744 Full

Ann Rheum Dis: first published as 10.1136/annrheumdis-2019-216656 on 7 February 2020. Downloaded from http://ard.bmj.
com/ on February 3, 2022 at Carol Davila University of Medicine

Rheumatoid arthritis
Clinical science
Efficacy of pharmacological treatment in rheumatoid

arthritis: a systematic literature research informing
the 2019 update of the EULAR recommendations for
management of rheumatoid arthritis
Andreas Kerschbaumer ‍ ‍,1 Alexandre Sepriano ‍ ‍,2,3 Josef S Smolen,1
Désirée van der Heijde ‍ ‍,2 Maxime Dougados,4 Ronald van Vollenhoven,5
Iain B McInnes,6 Johannes W J Bijlsma,7 Gerd R Burmester,8 Maarten de Wit ‍ ‍,9
Louise Falzon,10 Robert Landewé5
Handling editor Dimitrios T Abstract

Boumpas Key messages
Objectives To inform the 2019 update of the
►► Additional material is
European League against Rheumatism (EULAR)
What is already known about this subject?
published online only. To view recommendations for the management of rheumatoid
►► Since the 2016 update of the recommendations
please visit the journal online arthritis (RA).
(http://d x.doi.o rg/10.1136/ for the management of rheumatoid arthritis
Methods A systematic literature research (SLR)
annrheumdis-2019-216656). (RA), the body of evidence has grown vividly.
to investigate the efficacy of any disease-modifying Therefore, this systematic literature research
For numbered affiliations see antirheumatic drug (DMARD) (conventional synthetic (SLR) was performed to inform the 2019
and Pharmacy. Protected by copyright.

end of article. (cs)DMARD, biological (b) and biosimilar DMARD, European League against Rheumatism (EULAR)
targeted synthetic (ts)DMARD) or glucocorticoid (GC) task force with the summarised evidence
Correspondence to therapy in patients with RA was done by searching
Dr Andreas Kerschbaumer, on efficacy of conventional and targeted
Division of Rheumatology,
MEDLINE, Embase and the Cochrane Library for articles synthetic disease-modifying antirheumatic
Department of Medicine 3, published between 2016 and 8 March 2019. drugs (DMARDs), biological DMARDs and
Medical University of Vienna, Results 234 abstracts were selected for detailed glucocorticoids.
Vienna, Austria; assessment, with 136 finally included. They comprised
a ndreas.kerschbaumer@
meduniwien.ac.at
the efficacy of bDMARDs versus placebo or other What does this study add?
bDMARDs, efficacy of Janus kinase (JAK) inhibitors ►► Trials comparing biological DMARDs have
Received 17 November 2019 (JAKi) across different patient populations and shown similar efficacy, regardless of the
Revised 7 January 2020 head-to-head of different bDMARDs versus JAKi or underlying mode of action.
Accepted 8 January 2020
Published Online First
other bDMARDs. Switching of bDMARDs to other ►► Head-to-head trials between Janus kinase (JAK)
7 February 2020 bDMARDs or tsDMARDs, strategic trials and tapering inhibitors (JAKi) and tumour necrosis factor
studies of bDMARDs, csDMARDs and JAKi were inhibitor inhibitors did not reveal clinically
assessed. The drugs evaluated included abatacept, important differences in efficacy.
adalimumab, ABT-122, baricitinib, certolizumab ►► Drug tapering of DMARDs, including JAKi is
pegol, SBI-087, CNTO6785, decernotinib, etanercept, possible, especially in patients achieving stable
filgotinib, golimumab, GCs, GS-9876, guselkumab, remission.
hydroxychloroquine, infliximab, leflunomide, ►► Treating patients to target using MRI-defined
mavrilimumab, methotrexate, olokizumab, otilimab, remission does not lead to better outcomes
peficitinib, rituximab, sarilumab, salazopyrine, when compared with a conventional clinical
►► http://dx.doi.org/10.1136/ secukinumab, sirukumab, tacrolimus, tocilizumab, treat-t o-target strategy.
annrheumdis-2019-216653 tofacitinib, tregalizumab, upadacitinib, ustekinumab
►► http://dx.doi.org/10.1136/ and vobarilizumab. The efficacy of many bDMARDs How might this impact on clinical practice or
annrheumdis-2019-216655 and tsDMARDs was shown. Switching to another future developments?
►► http://dx.doi.org/10.1136/
tumour necrosis factor inhibitor (TNFi) or non-TNFi ►► This SLR, alongside with the safety SLR,
annrheumdis-2019-216821
bDMARDs after TNFi treatment failure is efficacious. provided the 2019 EULAR RA management
Tapering of DMARDs is possible in patients achieving recommendations task force with the emerged
long-standing stringent clinical remission; in patients evidence since 2016.
© Author(s) (or their with residual disease activity (including patients
employer(s)) 2020. Re-use
permitted under CC BY-NC. No in LDA) the risk of flares is increased during the
commercial re-use. See rights tapering. Biosimilars are non-inferior to their reference Introduction
and permissions. Published products. To provide the task force on the 2019 update
by BMJ. Conclusion This SLR informed the task force of the European League against Rheumatism
To cite: Kerschbaumer A, regarding the evidence base of various therapeutic (EULAR) recommendations for the pharmacolog-
Sepriano A, Smolen JS, regimen for the development of the update of EULAR’s ical management of rheumatoid arthritis (RA) with
et al. Ann Rheum Dis RA management recommendation. all available evidence that had emerged since the
2020;79:744–759. last update, systematic literature researches (SLRs)
744 Kerschbaumer A, et al. Ann Rheum Dis 2020;79:744–759. doi:10.1136/annrheumdis-2019-216656
Ann Rheum Dis: first published as 10.1136/annrheumdis-2019-216656 on 7 February 2020. Downloaded from http://ard.bmj.com/ on February 3, 2022 at Carol Davila University of Medicine
were performed. In 2016, three SLRs were conducted assessing variables, physical function, patient- reported outcomes and
efficacy of biological disease- modifying antirheumatic drugs measures of structural damage.
(bDMARDs),1 efficacy of glucocorticoids (GCs), conventional Sixteen research questions were defined according to the
synthetic (cs) and targeted synthetic (ts) DMARDs,2 and safety of Patient population, Intervention, Control, Outcome (PICO)
pharmacological treatments in RA.3 The 2019 update was based principle with the help of the steering committee. All typical RA
on two SLRs, one on safety and the present one on efficacy of study populations were included, methotrexate (MTX)- naïve
pharmacological interventions in RA. or generally DMARD- naïve patients, csDMARD insufficient
The body of evidence has grown vividly in the last 3 years, responders (IR), bDMARD- IR or tsDMARD- IR. Adequately
especially regarding tsDMARDs inhibiting Janus Kinase inhib- defined control groups receiving either placebo or active treat-
itor (JAKi), novel bDMARDs targeting new as well as established ment were mandatory for inclusion in this analysis. These
pathways and trials comparing bDMARDs to other bDMARDs involved the efficacy of bDMARDs with or without csDMARD
or tsDMARDs, providing important information on the compar- combination, head- head comparisons of bDMARDs and
to-
ative efficacy of these compounds.4 Further, studies on tapering switching between different bDMARDs, tapering and stopping
and stopping treatment broaden the information base for rheu- bDMARDs, as well as the efficacy of tsDMARDs and the respec-
matologists and patients on the question of possible disease tive head- head comparison to bDMARDs. Other research
to-
flares after tapering or cessation of drugs, once patients have questions involved biosimilars, switching between bsDMARDs
reached the clinical target. Strategic studies on how to optimally and respective boDMARD, the efficacy of csDMARDs and the
treat patients to target,5 using clinical and imaging targets have efficacy of GC (in combination with csDMARDs). All interven-
also answered important research questions.6 Finally, a large tions of interest are shown in online supplementary table S1.7.
number of trials compared the efficacy and safety of biosimilars A detailed description of the PICOs is shown in online supple-
(bs) DMARDs with those of their bio-originators (bo), including mentary table S1.8.
switching between boDMARD and respective bsDMARDs. Risk of bias (RoB) in individual studies was assessed at study
This SLR was conducted to update the evidence on efficacy of level using the Cochrane Collaborations Risk of Bias tool for
pharmacological interventions in RA. This involves the evidence randomised controlled trials (RCTs). The assessment was done
accrued since the last update of the treatment recommendations independently by two investigators (AK and AS). Differing

