ORIGINAL ARTICLE

DMARD-free remission as noveltreatment target in rheumatoid arthritis:A systematic literature review ofachievability and sustainability

M Verstappen ,1 E van Mulligen ,2 P H P de Jong,2 A H M van der Helm-Van Mil 1,2

ABSTRACTObjectives Although current treatment guidelines forrheumatoid arthritis (RA) suggest tapering disease-modifyinganti-rheumatic drugs (DMARDs), it is unclear whetherDMARD-free remission (DFR) is an achievable andsustainable outcome. Therefore, we systematically reviewedthe literature to determine the prevalence and sustainabilityof DFR and evaluated potential predictors for DFR.Methods A systematic literature search was performed inMarch 2019 in multiple databases. All clinical trials andobservational studies reporting on discontinuation ofDMARDs in RA patients in remission were included. Ourquality assessment included a general assessment andassessment of the description of DFR. Prevalence of DFRand its sustainability and flares during tapering and afterDMARD stop were summarised. Also, potential predictorsfor achieving DFR were reviewed.Results From 631 articles, 51 were included, comprising14 clinical trials and 5 observational studies. DFR definitiondiffered, especially for the duration of DMARD-free state.Considering only high- and moderate-quality studies, DFRwas achieved in 5.0%–24.3% and sustained DFR(duration>12 months) in 11.6%–19.4% (both relative to thenumber of patients eligible for tapering). Flares occurredfrequently during DMARD tapering (41.8%–75.0%) and inthe first year after achieving DFR (10.4%–11.8%), while lateflares, >1 year after DMARD-stop, were infrequent (0.3%–

3.5%). Many patient characteristics lacked association withDFR. Absence of autoantibodies and shared epitope allelesincreased the chance of achieving DFR.Conclusions DFR is achievable in RA and is sustainable in~10%–20% of patients. DFR can become an importantoutcome measure for clinical trials and requires consistencyin the definition. Considering the high rate of flares in thefirst year after DMARD stop, a DMARD-free follow-up of >12months is advisable to evaluate sustainability.

INTRODUCTIONIn rheumatoid arthritis (RA), early treatment,with disease-modifying antirheumatic drugs(DMARDs), aiming at sustained remission, isnowadays the key element of each manage-ment approach.1 2 As a result, RA has become

a controllable disease in which sustained clin-ical remission is achievable for an increasingnumber of patients, and tapering and discon-tinuation of DMARDs have become of emer-ging interest.3 Current internationalguidelines recommend tapering of DMARDsin RA patients with sustained remission.1 2

Nevertheless, these guidelines are less clearwhether DMARDs can be stopped, and thesystematic literature review supportive of themost recent EULAR guidelines was notfocused on DMARD cessation.4

Despite the recommendations in the guide-lines, tapering of DMARDs has not beenadopted structurally in many clinical prac-tices, presumably because the risk ofa disease flare5 and because the ability toachieve and sustain DMARD-free remission(DFR) is often considered unlikely.6 On theother hand, there is increasing interest in

To cite: Verstappen M, vanMulligen E, de Jong PHP, et al.DMARD-free remission as noveltreatment target in rheumatoidarthritis: A systematic literaturereview of achievability andsustainability. RMD Open2020;6:e001220. doi:10.1136/rmdopen-2020-001220

► Additional material ispublished online only. To viewplease visit the journal online(http://dx.doi.org/10.1136/rmdopen-2020-001220).

MV and EV contributed equally

Received 4 March 2020Revised 1 April 2020Accepted 2 April 2020

© Author(s) (or theiremployer(s)) 2020. Re-usepermitted under CC BY-NC. Nocommercial re-use. See rightsand permissions. Publishedby BMJ.1Department of Rheumatology,Leiden University MedicalCenter, Leiden, the Netherlands2Department of Rheumatology,Erasmus Medical Center,Rotterdam, the Netherlands

Correspondence toElise van Mulligen; elise.vanmulligen@erasmusmc.nl

Key messages

What is already known about this subject?► Although current treatment guidelines for rheumatoid

arthritis suggest tapering DMARDs when patients arein sustained remission, it is unclear whether DMARD-free remission is an achievable and sustainableoutcome.

What does this study add?► DMARD-free remission is achievable in rheumatoid

arthritis and is sustainable in ~10%–20% ofpatients.

How might this impact on clinical practice orfuture developments?► DMARD-free remission can become an important

outcome measure for clinical trials, though thisrequires consistency in the definition.

► We propose to incorporate a DMARD-free follow-upperiod for at least 1 year, to ensure that DMARD-freeremission is sustainable.

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achieving DFR, because this is currently the best proxy forcure.7 8 Clinical trials occasionally report on DFR, butusually not as the primary outcome. Absence of knowl-edge of DFR prevalence, its sustainability and the char-acteristics of patients achieving DFR currently hamperthe use of DFR as primary outcome.9

We aimed to expand the comprehension of the abilityto achieve and sustain DFR in RA. Therefore, we con-ducted a systematic literature search. In addition to theDFR prevalence and sustainability, potential predictorsfor achieving DFR were explored.

METHODSSearch strategy and selection criteriaThis systematic literature review was conducted in accor-dance with the Preferred Reporting Items for SystematicReview and Meta-Analysis (PRISMA) guidelines and theCochrane review handbook.10 11 The protocol was regis-tered in the International Prospective Register of Sys-tematic Reviews (CRD42019132558).12

The search strategy was developed and performed incollaboration with an experienced librarian (JS). Keyterms used for the search were ‘Rheumatoid arthritis’,‘Antirheumatic drugs’, ‘Discontinuation’ and ‘Remission’.These search items were translated intomultiplematchingsynonyms in order to broaden our results. All search ele-ments were combined with the Boolean operators AND/OR. PubMed, Embase, Web of Science, COCHRANELibrary, Emcare and Academic Search Premier were sys-tematically searched (supplementary table S1).All observational cohorts and clinical trials reporting on

discontinuation of DMARDs in RA patients, in remission,were included. Study selection was independently carriedout by two reviewers (MV and EvM). Cases of disagree-ment were discussed until consensus was reached. First,all obtained titles were screened, and subsequentlyabstracts were reviewed after which full-text articles werescreened for the predefined inclusion and exclusion cri-teria (supplementary table S2). If multiple articles werebased on the same study, the article which described theprevalence and sustainability of DFR most clearly wasselected. Subsequently, the article describing the longestfollow-up was used for data extraction.

