Ding ZY, Wang YJ, Yao DH, Tian T, Huang YH, Li YS. Intestinal fibrosis attenuates the prophylactic effect of anti-tumour necrosis factor therapy on the postoperative recurrence of Crohn’s disease. World J Gastrointest Surg 2025; 17(8): 106455 [PMID: 40949358 DOI: 10.4240/wjgs.v17.i8.106455]
Corresponding Author of This Article
You-Sheng Li, MD, PhD, Professor, Department of General Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People’s Hospital, No. 639 Zhizaoju Road, Huangpu District, Shanghai 200023, China. gisurgery9@126.com
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Retrospective Cohort Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Ze-Yu Ding, Dan-Hua Yao, Tao Tian, Yu-Hua Huang, You-Sheng Li, Department of General Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People’s Hospital, Shanghai 200023, China
Yu-Jie Wang, Department of Pharmacy, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People’s Hospital, Shanghai 200023, China
Author contributions: Ding ZY, Wang YJ, Yao DH, Tian T, Huang YH, and Li YS participated in the conceptualization of the study; Huang YH and Li YS designed the study; Ding ZY and Wang YJ acquired the data and performed statistical analysis; Ding ZY contributed to the drafting of the article. All authors contributed to interpreting the data, revised the article and approved the final version of the article.
Supported by the National Natural Science Foundation of China, No. 82200621; and the Original Research Projects, Shanghai Ninth People’s Hospital, No. 2022LHA08 and No. YBKB202220.
Institutional review board statement: All procedures performed in these studies involving human participants were in accordance with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study was approved by the ethics committee of Ninth People’s Hospital Affiliated Shanghai Jiao Tong University School of Medicine (Approval No. SH9H-2022-T423-1).
Informed consent statement: Informed consent was obtained from all individual patients included in the study.
Conflict-of-interest statement: This study was financially supported by grants from the National Natural Science Foundation of China, Original Research Projects, Shanghai Ninth People’s Hospital and the Industrial Support Foundation, Science and Technology Commission of Shanghai Municipality. The funding body had no role in the study design, data collection, analysis, interpretation or writing of the manuscript. All the authors report no relevant conflicts of interest for this article.
STROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.
Data sharing statement: The datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: You-Sheng Li, MD, PhD, Professor, Department of General Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People’s Hospital, No. 639 Zhizaoju Road, Huangpu District, Shanghai 200023, China. gisurgery9@126.com
Received: February 27, 2025 Revised: April 11, 2025 Accepted: June 25, 2025 Published online: August 27, 2025 Processing time: 180 Days and 6.3 Hours
Abstract
BACKGROUND
In the biologic era, postoperative recurrence (POR) of Crohn’s disease (CD) remains a significant concern. The underlying cause of this phenomenon remains unclear at present.
AIM
To examine whether intestinal fibrosis increases the likelihood of POR when anti-tumor necrosis factor biologics are used following ileocecal resection (ICR).
METHODS
We performed a single-centre, retrospective cohort study of patients with CD who underwent ICR. Recurrence was defined by endoscopy (Rutgeerts score ≥ i2), radiography (active inflammation in the neoterminal ileum) or surgery (another resection > 3 months post-ICR), and patients were categorised by the presence of intestinal fibrosis on histopathological evaluation.
RESULTS
Among 102 patients with CD who underwent ICR and received infliximab within 3 months, 69 (67.6%) had intestinal fibrosis. In addition, 60 patients (58.8%) experienced POR in various forms: 52.6%, 41.2%, and 10.8% had endoscopic, radiographic, and surgical recurrence, respectively. Patients with intestinal fibrosis experienced faster radiographic recurrence (log rank P = 0.03). After adjusting for risk factors associated with POR, intestinal fibrosis increased the risk of early radiographic recurrence (adjusted hazard ratio = 4; 95% confidence interval: 1.03-15.56; P = 0.045).
