Predictive value of blood concentration of biologics on endoscopic inactivity in inflammatory bowel disease: A systematic review

Table 5 Correlation between endoscopic outcome and biologic blood concentration

Ref.	Patients	Definition of primary endpoint	Biology	Cut-off value	Clinical outcome (Yes/Not)	SE	SP	PPV	NPV	AUC
Chaparro et al[12], 2018	IBD	Mucosal healing: (1) CD: SES-CD < 3; (2) UC: MES ≤ 1; and (3) CD in Postoperative setting: Rutgeerts < 2	ADA	7.2 μg/mL (TL)	Mucosal healing (35/59)	0.65	0.56	0.46	0.72	0.60
			IFX	3.4 μg/mL (TL)	Mucosal healing (58/30)	0.60	0.60	0.73	0.42	0.63
Ungar et al[28], 2016	IBD	Mucosal healing: (1) CD: SES-CD < 3; (2) UC: MES ≤ 1	ADA	7.1 μg/mL (SL)	Mucosal healing	0.32	0.85	0.51	0.72	0.70
			IFX	6 μg/mL (SL)	Mucosal healing	0.39	0.85	0.70	0.62	0.75
Yarur et al[29], 2016	IBD	Mucosal healing: Lack of any inflammatory findings in the intestinal mucosa	ADA	7.8 μg/mL (SL)	Mucosal healing (19/47)	0.61	0.95			0.76
		Histological healing: Lack of histologic inflammation on biopsies obtained during colonoscopy	ADA	7.5 μg/mL (SL)	Histological healing (20/46)	0.62	0.83			0.73
Roblin et al[26], 2014	IBD	Mucosal healing: (1) CD: Disappearance of all ulcerations; (2) UC: MES < 2	ADA	4.9 μg/mL (TL)	Absence of mucosal healing (16/24)	0.66	0.85	0.88	0.51	0.77
Morita et al[18], 2016	UC	Mucosal healing: UCEIS: The bleeding descriptor and the erosions and ulcers descriptor were both 0, and the vascular pattern descriptor was 0 or 1	ADA	10.3 μg/mL (TL)	Mucosal healing (Absence)	0.82	0.80			0.87
			IFX	2.7 μg/mL (TL)	Mucosal healing (11/20)	0.83	0.89			0.93
Morita et al[19], 2016	CD	Mucosal healing: Endoscopic score based on the modified Rutgeerts’ scoring system: 0 (No lesions or scar) or 1 (≤ 5 apthous lesions)	ADA	7.90 μg/mL (TL)	Mucosal healing (14/28)	0.69	0.86			0.79
Strik et al[27], 2019	PfCD	Fistula closure: Absence of active drainage at gentle finger compression and/or fistula healing on magnetic resonance imaging	ADA	5.9 μg/mL (SL)	Fistula closure (13/6)					0.89
			IFX	5.0 μg/mL (TL)	Fistula closure (32/15)					0.92
Plevris et al[24], 2020	PfCD	Perianal fistula healing: No spontaneous discharge or no discharge on palpation in the absence of seton drainage; Perianal fistula closure: Absence of an external skin opening	ADA	9.8 μg/mL (TL)	Fistula closure (15/20)	0.93	0.75			0.86
			ADA	6.8 μg/mL (TL)	Fistula healing (21/14)	1.00	0.79			0.90
			IFX	7.1 μg/mL (TL)	Fistula healing (18/11)	0.78	1.00			0.93
			IFX	7.1 μg/mL (TL)	Fistula closure (13/16)	0.64	1.00			0.97
Zittan et al[30], 2016	CD	Mucosal healing: Absence of any ulceration in all ileocolonic segments	ADA	8.14 μg/mL (TL)	Mucosal healing (35/25)	0.91	0.76	0.84	0.86
Juncadella et al[16], 2018	CD	Endoscopic remission: Absence of a mucosal break for CD, a Rutgeerts score of ≤ 1 for CD with ileocolonic resection, a Mayo endoscopic score of ≤ 1 for UC. Histological healing: Absence of any sign of active inflammation including erosions, abscesses, or neutrophil infiltration	ADA	12 μg/mL (SL)	Endoscopic remission (20/25)	0.80	0.68
			ADA	12.2 μg/mL (SL)	Histological healing (13/28)	0.57	0.85
	UC		ADA	16.2 μg/mL (SL)	Endoscopic remission (7/20)	0.85	0.61
			ADA	16.2 μg/ mL (SL)	Histological healing (3/23)	1.00	0.83
Papamichael et al[23], 2016	UC	Short term mucosal healing: (1) MES ≤ 1 at weeks 10-14; (2) MES ≥ 2 at baseline	IFX	15 μg/mL week 6 (SL)	STMH at weeks 10-14 (54/47)	0.60	0.74	0.73	0.62	0.64
			IFX	2.1 μg/mL week 14 (SL)		0.84	0.62	0.78	0.71	0.64
Papamichael et al[20], 2017	UC	Short term mucosal healing: (1) MES ≤ 1 at weeks 8-14; (2) MES ≥ 2 at baseline	ADA	9.4 μg/ mL week 4 (SL)	STMH at weeks 8-14 (12/31)	0.67	0.77	0.50	0.87
			ADA	7.5 μg/mL week 4 (SL)	STMH at weeks 8-14	0.89	0.59	0.47	0.93