Data extractionA standardised data collection form was used to extract thefollowing information: study design, patient characteristics,interventions, glucocorticoids (GCs) usage, organisation offollow-up, outcome measures and loss to follow-up (supplementary table S3). Furthermore, data regarding eligibilitycriteria for tapering, taperingmethods, numbers of patientstapering, description and timing of achieving DFR, sustain-ment of DFR over time and the occurrence of flares wereextensively explored. Also, information regarding predic-tors of DFR was collected. Data extraction was done inde-pendently by two reviewers (MV and EvM), anddisagreements were discussed until consensus was reached.

If the methods were incomplete or unclear, the meth-ods of the original study could be used if a reference wasavailable. Clinical trials and observational studies werehandled separately, because of fundamental differencesin the study design, which could influence achievementand sustainment of DFR, that is, protocolised versus non-protocolised tapering, frequency ofmonitoring and dura-tion of follow-up.

Quality assessmentOur study quality assessment consisted of two parts, namelya general assessment and an assessment of the descriptionof DFR. For the general quality assessment, we used 13predefined quality criteria, which were based onCochraneguidelines (supplementary table S4).11 The general studyquality was considered ‘good’ if >75% (≥10 items) of thesecriteria were scored positive. For the DFR quality assess-ment, we used the following criteria: (1)‘DFR definition’,referring to whether a definition (eg, remission criterion)of DFR was included, and (2)‘DFR duration’, referring towhether information on the time between DMARD stopand being appointed as DFR (i.e. the duration of DMARD-free status) was reported. Specific emphasis was put on theduration ofDMARD-free state since this attains insight intothe sustainability of DFR. When both DFR quality criteriawere scored positive, DFR quality was regarded as ‘good’.Studies were regarded as ‘high quality’ if the general

quality, as well as the DFR quality, was good. When thegeneral study quality was good but only oneDFR-criterionwas fulfilled, studies were regarded as ‘moderate quality’.Studies lacking both DFR criteria, or without a good gen-eral quality assessment, were scored as ‘low quality’.

Data analysisExtracted data were used to calculate DFR prevalence,defined as the proportion of patients achieving DFR,compared with those eligible for tapering medication.For each prevalence, the CI was calculated. Patientswere considered eligible for tapering when they hadachieved remission and subsequently were allowed tostart tapering their medication. GCs were also consideredas DMARDs. We specifically chose not to use the totalstudy population as the denominator, because in somestudies specific groups of patients were not allowed totaper their medication due to study protocol.Sustained DFR (SDFR) was defined as the percentage of

patients with a DFR duration of >12 months since DMARDstop, relative to the number of patients eligible for tapering.Reported flares were categorised and summarised accord-ing to the time period in which they occurred: (i) duringtapering, (ii) in the first year after achieving DFR (‘earlyflares’) and (iii) aftermore than1 year ofDFR (‘late flares’).Results on DFR were summarised in a narrative overview,also in relation to study quality. Due to expected hetero-geneity in study design and study populations, pooled effectestimates were not calculated.Additionally, the data were reviewed on potential pre-

dictors for achieving DFR. We used the samemethods for

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data extraction and assessment as described for DFR pre-valence. Predictors of DFR were summarised. Results onvariables evaluated in more than one high-quality ormoderate-quality article were graphically presented,based on statistical significance obtained with regressionanalysis. If univariate and multivariate analyses were bothconducted, results of the multivariate analysis were used.For each predictor, the number of studies and the totalnumber of patients within these studies were presentedand the direction of the effect was indicated.

RESULTSStudy selectionOur search resulted in 631 articles, of which 51 articleswere considered eligible for inclusion (figure 1). These51 articles comprised data from 19 studies, 14 clinicaltrials and 5 observational cohorts.

Quality assessmentBoth the quality of the study in general and the descrip-tion of DFR were evaluated, resulting in a final qualityrating. Eleven out of 14 clinical trials and two out of fiveobservational cohorts showed a good general quality(table 1). Notably, the tapering methods were betterdescribed for clinical trials than for observational cohorts.Of the 13 studies with a good general quality, seven ful-filled both quality criteria for DFR and were regarded ashigh quality. These seven high-quality studies comprisedfive clinical trials and two observational cohorts. Of theremaining six studies, two studies were of moderate qual-ity since only one DFR criterion was fulfilled. The fourother studies did not fulfil any DFR quality criteria andwere regarded low quality (table 1).Because of fundamental differences in study design, DFR

prevalence and flare rates from clinical trials and observa-tional cohorts were presented separately. Also, only high-quality or moderate-quality studies were presented in theresult section. Nonetheless, all prevalence, including thoseof low-quality studies, can be found in table 2.

