Original Article

Submitted: 7.12.2019 DOI: 10.1111/ddg.14308

Accepted: 3.6.2020
Conflict of interest
None.

Comparative efficacy and safety

of biologics in moderate to severe
plaque psoriasis: a multiple-treatments
meta-analysis
: Supporting information for this article is available on the WWW under
https://doi.org/10.1111/ddg.14308

Shanshan Xu1,2*, Xing Gao1,2*, Summary

Jixiang Deng1,2, Jiajia Yang1,2,
Faming Pan1,2
(1) Department of Epidemiology and
Biostatistics, School of Public Health,
Anhui Medical University, Hefei, Anhui,
China
(2) The Key Laboratory of Major Au-
toimmune Diseases, Anhui Medical
University, Hefei, Anhui, China
*The first two authors contributed
equally to the present article.
Objective: To compare the efficacy and safety of biologics for patients with modera-
te to severe plaque psoriasis.
Methods: We systematically reviewed 60 randomized controlled trials (34,020 par-
ticipants), which compared 14 biological drugs for treatment of moderate to severe
plaque psoriasis. The main assessment criteria were ≥ 90 % reductions in Psoriasis
Area and Severity Index (PASI 90) and the number of patients who reported treat-
ment-emergent adverse events (AEs). Secondary criteria were ≥ 75 % reductions in
Psoriasis Area and Severity Index (PASI 75), Physician’s Global Assessment 0/1 (PGA
0/1) and infections.
Results: This network meta-analysis showed that biologics were significantly more
effective than placebo. Ixekizumab, risankizumab, and bimekizumab were among the
most effective treatments, and tildrakizumab, guselkumab and risankizumab were
better than the other drugs with respect to safety. Risankizumab and guselkumab
performed relatively stable with respect to both efficacy and safety. At the class level,
blockers of interleukin (IL)-17A showed favorable efficacy while inhibitors of the p19
subunit of IL-23 were best tolerated of all efficient biologics.
Conclusions: Ixekizumab was the most effective biologic in PASI 90, while IL-23p19
inhibitors, risankizumab and guselkumab performed relatively stable with respect to
efficacy and safety.

Introduction The internal drugs for psoriasis mainly include conven-

Psoriasis is a chronic inflammatory skin disease, with an esti-
mated prevalence of 2–3 % globally [1, 2]. Plaque psoriasis is
the most common type, accounting for approximately 90 %
of cases [3]. The disease is prone to recurrence, and most pati-
ents require long-term treatment, which seriously affects their
quality of life and leads to a heavy disease burden [1, 3]. Mild
plaque psoriasis only needs externally applied drug treatment,
but moderate to severe plaque psoriasis requires internal me-
dication or combined therapy treatment. Therefore, selecting
a treatment with good efficacy and safety will have a positive
impact on the lives of patients with psoriasis.
tional systemic drugs, small molecules and biological agents.
Sbidian et al. showed that the biologics were significantly
more effective than the small molecules and the conventional
systemic agents [4]. Tumor necrosis factor-α (TNFα), inter-
leukin (IL)-23 and IL-17A are considered to be key targets for
the treatment of moderate to severe plaque psoriasis [3, 5].
In addition, there are other therapeutic targets such as IL-17
receptor and IL-17A & IL-17F [6, 7]. To date, a large num-
ber of randomized controlled trials have studied the efficacy
and safety of these drugs, however, only a few studies have
compared the efficacy or safety of different biological agents
[8–10]. Meanwhile, several meta-analysis studies [11–13]

