number of Number of
Dosage of evaluation patients patients patients
of response achieving PASI achieving PASI achieving
50 response 75 response PASI
90 response
Papp, 2005 Placebo 193 12 18 6 1
Etanercept 25 mg biw 196 12 126 67 21

JEADV 2014, 28, 1633–1653

Etanercept 50 mg biw/qw 194 12 150 96 40
Placebo (LOCF) 193 24 ND 6 ND
Etanercept 25 mg biw 196 24 ND 88 ND
Etanercept 50 mg biw/qw 194 24 ND 105 ND
Papp, 2008 Placebo 410 12 41 15 3
Ustekinumab 45 mg (≤100 kg) 297 12 259 218 146
Ustekinumab 90 mg (>100 kg) 121 12 106 86 50
Placebo (LOCF) 410 24 41 15 3
Ustekinumab 45 mg (≤100 kg) 297 24 270 230 170
Ustekinumab 90 mg (>100 kg) 121 24 107 95 58
Placebo (LOCF) 410 28 41 15 3
Ustekinumab 45 mg (≤100 kg) 297 28 270 217 152
Ustekinumab 90 mg (>100 kg) 121 28 108 88 49
Biologics in psoriasis: a meta-analysis at relevant time points

Placebo 410 12 41 15 3
Ustekinumab 45 mg 409 12 342 273 173
Ustekinumab 90 mg 411 12 367 311 209
Placebo (LOCF) 410 24 41 15 3
Ustekinumab 45 mg 409 24 366 292 202
Ustekinumab 90 mg 411 24 376 335 240
Placebo (LOCF) 410 28 41 15 3
Ustekinumab 45 mg 409 28 369 276 178
Ustekinumab 90 mg 411 28 380 314 217
Reich, 2005 Placebo 77 10 6 2 1
Infliximab 5 mg/kg 301 10 274 242 172
Placebo 77 24 6 3 1
Infliximab 5 mg/kg 301 24 248 227 161
Saurat, 2008 Placebo 53 12 14 8 4
Adalimumab 40 mg eow 108 12 98 83 53
Placebo 53 16 16 10 6
Adalimumab 40 mg eow 108 16 95 86 54
Strober, 2011 Placebo 72 12 ND 5 3
Etanercept 50 mg biw 139 12 ND 55 19
1637

© 2013 European Academy of Dermatology and Venereology

 1638

Table 1 (Continued)

Author, year Comparator and Patients (n) Week Number of Number of Number of
Dosage of evaluation patients patients patients
of response achieving PASI achieving PASI achieving

JEADV 2014, 28, 1633–1653

50 response 75 response PASI
90 response
Tyring, 2006 Placebo 307 12 43 15 3
Etanercept 50 mg biw 311 12 229 147 65
Placebo (LOCF) 307 24 43 15 3
Etanercept 50 mg biw 311 24 264 187 87
Van de Kerkhoff, 2008 Placebo 46 12 4 1 1
Etanercept 50 mg qw 96 12 66 36 13
Placebo (LOCF) 46 24 4 1 1
Etanercept 50 mg qw 96 24 75 64 38
(b) Data abstracted from non-placebo controlled studies included in the sensitivity analyses
Barker, 2001 Infliximab 5 mg/kg 653 10 579 487 291
Infliximab 5 mg/kg 653 14 562 473 310
Infliximab 5 mg/kg 653 22 530 473 306
Griffiths, 2011 Etanercept 50 mg biw 347 12 286 197 80
Ustekinumab 45 mg 209 12 181 141 76
Ustekinumab 90 mg 347 12 320 256 155
Ustekinumab 45 mg (≤100 kg) 151 12 136 109 32
Ustekinumab 90 mg (>100 kg) 103 12 93 67 33
Sterry, 2010 Etanercept 50 mg qw/qw 373 12 ND 135 ND
Etanercept 50 mg qw/qw 373 24 ND 231 ND
Etanercept 50 mg biw/qw 379 12 ND 207 ND
Etanercept 50 mg biw/qw 379 24 ND 265 ND
Strohal, 2012 Etanercept 50 mg qw/qw 137 12 117 83 39
Etanercept 50 mg qw/qw 137 24 123 104 66
Etanercept 50 mg biw/qw 136 12 93 51 15
Etanercept 50 mg biw/qw 136 24 111 82 45
Thacß i, 2010 Adalimumab 40 mg eow 364 12 ND 267 ND
Adalimumab 40 mg eow 364 16 ND 258 183

PASI, Psoriasis Area and Severity Index; LOCF, Last Observation Carried Forward; ND, No data provided
Lluıs Puig et al.

© 2013 European Academy of Dermatology and Venereology

Biologics in psoriasis: a meta-analysis at relevant time points 1639

Table 2 Pooled efficacy data at the primary endpoint times to plateau of PASI 75 response rate plots in clinical trials),13
(pooled risk difference vs. placebo) and at the recommended time point for assessing treatment
Treatment PASI 50 (%) PASI 75 (%) PASI 90 (%) failure according to the SmPCs.
[95% CI] [95% CI] [95% CI] 2 Only approved treatment regimens indicated for therapy of
Adalimumab† 66.4 (62.4–70.5) 63.0 (59.3–66.7) 36.5 (25.7–47.4)* plaque psoriasis according to the respective SmPC were
Etanercept 52.2 (47.1–57.3) 31.0 (26.6–35.4) 10.7 (7.8–13.6) included in the meta-analysis. Thus, for ustekinumab, only
25 mg
weight-based efficacy data (45 mg for patients with body-
biw or
50 mg qw‡ weight ≤100 kg, 90 mg for patients with bodyweight
Etanercept 62.0 (57.8–66.1) 43.5 (40.0–47.1) 19.3 (16.6–22.0) >100 kg) were considered. In the case of etanercept, different
50 mg biw‡ treatment regimens were considered separately, including
Infliximab§ 80.5 (74.4–86.5) 75.7 (72.1–79.3) 49.5 (45.6–53.4) etanercept 25 mg twice weekly (biw), etanercept 50 mg
Ustekinumab 76.4 (72.5–80.2) 70.1 (65.8–74.3) 47.2 (42.6–51.8) weekly (qw), etanercept 50 mg biw for the first 12 weeks fol-
45 mg‡,¶
lowed by 50 mg qw and finally, etanercept 50 mg biw.
Ustekinumab 76.8 (71.7–81.9) 66.5 (60.2–72.9) 35.5 (29.0–42.0)
90 mg‡,¶ 3 All trials used in the meta-analysis compared the respective
biologics vs. placebo. Evidence on placebo response beyond
*DerSimonian-Laird pooled risk difference.
12 weeks is limited, as clinical trials are usually designed with
†Evaluation of response at week 16.
‡Evaluation of response at week 12. a cross-over phase from placebo to active treatment after the
§Evaluation of response at week 10. primary efficacy endpoint has been measured. Thus, a last
¶Efficacy (PASI response rates) based on recommended posology as per observation carried forward (LOCF) approach was used for
the approved SmPC: ustekinumab 45 mg for patients with bodyweight the placebo group at week 24. This approach uses the last
≤100 kg, and ustekinumab 90 mg for patients with bodyweight >100 kg. observed efficacy data in the clinical trial (which usually coin-
SmPC, Summaries of Product Characteristics; PASI, Psoriasis Area and
cides with the endpoint). In addition, the available clinical
Severity Index; CI, confidence intervals
evidence shows that placebo efficacy does not increase
significantly from the endpoint until week 24 assessment.14,15
ustekinumab; randomized trial; English language and published Using LOCF data for the placebo group qualifies as an accept-
from 1 January 2001 to 1 May 2012. able approach, as it is consistent with current clinical evidence
and allows for minimizing population effects on a study basis.
Inclusion and exclusion criteria 4 In the case of etanercept the response rates at week 12
To be considered for inclusion in the meta-analysis, the studies corresponding to the measure at the endpoint and SmPC
had to meet the following inclusion criteria: Patients (human) were pooled for arms where patients received 50 mg biw for
with a diagnosis of moderate-to-severe plaque psoriasis; the first 12 weeks.
placebo-controlled studies; PASI 75 as main outcome; 5 In case of a missing outcome value, we have contacted the
assessment of primary efficacy endpoint at 10, 12 or 16 weeks; authors to retrieve the data.
random and blinded allocation of participants in the treatment
and control group, and finally, trial publication as part of full Statistical methods
articles in peer-reviewed journals. Meta-analyses were done using the fixed (Mantel–Haenszel)
Only biologics currently authorized in the EU as of May 2012 or random-effects (DerSimonian & Laird) model in the meta-
were included in the analysis. Likewise, only authorized treat- analytic statistical package in STATA version 10.0 (StataCorp
ment regimens were included (i.e. combined therapy was not LP, College Station, TX, USA) depending on heterogeneity
included); observational, retrospective studies, case reports/ser- across individual studies. These estimations take into consid-
ies and review articles were also not included. eration the within-study comparison as well as differences
between studies. Heterogeneity was studied by the I2 statistic
Data extraction proposed by Higgins and Thompson.16
The inclusion criteria for the analysis were applied by one For the comparative models, the weighted RD was calculated
researcher and verified by another. There were no discrepancies based on weighting of individual results by the inverse variance;
between the researchers. Data extracted from each trial included this limits the impact of studies with wide confidence intervals
the main study and patient characteristics as well as results from (CIs). The study-specific standard errors for the estimated RD
outcome parameters and time points. The following criteria were used to account for within-study variation.
were applied for data extraction: To address the optimal reporting of meta-analyses, we used
1 To consider consistent time points for the analysis, data were the recent revision of the PRISMA (Preferred Reporting Items
extracted at three different time points: at the primary for Systematic reviews and Meta-Analyses) and we adopted the
endpoint time, at week 24 (end of induction phase according definitions proposed by the Cochrane Collaboration.17

JEADV 2014, 28, 1633–1653 © 2013 European Academy of Dermatology and Venereology
1640 Lluıs Puig et al.