for RA, published by EULAR in 2016.7 Another SLR focusing assessments were discussed until consensus was reached.
on safety of pharmacological treatments in RA is published Due to the heterogeneity of the available studies, no meta-
separately.8 analysis was performed, and results will be reported narra-
tively. Descriptive forest plots were created using RevMan V.5.3
(Copenhagen: The Nordic Cochrane Centre, The Cochrane
Methods Collaboration, 2014).
The EULAR updated standard operating procedures were
followed,9 and an SLR protocol was developed and approved by
the steering committee. Results
Studies eligible for inclusion in this SLR were randomised, The study selection process involved 15 037 references. After
controlled, double- blind trials investigating csDMARDs, deduplication, 7876 remained for title and abstract screening, of
bDMARDs (bo and bsDMARDs), tsDMARDs or GCs in adult which 234 were selected for full article review and 136 articles
patients with RA classified according to the 2010 American finally included. A detailed flow chart is depicted in figure 1.
College of Rheumatology (ACR)/EULAR or the ACR 1987 Details of all studies included are shown in online supplementary
criteria. This SLR was considered to further update the available table S2.1.
evidence since the previous SLRs, therefore, articles published RoB was considered as low for most RCTs included. RCTs were
between 1 January 2016 and 8 March 2019 with no language rated as having an unclear RoB most commonly due to insuffi-
restriction were searched. Additionally, studies presented as cient reporting of random sequence generation and/or allocation
conference abstracts at the EULAR and ACR annual meetings concealment. Due to their unblinded nature, open-label studies
from 2016 to 2018 were also eligible for inclusion. References of were considered as having a high RoB. Trials reported in confer-
original articles published on submission of the manuscript (after ence abstracts were not assessed regarding RoB due to limited
the data cut), but with respective conference abstracts included information. Results of the RoB assessment are shown in online
before, were included in the reference list. supplementary table S2.2.
The initial literature search was conducted by an experienced Characteristics of each trial for which data were extracted
librarian (LF) using Medline, Embase, The Cochrane CENTRAL (study size, PICOs), baseline characteristics (online supplemen-
Register of Controlled Trials (Central) and the EULAR/ACR tary table S2.3–S2.12), results of studies and summary data for
abstract archives as information sources. The detailed search each intervention group (online supplementary table S3.1–S3.13)
strategy for each database is shown in the online supplementary as well as the respective citations (section 4 in the online supple-
tables S1.1–S1.6. mentary appendix) are shown in the supplement. A summary
The study selection process was conducted independently by of included trials and therapies investigated is shown in table 1.
two investigators (AK and AS) and discussed until agreement was
achieved. A senior methodologist (RL) was consulted in the case
of uncertainties. After the initial title and abstract screening for Efficacy of csDMARDs (or combination of csDMARDs) versus
identification of reports of potential interest, a detailed assess- other csDMARDs
ment for eligibility of preselected articles was done. Data of Five trials (all with unclear or high RoB) investigated the efficacy
eligible studies were extracted based on standardised methods of csDMARDs alone or in combination versus other csDMARDs
using pivotal forms. Variables of interest were predefined in (see table 1). Baseline characteristics and detailed results are
the review protocol, including signs and symptoms of arthritis shown in online supplementary table S2.12 and online supple-
and commonly used composite measures, respective core set mentary table S3.13, respectively.
Kerschbaumer A, et al. Ann Rheum Dis 2020;79:744–759. doi:10.1136/annrheumdis-2019-216656 745
Figure 1 PRISMA flow chart describing the study selection process. DMARDs, disease-modifying antirheumatic drugs; PRISMA, Preferred Reporting
Items for Systematic Reviews and Meta-Analyses; SLR, systematic literature research.
The open-label CareRA trial (high RoB) stratified very early, molecules targeting B- cells (SBI-087, BCD-020),13 14 inter-
csDMARD naive patients based on their risk factors (presence feron-6 (IL-6) receptor (sarilumab),15 16 IL-6 cytokine (siru-
of erosions, disease activity, rheumatoid factor and anticitrul- kumab, olokizumab, vobarilizumab),17–22 GM- CSF receptor
linated protein antibodies) into high and low risk.10 High-risk (mavrilimumab) and GM-CSF cytokine (otilimab).23–25 IL-12/23

patients were randomised to three different csDMARD regimens inhibition (ustekinumab) and IL23i (guselkumab) did not show
(Combination therapy for early Rheumatoid Arthritis (COBRA) significant differences from placebo. Molecules targeting IL-17A
classic: methotrexate (MTX)+sulfasalazine (SSZ) + prednisone (secukinumab, CNTO6785),26–28 and CD4 (tregalizumab)
60 mg step-down vs COBRA Slim: MTX+prednisone 30 mg showed no or only minor efficacy compared with placebo
step-down vs COBRA Avant Garde: MTX+leflunomide (LEF) (and lower efficacy compared with abatacept (ABA) as active
+ prednisone 60 mg step-down). Low-risk patients were either comparator) in different patient populations.29 Primary efficacy
randomised to MTX tight-step up or COBRA Slim). The treat- outcomes are summarised in table 2, baseline characteristics are
ment arms investigated in high-risk patients showed comparable shown in online supplementary table S2.3 and secondary effi-
efficacy in achieving the primary endpoint (Disease Activity cacy outcomes in online supplementary table S3.1.
Score of 28 joints (DAS28)-C reactive protein (CRP) <2.6) at
week 52 for COBRA Classic (64.3%, 63/98).
COBRA Slim (60.2%, 59/98) and COBRA Avant Garde Trials comparing bsDMARDs to boDMARDs
(62.4%, 58/93, p=0.840). In low-risk patients, COBRA-Slim Twenty-four non- inferiority trials (12 with low RoB) inves-
and MTX-tight step up also showed comparable efficacy at week tigated the bioequivalence of bsDMARDs to their respective
52 (67.4%, 29/43 vs 57.4%, 27/47, p=0.329). However, the boDMARDs. All showed conclusive comparable results, irre-
area under the curves for mean DAS28-CRP change from base- spective of the compound (adalimumab (ADA), etanercept,
line as well as time-to-remission were favouring MTX plus pred- infliximab and rituximab; for bsDMARD studied see table 1,
nisone combination therapy. Radiographic damage was minimal online supplementary table S2.10 and online supplementary
and comparable across all treatment arms. Sustained and compa- table S3.11).30–55
rable efficacy was shown after 2 years of treatment in high-risk Switching between biosimilars and bio- originators revealed
patients.11 no changes in efficacy in trials of one ADA (SB5, low RoB),56
Investigation of LEF plus SSZ plus hydroxychloroquine (HCQ) three etanercept (two with low RoB: GP2015, LBEC0101;
triple therapy compared with MTX+SSZ+ HCQ triple therapy CHS-0214: conference abstract—RoB not assessed),32 57–59 and
or LEF alone in a 48-week double-blind RCT was terminated two infliximab biosimilars (SB2, CT-P13, both low RoB).60 61
early due to gastrointestinal complications in the LEF +SSZ+ Detailed characteristics and results of the studies are shown in
HCQ arm. Conventional triple therapy (MTX+SSZ+ HCQ) online supplementary tables S2.11 and S3.11.
was superior to LEF +SSZ+ HCQ and LEF alone (ACR20: 87%
vs 46%, p<0.01, 87% vs 36%, p<0.001, respectively), with no
apparent efficacy benefit of the LEF triple therapy compared Head-to-head studies (bDMARDs)
with LEF alone at week 48 (ACR20: 46% vs 36%, p>0.05).12 Seven bDMARD head-to-head studies were included (six with
low RoB; one high RoB). Efficacy results are summarised in
Efficacy of bDMARDs, alone or in combination with table 3 (baseline characteristics and detailed efficacy outcomes
csDMARDs, in csDMARD and bDMARD-IR patients with are shown in online supplementary tables S2.3 and S3.2.).
(established) RA The Optimal Management of patients with rheumatoid
Trials comparing bDMARDs to placebo with or without arthritis who Require Biologic Therapy (ORBIT) trial (high
csDMARD background therapy (21 articles/abstracts, 7 with RoB), an open- label non-inferiority RCT comparing B- Cell
low RoB) showed effective reduction of signs and symptoms depletion (rituximab) to tumour necrosis factor inhibitor (TNFi)
for several different modes of action (see table 1), including therapy in csDMARD-IR and bDMARD-naïve patients, found
Table 1 Interventions and therapeutic compounds of trials included for review

Intervention No of articles/ abstracts* Therapeutic compound Target
csDMARDs, csDMARD combination, 5 Tacrolimus +methotrexate (MTX) versus FKBP12; dihydrofolate reductase
Glucocorticoids versus other csDMARDs leflunomide+MTX +purine metabolism; dihydroorotate
or placebo (10–12 130 131) MTX+sulfasalazine + glucocorticoids versus dehydrogenase
MTX +glucocorticoids versus MTX +Leflunomide
+Glucocorticoids
MTX versus MTX+glucocorticoids
MTX+sulfasalazine + Hydroxychloroquine versus
leflunomide +sulfasalazine + hydroxychloroquine
versus leflunomide monotherapy
bDMARD ±csDMARDs versus placebo 21 BCD-020 CD-20
(13–29 132–136) SBI-087
Tregalizumab CD-4
Abatacept CD-80/CD-86
Certolizumab pegol TNF
Olokizumab IL-6
Sirukumab
Sarilumab IL-6 receptor
Vobarilizumab
CNTO6785 IL-17
Secukinumab
Otilimab GM-CSF
Mavrilimumab GM-CSF receptor