Clinical trialsStudy characteristicsStudy populations varied in RA classification (1987 vs2010 criteria), disease stage/duration (early vs estab-lished) and disease activity (supplementary table S5).Overall, trials were performed in two ‘settings’: early,DMARD-naïve RA and established RA. Studies includingearly RA had a treat-to-target approach, and when remis-sion was achieved, DMARDs were tapered. This was allconducted in a relative short period of time (n=7).13–19

The established RA studies (disease duration 3.1–11.3years, n=6) either included patients with active diseasewho first changed DMARD treatment and subsequentlybecame eligible for tapering (n=2)20 21 or selectedpatients who were in longstanding remission and weredirectly considered eligible for tapering (n=4).22–25 Allestablished RA studies were of low quality, except 1 which

was of moderate quality.18 One study, including patientsin sustained remission, did not report disease duration.19

DMARD taperingTapering of DMARDs was initiated when patients fulfilledthe study-specific eligibility criteria for tapering, in whichsome were stricter than others (supplementary table S5).Methods of tapering varied from immediate DMARD stopto one-by-one gradual tapering of DMARDs over thecourse of a year. In general, tapering of biologic DMARDstook place before tapering of conventional syntheticDMARDs. Flare rates during tapering ranged from41.8% to 75.0% (table 2, figure 2).

Definitions of DMARD-free remissionOverall, the remission criterion used to define DFR wasmainly DAS44 or DAS28 remission. The DFR rates wereeither given as a point prevalence, thus at the moment ofDMARD stop, or combined with aminimal DFR period ofseveral months (table 2, figure 2). Nevertheless, moststudies did not putmuch emphasis on aminimal durationof the drug-free state as a requirement to achieve DFR.Importantly, three studies that clearly defined DFR (twohigh-quality, one moderate-quality) allowed i.a. or oralGCs during DFR, without reporting the actual use.13 17 18

Prevalence of DMARD-free remissionIn the five high-quality clinical trials, the reported preva-lence of DFR (DFR <12 months) ranged from 5.0% to24.3% (relative to the number of patients eligible fortapering). The two moderate-quality studies reporteda DFR prevalence of 5.9% and 21.9% (table 2, figure 2),respectively. When studies that allowed GCs while beingin DFR were excluded, DFR occurred in 5.0%–23.0%.SDFR (DFR >12months) was only reported in two clinicaltrials and showed a prevalence of 11.6% and 19.4% (rela-tive to patients eligible for tapering).Evaluation of DFR prevalence, in high-quality andmod-

erate-quality studies, in relation to the trial ‘settings’ washampered by the fact that only one study was performedin established RA where DMARDs were tapered afterprolonged remission,18 revealing a DFR prevalence of5.9% compared with the prevalence of 5.0%–24.3% instudies that tapered DMARDs in early RA.13–17 32

Early flares (≤12 months after DMARD-stop) werereported in one high-quality study and occurred in10.4% of patients eligible for tapering. Late flares (>12months after DMARD-stop) were reported by anotherstudy and occurred in 3.5% of patients (table 2).

Observational cohortsStudy characteristicsPatients included in the observational cohorts were diag-nosed between 1986 and 2011 (n=5). Patients in the obser-vational cohorts were, compared with clinical trials,included in an earlier time period, but had a longer follow-up. Diagnosis was based on the 1987 criteria27 29 31 or

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expert opinion.28 30 Treatment was less protocolised com-pared with the clinical trials, and a treat-to-target approachwas only used in three studies,27–29 of which two had a highquality (table 2).

DMARD taperingEligibility for tapering was only clearly reported in onestudy.28

Definitions of DMARD-free remissionRemission within DFR was defined as the absence ofclinical synovitis (table 2), except for one study thatused a DAS28 cut-off (DAS28<2.6).28 All five observa-tional cohorts reported on SDFR (DFR >12 months),whereas one also reported on DFR after 6 months. Intwo studies, of which one was a high-quality study, i.a.

and oral GC were allowed while being in DFR; the actualuse was not reported.

Prevalence of DMARD-free remissionDFR prevalence (<12 months) was 23.6% of patients eli-gible for tapering and was reported in one high-qualitystudy.28 The prevalence of SDFR ranged from 11.8% to17.8% (relative to patients eligible for tapering)(table 2,Figure 2).27 28 If we exclude the studies that allowed GCsduring DFR, one high-quality study remained with anSDFR prevalence of 17.8%.27 We did not compare DFRprevalence between studies that did and did not applya treat-to-target approach, because all studies withouta treat-to-target approach were of low quality.Early flares (≤12 months after DMARD stop) were

reported in one high-quality study and occurred in

Records identified through

database searching

(duplicates removed)

(n=631)

Included titles

(n=466)

Included abstracts

(n=138)

Articles excluded based on title

(n=165)

Articles excluded based on abstract

(n=328)

Articles included in analysis

(n=51)

Full‐text articles excluded (n=87)

Full text not available (n=8)

No discontinuation of all DMARDs (n=43)

DMARD discontinuation not clearly described (n=20)

Other type of literature: reviews, correspondence, case‐reports (n=10)Focus on discontinuation DMARDs due to adverse events,

not due to remission (n=6)

Screeningoftitles

Screeningofabstracts

Screeningoffulltext

Identification

Eligibility

Included

51 articles:

14 clinical trials

5 observational cohorts

Screening

Figure 1 Flow diagram of study selection. DMARDs, disease-modifying antirheumatic drugs.

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Tab

le1

Asses

smen

tofg

eneral

stud

yqua

lityan

dDFR

qua

lity,

resu

lting

infin

alca

tego

rizationas

high

,mod

erateor

low-qua

litystud

y

Clin

ical

trials

Obse

rvationa

lstudies

BeS

tIM

PROVED

AVERT

tREACH

U-A

CT-

early

ACT-

RAY

ElM

iedan

yet

alPRIZE

RETRO

Ten

Wolde

etal

SUPRISE

Bro

cqet

alKita

etal

DREAM

trial

Leiden

EAC

DREAM

coho

rtTiip

pan

na-

Kinnu

nenet

alESPOIR

ERAS

DMARD-free

remission

DFR

definition

(des

criptio

nof

DFR

crite

ria)

++

++

++

--

--

--

--

++

-+

+

DFR

duration

(des

criptio

nof

DFR

period)

++

++

+-

+-

--

-+

+-

++

-+

+

DFR

-qua

lity

✓✓

✓✓

✓±

±±

±✓

✓+

+

Study

population

Selec

tionof

patients

(des

criptio

ninclus

ion/

exclus

ioncrite

ria)

++

++

++

++

++

++

++

++

++

+

Criteria

forRAdiagn

osis

++

-+

++

++

++

++

++

+-

++

+

Bas

elinech

arac

teris

tics

(des

criptio

nof

charac

teris

tics)

++

++

++

++

++

++

++

++

++

+

Ran

domisation

ford

ifferen

tstud

ytrea

tmen

ts

++

++

++

++

++

+-

--

n.a.