Results measured as outcome. Sixteen of these publications were placebo

Literature review
Literature searches identified twenty-one publications describing
randomized clinical trials of biologics in the treatment of
moderate-to-severe psoriasis where PASI improvement was
controlled studies and were used in the meta-analysis. In the
sensitivity analysis five studies without placebo control arm were
also included. The systematic literature review process is pre-
sented in Figure 1.

%
Study Weight
ID RD (95% CI) (M-H)

etanercept 25 mg biw or etanercept 50 mg qw

Gottlieb 2003 0.59 (0.45–0.74) 1.96
Leonardi 2003 0.44 (0.34–0.53) 5.74
Papp 2005 [CONSORT] 0.55 (0.47–0.63) 6.81
van de Kerkhoff 2008 0.60 (0.48–0.72) 2.18
M-H Subtotal (I-squared = 52.1%, P = 0.100) 0.52 (0.47–0.57) 16.68
D+L Subtotal 0.54 (0.46–0.61)
.
etanercept 50 mg biw
Papp 2005 [CONSORT] 0.68 (0.61–0.75) 6.77
Tyring 2006 0.60 (0.53–0.66) 10.81
Leonardi 2003 0.59 (0.51–0.68) 5.77
M-H Subtotal (I-squared = 44.5%, P = 0.165) 0.62 (0.58–0.66) 23.36
D+L Subtotal 0.62 (0.57–0.68)
.
adalimumab
Gordon 2006 0.62 (0.46–0.78) 1.69
Saurat 2008 [CHAMPION] 0.58 (0.44–0.72) 2.49
Menter 2008 [REVEAL] 0.68 (0.64–0.72) 18.71
M-H Subtotal (I-squared = 12.6%, P = 0.319) 0.66 (0.62–0.70) 22.89
D+L Subtotal 0.66 (0.61–0.71)
.
infliximab
Reich 2005 [EXPRESS I] 0.83 (0.76–0.90) 4.29
Gottlieb 2004 [SPIRIT] 0.75 (0.64–0.87) 2.36
M-H Subtotal (I-squared = 25.9%, P = 0.245) 0.80 (0.74–0.87) 6.65
D+L Subtotal 0.81 (0.73–0.88)
.
ustekinumab 45 mg
Leonardi 2008 [PHOENIX 1] 0.75 (0.68–0.81) 7.09
Papp 2008 [PHOENIX 2] 0.77 (0.72–0.82) 12.06
M-H Subtotal (I-squared = 0.0%, P = 0.580) 0.76 (0.72–0.80) 19.15
D+L Subtotal 0.76 (0.73–0.80)
.
ustekinumab 90 mg
Leonardi 2008 [PHOENIX 1] 0.76 (0.68–0.84) 4.73
Papp 2008 [PHOENIX 2] 0.78 (0.71–0.84) 6.54
M-H Subtotal (I-squared = 0.0%, P = 0.715) 0.77 (0.72–0.82) 11.27
D+L Subtotal 0.77 (0.72–0.82)
.
M-H Overall (I-squared = 86.1%, P = 0.000) 0.67 (0.65–0.69) 100.00
D+L Overall 0.67 (0.61–0.72)

–0.9 0 0.9

Figure 2a Forest plot depicting meta-analysis of PASI 50 efficacy results at the primary endpoint. RD, risk difference; M-H, Mantel-
Haenszel; D+L, DerSimonian & Laird.

JEADV 2014, 28, 1633–1653 © 2013 European Academy of Dermatology and Venereology
Biologics in psoriasis: a meta-analysis at relevant time points 1641

%
Study Weight
ID RD (95% CI) (M-H)

etanercept 25 mg biw or etanercept 50 mg qw

Gottlieb 2003 0.28 (0.16–0.40) 1.69
Leonardi 2003 0.30 (0.23–0.38) 4.96
Papp 2005 [CONSORT] 0.31 (0.24–0.38) 5.88
van de Kerkhoff 2008 0.35 (0.25–0.46) 1.88
M-H Subtotal (I-squared = 0.0%, P = 0.826) 0.31 (0.27–0.35) 14.42
D+L Subtotal 0.31 (0.27–0.36)
.
etanercept 50 mg biw
Papp 2005 [CONSORT] 0.46 (0.39–0.54) 5.85
Tyring 2006 0.42 (0.36–0.48) 9.35
Leonardi 2003 0.46 (0.38–0.54) 4.99
Gottlieb 2011 0.49 (0.38–0.59) 2.78
Strobber 2011 0.33 (0.23–0.43) 2.87
M-H Subtotal (I-squared = 38.4%, P = 0.165) 0.44 (0.40–0.47) 25.84
D+L Subtotal 0.43 (0.39–0.48)
.
adalimumab
Gordon 2006 0.49 (0.34–0.65) 1.46
Saurat 2008 [CHAMPION] 0.61 (0.48–0.74) 2.15
Menter 2008 [REVEAL] 0.64 (0.61–0.68) 16.18
M-H Subtotal (I-squared = 44.2%, P = 0.167) 0.63 (0.59–0.67) 19.79
D+L Subtotal 0.61 (0.53–0.69)
.
infliximab
Reich 2005 [EXPRESS I] 0.78 (0.72–0.84) 3.71
Menter 2007 [EXPRESS II] 0.74 (0.68–0.79) 7.57
Gottlieb 2004 [SPIRIT] 0.82 (0.73–0.91) 2.04
Chaudari 2001 0.64 (0.31–0.96) 0.33
M-H Subtotal (I-squared = 15.7%, P = 0.313) 0.76 (0.72–0.79) 13.65
D+L Subtotal 0.76 (0.72–0.80)
.
ustekinumab 45 mg
Leonardi 2008 [PHOENIX 1] 0.71 (0.64–0.78) 6.13
Papp 2008 [PHOENIX 2] 0.70 (0.64–0.75) 10.42
M-H Subtotal (I-squared = 0.0%, P = 0.836) 0.70 (0.66–0.74) 16.55
D+L Subtotal 0.70 (0.66–0.74)
.
ustekinumab 90 mg
Leonardi 2008 [PHOENIX 1] 0.65 (0.56–0.75) 4.09
Papp 2008 [PHOENIX 2] 0.67 (0.59–0.76) 5.65
M-H Subtotal (I-squared = 0.0%, P = 0.750) 0.67 (0.60–0.73) 9.75
D+L Subtotal 0.67 (0.60–0.73)
.
M-H Overall (I-squared = 95.0%, P = 0.000) 0.57 (0.55–0.58) 100.00
D+L Overall 0.54 (0.47–0.62)

–0.959 0 0.959

Figure 2b Forest plot depicting meta-analysis of PASI 75 efficacy results at the primary endpoint. RD, risk difference; M-H, Mantel-
Haenszel; D+L, DerSimonian & Laird.

Sixteen publications of placebo-controlled studies with seven studies of etanercept14,18–23 (n = 2.367), four of inflix
biologics including 6.905 patients (4.483 with biologic treatment imab15,24–26 (n = 1.072), three of adalimumab27–29 (n = 1.470)
and 2.422 with placebo) met the predefined inclusion criteria: and two of ustekinumab30,31 (n = 1.996). All studies reported

JEADV 2014, 28, 1633–1653 © 2013 European Academy of Dermatology and Venereology
1642 Lluıs Puig et al.

