Table 2

Primary efficacy outcomes of trials comparing biological DMARDs with or without background csDMARD therapy to placebo

Study	Risk of bias	Treatment	N	Time point (weeks)	Primary endpoint	Outcome	P value
Damjanov 201613	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
Mazurov 201814	Abstract	BCD-020 600 mg+MTX	107	24	ACR 20 (%)	66	<0.001
Fleischmann 2017 (TARGET)15	Low	Placebo +csDMARDs	181	12/24	ACR 20 (%) / ΔHAQ-DI	34/−0.3	Reference
		SLM 150 mg Q2W+csDMARDs	181			56/−0.5	<0.001
		SLM 200 mg Q2W+csDMARDs	184			61/−0.6	<0.001
Tanaka 2018b (KAKEHASI)16	Abstract	Placebo +MTX	82	24	ACR 20 (%)	15	Reference
		SLM 150 mg Q2W+MTX	81			68	<0.001
		SLM 200 mg Q2W+MTX	80			58	<0.001
Aletaha 2017 (SIRROUND-T)17 18	Low	Placebo±csDMARDs	294	16	ACR 20 (%)	24	Reference
		SKM 50 mg Q4W±csDMARDs	292			40	<0.001
		SKM 100 mg Q2W±csDMARDs	292			45	<0.001
Takeuchi 2017 (SIRROUND-D)19	Unclear	Placebo +csDMARD	556	16/52	ACR 20 (%)/ΔmTSS	26/1.96	Reference
		SKM 50 mg Q4W+csDMARD	557			55/0.35	<0.001
		SKM 100 mg Q2W+csDMARD	557			54/0.3	<0.001
Takeuchi 2016 (RA0083)20	Low	Placebo +MTX	29	12	ΔDAS28-CRP	−0.64	Reference
		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 comparison	78	NR
		VBM 150 mg Q4W	62			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 (EARTH EXPLORER 1)23	Low	Placebo +MTX	81	12/24	ACR 20 (%)/ΔDAS28-CRP	25/−0.68	Reference
		MVM 150 mg Q2W+MTX	79			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. Q4W±MTX	213			35	<0.001
		SEC 3×10 mg/kg i.v. Q2W/75 mg s.c. Q4W±MTX	210			35	<0.001
Mease 201827	Unclear	Placebo +MTX	51	16	ACR 20 (%)	41	Reference
		CNTO6785 15 mg Q4W+MTX	52			52	NS
		CNTO6785 50 mg Q4W+MTX	51			47	NS
		CNTO6785 100 mg Q4W+MTX	51			37	NS
		CNTO6785 200 mg Q4W+MTX	52			40	NS
Dokoupilova 2018 (REASSURE2)28	Unclear	Placebo +csDMARDs	81	24	ACR 20 (%)	27	Reference
		SEC 150 mg+csDMARDs	81			38	0.157
		SEC 75 mg+csDMARDs	80			38	0.200
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
Bi 2018 (RAPID-C)132	High	CZP +MTX	316	24	ACR 20 (%)	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	0.877
		GKM 50 mg Q8W+MTX	55			38	0.101
		GKM 200 mg Q8W+MTX	54			44	0.101

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.