Blin

ding

ofstud

ytrea

tmen

t

±±

+±

++

-+

-+

--

--

n.a.

Interven

tion

Trea

tmen

tstrateg

ies

(des

criptio

nof

strategies

)

++

++

++

++

++

++

++

++

+-

+

Cut-offpoint

tapering

(des

criptio

nof

cut-off

point)

++

++

++

++

++

++

++

-+

--

-

Taperingmetho

d(des

criptio

nof

metho

ds)

++

++

++

++

++

-+

--

--

--

-

Follo

w-u

pOrgan

isationfollo

w-up

(freq

uenc

yof

mon

itorin

g)+

++

++

++

++

++

+-

++

++

--

Lost

tofollo

wup

(des

criptio

nof

LTFU

)+

++

++

+?

??

-+

++

--

++

++

Dataan

alys

isan

dprese

ntation

Outco

mereportin

g+

++

++

++

++

++

++

++

+-

?+

Ana

lysistech

nique

s(des

criptio

nof

tech

nique

s)

++

++

++

++

++

+-

-+

++

+?

?

Missing

data(han

dlin

gof

missing

data)

++

??

+?

-±

??

??

-?

+?

??

?

Con

tinue

d

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11.8% of patients eligible for tapering. Late flares werereported by the other high-quality study and were seen in0.3% of patients eligible for tapering (table 2).

Predictors of DFRAll factors that were analysed for their potential associa-tion with achieving DFR were evaluated (supplementarytable S6). Due to heterogeneity in evaluated effect esti-mates, effect sizes could not be compared and meta-analyses not performed. For predictors that were studiedin more than one high-quality or moderate-quality study,the association with achieving DFR is summarised in fig-ure 3 (see also supplementary table S7). The figureincludes information on the number of studies with/with-out an association with DFR, the total number of patientsin these studies and the directionality of the effect (ifpresent). The absence of autoantibodies and HLA-shared epitope alleles were predictive for achievingDFR. Many patient characteristics (eg, age, body massindex, swollen joint count (SJC), estimated sedimenta-tion rate (ESR), erosions at baseline) were not associatedwith the chance of achieving DFR. For some, character-istic findings were inconsistent. Results on symptom dura-tion, for example, showed ambiguous results(supplementary table S6/7).

DISCUSSIONThis systematic literature review was conducted in accor-dance with PRISMA guidelines and provides insight intothe occurrence and sustainability of DFR in RA. Theprevalence of DFR (DFR≤12 months) was 5.0%–

24.3%,14–17 32 while SDFR (DFR>12 months) was achiev-able in 11.6%–19.4% of patients eligible for tapering.Remission criteria used to define DFR varied widely,

and the temporal aspect (sustainability) varied as well orwas not reported. Moreover, in some studies, concomi-tant use of GC was allowed while patients were in DFR.This might falsely inflate DFR prevalence, but to whatextent this occurred is unclear as actual use was notreported. Exclusion of aforementioned studies did notaffect our results. To increase homogeneity, quality cri-teria were used, and final conclusions were only based onhigh-uality and moderate-quality studies, which resultedin a narrative overview of DFR prevalence (figure 2).We observed different DFR prevalence depending on

the duration of the DFR period. To allow a fair compar-ison of DFR prevalence, we categorised the duration ofDFR in groups. SDFR was defined as a DMARD-free per-iod >12 months. Higher prevalence was observed whenDFR had a less stringent criterion for sustainability (fig-ure 2). In line with this, flares occurredmost often duringtapering and in the first months after DMARD stop. Thistime effect underlines the relevance of defining sustain-ability of DFR in future studies.DFR and SDFR might be fundamentally different.

Short-term DFR might indicate that disease activity wassuppressed, but not necessarily resolved, and could reviveT

able

1Con

tinue

d

Clin

ical

trials

Obse

rvationa

lstudies

BeS

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PROVED

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Gen

eral

stud

yqua

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✓✓

✓✓

✓✓

✓✓

✓✓

✓✓

✓

Combined

qua

lity

HQ

HQ

HQ

HQ

HQ

MQ

MQ

LQLQ

LQLQ

LQLQ

LQHQ

HQ

LQLQ

LQ

Studieswereas

sessed

forq

ualityof

DMARD-freeremission

:tha

tis,whe

ther

definition

(yes

‘+’or

no“–”)an

ddurationof

drug-free

statewerereported(yes

‘+’or

no“–”).D

FRqua

litywas

cons

idered

good

(“✓”)whe

nbothite

msweresc

ored

as‘+’,an

dmod

erate(‘±

’)whe

non

lyon

eof

twowas

scored

asgo

od.S

ubse

que

ntly,s

tudieswereas

sessed

onge

neralstudyqua

lity.