CONCLUSION
Despite the limited sample size, our study revealed a strong correlation between radiographic POR and intestinal fibrosis in patients who received postoperative anti-tumor necrosis factor α prophylaxis.
Core Tip: In a real-world cohort of Crohn’s disease patients with curative ileocecal resection, endoscopic postoperative recurrence (POR), radiographical POR and surgical POR rates were 52.6%, 41.2%, and 10.8%, respectively. Intestinal fibrosis increased the risk of radiographical POR and surgical POR despite biologic prophylaxis. After adjusting for disease severity, fibrosis was significantly associated with accelerated rPOR progression. Higher serum trough levels may delay endoscopic POR onset. These findings highlight the need for improved treatments for patients with Crohn’s disease with prolonged disease and fibrosis.
Citation: Ding ZY, Wang YJ, Yao DH, Tian T, Huang YH, Li YS. Intestinal fibrosis attenuates the prophylactic effect of anti-tumour necrosis factor therapy on the postoperative recurrence of Crohn’s disease. World J Gastrointest Surg 2025; 17(8): 106455
Crohn’s disease (CD) is a chronic and progressive immune-mediated inflammatory bowel disease (IBD) characterised by transmural inflammation affecting any segment of the gastrointestinal tract[1]. Currently, this condition remains incurable and can be managed only by medicinal therapy. Surgery is considered the last resort when complications such as fistula, abscess or stricture arise[2]. After surgical resection, a significant proportion of patients experience the development of new lesions at the site of ileocolonic anastomosis, which is defined as postoperative recurrence (POR)[3]. POR can be characterised by several modalities, including endoscopic, clinical, radiographic and surgical recurrence[4-10]. Endoscopic POR (ePOR) is regarded as the gold standard for identifying the POR of CD[2,11], and the Rutgeerts score (RS) is a recognised and widely utilised endoscopic instrument for evaluating CD activity in patients after ileocecal resection (ICR) and ileocolic anastomosis[12]. It has been reported that ePOR manifests in 70%-90% of patients within 12 months post-surgery[2,5].
To reduce the high incidence of POR, the American Gastroenterological Association guidelines recommend the utilisation of biologic therapy prophylaxis against POR in high-risk patients, which includes those with multiple prior surgeries for CD, who actively smoke, who have penetrating or stricturing phenotypes, and who are younger than 30 years at the time of surgery[9]. Despite substantial advances in medicinal treatment, such as infliximab (IFX) and adalimumab (ADA), the current risk of a second surgical resection is approximately 24.5%, whereas the risk for a third resection is approximately 5.3%[13]. The underlying risk factors contributing to the high recurrence rate remain unclear; however, a study noted that the proportion of resections for obstructive indications among all CD-related bowel surgeries increased from 10.8% in 1998 to 29.1% in 2020 after the introduction of IFX[14]. Current data indicate that approximately 30% of patients with stricture require surgical intervention following a median duration of 12 months of anti-tumor necrosis factor (TNF)-α medication[15]. Anti-TNF therapy seems to lack long-term therapeutic benefits for people with stricturing CD. The eighth scientific workshop of the European Crohn’s and Colitis Organisation (ECCO) mentioned that histological findings on surgical specimens may affect POR[16]. The structural alterations underlying obstructive symptoms may be pivotal in the management of POR.
Intestinal stricture can be categorised into two types based on pathophysiological characteristics: Inflammatory-predominant stricture and fibrotic-predominant stricture. Intestinal fibrosis is defined by the accumulation of extracellular matrix and the proliferation of mesenchymal cells[17,18]. In the REMIND cohort, CD transmural lesions, including intestinal fibrosis at the ileal margin, were strongly associated with early ePOR[19]. Regrettably, there is currently no antifibrotic medication specially designed for fibrosis. Anti-TNF agents are still recommended as the first choice for patients with fibrostenosis[20]. Nevertheless, there is scant evidence substantiating the efficacy of anti-TNF therapy in reducing POR in patients with fibrostenotic CD. The ability to prevent POR in patients with fibrostenotic CD remains uncertain. The optimal time and trough concentrations of anti-TNF medication may vary across patients with different phenotypes of CD. This study aimed to assess the influence of intestinal fibrosis on the efficacy of anti-TNF biologics in preventing POR.