© 2020 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/20201901
47
 Original Article Biologics in plaque psoriasis
have compared the efficacy and safety of multiple biological
agents, but only one study [4] conducted a secondary analysis
for different targets, though it did not include all existing
biological agents.
We report an overview of all randomized controlled
trials comparing the efficacy and safety of 14 biologic agents
for the treatment of moderate to severe plaque psoriasis. In
addition to the traditional meta-analysis, we focused on a
multiple-treatments meta-analysis, also known as Bayesian
network meta-analysis, which combines direct and indirect
comparison data for analysis. The purpose of this study was
to conduct a multiple-treatments meta-analysis that provides
evidence-based data to further guide clinical decisions.
Materials and methods
This multiple-treatments meta-analysis was conducted in
agreement with the modified 32-item PRISMA extension
statement for network meta-analysis (NMA) 2015 [14].
Search strategy
An electronic search of the literature using PubMed, Web of
Science and the Cochrane Library was conducted by two re-
searchers separately up to March 13, 2019, who searched for
publications on the clinical efficacy and safety of biological
drugs in the treatment of moderate to severe plaque psoriasis.
The references from these articles were also screened to find
other potentially relevant trials. Keywords and search stra-
tegy are shown in the online Appendix.
Selection criteria
Studies that meet all of the following criteria were included:
(1) the subjects were patients with the diagnosis of moderate
to severe plaque psoriasis; (2) the intervention measure in the
experimental group was biological agents, and the control
group was another biological agent or placebo; (3) the paper
provided detailed data on efficacy and safety; (4) the studies
were double-blind randomized controlled trials; (5) the stu-
dies were published in English.
Studies that meet any of the following criteria were
excluded: (1) the total sample size was less than 30; (2) ca-
se-control studies, cohort studies, reviews, meta-analyses,
meeting abstracts, case reports or unpublished articles.
Data extraction
The two researchers (Shanshan Xu and Xing Gao) extrac-
ted the data together and independently, including general
information and outcomes. General information included
the following indicators: first author’s name, publication
48 © 2020 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/20201901
year, follow-up time, treatment strategy, route of administ-
ration, sample size, age, gender, weight, Psoriasis Area and
Severity Index (PASI) and disease duration. Outcome variab-
les included the following parameters: PASI reductions from
baseline of 75 % or more (PASI 75), 90 % or more reductions
in PASI (PASI 90), Physician’s Global Assessment of “clear”
or “minimal” (PGA 0/1), adverse events (AEs) and infections.
We defined 16 weeks as the end point for efficacy and safety
analysis. If 16-week data were not available, the data point
closest to 16 weeks was given preference. The data we extrac-
ted excluded cases where patients stopped or withdrew due to
treatment failure before reaching the end point. The quality
of the included studies was assessed using the modified Jadad
scale [15]. A study with a score < 4 was considered low qua-
lity and high risk, otherwise, the study was considered high
quality. Any disagreements were resolved via discussion with
Faming Pan. If any significant data of the above characteri-
stics were not provided in the original articles, the correspon-
ding authors were contacted for this information by e-mail.
Statistical analysis
Traditional pair-wise meta-analysis was performed using
STATA 11.0 (College Station, TX, USA) and WinBUGS
1.4.3 (MRC Biostatistics Unit, Cambridge, UK) was used for
Bayesian network meta-analysis. Firstly, we did traditional
pair-wise meta-analysis by synthesizing studies that com-
pared the same interventions to incorporate the assumption
that different studies assessed different treatment effects. The
analysis was repeated according to the classification of diffe-
rent drug targets. The relative risk (RR) and 95 % confidence
