Infliximab trough level combined with inflammatory biomarkers predict long-term endoscopic outcomes in Crohn’s disease under infliximab therapy

Table 1 Clinical characteristics of Crohn‘s disease patients with endoscopic remission

Variable	Week 14 (after initial IFX therapy)			Week 54 (after initial IFX therapy) n = 54
	Total, n = 93	ER at week 54, n = 67	EA at week 54, n = 26	Total, n = 54	ER at week 108, n = 42	EA at week 108, n = 12
Median age in yr, mean ± SD	28.96 ± 9.37	29.03 ± 10.09	28.77 ± 7.39	27.57 ± 10.13	26.93 ± 9.87	29.83 ± 11.13
Course in yr, median (IQR)	3.0 (1.0, 6.0)	2.0 (1.0, 6.0)	3.5 (2.0, 8.3)	2.0 (1.0, 5.0)	2.0 (1.0, 5.0)	2.0 (1.3, 8.5)
Male sex, n (%)	55 (59.1)	43 (64.2)	12 (46.2)	35 (64.8)	28 (66.7)	7 (58.3)
Disease location, n (%)
L1 (terminal ileum)	18 (19.4)	14 (20.9)	4 (15.4)	10 (18.5)	9 (21.4)	1 (8.3)
L2 (colon)	11 (11.8)	6 (9.0)	5 (19.2)	5 (9.3)	4 (9.5)	1 (8.3)
L3 (ileocolon)	64 (68.8)	47 (70.1)	17 (65.4)	39 (72.2)	29 (69.0)	10 (83.3)
L4 (upper digestive tract)	22 (23.7)	15 (22.4)	7 (26.9)	14 (25.9)	11(26.2)	3 (25.0)
Disease behavior, n (%)
B1 (no)	19 (20.4)	15 (22.4)	4 (15.4)	13 (24.1)	9 (21.4)	4 (33.3)
B2 (stenosis)	11 (11.8)	9 (13.4)	2 (7.7)	6 (11.1)	5 (11.9)	1 (8.3)
B3 (penetration)	40 (43.0)	27 (40.3)	13 (50.0)	23 (42.6)	18 (42.9)	5 (41.7)
B2 (stenosis) + B3 (penetration)	23 (24.7)	16 (23.9)	7 (26.9)	12 (22.2)	10 (23.8)	2 (16.7)
Perianal diseases, n (%)	55 (59.1)	38 (56.7)	17 (65.4)	32 (59.3)	25 (59.5)	7 (58.3)
Previous medical therapy, n (%)	64 (68.8)	46 (68.7)	18 (69.2)	34 (63.0)	25 (59.5)	9 (75.0)
Previous surgical therapy, n (%)	15 (16.1)	11 (16.4)	4 (15.4)	8 (14.8)	8 (19.0)	0 (0.0)
Laboratory indicators, mean ± SD
Fecal calprotectin, μg/g	399.96 ± 562.47	178.62 ± 242.38	970.35 ± 734.49	353.17 ± 557.71	178.57 ± 276.56	964.25 ± 830.56
IFX trough level, μg/ml	6.12 ± 3.72	7.23 ± 3.48	3.25 ± 2.67	3.80 ± 2.25	4.37 ± 2.02	1.80 ± 1.90
White blood count, × 109/L	5.32 ± 1.87	5.16 ± 1.47	5.73 ± 2.65	5.27 ± 1.41	5.27 ± 1.43	5.28 ± 1.41
Hematoglobin, g/L	128.37 ± 20.42	130.96 ± 20.03	121.69 ± 20.27	136.59 ± 16.06	136.79 ± 16.94	135.92 ± 13.13
Platelet, × 109/L	210.66 ± 69.77	202.36 ± 58.34	232.04 ± 90.94	205.02 ± 46.19	204.62 ± 45.82	206.42 ± 49.54
Erythrocyte sedimentation rate, mm/h	9.88 ± 12.25	6.89 ± 7.96	17.46 ± 17.28	7.31 ± 10.35	6.33 ± 6.89	10.75 ± 17.97
Albumin, g/L	42.13 ± 4.17	42.65 ± 3.93	40.77 ± 4.54	44.51 ± 3.40	44.99 ± 3.38	42.85 ± 3.02
C-reactive protein, mg/dl	2.98 ± 5.43	1.82 ± 2.77	5.96 ± 8.69	1.99 ± 3.18	1.23 ± 1.79	4.66 ± 5.19

