Is tumor necrosis factor-α monoclonal therapy with proactive therapeutic drug monitoring optimized for inflammatory bowel disease? Network meta-analysis

Table 1 Summary baseline characteristics

Disease type	Study type	Comparison	Anti-TNF-α monoclonal antibody type	Ref.
IBD	RCT	Proactive vs empiric	IFX	Vande Casteele et al[21]
	Observational study	Proactive vs empiric	IFX	Sánchez-Hernández et al[22]
				Lee et al[25]
				Guidi et al[29]
				Kelly et al[30]
				Bossuyt et al[31]
			IFX + ADA	Ponte et al[23]
			ADA	Papamichael et al[28]
				Capoulas et al[27]
		Proactive vs reactive	ADA	Papamichael et al[26]
			IFX	Papamichael et al[28]
UC only	Observational study	Proactive vs empiric	IFX	Fernandes et al[24]
	RCT	Proactive vs empiric	ADA	Panés et al[33]
CD only	Observational study	Proactive vs empiric	IFX	Fernandes et al[24]
	RCT	Proactive vs reactive	ADA	D'Haens et al[32]
	RCT	Proactive vs empiric	ADA	Panés et al[33]
Baseline indicator		OR1/SMD2 (95%CI)	P, I2	Balanced or not
Male sex, n (%)		1.106 (0.936, 1.307)1	0.283, 16.9	Yes
CD, n (%)		1.114 (0.872, 1.422)1	0.299, 16.6	Yes
Age, yr, median (%)		-0.042 (-0.432, 0.348)2	0.000, 96.23	Yes
Baseline remission, n (%)		1.263 (0.780, 2.046)1	0.406, 0.0	Yes
Active smoker, n (%)		0.974 (0.633, 1.499)1	0.141, 45.1	Yes
Duration of disease, y, median (%)		-0.034 (-0.216, 0.148)2	0.003, 72.33	Yes
Prior surgery, n (%)		1.075 (0.690, 1.675)1	0.923, 0.0	Yes
CRP concentration (mg/L) (%)		0.463 (-0.171, 1.097)1	0.000, 98.23	Yes

¹Odds ratio.

²Standardized mean difference.

³Substantial heterogeneity.

TNF-α: Tumor necrosis factor-α; ADA: Adalimumab; CD: Crohn's disease; RCT: Randomized controlled trial; IBD: Inflammatory bowel disease; IFX: Infliximab; UC: Ulcerative colitis.

Table 2 Sub-analyzed outcomes of proactive therapeutic drug monitoring vs conventional management in inflammatory bowel disease