Criteria

forg

eneral

stud

yqua

lityco

uldbesc

ored

:‘+’indicatingsu

fficient,“-”

indicatingno

tsuffic

ient,‘±’indicatingmod

erate,

‘?’indicatingun

clea

rreportin

gan

dqua

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uldno

tbeas

sessed

.Studyqua

litywas

cons

idered

good

(“✓”)whe

nminim

ally75

%(10ite

ms)

weresc

ored

as‘+’.DFR

,DMARD-freeremission

;DMARD,d

isea

se-m

odify

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ti-rheu

matic

drug;

LTFU

,los

ttofollo

w-up;n

.a.,no

tap

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le;R

A,rhe

umatoidarthritis.T

heco

mbined

stud

y-qua

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cons

idered

high

(‘HQ’)whe

nbothDFR

qua

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dstud

yqua

litywerego

od.Itw

asco

nsidered

mod

erate(‘M

Q’)whe

nDFR

qua

litywas

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erate,

andstud

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good

.Low

(‘LQ’)indicates

stud

ieswith

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qua

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stud

yqua

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Tab

le2

Preva

lenc

eof

DMARD-freeremission

andfla

res

Tap

ering

DMARD-freeremission

Study

Inclus

ion

period

NStudypop

charac

t†Treatmen

t/Interven

tion

FUTap

ering

criteria

N

Flares

during

tapering

(definition

flare)

%DFR

achiev

ed*(≤12

m)

Tim

ein

DFR

(months

)Early

flares

(≤12

m)

%Sus

tained

DFR

**(>12

m)

Late

flares

(>12

m)

DefinitionofD

FR

Clinical

trials

BeS

t13

2000

–20

0850

8EarlyRA

1987

ACRcrit

HDAat

BL

1:Mon

othe

rapy(126

)2:

Step-upco

mbi(12

1)3:

Initial

combi(13

3)4:

Com

biw

ithIFX(128

)After

2ytaperingpos

sible.

60m

(5y)

Tapering:

DAS44

<2.4

DMARDstop

:DAS44

<1.6

min

6m

--

22.6%

‡

(115

/508

)5

10.40%

53/508

11.6%

‡

(59/50

8)at

5yFU

-

DAS44

<1.6

DAS44

≥1.6

DAS44

<1.6

min

12m

IMPROVED14

2007

–20

1047

9EarlyRA

2010

ACRcrit

HDAat

BL

0-4m

MTx

+Pred.

60m

(5y)

DAS44

<1.6

--

23.0%

(110

/479

)12

-19

.4%

(93/47

9)at

5yFU

3.5%

(17/47

9)at

5yFU

>4-8m

DAS28

<1.6:

taper

DAS28

>1.6:

1:Triple

csDMARDs

2:ADA+MTx

DAS44

<1.6or

Boo

lean

DAS44

<1.6or

Boo

lean

12m

AVERT15

2010

–20

1435

1EarlyRA

Diagn

osisby

experto

pinion

HDAat

BL

ACPA+

0–52

w

>52

w

1:ABA+MTx

(119

)2:

ABA(116

)3:

MTx

(166

)With

drawal

18m

DAS28

-CRP<3.2

223

-18

.4%

(41/22

3)5

--

-

DAS28

<2.6

tREACH16

2007

–20

1128

1EarlyRA

2010

ACRcrit

HDAat

BL

1:Triple

therap

y(183

)2:

MTx

(98)

Taperingat

anytim

ein

FU.

24m

DAS44

<1.6

min

2visit

141

41.8%

59/141

5.0%

(7/141

)6

--

-

(DAS44

≥2.4)

DAS44

<1.6

U-A

ct-E

arly

17

2010

–20

1231

7EarlyRA19

87/

2010

ACRcrit

HDAat

BL

1:TC

Z+MTx

(106

)2:

MTx

(103

)3:

TCZ(108

)Ta

peringat

anytim

ein

FU

24m

DAS28

<2.6

SJC

<4min

24w

--

24.3%

‡

(77/31

7)3

--

-

DAS28

<2.6&SJC

≤4

ACT-R

AY18

2009

–20

1355

6Estab

lishe

dRA

1987

ACRcrit

HDAat

BL

0–52

w

>52

w

TOCI+

MTx

orTO

CI(27

9/27

7)T2

T+tapering

(472

)

12-

36m

DAS28

<2.6

min

12w

472

42.4%

200/47

25.9%

‡

(28/47

2)Single

timep

oint

--

-

(Exp

ert

opinion)

DAS28

<2.6

ElM

iedan

yet

al19

-15

7RAdurationn.r.

2010

ACRcrit

Rem

ission

atBL

Arm

1–3:

Taper

DMARDs

Arm

4:StopallD

MARDs

Arm

5:Con

trol

12m

DAS28

<2.6

min

6m

3275

.0%

§24

/32

21.9%

(7/32)

12-

--

(DAS>3.2)

DAS28

<2.6

PRIZE20

2009

–20

1230

6EarlyRA

1987

ACRcrit

HDAat

BL

0–52

w52

–91

w

91–11

7w

ETA

+MTx

ETA

+MTx

orMTx

orplace

bo

With

drawal

29m

DAS28

<3.2

132

-46

.9%

(62/13

2)22

-24w

--

-

DAS28

<2.6

Con

tinue

d

Rheumatoid arthritis

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Tab

le2

Con

tinue

d

Tap

ering

DMARD-freeremission

Study

Inclus

ion

period

NStudypop

charac

t†Treatmen

t/Interven

tion

FUTap

ering

criteria

N

Flares

during

tapering

(definition

flare)

%DFR

achiev

ed*(≤12

m)

Tim

ein

DFR

(months

)Early

flares

(≤12

m)

%Sus

tained

DFR

**(>12

m)

Late

flares

(>12

m)

DefinitionofD

FR

RETRO

21

2010

–20

1310

1Estab

lishe

dRA

2010

ACRcrit.

