N. Simons1, Y. Degboé1, T. Barnetche2, A.

Cantagrel1,
A. Ruyssen-Witrand1, A. Constantin1
1
Department of Rheumatology, Purpan Hospital, Toulouse III University, Toulouse, France;
2
Department of Rheumatology, FHU ACRONIM, Pellegrin Hospital, Bordeaux University,
Bordeaux, France.

There is no hierarchy in the use of biotherapies (bDMARDs) in psoriatic arthritis (PsA) and no published head-to-head
,

functional outcomes in PsA.

respectively.

All bDMARDs showed higher ACR20 response rates and better HAQ-DI mean reduction compared to placebo.

between bDMARDs in PsA.

psoriatic arthritis, DMARD, meta-analysis

Clinical and Experimental Rheumatology 2020; 38:Clinical

508-515.and Experimental Rheumatology 2020
 in PsA, but these meta-analyses do not
- include all available bDMARDs (11),
Thomas Barnetche, PhD tory disease which associates arthritis do not systematically assess their im-
Alain Cantagrel, MD, PhD
and psoriasis. Up to 30% of patients pact on enthesitis, dactylitis, skin and
Adeline Ruyssen-Witrand, MD, PhD
Arnaud Constantin, MD, PhD affected by psoriasis will develop PsA, functional outcomes (12–19) or do
based on the CASPAR criteria (1). The not analyse separately novel biologics,
Please address correspondence to:
disease is strongly associated with a re- which does not account for their differ-
duced quality of life, its burden being ent mechanisms of action (11).
Hopital Pierre-Paul Riquet, similar to rheumatoid arthritis and axial The purpose of our meta-analysis is to
spondyloarthritis (2). Nearly half of pa-
tients will present with bone erosions currently marketed bDMARD classes
E-mail: numa.simons@gmail.com within two years of disease onset (3). (TNF inhibitors, IL12/23 inhibitors,
The treatment of PsA is complex and IL17 inhibitors and CTLA4-Ig) in
there is still no universal consensus re- terms of both articular and extra-ar-
© Copyright CLINICAL AND garding remission criteria even though ticular outcomes, in order to guide the
EXPERIMENTAL RHEUMATOLOGY 2020. treatment guidelines are available clinical prescription of third-line drugs
from the EULAR and GRAPPA study according to the clinical presentation of
groups (4, 5). First-line treatments in- the disease.
clude NSAIDs and local glucocorti-
coid injections. Second-line therapies
include conventional synthetic dis- This meta-analysis has been performed
ease-modifying anti-rheumatic drugs in accordance with the Preferred report-
(csDMARDs) such as methotrexate, ing items for systematic review and me-
ta-analysis protocols (PRISMA) (20).
line treatments include biological
DMARDs (bDMARDs) and targeted
synthetic DMARDs (tsDMARDs), The search was conducted on 15 March
such as JAK inhibitors and phospho- 2017 and updated on 5 February 2018.
diesterase-4 (PDE4) inhibitors. PsA It was conducted through the MedLine,
management also covers patient edu- Cochrane and Embase databases, us-
cation, weight reduction, smoking ces- ing the following keywords: “(TNF OR
sation, exercising, joint protection and abatacept OR adalimumab OR certoli-
stress management (7).
bDMARDs have been allowed as third-
line treatments in PsA since the early
2000s. TNF inhibitors include mono- -
clonal antibodies targeting TNF (adali- strict the results to randomised con-
trolled trials. Manual research was also
and golimumab) and soluble TNF re- conducted through the 2016 and 2017
ceptors (etanercept). Ustekinumab tar- ACR and EULAR Congress abstracts.
gets the p40 subunit of IL-12/23. Ixeki-

Abatacept targets CTLA4 and blocks We focused on original randomised

T-cell co-stimulation signals. New tar- controlled trials evaluating one or more
gets are currently investigated, such as marketed bDMARDs versus placebo in
the p19 subunit of IL-23 (guselkumab, adults suffering from PsA. No restric-
tion was applied to prior bDMARD
Partner Fellowship supported by Celgene use, duration of study or primary or sec-
bDMARDs are an expensive treatment ondary endpoints. Patients in the study
option and their prescription does not treatment arm received a bDMARD at
always trigger an adequate clinical re- a dosage approved for the treatment of
years, and research support from Abbvie, sponse: results from the DANBIO reg- PsA by either the European Medicines
istry show that only 54% of patients Agency (EMA) or the Food and Drugs
received honoraria for consultancies from
treated with anti-TNF agents satisfy the Administration (FDA). No restriction
EULAR good response criteria (10). -
The other co-authors have declared no Meta-analyses have been performed -
competing interests. on ACR20, PASI and HAQ outcomes date the CASPAR criteria (21).