MATERIALS AND METHODS
Study population
In this retrospective cohort study, patients with CD who underwent ICR from July 2016 to June 2023 at Shanghai Ninth People’s Hospital were identified using electronic records. The inclusion criteria were as follows: (1) ICR via an open or laparoscopic approach with one- or two-stage ileocolonic anastomosis extending to uninvolved tissue; (2) Prophylaxis defined as biologic therapy initiation within 3 months postoperatively; and (3) Initial postoperative colonoscopy or cross-sectional imaging (computed tomographic enterography or magnetic resonance enterography) conducted within 6 months post-surgery or post-restoration of bowel continuity. Patients who underwent other resection procedures, including hemicolectomies, multiple ileal resections, and stricturoplasties, or who had a permanent or diverting loop ileostomy were excluded from the study. Biologics that commenced after 3 months were excluded from prophylaxis considerations due to potential confounding factors, including clinical or biochemical recurrence, which were not evaluated in the present study[21]. Furthermore, patients who experienced endoscopic or radiographic recurrence during the initial postoperative ileocolonoscopy assessment, as well as those with incomplete data, were excluded from the study (Figure 1). All inclusion criteria and data collected were confirmed via manual chart review. Patients were not required to be biologic-naïve prior to surgery. All patients provided written informed consent, and the procedures were performed in accordance with the ethical standards of the Declaration of Helsinki.
Figure 1 Flowchart of the patients included in this study.
CD: Crohn’s disease; ICR: Ileocecal resection; IFX: Infliximab.
Data collection
Baseline demographic information, including sex and age, was collected. Information specific to the disease was collected, covering the extent of disease as defined by the Montreal classification, disease duration, and preoperative and postoperative treatment regimens, including prior exposure to biologic therapies (IFX, ADA, vedolizumab, ustekinumab) and laboratory values. The operative details included the anastomosis type, diverting ileostomy use and histology.
Full-thickness intestinal samples obtained during surgery were sectioned at 5 μm thickness. One section was stained with haematoxylin and eosin for structural assessment, and another with Masson’s trichrome to evaluate fibrosis. An experienced pathologist (Wen-Wen Xia), blinded to clinical information, graded fibrosis severity in the most affected areas using a semi-quantitative scoring system[22]. Fibrosis was classified as non-fibrotic (score 0) or fibrotic (scores 1-4).
Postoperative IFX prophylaxis and serum trough levels were recorded. The evaluation of serum trough levels was performed during the initial postoperative colonoscopy or cross-sectional imaging. The initiation timing of biologic therapy was determined by the date of the first medication dose administered to the patient after the ICR. Clinical guidelines recommend that all patients with CD undergo endoscopic evaluation within 6-12 months after surgery to detect early endoscopic recurrence[23-25]. Therefore, all patients in this study underwent their initial endoscopic assessment at 6 months postoperatively. Patients were subsequently required to undergo a second endoscopic evaluation during the first postoperative year. Annual endoscopic examinations were subsequently performed for all follow-up participants until the occurrence of the primary outcome. In cases where endoscopic evaluation was not feasible at the scheduled time points, computed tomographic enterography or magnetic resonance enterography was used as an alternative. Endoscopy reports were reviewed for documentation of an anastomotic assessment with a RS[12]. In instances where documentation was absent, text and images from endoscopy reports were utilised to retrospectively assign a RS. Reviewers underwent training on Rutgeerts scoring, retrospective application and interobserver validation. Radiographic study reports were gathered and classified as active or inactive by expert IBD radiologists, according to the imaging features outlined in the Society of Abdominal Radiology CD consensus guidelines[26]. The imaging criteria for POR included the presence of active disease proximal to the neoterminal ileum, intestinal wall thickening, luminal narrowing exceeding 50% of the normal diameter, mural hyperenhancement, length of diseased segments, upstream stasis and dilation, mural fat deposition, pseudosacculations, fibrofatty proliferation, and features indicative of penetrating disease.