interval (CI) of clinical efficacy and safety parameters were
calculated for each enrolled study. Heterogeneity was asses-
sed by Dixon’s Q test and I 2 statistics. When the heterogenei-
ty was statistically significant (P < 0.1 or I 2 > 50 %), we used
the random effects model to evaluate the overall effect, other-
wise, we used the fixed effect model. Meta-regression analy-
ses were performed by publication year, time of follow-up,
research quality (Modified Jadad score), age, female to male
ratio, disease duration and PASI scale to explore the sources
of heterogeneity. Sensitivity analysis was conducted to as-
sess the stability of the overall results. Publication bias was
evaluated by Funnel plot and Egger’s test. Secondly, in Win-
BUGS, we used the Markov chain Monte Carlo method to fit
the random effects model in the Bayesian framework to ana-
lyze the efficacy and safety of all treatments in the network.
Subsequently, 50,000 simulations were performed on four
chains to estimate the sampling parameters. At least 20,000
simulated initial burn-ins were used, and convergence was
affirmed by visual inspection of the Brook-Gelman-Rubin di-
agnostic and history plots. The outcomes of the network me-
ta-analysis were expressed in RRs and 95 % credible interval
Original Article Biologics in plaque psoriasis
(95 % CrI) relative to the other treatments or placebo (95 %
CrI was used in network meta-analysis, and 95 % CI was
used in the traditional meta-analysis. There was no actual
difference between the two, which were both interval estima-
tes of outcome variables). Rankograms were used to assess
the probability of each rank for these treatments. In additi-
on, the surface under the cumulative ranking curve (SUCRA)
was used to analyze the ranking of individual drugs or tar-
gets in different outcomes. We also assessed the inconsistency
of the direct and indirect results of the meta-analysis by a
DerSimonian-Laird method. Besides, deviance information
criterion (DIC) of fixed-effects and random-effects models
were compared to assess the stability of this study. A two-
tailed P < 0.05 was considered statistically significant.
Results
Literature search and study characteristics
The electronic searches yielded 17,555 relevant studies, of
which 7,949 potentially eligible articles were screened after
9,606 articles were excluded due to duplication. After revie-
wing the titles and abstracts, 7,842 articles were excluded
and only the full text of 107 articles was read. 47 of the-
se publications did not meet the eligibility criteria and were
excluded (Figure 1). Overall, 60 trials [6–10, 16–70] from
© 2020 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/20201901
2001 to 2019 comprising 26,344 plaque psoriasis patients
treated with fourteen biological drugs (a brief introduction to
the 14 biological agents is provided in the Appendix [online
Supplement only]) and 7,676 patients who received placebo
were used for multiple-treatments meta-analysis (Table S1,
online supplement only). Figure S1 (online supplement only)
shows the network of eligible comparisons for the Bayesian
network meta-analysis for efficacy and safety. A total of 66
RCTs were included in the 60 enrolled articles, most of which
were two-arm trials, and only 14 were three-arm trials. The
disease duration was 17.93 ± 2.18 years, and the overall mean
baseline score at study entry was 20.43 ± 4.85 for disease
severity (PASI). The overall quality of studies was rated as
good, the mean of Modified Jadad score was 5.9 (range 4–7).
Traditional pair-wise meta-analysis
The rate of PASI 90 of 14 biologics was significantly higher
than that of placebo (Figure 2a). The incidence of AEs of nine
biologics was significantly higher than that of placebo, and
there were no statistical differences between the other five
drugs (certolizumab pegol, guselkumab, mirikizumab, risan-
kizumab, tildrakizumab) and placebo (Figure 2b). Of the 66
trials, there were twelve pair-wise comparisons between the
14 biologics, including seven biological agents (infliximab,
ustekinumab, briakinumab, secukinumab, ixekizumab,
Figure 1 Flowchart of study selection.
49
 Original Article Biologics in plaque psoriasis