Ustekinumab IL-12/23
Guselkumab IL-23
bDMARDs versus other bDMARDs (4 62–66 8 Rituximab versus etanercept/adalimumab CD-20 versus TNF
137 138
) ABT-122 versus adalimumab TNF/IL-17A versus TNF
Certolizumab pegol versus adalimumab TNF
Sirukumab versus adalimumab IL-6 versus TNF
Sarilumab versus adalimumab IL-6 receptor versus TNF
Secukinumab versus abatacept IL-17 versus CD-80/CD-86
Mavrilimumab versus golimumab GM-CSF versus TNF
bDMARD induction versus csDMARD 5 Certolizumab pegol versus MTX TNF
induction in early disease (69–72 139) Abatacept versus MTX CD-80/CD-86
Infliximab versus MTX TNF
Tocilizumab versus MTX IL-6 receptor
Switching between bDMARDs (4 67 68) 3 Certolizumab pegol versus adalimumab TNF
Abatacept; rituximab; tocilizumab versus adalimumab; CD-80/CD-86; CD-20; IL-6 receptor
certolizumab; infliximab; golimumab; etanercept versus TNF
Sarilumab IL-6 receptor
Tapering of bDMARDs/tsDMARDs or 25 Abatacept CD-80/CD-86
csDMARDs (107–124 126–128 140–145) Tocilizumab IL-6 receptor
Adalimumab; certolizumab pegol; etanercept; TNF
infliximab;
csDMARDs
Glucocorticoids
Strategic studies (6 146) 2
tsDMARDs±csDMARDs versus placebo 32 Baricitinib JAK 1/2
(73–100 125 147–152) Decernotinib JAK 3
Filgotinib JAK 1
GS-9876 SYK
Peficitinib JAK 1
Tofacitinib JAK 1/3
Upadacitinib JAK 1
tsDMARDs±csDMARDs versus 5 Baricitinib versus adalimumab JAK 1/2 versus TNF
bDMARDs±csDMARDs (101–106) Tofacitinib versus adalimumab JAK 1/3 versus TNF
Upadacitinib versus adalimumab JAK 1 versus TNF
Continued

Table 1 Continued
Intervention No of articles/ abstracts* Therapeutic compound Target
30–34 36–55
bsDMARDs versus boDMARDs ( ) 24 Adalimumab: ABP 501, AdaliRel, BI 695501, CinnoRA, TNF
FKB327, GP2017, PF-06410293, SB5, ZRC 3197
Etanercept: CHS-0214, GP2015, HD203, LBEC0101 TNF
Infliximab: BCD-055, CT-P13, NI-071, PF-06438179/ TNF
GP1111, SB2
Rituximab: BCD-020, CT-P10, DRL-RI, GP2013 CD-20
Switching between bsDMARDs and 6 Adalimumab: SB5 TNF
boDMARDs (32 35 56–61 153) Etanercept: GP2015, CHS-0214, LBEC0101 TNF
Infliximab: SB2, CT-P13 TNF
*Studies answering multiple research questions account for mismatch between included articles/abstracts and numbers in this table. References of manuscripts published after
the SLRs data cut, with the respective conference abstracts included before, are shown, but were not counted.
bDMARD, biological disease-modifying antirheumatic drug; boDMARD, biooriginator disease-modifying antirheumatic drug; bsDMARD, biosimilar disease-modifying
antirheumatic drug; CD, cluster of differentiation; csDMARD, conventional synthetic disease-modifying antirheumatic drug; GM-CSF, granulocyte-macrophage colony-stimulating
factor; IL, interleukin; JAK, Janus kinase; SYK, spleen tyrosine kinase; TNF, tumour necrosis factor; tsDMARD, targeted synthetic disease-modifying antirheumatic drug.
that RTX is non-inferior to TNFi over 52 weeks regarding clin- (101/146, 69%) compared with 52% in the second TNFi group
ical efficacy.62 (OR 2.12; 95% CI 1.31 to 3.46; p=0.003).68 bDMARD thera-
Sarilumab monotherapy showed clinical and functional supe- pies in early RA patients.
riority compared with ADA monotherapy in patients who were Five reports on induction therapy with bDMARDs in early
intolerant or inadequately responding to MTX.63 disease were included (two with low RoB), baseline characteris-
Mavrilimumab (targeting GM- CSFR) was compared with tics are shown in online supplementary table S2.5 and results in

golimumab in a 24-week phase 2b trial of csDMARD and/or online supplementary table S3.4.
TNFi-IR patients and had similar efficacy.64 In DMARD naïve patients with poor prognostic factors, CZP
ABT-122, a bispecific dual variable domain immunoglobulin in combination with dose optimised MTX (C- EARLY) was
targeting TNF and IL-17A, exhibited similar efficacy rates in the shown to be superior to placebo +MTX, with 28.9% of patients
120 mg arm as ADA in MTX-IR patients over 12 weeks.65 achieving sustained DAS28 <2.6 at week 40 and week 52 in the
The SIRROUND- H study investigated superiority of siru- combination arm compared with 15% of patients in the MTX
kumab (IL-6i) monotherapy over ADA monotherapy in MTX- arm.69
IR, bDMARD naive patients. The study failed to meet one In the AVERT-2 study, ABA+MTX did not show superiority
of its coprimary endpoints with no significant differences in to placebo +MTX regarding SDAI remission (≤3.3) at week 24
ACR50% response rates at week 24; the other primary endpoint (21.3% ABA+MTX vs 16% placebo +MTX), the primary effi-
(DAS28-ESR mean change from baseline at week 24) was met.66 cacy endpoint.70
The EXXELERATE study did not show superiority of certoli- DINORA compared infliximab +MTX treatment to MTX
zumab pegol compared with ADA and therefore failed to meet or placebo treatment only. INF+MTX showed superiority
its primary endpoint, showing similar ACR20% response rates to placebo only, but not to MTX monotherapy, in achieving
at week 12.4 sustained remission (no swollen joints, ≤2 tender joints and an
acute phase within the normal range) after 1 year (32% vs 14%
Switching between different bDMARDs vs 0% for INF+MTX, MTX and placebo, respectively).71
Three trials on switching between different bDMARDs were TCZ monotherapy as well as combination therapy of TCZ
included (see online supplementary table S2.4 and online supple- with MTX was clinically superior to MTX therapy in early RA
mentary table S3.3 for details). patients. Inhibition of radiographic damage was found to be
EXXELERATE also studied the efficacy of single- blinded significantly greater with 8 mg/kg TCZ intravenous +MTX
switching to a second TNFi (without washout) in patients with than in the MTX monotherapy arm modified total Sharp score
primary non- response to either certolizumab pegol or ADA (ΔmTSS 0.08 vs 1.14). TCZ 8 mg/kg intravenous monotherapy
(unclear RoB). Twelve weeks after switching 58% (ADA to showed less radiographic progression than MTX monotherapy
certolizumab pegol) and 62% (certolizumab pegol to ADA) of (ΔmTSS 0.26 vs 1.14, p value not reported).72
patients achieved DAS28-ESR≤3.2 or a DAS28-ESR reduction
of 1.2 or more.4 Efficacy of tsDMARDs (JAKi)
An exploratory analysis of the EXTEND trial, an open-label In total, 32 articles/abstracts on tsDMARDs were included
extension study of the ASCERTAIN trial, investigated patients (see table 1); 16 trials were regarded as having low RoB. Base-
switched from tocilizumab (TCZ) to sarilumab (conference line characteristics and efficacy outcomes are shown in online
abstract). After 12 and 24 weeks about one-third of patients supplementary tables S2.8 and S3.9, respectively.
non-responders to TCZ achieved clinical response (Clinical Decernotinib (JAK- 3i) and peficitinib (non-selective JAKi)
Disease Activity Index (CDAI) ≤10; ACR70) after switching to were effective as monotherapy and in combination with
sarilumab.67 csDMARDs or MTX in various populations.73–82
The open-label ROC trial (high RoB) investigated patients Filgotinib (JAK-1 selective JAKi) was effective in reducing
who failed one TNFi therapy, comparing non-TNFi therapies signs and symptoms of RA as well as improving physical function
(ABA, RTX, TCZ) to a second TNFi drug. The primary efficacy and patients quality of life in two phase II studies investigating
endpoint, superiority in EULAR good or moderate response at MTX-IR patients in combination with MTX (DARWIN 1) and
week 24, was met with higher responses in the non-TNFi group as monotherapy (DARWIN 2).83
Table 2 Primary efficacy outcomes of trials comparing biological DMARDs with or without background csDMARD therapy to placebo
Time point
Study Risk of bias Treatment N (weeks) Primary endpoint Outcome P value
13
Damjanov 2016 High Pbo/Pbo/Pbo+MTX 40 16 ACR 20 (%) NR Reference
SBI-087/Pbo/Pbo+MTX 43 NR NS
SBI-087/SBI-087/Pbo+MTX 42 NR NS
SBI-087/Pbo/SBI-087+MTX 43 NR NS
SBI-087/SBI-087/SBI-087+MTX 41 NR 0.046
Mazurov 201814 Abstract Placebo +MTX 52 24 ACR 20 (%) 29 Reference
BCD-020 600 mg+MTX 107 66 <0.001
Fleischmann 2017 Low Placebo +csDMARDs 181 12/24 ACR 20 (%) / ΔHAQ-DI 34/−0.3 Reference
(TARGET)15 SLM 150 mg Q2W+csDMARDs 181 56/−0.5 <0.001
SLM 200 mg Q2W+csDMARDs 184 61/−0.6 <0.001
Tanaka 2018b Abstract Placebo +MTX 82 24 ACR 20 (%) 15 Reference
(KAKEHASI)16 SLM 150 mg Q2W+MTX 81 68 <0.001
SLM 200 mg Q2W+MTX 80 58 <0.001
Aletaha 2017 Low Placebo±csDMARDs 294 16 ACR 20 (%) 24 Reference
(SIRROUND-T)17 18 SKM 50 mg Q4W±csDMARDs 292 40 <0.001
SKM 100 mg Q2W±csDMARDs 292 45 <0.001
Takeuchi 2017 Unclear Placebo +csDMARD 556 16/52 ACR 20 (%)/ΔmTSS 26/1.96 Reference
(SIRROUND-D)19 SKM 50 mg Q4W+csDMARD 557 55/0.35 <0.001
SKM 100 mg Q2W+csDMARD 557 54/0.3 <0.001
Takeuchi 2016 Low Placebo +MTX 29 12 ΔDAS28-CRP −0.64 Reference