509
 Fig. 1. Flow chart. Data extraction
RCT: randomised controlled The following data were extracted
trial, PsA: psoriatic arthritis.
-
ence and year of the trial, duration of
study, primary endpoints, secondary
endpoints, intervention design, num-
ber of patients enrolled, inclusion cri-
teria, prior bDMARD use and baseline
characteristics of the study population
(age, sex ratio, length of time since dis-
ease onset, number of swollen joints,
number of tender joints, disease activ-
ity VAS as stated by the patient, CRP
levels, presence of enthesitis or dacty-
litis). For the meta-analysis, the follow-
ing criteria were recorded: number of

Table I. Detail of included studies.

Study Year Duration Primary endpoint Treatment Prior bDMARD use Patients

Mease 2000 12 weeks PsARC Etanercept No TRT: 30

PBO: 30
Mease et al. Arthritis Rheum 2004 24 weeks ACR20 Etanercept No TRT: 101
PBO: 104
IMPACT
Antoni et al. Arthritis Rheum
PBO: 52
IMPACT2
Antoni et al. Ann Rheum Dis
PBO: 100
ADEPT
Mease et al. Arthritis Rheum 2005 12 weeks ACR20 Adalimumab No TRT: 151
Sharp score PBO: 162
Genovese et al. J Rheumatol 2007 12 weeks ACR20 Adalimumab No TRT: 51
PBO: 49
GO-REVEAL
Kavanaugh et al. Arthritis Rheum 2009 24 weeks ACR20 Golimumab No TRT: 146
PBO: 113
RAPID-PSA
Mease et al. Ann Rheum Dis
PBO: 136
GO-VIBRANT
Kavanaugh et al. Arthritis Rheum 2017 24 weeks ACR20 Golimumab No TRT: 241
PBO: 239
OPAL BROADEN
Mease et al. NEJM 2017 12 weeks ACR20 Tofacitinib No PBO: 105
HAQ-DI Adalimumab ADA: 106
PSUMMIT1
McInnes 2013 24 weeks ACR20 Ustekinumab No U45: 205
PBO: 206
PSUMMIT2
Ritchlin et al. Ann Rheum Dis 2014 24 weeks ACR20 Ustekinumab Yes (58%) U45: 103
PBO: 104
FUTURE1
Mease et al. NEJM 2015 24 weeks ACR20 Secukinumab Yes (28%) S150: 202
PBO: 202
FUTURE2
McInnes 2015 24 weeks ACR20 Secukinumab Yes (35%) S150: 100
PBO: 98
SPIRIT P1
Mease et al. Ann Rheum Dis
Adalimumab PBO: 106
SPIRIT P2
Nash
PBO: 118
ASTRAEA
Mease et al. Ann Rheum Dis 2017 24 weeks ACR20 Abatacept Yes (60%) TRT: 213
PBO: 211
ACR: American College of Rheumatology; PASI: psoriasis area severity index; bDMARD: biological disease-modifying anti-rheumatic drug; PsARC: psoriatic arthritis
response criteria; HAQ-DI: health assessment questionnaire disability index; TRT: treatment; PBO: placebo.

510 Clinical and Experimental Rheumatology 2020

criteria, ACR50 response criteria, and
ACR70 response criteria, number of
enthesitis-free patients and number of
dactylitis-free patients, number of pa-

criteria and PASI90 response criteria at

the time of primary criteria evaluation,
which was ranging from 12 to 24 weeks
and the HAQ-DI mean score variation
from baseline. Enthesitis and dactylitis
outcomes were assessed as difference
from baseline. When not explicitly re-
ported, enthesitis and dactylitis reso-
lution was considered achieved if the
evaluation criteria (Leeds Enthesitis In-
dex, Maastricht Ankylosing Spondylitis
Enthesitis Score, Leeds Dactylitis Index
or Dactylitis Severity Score) was equal