%
Study Weight
ID RD (95% CI) (M-H)

etanercept 25 mg biw or etanercept 50 mg qw

Gottlieb 2003 0.11 (0.02–0.19) 1.70
Leonardi 2003 0.11 (0.06–0.16) 4.98
Papp 2005 [CONSORT] 0.10 (0.06–0.15) 5.90
van de Kerkhoff 2008 0.11 (0.03–0.19) 1.89
M-H Subtotal (I-squared = 0.0%, P = 0.991) 0.11 (0.08–0.14) 14.47
D+L Subtotal 0.11 (0.08–0.14)
.
etanercept 50 mg biw
Papp 2005 [CONSORT] 0.20 (0.14–0.26) 5.87
Tyring 2006 0.20 (0.15–0.25) 9.38
Leonardi 2003 0.21 (0.15–0.28) 5.01
Gottlieb 2011 0.22 (0.14–0.29) 2.79
Strobber 2011 0.10 (0.02–0.17) 2.88
M-H Subtotal (I-squared = 49.0%, P = 0.098) 0.19 (0.17–0.22) 25.93
D+L Subtotal (0.15, 0.23)
0.19 (0.15–0.23)
.
adalimumab
Gordon 2006 0.24 (0.12–0.37) 1.46
Saurat 2008 [CHAMPION] 0.39 (0.26–0.51) 2.16
Menter 2008 [REVEAL] 0.43 (0.39–0.47) 16.23
M-H Subtotal (I-squared = 73.8%, P = 0.022) 0.41 (0.38–0.45) 19.85
D+L Subtotal 0.37 (0.26–0.47)
.
infliximab
Reich 2005 [EXPRESS I] 0.56 (0.50–0.62) 3.72
Menter 2007 [EXPRESS II] 0.45 (0.39–0.50) 7.60
Gottlieb 2004 [SPIRIT] 0.56 (0.45–0.66) 2.04
M-H Subtotal (I-squared = 75.6%, P = 0.016) 0.49 (0.46–0.53) 13.36
D+L Subtotal 0.52 (0.43–0.60)
.
ustekinumab 45 mg
Leonardi 2008 [PHOENIX 1] 0.45 (0.37–0.53) 6.15
Papp 2008 [PHOENIX 2] 0.48 (0.43–0.54) 10.46
M-H Subtotal (I-squared = 0.0%, P = 0.494) 0.47 (0.43–0.52) 16.61
D+L Subtotal 0.47 (0.43–0.52)
.
ustekinumab 90 mg
Leonardi 2008 [PHOENIX 1] 0.28 (0.19–0.38) 4.10
Papp 2008 [PHOENIX 2] 0.41 (0.32–0.49) 5.67
M-H Subtotal (I-squared = 70.2%, P = 0.067) 0.36 (0.29–0.42) 9.78
D+L Subtotal 0.35 (0.23–0.47)
.
M-H Overall (I-squared = 96.3%, P = 0.000) 0.33 (0.31–0.34) 100.00
D+L Overall 0.29 (0.22–0.37)

–0.661 0 0.661

Figure 2c Forest plot depicting meta-analysis of PASI 90 efficacy results at the primary endpoint. RD, risk difference; M-H, Mantel-
Haenszel; D+L, DerSimonian & Laird.

PASI 75 as the primary efficacy measure at different time points biologic treatments showed superior responses compared to
and most of them also reported PASI 50 and PASI 90 measures. placebo (Table 1a). Data abstracted from non-placebo con-
Baseline demographic characteristics (age, gender or disease trolled studies included in the sensitivity analyses are detailed in
duration) were similar between trials and consistently all Table 1b.

JEADV 2014, 28, 1633–1653 © 2013 European Academy of Dermatology and Venereology
Biologics in psoriasis: a meta-analysis at relevant time points 1643

Efficacy results at the primary endpoint
According to this meta-analysis at the primary endpoint times
(Table 2, Fig. 2), infliximab (at week 10) has the greatest
probability of response with respect to placebo for all PASI-
based efficacy measures (PASI 50, PASI 75 and PASI 90). As
regards PASI 75, the relevant efficacy measure at the endpoint
in clinical trials, infliximab (at week 10) has the greatest proba-
bility of achieving PASI 75 response (RD 75.7%, 95% CI
72.1%–79.3%) followed by ustekinumab 45 mg (at week 12)
(RD 70.1%, 65.8%–74.3%), ustekinumab 90 mg (at week 12)
(RD 66.5%, 60.2%–72.9%), adalimumab (at week 16) (RD
63.0%, 59.3%–66.7%), etanercept 50 mg biweekly (at week 12)
(RD 43.5%, 40.0%–47.1%) and etanercept 25 mg biweekly or
50 mg weekly (at week 12) (RD 31.0%, 26.6%–35.4%).
Efficacy results at the recommended time point for
assessing failure as per the approved SmPCs
According to this meta-analysis at the recommended time point
as per the approved SmPCs (Table 3, Fig. 3), ustekinumab (at
week 28) rendered the greatest probabilities of response in all
PASI measures (PASI 50, PASI 75 and PASI 90).
According to the SmPC-based recommendation regarding
withdrawal (and switching) of biologics, PASI 50 response is the
threshold for efficacy and therefore not achieving this outcome
is a relevant measure of failure in clinical practice. In this regard,
ustekinumab 45 mg (at week 28) has the greatest probability of
achieving PASI 50 response (RD 80.7%, 77.2%–84.2%), followed
by ustekinumab 90 mg (at week 28) (RD 80.9%, 76.5%–85.4%),
adalimumab (at week 16) (RD 66.4%, 62.4%–70.5%), etanercept
At week 24, in terms of PASI 75 response (a relevant efficacy
measure in clinical practice), ustekinumab 45 mg has the
greatest probability of achieving this outcome (RD 75.5%,
71.5%–79.4%), followed by ustekinumab 90 mg (RD 75.0%,
69.3%–80.7%), infliximab (RD 69.2%; 64.1%–74.4%),
adalimumab (RD 63.3%, 59.4%–67.1%), etanercept 50 mg
biweekly (RD 55.3%, 50.6%–60.1%), 50 mg biweekly (RD
51.0%, 43.6%–58.4%) and etanercept 25 mg biweekly or 50 mg
weekly (RD 48.8%, 37.7%–59.9%).
Sensitivity analysis
To incorporate the maximum amount of clinical evidence into
the meta-analysis a sensitivity analysis, including results from
studies without a placebo control arm, was carried out
(Table 1b). Five clinical trials on biologics without a placebo-
controlled arm accounting for 2.947 patients were included in
the sensitivity analysis: three studies of etanercept5,32,33
(n = 1.372), and one of infliximab34 (n = 653), adalimumab35
(n = 366) and ustekinumab5 (n = 556), respectively. In this sen-
sitivity analysis, for those trials without placebo arm a pooled
placebo response rate derived from all placebo arms was used. In
this case, for the relevant parameters from a clinical practice per-
spective (PASI 50 and PASI 75), the results obtained in the three
Table 3 Pooled efficacy data at the recommended time point for
assessing failure as per approved SmPCs (pooled risk difference
vs. placebo)
Treatment PASI 50 (%) PASI 75 (%) PASI 90 (%)
[95% CI] [95% CI] [95% CI]

50 mg biweekly (at week 12) (RD 62.0%, 57.8%–66.1%) and e- Adalimumab† 66.4 (62.4–70.5) 63.0 (59.3–66.7) 36.5 (25.7–47.4)*
tanercept 25 mg biweekly or 50 mg weekly (at week 12) (RD Etanercept 52.2 (47.1–57.3) 31.0 (26.6–35.4) 10.7 (7.8–13.6)
25 mg biw
52.2%, 47.1%–57.3%). No PASI 50 data are available for
or 50mg qw‡
infliximab. Etanercept 62.0 (57.8–66.1) 43.5 (40.0–47.1) 19.3 ( 16.6–22.0)
Psoriasis Area and Severity Index 75 is also a relevant efficacy 50 mg biw§
measure at the moment of evaluation of response in clinical Infliximab¶ ND 67.1 (59.6–74.5) ND
practice as it defines treatment success and achieving this Ustekinumab 80.7 (77.2–84.2) 71.2 (67.0–75.4) 52.0 (47.4–56.6)
outcome goal justifies the continuation of treatment without 45 mg**,††
changes. In this regard, ustekinumab 45 mg (at week 28) has the Ustekinumab 80.9 (76.5–85.4) 69.3 (63.2–75.5) 39.1 (32.5–45.8)
90 mg**,††
greatest probability of achieving PASI 75 response (RD 71.2%,
67.0%–75.4%), followed by ustekinumab 90 mg (at week 28) *DerSimonian-Laird pooled risk difference.
†Evaluation of response at week 16 (after 10 SC doses of adalimumab
(RD 69.3%, 63.2%–75.5%), infliximab (at week 22) (RD 67.1%,
40 mg).
59.6%–74.5%), adalimumab (at week 16) (RD 63.0%,
‡Evaluation of response at week 12 (after 24 SC doses of etanercept
59.3%–66.7%), etanercept 50 mg biweekly (at week 12) (RD 25 mg or 12 SC doses of etanercept 50 mg).
43.5%, 40.0%–47.1%) and etanercept 25 mg biweekly or 50 mg §Evaluation of response at week 12 (after 24 SC doses of etanercept
weekly (at week 12) (RD 31.0%, 26.6%–35.4%). 50 mg).
¶Evaluation of response at week 22 (after 4 doses of infliximab (sic)).
Efficacy results at the end of the induction phase (week 24) **Evaluation of response at week 28 (after 3 SC doses of ustekinumab
45 mg or 90 mg in week 0. 4 and 16).
According to this meta-analysis, ustekinumab (at week 24),
††Efficacy (PASI) based on recommended posology as per the approved
rendered the greatest probabilities of response in all PASI-
SmPC: ustekinumab 45 mg for patients with bodyweight ≤100 kg. and
based outcome measures (PASI 50, PASI 75 and PASI 90 ustekinumab 90 mg for patients with bodyweight >100 kg.
response RD) at the end of the induction phase (week 24) SmPC, Summaries of Product Characteristics; PASI, Psoriasis Area and
(Table 4, Fig. 4). Severity Index ; CI, confidence intervals

JEADV 2014, 28, 1633–1653 © 2013 European Academy of Dermatology and Venereology
1644 Lluıs Puig et al.