Figure 2 Forest plots of multiple-­

treatments meta-analysis results for
efficacy (a) and safety (b) with pla-
cebo as reference compound.
Abbr.: ADA, Adalimumab; ETAN,
Etanercept; INF, Infliximab; CER,
Certolizumab pegol; UST, Ustekinu-
mab; BRI, Briakinumab; MIR, Miri-
kizumab; BIM, Bimekizumab; SEC,
Secukinumab; RIS, Risankizumab;
BRO, Brodalumab; IXE, Ixekizumab;
TIL, Tildrakizumab; GUS, Guselku-
mab; PBO, placebo; PASI, Psoriasis
Area and Severity Index; AEs, adver-
se events.

tildrakizumab, certolizumab pegol) versus etanercept, four safety, being safer than bimekizumab and infliximab
biologicals (secukinumab, risankizumab, brodalumab, ix- (Figure 5). The ranking of secondary outcomes is shown in
ekizumab) versus ustekinumab, and guselkumab versus Figure S2 (online supplement only). Ixekizumab remains the
adalimumab (Table S2 online supplement only). The results most efficient in PASI 75.
showed that the levels of PASI 90 of the former biological The inhibitors of IL-17A, IL-17A & F, IL-17R, and IL-
agents were significantly higher than that of the latter (all RR 23p19 were the most effective, and IL-23p19, IL-23/12p40,
> 1, P < 0.05), except that the differences between certolizu- and IL-17R were the safest targets (Figure 5). All target bio-
mab pegol versus etanercept and infliximab versus etanercept logics were more effective than placebo. TNFα blockers were
were not statistically significant. Additionally, there was no less efficient than the others except IL-17A & F. The AEs
difference in the incidence of AEs in the twelve direct compa-
risons (Table S2, online supplement only). The secondary in-
dicators (PASI 75, PGA 0/1, infections) and the comparisons
at the class level are also detailed in Table S2 (online sup-
plement only). Heterogeneity in pairwise meta-analysis was
generally moderate. For different targets, the heterogeneity
disappeared or decreased significantly.

Bayesian network meta-analysis

Ixekizumab, risankizumab, and bimekizumab were among

the most effective treatments, and tildrakizumab, guselku-
mab, and risankizumab were better than the other drugs
on safety. We ranked fourteen drugs according to the main
dimensions (Figure 3). The clinical efficacy of the 14 inhibi-
tors was significantly superior to placebo (Figure 4). Ixeki-
zumab, risankizumab, and secukinumab had a very similar
profile of comparative efficacy, being more effective than
adalimumab, certolizumab pegol, etanercept, tildrakizu-
mab, and ustekinumab. In terms of safety, no significant
differences were found between adalimumab, mirikizumab,
tildrakizumab with placebo, while the AEs of the others
were higher than that of placebo. Tildrakizumab, guselku-
mab, and risankizumab had undifferentiated comparative
Figure 3 Ranking of biological drugs according to efficacy
and safety. Drugs with good efficacy or safety have low rank
numbers.
Abbr.: ADA, Adalimumab; ETAN, Etanercept; INF, Infliximab;
CER, Certolizumab pegol; UST, Ustekinumab; BRI, Briakinu-
mab; MIR, Mirikizumab; BIM, Bimekizumab; SEC, Secukinu-
mab; RIS, Risankizumab; BRO, Brodalumab; IXE, Ixekizumab;
TIL, Tildrakizumab; GUS, Guselkumab; PBO, placebo; PASI,
Psoriasis Area and Severity Index; AEs, adverse events.

50 © 2020 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/20201901
Original Article Biologics in plaque psoriasis

Figure 4 Efficacy and safety of the fourteen drugs (RR 95 % CrI). Drugs are reported in alphabetical order. Results are the
RRs in the column-defining treatment compared with the RRs in the row-defining treatment. For efficacy, RRs higher than 1
favor the column-defining treatment (i.e., the first in alphabetical order). For safety, RRs lower than 1 favor the first drug in
alphabetical order. To obtain RRs for comparisons in the opposite direction, reciprocals should be taken (e.g., the RR for BRI
compared to ADA is 1/0.32 = 3.13). Significant results are in bold. Abbr.: ADA, Adalimumab; ETAN, Etanercept; INF, Infliximab;
CER, Certolizumab pegol; UST, Ustekinumab; BRI, Briakinumab; MIR, Mirikizumab; BIM, Bimekizumab; SEC, Secukinumab; RIS,
Risankizumab; BRO, Brodalumab; IXE, Ixekizumab; TIL, Tildrakizumab; GUS, Guselkumab; PBO, placebo; PASI, Psoriasis Area and
Severity Index; AEs, adverse events.