dactylitis or enthesitis score superior to

drop-out option in the placebo group,

we used data as presented at the end
of the double-blind period. All results
were obtained from an intent-to-treat to placebo, pooled per class (higher is better).
population. When data were unavail-
able, we contacted the research team in Heterogeneity was assessed according 4303 patients (bDMARDs: n=2168;
order to obtain further information. to Cochran’s Q-test and I2 values. Cal- placebo: n=2135) were included in our
culations were made with the Cochrane primary analysis. The mean age at base-
RevMan 5.3 software. p-values less line ranged from 43.5 to 52.6 years. The
Risk of bias was evaluated using the percentage of female subjects ranged
Cochrane Collaboration’s Assessment from 29 to 60%. The average duration
Tool (22). of the disease ranged from 3.4 to 11.7
years.
The search yielded 324 original results.
The meta-analysis was restricted to 304 articles were excluded after title
treatment arms using the dosage ap- screening and 3 were excluded after full All of the studies were of good quality,
proved by the EMA or the FDA for PsA. text screening because the dosage used as evaluated per the Cochrane Collabo-
Analysis was performed on the total was not the standard one (Fig. 1). The ration’s Assessment Tool (22) (Supple-
population at the end of the double- 17 remaining articles were included in mentary Fig. 1).
blind period. Only one intervention the meta-analysis, after assessment by
group was compared to the placebo NS and ARC. Meta-analysis
in the analysis except when detailed All the randomised, placebo-controlled Higher ACR20 response rates were
data wasn’t available, in which case trials included in our meta-analysis shown for all bDMARDs in comparison
we used pooled numbers for treatment were published between 2000 and to placebo, with RRs (95%CI) rang-
arms (23). Enthesitis and dactylitis out- 2017. Two RCTs studied etanercept ing from 3.21 (2.52, 4.08) for anti-TNF
comes were assessed using the number agents, 2.58 (2.04, 3.27) for anti-IL17
of enthesitis-free or dactylitis-free pa- studied adalimumab (28-30), 2 studied agents, 1.95 (1.52, 2.50) for usteki-
tients at the time of evaluation reported golimumab (31, 32), 1 studied certoli- numab to 1.77 (1.31, 2.39) for abata-
to the number of patients with enthesi- cept (Fig. 2). The same trends were ob-
tis or dactylitis at baseline. 35), 2 studied secukinumab (23, 36), 2 served for ACR50 response rates, with
Meta-analysis was performed to as- - RRs (95%CI) ranging from 6.47 (4.57,
sess the relative risk (RR) with 95% ied abatacept (39) (Table I). 9.17) for anti-TNF agents, 4.22 (2.83,
The double-blind period ranged be- 6.28) for anti-IL17 agents, 2.78 (1.81,
study and pooled for the 4 different tween 12 and 24 weeks. Eight RCTs 4.27) for ustekinumab to 1.56 (0.99,
bDMARD classes marketed for PsA. allowed prior bDMARD use. In total, 2.46) for abatacept (not statistically sig-

Clinical and Experimental Rheumatology 2020 511

 The RRs (C95%CI) for enthesitis reso-
lution in comparison to placebo ranged
from 2.31 (1.60, 3.34) for anti-IL17
agents, 1.99 (1.36, 2.90) for anti-TNF
agents to 1.41 (1.02, 1.95) for usteki-
numab (Fig. 3).
The RRs (C95%CI) for dactylitis reso-
lution versus placebo ranged from 2.65
(1.79, 3.94) for anti-IL17 agents, 2.07
(1.38, 3.12) for anti-TNF agents to 1.42
(0.97, 2.08) for ustekinumab (not statis-

Higher PASI75 response rates were

shown for most bDMARDs in compari-
son to placebo, with RRs (CI95%) rang-
ing from 8.51 (4.56, 15.90) for anti-TNF
agents, 5.14 (3.16, 8.36) for anti-IL17
agents, 6.36 (3.49, 11.60) for usteki-
numab to 1.62 (0.89, 2.96) for abata-

5). PASI90 response rates followed the

same trends, with RRs (95%CI) ranging
Fig. 3. Risk ratio (95%CI) for bDMARDs in terms of enthesitis reduction compared to placebo, from 8.76 (3.84, 20.01) for anti-TNF
pooled per class (higher is better).
agents, 4.95 (2.85, 8.61) for anti-IL17
agents to 11.57 (5.46, 24.52) for usteki-
numab (no data available for abatacept)
(Suppl. Fig. 5).
Higher HAQ-DI reductions were shown
for most bDMARDs compared to pla-
cebo, with mean differences (95%CI) of
-0.31 (-0.42, -0.20) for anti-TNF agents,
-0.26 (-0.33, -0.20) for anti-IL17 agents
and -0.13 (-0.25, -0.01) for abatacept
(no data available for ustekinumab)
(Suppl. Fig. 6).