IFX: Infliximab; IQR: Interquartile range; SD: standard deviation; EA: Experimental adhesive; ER: Endoplasmic reticulum.

Table 2 Predictive indicators of endoscopic relapse in Crohn's disease patients with endoscopic remission

Variable	Week 14 (after initial IFX therapy), n = 93				Week 14 (after initial IFX therapy), n = 54
	Predict endoscopic relapse at week 54				Predict endoscopic relapse at week 108
	Univariate analysis		Multivariable analysis		Univariate analysis		Multivariable analysis
	OR (95%CI)	P value	OR (95%CI)	P value	OR (95%CI)	P value	OR (95%CI)	P value
Median age in year, median (IQR)	0.997 (0.950-1.047)	0.904	—	—	1.028 (0.967-1.093)	0.381	—	—
Course in year, median (IQR)	1.054 (0.945-1.176)	0.346	—	—	1.065 (0.906-1.253)	0.444	—	—
Male sex, n (%)	0.478 (0.191-1.199)	0.116	—	—	0.700 (0.188-2.607)	0.595	—	—
Disease location, n (%)
L1 (terminal ileum)	0.413 (0.114-1.495)	0.178	—	—	1.158 0.117-11.454)	0.900	—	—
L2 (colon)	1.453 (0.430-4.908)	0.548	—	—	3.000 (0.341-26.427)	0.322	—	—
L3 (ileocolon)	—	—	—	—	—	—	—	—
L4 (upper digestive tract)	1.277 (0.452-3.612)	0.645	—	—	0.939 (0.215-4.113)	0.934	—	—
Disease behavior, n (%)
B1 (no)	—	—	—	—	—	—	—	—
B2 (stenosis)	0.889 (0.345-2.294)	0.808	—	—	0.600 (0.141-2.561)	0.490	—	—
B3 (penetration)	1.860 (0.658-5.264)	0.242	—	—	0.700 (0.188-2.607)	0.595	—	—
B2 (stenosis) + B3 (penetration)	—	—	—	—	—	—	—	—
Perianal diseases, n (%)	1.442 (0.562-3.696)	0.446	—	—	0.952 (0.259-3.502)	0.941	—	—
Previous medical therapy, n (%)	1.027 (0.386-2.736)	0.957			2.040 (0.481-8.650)	0.333
Previous surgical therapy, n (%)	0.926 (0.266-3.218)	0.903	—	—	—	—	—	—
Laboratory indicators, median (IQR)
Fecal calprotectin, μg/g	1.003 (1.002-1.005)	0.000	1.002 (1.001-1.004)	0.002	1.002 (1.001-1.004)	0.001	NS	NS
IFX trough level, μg/mL	0.650 (0.532-0.796)	0.000	0.666 (0.514-0.862)	0.002	0.470 (0.289-0.766)	0.002	0.466 (0.247-0.877)	0.018
White blood count, x 109/L	1.167 (0.921-1.478)	0.201	—	—	1.004 (0.636-1.586)	0.986	—	—
Hematoglobin, g/L	0.977 (0.954-1.000)	0.053	—	—	0.997 (0.957-1.038)	0.867	—	—
Platelet, x 109/L	1.006 (0.999-1.013)	0.081	—	—	1.001 (0.987-1.015)	0.904	—	—
Erythrocyte sedimentation rate, mm/h	1.073 (1.028-1.120)	0.001	NS	NS	1.035 (0.978-1.096)	0.239	—	—
Albumin, g/L	0.895 (0.800-1.002)	0.054	—	—	0.821 (0.667-1.010)	0.062	—	—
C-reactive protein, mg/dL	1.245 (1.080-1.435)	0.003	NS	NS	1.389 (1.070-1.804)	0.014	1.590 (1.007-2.510)	0.047

IFX: Infliximab; NS: Not significant; CI: Confidence interval; IQR: Interquartile range; OR: Odds ratio.