of IL-23p19 inhibitors were comparable to that of placebo,
while the others were higher than placebo. Additionlly, the
blockers of IL-23p19 were safer than TNFα, IL-17A, IL-
17A & F, and IL-17R (Figure 6).
There was no statistically signifcant inconsistency in 52
cycles within the network for the main outcomes. The DIC of
fixed effect model and random effects model were very close,
indicating that the results were stable (data not shown).
Results of meta-regression, sensitivity analysis
and publication bias
In the meta-regression analysis used to assess potential bias
of publication year, time of follow-up, research quality, age,
female to male ratio, disease duration and PASI, the RR of
efficacy, safety and the final rankings did not substantially
change. Sensitivity analysis showed that regardless of which
study was removed, the overall statistical significance did not
change, indicating that the statistical results were stable. The
funnel plots of efficacy and safety were symmetric, and Eg-
ger’s test did not find significant publication bias in PASI 90
and AEs (P > 0.05) (data not shown).
Discussion
Our analysis was based on 60 studies including 34,020 indi-
viduals randomly assigned fourteen drugs involving six tar-
gets. All biologics were effective in achieving PASI 90. The
results of direct comparison and comprehensive comparison
showed that there was no significant difference in AEs bet-
ween tildrakizumab, mirikizumab, and placebo.
Although network meta-analysis cannot provide the
highest level of evidence to select the best biologics, it may
contribute to the selection of biologics for acute treatment of
plaque psoriasis. In terms of efficacy, ixekizumab, risankizu-
mab, and bimekizumab outperformed the other drugs, and
regarding safety, tildrakizumab, guselkumab, and risankizu-
mab were more tolerated than the other drugs, although no
significant differences were found among them. These results
have potential clinical implications and should be considered

© 2020 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/20201901
51
 Original Article Biologics in plaque psoriasis

in the development of clinical practice guidelines [71]. The-

Figure 5 Ranking of six target drugs according to efficacy
and safety. Drugs with good efficacy or safety have low rank
numbers.
Abbr.: TNFα, tumor necrosis factor-alpha; IL-17A & F, inter-
leukin-17A and interleukin-17F; IL-17R, IL-17 receptor; IL-23p19,
p19 subunit of IL-23; IL-17A, interleukin-17A; IL-23/12p40, p40
subunit of IL-23 and IL-12; PBO, placebo; PASI, Psoriasis Area
and Severity Index; AEs, adverse events.
se results suggest that the most effective treatment may not
be the safest. The drugs in the lower left corner of Figure 3
strike a good balance between efficacy and safety, thus ri-
sankizumab and guselkumab may be the best choice for the
treatment of moderate to severe plaque psoriasis. Similarly,
anti-IL-23p19 might be the best strategy for therapeutic tar-
gets. However, this conclusion is not completely consistent
with the results of other meta-analyses. Sawyer et al. [13]
showed that brodalumab was associated with a higher like-
lihood of sustained PASI response. Xu et al. [12] concluded
that briakinumab performed relatively stable in terms of effi-
cacy and safety. Geng et al. [11] declared that infliximab may
be a superior option compared to other drugs. The reason for
the inconsistency may be that none of the above meta inclu-
ded all biologics for analysis, especially IL-23p19 inhibitors
that until recently were undergoing extensive phase III trials.
Risankizumab and guselkumab are monoclonal antibo-
dies targeting the p19 subunit of IL-23, and these inhibitors
are at least as effective as other targets, and are especially
superior to inhibitors of TNFα (adalimumab, etanercept,

Figure 6 Efficacy and safety of the six targets (RR 95 % CrI). Results are the RRs in the column-defining treatment compared
with the RRs in the row-defining treatment. For efficacy, RRs higher than 1 favor the column-defining treatment (i.e., the first in
alphabetical order). For safety, RRs lower than 1 favor the first drug in alphabetical order. To obtain RRs for comparisons in the
opposite direction, reciprocals should be taken. Significant results are in bold.
Abbr.: TNFα, tumor necrosis factor-alpha; IL-17A & F, interleukin-17A and interleukin-17F; IL-17R, IL-17 receptor; IL-23p19, p19 sub-
unit of IL-23; IL-17A, interleukin-17A; IL-23/12p40, p40 subunit of IL-23 and IL-12; PBO, placebo; PASI, Psoriasis Area and Severity
Index; AEs, adverse events.

