Table 2

Prevalence of DMARD-free remission and flares

							Tapering			DMARD-free remission
Study	Inclusion period	N	Study pop charact†	Treatment/Intervention		FU	Tapering criteria	N	Flares during tapering (definition flare)	% DFR achieved* (≤12 m)	Time in DFR (months)	Early flares (≤12 m)	% Sustained DFR** (>12 m)	Late flares (>12 m)
Study	Inclusion period	N	Study pop charact†	Treatment/Intervention		FU	Tapering criteria	N	Flares during tapering (definition flare)	Definition of DFR		Early flares (≤12 m)	% Sustained DFR** (>12 m)	Late flares (>12 m)
Clinical trials
BeSt¹³	2000–2008	508	Early RA 1987 ACR crit HDA at BL	1: Monotherapy (126) 2: Step-up combi (121) 3: Initial combi (133) 4: Combi with IFX (128) After 2y tapering possible.		60 m (5y)	Tapering: DAS44<2.4 DMARD stop: DAS44<1.6 min 6 m	-	-	22.6%‡ (115/508)	5	10.40% 53/508	11.6%‡ (59/508) at 5y FU	-
BeSt¹³	2000–2008	508	Early RA 1987 ACR crit HDA at BL			60 m (5y)	Tapering: DAS44<2.4 DMARD stop: DAS44<1.6 min 6 m	-	-	DAS44<1.6		DAS44≥1.6	DAS44<1.6 min 12 m	-
IMPROVED¹⁴	2007–2010	479	Early RA 2010 ACR crit HDA at BL	0- 4 m	MTx + Pred.	60 m (5y)	DAS44<1.6	-	-	23.0% (110/479)	12	-	19.4% (93/479) at 5y FU	3.5% (17/479) at 5y FU
IMPROVED¹⁴	2007–2010	479	Early RA 2010 ACR crit HDA at BL	>4-8 m	DAS28<1.6: taper DAS28>1.6: 1: Triple csDMARDs 2: ADA+MTx	60 m (5y)	DAS44<1.6	-	-	DAS44<1.6 or Boolean			DAS44<1.6 or Boolean 12 m
AVERT¹⁵	2010–2014	351	Early RA Diagnosis by expert opinion HDA at BL ACPA+	0–52 w >52 w	1: ABA+MTx (119) 2: ABA (116) 3: MTx (166) Withdrawal	18 m	DAS28-CRP<3.2	223	-	18.4% (41/223)	5	-	-	-
AVERT¹⁵	2010–2014	351	Early RA Diagnosis by expert opinion HDA at BL ACPA+	0–52 w >52 w	1: ABA+MTx (119) 2: ABA (116) 3: MTx (166) Withdrawal	18 m	DAS28-CRP<3.2	223	-	DAS28<2.6		-	-	-
tREACH¹⁶	2007–2011	281	Early RA 2010 ACR crit HDA at BL	1: Triple therapy (183) 2: MTx (98) Tapering at any time in FU.		24 m	DAS44<1.6 min 2 visit	141	41.8% 59/141	5.0% (7/141)	6	-	-	-
tREACH¹⁶	2007–2011	281	Early RA 2010 ACR crit HDA at BL			24 m	DAS44<1.6 min 2 visit	141	(DAS44≥2.4)	DAS44<1.6		-	-	-
U-Act-Early¹⁷	2010–2012	317	Early RA 1987/2010 ACR crit HDA at BL	1: TCZ+MTx (106) 2: MTx (103) 3: TCZ (108) Tapering at any time in FU		24 m	DAS28<2.6 SJC<4 min 24 w	-	-	24.3%‡ (77/317)	3	-	-	-
U-Act-Early¹⁷	2010–2012	317	Early RA 1987/2010 ACR crit HDA at BL			24 m	DAS28<2.6 SJC<4 min 24 w	-	-	DAS28<2.6 & SJC≤4		-	-	-
ACT-RAY¹⁸	2009–2013	556	Established RA 1987 ACR crit HDA at BL	0–52 w >52 w	TOCI +MTx or TOCI (279/277) T2 T+ tapering (472)	12-36 m	DAS28<2.6 min 12 w	472	42.4% 200/472	5.9%‡ (28/472)	Single timepoint	-	-	-
ACT-RAY¹⁸	2009–2013	556	Established RA 1987 ACR crit HDA at BL	0–52 w >52 w	TOCI +MTx or TOCI (279/277) T2 T+ tapering (472)	12-36 m	DAS28<2.6 min 12 w	472	(Expert opinion)	DAS28<2.6		-	-	-
El Miedany et al¹⁹	-	157	RA duration n.r. 2010 ACR crit Remission at BL	Arm 1–3: Taper DMARDs Arm 4: Stop all DMARDs Arm 5: Control		12 m	DAS28<2.6 min 6 m	32	75.0% § 24/32	21.9% (7/32)	12	-	-	-
El Miedany et al¹⁹	-	157	RA duration n.r. 2010 ACR crit Remission at BL	Arm 1–3: Taper DMARDs Arm 4: Stop all DMARDs Arm 5: Control		12 m	DAS28<2.6 min 6 m	32	(DAS>3.2)	DAS28<2.6		-	-	-