(RA0083)20 OKZ 60 mg Q4W+MTX 32 −2.18 <0.001
OKZ 120 mg Q4W+MTX 32 −2.45 <0.001
OKZ 240 mg Q4W+MTX 36 −2.68 <0.001
Dorner 201721 Abstract (Open-Label) TCZ 162 mg QW 60 12 ACR 20 (%), no formal 78 NR
VBM 150 mg Q4W 62 comparison 73
VBM 150 mg Q2W 62 77
VBM 225 mg Q2W 63 81
Weinblatt 201722 Abstract Placebo +MTX 69 12 ACR 20 (%) 62 Reference
VBM 75 mg Q4W+MTX 69 75 NS
VBM 150 mg Q4W+MTX 70 81 NS
VBM 150 mg Q2W 68 78 NS
VBM 225 mg Q2W 69 72 NS
Burmester 2017b Low Placebo +MTX 81 12/24 ACR 20 (%)/ΔDAS28- 25/−0.68 Reference
(EARTH EXPLORER 1)23 MVM 150 mg Q2W+MTX 79 CRP 51/−1.9 <0.001
MVM 100 mg Q2W+MTX 85 61/−1.64 <0.001
MVM 30 mg Q2W+MTX 81 73/−1.37 <0.001
Buckley ACR 201824 25 Abstract Placebo +MTX 37 12 DAS28-CRP <2.6 (%) 3 Reference
OTM 22.5 mg +MTX 37 5 0.547
OTM 45 mg+MTX 37 16 0.077
OTM 90 mg+MTX 37 19 0.053
OTM 135 mg+MTX 37 14 0.122
OTM 180 mg+MTX 37 14 0.134
Tahir 2017 (REASSURE)26 Unclear Placebo±MTX 214 24 ACR 20 (%) 19.6 Reference
SEC 3×10 mg/kg i.v. Q2W/150 mg s.c. 213 35 <0.001
Q4W±MTX
SEC 3×10 mg/kg i.v. Q2W/75 mg s.c. 210 35 <0.001
Q4W±MTX
Mease 201827 Unclear Placebo +MTX 51 16 ACR 20 (%) 41 Reference
CNTO6785 15 mg Q4W+MTX 52 52 NS
Dokoupilova 2018 Unclear Placebo +csDMARDs 81 24 ACR 20 (%) 27 Reference
(REASSURE2)28 SEC 150 mg+csDMARDs 81 38 0.157
SEC 75 mg+csDMARDs 80 38 0.200
Continued

Table 2 Continued
Time point
Study Risk of bias Treatment N (weeks) Primary endpoint Outcome P value
van Vollenhoven 201829 Low Placebo +MTX 79 12 ACR 20 (%) 35 Reference
TLM 25 mg+MTX 80 42 0.395
TLM 100 mg+MTX 78 47 0.165
TLM 200 mg+MTX 76 44 0.274
Bi 2018 (RAPID-C)132 High Placebo +MTX 113 24 ACR 20 (%) 24 Reference
CZP +MTX 316 55 <0.001
Smolen 2017a133 Low Placebo +MTX 55 28 ACR 20 (%) 40 Reference
UKM 90 mg Q8W+MTX 55 53 0.877
UKM 90 mg Q12W+MTX 55 55
GKM 50 mg Q8W+MTX 55 38 0.101
GKM 200 mg Q8W+MTX 54 44
Detailed results of risk of bias analyses are shown in online supplementary table S2.2 in the supplementary appendix.
Δ, change from baseline; ACR, American College of Rheumatology response criteria; csDMARD, conventional synthetic disease-modifying antirheumatic drugs; CZP, certolizumab
pegol; DAS28-CRP, Disease Activity Score of 28 joints with C-reactive protein; GKM, guselkumab; HAQ-DI, Health Assessment Questionnaire Disability Index; i.v., intravenous;
mTSS, modified total Sharp score; MTX, methotrexate; MVM, mavrilimumab; NR, not reported; NS, not significant; OKZ, olokizumab; OTM, Otilimab; Pbo, placebo; s.c.,
subcutaneous; SEC, secukinumab; SKM, sirukumab; SLM, sarilumab; TCZ, tocilizumab; TLM, tregalizumab; UKM, ustekinumab; VBM, vobarilizumab.
GS-9876, an oral spleen tyrosine kinase inhibitor did not Key outcomes are summarised in table 4. Figure 2 shows
show clinical efficacy compared with placebo.84 descriptive forest plots using ACR 20/50 and 70 response rates.
Baricitinib (BARI) (JAK-1/2i) showed efficacy compared with Figure 3 summarises outcomes of trials investigating the efficacy