%
Study Weight
ID RD (95% CI) (M-H)

etanercept 25 mg biw or etanercept 50 mg qw

Gottlieb 2003 0.59 (0.45–0.74) 2.10
Leonardi 2003 0.44 (0.34–0.53) 6.15
Papp 2005 [CONSORT] 0.55 (0.47–0.63) 7.29
van de Kerkhoff 2008 0.60 (0.48–0.72) 2.33
M-H Subtotal (I-squared = 52.1%, P = 0.100) 0.52 (0.47–0.57) 17.87
D+L Subtotal 0.54 (0.46–0.61)
.
etanercept 50 mg biw
Papp 2005 [CONSORT] 0.68 (0.61–0.75) 7.25
Tyring 2006 0.60 (0.53–0.66) 11.58
Leonardi 2003 0.59 (0.51–0.68) 6.19
M-H Subtotal (I-squared = 44.5%, P = 0.165) 0.62 (0.58–0.66) 25.03
D+L Subtotal 0.62 (0.57–0.68)
.
adalimumab
Gordon 2006 0.62 (0.46–0.78) 1.81
Saurat 2008 [CHAMPION] 0.58 (0.44–0.72) 2.67
Menter 2008 [REVEAL] 0.68 (0.64–0.72) 20.04
M-H Subtotal (I-squared = 12.6%, P = 0.319) 0.66 (0.62–0.70) 24.52
D+L Subtotal 0.66 (0.61–0.71)
.
ustekinumab 45 mg
Leonardi 2008 [PHOENIX 1] 0.80 (0.74–0.86) 7.59
Papp 2008 [PHOENIX 2] 0.81 (0.77–0.85) 12.92
M-H Subtotal (I-squared = 0.0%, P = 0.865) 0.81 (0.77–0.84) 20.51
D+L Subtotal 0.81 (0.77–0.84)
.
ustekinumab 90 mg
Leonardi 2008 [PHOENIX 1] 0.83 (0.77–0.90) 5.07
Papp 2008 [PHOENIX 2] 0.79 (0.73–0.85) 7.01
M-H Subtotal (I-squared = 0.0%, P = 0.366) 0.81 (0.76–0.85) 12.08
D+L Subtotal 0.81 (0.77–0.86)
.
M-H Overall (I-squared = 90.9%, P = 0.000) 0.67 (0.66–0.69) 100.00
D+L Overall 0.66 (0.60–0.73)

–0.895 0 0.895

Figure 3a Forest plot depicting meta-analysis of PASI 50 efficacy results at the recommended time point for assessing failure as per the
approved SmPCs. RD, risk difference; M-H, Mantel-Haenszel; D+L, DerSimonian & Laird.

meta-analyses (Tables 5, 6 and 7) were similar. For infliximab,
this sensitivity analysis provides an estimate of the PASI 50 RD
at the time point for assessing failure as per the approved SmPC
(30% primary failure rate, with 95% CIs non overlapping with
those corresponding to ustekinumab), which was not available
in the initial meta-analysis.
A second sensitivity analysis was carried out excluding phase
II clinical trials, which allowed for minimization of publication
bias (Begg P-value = 0.119). In this case, three studies were
excluded from the analysis: one each for adalimumab,27 inflix-
imab24 and etanercept,14 respectively. In this second sensitivity
analysis, the results obtained in the three meta-analyses
(Tables 5, 6 and 7) were also similar across all PASI measures
(PASI 50, PASI 75 and PASI 90).
In addition, a sensitivity analysis was carried out using
efficacy results regardless of the weight-based dosing recom-
mended in the SmPC. In this case, the results obtained in
the three meta-analyses (Tables 5, 6 and 7) were similar for

JEADV 2014, 28, 1633–1653 © 2013 European Academy of Dermatology and Venereology
Biologics in psoriasis: a meta-analysis at relevant time points 1645

%
Study Weight
ID RD (95% CI) (M-H)

etanercept 25 mg biw or etanercept 50 mg qw

Gottlieb 2003 0.28 (0.16–0.40) 1.85
Leonardi 2003 0.30 (0.23–0.38) 5.41
Papp 2005 [CONSORT] 0.31 (0.24–0.38) 6.41
van de Kerkhoff 2008 0.35 (0.25–0.46) 2.05
M-H Subtotal (I-squared = 0.0%, P = 0.826) 0.31 (0.27–0.35) 15.71
D+L Subtotal 0.31 (0.27–0.36)
.
etanercept 50 mg biw
Papp 2005 [CONSORT] 0.46 (0.39–0.54) 6.38
Tyring 2006 0.42 (0.36–0.48) 10.19
Leonardi 2003 0.46 (0.38–0.54) 5.44
Gottlieb 2011 0.49 (0.38–0.59) 3.02
Strobber 2011 0.33 (0.23–0.43) 3.13
M-H Subtotal (I-squared = 38.4%, P = 0.165) 0.44 (0.40–0.47) 28.16
D+L Subtotal 0.43 (0.39–0.48)
.
adalimumab
Gordon 2006 0.49 (0.34–0.65) 1.59
Saurat 2008 [CHAMPION] 0.61 (0.48–0.74) 2.34
Menter 2008 [REVEAL] 0.64 (0.61–0.68) 17.62
M-H Subtotal (I-squared = 44.2%, P = 0.167) 0.63 (0.59–0.67) 21.56
D+L Subtotal 0.61 (0.53–0.69)
.
infliximab
Menter 2007 [EXPRESS II] 0.67 (0.60–0.75) 5.92
M-H Subtotal (I-squared = .%, P = .) 0.67 (0.60–0.75) 5.92
D+L Subtotal 0.67 (0.60–0.75)
.
ustekinumab 45 mg
Leonardi 2008 [PHOENIX 1] 0.74 (0.68–0.81) 6.68
Papp 2008 [PHOENIX 2] 0.69 (0.64–0.75) 11.36
M-H Subtotal (I-squared = 18.6%, P = 0.268) 0.71 (0.67–0.75) 18.03
D+L Subtotal 0.71 (0.67–0.76)
.
ustekinumab 90 mg
Leonardi 2008 [PHOENIX 1] 0.70 (0.60–0.79) 4.46
Papp 2008 [PHOENIX 2] 0.69 (0.61–0.77) 6.16
M-H Subtotal (I-squared = 0.0%, P = 0.922) 0.69 (0.63–0.75) 10.62
D+L Subtotal 0.69 (0.63–0.75)
.
M-H Overall (I-squared = 94.2%, P = 0.000) 0.55 (0.53–0.57) 100.00
D+L Overall 0.51 (0.43–0.59)

–0.809 0 0.809

Figure 3b Forest plot depicting meta-analysis of PASI 75 efficacy results at the recommended time point for assessing failure as per the
approved SmPCs. RD, risk difference; M-H, Mantel-Haenszel; D+L, DerSimonian & Laird.

JEADV 2014, 28, 1633–1653 © 2013 European Academy of Dermatology and Venereology
1646 Lluıs Puig et al.