	Outcome type	Subgroup type	Study (n)	OR (95%CI)	P, I2 (heterogeneity)	P value from meta-regression	Publication bias (Begg’s, Egger’s)	Grade
Efficacy outcome	Clinical remission	Total (%)	10	1.281 (0.972, 1.688)	0.002, 65.92		0.194, 0.0004	Moderate
		Disease type
		IBD (%)	5	0.887 (0.671, 1.174)	0.390, 2.8	0.0283	0.050, 0.0904	Moderate
		UC (%)	3	1.563 (1.063, 2.298)1	0.058, 64.82		0.602, 0.112	Low
		CD (%)	2	2.412 (0.889, 6.544)	0.032, 78.12		0.317, -	Low
		Study type
		RCT	4	1.393 (1.182, 1.641)1	0.771, 0.0	0.861	0.497, 0.467	High
		Observational (%)	6	1.305 (0.691, 2.464)	0.000, 78.82		0.851, 0.376	Moderate
		Comparison
		Proactive vs empiric (%)	8	1.330 (0.959, 1.843)	0.003, 68.22	0.746	0.805, 0.755	Moderate
		Proactive vs reactive (%)	2	1.074 (0.461, 2.501)	0.036, 77.22		0.317, -	Low
		Monoclonal type
		IFX (%)	6	1.368 (0.724, 2.585)	0.000, 77.72	0.954	0.851, 0.390	Moderate
		ADA (%)	3	1.416 (1.196, 1.676)1	0.793, 0.0		0.602, 0.404	Low
	Need of surgery (all observational)	Total (%)	9	0.525 (0.243, 1.130)	0.001, 71.32
		Disease type
		IBD (%)	7	0.354 (0.155, 0.804)1	0.007, 66.02	0.140	0.548, 0.556	Moderate
		Comparison
		Proactive vs empiric (%)	7	0.694 (0.282, 1.707)	0.002, 72.12	0.353	0.293,0.993	Moderate
		Proactive vs reactive (%)	2	0.237 (0.101, 0.558)1	0.302, 6.2		0.317, -	Low
		Monoclonal type
		IFX (%)	6	0.571 (0.233, 1.402)	0.001, 75.32	0.672	0.851, 0.841	Moderate
		IFX + ADA (%)	2	0.137 (0.032, 0.588)1	0.563, 0.0		0.317, -	Low
	Treatment discontinuation (all observational)	Total (%)	7	0.395 (0.130, 1.205)	0.000, 85.72		0.812, 0.677	Moderate
		Disease type
		IBD	5	0.377 (0.078, 1.831)	0.000, 90.02	0.793	0.806, 0.998	Moderate
		Comparison
		Proactive vs empiric (%)	5	0.494 (0.196, 1.248)	0.046, 58.82	0.412	0.462,0.045	Moderate
		Proactive vs reactive (%)	2	0.394 (0.018, 8.742)	0.000, 94.92		0.317, -	Low
		Monoclonal type
		IFX (%)	5	0.494 (0.142, 1.715)	0.000, 90.02	0.938	0.624, 0.705	Moderate
		ADA (%)	2	0.125 (0.015, 1.027)	0.808, 0.0		0.317, -	Low
	Endoscopic remission	Total (%)	4	1.435 (1.089, 1.890)1	0.169, 40.4		0.089, 0.093	Moderate
	Clinical relapse	Total (%)	2	0.513 (0.294, 0.895)1	0.294, 9.2		1.000, -	Low
	Anti-drug antibodies	Total (%)	2	0.234 (0.116, 0.474)	0.703, 0.0		0.317, -	Low
Safety	Adverse events	Total (%)	10	0.579 (0.391, 0.858)1	0.001, 67.22		0.586, 0.377	Moderate
		Disease type
		IBD (%)	6	0.301 (0.157, 0.576)1	0.649, 0.0	0.0403	0.348, 0.427	High
		UC (%)	2	0.987 (0.817, 1.193)	0.732, 0.0		0.317, -	Low
		CD (%)	2	0.427 (0.107, 1.711)	0.002, 89.42		0.317, -	Very low
		Study type
		RCT (%)	4	0.951 (0.804, 1.124)	0.839, 0.0	0.0113	0.174, 0.753	High
		Observational (%)	6	0.246 (0.146, 0.413)1	0.698, 0.0		0.348, 0.477	High
		Comparison
		Proactive vs empiric (%)	7	0.577 (0.346, 0.964)1	0.002, 72.0	0.872	0.453, 0.113	High
		Proactive vs reactive (%)	3	0.464 (0.175, 1.235)	0.084, 59.7		0.602, 0.253	Moderate
		Monoclonal type
		IFX (%)	5	0.264 (0.153, 0.455)	0.428, 0.0	0.0213	0.142, 0.108	High
		ADA (%)	5	0.923 (0.760, 1.120)	0.323, 14.3		0.050, 0.0084	High
	Acute infusion reactions	Total (%)	4	0.572 (0.235, 1.390)	0.163, 41.4		0.308, 0.168	Moderate
	Delayed hypersensitivity	Total (%)	2	0.719 (0.017, 29.584)	0.079, 67.7		1.000, -	Moderate

¹Signicicant differences.

²Substantial heterogeneity.

³Source of heterogeneity.

⁴Existence of publication bias.

ADA: Adalimumab; CD: Crohn's disease; RCT: Randomized controlled trial; IBD: Inflammatory bowel disease; TDM: Therapeutic drug monitoring; IFX: Infliximab; UC: Ulcerative colitis.