Outcomes
The primary outcome was the duration until the onset of POR, defined by endoscopic criteria (RS ≥ i2), radiographic criteria, or surgical criteria (necessity for reoperation or strictureplasty at the ileocolonic anastomosis site). Secondary outcomes were evaluated at 12 ± 6 months following therapy initiation and included ePOR and rPOR.
Statistical analysis
Baseline characteristics were described. Normal and nonnormal continuous variables were presented as the means and standard deviations or medians and ranges. Categorical variables were presented as frequencies and proportions and were compared via the χ2 test. Normally and nonnormally distributed continuous variables were compared using Student’s t test and the Mann-Whitney U test. The primary composite outcome survival analysis used Kaplan-Meier curves, with patients censored at any primary outcome event or last follow-up. The results were compared via the log-rank test. Adjusting for clinically relevant covariates, univariate and multivariate Cox regression analysis was used to assess the influence of the composite outcome of intestinal fibrosis. To assess secondary outcome remission rates among the groups, logistic regression was used. Our analyses employed R (4.1.0, R Foundation for Statistical Computing, Vienna, Austria) and the survival package (3.2-11, https://CRAN.R-project.org/package=survival).
RESULTS
Baseline and operative characteristics
Among the 130 patients with CD who underwent surgery, 102 (78.5%) received postoperative IFX prophylaxis, with a median follow-up length of 91.5 weeks. The majority were male (67.6%), 69.6% had penetrating CD, 75.5% had ileocecal disease, 15.7% had extraintestinal symptoms, 47.1% had previous biologic exposure, and 31.4% had prior resection. A total of 28.4% had perianal involvement. At surgery, the median age was 35 years [interquartile range (IQR): 29.5-42.25 years], and the median body mass index was 18.57 ± 2.57 kg/m2. Patients lacking intestinal fibrosis by histologic examination were more likely to present with intestinal perforation as the initial surgery indication (75.8% vs 53.6%, P = 0.032). Within 30 days before the ICR, 35/102 patients received corticosteroids. Most patients (84.3%) underwent side-to-side anastomosis. Histopathology revealed that 93.1% of the patients had ulceration and 30.4% had mesenteric lesions. A total of 58.8% had lymphocytic enlargement, 34.3% had granulomas, and 16.7% had plexitis, which were related to POR.
Postoperative management
Of the total cohort, nine (8.8%) patients received a postoperative immunomodulator together with a biologic. Postoperative biologic prophylaxis was started in 63 (61.8%) patients within 6 weeks following ICR and in 39 (38.2%) after 6 weeks. The median serum trough level of biologics was slightly higher in the intestinal fibrosis-free group [3.2 μg/mL (IQR: 0.4-10) vs 4.55 μg/mL (IQR: 1.45-6.575), P = 0.225]. The patients’ baseline characteristics before and after ICR are shown in Table 1.
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
During follow-up, 60 patients (58.8%) achieved the primary outcome, with 40 (52.6%) having ePOR, 35 (41.2%) having radiographic POR (rPOR), and 11 (10.8%) having surgical POR (sPOR). Patients with intestinal fibrosis were more likely to have rPOR or sPOR (63.8% vs 48.5%, P = 0.571; 48.3% vs 25.9%, P = 0.051; 14.5% vs 3%, P = 0.099, respectively). However, all POR rates were not significantly different. For patients who met the primary outcome, the median time to the first occurrence was 44 weeks (IQR: 25.25-76) (Table 2). The intestinal fibrosis of the samples did not affect the time until the primary composite outcome that was achieved according to the Kaplan-Meier test (log rank P = 0.413) (Figure 2). Individually, ePOR and sPOR progression times did not differ according to intestinal fibrosis development. Nevertheless, the time until the rPOR was significantly faster in patients with intestinal fibrosis according to the Kaplan-Meier method (log rank P = 0.668, log rank P = 0.03, and log rank P = 0.087 for patients with ePOR, rPOR, and sPOR, respectively) (Figure 2).