Table 3 Predictive value of indicators on endoscopic relapse

	Youden index	Sensitivity	Specificity	Positive predictive value	Negative predictive value	Area under the ROC curve	P value
Predictors at week 14 of Endoscopic relapse at week 54
ITL ≤ 5.6 μg/mL	0.61 (0.41-0.72)	0.92 (0.75-0.99)	0.69 (0.56-0.79)	0.53 (0.44-0.62)	0.96 (0.86-0.99)	0.83 (0.73-0.90)	< 0.001
FCP > 238 μg/g	0.64 (0.38-0.78)	0.73 (0.52-0.88)	0.91 (0.82-0.97)	0.76 (0.59-0.88)	0.90 (0.82-0.94)	0.82 (0.72-0.89)	< 0.001
ITL ≤ 5.6 μg/mL and FCP > 238 μg/g	0.63 (0.40-0.80)	0.69 (0.48-0.86)	0.94 (0.85-0.98)	0.82 (0.63-0.92)	0.89 (0.82-0.93)	0.82 (0.72-0.89)	< 0.001
ITL ≤ 5.6 μg/mL or FCP > 238 μg/g	0.62 (0.47-0.74)	0.96 (0.80-1.00)	0.66 (0.53-0.77)	0.52 (0.44-0.60)	0.98 (0.87-1.00)	0.81 (0.71-0.88)	< 0.001
Predictors at week 54 of Endoscopic relapse at week 108
ITL ≤ 2.1 μg/mL	0.68 (0.40-0.87)	0.75 (0.43-0.95)	0.93 (0.81-0.99)	0.75 (0.49-0.90)	0.93 (0.83-0.97)	0.85 (0.72-0.93)	< 0.001
CRP > 3.0 mg/dL	0.45 (0.20-0.68)	0.50 (0.21-0.79)	0.95 (0.84-0.99)	0.75 (0.41-0.93)	0.87 (0.79-0.92)	0.73 (0.60-0.84)	0.012
ITL ≤ 2.1 μg/mL and CRP > 3.0 mg/dL	0.33 (0.08-0.58)	0.33 (0.10-0.65)	1.00 (0.92-1.00)	1.00 (1.00-1.00)	0.84 (0.78-0.89)	0.67 (0.53-0.79)	0.019
ITL ≤ 2.1 μg/mL or CRP > 3.0 mg/dL	0.80 (0.50-0.93)	0.92 (0.62-1.00)	0.88 (0.74-0.96)	0.69 (0.49-0.84)	0.97 (0.85-1.00)	0.90 (0.79-0.96)	＜0.001

ITL: Infliximab trough level; FCP: Fecal calprotectin; CRP: C-reactive protein; ROC: Receiver operating characteristic.

Table 4 Previous research of infliximab trough level on deep remission in inflammatory bowel disease