Rem

ission

atBL

1:Con

tinue

(38)

2:Ta

pering(36)

3:StopDMARD(27)(6

m50

%)

12m

DAS28

<2.6

min

6m

2751

.9%

(14/27

)48

.1%

(13/27

)6

--

-

(DAS28

>2.6)

DAS28

<2.6

Ten

Wolde

etal22

-28

5Estab

lishe

dRA

1987

ACRcrit

Rem

ission

atBL

1:Con

tinue

(142

)2:

Switc

hplace

bo(143

)12

mARAremission

(5/6

crit)

143

37.1%

§(53/14

3)58

%(83/14

3)12

--

-

(Syn

ovitis)

ARAremission

(5/6)

Brocq

etal23

1995

–20

0521

Estab

lishe

dRA

2010

ACRcrit

Rem

ission

atBL

TNFi

trea

tmen

tatinc

lusion

Interven

tion:

abrupts

topTN

Fi

12m

DAS28

<2.6

min

6m

757

.1%

§(4/7)

28.6%

‡

(2/7)

12-

--

(DAS28

>3.2)

DAS28

<2.6

SURPRISE24

2009

–20

1223

3Estab

l.RA19

87ACRcrit

HDAat

BL

0–52

w>52

wTC

Z+MTx

orTC

ZStopTC

Z24

mDAS28

<2.6

5366

%§

(35/53

)26

.4%

‡

(14/53

)12

--

-

(n.r.)

DAS28

<2.6

Kitaet

al25

2008

–20

0913

EarlyRA

2010

ACRcrit

HDAat

BLACPA+

0–52

w>52

wTrea

t-to-targe

tStopallD

MARDs

24m

SDAI&

BME-

33%

onMRI

520

%§

(1/5)

60%

‡

(3/5)

12-

--

(n.r.)

SDAIrem

ission

DREAM

trial26

2008

–20

1018

7Estab

lishe

dRA

1987

ACRcrit

LDAat

BL

Taperingafter4y

TCZ

mon

othe

rapy

12m

DAS28

<3.2

187

72.5%

§(136

/187

)9.1%

‡

(17/18

7)12

--

-

(DAS28

>3.2)

DAS28

<2.6

Definition

ofDFR

Obse

rvationa

lstudies

Leiden

EAC27

1993

–20

1188

9EarlyRA

1987

ACRcrit.

HDAat

BL

1993

–19

9519

96–19

9819

99–20

04>20

05

NSAIDs

Mild

DMARDs

Initial

MTx

DASstee

red

1-18

y-

--

-12

-17

.8%

(158

/889

)after1-18

yFU

0.3%

(3/889

)

Nosyno

vitis

min

12m

DREAM

coho

rt28

2006

–20

0922

9EarlyRA

experto

pinion

(79%

1987

)HDAat

BL

Trea

t-to-targe

t,stee

redat

DAS28

<2.6:

Initial

MTx

mon

othe

rapy,

ifDAS28

>2.6+

SSZ

ifDAS28

>3.2TN

Finhibito

r

5yDAS28

<2.6

min

6m

--

23.6%

‡

(54/22

9)6

11.8%

(27/22

9)11

.8%

‡

(27/22

9)after5y

FU

-

DAS28

<2.6

DAS28

>2.6

DAS28

<2.6

min

6m

Tiip

pan

na-

Kinnu

nen

etal29

1986

–19

8970

EarlyRA19

58/

1987

crit.

HDAat

BL

Saw

toothstrategy

15y

Clinical

remission

¶or

minor

disea

seac

tivity

--

28.6%

‡

(20/70

)-

12.9%

(9/70)

15.7%

‡

(11/70

)after15

yFU

-

ARAremission

‡‡

ARAremission

ESPOIR

30††

2000

–20

0553

3EarlyRA

Clinical

diagn

osis

HDAat

BL

Trea

tedwith

cDMARDs

5y-

--

-12

-5.4%

(29/53

3)-

Nosyno

vitis

min

12m

Con

tinue

d

RMD Open

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Tab

le2

Con

tinue

d

Tap

ering

DMARD-freeremission

Study

Inclus

ion

period

NStudypop

charac

t†Treatmen

t/Interven

tion

FUTap

ering

criteria

N

Flares

during

tapering

(definition

flare)

%DFR

achiev

ed*(≤12

m)

Tim

ein

DFR

(months

)Early

flares

(≤12

m)

%Sus

tained

DFR

**(>12

m)

Late

flares

(>12

m)

DefinitionofD

FR

ERAS31††

1986

–19

9689

5EarlyRA

1987

ACRcrit.

HDAat

BL

Rhe

umatolog

istp

referenc

e,predom

inan

tlyMTx

,SSZ,H

CQ

10y

--

--

12-

9.4%

(84/89

5)-

Nosyno

vitis

min

12m

High-qua

litystud

iesareindicated

indarkgree

n,mod

erate-qua

litystud

iesareindicated

inlig

htgree

n,an

dlow-qua

litystud

iesareindicated

inwhite.

* Perce

ntag

eof

patientswho

achiev

edDFR

divided

bypatientseligible

fortapering.

**Perce

ntag

eof

patientswho

sustaine

dDFR

formorethan

12mon

thsdivided

bypatientseligible

fortapering.

‡Poten

tialu

seof

intra-artic

ular

orsystem

icco

rticos

teroids,

orus

eof

GCSwas

notc

learlydes

cribed

due

towhich

usewas

dou

btful.

§DMARDsweredisco

ntinue

dab

ruptly

with

outg

radua

ltap

eringmetho

d.

¶Clinicalremission

defined

asno

tend

erjoints,n

osw

ollenjoints,n

ojointp

ainbyhistory,ESR<30

(female/<20

(male)form

inim

al12

mon

ths.Orp

rolong

edsymptom-freepha

seof

disea

sewith

minor

disea

seac

tivity

.†Lo

ngstan

dingRAwas

defined

asadisea

sedurationof

morethan

2ye

ars.Allsh

orterd

isea

se-an

dsymptom

durations

wereclas

sifie

das

early

RA.Inthesu

pplemen

tary

table(S1)

spec

ificduration

ofdisea

sean

dsymptom

durationca

nbefoun

d.