Figure 2 Kaplan-Meier curve.
A: Kaplan-Meier curve for postoperative recurrences of Crohn’s disease (including endoscopic, radiographic and surgical) according to the existence of intestinal fibrosis; B-D: Kaplan-Meier curves for endoscopic postoperative recurrence (B), radiographic postoperative recurrence (C), and surgical recurrence (D), according to the existence of intestinal fibrosis.
Table 2 Postoperative recurrence by development of intestinal fibrosis, n (%).
When analysing the efficacy outcomes of anti-TNF prophylaxis at 12 ± 6 months following ICR, 39.5% (32/81) of the patients had ePOR, and 41.7% (20/48) had rPOR. Notably, the patients with intestinal fibrosis had a much higher proportion of rPOR than patients without intestinal fibrosis had in the short period following ICR (51.5% vs 20%, P = 0.04). This discrepancy was not observed for patients with ePOR (38.2% vs 42.3%, P = 0.723) (Figure 3).
Figure 3 Rates of endoscopic and radiographic postoperative recurrence at 12 ± 6 months after therapy initiation, according to the existence of intestinal fibrosis.
ER: Endoscopic recurrence; RR: Radiographic recurrence.
According to univariate Cox regression, the development of intestinal fibrosis in the specimens was not associated with the progression of a primary composite outcome, ePOR or sPOR [any POR, hazard ratio (HR) = 1.28, 95% confidence interval (CI): 0.71-2.92, P = 0.416; ePOR, HR = 1.19, 95%CI: 0.59-2.39, P = 0.626; sPOR, HR = 4.47, 95%CI: 0.57-34.91, P = 0.154] but was associated with the progression of rPOR (HR = 2.16, 95%CI: 1.1-5.22, P = 0.046). After we adjusted for clinically relevant predictors such as age at surgery, penetrating disease, exposure to corticosteroids, prior CD-related surgeries, plexitis, the timing of biologics prophylaxis and trough level, the multivariate analysis revealed that the development of intestinal fibrosis was still associated with faster progression of rPOR (HR = 4, 95%CI: 1.03-15.56, P = 0.045) (Table 3). For ePOR, only the trough level of IFX was significantly associated with this outcome, which indicates that maintaining a higher level of biologics may effectively delay the progression of ePOR (HR = 0.87, 95%CI: 0.76-0.99, P = 0.038). For rPOR, there was no other independent factor affecting the progression of recurrence other than intestinal fibrosis. According to the multivariate Cox regression model, intestinal fibrosis was associated with an increase in rPOR (HR = 4, 95%CI: 1.03-15.56, P = 0.045). No factor was found to be relevant to the development of sPOR (Table 3).
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
In this single-centre cohort of patients with CD who received anti-TNFα prophylaxis after surgical resection, the presence of intestinal fibrosis was strongly linked to a high likelihood of developing POR, particularly as measured by radiographic assessments. Even after adjusting for preoperative corticosteroid exposure and other factors associated with a high risk of POR per guidelines, intestinal fibrosis remained significantly correlated with an accelerated occurrence of rPOR compared with the absence of intestinal fibrosis. The eighth ECCO scientific workshop of ECCO reviewed POR risk factor data by experts and proposed that the histological characteristics of surgical specimens that predict POR are still controversial[16]. Whether microscopic resection margins increase ePOR or rPOR is unclear. CD transmural lesions, including intestinal fibrosis at the ileal margin, were highly related to early ePOR in the pivotal REMIND cohort, demonstrating that chronic inflammatory burden significantly affects CD severity[19]. Our data corroborate the findings of previous trials indicating that intestinal fibrosis leads to early POR.