placebo in csDMARD- IR (RA-BUILD) patients,85 86 MTX-IR of bDMARDs and tsDMARDs (based on their mode of action)
87 88
patients, and in early RA as monotherapy or in combination compared with placebo.
with MTX.89 90
Upadacitinib proved to be efficacious versus placebo in phase Strategy trials
3 trials of various RA populations, MTX-naive,91 csDMARD/ IMAGINE-RA, a non-blinded strategic trial (high RoB) which
MTX-IR,92–98 bDMARD-IR (SELECT-BEYOND)99 100 and enrolled patients with stable, controlled disease activity
tsDMARD versus bDMARD head-to-head trials. (DAS28-CRP ≤3.2 and no swollen joints), compared an MRI
Five reports on three different head-to-head trials (three with guided with a purely clinical treat-to-target strategy. The trial did
low RoB) comparing tsDMARDs to ADA were included. Base- not meet its coprimary endpoints at month 24, as no differences
line characteristics are shown in online supplementary table S2.9 in DAS28-CRP<2.6 rates (85% vs 88%, respectively) or differ-
and detailed efficacy results in online supplementary table S3.10. ences in the proportion of patients who had no radiographic
In RA-BEAM, BARI 4 mg+MTX was shown to be superior progression (66% vs 62%) were observed. However, in the MRI-
to ADA 40 mg Q2W+MTX clinically (ACR20 at week 12: 70% T2T group, more patients needed treatment escalation (73% vs
vs 61%, p=0.014; ΔDAS28-CRP at week 12: −2.24 vs −1.95, 17%) and initiation of bDMARD therapy (46% vs 2%) accom-
p<0.001) and functionally (ΔHAQ at week 12: −0.66 vs −0.56, panied by higher costs and three times more serious adverse
p≤0.01). Regarding structural progression, ADA and BARI were events.6
superior compared with placebo (change from baseline in mTSS
at week 24: BARI: 0.41 vs ADA: 0.33 vs placebo: 0.9, p vs
placebo <0.001).101 102 Regarding core set variables, the differ- Tapering and stopping therapy
ences related to patient reported outcomes and CRP, but not to In total 25 studies (three with low RoB) investigated tapering
swollen joint counts (SJCs). and/or stopping csDMARD, bDMARD or tsDMARD therapy.
ORAL strategy investigated the non-inferiority of tofacitinib Primary results are shown in table 5, baseline characteristics
5 mg two times per day with or without MTX compared with are shown in online supplementary table S2.7 and secondary
ADA 40 mg Q2W+MTX. Non-inferiority was demonstrated outcomes are shown in online supplementary tables S3.6, S3.7
for tofacitinib +MTX versus ADA +MTX (ACR50 at week 24: and S3.8
46% vs 44%, difference: 2%; 98.34% CI −6% to 11%), but
not for tofacitinib monotherapy versus ADA +MTX (ACR50 Tapering and stopping csDMARDs or GCs
at week 24: 38% vs 44%; −6% (−14%–3%)) or versus tofaci- MUSICA, a double- blind, non- inferiority RCT (low RoB)
tinib +MTX (ACR 50 at week 24: 38% vs 46%; −8% (−16%– investigated randomised MTX dosage reduction to 7.5 mg/
1%)).103 104 week compared with continuation of 20 mg/week in MTX-IR
Upadacitinib+MTX was shown to be superior to ADA +MTX patients with open-label ADA initiation. The mean DAS28-CRP
in SELECT-COMPARE in both coprimary endpoints (ACR20 at was statistically lower in the standard-dose group (3.75 vs 4.12,
week 12: 70.5% vs 63%, p<0.05; DAS28-CRP<2.6 at week p=0.014) and non-inferiority of high versus low MTX dosage
12: 28.7% vs 18%, p<0.001), with radiographic superiority of was therefore not shown (ΔDAS28-CRP 0.37 (95% CI 0.07 to
upadacitinib +MTX vs placebo +MTX (ΔmTSS at week 26: 0.66) at week 24; NI-margin: 15%=0.56).107 Thus, a mandatory
0.24 vs 0.92, p<0.001) and numerically similar results between dose reduction from 20 to 7.5 mg MTX weekly seems too low
upadacitinib +MTX and ADA +MTX (ΔmTSS at week 26: for combination therapy with a TNFi.
0.24 vs 0.10).105 106 Also in this study, the differences related to A Canadian open-label RCT (high RoB) reported no differences
patient-reported outcomes and CRP, but not to SJCs. in DAS28-ESR change after patients treated with certolizumab
Table 3 Head-to-head studies comparing bDMARDs to other bDMARDs
Risk of ACR20 ACR50 ACR70 DAS28 <2.6 CDAI ≤2.8
Population Study bias Treatment N Primary endpoint P value (%) (%) (%) (%) (%) ΔHAQ
MTX-IR Burmester 2017 Low ADA 40 mg Q2W 185 ΔDAS28-ESR at week 24 <0.001 58 30 12 7 3 −0.43
(MONARCH)63 137 SLM 200 mg Q2W 184 72 46 23 27 7 −0.61
Smolen 2016 Low ADA 40 mg Q2W+MTX 454 ACR 20 (%) at week 12 0.532 71 22
(EXXELERATE)4 CZP 400/200 mg Q2W+MTX 454 69 25
Taylor 2018 Low ADA 40 mg Q2W 186 ACR 50 (%) + ΔDAS28-ESR at Reference 57 32 13 8 −0.52
(SIRROUND-H)66 SKM 50 mg Q4W 186 week 24 0.306/0.013 54 27 12 13 −0.51
SKM 100 mg Q2W 187 0.464/ <0.001 59 35 16 20 −0.53
Genovese 2018b65 Low ADA 40 mg Q2W+MTX 56 ACR 20 (%) at week 12 Reference 68 48 21 30 7 −0.6
ABT-122 60 mg Q2W+MTX 55 0.863 62 35 22 22 7 −0.6
ABT-122 120 mg Q2W+MTX 56 0.414 75 46 18 38 11 −0.6
ABT-122 120 mg QW +MTX 55 0.196 80 47 36 42 11 −0.9
csDMARD-IR Porter 2016 (ORBIT)62 High Anti-CD20 (RTX) 140 ΔDAS28-ESR (non-i nferiority) at 0.24 66 49 23 23 −0.49
TNFi (ETA/ADA) 134 week 52 71 45 26 21 −0.38
Kerschbaumer A, et al. Ann Rheum Dis 2020;79:744–759. doi:10.1136/annrheumdis-2019-216656

TNF-IR Blanco 2017 (NURTURE Low Placebo +csDMARD 138 ACR 20 (%) at week 24 Reference 18 9 5 −0.3
1)138 ABA 500/750/1000mg+csDMARD 138 <0.05 43 28 12 −0.6
SEC 10 mg/kg i.v. +150 mg s.c. 137 0.031 31 17 10 −0.4
Q4W+csDMARD
SEC 10 mg/kg i.v. +75 mg s.c. 138 0.092 28 12 5 −0.3
Q4W+csDMARD
Mixed cs/bDMARD- Weinblatt 2018 (EARTH Low GLM 50 mg Q4W 68 ACR 20/50/70%, DAS28-CRP <2.6, 0.666/0.293/0.156/0.108/0.208 66 43 26 29 18 −0.64
IR EXPLORER 2)*64 MVM 100 mg Q2W+MTX 70 ΔHAQ>0.22 at week 24 62 35 16 17 6 −0.44
Results of secondary efficacy outcomes are shown at the time point of the primary endpoint.
*Study not powered to formally compare the treatments. Detailed results of risk of bias analyses are shown in online supplementary table S2.2 in the supplementary appendix.
Δ, change from baseline; ABA, abatacept; ACR, American College of Rheumatology; ADA, adalimumab; bDMARDs, biological disease-modifying antirheumatic drugs; CDAI, clinical disease activity index; CRP, C-reactive protein; csDMARDs, conventional synthetic
disease-modifying antirheumatic drugs; CZP, certolizumab pegol; DAS28, Disease Activity Score of 28 joints; ESR, erythrocyte sedimentation rate; ETA, etanercept; GLM, golimumab; HAQ, Health Assessment Questionnaire; i.v., intravenous; MTX, methotrexate; MVM,
mavrilimumab; RTX, rituximab; SEC, secukinumab; SKM, sirukumab; SLM, sarilumab; TNFi, TNF inhibitor; TNF-IR, tumour necrosis factor-insufficient responder.
751
plus csDMARD had been randomised to continue combination
therapy or discontinue csDMARDs (−2.1 vs −2.1).108–110
ΔmTSS
ADA, adalimumab; BARI, baricitinib; CRP, C-reactive protein; DAS28, Disease Activity Score of 28 joints; EULAR, European League against Rheumatism; HAQ, Health Assessment Questionnaire; JAK, Janus kinase; mTSS, modified total Sharp Score; MTX, methotrexate;
The SEMIRA trial (conference abstract) investigated patients
0.41*
0.33*
0.24†
0.92†
0.9*
0.1†
NR
NR
NR
treated with TCZ ±csDMARD therapy who also had stable GC
therapy of 5 mg/day, comparing blinded tapering of GCs with
continuation of GCs. A significant increase of disease activity
ΔHAQ
−0.34
−0.66
−0.56
−0.58
−0.54
−0.52
−0.28
−0.49
−0.6
(ΔDAS28-ESR) was seen in the discontinuation group compared
with continuation (0.613, 95% CI 0.346 to 0.879, p<0.001).
Boolean rem.
Sixty-six per cent of patients discontinuing remaining in stable

ACR/EULAR
DAS28 ≤3.2 without experiencing disease flares, compared with

77% (RR 0.833, 95% CI 0.714 to 0.972, p=0.021) in the stable
CDAI ≤2.8 (%) (%)
9.8
GC group.111
1
7
5
8
9
2
4
Several trials (one low RoB, one unclear RoB, one high RoB)
showed non-inferiority of MTX tapering versus continuation in
patients receiving ongoing (long-term) TCZ therapy.112–114
2
8
7
3
8
14
13
13
10
A substudy of the CareRA study investigated randomised

step-down from COBRA Avant- Garde (MTX+LEF + initial
DAS28 <2.6 (%)
prednisone 30 mg step-down) to either MTX (15 mg/week) or

LEF (20 mg/day) monotherapy if they achieved an DAS28-CRP
≤3.2 after treatment induction during period of 40–52 weeks
4
6
24
19
31
28
21
18
29
of therapy. After 65 weeks, significantly more patients achieved

ACR 50 ACR 70
DAS28-CRP <2.6, CDAI ≤10 or SDAI ≤11 in the MTX arm

(%)
(30/32, 93.8%; 32/32, 100%; 32/32, 100% respectively) than in

5
5
19
13
25
21
18
14
25
the LEF arm (19/26, 73.1%, p=0.031; 21/26, 80.8%, p=0.009;

22/26, 84.6%, p=0.021)115 116 bDMARD tapering.
(%)
17
45
35
46
45
44
38
15
29

The POET study, a large open- label RCT (high RoB)
ACR20
randomised patients in stable low disease activity for 6 months

(%)
(DAS28-ESR ≤3.2 or based on rheumatologists’ impression) to

40
70
61
71
71
65
73
36
63
either stop or continue their TNFi therapy, comparing propor-

tions of patients experiencing a disease flare (DAS28-ESR ≥3.2
UPA versus PLC:<0.001 /
BARI versus PLC:<0.001;
BARI versus ADA <0.01
+ DAS28-ESR change from baseline >0.6) during 12 months.