%
Study Weight
ID RD (95% CI) (M-H)

etanercept 25 mg biw or etanercept 50 mg qw

Gottlieb 2003 0.11 (0.02–0.19) 1.96
Leonardi 2003 0.11 (0.06–0.16) 5.75
Papp 2005 [CONSORT] 0.10 (0.06–0.15) 6.82
van de Kerkhoff 2008 0.11 (0.03–0.19) 2.18
M-H Subtotal (I-squared = 0.0%, P = 0.991) 0.11 (0.08–0.14) 16.70
D+L Subtotal 0.11 (0.08–0.14)
.
etanercept 50 mg biw
Papp 2005 [CONSORT] 0.20 (0.14–0.26) 6.78
Tyring 2006 0.20 (0.15–0.25) 10.83
Leonardi 2003 0.21 (0.15–0.28) 5.78
Gottlieb 2011 0.22 (0.14–0.29) 3.22
Strobber 2011 0.10 (0.02–0.17) 3.32
M-H Subtotal (I-squared = 49.0%, P = 0.098) 0.19 (0.17–0.22) 29.93
D+L Subtotal 0.19 (0.15–0.23)
.
adalimumab
Gordon 2006 0.24 (0.12–0.37) 1.69
Saurat 2008 [CHAMPION] 0.39 (0.26–0.51) 2.49
Menter 2008 [REVEAL] 0.43 (0.39–0.47) 18.73
M-H Subtotal (I-squared = 73.8%, P = 0.022) 0.41 (0.38–0.45) 22.92
D+L Subtotal 0.37 (0.26–0.47)
.
ustekinumab 45 mg
Leonardi 2008 [PHOENIX 1] 0.55 (0.47–0.62) 7.10
Papp 2008 [PHOENIX 2] 0.50 (0.45–0.56) 12.07
M-H Subtotal (I-squared = 0.0%, P = 0.398) 0.52 (0.47–0.57) 19.17
D+L Subtotal 0.52 (0.47–0.57)
.
ustekinumab 90 mg
Leonardi 2008 [PHOENIX 1] 0.38 (0.28–0.48) 4.74
Papp 2008 [PHOENIX 2] 0.40 (0.31–0.49) 6.55
M-H Subtotal (I-squared = 0.0%, P = 0.826) 0.39 (0.32–0.46) 11.29
D+L Subtotal 0.39 (0.32–0.46)
.
M-H Overall (I-squared = 96.3%, P = 0.000) 0.31 (0.30–0.33) 100.00
D+L Overall 0.26 (0.18–0.35)

–0.623 0 0.623

Figure 3c Forest plot depicting meta-analysis of PASI 90 efficacy results at the recommended time point for assessing failure as per the
approved SmPCs. RD, risk difference; M-H, Mantel-Haenszel; D+L, DerSimonian & Laird.

the relevant parameters from a clinical practice perspective
(PASI 50 and PASI 75) for all biologics except for the two
approved doses of ustekinumab, resulting in ustekinumab
90 mg yielding a higher probability of response than us-
tekinumab 45 mg.
Finally, a fourth sensitivity analysis was carried out to capture
different time points for assessing response. In the case of
ustekinumab, to capture conditions where the recommended
evaluation of response differs from the SmPC36 (namely, when
ustekinumab treatment should be stopped in case of inadequate
response by 16 weeks after starting treatment) instead of efficacy
at week 28 (after three doses), results at week 16 (after two
doses) were explored. In the case of infliximab, to capture a
probably incidental mistake in the SmPC13, results after three

JEADV 2014, 28, 1633–1653 © 2013 European Academy of Dermatology and Venereology
Biologics in psoriasis: a meta-analysis at relevant time points 1647

Table 4 Pooled efficacy data at the end of induction phase (week 24) (pooled risk difference vs. placebo)
Treatment PASI 50 (%) PASI 75 (%) PASI 90 (%)
[95% CI] [95% CI] [95% CI]
Adalimumab 64.3 (49.0–79.6) 63.3 (59.4–67.1) 45.7 (42.1–49.3)
Etanercept 62.3 48.8 25.4 (14.5–36.2)*
25 mg biw (53.1–71.5)* (37.7–59.9)*
or 50 mg qw
Etanercept ND 51.0 (43.6–58.4) ND
50 mg biw/
50 mg qw
Etanercept 68.1 (63.5–72.8) 55.3 (50.6–60.1) 27.8 (23.6–31.9)
50 mg biw‡
Infliximab 74.2 (69.1–79.4) 69.2 (64.1–74.4) 50.6 (45.3–55.9)
Ustekinumab 80.7 (77.2–84.2) 75.5 (71.5–79.4) 58.2 (53.7–62.8)
45 mg†
Ustekinumab 79.6 (74.9–84.2) 75.0 (69.3–80.7) 48.5 (41.7–55.3)
90 mg†

*DerSimonian-Laird pooled risk difference.

†Efficacy (PASI) based on recommended posology as per the approved SmPC: ustekinumab 45 mg for patients with bodyweight ≤100 kg. and us-
tekinumab 90 mg for patients with bodyweight >100 kg.
‡This posology is not approved; therefore is not included in the analysis or conclusion.
SmPC, Summaries of Product Characteristics; PASI, Psoriasis Area and Severity Index ; CI, confidence intervals

doses (week 14) were also explored instead of efficacy after four
doses (week 22).
In this case, the results obtained in the meta-analyses at the
recommended time point for assessing primary failure with
weight-based dosing as per the SmPC (Table 6) were similar for
the clinically relevant parameters (PASI 50 and PASI 75) for us-
tekinumab 45 mg, having the greatest probability of achieving
PASI 50 and PASI 75 response. In terms of PASI 50, us-
tekinumab 45 mg has the greatest probability of achieving
response, followed by ustekinumab 90 mg, infliximab, ada-
limumab and etanercept; the corresponding approximate failure
rates are 22%, 26%, 30%, 35%, and 36%–43%, respectively, with
marked overlap of 95%CIs. In terms of PASI 75, ustekinumab
45 mg yielded the greatest probability (approximate RD 71%) of
achieving a satisfactory response, followed by infliximab,
adalimumab, ustekinumab 90 mg, and etanercept, but the 95%
CIs of both doses of ustekinumab, adalimumab and infliximab
overlapped.
Discussion
From a regulatory point of view, the approved SmPCs establish
the recommended framework of use in clinical practice, and in
this regard, the meta-analyses comparing the clinical efficacy of
biologics in the treatment of moderate-to-severe psoriasis that
have been published to date usually present two important
limitations.
First, comparative efficacy has been only estimated at the
moment in which primary efficacy endpoint was measured in
the randomized clinical trials (week 10, 12 or 16 for infliximab,
etanercept/ustekinumab and adalimumab respectively) or at the
end of the induction phase (week 24), and not at the time point
in which a decision should be made regarding withdrawal (and
switching) of the biologic according to the approved SmPCs
(week 12, 16, 14–22 or 28 for etanercept, adalimumab,
infliximab and ustekinumab, respectively), depending on
whether the threshold for efficacy is reached (namely, PASI 50
response).13,37 Calculation of failure RDs is important for
cost-efficacy estimations, as both dose intensification and
switching to another biologic imply cost increases (the loading
phase of treatment is more expensive than maintenance
treatment for any given biologic).
Secondly, the doses in the clinical trials of ustekinumab did
not correspond in all patients to the approved weight-based
dosing recommendations and therefore response rates should be
analysed by baseline weight groups (≤100 kg or >100 kg) to
properly inform decision making by reflecting the approved
conditions of use in clinical practice. As shown in our analysis,
response rates to ustekinumab 90 mg when only patients
weighing >100 kg are considered are lower than in the
original publications of ustekinumab trials, where baseline
randomisation was stratified according to weight (≤90 kg or
>90 kg),5,30,31 but doses were not weight-based.
In addition, when it comes to the available meta-analyses,
some of them do not include the most recently approved
alternatives (i.e. ustekinumab), and the most recent clinical evi-
dence (i.e. comparative studies of briakinumab vs. etanercept) is
generally lacking.
The relevance of this study, which seeks to minimize the
above mentioned limitations, lies in its potential application
in clinical practice. The present analysis is not limited to
the effects of treatment on PASI 75 response rate at the pri-
mary endpoint of the clinical trials, with limited implications

JEADV 2014, 28, 1633–1653 © 2013 European Academy of Dermatology and Venereology
1648 Lluıs Puig et al.

%
Study Weight
ID RD (95% CI) (M-H)

etanercept 25 mg biw or etanercept 50 mg qw

Gottlieb 2003 0.64 (0.50–0.78) 2.83
Leonardi 2003 0.55 (0.46–0.64) 8.30
van de Kerkhoff 2008 0.69 (0.58–0.81) 3.15
M-H Subtotal (I-squared = 49.4%, P = 0.138) 0.60 (0.54–0.67) 14.28
D+L Subtotal 0.62 (0.53–0.71)
.
etanercept 50 mg biw
Tyring 2006 0.71 (0.65–0.76) 15.64
Leonardi 2003 0.63 (0.55–0.71) 8.35
M-H Subtotal (I-squared = 58.4%, P = 0.121) 0.68 (0.63–0.73) 23.99
D+L Subtotal 0.68 (0.60–0.75)
.
adalimumab
Gordon 2006 0.64 (0.49–0.80) 2.44
M-H Subtotal (I-squared = .%, P = .) 0.64 (0.49–0.80) 2.44
D+L Subtotal 0.64 (0.49–0.80)
.
infliximab
Reich 2005 [EXPRESS I] 0.75 (0.67–0.82) 6.21
Menter 2007 [EXPRESS II] 0.74 (0.67–0.81) 9.09
M-H Subtotal (I-squared = 0.0%, P = 0.916) 0.74 (0.69–0.79) 15.30
D+L Subtotal 0.74 (0.69–0.79)
.
ustekinumab 45 mg
Leonardi 2008 [PHOENIX 1] 0.80 (0.74–0.86) 10.25
Papp 2008 [PHOENIX 2] 0.81 (0.77–0.85) 17.44
M-H Subtotal (I-squared = 0.0%, P = 0.865) 0.81 (0.77–0.84) 27.69
D+L Subtotal 0.81 (0.77–0.84)
.
ustekinumab 90 mg
Leonardi 2008 [PHOENIX 1] 0.81 (0.74–0.88) 6.84
Papp 2008 [PHOENIX 2] 0.78 (0.72–0.85) 9.46
M-H Subtotal (I-squared = 0.0%, P = 0.574) 0.80 (0.75–0.84) 16.30
D+L Subtotal 0.80 (0.75–0.84)
.
M-H Overall (I-squared = 78.4%, P = 0.000) 0.73 (0.71–0.75) 100.00
D+L Overall 0.72 (0.68–0.77)