Despite the potential risk of intestinal fibrosis in early POR, data on how effectively anti-TNF medications prevent POR in patients with structural damage are scarce. In the CREOLE study, recent and severe obstruction symptoms were associated with anti-TNF biologic therapy success, suggesting that prolonged fibrostenotic symptoms may signify irreversible intestinal damage and reduced treatment success[27]. A cell module consisting of additional collagen type I alpha 1+ inflammatory fibroblasts was linked to anti-TNF medication nonresponsiveness[28]. Beginning anti-TNF therapy after the infected intestinal portions are resected prophylactically may prevent recurrence. The PREVENT trial revealed that, compared with placebo, IFX initiation within 45 days postoperatively in high-risk individuals (those who smoked or had prior resection or penetrating or perianal disease) significantly reduced ePOR at 18 months (51.3% vs 22.4%, P < 0.001)[10]. A cohort study of 278 patients with CD demonstrated that starting anti-TNF prophylaxis within 4 weeks after ICR reduced POR[29]. Previous experience suggests that early postoperative use of anti-TNF biologics may help prevent disease recurrence. In our study, this variable was controlled by ensuring consistent timing of biologic initiation between two groups. Under this condition, we observed that the presence of intestinal fibrosis compromised the prophylactic efficacy of anti-TNF therapy. rPOR is faster for patients with intestinal fibrosis (HR = 2.164, P = 0.046).
After PREVENT, the POCER trial revealed that a step-up treatment method based on CD recurrence risk with endoscopy at 6 months postoperatively prevented POR better than standard drug therapy alone with endoscopic surveillance after 18 months[6]. A higher 4-month ADA drug concentration was related to considerably less objective inflammation and a lower dose increase rate in the intensive therapy group of the STRIDENT study[30]. There is growing body of evidence supporting the notion that higher concentrations of anti-TNF biologics can reduce recurrence and prolong remission[31,32]. In our study, we accounted for this factor by ensuring comparable trough levels between groups. Under these conditions, intestinal fibrosis was still associated with reduced prophylactic efficacy of anti-TNF therapy.
Nevertheless, the findings of the present study did not prove that early anti-TNF treatment after ICR protects patients with intestinal fibrosis. Based on the multivariate Cox regression analyses, our data suggest that maintaining a higher serum trough level prevents ePOR in patients with intestinal fibrosis. This phenomenon may be related to the characteristics of CD surgery. Routine CD-related surgery does not require extensive resection. Even with microscopically inflamed margins, bowel-sparing surgeries remain the objective[16]. A recent Dutch study examined the ICR resection margins of 106 patients with CD. A total of 27% of the proximal specimen margins and 15% of the distal specimen margins showed active inflammation[33]. Thus, patients receiving ICR may continue to suffer structural damage, and patients with intestinal fibrosis are at increased risk.
We also discovered that more patients will have rPOR within 12 months of ICR (46% vs 27.3%, P = 0.124). According to the univariate and multivariate Cox regression analyses, intestinal fibrosis only predicted rPOR, not endoscopic or sPOR. Several factors may contribute to this phenomenon. The RS is the gold standard for postoperative disease activity and correlates well with clinical outcomes, including hospitalisation and repeat surgery[11,34]. Whether radiography can be used in addition to endoscopy to assess POR is still disputed. Compared with ePOR, rPOR may overlook early mucosal surface lesions but may be more sensitive to transmural disease activity because of transmural inflammation and structural damage in patients with CD[21,35]. A retrospective, observational cohort study indicated that 54.2% of patients had endoscopic-radiographic concordance, whereas 41.7% (n = 90) had E-/R+ discordance[35]. Researchers reported a 54.2% POR detection accuracy with cross-sectional imaging. Imaging had high sensitivity (89.3%) but low specificity (31.8%) (predictive values of 45.5% positive and 82.4% negative)[35]. Cross-sectional enterography is better at evaluating intramural and mesenteric disease, which may explain our study’s results since patients with intestinal fibrosis have extensive structural damage.