ADA:<0.05/<0.001
About 20% of patients could stop their TNFi therapy without

MTX, methotrexate; NI, non-inferiority; NR, not reported; OD, once daily; PLC, placebo; S, superiority; TOFA, tofacitinib; UPA, upadacitinib.
experiencing a flare, but among those who continued TNFi

Table 4 Major efficacy outcomes of head-to-head studies comparing JAK inhibitors to adalimumab
UPA versus
Reference
therapy 50% did not experience a flare (TNFi stopping: 18.2%

P value
<0.001;
<0.001
0.051
vs TNFi continuation: 51.2%, p<0.001; HR 3.50; 95% CI 2.60

to 4.72).117 118
In C- OPERA, Japanese patients discontinued or continued
ACR 20 (%) at week 12
ACR 50 (%) at week 24
ACR 20 (%)+DAS28-
CRP<2.6 at week 12
certolizumab pegol after achieving DAS28-ESR ≤3.2 at week

Primary endpoint
52. At week 104, 29.3% of patients who stopped certolizumab

pegol could maintain SDAI remission, compared with 41.5% of
patients continuing (p=0.026). Significantly more radiographic
progression occurred in patients who stopped certolizumab until
Results of secondary efficacy outcomes are shown at the time point of the primary endpoint.
week 104 (ΔmTSS at week 104 0.66 vs 3.01, p=0.001).119

In C- EARLY, a trial investigating certolizumab +MTX in
487
330
TOFA 5 mg two times 384
TOFA 5 mg two times 376
327
UPA 15 mg OD +MTX 651

488
386
651
N
csDMARD naive patients with early RA, patients who achieved

DAS28-ESR≤3.2 at year 1 were either continued on CZP every
2 weeks, increased dosing interval of CZP (to every 4 weeks)
BARI 4 mg+MTX
Placebo +MTX
Placebo +MTX
per day+MTX
or stopped CZP completely. Although the trial failed to meet

per day+PLC
ADA 40 mg
ADA 40 mg
ADA 40 mg
Q2W+MTX
Q2W+MTX
Q2W+MTX
Treatment
its primary endpoint (% of patients in DAS28-ESR≤3.2 without

flare at week 104), similar results for CZP Q2W versus interval
prolongation to CZP every 4 weeks (48.8% vs 53.2%, p=0.112)
were seen. Furthermore, 39.2% of patients could stop CZP
Risk of
completely and maintain DAS28-ESR ≤3.2 but the difference

bias
Low
Low
Low
compared with continuation was significant (48.8% vs 39.2%,

p=0.041).120
design
Study
Further studies investigated the discontinuation of TCZ

NI
S
after combination therapy with MTX (SURPRISE study) and

Taylor/Keystone 2017 (RA-
achieving DAS28-ESR <2.6: sustained DAS28-ESR <2.6 and

Fleischmann 2017/Strand
(SELECT-COMPARE)105 106
Fleischmann ACR 2018
DAS28-ESR ≤3.2 rates were more frequent in patients receiving

EULAR 2018 (ORAL-
concomitant MTX compared with TCZ monotherapy after

104 weeks (24% vs 14%, p=0.005; 55% vs 27%, p=0.005).121
Strategy)103 104
BEAM)101 102
*Week 24.
†Week 26.
Tapering TNFi dose by 33% in patients with DAS28-ESR ≤3.2

Study
for 3 months did not lead to increased flare rates (12% vs 16%,
HR: 0.90, 95% CI 0.23 to 3.48, p=0.873), reducing the TNFi
Figure 2 Forest plots showing risk ratios of ACR 20, 50 and 70 responses in trials comparing JAK inhibitors+MTX to adalimumab +MTX in MTX-IR
patients. 1, tofacitinib; 2, upadacitinib; 3, baricitinib. ACR, American College of Rheumatology; IR, insufficient responder; M-H, Mantel-Haenszel; MTX,
methotrexate; JAK, Janus kinase.
dose by 66% resulted in not statistically significantly different Tapering of tsDMARDs

flare rates (DAS28-ESR >3.2 and ΔDAS28-ESR ≥0.6) compared The RA- BEYOND study randomised patients from four
with treatment continuation (29% vs 16%, HR 2.52, 95% CI trials of BARI at 4 mg who had achieved stable CDAI ≤10
0.85 to 7.48, p=0.097).122 to either continue BARI 4 mg or reduce dose to 2 mg. While
A novel tapering strategy, using a biomarker, matrix metal- more patients who continued full dose maintained CDAI low

loproteinase (MMP-3), or combined SDAI +MMP-3- guided disease activity compared with those who reduced the dose
tapering of bDMARDs in patients achieving SDAI ≤3.3 and (93% vs 83%, p<0.001 at 3 months; 87% vs 75%, p<0.001,
normalisation of MMP-3 showed non- inferiority at week 52 at 6 months; 80% vs 67%, p<0.01 at 12 months for BARI
as compared with just clinically guided maintenance of SDAI 4 mg continuation vs dose reduction to BARI 2 mg, respec-
≤3.3.123 Open- label interval prolongation in patients with tively), a majority of patients maintained their good disease
high ADA trough levels (defined as >8 µg/mL) did not lead to state despite dose reduction. Further, in patients being in
increased disease activity (using DAS28-ESR, CDAI or SDAI).124 CDAI ≤2.8 at randomisation, fewer patients lost their disease
activity state. Of those who flared after dose reduction, the
majority (66.7%) regained their CDAI <10 state within 24
weeks after dose increase to 4 mg. Thirteen of the 16 patients
not regaining their CDAI <10 state after 24 weeks were able
to do so at a subsequent time point.125
Combined bDMARDs and csDMARDs tapering and/or stopping

IMPROVED, a Dutch strategy trial (high RoB) aimed at drug
free remission in patients with early RA and undifferentiated
arthritis. After 5 years, 15%–20% (p=0.374) of patients could
achieve drug-free remission.126
Dose reduction (by 50%) or stopping either csDMARDs,
bDMARDs or both compared with dose continuation was inves-
tigated in a study of patients achieving stable DAS28-ESR <2.6
for at least 6 months (high RoB). In the control group 6.5% of
patients flared, while 42%–77% flared after dose reduction or
stopping therapy completely.127
The TARA study compared csDMARD tapering with
bDMARD tapering in patients who had long-standing combi-
nation therapy and found no significant differences in the flare
(defined as DAS44 >2.4 and/or SJC >1) ratio between both
groups (HR 0.91; 95% CI 0.68 to 1.22; p=0.55).128
Figure 3 Efficacy of different targets of biological and targeted
synthetic disease-modifying drugs compared against placebo, shown
across major clinical trial outcomes of randomised controlled trials Discussion
published from 2016 to 2018. ACR, American College of Rheumatology This SLR was performed to inform the task force for the 2019
response criteria; CD, cluster of differentiation; DMARD, disease- update of the EULAR recommendations for the management of
modifying antirheumatic drugs; EULAR, European League against RA on the efficacy of various DMARDs as presented in publica-
Rheumatism; GM-CSF, colony-stimulating factor; HAQ, Health tions from 2016 to March 2019. These publications covered a
Assessment Questionnaire; IL, interleukin; JAK, Janus kinase; mTSS, total of 32 DMARDs.
modified total Sharp score; Syk, spleen tyrosine kinase; TNF, tumour The SLR confirmed the high efficacy of csDMARD plus GC
necrosis factor. combination therapy as well as the efficacy of TNFi, IL-6Ri, ABA
Table 5 Primary outcomes of studies investigating csDMARD, bDMARD and tsDMARD tapering and stopping
Study Primary outcome Endpoint (week) Treatment arm N Result P value
csDMARD tapering
Kaeley 2016 (MUSICA)107 Mean DAS28-CRP 24 ADA 40 mg Q2W+7.5 mg MTX 154 4.12 0.014
ADA 40 mg Q2W+20 mg MTX 155 3.75
Keystone 2016 (CAMEO)144 ΔDAS28-ESR 24 ETN 50 mg QW; MTX discontinuation 98 0.5 0.815
ETN 50 mg QW +MTX continuation 107 0.04
Pope EULAR 2017/ACR ΔDAS28-ESR 76 CZP +csDMARD continuation 37 −2.1 NR
2018/2019108–110
CZP +csDMARD discontinuation 44 −2.1
Burmester ACR 2018 (SEMIRA)111 ΔDAS28-ESR 24 TCZ ±csDMARDs; GC tapering 131 0.538 <0.001
TCZ ±csDMARDs; GC continuation 128 −0.075
Pablos 2018 (JUST-ACT)112 ΔDAS28-ESR week 16 week 28 28 TCZ 8 mg/kg+MTX 82 0.007 95% CI −0.40 to 0.27
TCZ 8 mg/kg+PLC 82 0.073
Kremer 2018 (COMP-ACT)113 ΔDAS28-ESR week 24 week 40 40 TCZ 162 mg s.c. +PLC 147 0.46 95% CI 0.045 to 0.592
TCZ 162 mg s.c. +MTX 147 0.14
Edwards 2018 (ACT-TAPER)114 Pat. Maintaining EULAR good/moderate response from 60 TCZ 8 mg/kg Q4W+PBO 136 77% 0.036
week 24–60
TCZ 8 mg/kg Q4W+MTX 136 65%
Stouten 2018 (CareRA)115 116 DAS28-CRP <2.6 65 MTX +LEF->MTX 15 mg/week 32 94% 0.031
MTX+LEF->LEF 20 mg/day 26 73%
bDMARD tapering
Oba 2017/Tanaka ACR 2018 1-year sustained discontinuation rate of INF 106 INF 3 mg/8 mg/10 mg/kg Q8W based on TNF 170 24% 0.631
(RRRR)140 141 levels
INF standard 3 mg/kg Q8W 167 21%
Chatzidionysiou 2016 (ADMIRE)142 DAS28 <2.6 at week 28 28 ADA +MTX continuation 16 94% 0.001
ADA discontinuation; MTX monotherapy 16 33%
Ghiti Moghadam 2016/2018 % of pat. DAS28 ≥3.2 + ΔDAS28 >0.6 for 1 year 52 Stopping TNFi 531 51% <0.001
(POET)117 118