–0.88 0 0.88

Figure 4a Forest plot depicting meta-analysis of PASI 50 efficacy results at the end of the induction phase (week 24). RD, risk differ-
ence; M-H, Mantel-Haenszel; D+L, DerSimonian & Laird.

in daily clinical practice, but includes other clinically rele-
vant time points and efficacy outcomes that guide therapeu-
tic decisions such as withdrawal or optimization of the
biologic treatment (at time points defined by the SmPCs or
at the end of induction phase).
Using one extensive data set provides robust insight of the
comparative efficacy at three different time points, and this is
the first meta-analysis comparing efficacy of biologics at all three
time points.
The meta-analysis at the end of induction phase (week 24)
offers the possibility to compare all biologics using the same
time point. This represents an advantage with respect to previ-
ously published meta-analyses limited to primary endpoints and
allows for comparison of all biologics in the same conditions,

JEADV 2014, 28, 1633–1653 © 2013 European Academy of Dermatology and Venereology
Biologics in psoriasis: a meta-analysis at relevant time points 1649

%
Study Weight
ID RD (95% CI) (M-H)

etanercept 25 mg biw or etanercept 50 mg qw

Gottlieb 2003 0.51 (0.36–0.65) 1.93
Leonardi 2003 0.40 (0.32–0.48) 5.66
Papp 2005 [CONSORT] 0.42 (0.34–0.49) 6.71
van de Kerkhoff 2008 0.64 (0.54–0.75) 2.15
M-H Subtotal (I-squared = 81.5%, P = 0.001) 0.45 (0.41–0.50) 16.45
D+L Subtotal 0.49 (0.38–0.60)
.
etanercept 50 mg biw / 50 mg qw
Papp 2005 [CONSORT] 0.51 (0.44–0.58) 6.68
M-H Subtotal (I-squared = .%, P = .) 0.51 (0.44–0.58) 6.68
D+L Subtotal 0.51 (0.44–0.58)
.
etanercept 50 mg biw
Tyring 2006 0.55 (0.49–0.61) 10.66
Leonardi 2003 0.56 (0.47–0.64) 5.69
M-H Subtotal (I-squared = 0.0%, P = 0.955) 0.55 (0.51–0.60) 16.35
D+L Subtotal 0.55 (0.51–0.60)
.
adalimumab
Gordon 2006 0.61 (0.46–0.76) 1.66
Menter 2008 [REVEAL] 0.63 (0.60–0.67) 18.45
M-H Subtotal (I-squared = 0.0%, P = 0.713) 0.63 (0.59–0.67) 20.11
D+L Subtotal 0.63 (0.59–0.67)
.
infliximab
Reich 2005 [EXPRESS I] 0.72 (0.65–0.78) 4.23
Menter 2007 [EXPRESS II] 0.68 (0.60–0.75) 6.20
M-H Subtotal (I-squared = 0.0%, P = 0.425) 0.69 (0.64–0.74) 10.43
D+L Subtotal 0.70 (0.65–0.75)
.
ustekinumab 45 mg
Leonardi 2008 [PHOENIX 1] 0.78 (0.72–0.85) 6.99
Papp 2008 [PHOENIX 2] 0.74 (0.69–0.79) 11.89
M-H Subtotal (I-squared = 21.4%, P = 0.259) 0.75 (0.72–0.79) 18.87
D+L Subtotal 0.76 (0.71–0.80)
.
ustekinumab 90 mg
Leonardi 2008 [PHOENIX 1] 0.75 (0.66–0.84) 4.67
Papp 2008 [PHOENIX 2] 0.75 (0.67–0.82) 6.45
M-H Subtotal (I-squared = 0.0%, P = 0.963) 0.75 (0.69–0.81) 11.11
D+L Subtotal 0.75 (0.69–0.81)
.
M-H Overall (I-squared = 90.8%, P = 0.000) 0.62 (0.61–0.64) 100.00
D+L Overall 0.62 (0.56–0.68)

–0.847 0 0.847

Figure 4b Forest plot depicting meta-analysis of PASI 75 efficacy results at the end of the induction phase (week 24). RD, risk differ-
ence; M-H, Mantel-Haenszel; D+L, DerSimonian & Laird.

when the maximal clinical efficacy is achieved regardless of the
speed of action of each agent. Choosing week 12 as a primary
endpoint for head-to-head comparative trials including etaner-
cept5,22,23 has been criticized on account that 12 weeks is not an
adequate time frame to assess the efficacy of etanercept,38 and
providing a similar time frame for efficacy comparison of all
biologics (24 weeks, after the induction phase of treatment) may
serve as basis for eventual economic analyses.
The main differences between the present and a previously
published meta-analysis10 of efficacy outcomes at the end of
induction phase (week 24) reside in our including the weight-
based dosing efficacy data for ustekinumab as well as the placebo

JEADV 2014, 28, 1633–1653 © 2013 European Academy of Dermatology and Venereology
1650 Lluıs Puig et al.

%
Study Weight
ID RD (95% CI) (M-H)

etanercept 25 mg biw or etanercept 50 mg qw

Gottlieb 2003 0.21 (0.10–0.32) 2.23
Leonardi 2003 0.19 (0.13–0.25) 6.53
van de Kerkhoff 2008 0.37 (0.27–0.48) 2.48
M-H Subtotal (I-squared = 76.8%, P = 0.013) 0.24 (0.19–0.28) 11.24
D+L Subtotal 0.25 (0.14–0.36)
.
etanercept 50 mg biw
Tyring 2006 0.27 (0.22–0.32) 12.31
Leonardi 2003 0.29 (0.22–0.36) 6.57
M-H Subtotal (I-squared = 0.0%, P = 0.610) 0.28 (0.24–0.32) 18.88
D+L Subtotal 0.28 (0.24–0.32)
.
adalimumab
Gordon 2006 0.31 (0.17–0.45) 1.92
Menter 2008 [REVEAL] 0.47 (0.43–0.51) 21.30
M-H Subtotal (I-squared = 79.4%, P = 0.028) 0.46 (0.42–0.49) 23.22
D+L Subtotal 0.40 (0.25–0.56)
.
infliximab
Reich 2005 [EXPRESS I] 0.52 (0.46–0.58) 4.89
Menter 2007 [EXPRESS II] 0.50 (0.42–0.57) 7.15
M-H Subtotal (I-squared = 0.0%, P = 0.568) 0.51 (0.45–0.56) 12.04
D+L Subtotal 0.51 (0.46–0.56)
.
ustekinumab 45 mg
Leonardi 2008 [PHOENIX 1] 0.61 (0.54–0.69) 8.07
Papp 2008 [PHOENIX 2] 0.57 (0.51–0.62) 13.72
M-H Subtotal (I-squared = 0.0%, P = 0.335) 0.58 (0.54–0.63) 21.79
D+L Subtotal 0.58 (0.54–0.63)
.
ustekinumab 90 mg
Leonardi 2008 [PHOENIX 1] 0.50 (0.40–0.61) 5.39
Papp 2008 [PHOENIX 2] 0.47 (0.38–0.56) 7.44
M-H Subtotal (I-squared = 0.0%, P = 0.666) 0.48 (0.42–0.55) 12.83
D+L Subtotal 0.48 (0.42–0.55)
.
M-H Overall (I-squared = 93.7%, P = 0.000) 0.44 (0.42–0.45) 100.00
D+L Overall 0.41 (0.33–0.49)

–0.686 0 0.686

Figure 4c Forest plot depicting meta-analysis of PASI 90 efficacy results at the end of the induction phase (week 24). RD, risk differ-
ence; M-H, Mantel-Haenszel; D+L, DerSimonian & Laird.

response (in this study a LOCF placebo response has been used),
and our wider selection of studies.
In the short term (at the primary endpoint), infliximab is the
biologic with the highest RDs as regards both PASI 75 and PASI
90 responses, followed by ustekinumab 45 mg, ustekinumab
90 mg, adalimumab and etanercept. Nevertheless, using differ-
ent time points for different biologics (10, 12 or 16 weeks) limits
the clinical relevance of these results, especially taking into
account that not all these time points are those when treatment
failure or efficacy should be assessed according to the SmPCs or
clinical guidelines.
The comprehensive set of sensitivity analyses we have carried
out confirms the robustness of our results and highlights
the need for efficacy comparison according to the weight-based