In a previous study, researchers also reported that patients undergoing E-/R+ experienced more rapid subsequent endoscopic recurrence (HR = 4.16, P = 0.033) and increased rates of subsequent endoscopic (43.8% vs 22.7%) and surgical (20% vs 9.5%) POR than did patients undergoing E-/R- (median follow-up, 4.5 years)[35]. These findings suggest that as features of radiologic disease severity progress, CD activity begins to manifest as an endoscopically visible mucosal pathology at higher rates. With a longer period of follow-up, the incidence of ePOR in our data may increase, and the results of Cox regression should be re-evaluated.
Our study’s strengths include the collection of detailed clinical information, such as histologic results and available endoscopic and radiological data, in a population of postoperative patients with CD, with a median follow-up time of 2 years. Moreover, to our knowledge, this is the first study assessing the clinical impact of histologic changes on the prophylactic efficacy of anti-TNF agents in a postoperative CD population. However, there are several limitations.
Notably, the mean serum trough level in the non-fibrotic group was slightly higher than in the fibrotic group, and the potential influence of this difference warrants further investigation in larger cohorts with more rigorous study designs. Moreover, to the best of our knowledge, there are currently no published studies specifically investigating the role of anti-drug antibodies in diminishing the prophylactic efficacy of IFX in the setting of POR, despite the widely acknowledged negative impact of such antibodies on IFX efficacy[36-38]. Due to technical limitations, our study was unable to include data on anti-drug antibodies, which represents a limitation in the comprehensiveness of our conclusions. Missing data in endoscopic and radiographic evaluations may limit the power of our data. Ileocolonoscopy at 6-12 months following surgical resection is the gold standard for objective postoperative monitoring of patients with CD, but it has many limitations and was not routinely performed on this cohort. Objective standards such as the MONITOR index may improve rPOR assessment robustness. The retrospective and observational nature predisposed patients to potential residual confounding, since patients receiving anti-TNF drugs within 6 weeks of ICR were more likely to have prior therapy, indicating more severe disease. We could not account for remnant diseases following ICR that may have continued other IBD therapies or postoperative complications that delayed medication. Additionally, this study was conducted at one academic institution, which may restrict its generalisability.
CONCLUSION
In this real-world cohort of patients with CD who underwent curative ICR, the rates of ePOR, rPOR, and sPOR were 52.6%, 41.2% and 10.8%, respectively. Patients presenting with intestinal fibrosis demonstrated an increased likelihood of developing rPOR and sPOR when receiving biologic prophylaxis. Upon adjusting for disease severity characteristics, a significant association was identified between intestinal fibrosis and accelerated progression of rPOR. Maintaining an elevated serum trough level may postpone the onset of ePOR. These findings underscore the necessity for improved therapeutic strategies for patients experiencing prolonged disease courses and intestinal fibrosis in the postoperative context. Utilising therapeutic drug monitoring to maintain the trough levels of biologics may be a viable approach.
ACKNOWLEDGEMENTS
The authors would like to thank Dr. Wen-Wen Xia for her valuable contribution to the histopathological evaluation of tissue fibrosis.
Footnotes
Provenance and peer review: Unsolicited article; Externally peer reviewed.
Peer-review model: Single blind
Specialty type: Gastroenterology and hepatology
Country of origin: China
Peer-review report’s classification
Scientific Quality: Grade B
Novelty: Grade B
Creativity or Innovation: Grade B
Scientific Significance: Grade B
P-Reviewer: Cseh A S-Editor: Wang JJ L-Editor: A P-Editor: Xu ZH
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