Table 5

Primary outcomes of studies investigating DMARD dose reduction and withdrawal

Study	RoB	Primary outcome	Wk	Treatment arm	n	Result	P value/95% CI
csDMARD dose reduction/stopping
Pope 202045	High	DAS28 LDA+maintenance of ΔDAS28 ≥1.2 NI margin: 0.6	72	CZP 200 mg Q2W+csDMARD (continuation)	43	72%	UL 90% CI: 19.1%; one-sided 0.402 (NI not met)
Pope 202045	High	DAS28 LDA+maintenance of ΔDAS28 ≥1.2 NI margin: 0.6	72	CZP 200 mg Q2W monotherapy (csDMARD stopping)	45	69%	UL 90% CI: 19.1%; one-sided 0.402 (NI not met)
Cohen 2019 (ORAL Shift)46	Low	LSM ΔDAS28-4-ESR NI margin: 0.6	24–48	TOFA 11 mg MR OD+MTX (continuation)	266	0.0	95% CI: 0.12 to 0.48 (NI met)
Cohen 2019 (ORAL Shift)46	Low	LSM ΔDAS28-4-ESR NI margin: 0.6	24–48	TOFA 11 mg MR+PBO (MTX stopping)	264	0.3	95% CI: 0.12 to 0.48 (NI met)
Lillegraven 2021 (ARCTIC REWIND)44	High	Flare (DAS44>1.6 + ∆DAS44>0.6 + SJ≥2) NI margin 20%	52	csDMARD continuation	78	6%	RD 19%; 95% CI: 8% to 30% (NI not met)
Lillegraven 2021 (ARCTIC REWIND)44	High	Flare (DAS44>1.6 + ∆DAS44>0.6 + SJ≥2) NI margin 20%	52	csDMARD 50% dosage reduction	78	26%	RD 19%; 95% CI: 8% to 30% (NI not met)
bDMARD dose reduction and/or stopping with ongoing csDMARD therapy
Bertrand 2021 (TapERA)47	High	Sustained DAS28-ESR<2.6 NI margin: 10%	24	ETA 50 mg QW (continuation)±csDMARD	34	76%	−5% to 41% (NI not met, margin 10%)
Bertrand 2021 (TapERA)47	High	Sustained DAS28-ESR<2.6 NI margin: 10%		ETA 50 mg EOW (interval increase) ± csDMARD	32	59%	−5% to 41% (NI not met, margin 10%)
Sanmarti 2019 (ToSpace)48	High	Sustained DAS28-ESR<2.6	48	TCZ 162 mg QW (continuation)±csDMARD	89	90%	0.004
Sanmarti 2019 (ToSpace)48	High	Sustained DAS28-ESR<2.6	48	TCZ 162 mg Q2W (interval increase) ± csDMARD	90	73%	Reference
Verhoef 2019 (REDO)49	Low	ΔDAS28-CRP NI margin: 0.6	24	RTX 1000mg±csDMARD (continuation)	28	−0.35	Reference
				RTX 500 mg (dose reduction) ± csDMARD	58	0.05	0.29 95% CI: −0.08 to 0.65 NI not met
				RTX 200 mg (dose reduction) ± csDMARD	54	−0.38	−0.02 95% CI: −0.39 to 0.35
Lillegraven EULAR 2020 (ARCTIC REWIND)50	Conference abstract	Flare (DAS44>1.6 + ∆DAS44>0.6 + SJ≥2) NI margin: 20%	52	TNFi (continuation)+csDMARD	41	4.9%	RD 57.9% to 95% CI: 42.0 to 73.8 NI not met
Lillegraven EULAR 2020 (ARCTIC REWIND)50	Conference abstract	Flare (DAS44>1.6 + ∆DAS44>0.6 + SJ≥2) NI margin: 20%	52	TNFi (dose reduction+withdrawal) + csDMARD	43	62.8%	RD 57.9% to 95% CI: 42.0 to 73.8 NI not met
Emery 2020 (PREDICTRA)51	Low	Flare rate (DAS28-ESR≥2.6)	40	ADA 40 mg Q3W (interval increase) ± csDMARDs	102	36%	NR
Emery 2020 (PREDICTRA)51	Low	Flare rate (DAS28-ESR≥2.6)	40	PBO (stopping)±csDMARDs	20	45%	NR
Tanaka 2020 (RRRR)52	High	Sustained treatment discontinuation	54	INF 3 mg/kg Q8W (stopping)+MTX	167	22%	RD 2.2% 95% CI: -6.6% to 11.0% p=0.631
Tanaka 2020 (RRRR)52	High	Sustained treatment discontinuation	54	INF TDM Q8W (stopping)+MTX	170	24%	RD 2.2% 95% CI: -6.6% to 11.0% p=0.631
Tapering and stopping of csDMARDs or bDMARDs
Curtis 2021 (SEAM-RA)57	Low	Flare rate (SDAI>3.3 or SDAI score of>11 at any time)	48	ETA 50 mg QW+MTX (combination continuation)	51	52.9%	0.006
				ETA 50 mg QW monotherapy+MTX withdrawal	101	49.5%	0.004
				MTX monotherapy+ETA withdrawal	101	28.7%	Reference
Van Mulligen 2019 (TARA)54	High	% of flares (DAS>2.4 and/or SJC>1)	0–52	csDMARD withdrawal	94	33%	24% to 43% Reference
Van Mulligen 2019 (TARA)54	High	% of flares (DAS>2.4 and/or SJC>1)	0–52	TNFi withdrawal	95	43%	33% to 53% p=0.17
Van Mulligen 2020 (TARA)55	High	% of flares (DAS>2.4 and/or SJC>1)	52–104	csDMARD tapering (first year) + TNFi continuation+tapering (second year)	94	61%	50% to 71% Reference
Van Mulligen 2020 (TARA)55	High	% of flares (DAS>2.4 and/or SJC>1)	52–104	TNFi tapering (first yr) + csDMARD continuation+tapering (second yr)	95	62%	52% to 72% p=0.84
Emery ACR 2019 (AVERT-2)54	Conference abstract	% of patients with SDAI≤3.3	48	ABA 125 mg QW+MTX (continuation)	50	74%	NR
				ABA 125 mg Q2W+MTX ->PBO (ABA withdrawal) + MTX	50	46%	NR
				ABA 125mg+PBO (MTX withdrawal)	47	57%	NR
Tascilar 2021 (RETRO)59	High	Relapse-free remission (DAS28-ESR<2.6)	52	Continue DMARDs	93	81%	Reference
				Taper DMARDs	93	57%	HR 3.02 (95% CI: 1.69 to 5.4)
				Stop DMARDs	96	43%	HR 4.34 (95% CI: 2.48 to 7.6)

ABA, abatacept; ADA, adalimumab; bDMARD, biological DMARD; csDMARD, conventional synthetic disease-modifying antirheumatic drug; CZP, certolizumab-pegol; DAS, Disease Activity Score; ESR, erythrocyte sedimentation rate; ETA, etanercept; INF, infliximab; LSM, least squares mean; MR, modified-release; NI, non-inferiority; NR, not reported; OD, once daily; PBO, placebo; QW, every week; Q2W, every 2 weeks; RD, risk difference; RD, risk difference; RoB, risk of bias; RTX, rituximab; SDAI, Simplified Disease Activity Index; SJC, swollen joint count; TCZ, tocilizumab; TDM, therapeutic drug monitoring; TNFi, tumour necrosis factor alpha inhibitor; TOFA, tofacitinib; UL, upper confidence limit; Δ, change from baseline.