JEADV 2014, 28, 1633–1653 © 2013 European Academy of Dermatology and Venereology
Biologics in psoriasis: a meta-analysis at relevant time points 1651

Table 5 Pooled efficacy data at the primary endpoint times. Sensitivity Analysis (pooled risk difference vs. placebo)
Treatment PASI 50 (%) PASI 75 (%) PASI 90 (%)
[95% CI] [95% CI] [95% CI]
I. inclusion of studies without placebo control arm
Adalimumab 66.4 (62.4–70.5) 64.3 (61.3–67.3) 40.7 (33.2–48.3)*
Etanercept 25 mg biw or 50 mg qw 58.3 (47.2–69.5)* 35.5 (27.8–43.2)* 13.8 (7.9–19.6)*
Etanercept 50 mg biw 63.9 (58.5–69.2)* 44.5 (39.7–49.4)* 17.9 (14.0–21.7)*
Infliximab 78.5 (75.5–81.5) 72.5 (69.9–75.1) 49.1 (42.3–56.0)*
Ustekinumab 45 mg 77.0 (73.7–80.4) 69.7 (66.0–73.4) 45.6 (41.6–49.6)
Ustekinumab 90 mg 77.5 (73.1–81.8) 65.2 (59.9–70.6) 34.4 (29.9–39.8)
II. phase II studies excluded
Adalimumab 66.8 (62.6–70.9) 64.0 (60.2–67.8) 42.5 (38.9–46.0)
Etanercept 25 mg biw or 50 mg qw 51.3 (45.8–56.7) 31.4 (26.7–36.2) 10.7 (7.6–13.8)
III. efficacy regardless of patient’s weight
Ustekinumab 45 mg [all weights] 73.5 (69.9–77.1) 63.4 (59.6–67.2) 40.8 (37.0–44.7)
Ustekinumab 90 mg [all weights] 77.9 (74.6–81.3) 68.7 (65.0–72.3) 44.2 (40.4–48.1)

*DerSimonian–Laird pooled risk difference.

PASI, Psoriasis Area and Severity Index; CI, confidence intervals

dosing recommendations for ustekinumab, especially as regards
primary endpoint calculations. In this regard, the efficacy results
of ustekinumab differ significantly from those in other published
meta-analyses10 and cost-efficacy calculations12 because of their
usage of efficacy data not derived from weight-based dosing,
which limits their usefulness or applicability to daily clinical
practice (to date, weight-based dosing of ustekinumab has been
taken into account in only one meta-analysis).9
Pooled efficacy data at the recommended time points to assess
primary failure (Table 3) show that the probability of primary
failure with ustekinumab, regardless of the dose, is approxi-
mately 19%, much lower than those of infliximab (30%) ada-
limumab (34%) or etanercept (38% to 48%), with no
overlapping of the 95%CIs, except for infliximab (Table 6) and
adalimumab. This has potentially important economic implica-
tions, taking into account the cost of switching to another bio-
logic therapy (higher than that of maintenance), which should
be considered in this significant proportion of patients.
As regards pooled efficacy data at the end of the induction
phase (week 24), the PASI 75 RDs (Table 4) are highest for
ustekinumab 45 mg (76%) and ustekinumab 90 (75%), followed
by infliximab (69%, with 95% CI values overlapping those of

Table 6 Pooled efficacy data at the recommended time point for assessing failure as per approved SmPCs. Sensitivity Analysis (pooled
risk difference vs. placebo)
Treatment PASI 50 (%) PASI 75 (%) PASI 90 (%)
[95% CI] [95% CI] [95% CI]
I. inclusion of studies without placebo control arm
Adalimumab 66.4 (62.4–70.5) 64.2 (61.2–67.2) 40.7 (33.2–48.3) *
Etanercept 25 mg biw or 50 mg qw 58.3 (47.2–69.5)* 35.5 (27.8–43.2)* 13.8 (7.9–19.6) *
Etanercept 50 mg biw 63.9 (58.5–69.2)* 44.5 (39.7–49.4)* 17.9 (14.0–21.7)*
Infliximab [week 22] 70.4 (66.6–74.3) 68.0 (64.7–71.4) 45.6 (41.7–49.6)
Infliximab [week 14] 75.3 (71.8–78.9) 68.9 (65.5–72.2) 46.2 (42.3–50.2)
II. phase II studies excluded
Adalimumab 66.8 (62.6–70.9) 64.0 (60.2–67.8) 42.5 (38.9–46.0)
Etanercept 25 mg biw or 50 mg qw 51.3 (45.8–56.7) 31.4 (26.7–36.2) 10.7 (7.6–13.8)
III. efficacy regardless of patient’s weight
Ustekinumab 45 mg [all weights] 79.8 (76.6–83.1) 64.9 (61.1–68.7) 44.1 (40.3–48.0)
Ustekinumab 90 mg [all weights] 82.0 (78.9–85.1) 72.3 (68.7–75.8) 51.6 (47.7–55.4)
IV. different time point for evaluating response
Infliximab [week 14] ND 70.9 (63.7–78.0) ND
Ustekinumab 45 mg [week 16] 77.5 (73.7–81.2) 70.9 (66.7–75.1) 49.6 (45.0–54.2)
Ustekinumab 90 mg [week 16] 74.0 (68.6–79.4) 63.2 (56.8–69.7) 38.7 (32.0–45.3)

*DerSimonian-Laird pooled risk difference.