Papamichael et al[22], 2018	UC	Endoscopic healing: a Mayo endoscopic sub-score of ≤ 1. Histological healing: No or only focal mild active inflammation	IFX	7.5 μg/mL (TL)	Endoscopic healing (31/39)	0.77	0.62	0.62	0.77
			IFX	10.5 μg/mL (TL)	Histological healing (28/41)	0.54	0.78	0.63	0.71
Papamichael et al[21], 2018	CD	Endoscopic remission: Absence of any mucosal break, a Rutgeerts score of ≤ 1 for CD with ileocolonic resection. Histologic remission: Absence of active inflammation	IFX	9.7 μg/mL (SL)	Endoscopic remission (62/34)	0.57	0.73	0.80	0.48
			IFX	9.8 μg/ mL (SL)	Histological remission (43/44)	0.63	0.66	0.64	0.64
Feng et al[14], 2019	CD	Mucosal healing: Complete absence of any sign of ulceration	IFX	4.85 μg/mL week 14 (SL)	Mucosal healing (82/59)	0.67	0.80			0.80
			IFX	2.85 μg/mL week 30 (SL)	Mucosal healing (59/50)	0.73	0.84			0.78
Dreesen et al[31], 2020	CD	Endoscopic remission: (1) CDEIS < 3 at weeks 12 and 54; (2) Absence of ulceration at weeks 12 and 54	IFX	23.1 mg/L week 2 (TL)	Endoscopic remission at week 12 (54/42)	0.56	0.80	0.72	0.65	0.67
			IFX	10.0 mg/L week 6 (TL)	Endoscopic Remission at week 12 (37/65)	0.37	0.89	0.76	0.59	0.64
			IFX	10.6 mg/L week 54 (TL)	Absence of ulceration at week 54 (59/24)	0.94	0.42	0.49	0.92	0.71
Imaeda et al[15], 2014	CD	Mucosal healing: Endoscopic score based on the modified Rutgeerts’ scoring system: 0 (No lesions or scar) or 1 (≤ 5 apthous lesions)	IFX	4.0 μg/mL (TL)	Mucosal healing (20/58)	0.71	0.70			0.63
EI-Matary et al[32], 2019	PfCD	Healing perianal fistula: Decrease or cessation of fistula drainage, as reported by patients and confirmed by treating physicians; Healed fistula: Closure of a previously identified fistula opening, as reported by treating physicians	IFX	12.7 μg/mL (TL)	Fistula healing (14/13)	0.62	0.65			0.80
Kang et al[17], 2019	PCD	Mucosal healing: SES-CD 0	IFX	4.2 μg/mL (TL)	Mucosal healing	0.65	0.70	0.67	0.68	0.68
		Partial mucosal healing: SES-CD < 3	IFX	3.7 μg/mL (TL)	Partial mucosal healing	0.70	0.71	0.79	0.61	0.73
Hanzel et al[33], 2019	IBD	Endoscopic remission: (1) CD: SES-CD ≤ 4; (2) UC: MES ≤ 1; Clinical remission: (1) CD: mean daily stool frequency of ≤ 1.5, abdominal pain ≤ 1; (2) UC: a rectal bleeding score of 0, a stool frequency score of ≤ 1	VDZ	22.0 μg/ mL week 6 (TL)	Combined Remission (Endoscopic Remission AND Clinical Remission) within the first year of treatment (16/35)	0.77	0.73	0.72	0.88	0.73
			VDZ	8.0 μg/ mL week 22 (TL)		0.79	0.75	0.65	0.86	0.82
Dreesen et al[13], 2018	UC	Mucosal healing: MES ≤ 1	VDZ	28.9 μg/ mL week 2 (TL)	Mucosal healing at week 14 (32/22)	0.73	0.62	0.59	0.75	0.70
			VDZ	13.9 μg/mL week 14 (TL)	Mucosal Healing at week 14 (32/22)	0.85	0.54	0.48	0.88	0.72
	CD	Mucosal healing: Complete absence of ulcerations	VDZ	13.6 μg/mL week 22 (TL)	Mucosal healing at week 22 (10/33)	0.69	0.71	0.83	0.52	0.70
Pouillon et al[25], 2019	UC	Histological healing: Nancy Histological Index ≤ 1	VDZ	25.0 μg/mL (TL)	Histological healing (18/17)	0.77	0.71	0.74	0.75	0.75
Yacoub et al[34], 2018	CD	Mucosal healing: (1) Absence of any ulcerations during endoscopy; (2) The absence of significant intestinal inflammation on MRI	VDZ	18.0 μg/mL week 6 (TL)	Mucosal healing within the first year of treatment (18/21)	0.80	0.63	0.73	0.71	0.70
	UC	Mucosal healing: (1) MES ≤ 1; (2) The absence of significant intestinal inflammation on MRI	VDZ	18.0 μg/mL week 6 (TL)	Mucosal healing within the first year of treatment (24/19)	1.00	0.75	0.88	1.00	0.75

IBD: Inflammatory bowel disease; CD: Crohn’s disease; UC: Ulcerative colitis; PCD: pediatric Crohn’s disease; IFX: Infliximab; ADA: Adalimumab; VDZ: Vedolizumab; SE: Sensitivity; SP: Specificity; PPV: Positive prospective value; NPV: Negative prospective value; AUC: Area under the curve; SL: Serum level; TL: Trough level.