††Onlyminim

alinform

ationco

uldbeex

trac

tedfrom

theartic

lesin

which

thisstud

ywas

men

tione

d.T

herefore

inform

ationismissing

,which

isno

tdue

toinsu

fficient

qua

lityof

theartic

le.

‡‡ARAremission

:morning

stiffne

ssab

sent

(orn

otex

ceed

ing15

min),no

fatig

ue,n

ojointp

ainbyhistory,no

jointten

derne

ss,n

ojointo

rten

don

shea

thsw

elling,

noelev

ationof

ESR(in

5/6,

fatig

ueis

notinc

luded

inthecrite

ria).

ACR,A

merican

College

ofRhe

umatolog

y;ABA,A

batac

ept;BL,

bas

eline;

bDMARDs,

biologica

lDMARDs;

crit,

crite

ria;c

sDMARDs,

conv

entio

nalD

MARDs;

DAS,D

isea

seActivity

SCORE;D

FR,

DMARD-freeremission

;Estab

l.,es

tablishe

d;E

TA,e

tane

rcep

t;FU

,follow-up;H

CQ,h

ydroxy

chloroquine

;HDA,h

ighdisea

seac

tivity

;IFX

,inflixim

ab;L

DA,low

disea

seac

tivity

;rem

,rem

ission

;MTx

,metho

trex

ate;

n.r.,n

otreported;R

A,rhe

umatoidarthritis;S

SZ,s

ulfasa

lazine

;SJC

,swollenjointc

ount;T

CZ,toc

ilizu

mab

;TNF,

tumor

necros

isfactor;T

NFi,T

NF-αinhibito

r.

Rheumatoid arthritis

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after the disappearance of suppressive treatment. More-over, early flares (≤12 months after DFR) occur moreoften than late flares (>12 months after DFR), whichmight indicate that autoimmunity was not completelysilenced. In our opinion, patients in SDFR (DFR>12months) better resemble silencing of autoimmunity andmay have achieved a proxy for cure. Therefore, SDFR canbecome an important outcome for clinical trials. Becauselate flares (often occurring years after DMARD-stop)might be pathophysiologically different from early flares,it is an interesting subject for future studies to explore thetriggers or pathophysiologic mechanisms involved in latereactivation of the autoimmune process.Notably, despite differences in study design, the DFR

prevalence observed in observational cohorts and clinicaltrials was comparable. This supports the robustness of theobserved frequencies. We were unable to investigate howlong remission should be sustained before tapering canbe initiated, because too few high-quality studies wereperformed in patients with established RA and longstand-ing remission. Additionally, due to an insufficientamount of studies, nothing can be said about the changeof achieving DFR after treatment with certain conven-tional or biologic DMARDs.We could not evaluate whether the method of tapering

influenced the frequency of SDFR. It has been suggestedthat gradual tapering results in less flares compared withabrupt cessation.2 Also, the stringency of the remissioncriterion for initiation of tapering might be of influence,whereby less stringent criteria might increase the risk offlares. Evaluation of themethods of DMARD tapering wasbeyond the scope of this review, and a relevant subject forfurther studies as insight into the most effective taperingmethod may positively influence the chance to achieveSDFR. Another issue for further studies is the assessment

of the likelihood to achieve remission for patients thatflare after having been in DFR. From studies on patientsthat flared during tapering, it is known that the majorityof patients achieve remission by restarting the sameDMARD.33 Whether this is similar for patients that flareafter DMARD stop is not yet systematically studied.Studying the prevalence of DFR and predictors for DFR

does not answer the question whether the absence ofclinical signs and symptoms without treatment exhibitedthe natural course of RA in these patients,34 or wasinduced by DMARD treatment. This could not beanswered within our SLR, nor could we compare studiesfor treatment intensity (eg, reflected by treat-to-target)due to the lack of high-quality studies without a treat-to-target approach. One high-quality study compareda treat-to-target approach that aimed for a DAS<1.6 withan approach that aimed for a DAS<2.4 and reported thatpatients achieved DFR more often when aimed fora DAS<1.6 (18% vs 8%, respectively), suggesting thatintensive treatment is helpful in inducing DFR.35 How-ever, the clinical trials rarely used DFR as a primary out-come, and, therefore, the question to what extent thefrequency of DFR can be achieved by treatment remainsa subject for future studies.Although we tried to find predictors for DFR, it remains

uncertain which patients are able to stop their DMARDssuccessfully. Meta-analyses could not be performed dueto the heterogeneity of studies and effect estimates.Therefore, we summarised and graphically presenteddata on predictors using predefined criteria, but thismethodology is far less optimal than meta-analysis. Sev-eral patient characteristics (eg, age, SJC, ESR and erosive-ness) were not associated with a higher chance ofachieving DFR. Results on symptom duration were con-flicting, as the relation between DFR and symptom

Figure 2 Summary of flare rate and DFR prevalence, all as percentage of the number of patients that were eligible for DMARDtapering, depicted on a timeline. DFRprevalencewasgroupedby the duration ofDFR.Data are presented asDFRpercentage (CI). Datawere based on high-quality or moderate-quality studies. Prevalence andCIs were calculated using the number of DFR patients dividedby the number of patients eligible for tapering. Results from observational studies are indicated in italic. *indicates that studies thatallowed the use of i.a. or systemic corticosteroids in patients that were considered to be in DFR(absolute number of patients that usedcorticosteroids after DMARDstopwas not reported) or use inDMARD-free statuswasnot clearly reported. X indicatesmoderate-qualitystudies. DMARD, disease-modifying antirheumatic drugs; DFR, DMARD-free remission; SDFR, sustained DMARD-free remission.

