Efficacy and safety of adalimumab in comparison to infliximab for Crohn's disease: A systematic review and meta-analysis

Table 1 Characteristics of selected studies

Ref.	Study design	Patientinclusion criteria	ADA/IFX, n	Definition of remission	Definition of secondary loss of response	Induction of response/remission in wk	Maintenance of response/remission in wk	Adverse events	NOS
Zorzi et al[6], 2012	Retrospective	Active CD	49/44	CDAI < 150	No improvement or worsening	4/6	54	Multiple	6
Kestens et al[4], 2013	Retrospective	Naïve CD	100/100	NS	NS	NS	54	Multiple	9
Ma et al[17], 2014	Retrospective	Naïve CD	101/117	NS	Requiring dose escalation	NS	NS	NS	8
Tursi et al[15], 2014	Retrospective	CD	67/59	HBI ≤ 5	NS	6-14	NS	Multiple	8
Cosnes et al[12], 2016	Prospective	Naïve CD	264/127	CDAI < 150	Disease activity	NS	26	Multiple	8
Varma et al[8], 2016	Retrospective	Naïve CD	18/63	CDAI < 150	NS	12	48	Multiple	7
Narula et al[9], 2016	Prospective	Naïve CD	111/251	HBI < 5	Dose escalation	12	48	Multiple	8
Bau et al[14], 2017	Retrospective	Refractory CD	62/68	NS	NS	NS	168	Multiple	5
Otake et al[5], 2017	Retrospective	CD	29/39	CDAI < 150	Multiple	NS	54	NS	8
Doecke et al[16], 2017	Retrospective	CD	144/183	CDAI ≤ 150	NS	14	NS	NS	7
Benmassaoud et al[7], 2018	Retrospective	Naïve CD	77/143	HBI ≤ 4	Need for dose escalation	12	48	Multiple	8
Di Domenicantonio et al[13], 2018	Retrospective	Naïve CD	505/367	NS	NS	NS	NS	Multiple	9
Macaluso et al[10], 2019	Retrospective	Naïve and non-naïve CD	Naïve: 214/107; non-naïve: 47/47	NS	NS	12	48	Multiple	9
Kaniewska et al[11], 2019	Retrospective	CD	95/82	CDAI < 150	NS	NS	48	Multiple	7

CD: Crohn's disease; ADA: Adalimumab; IFX: Infliximab; CDAI: Crohn's disease activity index; HBI: Harvey Bradshaw Index; NOS: Newcastle-Ottawa Quality Assessment Scale; NS: Not stated.

Table 2 Subgroup analysis

Outcomes of interest	Subgroup analysis
	Grouping criteria	Categories	Studies, n	Patients, n	OR	95%CI	I2, %	P value
Induction of response	Anti-TNF naivety	Naïve	3	727	1.17	(0.80-1.70)	0	0.41
		Non-naïve	3	313	1.44	(0.55-3.78)	47	0.46
	Use optimization	Yes	5	1040	1.27	(0.93-1.74)	0	0.14
		No	0	0	-	-	-	-
Induction of remission	Anti-TNF naivety	Naïve	2	392	1.08	(0.68-0.72)	0	0.75
		Non-naïve	2	420	1.15	(0.67-1.96)	0	0.62
	Use optimization	Yes	3	731	1.08	(0.76-1.55)	0	0.66
		No	1	81	1.69	(0.34-8.44)	-	0.52
Maintenance of response	Anti-TNF naivety	Naïve	5	1468	1.08	(0.72-1.62)	63	0.71
		Non-naïve	3	354	1.10	(0.64-1.90)	0	0.73
	Use optimization	Yes	6	1645	1.12	(0.77-1.63)	62	0.57
		No	1	177	0.64	(0.18-2.29)	-	0.50
Maintenance of remission	Anti-TNF naivety	Naïve	3	442	1.39	(0.92-2.11)	0	0.12
		Non-naïve	3	328	1.24	(0.56-2.72)	53	0.59
	Use optimization	Yes	3	458	1.41	(0.95-2.09)	0	0.09
		No	3	312	1.18	(0.46-2.99)	55	0.73
Secondary loss of response	Anti-TNF naivety	Naïve	3	353	1.09	(0.54-2.18)	42	0.81
		Non-naïve	3	947	0.91	(0.46-1.80)	72	0.78
	Use optimization	Yes	5	1247	1.07	(0.69-1.67)	56	0.75
		No	1	53	0.48	(0.13-1.68)	54	0.99
Overall adverse events	Anti-TNF naivety	Naïve	5	1184	0.67	(0.50-0.89)	1	0.005
		Non-naïve	4	469	0.41	(0.31-1.31)	79	0.13
	Assessment time	≤ 48 wk	6	1323	0.50	(0.33-0.76)	41	0.001
		> 48 wk	2	330	1.00	(0.62-1.60)	0	0.98
Severe adverse events	Anti-TNF naivety	Naïve	3	1021	0.88	(0.40-1.92)	73	0.74
		Non-naïve	4	526	0.45	(0.03-6.51)	81	0.56
	Assessment time	≤ 48 wk	4	746	1.32	(0.80-2.19)	0	0.28
		> 48 wk	3	801	0.52	(0.09-3.05)	80	0.47
Opportunistic infections	Anti-TNF naivety	Naïve	4	1654	0.78	(0.54-1.14)	0	0.21
		Non-naïve	2	256	1.88	(0.93-3.82)	0	0.08
	Assessment time	≤ 48 wk	3	782	0.85	(0.56-1.28)	0	0.43
		> 48 wk	3	1128	1.12	(0.38-3.24)	57	0.84