PRIZE²⁰	2009–2012	306	Early RA 1987 ACR crit HDA at BL	0–52 w 52–91 w 91–117 w	ETA+MTx ETA+MTx or MTx or placebo Withdrawal	29 m	DAS28<3.2	132	-	46.9% (62/132)	22-24 w	-	-	-
PRIZE²⁰	2009–2012	306	Early RA 1987 ACR crit HDA at BL	0–52 w 52–91 w 91–117 w	ETA+MTx ETA+MTx or MTx or placebo Withdrawal	29 m	DAS28<3.2	132	-	DAS28<2.6		-	-	-
RETRO²¹	2010–2013	101	Established RA 2010 ACR crit. Remission at BL	1: Continue (38) 2: Tapering (36) 3: Stop DMARD (27)(6 m 50%)		12 m	DAS28<2.6 min 6 m	27	51.9% (14/27)	48.1% (13/27)	6	-	-	-
RETRO²¹	2010–2013	101	Established RA 2010 ACR crit. Remission at BL			12 m	DAS28<2.6 min 6 m	27	(DAS28>2.6)	DAS28<2.6		-	-	-
*Ten Wolde et al²²*	-	285	Established RA 1987 ACR crit Remission at BL	1: Continue (142) 2: Switch placebo (143)		12 m	ARA remission (5/6 crit)	143	37.1% § (53/143)	58% (83/143)	12	-	-	-
*Ten Wolde et al²²*	-	285	Established RA 1987 ACR crit Remission at BL	1: Continue (142) 2: Switch placebo (143)		12 m	ARA remission (5/6 crit)	143	(Synovitis)	ARA remission (5/6)		-	-	-
Brocq et al²³	1995–2005	21	Established RA 2010 ACR crit Remission at BL	TNFi treatment at inclusion Intervention: abrupt stop TNFi		12 m	DAS28<2.6 min 6 m	7	57.1% § (4/7)	28.6%‡ (2/7)	12	-	-	-
Brocq et al²³	1995–2005	21	Established RA 2010 ACR crit Remission at BL	TNFi treatment at inclusion Intervention: abrupt stop TNFi		12 m	DAS28<2.6 min 6 m	7	(DAS28>3.2)	DAS28<2.6		-	-	-
SURPRISE²⁴	2009–2012	233	Establ. RA 1987 ACR crit HDA at BL	0–52 w >52 w	TCZ+MTx or TCZ Stop TCZ	24 m	DAS28<2.6	53	66% § (35/53)	26.4%‡ (14/53)	12	-	-	-
SURPRISE²⁴	2009–2012	233	Establ. RA 1987 ACR crit HDA at BL	0–52 w >52 w	TCZ+MTx or TCZ Stop TCZ	24 m	DAS28<2.6	53	(n.r.)	DAS28<2.6		-	-	-
*Kita et al²⁵*	2008–2009	13	Early RA 2010 ACR crit HDA at BL ACPA+	0–52 w >52 w	Treat-to-target Stop all DMARDs	24 m	SDAI & BME-33% on MRI	5	20% § (1/5)	60%‡ (3/5)	12	-	-	-
*Kita et al²⁵*	2008–2009	13	Early RA 2010 ACR crit HDA at BL ACPA+	0–52 w >52 w	Treat-to-target Stop all DMARDs	24 m	SDAI & BME-33% on MRI	5	(n.r.)	SDAI remission		-	-	-
DREAM trial²⁶	2008–2010	187	Established RA 1987 ACR crit LDA at BL	Tapering after 4y TCZ monotherapy		12 m	DAS28<3.2	187	72.5% § (136/187)	9.1%‡ (17/187)	12	-	-	-
DREAM trial²⁶	2008–2010	187	Established RA 1987 ACR crit LDA at BL	Tapering after 4y TCZ monotherapy		12 m	DAS28<3.2	187	(DAS28>3.2)	DAS28<2.6	Definition of DFR		-	-
Observational studies
Leiden EAC²⁷	1993–2011	889	Early RA 1987 ACR crit. HDA at BL	1993–1995 1996–1998 1999–2004 >2005	NSAIDs Mild DMARDs Initial MTx DAS steered	1-18y	-	-	-	-	12	-	-	17.8% (158/889) after 1-18y FU	0.3% (3/889)
Leiden EAC²⁷	1993–2011	889	Early RA 1987 ACR crit. HDA at BL	1993–1995 1996–1998 1999–2004 >2005	NSAIDs Mild DMARDs Initial MTx DAS steered	1-18y	-	-	-	-	12	No synovitis min 12 m	-		0.3% (3/889)
DREAM cohort²⁸	2006–2009	229	Early RA expert opinion (79% 1987) HDA at BL	Treat-to-target, steered at DAS28<2.6: Initial MTx monotherapy, if DAS28>2.6+ SSZ if DAS28>3.2 TNF inhibitor		5y	DAS28<2.6 min 6 m	-	-	23.6%‡ (54/229)	6	11.8% (27/229)	11.8%‡ (27/229) after 5y FU	-