PASI, Psoriasis Area and Severity Index; CI, confidence intervals

JEADV 2014, 28, 1633–1653 © 2013 European Academy of Dermatology and Venereology
1652
Table 7 Pooled efficacy data at the end of induction phase (week 24). Sensitivity Analysis (pooled risk difference vs. placebo)
Treatment PASI 50 (%) [95% CI]
I. inclusion of studies without placebo control arm
Adalimumab 64.3 (49.0–79.6)
Etanercept 25 mg biw or 50mg qw 68.0 (53.9–82.1)*
Etanercept 50 mg biw/50 mg qw 73.5 (65.6–81.5)
Etanercept 50 mg biw† 68.1 (63.5–72.8)
Infliximab 73.6 (70.7–76.6)
II. phase II studies excluded
Adalimumab ND
Etanercept 25 mg biw or 50 mg qw 59.2 (52.0–66.4)
III. efficacy regardless of patient’s weight
Ustekinumab 45 mg [all weights] 79.1 (75.8–82.4)
Ustekinumab 90 mg [all weights] 81.5 (78.4–84.6)
*DerSimonian-Laird pooled risk difference.
†This posology is not approved; therefore these data are not included in the analysis or conclusion.
PASI, Psoriasis Area and Severity Index; CI, confidence intervals
ustekinumab and adalimumab), adalimumab (63%) and etaner-
cept (49%–51%). Interestingly, the confidence intervals for the
PASI 50 and PASI 90 RD calculations for adalimumab, inflix-
imab and ustekinumab show significant overlapping, suggesting
that at the end of the induction phase the approximate rates of
failure (e.g. 20%–36%) and optimal response (46%–58%) do
not differ significantly among those biologics.
Conclusion
The objective of this meta-analysis was to evaluate efficacy rates
of biologics for moderate-to-severe plaque psoriasis at clinically
significant endpoints and provide the basis for indirect compari-
sons. Its results are not intended to be directly extrapolated as
regards effectiveness (which depends on real life clinical practice),
but may provide the basis for cost-efficacy analyses, the results of
which will depend on the cost of biologic drugs in each country.
According to the results of the present meta-analysis, inflix-
imab is the most efficacious alternative at the endpoint (10
weeks), followed by ustekinumab (12 weeks), adalimumab (16
weeks) and etanercept (12 weeks). These results are consistent
with previously published meta-analyses. Nevertheless,
according to the present meta-analysis, ustekinumab is the most
efficacious alternative (followed by infliximab, adalimumab and
etanercept) in terms of clinically significant outcome measures,
namely PASI 75, or achievement of therapeutic goal, at the end
of the induction period (week 24), and PASI 50, denoting lower
probability of primary failure) when assessment of failure is
required according to the SmPCs.
Acknowledgments
The authors acknowledge the support of PERTICA (sponsored
by Janssen-Cilag, S.A.) in the statistical analysis and review of
this manuscript.
JEADV 2014, 28, 1633–1653
Lluıs Puig et al.
PASI 75 (%) [95% CI] PASI 90 (%) [95% CI]
63.3 (59.4–67.1) 40.5 (25.1–55.8)*
54.6 (44.2–65.1)* 31.2 (16.6–45.8)*
58.2 (48.5–67.9)* 32.4 (24.3–40.4)
55.3 (50.6–60.1) 27.8 (23.6–31.9)
68.8 (65.8–71.8) 47.3 (44.2–50.5)
63.5 (59.5–67.5) 47.0 (43.3–50.7)
48.4 (34.5–62.4) 24.2 (18.8–29.6)
69.3 (65.6–72.9) 50.3 (46.4–54.2)
78.1 (74.8–81.4) 58.2 (54.3–62.0)
References
1 Heydendael VM, Spuls PI, Opmeer BC et al. Methotrexate versus cyclo-
sporine in moderate-to-severe chronic plaque psoriasis. New Engl J Med
2003; 349: 658–665.
2 Roberson ED, Bowcock AM. Psoriasis genetics: breaking the barrier.
Trends Genet 2010; 26: 415–423.
3 De Korte J, Sprangers MA, Mombers FM et al. Quality of life in patients
with psoriasis: a systematic literature review. J Investig Dermatol Symp
Proc 2004;9:225–230.
4 Pathirana D, Ormerod AD, Saiag P et al. European S3-guidelines on the
systemic treatment of psoriasis vulgaris. J Eur Acad Dermatol Venereol
2009; 23(Suppl 2): 1–70.
5 Griffiths C, Strober B, Van de Kerkhof P et al. Comparison of us-
tekinumab and etanercept for moderate to severe psoriasis. N Engl J Med
2010; 362: 118–128.
6 Brimhall AK, King LN, Licciardone JC, Jacobe H, Menter A. Safety and
efficacy of alefacept, efalizumab, etanercept and infliximab in treating
moderate to severe plaque psoriasis: a meta-analysis of randomized
controlled trials. Br J Dermatol 2008; 159: 274–285.
7 Schmitt J, Zhang Z, Wozel G, Meurer M, Kirch W. Efficacy and
tolerability of biologic and nonbiologic systemic treatments for
moderate-to-severe psoriasis: meta-analysis of randomized controlled
trials. Br J Dermatol 2008; 159: 513–526.
8 Bansback N, Sizto S, Sun H, Feldman S, Willian MK, Anis A. Efficacy of
systemic treatments for moderate to severe plaque psoriasis: systematic
review and meta-analysis. Dermatology 2009; 219: 209–218.
9 Reich K, Burden AD, Eaton JN, Hawkins NS. Efficacy of biologics
in the treatment of moderate to severe psoriasis: a network meta-
analysis of randomized controlled trials. Br J Dermatol 2012; 166:
179–188.
10 Lucka TC, Pathirana D, Sammain A et al. Efficacy of systemic
therapies for moderate-to-severe psoriasis: a systematic review and
meta-analysis of long-term treatment. J Eur Acad Dermatol Venereol
2012; 26: 1331–1344.
11 Lin VW, Ringold S, Devine EB. Comparison of Ustekinumab With Other
Biological Agents for the Treatment of Moderate to Severe Plaque
Psoriasis: a Bayesian Network Meta-analysis. Arch Dermatol 2012; 15:
1–8.
12 Ferrandiz C, Garcıa A, Blasco AJ, Lazaro P. Cost-efficacy of adalimumab,
etanercept, infliximab and ustekinumab for moderate-to-severe plaque
psoriasis. J Eur Acad Dermatol Venereol 2012; 26: 768–777.
© 2013 European Academy of Dermatology and Venereology
Biologics in psoriasis: a meta-analysis at relevant time points
13 Puig L. Induction phase, primary endpoint, time to decide on primary
failure, and therapeutic goals in biologic treatment of psoriasis. J Eur Acad
Dermatol Venereol 2013; 27: e257–e260.
14 Gottlieb A, Matheson R, Lowe N et al. A randomized trial of etanercept
as monotherapy for psoriasis. Arch Dermatol 2003; 139: 1627–1632.
15 Reich K, Nestle F, Papp K et al. Infliximab induction and maintenance
therapy for moderate-to-severe psoriasis: a phase III, multicentre,
double-blind trial. Lancet 2005; 366(9494): 1367–1374.
16 Higgins J, Thompson S. Quantifying heterogeneity in a meta-analysis.
Stat Med 2002; 21:1539e58.
17 Higgins JPT, Green S, eds. Cochrane handbook for systematic reviews of
interventions. Version 5.1.0 [updated March 2011]. The Cochrane Colla-
boration, 2011. URL www.cochrane-handbook.org (last accessed: 22
December 2012).
18 Leonardi CL, Powers JL, Matheson RT et al. Etanercept as monotherapy
in patients with psoriasis. N Engl J Med 2003; 349: 2014–2022.
19 Papp KA, Tyring S, Lahfa M et al. A global phase III randomized con-
trolled trial of etanercept in psoriasis: safety, efficacy, and effect of dose
reduction. Br J Dermatol 2005; 152: 1304–1312.
20 Tyring S, Gottlieb A, Papp K et al. Etanercept and clinical outcomes,
fatigue, and depression in psoriasis: double-blind placebo-controlled
randomised phase III trial. Lancet 2006; 36: 29–35.
21 van de Kerkhof PC, Segaert S, Lahfa M et al. Once weekly administration
of etanercept 50 mg is efficacious and well tolerated in patients with
moderate-to-severe plaque psoriasis: a randomized controlled trial with
open-label extension. Br J Dermatol 2008; 159: 1177–1185.
22 Strober BE, Crowley JJ, Yamauchi PS, Olds M, Williams DA. Efficacy and
safety results from a phase III, randomized controlled trial comparing the
safety and efficacy of briakinumab with etanercept and placebo in patients
with moderate to severe chronic plaque psoriasis. Br J Dermatol 2011;
165: 661–668.
23 Gottlieb AB, Leonardi C, Kerdel F et al. Efficacy and safety of bria-
kinumab vs. etanercept and placebo in patients with moderate to severe
chronic plaque psoriasis. Br J Dermatol 2011; 165: 652–660.
24 Chaudhari U, Romano P, Mulcahy LD, Dooley LT, Baker DG, Gott-
lieb AB. Efficacy and safety of infliximab monotherapy for plaque-
type psoriasis: a randomised trial. Lancet 2001; 357(9271): 1842–
1847.
25 Gottlieb AB, Evans R, Li S et al. Infliximab induction therapy for
patients with severe plaque-type psoriasis: a randomized, double-
blind, placebo-controlled trial. J Am Acad Dermatol 2004; 51: 534–
542.
26 Menter A, Feldman S, Weinstein G 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.
JEADV 2014, 28, 1633–1653
1653
27 Gordon K, Langley R, 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: 598–606.
28 Saurat JH, 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(3): 558–566.
29 Menter A, Tyring S, Gordon K et al. Adalimumab therapy for moderate
to severe psoriasis: A randomized, controlled phase III trial. J Am Acad
Dermatol 2008; 58(1): 106–115.
30 Leonardi C, Kimball A, Papp K 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-con-
trolled trial PHOENIX 1. Lancet 2008; 371: 1665–1674.
31 Papp K, Langley R, Lebwohl M et al. Efficacy and safety of ustekinumab,
a human interleukin-12/23 monoclonal antibody, in patients with
psoriasis: 52-week results from a randomised, double-blind, placebo-con-
trolled trial PHOENIX 2. Lancet 2008; 371: 1675–1684.
32 Sterry W, Ortonne JP, Kirkham B et al. Comparison of two etanercept
regimens for treatment of psoriasis and psoriatic arthritis: PRESTA
randomised double blind multicentre trial. BMJ 2010 Feb; 2(340): c147.
33 Strohal R, Puig L, Chouela E et al. The efficacy and safety of etanercept
when used with as-needed adjunctive topical therapy in a randomised,
double-blind study in subjects with moderate-to-severe psoriasis (the
PRISTINE trial). J Dermatolog Treat 2013; 24: 169–178.
34 Barker J, Hoffmann M, Wozel G et al. Efficacy and safety of infliximab vs.
methotrexate in patients with moderate to severe plaque psoriasis: results
of an open-label, active-controlled, randomized trial (RESTORE 1). Br J
Dermatol 2011; 165: 1109–1117.
35 Thaci D, Ortonne P, Chimenti S et al. A phase IIIb, multicentre,
randomized, double-blind, vehicle-controlled study of the efficacy
and safety of adalimumab with and without calcipotriol/beta-
methasone topical treatment in patients with moderate to severe
psoriasis: the BELIEVE study. Br J Dermatol 2010; 163:
402–411.
36 NICE Technology appraisal, Psoriasis - ustekinumab (TA180).
Ustekinumab for the treatment of adults with moderate to severe
psoriasis. 2009. reviewed on January 2010. URL http://www.nice.org.
uk/nicemedia/pdf/TA180Guidance.pdf (last accessed: 22 December
2012).
37 Puig L, Dauden E, Carrascosa JM. Commentary on European and British
guidelines for the treatment of psoriasis. Actas Dermosifiliogr 2010; 101:
285–290.
38 Kuhn A, Luger TA. Psoriasis: is ustekinumab superior to etanercept for
psoriasis? Nat Rev Rheumatol 2010; 6: 500–501.
© 2013 European Academy of Dermatology and Venereology