Intestinal fibrosis attenuates the prophylactic effect of anti-tumour necrosis factor therapy on the postoperative recurrence of Crohn’s disease

Table 1 Comparison of baseline patient characteristics and operative details by postoperative histopathology, n (%)

Variables	Total patients (n = 102)	Patients with intestinal fibrosis (n = 69)	Patients without intestinal fibrosis (n = 33)	P value
Gender				0.549
Female	33 (32.4)	21 (30.4)	12 (36.4)
Male	69 (67.6)	48 (69.6)	21 (63.6)
BMI, kg/m2	18.57 ± 2.57	18.54 ± 2.58	18.64 ± 2.61	0.863
Disease duration, months	55.5 (8.75, 115)	60 (7.5, 118.5)	51 (14.5, 87)	0.673
Age at ICR, year	35 (29.5, 42.25)	35 (28, 42)	35 (31.5, 43.5)	0.601
Montreal classification A				0.169
< 16	8 (7.8)	4 (5.8)	4 (12.1)
16-40	74 (72.5)	54 (78.3)	20 (60.6)
> 40	20 (19.6)	11 (15.9)	9 (27.3)
Montreal classification L				0.437
Ileum	12 (11.8)	9 (13)	3 (9.1)
Colon	4 (3.9)	3 (4.3)	1 (3)
Ileocecal	77 (75.5)	53 (76.8)	24 (72.7)
Extensive	9 (8.8)	4 (5.8)	5 (15.2)
Montreal classification B				0.002
Nonstricturing, nonpenetrating	1 (1)	1 (1.4)	0 (0)
Stricturing	30 (29.4)	27 (39.1)	3 (9.1)
Penetrating	71 (69.6)	41 (59.4)	30 (90.9)
Perianal	29 (28.4)	20 (29)	9 (27.3)	0.858
Extraintestinal manifestations	16 (15.7)	11 (15.9)	5 (15.2)	0.918
Perforation caused initial surgery	62 (60.8)	37 (53.6)	25 (75.8)	0.032
Prior CD-related surgeries				0.48
0	70 (68.6)	50 (72.5)	20 (60.6)
1	20 (19.6)	12 (17.4)	8 (24.2)
≥ 2	12 (11.8)	7 (10.1)	5 (15.2)
Prior IBD medication exposures
5-ASA	50 (49)	33 (47.8)	17 (51.5)	0.727
Corticosteroid	35 (34.3)	27 (39.1)	8 (24.2)	0.138
Immunomodulator	37 (36.3)	24 (34.8)	13 (39.4)	0.65
Anti-TNFα therapy (IFX/ADA)	42 (41.2)	26 (37.7)	16 (48.5)	0.3
Other biological (VDZ/UST)	6 (5.9)	5 (7.2)	1 (3)	0.661
Preoperative laboratory data
Haemoglobin, g/L	114 (100, 126.5)	115 (102, 127)	108 (98.5, 125.5)	0.319
WBC, × 109/L	5.6 (4.1, 7.96)	5.6 (4.58, 7.15)	5.6 (3.815, 8.7175)	0.815
CRP, mg/L	16.35 (3.2675, 40.4)	15.12 (3.1225, 40.0925)	19.355 (3.6375, 40.5025)	0.445
Alb, g/L	36.73 ± 5.8	37.53 ± 5.887	35.03 ± 5.307	0.047
ESR, mm/hour	15.5 (6, 34.25)	14 (6, 35)	22 (9, 34)	0.438
Anastomosis type				0.888
Side-to-side	86 (84.3)	59 (85.5)	27 (81.8)
End-to-side	13 (12.7)	8 (11.6)	5 (15.2)
End-to-end	3 (2.9)	2 (2.9)	1 (3)
Pathology
Ulceration	95 (93.1)	63 (91.3)	32 (97)	0.423
Lymphocytic infiltration	60 (58.8)	44 (63.8)	16 (48.5)	0.197
Mesenteric lesion	31 (30.4)	19 (27.5)	12 (36.4)	0.365
Granuloma	35 (34.3)	22 (31.9)	13 (39.4)	0.455
Plexitis	17 (16.7)	9 (13)	8 (24.2)	0.156
Postoperative immunomodulator therapy	9 (8.8)	7 (10.1)	2 (6.1)	0.714
Timing of postoperative prophylactic biologic therapy, weeks	5.5 (4, 9)	6 (4, 10)	5 (4, 8)	0.682
Serum trough level of anti-TNF biologic (μg/mL)	3.4 (0.4, 5.725)	3.2 (0.4, 10)	4.55 (1.45, 6.575)	0.225