DREAM cohort²⁸	2006–2009	229	Early RA expert opinion (79% 1987) HDA at BL			5y	DAS28<2.6 min 6 m	-	-	DAS28<2.6		DAS28>2.6	DAS28<2.6 min 6 m	-
Tiippanna-Kinnunen et al²⁹	1986–1989	70	Early RA 1958/1987 crit. HDA at BL	Sawtooth strategy		15y	Clinical remission¶ or minor disease activity	-	-	28.6%‡ (20/70)	-	12.9% (9/70)	15.7%‡ (11/70) after 15y FU	-
Tiippanna-Kinnunen et al²⁹	1986–1989	70	Early RA 1958/1987 crit. HDA at BL	Sawtooth strategy		15y	Clinical remission¶ or minor disease activity	-	-	ARA remission‡‡			ARA remission	-
ESPOIR³⁰ ††	2000–2005	533	Early RA Clinical diagnosis HDA at BL	Treated with cDMARDs		5y	-	-	-	-	12	-	5.4% (29/533)	-
ESPOIR³⁰ ††	2000–2005	533	Early RA Clinical diagnosis HDA at BL	Treated with cDMARDs		5y	-	-	-	-	12	-	No synovitis min 12 m	-
ERAS³¹ ††	1986–1996	895	Early RA 1987 ACR crit. HDA at BL	Rheumatologist preference, predominantly MTx, SSZ, HCQ		10y	-	-	-	-	12	-	9.4% (84/895)	-
ERAS³¹ ††	1986–1996	895	Early RA 1987 ACR crit. HDA at BL	Rheumatologist preference, predominantly MTx, SSZ, HCQ		10y	-	-	-	-	12	-	No synovitis min 12 m	-

High-quality studies are indicated in dark green, moderate-quality studies are indicated in light green, and low-quality studies are indicated in white.
*Percentage of patients who achieved DFR divided by patients eligible for tapering.
**Percentage of patients who sustained DFR for more than 12 months divided by patients eligible for tapering.
‡Potential use of intra-articular or systemic corticosteroids, or use of GCS was not clearly described due to which use was doubtful.
§DMARDs were discontinued abruptly without gradual tapering method.
¶Clinical remission defined as no tender joints, no swollen joints, no joint pain by history, ESR<30(female/<20(male) for minimal 12 months. Or prolonged symptom-free phase of disease with minor disease activity.
†Longstanding RA was defined as a disease duration of more than 2 years. All shorter disease- and symptom durations were classified as early RA. In the supplementary table (S1) specific duration of disease and symptom duration can be found.
††Only minimal information could be extracted from the articles in which this study was mentioned. Therefore information is missing, which is not due to insufficient quality of the article.
‡‡ARA remission: morning stiffness absent (or not exceeding 15 min), no fatigue, no joint pain by history, no joint tenderness, no joint or tendon sheath swelling, no elevation of ESR (in 5/6, fatigue is not included in the criteria).
ACR, American College of Rheumatology; ABA, Abatacept; BL, baseline; bDMARDs, biological DMARDs; crit, criteria; csDMARDs, conventional DMARDs; DAS, Disease Activity SCORE; DFR, DMARD-free remission; Establ., established; ETA, etanercept; FU, follow-up; HCQ, hydroxychloroquine; HDA, high disease activity; IFX, infliximab; LDA, low disease activity; rem, remission; MTx, methotrexate; n.r., not reported; RA, rheumatoid arthritis; SSZ, sulfasalazine; SJC, swollen joint count; TCZ, tocilizumab; TNF, tumor necrosis factor; TNFi, TNF-α inhibitor.