Study design	Optimal cut-off value	Predictive content	Yes/No, n	SE	SP	PPV	NPV	AUC
A retrospective observational single-center study in China	4.85 μg/mL at week 14	Mucosal healing (complete absence of any sign of ulceration)	82/59	67%	80%			0.80
	4.85 μg/mL at week 14	Mucosal healing (CDEIS of < 3)	84/57	68%	83%			0.79
	2.85 μg/mL at week 30	Mucosal healing (complete absence of any sign of ulceration)	59/50	73%	84%			0.78
	2.85 μg/mL at week 30	Mucosal healing (CDEIS of < 3)	62/47	68%	81%			0.73
A retrospective observational single-center study in China	2.50 μg/mL at week 14	Mucosal healing (SES-CD/Rutgeerts of 0 or 1) at week 52	31/42	87%	60%			0.70
	2.50 μg/mL at week 14	Sustained remission (no treatment failure, no need for surgery or intensification of IFX nor new introduction during IFX therapy) at week 52	70/38	64%	63%			0.70
A prospective multicenter study in Spanish	3.40 μg/mL	(1) SES-CD<3 for CD patients; (2) Rutgeerts score < i2 for CD patients in the postoperative setting; and (3) Mayo endoscopic score < 2 for UC patients	58/30	60%	60%	73%	42%	0.63
A multicenter, randomized, double-blind, controlled trial in Europe	23.10 mg/L at week 2	Endoscopic remission (CDEIS < 3) at week 12	54/52	56%	80%	72%	65%	0.67
	10.00 mg/L at week 6	Endoscopic remission (CDEIS < 3) at week 12	54/52	37%	89%	76%	59%	0.64
	10.60 mg/L (dose escalation to 10 mg/kg)	The absence of ulcers at week 54	85/51	94%	42%	49%	92%	0.71
A retrospective multicenter study in United States	9.70 μg/mL	Endoscopic remission (absence of any mucosal break (ulceration or erosion)/Rutgeerts score of ≤ i1)	62/34	57%	73%	80%	48%	0.65
	9.80 μg/mL	Histologic remissions (absence of active inflammation)	43/44	63%	66%	64%	64%	0.62
	2.20 μg/mL	Biochemical remission (CRP ≤ 5 mg/dL)	48/23	92%	35%	75%	67%	0.64
A retrospective observational single-center study in Japan	4.00 μg/mL	Mucosal healing (modified Rutgeerts scoring system: 0 or 1) after 30 days	20/58	71%	70%			0.63
	0.60 μg/mL	CRP normalization (≤ 0.3 mg/dL)	28/22	73%	62%			0.67
	1.00 μg/mL	Serum albumin normalization (≥ 4.0 mg/dL)	17/33	67%	71%			0.72
	1.10 μg/mL	Fecal calprotectin (≥ 300 μg/g)	13/25	72%	56%			0.63
A retrospective cross-sectional multicenter study in South Korea	4.20 μg/mL	Mucosal healing (SES-CD = 0)	51/54	65%	70%	67%	68%	0.68
	3.71 μg/mL	Partial mucosal healing (SES-CD < 3)	63/42	70%	71%	79%	61%	0.73
	3.26 μg/mL	Clinical remission (PCDAI < 10)	95/10	71%	100%	100%	73%	0.90
	2.52 μg/mL	Biochemical remission (CRP < 0.3 mg/dL)	87/18	86%	56%	90%	46%	0.71
A prospective cohort multicenter study in Canada	8.02 μg/mL	Histologic remission (an absence of active chronic inflammation)	56/48	79%	68%			0.72
	8.27 μg/mL	Sustained histologic remission (histologic remission documented at both the baseline and follow-up colonoscopies)	36/16	88%	72%			0.77
A retrospective cross-sectional study in United Kingdom	7.10 μg/mL	Fistula healing (no spontaneous discharge or no discharge on palpation in the absence of seton drainage)	18/11	78%	100%			0.93
	7.10 μg/mL	Fistula closure (the absence of an external skin opening)	13/16	64%	100%			0.97

SE: Sensitivity; SP: Specificity; PPV: Positive predictive value; NPV:Negative predictive value; AUC: Areas under the curve; CDEIS: Crohn’s disease endoscopic index of severity; SES-CD: Simplified endoscopic score for Crohn’s disease; CD: Crohn’s disease; UC: Ulcerative colitis; CRP: C-reactive protein; PCDAI: Pediatric Crohn’s disease activity index.