anti-TNF: Anti-tumor necrosis factor; OR: Odds ratio; CI: Confidence interval.

Table 3 GRADE evidence profile

Quality assessment-No. of studies	Quality assessment-study design	Quality assessment-risk of bias	Quality assessment-inconsistency	Quality assessment-indirectness	Quality assessment-imprecision	Quality assessment-Publication bias	Summary of findings-number of patient, with IFX	Summary of findings-number of patient, with ADA	Summary of findings-effect, relative (95%CI)	Summary of findings-effect, absolute (95%CI)	Summary of findings-effect, Quality
Induction of response
5	Observational study	Not serious	Not serious	Not serious	Not serious	Not found	403/525	417/515	OR: 1.27 (0.93-1.74)	768 per 1000	⨁⨁◯◯
Induction of remission
4	Observational study	Not serious	Not serious	Not serious	Not serious	Not found	368/494	244/318	OR: 1.11 (0.78-1.57)	745 per 1000	⨁⨁◯◯
Maintenance of response
7	Observational study	Not serious	Not serious	Not serious	Not serious	Not found	611/896	639/932	OR: 1.02 (0.83-1.25)	682 per 1000	⨁⨁◯◯
Maintenance of remission
6	Observational study	Not serious	Not serious	Not serious	Not serious	Not found	255/442	219/328	OR: 1.26 (0.87-1.82)	577 per 1000	⨁⨁◯◯
Secondary loss of response
6	Observational study	Not serious	Not serious	Not serious	Not serious	Not found	191/704	172/603	OR: 1.01 (0.65-1.55)	271 per 1000	⨁⨁◯◯
Overall adverse events
8	Observational study	Not serious	Not serious	Not serious	Not serious	Not found	364/900	205/753	OR: 0.62 (0.42-0.91)	404 per 1000	⨁⨁◯◯
Severe adverse events
7	Observational study	Not serious	Not serious	Not serious	Not serious	Not found	139/859	80/688	OR: 0.75 (0.32-1.72)	162 per 1000	⨁⨁◯◯
Opportunistic infection
6	Observational study	Not serious	Not serious	Not serious	Not serious	Not found	144/988	85/922	OR: 0.96 (0.66-1.40)	146 per 1000	⨁⨁◯◯

GRADE Working Group grades of evidence: High quality (⨁⨁⨁⨁): Further research is unlikely to change our confidence in the estimate of effect; Moderate quality (⨁⨁⨁◯): Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; Low quality (⨁⨁◯◯): Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; Very low quality (⨁◯◯◯): We are very uncertain about the estimate. ADA: Adalimumab; IFX: Infliximab; OR: Odds ratio; CI: Confidence interval.