52 © 2020 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/20201901
Original Article Biologics in plaque psoriasis
certolizumab pegol). Studies have shown that IL-23 is invol-
ved in the production and biological effects of TNFα [72–74].
Combined with the results of this study, it can be assumed
that anti-IL-23 therapy also has a possible inhibitory effect
on the TNFα signaling pathway. The results showed that the
selective IL-23 inhibitor targeting the p19 subunit upstream
of the Th17 cell pathway was superior to the highly effective
IL-17A inhibitor in terms of safety, because it can reduce the
risk of inflammatory bowel disease or candida infection cau-
sed by IL-17A inhibitor. At the same time, the selective IL-23
inhibitor does not affect the IL-12 dependent cascade, which
reduces IL-17A production by T-cells in the skin and promo-
tes the anti-inflammatory effect by stimulating production of
interferon (IFN)-λ and IL-10. Thus the IL-23 selective inhi-
bitor is superior to non-selective inhibitors that also influence
the IL-12 cascade [3, 5, 72]. In addition, an animal study [75]
has shown that IL-12 may have an inhibitory effect on the oc-
currence and progression of skin inflammation. The PASI 90
of the p40 inhibitor (ustekinumab) was significantly lower
than that of the IL-23p19 inhibitors (risankizumab, gusel-
kumab), which may be because the p40 inhibitor inhibited
both IL-23 and IL-12. However, further research is needed to
improve our understanding of the pathological mechanisms
of the different targets.
The objective of this study was to compare the evidence
for efficacy and safety of these biologics. Even though some
of these drugs will at some point be off patent and available
in generic form at reduced cost, they may only be used in pa-
tients after failure of Disease-modifying antirheumatic drugs
(DMARDs), because they still are very expensive compared
with conventional drugs, such as methotrexate. Despite the
increasing number of randomized trials assessing drugs for
psoriasis in recent years, the total number of studies and pa-
tients remains low compared to rheumatoid arthritis [76].
Limited by the relatively small number of studies and with
no available head-to-head comparisons in the literature,
multiple-treatments meta-analysis can help identify the best
treatment. Instead of simply analyzing a set of randomized
controlled trials (RCTs) comparing intervention A versus
intervention B, multiple-treatments meta-analysis can infer
the effect of intervention A on intervention B by comparing
the effects of A and B on a common comparator C (usually
placebo) [77].
There are several limitations in this study. Firstly, indus-
try sponsorship bias can occur when a pharmaceutical spon-
sor favours its own product in placebo-controlled or active
comparator trials, or the highest dose of its own drug in a tri-
al comparing multiple doses [78]. Therefore, the potential ef-
fect of financial interests on medical publications should be a
concern. In our study, no drug manufacturing company was
involved in the study design, data collection, data analysis,
data interpretation, writing of the report, or in the decision
© 2020 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/20201901
to submit the report for publication. Secondly, due to data
limitations, this study cannot analyze the effects of different
doses and administration routes on outcomes, and almost all
the placebo groups in the RCT trials switched to the active
drug after the induction period, generally 12–24 weeks, so
we could not explore long-term efficacy and safety. Not all
therapies may have reached their maximal response by that
time point. Therefore, interpretation and implementation of
the findings of this study should primarily be considered for
short-term treatment. Finally, we did not investigate import-
ant outcomes such as social function and mental health, al-
though this does not affect the promotion and application of
this research.
Conclusions
Ixekizumab, risankizumab, and bimekizumab were the most
effective treatments, and tildrakizumab, guselkumab, and
risankizumab outperformed all others in terms of safety.
Risankizumab and guselkumab also performed well in terms of
efficacy. Our study may help clinicians to adapt a choice of new
drugs to the needs of individual patients, and could provide the
basis for the modification of clinical practice guidelines.
Funding
The study was sponsored by the National Natural Science
Foundation of China (81273169, 81573218 and 81773514,
82073655).
Correspondence to
Faming Pan, MD
Department of Epidemiology & Biostatistics
School of Public Health
Anhui Medical University
81 Meishan Road
Hefei, Anhui, 230032, China
E-mail: famingpan@ahmu.edu.cn
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