In our meta-analysis, all bDMARDs

proved superior to placebo in terms of
the ACR20 response rates and HAQ-DI
mean reductions. Not all bDMARDs

ACR50/70 response rates, higher rates

of enthesitis or dactylitis resolution
or higher PASI75/90 response rates in
comparison to placebo.
Risk ratio (95%CI) for bDMARDs in terms of dactylitis reduction compared to placebo, This meta-analysis assessed the relative
pooled per class (higher is better).
classes of bDMARDs in terms of both
patients showed similar results concern- articular and extra-articular outcomes,
response rates, with RRs (95%CI) of ing ACR20 response rates, with RR in RCTs conducted in PsA. We selected
8.89 (5.98, 13.21) for anti-TNF agents, (95%CI) ranging from 3.14 (2.44, 4.05) 17 high-quality (22) RCTs comparing
8.84 (3.65, 21.39) for anti-IL17 agents, for anti-TNF agents, 2.75 (1.80, 4.21) for bDMARDs to placebo using the Med-
3.90 (1.81, 8.39) for ustekinumab and anti-IL17 agents, to 1.86 (1.43, 2.42) for Line, Cochrane and Embase databases,
1.56 (0.82, 2.96) for abatacept (not sta- ustekinumab, except for abatacept with and compiled the most relevant and fre-
RR (95%CI) of 1.23 (0.90, 1.68) (not quently reported response criteria for
Analysis focused on bDMARD naïve arthritis, enthesitis and dactylitis, skin

512 Clinical and Experimental Rheumatology 2020

 39, 43). Lastly, one study only reported
pooled numbers for both treatment
arms, which we chose to include in the
analysis (23). We chose to focus on ab-
solute enthesitis or dactylitis reduction
and not composite indexes in order to
obtain analysable data.
Concerning skin outcomes, our meta-

higher PASI75 and PASI90 response

rates compared to placebo, except for
abatacept which did not display statis-

in terms of the PASI75 response crite-

ria (no data for the PASI90 response
criteria). The authors attribute the lack
-
dermal bioavailability (39). Recent
network meta-analyses corroborate our
results concerning skin outcomes com-
pared to placebo (44, 45) and, in this
respect, IL-17 inhibitors seem to be the
most effective treatment. Moreover,
-
Fig. 5. periority of ustekinumab (46), secuki-
to placebo, pooled per class (higher is better). over

involvement and quality of life. We fo- meta-analysis shows that all avail- secukinumab (50) over ustekinumab.
cused this analysis on bDMARDs and able bDMARDs have a strong relative Concerning functional outcomes, all
did not include tsDMARDS such as RCTs analysed showed a statistically
apremilast or Jak inhibitors. RCTs that criteria compared to placebo. Only
did not use the marketed treatment po- abatacept fails to display superiority versus placebo. The data provided for
sology (40-42) were excluded in order over placebo regarding the ACR50 and ustekinumab could not be analysed as
ACR70 response criteria, for which it was a median reduction. Only one
to their use in clinical practice. the authors involved the lower propor- previous meta-analysis assessed HAQ
The selected RCT publication date cov- tion of bDMARD-naive patients (40%) improvement for PsARC responders
ers 2000 to 2017, and therefore displays (39). Those results are consistent with
disparities, such as the duration of the previously published analyses (11, 14– statistical evidence to demonstrate dif-
disease at inclusion, ranging from 3.5 18). The ACR20 evaluation criteria is ferences in effectiveness between anti-
years to 11.4 years, the severity of the TNF agents (51).
disease or the duration of the double-
blind period which spans 12 to 24 the form of a DAPSA evaluation of dis-
weeks. One limitation arises from the ease activity (39). bDMARDs in PsA in 2018 on both ar-
Concerning dactylitis outcomes, our ticular, enthesitis, dactylitis, skin, and
on bDMARD-naive populations with meta-analysis shows a statistical dif- functional outcomes. On the one hand,
better treatment response rates than ference compared to placebo for anti- all bDMARDs showed higher ACR20
previously exposed populations (4). In TNF and anti-IL17 agents, but not for response rates and a better HAQ-DI
the RCTs evaluating TNF inhibitors, anti-IL12/23 agents. We encountered mean reduction compared to placebo.
only the RAPID-PsA trial allowed 20% methodological issues on incorporating On the other hand, this meta-analysis
of its population to have prior exposure enthesitis and dactylitis outcomes in the highlights the variability in terms of
to anti-TNF agents. In those evaluating present meta-analysis. Firstly, no data -
anti-IL17 agents, anti IL12/23 agents were reported on enthesitis and dactyli- thesitis-free or dactylitis-free response
and abatacept, four out of seven al- tis outcomes in three studies evaluating rates and PASI75/90. The results of on-
lowed some of the randomised patients anti-TNF agents (24, 25, 28). Secondly, going head-to-head studies are needed
(28% to 60%) to have had prior expo- three other studies reported those out-
sure to bDMARDs (Table I). comes solely as composite index re- -
Concerning articular outcomes, our duction and could not be analysed (29, tween bDMARDs in PsA.

Clinical and Experimental Rheumatology 2020 513

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