Table 2

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

Population	Study	Risk of bias	Treatment	n	Week	Primary endpoint	Outcome	P value
bDMARD treatment versus placebo
MTX-IR	Nasonov 2021 (CREDO 1)15	Low	Placebo+MTX	143	12	ACR20	34.3 (49)	Ref.
			OKZ 64 mg Q2W+MTX	143			98 (68.5)	<0.001
			OKZ 64 mg Q4W+MTX	142			101 (71.1)	<0.001
MTX-IR	Mazurov EULAR 2021 (SOLAR)19	Conference abstract	Placebo+MTX	50	12	ACR20	20 (40)	Ref.
MTX-IR	Mazurov EULAR 2021 (SOLAR)19	Conference abstract	LEV 162 mg QW+MTX	99	12	ACR20	70 (71)	<0.001
csDMARD-IR	Liang 202013	High	Placebo+csDMARD	33	24	ACR20	10 (30.3)	Ref.
csDMARD-IR	Liang 202013	High	OPI 25 mg QW+csDMARD	64	24	ACR20	49 (76.6)	<0.001
LEF-IR	Behrens 2021 (AMARA)14	Low	Placebo+LEF	47	24	ACR50	7 (14.9)	Ref.
LEF-IR	Behrens 2021 (AMARA)14	Low	RTX 1000 mg (d1, d15) + LEF	93	24	ACR50	25 (26.9)	0.081
TNF-IR	Feist ACR 2021 / Feist 2022 (CREDO 3)16 17	Low	Placebo+MTX	69	12	ACR20	28 (40.6)	Ref.
			OKZ Q2W+MTX	138			84 (60.9)	0.003
			OKZ Q4W+MTX	161			96 (59.6)	0.004
tsDMARD treatment versus placebo
MTX naïve early RA	Van Vollenhoven 2020 (SELECT EARLY)24 25	Low	MTX	314	12 24	ACR50 DAS28-CRP<2.6	88 (28) 60 (19)	Ref.
			UPA 15 mg OD	317			165 (52) 152 (48)	<0.001 <0.001
			UPA 30 mg OD	314			176 (56) 157 (50)	<0.001 <0.001
MTX naïve early RA	Westhovens 2021 (FINCH 3)28	Low	Placebo+MTX	416	24	ACR20	297 (71.4)	Ref.
			FIL 200 mg OD+MTX	416			337 (81)	<0.001
			FIL 100 mg OD+MTX	207			166 (80.2)	0.017
			FIL 200 mg OD+Placebo	210			164 (78.1)	0.058
MTX-IR	Li 2020 (RA-BALANCE)22 23	Unclear	Placebo+MTX	145	12	ACR20	47 (32.4)	Ref.
MTX-IR	Li 2020 (RA-BALANCE)22 23	Unclear	BARI 4 mg OD+MTX	145	12	ACR20	93 (64.1)	<0.001
csDMARD-IR	Kameda 2020 (SELECT SUNRISE)26	Low	Placebo+csDMARD	49	12	ACR20	21 (42.9)	Ref.
			UPA 7.5 mg OD+csDMARD	49			37 (75.5)	<0.001
			UPA 15 mg OD+csDMARD	49			41 (83.7)	<0.001
			UPA 30 mg OD+csDMARD	50			40 (80)	<0.001
bDMARD-IR	Genovese 2019 (FINCH 2)27	Low	Placebo+csDMARD	148	12	ACR20	46 (31.1)	Ref.
			FIL 100 mg OD+csDMARD	153			88 (57.5)	<0.001
			FIL 200 mg OD+csDMARD	147			97 (66)	<0.001
RANKL inhibition versus placebo
≥ 1 erosion+elevated CRP/ESR+RF/ACPA positive	Takeuchi 2019 (DESIRABLE)20	Low	Placebo+csDMARD	211	48	ΔmTSS	1.49	Ref.
			DEM 60 mg Q3M+csDMARD	205			0.72	0.006
			DEM 60 mg Q6M+csDMARD	201			0.99	0.024
DAS28-CRP ≤5.1 + 1 erosion in HR-pQCT	So 202121	Low	Placebo+csDMARD	55	48	Healing of erosions in HR-pQCT	13%	Ref.
DAS28-CRP ≤5.1 + 1 erosion in HR-pQCT	So 202121	Low	DEM 60 mg Q6M+csDMARD	55	48	Healing of erosions in HR-pQCT	18%	0.45

ACPA, anti-citrullinated protein antibodies; ACR, American College of Rheumatology; b, biologic; BARI, baricitinib; CRP, C reactive protein; cs, conventional synthetic; d, day; DAS, Disease Activity Score; DMARD, disease-modifying antirheumatic drug; ESR, erythrocyte sedimentation rate; HR-pQCT, high-resolution peripheral quantitatice CT; IR, insufficient response; LEF, leflunomide; LEV, levilimab; mTSS, modified total Sharp Score; MTX, methotrexate; OD, once daily; OKZ, olokizumab; OPI, opineracept; PBO, placebo; Q3M, every 3 months; Q6M, every 6 months; QW, weekly; Q2W, every 2 weeks; RANKL, receptor activator of nuclear factor kappa-Β ligand; Ref, Reference; RF, rheumatoid factor; RTX, rituximab; TNF, tumour necrosis factor alpha; ts, targeted synthetic; UPA, upadacitinib; Δ, change from baseline.