Continuation of TNFi 286 18%
Atsumi 2017 (C-OPERA)119 ΔmTSS 104 CZP +MTX continuation 108 0.66 0.001
Stopping CZP; MTX+PLC 71 3.01
Kaneko 2018 (SURPRISE)121 TCZ free rate 104 stopping TCZ; MTX monotherapy 49 67% 0.001
stopping TCZ; No DMARD 53 29%
Weinblatt 2017 (C-EARLY)120 DAS28-ESR ≤3.2 without flares during week 52–104 104 CZP 200 mg Q2W+MTX (standard) 84 49% Reference
CZP 200 mg Q4W+MTX (reduced frequency) 126 53% 0.112
Placebo +MTX (CZP stopped) 79 39% 0.041
Ibrahim 2017 (OPTIRRA)122 Flare rate (ΔDAS28 ≥0.6 + DAS28 >3.2 + ΔSJC OR 24 TNFi 33% tapering; csDMARD 26 12% 0.873
ΔDAS28 >1.2 + DAS28 >3.2)
TNFi 66% tapering; csDMARD 21 29% 0.097
Control; csDMARD continuation 50 16% Reference
Bouman 2017 (DRESS)145 Incidence of major flare (ΔDAS28-CRP >1.2 or ΔDAS28- 144 TNFi dose reduction extension 115 17% 3%, 95% CI -10%
CRP >0.6+DAS28-CRP ≥3.2 for >12 weeks) to 15%
Usual care extension 57 14%
l’Ami 2018124 ∆DAS28-ESR 28 ADA 40 mg Q3W±MTX 27 −0.14 0.01
ADA 40 mg Q2W±MTX 27 0.3
tsDMARD tapering
Takeuchi 2019 (RA-BEYOND)125 CDAI ≤10 12 Continued BARI 4 mg±csDMARD 281 93% <0.001
BARI Step-down 2 mg±csDMARD 278 83%
Δ, change from baseline; ACR, American College of Rheumatology; ADA, adalimumab; BARI, baricitinib; bDMARD, biological disease-modifying antirheumatic drug; CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; csDMARDs, conventional synthetic disease-modifying
antirheumatic drugs; CZP, certolizumab pegol; DAS28, Disease Activity Score of 28 joints; ESR, erythrocyte sedimentation rate; ETN, etanercept; EULAR, European League against Rheumatism; GC, glucocorticoid; INF, infliximab; LEF, leflunomide; mTSS, modified total Sharp Score; MTX,
methotrexate; MTX, methotrexate; PLC, placebo; SJC, swollen joint count; TCZ, tocilizumab; TNFi, tumour necrosis factor inhibitor; tsDMARD, targeted synthetic DMARD.
and rituximab as well as bsDMARDs in csDMARD (including more costs in the imaging group, further confirming that
MTX) IR patients. With respect to bsDMARDs, switch (including stringent clinical remission is a sufficient treatment target and
multiple switch) studies between bs and boDMARDs confirmed that imaging remission not only fails to convey better effi-
long-term safety and efficacy of biosimilars. Like bDMARDs, cacy, but may constitute a potentially dangerous and costly
JAKi are efficacious in patients with RA. Several trials compared overtreatment.6
one bDMARD class (usually TNFi agents) with bDMARDs of Tapering studies revealed that dose reduction of JAKi and
other classes revealing similarity of response. Likewise, head-to- bDMARDs is feasible and that when starting dose reduction in
head trials between JAKi and anti-TNF did not reveal clinically sustained stringent remission less patients flare when compared
important differences regarding efficacy. with start of tapering just in sustained low disease activity.125
In patients who failed a TNFi or other bDMARDs, Importantly, patients who flare can mostly (70%–80%) regain
tsDMARDs and also bDMARDs of the same or other classes their prior good response.
revealed generally similar clinical efficacy4 99 100 or relatively The results of this SLR were presented to the task force and,
small differences.68 Of interest (and part of the previous together with the safety SLR,8 formed the basis for the update of
research agenda), sarilumab, an anti-IL-6R antibody, showed the EULAR RA management recommendations.
efficacy in patients who had an IR to TCZ, another IL-6Ri,67
and in a study published after this SLR, TNFi showed efficacy Author affiliations
1
after failure of JAKi.129 Medical University of Vienna, Vienna, Austria
2
Leiden University Medical Center, Leiden, The Netherlands
A strategy trial comparing treatment aimed at clinical 3
NOVA Medical School, Universidade Nova de Lisboa, Lisbon, Portugal
remission to therapy aimed at remission by MRI showed no 4
Hospital Cochin, Paris, France
difference in clinical outcomes, but more adverse events and 5
Amsterdam Rheumatology Center, Amsterdam, The Netherlands

6
University of Glasgow, Glasgow, UK 5 Smolen JS, Breedveld FC, Burmester GR, et al. Treating rheumatoid arthritis to target:
7
University Medical Center Utrecht, Utrecht, The Netherlands 2014 update of the recommendations of an international Task force. Ann Rheum Dis
8
Charité – University Medicine Berlin, Berlin, Germany 2016;75:3–15.
9
EULAR Standing Committee, Zurich, Switzerland 6 Møller-Bisgaard S, Hørslev-Petersen K, Ejbjerg B, et al. Effect of magnetic resonance
10
Northwell Health, New York, New York, USA imaging vs conventional Treat-to-Target strategies on disease activity remission
and radiographic progression in rheumatoid arthritis: the IMAGINE-RA randomized
Correction notice This article has been corrected since it published Online First.
clinical trial. JAMA 2019;321:461–72.
Table 5 formatting has been corrected and the MONARCH study line in table 3
7 Smolen JS, Landewé R, Bijlsma J, et al. EULAR recommendations for the
transposed.
management of rheumatoid arthritis with synthetic and biological disease-modifying
Contributors All authors contributed and finally approved the current manuscript. antirheumatic drugs: 2016 update. Ann Rheum Dis 2017;76:960–77.
8 Sepriano A, Kerschbaumer A, Smolen JS, et al. Safety of synthetic and biological
Funding European League Against Rheumatism.
DMARDs: a systematic literature review Informing the 2019 update of the EULAR
Competing interests AK: Honoraria from Bristol-Myers Squibb, Celgene, Gilead, recommendations for the management of rheumatoid arthritis. Ann Rheum Dis
Merck Sharp and Dohme, Novartis and Pfizer. AS: Honoraria as speaker: JSS: 2020;79:747–57.
Grants from Abbvie, Astra-Zeneca, Janssen, Lilly, Novartis, Roche and honoraria 9 van der Heijde D, Aletaha D, Carmona L, et al. 2014 update of the EULAR
from Abbvie, Amgen, Astra-Zeneca, Astro, BMS, Celgene, Celltrion, Chugai, Gilead, standardised operating procedures for EULAR-endorsed recommendations. Ann
ILTOO, Janssen, Lilly, MSD, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, UCB. Rheum Dis 2015;74:8–13.
DvdH: Received consulting fees from AbbVie, Amgen, Astellas, AstraZeneca, BMS, 10 Verschueren P, De Cock D, Corluy L, et al. Effectiveness of methotrexate with
Boehringer Ingelheim, Celgene, Daiichi, Eli-Lilly, Galapagos, Gilead, Glaxo-Smith- step-down glucocorticoid remission induction (cobra slim) versus other intensive
Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB treatment strategies for early rheumatoid arthritis in a treat-to-target approach:
Pharma and is Director of Imaging Rheumatology bv. MD: Received research grants 1-year results of CareRA, a randomised pragmatic open-label superiority trial. Ann
from and honorarium fees for his participation at advisory boards and/or symposium Rheum Dis 2017;76:511–20.
organised by PFIZER, UCB, ABBVIE, LILLY, NOVARTIS, BMS, ROCHE, UCB, MERCK. 11 Stouten V, Joly J, De Cock D. Sustained effectiveness after remission induction
RvV: Research Support and Grants: BMS, GSK, Lilly, Pfizer, UCB Pharma. Consultancy, with methotrexate and step-down glucocorticoids in patients with early
honoraria: AbbVie, AstraZeneca, Biotest, Celgene, GSK, Janssen, Lilly, Novartis, Pfizer, rheumatoid arthritis following a treat-to-target strategy after 2 years. Arthritis
Servier, UCB. IM: grants from Astra Zeneca, UCB, BMS, Janssen, GSK, Compugen, and rheumatology Conference: american college of rheumatology/association of
Boehringer, Celgene and honoraria from Abbvie, BMS, Janssen, Novartis, UCB, Astra rheumatology health professionals annual scientific meeting, ACR/ARHP 2017
Zeneca, Celgene, Causeway, Lilly, Leo, Novimmune. JWB: Honoraria as speaker and United states, 2017.
for consulting: Abbvie, Lilly, MSD, Roche, Sanofi, SUNGB: Honoraria as speaker and 12 Register KA, Cannella AC, Mikuls TR. Leflunomide, sulfasalazine and
for consulting: Abbvie, BMS, Gilead, Lilly, MSD, Pfizer, UCB, Roche, Sanofi. MdW: hydroxychloroquine for rheumatoid arthritis: efficacious but poorly tolerated.
Over the last 2 years Stichting Tools has received fees for lectures or consultancy for Arthritis and rheumatology Conference: american college of rheumatology/