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duration was non-significant, but showed a strong ten-dency towards significance in part of the studies. Further-more, it is known that the association with DFR is notlinear but refined to a short period of time30 (ie, thewindow of opportunity), and associations may remainundetected if symptom duration is analysed asa continuous variable. Absence of autoantibodies wasthe best predictor for DFR. Although effect sizes werenot involved in our analyses, the absence of autoantibo-dies alone is not sufficient to accurately guide taper deci-sions in daily practice. Therefore, effective pursuit ofSDFR in clinical practice requires more insight into sub-sets of patients that are likely to achieve SDFR.

Acknowledging the importance of the autoantibodystatus as predictor, the SDFR prevalence will be differentfor autoantibody-positive and autoantibody-negativepatients. We could not stratify the results on SDFR pre-valence for autoantibody status as the prevalencereported in the included cohorts and trials was not alwaysstratified for autoantibodies. However, the studies thatincluded information on autoantibody status in theirpatient characteristics reported that 52%–100% ofpatients were autoantibody positive (supplementarytable S5).Since conducting a thorough systematic literature

review is time demanding, a time gap exists between

-2000 -1000 0 1000 2000

Shared epitope (y/n)

Erosive at baseline (y/n)

(higher) SHS score at baseline

An�-CCP (posi�ve, y/n)

RF (posi�ve, y/n)

(higher) CRP

(higher) ESR

(higher) HAQ at baseline

(higher) SJC at baseline

(higher) DAS at baseline

Symptom dura�on

Smoking (y/n)

BMI

Gender (male)

(higher) Age

Size of combined study populations

Not associated with achieving DFRNegatively associated with achieving DFRPositively associated with achieving DFR

3

2

1

0

1

1

2

0

1

0

0

0

0

2

2

1 2

1

2

1

1

1

2

2

12

2

2

1

2

Not associated Associated

Figure 3 Overview of studied predictors of achieving DMARD-free remission. Data are presented from variables that werereported in >1 study, based on statistical significance obtained in regression analysis. If both univariable and multivariableregression was applied, the result of the multivariable regression was used. Presented are the absence (left panel) and presenceof an association with achieving DFR over time (right panel), the number of studies is indicated per predictor, the total number ofpatients in these studies is plotted on the x-axis. The directionality of the effect is indicated in colours, green indicates anincreased risk of achieving DFR, red indicates a decreased risk of achieving DFR. For symptom duration, no differentiation wasmade for analyses using this as continuous or categorical variable. BMI, body mass index; CRP, C reactive protein; DAS,Disease Activity Score; ESR, estimated sedimentation rate; HAQ, Health Assessment Questionnaire; RF, rheumatoid factor;SJC, swollen joint count.

Rheumatoid arthritis

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the actual literature search (March 2019) and publica-tion of the results. As a result, relevant articles in thistime interval are not included. A non-systematic screen-ing of articles published in this period revealed theBioRRA study,36 published in December 2019. Thisstudy focuses on predictors of flare after DMARD cessa-tion and reported a 52% flare rate (DAS28-CRP≥2.4)after abrupt DMARD cessation. Predictors of flareswere, among other things, absence of Boolean remissionat baseline, RF positivity and IL-27. Biomarkers predic-tive of DFR, as identified in other recent studies, werecalprotectin levels and several serum protein levelsamong which SAA.37 38 Calprotectin and SAA are bothacute phase reactants. However, none of these markerswere yet validated in independent studies.From the patients’ perspective, achieving SDFR is ben-

eficial; it was recently reported to be associated withnormalisation of functional disability and resolution ofsymptoms, for example, fatigue.27 Unfortunately, clini-cal trials infrequently evaluated SDFR. If future trialswould be designed with DFR/SDFR as primary outcome,consensus of the definition of remission and the dura-tion of DMARD-free state is required to promote com-parability of findings between studies. This may requireOMERACT Initiatives.In conclusion, DFR is achievable in RA and is sustainable

in ~10%–20% of patients. DFR can become an importantoutcome measure for clinical trials and requires consis-tency in the definition. Considering the relative short fol-low-up after DMARD stop in current clinical trials and thehigh rate of flares in the first year after DMARD stop, wepropose to incorporate a DMARD-free follow-up of at least1 year, to ensure that DFR is sustainable.

Acknowledgements We would like to thank J. Schoones, librarian of LeidenUniversity Medical Centrum, for constructing and carrying out the literature search.

Contributors MV and EvM made a substantial contribution to the acquisition andanalysis of the data. All authors made a substantial contribution to the interpretationof the data and the conception and design of the work. All authors approved the finalversion of the manuscript.

Funding The research leading to these results has received funding from theEuropean Research Council (ERC) under the European Union’s Horizon 2020research and innovation program (starting grant, agreement no 714312) and fromthe Dutch Arthritis Foundation. The funding source had no role in the design andconduct of the study; collection, management, analysis, and interpretation of thedata; preparation, review, or approval of the manuscript; or decision to submit themanuscript for publication.

Competing interests None declared.

Patient consent for publication Not required.

Ethics approval Research ethics approval was not obtained since this was notapplicable for this type of study.

Data sharing statement All data relevant to the study are included in the article oruploaded as supplementary information.

Provenance and peer review Not commissioned; externally peer reviewed.

Open access This is an open access article distributed in accordance with theCreative Commons Attribution Non Commercial (CC BY-NC 4.0) license, whichpermits others to distribute, remix, adapt, build upon this work non-commercially,and license their derivative works on different terms, provided the original work isproperly cited, appropriate credit is given, any changes made indicated, and the useis non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

ORCID iDsM Verstappen http://orcid.org/0000-0002-7850-5063E van Mulligen http://orcid.org/0000-0003-1900-790XA H M van der Helm-Van Mil http://orcid.org/0000-0001-8572-1437

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