BMI: Body mass index; ICR: Ileocecal resection; CD: Crohn’s disease; IBD: Inflammatory bowel disease; 5-ASA: 5-aminosalicylic acid; IFX: Infliximab; ADA: Adalimumab; VDZ: Vedolizumab; UST: Ustekinumab; WBC: White blood cell; CRP: C-reactive protein; Alb: Albumin; ESR: Erythrocyte sedimentation rate; anti-TNF: Anti-tumor necrosis factor.

Table 2 Postoperative recurrence by development of intestinal fibrosis, n (%)

Variables	Total patients	Patients with intestinal fibrosis	Patients without intestinal fibrosis	P value
All recurrence	60 (58.8)	44 (63.8)	16 (48.5)	0.142
Endoscopic recurrence	40 (52.6)	28 (54.9)	12 (48)	0.571
Radiographic recurrence	35 (41.2)	28 (48.3)	7 (25.9)	0.051
Surgical recurrence	11 (10.8)	10 (14.5)	1 (3)	0.099

Table 3 Hazard ratios for postoperative recurrence (univariate and multivariate)

Variables	Any POR HR (95%CI)	Endoscopic POR HR (95%CI)	Radiographic POR HR (95%CI)	Surgical POR HR (95%CI)
Univariate
Intestinal fibrosis	1.275 (0.71-2.292)	1.19 (0.592-2.391)	2.164 (1.096-5.223)	4.465 (0.571-34.912)
Multivariate
Age at surgery	0.989 (0.947-1.034)	1.013 (0.959-1.07)	0.986 (0.925-1.05)	0.957 (0.856-1.071)
Intestinal perforation	1.225 (0.499-3.003)	0.839 (0.274-2.564)	1.891 (0.454-7.879)	1.231 (0.135-11.194)
Corticosteroid use prior to surgery	1.325 (0.594-2.956)	1.737 (0.617-4.892)	1.601 (0.51-5.032)	1.965 (0.172-22.438)
Prior CD-related surgery
n = 1	1.177 (0.374-3.704)	1.916 (0.368-9.973)	0.948 (0.165-5.452)	9.313 (0.892-97.21)
n ≥ 2	1.643 (0.582-4.637)	1.751 (0.466-6.58)	2.906 (0.682-12.377)	2.669 (0.142-50.241)
Intestinal fibrosis	2.202 (0.813-5.964)	1.653 (0.384-7.112)	4.004 (1.031-15.555)	8.936 (0.425-188.102)
Submucosal plexitis	0.785 (0.247-2.496)	1.346 (0.266-6.821)	0.563 (0.094-3.357)	1.216 (0.045-33.067)
Prophylactic biologic therapy initiated within 6 weeks postoperatively	0.754 (0.319-1.782)	0.491 (0.172-1.401)	0.472 (0.126-1.766)	0.446 (0.034-5.927)
Serum trough level of anti-TNF biologic	0.934 (0.849-1.028)	0.865 (0.755-0.992)	0.913 (0.807-1.032)	0.764 (0.497-1.174)

POR: Postoperative recurrence; HR: Hazard ratio; CI: Confidence interval; CD: Crohn’s disease; anti-TNF: Anti-tumor necrosis factor.