contributions of Maarten de Wit from Abbvie, Celgene, Eli Lilly, Janssen-Cilag and association of rheumatology health professionals annual scientific meeting, ACR/
Pfizer. LF: none. RL: Received consulting fees from AbbVie, BMS, Celgene, Eli-Lilly, ARHP 2016 United states Conference start: 20161111 Conference end: 20161116,
Galapagos, Gilead, Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Roche, UCB 2016:2014–5.
and is Director of Rheumatology Consultancy bv. 13 Damjanov N, Tlustochowicz M, Aelion J, et al. Safety and efficacy of SBI-087, a
subcutaneous agent for B cell depletion, in patients with active rheumatoid arthritis:
Patient and public involvement statement The task force on this project results from a phase II randomized, double-blind, placebo-controlled study. J
involved a PPI representative (MdW), member of the EULAR Standing Committee of Rheumatol 2016;43:2094–100.
People with Arthritis/Rheumatism in Europe, who contributed during all task force 14 Mazurov V, Denisov L, Gordeev I, et al. SAT0206 Results of the alterra clinical trial
meetings, especially to take patient perspectives into account and refine research – the efficacy of the alternative dosing regimen for rituximab biosimilar in bdmards
questions. naive patients with rheumatoid arthritis. Ann Rheum Dis 2018;77:963.
Patient consent for publication Not required. 15 Fleischmann R, van Adelsberg J, Lin Y, et al. Sarilumab and Nonbiologic disease-
modifying antirheumatic drugs in patients with active rheumatoid arthritis and
Provenance and peer review Not commissioned; externally peer reviewed.
inadequate response or intolerance to tumor necrosis factor inhibitors. Arthritis
Data availability statement All data relevant to the study are included in the Rheumatol 2017;69:277–90.
article or uploaded as online supplementary information. 16 Tanaka Y, Wada K, Takahashi Y. Efficacy and safety of sarilumab plus methotrexate
Open access This is an open access article distributed in accordance with the in a phase 3 trial in Japanese patients with active rheumatoid arthritis (KAKEHASI).
International journal of rheumatic diseases Conference: 20th asia pacific league of
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
associations for rheumatology congress, APLAR 2018 Taiwan (republic of china),
permits others to distribute, remix, adapt, build upon this work non-commercially,
2019:200.
and license their derivative works on different terms, provided the original work is
17 Aletaha D, Bingham CO, Tanaka Y, et al. Efficacy and safety of sirukumab in patients
properly cited, appropriate credit is given, any changes made indicated, and the use
with active rheumatoid arthritis refractory to anti-TNF therapy (SIRROUND-T): a
is non-commercial. See: http://c reativecommons.org/licenses/by-nc/4.0/.
randomised, double-blind, placebo-controlled, parallel-group, multinational, phase 3
ORCID iDs study. Lancet 2017;389:1206–17.
Andreas Kerschbaumer http://orcid.org/0000-0002-6685-8873 18 Tanaka Y, Bingham C, Aletaha D. Sirukumab, an anti-IL-6 cytokine monoclonal
Alexandre Sepriano http://orcid.org/0000-0003-1954-0229 antibody, significantly improves physical function and reduces morning stiffness in
Désirée van der Heijde http://orcid.org/0000-0002-5781-158X patients with active rheumatoid arthritis despite anti-TNF therapy: results from a
Maarten de Wit http://orcid.org/0000-0002-8428-6354 global, randomized, placebo-controlled, phase 3 trial. Arthritis and rheumatology
Conference: american college of rheumatology/association of rheumatology health
professionals annual scientific meeting, ACR/ARHP 2016 United states Conference
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Ann Rheum Dis: first published as 10.1136/annrheumdis-2019-216656 on 7 February 2020. Downloaded from http://ard.bmj.

com/ on February 3, 2022 at Carol Davila University of Medicine

Efficacy of pharmacological treatment in rheumatoid

Handling editor Dimitrios T Abstract

and Pharmacy. Protected by copyright.

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Table 1 Interventions and therapeutic compounds of trials included for review

and Pharmacy. Protected by copyright.

Kerschbaumer A, et al. Ann Rheum Dis 2020;79:744–759. doi:10.1136/annrheumdis-2019-216656 747

and Pharmacy. Protected by copyright.

and Pharmacy. Protected by copyright.

Kerschbaumer A, et al. Ann Rheum Dis 2020;79:744–759. doi:10.1136/annrheumdis-2019-216656 749

and Pharmacy. Protected by copyright.

Kerschbaumer A, et al. Ann Rheum Dis 2020;79:744–759. doi:10.1136/annrheumdis-2019-216656

Sixty-­six per cent of patients discontinuing remaining in stable

DAS28 ≤3.2 without experiencing disease flares, compared with

A substudy of the CareRA study investigated randomised

prednisone 30 mg step-­down) to either MTX (15 mg/week) or

of therapy. After 65 weeks, significantly more patients achieved

DAS28-­CRP <2.6, CDAI ≤10 or SDAI ≤11 in the MTX arm

(30/32, 93.8%; 32/32, 100%; 32/32, 100% respectively) than in

the LEF arm (19/26, 73.1%, p=0.031; 21/26, 80.8%, p=0.009;

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randomised patients in stable low disease activity for 6 months

(DAS28-­ESR ≤3.2 or based on rheumatologists’ impression) to

either stop or continue their TNFi therapy, comparing propor-

+ DAS28-­ESR change from baseline >0.6) during 12 months.

About 20% of patients could stop their TNFi therapy without

experiencing a flare, but among those who continued TNFi

therapy 50% did not experience a flare (TNFi stopping: 18.2%

vs TNFi continuation: 51.2%, p<0.001; HR 3.50; 95% CI 2.60

ACR 50 (%) at week 24

certolizumab pegol after achieving DAS28-­ESR ≤3.2 at week

52. At week 104, 29.3% of patients who stopped certolizumab

week 104 (ΔmTSS at week 104 0.66 vs 3.01, p=0.001).119

TOFA 5 mg two times 384

TOFA 5 mg two times 376

UPA 15 mg OD +MTX 651

csDMARD naive patients with early RA, patients who achieved

or stopped CZP completely. Although the trial failed to meet

its primary endpoint (% of patients in DAS28-­ESR≤3.2 without

completely and maintain DAS28-­ESR ≤3.2 but the difference

compared with continuation was significant (48.8% vs 39.2%,

Further studies investigated the discontinuation of TCZ

after combination therapy with MTX (SURPRISE study) and

achieving DAS28-­ESR <2.6: sustained DAS28-­ESR <2.6 and

DAS28-­ESR ≤3.2 rates were more frequent in patients receiving

concomitant MTX compared with TCZ monotherapy after

Tapering TNFi dose by 33% in patients with DAS28-­ESR ≤3.2

dose by 66% resulted in not statistically significantly different Tapering of tsDMARDs

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Combined bDMARDs and csDMARDs tapering and/or stopping

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754 Kerschbaumer A, et al. Ann Rheum Dis 2020;79:744–759. doi:10.1136/annrheumdis-2019-216656

and Pharmacy. Protected by copyright.

Kerschbaumer A, et al. Ann Rheum Dis 2020;79:744–759. doi:10.1136/annrheumdis-2019-216656 755

and Pharmacy. Protected by copyright.

756 Kerschbaumer A, et al. Ann Rheum Dis 2020;79:744–759. doi:10.1136/annrheumdis-2019-216656

Sixty-six per cent of patients discontinuing remaining in stable

prednisone 30 mg step-down) to either MTX (15 mg/week) or

DAS28-CRP <2.6, CDAI ≤10 or SDAI ≤11 in the MTX arm

(DAS28-ESR ≤3.2 or based on rheumatologists’ impression) to

+ DAS28-ESR change from baseline >0.6) during 12 months.

certolizumab pegol after achieving DAS28-ESR ≤3.2 at week

its primary endpoint (% of patients in DAS28-ESR≤3.2 without

completely and maintain DAS28-ESR ≤3.2 but the difference

achieving DAS28-ESR <2.6: sustained DAS28-ESR <2.6 and

DAS28-ESR ≤3.2 rates were more frequent in patients receiving

Tapering TNFi dose by 33% in patients with DAS28-ESR ≤3.2